Organophosphorus Chemistry (SPR Organophosphorus Chemistry (RSC)) (Vol 29)

Organophosphorus Chemistry

Volume 29

A Specialist Periodical Report

Organophosphorus Chemistry Volume 29

A Review of the Literature Published between July 1996 and June 1997

Sen io r Reporter D. W. Allen, Sheffield Hallam University, Sheffield, UK J. C. Tebby, Staffordshire University, Stoke-on-Trent, UK

Reporters N. Bricklebank, Sheffield Hallam University, UK 0. Dahl, University of Copenhagen, Denmark J. A. Grasby, University of Sheffield, UK C. D. Hall, King's College, London, UK M. C. Salt, Staffordshire University, Stoke-on- Trent, UK R. N. Slinn, Nantwich, UK J. C. Van de Grampel, University of Groningen, The Netherlands B. J. Walker, The Queen's University of Belfast, UK D. M. Williams, University of Sheffield, UK

ROYAL SOCIETY OF CHEMISTRY

ISBN 0-85404-319-5 ISSN 0306-07 13

0 The Royal Society of Chemistry 1999

All rights reserved

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Introduction

Following the retirements of long serving authors reported in the introduction to volume 28, we have to note futher changes to the team. After acting as Senior Reporter since volume 15, Brian Walker has now relinquished this role, which has been taken on by John Tebby. Happily, Brian continues as an author, now contributing the ‘Quinquevalent Phosphorus Acids’ chapter instead of the ‘Ylides and Related Compounds’ chapter which he has written since volume 13! We also have to note with regret that Otto Dahl has decided to retire from authorship of the ‘Tervalent Phosphorus Acid Derivatives’ chapter, having also contributed since volume 15. We thank Brian and Otto for sustained comprehensive and critical writing in these areas over many years. We are delighted to report that Terry Kee has agreed to take over Otto Dahl’s chapter in the next volume. Sadly, this will also be the final volume to which Jane Grasby and David Williams will contribute the ‘Nucleotides and Nucleic Acids’ chapter, and we thank them for their efforts over the last four years. On a brighter note, we welcome Neil Bricklebank as the new author of the ‘Ylides and Related Compounds’ chapter, J. C. Van der Grampel as the new author of the ‘Phosphazenes’ chapter, and also Mike Salt joins Robert Slinn as the co-author of the ‘Physical Methods’ chapter.

Activity in the area covered by the ‘Phosphines and Phosphonium Salts’ chapter, which also covers the chemistry of low coordinate px bonded compounds, has continued at a high level, particularly with regard to the synthesis of new phosphines, although without major advances, doubtless reflecting the relative maturity of the area. Similarly, nothing of great note has emerged in the tervalent phosphorus acid derivatives area. The same, perhaps, could also be said of the area of ylide chemistry, although the application of phosphorus-based ylides in general synthetic chemistry continues unabated, and Warren’s group, in particular, has continued to develop the chemistry of phosphine oxide-based ylides.

This year’s literature on nucleotide and nucleic acid chemistry has been dominated by interest in internucleoside linkages, and a number of novel approaches in this area have been described. In some cases, these have also extended to oligonucleotides. Some novel nucleotide analogues have been described. One of the most exciting areas in nucleic acid chemistry is the application of in-vitro selection techniques, and these have been reviewed for the first time.

Biological chemistry and its needs increasingly dominate the phosphorus(v) acids’ area and the majority of novel results relate to compounds derived from phosphonic and phosphinic, rather than phosphoric acids. Numbers of studies of compounds related to inositol and to carbohydrates continue to appear, although few contain truly novel results. Phosphorus-containing analogues of amino acids

V

Vi Inlrociuction

and peptides of a wide variety of types continue to be of interest, as do phosphate isosteres, particularly those containing fluoro- or difluoro-methyl groups. Some new methods of synthesis of fluoroalkyl phosphorus compounds have been reported but more convenient methods are still urgently required. The number of reports of enantioselective and asymmetric synthesis, often but not exclusively involving P-stabilised carbanions, continues to increase. There is a growing interest in a-ketophosphonates and the number of three-membered phosphorus- containing rings implicated as reactive intermediates continues to expand.

In the hypervalent area of phosphorus chemistry a configurationally stable tris(tetrachlorobenzenedio1ato) phosphate ion has been synthesised. The growing importance of hydridophosphoranes in coordination chemistry has led to the apprearance of a useful review. The superbase properties of the commercially available proazaphosphatrane has been extended to the catalysis of the silylation of sterically hindered alcohols and phenols.

The almost inexhaustible number of applications for phosphazenes ensures that interest in this area continues to be strong. Polyphosphazenes are playing an important role in the preparation of new block copolymers and in grafting processes, leading to extended applications in the production of flame retardants, membranes, hydrogels and to drug delivery polymers. The complexation of phosphazenes with a wide range of transition metals continue to be exploited. Studies of phosphazenes in organic synthesis have extended their usefulness, e.g. to the synthesis of pyridines. Their selectivity in clathrate formation with arenes is an interesting development. The multifunctionality of cyclophosphazenes continues to be exploited as starting materials for the preparation of polypodants and various dendrimers (up to 8th generation).

In physical and theoretical methods there has been a notable increase in the use of recently developed techniques - most of which have trendy acronyms. Thus DRAMA 3'P NMR has been used to determine internuclear P-P distance in a phosphine sulfide 4,8-residue substituted decapeptide, and XANES has been applied to structural studies of phosphine selenides. In the mass spectral field MALDI-TOF has been found to be better than FAB for the determination of the mass spectra of nucleotide triphosphates, LA-FTICR has been used to study tris(cyanoethy1)phosphine and metaphosphates have been detected for the first time by laser photoionisation MS. ERMS was shown to be a powerful technique for the analysis of structurally similar organophosphate insecticides (OPs) and trace quantities of OPs can be determined by CI using water as the ionising agent.

The 14th International Conference on Organophosphorus Chemistry (ICPCXIV), held in Cincinnati from 12 to 17 July, 1998, was highly successful and enjoyable. Cincinnati, bordered by the Ohio river, is of a manageable size and has a variety of cultural attractions, friendly people and good, cheap public transport. The enormous range of organic, inorganic and biological chemistry together with materials science covered in 240 oral presentations and 300 posters offered something of interest for everyone of the 550 participants. The biological and biologically related chemistry sessions provided the majority of the truly novel results, while the traditional organic chemistry sessions were somewhat disappointing overall. We look forward to ICPCXV in Japan in 2001.

Contents

Chapter 1 Phosphines and Phosphonium Salts By D. W. Allen

1 Phosphines I . 1 Preparation

I . 1.1 From Halogenophosphines and Organometallic Reagents

1. I .2 Preparation of Phosphines from Metallated Phosphines

1. I .3 Preparation of Phosphines by Addition of P-H Unsaturated Compounds

1. I .4 Preparation of Phosphines by Reduction 1,1.5 Miscellaneous Methods of Preparing

Phosphines

Nucleophilic Attack at Carbon

Nucleophilic Attack at Other Atoms

I .2 Reactions of Phosphines I .2.1 1.2.2 Nucleophilic Attack at Halogen 1.2.3 1.2.4 Miscellaneous Reactions of Phosphines

2 Halogenophosphines 2.1 Preparation 2.2 Reactions

3 Phosphine Oxides and Related Chalcogenides 3.1 Preparation 3.2 Reactions 3.3 Structural and Physical Aspects 3.4 Phosphine Chalcogenides as Ligands

4 Phosphonium Salts 4.1 Preparation 4.2 Reactions

5 P,-Bonded Phosphorus Compounds

1

1 1

1

4

10 12

12 18 18 19 21 23

25 25 25

27 27 31 32 33

34 34 37

39

Organophosphorus Chemistry, Volume 29 0 The Royal Society of Chemistry, 1999

vii

... Vl l l

Chapter 2

Chapter 3

Chapter 4

6 Phosphirenes, Phospholes and Phosphinines

References

Pentaco-ordinated and Hexaco-ordinated Compounds By C. D. Hall

1 Introduction

2 Acyclic and Monocyclic Phosphoranes

3 Bicyclic and Tricyclic Phosphoranes

4 Hexaco-ordinate Phosphorus Compounds

References

Tervalent Phosphorus Acid Derivatives By 0. Dahl

1 Introduction

2 Nucleophilic Reactions 2.1 Attack on Saturated Carbon 2.2 Attack on Unsaturated Carbon

3 Electrophilic Reactions 3.1 Preparation 3.2 Mechanistic Studies 3.3

3.4 Miscellaneous

Use for Nucleotide, Sugar Phosphate, Phospholipid, or Phosphoprotein Synthesis

4 Reactions involving Two-coordinate Phosphorus

References

Quinquevalent Phosphorus Acids By B. J . Walker

Con tents

1 Introduction

2 Phosphoric Acids and their Derivatives 2.1 2.2 2.3 Selected Biological Aspects

Synthesis of Phosphoric Acids and their Derivatives Reactions of Phosphoric Acids and their Derivatives

44

47

68

68

70

71

79

81

83

83

83 83 83

84 84 87

89 90

93

94

97

97

97 97

106 110

Con tents ix

3 Phosphonic and Phosphinic Acids 3.1 Synthesis of Phosphonic and Phosphinic Acids and

their Derivatives 3.1.1 Alkyl, Cycloalkyl, Aralkyl and Related Acids 3.1.2 Alkenyl, Alkynyl, Aryl, Heteroaryl and

Related Acids 3.1.3 Halogenoalkyl and Related Acids 3.1.4 Hydroxyalkyl and Epoxyalkyl Acids 3.1.5 Oxoalkyl Acids 3.1.6 Aminoalkyl and Related Acids 3.1.7 Sulfur- and Selenium-containing Compounds 3.1.8 Phosphorus-Nitrogen Bonded Compounds 3.1.9 Phosphorus-containing Ring Systems Reactions of Phosphonic and Phosphinic Acids and their Derivatives

3.2

3.3 Selected Biological Aspects

4 Structure

References

Chapter 5 Nucleotides and Nucleic Acids By Jane A . Grasby and David M. Williams

1 Introduction

2 Mononucleotides 2.1 Nucleoside Acyclic Phosphates

1.2.1 Mononucleoside Phosphate Derivatives 1.2.2 Polynucleoside Monophosphates

2.2 Nucleoside Cyclic Phosphates

3 Nucleoside Polyphosphates

4 Oligo- and Polynucleotides 4.1 DNA Synthesis 4.2 RNA Synthesis 4.3 The Synthesis of Modified Oligodeoxynucleotides

and Modified Oligoribonucleotides 4.3.1 Oligonucleotides Containing Modified

4.3.2 Oligonucleotides Containing Modified

4.3.3 Oligonucleotides Containing Modified Bases

Phosphodiester Linkages

Sugars

111

111 111

114 117 120 122 123 131 133 134

136 145

147

149

161

161

161 161 161 167 173

176

184 184 188

188

188

197 20 1

5 Linkers 209

X Con tents

6 Interactions and Reactions of Nucleic Acids with Metal Ions 216

7 Nucleic Acid Structures

References

Chapter 6 Ylides and Related Species By N . Bricklebank

1 Introduction

2 Methylene Phosphoraries 2.1 Preparation and Structure 2.2 Reactions of Methylene Phosphoranes

2.1.1 Aldehydes 2.2.2 Ketones 2.2.3 Ylides Coordinated to Metals 2.2.4 Miscellaneous Reactions

3 Synthesis and Reactions of Phosphonate Anions

4 Structure and Reactivity of Lithiated Phosphine Oxide Anions

5 Selected Applications in Synthesis 5.1 Biologically Active Compounds 5.2 Heterocyclic Synthesis 5.3

5.4 Miscellaneous Reactions

Tetrdthiafuhalene Derivatives and Related Organic Material

References

Chapter 7 Phosphazenes By J . C. Vun de Grumpel

1 Introduction

2 Linear Phosphazenes

3 Cyclophosphazenes

4 Polyphosphazenes

218

220

23 1

23 1

23 1 23 1 239 239 239 240 244

246

249

252 252 254

258 260

262

269

269

269

275

28 1

5 Crystal Structures of Phosphazenes and Related Compounds 287

References 293

Contents

Chapter 8 Physical Methods By R. N. Slinn and M. C. Salt

1 Theoretical and Molecular Modelling Studies 1.1 1.2

Studies Based on Molecular Orbital Theory Studies Based on Molecular Mechanics and Molecular Dynamics

2 Nuclear Magnetic Resonance Spectroscopy 2.1 2.2

2.3 2.4

2.5

Biological and Analytical Applications Applications including Chemical Shifts and Shielding Effects 2.2.1 Phosphorus-3 1 NMR 2.2.2 Selenium-77 NMR 2.2.3 Carbon-13 NMR 2.2.4 Hydrogen-1 NMR 2.2.5 Other Nuclei/Multinuclear/General NMR Restricted Rotation and Pseudorotation Studies of Equilibria, Configuration and Conformation Spin-Spin Couplings

3 Electron Paramagnetic (Spin) Resonance Spectroscopy

4 Vibrational and Rotational Spectroscopy 4.1 Vibrational Spectroscopy 4.2 Rotational Spectroscopy

5 Electronic Spectroscopy 5.1 Absorption Spectroscopy 5.2 Fluorescence and Chemiluminescence Spectroscopy 5.3 Photoelectron Spectroscopy

6 X-Ray Structural Studies 6.1 X-Ray Diffraction (XRD)

6.1.1 Two-coordinate Compounds 6.1.2 Three-coordinate Compounds 6.1.3 Four-coordinate Compounds 6.1.4 Five- and Six-coordinate Compounds X-Ray Absorption Near Edge Spectroscopy (XANES)

6.2

7 Electrochemical Methods 7.1 Dipole Moments 7.2 Cyclic Voltammetry and Polarography 7.3 Poten tiometric Met hods

xi

300

300 300

303

303 303

304 304 307 308 3 10 3 10 3 10

31 1 31 1

3 12

3 14 3 14 316

316 316 316 317

3 17 3 17 317 318 3 19 3 23

325

325 325 325 326

xii Contents

8 Thermochemistry and Thermal Methods

9 Mass Spectroscopy/Spectrometry

10 Chromatography and Related Techniques 10.1 Gas Chromatography and Gas Chromatography-

Mass Spectroscopy (GC-MS) 10.2 Liquid Chromatography

10.2.1 High-performance Liquid Chromatography

10.2.2 Thin-layer Chromatography (TLC)

Electrokinetic Chromatography (MEKC)

and LC-MS

10.3 Capillary Electrophoresis (CE) and Micellar

1 1 Kinetics

References

Author Index

327

328

330

330 33 1

33 1 33 1

332

332

333

343

Abbreviations

BAD cDPG CE CK CPE

cv DETPA DMAD DMF DMPC DRAMA DSC DTA ERMS

EXAFS FAB

HPLC

MALDI MEKC MIKE PAH

PMEA SATE SIMS SSAT SSIMS TAD tBDMS TFA TGA TLC TOF XANES

CPmP

ESI-MS

FPmP

LA-FTICR

QDA

Benzamide adenine dinucleotide Cyclodiphospho-D-glycera te Capillary electrophoresis Creatine kinase Controlled potential electrolysis 1 -(2-chlorophenyl)-4-met hoxylpiperidin-2-yl Cyclic voltammetry Di(2-et hyl hexyl) thiophosp horic acid Dimethylacetylene dicarboxylate Dimethy lformamide Dimyristoylphosphatidylcholine Dipolar restoration at the magic angle Differential scanning calorimetry Differential thermal analysis Energy resolved mass spectrometry Electrospray ionization mass spectrometry Extended X-ray absorption fine structure Fast atom bombardment 1 -(2-fluorophenyl)-4-methoxylpiperidin-2-yl High-performance liquid chromatography Laser ablation Fourier Transform ion cyclotron resonance Matrix assisted laser desorption ionization Micellar electrokinetic chromatography Mass analyserion kinetic energy Polycyclic aromatic hydrocarbons Hydroquinone-0, 0’-diacetic acid 9-[2-(phosphonomethoxy)ethyl] adenine S-acyl-Zthioethyl Secondary ion mass spectrometry Spermidinehpermine-N 1 -acetyltransferase Static secondary ion mass spectrometry Thiazole-4-carboxamide adenine dinucleotide tert- Butyldimethylsilyl Trifluoroace t ic acid Thermogravimetric analysis Thin-layer chromatography Time of flight X-Ray absorption near edge spectroscopy

... X l l l

1 Phosphines and Phosphonium Salts

by D. W. ALLEN

1 Phosphines

1.1 Preparation I . I . I From Halogenophosphines and Organometallic Reagents. - A short review has appeared of synthetic approaches to ferrocenylphosphines possessing planar- chirality, in which the reactions of lithiated ferrocenyl systems with halogenophosphines are the favoured route '. Among new ferrocenylphosphines prepared in this manner are the triphosphine 12, and the chiral oxazolinylferrocenylphosphines z3 and 34. The reaction of chlorodiphenylphosphine with 1,2,3-trimethylcyclopentadienyllithium surprisingly proceeds regiospecifically, but the outcome is very temperature dependent. Below - 10 "C, the phosphine 4 is formed, but rearranges in solution at 25 "C to give 5 via a 1,5- sigmatropic transposition. Treatment of 5 with further butyllithium and then chlorodiphenylphosphine provides the diphosphine 65 as the major product, although other isomeric diphosphines can also be detected, arising from 6 by rearrangement processes5.

1 R = Phor Pr'

. . R e p p h 2 Me 4

\ PPh2 R

2 3

5 6

Metallation of the bis(bromoviny1)benzene 7 with t-butyllithium, followed by treatment with phenyldichlorophosphine, provides a route to the benzo-


1

2 Organophosphorus Chemistry

phosphepin system 8, which has a tendency to eliminate phenylphosphinidene with the formation of naphthalene. Related arsenic, antimony, and bismuth systems have also been prepared in a similar way6. Two groups have reported the synthesis of chiral helical diphosphines, e .g . , 9, using the organolithium route798. A new efficient route to the atropisomeric chiral diphosphines 10, some of which have the additional feature of stereogenic phosphorus atoms, has been de~eloped'.'~. Routes to new types of chiral atropisomeric diphosphenes, e.g. , 11 and 12, have also been reported''. Treatment of the diaza-

7

@ Ar'-P P-Ar'

A; 'A? 10 R=MeorOMe

Ar' = Ph or ptolyl A$ = alkyl, 2-fury1 or 2-thienyl

8 9

' N

M e q - P P h 2

Me73-pph2 \ / 11 12

phospholidine 13 with t-butyllithium, followed by phenyldichlorophosphine, results in an unusual rearrangement with the formation of the chiral diphosphine 14, a new class of C2-symmetric ligand 12. The reactions of o-lithiophenoxides with chlorodiphenylphosphine, followed by treatment with chlorotrimethylsilane, give the silylated phosphinophenols 15 from which the silyl group is easily removed by treatment with methanol to give the free pho~phinophenol'~. The same strategy has been used for the synthesis of the phosphinonaphthols 1614. In related work, it has been shown that o-sodiophenyldiorganophosphinite esters rearrange to form the sodiophosphinophenoxides l?'.

Ortho-lithiation of an O-protected rn-fluorophenol, followed by treatment with phosphorus tribromide and aqueous acid deprotection, has given the phosphino- phenol 18. In the presence of potassium t-butoxide in an aprotic solvent, this is converted into the non-planar system 19, which exhibits pyroelectric properties 16. An organolithium route to the alkynylphosphine 20 has been developed. The same paper also reports a new route to the lithiated alkynylphosphine 21 and a study of its reactivity towards ele~trophiles'~. Diastereoselective lithiation of

I: Phosphines and Phosphonium Salts 3

13 14

15 R' = Me, Et, But, Ph or NMe 16 R' = H or NMe2 17 R = Me, Et, Ph or Pr' R2 = H, Me or But R3 = H or But

R2 = Ph, But, Pr' or NMe2

chiral hydrazones provides a novel enantioselective synthesis of chiral phosphines, e.g. , 22, which may then be transformed into chiral 2-phosphino-ketones and h alcohol^'^*'^. Organolithium reagents have also been utilised in the synthesis of the chiral phosphines 23*', the heteroarylphosphine 2421, and further

18 19 20 21

PR22

22 23 n = O o r l

synthesis of phosphinocarborane derivatives22. Selective P-C coupling occurs in the reaction of the lithium phosphinoenolate 25 with chlorodiphenylphosphine, to give the new diphosphine 2623. Full details of the synthesis of bis- and tetrakis-(diphenylphosphino) tetrathiafulvalenes e.g., 27, have now appeared24. Both Grignard and organolithium procedures have been employed in the synthesis of a wide range of functionalised arylphosphines, e.g., 28, which can be linked to a chiral skeleton25, and also in the synthesis of the chiral amino- akylphosphines 2926927. A much improved route to the rn-aminoarylphosphine 30 is provided by the reaction of N-bis(trimethylsily1)-protected-aminophenyl


Li[PhpPCH-C=NPh~] ph2pk fi- N P h2

Ph2P 0 :I 0

25 26 27

R R

R R

-YNMe2

' 'w 30 n = 1-3 28 R = Br, -C=CSiPhs,

-C=CPh or Ph 29 R = Pr'or Ph

Grignard reagents with halogenophosphines, followed by desilylation with methanol. Some of these compounds have also been prepared directly from m- iodoaniline by treatment with either phenylphosphine or diphenylphosphine in the presence of a palladium complex. The amino group has subsequently been converted into a guanidinium cationic moiety, rendering the phosphine water- soluble2*. Grignard procedures have also been used in the synthesis of the chiral secondary phosphine 3129, and of (E)-diphenyl(l-phenyl-2-bromovinyl) phos- phine3*. A Grignard-like procedure has been used in the synthesis of silylphosphines e.g. , 32, via the reactions of hindered halogenosilanes with magnesium and the appropriate halogenophosphine. The same strategy has also been applied in the synthesis of related germyl- and stannyl-phosphines3' .

Me

Me

Me Me

31 32

Triphenylstannyldiphenylphosphine has been prepared via the use of sodium triphenyl~tannide~~. Full details have now appeared of the use of organozinc reagents bearing reactive functional groups in the synthesis of polyfunctional and chiral pho~ph ines~~ . Applications of organotitanium and organozirconium reagents have also appeared. Thus, treatment of the titanacyclobutenes 33 with two equivalents of dichlorophenylphosphine has given the diphosphacyclopentenes 3434. In contrast, reactions of zirconacyclopentanes with chlorodiphenylphosphine, even when present in quantities sufficient for reaction with two zirconium-carbon bonds, afford only a monophosphine, e.g. , 3535.

I . 1.2 Preparation of Phosphines from Metallated Phosphines. - The first soluble crystalline potassium salt (36) of a primary phosphine has been prepared, and its

I : Phosphines and Phosphonium Salts

Me

5

33 R = Ph, Me or Et 34 R = Ph, Me or Et 35

structure studied by X-ray ~rystallography~~. A series of Iithiopolyphosphides, e .g . , 37, has been prepared and structurally ~haracterised~’. Lithium bis(triphenylsily1)phosphide has been shown to exist as a dimer in the solid state. The related bis(tri-isopropylsily1)phosphide exists as a cyclic t ~ i m e r ~ ~ . The reaction of bis(chloromethyldimethylsilyl)amine with three equivalents of lithium diisopropylphosphide gives the phosphinoamide salt 38 under certain conditions and its solid state structure has been studied39.

L~[(P~$P)~P] [LiN(SiMe2CH2PPr$)2 12 LiCl

36 37 38

Interest has continued in the generation of phosphide anions from elemental phosphorus and phosphine, under superbasic condition^^-^^, and also in the application of borane-protected phosphide reagents in synthesis. These reagents are easily generated, e .g . , by alkali metal cleavage of phenyl group from the triphenylphosphine-borane complex, and can subsequently be applied in reactions with alkyl halides and tosylates to form new phosphines, from which the protecting group is easily removed. Thus, in the past year, they have been used in the synthesis of alkyldiphenylphosphine-borane complexes43, various dialkylami- nophosphines, e.g. , 39, (capable of further elaboration)44, and a range of chiral diphosphines, e.g. , 4045, 4146, 4247748, 4349, and 44, isolated as the dioxide5’. The reaction of the borane complex of lithium dicyclohexylphosphide with o-chloro- alkyltrialkylammonium salts provides a route to a new family of water-soluble phosphines, e .g . , 45, of interest in homogeneous catalysis5’. Well established reactions of phosphide reagents, notably lithium diphenylphosphide, with alkyl halides and sulfonate esters, have again featured as the key P-C bond-forming step in the synthesis of new phosphines, many of them chiral, including 46 (in which four stereogenic carbons dictate the orientation of the P-phenyl groups)52, the camphor-based systems 4753, the carbohydrate-based systems 4854, 4955, and 5056, the triphosphines S157 and 5258, and the phosphinoalkylnitriles 5359. The synthesis of the phosphinoaldehyde 54 has been re-investigated, and an improved route developed, which involved the reaction of lithium diphenylphosphide (rather than sodium diphenylphosphide) with bromoacetaldehydediethylacetal as


42 X = 2,6-pyridinediyl, 43 1 ,&naphthalenediyl or 2,2'-biphenylylene

PPh2 ti 46 47 R', R2, R3 = H or PPh2

49 50

N LPPh2 R2P(CH2)"CN

52 53 R = Ph, Pr' or Cy n = 3,6 or 10

44 45

P h 2 P q . * o M e

'OH

OH 48

PhZPCHzCHO

54

the key step6'. The reaction of lithium diphenylphosphide with arenesulfonyl chlorides results in the formation of the diphenylarylsulfophosphamides 55, which have been shown to undergo cathodic cleavage of the phosphorus-sulfur bond, to give, eventually, diphenylphosphinic acid and the arenethiol, characterised as the thiomethyl ether61. The lithium phosphaguanidine system 56 has been isolated from the reaction of lithium bis(trimethylsily1)phosphide with diphenylcarbodiimide62. With boron trihalides, lithium bis(trimethylsily1)phosphide gives the dimeric systems 5763. An improved route to tris(trimethylsily1)- phosphine involves the reaction of dichloro(piperidino)phosphine, trimethyl- chlorosilane, and lithium powder in refluxing THFa. Dimetallophosphide

I : Phosphines and Phosphonium Salts 7

?h Me3SiN ,Ph

X MesSi, ,B\ ,SiMe3

Ar-S-PPh2 ~ e 3 S i / '\B/P'SiMe3 II 0

55 56 57 X=CIorBr

FNt 0 II y.:'i+

Me3SiN Ph X Ph

reagents, e.g., dilithium phenylphosphide, have received wide application for the synthesis of heterocyclic phosphines, e.g., the 7-phosphabicyclo[2.2. llheptanes 5865,66, the chiral phosphetane 5967, the chiral bicyclic system 6068, and the bis(phospho1ane) 6169. These reagents have also been utilised in the synthesis of chiral, acyclic polydentate phosphine ligands, e.g , 6270. Monometallation of organosilylphosphines, followed by treatment with alkyl or alkenyl halides, has

58 R=MeorPr ' 59 60

Q CH2CHCH2PPh2 /

PhP,

Me0 d Q h 3 v l e CH2CHCH2PPhz , 1 I OMe Me0 Me

61 62

given a range of reactive silylphosphines, some of which have been transformed into heterocyclic phosphines in subsequent reactions71. A new stereoselective synthesis of phosphiranes 63 is provided by the reaction of monolithiated primary phosphines with ethaneditosylates, followed by metallation of the intermediate secondary phosphine with butyllithium7*. Monolithium phenylphosphide is the key reagent in the synthesis of the bis(sec0ndary)phosphine 64, which, on treatment with four equivalents of butyllithium, gives rise to the macrocyclic system 6573.

Interest in the chemistry of phosphines metallated at carbon has also been

63 R = Ph, mesityl or 1 -adamantyl

64 65


maintained. The Ph2PCH2Li. TMEDA adduct has been shown to exist as a dimer in the solid state, rather than a monomer, as previously reported74. The reactions of lithiomethyldimethylphosphine with halogeno-phosphines, -arsines, -stibines, and bismuthines enable the synthesis of a wide range of polydentate donor l i g a n d ~ ~ ~ . Karsch's group has also explored the reactions of lithium bis(phos- phin0)methanides with organo-silicon, -germanium, and -tin halide^^^-^^. Treat- ment of spiro[2.4]hepta-4,6-diene with phenylphosphine and butyllithium results in the formation of metallated phosphine 66, which with ferrous chloride, gives the ferrocenophane 6779. The ferrocenophane 68 has been shown to undergo a living anionic ring-opening polymerisation on treatment with butyllithium, to form the phosphinoferrocene polymer 6980. The phosphinoamidomethanide 70 has been prepared from the reaction of lithium bis(trimethylsily1)phosphide with benzonitrile. Its reaction with trimethylsilyl chloride provides a novel access to the phospha-alkene 718'. The borane-protected phosphinomethanide 72 has been used in the synthesis of the chiral tridentate ligand 73, via its reactions with 2,6- bis(bromoethyl)pyridine82.

66

Q Fe P-Ph

-I-/

0 68

BuLi

THF -

[ P hC( PSiMe3) ( NSiMe3)lLi

70

67

Ph1

I Fe

69

Ph

N(SiMe& Me3S i P = C

71

OMe Me0 73

(3L3 CH2Li

72

While lithiophosphide reagents dominate this area of phosphine synthesis, applications of sodio- and potassio-phosphide reagents continue to appear. The

1: Phospliines and Phosphonium Salts 9

photo-assisted SRN 1 reactions of sodium diphenylphosphide with halogenoada- mantanes have been studieds3, and a sodium diphenylphosphide-tosylate route has been used in the synthesis of the chiral diphosphine 7484. Conventional applications of potassium diphenylphosphide have been made in the synthesis of the diphosphines 7585, the chiral 3-diphenylphosphinopyrrolidine 7686, the chiral phosphine 77 (obtained in an improved four-step route from D-mann i t~ l )~~ , the phosphinoalkylarenes 7888, and also in the phosphino-functionalisation of silses- quioxanesp9. Chiral, water-soluble, secondary phosphines, e.g. , 79, capable of further elaboration to chiral tertiary phosphines and diphosphines, have been obtained from the reactions of primary arylphosphines with fluorobenzene- sulfonates, displacement of the fluorine substituent occurringg0. In related work, displacement of fluorine from fluorophenylacetic acids or fluorobenzylamines with potassium diorganophosphide reagents has given the functionalised chiral phosphines 80, which have then been transformed into related phosphino-functional amino-acid systems". An anionic complex of potassium diphenylphosphide with boratabenzene has been characterised, and its coordination chemistry studied92.

Metallophosphide reagents have also found extensive use in the synthesis of

t

74

PPh2 H

ph2;;R 0 xo>+pph2 H 0 Ph2P

75 R = H, OMe or OEt 76 n

78 X = O o r C H * 79 Ar = Ph, mesityl 80 X = NH2 or C02H Y = H o r F or Pt3C8H2

systems in which phosphorus is bonded to atoms other than carbon, e.g., boron, silicon, germanium, and tin. Many of these have novel cage-like structures, often involving several different p-block elements. Examples of phosphorus-silicon system^^"^^ include 8193 and 8294. The reaction of a diphosphide reagent with tin tetrachloride resulted in various products, including the cage-compound 8399. Other phosphorus-tin heterocyclic systems have also been describedlm. Both linear'" and cyclic'o2 phosphinoborane systems have been characterised, and a range of cage systems involving both phosphorus and boron, together with either silicon, germanium, or tin, has also been d e s ~ r i b e d ' ~ " ' ~ ~ .


Ph

P $ S i M e

Ph p\ Si-

Me2 Me2

R R P-R

ClSn R R SnCl

P-R R R

/,p-pJ

\ I

81 82 83 R = Bu'

The synthesis and characterisation of organophosphide derivatives of other metallic elements continues to attract attention, and the past year has seen further examples of systems involving aluminium'06-'08, gallium'09-' ", indium' ' I -

' 13, titanium' 14, and zirconium' 15-' 17. In addition, organophosphide derivatives of niobium' 1 8 , tantalum' 19, and have also been described.

1.1.3 Preparation of Phosphines by Addition of P-H to Unsaturated Compounds. - Mechanistic aspects of the addition of P-H bonds to alkenes and alkynes have been reconsidered in the light of new activation methods. In the case of additions of diphenylphosphine, radical and ionic routes are indistinguishable, a duality of mechanism being apparent, the coexistence of the two routes bringing about a competition which depends on conditions'22. The additions of phosphine to simple alkenes, and bicyclic secondary phosphines, e.g., 9- phosphabicyclo[4.2. llnonane, with linear, long chain, terminal alkenes, has been studied by an in-situ 31P NMR t e c h n i q ~ e ' ~ ~ , ' * ~ . The phosphines 84 and 85 have been isolated from the free radical addition of phosphine to ~t-pinene'~'. The key step in the synthesis of the chiral triphosphine 86 is the addition of diphenylphosphine to the bis(-)-menthy1 ester of a benzylidene malonic acid'26. Photochemical addition of diphenylphosphine to N-ally1 groups is the crucial step in the synthesis of the triphosphine 87127. Photochemical initiation has also

M& M G P H ~ CH2PPh2

I PPh2 CH2PPh2

Ph-CH-Cv

84 85 86

87

been used in the addition of diphenylphosphine to trichlorovinylsilane, giving the phosphine 88, a key intermediate in the synthesis of phosphinoalkyl- functionalised silsesquioxanes' 28. Primary and secondary phosphines bearing

1: Phosphines and Phosphonium Salts 11

trimethylsilyl groups appear to behave normally in addition reactions with alkenes. This approach has been used in the synthesis of heterocyclic systems, e.g., 89'29, and new cycloalkylphosphines, e.g. , 90130. Addition of primary and secondary phosphines to alkenes bearing water-solubilising groups has given a new series of water-soluble phosphines and diphosphines, e.g., 9113', 92132, and 93133. Another route to water-soluble systems is offered by the base-promoted addition of bis(primary)phosphines to vinylphosphonates, to give 94'34. In related work, reduction of bisphosphonates with lithium aluminum hydride to generate new primary phosphine functionalities, followed by their reaction with formaldehyde has provided further water-soluble systems, e.g., 95l 35. The reaction of diphenylphosphine with aromatic o-hydroxyaldehydes and a diester of a diboronic acid has given 1,3,2-dioxaborinane systems, e.g., 96 which bear

R - P E X R 2 P d

88 89 R = H or Me3Si 90 R = Me3Si or H X = PPh, PNEt2 or SiMe2

0 Me Na03S\ <S03Na

N a O 3 S Y p %SO& P Ph2P NH-A-CH2S03- M+

I Me

91 M+ = Na+ or R4N+ 92

Ho+r\/F k % P p p b n OH

HO 93 n = 1 or2

( HOCH2)2Pr\S/X~nP(CH20H~2

95 X = (CH2)3 or &eH4


phosphino fun~tionalities'~~. Interest in P-H addition to coordinated alkenes has continued, with examples of regiospecific addition to coordinated allenyl systems'37, and addition of secondary phosphines to cationic dienyl tricarbonyl iron complexes'38, having appeared. A study of platinum catalysis in the addition of a hindered primary phosphine to acrylonitrile has provided further insight into the m e ~ h a n i s m ' ~ ~ . Addition of diphenylphosphine to a P-coordinated propargylphosphine has also been described". Borane adducts of primary and secondary phosphines also behave normally in hydrophosphination of alkenes. Thus, e.g. , both !I7 and 98 have been isolated from addition of a borane- protected primary phosphine to methyl acrylate and dimethyl vinyl- ph~sphonate '~ ' . Similarly, the borane adduct of diphenylphosphine adds to a diene obtained from D-mannitol to give the chiral diphosphine !Ell4*.

R - P P X + BH3

97 X = C02Me or P(O)(OMe)2 98 X = C02Me or P(0)(OMe)2 99 R = Me or Ph R = Me or Ph

I . 1.4 Preparation of Phosphines by Reduction. -- Although relatively few examples have appeared this year, trichlorosilane has remained the reagent of choice for reduction of phosphine oxides, usually in the final stage of a synthetic route. Examples of phosphines prepared in this way include the new chiral phosphetanes and the atropisomeric diphosphine 102145. A new route to 'chiraphos' (103) involves as the key step the reduction of the diphosphine oxide 104 with sodium borohydride, to give 'chiraphos dioxide', which after resolution, is then reduced to 'chiraphos' using trichl~rosilane'~~. A range of secondary phosphines bearing bulky groups has been obtained by reduction of related monochlorophosphines with lithium aluminum h ~ d r i d e ' ~ ~ . Treatment of the alkenylphosphine 105 with ethylmagnesium bromide in the presence of bis(tripheny1phosphine) nickel(I1) chloride gave (E)-diphenyl(4- undecenyl)phosphine, cleavage of the methoxy group having taken place. The alkylmagnesium halide was shown to be the exclusive hydride source. In contrast, treatment of 105 with either methylmagnesium or phenylmagnesium chloride gave a mixture of 106 and 107'48.

1.1.5 Miscellaneous Methods of Preparing Phosphines. - The synthesis and properties of phosphorus-containing cryptand ligands has been reviewed'49. The basic principles for the synthesis of functionalised phosphorus-containing heterocyclic systems have been summarised, relating to the chemistry of phosphabicyclohexanes, dihydrophosphinines, phosphabicyclooctadienes, and phosphabicyclooctenes'50. Ethylene acetals (108) of the 9-oxa-2- phosphabicyclo[4.4.0]-5-one system have been preparedI5'. Methods for the

I : Phosphines unti Phosphonium Salts 13

Q+ PPh2

100 X = O o r S

Met;;

PhpP H

103

R I

OYPPh2 101 n=Oor l 1 02

0

OMe

Ph2P II 0

104

p/ Ph / Me%

I Ph

106 R=MeorPh

synthesis of P-chiral monophosphines

Ph 1 05

R

Me p/ Ph I Ph

107 R=MeorPh

bearing a bulky group have been appraised, and a range of compounds bearing the 2-adamantyl group prepared, starting from P-chlorooxazaphospholidine ' 52. An easy route to tris(trifluoromethy1)phosphine has been developed, involving a three component system consisting of tris(diethylamino)phosphine, bromotrifluoromethane and triphenylphosphite, in HMPA'53. A very similar approach has been used in the synthesis of the unsymmetrical diphosphine 109' 54. Addition of hydrophilic thiois to vinylphosphines has been employed in the synthesis of water-soluble phosphinoethyl sulfonatoalkyl t h ioe the r~ '~~ . Substitution, addition, and rearrangement reactions of easily accessible derivatives of carbohydrates with diphenylvinylphosphine and 2-mercaptoethyldiphenylphosphine have given a series of chiral bidentate P-thioethylphosphine ligands, e.g., 110' 56. Glycosidation of 2-hydroxyphenyldiphenylphosphine affords a simple route to carbohydrate- substituted phosphines, e.g. , 11 1 '". Other routes to carbohydrate-phosphine systems have also been de~cribed'~'. A brief review has appeared of the synthesis, chemistry and application in catalysis of atropisomeric phosphines, in particular dinaphthophospholes and dinaphthophosphepins' 59. Further atropisomeric systems have been prepared by phosphitylation of the phenolic group of the phosphine 112160*'61.

Routes to the chiral ferrocenyldiphosphines 113 have been developed, via the use of the chiral oxazaphospholidine borane 11416*. Routes to other chiral ferrocenylphosphines have also been developed, including the boranato-functionalised systems 115163, and the Cz-symmetric diphosphine 116, having only the planar chirality of the ferrocene system'@. Full details have now appeared of the palladium-promoted asymmetric Diels-Alder reaction between 1 -phenyl-3,4-di-


108 109

111 R'=HorOH, R2=HorOH, R3=OHorNHAc 112

methylphosphole and substituted vinyldiphenylphosphines, which give the P- chiral diphosphine (117, E = P)16'. Related work involving cycloaddition to vinyldiphenylarsine has given the chiral phosphinoarsine system (1 17, E = As; R' = R2 = H)166. Similar addition of phenyldivinylphosphines have given the diphosphines 118, which have two phosphorus and three or four carbon stereogenic Quaternization of bis(dipheny1phosphino)ethane with o-

116 117 R', R2 = H or Me 118 R' = H or Me, R2 = H or Me

iodopropyltriarylphosphonium salts to give the diphosphonium salts 119, followed by alkaline hydrolysis, and final reduction of phosphine oxide moieties with trichlorosilane, are the key steps in the synthesis of a range of unsymmetrical triphosphine ligands (120)169. The presence of o-methoxyphenyl substituents in the diarylphosphinite-borane adducts 121 results in a remarkable rate enhancement effect in their reactions with organolithium reagents to form the chiral phosphine-boranes 122I7O. Double-labelling techniques have established an intra-

1: Phospiiines and Pliosphonium Sults 15

BH3 t

BH3 t

A I ~ ~ ( C H ~ ) ~ ~ ( C H ~ ) ~ P P ~ ~ A ~ ~ P ( C H Z ) ~ P ( C H ~ ) ~ P P ~ ~ Ph-P-OC6HII Ph-P-I7 I I

21- Ph Ar Ar I Ph2

119 120 Ar = Ph, pCIC6H4 or PFCsH4 121 122

molecular mechanism which involves pentacovalent P intermediates for the rearrangement of the o-lithiophenylalkyl esters 123 to the phosphines 124 and related derivative^'^'. The chemistry of phosphinobenzaldehydes, notably 125, has continued to develop. Further examples of Schiff's base condensations to give hybrid ligands have been described, e.g., 12617*, 127173, and 128'74. The phosphine 125 has been converted into the cyclam system 129 bearing a pendant

123 Ar = Ph or B-naphthyl 124 n = 1 or2 X = lone pair or 0 or BH3

125

Me

Ph2P CH=NCH2CHz PPh2

126 127

128 129

p h o ~ p h i n e ' ~ ~ . Schiff's base formation is also the key step in the synthesis of new hybrid, chiral ligands from the phosphines 130176 and 131 177. Conformational diastereoisomerism in the phosphino-imines 132 has been studied by NMR 178.

Silylation of the diphosphinodiol 133 (obtained by de-acetalisation of the chiral diphosphine DIOP) has given a range of new chiral ligands 134, in which the bulky silyloxy groups fix the chiral en~ironment'~'. The reaction of hydroxyalk- yldiphosphines with o-sulfobenzoic anhydride in the presence of a base provides a new route to chiral sulfonated, water-soluble, phosphines, e.g., 135180. The heteroarylphosphine 136 has been obtained via the direct reaction of an N- protected aminothiazole with phosphorus tribromide'*'.

16

OMe


H

HO "('PPh2

HO& PPh2 H

130 131 132

R 3 S i O e PPh2 &!fpph2 0

PPh2 R3Si0 ' S03-M+ PPh2 H

134 R3Si = Me3Si, ButMe2Si, Pr'3Si or Ph3Si

135

133

H 2 N 4

136

A standard combinatorial synthetic approach has been used to give a 63- member library of phosphine-functionalised peptides. The approach is based on the peptide chemistry of phosphino-aminoacids, e.g., 137, the phosphorus of which is protected (as the sulfide) during the synthetic procedure, and then deprotected via the use of iodomethane, followed HMPT182. Further examples of polymer-based phosphines have been d e ~ c r i b e d ' ~ ~ * ' ~ ~ . The synthesis of phosphino-terminated dendrimers continues to attract attention, and several new systems have been ~ r e p a r e d ' ~ ~ - ' ~ ~ . A useful approach is the surface functionalisation of dendrimers bearing secondary amino groups, using hydroxymethyldiphe- nylphosphine, to form aminomethylphosphine ~ n i t s ' ~ ~ " ~ ~ . A similar approach has been used in the phosphino-functionalisation of aminoalkyl-P-cyclodextrin systems'88. Treatment of ferrocenylmethyltrimethyIammonium iodide with tris(hydroxymethy1) phosphine has given the ferrocenylmethylphosphine 138 as an air-stable solid, which undergoes the usual transformation reactions of hydroxymethylphosphines, enabling the synthesis of a number of new systems, e.g., 139189. On treatment with aqueous sodium metabisulfite, 138 is converted into the primary phosphine 140, an air-stable orange solid"*. Formylation of the triphosphine 141 has given the new, water-soluble triphosphine 142'". Stannyla- tion of hydroxyalkylphosphines has also been reported, to give, e .g . , 14319*.

0

137

@-CH2P(CH20H)2

I

Fe

@ 138

I

P

@ 139 @ 140

R

Me2P- CH PH2 P P ( C H 2 0 H ) z

P h - p L P ( C H 2 0 H ) 2 OSnMe3

Ph-P L P H 2

141 142 143


Intramolecular coupling of bisalkynylphosphines occurs in the presence of a transient zirconocene-benzyne complex to give the zirconocycle 144, which, on subsequent treatment with hydrogen chloride or phenylantimony dichloride, gives the phosphete 145 and the benzostibinine phosphete 146, re~pectively'~~. The utility of phosphazirconacycles, e.g., 147, in metallacycle transfer reactions leading to main group phosphacycles, has been explored. Thus, e.g., with phenyldichlorophosphine, 147 yields the cyclotetraphosphine A P16-macrocyclic system 149, has been obtained from the reaction of o-bis(phosphin0)benzene with a trihydridozirconium complex'95. The MO(CO)~ fragment has been used to protect tripodal phosphines, e.g., 150 from oxidation and P-C cleavage during functiona- lization of their cyclohexane backbone. The C-functionalised phosphines are liberated from the complexes by a combined photochemical-oxidation process196.

Ph

Ph Ph I A

cP2 Ph Ph Ph 144 1 45 146 1 47

Ph- -

Ph 1 P

P .P< )P--Ph

A Ph

148

R R

P h z P w P P h 2

4 PhpP' 150 R = CH20H, CH20Me

or CH20CH2CH20Me

Full details have now appeared of the stereoselective synthesis of 1,5,9- triphosphacyclododecane systems by oxidative liberation from molybdenum and chromium complexes of the macrocycle, obtained by coordination-template controlled reactions197. Molybdenum complexes have also been used in the coordination-template dependent synthesis of the macrocyclic P,S system 151 19*.

A non-template synthesis of the 14-membered P2S2 macrocycle, 152, isolated in two isomeric forms, has been describedlW. Halogenation of the cyclometallated phosphine 153 leads to a rearrangement, with the formation of the di- phosphinobiphenyl system 154, from which the free diphosphine can be liberated

Ph

cp3 S

WS 3 Ph

Q P R2AuX

opR2Aux 151 1 52 153 R = PhorEt 154


on treatment with cyanide2''. An electrochemical route to diphenyl(tributy1- stanny1)phosphine has been developed, which involves the electrolysis of a mixture of chlorodiphenylphosphine and tributylstannyl chloride at a sacrificial magnesium anode in DMF201. White phosphorus undergoes alkylation and arylation with organic halides in the presence of electrochemically-generated Ni(0) complexes, to give mixtures of phosphines and the related phosphine oxides202. Arylation of primary or secondary phosphines has been achieved on treatment with aryl iodides (bearing a wide variety of substituents) in the presence of a Pd(0) complex, enabling the synthesis of functionalised arylphosphines, e.g., W 2 0 3 . The phosphine 156 has been prepared via the reaction of lithiomethyl- (pheny1)sulfide with triphenylphosphite, and then converted into chalcogenide derivatives2M, and also complexed with gold205. Phosphonato-functionalised triarylphosphines, e.g., 157, have been obtained by the reaction of lithiophenyl- phosphines with diethyl phosphorochloridate. Hydrolysis of the phosphonate ester provides water-soluble phosphines, e.g. , 158206. A route to the chiral phosphinoalkyloxazolines 159 has been developed which involves the reaction of a P-phosphinopropionic acid derivative with an amino-acid followed by cyclisation of the intermediate amide-acid207. A range of bulky phosphines, e.g. , 160 has been prepared, which possess functionalities which make possible their attachment to a chiral system, creating a chiral 'pocket' which act as mimics of natural ion-channel systems208. Routes to the new C2-symmetrical diphosphines 161 and 162 have also been developed209.

1.2 Reactions of Phosphines 1.2.1 Nucleophilic Attack at Carbon. - The generation of reactive intermediates by the addition of phosphines to unsaturated esters, and their subsequent reactions, continues to attract interest. Adducts of phosphines with buta-2,3- dienoates and but-2-ynoates are key intermediates in the formation of [3 + 21 cycloadducts of the unsaturated esters with [ 6 O ] - f ~ l l e r e n e ~ ~ ~ ~ ~ " . In similar vein, the reaction of triphenylphosphine, dimethyl acetylenedicarboxylate, and [60]- fullerene has given a methano [60]-fullerene system in which a stable ylide moiety is attached to the c60 unit212. The formation of vinylphosphonium salts by protonation of the initial adduct from the reaction of triphenylphosphine with dimethyl acetylenedicarboxylate is the key step in directing the course of reactions of the above system with butane-2,3-dione monoxime, and 3- chloropentanedione, Triphenylphosphine also catalyses the reactions of methyl 2,3-butadienoate with aromatic or heteraromatic N- tosylimines, giving nitrogen heterocycles. The initial key intermediate is the zwitterion 163215. The conjugate addition of oximes to ethyl propiolate to give 0- vinyl oximes is catalysed by triphenylphosphine, this reaction presumably also involving a vinylphosphonium intermediate2I6. Transition state structures for the addition of maleic anhydride and methyl phenylpropiolate to 1 -phenyl-3,4- dimethylphosphole have been investigated by a computational study2". Full details have now appeared of the characterisation of the zwitterionic adducts 164 from reactions of tri-isopropylphosphine with 2-cyanoacrylates, and of their subsequent reactions with a variety of reagents218. The molecular structures of

I: Phosphines und Phosphonium Sults 19

Php P q C o ” (PhSCH2)3P

C02H 155 156 157

158 159 R’ = H or Ph, R2 = Me, PhCH2, Pr‘ or Ph

160

161 162 X = CH2 or NMe

zwitterionic adducts of acrylic acid with triphenylphosphine and 1,2- bis(diphenylphosphino)ethane, respectively, have been studied by X-ray techniques2I9. The phosphine-catalysed dimerisation of alkyl acrylates has been reviewed220. The reactions of phosphines (and other trivalent phosphorus species) with quinones continue to attract interest, and this area has also been reviewed22’. The stabilised ylide 165 has been isolated from the reaction of triphenylphosphine with 2,6-di-t-butyl- I ,4-benzoquinone. In contrast, the related reactions of triphenylarsine and triphenylstibine take a different course, aryloxyarsonium betaines 166, and the stibonium ylide 167, resulting222.

1.2.2 Nucleophilic Attack at Halogen. ~ Nucleophilic attack at iodine is probably initially involved in the reaction of the iodoketone 168 with triphenylphosphine, which, at 80°, results in the formation of the alkoxyphosphonium salt 169. On heating to 1 50°, this eliminates triphenylphosphine oxide with the formation of the cycloalkyl iodide 170223. Cyanogen iodide acts as a positive iodine source in its reaction with triphenylphosphine. providing a reagent system which transforms alcohols into iodoalkanes in high yield224. A mild and efficient method for


1 63 164 R=MeorEt

0-

165 166 167

1 68 169 170

converting alcohols and tetrahydropyranyl ethers into bromides with inversion of configuration is provided by a combination of triphenylphosphine with 2,4,4,6- tetrabromo-2,5-cyclohexadienone in dichloromethane or acetonitrile, which is reported to involve the phosphonium salt 171 as the key intermediate225. The structures of tertiary phosphine-iodine adducts have been reconsidered in the light of detailed spectroscopic and conductivity studies. The adducts are now described in terms of a charge-transfer complex of a donor iodide ion with the acceptor iodotriorganophosphonium cation, rather than a discrete ionic structure or a molecular charge-transfer complex. Previously reported solution data for the triphenylphosphine-iodine system, for which the ionic formulation was favoured, are now said to be in agreement with the formation of products of hydrolysis of the adduct in the presence of traces of water226. A structural study of the iodine adduct of butyl(isopropy1)iodophosphine has revealed a largely ionic structure involving bridging polyiodide anions227. A similar solid state study of the adduct of chlorine and triphenylphosphine formed in dichloromethane solution has revealed a novel dinuclear ionic structure 172, involving long chlorine-chlorine contacts228.

Ph$Br O*Br

Br

171

[PhsbCI- -el- -CIbPh,]CT

172

I : Phosphines and Phosphonium Subs 21

1.2.3 Nucleopltilic Attack at Other Atoms. - A convenient route to phosphine- borane complexes is afforded by treatment of N-methylmorpholine-borane derivatives with the p h o ~ p h i n e ~ ~ ~ . The crystal structure of the dicyclohexylphosphine-borane complex has been reported230. Stable, distillable borane adducts of primary phosphines have been obtained by an exchange reaction with the borane adduct of dimethyl sulfide, and their reactions with aldehydes explored23'. The hydroboration of o-alkenyldiphenylphosphines has been investigated. In the presence of an equimolar quantity of borane, the expected phosphine-borane complex is formed. Attack on the double bond only occurs in the presence of excess borane. With the bulky borane, 9- borabicyclononane, cyclisation products, e.g. , 173, are formed as a result of an intramolecular addition to the double Reversible adduct formation between phosphine and primary phosphines with triarylboron compounds has been reported, the adduct decomposing on heating234. A range of adducts of 1 , 1'-bis(dipheny1phosphino) ferrocene with boranes, thiaboranes, and carboranes has been described235. Adducts of tris(trimethylsi1yl)phosphine with gallium halides236 and phenylaluminuim compounds have been ~ha rac t e r i s ed~~~ .

173 n = l or2

Two studies phosphines on

have been reported on mechanistic aspects of the attack of the oxygen-oxygen bond of ring-substituted 1, 2-dioxolanes.

Factors which control regioselectivity of attack have been explored238, and rate studies are consistent with the initial formation of metastable phosphoranes as the rate-determining step, these then undergoing decomposition by several ionic routes239. The reactions of phosphines with dibenzoyl peroxide have been studied by ESR techniques and phosphorus-centered radical intermediates trapped240. The oxidation of triphenylphosphine by hydrogen peroxide in pyridine has been shown to be catalysed by ir0n(II1)~~'. A study of the oxidation of triphenylphosphine with potassium peroxodiphosphate in the presence of '*O-labelled water has shown that the phosphate salt is the origin of the oxygen of the P=O bond242. A pyrazine-based polymeric complex of oxodiperoxochromium(V1) is a new stable, mild, efficient oxidant and has been shown to oxidise phosphines to the related phosphine Triarylphosphines are thought to attack at carbonyl oxygen of the chromene-dione system 174, and the reactions lead eventually to the quite surprising formation of methyl diarylphosphinate esters, and the arylamine 175. Trialkylphosphines behave differently, the phosphinamide 176 being formed244. Phosphine-cleavage of sulfur-sulfur bonds has been utilised for the synthesis of stable thiobenzaldehyde~~~', and for the initiation of ring- opening polymerisation reactions246.

22 Orgmophosphorus Chemistry

174 175 176

Mitsunobu chemistry continues to attract attention, and many new synthetic applications have appeared. Its applications in alkaloid synthesis have been reviewed247. The formation of benzoic anhydride in Mitsunobu-promoted ester- ifications involving benzoic acid is a troublesome side reaction, but anhydride formation can be prevented by the use of p-nitrobenzoic acid as an alternative248. The effect of the microenvironment surrounding the active sites on kinetics and yield in polymer-supported Mitsunobu esterification systems has been ex- p l ~ r e d ~ ~ ~ . Combinations of triphenylphosphine with diethyl azodicarboxylate and tributylphosphine with azodicarbonyldipiperidide have been used to promote an unusual tandem cyclisation - Stevens rearrangement process250. An unusual intramolecular Mitsunobu procedure has been described in which an amide acts as the n~c leoph i l e~~’ . Improvements on the original conditions have been introduced for sulfonation of alcohols with inversion of configuration by the Mitsunobu reaction252. A double inversion Mitsunobu process, involving sulfonation followed by displacement with azide, enables equatorial hydroxyl groups to be converted into the related equatorial azides, axial hydroxyl group being unaffected253. Among other application of Mitsunobu chemistry are the synthesis of chroman-4-ones via aldol-Mitsunobu reactions254, the conversion of 0-ethers of benzylic secondary alcohols into esters255, an alternative route to 1 -(primary a1 kyl )benzot r iaz~les~~~, the synthesis of reversed azole n ~ c l e o s i d e s ~ ~ ~ , N -gly cosy - lated disymmetric fused heterocyclic systems258, thiofunctionalised pento- f ~ r a n o s e s ~ ~ ~ , and a remarkable stereocontrolled fragmentation reaction in macrolide antibiotic chemistry260. The Staudinger reaction of tertiary phosphines with azido compounds has been applied in the synthesis of macrocyclic and cage- like compounds, e.g. , 17726’3262. The reaction of a,o-diphosphines with an azide of a carbofunctional diarylthiophosphoric acid is the key step for the design of the core of an extended series of phosphorus-containing d e n d r i m e r ~ ~ ~ ~ . Attack at only one of the phosphine functionalities in 1, 2-bis(diphenylphosphino)benzene (and cis- 1,2-bis(diphenyIphosphino)ethene) occurs in their reactions with a range of organic azides, giving phosphino-phosphazenes, e.g. , 178264.

177 X = 0 or NH 178 R = MeSSi, pCNC6H4, PhCO or Ph2P(O)

1: Phosplzines and Pliosplzonium Salts 23

1.2.4 Miscellaneous Reactions of' Phosphines. - Gas phase pyrolysis of diallyl(4- fluoropheny1)phosphine and allyl( t-buty1amino)phenylphosphine results in the formation of 1 -(4-fluorophenyl)- 1 -phosphabutadiene and 1 -phenyl-2(t- butyl)iminophosphene, respectively, as the primary products, which then give rise to [4 + 21 and [2 + 21 cycloaddition products265. The phosphines 179 have been prepared by the reaction of the pyrazolate anion with tris(pentafluorophenyl)phosphine, para-substitution being proved by NMR and crystallographic studies266. Whereas insertion of a methylene group into a boron- hydrogen bond occurs when tertiary phosphine-boranes are heated with a samarium carbenoid reagent, the related reaction of secondary phosphine-borane complexes proceeds with methylene insertion into the phosphorus-hydrogen bond267. Evidence for the formation of radical polycation species has been presented in the electrochemical oxidation of phosphines containing two or three tetrathiafulvalene moieties, e .g . , 180268. The reactions of cation radicals generated from trivalent phosphorus compounds by y-irradiation or anodic oxidation have been reviewed269.

1 79 180

The chiral phosphine 181 has been resolved with the aid of a new chiral amine-palladium complex270. The tetraphosphine 182 has been separated into diastereoisomers, which have then been subsequently resolved27'. A chiral amine-palladium complex has also been used to resolve methylphenylbenzyl- p h ~ s p h i n e ~ ~ ~ . The tetraphosphino-l,3-butadiene 183 has been obtained (as a molybdenum carbonyl complex) from photolysis of molybdenum carbonyl complexes of 1,2-bi~-diphenylphosphinoethyne~~~. The phosphines 184 have been obtained from the reactions of diethyltrimethylsilylphosphine with a series of ben~ylideneindanones~~~. Factors affecting the basicity of phosphines continue to attract the attention of the theoreticians2757276. The tetraphosphacubane system 185 has been shown to act as an unprecedentedly strong base in the gas phase, but not in solution277. A theoretical study of the reactivity of the tetraphosphacubane system has also appeared278. Dimethyl- amino-substituted triarylphosphines exhibit dual fluorescence in polar sol- v e n t ~ ~ ~ ~ . Solution studies of the conformation of the %membered ring system 186 have been reported280. Significant double bond character is reported to be present in the phosphorus-carbon bonds of triarylphosphines, according to the results of an ab-initio study28'. A new approach for estimating the effective steric impact of bulky tertiary alkylphosphine ligands has been developed282. The uses of trialkylphosphine complexes of rhodium as homogeneous catalysts have been reviewed283. X-Ray studies of chelating a,o-bis(dialky1- phosphin0)alkanes (which are liquid at room temperature) have been carried out at low temperatures, and the structural data used to rationalise their

24 Orgunophosphorus Chemistry

I - , A (P~~P)~C=CH-CH=C(PP~Z)~

Ph2PnP P PPh2 A A

Ph2P Ph Ph 181 182 183

OSiMe3 R2 9

* 7 H - & - R 3 PEt2

H R' . Ph

OSiMe3 R2 9

* 7 H - & - R 3 PEt2

H R' . Ph 184 R'=HorMe

R2 = H, CI or NO2 R3 = H or Me0

185 R = Me or But 186

properties as l i g a n d ~ ~ ~ ~ . Sulfonation of arylphosphines continues to be used as a strategy for the synthesis of water-soluble systems285, and the use of such ligands in rhodium-catalysed hydroformylation procedures has been re- viewed286. Treatment of the monomeric ether-phosphine ligands 187 with tetraethoxysilane under sol-gel conditions has given a series of polysiloxane- bound ether-phosphine l i g a n d ~ ~ ' ~ . The chiral phosphine 188 has been used as a ligand in a palladium-catalysed enantioseletive substitution reaction288. The phosphino-benzoate esters 189 have been subjected to a rhodium-catalysed stereoselective hydroformylation to give the phosphino-aldehyde 190289. Elec- trospray and Fourier Transform ion cyclotron resonance spectrometric techniques have been used to study the interaction of tris(2-cyanoethy1)phosphine with metal ions290.

(MeO)&i(CH2),P( Ph)CH&H20Me

187 n = 3 , 6 o r 8 2 PPh2

9

Me 189

188

qx PPh2

190

1: Phosphines und Phosphonium Sults 25

2 Halogenophosphines

2.1 Preparation. - The new sterically crowded dichlorophosphine 191 has been prepared via the reaction of an aryllithium reagent with phosphorus trichloride. This dichlorophosphine serves as a precursor for the related phosphinic acid ArP(O)(OH)H, the primary phosphine ArPH2, and the diphosphene ArP=PAr29'. Interest continues in the direct halogenophosphonation of heterocyclic systems. Thus, treating N-methylpyrrole with phosphorus tribromide in pyridine gives initially the 2-dibromophosphino system 192. However, at room temperature, this rearranges to the 3-isomer 193, in almost quantitative yield292. Similarly, the reactions of N-alkylindoles with phosphorus trihalides also result in the formation of the 3-dihalogenophosphino-derivatives 194293. _,

Heterocyclic halogenophosphines, e.g. , 195 have been isolated from the reactions of phosphonium ylides, bearing trimethylsilyl groups at the ylidic carbon, with phosphorus t r i h a l i d e ~ ~ ~ ~ . Related reactions with the ylide Ph3P=C(PC12)2 have given the 1,3-diphosphanaphthalene system 196, which, with gallium trichloride is converted into the lox-system 19'7, involving two coordinate phosphorus295. The functionalised halogenophosphines 198 have been prepared by the uncatalysed electrophilic addition of phosphorus trihalides to a lko~yace ty lenes~~~. The formation of an unstable intermediate phosphirenium halide in these reactions was also demonstrated297. 1 -Alkylpyridinium bromides having an activated N-methylene group have been shown to react with phosphorus trichloride to give the (dichlorophosphinomethylene) pyridinium ylides 199, except where a more reactive 2(or 4)-alkyl substituent is present, when dichlorophosphonylated anhydrobases, e.g., 200, are formed preferen t iaiiy298.

2.2 Reactions. -- Organoiodophosphines, and phosphorus tri-iodide, have been shown to undergo equilibrium formation of phosphine-phosphonium dimers. The association may proceed further, and result in the formation of P-P bonds by elimination of iodine299. Certain diiodo(organo)phosphines also react with THF to give tetraorganocyclotetraphosphines, 1,6diiodobutane, and other pro- d u c t ~ ~ ~ ~ . Diorganophosphinic iodides have been isolated from the reactions of 1- adamantyl- and phenyl-diiodophosphine with 1-hydr~xyadamantane~". The


PPh3

X.pKp,X

Ph3P A PAPPh3 I

X 195 196 R’, R2= H or Me 197

198 R1 = H or alkyl 199 R = C02R’ or COPh 200 R2 = alkyl X = CI or Br

reactions of 5-chlorodibenzophosphole 201 and di-r-butylchlorophosphine with aluminium chloride have been explored. The former gives rise to a P-P system 202, whereas, under the same conditions, the latter gives the simple salt [ButZ PCI2] A1C14302. The ylidyl substituent in the chlorophosphines 203 causes a significant lengthening of the phosphorus-chlorine bond, to the extent that, for R = Me2N, an ionic structure is considered to be present in dichloromethane solution303. P--P-bonded compounds, e.g. , 204, have been isolated from the reactions of r-butyl(trimethylsily1)chlorophosphine with dicyclopentadienyldi- methylzirconium in the presence of a copper(1) catalyst3w. A family of bis(tri- chlorosily1)phosphines (205) has been obtained from the reactions of

201 202

Ph

P h3P = C, B U i Me SiCI3

R I Me /p-p:B”t Sic13

P-CI R-P,

203 R = Me or Me2N 204 205 R = But, l-adamantyl, (Me3Si)2CH or Pr12N

organodichlorophosphines with trichlorosilane or hexachlor~dis i lane~~~. Treat- ment of the isoprene-phosphorus trichloride adduct with magnesium or hexa- chlorodisilane gives the heterocyclic system 206, which, in the presence of an

I: Phosphines and Phosphonium Salts 27

excess of the above reagents is converted into the diphosphine 207, isolated as a mixture of diastereois~mers~~~. The phosphirane 208 has been isolated from the reaction of bis(pentamethylcyclopentadieny1)chlorophosphine with lithium bis(- trimethylsily1)amide in refluxing hexane, and its reactions with dimethyl acetylenedicarboxylate and diethyl azodicarboxylate studied307. The triplet ground state phosphinyl diradical209 has been prepared by photoinduced dissociative electron capture by the related bisphosphinous chloride in the presence of an electron-rich alkene at 11OK3'*. A new route to free acylphosphines is promised by the isolation of acylphosphine-iron complexes from the reactions of lithium acyl- tetracarbonylferrates with chlor~diphenylphosphine~~~. New chiral phosphinous esters of a partially protected glucofuranose system have been obtained from the reactions of chiral diorganophosphines with a free alcohol group of the carbohydrate molecule310. Reactions with amino compounds have also been reported3". With 5-fluorouracil, chlorodiphenylphosphine gives the N-phosphino system 2lO3I2. Further studies of the reactions of diphenylphosphinous isocyanate with nitrilimines have also been reported3I3.

Me

I Me'cp-pa d Me CI

206 207

+ 209

208

I PPh2

210

3 Phosphine Oxides and Related Chalcogenides

3.1 Preparation. - A series of phosphetane oxides (211), bearing chiral groups at phosphorus, has been prepared from the appropriate chiral dichlorophosphine in a standard synthetic procedure for the phosphetane system3I4. The related P- menthylphosphetane oxide (21 1, R* = menthyl) can be metallated at the a-carbon using lithium tetramethylpiperidide, and subsequent treatment with a chlorosilane gives the chiral a-silylphosphetane oxide 212, which can be reduced to the related phosphine using trichl~rosilane~'~. A route to the menthylphosphetane sulfide 213 has been developed, and this can also be metallated and alkylated at the ~x-carbon~'~. Further development of synthetic routes to chiral 5-phenyl- dibenzophosphepin-oxide systems, e.g. , 214 has been reported317. The phosphine oxide 215 undergoes metallation ortho to the diphenylphosphinoyl group on


treatment with lithium tetramethylpiperidide. Subsequent iodination and Ullmanii coupling has given the biphenylic diphosphine dioxide 21(i3I8.

21 1 R* = e.g. (S)-bornyl 21 2 or (1 R)-isopinocamphenyl

0 K,

S II Men-rl

21 3

214 215 216

Chiral phosphine oxides 217 have been obtained in high enantiomeric purity by treatment of diastereoisomeric carbohydrate esters of methyl(pheny1)- phosphinic acid with a Grignard reagent3 19. The optically-active phosphine- borane 218 is oxidised to the phosphine oxide 219 (X=O) by m-chloroperben- zoic acid with almost complete retention of configuration at phosphorus. Oxidation of 218 with iodine in the presence of water occurred with inversion of configuration, again with high stereospecificity. With sulfur in the presence of N-methylmorpholine, the related phosphine sulfide 219 (X = S) is formed, again with the retention of c~nfiguration~~'. The course of the reaction of diphenylphosphine sulfide with dihaloalkanes depends on the length of the alkane chain, the nature of the halogen, and the conditions. With dihalomethanes, products are either the halomethylphosphine sulfide, or the reduction product diphenyl(methy1) phosphine sulfide. With 1,2-dibromoethane, ethylene is evolved and tetraphenyldiphosphinedisulfide is formed. Longer chain a,w-dibromoalk- anes give the related a,w-alkylenediphosphine d i s~ l f ides~~ l . A route to the nitronylnitroxyl radical-substituted phosphine oxides 220 has been reported322. The phosphine oxide 221 is the stable product resulting from thermal isomerisation of the mixture of prototopic isomers formed in the reaction of N- benzylarylimidoyl chlorides with ethyl diphenylph~sphinite'~~. The aminoalkylphosphine oxides 222 have been isolated from addition of diphenylphosphine to imines derived from 7-amino- 1,3,5-tria~aadamantane~~~. Addition of dimethylphosphine oxide to a C=N unit is the key step in the synthesis of the phosphine oxides 223325.

A series of N-substituted (aminomethy1ene)diphenyIphosphine oxides has been obtained from the reaction of diphenylphosphine oxide, paraformaldehyde, and a secondary amine under modified Mannich conditions326. A route from the arylaminovinylphosphine oxides 224 to the quinolyl system 225 has been developed327. The enaminophosphine oxides 226 have been obtained by addition

I : Phosphines und Phosphonium Sults 29

0

217 R = eMeOC&l4 or Pr” 21 8 219 220

0 II

0 0 II II

Ph2P-CH-N=CHPh R’NHCHR2PPh2

CF3 I Ar

221 Ar = m,pFC6H4 222 R’ = 1,3,5-triazaadarnant-7-~1 223 R2 = aryl

of amines to allenylphosphine oxides and subsequently reduced by hydride reagents to the aminoalkylphosphine oxides 227328. The reduction of a-alkyl-P- ketophosphine oxides cg., 228 with lithium borohydride in the presence of titanium tetrachloride proceeds with high anti-diastereoselectivity to give the corresponding P-hydroxyalkylphosphine oxides, e.g. , 229329.

224 225 R’ = Me or OMe R2 = H, Me or ptolyl R3 = Ph or o-tolyl

226

0 0 0 II II II

R ~ N H o

R1& IPhp Ph2PCH(Me)CPh Ph2PCH(Me)CH(OH)Ph

227 228 229

A diastereoselective preparation of or-hydroxyalkylphosphine oxides 230 is offered by the reaction of lithiated t-butyl(pheny1)phosphine oxide with carbonyl compounds330. The same group has also studied the reactions of the above lithiated secondary phosphine oxide with bis(haloalky1) reagents, which afford a series of doubly chiral diphosphine dioxide ligands, e.g., 23133’. Further progress in the synthesis of highly functionalised alkyldiphenylphosphine oxides has been reported by Warren’s group, much of it focused upon the reactions of a-lithiated alkyldiphenylphosphine oxides with e l e c t r o p h i l e ~ ~ ~ ~ ‘ ~ ~ ~ . Support has grown for the view that a-lithiated alkyldiphenylphosphine oxides are not configurationally stable, even at -78°C3357336. Among new systems prepared by Warren’s group are 232337933g, 233339, and 234340.

The fluoroalkylphosphine oxides 235 are formed via a rearrangement process in the reactions of difluoroallylic alcohols with chlorodiphenylphosphine in the


230

0

P h p ! v R

HO Me

231 232 R’ = H,OH, Me or Ph R2 = H, Me, Ph or OH

Ph2!+ R’

OH

233 R = CHO or CH20H 234 R’ = Me, Bu or Ph, R2 = H or Me

presence of t r ie th~lamine~~’ . A new route to diphenylalkenylphosphine oxides is provided by the reactions of the diphenylphosphinoyl radical (obtained by treatment of diphenylphosphine oxide with a manganese(II1) complex) with alkenes. Thus, e.g. , with dihydropyran, 236 is formed342. Several pyridyl(and 8- quinoly1)oxymethylenephosphine oxides, e. g., 237 have been obtained via the reaction of chloromethyldimethylphosphine oxide with the sodium salts of hydroxypyridines and 8-hydro~yquinol ine~~~. Intramolecular cyclisation of the allenyldiphenylphosphine oxide 238 provides an efficient route to the dihydro- furylphosphine oxides 239344. The fl-ketophosphine chalcogenides 240 have been obtained from the reactions of enamines with chlorodiphenylphosphine in the presence of triethylamine, followed by treatment with oxygen, sulfur, or selenium, and then acidic hydrolysis345. Phosphine oxides bearing cyclo- pentenone groups, e.g. , 241, have been prepared via the tandem reaction of C- lithiated alkyldiphenylphosphazenes with dimethyl acetylenedicarboxylate and me th~ l rna lea t e~~~ . A series of difunctional phosphine oxides (242) has been prepared and used as reactive monomers in the synthesis of fire-resistant p o ~ y r n e r s ~ ~ ~ - ~ ~ ’ .

CH2CHp0SiMe2Bu‘ 0 0 OMEM /

RCH=C=C Php!*R’ a 0 PPhp II

F F 0 N On’’ PMe2 0 235 R’, R2 = H or Et 236 237 238

239 R = alkyl or aryl 240 n = 0-2 or 7 X = 0, S or Se

241 242 R = Me or Ph X = NCO, NH2 or C0pH

I : Pliosphines unci Phosphonium Sults 31

3.2 Reactions. - On heating, the phosphine oxides 243 do not aromatise but undergo a series of rearrangements via diradical intermediates to form various cyclised products, e.g. , 244 and 2453517352. The tetracyclic system’ 245 has been isolated as two thermally stable rotamers, as a result of completely hindered rotation about the ring-P(0)Ph2 bond353. A simpler, more efficient procedure has been developed for the conversion of the phosphabicyclo[3.1 .O]-hexane oxides 246 into the hexahydrophosphinine oxides 247, involving catalytic hydrogenolysis under pressure in the presence of a base354. The importance of the 3-phosphabicyclo [3.1 .O]hexane-3-oxide system 246 as an intermediate for the synthesis of dihydro-, tetrahydro-, and hexahydro-phosphinines, and also phosphinines, has been reviewed355. Nucleophilic additions to the carbonyl group of 248 have provided a series of derivatives of this bicyclic system356. Enantioenrichment of the phospholane system 249 has been achieved by lithiation at a ring carbon adjacent to phosphorus, using butyllithium in the presence of (-)-sparteine, followed by p r ~ t o n a t i o n ~ ~ ~ .

243 X = ptolyl or H 244 R=Bu” R = Bun, Ph or Mes

H,

245 Ar = ptolyl

246 R = BuorPh 247 248 R=HorPh, X = O o r S 249

The phosphine sulfide 250 has been prepared by the reaction of tris(ch1oro- methy1)phosphine sulfide with sodium dia l ly l i s~cyanura te~~~. Borylation of 251 in the presence of 1,3,5-triazaadamantanes has given the salts 252 involving the 1,3,2,5-dioxaborataphosphorinane ~ys tem”~ . A regiospecific route to the diben- zo[b,e]phosphininone system 253 is provided by treatment of the phosphine oxide 254 with lithium diisopropylamide, the reaction being a new double anionic equivalent of the Friedel-Crafts reaction360. The reaction of N-methyl-N- trimethylsilylaminomethyldimethylphosphine oxide (255) with various peptoid acyl chlorides has given a series of peptoids bearing organoaminomethyldimethyl- phosphine oxide The atropisomeric phosphine oxides 256 have been shown to racemise very rapidly in solution362. Tertiary phosphine oxides have been shown to act as nucleophilic catalysts in the aqueous hydrolysis of diphenyl chlorophosphate in a ~ e t o n i t r i l e ~ ~ ~ . The formation of phosphorus-centred radicals from acylphosphine oxide photoinitiators has been studied by 3’P-, 13C-, and


' H-CIDNP and ESR technique^^^. A laser flash photolysis and time-resolved ESR study of the formation of phosphinoyl radicals from benzoyldiphenyl- phosphine oxide and 257 has appeared365. The addition of dialkylphosphoryi radicals to a fullerene system has also been Interest in adducts of phosphine oxides with proton donors, notably

has continued. phenols3673368 and

R

d

other solvcnt

250 R = ally1 251 R = H or pCICsH4 252 R = H or pCICsH4 X = H, CI or NH2

0 go O'/

\

253

256 R = H, Me or Tf

3.3 Structural and Physical

254 255

257 R' = OMe, R2 = 2,2,4-trimethylpentyI

Aspects. - A theoretical approach (density functional theory) has been used to explore the nature of the phosphorus- chalcogen bond in the species Me3P=E (E=O, S, Se or Te; and also X=BH3, CH2, and NH) in terms of the relative strengths of 0- and x-bonding components. Down the group from oxygen to tellurium, the overall bond strength decreases from 544 kJmol-' to 184 kJmol-', but the x-bonding component becomes more significant with respect to the o-bond. For E = BH3, the phosphorus-boron bond energy is only 166 kJ mol-' 371. The first measurements of the enthalpies of combustion, sublimation, and fusion of triphenylphosphine sulfide have enabled estimates of its enthalpy of formation to be derived, the P=S bond enthalpy being 394 kJ mol-' 372. Dipole moment and infrared studies indicate that, in solution, the 2-(thiophosphoryl)-1,3-dithianes 258 exist mainly as an equilibrium mixture of two chair-like conformations in which the thiophosphoryl group is axially oriented373. In contrast, a solid state


crystallographic study of the related 2-(diphenylphosphinoy1)- 1,3-dioxane 259 has shown that the phosphinoyl group occupies an equatorial position374. Structural studies of the related 5-membered ring systems 260 have shed light on solid state conformations and anomeric effects between ring sulfurs and phosphorus375. An understanding of the conformational properties of 2- (hydroxypenty1)diphenylphosphine oxide (and its acetate) has been gained via a combination of solid state crystallographic, solution spectroscopic, and modelling A solution N M R and solid state crystallographic study has been reported for the C-lithiated phosphine oxide 261 in which the lithium ion is associated with the phosphoryl oxygen, and the (axial) carbanionic carbon is almost planar377. Among other structural studies of phosphine chalco- g e n i d e ~ ~ ~ ~ ” ~ ~ are those of 262379, a series of 1-(hydroxya1kyl)dimethylphosphine sulfides380, and 263382. Electron impact mass spectra of several five- and six- membered heterocyclic phosphine oxides, e.g. , 264, reveal the loss of oxopho- sphene moieties ( R - P z O ) ~ ~ ~ . The reactivity of the trimethylphosphine oxide radical cation has been investigated using ion-molecule reactions in a mass spectrometer384.

258 R’ = Me or Ph R2 = H or But

R

259 260 X = 0, S or Se

0 I I

Ph2PCH2CH2iMe31-

262 R = OCH2CH20Me 263

D p = O Li+(thf)2

261

$‘ d’k

264 R = Ph or V B u t

Me‘

3.4 Phosphine Chalcogenides as Ligands. - This remains an area of considerable activity. The coordination chemistry of the bidentate ligand systems 265385 and

has received attention. Complexes of macrocyclic phosphine oxides bearing a NS2PO donor set have been cha rac t e r i~ed~~~ . Differences in the ability of the phosphinoyl centres in the unsymmetric vinylenediphosphine oxides 267 to complex with phosphorus pentafluoride have been studied by I9F N M R techni- q u e ~ ~ ~ ~ . Complexes of triphenylphosphine oxide with ~ o p p e r ( I 1 ) ~ ~ ~ and organo- l a n t h a n ~ m ( I I 1 ) ~ ~ ~ acceptors have been reported. Copper(I1) and cobalt(I1) complexes of polymer-supported triphenylphosphine oxide have also been characterised, and shown to absorb sulfur dioxide39’. Silver and gold complexes of polydentate thioether-phosphine chalcogenides e. g., 268 have been cha rac- t e r i ~ e d ~ ~ ~ . On treatment with benzylmanganese-pentacarbonyl, triphenylphosphine-oxide, -sulfide and -selenide undergo cyclomanganation to form the


heterocyclic system 269393. Complexes of tetraalkyldiphosphine disulfides with metal carbonyl acceptors have been prepared by both photochemical and thermal routes3". Several groups have described complexes of phosphine sulfide and selenide ligands, both simple and chelating, with copper, silver and gold acceptor^^^^-^^^.

265 266 267 R = Etor Ph

Ph, ,Ph

M n (CO) 4

269 X = 0, S or Se

Ph2P s PPtl2 II II

X 268

X

4 Phosphonium Salts

4.1 Preparation. - Conventional quaternization procedures have been used for the synthesis of a series of o-phenylalkyltrimethylphosphonium salts 270399, the triphosphonium salt 27I4Oo, the amidoalkylphosphonium salts 272401, and the tetraphosphonioporphyrin system 273402. Porphyrins bearing a meso-phosphonium substituent, e.g., 274, have been obtained from the reaction of the related trimethylammoniomethylporphyrin iodide with tertiary phosphines or diphos- phines403. Electrochemical oxidation of zinc tetraphenylporphyrin in the presence of bis(dipheny1phosphino)ethyne (0.5 mol) leads to the formation of the p- bridged dimer 27S4O4. The reaction of benzyl- and thienylmethyl-alcohols, bearing tertiary amino substituents, with triphenylphosphonium bromide, in dichloromethane, chloroform or acetonitrile, with azeotropic removal of water, provides an improved route to substituted (hetero)arylmethylphosphonium salts405. The silica bound 'two headed' (bicipital) bis(tetraary1phosphonium) salt 276 has been obtained via a conventional Horner approach via the related bromoarene, triphenylphosphine and either nickel(I1) bromide or palladium(I1) acetate. This system gives unusually high catalytic rate enhancements in some nucleophilic substitution reactions, suggesting cooperation between the neighbouring phosphonium centres406. A practical route to chiral and achiral phosphonium salts from tertiary phosphine-borane complexes has been developed, entailing the reaction of the complex with an alkyl halide in a 1-octene-THF solvent system. The phosphonium salt simply crystallises from the solvent as the reaction proceeds. Phosphine-boranes also react with aryl halides, but need the presence of nickel(I1) bromide as catalyst407. Coordination template-assisted


R R

R R 274 R = Me, Et or CH2CH2C02P$

275 0 Q

278 +PPh3 B f


nickel(I1)-catalysed formation of arylphosphonium salts has been employed in the synthesis of two series of phosphonium phenolate betaines, 277 and 278, which have been found to exhibit negative solvatochromism408. The phosphonium zwitterion 279 has been obtained from the reaction of triphenylphosphine with 2,3-dichloro-4-oxo-2-butenoic acid (or its esters), followed by treatment with triethylamine409. Treatment of l-acyl-Zbromoalkynes with triphenylphosphine has given the acylethynylphosphonium salts 2804'0. Polymers bearing phosphonium groups have been prepared from a l k ~ n y l - ~ ' and pr~pargyl -~ '* phosphonium salts. The phosphonio-borato betaines 281 have been obtained from the reaction of simple ylides with dimethylaminobis(trifluoromethyl)borane4'3. Adducts of cyanomethylenetriphenylphosphorane with acyl-isocyanates and -thiocyanates undergo cyclisation with hydrogen chloride to form the salts 282, from which phosphonium betaines can be easily obtained4I4. Routes to heterocyclic betaines, e.g., 283, have also been developed4153416. The reaction of the tributylphosphine - carbon disulfide adduct with norbornene has given the zwitterion 284, which, in solution, dissociates to form the ylide 285 from which 2- alkylidene-l,3-dithiolanes can be formed417. Treatment of trialkyphosphine- carbon disulfide adducts with the complex [Cpz ZrHCI], gives the reactive complex 286, from which phosphonium salts, e.g. , 287, can be prepared by alkylation or a ~ y l a t i o n ~ ' ~ . Improved routes to the phospholenium salts 288 have been reported, and the reactions of this system with butyllithium and potassium t-butoxide studied4I9. The spirocyclic Meisenheimer complex 289 has been

oc" PR3 aN=N 6Ph3

277 R=BuorPh 278 X = F, CI, Me or Ph X = CI, Br, But or Ph

0

+ Ph36-CH-B(CF3)2 I I

cl* Ph3P 0- R-C-C=C-PPh3 f: B r R NMe2 279 280 R = Ph or 2-thienyl 281 R = H orMe

H H

R Ph2C H H 282 X = O o r S 283 284 285


isolated from the reaction of a 2,3-dihydroxypropylphosphonium salt with picryl fluoride420. Phosphonio-substituted-tetrahydro- 1,3-diphosphinines and -tetrahydro- 1,2,6-azadiphosphinines, e.g., 290 have been prepared42’. Hexaalkyl- bisphosphonium salts [R3P-PR3I2+ 2X-, have been obtained from the electrochemical oxidation of trialkyphosphines, presumably via the reaction of an initially formed trialkylphosphonio cation radical with a second molecule of the phosphine, followed by an oxidation step422. A wide variety of phosphonium salts bearing unusual anions has also been described, including p o l y h a l i d e ~ ~ ~ ~ ~ ~ ~ ~ fullerene radical anions4257426, s i l s e sq~ ioxane~~~ , a semiconducting complex thio- l a t ~ n i c k e l a t e ~ ~ ~ , and the triphenylmethanide ion429.

SR

SR B&<H X-

R

286 R=MeorBu 287 R = Me, MeCO or PhCH2 288 R=HorMe

No2 289

Ph 290

4.2 Reactions. - As part of a wider study of the chemistry of norbornyl- phosphorus compounds, it has been reported that the salt 291 undergoes alkaline hydrolysis with the expected loss of a benzyl group to give the phosphine oxide 292430. Alkaline hydrolysis of the phosphonium squarate betaine 293 proceeds with ring-opening to form the stable ylide 294431. A study of the solvolysis of triorgano(pheny1thio)phosphonium salts has shown that, unlike in the hydrolysis of conventional phosphonium salts, the nature of the organo substituents at phosphorus has little effect on the overall rate432. Lipophilic phosphonium-nucleobase conjugates, e.g., 295, have been shown to facilitate the transport of nucleotide monophosphates across cell membranes433. Polymer-bound phosphonium salts, e.g. , 296, have been used as traceless supports in solid phase synthesis via alkaline hydrolysis or Wittig reaction conditions434.

Electrochemically-promoted reversible interconversion of alkyltriphenylphosphonium salts and the related ylides has been shown to occur in the presence of benzophenone oxime O-methyl ether as a mediator, providing an example of e lec t ro~hromism~~~. Nucleophilic addition to vinylphosphonium salts has again been widely used as a means of generating ylides, and for the synthesis of heterocyclic system^^^^-^'. New developments include the catalysis of addition of


Me I- 29 1

, Me

292 293 294

295 296

Grignard reagents to vinyltriphenylphosphonium bromide, using e .g . , CuBr- Ag2C03,44' and the copper(1)-promoted addition of potassium dialkylphosphites to give the ylides 2 9 , used for the synthesis of a l ly lpho~phonates~~~. Treatment of the zwitterionic system 298 with acetyl chloride in a 1:l molar ratio affords the heterocyclic system 299 use of a large excess of acetyl chloride gives the salt 3OOU3. The reactions of acyltributylphosphonium ions (prepared in-situ from an

Me' 0 1 1

ph3bj\ /P(OR)2 + Me R36-CHMe-SiMe&I CI- R3P-CHMe-SiMe2-S-

297 298 R=alkyl 299 300

acid chloride and tributylphosphine) with Grignard reagents provide a convenient, one-pot, route to ketonesM4. Alkoxytriphenylphosphonium tetrafluoroborates, (generated by constant current electrolysis of an alcohol, triphenylphosphine, and triphenylphosphonium tetrafluoroborate in dichloromethane), undergo thermal decomposition in THF to form fluoroalkyl systems in which the hydroxyl group of primary or secondary alcohols is replaced by fluorine445. N-Substituted aminotri- phenylphosphonium tribromides have been used for the regiospecific bromination of substituted phenols446. The reactivity of the radical ion 'CH2 PH3+ and its isomer CH3 PH2+' have been compared using a dual cell FT ICR mass spectrometerM7. The triphenylphosphonium radical cation has been characterised by ESR techniques448. Donor-acceptor complexes have been obtained from combination of tetraphenylphosphonium chloride or bromide with iodobenzene in acetonitrile, which involve interaction of the halide ion of the salt with iodine. The adducts have been characterised by X-ray studiesa9. The binding properties of 1,3-

1: Phosphines and Phosphonium Sults 39

bridged calix[5]crown systems towards phosphonium cations have been studied by ‘H NMR, but the receptor is fairly u n s e l e ~ t i v e ~ ~ ~ . Further studies of cation-cation interactions between phenylphosphonium ions, involving multiple phenyl ‘em- braces’ have been The crystal structure of a triphenylphosphonium salt involving the [nido-B1 1H14] anion has been described453.

5 P,-Bonded Phosphorus Compounds

A review of the area has appeared454. Routes to the bis(diphosphene) 301455 and the cis-bis(phosphido)diphosphene have been described, the latter arising simply from the reaction of tris(t-buty1)silylsodium with white phosphorus in dimethylformamide. The X-ray structure of the diphosphene 303, (R = But) has been refined, enabling calculations of electron density distribution and further insight into the nature of the P=P bond457. Molybdenum complexes of 303, (R = CF3) have also been chara~terised~’~. Yoshifuji has reviewed the work of his group on addition of dichlorocarbene to sterically protected diphosphenes and ph~spha-al lenes~~~. Further reports have appeared of the formation of phosphaalkenes in the pyrolysis of ally I p h o s p h i n e ~ ~ ~ ~ ~ ~ ~ ’ . Divinylphosphine has been shown to undergo a base-induced rearrangement to form 3-phospha- 1,3-penta- diene, which is sufficiently stable to be detected at room temperature by 31P N M R spectroscopy, and trappable by the addition of 2-propane thiol to the reaction mixture462. A series of phenylphosphaethenes having two to four P=C units per benzene ring, e.g. , 304, has been prepared by the reaction of the appropriate aromatic aldehyde with lithium (2,4,6-t ri-t-buty lphenyl)( trimethyl- ~ i l y l ) p h o s p h i d e ~ ~ ~ * ~ ~ . A route to the p-diphosphaquinone system 305 has been developed465. Strategies for the synthesis of o-diphosphaquinones have also been explored, but as yet this system evades isolation466. Treatment of the phosphi- noalkynes 306 with butyllithium and subsequently copper(1) chloride has given the bis(phospha-alkene) 307, as a chelated copper complex, from which the free ligand can be isolated by treatment with aqueous ammonia467. The coordination chemistry and photochemistry of this type of system has also been studied by Y oshifuji’s

The dehydrochlorination of a-chlorophosphines, e.g. , 308, in the gas phase over solid potassium carbonate, provides a general route to the reactive phosphaalkenes 309, characterised by chemical trapping470. A new route to the bromo- functional phospha-alkene 310 has been described. Treatment of this compound with Grignard reagents in the presence of a palladium(0) complex has given a series of phospha-alkenes (31 Phospha-alkenes bearing cyclopropyl or cyclobutyl substituents at the carbon of the P=C system have been prepared from the reaction of tris(trimethylsily1)phosphine with appropriate acid chlorides472. Routes to phospha-alkenes bearing heterocyclic substituents at the carbon of the double bond have also been d e ~ e l o p e d ~ ~ ~ . ~ ~ ~ . A series of p,-bonded systems involving ferrocenyl substituents at phosphorus, e.g., 312, has also been pre- pared475. The easily accessible, reactive, phospha-alkene HP=C(F)NEtZ has been shown to react with halophosphines or haloarsines to give P-phosphino- or P-


R R

R R 303

P=P\ But3Si-P P-SiBu$

I t Na Na

302

Ar

Ar R-CeC-P,

H 306 R = Me, pentyl, Me3Si, But,

Ph, ptolyl or 2-fury1 Ar = 2.4,6-6Ut3C&

R: /H R2 - C -P\

CI' R3 308 R' = H or Me, R2 = H, R3 = Me or Ph

Ar 3 P

0 P

3 Ar

305 Ar = 2,4,6-But3CsH2

Ar i

R

R I Ar

307

OTms

@-p=.: I R

Fe

312 R = But, Ph or Fc

arsino-substituted fluorophospha-alkenes of the type R*E-P=C( F)NEt, (E = P or As)476. Treatment of the phospha-alkene (Me& C=PCl with in-situ generated carbene complex anions results in stereoselective P-C coupling to form 2- phosphabutadiene complexes, e.g. , 313, which undergo subsequent thermal

1: Phosphines cmd Phosphonium Sults 41 .

isomerisation to form 2,3-dihydrophosphete complexes, e.g., 314477. A new theoretical consideration of the Cope rearrangement 315 - 316 has appeared47g. Cycloaddition of phospha-alkene~~'~ and pho~pha-ketenes~~' to 2H-phospholes, and of hydrogen isocyanide to phospha-alkenes and dipho~phenes~~' , have also received theoretical treatment. The cycloadducts 317 have been isolated from the reactions of the phospha-alkene CF3P = CF2 with phospha-alkynes and phospha- a l k e n e ~ ~ ~ ~ . Homo-Diels-Alder reactions of the triphospha-Dewar benzene 318 with alkynes and phospha-alkynes have been explored, and a number of polycyclic adducts cha ra~ te r i sed~~~ . The first germaphospha-allene 319 has been obtained. Methanol and methyllithium react regiospecifically at the Ge=C bond. In the absence of trapping agents, 319 gives rise to two types of dimer, one involving two Ge=C bonds, the other involving one Ge=C bond and the C=P bond484. Further studies of the reactivity of phospha-allenes, phospha~a-allenes~~~, and phosphake- t e n e ~ ~ ~ ~ have appeared. Radical cations have been characterised in the electrochemical oxidation of diph~spha-allenes~~~. Thiyl and alkoxyl radicals have been shown to add to one of the phosphorus atoms of diphospha-allenes to form phosphavinyl o - r d d i ~ d l s ~ ~ ~ . [2 + 41-Cycloadducts of the methylenephosphonium salt 320 with electron-rich hydrocarbons, e.g., anthracene or fulvene, have been c h a r a ~ t e r i s e d ~ ~ ~ . The chemistry of phospha-alkenes bearing complexed metallo substituents at phosphorus has developed as also have other areas of phospha-alkene coordination c h e m i ~ t r y ~ ~ * > ~ ~ ~ .

fM(C0)5 OEt

'C= CH Ph @ PH

I PH

( Me3Si)2C = P

E t d 313 M=Cro rW 31 4 315 316

Me%Ge=C=PAr [But&CHSiMe3]AICld- R P

317 R = Me2N. Et2N, Pri2N or But

318 319 Ar =2,4,6-But3C6H2 320

The influence of fluorine as a substituent at phosphorus in two coordinate P=C, P=Si, P=O and P=S systems has received theoretical consideration in connection with their rearrangement to three-coordinate phosphorus species494. The reactions of P=C and P=N systems with the complex [Cp2ZrHCI], have been reviewed495. The reactions of iminophosphenes with a zirconium-benzyne complex have also been investigated, leading to the isolation of new Zr, N, P- heterocyclic systems496. New P-aminoiminophosphene systems have been pre- pared497. The cycloadducts 321 are formed in the reactions of the iminophosphene CIP=NAr (Ar = 2,4 6 - B ~ ' 3 C6H2) with dialkylarninoalkyne~~~~. Alkoxy- and dialkylamino-triorganotin compounds have been shown to add to the phosphorus atom of P-dialkylaminoiminophosphenes with the formation of P-


stannylated iminophosph~ranes~~~. Crystallographic and spectroscopic studies of iminophosphenes have also a ~ p e a r e d ' ~ - ~ ' ~ . The first stable iminoarsene (322) has been cha rac t e r i~ed~~ . The chemistry of phospha- and arsa-silenes has been reviewed505. Sterically unhindered phospha-silenes, e.g., 323, have been obtained from the flash vapour phase thermolysis of cyclosilaphosphines506. Evidence has been provided of the formation of a phosphasilene bearing a complex metallo- substituent at pho~phorus~'~.

CI,

NR2 Ar-As=N-Ar Me2Si=PR

322 Ar = 2,4,6-(CF3)3C6H2 323 R = But or Ph

R Rr 321 Ar = 2,4,6-But3CeH2

A theoretical study of the intermediates involved in the formation of phospha- propyne from pyrolysis of vinylphosphirane has led to a new route to phospha- alkynes. Thus, pyrolysis of trimethylsilyl(1-phosphirany1)diazomethane has yielded Me3SiC = P, via an intermediate I-phosphiranylmethylene508. Regioselec- tivity in the [3 + 21 cycloaddition reaction between phosphaethyne and diazomethane has been studied by theoretical technique?, and further examples of reactions of this type described5". Cycloaddition of phospha-alkynes with silylenes has also been reported5". The primary phosphine 324 has been isolated from the addition of diethylphosphite to t-b~tylphosphaethyne"~. The chemistry of phospha-alkyne cyclotetramer systems has been reviewed5I3, and the first examples of platinum(I1) complexes of such cage systems described5I4. Aspects of the reactivity of coordinated phospha-alkynes have received further study5I5, and a remarkable metal-mediated double reduction of t-butylphosphaethyne to the complexed fluorophosphine 325 described5I6. Phosphorus-carbon-aluminium cage structures have been isolated from the reactions of kinetically stable phospha-alkynes with trialkylaluminium corn pound^^'^, and new phosphaborane systems have been obtained from the reactions of phospha-alkynes with polyhe- dral b o r a n e ~ ~ ' ~ ~ ~ ' ~ . Further studies of iso-phospha-alkyne coordination chemistry have appeared520. The reactivity of the ion 326 has been explored5*'.

0 II

[(EtO)qPj2C-But I Bu'CH~PHF [Ar-N=P]' PH2

324 325 326 Ar = 2,4,6-But3C6H2

The chemistry of phosphinidene and phosphenium systems continues to be an active area. The electronic configurations of vinylnitrene and vinylphosphinidene have been compared in a theoretical study, which predicts that both have triplet ground states522. A triplet ground state is also found for phenylphosphinidine, whose properties are very similar to those of methylph~sphinidene~~~. A theoretical consideration of factors affecting the singlet-triplet energy separation in phosphinidenes has concluded that the singlet state is favoured by substituents

1: Phosphines and Phosphoniurn Salts 43

having x-type lone pairs, e.g. , dialkylamino and dialkylphosphino, whereas the triplet state is favoured by hyperconjugative substituents, e.g., alkyl, boryl, and ~ i l y 1 ~ ~ ~ . Phenylphosphinidene forms adducts on treatment with heterocyclic carbenes, which have been formulated either as phospha-alkenes, e.g., 327, or as phosphinidene complexes, e.g. , 328525,526. The latter formulation is favoured by the observation that treatment of the adduct with borane results in the formation of a bis(borane) complex, e.g. , 329, indicating the availability of two lone pairs at phosphorus527. The area of metal-complexed phosphinidenes (and related N and As systems) has been reviewed528, and a number of new systems d e ~ c r i b e d ~ ~ ~ - ~ ~ l . The reactivity of metal-phosphinidene complexes with a l k y n e ~ ~ ’ ~ and also with carbonyl corn pound^^^^-^^^, has been explored. The 6x-aromatic phosphenium salt 330 has been characterised. The related system in which the double bond is reduced behaves as a typical covalent ch lo roph~sph ine~~~ . Examples of phosphenium ions stabilised by intramolecular N -+P coordination, e.g., 331 have been d e s ~ r i b e d ~ ~ ~ * ~ ~ * . The chemistry of ylidic 4n-4-membered ring systems, e.g. , 332 has been reviewed539, and new studies of their synthesis and reactivity re- ported540754’. Further studies have also been reported of other phosphenium systems involving ylidyl s u b s t i t ~ e n t s ~ ~ ~ , ~ ~ ~ , and also the ‘phosphinophosphini- dene-phosphoranes’ 333544.

Mes I Mes I

Ph I I I Mes Mes Mes 327 328 329 330

331 R = H or Ph 332 333

Further progress has been reported in the chemistry of cr3h5-p,-bonded systems. Full details of such systems stabilised by intramolecular coordination, as in, e.g. , 334, have been described545. The kinetically stable system 335 has been prepared and its solid state structure determined546. The P-halobis(imino)-03hS- phosphoranes 336 have also been prepared547, and detailed NMR studies of bis(imino) phosphoranes reported548. Quin’s group has continued studies of the generation and characterisation of reactive c ~ ~ ~ ~ - s y s t e m s , e.g., Methods for the generation of monomeric metaphosphate esters in solution have been investigated552. A theoretical approach has been used to probe the mechanism of the reaction between phosphanylnitrenes 338 and b ~ r a n e s ~ ~ ~ . The thiophosphonic anhydride 339 behaves as a source of the dithioxophosphorane

337549-55 I

44 Orgcrnophosphorus Chemistry

340, trappable with suitable dienes. Thus, e .g . , on heating 339 with norborana- diene at 80 OC, the 1,2-thiaphosphetane 341 is formed554.

NAr /,FH2 ArN=P'

I ( Me3Si)3C - ?\

NMes* X

335 Mes* = 2,4,6-But3C6H2 336 Ar = 2,4,6-But3C~H2 X = CI, Bror I

334 X = S o r S e CR2 = CH2, CMe2 n = 1-3

337 338 339 Fc = ferrocenyl 340 341

6 Phosphirenes, Phospholes and Phosphinines

A study of the reactivity of I-chloro-1H-phosphirenes 342 with nucleophiles has shown that the chlorine is easily replaced555. Ab initio calculations suggest that 1H-phosphirenes invert their configuration at phosphorus by a rotation of the PX group above the C2 moiety, rather than by the more usual trigonal inversion pathway involving a C*,-transition state556. Related calculations on the aromaticity of 1H-phosphirenium cations 343 have shown that the (T* ABMO associated with the P-X bond acts like an empty p - ~ r b i t a l ~ ~ ~ . A facile route to the phosphirenium salts 344 is afforded by the reaction of the phosphiranium salt 345 with a l k y n e ~ ' ~ ~ . The Pv-azaphosphirene system 346 has been obtained from the reaction of an iminophosphene with terminal a l k y n e ~ ~ ~ ~ .

342 343 R1 = Ph, But or 1-adamantyl 344 R1, R2 = Me or Ph R2 = alkyl X = F, CI, Br or I

OTf-

P t f Me 345

I?\ But NR2

346 R' = Bu, But, Et2NCH2, MeOCH2 or Me02C R2 = 2,4,6-But&H2

I : Phosphines and Phosphonium Sults 45

Activity in the phosphole area continues at a high level. The reaction of 2,3- dimethylbutadiene with phenyldibromophosphine at 0 OC, followed by treatment with a-picoline, has given I-phenyl-3,4-dimethylphosphole (347) as the principal product, together with the bis(oxide) 348. The latter also forms on air-oxidation of the phosphole 347560. Routes have also been developed to the phospholes 349 which bear a bulky exocyclic phosphorus substituent. Structural studies reveal that the usual pyramidal configuration at phosphorus is significantly flattened, suggesting an enhancement of aromatic delocalisation in the phosphole ring. .

Reactivity studies of 349, (R = But) have shown that the ring, normally resistant to electrophilic substitution, undergoes Friedel-Crafts acylation to give 350 as the main product. The corresponding oxides of reactive cyclic dienes, readily dimeri~ing~~'-'@.

4

349, as expected, behave as very

d' d C O M e

I Ph

347 348 349 R=MeorBut 350

A stereochemical study has shown that the diphosphole 351 (having both axial chirality and chiral phosphorus atoms) can be separated by chromatography into diastereoisomeric diphosphole sulfides. These have then been reconverted into the parent diastereoisomeric diphospholes, which have been shown to re-equilibrate in solution565. Metal complexes of 351 have also been ~ h a r a c t e r i s e d ~ ~ ~ . The reactions of phospholide anions with halogenophosphines have been used to prepare P-phosphinopho~pholes,~~~~~~~ e.g., 352s68, which shows no unusual structural features. Routes to a-functionalised phospholide anions, e.g., 353, have been developed, such reagents having potential as building blocks for the synthesis of phosphorus analogues of porphyrin macrocyclic systems5697570. An efficient route to the 2-phosphinophosphindoles 354 has also been described, involving a zirconocene-benzyne intermediate57'. A similar approach has also been used in the synthesis of the fused system 355572.

A theoretical study of the Diels-Alder reactions between 1,3-butadiene and, respectively, cyclopentadiene and 2H-phosphole, has revealed a remarkable similarity between the two reactions573. Further studies of photocycloaddition reactions of phosphole moieties have also been reported574. Transition metal complexes of phospholide anions continue to attract attention575, and in particular the chemistry of phosphaferrocene systems remains a major i n t e r e ~ t ~ ~ ~ - ~ ~ ~ . The past year has also seen significant activity in the chemistry of di- and triphospholes, related polyphospholide anions, and also heterodiphosphole systems. Routes have been developed to the diphosphonio- 1,2-diphospholes 356,


351 352 353 X = Ph, 2-pyridyl or C02Et

354 R' = Ph or But, R2 = H or Ph 355

a cyclic 6n-system showing considerable flattening of bond angles at the 03- phosphorus atom580, the diphosphonio- 1,2,4-triphospholide salts 35758 and the 2-diphenylphosphino-1,3-diphospholides 358582. Examples of polyphosphaferro- cenes derived from di- and tri-phospholide anions have been Further studies of the [4 + 21 cycloaddition reactions of 1,3-diphospholes and 1,2,4-triphosphoIes have also been reported58s. The synthesis and reactivity of the sterically crowded 1,2,4-triphosphoIe 359 has been explored, this system exhibiting an enhanced degree of aromaticity compared with simple p h o s p h ~ l e s ~ ~ ~ ~ ~ ~ ~ . A route to the 1,4,2-diphosphastiboIide salt 360 has been described588, together with its use in forming a variety of polyheterornetallo~enes~~~-~~', and a new phosphorus-antimony c a g e - ~ y s t e m ~ ~ ~ . Routes to the thia- and selena-diphospholes 361 have also been d e ~ c r i b e d ~ ~ ~ . ~ ~ ~ . Once again, there has been significant activity in the area of azaphosphole ~ h e m i s t r y ' ~ ~ - ~ ~ ~ , including the synthesis of the dipolar system 362602 and the 1,2,3,4-diazddiphospholide salt 363603. Also of interest are the results of ab-initio calculations on 1,3,2-diazaphospholes and the related 1,3,2-diazaphospholenium ion 364, which show that the latter is significantly delocalised, with an aromaticity comparable to pyrrole604. Two groups have reported theoretical studies of pentaphosphole (365). In contrast to the parent system of phosphole (C4H4PH), pentaphosphole is apparently planar, with a larger aromatic delocalisation energy605. Nevertheless, several possible Diels-Alder type dimeric forms were found to be significantly more stable than 365, and since it is not possible to introduce a stabilising substituent at one of the o*-phosphorus atoms, the likelihood of a successful synthesis of this system is smaPo6.

A new route to the phosphinine system is provided by the rearrangement of 1- alkynyl- 1,2-dihyrophosphetes 366, giving the substituted phosphinines 367607. Phosphinines bearing dialkylboryl groups, e.g., 368, have been obtained by the reactions of 3-dialkylborylstannoles with phospha-alkynes6". Interest has also continued in the coordination chemistry of p h o s p h i n i n e ~ ~ ~ ~ - ~ ' ~ , including that of the new ligand system 3696'4. The 1,3,2-diazaphosphinine 370 is a versatile precursor to other phosphinine systems, undergoing stepwise addition-elimination reactions on heating with alkynes in toluene to give, respectively, the 1,2- azaphosphinines 371 and ' the phosphinines 3726'5. The Diels-Alder reaction

1: Phospliines and Phosphonium Suits 47

Ph 6Ph3

Ph36*P 2OTf-

PPh2 R

356 R = Me or Ph 357 X = ha1 or Mes 358 R’ = Ph or Et R2 = Ph, Et or But

x R

I CH(SiMe3)2

359 360 361 X = S, R = 1-adamantyl X = Se, R = But or Np

362 363 364 365

between 1,3,5-triphosphabenzene and phospha-acetylene to yield tetraphospha- barrelene has been examined by theoretical techniques, and compared with the carbon analogue between benzene and acetylene616. The reactivity of ring substituents in the 1 ,3-h5-diphosphinine system has also been

366 R’ = Ph or CsH13 R2 = Ph or Et

367 368

369 370 371 372

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113 1 I4

1 I5

1 I6 1 I7 118

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I24

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232 233 234

235 236

237

238 239

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245 246

247 248 249 250 25 1

252

253 254

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I : Pliosphines und Phosphonium Sults 57

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304 305

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307 308 309

310

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31 3

314 31 5

316 317

318 319

320 32 1

322

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Tetrahedron:


323

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325

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327 328 329

330 33 1

332

333

334

335 336

337 338 339 340 34 I

342 343

344 345

346 347

348

349

350

35 1

352 353

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370 37 1 372 373

374

375

376 377

378 379

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38 1

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419

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427 428

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436 43 7 438 439

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474

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47 8 479

480 48 I

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48 5

486

487

488

489

490

49 I

492

493 494

495 496

497 498

499 500

50 I

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502

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507 508

509 510 51 1 512

513 514

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52 1

522 523

524

525 526

527

528

529 530

53 1

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532

533 534

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536 537

538

539 540

54 1 542

543 544

545

546 547

548

549

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55 1 552

553

554

555

556 557 558

559

560

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66 Orgunopirosphorus Chemistry

56 1

562 563

564

565

566

567

568

569

570 57 I

572

573 574

575

576

577

578 5 79

580 58 1

582 583

584

585

586

587 588

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I : Phosphines uncl Phosphonium Sults 67

589

590 59 1 592 593

594 595 596 597

598

599 600

60 1 602 603

604 605

606 607 608 609

610 61 1

612

61 3 614 61 5 616 61 7

M. D. Francis, D. E. Hibbs, M. B. Hursthouse, C. Jones amd K. M. A. Malik, Chem. Commun., 1996, 1591. S . J. Black and C. Jones, J. Orgunomel. Chem., 1997,534,89. S . J . Black, M. D. Francis and C. Jones, J. Chem. SOC., Dalton Truns., 1997,2183. S . J. Black, M. D. Francis and C. Jones, Chem. Commun., 1997,305. E. Lindner, E. Bosch, C. Maichle-Mossmer and H. Abram, J. Orgunomet. Chem., 1996,524, 67. M. Regitz and S. Krill, Phosphorus, Sulfur, Silicon, Relut. Elem., 1996,115,99. B. Manz, U. Bergstrasser, J. Kerth and G. Mass, Chem. Ber.lReceui1, 1997, 130, 779. B. Manz and G Mass, Tetruheclron, 1996,52, 10053. N. G. Khusainova, T. A. Zyablikova, R. G. Reshetkova and R. A. Cherkasov, Zh. Obshch. Khim., 1996,66,416 (Chem. Abstr., 1996,125,328 935). A. M. Kibardin, T. V. Gryaznova, A. N. Pudovik and V. A. Naumov, Zh. Obshch. Khim., 1996,66, 1455 (Chem. Abstr., 1997,126, 171 653. G. Baccolini, A. Munyaneza and C. Boga, Tetruheclron, 1996,52, 13 695. S. V. Chapyshev, U. Bergstrasser and M. Regiti, Khim. Geterotsikl. Soedin., 1996,67 (Chem. Abstr., 1996, 125, 168 160). A. Schmidpeter, F. Steinmuller and H. Noth, Chem. Ber., 1996,129, 1493. H-P. Schrodel and A. Schmidpeter, Chem. Ber.lReceui1, 1997, 130,89. C. Charrier, N. Maigrot, L. Ricard, P. Le. Floch arid F. Mathey, Angew. Chem., Znt. Ed. Engl., 1996,35, 2133. R. R. Sauers, Tetruhedron, 1997,53,2357. M. N. Glukhovtsev, A, Dransfield and P. von R. Schleyer, J. Phys. Chem., 1996, 125,168 141. L. Nyulaszi, Inorg. Chem., 1996,35,4690. N. Avarvari, P. Le Floch, C. Charrier and F. Mathey, Heferouf. Chem., 1996,7,397. B. Wrackmeyer and U. Klaus, J. Organomet. Chem., 1996,520,2 1 1. K. Waschbusch, P. Le Floch, L. Ricard and F. Mathey, Chem. Ber.lReceui1, 1997, 130,843. P. Le Floch, L. Ricard and F Mathey, Bull. SOC. Chim. Fr., 1996,691. P. Le Floch, S. Mansuy, L. Ricard, F. Mathey, A. Jutand and C. Amatore, Orgunometallics, 1996, 15, 3267. P. L. Arnold, F. G. N. Cloke, K. Khan and P. Scott, J. Organomef. Chem., 1997, 528,77. P. L. Arnold, G. N. Cloke and P. B. Hitchcock, Chem. Commun., 1997,481. B. Breit, Chem. Commun., 1996, 2071. N. Avarvari, P. Le Floch and F. Mathey, J. Am. Chem. Soc., 1996,118, 11978. S. M. Bachrach and P. Magdalinos, THEOCHEM, 1996,368,l. E. Fluck, G. Heckmann, E. Gorbunowa, M. Westerhausen and F. Weller, J. Orgu- nomet. Chem., 1997,529,223.

2 Pentaco-ordinated and Hexaco-ordinated Compounds

BY C. D. HALL

1 Introduction

As the topic of organophosphorus chemistry in general and hypervalent phosphorus chemistry in particular matures, so researchers in the field are able to provide substantial compilations of current knowledge in the area. Mironov et al. have summarised the reactions of five-coordinate phosphorus compounds containing P-H, P-N, and P-X (X=halogen) bonds with carbonyl compounds, imines and alkenes to afford new five- and six-coordinate phosphorus compounds. Incidentally, a review of the coordination chemistry of hydrido- phosphoranes2, although included last year, is worth another mention in this context as a topic of growing importance. Hexaco-ordinate phosphorus anions (e.g. PF6-) are common enough but it has only recently been realised that neutral compounds may also contain hexaco-ordinate phosphorus. A timely and comprehensive review of this to complement the extensive information comparing hypervalent phosphorus and silicon species3b is cited again in this year’s review despite its inclusion in Vol. 28.

The novel cyclic phosphonite 1 has been used to prepare two cyclic tetraoxyphosphoranes (2,3) by oxidative addition.4a Pentaoxyphosphoranes (46) were also prepared by reaction of the appropriate phosphite with diol (7a or 7b). X-ray crystallography revealed hexacoordinate structures for 2 and 6 but 3-5 have pentacoordinate, tbp geometries. The eight-membered ring occupies the equatorial position in compounds 3 and 4 and the ring adopts an anti-chair conformation which precludes interaction of the sulfonyl oxygen atom with phosphorus. It is interesting to note that such a conformation places the phenyl group of 3 in a unique axial position. In the tbp of 5, the eight-membered ring occupies axial-equatorial sites in a syn twist-boat conformation. By contrast, in the highly fluorinated analogue 6a, oxygen donation from the sulfonyl group resulted in displacement from a square pyramid to 82.2% octahedral character compared to 27.9060 octahedral character in 2; These two phosphoranes provide the longest (2.646A for 2) and shortest (1.936A for 6) P-0 bond distances from a sulfone group. Reaction of 5 with catechols at 90°C is considerably faster than the analogous reaction with 4 but replacement of the sulfonyl group of 5 by sulfur gives a hexaco-ordinate structure (8) which is even more reactive towards catechols .4b


68

2: Pentuco-ordinuted and Hexuco-orciinuted Compounds 69

6a, Ar = c6F5 5 b. Ar = Ph

7a. R = But b, R=Me

Finally in this section, it will come as no surprise to learn that pentacoordinate structures continue to feature as intermediates in the solvolysis of phosphonium salts, specifically a series of alkylphenyl thiophenoxyphosphonium chloride~.~


2 Acyclic and Monocyclic Phosphoranes

Phosphorus pentachloride reacted with anthrone 9d9b at room temperature to give tetrachlorophosphorane 10) which decomposed on heating with more PC15 to form 9,l O-dichloroanthracene (1 2) presumably via 1 1 .6 The analogous reaction of PC15 with 1-hydroxyanthrone (13) was considerably more complicated, however, and proceeded via (14) to give (15).

0 OH

9a 9b 1 pc15 & heat, PC15

-POCIS

10 Zi3’P,-6O

CI

CI 12 1 -PC13, HCI

11

& __t PC15

\

13 L

14

CI P(O)CI2

-& 15

Phosphites (e.g. 16a and 16b) react with the perfluorinated diketones 17a and 17b to form a series of pentaoxyphosphoranes (18-21). Compound 20 crystallised in two similar conformations and single crystal X-ray structures of both molecules showed trigonal bipyramidal geometry about phosphorus with slightly different degrees of distortion towards the rectangular pyramid c~nfiguration.~ Likewise, phosphoramidites 22a,b reacted with 23 to form bicyclic phosphoranes 24a,b but 22c,d, with one or three phenyl groups attached to the ring, failed to react.

lSa, R = Et b. R = Ph

17a, RF = CF(CF& 18 R = Et, RF = CF(CF3)2 19 R = Et, RF = (CF2)2CF3 20 R = Ph, RF = CF(CF3)2 21 R = Ph, RF = (CF2)2CF3

b, RF = (CF2)2CF3

2: Pen taco-orciinated and Hexuco-ordina ted Compounds 71

CF&OCOC2F5 23

/R R'-N P - N m C ,

0 'N\R3

22a, R1,R2,R3 = Me; R = CH2CH2CI R' 24 b, R',R2,R3=Me; R = H

c, R',R2 = Me; R3 = Ph; R = CH2CH2CI d, R',R2,R3 = Phi R = CH2CH2CI

Ester exchange of the oxyphosphorane 25 with ribonucleosides 26a-d gave a series of interesting, but labile, spirophosphoranes (27 a-d) which were characterised by MS and 'H/31P nmr in solution. Hydrolysis of 27a, followed by acetylation gave 28 with a high degree of regioselectivity.*

Ph

[email protected] 0-PI

I OMe OMe

25

27a

+

Ho\

HO %Base OH

26a, Base= U b, Base=A c, Base=G d, Base=C

i, H20

ii, Ac20, pyridine

pyridine

Base

0

A& Ph

Ph 27a-d

Me0-k.'

oH 28

The trihalophosphorane 29 reacted with epichlorohydrin (30) at - 70 "C in a highly regioselective fashion to give 95% of a 1:l addition product 31 which decomposed on heating to 32.' Various analogous reactions with 33 and 34 are also discussed within the same paper.

3 Bicyclic and Tricyclic Phosphoranes

The section begins with reports of two mechanistic studies relevant first to phosphate ester hydrolysis and secondly to an olefin-forming reaction akin to the Homer-Wadsworth-Emmons reaction but involving a spirooxyphosphoranyl


29 30 31 1 heat

aoj?n ' 0 0 ' a o \ P B r p ' o/ a o ; P < 0 CI + CICH(CH2C1)2

33 34 32

carbanion. In the first, Verkade and Wroblewski report kinetic data on the alkaline hydrolysis of the bicyclic phosphorus esters 35a,b and 36.'' The bicyclic phosphinate 36 hydrolysed 200 times faster than 35a and the rate enhancement was found to be entirely enthalpic. The X-ray crystallographic structures of 35a and 36 revealed no evidence of strain within either bicyclic framework. Thus the rate enhancement was attributed to the greater ease with which 36 achieved the pentaco-ordinate intermediate state 38 compared to the formation of 37 from 35a. This result also suggests that there is no stereoelectronic effect from the equatorial oxygens of 37 on the rate of hydrolysis. Finally the lo3-fold rate enhancement of the bicyclic phosphorus esters over their acyclic counterparts was attributed largely to solvation effects.

35a, z=o b, Z = S

OH

37

36 38

The second mechanistic paper involved the reactivity of carbanions a to pentaco-ordinated phosphorus in spirooxyphosphoranes. ' In particular, the reaction of 39 with benzaldehyde at - 78 "C was studied in detail. The products were 40 and a mixture of E and Z alkenes (41a,b). The preliminary mechanistic results suggested that the E,Z selectivity was determined by a combination of kinetic and thermodynamic control.

Reaction of the nitrile-imine 42 with the phosphonite 43 gave the bicyclic phosphorane 46 via intermediates 44 and 45. The structure of 46 was confirmed by elemental analysis, IR, ' H/3'P nmr and finally X-ray crystallography which revealed that the bicyclic structure was almost planar. I 2

2: Pentuco-ordinuted und Hexuco-ordinateti Compounds 73

Ph C02Me *

i, LiHMDS/-78 "C

ii, PhCHO C a M e

0 0 39 40 41 a 41b

. 46 #'P, -76

I

L 44

Reaction of the benzoxazaphospholine 47 with the hydroxymethyl bicyclic phosphite 48 gave the polycyclic compound 51 by dimerisation of the intermediate SO. A similar reaction of 47 with pentamethylene diol (52) gave an unsymmetrical spirophosphorane (54) with a P-C bond via 53.13

yHpNEt2

I 47

In a continuation of earlier studies, Malenko et al. have shown that bromination of tris(N-trifluoroacety1amide)-phosphine (55) gives a mixture of bicyclic


47 + HO(CH2)sOH - 52 53 54

phosphorane products (56a,b) and the bromophosphonium salt 57 in a ratio which depends upon the reaction conditions. In refluxing benzene the mixture of diastereomeric phosphoranes predominates whereas at 5-8 "C, 60%) of the product mixture is the salt.I4

(CF3C0.NMe)3P 55

Me Me Me

+ (CF3C0.NMe)36Br B r CF O,$l CF3

Br xN'p\OxNCOCF3 I I

Me Me Me 56a 56b 57

Also in a sequel to earlier worki5", Krishnamurthy et al. report that the oxidative addition of tetrachloro-o-benzoquinone (59) to h3-cyclotriphos- phazanes 58 results in an 'unprecedented ring contraction-rearrangement' to give diazadiphosphetidines of type 61 probably via intermediates of type 60 similar to the structure originally envisaged for the product.15 The structure of 61b was confirmed by X-ray crystallography and the 31P spectra revealed the presence of two isomers in each case, the second one being assigned structure 62 or 63.

63 62 61a,b

either

The reaction of 64 with 59 gave the (r3/05P species 65, stable only in solution and identified by 31P nmr and the a5P/05P species, 66a,b. An unambiguous

2: Pen tuco-ordinated und Hexuco-orciina ten Compounds 75

assignment of the structure to either 66a or 66b proved impossible but the compound reacted with water to give the phosphorate 67 whose structurc was established by X-ray crystallography. l6

a > P - c c 1 2 - F ? ? y J -

64

59 . CCI2 - F!!D

0

65

or

CI CI 66b

Me2N K 9 t;l+

Me2N

Schmutzler el al. have also shown that chloromethyl dichlorophosphine (68) reacts with the bis(trimethylsily1)urea (69) to form the <r305-diphosphorus compound 70. Subsequent reaction of 70 with hexafluoroacetone (71) resulted in an unusual rupture of the P-P bond to form 75 and the spirophosphorane 76 via 72-74. Another unusual reaction of 77 with 78 gave the spirophosphorane 79 and X-ray crystal structures of 76 and 79 showed a large deviation from both the idealised coordination geometries at phosphorus. "


CI /

2 CICH2-P, 0 II h

H3C 2 H3C-N/CxN-CH3 I 1

(CH3)3S/ Si(CH3)3 69

H O I I I /cF3 CI-C-P-0-CH

I I

I F3C-C- 0 cF3

75 CF3

+ c- 0

70

74

71 c-

73

77 0 79

Reaction of h3P-h3P-diphosphane 80 with 71 gave a mixture of products from which the tricyclic phosphorane 81 was isolated and its structure determined by X-ray crystallography. The coordination geometry at phosphorus is a distorted tbp with a very long equatorial P--C(CF& bond of 193.2 pm."

In a related study involving oxidative addition of pertluorodiketones to tricoordinate phosphorus, reaction of 82 with 83 gave good yields of 86a-d probably via 84 and 85 as mechanistic intermediates." The course of the reaction

2: Pen taco-ordinated und Hexuco-orclinuted Compounds 77

0

85

depends on the steric demand of the N-3 substituent (R) since with R = Me (87) the bicyclic product 88 was formed exclusively.

ci 88

Reaction of the hydroxyketone 89 with dichlorophosphines Wa,b gave the unstable phosphonites 91a,b which were trapped in the case of 91a as 92a by hexafluoroacetone. Concerted, thermal decomposition of 91a,b gave 94 and a mixture of diastereomeric phosphinates 95a,b via the intermediate bicyclic phosphoranes 93a,b.20

Metallated spirobicyclicphosphoranes %a-c were found to undergo carbonyl substitution reactions with triphenylphosphine in toluene to form (97a-c) and the isolated products were characterised by IR, 'H nmr, elemental analysis and thermo-gravimeteric studies.21 There was no evidence for insertion of CO into the pentaco-ordinate P--Mn bond.

The commercially available proazaphosphatrane (98) has now been shown to be an efficient catalyst for the silylation of tertiary alcohols and hindered phenols by TBDMS.** Evidence is presented to suggest that 99, with a transannular N-P bonding component, is the effective intermediate in the catalytic cycle.

Superbase 98 has also been employed to promote the efficient dehydrohalogenation of a wide range of alkyl bromides at room temperature in

78 Orgunophosph or us Chemistry

2 F3cnfph OH 0 rh 89

RPC12 9Oa, R = Me

b, R = Ph O n P h CF3 0

acet~ni tr i le .~~ It was suggested that the mechanism involved deprotonation of the solvent whose conjugate anion then abstracted a proton from an intermediate carbocation (Scheme 1 ) .

D I Me

98 + CD3CN

RBr = R+ + B r

R+ t -CD2CN - HCD2CN + alkene

Scheme 1

2: Pentaco-ordinaten and He.~aco-ortiinatetl Cornpounds 79

During an investigation of the N',N7-dialkylation of cyclenphosphine oxide hydrate, it was found that heating 100 at 150°C gave the diphosphorane 101 which was separated by crystallisation (Et20-CH2C12) and characterised by ' H, I3C and 31P nmr.24 Hydrolysis of 101 at pH >12 gave 102 possibly via 100.

Reaction of the tetra-t-butyl calixarene 103 with PCI5 gave rise to an unusual calixarene 104 containing 4-, 5- and 6-coordinate phosphorus. The isolated molecule, which was characterised by 3'P nmr and X-ray crystallography, adopted a non-standard geometry between partial cone and 1,2-alternate conformations.2'

But But

PC16 -4HCI

+ 3PC15 - I

OH OH 103

CI 104

4 Hexaco-ordinate Phosphorus Compounds

The synthesis and remarkable resolution of a conJigurationaffy stable tris(tetra- chlorobenzene diolato) phosphate ion (105) has been achieved. The electron withdrawing effect of the twelve chlorine atoms in the three benzene rings apparently stabilises the molecule so that solutions of 105 at room temperature


107

7 PAQ 106

CI 108 +

11 la,b

showed no variation of the specific rotation ([a3D2O = - 375) with time. The near perfect octahedral structure and absolute phosphorus configuration (P) of 105 (crystallised from EtOAc) were confirmed by X-ray crystallography.26

Oxidative addition of tetrachloro-o-benzoquinone (59) or phenanthraquinone (106) to 107 gave 108 and 109 respectively. Chlorine was also displaced from phosphorus by p-toluidine and dimethy lamine to give another four compounds (1 10a,b and 11 la,b) with similar structures. X-ray crystallographic studies of 108, 109, llOa and l l l a revealed hexacoordination by virtue of donor action by sulfur as part of an eight-membered ring. Within this series, the geometries were displaced along a coordinate from sqp towards octahedral at levels ranging ftom 24% .to 7 1 YO. The respective P-S distance decreased along the series from 3.04A to 2.48A as the octahedral character increased. The changes in 31P chemical shift throughout the series correlated with the extent of octahedral character and analysis of the data provided an estimate of the lower limit to the electrophilicity of phosphorus that will induce formation of hexaco-ordinate geometry.27

Finally, to end at what is essentially the beginning (at least of this chapter!)

2: Pen taco-ordinuted and Hexaco-ordinateil Compounds 81

Cavell el al. have synthesised and characterised a series of neutral, hexaco- ordinate phosphorus compounds containing divalent, tridentate diphenol imine, azo and thio ligands.28 For example, the reaction of silylated Schiff base ligands (e.g. 112) with PCI5 gave the neutral, hexacoordinate compound 113 by elimination of two equivalents of Me3SiC1. Structures of this type were characterised by MS, multinuclear (including solid state) nmr and X-ray crystallography. Compound 113 crystallised with three independent molecules and half a molecule of acetonitrile per unit cell. The geometry was octahedral, all the cis- 0-P-Cl angles were within 2" of the idealised 90" geometry and the largest deviation from 90 " was the C1( 13)-P( 1)-N( 1) angle at 95.4 ". The thio(bispheno1) derivative 114 was also prepared and its X-ray crystal structure again showed a strongly bonded six-coordinate phosphorus compound but in this case, in contrast to the imine (and analogous azo) structure, the molecule adopted afac coordination rather thap a rneriodinal disposition of the 0-N ligands. The P-S bond distance (at 2.33 1A) is the shortest yet observed for y-S internal coordination and approaches the $ngle bond distance29 of ca. 2.1A and the sum of the single covalent radii (2.14A) for phosphorus and sulfur.

N PC15

112 113 ' -

114

References

1

2 3

4

V. F. Mironov, R. A. Cherkasov and 1. V. Konovalova, Russ. J. Gen. Chem., 1996, 66 (3), 409. K. N. Gavrilov and I. S. Mikhel', Russ. Chew. Rev., 1996,65 (3), 225. (a) C. Y. Wong, D. K. Kennepohl and R. G. Cavell, Chem. Rev., 1996, 96, 1917; (b) R. R. Holmes, G e m . Rev., 1996,%, 927. (a) A. Chandrasekaran, R. 0. Day and R. R. Holmes, Inorg. Chem., 1997,36,2578;

82 Orgunophospllorus Chemistry

5 6

7

8

9

10 1 1 12

13

14

15

16

17

18

19 20

21 22 23 24

25

26

27

28 29

(b) R. R. Holmes, A. Chandrasekaran and R. 0. Day, Phosphorus, Sulfur unci Silicon, Relut. Chem., 1997, 120-121,43 I . G. Aksnes, Phosphorus, Sulfur und Silicon, Relut. Chem., 1996, 115,43. A. A. Kutyrev, S. J. Fomin, and V. V. Moskva, Russ. J. Gen. Chem., 1996, 66 ( S ) , 757. A. Kadyrov, I. Neda, T. Kaukorat, R. Sonnenburg, A. Fischer, P. G . Jones and R. Schmutzler, Chem. Ber., 1996, 129, 725. X. Chen, N.-J. Zhang, Y. Ma, and Y.-F. Zhao, Phosphorus, Sulfur unci Silicon, Relut. Chem., 1996, 118,257. V. F. Mironov, 1. V. Konovalova, and M. G . Khanipova, Russ. J. Gen. Chem., 1996, 66 ( I ) , 66. A. E. Wroblewski and J. G. Verkade, J. Am. Chem. Soc., 1996,118, 10168. M. L. Bojin, S. Barkallah, and S. A. Evans Jr., J. Am. Chem. Soc., 1996,118, 1549. V. I. Namestnikov, Yu. G. Trishin, and V. K. Bel’skii, Russ. J. Gcw. Chem., 1996,66 (8), 1367. M. A. Pudovik, S. A. Terent’eva, and A. N. Pudovic, Russ. J. Gen. Chem., 1996, 66 (3), 355. L. I . Nesterova, D. M. Malenko, V. V. Pirozhenko, and A. D. Sinitsa, Russ. J . Gen. Chem., l997,67 ( I ) , 151. (a) S. Narasimhamurthy, N. Thirupathi, R . Murugavel and S. S . Krishnamurthy, Phosphorus, Sulfur and Silicon, Relut. Chem., 1994, 93-94, 221; (b) N. Thirupathi, S. S. Krishnamurthy, and J. Chandrasekhar, J. Chem. Soc., Chem. Commun., 1996, 1703. J. Krill, I. V. Shevchenko, A. Fischer, P. G. Jones and R. Schmutzler, Chem. Ber. Receuil, 1997, 130, 1479. I. Neda, V. A. Pinchuk, A. Thonnessen, L. Ernst, P. G. Jones, and R. Schmutzler, 2. Anorg. Allg. Chem., 1997,623, 1325. S. Volbrecht, A. Vollbrecht, J. Jeske, P. G. Jones, R. Schmutzler and W.-W. du Mont, Chem. Ber. Recuiel, 1997, 130, 819. I. Neda, C. Muller and R. Schmutzler, J. Fluorine Chem., 1997,86, 109. V. G. Ratner, E. Lork, K. I . Pashkevich, and G.-V.Roschenthaler, J. Fluorine Chem., 1997,85, 129. B. N. Anand and R. Bains, Indiun J. Chem., 1997,36A, 77. B. A. D’Sa and J. G. Verkade, J. Am. Chem. Soc., 1996,118, 12832. S. Arumugam and J. G. Verkade, J. Org. Chem., 1997,62,4827. I . Gardinier, B. F. Chuburu, A. Roignant, J. J. Yaouanc and H. Handel, J. Chem. Soc., Chem. Commun., 1996,2157. H. Thonnessen, P. G. Jones, R. Schmutzler and J. Gloede, Acru Crystullogr.. Smt. C., 1997, C53, 1310. J. Lacour, C. Ginglinger, C. Grivet and G. Bernardinelli, Angew. Chem., Int. Ed. Engl., 1997,36 (6), 608. D. J. Sherlock, A. Chandrasekaran, R. 0. Day, and R. R. Holmes, J. Am. Chem. Soc., 1997, 119, 1317. C. Y. Wong, R. McDonald, and R. Cavell, Inorg. Chem., 1996,35,325. L. Pauling, ‘The Nature of the Chemical Bond’, 3rd Ed., Cornell, Ithaca, NY, 1960.

3 Tervalent Phosphorus Acid Derivatives

BY 0. DAHL

1 Introduction

A review on the reaction of quinones with phosphorus-containing reagents, including phosphites, phosphinites, and phosphonites, has appeared. ' Another review has been published on the synthesis and reactivity of tervalent fluoro- alkoxy derivatives of phosphorus.2

2 Nucleophilic Reactions

2.1 Attack on Saturated Carbon. - The synthesis of 2-chloroethylphosphonic acid (1) has been opt imi~ed .~ The best yield and purity was obtained by heating triisopropyl phosphite with an excess of I -bromo-2-chloroethane, followed by acid hydrolysis. Diethyl 3-bromopropylphosphonate (2) was prepared in 76% yield by the addition of one mol of triethyl phosphite to three mol of boiling 1,3-dibromopropane, thus largely avoiding the competing Arbuzov reaction with the bromoethane liberated during the r e a ~ t i o n . ~ A precursor (3) of a phosphinic acid transition state analogue has been prepared by opening of a p-lactone with dimethyl phenylph~sphonite.~ The easily generated lithiated diaminophosphine borane complex 4 can be alkylated, and even arylated, to give a range of aminophosphine borane complexes (5) useful for syntheses of dichlorophosphines.6 Some a-haloketones have been protected as the silyl enol ethers 6 and then gave the normal Arbuzov products with triethyl p h ~ s p h i t e . ~

2.2 Attack on Unsaturated Carbon. - The kinetics and mechanism of the reaction of trimethyl phosphite with substituted benzylideneacetophenones have been studied.' The proposed mechanism change from rate-limiting attack on the carbonyl carbon to attack on the carbon atom p to the carbonyl group when the benzene rings are substituted with electron-withdrawing substituents (Scheme I) . Cyclic enones, e.g. 7, react sluggishly with silyl phosphites and give mixtures of 1,2- and 1,6adducts. A catalytic amount of trimethylsilyl triflate has now been found to give 1,6adducts, e.g. 8, regioselectively and in high yields at O"C.9 Trialkyl phosphites with o-phthalaldehyde and Lewis acid catalysts gave labile I - dialkoxyphosphorylisobenzofurans 9 which could be trapped with dienophiles. l o


83


'Cl Li R 4 5 R = primhec.

alkyl or aryl

(Et0)3P + X x C 0 2 R 6

An efficient route to enantiopure piperidin-2-ylphosphonic acid (10) has been published. ' ' It involves a tin tetrachloride catalysed addition of trimethyl phosphite to the oxazolopiperidine 11 to give 12, which could be separated in pure diastereomers.

Y

ki

kl

+ (Me0)3P + L

3 Electrophilic Reactions

Scheme 1

(Me0)3P+

OMe

3.1 Preparation. - the first aminobis(dialky1amino)phosphines (13) have been prepared and characterised.'* They can be stored for weeks at low temperatures, but oligomerise slowly at room temperature in solution to 14. Some I-methoxy- (15) and 1 -dialkylaminophosphirenes (16) have been prepared from the corresponding 1 -chlorophosphirenes. l 3 The first examples of bicyclophosphites

3: Tervulent Phosphorus Acid Derivutives 85

OSiMe3

TMSOTf + (R0)2P-OSiMe3 -

8 7

BFrE120 + (R0)sP -

Lil CHO

Ph. 'n

@O 1 - Diels-alder adduct

9

11

10 12

derived from alkane-l,2,3-triols, 17 and 18, were obtained from the alcohol and tris(dimethy1amino)phosphine. l4

(RzN)2PCI + LiNH2 - (R~N)zP-NH~ -35 "C

13 R = Pr', Cy or Ph 14 n = 3 and 4 mainly

I I OMe NR2

15 R = But or Ph 10 R = Et, Pr' or Tms OTr

OH + (MeN)3P - TrO

OH 17 18 R = Et, Ph or <?

Ph OTr N-N,

Some labile quinoxaline-2,3-diyl diphosphites (19) were prepared from quinoxaline-2,3-diol and characterised by further reactions. l 5 Similar diphosphites


derived from resorcinol, e.g. 20,16 and l,l’-bi-2-naphthol, 21 l 7 have been prepared and studied as ligands for Pt(I1) and Rh(1). The bis(ary1amino)phosphines 22 were prepared by standard methods for use as ligands.I8 Aminophosphines with strongly electron-withdrawing groups on nitrogen, the tosyl derivatives 23 and 24, were prepared as shown, and their properties as ligands for tungsten examined. l 9

R’

0 19 R’,R2 = H or Me 20

21 R = H o r M e 22 R = H o r M e

Ts I

PhPC12 n Ph2PCI A Et3N H N Et3N I I

[)-Ph - Ts-N H-TS - Ts-N N-Ts

PPh2 PPh2 I Ts

23 24

The macrocyclic diphosphonite 25 was obtained in good yield from phenylbis- (diethylamino)phosphine.20 A new calix[4]arene tetrakis(dimethy1phosphinite) (26) has been synthesised and its X-ray crystal structure determined.*’ Both in

b Bu‘ 4

26 27

3: Tervalent Phosphorus Acid Derivutives 87

solution and in the solid state 26 has a symmetrical cone structure, although the cone is strongly elliptical in the solid state. A series of new calix[4]resorcinol- arenes, substituted with four to eight tervalent phosphorus groups, were prepared from the alcohol 27 and various tervalent phosphorus acid amides.22

Some 1,3,2-oxazaphospholidin-4-ones (28) were prepared as shown.23 The diastereomeric compounds (R2 = H) were formed as predominantly the cis isomers which isomerised to the more stable trans isomers at room temperature. Diphenylchlorophosphine with 5-fluorouracil gave a mixture of the di-0-substituted compound 29 and the di-N-substituted compound 30, from which 30 could be isolated by precipitation with ~ e n t a n e . ~ ~ The structures follow from NMR and an X-ray crystal structure of 30.

R’-

P--Ph R 2 z > P d P h

Me

+ PhPC12 PY

Me 28 R’ = Me or Ph, R2 = H;

R1 = R2 = Me

O-PPh2

Et3N

I PPh2

+ 2Ph2PCI - benzene

Ph2P-0 H

29 30

3.2 Mechanistic Studies. - A new efficient catalyst, benzimidazolium triflate (31), has been found for the reaction of phosphoramidites with alcohols.25 It is well soluble (0.4 M) in acetonitrile and gives much faster couplings with unreactive nucleoside phosphoramidites than tetrazole or 5-(4-nitropheny1)tetrazole. The mechanism probably involves nucleophilic catalysis, since a phosphoro- benzimidazolidite (32) was formed quickly when 31 was mixed with a phosphoramidite in the absence of alcohol. Another efficient type of catalyst for phosphoramidite oligonucleotide synthesis is the 5-thiotetrazoles 33.26 Chlorotri- methylsilane has been shown to catalyse the reaction of tervalent phosphorus amides with alcohols.27 The reagent should be freshly distilled to avoid side reactions from hydrogen chloride impurities, and 0.3-0.6 mol equivalents is shown to give high yields of products, e.g. 34. The mechanism of activation is presumed to involve salt-like intermediates between chlorotrimethylsilane and the phosphorus reagent which react either direct with the alcohol or via a tervalent phosphorus chloride. A mechanism via a silyl ether and a tervalent phosphorus chloride seems another possibility.

A nucleoside methylphosphonamidite (35) derived from indole was shown to couple with a 3’-protected thymidine to give the methylphosphonite 36 in the presence of DBU.28 This is a rare example of base catalysis of such reactions. The reaction was shown to be stereoselective. Similar indole derived cyclic phosphor-


H

MesSiCl "VT + (Me*N)3P - Me2N-P

' 0

N-N, THF

34 OH R

33

TBDMso-P 0,

Me 7 - 8

35

+

-+

OTBDMS

OTBDMS

DBU -

DBU

TBDMso-v ":-OY

OTBDMS

TBDMsov 37 equatorial

OH Rp-39

3: Tervulent Phosphorus Acid Derivutives 89

amidites, e.g. 37, could be prepared in a 12:l equatoria1:axial ratio.29330 This mixture with alcohols and DBU catalysis gave only one stereoisomer of a phosphite, e.g. 38, because the equatorial isomer reacted much faster than the axial isomer. The reactions were used to prepare pure stereoisomers of a dithymidyl phosphorothioate, e.g. 39.

3.3 Use for Nucleotide, Sugar Phosphate, Phospholipid, or Phosphoprotein Synthesis. - A new phosphorodiamidite, 4-cyano-2-butenyl tetraisopropylpho- sphorodiamidite (40), has been prepared as shown and used without purification to prepare deoxynucleoside phosphoramidites 41 .3' The yields are good, and the 4-cyano-2-butenyl group could be selectively removed after oligonucleotide synthesis like the analogous 2-cyanoethyl group; it is claimed that the phosphoramidites 41 are cheaper to manufacture in large scales than the corresponding 2- cyanoethyl phosphoramidites. Cyclodiphospho-D-glycerate 42, a natural compound which increases the lifetime of enzymes in certain thermophilic micro- organisms, has now been prepared in good yields by a route which involves phosphitylation of the intermediate 43 with dibenzyl diisopropylphosphoramidite (44).32 Many other phosphorus reagents were tried without success because of facile elimination reactions of 43.

0

P-NPr'2 NC

41

42

Some bioreversible oligonucleotide conjugates have been prepared using the thymidine phosphoramidites 45 as one of the monomers.33 The phosphoramidites were prepared in a one pot synthesis from 5'-dimethoxytritylthymidine as shown, and the ester group was shown to survive the mild deprotection conditions used for R = 2,6-dimethylphenyl. Since the substituted benzyl protection group was removed in the otherwise deprotected oligonucleotides by chymotrypsin, these compounds are promising orally available prodrugs of antisense oligonucleotides.

Several new functional phosphoramidites for the conjugation of reporter

90

+

0 8, OH

Orgumphosphorus Chemistry

Me

45 R = But or

Me

groups or other groups to oligonucleotides have been described this year. These include the phosphoramidites 46 derived from 4-aminocyclohexyl- I , 1 -di- methanol;34 the ester functionalised phosphoramidites 47, which were used to incorporate oligoamines post-synthetically in DNA oligonucleotides for cleavage of a hybridised RNA strand;35 the acridine containing phosphoramidites 48;36 the methidium phosphoramidite 49;37 and the 1,2-dideoxyribose derived phosphoramidites 50.38 A nucleoside phosphoramidite 51 containing a pyrene bound to N-4 of 5-methyIdeoxy~ytidine,~~ and a nucleoside phosphoramidite (52) where the base is a psoralen-thymine photoadduct4' have also been described.

Oligonucleotides containing an acyclic nucleoside analogue were prepared from the new phosphoramidite 53, derived from L-~erinol.~' They bound with reduced affinity to both DNA and RNA complements. An improved method has been found for the preparation of oligonucleoside N3'-P5' ~hosphoramidates .~~ It uses 3'-amino-5'-nucleosidyl phosphoramidites 54 as the monomers, and depends on a tetrazole catalysed exchange of the phosphoramidite diisopropylamino group with the nucleoside 3'-amino group to give the phosphoramidites 55 and, after iodine-water oxidation and deprotection, the N3'-P5' phosphoramidates. The exchange equilibrium is displaced towards 55 by using 15 eq. of 54 and by repeating the coupling after oxidation; in this way a 92-95% coupling eficiency could be obtained. Oligonucleotides modified with phenylphosphonate or phenyl- phosphonothioate linkages have been prepared from nucleoside phenylphos- phonamidites 56 which were obtained as shown.43 The stereorandom phenylphosphon(othio)ate modifications gave only small depressions (0.3- 1 ''C per modification) of the melting temperatures against complementary DNA and RNA.

3.4 Miscellaneous. - - Several new optically active tervalent phosphorus acid derivatives have been prepared for use as ligands in asymmetric metal catalysed reactions. These include the cyclic diaminophosphines 57,@ the cyclic bisamino- phosphine 58,45 and the compounds 59,46 60,47 61 ,48 and 6249 containing a I , 1'- binaphthalene group as the chiral inducer. A new diphosphoramidite (63) has been used for improved regioselectivity of rhodium-catalysed hydroformy lations of alkene~.~' A new sterically hindered chiral phosphite (64) derived from glucose and a Cu(1) complex of 64 have been ~ r e p a r e d . ~ '

3: Tervalent Phosphorus Acid Derivatives 91

D M T r O d # w o " 0, 0

N C m O O DMTDFNH-x 0, P-NPr'2 NC-00P-NPr'2

46 X = biotinoyl, CO-fluoresceinyl, 47 R = Et, n = 1 or CO-(CH2)5-NHCOCF3 or R = CH2Ph, n = 3 CO-(CH2)s-NH( NH-Bu'bz) biotinoyl

48 n = 3 - 5

0, 49 NC-00P-NPr'2

N C m O O 0, P-NPri2

51

N-NMX H DMTavH

50 X = biotinoyl, COCF3, Fmoc or COcholesteryl

DMTa$ wo H C02Me

N C m O , 0, P-NPr'2

52


DMTrO

0, $NL H

NCW,~, P-NPr'2

53

Pri2N-P P-CN

@ C ( O ) O p B a s e + \ O p B a s e N C m O , HN, P-0 p B a s e

tetrazde - NH2 NHTr NHTr

54 55

vase, DMTrO

DMTrdNu PhPC12 + 2 Pri2NH - I - - . - - - - '\,,, Pri2 Et PrI2N

0, Ph/ P-NPt2

56

3: Tervulent Pitosphonis Acid Derivatives 93

4 Reactions involving Two-coordinate Phosphorus

The first 1,3,2-diazaphosphinines 65 have been prepared as shown.52 These very reactive molecules are versatile precursors to 1 ,2-azaphosphinines 66 and phosphinines 67, which are formed by highly regioselective [4 + 21 cycloaddi- tions between 65 and alkynes. The 2-halo- 1,3,2-diaZaphospholenes 68, when heated above 250 "C, eliminated butyl halide to form 1,3,2-diazaphospholes 69.53 A 1,2,4-thiadiphosphoIe (70)54 and the 1,2,4-selenadiphospholes 7155356 have been prepared and characterised by X-ray crystal structure determinations.

65 R=Bu'orPh 66 67

68 X = CI or Br 69 70 Ad = l-adamantyl 71 R = But or CMe2Et

An ionic 2-chloro- 1,3,2-diazaphosphoIene (72) was prepared from a silicon precursor (73).57 Since the saturated analogue 74 was covalent, the phosphenium ion 72 is probably stabilised by having an aromatic 67t electron structure. The phosphadiazonium compound 75 with a sterically hindered phenol or aniline gave the phosphenium ions 76;'* this constitutes a new preparative route to phosphenium ions. A series of phosphenium ions (77), stabilised by two intramolecular dative P-N bonds, has been prepared, and the X-ray crystal structure of one (77, X = H, Y = PF6) determined.59

The new P-alkoxyiminophosphine 78 was prepared from the P-chloro analogue and shown to exist in a trans configuration, contrary to other known P- alkoxyiminophosphines.60 Some very hindered diphosphenes (79) have been prepared and their behaviour upon reduction with alkali metals or at an electrode studied . '


BU' But BU' I I I

N [>-Cl (>sic12 + P a 3 - cN>+ CI-

I I I But But But

73 72 74

75 I

GaCI4- 76 X = O o r N H

LNMe2

Y = halogen, BF4, BPh4 or PF6 77 X = H, CI or Br

78

References

79 R' = 2,6dimethylphenyl or rnesityl R2 = H or Me

1 2

3

A. A. Kutyrev, Russ. J. Gen. Clwm., 1996,66,460-476. V. F. Mironov, I. V. Konovalova, L. M. Burnaeva, and E. N. Ofitserov, Usp. Khim., 1996, 65, 1013-1051 (Chem. Absrr.. 1997, 126, 157529~). L. Cauret, J.-C. Brosse, D. Derouet, and H. D. Livonniere, Bull. Suc. Chim. Fr., 1997,134,463; Syn. Commun., 1997,27,647.

3: Tervalent Phosphorus Acid Derivutives 95

4

5

6 7

8

9

10 1 1

12

13

14

15

16

17

18

19

20

21

22

23

24

25 26

27

28 29 30 31

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32 33 34

35

36 37

38

39

40 41 42

43

44 45

46

47 48

49

50

51

52 53

54

55

56 57 58

59

60 61

M. J. Earle, A. Abdur-Rashid, and N. D. Priestley, J. Org. Chem., 1996,61,5697. R. P. Iyer, N. Ho, D. Yu, and S. Agrawal, Bioorg. Med. Chem. Lett., 1997,7,871. S. Su, R. S. Iyer, S. K. Aggarwal, and K. L. Kalra, Bioorg. Med. Chem. Lett., 1997, 7 , 1639. M. Endo, Y. Azuma, Y. Saga, A. Kuzuya, G. Kawai, and M. Komiyama, J. Crg. Chem., I997,62,846. K. Fukui, K. Iwane, T. Shimidzu, and K. Tanaka, Tetrahedron Lett., 1996,37,4983. E. N. Timofeev, I. P. Smirnov, L. A. Haff, E. I. Tishchenko, A. D. Mirzabekov, and V. L. Florentiev, Tetraheclron Lett., 1996,37,8467. T. )I. Smith, M. A. Kent, S. Muthini, S. J. Boone, and P. J. Nelson, Nucleosides Nucleotides, 1996, 15, 1581. A.A.-H. Abdel-Rahman, 0. M. Ali, and E. B. Pedersen, Tetrahedron, 1996, 52, 1531 I . W. R. Kobertz, and J. M. Essigmann, J. Am. Chem. Soc., 1997,119,5960. K. S. Ramasamy, and W. Seifert, Bioorg. Mecl. Chem. Lett., 1996,6, 1799. S . N. McCurdy, J. S. Nelson, B. L. Hirschbein, and K. L. Fearon, Tetrahedron Lett., 1997, 38,207. M. Mag, J. Muth, K. Jahn, A. Peyman, G. Kretzschmar, J. W. Engels, and E. Uhlmann, Bioorg. Med. Chem., 1997,5,2213. H. Tye, D. Smyth, C. Eldred, and M. Wills, Chem. Commun., 1997, 1053. G. Brenchley, M. Fedouliff, E. Merifield, and M. Wills, Tetrahedron: Asymmetry, 1996,7, 2809. K. Nozaki, N. Sakai, T. Nanno, T. Higashijima, S. Mano, T. Horiuchi, and H. Takaya, J. Am. Chem. Soc., 1997,119,4413. S. Cserepi-Szucs, and J. Bakos, Chem. Commun., 1997,635. K. Nozaki, H. Kumobayashi, T. Horiuchi, H. Takaya, T. Saito, A. Yoshida, K. Matsumura, Y. Kato, T. Imai, and T. Miura, J. Org. Chem., 1996,61,7658. A. H. M. de Vries, A. Meetsma, and B. L. Feringa, Angew. Chem., Int. Ed. Engl., 1996,35,2374. A. van Rooy, D. Burgers, K. C. J. Dennis, and W. N. M. van Leeuwen, Recl. Truv. Chim. Pays-Bas, 1996,115,492. M. Stolmar, C. Floriani, G. Gervasio, and D. Viterbo, J. Chem. SOC., Dalton Trans., 1997, 1 1 19. N. Avarvari, P. Le Floch, and F. Mathey, J. Am. Chem. Soc., 1996,118, I 1978. A. M. Kibardin, T. V. Gryaznova, A. N. Pudovik, and V. A. Naumov, Russ. J. Gen. Chem., 1996,66, 14 18. E. Lindner, E. Bosch, C. Maichle-Moessmer, and U. Abram, J. Orgunometal. Chem., 1996, 524,67(Chem. Abstr., 1997, 126, 131543~). V. Caliman, P. B. Hitchcock, J. F. Nixon, and N. Sakarya, Bull. Soc. Chim. Belg., 1996, 105,675. M. Regitz, and S. Krill, Phosphorus, Sulfur, Silicon, 1996, 11599. M. K. Denk, S. Gupta, and R. Ramachandran, Tetruhecfron Lett., 1996,37,9025. N. Burford, T. S. Cameron. J. A. C. Clyburne, K. Eichele, K. N. Robertson, S. Sereda, R. E. Wasylishen, and W. A. Whitla, Inorg. Chem., 1996,35, 5460. J. P. Bezombes, F. Carre, C. Chuit, R. J. P. Corriu, A. Mehdi, and C. Reye, J. Organometal. Chem., 1997,535,81. N. Potschke, M. Nieger, and E. Niecke, Actu Chem. Scand. 1997,51,337. S . Shah, S. C. Burdette, S. Swavey, F. L. Urbach, and J. D. Protasiewicz, Organometallics, 1997,16, 3395.

4 Quinquevalent Phosphorus Acids

BY B. J. WALKER

1 Introduction

Biological aspects of quinquevalent phosphorus acid chemistry, quite separate from nucleotide chemistry, have taken on increasing importance over the last few years. Throughout this year's report, although not pretending to offer comprehensive coverage of these aspects, there is an attempt to reflect this.

2 Phosphoric Acids and their Derivatives

2.1 Synthesis of Phosphoric Acids and their Derivatives. - Among various approaches to phosphate esters the phosphorylation of phenols with dialkyl cyanophosphonate' and the synthesis of triaryl phosphates under phase-transfer conditions2 are worthy of mention. Mixed trialkyl phosphates are also reported to be formed by brief cathodic electrolysis of the reaction of dialkyl phosphonates with aromatic aldehydes and ketones, presumably by rearrangement of the initial a-hydroxy compound^.^ Further reports have appeared of the generation of metapho~phates~ by various methods. The synthesis of analogues 1 of farnesyl pyrophosphate which incorporate photoactive esters has been r e p ~ r t e d ; ~ both compounds are competitive inhibitors of farnesyl transferase.

Numerous reports of the synthesis of cyclic analogues have appeared. The cyclophosphamidic chloride 2 has been prepared as a single enantiomer and


97


converted into a variety of phosphamides by reaction with amino acid and peptide esters.6 Bicyclic phosphotriamidates 37 and the novel phosphordiamidates 48 have been reported. One example of the latter compounds shows subnanomolar activity against HIV protease. A one-pot reaction has been used to generate the novel cyclic phosphate-phosphonates and thio and seleno analogues 5.' A method for the large scale synthesis of the primary methanogen metabolite, cyclodiphospho D-

glycerate (cDPG) (6) in ten steps from mannitol with 30% overall yield has been reported. l o A variety of dioxaphosphacin 6-oxides (7) have been synthesised from 1, I -bis(2-hydroxy-5-chlorophenyl)ethanes and phosphoric dichlorides and their structures investigated by I H NMR and X-ray diffraction. I

OH 2 3 4

Me 5 Z = S o r S e

\

6

7

Interest in phosphorus-containing calixarenes continues. Structures reported include hexa(diethoxyphosphoryloxy)caIix[6]arene (8),'* inherently chiral 1,2- bridged calix[4]arene diphosphates, l 3 and a calixarene like C3 symmetric receptor with a phosphate function at the cavity bottom.14 The purification of phosphate substituted calixarenes has been studied by chiral HPLCi3 and by normal reverse phase HPLC. l 5 Mono(6-O-diphenoxyphosphoryl)-f3-cyclodextrin (9) and mono(6-O-ethoxyhydroxyphosphoryl)-f3-cyclodextrin (10) have been synthesised and show enantioselective inclusion of D and L amino acids (e.g. 3.6 for D/L serine in the case of 9).16

A number of P(V) acid containing dendrimers have been synthesised. Examples include those starting from a hexachlorotriphosphazene cg. 11 which could be complexed with iron or tungsten compounds,18 compounds up to seven generation possessing terminal P(S)(N-ally12)Cl fragments which can be further

4: Quinquevalent Phosphorus Acids 99 .

fun~tionalised,'~ and molecules containing P=S groups which on treatment with methyl triflate undergo S-alkylation to give, cg. 12.20

8 9 R' = R2 = Ph 10 R' = Et, R2 = H

Ph

I I Ph SMe n

CH=N--N-CH2-P~N~-P Me I + ( O e C H 0 ) 2 ]

nCF3S03- 12

Over 40 reports on inositol phosphate chemistry have appeared during the review period. myo-Inositol 3-phosphate has been synthesised in four steps from myo-inositol by reaction, following appropriate protection, with (2R,4S,5R)-2- chloro-3,4-dimethyl-5-phenyl- 1,3,2-0xazaphospholidin-2-one, crystallisation of the required diastereomer and finally deprotection.2' Efficient syntheses of all four regioisomers of myo-inositol monophosphate have also been reported.22 A number of inositol monophosphatase inhibitors, e.g. 1323 and have been reported. Compound 15 was predicted to be a submicromolar inhibitor of the monophosphatase and following synthesis from the epoxide 14 this was confirmed.24 myo-Inositol-2-phosphate conjugates of the anti-proliferative flavanoid quercin have been prepared in order to increase the water soIubility of the The conjugates showed a dramatic increase in solubility over quercin and maintained substantial biological activity.

Reports of the synthesis, structure and properties of inositol triphosphates and

I I

OBn I

OH 13 14

I

OH 15


their analogues and mimics continue to appear. These include the preparation of D-16 and L-17 myo-inositol 1,4,6-tri~phosphate,~~ the u-galactopyranosyl analogue of the l ,2,6-tripho~phate~~ and phosphonate analogues of myo-inositol l ,2- bis- and 1,2,6-tri~phosphates.~~ An X-ray crystal structure of 2,4,6-tri-O-benzyl- myo-inositol 1,3,5-tris(dibenzylphosphate) has been reported.29 The synthesis of racemic 6-deoxy-6-hydroxymethyl scyllo-inositol 1,2,4-trisphosphate 18, a highly potent agonist at the platelet D-myo-inositol 1,4,5-trisphosphate receptor, has been rep~rted.~' Reports of ring fluorinated analogues include 2-deoxy-2-fluoro myo-inositol 1,4,5-trisphosphate (19) which is a potential probe of the polypho- sphoinositide pathway of cellular ~ignalling.~' Phosphorofluoridate analogues, e.g. 20, of myo-inositol 1,4,5-tris(phosphate) have been prepared and their biological activity towards inositol P3,5-phosphatase in~est igated.~~ A concise route to the disaccharide mimic 21 of 1 D-myo-inositol 1,4,5-trisphosphate has been reported; 21 shows Ca2'- mobilising activity at a similar level to that of myo-inositol 1,4,5-trisphosphate itself.33 Chiral cyclopentane-based mimics, e.g. 22 and 23, of trisphosphates have also been prepared and Ca2+ mobilisation studies on these compounds demonstrate thaf possess a six-membered ring can be designed.34

effective mimics which do not

19 20 21

H2O3PO, CH20P03H2

OP03H2 H2O3PO a O H

OH OH 22 23

A number of tetraphosphate analogues, e.g. 24, have been prepared with a view to increasing cell membrane permeation proper tie^.^^ Routes to 3,4,5,6-tetrakis- phosphates, e.g. 25, of DL- 1,2-dideoxy- 1,2-difluoro-myo-inositol and DL- 1,2- dideoxy-l,2-difluoro-scyllo-inositol have been reported.36 The fluoro substituents were introduced using DAST to displace hydroxy groups. However, the difluorina- tion could not be achieved in one step due to competing formation of a 1,4-anhydro derivative. The synthesis, from myo-inositol monobenzoate derivatives, of all four

4: Quinquevulent Phosphorus Acids 101

possible regioisomers of myo-inositol pentakisphosphate has been achieved.37 The regioselective synthesis of ‘caged’ inositol hexaphosphate derivatives, e.g. 26, has been re~orted.~’ ‘Caged’ derivatives are biologically inert but photosensitive precursors, which can be ‘released’ inside cells by laser flash photolysis.

(AcOCH20)2(0) PO’’ ’OP (0) ( OCH~OAC)~ 2-03p0Q 2-03 PO‘ -oPo~*-

R

OP(O)(OCH20Ac)2 0~0,~-

25

(AcOCH20)2(0)PO

24 R = CI, OMe, OCOPr

0 P03N a2

Na203P0 OP03Na2

Numerous reports relating to phosphatidylinositols and the corresponding phosphates have appeared. Phosphate examples include the rnon0-27~~, di-2ZS4O and tri-294’ esters. The last compound is involved in intracellular signal transduc- tion. Various approaches to generate inhibitors of phosphatidylinositol-specific


phospholipase C have been reported. Compounds 30 containing modified inositol substitution have been prepared, kinetically evaluated and shown to be competitive inhibit01-s.~~ A structure-activity study has been used to evaluate the importance of both the lipid portion and the inositol phosphate group for binding to the enzyme.43 The phosphonate analogue 31 was found to be among the best inhibitors of those compounds studied. Phosphorothiolate analogues 3244 of phosphatidylinositol 3,4,5-triphosphate and 3345 of phosphatidylinositol have been synthesised. In compound 33 the key phosphothiol ester bond formation is carried out using phosphoramidite chemistry. Full details of the synthesis, using phosphite chemistry, of 2,6-di-O-cr-~-mannopyranosylphospha- t id yl-r>-myo-inositol (34) have appeared .46 The synthesis, using phosphoramidi te chemistry, of photo-activatable derivatives has also been reported.47T48 In one case4' a doubly tritium-labelled analogue 35 has been prepared. The enzyme-

HO

HO OCOR

II 0-P-0

I HO1*;:llocoR HO' 0- I HO' '0- OH a-D-mannapyranosyl

OH OH 33 34

0- 36 X=OH,Y=H 37 X=H,Y=OH

4: Quinquevalent Phosphorus Acids I03

mediated synthesis of the two diastereomeric forms 36 and 37 of phosphatidyl glycerol has been achieved by phospholipase D-catalysed transphosphatidylation of natural phosphatidyl choline with (R)- and (9-isopropylidene glycerols.49

Changing the conditions in phosphorylation of monosaccharides with diphenyl chlorophosphate reportedly leads to the glycosyl chlorides rather than the glycosyl phosphates (Scheme l).50 A stable carbocyclic analogue (38) of 5- phosphoribosyl- 1 -pyrophosphate has been prepared in 40/0 overall yield as a single enantiomer with the natural configuration." Both diastereomers of 39 have been synthesised as anhydroalditol substrate mimics in order to study the mechanism of L-fucose 1 -phosphate aldose and other class I1 metal-dependent aldo~es.~* Carbocyclic analogues, including the phosphonate 40, have been synthesised and evaluated as transition state mechanism-based inhibitors of 3- deoxy-~-manno-2-octulosonate-8-phosphate ~ y n t h a s e . ~ ~ The synthesis of a number of complex carbohydrate phosphates have been reported. These include the pyran carboxylic acid analogue 41 of GLA-60, 41 showed potent endotoxin activity,54 complex disaccharide phosphate^,^^ and phosphorylated branched oligosaccharides which are fragments of the phosphoglycdn portion of Leish- mania major lipopho~phoglycan.~~ Both phosphoramidite- and hydrogenphosphonate-based phosphorylation methods are commonly used. Trisaccharide analogues of monoenomycin A 12 have been synthesised by chemoenzymic methods and shown to be antibiotically

. .

HO OH 39

Bu"Li -yd A ac, + LiOP(O)(OPh),

Scheme 1

H O C H 2 9 : ,C02H

H203PO' * NHCOCl3H27 ( H O ) 2 F L o T c " " OH to

HO - - OCOC13H27

H23C11 OH 40 41


Methods have been developed for avoiding side reactions in the global phosphorylation of peptides containing oxidation sensitive amino acids such as tryptophan, methionine or cy~teine.'~ Base-labile, biologically relevant phospho- peptides, e.g. 42, have been synthesised under very mild conditions through the use of heptyl esters as enzyme-labile protecting groups.60 A new, efficient solid- phase phosphorylation method suitable for phosphoserine and phosphothreo- nine-containing peptides has been reported.6' The key is the conversion of hydroxy groups into bis(pentafluoropheny1) phosphate triesters by reaction with bis(pentafluoropheny1) chlorophosphate (43) and the ready deprotection of the triesters to give monoesters under acidic conditions. Both Cbz and Fmoc protected tyrosine phosphoramidates 44 have been prepared by reaction of the protected tyrosine oxy-anion with N,N'-dialkylphosphoramidic chloride (Scheme 2).62 The P-N bonds are stable towards 20% piperidine in DMF and are cleaved quantitatively with 950/0 TFA. Fmoc-0,O-(dimet h y1phospho)-L- tyrosine has been converted into the stable fluoride 45 by treatment with (diethy1amino)sulfur trifluoride or cyanuric fluoride. Compound 43 was used in the coupling of phosphotyrosine to sterically hindered amino acids.63 A solid phase synthesis of phosphorylated tyrosine containing proteins has been reported.64

H-Ser-Thr-Ser-Thr-Pro-OH

CH2-0-P(OH)* I I 1 ( F5e y a 0 42 43

OH 0 - i. ii 0 CH CH

XNHAL02B" XNHAL02B" 44

X = Cbz or Fmoc 0 I1

Reagents: i, LDA; ii,(RNH)2PCI Scheme 2

46

4: Quinquevalent Phosphorus Acids 105

The phenylacetyl N-protecting group can be removed using penicillin G acylase under mild conditions which preserve sensitive peptide bonds, C-terminal esters and phosphate groups.65 A novel phosphate prodrug system 46 for amines, amino acids and peptides has been reported.66

A new reagent 47 for the synthesis of phospholipids has been introduced and used in the synthesis of, e.g. , 48 and derived phospholipid analogues.67 Novel N- linked phospholipid analogues have been prepared by the reaction of 2-chloro-3- methyl- 1,3,2-oxazaphosphacyclopentane 2-oxide (49) with long chain primary and secondary amines followed by ring opening of the phosphorus heterocycle with methanol or ethanol.68 The novel phosphorylation agent 50, prepared from 2-hydroxyethyl azide and phosphoryl trichloride, has been used in a synthesis of racemic ethanolamine plasmalogen 51 .69 'Defective' phospholipids possessing one normal CI6 carbon chain and one shorter chain terminated with methoxy, hydroxy or carboxy groups have been ~repared.~' The synthesis of polyunsatu- rated phospholipids creates difficulties due to the sensitivity of the unsaturated chain during phosphate ester deprotection. Various approaches have been reported to overcome this difficulty and enable the synthesis of unsaturated lysophosphatidic acid mimics, e. g. 52.7' Three different stereoisomers of the phosphatidic acid analogue 53 have been synthesised from tartaric acid and erythritol and found to aggregate differently on complexation with Ca2+ ions7* Individual enantiomers of cyclic lipoidal ammonium salts 54 have been prepared and shown to inhibit protein kinase C.73

CH20POCH2 CH2iMe3 n 0 I 0, ,NMe

E t 2 N F ? ? D 0 0- 8 dp\,l C12POCH2CH2N3 I I

47 48 49 50

0 + 0

~ , ~ ~ ~ , ~ o ~ o - - b ( - o ~ I NH3 2-02p, I1 ,GH2h-x1R

0 0- 0 C11 H23-CO' 51 52 X = NH. 0

n= 2,3,4

2-0xa-4-aza-3-phosphabicyclo[3.3.0]octanes 57 have been synthesised, and isolated as individual diastereomers, from the reaction of phosphoro-55 and phosphothio-56 dichlorides with ~ - p r o l i n o l . ~ ~ The 2-mercapto- 1'3'2-diazapho-

I06 Organophosphorus Chemistry

sphorine-2,4-dithione 59 has been prepared by the reaction of the enamine 58 with P& in the presence of ~ y r i d i n e ~ ~ and optically active carotenoid selenopho- sphates derived from (3R, 3'S)-zeaxanthin have been synthesised for the first time.76

X II

55 x=o ( 2 7 . 0 CHpOH + RPCh - H 56 X = S A

R X

Q- 57

R = OEt, SEt, PhO, Et2N, efc

FN

58 59

2.2 Reactions of Phosphoric Acids and their Derivatives. - Phosphates 60 derived from optically pure secondary benzylic alcohols undergo base-induced rearrangement to the corresponding or-hydroxyalkylphosphonates 61 with retention of configuration and >94% ee (Scheme 3).77 A comparison, including a theoretical study, of the relative effectiveness of o-iodobenzoate and the analogues 62 and 63 in promoting cleavage of p-nitrophenyldiphenyl phosphate has been carried out and shows that o-iodobenzoate reacts approximately 50x faster than its analogue^.^' Recent published theoretical calculations question current ideas of the detailed mechanism of hydrolysis of phosphate esters by hydroxide ion.79

H O O=P(OEt)2 I I I i, ii I

~ 2 - - c , ,P(OEt)2 - ~ 2 - - c , 4 0 4 OH

R' R' 60 61

Reagents: i, W L i , TMEDA, Et20, -78 "C; ii, CH&@H

Scheme 3

0- 62

0- 63

Many further examples of reactions in which phosphate anions act as leaving groups have been reported. Palladium-catalysed reactions of cyclic ketene acetal phosphates, e.g. 64, are reported to offer advantages over the corresponding


triflates in the functionalisation of lactones and have been used in new routes to medium- and large-ring ethers (65).80 Regioselective cross coupling reactions of allylic alcohol derivatives 66 with allylic organometallic reagents have been accomplished using bis(2,2,2-trifluoroethyl) phosphate as a leaving group." Reactions with barium alkyls showed good a,a'-selectivity to give 67 while those with Grignard reagents displayed a,y'-selectivity to give 68. The reaction of the D-

glucofuranose 3,5,6-bicyclothionephosphate 69 with aprotic nucleophiles has been studied and shown to occur with heterolytic cleavage of the C-6 carbon- oxygen bond.82

64 65

R & / - / R' R

a,a'-product 67

S=

a,.j-product 68

A variety of reactions of phosphates which involve radical intermediates have been reported. Phosphoenol radical cations 70 have been generated in solution for the first time and studied by cyclic voltammetry and EPR.83 Sterically hindered examples undergo P-0 cleavage to give 71 (Scheme 4). C- Glycosides 73 have been prepared by samarium diiodide-initiated stereoselective homolytic coupling of glycosyl phosphates 72 with aldehydes and ketone^.'^ In a study to model the anaerobic strand scission of 4'-DNA radicals the phosphate 74 has been p h o t o l y ~ e d . ~ ~ ESR evidence supports a mechanism involving C-0 bond cleavage leading to the ally1 radical 75. Experiments with deuterium labelled substrates have shown that in t-butanol, but not in benzene, as solvent P-(phosphatoxy)alkyl radical migration of 76 to give 77 and 78 takes place via a fragmentation-recombination mechanism.86 Similar rearrangements of the radicals 79, 80 and 81 have been the subject of a theoretical


0

72

Mes = M e q e Me Me* R

Me 71

Scheme 4

73

CH2OTBDMS hv COBu' -

0 I

74 (Et0)2P=O

0 1

(Et0)2P=O

' b C H 2 0 T B D M S -"+ Ph e C H 2 0 T B D M S

- - -5' 1

75

0 II

H OP(OEt)2

phseY3 AlBN

Bu3SnH - ' 0 '

II H OP(OEt)2

76 0


The use of a phosphoramide group to stabilise the carbanion allows an aza- [2,3]sigmatropic rearrangement of 82 to give 83.88 Earlier suggestions that bis- glycoaldehyde phosphodiester 84 undergoes rapid intramolecular aldolisation in alkaline solution to give 85 and 86 have been confirmed by electrospray MS and deuteration studies.89

82 83

YH ?H

84

Chiral quinquevalent phosphorus amides have been used extensively in asymmetric synthesis. The Cz-symmetric ligands related to BINOL have been resolved via the corresponding cyclic phosphoramidate 8790 and N-methylated phosphorothioamidate 88, in each case prepared from the corresponding chlorophosphate derivative.” The asymmetric allylation and crotylation of aromatic aldehydes with allylic trichlorosilanes 89 occurs with >88% ee in the presence of stoichiometric amounts of either the chiral phosphonamides 90 or 91, although different enantiomers are obtained in each case.92 Highly selective asymmetric aldol reactions of silyl enolates 92 with aldehydes have been achieved with antilsyn ratios as high as 99/1 and ees up to 99% in the presence of catalytic amounts of the chiral phosphonamide 93.93 A highly ordered chair- like transition state involving a hexaco-ordinate silicon species is suggested to account for the high levels of ee observed. A key step in a highly stereocontrolled synthesis of 4-methoxytrinems is resolution via the 1,3,2-0xazo- phospholanes 94.” Diferrocenyldithiadiphosphetane disulfide (95) has been reported to react with

bicyclic dienes to form four- and six-membered phosphorus and sulfur-containing rings which are characterised by X-ray crystallography in several cases.95 Phosphate and thiophosphate triesters react with or-diazoacetates in the presence of BF3.etherate as a catalyst to give, respectively, 0-alkoxycarbonylmethyl phosphates 96 and S-alkoxycarbonylmethyl phosphate^.^^

The X-ray crystal structural analysis of the optically active 2-chloro-l,3,2- diaza-phospholidine 2-oxide 97 has been reported.97 Reactions of 97 with chiral amino alcohols lead to ring opening and formation of the 1,3,2-


Me0

Me0

87 88

?H

0 NR3R3 RCHO + C13Si AR2 % OH

89

90 R3R3 = (CH& 91 R3 = Pr"

anti

oxazaphospholidines, e.g. 98. The 13C NMR spectral parameters of 2-thiono-2- diet hy lamino-3-subs ti tuted- 1 ,3,2-oxazaphospholidines (99) have been reported.98

2.3 Selected Biological Aspects. - The catalytic antibody-mediated hydrolysis of the insecticide paraoxon (100) and analogues 101 have been investigated with a view to developing antibodies for use in the treatment of insecticide poisoning.99 Two-dimensional 1H-31P inverse NMR spectroscopy has been applied to the detection of trace amounts of organophosphorus compounds related to the Chemical Weapons Convention and it is proposed that developments of this technique will allow accurate analysis without the need for sample 'spiking'. loo

The inhibition of 6-chymotrypsin with optically active hexahydro-4H-l,3,2- benzodioxaphosphorin 3-oxides 102 has been investigated. Comparison of ' P NMR shifts is used to show that a covalent bond is formed by phosphorylation of a serine residue and that this takes place with either inversion at P or a mixture of inversion and retention depending on the stereochemistry of the inhibitor.


95 S

Fc-cK S

'Fc

0 BF3.Et20 II

(R10)3P=0 + R20COCHN2 * R20COCH20P(OR')2 96

H

*N 2: - 0 CI

Mewph n /p\

I \

0, ,NXAr 'Ph

S NEt2

97 98 99 x = sop, co

Enzyme-catalysed desulfuration of steroids plays an important role in steroid biosynthesis and may provide a source of steroids in the growth and proliferation of breast cancer. Inhibition studies of estrone sulfatase with both steroidal and non-steroidal phosphate compounds have now shown that the best inhibitors contain phosphate mono anions and that the basic structure for inhibition does not require the steroid nucleus.'**

a ; < 0 4 3 - N o 2 0' ' 0

102

3 Phosphonic and Phosphinic Acids

3.1 3.1.1 Alkyl, Cycloalkyl, Aralkyl and Related Acids. -- Both alkane- and alkenephosphonates have been prepared by electrochemical phosphorylation of alkenes with a variety of P"' acid derivatives.Io3

Synthesis of Phosphonic and Phosphinic Acids and their Derivatives


A number of phosphonate and phosphinate derivatives where the phosphorus atom is directly bonded to non-aromatic cyclic systems have been reported. The synthesis and reactions of a number of compounds with the general structure 103 have been reported. '04 Enantiomerically pure cyclopropanephosphonic acids which are constrained analogues of the GABA antagonist phaclophen, have been prepared by stereocontrolled Michael addition of a-anions derived from chiral chloromethylphosphonamides 104 to a,&unsaturated esters followed by in situ cycl i~at ion. '~~ Other asymmetric syntheses include those of (R)- and (9-piperidin-2-ylphosphonic acid (105) via the addition to trialkyl phosphites to iminium salt equivalents'06 and 4-thiazolidinylphosphonate 106 by catalytic asymmetric hydrophosphonylation of 3-thiaz0line."~ In the latter case both titanium and lanthanoid (which give much better e.e. values) chiral catalysts are used.

H 103 R=OEt,CI; X = O , S

Me

'04 I LDA,THF

The Stille cross-coupling reaction between various heteroarylstannanes and ring-brominated benzylphosphonates (107) has been used to prepare heterobiaryl phosphonates 108.'08 A key step in the synthesis of individual optical isomers of 2-hydroxymethyl-4-[3-(diethoxyphosphinyl)propyl]-5-alkylpiperazines 109 as CPP analogues is the alkylation of protected 5-alkyl-2-hydroxymethylpiperazines with (3-bromopropy1)phosphonate (Scheme 5). '09 Compound 110, a new member


of the 2,3-aziridino-y-lactone family, has been prepared in fifteen steps from D-

lyxose."' A study of the reaction of 110 with nucleophiles reveals quite different reaction pathways depending on the hardness or softness of the nucleophile used. The synthesis of the C3 symmetric macrocycle 11 1 carrying pendant phosphonate groups has been described. ' ' '

i, ii ___)

I

Y;)) OH

109 0 II

Reagents: i, B~(CHZ)~P(OE~)~, Na2CO3; ii, 10% HCI Scheme 5

0 (MeO)&H,. , a0 07, ,CH2P(OMe)2 II

N Cbz

110

Model studies for the syntheses of phosphonate analogues of sphingomyelin and ceramide 1 -phosphate from pentaco-ordinate phospholene 112 have been reported."* Compound 112 undergoes ring opening on reaction with dialkyl azodicarboxylates to give 113 which reacts with sodium borohydride stereoselec- tively to give predominantly trans-114 (Scheme 6). The preparation has been described, via phosphorus chloride methods, of the potential haptens 115 for the production of phospholipase A2-like catalytic antibodies. ' I 3


Reagents:

Me

+p OEt

OEt

i

R02C0"NC02R H

112 113 R = CH2CC13

i, R02CN=NC02R; ii, NaBH4 Scheme 6

ii __c

N (Et0)2P=O "70f0 i

114

,O(CH2)nC02H Me(CH2)"PO-CH 0

I \ I I OH OPOCH2CH2hMe3

I 0-

115 n=9,15

3.1.2 Alkenyl, Alkynyl, Aryl, Heterouryl und Related Acids. - Alkenyl- phosphonates have been prepared by the dehydration of 0-hydroxyphosphonates with DCC and CuC12, l4 by dehydrohalogenation of P-bromoalkylphosphonates with triethyl orthoformate,'I5 and from alk-1-ynylphosphonates 116 by hydrogenation using Lindlar's catalyst (to give the cis-isomer 118) and by stereoselective addition of alkylcuprates to give 117 (Scheme 7).' A convenient

0 1 1

R-C=C-P(OEt)2 116

0 Y 11

R X p ( o E t ) 2 H H

117 118

Reagents: i, R'pCuLi, Et20; ii, NH&I, H20; iii, H2, 10% Pd (Lindlar), MeOH

Scheme 7

0 ROH II

0 II

(Et0)2PCH2COpH + (HCHO)3 - (Et0)2PC--CH2OR I I

120 CH2 119

0 II

(R' 0 ) 2 p ~ c 0 x

121 X = OR2 122 X = NH2

0 11

R2AIC I ( cG s#PcoEe2 RAlClZ L " s H

0 II (Et0)2PCHpC02Et + HS(CH2)SH 7

123

4: Quinquevdent Phosphorus Acids 115

route to 1 -alkoxymethylvinylphosphonates 120, involving the piperidine catalysed condensation of diethylphosphonoacetic acid (1 19) with paraformaldehyde in the presence of primary or secondary alcohols, has been reported. ' l 7 Carboxyal kenyl- 121 and aminocarbony lalken y I- 122 phosp hona tes and alkenylbisphosphonate derivatives have been synthesised and their molecular structure studied by a variety of spectroscopic methods. ' Phosphonoketene dithioacetals 123 have been obtained in good yields by the reaction of phosphono acetates with an excess of thiols in the presence of alkylaluminium chlorides."'

There have been many reports of syntheses of halogenovinylphosphonates, with particular emphasis on fluorinated examples. (2)-Diethyl a-chlorovinylphosphonates 125 have been prepared in a one-pot reaction from diethyl trichloro- methylphosphonate by treatment with butyllithium and a1dehydes.l2' The intermediate bisphosphonate 124 undergoes Wadsworth-Emmons olefination to give 125. The major products of the reaction of triethyl phosphite with 3- fluoropropanoyl chloride are the a-(3-fluoropropanoyloxy)vinylphosphonate 126 and the phosphonate-phosphate 127. 1 2 ' Peterson-type reactions have been used to synthesise a-fluorovinylphosphonates 129 from a-fluoro-a-lithio-a-trimethylsi- lylmethylphosphonate 128.'22 Various perfluoroviriylphosphonates, for example,

0 OLi 0 ?\ II II BuLi CI, ,P(OEt)2 RCHO P(OEt12 - - !?

C13CP(OEt)2 - C Et20 Li' 'E(OEt), CI' 'L(OEt)2 R CI

0 124

0 125

' I o - R A E RCHO c II

LI / P(OEt)2 Me3Si ' 1 , ' P( 0 E t)2

128 129

F O F

130

(Et0)2POSiMe3

F (Et0)2P \

F F 131

I I6 Organophosphorus Chemistry

130 and 131, have been prepared by the reaction of trimethylsilyl phosphites with perfluoroalkenes'23 and perfluoroepoxides.

Reports of examples of arylphosphonates include those of water-soluble phosphinic-polyphosphonic acids, e.g. 132,'25 and the phosphonate 133 which when coupled to alcohols, to give e.g. 134, act as linkers to proteins in experiments intended to generate antibodies to catalyse cationic cyclisation reactions.'26 Novel water-soluble phosphonate-substituted phthalocyanines have been prepared.'27 The phosphonate esters 135 are insoluble in water but can be hydrolysed by hydrochloric acid to give the water-soluble phosphonic acids 136. Aromatic phosphonate-phosphines 137, and their air-stable complexes, have been obtained from the reaction of 4-halogeno-substituted phenylphosphonates with lithium diphenylphosphide. 128

But But,

132

Me H

133 134

0 I I

( W 2 P

0 II

I1 P(OW2

135 R = Et, M = Z n , C u 136 R = H , M = Z n , C u

137

New mercaptoaryl- and mercaptoheteroaryl-phosphonates (139) have been prepared by ortho-lithiation of the corresponding 0,O-diisopropyl S-aryvhetero- aryl phosphorothioates 138 followed by sulfur to carbon rearrangement.'29 A simple and efficient synthesis of the 2-substituted 3-diethylphosphono 5-methyl- furans 141 from the ketal phosphonate 140 has been reported.13' Acylation of a-

4: Quinquevulenl Phosphorus Acids 117

lithiated 140 followed by acid-induced Paal-Knorr cyclisatiori gives 141 in excellent yield (Scheme 8). The Lewis acid-promoted reaction of trialkyl phosphites with o-phthalaldehyde provides a synthesis of 1 -dialkoxyphosphorylisobenzofurans 142, which in turn undergoes Diels-Alder reactions with a variety of dienophiles to give, for example, 143.13'

0 0 I I R Li I I

(Pr'0)2P-S-Ar - (Pri0)2P-Ar-SH 138 139

EtO, PEt i, ii EtO, PEt (Et0)2PCH2CH2CMe - (Et0)2PCHCH2CMe

I

Reagents: i, LDA, THF; ii, R'C02Et; iii, HCI, H20

140 COR'

Scheme 8

141

0

3.1.3 Halogenoalkyl and Reluted Acids. -- A wide range of a-fluoroalkylphosphonates have been prepared by a variety of methods (fluorinated amino acid analogues are discussed in 3.1.6).

Reactions of a-fluoroalkylphosphonate carbanions are becoming methods of choice since these avoid the use of fluorinating agents in the laboratory. A large number of a-fluoroalkylphosphonates (145) have been prepared by the reaction of the monofluorosilyllithium phosphonate 144 with alkyl halides. 13* Both zinc and copper species have been used to synthesise a-fluoroallylphosphonates. 1337134 A new class of a,a-difluorophosphonate analogues, e.g. 147 and 148, of phosphoenol pyruvate have been prepared by the alkylation of the organozinc phosphonate 146 in the presence of cuprous bromide at room ternperat~re '~~ and the a,a-difluoroallylphosphonates 150 have been obtained by reactions of the radical derived from the coppedzinc compound 149 with terminal acetylenes. 134 Cuprous bromide-promoted coupling reactions of 146 with aryl iodides have been used to synthesise aryl(difluoromethy1)phosphonates 151 in moderate to good yields' 35 while the 4-hydroxyphenyldifluoromethylphosphonate 152 is the product of the Ce"'-mediated reaction of lithiated(difluoromethy1)phosphonate with benzoquinone monoketal. 136 1 -Fluoromethylphosphonocarboxylates 154


are now available in excellent yield by a one-pot reaction of the lithium carbanion 153 with chloroformates followed by acid hydrolysis (Scheme 9).137 Both epimers of (difluoromethy1)phosphonate azasugars 155, designed as inhibitors for glycosyl transferases, have been prepared by nucleophilic ring-opening arabino-, ribo-, and xylo-furanosylamine with (1ithiodifluoromethyl)phosphonate. '38

O F 0 I I I RX I I

(Et0)2P-C-SiMe3 - (Et0)2PCHFR I i i

144 145

0 II 0

I I 0 (Et0)2PCF2CH2CC02H II

146 147 148

(EtO)nPCF2CH=CHC02H I 1 CH2

( EtO)2PCF2ZnBr

0 RCEC-H, DMF I I

0 II

(Et0)2PCF2Cu.ZnBr R *c, P(OW2

F2 1 49 150

0

151

0

152

0 I II iii, iv II

O F O F I I I I I I

I I

0 II

(Et0)2P-CBr2F - (EtO)pPCSiMe3 - (EtO)2P-C-SiMe3 - (Et0)2PCHFCO2R

i i c02r 153

Reagents: i, Me3SiC1, 2 x Bu"Li, THF; ii, CIC02R; iii, EtOH; iv, 2 MHCl

Scheme 9

0

154

i i

BnO R2 155

4: Quinquevulent Phosphorus Acids I19

Methods involving electrophilic fluorination have been used to prepare a number of fluorophosphonates. Examples include benzylic a,a-difluoromethylphosphonates, e.g. 157, by the reaction of the carbanion of 156 with N- fluorobenzenesulfonimide (NFBS) (Scheme lo), which is claimed to be superior to DAST,'39 and (a,a-difluoroprop-2-ynyl)phosphonates 159 by the direct di- fluorination of the a-ketophosphonate 158 (Scheme 1 l).140 Compound 158 is prepared by Pfitzner-Moffatt oxidation of the corresponding alcohol and it is worth noting that few such oxidations of a-hydroxyalkylphosphonates have been reported.

R 0 0 (R0)2PCH2wCH2P(OR)2 R II i, ,i (WzPCF2 II w C F z W R ) z

___)

156 157

Scheme 10

Reagents: 5.5 x NaHMDS, THF; ii, 7.3 x NFluorobenzenesulfonimide, THF

0 0 0 II I I II I1 II II 0 OH

(Et0)2PCHC=CR - (Et0)2P-C-CECR - (Et0)2PCF&=CR 158 159

Reagents: i, 5 x Me2N(CH2)3N=C=NEt.HCI, CI2CHCO2H, DMSO, PhMe, 0 "C; ii, 20 x DAST, CH2C12,O "C

Scheme 11

A solution to the problem of attaching a difluorophosphonato group to a secondary carbon centre is provided by Diels-Alder reactions of the dienophile 160 to give, for example, 161 and 162. 14' Trifluoromethylated cyclopropylpho- sphonates 164 have been conveniently synthesised in moderate to good yields by the reaction of phosphorus or arsenic ylides with diisopropyl (E)-(3,3,3- trifluoroprop- 1 -en- 1 -yl)phosphonate 163; the arsenic ylide reactions give higher yields and require milder conditions. 142 Phosphonate-containing fluorinated vinyl ethers, e.g. 165, have been prepared as monomers for specialist polymers using an alkylation reaction of tetraethyl pyrophosphite as the key step (Scheme 12).143 A number of co- and ter-fluorocarbon polymers containing phosphonate and phosphonic groups have been reported. '44 These polymers can be processed into films and show promising electrochemical properties. The phosphatase inhibitor 166, designed from an X-ray structure of a PTPlB- bound ligand, has been synthesised in twelve steps from 1,3-dihydroxynaphthalene. 145

Syntheses of a-chloroalkylphosphonates include a-bromo- and a-iodobenzyl- phosphonates 167 by reaction of suitably activated ol-hydroxybenzylphospho- nates with ally1 bromide or methyl iodide146 and dichloroalkylphosphonates 168, and hence chloro alkynes and terminal alkynes, from diethyl trichloro- methylphosphonate. '47 A variety of approaches to 1 -chloroalkylphosphinates 169 have been investigated and the best method is reported to involve

120 Orgunophosphorus Chemisrry

?Me OM.

h 161

162 X = C&Et, N a , SOzPh YnCH.0

x = P. As 163

i - CF2CICFCIO(CF2)3P(OEt)2

.. 164

it - CF2=CF-O(CF2)3P(OEt)2 1 in

R CF2=CF-O(CF2)3P(OEt)2

165 Reagents: i , (EtO)2P-O-P(OEt)2, hv, CFpQCFCI,; ii, Zn, DMF; iii. H A , OMF

Schomr 12

OH I

monochlorination at phosphorus of diethyl 1 -chloroalkylphosphonates followed by P-C bond formation by reaction with Grignard reagents (Scheme 13).'48 The synthesis of amides and esters of dichloromethylenebisphosphonates 170 by phosphorylation of the appropriate phosphorus-stabilised carbanion has been reported. 149

3.1.4 Hydroxyalkyl and Epoxyalkyl Acids. - The reaction of aldehydes or ketones with dialkyl hydrogenphosphonate continues to be widely used for the synthesis of a-hydroxyalkylphosphonates' 50715' and magnesium oxide has been reported to be an effective catalyst for the reaction.I5' The reaction has been used in enantioselective synthesis. For example, in the preparation of chiral a$- dihydroxyphosphonic acids 171 and 172 (Scheme 14), with preferential formation of the syn-isomer 171 ,Is2 and the statin analogue 2-amino- 1 -hydroxy-3- phenylpropylphosphonic acid (173) (Scheme 15). 153 Catalytic asymmetric

4: Quinqucvolent Phosphorus Acids 121

0 POClJ II R2MgCI II

1

0 0 II

(Et0)2PCHCIR’ - CI-P-CHCIR’ - R2-PCHCIR2

OEt

Scheme 13

OEt 169

R z ,P-CCI2-P<

0 Z,ll

Z Z 170 Z = OR, NR2

0 OR’

(Et0)2POSiMe3 + (EtO)z!J’ R2 + (Et0)2k&2 1

a

0 OH OH 171

Scheme 14

i,ii H

P(OH12 R’oTNyCHo Ph - 173 0

I1 Reagents: i, (Et0)2PH; ii, HCI, H20

Scheme 15

OH

0 Scheme 16

OH

0 Scheme 17

172

synthetic methods giving up to 95% ee and involving chiral lanthanoid and titanium alkoxide catalysts (Scheme and lanthanoidbis(BIN0L) (LLB) catalysts (Scheme 1 7)’55 have been reported.


The enantiomers of a number of 1 -aryl- 1 -hydroxymethanephosphonates have been separated by chiral HPLC'56 and 1-acyloxyphosphonates 174 and 175 have been resolved by lipase-catalysed hydrolysis to give individual enantiomers of the corresponding 1 -hydroxyalkylphosphonates. 57 Phosphonate analogues, e.g. 177, of sialic acids have been prepared' 589159 by the indium-mediated allylation of unprotected carbohydrates 176 in aqueous solution (Scheme 1 8).15' Note that the ozonolysis step incurs loss of carbon and generates an aldehyde which cyclises to give the product shown.

OCOR2 I

0 174 R' = PhCH2CH2, R2 = CH2CI 175 R' = R2 = Me

H : o T O H . l-ili ... ~ HO*FtoH)2 AcNH

HO 176 177

N HAc t!iua, 176

H d

Br, EtOH, H20; ii, 0 3 , MeOH, -78 "C; iii, Me2S, MeOH, -78 "C

Scheme 18

2-H ydroxyalkylphosphonates have been prepared by reduction of the corresponding ketones. These include phosphonomalate esters by highly diastereoselective reduction of 3-phosphonopyruvates with NH3.BH3I6' and both 2- hydroxyalkyl-phosphonates, e. g. 178, and thiophosphonates by asymmetric hydrogenation using chiral ruthenium catalysts. 1 6 ' An enantioselective synthesis, from 179, of both enantiomers of phosphonothrixin 180 and their absolute stereochemistry have been reported.'62 The epoxide 179 was prepared from 2- methyl-3-hydroxymethyl- 1.3-butadiene via a Sharpless epoxidation.

OH 0 (S)-BINAP It

MeCOCH2P(OEt)2 !? * Me&p(0w2

1 78 Ru cat., H2

&!tOHl2

HO OH 1 79 180

3.1.5 Oxoalkyl Acids. - P-Ketophosphonates have been synthesised in good yields by treatment of the carbanion of diethyl phosphonoacetic acid with acyl


chlorides (Scheme 19).'63 The reaction of enamines derived from cyclic ketones with P'" chlorides, followed by oxidation is also reported to provide p- ketophosphonates. These reactions offer alternatives to the Arbuzov reaction of a-halogeno ketones, which often give poor yields. y,&-Unsaturated p- ketophosphonates 181 have been prepared in two steps from tertiary a-allenic alcohols 182 and used in the synthesis of the terpenoid (Q-a -a t l an t~ne . '~~ The reaction of a,P-unsaturated monoterpenic ketones with the anion of diethyl hydrogenphosphonate results in Michael addition to give, e.g. 183 from (+)-2- caren-4-one in excellent yield. 166

8 i ii R (Et0)2PCH&02H - (Et0)2PCH2COR

Reagent: i, BuLi, THF; ii, RCOCl Scheme 19

OH

R' &c+cH2 Me Me R2

181 182 183

a-Ketophosphonates are readily enolised and an X-ray structure of 184 (R = Ph) shows the enol tautomer in the solid state.167 Compounds 184 are converted into the corresponding enolacetates 185 at room temperature on treatment with acetic anhydride and triethylamine. The major interest in a- oxophosphonates stems from the antiviral properties of phosphonoformates and their analogues. The instability of phosphonoformic acid and anion creates many synthetic problems. A novel esterification method involving the reaction of phenyl dichlorophosphonoformate with silyl ethers has been used to prepare 186 (Scheme 20).'68 These esters were tested against HSVl infected human lung fibroblast cells and in some cases were more active than the current drug Foscarnet 187. Various bioreversible prodrugs, e.g. 188, of Foscarnet have been prepared and their hydrolysis, in vivo systemic bioavailability, and antiviral activity e~a1ua ted . l~~ Compound 188 was the best prodrug of those studied. Four novel functionalised acylphosphonates, 189, 190, 191, and 192 have been synthesised by Arbuzov reactions of the corresponding acyl chloride and evaluated as phosphonoformate analogues. I7O

3.1.6 Aminoalkyl and Related Acids. - The continuing and increasing interest in aminoalkyl-phosphonates and phosphinates has led to a large number of preparative reports incorporating a wide range of synthetic methods. The addition of dialkyl hydrogenphosphonates to imines continues to be a popular approach. Examples using this method include the synthesis of 1 - (benzylamino)benzylphosphonates 19317' and 1 -(2-furyl)aminomethylphosphonic acid (l!~)'~~ and phosphonates 195. 173 In the last case chirally-substituted imines


184 R = Ph, Me 165

0 OH

I

f i, ii II I PhOCOPC12 - PhOCOP-OCH2CHR f PhTjH3

0- 186

Reagents: i, RCH(OSiMe3)CH20SiMe3; ii, H20, dioxan, PhNH2

Scheme 20

0

- 0 0 0,II II P h O C O ! - O C H 2 ~ C O R I - Ho>y P-0- Na’

-0’ 0- Na+ 0- Na+ P-C-O-

187 188

Me%;;O- 0 Na’

0- Na+

0 190

NH2 Ar

0

(f3O);dA NHCH2Ph

193 194

189

191 R = H 192 R = M e

HOCH2 ,0(-&!(0Ct+ Ph)2

HN,;e Ph

195

are used and moderate levels of diastereoselectivity are obtained. Related condensation methods such as the Pudovik and analogous reactions continue to be investigated. For example, a wide range of 1 -aryl- 1-aminomethylphosphonates have been prepared in moderate to good yields by the reaction of aryl aldehydes, hexamethyldisilazide and diethyl hydrogenphosphonate using solid acidic alumina as a catalyst (Scheme 21)’74 and phosphinate analogues 196 have been obtained from multi-component reactions of dichlorophenylphosphine, benzylcarbamate and aryl aldehydes using acetyl chloride as solvent. 175 Various novel aminoalkylbisphosphonates, e.g. 1 W, have been prepared using dialkyl acetals 198 as synthetic equivalents of formylphosphonate. 176 The ethyl phosphonite acetal 199 has also been used to synthesise aminoalkylphosphinates 200 but in this case presumably as a protecting group.”’

The Beckmann rearrangement of oxime mesylates initiated by Tic14 has been applied to the preparation of 1,2-dehydro- 1 -aminoalkylphosphonates, e.g. 201, through trapping of the intermediate with triethyl p h 0 ~ p h i t e . I ~ ~ Oximes of a- ketophosphonates are often difficult to reduce to the corresponding 1 -aminoalk-

4: Quin y ue vulen t Phosphorus A cicis 125

N+CHAr f/ A1203 ArCHO + HN(SiMe& + (Et0)2PH -

(acidic) Ar P(OEt)2

Scheme 21

NHCbz NHCbz

,( ,CI RXH /I ,XR f: CH3COCI

Ph Ar F\Ph Ar PhPC12 + PhCH20CNH2 + ArCHO -

0 197

H 199

0 0 196

CH~CONH 200

ylphosphonate and normally require the prior formation of oxime esters. An alternative method of conversion, involving oxidation to the 1 -nitro compound followed by reduction, has now been reported (Scheme 22).'79 Reductive amina- tion of ct-ketophosphonates has been used to prepare 202 in poor to moderate yields (Scheme 23).'" The success of the reaction depends on the amine and of those used only diphenylmethylamine provided a product. However, similar reactions with fLketophosphonates were successful using a variety of amines. High levels of asymmetric induction (>970/0 ee) have been achieved by the asymmetric hydrogenation at low pressure and 30 ?C of 1 -(formamido)alkenyl- phosphonates 203 using (3- and (R)-BINAP complexes as catalysts. Indivi- dual enantiomers of a wide variety of 1 -aminoalkylphosphonates have been obtained by separation of their N-3,5-dinitrobenzoyl derivatives by chiral HPLC using fluorocarbinol stationary phases. 18*

The Rh" acetate catalysed decomposition of dimethyl a-diazobenzylpl lospho- nate (204) in the presence of primary amines and amides offers a simple route to the corresponding a-aminophosphonates. 183 I -Aminocycloalkylphosphonates 205 have been synthesised from the corresponding cycloalkylphosphonate via electrophilic azidation of the phosphonate carbanion followed by catalytic hydrogenation. lg4

Phosphono analogues 206 of glutathione have been prepared as inhibitors of glutathione S-transferases. 1 -Aminophosphonate structures have potential as haptens in a number of areas and examples of such compounds reported include 207'86 and 208. *87 The N-hydroxy-1 -aminophosphonates 208 were prepared from


i

Reagents: i, I , CH2C12; ii, LiBH4, Me3SiC1, THF b,, Scheme 22

0 Reagents: i, Ph2CHNH2, THF; ii, NaBH(OAc)3; iii, HCI, H20; i v , , & J

R = Me, Et, Bu', PhCH2CH2,

Scheme 23

202

NHCHO

205 n = 1,2,3

the corresponding 1 -hydroxyalkylphosphonates using a Mitsunobu reaction (Scheme 24) for use in raising antibodies capable of kinetically resolving N- hydroxy-a-amino acid derivatives.

Various solid-phase syntheses have been reported including the phosphinic acid dipeptide analogues 209 which were constructed by coupling the appropriate Wang Resin-bound amino acid to the phosphinate carboxylic acid 210 using Fmoc chemistry. I** Similar phosphinate carboxylic acid derivatives (21 1) protected at phosphorus as their 1-adamanyl esters have also been used in solid- phase synthesis directed towards zinc metallo protease inhibitors. 18'


NH2

206 R = Me, Et, Pr', Bu

OH

RAP(OCH2Ph)2 II Ph02C I 0 II

0 + L Bac,o,NyP(ocH2Ph)z PhOCONHOBoc

R

. OH 207

Ph02C 0 I I1

P(OCH2Ph)2 H O K N y

R 208

Reagents: i, DEAD, Ph3P, THF, room temp.; ii, TFA, CH2CI2

Scheme 24

R'

209 R = H, X = NH-amino acid 210 R = alkyl, X = OH

(1 -idamantyl) 21 1

An efficient asymmetric synthesis of P-aminoalkylphosphonates 212 via addition of phosphonate carbanions to enantiopure sulfinimines has been reported (Scheme 25).190 A range of novel 3-phosphonocyclobutyl amino acids have been prepared via the versatile intermediate 3 -0xocyc10 bu t ylphosphonate (2 13) (Scheme 26).19' Sphingosine- 1 -phosphonate (215) has been synthesised from the 2-NY3-0-protected 1 -0-mesyl derivative 214 of sphingosine via conversion to the bromide and an Arbuzov reaction with trimethyl phosphite. 192 Chain extension of 215 provided a route to homo-sphingosine- 1 -phosphonate (216).

The synthesis of various phosphonate analogues of aspartic acid, glutamic acid and their homologues and serine phosphate have been reported. The kynurenine phosphinic acid analogue 217 and the corresponding phosphinate 218 have been synthesised from N-protected 2-amino P-propiolactone (Scheme 27). '93 Kinetic resolution was achieved by esterase-selective hydrolysis of the carboxylate group in the diester.

The CHF and CF2 groups are superior to CH2 as isosteres of oxygen and this has led to extensive interest in their chemistry. The a-difluorophosphonate analogues of the phosphates of L-serine (219), L-threonine (220), and L-allothreonine (221) have been prepared by highly enantioselective reactions of difluoromethylpho- sphonate carbanion with chiral esters.'94 Lipase PS catalysed acetylation of prochiral 173-propandiol alkylphosphonates 222 is reported to be highly enantioselective and the resulting monoacetate enantiomers 223 have been used to synthesise a series of o-phosphono-a-amino acids, 224 and 225.'95 Other routes to 225, one of


Reagents: i, (R0)2hle, NaHMDS, THF, -78 "C; ii, 2 x TFA, MeOH, 3h, room temp.

Scheme 25

21 3

J v, vi

0

H 2 N e ;(OH),

Reagents: i, BuLi. THF; ii, -)-Oh; iii, H2, Pd/C, MeOH; iv, NaI04, RuC13, CH2C12, H20; CI

v, NH*OH, H20; vi, H2, Rh/AI2O3, MeOH

Scheme 26

NHCbz 217 R = H 218 R = Me

Reagents: i, PhP(OMe)*; ii, 6MHCI; iii. Medo, EtOH

Scheme 27

0 B Y E " ~ c F < P ( O E t ) 2 I I

C0pH 219 R = H 220 R = -Me 221 R = - - - M e

0 NH2

H02CJ'(CHz)fx2 b((OEt)2 Ho>z-iiOEt)2 HO AcO ''>Z-!(OEt)p

222 223 Z = CHp, CH2CH2, CH2CF2, CH20 224 X=H, n = 0 , 1 225 X=F, n = l


which gave a single enantiomer, have also been reported.J96A number of non- fluorine containing o-phosphono-cr-amino acids have also been prepared. (9-2- Amino-2-methyl-4-phosphonobutyric acid 227 has been obtained, as an antagonist for metabotropic glutamate receptors, from L-alanine via reaction of diethyl phosphite anion with the iodide 226 (Scheme 28). J97 Alternative syntheses involving the addition of carbon nuclcophiles to various phosphonates have been reported. These include preparation of 2-imino-5-phosphonopentanoic acid derivatives 229 by the Pd(0)-catalysed Michael addition to the vinylphosphonates 228, 19* and highly diastereoselective, similar conjugate additions of Schollkopf's bislactim (230) to give 232 and 233.200 Enantioselective synthesis of both

226

? Reagents: i, (Et02)PNa, PhH, 80 "C; ii, 6 MHCI, reflux; iii,

Scheme 28

228

0 R2 CO2Et Pd(O), base P

Ph

229

Me OEt

OEt 230

232

MeYPh

? Reagents: i, B,-P(OEt)2; ii, 6MHCI; iii,

Scheme 29


enantiomers of 2-amino-6-phosphonohexanoic acid 234 has been achieved by highly diastereoselective alkylation of imidazolidinones (Scheme 29).20'

A variety of phosphonate analogues of tyrosine phosphate and related structures have been reported. These include ~-2,3,5,6-tetrafluoro-4-(phosphono- methy1)phenylalanine (236) which was obtained through alkylation of the

CH2Br 0

Ph F*l __ ( H o ) ' ' c H ~ ~

so2 0 Ph F C02H

y 2 F

& N f l N + +

235 236 (RO)2P=O

Me.- qj, mMe OH j(0Et)2 Me..+OH 3(0Et)2

___) + / / /

\ \ \

CbzNH CbzNH CbzNH

C02Me C02Me C02Me

J ii-iv 237

0 II

HO P(OEt)2

CbzNH 3- CbzNH $j C02Me C02Me

238 239 Reagents: i, (Et))3P, TiCI4, CH2CI2; ii, Swern oxidation; iii, pTsOH, H20; iv; 3% HCI, MeOH;

:: v, (Et0)2PH, THF, AI-Li-(R)-BINOL

Scheme 30

0"7(0H)2

R < q

H2N ' C02H

240 X, Y, Z = N or CH

H2N*CO2H

241


camphor sultam carbanion 235 with de values as high as 94Y0202 and hydroxy- methylenephosphonate analogues, e.g. 239, which were converted into their monofluoromethylenephosphonate analogues.2o3 Compound 239 was obtained by two separate routes: enantioselective phosphorylation of the C2 symmetric acetal 237 with triethyl phosphite and asymmetric addition of diethyl phosphite to the aldehyde 238 in the presence of Al-Li-(R)-BINOL as a catalyst (Scheme 30). Various related heterocyclic analogues which are NMDA antagonists, e.g. 240 and 241 ,204 including 14C-labelled examples,205 have also been prepared.

Reports of syntheses of phosphonopeptides include a new, efficient approach to the antineoplastic agent sparfosic acid (242).206 An ion-pair reverse-phase HPLC method for the separation of phosphonodipeptides has been developed.207

CO~BU' C02H I I CH 0 y 2 I I :: - - (H0)2PCH&ONHCHCQH

H2N A:02Bd 242 (Et0)2PCH&02H +

3.1.7 Sulfur- and Selenium-containing Compounds - a-Sulfenylation and a- selenylation of 1-phosphoryl sulfoxides 243 has been used to prepare the a- methylsulfenyl-a-phosphorylsulfoxides 244 and the analogous a-phenylselenides with low levels of diastereoselectivity.208 Similar sulfenylation of (+)-(S)- dimethoxyphosphorylmethyl p-tolyl sulfoxide (244, R' = Me, R2 =p-tolyl) followed by Wadsworth-Emmons olefination provided an enantioselective

0 SMe I I I I BuLi, MeS02SMe I I I

( R'0)2PCH2SR2 * (R'0)2PCHzR2

0 243 244

(R)- Or (9-246

Reagents: i, [MeNCS],; ii, HCI, H20, CH3CN; iii, H202, AcOH, HC02H; iv, KOH, H20

Scheme 31

catalyst 8 /ZR2 0 II

(R10)2PCH=N2 + R2Z-ZR2 - (R10)2PCH, ZR2

247 Z = S 248 Z = S e


synthesis of ketene dithioacetal mono-S-oxides. The synthesis of individual enantiomers of the a-phosphono sulfonate 246, a potent squalene synthetase inhibitor, via sulfurisation of the chiral phosphonate carbanion 245 has been reported (Scheme 31).*09 Formal carbene insertion into S--S and Se-Se bonds to give dithio-247- and diseleno-248-acetals has been achieved by the decomposition of diazomethylphosphonate using a variety of catalysts.*"

Lawesson's reagent has been used to convert a,a-difluoromethylphosphonates into the corresponding sulfides 249 in good to excellent yields.*" The sulfides 249 can be converted back into the phosphonates by treatment with either dimethyl- dioxirane or perfluoro-cis-2-butyl-3-propyloxaziridine. The naphthalene deriva-

0 S I1 Lawesson's I -1

R ' C F ~ P ( O R ~ ) ~ - R 'CF~P(OR~)~ reagent

249

: O - @

s,, ' S , SQP p//s ks'p*s MeO' 'S' 'OMe

250 251

30 x HOCH2CH20H. PhMe

s,, 3, p's'p*s

252 253

254

But I

255 256

\ Ph

257


tive 250 of Lawesson's reagent has been prepared by the reaction of 1- methoxynaphthalene with P4S10.2'2 The reaction of 250 with methanol gives 251. Similar reactions of the unsubstituted naphthalene analogue 252 with a large excess of ethylene glycol in refluxing benzene to give 253, or at higher temperature to give 254, have also been reported.*13 New phosphorus-sulfur- and -seleno-heterocycles have been prepared. For example, 256 from 1,2,4- triphospholes 25S214 and 257 from the reaction of Lawesson's reagent with y- ketophosphonate~.~'~

3.1.8 Phosphorus-Nitrogen Bonded Compounds. - Various reports on the synthesis and chemistry of N-diphenylphosphinylimines have appeared. These include the synthesis of novel N-diphenylphosphinyltroponimine (258), which as might be expected is highly polarised with a low lying LUM0.2'6 Reactions of 258 with enolates or enamines of cyclic ketones gave low yields of azaazulene derivatives, e.g. 259. Asymmetric synthesis of aziridines 261, and hence monochiral cis-aziridine carboxylates, has been achieved by an am-Darzens condensation of N-diphenylphosphinylimines with the chiral enolate 260 derived from bromoacetylcamphorsultam.2'7 Other examples of N-

258 259

THF. -78 "C

260 261 0 I I PPh2

Ph2P-N=CH 0 I I O R + CH2=CH-C\H ?' - ZhCI2 &- 262 Li R

0 I I

PhpPN=CHFc + R2Zn

0 I I

Fc-bH-NHPPh2

263

I R

I34 Orgunophosphorus Chemistry

diphenylphosphinylaziridines reported include 262 which undergoes efficient SN2' ring-opening with a variety of nucleophiles.2'8 Optically active N - (diphenylphosphiny1)-ferrocenyl amines 263 with good e.e.s have been prepared by the asymmetric addition of dialkylzinc compounds to ferrocenyldiphenylphosphinylimines in the presence of chiral p-amino alcohol^.^'^

Chird phosphorus-nitrogen compounds, especially 264220 and analogues, have been used extensively in asymmetric synthesis and examples are given elsewhere in this chapter. The chiral catalyst 265, combining a phosphinamide and a dioxaborolidine, has been prepared and used in the asymmetric reduction of ketones to give e.e.s up to 59Y0.~~'

Ph Ph

3. I . Y Phosphorus-containing Ring Systems. - A range of new chiral oxazaphospholidine oxides 266 and 267 have been synthesised and used as catalysts in asymmetric reductions of ketones with diborane.222 Mannich-type cyclisation reactions of 5-amino-3-benzylthio-4-cyano(ethoxycarbonyI)pyrazoles with dichlorophenylphosphine and aromatic aldehydes in the presence of cation exchange resin have been used to prepare a number of 6-oxo-6-phospha-4,5,6- trihydroimidazolo[ I ,2-b]pyrazoles, e.g. 268.223 Some of these compounds have herbicidal activity and this report is typical of a number of similar ones in the Chinese literature. A number of metallocycles, e.g. 269, have been reported as products from reactions of transient zirconocene-benzyne intermediates with phosphaimines followed by sulfuration or ele en at ion.^^^

266 267 268 269 X = S, Se

Addition of methyl phosphinate to 2-(R)-methoxy-3-oxapentanedial gives, after acylation, all possible diastereoisomeric 3-phosphapentopyranoses (270) in very poor yield.225 The synthesis of novel 1,3-oxazacyclophosphamides, e.g. 271, bearing a sugar structure has been achieved by the reaction of amino sugars with phosphoric chlorides.226 Facile synthesis of the phosphorus heterocycles 273 and 274 has been accomplished in a one-pot reaction by the in situ generation of bis(trimethylsi1yl)phosphonite (272) from ammonium phosphonite followed by


Reagents;

270

0 TMSO, I I

i [ P-H HRP-H - ONH4 I T M S ~

272

i, Pr12NEt, TMSCI; ii, 8

275

Scheme 32

CH20H 0 II P

H2,Pd/C, UMe 0 DCC, o0 F;Y w DMAP, THF

$‘OR & I i R 276 277 278 R=H, Y =CH2

279 R = Me, Y = 0

0

PhP ----c W(C0)s 283

e n ’ 281

- /P, O 1‘0

282 OH

284


alkylation (Scheme 32).227 Phosphinane 1 -oxides 276 have been obtained by hydrogenation under medium pressure of the bicyclic dichlorocyclopropanes 275, themselves synthesised by dichlorocarbene addition to 2,5-dihydro- 1 H-phosphole oxides.228 1 -0xo-2-oxa- 1 -phosphabicyclo[2.2.2]octane 278 has been prepared by a multi-step sequence from hypophosphorous acid, the final step involving intramolecular esterification of the 1 -hydroxy- 1 -oxophosphorinane 277.229 In strong base (278) hydrolyses two orders of magnitude faster than the bicyclic phosphate 279, a rate enhancement which is attributed to the greater ease with which 278 achieves the penta-coordinate transition state. The cyclic phosphonate 280 adds to imines and aldimines in the expected manner to give, for example, 281.230 However, reaction of 280 with chloral (but not other aldehydes tried) leads to an unusual ring-expansion to give the benzodioxaphosphepinone 282. The heterocycles 284 and 285 have been synthesised by trapping of the phenyl- phosphidene complex 283 with benzophenone and fluorcnone, re~pectively.~~'

3.2 Reactions of Phosphonic and Phosphinic Acids and their Derivatives. -- 1-(3- Pyridy1)- 1 -aminomethylphosphonate esters undergo normal conversion to the corresponding phosphonic acid on acid hydrolysis. However, the 2- and 4-pyridyl isomers, 286 and 287 respectively, suffer P-C bond cleavage to give the aminomethylpyridines and phosphoric acid under the same conditions.232 On basic hydrolysis of 286 and 287 no P-C bond cleavage occurs and the monoesters are the only products. 2-Fluoro-3-oxo-2-phosphonoacetates 288 also undergo P- C cleavage on treatment with magnesium chloride fluoro-2- ket o esters. 233

NHR 20% HCI - ArCH2NHR

Ar P(OEt)2

and so provide a route to 1-

+ (H0)3P=O

286 Ar = a 287 A r - 0

COR 288

The reaction of diphenyl methylphosphonate with lithium alkoxides gives phenyl alkyl methylphosphonates even with hindered alcohols and, in the case of chiral alcohols, with high diastereoselectivity at phosphorus.234 [Hydroxy(pho- sphoryloxy)h)iodo]benzenes 289, prepared from reactions of iodosobenzene with phosphonic or phosphinic acids react with ketones, esters or phenyl acetylene to give esters 290.~~' Racemic 1 -hydroxy-4-(3-phenoxyphenyl)butylphosphonate diethyl ester undergoes stereoselective acetylation in the presence of a lipase to

4: Quinqiievalent Phosphorus Acids 137

give the (9-(-)-acetate 291 in up to 95% optical purity (see also ref. 209).236 A kinetic study on the alkaline hydrolysis of 4-substituted-phenyl ethyl benzylphosphonates has been reported and the results interpreted in terms of an associative mechanism.237 Uranyl cations mediate the hydrolysis of aggregated and non- aggregated 4-nitrophenyl phosphodiesters under mildly acidic conditions, giving rate enhancements of up to 1000 fold.238 Phosphinic acids, which can act as inhibitors of metalloproteases, are frequently made by the hydrolysis of the corresponding esters in the final step in their synthesis. It is now reported that the acid hydrolysis of such esters, e.g. 292, is accelerated by the presence of an amide

The selenophosphate 293 reacts with terminal acetylenes in the presence of a palladium tetraphosphine catalyst to give vinylphosphonates 294.240

0 & R4 R4 0 ! R' MeCN I1 R3

(PhlO)" + HOP< - Ph-I-0-P-R' I

R2 OH A2 289 O 290

R 3 mol%, PhSeP(OPh)2 + RC=CH

Pd(PPh3)4, THF PhSe 0 293 294 R = alkyl or atyl

Theoretical studies have led to the choice of (1 S, 2S)-1 -phenyl-2-benzy1-2-(2- propy1amino)ethanol as the chiral auxilary in the 1,3,2-0xazaphospholane 295 for use in stereoselective electrophilic a m i n a t i ~ n . ~ ~ ' The experimental results confirm the theoretical studies, de values up to 83% being obtained (Scheme 33).

Reagents: i, LDA; ii, Bub2CN=NC02But Scheme 33

Regioselective alkylation of ketones has been achieved using phosphonate as a temporary-activating For example, alkylation of P-ketophosphonates gives 296 which are dephosphorylated to form the corresponding substituted ketone 297 on treatment with butyllithium followed by LITHAL. The reaction of salicylaldehydes with phosphonoacetates and phosphonoacetonitriles under


Knoevenagel conditions has been investigated and shown to provide 1,2-benzoxa- phosphorins 298 and 299, the ratio of which depends on the reaction condi- t i o n ~ . ~ ~ ~ Michael addition reactions of vinylphosphonates continue to be used in synthesis. Such additions of compounds containing an active methylene group has been used to prepare 6-oxoalkylphosphonates, e. g. 300.244 Base-induced Michael additions of various secondary biphosphines to vinylphosphonates have been used to prepare water-soluble diphosphine tetraphosphonates 301 for use as ligands for dioxorhenium compounds.245 The stereochemistry of the tin tetrachloride-promoted reaction of both pre-coordinated and free P,y-unsaturated-a- ketophosphonates 302 with silylenolates has been investigated.246

0 0

( E t O ) i d 6 R 3 i’ BuLi R’&R3 ii, LiAIH4

R 2

297

Ri ‘R2

296

Y = C02R2, CN

Ph 0 1

0

298 299

0 I I

o’2pnco2Et NaOMe

DMF ( R 1 0 ) 2 b ( 4 + R’CH2C02Et -

Ph R2 300

0 4 x p ; ( O R ) Z f: ?

H2P-X-PH2 * [( R0)2PCH&H&P-X- P[CH2CH2P(OR)2]2 301 KOBU‘

x =El, CH2CH2

0 II

(Eto)2pY+Me 0

302 SnCI4 + ___)

Me Ph

0 Me 0

(Et0)2pv+#; II OSiMe3

Me

Harger and his co-workers have continued to investigate substitution and other reactions of P(V) acid derivatives which show unexpected comparative rates or


rearrangements. The diamide 305 is formed more quickly from the reaction of diethylamine with the dichloride 303 than from a similar reaction of the amidic

s c I I I/ / PhCH2P\

304 NEt2

S //

PhCH=P\

CI 306

chloride 304247 A reasonable explanation

2 PhCHpP(NEf&

305

S //

PhCH=P \ NEt2

307

for these results, and one which has been used previously for analogous observations, is that the reaction of 303 proceeds viu an E1,B-like elimination to give 306 and 307 as intermediates. The reaction has also been shown to be very sensitive to the acidity of the benzylic C- H bond in 303.248 Three-membered rings containing phosphorus have been suggested as intermediates to explain rearrangements and observed stereochemistry. The base-induced rearrangement of N, 0-di-derivatives of hydroxylamine, e.g. 312, is well known. However, in the case of 308 and 309 the N- and 0- phosphinoyl groups can change places, possibly via the phosphorane intermedi-

0 0 II II

Ph2PNHOPAr2

308 Ph, Ar\ .Po IP\ II + ,p\ II

0 8 7 PhNH OPAr2 ArNH OPAr2 II 310 31 1

Ar2PNHOPPh2 309

/p 0- 0- o* I PAr2

Ph2p\N-bAr2 \ / Ph2P-N' \ / 0 0

31 2 31 3 31 4

BCH2

0 0 0 R4N+ -0Me II II II

0 II

A NHBU'

- -P-OR CH2--P-OR - MeO--P-OR + MeO--P-OR 4

MeOH'THF * [ 'N&' ] ButNHCH2 Me+ ( S p)-3 1 5

R = k' ge Me

31 6 31 8 BU' 317


ates 313 and 314, before rearrangement and so both compounds give similar mixtures of products 310 and 311.249 The (&)-isomer 315 of the phosphonami- date derived from (-)-menthol undergoes rearrangement on treatment with methoxide to give a mixture of 318 entirely as its (&)-isomer and 317 very largely as its (Sp)-isomer.250 It is suggested that the reaction proceeds via the azapho- sphiridine oxide intermediate 316 which undergoes methoxide-induced ring- opening in two modes, P-N bond cleavage to give 317 with retention of configuration at phosphorus and P-C cleavage to give 318 with inversion at phosphorus.

a-Diazoalkylphosphonates have proved increasingly useful synthetic intermediates and interest in their chemistry continues. Carbene or carbenoid intermediates are readily formed on catalytic decomposition of these compounds and examples of insertion into a l k ~ l - H , ~ ~ ' N-H,252 S-S and Se-Se,253 and Ar-H254 bonds have been reported. Trans-3-carboxy-2-(diethoxyphosphoryI)cyclopentanone (320), a key precursor of sarkomycin, has been prepared by rhodium acetate-catalysed decomposition of 319 followed by o ~ o n o l y s i s ~ ~ ' and, using the same catalyst, 1- ethoxycarbonyl- 1 -diazomethylphosphonate 321 reacts with the N-H bond in carbamates, amides, ureas or aromatic amines to give access to a range of N - substituted-2-aminophosphonates, e.g. 322.252 The products from the reaction of a-diazomethylphosphonate with disulfides and diselenides depend on the catalyst and conditions For example, in the presence of boron trifluoride-etherate dithio and diseleno acetals 323 are formed while the use of rhodium acetate converts disulfides into 1 -thiomethylphosphonates 324. The rhodium(1 I) catalysed decomposition of a variety of a-diazo-P-ketophosphonates, e.g. 325, has been studied and shown to give mixtures of products, e.g. 326 and 327, from Wolff rearrangement and C-H insertion reactions, respectively.254 Thermolysis of 1 - diazo-2-oxo-(2-N,N-disubstitutedaminophenyl)ethylphosphon~tes gives rise to 2-

0 0 0

Rh(0Ac)d @ Ef)2 03. MeOH &'I P(OEt)2 - - CH2C12

- N2 C02H

319 320

0 0 II R'NH2 II

( E t 0 ) 2 p ~ C 0 2 E t Rhp(OAc)4, PhCHJ (Et0)2pxc02Et H NHR' N2

321 322

BFS.Et20 f: /XR2 0 II

(R10)2PCH=N2 + R2X-XR2 - (R10)2PCH, XR2

CHzC12

323 X = S , S e

0 0 II RMOAch I I

(Me0)2PCH=N2 + R-S-S-R (Me0)2PCH2SR 324

CH&


O*P(OMe), OH 0 "G 0 0 Me)2 RIG 11% Me)2

/ R2 \ Rh" R2 / - +

/ x \ x \ x 325 326 327

oxoindolinium salts 328 via intramolecular trapping of the Wolff rearrangement product and the ylide 329 by direct attack of the carbene on nitrogen.255 The carbanion of the a-diazomethylphosphoramidate 330 reacts with diaminochlor- ophosphines to give nitrilimines 331 (Scheme 34).256 Variable temperature NMR studies on examples containing chiral substituents demonstrate that 331 possesses

0 0 I I i ii

( Rpl N)2PCHN2 - (R2' N)2b(- C=iJ=N-P( NR22)2 330 331

Reagents: i, BuLi; ii, CIP(NR22)2 Scheme 34

5

S I I t

332

tc0,NPh c 4 R21 pRpR21 II

Rp1P-C=C=NPR2' *

0 0 Ph I R2X 333

R2';R2 x- S & m Na

X- 1

' H 334 R2'p*S

335


a bent allenic structure. The phosphine nitrilimines 332 undergo [2 + 31 cycloaddi- tions with electron-poor dienophiles to give, e.g. 333, while the nitrilimine phosphonium salts 334, obtained by alkylation of 332, undergo cycloaddition to electron-rich dipolarophiles such as norbornadiene to give 335.257

a-Oxoalkylphosphonates have potential in synthesis due to their high reactivity. The phosphonothioformate 336 reacts with hydroxylamine in pyridine to give mainly diisopropyl phosphoramidate (338).258 The reaction is suggested to involve initial formation of 337 followed by a Lossen rearrangement and the observation of a transient intermediate, possibly 337, by 31P NMR supports this. The oximes, e.g. 339, of methyl benzoylphosphonamidates undergo Beckmann rearrangement on refluxing in toluene to give N-benzoylphosphorodiamidates, e.g. 340259 while diethyl benzoylphosphonate (341) undergoes lanthanoid- induced reactions with electrophiles;260 for example, benzaldehyde and oxirane give 342 and 343, respectively.

336 337

PhCH3 0 NOOH

I heat

NH2OH II II MeOrCOPh - MeOP-C-Ph - 0

II

NEt2 NEt2

339

0 I I

(P$O)qPNH2

338

0 II

I MeO-P-NHCOPh

NEt2 340

0

Sm12 I

R PhCHO II (Et0)2PCOPh - (Et0)2PCH-OCOPh

Ph 341

SmI2 1 &Et

PhC02CHCH2I I Et 343

342

Double labelling has been used under the endocyclic restriction test to show that the transfer of phosphorus from oxygen in 344 to carbon to give 345 takes place by an intramolecular mechanism.261 The stereochemistry of an interconversion involving stereogenic phosphorus excludes the classic in-line S N 2 pathway and suggests a mechanism involving apical addition to phosphorus followed by pseudorotation and loss of the apical alkoxy leaving group. On thermolysis or in the presence of a Lewis acid catalyst the 2-azaallylphosphonate 346 undergoes reversible phosphorotropic rearrangement to give 347.262 The complexing properties of a number of phosphinic acid analogues 348 of glycine with Co(II), Ni(II), and Cu(I1) have been investigated263 and there have been several reports of metal extraction using phosphonic acids.264

4: Quinquevalent Pltosphorus Acids 143

344 n = 1 , 2

345

'"7(OEt)2 O"7(OEt)2

heat L &CH-N=CHPh

346 &CH=NCHPh 347 - or BF3.Et20

348 R = H, Me, But, Ph

Radical centres have been generated in the p-, and y-267 positions in alkylphosphonates with a view to side chain-functionalisation. For example, a- radicals, of e.g. 349, have been obtained by the reaction of tri-n-butyltin hydride with a-halogeno-, a-thio-, or a-seleno-alkylphosphonates under various condi- tOns265266 and trapped by alkenes to provide a new route to extended chain phosphonates, e.g. 350 (Scheme 35). In one case the method has been applied to the synthesis of the cyclopentanoid antibiotic methylenomycin B.2657268 Similar reactions have been carried out using p- and y-halogeno phosphonates to generate the corresponding radical followed by trapping with alkenes to give longer chains.267 As might be expected yields in many of these reactions are variable. A detailed study of the addition of P-H compounds to alkenes and alkynes (the Pudovik reaction), including a comparison of different initiation methods for both radical and ionic mechanisms, has been reported.269 The novel nitroxyl radical 351 has been generated and shown to be a superior alternative to TEMPO as a chain-transfer agent in polymerisation reactions.270

i [ ' ':LR2l

0 R' I I /

(Et0)2P-C\-X - (Et0)zP-Ci COR2

349 X = CI, Br, S R , SeR

Scheme 35 Reagents; i, Bun3SnH, AIBN; ii, A 4

II 0 R' R3

II I (Et0)2P-CCH2CH2CH


The reaction of diethyl isocyanomethylphosphonate with acyl chlorides generates the a-ketoimidoyl chlorides 352 which form a new class of nitrile ylides 353 on treatment with tr ieth~lamine.~~' The ylides (353) are trapped in situ by alkenes to give phosphoryl pyrrolines or pyrroles. (Diisopropoxyphosphory1)nitrile oxide (354), which is stable up to O"C, reacts with substituted cyclopropenes to give phosphonate-substituted bicycles 357, isoxazoles 355 or oxazines 356 depending on the cyclopropene The enantioselective borohydride reduction of N- diphenylphosphinyl imines, e.g. 358, using chiral Co(1 I) complexes catalysts provides a new route to optically active amines, with e.e. values up to go%, through hydrolysis of the initial reduction Reaction of the bis(ch1oro- methy1)phosphoramidate 359 with phosphoryl chloride in the presence of a tertiary amine provides bis(chloromethy1)phosphoryl chloride via decomposition of the initially formed adduct 360.274 Both deuterium and oxygen-18 kinetic isotope effects on the generation of metaphosphate from thermolysis of the oxaphosphabicyclic derivatives 361 have been reported and interpreted.275 Mof- fat's ylide (362, R' = R2 = Ph) has been extensively used in the synthesis of vinylphosphonates particularly in nucleotide chemistry. A general method for the synthesis of a range of ylides (362) and examples of their synthetic use has now been reported.276

0 ! CH2C'2 R&,N,P(OEt)2 I1 (Et0)2PCH&=C + RCOCI

CQMe 353

0 Et3N II

354

0 CI II I

(P~O)~P-C=NOH - (P~~O)~PC=~--O-

n

0 CI n MF! U

355 356 357 Y I


0 Me II /

P h2P N= C, Ar

358

0 Ph

Me

Chiral Con cat. I t * / * Ph2PNH-CY

NaBH4

90% ee

R CHC13 R (CICHZ)~PNHM~ + CI3P(O) -

Et3N 359 360

n

361 Y = OEt, NEt2

0 0 R3*P II NaH II

0 II

(R1O)2PCH20Tf (R'0)2PCH26R32 - (R'0)2P-CH=PR32 TfO- 362

3.3 Selected Biological Aspects. - Phosphonate and phosphinic acids and their derivatives have been widely used in haptens. Examples additional to those already discussed in other sections include the phosphonic acid anion 363 which was an alternative to the preferred but synthetically inaccessible structure 364.277 The mechanism-based probe 365 has been synthesised and shown to modify a bacterial phosphotriesterase. This strategy for generating a probe is general and should allow the isolation of a host of unique catalysts.278

0

0' 'Me Po-

The steroidal phosphonic acid derivatives 366 and 367 have been synthesised and studied as potential drugslprobes for therapies in the treatment of infections due to various parasitic protists, including the AIDS associated Pneurnocystis ~ a r i n i i . ~ ~ ~ The phosphinate analogue 368 of glutathionyl spermidine has been synthesised for use against the protozoal parasites from Trypanosoma and


Leishmania.280 Various reports on studies of antiviral agents have appeared. The three-dimensional structure of five HIV protease inhibitors, including the phosphonate 369, of the N-tertiarybutoxycarbonylphenylalanyl enol family have been investigated by NMR and molecular modelling.28' The problem of poor cell- penetration by the highly ionic phosphonoformate antiviral agent has been addressed by the synthesis of a variety of bioreversible prodrugs.282

The phosphinic acid polyamine analogue 370 is reported to be an effective inhibitor of purified human spermidine/spermine-N 1 -acetyltransferase (SSAT) and is claimed to be only the second example of a functional, non-superinducing inhibitor of human SSAT.283 The long-chain phosphonate analogues 371 and 372 are reported to exhibit cytostatic activity in ~ i t r o . ~ ~ ~

0

P(CH~)~NH(CH~)~NH(CH~)SNHE~ Me,l I

HO' 370

0- 371

0- NH2 372

Two distinct phosphorus structures, 373285 and 374,286 are reported to be potent inhibitors of endothelin-converting enzyme and neutral endopeptidase. The latter compound is also a potent inhibitor of angiotensin-converting enzyme.286

CONH-X-OH

N-NH 373


The potential roles in binding and catalysis for the binuclear metal centre found within bacterial phosphotriesterase have been evaluated by the study of inhibitory properties of a wide range of substrate and product mimetic^.^^^ Phosphonates bearing fluoro or hydroxy substituents at the methylene position were non-competitive inhibitors while phosphoramidates were inactive. Highly potent irreversible inhibitors of neutrophil elastase have been generated by selection from a rdndomised DNA-valine phosphonate library.288 An investigation of the structural requirements of a series of benzylphosphonic acid inhibitors of human prostatic acid phosphatase has allowed SARs to be defined and led to a highly potent series of inhibit01-s.~~~ The first hydrolytically stable phosphocrea- tine analogues (375) in which the NH-P link is replaced by the CH2-P isostere have been synthesised and shown to inhibit creatine kinase (CK) with activities in the low mM range.290 Compound 375 (n = 1) is the most potent known inhibitor of CK.

4 Structure

The conformations of cis- and trans-3-(methoxycarbonyI)-2-methoxy-2-oxo- 1,2- oxaphosphorinane (376) have been studied by variable temperature ' H and "P NMR spectroscopy and semi-empirical calculation^.^^' An X-ray structure of the trans-isomer was also carried out. For the cis-isomer but not the trans, the results indicate an important change in conformer distribution with temperature. Semi- rigid phosphonamide ligdnds 377, 378 and 379 have been synthesised and their conformation in solution determined by low-temperature NMR and nOe difference The X-ray structures of both the free ligands and their complexes have been determined for 377 and 379. An NMR, IR and X-ray study of the complex 380 is reported to represent the first structural analysis of an organotransition metal-derived phosphonic acid.293 Studies of alcoholic solutions of acylphosphonates 381 by 31P NMR indicates the formation of substantial amounts of the hemiketals 382.294 The large difference in chemical shift (-20 ppm) between 381 and 382 makes 3'P NMR a particularly suitable method for studying the rates and equilibria of hemiketal formation in these systems. The synthesis, physical, chemical and spectroscopic (including 31P NMR) properties of a range of phosphinous, phosphinic and thiophosphinic amides, e.g. 383, have been reported.295 The mass spectra of new phosphorylated derivatives of a- hydroxy- and a-amino phosphonate derivatives of aliphatic, alicyclic and heterocyclic compounds have been a n a l y ~ e d . ~ ~ ~

The ESR spectra of diphosphorylated pyrrolidinoxyl radicals, e.g. 384 and 385, have been studied over a large temperature range.297 The trans-isomer of 384 showed no line alternation while dramatic changes in the spectra as a function of


U 377 x = s 378 X = O

379

0 0 0 OR2 II I I II /

(Me0)2P-C--R' + R20H (MeO)*P-C,R'

OH 381 382

0 I I,Ph

CICH2P, NPs

383

temperature were observed for 385. A four-site chemical exchange model including both ring-inversion and hindered rotation around P-C bonds explains these changes. The addition of several photochemically generated phosphonyl radicals (386) to C60 and C70 have been studied by ESR.298 The unpaired electron in the mono-adducts is mostly restricted to the two fused six-membered rings bearing the substituent at one of their points of fusion.

A study of the effect of aromatic halogeno substituents on chromatographic retention and enantioselectivity in the aminophosphonate 387 has been reported. 299

384 385 386 R = Me, Et, Pri 387 X = H, CI, Br, F


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Bojilova, Anka; Nikolova, R.; Ivanov, Christo; Rodios, Nestor A.; Terzis, A.; Rap- topoulou, C. P., Tetruhedron, 52(38), 12597-12612 (1996). Karimov, K. R.; Shakhidoyatov, Kh. M.; Balovitdinov, A. B.; Niyazova, Zh. M., Ov. Vyssh. Uchebn. Zuved., Khim. Khim. Tekhnol., 39(3), 13 1 - 1 32 (1 996). Reddy, V. Sreenivasa; Katti, Kattesh V.; Volkert, Wynn A., J. Chem. Soc., Dulton Truns., 23,4459-4462 (1 996). Telan, Leila A.; Poon, Chi-Duen; Evans, Slayton A., Jr., J. Org. Chem., 61(21),

Harger, Martin J. P., Tetruhedron Lett., 37(45), 8247-8248 (1996). Harger, Martin J. P.; Human, Barbara T., J. Chem. Rex, ( S ) , ( I I ) , 490-491 (1996). Harger, Martin J. P., Tetrahedron Lett., 38(25), 4507-4508 (1997). Harger, Martin J. P.; Sreedharan-Menon, Ramesh, J. Chem. Soc., Perkin Truns. I ,

Mikolajczyk, Marian; Zurawinski, Remigiusz; Kielbasinski, Piotr; Wieczorek, Michal W.; Blaszczyk, Jaroslaw; Majzner, Wieslaw, Synthesis, (3), 356-365 ( I 997). Ferris, Leigh; Haigh, David; Moody, Christopher J., J. Chem. Soc., Perkin Truns. I ,

Mikolajczyk, M.; Mikina, M.; Graczyk, P. P.; Balczewski, P., Synthesis, (lo), 1232- 1238 (1996). Collomb, Didier; Chantegrel, Bernard; Deshayes, Christian, Tetruhedron, 5231,

Leost, Francoise; Chantegrel, Bernard; Deshayes, Christian, Tetrahedron, 53(22),

Faure, Jean-Luc; Reau, Regis; Wong, Ming Wah; Koch, Rainer; Wentrup, Curt; Bertrand, Guy, J. Am. Chem. Soc., 119( 12), 28 19-2824 (1 997). Palacios, Francisco; Pagalday, Jaione; Piquet, Valerie; Dahan, Francoise; Baceiredo, Antoine; Bertrand, Guy, J. Org. Chem., 62(2), 292-296 (1997). Salomon, Claudio J.; Breuer, Eli, J. Org. Chem., 62( 12), 3858-386 1 (1997). Breuer, Eli; Zaher, Hisham; Tashma, Zeev; Gibson, Dan, Heteroat. Chem., 7(6),

Suzuki, K.; Taniguchi, Y.; Nagata, K.; Kitamura, T.; Fujiwara, Y.; Nagafuji, A.; Makioka, Y .; Takaki, K., Kidorui, 28,284-285 (1996). Tollefson, Michael B.; Li, James J.; Beak, Peter, J. Am. Chem. Soc., 118(38), 9052- 9061 (1996).

Lett., 38( 14), 240 1 - 2404 ( 1997).

1055-1059 (1997).

(6), 563-564 (1997).

Lett., 38(26), 4567-4570 ( 1 997).

7455-7462 (1996).

(4), 527-532 (1997).

24,2885-2888 (1996).

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7557-7576 (1997).

5 1 5-520 (1996).


262

263

264

265 266 267

268 269

270

27 1

272

27 3

274

275 276 277 278

279

280

28 1

282

283

284

285

286

Onys’ko, P. P.; Kim, T. V.; Kiseleva, E. I.; Sinitsa, A. D., Zh. Obshch. Khim., 66(6),

Rohovec, Jan; Lukes, Ivan; Vojtisek, Pavel; Cisarova, Ivana; Hermann, Petr, J. Chem. SOC., Dalton Trans., 13,2685-2691 (1996). Herlinger, A. W.; Chiarizia, R.; Ferraro, J. R.; Rickert, P. G.; Horwitz, E. P., Solvent Extr. Ion Exch., 15(3), 401-416 (1997). Balczewski, Piotr, Tetrahedron, 53(6), 21 99-221 2 (1997). Balczewski, Piotr; Pietrzykowski, Witold M., Tetrahedron, 53(21), 7291-7304 (1997). Balczewski, Piotr; Pietrzykowski, Witold M., Tetruheclron, 52(44), 13681 - I3694 ( I 996). Balczewski, Piotr, Heteroat. Chem., 8( I ) , 67-69 (1997). Semenzin, Delphine; Etemad-Moghadam, Guita; Albouy, Dominique; Diallo, Ousmane; Koenig, Max, J. Org. Chem., 62(8), 241 4-2422 (1 997). Grimaldi, Sandra; Finet, Jean-Pierre; Zeghdaoui, Abdelhamid; Tordo, Paul; Benoit, Didier; Gnanou, Yves; Fontanille, Michel; Nicol, Pascal; Pierson, Jean-Francis, Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem. ), 38( 1 ), 65 I -652 ( 1997); Benoit, Didier; Grimaldi, Sandra; Finet, Jean Pierre; Tordo, Paul; Fon tanille, Michel; Gnanou, Yves, Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.), 38( I), 729-730 (1 997). Huang, Wei-Sheng; Zhang, Yi-Xin; Yuan, Chengye, J. Chem. SOC., Perkin Trans. I ,

Al-Dulayymi, Juma’a R.; Baird, Mark S.; Pavlov, Valeriy; Kurdjukov, Alexander I., Tetrahedron, 52(26), 8877-8888 (1996). Sugi, Kiyoaki D.; Nagata, Takushi; Yamada, Tohru; Mukaiyama, Teruaki, Chem. Lett., (6), 493-494 (1 997). Pudovik. M. A.; Terent’evd, S. A,; Pudovik, A. N., Zh. Obshch. Khim., 66(1 I ) , 1919 (1 996). Jankowski, Stefan; Rudzinski, Juliusz, Heterout. Chem., 7(5), 369-374 (I 996). Xu, Yibo; Flavin, Michael T.; Xu, Ze-Qi, J. Org. Chem., 61(22), 7697-7701 (1996). Mu, YongQi; Gibbs, Richard A., Bioorg. Med. Chem., 5(7), 1327-1 337 (1997). Lo, Lee-Chiang; Lo, Chih-Hung L.; Janda, Kim D., Bioorg. Med. Chem. Letf.,

Beach, David H.; Chen, Franklin; Cushion, Melanie T.; Macomber, Roger S.; Krudy, George A.; Wyder, Michael A.; Kaneshiro, Edna S., Antimicrob. Agents Chemother., 41(1), 162-168 (1997). Chen, Shoujun; Lin, Chun-Hung; Walsh, Christopher T.; Coward, James K., Bioorg. Med. Chem. Lett., 7(5), 505-5 10 ( I 997). Boulanger, Yvan; Larocque, Alain; Khiat, Abdesslem; Deschamps, Francois; Sauve, Gilles, Tetrahedron, 53( 12), 423 1-4238 (1997). Briggs, Andrew D.; Camplo, Michel; Freeman, Sally; Lundstrom, Jan; Pring, Brian G., Eur. J. Pharm. Sci., 5(4), 199-208 (1997). Wu, Ronghui; Saab, Nada H.; Huang, Huatao; Wiest, Laurie; Pegg, Anthony E.; Casero, Robert A., Jr.; Woster, Patrick M., Bioorg. Med. Chem., 4(6), 825-836 (1 996). Brachwitz, H.; Oelke, M.; Bergmann, J.; Langen, P., Bioorg. Med. Chem. Lett.,

De Lombaert, Stephane; Stamford, Lisa B.; Blanchard, Louis; Tan, Jenny; Hoyer, Denton; Diefenbacher, Clive G.; Wei, Dongchu; Wallace, Eli M.; Moskal, Michael A.; et al., Bioorg. Med. Chem. Lett., 7(8), 1059-1064 (1997). McKittirck, Brian A.; Stamford, Andrew W.; Weng, Xiaoyu; Ma, Ke; Chackala-

936-941 (1996).

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6(17), 21 17-2120 (1996).

7( 13), 1739- 1742 (1997).


287 288

289

290

29 1

292

293

294

29 5

296

297

29 8

299

mannil, Samuel; Czarniecki, Michael; Cleven, Renee M.; Fawzi, Ahmad B., Bioorg. Mecl. Chem. Lett., 6( 14), 1629- I634 ( 1996). Hong, Suk Bong; Raushel, Frank M., J. Enzyme Znhib., 12(3), 191-203 (1997). Charlton, Josephine; Kirschenheuter, Gary P.; Smith, Drew, Biochemistry, 36( lo),

Beers, Scott A.; Schwender, Charles F.; Loughney, Deborah A.; Malloy, Elizabeth; Demarest, Keith; Jordan, Jerold, Biuurg. Med Chem., 4( lo), 1693- 1 70 1 (1 996). Bergnes, Gustave; Kaddurah-Daouk, Rima, Biuorg. Med Chem. Lett., 7(8), 102 1 - I026 ( 1997). Tasz, Maciej K.; Rodriguez, Oscar P.; Cremer, Sheldon E.; Hussain, M. Sakhawat; Mazhar-ul-I-Iaque, J. Chem. Suc., Perkin Truns. 2 , (lo), 222 1-2226 ( I 996). Delangle, Pascale; Dutasta, Jean-Pierre; Van Oostenryck, Luc; Tinant, Bernard; Declercq, Jean-Paul, J. Org. Chem., 61(25), 8904-89 14 (1 996). Deemie, Robert W.; Fettinger, James C.; Knight, D. Andrew, J. Orgunornet. Chem.,

Katzhendler, Jehoshua; Ringel, Israel; Karaman, Rafik; Zaher, Hisham; Breuer, Eli, J. Chem. Suc., Perkin Truns. 2, (2), 341-349 (1997). Maier, Ludwig; Diel, Peter J., Phosphorus, Sulfur, Silicon, Relut. Elem., 115, 273-300 (1996). Zamkova, V. V.; Lyuts, A. E.; Dzhiembaev, B. Zh.; Butin, B. M.; Tukanova, S. K., Izv. Nuts. Akacl. Nuuk Resp. Kuz., Ser. Khim., ( 5 ) . 27-32 (1994). Rockenbauer, Antal; Mercier, Anne; Le Moigne, Francois; Olive, Gilles; Tordo, Paul, J. Phys. Chem. A , 101(44), 7965-7970 (1997). Tumanskii, B. L.; Bashilov, V. V.; Bubnov, N. N.; Solodovnikov, S. P.; Sokolov, V. I., Mul. Cryst. Liq. Cryst. Sci. Technul., Sect. C, 8( 1-2). 61-64 (1996). Pirkle, William H.; Gan, Kevin Z.; Brice, L. Jonathan, Tetruhedrun: Asymmetry,

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538( l-2), 257-259 (1997).

7( lo), 28 13-28 I6 (1996).

5 Nucleotides and Nucleic Acids

BY JANE A. GRASBY AND DAVID M. WILLIAMS

1 Introduction

This year’s nucleotide and nucleic acid literature has been dominated by interest in internucleoside linkages. A number of approaches to novel internucleoside linkages in dimers have been published in addition to stereoselective routes to phosphorothioate and methylphosphonate linkages. In some cases these studies have also extended to the oligonucleotide level. In addition a number of novel nucleotide analogues have been described. One of the most exciting areas in the field of nucleic acid chemistry is the application of in vitro selection techniques and these are reviewed for the first time.

2 Mononucleotides

2.1 Nucleoside Acyclic Phosphates 2.1. I Mononucleoside Phosphate Derivatives. - Prodrug forms of nucleoside monophosphates have featured regularly in this section. There has been less literature on the subject this year. Prodrugs aim to deliver the nucleoside monophosphates in vivo which are then converted into their bioactive triphosphates. A series of lipid diester analogues of AZT monophosphate (1 a-f) have been synthesised and evaluated for anti-HIV activity. The analogues with a phosphate diester bearing a chiral alkyl substituent showed a strong stereochemical preference for anti-HIV activity, whilst aromatic groups in the oxyalkyl ether afforded compounds with a higher potency than AZT. A prodrug

~~~~~ ~ ~~

Organophosphorus Chemistry, Volume 29 The Royal Society of Chemistry, 1999

161

162 Organophosphorus Chemiscry

of 5’-aminoAZT (2) designed to deliver the corresponding mono- phosphoramidate in vivo has been reported.2 However, the compound displayed only poor activity.

The 5’-phosphoramidate prodrugs 3 of the nucleoside analogue d4A have been prepared as potential membrane-soluble prodrugs of the free nucleotide.2 The anti-viral potency and selectivity of the derivatives was found to be considerably better than that of the parent nucleoside analogue. Other prodrugs of d4T have also been synthesised, which include the salicylphosphate analogues 4a-d for which the nature of the substituent on their efficacy has been studied. These were prepared in good yield by reaction of d4T with the appropriate salicylchloropho- sphite, followed by oxidation with t-butylhydroperoxide. The analogues are proposed to be converted either chemically or enzymatically into d4T monopho- ~ p h a t e . ~ The mechanism of action of this type of prodrug has been investigated in human lymphocytes using So324 (3, a prodrug of d4T.4 Although d4T-monophosphate is released and subsequently converted intracellularly into the corresponding triphosphate, another major metabolite of the prodrug, alaninyl d4T- MP (6), was also identified. It was suggested that this latter metabolite may act as an intra- and/or extracellular depot form of d4T and/or d4T-MP thereby explaining the superior anti-retroviral activity of So324 over d4T in cell culture.

The 5’-phosphatidylnucleosides 7 have been prepared by phospholipase I)-

3

0 0

4a X=N02

d X=Me

b X=CI C X = H

II It

I I AH mT I I

-0-P-0

AH mT PhO-P-0

Me-C-H Me-C-H

catalysed trans-phosphatidylation of dipalmitoyl phosphatidylcholine and the respective free nucleosides. The nucleoside conjugates displayed increased antitumour activity compared to the parent compound^.^.^

The chemical reactivity of 2’-deoxy-2’-thiouridine 3’-(p-nitrophenyl phosphate) (S), in which the 2’-hydroxyl is replaced with a 2’-thiol group, has been studied using 31P NMR and UV spectroscopy. Although similar to the hydrolysis of ribonucleotides, the rate of thiolate attack on the adjacent phosphatediester bond was determined to be lo7 fold slower than that of the corresponding a l k ~ x i d e . ~ A study of the properties of 2’-deoxy-2’-fluorouridine 3’-(p-nitrophenyl phosphate)

5: Nucleoticles and Nudeic Acids I63

RO

0-P-0

7 R = palmitoyl, X = H, F

(9) has revealed an RNA-like 3’-endo sugar conformation and that the 2’-fluoro substituent increases the rate of hydrolysis relative to the 2’-deoxy compound.8

The adenosine 3’-O-phosphate esters 10 have been prepared as model compounds to study ribonucleotide cleavage with a number of different metal ions.’

HO

V O H

10 n = 1 or2

The efficient syntheses of 2’-deoxyribonucleoside 3’-0- and 5’-O-phosphorodithioates 11 & 12 has been described.” In each case phosphorylation of either the 3‘-0- or 5’-O-protected nucleoside with 2-chloro- 1,3,2-dithiaphospholane, followed by oxidation with sulfur gives the 2-thio-l,3,2-dithiaphospholane 13. Compound 13, upon DBU-catalysed reaction with 2-cyanoethanol gives 14 via loss of episulfide. Treatment with aqueous ammonia afforded the desired compounds 11 & 12.

The preparation of nucleosidephosphorofluoridate (15), phosphorofluori- dothioate (16), and phosphorofluoridodithioate (17) monoesters in high yield from the corresponding nucleoside H-phosphonates has been described. The

164

Hov 0 I

-s-P=S I

OH

11


12 13 Nuc = 3-O-nucleoside 14 or 5’-O-nucleoside

15 16 17

synthesis involves conversion of the respective H-phosphonates into the corresponding pyridinium metaphosphate species 18-20 following reaction with trimethylsilyl chloride followed by iodinelpyridine. Subsequent reaction of the respective intermediates 18-20 with triethylamine trishydrofluoride gave the desired compounds in quantitative yield.

X II

I NUC-0-P-Y

18 X = Y = O 19 x=o, Y = S 20 X = Y = S

A new route to nucleoside 3’-H-phosphonate building blocks 21 involves the initial preparation of ammonium aryl H-phosphonates 22 by heating the appropriate phenol under reflux with phosphorus trichloride, followed by treatment with ammonia. The ammonium salt of 4-methylphenyl H-phosphonate is highly crystalline and its triethylammonium salt can be condensed with the nucleoside in the presence of pivaloyl chloride to give, after hydrolysis, 21 in essentially quantitative yield. l 3

A new H-phosphonothionylating reagent, 9-fluorenemethyl H-phosphonothioate (23) has been developed for the preparations of nucleoside H-phosphonothioate 24 nucleoside phosphorothioate 25, and nucleoside phosphorodithioate 26. l4

The ‘abbreviated’ NAD(+) analogues 27-29 in which the ribosediphospho- ribose linkage with the adenine is replaced with an anionic phosphonate function have been prepared.I5-l7

The phosphonate derivatives of the dihydroisoxazole nucleosides 30 have been obtained in good yield via 1,3-dipolar cycloaddition reactions of the nitrile oxide 31 with corresponding vinyl nucleoside bases such as 32.18

5: Nucleotides und Nucleic Acids 165

Cl

N H ' ~

21 6 = SMeC, AbZ, CbZ, Gib, {KL I

0 II

I R-O-P-O- kH4

S S II II

I I 0- S-

NUC- 0- P-0- NUC -0- P-0-

25 26

CONH2

I

A 0 r" iJ

O P 0- P-0- (CH2)n I -A- 0-

27 R = H,(R) or (S)-CHs, CH20H 28 n = 6 , 7 , 8

* - p D C O N H 2

R P H O - P l

A new series of prodrugs (33) of the antiviral agent 9-[2-(phosphonomethox- y)ethyl] adenine (PMEA) incorporating carboxyesterase-labile S-acyl-2-thioethyl (SATE) moieties as transient phosphonate-protecting groups have been prepared from PMEA and an S-acylthioethanol derivative in the presence of MSNT. The bis(tBu-SATE)PMEA was found to be more stable than the previously reported


0 EtO, I I

N-0 30 B = C , U,T,A

0 EtO, I I

EtO/ ‘-\ + k0-

31

NHMrnt

/I 32

33 R = Me, Pr‘, But, Ph

pivaloyloxymethylphosphonate prodrug bis(P0M)PM EA in human gastric juice and human serum and offers better potential for oral administration.” A new synthetic route to PMEA gives yields of around 50% and involves using the Mitsunobu reaction for the condensation between adenine or other purine bases and the phosphonate 34.20 The procedure leads exclusively to the desired N9 alkylated purines. A number of modified PMEA derivatives have also been reported in which the adenine amino group has been replaced. These include 6-

R‘ I

0 XAN 0 II XAN II

0- O- 36 R’ = R2 = H

O g .

0 EtO, I I

35 X = H, NH2 EtO/ p-

34 R’ = H, R2= CH3 R’ = H, R2 = allyl, cyc lopropyl,

cyclo hexyl R’ = R2 = CH3 R’ = R2 = -(CHP)~-

5: Nucleotides and Nucleic Acids 167

substituted PMEA analogues 35-37,21-23 and the 6-hetarylpurines 38a-d obtained by Pd(0)-catalysed cross-coupling reactions of 9-[2-(diethoxyphosphonylmethox- y)ethyl]-6-iodopurine with heteroarylorganometallics.24 The tetrahydrofuranyl PMEA derivatives 39 have also been prepared,25 in addition to 8-azaadenine (40), 8-aza-2,6-diaminopurine (41), and 8-azaguanine (42).26 The 8-azacompounds were obtained from a mixture of N-7-, N-8-, and N-9-(2-(phosphonomethox- y)alkyl) derivatives following phosphonylation and showed no antiviral activity. Several other acyclic nucleoside phosphonates of 8-azapurines were also described. The incorporation of PMEA diphosphate 43 and related triphosphates by human DNA polymerases has been reported.27 The phosphorylation of PMEG 44 and the related (R)-PMPG 45 by GMP kinases has been reported.28 The latter compound proved to be an excellent substrate.

NH2 I

41 0-

0 0 0 II I I II

-O-P-O-P-O-P,,O~ A I I I 0- 0- 0-

43

0

0- 40

0

42 6-

0

44 0-

0- 45

2.1.2 Pofynucfeoside Monophosphates. - The novel nucleotide prodrugs 46 based on salicyl phosphate have been prepared by reaction of salicylate or phenyl


salicylate with phosphoryl chloride to produce a phosphorodichloridate intermediate which was reacted immediately with excess nucleoside. Hydrolysis to the corresponding nucleoside and nucleotide is thought to be mediated by attack of the salicyl carboxylate at phosphorus following removal of the ester group.29

0

46 R = Me, Ph, $ - o a o B i

bez OH R’ = H, N3

The dinucleoside monophosphates 47a-d containing four different 2’-deoxy-2’- alpha-C-branched nucleosides, have been prepared by coupling their appropriately protected phosphoramidites with 2’,3’-di-O-acetyluridine in the presence of tetrazole. Subsequent oxidation afforded the desired compounds, although the partial dehydration of the amide analogue during oxidation gave a mixture of amide and nitrile modified dinucleotide. The ratio of amide to nitrile modified dimer was found to depend on the oxidant. Several of the analogues were found to be highly resistant to cleavage by snake venom pho~phodiesterase.~’

I o=yo-

HO OH 47a, R = CH2C02H

b, R = CH2CONH2 C, R = --CH2CH20H

d, R = $qOH A series of 2‘-5’ oligoadenylate analogues (48) containing internucleoside and

ribose modifications has been prepared by solid-phase methods as potential interferon mimetics. ’

The syntheses of dinucleoside H-phosphonothioate diesters 49 via condensa-

5: Nucleoticies and Nucleic Acids 1 69

48 R = OH, H, OMe, NH2 or H

? R' = -0-P-0- or H

0- x=o,s; Y = O , S n = 2 o r 3

tion of H-phosphonate monoesters with a hydroxylic component in the presence of various coupling agents has been studied using 31P NMR spectroscopy and reaction conditions which eliminate or suppress side reactions have been designed. 32

ODmt 49

A study of the conformational properties of 2'-O-phosphorylated diuridylate 50 has been made by NMR and CD,33 whilst the hydrolytic properties of 50 and its 2'-thiophosphate counterpart 51 have been made.34

ov HO OH ov HO OH

50 51


A number of reports of the syntheses of dinucleoside phosphorothioates have been made. The large-scale phosphotriester synthesis of dinucleotides 52 in solution using a series of hydroxybenzotriazole activating agents (53) has been described.35 Yields are good (63%) even with 3'-O-unprotected thymidine as the 3'-nucleosidic component. A highly stereoselective route to give Rp-dinucleotide phosphorothioate triesters has been developed.36 The method employs (S)-(indol- 2-yl)propan-2-01 as a chiral auxiliary which produces the intermediate P(II1) compound as an axial (54) and equatorial species (55). The former predominates and its subsequent reaction with the nucleoside components followed by sulfurisation produced the triester in 97% e.e. Unfortunately, the triester protecting group could not be efficiently removed.

0

Qo-t=s OV CI

O R 52 R = H or CH&(O)-

OR

Qot=, CI OR 0

CI

54 55

A phosphotriester method has been developed for rapid synthesis of oligodeoxynucleoside phosphorodithioates in solution. Couplings are performed by the chemoselective oxygen activation of protected nucleoside dithiophosphate anions (56) with 4-nitro-6-trifluoromethylbenzotriazol-1-yl-oxy-tris(pyrrolidine)- phosphonium hexafluorophosphate (PyFNOP) (57) or 6-nitrotriazol-1 -yl-oxy- tris(pyrro1idine)-phosphonium hexafluorophosphate (Py NOP) (58).37 Under optimised conditions, coupling yields above 950/0 were achieved in between 10 and 20


minutes. A comparison of a series of S-protecting groups3* has shown that the specific removal of the 4-chloro-2-nitrobenzyl-group by thiophenolate is the most efficient in terms of competing side reactions at the nucleoside 5’-carbon.

Dmto-P ? RS-P=S

I 0-

CI Cl

57 58

The RNA dinucleotide phosphorothiolate, 3’-(thioinosylyl)-(3’-5’)-uridine 59 (IspU) containing a 3’-S-phosphorothiolate linkage has been prepared from 9-(3- deoxy-3-iodo-~-u-xylofuranosyl)hypoxanthine using Arbuzov chemistry. IspU was found to be a substrate for several RNA hydrolysing enzymes and is also labile to acid, base and silver ions.39 The analogue has also been used to study the

0

I

077 HO OH

I

HO OH

S OH I

-0-P=O I

O V HO OH

59 60 61

172 Orgunophosphorus Chernistry

metal ion requirements of the self-splicing group I intron from 7etrahymenn thermophifa40Phosphorothiola te dinucleotide analogues of uridine (60 & 61) have also been reported by other^.^'

A number of methods for the stereoselective syntheses of dinucleoside methylphosphonates have been described. A method applicable to the large scale synthesis involves the initial preparation of methanephosphonoaiiilidates 62 which can be separated by silica chromatography. These are subsequently converted into the methylphosphonate diesters 63 which may be converted stereospecifically into the dinucleoside methylphosphonates 64 upon reaction with a 3’-O-protected nucleoside in the presence of DBU and lithium ~hloride.~’ In an alternative method, the two diastereomeric methylphosphonates 65 can be separated and subsequently coupled with a 3’-O-protected nucleoside in the presence of an alkoxymagnesium chloride.43

Dmto-r/ e x PhHN-P=Z

1 Me

Dmto-r/ o x I

Mes-P=O I Me

Dmtov o x I

I Me-P=Z ov AcO X

Dmto-r/ P X Me-P=O

I

O Y C F 3 CF3

62 X=H,OMe; Z = O , S 63 64 65 X = H, OMe

The 3’-aminoacylated dinucleotides 66 have been prepared by reaction of N- FMOC amino acid fluorides with the P-cyanoethyl-protected dinucleotide. Deprotection with oximate removes all protecting groups without disturbing the aminoacyl linkage.44

0 I

-o-y=o

66

5: Niicleoticies and Nucleic Acids 173

The dithymidine phosphorothiofluoridates 67 have been prepared as a mixture of diastereoisomers following treatment of the methylselenyl ester precursors 68 with tetrabutylammonium fluoride.45 The base-catalysed hydrolysis of the phosphorothiofluoridates was found to be about four times slower than the corresponding phosphorofluoridates. The conversion of dinucleoside phosphorothioates 69 and dinucleoside phosphorodithioates 70 into the corresponding phosphorofluoridates 71 and phosphorothiofluoridates 72 respectively using iodine and triethylamine trishydrofluoride in acetonitrile has also been '

described.46 The conversions are rapid and occurred in excellent yield.

HoY "OY 0 0 I I

F-P=S MeSe-P=S I I

0-v HO

67

0Y HO

68

0 I

O=P-F I

OV DrntO

71

DmtoY 0 I

o=p-s- I

DmtO 69

0 I

S=P-F I

OV DrntO

72

0 I

S=P-S- I

OV DmtO

70

2.2 Nucleoside Cyclic Phosphates. - Two novel fluorescent analogues of the secondary messenger molecule cyclic ADP-ribose (cADPR) have been prepared.47 Reaction of E-NAD (73) with sodium bromide in DMF in the presence of triethylamine gave the 9-cyclic ADP-ribose 74 whilst the enzyme catalysed cyclisation using Apfysiu cufifornicu gives the N 1-alkylated (equivalent to N7 in adenine) product. The novel cyclic etheno-CDP-ribose 75 was obtained by the enzymatic route and by the chemical cyclisation, albeit in poor yield in the latter case. A 31P NMR characterisation of cyclic ADP-ribose (cADPR) and its 2'- phospho-cyclic ADP-ribose has been published.48

The synthesis of two novel caged compounds, 4,5-dimethoxy-2-nitrobenzyl 8- bromo-CAM P (caged 8-Br-cA M P) (76) and 4,5-dimet hoxy-2-ni trobenzyl 8- bromo-cGMP (caged 8-Br-cGMP) (77) by reaction of the respective cyclic

1 74 Organophosphorus Chemistry

HO OH 73

HO OH 74

0 4 -0-P=O

I o=i- 0 ‘ o$ P A0

HO OH 75

nucleotides with 4,5-dimethoxy-2-nitrobenzyldiazomethane has been described.49 Each compound was obtained as a mixture of axial (78) and equatorial (79) diastereoisomers, the former being more soluble are preferred for studying cellular signalling pathways. Photolysis of the compounds rapidly releases 8- bromo-CAMP and 8-bromo-cGMP which are hydrolysis-resistant analogues of the parent nucleotides CAMP or cGMP. After photolysis, the 8-bromo-cyclic nucleotides produced can be used for in situ studies of signalling pathways inside cells.

OMe OMe

,OMe R

OH 77

OH 76

RO 0 I I t

HO Ro’v+ HO 0572c. R = MeO @

79 78 B = 8-bromoG, 8-bromoA

OMe

The spirophosphate analogues 80 have been prepared by initial reaction of dichloromethylphosphate with the respective nucleosidic diol precursor^.^'

5: Nucleotirles und Nucleic Acids 175

The uracil, cytosine and 5-bromocytosine analogues displayed promising antiviral activity against HCMV. A more efficient route to these compounds employing P(II1) chemistry for the phosphorylation step has also been described. 5'

0 0 I I II

II II 0 0

80 B = G, C, U, T, 5-bromoC, 5-fluoroC 81

The dinucleoside dipyrophosphate 81 has been obtained in 30% yield following reaction of the nucleosides with a large excess of phosphoryl chloride in trirnethylpho~phate/DMF.~* Slow decomposition of 81 produces the corresponding nucleoside 3',5'-cyclic phosphate derivatives.

The synthesis of the cyclic 2'-deoxyribodinucleotides 82 by a solution-phase H- phosphonate method has been described in which a 5'-protected nucleoside-3'-H- phosphonate (83) is first coupled to a nucleoside 3'-H-phosphonate diester (84).53 Removal of the cyanoethyl group from the 3'-phosphonate group reveals an H- phosphonate monoester function which remains intact during oxidation of the internucleoside H-phosphonate diester linkage. After further deprotection, this 3'-H-phosphonate is reacted to produce the cyclic derivative 82 in 15% overall yield.

qo. - 0 7 - O Y /O

B IP*O 0

82 B = A , C , G,T

om'o-Pp 0 I

O=P-H I 0-

83 BP = protected base

" O Y P 0

I O=P-H

I OR


3 Nucleoside Polyphosphates

The first examples of supercharged nucleotide analogues (85-87) have been described, in which methylenebisphosphonic acid containing an additional ioni- sable acidic function has been incorporated into P,y-bridged derivatives of adenosine t r ipho~phate .~~ The compounds and their protected precursors were obtained following acid-catalysed reaction of the respective precursors (88-90) with adenosine 5'-phosphoromorpholidate in pyridine in yields of 8O,75 and 25%.

03 0- o'd 0 II I II

I I -0-P-CH-P-

0- 0-

HO OH a5

HO OH 86

HO,!/OH O P 0 I I I I I

0 II I II

HO- P-CH- P- OH I I I I I I OH OH OH OH OH OH

S03H 0

II I It HO-P-CH-P-OH HO-P-CH-P-OH

88 89 90

A carbocyclic NAD(+) analogue (91) incorporating a methylenebisphosphonate linkage in place of the natural pyrophosphate has been prepared as an inhibitor of ADP-ribosyl cyclase which is resistant to non-specific phosphatase degradation.55756 The analogue 91 was obtained in 25% yield following a Poulter coupling of the precursor 92 with adenosine 5'-methylenebisphosphonate.

HO OH I I

91 HO OH


UDP-pyridoxal93 has been prepared in good yield from uridine-S-phosphoromorpholidate and pyridoxal phosphate and found to activate the enzyme carbamoyl phosphate synthetase (CPaseII) which is involved in pyrimidine biosynthesis. 57

HO OH 93

Several novel diadenosine 5’,5”’-P- 1 ,P-4-tetraphosphate (AppppA) analogues (94 & 95) and an adenosine tetraphosphate analogue (96) have been prepared as competitive inhibitors of ADP-induced platelet aggregation. Among the various analogues, the P-2, P-3-monochloromethylene AppCHClppA was found to be particularly active.

R OH u II II I II II

I I I A O-P-0-P-CH-P-0-P-0

H HO R 94 R=OH,H; X = S

95 R=OH, H; X = O

O C I O C I O 0 II I II I II I1

-0-P-CH-P-CH-P-O-P-0 I I 0- 0-

96 HO OH

Benzamide adenine dinucleotide (BAD) (9) was shown to be a good inhibitor of both inosine monophosphate dehydrogenase type I and type I1 following its synthesis in excellent yield from the imidazolide 98 and 2’,3‘-O-acetonide of AMP.” Interestingly, attempts to obtain the monophosphate precursor of 98 by reaction of 3-(2,3-0-isopropylidene-~-~-ribofuranosyl)benzamide with phosphoryl chloride gave the 5’-chlorobenzamide riboside 99 as the major product. Instead, a route employing phosphorus(II1) chemistry was developed to give the desired compound. Non-hydrolyzable P-methylene analogues of BAD (100) and thiazole-4-carboxamide adenine dinucleotide (TAD) (101) have also been synthe- s i ~ e d . ~ ~ Both compounds were obtained in excellent yield upon treatment of 2’,3’- O-isopropylideneadenosine 5’-methylenebisphosphonate (102) with DCC which

178 Organophospkorus Chemistry

HO OH

97 HO OH 0x0

98

initially afforded P- 1 ,P-4-bis(2’,3’-0-isopropylideneadenosine) 5’-P- 1 ,P-2,P-3,P-4- dimethylenetetrakisphosphonate (103). Compound 103 was further converted with DCC to an unidentified active intermediate which upon reaction with 3- (2’,3’-O-isopropylidene-~-~-ribofuranosyl)benzamide or 2’,3’-0-isopropylidene- tiazofurin gave, after hydrolysis and deprotection, the desired compounds 100 and 101, respectively. Further studies from the same group6’ have identified the novel nucleoside bicyclic trisanhydride 104 in the reaction of a nucleoside-5’- methylenebisphosphonate with DCC. On the basis of 31P NMR evidence, the formation of 104 was proposed to arise from P-I,P-3- and P-2,P-3-dehydration of the initially formed P- 1 ,P-2,P-3,P-4-bismethylenetetraphosphonate 103. Inter- mediate 104 could be converted further into several other nucleotide analogues

The stable bisubstrate ligands 109 of phosphoglycerate kinase (PGK) in which adenylate is attached to non-scissile 1,3-bisphosphoglycerate analogues have been described.6’ The analogues form high-affinity complexes with PGK as determined by ‘H NMR.

A one-pot method for obtaining both nucleoside di- and triphosphates which can subsequently be separated has been described, in which the phosphorylated intermediate 110 obtained from the free nucleoside and phosphoryl chloride is treated with excess crystalline phosphoric acid.62 The triphosphateldiphosphate ratio can be altered by altering the nucfeophilicity of the organic base added to the reaction.

The triphosphate of 5-formyldUTP (111) has been prepared and its incorporation by several DNA polymerases has been studied.63 It was found to be incorporated well in place of TTP and could also substitute dCTP to some extent. The preparation of 5-azidoUTP (112) from UTP has been described. The analogue was found to be an inhibitor of C P a ~ e 1 1 . ~ ~ 2’-Deoxyuridine-5’-triphosphate labelled at the C5 position with the dye

methylene blue has been prepared and incorporated into oligonucleotides or DNA fragments by tailing with terminal t r a n ~ f e r a s e . ~ ~

The ribonucleoside triphosphate 113 of 6-aminopyrazin-2( 1 H)-one has been prepared65 using salicyl chlorophosphite as the phosphorylating agent. Although the 6-aminopyrazin-2( 1 H)-one was found to base pair effectively with 5-aza-7- deazaisoguanine within a DNA duplex, 113 was not incorporated by T7 RNA polymerase opposite this latter base in a template.65

The stereoisomers of dNTP (1 14a-c) with regard to 2’-deoxyribofuranose C- 1 ’

(101, 105-108).

5: Nucleoticlrs and Nitckic Acids 179

CONHz

CI

Ox0 99

0 0 I I I I

-0-P-CH2-P-0 I 0-

O X 0 101 O X 0 102

OH OH w

0 0 0

I I 0- 0- 0-

HO OH

0 II

37 HO OH

0

104


HO OH

0-P-CH2-P-0 I

105 Ho OH

0 0 0 It II II

MeCHN-CH2CH2-0-P-CH2-P-0 I

106 HO OH

0 II Me

HO OH

OH

108 1 07

0 0 0 I1 II II

-0-P-CX2CH2YCH2CX2-P-O-P-O I I 0-

109a, X = F, Y = CH2 Ho OH b, X=H, Y = O

Cl-P-0

;I pB HO

110

and C-4' carbon atoms have been synthesised and studied as substrates for several template-dependent DNA polymerases.66 None of' the studied enzymes utilized the L-dNTPs, indicating that template-dependent DNA polymerases are highly stereospecific with regard to dNTPs. Interestingly, template-independent

5: Nucleotitles unrl Nucleic Acids

0

181

HO 111 X=CHO 112 X=N3

0

0 I I

-0-P-0 I 0-

113 HO OH

terminal deoxynucleotidyl transferase showed less stereo differentiation, suggesting that the active centre of the latter enzyme forms no specific contacts with the nucleic bases of both nucleotide substrate and oligonucleotide primer.

0 0 0 I I I I I1

I I I 0- 0- 0-

-O-P-O-P-O-P-O-NUC

11&, NUC= /OB OH

B b, Nuc=

C, Nuc = /wB Several nucleoside analogue triphosphates (1 15a-d) have been prepared and

tested as termination substrates for a wide number of p ~ l y m e r a s e s . ~ ~ . ~ ~ A novel solid phase method for the synthesis of 2‘-amino-Y-deoxynucleoside

5’-triphosphates has been developed in which the 3’-azidonucleoside precursors are first linked to support-bound triphenylphosphine as their phosphinimines 116. Following conversion into the triphosphate, the desired 2’-amino-2’-deoxynucleoside 5’-triphosphates are released from the support by treatment with ammonia in the Staudinger

The nucleoside 3’-triphosphate analogue 1 177’ conjugated to the p-aminophe- nyfethyfamino linker has been obtained from EDCI-mediated coupling of the


0 0 0 I I II II

I I I -O-P-O-P-O-P-O-NUC

0- 0- 0-

115a, Nuc=

OH N3

b, NUC= 72 F N3

C, NUC=

OH

d, NUC=

F

0 0 0 II II II

-0-P-0-P-0-P-0

A- A- A- -P N

II (Ph)*PPh- $

116

corresponding 3’-triphosphate with the respective trifluoroacetyl protected aniline derivative. Immobilisation of 117 to an agarose matrix is also described.

117

The 2’-deoxynucleoside 5’-a-[P-borano]-triphosphates I18 have been used for PCR-based DNA sequencing.’* The method relies on the resistance of borano- phosphate linkages to nucleases, thus the positions of the boranophosphates can be revealed by exonuclease digestion, thereby generating a set of fragments that defines the DNA sequence. An abstract has also described the use of fluorescently labelled 2’-deoxynucleoside 5’-ct-[P-borano]-triphosphates for DNA seq~enc ing .~~

The 5’-deoxy-5’-thionucleoside-5’-triphosphates 1 19 have been chemically synthesised either by reaction of the respective 5’-iodo-5’-deoxynucleosides with

5: Nucleotides and Nucleic Acids I83

0 0 0 II II I I

-0-P-0-P-0-P-0 $Ha yJ 118 OH

PI-(S)-thiotriphosphate (120) or by condensation of the 5’-deoxy-5’-thionucleoside-5‘-monophosphates 121 with tributylammonium pyrophosphate in the presence of CDI.74 The latter method was more efficient. They were not substrates for T7 RNA polymerase.

119 B = A , U OH

0

120 121

A chemoenzymatic synthesis of the P-a-methyl 2’-deoxynucleoside triphosphates 122 has been described which involves reaction of the 5’-0-(methylpho- sphony1)-N-protected nucleosides with pyrophosphate in the presence of CDI.75 Removal of the base protection by treatment with penicillin amidase gave compounds 122 leaving the labile a-methylphosphonate intact. A number of 2’- deoxythymidine 5’-triphosphate and 3’-azido-2’,3’-dideoxythymidine 5’-triphosphate analogues (123) containing a hydrophobic phosphonate group have also been synthesised and evaluated as substrates for several viral and mammalian polymerases. Some y-ester (124) and y-amide (125) derivatives of dTTP and 3’- azido-Y,3’-dideoxythymidine 5’-triphosphate (AZTTP) were also synthesized and studied. The y-phenylphosphonate triphosphate 126 and its conjugation to biotin and fluorescein labels has also been described.76

A series of myristoyl nucleoside di- and triphosphates (127) has been synthesised as membrane permeable prod rug^.^^ Whilst the latter could be obtained by reaction of a suitable mixed anhydride of the acyl compound with the respective nucleotide in DMF, a novel and more efficient route to the diphosphate analogues involved treating myristoylimidazole with the diphosphate in the presence of methyl iodide. Methylation at the N-1 of the imidazolide presumably increases its reactivity toward the nucleotide.


0 0 0 I1 II I1

-0-P-0-P-0-P-0 I I

OH 1 22

124 x

0 0 0 II I1 II

R-P-0-P-0-P-0 I I

X 123 R = Me, Ph; X = N3, OH

E f t PhNH-P-0-P-0-P-0

I I

125 x

0 0 0 II II I1

Ph-P-0-P-0-P-0 0- I 0- I b- y

OH 126

r 127 n = l o r 2 OH

Some triphosphate derivatives (128 & 129) of carbocyclic nucleoside analogues containing hydrolytically-stable phosphonate modifications have also been synthesised and shown to be potent substrates for terminal deoxynucleotidyl- transferase and HIV reverse t ran~cr ip tase .~~

0 0 0 II II II

I 1 I

128 129

0 0 0

I I I B OCH2P-O-PCBr2P-O- I1 I1 II

-O-P-CH2-P-O-P-CI-i2O”$f- yy 0- 0- 0- 0- 0- 0-

4 Oligo- and Polynucleotides

4.1 DNA Synthesis. - Although the solid phase synthesis of oligodeoxyribonucleotides is relatively routine modifications to existing methodologies continue to be suggested. The type of solid support used, and the methodology of attachment

5: Nucleotirks and Nucleic Acids 185

of the first nucleoside to this support, has received some attention this year. Hydroquinone-0,O’-diacetic acid (QDA) has been described as an alternative to the commonly used succinate linker for attachment of nucleosides to controlled pore glass or polystyrene supports ( The removal of oligoribonucleotides and oligodeoxyribonucleotides from the QDA support post chain assembly requires a two to five minute exposure to aqueous ammonia. An alternative to ammonia deprotection and liberation from solid support is required for the synthesis of oligonucleotides which contain reactive functional groups. A comparative study of the cleavage efficiency of oligonucleotides from succinyl, phthaloyl, oxalyl, 2-(2-nitrophenyl)ethyl, 9-fluorenylmethyl, and other linked supports (131a-g) with 0.5M DBU has been undertaken8’ When small oligonucleotides containing thymine are synthesised, a decrease in cleavage efficiency is observed with best yields being obtained from oxalyl, 2-(2-nitrophenyl)ethyl and 9-fluorenylmethyl linked supports. Side reactions occurring with the thymine containing oligomers appear to result from deprotonation of the nucleobase by DBU.

b 0 I

,c - CH2 - 0 0 - 0- CH2 - :- N-@ 0’ H

130

An alternative solid support for oligonucleotide synthesis has been investigated. A non-porous support of a polytetrafluoroethylene core surrounded by a thin layer of polystyrene was found to give comparable results to wide pore controlled pore glass for the synthesis of long oligonucleotides.8’ Poly(N- acryloylmorpholine) has been investigated as a new soluble polymeric support for the liquid phase synthesis of oligonucleotides.82 The first nucleoside is attached to the support via the 3’-hydroxyl group by treatment with DCC and DMAP to yield 132. Chain assembly using phosphoramidite chemistry required the use of tert-butyl hydroperoxide rather than the conventional iodinelwater oxidation step because of the thioether linkage in the support.

The detritylation of support bound oligonucleotides during DNA synthesis has been studied. The efficiency of oligomer synthesis on a large scale can be enhanced by the use of more concentrated dichloroacetic acid solutions.83

Depurination of 2’-deoxyadenosine and 2’-deoxyguanosine containing oligomers during the detritylation step of solid supported DNA synthesis has been studied.84 It was concluded that a 15% solution of dichloroacetic acid was the preferred detritylation reagent to balance the requirement for rapid removal of the protecting group and minimum depurination. A method for removal of depurinated DNA sequences prior to release of the oligonucleotide from the support has been described by Landegren and c o - w o r k e r ~ . ~ ~ ~ ~ ~ The methodology utilises the disiloxyl reagent 133.

186 Orgunophosphorus Chemislry

131a

131c

131b

0 131d

DmtO

PA 0

o + o \ / q r [ - l 0 0' 'C-N-i H OH

Dm'ox! 131f 0 131e

1319

5: Nucleotides und Nucleic Acids I87

An alternative approach to the synthesis of random oligonucleotides which code for different proteins has been de~cribed.~' Trinucleotide phosphoramidites 134 coding for all 20 amino acids have been synthesised and utilised to assemble oligodeoxyri bonucleotide libraries.

V O R " 134 R = 2-chlorophenyl

An alternative protecting group for the internucleoside phosphodiester bond compatible with phosphoramidite chemistry has been suggested.88 The required phosphitilating agent bis[N,N-diisopropylamino]-(4-cyano-2-butenyloxy)phosphine (135) was prepared and used to synthesise the required monomers. Following oligonucleotide assembly the protecting group is removed by a 6- elimination in the presence of aqueous ammonia.

Gaseous amines such as ammonia or methylamine under pressure have been investigated to achieve mild and rapid deprotection conditions for oligonucleotides. For example, oligodeoxyribonucleotides having a (tert-buty1)phenoxyacetyl group for the protection of the exocyclic amino function of cytosine, adenine and guanine were released from controlled-pore glass supports and fully deprotected by ammonia or methylamine under gas phase conditions, at room temperature, within 35 or 2 min respe~tively.~' N-Pent-4-enoyl nucleoside phosphoramidites and H-phosphonates have been utilised for the large scale synthesis of oligonu- cle~tides.~~Gaseous ammonia can be used as an alternative deprotection reagent for these oligomers.

A universal support for oligonucleotide synthesis has been described (136). The support was synthesised from 1,4-anhydro-~-ribitol.~~

Oligonucleotides containing L-nucleosides have been synthesised using conventional synthesis method~logies.~~ The substitution of one or more L-deoxynucleoside for its naturally occurring D-counterpart decreased the stability of duplexes.

188

0


136

4.2 RNA Synthesis. - Methods for the synthesis of RNA are now routine but less efficient than DNA synthesis. The most popular phosphoramidite reagents employ acyl protecting groups for the ’exocyclic amino functions of the nucleosides, dimethoxytrityl for the 5’-hydroxyl function and 2’-O-tert-butyldimethylsilyl (tBDMS) for the 2’-hydroxyl function. The silyl protecting group is usually removed by treatment with 1 M TBAF or tr iethylamine.3HF. Acidic deprotection conditions have also been developed for removal of tBDMS groups.”

An alternative to the use of silyl protection in RNA synthesis employs modified acetals such as 1 -(2-fluorophenyl)-4-methoxylpiperidin-4-y1 (Fpmp) and 1 -(2- chloro-4-methylphenyl)-4-methoxylpiperidin-4-yl (Ctmp) groups. An improved synthesis of the enol ethers required to introduce these protecting groups has been de~ised.’~

’ P cross-polarisation magic angle spinning NMR spectra have been measured for various linear and branched di- and tri-ribonucleotides (e.g. protected r(ApU), r(ApUpU), r(A(2’pU)3’pU) and d(TpsTpsT)) attached to a controlled pore glass solid support. The technique readily distinguished the oxidation state of the phosphorus atom (phosphate versus phosphite), the presence or absence of a protecting group attached directly to phosphorus (cyanoethyl), and other large changes in the phosphorus chemistry (phosphate versus phosphorothioate). However, differences in configurational details remote from the phosphorus atom, such as the attachment position of the ribose sugar (2’-5’ versus 3’ -S) , or the particulars of the nucleotide bases, could not be resolved. When different stages of the oligonucleotide synthetic cycle were examined, it was revealed that the cyanoethyl protecting group was removed during the course of chain assembly.95

Methodologies for rolling circle transcription of catalytic RNAs from a circular DNA template have been described in more detail.96 The catalytic RNAs self- cleave during the transcription reaction.

4.3 The Synthesis of Modified Oligodeoxynucleotides and Modified Oligoribonu- Cleo tides 4.3. I Oligonucleotides Containing Modified Phosphodiester Linkages. - Phos- phorothioate containing oligodeoxyribonucleotides and oligoribonucleotides continue to be of interest because of their enhanced stability to nucleases and their use in stereochemical analysis and mechanistic investigations of protein enzymes and ribozymes. The extent of longmer formation in the synthesis of


phosphorothioate containing oligodeoxynucleotides has been thoroughly investigated and found to depend on the base composition and contact time and acidity of the activator employed in the phosphoramidite synthesis cycle.97 A phosphorothioate dimer building block strategy (137) has been used to assemble phosphorothioate oligonucleotides and results in reduced n- 1 imp~rity.~'

137 X = S , Y = O , B = T x=o, Y - s , B=CbZ

The synthesis of phosphorothioate RNA has also received attention. The sulfurisation time and the amount of sulfurising reagent (Beaucage reagent) have been optimised and methodologies for the purification of phosphorothioate RNA have been in~est igated.~~ The use of EDITH (138) in the synthesis of phosphorothioate containing RNA has also been investigated. loo*lo' This reagent produces sulfurisation of the phosphite triester linkage in 2 minutes and can be used in low concentration. The results with this reagent are claimed to be better than with the Beaucage reagent. The stereocontrolled synthesis of diribonucleoside phosphorothioates has been reported. The synthesis utilises S-O-dimethoxytrityl-2'-0-(tert- butyldimet hylsilyl)-3'-0-(2- thiono- 1 ,3,2-oxat hiaphospho1anyl)ri bonucleoside derivatives which could be separated into individual isomers by column chromatography. ] '* The stereoselective preparation of an all Rp-phosphorothioate containing oligoribonucleotide has been described. The synthetic approach involves the use of H-phosphonate monomers which due to stereoselectivity in the coupling step produces mainly Sp-H-phosphonate linkages. Stereospecific sulfurisation produces largely Rp-phosphorothioate linkages. Subsequent treatment of the oligomer with Nuclease P1 (from Peniciffium citrinum) catalyses the hydrolysis of any remaining Sp-linkages. Io3

Neutral pro-drugs of phosphorothioate oligonucleotides have been of interest for some time. The S-acyloxyalkyl prodrugs 139 have been prepared via alkylation of phosphorothioate-containing DNA. Under hydrolytic conditions, the phosphorothioate is liberated without any concomitant desulfurisation. '04

Phosphorodithioate internucleoside linkages are resistant to nuclease degradation but do not introduce a chiral centre at phosphorus. Methodologies for the synthesis of phosphorodithioate DNA based on P(II1) chemistry have existed for some years. A phosphotriester methodology has been developed for assembly of


138 139 R = Me, Pr', But

phosphorodithioate internucleoside linkages based on the coupling of protected nucleoside dithiophosphate anions (140a) with a 3'-support bound nucleoside. ' 0 5

Chemoselective oxygen activation is afforded by use of 4-nitro-6-trifluoromethylbenzotriazol- 1 -yl-oxy-tris(pyrro1idine)-phosphonium hexafluorophosphate (140b). Oligonucleotides with 5'-dithiophosphate have been prepared by reacting 0-(9-fluorenemethyl) H-phosphonothioate (141) with an appropriately protected oligonucleotide and then sulfurising the oligonucleotide with elemental sulfur. Io6

The resultant oligonucleotides are resistant to the action of alkaline phosphatase and do not act as substrates for T4-polynucleotide kinase. A thorough investigation of the biochemical and physicochemical properties of DNA oligomers containing phosphorodithioate linkages has been reported. 107*108

Dm"Y 140b

Cl Cl ko- 141

S II .P-O- I H

Synthetic strategies for the formation of methylphosphonate internucleoside linkages are also well established. The introduction of a methyl phosphonate linkage also creates a chiral centre at phosphorus. Phosphoramidite dimer synthons with Rp-methyphosphonate linkage (142) have been prepared and utilised to prepare methyl phosphonate oligonucleotides with Rp-methylphosphonate linkages at every other position and oligonucleotides with alternating


phosphate diester and Rp-methylphosphonate linkages.'" These oligonucleotides bind to RNA with a higher affinity than those with racemic methylphosphonate linkages. A dimer block coupling strategy has also been used to assemble oligonucleotides with alternating phosphate diester and phosphonoacetate linkages (143). ' l o Prior to phosphitilation of the dimer, the epimeric phosphonoacetates could be separated by normal phase HPLC. Synthesis of an all-Rp and an all-Sp methylphosphonate has been reported using a Grignard activated coupling with t-butylmagnesium chloride. ' I I Oligonucleotides with methylphosphonate linkages containing 2-aminopurine and 2-pyrimidinone bases have been synthesised using reagent 144a and 144b.'12-"3

Dmtovp I I

? H3C-P=0

owp 0,

NC-oO P-NPr'2 142

Dm"v 0 0 I I I

MeO-C-CH*-P=O

ov I

N C o O , P - - N P + 2 0,

143

144a, Pac = phenoxyacetyl 144b

Oligomers in which one of the bridging oxygens has been replaced by carbon have also been of interest. Caruthers and co-workers have reported the synthesis of oligonucleotides with 3'-C-O-P-5' linkages using a dimer block assembly synthon 145 and the assembly of oligomers containing 5'-deoxy-5'-methylidyne phosphonate linkages using 146.' '',115

A dimer block assembly strategy has also been used to prepare oligonucleotides in which acetylinic linkers join together nucleosides. The phosphoramidite reagents 147a-d were utilised during conventional oligonucleotide synthesis. l 6

The resultant oligomers destabilised duplex structures. A method for the synthesis of N3'-P5' phosphoramidite internucleoside

linkages has been reported. The solid-supported chain assembly, which proceeds from 5'-3' utilises a support bound 3'-dideoxyamino nucleoside coupling with a


145 O \ t

147a, X = O 147b, X = S

I

O i L Y 0.

NC-O/ p- Pr’2

146

147c, R = H, R’ = OMe 147d, R = OMe, R’ = H

5’-phosphite synthon (148).’ ’’ Following oxidation, removal of the 3’-N-trityl group allows further chain elongation. The synthesis of oligonucleotides of uniformly modified oligodeoxyribonucleotide N3’-P5’ phosphoramidates containing 2’-fluoro-2’-deoxypyrimidine nucleosides has been accomplished using an amidite transfer reaction. The 3’-amino group of solid phase-supported 2’-fluoro- 2’-deoxynucleoside was used as an acceptor and 5’-diisopropylamino phosphoramidite as a donor of a phosphoramidite group in the tetrazole-catalysed exchange reaction. Subsequent oxidation with aqueous iodine resulted in formation of an internucleoside phosphoramidate diester. The lower nucleophilicity of the amine with the neighbouring fluorine resulted in poorer coupling yields. l 8

Pri2N-

NH

148 Tr I


A T-T dimer with a hexafluoroketal linkage has been prepared and derivatised for DNA synthesis as an H-phosphonate (149). ' l9 Oligonucleotides containing the ketal linkage displayed poorer binding to complementary DNA and RNA than their unmodified counterparts. The synthesis and properties of oligoribonucleotide analogues having formacetal internucleoside linkages has been reported using the dimer block reagent 150 for their assembly.'20 The resultant oligomers have slightly enhanced melting temperatures when hybridised to complementary RNA. Conformationally restricted acetal linkages have also been included in oligonucleotides using the H-phosphonate dimers 151a & b. 1 2 ' Oligonucleotides containing 151a lower the melting temperature of duplex by 8 "C, whereas those containing the other isomer (151b) did not bind to a complementary DNA. Chimeric oligonucleotides containing dimethylene sulfone-l52a, methylsulfide- 152b and methylsulfoxide-152c linked oligonucleotides have also been synthesised. ' 22

Dmto-H O V O

0-P 0 I

O=P-O- Et&-i I H

151a

0- 150

0 I

I H

151b

-O-P=O Et&H

Various oligonucleotides containing amide linkages have been prepared this year. A dimer block coupling strategy employing the phosphoramidite reagents 153a-c has been used to construct oligomers containing amide and thioamide linkages. 123.124 The incorporation of hydrophobic substituents on the amide

1 94 Orgunophosphorus Chemistry

0 I

NVIT

152a

0 I

NVIT

152b

0 I

NVIT

152c

functionality has also been investigated using 154. 12' The novel phosphoramidite 155 containing an amide linkage has been prepared from L-serine-P-benzyl ester.*26 Solid phase synthesis of oligomers with entirely amide linkages (156) has been d e ~ c r i b e d . ' ~ ~

0 I

N C m O 0 P-NPri2

Dmto-P

P 0 H N P 0

NC-00P-NPri2 I

153a 153b 153c n = 0, X = NH, m = 1, Y = CO n = 1, X = NH, m = 0, Y = CO n = O , X=CO, m = l , Y = N H

P = 4,4,4-?ris-?ert-butyltrityl or prnethoxybenzyloxymethyl

P = 4,4',4"-tristeRbutyltrityl

P O Y O

HNP 0 DrntO f Y 0 - p 0 N P r ' 2

0J NCmO,P-NPr '2 N C v - O I

154 155

5: Nucleorides and Nucleic Acids 195

NH I

o=c

NH I +

156

Peptide nucleic acid (PNA) has received considerable attention for several years as a candidate for antisense exploitation. 128 Several publications have addressed the physical and biological proper tie^,'^^ applications' 30-132 and char- a~ te r i sa t ion '~~ of PNA and modified PNAs. One problem associated with PNA is its poor solubility. There has therefore been interest in the synthesis of mixed PNA-DNA chimeras134 and the introduction of charge into the PNA monomer itself. 135 Phosphonate PNA 157a has been prepared using the aminomethylphosphonate 157b. Proline derived PNA monomers 158 have been described.136

T 0

lNL 0Qp I -0' I

0 B u: I Dmto"vAw 98 P-OH 0- I H 0 - q N

0Qp -0' 1

.MN. \ OH 157a 157b R = T or CbZ 158 B = T o r A

2S, 4R 2s, 4s 2 R, 4s 2R, 4R

A dimer block assembly strategy has been utilised to synthesise oligonucleotides with a triazole (159a & b)'37 or imidazole (159c & d)138 internucleoside linkage.

DNA containing 2', 5'-phosphodiester linkages (160) has been prepared and its properties have been investigated. 139-141 The 2',5'-linked DNA was found to


0 I

Jwv.

159b

0 I

JWIP

0 I

.hMp

159c 159d

selectively bind complementary RNA but not DNA. The fast atom bombardment mass spectra of 2',5'- and 3',5'-linked dinucleoside monophosphates have been studied. '42 interestingly both isomers exhibit a similar fragmentation pattern.

0 I

-0-P=O I

OV 0

I .nnnr

160

Circular oligonucleotides DNA structure and their

(DNA dumbbells) are of interest for the study of resistance to exonucleases. Lim and Hunt have

compared enzymatic and chemical methodologies for the synthesis of circular DNA. Chemical ligation utilising cyanogen bromide was found to be faster and less costly than the use of DNA ligase.'43

Shabarova and colleagues have developed a chemical ligation procedure for the introduction of pyrophosphate linkages into oligodeoxyribonucleotides. '41 Circular DNAs containing the pyrophosphate linkage have been prepared and their properties have been studied.'45 A methodology for the inclusion of trisubstituted pyrophosphate linkages in mixed oligodeoxy- and oligoribonucleotides and in oligoribonucleotides has been developed. 146 The oligoribonucleotides containing the modified linkage have been used to study RNA protein interactions by chemical cross-linking to lysine residues in the proteins.'47


4.3.2 Oligonucleotides Containing ModiJied Sugars. - Several functional groups have been added to the sugar moiety of nucleosides in oligodeoxynucleotides. Oligodeoxy nucleo tides containing 4-C-met hox ymet h yl t h ymidine and 4-C aminomethylthymidine have been prepared using phosphoramidite reagents 161a & b.148 The modified thymidines were synthesised from 4-C- cHhnrn C F&OH D m v N

hydroxymethylthymidine and then protected for DNA synthesis. Oligonucleotides containing these modifications form stable duplexes with complementary DNA and RNA and exhibit enhanced stability to nucleases. 3’- Deoxy-3’-C-(hydroxymethyl)thymidine and 5’-deoxy-5’-C-(hydroxymethyl)- thymidine have been prepared and used for the synthesis of novel oligodeoxynucleotides containing extended internucleoside linkages. 149 Two synthetic routes have been devised to 4‘-C-acylthymidines and the resultant compounds have been suitably-protected for oligomer assembly 162.I5O 5’-C-Hydroxymethyl- and 5’-C- hydroxypropylthymidine have been prepared and introduced into oligonucleotides using the phosphoramidite synthons 163a & 163b.I5’ 1 -(2-Bromo-2-deoxy- p-u-ri bofuranosy1)adenine and 1 -(2-bromo-2-deoxy-~-~-arabinofuranosyl)adenine have been synthesised from the corresponding 2’-0-triflates and incorporated into oligomers using the phosphoramidite reagents 164a & 164b.15* 2’-0- Methoxymethyluridine has been incorporated into oligoribonucleotides using the H-phosphonate 165.’53 An improved synthesis of the fully protected 2’-0-( 13C) methylguanosine phosphoramidite derivative 166 has been reported. 154

AcO,

R DmtO$ Dmtop 0

NCmO/ p\Npri, N C m 0 , P - N P r ‘ 2 0, N C m O , 0, P-NPr$

162 R = Me, Et, Ph 163a 163b

Oligonucleotides containing 2’-O-aminopropyl-substituted RNA have been synthesised. The 2’-0-(aminopropyl)adenosine, 2’-0-(aminopropyl)cytidine, 2‘- 0-(aminopropyl)guanosine, and 2’-0-(aminopropy1)uridine (APU) were prepared


0

164a, R’ = H, R2 = Br b, R’ = Br, R2 = H

I H-P=O

I 0- Et3h-I

165

from the ribonucleoside, protected, and incorporated into an oligonucleotide using conventional phosphoramidite chemistry using reagents 167a-dI5’ Incor- poration of aminopropyl nucleoside residues into point-substituted and fully modified oligomers does not decrease the affinity for complementary RNA compared to 2’-O-alkyl substituents of the same length. However, two APU residues placed at the 3’-terminus of an oligomer gives a 100-fold increase in resistance to exonuclease degradation, which is greater than observed for phosphor0 t hioate oligomers.

\ N 4 O

167a, B = ABL O%

b, B = CBz C, B = U d, B = GIbu

Nucleosides with an extra methylene or ethylene group attaching the base to the sugar (168a & b) have been synthesised as the corresponding protected phosphoramidites and used to assemble oligomers. 57 Hammerhead ribozymes, in which one or more of the nucleosides in the catalytic core which tolerate 2’-deoxynucleoside substitution is replaced by a homo-N-nucleoside, have been synthesised. The resultant ribozymes did not possess catalytic activity. Novel oligonucleotides containing a 3’-a-C-methylene phosphodiester bridge have been synthesised utilising phosphoramidite chemistry. The key building-block 1 -[3 ”- O-beta-cyanoethyldiisopropylaminophosphiryl-2,3-dideoxy-5-O-dimethoxytri- phenylmethyl-3-C-(hydroxymethyl)-~-~-ribofuranosyl]thymine (169) was prepared in a stereoselective manner from thymidine. 15*

Disaccharide nucleosides occur naturally in antibiotics and as modified nucleo-

5: Nucleotides and Nucleic Acids I99

OH 168a

OH 168b

sides in tRNA. The 2’-O-ribofuranosyl nucleoside 170a was synthesised by condensation of N- and 3’,5’-protected ribonucleosides with 1 -O-acetyl-2,3,5-tri- O-benzoyl-P-D-ribofuranose in the presence of tin(1V) chloride and this modification has been incorporated into oligonucleotides using reagent 170b.’59

DmtO

BzO

I O=P-0-

I

OH BzO OBz 17Oa 170b

The automated synthesis of branched oligodeoxynucleotides has been accomplished using 2’-O-levulinyl- or 5’-O-levulinyl-proteted arabino-uridine derivatives 171a & 172b as the branching monomers.’60 Selective removal of the levulinyl groups is accomplished using 0.5 M hydrazine hydrate in a pyridine- acetic acid-water buffer. The affinity of the branched oligomers towards complementary DNA has been evaluated by thermal denaturing experiments. Enhanced affinity of a branched oligomer compared with the corresponding linear reference is attributed to bimolecular triple helix formation.

NC-~,P-NP& 0.

171 R = Lev, R’ = Dmt 172 R = Dmt, R’ = Lev

Seela and co-workers have synthesised DNA in which xylose entirely replaces ribose sugar.I6’ To achieve this the synthesis of the monomer reagents has been


expanded to include a guanine synthon as its H-phosphonate or phosphoramidite derivative (173 a & b). Xylose nucleosides were also attached to controlled pore glass via a succinate linker. A phosphoramidite derivative of 1 -(P-D-glucopyrano- sy1)thymine has been incorporated into oligonucleotides. ‘62,163 Oligonucleotides containing 1 -(P-D-galactopyranosy1)thymine have also been synthesised. Per- iodate oxidation of the sugar has been investigated with a view to using the resultant oligomers for protein-DNA cross-linking experiments. 164

173a 173b

Catalytic RNAs containing (-)-carbodine (carbocyclic cytidine) and (-)-arister- omycin (carbocyclic adenosine) have been synthesised using reagents 174a & 174b.165 The hammerhead ribozymes still exhibit considerable catalytic activity. Carbocyclic thymidines with 6‘-a-methyl and 6’-a-hydroxymethyl substituents have been prepared and incorporated into oligomers using the phosphoramidites derivatives 175a & 175b.166

. .

6 &BDMS I NC-o,P-NPr‘2 0.

N C m o / p L N p r i 2

174a, B = CbZ b, B = AbZ

175a, 6 = U or CbZ, R = H b, B = U or CbZ, R = OBz

Hamm and Piccirilli have prepared oligodeoxyribonucleotides containing the modified nucleosides 2’-deoxy-T-mercaptocytidine and 2‘-deoxy-2’-mercaptouri- dine using the phosphoramidite reagents 176a & 176b.’67 Removal of the S-trityl group was afforded by treatment with silver (I) ions. Reaction of the silver- oligonucleotide complex with 2-2’-dipyridyldisulfide yielded the 2’-(2-pyridyl- dithio) derivative. Oligonucleotides could be stored as the disulfide and then liberated prior to use with DTT.

Dmtov 0, STr

NC-0,P-NPri2

17&, B = CbZ b, B = U

5: Nucleotides and Nucleic Acids 20 1

4.3.3 Oligonucleotides Containing Modijied Bases. - Oligonucleotides containing modified nucleobases continue to be of interest. Modified nucleosides are often used in the study of DNA-protein interactions, RNA-protein interactions and catalytic RNA. In addition, modifications are made to attach possible linker sites and confer properties such as ambivalent base pairing, fluorescence and enhanced stability of the oligomers to nucleases. The protected phosphoramidite derivative of 5-trifluoroethoxycarbonyl-2'-deoxycytidine 177 has been utilised in oligonucleotide synthesis. The reagent was prepared from N4-acetyl-5-iodo-2'- deoxycytidine by palladium catalysed carbonylation in the presence of carbon monoxide and trifluoroethanol. Deprotection of the oligonucleotide with methanolic solutions diaminoethane, 1,3-diaminopropane, 1 ,Cdiaminobutane, 1 $-diaminohexane or I ,7-diaminoheptane yields oligomers which can be further derivatised. This reagent has been employed to introduce thiol groups into DNA. After deprotection the primary amines are treated with N-succinimidyl-3-(2- pyridy1dithio)propionate and then with DTT to yield the free thiol. 5',5'-Disulfide linked oligomers 178 have been synthesised using this methodology. 16' This work has also been extended to the 2'-deoxyuridine series.17'

0. NC-O~P-NPli2

177 DNA 178 DNA

Oligodeoxyribonucleotides and oligoribonucleotides where the nucleobase analogue is a simple aromatic group have received some interest over the past year. Kool and co-workers have developed a methodology for C-glycoside formation and have synthesised 1 -naphthyl, 2-naphthy1, 9-phenanthrenyl and 1 - pyrenyl deoxynucleosides 179ad. These polycyclic compounds have been incorporated into DNA via their phosphoramidite derivatives. 71 C-phenyl, C-p- aminophenyl and C-naphthyl ribofuranosides have been prepared and incorporated into catalytic RNAs using the phosphoramidite reagents 18Oa-c. 1727173 The hammerhead ribozymes had enhanced rates of reaction.

A new method for the synthesis oligonucleotides containing of 5-formyl-2'- deoxyuridine has been described. '74 The protected phosphoramidite of 5-( 1,2- dihydroxyethyl)-2'-deoxyuridine (181) was prepared from 5-iodo-2'-deoxyuridine in seven steps. Following deprotection of the oligomer, subsequent oxidation of the diol with sodium periodate yielded the formyl function which could also be reduced with sodium borohydride to yield the 5-hydroxymethyl compound. An


DMov 0. OtBDMS

NC-~~P-NP~:

alternative methodology for the synthesis of oligonucleotides containing 5- formyl-2'-deoxyuridine which does not require protection of the formyl moiety has also been d e ~ c r i b e d . ' ~ ~ The oligomer assembly utilised very base labile protection for the other nucleobases in the sequence allowing rapid deprotection with a mixture of aqueous ammonia and methanol. The reagent 182 has been utilised to synthesise oligomers containing S-carboxy-2'-deoxyuridine. 176 The carboxyl function was introduced by photosensitised oxidation of thymidine.

0, NC-O, 0, P-NPr'2 NC-O/P-NPr'2

181 R = COCH3 182

The H-phosphonate derivative of a tricyclic carbazole-like 2'-deoxycytidine (183) analogue has been synthesised via a Stille biaryl coupling on 5-iodo-2'- deoxyuridine followed by cyclisation. 177 The carbazole nucleoside was incorporated in oligonucleotides and shown to pair specifically with guanine. Duplexes resulting from the carbazole analogue and complementary RNA have elevated


melting temperatures. Oligodeoxyribonucleotides containing the nucleoside analogue 1-(2-deoxy-P-D-ribofuranosyl) imidazole-4-carboxamide were synthesised by solid phase phosphoramidite technology using 184.”* Melting studies of oligonucleotides containing the analogue indicated that it preferentially pairs with T rather than dC.

BZ

183 184

The dinucleotide phosphoramidite building block 185 can be utilised to synthesise oligomers containing a pyrimidine(6-4)pyrimidone photoproduct. 179

The unstability of the photoproduct to base necessitated the use of 4-t-(butylphe- noxy)-acetyl protecting groups for dA, dG and dC allowing deprotection of the oligomers in aqueous ammonia at room temperature in two hours.

0

N Pr‘2 . / ‘0-P

‘CN

185

04-Methyl- and 02-methyl uridine have been incorporated into RNA using the phosphoramidite synthons 186a & l a b . The deprotection of these oligoribonucleotides was achieved with DBU in methanol due to the sensitivity of the modification to nucleophiles. I8O An improved synthesis of a 2-t-butyldimethylsilyl protected phosphoramidite derivative of 4-thiouridine has also been described 187.I8’ The corresponding Fpmp reagent 188 has also been reported.18’ Modified hammerhead ribozymes in which 3-deazaadenosine replaces one of the essential adenosines have been prepared using reagent 189. 18*

Leumann and co-workers have synthesised the nucleoside analogues 7-(2’- deoxy-a-D-ribofuranosy1)hypoxanthine and 7-(2’-deoxy-P-~-ribofuranosyl)hy-


0

OtBDMS 0,

NC-O/P-NPr5 186a 186b

S f - V C N

N A

187

HN L P h

Dm"k 0, OtBDMS

NC---O/P-NPr: 189

poxanthine and derivatised them for DNA synthesis as 190a & lWb.'83'184 The synthons were used to incorporate the modified nucleosides into tripler forming oligodeoxynucleotides, designed to bind to DNA in the parallel (pyrimidine. purine-pyrimidine) motif. The oligonucleotides where found to form hypoxanthine:G-C base triple with equivalent or to slightly increased (1 0-fold) stability compared with a control oligodeoxynucleotide in which the hypoxanthine residue is replaced by 5-methylcytidine. The C-nucleoside 2-amino-5-(2'-deoxy-P-u-ribo- furanosy1)pyridine and its 3-methyl and 2'-O-methyl derivatives have been synthesised and incorporated as protonated cytidine equivalents in homopyrimi- dine oligodeoxynucleotides using the phosphoramidite reagents 1 9 1 a - ~ . ' ~ ~ Melting temperature measurements indicate that oligonucleotides containing the analogue or its 3-methyl derivative have a higher affinity to double-stranded DNA over the pH range of 6-8 than, 5-methylcytidine containing oligonucleotides.

6,7-Dimethyl- 1 -(2-deoxy-P-~-ribofuranosyl)isopterin has been prepared from 6,7-dimethyl- 1 -(2-deoxy-3,5-di-O-p-toluoyl- P-D-ribofuranosyl)lumazine via thia- tion and displacement of the thio function with ammonia and then converted into the corresponding N-4-benzoyl and N-4-p-nitrophenylethoxycarbonyl phosphoramidite 192. lg6 Mixed oligonucleotides containing 6,7-dimethylisopterin as a modified base have been synthesised using a solid phase phosphoramidite strategy.

6-Methylthiopurine phosphoramidite 193 has been prepared and incorporated in to oligomers. '87 An improved synthesis of the 2'-deoxy-2-fluoroinosine nucleoside has been described.Ig8 The key step in the reaction sequence is the mild


- 190a lWb, R = H or OMe

Y H R ~

191a, R1 = Bz, R2 = R3 = H b, R1 = Pac, R2 = Me, R3 = H c, R1 = Pac, R2 = H, R3 = OMe

192 R = bz or npeoc

fluorination of 3‘,5’-0-tertbutyldimethylsilyl-6-O-p-nitrophenylethylguanos~ne with polyvinylpyridinium polyhydrogenfluoride and 0-silyl deprotection with triethylamine trishydrofluoride. The derived 5’-dimethoxytrityl-2-fluoroinosine- 3’-phosphoramidite 194 was incorporated into lo-, 15- and 20-mer oligonucleotides containing up to 7 non-natural bases. Deprotection of the oligomers with 1,4-diaminobutane resulted in oligomers containing N2-aminobutyl-2’-deoxyguanosine. A phosphoramidite with an aminopropyl group placed at the N-2- position of 2’-deoxyguanosine (195) has been synthesised from 2-chloro-2’- deoxyguanosine and incorporated into oligonucleotides. This modification shows enhanced binding properties against both DNA and RNA targets and is useful for conjugating other functionalities.

A methodology for the introduction of imidazole residues into DNA has been described by Min and Verdine. 190 An 06-phenylinosine residue incorporated into


SMe

Dm,o$

NC-~/P--NPI$ 0,

193

0,

NC-O/P-NPr'2 194

DNA by phosphoramidite chemistry was converted into 6-histaminylpurine post chain assembly by treatment with histamine. The resultant oligomers could be captured on a Ni2+ His tag affinity column. Oligonucleotides containing 6N-([C- 1 3lmethyl)adenine and 2-N-([C- 1 3lmethyl)guanine have been prepared using the deprotection step to introduce the [C- 13lmethylamine group. 1 9 * 2'-Deoxy-6-0- (pentafluoropheny1)inosine (196a) and 2'-deoxy-2-fluoro-6-0-[2-(4-nitrophenyl)- ethyllinosine (196b) were employed as precursors of the N-methylated nucleosides. Deprotection was carried out using aqueous [ '3C]methylamine.

F

The solid phase synthesis of oligonucleotides containing a site-specific modified psoralen derivative has been accomplished using reagent l!w9* The base


sensitivity of the modified nucleoside necessitated the use of very base labile (phenoxyacetyl) protection for the unmodified nucleosides. Deprotection of the oligonucleotides was achieved with a 10% solution of DNA in methanol. After hybridisation to a complementary oligonucleotide, the modified oligomer could be cross-linked to the target upon UV irradiation.

NCm0,P-NPr12 0,

197

The synthesis of oligonucleotides containing the modified nucleobase 5-aza-7- deazaisoguanine has been accomplished using the protected phosphoramidite reagent 198.65 This modified nucleobase is the complementary H-bond donor- acceptor-acceptor purine to the pyrimidine analogue 6-aminopyrazin-2( 1 H)- one. ‘93 A series of melting experiments suggests that the purine:pyrimidine analogue base pair contributes to the relative stability of a duplex structure approximately the same as an A:T base pair.

‘N’

N’ A H

198

Seela and co-workers have prepared oligonucleotides containing 7-iodo- and 7-bromo-7-deaza-2’-deoxyguanosine using either the phosphoramidites or H- phosphonates. 194 A series of 7-halogenated-7-deaza-8-aza derivatives of guanosine suitable for oligomer assembly has also been prepared.lg5 Oligomers containing these modifications have a higher melting temperature than their unmodified counterparts when bound to complementary RNA but not DNA. Protected 7-deazaguanosines which are methylated at the 7 and/or 8 position


198 that are suitable for DNA assembly have also been synthesised and subjected to structural characterisation. '96-198 An improved building block for the synthesis of oligonucleotides containing 2'-deoxyisoguanosine in which diphenylcarbomyl protection was employed has been reported. 199-202 Oligonu- cleotides containing 2'-deoxyisoguanosine have been employed to study tetra- plex formation.

The synthesis and hybridisation properties of oligodeoxynucleotides containing 74 1 -propynyl)-7-deaza-2'-deoxyguanosine and 74 1 -propynyl)-7-deaza-2'-deoxyadenosine have been described. The suitably protected nucleosides 199a and 199b were synthesised and incorporated into 01igomers.~~~ Thermal denaturation of these oligomers hybridised to RNA demonstrates an increased stability relative to 7-unsubstituted deazapurhe and unmodified controls.

NC,,,~~ 0. P-NP~'~

199b

Derivatives of 6-(2-substituted vinyl)-2-aminopurine have been incorporated into oligonucleotides using the phosphoramidite reagent 200.204 The free nucleoside has been demonstrated to cross-link with cytidine and guanosine.

A series of chloro-, fluoro- and nitro-protected nucleoside phosphoramidite derivatives of quinazoline-2,4-dione (201) has been prepared and their ability to form DNA triplexes has been assessed.205

R o x

0. 0. NC-OH P-NPr'2

N C m 0 , P - N P r i 2

200, R = Me or TMS 201, X = F , Y = Z = H X=CI, Y = Z = H X = Z = H , Y = C I X = Y = H , Z = C I X = Z = H , Y = N 4

5: Nucleotiiies und Nucleic Acids 209

5 Linkers

A new family of non-nucleosidic phosphoramidite reagents derived from either esters or amides of 2,2-bis(hydroxymethyl)malonic acid has been prepared (202a- b).206 The phosphoramidite reagents have been used to prepare 5’-phosphorylated oligonucleotides as well as hydrophobic, pol yamino and fluorescent labelled oligonucleotide analogues. A related method for the solid phase synthesis of 3’- phosphorylated oligonucleotides has been descri bed.207 The chain assembly is carried out by phosphoramidite strategy on solid support (203). 3’-Phosphory- lated chimeric oligonucleotides containing methyl phosphotriester and methyl phosphonate internucleosidic linkages have been prepared using the malonate derived support. A series of disulfide solid supports has been prepared and investigated in oligonucleotide syn thesis.208

OR

NC-0. OR P-0 I . NPrI2 0

R = n-Oct 202a, R = Et

<O--P-NP&

202b, R = COCF3, Fmoc or dansyl NC-04 &

203

Gait and co-workers have introduced disulfide cross-links into RNA to study the inter-domain distances in the Hairpin ribozyme. The cross-link 204 is introduced by post synthetic derivatisation of 2’-amino-2’-deoxynucleosides in the RNA.209 Sigurdsson and Eckstein have reported the modification of 2’-amino groups in oligoribonucleotides, through their reaction with aliphatic isocyanates, to give the corresponding 2’-urea Modification with (2-isocyana- to)ethyl 2-pyridyl disulfide (205) enabled subsequent coupling to other thiols or to thiol-reactive electrophiles.

205


Reagent 206 has been prepared that allows disulfide cross-links to be introduced into nucleic acids during solid-phase synthesis.2’ The disulfide is formed between thioalkyl tethers at the N-3-position of thymidines and stabilises the termini of nucleic acid helices. Disulfide linked triplexes have been studied.212

~ B D M S 0 I .

206 NC-O/ P-N p+2

A linker containing a 2,4-bis(4-carboxyphenoxy)-6-methoxy-S-triazine amide group was introduced into a oligonucleotide using reagent 207. However, an aliphatic non-nucleotide linker was found to be more effective than an aromatic linker derived from 207, in stabilising oligonucleotides triplexes.213

0

H - - I

N’ A N

DmtO-(CH2)6-N-C “O0ANAO*r: C-N-(CH2)s-O-P-H H I1

0- 207 Et$H

A series of oligonucleotides covalently linked to an 9-amino-6-chloro-3-meth- oxyacridine via a variable length linker was prepared using L-threoninol derived phosphoramidite reagents 208. Although all of the modified oligonucleotides could bind to the complementary oligonucleotides, the behaviour of intercalation of the acridine ring .was strongly affected by linker length and the base- sequence.214721 A series of Rhodanol phosphoramidite derivatives (209) has been synthesised and used in oligomer A new methidium intercalator phosphoramidite has been ~ y n t h e s i s e d . ~ ~ ~ A dialkyl-substituted anthraquinone derivative (210) has been synthesised and attached to an oligodeoxynucleotide bearing a primary amino group to examine the efficiency and specificity for cross- linking to complementary sequences of DNA.218 Covalent modification of the target DNA was induced by exposure to near UV Ferrocene has been linked to oligonucleotides using a similar strategy (21 l).219

The synthesis of a sapphyrin-oligonucleotide conjugate has been accomplished using reagent 212.220 The sapphyrin-oligonucleotide conjugate produces photo- damage on a complementary oligonucleotide target when irradiated at wavelengths above 620 mm. Conjugates of oligonucleotides with chlorin-type photo-

5: Nucleotides and Nucleic Acids 21 1

Dmto$:e' N--C-(CHz)"-N , H G ' N

CI 208 n = 3-5 NC-00P-NPr12

**-b 0

21 0

g0-b 0

Q 211

sensitizers have been prepared using a post oligonucleotide synthesis assembly strategy involving a 3'-activated phosphate.221

0 II

1 H

.O-P-O- +HNEt3

21 2

A fluorescent Hoechst 33258 derivative has been prepared in which a hexa(ethy1ene glycol) linker is attached to the terminal phenol residue. Conjuga- tion of this derivative to DNA sequences was accomplished by a reversed


coupling protocol. The 5'-terminal nucleoside residue of a fully protected DNA sequence was converted into a terminal phosphoramidite. In the presence of the Hoechst derivative and tetrazole, the final coupling reaction is achieved to generate the conjugated nucleic acid 213.222 The properties of oligomers bearing the Hoechst derivative have been The synthesis of oligonucleotides containing 5-amino-(carboxyfluorescein)-2'-deoxyuridine has been achieved using reagent 214.224 Oligonucleotides containing 5-( 1 -pyrenylethynyl)-2'-deoxyuridine have been synthesised by palladium catalysed

H

21 3

OCO(CMe)3 /

OCO(CMe)3

0,

NC-O/P-NPr'2 214

Methods for the introduction of flavin analogues to the 5'-end of oligonucleotides have been investigated. Surprisingly, after reaction of the corresponding alcohol with 2-cyanoethyl N,N-diisopropylchlorophosphoramidite, the flavin phosphoramidates 215a & 215b were isolated instead of the expected phosphor-

0 0

0 I

O=P-H I 0-

215c, n = 3 d, n = 6

NPR$ 215a, n = 3

b, n = 6

5: Nucleotides und Nucleic Acids 21 3

amidite derivatives. Flavin H-phosphonates 21% & 215d were found to be suitable for the preparation of flavin-oligonucleotide adducts.226

An alternative reagent (216) has been prepared for the synthesis of biotinylated oligonucleotide^.^^^ In this case the protection used for the biotin moiety is base labile rather than the conventional dimethoxytrityl. The photo-crosslinking behaviour of oligonucleotide constructs, incorporating photoactive residues 217ad at a defined position, has been examined in the presence of their DNA and RNA complementary targets.228 The X-ray crystal-structure of the photoproduct formed between 4-thiothymidine and adenosine upon near UV irradiation has been reported.229

21 6 R = tert-butylbenzoyk, benzoyl-, phenoxyacetyk, frans-cinnamoyl

0

r OH

217a, X = -(CH2)2CONH(CH2)2NHCOCH2- b, X = -(CH2)2CONH(CH2)4NHCOCH2- C, X = -NH(CH2)2NHCOCH2- d, X = -C=CH*NHCOCH2-

A method for the solid phase synthesis of 3'-modified oligonucleotides has been described.230 The general synthetic scheme involved the immobilisation of 5'- DMTr-T to CPG via a sulfonate linker, 218, oligonucleotide synthesis and


subsequent basic treatment to afford 3’-modified oligonucleotides containing a 2,3’-anhydronucleoside moiety. These compounds were transformed into 3’- substituted oligonucleotides such as a 3’-deoxy-3’-azido species. Oligonucleotides bearing 3’-mercaptoalkyl or 3’-aminoalkyl functions have been prepared using the solid supports (219a-d).23’

A derivatised solid support (220a) and a phosphoramidite reagent (220b) have been prepared which mimic an abasic site and allow the conjugation to oligonucleotides of biotin, cholesterol, and the synthesis of oligonucleotides containing primary amino

DmtO

V 220a

N C o O , 0, P-NPri2

220b

Site-specific recombinases and topoisomerases catalyse the breaking and rejoining of the phosphodiester bonds of DNA. Both classes of enzymes do so through the formation of a covalent intermediate involving a phosphodiester bond with a hydroxylated amino acid (usually tyrosine). Hecht and co- workers have utilised oligonucleotides containing 5’-thio, 5’-amino, and 5’- hydroxymethylene synthesised using the phosphoramidite reagents 221a-c to form unnatural internucleoside linkages.233 The linkages were formed by utilising the modified oligomers to displace a Topisomerase-I-DNA covalent complex.

Oligonucleotides that bear a 3’-phosphoryltyrosine residue linked to the phosphoryl group via a phenolic hydroxyl group are effective substrates for the assay of ligation by the FLP recombinase and mammalian Topisomerase-I. A series of oligonucleotides (222a-f) bearing several modified 3’-phosphoryl sub- s tituen ts has been syn t hesised. 234 Oligonucleotides bearing a 3’-phosp horyltyro- sine residue N-substituted on tyrosine with the bulky fluorescent groups dansyl and pyrene are ligated effectively by the FLP recombinase and the dansyltyrosine derivative is used as effectively as the tyrosine adduct by mammalian topoisome- rase I.

The synthesis of a new C-branched spermine derivative and its ability to stabilise DNA duplexes and triplexes has been The C-branched


D m t S v A b z M m t H N y A b z DmtO ’eJ 0, 0,

NC-00P-NPr‘2 NC-OHp-Np+2 N C o 0 , P - N P r i 2 0,

221 a 221 b 221 c

spermine was converted into the corresponding 0-(2-~yanoethyl)-(N ,N-diisopro- py1)phosphoramidite block 223a for incorporation at the 5’-end of DNA. It was also coupled to the 2’ of ara-U through a phosphate bridge, leading to the

P-oligo

H2N CONH2

222a

P-oligo

NH2 2224

S-N

0

222b

P-oligo I NH

222e

P-oligo I 0

I

? C02NH

P-oligo I 0

P C02NH2

222c

P-oligo I

0 2221

partially protected 3’-hydroxy derivative, which was either converted into the 0- (2-cyanoethyl)-(N,N-diisopropyl)phosphoramidite 223b or to the 3’-succinate 223c. This enabled the synthesis of three oligonucleotides with tethered spermine at the 5’-end, with tethered spermine in the middle of the DNA strand, and with spermine at the 2’-end.

The synthesis of duplex DNA containing a spin-labelled analogue of 2’- deoxycytidine has been reported.237 The synthesis utilised the reagent 224.


H

pacN?

D m t o ~ u ;Me

OR

O - L O ~ ~ V N H P ~ C

N-Pac Pac

LNHPac

I 223b, R = P , ; N ' ~ ' ~ ~ ~ ~

2 2 3 ~ , R = -CO(CH,),CONH(CH,),CoNH(CH2)~~

0, NC-OcP-NPr'2 224

6 Interactions and Reactions of Nucleic Acids with Metal Ions

The metal ion catalysed hydrolysis of polynucleotides continues to be of interest. The Zn2+ promoted hydrolysis of short oligoribonucleotides has been The results obtained show that the presence of an adjacent phosphate group enhances the metal ion promoted hydrolysis of phosphodiester bonds. The effect of dianionic monophosphate groups is 10-fold larger than that of the mono- anionic phosphodiester bond. Chimeric DNNRNA molecules, containing RNA nucleotides embedded in DNA sequences, have been used as substrates for studying the transesterification of RNA.239 The substrates display the simplicity of dinucleotide substrates while possessing the multiple phosphate and nucleobase metal-binding sites found in polyribonucleotides.

Various metals have been complexed to oligonucleotides to produce hydrolytic or oxidative cleavage of a target nucleic acid. Lanthanide complexes covalently attached to oligonucleotides are known to cleave single-stranded

5: Nucleoticies and Nucleic Acids 217

RNA in a sequence-specific manner. RNA in a duplex is considerably more resistant to strand scission. To overcome this limitation, lanthanide complexes covalently linked to oligodeoxyribonucleotides have been targeted to a partially complementary RNA at a bulged site, in a duplex region.40 Strand scission occurred at or near the bulge. A manganese cationic porphyrin covalently linked to the 5’-end of an antisense oligonucleotide has been shown to mediate sequence-specific oxidative lesions on a mRNA target when activated by KHS05.24’ Sequence-specific cleavage of an oligodeoxyribonucleotide by a major-groove-positioned iron-bipyridine complex tethered to C-5 of deoxyuridine has been described.242

In the presence of oxygen donor compounds, a functionalised salen-nickel complex (225) has been demonstrated to poorly cut double-stranded DNA but to induce strong cleavages at guanine residues in the single-stranded region of hairpin o l igon~cleo t ides .~~~ The chemistry of RNA degradation by Fe bleomycin has been studied.244

‘NH3 225

There is considerable interest in the role of metal ions in ribozyme catalysed cleavage of RNA. Evidence has been presented which suggests that direct coordination of a Mg2+ ion with the pro-R-oxygen of the scissile phosphate in the transition-state of a hammerhead ribozyme catalysed reaction may not take place.245 In last year’s review, the synthesis of substrates of the hammerhead ribozyme that consisted entirely of deoxynucleotides with the exception of the single mandatory ribonucleotide at the cleavage site which contained either a 5’- oxy- or 5’-thio-leaving group was discussed. Experiments with these substrates suggested that the departure of the S-leaving group was not the rate-limiting step of a hammerhead ribozyme-catalysed r e a ~ t i o n . ~ ~ ~ - ~ ~ * A natural all-RNA substrate that contained a 5’-thio-leaving group at the cleavage site has recently been synthesised and investigated.249 From this study, it was suggested that the attack by the 2’-oxygen at the phosphorus atom is the rate-limiting step only for the substrate that contained a 5’-thio group and that the departure of the 5’-leaving group is the rate-limiting step for the natural all-RNA substrate in both enzymatic and non-enzymatic reactions. Ribonuclease-P has been converted to a CD2+ dependent ribozyme by a single Rp-phosphorothioate modification in the precursor transfer-RNA at the RNase-P cleavage site.250 In contrast to the


hammerhead and RNase-P catalytic RNAs, it has been suggested that metal ions do not play a catalytic role in the hairpin ribozyme catalysed r e a ~ t i o n . ~ ~ l - ~ ~ ~

Hammerhead ribozyme variants, each containing an abasic site mimic (226) at a specific position of the catalytic core have been synthesised. The activity of each of the variants is significantly reduced. In some cases catalytic activity can be rescued by exogenous addition of the missing n ~ c l e o b a s e . ~ ~ ~

5‘ 1

-0-P=O I

1 3’

226

7 Nucleic Acid Structures

Studies on the structure of nucleic acids continue to be of great importance. X- ray crystallography, NMR and mass spectral characterisation are the most important techniques employed in this regard. Fluorescence studies of nucleic acids have been of interest for some time. Since none of the common nucleobases are intrinsically fluorescent, these studies normally involve the attachment of a fluorophore by a chemical linker. This year two studies have employed the fluorescent nucleobase 2-amino purine as a structural probe to observe conformational changes in RNA. Synthetic oligoribonucleotides in which the fluorescent nucleobase replaced one of the natural nucleobases were utilised in these experiments. 256*257

The bending of DNA has been studied by joining a pair of triplex forming oligonucleotides by a variable length

The structures of several modified oligonucleotides have been elucidated by N MR techniques. A duplex oligonucleotide containing a single 1 -(2-O-methyl-P- r,-aribinofuranosyl)thymine,260 a self-complementary duplex containing an alpha-anomeric t hymidine, 261 a duplex containing 3, N-3-etheno-2’-deoxycytidine opposite thymidine262 and adenine263 have all been studied. The structure of an oligodeoxyribonucleotide with methylphosphonate linkages bound to an oligoribonucleotide has been reported.264 The structure of formacetal and 3’-thiofor- macetal linkages in duplexes have also been

The solution structure of a 2-base DNA bulge complexed with an enediyne cleaving analogue has been reported.266 The tetramer formed from d(5mCCTCC) (where 5mC is 5-methylcytidine) has been studied by NMR.2679268 d(CpG) Steps in oligonucleotides have been studied in detail by NMR.269 The structures of oligodeoxyribonucleotides and oligoribonucleotides containing 5-fluorouracil have been reported.270 NMR spectroscopy has also been used to examine the


adduct of the antitumour antibiotic hedamycin with an oligon~cleotide~~' and the structure of the oligosaccharide calicheamicin bound to a self complementary DNA.272 The binding of a cobalt(II1) complex to a duplex DNA has also been investigated by NMR.273

NMR studies of RNA have greatly benefited from isotope labelling which allows the introduction of C-13 and N-15. A method to generate isotope-labelled DNA for NMR studies has been described.274 The structure of a series of RNA hairpin loops containing the GNRA consensus sequence has been studied by NMR.275 The structure of a duplex containing GU mismatches has also been determined. 276

One of the most exciting developments in the chemistry of nucleic acids over the last few years has been the development of the technique of in vitro selection. In vitro selection is a nucleic acid based combinatorial chemistry technique in which RNA or DNA with a desired property is isolated from a pool of random molecules. The technique and progress in the area has been reviewed by Breaker.277 Structures of RNA ligands that bind to FMN, ATP, arginine and citrulline have been reported and reviewed.278 Highlights this year have included the selection of an RNA that binds to D-arginine and demonstration that the L-

isomeric RNA binds to ~ - a r g i n i n e ~ ~ ~ and isolation of an L-RNA that binds D-

adenosine using the same strategy.280 Libraries containing modified nucleic acids have also been employed, Ligands which bind to human keratinocyte growth factor have been isolated, containing RNA with 2'-fluoro and 2'-amino modifications.281 Catalytic RNAs and DNAs have also been isolated using this technique. RNA molecules which catalyse ligation of phosphodiester bonds283 have been isolated. DNA molecules which catalyse the cleavage of RNA and DNA have also been

The crystal structure of an unmodified hammerhead RNA in the absence of divalent metal ions has been solved.286 The X-ray crystal structure of the oligonucleotide d(GGCGAATTGG) has been described.287 It was designed to contain the d(G.GC)2 fragment and thus provide the basic repeat unit of a DNA triple helix. Parameters derived from this crystal structure enabled construction of models of both parallel and antiparallel triple helices. A variety of physical techniques has been used to investigate the structure of DNA containing the deoxyribosyl derivative 5-nitr0indole.~~~

A new method for building three-dimensional structures of DNA sequences has been developed.2897290

Mass spectrometry of nucleic acids continues to develop rapidly. The uses of electrospray ionisation (ESI) and matrix-assisted-laser-desorptionhonisation time of flight (MALDI-TOF) mass spectrometry (MS) in DNA sequence analysis has been discussed.29' A method for combining HPLC and negative ion mode ESI for the analysis of oligonucleotides has been described.292 An on-line clean up procedure for oligonucleotides for use in conjunction with ESI-MS has been reported.293 The stoichiometries of DNA-protein complexes have been determined.294 Reduction in charge states and suppression of sodium adduction during ESI-MS has been achieved by the addition of organic acids and bases.295 Charge distribution as a function of counter-ion concentration has been investi-


gated.296 Positive ion ESI-MS has been used for D N A and RNA samples.297 Procedures for the interpretation of mass spectra from collision-induced dissociation of oligonucleotides produced by electrospray with a view to obtaining sequence information have been In the area of MALDI-TOF MS most reports have concentrated on the choice of matrix and c o - m a t r i ~ . ~ ~ ~ - ~ ~ ~ Quantitative detection of oligonucleotides has also been studied and a nuclease assay based on MALDI-TOF MS detection has been Peptide- oligonucleotide conjugates3I0, PNA'33 and methylphosphonate containing oligonucleotide~~ I I have been characterised. Sequencing strategies for short oligomers using calf spleen phosphodiesterase have been reported.312 Very accurate masses with less than 10 pmol of sample can be obtained using MALDI-TOF MS.313

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K. A. SannesLowery, D. P. Mack, P. F. Hu, H. Y. Mei, and J. A. Loo, J. Am. Soc. Muss Spectrom. , 1997,8, 90-95. J. S. Ni, S. C. Pomerantz, J . Rozenski, Y. H. Zhang, and J. A. McCloskey, Anal. Chem., 1996,68, 1989- 1999. D. P. Little, D. J. Aaserud, G. A. Valaskovic, and F. W. McLafferty, J. Am. Chem.

D. P. Little, A. Braun, B. DarnhoferDemar, A. Frilling, Y. Z. Li, R. T. McIver, and H. Koster, J. Mol. Med., 1997,75, 745-750. S. W. Cheng and T. W. D. Chan, Rupiri Commun. Muss Spectrom., 1996, 10, 907- 910. N. P. Christian, L. Giver, A. D. Ellington, and J. P. Reilly, Rupid Commun. Muss Spectrom., 1996, 10, 1980- 1986. I. G. Gut, W. A. Jeffery, D. J. C. Pappin, and S. Beck, Rupid Commun. Muss Spectrom., 1997, 1 1 , 43-50. T. A. Simmons and P. A. Limbach, Rupici Commun. Muss Spectrom., 1997, 11, 567- 572. N. X. Xu, Z. H. Huang, J. T. Watson, and D. A. Gage, J. Am. Soc. Muss Spectrom.,

Q. J. Yan, S. C. Yang, Y. Cai, S. Q. Wang, and B. Z. Zhu, Acta Biochim. Biophys. Sin., 1997,29, 475-480. Y. F. Zhu, N. I. Taranenko, S. L. Allman, S. A. Martin, and C. H. Chen, Rupid Commun. Muss Spectrom., 1996, 10, 1 59 1 - 1 596. B. A. Bruenner, T. T. Yip, and T. W. Hutchens, Rapid Commun. Mass Spectrum.,

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68,2141-2146.

6 Ylides and Related Species

BY N. BRICKLEBANK

1 Introduction

The format of this chapter is similar to that used in previous volumes. The first section deals with methylene phosphoranes and their Wittig reactions, the second looks at the Horner-Wadsworth-Emmons reaction of phosphonate anions and the third the structure and reaction of lithiated phosphine oxides - an area which continues to receive particular attention. The majority of reports concerning ylides relate to their use in synthesis and in the final section some of these applications are reviewed.

During the past year several other reviews have been published which cover different aspects of ylide chemistry. The mechanism and stereochemistry of the Wittig reaction has been reviewed.' Lawrence2 has surveyed methods of alkene synthesis involving the Wittig, Horner-Wittig and the Horner-Wadsworth- Emmons reactions. A comprehensive review of fluorine containing phosphonium ylides and related nitrogen, arsenic and antimony compounds has a ~ p e a r e d . ~ A short report of functionalised organophosphorus monomers and pharmacuetical intermediates includes a section on Wittig reagents?

2 Methylene Phosphoranes

2.1 Preparation and Structure. - The structure of triphenylphosphine benzylidene 1 has been reported.' The Ph3P=CHPh molecules associate as pairs through the formation of weak intermolecular C-H . . . C hydrogen bonds between the ortho-H atom of the benzylidene group of one molecule and the carbanion- carbon of the other.

Ph

Ph 1


23 1


Density functional theory has been used to calculate the P-E bond energies and orbital populations of trimethylphosphine chalcogenides and related compounds.6 The results indicate that Me3P=CH2 has a n-bond order of 0.5. The equilibrium acidities in DMSO solution and gas-phase homolytic bond dissociation energies of tributylphosphonium ylide precursors have also been determined.7

High-spin cation radicals 2 and 3 can be obtained by oxidation of the parent methylene phosphoranes.8 Dication radical 2 has a triplet state as evidenced from a A M , = + 2 ESR transition exhibiting hyperfine coupling to two identical phosphorus nuclei. The trication radical 3 possesses a quartet state with D = 262 MHz and E=O MHz and exhibits a A M s = + 3 ESR transition. The archetypal methylene phosphorane H3P+CH2' has been investigated in the gas phase using ion cyclotron resonance mass spectrometry.'

A new route to so-called instant ylides has been reported." These are obtained from powder mixtures of alkyltriphenylphosphonium salts and potassium hydride in a 1:l mole ratio. Addition of tert-butylmethyl ether results in the generation of the triphenylphosphino-alkanide. These simple phosphonium salt/ KH mixtures are said to offer little advantage over sodium amide based instant ylides. However, those containing hetero-substituted phosphonium salts have a much longer shelf life than their sodium amide counterparts.

A novel methanofullerene (4) containing a stable phosphorus ylide has been obtained from the reaction of C60 with triphenylphosphine and dimethyl acetylenedicarboxylate. I An improved route to benzyl-, thienyl- and dimethylamino- phenyl-substituted phosphonium salts has been described (scheme 1). I 2 The new method has several advantages over previous routes, including high yields and ease of purification.

During the past twelve months a number of new phosphonium betaines and zwitterions has been reported. Reaction of ylides with acylisocyanates or acylisothiocyanates in methanol proceeds via a cyclization yielding pyrimidine substituted triphenylphosphonium salts (5) which can be converted into the corresponding betaines. l 3 The crystal structures of triphenylphosphonium-carboxylate betaines 6 and 7 have been reported.I4 Betaines 6 and 7 were obtained

6: Ylides uncl Related Species 233

4

from the reaction of Ph3P and Ph2P(CH2)2PPh2 respectively with acrylic acid in ethyl acetate/acetone. Reaction of Ph3P with fumaric acid under identical conditions did not produce the expected betaine but decarboxylates in situ producing 6. As might be expected 6 and 7 form adducts with water and acetone through extensive hydrogen bonding interactions leading to ring or chain type assemblies. Similarly, reaction of 'Pr3P and 2-cyanoacrylates, CH2(CN)C02R (R = Me, Et), leads to the formation of zwitterions 8 and 9.15 X-Ray analysis of 9 provides evidence for the delocalisation of the negative charge to the CO and CN functions. Reaction of phosphine 10 with benzophenone produces phosphonium- boryl betaine 11, whereas reaction of 10 with benzoyl(pheny1)diazomethane leads to the phosphaazoniaboratacyclopentadiene 12 (scheme 2). l 6

A 5 x=o,s

RCH20H + Ph$H B r - RCH2bPh3 B r R = Ph, 2-thieny1, p(M%N)C6H4-

Scheme 1

CN p+\t -/

CN Pr'-P-CH2-C

\ \

-/ Pri-P-CH2-C

t

Pr" C a M e P$' C02Ef

The syntheses and reactions of silyl-substituted ylides have attracted particular attention.'7-24 Schmidbaur and c o - ~ o r k e r s ' ~ ~ ' ~ have reported some reactions of


Ph2P phXBu BBup

10 E * PhC-CPh

phMBu Ph2 Ph2C dBBU2

11 0

12 Scheme 2

dialkylaminophosphonium ylides with silyl reagents. A series of ylides bearing silyl groups (13) were prepared either by trans-ylidation of (R12N)3P=CH2 and R23SiX (X=Cl, OTf) or through the action of a base on the corresponding silylated phosphonium salts.’* The bis-ylides 14 were obtained in the same way by using difunctional silanes. All of these ylides are thermally stable, distillable, liquids. The structures of ylides 15 have been characterised crystallographically and feature a trigonal-planar ylidic-carbon and short ylidic C-P and C-Si bonds. l 9 Reaction of the C-silylated phosphonium salt [‘Bu3P=CH(SiMe3)]A1C14

H

SiR32 (R2lN)3P=C(

13 R1 = Me, Et; R2 = Me, CI, Br, OMe, Pr‘O, NMe2

SI R22 Sit73

\ I H H SiR3

(R2’N)3P=C0 ‘C=P(NRz1)3 (Me2N)3P=C,

14 R1 = Me, Et; R2 = Me, OMe, OEt, NMe2 15 R3 = Me3, MePh

with an excess of AlCI3 leads to phosphorane 16 which has also been characterised crystallographically.20 Diphosphapentalenes 17 and diphosphaazulenes 18 were prepared by the cycloaddition of (R’2N)2PC=CP(NR12)2 (R’ = Me, Et) and R202CC = CC02R2 (R2 = Me, Et).2’ The reaction of Ph2PC = CPPh2 and Me02CC = CC02Me gives diphosphacyclopentazulene 19.21 A series of interesting phospholides has been synthesised by Schmidpeter and c o - w o r k e r ~ . ~ ~ ~ ~ ~ Reductive condensation of Ph3P=C(SiMe3)2 and PC13 or PBr3 yields the triphospholide cations 20.22 The reaction proceeds via the formation of trihalopho- spholanes 21. Oxidation of 20 with X2 regenerates 21. Methylation of diphospholide 22 with methyltriflate generates the diphosphole 23.23 A single- crystal X-ray analysis of 23 revealed that the 6n-aromatic system is preserved, in contrast to the situation in the other known phospholes. The methylated phosphorus atom displays a flat pyramidal geometry, the sum of the angles being 339 ’, and thus represents an intermediate between a phosphine and a bis(methy-

6: Ylides and Related Species 235

I 6 17 R' = Me, Et

Me2N Me02C

Me0&

M e 0 2 C C ~ c 18 R2 = Me, Et 19

1ene)phosphorane. Condensation of Ph3P=C(SiMe3)2 with PC13 or PBr3 produces the cyclic trimers [(Ph3P=CPX)3] which undergo dissociation in solution producing 24.24 Not surprisingly, the halide ions, halophosphine and phosphenium moieties in 24 undergo rapid exchange.

20 X = CI, Br 21 X=CI, Br 22 X = CI, Br

23 24 R = X = C I , Br R=Ph, X = C I

Structyral analysis of ylidic chlorophosphine 25 revealed a P-C1 bond length of 2.262( l)A.25 This is the longest P-CI bond in an acyclic chlorophosphine reported to date. Reaction of the phosphonium salt [(rn-CH3C6H4)CH2PPh3]Br with PC13 in the presence of triethylamine gives phosphorane 26.26 The analogous ethyl- substituted derivative has also been prepared (scheme 3).26 Dichlorophosphino ylides 27 readily lose a chloride ion to Lewis acidic metal chlorides producing cationic species 28 (scheme 4).27 NMR and X-ray structural data for 28 show that a considerable amount of the phosphenium charge is transferred to the phosphonium ion, leading to a chlorophosphaalkene structure. This is demonstrated by the GaC14 adduct which shows definite contacts between the anion and cation


such that the coordination sphere of the P(II1) atom is not the expected two- coordinate "-trigonal but tetra-coordinate Y-trigonal b i~yramida l .~~ Condensa- tion of ylidyl dihalophosphines with trimethylsilyl ylides affords bis(ylidy1)phosphenium halides 29 (scheme 5).28

/o Ph

P I Ph3P=C,

CI PCI?

Ph3P=C< ,Me

25 26

/E' PC13 Et i, Na(N(SiMe&], C6H6

ii, MesSiCl [Ph3PCH2Et]Br * Ph3P=C\ - Ph3P=C

SiMe? PCI2 Scheme 3

\ + MCI, Me3Si \

/

27

Me3Si C=PC12 - ,C=P-CI

28 I Ph3P Ph3P

(M = Al, Ga, n = 3; M = Sn, n = 4)

Scheme 4

MCI" +1-

Structural analysis of 29 reveals an essentially planar PCPCP skeleton with (E),(E)-conformation. Phosphenium salts 29 are protonated at an ylidic carbon atom with the concomitant re-association of the halide to the central phosphorus atom. They are oxidised at the central phosphorus atom, by halogen or ortho- quinones, giving phosphonium salts, or by elemental sulfur or selenium to

-2 MqSiCl Ph 2 Ph3P=C + PC13

\

29 SiMe3

Ss. E W Sex, EtpNH

Ph Ph

Ph3P 'P'PPh3 // = Ph3P A PA II PPh3CT

30 E X E

E = S, Se Scheme 5

6: Ylides und Related Species 237

produce bis(ylidy1)thio- or seleno-phosphinyl halides 30 (scheme 5).28 Dipho- sphinine 31 and azadiphosphinine 32 are obtained from the condensation of (E)- Ph3P=CHC(Ph)=CHP+PPh3 with Ph3P=C(PC12)2 and PhN(PC12)2, respectively. Again, the P(II1) ring members can be oxidised by elemental sulfur to give the mono- or di-thioxo derivative^.^^

The cycloaddition reaction of azides with the products generated in situ from the condensation of Ph3P=C(SiMe3)2 with PC13 leads to phosphoniotriazaphos- pholes 33 and to the zwitterionic phosphoniotriazaphospholide 34.30 Heterocycle 34 is unstable, undergoing cycloreversion, forming Ph3P=C=N2 as an intermediate, eventually yielding diphosphonio-diazaphospholide chloride 35 as the final product. The structure of (35) was determined crystallographically. Di- methylaminobis(trifluoromethyl)borane, (CF3)2BNMe2, forms adducts 36 with methylenephosphoranes Ph3P=CHR (R = H, Me).3'

H CFQ I I - N=N N=N

N=N Ph3P-C--BNMe2 /Abph3X- $ x , P h 3 P h 3 P A p r b P h & r R I I CF3

P 33 X = AICI4-, GaCI4-, CF3S03- 34 35 36 R = H, Me

Cyclic aza-ylides can be generated from the cyclic aminophosphonium salts 37.32 The ylides thus formed were treated with a-chlorovinyl sulfone in the presence of sodium hydride to give sulfonylethylenes.

Ph,+,ph Qh" 37 n = 1 , 2

The synthesis and properties of ylidic four-membered rings with four 7c-

electrons provides the subject for a short review by we be^-.^^ The reactions of 1,1,3,3-tetrakis(dirnethylamino)- 1 h5,3h5-diphosphete (38) with Ph2PCI and Me1 form the basis of a study by Rosche et ~ 1 . ~ ~ These reactions are summarised in (scheme 6).

The reactions of phosphoryl-substituted ylides 39 with PF5 in MeCN solution have been investigated using 3'P and I9F NMR s p e c t r o ~ c o p y . ~ ~ * ~ ~ Generally, the reactions produced the cis-chelated adducts i. e. [392PF4]+PF6-, though, depending upon the R group and the temperature, the linear species [392PF5] and [39(PF&]could also be identified in solution.

238 Orgonophosphorus Chemistry

The first ylides bearing the trifluoromethyl group have recently been reported (scheme 7).37 Unfortunately, the ylides are thermally unstable but can be trapped as the corresponding 1 ,2,h5,05-oxaphosphetanes.

Bu3p4:b C 1 3 C 0 6 p h 3 B , , - H3C - H

40 41

p 2 H I

(Me2N)2P-C-PPh2 Ph2PCI (Me2N)2P-CH Ph2PCI ( Me2N)2P-C I :+ I 7 I I II ____) I i:: I

CT 38 cr HC-P(NMe2)2 HC- P( N Me2)2 H2C-P(NMe2)2

1 Me1 I Li[N(SiMe&]

Me H I * ,PPh2 BuLi (Me2N)2P-C-Me (Me2N)2P-C c-- I :+ I II II

(Me2N)2P-C' II I I

HC-P( N Me& HCzP(NMe2)2 HC-P(NMe2)2 1-

Scheme 6

R2PCF3 CH30S02CF3 [ R2p[::]' CF3S03- Li[N(SiMe3)2] * R2P\\ /cF3 - F3CCOCF3 Y J e R-P

R = NEt2, Me, Pr' CH2 R' I Scheme 7 -3

PPh3 C02Me II PPh3 Me02C-C - CH= C I I \

Me02C-C-CH=CHCOR CR~=CHCOR'

42 R = 2-fury1, 2-thienyl 43 R' = 2-furyl, 2-thienyl; R2 = CF3, C3F7

'R J 44 R = Ph, 2-thienyl

Tri-n-butylphosphine carbon disulfide adduct, Bu3P+CS2-, reacts with norbornene producing ylide 40.38 Treatment of phosphonium salt 41 with butyl lithium in THF yields the corresponding ylide, which can be stabilised by abstraction of the trichloromethyl Reaction of phosphonium salts [Ph3PCH2COR]Br (R = 2-furyl, 2-thienyl) with methylpropynoate in the presence of potassium carbonate produces phosphoranes 42 as the main product.40 Compound 42 can be further treated with R2C-CC02Me (R2=CF3, C3F7) giving ylides 43 which undergo an intra-molecular Wittig reaction producing the corresponding dimethyl 4-(a-furyl)- or 4(a-thienyl)-6-perfluoroalkylisophthalates in high yields.40 Phosphonium salts 44 are produced in 80% yields by nucleophilic substitution of RCOC = CBr (R = Ph, 2-thienyl) and Ph3P in diethyl ether.41

6: Ylides und Reluted Species 239

2.2 Reactions of Methylene Phosphoranes 2.2.1 Aldehydes. - Yavari et aZ.42-45 have thoroughly investigated the synthesis of vinyl phosphonium salts, obtained by protonating the reactive intermediates produced in the 1 : 1 reactions of Ph3P and dialkyl acetylenedicarboxylates, R02CC = CC02R (R = Me, Et, ‘Bu). These salts then undergo intramolecular Wittig reactions producing a variety of heterocyclic species. Substituted alkenes, R’CH2CH=CHR2 or R’CH(CH3)CH=CHR2 have been obtained from the reaction of vinyltriphenylphosphonium salts with aryl-aldehydes or Grignard reagents.46747 The stereoselectivity of the reactions is dependent on the nature of the substituents on the benzene ring of the aldehydes; electron-donating groups give the (E)-isomer, whereas electron withdrawing groups give the (Z)-isomer as the major product.

The synthesis of ethynylpyridines from the Wittig reaction of Ph3P=CHCl and pyridinecarbaldehyde has been described.48 Aldehydes react with bromo- or h ydroxy-met hylene-phosphonium salts, [Ph3P(CHz),Br]Br and [Ph3P(CH*),OH]Br repectively, under phase-transfer Wittig conditions, producing o-bromoalkenes, which can be N- or C-alkylated to give the corresponding o-az~lylalkenes.~~ o-Azolylalkenes were also prepared by direct Wittig reaction of phosphonium salt 45 with aromatic aldehydes.49

Normally stable sulfonyl ylide 46 reacts with benzaldehyde derivatives under the influence of microwave irradiation to produce a,p-unsaturated s ~ l f o n e s . ~ ~ p- Silylated olefins are obtained from the corresponding aldehydes or ketones and [Ph3PCH#.”

45 X = N, CH; n = 3,4,5 46

2.2.2 Ketones. - Ylides 47 were produced from the reportedly complex reactions of Ph3P, R02CC = CC02R (R = Me, Et, ‘Bu) and 3-~hloropentane-2,4-dione,~~ or 5-methylcyclopentane- 1,2,4-trione. 53 Vinylketones react with stabilised ylides in polar solvents to produce carboalkoxyphosphoranes However, if the same reaction is carried out in non-polar solvents then acylphosphorane 49 and an acrylic ester are obtained.54 It has been reported that the reactions of ketones with stabilised ylides, which are usually unreactive under normal conditions, can be accelerated by microwave irradiation in a domestic microwave oven - without the use of solvents.55 The advantages of this new route include improved yields and shorter reaction times.

47 R = Me, Et, But 48 R = Me, Et

PPh3

H

// R(0)C-C,

49 R = Me, Et


The mechanism of Wittig olefination has, for many years, been the subject of intensive investigation especially with regard to the nature of the intermediates formed during the reaction. Whereas the key role of oxaphosphetane intermediates has been established unequivocally, the involvement of betaine intermediates remains controversial. However, a Russian team, led by Ustynyuk, has reported what they claim to be the first experimental evidence for the formation of betaines in the reaction of ylides, Ph3P=CHR (R=Et, Ph), with Michler's ketone, (p- Me2NC6H&=S (scheme 8).56 The reactions were carried out in THF solution under somewhat specialist conditions, i.e. a totally sealed vacuum system at a pressure of loF3 mmHg. The betaine intermediates 50 were characterised using multi-nuclear NMR spectroscopy by comparison with the stable organosilicon- betaine 51. Specifically, the presence of the chiral centre in 50 means that the aromatic rings are diastereotopic and so the 'H spectrum contains two singlets from the Me2N groups and two AA'XX' multiplets from the benzene ring protons. Similarly, the I3C spectrum contains two @so-carbon atom signals.

NMe2 I Me2N

1 NMe2 50

Scheme 0

Me2"

H Ph I I

I I Me Ph

Et$-C-Si-S-

51

2.2.3 Ylides Coordinated to Metals. - The structure of a barium complex (52) of methylbenzylidenetriphenylphosphorane has been reported. 57 The Ba2+ ion is in contact with both the ylidic- and the benzylic-carbon atoms. Ab initio calculations and NPA charge analysis indicate that the ylidic moiety is highly polarised, P'-C-.

In a very comprehensive study by Finn and c o - ~ o r k e r s ~ ~ ~ ~ ~ the synthesis, properties and reactions of several titanium-substituted ylides are described. The complexes were prepared from titanium alkoxides and (Me2N)3P=CH2 (scheme 9). The structure of one of the complexes was determined crystallographically which showed it to exist as a chloride bridged dimer (53). The ylidic P-C distance and ' J p c coupling constant are charactersitic of a P-C single bond which, together with the six-coordinate nature of the Ti centres, verify the zwitterionic nature of the species in both the solid state and in solution.58 The titanium ylide

6: Ylides and Reluted Species

Me Me

24 1

complexes described by Finn react with carbonyl compounds to produce (E)- vinylphosphonium salts which can be converted to allenes after deprotonation and condensation with a second carbonyl compound.59

H Na[N(SiMe&] (M%"P=C, 1 TiCI,, (OPr')bn

(OP&-n PhMe_ [IMe2N)3&Cp2

(Me2N)3P=CH2 TiCln (OPri)bn

n = 2 , 3 Scheme 9

(Me2N)3P,C,H cI CI, I CI I OPr'

,Ti: ;Ti: Pr'O I CI I CI

CI c H' 'P(NM@)3 53

Zirconium complexes 54 were obtained from R3P'CSz- (R = Me, Bu) adducts and [(q5-C5H5)2ZrHCl],.60 The complexes were treated with a variety of electrophiles to give S-substituted phosphonium salts.

54 R = Me, Bu

The molecular structure of the iron-diphosphinine (55) has been reported.6' The reactions of Ph3P=CH2 with a number of cationic piano-stool ironcarbonyl complexes have been investigated.62 With dicarbonyl complexes [(q5-C5H5)(CO)z- FeL]PF6 [L = P(OMe)3, P(OEt)3, PPh2(OMe)] nucleophilic attack on a coordinated carbonyl by the ylide occurs, yielding ylidyl complexes 56. In contrast, monocarbonyl complexes [(q5-C5H5)(CO)FeLP(OR)3]PF6 [L = P(OMe)3, PMe3, R = Me; L = P(OEt)3,R = Et], undergo Arbuzov-type dealkylation reactions yielding [(q5-C5H5)(CO)LFe{ P(O)(OR)z)]. The differences in reactivity were attributed to the increased back-donation ability of the iron to a ligand which induces a change in the reaction site from a carbonyl carbon to an a-carbon in a phosphite ligand.


co 0

55 56 L = P(OMe)3, P(OEt)3, PPh2(OMe)

Keto-stabilised ylides, Ph3P=CHCOR (R = Me, Ph, OMe), can coordinate to metals either through the oxygen or the ylidic-carbon. A study of the interaction of such ylides with cationic palladium(I1) complexes 57 observed both coordination modes, the actual mode adopted depending upon the nucleophilic character of the ylide and the nature of the other ligands coordinated to the The observations are summarised in (scheme 10). Thus, with 57 (L = PPh3, L = THF) the ylides coordinate through oxygen, irrespective of their nucleophilic character, producing complexes 58. However, with 57 (L = pyridine, L' = THF) then Ph3P=CHCOMe, which is a poor nucleophile, coordinates through the oxygen giving a complex with structure 58, whereas the more nucleophilic Ph3P=CHC02Me coordinates through the carbon, producing 59. Similarly, when Ph3P=CHC02Me reacts with 57 (L = L' = MeCN) then a C-coordinated ylide complex is obtained. However, less nucleophilic ylides react with 57 (L = L'= MeCN) to give a mixture of 0- and C-coordinated products! In a related set of experiments, cyano-stabilised ylide Ph3P=CHCN was treated with cationic palladium complexes 57 (L = PPh3, P(OMe)3; L' = THF) to yield complex 60, in which the ylide is coordinated through the N-atom, an unexpected coordination mode for this ylide.64 Reaction of Ph3P=CHCN with 57

H PhsP=C,

, COR2 I

4

H bPh3 58

- 57

Reagents: i, R' = H, Me; L = PPh3; L = THF; R2 = Ph, Me, OMe ii, R' = H; L = Py; L' = THF; R2 = OMe

Scheme 10

Me2 59

L

60 R' = H, R2 = Ph, OM; R' = Me, R2 = Ph

61 R = H, Me

6: Ylides unii Reluted Species 243

(L = L' = MeCN) in a 2:l mole ratio yields the bis-ylide complex 61 in which one ylide is coordinated through its nitrogen and the second through its carbon atom. Complex 62, in which the ylide acts as a C,N-bridging ligand, is obtained by the action of a further equivalent of Ph3P=CHCN on 61 or from the reaction of 57 (L = L' = MeCN) with Ph3P=CHCN in a 1:l mole ratio.@

-

H I

H

R 62 R = H, Me

2t

The reaction of keto-stabilised ylides with trans-[PtC12(NCR)2] (R = C6F5, Me) does not lead to the expected bis-ylide complexes, but to N-bonded P-iminopho- sphorus ylide complexes, 63 and 64, or iminophosphordne complexes 65, depending upon the nature of the ylide, R and the reaction condition^.^^

H

"Ti2 R' 0

63 R' =CsF5, R2 = OEt 64 R1=C6F5, R2=OEt R' = Me, R2 = OMe R' = c6F5, R2 = OMe

65

OEt

Zeise's salt, K[Pt(CN)CI3], reacts with one or two equivalents of keto-stabilised ylides to give the mono- or bis-ylide complexes, trans-[PtCI2(q2-C2H2)(ylide)] or trans-[ Pt Cl*( ylide)2] respectively. Upon heating, trans- { PtC12[CH(PPh3)COCH3I2} undergoes cycloplatination to give 66.66

H OEt ppj The reactions of bis(tripheny1phosphino)isophosphindolide salts (67) with

mercury (11) salts have been reported (scheme 11).67 67 reacts with HgCl2 ar,d


H20 or MeOH producing a phosphinito complex which is converted into the dimercury complex 68 by excess HgC12. However, if Hg(OAc)2 is used instead of HgC12 then a phosphonium salt (69) is obtained as the final product (scheme 1 2 p 7

67 X = Br, CF3S03

67 + HgC12 X = CF3SO3

68 Scheme 11

PPh3

Scheme 12

PPh3 69

Ytterbium-ylide complex [(v '-~Bu~C~H&Y b(Cl)(CH2PMePh2)] was obtained from the reaction of Li[CH2CH2PPh2] and [(~5-tBu2C6H~)~YbC1.Licl].68

2.2.4 Miscellaneous Reactions. -- Wittig technology has been used to prepare ylide-, phosphate-, phosphite- and phosphinate-terminated d e n d r i m e r ~ , ~ ~ and calixarenes bearing pyridyl podands on their upper rim.70

The incompletely condensed silsesquioxane [(c-C~H 1 1)7Si709(OH)3] has been shown to react rapidly with methylenetriphenylphosphorane to afford the salt

Reaction of ketenylidene- or thioketenylidenetriphenylphosphoranes with a$- unsaturated carbonyls, e.g. 2-benzylidene- 1,3-indandione yields pyranones and thioxopyranones 70.72 Treatment of the same phosphoranes with o-chloroanil (tetrachloro- 1,2-benzoquinone) yields 71 .73 Ketenylidenetriphenylphosphorane

{ [Ph3PCH31[(c-C6H 1 I )7Si7010(OH)31 1 e 7 '

6: Yliiies und Related Species 245

has also been utilized in the one-pot synthesis of tetronic acids, tetronates, coumarins and benzoxepinones, through its reactions with carboxylic esters bearing OH, NHR or SH g ro~ps . ’~

70 X = 0, S 71 X = 0, S

The reaction of 2-amino-1 ,Qquinones and Ph3P=CHC02R (R = Me, Et) proceeds viu 1,2- and 1,4-addition reactions to yield the pyrroline-ylide phosphorane 72.75 2-Cyclopropylidenephenoxyethanes 73 are readily obtained in high yields from

the Wittig reaction of a-phenoxyethanones and (3-bromopropyl)-triphenylphosphonium bromide.76 The reaction of carbonyl compounds with sulfur-, selenium- or tellurium-substituted phosphoranes produces vinyl sulfides, selenides or tellurides with preferential (Z)-c~nfiguration.~~ Spirophosphoranes 74 are reported to react with aldehydes to produce (2)-olefins prefer en ti all^.^^ (Z)-Olefins have also been obtained, in high yields, via an autoxidation process in salt-free condition^.^^ * PPh3

CHC02R

R

D=( CH20Ph

.CH2Cq2R

72 R = Me, Et 73 R = Me, Ph, 2-thienyl 74 R = Et, Bu”, Bu‘

Acyclic phosphoranes bearing a fluoroalkyl side chain (75), undergo intramolecular Wittig reactions when heated, producing cyclic benzoates.80 Shen and Gao8’ have reported a stereoselective synthesis of trifluoromethylated a-chloro- u, P-unsaturated esters and nitriles by employing trifluoromethylated phosphoranes (scheme 13).

Alkylidenephosphoranes have been utilized in the synthesis of new heteropoly- cyclic systems containing the 1,2-benzothiazine- 1,l -dioxide skeleton.82 Wittig reactions have also been used in the one-pot conversion of diethyl isopropylidene-L-tartrate into bis-enones (scheme 14), which were subsequently converted into seven-membered cyclic ureas, which are useful intermediates in the synthesis of HIV-proteinase inhibit01-s.~~ The reactions of alkylidenephosphoranes with a variety of nitrating agents (including N2O4, EtONO, and Me*NCH:CHN02)


OEt R

ph3p+Co2Me

C02Ef

75 R = CF3, C2F5, C3F7

-0, C /cF3 Ph36 0- -Ph3P0 F3CHR' + F3CHCl I I

I I

COCF3 / 'R2- - Ph3P=C CI-C-C-CF3 - R2 CI R2 R'

Ph3P=C

kl kl R' R2 R' = CO~BU', CN; R2 = Bu", Bus, PhCGC, B u C S , Ph Reagents: i, R2Li or R2MgCI, THF, N2; ii, NCS, THF, N2

Scheme 13

have been reported.84 As might be expected, the outcome of these reactions was greatly influenced by the nature of the ylide s u b s t i t ~ e n t s . ~ ~

E t o 2 c ~ c o 2 E t Ph3P=CHlR D

O x 0 R = CO2Et, CN

Scheme 14

3 Synthesis and Reactions of Phosphonate Anions

The preparations of a number of synthetically valuable phosphonates, including a,B-unsturated p h o s p h ~ n a t e s , ~ ~ and phosphonoketene dithioacetals 76,86 have been reported. A new approach to highly substituted phosphonates has been described.87 The method utilizes phosphonyl-substituted radicals derived from iodoalkylphosphonates and the Bu3SnH/Et3B/02 reagent system. For example, (Et0)2P(0)(CH2),CHRI (n = 0-2; R = H, Me, Et, n-hexyl) and H2C = CHR2 (R2 = Pr, n-pentyl, OBu, OAc, OEt, Ac) yield (Et0)2P(0)(CH2),CHRCH2CH2R2 in 50-89Y0 yields. Chromium(0) complexes of arenes bearing alkenyl substituents have been obtained from the reaction of chromium-benzylphosphonates and unsaturated aldehydes (scheme 1 5).88 Diethylcrotonylphosphonate reacts with SnC14 to give either a bis complex, where the ligands coordinate to the tin through the phosphoryl oxygens, or a mono-chelated complex in which both the phosphoryl and the carbonyl oxygens coordinate to the metal. Both complexes react with (Z)- or (E)- 1 -phenyl-1 -(trimethylsilyloxy)- 1 -propene to give phosphonate 77 in quantitative yield.89

The Horner-Wadsworth-Emmons reaction between bis(benzy1oxy)benzalde- hydes and an ester-substituted benzylphosphonate or triethylphosphonoacetate, yield the correponding stilbene or cinnamate derivatives, respe~tively.'~ These are crucial steps in the synthesis of chiral AB2 monomers which are themselves valuable dendrimer p r e c ~ r s o r s . ~ ~ Standard Horner-Wadsworth-Emmons reactions between P-ketophosphonates and aldehydes have been used in the synthesis

6: Ylides und Reluted Species 247

0 ““)*lOTS 0

II S P(OEt)2

S R Me

( C 6 2 ) + ( Me

76 R = H, CH(OMe3)OH; n = 2,3 77

I

co oc/7r--co

of cholestadienone 78,9’ and the furan 79.92 Asymmetric Horner-Wadsworth- Emmons reactions have been utilized in the synthesis of exocyclic a,P-unsaturated esters 80 from the corresponding cyclic ketones.93 The reactions can be accomplished with an E/Z ratio of 9:1, the stereochemical control being influenced by the bulky triphenylmethyl protecting group.

0

R J g CH20H ph3c0Y0R1 0

79 R = Me2CHCH2, Ph, 2,5-(Me0)2C6H3 80 R = Me, Et; R’ = Ac, ti

Ethyl phosphonoacetate reacts with 3-keto-substituted thiophenes to give 81 which are precursors to bridged dithienylethylenes such as 82.94 The synthesis of a-ylidene-y-amidobutyronitriles, RCONH(CH2)2C(CN) = CR2R” (R = NPh2, R2 = R” = Me; R = R2 = Ph, R” = H, Me, Ph), has been achieved by the reaction of the phosphonates RCONH(CH2)2CHCNP(O)(OEt)2 (R = NPh2, Ph) with ketones.95 The enantioselective synthesis of allenecarboxylates is accomplished by asymmetric Horner-Wadsworth-Emmons reaction of chiral phosphonoacetate-

248 Organuph osphurus Chemistry

naphthol derivatives 83.96 Achiral phosphonoacetates react with 4-tert-butylcy- clohexanone in the presence of a chiral base to give 84 in up to 52% ee.97 Phosphonates bearing nitrile substituents react with alkenes producing phosphor- ylpyrrolines 85 or pyrroles

R

R

81 = Me, Bun

H% 6 84 R = CN, C02Me

82 = Me, Bu

‘CO2Me 85

83 R = H, Me, Me3Si, Ph

Ph’ 86

The synthesis and reactions of phosphonates containing perfluorinated groups have attracted particular attention. Pedersen and co-workersg9 have prepared a series of novel phosphonates bearing peduorovinylether groups (87). Yokomatsu et al. loo have described the stereospecific synthesis of a,a-difluoroallylphosphonates, e.g. (E)-PhCH=CHCF,P(O)(OEt)2. Excellent (E) or (Z) selectivity has been reported for the reaction of arylalkylketones or aldehydes and methyl bis(trifluoroethy1)phosphonoacetate using a Sn(OS02CF3)2 catalyst in the presence of N-ethylpiperidine. lo’ The synthesis of fluorinated vinylphosphonates, bis- and tris-phosphonates by successive Wittig-Homer-Emmons and Michael addition has been reported. ‘02 The regiospecific direction of Michael addition is dependent on the substitution pattern of the vinylphosphonates. Thus, the pentafluorophenyl substituted phosphonate C~FSCH=CHP(O)(OE~)~ reacts with diethylphosphite to give the tris-phosphonate p-(EtO)2(O)PC6F4CH2CH[- P(0)(OEt)2]2 in which the para-fluorine atom of the C6F5 unit undergoes nucleophilic substitution while a simultaneous nucleophilic addition of the phosphonate group to the vinylic double bond occurs. Fluorinated analogues of abscisic acid (88) have been synthesised from triethylphosphono-2-fluoroacetate

Me Me Me

88


and a-ionone derivative^."^ Conventional Horner-Wadsworth-Emmons and Wittig condensations have been utilized in the fluorination of odd-numbered side chain positions of retinals.IM

Treatment of diethyltrichloromethylphosphonate with butyllithium followed by an aldehyde or cycloalkenone leads to a-chlorovinylphosphonates (89). Io5

Pyranosic 3,4-enuloses exhibit anomalous behaviour when treated with the enolate of dimethyl(methoxycarbony1)-methylphosphonate, leading to phosphorylated products. '06 The synthesis of a-(alky1)methylene-y-iodo-y-butyrolactones has been accomplished in high yields, but with poor selectivity, from the reaction of a-phosphono-y-iodo-y-butyrolactones and aldehydes. '07

0

89

4 Structure and Reactivity of Lithiated Phosphine Oxide Anions

The solid state and solution structures of lithiated phosphine oxides and related species continues to attract attention with a particular emphasis on the stereochemical aspects; the groups of Denmark and Warren continue to make seminal contributions to this area. Denmark and co-workers"' have carried out an ab initio study of the P-C bond rotation in 2-0x0- and 2-thioxo-2-methyl-l,3,2- diazaphosphorinanes 90 and 1,3,2-diazaphospholidine 91 anions. Data show that for the six-membered ring species 90, the thioxo derivatives have a higher observed P-C rotational barrier. The theoretical data are confirmed by X-ray crystallographic analysis of the lithiated thioxo-derivative 92. Similar observations were made for the five-membered ring analogues 91. The N-R moieties in 90,91 and 92 provide a steric contribution to the P-C rotation. Thus, in order to provide further understanding of the electronic contributions to anion conformation, the same workers have studied the solid state and solution structure of the lithiated P-benzylphosphorinane- 1 -oxide 93. I o 9 Warren and co-workers' l o have

used ab initio calculations to determine the structures of lithiated phosphine oxides in THF. These calculations were then extended to the docking of a carbonyl compound onto a lithiated phosphine oxide in order to provide an explanation for the anti selectivity of the Horner-Wittig reaction. Warren's group


has also been investigating the configurational stability of lithiated phosphine oxides at -78°C in THF solution, which they describe as typical reaction conditions." ' Configurational stability is most frequently determined using either enantiomerically enriched or diastereomerically pure reagents; in their study Warren and co-workers' ' have employed both approaches. Thus, lithiation of either syn- or anti-isomers of phosphine oxide 94, followed by quenching with methanol after 45 minutes, produced a 46:54 mixture of the syn- and anti- isomers. Similarly, lithiation of optically active phosphine oxide 95, followed by

PhzP0 94

in situ quenching with Me3SiCI and

PhZPO 95

cyclobutanone, indicate that the lithium derivatives are not configurationally stable even on the timescale of their reaction with these electrophiles. In a related set of experiments, the same workers have used the Hoffmann test (the reaction of a racemic organolithium with a phenylalanine-derived aldehyde) to demonstrate the configurational instability of lithiated diphenylphosphine oxides. ' In this reaction, ethyldiphenylphosphine oxide was treated with a phenylalanine-derived aldehyde to give four diastereomeric alcohols (scheme 16). The relative stereochemistry of the products was determined using a combination of synthetic and crystallographic techniques. ' The stereochemical integrity of lithiated phosphine oxides has been also been investigated in their reaction with cyclobutanone under 'internal quench' conditions.' l 3 Whereas the reactions of lithiated chiral phosphine oxides with aldehydes show no stereoselectivity, those with ketones (such as cyclobutanone or valerophenone) and Me3SiCI are reported to proceed with excellent levels of syn selectivity. ' l 4 In contrast, the reactions of lithiated chiral phosphine oxides with ketones and methyl iodide are moderately anti selective. l4

p h G M e ph&Me

(PhCH2)2N Ph2PO (PhCH2)2N PhZPO P h G H PhZPEt anti, anti syn, syn

i, ii

(PhCH2)2N P h G M e Ph+Me

(PhCH&N PhzPO (PhCH&N Ph2PO anti, syn syn, anti

Reagents and conditions: i, BuLi, THF, -78 "C, 6 h; ti, NH&I

Scheme 16

A widely used first step in Horner-Wittig reactions is the lithiation of a

6: Ylides anti Related Species 25 1

phosphine oxide using butyllithium or lithiumisopropylamide at - 78 "C in THF, and, indeed, methyldiphenylphosphine oxide is readily lithiated under these conditions. However, when lithium bis(trimethylsily1)amide is used as the lithium source, metallation does not occur, the adduct 96 being obtained instead.lI5 This result, and associated MO calculations, have been used to investigate the mechanism of proton abstraction in phosphine oxides by alkali metal reagents.'I5

OH 0 II

H PPh2 2 7 RAC@Et >go% EtO OEt

Reagents and conditions: i, LDA or KDA, THF, NO, -1 10 "C, 2 h; ii, THF, aldehyde; iii, H20, room temp.; iv, KOBU', THF, N2, 0 C"

Scheme 17

[(Me3Si)pNLi-O=PMeIJh21 96

Me R I

? I P~~PCH~CH=CHCCH~CHPOH

R R YH

Ph2PCH2CHPh Ph2PCH2SiMe3 97 98 99 R = H, Me

0 II

P h 2 P T Bt ii. i. BuLi RCHO * R V B t

OEt OEt

101

100 R = C7H15, Ph, Ph(CH2)2; Bt = Benzotriazol-1-yl

Scheme 18

O rx (3 '"'9 SR NJ

R 4 s R2 R = Me, x = 0, CH2 102 R' = Ph, PMeOC6H4, ethienyl, mBC6H4 R - Bu", X = O R2 = Me; X = 0, CH2

R2=Bu", X = O

On the synthetic side, single diastereomers of P-keto phosphine oxides have been generated from intermolecular acylation of phosphine oxides using either chiral esters or chiral phosphine oxides. In most cases, reduction of the ketone products was not affected by the presence of extra chiral centres.'I6 Addition of metallated phosphine oxides to proline-derived ketoaminals provides a new route to optically active P-hydroxy phosphine oxides. l 7 The P-hydroxy phosphine oxide 97 has been prepared by the caesium fluoride mediated reaction of silyl- substituted phosphine oxide 98 and benzaldehyde."* The synthesis of two (E)-(6- hydroxy-2-hexen- 1 -yl)diphenylphosphine oxides (99) has been reported. l 9 The Horner- Wittig reactions of these compounds with various carbonyl compounds


have been investigated."' Kirschning et af. I2O have reported a new route for the asymmetric formylation of aldehydes which requires the use of a metallated phosphine oxide (scheme 17). This new method furnishes the desired a-hydroxy- carboxylates with high enantiomeric purity (ee > 90%). Phosphine oxide 100 undergoes selective Horner-Wittig reactions with aldehydes (scheme 18) as a step in the production of P,y-unsaturated esters and p-lactams.12' Allylic phosphine oxide-ylides, generated by the deprotonation of (Z)-alkenyldiphenylphosphine oxides with butyllithium, have been used to prepare trans-1,3-diene~.'~~ The (EE) ratios of the dienes so formed are 1:99 with straight chain aldehydes, 2:98-4:96 with p-branched aliphatic aldehydes and 4:96-694 with aromatic aldehydes. Aromatic aldehydes are also reported to undergo selective Horner-Wittig reactions with (2,2,2,-trifluoroethyI)phosphono sulfoxides producing cis-a,p-unsaturated sulfoxides and The synthesis of S,N-acetals of formyldiphenylphosphine oxide 101 has been described. 124 The lithiated anion of 101 reacts with aldehydes, RCHO (R = Ph, p-MeOC6H4, 2-thieny1, m-BrC6H4), producing S,N-ketene acetals 102 in high yields. Acetals 102 were then selectively hydrolysed to the corresponding S-thioesters. The lithiated anions of 101 did not react with ketones or pi~a1dehyde.I~~ Phosphonate adducts are the major products from the reaction of Horner-Wittig reagents with 1 ,3-dioxo-A2+"- indanmaloni trile. ' 25

5 Selected Applications in Synthesis

5.1 Biologically Active Compounds. - In a series of papers, Thomas and co- workers'26-128 have described the total synthesis of milbemycin E (103). One of the key steps in this synthesis was the preparation of phosphonium salt 104127 and the investigation of its reactions with hydroxybutenolides. 1 2 * Mikolajczyk et af.12' have reviewed the total synthesis of the antibiotic sarkomycin, a process which involves use of Horner-Wittig reactions. The Wittig reaction has been utilized in the synthesis of Bullfrog bile sterol 5P-ranol (105) (scheme 19).I3O Wittig reactions of 1-[3,5-0-( 1,1,3,3-tetraisopropyldisiloxane- 1,3diyl)-P-~-erythro- pentafuranos-2-ulosyl]uracil with Ph3P=CHC02R (R = Et, 'Bu) give exclusively the (Z)-2'-[(alkoxycarbonyl)methylene] derivatives in high yields (scheme 20). l 3

These derivatives are precursors to 2'[(alkoxycarbonyl)methylene]-2'-deoxyuri- dines which are potential ribonucleoside diphosphate reductase (RDPR) inhibitors. A novel synthesis of the nucleotide antimetabolites, 2'-deoxy-4'-thiocytidines, from D-glucose, has been described (scheme 21).'32 A key step in the synthesis of isoplagiochin A (106) is the macrocyclization of phosphonium salt 107 by an intramolecular Wittig r e a ~ t i 0 n . I ~ ~ Wasserman and P e t e r ~ e n ' ~ ~ have developed a convergent synthesis of the pentapeptide postatin. The method involves the oxidative cleavage of acylphosphorane 108. Ylides such as 109 have been coupled with a chiral epoxydienal (I 10) to afford (a-1)-functionalised leukotriene A4 (LT&) methyl ester analogues. 135 Annonaceous acetogenins represent a large class of natural products, many of which are of medicinal value. A dominant structural feature of many annonaceous acetogenins is two linked tetrahydrofuran

6: Ylides und Reluted Species

Me I

Me'

253

Me I H

dMe 1 03

0

I .

Me' *rn OSiMepBu' '0

+PPh3 1-

104

H I

1 05

Scheme 19

0

Ph3P = C HC02R

CH2CI2/THF, room temp.

R = Et, Bu' Scheme 20

BdPhSiO+CH - i, ii Bu'PhSiO

H= I

OBn OBn

Reagents and conditions: i, Ac20, DMSO, [Ph3PCH3]Br; ii, NaH, t-amylalcohol 74%

Scheme 21

rings flanked by two hydroxy groups -- a unit which contains four stereocentres and which can therefore form up to 64 stereoisomers. Sinha et have described an efficient methodology which will allow the synthesis of 32 of these isomers. The new route involves the Wittig coupling of two fragments, phosphonium salt 111 and aldehyde 112, both of which contain two of the stereogenic centres. The effectiveness of this new procedure was demonstrated by the total synthesis of trilobacin.


HO Q-Q

OH

Me02C p OMe

B f 106 107

PhCH202C-Val-Val-N Me I H R

108 109

H 110

111 112

Wittig reagents have also been utilized in the synthesis of several other compounds; (4R,7Z, 1 12)-(-)-4-rnethylheptadeca-7,11 -dienoic acid, a member of the sporthrix series; 137 the alkaloid (f)-lyc~podine, '~* and derivatives of L-

fructose in which the carbon-backbone has been lengthened. 139

5.2 Heterocyclic Synthesis. - The reactions of phosphorus ylides with phenanthrene-9,lO-quinone (1 13) have been used to prepare phenanthrene [9, 10-XI-fused compounds with four, five, and six membered heterocyclic rings. 140 (E)-4- carbethoxymethylene-1,2,3,4-tetrahydro-2-quinolones 114 have been obtained from the stereoselective reaction of 3-hydroxy- 1,2,3,4-tetrahydroquinoline-2,4- diones and ethyl(tripheny1phosphoranylidene)acetate. 14' N-trifluoroacetylanilines 115 react with Ph3P=CO,Et producing enamine derivatives 116 as a mixture of (E)- and (Z) - i~omers . ' ~~ Enamines 116 are useful precursors for the synthesis of indoles and quinolones. 142

Oxadiazoles 117 and oxazinones 118 have been obtained from the Wittig reaction of ketenylidene triphenylphosphorane and carboxylic hydrazides, NH2NHCOR (R = Me, CHMe2, Bu, Ph, CH2Ph) and a-hydroximino carboxylic esters, R02CC(Ph) = NOH (R = Et, CHMe2, cyclohexyl, CH,Ph), re~pectively. '~~ Similarly, related hydrazones react with ylides to give pyridazinones (scheme 22). Highly functionalised a,P-unsaturated-y-butyrolactones have been prepared by the Ph3P catalysed cyclisation of a-ketoesters, a-ketonitriles or oI,a,a-

6: Ylicies cind Reluted Species 255

I R'

113 114 R' = H, CH3, Ph; R2 = Bu", Ph, CH2Ph

H 115 X = CN, C02Et; R = Br, I

H 116

trifluoroacetophenone and dimethyl acetylenedicarboxylate (scheme 22). '45 Na- sielski and c o - ~ o r k e r s ' ~ ~ " ~ ~ have obtained 2- and 3-vinylindolizines by the Wittig olefinatiori of 2-acetylindolizine and 3-acylindolizine respectively. A new one-pot synthesis of substituted pyrimidothienopyriadazines has been reported. 14*

OR

MexoFMe N-N 0 117 118

Vinylamino phosphorane 119 reacts with a,P-unsaturated aldehydes to give a mixture of 2-arylpyridine and 4-dihydropyridine derivatives (scheme Like- wise, dihydropyridines were also formed in the reaction of 119 with aromatic

256 Orgumphosphorus Chemistry

aldehydes (scheme 24) and from the reaction of analogous vinylamino phosphorane 120 with aromatic aldehydes (scheme 25). These results contrast with previous studies of the behaviour of vinylamino phosphoranes towards carbonyl compounds, such as ethyl glyoxalate, diethyl ketomalonate and pyruvonitrile, which gave (Qazadiene products. A mechanism accounting for these obser~a- tions was proposed which involved an initial nucleophilic attack of the &carbon atom of the vinyl side-chain on the carbonyl-carbon atom.'49 In contrast, imino phosphorane 121 reacted with aromatic aldehydes, in the expected aza-Wittig fashion, to give 4-arylpyridine derivatives after dehydrogenation of the resulting dihydropyridine (scheme 26). 149

Ph3P=N 119

A

RCHZCHO RANI'/ / H I

m C O 2 E t EtOzCy), C02Et

+

H

40% Scheme 24

0 Ar 0

160°C

Pd/C +ArCHO -

H Ar = MeC6H4, MeOCsH4, CIC6H4

-N=PPh3 120

Scheme 25

C02Et

Ph3P=N A C02Et

121

RCH=CHCHO

PhN02, reflux

Scheme 26

bC..' C02Et

Benzopen ta t hiepin reacts with phosphonium ylides, [(p-RC6H4CH2)PPh3]Cl (R=MeO, Me, H, C1, NOz) to form a mixture of benzotetrathiepins 122 and benzotrithiins 123."' Coppola et af. I s ' have developed a strategy for the synthesis of highly functionalised thiophene-3-carboxylates 124 and alcohols. The thiophene skeleton is assembled from three components, a benzylmercaptan, an aldehyde and a vinyl phosphonate via an intramolecular Wittig reaction (scheme 27). Wittig reactions have also been utilized in the synthesis of thienothiazinoisoin- dolones 125.Is2 The synthesis of dimethano-bridged tetrahydrothia-[21]-, -[23]-


a s - s m R 122 R = S'S MeO, Me, H, CI, NO2 123 R = MeO, Me, H, CI, NO2 R

SH

i, 2 BuLi o "̂" ii, RCHO

9

0

& 124 f-

Scheme 27

cq-& I

0 125

- - 126

127

CH2ijPh3Br

129

qQ Me C02Me C02Me

130


and -[25]-annulenes, 126,127 and 128 respectively, has been accomplished through a double Wittig reaction of phosphonium salt 129 with 6-ethynylcyclohepta-1,3,5- triene- I -carbaldehyde and/or its vinologous aldehyde analogue, followed by intramolecular coupling of the resulting bis-ethynyl sulfides. 53 Wittig and Wittig- Horner reactions have been extensively employed in the synthesis of heptalenes bearing extended 7c-systems as substituents. 154 One of the major intermediates utilized in the synthesis was the heptalene-substituted phosphonium salt 130.

5.3 Tetrathiafulvalene Derivatives and Related Organic Materials. - Wittig-type reactions and reagents continue to play an important role in this burgeoning field of research. Some examples of the types of compounds being prepared using these routes are illustrated here.

An improved synthesis of the powerful electron donors EDSEDT-TTF (131) ( X = S ) and EDSEDO-TTF (131) (X=O) has recently been r e ~ 0 r t e d . l ~ ~ The analogous donors 132 have also been prepared for the first time, using the new precursor [4,5-bis(2-cyanoethyIseleno)-l,3-dithiol-2-yl]triphenylphosphonium tetrafluoroborate (133). 155 The synthesis and spectral properties of poly(ary1enevi- nylenes) incorporating 2-methoxy-5-(2'-ethylhexyloxy)-p-phenylene fragments in the polymer chain have been reported.'56 The compounds were obtained from the reactions of 2-methoxy-5-(2-ethyIhexyloxy)- 1,4-~ylylenebis(triphenyl phosphonium) bromide (134) and terephthaldehyde 1,4-naphthalene-dicarbaldehyde or

131 X = S , O 132 X = S, Se

135 R = C02CH3, CH3, H 136 R = C02CH3, CH3, H R-R = (CH=CH)2, (SCH2CH2S) R-R = (CH=CH)2, (SCH~CHPS)

9,IO-anthracenedicarbaldehyde. 56 Wittig olefination of phosphoranes 135, or Wittig-Horner olefination of phosphonates 136, bearing the 1,3-dithiol-2-ylidene moiety, produces (2E) 4-( 1,3-dithiol-2-ylidene)but-2-enals after acid hydrolysis. The latter are useful intermediates for the synthesis of polyenic analogues of TTF.'57 Wittig reactions have also been used in the synthesis of novel bis(l,3- dithiole) compounds containing a di(2-thieny1)methane unit, 157 and the related 2,2'-bis( 1,4-dithiafulven-6-yI)-3,3'-bithienyl (137). 58 Long-chain substituted TTF

6: Ylides und Related Species 259

derivatives 138 have been obtained by condensation of alkylenedithio bis( 1,3- dithiole-2-triphenylphosphonium) perchlorates and 2-ethylseleno-4-heptadecyl- 1,3-dithiolium tetrafluorobordte in the presence of Et3N (scheme 28). 159 The analogous hexadecylethylenedithio-substituted derivatives 139 were also prepared, but by a P(OEt), promoted coupling r e a ~ t i 0 n . l ~ ~ Neat P(OEt)3 was used as the solvent for the reaction of 1,3,4,6-tetrathiapentalene-2,5-dione with aromatic aldehydes (scheme 29). 160 The resulting disubstituted tetrathiapenta- lenes 140 are precursors for the formation of conducting polymers. Bis(pheny1e- nedithi0)tetrathiafulvalene (BPhDT-TTF) (141) was prepared by a similar route from 2-0~0-1,3-dithiolo[4,5 bJ[l,4]benzodithiin (142).

H3C&CHS-(CH2)"-S

- HCOzCH3 /=(c17H35

Ph$ sxs H Ph36 sxs H + ,YS SeEt

XS Et3N, room temp.

-

i 2 clod-

H3CQCHS-( CH2) "-SHC02CH3 -

kS xs

C17H35 s4=Js

C17H35 138

Scheme 28

'sHc@Me

H sws

S "x:


o+sfis)=o s s S

S

+ RCHO - P(OEt)3 RHC=(I +R

140 R = Ph, pCF&H4. 2-fury1, pMeOC6H4, 2-thienyl, 3-thienyl

Scheme 29

141 142

Octamethylferrocene-1 , 1 '-dicarbaldehyde undergoes Wittig-Horner reactions with phosphonates derived from sulfur-heterocycles 143 yielding fulvalene-substituted ferrocenes 144 (scheme 30). 162 Dimeric, conjugated, p-quinodimethane analogues 145 have been prepared from the corresponding dithiolephosphonates and oxadianthraquinone. 163

Me

Me*:o Me

Me

Me

Me

0 I I

143 + (MeO)*P-R

Me# Me Fe

Me

Me 144

Scheme 30

R

HR

+o+

H R R

R R H 145 R = H, SMe

5.4 Miscellaneous Reactions. - Finn and co -worker~ '~~ have reported the one- pot double deoxygenation of simple alkyl- and polyether-tethered aromatic

6: Ylides und Related Species 26 1

aldehydes, using titanium(1V)-ylide complexes,58759 to give macrocyclic allenes in high yields and without recourse to slow-addition techniques (scheme 3 1). Mallory et af.165 have utilized phosphonium salt 146 for the construction of phenancenes, e.g. [ 1 llphenancene 147, a family of polycyclic aromatic compounds with an extended phenanthrene-like structural motif. Phosphonium salts 148 have been used in the stereospecific synthesis of (Z)- and (E)-stilbenes (scheme 32).’66 The reaction is carried out using non-typical Wittig conditions, i.e. KOH in the presence of 18-crown-6 as the base. With benzyltriphenylpho- sphonium iodide, 148 (L=Ph), then the product is always the (Z)-stilbene, whereas with benzyldiphenylchlorophosphonium iodide, 148 (L = Cl), then (E)- stilbenes are the exclusive product.

V U

Scheme 31 I ,

n = 2-10

R,’ 1-

Ph-’6-CH2

148 + - R2 ---@=+ R3

P d

R 3 0 C H 0

R’ = Ph, CI; R2 = MeO, Me, H, CF3, CN; R3 = MeO, Me, H, CF3, CN, NOp

Scheme 32

Fretz16’ has prepared a L-phenylalanine derivative substituted with a keto-ylide (149). The ylide function of 149 acts as a stable precursor to a vicinal tricarbonyl moiety which is readily obtained by oxidation of the phosphoranylidene group with oxone. Ylide 149 has been utilized in the solid-phase synthesis of peptides containing the vicinal tricarbonyl moiety. 16*


A F-NH CO2H

1 49

The synthesis of tricarbonylchromium(0) complexes of mono-, di- and trisubstituted cyclopropanes, e.g. 150, has been accomplished through the reaction of tricarbonyl(styrene) chromium(0) complexes 151 with phosphorus and sulfur ylides.

SiMe3 R /

150 151 R = H, SiMe3

Synthesis of trifluoromethylated compounds 152 has been achieved via ester- enolate [2,3]- Wit tig and [3,3]-Ireland-Claisen rearrangements. I7O Perfluorocyclo- butane phosphonium ylides, e.g. 153, have been used as a 'masked' fluoride anion source in their reactions with alcohols and carboxylic acids which lead to alkyl- and acyl-fluorides.17' Ylides 153 are also reported to cleave Si-C and Si-0 bonds, cause dimerisation of fluoro-olefins, and also react with acid chlorides or other activated aromatic compounds under halogen exchange. 72

R v O M e

OH 152 R = CHzOBn, CHpCH20Bn, n-C5H11, c-C6Hl1, CH(CH3)Ph 153

Reaction of (E)-5,5'dimesitylbifuranylidenedione (154) with Ph3P=CHC02Me yielded not only the expected Wittig product 155 but an unusual fused dimeric product (156).'73


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6: YIicles and Rehted Species 267

119

120 121 122 123 124 125 126 127

I28

I29

130 131 132

133

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136 137 138

139

140 141 I42 143 144

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154 I55 I56

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157 158 159

160 161 162 163 164 165

166 167 I68 I69

170 171 I72 I73

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7 Phosphazenes

BY J. C. VAN DE GRAMPEL

1 Introduction

This review covers phosphazene literature over the period June 1996 to June 1997 (Chemical Abstracts Vols. 125 and 126) and comprises linear phosphazenes including compounds derived thereof (Section 2), cyclic phosphazenes (Section 3) and polyphosphazenes (Section 4). Structural data have been summarized in Section 5. Subjects in Sections 2 and 3 are arranged in the following sequence, reviews, theoretical studies, physico-chemical and chemical studies, and finally applications. For polyphosphazenes (Section 4) the greater part of literature has been arranged around central subjects.

2 Linear Phosphazenes

Force field calculations have been carried out for compounds C13PNPOC12 and C13PNPC12NPOC12. Conformations, bonding and flexibility have been discussed. ' In order to get some insight in chain flexibility of phosphazene polymers, ab initio MO calculations have been applied to study conformation, chain flexibility, and charge density of valence electrons in the linear trimer Me( NPC12)3 Me. *

Many papers have appeared on the chemistry of linear phosphazenes, varying from electron-rich ligands in various systems to starting materials in the preparation of organo-substituted polyphosphazenes.

Reaction of the silylated phosphoranimine Me3SiNPMe3 with CoBr2, CoI2 or ZnI2 at 180 "C in the presence of NaF leads to compounds with general formula [MX(NPMe& [M = Co, X = Br (la); M = Co, X = I (Ib); M = Zn, X = I ( l ~ ) ] . ~ Using the same procedure, but at 200-210 "C, compounds [ZnX(NPEt3)]4 [x = I (Id); X = Br (le)] can be prepared from ZnX2 (X = I, Br,) and Me3SiNPEt3, and [ZnBr(NPMe3)I4, ( I f ) from ZnBr2 and Me3SiNPMe3.4 All these complexes form heterocubane structures in which each metal atom is linked to three nitrogen atoms with bond angles close to 90 ".

Donor-acceptor complexes, e.g. [ZnI2(Me3SiNPEt3)]2 (2), can be obtained from ZnX2 (X = I, CI) and the corresponding silylated phosphoranimine at 40 *C4

Organomanganese phosphoraneiminato complexes with a heterocubane struc-


269


1, PMe3 Me3P, ,M-N'

N-M'

Me3P PMe3

lb , M = C O c, M = Zn

PEt3 I

Et3P 2

ture have been prepared from the bromo derivative [MnBr(NPEt3)I4 with organolithium reagent^.^ The reaction between MoNCl3 and Me3SiNPMe3 affords a divalent cation [Mo(NPMe3)4I2+ in which the molybdenum atom is surrounded tetrahedrally by four nitrogen atoms of the NPMe3 groups with NMoN bond angles varying from 106.3 to 1 12.6 o.6 Complicated ionic complexes have been obtained by reaction of ZrC14 and HfC14 with Me3SiNPMe3 in the presence of NaF, viz. [Zr3C16(NPMe3)5]'[Zr2c16(NPMe3)3]- and [Hf3C16(NPMe3)5]'[Hf2cl7(NPMe3)2]-, It has been shown that formation of these compounds occurs via a donor-acceptor complex like MC14.Me3SiNPMe3 (M = Zr, Hf).7

The reaction of antimony trifluoride and Me3SiNPEt3 at room temperature offers a dimer with formula [SbF2(NPEt3)]2 (3). Substitution of a second fluorine can be achieved at 100°C, giving the dimeric compound [SbF(NPEt3)2]2 (4). In both compounds the central part of the molecule consists of a four-membered SbN ring.*

3 - 4

The donor-acceptor complex BF3.Et02 reacts with Me3SiNPEt3 in an exchange reaction to give a complex with formula BF3.Me3SiNPEt3.9 A dimeric compound [BF*(NPR3)]2 (R = Me, Ph) is formed in the reaction of BC13 and Me3SiNR3 in CH2C12 with elimination of Me3SiC1. In these dimers the boron and nitrogen atoms form an almost flat four-membered ring, each boron atom being connected to two nitrogen and two chlorine atoms. "B NMR data point to a monomer- dimer equilibrium. Also ionic species have been reported, viz. [B*C13(NPEt3)2]'BC14-and [B2C12(NPPr'3)3]+BCl4-, with tricoordinated and tetracoordinated boron atoms.'

Application of phosphoranimines as electron-donating reagents in organic chemistry has led to a number of interesting compounds. Substitution reactions

7: Phosphazenes 27 1

on halogenated quinones C602X4 (X = F, C1) with Me3SiNR3 (R3 = Ph3, Ph2Me, PhMe2) generate mono(phosphoraniminy1) derivatives (5). These compounds are highly coloured and show reversible two-electron redox behavior. lo

0 0 '$1 Me3SiNPR3 10""' X X

0 6 5

Cationic complexes of 5 with Rh(1) have been reported." Reactions of 1,3- dicyano-2,4,5-tetrafluorobenzene with Me3SiNPR3 (R3 = Ph3, Ph2Me) give mono- and disubstituted derivatives. Only monosubstituted derivatives are obtained when using 1,2- or 1,4-dicyanotetraAuorobenzene as starting material. In all cases substitution takes place at the para position with respect to the CN group(s), except for the 1,4-isomer where only ortho (or meta) substitution can occur. All phosphoranimino derivatives react with [Rh(cod)C1I2 in the presence of AgC104 to give cationic Rh(1) complexes. Dimeric and polymeric structures have been proposed for the Rh(1) complexes. ' I

The [(Me2N)3P=N] group has been used as an electron donor in the second- order NLO-chromophore with formula 1 -[(Me2N)3P=N]-4-N02-C6H4 (6), resulting in a higher second-order polarizability than observed for 4-nitroaniline. I 2

6

Cationic polymerization of phosphoranimines initiated by small amounts of PC15 in dichloromethane at ambient temperature offers a new route for the preparation of polyphosphazenes. Initiation of Me3SiNPC13 gives poly(dich1oro- phosphazene) with a narrow molecular weight distribution. The polymerization can be characterized as a living cationic polymerization.

PC15/CH& Me3SiNPCI3 * -[NPC&-

Poly(organophosphazenes) can be prepared from the corresponding organo- substituted phosphoranimines. l4 Reaction of the living polymer (NPC12)n with an organo-substituted phosphoranimine leads to the formation of block-copolymers. I Poly(fluorophosphazenes) can be prepared by a PC15-induced polymerization at ambient temperature from a fluorophosphoranimine. In this way Me3SiNPPhF2 yields (NPPhF),. Block-copolymers of the tyy: (NPC12)n(NPPhF), have been synthesized from (NPClZ), and Me3SiNPPhF2. Cationic polymerization of Me3NPC13 at ambient temperature initiated by


N { [CH2CH2N(H)P(OCH2CF3)2NPC13]+[PClb]- } 3 instead of PC15 results in the formation of triarmed-star polyphosphazenes. l7

New phosphormimines have been prepared by treatment of Me3SiN- P(0Ph)RMe (R = Bun, Hex") with Bu"Li and subsequently with electrophiles ECl (E = Me3Si, Ph2P) to afford Me3SiNP(OPh)RCH2E (>.I8

i, Bu"Li Me3SiNP(OPh)RMe 7 Me3SiNP(OPh)RCH2E

R = Bun, E = SiMe3; R = Hex", E = SiMe3 7

E = PPh2

Anionic polymerization of phosphoranimine Me3SiNP[OCH2C(N02)2Me]3 has been reported to occur at room temperature." The facile polymerization has been ascribed to the strongly electronegative character of the OCH2C(N02)2Me groups.

The oxidation of LiN(PPh2)3 by BiBr3 or Sb13 (molar ratio 3:l) at room temperature gives elemental Bi or Sb and a linear phosphazene Ph2PNP(Ph2)P(Ph2)NPPh2. The analogous reaction of LiN(PPh& and Ad3 appears to be strongly dependent on the reaction conditions applied. At room temperature LiN(PPh2)3 and Ad3 (molar ratio 3:l) react to give the linear phosphazene mentioned before and an eight-membered ring @),whereas at 80 "C only the linear compound has been formed together with elemental arsenic. A seven-membered cation (9) results changing the molar ratio from 3: 1 to 2: 1 .20

The application of PNS and PNSe linear systems for the formation of main group metallacycles has been reviewed.21 Cyclic metal complexes have been prepared from [SP(Ph2)NP(Ph2)S] - and Pt(1I) compounds.The X-ray structure of { Pt(PPh,)[N(SPPh2),]} 'CI - (10) has been reported.22

CI' bPh3 10

New phosphazene ligands, Ph2P(S)NPPh2-PPh2NP(S)Ph2 and Ph2P(Se)NPPh2-PPh2NP(Se)Ph2 have been obtained by oxidation of Ph2PNPPh2-PPh2NPPh2 by sulfur and selenium, respectively. Reaction of the

7: Phosphuzenes 273

selenium-containing derivative with R u ~ ( C O ) , ~ in the presence of Me3NO affords cluster 11 containing three Ru atoms.23

I 1

The linear phosphorus-nitrogen compound Pri2P(S)N( H)P(S)Pri2 reacts with PtC12(cod) to afford the complex Pt{N[P(Pr12)S]2}2 (12) in which the metal is coordinated to two phosphazene ligands via the sulfur atoms. Complexation takes place via deprotonation (NH +N). Reaction with PdC12(cod) offers the analogous compound Pd{N[P(Pr'2)S]2}2 (13) in combination with a partly deprotonated species, [Pd{ N[P(Pri2)SI2} { HN[P(Pri2)SI2}]+ (14).24 The preparation of an analogous chelating reagent Ph2P(0)NH(Se)Ph2 and its potassium salt K[Ph2P(O)NP(Se)Ph,] has been described.25 Reaction of K[Ph2P(O)NP(Se)Ph2] with PdC12(cod) gives Pd[Ph2P(0)NP(Se)Ph2l2 (15) in which palladium is coordinated to two oxygen atoms and two selenium atoms. In the analogous reaction of K[Ph2P(O)NP(Se)Ph,] with PtClz(cod) only the two chlorine atoms are replaced, resulting in Pt[Ph2P(0)NP(Se)Ph2]cod ( 16).25

12, M = P t 13, M = P d

14 15 16

Six-membered rings 1 H- 1, 2h5-azaphosphinin-6-ones were formed by treating N-alkoxycarbonylphosphazenes RCH2P(Ph2)NC02Me (R = Me, Et, Pr", Pr', CH2CH=CH2, CH2C6H5) consecutively with Bu"Li and dimethylacetylene dicarboxylate (DMAD).26 The analogous reaction with RCH*P(Ph*)=NPh (R = H, Me, CH2CH=CH2) gives an azophosphole, which can be hydrolysed to a cy~lopentenone.~~ Phosphazenyl enamines react with DAMD in refluxing dichloromethane exclusively to 2-pyrrolones with the phosphazenyl group on the 4- position. In refluxing toluene 2-pyridones are formed in addition to 2-pyrrolones.28 Phosphazenes Bu3P=NCH2Ph and Ph3P=NCH2Ph react with aliphatic acid chlorides or mixed acid anhydrides to give carboxamides. In the case of phenylacetic acid chloride, a competitive reaction takes place leading to produce a mixture of the corresponding carboxamide and a phosphonium salt. It has been argued that the acid CH2 protons of PhCH2COCl are responsible for this


difference in behavior. Reaction conditions to suppress the salt formation have been presented .29

The use of N-vinylic phosphazenes Ph3PNC(R')CHR2 in aza-Wittig reactions offers a facile entrance to the synthesis (azadienemediated synthesis) of a large variety of organic corn pound^.^^^^* A few examples may serve as illustration. Reaction of MeP(Ph2)NCHCHC02Et with p-No2C6H4CHO gives the 2-azadiene MeCHNCHCHCOzEt, that can be readily converted with a second phosphazene molecule into a d ihydr~pyr id ine .~~ Reaction of Ph3PNC(Ph)CHPh with ethyl glyoxalate leads to the 2-azadiene EtOC(O)CHNC(Ph)CHPh that in turn can react with a second molecule ethyl glyoxalate to a 5,6-dihydr0-2H1,3-oxazine.~~

Aza- Wittig reactions of triphenylphosphoranylideneamino- 1,4-benzoquinones with aryl isocyanates and aryl chlorides have been reported.32 Triphenylpho- sphine undergoes a Staudinger reaction with a-azidophenylacetonitrile to give a triphenylphosphazine PhC(CN)NNPPh3 or [PhC(CN)2]-(Ph3PNH2)', depending on the molar ratio phosphine/azidophenylacetonitrile. Reaction of Ph3P with a-azidodiphenylacetonitrile affords a phosphazide with the formula Ph2C(CN)NNNPPh3.33

Phosphazene bases are still being widely used as reactive tools in organic The synthesis of a large number of novel bases has been reported,

the number of phosphorus atoms involved varying from two to seven.42 Linear systems appear to be weaker bases than branched types. The highest base strength (pKBH+ = 46.9 in acetonitrile) has been observed for 17.42

17

Phosphazene bases have been applied as catalyst for ring opening polymerization of lactams by generating lactam anions.43 From the available data one can conclude that the base strength PKBH+ has to be greater than 27 (in acetonitrile) in order to be effective. Ring opening polymerizations of ethylene oxide or cyclotrisiloxane lead to well-defined polymers, when initiated by organolithium compounds in combination with the phosphazene bases Et-P2 or ~ - B u - P ~ . ~ ~ ~ ~ A kinetic study has been performed for the ring opening polymerization of hexacyclotrisiloxanes by BuSLi in the presence of Et-P2.4s The phosphazene base t-Bu-P4 has been applied in combination with BunLi in the preparation of a block copolymer of polystyrene and poly(ethy1ene)o~ide.~~

Linear phosphazenes as [CI3P(NPCI2)nNPC13]+(PC16)- and C13PNPOC12 have been used as equilibrating and/or condensing organo-substituted poly-

7: Phosphazenes 275

sil~xanes!~-~' Other catalytic applications of linear phosphazenes involve the preparation of silicate resins containing amino groups,52 preparation of silanol- free organosiloxane copolymer^,^^ and depolymerization of silicon rubber.54

Kinetic studies of the condensation reaction of trimethylethoxysilane and pentamethyldisiloxanol in the presence of (C13PNPC13)+ ions as catalyst have indicated a complicated condensation process.55

X-Ray structure determinations of some miscellaneous compounds containing linear phosphazene ~ n i t s ~ ~ - ~ ~ are summarized in Section 5.

3 Cyclophosphazenes

The aminolysis of (NPC12)3 with long chain diamines H2N(CH2)"NH2 has been reviewed. The application of alumina impregnated with potassium hydroxide has been mentioned as essential for the preparation of dendrimers (up to generation 8).66,67 Cyclophosphazenic polypodants (NP[OCH2(CH20CH2),CH2OR]2)3 (18a-18c) can be prepared from (NPCI2j3 and polyethylene glycol monoalkyles- ters.

18a, n = 2, R = C4H9 b, n = 3, R = C12H25 C, n = 4, R = C ~ H ~ ( C B H ~ T ) - ~

These polypodants have been described as powerful complexing agents towards alkali metal ions and hence strong anion activators.68 Some tris(ary1- dioxy) derivatives of (NPCI2j3 have been reviewed including their ability to form clathrates with aromatic organic molecules such as benzene, styrene, etc. Selec- tivity for inclusion of aromatic molecules has been discussed in relation to the structure of the host rn01ecules.~~

Theoretical and physico-chemical studies on cyclophosphazenes are still drawing interest. The alkoxyphosphazene-alkoxyphosphazane rearrangement has been studied by semi-empirical MO methods and non-local density functional methods. These calculations show that the preferential formation of an aap- alkoxyphosphazane over the aaa-form can be explained from a difference in transition state energy for the two configurations, pointing to a kinetically controlled rea~tion.~' Nonlinear optical properties for solutions of cyclophosphazenes in water and in HCl solution have been studied by experimental and theoretical methods. It turns out that ligand electron-donating capacity and protonation of an endocyclic nitrogen determine x3 values to a great extent." NMR studies on a number of aryl and aryloxy substituted cyclophosphazenes


and a polyphosphazene have shown the "N nucleus to be more sensitive to swbstituent effects than the 3 'P nucleus. 15N NMR data are therefore useful tools for structure e l ~ c i d a t i o n . ~ ~ Kinetic studies on the nucleophilic substitution of an imidazolyl group in (NPIm2)3 (Im=imidazolyl) by a OC6H4N02-4 group in a water/THF solution (pH range 5.5-7.5) suggest a two-step mechanism, viz. formation a pentacoordinated intermediate formed by the attack of phenolate on protonated (NPIm2)3, followed by cleavage of the intermediate in N3P3Im5(C6H4No2-4) and i m i d a ~ o l e . ~ ~ Phenolysis of (NPC12)3 in a two-phase system with Bun4NBr as phase transfer catalyst follows a non-geminal pathway with second order kinetics, the reaction rate reduces with increasing degree of s u b s t i t ~ t i o n . ~ ~ Study of the liquid-crystalline phase transition of hexakis(4- OC6H,&H40R-4) derivatives of (NPC12)3 (R = CnHZn+l, n = 6-12) by FT-IR, X- ray diffraction, DSC, and polarizing microscopy shows an increase of the temperature range of the mesomorphic phases with increasing length of the alkyl chain.75 The behavior of cyclophosphazenes and polyphosphazenes at air-water interfaces in relation to their structure and substituents have been studied by Langmuir-Adam trough technique^.^^

A new synthesis for the cyclotriphosphazene (NPC12)2NPCINH2 has been reported. Treatment of (NPC12)2NP(NH2)2 with gaseous HCI in acetonitrile leads to formation of the mono(amino) derivative in high purity and yield. When the reaction was carried out in diethyl ether or dichloromethane, the HC1 salt of the starting material was formed.77 The reaction of the bulky adamantanamine and (NPC12)3 molar ratio 6:l in the presence of triethylamine as HCl scavenger leads to the formation of gem-NPC12[NP(Adaman)2]2 (Adaman = adamantanamino) and small amounts of the fully substituted product.78 The absence of non- geminal products has been explained from the size of the nucleophile that blocks an SN2 mechanism and forces the reaction to a S N l pathway. Aminolysis of (NPC12)d with adamantanamine leads to a fully substituted product, whereas partial substitution takes place with [NPC12]n.78 Synthesis of Pt(I1) and Pd(I1) complexes of the type MLC12, in which L = gern-NPPh2(NPPz2)2 (Pz = pyrazolyl) or gem-NPPh2(NPDmpz2)2 (Dmpz = 3,5-dimethylpyrazolyI) have been described. Spectroscopic data show that the metal is coordinated to Pz or Dmpz ligands via two geminal N centers (q2 coordination) (19). Reaction of gem- NPPh2(NPPz2)2.PtC12 with CuC12 yields a mixed complex with formula gem- NPP~~(NPPz~)~.P~CI~.CUCI~.~~

19 M=Pt,Pd

[ N P ( D ~ ~ Z ) ~ ] ~ has been used as a ligand for complexation of d'' metals. The

7: Phosphazenes 277

binuclear complexes [ZnClz(p, q 2, q 3- L)ZnC12] (20), [CuI(p,q 3, q 3-L)CuI] (2 I), [CDC12( p, q 3,q 3-L)CDC12] (22), and [Cul(p,q ,q 3-L)ZnC12] (23) (L = [NP(Dmpz)&) have been described, including a mononuclear species with formula q3-LHgC12.

X-Ray structure determinations show that, in compounds 21, 22, and 23, the metal is coordinated to two non-geminal exocyclic nitrogens and one endocyclic nitrogen (q3). In compound 20 two coordination modes are present, viz. q2 and q3. NMR studies reveal for these compounds a complex fluxional behavior.80

CI, ,Cl Zn

20 x,

21 M=CU, X = I , n = l 22 M=Cd, X=CI, n = 2 23 M=Cu, X = I , n = l

M=Zn, X=CI, n = 2

Me groups are omitted for clarity

Reaction of C U ( N O ~ ) ~ with 3-pyridylmethylaminopentaphenoxycyclotriphospha- zene leads to a complex with formula Cu( N3P3(0Ph)s[NHCH2(3- CSH4N)])2(N03)2, in which copper is surrounded by four oxygen atoms (nitrate groups) and two nitrogen (3-N) atoms (from two pyridyl groups) in a Jahn-Teller distorted octahedral geometry." A similar copper complex has been obtained from the reaction of Cu(NO3)Z and N3P3(OPh)5[NHCH2(2-C5H4N)].82 In this compound copper is surrounded by two oxygen atoms and four nitrogen atoms (3-N and amino-N) from two 2-pyridyl groups. The reaction involving PtCl2 and Co(NO3)2 yields Pt{ N3P3(0Ph)5[NHCH2(2-C5H4N)])C12 (24) and Co(N3- P3(OPh),[NHCH2(2-C5H4N)])(N03)2 (25), respectively. In the platinum complex the metal ion is coordinated to two nitrogens (from one pyridinylmethylamino

PPma, ,2Pma "P'"

2 Pma,II

24

2 Pma,-,2 Pma

2 Pma = 2-pyridylmethylamino


group) and two chlorines, forming an almost planar square. The distorted tetrahedral coordination around Co is formed by two oxygens (nitrate group) and two nitrogens, one of the pyridyl group, the other a NP ring nitrogen.82

Deprotonation of P-trans-[NPPh(cyclo-HexNH)]4 with BuLi in toluene has been reported to give the tetravalent anion [NPPh(cyclo-HexN)]~-. With an excess of RuLi and THF as a solvent, a crystalline compound Li6([NPPh(cyclo- HexN)I4(CH2=CH0)2} .4THF has been formed.83 The central part of the molecule consists of a tetravalent phosphazene anion with phenyl groups in an equatorial position and the amino groups in an axial position. This arrangement divides the molecule into two coordination spheres, each consisting of a Li3 cluster, two THF groups and one enolate

Syntheses of alkoxy and aryloxy substituted cyclophosphazenes still forms an important research item, in particular as the knowledge thus obtained can be used for the preparation of the corresponding polymers.

Phenolysis of (NPC12)3 by sodium salts Na(OC6H4R-4) (R=Me, OH, Bu', OPh, CPh3, OPh, and OCH2Ph) and alcoholysis by Na[OCH2C6H4(0CH2Ph)-4] have shown to afford fully substituted derivatives very easily, indicating that the paru positioned group R does not act as a steric barrier for complete substitution. Substitution reactions with (NPC12)4, C13PNPOC12, and (NPC12), are included in this study. It has been suggested that orientation and interactions observed for the small molecule models can be transferred to the polymer analogues.84 Another example of a small molecule study concerns the preparation of { NP[O- C6H3(oCoMe-3)(Co2H-4)]2} 3.85

Synthesis of mono and disubstituted products (NPC12)2NPCl(OC6H2Bu'3- 2,4,6) and (NPC12)2NP(OC6H2Me-4-Bu'2-2,6)2 and two P-P coupled bicyclopho- sphazenes [(NPC12)2NP(OC6H3But2-2,6)NPC1(NPCI2)2] and ( [NP(OC~H~BU'~- 2,6)2]2NP(OC6H3Bu'2-2,6)} 2 have been reported for reactions of (NPC12)3 with corresponding sodium aryloxides. The formation of bicyclic compounds has been explained by a metal-halogen exchange mechanism.86

As already described before, the phosphazene ring can serve as starting point for the synthesis of d e n d r i m e r ~ . ~ ~ . ~ ~ An interesting study describes the formation of dendrimers starting from (NPC12)3. In the first step all chlorine atoms are substituted by HOC6H4CHO-4, giving [NP(OC6H4CH0-4)2]3, whereas the second step involves condensation of aldehyde functions by H2NN(Me)P(S)C12. By repeating this reaction a dendrimer with 1536 aldehyde functions (eighth generation) could be ~ynthesized.'~

The cyclic system [NP(OC6H&H0-4)2]3 has also been used for the synthesis of a multidentated ligand { NP[OC6H4(CH=CHCN-4)]2}3 with 12 coordination sites (6 C=C and 6 CN). I t has been demonstrated that Pt(0) is coordinated exclusively to the olefin site, whereas Pt(I1) and Rh(1) are linked to the CN group. A combination of Pt(0) and Pt(I1) uses all coordination sites. Electrochemical studies of these metal complexes have shown that the cationic and anionic processes are influenced by the strongly electronegative character of the phosphazene ring.88 The formyl groups in [NP(OCbH&HO-4)2]3 can be transformed into CH2CI functions in a two-step rea~t ion . '~ Coupling reaction at the CH2CI site with polystyryllithium leads to the formation of a polystyrene with 5 benzylic

7: Phosphazenes 279

groups at the polymer end when an excess of the phosphazene reagent is used. A star-shaped polymer with a phosphazene core can be prepared using an excess of poly~tyryllithium.~~

The reaction of (NPC12)3 with 2-allylphenolate at ambient temperature in the presence of a phase transfer catalyst has been reported to produce the monomer (NPC12)2NPCl[OC6H4(CH2CH=CH2)-2], which undergoes radical copolymerization with styrene, methyl methacrylate, and vinylbenzyl chloride. Reactivity ratios calculated according to the terminal model show the phosphazene monomer less reactive than the organic monomers. Molecular weights decrease with increasing phosphazene content in the feed.” Comparable results have been obtained for related cyclophosphazenes (NPR2)2NPR[OC6H4(CH2CH=CH2)-2] with R = OPh or OCH2CF3, when subjected to copolymerization with styrene, methyl methacrylate, and vinylbenzyl chloride. The glass temperature decreases with increasing phosphazene content in the copolymer, whereas the thermal stability increases.” Characterization of the copolymers with GPC, light scat- tering and viscometry shows that the polymer chains to have a high degree of stiffness and a lack of rotational freedom in solution.92 The bifunctional monomer trans-[NP(OPh)2]2N P(OPh)OC6H4CO*H-4 has been prepared from (NPC12)3 by a multistep synthesis: introduction of OC6H4C02Me-4 and OPh group, followed by hydrolysis of the ester group. Treatment with thionyl chloride gave the corresponding acid chloride, which can be applied in a polycondensation reaction with bisphenol A to give a polyester (26) with the phosphazene entity being part of the polymer chain. Lower molecular weight polymers have been obtained using the cis isomer.93

r

26 L

Complexation of quinoline derivative [NPC1(8-O-C9H6N)]3 with 3d transition metal ions Cu(II), Co(II), and Ni(I1) occurs probably via exocyclic nitrogen and oxygen atoms.94 Inclusion adducts of tris (0-pheny1enedioxy)cyclotriphosphazene and polyethylene or poly(ethy1ene oxide) have been characterized by DCS and X- ray method^.^' The tetramer (NPC12)4 reacts with ferrocene-1,l’-diol in a non- geminal pattern to the transannular bridged derivative (NPC12)2(NPCI)2( 1,l’- 02C IoHsFe) (27), whereas spiro compounds with general formula (NPC12)~NP(l,I’-E2C~oH8Fe) with E = S (28), or Se (29) are obtained by geminal substitution with the corresponding 1,l’-dilithioferrocene dithiolate or seleno- late.96

Only the geminal isomer (NPC12)2NP(2-SC~NH4)2 (30) was formed in the reaction of (NPC12)3 with an excess of pyridine-2-thiol in presence of triethylamine. An S N I type substitution has been proposed for the second substitution


27 28 E = S 29 E = Se

step. An X-ray structure determination of compound 30 reveals a striking interaction between the exocyclic nitrogens and the adjacent p h o ~ p h o r u s . ~ ~

I1 I

N ChP, +I2

30

The number of papers dealing with P-C bonded ligands is limited. Spiro compounds 31 and 32 are formed by the reaction of aminodiphenylphosphine oxide and 5-aminobenzo[b]phosphindol-5-one in the presence of Appel's reagent (triphenylphosphine and carbon tetra~hloride).~~

31 32

A new olefin-substituted cyclotriphosphazene (NPCl2),NPPr'[C(O0CO- Me)=CH2] (33) and a bicyclic phosphazene [(NPCl2)2NPPr']2C(OH)Me (34) with a carbon bridge between the two phosphazene rings have been prepared by the reaction of (NPC12)2NPPr'H and MeCOCl. In the reaction sequence proposed, nucleophilic addition of the hydrocyclophosphazene and MeCOCl has been considered as the first step.w

0 I1

,CMe 0. ?H

33 34

7: Ph osphazenes 28 I

In TGA experiments, copolymers derived from the precursors 33 and styrene exhibit a two-step decomposition process. loo The homopolymer derived from (NPC12)2NPMe(CH2C6H4CH=CH2) as well as the corresponding copolymers with styrene show a one-step decomposition with elimination of HCI. loo

Two papers concerning thionylphosphazenes are mentioned here. Fluorination of NPCl2[NS(O)XI2 (X=CI, F, Ph) and (NPC12)2NS(0)X (X=Cl, F, Ph) with KS02F in bulk shows only substitution at the phosphorus centers according to a geminal substitution pattern. lo' Also, in reactions with sodium alkoxides (NaOBu", NaOCH2CF3) and sodium phenoxide compounds (N PC12)2NS(O)X (X = CI, F) show a greater reactivity with respect to the phosphorus center, PC12 > PCl(0R) > S(0)X.'O2

Industrial application of cyclophosphazenes is still attracting interest. Studies on the friction behavior of N3P3(0C6I-I4F-4)6-"(OC6H4CF3-3)n (35) have shown this class of compounds to be excellent lubricants in low speed system^.'^' Degradation at high temperature has been investigated by GC-MS, FT-IR, and NMR.lo4

35

Amino, hydroxy, and aryloxy derivatives have been used as flame retardants in thermoset resins. '05-108 Combination of methacryloyl entities and alkoxy groups in N3P3[0CH2CH20C(0)CMe=CH2]x(OPrn)6-x leads to UV curable fire retardants. ' 09 UV curable cyclophosphazenes possessing methacryloyl entities have been used in scratch-resistant coating materials. "O,' ' Compounds [NPClN(Et)CH2CH20H]3 and [NPCIN(Et)CH2CH2OH],NP[N(Et)CH2- CH20H]2 are described as possible cross-linking agents in the manufacturing of polyurethanes. ' l 2 The application of a diamino-tetrakis(p-bromophenoxy)cyclotriphosphazene as curing agent for bisphenol A-epoxide resins has been reported. ' l 3 Mixtures of novolac and triphosphazenes bearing photosensitive groups have been claimed as a photoresist material.'I4 The use of NP(Im)2[N- PIm(NHCH2CH=CH2)]2 as degradable cross-linker202 will be discussed in Section 4.

X-Ray structure determinations of some miscellaneous cyclic compounds' "-' 2o

are summarized in Section 5.

4 Polyphosphazenes

In this Section polymers are discussed having a P--N or P-N-S backbone or polymers in which cyclic phosphazenes form a part of the backbone. Organic


polymers with phosphazene entities as side groups have been reviewed in Section

A number of general reviews on polyphosphazenes have appeared. 121-125

Specific reviews on polyphosphazenes deal with radiation graft polymeriza- t i ~ n , ' ~ ~ ' ' 27 anionic polymerization,128 hydrogel microspheres, 129 controlled biode- gradabilit~, '~' coatings, 1 3 ' and membrane separation. 132

A computational study of phosphazene oligomers has shown a profound influence of intramolecular interactions on the backbone conformation. A NP bonding model in terms of an ionic a-bond and a n-bond induced by negative hyperconjugation has been proposed. 133 Molecular dynamics simulations have been carried out for (NPC12)n134 and [NP(OC6H4Me-4)2]n. 135 Calculations for (NPC12), show the lowest energy for a model in which the NP backbone has quasi-planar trans-cis (TC) conformation packed in a monoclinic cell. oThe difference between single and double NP bond was calculated to be 0.05 This agrees with results from density functional calculation^'^^ and recently obtained X-ray data. Application of MD simulations and EDXD measurements to amorphous [NP(OC6H4Me-4)2], leads to the conclusion that the backbone conformation can be described as [TCln (trans-cis-trrms-cis) rather than as [T3C], (trans-trans- trans-cis).

Transition temperatures have been measured for different phase transitions in [NP(OCHZCF3)2], films. It could be demonstrated that phosphazene chain fragments are oriented parallel to the surface of the film.136 The high temperature movement of ethyl groups in (NPEt2),, studied by solid-state NMR, can be described as a fast and complete rotation around the P-CH2 Mixed phenoxy and 4-cyanophenoxy substituted polyphosphazenes have been studied by DSC, TGA, X-ray diffraction, and polarizing microscopy. It was shown that introduction of cyano groups decreases the crystal-liquid crystal transition temperature, as well as reduces the crystallinity when compared with [NP(OPh)2],. 139 Combined thermal and spectroscopic studies of [NP(OC6H4Pri- 4)2], show an orthorhombic and a monoclinic crystalline phase, and a 2- dimensional pseudo-hexagonal mesophase. 140 Films of [NP(OPh)2]n and [NP(OC6H4R-4)2In [R =OMe, COlEt, C02H] have been studied by SSIMS (static secondary ion mass spectrometry).14' The poly(thiaph0sphazene) ([NP(NHBu")2]2[NS(0)NHBun]},, has been used as polymer matrix for phosphorescent oxygen sensors. For phosphorescent dyes, Pt(octamethy1porphyrin) and Ru(4,7-diphenylphenanthroline), the air quenching data show a linear relationship between the reciprocal luminescence and the air pressure. 142 The large values for oxygen diffusivity point to a high free volume polymer.'43

As already mentioned in Section 3 the PC15 induced polymerization of phosphoranimines forms a facile route for the preparation of polyphosphazenes.'"I7 Also the anionic polymerization of Me3SiNP[OCH2C(N02)2Me]3, affording (NP[OCH2C(N02)2Me]2}n, has been reported before. l 9 Thermal polymerization of Me3SiNPEt2(0CH2CF3) in presence of initiators as Bu"4NF and NaOPh has been reported.I4 Treatment of (NPPhEt), with Bu"Li and subsequently with Me3SiC1 affords a new organo-substituted polyphosphazene, (NPPhEt),[NPPhCH(Me)SiMe3]y.18 Similar reactions with (NPMeR), with

35

7: Phosphuzenes 283

R = Bu" or Hex" give (NPMeR),[NPR(CH2SiMe3)Iy. Replacing Me$3iCl by ferrocenecarboxylaldehyde in the presence of NH4CI (proton donor) results in the formation of (NPMeR),[NPR(CH2CH(OH)(CpFeCp))],,.'8

Heating Me3SiNPCH2C(Me)=C(Me)CH20Ph (36) during 14 days at 190 "C yields a novel type polymer with formula [NPCH2C(Me)=C(Me)CH2In (37). 145

I 1

OPh I

Me

190 "C

36 37

The reaction of [NPC12], with adamantanamine in presence of NaOCH2CF3 shows the formation of poly[bis(adamantanamino-co-trifluoroethoxy)phospha- ~ene] .~ ' Based on the small molecule concept, polymers [NP(OC6H4R-4)2]", (R = OPh, OCHzPh, Bu'), [NP(OC~H~CP~~-~)I.~C~O.~]~, and [NP(OCH2- C6H4OCH2Ph-4)2], have been prepared.@ Complex formation of [NP(NHR)2]n (R = Pr", Bun) with AgN03 has been found to occur via coordination of Ag+ to backbone and amino group nitrogens. The maximum content of AgN03 in these complexes, expressed as the molar ratio AgN03/NP, amounts to 0.5.146 The reaction of (NPC12)" and 2-(2-hydroxyphenyl)phenol offers a soluble, non-cross- linked polymer in which each 2-(2-phenoxy)phenoxy group is attached to one phosphorus atom. In line with this result spiro derivatives are formed when (NPC12)3 is used as phosphazene reagent. 147 The polymers [NPOPh(4-maleimido- phenoxy)], and [NPOPh(4-phthalimidophenoxy)ln have been prepared via a multi-step synthesis. Inclusion of these polyphosphazenes in polyimide resins led to an increase of the fracture toughness and an enhancement of the thermo- oxidative stability. 148 Some miscellaneous synthetic studies on polyphosphazenes include the photooxidation of [NP(OC6H4Pri-4)2]n, 149 reaction of (NPC12), with Me(OCH2CH2)20H and p-MeO-C6H50H followed by 31P NMR,'" and the solution behavior of [NP(NHC6H5)2]nI5' and [NP(OCH2CH2Ph)2],.'52

A new procedure to couple [NP(OC6H40H-4)2]n to silica networks consists in the hydrolysis of a solution of Si(OEt), and freshly prepared polyphosphazene in ethanol. The hydrolytic sensitivity of this homogeneous phosphazene-silica matrix can be decreased by heating at 200"C.'53 When irradiated with heavy ions, cluster formation of Si02 has been observed. 154 Beside [NP(OC6H4OH-4)2],

~)o.~[OC~H~(N=NC~H~NO~-~)-~, (OH-4)]1.6)n3 and {NP[(OCH2CH2)20- H]O.~[(OCH~CH&OM~]~ .2}" were allowed to react with Si(OEt), under hydrolytic ~0nd i t ions . I~~ The rate of hydroxyapatite formation from CaHP04.2H20 and Ca4(P04)20 in aqueous solution is influenced by the presence of { NP[OC&(C02Na)-4]2}n. The same holds for the morphology of the hydoxy- apatite formed.156

Grafting reactions on polymers offers the opportunity to modify the surface of the polymer and hence the properties of the bulk material. Light-induced radical

also [NP(OC6H40H-4)0.8(OCH2CF3) 1.2111, { NP(OC6H4OH-


grafting of acrylate monomers containing a photostabilizing group, viz. acrylates of 2,2,6,6-Me4-piperidin-4-01 or 1 ,2,2,6,6-Me5-piperidin-4-ol, onto { NP[OC6H4(CH2C6H5)-4]2}n leads to a graft copolymer with a higher stability towards photo-oxidation and thermo-oxidation than the starting polymer. The amount and distribution of the graft entities determines the copolymer stability. 157*158 Light-induced radical grafting reactions of poly(viny1 acetate) on [NP(OC&&-4)2] with R = Me, Et, and Bus have been d e ~ c r i b e d . ' ~ ~ Kinetic measurements show the reactivity of polyphosphazenes in these reactions to be dependent on their crystallinity. 16' Graft copolymers (compound 38 may serve as an example) have been obtained by a radical grafting reaction of maleic anhydride onto [NP(OC6H4R-4)2]n (R = Me, Et, Pf , Bus, But, and CH2c6H5).l6'

The resulting copolymers allow for further derivatization. 161*162

In a reversed approach a poly(organophosphazene) containing phenoxy, 4- ethylphenoxy, and 2-methoxy-4-allylphenoxy substituents has been grafted onto poly(viny1 alcohol). 63

Solid polymer electrolytes are still subject of investigation. The following { NP[O(CH2CH20)2Me]2}, (MEEP) analogues have been described: those with linear etherical side groups, {NP{[O(CH2CH,0)mMe]},), with m = 1-6, 8, those with a combination of alkoxy groups and linear etherical side groups {NP[O(CH~),Me],[O(CH~CH~O)2Me],,}n with m = 2-9 and x r y 1, those with branched etherical side groups { NP{ OCH2CH[CH20(CH2CH2O)mR][O(CH2- CH20),R]}2}, with R = Me, m = 0-3, and R = Bu", Pr', m = 1, and those with crown ether side groups. 1649165 The conductivity of the LiS03CF3 complex with {NP[OCH2CH(CH20CH2CH20Me)(OCH2CH20Me)]2}n is comparable with that of MEEP; however, the former polymer exhibits a greater room temperature macroviscosity. 164 A larger dimensional stability has been found for all polymers { NP(OCH2CH[CH20(CH2CH20)mMe][O(CH2CH,o),Me]}2}n when compared with their analogues with linear side groups.'65 For a number of MEEP analogues in which the ethyleneoxy side groups differ with respect to their

CH20)7Me]0.334)n in combination with LiN(S02CF3)2 shows a 2.5 times larger conductivity than MEEP. Maximum values have been obtained for a monomer/ Li salt ratio equal to 8. In the conductivity experiments LiN(S02CF3)z appears to be more effective than LiS03CF3.'66 A combination of (NP[O(CH2- CH20)7Me]2)n (MEEP 7) and LiC104 has been applied as anode in a solid electrolyte cell Li/Li+-MEEP-7/fullerene or fluorinated fullerenes. 167*168 Develop-

length, polymer ~ ~ ~ [ ~ ~ ~ ~ 2 ~ ~ 2 ~ ~ 2 ~ ~ 1 0 . 3 3 3 [ ~ ~ ~ ~ 2 ~ ~ 2 ~ ~ 3 ~ ~ 1 0 . 3 3 3 [ ~ ~ ~ ~ 2 -

7: Phosphazenes 285

ment of a new solid electrolyte cell involves a combination of Na-montmorillonite and MEEP. 169*170 Blends of poly(ethy1ene oxide) and a poly(fluoroa1koxy)phosphazene (PNF-200) whether or not in combination with plasticizers have been synthesized and investigated with respect to their conductivity in combination with LiS03CF3 as e l e ~ t r o l y t e . ' ~ ' - ' ~ ~ The ternary system poly(ethyleneoxide)/ PNF-200/poly(epichlorohydrin) has been investigated. 174*175 The electrochemical polycondensation of (NPC12)3 and quinone in the presence of a phase transfer catalyst in acetonitrile proceeds via quinone radical anions and quinone dianions. A study of the polymer, being formed at the electrode surface, shows the presence of mono and bis(organ0)-substituted phosphorus atoms belonging to the six- membered NP rings. Four of the six chlorine atoms per phosphazene are being replaced, which leads to a three-dimensional network.1767177 Doping of electrochemically prepared poly(cyc1ophosphazene-benzoquinone) films with iodine induces the possibility of charge transport in the films. Raman spectra suggest that iodine is bonded to the polymer matrix through the oxygen atom of the POC linkage.17' The iodine-polyphosphazene complex has been applied to the potentiometric detection of B u ~ ~ P ~ ~ . ~ ~ ~

Thin films of (NPMe2), have been applied to develop a water-resistant humidity sensor. Preliminary experiments showed the polymer film to be highly sensitive and reliable both at low and high humidity.'807181 Sulfonation of polyphosphazenes [NP(OC6H4Me-3)0PhIn and [ NP(OC6H4Me-4)OPhln by SO3 gives partly sulfonated derivatives, the S03H group being attached to the aromatic ring. Methylphenoxy groups are preferably sulfonated as compared with the phenoxy groups. Variation of sulfonation affords polymers that only swell, but not dissolve in aqueous media, and thus can be used as stable membrane materials. 1829183 Sulfonation of the analogous ethyl derivatives leads to a high degree of decomposition.'82 Treatment of { NP(OCH2CF3),- [(OCH2CH2)2NH2lY} (x + y = 2) with 1,2-oxathiolane-2,2-dione yields partly alkyl sulfonated polymers with the formula (NP(OCH2CF3),[(0CH2CH2)2- NH2]y[(OCH2CH2)2NH(CH2)3S03H)]z}n (x + y + z = 2). The sulfonated polymers thus obtained have been claimed for numerous app1i~ations.I'~ It has been demonstrated that membranes of polyphosphazene [NP(OPh)2]n and the cross-linkable polymer { NP(OC6H40Me-4),[0C6H4(2-Bun-4)],[OC6H4(CH2CH- CH2)2]z}n (x + y + z = 2) allow for control of separation parameters when varying the permeate pressure. Processes appeared to be reversible. Polymer-solvent interactions in these polymers have been studied by NMR techniques.'86 The oxygen gas permeability of membranes of polymers [NP(NHBun)2-,- (NHCH2CH=CH2)& have been investigated as a function of polymer composition and degree of cross-linking initiated by irradiati~n."~~"' The industrial product Eypel-F, a polyphosphazene bearing OCH2CF3 groups, has been applied as coating material in hollow polypropylene fibers used in capillary electrophoresis. The phosphazene coated material shows a good stability.Is9

The biomedical use of polyphosphazenes for drug delivery and controlled release systems still draws considerable a t t en t i~n . '~ ' - ' ~~ It has been demonstrated for the degradable polymer [NP(NHCH2C02Et)2]n that the rate of degradation increases by partially replacement of the ethyl glycinate groups by small amounts


of the depsipeptide group NHCH2CO2CHMeCO2Et. Implant devices based on phosphazene polymers containing ethyl phenylalanate and/or ethyl glyciiiate groups and loaded with mitomycin C can be used for controlled drug release, the rate of which can be controlled by the composition of the amino acid Introduction of (a-amino-o-methyl-poly(ethy1ene oxide) groups in [NP(NHCH2C02Et)2], also results in a redued hydrolytic stability, although the effect is less pronounced than for the introduction of depsipeptide groups.'97 Surface modification of nanoparticles consisting of amino acid ester substituted polyphosphazenes by { NP(NHCH~CO~E~)~.~[NH(CH~CH~O),M~]O. 1 ) , has been rep~r ted . '~ ' The study of drug release for the polymer matrix [NP(NHCH2C02- Et)(0C6H4Me-4)ln/inulin shows an increased degradation by the presence of the hydrophilic macromolecule inulin. Release of inulin can be controlled by pH and inulin 10ading.I~~ Promising results have been obtained with in vitro and in vivo controlled drug release for a polyphosphazene matrix with phenylalanine ethyl ester, imidazole, and chlorine as side groups (ratio 10.7:1:2.5) and loaded with naproxen.200

The concept of controlled hydrolytic stability based on substituted phosphazenes can be extended to organic polymers. Free radical polymerization of acrylic acid in aqueous solution in presence of 39 yields a degradable hydrogel with imidazolyl groups as controlling sites with respect to the hydrolytic stability.201

Chemical methods have been described to obtain a controlled number of carboxylic groups at the surface of poly(phenoxy)(methylphenoxy)phosphazenes.202 Characterization of polyelectrolyte [NP(OC6H4CO2H-4)2], (PCPP) using aqueous GPC has been reported.*03 It has been suggested that residual OH- containing monomeric units are responsible for the degradation of PCPP in aqueous solution.204 Coacervation of PCPP by means of NaCl solutions appears to be an elegant method for formation of hydrogel microspheres. The size of the microspheres depends on NaCl concentration, time of droplet formation, and polymer concentration. Reproducible results have been obtained.205 Polypho- sphazenes { NP(OC6H4C02H-4)x[0(CH2CH20),Me]2-x} have a higher solubility in aqueous media and a more compact structure than PCPP.2069207 Polymers { NP(OC6H4C02Na-4),[0(CH2CH20)2Me]2_,} cross-linked by @Co y radiation have been investigated with respect to their swelling properties in electrolyte solutions. The degree of swelling appears to be depend on the radiation dose, pH and ionic strength of the solution, as well as the charge of cations present.2o'

7: Phosphazenes 287

5 Crystal Structures of Phosphazenes and Related Compounds

The following compounds have been examined by diffraction methods. Distances are given in picometres and angles in degrees. Standard deviations are given in parentheses.

Compound Comments Ref.

l b . 3CH2C12

IC .3CH2C12 { ZnC12[Me3SiNP( CH2)&Me3]) 2

2

ZnIz[MezSi( NPE t 4 2 1

[ZnBr(NPMe3)I4 . CH2C12

[MnR(NPEt3)14 R = Me R=C=CPh R = C z C'C6€14Me-4 R = C E C-SiMe3

[Mo(NPMe3)]&12 . CH2C12

ZrC14(Me3SiNPPhR) .0.5 CEI2C12

[Zr~C16(NPMe3)5]+[Zr2Cl,,(NPMe3)3] - . 3CHzC12

[Hf3C16(NPMe3)5]'[Hf2C17(NPMe3)2] -. 5CH2C12

5

I,~-(NPP~~)~-~,~-(CN)~-C~FI 1,3-(NPPh2Me)2-4,6-(CN)2-C6F2 1-(NPPh3)-3-(NPPh2Me)-4,6-(CN)2-C6F2 9

10

Phz( Se)PNP(Ph2)P(Ph,)NP( Se)Phz

av. NP 158.5(4)

av. NP 158.1(7)

NP 160.8(2)

NP 160.7(5)

NP 161.6(2)

NP 156.8(8)

NP 157.3(4) NP 157.9(3) NP I58.1(4) NP 157.2(4)

av. NP 161.4(6)

NP 161.5(2)

av. =NP(cation) 160.0( 10) av. = NP(cation) 161.9(9) av. NP(anion) 159.9(20)

av. =NP(cation) 159.0( 10) av. = NP(cation) 164.6(9) av. NP(anion) 160.0(10)

av. NP 156.6( 12)

NP 160.4(4)

NP 162.9(2)

NP 160.4(3)

NP 160.2(2)

av. NP 163.8(3)

av. endo NP 163.4(3) exo NP 155.7(4)

NP 159.7(2)

NP 157.9

av. NP 158.2(9)

av. NP 157.2(7)

NP 157.0(5)- 161.2(5) APNP 136.0(4)- 139.1(4)

boat av. NP 159.4(4) /PNP 124.6(3)

av. /PNP 136.3(8) NP 155.9(7)- 161.8(6)

3 3

4

4

4

4

5 5 5 5

6

7 7

7

8

8

9

9

9

9

9

10

I I

1 1

1 1

20

22

23

288

Ph2( AuCI)PNP( Ph,)P(Ph,)NP( AuCI)Ph2

I 1

12

13

14

SP(Ph2)NHPOPh2

15

16

Ph2C(CN)N"PPh2

[P~~PNH~]+[C(CN)~PII] -

Ph3PNNNC( CN)2Ph

[(Me2N)3PNP(Nme2)(NHBu')NP(NMe2)3] . HPF6

(no standard deviations given)

(no standard deviations given)

N3S3NPPhPyr[N(cyclo-Hex)2] Pyr = C4H8N

N3S3NPPh2Morph

(Me3Si)3CP( =CH2)NMes* Mes* = C6H2But3-2,4,6

Moqh = C4HgNO

[Ph3PNHJCI -

(NH2)2P(0)NP(NH2)3


NP 158.1(10), 164.0(10) /PNP 128.7(7)

NP 160.0(6)- 166.0(5) /PNP 117.4(3), 131.3(3) / NPN 107.2(2), 1 1 1.9(3)

av.NP 158.1(6) / PNP 135.0(2)

av. NP 159.3(5) L PNP 130.2(2)

non-protonated ring av. NP 158.9(7) /PNP 128.2(7) protonated ring av. NP 164.5(7) /PNP 128.7(6)

av. NP 167.5(6) /PNP 133.5(3)

ring a (envelope) av. NP 158.1(4) /PNP 132.1(3) ring b (boat) av. NP 159.5(9) /PNP 123.7(2)

NP 156.6(8), 160.0(7) /PNP 126.8(5)

NP 163.7(2)

NP 162.2(2)

NP 164.2(2)

N(Me2)P 161.9-165.8 N(Bu')P 165.9 N(P)P 155.4-158.1 /PNP 141.5,142.6 /NPN 105.8, 114.7

N(Me2)P 160.3-167.2 N(bu')P 167.7 N(P)N 149.8-160.2 /PNP 138.6-157.7 /NPN 109.5-1 13.6

NP 159.0(4) NP(Pyr) 162.2(4), 164.3(4)

NP 162.2(3) N(Morph)P 164.6(3)

NP 155.6(2)

/NPN 105.l(2)-l18.1(2)

NP 162.1(2)

av. N(P)P 158.8(5) av. N(H2)P(0) 166.1(4) av. N(H2)P 163.7(3)

23

23

24

24

24

25

25

25

33

33

33

42

42

56

57

58

59

60

7: Phosphazenes

/ PNP I30.9( I) , I33.3( I )

av. N(P)P 158.6(2) av. N(H2)P 162.2(3) 1( PNP I33.0(2) I NPN lOOS(2)- 12 1.3(2)

/NPN 101.9(1)-119.9(1)

[(NH2)Ph2PNPPh2(NH2)]2+[SbCl,l-[Cl]-. CHCI3 two independent anions in the unit cell av. N(P)P 156(1)-161(1) / PNP 128.5(8), 135.0(8) av. /NPN 120.5(6)

(Me2N)3PNMe. H20

(Me2N)3PNMe. 1.75 H 2 0

(Me2N3PNMe. CH3COOH

(Me2N)3PNP(NMe2)2NH. H 2 0

(Me2N)3PNP(NMe&NH .2.25 H 2 0

Ph3PNSiMe3. TCI

Ph3PNT

(NPC12)2NPCINH*

N(me)P 1 5 6 3 1) / NPN 101.5( 1)- 120.4( 1)

two independent molecules in the unit cell av. N(Me)P I56.6(2) / NPN 101.2( 1)- 1 1 5.2(2)

N(Me)P 159.0(2) (NPN 103.7(1)-112.4(1)

N(H)P 156.5(2) N(P)P 155.5(2), 160.4(2) N(Me2)P 164.2(2)- 168.9(2) / PNP 132.4( 1) / N(P)PN(H) 124.0( 1) remaining INPN 101.0(1)- I21.6( 1)

N(H)P 157.7(3) N(P)P 154.2(2), 158.9(2) N(NMe2)P 163.0(3)- 167.2(3) / PNP 142.0(2) L N(P)PN(H) 121.1( 1) remaining /NPN 103.1(2)- 1 1 9 3 I )

two independent molecules, in the unit cell av. N(H)P 158.4(2) av. N(P)P 154.4(6), 159.7(4) N(NMe2)P 163.9(3)- 166.8(2) LPNP 133.5(2), 139.7(2) /N(P)PN(H) Il9.8(1), 121.0(1) remaining / NPN 100.2( 1) - 121.6( 1)

NP 160.0(3)

NP 159. I(3)

endocycl.: av. NP(CINH2) 161.7(2) av. NP(CI2) I58.7(2), 159.5(2) av. /PNP 121.2 (2) INPN 117.1(2)-119.2(2) exocycl.: NP 163.6(4)

289

61

62

63

63

63

64

64

64

65

65

77

endocycl: 78

Organophosphorus Chemisrry 290

Adaman = adamantianamino

20. MeCN

21 .0.5 CHIC12

22 . CFI2C12

23

NP 156.7(6)-161.3(5) av. /PNP 123.4(2) av. /NPN 115.9(4) exocycl.: NP 162.2(6)- 166.8(6)

endocycl: NP 155.6(6)- 159.6(6)

/NPN 115.6(3)-119.5(3) exocycl.: NP 165.1(7)- 169.0(7)

endocycl . : av. NP 157.9(4) av. / PNP 121.3 (2) av. / NPN 118.4(3) exocycl.:av. NP 168.9(4)

endocycl.: NP 157.5(5)-161.0(5) /PNP 113.9(3)-117.5(3) /NPN 116.0(2)-117.1(2) exocycl. : NP 167.1 (5 ) - 1 68.0( 5)

endocycl.: NP 155.1(9)-161.9(9) /PNP 116.2(5)-123.3(5)

exocycl.:

endocycl.: NP 156.3(3)- 158.8(3) / PNP 120.8(2)- 124.4(4) I NPN 1 14.7(2)- 1 18.7(2) exocycl.: NP 162.8(3)

endocycl.: NP 156.6(7)- 159.5(7)

/ PNP I 16.4(4)- I20.9(4)

/NPN 1 15.6(5)- 1 19.5(5)

/ PNP 121.5(4)- 124.1(4) /NPN 115.2(3)-117.2(3) exocycl.: NP 165.4(7)

endocycl . : NP 156.2(3)- 160.5(3)

/NPN 116.2 (2)-118.0(2) exocycl.: NP 162.3(3)

endocycl.: NP 150(2)-162(3) av. /PNP 121(2) av. lNPN 1 l8(1) exocycl.: NP 170(2)

endocycl . : NP 155(1)-165(1) LPNP 122.2 (6)-126.1(6)

exocycl.: NP 159( 1)

endocycl.: NP 160.3(6)- 163.5(6)

/PNP 121.0 (2)-122 (9)

/NPN 113.4(5)-116.9(5)

/PNP 124.0(3)- 127.6(4)

80

80

80

80

81

82

82

82

82

83

7: Pltosphazenes 29 1

OP( OChH4B U' -4)2NP( OC6H4But-4)3

(NPC12)2NPCl(OC6H2But3-2,4,6)

27

28

29

30

31

32

33

34

/NPN 110.0(3)-112.9(3) exocycl.: av. NP 162.3(4)

NP 156.6(4)-158.9(4) / PNP 122.0(2)- I23.7(2) /NPN 116.9(2) - 117.6(4)

av. NP 157.9(3) / PNP 121.1(2)-123.7(2)

NP 156.9(2)- 158.3(2) /PNP 121.8(1)-122.9(1)

LNPN I16.2( 1)- 11 8.1(1)

/NPN 116.3(1)-117.0(1)

NP 156.2(4)-158.8(5) / PNP 120.1(3)- 122.8(3) av. /NPN 117.8(3)

two independent molecules in the unit cell NP 1 55.2( 5 ) - 1 57 .O( 5) / PNP 133.1(3)- 1 36.3(3) / NPN 1 2 0 3 3)- 12 I .6(3)

linear NP 149.5(4); 157.8(5) / PNP 157.0(3)

molecule on minor plane av. NP 158(1) /PNP 119.3(1) /NPN 1 l5.8(1); 119.9(9)

NP 155.1(3)-157.3(2) LPNP 130.1(2)-135.6(2) / NPN 120.8(2)- 122.O( 1)

NP 155.3(3)-159.6(2) / PNP 134.3( 1)- 139.0(2) I NPN 1 19.4( I)- 122.7( I) NP 152.8(8)-159.2(5) /PNP 134.3(3)-141.7(4) /NPN 118.9(2)-122.8(3)

NP 156.3(4)-160.1(4)

INPN 117.9(2)-120.6(2) / PNP no values reported

av. NP 159.7(3) av. /PNP 122.5(3) av. /NPN 117.2(2)

av. NP 160.3 (3) av. f PNP 122.2(5) av. /NPN 117.7(4)

NP 155.5(3)-158.4(4) I PNP 119.5(3)-122.2(2) /NPN 115.9(2)-119.8(2)

/PNP 119.2(2)-122.7(2) f NPN 115.1(2)-120.0(2)

NP 155.8(3)-162.4(3)

84

84

84

84

84

84

86

96

96

96

91

98

98

99

99

292

c~s-NPF~[NS(O)P~]~

[NP(OC,jH4F-4)2]2NP(spiro- 1 ,2-02C6H4)

mP( OC6H4F-4)2]2NP( spiro-2,3-02CloH6)

I 1

NPEt,S(CI)NPE t2NS( CI)


av. NP 156.9(1) NS 157.1(2)-159.0(2) /NPN I19.0(1) /NSN 112.3 (1)

/SNS 122.3(1)

NP 156.0(4), 159.5(6) av. NS 15 1.8(6)

NP 156.9(2)- I58.6(2) av. NS 154.0(2)

endocycl.:

/ PNS 1 19.6( 1 ) - 123.2( 1)

NP 155.7(4)-161.5(3) / PNP 1 16.9(2)- 122.0(2) /NPN 112.0(2)-120.4(2) exocycl.: NP 165.1(4)

six independent molecules in the unit cell

L NPN 1 16.2(4)- 120.1(4) /PNP 119.7(5)-123.1(4)

/PNP 121.7(1) 123.0(1) /NPN 116.3( 1)-117.9(1)

(PNP 122.2(2)-123.3(2) av. LNPN 117.2(1)

/ NPN 1 19.3( 1)- 121.4( 1)

two independent molecules in the unit cell endocycl.:

av. LNPN 114.2(1) exocycl.: av. NP 156.0(4)

NP 160.8(3)-164.2(2) NS 153.5(2)-156.1(3) av. / NPN 1 17.8( 1)

av.NP 164.4(6) av. NS I5 I .0(5) /NPN 117.6(3)

two independent molecules in the unit cell av. NP 164(1) av. NS 151(1) av. NPN I19.4(6)

NP 154.2(7)-(158.3(6)

NP 157.6(2)- 159.3(2)

NP 156.7(3)- 158.5(3)

LPNP 133.6(2)-139.3(2)

NP 159. I(2)- 161.5(3)

100

101

101

115

116

1 I7

117

119

120

120

120

7: Phosphazenes 293

1

2 3

4 5

6

7 8

9

10

11

12

13

14

I5

16 17 18

19

20

21 22 23

24

25

26 27

28 29

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182 I83

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J. C. Pivin, G. Brusatin, M. Guglielmi, G. Facchin, and M. Gleria, Nucl. Instrum. Methods Phys. Rex B., 1996,112,294. M. Guglielmi, G. Brusatin, G. Facchin, M. Gleria, R. De Jaeger, and M. Musiani, J. Inorg. Organomet. Polym., 1996,6,221. K. S. Tenhuisen, P. W. Brown, C. S. Reed, and H. R. Allcock, J. Muter. Sci.: Muter. Me(/., 1996,7, 673. M. Gleria, F. Minto, R. Scrima, and V. Borzatta, J. Appl. Polym. Sci., 1996, 61, 1675. F. Minto, V. Borzatta, and M. Gleria, J. Inorg. Organomet. Polym., 1996,6, 171. F. Minto, L. Fambri, and M. Gleria, Macromol. Chem. Phys., 1996,197,3099. L. Fambri, F. Minto, and M. Gleria, J. Inorg. Organornet. Polym., 1996,6, 195. G. Fontana, F. Minto, M. Gleria, G. Facchin, R. Bertani, and G. Favero, Eur. Polym. J., 1996,32, 1273. F. Minto, G. Fontana, R. Bertani, G. Facchin, and M. Gleria, J. Inorg. Organomet. Polym., 1996,6, 367, L. Pemberton and R. De Jaeger, Chem. Muter., 1996,8, 1391. H. R. Allcock, S. J. M. O’Connor, C. G. Cameron, D. Olmeijer, and M. E. Napierala, PCT Int. Appl., WO 9627630 A 1. H. R. Allcock, S. J. M. O’Connor, D. L. Olmeijer, M. E. Napierala, and C. G. Cameron, Macromolecules, 1996,29, 7544. S . Sanderson, T. Zawodzinski, R. Hermes, J. Davey, and H. Dai, Proc.-Electrochem. Soc., 1997,96(17), 136. F. Okino, N. Liu, S. Kawasaki, and H. Touhara, Proc.- Electrochem.Soc., 1996,96- 10, 191. N. Liu, H. Touhara, F. Okino, S. Kawasaki, and Y . Nakacho, J. Electrochem. SOC., 1996,143,2267. J. C. Hutchison, R. Bissessur, and D. F. Shriver, Chem. Mater., 1996,8, 1597. J. C. Hutchison, R. Bissessur, and D. F. Shriver, Mater. Res. SOC. Symp. Proc., 1997, 457,489 (Chem. Abstr., 1996,125, 116001). J. L. Acosta and E. Morales, Rev. Plast. Mod, 1996,72, 39 (Chem. Abstr., 1996,125, 223290). L. Acosta and B. Morales, Solid State Ionics, 1996,91,75. E. Morales and J. L. Acosta, Solid State Ionics, 1997, %, 99, C. Del Rio and J. L. Acosta, Polym. Bull., 1997,38,63. C . Del Rio, P. J. Martin-Alvarez, and J. L. Acosta, Polym. Bull., 1997,38, 353. J. Li and M. Josowicz, Chem. Mater., 1997,9, 1451. M. A. Josowicz and G. J. Exharhos, U.S. Pat., US 5569736 A. M. Josowicz, J. Li, C. F. Windisch, Jr., G. J. Exarhos, D. R. Baer, W. D. Samuels, and M. D. Ulmen, Chem. Muter., 1997,9, 1285. J. Li, J. Janata, and M. Josowitz, Electroanalysis, 1996,8, 778. R. Anchisini, G. Faglia, M. C. Gallazzi, G. Sberveglieri, and G. Zerbi, Sens. Actuators, 1996, B35,99. R. Anchisini, G. Faglia, M. C. Gallazzi, G. Sberveglieri, and G. Zerbi, in Proc. P. Ital. Conf Sens. Microsyst., ed. C . Di Natale and A. D’Amico, World Scientific, Singapore, 1996, 74. R. Wycisk and P. N. Pintauro, J. Membr. Sci., 1996, 119, 155. P. N. Pintauro, in 10th Int. Forum Electrolysis Chem. Ind., Electrosynthesis, Lan- caster, N.Y., 1996,52 (Chem. Abstr. 1997, 126, 104998). H. R. Allcock, E. H. Klingenberg, and M. P. Weller, U.S. Pat., US 5548060 A.

7: Phosphazenes 299

185

186

187 188 189 I90

191

192 193 194 195 196

197 198

199

200

20 1 202

203 204

205 206

207

208

E. S. Peterson, M. L. Stone, C. J. Orme, F. F. Stewart, and R. L. Cowan, Sep. Sci. Technol., 1997,32,54 1 . F. F. Stewart, E. S. Peterson, S. C. Busse, and C. J. Orme, Chem. Muter., 1997, 9, 155. M. Kajiwara and T. Kimura, J. Mater. Sci., 1996,31, 5457. M. Kajiwara and T. Kimura, J. Mater. Sci., 1996,31, 6659. X. Ren, P. Z. Liu, A. Malik, and M. L. Lee, J. Microcolumn Sep., 1996,8, 535. A. K. Andrianov, S. A. Jenkins, L. G. Payne, and B. E. Roberts, U.S. Put., US 5529777 A. S. Cohen, A. K. Andrianov, M. Wheatley, H. R. Allcock, and R. S. Langer, U.S. Pat., US 5562099 A. S. Jenkins, L. A. Payne, Y. Lu, and B. Roberts, PCT Int. Appl., WO 9640294 Al. W. E. Hennink and A. Bout, PCT Int. Appl., WO 9707226 Al. M. Grunze and M. Schrenk, Ger. Offen., DE 1961 3048 Al. Y. S. Sohn, H. Raek, Y. H. Cho, and 0. S. Jung, PCTInt. Appl., WO 9712891 A l . E. Schacht, J. Vandorpe, J. Crommen, and L. Seymour, in A h . Biomater. Biomed. Eng. Drug Delivery Sy.st, ed., N. Ogata, Springer, Tokyo, 1996, 81. J. Vandorpe and E. Schacht, Polymer, 1996,37,3 141. J. Vandorpe, E. Schacht, S. Stolnik, M. C. Garnett, M. C. Davies, L. Illum, and S. S. Davis, Biotechnol. Bioeng., 1996,52,89. S . M. Ibim, A. A. Ambrosio, D. Larrier, H. R. Allcock, and C. T. Laurencin, J. Controlled Release, 1996,40, 31. A. Conforti, S. Bertani, S. Lussignoli, L. Grigolini, M. Terzi, S. Lora, P. Caliceti, F. Marsilio, and F. M. Veronese, J. Pharm. Pharmacol., 1996,48,468. A. Grosse-Sommer and R. K. Prud’homme, J. Controlled Release, 1996,40, 261. H. R . Allcock, C. T. Morrissey, W. K. Way, and N. Winograd, Chem. Mater., 1996, 8,2730. A. K. Andrianov and M. P. Le Golvan, J. Appl. Polym. Sci., 1996,60,2289. A. K. Andrianov, M. P. Le Golvan, S. S. Sule, and L. G. Payne, Polym. Mater. Sci. Eng., 1997,76, 369. A. K . Andrianov, J. Chen, and L. G. Payne, Polym. Muter. Sci. Eng., 1997,76,365. A. K. Andrianov, J. R. Sargent, S. S. Sule, M. P. Leglovan, and L. G. Payne, Polym. Muter. Sci. Eng., 1997,76, 367. A. K. Andrianov, L. A. Payne, J. R. Sargent, and S. S. Sule, PCT Int. Appl., WO 9640254 A 1 . H. R. Allcock and A. M. A. Ambrosio, Biomuteriuls, 1996,17,2295.

8 Physical Methods

BY R. N. SLINN AND M. @. SALT

While section 1 contains theoretical studies of general interest, studies relating to specific physical methods will be found in the appropriate section as in Volume 28. Compounds in each subsection are usually dealt with in the order of increasing coordination number of phosphorus. In the formulae, the letter R normally represents hydrogen, alkyl or aryl, while X represents an electronegative substituent, Ch represents a chalcogenide (usually oxygen or sulfur) and Y and Z are used to represent groups of a more varied nature.

1 Theoretical and Molecular Modelling Studies

1.1 Studies Based on Molecular Orbital Theory. - The geometries and energies of the conformers of the open-chain polyphosphorus hydrides, P,H,+* (for n = 2 - 9), have been studied by semi-empirical PM3 MO methods and the results tested using ub initio calculations.’ All the results for P2H4 and P3H5 by PM3 methods are consistent with the experimental and ub initio data. From the analysis of P3H5 and P4H6 results it is concluded that ‘gauche’ interactions between adjacent lone electron-pairs and also between the polar P-H and adjacent P-P bonds are important for predicting the stable conformer of open- chain phosphines. The calculations for n > 4 further support this conclusion. Ab initio calculations carried out on tetrafluorodiphosphine, P2F4, up to the MP2/6- 3 1 1 +G* level, provided harmonic force constants and vibrational frequencies along with IR and Raman intensities for the most stable conformer.* The calculations indicate that the gauche conformer was the less stable rotamer with 2.3 kcal mol- higher energy and possessing an IR band at > 800 cm-I (hence its absence in the vibratiopal spectrum at ambient temperature). Its predicted P-F distance was > 0.031 A longer than experimental data. The potential function governing conformer interchange and the change in internal rotation were also predicted from ab initio calculations.

Ab initio calculations carried out on three 1,3,2-diazaphosphole derivatives, eg., 1, at the MP2/6-31 lG(d,p) level, gave rise to structural and energy data that are interpreted in context of its a r~mat ic i ty .~ The 1,3,2-diazaphospholenium ion 2 also has a substantial degree of aromatic stabilisation energy (24.0 kcal mol-I); in fact it is comparable to that of pyrrole. Cyclic delocalisation is supported by an analysis of computed charge distribution data, natural bond orbital data, bond


300

8: Physical Methods

m m N+ ,NR HN, +,NH

P P 1, R = H, anion 2

30 1

lengths and magnetic susceptibility data. Two important addition reactions between 2H-phosphole and (a) phosphaethene, (b) phosphaketene have been investigated using ab initio calculations. In the case (a), all 4 possible Diels-Alder reactions between 2H-phosphole and phosphaethene (Fig. 1) were examined at various levels including HF, MP4SDQ, CCSD(T) and CASSCF.4 Analysis at the MP4SDQ/6-3 1 G*//HF/6-31 G* level indicated that these reactions are exothermic by 34-38 kcd mol-' and have low activation energies of 5-7 kcal mol-I. The P-P/ C-C regioisomer products are lower in energy than the C-P isomers and, within each pair, the exo- is lower in energy. At low computational levels, the smallest activation energy is for the reaction leading to the C-P endo-product. Larger basis sets, electron correlation, and solvent favour the transition state leading to the experimentally-observed P-P/C-P endo-isomer (Fig. 1) The dimerisation of phosphole is, therefore, kinetically controlled. Based on geometric and electronic density analysis, the reactions are concerted and synchronous. In the case (b), Staudinger [2 + 21 and Diels-Alder [4 + 21 addition reactions between 2H-phosphole and phosphaketene (Fig. 2) were investigated at the MP4SDQ/6-3 1 G*// MP2/6-3 1 G* +ZPE level.5 It was found that the Diels-Alder reaction is favoured kinetically by 6 kcal mol- and thermodynamically by 4 kcal mol- over the Staudinger reaction. This is in contrast to the reaction between ketene and cyclopentadiene, for which the Diels-Alder reaction has a 12 kcal mol-' higher activation energy than the Staudinger reaction. In both reactions (Staudinger and Diels-Alder), phosphaketene reacts at P=C rather than at C=O, as does ketene in the parent Staudinger reaction. The transition state structure of the phospha-Staudinger reaction has a closed ring, but the second bond is formed employing the phosphaketene P lone- pair rather than the former P=C bond. Like the parent reaction, the phospha- Staudinger reaction does not follow the [n2s] + [n2a] pathway.

Figure 1 'H

The molecular and electronic structure of P- and C-halogen-substituted phosphaalkenes have been studied using quantum-chemical calculations together with X-ray diffraction data.6 The introduction of an electronegative


Figure 2

halogen atom had little effect on the intramolecular bond angle distribution, but it had a noticeable effect on the P=C bond length. In the P-substituted phosphaalkenes, the bond length is noticeably shorter (due to increased polarisation), whereas in C-substituted phosphaalkenes the effect of halogen atoms is less pronounced and decreasing the P=C bond polarisation leads only to a slight elongation. A considerable elongation of the P-halogen bond in comparison with three-coordinate phosphorus compounds is a peculiarity of the molecular structure of P-substituted phosphaalkenes. Ab initio calculations have aided the structure determination of diphosphaallenic radical cation^.^ It is found that oxidation of the allenic -P=C=P- structure leads to the formation of two rotamers with HPPH dihedral angles of 45" and 135". The 'fluorine' effect on the stability of phosphaalkenes, phosphasilenes, oxopho- sphines, thioxophosphines and their rearranged isomers have also been studied using ab initio

The structures of fluorophosphine, PH2F, and chlorophosphine, PH2C1, have been determined by ab initio calculations: and the pyramidal geometry of the X 2A1 ground state of the PF3+ cation has been confirmed." An ab initio study of the internal rotation levels of the terminal methyl group in the ethylphosphine molecule CH3CH2PH2 has been undertaken. ' Ab initio calculations on ethyldi- fluoro-, ethyldichloro-, and ethyldimethyl-phosphines, C H ~ C H ~ P X Z ' 2-14 have been compared with conformational stabilities obtained from temperature-dependent FT-IR spectra recorded in liquefied xenon solutions. Theoretical gas-phase proton affinities of arylphosphines have also been reported at the MP2 level.I5

The electron distribution in PCls has been studied by ab initio calcuIationsyi6 and the radical cation of trimethylphosphine oxide, Me3P+-O', has also been examined. l 7

Phosphorus nuclear magnetic shielding anisotropy in (1 -hydroxyalkyl)dimethylphosphine sulfides has been studied using the IGLO method,I8 and the tautomeric stability, molecular structure, and internal rotation of methylphosphonic dicya- nide MeP(O)(CN)*, dicyanomethoxyphosphine MeOP(CN)2, and their isocyano analogues have been extensively followed using ab initio ca l~u la t ions .~~

An unusually-large value of coupling constant, Jpp, for a solid triphenylpho-

8: Physicul Methods 303

sphine phosphadiazonium cationic complex, [Mes*NP-PPh3]+, and proof of the negative sign of J from 2D spin-echo experiments has been confirmed by semi- empirical MO calculations at the INDO level.20 Ab initio investigations of the nucleophilic ring opening of 1,3,2-0xathiaphospholane,~~ on the isomers of P2S2,22 of the electronic structures of (carboxy-alkeny1)-phosphonic acids23 and some fluoropho~phonates~~ have also been undertaken. An ub initio study of the nucleophilic attack of trimethyl phosphate25 has been examined in considerable detail.

Reactions of phosphine with hexacyclo[6.6.0.02~6.03~'3.04~ I .0579]tetradecan- 10- one derivatives have been rationalised with the aid of semi-empirical PM3 calculations and the mechanism discussed, (Scheme 1, structures 3-5).26 Ab initio calculations have been performed on the molecular structure of a cyclen- phosphorane species and the tautomerism between the pentacoordinate (cy- c1en)PH and the tricoordinate H ( ~ y c l e n ) P . ~ ~ Semi-empirical MNDO methods have been employed in a study of the molecular structures of triphenylpho- sphoranes28 and C2C16N4P2, the product from the reaction of dicyanodiamide with PCl5 .29 A cyclopen tadien ylnio bium( I I I) complex, (C5 H4Me)N bCl2( PEt,),, has been studied by X-ray and ub initio methods and confirmed to have a 'four- legged piano stool' ge~metry.~'

5 3 4, R = Ph, OEt Scheme 1

Finally, other MO methods have been used to study the phosphaalkyne cyclotetramer system," the ring angles in the four-membered cyclodi- p h o ~ p h a z a n e s , ~ ~ and to confirm the structures of two chloro(piperidy1)cyclotri- (pho~phazenes) ,~~ and that of 2,4,4,6,6-pentachloro-2-(piperidyl)-cyclotri- ( p h ~ s p h a z e n e ) . ~ ~

1.2 Studies Based on Molecular Mechanics and Molecular Dynamics. - Mole- cular dynamics simulations (CHARMm) of poly[bis(chloro)phosphazene]35 and poly[di-(4-methylphenoxy)phosphazene]36 have given structural and conformational data.

2 Nuclear Magnetic Resonance Spectroscopy

2.1 Biological and Analytical Applications. - NMR spectroscopy studies on organophosphorus compounds possessing biological activity, and relevant analytical applications are included in the appropriate sections.


2.2 Applications including Chemical Shifts and Shielding Effects

2.2.1 Phosphorus-31 N M R . - Positive chemical shifts, 631p, are downfield of the external reference 85% phosphoric acid, and are usually given without the appellation ppm. One-coordinate compounds studied include phosphaalkynes and their cycl~tetramerisation.~' Two-coordinate compounds. The 31P NMR data of the simple phosphaalkenes R'CH=PR (R/R' = H/H, H/Me, H/Et, Me/H, Me/ Me, Ph/H, and Ph/Me) have been reported for the first time,37 with 6 in the range +179 to +285, and found to be consistent with the proposed structures. Stereochemistry of the (Z)- and (E)-isomers was established according to the cis- rule. The 31P and 15N NMR data of a series of 40 iminophosphines, R-P=N-R', revealed that their E/Z stereochemistry can be predicted on the basis of a simultaneous comparison of the values of 631p and ' J P N . ~ ~

Three-coordinate compounds. Primary and secondary a-chlorophosphines, R 'CH(Cl)PHR, precursors of the above ph~sphaa lkenes ,~~ have been characterised using 31P, 13C, and 'H NMR, together with mass spectroscopy. The 83lp

values were in the range - 105 (R = R' = H) to -23.6 (R = Ph, R' = Me), again generally in good agreement with the proposed structures. Radical reactions between trimethylsilylphosphines, Me3SiPH2 or (Me3Si)2PH, and mono- and di- alkenes have been studied and new compounds characterised using spectroscopic data (including 31P, 13C, and 'H NMR).39 The primary phosphine [(EtO)2- P(0)]2C(PH2)CMe3 has been prepared and the product identified using 31P NMR spectroscopy.m A new cyclic chlorophosphite (6) has also been prepared and its

MewcMe3

31P NMR solid-state spectrum (6 = 165.7) used for structure ~onfirmation.~' Extensive 31P NMR studies have been carried out to investigate possible mechanisms into the generation and trapping of monomeric metaphosphate esters (ROP02) in solution.42 The generation of alkyl-substituted monomeric metaphosphate esters (e.g., R = Me), via condensation of alkyl phosphorodichloridates with a novel disodium pyrocarbonate salt, was shown to involve cyclic pyrocarbonate phosphate, which decomposed in situ with release of 3 mol of C 0 2 to form the metaphosphate. The monomer thus formed spontaneously self-condensed to produce polymeric species with P-0-P bonds having characteristic 31P NMR signals clustered in the 6 = - 12 and -24 regions. In the presence of styrene oxide, polymerisation was avoided, trapping reactions occurred, and these were studied with the aid of 3'P NMR spectroscopy.

Four-coordinate compounds. The cyclic phosphine oxide 7 and its Li' salt were found to exhibit very similar 631p values (A631p=O), whereas in a similar


comparison of the oxide 8(X) = 0) and sulfide 8(X) = S), the corresponding values were shifted strongly downfield (A 831p= +18.4) and upfield ( A 6 3 1 p = - 13.5) re~pectively.4~ P-Zwitterionic species 9, and their reaction products, have been characterised using 3'P, 13C, 'H NMR and IR and X-ray diffraction studiesM The 3'P chemical shift anisotropies for the triphenylphosphine ligands in the solid, octahedral, chromium(0) triphenylphosphine derivatives 10 and cis- and trans-11 have been measured,45 and it was found that the major changes in the shift tensors occur for the and 622 components perpendicular to the Cr-P bond direction. The individual tensor components of the 631p shifts were clearly more important than the isotropic values in providing information on the Cr-P bonding. New a-(2-benzoxazolyl)oxyacetoxyalkyl phosphonates cycles 13, 1447 and 1s4* have been prepared and characterised spectroscopy, amongst other techniques.

1246 and hetero- using 31P NMR

7 8 X = O , S

Pri3P+CH2-(CN)C02R Cr(C0)5(PPh3) Cr(C0)4(PPh3)(CS) 9 R = Me, Et 10 11 cis- and trans-

u o A o , C H 2 C 0 2 C H R' P(0)(0R2)2

12 R' = Me, Et, Pr, Ar; R2 = Me, Et, Pr, Pr' 13

14 15

In the heterocycle 16, 3'P and 77Se high-resolution solid-state NMR spectroscopy was used to study structural proper tie^.^^ Both 3'P CP/MAS and 77Se CP/ MAS experiments revealed that the asymmetric unit consists of two independent molecules with a different geometry around phosphorus and selenium centres. The established values of anisotropy and asymmetry parameters reflected the distortion of the phosphorus environment, and correlated with X-ray diffraction data. 3'P NMR spectroscopy has been used to follow a new type of P-decomposition in diphosphorylated amines5' and to characterise new organophosphorus compounds with -N-P(0)-N- linkage^.^' A series of dioxaphosphocin-6-oxides (17), of varying substituent X, have been characterised by using 3'P NMR and


other spectroscopic methods,52 the 'H NMR data being mentioned elsewhere. The 31P NMR shielding tensors of diethyl [5,6-dichloro-l,3-benzodioxo-(2)]phosphonate were measured in a single crystal,53 and two slightly different molecules found in the unit cell. The principal directions, corresponding to 022 and 033, lie in the pseudo-mirror planes spanned by the O=P-C7 molecular fragments, and the most shielded directions are almost parallel to the P=O bonds. The 3'P NMR spectra of bis(y1ide)-substituted phosphenium halides revealed an essentially planar structure of the PCPCP skeleton with E,E-c~nformation.~~ As shown by the solvent-dependent spectra, they dissociate in polar media to produce the first examples of chalcogenoxo-phosphonium halides.

16 17

The 631p values of several phosphazinium bromides, e.g. , 18, have been studied55 and show a much smaller variation in chemical shift (6=35-38) compared with their free bases (6 = 14-20). The complex reactions of iodine with tert-butyl(isopropy1)iodophosphine to produce several tert-butyl(isopropy1)diio- dophosphonium iodides56 has been followed in solution by 31P and 'H NMR spectroscopy. 3'P NMR spectroscopy has also been used in the characterisation of new phosphorus-crown compounds containing the thiophosphoryl and c y c l o p h o ~ p h a z e n e s ~ ~ ~ ~ ~ and polyphosphazenes.60

[(C,H,),P=N(H)N=C(CH3(Bui)]+ B f 18

Five- and six-coordinate compounds. Evidence for an increase in coordination geometry to pseudo-trigonal bipyramid and TBP in respective cyclic phosphites and phosphates containing sulfur (via sulfur donor action) has been illustrated using 31P NMR spectroscopy and X-ray diffraction studies, e.g, 19, whereas in a cyclic phosphite (6) with a methylene group in place of the sulfur atom this was not observed.41 The sulfonyl-substituted oxyphosphoranes 20-24 have been examined structurally by NMR spectroscopy and X-ray diffraction.6' 3'P and ' H NMR spectral data indicated the presence of two isomeric forms for each of the phosphoranes 20-22.

A 3'P-27A1 J-coupling constant for trimethylphosphine bound to the Lewis acid of Zeolite HY has been determined by 27Al to "P INEPT methods,62 since coupling could not be resolved for this resonance (6= -49) in the 3'P MAS NMR spectrum. The coupling was consistent with a five-coordinated aluminium Lewis acidtrimethyl phosphine complex, and thus a four-coordinated Lewis acid site. Bi- and tricyclic penta- and hexacoordinated-phosphoranes 25-28 have been


CI CMe3

19

21

studied by 31P NMR spectroscopy and the data discussed with respect to the differing ring sizes and coordination number of p h o s p h ~ r u s . ~ ~

Hexacoordination in phosphoranes 29-31 has been substantiated by their high field 831p values and X-ray crystal structures.@ In the series of N- and CI-bonded bicyclic tetraoxyphosphoranes 32-36, hexacoordination (via sulfur donor action) has been revealed by X-ray studies and correlated with 31P NMR spectral data.65 Increased 31P NMR shielding accompanied the chloro derivatives 32, 35, while increased x P-N back-bonding resulted in the least-shielded members (34,36, and 37) containing the less electronegative N atom. These changes in 8 3 1 ~ values correlated with the extent of octahedral character, where the more-shielded P atom has the greater octahedral character.

2.2.2 Selenium-77 NMR. - 31P and 77Se high-resolution solid-state NMR spectroscopy were used to study structural properties of the heterocycle 16,49 revealing that the asymmetric unit consists of two independent molecules with a


Me&

Me3C Me3C CMe3

25

27

26

Me3C CMe3 28

different geometry around the P and Se centres. Solid-state 31P CP/MAS and 77Se CP/MAS NMR spectroscopic studies have been carried out on the structure and dynamics of organophosphorus dichalcogenides RR'P(S)XX(S)PRR', for X = S, Se.66. 67 The NMR data was also used to study different polymorphic forms. The analysis of 77Se satellites in the 31P NMR and the 77Se NMR of new heteronorbornanes 38 has been carried out.68 This offered a way to derive the connectivity of the P and Se atoms based on the PP and SeP coupling constants, providing a powerful method for the structure elucidation of phosphorus-selenium heterocycles. Di-tert-bwtyl(N-pyrro1yl)- phosphinyl chalcogenides (Me3C)2XNR2 (X = P=S, P=Se), and the parent phosphine (X = P), have also been studied by multinuclear, including 77Se, N M R spectro~copy.~~

2.2.3 Carbon-13 NMR. - Much data on 813c values is included with other references to 31P and multinuclear NMR spectroscopy. New methyl phosphonates, containing an active alkyltin group, have been characterised using mainly I3C NMR spectros~opy.~~ A range of cyclic organo(silyl)phosphines, e.g. , 39, have been characterised by 13C, 'H and 31P NMR spectro~copy,~' and similarly for other organophosphorus corn pound^.^^‘^' The effect of the chain length and temperature on the ordering of alkylphosphonate monolayers on Zr02 has also been investigated following a detailed I3C solid-state NMR

8: Physical Methods 309

31

30

Me

I CMe3 CI

32 R = C I 33 R = NHC6H4Me 34 R = NMe2

35 R = C I 36 R = NHCHzCeH5 37 R = NMe2

H I

Me2Si Cp> P I H 39


2.2.4 Hydrogen-1 N M R . - ' H NMR data is also included with other multinuclear references. In a series of dioxaphosphocin 6-oxides (17) of varying substituent X, 6IH values for the methine at the C bridge occurred between 6 6.1 5 and 6.40, suggesting a common environment and one conformer, but the presence of more than one conformer could not be entirely eliminated.52 The downfield shift of the methine proton was attributed to the CC13 group. 'H NMR, together with other physical methods, has been used in the characterisation of new phosphorus containing aryl cyanate ester monomers,82 and polyphosphazene block copolymer^.^^ Other uses of 'H NMR, together with otherlmultinuclear NMR techniques, are m e n t i ~ n e d . ~ ~ - ~ ~ Phosphinimino- cyclotrithiazenes 40 have been so characterised, using 'H and 3'P NMR.90 A phosphonate analogue of sialic acid has been shown to exist exclusively as the p- sialoside of sialic acid in solution by 'H NMR spec t ro~copy .~~

40 R = EtpN, B u ~ N

2.2.5 Other NucleilMultinuclearIGeneral NMR. ~ I9F NMR, together with 'H NMR spectroscopy, has been used in the characterisation of new perfluoroalkyli~ophthalates.~~ Phosphoryl group-metal ion interactions have been studied using I7O NMR s p e c t r o s c o ~ y . ~ ~ Other NMR studies have been carried O U ~ , ~ ~ - ~ ~ ~ and include conformational studies on the semirigid macrocyclic phosphonamides 41-43,1°2 characterisation of a new ethynyl-h5- [ 1,3]diphosphinime (44), lo3 and structural studies on a 3-methylphosphole (45). Io9 The complex t riphen ylphosphineacet y lmet h ylene-t rimet h y It in nitrate has been characterised using a combination of 14N NMR, 'I9Sn Moessbauer and IR spectroscopy.' lo A very interesting recent development is the use of DRAMA (Dipolar Restoration At the Magic Angle) 31P NMR spectroscopy to measure the 31P-31 P internuclear distance between phosphine-sulfide substituted side- chains on the fourth and eighth residues of a 12-residue helical peptide. ' ' ' 2.3 Restricted Rotation and Pseudorotation. - Studies on pseudorotation include the solvoly sis of phosphonium compounds having a thiophenoxy group linked to phosphorus, 123 and the stereoisomerisation of hexacoordinate phosphates bearing an oxaphosphetane ring.'24 The first characterisation of a 10-P-5 spiro-phosphorane with an apical carbon-equatorial oxygen ring, and studies on pseudorotation of the stereoisomers 46, 47 have been carried out using a combination of NMR and kinetics. 125 The inhibition of pseudorotation in solid chlorophosphoranes with trichloromethyl substituents has been followed using 35Cl NQR techniques.'26

8: Physical Methods 31 1

41 42

U

R*R

R 43 44 45 R = Pr', Bu'

@ gr F3C CF3

46 47

2.4 Studies of Equilibria, Configuration and Conformation. - Alcoholic solutions of acylphosphonates have been shown to contain considerable amounts of hemiketals by examination by 31P NMR spectroscopy.'27 Because of the great difference between the 31P chemical shifts of acylphosphonates (631p - 0) and their hemiketals 17-21), 31P NMR spectroscopy was shown to be a suitable method for studying the rates and equilibrium of hemiketal formation of acylphosphonates with different alcohols.

2.5 Spin-Spin Couplings. - The structure of tertiary 2-phosphinyl-phenol derivatives has been established by IR, X-ray studies and 31P NMR spectroscopy, the latter giving 2Jpc values for the preferred trans arrangement of the phenoxy group in solution.'28 The trans arrangement of the phenoxy group is preserved and, because of steric hindrance, the 0 substituents are tilted towards the P atom and thus induce large through-space coupling constants.

Interesting coupling constants reported include an unusually large value of Jpp


for a solid triphenylphosphine phosphadiazonium cationic complex, [Mes*NP-- PPh3]+. The two P nuclei are strongly spin-spin Soupled ('Jpp = 405 Hz), despite the unusually-long P-P separation (rp,p = 2.645A).20 A 31P-27Al J-coupling constant for trimethylphosphine bound to the Lewis acid of Zeolite HY has been determined by 27Al to 31P INEPT methods,62 since coupling could not be resolved for this resonance (6 = -49) in the 31P MAS NMR spectrum. The coupling (207 Hz) was consistent with a five-coordinated aluminium Lewis acidhimethyl phosphine complex, and thus a four-coordinated Lewis acid site. Di-tert-butyl(N- pyrroly1)phosphinyl chalcogenides (Me3C)2XNR2 (X = P=S, P=Se), and the parent phosphine (X = P), have been studied by multinuclear, including 77Se NMR, spec t ro~copy .~~ The preferred orientation of the pyrrolyl group in the parent phosphine was seen from the coupling constants 2Jpc,2,=+35.4 Hz and 2Jpc(s)= -9.3 Hz, typical of C(2) in syn and C(5) in anti positions with respect to the assumed axis of the P lone-pair.

3 Electron Paramagnetic (Spin) Resonance Spectroscopy

The isotropic hyperfine coupling constants of the diphosphaallenic radical cation [ArPCPAr]'+ have been measured by EPR spectroscopy after electrochemical oxidation of ArP=C=PAr and ArP=13C=PAr in THF. The two 31P constants and the 13C coupling were close to 90 M H z . ~ Taking HP=C=PH as a model compound, ab initio calculations support the EPR results. Oxidation of the allenic -P=C=P- structure leads to the formation of two rotamers with HPPH dihedral angles of 45 and 135 ', the two structures being compatible with the Jahn-Teller distortion of the allene. Phosphaalkene derivatives of furan and thiophene in T H F solutions (with the ring bound to the C atom of the -P=C< bond) formed radical anions with a K mirror at 255 K, which were studied by EPR in both the liquid and solid states.129 The resulting hyperfine constants compared well with ab initio calculated values on radical anions formed from model phosphaalkenes.

Chemical and electrochemical reduction of sterically-protected diphosphenes [ArP=PAr] gave the stable radical anions [DmpPPDmp]'-, [DmtPPDmt]'- , and [DxpPPDxp]'- , where Dmp = 2,6-dimesitylphenyl-, Dmt = 2,6-dimesityl-p-tolyl-, and Dxp = 2,6-di(m-~ylyl)-phenyl-.~~~ EPR data indicate that the unpaired spins reside in P=P n* molecular orbitals. Chemical reduction of the three diphosphenes in THF using sodium metal, or sodium naphthalenide, yielded sodium salts Na[ArPPAr] showing additional EPR signals attributed to the presence of ion-paired species. No ion-pairing was detected by EPR spectroscopy for the corresponding magnesium, potassium or lithium salts of DmpP=PDmp. Potas- sium reduction of DmpP=PDmp in THF gave EPR-silent solutions, analysed by 31P NMR as containing DmpP(H)K : quenching with degassed water or trifluoroacetic acid gave DmpPH2. The radical anion formed by the sodium metal reduction of bis(2,6-dimesityl-4-methylphenyl)-phosphaarsene has been studied by X-band EPR.I3'

EPR spectroscopy has been used in an extensive study of electron addition to


trimethyl phosphine sulfide, Me3PS. 132 Exposure of dilute solutions, in d4- methanol - water glasses, to ionizing radiations at 77 K gave the parent radical anion Me3P'S-, shown as having a trigonal bipyramidal structure, characteristic of phosphoranyl radicals. The pure compound exhibited similar features, with resolved proton splitting. Doublet features assigned to the parent cation Me3P- S" were observed for solutions in CFC13, and also in the pure compound, the latter also giving features assigned to H2C'P(Me2)S andor H2C'P(Me2)SH+ radicals. On annealing to 140 K, doublet features with a considerably-reduced 3 i P hyperfine splitting, assigned to the phosphoryl radical Me2P'S, were revealed for the pure compound. Further EPR splitting features at 77 K (triplets), 140 K (septets) and higher temperatures, and possible mechanisms for the formation of the Me2P'S radicals have been discussed (Scheme 2), with preference for electron return to give electronically-excited (Me3PS)* molecules, which dissociate to give 'CH3 and Me2P'S radicals. Hindered rotation of the two CH3 groups in the Me2P'S radical accounts for the reversible change from 3 to 7 lines.

(Me3PS)' - Me* + Me2P'S

Scheme 2

Spin-trapping of phosphorus-containing radicals and their resultant spin- adducts have been studied by EPR spectroscopy. The reactions of dibenzoyl peroxide with P(OPh)3, P(OEt)3 and PPh2H were studied by an EPR technique combined with ~pin-trapping, '~~ the intermediate P-centred radicals, e.g. (PhO)3- P(OC(O)Ph), being trapped by N-benzylidene-t-butylamine N-oxide (PBN) and 5,5-dimethyl-l-pyrroline N-oxide (DMPO). The resultant spin adducts, e.g. PhCH (P(OPh),(OC(O)Ph)} NButO', with a characteristic hyperfine coupling constant, were observed. From the identification of the trapped radicals, possible mechanisms of the reactions were proposed. The hyperfine coupling constants due to P-H and P atoms exhibited a large temperature dependence for phosphor- any1 - PBN spin adducts, while the dependence was small for phosphinyl- PBN spin adducts. The conformational positions of the adducts of PBN and DMPO were considered in terms of the P and H constants.

A new spin-trap, 5-(diethoxyphosphorylmethyl)-5-methyl-4,5-dihydro-3H- pyrrole N-oxide (48), 134 and its hydroxyl- and superoxide-spin adducts, have been compared with the analogues obtained with 5-(diethoxyphosphoryl)-5- methyl-4,5-dihydro-3H-pyrrole N-oxide (49; DEPMPO) and with 5,5-dimethyl- 1 - pyrroline N-oxide (50; DMPO), and overall the spin trapping behaviour of 48 was found to be more similar to that of DMPO than DEPMPO.

0- 0- 48 49 DEPMPO 50 DMPO

Two interesting EPR studies of the spin adducts of dialkylphosphonyl- and


dialkyl-phosphoryl radicals with fullerenes have been undertaken. The first study examined the addition of photochemically-generated phosphonyl radicals [P(O)(OR)2]' (R = Me, Et, Pr') to C6o-f~llerenes,'~~ the products undergoing dimerisation. Addition of Pt(PPh3)4 to these dimers, (RO)2(O)PCm- C60P(0)(OR)2, gave the metallo-complexes (R0)2(0)PPtL,Cw- C60PtL2P(0)(OR)2, which dissociated in visible light to form C60PtL2P(O)(OR),. Multiple addition of [P(O)(OMe)2]' to ellipsoidal C7o-fullerenes gave allylic radicals containing 3 or 5 phosphonyl groups. In the other study,'36 the addition of dialkylphosphoryl radicals to [bis(p-methoxyphenyl)methano]fullerene, C ~ O C ( C ~ H ~ O M ~ - P ) ~ , produced a minimum of 7 isomers each differing in its hyperfine coupling constant.

EPR spectroscopy has been used to determine the bonding and structure in copper(I1) complexes with N-(thio)-phosphorylated thioamides 51 137 in a study of the role of hydrogen atoms and hydroxyl radicals in glycerol-1-phosphate degradation, 138 and in a thermo- and surface-chemistry study of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) bilayers in the (La + H20) phase.'39 EPR spectroscopy has also been used to characterise novel oligo(cation radicals) of methylene p h o s p h ~ r a n e s ' ~ ~ and di(cation radicals) of a 1,3-phenylene-bk(methylene phosphorane) (52). 14'

0 s It I I II

-P-c- fQTC 51

0 II

-P-

52

4 Vibrational and Rotational Spectroscopy

4.1 Vibrational Spectroscopy. - IR and Raman spectra of tetrafluorodiphosphine, P2F4, and the absence of the gauche conformer in the spectra at ambient temperature, have been investigated with the aid of theoretical ab initio calculations.2 FT-IR spectra of some C H ~ C H ~ P X Z molecules (X = F, C1, CH3) were recorded in xenon solutions as a function of temperature ( - 60 to - 100 "C), and, with the aid of ab initio calculations, conformational analysis carried O U ~ . ' ~ - ' ~ The use of IR spectroscopy (as a complementary technique) in the characterisation of organophosphorus compounds was abundant in the literature. Some applications of this have been cited earlier, particularly for the identification of PH groups in the syntheses of cyclic organo(sily1)-phosphines (39),7' and other characteristic groups in phosphiniminocyclotrithiazenes 40 for R = Et2N and B u ~ ~ N . ~ '

IR spectroscopy has been specifically used in the investigation of the nature of


the coordinate bond in di(2-ethylhexyl) methanediphosphonic acid and its Cu(II), Fe(III), Eu(III), Th(IV), and U(V1) metal complexes. 14* The spectra, compared with the Ca and Na salts, revealed that the vibrational P-0 stretching frequencies {Uasym (POO-), and Usym (POO-)} of the ligand are sensitive to the nature of the metal ion present in the compound. The dramatic variation in uaSym (POO-) with metal ion indicated a wide range in strength of the metal-diphosphonate interactions. The shift of both UaSym (POO-) and usym (POO-) to lower energies, relative to their values in the Na salt, indicated sym. coordination of the phosphonate groups through the chelate and/or bridging interactions. I t was also found that the difference, Au, between the POO- stretching frequencies [Uasym (POO-) -

uSym (POO-)] became smaller as the ionic potential of the metal ion increased. IR investigation of a new organic cyclohexaphosphate, bis[ 1 -(2-aminoethyl)-piperazinium]cyclohexaphosphate hexahydrate (53), has been supported by a detailed theoretical group analysis applied to P6OI8 with &h ideal local symmetry.143

FTIR and Raman spectra of polydialkoxyphosphazenes, [P(OCmH2m+1)2 = N],, for m = 1 - 9, have been studied between - 100 and + 100 "C, 144 and demonstrate that the temperature-dependent conformational changes which occur in amorphous and mesomorphic phases are due to internal rotation about the P-0, C-0, and C-C bonds in the side-chains. The main chain does not change its form and presumably has a helical structure. The photooxidation of poly-[bis(4-isopropylphenoxy)phosphazene] under accelerated conditions has been followed by FTIR (and UV-visible) spectroscopy. 145

The structures of both tert-butylaminotriphenylphosphonium iodide dichloride and the dibromide have been determined by Raman spectro~copy, '~~ the former [IC12]- species having a non-centrosymmetric- and the latter [IBrzl- with a centrosymmetric-structure. The Raman spectra of compounds R2NPX2 (for R = Me and Et; X = F, C1, and Br) have been studied'47 and calculations have explained the formation of the contours of the Raman lines in the 670-705 cm-I range, corresponding to the totally symmetric vibrations of the P-N bond in the molecule. Raman spectroscopy has also been used in the assignment of the photo-luminescence of a new mixed-ligand copper(1) polymer [ { (Ph3P)2Cuz(p- Cl)2(p-pyrazine)},], with the emission maximum at 16340 cm- ' assigned to Cu(1) to pyrazine charge-transfer. 148 IR spectroscopy has been utilised in the characterisation of Langmuir and Langmuir-Blodgett films of diphenylbis(octadecy1ami- no)phosphonium bromide. 149 An investigation of a series of 4-alkyl-2,6,7-trioxa- 1 -phospha-bicyclo[2.2.2]octanes (54) was carried out using online-FTIR spectra, together with mass spectra, following capillary-GC separation. ' 50

54 R = Me, Et, Pr, Bu, Pe, NO2; X = 0, S


4.2 Rotational Spectroscopy. - Millimetre-wave spectra, extending rotational spectroscopy into the 100-470 GHz frequency range, and ab initio calculations have confirmed structures of the short-lived PH2F and PH2CI m~lecules .~ The structural and conformational properties of 1,2-diphosphinoethane have been studied using microwave spectroscopyl'' in the 11.0-38.0 GHz region at -40°C. The gas phase structure was found to consist of a complex equilibrium mixture of several rotameric forms, with four conformers (two P-C-C-P anti and two P-C- C--P gauche, having different orientations of the phosphino group) being assigned.

5 Electronic Spectroscopy

5.1 Absorption Spectroscopy. - UV-visible spectroscopy was mainly used as a complementary technique in structure elucidation, particularly (with FTIR) for following the photooxidation under accelerated conditions of poly[bis(4-isopro- pylpheno~y)phosphazene],'~' and in the characterisation of Langmuir and Lang- muir-Blodgett films of diphenylbis(octadecy1amino)phosphonium bromide.149 Specifically, a UV-visible spectral study of several a-propylamino-phosphonic acid methyl esters (55) has been undertaken.152

Pr"' 55 X = H, OH, CI, NO2

5.2 Fluorescence and Chemiluminescence Spectroscopy. - The fluorescence excitation spectrum of PF3 at 9-1 3 eV, using monochromatised synchrotron radiation, has been examined to resolve the pyramidal geometry of the X2AI ground state of the PF3+ cation, which was also confirmed by ab initio calculations." Dimethylamino-substituted triphenylphosphines exhibit dual fluorescence in polar solvents, and fluorescence-decay measurements have shown that the photo-induced intramolecular charge-transfer process occurs in a few picoseconds, even in weakly-polar solvents.

A transient absorption band, with a profile similar to that of the dimethylani- line radical cation, was observed in polar solvents by time-resolved picosecond absorption spectroscopy.

Chemiluminescence has been used to assess phosphatidylcholine oxidation,154 and to measure the kinetics of decomposition of hydroperoxides formed during the oxidation of soya phosphatidylcholine. The direct chemiluminescence method correlated well with other methods of determining oxidation 'status' (chemical, UV, HPLC, and microcalorimetry), and it was concluded that chemiluminescence was an ideal method for estimating the oxidation of phosphatidylcholine (and phospholipids in general). Kinetics measurements revealed that


the reaction order changed from 2 to 1 as the decomposition proceeded and the hydroperoxides were consumed. Possible mechanisms of the decomposition were discussed.

5.3 Photoelectron Spectroscopy. - Photoelectron spectroscopy has been used successfully to characterise, for the first time, the gas phase structures of two very reactive silylidenephosphines, Me2Si = PBu' and Me& = PPh.' l 2 The first ionisation potentials at weaker energy are associated with ejection of an electron from the 7c Si = P bond. The ionisations of the phosphorus lone-pair were observed at higher energy.

6 X-Ray Structural Studies

6.1 X-Ray Diffraction (XRD) 6.1. 1 Two-coordinate Compounds. - X-Ray diffraction studies, together with quantum-chemical calculations, have been used to explain peculiarities in the molecular and electronic structures of halogen-substituted phosphaalkenes.6

The effect of steric crowding on the structure of phospholes has been examined using single-crystal X-ray diffraction analysis. XRD studies on both 1 -(2,4,6- triisopropylphenyl)-3-methyl-phosphole 45 (R = i-Pr)lo9 and 1 -(2,4,6-tri-tert-butylphenyl)-3-methylphosphole 45 (R = t-Bu)lS6 have revealed that the bulky P( 1)- substituents reduce the phosphole pyramidal character. In the 2,4,6-triisopropylphenyl-substituted phosphole, with respect to the C2-P-CS plane of the phosphole ring, the ips0 carbon of the benzene ring was deflected by only 58.0" compared with 66.9 O in the uncrowded 1-benzyl phosphole. The two rings are in orthogonal planes in the crystal, but this relation is not retained in solution, as shown by NMR studies. XRD analysis of the 2,4,6-tri-t-butylphenyl-substituted phosphole revealed that the phosphorus pyramid was drastically flattened, with the normal out-of-plane angle of 65 " reduced to 45.9 ". Consistent with strong electron delocalisation, the C3-C4 bond-length was dramatically shortened relative to that for other phospholes, and the Bird index of aromaticity was 56.5, almost equivalent of that found in pyrrole. The crystal structure of 3,5-di(adamant-1 -yl)- 1,2,4-thiadiphosphoIe (56) has also been determined by XRD.'57

56 Ad = 1-adamantyl

XRD analysis of 1 , 1 , 1,3,3,3-hexafluoro-2-propanyloxy-(2,4,6-tri~t-butylphenyl- imino)phosphine (57)lS8 revealed a P=N bond-length of 1.526 A, the shortest ever observed in trans (E)-iminophosphines. X-Ray structural analysis of the diphosphene DmpP=PDmp,where Dmp = 2,6-dimesitylphenyl-, also rtvealed a trans configuration (about P=P) and a short P=P bond-length of 1.985 A.lS9 The


X-ray crystal structure of the novel organoantimony cage compound C4Bu14P4Sb2 (58) displayed weak intermolecular interactions. 160

But

57 58

6.1.2 Three-coordinate Compounds. - XRD analysis of (E)-diphenyl( 1 -phenyl-2- bromoviny1)-phosphine (59) revealed the molecule to be pyramidal, but with the C-P bond-lengths unsymmetrical due to differences in the CPC bond-angles. 1 6 '

The C-P bond-lengths were significantly longer than those in Ph3P approaching values characteristic of trialkyl derivatives. Enantiomers of the first helical, chiral phosphines, rac-[5]- and rac-[6]-heliphos (60), have been separated and the crystal

@ PPh2 PPh2

( €) P h2PC( P h)=CBrH \ /

59 60

61 62

Bu:

64

Me& Me

CMe3 65


structure of [5]-heliphos obtained by XRD. 162 The structures of the 'pyroelectric' 4,8,12-trioxa- 12c-phospha-4,8,12,12c-tetrahydrodibenzo[cd,mn]pyrene (61), I 63 of oligo(thioary1ene)cyclophosphonites 62,164 of the Diels-Alder cyclo-adducts 63, 64, 165 and of a rotational isomer of a 1,2-dipheny1-3,4-diphosphinidenecyclobutene (65)'66 have been determined by X-ray crystallographic analysis.

The 5,6-benzo- l-methyl-3-R-l,3,2-diazaphosphorin-4-one 66 has been characterised by XRD. The crystal structure displayed a half-boat conformation for the phosphorinone ring, with the phosphorus atom lying out of the plane. XRD analysis of the reaction products 67 and 68 obtained respectively from the reaction of 1,5-dimet hyl-2,3,3,4-tetrachloro- 1,5,2,4-diazadiphosphorinan-6-0ne and 2,3-dihydroxynaphthalene with catechol, revealed that the nine-membered rings adopt essentially-identical tub-conformations in which the P and 0 atoms are coplanar, and the P-C-P angles across the CCl2 bridge are wide (- 119 O).I6* The structures of benzodiphosphadihydropentalene 69169 and the phosphacycles 70-73I7O have also been determined by X-ray crystallography.

66 R' = 2-morpholinoethyl; R2 = CH2CH2CI 67 68

CMe3 69

Ph Mes 1

Ph v

Ph

HPh

P A Ph Ph 70 71 R' = CsH2But3-2,4,6

Ph- -PI /p\ ,P- -Ph Mes*P/p\ B u t 2 ! 3 n ~ P - -Ph P A Ph

Ph HPh 72 73

6.2.3 Four-coordinate Compounds.-- The structures of phosphazenes have been determined by XRD techniques. The uncharged, strong phosphazene bases (Me2N)3P=NMe (74)j7' and (Me2N)3P=NP(Me2N)2 = NH (75),'72 their


hydrates, and also an acetate of 74 have been studied in detail. The structure of the anhydrous base 75 shows no distinct intermolecular interactions but in each of the monohydrates of phosphazenes 74 and 75 a centrosymmetric dimer of the formula units is formed by hydrogen-bonding ( O H . . . N ) arranged in a centrosymmetric 4-membered ring. In the other hydrates (74, 1.75 H 2 0 ) and (75, 2.25 H20), unlimited chains are formed by hydrogen-bonding (OH. . -N and OH.. .O) and between (respectively) 2 rings and 5 rings, each ring linked with alternating H20 molecules. In spite of the high basicities of the phosphazenes, all the hydrate structures are molecular adducts and are not ionic. However, the monoacetate of 74 is clearly ionic with an ion-pair being formed by a bifurcated 3-centre hydrogen-bond NH(".O), from the protonated N atom of the base cation to both 0 atoms of one and the same acid anion. XRD analysis of two new spirocyclotriphosphazenes 76 and 77 revealed that both have a planar cyclotriphosphazene ring with less overall molecular rigidity compared with the tri- spirocyclic analogue 78. 173 Studies on the copper(I1) nitrate-, platinum(I1)

(Me2N)3P=NMe (Me2N)3P=NP(Me2N)3=NH

74 75

76 77 78

79 80

8: Physical Methocis 32 1

chloride-, and cobalt(I1) nitrate-complexes of pentaphenoxy(2-pyridylmethyl amino)cyclotriphosphazene (79) revealed the differing coordination behaviour of the multifunctional ligands. '74 Some fluorinated cyclothiaphosphazenes have also been examined by XRD';' and the PN and SN bond-lengths in 80 found to vary between 1.571 to 1.590 A. XRD has also been useful in the characterisation of poly-phosphazene homopolymers and copolymers. 176 The first single crystal X- ray structure of the phosphazinium bromide [(C6H5)3P=N(H)N=C(CH3) ('-Bu)]+ Br- (18) revealed the presence of nearly unaffected N-N bond distance and hydrogen-bonding with the bromide ion." Of related compounds, the crystal structure of the new chiral, C3-symmetric, macrobicyclic cage tris(phosphazide) 81 has been determined.'77

The crystal structure of 5-ethoxycarbonyl-5-(triphenylphosphoranylidene- amin0)-5,6-dihydroimidazo[2,1 -a]isoquinoline (82) has been determined by X-ray analysis. 17' In the X-ray structural characterisation of the phosphiniminocyclo- trithiazene 40 (R = Et2N),90 the angle at P-N(4)-S(l) was found to be 135 O. This is the largest observed so far !nd was accompanied by the shortest exocyclic S( 1)- N(4) bond-length of 1.537 A. When R = Bu2N, the corresponding bond-angle was 119.3" and in the unit cell two types of molecules were observed yith a slightly differing degree of deviation of the tricoordinate S atom at 0.664 A and 0.673 A from the mean plane N( l)-S(2)-N(2)-S(3)-N(3). The X-ray structure of Et4P2N4S2C12 (83) revealed an eight-membered ring in a distorted boatoconforma- tion with significantly different S-Cl bond-lengths of 2.238 and 2.421 A. Whereas in the cpmplex (W), the [R4P2N4S2I2+ cation is planar with a S-N bond-length of 1.51 A, consistent with a locdlised tt-bonded s t r ~ c t u r e . ' ~ ~ Cyclic- [K{ N(H)C(Ph)C(H)PPh2=NSiMe3>(tmen)],, 85, (tmen = Me2NCH2CH2NMe2), has been characterised as a dinucledr complex with each of the two K atoms in a different coordination environment. A new diazadihydrophosphinine (86)'" and ethynyl-15-[ 1,3]diphosphinine (44) lo3 have also been characterised using XRD.

, cHex

P h 2 P T p h I

I L

Me3SiNlK;N

Me0 85 L = Me2N(CH2)2NMe2 86


X-ray structural analysis of phosphorylated diisothiourea 87 revealed that the coordination around the P atom is a distorted tetrahedron and the molecule has moieties slightly out of plane around O=P-N-C=N, with stronger intermolecular hydrogen-bonds.I8* The X-ray crystal structure of N,N'-diethylaminomethylene- phosphonic acid (88) showed the molecule to be present as the N-protonated zwitterion. The unusually-large P-C-N bond-angle of 120.1 O is due to steric factors arising from the eclipsed conformation of the Et methylene C atoms of the ethyl group and phosphonate 0 atoms.ls3 The X-ray crystal structure of diethyl 1 -(p-toluenesulfoiiamido)-p-chlorophenylmethylphosphona te has confirmed the non-equivalence of the two ethoxy groups.88 The stereoisomers of novel cyclic phosphate-phosphonates (89) have been isolated and a cis configuration and chair-preferred conformation of one isomer confirmed by XRD.184 A new organic cyclohexaphosphate, bis[ 1 -(2-aminoethyl)-piperazinium] cyclohexaphosphate hexahydrate (53), has been characterised by XRD'43 as having infinite layers of inorganic polyanions approximately parallel to the (001) planes, with organic cations sandwiched between these layers. OW--HO-0 and N-H-0 hydrogen-bonds linked P6018 groups, respectively, in a layer and in successive layers as to build a framework in a three-dimensional way.

M:F2p\0 S II YNo2 P(O)(OEt)z

[( Pri0)2P(0)N HC(: NH)SI2CH2CH2 Et2NCH2P(O) (OH)2

89 Me 87 88

The X-ray crystal structures of semirigid macrocyclic phosphonamides and complexes 41-43,Io2 of 2-N,N-diisopropylamino- 1 ,3,2-h5-oxaselenaphospholane 2-selenone ( 16),49 and of 1 -(o-methylphenyl)-2-(p-methoxyphenyl)- 1,3,2-diazaphospholidine-4-thione 2-sulfide (90)185 have also been determined. The X-ray structural characterisation of (1) DmpP(O)(OH)H, revealed the existence of dimeric phosphinic acids associated by hydrogen-bonding in a manne: analogous to carboxylic acid dimers.159 The P-0 distances are 1.508 and 1 S21 A, and O-H and O-H...O distances are 1.064 and 1.464 A, consistent with localised hydrogen-bonding. The configurational stability of lithiated diphenylphosphine oxides has been investigated186 using the Hoffmann test and by determining the relative stereochemistry of the products using the crystal structures of (2S* ,3S*,4R *)-2-(N,N-dibenzylamino)-4-diphenylphosphinoyl- 1 -phenylpentan- 3-01, and (2S*,4S*)-2-(N,N-dibenzylamino)-4-diphenylphosphinoyl-l-phenylpentan-3-one (92, 93). The crystal structures of some tertiary phosphine betaine adducts, 187 of some new I h5,4h5-diphosphaazulenes (94), 18' and of phospholan diol sugar derivatives 95189 have been determined by X-ray analysis. The structure of hexa(diethoxyphosphoryloxy)-calix[6]arene (96) has been confirmed by X-ray analysis.190 The molecule exists in a centrosymmetric flattened 1,2,3- alternate conformation, in which diametrically-opposed benzene rings are par-

8: Ph ysicul Methods 323

allel. Four phosphoryl groups are oriented away from the ring, while two other groups are self-included in the macrocycle cavity. The XRD analysis of 2- phosphoryl-, 2-t hiop hosphoryl- and 2-selenophosphoryl-su bsti tu ted 1,3 -di thio- lanes (97) has revealed, in all three compounds, that the 1,3-dithiolane ring adopts a twist conformation with the Ph2PX group being pseudo-axial."' The structural data confirms an anomeric effect operating in these compounds.

S

90 91 92 Mes = 2,4,6-tnmethylphenyl

93

M0-N NMe2

Me02C \ / /Co2R'

MeN-P

NMe2 I 1 OP(O)(OEt); Meo2c% C02Me Me

94 R =Me, R 1 = Et 95 R=Et, R 1 = M e

96 s x

97 X=O,S, Se

The structures of a naphthalene-dithiaphosphetane 2,4-disulfide 98, 192 and of six- and eight-membered oxaphospha-heterocycles 99, have been characterised by XRD. P-Chiral phosphinic chlorides, with S configuration at the P atom (101), have been examined by X-ray ~rys ta l lography. '~~ An X-ray crystallographic study of the reagent Ph3PC12 has revealed it to be an unusual dinuclear ionic species, [Ph3PCl+-Cl--+ClPPh3]-CI, 102, containing long CI-Cl contacts. 195

The structure of tert-butylaminotriphenyl-phosphonium iodide dichloride has been shown to be non-centrosymmetric by XRD analysis and Raman spectroscopy. 146 The new photoluminescent, mixed-ligand copper(1) polymer, [ { (Ph3P)2Cu2(p-C1)2(pL'pyrazine)],], has been examined by XRD. 14* The polymer consists of (PPh3)(pyz)Cu(pC12)Cu(pyz)(PPh3) units in which pyrazine ligands bridge Cu pairs to form a chain of dimers.

6.1.4 Five- and Six-coordinate Compounds. - The first characterisation of a 1O-P- 5 spiro-phosphorane bearing an apical C-equatorial 0 ring (46), and its thermodynamically more-stable apical O-equatorial C ring pseudorotamer 47, has been achieved by X-ray crystallography. Similarly, intra- and intermolecular hydrogen-bonding isomers of P-H (apical) phosphoranes 103 have been ~harac te r i sed . '~~ Cyclic amino phosphoranes with six- and eight- membered rings (104, 105) have been compared with cyclic aminophosphites and their conformations compared by X-ray crystallography. 197 Bi- and tri-cyclic


OMe I

9a 99

[Ph3PCI+-CI--+CIPPh3]Cl

101 102

penta and hexa-coordinated phosphoranes with varying ring sizes as in 25-28,63 and sulfon yl-su bs ti tu ted ox yphosphoranes 20-24, containing eigh t-membered rings of varying ring conforrnationl6 have been similarly characterised.

Six-coordinate phosphoranes containing the ligands C6H3(CH2NMe2)2-2,6 (30) and its mono-protonated form 31 have been compared by XRD studies.64 In both cases the compounds exhibited slightly-distorted octahedral geometry. In 30, only one NMe2 group is coordinated to the P atom with an N-P bond-length of 2.063 A. However, in 31, the NMe2 group is coordinated to the P atom with an N-P bond-length of 2.007 A, while the dimethyl ammonium substituent is pointing away from the P atom and forming a hydrogen-bridge with two 0 atoms. X-Ray studies of a series of N- and C1-bonded bicyclic tetraoxyphosphoranes (32-36) revealed hexacoordination due to donor action by S, which is present as part of an eight-membered ring system.65 The series of compounds had geometries that were displaced along a coordinate from a square pyramid to an


octahedron, ranging from 24 to 7!%, and the respective P-S distance decreased along this series from 3.04 to 2.48 A as the octahedral character increased.

6.2 X-Ray Absorption Near Edge Spectroscopy (XANES). - X-ray absorption spectra of atoms display sharp discontinuities (‘absorption edges’) at wavelengths immediately beyond the absorption maxima, characteristic of the element. This arises since, at the absorption maximum, the energy of the X-ray photon exactly matches the energy required to just eject the highest-energy K electron of the element, but, immediately beyond this wavelength, the energy of the radiation is insufficient to bring about removal of a K electron and an abrupt decrease in absorption occurs. Examination of the ‘near edge’ energy region (up to 40 eV above the edge, before EXAFS oscillations begin) is ideal for XANES, and can provide information about vacant orbitals, electronic configuration and site symmetry of the absorbing atom. In fact, XANES provides complementary information to EXAFS (Extended X-ray Absorption Fine Structure), which provides information about the surrounding atoms.

The usefulness of XANES measurements, a relatively-new X-ray structural technique for analysing the local environment of an absorbing atom, has been demonstrated at the phosphorus K edge for some triorganophosphine selenides, R3P=Se.I9* Using XANES as a fingerprint method, information about the influence of the 1st and higher coordination shells on the XANES spectra were obtained, including the effect of the electronegativity of the P-bound substituents. Also, an aromatic substituent in the 1st shell strongly influenced the shape of the XANES resonances as compared with an aliphatic substituent, evidenced by a splitting of the white line. This was probably due to the formation of a delocalised n-electron system, which shortens the P-C,,, bond-length because of its possible mesomeric effect.

7 Electrochemical Methods

7.1 Dipole Moments. - Dipole moments and molar Kerr constants of complexes of phenols with phosphoryl compounds were studied to establish the structure of the complexes and obtain the parameters { pH, A(mK)s, 1nK and 60) characterising the proton acceptor ability of these corn pound^.'^^ The new parameter A(mK)s, structural additive difference of the molar Kerr constant, made it possible to determine changes of polarity and polarisability of the systems during complex formation. The molecular pyroelectric, 4,8,12-trioxa- 12c- phospha-4,8,12,12c-tetrahydrodibenzo[cd,mn]pyrene (61), was found to have a dipole moment of 3.3 k 0.2 D, the direction of which was unambiguously assigned with respect to the molecular coordinates. 163

The conformations of ortho-substituted phospha-h5azenes, Ph3P=NC6H4X, 106, have been determined in solution by dipole moment and IR spectroscopic techniques.2m Derivatives with alkyl substituents have bisecting conformations, where the angle of rotation of the aromatic group with respect to the N-Csp’


bond is between +30 O, whereas in the alkoxy-substituted derivatives the angle of rotation is 90 '.

PhzP=NCejH4X (ortho)

106 X = H, Me, Et, OMe, OEt

7.2 Cyclic Voltammetry and Polarography Cyclic voltammetry analysis of the mechanism of electrochemical reduction of nickel(I1) complexes with some ligands, of the Ir-acceptor type, has been successfully undertaken.20'

In the reduction with 2,2'-bipyridyl, redox reactions are absent and the limiting stage is the transfer of the 2nd electron, [AE, being - 60 to - 70 mV. Reduction of the nickel(I1) complex with PPh3, ("Pr0)3P, PhP(OBu)z, or (Ph0)3P is limited by the transfer of the 1st electron and is accompanied by comproportionation (PPh3, AE,= 90 mV) and disproportionation reactions (phosphites, AE,< 0). The redox properties of some transition metal-cinnamonitrile cyclo-phosphazene derivatives, e.g. , 107-109 have been stuclied by cyclic voltammetry (CV) and controlled potential electrolysis (CPE) in arrotic media.202

[Pt(q2-( €)-PhHC=CHCN)(PPh&] ~ ~ ~ ~ s - [ P ~ ( C F ~ ) ( ( € ) - P ~ H C = C H C N ) ( P P ~ ~ ) ~ ] [ B F ~ ]

107 1 08

tfans-[(Ph3P)gPt(~3,~-( €)-PhHC=CHCN)Pt(CF3)(PPh3)2][BFJ

109

In the equilibrium reaction of trimethyl phosphite with benzylideneacetophenones to produce 1,2-oxaphospholes 110 the second-order rate constants for the formation of 110 have been determined using a polarography method, and the rate constants for the decomposition reaction were calculated from the equilibrium constants. *03

7.3 Potentiometric Methods. - - Potassium trithiocarbonate has been used as a reductant (-S-S- reduction cleavage) for the potentiometric (and spectrophoto- metric) determination of the disulfides of dithio-phosphinic acids in DMF-H20 medium at millimolar levels.204 The protonation equilibria for N,N'-diethylami- nomethylenephosphonic acid (88)' 83 were elucidated from both potentiometric titration and determination of the pH dependence of the NMR chemical shift (831 p), and protonation constants for aminoalkanephosphonates RCH(NH2)P(0)(OEt)2205 and the acidity constant of di(2-ethylhexy1)thiophosphoric acid (1 1 1)206 have also been obtained potentiometrically.


8 Thermochemistry and Thermal Methods

Theoretical calculations for thermochemical parameters of 22 primary alkyl phosphines, RPH2, have been carried These included heats of formation, in liquid and gaseous phases, and heats of evaporation, for R = H to Clo alkyl, cyclopentyl and cyclohexyl, and R = H2P to H2P(CH2)4 phosphines. Calorimetric (and dielectric) investigations of the phase transformations and glass-liquid transition on heating supercooled liquid triphenyl phosphite, (Ph0)3P, have been studied by differential scanning calorimetry (DSC) and fixed-frequency dielectro- metry.208 The first measurements of the enthalpies of combustion, sublimation and fusion of an organophosphorus sulfide, Ph3P=S, have been reported, and used to derive the enthalpies of formation of solid, liquid, and gaseous Ph3P=S as ArHO,,, = (63.20 k 2.56), (82.48 k 2.57), and (206.0 k 7.3) kJ mol-' re~pectively.~'~ From this data, the P=S double bond enthalpy is 394 kJ mol-I, in good agreement with earlier reaction calorimetry results. The enthalpies of hydrogen- bonding (AHhb) and tautomeric transformation (AH,,) of cyclic phosphorus acids, e.g. 112, of different space groups have been determined.210

Me<o\P(0)H Me o/

112

Acyclic and six-membered cyclic phosphorous acids, except salicylic derivatives, exist in a form containing the P(0)H fragment and have AH,, values in the gaseous phase of - 70 kJ mol- ', and values for 1,3,2-dioxophospholanic analogues are -40 kJ mol-'. Calorimetric studies, in a heat-flow reaction calorimeter on the reaction of dithiophosphoric acid 0,O-dialkyl esters, (RO)*P(S)SH, with zinc oxide, have been used to determine the reaction kinetics.2' I

The crystal structure of a new organic cyclohexaphosphate hexahydrate (53) has been earlier confirmed by XRD and IR spectro~copy, '~~ but it has also been found that two H 2 0 molecules are lost at room temperature to give a stable tetrahydrate phase. This structural reorganisation has been discussed on the basis of hydrogen-bonds to the oxygen atoms of water by thermogrdvimetric- and differential thermal-analysis (TG-DTA), and differential scanning calorimetry (DSC). The thermal decomposition behaviour of phosphiniminocyclotrithiazenes, R3P=NS3N3, 113, has been studied for the first time using TG, DT and DSC methods.*12

RsP=NS3N3

113 R = Ph, C5HION. OC4H8N-, MeNC4H8N-


DSC and TGA methods have also been employed in the characterisation of polyphosphazene homopolymers and copolymer^'^^ and, together with DMTA, in the characterisation of new phosphorus (and other heteroatom)-containing aryl cyanate ester monomers and networks.82

9 Mass Spectroscopy IS pec trome try

There are numerous publications using mass spectroscopy as a complementary analytical technique for structure elucidation. On account of the diverse range of ionisation techniques now available, the compounds examined are covered in order of increasing coordination number of phosphorus. Tris(2-~yanoethyl)phosphine, P(CH2CH2CN)3, has been studied by Laser-

Ablation Fourier Transform Ion-Cyclotron Resonance (LA-FTICR) and Elec- troSpray-Ionisation mass spectrometry (ESI-MS), particularly with regard to its interaction with some alkali metal (AM)- and transition metal (TM)-monocat- ions.213 These two different ionisation and mass spectrometry techniques are complementary for this phosphine, and [M+H]+ or [M+AM]+ ions were observed using both techniques. Corresponding species, [M+TM]+, were observed for Cu, Ag, Co and Ni using LA-FTICR. In the negative-ion LA spectra, the phosphine provides a source of CN- ions, forming metal-cyanide cluster anions, [MX(CN),+~]-, predominant for Cu and less so for Ag, Co, and Ni. Loss of acrylonitrile from the metal complexes is also one of the main decomposition pathways which can be observed in both positive- and negative-ion modes, giving [M(CH2CH2CN),]' (x = 1 or 2) and [M(CN){P(CH2CH2CN)2}]- ions respectively. The laser-plasma mass spectrum of PPh3 (and AsPh3) and time-of-flight (TOF) mass spectrum of collision-induced dissociation of clusters P-Ph (and As- Ph) cations with nitrogen have been recorded on a tandem TOF mass spectrometer by direct laser ablation of PPh3 and AsPh3,*I4 with the PPh4+ and AsPhz+ peaks at maximum abundance. Laser photoionisation mass spectrometry has provided the first detection of the isolated dioxophosphoranes (metaphosphates), CH3P02 and CH30P02, which are key intermediates in the combustion of dimethyl methylphosphonate.2'5 A newly-developed flame-sampling laser ionisation mass spectrometer has provided concentration profiles of CH3P02 and CH30P02 throughout the flame zone of a premixed, low-pressure H2/02/Ar flame, seeded with dimethyl methylphosphonate. The gas-phase ion-molecule reactions of the phosphonium ion, OP(OCH&+, formed by electron impact with neutral trimethyl phosphite have been studied in a quadrupole ion trap mass spectrometer.216 Reactions observed include competing methoxy transfers between OP(OCH3)2+ and the neutral species to yield a phosphenium ion, :P(OCH3)2+, or the tetracoordinate P(OCH3)4+ ion. Background water in the quadrupole ion trap gives an adduct with OP(OCH3)2+ which protonates neutral trimethyl phosphite, as shown by triple mass spectrometric experiments. Che- mical ionisation reactions, supported by ab initio calculations, were performed to investigate the unimolecular loss of methanol from protonated trimethyl phosphite.


The mass spectrometric behaviour of eight o-hydroxyalkyltriphenylphospho- nium bromides has been studied with the aid of mass-analyser kinetic energy (MIKE) spectrometry and fast-atom bombardment (FAB) ionisation mass ~pec t romet ry .~ '~ The fragmentation mechanism for ions at m/z 275, 289, 303 . . . has been established and all the compounds show [2M+Br]+ ions from association by hydrogen-bonding. Tributyl phosphate and bis(2-ethylhexyl) phosphate (on silicon carbide and kaolin) airborne microparticles have been detected using an apparatus for real-time mass spectrometridmass spectrometric (MS/MS) analysis by laser ablation in an ion trap.218 'Semi-volatile' organics, including dimethyl methylphosphonate and malathion, have been directly detected 'online' in air at ppt levels, using membrane introduction ion trap mass ~pec t romet ry .~ '~ Charge exchange ionisation was used for a variety of semi-volatile compounds and produced enhanced responses compared with electron ionisation. Electro- spray ionisation mass spectrometry (ESI-MS) has been utilised for the detection and identification of a series of organophosphorus compounds used as potential chemical warfare agents.220 In the positive-ion mode, prominent [M+H]+ ions were obtained for all of the compounds examined, and in the negative-ion mode [M-HI- ions were obtained for all of the compounds except the trialkyl phosphates, suggesting that a P-OH moiety is a prerequisite for negative-ion formation. The principal fragmentation pathways were established by tandem mass spectrometry (ESI-MS/MS). Energy Resolved mass spectrometry (ERMS), a powerful technique in the differentiation of structurally-similar compounds, has been used in a similar area in the analysis of series of organophosphonates221 and organophosphates.222 ERMS provides an additional level of specificity to that from conventional fixed-energy MS/MS, with not only m/z and intensity of the product ions given, but also the energy at which the product ions are formed, all of this data being supplied without any loss in sensitivity.

The mass spectra of cyclic phosphonate esters (114)223 and new 3-methyl- 2(3H)-benzoxazolone hydrazone phosphorylated compounds 1 15224 and substituted phosphoryl compounds225 have aided their structure elucidation. Matrix- Assisted Laser Desorption Ionisation (MALDI) mass spectrometry is a relatively-new technique used for analysis of large and/or non-labile molecules. A comparative study of MALDI and FAB mass spectrometry of the nucleoside triphosphates dATP, dTTP, dCTP, and dGTP226 has shown that MALDI gave clear molecular ions with minimal fragmentation, whereas FAB gave more fragment ions and weaker parent peaks. The electron impact mass spectra of 4- substituted dinaphtho[ 1,3,2]dioxaphosphepin 4-oxides/sulfides 1 16227 and 8-substituted-dinaphth0[2,1 -d: 1',2',g][ 1,3,6,2]dioxahiaphosphocin 8-oxides 1 17228 have been studied and their fragmentation processes established. The di- naphthothiophene cation at m/z 284 is a predominant daughter ion in 116 4- sulfides, and in oxide 117 the loss of aryloxy radical from the molecular ion is characteristic, both features being supported by high-resolution mass spectral data.

A series of substituted bis(phen0xy)phosphazene polymers has been characterised using static secondary ion mass spectrometry (SIMS),229 and the electron impact mass spectra of the pentacoordinate phenanthrospiroazatrioxaphospha-


nones 1 18230 exhibited characteristic fragmentation patterns used for structural assignment.

115 X = 0, S; R = Me, Et 116 X = 0, R' = ArO 114 X = S, R' = NR22, SR2

117 118 R = H, Me, Pr', Bu', PhCH2

10 Chromatography and Related Techniques

10.1 Gas Chromatography and Gas Chromatography-Mass Spectroscopy (GC- MS). -- The elemental compositions of a mixture of alkyl and aryl phosphates have been determined using gas chromatography separation and atomic emission spectrometric detection, with signals for C, H, C1, P, and 0 used to specify and assign a particular structure against reference corn pound^.^^' The organophosphorus pesticides (OPs) dimethoate and fenitrothion have been determined in estuarine samples by, first, C- 18 solid-phase extraction and, then, quantification by high-resolution capillary gas chromatography with nitrogen-phosphorus detection.232 Comparison of the GC-MS spectra showed that ions at m/z 87, 93, and 229 for dimethoate, and at m/z 109,260, and 277 for fenitrothion are suitable for selective ion monitoring for quantification. A new GC-MS method for mass spectrometric trace analysis using ion-trap detectors, based on water-chemical ionisation (CI), has been used very successfully for the environmental determination of a wide range of organic substances, including O P S . ~ ~ ~ The use of water-CI MS results in significantly-lower response differences compared with electron ionisation (EI). The photooxidation products of poly[bis(4-isopropyl-phenoxy)- phosphazene] have been identified as acetone, acetophenone and phenol using GC-MS and other techniques. 145 An homologous series of 4-alkyl-2,6,7-trioxa-1- phospha-bicyclo[2.2.2]octanes (54) has been separated by capillary GC and the resultant compounds investigated by coupled MS and FTIR.'" Ion-trap EI and CI mass spectra and retention parameters of symmetrical diesters of alkylpho-

8: Physicul Metlzods 33 1

sphonic recorded using a capillary GC-MS system.

and symmetrical 0,O-dialkyl methylpho~phonates~~~ have been

10.2 Liquid Chromatography

10.2.1 High-performance Liquid Chromatography and LC-MS. - One of the rotational isomers of a 1,2-diphenyl-3,4-diphosphinidenecyclobutene, i. e. the ligand of 65, has been analysed by a chiral LC column, whereas the other was confirmed by XRD. 166 Phosphatidylcholine oxidation has been measured by a variety of new techniques, including HPLC. 154-155 Reversed-phase HPLC has been used to study the chromatographic characteristics of some calix[n]arenes (n = 4, 6, 8) functionalised at the lower rim of the macrocycle by phosphoryl

The influence of the size and conformation of the macrocycle skeleton and the nature of substituents, at the lower and upper rims, on chromatographic behaviour has been determined. The retention-times of calix[n]arenes are determined mainly by the presence of hydrophobic tert-butyl groups at the upper rim of the macrocyclic ring.

Fourteen 0-ethyl 0-phenyl N-isopropyl phosphoroamidothioate enantiomers, containing 'P as a chiral centre, have been separated by HPLC on a chiral stationary phase,237 and eleven zinc dialkyl dithiophosphates Zn[(RO)*PS&, normally present in lubricating oil additives, have been separated by normal- phase HPLC.238 Thermospray LC-MS has been used to detect aqueous samples of alkylphosphonic and trace ppb levels of organic phosphonates (in water) have been determined using liquid chromatography/particle beam mass spectrometry.240 In this case, the aqueous samples were evaporated, methylated with diazomethane, and the totally-methylated phosphonates subjected to LC/ MS using the particle-beam interface. The derivatives were clearly identified by both their EI and CI mass spectra. The R- and S-enantiomers of a-phosphonosulfonic acids have been completely resolved by HPLC using a chiral AGP column,24' the separation also being achieved by capillary electrophoresis using a chiral selector. Organic phosphates have been determined at trace levels by column-switching high-performance anion-exchange chromatography using online pre-concentration on Ti02,242 and the method was successfully applied to the analysis of the phosphorylation products of a heptapeptide. HPLC has been used also for the determination of the kinetics (and mechanism) of the facile, selective dephosphorylation of 2-phosphorylated and 2'-thiophosphorylated dinucleotides to give UpU.243

20.2.2 Thin-layer Chromatography. - Fourteen newly-synthesised organophosphorus compounds have been separated by TLC, and a study made of their Rf values and structures for the aryloxyphenylthiophosphonyl hydrazides.2a When electron-donor solvents were used as mobile-phase, there were carbonyl displacement effects and the order of Rf values was reversed. In another study (by HPTLC), a correlation between the molecular structures of sixteen 0-ethyl, N-isopropyl phosphoro(thioureido)thioates and their observed Rf values has been checked against a computer-assisted Rf prediction system for these


compounds.245 Good agreement was obtained between experimental results and the predicted data, which is based on physico-chemical parameters.

10.3 Capillary Electrophoresis (CE) and Micellar Electrokinetic Chromatography (MEKC). - Di(2-ethylhexyl) thiophosphoric acid (DEHTPA) has been earlier characterised by potentiometric titration, and quantified by capillary zone electrophoresis with carbonate buffer, operating at -20 kV, and using UV detection at 210 nm.206 Also, a comparison has been made of capillary electrophoresis (CE) and liquid chromatography (LC) for the enantiomeric separation of a-phosphonosulfonic acids, where CE used P-cyclodextrin as chiral selector in a borate. electrolyte.241 Alkylphosphonic acids, at trace levels in water, have been determined by CE coupled online with flame photomeric detection,246 and alkylphosphonic acid esters have been separated and determined by CE using indirect UV detection.247

Polycyclic aromatic hydrocarbons (PAHs) have been separated by MEKC using a double alkyl chain di(2-ethylhexyl) phosphate as anionic micellar pseudostationary phase.248 Phospholipids have been separated from soya le- cithins by MEKC, deoxycholic acid being used for micelle formation.249 Separa- tion was tested according to solvent polarity and column temperature, with a high n-propanol concentration and a column temperature of 15 "C being ideal. Online MEKC/MS with electrospray ionisation, and atmospheric-pressure CI, interfaces have been used in the separation and detection of standard compounds, including tetraphenylphosphonium chloride.250

11 Kinetics

Many references to kinetic measurements may have already been covered earlier with other physical methods. These include studies on pseudorotation of stereoisomers of a 10-P-5 spiroph~sphorane, '~~ on the formation rate of acylpho- sphonate hemike ta l~ , '~~ on the rate of decomposition of hydroperoxides formed by the oxidation of soya pho~phatidylcholine,'~~ on the kinetics of the reaction of trimethyl phosphite with benzylidene ace top hen one^,^^^ calorimetric studies on the reaction kinetics of dithiophosphoric acid 0,O'-dialkyl esters with zinc oxide,2' ' and the kinetics of selective dephosphorylation of 2'-phosphorylated and 2'-thiophosphorylated d in~c leo t ides .~~~

The kinetics of the Diels-Alder reaction of tetracyclone with phosphaalkyne Me3CCP have been examined in toluene at llO"C, and the rate constants ca l c~ la t ed .~~ ' The HH*/DD* kinetic isotope effects for hydrogen exchange between methanol and diphenylphosphine in the liquid state, and for hydrogen exchange between methanol and dimethylphosphine in the vapour state, have been established for forward and backward exchange.252 Using dynamic NMR spectroscopy, the kinetic H/D/T isotope effects and solid state effects on the tautomerism of the conjugate porphyrin monoanion Por-H- have also been examined.253 The gas-phase thermolysis of diallyl(4-fluorophenyl) and allyl(t- buty1amino)phenyl phosphines has been studied in and the kinetics of


the oxidation of phosphinic, phenylphosphinic and phosphorous acids by bis(2,2’-bipyridyl)copper( 11) permanganate have been

The mechanism for the fragmentation of a phenyl phosphonamidic acid which involves initial formation of phenyl dioxophosphorane, PhP02, has been supported by the observation of first-order kinetics.256

The kinetics of the carbamoylation reaction of alkyl isothiocyanates with diphenylphosphinic hydrazide, Ph2P(O)NHNH2, in benzene,257 and of the same reaction in the presence of saturated nitrogen heterocycles (as catalysts),258 have been studied in detail.

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8: Physicul Methods 34 I

22 1

222

223

224 225

226

227 228

229

230 23 1 232

233

234

235

236

237

238

239 240

24 1 242 243 244

245

246

247

248 249

M. W. Wensing, A. P. Snyder, and C. S. Harden, Proc. ERDEC Sci. Con- Chem. Biol. Def. Res. 1995, Publ. 1996, 735. M. W. Wensing, A. P. Snyder, and C. S. Harden, Proc. ERDEC Sci. Con$ Chem. Biol. Def. Res. I995, 1996, 727. Z. Cheng, Huuxue Yunjiu Yic Yingyong, 1996, 8, 207 (Chem. Abstr., 1997, 126. 60 014). V. Maniu and M. Culea, Rupid Commun. Muss Spectrom., 1997, 1 I , 235. V. V. Zamkova, A. E. Lyuts, B. Zh. Dzhiembaev, B. M. Butin, and S. K. Tukanova, Izv. Nut Akurl. Nuuk Resp. K m , Ser. Khim., 1994, 5, 27 (Chem. Abstr., 1997, 126, 8209) K. Burgess, D.H. Russell, A. Shitangkoon, and A.J. Zhang, Nucleosicles Nucleotides, 1996,15, 1719. C. N. Raju and G. S. Reddy, Indiun J. Heterocycl. Chem., 1996,6, 119. P. M. Reddy, C. D. Reddy, and C. N. Raju, Indiun J. Heterocycl. Chem., 1997, 6, 173. G. S. Groenewold, R. L. Cowan, J. C. Ingram, A. D. Appelhans, J. E. Delmore, and J. E. Olson, S u r - Interfuce A n d , 1996,24, 794. N-J. Zhang, H-Y. Lu, X. Chen, and Y-F. Zhao, Chin. Chem. Lett., 1997,8,629. G. Becker, A. Colmsjoe, and C. Oestman, Anul. Chim. Actu, 1997,340, 181. V. K. Karamfilov, T. W. Fileman, K. M. Evans, and R. F. C. Mantoura, Anal. Chim. Actu, 1996,335, 5 1. H. Merten, H. Richter, and A. Landrock, GIT Fuchz Lab., 1996, 40, 1008 (Chem. Abstr., 1997, 126, 139 279). M. Sliwakowski, Proc. ERDEC Sci. ConJ Chem. Biol. Def: Res. 1995, Publ. 1996, 71 1. M. S. Sokolowski and M. Sliwakowski, Proc. ERDEC Sci. Con$ Chem. Bid. Def. Res. 1994, Pub. 1996,561. 0. 1. Kalchenko, J. Lipkowski, R. Nowakowski, V. I. Kalchenko, M. A. Visotsky, and L. N. Markovsky, J. Chromutogr. Sci., 1997,35,49. R. Y. Gao, G. S. Yang, H. 2. Yang, Z. Y. Chen, and Q. S. Wang, J. Chromutogr., A, 1997,763, 125. N. Lambropoulos, T. J. Cardwell, D. Caridi, and P. J. Marriott, J. Chromutogr., A, 1996,749, 87. W. R. Creasy, Proc. ERDECSci. Conf. Chem. B i d DeJ Res. 1994, Publ. 1996, 31. J. Klinger, F. Sacher, H. J. Brauch, and D. Maier, Actu Hyrlrochim. Hyrlrobiol., 1997,25, 79. A. E. Bretnall, M. M. Hodgkinson, and G. S. Clarke, Chirulity, 1997,9, 104. Y. Ikeguchi and H. Nakamura, Anul. Sci., 1997,13,479. H. Tsuruoka, K. Shohda, T. Wada, and M. Sekine, J. Org. Chem., 1997,62,2813. C. Guo, R. Zhang, J. Jiang, and X. Yang, Nunjing Huugong Duxue Xuebuo, 1995, 17, 105(Chem. Abstr., 1997, 126,98617). Q-S. Wang, B-W. Yan, and H-2. Yang, J. Plunur Chromatogr.-Mod. TLC, 1997,10, 118. C. E. Kientz, E. W. J. Hooijschuur, and U. A. Th. Brinkman, J. Microcolumn Sep., 1997, 9, 253. J-P. Mercier, Ph. Morin, M. Dreux, and A. Tambute, J. Chromutogr., A , 1997, 779, 245. C. Akbay, S. A. Shamsi, and I. M. Warner, Electrophoresis, 1997, 18, 253. K. Verleysen and P. Sandra, J. High Resolut. Chromutogr., 1997,20,337.


250

25 1

252 253

254 255 256

257

258

H. Ozaki and S. Terabe, Bunseki Kugakkai, 1997,46,421 (Chem. Abstr., 1997, 127, 96 218). V. D. Kiselev, I. I . Patsanovskii, E. A. Kashaeva, E. V. Popova, C. Mueller, R. Schmutzler, E. A. Ishmaeva, and A. 1. Konovalov, Zh. Org. Khim., 1996, 32, 1853 (Chem. Abstr., 1997,127,50 731). A. Wawer and J. Szydlowski, Pol. J. Chem., 1996,70, 1554. J. Braun, R. Schwesinger, P. G. Williams, €1. Morimoto, D. E. Wemmer, and M-H. Limbach, J. Am. Chem. Soc., 1996,118, I 1 101. E. Ocando-Mavarez, G. Martin, and A. Andrade, Heteroat. Chem., 1997,8,91. K. Mohnot, P. K. Sharma, and K. K. Banerji, J. Indian Chem. Soc., 1997,74, 12. G. S. Quin, S. Jankowski, and L. D. Quin, Phosphorus, Surfur, Silicon Relat. Elem., 1996, 11593. N. I. Yanchuk, Zh. Obshch. Khim., 1996, 66, 1473 (Chem. Abstr., 1997, 126, 144 327). N. I. Yanchuk, Zh. Obshch. Khim.,1996,66, 1287 (Chem. Abstr., 1997,126, 104 149).

Author Index

In this index the number in parenthesis is the Chapter number of the citation and this is followed by the refirence number or numbers of the relevant citalions within that Chapter.

Aaserud, D.J. (5) 299

Abboud, K.A. (1) 428 Abdel-Rahman, A.A.-H. (3) 39 Abdou, W.M. (1) 222; (6) 140 Abdur-Rashid, A. (3) 32; (4) 10 Abe, M. (1) 238 Abed, J.C. (1) 349; (8) 82 Abell, C. (4) 126 Abid, A. (5) 188 About-Jaudct, E. (4) 114, 130, 184 Abram, H. (1) 593 Abram, S. (7) 3 Abram, U. (3) 54; (7) 3; (8) 157 Abras, A. (1) 32 Abu-Shanab, O.L. (7) 148 Abu Sheikha, G. (8) 76 Acedo, M. (5) 191 Achiwa, K. (1) 47 Acosta, J.L. (7) 171-175 Adachi, T. (6) 153 Adam, D. (8) 34 Adamiak, R.W. (5) 257 Adkins, T.W. (4) 11 1 Afarinkia, K. (4) 167 Aganov, A.V. (8) 137 Agarwal, M. (1) 298 Aggarwal, S.K. (3) 34 Agrawal, S. (3) 33; (5) 90, 104 Ahlcmann, J.-T. (1) 504 Ahn, K.H. (1) 3,4 Airey, A.L. (1) 271 Airola, K. (1) 475 Ailken, A.R. (1) 417; (6) 38 Aka, B. (1) 407 Akagi, M. (5) 92 Akasaka, T. (1) 212; (6) 11

Abboud, J.-L.M. (1) 277 Akbay, C. (8) 248 Akiba, K. (6) 78; (8) 124, 125, 196 Akiyama, T. (5) 258,259 b n e s , G. (1) 432; (2) 5; (8) 123 Aladzhcva, I.M. ( I ) 321, 397; (6)

Alajarin, M. (1) 26 I, 262; (8) 177 Al Badri, A. (1) 473 Albanov, A.I. (1) 42 Albarct, C. (4) 100 Albcricio, F. (5) 80 Albert, J. (1) 270 Alberti, A. (1) 488 Albcrti, M. (7) 77 Albcrtsson, A.-C. (8) 154 Albouy, D. (1) 122; (4) 269 Alcaraz, G. (1) 489; (6) 20 Alcudia, A. (1) 3 19 Alcudia, F. (1) 3 19 Al-Diab, S.S. (8) 70 Aldrich, J.V. (5) 3 10 Al-Dulayymi, J.R (4) 272 Alcmany, L. (4) 5 1 Alcwood, P.F. (4) 64 Alcxandcr, J.B. (1) 485 Alexandcr, N.C. (1) 38 1 Alexandra, M.Z. (4) 212 Alexandratos, S.D. (1) 249 Alcxandrova. L.A. (5) 76 AIrcrov, K.V. (4) I77 Ali, O.M. (3) 39 Allain. L.R (1) 32

35,36; (8) 107, 108

Allcock, H.R. (7) 13-17,76,78,84, 95,123,124,156,164,165,184, 191, 199,202,208; (8) 60,83

Allccr, E. (4) 183; (8) 178 Allen, D.W. (1) 408

Allen, RE. (1) 107 Allman, S.L. (5) 307 Almer, H. (5) 103 Almond, M.J. (1) 394 Alonso, C. (7) 3 1 Alonso, F.J.G. (7) 147 Al-Shali, S. (7) 84 Altmann, K.H. (5) 137,138,166 Alvarcz, R (6) 104 Alvarcz Gonzalcz, R. (5) 48 hvarcz-GutiCrrcz, J.M. ( I ) 346; (7)

26,27 AlvmZ-Saranda, R (6) 148 Amano, H. (1) 320 Amano, J. (7) 107 Amato, M.E. (7) 134; (8) 35 Arnatorc, C. (1) 6 1 1 Ambrosio, A.A. (7) 199,208 Amcr, A. (1) 423,446; (8) 146 Aminova, RM. (1) 512; (8) 40 An, Y.Z. (5) 15 1 Anand, B.N. (2) 21 Anchisini, R (7) 180, 181 Andcrson, C. (1) 184; (4) 102 Andcrson, N.G. (1) 252 Andcrsson, F. (4) 205 Ando, N. (1) 47 Andrade, A. (1) 265,460; (8) 254 Andrci, G. (5) 22.26 Andrcotti, D. (4) 105 Andriamiadanarivo, R (7) 4 1 Andrianov, A.K. (7) 129, 190,191,

Andrieu, J. (1) 23 Andrijcwski, G. (8) 205 Aneja, R (4) 41 Aneja, S.G. (4) 41

203-207

343


Barton, D.H.R (1) 24 1 Bartsch, R (1) 531,577,583 Bashilov, V.V. (1) 366; (4) 298; (8)

Bashkin, J.K. (5) 239 Batalova, T.A. (3) 17; (8) 116 Batra, R (4) 85 Batsanov, AS. (6) 5 Bauer, A. (1) 204,398; (6) 19 Baucr, W. (1) 3 12; (3) 24; (7) 20 Baumann, T. (6) 95 Baumann, W. (1) 177 Baumstark, A.L. (1) 239 Baxlcy, G.T. (1) 132,133 Beabealashvilli, RS. (5) 68 Beach, D.H. (4) 279 Bcachlcy, O.T. (1) 110.112 Bcak,P. (1) 171; (4)261 Beaton, G. (5) 106,108 Beaucage, S.L. (5) 89,157 Becher, G. (5) 195 Bcchcr, J. (6) 155 Beck, S. (5) 303 Bcck, T.A. (5) 109 Bcclicr, G. (1) 482; (8) 23 1 Bakers, H. (8) 9 Becquct, R (7) 1 Bedford.RB. (1)492.515,516 Beers, S.A. (4) 289 Begq, S. (7) 86, 118 Beghetto, V. (1) 146 Beglcy. M.J. (6) 173; (7) 62 Begnini, M.L. (6) 77

Bchr, J.P. (5) 188 Bchrman, E.J. (5) 52 Beigelman, L. (5) 172, 173,255 Bckker, A.R (3) 14, 17,22; (8) 116 Belaj, F. (7) 119; (8) 29 Belciug, M.P. (8) 98 Belctskaya, l.P. (1) 486,498,559 Belgradcr, P. (5) 133 Bcll, C. (5) 28 1 Bellanato, J. (4) 1 18 Bcller, M. (1) 157 Bellon, L. (5) 158 Bellucci, G. (6) 166 Bel'skii, V.K. (2) 12; (3) 14.16.17,

Bcnabra, A. (1) 319 Benaglia, M. (1) 488 Benalilii, R (1) 22 Bcnayoud, F. (4) 140 Ben Dhia, M.T. (4) 215 Bendig, J. (5) 49 Benincori, T. (1) 11, 143 Benlian, 8. (4) 29 '

135, 136

Behr, J.-B. (4) 138

20; (8) 116, 161, 164

Angelakos, c. (7) 102 Angermaicr, K. (I) 204 Ankersmit, H.A. (1) 172 Antipin, M.Y. (3) 15 Antognazza, P. ( I ) 11, 143 Antoniades, H.N. (4) 25 Aoki, S. (1) 402 Aoki, Y. (1) 574 Aoyagi, K. (1) 35 Aoyagi, M. (5) 152 Aparicio, D. (1) 327,328 Apffel, A. (5) 292 Appel, W.F. (6) 171,172 Appclhans, A.D. (7) 141; (8) 229 Aquaro, S. (5) 4 Arai, S. (4) 107 Arai, T. (4) 155 Aramini, J.M. (5) 261 Arbuzova, S.N. (1) 40,42 Arduengo, A.J. (1) 525-527 Ariola, K. (3) 12 Arlibie, T. (1) 575 Armstrong, D.R. (6) 110, 115 Amccke, R (1) 450 h e y , D.S.J. (1) 530 Arnold, D.P. (1) 403 Arnold, J.RP. (5) 286 Arnold, L.J. (5) 43, 109 Amold, P.L. (1) 612,613 Arnold, W. (1) 10 Arques, A. (1) 26 1 Arsanous, M.H.N. (6) 75 Arslan, T. (5) 233 Arumugam, S. (2) 23 Arzumanov, A.A. (5) 66 Asami, T. (6) 103 Ashendel, C.L. (4) 73 Atkins, M.B. (5) 43 Attolini, M. (4) 198 Atwood, J.D. (1) 382 Auberti, A.M. (5) 19 Auge, P. (4) 100 Autry, M.E. (5) 239 Avarvari, N. (1) 607,6 15; (3) 52 Averin, A.D. (1) 498,559 Avino, A. (5) 80

Awad. RW. (1) 244 Awano, H. (5) 5.6 Ayman, W. (6) 144 Ayupova, E.I. (1) 136 Azhayev, A. (5) 206,208 Azuma, Y. (3) 35

Aw, B.-H. (1) 165, 166

Baban, J.A. (4) 146, 179 Babkin, Yu.A. (4) 103

Baccar, B. (1) 345; (4) 164,215 Baccolini, G. (1) 599 Baccircdo, A. (4) 257; (8) 104 Bach, H. (1) 286 Bachrach, S.M. (1) 479, 480, 573,

616; (8) 4.5 Badn, A.A. (8) 129 Back, H.-H. (1) 3; (7) 195 Bacr, D.R (7) 178 Bacr, T. (4) 192 Baeschlin, D.K. (5) 122 Baharfar, R (1) 214, 438; (6) 52,

Bahrmann, H. (1) 285,286 Bailly, C. (5) 243 Bains, R. (2) 2 1 Baird, M.S. (4) 272 Bakos, J. (3) 47 Balabanova, T.S. (8) 204 Balakin, K.V. (5) 225 Balavoine, G.G.A. (1) 565,566,579 Balczcwski, P. (4) 210,253,265-

268; (6) 87 Bald, R. (5) 279,280 Baldan, A. (5) 82 Baldwin, RA. (1) 236 Balema, V.P. (1) 304 Balovitdmov, A.B. (4) 244 Balucva, AS. (1) 136, 358, 359,

415,416; (6) 16 Balzarini, J. (5) 1-4,22,26 Bandini, E. (4) 152 Bandoli, G. (1) 396 Bandyopadhyay, A.R. (1) 220 Bancrjce, A. (4) 236 Bancrji, K.K. (8) 255 Bankaitisdavis, D.M. (5 ) 106 Banks, M.R. (1) 552; (4) 4; (8) 42 Bannwarh, W. (4) 59 Bansal, RK. (1) 298 Barany, G. (5) 100,101 Barashkov, N.N. (6) 156 Barawkaw, D.A. (5) 224 Barbas, C.F., 111 (4) 186 Barboiu, M. (7) 94 Barbour, L.J. (1) 135 Bardaji, M. (1) 185, 187 Barkallah, S. (1) 345; (2) 11; (4)

Barlow, S.J. ( I ) 406 Barofsky, D.F. (5) 3 10 Barr, D. (6) 110 Barrish, J.C. (4) 188 Bartczak, T.J. (1) 378 Bartlett, M.G. (5) 3 1 1 Bartley, S.L. (1) 24 Bartoli, G. (1) 329

53

164

Author index 345

Bo~witzky, A. (1) 156 Borzatta, V. (7) 157, 158 Bosch, E. (1) 593; (3) 54; (8) 157 Bosch, I. (7) 29 Bosco, M. (I) 329 Bosc, S. (4) 78 Bosscher, G. (7) 99,100 Botting, N.P. (3) 5; (4) 193 Boubekcur, K. (1) 24 Bougauchi, M. (4) 155 Boukraa, M. (1) 345; (4) 164 Boulajoun, I. (8) 115 Boulanger, Y. (4) 28 1 Boulos, L.S. (6) 75, 125 Bourumeau, K. (1) 141,231 Bout, A. (7) 193 Boutwine. A.S. (5) 221 Boutton, C. (1) 16; (8) 163 Boyd, E.A. (4) 227 Boyd, M.E.K. (4) 227 Brachwitz, H. (4) 284 Bracken, K. (4) 238 Brade, H. (4) 55 Bradcy, D.C. (1) 234 Braga, A.L. (6) 77 Braich, R (5) 95 Brandsma, L. (1) 40-42 Brandt, K. (8) 59 Brandt, P.F. (1) 71, 129, 130; (8)

Brandt, T.A. (1) 288 Brankovic, D. (1) 254 Brauch, H.J. (8) 240 Braucr, D.J. (1) 147,413; (6) 31 Brault, D. (5) 221 Braun, A. (5) 300 Braun, J. (7) 38; (8) 253 Braunstcin. P. (1) 23,128 Bravic, G. (1) 322 Breaker, RR (5) 277,284 Breen, T.L. (1) 116, 117, 194; (8)

Brcidung, J. (8) 9 Breit,B. (1)289,517,614 Breitsameter, F. (1) 303; (6) 25 Bremncr, M. (5) 160 Brenchley, G. (1) 12; (3) 45 Brenna, E. (I) 11, 143 Breslow, RC. (5) 141 Brctnall, A.E. (8) 24 1 Brew, E. (4) 258,259,294; (8) 8 I,

Breuer, T. (7) 42 Brevnov, M.G. (5) 164 Brice, L.J. (4) 156,299 Brigando, C. (4) 29 . Briggs, A.D. (4) 169,282

39,71

170

127

Bennani, Y.L. (4) 220 Benner, S.A. (5) 65, 122, 193 Bennett, M.A. (1) 200 Benoit, D. (4) 270 Bentrude, W.G. (8) 95 Bentzlcy, C.M. (5) 3 12 Benzaria, S. (5) 19 Berdyshev, D.V. (8) 24 Berens, U. (1) 85 Berg, T. (1) 18, 19 Berge, 0.-G. (4) 204 Bergemann, C. (6) 139 Bergens, S.H. (1) 126 Berger, D.J. (1) 508 B e r g m a , J. (4) 284 Bergncs, G. (4) 290 Bergrath, K. (1) 285 Bergstracsser, U. (1) 483,595,600;

(8) 94, 165 Bergstrom, D.E. (5) 178,242 Bcrk, J.D. (4) 176 Berkowitz, D.B. (4) 194 Berlin, K.D. (4) 1 1 ; (8) 52 Berlin, Y.A. (5) 225 Bcrl'skii, V.K. (1) 30 Bermcjo, M.R. (1) 391 Bernard, A.M. (6) 76 Bcmardinelli, G. (1) 473; (2) 26; (8)

Bcrnicr. J.L. (5) 243 Butani, R (6) 66; (7) 88, 161, 162;

Bertani, S. (7) 200 Berthod, T. (5) 175,176 Bertrand, G. (1) 540; (4) 256,257;

Besidski, Y. (4) 204 Bestmann, H.J. (6) 54,84 Beswick, M.A. (1) 107; (6) 65 Beuschel, G. (7) 13 1 Beutenmiiller, E.W. (1) 8 Bcvcrs, S. (5) 182 Bcvcnvijk, V. (1) 474 Beycr, B.D. (4) 209 Bezcncon, 0. (7) 35 Beziat, Y. (4) 116 Bezombes, J.-P. (1) 538; (3) 59 Bezuglov, V. (6) 135 Bhargava, S.K. (1) 200 Bhattacharyya, P. (1) 3 1 1 Biaggio, F.C. (4) 208 Bibilashvili, RS. (5) 67 Bickelhaupt, F. (1) 471,474 Bickncll, W. (5) 27 1 Bieger. K. (8) 18 1 Bicnlein, F. (I) 76, 8 1 Bifulco, G. (5) 272

129

(8) 202

(8) 104

Bigey, P. (5) 130 Biller, S.A. (4) 209 Binder, H. (1) 99, 100, 102 Binet, L. (6) 155 Binger, P. (1) 483; (8) 165 Bin Hy (1) 24 1 Birchhirschfeld, E. (5) 8 1 Bishop, R (7) 69 Bisscssur, R (7) 169,170 Bissingcr, P. (1) 76 Bitterer, F. (1) 90, 147 Bizdcna, E. (5) 153 Black, S.J. (1) 590-592; (8) 160

Blades, K. (1) 341; (4) 136,141 Blake, A.J. (1) 531; (4) 21 Blanchard, L. (4) 285 Blanchard, P. (6) 94 Blaser, A. (5) 185 Blaszqk, J. (1) 375; (4) 190,208,

251; (6) 129; (8) 49,67, 191 Blaurock, S. (1) 74, 119 Blohom, B. (6) 160 Blokhin, Y.I. (3) 20; (8) 164 Blouin, M. (4) 165 Blower, P.J. (1) 198 Blumstein, A. (1) 4 1 1 Boal, J.H. (5) 89, 157 Bdcskci, Z. (I) 563, 564; (8) 109,

Boduszck, B. (4) 232 B w k , P. (6) 77 Bochm, D. (1) 584 Boehmer, V. (1) 450 Bohringer, M. (1) 482 Boele, J. (7) 42 Bocrncr, A. (1) 57, 177, 180 Boga, C. (1) 599 Bojilova, A. (4) 243 Bojin, M.L. (2) 1 1 Boldt, P. (7) 12 Boldyreva, E.F. (5) 163 Bollmark, M. (5) 1 I, 12.46 Bolourtchian, M. (6) 5 1 Bond, M . R (1) 568 Bondarenko, N.A. (I) 363 Bongert, D. (1) 99,100 Bongini, A. (4) 152 Bonora, G.M. (5) 82 Boonc, S.J. (3) 38; (5) 232 Borchardt, RT. (4) 66 Bordwcll, F.G. (7) 42 Borisenko, A.A. (1) 498,559 Borisova, I.V. (1) 443; (6) 56 Borkenhagcn, F. (8) 167 Bomnann, H. (1) 37 Bortolus, P. (7) 127

Blackbum, G.M. (5) 5446.61

I56


Briley, J.D. (5) 72 Brimacornbe, J.S. (4) 56 Brinek, J. (7) 77 Brinlanan, U.A.T. (8) 246 Brisset, H. (6) 94 Brock, M. (7) 120; (8) 179 Brodney, M.A. (6) 138 Brody, M.S. (6) 59, 164 Broger, E.A. (1) 10 Brondyke, E.J. (6) 165 Brookes, H.C. (1) 201 Broschk, B. (1) 482 Brosse, J.-C. (3) 3 Broussier, R (1) 5 Brovarets, V.S. (1) 440 Brown, D.M. (5 ) 288 Brown, J.M. (1) 21, 152 Brown, P.W. (7) 156 Brown, T. (5) 134 Bruckmann, J. (1) 284,483; (8) 165 Brucnner, B.A. ( 5 ) 308 Bruice, T.C. (5 ) 9 Brunelle, D.J. (1) 246

Bninctte, J.P. (1) 369 Brunncr, H. (1) 7,69; (8) 162 Brusatin, G. (7) 153-155 Brusova, G.P. (1) 1 18 Bnrzlk, K.S. (4) 45 Bubnov, N.N. (1) 366; (4) 298; (8)

Buchatskii, A.G. (5 ) 225 Buck, RT. (4) 183 Buckingham, M.R (7) 105 Budesinsky, M. (5 ) 26 Budnikova, Y.G. (1) 202; (8) 200 Buchncr, M. (1) 93,532 Burger, H. (1) 413; (6) 31; (8) 9 Buhr, C.A. (5) 203 Bujacz, G.D. (1) 375; (8) 191 Burdette, S.C. (3) 61; (8) 130 Burford,N.(1)502,521;(3)58; (8)

Burgers, D. (3) 50 Burgess, K. (8) 226 Burghart, A. (4) 83 Burgin, A.B. (5 ) 173 Burke, B.W. (5) 100 Burke, S.D. (4) 1 11 Burke, T.R., Jr. (4) 145 Burkus, F.S., I1 (7) 47 Burlina, F. (5) 165 Bumaeva, L.M. (3) 2 Bums, C.J. (I) 530 Burns, M.R (4) 5 1 Burton, D.J. (4) 143,144; (6) 3,99 Buslacv, YwA. (1) 388; (6) 35,36;

Brunet. J.-J. (1) 309

135,136

20

(8) 106-108 Busse. S.C. (7) 186; (8) 120 Busson, R ( 5 ) 156 Butin, B.M. (1) 151, 356; (4) 296;

Butlcr, I.R. (1 ) 2 Butlcr, I.S. (8) 45 Butler, J.M. ( 5 ) 133 Butler, K.E. (6) 165 Butskii, V.D. (1) 388; (6) 36; (8)

Buzik, K.S. (4) 44 Buzin, F.-X. (1) 67, 3 14, 3 16; (8)

Bykhovskaya, O.V. (1) 321, 397;

Byun, Y. (7) 80

(8) 225

108

194

(6) 35; (8) 107

Cabioch, J.-L. (1) 470; (8) 37 Cacciapaglia, R ( I ) 450 Cadena, M. (I) 270; (4) 4 Cadet, J. (5 ) 175, 176 Cadogan, J.I.G. (1) 552; (8) 42 Cahard, D. (5) 4 Cai, X.H. ( 5 ) 13 1 Cai, Y. (5 ) 306 Cain, RJ. (5) 212 Calabrcse, J.C. (1) 525,526 Calias, P. (4) 25 Caliccti, P. (7) 126,200 Caliman, V. (1) 514, 585, 586; (3)

55; (4) 214; (8) 99 Calogcropoulou, T. ( 5 ) 1 Camchi, R (4) 94, 152 Camcron, C.G. (7) 164, 165 Camcron, T.S. (1) 521; (3) 58 Caminadc, A.-M. (1) 149, 185- 187,

Caminiti, R. (7) 135; (8) 36 Campbcll, G.C. (7) 43 Campbell, M.M. (4) 133,196 Camplo, M. (4) 169,282 Cano, F.C. (6) 48

Cantrill, A.A. (4) 217,218 Cao, P. (1) 52,65,66 Cao. W. (6) 40,80; (8) 84 Caon, 1. (4) 5 Capkova, J. (1) 259 Cappcllacci, L. (8) 76 Cappemcci, A. (1) 309 Carcas, K. (1) 417; (6) 38 Cardwcll, T.J. (8) 238 Carenza, M. (7) 126 Caridi, D. (8) 238 Carlin, C.M. (I) 242; (8) 105

263; (4) 17-20; (6) 69; (7) 87

Cantin, L.-D. (4) 105

Carmalt, C.J. (1) 527 Carmi, N. ( 5 ) 284 Carr, S.F. (5 ) 58.59 Carrahcr, C.E.J. (7) 121 Carran, J. (4) 122. 132,137, 147 Carrano, C.J. (1) 568 Carrc, F. (1) 537, 538; (3) 59; (8)

Carrcy, E.A. (5) 57 Carriedo, G.A. (7) 72,139,147 Carroll, P.J. (1) 235 Caruthcrs, M.H. ( 5 ) 106, 108, 114,

Casabo, J. (1) 199,387 Cascro, RA., Jr. (4) 283 Cassagnc, M. (1) 40 1 Catalano, J.G. (4) 7 1 Catalano, V.J. (1) 140 Catteau, J.P. ( 5 ) 243 Caulton, K.G. (1) 282 Cauret, L. (3) 3 Cavalla, D. (1) 333; (6) 116 Cavdarci, 0. (7) 8 1 Cavell, R G . (1) 264; (2) 3, 28; (7)

Cca, P. (8) 149 Ccch, D. (5 ) 64,69,70 Ccch, T.R. (5) 39,40 Ccnac, N. (1) 495,572 Ccntinkaya, B. (7) 86 Ccrcghctti, M. (1) 9, 10 Ccsarotti, E. ( I ) 11, 143 Cculcmans, G. (5) 136 Chackalamannil, S. (4) 286 Chae. H.K. (7) 97 Chaikovskaya, A.A. (1) 292,293 Chakcl, J.A. (5) 292 Chalrhmakhchcva. O.G. (3) 26; (5)

Chan, C.M.Y. (1) 1 1 1

Chan, K.S. (1) 176

Chan, T.W.D. (5) 301 Chandrasckaran, A. (2) 4, 27; (8)

Chandrasekhar, J. (2) 15 Chandrasekhar, V. (7) 79 Chang, C.P. (7) 148

Chang, F.H. (8) 72

Chang, Y.F. (5 ) 28 1

Changenet, P. (1) 279; (8) 153 Chantcgrcl, B. (4) 254,255 Chao, Q. (5 ) 5 1

64

115

10,11

135

C h q E.W.-K. (1) 331

Chan, T.-H. (4) 159

41,61,65

Chang, C.-W.T. (1) 207

Chang, N.-y. (8) 25

Chang, Y.-T. (4) 22,27,37

Aufhor Index 341

Chao, S.-H.L. (1) 112 Chapell, B.J. (1) 360 Chapman, R.D. (7) 19 Chapyshev, S.V. (1) 600 Charfi, M. (8) 143 Charlton, J. (4) 288 Charrier, C. (1) 582,603,607 Chasseau, D. (1) 322 Chattopadhyay, S. (6) 137 Chattopadhyaya, J. (5) 235,236 Chaudhry, U. (6) 90 Chaudhuri, N.C. (5) 171 Chaudret, B. (1) 185, 187 Chauvin, R (1) 309 Chazin, W.J. (5) 272 Che, C.M. (1) 174 Chen, C.H. (5) 307 Chen, C . 4 . (4) 39 Chen, C.-Y. (1) 223; (8) 26 Chen, F. (4) 279 Chen, G. (8) 11 1 Chen, J. (4) 38,47,48; (7) 205 Chen, J.Y. (5) 242 Chen, M.S. (5) 27 Chen, R. (4) 175 Chen, R-T. (4) 16 Chen, RY. (4) 9; (8) 87, 88, 100,

184,185 Chen, S. (4) 280 Chen, T. (I) 103-105; (8) 101 Chen, W. (5) 20 Chen, X. (2) 8; (8) 75,93,230 Chen, Y.M. (5) 196-199 Chen, Y.W. (7) 146 Chen, Y.-X. (1) 239 Chen, Z. (1) 65,66 Chen, Z.Y. (8) 237 Chen-Chamg, Y.W. (7) 109 Cheng, C.R. (1) 167 Cheng, H.S. (7) 103 Chcng, J.-P. (6) 7 Chcng, S.W. (5) 301 Chcng, X.H. (5) 294,295 Cheng, Z. (8) 223 Chenit, M. (1) 487; (8) 7

Cherkasov, R.A. (1) 409,597; (2) 1 Chemega, A.N. (1) 500; (8) 6 Cheruvallath, Z.S. (3) 31; (5) 35, 88 Chiadimi, M. (3) 11; (4) 106 Chiappe, C. (6) 166 Chiarizia, R. (4) 264; (8) 142 Chickos, J.S. (1) 372; (8) 209 Chicotc, M.T. (6) 65 Chiesi-Villa, A. (3) 2 I Chik, T.W. (1) 174 Childerhouse, N.D. (1) 393

Chm-Ymg, Y.W. (8) 72

Chitsaz, S. (7) 8 Chivers, T. (1) 371; (6) 6; (7) 120;

(8) 179 Cho, C.-W. (1) 3,4 Cho, K.Y. (6) 103 Cho, Y.H. (7) 97,195 Chock, J. (5) 8 Choi, J.S. (4) 233 Choi, K.S. (7) 113 Choi, N. (4) 240; (8) 183 Chojnowski, J. (7) 55 Chou, P.K. (1) 447; (6) 9 Chow, T.J. (1) 223; (8) 26 Christian, N.P. (5) 302 Chrostowska-Scnio, A. ( I ) 506; (8)

Chuang, J.R. (7) 109 Chuburu, B.F. (2) 24 Chuit, C. (1) 537, 538; (3) 59; (8)

Chung, G. (8) 27

Chung. Y.W. (7) 103 Churchill. M.R (1) 110,112,382 Cicslak, J. (5) 14 Cihlar, T. (5) 27 Cimpocsu, M. (7) 94 Circlli, A.F. (6) 106 Cisarova, I. (4) 263 Cispcr, M.E. (8) 219 Cladc, J. (8) 198 Clacsson, A. (4) 204,205 Clardy, J. (8) 189 Claridgc, T.D.W. (1) 2 1 Clark, J.H. ( I ) 406

Clarke, G.S. (8) 241 Classen, R (6) 101 Clayden, J. (1) 340 Clcgg, W. (1) 137 Clcmcntis, G. (3) 8; (8) 203 Clcvcn, R.M. (4) 286 Clivio, P. (5) 228,229 Cloke, F.G.N. (1) 612,613 Clyburnc, J.A.C. (1) 502,521,527;

Coatcs, J.A.V. ( 5 ) 50 Cockcrill, G.S. (4) 136 Coggio, W.D. (7) 106 Cohcn. S. (7) 191 Colaprct, K.A. (1) 252 Cole, D.L. (3) 3 1; (5) 88,97,98 Cole-Hamilton, D.J. (1) 283 Coll, J.B. (7) 142 Coliignon, N. (4) 114, 130, 184 Collins, J.G. (5) 273 Collomb, D. (4) 254

112

64

Chug, S.-K. (4) 22.27.37

Clark, T. (1) 555-557; (3) 13

(3) 58

Colmsjoe, A. (8) 23 1 Combes-Chamalct, C. (7) 98; (8)

Comotti. A. (7) 138; (8) 117 Conde, S. (4) 200 Condeiu, C. (4) 234,235 Conforti, A. (7) 200 Connolly, B.A. (5) 18 1 CONOY, G.M. (1) 446 Consiglio, G. (8) 85 Conslantinou, M. (8) 183 Cook, A.F. (5) 110 Cook, P.D. (5) 155,189 Cook, S.D. (4) 89 Cookc. J.A. ( I ) 237 Cool, T.A. (8) 215 Corain, B. (1) 396 Cordi, A.A. (4) 206 Cornforth, J. (4) 125 Corriu, RJ.P. (1) 17,537,538; (3)

Cort, A.D. (1) 450 Cortina, J.L. (8) 206 Cosman, M. (5) 263 Cosstick, R (5) 30,39,40 Costa, V.E.U. (8) 73 Costa dc S o w , M. (8) 182 Costcs, B. (7) 105 Costisella, B. (4) 13 Cottier, L. (4) 172, 173 Couch, K.M. (4) 11; (8) 52 Couret, C. (1) 274 Cowan, J.A. (5) 252 Cowan, RL. (7) 141, 185; (8) 229 Coward, J.K. (4) 280 Cowlcy, A.H. (1) 457, 526, 527,

Craig, D.C. (1) 452 Craik, D.J. (5) 271 Cramer, C.J. (1) 522 Cramer, F. (3) 27 Cranc, C.A. (8) 83 Crane, C.E. (7) 13, 15 Crasnier, F. (7) 66.67, 1 I5 Creasy, W.R (8) 239 Cremer, S.E. (1) 430; (4) 104,291 Crich, D. (4) 86; (8) 86 Cristau, H.J. (1) 401,419; (4) 116;

(7) 98; (8) 173 Crombic, L. (6) 173 Crommcn, J. (7) 196 Cross, RJ . (1) 385,386 Csaszar, A.G. (8) 22 Cserepi-Sziics, S. (3) 47 Culbcrtson, B.M. (7) 121 Culea, M. (8) 224 Cullinan, D. (5) 262,263

173

59; (8) 64

568


Cummins, C.C. (8) 122 Cummins, L.L. (5) 107, 108, 155 Cupertino, D. (7) 24 Curnow, O.J. (1) 79 Cushion, M.T. (4) 279 Cypryk, M. (7) 55 Czarniccki, M. (4) 286

Dabkowski, W. (3) 27 Dahan, F. (1) 540; (4) 257 Dahl, 0. (5) 37,38,105,129 Dahlhoff, W.V. (6) 139 Dai, H. (7) 166 Dai, Q. (4) 175; (8) 87,88 Daily, W.J. (5) 43, 109 Dal, Y.Q. (5) 313 d'Alarcao, M. (4) 25 Dalcy, C.J.A. (1) 126 Dalhoumi, H. (4) 102 Dallacroce, P. (6) 82 Dambachcr, T. (7) 42 Damha, M.J. (5) 95 Damon, R.E. (6) 151 Dance, I.G. (1) 290, 451, 452;

Dang, C. (5) 28 1 Danion, D. (1) 439 Danion-Bougot, R (1) 439 Danjo, H. (1) 183 Dantzman, C.L. (5) 7

Darnhofer Demar, B. (5) 300 D'Arrigo, P. (4) 49 Darvcsh, K.V. (1) 502 Darwish, B. (6) 173 Da Silva, M.F.C.G. (7) 88; (8) 202 Dat, Y. (1) 506; (8) 112 Datsenko, S. (1) 577 Dauban, P. (4) I10 Daubcndick, S.L. (5) 96 Dautant, A. (5) 287 Davey, J. (7) 166 David, M.-A. (1) 485 Davidson, F. (7) 43 Davidson, M.G. (6) 5, 110, 115 Davics, D.B. (8) 59 Davies, RL. (1) 2 Davies, RP. (6) 115 Davis, A.P. (1) 253 Davis, W.M. (1) 92 Day, M.W. (1) 230 Day, R.O. (2) 4,27; (8) 41,61,65 Dcadman, J. (4) 146, 171, 179 Dean, P.A.W. (1) 452 De Bue, G. (6) 147 dc Cian, A. (1) 60,574

213

Durn, J.-C. (1) 565,566,579

Decken, A. (1) 457 Declcrcq, E. (5) 14.22.26, 156 Declercq, J.-P. (4) 292; (8) 57, 102 h u t , J.L. (5) 226 Decroix, B. (6) 152 Dcemic, RW. (4) 293 de Ferra, L. (4) 49

Dc Jaegcr, R (7) 155, 163 Dcjardm, S. (7) 130 Dclangle, P. (4) 292; (8) 57, 102 de b r a , A . R (6) 104 Delgado, 0. (5) 22 1 Della Bona, M.A. (1) 488 Dclmorc, J.E. (7) 141; (8) 229 Delogu, G. (4) 9 1 De Lombacrt, S. (4) 285 Delossantos, C. (5) 262,263 Del KO, C. (7) 174, 175 Demaison, J. (8) 9 Demarcst, K. (4) 289 Dcmartin, F. (1) 11, 143 Dcmcsmackcr, A. (5) 1 16, 123- 125 De Montis, A. (8) 76 Dempcy, RO. (5) 9

148; (8) 37

Dehnkkc, K. (1) 449; (7) 3-9,65

h i s , J.-M. (1) 141, 231,470; (4)

Denk, M.K. (1) 536; (3) 57 Dcnmark, S.E. (1) 377; (4) 93; (6)

108,109; (8) 43 Dennis, K.C.J. (3) 50 Dennis, S.M. (1) 568 Dcplano, P. (1) 226 Dcprce, G.J. (1) 393 de Roos, M.E. (6) 171, 172 Derouct, D. (3) 3 Desaubry, L. (5) 71 Deschamps, B. (1) 570 Deschamps. F. (4) 28 1 Descoks, G. (4) 172.173 Deshaycs, C. (4) 254,255 Desponds, 0. (1) 3 18 Deubelly, B. (1) 76 Devlin, T. (5) 104 de Vries, A.H.M. (3) 49 Dhalhoff, W.V. (1) 54 Dhamelincourt, P. (7) 1 Diallo, 0. ( I ) 122; (4) 269 Dias, H.V.R. (1) 525,526 Diaz, A. (5) 80, 191 Diaz, E. (4) 1 Diaz-Cortcs, R (6) 92 Dibowski, II. (1) 28 Dickinson, L. (8) 77 Dickson, J.K., Jr. (4) 209 Didiuk, M.T. (1) 148 Dieckbrcdcr, U. (6) 37

Dieckmann, T. (5) 278 Diefenbach, U. (7) 81,82; (8) 174 Diefenbacher, C.G. (4) 285 Diel, P.J. (4) 295 Dierkes, P. (1) 48 Dietliker, K. ( I ) 364 Dillon, K.B. (1) 458 DiMarco, J.D. (4) 209 Dimmig, T. (8) 2 1 1 Dimov, D.K. (1) 429 Dinaut, A.N. (4) 139 Dincva, M.A. (5) 75

Ding, M.-W. (6) 49 Ding, W. (6) 40.80; (8) 84 Dinjus, E. (1) 59 DiRenzo, A. (5) 99 Dishington, A.P. (7) 39 Distefano, M.D. (4) 5 Dittmar, T. (1) 413; (6) 3 1 Dittrich, U. (7) 50,5 1 Divc, V. (4) 189 Do, J. (7) 80 Do, Y. (7) 80 Dodd, RH. (4) 110 Dohcrty, S. (1) 137 Dokuchaev, A.S. (1) 358 Dolgushina, T.S. (1) 313 Dolinnaya, N.G. (5) 144 Domalcwski, W. (8) 200 Dombrowski, A. (1) 307 Donaghy, K.J. (1) 235 Donati, D. (4) 94 Donnadieu, B. (1) 193, 309, 418,

571,572; (6) 60 Dontha, N. (5) 13 I Dopico, P.G. (6) 59 Dorc, A. (4) 129 Doronina, S. (5) 188 Dorrenbach, F. (1) 147 Dotzler, M. (7) 20 Doughty, S.W. (7) 70 Douthwaite, RE. (7) 39 Doxsexz, K.M. (1) 34 Drabowicz, J. (4) 190 Drach, B.S. (1) 414,440; (6) 13 Driigcr, G. (6) 120 Dranslield, A. (1) GO5 Drcan, P. (8) 9 Dreihaupl, K.H. (6) 18, 19 Dreschcr, M. (4) 157 Dresen, S. (1) 253 Drew, M. (8) 247 Dricss. M. (1) 38,94,505,507 Drioli, E. (7) 132 Drozd, V.N. (1) 420 Drysdalc, M.J. (4) 183'

Ding, F.-J. (8) 1

Author Index 349

D'Sa, B.A. (2) 22 Duarte, V. (5) 241 Dubois, P. (1) 405; (6) 12 Duckworth, G. (5) 181 Ducslcr, E.N. (1) 103-105; (8) 101 Duff, R.J. (5) 244 du Mont, W.-W. (1) 227,305,306;

(2) 18; (8) 56 Du Mortier, C.M. (6) 106 Dunbar, K.R. (1) 24 Dupois, A. (1) 579 Dupuis, L. (1) 193,496; (4) 224 h a n d , S. (1) 209 h a n d , T. (6) 135

Dussy, A. (5) 150 Dutasta, J.-P. (4) 292; (8) 57,102 Dvorakova, H. (5) 26 Dvorkin, A.A. (4) 12; (8) 190 Dyatkina, N.B. (5) 66,78 Dyer, G. (1) 169 Dzeja, C. (5) 49 Dzekhtser, S. (1) 254 Dzhiembacv, B.Zh. (4) 296; (8)

Dutig, J.R (8) 2, 12-14

225

Earle, M.A. (7) 34 Earlc, M.J. (3) 32; (4) 10 Earnshaw, D.J. (5) 39,209 Easterficld, H.J. (4) 136 Eaton, B.E. (5) 283 Ebetino, F.H. (4) 176 Echenique, J. (4) 167 Echstein, F. (5) 74,209,210,256 Eckstcin, K. (8) 68 Edwards, M. (7) 102 Edwards, P.G. (1) 197, 275, 276,

281; (8) 15 Edzina, A. (6) 159 Efmov, V.A. (3) 26; (5) 135 Efmtseva, E.V. (5) 159,162-164 Eggen, M.J. (4) 194 Ehle, M. (1) 555; (3) 13 Eichelc, K. ( I ) 521; (3) 58; (8) 20 Eickhoff, H. (5) 8 1 Eisenberg, M. (5) 262,263 Eisentrilger, T. (7) 12 Eisfcld, W. (1) 509 Elass, A. (7) 1 Eldred, C. (3) 44 Eldrup, A.B. (5) 129 Eldsaeter, C. (8) 154,155 Elgendy, S. (4) 146, 171, 179 Elgucro, J. (1) 266,277 El Houar, S. (6) 154 Elias, A.J. (7) 116; (8) 58

El-Khoshnieh, Y.O. (1) 222

Ellcnstcin, A. (6) 165 Ellmann, J. (1) 3 12; (3) 24; (7) 20;

Ellingcr, Y. (1) 487; (8) 7 Ellington, A.D. (5) 21 1,302 Ellis, D. (1) 127 Ellrnerermullcr, E.P. (3) 23 El Mkadmi, M. (1) 274 Elokhina, V.N. (1) 410; (6) 41

Elsegood, M.RJ. (1) 137 Elsevier, C.J. (1) 173 Endcrs, D. (I) 18,19 Endo, M. (3) 35 Engels, J.W. (3) 43 Engemann, C. (8) 198 Englert, U. (1) 138 Enkelmann, V. (1) 425 Ephretikhine, M. (1) 575 Erdmann, P. (5) 150 Erdmann, V.A. (5) 250,279,280 Eriksson, L.A. (1) 523 Eritja, R (5) 80, 191 Ennark, F. (8) 53

Ernst, L. (2) 17 Errington, W. (4) 191; (8) 78 Escalantc, J. (4) 86; (8) 86 Escluichc, L. (1) 199,387 Escobar, M. (6) 90 Escudie, J. (1) 274,484,528 Esipov, D.S. (5) 163 Esmaili, A.A. (6) 44 Essigmann, J.M. (3) 40; (5) 192 Esswcin, B. (7) 44,46 Emad-Moghadam, G. (1) 122; (4)

Etkin, N. (1) 195 Evans, A.C. (6) 165 Evans, A.P. (1) 288 Evans, K.M. (8) 232 Evans, S.A., Jr. (2) 11; (4) 246; (6)

Evans, W.J. (1) 121 Evina, C.M. (4) 138 Exarhos, G.J. (7) 71, 177, 178

El-Kho~y, M. (6) 10

(8) 74

El-Smahy, F.A. (1) 221

Ermolinsky, B.S. (5) 159, 162-164

269

89

Fabbri, D. (1) 159; (4) 91 Fabre, J. (6) 155 Facchin, G. (6) 66; (7) 88,153-155,

161, 162; (8)202 Fagan, P. (5) 191 Faglia, G. (7) 180, 181 Failla, S. (8) 85

Faja, M. (5) 94 Fallon, R (5) 134 Falorni, M. (4) 109 Falvcllo, L.R. (6) 63.64 Fambn, L. (7) 127, 159, 160 Famulok, M. (5) 285 Fan, 2. (5) 53 Fantin, G. (7) 85 Farias, P.A.M. (5) 131 Farley, M. (4) 102 Farrow, M.A. (5) 147 Farrugia, L.J. (1) 127,385,386 Fath, M. (6) 21; (8) 188 Faulhammcr, D. (5) 285 Faure, B. (4) 29 Faure, J.-L. (4) 256 Favero, G. (7) 161 Favre, A. (5) 165,228,229 Favre, G. (5) 241 Fawzi, A.B. (4) 286 Fawzi, R (1) 196 Faza, N. (7) 5 Fearon, K.L. (3) 42; (5) 117 Fedor, M.J. (5) 25 1 Fedorova, O.A. (5) 144 Fedodoff, M. (1) 12; (3) 45 Feher, F.J. (1) 427; (6) 71 Feigon, J. (5) 278 Fcistaucr, H. (4) 160 Fcitcrs, M.C. (4) 72 Fcng, D. (6) 121 Feng, X. (1) 174 Feng, Y.-P. (8) 75 Fenske, D. (1) 449,456,529; (7) 9 Ferguson, C.G. (4) 168 Fcrguson, M.A.J. (4) 56 Fcringa, B.L. (3) 49 Fcrmandjian, S. (5) 269 F e d , M.C. (1) 195 Fernandcz, I. (1) 3 19 Fcrnandez, M.C. (4) 199,200 Femiindez, S. (6) 63,64

Fernandcz-Catuxo, L. (7) 147 Ferrari, C. (8) 208 F~rratis, J.P. (6) 156 Fcrraro, J .R (4) 264; (8) 142 Fcms, K.F. (7) 71 Fcrris, L. (4) 183,252 Fcrmti, P. (5) 82 Feshchenko, N.G. (1) 299-301 Feshin, V.P. (8) 16 Fessner, W.-D. (4) 52 Fettinger, J.C. (1) 206; (4) 293; (8)

Fiaud, 1.42. (I) 357 Fiedler, S. (6) 161

Fhandcz-Castaiio, C. (7) 33

30


Field, L.D. (1) 154 Figuicre, P. (1) 407 Fileman, T.W. (8) 232 Filgueiras, C.A.L. (1) 32 Filippova, A.P. (1) 358 Fillcr, R. (5 ) 20 Findeisen, M. (4) 58 Finct, J.-P. (4) 270 Finn, M.G. (6) 58.59, 164 Finn, P.J. (5) 134 Firuien, D.C. (7) 11 Finochiaro, P. (8) 85 Fischcr, A. (1) 14, 380. 583; (2) 7,

Fischcr, J. (1) 60, 574 Fischer, R.D. (1) 390 Fischcr, S. (5 ) 292 Fisher, K.J. (1) 290; (8) 213 Fislhaber, P. (5 ) 237 Fitz.patrick, R.J. (7) 76 Fitzsimmons, B.W. (7) 70 Fitzwatcr, T. ( 5 ) 28 1 Flavin, M.T. (1) 254; (4) 276; (5 )

Flcming, J.S. (1) 197 Flctschingcr, M. (7) 42 Florentiev, V.L. (5) 2 17 Florian, J. (4) 79 Floriani, C. (3) 21,51 Fluck, E. (1) 617; (6) 34, 61; (8)

16; (7) 59; (8) 18, 168

20; (6) 85

103

177,178 FOCCS-FOCXS, C. (1) 262; (7) 33; (8)

Fodda, R (1) 344 Fogagnolo, M. (7) 85 Foldespapp, 2. (5 ) 8 1 Fomin, S.J. (2) 6 Fomitchcva, M.V. ( 5 ) 159,162-164 Fondo, M. (1) 391 Fonscca, I. (6) 48 Fontana, G. (7) 161, 162 Fontanille. M. (4) 270 Fontecave, M. (5 ) 226 Fookes, C.J.R. (4) 225 Forcman, J.P. (1) 275,276,281; (8)

15 Forcman, M.RSt.J. (1) 554; (4) 95,

212; (8) 192 Forcst, E. (5 ) 175 Forster, G.E. (7) 62 Fortier, P.-L. (4) 100 Fortunati, T. (6) 55 Fortuniak, W. (7) 55 Fourmigue, M. (1) 24,268 Fourrey, J.L. (5 ) 165,228,229 Fraanje, J. (1) 173; (4) 90 France, J. (7) 40

Francesch, A. (6) 104 Franchetti, P. (8) 76 Francis, D.J. (7) I12 Francis, M.D. (1) 588, 589, 591,

592; (8) 160 Frcddi, G. (7) 144 Frccman, J. (4) 102 Frccman, S. (4) 21,36, 169,282 Freier, S. ( 5 ) 155 Freitag, W. (7) 13 1 French, R (7) 40 Frcml, C. (1) 1 15 Frenzcn, G. (7) 8 Frctz, H. (4) 63; (6) 167, 168 Frcy, R. (1) 109 Frier, C. ( 5 ) 226 Friesen, RW. (4) 165 Frilling, A. (5 ) 300 Frings, S. ( 5 ) 49 Fritz, G. (1) 37,544 Fritz, H. (7) 42 Froehler, B.C. (5 ) 203 Frohning, C.D. (1) 286 Frolovskii, V.A. (1) 326 Fromm,K. (1) 119 Fronczck, F.R (1) 567 Froyen, P. (1) 224 Fruchicr, A. (1) 266 Fly, J.V. (5 ) 273 Fryzuk, M.D. (1) 39,73 Fu, C. (6) 50 Fu, G.C. (1) 92,578 Fu, H.X. (1) 56 Fu, T.Y. (1) 370 Fuchs, P.L. (7) 36.37 Fuchs, S. (1) 204,205 Fiilop, F. (1) 399 Fuji, K. (1) 362; (6) 96 Fujii, A. ( 5 ) 5 Fujii, M. (5) 127 Fujii, Y. (8) 131 Fujimoto, T. (6) 32 Fujiwara, Y. (4) 260 Fukazawa, Y. (1) 362 Fukui, K. (3) 36; ( 5 ) 214.2 15 Fukushima, M. (6) 102 Furstc, J.P. ( 5 ) 250,279,280

Gaertner, P. (4) 80 Gage, D.A. (5 ) 305 Gait, M.J. ( 5 ) 146, 147,209 Gal, Y.-S. (1) 412 Galanopoulos, T. (4) 25 Galazzi, M.C. (7) 144 Galconc, A. (5) 272 Galishev, V.A. (1) 313

Galkin, V.I. (1) 409.5 12; (8) 40 Gallaghcr, M.J. (4) 225 Gallazzi, M.C. (7) 137, 180, 181 Gallois, B. ( 5 ) 287 Galt, RH.B. (1) 25 1 Galvez-Ruano, E. (4) 1 18 Gamble, M.P. (4) 221 Gan, K.Z. (4) 299 Gancarz, R (4) 153 Gandour, RD. (4) 73 Ganesh, K.N. (5 ) 132,224 Ganeshan, K. (5 ) 95 Gancshpurc. P.A. (1) 220 Gangamani, B.P. (5) 132 Gani, D. (4) 23,24,6 I ; ( 5 ) 48 Ganoub, N.A.F. (6) 140 Gankr, B. (1) 138 Gao, J. (4) 158; (8) 89 Gao, RY. (8) 237 Gao, S. (6) 8 1 Gao, W. (8) 77 Gao, X.L. (5 ) 265,266 Garbay, C. (4) 202 Garbwma, I.A. (8) 144 Garcia, A. (7) 139 Garcia, C.D. (5 ) 43 Garcia, G.B. (8) 182 Garcia, J. (1) 327,328 Garcia, M. (6) 135 Garcia, RG. (5 ) 80 Garcia-Alonso, F.J. (7) 72 Garcia-Barradas, 0. (4) 201 Garcia-Granda, S. (1) 266; (8) 18 1 Gard, G.L. (4) 123 Gardinier, I. (2) 24 Gardon. V. (1) 259 Garnett, M.C. (7) 198 Garnovskii, A.D. (8) 106 Garrett, C.E. (1) 578

Gaspar, P.P. (1) 72,508 Gates, D.P. (7) 102 Gaumont, A.-C. (1) 141,231,470;

Gaus, H.J. (5 ) 107 Gautheron, B. (1) 5,496; (4) 224 Gautier, I. (4) 16 1 Gavrilov, K.N. (2) 2 Gavrilova, E. (I) 474 Gawdzik, B. (6) 119 Gclpke, A.E.S. (4) 90 Genet, J.-P. (1) 162; (4) 161 Genge, A.RJ. (1) 392 Genieser, H.G. (5 ) 62 Genkina, G.K. (4) 2 Gcnov, D.G. (1) 376 Geoffrey, M. (1) 473,'487; (8) 7,

GSC, M.-B. (4) 116

(8) 37

Author Index

129 Germann, M.W. (5 ) 261 Gerson, F. (1) 268 Gervasio, G. (3) 5 1 Gevrey, S. (8) 216 Gharbaoui, T. (3) 11; (4) 106 Ghassemi, H. (1) 347,348 Ghassemzadeh, M. (1) 449 Ghiviriga, I. (1) 256 Ghizzoni, S.B. (4) 170 Gi, H.J. (5 ) 18 Giacomelli, G. (4) 109 Gibbs, RA. (4) 277 Gibson, A.M. (1) 392 Gibson, D. (4) 259 Gibson, N.J. (5 ) 134 Gibson, S.E. (6) 169 Gibson, V.C. (1) 458 Gieray, R.A. (8) 218 Giesbrecht, G.R (1) 39 Gicse, B. (4) 85; (5) 150 Gil, J.M. (6) 107 Gil, R. (6) 169 Gilardi, R. (4) 234 Gilbertson, S.R. (1) 182, 207; (8)

Gill, F. (5 ) 253,254 Gilson, D.F.R (8) 45 Ginglinger, C. (2) 26 Girard, J. (5 ) 133 Giraudeau, A. (1) 404 Giver, L. (5) 302 Glabe, A . R (4) 170 Gladiali, S. (1) 159 Glania, C. (7) 12 Glaser, P.B. (1) 106 Gleiter, R (1) 94 Glaia, M. (7) 85,88, 127, 135, 149,

111

153-155, 157-162; (8) 36, 145, 202

Glick, G.D. (5) 2 12 Gloede, J. (2) 25; (4) 13 Glueck, D.S. (1) 139,485 Glukhovtscv, M.N. (1) 605 Gmeher, J. (1) 425; (5 ) 270 Gnanou, Y. (4) 270 Goddard, R. (1) 8 Godfrey, S.M. (1) 226,228; (8) 195 Goldenitz, J. (7) 12 Goller, A. (1) 555-557; (3) 13 Goerg, M. (1) 153 Goerlich, J .R (1) 325,526; (8) 18 Goerls, H. (1) 59; (8) 162 Gocsmann, H. (7) 9 Goetz-Grandmont, G.J. (1) 369 Goldberg, I.H. ( 5 ) 266 Goldstein, B.M. (5 ) 58,59; (8) 76

Golemmc, G. (7) 132 Gololobov, Y.G. (1) 218; (6) 15; (8)

Gomez, E. (7) 13 9 Gomez, F. (7) 139 Gomez, M.A. (7) 139 Gomez-Elipe, P. (7) 147 Gomez-Forncas, E. (1) 39 1 Gomez-Paloma, L. ( 5 ) 272 Gomtsyan, A. (4) 105 Gonen, 0. (8) 114 Gonera, G. (4) 172 Gonzales, C. (5 ) 173 Godlez, A. (7) 29 Gonzalcz, P.A. (7) 147

Gonzalcz Sicrra, M. (1) 368 Good, L. (5 ) 128 Goodwin,N.J. (1) 189, 190 Gopalakrishnan. J. (8) 90 Goppola, G.M. (6) 151 Gorbunowa, E. ( I ) 6 17; (8) I03 Gorichko, M.V. (1) 53 Gorin, B.I. (4j 168 Gorls, H. (1) 7 Gosain, A. (1) 389 Gosney, I. (1) 552; (4) 4; (8) 42 Gosselin, G. (5) 19,66 Gotfredscn, C.H. (5 ) 260 Goto, M. (4) 62 Goto, T. (7) 1 I0 Gotschy, B. ( I ) 425 Gottikh, M.B. ( 5 ) 144 Goubitz, K. (1) 173; (4) 90 Goudreau, P.N. (5 ) 294 Gougoutas, J.Z. (1) 252; (4) 209 Goumri, S. (8) 104 Gounev, T.K. (8) 14 Gouverneur, V. (4) 187 Gouygou, M. (1) 565,566,579 Grabowski, G. (4) 172

44

Go~Icz-BcI~o, C. (4) 126

Gracqk, P.P. ( I ) 373-375; (4) 210, 253; (8) 191

Graff, D. (5) 108 Graingcot, V. (4) 29 Graja, A. (1) 426 Gramlich, V. (6) 162 Granbcrg, K. (1) 260 Granell, J. ( I ) 270 Granik, V.G. (4) 75 Grant, D. (5) 203 Grasby, J.A. (5 ) 180,253,254 Grassi, A. (7) 134; (8) 35 Gravcs, D. (4) 25 Gray, G.N. ( 5 ) 157 Gray, M. (1) 360 Grebe, J. (7) 65

351

Green, D. (4) 146,171,179 Greig, M.J. (5) 155,296 Grenier, 1. (1) 419 Greniser, J. (6) 133 Grculich, K.O. (5 ) 81 Grev, RS. (1) 508 Grey, C.P. (8) 62 Grifantini, M. (8) 76 Griffcy, R.H. (5 ) 155,296,3 1 1 Griffin, RG. (8) 122 Grifith, 0. (4) 43 Grigolini, L. (7) 200 Grikina, O.E. (8) 19 Gnmaldi, S. (4) 270 Grim, s. ( 5 ) 99 Grishchcnko, A.E. (7) 136 Grishlixn, E.V. (1) 3 10 Gritsenko, O.M. (5) 164 Grivet, C. (2 ) 26 Grobc, J. (1) 192,476,482,510 Groger, H. (1) 325; (4) 107 Grocncwold, G.S. (7) 141; (8) 229 Grollman, A.P. (5) 262,263 Gromova, E.S. (5) 164 Gross, A. (6) 54 Grosse, A.C. (3) 7 Grosse-Sommer, A. (7) 20 1 Grossmann, G. (1) 380; (8) 18 Grote, C.W. (4) 112 Grozinger, C. (8) 77 Grubbs, RH. (1) 5 1,230 Griin, M. (7) 7 Griinefeld, J. (1) 43 1 Gruetzmachcr, H. (I) 489; (6) 20 Gnmcich, J.A. (7) 145 Grunze, M. (7) 194 Gryaurov, S.M. (5) 118 Gymova, T.V. (1) 598; (3) 53

Gu, X. (7) 142 Guan, J. (1) 390 Gudal, D. (1) 503,543,548; (6) 67;

Gudima, A. ( 1) 4 18; (6) 60 Gudina, N.N. (8) 200 Gukguen, C. (1) 332-334; (4) 184;

Gucnot, P. (1) 470; (8) 37 Gucrin, C. (1) 17 Gucrra, M. (1) 488 Guglielmi, M. (7) 153-155 Guhrs, K.H. ( 5 ) 8 1 Guillemin, J.-C. (1) 462 Guillcn, F. (1) 357 Guillcrm, G. (4) 138 Guinosso, C.J. ( 5 ) 155 Guionneau, P. (1) 322

Gu, Q.-M. (4) 40

(8) 38

(5 ) 205; (6) 113, 114, I I6


Gullyacva, Zh.R (1) 373; (8) 200 Gunduz, N. (7) 86 Gunzner, J.L. (4) 80 Guo, C. (1) 66; (8) 244 Gupta, K.C. (5) 227,23 1 Gupta, N. (1) 298 Gupta, R (1) 298 Gupta, S. (1) 536; (3) 57 Guran, C. (7) 94 Gurudutt, V.V. (8) 76 Gusarova, N.K. (1) 40-42 Gusev, D.V. (3) 20; (8) 164 Guske, W. (7) 54 Gut, I.G. (5 ) 303 Gutteridgc, S. (5 ) 3 12 Guy, A. (5 ) 175, 176 Guymer, N.K. (1) 392

G m a n , A. (4) 1 ~ C V , A. ( 5 ) 206-208,238

Haag, D. (1) 45 Haber, S . (1) 555; (3) 13 Hackney, M.L.J. (1) 129 HadZicld, P.S. (1) 25 1 Hadi, G.A.A. (1) 1 19 Haeberlcn, U. (8) 53 Haeberli, P. (5) 99 Haegele, G. (6) 101 Hassgcn, D. ( I ) 499 HaK, L.A. (3) 37; (5 ) 2 17 Hagcn, V. (5) 49 Hager, A.J. (5 ) 282 Haginoya, N. (5) 168,170 Hahn, F.E. ( I ) 54 1 Haiduc, I. (8) 32 Haigh, D. (4) 183,252 Hall, C.D. (3) 8; (8) 203 Hall, J. (5) 240 Hall, L.D. (4) 2 17 Hallgren, C. (6) 139 Haltiwanger, R.C. (1) 129 Haly, B. (5 ) 158 Hamada, Y. (1) 68 Hamilton, A. (5) 134 Hamm, M.L. ( 5 ) 167 Hammer, RP. (5) 100, 101 Hammerschmidt, F. (4) 77, 157 Hammond, G.B. (4) 140 Hampel, A. ( 5 ) 252 Han, B.-H. (4) 16 H a , L.-B. (4) 240 Hanaoka, K. (5 ) 6 Hanawalt, E.M. (1) 34 Hanci, W. (4) 10 1 Hancock, W.S. (5 ) 292 Handel, H. (2) 24

Haner, R. ( 5 ) 240 Hanessian, S. (1) 260; (4) 105,220 Hanrahan, J.R (4) 191; (8) 78 Hans, J.J. (4) 11 1 Hansen, H.J. (6) 154 Hara, R (1) 35 Harden, C.S. (8) 220-222 Harder, S. (6) 57 Hardmg, 1.S. (1) 234 Hardt, W.D. (5) 250

Harindranah, N. (5) 89 Harms, A.C. ( 5 ) 293,294 Harms, K. (7) 4,9 Harney, D.W. (6) 130 Harris, RK. (1) 368 Harrod, J.F. (1) 114 Hartmann, B. ( 5 ) 269 Hartmann, E. (8) 198 Hartmann, F. (7) 63, 64; (8) 171,

Hartmann, RK. (5 ) 250 Hartsel, S.A. ( 5 ) 3 1 Haruna, M. (4) 113 Harvey, P.J. (1) 248 Hasan, A. (5) 73 Hasbrouck, L.J. (1) 242; (8) 105 Hasenfralz, C. (7) 42,64; (8) 172 Hassan, A.E.A. (6) 131 Hassclgrcn, C. (1) 452 Hasslcr, K. (I) 95,96 Hatam, M. ( I ) 325 Hatana, K. (1) 68 Hausen, H.-D. (1) 99, 100, 102 Hausler, T. (1) 91 Hayakawa, K. (3) 9 Hayakawa, S. (1) 342 Hayakawa, T. (7) 108 Hayakawa, Y. (3) 25 Hayase, T. (4) 2 19 Hayashi, S. (6) 123 Hayashi, T. (1) 183 Hayes, H. (4) 43 Hayncs, RK. (1) 330,33 1 Hma, B.G. (6) 91

Hargcr, M.J.P. (4) 247-250

172

He, H.-W. (8) 46 Hc, L.-N. (1) 43; (8) 100, 185

He, S.-J. (8) 97 Hc. M. (8) 2 17

Hc,X.(8)217 He, Z.J. (4) 74 Hebbold, M. (1) 477 Hecht, S.M. ( 5 ) 233,244 Hcck, H. (6) 9 Hcckcl, M. ( I ) 76; ( 5 ) 161 Hcckmann, G. (1) 99, 100, 102,

617; (6) 34,61; (8) 103

Hcgemann, M. (1) 482 Hcgg, L.A. (5 ) 25 1 Hcim, U. (1) 489; (6) 20 Heinemann, F. (1) 584 Hcinicke, J. ( I ) 13-15; (8) 128 Held, H. (4) 52 Hclcne, C. (5 ) 221 Hcmberger, P.H. (8) 219 Hcmling, H. ( I ) 3 1 Henary, M. (8) 148 Hendan, B.J. (1) 89 Henderson, W. (1) 189, 190, 290;

Hcndnx, C. (5 ) 156 Henner, B.J.L. (1) 17 Hennig, L. (4) 58 Hennig, R (1) 465-467; (8) 169 Hcnningfeld, K.A. ( 5 ) 233 Hennink, W.E. (7) 193 Henry, Y. (7) 105 Hcrbcrhold, M. (7) 96 Hcrbst-Irmcr, R (8) 63,197 Hcrd. 0. (1) 90,203 Hadcwijn, P. (5 ) 136,156,159,164 Hcrlingcr, A.W. (4) 264; (8) 142 Hcrmann, P. (4) 263 Hcnnes, R (7) 166 Hcrnandez-Laguna, A. (4) 118; (8)

Hcrrcros, M. (1) 277 Hcmnann, G.F. (4) 57 Hcmnann, W.A. (1) 286 Herschlag, D. (5 ) 255 Hersh, W.H. (3) 19 Hessler, A. (1) 28,90,203 Hesslcr, G. (1) 147 Heus, H.A. ( 5 ) 275 Hcuser, A. (4) 65 Heydt, H. (1) 472,555,557; (3) 13 Hey-Hawkins, E. (1) 62, 74, 115,

Hibbs, D.E. (1) 21,516,588,589 Hickman, D.T. (1) 127 Hidaka, J. (5 ) 127 Hicmstra, H. (4) 90 Higashi, M. (4) 97 Higashijima, T. (1) 161; (3) 46 Higuchi, H. (6) 153 Hii, K.K. (1) 178; (8) 96 Hildbrand, S. (5 ) 185 Hill, A.F. (1) 492,5 15, 5 16 Hill, D.R (1) 24 I Hill, F. (5 ) 288 Hill, L. (1) 4 17; (6) 38 Hillcbrccht, H. (1) 489; (6) 20 Hindsgaul, 0. (6) 139 .

Hingst, M. (1) 203

(8) 213

23

119,304

Author Index 353

Hiraiwa, H. (6) 153 Hirata, M. (4) 32 Hirose, K. (1) 320 Hirose, T. (8) 2 1 Hirschbein, B.L. (3) 42; (5) 117 Hitchcock, P.B. (1) 2 I 1, 5 14, 576.

585-587, 613; (3) 55; (4) 214; (8) 99, 180

Hixon, M. (4) 52 Ho, D. (1) 423; (8) 146 Ho, H. (3) 33 Ho, N.H. (5) 104 Hobi, M. (6) 162

Hockless, D.C.R (1) 200,558 Hockova, I). (5) 15-17 Hdglunson, M.M. (8) 24 1 Hodgson, P.K.G. (1) 552; (4) 4; (8)

Hocks, T.H.L. (4) 72 Hoffmann, A. (1) 5 17; (7) 96 Hoflinann, C. (5) 62 Hoffmann, H.M.R (6) 93 Hoffmann, J. (1) 555; (3) 13 Hoffmann, R (8) 9 1 Hoffmann, T. (8) 91 Hofinger, A. (4) 55 Hofmann, M. (5) 191 Hogan, M.E. (5) 258,259 Hogen-Esch, T.E. (1) 429 Hogrcfc, R.I. (5) 109 Hoic, D.A. (1) 92 Hokelek, T. (7) 86, 118 Holand, S. (1) 569 Holletz, T. (5) 69,70 Holmes, C.E. (5) 244 Holmes, RR (2) 3, 4, 27; (8) 41,

H m k , M. (5) 2 1-24

42

61,65 Holy, A. (5) 15-17,21-24,26,28 Holz, J. (1) 57, 177, 180 Honeyman, C.H. (1) 80; (7) 14; (8)

Hong, J.E. (4) 242 Hong, J . 4 . (1) 433; (4) 14 Hong,M.-C. (1) 158 Hong, S.B. (4) 287 Horde, W. (1) 37 Honma, T. ( 1) 25 8 Hooijschuur, E.W.J. (8) 246 Hopkins, P. (5) 237 Hopkins, S.A. (5) 43 Hopper, D.W. (4) 71 Hor, T.S.A. (1) 165 Horiuchi, T. (1) 160, 161; (3) 46,

48; (8) 139 Homes, J. (8) 198 Homozdiari, P. (4) 61

60

Horn, G. (7) 131 Horska, K. (5) 28 Horstman, S. (7) 61 Horwitz, E.P. (4) 264; (8) 142 Hossain, M.B. (4) 1 1 ; (8) 52 Hossain, N. (5) 156 Hosztafi, S. (1) 247 Hoveyda, A.H. (1) 148 Howard, J.A.K. (1) 458; (6) 5 Howard, S.T. (1) 275,276,281; (8)

Howell, B.A. (1) 400 Hoycr, D. (4) 285

Hu, D. (1) 584

Hu, P.F. (5) 297

Huang, H. (4) 283; (6) 40; (8) 84 Huang, M. (5) 133 Huang, R. (8) 214 Huang, T. ( I ) 43

I5

Hu, C.-L. (6) 90

Hu, L.-M. (8) 46

Hum, 2.-W. (6) 7

Hung, W.-F. (6) 49 Huang, W.4. (4) 27 I ; (6) 98 Huang, X. (6) 50 Huang, Y. (8) 45 Huang, Z. (4) 139 Huang, Z.H. (5) 305

Hubieki, M.P. (4) 73 Huc, I. (5) 188 Hudson, A. (1) 488 Hudson, H.R (4) 121 Hughes, I. (1) 434 Hui, K.N. (1) 174 H u h , P.G. (7) 34

Hunt, C. (5) 143 Hunt, J.T. (4) 188 Hunter, C.A. (5) 289,290 Hunzikcr, J. (5) 184 H m a n , B.T. (4) 248 Hursthousc, M.B. (1) 21,516,588,

589; (8) 59 Husken, D. (5) 240 Husman, W. (4) 146,171,179 Hussain, M.S. (4) 291 Husson, H.-P. (3) 11; (4) 106 Hustedt, E. (5) 237 Hutchens, T.W. (5) 308 Hutchinson, E.J. (5) 55,56 Hutchison, J.C. (7) 169, 170 Huttner, G. (1) 58,79,93,532 Hutton, G.P. (6) 1 10 Huy, N.H.T. ( I ) 533,534 Huynhdinh, T. (5) 77 Hwang, J.J. (7) 146; (8) 72

Huang, Z.-Z. (6) 50

Hung, S.-C. (4) 50,84

Hyatt, D. (8) 183 Hyla-Krispin, I. (1) 94 Hyrup, B. (5) 122

Iatscnko, A.V. (4) 12; (8) 190 Ibim, S.M. (7) 199 Ichikawa, J. (4) 119; (6) 86 Ichikawa, Y. (1) 468,469; (8) 166 Idc, H. (5) 63 Igau, A. (1) 193, 418, 495, 496,

Ignat'eva, S.N. (1) 324 Ignatiev, N.V. (1) 577 Ihara, T. (5) 219 Iida, A. (8) 189 Ikai, K. (8) 189 Ikcda, I. (1) 164 Ikcguchi, Y. (8) 242 Ikcyama, M. (7) 107 Illin, E.G. (1) 388; (6) 35, 36; (8)

Illicn, B. (6) 94 Imai, T. (3) 48 Imai, Y. (8) 139 Imamoto, T. (1) 170,267,320 Imbach, J.L. (5) 19,66 Immel, F. (1) 510 Imwinkclried, P. (5) 150 Inagalii, K. (1) 145 Ingram, J.C. (7) 141; (8) 229 Inoue, K. (7) 89,93 Inouc, Y. (4) 2 I9 Inubushi, Y. (1) 533,534; (4) 231;

Ionin, B.I. (1) 30; (8) 161 lonin, S.P. (1) 292 Ionkin, A.S. (1) 561 Isaia, F. (1) 226 Isamo, T. (7) 4 1 Iscki, K. (4) 92 Ishida, M. (4) 119; (6) 86 Ishii, K. (1) 435 Ishii, Y. (4) 62 Ishmacva,E.A. (1) 64,373,512; (8) 40,200,25 1

Isoda, S. (7) 68 Isomura, s. (4) 113 Itaya, T. (7) 89,93 Ito, K. (4) 113,216 Ito, S. (1) 258 Ivanov, C. (4) 243 Ivanovskaya, M.G. (5) 146, 147 Iverson, B.L. (5) 220 Ivonin, S.P. (1) 293 Iwai, S. (5) 179 Iwanc, K. (3) 36; (5) 215

571,572; (4) 224; (6) 60

106- 108

(8) 193


lwiisaki, G. (3) 9 Iycr, RP. (3) 33,34; (5 ) 90, 104

Jacobsen, C.S. (1) 16; (8) 163 Jncobsen, H. (1) 457 Jacobsen, J.P. (5 ) 260 Jacobson, M.K. ( 5 ) 48 Jndhav, V.R (5 ) 224 Jaeger, A. (1) 287 Jaeger, J.A. (5 ) 109 Jaeger, R (7) 2 Jagerovic, N. (1) 266 Jahn, K. (3) 43 Jakcman, D.L. (5 ) 6 1 James, T.L. ( 5 ) 264 Janaswamy, S. (7) 56 Janata, J. (7) 179 Janda, K.D. (4) 99,278 Jang, W.B. (4) 242 Janik, J.F. (1) 236 Jaikowska, J. (5) 14 Jaukowski, S. (1) 549,550; (4) 275;

Jansen, M. (8) 198 Jailssen, RA.J. (1) 308; (6) 8; (8)

Janssen, R.C. ( 5 ) 283 Jarvis, A.N. (4) 217,218 Jastorff, B. (4) 35; (5 ) 62 Jaszay, Z.M. (3) 8; (8) 203 Jaun, B. (7) 35 Jaworska-Maslanka, M. (5 ) 11 1 Jayaram, H.N. (8) 76 Jcanjean, M. (1) 569 Jcffery, J.C. (1) 198 Jeffery, W.A. (5 ) 303 Jckcl, A.P. (7) 100, 101; (8) 175 Jcllinek, D. ( 5 ) 28 1 Jclonck, S. (1) I19 Jcnkins, D.J. (4) 33,34 Jcnkins, I.D. (1) 248 Jcnkins, L.A. ( 5 ) 239 Jenkins, S.A. (7) 190,192 Jcnnings, S. ( 5 ) 28 1 Jcnsen, O.N. (5) 3 10 Jcromc, R. (1) 405; (6) 12 Jcskc, J. (1) 227, 305, 306, 477,

535; (2) 18; (8) 56 Ji, G.-Z. (7) 42 Ji, H. (1) 574 Ji, J. (5) 266 Jia, G. (1) 70 Jian, 1. (4) 197 Jiang, H. (4) 98 Jiang, J. (8) 244

(8) 256

140,141

Jiangbaucom, P. ( 5 ) 133 Jiao, X.-Y. (4) 86; (8) 86 Jin, R.-H. (1) 402 Jin, 2. (7) 36.37 Jindrich, J. (5) 26 Jiracek, J. (4) 189 Jiralcrspong, S. (4) 5 1 Jiritouzin. M. (4) 213; (8) 47 Jitaru, 1. (7) 94 Joanteguy, S. (1) 506; (8) 112 Jochcm, G. (1) 295,303,542,580;

(6) 23,25,26,28,29; (8) 54 Johari, G.P. (8) 208 Johnson, B.F.G. (1) 53 1 Johnson, K.J. ( 1 ) 400 Johnson, M.J.A. (8) 122 Johnson, RA. (5 ) 19,71 Johnson, S.E. (1) 302 Johnson, W.T. (5 ) 178 Johnston, M.V. ( 5 ) 3 12 Jolivct, A. (1) 17 Jolly, P.W. (1) 471 Jona, H. (1) 258 Jones, B.C.N.M. (5 ) 40 Jones, B.P. (4) 239 Joncs, C. (1) 492, 514-516, 588-

592; (8) 160 Jones, P.G. (1) 13, 14, 218, 227,

305, 306, 361, 380, 431, 477,

(4) 230; (6) 15; (7) 59; (8) 18, 44,48,56,92, 128, 167, 168

531,535,583; (2) 7, 16-18,25;

Jones, R.A. ( 5 ) 53 Joncs, R.C.F. (6) 173 Jones, S. ( 5 ) 180 Jones, W.D. (8) 76 Jordan, G. (1) 42 1 Jordan, J. (4) 289 Jorgcnscn, P.N. ( 5 ) 106 Jorgcnscn, T. (5 ) 9 1

Jouaiti, A. (1) 473,487; (8) 7, 129 Jouanno, C. (5 ) 116, 123 Jouini, A. (8) 143 Juaristi, E. (4) 20 1 Juckcr, F.M. (5 ) 274,275 Jugc, S. (1) 162,407 Jun, W. (4) 121 Jung, B. (1) 53 Jug , K.E. (5 ) 140 Jung, O.S. (7) 97, 195

Jungo, T. (5 ) 150 Jurig, A. (6) 120 Jwsic, B.S. (1) 217

JOSOW~CZ, M. (7) 176-179

Jung, Y.-G. (1) 433

Just, G. (3) 28-30; ( 5 ) 36 Jiang, Q. (1) 52,65,66 Jutand,A.(1)611

Juvinpedretti, V.M. (7) 106 Juwik, P. (1) 224

Kaasjager, V.E. (1) 173 Kabachnik, M.I. (1) 321,388,397;

Kaboudin, B. (4) 15 1, 174 Kacpcrcyk, W. (5) 11 1 Kaddwah-Daouk, R (4) 290 Kadushkin, A.V. (4) 75 Kadyrov, A.A.(2) 7; (4) 124 Kadyrov, R (1) 13-15; (8) 128 Kaeser, M. (1) 138 Kafmski, P. (4) 153, 180 Kaka, S. (6) 141 Kahn, 0. (1) 322 Kajiwara, M. (7) 75, 187,188 Kajiyama, K. (8) 196 Kakkar, V.V. (4) 146,171,179 Kalbitzer, H.R (8) 91 Kalchcnko, 0.1. (4) 15; (8) 236 Kalchenko, V.I. (4) 12,15; (8) 190,

Kalgutar, R (1) 561,563; (8) 109 Kalinichenko, E.N. (5 ) 67,68 Kalinkina, A.L. (3) 26 Kalisch, B.W. (5 ) 261 Kallcn, J. (7) 40 Kaloun, E.B. (1) 162 Kalra, K.L. (3) 34 Kamberger, W. (6) 84 Kamel, A.A. (1) 222 Kamcpalli, S. (1) 568 Kamijo, K. (1) 545 Kaminski,O. (1)491 Kamiya, H. (5 ) 179 Kaneoka, K. (4) 226 Kaneshiro, E.S. (4) 279 Kancvskii, I.E. (5 ) 145

Kang, H.M. ( 5 ) 2 18 Kant, M. (4) 128 Kao, H.-M. (8) 62 Kappe, T. (6) 141 Karagiuosoff, K. (1) 97,456; (8) 68 Karman, R (4) 294; (8) 127 Karamfilov. V.K. (8) 232 Karclson, M. (1) 560 Kargin, Yu.M. (1) 202; (8) 200 Karimov, K.R (4) 244 Karlsson, A. (5 ) 4 Karlsson, S. (8) 154 Karpeisky, A.M. (5 ) 173 Karra, S.R (1) 135

(4) 2

236

Kang, B.-S. (1) 55, 158

Karsch, H.H. (1) 75-78,.81,541; (6) 17

Author Index 355

Kasashima, E. (1) 468; (8) 166 Kashacva, E.A. (8) 25 1 Kashevarov. S.V. (8) 137 Kashiwagi, T. (1) 347 Kasihara, M. (1) 435 Kasradze, V.G. (1) 84 Kataoka, M. (3) 25 Katiyama, K. (8) 125 Kato, M. (7) 75 Kato, Y. (3) 48; (8) 189 Katritzky, A.R (1) 256; (6) 121 Katti, K.V. (1) 134, 135, 191; (4)

245; (7) 10 Katti, S.B. (5) 142 Katzhcndlcr, J. (4) 294; (8) 127 Kaujinann, G. (1) 369 Kaufinann, T.S. (1) 255 Kaukorat, T. (1) 36 1; (2) 7; (4) 230;

Kaupp, U.B. (5) 49 Kavitake, B.P. (5) 213 Kawabaka, T. ( I ) 362 Kawahara, S. (5) 93 Kawai, G. (3) 35 Kawai, H. (4) 3 Kawamoto, A.M. (4) 133, 196 Kawanami, H. (1) 463,464 Kawasaki, S. (7) 167,168 Kay, J.Y. (7) 146 Kayushin, A.L. (5) 87 Kazankova, M.A. (1) 296,297,498,

Kazennova, N.B. (1) 1 18 Kazmierski, K. (7) 55 Kazuhiro, K. (6) 145 Ke, D.-Y. (7) 90-92 Keana, J.F.W. (4) 43 Keck, H. (1) 384,447; (8) 17 Kee, T.P. (1) 178; (8) 96 Keefc, A.D. (1) 234 Keeney, A. (4) 122 Keglevich, G. (1) 150, 354, 355,

(8) 92

559

383, 551, 561-564; (4) 228; (8) 109,156

Kehler, J. (5) 37,38, 105 Kehr, G. (8) 69 Keinan, E. (6) 136 Keisdcc, K. (6) 123 Keitel. 1. (4) 13 Keller, M. (1) 352; (7) 104 Keller, U. (1) 76 Kempe, R (1) 177 Kempe, T. (5) 89 Kenji, 0. (6) 96 Kennard, 0. (5) 287 KCMC~Y, G. (4) 108 Kennepohl, D.K. (2) 3

Kenny, J.W. ( 1 ) 574 Kent, M.A. (3) 38; (5) 232 KentUlcrnaa, H.I. (1) 384,447; (6)

Koogh, D.W. (8) 30 Kerbal, A. (1) 274,528 Kern, R (1) 58 Ken, W.J. (1) 87 Kemgan, F. (4) 227 Kersinski, RA. (1) 376 Kerth, J. (1) 595 Keraii, G.M. (1) 563,564; (6) 133;

(8) 109, 156 Kcssclring, R (5) 166 Keynes, M.N. (7) 34 Keyte, R (7) 24 Khaikin, L.S. (8) 19 Khalil, M.I. (8) 110 Khamnei, S. (5) 29 Khan, K. (1) 612 Khan, S.I. ( I ) 121; (8) 148 Khanipova, M.G. (2) 9 Khayat, A. (4) 25 Khazicva, L.R. (8) 207 Khiar, N. (1) 3 I9 Khiat, A. (4) 28 1 Khilevich, A. (1) 254 Khlebnikova, T.B. (1) 84 Khodorliovsky, V. (6) 159 Khomutov, A.R (4) 177 Khomutov, RM. (4) 177 Khrustalev, V.N. (1) 443 Khurs, E.N. (4) 177 Khusainova, N.G. (1) 597 Kiau, S. (1) 35 1-353 Kibardin, A.M. (1) 598; (3) 53 Kida, T. (1) 164 Kielbasinski, P. (4) 251; (6) 129 Kientz, C.E. (8) 246 Kiessling, L.L. (5) 7 Kharada, T. (1) 6 Kikuchi, A. (7) 1 1 1 Kilgour, D. ( I ) 552; (4) 4; (8) 42 Kilian, P.J. (4) 213; (8) 47 KiliG, A. (7) 86, 1 18 Kilic, Z. (7) 86,118 Kim, B. (6) 103 Kim, C.U. (4) 53 Kim, D.Y. (4) 163,233 Kim, K.B. (5) 52 Kim, K.D. (7) 114 Kim, K.M. (7) 97 Kim, S.H. (7) 36 Kim, S.J. (7) 114 Kim, T.V. (1) 323; (4) 262 Kimrnich, B.F.M. ( I ) I63 Kimura, E. (1) 175

9; (8) 17

Kimura, K. (4) 3 Kimura, T. (7) 52, 187, 188 Kimura, Y. (3) 9 Kindermann, M.K. (1) 13, 14; (8)

Kino, K. (5) 174 Kinoshika, T. (I) 362 Kirchmeier, RL. (7) 116, 117; (8)

Kirchner, J. (5) 237 Kirk, G.G. (1) 87 Kirklin, D.R (1) 372; (8) 209 Kirschenheutcr, G.P. (4) 288 Kirschning, A. (6) 120 Kiselcv, V.D. (8) 25 1 Kiscleva, E.I. (1) 323; (4) 262 Kishimoto, S. (4) 92 Kitamura, M. (4) 1.8 1 Kitamura, T. (4) 260 Kitano, K. (6) 132 Kitazumc, T. (6) 170 Kivekas, R (1) 22, 199,387 Kiyoshi, T. (6) 96 Klapokc, T.M. (8) 33,34 Klkck, A. (6) 141 Klaus, U. (1) 608 Klciner, H.-J. (1) 285,286 Klem, RE. (5) 109 Klcss, A. (1) 57,177 Klingenberg, E.H. (7) 184 Klingcr, C. (1) 542; (6) 28; (8) 54 Klinger, J. (8) 240 Klinkhammer, E. (1) 138 Klinowski, J.J. (8) 67 Klintschar, G. (1) 95 Klootwijk, A. (1) 471 Klopchm, P.G. (5) 97,98 Klose, G. (8) 53 Kloss, M. (1) 14 Klug, A. (5) 286 Klug, C.A. (8) 11 1 Klussmann, S. (5) 279,280 Knayev, V.N. (1) 420 Knies, w. (7) 54 Knight, D.A. (1) 206; (4) 293 Knight, D.J. (5) 50 Knobler, C.B. (1) 302 Knoch, F.A. (1) 312; (3) 24; (7) 20;

Knochcl, P. (1) 33,44,209; (3) 6 Knoll, C. (8) 2 1 1 Knouzi, N. (1) 484 Knowles, P.J. (8) 10 Knowles, S.K. (5) 109 Kobayashi, T. (7) 68 Kobayashi, Y. (4) 92 . Kobcrtz, W.R (3) 40; (5) 192

128

58

(8) 74


Kobuyashi, 1. (6) 153 Koch, K.A. (7) 18 Koch, R (4) 256 Kockritz, A. (4) 128 Kodama, Y. (1) 175 Kocnig, M. (1) 122; (4) 269 Kcesling, M. (1) 13; (8) 128 Koessler, J.L. (7) 41 Kostler, W. (1) 109 K o f d , T. (5) 115,149 Koga, K. (6) 97 Koidan, G.N. (8) 6 Koide, T. (1) 445 Koike, T. (I) 175 Kois, P. (5) 2 16 Kojima, M. (7) 140 Kojima, S. (6) 78; (8) 124, 125, 196 Kolczak, U. (1) 364 Kolesnik, V.D. (4) 166 Kollcger, G.M. (1) 95 Kolodiazhnyi, 0.1. (1) 3 10 Kolomeitscv, A.A. (1) 153; (6) 37 Komarov, I.V. (1) 53 Komarova, L.I. (8) 144 Komiyama, M. (3) 35; (5) 249 Kong, M.S. (4) 163 Kon'kin, A.L. (8) 137 Konno, T. (6) 170 Konovalov, A.I. (8) 207,2 10,25 1 Konovalova, I.V. (2) I , 9; (3) 2 Kon'shin, M.Y. (8) 16 Kooijman, H. (1) 172,474 Kool, E.T. (5) 96, 171 Koptyug, I.V. (1) 365 Korcynski, D. (5) 1 1 1 Korkin, A.A. (1) 500; (8) 6 Korncr, S. (5) 150 Kornilov, M.Yu. ( I ) 53 Korobka, A. (5) 262,263 Korobko, V.G. (5) 163 Korosteleva, M.D. (5) 87 Koroteev, A.M. (3) 14 Koroteev, M.P. (3) 14; (4) 82 Korshun, V.A. (5) 225 Kosachev, I.P. (4) 103 Kosch, W. (5) 87 Koshinuma, M. (8) 139 Kosma, P. (4) 55 Koster, H. (5) 300 Kostitsyn, A.B. (1) 472 Kotov, S.V. (4) 143, 144; (6) 99 Kouf'aki, M. (5) 1 Kourkine, I.V. (1) 139 Kovacs, I. (1) 37,544 Kovalev, V.V. (1) 388; (6) 35, 36;

(8) 107, 108 Kovk, M. (6) 141

Kozai, T. (7) 52 Kraatz, H.-B. (8) 30 Krabbenhoft, H.O. (1) 246 Krachmcr, R. (4) 57 K r h e r , P. (7) 12 Kracmcr. R. ( I ) 149 Kragl, U. (4) 57 Krajewska, D. (5) 10 Kral, V. (5) 220 Krannich, L.K. (1) 108 Kranz, M. (6) 108 Krasmski, A. (5) 14 Krause. E. (5) 49 Krause, W.E. (7) 78 Krauter, J.G.E. (1) 157 Krautschcid, H. (1) 37 Krawczyk, H. (4) 117 Krawiecka, B. (4) 28 Krayevsky, A.A. (5) 66,78 Krebs, B. (1) 192,476,5 10 Krebs, F.C. (1) 16; (8) 163 Krcimeyer, A. (5) 77 Krejmva, R (5) 28 Krepinsky, J.J. (5) 234 Kr&chmann,M. (7) 81,82; (8) 174 Kretzschmar, G. (3) 43 Kreutz, O.C. (8) 73 Kreutzbergcr, C.R (7) 19 Krieger, M. (7) 4 Krill, J. (2) 16; (8) 168 Krill, S. (1) 567,594; (3) 56 Krishnamurthy, S.S. (2) 15 Krivchun, M.N. ( I ) 30; (8) 161 Krogh-Jespcrsen, K. (4) 78 Krol, S. (1) 426 Krot0,H.W. (1)211 Krotz, A.H. (5) 97.98 Krudy, G.A. (4) 279 Kruegcr, K. (1) 380; (8) 18 Krugcr, C. (1) 147,284, 457,483;

Kruger, V. (1) 67, 144.3 15 Kubiak, R.J. (4) 44 Kubono, K. (7) 68 Kuchen, W. (1) 384,447; (6) 9; (8)

Kucherenko, A. (1) 254 Kudrevich, S.V. (4) 127 Kudrin, Z. (8) 205 Kudyravtsev, V.Y. (8) 207 Kiihl, 0. (1) 74 Kuehnle, F.N.M. (7) 35 Kucng, E. (4) 59 Kiinzcl, A. (1) 504 Kuhnel, M. (1) 90 Kuimelis, RG. (5) 222,246-248 Kukharcva, T.S. (3) I5

(8) 165

17

Kuklcv, D. (6) 135 Kukovincts, O.S. (1) 84 Kulichikhin, V.G. (7) 136 Kulickc, K.J. (5) 150 Kulkami, S. (5) 3 10 Kumamoto, T. (6) 97 Kumar, A. (5) 142 Kumar, P.K.R (5) 227, 231, 245,

Kumar, P.T. (6) 9 1 Kumar, V.A. (5) 132 Kumaraswamy, S. (4) 150 Kununcr, M. (7) 11 Kummcr, S. (1) 584 Kumobayashi, H. (3) 48 Kunalh, A. (4) 13 Kunze, T. (4) 185 Kuo, L.Y. (5) 8 Kupka, T. (8) 59 Kurakata, S.-i. (4) 54 Kurata, T. (4) 3 Kurdjukov, A.I. (4) 272 Kurdyumova, N.R (4) 115 Kurita, J. (1) 6 Kuroda, A. (1) 362 Kuroki, Y. (4) 92 Kustos, M. (1) 185 Kutytev, A.A. (1) 221; (2) 6; (3) 1 Kuuscla, S. (5) 238 Kuylycheskiely, E. (5) 135 Kumclsova. S.A. (5) 145 Kuzuya, A. (3) 35 Kwiatkowski, M. (5) 85,86 Kwon, O.Y. (6) 103; (8) 27 Kwon, Y. (8) 27 Kwon, Y . 4 . (4) 27 Kyunkcl, LA. (8) 126 Kyuz, K.V. (I) 440

249

Labarre, J.-F. (7) 66,67, 115 Labarre, M.-C. (7) 66.67, 115 Lacassin, F. (8) 104 La Colla, P. (8) 76 Lacour, J. (2) 26 LQe, M. (I) 192,476,510 Lafuente, C. (8) 149 Lagier, C.M. (1) 368 Lahti, P.M. (1) 563; (8) 109 Laing, J.C.P. (1) 152 Lake, C.H. (1) 108,110,112 Lakoba, E.I. (1) 201

Lam, F. (1) 176

Lamartine, R (6) 70 . Lamb, S. (6) 5

Lallo~, M.-N. (4) 187

Lam, W.W.-L. (1) 330.33 1

Author Index 357

Lambropoulos, N. (8) 238 Lammertsma, K. (1) 567 Lampe, D. (4) 3 1 Lampe, T.F.J. (6) 93 Lamprecht, A. (1) 268 Lance, M. (1) 575 Landegrcn, U. (5) 85,86 Landini, D. (7) 68 Landis, C.R (1) 163 Landrock, A. (8) 233 Lang, H. (1) 532; (6) 121 Lange, H. (1) 94 Langen, P. (4) 284 Langer, F. (1) 33 Langcr, R.S. (7) 19 1 Lao, X.-F. (1) 210 Lapina, N.N. (8) 144 Lappe, P. (1) 285,286 Lappcrt, M.F. (8) 180 Lapteva, L.I. (8) 207,210 Larocquc, A. (4) 28 1 La Rosa, C. (6) 82 Larrk, C. (1) 263; (4) 20 Larrier, D. (7) 199 Larsen, B.S. (5) 3 12 Larsen, J. (8) 163 Larsen, P.S. (I) 16; (8) 163

Laschi, F. (7) 79 Lash, R.P. (8) 119 Lassallc, L. (1) 462 Latham, J.E. (6) 142 Latscha, H.P. (6) 21; (8) 188 Lau, W.L. (4) 43 Laugaa, P. (5) 228 Launay, N. (4) 17; (7) 87 Laurencin, C.T. (7) 199 Lauterbach, C. (8) 198 Lavenot, L. (1) 13 1 Lavey, B.J. (4) 99 Lawless, G.A. (1) 576 Lawless, L.J. (1) 253 Lawrencc, A.J. (5) 30 Lawrence, M.R (4) 209 Lawrcncc, N.J. (6) 2 Layland, N.J. (1) 25 1 Lazraq, M. (1) 274 LeBlanc,B.(1)217 Lebuis, A-M. (1) 1 14

L i d g ~ c , M.-L. (4) 19

Lee, B.-Y. (4) 237 Lcc, C.-W. (6) 107 Lee, D.Y. (7) 114 Lee, H. (7) 114 Lee, H.H. (4) 14 Lee, H.M. (1) 70 Lee, K. (4) 163 Lee, M.L. (7) 189

Lee, s. (1) 3,4; (7) 97 Lee, S.B. (1) 433 Lcc, S.Y. (4) 242 Lee, V.Y.R (1) 223; (8) 26 Lee, Y.A. (7) 97 Lccper, F.J. (4) 126 Lecson, P.D. (3) 5; (4) 193 Lefcbcr, C. (1) 177 Lcfcbvrc, A. (5) 269 Lefevre, V. (1) 506; (8) 112 Lc Floch, P. (1) 508, 603, 607,

Leglovan, M.P. (7) 206 Lc Goastcr, C. (1) 50. 142 Lc Golvan, M.P. (7) 203,204 Legoupy, S. (1) 462 Legrand, C. (1) 5 Lehncrt, H. (7) 49 Leininger, S. (1) 483; (8) 94, 165 Leis, J. (1) 560 Leisc, M. (1) 532 Lcjczak, B. (4) 153 Lcrnan, J.T. (I) 121 L e M e ~ , C . ( i ~ 3 1 5 Lemcnovskii, C.A. (I) 1 18 Lemmouchi, Y. (7) 130 Lc Moignc, F. (4) 297; (8) 134 Lcont'cva, I.V. :6) 35, 36; (8) 107,

Leost, F. (4) 255 Lequeux, T.P. (4) 136, 141 Lemer, RA. (4) 186 Leroy, J.L. (5) 267,268 Lescot, E. (5) 269 Lescrinier, E. (5) 156 Lesiak, K. (5) 59,60 Lesnik, E. (5) 155 Lcsnikowski, Z. (5) 1 1 1 Lcsvier, M. (1 1 470; (8) 37

609-611,615; (3) 52

108

L C U ~ ~ I U I , C.J. (5) 183-185 hung, P.-H. (I) 165-168 Lcung, w.-P. (1) 1 1 1 Le Van, D. (1) 476,482,5 10 Lcvsen, S.M. (1) 430; (4) 104 Lcvy, K. (5) 99 Lcw, B.M. (1) 139 Lcwkowski, J. (4) 172, 173 Lezourct, P. (1) 4 19 Li, B. (1) 574; (4) 16 Li, C. (1) 282 Li, D.-G. (1) 123, 124; (8) 113 Li, J. (7) 10, 11, 176, 179 Li, J.J. (1) 171; (4) 261 Li, L. (5) 3 13 Li, L.-P. (1) 223; (8) 26 Li, R (1) 384 Li, S.-L. (1) 213; (6) 14; (8) 187

Li, W. (4) 53 Li, X. (1) 72,408 Li, Y.-M. (4) 16 Li, Y.Z. (5) 300 Liable-Sands, L.M. (1) 106, 236,

485; (7) 102 Liang, M. (7) 102 Liao, R-A. (8) 93 Liboska, R (5) 25 Lichtenwaltcr, K. (5) 292 Licbman, J.F. (1) 372; (6) 209 Lillet, D. (4) 100 Lim, C. (5) 143; (8) 25 Limbach, H.H. (7) 38; (8) 253 Limbnch, P.A. (5) 304 Lin, C.-H. (4) 280 Lin, K.-J. (1) 223; (8) 26 Lin, K.Y. (5) 119 Lin, L. (1) 254 Lin, W.O. (8) 182 Lindcnberg, F. (1) 62 Lindhorst, T.K. (6) 139 Lindley, C.J. (4) 30 Lmdner, E. (1) 287,593; (3) 54; (8)

Lindsay, A.J. (7) 105 Linti, G. (1) 109 Lipkowitz, K.B. (7) 134, 135; (8)

Lipkowski, J. (4) 12, 15; (8) 190,

Litinar, K.E. (1) 244 Little, D.K. (4) 188 Little, D.P. (5) 299,300 Litvinov, I.A. (1) 416; (6) 16 Liu, B. (6) 7 Liu, C. (4) 3 1; (8) 214 Liu, C.L. (5) 293 Liu, F. (8) 214 Liu, H. (4) 53; (8) 214 Liu, H.-L. (1) 428 Liu, H.-Y. (4) 223 Liy J. (1) 254 Liu, L. (1) 43 Liu,N. (7) 167, 168 Liu, P.Z. (7) 189 Liu, Q. (1) 55 Liu, Q.-T. (1) 158 Liu, RQ. (6) 122 Liu, W.-Q. (4) 202 Liu, X.H. (5) 41,54 Liu, Y. (4) 16 Liy Z. (1) 370 Liy Z.-J. (8) 46 Livant, P.D. (1) 379 Livantsov, M.V. (1) Livonnicrc, H.D. (3) 3

157

35,36

236


Liyanage, S.S. (1) 197 Llamas-Botia, J. (7) 33 Llamas Saiz, A.L. (8) 178 Lloyd, J. (4) 188 LO, C.-H. (4) 278 Lo, L.-C. (4) 278 bakes, D. (5) 288 Lobana, T.S. (1) 389 Lobanov, D.I. (1) 321,397 Lochmann, T. (5) 137 LoeMer, J. (6) 74, 143 Loew, A. (1) 497; (3) 12 Logan, J.V.H. (4) 209 Loginova, I.V. (1) 409 Logunov, A.P. (1) 151,356 Loi, A.G. (8) 76 Loken, B.H. (1) 172 Lokshin, B.V. (8) 144 Lombardo, G.M. (7) 134, 135; (8)

Lornoro, G. (6) 166 Long, J.M. (1) 2 I Longato, B. (1) 396 Longeau, A. (1) 44,209; (3) 6 Longmire, J.M. (1) 46,49 Lonnbcrg, H. (5) 206-208,238 Loo, J.A. (5) 297 Lopez, M.C. (8) 149 Lopez, S. (6) 104 Lopez de Luzuriaga, J.M. (1) 205 Lopez-Lazaro, A. (1) 262; (8) 177 kpez-Leonardo, C. (7) 33 Lopez-Ortiz, F. (1) 346; (7) 26-28,

Lora, S. (7) 126,200 Lorenzo, A. (8) 178 Lorey, M. (5) 3 Lorin, C. (1) 259 Lork, E. (2) 20; (6) 37 Loughney, D.A. (4) 289 Lovat, P.A. (1) 127 Love, J.B. (1) 73 Lu, G. (1) 55

35,36

72

Lu, G.-T. (1) 158 Lu, H.-Y. (8) 230 Lu, R.-J. (4) 223

Lu, S.-M. (6) 49 Lu, S.J. ( I ) 56, 158

Lu, X. (1) 215 Lu, X.J. (5) 289,290 Lu, Y. (7) 192 Lube, M.S. (1) 63 Lucas, L.H. (4) 102 Luczak, J. (8) 205 Luczak, T. ( I ) 375; (8) 191 Ludanyi, K. (1) 383,55 I Luth, B. (1) 482

Lukashev, N.V. (1) 498,559 Lukcs, 1. (4) 263 Luna, A. (8) 2 16 Lundstroem, J. (4) 169,282 Luo, D.B. (5) 13 1 Lussignoli, S. (7) 200 Lust, D.A. (1) 252 Lustig, C. (6) 5 Lutz, F. (1) 147,457 Lutz, M. (6) 57 Luzikova, E.V. (1) 296,297 Ly, T.Q. (3) 18 Lynn, D.M. (1) 5 1 Lyon, D.K. (1) 132,133 Lyscnko, K.A. (3) !5 Lyuls, A.E. (4) 296; (8) 225 Lyzwa, P. (4) 190; (8) 205

Ma, D. (4) 197 Ma, K. (4) 286 Ma, X. (8) 214 Ma, Y. (2) 8 Ma, Z. (4) 197 McAulilTc, C.A. (1) 226,228,391;

Macca, C. (8) 206 McCarty, B. ( I ) 574 Macciantelli, D. (1) 488 McCloskey, J.A. (5) 298.3 11 McClurc, C.K. (4) 112 McCurdy, S.N. (3) 42; (5) 117 McDonald, M.A. (1) 558 Macdonald, P.M. (5) 95 McDonald, R (1) 126; (2) 28 Macdonald, T.L. (4) 71 McDowell, J.A. (5) 276 McElhanon, J.R (6) 90 McFarlane, W. (1) 29, 165, 167; (8)

McGarry, P.F. (1) 365 McGeorge, G. (1) 368 McGrath, D.V. (6) 90 McGrath, J.E. (1) 347-349; (8) 82 McGrath, T.D. (1) 453 McGrcgor, A. (5) 18 1 McGuigan, C. (4) 68; (5) 2, 4; (8)

Machado, I.L.F. (7) 88; (8) 202 McIver, RT. (5) 300 Mack, A. (1) 5 13; (8) 3 1 Mack, D.P. (5) 297 Mack, L.L. (7) 76 Mackcnzic, A. (4) 68; (8) 80 Mackewitz, T.W. (8) 94 McKittirck, B.A. (4) 286 Macko, L. (5) 150

(8) 195

79

80

McLafferty, F.W. (5) 299 McLaughlin, L.W. (5) 182, 222,

Macmillan, E.W. (5) 110 MacNicol, D. (7) 69 Macomber, RS. (4) 279 McPartlin, M. (1) 317; (7) 98; (8)

McPhail, A.T. (1) 237 Macridcs, T.A. (6) 130 Macshri, I. (6) 133 McSwiggen, J.A. (5) 173 Madhusudanan, K.P. (5) 142 Macda, H. (1) 444,445 Macda, M. (5) 204

Maffei, M. (4) 198 Mag, M. (3) 43 Magdalinos, P. (1) 616 Ma&, D.R (4) 209 Magull, J. (1) 449; (7) 4.9 Mahicu, A. (1) 496; (4) 224 Mahon, M.F. (4) 3 1 Mahran, A.M. (6) 144 Maia, A. (7) 68 Maichlc-MBssmcr, C. (1) 196,593;

(3) 54; (8) 157 Maier, D. (8) 240 Maier, L. (4) 295 Maigali, S.S. (6) 72,73 Maigrot, N. (1) 582,603 Maishinova, G.T. (1) 15 1,356 Maitra, K. (1) 140 Majoral, J.-P. (1) 149, 185-187,

193, 263, 418, 495, 496, 571,

223,246-248

173,183

Makl, G. (1) 465-467; (8) 169

572; (4) 17-20.224; (6) 60,69; (7) 87

Majumdar, A. (5) 59 Majmer, W.R (1) 374, 375; (4)

251; (6) 129; (8) 191 Mak, T.C.W. (1) 11 1, 174,219; (6)

14.68; (8) 187 Makino, K. (5) 63 Makioka, Y. (4) 260 Makleit, S. (1) 247 Makriyannis, A. (5) 1 Malakova, H. (8) 204 Malamidou-Xenikaki, E. (1) 244 Maldonada, L.A. (6) 92 Malenko, D.M. (2) 14 Malenkovskaya, M.A. (4) 67 Malik, A. (7) 189 Malik, K.M.A. (I) 5 16,588.589 Malkicwicz, A. (5) 154 Malley, M.F. (1) 252 Mallory, C.W. (6) 165 Mallory, F.B. (6) 165

Author index 359

Malloy, E. (4) 289 Malmstroem, T. ( I ) 184 Maloney, L. (5) 99 Malysheva, S.F. (1) 40,42 Mamacv, V.M. (8) 24 Manabc, S. (4) 88 Manalili, S.M. (5) 155,3 11 Manasova, E.V. (5) 225 Mandolini, L. (1) 450 Maniu, V. (8) 224 Manners, I. (1) 80; (7) 14-16, 102,

122, 125, 142, 143; (8) 60,83 Mano, S. (1) 161; (3) 46 Manorharan, M. (5) 189 Mansour, T.S. (5) 50 Mansuy, S. (I) 6 1 1 Mantoura, RF.C. (8) 232 M a , B. (1) 595,596 Mao, J. (1) 379 Mar, A. (1) 254 Marcantoni, E. (1) 329 Marchand, C. (1) 50,489; (6) 20 Marchcnko, A.P. (8) 6 Marchioro, C. (4) 94 Marco, C. (7) 139 Marck, J. (4) 213; (7) 77; (8) 47 Marfurl, J. (5) 183,184 Marindti, A. (1) 67, 144,3 14-3 16;

(4) 147; (8) 194 Mario, J.P., Jr. (6) 138 Markovskii, L. (1) 504 Markovsky, L.N. (4) 12, 15; (8)

Markus, A. (4) 57,58 Marriott, P.J. (8) 238 Marschner, C. (1) 25 Marshall, W.J. (1) 526 Marshall, W.S. (5) 31, 108 Marsilio, F. (7) 200 Marsmann, H.C. (1) 89

Martelli, G. (4) 152 Martens, J. (1) 325; (4) 107,222 Martens, R (1) 305 Martichonok, V. (4) 158; (8) 89 Martin, A. (7) 11 Martin, B. (1) 50 Martin, G. (1) 265, 460, 461; (8)

Martin, M.M. (I) 279; (8) 153 Martin, N. (6) 163 Martin, S.A. (5) 307 Martin, S.F. (4) 42

Martincz-Nunez, M. (1) 347 Marlin-Villamil, R. (6) 48 Maruo, Y. (5) 219

190,236

MarStokk, K.-M. (8) 151

254

M a r t i n - A l v ~ ~ ~ , P.J. (7) 175

Marvin, W.B. (5) 43,109 Marwood, R.D. (4) 33 M a , A. (5) 150 Marziano, I. (1) 576 Maslcnnikova, V.I. (3) 22 Masojidkova, M. (5) IG, 22-24,26 Masoumi, Z. (7) 142,143 Mass, G. (1) 595,596 Massa, W. (7) 5,6 Masscy, J.A. ( I ) 80 Massil, T. (1) 417; (6) 38 Masson, S. (4) 129 Mastryukova,T.A. (1) 321,397; (4)

Masuko, T. (7) 140 Mataka, J. (4) 45 Matem, E. (1) 37,544 Mathews, K. (6) 4 Mathey, F. (1) 454, 508,533,534,

569, 570, 582, 603, 607,

(8) 193

2; (6) 35,36; (8) 107, 108

609-611, 615; (3) 52; (4) 231;

Mathieu, S. (1) 484 Matlock, S.V. (6) 127 Matrosov, E.I. ( I ) 397 Matschiner, R (7) 12 Matsubara, H. (6) 153 Matsuda, A. (5) $6, 152, 168-170;

(6) 131, 132 Matsuda, S. (5) 174 Matsuki, H. (4) 119; (6) 86 Matsumoto, K. (4) 203 Matsumoto, S. (1) 445 Matsumura, K. (3) 48 Matsunaga, S. (3) 9 Matt, D. (I) 60 Matteoli, U. (1) 146 Mattcucci, M.D. (5) 1 19, 12 1, 177 Matthews, J.L. (7) 35 Matthews, RW. (8) 183 Matulicadamic, 1. (5) 172, 173,249 Matyjaszewski, K. (7) 128; (8) 176 Maufict, 0. (5) 269 Maury, C. (3) 11; (4) 106 M a w , G. (5) 19 Max, E.E. (5) 89 Maxwell, M. (4) 25 Maycr, A. (1) 423,446; (8) 146 Mayer, H.A. (1) 196,287 Maynard, D.F. (1) 344 Mazac, J. (1) 259 Mazhar-ul-Haque, M. (4) 29 1 Mazorati, L. (4) 208 Mbianda, X. (4) 116 Mcdici, A. (7) 85 Mcctsma,A. (3) 49; (7) 99, 101; (8)

175

Mchdi, A. (1) 537,538; (3) 59; (8)

Mei, H.Y. (5) 297 Meidine, M.F. (1) 21 1 Meier, C. (5) 3 Mcier, E.J.M. (4) 101 Meiscl, M. (1) 424 Meldgaard, M. (5) 160 Melcndez, F.J. (8) 11 Mclcnewski, A. (5) 199,201 Mcmegcr, W., Jr. (7) 43 Mcnchi, G. (1) 146 Mcng, Q. (1) 260 Mcng, S . 4 . (7) 74 Mcnger, F.M. (4) 70 Menger, M. (5) 256 Mcrcier, A. (4) 297; (8) 134 Mercicr, J.-P. (8) 247 Mercier, R (1) 349; (8) 82 Merckling, F.A. (4) 101 Mcrcuri, M.L. (1) 226 Mcrdcs, R. (1) 162 Mcrifield, E. (1) 12; (3) 45 Mcrk, B. (6) 21; (8) 188 Mcrkoci, A. (8) 206 Merkulov, AS. (1) 181 Merten, H. (8) 233 Mcshkov, S.V. (3) 14; (5) 159,162.

Mctail, V. (8) 112 Mcunicr, B. (5) 130.24 1 Meunier, P. (1) 193,496,571,572;

Mcyer, A. (5) 66 Mcycr, Y.H. (1) 279; (8) 153 Meycr zu Khker, R (7) 3 Miao, F.-M. (8) 88 Michalik, M. (1) 155 Michalski, I. (3) 27; (4) 28 Michcl, J. (5) 205 Michelin, RA. (7) 88; (8) 202 Middlemiss, D. (I) 87 Middleton, P.J. (5) 151 Midura. W.H. (4) 208 Mihai, C. (4) 45 Mikhailopulo, LA. (5) 67,68 Mikhailov, S.N. (5) 159, 162-164 Mikhel', I.S. (2) 2 Mikina, M. (4) 2 10,253 Mikolajcqk, M. (1) 373-375; (4)

190,208,210,25 1,253; (6) 129; (8) 191

64

163

(4) 224

Milius, W. (7) 96 Miller, B.E. (1) 133 Miller, D.H.J. (1) 249 Millcr, J .R (1) 198 Miller, RW. (1) 518,519


Munyancza, A. (1) 599 Murano, T. (4) 134, 135; (6) 100 Muraoka, K. (7) 93 Murata, S. (1) 212; (6) 1 1 Murphy, C.T. (4) 30 Murray, J.B. (5) 286 Murray, K.K. (5) 291 Murray, M. (8) 115 Murthy, G.S. (7) 56,57; (8) 55 Mumgavel, R (2) 15 Musaev, D.G. (8) 122 Musiani, M. (7) 155 Musicrforsyth, K. (5) 100,101 Musin, RR (1) 416; (6) 16 Musin, RZ. (1) 136 Musker, W.K. (1) 280; (4) 170 Mustalumov, E.R (1) 415,416; (6)

Mu& J. (3) 43 Mulhini, S. (3) 38; (5) 232 Myshakin, E.M. (8) 24 Myuller, K. (1) 512; (8) 40

16

Miller, W.K. (1) 132, 133 Mills, O.S. (6) 127, 128 Mills, S.J. (4) 26 Milosavljevic, E.B. (1) 574 Min, C.H. (5) 190 Min, D. (7) 80 Min, Y.K. (6) 103 Minami, T. (4) 119; (6) 86 Minkhadzhldinova, D.R (8) 138 Minowa, T. (4) 178 Minto, F. (7) 85,127, 149, 157-162;

(8) 145 Miquel, Y. (1) 57 1 Mirkin, C.A. (1) 88 Mironov, V.F. (2) 1,9; (3) 2

Miroshnikov, A.I. (5 ) 87 Mirzabekov, A.D. (3) 37; (5) 217 Mischchcnko, N. (1) 414; (6) 13 Mishra, P.K. (4) 112 Mishra, S.P. (1) 448; (8) 132 Misiura, K. (5) 45; (8) 49 Mitani, M. (1) 435 Mitchell, H.J. (1) 332; (6) 114, 115 Mittakanti, M. (1) 229 Miura, S. (6) 132 Miura, T. (3) 48 Miyake, Y. (1) 240; (8) 133 Miyata, K. (7) 93 Miyoshi, K. (6) 62 Mizuno, H. (8) 189 Mizusaki, H. (7) 75 Mo, 0. (1) 277,278

Modro, A.M. (8) 98 Modro, T.A. (4) 7, 120; (6) 105; (8)

Mohlen, M. (7) 9 Moellcndal, H. (8) 15 1 Moller, M. (7) 44-46 Moeui, A. (1) 101 Mohamed, N.R (6) 144 Mohamed-Hachi, A. (4) 114, 130 Mohan, T. (7) 56 Mohan, V. (5) 155,158, 189 Mohebbi, A. (8) 114 Mohnot, K. (8) 255 Mob, B. (1) 51,230 Moinet, C. (1) 357 Mojtahedi, M.M. (6) 5 1 Mok, K.F. ( I ) 165, 167, 168 Mokeeva, V.A. (8) 126 Molenbcrg, A. (7) 44,45 Molin, H. (4) 204 M o l i P. (1) 261,262; (6) 149; (7)

33; (8) 177, 178 Molko, D. (5) 175,176

Mkoshnichenko, V.V. (1) 299-301

~oehizuki , r r . (1) 342; (4) 54

98

Moll, M. (1) 3 12; (3) 24; (7) 20; (8)

Mollcr, U. (5) 64 Monia, B.P. (5) 155 Moody, C.J. (4) 183,252 Moon. C.W. (4) 1 1 I Mwrhoff, C.M. (3) 7 Moors, E.H.M. (5) 275 Mootz, D. (7) 63,64; (8) 171,172 Moradci, O.M. (6) 106 Morales, B. (7) 172 Moralcs, E. (7) 17 I, I73 Moravcova, J. (1) 259 Moreau, S. (5) 205 Morel, E. (7) 105 Mori, I. (3) 9 Moriarty, RM. (4) 234,235 Morimoto, H. (7) 38; (8) 253 Morimoto, T. (1) 47 Morin, F.G. (8) 77 Morin, Ph. (8) 247 Morise, X. (1) 470; (4) 148; (8) 37 Morishima, H. ( I ) 258 Morita, H. (5) 63 Morita, Y. (7) 71 Moriya, K. (7) 75

Morken, J.P. (1) 148 Morohuma, K. (8) 122 Moms, A.D. (4) 206 Momsscy, C.T. (7) 13,202 Morse, K.W. (1) 229 Mortlock, A. (7) 39 Moskal, M.A. (4) 285 Moskva, V.V. (2) 6 Moss, RA. (4) 78,238 Motevalli, M. (1) 234 Motoyoshiya, J. (6) 123 Monon, M. (7) 88; (8) 202 Mphahlele, M.J. (4) 120; (6) 105 Mu, Y.Q. (4) 277 Muccioli, A.B. (7) 39 Muddiman, D.C. (5) 295 MiiUa,C.(1)531,577,583; (2) 19;

Mucller. D. (4) 57,58 Mueller, T.J.J. (6) 88 Miiller, U. (1) 1 15; (7) 8 Mujeeb, A. (5).264 Mukaiyama, T. (4) 273 Mulhearn, D.C. (1) 479; (8) 4 Mullah, N.N. (8) 95 Muller, G. (1) 76; (7) 105 Mullcr, H. (6) 160, 161 Mullcr, L.-P. (1) 305 Munoz, J.A. (1) 199,387 Munoz, W. (1) 46 1

74

Morim, J.-P. (8) 216

(8) 48,251

Nabiev, Sh.Sh. (8) 147 Nada, A.A. (6) 144 Naesens, L. (5) 4 Nagafbji, A. (4) 260 Nagata, K. (4) 260 Nagata, T. (4) 273 Nagatsugi, F. (5) 204 Nagel, S. (1) 90 Nagel, U. (1) 86 Nago, Y. (6) 102 Nair, C.P.R (7) 112 Nair, P.R (7) 112 Nair, V. (5) 5 1 Nakacho, Y. (7) 168 Nakagawa, A. (5) 169 Nakamoto, M. (8) 125 Nakamura, A. (8) 139 Nakamura, H. (7) 140; (8) 242 Nakamura, K. (I) 179; (4) 162; (6)

Nakamura, M. (4) 119; (6) 86 Nakano, H. (3) 10; (4) 131 Nakano, T. (3) 9 Nakashima, S. (5) 204 Nakatsuji, Y. (1) 164 Nakazawa, H. (6) 62 Nakhamanovich, AS. (1) 410; (6)

Namane, A. (5) 77 Namestnikov, V.I. (2) 12 Nanayakkara, V.K. (1) 447; (6) 9 Nanno. T. (1) 161; (3) 46 Napierala, M.E. (7) 164, 165

62

41

Aurhor Index 361

Nar, H. (7) 10 Narasaka, K. (I) 342 Narasimhamurthy, S. (2) I5 Nardin, G. (6) 66 Naryshkin, N.A. (5) 146,147 Nash, C.P. (1) 280 Nasielski, J. (6) 146, 147 Natu, A.A. (5) 224 Naumann, C. (1) 285 Naumov, V.A. (1) 598; (3) 53; (8)

Navarro, R. (6) &,64 Neda, I. (1) 361; (2) 7, 17, 19; (4)

Ncddcn, H.G. ( I ) 86 Nefedora, M.N. (1) 366; (8) 136 Nekdov, O.M. (1) 472 Neganova, E.G. (1) 486 Negayama, S. (7) 89 Neidlein, R. (4) 160 Neiger, M. (1) 98 Ncilands, 0. (6) 159 Nelson, A. (1) 333,340; (6) I16 Nelson, J.H. (1) 140,574 Nelson, J.M. (7) 13-17; (8) 60,83 Nelson, J.S. (3) 42; (5) 117 Nelson, P.J. (3) 38 Nelson, P.S. (5) 232 Nesbitt, S. (5) 25 1 Nesterova, L.I. (2) 14 Nesterova, N.P. (1) 388 Net, G. (1) 69 Netchitailo, P. (6) 152 Neumann, B. (1) 490,491,520 Neumiiller, B. (1) 1 13; (6) 34; (7)

Neutermans, W.D.F. (4) 64 Newman, P.D. (1) 385,386 Newton, C. (1) 48 Ng, RA. (4) 1 I I Ngguyen, T. (5) 237 Ngo, D.C. (7) 84,106 Nguyen, M.T. (1) 481, 494, 523,

524,553; (8) 8 Ni, J.S. (5) 298 Nicholson, B.K. (1) 190,393 Nicol, P. (4) 270 Nicolaidcs, D.N. (1) 244 Nicolaou, K.C. (4) 80; (5) 272 Nicolaou, M.G. (4) 66 Nieckarz, G.F. (1) 133 Niecke, E. (1) 98, 307, 475, 497,

501, 503, 546, 548; (3) 12, 60; (7) 58; (8) 38, 158

28

230; (8) 48,92, 167

5

Nief, F. (1) 120 Nieger, M. (1) 307,475,497,499,

501,543,546; (3) 12,60; (6) 67;

(7) 58; (8) 158 Nielsen, N.K. (5) 16C Nielscn, P.E. (5) 128-13 1 Nierlich, M. (1) 575 Nieschalk, 1. (4) 122 Nifantb, E.E. (3) 14- 17,20,22; (4)

67,82; (8) 116, 164 Nikanorov, V.A. (6) 39 Nikitin, E.V. (1) 422; (4) 103 Nikolaev, A.V. (4) 5b Nikolova, R (4) 243 Nikonov, G.N. (I) !18, 136, 324,

Nilov, D.B. (4) 75 Nilsson, M. (5) 85, 86 Ninorcillc, S. (1) 5 Nishhara, Y. (I) 35 Nishijima, M. (4) 54 Nishirnura, T. (1) 258 Nitta, M. (4) 216 Niwa, K. (7) 110 Nixon, J.F. (1) 514,53 1, 577,585-

587; (3) 55; (4) 214; (8) 99 Niyazova, 2h.M. (4) 244 Noe, F. (7) 88; (8) 202

358,359,415,416; (6) 16

NOth, H. (1) 97,103-105,421,466, 493,542,580,581,601; (6) 22, 23,27-29; (8) 54, 101, 169

Nogradi, M. (6) 133 Noiret, N. (6) 79 Nojima, M. (1) 238 Nolan, S.P. (1) 282 Nolte, A. (5) 279,280 Nolte, R.J.M. (4) 72 Nolterneyer, M. (1) 504 Nornura, Y. (5) 168,170 Nonin, S. (5) 267,268 Norman, A.D. (1) 71,129, 130; (8)

Norman, N.C. (1) 457 Notario, R. (1) 277 Noh, H. (8) 54 Novak, T. (1) 354; (4) 228 Novikova, T.S. (6) 156 Novosad, J. (4) 212, 213; (8) 47,

Nowakowski, R. (4) 15; (8) 236 Nowotny, M. (1) 53 1 Noyori, R (3) 25; (4) 18 1 Nozaki, K. (I) 145, 160, 161; (3)

46,48; (6) 145 Nthcnge, J.M. (I) 139 Nunez, A. (7) 73 Nunez, 0. (7) 73 Nupponcn, H. (4) 149 Nyburg, S.C. (4) 167 Nyulaszi, L. (1) 509,562,606

39.71

192

Oakley, RM. (6) 115 Oaskabe, N. (4) 6 Obara, R (6) 119 Obert, G. (5) 19 OBrien, P. (1) 332-339; (6)

Ocando-Mavarez, E. (1) 265, 460,

O'Connor, D. (5) 220 O'Connor, S.J.M. (7) 164, 165 ODonnell, C.J. (4) 11 1 O'Donovan, B.F. (1) 21 1 Oehme, G. (1) 155,156 Oclkc, M. (4) 284 Ocslman, C. (8) 23 1 Ofitscrov, E.N. (3) 2 Ogasawara, M. (1) 282 Ogawa, A. (3) 9; (5) 169 Ogawa, S. (6) 150 Oh, D.Y. (4) 242; (6) 107 O'Hagan, D. (4) 122 Ohkouchi, M. (1) 26 Ohkubo, M. (1) 258 Ohmori, H. (1) 68,444,445 Ohms, G. (1) 380; (8) 18 Ohta, A. (6) 157,158 Ohta, K. (6) 32 Ohta, T. (1) 145, 160 Ohtsu, T. (5) 127 Ohtsuka, E. (5) 179 Ohyama, Y. (5) 63 Ojea, V. (4) 199,200 Ojima, J. (6) 153 Okamoto, J. (1) 444 Okamoto, Y. (1) 468; (8) 166 Okauchi, T. (4) 119; (6) 86 Okazaki, R (1) 245,5 1 1 Okazalu, T. (4) 46 Okino, F. (7) 167,168 Okruszck, A. (5) 10,102 Ohmura, J. (4) 62 O'Leary, M.H. (1) 550 Olesiak, M. (5) 10 Olive, G. (4) 297; (8) 134 Oliver, J.S. (5) 44 Olivicri. A.C. (1) 368 Olmcijcr, D. (7) 164, 165 Olmos, M.E. (1) 205,395 Olmstead, M.M. (1) 101 Olsen, C.E. (5) 160 Olson, J.E. (7) 141; (8) 229 Olson, L.P. (5) 9 O'Ncil, LA. (5) 30 Oniciu, D.C. (1) 256 Ono, A. (5) 152,170 Onysko, P.P. (1) 323; ( d ) 262 Ootorno, R (7) 11 I

110-1 14,116-1 18; (8) 186

461; (8) 254


Oretskaya, T.S. (5) 145-147 Orita, M. (5) 249 Oritani, T. (1) 225 Orme, C.J. (7) 185, 186; (8) 120 Osakabe, N. (4) 226 Osbom, H.M.I. (4) 217,218 Osbom, J.A. (1) 48 Osborne, S.E. (5) 21 1,212 Oshikawa, T. (4) 6,97,226; (8) 189 Oshovsky, G.V. (1) 18 1 Osipova, T.I. (4) 177 Oskam, N. (6) 124 Osman, F.H. (1) 22 1 Ostcr, T. (1) 499 Ostroukhova, 1.1. (8) 147 Ostrowski, A. ( I ) 535 Othman, M. (6) 152 Ott, A.J. (6) 139 Ottaway, C. (7) 42 Otten, P.A. (6) 124 Ouadi, A. (4) 2 18 Ovchinnikov, V.V. (8) 207,210 Ovechkina, E.V. (1) 409 Owens, S. (5) 155 Oyelcre, A.K. (5) 44 Ozaki, H. (8) 250 Ozaki, S. (4) 32 Ozola, V. (5) 13

Pabel, M. (1) 558 Pachera, R. (4) 94 Pack, M.M. (6) 139 Packard, G.K. (4) 11 1 Padmanabha, K.K. (1) 125 Padwa, A. (6) 138 Padyukova, N.S. (5) 159 Paetzold, E. (1) 155, 156 Pagalday, J. (4) 257 Page, M.I. (1) 25 1 Pagliarin, R (4) 24 1 Pagratis, N.C. (5) 28 1 Paine, R T . (1) 103-105; (8) 101 Palacios, F. (1) 327, 328; (4) 257;

Paleari, L. (4) 24 1 Palecek, E. (5) 13 1 Palma, G. (7) 126 Palyutin, F.M. (1) 422 Pandcy, G. (1) 298 Paneth, P. (1) 550 Pang, Z. (7) 142 Panigrahi, G. (5) 234 Panina, E.V. (3) 22 Pankiewicz, K.W. (5) 58-60 Panunzio, M. (4) 94, 152 Papageorgiou, C. (7) 40

(7) 30,3 1

Papa , G. (4) 241 Paplcwski, M. (8) 9 Pappalardo, G.C. (7) 134, 135; (8)

Pappin, D.J.C. (5) 303 Parasuk, V. (1) 522 Pardi, A. (5) 275 Parel, S.P. (5) 183, 185 Paris, P.L. (5) 171 Park, J. (1) 3,4

Park, N.K. (6) 103 Park, P. (7) 102 Park, S.H. (7) 97 Parkanayi, L. (8) 189 Parmec, E.R (6) 127,128 Parra, A. (4) 4 1 Parry, R.J. (4) 51 Parvez, M. (7) 78, 84,95, 120; (8)

Pascual, 1. (6) 63 Pasenok, S.V. (6) 171,172 Pashkevich, K.I. (2) 2C Pastor, A. (6) 149 Pakl, B.K. (5) 74 Patcl, D.J. (5) 262,263 Patcl, G. (4) 146, 171, 179 Patel, RN. (4) 236 Patcl, S.T. (1) 341 Patil. S.V. (5) 213 Patin, H. (1) 131; (6) 79 Patsanovskii, 1.1. (1) 64, 373, 512;

Paul, C.H. (5) 83 Paul, S. (1) 389 Pauling, L. (2) 29 Pavcy, J.B.J. (5) 30 Pavlopoulos, S. (5) 27 1 Pavlov, V. (4) 272 Pawelkc, G. ( 1) 4 13; (6) 3 1 Payne, L. (7) 192 Payne, L.G. (7) 129, 190,204-207 Peacock, R.D. (1) 127,385,386 Pearce, E.J. (1) 246 Pearson, N.D. (4) 183 Peckham, T.J. (1) 80 Pedcrscn, E.B. (3) 39; (5) 149 Pedersen, S.D. (4) 143, 144; (6) 99 Pcderson, 0.5 (5) 160 Pedrini, P. (7) 85 Pcdrocchi-Fantoni, G. (4) 49 Pegg, A.E. (4) 283 Peiffer, G. (4) 198

Pelcman, B. (4) 204,205 Pclicano, H. (5) 19 Pcllerin, B. (1) 470; (8) 37

35.36

Park, K.-K. (4) 237

179

(8) 40,200,25 1

Pelkz-hango, E. (7) 28, 72

Pellon, P. (1) 50, 142 Pemberlon, L. (7) 163 Pennington, W.T. (1) 236

Pcracchi, A. (5) 255 Perboni, A.D. (4) 94, 108 Percy, J.M. (1) 341; (4) 136, 141 Perdigon, J.A. (7) 152 Percdy, M.K. (6) 133 Pcrcq I. (6) 163 Perez-Jidneq C. (1) 199,387 Peringcr, P. (3) 23 Perlikowska, W. (4) 120; (6) 105 Pcmo, C.F. (5) 4 Pcrra, G. (8) 76 Pwriott, L.M. (1) 573 Pestana, D.C. (1) 101 Peters, C. (8) 94 Peters, D. (1) 285,286 Peters, E.-M. (7) 42 Peters, K. (7) 42 Pctcrsen, A.K. (6) 134 Peterson, A.C. (1) 430; (4) 104 Pclason, E.S. (7) 150, 185, 186; (8)

Peterson, M.J. (6) 1 Petillot, Y. (5) 175, 176 Petkov, D.D. (5) 75 Pctnehaq, I. (3) 8; (8) 203 Pctretta, M. (5) 150 Pctrovskii, P.V. (1) 32 1 Petrukhina, O.E. (8) 200 Peukert, S. (4) 85 Peyman, A. (3) 43 Pezzin, G. (7) 126 Pfaendler, H.R (4) 69 Pfister-Guillouzo, G. ( I ) 506; (8)

Pfleiderer, W. (5) 186 Phan, A.T. (5) 267 Phillips, J .R (7) 22 Phillips, L.R (5) 157 Phillips, S.H. (1) 427; (6) 71 Phung, N. (4) 138 Pianka, M. (4) 12 1 Piccirilli, J.A. (5) 167 Pickctt, C.J. (1) 577 Piel, N. (5) 87 Picks, U. (5) 166 Pierson, J.-F. (4) 270 Pietnykowski, W.M. (4) 266, 267;

Pietschnig, R (1) 475 Piettre, S.R (4) 21 1 Pichnka, T. (7) 35 Pihlaja, K. (1) 560 Pilard, J.-F. ( I ) 61

Pcpcr. v. (4) 222

120,121

112

(6) 87

A uihor Index 3 63

Pilati, T. (1) 11, 143 Pilloni, G. (1) 396 Pilz, A. (7) 8 Pinchuk, A.M. (1) 181,293 Pinchuk, V.A. (1) 218; (2) 17; (6)

Pinkcrton, A.A. (7) 10, 11 Phtauro, P.N. (7) 182, 183 Piquet, V. (4) 257 Piras, P.P. (6) 76 Pirio, N. (1) 193,496,571; (4) 224 Pirklc, W.H. (4) 156,299 Phzhenko, V.V. (2) 14; (4) 12; (8)

Pirmng, M.C. (5) 43 Pisarevskii, A.P. (1) 416; (6) 16 Pitter, S. (1) 59 Pittman, C.U.J. (7) 121 Pivin, J.C. (7) 154 Plaza, P. (1) 279; (8) 153 Plenat, F. (1) 401; (7) 98; (8) 173 Podda, D. (7) 68 Podzigun, G.I. (8 ) 28 Poetschkc, N. (i) 501; (3) 60; (8)

Pohjala, E. (4) 149 Pohl, D. (8) 74 Polezhacva, N.A. (1) 409 Poli, R (8) 30 Polozov, A.M. (4) 96 Pombeiro, A.J.L. (8) 202 Pombciro, L. (7) 88 Pomeranb, S.C. (5) 298 Pon, RT. (5) 79,261,270 Ponomarev, G.V. (1) 403 Poon, C.-D. (4) 246; (6) 89 Poopeiko, N.E. ( 5 ) 68 Popov, K.A. (4) 96 Popova, E.V. (1) 64, 5 12; (8) 40,

Porcheddu, A. (4) 109 Pore, V.S. (6) 91 Porschke, D. (5) 256 Porter, K.W. (5) 72 Porwoiik, I. (8) 59 Potekhin, K.A. (1) 3 13 Potier, P.F. (5) 188 Potrxbowski, M.J. (8) 49.66.67 Potter,B.V.L. (4) 26,30,31,33,34 Poulain, S. (6) 79 Powell, D.R (1) 163 Powell, H.R. (1) 336; (6) 112; (8)

Power, P.P. (1) 101 Poyncr, D.R (4) 36 Pradella, F. (7) 127, 149; (8) 145 Pradere, J.-P. (1) 439

15; (8) 44,48

190

158

25 1

186

Prakash, 0. (4) 235 Prakash, T.P. (5) 139, 140 Pratviel, G. (5) 24 1 Pravia, K. (1) 344 Prcchtl, F. (6) 169 Prccigoux, G. (5) 287 Prcdvoditclcv. D.A. (4) 67 Preisenberger, M. (1) 398 Prestwich, G.D. (4) 38,40,47,48 Prcvote, D. (6) 69 Prchdo, O.V. (1) 367; (8) 199 Prchdo, V.V. (1) 367; (8) 199 Pricstlcy, N.D. (3) 32; (4) 10 Prill, M. (1) 192 Primrosc, A.P. (7) 95 Principato, B. (4) 198 Pring, B.G. (4) 169,282 Prisyazhnyuk, A.V. (8) 24 Pritchard, RG. (1) 228; (8) 195 Pritzkow,H. (1) 38,94,507; (6) 21;

Profit, A.A. (4) 47 Prokhorcnko, I.A. (5) 225 Prokhorova, S.R (1) 358 Prokopcnko, V.P. (1) 323 Protasicwicz, J.D. (1) 291; (3) 61;

(8) 130, 159 Pruckncr, A. (6) 83 Prud'hommc, RK. (7) 201 Przibillc, G. (4) 10 1 Pudovik, A.N. (1) 598; (2) 13; (3)

Pudovik, M.A. (2) 13; (4) 274; (8)

Puclm, M. (8) 63, 197 Piintcncr, K. (1) 33 Pugashova, N.M. (4) 82 Pullcn, A.E. (1) 428 Pupciko, N.E. (5) 67 Puplovskis, A. (6) 159 F'uri, N. (5) 235,236 Puschl, A. (5) 37.38.105 Putzas, D. (7) 42 Pyali, R. (1) 527 Pyzowski, J. (5) 42

(8) 188

53; (4) 274; (8) 50

50

Qi, M. (4) 142 Qiao, S. (1) 92 Qing, J. (1) 347,348 Qiu, W. (4) 143, 144; (6) 99 Qiu, Z.-M. (4) 143, 144; (6) 99 Quasdorff, B. (1) 49 1

Quin, G.S. (I) 549; (8) 256 Quin, L.D. (1) 549-551, 561-564;

Quasdofl, J.-M. (1) 490

(8) 109, 156,256

Quintela, J.M. (4) 199,200; (6) 148

Raab, K.M. (1) 465 Raabc, G. (1) 19 Rabe, G.W. (1) 36 Radinov, R (1) 208 Radkowski, K. (1) 54 Ragcot, A. (1) 9.10 Raghu, K.V. (8) 5 1 Ragulh, V.V. (3) 4; (4) I15 Rahbamoohi, H. (1) 106,237 Raithby, P.R (1) 107,336; (6) 112,

115; (8) 186 Raju. C.N. (8) 227,228 Rajur, S.B. (5) 222 bachandran , R (1) 536; (3) 57 Ramasamy, K.S. (3) 41; (5) 126,

189 Ramazani, A. (1) 213, 216, 436,

437; (6) 42-45 Ramdane, H. (1) 484 Ramircz dc Arellano, M.C. (6) 65 Ramos-Vieira, A. (7) 151 Ramwy, J.M. (8) 218 Ramzacva, N. (5) 194,195 Ranaivonjatovo, H. (1) 274, 484,

Rancurel, C. (1) 322 Rangaswamy, J.R (1) 125 Rangc, G. (4) 57 Rao, K.S. (8) 5 1 Rao, M.N.S. (7) 56,57; (8) 90,212 Rao, M.V. (5) 181 Raphy, J. (4) 217 Rapbpoulou, C.P. (4) 243 Rasadhina, E.N. (3) 16,17; (8) 116 Rasc, R (7) 12 Rasmusscn, P.B. (5) 149 btavclomanana-Vidd, V. (4) 16 1 Ratncr, V.G. (2) 20 bushel, F.M. (4) 287 Raut, S.V. (1) 417; (6) 38 Rautschek, H. (7) 50.5 1 Ravikumar, V.T. (3) 3 1; (5) 35.88,

Rayner, B. (5) 66 Reau, R (1) 540; (4) 256 Reddy, B.S. (4) 11; (8) 52 Reddy, C.D. (4) 1 1; (8) 5 1.52.228 Reddy, G.S. (8) 227 Rcddy, P.M. (4) 11; (8) 52,228 Rcddy, V.S. (1) 134, 135, 191; (4)

R d , C.S. (7) 156 Reed, RW. (1) 264 Rccs, N.E. (1) 137

528

97,98

245

364 Organophosphorus Chemistiy

Rees, N.H. (1) 165,167 Reese, A. (5) 237 Reese. C.B. (5) 13,41,94 Reetz, M.T. (1) 8, 188

Regitz, M. (1) 277, 472,483, 509, 513,517,540,555,594,600; (3) 13,56; (8) 31,94, 165

RWVCS, S.D. (7) 13-15; (8) 60,83

Regius, C.T. (1) 29; (8) 79 Regnat, D. (1) 285,286 Regnouf-dc-Vains, J.B. (6) 70 Rehder, D. (1) 273 Rehnberg, N. (4) 28 Reid, G. (1) 392 Rcifer, E.M. (1) 192 Reilly, J.P. (5) 302 Reilly, P.T.A. (8) 2 18 Reiter. L.A. (4) 239 Reitman, M.S. (5) 110 Ren, RX.F. (5) 171 Ren. X. (7) 189 Rettig, K. (1) 90 Rettig, S.J. (1) 39,73 Rettig, W. (1) 279; (8) 153 Reven, L. (8) 77 Revina, N.V. (8) 147 Reyd, C. (1) 537,538; (3) 59; (8) 64 Reynolds, C.A. (7) 70 Reynolds, J . R (1) 428 Reynolds, K.A. (6) 58,59 Reynolds, M.A. (5) 109,264 Re& V.S. (8) 28 Reznikov, A.N. (1) 30; (8) 161 Rheingold, A.L. (1) 36, 106, 236,

485; (7) 102 Rhie, D.Y. (4) 233 Rhiel, M. (7) 6 Ricxd, L. (1) 120, 144, 314-316,

534, 603, 609-611; (4) 231; (8) 193, 194

Ricc, J.S. ( 5 ) 265 Riche, C. (5) 229 Richert, C. (5) 122,309 Richter, H. (8) 233

Rickcrt, P.G. (4) 264 Riddcll, F.G. (1) 399 Riddle, S. (4) 45 Ricgel. B. (1) 102,526 Riegel, N. (1) 407 Riekel, C. (6) 161

Rilcy, A.M. (4) 30,34 Riley, T.A. (5) 43, 109 Ringeiscn, U. (4) 101 Ringcl, I. (4) 294; (8) 127 hou, A. (6) 94

Richter, R (1) 76-78; (6) 17

Ricse, u. (7) 5

Ripoll, J.L. (1) 506; (8) 112 Risky, J.M. (1) 242; (8) 105 fist, G. (1) 364 Ritzeler, 0. (4) 58 Rivas. G. (5) 131 Rim, J.D. (1) 254 Rim, T.M. (1) 254 Rizzoli, C. (3) 21

Roberts, B.E. (7) 190,192 Roberts, C. (5) 139 Roberts, S.M. (5) 78 Robertson, K.N. (1) 521; (3) 58 Robinson, B.H. (1) 381; (5) 237 Robinson, K.D. (1) 72 Robl, C. (1) 542; (6) 28; (8) 54 Robles, J. (5) 222,223 Roche, D. (7) 4 1 Rockenbauer, A. (4) 297 Rodewald, D. (1) 273 Rodi, A.K. ( I ) 528 Rodios, N.A. (4) 243 Rodriguez, G.L. (1) 83 Rodriguez, J.G. (6) 48 Rodriguez, L. (1) 46 1 Rodriguez, O.P. (4) 291 Rodriguez-Morgadc, S. (7) 32 R d c r , T. (6) 84 Roemer, S. (4) 35 Rosch, N. (1) 90 Roeschcnthaler, G.-V. (1) 153; (2)

Roesky, H.W. (1) 504 Roestamadji, J. (4) 156 Rogcrson, M. (I) 399 Rohonczy, J. (8) 53 Rohovec, J. (4) 263 Roignant, A. (2) 24 Rokita, S.E. (5) 2 18 Rollin, P. (1) 259 Romakhin, AS. (1) 422; (4) 103 Romanenko, E.A. (1) 414,440; (6)

Romanenko, V.D. (1) 500,547; (8)

Romingcr, RL. (1) 382 Roncali, J. (6) 94 Roqai, C.M. (1) 369 Roques, B.P. (4) 202 Rosch, R (5) 23 1 Rosche, F. (6) 34,61 Roscoe, J. (I) 169 RosC, J. (1) 128 Rosemeyer, H. (5) 161, 199 Roscnblum, D.B. (1) 1 10 Rosenbohm, C. (5) 9 1 Rosler, A. (5) 186

Robb, J.B., I1 (8) 12-14

20; (4) 123, 124; (6) 37

13

6

Ross, B.R (5) 155 Ross, F.C. (3) 5; (4) 193 Rossi, J.C. (6) 135 Rossi, RA. (1) 83 Robe, J. (1) 413; (6) 31 Rotter, H.W. (7) 42 Roubaud, V. (8) 134 Roucou, A. (1) 13 1 Routier, S. (5) 243 Rovnyak, D. (8) 122 Roy, S. (4) 105 Royappa, A.T. (5) 83 Royer, J. (3) 11; (4) 106 Royo, F.M. (8) 149 Rozantscv, G.G. (1) 326 Roxnski, J. (5) 136,159,298 Rozhko, L.F. (3) 4 Romen. E. (5) 120,153 Ruban, A. (1) 546,548; (7) 58 Rubiales, G. (7) 30.3 1 Rubinsbjn, S. (7) 48.53 Rudolf, M.T. (4) 35 Rudolph, M.J. (5) 110 Rudzevich, V.L. (1) 547 Rudzinski, J. (4) 275 Ruedi, P. (4) 101 Ruelkc, RE. (1) 173 Rufieux, V. (1) 128 Ruhlandt-Senge, K. (1) 101 Ruhlmann, L. (1) 404 Ruhnau, F.C. (7) 137 Ruiz, M. (4) 199,200 Rumney, S. (5) 171 Runsink, J. (1) 19 Ruppert, 0. (6) 162 Russell, D.H. (8) 226 Russell, M.G. (1) 333; (6) 116 Ruthe, F. (1) 535 Ryan, M. (4) 43 Ryglowski, A. (4) 180 Ryumtscv, E.I. (7) 136

Saab, N.H. (4) 283 Saad, M. (6) 161 Saba, C.S. (7) 104 Sablong. R (1) 48 Sacher, F. (8) 240 Sachett, C.M.M. (8) 182 Sadovskii, Y.S. (1) 363 Sadowski, P.D. (5) 234 Sadun, C. (7) 134; (8) 35 Sahyan, G.P. (1) 363 Saga, Y. (3) 35 Sagadeev, E.V. (8) 2 10 Sahasrabudhc, P.V. (5) 270 Said, M.A. (8) 63,197

Author Index 365

Schmidt, D. (1) 567

Schmidt, J.B. (4) 188 Schmidt, M. (1) 421,581; (6) 22,29 Schmidt, RR (4) 192 Schmidt, S. (4) 77; (5) 209 Schmistchen, F.P. (1) 28

Schmutzler, R (1) 218, 306, 325,

25; (4) 230; (6) 15; (8) 18,40, 44,48,92, 167, 168,251

Schmidt, H.-G. (1) 504

Schmittcl, M. (1) 351-353; (4) 83

361,512,531,583; (2)7, 16-19,

Schnabel, RC. (1) 530 Schnackerz, K.D. (5) 48 Schncider, A. (4) 52 Schneider, B.P. (8) 76 Schneider, M. (4) 13 Schneller, T. (1) 287 Schnick, W. (7) 60,61 Schobert, R (6) 74,143 Schoetzau, T. (5) 69,70 Schofer, S.J. (1) 88 Schonholzer, P. (1) 9 Schoo, H.F.M. (7) 101; (8) 175 Schreiner, E.P. (6) 83 Schrenk, M. (7) 194 Schrock, RR (8) 122 Schrael, H.-P. (1) 294, 493, 581,

Schrocdcr, E.K. (8) 73 Schrott, M. (1) 543; (6) 67 Schubat,D.M. (1) 71,129, 130; (8)

Schubert, F. (5 ) 64 Schiitz, W. (1) 425 Schull, T.L. (1) 206 Schulte, A.C. (8) 91 Schultz, C. (4) 35 Schultz, RG. (5) 118 Schultz, W.J. (7) 106 Schulz, A. (8) 34 Schulz, J. (4) 23.24 Schulz, M. (8) 53 Schulm, S. (4) 65 Schumann, H. (1) 3 1 Schumann, I. (1) 520 Schurko, RW. (8) 20 Schuster, M. (8) 68 Schwalbc, C.H. (4) 21 Schwartz, D.A. (5) 43,109 Schwarz, W. (1) 99,100,102 Schwcighofer, A. (1) 384,447; (6)

Schweizer, W.B. (7) 35 Schwendcr, C.F. (4) 289 Schwcnk, H. (1) 109 Schwesinger, R (7) 12, 3'8.42.63,

602; (6) 22,24,27,30

39.71

9;(8) 17

Said, M.M. (6) 72,73 Saida, Y. (4) 107 Said, M.R (6) 5 1 Saint-Clair, J.-F. (4) 129 Saint-Diaz, C.I. (8) 23 Saintome, C. (5) 228,229 Sainz-Diaz, C.I. (4) 118 Saito, I. (5) 174 Saito, S. (1) 179 Saito, T. (3) 48 Saiz, E. (7) 151, 152 Sakai,N. (I) 161; (3) 46 Sakai, T. (6) 32 Sakqa,N. (1) 586,587; (3) 55; (4)

214; (8) 99 Sakata, S. (6) 132 Sakhibullina, V.G. (1) 409 Sakurai, M. (1) 362 Salamonczyk, G. (4) 28 Salek, S.N. (1) 198 Salhi, F. (6) 160 Salisbury, S.A. (5) 288 Salo, H. (5) 206,208 Salomon, C.J. (4) 258; (8) 81 Salunkhe, M.M. (5) 213 Salzer, A. (1) 138 Salmer, U. (I) 479,480; (8) 4,5 Sambri, L. (1) 329 Saniuel,E.(l) 114 Samucls, W.D. (7) 7 1, 178 Sanchez, L. ( 6 ) 163 Sanchez, M. (1) 540 Sanchez-Andrada, P. (1) 26 1 Sandberg, M.P. (4) 204 Sandblom, N. (1) 371; (6) 6 Sanderson, S. (7) 166 Sandra, P. (8) 249 Sanghera, J.B. (4) 183 Sanghvi, Y. (5) 158

Sanmartin, J. (I) 391 Sannes Lowery, K.A. (5) 297 Sannicolo,F. (1) 11, 143 Sano, S. (6) 102 Sansom, P.I. (5) 220 Santarsierio, B. (1) 264 Santiago, A.N. (1) 83 Santiago-Garcia, R. (8) 18 1 Sanvito, G. (7) 144 Saquct, M. (4) 129 Sardarian,A.R (4) 151,174 Sarfo, J.K. (1) I89 Sargent, J.R (7) 206,207 Sarikahya, F. (1) 394 Sarracino, D. (5) 309 Sasai, H. (4) 107, 155 Sasaki, S. (5) 204; (8) 13 1

sang& s. (1) 545

Sasaki, T. (6) 132 Sasmor, H. (5) 155,296 Sastre, A. (8) 206 Satish, A.V. (7) 42 Satish, S. (1) 220 Sato, M. (4) 195 Sato, N. (6) 145 Sato, R (6) 150 Sattler, E. (1) 37,544 Sauers. RR (1) 604; (8) 3 Sauve, G. (4) 28 1 Savelova, V.A. (1) 363 Savignac, P. (1) 470; (4) 122, 132,

137, 147, 148, 161, 184; (8) 37 Savochkina, L.P. (5) 67,68 Sawaki, Y. (4) 3 Sawycr, Y. (1) 25 1 Sbervcglieri, G. (7) 180, 18 I Scanlon, T.H. (1) 137 Scarcelli, D. (4) 49 Schacht, E. (7) 130,196-198 Schaefer. J. (8) I1 1 Schtifcrs, M. (1) 3 1 Schambcrger, J. (1) 3 12; (3) 24 Schareina, T. (1) 156

Schauer, S.J. (1) 108 Scheffer, M.H. (1) 520 Scheler, U. (1) 368 Schcllc, C. (8) 74 Schenk, H. (4) 90 Schepers, G. (5) 164 Scheuer-Larsen, C. (5) 9 1 Schiavon, C. (1) 146 Schiavon, 0. (5) 82 Schick, G. (1) 497; (3) 12

Schieck, N. (1) 94 Schier, A. (1) 232,233,303, 395;

Schilder, A. (1) 425 Schilf, W. (8) 118 Schinazi. R.F. (5) 18 Schinkels, B. (1) 546; (7) 58 Schlemper, H. (7) 42 Schleyer, P.von R (1) 605 Schloss, J.V. (4) 52 Schlosscr, M.S. (6) 10, 122 Schmaljohann, D. (1) 198 Schmid, G. ( I ) 128 Schmid, R (1) 9 Schmidbaur, H. (1) 204,205,232,

233,395,398; (6) 18, 19 Schmidpctcr, A. (1) 294,295,303,

421, 493, 542, 580, 581, 601,

Scharf, H.-D. (1) 45

Schichann, H. (7) 49-5 1

(6) 25

602; (6) 22-30; (8) 54 Schmidt, A. (7) 20


Shuto, S. (5) 5,6; (6) 13 1 Shvets, A.A. (1) 363 Siberdt, F. (6) 146 Sidorenkova, H. (1) 487; (8) 7 Sicgl, H. (1) 95 Siclcr, J. (1) 62 Sicrzchala, A. (5) 102 Sigl, M. (1) 232,233 Sigurdsson, S.T. (5) 209,210 Sih, C.J. (5) 47 Silaghdurnitrcscu, I. (8) 32 Sillanpa&, R (1) 22, 199,387 Silva, A.L. (6) 92 Silveira, C. (6) 77 Silvcrt, D. (1) 502 Simmons, T.A. (5) 304 Simon, C. (1) 247; (5) 4 1 Simon, F. ( I ) 529 Simon, P. (8) 57 Simonet, J. (1) 61 Simonov, Y.A. (4) 12; (8) 190 Simonutti, R (7) 137, 138; (8) 117 Simpkms, N.C. (7) 39 Simpson, C.K. (3) 19 Simpson, J.H. (1) 252.38 1 Simpson, M.C. (1) 283 Sinerius, G. (4) 52 Singewald, E.T. (1) 88 Singh, S.K. (8) 154, 155 Singlcr, R (7) 150; (8) 119, 121 Sinha, A. (6) 136 Sinha, C.S. (6) 136 Sinitsa, A.D. (1) 323; (2) 14; (4)

Sint, T. (8) 76 Sisti, M. (4) 24 1 Siwy, M. (8) 59 Sixou, S. (5) 24 1 Skolimowski, 1. (8) 118 Skordalakes, E. (4) 146,171, 179 Skowronska, A. (1) 572 Skowonski, R (4) 172,173 Skrypina, N.A. (5) 67 Shortsov, N.K. (1) 30; (8) 161 Sladck, A. (1) 205 Slany, M. (1) 186, 187; (4) 18, 19 Slawin,A.M.Z. (1) 311,554; (3) 18;

Sliwakowski, M. (8) 234,235 Sliwka, H.-R (4) 76 Sluggctt, G.W. (1) 365 Slujic, L. (1) 574 Smail, S.J. (1) 79 Smallheccr, J.M. (4) 8 Smcyers, I.G. (8) 11,23 Smimov, I.P. (3) 37; (51 217 Smith, C.J. (1) 135, 191

262

(4) 95; (7) 22-25; (8) 192

64; (8) 171,172,253 Scoblov, A.Y. (5) 76 Scoponi, M. (7) 127, 149; (8) 145 Scott, B.C. (1) 530 Scott, P. (1) 612 Scott, W.G. (5) 286 Scowen, I.J. (7) 98; (8) 173, 183 Scremin, C.L. (5) 157 Scrima, R (7) 157 Scrinivasin, S.A. (1) 347 Scrivanti, A. (1) 146 Sctypina, N.A. (5) 68 Scudder, M.L. (1)45 1, 452 Scunia, M.A. (5) 43 Sea, K. (4) 6 Sebastian, D. (4) 60 Sedov, A.L. (4) 75 See, R.F. (1) 382 Seebach, D. (7) 35 Seeberget, P.H. (5) 106 Seela, F. (5) 161, 194-202 Scidman, M. (5) 59 Scifert, W. (3) 41; (5) 126, 148 Seitz, S.P. (4) 8 Scki, H. (1) 320 Scki, M. (7) 108 Sekme, M. (5) 33,34,93; (8) 243 Sekljic, H. (4) 55 Seliger, H. (5) 8 1,23 1 Selim, A.I. (4) 182 Selke, R (1) 85, 180 Scllo, G. (4) 24 1 Selvaratnam, S. (1) 165, 167, 168 Selvi, R (4) 150 Semenzin, D. (1) 122; (4) 269 Semizarov, D.G. (5) 66 Seinkin, V.N. (1) 426 Senn, M. (5) 150 Senthamizh, R. (4) 150 Scnthivel, P. (8) 55 Senturk, O.S. (1) 394 Seo, K. (4) 97,226 Seoane, C. (6) 163 Septak, M. (5) 84 Sequeira, L.J. (1) 458 Sereda, S. (1) 521; (3) 58 Serkov, I. (6) 135 Serova, T.M. (1) 324,359 Senti, S. (4) 49 Sessler, J.L. (5) 220 Seto, N. (1) 68 Seymour, L. (7) 130,196 Shabarova, Z.A. (5) 144-147 Shadyro, 0.1. (8) 138 Shah, S. (3) 61; (8) 130 Shalihidoyatov, W.M. (4) 244 ShoWmin, D.B. ( I ) 414; (6) 13

Shakirov, M.M. (4) 166 Shamsi, S.A. (8) 248 Sharma, A.K. (5) 227; (6) 137 Sharma, P.K. (8) 255 Sharman, W.M. (4) 127 Sharpatyi, V.A. (8) 138 Shaw, B.R (5) 72.73 Shaw. R A . (8) 59 Shchepinov, M.S. (5) 230 Sheats, J.E. (7) 121 Sheehan, S.M. (6) 138 Shefield, J.M. (1) 228; (8) 195 Shcinkman, A X . (1) 254 Sheldrick, W.S. (1) 90,91 Shcn, Q. (4) 194 Shen, Y. (1) 441,441; (4) 142; (6)

46,47,8 1 Shen, Z. (8) 2 Shephard, D.S. (1) 53 i Sheppard, T.L. (5) 14 1 Sherlock, D.J. (2) 27; (8) 41,65 Shestakova, A.K. (1) 443 Shestakova, A.V. (6) 56 Shevchcnko, I.V. (2) i6; (8) 168 Shi, D.-Q. (6) 49 Shi, G.-Q. (4) 80 Shi, J. (1) 55 Shi, J.-C. (1) 158 shi, x. (1) 88 Shibasaki, M. (4) 107,155 Shibata, T. (4) 219 Shibuya, S. (4) 134, 135, 154, 178,

S h a , K. (1) 402 S h a z a k i , N. (5) 6 Shimek, G.L. (1) 236 Shimidzu, T. (3) 36; (5) 2 I5 Shimizu, M. (5) 179 Shin, G.-C. (4) 237 Shinohara, N. (1) 455 Shinoya, M. (1) 175 Shiozaki, M. (4) 54 Shipov, A.E. (4) 2 Shiraishi, H. (5) 13 1 Shirakawa, E. (1) 160 Shiro, M. (1) 179 Shirokova, E. (5) 78 Shitangkoon, A. (8) 226 Shoemaker, RK. (4) 194 Shohda, K. (5) 33,34; (8) 243 Shon, K.-H. (4) 237 Shrccve, J.M. (7) 116, 117; (8) 58 Shriver, D.F. (7) 169, 170 Shtyrlin, V.G. (8) 137

195,203; (6) 100

Shu, L.-H. (1) 2 10 Shubnikov, A.M. (1) 3 13 Shultz, L.A. (5) 284

Author Index

Smith, D. (4) 288 Smith, D.E. (5) 274 Smith, F.W. (5) 278 Smith, M.B. (1) 31 I; (7) 23,25 Smith, M.P. (4) 43 Smith, P.B. (8) 220

Smith, R J . (1) 198 Smith, T.H. (3) 38; (5) 232 Smolenskova, V.N. (3) 15 Smolii, O.B. ( I ) 414; (6) 13 Smyth, D. (3) 44 Snaith, R. (6) 110,115 Sneddon, L.G. (1) 235 Snicckus, V. (1) 360 Snoeck, R (5) 22 Snyder, A.P. (8) 220-222 Soai, K. (4) 2 19 Sochacka, E. (5) 154 Sochacki, M. (5) 59 Soederberg, J. (4) 205 Sofue, S. (4) 32 Soh, Y.S. (7) 97, 195 Soifcr, G.B. (8) 126 Sokolinskaya, N.R. (3) 20; (8) 164 Sokolov, V.1. (I) 366; (4) 298; (8)

Sokolowski, M.S. (8) 150,235 Soliman, F.M. (6) 72,73 Solladie, A. (7) 4 1 Solodovnikov, S.P. (1) 366; (4) 298;

(8) 135, 136 Solomoichenko, T.N. (1) 363 Solomons, K.RH. (4) 21,36 Solov'eva, N.P. (4) 75 Sommcrdijk, N.A.J.M. (4) 72 Song, H.-L. (1) 123,124; (8) 113 Song, Q.L. (5) 13,94 Song, Y. (1) 272 Sonnenburg, R (2) 7 Sonnichsen, S.H. (5) 130 Sopchik, A.E. (8) 95 Sonente, A. (6) 55 Sosabowski, M.H. (1) 201 Soucek, M.D. (7) 148 Souli, C. (5) 1 Sournics, F. (7) 66,67, 115 Sousa, A. (1) 391 Sowerby, D.B. (7) 62 S o m i , P. (7) 137, 138; (8) 117 Spannenberg, A. (1) 177 Spassova, M. (5) 216 Spatz, J.P. (7) 46 Spek, A.L. (1) 172,173,471,474 Spencer, J.T. (1) 5 18,5 19 Spiegel, A. (1) 209 Spielmann, H.P. (5) 260

Smith, R.D. (5) 293-295

135,136

Spiers, I.D. (4) 21 Spinclla, A. (6) 55 Spirikhin, L.V. (1) 84 Spitsina, N.G. (1) 426 Spunta, G. (4) 152 Sreedharan-Mcnon, R (4) 250 Srinivas, J. (7) 57; (8) 55,90 Srinivasamurthy, G. (8) 90 Srivatsa, G.S. (5) 97 Stacey, N.A. (6) 127 Stadler, C. (4) 35 Stahl, A.E. ( I ) 83 Stamford, A.W. (4) 286 Stamford, L.B. (4) 285 S t m i , H. (6) 95 Stammlcr, H.-G. (1) 490,491,520 Stanforth, S.P. (6) I42 Stankovic, C. (4) 207 Staples, RJ. (7) 117 Starikova, Z.A. (1) 397 Starosta, A. (5) 154 Starshinov, A.A. (1) 359 Stash, A.I. (3) 16, 17; (8) 1 Stassinopoulos, A. (5) 266 Stavenger, R.A. (4) 93 Stawinski, J. (5) 1 1 , 12, 14

103

21,49 Stec, W.J. (5) 10, 42, 45,

Steel, P.G. (6) 126, 128 Stcfaniak, L. (8) 118,200 Steffen, J.-P. (4) 83 Skimann, M. (1) 196 Stcincr, A. (1) 107; (7) 83 Stehdlcr , F. (1) 60 1

6

32.46,

02; (8)

Stelzer, 0. (1) 28,90,91, 147,203 Stelzner, A. (5) 81 Stcnzel, V. (1) 227; (8) 56 Stcphan, D.W. (1) 116, 117, 194,

195; (8) 170 Stem, C.L. (1) 88 Stetsenko, D.A. (5) 230 Stevenson, D.E. (7) 105 Stewart, B.H. (4) 207 Stewart, F.F. (7) 150, 185, 186; (8)

Stirling, D. ( 1 ) 385,386 Stock, N. (7) 60 Stockley, P.G. (5) 181 Stoddard, B.L. (5) 286 Stoenescu, C. (4) 4 1 Stbssel, P. (1) 196 Stoeva, V. (7) 143 Stolmar, M. (3) 21,51 Stolnik, S. (7) 198 Stone, M.L. (7) 150,185; (8) 121 Storozhev, T.V. (6) 39

119-121

367

Stoye, D. (7) 131 Strengcr, I. (1) 115 Streubel, R (1) 477,535 Strini, A. (4) 49 Strittmatter, M. (1) 351,352 Strornberg, R (5) 103, 120, 135,

Sbomburg, B. (7) 82; (8) 174 Struchkov, Yu.T. (1) 313,397,416; (3) 15; (6) 16

Studelska, D.R (8) 1 1 1 Studley, J.R (4) 22 1 Studnev, Yu.N. (1) 326 Stiirmer. R (1) 33 Sturgeon, K.L. (4) 170 Sy J.Y. (5) 274

Sudharshan, M. (7) 34 Sudheendra, RM.N. (8) 55 Sudmale, I. (6) 159 Sueishi, Y. (1) 240; (8) 133 Sucmune, K. (4) 134, 135; (6) 100 Sugi, K.D. (4) 273 Sugiyama, H. (5) 174 Sugiyama, M. (7) 89 Sukhanov, L.P. (8) 147 Sule, S.S. (7) 204,206,207 Sdsky, R B . (4) 209 Sumida, Y. (1) 238 Sun, H. (7) 133

153

sy s. (3) 34

Sun, H.-L. (1) 123; (8) 113 Sun, W.-Q. (1) 210 Sund, C. (5) 235,236 Supuran, C.T. (7) 94 Surendran, N. (4) 207 Susuh, T. (7) 75 Sutherland, J.D. (4) 89 Sutoh, H. (6) 132 Sutter, J.-P. (1) 322 Suurkuusk, M. (8) 154,155 Suwinski. J. (1) 257 Suzuki, K. (4) 260; (8) 189 Suzuki, N. (1) 35 Suzuki, T. (1) 2 12; (6) 1 1

Swamy, K.C.K. (4) 150; (8) 63,197 Swamelatha, U. (8) 212 Swavey, S. (3) 61; (8) 130 Swccney, J.B. (4) 217.218 Swiegers, G.F. (1) 271 Swiss, K.A. (1) 377; (6) 108, 109;

Switzcr, C. (5) 139,140 Sykara, G.D. (8) 59 Symons, M.C.R (1) 448; (8) 132 Synak, M. (4) 72 Szalontai, G. (1) 561 .

Swahn, B.-M. (4) 204,205

(8) 43

3 68 0rganophoJphom.s Chemistty

(4) 228 Tokitoh, N. (1) 245 Tollefson, M.B. (1) 171; (4) 261 Tolmachev, A.A. (1) 181,292,293 Tolstikov, A.G. (1) 84 Tolsliova, O.V. (1) 84 Tomas, A. (3) 11; (4) 106 Toomcy, L.M. (1) 110 Toplis, D. (6) 173 Tordo, P. (4) 270,297; (8) 134 Torreillcs, E. (1) 4 19 Torrence, P.F. (5) 29 Torres, T. (7) 32 Toto, S.D. (1) 280 Totschnig, K. (3) 23 Touhara, €I. (7) 167, 168 Touil, S . (4) 2 15 Toupet, L. (1) 50,142,439 Toure, S.A. (1) 439 Touzin, J. (7) 77 Toyota, K. (1) 455,463,464,468,

Tran Huy, N.H. (4) 231; (8) 193 Travers, K. (5) 8 Trimarw, L. (1) 11, 143 Trinkhaus, S. (1) 180 Trishin, Yu.G. (2) 12 Trohov. B.A. (1) 40-42 Trogu, E.F. (1) 226 Trost, B.M. (1) 25,208 Tmcl, 1. (4) 114, 130 Tsai, M.-D. (4) 45 Tse, H.L.A. (5) 50 Tso, P.O.P. (5) 112,113 Tsotinis, A. (5) 1 Tsuboi, S. (6) 123 Tsubouchi, A. (5) 9 Tsuchiya, T. (1) 6 Tsuji, K. (8) 13 1 Tsukamoto, M. (4) 18 1 Tsuruoka, H. (5) 33,34; (8) 243 Tsuruta, H. (1) 170 Tsuzuki, S. (8) 2 1 Tsvelkov, E.N. (1) 363; (3) 4; (4)

Tuckett, RP. (8) 10 Tukanova, S.K. (4) 296; (8) 225 Tumanskii, B.L. (1) 366; (4) 298;

Tungler, A. (1) 354; (4) 228 Tur, D.R (7) 136; (8) 144 Turk, M. (4) 5 Turkov. V.K. (7) 136 Turnbull, M.M. (1) 79 Turnbull, W.B. (1) 399 Turner, D.H. (5) 276 ,

Two, N.J. (1) 365

469,545; (8) 166

115

(8) 135,136

Szarka, L.J. (4) 236 Szcillosy, A. (6) 133 Szostak, J.W. (5) 282 Szydlowski, J. (8) 252 Szymanowicz, D. (5) 45

Tachibana, J. (4) 62 Tada, T. (1) 362 Taira, K. (5) 245,249; (8) 21 Tajima, K. (8) 139 Takagi, M. (5) 219 Takagi, R (6) 78 Takahashi, C. (4) 226 Takahashi, J.N. (4) 170 Takahashi, K. (7) 113 Takahashi, M. (4) 92 Takahashi, T. (1) 35 Takaki, K. (4) 260 Takasugi, M. (5) 22 1 Takaya, H. (1) 145, 160, 161; (3)

46,48; (6) 145 Takayasu, T. (4) 2 16 Takeda, M. (7) 108 Takeda, N. (1) 245 Takenaka, S. (5) 2 19 Tamami, B. (1) 243 Tamao, K. (1) 179 Tambute, A. (8) 247 Tan, B. (1) 348 Tan, J. (4) 285 Tanabe, K. (8) 2 1 Tanaka, A. (1) 225 Tanaka, K. (3) 36; (5) 214,215 Tanaka, M. (4) 240 Tang, C.C. (4) 74 Tanigaki, T. (7) 93 Taniguchi, M. (7) 110 Taniguchi, Y. (4) 260 Tanner, D.B. (1) 428 Tao, A. (4) 234,235 Taphanel. M.-H. (8) 2 16 Tarancnko, N.I. (5) 307 Tarazona, M.P. (7) 15 1, 152 Tarnowski, A. (4) 192 Tashev, E. (1) 343 Tashiro, K. (7) 75 Tashma, Z. (4) 259 Tasz, M.K. (4) 291 Talsuta, T. (4) 54 Tavener, S.J. (1) 406 Taylor, B.F. (5) 55 Taylor, N.J. (1) 360 Taylor, P.C. (4) 191; (8) 78 Taylor,R (1)211;(7)55 Taylor, S.D. (4) 139 Tchcrezov, S.V. (4) 96

Tchkhoua, C. (1) 347,348 Tea, C.G. (1) 439 Tebby, J.C. (1) 350,376 Tehim, A. (1) 260 Tclan, L.A. (4) 246; (6) 89 Tembe, G.L. (1) 220 Tenhuisen, K.S. (7) 156 Tepper, M. ( 1) 9 1,203 Terabc. S. (8) 250 Terato, H. (5) 63 Tmt'eva, S.A. (2) 13; (4) 274; (8)

Terfott, A. (1) 7; (8) 162 Terikovskaya, T.E. (1) 292,293 Tejerina, B. (1) 266 Termaten, A. (1) 474 Terron, G. (1) 487; (8) 7 Terry, M. (1) 82 Terwilliger, T.C. (5) 294 Terzi, M. (7) 200 Tcrzis, A. (4) 243 Teshclkova, RG. (1) 597 Texidor, F. ( I ) 22 Thadani, A.N. (4) 139 Thatchcr, G.RJ. (4) 168 Theil, F. (5) 78 Thiel, W. (8) 9 Thiem, J. (6) 139 Thmpathi, N. (2) 15 Thoen, K.K. (1) 447; (6) 9 Thocnncsscn,H.(1)218;(2) 17,25;

(4) 230; (6) 15; (8) 44, 48, 92, 167

50

Tholey, A. (8) 91 Thomaier, J. (1) 489; (6) 20 Thomas, C.J. (7) 57 Thomas, E.J. (6) 126-128 Thomas, K.R.J. (7) 79 Thomas, M. (5) 165 Thornton-Pett, M. (1) 178; (8) 96 Thorup, N. (1) 16; (8) 163 Thum, 0. (4) 48 Tian, W. (8) 97 Timofecv, E.N. (3) 37; (5) 217 Tinant, B. (4) 292; (8) 57,102 Tiripiwhio, A. (1) 23 Tishchenko, E.I. (3) 37; (5) 217 Tissot, 0. (1) 565,566 Tiwary, D. (1) 448 Tkachcnko, S.E. (1) 324,359 Tkachev, A.V. (4) 166 Toda, F. (7) 69 Toeke, L. (8) 203 Togni,A. (1) 1; (6) 162 Tohkai, N. (1) 362 Tok, O.L. (6) 39 Toke, L. (1) 150, 354, 383; (3) 8;

Aufhor. Index 3 69

Tuschl, T. (5) 256 Tworowska, I. (3) 27 Tyagi, S. (4) 11; (8) 52 Tye, H. (3) 44 Tyler, D.R (1) 132, 133 Tymkk, A.A. (4) 188

Uchimaru, T. (8) 2 1 Uchimura, M. (8) 189 Udseth, H.R (5) 295 Udupa, M.R (8) 212 Ueda, Y. (6) 62 Ueki, M. (4) 62 Uemura, K. (5) 204 Ueno, Y. (5) 152, 168-170 Ugarha, I.G. (1) 15 1,356 UghettomonCrn, J. (5) 77 Ugozzoli, F. (1) 23 Uhl, F.M. (1) 400 Uhlmann, E. (3) 43 Uhm, 13.1. (8) 45 Ujszaszy, K. (1) 383,564; (8) 156 Ulmen, M.D. (7) 178 Umctani, H. (6) 170 Umezawa, M. (7) 11 1 Uozumi, Y. (1) 183 Urata, H. (5) 92 Urbach, F.L. (3) 61; (8) 130 Urieta, J.S. (8) 149 Umezius, E. (1) 29 1; (8) 159 Urpi, F. (7) 29 Umolabeitia, E.P. (6) 63,64 Usman, N. (5) 99,173,249,255 Ustynuk, Yu.A. (1) 443; (6) 56 Usui, T. (4) 6,226 Uzelmeicr, C.E. (1) 24 Uziel, J. (1) 162,407

Vaghcfi, M.M. (5) 109 Vainiotalo, P. (4) 149 Valaskovic, G.A. (5) 299 Valentin Hanscn, P. (5) 149 Van A m h o t , A. (5) 136, 156, 159,

van Boom, J.H. (5) 135,244 164

~andcGrampe1,J.C. (7)99-101;(8) 175

van dcr Gcn, A. (6) 124 Van Dcr Helm, D. (4) 1 1; (8) 52 Vandcrlaan, A.C. (5) 135 van dcr Marel, G.A. (5) 244 van dcr Sluis, M. (1) 47 1,474 Vandesande, J.H. (5) 26 1 Vandorpe, J. (7) 130,196-198

van Hcijenoort, Y. (4) 57 Van Keer, A. (1) 481, 494, 523,

524,553; (8) 8 van Kotcn, G. (1) 172 van Lceuwen, P.W.N.M. (1) 173;

van Licr, J.E. (4) 127 Van Meergvelt, L. (1) 414; (5) 287;

Van Oostenryck, L. (4) 292; (8) 57,

Vanquickcnborne, L.G. (1) 48 1,

van Rooy, A. (3) 50 Vansco, G.J. (7) 2 Varbanov, S. (1) 343 Varnai, P. (1) 509 Vaschcnko, E.V. (1) 367; (8) 199 Vasqucz, P.C. (1) 239 Vassilcva, V. (1) 343 Vassiliou, S. (4) 189 Vasyanina, L.K. (3) 15, 16,22 Vazquez, P. (7) 32 Vedcjs, E. (6) 1 Vccman, W.S. (7) 137 Vciga, M.C. (6) 148 Veits, Yu.A. (1) 486 Veldman, N. (1) 47 1,474 Vepsalainen, I. (4) 149 Vercauteren, J. (5) 205 Verdine, G.L. (5) 190 Vcrgotcn, G. (7) 1 Verkade, J.G. (2) 10,22,23; (4) 229 Vcrleysen, K. (8) 249 Vcron, M. (5) 62 Vcroncse, F.M. (5) 82; (7) 200 Vichier Guerre, S. (5) 66 Vidal, A. (1) 261; (6) 135 Vidal, C. (7) 67, 115 Vidal, J.P. (6) 135 Vij, A. (7) 117; (8) 58 Vilaplana, J.M. (6) 149 Vilarrasa, J. (7) 29 Vilkov, L.V. (8) 19 Vinadcr, M.V. (1) 261 Vinod, T.K. (4) 43 Viscardi, G. (7) 144 Visotsky, M.A. (4) 15; (8) 236 Visscher, K.B. (7) 78.84 Vitcrbo, D. (3) 5 1 Vlieghe, D. (5) 287 Voegcl, J.J. (5) 65, 193 Vogel, C. (6) 139 Vogl, G. (7) 54 Vogt, H. (1) 424; (7) 59 Vojtisek, P. (4) 263

(3) 50

(6) 13

102

494,523,524,553; (8) 8

van Hcijcnoort, J. (4) 57,58 Volbrecht, S. (2) 18

Volkcrt, W.A. (1) 134; (4) 245 Volkov, E.M. (5) 146 Vollbrecht, A. (1) 306; (2) 18 Vollmerhaus, R (7) 120; (8) 179 Voncente, J. (6) 65 von dcr Goenna, V. (1) 548 von Itzstcin, M. (1) 248; (4) 159 Vonkrosigk, U. (5) 177 von Matt, P. (5) 137, 138 von Schnering, H.G. (1) 37; (7) 42 Vorherr, T. (4) 59 Vorontsov, E.V. (6) 39 Votruba, I. (5) 28 Vriezc, K. (1) 172,173 Vu, C.Q. (5) 48 Vylc, J.S. (5) 6 1, 180 Vysotsky, M.A. (4) 12; (8) 190

Wada, T. (5) 33,34,93; (8) 243 Wagatsuma, W. (6) 150 Wagman, A.S. (4) 42 Wagner, J. (4) 186 Wagner, 0. (1) 555; (3) 13 Wagner, RW. (5) 203 Wagner, T. (1) 138 Waid, RD. (7) 106 Wakabayashi, T. (4) 54 Walczak, K. (1) 257 Waldmann, H. (4) 60,65 Waldner, A. (5) 124,125 Waldvogcl. S.R (1) 188 Walker, K.L. (5) 97 Walker, M.A. (1) 250 Walker, 0. (1) 58,93 Wallace, E.M. (4) 285 Walsh, C.T. (4) 280 Walter, C. (4) 52 Walton, D.RM. (1) 21 1 Waltz, M. (1) 98 Walz, L. (7) 42 Wan, H. (4) 7 Wan, J.-L. (8) 88 Wancewicz, E. (5) 155 wandrey, c. (4) 57 Wang, A.L. (1) 56 Wang, B. (1) 567; (3) 19 Wang, C. (1) 574; (8) 214

Wang, G.Y. (5) 148.15 1

Wang, H.Q. (1) 56,158 Wang, J. (5) 121, 131

Wang, Q. (3) 11; (4) 106; (6) 10;

Wang, Q.S. (8) 237,245

Wang, D.-S. (4) 39

Wang, H.-G. (8) 185

Wang, J.-C. (3) 28-30; (5) 36

(8) 217


Wang, S.Q. (5) 306 Wang, X. (I) 182 Wang, X.D. (1) 56 Wang, Y.M. (4) 74 Wang, Z. (7) 116

Warnecke, J.M. (5) 250 Warner, 1.M. (8) 248 Warner, P.M. (1) 478 Warner, S. ( I ) 502 Warren, S. (1) 317, 332-340; (6)

Warshel, A. (4) 79 Waschbusch, K. (1) 609 Waschbusch, R (4) 122, 132, 137,

Wasserman, H.H. (6) 134 Wasylishen, RE. (1) 521; (3) 58;

Watanabe, K.A. (5) 5840,216 Watanabc, M. (6) 132 Watanabc, Y. (4) 32,46 Watkins, C.L. (1) 108 Watson, J.T. (5) 305 Watt, G.M. (4) 56 Wawer, A. (8) 252 Wawrzencqk, C. (6) 119 Way, W.K. (7) 202 Weakley, T.J.R (1) 34, 132,133 Webb, G.A. (8) 118 Webb, T.R. (1) 379 Weber, L. (1) 490, 491, 520, 539;

Wedgwood, O.M. (5) 2 Wehman, P. (1) 173 Wei, C.F. (5) 199-202 Wei, D. (4) 285 Weigt, A. (4) 128 Weiler, K. (5) 155 Weimar, V. (4) 69 Weinberger, S.R (5) 3 13 Weinmann, R (1) 3 1 Weinstein, L.B. (5) 39,40 Welch, A.J. (1) 453 Welker, M.F. (7) 19 Weller,F. (1) 617; (6) 61; (7) 7,65;

Weller, M.P. (7) 184 Welling, L.L. (1) 200 Wells, R.L. (1) 63, 106,236,237 Welzel, P. (4) 57,58 W e r n e r , D.E. (5) 191; (7) 38; (8)

Wen, T.-B. (1) 55, 158 Wendeborn, S. (5) 116,123-125 Wendt, H.D. (7) 49 Weng, X. (4) 286

Wang, Z.-X. (8) 180

110-1 18; (8) 186

147

(8) 20

(6) 33

(8) 103

253

Wengel, J. (5) 91, 160,260 Wengrovius, J.H. (7) 53 Wensing, M.W. (8) 221,222 Went, M.J. (1) 198 Wentrup, C. (4) 256 Werner, B. (1) 1 13 Werner, J.H. (8) 215 Wessels, P.L. (8) 98 Wessolowski, H. (4) 123 Westerhausen, M. (1) 617; (8) 103 Westwick, J. (4) 30 Wheatley, M. (7) 191 Wheeler, J.W. (1) 350 Wheeler, P.D. (5) 155 White, A.J.P. (1) 165, 166, 168,

492,515; (6) 169 White, M.L. (7) 47, 128; (8) 176 White, P.S. (1) 63,237; (8) 33 White, R (1) 344 Whitesides, G.M. (4) 158; (8) 89 Whitla, W.A. (1) 502, 521; (3) 58;

Whitnall, M.R (1) 178; (8) 96 Whittal, RM. (5) 3 13 Whltten, W.B. (8) 218 Wiberg, N. (1) 97,456 Wichern, J. (7) 12 Wicht, D.K. (1) 139 Wickham, G. (5) 27 I Widhah, M. (1) 20 Widlanski, T. (4) 102,156 Wieczorek, M.W. (1) 374,375; (4)

190, 208, 251; (6) 129; (8) 49, 67,191

(8) 20

Wiecmrek, P. (4) 153 Wicderholt, K. (5) 222 Wiegand, T.W. (5) 283 Wienk, M.J. (1) 308 Wienk, M.M. (8) 140,141 Wienk, M.W. (6) 8 Wieringa, RH. (7) 100 Wiesemann, F. (7) 11 Wiest, L. (4) 283 Wild, S.B. (1) 27 1,558 Wilk, A. (5) 89, 157 Wilkens, H. (1) 535 Wilkes, R.D. (1) 34 1 W i b o n , M.P. (1) 154 Willaredt, J. (7) 42 Willett, G.D. (1) 290; (7) 116; (8)

213 Williams, D.J. (1) 165, 166, 168,

311,492,515;(6) 169;(7)24 Williams, D.M. (5) 61 Williams, I.D. (1) 70, 174 Williams, P.G. (7) 38; (8) 253 Williams, RM. (6) 164

Williamson, M.P. (5) 61 Willis, A.C. (1) 200,271 W&,M. (1) 12; (3) 44.45; (4) 221 Wilson, S.R (1) 377; (6) 108,109;

Willon-Ely. J.D.E.T. (1) 492.5 15 Wimmer, N. (4) 55 Wimmcr, P. (1) 20 Wincolt, F. (5) 99,249 Windisch, C.F., Jr. (7) 178 Winkler, U. (1) 94,507 Winnemaller, J. (1) 476 Winruk, M.A. (7) 142,143 Winniman, M. (5) 107 Winograd, N. (7) 202 Winter, H. (7) 101; (8) 175 Winter, M. (1) 532 Wirz, J. (1) 364 Wisian-Neilson, P. (7) 18, 145 Wit, J.B.M. (1) 471 Witt, E. (1) 75.77.54 I Wittig-Kochlcr, S. (8) 21 1 Wadislaw. B. (4) 208 Wocvadlo, S. (7) 6 Warner, A. (1) 97 Wolf, RM. (5) 116, 123, 124 Wong, C.-H. (4) 50.84 Wong. C.Y. (2) 3,28 Wong, K.-T. (4) 93 Wong, M.W. (4) 256 Won& W.K. (1) 174; (6) 68 Wong, Y.-L. (4) 70 Woo, H.G. (1) 114 Wood, N.P. (1) 34 Woodtoffe, T.M. (1) 317; (7) 98;

Woollins, J.D. (1) 31 1,554; (3) 18;

(8) 43

(8) 173

(4) 95,212,213; (7) 21-25; (8) 47,192

Woolton, J.L. (8) 148 Worm, K. (1) 28 WGrncr, A. (1) 456 Womann, R (7) 12 Wostcr, P.M. (4) 283 Wozni& L.A. (5) 42 Wrackmeycr, B. (1) 608; (8) 69 Wright, D.S. (1) 107; (7) 83 Wroblewslii, A.E. (2) 10; (4) 229

Wu, D. (1) 55 Wu, G. (8) 122

WU, B.-M. (1) I 1 1

WU, H.-M. (1) 210 WU, H.-S. (7) 74,90-92 WU, M.-J. (6) 90 Wu, Q.Y. (5) 293 Wu, R (4) 283 WU, S.-H. (1) 210

Author Index 37 1

WU, T.-J. (6) 49 Wurthwein, E . 4 . (1) 482 Wulff-Molder, D. (1) 424 Wyatt,P. (1)317,334;(6) 113 Wycisk, R (7) 182 Wyder, M.A. (4) 279

Xia, C.-G. (1) 123, 124; (8) 113 Xia, W. (4) 41 Xiang, G.B. (5) 182 Xiang, Y.J. (5) 18 Xiao, D. (1) 65,66 Xiao, W.-J. (6) 49 Xic, J. (5) 90 Xin, S. (1) 114 Xin, Y.-C. (4) 159

Xu, C. (6) 50 Xing, X.-D. (8) 97

XU, C.-B. (8) 97 XU, D.-X. (1) 158 XU, J.-F. (1) 2 10 Xu, J.X. (1) 176 Xu, N.X. (5) 305 Xu, P. (3) 19 Xu, Q.H. (5) 100,101 Xu, Y. (4) 276; (6) 85 Xu, Y.Z. (5) 187 Xu, Z. (1) 2 15

Xue, F. (6) 68 XU, Z.-Q. (1) 254; (4) 276; (5) 20

Yabui, A. (8) 189 Yafai, F. (4) 36 Yagi, T. (6) 102 Yahya-Zadeh, A. (1) 213; (6) 43 Yakhvarov, D.G. (1) 202

Yamada, I. (1) 26,27 Yamada, K. (6) 132 Yamada, T. (4) 273 Yamagami, K. (5) 5 Yamagishi, T. (1) 26, 27; (4) 154,

Yamaguchi, H. (1) 212; (6) 1 1 Yamaguchi, M. (1) 26,27 Yaniaguchi, S. (1) I79 Yamamoto, G. (6) 153 Yanamoto, H. (4) 8 1 Yarnamoto, I. (6) 32 Yamamoto, K. (5) 127; (6) 153

Yamamoto, T. (4) 46 Yamamura, S . (4) 162 Yaniana, K. (3) 10; (4) 13 1 Yanianoi, Y. (1) 267

Yakout, E.4.M.A. (6) 125

203

Yamamoto, s. (7) I 1 1

Yamashita, M. (4) 97,226; (8) 189 Yamashita, T. (4) 3 Yamashita, Y. (6) 157, 158 Yamshita, M. (4) 6

Yan, C. (1) 254 Yan, Q.J. (5) 306 Yanagisawa, A. (4) 8 1 Yanchuk, N.I. (8) 257,258 Yanez, M. (1) 277,278 Yang, C. (6) 165

Yang, G.S. (8) 237

Yang, M. (8) 218 Yang, S.C. (5) 306

Yang, X. (8) 244

Yan, B.-W. (8) 245

Yang, G.-F. (4) 223

Ymg, H.-2. (4) 223; (8) 237,245

Yang, w. (1) 43

Yang, X.-F. (8) 100 Ymg, X.-J. (8) 97 YMg, Y.C. (7) 109 Yang, Y.Z. (6) 3 Yang, Z. (4) 80, 197; (7) 103

Yanovsky, A.I. (1) 39 7 Yao, J. (I) 441,442,458; (6) 46,47 Yao, X.-K. (8) 185 Yao, Y. (1) 126 Yaouanc, J.J. (2) 24 Yap, G.P.A. (1) 36,485 Yarkova, E.G. (8) 200 YashunsLy, D.V. (1) 403 Yasuc, K. (4) 81 Yasui, S. (1) 269 Yasuike, S. (1) 6 Yavari, I. (1) 213, 214, 216,

Yavari, Y. (6) 42-45 Yazbak, A. (6) 136 Ye, B. (4) 145 Yegmch, H. (1) 243 Ychta, A. (7) 142, 143

Yano, s. (7) 75

436-438; (6) 52.53

Yco, w.-s. (1) 433 Ycug, L.-L. (1) 330,33 1 Yi. T. (6) 80 Yiidiz, M. (7) 86, 118 Yiotakis, A. (4) 189 Yip, P.F. (5) 275 Yip, T.T. (5) 308 Yohihuji, M. (8) 166 Yokomatsu, T. (4) 134, 135, 154,

Yokoyama, K. (6) 102 Yom, J.W. (3) 19 Yonci, S . (5) 174 Yoon, H.S. (7) I 1 3 Yoon, T.H. (1) 347

178, 195,203; (6) 100

Yoshida, A. (3) 48 Yoshida, M. (5) 63 Yoshida, S. (6) 103 Yoshida, T. (6) 153 Yoshida, Y. (4) 178 Yoshifuji, M. (1) 455, 459, 463, 464,468,469,545; (8) 13 1

Yoshimura, M. (4) 18 1 Yoshimura, Y. (6) 132 Young, K.J. (5) 180,253,254 Yu, D. (3) 33; (5) 90, 104 Yu, H. (6) 15 1 Yu, S. (8) 214

Yuan, C. (4) 271; (6) 98

Yuan, G. (8) 217 Yun. H. (7) 80 Yurchenko, RI. (1) 301

Yu, S.Y. (5) 79

Yuan, C.4. (4) G6

Zabarylo, S.V. (5) 95 Zabirov, N.G. (8) 137 Zablocka, M. (1) 495,572 Zadlo, A. (1) 378 Zagorowska, I. (5) 257 Zagumennov, V.A. (4) 103 Zahcr, H. (4) 259,294; (8) 127 Zain, R (5) 12,32 Zaitseva, G.V. (5) 67,68 Zakharov, A.V. (8) 137 Zamaraev, K.I. (1) 84 Zamkova, V.V. (4) 296; (8) 225 Zancllo, P. (7) 79 Zanetti, N.C. (8) 122 Zanin, A. (1) 305 Zanotto, L. (6) 66 Zantour, H. (1) 345; (4) 164.2 15 Zapechel'nyuk, L.E. (8) 137 Zapf, A. (1) 157 Zatorski, A. (5) 58,59 Zawodzinski, T. (7) 166 Zeghdaoui. A. (4) 270 Zchl, A. (5) 70 Zehnder, M. (5) 150 Zcldin, M. (7) 121 Zcmlyanshy, N.N. (1) 443; (6) 56 Zcnncck, u. (1) 584

Zerba, G. (7) 180, 181 Zcmova, E.V. (8) 24 Zhang, A.J. (8) 226

Zhang, D. (4) 98

Zhang, F.J. (5) 47 Zhang, H. (1) 348

Ze-Qi, X. (6) 85

Zhang, c. (7) 18 Zhang, D.-W. (1) 2 10


Zhang, J. (1) 43; (4) 238

Zhang, L. (6) 68

Zhang, L.H. (5) 245,249 Zhang, M. (4) 98

Zhang, P.M. (5) 178 Zhang, P.Z. (5) 41,94 Zhang, Q.M. (5) 174 Zhang, R (8) 244 Zhang, W. (1) 164 Zhang, X. (1) 46,49,52,65,66,82 Zhang, X.R (5) 54 Zhang, Y. (1) 350 Zhang, Y.H. (5) 298

Bang, J.-X. (1) 405; (6) 12

Zhang, L.-F. (8) 1

Zhang, N.-J. (2) 8; (8) 75,230

Zhang, Y.-X. (4) 271 Zhang, Y.-Z. (6) 98

Zhao, B.P. (5) 234 Zhao, K. (5) 18 Zhao, Y.-F. (2) 8; (8) 75,230 Zheng, C. (4) 197 Zheng, D.H. (1) 234 Zheng, L. (8) 214 Zhilinskaya, E.A. (8) 19 Zhou, D.M. (5) 245,249 Zhou, J. (4) 9; (8) 184, 185 Zhou, P. (1) 41 1 Zhou, w. (5) 90 Zhou, Y.Z. (5) 112-1 14 Zhu, B.Z. (5) 306 Zhu, G. (1) 49,52,65,66,82 Zhu, L.M. (5) 57 Zhu, Y.F. (5) 307 Zhu, Z. (6) 80 Ziegler, T. (1) 371,457; (6) 6

Zicsscl, R (1) 60 Zillcr, J.W. (1) 121 Zimmer, H. (1) 423,446; (8) 146 Zimmerman, R (6) 84 Zmk, J.I. (8) 148 Zipsc, H. (4) 87 Zon, J. (6) 119 Zotti, G. (1) 11 Zouh, H. (8) 69 Zsolnai, L. (1) 532 Zubov, D. (5) 87 Zuchi, Gh. (8) 152 Zurawinslii, R (4) 25 1; (6) 129 Zverev, D.V. (6) 39 Zwancnburg, B. (4) 72 Zyablikova, T.A. (1) 597 Zygmunt, J. (4) 153

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