ORGANIC REACTION MECHANISMS 1984 - Startseite...2 Organic Reaction Mechanisms 1984 function of the pK, of ArOH and therefore also of the C--O bond length. This implies that there is

ORGANIC REACTION MECHANISMS 1984

An annual survey covering the literature dated December 1983 through November 1984

Edited by

A. C. KNIPE and W. E. WATTS, University of Ulster, Northern Ireland

A n Interscience@ Publication

JOHN WILEY & SONS Chichester - New York - Brisbane - Toronto - Singapore

ORGANIC REACTION MECHANISMS * 1984

ORGANIC REACTION MECHANISMS 1984

An annual survey covering the literature dated December 1983 through November 1984

Edited by

A. C. KNIPE and W. E. WATTS, University of Ulster, Northern Ireland

A n Interscience@ Publication

JOHN WILEY & SONS Chichester - New York - Brisbane - Toronto - Singapore

Copyright @ 1986 by John Wiley & Sons Ltd.

All rights reserved.

No part of this book may be reproduced by any means, nor transmitted, or translated into a machine language without the written permission of the publisher.

Library of Congress Catalog Card Number 66-23143

British Library Cataloguing in Publication Dnta:

Organic reaction mechanisms : an annual survey covering the literature dated December 1983 through November 1984.

1. Chemistry, Physical organic-Periodicals 2. Chemical reactions-Periodicals I. Knipe, A. C. 547.1'394'05 QD476

ISBN 0 471 90797 9

-1984

11. Watts, W. E.

Phototypeset by Macmillan India Ltd. Printed and bound in Great Britain by the Bath Press, Bath, Avon

Contributors

A. ALBERT1

D. C. BILLINGTON

C. CHATGILIALOGLU

D. J. COWLEY

R. A. COX

M. R. CRAMPTON

G. W. J. FLEET

R. B. MOODIE

C. J. MOODY

R. A. MORE O’FERRALL

A. W. MURRAY

M. I. PAGE

R. M. PATON

J. SHORTER

W. J. SPILLANE

C. I. F. WATT

Istituto dei composti del carbonio, Con- tenenti eteroatomi e lor0 applicazioni, Consiglio Nationale delle Ricerche. Bologna, Italy

Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex

Istituto dei cornposti del carbonio, Con- tenenti eteroatomi e lor0 applicazioni, Consiglio Nationale delle Ricerche, Bologna, Italy

Department of Chemistry, University of Ulster

Department of Chemistry, University of Toronto, Canada

Department of Chemistry, Durham Uni- versity

Dyson Perrins Laboratory, Oxford Uni- versity

Department of Chemistry, University of Exe ter

Department of Chemistry, Imperial Col- lege of Science and Technology, London

Department of Chemistry, University Col- lege, Dublin, Ireland

Department of Chemistry, University of Dundee

Department of Chemical Sciences, Huddersfield Polytechnic

Department of Chemistry, University of Edinburgh

Department of Chemistry, University of Hull

Chemistry Department, University Col- lege, Galway, Ireland

Department of Chemistry, University of Manchester

V

The present volume, the twentieth in the series, surveys research on organic reaction mechanisms described in the literature dated December 1983 to November 1984. In order to limit the size of the volume, we must necessarily exclude or restrict overlap with other publications which review specialist areas (e.g. photochemical reactions, biosynthesis, electrochemistry, organometallic chemistry, surface chemistry and heterogeneous catalysis). In order to minimize duplication, while ensuring a comprehensive coverage, the editors conduct a survey of all relevant literature and allocate publications to appropriate chapters. While a particular reference may be allocated to more than one chapter, we do assume that readers will be aware of the alternative chapters to which a border- line topic of interest may have been preferentially assigned.

We welcome one new contributor, Dr. R. A. More O’Ferrall who is well known for his use of energy contour diagrams as an aid to interpretation of transition state character. His expertise is particularly appropriate to the elimination chapter which was previously written by Professor A. F. Hegarty, of the same department and to whom we extend our thanks for his annual contribution since we assumed editorship in 1977.

On behalf of the contributors we are pleased to acknowledge the many very favourable reviews of this now well established series which have appeared in professional journals. A common feature of such reviews has been an appreci- ation that the volume provides a comprehensive, yet readable, insight into the recent literature without recourse to other information retrieval techniques which may be relatively unsuitable for mechanistic topics. This was of course the aim of Brian Capon, John Perkins and Charles Rees when they launched Organic Reaction Mechanisms twenty years ago. We have attempted to maintain the standards set by the original editors and must acknowledge the sustained efforts of our team of experienced contributors, the publication and production staff of John Wiley and Sons, and Dr. N. Cully who compiled the subject index.

A.C.K. W.E.W.

vii

Contents

1 . 2 . 3 . 4 . 5 . 6 . 7 . 8 . 9 .

10 . 11 . 12 . 13 . 14 . 15 .

Reactions of Aldehydes and Ketones by M . I . Page . . . . . . . . . . . . . . Reactions of Acids and their Derivatives by W . J . Spillane . . . . . . . .

Radical Reactions: Part 2 by D . J . Cowley ..................... Oxidation and Reduction by G . W . J . Fleet ..................... Carbenes and Nitrenes by C . J . Moody ........................ Nucleophilic Aromatic Substitution by M . R . Crampton . . . . . . . . . . Electrophilic Aromatic Substitution by R . B . Moodie . . . . . . . . . . . .

Nucleophilic Aliphatic Substitution by J . Shorter . . . . . . . . . . . . . . . . . Carbanions and Electrophilic Aliphatic Substitution by C . I . F . Watt Elimination Reactions by R . A . More O’Ferrall . . . . . . . . . . . . . . . . . Addition Reactions-1 . Polar Addition by D . C . Billington . . . . . . . Addition Reactions-2 . Cycloaddition by R . M . Paton . . . . . . . . . . . Molecular Rearrangements by A . W . Murray . . . . . . . . . . . . . . . . . . .

Radical Reactions: Part 1 by A . Alberti and C . Chatgilialoglu .....

Carbocations by R . A . Cox . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 33 87

139 179 227 249 269 283 303 333 361 385 401 431

Author Index. 1984 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 Subject Index. 1980-1984 ........................................ 581

ix

Organic Reaction Mechanisms 1984 Edited by A. C. Knipe and W. E. Watts 0 1986 John Wiley & Sons Ltd.

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives

M. I. PAGE

Department of Chemical & Physical Sciences, Huddersfield Polytechnic

Formation and Reactions of Acetals and Ketals . . . . . . . . . . . . Reactions and Formation of Glycosides . . . . . . . . . . . . . . .

Non-enzymic Reactions . . . . . . . . . . . . . . . . . . . . 5 Enzymic Reactions. . . . . . . . . . . . . . . . . . . . . . 7

Reactions and Formation of Nitrogen Bases . . . . . . . . . . . . . 8 Schiff Bases and Related Species. . . . . . . . . . . . . . . . . 8 Hydrazones, Oximes, and Related Compounds . . . . . . . . . . . . 12

Aldol and Related Reactions . . . . . . . . . . . . . . . . . . . 14 Other Addition Reactions . . . . . . . . . . . . . . . . . . . . 16 Enolizatioa and Related Reactions. . . . . . . . . . . . . . . . . 22 Hydrolysis and Other Reactions of Enol Ethers and Related Compounds . . . 25 Other Reactions . . . . . . . . . . . . . . . . . . . . . . . 26 References . . . . . . . . . . . . . . . . . . . . . . . . . 27

1 5

Formation and Reactions of Acetals and Ketals

The length of the C-0 bond in ethers and esters increases with increasing electron withdrawal in the substituent attached to oxygen and as the carbon changes through methyl, primary, secondary, and tertiary. There is an inverse linear correlation between the bond length C - O R and the pK, of ROH. Although increasing the polarity of bonds is traditionally associated with shorter and stronger bonds the evidence does not support this for carbon-heteroatom bonds in general. It is therefore suggested that longer C-0 bonds are associated with an increase in the contribution from the ionic valence bond tautomer 6 OR.' The trends in the lengths of the bonds at the acetal centre of axial aryl tetrahydropyranyl acetals (1) noted earlier have been confirmed. The C-OAr bond length increases whilst the ring C- 0 bond length decreases with decreasing pK, of ArOH. These effects on bond lengths practically disappear on going to the a-glucopyranosides, presumably because of the four oxygen substituents. For equatorial tetrahydropyranyl acetals, the more electron-withdrawing O R group is associated with a longer exocyclic C- OR bond and a shorter endocyclic bond. Stereoelectronically this cannot be attributable to oxygen lone-pair donation and is thought to arise from IJ C-0 bond donation.'

The rate constants for the spontaneous hydrolysis of aryl acetals is a linear

1

2 Organic Reaction Mechanisms 1984

function of the pK, of ArOH and therefore also of the C--O bond length. This implies that there is a linear region in the first half of the reaction coordinate for cleavage of the C-0 bond.3

Kinetic solvent isotope effects for the acid-catalysed hydrolysis of benzaldehyde acetals show little variance, k,+/k,+ = 3.2k0.2, over a lo3 change in reactivity. Together with the invariance of the BrQnsted a value for general acid catalysis this is taken to indicate rate-limiting diffusional separation of the aggregate (2). Weakly basic leaving alcohols, ROH, and stable oxo-carbocations cause a change in the rate- limiting step to formation of (2). These arguments would not be valid if the hydronium ion and general-acid-catalysed reactions occurred by different mechanisms."

A - HOR do*' A~CHAOR'

The secondary kinetic deuterium isotope effect for general-acid-catalysed hydrolysis of benzaldehyde ethyl phenyl acetal increases from 1.06 to 1.26 as the pK, of the catalyst increases. This is inconsistent with rate-limiting diffusion apart of the ion- pair formed rapidly and re~ersibly.~ As previously shown, the BrQnsted a value decreases from 0.7 to 0.5 as substituents in the phenoxy leaving group become more electron-withdrawing. Also as described earlier the BrQnsted coefficient is thought not to be a measure of the degree of proton transfer but is an indication of the ease of cleavage of the C 4 A r bond.5

Although the rate nf the acid-catalysed hydrolysis of benzaldehyde di-terr-butyl acetal is 10' faster than the corresponding diethyl acetal, the BrQnsted a values for general acid catalysis are the same. It seems that the rate acceleration associated with relief of steric strain does not affect the degree of concertedness of the proton transfer and the C-0 bond-breaking processes. The electronic effect appears to be the dominant feature controlling concertedness.6

Stereoelectronic effects in acetal hydrolysis have been reviewed.' The solvent dependence of secondary deuterium isotope effects on the

hydronium-ion-catalysed hydrolysis of acetaldehyde diethyl acetal and ethyl vinyl ether suggests that the ethoxyethyl cation intermediate (3) becomes sufficiently unstable in aqueous dioxan for the mechanism to become concerted ((4) and (5)).'

The rate of the pH-independent hydrolysis of 2-(4nitrophenoxy)tetrahydropyran in water-aprotic solvent mixtures may be correlated with a variety of parameters. The solvent effects are dominated by changes in entropies of activation. Dispersion effects are not dominant and the solvent exerts its effect mainly by hydrogen bonding in the dipolar transition state.g

Sulphonaphthoxyacetic acids act as general acid catalysts for the hydrolysis of 2- (p-nitrophen0xy)tetrahydropyran (6) and are 20-fold more effective than the reactivity predicted from their pK,. This could be attributable to the sulphonate

1 Reactions of Aldehydes and Ketones and their Derivatives 3

H

( 5 ) (6)

anion stabilizing the incipient carbonium ion or to a hydrophobic interaction between the catalyst and substrate."

The general-acid-catalysed hydrolysis of 2-(2,2,2-trifluoroethoxy)tetrahydropyran shows a Br$nsted a value of 0.7, similar to that for benzaldehyde 0-ethyl 0-2,2,2-trifluoroethyl acetal hydrolysis. There is no general acid catalysis observed in the hydrolysis of the tetrahydropyran ethyl acetal and it is suggested that hydrolysis occurs by the classical A1 mechanism."

The effect of substituents on the equilibrium constant for dimethyl acetal formation from substituted acetophenones has been determined in methanol, water, and dodecane. The Hammett p" values in these solvents are 1.73, 0.99, and 1.81, respectively, which is interpreted by the inductive effect on the stability of the ketone and specific inhibition of acetal solvation."

The 13C-NMR spectrum of N-acetyl-L-phenylalanil in the presence of a- chymotrypsin shows a signal attributable to the formation of a hemiacetal. At pH =- 7 two signals for the hemiacetal appear which are pH-dependent but the reason for this is not known.I3

The acid-catalysed hydrolysis of 2-methoxy-2-phenyltetrahydrofuran at pH 6 involves rate-limiting formation of the oxocarbocation with exocyclic cleavage of the C 4 M e bond. Below pH 5 the rate-limiting step changes to breakdown of the hemiketal intermediate (7). Hydroxide ion catalysis makes hemiketal decomposition faster at higher pH whereas acid catalysis for this step is slower than formation of the oxo-carbocation. '

Monomeric 3-mercaptopropanol has been characterized in the gas phase and is not in equilibrium with the thio-hemiacetal (8).'*

The chemistry of cyclopropanone hemiacetals has been reviewed.I6 Acid-catalysed dehydration of the 4-methylene-l,3-dioxolane (9) or the keto vinyl

ether (10) gives the benzofuran (11) presumably via the same intermediate oxo- carbocations."

4 Organic Reaction Mechanism 1984

H O phk3

Me

Me

I Me

Tetrahydrofurfural acetals give the expected carbocations in fluorosulphonic acid which then rearrange to (12).’*

Lactam acetals (13) undergo exchange of the methoxyl groups through the imminium ion (14) or the corresponding enamine.lg

The 1,3-dioxolane (15) ring-opens upon treatment with alane RAlMe,. Nucleophilic attack on the ketal methylene allows one of the ketal oxygens to open the epoxide aided by the Lewis acid catalyst.20

The kinetic evidence for the mercury( 11)-promoted hydrolysis of 2,2-diphenyl-1,3- thiolane is compatible with rate-limiting intermolecular attack of water on the Hg2 +-S,S-acetal adduct ( 16).21 The kinetics differ completely from those previously reported for the 0,S-acetal.22

Hydrolysis of 2-methylene-l,3-dithiolane proceeds by rate-limiting carbon protonation to give the carbocation as an intermediate above pH 3 and at zero buffer concentration. With increasing buffer concentration hydration of the carbocation becomes progressively rate-limiting. Below pH 2 breakdown of the orthoester (17) is the slowest step.23

“H3?Me N O M e

I

I Reactions of Aldehydes and Ketones and their Derivatives 5

a,/?-Unsaturated ketones react selectively in the presence of a saturated ketone with ethylene glycol if 2,4,6-collidinium p-toluenesulphonate is used as a catalyst. Steric shielding of the proton in the salt is suggested to be responsible for this chem~selectivity.’~

Hemiacetal formation from substituted aromatic aldehydes and methanol in methanol4ioxan mixtures has been observed.”

Chemoselective reductive cleavage of ketals and acetals is also observed using monochloroborane etherate as the reducing agent.’6

The kinetics and mechanisms of radical reactions of cyclic acetals have been reviewed.”

Reactions and Formation of Glycosides

Non-enzymic Reactions Examination of 1 1 1 carbohydrate derivatives from the Cambridge Crystallographic Data Base shows that all a- and B- glycosides exist with the exo-oxygen in a conformation with lone pairs antiperiplanar to the C( 1)-ring-oxygen bond. It is sometimes forgotten that the ex0 anomeric effect exists and in terms of double- bond-no-bond resonance (18) would be expected to lead to a shorter C(l)-exo- oxygen bond and a longer C(1)-ring-oxygen bond. This is indeed found in the B- glycosides although ring C(l)--O bonds are near the standard value. In the axial a- glycosides there is relatively little difference between ring and ex0 C( 1)--0 bonds, although both are shorter than the standard but longer than that found in the B- anomers. Of course, when interpreting these observations it should be remembered that any CX, grouping has a reduced C-X bond length because of the electronegativity of X.”

The ratio of rates of departure of pyridines from a- and B-glycosyl and -xylopyranosyl pyridinium salts (19) and (20) are about 80 and 10, respectively. In glycosyl transfer there is thus no evidence to support the too readily accepted notion that antiperiplanar lone pairs of electrons on oxygen favour departure of the leaving group. An often neglected point in the use of stereoelectronic effects to rationalize


experimental observations is the presumably variable interaction between orbitals which is dependent upon the degree of bond breaking in the transition state. Since the transition state for glycosyl transfer strongly resembles the intermediate oxo- carbocation the antiperiplanar lone-pair hypothesis is of limited importance. It is suggested that the antiperiplanar lone-pair hypothesis is a special case of the principle of least nuclear motion.29

The acid-catalysed hydrolysis of 9-(/3-~ribofuranosyl)purine proceeds by rate- limiting departure of the mono- and di-protonated purine and formation of the glycosyl oxo-carbocation at high acid concentration. In less acidic solution opening of the imidazole ring occurs.Jo The alkaline hydrolysis of 94 1 -alkoxyethyl)purines involves rate-limiting attack of hydroxide ion on C(8) of the purine.31

The rate of the acid-catalysed hydrolysis of 3-/3-C-ribofuranosylwye (21), the most probable structure for wyosine, is ca. lo6 faster than common nucleosides which is attributable to the 3-methylguanosine residue. A reduction in steric repulsion between the Cmethyl and 3-ribofuranosyl groups is thought to be responsible for the rapid hydrolysis. Under alkaline conditions the glycosidic bond and the base moiety of (21) are cleaved c~rnpetitively.~~

The energy of activation for the acid-catalysed hydrolysis of sucrose does not change with temperature over the range 0-60". This is in contrast to previous results

HO OH

0 II

I Rib Me

R \I

+ Yii,,,,

Y

Ql 0' Me


which often involved a comparison of observations made at different concentrations of sucrose and acid.33 NMR evidence suggests that 1,4-anhydro-6-azido-2,3-di-O-benzoyl-6-deoxy-~-~

galactopyranose from l-O-acetyl-2,3-di-O-benzoyl-4,6-bis-O-(methylsulphonyl)-a- Dglycopyranose by treatment with sodium azide occurs by neighbouring-group participation of the C(l) ~ x y - a n i o n . ~ ~ A kinetic study of the conversion of carbohydrate 1,2-orthoesters to 1,Ztrans-

glycosides suggests that the isomerization occurs by an intramolecular mechanism via the acyloxonium ion (2Z).35

The kinetics of the base-catalysed rearrangement of glyoxal and 3-deoxy-D erythro-hexos-2-ulose have been compared in different solvents.36

In the final phase of the formose reaction, sugars are formed by the reaction of glycolaldehyde, glyceraldehyde, and dihydroxyacetone. A quantitative analysis of intermediates suggest that metal-ion-catalysed aldol reactions occur.37

The Knoevenagel reaction of aldehydo sugars with active methylene compounds has been inve~tigated.~~

The acid-catalysed hydrolysis of O-(2-hydroxypropyl)cellulose forms 1,2-04 1-2- 0-( 1 -methyl- 1,2-ethanedicyl-a-~glucose acetals. The mechanism of this transform- ation has been discussed.39

The influence of amine basicity on the thermal degradation of N-substituted 1- amino- 1 -deoxyfructoses has been e~amined.~'

The stereochemistry of the addition of nucleophiles to nitroalkene derivatives of pyranosides has been investigated?l

Enzymic Reactions Better leaving groups decrease the kinetic isotope effect (kH/kD) for isotopic substitution at the anomeric carbon for the acid-catalysed hydrolysis of aryl-B-p glycopyranosides, as expected for an A1 mechanism. However, the a-deuterium effect for the B-Dglucosidase- and jhxylosidase-catalysed hydrolysis of substrates increases with better leaving aglycon groups, which is interpreted in terms of a mechanism with S,2 characteristic^.^^

Glucokinase catalyses the phosphorylation of glucose with positive cooperativity. The solvent isotope effect at low concentrations of glucose is inverse, k(D,O)/k(H,O) = 3.5, but at high concentrations it is normal, k(H,O)/k(D,O) = 1.3. These observations are consistent with two forms of the enzyme with either an increse in the affinity in D20 of glucose for the enzyme form with the lower affinity in HzO or a decrease in their rate of interconversion in D20.43

There seems to be increasing evidence of single enzymes showing bifunctional activity. A recent example is an enzyme with separate kinase and phosphatase catalytic sites which is important in carbohydrate rne tabol i~m.~~

The activity of a-amylase immobilized by coupling to cellulose or carboxymethyl- cellulose depends on the pH of the coupling reaction and is interpreted in terms of regulation of electrostatic interaction^.^^ A new class of em-glucanases which give malto-oligosaccharides having the a-

configuration have been classified as e~o-cr-amylases.~~

8 Organic Reaction Mechankms 1984

Reactions and Formation of Nitrogen Bases

Schiy Bases and Related Species The chemistry of Schiff bases has been re~iewed.~’

It has been claimed that the pH-independent hydrolysis of the imines of 2- hydroxybenzaldehyde and of 2-hydroxy-1-naphthaldehyde occur by water attack on the neutral imine (the diploar ion). The generally accepted pathway of hydroxide ion attack on the protonated imine is excluded on the basis of relative rates between the two imines although this arises largely from a difference in pK, of the two imines. Similarly the phenQxide ion is only 1.5-fold more reactive than the undissociated phenol in the rate of imine formation and yet this has been interpreted as evidence for intramolecular general base catalysis by phenoxide ion in imine formation.48

The pH-independent hydrolysis of the imine (23) is thought to proceed by the addition of water to the aminoquinone t a ~ t o m e r . ~ ~

The presence of enolimine tautomers formed during the hydrolysis of Schiff bases of B-diketones retards the rate of reaction. An intermediate containing adjacent positive charges is thought to be responsible for a rate acceleration in other cases by enhancing the‘rate of carbinolamine f~rmation.~’

The hydrolysis of bis(2-pyridy1amino)phenylmethane involves initial transform- ation to the Schiff base 2-(benzylideneamino)pyridine.”

Intramolecular general base catalysis has been suggested for carbinolamine formation during the hydrolysis of Schiff bases formed from pyridoxal phosphate (24). However, no experimental evidence has been presented to support this claim. Hydrolysis of the imine occurs by attack of hydroxide ion and water on the iminium ion at alkaline pH. Compared with other aldehydes pyridoxal phosphate gives imines with a more basic nitrogen and a more favourable equilibrium constant for their f~rmation.~’

The reactions of hydroxide ion with ferrocenyliminium ions (25) are faster in 1 : 1 water: acetonitrile than in water and proceed by rate-limiting addition to the iminium ion. The ferrocenyl group is strongly electron-donating but the difference in reactivity between aryl and ferrocenyl substrates is not large. Water is ca. lo8 -fold less reactive towards (25) than is hydroxide ion.53

The hydrolysis of the Schiff base derived from 2-methoxyethylamine and a- hydroxyisobutyrophenone is catalysed by borate ion and shows a saturation phenomenon with respect to increasing concentration of borate. These specific effects must involve the hydroxyl group as they are not observed in other systems and are attributed to the intermediate formation of a borate-substrate complex (26), although hydrolysis is suggested to occur by intramolecular transfer of boron- coordinated hydroxide ion (27).54


Fc \ t

R /C=NRz

The activation volumes for hydroxide ion attack on Schiff bases coordinated by iron( 11) complexes in binary aqueous solvent mixtures vary with the nature of the complex but are similar in water. Solution of hydroxide and the complex are presumably important in determining reactivity as a function of pre~sure.~

The nucleophilic addition to tetrahydropyridinium salts has been reviewed with a particular emphasis on stereoelectronic effects.56

Hydroxide ion attack at C(2) of the substituted quinolinium cation (28) is faster than addition to C(4), the thermodynamically favoured site. Equilibrium constants for these pseudo-base formations have been determined.57

The pyridoxamine model compound (29) with an intramolecular general base catalyst catalyses the conversion of the ketimine to the aldimine intermediate. Although the rate enhancement is small the product amino acid shows an enantiomeric excess of up to 96%. This has been attributed to intramolecular general-acid-catalysed protonation of the ketimine (30).58

It has been suggested that the amine exchange reaction of the Schiff base (31) in ethanol cyclohexane is facilitated by the alcohol hydrogen bonding to the phenolic group.

The tetrahedral intermediates formed by nucleophilic addition of amines to benzaldehyde in dimethyl sulphoxide have been observed directly by 'H-NMR spectroscopy.60

Various linear free energy relationships and their variation with solvent have been reported for the formation of Schiff bases.61

The formation of the Schiff base from pyridoxal5'-phosphate and n-hexylamine is thought to be intramolecularly catalysed.62

The partitioning of the imine intermediate formed from ammonia and ben- aldehyde to benzonitrile and benzoic acid has been described.63

Based on substituent effects, it has been suggested that Schiff base formation from (32) and amines proceeds by rate-limiting general-acid-catalysed addition of the amine to the enol of (32).64


(29 )

NR /I

0

0 0 / I II

Ar -c-CH,-C-NHAr

The nicotine metabolite (33) is in equilibrium (K N 1) with the iminium ion (34)at neutral pH. There is no evidence for intermediate formation of the ~arbinolamine.~~ The corresponding primary aminoketone exists predominantly ( > 99 %) as the corresponding cyclic imine.66

The Wadsworth-Emmons reaction of phosphoramidates to give C=N systems has been reviewed.67

Solvent and substituent effects on the isomerization of imines have been reported.6 *

In vertebrate vision, 1 1-cis-retinal bound to opsin oia a protonated Schiff base (rhodopsin) is photochemically isomerized to its all-transcongener which is then hydrolysed to all-trans-retinal and -opsin. In order for rhodopsin regeneration to occur, all-trans-retinal must be thermally isomerized to its 1 1-cis-congener. Contrary to an earlier report, unprotonated retinal Schiff bases are isomerized very slowly at room temperature whereas isomerization is acid-catalysed. As expected, Schiff bases formed from secondary amines readily undergo isomerization by a mechanism involving nucleophilic catalysis.69. 'O

Cram selectivity is enhanced in the reaction of imines with alkyl-9-BBN. The low Cram selectivity in the reaction of allylic organometallic compounds with chiral


aldehydes having no ability to be chelated is presumably determined by steric factors at the chiral centre. Imines may came the a-chiral centre to take up the axial position and selectivity depends on both the original steric factor of the chiral centre and the steric influence of ligand L (35).71

DL-y-Carboxyglutamic acid reacts quantitatively with formaldehyde to give 4,4- dicarboxyproline in a pH-independent reaction. It has been suggested that cyclization occurs by an intramolecular Mannich-type mechanism in which a carbanion attacks the initially formed iminium ion (36).”

Recent advances in the chemistry of enamines have been reviewed.73 Enamines with B-hydrogens react with trifluoroacetonitrile to give 2,4-

bis(trifluoromethy1)pyrimidines via, it is thought, the intermediate formation of four-membered ring a m i d i n e ~ . ~ ~

Mono-protonated primary-tertiary diamines catalyse deprotonation of ketones by forming iminium ions which are transformed into enamines by intramolecular general base catalysis using the tertiary amino group. The pro-s-deuteron is selectively removed 12-20 times more rapidly than the pro-R-deuteron in deuterated methoxyacetone using (37) as a catalyst. This is the result of a steric effect of the methoxy ~ubs t i tuent .~~

Changing the a-carbon from primary to secondary has little effect upon the pK, for a-deprotonation of aldimines but increases the pK, for ketimines; this has been attributed to steric effects. The syn-configuration of the anions (38) is estimated to be at least 4 kcal mol-’ more stable than the anti-isomer, although the latter is preferred in endocyclic i m i n e ~ . ~ ~

CH,NMe,

The rate of the reaction of N,2,6-trichlorobenzoquinone imine with sodium thiosulphate in water-ethylene glycol mixtures increases with increasing dielectric constant of the medium and has been interpreted in terms of a highly solvated transition state.’


Hydrazones, Oximes, and Related Compounds The acid-catalysed hydrolysis of benzylidenesalicylohydrazides shows a p+ of - 0.9 and is thought to involve rate-limiting attack of water on the protonated substrate

The bimolecular reaction of methoxide ion with (z)-hydrazonoyl chlorides gives stereospecifically the (z)-methylhydrazonate (40). However, with poorer leaving groups than chloride a mixtures of stereoisomers is formed. If it is assumed that the addition and elimination steps are stereoelectronically controlled then the tetrahedral intermediate (41) should be formed which should collapse rapidly to (40).79

2-Aminoalkylhydrazones, but not the 3-derivatives, exist in both the acyclic and the cyclic perhydrotriazine form. The equilibrium depends on the nature of the substituents.80 The acylhydrazones of benzoylacetone and benzoylacetaldehyde exist as pyrazolinol (42) and enamine tautomers."

The reaction of a-N-methylaminopropionamide with formaldehyde in aqueous solution gives imidazolidinones by rate-limiting attack of the amido group on formaldehyde with intramolecular general base catalysis (43)."

1 -Phenylazo-Znaphthols exist in equilibrium with the corresponding hydrazone- ketone.83

The equilibrium constant between some amino-oximes (44; X = NOH) and amino-aldehydes (44; X = 0) and their corresponding cyclic tautomers (45) in aprotic polar solvents have been determined.84

The rate of E-z isomerization of 0-acylaldoximes in glacial acetic acid is competitive with dehydration to give nitriles."

The acid-catalysed reaction of the isooxazole (46) proceeds through rate-limiting enolization of ring-opened oxime or may give the amidonitrile as product depending mainly on the substituent R2.86

Under Beckmann conditions a-azidosteroidal oximes give mono- and di-cyano derivatives, presumably by initial C-C bond cleavage (47).87

(39).7

Me I

O H

\ / N

Meo&

R

N, k"" Ph

Ar COR


(46)

0 1 1

Ph-CH=CH-C-Ph

(49)

02 X

(47)

Me,N, LI N" '0

@ Me

I But

(53) (54)

High axial selectivity is observed in the alkylation of the dimethylhydrazones of 2- cyano-4-tert-butylcyclohexanone but not with the 2-alkoxycarbonyl-substituted derivatives. It has been suggested that selectivity may be related to coordination face selectivity. A carbomethoxy group in the 2-position may force the dimethylamino group anti by chelation (48).**

14 Organic Reaction Mechanisms I984

The lithium salts of tert-butyl and trityl hydrazones react with Michael acceptors by both ionic and thermal pathways.89

Aldol and Related Reactions

The kinetics of hydration and retro-aldol reactions of chalcone (49) to benzaldehyde and acetophenone have been determined in aqueous solutions of sodium hydroxide. The equilibrium constant for aldol adduct formation is 4.3 M-’ and that for dehydration 25.90

The rates of the thermal retro-aldol reactions of B-hydroxy-esters correlate with calculated strain energies. The release of steric strain has previously been thought to be unimportant in these reactions.”

The reverse Michael cleavage of 7-oxabicyclo[2.2.l]-heptanes and -heptenes is a formally unlikely 5-endetrig process (50). Similarly retro-aldol reactions occur in acid solution (51). The ease of these reactions has been attributed to favourable geometric alignments of the bonding and anti-bonding orbitals of the bridging oxygen and its neighbouring carbons rather than to the release of strain energy.92

The degradation of B-dicarbonyl phenolates (52) is inhibited by hydroxide ion because of ionization of the e n 0 1 . ~ ~

Pyridinium salts can be used as an enolate transferring agent. For example, the base-catalysed addition of acetophenone to an NAD analogue gives the intermediate (53) which can then be reacted with carbonyl acceptors to give aldol products. No hydride transfer from (53) is observed.94

The effect of solvent and cation on the ratio of C- to 0-alkylation of the enolate of ethyl acetoacetate in the presence of picric acid has been in~estigated.’~

Condensation of 2,5,5-trimethylhexa-2,3-dien-&al with malonitrile gives the unexpected product (54). The initially formed aldol product is thought to undergo a thermal cyclization to give an imino-2,5-cyclohexadienone which then reacts with more ma l~n i t r i l e .~~

A kinetic analysis of the reaction of formaldehyde and acetaldehyde to give pentaerythritol has allowed for a non-steady concentration of the carbanion intermediate.”

The development of highly stereoselective aldol and related C--C bond-forming reactions continues to be a dominant theme. Most methods utilize enolate mono- anions of a ketone, an ester, or their equivalent. Selective aldol condensations occur with quaternary ammonium enethiolates generated from (z)-N,N-dimethyl-S- trimethylsilylketene S,N-acetals (55) with benzaldehyde in the presence of a Lewis acid. There is very little hard evidence to elucidate the mechanisms of these reactions.98

It appears to be very difficult to achieve asymmetric carbon-carbon bond-forming reactions controlled by the non-covalent interaction of chiral ligands to substrates. The magnesium salt of ally1 tolyl sulphone undergoes asymmetric addition to acetone under the influence of achiral ligand derived from L-proline which is the first example of ligand controlled chiral induction.99

z-Lithium enolates, formed from n-alkyl tert-butyl ketones and lithium diisopro-


pylamide, react with benzaldehyde to give syn-aldols. The enolization step is slow with sterically hindered ketones. In non-polar solvents syn-anti equilibration occurs which can be rationalized by extensive negative charge delocalization in the transition state compared with that in the reactants or products."'

Crotyl- and a-methylallyl-dichlorotin derivatives can react with aldehydes to give four isomeric adducts: threo, trans, erythro, and cis. Their rearrangements, probably through transition states with bicyclononane structures such as (56), give stereospecifically trans- or cischlorotetrahydropyrans. A cis-stereoconvergent synthesis is obtained using l-buten-3-yl-n-butyldichlorotin.'01

H RHssiMe3 NMe,

Ph

(57)

ph!--rMe I \

O X N H R Me O X N H Sn R Me

Sn

' The stereochemical course of stannous-triflate-mediated aldol-type reactions is

dramatically altered by the addition of tetramethylethylenediamine as a ligand.'" The Erlenmeyer-Ploechl reaction of hippuric acid and benzaldehyde gives a

benzylideneoxazolone from the intermediate aldol product (57) and excess a1deh~de.I'~

It is still a problem to achieve high asymmetric induction in aldol reactions of methyl ketones and acetic acid derivatives. A chiral oxazolidine (58), prepared from a chiral 1,2-amino-alcohol and a methyl ketone, treated with lithium diisopropyl- amide generates a lithium azoenolate which, upon addition of stannous chloride, gives the chiral cyclic azoenolate (59). Subsequent reaction with aldehydes gives aldol products of 58-86 % enantiomeric e~cess.' '~

Examples of titanium-tetrachloride-promoted aldol reactions of silyl enol ethers have been reviewed.lo5

Ethylene chloroboronate generates enolboronates from carbonyl compounds which show very high erythro-diastereoselectivity with both aliphatic and aromatic aldehydes. The transition state is assumed to be the usual pericyclic boat-like configuration. O6

The aldol reaction of the ethyl mercaptoacetate dianion with carbonyl compounds gives adducts which may be treated with ethyl chloroformate in the presence

16 Organic Reaction Mechanisms 1.984

of trivalent phosphorus to give E-isomers of a,S-unsaturated esters. The mechanism is thought to involve the intermediate formation of a thiirane.'07

There have been many other reports and reviews of the stereoselective aldol reactions.'08

Other Addition Reactiondog

Aldehyde analogues of normal alcohol substrates induce adenosinetriphosphatase activities of various kinases. It is thought that the hydrated aldehydes are the activators of these reactions."' This observation provides a basis for measuring the rates of hydration and dehydration of aldehydes by "0-transfer from the aldehyde or its hydrate to phosphate. For a series of heavily hydrated aldehydes there is little variation in the dehydration rate constants over a lo3 change in equilibrium constants for hydration. This presumably reflects the greater effect of substituents a to the aldehyde on the electrophilicity of the carbonyl carbon of the free aldehyde than on the pK of the gem-diol of the hydrated form.'"

The reversible hydration of 1,3-dichloroacetone in the presence of aerosol-OT reversed micelles in hexane shows different kinetic behaviour from that in aqueous dioxan. Proton inventories indicate the participation of a second water molecule acting as a general base catalyst."'

The rate constant for the uncatalysed hydration of trifluoroacetophenone is 3.2 s- '. The reaction is not subject to acid catalysis and although basecatalysed the BrQnsted j value is very small. The reaction of hydroxylamine shows a change in rate-limiting step with increasing concentration of catalysing acid. Several rate and equilibrium constants for the addition of nucleophiles to trifluoroacetophenone have been reported.'I3

Calculation of the deprotonating factor (the degree of activation brought about by proton removal) and the proton-activating factor (the degree of activation brought about by protonation of the substrate) for the hydration of aldehydes confirms earlier interpretations that this occurs by general acid catalysis (60) rather than the kinetically equivalent general base mechanism.' l4

Molecular orbital calculations suggest that the hydration of ketene to form the ketone hydrate is favoured over formation of acetic acid. This is in contrast to protonation which favours proton transfer to the &xirbon."s

The transition-state structure for the gas-phase addition of water to formaldehyde has been characterized by quantum-mechanical calculations.' l 6

The participation of solvent water in the hydration of formaldehyde, ketenimine, and formamidines and in keto-enol tautomerism has been reviewed."

l-Arylmethyl substituents favour the open-chain tautomer if steric effects occur in the ring-closed form of 1-hydroxyphthalan (61) and related structures."'

The first report of the efficiency of intramolecular hydride transfer indicates that the effective molarity is high, as expected on the basis of entropy changes between inter- and intra-molecular systems. Intramolecular hydride transfer in the alkoxide (62) shows an E.M. of 6 x lo6 M compared with an analogous intermolecular proce~s.' '~ In the crystal structures of related polycyclic hydroxyketones the


hydrogen to be transferred is 2.3-2.5 A from the carbonyl carbon and shows an angle 0 2 - - - - H of 96-99'. The carbonyls show small pyramidalizations of 0.01-0.02 A."'

The diastereocontrolled reduction of 2-amino- or 2-hydroxy-ketones to give optically active threo-l,2-amino-alcohols or 1 ,2-diols, respectively, may be per- formed using hydrosilanes in the presence of a catalytic amount of tetrabutylam- monium fluoride in hexamethylphosphoric acid. In remarkable contrast erythro- selective reduction may be achieved under acidic conditions of trifluoroacetic acid. The threo-selectivity has been attributed to the bulky (BuiN') (R,SiHF-) species which attacks the ketone carbonyl carbon according to the Felkin transition-state model. The acid-catalysed pathway may be rationalized by Cram's proton-bridged cyclic model.''0

I L HO CH,Ar

H

Lithium aluminium hydride modified by chiral amines reduces prochiral cyclic ketones to give optically active cyclic alcohols in high enantiomeric excess.'

Benzylidene acetals of 1,2- and 1,3-glycols are easily cleaved by diisobutyl- aluminium hydride in toluene to give the corresponding monobenzyl ethers. In most cases cleavage occurs selectively at the least hindered site. Although this has rationalized by intramolecular hydride transfer (63) an intermolecular mechanism is not excluded.' "

The hydroxide-ion-catalysed Cannizzaro reaction of 4nitrosobenzaldehyde in aqueous dioxane gives equimolar quantities of 4,4'-diformylazoxybenzene and 49'- dicarboxyazoxybenzene by rate-limiting hydride ion transfer from the normal initially formed adduct.' '3

Zinc ion accelerates the reduction of 2-pyridinecarbaldehyde by dihydroquinoline derivatives in aqueous solution. Kinetic complexities in catalysis disappear when the reaction is studied under deoxygenated dark conditions.' 24

The optical yield in the asymmetric reduction of ethyl benzoylformate with a chiral NADH model compound varies with the extent of reaction. This has been


attributed to the oxidized NADH model forming a magnesium ion complex with unreacted NADH model compound."'

A previously proposed correlation between the stereospecificity of nicotinamide coenzyme-dependent dehydrogenases that reduce carbonyls and the value of the equilibrium constant for the catalysed reactions has been justifiably criticized.1z6

The pH dependence of the reaction catalysed by lactate dehydrogenase, where pyruvate adds covalently to NAD to give a NAD-pyruvate adduct, suggests similar binding modes for enol pyruvate, ketopyruvate, and lactate. It has been suggested that, although the enzyme provides a general catalyst, general acid catalysis occurs externally by buffers.lz7

Steric inhibition of resonance has been invoked in interpretation of the dissociation constants of cyanohydrins of substituted acetophenones.' 28

The reaction of aromatic ketones with diethylphosphorocyanidate in the presence of lithium cyanide gives cyanophosphates which yield a,p-unsaturated nitriles on treatment with boron trifluoride etherate.' 29

Surprisingly, hydroxynitrile lyase, the enzyme from bitter almond which catalyses the formation and breakdown of cyanohydrins, uses flavin adenine dinucleotide as a coenzyme. Flavoproteins usually catalyse true redox processes. 3-0xo-3- phenylpropyne and 3-0x0-3-phenylpropene are active-sitedirected inhibitors of the flavoprotein hydroxynitrile lyase. In cyanohydrin formation the enzyme is thought to form a thio-hemiacetal with the aldehyde substrate using a cysteine thiol group. Cyanide binding to N(5) of the isoalloxazine moiety of the coenzyme and carbonyl carbon binding to N(4a) gives a species (64) which is thought to rearrange to cyanohydrin. The chemical logic of this mechanism is not obvious.130

Pyrylium cations (65) coexist in water with the enedione pseudo-base (66) and its anion and a small amount of its en01.I~' With amines the cations give pyridinium ions through the intermediate formation of the enamine-ketone (67), but are less reactive than the less nucleophilic aromatic amines. This has been attributed to a larger proportion of the imine tautomer with aromatic amines.' 32 The synthetic utility of these reactions and the optimum conditions required have been dis-

'34 Water-soluble pyrylium salts react with the lysine residues of gelatin and a-chymotrypsin, but although the pseudo-base (66) reacts with free lysine there is no reaction with the proteins.

The reaction of secondary amines with 2,4,6-triphenylpyrylium ions to give ring- opened divinylogous amides is base-catalysed, whereas that with primary amines is not. It has been suggested that for the latter formation of the intermediate (68) is rate- limiting, whereas for secondary amines proton transfer from the analogous intermediate becomes the rate-limiting step.136

Pentane-2,4-dionate salt reacts with dimethyldichlorosilane to give a pyrylium salt, while the trifluoromethyl analogue gives the corresponding neutral pyrany- lidene complex. The proximity of the highly electronegative trifluoromethyl group reduces the basicity of the ring oxygen which probably hinders the formation of the pyrylium salt.' 37 The use of pyrylium salts for transforming amino groups into other functionalities has been reviewed.' 38

The Cram Rule has been reviewed.'39

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ORGANIC REACTION MECHANISMS 1984 - Startseite...2 Organic Reaction Mechanisms 1984 function of the pK, of ArOH and therefore also of the C--O bond length. This implies that there is