Metal triflate catalysed organic transformations

Michelle Claire Lawton

Thesis submitted in fulfillment of the requirements for the degree

Philosophiae Doctor

Chemistry

in the

Faculty of Science

of the

University of Johannesburg

Promoter Prof DBG Williams

June 2009

Contents

Synopsis i ndash ii

Abbreviations iii ndash v

List of figures and tables vi ndash xix

Chapter 1 Lewis acids-A Literature Overview

Section Heading Page

11 The history of the acid-base theory 1 ndash 6

12 Lewis acids in catalysis ndash a focus on metal triflates 6 ndash 44

13 The ranking of Lewis acids - introduction 44 ndash 45

131 Thermodynamic measurements 45 ndash 51

132 Spectroscopic measurements 51 ndash 56

133 Comparative studies 57 ndash 64

14 Lewis acids in aqueous media 64 ndash 75

15 Conclusions 75 ndash 76

16 References 77 ndash 82

Chapter 2

Metal triflates in protection group chemistry

21 Introduction 83

22 Acetal formation using aluminium triflate 84 ndash 91

23 Catalyst recycling 91 ndash 92

24 Deprotections 92 ndash 97

25 Other protecting groups 97 ndash 99

26 Other metal triflates 99 ndash 100

27 Tetrahydropyranyl ethers (THP) 100 ndash 104

28 Two protection groups 104 ndash 106

29 Conclusions 107

Chapter 3

The drying of organic solvents

31 Introduction 110 ndash 111

32 Choice of analytical method ndash Karl Fischer 111 ndash 114

33 Limits of the Karl Fischer method 114 ndash 116

34 Choice of solvents 116 ndash116

35 Methods of drying the solvent 116 ndash 117

351 Traditional drying methods 117 ndash 119

352 Drying reagents 119

353 Preparation of desiccants 119

36 The alcohols 120 ndash 126

37 Acetonitrile 126 ndash 128

38 Dichloromethane (DCM) toluene and tetrahydrofuran

(THF) 128 ndash 134

39 Discussion 134

311 References 136

Chapter 4

Investigations on the role of water in metal triflate catalysed reactions

42 The arguments for and against triflic acid as the true

catalyst taken from the literature

138 ndash 145

43 The Mukaiyama aldol Reaction 146

431 Introduction 146

432 Metal salt catalysed Mukaiyama aldol reaction 146 ndash 152

433 The possible role of water in the Mukaiyama Aldol

reaction

152 ndash 158

44 A perspective of metal triflates in organic solvents 158

441 On solvation of the metal triflates in dry organic

solvents

159 ndash 162

442 The possible role of water in organic solvents 162 ndash 163

45 The case for 26-di-tert-butyl-4-methyl-pyridine 163 ndash 165

46 Summary 165 ndash 165

47 Carbocation formation 165

471 Carbocation formation in wet and dry solvents 165 ndash 175

472 The proton and the sterically hindered base ndash Xray

crystallography

176 ndash 177

48 Friedel-Crafts alkenylation reactions of arenes 177

481 Optimising the reaction 177 ndash 179

482 Reactions in dry solvent 179 ndash 181

Chapter 5

Ranking of Lewis acids

51 Introduction 186

52 Lewis acidity from NMR resonance shifts 187 ndash 202

53 Infrared Spectroscopy (IR) 202 ndash 206

54 Conclusions 207

55 References 208

Summary of conclusions and future research 209 ndash 211

Chapter 6

Experimental data and characterisation

61 Standard experimental techniques 212

611 Chromatography 212

612 Anhydrous solvents and reagents 212

62 Spectroscopical and spectrometrical methods 212

621 Nuclear Magnetic Resonance Spectroscopy (NMR) 212 ndash 213

622 Mass spectroscopy (mz) 213 ndash 213

623 Infrared spectroscopy (IR) 200 ndash 200

63 Melting Points 213

64 Chemical methods 214

641 General procedure for acetal formation 214

642 General procedure for TBDMS protection of alcohols 226

643 General procedure for the tetrahydropyranylation of

alcohols

645 Standard procedure for Karl Fischer measurements 232

646 TMS protection of propiophenone 234

647 General procedure for the Mukaiyama Aldol reaction 234

648 General procedure for carbocation formation 236

649 Synthesis for [bmim][OTf] 236 ndash 237

6410 Crystal data 238 ndash 239

6411 General procedure for Friedel Crafts alkenylation 239

6412 Ranking of Lewis acids using NMR spectroscopy 240

6413 Determination of equilibrium constants 241

6414 Ranking of Lewis acids by Infrared Spectroscopy (IR) 241

65 References 242

Appendix A 243 - 283

Synopses The research described in this thesis was directed at advancing the application of metal

triflates Al(OTf)3 in particular in organic synthesis on the one hand and to contribute to

the understanding of the underlying basis for their catalytic activity The study was

undertaken against the background and on the bases of a detailed literature study of metal

triflates their chemical and catalytic properties and applications thereof Amongst others

it deals with the possible role of metal-bound water that give rise to Broslashnsted type acidity

and that this induced Broslashnsted acidity may be responsible for the catalytic activity that is

observed

The study was prompted by the realisation that Al(OTf)3 was largely neglected as a

potential reusable catalyst This is in marked contrast to the attention paid to other metal

triflates the rare earth metals in particular Earlier work in this laboratory has shown that

Al(OTf)3 is stable in water from which it can be recovered easily for reuse In addition it

showed promise as a Lewis acid catalyst and is relatively soluble in several organic

solvents

New applications for the use of Al(OTf)3 have now been demonstrated These include the

efficient formation of acetals from aldehydes and ketones The conversions can be carried

out in an alcoholorthoester mixture or preferably in neat orthoester Other metal triflates

notably Sc(OTf)3 and In(OTf)3 are useful alternative catalysts Al(OTf)3 can be easily

recycled without loss of activity This methodology also can be applied to aldehydes and

ketones containing TBDMS groups without effecting deprotection of the ethers In view

of the sensitivity of the TBDMS groups to hydrolysis in the presence of triflic acid the

results suggest little hydrolysis (or alcoholysis) of the metal triflates in the protic solvents

used which would generate trifluoromethanesulfonic acid as a consequence of such

metal based hydrolysis Al(OTf)3 was also found to be a good catalyst for the formation

of THP ethers It proved to be excellent for Friedel Crafts reactions using alkynes as

substrates Al(OTf)3 together with other triflates offers a mild alternative to the more

traditional water sensitive Lewis acids eg BF3 AlCl3 and TiCl4 which are difficult to

recover and require the use of extremely dry solvents

On the basis of published literature it was known that metal triflates showed catalytic

activity in both aqueous and non-aqueous solutions In aqueous solutions the possibility

of catalysis by a dual mechanism namely Lewis and Broslashnsted acid catalysis cannot be

ruled out Nevertheless some metal triflates can be regarded as essentially Lewis acids

while others can be regarded as essentially Broslashnsted acids when operating in aqueous

environments Evidence was obtained that Al(OTf)3 tended to function to a significant

extent as a Broslashnsted acid in aqueous environments Here generation of retinyl cations in

the presence of Al(OTf)3 was used as the probe reaction These cations are intensely blue

coloured and consequently easily detected It was found that the cation generation

proceeded exclusively as a Broslashnsted-type acid-promoted process In order to establish if

Al(OTf)3 can function purelyessentially as a Lewis acid in an organic solvent it was

necessary to investigate methods for the drying of organic solvents to preclude the

formation of H2O-M(OTf)3 adducts which would be strongly Broslashnsted acidic The most

successful methods were then applied in further work It could thus be demonstrated that

Al(OTf)3 shows Lewis catalytic activity in extremely dry (low ppm water content)

organic solvents specifically for the Friedel-Crafts reactions mentioned above

Finally several approaches towards the quantitative measurement of Lewis acidity were

applied and evaluated The application of these approaches to establish a ratingranking

of Lewis acidity of metal triflates was complicated by the low solubility of these

compounds in most aprotic organic solvents Another difficulty was to identify suitable

probes that could be applied over a wide range of Lewis acidity While the perennial

problem of Lewis acid-base theory namely the ranking of Lewis acids has still to be

solved it appears that induced chemical shifts (NMR) offer a valuable basis for this

rating Here IR UV-Vis and NMR techniques were all employed with variable success

Abbreviations

Aring angstrom

Bmim 1-butyl-3-methylimidazolium

Bn benzyl

Bu butyl

C coulomb

degC degrees Celcius

CIMS chemical ionization mass spectroscopy

CL confidence level

COSY correlation spectroscopy

CPL ε-caprolactone

Cy cyclohexyl

d doublet

dba dibenzylidene acetone

DCM dichloromethane

dd doublet of doublets

DHP dihydropyran

DL detection limit

DMF NNndashdimethylformamide

DTBP 26-di-tert-butylpyridine

DTMP 26-di-tert-butyl-4-methylpyridine

Eq equivalents

EIMS electron ionization mass spectroscopy

EtOH ethanol

Et3N triethylamine

GC gas chromatography

h hour

HRMS high resolution mass spectroscopy

HSAB hard-soft-acid-base

IR infrared

i-Pr iso-propyl

Kh hydrolysis constant

mp melting point

MSA methanesulfonic acid

MeOH methanol

Me methyl

n number of measurements taken

NMR nuclear magnetic resonance

OAc acetate

OTf trifluoromethanesulfonate (triflate)

PCL poly(ε-caprolactone)

PDI polydispersity

Ph phenyl

ppm parts per million

p-TsOH para-toluenesulfonic acid

q quartet

ROP ring opening polymerisation

RSD relative standard deviation

rt room temperature

s singlet

Std dev standard deviation

t triplet

t-Bu tert-butyl

TBDMS tert-butyldimethlsilyl

TES triethylsilyl

THF tetrahydrofuran

THP tetrahydropyran

TIPS triisopropylsilyl

TLC thin layer chromatography

TMS trimethylsilyl

Triflimide bis(trifluoromethane)sulfonimide

Triflate trifluoromethanesulfonate (the contraction lsquotriflatersquo is used throughout this

thesis)

UVVis ultra violetvisible light spectrophotometry

VL valerolactone

WERC water exchange rate constant

wrt with respect to

wv weight per volume

List of figures and schemes

Scheme

Figure Heading Page

Scheme 11 Regioselective deacetylation of compound 1 9

Scheme 12 Anomeric deacetylation using Nd(OTf)3 10

Scheme 131 Reaction between difluoropropargyl bromide (15) and

benzaldehyde (16) 11

Scheme 132 Indium-mediated Barbier-type reaction of 19 with

different aldehydes in aqueous media 12

Scheme 14 Proposed mechanism 13

Scheme 15 Lewis acid mediated alkylation of 3-hydroxy-2-napthoate

with 1-(2-naphthyl)ethanol 14

Scheme 16 Alkylation of 26 using La(OTf)3 15

Scheme 17 Proposed mechanism of alkylation reaction 17

Scheme 18 Metal triflate catalysed ROP of CPL or VL 18

Scheme 19 A plausible mechanism of the ROP of CPL by Sc(OTf)3

via an activated monomer mechanism 20

Scheme 110 Synthesis of β-enaminones catalysed by Yb(OTf)3 21

Scheme 111 Cleavage of benzylidene acetals using Er(OTf)3 21

Scheme 112 Allylation of acetophenone with diallyldibuyltin

catalysed In(OTf)3 23

Scheme 113 Metal triflate catalysed allylation 24

Scheme 114 Proposed mechanism of acyclic transition state of

allylation reaction 26

Scheme 115 Reaction of 7-methyl-1-phenyloct-6-en-3-one oxime 34

catalysed by aluminium triflate 26

Figure 11 Active oxime-derived intermediates 27

Scheme 116 Al(OTf)3 catalysed ring opening of styrene oxide with

alcohols 29

Scheme 117 Opening of glycidyl ether with alcohol and Al(OTf)3 30

Figure 12 Chelation of Al(OTf)3 to glycidyl ether 31

Scheme 118 Reaction between 2-phenylenediamine 40 and benzoin 41

catalysed by Ga(OTf)3 33

Scheme 119 Proposed mechanism for Ga(OTf)3-catalysed reaction of

2-hydrochalcones with o-phenylenediamine 35

Scheme 120 Reaction between iastoic anhydride p-

methylbenzaldehyde and ammonium acetate 36

Scheme 121 One pot synthesis of 23-dihydroquinazolin-4(1H)-ones

Scheme 122 Proposed mechanism for the formation 0f 23-

dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones 39

Scheme 123 [3+2] cycloaddition reaction of 2-aryl-N-tosylaziridines

with different nitriles catalysed by Cu(OTf)2 39

Scheme 124 Mechanism for the [3+2] cycloaddition reaction of 2-aryl-

N-tosylaziridine with nitriles 41

Scheme 125 Claisen rearrangement of allyl 1-naphthyl ethers catalysed

by Bi(OTf)3 41

Scheme 126 Claisen rearrangement of 2-substituted allyl 1-naphthyl

ethers catalysed by Bi(OTf)3 41

Scheme 127 Protection of carbonyl compounds catalysed by Y(OTf)3 42

Figure 13 Electrostatic or covalent nature of Lewis acids 50

Figure 14 Complexation of acid to acyl oxygen atom 51

Figure 15 Phenalen-1-one 52

Figure 16 Lewis acid bound to Lewis base 53

Figure 17 C5H9O3P 54

Figure 19 Crotonaldehyde 55

Figure 110

1H chemical shift differences of protons of

crotonaldehyde versus the H3 chemical shift difference

on complexation with various Lewis acids

Figure 111 Plot of δcis against K 59

Figure 112 Least square plot of Childsrsquo Lewis acid scale against AN

values 61

Figure 113 Perfluorophenyl boron Lewis acids 63

Figure 114 Graph comparing relationship between Gutmanns method

and that of Childs 63

Scheme 128 Ln(OTf)3 catalysed aldol reaction of 63 with

formaldehyde 65

Scheme 129 Aldol reaction between 1-trimethylsiloxycyclohexene

(64) and benzaldehyde catalysed by Ln(OTf)3 66

Figure 115 Yield of aldol product 67

Scheme 130

Aldol reaction between benzaldehyde and 1-phenyl-1-

(trimethylsiloxy)propene catalysed by various Lewis

Scheme 131 Aldol reaction of glucose-derived silyl ether with aqueous

formaldehyde catalysed by Lewis acids 69

Scheme 132 Tin-mediated allylation of carbonyl compounds catalysed

by InCl3 69

Scheme 133 Transmetallation from allytin with InCl3 70

Scheme 134 Michael addition of β-ketoesters with methyl vinyl ketone

catalysed by Yb(OTf)3 71

Scheme 135 Direct-type catalytic Mannich reaction of benzaldehyde

aniline and cyclohexanone in water 72

Scheme 136 Biginelli reaction of p-anisaldehyde ethyl acetoacetate

and urea 73

Chapter 2 Metal triflates in protection group chemistry

Scheme

Figure Heading Page

Scheme 21 Mechanism of acid catalysed acetal formation 84

Scheme 22 Al(OTf)3 catalysed acetal formation in the presence of

alcohol andor drying reagent 84

Scheme 23 Acetalisation of benzaldehyde with

trimethylorthoformate catalysed by Al(OTf)3 92

Scheme 24 Acetal deprotection in an aqueous solution of

trifluoroacetic acid 93

Scheme 25 Deprotection of acetals catalysed by Al(OTf)3 93

Scheme 26 Hydrolysis of acetal 96

Scheme 27 TBDMS protection of 2-phenylethanol and para-

bromophenol 98

Scheme 28 Mechanism of acid catalysed THP ether formation 101

Scheme 29 THP protection catalysed by Al(OTf)3 102

Scheme 210 Mechanism for the hydrolysis of 227 103

Chapter 3 The drying of organic solvents

Scheme

Figure Heading Page

Scheme 31 Interaction of metal and a water molecule to form a

Broslashnsted acid 110

Scheme 32 Standard reaction of Karl Fischer titration 112

Figure 31 Karl Fischer measuring cell and electrodes 113

Figure 32 Karl Fischer anode and cathode 114

Figure 33 Graph indicating decreasing water content in methanol

over time 122

Figure 34 Graph indicating decreasing water content in ethanol

over time 124

Figure 35 Graph indicating decreasing water content with

increasing silica mesh size 132

Figure 36 Graph of residual water content in THF after drying with

various desiccants under given conditions 133

Chapter 4 The role of water in metal triflate catalysed reactions

Scheme

Figure Heading Page

Scheme 41 Hydrolysis of a metal 138

Scheme 42 Hydrolysis of organic compounds 138

Figure 41 Effect on the pKa of increasing steric requirements of the

alkyl groups in the 26 positions (in 50 ethanol) 139

Scheme 42 Ionisation of 26-di-tert-butyl pyridine 139

Scheme 44 Direct type catalytic Mannich reaction of benzaldehyde

Scheme 45 Metal triflate catalysed acylation of alcohols 141

Scheme 46 Benzoylation of hex-2-en-1-ol using metal triflates 142

Scheme 47 Possible source of triflic acid in acetylation reaction 144

Figure 42 Resorcinarene isomers 144

Figure 43 Enhanced Broslashnsted acid 145

Scheme 48 Base catalysed aldol reaction 146

Scheme 49 Mukaiyama aldol reaction 146

Scheme 410 Mukaiyama aldol reaction catalysed by a Lewis acid 147

Scheme 411 Mukaiyama aldol reaction showing silyl ether removed

by water 153

Scheme 412 The Mukaiyama aldol reaction 154

Figure 44 Benzaldehyde showing 1H chemical shifts in CD2Cl2 156

Figure 45 Activation of benzaldehyde by metal triflate 157

Figure 46 1H NMR of benzaldehyde complexed to ScCl3 157

Figure 47 NMR peaks showing the difference between fast

intermediate and slow exchange of ligands 158

Figure 48 Possible cluster formations versus free ion formation of

metal triflate in organic solvents 160

Scheme 413 Typical SN2 reaction 161

Scheme 414 Activation of the aldehyde by the Lewis acid in dry

organic solvent 161

Scheme 415 Formation of Broslashnsted acidity through polarisation of

water by a Lewis acid 163

Scheme 416 Interaction of DTBMP with protic solvent to form

nucleophile 164

Scheme 417 Carbocation formation using retinyl acetate 166

Figure 49

UVVis scan of retinyl acetate and its corresponding

carbocation showing the typical wavelengths and colours

of the solutions

Figure 410 Solvation of carbocation by nitrobenzene 168

Figure 411 1-butyl-3-methylimidazolium triflate ([bmim][OTf]) 170

Scheme 418 Common ion effect on Al(OTf)3 in [bmim][OTf] 171

Figure 412

UVVis scan showing the different intensities of

carbocation formation with triflic acid and Al(OTf)3 in

Figure 413 UVVis scan of Al(OTf)3 and retinyl acetate in dry DCM 173

Figure 414 DSC scan of standard Al(OTf)3 174

Figure 415 DSC scan of dried Al(OTf)3 175

Figure 416 Crystal structure of protonated DTBMP with OTf-

counterion 176

Scheme 419 Friedel-Crafts reaction of p-xylene with phenylacetylene 178

Chapter 5 Ranking of Lewis acids

Scheme

Figure Heading Page

Figure 51 Proton numbering used on crotonaldehyde 188

Figure 52 1H chemical shift differences of crotonaldehyde versus

the various Lewis acids 189

Figure 53 Carbon numbering used on croton aldehyde 190

Figure 54 13C chemical shift differences of crotonaldehyde versus

Figure 55 Atom numbering on trans-cinnamaldehyde 192

Figure 56 13C chemical shift differences of trans-cinnamaldehyde

versus the various Lewis acids 193

Figure 57 Diphenylphosphinobenzaldehyde chelated to a metal

triflate 195

Figure 58 UVVis spectrum of adduct formation between Lewis

base and Lewis acid 199

Figure 59 UVVis spectrum of 4-methyl-3-aniline in DCM 200

Figure 510 UVVis spectrum of 4-nitrodiphenylaniline in THF 201

Figure 511 UVVis spectrum of 4-nitrodiphenylaniline coordinated

to Lewis acid 201

List of tables

Table Heading Page

Table 11 Yields obtained for the anomeric deacetylation of

compound 1 using lanthanide triflates 9

Table 12 Yields obtained for anomeric deacetylation of selected

sugars using metal triflates 10

Table 13

Yield of reaction between difluoropropargyl bromide

and benzaldehyde in different solvent systems with

different additives

Table 14 Indium mediated Barbier-type reaction of 19 with

Table 15 Effects of catalysts on the reaction between 3-hydroxy-2-

naphthoate and 1-(2-naphthyl)ethanol 15

Table 16 Alkylation of 26 with acid-sensitive functional group

substituted benzylic alcohols 16

Table 17 Alkylation with various catalysts 16

Table 18 Sc(OTf)3 catalysed ROP of CPL and VL in the presence

of various amounts of n-BnOH 18

Table 19 The ROP of CPL by M(OTf)3 in ionic liquids 19

Table 110 In(OTf)3 catalysed peracetylation of carbohydrates 22

Table 111 Effect of different triflates on the allylation of

acetophenone with diallyldibuyltin 23

Table 112 Allylation of ketones with diallyldibutyltin catalysed

with In(OTf)3 25

Table 113 Cyclisation of non-activated unsaturated oximes

catalysed by Al(OTf)3 28

Table 114 Yields of products obtained from reactions with selected

epoxides in various alcohols 30

Table 115 Products obtained from reactions with selected epoxides

with various amines 32

Table 116 N-Methylaniline reactions with epoxides 32

Table 117

Yield quinoxaline derivative from the reaction 12

diamines were reacted with 12 diketones catalysed by

Ga(OTf)3

Table 118 Yields obtained in the one pot synthesis of 23-

dihydroquinazolin-4(1H)-ones catalysed by Ga(OTf)3 37

Table 119 Yields obtained in the one pot synthesis of quinazolin-

4(3H)-ones catalysed by Ga(OTf)3 38

Table 120 Cu(OTf)2 mediated [3+2] cycloaddition reactions of

aziridines and nitrile 40

Table 121 Amination of benzyl alcohols with various sulfonamides

catalysed by AgOTf 43

Table 122 Equilibrium constants and spectral data for complexes of

Lewis acids with ketones 46

Table 123 Free energies of complex formation 47

Table 124 Equilibrium constants for complex formation 47

Table 125 Comparison of Lewis acid ranking by different methods 49

Table 126 Boron trihalides 51

Table 127 Δ Carbonyl shifts of metal halides with phenalen-1-one 52

Table 128 Relative acidity of Lewis acids towards various reference

bases at 28 degC 54

Table 129 1H and 13C NMR chemical shift differences on

complexation with crotonaldehyde 55

Table 130 ΔνC=O and pK values of metal halides with phenalen-1-

one 57

Table 131 Chemical shifts and equilibrium constants for equation 9 58

Table 132 Summary of spectroscopic and structural trends for MX3

(9-fluorenone) 62

Table 133 Yields reaction of 63 with formaldehyde catalysed by

Ln(OTf)3 65

Table 134 Yields reaction between 1-trimethylsiloxycyclohexene

Table 135 Mukaiyama aldol reactions in water catalysed by InCl3 68

Table 136 Indium trichloride promoted tin mediated allylation of

aldehydes 70

Table 137 Direct-type catalytic Mannich reaction of benzaldehyde

Table 138 Reaction between p-anisaldehyde ethyl acetoacetate and

urea catalysed by a variety of Lewis acids 74

Table 139

Yields reaction between p-anisaldehyde ethyl

acetoacetate and urea catalysed by a variety of Lewis

acids in the presence of a Broslashnsted acid

Table 140 Reactions between p-anisaldehyde ethyl acetoacetate

and urea catalysed by a variety of Broslashnsted acids 75

Table Heading Page

Table 21 Al(OTf)3 catalysed acetal formation of aldehydes and

ketones 85

Table 21 cont Al(OTf)3 catalysed acetal formation of aldehydes and

ketones 86

ketones 90

Table 23 Al(OTf)3 recycling experiments using benzaldehyde as

the substrate 92

Table 24 Yield deprotection of acetals catalysed by Al(OTf)3 94

Table 25 Yield deprotection of acetals catalysed by a variety of

metal triflates 94

Table 26 Yield deprotection of acetals in water 95

Table 27 Yield deprotection of acetals in water after one hour 96

Table 28 Yield of alcohol for TBDMS deprotection 100

Table 29 THP protected primary alcohols in reactions catalysed by

Al(OTf)3 102

Table 210 Deprotection of THP ethers using different metal triflates 103

Table 211 Yield TBDMS protected substrates 104

Table 212 Yield of acetal formation with a variety of metal

triflates 105

Table 213 Acetal formation in the absence of added alcohol 106

Table Heading Page

Table 31 Result of Karl Fisher titration of hydranal 100 ppm water

standard 115

Table 32 Results of Karl Fischer titration of lsquowet solventsrsquo 117

Table 33 Results of Karl Fischer titration of solvents dried by

traditional methods 118

Table 34 Results of Karl Fischer titration of THF dried by

SilicaSodium 118

Table 35 Results of Karl Fischer titrations of methanol dried over

3Aring molecular sieves (5 wv) 120

Table 38 Results of Karl Fischer titrations of ethanol dried over

Table 311 Results of Karl Fischer titrations of methanol and ethanol

dried over KOH powder 125

Table 312 Results of Karl Fisher titrations of acetonitrile dried over

3Aring molecular sieves and neutral alumina 127

Table 313 Results of Karl Fisher titrations of toluene DCM and

THF dried over 3Aring molecular sieves and silica 129

Table 314 Results of Karl Fischer titrations of THF dried over 3Aring

molecular sieves (20 wv) 129

Table 315

Results of Karl Fischer titrations for THF dried by

passing over columns of various types of silica and

alumina

Table Heading Page

Table 41 Conversions () of metal triflate catalysed benzoylations 142

Table 42 Yield of acetylation reactions 143

Table 43 Yield of aldol product from different metal triflates 148

Table 44 Results of Mukaiyama aldol reaction 149

Table 45 Average pH readings of Lewis acids in THF H2O

mixture 150

Table 46 Comparison of pH and pKh values 151

Table 47 Yield aldol reactions in dry THF 154

Table 48 Yield aldol reactions carried out in dry DCM 155

Table 49 Change in chemical shift of benzaldehyde on

complexation of metal triflate 156

Table 410 Dielectric constants of several organic solvents 160

Table 411 Rate of SN2 reaction in Scheme 413 in different

solvents 161

Table 412 Yield aldol reactions carried out in the presence of

DTBMP 164

Table 413 pH measurements of Lewis acids in THFH2O with and

without DTBMP 164

Table 414 Variation of λmax and absorptivity of the retinyl

carbocation 167

Table 415 Results of carbocation formation in nitrobenzene 169

Table 416 Results of carbocation formation in DCM 172

Table 417 Crystal data of protonated 26-di-tertbutyl-4-methyl

pyridine 178

Table 418 Yield of Friedel-Crafts alkenylation reactions

catalysed by various M(OTf)x 178

Table 419 Yield of Friedel-Crafts alkenylation reactions in

various amounts of p-xylene 179

Table 420 Yield of Friedel-Crafts alkenylation reactions with

alternative aromatic systems 179

Table 421 Friedel-Crafts alkenylation reaction in dry solvent 180

Table Heading Page

Table 51

1H NMR chemical shift differences (Δδ) of

crotonaldehyde on complexation with various Lewis

Table 52

13C NMR chemical shift differences (Δδ) of

Table 53

1H and13C chemical shift differences (Δδ) of trans-

cinnamaldehyde in [bmim][OTf] on complexation with

various metal triflates

Table 54 31P NMR chemical shift differences (Δδ) of phosphorus

compounds on complexation with various metal triflates 194

Table 55 1H chemical shift differences (Δδ) of crotonaldehyde on

complexation with various metal triflates 197

Table 56 Δλ of probe on addition of a Lewis acid 201

Table 57 Δν (cm-1) of pyridine on complexation with various

Lewis acids in [bmim][OTf] 203

Table 58 Δν (cm-1) of electron-poor pyridine derivatives on

complexation with various Lewis acids in [bmim][OTf] 205

Table 59 Δν (cm-1) of electron rich pyridine derivatives on

Chapter 1

Lewis acids-A Literature Overview

11 The history of the acid-base theory

Introduction

In the middle of the seventeenth century acids and bases were classified by the fact

that when they were added to each other they formed a salt usually resulting in the

liberation of water1 Towards the end of the century Boyle23 placed more significance

on the properties of the acid and stressed characteristics such as acids will dissolve

many substances they will precipitate sulfur they change blue plant dyes red and

they lose these properties when they come into contact with alkalis

The first ldquomodernrdquo theory was put forward at the end of the eighteenth century by

Lavoisier24 He regarded oxygen as the necessary element for acidity His views led

to the assumption that acids were formed by a reaction of a lsquoradicalrsquo with oxygen

Davy (in around 1810-15)23 showed that hydrochloric acid contained no oxygen and

soon recognised that hydrogen was the essential element for acidity Liebig (in

1838)2-4 followed up this work and defined an acid as a compound that contained

hydrogen and in which the hydrogen could be replaced by a metal

The next theory that was generally accepted was that of Arrhenius (in 1880)24 His

definition of acids and bases was based on the assumption that when dissolved in an

aqueous solution acids will dissociate into hydronium ions and anions and bases into

hydroxyl ions and cations Even though this theory had limitations when it came to

non-aqueous systems it was generally accepted for the next thirty to forty years4

Development of theories

The latter end of this period saw the development of three main theories of acids and

bases1349 namely the solvent-system theory the electron pair theory and that of the

proton The solvent system theory was established by Franklin567 in 1905 He

extrapolated from the theory that water ionises into hydronium and hydroxyl ions

reasoning that ammonia must then ionise into ammonium and amide ions Thus

compounds like ammonium chloride in ammonia are acids and those like sodium

amide in ammonia are bases (equations 1 and 2)

NH4Cl + NaNH2 NaCl + 2NH3

HCl + NaOH NaCl + (1)

acid base salt solvent

Cady and Elsey9 who are often accredited with the solvent-system theory13 described

an acid as a solute that produces a cation that has characteristics of the solvent and a

base as a solute which will produce the anion that is characteristic of the solvent

Smith10 later extended this definition with his work on selenium oxychloride His

definition of an acid as an electron pair acceptor from the solvent and the base as an

electron pair donor to the solvent clearly shows for the first time3 the influence of

Lewisrsquos12 1923 definition of acids and bases

The electron pair theory first put forward by G N Lewis11 in 1916 was again

published in his more famous monograph in 192312 In this book Lewis also

independently put forward the proton idea and the generalised solvent-system theory

for acids and bases5

The initial theory put forward by Lewis failed to create any interest there is almost no

reference made to it in the literature for the next fifteen years5 During this period

there was however extensive developments made on the proton and the solvent-

system theories5

In the same year that Lewisrsquos monograph appeared Broslashnsted13 and Lowry14

independently put forward their definitions on the proton theory of acids and bases

This definition is still in use today and defines an acid as a proton donor and a base as

a proton acceptor

During the next fifteen years several scientists developed electronic classifications

which were along similar lines as those developed by Lewis In 1927 Sidgwick15 put

forward his electronic theory for coordination chemistry Here he noted that transition

metal atoms generally complete a stable electronic configuration by accepting

electron pairs from the ligands He named the process coordinate bond formation and

created the terms ldquodonorrdquo and ldquoacceptorrdquo

In 1925 Lapworth1617 divided reactants into electron poor (cationoid) and electron

rich (anionoid) This work was later further developed by Robinson18 who extended

the category of electron poor reactants to include neutral molecules with incomplete

octets as well as oxidising agents Similarly the electron rich category was extended

to include neutral molecules with lone pairs and reducing agents

Ingold1920 made a classification based on redox chemistry between 1933 and 1934

He suggested that earlier work that had been done in this area by workers such as H

S Fry and J Stieglitz should include those reactions where there is a degree of

electron transfer due to the limited donation or sharing of electrons and not just

include the reactions where there is complete electron transfer

It is in this work where Ingold first proposed the term electrophile for such

generalised oxidising agents or electron acceptors and the term nucleophile for

generalised reducing agents or electron donors5

In 1938 Lewis published another paper on acids and bases21 This paper contains the

details that his first paper lacked5 Here definitions and examples along with

supporting data21 were also provided

Lewisrsquos second attempt at his definition did not meet the same destiny as the first and

was widely brought to the attention of the scientific community through symposia

The resulting symposium papers were published in two volumes2223 the second of

which was published largely due to the interest that was stimulated by the first23

Usanovich24 put forward his definition of acids and bases in 1939 This theory is not

well-known as it was published in a Russian journal that was relatively inaccessible to

non Russian speakers25 His definition reads as follows An acid is any chemical

species which reacts with bases gives up cations or accepts anions or electrons and

conversely a base is a chemical species which reacts with acids gives up anions or

electrons or combines with cations The greatest criticism of this definition is that it

is too sweeping as it includes all Lewis acid-base reactions as well as redox chemistry

and that one may by the same token simply use the term ldquoreactantrdquo

A review was published in 1940 by Luder3 outlining the comparisons between the

newer electronic theories and the older theories of acids and bases He also added to

Lewisrsquos work by way of examples and showed how the theory could be used as a

systematising tool for chemical reactions This work was later expanded into a book

entitled ldquoThe Electronic Theory of Acids and Basesrdquo26

It was around this time that workers started to describe Lewisrsquos theory in terms of

quantum mechanics all previous theories had been based on the Bohr atom model

Mulliken was one of the first to attempt a quantum mechanical explanation in his

series of papers beginning in 195127 His original attraction to the subject was to

explain a class of weak Lewis adducts known as charge transfer complexes

The wave function for a one-to-one charge transfer adduct can be expressed by

equation 3

ψ ψ ψAB = a 0 (AB) + b 1 (A-B+) (3)

ψ0 (AB) = the wave function in the absence of charge transfer

ψ1 (A-B

+) = the wave function after the net transfer of one electron from base B to acid

By applying the second-order perturbation theory to equation (3) Mulliken was able

to derive the expression (4) for energy EAB of a weak AB complex27

β 01 EoSo1( )_ 2

E1_ Eo( )

EAB = Eo_

E0 = the energy of the state ψ0 (AB)

E1 = the energy of the excited state ψ1 (A-B

β01 = is the resonance integral between ψ0 (AB) and ψ1 (A-B

S01 = the overlap integral

In general this equation is the lsquosumrsquo of an electrostatic energy term I and the charge

transfer or covalent term energy term II (in equation 4)

In 1967 Hundson and Klopman28-32 used the perturbation molecular orbital theory to

derive a version of equation (4) to explain the role that certain ground state properties

of the acids and bases play in determining the course of adduct formation (given by

equation 5)

ψ ψAB = a A + b Bψ (5)

Varying degrees of donation can be shown by the ratio a2b2 The expression for

energy is shown by equation (6)

Σ ΣΔΕ β_ qsqt

Rstε+ 2 (CsmCtn st )2

(Em _ En )occupied orbtals mof speciesB

unoccupied orbtals nof speciesA

ΔE = energy gained or lost

q = electron density in atomic orbitals

R = distance between atoms s and t

csm= coefficient of atomic orbital m in molecular orbital r where r refers to the

molecular orbitals on one molecule ans s refers to those of the other

β = resonance intergral

E = energy of the molecular orbital

Again the first term represents electrostatic effects and is dependent on the net charge

densities and the radii of the donor and acceptor atoms (s and t) The second term

represents covalency combining the functions of overlap symmetry and energy of the

donor and acceptor orbitals (m and n) It is assumed that these lsquofrontierrsquo orbitals

correspond to the traditional acceptor and donor orbitals of the original Lewis

definition5 Klopman suggested that on the basis of equation (6) acid-base reactions

could be divided into those which are dominated by lsquocharge controlrsquo (term I) and

those dominated by lsquoorbital controlrsquo (term II)5

Conclusions

The use of the Lewis acid definition is widespread in both teaching and research

however it is not without criticism143334 There is a view that the definition is too

extensive and because of this it includes all chemical reactants Unlike the Broslashnsted

definitions the Lewis definitions can not be quantified It has also been expressed that

the properties of Lewis acids arise due to their action on any H2O present in the

system thus releasing a proton33 This particular aspect is important because it forms

the basis of one aspect of the present study

The acid-base theories most commonly used by chemists today are those of Broslashnsted-

Lowry (usually referred to as a Broslashnsted acid or base) and that of Lewis (referred to

as a Lewis acid or base) The remainder of this literature review shall focus mainly on

Lewis acids and bases their roles in catalysis how they have been used in aqueous

media and previous attempts at ranking them Much of the review will look at metal

triflates a relatively new family of Lewis acids that have started to replace the more

traditional Lewis acids

12 Lewis acids in catalysis ndash a focus on metal triflates

Lewis acid catalysis is a well documented practice in chemistry today35 They are

used for industrial36 and for pharmaceutical processes37 Lewis acids are important

because they enable reactions to be done under milder conditions and offer unique

reactivities and selectivities3839

Traditional Lewis acids (for example AlCl3 BF3 and TiCl4) have been used to

successfully catalyse well known transformations such as the aldol and the Friedel-

Crafts reactions4041 However these catalysts are often required in stoichiometric or

sub-stoichiometric amounts and are decomposed or deactivated by even small

amounts of water4142 These traditional Lewis acids are also non recoverable from

reaction mixtures

The strict definition of a catalyst is a substance that can cause a change in the rate of a

chemical reaction and is itself not consumed in the reaction A catalysts works by

lowering the activation energy of a reaction Because a catalyst is not used up in the

reaction it is essentially recyclable and can therefore be used in sub-stoichiometric

amounts

Activators and promoters work in similar ways to catalysts ie by lowering the

activation energy of the reaction However they are consumed or altered during the

reaction and are usually used in stoichiometric amounts Despite this activators and

promoters are often referred to as catalyst in the literature For example In

Vorbruumlggenrsquos many papers on glycosylation trimethylsilyl trifluoromethanesulfonate

(TMSOTF) is called the ldquocatalystrdquo but it is used in stoichiometric amounts as it is

changed in the reaction often into trimethylsilyl acetate (TMSOAc)43

In this thesis the term lsquocatalystrsquo is used to typically denote an entity which facilitates a

given reaction typically where the activator does not participate in the reaction and

where it is used in small amounts relative to the substrates (ie a ldquocatalystrsquo in ther

strict sense of the word) but instances will be cited where the activator is present in

larger amounts up to stoichiometric amounts

Many of the more sensitive catalysts may be catalyst precursors For example BCl3

may hydrolyse in the presence of water to form Cl2BOH and HCl and the former may

be the active catalyst or the active catalyst may be a more complex system such as

such as H+ [Cl3B-OH]- In such cases the BCl3 is a catalyst precursor With respect to

metal triflates (triflates is an accepted contraction for trifluoromethanesulfonates that

is used throughout this thesis) in particular in coordinating solvents or water the

system provides solvent in the inner sphere and triflate counter ions in the outer

sphere44 It is these coordinated protic solvents or water molecules that appear to be

the active catalyst in at least some cases as will be seen in later parts of this thesis

(see Chapter 4)

In the past three decades there has been a growing interest in metal triflates Unlike

the more traditional Lewis acid catalysts metal triflates can be added in catalytic

amounts they can be recovered and are reusable without loss of activity In most

cases they are stable and can work as Lewis acids in water

Kobayashi42 wrote a review in 2002 on rare earth metal triflates in organic synthesis

Included in this review are many comparative studies of other triflates This

comprehensive work contains over four hundred references and is an indication of the

growing interest in the field of metal triflates in catalysis

The following discussion is a review of the literature on catalysis using metal triflates

during the past five years It also serves to show the diversity of organic

transformations for which metal triflates have been used

Rare earth metal triflates are dealt with as a group mdash this literature is by far the most

voluminous Group III triflates are dealt with separately as a lot of work can be found

on In(OTf)3 and because of our own successes with Al(OTf)3 There are of course

numerous other triflates that have been used in many other transformations these

have been discussed under the heading Other

Rare earth metal triflates

Rare earth metal triflates have been employed in a plethora of organic

transformations42 They are readily prepared by heating the corresponding metal

oxides or chlorides in an aqueous trifluoromethanesulfonic acid (TfOH) solution

These metal triflates are stable and work as Lewis acids in aqueous media42

Recently the lanthanide triflates were found to effectively catalyse the regioselective

deacetylation of anomeric acetates45 (Scheme 11)

OAcMeOOC O

MeOOC OHLn(OTf)3MeOH 0 oC

OMeOOC

BnO OAc

O(OTf)3M

Scheme 11 Regioselective deacetylation of compound 1

Compound 1 (methyl-123-tri-O-acetyl-3-O-benzyl-β-L-idopyranuronate) was

selected to screen a variety of lanthanide triflates for their efficiency in catalysing the

deacetylation of anomeric acetates The reaction was carried out using 5 mol of the

triflate in anhydrous methanol (Table 11) The selectivity in the reaction for

methanolysis of the anomeric acetate may be explained by a favoured six-membered

chelate structure involving the ring oxygen

Table 11 Yields () obtained for the anomeric deacetylation of compound 1 using

lanthanide triflates

Lanthanide Reaction

timea (min) Yield ()b

Yb(OTf)3 180 70

Eu(OTf)3 90 85

Sm(OTf)3 90 92

Nd(OTf)3 90 95 a Reactions were carried out in anhydrous MeOH (24 mL) containing starting material

(50 mg 011 mmol) and 5 mol Mx(OTf)3 at 0 degC b Isolated yield after purification

by flash chromatography

When using Nd(OTf)3 it was found that the catalyst could be recycled from the

aqueous layer and used without loss of reactivity at least three times This catalyst

was then used with other substrates (Scheme 12) and found to effectively deactylate

the anomeric position under similar conditions to afford excellent yields

AcOAcOAcO

AcOAcO

AcO COOMe

OAc Nd(OTf)3

MeOH rt 4 h

Nd(OTf)3

MeOH rt 4 h

AcOAcO

AcO COOMe

Scheme 12 Anomeric deacetylation using Nd(OTf)3

This method was also tested on sugars that contained an acetyl group in the C-6

primary position Again the selectivity for the anomeric acetate was maintained with

all of the triflates used (Table 12) good yields were obtained in all cases but

Nd(OTf)3 again showed the highest yields

Table 12 Yields obtained for anomeric deacetylation of selected sugars using

metal triflates

Starting

material Product

Yb(OTf)3a

Yield ()

Eu(OTf)3a

Yield ()

Sm(OTf)3a

Yield ()

Nd(OTf)3a

Yield ()

AcOAcAcOAcOAcO H

OAcOAcO

85 81 85 81

OAcAcOAcO

AcO CH2OAc

AcOAcO

AcO CH2OAc

68 78 82 82

OAcAcOAcOcO

CH2OAc

AcOAcOAcO

CH2OAc

61 62 79 81

HAcOAcOAcO

CH2OAc

AcOAcOAcO

CH2OAc

67 62 67 68

a Reactions carried out in anhydrous MeOH (6 mL) containing starting material (100 mg) and 5 mol Lx(OTf)3

at rt Yields were obtained after purification by flash chromatography

Propargyl alcohols are known to be versatile building blocks in organic synthesis46

Previously Wang and Hammond47 reported a process for making ββ-

difluorohomopropargyl alcohols Following on from this work Armitsu and

Hammond48 have now reported the use of lanthanide metal triflates in an indium-

mediated preparation of ββ-difluorohomopropargyl alcohols

The indium metal-mediated reaction between benzaldehyde and difluoropropargyl

bromide (Scheme 13) was examined to determine the effect of the solvent on the

reaction and then the effect of adding a metal triflate as a Lewis acid catalyst was

investigated (Table 13) The solvent system THFH2O was found to be the most

effectivemdashwhen anhydrous THF was used the reaction did not proceed at least in the

case of the uncatalysed reaction (Table 13 entry 5) Eu(OTf)3 afforded highest yields

and was used in the subsequent studies

OIn (10 eq)

Lewis acid additive (5 mol)

THFH2O 40 oC 20h

+ TIPS CF2

215 16 17 18

Scheme 131 Reaction between difluoropropargyl bromide (15) and benzaldehyde

Table 13 Yield of reaction between difluoropropargyl bromide and benzaldehyde in

different solvent systems with different additives

Entry Solvent Eq of 16 Additive Yield ()a

1 H2OTHF (41) 11 - 206

2 H2OTHF (41) 11 - 3112

3 H2OTHF (41) 11 - 257

4 Satd NH4Cl(aq)THF (41) 11 - 204

5 THF 11 - No reaction

6 DMF 11 - Complex mixture

7 H2OTHF (41) 22 - 298

8 H2OTHF (41) 33 - 364

9 H2OTHF (41) 11 Sc(OTf)3 424

10 H2OTHF (41) 11 Er(OTf)3 647

11 H2OTHF (41) 11 Eu(OTf)3 788

12 H2OTHF (41) 11 Tb(OTf)3 7610

13 H2OTHF (41) 11 Sm(OTf)3 489

14 H2OTHF (41) 11 Y(OTf)3 4713

15 H2OTHF (41) 11 Ce(OTf)3 778 a Yield determined by 19F NMR

In another study (Scheme 132) compounds of the type 19 were used as substrates

The effects of the substituents R were then examined by using the optimal conditions

that had been found in the previous experiments

BrF + R

In (10 eq)Eu(OTf)3 (5 mol)

H2OTHF (41) 40 oC 20h

19 20 Scheme 13 Indium-mediated reaction of 19 with different aldehydes in aqueous

Triethylsilyl and triisopropylsilyl were found to be the most effective groups (Table

14) and TES was subsequently used in the reactions with the other aldehydes

Table 14 Indium mediated reaction of 19 with different aldehydes in aqueous media

Entry R Rrsquo Yield ()a

1 TIPS Ph 68

2 TES Ph 72

3 TMSb Ph 41

4 n-Hexb Ph 55 5 Phb Ph 35 6 TESb 4-Me-C6H4 65 7 TESb 4-MeOC6H4 61 8 TESb 3-MeO-C4H4 60 9 TESb 24-(MeO)2-C6H3 73 10 TESb 4-OH-C6H4 62 11 TESb 4-Cl-C6H4 71 12 TESb 2-F-C6H4 65 13 TESb 4-NO2-C6H4 No reaction 14 TESb Et 52 15 TESb (CH3)2CH 69 16 TESb BzOCH2 65

a Isolated yield b The reaction was sonicated for 12 h c The reaction was sonicated for 6 h

To date no satisfactory explanation for the results in particular the role of the Lewis

acid has been proposed Studies to elucidate the mechanism are still underway4950

However it is tempting to suggest that the Lewis acid increases the rate of the reaction

of a carbanion type intermediate with the aldehyde at the expense of dimer formation

(18 scheme 14)

In (reducing agent)

M+3 (Lewis acid) TIPSF

Scheme 14 Proposed mechanism

The Friedel-Crafts alkylations using alcohols and triflates has been previously

reported51-53 However these reactions usually required more than 5 mol of the

triflate and the functional groups of the substrates have been limited to a few

examples

The lanthanide triflates as well as scandium triflate were found to effectively

catalyse benzylation using secondary benzyl alcohols in Friedel-Crafts type

reactions54 The combination of a secondary benzyl alcohol and a metal triflate in

nitromethane gave products in high yields The reaction presumably proceeds via the

carbocation intermediate shown in Scheme 15

OHHO CO2Me

+Lewis acid

CH2Cl2 or CH3NO2

HO CO2Me

22 23 24Carbocation intermediate

Scheme 15 Lewis acid mediated alkylation of 3-hydroxy-2-napthoate with 1-(2-

naphthyl)ethanol

The reaction between 3-hydroxy-2-naphthoate and 1-(2-naphthyl)ethanol was

examined to compare the efficacy of a variety of Lewis acids (Table 15) Titanium

tetrachloride failed to catalyse the reaction and a stoichiometric amount of BF3OEt2

had to be added before an acceptable yield of the product was obtained On the other

hand the metal triflates all showed promising results and La(OTf)3 even afforded a

98 yield when 10 equivalents of water were added to the reaction mixture

Table 15 Effects of catalysts on the reaction between 3-hydroxy-2-napthoate and 1-

(2-naphthyl)ethanol

Entry Lewis acid Loading

mol Time h Yield ()

1a TiCl4 100 1 6

2a BF3OEt2 100 1 96

3a BF3OEt2 10 1 6

4b La(OTf)3 1 05 99

5b La(OTf)3 01 1 98

6b La(OTf)3 001 24 93

7b La(OTf)3 1 15c 98

8b Yb(OTf)3 1 033 96

9b Yb(OTf)3 01 025 94 a Reaction conditions DCM (250 mmolL) 0 degC b Reaction conditions

nitromethane (250 mmolL) 100 degC c H2O (10 eq) was added

Once the optimum conditions had been established the same reaction was used to

examine the effect of groups R (reagent 25) on the yield of the reaction (Table 16)

as well as the effects of acid sensitive functional groups in position Rrsquo(reagent 26) on

the outcome (Table 17) of the reaction (Scheme 16)

OHHO CO2R

+1 mol La(OTf)3

HO CO2R

R25 26 27

CH3NO2

Scheme 16 Alkylation of 26 using La(OTf)3

Table 16 Alkylation of 26 with acid-sensitive functional group substituted benzylic

alcohols

Entry R Rrsquo time Yield ()

1 H Me 15 min 99

2 OSiR3a Me 2 h 93

3 OAc Me 6 h 95

4 OBn Me 14 h 97

5 OH Me 25 h 65 a SiR3 = tert-butyldimethylsilyl

Table 17 Alkylation with various catalysts

Entry R Rrsquo triflate time Yield ()

1 H Me Hf 5 min 89

2 H Me H+a 15 min 87

3 H Me Sc 15 min 99

4 H Me Yb 25 min 99

5 H Bn La 25 h 99

6 H t-Bu La 19 h 59

7 H t-Bu Sc 20 min 89

a TfOH 3 mol

The catalytic activity of Sc(OTf)3 (1 mol) was found to be almost the same as that

of TfOH at 3 mol La(OTf)3 and Yb(OTf)3 at 1 mol were found to be less reactive

than 1 mol of TfOH The catalytic activity increased in order La(OTf)3 lt Yb(OTf)3

lt TfOH (1 mol) lt TfOH (3 mol) asymp Sc(OTf)3 ltlt Hf(OTf)3

It is postulated by the authors that the metal triflates may hydrolyse to form triflic acid

which may aid in the catalysis of these reactions They do however point out that it

has been documented by Kobayashi et al55 that the rare earth metal triflates are stable

in water Also La(OTf)3 and Yb(OTf)3 showed poorer catalytic activity than triflic

acid for these reasons the authors deduce that the formation of triflic acid in these

reactions generates such small amounts of TfOH as to be inconsequential

A proposed mechanism for the reaction is shown in Scheme 17 The mechanism

proposes the intermediate of a benzylic carbocation which may form the dibenzyl

ether eliminate H+ to generate the corresponding styrene or react with the nucleophile

to yield the product Both the styrene and the dibenzyl ether products were found in

trace amounts lending credence to the presence of the carbocation intermediate

Nucleophile

Olefin

Triflate

H2OOHAr

Triflate Ar O Ar

Products

2-naphthyl 29Byproducts

Ar = Ph

Ar = 2-naphthyl

Scheme 17 Proposed mechanism of alkylation reaction

Research on environmentally friendly aliphatic polyesters has received considerable

attention because of their biocompatibility and biodegradability56 However there are

only a few reports where metal triflates have been used to catalyse the polymerisation

process5758

The ring opening polymerisation (ROP) of lactones by rare earth metal triflates and

Sc(OTf)3 has been reported59 The immobilisation of the triflates in ionic liquids was

also successfully investigated for this purpose

Various metal triflates were examined for their ability to catalyse the ROP of ε-

caprolactone (CPL Scheme 18) Sc(OTf)3 was the most effective and gave a

quantitative conversion to the desired poly(ε-caprolactone) (PCL) in just two hours

The polydispersity (PDI MwMn) was small being 11 Sc(OTf)3 was then used in

further investigating the ring opening of lactones

2 mol M(OTf)x

toluene 25 oCO

Scheme 18 Metal triflate catalysed ROP of CPL or VL

The role of protic additives was investigated in the ROP of CPL as well as δ-

valerolactone (VL Table 18) Various amounts of n-BnOH were then added to the

reaction mixture When an excess of n-BnOH was added to the reaction mixture

polymerisation was accelerated rather than terminated and it was also seen that Mn

decreases as the amount of n-BnOH increases Interestingly Sc(OTf)3 catalyses the

ROP of VL which has a lower ring strain than CPL at a higher rate than that of CPL

Table 18 Sc(OTf)3 catalysed ROP of CPL and VL in the presence of various amounts

of n-BnOH

Entry Monomer n-BnOH

Mol Time (h)

1 CPL 0 4 gt99 6900

2 CPL 2 23 gt99 3500

3 CPL 5 2 gt99 2400

4 CPL 10 2 gt99 1600

5 VL 0 15 96 4300

6 VL 2 1 95 2900

7 VL 5 1 97 1900

8 VL 10 1 95 1400 a Sc(OTf)3 2 mol (002 mmol) CPL or VL 10 mmol toluene 10 mL temp 25 degC (CPL) or 0 degC (VL) b

Estimated by size exclusion chromatography (CHCl3 polystyrene standards)

Table 19 The ROP of CPL by M(OTf)3 in ionic liquidsa

Entry M(OTf)3 X- Time (h) Yield () Mn

1 Sc [BF4]- 2 d 0 -

2 Y [BF4]- 7 d 29 500

3 La [BF4]- 2 d 29 300

4 Ceb [BF4]- 6 d 32 600

5 Nd [BF4]- 6 d 30 500

6 Eu [BF4]- 2 d 0 -

7 Gd [BF4]- 5 d 30 600

8 Yb [BF4]- 4 d 27 500

9 Lu [BF4]- 3 d 26 500

10 Sc [PF6]- 42 80 2500

11 Y [PF6]- 53 83 2800

12 La [PF6]- 46 100 3700

13 Ceb [PF6]- 47 100 3500

14 Nd [PF6]- 35 100 2700

15 Eu [PF6]- 49 100 2400

16 Gd [PF6]- 48 100 3400

17 Yb [PF6]- 48 43 1600

18 Lu [PF6]- 47 100 4400

19 Sc [SbF6]- 30 87 900

20 Y [SbF6]- 48 99 1800

21 La [SbF6]- 42 100 1800

22 Ceb [SbF6]- 29 100 1700

23 Nd [SbF6]- 43 100 1700

24 Eu [SbF6]- 48 4 1500

25 Gd [SbF6]- 29 100 2500

26 Yb [SbF6]- 48 82 1400

27 Lu [SbF6]- 80 80 1100 a Polymerisation conditions M(OTf)3 20 micromol ionic liquid ([Bmim]X) 050 mL CPL 011 mL (099 mmol)

toluene 10 mL temp 25 degC N2 b Ce(OTf)4

Ionic liquids were then screened with the idea to use them to immobilize the triflates

(Table 19) All reactions in [Bmim][PF6] (Bmim = n-butyl-3-methylimidazolium)

proceed smoothly compared to those in the other two ionic liquids and afforded high

yields of PCL in average time periods [Bmim][SbF6] showed similar results to

[Bmim][PF6] However with Sc Eu Gd and Lu the phases became inseparable

suggesting to those authors some kind of interaction between the cation of the ionic

liquid and the triflate

The formation of benzyl esters in an early stage of polymerisation was confirmed by

the consumption of BnOH as shown by TLC analysis and the 1H NMR spectrum of

the reaction mixture A possible reaction mechanism was proposed by the authors

(Scheme 19) in which the Sc(OTf)3 coordinates to the CPL to afford the cationic

complex 30 which is attacked by the alcohol to produce the corresponding ester A

rapid equilibrium exists between 31 32 and 33 under which Sc(OTf)3 preferentially

binds to CPL to form 30 The free hydroxy ester 33 can serve as an alcohol

nucleophile and attacks the electrophilic 30

Sc(OTf)3

O(TfO)3Sc

OSc(OTf)3

Sc(OTf)3

Propagation

Scheme 19 A plausible mechanism of the ROP of CPL by Sc(OTf)3 via an activated

monomer mechanism

Ytterbium triflate was reported to catalyse the synthesis of β-enaminones under

solventless conditions (Scheme 110)60 The method was efficient on both cyclic and

acylic ketones aromatic as well as aliphatic amines and in all cases excellent yields

were achieved The reactions were allowed to proceed at room temperature for 12

hours in the presence of only 001 mol of the catalyst

R NH2+

001 molYb(OTf)3

12 h rt Scheme 110 Synthesis of β-enaminones catalysed by Yb(OTf)3

Benzylidene acetals have been effectively cleaved in the presence of Er(OTf)361

Reactions were carried out in nitromethane using 1-5 mol of the triflate and the

reactions proceeded quickly and with high yields (Scheme 111) The solvent was

then changed to acetic anhydride and the reactions repeated with the view of isolating

the preacetylated product These reactions were also successful and showed good

yields

Er(OTf)3 1 - 5 mol HO

CH3NO2 Scheme 111 Cleavage of benzylidene acetals using Er(OTf)3

Group III metal triflates

Indium triflate

Peracetylation of carbohydrates catalysed by indium triflate under solvent-free

conditions has been reported62a It was found that 005 mol of In(OTf)3 successfully

catalysed the peracetylation of various sugars in acetic anhydride after a period of 1

hour at 0 degC (Table 110)

Table 110 In(OTf)3 catalysed peracetylation of carbohydrates

Entries Carbohydrate Product Yield ()

AcOAcO

OHHOHO

OAcAcOAcO

OHHOHO

OAcAcOAcO

AcOH3C

OH HO O

OAcOAc

OAc AcO 97

OAcAcOAcO

OHHOHO

OAcAcOAcO

OHHOHO

OHAcHNHO

OAcAcHNAcO

a Reaction conditions In(OTf)3 (005 eq) in Ac2O (30 equiv) 1 h 0 degC (reactions1-5) or 0 degC to rt (reactions 6-7)

The compatibility of this reaction with commonly used protection groups was

investigated TBDPS and benzylidene acetals were stable under the reaction

conditions while TMS-and-TBS were deprotected The mechanism of the

peracetylation of galactose was examined The reaction proceeds in the presence of

005 mol of TfOH However the reaction does not proceed when 26-di-tert-

butylpyridine (DTBP) is added to the reaction mixture with In(OTf)3 This suggested

to the authors that triflic acid is the catalytic species

The reaction mixture containing the In(OTf)3 and DTBP was allowed to stir for one

day and 11 yield of the peracetylated product was obtained indicating to the

authors that there could be a dual pathway the In(OTf)3ndashcatalysed pathway being the

slower of the two The possibility of the pyridinium acid catalysing the reaction

(albeit slowly) was ignored by the authors Given the anomalous base behaviour of

DTBP as shown by Brown62b the latter hypothesis remains feasible Brown showed

that DTBP is an unusually weak base compared to other 26-dialkylpyridines

The effects of other catalysts on the acetylation of glucose were also determined

In(OTf)3 was compared to InBr3 and InCl3 Both of the alternative Lewis acids

catalysed the reaction at a much lower rate than the triflate InBr3 being the slower of

the two It was concluded that the relative strengths of the acids generated in the

reaction TfOH gt HBr gt HCl accounted for the differential activity observed in the

reactions The generation of these protic acids assumes the hydrolysis of the InX3

salts at least to some extent

The allylation of various ketones with diallyldibutyltin was successfully catalysed by

In(OTf)364 The reaction between acetophenone and diallyldibutyltin (Scheme 129)

was investigated to determine the effects of different solvents on the reaction The

results showed that DCM gave superior results over the other solvents such as MeCN

ether and THF

O+ SnBu2

2 H3C OH

Ph10 mol M(OTf)3

Solvent rt 12h

Scheme 112 Allylation of acetophenone with diallyldibuyltin catalysed In(OTf)3

This reaction (Scheme 112) was also used to determine the efficacy of other metal

triflates to catalyse this reaction (Table 111) In(OTf)3 and Y(OTf)3 showed the most

promising results and afforded 95 and 86 yields of the allylated product

respectively

Table 111 Effect of different triflates on the allylation of acetophenone with

diallyldibuyltin

Entry Metal triflate Yield

1 In(OTf)3 95 2 Yb(OTf)3 74 3 AgOTf 71 4 Y(OTf)3 89 5 Cu(OTf)2 51 6 Zn(OTf)2 48

a Isolated yields

Once the optimal conditions were obtained (10 mol In(OTf)3 DCM rt 12 h) a

variety of ketones was examined (Scheme 113 Table 112) High yields were

obtained in the majority of cases

O+ SnBu2

2 R2 OH

R110 mol M(OTf)3

Solv rt 12 h Scheme 113 Metal triflate catalysed allylation

Interestingly meta-substituted aromatic compounds underwent allylation more

efficiently than the para-substituted analogue aliphatic ketones afforded the allylation

products in moderate to good yields Benzophenone also reacted smoothly to give

products in a reasonable yield To confirm that the reaction system could be applied to

aldehydes p-anisaldehyde was used which usually reacts slowly in allylation

reactions Under these conditions an 80 yield of the homoallylic alcohol was

obtained (Table 112 entry 16)

Table 112 Allylation of ketones with diallyldibutyltin catalysed with In(OTf)3

Entry R1 R2 Yield

1 Ph CH3 95

2 p-FC6H4 CH3 81

3 p-ClC6H4 CH3 75

4 p-BrC6H4 CH3 86

5 p-NO2C6H4 CH3 66

6 m-BrC6H4 CH3 93

7 m-CF3C6H4 CH3 90

8 p-MeC6H4 CH3 58

9 p-NH2C6H5 CH3 -

10 Ph Ph 42

14 CH2CH2CH3 CH3 45

15 CH2CH(CH3)2 CH3 27

16 p-MeOC6H4 H 80

a Isolated yields

The mechanism of the reaction was studied by 1H NMR and ESI mass spectrometry

and an acyclic transition state has been proposed as follows in Scheme 114

In(OTf)3

O(TfO)2In

SnBu2OTf

OBu2Sn

2 Scheme 114 Proposed mechanism of acyclic transition state

Aluminium triflate

Regioselective cycloisomerisation of non-activated unsaturated oximes catalysed by

aluminium triflate has been reported65 The reaction afforded 5- 6- and 7- membered

rings containing oxygen and nitrogen The model reaction using oxime 34 (Scheme

115) was used to determine the efficacy of different metal triflates on the

cycloisomerisation reaction and the effect of different solvents

Catalyst (20 mol)Refluxing solvent

Scheme 115 Reaction of 7-methyl-1-phenyloct-6-en-3-one oxime 34 catalysed by

aluminium triflate

No cyclisation occurred when Cu Fe and Sn triflates were used in which cases only

ketone 37 was formed However the desired seven membered ring 35 formed in good

yield when Al(OTf)3 was used as the catalyst in boiling nitromethane When Al(OTf)3

and dichloroethane were used a 73 conversion was seen of which 59 was the six

membered ring 36 Triflic acid failed to catalyse this reaction and gave only 22 of

the ketone 37 bringing an argument against TfOH being the true catalyst

Al(OTf)3 in nitromethane or dichloroethane was then used with a variety of oximes to

determine the scope of the reaction (Table 113) Oximes bearing trisubstituted double

bonds (Table 113 Entries 1 and 2) afforded seven membered ring structures in high

yields When the oxime contained disubstituted olefins (Entries 3-6) the reactions

resulted in 5 or 6 membered cyclic structures depending on the chain length between

the oxime moiety and the double bond of the starting material When the double bond

in the original material was terminal no cyclic structure was formed the reaction

resulted in amides through a type of Beckman rearrangement

The regioselectivity of the reaction is explained through electrophilic attack by the

oxime proton once the ndashOH as been activated by the highly electrophilic Al3+

species followed by nucleophilic attack of the oxime oxygen atom on the carbocation

so generated via the intermediates shown in Figure 11

Al(OTf)3

NOAl(OTf)3

O-H activated intermediate Alkene-promotedCarbocation intermediate

Figure 11 Active oxime-derived intermediates

Table 113 Cyclisation of non-activated unsaturated oximes catalysed by Al(OTf)3

Entry Substrate Solvent Product Isolated

Yield ()

2 N OH

(CH2Cl)2

82 (11)

Acetylations of alcohols phenols and thiophenols could be carried out with catalytic

amount of Al(OTf)366 A variety of primary secondary benzylic and cyclic alcohols

was successfully acetylated using 01 mol Al(OTf)3 with acetic anhydride under

solventless conditions in excellent yields in under a minute The system was also used

successfully to acetylate thiophenols

Al(OTf)3 was found to be a highly effective Lewis acid catalyst for the ring-opening

of a variety of epoxides by a range of alcohols The reactions provided products in

very high yields and often with high selectivity67a

Initially work was carried out on styrene oxide was used with Al(OTf)3 and varying

amounts of ethanol (Scheme 116) This system was subjected to various temperatures

until optimal conditions were established

Al(OTf)338

39 Scheme 116 Al(OTf)3 catalysed ring opening of styrene oxide with alcohols

The scope of Al(OTf)3 as a Lewis acid catalyst for epoxide opening was then

determined by changing the catalyst loading the types of alcohols used and the

substrates employed (Table 114)

The reactions with styrene oxide proceeded smoothly and in the majority of the cases

were regioselective This is due to the stabilisation of the carbocation intermediate by

resonance the phenyl ring In contrast butylene oxide forms an almost 5050 ratio of

isomers where the nucleophile attacks at either end of the epoxide

When styrene oxide is reacted with ethanol in the absence of a catalyst only 5 yield

of the glycol ether is obtained after 24 hours Triflic acid also failed to catalyse this

reaction when 0005 mol TfOH was added to the reaction mixture only 4 of the

glycol ether was formed after 24 hours

Table 114 Yields of products obtained from reactions with selected epoxides in

various alcohols

Entry Product

1 39 R = Me 0 1 8 94

2 39 R = Et 94 95 -a -a

3 39 R = nPr 93 97 92 (4)b -a

4 39 R= iPr 91 92 -a -a

5 39 R = 2-Bu -a 14 97 96 (4)b

6 39 R = tBu -a 77 77 -a

-a 41 (34)b -a -a

-a 31 (24)b -a -a

-a 55 88 -a

-a 21 42 62

-a -a 89 -a

OCH2CH3

OHOCH2CH2CH3

OHOCH(CH3)2

OHOCH2CH2CH2CH3

a Reactions not performed b Yields in parenthesis refer to the other regioisomer

To test the Al(OTf)3 on epoxides containing different structural motifs glycidyl ethers

were used (Scheme 117) In contrast to the above results the main product formed

from these reactions was the secondary alcohol where the nucleophile had favoured

the attack on the less hindered side of the epoxide electrophile

EtOHAl(OTf)3 R

1o alcohol 2o alcohol Scheme 117 Opening of glycidyl ether with alcohol and Al(OTf)3

This is presumably due to Al(OTf)3 forming a chelate structure with the oxygen atom

of the epoxide and the oxygen of the glycidyl ether (Figure 12) This would decrease

the Lewis acidity of the metal which would usually activate the internal carbon atom

such that it plays a dominant role This is supported by the notion that acid-catalysed

epoxide ring opening reactions are borderline SN2 reactions67b implying significant

SN1 type character in the transition state The proposed chelate structure should have

the effect of shifting the mechanism to favour the SN2 like transition state more fully

accounting for the shift to regioselective from the more hindered to the less hindered

position

(OTf)3 Figure 12 Chelation of Al(OTf)3 to glycidyl ether

The aminolysis of epoxides was reported to be catalysed efficiently by Al(OTf)3 to

afford a variety of amino alcohols in high yields68 Using aniline as the nucleophile

with a variety of epoxides reactions were carried out using 10 mol Al(OTf)3 in

toluene DCM and ether to determine the effect of solvents on the reaction From the

results it was clear that reactions carried out in toluene were far superior to those

carried out in the other solvents

It was also clear from these initial experiments that higher concentrations of Al(OTf)3

were required for aminolysis than for alcoholysis of epoxides67a Presumably the

nitrogen atom of the amine group and the oxygen atom of the epoxide compete for

complexation to the Al(OTf)3 Since oxygen and nitrogen are both hard but different

Lewis bases there would be a differential competition for the metal centre A variety

of alkyl and arylamine nucleophiles were then used in reactions with selected

epoxides to determine the steric and electronic effects they would have on the reaction

(Table 115)

Table 115 Products obtained from reactions with selected epoxides with various

aminesa

Product Yield ()

Al(OTf)3

Yield ()

Al(OTf)3

Yield ()

10 mol

Al(OTf)3

48 75b -

45 80b -

14 - 43c

31 (31)cd

- 35 (34)cd

a 12 eq amine 100 degC 5 h b Isolated yields () c 24 h reaction time d Yields in parentheses refer to other

regioisomer

In general the alkyl-amines (Table 115) were found to be harder nucleophiles and

therefore compete more efficiently for the Al(OTf)3 than the aromatic amines (Table

116) Higher catalyst loadings andor longer reaction times were required for reaction

with diethylamine and isopropylamine than the aromatic amines

Table 116 N-Methylaniline reactions with epoxidesa

Product Yield ()

Al(OTf)3

Yield ()

Al(OTf)3 OH

a 12 eq amine 100 degC 5 h

Reactions with less active nucleophiles were also successful and several reactions

showed that the catalyst was suitable for recovery and reuse without loss of activity

After the reaction the catalyst was extracted in to the water layer which was

subsequently removed under vacuum at elevated temperature

Gallium triflate

Gallium triflate has been used to catalyse the synthesis of quinoxaline derivatives69

An initial solvent study was carried out using the condensation reaction between 12-

phenylenediamine 40 and benzoin 41 (Scheme 118) Reactions were complete in

polar solvents such as ethanol methanol and acetonitrile in as short a period as five

minutes with conversions to product 42 being quantitative The reaction carried out in

water although slower (30 minutes) was also successful and gave an 85 yield

Ethanol was chosen as the solvent for further work due to its wide availability and

relatively low toxicity Both 5 mol and 1 mol of the catalyst gave quantitative

conversion to product 42 in 5 minutes while 01 mol gave only 85 conversion

O O5 mol Ga(OTf)3

solvent

40 41 42 Scheme 118 Reaction between 2-phenylenediamine 40 and benzoin 41 catalysed by

Ga(OTf)3

Using these optimised conditions a variety of 12-diamines was reacted with 12-

diketones (Table 117) The quinoxaline derivatives were formed in high yields

Table 117 Yield () quinoxaline derivative from the reaction 12-diamines were

reacted with 12-diketones catalysed by Ga(OTf)3

Entry Product Time

5 gt99

360 90

10 gt99

O 10 gt99

240 90

OO 10 98

The Ga(OTf)3 catalyst could be recovered from the solvent and was reused without

loss of activity in ten repetitive reaction cycles

A mechanism for the reaction of o-phenylenediamine with 2-hydroxychalcone

derivatives to form 24-disubstituted 15-benzodiazepine was proposed (Scheme

119) Ga(OTf)3 forms a chelate structure with the 2-hydroxychalcone which

facilitates the dehydration process The 2-hydroxy group in the chalcone makes the

αβ-unsaturated carbonyl more reactive towards the addition of NH

(OTf)3Ga

Ga(OTf)3

H2N NH2

(OTf)3Ga

Scheme 119 Proposed mechanism for Ga(OTf)3-catalysed reaction of 2-

hydrochalcones with o-phenylenediamine

The one pot synthesis of 23-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-

ones was found to be effectively catalysed by Ga(OTf)3 in a highly selective

reaction70 A model reaction was carried out using iastoic anhydride p-

methylbenzaldehyde and ammonium acetate under various different reaction

conditions (Scheme 120)

+ NH4OAcNH

NHCatalyst

CH3 Scheme 120 Reaction between iastoic anhydride p-methylbenzaldehyde and

ammonium acetate

A range of different triflates was examined using ethanol as the solvent Ga(OTf)3

was by far the superior Lewis acid catalyst 1 mol was sufficient to catalyse the

reaction When other solvents were used such as THF water and acetonitrile the

yields dropped dramatically

The scope of the study was then expanded by looking at the effect of electron

withdrawing or donating groups on the aromatic rings (Scheme 121)

NH4OAc or R3NH2 N

NCatalyst

R2CHOR1 R3

Scheme 121 One pot synthesis of 23-dihydroquinazolin-4(1H)-ones catalysed by

Ga(OTf)3

The reaction afforded the desired products in high yields (Table 118) The effect of

substitutuent groups on the aromatic ring had no obvious effects on the yield Good

yields were also obtained with reactions that were carried out with aromatic

heterocyclic aldehydes and anthranilamide

Table 118 Yields obtained in the one pot synthesis of 23-dihydroquinazolin-4(1H)-

ones catalysed by Ga(OTf)3

Entry R1 R2

NH4OAc

1 H p-(CH3)C6H4 NH4OAc 50 86

2 H 24-(OCH3)2C6H3 NH4OAc 45 90

3 H p-(N(CH3)2)C6H4 NH4OAc 35 88

4 H p-(OH)C6H4 NH4OAc 50 86

5 H m-(F)C6H4 NH4OAc 50 85

6 H p-(Cl)C6H4 NH4OAc 35 89

7 H o-(NO2)C6H4 NH4OAc 70 71

8 H p-(NO2)C6H4 NH4OAc 60 73

9 H 2-Furyl NH4OAc 40 91

10 H 2-Pyridyl NH4OAc 50 88

11 Cl p-(CH3)C6H5 NH4OAc 50 86

12 Cl p-(OCH3)C6H4 NH4OAc 40 83

13 Cl p-(F)C6H4 NH4OAc 55 83

14 Cl p-(NO2)C6H4 NH4OAc 50 80

15 H p-(OH)C6H4 sBuNH2 55 83

16 H p-(Cl)C6H4 nBuNH2 50 89

17 H p-(NO2)C6H4 nPrNH2 50 87

18 H p-(Cl)C6H4 C6H5NH2 60 82 a Isolated yields

During the initial solvent study it was discovered that if the reactions were carried out

in DMSO the condensation reaction is followed by oxidation and the products

formed are the quinazolin-4(3H)-ones Reactions with the various aldehydes

containing electron donating or electron withdrawing groups on the aromatic ring

were carried out (Table 119) The products were obtained in high yields in all cases

Table 119 Yields obtained in the one pot synthesis of quinazolin-4(3H)-ones

catalysed by Ga(OTf)3

Entry R1 R2 Time

1 H p-(CH3)C6H4 50 84

2 H C6H4 55 83

3 H 24-(OCH3)2C6H3 50 89

4 H 34-(CH2O2)C6H3 55 84

5 H p-(N(CH3)2)C6H4 55 87

6 H p-(OH)C6H4 50 92

7 H m-(F)C6H4 55 84

8 H m-(Cl)C6H4 55 86

9 H p-(Cl)C6H4 55 89

10 H m-(NO2)C6H4 70 82

11 H p-(NO2)C6H4 65 81

12 H 2-Furyl 55 80

13 Cl p-(Cl)C6H4 60 79 a Isolated yields

A tentative mechanism was proposed for the formation of 23-dihydroquinazolin-

4(1H)-ones and quinazolin-4(3H)-ones (Scheme 122) The first step probably

involves the condensation of isatoic anhydride 48 with ammonia and then

anthranilamide 49 could be produced with the liberation of carbon dioxide The

intermediate 50 is obtained by the condensation of 49 with aldehydes promoted by

Ga(OTf)3 The amide in intermediate 50 is tautomerised in the presence of Ga(OTf)3

while the imine part of this intermediate is activated by Ga(OTf)3 Thus intermediate

51 is converted to 52 by intramolecular nucleophilic attack of the nitrogen atom on

the imine carbon Subsequently 23-dihydroquinazolin-4(1H)-ones 53 could be

formed by a 15-proton transfer Finally product 54 is obtained by oxidation using

DMSO as a solvent

NH4OAc

CO2 NH2

RCHOGa(OTf)3

Ga(OTf)3

2 Ga(OTf)3N

48 49 50

51 52 53

(Ga(OTf)3)

Scheme 122 Proposed mechanism for the formation 0f 23-dihydroquinazolin-4(1H)-

ones and quinazolin-4(3H)-ones

Other triflates

Copper(II) triflate or zinc(II) triflate promotes the cycloaddition reactions of α-alkyl

or aryl substituted N-tosylaziridines with nitriles71 A [3+2] cycloaddition reaction

was carried out on 2-phenyl-N-tosylaziridine in acetonitrile at 60 degC for 30 minutes

with a number of Lewis acids (Scheme 123)

RCN Cu(OTf)2

65 oC 30 min N

Ts Scheme 123 [3+2] cycloaddition reaction of 2-aryl-N-tosylaziridines with different

nitriles promoted by Cu(OTf)2

Although both triflates promoted the reaction Cu(OTf)2 was the superior promoter

Further studies showed that optimal reaction conditions required 1 equivalent of the

metal triflate and reactions to be performed at 60 degC

Using this approach various nitriles were reacted with 2-aryl-N-tosylaziridines (Table

120) Good yields were obtained in all cases The study was extended to cycloalkyl

benzyl and n-octyl substituted aziridines Previously reported methods for these

substrates have been unsuccessful72 when the reactions were carried out using

copper(II) triflate good yields of the products were obtained (Table 120 Entries 8-

Table 120 Cu(OTf)2 promoted [3+2] cycloaddition reactions of aziridines and nitrilea

Entry Aziridine Nitrile Product Yield ()b

82 (91)c

NPh CH3

NPh Ph

Ts(C6H4)Me-4 CH3CN N N

(C6H4)Me-4

(C6H4)Me-4 PhCN N N

(C6H4)Me-4

CH3CN N N

(C6H4)Cl-4

PhCN N N

(C6H4)Cl-4

7 N Ts CH3CN N

Ts 62 (93)c

8 N Ts PhCN N

NTsC6Cl4H4

a In all cases the nitrile served as a solvent b Isolated yields after column chromatography c Yield was determined

by 1H NMR analysis of crude reaction mixture

The mechanism for the [3+2] cycloaddition reaction between 2-aryl-N-tosylaziridine

with nitriles is illustrated in Scheme 124 Copper is coordinated to the nitrogen atom

of 1a generating 56 the subsequent cyclcoaddition reaction results in the formation

of the imidazoline 58

TsCu(OTf)2

Ts Cu(OTf)2Ph

NCu(OTf)2

55 56 57 58

Scheme 124 Mechanism for the [3+2] cycloaddition reaction of 2-aryl-N-

tosylaziridine with nitriles

Bismuth triflate has been reported to catalyse the Claisen rearrangement of allyl

naphthyl ethers to afford the corresponding ortho-allyl naphthol derivatives in good to

moderate yields73 The naphthol derivatives were allylated according to Scheme 125

and the rearrangement was then carried out using 20 mol Bi(OTf)3 in acetonitrile

Allyl 1-naphthyl ethers with various substituents on the aromatic ring reacted

smoothly to give the corresponding ortho-allyl naphthols in good yields Similarly

Reactions carried out with 14-di(allyloxy)naphthalene gave clean doubly rearranged

products The other di(allyloxy) naphthalenes that were tested gave mixtures of di and

mono rearranged products (Scheme 125)

Cs2CO3 DMF60 - 100

Bi(OTf)3 xH2O 20 mol

OH R3R4

R1 R1 R1R2R2R2

MeCN reflux

Scheme 125 Claisen rearrangement of ally 1-naphthyl ethers catalysed by Bi(OTf)3

The study was extended to include 2-substited 1-naphthyl ethers and diallyloxy

naphthalenes The 2-substituted ethers afforded the para-allyl naphthols in excellent

yields in these cases the ortho-Claisen rearrangement is followed by a [3+3]

rearrangement (Scheme 126)

Cs2CO3 DMF74 - 95

MeCN reflux

Scheme 126 Claisen rearrangement of 2-substituted allyl 1-naphthyl ethers catalysed

by Bi(OTf)3

Carbonyl compounds have been chemoselectively protected using Y(OTf)3 as a

catalyst74 By using 2-mercaptoethanol 12-ethanedithiol and 13-propanedithiol

aldehydes and ketones were converted into their corresponding oxathiolanes

dithiolanes and dithiane derivatives in the presence of 5 mol Y(OTf)3 in acetonitrile

and no drying reagent is necessary (Scheme 127)

R2Y(OTf)3 5 mol

CH3CN rt

R1 R2 Scheme 127 Protection of carbonyl compounds catalysed by Y(OTf)3

Various aliphatic aromatic and heterocyclic aldehydes underwent protection at room

temperature to give the corresponding products in high yields Ketones required reflux

conditions before satisfactory results were obtained The Y(OTf)3 catalyst could be

recovered from the aqueous layer and reused

AgOTf catalysed the direct amination of benzyl alcohols with sulfonamides75 This

process required no preactivation of the primary alcohols into better leaving groups

The reaction is also relatively environmentally friendly as water is the by-product

An initial solvent study on the reaction between p-chlorobenzyl alcohol and p-

toluenesulfonamide in the presence of 5 mol AgOTf showed that the reactions

proceeded optimally in nitromethane From this study it was also seen that by

changing the ratio of alcohol or amine yields and selectivities also changed If 15 or

2 equivalents of the amine were used mono-substituted products were produced

However if 2 equivalents of alcohol were added the product was disubstituted

A range of Lewis acids was also examined using the above reaction Cu(OTf)2

Sc(OTf)3 and Bi(OTf)3 all catalysed the reaction and gave the corresponding products

in high yields and selectivities However the workers chose AgOTf to continue the

investigations Even though it was not the top-performing catalyst it showed the best

selectivity overall

Under the optimal conditions found (2 equivalent amine 5 mol AgOTf

nitromethane) a variety of primary alcohols were reacted with different sulfonamides

(Table 121) When toluene-4-sulfonamide was reacted with structurally and

electronically diverse alcohols (Entries 1-4) the desired products were formed in

good yields

Table 121 Amination of benzyl alcohols with various sulfonamides catalysed by

AgOTfa

Entry Productb Yield

a Reaction conditions 1 mmol alcohol 2 mmol sulfonamide 5 mol AgOTf in 5 mL nitromethane 100 degC 8 h b

Isolated yields

The presence of a strong electron withdrawing (NO2) group was detrimental to the

reaction (Entry 5) and no product was formed Reactions of p-chlorobenzyl alcohol

(Entries 7-9) were also successful

Conclusions

From the above discussion it is clear that metal triflates can be used efficiently as

Lewis acid catalysts in a plethora of organic transformations Metal triflates are

reported to be water tolerant and can even be recovered from the aqueous layer to be

recycled and reused with out loss of activity More traditional Lewis acids are

deactivated or decomposed by even the smallest amounts of water This clearly

demonstrates the advantages of metal triflates as Lewis acid catalysts It is also clear

that some differences of opinion exist as to the hydrolysis of metal triflates in water to

form triflic acid This issue is important as it forms part of the present study

13 The ranking of Lewis acids

Introduction

Lewis acids play an important role in all areas of chemistry there are literally

thousands of references to Lewis acids in the literature (Sci finder search as of

January 2009 produces ca 50000 hits) New kinds of Lewis acids are being

synthesised on a continual basis76 and the yields of existing reactions are being

improved by their use76 The ldquotrickrdquo is to try to determine the correct Lewis acid for

the reaction at hand7778 When a Broslashnsted acid is needed pKa measurements inform

us of the acid strength and in this way we are able to determine at least to some

extent if the acid is suitable for our reaction When using Lewis acids matters are

more complex

The quantitative measurement of Lewis acidity appears to be one of the perennial

problems of the Lewis acid-base theory Lewis himself pointed out that a given series

of compounds would not exhibit a uniform relative acid (or base) strength79 Relative

acidity (or basicity) would be dependent on the reference acid (or base) used80

Despite this attempts by many researchers from as far back as the 1950rsquos have been

made to quantify the strength of Lewis acids However there is still no uniform

quantitative measurement for Lewis acidity across a broad range of Lewis acids

Perhaps the closest method for actual values for Lewis acidity would be the

calculation of the enthalpy change accompanying the formation of the acid-base

adduct in the gas phase81 so as to eliminate any solvent effects This is however not

possible for a wide range of compounds and alternative more manageable methods

have to be found

Measurements that have been carried out to try to rank Lewis acids in order can be

broadly broken down into two categories namely a) thermodynamic measurements

and b) measurements carried out spectroscopically This review deals with literature

that covers both of these categories separately as well as the literature that deals with

comparative studies

131 Thermodynamic measurements

Equilibrium constants

Interest in this work started with the investigation of the interaction of iodine with

aromatic hydrocarbons such as benzene82 In this investigation the equilibrium

constants were calculated in different solvents by using ultraviolet absorption making

use of the slight shifts in the UV spectra between the iodine-complexed benzene and

the free benzene The equilibrium constant is calculated by K = (Br2middotA)(Br2)(A)

where A represents the aromatic compound The concentrations are determined from

the UV readings While UV spectroscopy represents a spectroscopic method the

results being in the form of equilibrium constants represent thermodynamic data

Keefer and Andrews83 then used this method to determine the equilibrium constants

for bromine with benzene and its derivatives It was not the intent of that paper to

rank the Lewis acidity of the halides However the results along with the data found

in a paper by Blake et al84 which deals with the Kc of complexes of I2 and Br2 with

naphthalene have been cited for this purpose in a later paper by Scott85 In his work

the heats of formation are emphasised

Complexes of iodine monochloride with benzene and certain derivatives were

investigated by examining equilibrium constants86 It was found that ICl functions as

a much stronger acid in these types of reactions than Br2 or I2 The order was found to

be ICl gt I2 gt Br2

Work started by Moodie87 in which he complexed BF3 to three different types of

acetophenones and calculated equilibrium constants was continued by Mohammad et

al88 A range of Lewis acids was complexed to different ketones and by calculating

their Kc values their relative acidities were determined (Table 122)

Table 122 Equilibrium constants and spectral data for complexes of Lewis acids with

ketones

Acid 4-Methoxyacetophenone 44rsquo-Dimethoxybenzophenone

Δλ pK Δλ pK

GaBr3 66 -057 91 -061

GaCl3 63 -057 89 -051

ZnBr2 37 -052 48 -051

ZnCl2 39 -052 50 -039

BF3 59 +063 90 +251

Table 122 shows that in ether the order of acidity based on the Kc calculated by the

formula K = [Adduct][MXn][Ketone] for each acid-ketone combination used the

observed equilibrium was formulated by equation 7 was found to be GaBr3 ~ GaCl3 ge

ZnBr2 ~ ZnCl2 gt BF3 Moodiersquos87 data for BF3 with 4-methoxyacetophenone were not

comparable to the data found in the later study None of the other adducts is similar to

those studied by Moodie and there is consequently no bases for their comparison

Interestingly the benzophenone base gave more consistent results than the

acetophenone adducts possibly because itrsquos less basic than acetophenone

O1R2RC + MXn(Et2O)m O1R2RC MXn(Et2O)m-1 + Et2O 7

When an aniline is used as the reference base we see that the order of Lewis acidity

changes89 The equilibrium constants for Lewis acids complexed to unhindered

aniline bases show an order of acidity BF3 ge GaBr3 ~ GaCl3 ~ SnCl4 gt SnBr4 gt ZnBr2

~ ZnI2 gt SbCl3 In this series it can be seen that BF3 is ranked as the strongest acid

Heat of complex formation

On the basis of free energy of complex formation (Table 123) the decreasing acid

strength was found to be ICl gtgt BrCl gt IBr gt gtI2 gt Br2 gtgt Cl2 which is in agreement

with the previous results85 The acid strength of the various halogens was determined

by calculating the heats of formation of trihalogens where the halide ion acts as the

base and the halogen acts as the acid85 The order of ranking obtained on the bases of

free energy of complex formation were found to be comparable to those previously

reported where equilibrium constants have been calculated (Table 124)838490

Table 123 Free energies of complex formation

Base rarr

Aciddarr I-(aq)a Br-(aq)a Cl-(aq)a H2O(l)a

ICl(g) -143 -86 -57 -27 BrCl(g) - -578 - (-20) IBr(g) -1066 -530 -404 -181 I2(g) -459 -216 -114 -070

Br2(g) - -144 +004 +0226 Cl2(g) - - +44 +165

aΔFdeg in Kcalmole at 25 degC

Table 124 Equilibrium constants for complex formation838490

Base rarr

Aciddarr Benzene p-Xylene Hexamethyl

-benzene

Naphalen

ICl 054 151 227 139 I2 015 031 135 025

Br2 011 023 - -

By using NN-dimethylacetamide heats of complex formations were used to determine

the Lewis acidities of ICl SO2 Br and I290 The order of acidity compares well with

the previous data90 The data were also compared to the polarity and the dipole

moment of the different acids9293

The heat released on formation of an acid-base complex should be increased by an

acid with a large polarisability and a high dipole moment91 The polarisabilities92 of

these acids decrease in the order I2 gt ICl gt Br2 gt gt SO2 The dipole moments93 for I2

and Br2 are zero for ICl 12 Debye and for SO2 16 Debye

From the heats of complex formation the relative acidities were determined to be ICl

gt I2 gt SO2 gt Br2 The data show the importance of both polarisability and the dipole

moment when determining relative acidities ICl has a high dipole moment and a large

polarisability and because of this is the strongest acid Iodine has no dipole moment

but is still a stronger acid than SO2 as it is more polarisable Bromine also has no

dipole moment is more polarisable than SO2 but much less than I2 so it is the

weakest acid The relative acidities of SO2 and Br2 are interchangeable towards a

polar and non-polar donor respectively

Other thermodynamic data

Lewis acids have also been ranked according to a quantity known as the selectivity

parameter9495 The selectivity parameter is the relative ability of an acid to catalyse

the isomerisation of methylpentanes to 22-dimethylbutane and n-hexane and the

simultaneous deprotonation of carbonium ion intermediates A ldquoperfectrdquo acid allows

the isomerisation to occur without hydrogen exchange while a ldquopoorrdquo acid is unable

to stabilise the ion and hydrogen exchange occurs The selectivity parameter is the

ratio of isomerisation to exchange rate constants kisokex equiv (IE) This parameter

allows the ranking of strong acids

In the first paper that appeared on the matter94 the selectivity parameter was used to

rank the acidities of SbF5 TaF5 and NbF5 in HBr HCl HF HSO3F and CF3SO3H In

general the order found was SbF5 gt TaF5 gt NbF5 But the acidity of these systems was

found to be concentration dependent

The second paper by that author95 ranks 2M mixtures of Lewis acids in HBr while a

number were also reported in HF HBr was chosen as the common solvent for the

range of Lewis acids as metal fluorides would be stable and not undergo fluoride ndash

bromide exchange The relative strength of the Lewis acids in HBr was found to be

AlBr3 gt GaBr3 gt TaF5 gt BBr3 gt (TiF4 BF3 HF4)

The relative acidities determined in this study were compared to those found by other

methods (Table 125) The data are in general agreement for a wide variety of

techniques

Table 125 Comparison of Lewis acid ranking by different methods

Order Method Ref

BF3 gt TaF5 gt NbF5 gt TiF4 gt PF5 gt SbF3 gt WF6

gtgt SiF4 ~ CrF3

Solvent extraction of

ArH+MFn+1-

AsF5 ~ BF3 gt PF3 ~ WF6 gt NbF5 gt SiF4 ~ CrF3 Solubility of Lewis acids 97

SbF5 gt AsF5 gt BF3 gt PF5 Decomposition of

complex

AsF5 gt PF5 gt BF3 Displacement reaction 99

BF3 = SbF5 = AsF5 = PF5 gt GeF4 gt TeF6 gt InF5 gt

Salt formation 100

AsF3 gt BF3 gt SiF4 gt AsF5 gt PF3 F- transfer from SF6- 101

AsF5 gt PF5 gt BF3 gt SiF4 gt AsF3 gt SF4 SF5 Ion cyclotron

spectroscopy

SF5 gt TaF5 gt NbF5 BF3 gt TiF4 gt HfF4 Selectivity 103

SbF5 gt TaF5 ~ NbF5 Conductivity 104

SbF5 ~ PF5 gt BF3 Solvolysis constants salt

formation

SbF5 gt AsF5 = BF3 gt PF5 = SnF4 = ReF6 = WF6 =

MoF6 = VF6 gt IF5 = TeF6 = GeF4 = TaF5 = NbF5

gt SeF4 = SiF4 = TiF4 gt SbF3 = AlF3 = CrF3 =

Solubility salt formation 106

The methods referred to in Table 125 are not discussed in further detail in this review

as they have found only limited application in the literature

A scale for Lewis acidity was calculated by using a dual parameter equation107 This

equation is based on a combination of electrostatic and covalent factors that contribute

to adduct formation108 Equation (8) was used to determine Lewis acidity in terms of

the parameter

Ž = Z rk2 ndash 77Xz + 80 (8)

Ž = charge number of atomic core

rk = ionic radius

Zrk2 = related to electrostatic forces

Xz = electronegativity of elements in the valence state (related covalent

bond strength)

The electronegativity (Xz) of the metal ions is plotted against the electrostatic forces

parameter (Zrk2) (Figure 13) Three clear areas of acidity can be seen for metal ions

in which electrostatic forces dominate Ž values are gt 066 Acids which are clearly

dominated by electronegativity (large covalent property) are found in the right bottom

of the graph Their Ž values are below zero The borderline acids lie between these

two and have Ž value that range between zero and 066

Figure 13 Electrostatic or covalent nature of Lewis acids

The calculated Ž value gives a quantitative classification for Pearsonrsquos qualitative

description of hard and soft acid and bases107 and is in good agreement with Pearsonrsquos

132 Spectroscopic measurements

IR spectroscopy

Ethyl acetate was used as an infrared probe by Lappert109 to rank the acidity of a

number of group III and IV Lewis acids Complexation of the acid to the acyl oxygen

atom (Figure 14) requires perturbation of the C=O bond and the strength of the

donor-acceptor bond will be reflected in the extent of polarisation of the C=O bond

This may be measured by the change in the C=O bond stretching frequency (ΔνC=O)

Figure 14 Complexation of acid to acyl oxygen atom

Table 126 shows the results of the change in wavenumber when the boron trihalide

complexes to ethyl acetate110111112

Table 126 Boron trihalides

X in base

acetate

Δν (cm-1)

- ΔHf

(kcal mol-1)

F 119 317

Cl 176 395 (379)9

Br 191 445 (435)9

` The results show the order BBr3 gt BCl3 gt BF3 for Lewis acidity This method was

also used to determine the acidities of the group III chlorides and bromides Using

ethyl acetate as the reference base the relative acceptor strengths for the trichlorides

was found to be B gt Ga gt Al gt In and for the tribromides B gt Al gt In (results for

GaBr3 were not available) This order appears reasonable as it reflects the metalrsquos

ability to accept electron density from the base109 Paulingrsquos electronegativity order

for these acids is B 20 Ga 16 Al 15

Silicon(IV) germanium(IV) and tin(IV) chlorides showed only weak interactions with

the ethyl acetate especially for SiCl4 (1SiCl4 2EtOAc) and GeCl4 (1GeCl4

2EtOAc) Tin chloride showed more distinct peaks The relative strengths were

ranked in the order SnIV gtgt GeIV gt SiIV

Phenalen-1-one (Figure 15) was used as an infrared probe to measure the acidities of

several acid halides113 Initially the spectra were measured using dilute solutions in

ether However the results were confused by strong solvent absorption The samples

were then made up in their solid form No correlation could be found between the

ΔνC=O and acid strength (Table 127) which may have been due to the fact that they

were solid samples

Figure 15 Phenalen-1-one

Table 127 Δ Carbonyl shifts of metal halides with phenalen-1-one

Acid ΔνC=O Solid state

stoichiometry

BF3 156 1 1

PhSnCl3 150 1 1

ZnCl2 120 1 1

SnBr4 157 2 1

ZnBr2 118 2 1

SnCl4 158 2 1

GaCl3 157 1 1

If these results are to be taken on face value the ranking of the Lewis acids would be

SnCl4 gt SnBr4 ~ GaCl3 ~ BF3 gt ZnCl2 gt ZnBr2 These results are contradictory to

those found elsewhere in the literature (see above discussions) and are consequently

not held to be reliable

Nuclear magnetic resonance spectroscopy

The ranking of Lewis acidity by NMR spectroscopy is based on the theory that

binding of the electron acceptor (Lewis acid) to the electron donor (Lewis base)

results in the reduction of electron density in the base resulting in a down-field shift

in the signals of the basic compound used (Figure 16) The more acidic the Lewis

acid the greater the shifts in the spectra and thus the Lewis acids can be ranked

H Figure 16 Lewis acid bound to Lewis base

A scale for Lewis acids was set up using a number of in organic halides and a variety

of ethers by looking at their 1H NMR shifts on complexation114 A value of 100 was

assigned to BCl3 the strongest Lewis acid in the study the other acids being

expressed as percentage of the effect observed for BCl3 The results in Table 128

show the trend in Lewis acidity towards the different ethers used The trend appears to

follow a Lewis acidity ranking of for BCl3 gt AlCl3 gt InCl3

Table 128 Relative acidity of Lewis acids towards various reference bases at 28 degC

Acid THF Di-n-butylether Di-ethylether

Hz Acidity Hz Acidity Hz Acidity

BCl3 640 100 752 100 790 100

AlCl3 518 81 640 85 672 85

i-C4H9CCl2 500 78 511 68 536 68

BiCl3a 480 75 - - - -

TiCl4 - - 526 70 600 76

InCl3b 410 64 - - - -

BF3 391 61 458 61 498 63

SnCl4 - - 384 51 - -

SnBr4c 256 40 00 0 - 0

(i-C4H9)2BCl 252 40 00 0 00 -

AsCl3 110 11 - - - 0

SnI4 00 0 - - 00 0

SiCl4 00 0 00 0 00 0

GeCl4 00 0 00 0 00 0

PCl3 00 0 00 0 00 0

(i-C4H9)3B 00 0 00 0 00 0 a By extrapolation from 03 acidbase ratio b By extrapolation from 025 acidbase ratio c At 80 acidbase ratio

The polycyclic phosphites C5H9O3P (Figure 17) and C6H9O3P (Figure 18) were used

to determine the acidities of boron Lewis acids through 1H NMR spectroscopy115 In

that study the acid strengths were found to be BH3 gt B(CH3)3 asymp BF3

C5H9O3P C6H9O3P

Figure 17 Figure 18

One of the most comprehensive studies carried out on ranking Lewis acidities by

NMR spectroscopy was that by Childs et al116 The Lewis acids employed were BF3

BBr3 SnCl4 SbCl5 TiCl4 BCl3 SiCl4 AlCl3 EtAlCl2 Et2AlCl Et3Al2Cl3 and Et3Al

The reference bases that were selected were examples of important classes of

compounds that undergo typical organic acid catalysed reactions eg crotonaldehyde

(Figure 19 Table 129) Here Δδ is the difference in chemical shift between the free

crotonaldehyde and its Lewis acid complex for a given signal

H3 Figure 19 Crotonaldehyde

Table 129 1H and 13C NMR chemical shift differences on complexation with

crotonaldehydea

Lewis acid Proton Δδ (ppm) Carbon Δδ (ppm)

H1 H2 H3 H4 C1 C2 C3 C4

BBr3 011 093 149 051

BCl3 -065 085 135 049 68 -37 317 43

SbCl5 017 078 132 048 69 -40 276 37

AlCl3 -020 076 123 047

EtAlCl2bc -020 077 125 047

BF3 -027 074 117 044 83 -33 261 31

EtAlCl2bcd -017 067 115 038

Et3Al2Cl3b -015 069 114 039

TiCl4 003 060 103 036

Et2AlClbc -015 055 091 030 94 -20 201 23

SnC4 -002 050 087 029 78 -28 192 23

Et3Al -034 042 063 023 a In ppm chemical shift of free base 1H δ = 947 (d H1) 610 (ddq H2) 693 (m H3) 202 (dd CH3) 13C δ =

1947 (C1) 1344 (C2) 1552 (C3) 190 (C4) Δδ is positive for a downfield shift Approximately 03 M solution

in DCM at -20 degC unless otherwise stated b At -60 degC chemical shift of uncomplexed base δ = 984 (H1) 61

(H2) 698 (H3) 205 (H4) c Written in monomeric form for simplicity d 21 crotonaldehyde ndash EtAlCl2

The H-2 H-3 and H-4 resonances of the crotonaldehyde were all found to be shifted

downfield on complexation to the Lewis acid The downfield shifts seen in H-3 were

the greatest while those seen in H-2 and H-4 were smaller in magnitude but showed a

linear relationship to those of H-3 The shifts of H-1 appear to be random This can be

seen in the plot (Figure 110) where Δδ of H-2 and H-4 are plotted against Δδ H-3 as

the Lewis acid varies

Figure 110 1H chemical shift differences of protons of crotonaldehyde versus the H3

chemical shift difference on complexation with various Lewis acids (+ Δδ H2 Δδ

H3 Δδ H4 Δδ H3 H1 Δδ H3)

What is also clear from Table 129 is that the Δδ of the signals in the 13C NMR

spectra follow the same trends The number of acids used in this study was lower than

that used in the 1H NMR study due to problems with solubility The shifts of C-1 (the

carbonyl carbon) appear to be random and unrelated to the shifts of the C-3 carbon

There is an upfield shift of the C-2 carbon in complexation which is a striking

difference These shifts are linearly related to the shifts of C-3 and C-4 but in the

opposite direction

Similar results were found for the other bases that were used in this study for example

cyclohex-2-enone All of the bases led to linear relationships for the shifts induced by

complexation with the Lewis acid This was interpreted to mean that it was possible to

set up a Lewis acid scale based on the shifts of the H3 protons

133 Comparative studies

In order to determine the relevance of a particular method for determining relative

Lewis acidities many comparative studies have been carried out The results of the

UVVis experiments carried out on phenalen-1-one113 that were discussed above

(Section 131) were compared to those obtained from equilibrium constants of the

adducts

No correlation could be found between the ΔνC=O and the pK values (Table130)

However the order of acidity according to the pK values is the same that is obtained

when making use of aniline bases91 with the exception of BF3 This acid comes at the

bottom of the list and not at the top It is clear from this result that boron has a higher

propensity to bind to nitrogen over oxygen It would appear then that the pK values

are more reliable for comparative purposes

Table 130 ΔνC=O and pK values of metal halides with phenalen-1-one

Acid ΔνC=O pK

BF3 156 -113

PhSnCl3 150 -114

ZnCl2 120 -148

SnBr4 157 -155

ZnBr2 118 -172

SnCl4 158 -266

GaCl3 157 lt-40

Satchell and Satchell117 carried out a comparative study on metal halides with amides

using NMR and equilibrium measurements The equilibrium constants and NMR data

were correlated for the 11 adducts of metal halides and two benzamides (Table 131)

in ether solution (Equation 9) The bases employed are free from steric effects

RC6H4CONH2 + M(Hal)n RC6H4C(NH2) O M(Hal)n

Table 131 Chemical shifts and equilibrium constants for equation 9

M(Hal)n m-Methoxybenzamide p-Nitrobenzamide

pK K -δcis -δtrans pK K -δcis

AsCl3 ca -

080 ca 63 ca 80 - - - -

SbCl3 -176 58 801 ca 74 - - -

BF3 -293 850 930 815 -186 72 ca 96

ZnBr2 -294 870 860 800 -217 148 890

ZnCl2 -294 870 558 802 -217 148 892

GaBr3 -340 2510 960 864 -249 310 1010

GaCl3 - - - - -253 340 1012

The existence of two NH signals indicated that in each case the acid bound to the

oxygen of the amide (Equation 9) rather than to the nitrogen atom This is typical of

systems in which there is double bound character in the C-NH2 bond which inhibits

free rotation and leads to chemically distinct NH atoms If the Lewis acid is bound to

the carbonyl oxygen significant electron density is donated to the C=O system by the

nitrogen atom thereby increasing the C-NH2 bond character The results in Table 131

show that a linear relationship was found between the shifts of the NH signal and the

equilibrium constants of the adducts This indicates that for these systems the NMR

shifts can be used as a guideline to relative Lewis acidities

In a follow up paper to this initial communication the authors found results that were

contrary to their initial findings118 In this study metal halides were complexed to

benzamides in diethyl ether The NMR shifts and equilibrium constants were

calculated

The values of K show the relative acidities for adducts with benzamides be AlCl3 gt

SnCl4 gt GaCl3 asymp GaBr3 gt ZnCl2 asymp ZnBr2 ge BF3gt PhSnCl3 gt SbCl3 gt AsCl3 Towards

substituted benzamides the order was BF3 asymp AlCl3 asymp GaBr3 asymp GaCl3 asymp SnCl4 gt ZnCl2

asymp ZnBr2 gt PhSnCl3 gt SbCl3 and towards perinaphthenone GaCl3 gtgt SnCl4 gt ZnBr2 gt

ZnCl2 gt PhSnCl3 gt BF3

While the lists show similar relative Lewis acidities with all bases the benzamides

differentiate the acids to a larger degree According the authors the lower position of

BF3 when complexed to the ketone is possibly due to boron preferring to bind to the

nitrogen over oxygen

The chemical shifts for the NH protons in the 1H NMR spectra for the adducts of 3-

methoxy and 4-nitro-benzamide with the metal halides could not be correlated with

the equilibrium constants (Figure 111) This is contradictory to previous

findings117and would suggest that for wider ranges of acids the heats of reactions and

the measurements of chemical shifts are not a good indication to relative acidities118

Figure 111 Plot of δcis against K

A bull 3-methoxybenzamide B 4-nitrobenzamide 1 AsCl3 2 SbCl3 3 PhSnCl3 4 BF3 5 ZnBr2 6 ZnCl2 7

GaBr3 8 GaCl3 9 AlCl3

In another study the Lewis acidities of trimethylchlorosilane -germane and -stannane

were investigated using two independent techniques calorimetry and 31P NMR

spectroscopy114 The heats of reaction and the equilibrium constants were determined

for the adduct of these Lewis acids with triphenylphosphine oxide and the data were

correlated to the shifts on the phosphorous NMR spectra using triphenylphosphine

oxide as the base

The enthalpies and equilibrium constants calculated showed the tin adducts to be

stronger Lewis acids than the germanium derivatives The results of silane adducts

were not reproducible until the experiments were carried out in strictly anhydrous

conditions at which stage they exhibited Lewis acidity similar to germanium

The order of acidity according to the calorimetric data was found to be Sn gt Ge gt Si

These findings correspond to most other findings in the literature83 However they are

in the opposite order to the findings of Graddon and Rana120121 who concluded that

trimethylsilane is a stronger acid than trimethylstannanne The excessive heats of

formation found for the silane adducts in the experiments carried out by Graddon and

Ranna are likely due to hydrolysis of the silane in the presence of moisture119

The shifts in the 31P NMR spectra for the complexation to triphenylphosphine oxide

in benzene are inconclusive For trimethylchlorostanne the shift obtained can be

correlated with the enthalpy data but is contrary to data found in literature122 No shift

is seen for (CH3)3GeCl This adduct also shows a very small ΔH value and the

experiment is not reproducible for (CH3)3SiCl Again this dataset brings into question

the validity of using NMR shifts for ranking Lewis acidity

A linear relationship was found between Gutmannrsquos acceptor number method123124

and Childsrsquos116 NMR method of ranking Lewis acidity when B(C6F5)3bullL L =

CH3COOEt (1) Et3PO (2) were synthesised and ranked along with other Lewis

acids125

The acceptor number method (AN) defined by Gutmann is based on the 31P chemical

shifts of triphenylphosphine oxide measured in solution The AN represents the

electrophilic properties of the solvent relative to hexane123124

These results confirmed the relative Lewis acidities BCl3 ~ AlCl3 gt B(C6F5)3 with

TiCl4 and SnCl4 being much weaker acids125125 The excellent correlation between

Gutmannrsquos AN and Childsrsquos 1H NMR method for these acids can be seen in Figure

112 Furthermore Lappert109 also gives two almost identical ΔνC=O values for EtOAc

adducts of these compounds

Figure 112 Least square plot of Childsrsquo Lewis acid scale against AN values 1 CH2Cl2

2 SnCl4 3 TiCl4 4 B(C6F5)3 5 AlCl3 6 BF3 7 SbCl5 8 BCl3 and 9BBr3 Best line fit AN = 9221C +

1598 (R2 = 097) AN 2-5 [ref 123] 1[refs 123-124 82ndash84] [ref 127] Childsrsquos data [ref 116] except 4 [ref 128]

Group 13 trihalide complexes of 9-fluorenone were prepared and characterised by

NMR IR and UVVis spectroscopy127 Where crystallisation was possible the

compounds were characterised by single crystal XRD These complexes were then

used to examine the suitability of certain parameters for the measuring of Lewis

acidity (Table 132)

The shift in carbonyl IR frequencies follows the same trends as those seen by

Lappert109 The UVVis spectra can be correlated with the theoretical data calculated

by Laszo129 However these data cannot be correlated with each other The shifts in

the 13C NMR spectra have a reverse order to all other parameter studies and seem to

have an almost inverse relationship with the ΔG

Solution dissociation energies are an indication of BDE (bond dissociation energy) for

simple Lewis acid-base complexes however in this study it is clear that ΔH is not an

indication of Lewis acid strength For example the ΔH for GaBr3 is the largest but has

the highest dissociation constant This suggests that the entropy term is important in

defining the Lewis acid ndash base interaction in solution

An alternative approach to determining the Lewis acidity is to study the distortion on

the crystal structure from the ideal tetrahedron expected from many systems129 From

these results it became clear that the deviation from planarity was related to the M-O

bond distance which is not a good measure for Lewis acidity for complexes with

dissimilar metals129

In summary it is clear from this study that none of these parameters gave a clear

indication of the Lewis acidity However the authors proposed that these parameters

together with kinetic data would make an ideal essential component in an analysis of

Lewis acidity

Table 132 Summary of spectroscopic and structural trends for MX3 (9-fluorenone)

Technique Parameter Trend

IR Δvc=o BCl3 gt AlBr3 gt GaCl3 gt GaBr3 gt AlCl3

UV-vis Δλmax BCl3 gt AlBr3 gt AlCl3 gt GaBr3 gt GaCl3 13C NMR ΔδC=O GaCl3 gtGaBr3 gt AlCl3 gt AlBr3 gt BCl3 1H NMR Keq at 298 K BCl3 gt AlBr3 gt AlCl3 gt GaBr3 gt GaCl3

Δ H GaBr3 gt BCl3 gt AlBr3 gtAlCl3 gt GaCl3

Δ G BCl3 gt AlBr3 gt AlCl3 gt GaBr3 gt GaCl3

XRD O(1)-C(9) AlBr3 gt AlCl3 gt BCl3 gt GaBr3 gt GaCl3

Σ(X-M-X) AlBr3 gt AlCl3 gt BCl3 gt GaBr3 gt GaCl3

Δox AlBr3 gt AlCl3 gt BCl3 gt GaBr3 gt GaCl3

The Lewis acids 59-62 (Figure 113) below were synthesised and their relative Lewis

acidities determined through two different NMR spectroscopic methods130 The first

method employed was that by Gutmann123124 The solvent used was changed from

THF to benzene due to polymerisation of the THF The second the method used was

that of Childs116

Figure 113 Perfluorophenyl boron Lewis acids 59-62

Two non-fluorinated boron acids B(C6H5)3 and B(OC6H5)3 were also compared in the

study The results using the Gutmann method showed that Lewis acidity increases

with the following order 59 lt 60 lt 61 lt 62 Childsrsquos method resulted in the order

been reversed 59 gt 60 gt 61 gt 62 Moreover the linear relationship between these two

methods that was previously reported124 was not seen in this study (Figure 114) This

suggests that the linear relationship does not exist for all Lewis acids but that different

bases will give different trends

Figure 114 Graph comparing relationship between Guttmannrsquos

method and that of Childs

Conclusions

What is evident from the discussion is that despite the challenges many attempts have

been made to quantify Lewis acidity Lappert109 suggested the use of the change in the

carbonyl stretching frequencies using IR spectroscopy The work of Childs111 is based

on NMR spectroscopy and the shift in 1H and 13C NMR spectra the greater the shift

the more acidic the Lewis acid Thermodynamic data have been calculated for many

Lewis acidndashbase adducts Amongst those data are equilibrium constants83 and heats of

complex formation85

The comparative studies that have been carried out test these methods for their

relevance for determining Lewis acidities Some of them find correlation between

methods but most of them find that the thermodynamic data based on equilibrium

constants or the energy released on the formation of an acidndashbase complex for

example are the most reliable In particular the equilibrium constants are found to be

especially consistent particularly when a wide variety of Lewis acids is being used

This said it would appear that spectroscopic data show limited application for ranking

Lewis acidity and may be primarily useful when fewer Lewis acids of a similar type

are being used

The statement of Lewis remains true and the quest for an absolute ranking of Lewis

acidity or for predicting Lewis acid behaviour in different solvents and with different

acceptors remains elusive The problem of Lewis acidity in aqueous media has yet to

be addressed

14 Lewis acids in aqueous media

Metal triflates have been found to act as Lewis acid catalysts in aqueous media or

water-containing solvents131-132 This is advantageous from an environmental point of

view and also eliminates the need for time-consuming drying of solvents and

reagents

The Mukaiyama Aldol reaction

The Mukaiyama aldol reaction was carried out using commercially available

formaldehyde and a variety of silyl enol ethers The reactions were catalysed by 5-10

mol Yb(OTf)3134 and the aldol products were obtained in high yields What makes

this reaction exceptional is the fact that commercial formaldehyde is an aqueous

solution A range of metal triflates was tested using the reaction between 63 and

formaldehyde (Scheme 128) After 24 hours all the lanthanum triflates used had

successfully catalysed the reaction to afford the desired aldol product yields (Table

OSiMe3Ln(OTf)3THF

CH2O aq Ph OH

63 Scheme 128 Ln(OTf)3 catalysed aldol reaction of 63 with formaldehyde

Table 133 Yields () reaction of 63 with formaldehyde catalysed by Ln(OTf)3

Yield ()

100 mol 20 mol

Entry Ln(OTf)3 24 h 1 h 36h

1 La(OTf)3 90 23 88

2 Pr(OTf)3 92 40 80

3 Nd(OTf)3 74 6 89

4 Sm(OTf)3 92 51 91

5 Eu(OTf)3 92 28 93

6 Gd(OTf)3 92 20 79

7 Dy(OTf)3 89 20 85

8 Ho(OTf)3 91 38 86

9 Er(OTf)3 90 44 83

10 Yb(OTf)3 94 5 94

The study was then expanded to include other aldehydes135 The model reaction

examined was 1-trimethylsiloxycyclohexene (64) with benzaldehyde (Scheme 129)

The reactions were carried out in a mixture of THFH2O (41)

OSime3

+PhCHOLn(OTf)3 10 mol

THFH2O (41) rt 20h

64 Scheme 129 Aldol reaction between 1-trimethylsiloxycyclohexene (64) and

benzaldehyde catalysed by Ln(OTf)3

The results of the reactions when different triflates were used can be seen in Table

134 The majority of the Ln(OTf)3 systems catalysed the reaction to afford the aldol

product in good yields Interestingly when the reactions were carried out in THF or

water alone the yields were low

Table 134 Yields () reaction between 1-trimethylsiloxycyclohexene (45) and

Ln(OTf)3 Yield () Ln(OTf)3 Yield ()

La(OTf)3 8 Dy(OTf)3 73

Pr(OTf)3 28 Ho(OTf)3 47

Nd(OTf)3 83 Er(OTf)3 52

Sm(OTf)3 46 Tm(OTf)3 20

Eu(OTf)3 34 Yb(OTf)3 91

Gd(OTf)3 89 Lu(OTf)3 88

The effect of different Yb3+ salts was also investigated to determine the role of the

counterion Only low yields of the aldol product were obtained when the Cl- OAc-

NO3- and SO4

2- salts were used in the reactions This suggests that the higher Lewis

acidity bought on by the less nucleophilic counterion promoted the desired reaction

To determine the effect of the amount of water on these reactions a model reaction

was used (Figure 115) where increasing amounts of water are added to sequential

reactions136

Figure 115 Yield () of aldol product

As can be seen from the Figure 114 above the best yields are obtained when 10 ndash

20 water is present relative to the THF The yields drop dramatically if the water

content is increased beyond this point

In a later study carried out by Kobayashi et al137 on the aldol reaction numerous

Lewis acids were used in a model reaction (Scheme 130) in an attempt to correlate

the catalytic activity of the Lewis acids in water and their hydrolysis constants and

their water exchange rate constants

PhCOH + Ph

OSiMe3

OH OMXn (02eq)

H2OTHF (91)rt 12 h

Scheme 130 Aldol reaction between benzaldehyde and 1-phenyl-1-

(trimethylsiloxy)propene catalysed by various Lewis acids

The reactions were carried out in a mixture of THFH2O (91) The reactions were

only really successfully catalysed by metal triflates the exception to this was a few of

the perchlorates where the yields were below 50 for the expected aldol adduct

The water exchange rate (represented by the water exchange rate constant WERC)

and the extent of hydrolysis (represented by the hydrolysis constant pKh) of the Lewis

acid in question play a large role in whether or not these reactions will proceed Metal

compounds that gave yields greater than 50 of the aldol product all have WERC gt

32 x 106 M-1s-1 and pKh values from 43 to 1008 In this context the word

ldquohydrolysisrdquo is taken to define the reaction of water with the Lewis acid to form the

corresponding metal hydroxide and H+

In summary it is believed that the pKh values allow the dissociation and hydration of

the metal as soon as it is added to the aqueous media and the fast WERC enables the

aldehyde to bind to the metal causing it to be activated and allowing attack by the silyl

The Mukaiyama aldol reaction was investigated by Loh et al138139 By using

Kobayashirsquos conditions they investigated the effects of InCl3 in H2O on the reaction

The results (Table 134) were inconsistent and showed a strong dependence on the

order in which the reagents and catalyst were added The heterogeneous nature of the

reaction mixture may have contributed to the inconsistencies of the results

Table 135 Mukaiyama aldol reactions in water catalysed by InCl3

Entry Aldehyde Silyl ether SequenceYield

1 A 51 OSime3

2 B 74

3 C 79

5 HCOCH2OH H2O C 80

Sequence A aldehyde + InCl3 then H2O then Silyl ether (15 h)

Sequence B aldehyde + InCl3 then H2O (15 h) then Silyl ether

Sequence C aldehyde + InCl3 then Silyl ether then H2O (15 h)

The aldol reaction of glucose-derived silyl enol ethers with commercially available

formaldehyde was investigated (Scheme 131)140 A range of Lewis acid catalysts was

investigated in which InCl3 afforded good yields and excellent selectivities The

corresponding triflate showed considerably lower yields as did Yb(OTf)3

TBDMSO

BnO OO

TBDMSO

Lewis acidCH2O (37 aq) rt

Scheme 131 Aldol reaction of glucose-derived silyl ether with aqueous formaldehyde

catalysed by Lewis acids

Allylation reactions

The allylation reaction of carbonyl compounds was reported to take place successfully

using a catalytic amount of Sc(OTf)3 in aqueous THF141 The reactions proceeded

smoothly in either a 91 or 41 mixture of THFH2O to afford the expected products

in high yields Unprotected sugars reacted directly to form the required adducts It

was found that Yb(OTf)3 was also an effective catalyst for these reactions

The tin-mediated allylation of carbonyl compounds was investigated in the presence

of InCl3 in water (Scheme 132)142 Yields obtained for the reactions were moderate to

high after 15 hours and in most cases the diastereoselectivities were good The InCl3

is believed not to play a large role in yields but plays a significant role in the outcome

of the of the final isomer ratio

Sn InCl3

H2O rtR1

OH OH+

anti syn Scheme 132 Tin-mediated allylation of carbonyl compounds catalysed by InCl3

Especially noteworthy is the high anti diastereoselectivity (98 de) observed (Table

135 entry 3 and 8) The level of diastereoselectivity of the reaction is lower when it is

carried out without InCl3 as the catalyst

Table 136 Indium trichloride promoted tin mediated allylation of aldehydes

Entry Aldehyde Halide Conditions Yield

Isomer

(antisyn)b

1 C6H5CHO Me Br Sn InCl3 H2O (15 h) 80 5050

2 C6H5CHO Ph Br Sn InCl3 H2O (15 h) 45d 991

3 C6H5CHO EtO2C Br Sn InCl3 H2O (15 h) 96 855

4 CH2BrCHO EtO2C Br Sn InCl3 H2O (15 h) 55 8020

5 3-C5H4NCHO EtO2C Br Sn InCl3 H2O (24 h) 51 8020

6 C6H11CHO EtO2C Br Sn H2O (18 h) 60 8515

7 C6H11CHO CO2Et

Br Sn InCl3 H2O (15 h) 65 6832

8 C6H11CHO EtO2C Br Sn InCl3 H2O (15 h) 65 991 aall reactions were carried out in 05-1 mmol scale b The isomer ratio was determined by 1H or 13C NMR c

Isolated yields d Balance of material is unreacted aldehyde

The strong preference of the reaction for the anti adduct suggests that transmetallation

is involved Transmetallation from allyltin with indium trichloride as Lewis acid

would proceed via SE2 process to produce compound 65 (Scheme 133) which would

further rearrange to compound 66 and its isomers 67 the former being favoured due to

its relative thermodynamic stability No isomerisation was observed by the authors

during the reactions The high anti selectivity can be explained by a six membered

transition state depicted in Scheme 133

SnBrR InCl3H2O

R InCl2 +

InCl265 66 67

R InCl266

InCl2RH

antiR = Ph 3-Pyr Cyclohexyl BrCH2 Scheme 133 Transmetallation from allytin with InCl3

Araki et al143 reported the allylation of aldehydes and ketones using catalytic

amounts of InCl3 in combination with aluminium or zinc metal These reactions were

carried out in a THFH2O (52) mixture at room temperature One disadvantage of

these reactions is that they are slow when compared to those that are catalysed by

stoichiometric amounts of indium they require days to complete Interestingly when

the reactions are carried out in anhydrous THF the yields drop dramatically and side

reactions occur

Michael additions

Ytterbium triflate was found to catalyse the Michael addition of β-ketoesters to αβ

unsaturated ketones in water143 Several Michael donors were used in a reaction with

methyl vinyl ketone (Scheme 134) in the presence of 10 mol Yb(OTf)3 in water

The reactions were stirred at room temperature for 5 days and quantitative yields were

obtained in all cases If the reactions are conducted without a catalyst a yield of only

40 is obtained after 14 days

+Yb(OTf)3

Scheme 134 Michael addition of β-ketoesters with methyl vinyl ketone catalysed by

Yb(OTf)3

Other reactions

Erbium triflate has been used for the aminolysis of epoxides in water145 Both

aliphatic and aromatic amines could be used and the corresponding β-amino alcohols

were afforded in high yields The reactions required only 5 mol of Er(OTf)3 and

typical reactions times were between 2-8 hours

The catalyst could be recycled from the aqueous layer of the workup mixture dried

under reduced pressure and heat and reused without loss of activity up to three times

The pH of a 01 M solution of Er(OTf)3 was found to be 59 only mildly acidic The

aqueous layer from the work up was found to be even less acidic with pH 66 It was

also determined that triflic acid was not the active catalyst by carrying out a reaction

using 10 mol triflic acid The yield of this reaction was only 23 after 7 hours at 25

degC in contrast to the same reaction carried out with 5 mol Er(OTf)3 which shows an

88 yield after 8 hours at room temperature

Bi(OTf)3 catalysed the direct-type Mannich reaction of cyclohexanone an aromatic

aldehyde and an aromatic amine146 These reactions proceeded smoothly in water to

give the corresponding β-amino ketone

Ph NH2+ + Conditions

Scheme 135 Direct-type catalytic Mannich reaction of benzaldehyde aniline and

cyclohexanone in water

Initial reactions were carried out using benzaldehyde aniline and cyclohexanone in

water (Scheme 135) These reactions were conducted using several different acids

(Table 136) in order to determine optimal reaction conditions

Table 137 Direct-type catalytic Mannich reaction of benzaldehyde aniline and

cyclohexanone in watera

Entry Conditions antisynb Yieldc ()

1 15 TfOH 7723 92

2 5 Bi(O2CCF3)3 7723 77

3 1 Bi(OTf)3 7228 94

4 5 Bi(OTf)3 8614 84

5 10 Bi(OTf)3 8317 97 a The reaction was conducted at 25 degC for 7 h in water b antisyn ratio calculated by 1H NMR c Isolated yield

When the catalyst loading of Bi(OTf)3 is changed from 1 mol to 5 mol it has a

positive effect on the stereoselectivity of the product By further increasing the

catalyst loading more the stereoselectivity is not improved 5 mol was thus chosen

as part of the standard conditions Triflic acid catalyses this reaction effectively and it

may be possible that the true catalyst when Bi(OTf)3 is used in the reaction is triflic

acid The model reaction (Scheme 135) was carried out using 5 mol Bi(OTf)3 to

which was added 15 equivalents (compared to Bi(OTf)3) of the sterically hindered

base 26-di-tert-butylpyridine The reaction was left to proceed for 7 hours at room

temperature after which the yield of the reaction was 83 (antisyn 7525) This

result indicates that a Lewis acid is involved in the process but as previously

indicated the pyridinium salt itself may catalyse the reaction a possibility for which

has to be specifically tested

When the reaction is repeated with no other catalyst besides the pyridinium base

itself the yield is 76 If the initial reaction is carried out with 5 mol Bi(OTf)3 and

a different proton scavenger K2CO3 the yield of the reaction is only 44 This

indicates that a Broslashnsted acid is involved in the process The optimal conditions were

then used on a variety of aldehydes and anilines Various substituted benzaldehydes

reacted with aniline or p-chloroaniline to give good yields

The Biginelli reaction is a condensation reaction between a β-ketoester an aldehyde

and urea under strongly acidic conditions146 The catalytic activities of metal

triflimides (triflimide is a contraction for bis(trifluoromethane)sulfonimide) as Lewis

acid catalysts for the Biginelli reaction were investigated and found to be effective147

The catalytic activity of different metal triflimides was investigated using the reaction

between p-anisaldehyde ethyl acetoacetate and urea (Scheme 136) Metal triflates

which are known to catalyse the Biginelli reaction148 were also used in this study for

comparative reasons

H2N NH2

REtO2C

MeO CHOMeO

M(NTf2)norM(OTf)n

water rt 24 h

Scheme 136 Biginelli reaction of p-anisaldehyde ethyl acetoacetate and urea

The reactions were carried out using 5 mol of the Lewis acid in water The metal

triflimides catalysed the reactions to afford moderate to good yields in all cases but

one The reaction with Zn(NTf2)2 only gave 8 of the reaction product (Table 18)

The reactions carried out with the metal triflates were very poor the yields were

below 10 in all cases

Table 138 Reaction between p-anisaldehyde ethyl acetoacetate and urea catalysed by

a variety of Lewis acidsa

Entry Lewis acids Yields ()

1 Ni(NTf2)2 59 65c 40d

2 Ni(OTf)2 Complex mixture

3 Cu(NTf2)2 65 70c 62d

4 Cu(OTf)2 lt10b

5 Zn(NTf2)2 8

6 Yb(NTf2)3 88 90c

7 Yb(OTf)3 lt5b

a The reactions conditions p-anisaldehyde (10 mmol) ethyl acetoacetate (10 mmol) urea (15 mmol) and a Lewis

acid in water (1 mL) 24 h at rt b Considerable amounts of inseparable by-products were accompanied by the

Biginelli product c The reaction was carried out for 72 h d The reaction was carried out at 70 degC

In an attempt to improve the yields of the reactions with the metal triflimides a

catalytic amount of a Broslashnsted acid was added to the reaction mixture (Table 139)

Interestingly the results showed considerable improvements in the yields

a variety of Lewis acids in the presence of a Broslashnsted acida

Entry Lewis acid Additive Yield ()

1 Ni(NTf2)2 CH3CO2H 84

2 Ni(NTf2)2 CF3CO2H 90

3 Ni(NTf2)2 HNTf2 71

4 Ni(NTf2)2 HCl 71

5 Ni(NTf2)2 CH3SO2H 92

6 Cu(NTf2)2 CF3CO2H gt95

7 Cu(NTf2)2 HCl gt95

8 Cu(NTf2)2 HNTf2 65

9 Cu(NTf2)2 HNTf2 gt95

10 Yb(NTf2)3 HCl 85 a The reactions conditions p-anisaldehyde (10 mmol) ethyl acetoacetate (10 mmol) urea (15 mmol) Broslashnsted

acid (5 mol) and a Lewis acid (5 mol) in water (1 mL) 24 h at rt

To determine whether the Broslashnsted acids would catalyse the reactions independently

the reactions were repeated with the Broslashnsted acids only as the catalysts The results

in Table 139 clearly indicate that the Lewis acid is required for improved activation

Table 140 Reactions between p-anisaldehyde ethyl acetoacetate and urea catalysed

by a variety of Broslashnsted acidsa

Entry Broslashnsted acid (pKa) Yield ()

1 CH3CO2H (47) lt5

2 CF3CO2H (023) 56

3 HCl (-23) lt5

4 HNTf2 (12) 33

5 CH3SO2H (-12) lt5

6 p-TsOH lt5 a The reactions conditions p-anisaldehyde (10 mmol) ethyl acetoacetate (10 mmol) urea (15 mmol) Broslashnsted

acid (5 mol) in water (1 mL) 24 h at rt b Values in parenthesis indicate the pKa of the acids

The pKa values of the acids are not indicative of their ability to catalyse the reactions

and more complex modes of activation are indicated As an example of this entries 4

7 and 10 in Table 138 are instructive The metal triflimides and HCl were used in

reactions in the presence of different aldehydes ethyl acetoacetate and urea In

reactions of varying levels of success

15 Conclusions

This literature overview has demonstrated the applicability of metal triflates to a

significant number of organic transformations It was demonstrated that these Lewis

acids in the majority of instances outperform traditional Lewis acid catalysts as

measured against various performance characteristics Amongst others many of the

metal triflates have been shown to be useful in catalytic quantities and also to be

readily recyclable They are not only water tolerant by may also be used to effect

catalysed reactions in binary (waterorganic solvent) solvent systems The call for

further investigation into the application of metal triflate-based Lewis acids is clear

This overview furthermore highlighted the many excellent efforts expended in

attempts to rank Lewis acids in general It points to the various successes and to some

of the difficulties experienced in executing this particular task This aspect also

indicates that there remains much work to be done in this area

The present study aims to address some of the issues raised Firstly it seeks to expand

on the types of reactions that may be effected by metal triflates with a focus on

Al(OTf)3 as catalyst Particular attention is given to the acetalisation reaction of

aldehydes and ketones in which the compatibility of some acid sensitive protecting

groups with the reaction in question is investigated Secondly work performed to

investigate the possible role of water in Lewis acid-mediated transformations is

detailed This aspect of the study raised secondary questions along the way and the

efforts to address these questions are also provided In particular one aspect of the

study called for what is termed herein ldquosuper dry solventsrdquo in which the water

content of the solvent is demonstrably in the low single-digit ppm region This work

required accurate measurement techniques as well as simple yet efficient method for

drying various solvents

This study also touches on the ranking of Lewis acids with a particular focus on the

metal triflates This investigation involved the use of NMR UVVis and infrared

spectroscopy in an attempt to determine a suitable ranking

16 References

1 Kolthoff I M J Phys Chem 1944 48 51

2 Walden P Salts Acids and Bases McGraw-Hill Book company New York N

Y 1929

3 Luder W F Chem Rev 1940 27 547

4 Bell R P Q Rev Chem Soc 1947 1 113

5 Jensen W B Chem Rev 1978 78 1-22

6 Franklin E C J Am Chem Soc 1905 27 820

9 Cady H P Elsey H M J Chem Ed 1928 5 1425

10 Smith G B L Chem Rev 1938 23 165

11 Lewis G N J Am Chem Soc 1916 38 762

12 Lewis G N Valence and the Structure of Atoms and Molecules The Chemical

Catalogue Co New York NY 1923 pp 144-142

13 Broslashnsted J Recl Trav Chim Pays-Bas 1923 42 718

14 Lowry T Chem Ind (London) 1923 42 43

15 Sidgwick N V The Electronic Theory of Valency Clarendon Press Oxford

1927 pp 60 and 116

16 Lapworth A Nature (London) 1925 115 625

17 Lapworth A Mem Proc Manchester Lit Phil Soc 1925 69 xviii

18 Robinson Outline of an Electrochemical (Electronic) Theory of the Course of

Organic Reactions Institute of Chemistry London 1932 pp 12-15

19 Ingold C K J Chem Soc 1933 1120

20 Ingold C K Chem Rev 1934 15 225

21 Lewis G N J Franklin Inst 1938 226 293

22 Acids and Bases a Collection of Papers Journal of Chemical Education Easton

Pa 1941

23 More Acids and Bases a Collection of Papersrdquo Journal of Chemical Education

Easton Pa 1944

24 Luder W F Zuffanti S The Electronic Theory of Acids and Bases Willey

New York NY 1946

25 Usanovich M Zhur Obschei Khim 1939 9 182

26 Huheey J E Keiter A E Keiter R L Inorganic Chemistry Principles of

Structure and Reactivity Harper Collins New York 1993

27 Mulliken R S Pearson W B Molecular Complexes A Lecture and Reprint

Volume Willey-Interscience New York NY 1969 (Contains complete reprints of

Mulliken papers)

28 Hudson R F Klopman G Tetrahedron Lett 1967 12 1103

29 Hudson R F Klopman G Theor Chim Acta 1967 8 165

30 Klopman G J Am Chem Soc 1968 90 223

31 Klopman G Sigma Molecular Orbital Theory Sinaoglu O Wiberg K B Ed

Yale University press New Haven Connecticut 1970 pp 115

32 Klopman G Chemical Reactivity and Reaction Paths Klopman G Ed Wiley-

Interscience New York NY 1974 Chapter 4

33 Bell R P Acids and Bases Meuthuenrsquos Monographs of Chemical Subjects

London 1969

34 Bell R P The Proton in Chemistry Meuthuenrsquos Monographs of Chemical

Subjects London 1959

35 Denmark S E Beutner G L Angw Chem Int Ed 2008 47 1560

36 Yoshida A Hao X Yamazaki O Nishikido J QSAR amp Comb Sci 2006 25

37 Tarasow T M Eaton B E Cell Mol Life Sci 1999 55 1463

38 Schinzer D Selectivities in Lewis acid Promoted Reactions Kluwer Academic

Publishers Dordrecht 1989

39 Lewis acids in Organic Synthesis Yamamoto H Ed Wiley-VCH Weinheim

40 Mukaiyama T Narasaka K Banno T Chem Lett 1973 1011

41 Olah G A Friedel-Crafts and Realated Reactions Wiley Interscience New

York 1973

42 Kobayashi S Sugiura M Kitagawa H Lam WWL Chem Rev 2002 102

43 Vorbruumlggen H Krolikiewiez K Angew Chem Int Ed 1975 14 421

44 Persson I Drsquo Angelo P De Panfilis S Sandstroumlm M Eriksson L Chem

Eur J 2008 14 3056

45 Tran A T Deydier S Bonnaffeacute D Le Narvor C Tetrahedron Lett 2008 49

46 (a) Mirinda P O Ramirez M A Martin V S Padron J I Org Lett 2006

8 1633 (b) Miura K Wang D Matsumoto Y Hosomi A Org Lett 2005

47 Wang Z Hammond G B J Org Chem 2000 65 6547

48 Arimitsum S Hammond G B J Org Chem 2006 71 8665

49 Alcaide B almendros P Mart T Angew Chem Int Ed 2006 45 4501

50 Miyabe H Ueda M Nishimura A Naito T Tetrahedron 2004 60 4227

51 Kobayashi S Eur J Org Chem 1999 15

52 Kawada A Mitamura A Kobayashi S Synlett 1994 545

53 Shiina I Suzuki M Tetrahedron Lett 2002 43 6391

54 Noji M Ohno T Fuji K Futaba N Tajima H Ishii K J Org Chem

2003 68 9340

55 Kobayashi S Nagayama S Busujima T J Am Chem Soc 1998 120 8287

56 a) Hayashi T Prog Polym Sci 1994 19 663 b) Chiellini E Solaro R Adv

Matter 1996 8 305 c) Okada M Prog Polym Sci 2002 27 87

57 a) Nomura N Taira A Tomioka T Okada M Macromolecules 2000 33

1497 b) Moller M Kange R Hendrik J J Polym Sci Part A Poly Chem

2000 38 2067 c) Deng X M Yuan M L Xiong C D Li X H Appl Poly

Sci 1999 71 1941

58 Reference 52 lists a further 20 references were rare earth metal triflates have been

used to catalyse ROP reactions or other polymer reactions

59 Nomura N Taira A Nakase A Tomioka T Okada M Tretrahedron 2007

63 8478

60 Epifano F Genovese Salvatore G Curini M Tetrahedron Lett 2007 48

61 Procopio A Dalpozzo R De Nino A Maiuolo L Nardi M Org Biomol

Chem 2005 3 4129

62 A)Bizier P N Atkins S R Helland L C Colvin S F Twitchell J R

Cloninger M J Carb Res 2008 343 2814 B) Brown H C Kanner B J

Am Chem Soc 1965 88 986

63 Smith B M Graham A E Tetrahedron Lett 2006 47 9317

64 Liu L Tang L Yu L Chang W Li J Tetrahedron 2005 61 10930

65 Chaminade X Chiba S Narasaka K Duntildeach E Tetrahedron Lett 2008 49

66 Kamal A Khan M N A Reddy K S Srikanth Y V V Krishnaji T

Tetrahedron Lett 2007 48 3813

67 A)Williams D B G Lawton M Org Biomol Chem 2005 3 3269 B) Parker

R E Isaacs N S Chem Rev 1959 737-799

68 Williams D B G Lawton M Tetrahedron Lett 2006 6557

69 Cai J J Zou J P Pan X Q Zhang W Tetrahedron Lett 2008 49 5302

70 Chen J Wu D He F Liu M Wu H Ding J Su W Tetrahedron Lett

2008 49 3814

71 Ghorai M K Ghosh K Kalpataru D Tetrahedron Lett 2006 47 5399

72 a) Hiyama T Koide H Fujita S Nozaki H Tetrahedron 1973 29 3137 b)

Wu J Sun X Xia H G Tetrahedron Lett 2006 47 1509

73 Ollevier T Mwena-Mbeja T M Tetrahedron Lett 2006 47 4051

74 Kante De S Tetrahedron Lett 2004 45 2339

75 Sreedhar R Reddy P S Reddy M A Neelima B Arundhathi R

76 Yamamoto H Futatuji K Angew Chem Int Ed 2005 44 1924

77 Acid catalysis in modern organic synthesis Volume 1 Yamamoto H Ishihara

K Ed Wiley-VCH Verlag GmbH amp Co Germany 2008

78 Acid catalysis in maodern organic synthesis Volume 2 Yamamoto H Ishihara

80 Satchell D P N Satchell R S Chem Rev 1969 69 3 251

81 Branch C S Bott S G Barron A R Organomet Chem 2003 666 23

82 Cromwell T M Scott R C J Chem Soc 1950 72 3825

83 Keefer R M Andrews L J J Am Chem Soc 1950 72 4677

84 Blake N W Winston H J A Patterson J Am Chem Soc 1951 73 4437

85 Scott R L J Am Chem Soc 1953 75 1550

87 Moodie R B ChemInd 1961 1269

88 Mohammad A Satchell D P N Satchell R S J Chem Soc (B) 1967 727

89 Mohammad A Satchell D P N J Chem Soc (B) 1967 403

91 Drago R S Wenz D A J Am Chem Soc 1962 84 526

92 Fairbrother F J Chem Soc 1962 847

93 Smith J W Electric Dipole Moments Butterworths London 1955 p 86

94 Kramer G M J Org Chem 1975 40 298

96 (a) McCauley D A Lien A P J Am Chem Soc 1951 73 2013 (b)

McCauley D A Higley W S Lien A P J Am Chem Soc 1956 78 3009

97 Henis J M S Mabie C A J Chem Phys 1970 53 2999

98 Brownstein S Can J Chem 1969 47 605

99 McDonald J D Williams C H Thompson J C Margrave J L Advan

Chem Ser 1968 72 265

100Clifford A F Morris A G J Inorg Nucl Chem 1957 5 71

101Rhyne T C Dillard J G Inorg Chem 1971 10 730

102Haartz J C McDaniel D H J Am Chem Soc 1973 95 8562

103Kramer G M J Org Chem 1975 40 298

104Hyman H H Quarterman L A Klipatrick M Katz J J J Phys Chem

1961 65 123

105 Clifford A F Kongpricha S J Inorg Nucl Chem 1961 20 147

106 Clifford A F Beachell H C Jack W M J Inorg Nucl Chem 1957 5 57

107 Zhang Y Inorg Chem 1982 21 3889

108 Drago R S Wayland B B J Am Chem Soc 1965 87 3571

109 Lappert M F J Chem Soc 1961 103 542

110 Bax C M Katritzky A R Sutton L E J Chem Soc 1958 1258

111 Brown H C Holmes R R J Am Chem Soc 1956 78 2173

112 Greenwood N N Perkins P G J Chem Soc 1960 1141

113 Mohammad A Satchell D P N Satchell R S J Chem Soc 1967 723

114 Deters J F McCusker P A Pilger Jr R C J Am Chem Soc 1968 90

115 Verkade J G King R W Heitsch C W Inorg Chem 1964 3 884

116 Childs R F Mulholland D L Nixon A J Can Chem 1982 60 801

117 Satchell D P N Satchell R S Chem Commun 1969 110

118 Satchell R S Bukka K Payne C J J Chem Soc 1975 541

119 Spencer J N Barton S C Cader B M Corsico C D Harrison L E

Mankuta M E Yoder C H Organometallics 1985 4 394

120 Graddon D P Rana B A J Organomet Chem 1977 140 21

122 Zeldin M Mehta P Vernon W P Inorg Chem 1979 18 463

123 Mayer U Gutmann V Gerger W Monatshefte Chem 1975 106 1235

124 Gutmann V Coord Chem Rev 1976 18 225

125 Beckett M A Brassington D S Coles S J Hursthouse M B Inorg

Chem Commun 2000 3 530

126 Doumlring S Erker R Froumlhlich R Bergander K Organometallics 1998 17

127 Beckett M A Strickland G C Holland J R Varma K S Polymer 1996

37 4629

128 Branch C S Bott S G Barron A R J Organomet Chem 2003 666 23

129 Laszo P Teston J Am Chem Soc 1990 112 8750

130 Britovsek G J P Ugolotti J White A J Organometallics 2005 24 1685

131 Kobayashi S Synlett 1994 9 689

132 Li C J Chem Rev 2005 105 3095

133 Loh T P Chua G L Chem Comm 2006 2739

134 Kobayashi S Chem Lett 1991 12 2187

135 Kobayashi S Hachiya I Tetrahedron Lett 1992 1625

136 Kobayashi S Hachiya I J Org Chem 1994 59 3590

138 Loh T P Pei J Cao G Q Chem Commun 1996 1819

139 Loh T P Pei J Koh S V Cao G Q Li X R Tetrahedron Lett 1997

38 3465

140 Loh T P Cao G Q Vittal J J Wong M W Chem Commun 1998 861

141 Hachiya I Kobayashi S J Org Chem1993 58 6958

142 Li X Loh T P Tetrahedron Asymm 1996 7 1535

143 Araki S Jin S J Idou Y Butsugan Y Bull Chem Soc Jpn 1992 65

144 Keller E Feringa B L Tetrahedron Lett 1996 1879

145 Procopio A Gaspari M Nardi M Oliverio M Rosati O Tetrahedron

Lett 2008 2289

146 Kappe C O Stadler A Org React 2004 63 1

147 Suzuki I Suzumura Y Takeda K Tetrahedron Lett 2006 47 7861

148 a) Paraaskar A S Dewker G K Sudalai A Tetrahedron Lett 2003 44

3305 b) Ma Y Qian C Wang L Yang M J Org Chem 2000 65 3864

21 Introduction As stated in the introduction chapter one of the aims of the research described in this thesis is

to expand the use of metal triflates Al(OTf)3 in particular in organic synthesis To this end

this chapter focuses on the use of these compounds in protection group chemistry This

follows our earlier work on the catalytic ring opening of epoxides

Acetalisation is probably the most important protection strategy for carbonyl groups1 Acetal

formation is most often achieved by treating aldehydes or ketones with an excess of lower

alcohols or diols in the presence of a drying reagent and a Lewis or Broslashnsted acid2 or by

removing water through the formation of an azeotrope with the solvent and the use of a Dean-

Stark trap1

Copper(II) tetrafluoroborate is an effective catalyst for the formation of acetals3 but the BF4-

counter ion is harmful to the environment Metal triflates have previously been reported to

catalyse acetalisation reactions45 In particular Bi(OTf)3 and In(OTf)3 have been found to

effectively catalyse this reaction While efficient there are drawbacks with these catalysts

Bi(OTf)3 requires the reactions to be carried out under reflux and suffers from relatively long

reaction times5 When reactions are carried out using In(OTf)3 an aqueous workup cannot be

used as the acetal undergoes rapid hydrolysis back to the corresponding carbonyl4 making

recycling of the catalyst difficult On a slightly different note polystyrene-supported

Al(OTf)3 has been used to catalyse dithioacetalisation and trans-dithioacetalisation reactions6

Perhaps the biggest drawback of these Lewis acid catalysts is that they require the presence

of either a solvent such as CH2Cl2 an alcohol in excess or two or more equivalents of the

orthoester

With the increasing interest in metal triflates and successes in these laboratories working with

aluminium triflate7-9 it was decided to investigate the efficacy of Al(OTf)3 in the formation

of acetals using a variety of aryl and alkyl aldehydes and ketones

22 Acetal formation using aluminium triflate

All the steps in acetal formation are fully reversible (Scheme 21) For this reason an excess

of anhydrous alcohol is used and water is removed from the system pushing the equilibrium

to the right and an acid catalyst is used to promote the reaction10 Water can also be removed

from the system by using a drying reagent such as an orthoester to push the equilibrium to

the right (Le Chatelierrsquos principle) promoting the formation of the acetal

HR+ C O

RH O R

H OO R

H + OH RH

O R HC O

Hemiacetal

oxonium cation

HR O R

HR OR H

H ROH2+

Scheme 21 Mechanism of acid catalysed acetal formation

With Le Chatelierrsquos principle in mind the initial acetal reactions were performed in the

presences of 10 equivalents of the desired alcohol (MeOH or EtOH) in order to drive the

reaction to completion and 2 equivalents of the corresponding orthoester which acts as a

drying reagent removing water from the system (Scheme 22) Strictly speaking aldehydes

provide acetals while ketones provide ketals In the following text the word ldquoacetalrdquo has been

used to denote either product

R2R1R2RO

1 mol Al(OTf)3ROH and or CH(OR)3

Scheme 22 Al(OTf)3 catalysed acetal formation in the presence of alcohol andor drying

reagent

The reactions were carried out using 1 mol Al(OTf)3 All reactions were allowed to run for

one hour at room temperature for the sake of comparison even though it was clear that some

reactions were over after a few minutes This was confirmed in a few instances by performing

the reaction in an NMR tube under similar conditions The reactions were quenched by

passing the reaction mixture through a plug of neutral alumina to remove the Al(OTf)3 The

volatiles were then removed under vacuum If further purification was necessary bulbndashtondash

bulb vacuum distillation was used

It is clear from Table 21 column A(1 h reaction 1mol Al(OTf)3 10 eq ROH 2 eq

orthoester) that with few exceptions the reactions afforded good to excellent yields of the

anticipated acetals Pleasingly anisaldehyde reacted smoothly under these conditions to give

products (Table 21 entries 1 and 2) The presence of an electron donating group (OCH3) on

the arene ring is known to retard acetal formation1 The electron density is donated into the

carbon of the carbonyl group making it less electrophilic and thus less available for attack by

the alcohol

Table 21 Al(OTf)3 catalysed acetal formation of aldehydes and ketones

a 1 h reaction 1mol Al(OTf)3 catalyst unless otherwise noted b 10 eq ROH 2 eq orthoester c Isolated yields d 2 eq orthoester no ROH e 12 eq of orthoester were used f Yields determined by 1H NMR spectroscopy g 2 h reaction h 5 h

Entry Product Aabc Yield ()

Bacd Yield ()

Caef Yield ()

MeO OMe

H3CO 21

88g 97h 75 g (90)

EtO OEt

H3CO 22

67g 90h 72 g (80)

76 88 gt98i

79 90 gt98i

MeO OMe

O2N 25

97 94h 82g (94)h

EtO OEt

O2N 26

92 91h 57g (75)h

reaction i gt98 implies quantitative reaction with no other products detected in concentrated samples in which spinning side bands are observable in the 1H NMR spectra of the products

Table 21 cont Al(OTf)3 catalysed acetal formation of aldehydes and ketones

a 1 h reaction 1mol Al(OTf)3 catalyst unless otherwise noted b 10 eq ROH 2 eq orthoester c Isolated yields d 2 eq orthoester no ROH e 12 eq of orthoester were used f Yields determined by 1H NMR spectroscopy g 2 h reaction h 5 h reaction i gt98 implies quantitative reaction with no other products detected in concentrated samples in which spinning side bands are

observable in this 1H NMR spectra of the product j Reaction carried out in DCM 2 h 4 eq of diol used

Bacd Yield ()

Caef Yield ()

MeO OMe

NO2 27

57 96 95

EtO OEt

NO2 28

64 92 gt98i

92 99 gt98i

72 93 96

11 OMeMeO

90 96 gt98i

12 OEtEtO

85 96 gt98i

78 74g gt98i

81 73g gt98i

Acetals of products substituted with deactivating groups were also readily formed in high

yields (Table 21 entries 3-8) Notably steric effects play a more significant role here than

those of electronics Ketones are known to react slower than aldehydes1 Nonetheless the

reactions with 4-nitroacetophenone give the corresponding acetals in gt90 yields When the

2-nitrobenzaldehyde is reacted the steric effect of the nitro group in the ortho position can be

clearly seen as the yields drop dramatically (Table 21 entries 7 and 8)

αβ-Unsaturated aldehydes (Table 21 entries 9-10) as well as aliphatic aldehydes (Table 21

entries 11-14) underwent smooth transformations to the corresponding methyl or ethyl acetals

in good to excellent yields The results of the reactions which are presented in Table 21

column B (2 eq orthoester no ROH) and C (12 eq of orthoester were used) shall be discussed

Green Chemistry

Increasingly people are becoming more aware of their environment Environmental events of

the past have illustrated the negative impacts that chemical activity can have on the

environment and human health11 Just one example of this is the negative ecological effect

that DDT had on the environment These kinds of environmental issues have shaped the

general publicrsquos opinion of chemicals in the last thirty or so years to the point where the

general belief is that all chemicals are toxic or otherwise hazardous11 These opinions have

motivated steps to be taken through legislation such that harmful or hazardous incidents do

not happen again11

As a result there is a big drive towards what is termed lsquogreen chemistryrsquo The definition of

green is ndash Green chemistry is carrying out chemical activities ndash including chemical design

manufacture use and disposal ndash such that hazardous substances will not be used and

generated11 Green chemistry includes all areas of chemistry from analytical to organic to

biochemistry It also encompasses all sectors of the chemical industry including

pharmaceutical and manufacturers of bulk chemicals11

Important areas of investigation in green chemistry11

bull Selection of starting material

The selection of the starting material is critical Is the substance benign If so will

using this substance mean having to use other toxic chemicals further on in the

process Hazards come in the form of flammability ozone depletion and ecosystem

destruction

bull Selecting reagents

The selection of reagents is similar to that of starting material in that they should be

assessed for their hazards In addition their effectiveness should be determined

including selectivity reaction efficiency and separation requirements Can the

reaction be done with other reagents that generate less waste Most importantly the

quantity needed in which to perform the reaction in question must be reduced

bull The selection of solvents and reaction conditions

The use of solvents in chemistry is usually unavoidable They also account for a large

amount of waste disposed of Are the solvents highly flammable or explosive Are

they hazardous to human health Chemicals such as chloroform are suspected

carcinogens Are the solvents being used environmentally benign Until several years

ago chlorofluorocarbons were used in refrigerators for cooling Later it was

discovered that these chemicals were responsible for ozone depletion and have

subsequently been phased out

bull Other

Other important areas of investigation include the design of safer chemicals Also

determining the mechanism of action to ensure that both humans and the environment

are safe and eliminating toxic functional groups

In light of the above it was therefore of interest to ascertain whether the acetalisation process

described in this chapter in any way conforms to some of the requirements of green

chemistry The manufacturing process of the triflate salts themselves may not conform to the

green chemistry requirements since it requires triflic acid which itself may not be

environmentally friendly However as will become clear the process to be described allows

recycling of the catalyst (minimising waste) is highly atom efficient (requiring only 12

equivalents of the orthoester produces virtually no by-products (gt95 yield) and avoids the

use of solvents

The orthoester has a dual role in the reaction it removes water but it can also act as a source

of the required alcohol in this way eliminating the need for the large excess of the solvent It

makes the reaction more atom efficient and eliminates the need to for large amounts of waste

to be disposed of at the end of the reaction Accordingly the reactions described above in

Table 21 Column A were repeated using only 2 equivalents of the orthoester and 1 mol of

the catalyst (Omitting the alcohol altogether)

Under these solventless conditions ie only 2 equivalents of the orthoester and the catalyst

the majority of the reactions afforded yields that were comparable with the reactions that had

been carried out in alcohol (compare Table 21 columns A and B) In fact in most cases the

yields are improved in the cases where the reactions are carried out under solventless

conditions This is especially evident in column B entries 5 6 and 10

Under the solventless conditions anisaldehyde (Table 21 column B) required an extended

reaction period before satisfactory yields of the acetals were obtained this is possibly due to

the effect of the methoxy deactivating group In contrast to the reactions carried out in

alcohol 4-nitroacetophenone also required a longer reaction time

In order to determine if the reaction could be made even more atom efficient the reactions

were repeated but this time only 12 equivalents of the orthoester were used in the presence of

1 mol of Al(OTf)3 Remarkably in the majority of the reactions the yields were improved

over those obtained using 2 equivalents of the orthoester (Table 21 column C) In most cases

quantitative yields were obtained In the case of 4-nitroacetophenone the reaction mixture

was biphasic under these conditions and initially the yields were poor However when the

reactions were allowed to proceed for 5 hours the yields improved considerably (Table 21

column C entries 7 and 8)

As already noted reactions that were carried out in an excess of the alcohol as solvent

afforded lower yields than those reactions that were carried out using only the orthoester

Al(OTf)3 is a hard Lewis acid and is oxophilic It is possible that in the reactions where an

excess of alcohol is used the oxygen atom from the MeOH or EtOH solvent competes with

the oxygen atom of the carbonyl group of the aldehyde or ketone for the aluminium metal

centre thereby reducing the activity of the catalyst

This competition would be largely removed by the absence of the alcohol solvent The Lewis

donor strengths of various solvents have been previously measured12 and methanol was

found to be one of the strongest donors for both hard and soft Lewis acids

The ldquotamingrdquo effect that the alcohols have on these reactions can be better seen from the

results presented in Table 22 (compare columns A and B) Here reactions carried out in the

presence of the alcohol and the corresponding orthoester gave high yields while those that

were carried out under solventless conditions (ie in the presence of only 2 equivalents of the

orthoester) afforded lower yields and in some cases no product at all

a1 hour reactions 1mol Al(OTf)3catalyst unless otherwise stated b10 eq ROH and 2 eq orthoester c2 eq orthoester no ROH dReactions carried out at -20 degC e12 eq of orthoester and 05 mol Al(OTf)3 30 min reaction time fIsolated yields

gYields determined by 1H NMR spectroscopy h5 h reaction time i2 h reaction time j5 mol Al(OTf)3 used kIf the reaction was allowed to proceed beyond one hour the product curiously reverted back to starting material

Entry Product Column A

Yield () abf Column B

Yield () acf Column C

Yield () adf

Column D Yield() degf

MeO OMe

96 63 98 92

EtO OEt

83h 75 89 92

MeO OMe

94hj 0 92 73 (92)i

EtO OEt

77 0 0 75 (82)i

MeO OMe

80 33 77 90

EtO OEt

83 33 80 93

OMe 222

86 0 gt98k 96

OEt 223

74 0 82 92

In cases where none of the desired products were formed (column B) the reactivity of the

system was high and led to a significant initial exotherm Presumably this increase in

temperature of the system gave rise to the substantial by-product formation that was seen

In order to circumvent this problem the reactions were carried out at ndash20ordmC and slowly

warmed up to room temperature still only using 20 equivalents of the orthoester and 1 mol

Al(OTf)3 (Table 22 column C) This move improved the yields dramatically

Even under these conditions reactions carried out with acetophenone and

triethylorthoformate were highly reactive and failed to afford any product On the other

hand furan derivatives are notoriously prone to polymerisation yet under these conditions

furfural afforded excellent yields of the desired acetals (Table 22 column entries 7 and 8)

Since high yields of the acetal products had been obtained previously by using 12 equiv of

the orthoester and 1 mol Al(OTf)3 (Table 21 Column C) this same methodology was

applied to the latter more reactive substrates using only 05 mol Al(OTf)3 and allowing the

reactions to proceed for 30 minutes Yields of greater than 90 were obtained for all but two

of the substrates (Table 22 entries 3 and 4) For these two cases the acetophenone products

slightly longer reaction times afforded high yields of the products It should be noted that

these are the only reaction conditions under which acetophenone diethylacetal could be

formed

23 Catalyst recycling

Previously Al(OTf)3 has been recycled from the aqueous layer of the workup mixture8 This

process involves removing the water under vacuum and heat and then drying the Al(OTf)3

under high vacuum This process is time consuming and once the Al(OTf)3 is dried steps

must be taken to ensure that it is not exposed to the atmosphere

In order to simplify this process recycling after acetalisation was carried out through

distillation of the product from the reaction vessel The reaction between benzaldehyde and

12 equivalents of trimethylorthoformate in the presence of 05 mol Al(OTf)3 was used as a

test reaction (Scheme 23)

O 05 mol Al(OTf)312 eq CH(OCH3)3 OMe

Scheme 23 Acetalisation of benzaldehyde with trimethylorthoformate catalysed by Al(OTf)3

The reaction was allowed to proceed for 30min after which the yield was determined by 1H

NMR spectroscopy The reaction mixture was distilled using bulb-to-bulb vacuum distillation

on a Kugelrohr vacuum apparatus Once all of the volatiles were removed the flask

containing the catalyst was allowed to cool and another reaction was performed in the same

vessel The catalyst was recycled successfully in this manner three times (Table 23) and

reused in successive reactions with little loss of activity

Table 23 Al(OTf)3 recycling experiments using benzaldehyde as the substrate

Run Yield ()abc

1 gt98

2 gt98

4 95 a30 min reaction time 05 mol Al(OTf)3 catalyst 12 eq trimethylorthoformate bDetermined by 1H NMR spectroscopy c

gt98 implies quantitative reaction with no other products detected in concentrated sample

24 Deprotections

Acyclic acetals are usually selected when mild hydrolysis is required otherwise the more

robust cyclic acetal can be used1 Their ease of hydrolysis depends on their substituents - the

relative rates follow the order CH2(OEt)2 [1] MeCH(OEt)2 [6000] Me2C(OEt)2 [18 x 107]1

The selective deprotection of an acyclic acetal using an aqueous solution of trifluoromethyl

acetic acid was reported to be successful (Scheme 24)13 This method of acetal removal is so

mild that the dioxolane and the dithiane remain intact while the aldehyde is produced in a

96 yield

OOOMeMeO

50 CF3COOHCHCl3 - H2O

0 oC 15 h96

Scheme 24 Acetal deprotection in an aqueous solution of trifluoroacetic acid

The use of metal triflates for deacetalisation has also been reported14 Erbium triflate was

found to catalyse the deprotection of benzylidene derivatives The reactions proceeded

smoothly at room temperature in the presence of 5 mol Er(OTf)3 in acetonitrile to afford

high yields of the desired products

To determine if Al(OTf)3 would be an effective Lewis acid for this process a variety of the

acetals that had being synthesised previously (Table 21 and Table 22) were used in a

reaction with 5 mol Al(OTf)3 in a mixture of THFH2O (82) at room temperature (Scheme

25) Vigorous stirring ensured that the reaction mixtures were homogeneous

5 mol Al(OTf)3

THFH2O (82) 24 h Scheme 25 Deprotection of acetals catalysed by Al(OTf)3

The reactions were allowed to proceed for 24 hours after which the crude products were

passed through a plug of neutral alumina to remove the active catalyst The products were

isolated by removing the volatiles under vacuum (Table 24)

Table 24 Yield () deprotection of acetals catalysed by Al(OTf)3

Acetal Product Yield ()

MeO OMe

H3CO 21

MeO OMe

O2N 25

O N2 55

EtO OEt

The results show that the acetals were successfully deprotected using Al(OTf)3 The 4-

nitroacetophenone dimethyl acetal (25) yield is lower which is probably due to the fact that

it is an insoluble solid in the THFH2O mixture

In order to determine if this phenomenon was unique to Al(OTf)3 the reactions were repeated

using the same conditions as above but with a variety of metal triflates amongst others also

making use of the THFH2O mixture

Table 25 Yield () deprotection of acetals catalysed by a variety of metal triflates

Acetal Product

In(OTf)3

Hf(OTf)4

Cu(OTf)2

Ca(OTf)2

MeO OMe

21 H3CO

100 100 100 21

MeO OMe

O2N 25

O N2 89 100 18 15

EtO OEt

100 100 43 19

The harder metal triflates appear to catalyse the hydrolysis of the acetals to a greater degree

than the softer Ca(OTf)2 Again 4-nitroacetophenone dimethyl acetal is the most resilient

acetalmdashonly Hf(OTf)4 deprotected the acetal to afford 100 yield of the starting ketone

Since there has been a lot of interest in metal triflates acting as Lewis acids in aqueous media

it was decided to carry out the same reactions in neat water to determine if they had the same

reactivity A set of control experiments was run alongside the catalysed analogues in which

the acetal was placed in water with no catalyst and simply stirred for 24 hours (Table 26)

Table 26 Yield () deprotection of acetals in water

Acetal Product

Al(OTf)3

In(OTf)3

Hf(OTf)4

No Cat

MeO OMe

H3CO 21

100 100 100 100

MeO OMe

O2N 25

O N2 100a 100a 100a 100a

OMeMeO

O16 22 26 0

EtO OEt

100 100 100 68

a reactions carried out at 80 ordmC to aid solubility

All of the aromatic acetals were completely deprotected under these conditions Conversely

the aliphatic acetal failed to undergo complete hydrolysis under any of the conditions used

What was surprising however was the results of the control experiment The aromatic

acetals underwent hydrolysis in each case in the absence of a catalyst The pH of the neat

deionised water was measured and was found to be 63 which is not out of the ordinary and

is near neutral All of the reactions were repeated and the same results were obtained in

duplicate runs The deprotection of the acetals under these conditions is most likely due to the

solvation of the acetal by the water leading to polarisation of the carbon oxygen bond

(Scheme 26) This polarisation allows ejection of the methoxide which either converts

rapidly to methanol or in any event remains highly solvated The carbenium intermediate

would also be stabilised by solvation Attack of water would eventually lead to the observed

carbonyl starting material

O OMeR R

Where S = water (solvation)

Scheme 26 Hydrolysis of acetal

In order to gauge the rate at which hydrolysis of the acetals takes place in water a study was

conducted in which the reactions were stopped after one hour (Table 27) Using the same

reaction conditions samples were taken from the reaction mixture and extracted with DCM

The solvent was then removed and the crude mixture was then analysed using 1H NMR

Table 27 Yield () deprotection of acetals in water after one hour

Acetal Product

Al(OTf)3

In(OTf)3

Hf(OTf)4

Sc(OTf)3

No Cat

MeO OMe

H3CO 21

100 100 100 100 97

MeO OMe

O2N 25

O N2 100a 100a 100a 100a 100a

EtO OEt

100 100 100 100 75

All reactions were essentially complete after one hour The intention of the study was to take

samples periodically over a 24 hour period As can be seen from the results this was not

necessary The rate of hydrolysis appears to be rapid for the aromatic acetals even when there

is no catalyst present This ability to deprotect acyclic aromatic acetals under such mild

conditions may afford excellent opportunities in synthetic organic chemistry where chemists

are often faced with challenges of trying to remove one protecting group while retaining

another sensitive group In such deprotection reactions an acid is typically employed13 to

facilitate the reaction but the present study shows that this may not be necessary Work to

further investigate the potential of this method is underway in our laboratories

25 Other protecting groups

Silyl ethers

The stability of common protection groups has been investigated in the presence of metal

triflates One example is in the study of In(OTf)3 catalysed peracetylation of carbohydrates15

During that work it was found that the benzylidene acetal and tert-butyldiphenylsilyl

(TBDPS) ethers were stable to In(OTf)3 in acetic anhydride at 0 degC On the other hand the

authors found that trimethylsilyl (TMS) and tert-butyldimethlsilyl (TBDMS) groups were

unstable under these conditions and readily hydrolysed15

There has been much debate in the literature1617 as to the possible role that triflic acid plays

in metal triflate catalysed reactions (this aspect forms part of the present study and is

discussed in detail in Chapter 4) The central issue of this debate revolves around whether or

not the metal triflates hydrolyse with trace water found in organic solvents to form triflic

acid which in turn would then catalyse or aid in the catalysis of the reaction The use of

protection groups that are typically removed by Broslashnsted acids in the presence of metal

triflates will allow a determination of the stability of such groups to the metal triflate solution

and the extent of their hydrolysis In an indirect way this approach allows the acid sensitive

protection group to be used as a probe for Broslashnsted acidity

The TBDMS group is a commonly used silyl protection group It is easily cleaved under mild

acidic conditions such as acetic acid water THF (3 1 1)1 These conditions are so mild

that the TBDMS group is removed in an 87 yield while TBDPS remains intact By using

this acid sensitive group in the presence of metal triflates any Broslashnsted acidity generated by

the metal triflates will lead to hydrolysis of the TBDMS group

The primary alcohols 2-phenylethanol and para-bromophenol were TBDMS protected by

treatment with 15 equivalents of pyridine base and 20 equivalents of TBDMSCl The

reaction was allowed to stir overnight in DCM (Scheme 27) to afford high yields of products

224 and 225 respectively

OH OTBDMS

224 (78)

15 eq Pyridine

OTBDMS

225 (80)

15 eq Pyridine

20 eq TBDMSCl

Scheme 27 TBDMS protection of 2-phenylethanol and para-bromophenol

The TBDMS protected substrates 224 and 225 were then both stirred for 5 hours in a

mixture of THFH2O (82) in the presence of 1 mol Al(OTf)3 at room temperature In the

control experiments these substrates were reacted under the same conditions in the presence

of 1 mol TfOH

After 5 hours the reactions were quenched with aqueous sodium bicarbonate and extracted

with DCM The volatiles were removed under vacuum The crude reaction mixtures were

then checked using 1H NMR spectroscopy Both reactions carried out using Al(OTf)3 showed

no signs of deprotection of the TBDMS group However reaction of substrate 224 with

TfOH showed 30 deprotection while substrate 225 showed no deprotection after being

reacted with TfOH for 5 hours

Since the reactions with Al(OTf)3 failed to show deprotection at 1 mol after 5 hours the

reactions were repeated using 5 mol Al(OTf)3 at room temperature for 10 hours As some

deprotection had been seen with TfOH these reactions were repeated at 1 mol TfOH for 10

Surprisingly substrate 225 showed no deprotection in either the Al(OTf)3 reaction or the

TfOH reaction after the extended reaction period On the contrary substrate 224 was

completely hydrolysed to the original alcohol after the 10 hour reaction with triflic acid the

substrate in the reaction with Al(OTf)3 again showed no signs of hydrolysis

It was clear that substrate 225 was a more stable compound this is probably due to the

deactivating effect of the bromine on the aromatic ring making the TBDMS group more

stable and less susceptible to attack by the acid The reactions were repeated at 80ordmC using 5

mol Al(OTf)3 or 2 mol TfOH respectively and were monitored by TLC

After 6 hours TLC analysis showed no deprotection in either reaction After 10 hours the

reactions were analysed by TLC Again the reaction with TfOH showed some deprotection

and 1H NMR analysis showed it to be 30 deprotected Complete deprotection in the

reaction with TfOH was seen after 22 hours On the other hand the reaction with Al(OTf)3

showed no deprotection after this time

From these results it is clear that if Al(OTf)3 does at all hydrolyse in solution to produce

triflic acid it does so in such small amounts so as not to influence the outcome of the

reactions The results further indicate that Broslashnsted acidity generated whatsoever by the

presence of Al(OTf)3 (see chapter 4 for more details) is insufficient to catalyse this hydrolysis

reaction

26 Other metal triflates

It is clear from the literature that different metal triflates behave differently under the same

conditions Acetophenone can undergo allylation with diallyldibutyltin in the presence of 10

mol In(OTf)3 to afford 95 yield of the desired product The same reaction with 10 mol

Zn(OTf)2 produces only 48 yield of the product18

There are many reasons for their different behaviour ranging from ionic radius charge

density hydrolysis constants or pH of the solutions (many of these parameters are discussed

in later chapters of this thesis) In an attempt to gain further understanding of the current

system the study was extended to include other metal triflates

Using the same methodology as before substrate 224 was stirred in a mixture of THFH2O

(82) for 10 hours in the presence of 5 mol M(OTf)x while substrate 225 the more stable

of the two was subjected to harsher conditions namely 5 mol M(OTf)x in a mixture of

THFH2O at 80 degC for 22 hours (Table 28)

As was seen previously no deprotection occurred when 224 was subjected to the Lewis

acids over a 10 hour period A small amount of hydrolysis occurred when Sc(OTf)3 and

In(OTf)3 were allowed to react with 225 These results also point against the formation of

triflic acid by hydrolysis of the metal triflates in solution and that if indeed it occurs it is in

such small quantities that the TBDMS protection group would not be relatively unaffected by

Table 28 Yield () of alcohol for TBDMS deprotection

Substrate Lewis Acid OH

Yield ()a

OTBDMS

Sc(OTf)3 0 In(OTf)3 0 Ca(OTf)2 0 Cu(OTf)2 0

Substrate Lewis Acid Br

Yield ()a

OTBDMS

a Yields determined by 1H NMR spectroscopy

27 Tetrahydropyranyl ethers (THP)

Satisfied that the work on the TBDMS protection had been relatively fully investigated the

study was extended to another protection group namely the tetrahydropyranyl ether (THP)

This protection group was one of the first generally used protection groups employed for

alcohols19 and is still widely used today20 THP ethers are easily formed by acid catalysed

addition of dihydropyran (DHP) onto primary secondary and tertiary alcohols19 The reaction

is said to proceed via protonation of the enol ether carbon generating a highly electrophilic

oxonium ion which is then attacked by the alcohol (Scheme 28)1 One of the drawbacks of

using this protection group is the introduction of a stereogenic centre which leads to

diastereoisomers when chiral alcohols are used and may make NMR interpretation complex

O OROH

Scheme 28 Mechanism of acid catalysed THP ether formation

The cleavage of the THP group can be brought about under mildly acidic conditions such as

HOAc THF H2O (4 2 1) at 45 ordmC21 These ethers are also labile to Lewis acids such as

MgBr222 in ether and ferric chloride on silica23 THP ethers are stable to strongly basic

conditions23

Reports can be found in the literature of THP protection being carried out using metal triflate

catalysis Karimi and Maleki24 showed that LiOTf could be used under mild conditions to

form tetrahydropyranyl ethers in excellent yields The reactions were carried out in refluxing

DCM using 16-20 equivalents of DHP in the presence of 06-07 mol LiOTf

The use of Bi(OTf)3middot4H2O was also reported for THP protection25 However these reactions

were carried out under solventless conditions (for particular substrates) This catalyst was

also found to be active for the deprotection of the THP group in the solvent mixture DMF-

With this knowledge at hand it was decided that the THP ethers could be used in a similar

fashion to the TBDMS group That is once the THP protected alcohols had been synthesised

it would be possible to determine their stability with the different metal triflates

Selected alcohols were allowed to react with 2 equivalents of DHP in DCM for 3 hours in the

presence of 10 mol Al(OTf)3 at room temperature (Scheme 29) after which the reactions

were quenched using an aqueous sodium bicarbonate solution followed by extraction of the

mixtures with DCM The volatiles were removed under vacuum and the products purified by

column chromatography to afford high yields of the THP protected products (Table 29)

R OH 1 mol Al(OTf)3DCM rt 3 h

Scheme 29 THP protection catalysed by Al(OTf)3

Table 29 THP protected primary alcohols in reactions catalysed by Al(OTf)3

Entry Substrate Product Yield ()

A noteworthy point here is that the procedure is mild enough to tolerate another functional

group such as the triple bond (Table 28 entry 3) Because an aim of the investigation was to

look at the deprotection of the THP group with metal triflates no further optimisation of the

reactions was carried out Possibilities for optimising the reaction include repeating them

under solventless conditions shortening the reaction time and using less DHP to improve

overall efficiency

The THP ethers (Table 28 entry 2 and 3) were then reacted with a range of metal triflates in

order to determine if they would be stable under the variety of conditions (Table 210) The

ethers were allowed to stir in methanol (not anhydrous) for three hours in the presence of 1

mol of the metal triflate as catalyst Workup was carried out using an aqueous sodium

bicarbonate solution followed by extraction with DCM The volatiles were removed under

vacuum and the crude products were examined by 1H NMR spectroscopy

Table 210 Deprotection of THP ethers using different metal triflates

Entry Substrate Lewis Acid PhOH

Yield ()

Al(OTf)3 68 Sc(OTf)3 100 In(OTf)3 100 Ca(OTf)2 0 Cu(OTf)2 0

Entry Substrate Lewis Acid Br

Yield ()

Entry Substrate Lewis Acid OH Yield ()

Substrates 226 and 227 (Table 210 entry 1 and 2) were successfully deprotected by triflates

of Al Sc and In triflates to afford high yields of the alcohols Reactions with Ca and Cu

triflates resulted in very little of the free alcohol if any affording only the starting material

A possible mechanism for the hydrolysis is shown in Scheme 210 for the substrate 227

+O MeOH

OMeO+ H+

H+ Scheme 210 Mechanism for the hydrolysis of 227

All of the metal triflates failed to successfully deprotect 228 (Table 210 entry 3) without

by-product formation In the reactions that had been carried out using Ca(OTf)2 and

Cu(OTf)2 only starting material was obtained The reactions that had been carried out with

the other metal triflates yielded a complex mixture of by-products apart from some starting

material It is possible that the alkyne functional group led to secondary reactions under these

conditions These reactions indicate that the THP protecting group could be readily installed

making use of the metal triflate catalysis The deprotections were less satisfactory but were

successful in several instances indicating a measure of catalyst selection should be applied as

and when the need arises

28 Two protection groups

Often during a synthesis an organic chemist will be required to use two or more protection

groups on a substrate at the same time When incorporating the second protecting group into

the molecule the first obviously needs to stay in place Alternatively when removing one the

other has to remain It was evident from the present study that the TBDMS group was stable

in the presence of Al(OTf)3 as well as a range of other triflates and from literature it is known

that acetals can be formed by other metal triflates45 What remained to be determined was if

an acetal could be formed on a substrate already containing a TBDMS group using the

different metal triflates as catalyst

Vanillin and salicyl aldehyde were successfully TBDMS protected by reacting them with 15

equivalents of pyridine in DCM and 2 equivalents of TBDMSCl overnight The reactions

were quenched with a brine solution containing CuCl2 (to assist in the removal of the

pyridine) and extracted with DCM The products were purified by column chromatography

to afford high yields of their respective TBDMS protected products 229 and 230 (Table

211 entry 1 and 2)

Table 211 Yield () TBDMS protected substrates

TBDMSO

OO 229

OTBDMS

Using conditions from the previous work that had been carried out on acetal formation with

Al(OTf)3 substrates 229 and 230 were reacted with 2 equivalents of trimethyl orthoester

and 10 equivalents of alcohol26 In order to optimise yields with respect to the Lewis acid the

reactions were allowed to proceed for 12 hours in the presence of 10 mol M(OTf)x after

which the mixture was passed through a small column of neutral alumina The excess solvent

was removed under vacuum and the product was analysed by 1H NMR spectroscopy (Table

Acetal formation was successful only with Al(OTf)3 when substrate 229 (Table 212 entry

1) was used resulting in an 86 yield of the desired acetal Interestingly Sc(OTf)3 and

In(OTf)3 hydrolysed the TBDMS protecting group from substrate 229 to afford 100 yield

of the original aldehyde Substrate 229 (Table 212 entry 1) contains an electron donating

methoxy group ortho to the TBDMS group This group increases the electron density on the

system facilitating the loss of the TBDMS This is unlike the stable aliphatic substrate 226

and the Br-stabilised aromatic molecule 227 (Table 210 entries 1 and 2)

Table 212 Yield () of acetal formation with a variety of metal triflatesa

Entry Substrate Lewis Acid

TBDMSO

231 Yield ()

TBDMSO

O Yield ()

Yield ()

TBDMSO

Al(OTf)3 86 10 4 Sc(OTf)3 0 0 100 In(OTf)3 0 0 100 Ca(OTf)2 0 80 20 Cu(OTf)2 0 92 8

OTBDMS

OMe 232

Yield ()

OTBDMS

O Yield ()

OTBDMS

a10 mol M(OTf)x 2 eq orthoester 10 eq MeOH 12 h

In contrast to these results only small amounts of deprotection were seen with Ca(OTf)2 and

Cu(OTf)2 while acetal formation did not take place

Very little hydrolysis of the TBDMS group of substrate 230 (Table 211 entry 2) was

observed in all cases This substrate has no electron donating group and the TBDMS group is

consequently stabilised by the electron-withdrawing aldehyde

The acetal formation reactions with substrate 230 were successful (Table 211) in virtually

all cases All of the metal triflates used catalysed the acetal formation reaction Again a small

amount of deprotection was seen with Sc and In triflates but no deprotection was noted with

Ca and Cu triflates suggesting that the acetal formation reaction occurs faster than the

deprotection reaction In this case as opposed to that of substrate 229 acetal formation is the

faster reaction

To determine if the acetal formation using substrate 230 could be improved with the triflates

of Al Sc and In the reactions were carried out again using solventless conditions a method

that has proved efficient previously in this study Substrate 230 was allowed to react with 2

equivalents of trimethylorthoester and 10 mol M(OTf)x for 12 hours after which the

mixture was passed through a small column of neutral alumina The excess solvent was

removed under vacuum and the product was analysed by 1H NMR spectroscopy (Table 213)

Table 213 Yield () Acetal formation in the absence of added alcohol

Substrate Lewis Acid

OTBDMS

OMe Yield ()

OTBDMS

O Yield ()

OTBDMS

Al(OTf)3 82 18 0

Sc(OTf)3 91 9 0

In(OTf)3 94 6 0

Cu(OTf)2 gt98 0 0

Ca(OTf)2 gt98 0 0

The yields of acetal product are much improved in all three cases What is also interesting to

note is that in the cases of Sc(OTf)3 and In(OTf)3 no deprotection of the TBDMS protecting

group occurred suggesting that under these conditions acetal formation takes place faster

than the hydrolysis of the TBDMS group

29 Conclusions

Al(OTf)3 offers a mild greener alternative for the formation of acetals from various

aldehydes and ketones The reaction may be performed in the presence of the

alcoholorthoester mixture or using neat orthoester The latter solvent-free procedure is

preferred Not only does this method improve the yields in most cases but it offers a

procedure that produces less waste Simple distillation of the product allowed for product

isolation in excellent yields The catalyst was recycled using simple techniques and could be

reused several times without loss of activity

TBDMS ethers were used as a probe in order to test for the hydrolysis of metal triflates in

protic or wet solvents and the concomitant formation of triflic acid This protection group is

known to be sensitive under acidic conditions Very little hydrolysis of the TBDMS group is

seen with metal triflates while full hydrolysis is seen with triflic acid suggesting that if the

metal triflates do hydrolyse (methanolysis) to form triflic acid in solution it is so little that it

does not affect the TBDMS protecting group This is advantageous from the point of view of

protection group chemistry where a chemist often needs a protection group to remain in place

while using a Lewis acid on another part of the molecule

Al(OTf)3 was found to be a good catalyst for the formation of THP ethers Moreover some of

the metal triflates were found to deprotect the aromatic THP ethers under mild conditions to

afford the alcohols in excellent yields

Finally the metal triflates were used to form acetals in the presence of the TBDMS group

when the reaction was carried out under solventless conditions the yields were much

improved and no hydrolysis of the TBDMS group was seen

These results as a whole are an important contribution to protection group chemistry the

metal triflates offers a mild alternative to method that have previously been used

Furthermore these mild alternatives can be used in the presence of other protection groups

This initial study into the hydrolysis of the metal triflates formed the basis for subsequent

chapters in this thesis where an in-depth investigation has been carried out into the hydrolysis

of the metal triflates and the role of water in metal triflate catalysed reactions

210 References

1 Kocieński P J Protecting groups Thieme New York 1994

2 Torok D S Fiueroa J J Scott W J J Org Chem 1993 58 7274

3 Kumar R Chakraborti A K Tetrahedron Lett 2005 46 8319

4 Leonard N M Oswald M C Frieberg D A Nattier B A Smith R C Mohan

R S J Org Chem 2002 67 5202

6 Borujeni K P Massah A R React Funct Polym 2006 66 1126

7 Williams D B G Lawton M Org Biomol Chem 2005 3 3269

8 Williams D B G Lawton M Tetrahedron Lett 2006 47 6557

9 Williams D B G Shaw M L Green M J Holzapfel C W Angew Chem Int

Ed 2008 47 560

10 Solomons T W G Fryhle C B Organic Chemistry 7th ed Wiley New York

11 Anastas P T Williamson T C Ed Green Chemistry Frontiers in Benign Chemical

Synthesis and Processes Oxford University Press New York 1998

12 Sandstroumlm M Persson I Persson P Acta Chem Scand 1990 44 653

13 Ellison R A Lukenbach E R Chiu C W Tetrahedron Lett 1975 499

14 Procopio A Dalpozzo R De Nino A Maiuolo L Nardi M Romeo G Org

Biomol Chem 2005 3 4129

15 Bizier N P Atkins S R Hellend Colvin S F Twitchell J R Cloninger M J

Carb Res 2008 343 1814

16 Ollevier T Lavie-Compin G Tetrahedron Lett 2004 45 49

17 Barret A G M Braddock D C Henschke J P Walker E D J Chem Soc

Perkin Trans 1 1999 873

19 Parham W E Anderson E L J Am Chem Soc 1948 70 4187

20 Greene T W Wuts P G Protective Groups in Organic Synthesis 2nd ed Wiley

New York 1991 31

21 Bernardy K F Floyd M B Poletto J Weiss M J J Org Chem 1979 44 1438

22 Kim S Ho Park J Tetrahedron Lett 1987 28 439

23 Fadel A Salaun J Tetrahedron 1985 41 1267

24 Karimi B Maleki J Tetrahedron Lett 2002 43 5353

25 Stephens R J Butler P L Clow C H Oswald M C Smith R C Mohan R

S Eur J Org Chem 2003 3827

26 Williams D B G Lawton M C Green Chem 2008 10 914

Chapter 3

31 Introduction

Metal triflates (trifluoromethanesulfonates) in aqueous media are thought to exhibit

not only Lewis acid activity but also Broslashnsted acid activity (see chapter 4) generated

by the direct interaction of the water and the metal (Scheme 31)

M+n + H2O M OHH

Lewis acid Broslashnsted acid Scheme 31 Interaction of metal and a water molecule to form a Broslashnsted acid

In order to determine whether metal triflates with a high propensity for showing

Broslashnsted acid activity in the presence of water are independently capable of Lewis

acid activity it is important to study their activity in completely dry solvents (see

chapter 4 for more details) Therefore the present study embarks on the evaluation of

the effectiveness of methods for drying a number of organic solvents

Chemists are often faced with the challenge of having to carry out reactions under dry

conditions These reactions involve solvents that require rigorous drying regimes The

literature on how to dry laboratory solvents can be contradictory1abcd For example

magnesium sulfate has been described as neutral1ab or acidic1cd as a good drying

reagent that is rapid in its action1ab or a slow drying reagent1d Aluminium oxide is

recommended mainly for the use in dessiccators1d while another group of workers

recommend it as the ultimate drying reagent for organic solvents2 The literature still

suggests procedures that are outdated such as the practice of drying solvents over

sodium which according to Plesch2 is carried out by organic chemists as more of a

ritual than an effective process Many recommendations fail to mention the

concentration of water that remains after the drying process is complete

Burfield3abcd wrote a comprehensive comparative series of papers on the drying of

solvents with different desiccants By using tritiated water he was able to determine

the trace amounts of water remaining in the sample after the drying process using

scintillation counting To our knowledge this is the only study of this kind that has

been done on laboratory solvents

Interest in dry solvents in the present instance stemmed from the work that was

carried out as described in chapter 4 of this thesis namely on the role of water in

Lewis acid catalysis Reactions that were carried out during the course of this work

required solvents that contained as little as 5 ppm water Although the literature

explains how to dry solvents the amount of remaining water content is generally not

stated Burfieldrsquos papers although comprehensive did not cover all of the solvents of

interest for the current work so it was decided to investigate the drying of organic

solvents more fully

The aim of this current investigation was to determine which of the desiccants was

capable of drying the desired solvents to a water content that was preferably below 5

ppm in order to use this knowledge in further investigations carried out in this thesis

32 Choice of analytical method ndash Karl Fischer

Several methods have been developed for the determination of water in organic

solvents They include the gravimetric method45 near infrared6 and the radio tracer

method3a None of these methods was completely satisfactory for the purposes of the

current investigation The gravimetric method employed by Trussel and Diehel5 and

by earlier workers4 for gas drying is limited as the results cannot be extrapolated to

the drying of solvents in the liquid phase The use of near infrared for the

determination of water content in organic solvents is a useful and rapid technique6

the detection limits of this method are reported to be 10 ppm63a Ideally for the

purpose of this study a method with lower detection limits was needed Also

measurements needed to be taken in a dry atmosphere ie inside a glove box which

discounted near infrared spectroscopy for the present investigation

Burfield3a developed a method of water determination using tritium labelled water

The method works by the addition of a specified amount of the labelled water to a

rigorously dried solvent and subsequent determination of the decrease in activity of

the solvent after treatment with various drying agents This method is extremely

accurate and the detection limits are as low as 01 ppm However the process is

laborious it requires two drying steps and also requires the use of scintillation

cocktails which further encumbers the process This method was found to be

inappropriate for the current investigation

Karl Fischer titration is another method for the determination of water in organic

solvents This process was first published by Fischer7 in 1935 Since then the method

has been developed and improved8 This method works on a simple standard reaction

(Scheme 32) and depending on the amount of sample used can detect lower than 2

ppm water The iodine acts as an oxidant for the alkylsulfite which becomes an

alkylsulfate In the process water is consumed and iodide is generated

ROH + SO2 + RN

2I- I2 + 2e-

[alcohol] [base](RNH)SO3R

[alkylsulfite salt]

(RNH)SO3R + H2O + I2 + 2RN 2(RNH)I + (RNH)SO4R

[alkylsulfite salt] [water] [iodine] [hyroiodic salt] [alkylsulfate salt]

Scheme 32 Standard reaction of Karl Fischer titration

What made the method more appealing for the current study was that the Karl Fischer

unit was able to be placed inside the glove box preventing the ingress of atmospheric

water into the system Atmospheric humidity is the biggest single cause of error in

Karl Fischer titration8 Water can enter the sample the titrant and the cell in this

manner This manoeuvre placing the Karl Fischer titrator inside the glove box led to

reliable data being generated for trace water determination as will become clear To

the best knowledge of the author the results presented represent the most sensitive

water detection experiments yet performed by Karl Fischer titration outside of those

conducted by the manufacture in setting up the specification sheet (See section 33)

Fundamentals of Karl Fischer Coulometry

As mentioned above Karl Fischer titration is based on a standard reaction (Scheme

32) Iodine generation takes place at the generator electrode which is incorporated in

the glass titration cell next to the measuring electrode (Figure 31)

Figure 31 Karl Fischer Measuring cell and electrodes

The glass titration cell consists of two parts namely the anode compartment and the

cathode compartment which are separated by a diaphragm in the case of the present

instrument set up The anode compartment holds the anolyte which contains the sulfur

dioxide imidazole and the iodide and methanol or ethanol can be used as solvent

The cathode compartment contains the catholyte which is a reagent containing an

ammonium salt

At the anode iodine is generated from iodide (Figure 32) The negative iodide ions

release electrons at the anode and form iodine This in turn will react (indirectly via

the sulfite sulphate oxidation) with the water present in the sample injected into the

titration cell At the cathode the positive hydrogen ions are reduced to hydrogen gas

being the main product that forms

From a coulometric point of view the two iodide ions (I-) each carry the charge of one

electron implying 96485 C per mole At the anode the two iodide ions are converted

into elemental iodine which reacts indirectly with one molecule of water (According

to the concepts of Scheme 32) From an electronic point of view 2 x 96485 C (twice

the charge on 1 mole of electrons) are needed for one mole of water or 1072 C for 1

mg of water

Figure 32 Karl Fischer anode and cathode

Therefore it is possible to measure the amount of iodine that has been released and

thus the amount of water that has reacted with the iodine by measuring the current

(amperes) over a period of time (seconds) This method assumes that all of the current

produced has been used for iodine production Coloumetry is an absolute method of

detection and can be used as a reference method for the determination of water

content8

33 Limits of the Karl Fischer method

In order to ensure maximum stability the Karl Fischer unit was placed in a glove box

In this way the atmosphere surrounding the equipment was controlled to contain 1

ppm or less of water throughout the experiments

The manufacturerrsquos (Mettler Toledo) documents8 for this instrument indicate a

detection limit of less than 5 ppm with good reproducibility (accuracy and precision)

for toluene and n-hexane Results were reported as low as 46 ppm plusmn 04 ppm and 15

ppm plusmn 02 ppm respectively

To determine the limits of the Karl Fischer apparatus 4 mL of a 100 ppm hydranal

water standard were used Since this standard had a water concentration an order of

magnitude higher than that required for the present purpose the addition of 10 ppm of

water was simulated as follows The instrument requires the entry of the mass of

sample added from which it performs its calculations to determine water content

Accordingly if the sample of say 0400 g was added and that mass was entered on

the instrument a reading of 100 ppm would be obtained If however a mass of 4000

g was entered for the same 0400 g sample a reading of about 10 ppm would be

obtained This approach of multiplying the masses by 10 was employed here (Table

31) It may be argued that a simple dilution of the analytical standard would have

sufficed However such an approach would bring about uncertainty as to the amount

of water added during the dilution process as a consequence of such water being

present in the solvent used for dilution and was therefore not applied

When 4 mL of the standard were used the readings obtained for the two samples were

9891 and 9765 ppm which values are well within the accepted range8

Table 31 Result of Karl Fischer titration of hydranal 100 ppm water standard

Reading

Hydranal

Std Mass

content

1 0401 72

2 0391 80

3 0386 75

4 0390 74

5 0391 75

6 0411 77

7 0381 76

8 0375 80

9 0370 70

10 0391 75

Average 75 ppm

Std dev 03 ppm

RSD 39

Although the values obtained in this experiment are lower than expected the results

are not entirely unsatisfactory The precision of the instrument is good as the standard

deviation is only 03 ppm The fact that the instrument was slightly under reading the

water content of the hydranal standard probably stems from the relatively small

amount of sample that was injected into the cell The accuracy of the Karl Fischer

increases as the amount of sample injected increases this is particularly evident at

very low concentrations of water9

34 Choice of solvents

The next step of the investigation involved the choice the solvents for drying The

following chapters of this thesis deal with the role of water in Lewis acid catalysis In

that work aprotic solvents have been used so as to reduce the possibility of the

formation of Broslashnsted acid type species during the course of the reactions by

hydrolysis of the Lewis acid or by other means

A review of the literature also shows that other than Burfieldrsquos studies3abcd which

cover solvents such as benzene dioxane acetonitrile and the alcohols no

comprehensive comparative study has been carried out on the effects of the different

drying reagents on several other every day laboratory solvents With this in mind

toluene THF and DCM were chosen for this study These three solvents are

commonly used in research laboratories as well as forming part of work still to be

described in this thesis For comparative purposes with Burfieldrsquos work methanol

ethanol and acetonitrile were also used in the current study

35 Methods of drying the solvent

In order to set the scene the water content of each of the solvents selected namely

DCM toluene THF acetonitrile methanol and ethanol was determined for the lsquowetrsquo

solvent The same bottle of lsquoanalytical reagentrsquo solvent was then used throughout the

study to avoid variance in initial water content The results of the lsquowetrsquo solvent

measurement are summarised in Table 32 Throughout the study 3 mL of the sample

were injected directly into the anolyte of the Karl Fischer (For ease of reading all

tables of individual measurements can be found in appendix A of this thesis and only

worked data are presented here)

Table 32 Results of Karl Fischer titration of lsquowet solventsrsquo

Solvents

Average sample weight

Residual water

contenta (ppm)

Std dev ppm RSD ()

DCM 4103 6 224 120 536 THF 2815 6 1078 066 062

Toluene 2765 6 2249 128 058 Acetonitrile 2553 6 1420 118 083 Methanol 2590 6 1751 044 025 Ethanol 2622 6 14283 380 027

a Outliers have been removed confidence level 95

The above results show the precision of the Karl Fischer especially at higher

concentrations of water where the relative standard deviations are below 1 The

results for DCM show a higher relative standard deviation which is still well within

acceptable limits

351 Traditional drying methods

Each of the solvents used in the current study can be traditionally dried by a particular

method in chemical laboratories Such methods can be found in most books on drying

of organic solvents9 Tetrahydrofuran is typically pre-dried over KOH pellets after

which it is dried by heating under reflux over sodium wire9 Benzophenone is used as

an indicator the characteristic blue colour indicating dryness9

Dichloromethane is perhaps the easiest of the three solvents to dry as it is the least

hygroscopic and heating over CaH2 appears to be the method of choice for this

solvent9 There is no indicator for DCM Toluene is most commonly dried by heating

over sodium9 and it can be pre-dried using CaCl2 CaH2 or CaSO49 Again

benzophenone is used as an indicator

Methanol and ethanol are dried using magnesium turnings and iodide in the ratio 5 g

05 g respectively per one litre of the alcohol9 The alcohol is heating with the Mg and

I2 until the Mg has dissolved Acetonitrile can simply be dried by using molecular

sieves9

Samples of these solvents dried in these various ways were subjected to Karl Fischer

titration to determine their water content (In our laboratories THF and toluene are

passed through a column of dried silica before being heated under reflux over sodium

and benzophenone) All samples were collected under nitrogen or in Schlenk tubes

kept under nitrogen and placed directly into the glove box The Karl Fischer readings

were carried out in a glove box so as to minimise any contamination from

atmospheric water (Table 33 and 34) within two hours of having been collected (see

section 38 for discussion on the potential role of the dried glass vessels in drying the

solvents stored therein)

Table 33 Results of Karl Fischer titration of solvents dried by traditional methods

Solvent

Desiccant Average sample weight

Residual water

contenta (ppm)

Std dev ppm

RSD ()

DCM CaH2 4154 6 129 127 988 Toluene SilicaSodium 2781 6 314 193 613

Acetonitrile 3Aring molecular sieves 2628 6 40 065 1606

Methanol MgI2 2603 6 536 058 108 a Outliers have been removed confidence level 95

Table 34 Results of Karl Fischer titration of THF dried by SilicaSodium

Experiment number

Residual water

contenta (ppm)

Std dev (ppm)

RSD ()

1 2836 6 1140 429 376

2 2650 6 440 066 150

3 2685 6 428 073 171 a Outliers have been removed confidence level 95

Initially THF dried over silicasodium gave the anomalous result of 114 ppm water

remaining in the solvent even though the characteristic blue colour of the ketyl

radical had formed According to this result no water had been removed by this drying

process In order to determine the accuracy of these results the drying experiments

were repeated (each repetition represents a separate experiment carried out

independently from each other This is the case for all experiments that were carried

out in triplicate during this work) As can be seen from Table 34 the initial result of

114 ppm of residual water that was obtained appears to be an outlier when compared

to the results of the repeat experiments where only approximately 43 ppm water

remained in the THF in both experiments These experiments show that the majority

of water can be removed using this method of drying and that the method is

repeatable

Acetonitrile was effectively dried over activated (at 250 degC for 24 hours) 3Aring

molecular sieves at a loading of 5 (wv) After 24 hours roughly 4 ppm water

remained in the solvent The drying of toluene was also found to be quite efficient

using the dual method of passing it over activated silica (dried in an oven at 250 degC

for 24 hours) and heating over sodium In this instance there was a decrease from

around 220 ppm water to approximately 30 ppm

352 Drying reagents

The next part of the study was to determine the efficacy of different drying reagents

for the solvents In all cases the drying of the solvents as well as the measurements

were carried out in a glove box Residual water content was determined by Karl

Fischer titration As before 3 mL of the solvent were injected directly into the anolyte

of the Karl Fischer cell

The following discussion relating to the investigation is broken up according to the

different solvents used Not all desiccants were used for each solvent An overview is

given at the end of the chapter

353 Preparation of desiccants

bull 3Aring molecular sieves Before the sieves were used they were washed

thoroughly with AR grade methanol dried on a rotary evaporator and then

placed in an oven at 250 degC for 24 hours

bull Silica and alumina All silica and alumina samples used in the study were

placed in glass beakers and covered with aluminium foil into which small

holes were punctured The beakers were then placed in an oven overnight at

300 degC to ensure that the silica and alumina samples were dry

36 The alcohols

The lower alcohols are more difficult to dry than their longer carbon chain

counterparts3d These solvents are hygroscopic and hygrophilic and pose a problem

for most bench chemists trying to work under dry conditions3d Many desiccants have

been suggested for the drying of these alcohols910 including KOH BaO CaO and

molecular sieves to name just a few

In this study ethanol and methanol were dried over activated 3Aring molecular sieves

Each of the alcohols (200 mL) was dried over 5 10 and 20 (weightvolume) of

the molecular sieves The water content of these samples was determined by Karl

Fischer titration after 24 48 and 72 hours and 5 days The experiments were repeated

three times to determine the accuracy of the methods The same procedure was carried

out using KOH pellets The results of these experiments are summarised in Tables 35

Table 35 Results of Karl Fischer titrations of methanol dried over 3Aring molecular

sieves (5 wv)

Time (h) n

Average sample

weighta (g)

Residual water

content (ppm)

Std dev

24 6 2672 753 074 098 24 6 2621 789 067 085 24 6 2557 777 062 080 48 6 2488 452 055 122 48 6 2571 489 047 096 48 6 2612 464 082 177 72 6 2612 329 041 125 72 6 2488 343 040 117 72 6 2612 354 049 138

5 days 6 2523 257 124 482 5 days 6 2584 266 120 451

5 days 6 2495 273 092 337 a Outliers have been removed confidence level 95

sieves (10 wv)

Time (h)

Average sample weighta

Residual water

content (ppm)

Std dev (ppm)

24 6 2688 407 093 229 24 6 2619 392 059 151 24 6 2624 419 041 098 48 6 2561 268 071 265 48 6 2508 293 071 242 48 6 2502 322 087 270 72 6 2612 224 042 188 72 6 2592 236 084 356 72 6 2505 263 063 240

5 days 6 2589 166 057 343 5 days 6 2573 182 058 319 5 days 6 2606 199 168 844

sieves (20 wv)

Time (h) n

Residual water

content (ppm)

Std dev

(ppm) RSD ()

24 6 2509 280 057 204 24 6 2609 292 042 144 24 6 2634 290 031 107 48 6 2496 211 046 218 48 6 2605 239 038 159 48 6 2556 244 087 357 72 6 2591 176 051 290 72 6 2541 188 055 293 72 6 2610 212 088 415

5 days 6 2575 97 099 1021 5 days 6 2542 104 049 471

Figure 33 Graph indicating decreasing water content in methanol over time

Table 38 Results of Karl Fischer titrations of ethanol dried over 3Aring molecular sieves

(5 wv)

Time (h) n

Residual water

content (ppm)

Std dev

(ppm) RSD

24 6 2699 2511 181 072 24 6 2637 2703 166 061 24 6 2662 2664 250 094 48 6 2648 1021 075 073 48 6 2639 1064 074 070 48 6 2633 1110 055 050 72 6 2664 549 093 169 72 6 2639 541 059 109 72 6 2639 563 123 218

5 days 6 2635 144 051 354 5 days 6 2631 141 049 348 5 days 6 2659 149 015 101

(10 wv)

Time (h) n

Residual water

content (ppm)

Std dev ppm

RSD ()

24 6 2668 1894 153 081 24 6 2666 1792 081 045 24 6 2638 1896 050 026 48 6 2645 678 051 075 48 6 2637 695 064 092 48 6 2640 712 058 081 72 6 2642 351 107 305 72 6 2624 359 073 203 72 6 2616 397 118 297

5 days 6 2611 114 113 991 5 days 6 2658 130 076 585 5 days 6 2619 124 089 718

(20 wv)

Time (h)

Residual water

content (ppm)

Std dev ppm

RSD ()

24 6 2639 1186 058 049 24 6 2641 1190 109 092 24 6 2630 1218 037 030 48 6 2643 231 076 329 48 6 2639 243 055 226 48 6 2666 277 079 285 72 6 2604 190 028 147 72 6 2612 194 056 289 72 6 2608 231 061 264

5 days 6 2651 69 035 507 5 days 6 2612 81 035 432

5 days 6 2599 95 050 526

The results show that activated molecular sieves are effective at removing water from

both methanol and ethanol However this method requires at least 72 hours and a 10

(wv) loading of molecular sieves to be effectual The trend in the precision of the

Karl Fischer is again evident in these experiments namely the higher the water

concentration the lower the standard deviation At lower water concentrations the

standard deviation increases despite which the standard deviations are mostly

acceptable

Figure 34 Graph indicating decreasing water content in ethanol over time

The graphs (Figures 33 and 34) show that the effectiveness of the molecular sieves

converges after some time and does not necessarily ultimately improve with loading

After 72 hours methanol had reached a similar level of dryness with 10 and 20

(wv) molecular sieves Leaving the methanol a further 2 days to dry showed some

improvement in the dryness of the samples in all cases The molecular sieves appear

to dry the ethanol more effectively than the methanol initially there is a rapid drop in

the water content and after 5 days the ethanol had reached a similar level of dryness in

all of the experiments

Burfield3d conducted a similar experiment in which he dried methanol and ethanol

over 3Aring molecular sieves 5 (wv) He does not indicate in his paper if the sieves

were activated by heat The initial water content of the methanol was found to be

1010 ppm and that of the ethanol 1500 ppm The alcohols stood for a period of 24

hours over the molecular sieves after which the tritiated water method3a showed the

residual water content to be 95 ppm and 99 ppm for methanol and ethanol

respectively The present study shows similar amounts of residual water for methanol

at the same loading of the molecular sieves while that for ethanol was found to be

higher (at 24 hours) but ultimately reaching much lower levels of residual water

These reductions in water content are remarkable Methanol showed a 90 reduction

in water content and ethanol a 93 reduction in water content after a contact period

of 72 hours In the current investigation the 5 (wv) experiment results indicated a

60 reduction in water content for methanol and an 82 reduction for ethanol after

24 hours The current study shows that the MgI2 method was more effective at

rapidly reducing the water content of the methanol the method requiring only two to

three hours for the magnesium to dissolve under refluxing conditions and a reduction

of 85 in the water content of the methanol is seen However improved ultimate

dryness is obtainable when using molecular sieves

Table 311 Results of Karl Fischer titrations of methanol and ethanol dried over KOH

powder

Solvent Desiccant Time (h)

Average sample

weight (g) n

Residual water

contenta (ppm)

Std dev ppm

RSD ()

Methanol KOH (10 wv) 24 2525 6 318 081 255

Methanol KOH (10 wv) 24 2555 6 339 099 292

Methanol KOH (10 wv) 24 2606 6 337 093 276

Ethanol KOH (10 wv) 24 2856 6 259 074 286

Ethanol KOH (10 wv) 24 2760 6 284 053 187

Ethanol KOH (10 wv) 24 2640 6 250 056 225

The initial results (not shown here) of the drying of the alcohols with KOH a well

known and recommended procedure were disappointing since it appeared to increase

the water content of these solvents However it transpired that this result was due to

the fact that the KOH was used in pellet form as supplied When these pellets first

powdered to a fine powder and then added to the alcohol which was left to stand for

24 hours before being distilled the expected results were obtained (Table 311)

37 Acetonitrile

Acetonitrile is a polar aprotic solvent with high solvating ability It has a high affinity

for water and can be difficult to dry11 Burfield11 found that P2O5 was particularly

efficient at removing water from acetonitrile A desiccant loading of 5 (wv) with 24

hours of static drying leaves a residual water content of 9 ppm The initial water

content was 2800 ppm which equates to a 99 reduction in water content A 5

(wv) loading of 3Aring molecular sieves resulted in a 98 reduction in water from the

acetonitrile after 24 hours

In the current investigation the acetonitrile was dried over activated 3Aring molecular

sieves using the same conditions as those used for the methanol and ethanol

experiments The acetonitrile was also dried in a separate experiment by passing it

through a column of activated neutral alumina The results of the experiments are

summarised in Table 312

Table 312 Results of Karl Fischer titrations of acetonitrile dried over 3Aring molecular

sieves and neutral alumina

Desiccant Time (h)

Residual water

contenta (ppm)

Std dev ppm

RSD ()

3Aring molecular sieves 5

24 2628 6 40 065 1606 48 2626 6 18 050 2841 72 - 6 ltdlb - -

24 2643 6 05 041 8367

48 - 6 ltdlb - -

Activated neutral alumina

10 (wv) -c 2966 6 61 062 1015

10 (wv) -c 2924 6 49 015 306

10 (wv) -c 2826 6 68 037 537

a Outliers have been removed confidence level 95 b ltdl below detection limits of Karl Fischer titrator C The

solvent was passed over a column of the desiccant

The results indicate that molecular sieves are indeed an effective method for the

drying of acetonitrile After just 24 hours at 10 (wv) loading the acetonitrile is

essentially lsquosuper dryrsquo (lt5 ppm water) In order to test the precision and accuracy of

the Karl Fischer titrations at these low levels of water the titrations were repeated

using the 24 hour 10 (wv) sample In this experiment however 10 mL of the

sample were injected into the cell instead of the customary 3 mL (Table312) The

results showed an average water content of 173 ppm with a standard deviation of

006 ppm This result gives us a slightly better indication of the water content of the

acetonitrile once it has been dried However using 10 mL of sample to obtain

analytical data with six repeats was not practical for our use of the Karl Fischer

apparatus as the titration cell quickly fills with the sample and needs to be emptied

and replenished with hydranal The large sample results in inefficient use of the

hydranal solution which may otherwise be used for a large number of further

titrations

The drying of acetonitrile by passage over activated neutral alumina (Table 312) also

showed excellent results in which a 96 reduction in water content is achieved This

method is simple and although not quite as effective as molecular sieves it is

advantageous from the point of view that it is far more rapid These experiments were

repeated three times to determine the accuracy of this method the results show that

the method is reproducible Passage through alumina and storage over molecular

sieves would seem be the optimum drying method

38 Dichloromethane (DCM) toluene and tetrahydrofuran (THF)

Toluene DCM and THF are common organic solvents that can be found in most

synthesis laboratories DCM and toluene are non polar aprotic solvents that are

relatively non hygroscopic On the other hand THF is a polar aprotic solvent that is

relatively hygroscopic and difficult to dry As mentioned above toluene and THF are

usually dried by heating over sodium and DCM is dried by distillation over CaH2

CaSO4 or other drying agents

In the current study it was observed that a solvent left in an oven-dried Schlenk tube

in the glove box was found to contain less water after a few days As glass is made

predominantly of silica it was decided to attempt to dry these three solvents by using

standard silica The solvents were also dried using 3Aring molecular sieves and the results

are summarised in Table 313

Table 313 Results of Karl Fischer titrations of toluene DCM and THF dried over 3Aring

molecular sieves and silica

Solvent Desiccant Time(h)

Residual water

contenta (ppm)

Std dev ppm

RSD ()

DCM 3Aring molecular sieves 10 (wv) 24 426 6 01 005 4167

Toluene 3Aring molecular sieves 10 (wv) 24 276 6 09 026 3023

THF 3Aring molecular sieves 10 (wv) 24 278 6 277 099 32

DCM Silicab na 422 6 13 031 2441 Toluene Silicab na 214 6 21 017 796

THF Silicab na 253 6 562 253 451 a Outliers have been removed confidence level 95 b Silica grade 12 pore size 22Aring mesh 28-200

Table 314 Results of Karl Fischer titrations of THF dried over 3Aring molecular sieves

(20 wv)

Time (h) n

Residual water

content (ppm)

Std dev (ppm)

RSD ()

24 6 3029 152 029 191 24 6 3027 143 012 084 24 6 3007 146 036 247 48 6 3034 59 021 356 48 6 3000 60 021 350 48 6 2998 64 010 156 72 6 2970 43 005 116 72 6 3016 42 018 429 72 6 2907 38 010 263

Both toluene and DCM were successfully dried with the 3Aring molecular sieves After

only 24 hours both solvents show a level of residual water of less than 1 ppm Not

unexpectedly the THF was more difficult to dry with the molecular sieves after 24

hours approximately 30 ppm water still remained in the sample that had been dried

over 10 (wv) of the sieves Increasing the amount of molecular sieves to 20 (wv)

drying agent (Table 314) led to improved reduction of the amount of residual water

in the THF after a 24 hours period to around 15 ppm while an additional 24 hours of

contact with the drying agent reduces the water content further to roughly 6 ppm It

was noted that leaving the THF for a further time period made little difference to the

water content These experiments indicated that activated 3Aring molecular sieves are

suitable for the storage of dried THF The experiments using 20 (wv) were repeated

three times and showed good repeatability

Pleasingly the experiments conducted by passing the solvent through a column of

silica worked equally well in the case of toluene and DCM The solvents were dried

rapidly and Karl Fischer titration of DCM indicated that only 13 ppm water remained

with only 21 ppm being present in the case of toluene Again THF proved more

difficult to dry and the residual water was found to be around 56 ppm

Encouraged by the initial results obtained from the drying of the solvents by silica it

was decided to extend the study to other types of silica with the view to investigating

the influence of pore size and mesh size on the efficacy of the drying agent The

solvent used for this study was THF Since this solvent is particularly difficult to dry

small variations in results should be conspicuous In all cases 10 (wv) of the drying

agent was used All experiments were carried out in the glove box and the results are

summarised in Table 315 The THF was simply passed over a column of the drying

agent specified collected and the water content thereof directly measured using Karl

Fischer titration

Table 315 Results of Karl Fischer titrations for THF dried by passing over columns

of various types of silica and alumina

Silica Average sample weight

Residual water

contenta (ppm)

Std dev ppm

RSD ()

Grade Pore size Mesh

636 60Aring 35-60 2871 6 1057 351 332 636 60Aring 60-100 2904 6 894 283 317 634 60Aring 100-200 2873 6 746 287 385 633 60Aring 200-425 2930 6 595 366 615 644 100Aring 100-200 2913 6 690 327 473 643 100Aring 200-425 2927 6 608 193 317

Flash silica 70-230 2980 6 825 118 143 Neutral alumina - 2966 6 61 062 102 Neutral alumina - 2924 6 49 015 306 Neutral alumina - 2826 6 68 037 537

The above table of results shows that the various types of silica are only moderately

effective in the drying of THF at this weight-to-volume loading What is interesting to

note is that the pore size of the silica appears to make very little difference to the

drying efficiency in this method (Table 315) When one compares the results

obtained for the 60 Aring 100-200 and 200-425 mesh silica with those obtained for 100 Aring

silica of the same mesh size it is apparent that the residual water remaining in the THF

is approximately the same with respect to the two pore sizes A possible explanation

for this is that the contact time of the solvent on the silica in this method is minimal so

as to render the pore size irrelevant In contrast when solvents are dried with

molecular sieves contact time with the sieves is for an extended period of time

On the other hand the mesh size appears to play a more significant role in the drying

of the solvent (Figure 35) The silica of mesh size 35-60 is relatively large grained

silica as the numbering of the mesh size increases the silica becomes finer As the

silica becomes finer its ability to remove water from the THF increases (Figure 35)

Higher mesh numbers (finer particles) provide greater surface area due to smaller

particle sizes as this aspect appears to be determinative of drying ability

Figure 35 Graph indicating decreasing water content with increasing silica mesh size

For comparative purposes with the DCM and toluene THF was also dried through a

column of activated neutral alumina (Table 315) This method proved very efficient

for the removal of water from the THF After only one passage over the alumina (10

(wv) a 94 reduction in the water content of the THF was seen This is a vast

improvement from the traditional drying methods This method also proved to be

repeatable

Figure 36 Graph of residual water content in THF after drying with various

desiccants under given conditions

In summary the results indicate that the most effective method of drying THF is by

passage over a column of neutral alumina (Figure 36) The use of 3Aring molecular

sieves successfully removes water from the solvents However this method of water

removal requires at least 48 hours to be as efficient as the alumina column method As

in the case of acetonitrile it would appear that the best method of drying this solvent

would be first passage over a column of neutral alumina and then storage over 3Aring

molecular sieves to ensure that the solvent remains dry

39 Discussion

The following chapter of this thesis (chapter 4) is concerned with the role of water in

Lewis acid catalysis in particular with metal triflates These Lewis acids are thought

to be able to form a type of Broslashnsted acidity in the presence of water in organic

solvent or in the presence of a protic solvent

The above study has shown that traditional drying methods can still leave solvents

with relatively high water content with respect to a catalyst The study showed THF

that had been dried over sodium still contained approximately 43 ppm water which

equates to 0024 mmol of water in 10 mL of the solvent If one uses a hypothetical

situation in which a typical reaction is carried out in the above mentioned 10 mL of

solvent using 100 mg of benzaldehyde and a catalyst for example Al(OTf)3 at a

loading of 10 mol (0094 mmol) the ratio of water to catalyst in the reaction

mixture would be 14 This ratio is relatively high for a solvent that would be

considered dry under normal circumstances (the THF was blue from the ketyl radical

from the benzophenone) especially if one considers that most of the metals used in

Lewis acid catalysis are capable of expanding their coordination sphere extensively

and that through this the Lewis acid is capable of forming another acidic species that

may influence the outcome of the reaction

310 Conclusions

Karl Fischer titration for the determination of water content in organic solvent proved

to be an effective analytical method By using the Karl Fischer apparatus in a glove

box errors due to atmospheric water where minimised Measurements were obtained

with high precision especially at higher water concentration At lower concentrations

of water it was found that the accuracy of this method increases with the amount of

sample introduced into the titration cell However when a large number of titrations

are needed this is not always a viable option

The most effective method of drying was found to be contact of the solvent with 3Aring

molecular sieves This technique worked for a broad spectrum of solvents including

the alcohols and THF which are notoriously more difficult to dry than solvents like

DCM and toluene The drawback of using the molecular sieves method however is

that it is time consuming Drying THF to a level that was acceptable for the current

study required 72 hours using 20 (wv) molecular sieves

Neutral alumina that has been activated in an oven overnight is an extremely efficient

way to dry organic solvents At just 10 (wv) loading a 94 reduction in the water

content of the THF was seen When the same method was used with acetonitrile a

96 reduction in water content was obtained This method has the advantage over

molecular sieves of been rapid Should the two methods be combined ie passage

over alumina followed by storage over molecular sieves low levels of water in the

organic solvent can be rapidly obtained and maintained

Some success was achieved by using activated silica as a drying reagent This method

was more efficient for the non polar solvents such as DCM and toluene Limited

success was realised with the drying of THF using silica A more extensive study

indicated that the pore size of the silica was irrelevant when using this method but

that mesh size played an important role As the silica becomes finer grained its

capacity for removing water from the organic solvent increases

A simple calculation highlights the importance of using dry solvents in Lewis acid

catalysis especially if the Lewis acid in question is subject to hydrolysis (eg TiCl4 or

BF3) The following chapter of this thesis investigates the role of water in Lewis acid

catalysis and highlights the importance of working in ultra dry solvents so as to

eliminate the possibility of forming a Broslashnsted acid species

38 References

1 a) Jacobs T L Truce W E Robertson G R Laboratory Practice of

Organic Chemistry Macmillan New York NY 1974 b) Roberts R M

Gilbert J C Rodewald L B Winegrove A S An Introduction to Modern

Experimental Organic Chemistry 2nd ed Holt Rineholt and Winston New

York NY 1974 c) Fieser L F Fieser M Reagent for Organic Synthesis

Wiley New York NY 1967 d) Vogel A I A Text Book of Practical

Organic Chemistry 3rd ed Longmans London 1964

2 Plesch P H Ed The Chemistry of Cationic Polymerisation Pergamon Press

Oxford 1963 682

3 a) Burfield D R Anal Chem 1976 48 2285 b) Burfield D R Smithers

R H J Org Chem 1978 43 3966 c) Burfield D R J Org Chem 1984

49 3852 d) Burfield D R Smithers R H J Org Chem 1983 48 2420

4 Bower J H J Res Nat Stand 1934 12 241

5 Trussell F Diehl H Anal Chem 1963 35 674

6 Meeker R L Critchfield F Bishop E F Anal Chem 1962 34 1510

7 Fischer K Angew Chem 1935 48 394

8 Fundamentals of the Coulometric Karl Fischer Titration with Selected

Applications Mettler Toledo Switzerland 2003

9 Perrin DD Armarego W L F Purification of Laboratory Chemicals

Pergamon Press New York 1988

10 Merck Drying Agents Catalogue 2005

11 Burfield D R Lee K H Smithers R H J Org Chem 1977 42 3060

Chapter 4 Investigations on the role of water in metal triflate catalysed reactions

41 Introduction

Another focus of this study is to contribute to the understanding of the role of water which

influences the activity of metal triflate as catalysts

The use of metal triflates as Lewis acid catalysts is now a well established practice amongst

chemists In 2002 Kobayashi1 wrote a comprehensive review containing over 400 references

on rare earth metal triflates in organic synthesis Included in this review are many

comparative studies to many other metal triflates Since this review was published the interest

in metal triflate catalysis has continued to grow2

Metal triflates are remarkable in that they are easy to handle when compared to the more

traditional Lewis acids ie many of them can be weighed using a balance open to the

atmosphere They can be used in catalytic amounts and they are recoverable and reusable

without loss of activity from reaction mixtures

Even more remarkable is the fact that metal triflates are known to act as Lewis acid catalysts

in the presence of water3a-d This is noteworthy as traditional Lewis acids such as AlCl3 and

TiCl4 hydrolyse in the presence of even the smallest amounts of moisture rendering them

ineffective as Lewis acid catalysts

On closer inspection of the literature however there seems to be some disagreement as to the

role that the metal triflate plays in catalysis Does the metal triflate itself catalyse the reaction

acting as a Lewis acid4 or does it undergo hydrolysis to form triflic acid which in turn

catalyses the reaction In the latter case the reactions could be Broslashnsted acid catalysed5

Alternatively reactions may be catalysed by a dual mechanism ie Broslashnsted assisted Lewis

acidity6

The reaction of metal compounds with water as given in standard inorganic textbooks is

often referred to as hydrolysis This is the reaction of MXn species with water such that water

is inserted into one or more of the M-X bonds (Scheme 41)

SnCl4 + 4H2O Sn(OH)4 + 4HCl H+ + Cl- Scheme 41 Hydrolysis of a metal

However organic chemists usually use the term hydrolysis for the cleavage of an organic

molecule or specific covalent bond with the agency of water (Scheme 42)

ROSi(CH3)3 + H2O ROH + HOSi(CH3)3 Scheme 42 Hydrolysis of organic compounds

In this chapter the term hydrolysis will refer to all reactions with water leading to the

formation of protons or their equivalent unless the context clearly refers to the type of

hydrolysis referred to in scheme 42 To some extent the two types of hydrolysis shall be

distinguished by the terms lsquoinorganic hydrolysisrsquo and lsquoorganic hydrolysisrsquo

42 The arguments for and against triflic acid as the true catalyst taken from the

literature

A great deal of work has been carried out by numerous people in an attempt to determine the

mechanism of metal triflate catalysis The question of whether or not metal triflates form

triflic acid in water containing organic solvents is not a trivial one From our own work on the

ring opening of epoxides the answer appears to be that triflic acid does not form and the

catalysis is Lewis acid driven4

When styrene oxide was ring-opened using ethanol in the presence of 00005 mol Al(OTf)3

a 94 yield of the glycol ether was obtained in 1 hour Even when 0005 mol TfOH was

used in the same reaction the product is formed in only 5 yield after 24 hours (at a catalyst

loading ten times greater than that of the Al(OTf)3) This strongly suggests that TfOH is not

the catalyst in these reactions

Similarly when Bi(OTf)3 was used in aqueous medium to catalyse the ring-opening of

epoxides7 it was far more efficient than TfOH When 10 mol of the bismuth triflate was

used in a reaction with aniline and cyclohexene oxide the expected product was afforded in

83 yield in 7 hours When the same reaction is carried out using 10 mol of TfOH the

product is obtained in only 28 yield in the same time period According to the authors this

suggests that the Lewis acid is involved in activating the epoxide

In 1969 Brown8 synthesised a range of sterically hindered 26-disubstituted pyridine

derivatives in order to study the effects of the substituents on the basicity of the molecules

The study showed that there was an increase in base strength as the substituent in the 26

positions became bulkier However the basicity of the pyridine series dropped dramatically

in the case of 26-di-tert-butyl pyridine (Figure 41)

Figure 41 Effect on the pKa of increasing steric requirements of the alkyl groups in the 26

positions (in 50 ethanol)

The authors suggest that the loss of basicity is due to the steric hindrance of the bulky-tert

butyl groups and the fact that they are cannot minimise strain by rotating about a C-C bound

the way for example isopropyl groups can This results in steric interactions with the

nitrogen-bound H+ ion and leads to a higher tendency to ionise (Scheme 43)

H3C CH3

CH3H3CN

CH3H3C

H3C CH3

CH3H3C

Scheme 43 Ionisation of 26-di-tert-butylpyridine

In a further study8 they showed that boron trifluoride reacts readily with 26-lutidine and 2-

tert-butylpyridine but failed to react with 26-di-tert-butylpyridine On the other hand 26-di-

tert-butylpyridine reacts with HCl forming the dihydrochloride product (the second HCl

molecule co crystallising in the solid state) The authors suggest that the base can be used to

separate a mixture of BF3 and HCl because of its differentiation between Broslashnsted acids and

even small Lewis acids

In the discussion that follows the work carried out by Brown has been used by other workers

to distinguish between Lewis acidity and Broslashnsted acidity 26-Di-tert-butylpyridine (DTBP)

and its derivative 26-di-tert-butyl-4-methylpyridine (DTBMP) may be used as proton

scavengers in reactions where there are possibilities for both Lewis and Broslashnsted activity

Once the base has been added the reaction should then be exclusively Lewis acid driven

Ollevier et al9 carried out a study on the Mannich reaction in water using Bi(OTf)3 A model

reaction (Scheme 44) was used to determine if triflic acid played a role in the mechanism

5 mol Bi(OTf)3 H2OH

Ph NH2

O NH OPh

41 42 43 44

Water 7 h

Scheme 44 Direct type catalytic Mannich reaction of benzaldehyde aniline and

The reaction was carried out using 5 mol Bi(OTf)3 one equivalent of benzaldehyde one

equivalent of aniline and three equivalents of cyclohexanone in water at room temperature for

seven hours The desired product was afforded in an 84 yield with a stereoselectivity of

8614 antisyn when the reaction was repeated with 15 mol of the base DTBMP 44 was

obtained in a 83 yield with a stereoselectivity of 7425 antisyn However this does not

indicate that a Lewis acid is necessarily responsible for the catalysis of the reaction When the

reaction is repeated without the Bi(OTf)3 and only the 15 mol DTBMP 44 is afforded in a

76 yield with a stereo selectivity of 7921 antisyn The Bi(OTf)3 catalysed Mannich

reaction was repeated this time in the presence of the proton scavenger K2CO3 and afforded

a 44 yield of 44 (7030 antisyn) The authors interpreted this to indicate that Broslashnsted

acidity was involved in the process When the reaction was carried out using 15 mol TfOH

the yield obtained was 92 but with lower stereo selectivity (7723 antisyn) The reaction

shows a clear preference for the anti product the excess of which is determined to some

extent by the reaction conditions The fact that some of the antisyn ratios are so close in

many instances complicates the interpretation of this data

It should also be noted that K2CO3 which the authors used as a proton scavenger generates

KOH in water This relatively strong base could produce Bi(OH)(OTf)2 which will reduce the

Lewis acidity of the catalyst accounting for the lower yield of the reaction a point which the

authors failed to make

In their investigation on the metal triflate catalysed acylation of alcohols Dumeunier and

Markoacute10 found triflic acid to be an active catalyst in the reaction In an attempt to benzoylate

45 (Scheme 45) no desired product 46 was formed when Sc(OTf)3 was used Surprisingly

the acid sensitive TES group was clipped off resulting in the diol 47 This was ascribed to

the action of triflic acid formed by the reaction of Sc(OTf)3 with water arising from the

dehydration of 45 (a side reaction that consumed 30 of the starting material 48) In contrast

the benzoylation of 49 resulted in the smooth formation of 410 in a 96 yield

OTES OBz

OTES OH

Bz2O CH2CN

10 mol Sc(OTf)3

SO2PhBz2O CH3CN

49 410 Scheme 45 Metal triflate catalysed acylation of alcohols

These results suggested to the authors that triflic acid was responsible for the deprotection of

the silyl ether In order to neutralise the acid the benzoylation of 49 was repeated but 26-di-

tert-butyl-4-methyl pyridine (DTBMP) a highly hindered base thought to only interact with

protons as discussed above8 was added to the reaction mixture No benzoylation of 49

occurred even after the reaction mixture was heated to 50 degC The authors suggest that this

result strongly points to triflic acid playing a prominent role in the reaction

In order to shed more light on the active species a model reaction was carried out (Scheme

46) using a variety of triflates The reactions were carried out with and without DTBMP the

addition of DTBMP and the results are summarised in Table 41

OH O Ph

O3 eq Bz2O

M(OTf)n MeCN Scheme 46 Benzoylation of hex-2-en-1-ol using metal triflates

Table 41 Conversions () of metal triflate catalysed benzoylations

Entry Metal Triflate

Conversion

1 Yb(OTf)3 99 15 11

2 Bi(OTf)3 40 15 8

3 In(OTf)3 34 15 3

4 Sc(OTf)3 63 15 2

5 Cu(OTf)2 3 - -

6 Sc(OTf)3 63 5 6

7 TfOH (8) 30 - - a Measured by capillary GC after calibration of the response for each component

Adding the hindered base dramatically suppressed the formation of the benzoylated product

in all cases The reaction was also carried out using 8 mol of triflic acid and a conversion of

30 was seen after 5 hours When a second portion of the acid was added (8 mol) after this

period a conversion of 82 was achieved This poorer conversion effected by triflic acid is

explained by the authors to be a result of the formation of water generated by the side

reaction (dehydration reaction of hex-2-en-1-ol) which could be responsible for attenuating

the acidity of the triflic acid To test the theory a 21 H2OTfOH solution was prepared in

acetonitrile and added to the reaction mixture Approximately the same yield (21) was

obtained after 20 minutes as previously The authors suggest that the results strongly support

the intervention of triflic acid as the active catalyst in these reactions and that water plays an

important role in modulating its activity

If TfOH is the causative agent in these reactions it can be questioned why its activity is not

modulated in the M(OTf)3 catalysed reactions assuming of course that these metal triflates

do hydrolyse to form triflic acid as the authors have suggested in this paper The authors fail

to address this issue in their article

The peracetylation of sugars was successfully carried out using 5 mol of In(OTf)3 in acetic

anhydride when stirred for 1 hour at zero degrees11 Triflic acid readily catalysed the

acetylation of galactose (Table 42 entry 1) However the reaction with glucose does not

proceed when 26-di-tert-butylpyridine (DTBP) is added to the reaction mixture with the

In(OTf)3 (Table 42 entry 3)

Table 42 Yield () of acetylation reactions

Entry Sugar Catalyst Time Yield

OHHOHO

TfOH (005 eq) 10 min 84

OHHOHO

In(OTf)3 (005 eq) 1 h 99

OHHOHO

In(OTf)3 (005 eq)

With DTMP 24 h 11

OHH2NHO

In(OTf)3 (005 eq)

1 h NR

The authors concluded that these acetylation reactions involved a dual pathway namely a

reaction catalysed by triflic acid presumably formed from when In(OTf)3 binds to the sugar

and a proton is released (Scheme 47) and a reaction catalysed by the Lewis acid In(OTf)3

OHH2NHO

+ In(OTf)3

OIn(OTf)2H2N

+ HOTf

Scheme 47 Possible source of triflic acid in acetylation reaction

The reaction involving a Broslashnsted acid could be suppressed by the addition of the hindered

base DTBMP However it should be noted that the addition of the primary base glucosamine

(not sterically hindered) suppressed both reactions (Table 42 entry 4) The lack of reactivity

seen in the presence of the amino group could also be ascribed to the coordination of the

metal centre to the nitrogen atom of the amine this decreasing the Lewis acidity of the metal

During their research on the Yb(OTf)3 catalysed preparation of calyx[4]resorcinarenes carried

out by Barrett et al12 a study was conducted on the isomerisation of the benzaldehyde-

derived resorcinarene 411 and 412 (Figure 42) It has been previously reported that the all

cis isomer 11 is consistent with Broslashnsted acid catalysis1314

411 412 Figure 42 Resorcinarene isomers

Their study of isomerisation over time was interpreted to be a Broslashnsted acid mechanism of

reversible cyclisation This interpretation was based on the suppression of the reaction

(isomerisation in particular) by the addition of the hindered base DTBMP

However the possibility of a dual mechanism operating throughout the reaction with at least

equal importance for both Broslashnsted and Lewis acidity was not considered This is because the

hindered base was only considered to be a ldquoproton spongerdquo and its reaction with the protic

product or the solvent ethanol to produce phenoxide or ethoxide ions was not considered

This omission is particularly noteworthy because the base was needed in such a vast excess in

order to suppress isomerisation The possibility that phenoxide or ethoxide ions so generated

could also deactivate Lewis acids was never considered The possibility of a dual mechanism

for the isomerisation reaction can therefore not be excluded

Further more the authors put forward from their work with metal triflate catalysed nitration

reactions15-16 and acetylations with AcOH17 that it would appear that these Lewis acids bind

to the ligand to form a chelate structure (Figure 43) These in turn will make stronger

Broslashnsted acids than the parent nitric or acetic acid

n(H2O)YbO

Figure 43 Enhanced Broslashnsted acid

The authors speculate that the chelates will undergo loss of triflic acid until equilibrium is

established with an associated gain of an inner sphere nitrate or acetate They indicate that

triflic acid or the enhanced Broslashnsted acidity is responsible for the promotion of the reaction

and not the Lewis acid directly

From the above discussion it is clear that there is no clear evidence in the literature as to

which moiety catalyses the reactions the Lewis acid metal triflate itself or the product of

hydrolysis (formed by the reaction with water or protic solvent) to form a protic acid

Another possibility suggested by Barrett is that another type of Broslashnsted acid is formed in

which the Lewis acid binds to the protic acid that is already present leading to the creation of

a Lewis-assisted Broslashnsted acid

The investigation that follows is an attempt to determine if the mechanism of metal triflate

catalysis is Broslashnsted acid driven Lewis acid driven or by a combination of the two and also

to what extent if any water plays a role in the catalysis

43 The Mukaiyama aldol Reaction

431 Introduction

The name aldol is given to a class of reactions between enolates (or enols) and carbonyl

compounds (Scheme 48) such as aldehydes and ketones18 The aldol reaction is almost

exclusively base catalysed Broslashnsted acid catalysed aldol reactions are known but are rare19

OH H H

Enolate

Scheme 48 Base catalysed aldol reaction

The Mukaiyama aldol reaction20 is a type of aldol reaction where the ketone is treated with a

silyl enol ether (Scheme 49) The reaction is Lewis acid catalysed Originally TiCl4 was

used while other catalysts that have been successfully employed in this reaction are InCl321

SmI222 and Bi(OTf)323

OSiMe3+ R3 C R4

Silyl enol ether Aldol

Lewis acid

Scheme 49 Mukaiyama aldol reaction

432 Metal salt catalysed Mukaiyama aldol reaction

In 1998 Kobayashi et al24 published a paper on work carried out on the Mukaiyama aldol

reaction using a range of Lewis acid catalysts including metal triflates chlorides and

perchlorates The objective of the investigation was to determine the correlation between the

catalytic activity of these Lewis acids in a THF-water mixture on the one hand and their

hydrolysis constants and water exchange rate constants on the other Benzaldehyde was

reacted with (Z)-1-phenyl-1-(trimethylsilyoxy) propene (Scheme 410) using 20 mol of the

Lewis acid in a THF H2O (91) mixture at room temperature for 24 hours

OSiMe3 O

+MXn 02eq

THFH2O (91)12 h rt413 414 415

Scheme 410 The Mukaiyama aldol reaction catalysed by a Lewis acid

This reaction is suitable for testing catalytic ability of the Lewis acids in aqueous media as

the silyl enol ether is sensitive to hydrolysis (of the organic type) under acidic conditions If

the Lewis acids hydrolyse in water the silyl ether will decompose and the aldol reaction will

proceed no further

This reaction has a two-fold purpose Firstly the results according to Kobayashi et al24 will

provide some indication as to the catalytic ability of the Lewis acid in aqueous media If the

Lewis acid undergoes hydrolysis slowly and conditions remain relatively non acidic the silyl

enol ether should remain stable and the aldol product should form Secondly and most

importantly to this investigation the reaction can also be used to determine if the metal

triflates hydrolyse to form Broslashnsted acid species If this is the case the silyl enol ether will be

clipped off affording little or no aldol product

The prior investigation (Table 43) shows that the rare earth metal triflates used in their

investigation all successfully catalysed the aldol reaction to afford good yields of the desired

product

That work formed the starting point of the present investigation In this work reactions were

carried out using the same conditions as previously described but non-rare earth metal

triflates were used here For comparative purposes several of the Lewis acids used by

Kobayashi24 were included as part of the present study

Table 43 Yield () of aldol product from different metal triflates24

Metal Triflate Yield ()

La(OTf)3 80

Ce(OTf)3 81

Pr(OTf)3 83

Nd(OTf)3 78

Sm(OTf)3 85

Eu(OTf)3 88

Gd(OTf)3 90

Tb(OTf)3 81

Dy(OTf)3 85

Ho(OTf)3 89

Er(OTf)3 86

Tm(OTf)3 85

Yb(OTf)3 92

Lu(OTf)3 84

Table 44 below shows the results of the reactions carried out in the present study Of

particular interest in this investigation was the reaction performed with Al(OTf)3 which gave

a poor yield of the aldol product and showed extensive silyl ether organic hydrolysis (79)

On the other hand Cu(OTf)2 Sc(OTf)3 Y(OTf)3 and Zn(OTf)2 afforded high yields of the

aldol product and showed relatively little silyl ether hydrolysis The 4 valent metals Hf and Zr

showed only hydrolysis of the silyl enol ether and no aldol product LiOTf failed to catalyse

the reaction and the 1H NMR spectrum of the product showed mainly starting material

remaining Triflic acid and TiCl4 also effected quantitative silyl ether hydrolysis as expected

From these results we can assume that those Lewis acids that catalysed the reaction to afford

high yields of the aldol product are good Lewis acid catalysts in aqueous media as they

appear to undergo weak inorganic hydrolysis Examples include Sc Cu and Y triflate

Table 44 Results of Mukaiyama aldol reaction

Lewis acid Yield ()a

Yield ()a

Hydrolysis of

Silyl ether

Yield () aStarting material

(silyl ether)

La(OTf)3 92 (80)b 8 0

InCl3 89 (68)b 3 8

CuCl2 86 (25)b 11 3

LiCl 6 (-)b 7 77

ScCl3 59 (70) 41 -

Er(OTf)3 56 (86)b 6 38

GaCl3 28 (-)b 56 16

ZnCl2 22 (10)b 0 78

AlCl3 0 (0)b 100 0

Cu(OTf)2 96 4 0

Sc(OTf)3 94 6 0

Y(OTf)3 89 11 0

Zn(OTf)2 77 2 21

Ca(OTf)2 42 28 30

In(OTf)3 41 59 0

Al(OTf)3 21 79 0

Zr(OTf)4 0 100 0

Hf(OTf)4 0 100 0

Li(OTf) 0 11 89

TiCl4 0 100 0

TfOH 0 100 0 a Yields determined by 1H NMR analysis b Yields in parenthesis refer to those of Kobayashi et al14

From Table 44 it can be seen that unlike the rare earth metal triflates several of the triflates

used in this investigation appeared quite susceptible to inorganic hydrolysis and gave rise to

in some form of Broslashnsted acidity (particularly those with a high charge density) If this was

the case then the pH of the solutions that cause silyl ether organic hydrolysis should be more

acidic relative to the pH of those that catalyse the aldol reaction In an attempt to rationalise

these results solutions were made up that mimicked the reaction mixtures (20 mol Lewis

acid in THF H2O) and the pH readings were taken of these solutions (Table 45) With the

clear exception of Sc(OTf)3 which is classified as a rare earth metal all of the Lewis acid

solutions with pH lt 4 caused the silyl enol ether to hydrolyse to an extent greater than 40

Table 45 Average pH readings of Lewis acids in THF H2O mixture

Lewis acid Ave pHbc Hydrolysis

TiCl4 -098 100 TfOH 034 100

Zr(OTf)4 138 100 Hf(OTf)4 160 100 GaCl3 214 56 ScCl3 254 41 AlCl3 273 100

Sc(OTf)3 275 6 In(OTf)3 277 59 Al(OTf)3 325 79 CuCl2 408 11 InCl3 432 6

Y(OTf)3 445 6 Cu(OTf)2 464 4 Zn(OTf)2 540 2

ZnCl2 549 0 Er(OTf)3 559 0 La(OTf)3 564 8 Ca(OTf)2 607 28

LiCl 830 7 LiOTf 889 11

a Readings were carried out at 25 degC (temperature-controlled water bath) b Average of 3 readings c Refer to values obtained

with a standard aqueous pH electrode

According to Kobayashi there is a correlation between the catalytic activity of the Lewis acid

in aqueous media and their WERC (water exchange rate constant) as well as their pKh (Kh =

hydrolysis constant)24 Cations with large pKh values ie gt43 hydrolyse weakly whereas

cations with pKh values lt43 are extensively hydrolysed and oxonium ions are formed25

It is under these latter conditions that we would expect to see a significant drop in the pH

values If we compare the pH values recorded in this study for the different Lewis acids with

the hydrolysis constants found listed in the literature25 (Table 46) there is a general

correlation between them The cations that are more readily hydrolysed show lower pH

values while the cations that hydrolyse with difficulty gave higher pH values This correlation

is more visible for the cations that are more difficult to hydrolyse

Table 46 Comparison of pH and pKh values

Lewis acid Ave pH Hydrolysis pKh25

Zr(OTf)4 138 100 022 Hf(OTf)4 160 100 025 Al(OTf)3 325 79 114

TiCl4 -098 100 230 easily hydrolysed GaCl3 214 56 260

In(OTf)3 277 59 400 InCl3 432 6 400 ScCl3 254 41 430

Sc(OTf)3 275 6 430 CuCl2 408 11 753

Cu(OTf)2 464 4 753 Y(OTf)3 445 6 770 Difficult to hydrolyse Er(OTf)3 559 0 790 La(OTf)3 564 8 850 Zn(OTf)2 540 2 896

ZnCl2 549 0 896 Ca(OTf)2 607 28 1285

LiCl 830 7 1364 LiOTf 889 11 1364 TfOH 034 100

The idea of invoking the hydrolysis constants may be useful but poses some problems if

applied in a simplistic fashion To simply write a pKh value for a given metal ion is to ignore

the potential effects of the counterion of that cation on the pKh value of that given metal

entity The pKh values cited in Table 46 are derived from previous work and were calculated

for a variety of metal salts including those of sulphates nitrates and chlorides These

constants would be useful for the particular metal with the particular counterions but not

necessarily useful for the extrapolation to other counterions

As a case in point salts of Zn+2 (if we accept that pKh values hold for all salts of a given

metal) are difficult to hydrolyse since they present with a pKh value of 896 This would

equally hold true of salts of Li+ which have a pKh value of 1364 (It should be remembered

at this stage that the pKh values were determined primarily from sulphates nitrates and

chloride salts of these metals) No chemist with any experience of organozinc or

organolithium compounds would support the view that such compounds are difficult to

hydrolyse Indeed the opposite view would be held

The converse would be true of certain compounds of tin(IV) SnCl4 is correctly held to

hydrolyse rapidly In contrast Bu3SnOH used as an anti-foulant in paints for marine

structures including ships is sufficiently long-lived to be a marine pollutant that disrupts the

reproductive cycles of many marine organisms26 These simple examples exemplify the

stance that pKh values should be used judiciously in the interpretation of other chemical data

In the present work the readerrsquos attention is drawn to the entries for In+3 and Sc+3 In(OTf)3

and InCl3 give pH values of 28 and 43 while leading to hydrolysis of the silyl enol ether to

the extent of 59 and 6 respectively Exactly the opposite result is obtained for Sc+3 ScCl3

gives a pH of 25 and hydrolysis of the enol ether of 41 while ScCl3 gives a pH of 28 but

shows hydrolysis of the enol ether of only 6 These results taken together with the

arguments above clearly indicate the situation to be more complex than a simple reliance

upon a single parameter purports There is an equally strong if not stronger correlation

between pH and the extent of hydrolysis of the enol ether than there is when using the pKh

values but even here there are some results that are difficult to rationalise (see for example

the entry for Ca(OTf)2 in Table 46) where even at high pH values some hydrolysis takes

place In this instance it is quite possible that the use of a combination of Broslashnsted-driven and

metal-driven mechanisms is the best approach to rationalising the outcomes

433 The possible role of water in the Mukaiyama aldol reaction

In this study and others still to be reported many metal triflates are not only tolerant to water

but at least in some cases require the presence of water to operate efficiently Kobayashi

although never expressed in this way has alluded to the importance of water in the catalytic

activity of metal triflates and has specifically ascribed the effect to the water exchange

phenomenon While not in disagreement with this view the results of the present

investigation suggest a more complex situation with regard to the referred to water exchange

rate constant

Kobayashi2427a indicated that metal triflates that are good Lewis acid catalysts in aqueous

media have fast WERC (water exchange rate constants) In a mixture of THFwater the metal

will preferentially bind to the water molecules present and that these will rapidly exchange

on the metal with other water molecules This phenomenon is said by Kobayashi not to occur

or to occur to a much slower extent with coordinating solvents such as THF Due to the rapid

exchange of the water molecule on the metal there is a chance for an aldehyde to bind to and

be activated by the metal and for the aldol reaction to occur

Against this background Kobayashi ascribed the lack of reactivity in dry THF to the slow

exchange between the THF coordinated metal and the aldehyde This suggestion cannot go

unchallenged in view of the fact that other metal coordinating species less likely to participate

in ligand exchange on metal cations (eg diamines27b and crown ethers) do not suppress the

catalytic activity of metal triflates27c Furthermore it has been demonstrated that in aqueous

solutions of Eu(OTf)3 the Eu3+ ion remains fully or nearly full coordinated to water even with

less than 5 water in THF27d The effect of low water concentration could well be associated

with the incomplete dissociation of Eu(OTf)3 the same situation should apply to other metal

triflates However an alternative explanation is tentatively afforded namely that the water is

an essential reagent to drive the reaction to completion by removing the silyl group of the

immediate product (Scheme 411)

OSiMe3

Scheme 411 Mukaiyama aldol reaction showing silyl ether removed by water

In the absence of water the poorly nucleophilic triflate will have to act as a nucleophile to

remove the silyl protecting group but in the process TMSOTf will be generated However

this is a very active silylating agent In this case the reaction would be at best reversible It is

therefore suggested that water (or possibly metal bound water as M-OH or M-OH2) plays the

role of the Cl- ion in the well known TiCl4ndashcatalysed or related Mukaiyama reactions

(Scheme 412) In this regard it is of interest to note that the majority of metal triflate

catalysed reactions which appear to be significantly enhanced by the presence of water

involves reactions of enol ether silyl enol ethers in particular1

OSiMe3

PhCHO TiCl4 CH2Cl2

TiCl3Cl -Me3SiCl

Me PhPhPh

ClCl Cl

Me PhPhPh

Scheme 412 The Mukaiyama aldol reaction

Even if the role of water is not directly involved in the immediate aldol reaction it must still

play a role in the hydrolysis of the metalated aldol product in order to return the metal to the

catalytic cycle

In order to further investigate the role of water THF was dried in the present study by

passing it over a column of activated alumina (see chapter 3 for details) The water content

was determined by Karl Fischer analysis and found to be 8 ppm The Lewis acids were dried

under vacuum at elevated temperature to remove water The aldol reactions were repeated

using the same conditions as before and to ensure that there was no influence from external

water the reactions were carried out in a glove box The results both in the presence and

absence of water are summarised in Table 47

Table 47 Yield () aldol reactions in dry THF

Lewis acid Yield () Aldol

THF H2O (91)

Yield () Aldol in dry

La(OTf)3 92 35 Y(OTf)3 89 83

InCl3 89 44 Zn(OTf)2 77 0 Sc(OTf)3 96 0a Cu(OTf)2 94 35

a Sc(OTf)3 polymerised the THF No desired reaction was detected

The question immediately arises whether this dramatic decrease in yield may be due to poor

solubility in dry THF Kobayashi made no comment in this regard In the present study it was

found that the effect could not be ascribed to low solubility since the metal triflates in

question displayed sufficient solubility in THF

(It is interesting to note that many metal triflates promote polymerisation of THF and that

such solutions cannot be kept for long periods of time This fact was included in the design of

these experiments and fresh solutions were always prepared)

Dichloromethane is a non-coordinating solvent and therefore even in the absence of water

this solvent should leave the metal open to the aldehyde for coordination and activation

(polarisation) for the aldol reaction to take place This would be in contrast to Kobayashirsquos

comments relating to the THF inhibiting such coordination in dry THF To determine if the

WERC was the only critical factor in these reactions the DCM was dried by passing it over a

column of alumina and Karl Fischer titration determined the water content to be only 2 ppm

The aldol reactions in this solvent were carried out in a glove box to prevent the ingress of

atmospheric water (Table 48)

Table 48 Yield () aldol reactions carried out in dry DCM

La(OTf)3 lt1 Sc(OTf)3 lt1

InCl3 lt1 Cu(OTf)2 lt1 Zn(OTf)2 lt1

The virtual total unreactivity in this medium could not be ascribed solely to the insolubility of

the triflates in the DCM It is true that most metal triflates have limited solubility in this

solvent but it has been used successfully in related reactions28 where lower solubility resulted

in lower reactivity but not in the cessation of reactivity

From these results it is clear that it is not only the WERC that is playing a role in these

reactions although this concept canrsquot be altogether discounted as being partly determinative

of the success of the reaction at this stage When these reactions are carried out in a dry non

binding solvent DCM which for all intents and purposes contains no water the aldehyde

should be free to bind to the metal of the triflate However the reaction does not proceed It

would appear that water plays an important and possibly different role from that implied by

invoking the WERC concept in these reactions It has already been indicated earlier in this

thesis that it may be an essential ingredient in the reaction medium In order to ensure the

success of the reaction

To ensure that the binding of the aldehyde takes place in DCM (a prerequisite for the aldol

reaction to take place) NMR experiments were carried out The chemical shifts of

benzaldehyde were determined in CD2Cl2 (Figure 44) The respective metal triflates and

chlorides were then added to the benzaldehyde DCM mixture Any change in the chemical

shift of the signals in the spectra provides an indication of coordination The NMR samples

were made up in the glove box using dry CD2Cl2 (dried by passage over activated alumina)

and the Lewis acids were pre-dried under vacuum at elevated temperature to remove water

788764755

Figure 44 Benzaldehyde showing 1H chemical shifts in CD2Cl2

Table 49 Change in chemical shift of benzaldehyde on complexation of metal triflate

Lewis Acid

Δδ H aldehyde

Δδ Ortho

protons

Δδ Para

protons

Δδ Meta

protons 1001 788 764 755

Sc(OTf)3 -0033a 0109 0108 0044

ScCl3 0054 0093 009 0029

In(OTf)3 -0015a 016 016 007

InCl3 0507 012 012 0064 aNegative values indicate an upfield shift

The results from the 1H NMR data (Table 49) not only provide direct evidence of metal

triflate solubility but also indicate that the aldehyde does in fact bind the metals in DCM In

all cases we see a shift in the 1H NMR spectra when the metal triflate or chloride is added to

the benzaldehydeDCM mixture indicating complexation of the metal This complexation

should in turn activate the aldehyde towards nucleophilic attack and the aldol reaction should

proceed (Figure45)

OSiMe3

M(OTf)3

Figure 45 Activation of benzaldehyde by metal triflate

It is of interest to note that on the addition of the metal salts to the aldehyde a single sharp

aldehyde peak (shifted from its original position as shown in Figure 46) is observed rather

than two peaks representing the complexed and uncomplexed aldehyde respectively (Figure

47)29 This situation points to the presence of only a single type of species in solution

(bound aldehyde) but may also represent the presence of rapid exchange of bound and free

aldehyde as shown pictorially in Figure 48 Low temperature NMR may have resolved this

question but was not pursued due to solubility problems (See chapter 5 for further discussions

on NMR) Any reduction in reaction rate in this solvent is unlikely to be due to exchange

phenomena

Figure 46 1H NMR of benzaldehyde complexed to ScCl3

Figure 47 NMR peaks showing the difference between fast intermediate and slow exchange

of ligands

Also noteworthy is the effect of the different Lewis acids on the aldehyde proton Both of the

metal triflates shift the aldehyde proton downfield the change in the shift is small Contrary

to this the metal chlorides shift the aldehyde peak upfield and the change in shift is much

greater this is possibly due to the chlorine atom interacting with the aldehyde proton this

would not occur with the oxygen atom of the triflate as it is electron deficient

44 A perspective of metal triflates in organic solvents

At this stage of the discussion it is important to give consideration to the manner in which

ionic compounds dissolve in organic solvents which vary widely in terms of polarity

dielectric constants and co-ordination abilities to metals

441 On solvation of the metal triflates in dry organic solvents

Judging by their high melting points and ease of dissolution in water it is reasonable to

assume that most metal triflates are ionic compounds The heat of solvation (qmx) of such

compounds in water will be given by equation 4130

qmx = umx ndash (wm ndash wx) eq 41

umx = the energy required to convert the ionic lattice into separate ions

wm = the energy released on solvation of the cation

wx = the energy released on solvation of the anion

The lattice energy of umx of metal salts of the type MX2 is extremely high (in the region of

500ndash700 KCalmol-1 range) This will ensure relatively low solubility in organic solvents with

low polarity (and therefore low dielectric constants) Even here ion associations rather than

free ion pairs will be obsereved30 which decreases the potential energy of ions in solution31

In fact association between cations and anions in solution (close ion cluster formation) has

been shown to be magnitudes higher in solvents with intermediate to low dielectric constants

such as acetone (22 є) than in solvents with high dielectric constants such as

dimethylsulfoxide (472 є) (Table 410)

Table 410 Dielectric constants of several organic solvents

Solvent Dielectric constant (є)31

Water 79

Dimethyl sulphoxide 472

Acetonitrile 375

Methanol 315

Ethanol 242

Acetone 22

Chlorobenzene 56

Tetrahydrofuran 76

Ether 45

Benzene 23

Pentane 18

The clusters will (because of lower potential energy) have considerably less polarising ability

(compare I and II Figure 48) for activating ligands (aldehydes) than the corresponding fully

charged metal species (irrespective of which solvent molecules are associated with the cluster

or free metal cation respectively) Furthermore the metal in the cluster is shielded from the

ligand by the close association of anions30

M3+M OTfTfO

I Cluster (close ion pair) II Free ion

OTf M OTf M OTF

Quadruplet

OTf M OTfTriplet

Examples of close ion pairs

Figure 48 Possible cluster formations versus free ion formation of metal triflate in organic

solvents

Even solvents with some coordinating properties (eg nitromethane and acetonitrile

preferred solvents for metal triflate catalysis) are poor solvents for most ionic compounds In

these cases there will remain a tendency to form clusters of close ion pairs (eg -+- +-+ +-+

+-+- +-+- etc)32

Furthermore solvents with a low dielectric constant have a low capacity for supporting

charge separation which is a necessary consequence of polarisation This is the reason for the

exceedingly large differences in rates of some SN2 reactions (Scheme 413) between neutral

species in different solvents31 This will also apply to the polarisation of aldehydes and the

likes thereof by Lewis acids

Et3N + CH3Iδ δ

Et3NMe IEt3N Me I Scheme 413 Typical SN2 reaction

Table 411 Rate of SN2 reaction in Scheme 413 in different solvents

Solvent Dielectric

constant (є) Rate (Ks )

Hexane 20 1

Chlorobenzene 56 1200

Acetonitrile 375 12000

In summation then the activation (polarisation) of aldehydes or related compounds by Lewis

acids in solvents of low dielectric constants and low coordinating ability can be expected to

be limited Secondly through the shielding effect of the counter ions of the clusters the rate

of exchange of the ligands (such as aldehydes) in the bulk solvent and the inner metal of the

clusters where interaction with the metals can take place will be slower

MSn OH

+ MSn-1

+ S eq 42

ClusterP = net charge

MnXm-1

Aldehyde inbulk solvent eq 43

Scheme 414 Activation of the aldehyde by the Lewis acid in dry organic solvent

Thus according to Kobayashi the slow exchange seen in equation 42 (Scheme 414) accounts

for his results and the slow exchange seen in equation 43 (Scheme 414) would account for

the results seen in the present investigation However as is clear from the foregoing poorly

catalysed reactions are not necessarily due to slow exchange between the ligand and the

solvated metal The decrease in the reaction rate may not be due to a simple solvent

exchange but may in contrast be rationalised on the basis of solvent-induced cluster or tight

ion-pair formation

442 The possible role of water in organic solvents

One now has to consider the effects of the small amounts of water in the organic solutions of

the metal triflates Due to its high dielectric constant and significant coordinating ability to

metal ions it is expected that water would have a dramatic effect on the properties of the

solutions It will quickly result in the solution of the metal ions and dissociation of the

lsquoclustersrsquo into smaller units eventually to close ion pairs and then eventually to free solvated

Kobayashirsquos results26 suggest that this occurs with the rare earth metal triflates at around 50

equivalents of water This assertion is based on the assumption that optimal catalytic activity

will be reached at the maximum degree of dissociation of the solute (triflate)

Along the way the Lewis acid capability of the metals is increased provided that rapid

exchange between the free aldehyde and the solvated metal can occur It is reasonable to

suggest that this rapid exchange will be possible with metals that can change their

coordination number over a wide range as is the case with the rare earth metals which have

coordination spheres of up to 12 ligands

One aspect of metal triflates which has to be addressed now is its possible source of Broslashnsted

acidity in protic solvents It is known that many higher valent metal species associate with

water or other protic solvents to generate Broslashnsted acids of varying acid strength (Scheme

415)34

M+n + H2O M(H2O)x

M(H2O)x-1OH+n-1

Broslashnsted acid

Scheme 415 Formation of Broslashnsted acidity through polarisation of water by a Lewis acid

These can be differentiated by different Kh values24 In a case where the Kh value is high the

question arises to what extent the metal salt will act as a Lewis acid and to what extent does

Broslashnsted acidity play a role (As has already been argued however one must exercise

caution when using an hydrolysis constant since amongst others the counter ion on the

metal plays an important role in the rate of hydrolysis) Other workers1112 claim that it is

possible to distinguish between these possibly by ascertaining the effect of an added hindered

base on the reaction rate

This attempt at rationalisation was aimed at indicating that Lewis acid acidity and catalytic

activity are complex phenomena that depend on many factors the presence of water in

particular

45 The case for 26-di-tert-butyl-4-methyl-pyridine From the results discussed earlier it is unlikely that the Mukaiyama aldol reaction is mainly

Broslashnsted acid catalysed since Broslashnsted acids so readily hydrolyse the enol ethers However

if the hindered base is added to the reaction medium one can expect that the Broslashnsted

acidityactivity will be suppressed allowing the reaction to proceed under Lewis acid

conditions

Therefore addition of the base to the reaction medium should have one of two effects 1) no

effect on the reaction where Lewis acids are almost exclusively present and 2) allow the aldol

reaction to proceed where previously the silyl ether was destroyed by Broslashnsted acidity

The Mukaiyama aldol reactions were therefore carried out in the presence of 26-di-tert-

butyl-4-methylpyridine (Table 412) Surprisingly the addition of the base generally resulted

in a rapid reduction of the reaction rate

Table 412 Yield () aldol reactions carried out in the presence of DTBMP

Lewis acid

Without

Yield ()

La(OTf)3 92 0 0

Sc(OTf)3 96 79 50

InCl3 89 99 0

Cu(OTf)2 94 65 0

Clearly the effect of the hindered base cannot be ascribed simply to the action of a proton

scavenger As stated earlier other authors also neglected to take into account the possible

interaction of the base with the protic solvent (Scheme 416) The base (nucleophile)

generated in this equilibrium will undoubtedly deactivate the Lewis acid present

N+ ROH

Scheme 416 Interaction of DTBMP with protic solvent to form nucleophile

Solutions of THFH2O (91) and metal triflates (in the same ratio as was used in the aldol

reactions) were made up and the pH measurements taken after which 15 equivalents of the

hindered base DTBMP were added to and the pH measurements were again recorded The

results are summarised in Table 413 The aqueous solutions of THF and triflate exhibit

higher pH values when large excesses of the base are added (15 equivalents)

Table 413 pH measurements of Lewis acids in THFH2O with and without DTBMP

Lewis acid pH in

THFH2O (91)

pH in THFH2O

(91) and 15 eq

La(OTf)3 629 678 Al(OTf)3 294 357 Sc(OTf)3 212 327 Cu(OTf)2 443 506

These results (Table 413) indicate that because of the lower basicity of this sterically

hindered base (see Figure 41) it is difficult to suppress the Broslashnsted acidity completely using

15 equivalents thereof This apparently explains why Barrett and others were required to use

such large excesses of the base (up to 1000 equivalents in some cases) However the

possibility at these large excesses of base that the solution will become alkaline particularly

in the case of metals with low Kh values was not considered

46 Summary

So far the investigation strongly suggested that some of the metal triflates formed a type of

Broslashnsted acidity in the presence of water in organic solvents These triflates cannot be used in

the aldol reaction because of their rapid destruction of the silyl ether Other metal triflates

with relatively low Kh values however effectively catalyse the aldol reaction On the other

hand these metal triflates are not only water tolerant but are particularly water dependent for

their successful catalysis Specifically the present study on the Mukaiyama aldol reaction

showed that without a certain amount of water present which has been shown to form an

amount of Broslashnsted acid the reactions do not proceed in both coordinating (THF) and non-

coordinating (DCM) solvents

47 Carbocation formation

471 Carbocation formation in wet and dry solvents

The formation of retinylic carbocations in a number of solvents was studied by Blatz and

Pippert35 By using low temperatures (between -35 degC and -50 degC) and rapid handling they

were able to detect the carbocations of retinyl acetate and retinol in a number of solvent-

Broslashnsted acid systems Treatment of retinyl acetate or retinol with a Broslashnsted acid results in a

carbocation being formed this carbocation is a characteristic blue colour and can be easily

measured using UVVis spectrophotometry (Scheme 417) They found the λmax of the cation

to be solvent dependent

Retinyl acetate

CH2+ HO

Acetic acidCarbocation

Scheme 417 Carbocation formation using retinyl acetate

Barrett et al12 then used the same protocol in his study of resorcinarenes In their study they

used retinol as the probe and found that [Yb(H2O)9(OTf)3] produced carbocations in THF

when AcOH and PhCO2H were added but not when resorcinol was added TfOH gave

carbocations and surprisingly so did [Yb(H2O)9(OTf)3] in MeNO2 in the absence of any

additives The conclusion drawn from the study was that the action of [Yb(H2O)9(OTf)3] on

the resorcinarene was the result of Broslashnsted acidity

To further investigate the role of water in metal triflate catalysed reactions and the possible

formation of Broslashnsted type acidity in the present study the reaction of retinyl acetate and

acid was explored This reaction was used in order to determine if solutions of the metal

triflates in organic solvents form a type of Broslashnsted acidity in the presence of water

In order to establish a working protocol experiments were initially carried out using Broslashnsted

acids A 22 x 10-5 M solution of retinyl acetate in ether was prepared and cooled to -50 degC in

an acetone dry ice bath to mimic Blatz and Pippertrsquos conditions35 The reactions are

performed at this temperature in order to prolong the lifetime of the carbocations35 At room

temperature the lifespan of the carbocation is so fleeting that spectrophotometric

measurements would be impossible35 In the present instance nitrogen was continuously

flushed across the optics of the spectrophotometer and the cells to eliminate condensation

The retinyl acetate was added first to the quartz cuvette and then the acid under investigation

was added A UVVis spectrum of the untreated solution of retinyl acetate shows its

characteristic absorption peak at around 289 nm (Figure 49) The Broslashnsted acids were then

added to fresh retinyl acetate solutions and their spectra were recorded The UVVis scans

were run over a period of time to ensure that the whole life-span of the carbocation was

recorded Carbocations were successfully formed using methanesulfonic acid triflic acid and

p-toluenesulfonic acid (Table 414)

Figure 49 UVVis scan of retinyl acetate and its corresponding carbocation showing the

typical wavelengths and colours of the solutions

Table 414 Variation of λmax and absorptivity of the retinyl carbocation

Acida Solvent λ max Absorption

Methanesulfonic acid Ether 604 0205

Triflic acid Ether 600 0491

p-Toluenesulfonic acid Ether 599 0151 a 50 uL of the acid were added to the 3 mL of retinyl acetate solution

The results show the characteristic wavelength of the retinylic carbocation which absorbs at

around 600 nm (Figure 411) Blatz35 showed the wavelength of the maximum absorption

(λmax) to be a slight function of the solvent it did not deviate more than a few nm to either

side of this wavelength

To determine if the metal triflates would yield carbocations on addition of the retinyl acetate

they had to be dissolved in a non protic solvent in order to eliminate any proton source The

metal triflates were found to be relatively soluble in nitrobenzene This was established after

much trial and error involving a large number of solvents

As a visual test Al(OTf)3 dissolved in nitrobenzene was added to a solution of retinyl acetate

which immediately turned blue Interestingly the carbocation was sustainable at room

temperature for several minutes This was in contrast to previous work which indicated that

low temperatures are imperative to the longevity of the carbocation This is possibly due to

the cation being stabilised by the solvating effects of the nitro groups (Figure 410)

Figure 410 Solvation of carbocation by nitrobenzene

Encouraged by these results the same visual tests were carried out using In(OTf)3 Hf(OTf)4

Yb(OTf)3 and Sc(OTf)3 All of these metal triflates tested formed sustainable carbocations in

nitrobenzene from retinyl acetate at room temperature

In order to carry out the investigation in a more quantitative manner Al(OTf)3 was chosen

because of previous successes that had been realised in the present study with this metal

triflate

Karl Fischer titration showed that the nitrobenzene used thus far from the bottle (Aldrich

product) contained 352 ppm of water The aim of the experiments was to determine whether

Al(OTf)3 formed the carbocation through the formation of Broslashnsted acidity The experiments

were to be repeated in the presence of the sterically hindered base DTBMP as a test for

Broslashnsted acidity Additionally the solvent would be dried as much as possible in an attempt

to prevent the formation of water promoted Broslashnsted-type acidity by the presence of water

Stock solutions of the retinyl acetate Al(OTf)3 DTBMP and triflic acid were made up in

nitrobenzene 15 mL of the retinyl acetate solution were added to the quartz cuvette To this

was added the solution either of the Lewis acid or Broslashnsted acid (Table 415)

Table 415 Results of carbocation formation in nitrobenzene

Solution Additive C+ formation Absorption

Retinyl acetatea Al(OTf)3d Positive 0314

Retinyl acetateb TfOHe Positive 0810

Retinyl acetate +

DTBMPc TfOH Negative 0

Retinyl acetate +

DTBMPc Al(OTf)3 Negative 0

a Retinyl acetate solution 10 M b Retinyl acetate solution 0001 M c DTBMP solution 3 molar equivalents per acid added

dAl(OTf)3 solution 01M e TfOH solution 001 M

Carbocations were formed when the Al(OTf)3 or the triflic acid solutions were added to the

retinyl acetate stock solutions (Table 415) The intensity of the carbocation formed with the

triflic acid was much greater than that formed with Al(OTf)3 especially considering that the

solutions used for the triflic acid experiments are far more dilute than those used in the

Al(OTf)3 experiments (0001M versus 10 M retinyl acetate respectively) This is to be

expected if the formation of the carbocation from the Al(OTf)3 is due to Broslashnsted acidity by

hydrolysis

In the next series of experiments the sterically hindered base was added to the reaction and

mixtures no carbocations are formed with either the triflic acid or the Al(OTf)3 This strongly

suggests that the metal triflate is forming a Broslashnsted-type acid in the presence of water

Pleasingly unlike previous work that had been carried out using this hindered base12 only

three equivalents of DTBMP had to be added before the reaction was quenched

However to be absolutely sure that the carbocations were being formed due to Broslashnsted

acidity the next step was to remove the water and thus the source of the protons from the

solvent The nitrobenzene was dried by passing it through a column of activated alumina and

the water content was determined by Karl Fischer titration to be 3 ppm The stock solution of

retinyl acetate was made up to the same dilutions as before However it was found that the

Al(OTf)3 was now insoluble in the dried nitrobenzene Even after vigorous stirring and mild

heating the Al(OTf)3 powder remained at the bottom of the volumetric flask This was not the

only instance of solubility problems with metal triflates in non-polar in particular in dry

non- polar solvents

Little information could be found on the solubilising effect of small amounts of water on

metal triflates in non-polar organic solvents It is reasonable to assume in view of earlier

discussions on the solvation of ionic compounds in organic solvents that small amounts of

water through solvation of ions will increase the solubility significantly In this regard it

may be of importance to note that the following general observation was made in all of the

relevant experiments in this study addition of the functionalised substrate such as the

aldehyde to the non-polar organic solvents resulted in the dramatic increase in the solubility

of the metal triflates It is suggested that the solvationligation of ions (cations in particular)

by functionalised substrates may be responsible for this phenomenon

A series of other dry non protic solvents was evaluated for the purpose of carrying out this

reaction with Al(OTf)3 The metal triflate has a very limited solubility in non-coordinating

solvents making the choice of solvent very difficult However ionic liquids with a non-

coordinating counter ion were considered to be a potential solution to this problem For this

1-butyl-3-methylimidazolium triflate ([bmim][OTf]) was prepared (Figure 411)

-OTf416

Figure 411 1-butyl-3-methylimidazolium triflate ([bmim][OTf])

The ionic liquid was prepared in the following way 1-chlorobutane and N-methylimidazole

were heated at 80 degC for 48 hours The resultant ionic liquid was then washed with ethyl

acetate to remove any unreacted starting material (the ionic liquid is immiscible with ethyl

acetate) The residual solvent in the ionic liquid was then removed under vacuum to yield 1-

butyl-3-methylimidazolium chloride ([bmim][Cl]) an ionic liquid An excess of LiOTf was

then added to this ionic liquid of [bmim][Cl] in water and the solution was allowed to stir for

24 hours in order for an ion exchange reaction to take place between the -Cl and the -OTf The

mixture was extracted with ethyl acetate and the residual solvent was removed under vacuum

Water and an excess of NaOTf was then added resulting in a biphasic system namely the

ionic liquid [bmim][OTf] and an aqueous solution of NaCl and excess NaOTf After 12

hours the aqueous layer was separated from the ionic liquid which was then dried under

vacuum at 80 degC for 72 hours

Karl Fischer titration of the [bmim][OTf] determined the water content to be 845 ppm water

The Al(OTf)3 readily dissolved in the ionic liquid However unexpectedly all attempts to

form carbocations in the ionic liquid failed The failure to generate Broslashnsted acidity in this

wet solvent may be due to the common ion effect in this case the triflate counter ions of the

ionic liquid (Scheme 418) which may suppress Broslashnsted acid formation by competing with

water molecules for coordination

Al(OTf)3 + H2O Al(OTf)2(OH) + OTf- + H+

BA OTf-

Al(OTf)3

BA =Al(OTf)3K

Scheme 418 Common ion effect on Al(OTf)3 in [bmim][OTf]

Al(OTf)3 was found to have some solubility in DCM A mixture of DCM and Al(OTf)3 was

allowed to stir at 35 degC overnight to generate a saturated solution after which it was allowed

to cool and the undissolved triflate settled to the bottom of the volumetric flask An aliquot of

the supernatant (5 mL) was measured out and the solvent removed under vacuum The

Al(OTf)3 that remained was weighed and it was found that 25 mg of Al(OTf)3 was soluble in

5 mL of DCM

Using this information stock solutions of Al(OTf)3 retinyl acetate DTBMP and triflic acid

were made up in DCM Karl Fischer titration determined the water content of the DCM from

the bottle to be 24 ppm UVVis spectrophotometry experiments were carried out as before

(Table 416)

Table 416 Results of carbocation formation in DCM

Solution Additive C+ Formation Absorption

Retinyl acetate +

a Retinyl acetate solution 001 M b Retinyl acetate solution 0001 M c DTBMP solution 3 molar equivalents as per acid

added d Al(OTf)3 solution 001M e TfOH solution 0001 M

Carbocations were formed when Al(OTf)3 or triflic acid were added to the retinyl acetate

solutions As was the case with the nitrobenzene solutions the intensity of the cation formed

with the triflic acid was greater than that formed with the Al(OTf)3 (Figure 412) When

DTBMP was added to the solutions no carbocation formation is seen in either case

The DCM was dried by passing it over a column of alumina that had been activated in an

oven at 250 degC for 24 hours Karl Fischer titration was then carried out on the DCM and the

water content was found to be 2 ppm The corresponding stock solutions as previously were

made up To ensure that no atmospheric water found its way into the samples all work was

carried out in the glove box

Figure 412 UVVis scan showing the different intensities of carbocation formation with

triflic acid and Al(OTf)3 in DCM

The interesting shifts that can be seen in the λmax of the above UVVis scans may be the result

of the different counter ions formed in the reactions ie -OTf and Al(OTf)4-

Carbocations were formed at a similar intensity as before when the experiments are carried

out using triflic acid in the dry DCM When attempts were made to form carbocations in dry

DCM with Al(OTf)3 the solution turned a very faint blue a slight absorption peak can be

seen on the UVVis spectrum (Figure 413)

Figure 413 UVVis scan of Al(OTf)3 and retinyl acetate in dry DCM

At such a low concentration of water this result was unexpected as most of the water and

therefore also the source of Broslashnsted acidity had been removed from the system However a

DSC (differential scanning calorimetry) analysis of the Al(OTf)3 showed that the salt

contains a relatively large amount of water (Figure 414) The sample of Al(OTf)3 for that

analysis was made up in an inert atmosphere (glove box) and the scan was conducted under a

blanket of nitrogen The results of the scan showed one endotherm peak at a temperature of

170 degC and another at 260 degC (Figure 414) The lower temperature peak was assumed to

belong to lsquoloosely boundrsquo water and the higher temperature peak to that of water bound

directly to the metal centre

Figure 414 DSC scan of standard Al(OTf)3

This water along with the small amount of water left in the DCM may have been the source

of the Broslashnsted acidity that was promoting the weak carbocation formation that was seen in

the previous experiments A sample of the same Al(OTf)3 was then dried under reduced

pressure at 120 degC for 48 hours and the DSC scan was repeated Both of the endotherm

peaks had disappeared (Figure 415)

Figure 415 DSC scan of dried Al(OTf)3

To determine if it was in fact water that had been removed from the Al(OTf)3 sample and not

residual TfOH a small portion of the dried Al(OTf)3 powder was exposed to the atmosphere

for 15 minutes A DSC scan of this sample was then recorded The endotherm peaks reappear

at both 170 degC and 260 degC This strongly suggests that the endotherm peaks are as a result of

water bound to the Al(OTf)3

The carbocation formation experiment was repeated using the dried Al(OTf)3 in dried DCM

Stock solutions were made up in the glove box As before solubility was a problem and the

solution had to be heated to 35 degC before the Al(OTf)3 became completely soluble in the

solvent When the Al(OTf)3 solution was added to the retinyl acetate solution the solution did

not turn blue Nevertheless after some time Al(OTf)3 could be seen accumulating slowly on

the bottom of the cuvette Around the fine powder a blue colour could be seen forming on the

interface of the powder and the solvent

A possible explanation of this phenomenon is the irreversible hydrolysis on the crystal faces

of the Al(OTf)3 that occurs on exposure to moisture to yield amphoteric patches of

aluminium oxide on the surface33 This observation has been made for certain types of

alumina surfaces and may account for the present phenomena

472 The proton and the sterically hindered base ndash X-ray crystallography

In(OTf)3 and DTBMP were dissolved in DCM The DCM was then allowed to evaporate

slowly allowing crystals to form The crystals were then analysed using X-ray

crystallography (Figure 416)

Figure 416 Crystal structure of protonated DTBMP with OTf- counterion (417)

Table 417 Crystal data of protonated 26-di-tertbutyl-4-methyl pyridine

C20H20F3N2O3S Dx = 1607 Mg mminus3

Mr = 42544 F000 = 884

Orthorhombic Pna21 Mo Kα radiation λ = 071073 Aring

a = 228420 (16) Aring Cell parameters from 3551 reflections

b = 90680 (6) Aring θ = 24ndash280deg

c = 84873 (6) Aring micro = 024 mmminus1

V = 17580 (2) Aring3 T = 296 (2) K

Z = 4 041 times 022 times 019 mm

The crystal structure shows a pyridium ion with no metal found in the crystal structure and

presumably In(OTf)2(OH) is formed in the process This is consistent with a previous finding

of this investigation (see section 45 The case for 26-di-tert-butyl-4-methyl-pyridine) The

crystals formed in the presence of In(OTf)3 are identical to those formed when the same

experiment is carried out using triflic acid The latter experiment also generated crystals

identical to those described in Figure 416 and Table 417 above

48 Friedel-Crafts alkenylation reactions of arenes

481 Optimising the reaction

So far in the investigation it has been established that the metal triflates can form Broslashnsted

type acidity to varying degrees in the presence of water in organic solvents In the case of the

Mukaiyama aldol reaction this results in the hydrolysis of the silyl enol ether Furthermore

Broslashnsted acidity has been shown to be causative in the formation of carbocations using

retinyl acetate and a metal triflate An X-ray structure determination on crystals formed upon

the reaction of In(OTf)3 with the sterically hindered base DTBMP showed that a proton binds

to the base and that triflate is the counter ion

Since a metal triflate may exhibit both kinds of activity (Lewis and Broslashnsted acidity) it needs

to be established whether the Broslashnsted acid or the Lewis acid drives the reaction or whether it

is a combination of the two Alternatively the question may be asked as whether such a metal

triflate can act purely as a Lewis acid in the absence of water or protic solvent The Friedel-

Crafts alkenylation (Scheme 418) reaction of arenes was chosen for this part of the

investigation as it is a proton-neutral reaction Once the water is removed from the reaction

there is no other source of protons available for the generation of Broslashnsted acidity In this

way the extent of Lewis acid catalysis can possibly be determined

The reaction between p-xylene and phenylacetylene (Scheme 419) is known to be catalysed

by In Sc and Zr triflates36 This served as a starting point for the current investigation Using

the same experimental procedure set out in the 2000 communication36 a range of metal

triflates (20 mol) was used in the reaction between p-xylene and phenylacetylene

Ph HM(OTf)n 20 mol85 oC

418 419 420 Scheme 419 Friedel-Crafts reaction of p-xylene with phenylacetylene

The reactions were carried out at 85 degC for 24 hours after which the yields were determined

by 1H NMR spectroscopy (Table 418) This was done by integration of the remaining

acetylene proton signal against the signal of the vinylic hydrogen in the product The yields

of the products were mostly poor many of the metal triflates failed to catalyse the reaction at

all (Table 418) but this may be due to solubility problems in the non-polar reaction medium

The problem was somewhat overcome by the addition of nitromethane to the p-xylene The

reactions were then repeated in this solvent mixture Several of the reactions were repeated

(Table 418) The yields of the products were generally if sometimes only slightly so

improved from the previous run In an attempt to try to further optimise the reactions those

metal triflates that had performed best were used in reactions where the amount of p-xylene

was systematically reduced (Table 419)

Table 418 Yield () of Friedel-Crafts alkenylation reactions catalysed by various M(OTf)x

Lewis acid

Reaction Yield ()a

Reactions +200 uL

nitromethaneYield ()a

Zr(OTf)4 53 58 Al(OTf)3 50 86 Cu(OTf)2 0 - Ca(OTf)2 0 - Hf(OTf)4 63 64 Zn(OTf)2 0 0 La(OTf)3 0 - Sc(OTf)3 68 100 Sm(OTf)3 0 0 Y(OTf)3 0 0

ScCl3 0 21 InCl3 50 53 TfOH 31 31

By decreasing the volume of p-xylene used in the reaction mixture the yields of the product

were greatly improved The results are summarised in Table 419

Table 419 Yield () of Friedel-Crafts alkenylation reactions in various amounts of

p-xylenea

Metal triflate

Yield ()b 8 mL p-xylene

Yield ()b

4 mL p-xylene

Yield ()b

2 mL p-xylene

Zr(OTf)4 53 68 100 Al(OTf)3 100 100 100 Sc(OTf)3 100 100 100 Hf(OTf)4 76 100 100

a p-xylene phenylacetylene (100 uL) nitromethane (200 uL) 20 mol M(OTf)x b Yield determined by 1H NMR

spectroscopy

The application of metal triflates in the Friedel-Crafts alkenylation reaction is expected to

have a wide application For example the study also showed that phenyl acetylene could be

successfully reacted with a wide range of aromatic systems including toluene anisole etc

using the same metal triflates (Table 420)

Table 420 Yield () of Friedel-Crafts alkenylation reactions with alternative aromatic

systemsa

Lewis Acid 10 mol

Yield ()b

Cumene 16 mL 48 h

Yield ()b

Anisole 16 mL 24 h

Yield ()b

Toluene 16 mL 48 h

Zr(OTf)4 71 gt 95 66 Al(OTf)3 47 gt95 77

a p-xylene phenylacetylene (100 uL) nitromethane (200 uL) 20 mol M(OTf)x b Yields determined by 1H NMR

spectroscopy products not isolated

482 Reactions in dry solvent

Once the optimal reaction conditions had been established the p-xylene and nitromethane

were dried Karl Fischer titration was carried out on the solvents to determine their water

content before and after drying Nitromethane from the bottle was found to contain 325 ppm

water Working in the glove box the solvent was passed through a column of activated

alumina and the dry nitromethane was found to contain 22 ppm water The p-xylene was

dried for 24 hours over 3Aring molecular sieves that had been activated in an oven at 250 degC The

dried p-xylene was found to contain 1 ppm water When the solvents were mixed in the same

ratio as they were used in the previous reaction mixture the Karl Fischer titration was

repeated on the solvent mixture and the water content was found to be 5 ppm This mixture

was then used for the reactions

The metal triflates were dried under high vacuum at 120 degC for 48 hours to remove all traces

of water DSC scans were carried out to ensure and confirm that the all of the metal triflates

were dry Additionally all preparation work took place in a glove box The scans showed no

endotherm peaks that are characteristic of the presence of water

The Friedel-Crafts alkenylation reactions were then repeated (Table 421) using the dry

solvents in order to determine to what extent Broslashnsted acidity plays a role in these reactions

Since for all intents and purposes the water had been removed from these reactions the

possibility of generating Broslashnsted acidity had also been eliminated

Table 421 Friedel-Crafts alkenylation reaction in dry solventa

Metal Triflate

Yield ()b Solvent from

bottle

Yield ()b Dry solvent

Zr(OTf)4 68 24 Al(OTf)3 100 100 Sc(OTf)3 100 74 Hf(OTf)4 100 35

TfOH 31 21 a 4 mL p-xylene 20 mol M(OTf)x 85 degC 24 h b Yields determined by 1H NMR spectroscopy

Table 421 shows that yield of the reactions decreases moderately to significantly when they

were carried out in dry medium except in the case of Al(OTf)3 The results indicate that the

reactions can be sustained in a thoroughly dried solvent and are in this case very probably

Lewis acid promoted However the higher activity in slightly wetter solvents could be due to

several effects including increased solubility andor solvation of ions resulting in improved

ionic dissociation and exchange of the metal triflates (solvation effects) 1H and 13C NMR

spectroscopy of phenyl acetylene in deuterated DCM suggests that Al(OTf)3 does bind to the

triple bond of the phenyl acetylene Complexation results in a clear downfield shift of the

acetylic hydrogen and triple bond carbons (from 531 ppm to 528 ppm in the proton

spectrum and from 838 ppm to 839 ppm in the 13C spectrum) The possibility of increased

activity due to the formation of a protic acid from water binding to the metal triflate is a

realistic possibility The phenomenon of increased catalytic activity of metal triflates in the

presence of water has been observed throughout this investigation

It is clear that Al(OTf)3 is a very active catalyst for the Friedel-Crafts alkenylation reaction

under investigation Reactions were performed under dry conditions using smaller amounts of

catalyst Only at a catalyst loading of 5 mol was a decrease in reactivity observed (ie 10

mol catalyst led to quantitative conversion to product) In this case the yield of the reaction

was 60

Despite the generally lower yields obtained in the Friedel-Crafts alkenylation reaction in dry

organic medium it appears as if this particular reaction is indeed primarily Lewis acid

catalysed in the case of Al(OTf)3 (and possibly for the other metal triflates used in this study-

although a large contribution from a Broslashnsted-acid catalysed mechanism may be the force

with those metal triflates that were severely affected by the drying ie Zr(OTf)4 and

Hf(OTf)4)

The effect of the lower water content on the triflic acid can be explained in terms of

diminished dissociation in a solvent with lower dielectric constant and poor solvating

properties There seems to be no simplistic trend with regards to water on the metal triflates

This may be due to the dual mechanism and the unpredictable reactivities and quantities of

the given Lewis acid and Broslashnsted acid that forms

In cases where metal triflates were not completely soluble in the reaction medium but some

portion remained as solid particles the contribution of a heterogeneous component to the

reaction cannot be excluded This possibility has not been investigated but should command

attention

49 Conclusions

Summation of results described in publications and new results outlined in this investigation

led to the conclusion that the presence of water (or other protic molecules) in organic solvents

can affect the catalytic activity of the metal triflates in different ways Not only can it

increase solubility but catalytic activity can be increased by solvation water complexation

while results in the formation of Broslashnsted acid activity The effect of water and other protic

solvents will generally not be easy to determine to predict or be ascribed to a specific factor

The dramatic effect of small amounts of water on the catalytic ability of metal triflates raises

the question of the effect of water on Lewis acid activity in general and as to the nature of the

nature of the active catalyst In the minds of most practising chemists Lewis acid catalysis

appears to play out as the simple activation of a substrate by a metal centre This study has

amply demonstrated that this is not the case Instead the reality appears to be one in which

water plays a critical if sometimes determinative role in the successful outcome of the

reaction In all likelihood many (if not most) reactions that are held to be purely Lewis acid

catalysed are either Broslashnsted acid catalysed (by complex Broslashnsted acids of the type MXnmdash

OH2) or co-catalysed by Broslashnsted-Lewis synergism in which hydrogen bonding and metal

bonding where a MmdashOH2 moiety lead to favourable transition states

Throughout all of the work of the present study water has shown to play a critical role In

only one case was this not so The study clearly points to the complexity faced when

considering Lewis acid catalysis at a fundamental level as has been done here It is quite

likely given the manifold reactions investigated here and the complex interplay between

Lewis and Broslashnsted acidity (the latter being almost ubiquitous in the presence of Lewis

acids) that the fundamental way in which chemists think of such activators should be

modified

Comparing the catalytic activity of metal triflates becomes particularly problematic when

water (or a protic solvent) is a potential reagent (eg in the Mukaiyama aldol reaction) Such

comparisons should preferably be carried out with model reactions that are inert to water

The results described suggest that metal triflates in water-containing solvents often catalyse

reactions by a dual mechanism (Lewis andor Broslashnsted acid mediated) and that the relative

importance of these two mechanisms differ from metal to metal The results further indicate

that the interpretation of the effect of the addition of the sterically hindered base to a reaction

medium should be interpreted with caution particularly where large excesses of the base are

An observation of particular importance is that some metal triflates are not only tolerant to

water but require water for their catalytic activity The sometimes dramatic effect of drying

the organic solvent on the metal triflate catalytic activity highlights the role of small amounts

of water in organic reactions in general

In turn this point focuses attention as to what is meant by using what organic chemists usually

term dry solvents The previous chapter highlighted the difficulties in drying organic solvents

and serves as a relief for the present work

410 References

1 Kobayashi S Sugiura M Kitagawa H Lam W W L Chem Rev 2002 102

2 Scifinder Scholar search of ldquoMetal Triflate Catalysisrdquo 2002-2009 ndash 307 hits

3 a) Kobayashi S Synlett 1994 9 689 b) Kobayashi S Chem Lett 1991 12 2187

c) Kobayashi S Ogawa C Chem Eur J 2006 12 5954 d) Keller E Feringa B

L Tetrahedron Lett 1996 37 1879

5 Bizier P N Atkins S R Helland L C Colvin S F Twitchell J R Cloninger

M J Carb Res 2008 343 2814

6 Noji M Ohno T Fuji K Futaba N Tajima H Ishii K J Org Chem 2003

68 9340

8 Brown H C Kanner B J Am Chem Soc 1966 88 986

9 Ollevier T Nadeau E Guay-Beacutegin A-A Tetrahedron Lett 2006 47 5351

10 Dumeunier R Markoacute I E Tetrahedron Lett 2004 45 825

M J Carb Res 2008 343 2814

12 Barrett A G M Braddock D C Henschke J P Walker E R J Chem Soc

Perkin Trans 1999 873

13 Curtis A D M Tetrahedron Lett 1997 38 4295

14 Pieroni O L Rodriquez N M Vuano B M Cabaleiro M C J Chem Res (S)

1994 188

15 Waller F J Barrett A G M Braddock D C Ramprasad D Tetrahedron Lett

1998 39 1641

16 Waller F J Barrett A G M Braddock D C Ramprasad D Chem Commun

1997 613

17 Barrett A G M Braddock D C Chem Commun 1997 351

18 Claydon J Greeves N Warren S Wothers P Organic Chemistry Oxford

University Press New York 2001

19 Smith M B March J Advanced Organic Chemistry Reactions Mechanisms and

Structure 5th ed Wiley New York 2001

20 Mukaiyama T Pure Appl Chem 1983 55 1749

21 Loh T-P Pei J Cao G-Q Chem Commun 1996 1819

22 Van de weghe P Collin J Tetrahedron Lett 1993 34 3881

23 Hollis T K Bosnich B J Am Chem Soc 1995 117

25 Baes C F Jr Mesmer R The Hydrolysis of Cations Wiley New York 1976

26 Hagger J A Depledge M H Galloway T S Marine Pollution Bulletin 2005 51

27 a) Kobayashi S Synlett 1994 9 689 b) Ding R Katebzadeh K Roman L

Bergquist K E Lindstrm U M J Org Chem 2006 71 352 c) Kobayashi S

Manabe K Acc Chem Res 2002 35 209 d) Dissanayake P Allen M J J Am

Chem Soc 2008 131 6342

28 Chaminade X Chiba Shunsuke C Narasaka K Duntildeach E Tetrahedron Lett

2008 49 2384

29 Drago R S Physical Methods in Chemistry Saunders 1976

30 Gould E S Mechanism and Structure in Organic Chemistry Holt Reinhart and

Winston 1959

31 Purcell K F Kotz J C Inorganic Chemistry Sauders 1977

32 Gladstone S Textbook of Physical Chemistry Macmillen 1953

33 Isaacs N S Physical Organic Chemistry Longman 1987

34 Smith M B Organic Synthesis McGraw-Hill Singapore 1994

35 Blatz P E Pippert D L J Am Chem Soc 1967 90 1296

36 Tsuchimoto T Maeda T Shirakawa E Kawakami Y Chem Commun 2000

37 Carruthers W Coldham I Modern Methods Inorganic Synthesis Cambridge

University Press UK 2004

Chapter 5

51 Introduction

The final aim of this investigation was to rank the metal triflates according to their Lewis

acid strength using spectroscopic methods This type of ranking had proved marginally

successful for other more traditional types of Lewis acids such as the metal halogens

However to our knowledge a study like this has not been undertaken for the metal

triflates

Despite attempts by many researchers the quantitative measurements of Lewis acid

strength across a broad range does not exist The quantitative measurement of Lewis

acidity appears to be one of the persistent problems of the acid-base theory Lewis

himself pointed out that relative acidity (or basicity) would depend on the choice of

reference base (or acid)

The most reliable method for determining the strength of a Lewis acid would be the

determination of the enthalpy change accompanying the formation of the acid-base

adduct in the gas phase1 This method also has its drawbacks it is not available to a wide

range of compounds and although it tells us the acidity in the gas phase the question

arises as to whether the data could be extrapolated to the solvent phase

The hard-soft acid-base (HSAB) concept was introduced in 1963 by Pearson2 and can

explain affinities between acids and bases that do not depend on electronegativity and

other related properties3 According to this principle hard acids prefer to bond to hard

bases and soft acids prefer to bond to soft bases Electrostatic interaction is presumed to

be the dominant source of stabilisation in the hard acid-hard base complex In the case of

soft acid-soft base complexes electron delocalisation between the frontier orbitals has

been thought to be the principal interaction4

The HSAB principles give us a good qualitative indication upon which to work

However we are unable to determine anything about the inherent strength of the acid or

Nevertheless there have been many successes in correlating relative Lewis acid strength

using an array of techniques (for a full review see Chapter 1) Childs carried out a study

using NMR spectroscopy by examining the shifts of complexed bases versus the

uncomplexed bases4 He was able to determine the Lewis acidity of a variety of acids

Other studies have been carried out using UVVis spectrophotometry to determine Lewis

acidity eg by the difference in the wavelength of complexed and uncomplexed carbonyl

groups Often spectroscopic information is applied in calculating equilibrium constants

which then forms the basis for ranking of the Lewis acids

The aim of the present investigation was to establish a ranking for a variety of metal

triflates with respect to Lewis acidity using NMR IR and UVVis spectroscopy and to

determine if the ranking found by these methods correlated with each other

52 Lewis acidity from NMR resonance shifts

Crotonaldehyde

The ranking of Lewis acids by NMR spectroscopy is based on the assumption that when

the Lewis acid (electron acceptor) binds to the electron donor (Lewis base) there is a

reduction of electron density on the Lewis base This reduction of electron density results

in a downfield shift in the NMR signals of the basic compound The stronger the Lewis

acid the more dramatic the shift on the NMR spectra These shifts can then be compared

to one another and a ranking obtained

One of the most comprehensive investigations carried out on the ranking of Lewis acids

using NMR spectroscopy was done by Childs et al4 In this investigation metal halides

were used as the Lewis acids The most successful probe (base) used in the investigation

was crotonaldehyde although others were also employed (this study is outlined more fully

in Chapter 1 section 132 of this thesis)

Childsrsquos study formed the starting point of the current investigation While investigating

the role of water in metal triflate catalysis (Chapter 4) it was found that the triflates had

some solubility in DCM and that this solubility increased when an aldehyde or other

functionalised organic compound was added to the mixture In light of these findings the

current NMR investigation was carried in deuterated DCM using (asymp 01 M)

crotonaldehyde (for numbering see Figures 51 and 53) as the probe An excess of 12

equivalents (with respect to the aldehyde) of the Lewis acid was used to ensure that all of

the aldehyde was coordinated to the metal The 1H and 13C NMR spectra in all instances

showed only one set of signals indicating complete (within the limits of NMR sensitivity)

coordination to the metal The 1H and 13C NMR results with respect to several Lewis

acids are recorded in Table 51 and 52 respectively

Figure 51 Proton numbering used on crotonaldehyde

Table 51 1H NMR chemical shift differences (Δδ) of crotonaldehyde on complexation

with various Lewis acids

signala

Croton

aldehyde

Δ δ on

addition

Al(OTf)3

Δ δ on

addition

Δ δ on

addition

Sc(OTf)3

Δ δ on

addition

Δ δ on

addition

In(OTf)3

Δ δ on

addition

H-1 947 -026 -016 -025 003 -006 -007

H-2 610 054 013 044 045 030 027

H-3 687 093 023 093 071 050 043

CH3 201 029 012 028 021 016 013 a Negative values indicate an upfield shift

The results show significant shifts for both H-3 and H-2 resonance in all cases (Table

51) Furthermore Al(OTf)3 and Sc(OTf)3 effect the greatest of these shifts particularly

with regard to H-3 The same trend is seen by the CH3 group However the shifts are of

smaller magnitude In every case the shifts are mutually consistent and can readily be

interpreted in terms of the relative Lewis acidity of the metals The following ranking is

therefore suggested Al(OTf)3 gt Sc(OTf)3 gt In(OTf)3 And for the chloride series ScCl3 gt

InCl3 gt AlCl3 (H-1 shifts did not correlate with the above suggested Lewis acid ranking

this may be due to anisotropic shielding induced by the oxygen-metal bond on the nearby

H-1 hydrogen) The order found for the chloride series appears to be anomalous with

respect to AlCl3 Other workers have found that AlCl3 gt InCl356 However probes

(bases) used in these studies were different In one case ethyl acetate was used5 and in

the other 9-fluorenone6 which could be a possible reason for the difference in the

rankings Childs4 did not use AlCl3 or InCl3 in his study

Figure 52 1H NMR chemical shift differences of crotonaldehyde versus the various

Lewis acids

4 Figure 53 Carbon numbering used on crotonaldehyde

Table 52 13C NMR chemical shift differences (Δδ) of crotonaldehyde on complexation

signala

Croton

aldehyde

Δ δ on

addition

Al(OTf)3

Δ δ on

addition

Δ δ on

addition

Sc(OTf)3

Δ δ on

addition

Δ δ on

addition

In(OTf)3

Δ δ on

addition

C-1 1941 111 04 116 175 04 29

C-2 1348 -20 05 -14 -15 03 -02

C-3 1544 219 02 221 1752 04 45

C-4 187 26 06 27 24 05 09 a Negative values indicate an upfield shift

The significant shifts seen in C-1 and C-3 following the same reasoning as before these

shifts appear to support Lewis acid acidity ranking Al(OTf)3 asymp Sc(OTf)3 gt In(OTf)3 The

chloride series remains the same as before

The measure of consistency found in this method strongly suggests that this may be a

valuable method for the ranking of Lewis acids particularly since the large number of

aldehydes available that will allow a great measure of fine tuning This is a subject of an

ongoing study in our laboratory

Figure 54 13C chemical shift differences of crotonaldehyde versus the various Lewis

Ionic liquids as a solvent for NMR spectroscopy

Work carried out previously in this investigation showed that the metal triflates were

soluble in ionic liquids in particular [bmim][OTf] (Chapter 4) In order to extend the

current study on the ranking of the metal triflates using NMR spectroscopy it was

decided to employ the use of ionic liquids as the solvent To do this a 10 mm NMR tube

was used in which the ionic liquid along with the aldehyde and the metal triflate was

placed A coaxial tube filled with deuterated benzene was then inserted into the 10 mm

NMR tube containing the ionic liquid (deuterated benzene was used due to its high

deuterium content when other deuterated solvents were used for these experiments for

example CDCl3 or CD3OD a lock could not be obtained on the NMR spectrometer)

Trans-cinnamaldehyde was used as the probe in these experiments (Figure 55 and Table

C3C2 C1

H2 Figure 55 Atom numbering on trans-cinnamaldehyde

Table 53 1H and13C chemical shift differences (Δδ) of trans-cinnamaldehyde in

[bmim][OTf] on complexation with various metal triflates

NMR signala

Trans-

cinnamaldehyde

δ ppm

Lewis acid Δδ H-1 Δδ H-2 Δδ C-1 Δδ C-2 Δδ C-3

Hf(OTf)4 003 005 13 -02 12

Sc(OTf)3 -016 -002 24 01 25

In(OTf)3 -0171 0047 17 00 16

Ca(OTf)2 -0074 0014 04 -04 02

Zn(OTf)2 -005 0038 29 03 26

Y(OTf)3 -0048 0145 31 03 33

Zr(OTf)4 -0107 004 23 -07 24

Al(OTf)3 -0076 0032 09 00 09

LiOTf -0017 0055 10 01 07 a Negative values indicate an upfield shift

The outcomes of these experiments show a strong correlation between the shifts in the

resonance of C-1 and C-3 (Figure 56) The shifts observed for C-2 appear to be random

There is no relationship between the data obtained for H-1 and H-2 and the results could

also not be linked to the resonance shifts observed in the carbon spectra No shifts were

seen for H-3 Due to the lack of correlations any ranking obtained from this method

would be inconclusive at best

Figure 56 13C chemical shift differences of trans-cinnamaldehyde versus the various

Lewis acids

Phosphorus NMR

Methoxycarbonylation reactions using phosphorus ligands are one of the focuses of

work in our laboratories Recently it was discovered that a metal triflate can co-catalyse

these reactions where previously they had been exclusively Broslashnsted acid catalysed6 In

light of these findings and in order to find out more about how the metal triflates worked

in these reactions phosphorus probes were used in an NMR study in an attempt to rank

the Lewis acidity of the metal triflates

Spencer et al7 conducted a study into the ranking of Lewis acids using 31P NMR

spectroscopy in which triphenylphosphine oxide was used as the probe along with

calorimetric techniques to determine the enthalpy changes and the equilibrium constants

The Lewis acids under investigation were trimethylchlorosilane -germane and -stannane

The workers found little correlation between the 31P shifts recorded and the

thermodynamic data

In the current study the NMR experiments were initially carried out by a colleague using

deuterated methanol This solvent was chosen as it mimics the reaction conditions of the

methoxycarbonylation reaction which was the reaction under investigation The probe

used was triphenylphosphine and a variety of metal triflates were used 8

The results showed that there was no shift in the 31P NMR chemical shifts on addition of

any of the Lewis acids which may be due to two factors Firstly the metal triflates are

relatively hard Lewis acids and the probe being used ie triphenylphosphine is a

comparatively soft Lewis base which would account for the absence of interaction

between the two Secondly the deuterated solvent is methanol which is itself a

coordinating solvent The metal ions of the triflate salts may preferentially coordinate to

the harder oxygen atom of the alcohol over the softer phosphorus atom

To establish if any coordination with phosphorus was possible the 31P NMR experiments

were repeated with several of the metal triflates in deuterated DCM a non-coordinating

solvent The phosphorus probes were also extended to include triphenylphosphine oxide

and diphenylphosphinobenzaldehyde The results are summarised in Table 54

Table 54 31P NMR chemical shift differences (Δδ) of phosphorus compounds on

complexation with various metal triflates

Phosphorus compound

δ uncomplexeda

Δ δ on addition

of Al(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of In(OTf)3

Triphenyl phosphine -511 071 1072 1006

Triphenyl phosphine oxide 2778 1195 1939 1749

Diphenylphosphino benzaldehyde -1044 4399 4399 4398

a Referenced to 85 phosphoric acid in water using a coaxial tube insert

Gratifyingly complexation of the metal triflates to the phosphorus centre was seen in each

case causing large downfield shifts in the resonance of the 31P signals A linear

relationship exists between the shifts found for triphenylphosphine and those of

triphenylphosphine oxide ie Sc(OTf)3 gt In(OTf)3 gt Al(OTf)3 The order of this series

differs from the order found with crotonaldehyde

Interestingly when diphenylphosphinobenzaldehyde is used as the probe the change seen

in the resonance of the 31P NMR signals are identical for the three metal triflates used

(ie 439 ppm) No precedence for these phenomena could be found in the literature

However a possible explanation could be the formation of a chelate (Figure 57) between

the phosphorus atom and the oxygen atom on the aldehyde to the metal of the triflate

This chelate would form a stable six membered ring and in so doing the phosphorus

would take on a formal positive charge Presumably the primary binding in the structure

is between the harder oxygen atom and the hard metal centres The secondary binding to

the phosphorus atom is rendered advantageous by virtue of the chelate structure and

leads to the observed similarities This would account for the fact that all of the metal

triflates used in the study appear to withdraw electrons at the same rate from this Lewis

base The strong downfield chemical shift is typical of metal bound P (III) atoms

(OTf)3M

Figure 57 Diphenylphosphinobenzaldehyde chelated to a metal triflate

What this work highlights is the need to exercise caution when using this method of

ranking It should be recommended that this method leads to relative ranking of the

Lewis acids that is relative to the probe (base) being used at the time rather than an

absolute method of ranking This is because each base has its own unique electronic

characteristics and will be affected by the Lewis acid in different ways This is unlike the

scale used for Broslashnsted acidity which uses proton acidity as a common feature

Equilibrium constants by NMR

NMR spectroscopy has been applied to determine the equilibrium constants (Keq) of

Lewis acid-base adducts and from this information a ranking of Lewis acidities should be

possible A 11 stoichiometry of the acid-base is generally assumed1 This method can of

course only be applied when there is slow exchange between the bound and unbound

ligand In this case it is assumed that the resonance shifts on the 1H NMR spectra of

unbound-base versus bound-base can be integrated and the respective concentrations

determined Here Keq = [acid-base complex][acid][base] This method assumes that the 1H NMR integral for the signal of a CH proton of a complexed molecule of the base in

question is directly proportional to the mole fraction of that species and may be related as

a proportional mole fraction to the integral on the same CH signal of the free base A

successful study of this kind was carried out by Branch et al1 where 9-fluorenone was

used as the probe and it was found that the ranking obtained from the NMR study could

be correlated to some other thermodynamic data obtained

In the current study crotonaldehyde was used as a probe in deuterated DCM Mixtures of

a 11 ratio of the aldehyde to metal triflate were carefully weighed out on a five decimal

balance Each solution for NMR was made up in 08 mL of deuterated DCM The

mixtures were stirred for 30 minutes at room temperature before the NMR spectra was

taken All spectra were recorded at 25 degC several metal triflates were investigates giving

comparable results therefore Table 56 contains results of only two of these triflates

namely Sc(OTf)3 and In(OTf)3

The results (Table 55) of the 11 12 14 etc ratio of metal to ligand were surprising in

that none of the spectra showed unbound crotonaldehyde Therefore clearly rapid

equilibrium between the bound and unbound aldehyde is established resulting in

weighted averaging of the signals9

In this case the following equation applies

δiave = (1-Nc) δic + Nc x δif

δiave = observed signal for nucleus i in NMR spectrum

δif = signal of nucleus i of free base (ligand)

δic = signal of nucleus i of complexed base (ligand)

Nc = mol fraction of complexed base (ligand)

Table 55 1H chemical shift differences (Δδ) of crotonaldehyde on complexation with

NMR signal

Croton aldehyde

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

18 aH-1 947 -027 -022 -015 -008

H-2 687 045 014 026 014

H-3 610 100 083 057 024

CH3 201 028 023 014 005

NMR signal

Croton aldehyde

Δ δ on addition

of In(OTf)3

Δ δ on addition

of In(OTf)3

Δ δ on addition

of In(OTf)3

Δ δ on addition

of InOTf)3

18 aH-1 947 -009 -008 -007 -006

H-2 687 027 019 010 008

H-3 610 049 037 021 017

CH3 201 014 007 004 003 a negative values indicate an upfield shift

In this case in principle the equilibrium constants should still be obtainable by calculation

provided that the equilibrium is not so for to the right ie to the complex that the amount

of free metal and of ligand cannot be accurately measured The linear relationship

between the signals H3 and CH3 of the complexed crotonaldehyde strongly suggest

almost quantitative complexation of both Sc(OTf)3 and In(OTf)3 in all cases The similar

results with other triflates therefore does not allow the ranking of the Lewis acidity in

this solvent A ranking using the NMR method would require the use of a more polar and

coordinating solvent to decrease the affinity of the ligand for the metal but then again the

ranking will be critically dependent on the chose of the solvent and will change from

solvent to solvent

Equilibrium constants UVVis

The calculation of equilibrium constants of acid-base adducts has been carried out using

data obtained by UVVis measurements10 In spectroscopic methods concentration is

directly proportional to absorptivity according to Beerrsquos law (Equation 1)

A = εbc 1

Where A = absorbance

ε = molar absorptivity

b = cell length (cm)

c = concentration (molL)

It has been found that the addition of the Lewis acid to specific types of Lewis bases

leads to a decreases in intensity of the absorption band of the free base and a new band

characteristic of the adduct usually appearing at a wavelength longer than that of the base

(Figure 58)9

Figure 58 UVVis spectrum of adduct formation between Lewis base and Lewis acid

Thus by using known concentrations of base and adding known concentrations of the

Lewis acid it is possible to determine the strength of a Lewis acid This is done by

calculating the Keq in the following way Keq = [acid-base complex][acid][base] The

concentrations are calculated from the absorptivity taken from the UVVis spectra9

In an attempt to rank metal triflates using this method a dilute solution (10-5 M) of 4-

methyl-3-nitroaniline was prepared in DCM and solutions of metal triflates of equal

molarity were also prepared The UVVis absorption profile of the free base was recorded

(Figure 59)

The absorption maximum of the base is seen at 424 nm When the solution of Al(OTf)3

was added no new absorption band was seen in fact no change in the spectrum was seen

at all (Figure 59) This behaviour was also observed when Sc(OTf)3 and In(OTf)3

solutions were added to the probe

Figure 59 UVVis spectrum of 4-methyl-3-aniline in DCM

Dilute solutions of 2-nitrodiphenylamine and 4-nitrodiphenylamine in DCM were

investigated as alternative probes The UVVis scans were carried out as before

However no complexation of the Lewis acid to the probe could be detected The lack of

coordination seen in these experiments may be due to the metal triflates forming close ion

pairs in the DCM and thus not been available to bind to the nitrogen This would be

particularly true due to the very low concentration of the probe (low in order to record a

UVVis spectrum of this chromophore) which would favour dissociation of a weak

complex

In an attempt to circumvent this problem dilute solutions of the same probes and the

metal triflates were made up in THF This solvent has better solvating capabilities than

DCM which may make metal ions more available for coordination to the nitrogen The

UVVis scans were then repeated These experiments showed a slight attenuation of the

original band (Figure 510 and Figure 511) when the Lewis acid solutions were added to

the probes

Satchell and Wardell10 observed the same phenomena in their work where on addition of

the Lewis acid the absorption band attributed to the base was simply reduced and no new

band characteristic of an acid-base adduct appeared According to these authors this was

ascribed to protonation of the aniline and the resultant anilinium ion absorbing at a much

shorter wavelength (bathochromic shift end absorption) than the parent base11

In the current study many other probes were evaluated (Table 56) and similar results

were obtained in each case ie attenuation of the original band

Figure 510 UVVis spectrum of Figure 511 UVVis spectrum of 4-

4-nitrodiphenylaniline in THF nitrodiphenylaniline coordinated to

Lewis Acid

Table 56 Δλ of probe on addition of a Lewis acid

Lewis base used Solvent Result

Pyridine THF Attenuation of original peak

2-Bromoanline THF Attenuation of original peak

4-Chloroaniline Ether No observable result

Diphenylaniline THF Attenuation of original peak

4-Nitroacetophenone Ether Attenuation of original peak

As a result equilibrium constants could not be calculated The possibility of using the

extent of attenuation of Lewis acid acidity is presently under investigation in our

laboratory

53 Infrared Spectroscopy (IR)

Given that only marginal success was found using NMR-based and UVVis approaches

to the ranking of the metal triflates according to equilibrium constants altogether another

method was sought

The ranking of Lewis acidity using IR spectroscopy has been reported5 When a Lewis

acid binds to a Lewis base such as the oxygen of the carbonyl group perturbation of this

bond occurs The strength of the donor-acceptor bond is reflected in the extent of the

weakening of the C=O bond This can be measured by the change in the bond stretching

frequency (Δν) on IR Lappert5 carried out a study in which ethyl acetate was used as a

probe and boron halides as the Lewis acids He found good correlation of his results with

other studies (as described in detail in Chapter 1 section 132)

Pyridine was used as an infrared probe by Yang and Kou11 to determine the Lewis acidity

of ionic liquids According to the study the presence of a band near 1450 cm-1 indicates

Lewis acidity whilst a band near 1540 cm-1 is indicative of Broslashnsted acidity With respect

to the current investigation this approach may have a two-fold advantage The metal

triflates are soluble in ionic liquids which should enable an IR study to be carried out

aimed at a possible ranking of the metal triflates In addition further information

regarding the induced Broslashnsted acidity arising due to the presence of the metal triflates

may be obtained

Yang and Kou studied CuCl2 FeCl3 and ZnCl2 in [bmim][Cl] In our study [bmim][OTf]

was the ionic liquid and the corresponding metal triflates were used We also repeated

Yangrsquos study of the chlorides in [bmim][OTf] and obtained the same ranking namely

ZnCl2 gt FeCl3 gt CuCl2 The reason behind the use of ndashOTf counter ion is so that the

ionic liquid would provide the same counter ions as the those provided by the metal

triflates guaranteeing the integrity of those species

In the current investigation metal triflates (11 equivalents) were added to pyridine in 03

mL of [bmim][OTf] The mixture was stirred at room temperature until complete

dissolution of the metal triflate was obtained Infrared spectra were taken of the

complexes using KBr pellets The results of the experiments are summarised in Table 57

The results indicate that the Lewis acids form a complex with the pyridine this can be

seen by a shift in the peak at around 1440 cm-1 which according to Yang11 indicates

Lewis acidity Closer inspection of Table 57 shows clear difference between the mono

and divalent metals on the one hand and the trivalent metals on the other

Table 57 Δν (cm-1) of pyridine on complexation with various Lewis acids in

[bmim][OTf]

Lewis acid cm-1 Δν (cm-1)Broslashnsted

acid coordination

Pyridine (original peaks) 14400 15893 NaOTf 14410 10 -a

LiOTf 14422 22 -a

Ca(OTf)2 14424 24 -a

Zn(OTf)2 14520 120 -a

Cu(OTf)2 14530 130 -a

Ba(OTf)2 14610 210 -a

LiCl 14860 460 -a

ScCl3 14870 470 -a

In(OTf)3 14880 480 15417 Al(OTf)3 14880 480 15412 Sc(OTf)3 14890 490 15403 Hf(OTf)4 14890 490 15412 Y(OTf)3 14890 490 15403 Er(OTf)4 14890 490 15396 Zr(OTf)4 14890 490 15431 Nd(OTf)3 14890 490 15415 Sm(OTf)3 14890 490 15461 La(OTf)3 14890 490 15439

InCl3 14890 490 -a

GaCl3 14890 490 15437 a ndash indicates no Broslashnsted acid coordination observed

With regard to the former and assuming that the extent of the shift in pyridine peak at

1440 cm-1 is indicative of Lewis acid acidity the following ranking of the Lewis acids

can be deduced LiCl gt Ba(OTf)3 gt Cu(OTf)2 gt Zn(OTf)2 gt Ca(OTf)2 gt LiOTf gt NaOTf

Interestingly pyridine seems to have a limit as a probe It would appear that it is only

effective for the softer Lewis acids where we see a range of shifts When we move to the

harder Lewis acids we see a maximum in the shift no matter which Lewis acid is added

These observations are similar to those observed in the 31P NMR study when

diphenylphosphinobenzaldehyde was used as a probe

It is therefore suggested that the interaction between pyridine and the Lewis acid results

in quantitative bond formation and placing a full positive charge on the nitrogen The

bond orders in all of these complexes are essentially the same resulting in similar

absorption frequencies and therefore a lack of discrimination between the different

metals This was not observed by Yang et al because they used a limited number of

metal salts

According to Yang11 a peak in the region of 1540 cm-1 indicates Broslashnsted acidity The

results of the current study (Table 57) indicate that a number of the metal triflates form a

type of Broslashnsted acidity in the ionic liquid These finding are in line with those found in

chapter 4 in which it was found that the metal triflates form Broslashnsted acidity in organic

solvents in the presence of water It should be noted here that although the [bmim][OTF]

was left under high vacuum at high temperature such organic liquids are notoriously

difficult to dry because of the ionic environment The remaining water in the ionic liquid

is most likely the cause of the Broslashnsted acidity seen in this study A noteworthy point

here is that none of the softer Lewis acids used in this study showed Broslashnsted acid

activity

In a further attempt to find a probe that could be used to rank the harder Lewis acids it

was thought that by making the probe more electron poor binding through the lone pair

on the nitrogen would be inhibited and in this way the probe may differentiate between

the harder Lewis acids

For the purpose of this aspect of the study several of the harder metal triflates were used

namely Al(OTf)3 Sc(OTf)3 and In(OTf)3 in order to determine if these probes could

discriminate between their electron withdrawing abilities The results are summarised in

Table 58

Table 58 Δν (cm-1) of electron-poor pyridine derivatives on complexation with various

Lewis acids in [bmim][OTf]

Probe and Peak of interest (cm-1)

ν (cm-1) on addition of Al(OTf)3

ν (cm-1) on addition of Sc(OTf)3

ν (cm-1) on addition of In(OTf)3

2 ndash Chloro ndash 6 ndash Methoxypyridine

14694 14694 14694 14694

2 ndash Chloro ndash 5 ndash Nitropyridine

144428 14463 14463 14463

26 - Difluoropyridine 14484 14484 14484 14484 25 ndash Dichloropyridine 14439 14439 14439 14439

From the outcome of these experiments is appears that by withdrawing electron density

from the nitrogen of the pyridine ring it the nitrogen has become a softer base by virtue of

electron density delocalisation and thus will no longer bond with the triflates which on

the whole are hard Lewis acids possibly accounting for the lack of complexation by the

metal triflates seen in the above results (Table 58)

The next logical step in the study was to add electron density onto the ring in an attempt

to make the nitrogen of the pyridine moiety harder and in this way it may discriminate

between the harder Lewis acids Infrared experiments were carried out in the same way

using pyridine derivatives that bearing electron donating moieties using three metal

triflates as before (Table 59)

Table 59 Δν (cm-1) of electron rich pyridine derivatives on complexation with various

Lewis acids in [bmim]][OTf]

246-Trimethylpyridine 16112 16400 16400 16400

23-Lutidine 15880 Suppression of signal

Suppression of signal

22rsquo-Dipyridine 14557 14834 14801 14791

The results show that the metal triflates do in fact bind to the electron rich pyridine

derivatives The signals of 23-lutidine and 23- lutidine are suppressed on the addition of

the Lewis acid and no conclusive results could be drawn from the spectra At best it

would appear that the 22rsquo-dipyridine base shows a ranking of the metal triflates of

Al(OTf)3 gt Sc(OTf)3 gt In(OTf)3 However the probe is not sufficiently sensitive to

distinguish Lewis acidity with ease

Numerous other probes for the infrared were also evaluated in this study but are not

discussed exhaustively Various compounds containing carbonyl groups were used but it

was found that instead of seeing a shift in the peak of interest the intensity of the peak

diminished on complexation of the metal triflate Phosphines such as triphenyl phosphine

and triphenylphosphine oxide were also studied little discrimination was seen between

the Lewis acids

It is possible that the use of harder bases possibility even anions is called for For

example it may be that sodium aryl amides (NaNRRrsquo) would be useful or even

phenoxides Due to time constraints these aspects could not be pursued but are put

forward as a possibility for future study in this area

55 Conclusions

What the above discussion highlights is that the acidity of Lewis acids should be looked

at in relative terms This stems from the fact that the measurements be it by NMR

spectroscopy IR etc not only measure the extent to which the acid accepts the electrons

from the base but also the extent to which the base is donating the electrons As was seen

in the NMR study different rankings can be obtained when different Lewis bases are

used Ideally one base should be used to rank all Lewis acids But as was shown in the

infrared study the softer Lewis acids could be ranked using pyridine but this probe was

unable to discriminate between the harder Lewis acids

As was mentioned in the beginning of this chapter the quantitative measurements of

Lewis acids is a perennial problem of the Lewis acid-base theory and becomes more

complicated when carried out with metal triflates Amongst others their solubility is

limited to very few solvents making spectroscopic studies difficult

In cases where Lewis acids form strong 11 complexes with ligands induced chemical

shifts appear to be a valuable method for ranking of Lewis acid acidity

References

2 Pearson RG J Am Chem Soc 1963 85 3533

3 Corma A Garcia H Chem Rev 2003 103 4307

6 Williams D B G Shaw M L Green M J Holzapfel C W Angew Chem

Int Ed 2008 47 560

8 Shaw M L Unpublished data University of Johannesburg 2009

10 Satchell D P N Wardell J L J Chem Soc 1964 4134

11 Yang Y Kou Y Chem Commun 2004 226

Summary of conclusions and suggested future research

Main conclusions

The application of Al(OTf)3 and other metal triflates as Lewis acid catalysts for organic

transformations has now been expanded to include reactions not previously investigated

with this compound as facilitator While the mechanism of activation in extremely dry

solvents may be through Lewis acidity (coordination of functionalised substrates to metal

cations) a dual mechanism (ie including Broslashnsted acidity) appears to be operative in

aqueous systems The relative importance of the two mechanisms differs from metal to

The role of water in all systems is yet to be established with certainty and may include

increasing the solubility of metal triflates solvation of metal cations or a source of

Broslashnsted acidity (through activation of water by coordination to metal cations) A starting

point for such investigation requires the availability of extremely dry organic solvents A

very successful method for the rapid drying of several organic solvents has been

identified

With respect to the identification of the Broslashnsted acid component of a possible dual

mechanism the formation of cations from retinyl acetate appears to be a proton specific

reaction However the assumed discrimination between Lewis and Broslashnsted acidity on

the basis of the effect of an added hindered pyridine should be interpreted with caution

particularly in cases where the base is added in a large excess

Comparing the catalytic activity is particularly problematic when water (or a protic

solvent) is a (potential) reagent (eg Mukaiyama aldol reaction) Such comparisons

should preferably be carried out with model reactions which are inert to water

The observation that some metal triflates are not only tolerant of water but require water

for their catalytic activity poses the question of the role of small amounts of water in

organic reactions in general This question is particularly relevant in light of the

difficulties experienced in drying organic solvents

Several methods which have been suggested for the comparison of Lewis acidity were

evaluated with respect to metal triflates While none of the methods proved to be ideal

with the view to establishing ranking of Lewis acidity induced NMR chemical shifts of

selected probes appeared to hold the most promise

Future research

There is a real need to establish and compare the solubility of metal triflates in different

organic solvents and to use this information to evaluate their catalytic activities on a

comparative molar basis Too many reactions in the literature proceed in low yield

without mention of whether activity was possibly precluded due to insolubility of the

metal triflates which was identified in the present study as particularly problematic in dry

solvents or when larger amounts of metal triflates are to be dissolved in given solvents

The effects of small amounts of water on metal triflate catalysed reactions in organic

solvents would constitute a useful area of research Similarly there is merit in studies

directed in establishing the role of water in metal triflate catalysed reactions carried out in

water In this regard model reactions should be selected that are completely inert to water

or at least such that water should not be a potential participant in the reaction (as is the

case for the hydrolysis of one of the reactants in the Mukaiyama aldol reaction)

A need exists for obtaining more information on the exact mode of activation of

substrates by metal triflates in non-polar non-coordinating organic solvents eg the

nature of exchange phenomena operating in these situations where non solvated partly

dissociated metal triflates are involved as against dissociated and solvated species in

aqueous or other protic media

The role of the counterion should be studied in more detail not only with a view to

obtaining better understanding but to suggest cheaper alternatives to the relatively

expensive triflates

In view of its green credentials the application of metal triflates Al(OTf)3 in particular

the identification of new opportunities in synthesis offers real rewards It will be

particularly useful to find applications where the more traditional catalysts fail due either

to a lack of (selective) activity or due to extreme sensitivity of the substrate eg the

extreme sensitivity of pyrroles and indoles to protic acids

Chapter 6

61 Standard experimental techniques

611 Chromatography

Thin-layer chromatography (TLC) was conducted on Merck GF254 pre-coated silica

gel aluminium backed plates (025 mm layer) Various solvent mixtures were used to

elute the chromatograms with a mixture of hexane and EtOAc usually being the

eluent of choice Compounds were visualised either by their fluorescence under UV

light (254 nm) or after spraying the TLC plate with a chromic acid solution and then

heating it over an open flame

Flash column chromatography (FCC) refers to column chromatography under

nitrogen pressure (ca 50 kPa) The columns were loaded with Merck Kieselgel 60

(230-400 mesh) and eluted with the appropriate solvent mixtures

612 Anhydrous solvents and reagents

Toluene was dried by passing it over activated alumina under nitrogen pressure (ca

50 kPa) The toluene was then heated over sodium-benzophenone under a nitrogen

atmosphere until the solution turned a deep blue colour The solvent was freshly

distilled before use Dichloromethane dichloroethane and 12-dimethoxyethane were

respectively heated over CaH2 under N2 with subsequent distillation Ethyl acetate

was distilled from K2CO3 using a Vigreux distillation column Hexanes were distilled

prior to use

62 Spectroscopical and spectrometrical methods

621 Nuclear Magnetic Resonance Spectroscopy (NMR)

NMR spectra were recorded using a Varian Gemini 2000 300 MHz spectrometer

The samples were made up in CDCl3 unless otherwise indicated The 1H NMR data

are listed in order chemical shift (δ reported in ppm and referenced to the residual

solvent peak of CDCl3 [δ = 724 ppm] or in the case of aromatic compounds to TMS

[δ = 000 ppm]) the multiplicity (s = singlet d = doublet q = quartet br s = broad

singlet dd = doublet of doublets dt = doublet of triplets dq = doublet of quartetsddd

= doublet of doublets od doublets ddt = doublet of doublets of triplets p = pentet sx

= sextet sp = septet) the number of integrated protons the coupling constant J

expressed in Hz and finally the specific hydrogen allocation Spin decoupling

experiments assisted with the determination of the coupling constants and hydrogen

allocation 13C NMR data are listed in the order chemical shift (δ reported in ppm

and referenced to the residual solvent peak of CDCl3 [δ = 770 ppm] and the specific

carbon atom allocation In some cases HSQC HMBC and COSY spectroscopy were

used to assist in the allocation of the spectra

622 Mass spectroscopy (mz)

Mass spectrometry was performed on the Thermo Double Focusing sector High

Resolution mass spectrometer Techniques included EIMS and CIMS

623 Infrared spectroscopy (IR)

A Tensor 27 spectrophotometer was used to record IR spectra using an ATR fitting

The data are listed with characteristic peaks indicated in wavenumber (cm-1)

63 Melting Points

Melting points were determined using a Gallencamp oil immersion apparatus and are

uncorrected

64 Chemical methods

Chapter 2

641 General procedure for acetal formation

The aldehyde or ketone (125 mmol) was added to a mixture of the anhydrous alcohol

and 1 mol (0059 g) of the Al(OTf)3 The orthoester (273 mL 25 mmol) was slowly

added to the mixture and the reaction was stirred at room temperature for one hour

The reactions were quenched by passing the reaction mixture through a plug of

neutral alumina to remove the Al(OTf)3 The volatiles were then removed under

vacuum If further purification was necessary bulb-to-bulb vacuum distillation was

1-(Dimethoxymethyl)-4-methoxy benzene1 (11)

MeO OMe

Yield 97 yellow oil

IR νmax (ATR diamond crystal neat) 1464 1301 1246 1049 785 cm-1 1H NMR (300 MHz CDCl3) δH 734 (d 2H J = 87 Hz H2 and H6) 686 (d

2H J = 90 Hz H3 and H5) 532 (s 1H acetal) 377 (s 3H OCH3)

328 (s 6H 2x OCH3) 13C NMR (75 MHz CDCl3) δC 1596 (C4) 1303 (C1) 1278 (C2 and C6) 1134

(C3 and C4) 1030 (acetal) 551 (OCH3) 525 (2 x OCH3)

HRMS (mz) Calculated [M ndash OMe]+ C9H11O2 = 1510765

Obtained = 1510753

1-(diethoxymethyl)-4-methoxy benzene2 (12)

EtO OEt

Yield 90 yellow oil

IR νmax (ATR diamond crystal neat) 2974 1511 1246 1034 772cm-1 1H NMR (300 MHz CDCl3) δH 736 (d 2H J = 93 and J= 06 Hz H2 H6)

685 (d 2H J = 87 Hz H3 H5) 543 (s 1H acetal) 376 (s 3H

OCH3) 376 ndash 345 (m 4H 2 x OCH2) 120 ( t 6H J = 71 Hz CH3) 13C NMR (75 MHz CDCl3) δC 19063 (COC3H) 1318 (ipso) 1280 (ortho)

1133 (meta) 1013 (acetal) 607 (2 x OCH2) 150 (2 x CH3)

HRMS (mz) Calculated [M ndash OEt]+ C10H13O2 = 165091

Obtained = 1650910

1-Chloro-4-(dimethoxymethyl) benzene3 (13)

Yield gt98 colourless oil

IR νmax (ATR diamond crystal neat) 2937 2830 1088 1052 808 cm-1 1H NMR (300 MHz CDCl3) δH 736 (d 2H J = 75 Hz H2 H6) 731 (d J =

66 Hz H3 H5) 535 (s 1H acetal) 329 (s 6H 2 x OCH3) 13C NMR (75 MHz CDCl3) δC 1366 (ipso) 1342 (para) 1283 (meta) 1283

(ortho) 1022 (acetal) 525 (2 x OCH3)

HRMS (mz) Calculated [M ndash OMe]+ C9H11ClO = 1560258

Obtained = 1569867

1-chloro-4-(diethoxymethyl)benzene2 (14)

IR νmax (ATR diamond crystal neat) 2975 2881 1087 1051 1015 cm-1 1H NMR (300 MHz CDCl3) δH 729 (d 2H J = 51 Hz H2 H6) 729 (d 2H J

= 75 Hz H3 H5) 545 (s 1H acetal) 360ndash356 (m 4H 2 x

CH2CH3) 120 (t 6H J = 71 Hz 2 x CH2CH3) 13C NMR (75 MHz CDCl3) δC 1376 (ipso) 1339 (para) 1282 (meta) 1230

(ortho) 1006 (acetal) 608 (2 x CH2CH3) 150 (2 x CH2CH3)

HRMS (mz) Calculated [M ndash OEt]+ C9H10ClO = 1690415

Obtained = 1690416

4-Nitroacetophenone dimethyl acetal (15)

MeO OMe

Yield 97 yellow solid

mp 612 ndash 634 degC

2H J = 93 Hz H3 H5) 317 (s 6H 2 x OCH3) 151 (s 3H CH3) 13C NMR (75 MHz CDCl3) δC (1501 (CNO2) 1475 (ipso) 1274 (meta) 1234

(ortho) 491 (2 x OCH3) 258 (CH3)

HRMS (mz) Calculated [M ndash CH3]+ C9H10NO4 = 1960604

Obtained = 1960593

EtO OEt

Yield 92 yellow oil

IR νmax (ATR diamond crystal neat) 12976 1520 1347 1045 857 cm- 1H NMR (300 MHz CDCl3) δH 810 (d 2H J = 78 Hz H2 and H6) 762 (d

2H J = 78 Hz H3 H5) 345 ndash 338 (m 2H CH2ACH3) 330 ndash 320

(m 2H CH2BCH3) 147 (s 3H CH3) 14 (t J = 63 Hz 6H 2 x

OCH2CH3) 13C NMR (75 MHz CDCl3) δC (1511 (ipso NO2) 1473 (ipso acetal) 1272 (C3

and C5) 1232 (C2 and C6) 1006 (Cα) 569 (2 x OCH2CH3) 268

(CH3) 151 (OCH3)

HRMS (mz) Calculated [M ndash OEt]+ C9H10NO4 = 1940812

Obtained = 1940811

o-Nitrobenzaldehyde dimethyl acetal4 (17)

MeO OMe

Yield 95 light yellow oil

IR νmax (ATR diamond crystal neat) 2937 1529 1359 1108 1055 cm-1 1H NMR (300 MHz CDCl3) δH 777 (d 2H J = 66 and 12 Hz H3 H6) 774

(d 1H J = 63 and 15 Hz H4) 756 (t 1H J = 78 and 11 Hz H5)

589 (s 1H acetal) 336 (s 6H 2 x OCH3) 13C NMR (75 MHz CDCl3) δC 148 (CNO2) 1325 (ipso) 1325 (C6) 1293

(C3) 1280 (C5) 1241 (C4) 997 (acetal) 544 (2 x OCH3)

HRMS (mz) Calculated [M ndash OMe]+ C8H8NO3 = 1660499

Obtained = 1660498

o-Nitrobenzaldehyde diethyl acetal4 (18)

EtO OEt

Yield gt98 light yellow oil

IR νmax (ATR diamond crystal neat) 2977 1529 1360 1108 1055 cm-1 1H NMR (300 MHz CDCl3) δH782 (d 1H J = 63 Hz H3) 777 (d 1H J =

78 Hz H6) 757 (dt 1H J = 60 and 13 Hz H5) 743 (dt 1H J = 78

and 15 Hz H4) 371 ndash 361 (m 2H 2 x OCH2ACH3) 360 ndash 350(m

2H 2 x OCH2BCH3) 122 (t 6H J = 72 Hz CH2CH3) 13C NMR (75 MHz CDCl3) δC 1336 (CNO2) 1324 (C6) 1291 (C3) 1280

1241 (C4) 983 (acetal) 634 (2 x OCH2) 150 (2 x CH3)

Obtained = 1800655

(33-Dimethoxy-1-propen-1-yl)-benzene3 (19)

Ph OMe

Yield gt98 yellow oil

IR νmax (ATR diamond crystal neat) 2932 1449 1190 1049 772cm-1 1H NMR (300 MHz CDCl3) δH 744 ndash 736 (m 2H ortho) 735 -726 (m 3H

meta para) 674 (d 1H J = 159 Hz PhCH=CH) 617 (dd 1H J =

161 and 50 Hz PhCH=CH) 497 (d 1H J = 11 and 45 Hz acetal)

338 (s 6H OCH3) 13C NMR (75 MHz CDCl3) δC 1360 (ipso) 1335 (para) 1285 (meta) 1280

(PhCH=CH) 1266 (para) 1256 (PhCH=CH) 1028 (acetal) 526 (2

x OCH3)

HRMS (mz) Calculated [M ndash OMe]+ C10H11O = 1470804

Obtained = 1470805

(33-Diethoxy-1-propen-1-yl)-benzene (110)

Ph OEt

IR νmax (ATR diamond crystal neat) 2975 1679 1120 1049 969 cm-1 1H NMR (300 MHz CDCl3) δH 740 (d 2H J = 78 Hz ortho) 730 ndash 723 (m

3H meta para) 670 (d 1H J = 162 Hz PhCH=CH) 620 (dd 1H J

= 162 and 51 Hz PhCH=CH) 372 ndash 367 (m 2H OCH2ACH3) 361

ndash 350 (m 2H OCH2BCH3) 124 (t 6H J = 70 Hz 2 x CH2CH3) 13C NMR (75 MHz CDCl3) δC 1361 (ipso) 1329 (PhCH=CH) 1285 (meta)

1280 (para) 1267 (ortho) 1266 (PhCH=CH) 1014 (acetal) 610 (2

x OCH2CH3) 152 (2 x OCH2CH3)

HRMS (mz) Calculated [M ndash OEt]+ C11H13O = 1610961

Obtained = 1610960

11rsquo-Dimethoxy-decane5 (111)

IR νmax (ATR diamond crystal neat) 2923 1219 1122 1055 769cm-1 1H NMR (300 MHz CDCl3) δH 430 (t 1H J = 59 Hz acetal) 325 (s 3H 2 x

OCH3) 152 (m 2H CH2CH3) 123 ndash 121 (m 14H CH3(CH2)7CH2)

082 (t 3H J = 65 Hz CH2CH3) 13C NMR (75 MHz CDCl3) δC 1045 (CH) 524 (OCH3) 324 (CH2CH) 318

(CH3CH2CH2) 295 ndash 293 (CHCH2(CH2)5) 246 (CH3CH2) 226

(CH2CH2CH) 140 (CH3)

Obtained = 1711741

11rsquo-Diethoxy-decane5 (112)

IR νmax (CHCl3) 2943 1222 1234 1064 765 cm-1 1H NMR (300 MHz CDCl3) δH 444 (t 3H J = 47 Hz acetal) 360 (m 2H

CH2A) 346 (m 2H CH2B) 155 (m 2H CH2CH) 124ndash198 (m

12H CH3CH2(CH2)6CH2) 175 (t 6H J = 75 Hz 2 x OCH3) 084 (t

3H J = 66 Hz CH3) 13C NMR (75 MHz CDCl3) δC 1030 (acetal) 607 (2 x OCH2CH3) 336

(CH2CH) 318 (CH3CH2CH2) 294ndash293 (CHCH2(CH2)5) 247

(CH3CH2) 226 (CHCH2CH2) 153 (2 x OCH2CH3) 141 (CH3)

Obtained = 1851902

Dimethoxymethyl-cyclohexane (113)

IR νmax (ATR diamond crystal neat) 2929 1215 1083 1048 754 cm-1 1H NMR (300 MHz CDCl3) δH 395 (d 1H J = 69 Hz acetal) 330 (s 6H 2 x

OCH3) 175ndash167 (m 4H H2A H3A H5A H6A) 163ndash150 (m 2H

H4) 121ndash110 (m 2H H2B H6B) 107ndash091 (m 2H H3B H5B) 13C NMR (75 MHz CDCl3) δC 1085 (acetal) 534 (2 x OCH3) 400 (C1) 280

(C3 and C5) 263 (C4) 257 (C4 and C6)

Obtained = 1271099

Diethoxymethyl cyclohexane (214)

IR νmax (ATR diamond crystal neat) 2925 2853 1130 1080 1056 cm-1 1H NMR (300 MHz CDCl3) δH 408 (d 1H J = 72 Hz acetal) 365 ndash 358 (m

2H OCH2ACH3) 355 ndash 340 (m 2H OCH2BCH3) 177 -167 (m 4H

H2A H3A H5A H6A) 162 -119 (m 2H H4) 114 (t 6H J = 72 Hz

CH2CH3) 106 ndash 087 (m 4H H2B H3B H5B H6B) 13C NMR (75 MHz CDCl3) δC 1067 (acetal) 615 (2 x OCH2) 407 (C1) 281

(C3 and C5) 264 (C4) 258 (C2 and C6) 153 (2 x OCH2CH3) 1HRMS (mz) Calculated [M ndash OEt]+ C8H15O = 1411274

Obtained = 1411275

55-dimethyl-2-phenyl-13-dioxane (215)

Yield 98White solid

IR νmax (ATR diamond crystal neat) 2960 1456 1392 1106 770 cm-1 1H NMR (300 MHz CDCl3) δH 751ndash748 (m 2H ortho) 738ndash734 (m 3H

meta para) 538 (s 1H acetal) 373 (d 2H J = 111 Hz OCH2A)

370 (d 2H J = 111 Hz OCH2B) 129 (s 3H CH3) 078 (s 3H CH3) 13C NMR (75 MHz CDCl3) δC 1384 (ipso) 1288 (para) 1283 (meta) 1261

(ortho) 1018 (acetal) 776 (2 x OCH2) 230 (CH3) 219 (CH3)

HRMS (mz) Calculated [M]+ C12H16O2 = 1921150

Obtained = 1921147

Dimethoxymethyl-benzene3 (216)

MeO OMe

IR νmax (ATR diamond crystal neat) 2975 1338 1094 1050 700 cm-1 1H NMR (300 MHz CDCl3) δH 745 - 750 (m 2H H-aromatic) 732 - 7393

(m 3H H-aromatic) 541 (s 1H CH(OCH3)2) 333 (s 6H 2 x CH3) 13C NMR (75 MHz CDCl3) δC 1381 (ipso) 1284 (para) 1282 (meta) 1267

(ortho) 1031 (CH) 526 (OCH3)

Obtained = 1210445

EtO OEt

Yield 92 dark yellow oil

IR νmax (ATR diamond crystal neat) 2963 1324 1089 1047 745 cm-1

H NMR (300 MHz CDCl3) δH 750ndash752 (m 2H H-aromatic) 730ndash740 (m

3H H-aromatic) 553 (s 1H CH(OCH3)2) 350ndash366(m 4H 2 x

OCH2) 126 (t 6H J = 705 Hz 2 x CH3) 13C NMR (75 MHz CDCl3) δC 1389 (ipso) 1280 (para) 1280 (meta) 1264

(ortho) 1013 (CH) 607 (OCH2) 150 (CH2CH3) 1HRMS (mz) Calculated [M ndash OEt]+ C9H11O = 1350804

Obtained = 1350807

(11-Dimethoxyethyl)-benzene4 (218)

MeO OMe

3H meta para) 320 (s 6H 2 x OCH3) 160 (s 3H CH3) 13C NMR (75 MHz CDCl3) δC 1420 (ipso) 1280 (ortho) 1274 (para) 1261

(meta) 1016 (acetal) 488 (2 x OCH3) 260 (CH3)

HRMS (mz) Calculated [M ndash CH3]+ C9H11O2 = 1510754

Obtained = 1510755

(11-Diethoxyethyl)-benzene4 (219)

EtO OEt

IR νmax (ATR diamond crystal neat) 2974 1219 1119 1049 772cm-1 1H NMR (300 MHz CDCl3) δH 756 (d 2H J = 156 Hz ortho) 740 ndash 726 (m

3H meta para) 355 ndash 345 (m 2H CH2ACH3) 343 ndash 333 (m 2H

CH2BCH3) 160 (s 3H CH3) 123 (t 6H J = 71 Hz 2 x CH2CH3) 13C NMR (75 MHz CDCl3) δC 1438 (ipso) 1280 (ortho) 1272 (para) 1272

(para) 1261 (meta) 1011 (acetal) 566 (2 x OCH2CH3) 271

(OCH2CH3)

Obtained = 1791067

11-Dimethoxy cyclohexane (220) MeO OMe

Yield gt98 dark yellow oil

IR νmax (ATR diamond crystal neat) 2937 1701 1102 1050 908cm-1 1H NMR (300 MHz CDCl3) δH 314 (s 6H 2 x OCH3) 161ndash157 (m 4H H2

H6) 150ndash142 (m 4H H3 H5) 138ndash135 (m 2H H4) 13C NMR (75 MHz CDCl3) δC 1000 (Cα) 473 (2 x OCH3) 326 (C2 C6) 254

(C4) 228 (C3 C5)

Obtained = 1130967

11-Diethoxy cyclohexane (221) EtO OEt

H NMR (300 MHz CDCl3) δH 343 (q 4H J = 71 Hz 2 x CH2CH3) 162 (m

2H H2 H6) 147 (m 2H H3 H5) 137 (m 1H H4) 115 (t 6H J =

71 Hz 2 x CH2CH3) 13C NMR (75 MHz CDCl3) δC 1000 (Cα) 547 (2 x OCH2) 338 (C2 C6) 256

(C4) 230 (C3 C5) 156 (2 x CH2CH3)

Obtained = 1281196

2-(dimethoxymethyl)-furan4 (222)

IR νmax (ATR diamond crystal neat) 2934 1464 1104 1053 734cm-1 1H NMR (300 MHz CDCl3) δH 737 (m 1H OCH) 639ndash637 (m 2H

OCH=CH2) 633ndash631 (m 2H OCH=CH2CH2) 540 (s 1H acetal)

331 (s 6H 2 x OCH3) 13C NMR (75 MHz CDCl3) δC 1508 (ipso) 1425 (OCH2) 1100 (acetal) 1084

(OCH=CH2) 980 (OCH=CH2CH2) 528 (2 x OCH3)

Obtained = 1110465

2-(diethoxymethyl)-furan4 (223)

IR νmax (ATR diamond crystal neat) 2977 1150 1052 1002cm-1 1H NMR (300 MHz CDCl3) δH 737ndash736 (m 1H OCH) 638ndash637 (m 2H

OCH=CH2) 639ndash631 (m 2H OCH=CH2CH2) 363ndash353 (m 4H 2 x

OCH2CH3) 121 (t 6H J = 78 Hz CH2CH3) 13C NMR (75 MHz CDCl3) δC 1518 (ipso) 1422 (OCH2) 1100 (OCH=CH2)

1080 (acetal) 962 (OCH=CH2CH2) 612 (OCH2CH3) (528 (2 x

Obtained = 1250597

642 General procedure for TBDMS protection of alcohols

To a solution of the alcohol (16 mmol) in DCM (5 mL) 15 equivalents of pyridine

base (24 mmol 020 mL) and 20 equivalents of TBDMSCl (32 mmol 0482g) was

added The mixture was stirred for 12 hours The reaction was quenched with a

saturated brine and CuSO4 solution and extracted with DCM The products were

isolated by column chromatography

1-tert-Butyldimethylsilyloxy-3-phenylpropane6 (224)

OTBDMS

Yield 80 colourless oil

TLC Rf 034 (251 hexanes-EtOAc) 1H NMR (300 MHz CDCl3) δH 731 ndash 728 (m 2H ortho) 727 ndash 720 (m 3H

ortho meta) 382 (t 2H J = 71 and 12 Hz CH2CH2O) 284 (t 2H J

= 72 Hz CH2CH2O) 089 (s 9H OSiC(CH3)3) 001 (s 6H

OSi(CH3)2) 13C NMR (75 MHz CDCl3) δC 1391 (ipso) 1291 (meta) 1282 (ortho) 1261

(para) 646 (CH2CH2O) 396 (CH2CH2O) 260 (C(CH3)3) 183

(C(CH3)3 -54 (OSi(CH3)2)

HRMS (mz) Calculated [M ndash tBu]+ C9H15OSi = 1790887

Obtained = 1790887

1-tert-Butyldimethylsilyloxy-4-bromophenyl7 (225)

OTBDMS

Yield 80 colourless liquid

IR νmax (ATR diamond crystal neat) 2929 1485 1252 803 779cm-1

TLC Rf 037 (hexanes-EtOAc) 1H NMR (300 MHz CDCl3) δH 730 (d 2H J = 73 Hz H3 H5) 670 (d 2H J

= 90 Hz H2 H6) 096 (s 9H OSiC(CH3)3) 017 (s 6H OSi(CH3)2) 13C NMR (75 MHz CDCl3) δC 1548 (ipso Br) 1323 (C3 C5) 1220 (C2 C6)

1136 (ipso O) 256 (C(CH3)3) 182 (C(CH3)3 -45 (OSi(CH3)2)

HRMS (mz) Calculated [M ndash tBu]+ C9H10BrOSi = 2289679

Obtained = 2289670

643 General procedure for the tetrahydropyranylation of alcohols

2 Equivalents of DHP (2 mmol 018 mL) were slowly added to a solution of Al(OTf)3

(01 mmol 0047g) in 25 mL of DCM The reaction mixture was stirred for 3 hours at

room temperature The reactions were quenched using an aqueous sodium bicarbonate

solution followed by extraction of the mixtures with DCM The volatiles were

removed under vacuum If further purification was necessary column chromatography

was used

2-Phenethyloxy-tetrahydro-pyran (226) O O

IR νmax (ATR diamond crystal neat) 2940 1134 1119 1027 698cm-1 1H NMR (300 MHz CDCl3) δH 730 718 (m 5H aromatic) 460 ( t 1H J =

345 Hz acetal) 400ndash389 (m 2H PhCH2CH2A) 378ndash365 (m 2H

OCH2A) 362ndash357 (m 1H PhCH2CH2B) 347ndash340 (m 1H OCH2B)

290 (t 2H J = 74 Hz PhCH2) 183ndash145 (m 6H H5H4H3)

13C NMR (75 MHz CDCl3) δC 1390 (ipso) 1290 (ortho) 1282 (meta) 1261

(para) 986 (C6) 682 (PhCH2CH2) 621 (C2) 363 (PhCH2) 306

(C5) 254 (C4) 194 (C3)

HRMS (mz) Calculated [M ndash C5H8O]+ C8H10O= 122076

Obtained = 1220727

2-(4-Bromo-phenoxy)-tetrahydro-pyran (227)

Yield 60 white solid

mp 566ndash584

TLC Rf 043 ( 101 hexanes-EtOAc) 1H NMR (300 MHz CDCl3) δH 735 (d 2H J = 66 and 21 Hz H3rsquo H5rsquo) 692

(d 2H J = 69 and 21 Hz H2rsquo H6rsquo) 535 (t 1H J = 30 Hz acetal)

383 (t 1H J = 55 Hz OCH2A) 360ndash355 (m 1H OCH2B) 197ndash193

(m 1H H3A) 185ndash180 (m 2H H5) 170ndash157 (m 3H H3B H4) 13C NMR (75 MHz CDCl3) δC 1561 (ipso) 1322 (C3rsquo C5rsquo) 1183 (C2rsquo C6rsquo)

1138 (para) 965 (acetal) 620 (C2) 302 (C5) 251 (C4) 186 (C3)

HRMS (mz) Calculated [M ndash C5H8O]+ C6H5BrO= 1719524

Obtained = 179521

2-Prop-2-ynyloxy-tetrahydro-pyran (228)

IR νmax (ATR diamond crystal neat) 2941 1119 1057 1025 870cm-1 1H NMR (300 MHz CDCl3) δH 482 (t 1H J = 30 Hz acetal) 430 (dd 1H J =

156 and 24 Hz equivCCH2A) 423 (dd 1H J = 156 and 24 Hz

equivCCH2B) 384 (t 1H J = 98 Hz OCH2A) 357ndash350 (m 1H OCH2B)

243 (t 2H J = 23 Hz HequivCCH2) 190ndash147 (m 6H H3 H4 H5) 13C NMR (75 MHz CDCl3) δC 967 (acetal)796 (HCequivCCH2) 740 (HCequivCCH2)

618 (C2) 540 (HCequivCCH2) 301 (C3) 252 (C3) 252 (C4) 190

HRMS (mz) Calculated [M ndash C8H12O2]+ C3H3O= 850659

Obtained = 850646

base (40 mmol 032 mL) and 25 equivalents of TBDMSCl (50 mmol 075g) were

4-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-benzaldehyde (229) TBDMSO

TLC Rf 042 (101 hexaneEtOAc)

1H NMR (300 MHz CDCl3) δH 981 (s 1H aldehyde) 737 (d 1H J = 21 Hz

H2) 734 ( dd 1H J = 78 and 21 Hz H5) 693 (d 1H J = 78 Hz

H6) 384 (s 3H OCH3) 097 (s 9H OSiC(CH3)3) 016 (s 6H

OSi(CH3)2) 13C NMR (75 MHz CDCl3) δC 1910 (C=O) 1516 (C3) 1513 (C4) 1309 (C1)

1262 (C2) 1207 (C6) 1100 (C5) 554 (OCH3) 255 (C(CH3)3) 184

(C(CH3)3 -46 (OSi(CH3)2)

HRMS (mz) Calculated [M ndash tBu]+ C10H13O3Si = 2090628

Obtained = 2090629

2-tert-Butyldimethylsilyloxybenzaldehyde8 (230)

OTBDMS

Yield 90 yellow oil

TLC Rf 054 (101 hexaneEtOAc) 1H NMR (300 MHz CDCl3) δH 1045 (s 1H aldehyde) 780 (d 1H J = 99 and

20 Hz H6) 744 (t 1H J = 78 and 19 Hz H5) 701 (t 1H J = 80

Hz H4) 686 (d 1H J = 84 Hz H3) 100 (s 9H OSiC(CH3)3) 026

(s 6H OSi(CH3)2) 13C NMR (75 MHz CDCl3) δC 1901 (C=O) 1589 (C2) 1357 (C4) 1283 (C1)

1215 (C5 C6) 1202 (C3) 256 (C(CH3)3) 163 (C(CH3)3 -43

(OSi(CH3)2)

Obtained = 1790523

tert-Butyl-(4-dimethoxymethyl-2-methoxy-phenoxy)-dimethyl-silane

Trimethyl orthoester (0166 mL 1 mmol) was slowly added to a mixture of 2-tert-

butyldimethyloxybenzaldehyde (05 mmol 0125 g) and 10 mol (0024 g) of the

Al(OTf)3 in methanol 10 mL The mixture was stirred at room temperature for one

hour The reaction was quenched by passing the reaction mixture through a plug of

neutral alumina to remove the Al(OTf)3 NMR spectra of the crude product was used

to determine the yield The isolated product could not be obtained due to the sensitive

nature of the acetal group The yield was obtained by the integration of the remaining

aldehyde peak and the newly formed acetal peak which both represent one proton

TBDMSO

2-tert-Butyldimethylsilyloxy dimethoxy methyl benzene (232)

butyldimethylsilyloxy-dimethoxymethylbenzene (050 mmol 0147 g) and 10 mol

(005 mmol) of the metal triflate the reaction was stirred for 12 hours after which the

mixture was passed through a small column of neutral alumina The excess solvent

was removed under vacuum at 40 degC No further purification was required to obtain a

product for characterisation Yields were then determined by 1H NMR spectroscopy

OTBDMS

Yield 94 Light yellow oil

IR νmax (ATR diamond crystal neat) 2931 1257 1091 1055 92cm-1 1H NMR (300 MHz CD3OD) δH 735 (d 1H J = 78 and 21 Hz H3) 711 (t

1H J = 711 and 16 Hz H5) 685 (t 1H J = 75 Hz H4) 674 (d 1H

J = 81 Hz H6) 550 (s 1H acetal) 320 (s 6H 2 x OCH3) 094 (s

9H OSiC(CH3)3) 016 (s 6H OSi(CH3)2) 13C NMR (75 MHz CD3OD) δC 1547 (C2) 1306 (C5) 1288 (C3) 1220 (C4)

120 (C6) 1010 (acetal) 538 (2 x OCH3) 263 (C(CH3)3) 192

(C(CH3)3 -40 (OSi(CH3)2)

Obtained = 2250946

Chapter 3

645 Standard procedure for Karl Fischer measurements

To make certain of accuracy all solvents were injected directly into the analyte

solution in the titration cell 3 mL of solvent were used for all measurements and the

water concentration was measured six times to determine precision Standard

deviation (Equation 1) and relative standard deviations (Equation 2) were calculated

for the data using the following equations

i=1(xi - μ)2

Eq 1 RSD = ( x) x 100σ Eq 2

σ = standard deviation (Eq 1)

N = number of replica data

x = sample mean

μ = population mean

= individual sample x

Outliers have been removed from the data using a 95 confidence level9 For raw

data see appendix A

The 3Aring molecular sieves (Sigma-Aldrich) were washed thoroughly with AR grade

methanol (Sigma-Aldrich) and placed in an oven at 250 degC for 24 hours All silicas

(Sigma-Aldrich) and alumina (Sigma-Aldrich) were placed in glass beakers covered

with aluminium foil into which small holes were made The beakers were then placed

in an oven overnight at 300 degC to ensure that the silicas and alumina were dry All

desiccants activated in the oven were allowed to cool inside the glove box Once the

columns had been loaded with the silica or alumina the desiccant filled the column to

a height of approximately 10 cm The organic solvents were allowed to flow over

these desiccants under the influence of gravity

Solvents used in this study

Tetrahydrofuran ndash E ndash lab direct limited HPLC Grade

Acetonitrile ndash Sigma Aldrich HPLC Grade

Dichloromethane ndash Sigma Aldrich AR Grade

Toluene ndash Sarchem (Merck) AR Grade

Methanol ndash ACE (associated chemical enterprises) AR grade

Chapter 4

The role of water in metal triflate mediated organic reactions

646 TMS protection of propiophenone

To make LDA

A solution of diisopropylamine (11 eq 14 mmol) in dry THF (5 mL) at -20 degC under

nitrogen was treated dropwise with n-Butyl lithium (15 eq 20 mmol) and stirred for

10 minutes

To make the silyl ether

The LDA was added to 3 mL of THF that had been cooled to -78 degC Propiophenone

(125 mmol 016 mL) in 3 mL of THF is then added to this solution at a slow rate so

as to keeping the internal temperature below -70 degC The mixture was stirred for 30

minutes at -78 degC TMSCl (14 eq 175 mmol 022 mL) in THF was added dropwise

at -70 degC and stirred for a further 30 minutes The mixture was then allowed to warm

to room temperature after which triethylamine 2 mL and 30 mL of pentene are added

The reaction was quenched aqueous sodium bicarbonate of soda and extracted with

DCM The extract was dried over MgSO4 and the volatiles were removed under

vacuum Purification was done using column chromatography

Trimethyl-(1-phenyl-propenyloxy)-silane (413)

647 General procedure for the Mukaiyama Aldol reaction

A mixture of benzaldehyde (05 mmol 50 uL) and 1-phenyl-1-

(trimethylsilyoxy)propene in 1 mL of THF was added to a solution of the THFH2O

(91) (15 mL) and the Lewis acid (011 mmol) at room temperature The mixture was

stirred for 12 hours The THFH2O was removed under vacuum Water was added and

the product was extracted using DCM Purification was done using column

chromatography

OSiMe3

TLC Rf 043 (101 hexaneEtOAc) 1H NMR (300 MHz CDCl3) δH 748 (d 2H J = 63 Hz ortho) 728 (m 3H

meta and para) 535 (q 1H J = 70 Hz CH) 176 (d 3H J = 66 Hz

CH3) 015 (s 3H SiCH3) 13C NMR (75 MHz CDCl3) δC 1498 (CSiMe3) 1392 (ipso) 1290 (meta) 1272

(para) 1251 (ortho) 1053 (C=CH3) 116 (C=CH3) 054 (OSiCH3)

HRMS (mz) Calculated [M ndash SiMe3]+ C9H10O = 1340735

Obtained = 1340732

1-phenyl-2-methyl-3-hydroxy-3-phenylpropane-1-one10 (415)

TLC Rf 046 (hexanesEtOAc 61) 1H NMR (300 MHz CD3OD) δH 798 (d 2H J = 80 Hz Ortho to ketone) 717

ndash 778 (m 8 H Aromatic H) 498 (d 1H J = 75 Hz CHOH) 386

(BrS 1H OH) 384 (dq 1H J = 75 75 75 and 75 Hz CHCH3)

105 (d 3H J = 75 Hz CH3) 13C NMR (75 MHz CD3OD) δC 2017 (carbonyl) 1437 (ArCCHOH) 1372

(ArCC=O) 13386 (para) 1294 ndash 1291 (4 x meta and 4 x ortho)

1285 (para) 774 (CHOH) 487 (CHCH3) 163 (CHCH3)

Obtained = 2250946

648 General procedure for carbocation formation

Stock solutions of retinyl acetate (001 M and 0001 Mdepending on the acid bieng

used) Al(OTf)3 (001 M) and TfOH (0001 M) in DCM were prepared 15 mL of the

retinyl acetate solution were then added to the quartz cuvette and 15 mL of the acid

were added to the retinyl acetate mixture The UvVis spectra of the mixtures were

recorded The UVVis scans were run over a period of time to ensure that the whole

life-span of the carbocation was recorded

When experiments required the use of DTBMP a stock solution of the base was made

up (3 molar equivalents per acid added) 1 mL of retinyl acetate was added to the

cuvette followed by the addition of the 1 mL of the base and then 1 mL of the acid

solution The UVVis spectra were recorded

Trifluoro-methanesulfonate-3-butlyl-1-methyl-3H-imidazol-1-ium

649 Synthesis for [bmim][OTf]

The ionic liquid was prepared in the following way 1-chlorobutane and N-

methylimidazole were heated at 80 degC for 48 hours The resultant ionic liquid was

then washed with ethyl acetate to remove any unreacted starting material (The ionic

liquid is immiscible with ethyl acetate) The immiscible solvent in the ionic liquid was

then removed under vacuum to yie1d 1-butyl-3-methylimidazolium chloride

([bmim][Cl]) an ionic liquid An excess of LiOTf (12 eq) was then added to this ionic

liquid of [bmim][Cl] in water and allowed to stir for 24 hours in order for an ion

exchange reaction to take place between the Cl- and the OTf- The mixture was

extracted with ethyl acetate and the residual solvent was removed under vacuum

Water and an excess of NaOTf was then added resulting in a biphasic system namely

the ionic liquid [bmim][OTf] and an aqueous solution of NaCl and excess NaOTf

After 12 hours the aqueous layer was separated from the ionic liquid which was then

dried under vacuum at 80 degC for 72 hours

IR νmax (ATR diamond crystal neat) 3115 2939 1574 1257 1166 cm-1 1H NMR (300 MHz C6D6) δH 887 (s 1H NHN) 762 (d 2H J = 222 Hz

CHCH) 418 (t 2H J = 70 Hz NCH2) 390 (s 3H NCH3) 182 ndash

177 (m 2H NCH2CH2) 127 ndash 120 (m 2H CH2CH3) 081 (t 3H J

= 72 Hz CH2CH3) 13C NMR (75 MHz C6D6) δC 1371 (NCN) 1237 (NCHN) 1225 (NCHN) 494

(NCH3) 358 (NCH2) 320 (NCH2CH2) 192 (CH2CH3) 129

(CH2CH3)

HRMS (mz) Calculated [M]+ C9H15F3N2O3S = 2880755

Obtained = 2880755

6410 Crystal data

26-Di-tert-butyl-4-methyl-pyridinium (417)

Mr = 42544 F000 = 884

Orthorhombic Pna21 Mo Kα radiation

λ = 071073 Aring

V = 17580 (2) Aring3 T = 296 (2) K

Data collection

CCD area detector

diffractometer 4104 independent reflections

Radiation source fine-focus sealed tube 2957 reflections with I gt 2σ(I)

Monochromator graphite Rint = 0052

T = 296(2) K θmax = 280deg

phi and ω scans θmin = 18deg

Absorption correction none 14028 measured reflections

Refinement

Refinement on F2 Secondary atom site location difference

Fourier map

Least-squares matrix full Hydrogen site location inferred from

neighbouring sites

R[F2 gt 2σ(F2)] = 0048 H atoms treated by a mixture of

independent and constrained refinement

wR(F2) = 0137 w = 1[σ2(Fo

2) + (00834P)2]

where P = (Fo2 + 2Fc

S = 098 (Δσ)max = 2220

4104 reflections Δρmax = 025 e Aringminus3

215 parameters Δρmin = minus058 e Aringminus3

1 restraint Extinction correction none

Primary atom site location structure-

invariant direct methods

Absolute structure Flack H D (1983)

Acta Cryst A39 876-881

Flack parameter 045 (16)

14-Dimethyl-2-(1-phenyl-vinyl)-benzene (420)

6411 General procedure for Friedel Crafts alkenylation reactions

Nitromethane (200 uL) was added to a mixture of p-xylene (4 mL) phenylacetylene

(10 mmol 100 uL) and metal triflate (020 mmol) The mixture was stirred under a

nitrogen atmosphere at 85 degC for 24 hours The reaction was quenched by passing the

reaction mixture through a plug of neutral alumina to remove the metal triflate after

which the volatiles were removed under reduced pressure to yield the pure product

IR νmax (ATR diamond crystal neat) 1487 1565 1578 1048 915 cm-1 1H NMR (300 MHz CD3OD) δH 730 ndash 710 (m 5H H9H10H11 H12 H13)

706 (s 1H H2) 706 (d 2H J = 18 H4 H5) 577 (d 1H J = 15 Hz

CH2A) 520 (d 1H J = 15 Hz CH2B) 235 (s 3H CH3(16)) 203 (s

3H CH3(15)) 13C NMR (75 MHz CD3OD) δC 1496 (C7) 1415 (C1) 1407 (C8) 1350 (C3)

1330 (C6) 1307 (C5) 1300 (C6) 1283 (C10 and C12) 1282 (C11)

1275 (C2) 1265 (C9 and C13) 1146 (C14) 210 (C16) 196 (C15)

HRMS (mz) Calculated [M]+ C16H16 = 2081252

Obtained = 2081240

Chapter 5

6412 Ranking of Lewis acids using NMR spectroscopy

Samples for NMR spectra recorded in deuterated DCM were prepared by adding

crotonaldehyde (01 mmol) to a mixture of CD2Cl2 (08 mL) and the Lewis acid (012

mmol) The mixtures were stirred at 30 degC for 30 minutes and spectra were recorded

at 25 degC

Spectra of samples dissolved in ionic liquid were recorded using a 10 mm NMR tube

with a coaxial insert filled with C6D6 in order to obtain a deuterium lock on the NMR

spectrometer The Lewis acids (012 mmol) were carefully weighed out and

bmim[OTf] (30 mL) was added To this trans-cinnamaldehyde (01 mmol) was added

and the mixture was stirred at 30 degC for 30 minutes The spectra were recorded at 25

Samples for 31P NMR spectra recorded in deuterated DCM were prepared by adding

the phosphorous compound (01 mmol) to a mixture of CD2Cl2 (08 mL) and the

Lewis acid (012 mmol) The mixtures were stirred at 30 degC for 30 minutes and

spectra were recorded at 25 degC

6413 Determination of equilibrium constants

NMR spectroscopy

The samples for NMR spectra recorded for the determination of equilibrium constants

were prepared in the same way as above The ratio of Lewis acid to crotonaldehyde

differed according to the desired outcome

Ratio Metal Triflate Crotonaldehyde

11 01 mmol 01 mmol

12 01 mmol 02 mmol

14 01 mmol 04 mmol

18 01 mmol 08 mmol

UVVis spectroscopy - A typical procedure

A dilute solution (10-5 M) of 4-methyl-3-nitroaniline was prepared in DCM Solutions

of the metal triflates of equal molarity were also prepared 15 mL of the 4-methyl-3-

nitroaniline solution was added to the cuvette The UVVis scan of the uncomplexed

base was recorded The acid solution (15 mL) was then added to the basic solution

and the UVVis scan of the complex was recorded

6414 Ranking of Lewis acids by Infrared Spectroscopy (IR)

Pyridine (028 mmol 03 mL) was added to a mixture of bmim[OTf] (03 mL) and the

Lewis acid (033 mmol) The mixture was stirred at 30 degC until the Lewis acid had

dissolved Infrared spectra were taken of the complexes using KBr pellets The

spectrum of bmim[OTf] was subtracted as the background before the initial

measurement IR spectra using the other probes were carried out in the same way

65 References

1 Tateiwa J Horiuchi H Uemura S J Org Chem 1995 60 4039

2 Du Y Tian F Synth Chem 2005 35 2703

3 Wiles C Watts P Haswell S J Tetrahedron 2005 61 5209

4 Gpinath R Haque S J Patel B K J Org Chem 2002 67 5842

5 Fujioka H Okitsu T Sawama Y Murata N Li R Kita Y J Am

Chem Soc 2006 128 5930

6 Ikawa T Hattori K Sajiki S Hirota S Tetrahedron 2004 60 6901

7 Kumar G D K Baskaran S J Org Chem 2005 70 4520

8 Goujon J Y Zammattio F Chetien J M Beaudet I Tetrahedron 2004

60 4037

9 Rorabacher D B Anal Chem 1991 63 139

10 Raju M Wenkert E J Org Chem 1980 45 1081

Raw data for tetrahydrofuran (THF) measurements THF from the bottle E ndash lab direct limited HPLC Grade

Reading Sample weight (g)Residual water content (ppm)

1 2765 CL 95

2 2874 1015 3 2874 1025 4 2749 1018 5 2868 1019 6 2761 1013

Average 2815 1018

THF dried over sodium

Reading Sample weight (g) Residual water content (ppm)

1 2933 1171 2 2780 1189 3 2806 1132 4 2951 1071 5 2867 1116 6 2838 1161

Average 2863 1140

1 2638 441 2 2656 435 3 2648 441 4 2675 449 5 2639 431 6 2641 446

Average 2650 440

1 2673 432 2 2702 422 3 2698 421 4 2657 434 5 2712 420 6 2668 436

Average 2685 428

THF from 3Aring molecular sieves (Sigma-Aldrich) 10 loading (wv) 24 hrs

1 2840 276 2 2795 290 3 2917 291 4 2647 272 5 2730 267 6 2762 271

Average 2782 278

THF dried over silica ‐ Grade ‐ 12 pore size ‐ 22Aring mesh 28‐200

1 3000 593 2 2906 572 3 2860 560 4 2880 520 5 2853 578 6 2800 550

Average 2883 562

THF dried over silica (Merck)‐ pore size ‐ 60Aring mesh 70‐230

1 2973 807 2 2960 CL 95

3 2965 824 4 3005 824 5 2993 837 6 2987 834

Average 2981 825

THF dried over silica ‐ Grade ‐636 pore size ‐ 60Aring mesh 35‐60

1 2900 1066 2 2942 1057 3 2735 1097 4 2902 1009 5 2854 1025 6 2894 1090

Average 2871 1057

1 2981 909 2 2821 896 3 2921 864 4 2922 866 5 2932 939 6 2848 889

Average 2904 894

1 2857 742 2 2889 763 3 2806 747 4 2838 712 5 2821 774 6 3027 739

Average 2873 746

1 2952 618 2 2959 597 3 2888 649 4 2933 598 5 2860 550 6 2987 560

Average 2930 595

1 2937 730 2 2872 716 3 2920 688 4 2903 646 5 2915 659 6 2933 702

Average 2913 690

1 2939 606 2 2953 624 3 2975 630 4 2967 613 5 2825 575 6 2901 603

Average 2927 608 THF from 3Aring molecular sieves (Sigma-Aldrich) 20 loading (wv) 24 hrs

1 3112 156 2 2998 151 3 3100 149 4 2976 153 5 2987 148 6 3001 153

1 3101 145 2 2964 143 3 2899 142 4 3112 CL 95

5 3103 143 6 2981 142

Average 3027 143

1 2899 146 2 2976 140 3 2988 147 4 2978 143 5 3100 149 6 3102 149

Average 3007 146

1 3004 59 2 2987 57 3 3003 58 4 3067 57 5 3076 61 6 3064 62

Average 3034 59

1 3044 61 2 2988 59 3 3000 58 4 2991 62 5 2989 62 6 2988 57

Average 3000 60

1 3014 63 2 2994 64 3 2983 61 4 2997 63 5 2996 62 6 3004 62

1 2864 43 2 2990 43 3 2999 44 4 2988 CL 95

5 3009 44 6 2968 43

Average 2970 43

1 3074 41 2 2998 41 3 2995 42 4 3031 45 5 3006 43 6 2994 40

Average 3016 42

1 3014 39 2 2918 38 3 2990 37 4 3011 37 5 3029 39 6 2948 39

Average 2985 38

THF from neutral alumina (Sigma-Aldrich) 10 loading (wv)

1 3004 55 2 3100 56 3 2713 54 4 2985 57 5 3005 56 6 3001 55

Average 2968 56

1 2934 49 2 2991 48 3 2997 48 4 2990 47 5 3010 CL 95

6 3084 46 Average 3001 48

1 2948 54 2 2789 53 3 2994 54 4 2783 55 5 2956 53 6 2973 56

Average 2907 54 Raw data for acetonitrile measurements Acetonitrile from the bottle Sigma Aldrich HPLC Grade

1 2568 1427 2 2371 1436 3 2666 1426 4 2559 1407 5 2598 1418 6 2554 1407

Average 2553 1420

Acetonitrile from 3Aring molecular sieves (Sigma-Aldrich) 5 loading (wv) 24 hrs

1 2646 45 2 2634 45 3 2574 38 4 2631 46 5 2645 40 6 2638 29

Average 2628 40

1 2604 19 2 2645 16 3 2673 26 4 2536 20 5 2645 13 6 2655 12

Average 2626 18

1 2654 mdasha 2 2674 mdasha 3 2658 mdasha 4 2643 mdasha 5 2644 mdasha 6 2675 mdasha

Average 2661 a Below detection limits of Karl Fisher

1 2652 12 2 2584 01 3 2652 02 4 2653 07 5 2657 02 6 2660 04

Average 2643 05

Acetonitrile from 3Aring molecular sieves (Sigma-Aldrich) 10 loading (wv)48 hrs

Acetonitrile dried from neutral alumina (Sigma-Aldrich) 10 loading (wv)

1 2963 69 2 2991 66 3 2953 58 4 2960 64 5 2965 56 6 2964 54

Average 2966 61

1 2913 CL = 95

2 2951 49 3 2923 51 4 2940 49 5 2925 50 6 2894 47

Average 2924 49

1 2943 67 2 2911 65 3 2863 73 4 2440 69 5 2895 64 6 2904 72

Average 2826 68 Raw data for methanol measurements Methanol from the bottle ACE (associated chemical enterprises) AR grade

1 2563 1748 2 2576 1746 3 2603 1757 4 2590 1749 5 2594 1754 6 2613 1755

Average 2590 1751

Methanol from 3Aring molecular sieves (Sigma-Aldrich) 5 loading (wv) 24 hrs

1 2689 758 2 2625 740 3 2664 751 4 2674 CL 95

5 2678 761 6 2702 756

Average 2672 753

1 2643 794 2 2598 786 3 2586 787 4 2633 798 5 2644 779 6 2635 792

Average 2621 789

1 2584 779 2 2552 768 3 2621 774 4 2556 781 5 2529 CL 95

6 2497 785 Average 2557 777

1 2703 417 2 2671 394 3 2712 409 4 2654 412 5 2648 398 6 2739 414

Average 2688 407

1 2568 398 2 2633 387 3 2574 397 4 2632 CL 95

5 2695 396 6 2613 386

Average 2619 393

1 2598 420 2 2648 418 3 2653 417 4 2589 424 5 2655 421 6 2599 412

Average 2624 419

1 2589 288 2 2498 273 3 2534 279 4 2477 284 5 2490 CL 95

6 2465 274 Average 2509 279

1 2541 292 2 2653 289 3 2666 287 4 2579 294 5 2534 299 6 2683 291

Average 2609 292

1 2695 293 2 2653 291 3 2648 288 4 2589 290 5 2648 293 6 2568 285

Average 2634 290

1 2529 462 2 2428 447 3 2484 451 4 2437 453 5 2590 448 6 2459 449

Average 2488 452

1 2491 493 2 2623 486 3 2626 489 4 2489 482 5 2564 495 6 2633 489

Average 2571 489

1 2615 463 2 2613 459 3 2608 470 4 2619 474 5 2558 467 6 2658 451

Average 2612 464

1 2575 275 2 2573 266 3 2640 268 4 2530 278 5 2458 264 6 2590 259

Average 2561 268

1 2530 283 2 2528 294 3 2530 285 4 2447 301 5 2550 CL 95

6 2463 298 Average 2508 292

1 2451 313 2 2500 324 3 2506 324 4 2519 334 5 2504 329 6 2533 312

Average 2502 323

1 2549 203 2 2428 211 3 2514 213 4 2437 216 5 2627 209 6 2419 213

Average 2496 211 Methanol from 3Aring molecular sieves (Sigma-Aldrich) 20 loading (wv) 48 hrs

1 2675 243 2 2423 236 3 2608 243 4 2630 234 5 2671 238 6 2620 241

1 2560 256 2 2508 247 3 2570 234 4 2457 246 5 2650 249 6 2593 234

Average 2556 244

1 2615 324 2 2613 327 3 2608 332 4 2619 335 5 2558 326 6 2658 330

Average 2612 329

1 2529 339 2 2428 342 3 2484 347 4 2437 337 5 2590 346 6 2459 345

Average 2488 343

1 2615 349 2 2613 358 3 2608 356 4 2619 CL 95

5 2558 359 6 2658 354

Average 2612 355

Methanol from 3Aring molecular sieves (Sigma-Aldrich) 10 loading (wv)72 hrs

1 2655 221 2 2550 232 3 2608 225 4 2618 224 5 2614 221 6 2626 222

Average 2612 224 Methanol from 3Aring molecular sieves (Sigma-Aldrich) 10 loading (wv)72 hrs

1 2645 CL 95

2 2633 236 3 2540 245 4 2540 246 5 2538 224 6 2658 231

1 2479 257 2 2428 264 3 2474 267 4 2537 254 5 2640 271 6 2471 263

Average 2505 263

1 2590 174 2 2570 180 3 2658 CL 95

4 2519 169 5 2598 183 6 2610 173

Average 2591 176

1 2539 184 2 2628 193 3 2464 191 4 2447 CL 95

5 2540 195 6 2629 183

Average 2541 189

1 2651 205 2 2450 211 3 2668 204 4 2678 224 5 2684 205 6 2526 221

Average 2610 212

Methanol from 3Aring molecular sieves (Sigma-Aldrich) 5 loading (wv) 5 days

1 2539 253 2 2628 243 3 2534 262 4 2417 274 5 2560 264 6 2459 243

Average 2523 257

1 2675 269 2 2560 274 3 2517 243 4 2606 273 5 2526 CL 95

6 2622 261 Average 2584 264

1 2460 274 2 2410 264 3 2584 289 4 2447 271 5 2580 264 6 2489 273

Average 2495 273

1 2574 167 2 2613 159 3 2588 173 4 2569 160 5 2608 164 6 2579 171

Average 2589 166

1 2489 189 2 2588 173 3 2524 183 4 2697 CL 95

5 2578 179 6 2559 183

Average 2573 181

1 2570 193 2 2590 187 3 2628 183 4 2620 194 5 2588 206 6 2638 229

Average 2606 199

1 2420 115 2 2590 96 3 2640 95 4 2669 89 5 2638 101 6 2490 88

Average 2575 97

1 2559 103 2 2478 107 3 2624 99 4 2497 111 5 2620 CL 95

6 2471 98 Average 2542 104

1 2641 124 2 2540 127 3 2596 104 4 2602 118 5 2606 99 6 2634 115

Average 2603 115

Methanol from pulverized KOH

1 2569 305 2 2548 312 3 2489 325 4 2548 316 5 2450 324 6 2548 324

Average 2525 318

1 2459 354 2 2657 334 3 2658 341 4 2549 342 5 2459 324 6 2548 341

Average 2555 339

1 2658 331 2 2642 324 3 2548 335 4 2548 342 5 2658 339 6 2549 351

Average 2600 337

Methanol from MgI2

1 2660 545 2 2385 537 3 2693 540 4 2683 531 5 2531 530 6 2667 533

Average 2603 536 Raw data for ethanol measurements Ethanol from the bottle ACE (associated chemical enterprises) 100

1 2650 14291 2 2537 14327 3 2618 14306 4 2653 14218 5 2673 14263 6 2598 14292

Average 2622 14283

Ethanol from 3Aring molecular sieves (Sigma-Aldrich) 5 loading (wv) 24 hrs

1 2701 2516 2 2694 2486 3 2698 2508 4 2704 2496 5 2699 2523 6 2700 2536

Average 2699 2511

1 2655 2676 2 2596 2715 3 2626 2705 4 2572 2691 5 2684 CL 95

6 2691 2720 Average 2637 2701

1 2658 2651 2 2645 2671 3 2632 2644 4 2651 2712 5 2671 2656 6 2713 2652

Average 2662 2664

1 2661 CL 95

2 2664 1882 3 2678 1887 4 2674 1892 5 2659 1891 6 2670 1887

Average 2668 1888

1 2665 1804 2 2650 1793 3 2638 1795 4 2659 1781 5 2675 1785 6 2709 1793

Average 2666 1792

1 2653 1904 2 2592 1899 3 2629 1895 4 2576 1889 5 2687 1896 6 2693 1895

Average 2638 1896

1 2651 1183 2 2689 1185 3 2628 1191 4 2581 1195 5 2685 CL 95

6 2597 1184 Average 2639 1188

1 2647 1206 2 2591 1193 3 2629 1196 4 2579 1189 5 2695 CL 95

6 2705 1184 Average 2641 1194

1 2661 1214 2 2647 1216 3 2539 1220 4 2657 1221 5 2672 1215 6 2604 1223

Average 2630 1218

Ethanol from 3Aring molecular sieves (Sigma-Aldrich) 5l oading (wv) 48 hrs

1 2643 CL 95

2 2692 1020 3 2639 1018 4 2586 1016 5 2693 1024 6 2633 1014

Average 2648 1018

1 2695 1065 2 2650 1076 3 2643 1065 4 2659 1054 5 2575 1059 6 2609 1063

Average 2639 1064 Ethanol from 3Aring molecular sieves (Sigma-Aldrich) 5l oading (wv) 48 hrs

1 2651 1107 2 2724 1106 3 2668 1113 4 2634 1111 5 2509 1119 6 2610 1104

Average 2633 1110

Ethanol from 3Aring molecular sieves (Sigma-Aldrich) 10 loading (wv) 48hrs

1 2541 672 2 2667 678 3 2648 679 4 2694 682 5 2649 685 6 2669 673

Average 2645 678

1 2666 694 2 2525 696 3 2636 689 4 2653 CL 95

5 2701 687 6 2643 703

Average 2637 694 Ethanol from 3Aring molecular sieves (Sigma-Aldrich) 10 loading (wv) 48hrs

1 2652 710 2 2591 717 3 2633 703 4 2579 719 5 2693 709 6 2693 713

Average 2640 712

1 2671 242 2 2644 229 3 2622 227 4 2654 231 5 2659 220 6 2610 237

Average 2643 231

1 2681 245 2 2634 249 3 2618 246 4 2634 236 5 2629 247 6 2640 237

Average 2639 243 Ethanol from 3Aring molecular sieves (Sigma-Aldrich) 20 loading (wv) 48 hrs

1 2666 267 2 2649 270 3 2636 281 4 2659 279 5 2680 276 6 2708 289

1 2661 532 2 2652 558 3 2634 553 4 2657 556 5 2680 548 6 2702 549

Average 2664 549

1 2646 541 2 2595 539 3 2632 537 4 2577 546 5 2690 548 6 2694 532

Average 2639 541

1 2652 569 2 2627 577 3 2666 574 4 2648 549 5 2609 CL 95

6 2630 549 Average 2639 564

1 2651 367 2 2592 339 3 2635 342 4 2586 346 5 2690 CL 95

6 2699 357 Average 2642 350

1 2647 368 2 2600 365 3 2639 352 4 2574 350 5 2689 362 6 2593 356

1 2663 387 2 2653 395 3 2538 397 4 2658 402 5 2585 417 6 2599 384

1 2649 190 2 2522 189 3 2634 187 4 2526 192 5 2683 194 6 2611 187

Average 2604 190

1 2655 189 2 2550 196 3 2608 197 4 2618 185 5 2614 196 6 2626 CL 95

Average 2612 193

1 2648 224 2 2556 226 3 2663 240 4 2524 231 5 2643 236 6 2612 229

Average 2608 231

Ethanol from 3Aring molecular sieves (Sigma-Aldrich) 5 loading (wv) 5 days

1 2569 139 2 2668 138 3 2584 144 4 2637 152 5 2690 146 6 2659 142

Average 2635 144

1 2591 133 2 2623 142 3 2726 146 4 2589 140 5 2664 139 6 2593 146

Average 2631 141

1 2641 148 2 2643 151 3 2706 147 4 2649 150 5 2704 149 6 2613 148

Average 2659 149

1 2529 120 2 2618 128 3 2614 119 4 2607 113 5 2660 103 6 2639 CL 95

Average 2611 117

1 2631 136 2 2663 125 3 2716 125 4 2609 139 5 2744 120 6 2583 135

Average 2658 130

1 2581 134 2 2653 131 3 2676 124 4 2549 110 5 2714 128 6 2543 118

Average 2619 124

1 2687 75 2 2655 69 3 2680 68 4 2659 64 5 2615 70 6 2609 69

Average 2651 69

1 2496 81 2 2589 76 3 2620 80 4 2680 79 5 2677 85 6 2609 85

Average 2612 81 Ethanol from 3Aring molecular sieves (Sigma-Aldrich) 20 loading (wv) 5 days

1 2541 92 2 2593 95 3 2663 87 4 2527 CL 95

5 2648 94 6 2619 97

Average 2599 93

Ethanol from pulverized KOH

1 2875 257 2 2975 249 3 2896 258 4 2846 260 5 2758 272 6 2785 258

Average 2856 259

1 2587 278 2 2846 291 3 2874 286 4 2795 CL 95

5 2876 279 6 2579 284

Average 2760 284

1 2579 251 2 2858 254 3 2548 254 4 2479 252 5 2797 249 6 2579 239

Average 2640 250 Raw data for dichloromethane (DCM) measurements DCM from the bottle (Sigma Aldrich AR Grade)

1 4167 263 2 4146 230 3 4154 222 4 4079 205 5 3923 226 6 4151 237

Average 4103 231

DCM from 3Aring molecular sieves (Sigma-Aldrich) 10 loading (wv) 24 hrs

1 4393 01 2 4172 02 3 4405 02 4 4183 00 5 4285 01 6 4168 02

Average 4268 01 DCM dried over silica ‐ Grade ‐ 12 pore size ‐ 22Aring mesh 28‐200

1 4198 15 2 4206 09 3 4149 09 4 4168 14 5 4286 15 6 4295 CL = 95

Average 4217 13

DCM dried over CaH2

1 4206 147 2 4357 121 3 3871 129 4 4215 114 5 4347 121 6 3927 140

Average 4154 129

CL = 95 indicates outlier has been removed confidence level 95

Apsects of this work have been published Journal publications

4 Williams D B G Lawton M C Green Chem Metal triflates On the Question

of Lewis versus Broslashnsted acidity Submitted

Conference proceedings

Oral Presentations at the following conferences

bull CATSA Richards bay (Nov 2007)

bull CATSA JHB (Nov 2005)

Poster Presentations at the following conferences

bull ISHC Florence Italy (July 2008)

bull ICOMC Rennes France (July 2008)

bull Frank Warren conference (Jan 2006)

bull SACI conference on organometallic chemistry and homogeneous catalysis (June

2005) (Poster won 1st prize)

Front page



Faculty of Science



June 2009

Table of Contents

Synopsis

Abbreviations

Figures and schemes

Chapter 1

Chapter 2

Chapter 3_12099

Chapter 4

Chapter 5


Chapter 6

Appendix A

Apsects of this work have been published

Contents

Synopsis i ndash ii

Abbreviations iii ndash v

List of figures and tables vi ndash xix

11 The history of the acid-base theory 1 ndash 6

12 Lewis acids in catalysis ndash a focus on metal triflates 6 ndash 44

13 The ranking of Lewis acids - introduction 44 ndash 45

131 Thermodynamic measurements 45 ndash 51

132 Spectroscopic measurements 51 ndash 56

133 Comparative studies 57 ndash 64

14 Lewis acids in aqueous media 64 ndash 75

Chapter 2

21 Introduction 83

22 Acetal formation using aluminium triflate 84 ndash 91

23 Catalyst recycling 91 ndash 92

24 Deprotections 92 ndash 97

25 Other protecting groups 97 ndash 99

26 Other metal triflates 99 ndash 100

27 Tetrahydropyranyl ethers (THP) 100 ndash 104

28 Two protection groups 104 ndash 106

29 Conclusions 107

Chapter 3

(THF) 128 ndash 134

39 Discussion 134

311 References 136

Chapter 4

138 ndash 145

reaction

152 ndash 158

solvents

159 ndash 162

crystallography

176 ndash 177

Chapter 5

51 Introduction 186

54 Conclusions 207

55 References 208

Chapter 6

alcohols

65 References 242

observed

solvents

Abbreviations

Aring angstrom

Bn benzyl

Bu butyl

C coulomb

CL confidence level

CPL ε-caprolactone

Cy cyclohexyl

d doublet

DCM dichloromethane

DHP dihydropyran

DL detection limit

Eq equivalents

EtOH ethanol

Et3N triethylamine

h hour

IR infrared

i-Pr iso-propyl

mp melting point

MeOH methanol

Me methyl

OAc acetate

PDI polydispersity

Ph phenyl

q quartet

rt room temperature

s singlet

t triplet

t-Bu tert-butyl

TES triethylsilyl

THF tetrahydrofuran

THP tetrahydropyran

TMS trimethylsilyl

thesis)

VL valerolactone

wrt with respect to

Scheme

Figure Heading Page

alcohols 29

by Bi(OTf)3 41

Figure 110

values 61

formaldehyde 65

Scheme 130

by InCl3 69

and urea 73

Scheme

Figure Heading Page

bromophenol 98

Scheme

Figure Heading Page

over time 122

over time 124

Scheme

Figure Heading Page

by water 153

organic solvent 161

nucleophile 164

Figure 49

of the solutions

Figure 412

counterion 176

Scheme

Figure Heading Page

triflate 195

to Lewis acid 201

List of tables

Table Heading Page

Table 13

different additives

with In(OTf)3 25

Table 117

Ga(OTf)3

bases at 28 degC 54

one 57

(9-fluorenone) 62

Ln(OTf)3 65

aldehydes 70

Table 139

Table Heading Page

ketones 85

ketones 86

ketones 90

the substrate 92

metal triflates 94

Al(OTf)3 102

triflates 105

Table Heading Page

standard 115

SilicaSodium 118

Table 315

alumina

Table Heading Page

mixture 150

solvents 161

DTBMP 164

without DTBMP 164

carbocation 167

pyridine 178

Table Heading Page

Table 51

Table 52

Table 53

Chapter 1

Introduction

system theories5

a proton acceptor

equation 3

ψ ψ ψAB = a 0 (AB) + b 1 (A-B+) (3)

ψ1 (A-B

β 01 EoSo1( )_ 2

E1_ Eo( )

EAB = Eo_

equation 5)

Σ ΣΔΕ β_ qsqt

Conclusions

reaction mixtures

amounts

(see Chapter 4)

OAcMeOOC O

OMeOOC

BnO OAc

O(OTf)3M

Lanthanide Reaction

Yb(OTf)3 180 70

Eu(OTf)3 90 85

Sm(OTf)3 90 92

AcOAcOAcO

AcOAcO

AcO COOMe

OAc Nd(OTf)3

MeOH rt 4 h

Nd(OTf)3

MeOH rt 4 h

AcOAcO

AcO COOMe

metal triflates

Starting

material Product

Yb(OTf)3a

Yield ()

Eu(OTf)3a

Yield ()

Sm(OTf)3a

Yield ()

Nd(OTf)3a

Yield ()

AcOAcAcOAcOAcO H

OAcOAcO

85 81 85 81

OAcAcOAcO

AcO CH2OAc

AcOAcO

AcO CH2OAc

68 78 82 82

OAcAcOAcOcO

CH2OAc

AcOAcOAcO

CH2OAc

61 62 79 81

HAcOAcOAcO

CH2OAc

AcOAcOAcO

CH2OAc

67 62 67 68

OIn (10 eq)

THFH2O 40 oC 20h

+ TIPS CF2

215 16 17 18

1 H2OTHF (41) 11 - 206

2 H2OTHF (41) 11 - 3112

3 H2OTHF (41) 11 - 257

4 Satd NH4Cl(aq)THF (41) 11 - 204

7 H2OTHF (41) 22 - 298

8 H2OTHF (41) 33 - 364

9 H2OTHF (41) 11 Sc(OTf)3 424

10 H2OTHF (41) 11 Er(OTf)3 647

11 H2OTHF (41) 11 Eu(OTf)3 788

12 H2OTHF (41) 11 Tb(OTf)3 7610

13 H2OTHF (41) 11 Sm(OTf)3 489

14 H2OTHF (41) 11 Y(OTf)3 4713

BrF + R

H2OTHF (41) 40 oC 20h

1 TIPS Ph 68

2 TES Ph 72

3 TMSb Ph 41

(18 scheme 14)

In (reducing agent)

examples

OHHO CO2Me

+Lewis acid

CH2Cl2 or CH3NO2

HO CO2Me

naphthyl)ethanol

(2-naphthyl)ethanol

mol Time h Yield ()

1a TiCl4 100 1 6

2a BF3OEt2 100 1 96

3a BF3OEt2 10 1 6

4b La(OTf)3 1 05 99

5b La(OTf)3 01 1 98

6b La(OTf)3 001 24 93

7b La(OTf)3 1 15c 98

8b Yb(OTf)3 1 033 96

OHHO CO2R

+1 mol La(OTf)3

HO CO2R

R25 26 27

CH3NO2

alcohols

1 H Me 15 min 99

2 OSiR3a Me 2 h 93

3 OAc Me 6 h 95

4 OBn Me 14 h 97

1 H Me Hf 5 min 89

3 H Me Sc 15 min 99

4 H Me Yb 25 min 99

5 H Bn La 25 h 99

6 H t-Bu La 19 h 59

a TfOH 3 mol

Nucleophile

Olefin

Triflate

H2OOHAr

Triflate Ar O Ar

Products

Ar = Ph

Ar = 2-naphthyl

process5758

2 mol M(OTf)x

toluene 25 oCO

of n-BnOH

Mol Time (h)

1 CPL 0 4 gt99 6900

2 CPL 2 23 gt99 3500

3 CPL 5 2 gt99 2400

4 CPL 10 2 gt99 1600

5 VL 0 15 96 4300

6 VL 2 1 95 2900

7 VL 5 1 97 1900

1 Sc [BF4]- 2 d 0 -

2 Y [BF4]- 7 d 29 500

3 La [BF4]- 2 d 29 300

4 Ceb [BF4]- 6 d 32 600

5 Nd [BF4]- 6 d 30 500

6 Eu [BF4]- 2 d 0 -

7 Gd [BF4]- 5 d 30 600

8 Yb [BF4]- 4 d 27 500

9 Lu [BF4]- 3 d 26 500

10 Sc [PF6]- 42 80 2500

11 Y [PF6]- 53 83 2800

12 La [PF6]- 46 100 3700

13 Ceb [PF6]- 47 100 3500

14 Nd [PF6]- 35 100 2700

15 Eu [PF6]- 49 100 2400

16 Gd [PF6]- 48 100 3400

17 Yb [PF6]- 48 43 1600

18 Lu [PF6]- 47 100 4400

19 Sc [SbF6]- 30 87 900

20 Y [SbF6]- 48 99 1800

21 La [SbF6]- 42 100 1800

22 Ceb [SbF6]- 29 100 1700

23 Nd [SbF6]- 43 100 1700

24 Eu [SbF6]- 48 4 1500

25 Gd [SbF6]- 29 100 2500

26 Yb [SbF6]- 48 82 1400

Sc(OTf)3

O(TfO)3Sc

OSc(OTf)3

Sc(OTf)3

Propagation

monomer mechanism

R NH2+

001 molYb(OTf)3

yields

Indium triflate

AcOAcO

OHHOHO

OAcAcOAcO

OHHOHO

OAcAcOAcO

AcOH3C

OH HO O

OAcOAc

OAc AcO 97

OAcAcOAcO

OHHOHO

OAcAcOAcO

OHHOHO

OHAcHNHO

OAcAcHNAcO

ether and THF

O+ SnBu2

2 H3C OH

Ph10 mol M(OTf)3

Solvent rt 12h

respectively

diallyldibuyltin

a Isolated yields

O+ SnBu2

2 R2 OH

R110 mol M(OTf)3

Entry R1 R2 Yield

1 Ph CH3 95

2 p-FC6H4 CH3 81

3 p-ClC6H4 CH3 75

4 p-BrC6H4 CH3 86

5 p-NO2C6H4 CH3 66

6 m-BrC6H4 CH3 93

7 m-CF3C6H4 CH3 90

8 p-MeC6H4 CH3 58

9 p-NH2C6H5 CH3 -

10 Ph Ph 42

14 CH2CH2CH3 CH3 45

15 CH2CH(CH3)2 CH3 27

16 p-MeOC6H4 H 80

a Isolated yields

In(OTf)3

O(TfO)2In

SnBu2OTf

OBu2Sn

Aluminium triflate

aluminium triflate

Al(OTf)3

NOAl(OTf)3

Yield ()

2 N OH

(CH2Cl)2

82 (11)

Al(OTf)338

various alcohols

Entry Product

1 39 R = Me 0 1 8 94

2 39 R = Et 94 95 -a -a

3 39 R = nPr 93 97 92 (4)b -a

4 39 R= iPr 91 92 -a -a

5 39 R = 2-Bu -a 14 97 96 (4)b

6 39 R = tBu -a 77 77 -a

-a 41 (34)b -a -a

-a 31 (24)b -a -a

-a 55 88 -a

-a 21 42 62

-a -a 89 -a

OCH2CH3

OHOCH2CH2CH3

OHOCH(CH3)2

OHOCH2CH2CH2CH3

EtOHAl(OTf)3 R

position

(Table 115)

aminesa

Product Yield ()

Al(OTf)3

Yield ()

Al(OTf)3

Yield ()

10 mol

Al(OTf)3

48 75b -

45 80b -

14 - 43c

31 (31)cd

- 35 (34)cd

regioisomer

Product Yield ()

Al(OTf)3

Yield ()

Al(OTf)3 OH

Gallium triflate

O O5 mol Ga(OTf)3

solvent

Ga(OTf)3

Entry Product Time

5 gt99

360 90

10 gt99

O 10 gt99

240 90

OO 10 98

(OTf)3Ga

Ga(OTf)3

H2N NH2

(OTf)3Ga

+ NH4OAcNH

NHCatalyst

ammonium acetate

NH4OAc or R3NH2 N

NCatalyst

R2CHOR1 R3

Ga(OTf)3

Entry R1 R2

NH4OAc

1 H p-(CH3)C6H4 NH4OAc 50 86

2 H 24-(OCH3)2C6H3 NH4OAc 45 90

3 H p-(N(CH3)2)C6H4 NH4OAc 35 88

5 H m-(F)C6H4 NH4OAc 50 85

7 H o-(NO2)C6H4 NH4OAc 70 71

8 H p-(NO2)C6H4 NH4OAc 60 73

13 Cl p-(F)C6H4 NH4OAc 55 83

15 H p-(OH)C6H4 sBuNH2 55 83

16 H p-(Cl)C6H4 nBuNH2 50 89

17 H p-(NO2)C6H4 nPrNH2 50 87

Entry R1 R2 Time

1 H p-(CH3)C6H4 50 84

2 H C6H4 55 83

3 H 24-(OCH3)2C6H3 50 89

4 H 34-(CH2O2)C6H3 55 84

5 H p-(N(CH3)2)C6H4 55 87

6 H p-(OH)C6H4 50 92

7 H m-(F)C6H4 55 84

8 H m-(Cl)C6H4 55 86

9 H p-(Cl)C6H4 55 89

10 H m-(NO2)C6H4 70 82

11 H p-(NO2)C6H4 65 81

12 H 2-Furyl 55 80

DMSO as a solvent

NH4OAc

CO2 NH2

RCHOGa(OTf)3

Ga(OTf)3

2 Ga(OTf)3N

48 49 50

51 52 53

(Ga(OTf)3)

Other triflates

RCN Cu(OTf)2

65 oC 30 min N

82 (91)c

NPh CH3

NPh Ph

(C6H4)Me-4

(C6H4)Me-4 PhCN N N

(C6H4)Me-4

CH3CN N N

(C6H4)Cl-4

PhCN N N

(C6H4)Cl-4

7 N Ts CH3CN N

Ts 62 (93)c

8 N Ts PhCN N

NTsC6Cl4H4

TsCu(OTf)2

Ts Cu(OTf)2Ph

NCu(OTf)2

55 56 57 58

Cs2CO3 DMF60 - 100

OH R3R4

R1 R1 R1R2R2R2

MeCN reflux

Cs2CO3 DMF74 - 95

MeCN reflux

by Bi(OTf)3

R2Y(OTf)3 5 mol

CH3CN rt

selectivity overall

good yields

AgOTfa

Isolated yields

Conclusions

Introduction

more complex

have to be found

comparative studies

be ICl gt I2 gt Br2

ketones

Δλ pK Δλ pK

GaBr3 66 -057 91 -061

GaCl3 63 -057 89 -051

ZnBr2 37 -052 48 -051

ZnCl2 39 -052 50 -039

BF3 59 +063 90 +251

Base rarr

Br2(g) - -144 +004 +0226 Cl2(g) - - +44 +165

Base rarr

-benzene

Naphalen

ICl 054 151 227 139 I2 015 031 135 025

Br2 011 023 - -

techniques

Order Method Ref

gtgt SiF4 ~ CrF3

ArH+MFn+1-

complex

Salt formation 100

spectroscopy

formation

the parameter

Ž = Z rk2 ndash 77Xz + 80 (8)

rk = ionic radius

bond strength)

IR spectroscopy

X in base

acetate

Δν (cm-1)

- ΔHf

(kcal mol-1)

F 119 317

Cl 176 395 (379)9

Br 191 445 (435)9

were solid samples

stoichiometry

BF3 156 1 1

PhSnCl3 150 1 1

ZnCl2 120 1 1

SnBr4 157 2 1

ZnBr2 118 2 1

SnCl4 158 2 1

GaCl3 157 1 1

BCl3 640 100 752 100 790 100

AlCl3 518 81 640 85 672 85

i-C4H9CCl2 500 78 511 68 536 68

BiCl3a 480 75 - - - -

TiCl4 - - 526 70 600 76

InCl3b 410 64 - - - -

BF3 391 61 458 61 498 63

SnCl4 - - 384 51 - -

SnBr4c 256 40 00 0 - 0

(i-C4H9)2BCl 252 40 00 0 00 -

AsCl3 110 11 - - - 0

SnI4 00 0 - - 00 0

SiCl4 00 0 00 0 00 0

GeCl4 00 0 00 0 00 0

PCl3 00 0 00 0 00 0

C5H9O3P C6H9O3P

Figure 17 Figure 18

crotonaldehydea

H1 H2 H3 H4 C1 C2 C3 C4

BBr3 011 093 149 051

BCl3 -065 085 135 049 68 -37 317 43

SbCl5 017 078 132 048 69 -40 276 37

AlCl3 -020 076 123 047

EtAlCl2bc -020 077 125 047

BF3 -027 074 117 044 83 -33 261 31

EtAlCl2bcd -017 067 115 038

Et3Al2Cl3b -015 069 114 039

TiCl4 003 060 103 036

Et2AlClbc -015 055 091 030 94 -20 201 23

SnC4 -002 050 087 029 78 -28 192 23

opposite direction

adducts

Acid ΔνC=O pK

BF3 156 -113

PhSnCl3 150 -114

ZnCl2 120 -148

SnBr4 157 -155

ZnBr2 118 -172

SnCl4 158 -266

GaCl3 157 lt-40

AsCl3 ca -

080 ca 63 ca 80 - - - -

SbCl3 -176 58 801 ca 74 - - -

BF3 -293 850 930 815 -186 72 ca 96

ZnBr2 -294 870 860 800 -217 148 890

ZnCl2 -294 870 558 802 -217 148 892

GaBr3 -340 2510 960 864 -249 310 1010

GaCl3 - - - - -253 340 1012

calculated

oxide as the base

acids125

acidity (Table 132)

Lewis acidity

that of Childs116

Conclusions

complex formation85

are being used

be addressed

reagents

OSiMe3Ln(OTf)3THF

CH2O aq Ph OH

Yield ()

100 mol 20 mol

1 La(OTf)3 90 23 88

2 Pr(OTf)3 92 40 80

3 Nd(OTf)3 74 6 89

4 Sm(OTf)3 92 51 91

5 Eu(OTf)3 92 28 93

6 Gd(OTf)3 92 20 79

7 Dy(OTf)3 89 20 85

8 Ho(OTf)3 91 38 86

9 Er(OTf)3 90 44 83

10 Yb(OTf)3 94 5 94

OSime3

THFH2O (41) rt 20h

NO3- and SO4

reactions136

PhCOH + Ph

OSiMe3

OH OMXn (02eq)

H2OTHF (91)rt 12 h

1 A 51 OSime3

2 B 74

3 C 79

5 HCOCH2OH H2O C 80

TBDMSO

BnO OO

TBDMSO

Sn InCl3

H2O rtR1

OH OH+

Isomer

(antisyn)b

7 C6H11CHO CO2Et

Br Sn InCl3 H2O (15 h) 65 6832

SnBrR InCl3H2O

R InCl2 +

InCl265 66 67

R InCl266

InCl2RH

reactions occur

Michael additions

+Yb(OTf)3

Yb(OTf)3

Other reactions

1 15 TfOH 7723 92

2 5 Bi(O2CCF3)3 7723 77

3 1 Bi(OTf)3 7228 94

4 5 Bi(OTf)3 8614 84

comparative reasons

H2N NH2

REtO2C

MeO CHOMeO

M(NTf2)norM(OTf)n

water rt 24 h

1 Ni(NTf2)2 59 65c 40d

3 Cu(NTf2)2 65 70c 62d

4 Cu(OTf)2 lt10b

5 Zn(NTf2)2 8

6 Yb(NTf2)3 88 90c

7 Yb(OTf)3 lt5b

4 Ni(NTf2)2 HCl 71

1 CH3CO2H (47) lt5

2 CF3CO2H (023) 56

3 HCl (-23) lt5

4 HNTf2 (12) 33

5 CH3SO2H (-12) lt5

15 Conclusions

16 References

Y 1929

1927 pp 60 and 116

Pa 1941

Easton Pa 1944

New York NY 1946

Mulliken papers)

London 1969

York 1973

Eur J 2008 14 3056

2003 68 9340

Sci 1999 71 1941

63 8478

Chem 2005 3 4129

Am Chem Soc 1965 88 986

2008 49 3814

Chem Ser 1968 72 265

1961 65 123

37 4629

132 Li C J Chem Rev 2005 105 3095

38 3465

Lett 2008 2289

Stark trap1

orthoester

HR+ C O

RH O R

H OO R

H + OH RH

O R HC O

Hemiacetal

oxonium cation

HR O R

HR OR H

H ROH2+

R2R1R2RO

reagent

the alcohol

Bacd Yield ()

Caef Yield ()

MeO OMe

H3CO 21

88g 97h 75 g (90)

EtO OEt

H3CO 22

67g 90h 72 g (80)

76 88 gt98i

79 90 gt98i

MeO OMe

O2N 25

97 94h 82g (94)h

EtO OEt

O2N 26

92 91h 57g (75)h

Bacd Yield ()

Caef Yield ()

MeO OMe

NO2 27

57 96 95

EtO OEt

NO2 28

64 92 gt98i

92 99 gt98i

72 93 96

11 OMeMeO

90 96 gt98i

12 OEtEtO

85 96 gt98i

78 74g gt98i

81 73g gt98i

Green Chemistry

not happen again11

destruction

bull Other

use of solvents

Yield () adf

MeO OMe

96 63 98 92

EtO OEt

83h 75 89 92

MeO OMe

94hj 0 92 73 (92)i

EtO OEt

77 0 0 75 (82)i

MeO OMe

80 33 77 90

EtO OEt

83 33 80 93

OMe 222

86 0 gt98k 96

OEt 223

74 0 82 92

formed

Run Yield ()abc

1 gt98

2 gt98

24 Deprotections

96 yield

OOOMeMeO

0 oC 15 h96

5 mol Al(OTf)3

MeO OMe

H3CO 21

MeO OMe

O2N 25

O N2 55

EtO OEt

Acetal Product

In(OTf)3

Hf(OTf)4

Cu(OTf)2

Ca(OTf)2

MeO OMe

21 H3CO

100 100 100 21

MeO OMe

O2N 25

O N2 89 100 18 15

EtO OEt

100 100 43 19

Acetal Product

Al(OTf)3

In(OTf)3

Hf(OTf)4

No Cat

MeO OMe

H3CO 21

100 100 100 100

MeO OMe

O2N 25

O N2 100a 100a 100a 100a

OMeMeO

O16 22 26 0

EtO OEt

100 100 100 68

O OMeR R

Acetal Product

Al(OTf)3

In(OTf)3

Hf(OTf)4

Sc(OTf)3

No Cat

MeO OMe

H3CO 21

100 100 100 100 97

MeO OMe

O2N 25

O N2 100a 100a 100a 100a 100a

EtO OEt

100 100 100 100 75

Silyl ethers

OH OTBDMS

224 (78)

15 eq Pyridine

OTBDMS

225 (80)

15 eq Pyridine

20 eq TBDMSCl

of 1 mol TfOH

reaction

Yield ()a

OTBDMS

Yield ()a

OTBDMS

O OROH

conditions23

overall efficiency

Yield ()

+O MeOH

OMeO+ H+

211 entry 1 and 2)

TBDMSO

OO 229

OTBDMS

TBDMSO

231 Yield ()

TBDMSO

O Yield ()

Yield ()

TBDMSO

OTBDMS

OMe 232

Yield ()

OTBDMS

O Yield ()

OTBDMS

faster reaction

OTBDMS

OMe Yield ()

OTBDMS

O Yield ()

OTBDMS

Al(OTf)3 82 18 0

Sc(OTf)3 91 9 0

In(OTf)3 94 6 0

Cu(OTf)2 gt98 0 0

Ca(OTf)2 gt98 0 0

29 Conclusions

210 References

R S J Org Chem 2002 67 5202

Ed 2008 47 560

Carb Res 2008 343 1814

New York 1991 31

Chapter 3

31 Introduction

M+n + H2O M OHH

solvents more fully

ROH + SO2 + RN

2I- I2 + 2e-

[alkylsulfite salt]

ammonium salt

mg of water

content8

Reading

Hydranal

Std Mass

content

1 0401 72

2 0391 80

3 0386 75

4 0390 74

5 0391 75

6 0411 77

7 0381 76

8 0375 80

9 0370 70

10 0391 75

Average 75 ppm

Std dev 03 ppm

RSD 39

Solvents

Residual water

contenta (ppm)

Std dev ppm RSD ()

DCM 4103 6 224 120 536 THF 2815 6 1078 066 062

acceptable limits

sieves9

Solvent

Residual water

contenta (ppm)

Std dev ppm

RSD ()

Experiment number

Residual water

contenta (ppm)

Std dev (ppm)

RSD ()

1 2836 6 1140 429 376

2 2650 6 440 066 150

repeatable

352 Drying reagents

36 The alcohols

sieves (5 wv)

Time (h) n

Average sample

weighta (g)

Residual water

content (ppm)

Std dev

24 6 2672 753 074 098 24 6 2621 789 067 085 24 6 2557 777 062 080 48 6 2488 452 055 122 48 6 2571 489 047 096 48 6 2612 464 082 177 72 6 2612 329 041 125 72 6 2488 343 040 117 72 6 2612 354 049 138

5 days 6 2523 257 124 482 5 days 6 2584 266 120 451

sieves (10 wv)

Time (h)

Residual water

content (ppm)

Std dev (ppm)

24 6 2688 407 093 229 24 6 2619 392 059 151 24 6 2624 419 041 098 48 6 2561 268 071 265 48 6 2508 293 071 242 48 6 2502 322 087 270 72 6 2612 224 042 188 72 6 2592 236 084 356 72 6 2505 263 063 240

5 days 6 2589 166 057 343 5 days 6 2573 182 058 319 5 days 6 2606 199 168 844

sieves (20 wv)

Time (h) n

Residual water

content (ppm)

Std dev

(ppm) RSD ()

24 6 2509 280 057 204 24 6 2609 292 042 144 24 6 2634 290 031 107 48 6 2496 211 046 218 48 6 2605 239 038 159 48 6 2556 244 087 357 72 6 2591 176 051 290 72 6 2541 188 055 293 72 6 2610 212 088 415

5 days 6 2575 97 099 1021 5 days 6 2542 104 049 471

(5 wv)

Time (h) n

Residual water

content (ppm)

Std dev

(ppm) RSD

24 6 2699 2511 181 072 24 6 2637 2703 166 061 24 6 2662 2664 250 094 48 6 2648 1021 075 073 48 6 2639 1064 074 070 48 6 2633 1110 055 050 72 6 2664 549 093 169 72 6 2639 541 059 109 72 6 2639 563 123 218

5 days 6 2635 144 051 354 5 days 6 2631 141 049 348 5 days 6 2659 149 015 101

(10 wv)

Time (h) n

Residual water

content (ppm)

Std dev ppm

RSD ()

24 6 2668 1894 153 081 24 6 2666 1792 081 045 24 6 2638 1896 050 026 48 6 2645 678 051 075 48 6 2637 695 064 092 48 6 2640 712 058 081 72 6 2642 351 107 305 72 6 2624 359 073 203 72 6 2616 397 118 297

5 days 6 2611 114 113 991 5 days 6 2658 130 076 585 5 days 6 2619 124 089 718

(20 wv)

Time (h)

Residual water

content (ppm)

Std dev ppm

RSD ()

24 6 2639 1186 058 049 24 6 2641 1190 109 092 24 6 2630 1218 037 030 48 6 2643 231 076 329 48 6 2639 243 055 226 48 6 2666 277 079 285 72 6 2604 190 028 147 72 6 2612 194 056 289 72 6 2608 231 061 264

5 days 6 2651 69 035 507 5 days 6 2612 81 035 432

5 days 6 2599 95 050 526

acceptable

powder

Average sample

weight (g) n

Residual water

contenta (ppm)

Std dev ppm

RSD ()

Methanol KOH (10 wv) 24 2525 6 318 081 255

Methanol KOH (10 wv) 24 2555 6 339 099 292

Methanol KOH (10 wv) 24 2606 6 337 093 276

Ethanol KOH (10 wv) 24 2856 6 259 074 286

Ethanol KOH (10 wv) 24 2760 6 284 053 187

Ethanol KOH (10 wv) 24 2640 6 250 056 225

37 Acetonitrile

Desiccant Time (h)

Residual water

contenta (ppm)

Std dev ppm

RSD ()

24 2628 6 40 065 1606 48 2626 6 18 050 2841 72 - 6 ltdlb - -

24 2643 6 05 041 8367

48 - 6 ltdlb - -

10 (wv) -c 2966 6 61 062 1015

10 (wv) -c 2924 6 49 015 306

10 (wv) -c 2826 6 68 037 537

titrations

Residual water

contenta (ppm)

Std dev ppm

RSD ()

(20 wv)

Time (h) n

Residual water

content (ppm)

Std dev (ppm)

RSD ()

24 6 3029 152 029 191 24 6 3027 143 012 084 24 6 3007 146 036 247 48 6 3034 59 021 356 48 6 3000 60 021 350 48 6 2998 64 010 156 72 6 2970 43 005 116 72 6 3016 42 018 429 72 6 2907 38 010 263

Fischer titration

Residual water

contenta (ppm)

Std dev ppm

RSD ()

repeatable

39 Discussion

310 Conclusions

38 References

Oxford 1963 682

41 Introduction

acidity6

literature

H3C CH3

CH3H3CN

CH3H3C

H3C CH3

CH3H3C

5 mol Bi(OTf)3 H2OH

Ph NH2

O NH OPh

41 42 43 44

Water 7 h

OTES OBz

OTES OH

Bz2O CH2CN

10 mol Sc(OTf)3

SO2PhBz2O CH3CN

OH O Ph

O3 eq Bz2O

Conversion

1 Yb(OTf)3 99 15 11

2 Bi(OTf)3 40 15 8

3 In(OTf)3 34 15 3

4 Sc(OTf)3 63 15 2

5 Cu(OTf)2 3 - -

6 Sc(OTf)3 63 5 6

OHHOHO

TfOH (005 eq) 10 min 84

OHHOHO

In(OTf)3 (005 eq) 1 h 99

OHHOHO

In(OTf)3 (005 eq)

With DTMP 24 h 11

OHH2NHO

In(OTf)3 (005 eq)

1 h NR

OHH2NHO

+ In(OTf)3

OIn(OTf)2H2N

+ HOTf

n(H2O)YbO

431 Introduction

OH H H

Enolate

OSiMe3+ R3 C R4

Lewis acid

OSiMe3 O

+MXn 02eq

THFH2O (91)12 h rt413 414 415

proceed no further

product

La(OTf)3 80

Ce(OTf)3 81

Pr(OTf)3 83

Nd(OTf)3 78

Sm(OTf)3 85

Eu(OTf)3 88

Gd(OTf)3 90

Tb(OTf)3 81

Dy(OTf)3 85

Ho(OTf)3 89

Er(OTf)3 86

Tm(OTf)3 85

Yb(OTf)3 92

Lu(OTf)3 84

Yield ()a

Hydrolysis of

Silyl ether

(silyl ether)

La(OTf)3 92 (80)b 8 0

InCl3 89 (68)b 3 8

CuCl2 86 (25)b 11 3

LiCl 6 (-)b 7 77

ScCl3 59 (70) 41 -

Er(OTf)3 56 (86)b 6 38

GaCl3 28 (-)b 56 16

ZnCl2 22 (10)b 0 78

AlCl3 0 (0)b 100 0

Cu(OTf)2 96 4 0

Sc(OTf)3 94 6 0

Y(OTf)3 89 11 0

Zn(OTf)2 77 2 21

Ca(OTf)2 42 28 30

In(OTf)3 41 59 0

Al(OTf)3 21 79 0

Zr(OTf)4 0 100 0

Hf(OTf)4 0 100 0

Li(OTf) 0 11 89

TiCl4 0 100 0

TiCl4 -098 100 TfOH 034 100

Y(OTf)3 445 6 Cu(OTf)2 464 4 Zn(OTf)2 540 2

LiCl 830 7 LiOTf 889 11

In(OTf)3 277 59 400 InCl3 432 6 400 ScCl3 254 41 430

Sc(OTf)3 275 6 430 CuCl2 408 11 753

ZnCl2 549 0 896 Ca(OTf)2 607 28 1285

LiCl 830 7 1364 LiOTf 889 11 1364 TfOH 034 100

rate constant

OSiMe3

PhCHO TiCl4 CH2Cl2

TiCl3Cl -Me3SiCl

Me PhPhPh

ClCl Cl

Me PhPhPh

catalytic cycle

THF H2O (91)

La(OTf)3 92 35 Y(OTf)3 89 83

788764755

Lewis Acid

Δδ H aldehyde

Δδ Ortho

protons

Δδ Para

protons

Δδ Meta

protons 1001 788 764 755

Sc(OTf)3 -0033a 0109 0108 0044

ScCl3 0054 0093 009 0029

In(OTf)3 -0015a 016 016 007

proceed (Figure45)

OSiMe3

M(OTf)3

phenomena

of ligands

Water 79

Acetonitrile 375

Methanol 315

Ethanol 242

Acetone 22

Chlorobenzene 56

Tetrahydrofuran 76

Ether 45

Benzene 23

Pentane 18

M3+M OTfTfO

OTf M OTf M OTF

Quadruplet

OTf M OTfTriplet

solvents

+-+- +-+- etc)32

Et3N + CH3Iδ δ

Solvent Dielectric

Hexane 20 1

MSn OH

+ MSn-1

+ S eq 42

MnXm-1

ion-pair formation

415)34

M+n + H2O M(H2O)x

M(H2O)x-1OH+n-1

Broslashnsted acid

particular

conditions

Lewis acid

Without

Yield ()

La(OTf)3 92 0 0

Sc(OTf)3 96 79 50

InCl3 89 99 0

Cu(OTf)2 94 65 0

N+ ROH

Lewis acid pH in

THFH2O (91)

pH in THFH2O

(91) and 15 eq

46 Summary

Retinyl acetate

CH2+ HO

triflate

Retinyl acetate +

hydrolysis

non- polar solvents

-OTf416

BA OTf-

Al(OTf)3

BA =Al(OTf)3K

5 mL of DCM

(Table 416)

Retinyl acetate +

Mr = 42544 F000 = 884

V = 17580 (2) Aring3 T = 296 (2) K

Lewis acid

Reaction Yield ()a

Reactions +200 uL

ScCl3 0 21 InCl3 50 53 TfOH 31 31

p-xylenea

Metal triflate

Yield ()b

4 mL p-xylene

Yield ()b

2 mL p-xylene

spectroscopy

systemsa

Lewis Acid 10 mol

Yield ()b

Cumene 16 mL 48 h

Yield ()b

Anisole 16 mL 24 h

Yield ()b

Toluene 16 mL 48 h

Zr(OTf)4 71 gt 95 66 Al(OTf)3 47 gt95 77

Metal Triflate

bottle

was 60

Hf(OTf)4)

attention

49 Conclusions

modified

410 References

M J Carb Res 2008 343 2814

68 9340

M J Carb Res 2008 343 2814

1994 188

1998 39 1641

1997 613

Chem Soc 2008 131 6342

2008 49 2384

Winston 1959

Chapter 5

51 Introduction

triflates

Crotonaldehyde

signala

Croton

aldehyde

Δ δ on

addition

Al(OTf)3

Δ δ on

addition

Δ δ on

addition

Sc(OTf)3

Δ δ on

addition

Δ δ on

addition

In(OTf)3

Δ δ on

addition

H-1 947 -026 -016 -025 003 -006 -007

H-2 610 054 013 044 045 030 027

H-3 687 093 023 093 071 050 043

Lewis acids

signala

Croton

aldehyde

Δ δ on

addition

Al(OTf)3

Δ δ on

addition

Δ δ on

addition

Sc(OTf)3

Δ δ on

addition

Δ δ on

addition

In(OTf)3

Δ δ on

addition

C-1 1941 111 04 116 175 04 29

C-2 1348 -20 05 -14 -15 03 -02

C-3 1544 219 02 221 1752 04 45

C3C2 C1

NMR signala

Trans-

cinnamaldehyde

δ ppm

Hf(OTf)4 003 005 13 -02 12

Sc(OTf)3 -016 -002 24 01 25

In(OTf)3 -0171 0047 17 00 16

Ca(OTf)2 -0074 0014 04 -04 02

Zn(OTf)2 -005 0038 29 03 26

Y(OTf)3 -0048 0145 31 03 33

Zr(OTf)4 -0107 004 23 -07 24

Al(OTf)3 -0076 0032 09 00 09

Lewis acids

Phosphorus NMR

thermodynamic data

Phosphorus compound

δ uncomplexeda

Δ δ on addition

of Al(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of In(OTf)3

(OTf)3M

NMR signal

Croton aldehyde

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

18 aH-1 947 -027 -022 -015 -008

H-2 687 045 014 026 014

H-3 610 100 083 057 024

CH3 201 028 023 014 005

NMR signal

Croton aldehyde

Δ δ on addition

of In(OTf)3

Δ δ on addition

of In(OTf)3

Δ δ on addition

of In(OTf)3

Δ δ on addition

of InOTf)3

18 aH-1 947 -009 -008 -007 -006

H-2 687 027 019 010 008

H-3 610 049 037 021 017

solvent to solvent

A = εbc 1

(Figure 58)9

(Figure 59)

complex

the probes

Lewis Acid

laboratory

method was sought

may be obtained

[bmim][OTf]

acid coordination

LiOTf 14422 22 -a

Ca(OTf)2 14424 24 -a

Zn(OTf)2 14520 120 -a

Cu(OTf)2 14530 130 -a

Ba(OTf)2 14610 210 -a

LiCl 14860 460 -a

ScCl3 14870 470 -a

InCl3 14890 490 -a

metal salts

activity

Table 58

14694 14694 14694 14694

144428 14463 14463 14463

the Lewis acids

55 Conclusions

References

Int Ed 2008 47 560

Main conclusions

identified

Future research

expensive triflates

Chapter 6

611 Chromatography

prior to use

63 Melting Points

uncorrected

64 Chemical methods

Chapter 2

MeO OMe

Yield 97 yellow oil

Obtained = 1510753

EtO OEt

Yield 90 yellow oil

Obtained = 1650910

Obtained = 1569867

Obtained = 1690416

MeO OMe

(ortho) 491 (2 x OCH3) 258 (CH3)

Obtained = 1960593

EtO OEt

Yield 92 yellow oil

(CH3) 151 (OCH3)

Obtained = 1940811

MeO OMe

(C3) 1280 (C5) 1241 (C4) 997 (acetal) 544 (2 x OCH3)

Obtained = 1660498

EtO OEt

1241 (C4) 983 (acetal) 634 (2 x OCH2) 150 (2 x CH3)

Obtained = 1800655

Ph OMe

x OCH3)

Obtained = 1470805

Ph OEt

Obtained = 1610960

Obtained = 1711741

Obtained = 1851902

(C3 and C5) 263 (C4) 257 (C4 and C6)

Obtained = 1271099

Obtained = 1411275

Yield 98White solid

Obtained = 1921147

MeO OMe

(ortho) 1031 (CH) 526 (OCH3)

Obtained = 1210445

EtO OEt

Obtained = 1350807

MeO OMe

Obtained = 1510755

EtO OEt

(OCH2CH3)

Obtained = 1791067

(C4) 228 (C3 C5)

Obtained = 1130967

2H H2 H6) 147 (m 2H H3 H5) 137 (m 1H H4) 115 (t 6H J =

(C4) 230 (C3 C5) 156 (2 x CH2CH3)

Obtained = 1281196

Obtained = 1110465

Obtained = 1250597

OTBDMS

(C(CH3)3 -54 (OSi(CH3)2)

Obtained = 1790887

OTBDMS

Obtained = 2289670

was used

(C5) 254 (C4) 194 (C3)

Obtained = 1220727

mp 566ndash584

1138 (para) 965 (acetal) 620 (C2) 302 (C5) 251 (C4) 186 (C3)

Obtained = 179521

618 (C2) 540 (HCequivCCH2) 301 (C3) 252 (C3) 252 (C4) 190

Obtained = 850646

1262 (C2) 1207 (C6) 1100 (C5) 554 (OCH3) 255 (C(CH3)3) 184

(C(CH3)3 -46 (OSi(CH3)2)

Obtained = 2090629

OTBDMS

Yield 90 yellow oil

1215 (C5 C6) 1202 (C3) 256 (C(CH3)3) 163 (C(CH3)3 -43

(OSi(CH3)2)

Obtained = 1790523

TBDMSO

OTBDMS

120 (C6) 1010 (acetal) 538 (2 x OCH3) 263 (C(CH3)3) 192

(C(CH3)3 -40 (OSi(CH3)2)

Obtained = 2250946

Chapter 3

i=1(xi - μ)2

Eq 1 RSD = ( x) x 100σ Eq 2

x = sample mean

data see appendix A

Chapter 4

To make LDA

10 minutes

chromatography

OSiMe3

Obtained = 1340732

Obtained = 2250946

(CH2CH3)

Obtained = 2880755

6410 Crystal data

Mr = 42544 F000 = 884

λ = 071073 Aring

V = 17580 (2) Aring3 T = 296 (2) K

Data collection

CCD area detector

T = 296(2) K θmax = 280deg

Refinement

Fourier map

neighbouring sites

wR(F2) = 0137 w = 1[σ2(Fo

2) + (00834P)2]

S = 098 (Δσ)max = 2220

706 (s 1H H2) 706 (d 2H J = 18 H4 H5) 577 (d 1H J = 15 Hz

1330 (C6) 1307 (C5) 1300 (C6) 1283 (C10 and C12) 1282 (C11)

1275 (C2) 1265 (C9 and C13) 1146 (C14) 210 (C16) 196 (C15)

Obtained = 2081240

Chapter 5

at 25 degC

NMR spectroscopy

11 01 mmol 01 mmol

12 01 mmol 02 mmol

14 01 mmol 04 mmol

18 01 mmol 08 mmol

65 References

Chem Soc 2006 128 5930

60 4037

1 2765 CL 95

2 2874 1015 3 2874 1025 4 2749 1018 5 2868 1019 6 2761 1013

Average 2815 1018

1 2933 1171 2 2780 1189 3 2806 1132 4 2951 1071 5 2867 1116 6 2838 1161

Average 2863 1140

1 2638 441 2 2656 435 3 2648 441 4 2675 449 5 2639 431 6 2641 446

Average 2650 440

1 2673 432 2 2702 422 3 2698 421 4 2657 434 5 2712 420 6 2668 436

Average 2685 428

1 2840 276 2 2795 290 3 2917 291 4 2647 272 5 2730 267 6 2762 271

Average 2782 278

1 3000 593 2 2906 572 3 2860 560 4 2880 520 5 2853 578 6 2800 550

Average 2883 562

1 2973 807 2 2960 CL 95

3 2965 824 4 3005 824 5 2993 837 6 2987 834

Average 2981 825

1 2900 1066 2 2942 1057 3 2735 1097 4 2902 1009 5 2854 1025 6 2894 1090

Average 2871 1057

1 2981 909 2 2821 896 3 2921 864 4 2922 866 5 2932 939 6 2848 889

Average 2904 894

1 2857 742 2 2889 763 3 2806 747 4 2838 712 5 2821 774 6 3027 739

Average 2873 746

1 2952 618 2 2959 597 3 2888 649 4 2933 598 5 2860 550 6 2987 560

Average 2930 595

1 2937 730 2 2872 716 3 2920 688 4 2903 646 5 2915 659 6 2933 702

Average 2913 690

1 2939 606 2 2953 624 3 2975 630 4 2967 613 5 2825 575 6 2901 603

1 3112 156 2 2998 151 3 3100 149 4 2976 153 5 2987 148 6 3001 153

1 3101 145 2 2964 143 3 2899 142 4 3112 CL 95

5 3103 143 6 2981 142

Average 3027 143

1 2899 146 2 2976 140 3 2988 147 4 2978 143 5 3100 149 6 3102 149

Average 3007 146

1 3004 59 2 2987 57 3 3003 58 4 3067 57 5 3076 61 6 3064 62

Average 3034 59

1 3044 61 2 2988 59 3 3000 58 4 2991 62 5 2989 62 6 2988 57

Average 3000 60

1 3014 63 2 2994 64 3 2983 61 4 2997 63 5 2996 62 6 3004 62

1 2864 43 2 2990 43 3 2999 44 4 2988 CL 95

5 3009 44 6 2968 43

Average 2970 43

1 3074 41 2 2998 41 3 2995 42 4 3031 45 5 3006 43 6 2994 40

Average 3016 42

1 3014 39 2 2918 38 3 2990 37 4 3011 37 5 3029 39 6 2948 39

Average 2985 38

1 3004 55 2 3100 56 3 2713 54 4 2985 57 5 3005 56 6 3001 55

Average 2968 56

1 2934 49 2 2991 48 3 2997 48 4 2990 47 5 3010 CL 95

6 3084 46 Average 3001 48

1 2948 54 2 2789 53 3 2994 54 4 2783 55 5 2956 53 6 2973 56

1 2568 1427 2 2371 1436 3 2666 1426 4 2559 1407 5 2598 1418 6 2554 1407

Average 2553 1420

1 2646 45 2 2634 45 3 2574 38 4 2631 46 5 2645 40 6 2638 29

Average 2628 40

1 2604 19 2 2645 16 3 2673 26 4 2536 20 5 2645 13 6 2655 12

Average 2626 18

1 2652 12 2 2584 01 3 2652 02 4 2653 07 5 2657 02 6 2660 04

Average 2643 05

1 2963 69 2 2991 66 3 2953 58 4 2960 64 5 2965 56 6 2964 54

Average 2966 61

1 2913 CL = 95

2 2951 49 3 2923 51 4 2940 49 5 2925 50 6 2894 47

Average 2924 49

1 2943 67 2 2911 65 3 2863 73 4 2440 69 5 2895 64 6 2904 72

1 2563 1748 2 2576 1746 3 2603 1757 4 2590 1749 5 2594 1754 6 2613 1755

Average 2590 1751

1 2689 758 2 2625 740 3 2664 751 4 2674 CL 95

5 2678 761 6 2702 756

Average 2672 753

1 2643 794 2 2598 786 3 2586 787 4 2633 798 5 2644 779 6 2635 792

Average 2621 789

1 2584 779 2 2552 768 3 2621 774 4 2556 781 5 2529 CL 95

6 2497 785 Average 2557 777

1 2703 417 2 2671 394 3 2712 409 4 2654 412 5 2648 398 6 2739 414

Average 2688 407

1 2568 398 2 2633 387 3 2574 397 4 2632 CL 95

5 2695 396 6 2613 386

Average 2619 393

1 2598 420 2 2648 418 3 2653 417 4 2589 424 5 2655 421 6 2599 412

Average 2624 419

1 2589 288 2 2498 273 3 2534 279 4 2477 284 5 2490 CL 95

6 2465 274 Average 2509 279

1 2541 292 2 2653 289 3 2666 287 4 2579 294 5 2534 299 6 2683 291

Average 2609 292

1 2695 293 2 2653 291 3 2648 288 4 2589 290 5 2648 293 6 2568 285

Average 2634 290

1 2529 462 2 2428 447 3 2484 451 4 2437 453 5 2590 448 6 2459 449

Average 2488 452

1 2491 493 2 2623 486 3 2626 489 4 2489 482 5 2564 495 6 2633 489

Average 2571 489

1 2615 463 2 2613 459 3 2608 470 4 2619 474 5 2558 467 6 2658 451

Average 2612 464

1 2575 275 2 2573 266 3 2640 268 4 2530 278 5 2458 264 6 2590 259

Average 2561 268

1 2530 283 2 2528 294 3 2530 285 4 2447 301 5 2550 CL 95

6 2463 298 Average 2508 292

1 2451 313 2 2500 324 3 2506 324 4 2519 334 5 2504 329 6 2533 312

Average 2502 323

1 2549 203 2 2428 211 3 2514 213 4 2437 216 5 2627 209 6 2419 213

1 2675 243 2 2423 236 3 2608 243 4 2630 234 5 2671 238 6 2620 241

1 2560 256 2 2508 247 3 2570 234 4 2457 246 5 2650 249 6 2593 234

Average 2556 244

1 2615 324 2 2613 327 3 2608 332 4 2619 335 5 2558 326 6 2658 330

Average 2612 329

1 2529 339 2 2428 342 3 2484 347 4 2437 337 5 2590 346 6 2459 345

Average 2488 343

1 2615 349 2 2613 358 3 2608 356 4 2619 CL 95

5 2558 359 6 2658 354

Average 2612 355

1 2655 221 2 2550 232 3 2608 225 4 2618 224 5 2614 221 6 2626 222

1 2645 CL 95

2 2633 236 3 2540 245 4 2540 246 5 2538 224 6 2658 231

1 2479 257 2 2428 264 3 2474 267 4 2537 254 5 2640 271 6 2471 263

Average 2505 263

1 2590 174 2 2570 180 3 2658 CL 95

4 2519 169 5 2598 183 6 2610 173

Average 2591 176

1 2539 184 2 2628 193 3 2464 191 4 2447 CL 95

5 2540 195 6 2629 183

Average 2541 189

1 2651 205 2 2450 211 3 2668 204 4 2678 224 5 2684 205 6 2526 221

Average 2610 212

1 2539 253 2 2628 243 3 2534 262 4 2417 274 5 2560 264 6 2459 243

Average 2523 257

1 2675 269 2 2560 274 3 2517 243 4 2606 273 5 2526 CL 95

6 2622 261 Average 2584 264

1 2460 274 2 2410 264 3 2584 289 4 2447 271 5 2580 264 6 2489 273

Average 2495 273

1 2574 167 2 2613 159 3 2588 173 4 2569 160 5 2608 164 6 2579 171

Average 2589 166

1 2489 189 2 2588 173 3 2524 183 4 2697 CL 95

5 2578 179 6 2559 183

Average 2573 181

1 2570 193 2 2590 187 3 2628 183 4 2620 194 5 2588 206 6 2638 229

Average 2606 199

1 2420 115 2 2590 96 3 2640 95 4 2669 89 5 2638 101 6 2490 88

Average 2575 97

1 2559 103 2 2478 107 3 2624 99 4 2497 111 5 2620 CL 95

6 2471 98 Average 2542 104

1 2641 124 2 2540 127 3 2596 104 4 2602 118 5 2606 99 6 2634 115

Average 2603 115

1 2569 305 2 2548 312 3 2489 325 4 2548 316 5 2450 324 6 2548 324

Average 2525 318

1 2459 354 2 2657 334 3 2658 341 4 2549 342 5 2459 324 6 2548 341

Average 2555 339

1 2658 331 2 2642 324 3 2548 335 4 2548 342 5 2658 339 6 2549 351

Average 2600 337

Methanol from MgI2

1 2660 545 2 2385 537 3 2693 540 4 2683 531 5 2531 530 6 2667 533

1 2650 14291 2 2537 14327 3 2618 14306 4 2653 14218 5 2673 14263 6 2598 14292

Average 2622 14283

1 2701 2516 2 2694 2486 3 2698 2508 4 2704 2496 5 2699 2523 6 2700 2536

Average 2699 2511

1 2655 2676 2 2596 2715 3 2626 2705 4 2572 2691 5 2684 CL 95

6 2691 2720 Average 2637 2701

1 2658 2651 2 2645 2671 3 2632 2644 4 2651 2712 5 2671 2656 6 2713 2652

Average 2662 2664

1 2661 CL 95

2 2664 1882 3 2678 1887 4 2674 1892 5 2659 1891 6 2670 1887

Average 2668 1888

1 2665 1804 2 2650 1793 3 2638 1795 4 2659 1781 5 2675 1785 6 2709 1793

Average 2666 1792

1 2653 1904 2 2592 1899 3 2629 1895 4 2576 1889 5 2687 1896 6 2693 1895

Average 2638 1896

1 2651 1183 2 2689 1185 3 2628 1191 4 2581 1195 5 2685 CL 95

6 2597 1184 Average 2639 1188

1 2647 1206 2 2591 1193 3 2629 1196 4 2579 1189 5 2695 CL 95

6 2705 1184 Average 2641 1194

1 2661 1214 2 2647 1216 3 2539 1220 4 2657 1221 5 2672 1215 6 2604 1223

Average 2630 1218

1 2643 CL 95

2 2692 1020 3 2639 1018 4 2586 1016 5 2693 1024 6 2633 1014

Average 2648 1018

1 2695 1065 2 2650 1076 3 2643 1065 4 2659 1054 5 2575 1059 6 2609 1063

1 2651 1107 2 2724 1106 3 2668 1113 4 2634 1111 5 2509 1119 6 2610 1104

Average 2633 1110

1 2541 672 2 2667 678 3 2648 679 4 2694 682 5 2649 685 6 2669 673

Average 2645 678

1 2666 694 2 2525 696 3 2636 689 4 2653 CL 95

5 2701 687 6 2643 703

1 2652 710 2 2591 717 3 2633 703 4 2579 719 5 2693 709 6 2693 713

Average 2640 712

1 2671 242 2 2644 229 3 2622 227 4 2654 231 5 2659 220 6 2610 237

Average 2643 231

1 2681 245 2 2634 249 3 2618 246 4 2634 236 5 2629 247 6 2640 237

1 2666 267 2 2649 270 3 2636 281 4 2659 279 5 2680 276 6 2708 289

1 2661 532 2 2652 558 3 2634 553 4 2657 556 5 2680 548 6 2702 549

Average 2664 549

1 2646 541 2 2595 539 3 2632 537 4 2577 546 5 2690 548 6 2694 532

Average 2639 541

1 2652 569 2 2627 577 3 2666 574 4 2648 549 5 2609 CL 95

6 2630 549 Average 2639 564

1 2651 367 2 2592 339 3 2635 342 4 2586 346 5 2690 CL 95

6 2699 357 Average 2642 350

1 2647 368 2 2600 365 3 2639 352 4 2574 350 5 2689 362 6 2593 356

1 2663 387 2 2653 395 3 2538 397 4 2658 402 5 2585 417 6 2599 384

1 2649 190 2 2522 189 3 2634 187 4 2526 192 5 2683 194 6 2611 187

Average 2604 190

1 2655 189 2 2550 196 3 2608 197 4 2618 185 5 2614 196 6 2626 CL 95

Average 2612 193

1 2648 224 2 2556 226 3 2663 240 4 2524 231 5 2643 236 6 2612 229

Average 2608 231

1 2569 139 2 2668 138 3 2584 144 4 2637 152 5 2690 146 6 2659 142

Average 2635 144

1 2591 133 2 2623 142 3 2726 146 4 2589 140 5 2664 139 6 2593 146

Average 2631 141

1 2641 148 2 2643 151 3 2706 147 4 2649 150 5 2704 149 6 2613 148

Average 2659 149

1 2529 120 2 2618 128 3 2614 119 4 2607 113 5 2660 103 6 2639 CL 95

Average 2611 117

1 2631 136 2 2663 125 3 2716 125 4 2609 139 5 2744 120 6 2583 135

Average 2658 130

1 2581 134 2 2653 131 3 2676 124 4 2549 110 5 2714 128 6 2543 118

Average 2619 124

1 2687 75 2 2655 69 3 2680 68 4 2659 64 5 2615 70 6 2609 69

Average 2651 69

1 2496 81 2 2589 76 3 2620 80 4 2680 79 5 2677 85 6 2609 85

1 2541 92 2 2593 95 3 2663 87 4 2527 CL 95

5 2648 94 6 2619 97

Average 2599 93

1 2875 257 2 2975 249 3 2896 258 4 2846 260 5 2758 272 6 2785 258

Average 2856 259

1 2587 278 2 2846 291 3 2874 286 4 2795 CL 95

5 2876 279 6 2579 284

Average 2760 284

1 2579 251 2 2858 254 3 2548 254 4 2479 252 5 2797 249 6 2579 239

1 4167 263 2 4146 230 3 4154 222 4 4079 205 5 3923 226 6 4151 237

Average 4103 231

1 4393 01 2 4172 02 3 4405 02 4 4183 00 5 4285 01 6 4168 02

1 4198 15 2 4206 09 3 4149 09 4 4168 14 5 4286 15 6 4295 CL = 95

Average 4217 13

DCM dried over CaH2

1 4206 147 2 4357 121 3 3871 129 4 4215 114 5 4347 121 6 3927 140

Average 4154 129

Front page



Faculty of Science



June 2009

Table of Contents

Synopsis

Abbreviations

Figures and schemes

Chapter 1

Chapter 2

Chapter 3_12099

Chapter 4

Chapter 5


Chapter 6

Appendix A


29 Conclusions 107

Chapter 3

(THF) 128 ndash 134

39 Discussion 134

311 References 136

Chapter 4

138 ndash 145

reaction

152 ndash 158

solvents

159 ndash 162

crystallography

176 ndash 177

Chapter 5

51 Introduction 186

54 Conclusions 207

55 References 208

Chapter 6

alcohols

65 References 242

observed

solvents

Abbreviations

Aring angstrom

Bn benzyl

Bu butyl

C coulomb

CL confidence level

CPL ε-caprolactone

Cy cyclohexyl

d doublet

DCM dichloromethane

DHP dihydropyran

DL detection limit

Eq equivalents

EtOH ethanol

Et3N triethylamine

h hour

IR infrared

i-Pr iso-propyl

mp melting point

MeOH methanol

Me methyl

OAc acetate

PDI polydispersity

Ph phenyl

q quartet

rt room temperature

s singlet

t triplet

t-Bu tert-butyl

TES triethylsilyl

THF tetrahydrofuran

THP tetrahydropyran

TMS trimethylsilyl

thesis)

VL valerolactone

wrt with respect to

Scheme

Figure Heading Page

alcohols 29

by Bi(OTf)3 41

Figure 110

values 61

formaldehyde 65

Scheme 130

by InCl3 69

and urea 73

Scheme

Figure Heading Page

bromophenol 98

Scheme

Figure Heading Page

over time 122

over time 124

Scheme

Figure Heading Page

by water 153

organic solvent 161

nucleophile 164

Figure 49

of the solutions

Figure 412

counterion 176

Scheme

Figure Heading Page

triflate 195

to Lewis acid 201

List of tables

Table Heading Page

Table 13

different additives

with In(OTf)3 25

Table 117

Ga(OTf)3

bases at 28 degC 54

one 57

(9-fluorenone) 62

Ln(OTf)3 65

aldehydes 70

Table 139

Table Heading Page

ketones 85

ketones 86

ketones 90

the substrate 92

metal triflates 94

Al(OTf)3 102

triflates 105

Table Heading Page

standard 115

SilicaSodium 118

Table 315

alumina

Table Heading Page

mixture 150

solvents 161

DTBMP 164

without DTBMP 164

carbocation 167

pyridine 178

Table Heading Page

Table 51

Table 52

Table 53

Chapter 1

Introduction

system theories5

a proton acceptor

equation 3

ψ ψ ψAB = a 0 (AB) + b 1 (A-B+) (3)

ψ1 (A-B

β 01 EoSo1( )_ 2

E1_ Eo( )

EAB = Eo_

equation 5)

Σ ΣΔΕ β_ qsqt

Conclusions

reaction mixtures

amounts

(see Chapter 4)

OAcMeOOC O

OMeOOC

BnO OAc

O(OTf)3M

Lanthanide Reaction

Yb(OTf)3 180 70

Eu(OTf)3 90 85

Sm(OTf)3 90 92

AcOAcOAcO

AcOAcO

AcO COOMe

OAc Nd(OTf)3

MeOH rt 4 h

Nd(OTf)3

MeOH rt 4 h

AcOAcO

AcO COOMe

metal triflates

Starting

material Product

Yb(OTf)3a

Yield ()

Eu(OTf)3a

Yield ()

Sm(OTf)3a

Yield ()

Nd(OTf)3a

Yield ()

AcOAcAcOAcOAcO H

OAcOAcO

85 81 85 81

OAcAcOAcO

AcO CH2OAc

AcOAcO

AcO CH2OAc

68 78 82 82

OAcAcOAcOcO

CH2OAc

AcOAcOAcO

CH2OAc

61 62 79 81

HAcOAcOAcO

CH2OAc

AcOAcOAcO

CH2OAc

67 62 67 68

OIn (10 eq)

THFH2O 40 oC 20h

+ TIPS CF2

215 16 17 18

1 H2OTHF (41) 11 - 206

2 H2OTHF (41) 11 - 3112

3 H2OTHF (41) 11 - 257

4 Satd NH4Cl(aq)THF (41) 11 - 204

7 H2OTHF (41) 22 - 298

8 H2OTHF (41) 33 - 364

9 H2OTHF (41) 11 Sc(OTf)3 424

10 H2OTHF (41) 11 Er(OTf)3 647

11 H2OTHF (41) 11 Eu(OTf)3 788

12 H2OTHF (41) 11 Tb(OTf)3 7610

13 H2OTHF (41) 11 Sm(OTf)3 489

14 H2OTHF (41) 11 Y(OTf)3 4713

BrF + R

H2OTHF (41) 40 oC 20h

1 TIPS Ph 68

2 TES Ph 72

3 TMSb Ph 41

(18 scheme 14)

In (reducing agent)

examples

OHHO CO2Me

+Lewis acid

CH2Cl2 or CH3NO2

HO CO2Me

naphthyl)ethanol

(2-naphthyl)ethanol

mol Time h Yield ()

1a TiCl4 100 1 6

2a BF3OEt2 100 1 96

3a BF3OEt2 10 1 6

4b La(OTf)3 1 05 99

5b La(OTf)3 01 1 98

6b La(OTf)3 001 24 93

7b La(OTf)3 1 15c 98

8b Yb(OTf)3 1 033 96

OHHO CO2R

+1 mol La(OTf)3

HO CO2R

R25 26 27

CH3NO2

alcohols

1 H Me 15 min 99

2 OSiR3a Me 2 h 93

3 OAc Me 6 h 95

4 OBn Me 14 h 97

1 H Me Hf 5 min 89

3 H Me Sc 15 min 99

4 H Me Yb 25 min 99

5 H Bn La 25 h 99

6 H t-Bu La 19 h 59

a TfOH 3 mol

Nucleophile

Olefin

Triflate

H2OOHAr

Triflate Ar O Ar

Products

Ar = Ph

Ar = 2-naphthyl

process5758

2 mol M(OTf)x

toluene 25 oCO

of n-BnOH

Mol Time (h)

1 CPL 0 4 gt99 6900

2 CPL 2 23 gt99 3500

3 CPL 5 2 gt99 2400

4 CPL 10 2 gt99 1600

5 VL 0 15 96 4300

6 VL 2 1 95 2900

7 VL 5 1 97 1900

1 Sc [BF4]- 2 d 0 -

2 Y [BF4]- 7 d 29 500

3 La [BF4]- 2 d 29 300

4 Ceb [BF4]- 6 d 32 600

5 Nd [BF4]- 6 d 30 500

6 Eu [BF4]- 2 d 0 -

7 Gd [BF4]- 5 d 30 600

8 Yb [BF4]- 4 d 27 500

9 Lu [BF4]- 3 d 26 500

10 Sc [PF6]- 42 80 2500

11 Y [PF6]- 53 83 2800

12 La [PF6]- 46 100 3700

13 Ceb [PF6]- 47 100 3500

14 Nd [PF6]- 35 100 2700

15 Eu [PF6]- 49 100 2400

16 Gd [PF6]- 48 100 3400

17 Yb [PF6]- 48 43 1600

18 Lu [PF6]- 47 100 4400

19 Sc [SbF6]- 30 87 900

20 Y [SbF6]- 48 99 1800

21 La [SbF6]- 42 100 1800

22 Ceb [SbF6]- 29 100 1700

23 Nd [SbF6]- 43 100 1700

24 Eu [SbF6]- 48 4 1500

25 Gd [SbF6]- 29 100 2500

26 Yb [SbF6]- 48 82 1400

Sc(OTf)3

O(TfO)3Sc

OSc(OTf)3

Sc(OTf)3

Propagation

monomer mechanism

R NH2+

001 molYb(OTf)3

yields

Indium triflate

AcOAcO

OHHOHO

OAcAcOAcO

OHHOHO

OAcAcOAcO

AcOH3C

OH HO O

OAcOAc

OAc AcO 97

OAcAcOAcO

OHHOHO

OAcAcOAcO

OHHOHO

OHAcHNHO

OAcAcHNAcO

ether and THF

O+ SnBu2

2 H3C OH

Ph10 mol M(OTf)3

Solvent rt 12h

respectively

diallyldibuyltin

a Isolated yields

O+ SnBu2

2 R2 OH

R110 mol M(OTf)3

Entry R1 R2 Yield

1 Ph CH3 95

2 p-FC6H4 CH3 81

3 p-ClC6H4 CH3 75

4 p-BrC6H4 CH3 86

5 p-NO2C6H4 CH3 66

6 m-BrC6H4 CH3 93

7 m-CF3C6H4 CH3 90

8 p-MeC6H4 CH3 58

9 p-NH2C6H5 CH3 -

10 Ph Ph 42

14 CH2CH2CH3 CH3 45

15 CH2CH(CH3)2 CH3 27

16 p-MeOC6H4 H 80

a Isolated yields

In(OTf)3

O(TfO)2In

SnBu2OTf

OBu2Sn

Aluminium triflate

aluminium triflate

Al(OTf)3

NOAl(OTf)3

Yield ()

2 N OH

(CH2Cl)2

82 (11)

Al(OTf)338

various alcohols

Entry Product

1 39 R = Me 0 1 8 94

2 39 R = Et 94 95 -a -a

3 39 R = nPr 93 97 92 (4)b -a

4 39 R= iPr 91 92 -a -a

5 39 R = 2-Bu -a 14 97 96 (4)b

6 39 R = tBu -a 77 77 -a

-a 41 (34)b -a -a

-a 31 (24)b -a -a

-a 55 88 -a

-a 21 42 62

-a -a 89 -a

OCH2CH3

OHOCH2CH2CH3

OHOCH(CH3)2

OHOCH2CH2CH2CH3

EtOHAl(OTf)3 R

position

(Table 115)

aminesa

Product Yield ()

Al(OTf)3

Yield ()

Al(OTf)3

Yield ()

10 mol

Al(OTf)3

48 75b -

45 80b -

14 - 43c

31 (31)cd

- 35 (34)cd

regioisomer

Product Yield ()

Al(OTf)3

Yield ()

Al(OTf)3 OH

Gallium triflate

O O5 mol Ga(OTf)3

solvent

Ga(OTf)3

Entry Product Time

5 gt99

360 90

10 gt99

O 10 gt99

240 90

OO 10 98

(OTf)3Ga

Ga(OTf)3

H2N NH2

(OTf)3Ga

+ NH4OAcNH

NHCatalyst

ammonium acetate

NH4OAc or R3NH2 N

NCatalyst

R2CHOR1 R3

Ga(OTf)3

Entry R1 R2

NH4OAc

1 H p-(CH3)C6H4 NH4OAc 50 86

2 H 24-(OCH3)2C6H3 NH4OAc 45 90

3 H p-(N(CH3)2)C6H4 NH4OAc 35 88

5 H m-(F)C6H4 NH4OAc 50 85

7 H o-(NO2)C6H4 NH4OAc 70 71

8 H p-(NO2)C6H4 NH4OAc 60 73

13 Cl p-(F)C6H4 NH4OAc 55 83

15 H p-(OH)C6H4 sBuNH2 55 83

16 H p-(Cl)C6H4 nBuNH2 50 89

17 H p-(NO2)C6H4 nPrNH2 50 87

Entry R1 R2 Time

1 H p-(CH3)C6H4 50 84

2 H C6H4 55 83

3 H 24-(OCH3)2C6H3 50 89

4 H 34-(CH2O2)C6H3 55 84

5 H p-(N(CH3)2)C6H4 55 87

6 H p-(OH)C6H4 50 92

7 H m-(F)C6H4 55 84

8 H m-(Cl)C6H4 55 86

9 H p-(Cl)C6H4 55 89

10 H m-(NO2)C6H4 70 82

11 H p-(NO2)C6H4 65 81

12 H 2-Furyl 55 80

DMSO as a solvent

NH4OAc

CO2 NH2

RCHOGa(OTf)3

Ga(OTf)3

2 Ga(OTf)3N

48 49 50

51 52 53

(Ga(OTf)3)

Other triflates

RCN Cu(OTf)2

65 oC 30 min N

82 (91)c

NPh CH3

NPh Ph

(C6H4)Me-4

(C6H4)Me-4 PhCN N N

(C6H4)Me-4

CH3CN N N

(C6H4)Cl-4

PhCN N N

(C6H4)Cl-4

7 N Ts CH3CN N

Ts 62 (93)c

8 N Ts PhCN N

NTsC6Cl4H4

TsCu(OTf)2

Ts Cu(OTf)2Ph

NCu(OTf)2

55 56 57 58

Cs2CO3 DMF60 - 100

OH R3R4

R1 R1 R1R2R2R2

MeCN reflux

Cs2CO3 DMF74 - 95

MeCN reflux

by Bi(OTf)3

R2Y(OTf)3 5 mol

CH3CN rt

selectivity overall

good yields

AgOTfa

Isolated yields

Conclusions

Introduction

more complex

have to be found

comparative studies

be ICl gt I2 gt Br2

ketones

Δλ pK Δλ pK

GaBr3 66 -057 91 -061

GaCl3 63 -057 89 -051

ZnBr2 37 -052 48 -051

ZnCl2 39 -052 50 -039

BF3 59 +063 90 +251

Base rarr

Br2(g) - -144 +004 +0226 Cl2(g) - - +44 +165

Base rarr

-benzene

Naphalen

ICl 054 151 227 139 I2 015 031 135 025

Br2 011 023 - -

techniques

Order Method Ref

gtgt SiF4 ~ CrF3

ArH+MFn+1-

complex

Salt formation 100

spectroscopy

formation

the parameter

Ž = Z rk2 ndash 77Xz + 80 (8)

rk = ionic radius

bond strength)

IR spectroscopy

X in base

acetate

Δν (cm-1)

- ΔHf

(kcal mol-1)

F 119 317

Cl 176 395 (379)9

Br 191 445 (435)9

were solid samples

stoichiometry

BF3 156 1 1

PhSnCl3 150 1 1

ZnCl2 120 1 1

SnBr4 157 2 1

ZnBr2 118 2 1

SnCl4 158 2 1

GaCl3 157 1 1

BCl3 640 100 752 100 790 100

AlCl3 518 81 640 85 672 85

i-C4H9CCl2 500 78 511 68 536 68

BiCl3a 480 75 - - - -

TiCl4 - - 526 70 600 76

InCl3b 410 64 - - - -

BF3 391 61 458 61 498 63

SnCl4 - - 384 51 - -

SnBr4c 256 40 00 0 - 0

(i-C4H9)2BCl 252 40 00 0 00 -

AsCl3 110 11 - - - 0

SnI4 00 0 - - 00 0

SiCl4 00 0 00 0 00 0

GeCl4 00 0 00 0 00 0

PCl3 00 0 00 0 00 0

C5H9O3P C6H9O3P

Figure 17 Figure 18

crotonaldehydea

H1 H2 H3 H4 C1 C2 C3 C4

BBr3 011 093 149 051

BCl3 -065 085 135 049 68 -37 317 43

SbCl5 017 078 132 048 69 -40 276 37

AlCl3 -020 076 123 047

EtAlCl2bc -020 077 125 047

BF3 -027 074 117 044 83 -33 261 31

EtAlCl2bcd -017 067 115 038

Et3Al2Cl3b -015 069 114 039

TiCl4 003 060 103 036

Et2AlClbc -015 055 091 030 94 -20 201 23

SnC4 -002 050 087 029 78 -28 192 23

opposite direction

adducts

Acid ΔνC=O pK

BF3 156 -113

PhSnCl3 150 -114

ZnCl2 120 -148

SnBr4 157 -155

ZnBr2 118 -172

SnCl4 158 -266

GaCl3 157 lt-40

AsCl3 ca -

080 ca 63 ca 80 - - - -

SbCl3 -176 58 801 ca 74 - - -

BF3 -293 850 930 815 -186 72 ca 96

ZnBr2 -294 870 860 800 -217 148 890

ZnCl2 -294 870 558 802 -217 148 892

GaBr3 -340 2510 960 864 -249 310 1010

GaCl3 - - - - -253 340 1012

calculated

oxide as the base

acids125

acidity (Table 132)

Lewis acidity

that of Childs116

Conclusions

complex formation85

are being used

be addressed

reagents

OSiMe3Ln(OTf)3THF

CH2O aq Ph OH

Yield ()

100 mol 20 mol

1 La(OTf)3 90 23 88

2 Pr(OTf)3 92 40 80

3 Nd(OTf)3 74 6 89

4 Sm(OTf)3 92 51 91

5 Eu(OTf)3 92 28 93

6 Gd(OTf)3 92 20 79

7 Dy(OTf)3 89 20 85

8 Ho(OTf)3 91 38 86

9 Er(OTf)3 90 44 83

10 Yb(OTf)3 94 5 94

OSime3

THFH2O (41) rt 20h

NO3- and SO4

reactions136

PhCOH + Ph

OSiMe3

OH OMXn (02eq)

H2OTHF (91)rt 12 h

1 A 51 OSime3

2 B 74

3 C 79

5 HCOCH2OH H2O C 80

TBDMSO

BnO OO

TBDMSO

Sn InCl3

H2O rtR1

OH OH+

Isomer

(antisyn)b

7 C6H11CHO CO2Et

Br Sn InCl3 H2O (15 h) 65 6832

SnBrR InCl3H2O

R InCl2 +

InCl265 66 67

R InCl266

InCl2RH

reactions occur

Michael additions

+Yb(OTf)3

Yb(OTf)3

Other reactions

1 15 TfOH 7723 92

2 5 Bi(O2CCF3)3 7723 77

3 1 Bi(OTf)3 7228 94

4 5 Bi(OTf)3 8614 84

comparative reasons

H2N NH2

REtO2C

MeO CHOMeO

M(NTf2)norM(OTf)n

water rt 24 h

1 Ni(NTf2)2 59 65c 40d

3 Cu(NTf2)2 65 70c 62d

4 Cu(OTf)2 lt10b

5 Zn(NTf2)2 8

6 Yb(NTf2)3 88 90c

7 Yb(OTf)3 lt5b

4 Ni(NTf2)2 HCl 71

1 CH3CO2H (47) lt5

2 CF3CO2H (023) 56

3 HCl (-23) lt5

4 HNTf2 (12) 33

5 CH3SO2H (-12) lt5

15 Conclusions

16 References

Y 1929

1927 pp 60 and 116

Pa 1941

Easton Pa 1944

New York NY 1946

Mulliken papers)

London 1969

York 1973

Eur J 2008 14 3056

2003 68 9340

Sci 1999 71 1941

63 8478

Chem 2005 3 4129

Am Chem Soc 1965 88 986

2008 49 3814

Chem Ser 1968 72 265

1961 65 123

37 4629

132 Li C J Chem Rev 2005 105 3095

38 3465

Lett 2008 2289

Stark trap1

orthoester

HR+ C O

RH O R

H OO R

H + OH RH

O R HC O

Hemiacetal

oxonium cation

HR O R

HR OR H

H ROH2+

R2R1R2RO

reagent

the alcohol

Bacd Yield ()

Caef Yield ()

MeO OMe

H3CO 21

88g 97h 75 g (90)

EtO OEt

H3CO 22

67g 90h 72 g (80)

76 88 gt98i

79 90 gt98i

MeO OMe

O2N 25

97 94h 82g (94)h

EtO OEt

O2N 26

92 91h 57g (75)h

Bacd Yield ()

Caef Yield ()

MeO OMe

NO2 27

57 96 95

EtO OEt

NO2 28

64 92 gt98i

92 99 gt98i

72 93 96

11 OMeMeO

90 96 gt98i

12 OEtEtO

85 96 gt98i

78 74g gt98i

81 73g gt98i

Green Chemistry

not happen again11

destruction

bull Other

use of solvents

Yield () adf

MeO OMe

96 63 98 92

EtO OEt

83h 75 89 92

MeO OMe

94hj 0 92 73 (92)i

EtO OEt

77 0 0 75 (82)i

MeO OMe

80 33 77 90

EtO OEt

83 33 80 93

OMe 222

86 0 gt98k 96

OEt 223

74 0 82 92

formed

Run Yield ()abc

1 gt98

2 gt98

24 Deprotections

96 yield

OOOMeMeO

0 oC 15 h96

5 mol Al(OTf)3

MeO OMe

H3CO 21

MeO OMe

O2N 25

O N2 55

EtO OEt

Acetal Product

In(OTf)3

Hf(OTf)4

Cu(OTf)2

Ca(OTf)2

MeO OMe

21 H3CO

100 100 100 21

MeO OMe

O2N 25

O N2 89 100 18 15

EtO OEt

100 100 43 19

Acetal Product

Al(OTf)3

In(OTf)3

Hf(OTf)4

No Cat

MeO OMe

H3CO 21

100 100 100 100

MeO OMe

O2N 25

O N2 100a 100a 100a 100a

OMeMeO

O16 22 26 0

EtO OEt

100 100 100 68

O OMeR R

Acetal Product

Al(OTf)3

In(OTf)3

Hf(OTf)4

Sc(OTf)3

No Cat

MeO OMe

H3CO 21

100 100 100 100 97

MeO OMe

O2N 25

O N2 100a 100a 100a 100a 100a

EtO OEt

100 100 100 100 75

Silyl ethers

OH OTBDMS

224 (78)

15 eq Pyridine

OTBDMS

225 (80)

15 eq Pyridine

20 eq TBDMSCl

of 1 mol TfOH

reaction

Yield ()a

OTBDMS

Yield ()a

OTBDMS

O OROH

conditions23

overall efficiency

Yield ()

+O MeOH

OMeO+ H+

211 entry 1 and 2)

TBDMSO

OO 229

OTBDMS

TBDMSO

231 Yield ()

TBDMSO

O Yield ()

Yield ()

TBDMSO

OTBDMS

OMe 232

Yield ()

OTBDMS

O Yield ()

OTBDMS

faster reaction

OTBDMS

OMe Yield ()

OTBDMS

O Yield ()

OTBDMS

Al(OTf)3 82 18 0

Sc(OTf)3 91 9 0

In(OTf)3 94 6 0

Cu(OTf)2 gt98 0 0

Ca(OTf)2 gt98 0 0

29 Conclusions

210 References

R S J Org Chem 2002 67 5202

Ed 2008 47 560

Carb Res 2008 343 1814

New York 1991 31

Chapter 3

31 Introduction

M+n + H2O M OHH

solvents more fully

ROH + SO2 + RN

2I- I2 + 2e-

[alkylsulfite salt]

ammonium salt

mg of water

content8

Reading

Hydranal

Std Mass

content

1 0401 72

2 0391 80

3 0386 75

4 0390 74

5 0391 75

6 0411 77

7 0381 76

8 0375 80

9 0370 70

10 0391 75

Average 75 ppm

Std dev 03 ppm

RSD 39

Solvents

Residual water

contenta (ppm)

Std dev ppm RSD ()

DCM 4103 6 224 120 536 THF 2815 6 1078 066 062

acceptable limits

sieves9

Solvent

Residual water

contenta (ppm)

Std dev ppm

RSD ()

Experiment number

Residual water

contenta (ppm)

Std dev (ppm)

RSD ()

1 2836 6 1140 429 376

2 2650 6 440 066 150

repeatable

352 Drying reagents

36 The alcohols

sieves (5 wv)

Time (h) n

Average sample

weighta (g)

Residual water

content (ppm)

Std dev

24 6 2672 753 074 098 24 6 2621 789 067 085 24 6 2557 777 062 080 48 6 2488 452 055 122 48 6 2571 489 047 096 48 6 2612 464 082 177 72 6 2612 329 041 125 72 6 2488 343 040 117 72 6 2612 354 049 138

5 days 6 2523 257 124 482 5 days 6 2584 266 120 451

sieves (10 wv)

Time (h)

Residual water

content (ppm)

Std dev (ppm)

24 6 2688 407 093 229 24 6 2619 392 059 151 24 6 2624 419 041 098 48 6 2561 268 071 265 48 6 2508 293 071 242 48 6 2502 322 087 270 72 6 2612 224 042 188 72 6 2592 236 084 356 72 6 2505 263 063 240

5 days 6 2589 166 057 343 5 days 6 2573 182 058 319 5 days 6 2606 199 168 844

sieves (20 wv)

Time (h) n

Residual water

content (ppm)

Std dev

(ppm) RSD ()

24 6 2509 280 057 204 24 6 2609 292 042 144 24 6 2634 290 031 107 48 6 2496 211 046 218 48 6 2605 239 038 159 48 6 2556 244 087 357 72 6 2591 176 051 290 72 6 2541 188 055 293 72 6 2610 212 088 415

5 days 6 2575 97 099 1021 5 days 6 2542 104 049 471

(5 wv)

Time (h) n

Residual water

content (ppm)

Std dev

(ppm) RSD

24 6 2699 2511 181 072 24 6 2637 2703 166 061 24 6 2662 2664 250 094 48 6 2648 1021 075 073 48 6 2639 1064 074 070 48 6 2633 1110 055 050 72 6 2664 549 093 169 72 6 2639 541 059 109 72 6 2639 563 123 218

5 days 6 2635 144 051 354 5 days 6 2631 141 049 348 5 days 6 2659 149 015 101

(10 wv)

Time (h) n

Residual water

content (ppm)

Std dev ppm

RSD ()

24 6 2668 1894 153 081 24 6 2666 1792 081 045 24 6 2638 1896 050 026 48 6 2645 678 051 075 48 6 2637 695 064 092 48 6 2640 712 058 081 72 6 2642 351 107 305 72 6 2624 359 073 203 72 6 2616 397 118 297

5 days 6 2611 114 113 991 5 days 6 2658 130 076 585 5 days 6 2619 124 089 718

(20 wv)

Time (h)

Residual water

content (ppm)

Std dev ppm

RSD ()

24 6 2639 1186 058 049 24 6 2641 1190 109 092 24 6 2630 1218 037 030 48 6 2643 231 076 329 48 6 2639 243 055 226 48 6 2666 277 079 285 72 6 2604 190 028 147 72 6 2612 194 056 289 72 6 2608 231 061 264

5 days 6 2651 69 035 507 5 days 6 2612 81 035 432

5 days 6 2599 95 050 526

acceptable

powder

Average sample

weight (g) n

Residual water

contenta (ppm)

Std dev ppm

RSD ()

Methanol KOH (10 wv) 24 2525 6 318 081 255

Methanol KOH (10 wv) 24 2555 6 339 099 292

Methanol KOH (10 wv) 24 2606 6 337 093 276

Ethanol KOH (10 wv) 24 2856 6 259 074 286

Ethanol KOH (10 wv) 24 2760 6 284 053 187

Ethanol KOH (10 wv) 24 2640 6 250 056 225

37 Acetonitrile

Desiccant Time (h)

Residual water

contenta (ppm)

Std dev ppm

RSD ()

24 2628 6 40 065 1606 48 2626 6 18 050 2841 72 - 6 ltdlb - -

24 2643 6 05 041 8367

48 - 6 ltdlb - -

10 (wv) -c 2966 6 61 062 1015

10 (wv) -c 2924 6 49 015 306

10 (wv) -c 2826 6 68 037 537

titrations

Residual water

contenta (ppm)

Std dev ppm

RSD ()

(20 wv)

Time (h) n

Residual water

content (ppm)

Std dev (ppm)

RSD ()

24 6 3029 152 029 191 24 6 3027 143 012 084 24 6 3007 146 036 247 48 6 3034 59 021 356 48 6 3000 60 021 350 48 6 2998 64 010 156 72 6 2970 43 005 116 72 6 3016 42 018 429 72 6 2907 38 010 263

Fischer titration

Residual water

contenta (ppm)

Std dev ppm

RSD ()

repeatable

39 Discussion

310 Conclusions

38 References

Oxford 1963 682

41 Introduction

acidity6

literature

H3C CH3

CH3H3CN

CH3H3C

H3C CH3

CH3H3C

5 mol Bi(OTf)3 H2OH

Ph NH2

O NH OPh

41 42 43 44

Water 7 h

OTES OBz

OTES OH

Bz2O CH2CN

10 mol Sc(OTf)3

SO2PhBz2O CH3CN

OH O Ph

O3 eq Bz2O

Conversion

1 Yb(OTf)3 99 15 11

2 Bi(OTf)3 40 15 8

3 In(OTf)3 34 15 3

4 Sc(OTf)3 63 15 2

5 Cu(OTf)2 3 - -

6 Sc(OTf)3 63 5 6

OHHOHO

TfOH (005 eq) 10 min 84

OHHOHO

In(OTf)3 (005 eq) 1 h 99

OHHOHO

In(OTf)3 (005 eq)

With DTMP 24 h 11

OHH2NHO

In(OTf)3 (005 eq)

1 h NR

OHH2NHO

+ In(OTf)3

OIn(OTf)2H2N

+ HOTf

n(H2O)YbO

431 Introduction

OH H H

Enolate

OSiMe3+ R3 C R4

Lewis acid

OSiMe3 O

+MXn 02eq

THFH2O (91)12 h rt413 414 415

proceed no further

product

La(OTf)3 80

Ce(OTf)3 81

Pr(OTf)3 83

Nd(OTf)3 78

Sm(OTf)3 85

Eu(OTf)3 88

Gd(OTf)3 90

Tb(OTf)3 81

Dy(OTf)3 85

Ho(OTf)3 89

Er(OTf)3 86

Tm(OTf)3 85

Yb(OTf)3 92

Lu(OTf)3 84

Yield ()a

Hydrolysis of

Silyl ether

(silyl ether)

La(OTf)3 92 (80)b 8 0

InCl3 89 (68)b 3 8

CuCl2 86 (25)b 11 3

LiCl 6 (-)b 7 77

ScCl3 59 (70) 41 -

Er(OTf)3 56 (86)b 6 38

GaCl3 28 (-)b 56 16

ZnCl2 22 (10)b 0 78

AlCl3 0 (0)b 100 0

Cu(OTf)2 96 4 0

Sc(OTf)3 94 6 0

Y(OTf)3 89 11 0

Zn(OTf)2 77 2 21

Ca(OTf)2 42 28 30

In(OTf)3 41 59 0

Al(OTf)3 21 79 0

Zr(OTf)4 0 100 0

Hf(OTf)4 0 100 0

Li(OTf) 0 11 89

TiCl4 0 100 0

TiCl4 -098 100 TfOH 034 100

Y(OTf)3 445 6 Cu(OTf)2 464 4 Zn(OTf)2 540 2

LiCl 830 7 LiOTf 889 11

In(OTf)3 277 59 400 InCl3 432 6 400 ScCl3 254 41 430

Sc(OTf)3 275 6 430 CuCl2 408 11 753

ZnCl2 549 0 896 Ca(OTf)2 607 28 1285

LiCl 830 7 1364 LiOTf 889 11 1364 TfOH 034 100

rate constant

OSiMe3

PhCHO TiCl4 CH2Cl2

TiCl3Cl -Me3SiCl

Me PhPhPh

ClCl Cl

Me PhPhPh

catalytic cycle

THF H2O (91)

La(OTf)3 92 35 Y(OTf)3 89 83

788764755

Lewis Acid

Δδ H aldehyde

Δδ Ortho

protons

Δδ Para

protons

Δδ Meta

protons 1001 788 764 755

Sc(OTf)3 -0033a 0109 0108 0044

ScCl3 0054 0093 009 0029

In(OTf)3 -0015a 016 016 007

proceed (Figure45)

OSiMe3

M(OTf)3

phenomena

of ligands

Water 79

Acetonitrile 375

Methanol 315

Ethanol 242

Acetone 22

Chlorobenzene 56

Tetrahydrofuran 76

Ether 45

Benzene 23

Pentane 18

M3+M OTfTfO

OTf M OTf M OTF

Quadruplet

OTf M OTfTriplet

solvents

+-+- +-+- etc)32

Et3N + CH3Iδ δ

Solvent Dielectric

Hexane 20 1

MSn OH

+ MSn-1

+ S eq 42

MnXm-1

ion-pair formation

415)34

M+n + H2O M(H2O)x

M(H2O)x-1OH+n-1

Broslashnsted acid

particular

conditions

Lewis acid

Without

Yield ()

La(OTf)3 92 0 0

Sc(OTf)3 96 79 50

InCl3 89 99 0

Cu(OTf)2 94 65 0

N+ ROH

Lewis acid pH in

THFH2O (91)

pH in THFH2O

(91) and 15 eq

46 Summary

Retinyl acetate

CH2+ HO

triflate

Retinyl acetate +

hydrolysis

non- polar solvents

-OTf416

BA OTf-

Al(OTf)3

BA =Al(OTf)3K

5 mL of DCM

(Table 416)

Retinyl acetate +

Mr = 42544 F000 = 884

V = 17580 (2) Aring3 T = 296 (2) K

Lewis acid

Reaction Yield ()a

Reactions +200 uL

ScCl3 0 21 InCl3 50 53 TfOH 31 31

p-xylenea

Metal triflate

Yield ()b

4 mL p-xylene

Yield ()b

2 mL p-xylene

spectroscopy

systemsa

Lewis Acid 10 mol

Yield ()b

Cumene 16 mL 48 h

Yield ()b

Anisole 16 mL 24 h

Yield ()b

Toluene 16 mL 48 h

Zr(OTf)4 71 gt 95 66 Al(OTf)3 47 gt95 77

Metal Triflate

bottle

was 60

Hf(OTf)4)

attention

49 Conclusions

modified

410 References

M J Carb Res 2008 343 2814

68 9340

M J Carb Res 2008 343 2814

1994 188

1998 39 1641

1997 613

Chem Soc 2008 131 6342

2008 49 2384

Winston 1959

Chapter 5

51 Introduction

triflates

Crotonaldehyde

signala

Croton

aldehyde

Δ δ on

addition

Al(OTf)3

Δ δ on

addition

Δ δ on

addition

Sc(OTf)3

Δ δ on

addition

Δ δ on

addition

In(OTf)3

Δ δ on

addition

H-1 947 -026 -016 -025 003 -006 -007

H-2 610 054 013 044 045 030 027

H-3 687 093 023 093 071 050 043

Lewis acids

signala

Croton

aldehyde

Δ δ on

addition

Al(OTf)3

Δ δ on

addition

Δ δ on

addition

Sc(OTf)3

Δ δ on

addition

Δ δ on

addition

In(OTf)3

Δ δ on

addition

C-1 1941 111 04 116 175 04 29

C-2 1348 -20 05 -14 -15 03 -02

C-3 1544 219 02 221 1752 04 45

C3C2 C1

NMR signala

Trans-

cinnamaldehyde

δ ppm

Hf(OTf)4 003 005 13 -02 12

Sc(OTf)3 -016 -002 24 01 25

In(OTf)3 -0171 0047 17 00 16

Ca(OTf)2 -0074 0014 04 -04 02

Zn(OTf)2 -005 0038 29 03 26

Y(OTf)3 -0048 0145 31 03 33

Zr(OTf)4 -0107 004 23 -07 24

Al(OTf)3 -0076 0032 09 00 09

Lewis acids

Phosphorus NMR

thermodynamic data

Phosphorus compound

δ uncomplexeda

Δ δ on addition

of Al(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of In(OTf)3

(OTf)3M

NMR signal

Croton aldehyde

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

18 aH-1 947 -027 -022 -015 -008

H-2 687 045 014 026 014

H-3 610 100 083 057 024

CH3 201 028 023 014 005

NMR signal

Croton aldehyde

Δ δ on addition

of In(OTf)3

Δ δ on addition

of In(OTf)3

Δ δ on addition

of In(OTf)3

Δ δ on addition

of InOTf)3

18 aH-1 947 -009 -008 -007 -006

H-2 687 027 019 010 008

H-3 610 049 037 021 017

solvent to solvent

A = εbc 1

(Figure 58)9

(Figure 59)

complex

the probes

Lewis Acid

laboratory

method was sought

may be obtained

[bmim][OTf]

acid coordination

LiOTf 14422 22 -a

Ca(OTf)2 14424 24 -a

Zn(OTf)2 14520 120 -a

Cu(OTf)2 14530 130 -a

Ba(OTf)2 14610 210 -a

LiCl 14860 460 -a

ScCl3 14870 470 -a

InCl3 14890 490 -a

metal salts

activity

Table 58

14694 14694 14694 14694

144428 14463 14463 14463

the Lewis acids

55 Conclusions

References

Int Ed 2008 47 560

Main conclusions

identified

Future research

expensive triflates

Chapter 6

611 Chromatography

prior to use

63 Melting Points

uncorrected

64 Chemical methods

Chapter 2

MeO OMe

Yield 97 yellow oil

Obtained = 1510753

EtO OEt

Yield 90 yellow oil

Obtained = 1650910

Obtained = 1569867

Obtained = 1690416

MeO OMe

(ortho) 491 (2 x OCH3) 258 (CH3)

Obtained = 1960593

EtO OEt

Yield 92 yellow oil

(CH3) 151 (OCH3)

Obtained = 1940811

MeO OMe

(C3) 1280 (C5) 1241 (C4) 997 (acetal) 544 (2 x OCH3)

Obtained = 1660498

EtO OEt

1241 (C4) 983 (acetal) 634 (2 x OCH2) 150 (2 x CH3)

Obtained = 1800655

Ph OMe

x OCH3)

Obtained = 1470805

Ph OEt

Obtained = 1610960

Obtained = 1711741

Obtained = 1851902

(C3 and C5) 263 (C4) 257 (C4 and C6)

Obtained = 1271099

Obtained = 1411275

Yield 98White solid

Obtained = 1921147

MeO OMe

(ortho) 1031 (CH) 526 (OCH3)

Obtained = 1210445

EtO OEt

Obtained = 1350807

MeO OMe

Obtained = 1510755

EtO OEt

(OCH2CH3)

Obtained = 1791067

(C4) 228 (C3 C5)

Obtained = 1130967

2H H2 H6) 147 (m 2H H3 H5) 137 (m 1H H4) 115 (t 6H J =

(C4) 230 (C3 C5) 156 (2 x CH2CH3)

Obtained = 1281196

Obtained = 1110465

Obtained = 1250597

OTBDMS

(C(CH3)3 -54 (OSi(CH3)2)

Obtained = 1790887

OTBDMS

Obtained = 2289670

was used

(C5) 254 (C4) 194 (C3)

Obtained = 1220727

mp 566ndash584

1138 (para) 965 (acetal) 620 (C2) 302 (C5) 251 (C4) 186 (C3)

Obtained = 179521

618 (C2) 540 (HCequivCCH2) 301 (C3) 252 (C3) 252 (C4) 190

Obtained = 850646

1262 (C2) 1207 (C6) 1100 (C5) 554 (OCH3) 255 (C(CH3)3) 184

(C(CH3)3 -46 (OSi(CH3)2)

Obtained = 2090629

OTBDMS

Yield 90 yellow oil

1215 (C5 C6) 1202 (C3) 256 (C(CH3)3) 163 (C(CH3)3 -43

(OSi(CH3)2)

Obtained = 1790523

TBDMSO

OTBDMS

120 (C6) 1010 (acetal) 538 (2 x OCH3) 263 (C(CH3)3) 192

(C(CH3)3 -40 (OSi(CH3)2)

Obtained = 2250946

Chapter 3

i=1(xi - μ)2

Eq 1 RSD = ( x) x 100σ Eq 2

x = sample mean

data see appendix A

Chapter 4

To make LDA

10 minutes

chromatography

OSiMe3

Obtained = 1340732

Obtained = 2250946

(CH2CH3)

Obtained = 2880755

6410 Crystal data

Mr = 42544 F000 = 884

λ = 071073 Aring

V = 17580 (2) Aring3 T = 296 (2) K

Data collection

CCD area detector

T = 296(2) K θmax = 280deg

Refinement

Fourier map

neighbouring sites

wR(F2) = 0137 w = 1[σ2(Fo

2) + (00834P)2]

S = 098 (Δσ)max = 2220

706 (s 1H H2) 706 (d 2H J = 18 H4 H5) 577 (d 1H J = 15 Hz

1330 (C6) 1307 (C5) 1300 (C6) 1283 (C10 and C12) 1282 (C11)

1275 (C2) 1265 (C9 and C13) 1146 (C14) 210 (C16) 196 (C15)

Obtained = 2081240

Chapter 5

at 25 degC

NMR spectroscopy

11 01 mmol 01 mmol

12 01 mmol 02 mmol

14 01 mmol 04 mmol

18 01 mmol 08 mmol

65 References

Chem Soc 2006 128 5930

60 4037

1 2765 CL 95

2 2874 1015 3 2874 1025 4 2749 1018 5 2868 1019 6 2761 1013

Average 2815 1018

1 2933 1171 2 2780 1189 3 2806 1132 4 2951 1071 5 2867 1116 6 2838 1161

Average 2863 1140

1 2638 441 2 2656 435 3 2648 441 4 2675 449 5 2639 431 6 2641 446

Average 2650 440

1 2673 432 2 2702 422 3 2698 421 4 2657 434 5 2712 420 6 2668 436

Average 2685 428

1 2840 276 2 2795 290 3 2917 291 4 2647 272 5 2730 267 6 2762 271

Average 2782 278

1 3000 593 2 2906 572 3 2860 560 4 2880 520 5 2853 578 6 2800 550

Average 2883 562

1 2973 807 2 2960 CL 95

3 2965 824 4 3005 824 5 2993 837 6 2987 834

Average 2981 825

1 2900 1066 2 2942 1057 3 2735 1097 4 2902 1009 5 2854 1025 6 2894 1090

Average 2871 1057

1 2981 909 2 2821 896 3 2921 864 4 2922 866 5 2932 939 6 2848 889

Average 2904 894

1 2857 742 2 2889 763 3 2806 747 4 2838 712 5 2821 774 6 3027 739

Average 2873 746

1 2952 618 2 2959 597 3 2888 649 4 2933 598 5 2860 550 6 2987 560

Average 2930 595

1 2937 730 2 2872 716 3 2920 688 4 2903 646 5 2915 659 6 2933 702

Average 2913 690

1 2939 606 2 2953 624 3 2975 630 4 2967 613 5 2825 575 6 2901 603

1 3112 156 2 2998 151 3 3100 149 4 2976 153 5 2987 148 6 3001 153

1 3101 145 2 2964 143 3 2899 142 4 3112 CL 95

5 3103 143 6 2981 142

Average 3027 143

1 2899 146 2 2976 140 3 2988 147 4 2978 143 5 3100 149 6 3102 149

Average 3007 146

1 3004 59 2 2987 57 3 3003 58 4 3067 57 5 3076 61 6 3064 62

Average 3034 59

1 3044 61 2 2988 59 3 3000 58 4 2991 62 5 2989 62 6 2988 57

Average 3000 60

1 3014 63 2 2994 64 3 2983 61 4 2997 63 5 2996 62 6 3004 62

1 2864 43 2 2990 43 3 2999 44 4 2988 CL 95

5 3009 44 6 2968 43

Average 2970 43

1 3074 41 2 2998 41 3 2995 42 4 3031 45 5 3006 43 6 2994 40

Average 3016 42

1 3014 39 2 2918 38 3 2990 37 4 3011 37 5 3029 39 6 2948 39

Average 2985 38

1 3004 55 2 3100 56 3 2713 54 4 2985 57 5 3005 56 6 3001 55

Average 2968 56

1 2934 49 2 2991 48 3 2997 48 4 2990 47 5 3010 CL 95

6 3084 46 Average 3001 48

1 2948 54 2 2789 53 3 2994 54 4 2783 55 5 2956 53 6 2973 56

1 2568 1427 2 2371 1436 3 2666 1426 4 2559 1407 5 2598 1418 6 2554 1407

Average 2553 1420

1 2646 45 2 2634 45 3 2574 38 4 2631 46 5 2645 40 6 2638 29

Average 2628 40

1 2604 19 2 2645 16 3 2673 26 4 2536 20 5 2645 13 6 2655 12

Average 2626 18

1 2652 12 2 2584 01 3 2652 02 4 2653 07 5 2657 02 6 2660 04

Average 2643 05

1 2963 69 2 2991 66 3 2953 58 4 2960 64 5 2965 56 6 2964 54

Average 2966 61

1 2913 CL = 95

2 2951 49 3 2923 51 4 2940 49 5 2925 50 6 2894 47

Average 2924 49

1 2943 67 2 2911 65 3 2863 73 4 2440 69 5 2895 64 6 2904 72

1 2563 1748 2 2576 1746 3 2603 1757 4 2590 1749 5 2594 1754 6 2613 1755

Average 2590 1751

1 2689 758 2 2625 740 3 2664 751 4 2674 CL 95

5 2678 761 6 2702 756

Average 2672 753

1 2643 794 2 2598 786 3 2586 787 4 2633 798 5 2644 779 6 2635 792

Average 2621 789

1 2584 779 2 2552 768 3 2621 774 4 2556 781 5 2529 CL 95

6 2497 785 Average 2557 777

1 2703 417 2 2671 394 3 2712 409 4 2654 412 5 2648 398 6 2739 414

Average 2688 407

1 2568 398 2 2633 387 3 2574 397 4 2632 CL 95

5 2695 396 6 2613 386

Average 2619 393

1 2598 420 2 2648 418 3 2653 417 4 2589 424 5 2655 421 6 2599 412

Average 2624 419

1 2589 288 2 2498 273 3 2534 279 4 2477 284 5 2490 CL 95

6 2465 274 Average 2509 279

1 2541 292 2 2653 289 3 2666 287 4 2579 294 5 2534 299 6 2683 291

Average 2609 292

1 2695 293 2 2653 291 3 2648 288 4 2589 290 5 2648 293 6 2568 285

Average 2634 290

1 2529 462 2 2428 447 3 2484 451 4 2437 453 5 2590 448 6 2459 449

Average 2488 452

1 2491 493 2 2623 486 3 2626 489 4 2489 482 5 2564 495 6 2633 489

Average 2571 489

1 2615 463 2 2613 459 3 2608 470 4 2619 474 5 2558 467 6 2658 451

Average 2612 464

1 2575 275 2 2573 266 3 2640 268 4 2530 278 5 2458 264 6 2590 259

Average 2561 268

1 2530 283 2 2528 294 3 2530 285 4 2447 301 5 2550 CL 95

6 2463 298 Average 2508 292

1 2451 313 2 2500 324 3 2506 324 4 2519 334 5 2504 329 6 2533 312

Average 2502 323

1 2549 203 2 2428 211 3 2514 213 4 2437 216 5 2627 209 6 2419 213

1 2675 243 2 2423 236 3 2608 243 4 2630 234 5 2671 238 6 2620 241

1 2560 256 2 2508 247 3 2570 234 4 2457 246 5 2650 249 6 2593 234

Average 2556 244

1 2615 324 2 2613 327 3 2608 332 4 2619 335 5 2558 326 6 2658 330

Average 2612 329

1 2529 339 2 2428 342 3 2484 347 4 2437 337 5 2590 346 6 2459 345

Average 2488 343

1 2615 349 2 2613 358 3 2608 356 4 2619 CL 95

5 2558 359 6 2658 354

Average 2612 355

1 2655 221 2 2550 232 3 2608 225 4 2618 224 5 2614 221 6 2626 222

1 2645 CL 95

2 2633 236 3 2540 245 4 2540 246 5 2538 224 6 2658 231

1 2479 257 2 2428 264 3 2474 267 4 2537 254 5 2640 271 6 2471 263

Average 2505 263

1 2590 174 2 2570 180 3 2658 CL 95

4 2519 169 5 2598 183 6 2610 173

Average 2591 176

1 2539 184 2 2628 193 3 2464 191 4 2447 CL 95

5 2540 195 6 2629 183

Average 2541 189

1 2651 205 2 2450 211 3 2668 204 4 2678 224 5 2684 205 6 2526 221

Average 2610 212

1 2539 253 2 2628 243 3 2534 262 4 2417 274 5 2560 264 6 2459 243

Average 2523 257

1 2675 269 2 2560 274 3 2517 243 4 2606 273 5 2526 CL 95

6 2622 261 Average 2584 264

1 2460 274 2 2410 264 3 2584 289 4 2447 271 5 2580 264 6 2489 273

Average 2495 273

1 2574 167 2 2613 159 3 2588 173 4 2569 160 5 2608 164 6 2579 171

Average 2589 166

1 2489 189 2 2588 173 3 2524 183 4 2697 CL 95

5 2578 179 6 2559 183

Average 2573 181

1 2570 193 2 2590 187 3 2628 183 4 2620 194 5 2588 206 6 2638 229

Average 2606 199

1 2420 115 2 2590 96 3 2640 95 4 2669 89 5 2638 101 6 2490 88

Average 2575 97

1 2559 103 2 2478 107 3 2624 99 4 2497 111 5 2620 CL 95

6 2471 98 Average 2542 104

1 2641 124 2 2540 127 3 2596 104 4 2602 118 5 2606 99 6 2634 115

Average 2603 115

1 2569 305 2 2548 312 3 2489 325 4 2548 316 5 2450 324 6 2548 324

Average 2525 318

1 2459 354 2 2657 334 3 2658 341 4 2549 342 5 2459 324 6 2548 341

Average 2555 339

1 2658 331 2 2642 324 3 2548 335 4 2548 342 5 2658 339 6 2549 351

Average 2600 337

Methanol from MgI2

1 2660 545 2 2385 537 3 2693 540 4 2683 531 5 2531 530 6 2667 533

1 2650 14291 2 2537 14327 3 2618 14306 4 2653 14218 5 2673 14263 6 2598 14292

Average 2622 14283

1 2701 2516 2 2694 2486 3 2698 2508 4 2704 2496 5 2699 2523 6 2700 2536

Average 2699 2511

1 2655 2676 2 2596 2715 3 2626 2705 4 2572 2691 5 2684 CL 95

6 2691 2720 Average 2637 2701

1 2658 2651 2 2645 2671 3 2632 2644 4 2651 2712 5 2671 2656 6 2713 2652

Average 2662 2664

1 2661 CL 95

2 2664 1882 3 2678 1887 4 2674 1892 5 2659 1891 6 2670 1887

Average 2668 1888

1 2665 1804 2 2650 1793 3 2638 1795 4 2659 1781 5 2675 1785 6 2709 1793

Average 2666 1792

1 2653 1904 2 2592 1899 3 2629 1895 4 2576 1889 5 2687 1896 6 2693 1895

Average 2638 1896

1 2651 1183 2 2689 1185 3 2628 1191 4 2581 1195 5 2685 CL 95

6 2597 1184 Average 2639 1188

1 2647 1206 2 2591 1193 3 2629 1196 4 2579 1189 5 2695 CL 95

6 2705 1184 Average 2641 1194

1 2661 1214 2 2647 1216 3 2539 1220 4 2657 1221 5 2672 1215 6 2604 1223

Average 2630 1218

1 2643 CL 95

2 2692 1020 3 2639 1018 4 2586 1016 5 2693 1024 6 2633 1014

Average 2648 1018

1 2695 1065 2 2650 1076 3 2643 1065 4 2659 1054 5 2575 1059 6 2609 1063

1 2651 1107 2 2724 1106 3 2668 1113 4 2634 1111 5 2509 1119 6 2610 1104

Average 2633 1110

1 2541 672 2 2667 678 3 2648 679 4 2694 682 5 2649 685 6 2669 673

Average 2645 678

1 2666 694 2 2525 696 3 2636 689 4 2653 CL 95

5 2701 687 6 2643 703

1 2652 710 2 2591 717 3 2633 703 4 2579 719 5 2693 709 6 2693 713

Average 2640 712

1 2671 242 2 2644 229 3 2622 227 4 2654 231 5 2659 220 6 2610 237

Average 2643 231

1 2681 245 2 2634 249 3 2618 246 4 2634 236 5 2629 247 6 2640 237

1 2666 267 2 2649 270 3 2636 281 4 2659 279 5 2680 276 6 2708 289

1 2661 532 2 2652 558 3 2634 553 4 2657 556 5 2680 548 6 2702 549

Average 2664 549

1 2646 541 2 2595 539 3 2632 537 4 2577 546 5 2690 548 6 2694 532

Average 2639 541

1 2652 569 2 2627 577 3 2666 574 4 2648 549 5 2609 CL 95

6 2630 549 Average 2639 564

1 2651 367 2 2592 339 3 2635 342 4 2586 346 5 2690 CL 95

6 2699 357 Average 2642 350

1 2647 368 2 2600 365 3 2639 352 4 2574 350 5 2689 362 6 2593 356

1 2663 387 2 2653 395 3 2538 397 4 2658 402 5 2585 417 6 2599 384

1 2649 190 2 2522 189 3 2634 187 4 2526 192 5 2683 194 6 2611 187

Average 2604 190

1 2655 189 2 2550 196 3 2608 197 4 2618 185 5 2614 196 6 2626 CL 95

Average 2612 193

1 2648 224 2 2556 226 3 2663 240 4 2524 231 5 2643 236 6 2612 229

Average 2608 231

1 2569 139 2 2668 138 3 2584 144 4 2637 152 5 2690 146 6 2659 142

Average 2635 144

1 2591 133 2 2623 142 3 2726 146 4 2589 140 5 2664 139 6 2593 146

Average 2631 141

1 2641 148 2 2643 151 3 2706 147 4 2649 150 5 2704 149 6 2613 148

Average 2659 149

1 2529 120 2 2618 128 3 2614 119 4 2607 113 5 2660 103 6 2639 CL 95

Average 2611 117

1 2631 136 2 2663 125 3 2716 125 4 2609 139 5 2744 120 6 2583 135

Average 2658 130

1 2581 134 2 2653 131 3 2676 124 4 2549 110 5 2714 128 6 2543 118

Average 2619 124

1 2687 75 2 2655 69 3 2680 68 4 2659 64 5 2615 70 6 2609 69

Average 2651 69

1 2496 81 2 2589 76 3 2620 80 4 2680 79 5 2677 85 6 2609 85

1 2541 92 2 2593 95 3 2663 87 4 2527 CL 95

5 2648 94 6 2619 97

Average 2599 93

1 2875 257 2 2975 249 3 2896 258 4 2846 260 5 2758 272 6 2785 258

Average 2856 259

1 2587 278 2 2846 291 3 2874 286 4 2795 CL 95

5 2876 279 6 2579 284

Average 2760 284

1 2579 251 2 2858 254 3 2548 254 4 2479 252 5 2797 249 6 2579 239

1 4167 263 2 4146 230 3 4154 222 4 4079 205 5 3923 226 6 4151 237

Average 4103 231

1 4393 01 2 4172 02 3 4405 02 4 4183 00 5 4285 01 6 4168 02

1 4198 15 2 4206 09 3 4149 09 4 4168 14 5 4286 15 6 4295 CL = 95

Average 4217 13

DCM dried over CaH2

1 4206 147 2 4357 121 3 3871 129 4 4215 114 5 4347 121 6 3927 140

Average 4154 129

Front page



Faculty of Science



June 2009

Table of Contents

Synopsis

Abbreviations

Figures and schemes

Chapter 1

Chapter 2

Chapter 3_12099

Chapter 4

Chapter 5


Chapter 6

Appendix A


reaction

152 ndash 158

solvents

159 ndash 162

crystallography

176 ndash 177

Chapter 5

51 Introduction 186

54 Conclusions 207

55 References 208

Chapter 6

alcohols

65 References 242

observed

solvents

Abbreviations

Aring angstrom

Bn benzyl

Bu butyl

C coulomb

CL confidence level

CPL ε-caprolactone

Cy cyclohexyl

d doublet

DCM dichloromethane

DHP dihydropyran

DL detection limit

Eq equivalents

EtOH ethanol

Et3N triethylamine

h hour

IR infrared

i-Pr iso-propyl

mp melting point

MeOH methanol

Me methyl

OAc acetate

PDI polydispersity

Ph phenyl

q quartet

rt room temperature

s singlet

t triplet

t-Bu tert-butyl

TES triethylsilyl

THF tetrahydrofuran

THP tetrahydropyran

TMS trimethylsilyl

thesis)

VL valerolactone

wrt with respect to

Scheme

Figure Heading Page

alcohols 29

by Bi(OTf)3 41

Figure 110

values 61

formaldehyde 65

Scheme 130

by InCl3 69

and urea 73

Scheme

Figure Heading Page

bromophenol 98

Scheme

Figure Heading Page

over time 122

over time 124

Scheme

Figure Heading Page

by water 153

organic solvent 161

nucleophile 164

Figure 49

of the solutions

Figure 412

counterion 176

Scheme

Figure Heading Page

triflate 195

to Lewis acid 201

List of tables

Table Heading Page

Table 13

different additives

with In(OTf)3 25

Table 117

Ga(OTf)3

bases at 28 degC 54

one 57

(9-fluorenone) 62

Ln(OTf)3 65

aldehydes 70

Table 139

Table Heading Page

ketones 85

ketones 86

ketones 90

the substrate 92

metal triflates 94

Al(OTf)3 102

triflates 105

Table Heading Page

standard 115

SilicaSodium 118

Table 315

alumina

Table Heading Page

mixture 150

solvents 161

DTBMP 164

without DTBMP 164

carbocation 167

pyridine 178

Table Heading Page

Table 51

Table 52

Table 53

Chapter 1

Introduction

system theories5

a proton acceptor

equation 3

ψ ψ ψAB = a 0 (AB) + b 1 (A-B+) (3)

ψ1 (A-B

β 01 EoSo1( )_ 2

E1_ Eo( )

EAB = Eo_

equation 5)

Σ ΣΔΕ β_ qsqt

Conclusions

reaction mixtures

amounts

(see Chapter 4)

OAcMeOOC O

OMeOOC

BnO OAc

O(OTf)3M

Lanthanide Reaction

Yb(OTf)3 180 70

Eu(OTf)3 90 85

Sm(OTf)3 90 92

AcOAcOAcO

AcOAcO

AcO COOMe

OAc Nd(OTf)3

MeOH rt 4 h

Nd(OTf)3

MeOH rt 4 h

AcOAcO

AcO COOMe

metal triflates

Starting

material Product

Yb(OTf)3a

Yield ()

Eu(OTf)3a

Yield ()

Sm(OTf)3a

Yield ()

Nd(OTf)3a

Yield ()

AcOAcAcOAcOAcO H

OAcOAcO

85 81 85 81

OAcAcOAcO

AcO CH2OAc

AcOAcO

AcO CH2OAc

68 78 82 82

OAcAcOAcOcO

CH2OAc

AcOAcOAcO

CH2OAc

61 62 79 81

HAcOAcOAcO

CH2OAc

AcOAcOAcO

CH2OAc

67 62 67 68

OIn (10 eq)

THFH2O 40 oC 20h

+ TIPS CF2

215 16 17 18

1 H2OTHF (41) 11 - 206

2 H2OTHF (41) 11 - 3112

3 H2OTHF (41) 11 - 257

4 Satd NH4Cl(aq)THF (41) 11 - 204

7 H2OTHF (41) 22 - 298

8 H2OTHF (41) 33 - 364

9 H2OTHF (41) 11 Sc(OTf)3 424

10 H2OTHF (41) 11 Er(OTf)3 647

11 H2OTHF (41) 11 Eu(OTf)3 788

12 H2OTHF (41) 11 Tb(OTf)3 7610

13 H2OTHF (41) 11 Sm(OTf)3 489

14 H2OTHF (41) 11 Y(OTf)3 4713

BrF + R

H2OTHF (41) 40 oC 20h

1 TIPS Ph 68

2 TES Ph 72

3 TMSb Ph 41

(18 scheme 14)

In (reducing agent)

examples

OHHO CO2Me

+Lewis acid

CH2Cl2 or CH3NO2

HO CO2Me

naphthyl)ethanol

(2-naphthyl)ethanol

mol Time h Yield ()

1a TiCl4 100 1 6

2a BF3OEt2 100 1 96

3a BF3OEt2 10 1 6

4b La(OTf)3 1 05 99

5b La(OTf)3 01 1 98

6b La(OTf)3 001 24 93

7b La(OTf)3 1 15c 98

8b Yb(OTf)3 1 033 96

OHHO CO2R

+1 mol La(OTf)3

HO CO2R

R25 26 27

CH3NO2

alcohols

1 H Me 15 min 99

2 OSiR3a Me 2 h 93

3 OAc Me 6 h 95

4 OBn Me 14 h 97

1 H Me Hf 5 min 89

3 H Me Sc 15 min 99

4 H Me Yb 25 min 99

5 H Bn La 25 h 99

6 H t-Bu La 19 h 59

a TfOH 3 mol

Nucleophile

Olefin

Triflate

H2OOHAr

Triflate Ar O Ar

Products

Ar = Ph

Ar = 2-naphthyl

process5758

2 mol M(OTf)x

toluene 25 oCO

of n-BnOH

Mol Time (h)

1 CPL 0 4 gt99 6900

2 CPL 2 23 gt99 3500

3 CPL 5 2 gt99 2400

4 CPL 10 2 gt99 1600

5 VL 0 15 96 4300

6 VL 2 1 95 2900

7 VL 5 1 97 1900

1 Sc [BF4]- 2 d 0 -

2 Y [BF4]- 7 d 29 500

3 La [BF4]- 2 d 29 300

4 Ceb [BF4]- 6 d 32 600

5 Nd [BF4]- 6 d 30 500

6 Eu [BF4]- 2 d 0 -

7 Gd [BF4]- 5 d 30 600

8 Yb [BF4]- 4 d 27 500

9 Lu [BF4]- 3 d 26 500

10 Sc [PF6]- 42 80 2500

11 Y [PF6]- 53 83 2800

12 La [PF6]- 46 100 3700

13 Ceb [PF6]- 47 100 3500

14 Nd [PF6]- 35 100 2700

15 Eu [PF6]- 49 100 2400

16 Gd [PF6]- 48 100 3400

17 Yb [PF6]- 48 43 1600

18 Lu [PF6]- 47 100 4400

19 Sc [SbF6]- 30 87 900

20 Y [SbF6]- 48 99 1800

21 La [SbF6]- 42 100 1800

22 Ceb [SbF6]- 29 100 1700

23 Nd [SbF6]- 43 100 1700

24 Eu [SbF6]- 48 4 1500

25 Gd [SbF6]- 29 100 2500

26 Yb [SbF6]- 48 82 1400

Sc(OTf)3

O(TfO)3Sc

OSc(OTf)3

Sc(OTf)3

Propagation

monomer mechanism

R NH2+

001 molYb(OTf)3

yields

Indium triflate

AcOAcO

OHHOHO

OAcAcOAcO

OHHOHO

OAcAcOAcO

AcOH3C

OH HO O

OAcOAc

OAc AcO 97

OAcAcOAcO

OHHOHO

OAcAcOAcO

OHHOHO

OHAcHNHO

OAcAcHNAcO

ether and THF

O+ SnBu2

2 H3C OH

Ph10 mol M(OTf)3

Solvent rt 12h

respectively

diallyldibuyltin

a Isolated yields

O+ SnBu2

2 R2 OH

R110 mol M(OTf)3

Entry R1 R2 Yield

1 Ph CH3 95

2 p-FC6H4 CH3 81

3 p-ClC6H4 CH3 75

4 p-BrC6H4 CH3 86

5 p-NO2C6H4 CH3 66

6 m-BrC6H4 CH3 93

7 m-CF3C6H4 CH3 90

8 p-MeC6H4 CH3 58

9 p-NH2C6H5 CH3 -

10 Ph Ph 42

14 CH2CH2CH3 CH3 45

15 CH2CH(CH3)2 CH3 27

16 p-MeOC6H4 H 80

a Isolated yields

In(OTf)3

O(TfO)2In

SnBu2OTf

OBu2Sn

Aluminium triflate

aluminium triflate

Al(OTf)3

NOAl(OTf)3

Yield ()

2 N OH

(CH2Cl)2

82 (11)

Al(OTf)338

various alcohols

Entry Product

1 39 R = Me 0 1 8 94

2 39 R = Et 94 95 -a -a

3 39 R = nPr 93 97 92 (4)b -a

4 39 R= iPr 91 92 -a -a

5 39 R = 2-Bu -a 14 97 96 (4)b

6 39 R = tBu -a 77 77 -a

-a 41 (34)b -a -a

-a 31 (24)b -a -a

-a 55 88 -a

-a 21 42 62

-a -a 89 -a

OCH2CH3

OHOCH2CH2CH3

OHOCH(CH3)2

OHOCH2CH2CH2CH3

EtOHAl(OTf)3 R

position

(Table 115)

aminesa

Product Yield ()

Al(OTf)3

Yield ()

Al(OTf)3

Yield ()

10 mol

Al(OTf)3

48 75b -

45 80b -

14 - 43c

31 (31)cd

- 35 (34)cd

regioisomer

Product Yield ()

Al(OTf)3

Yield ()

Al(OTf)3 OH

Gallium triflate

O O5 mol Ga(OTf)3

solvent

Ga(OTf)3

Entry Product Time

5 gt99

360 90

10 gt99

O 10 gt99

240 90

OO 10 98

(OTf)3Ga

Ga(OTf)3

H2N NH2

(OTf)3Ga

+ NH4OAcNH

NHCatalyst

ammonium acetate

NH4OAc or R3NH2 N

NCatalyst

R2CHOR1 R3

Ga(OTf)3

Entry R1 R2

NH4OAc

1 H p-(CH3)C6H4 NH4OAc 50 86

2 H 24-(OCH3)2C6H3 NH4OAc 45 90

3 H p-(N(CH3)2)C6H4 NH4OAc 35 88

5 H m-(F)C6H4 NH4OAc 50 85

7 H o-(NO2)C6H4 NH4OAc 70 71

8 H p-(NO2)C6H4 NH4OAc 60 73

13 Cl p-(F)C6H4 NH4OAc 55 83

15 H p-(OH)C6H4 sBuNH2 55 83

16 H p-(Cl)C6H4 nBuNH2 50 89

17 H p-(NO2)C6H4 nPrNH2 50 87

Entry R1 R2 Time

1 H p-(CH3)C6H4 50 84

2 H C6H4 55 83

3 H 24-(OCH3)2C6H3 50 89

4 H 34-(CH2O2)C6H3 55 84

5 H p-(N(CH3)2)C6H4 55 87

6 H p-(OH)C6H4 50 92

7 H m-(F)C6H4 55 84

8 H m-(Cl)C6H4 55 86

9 H p-(Cl)C6H4 55 89

10 H m-(NO2)C6H4 70 82

11 H p-(NO2)C6H4 65 81

12 H 2-Furyl 55 80

DMSO as a solvent

NH4OAc

CO2 NH2

RCHOGa(OTf)3

Ga(OTf)3

2 Ga(OTf)3N

48 49 50

51 52 53

(Ga(OTf)3)

Other triflates

RCN Cu(OTf)2

65 oC 30 min N

82 (91)c

NPh CH3

NPh Ph

(C6H4)Me-4

(C6H4)Me-4 PhCN N N

(C6H4)Me-4

CH3CN N N

(C6H4)Cl-4

PhCN N N

(C6H4)Cl-4

7 N Ts CH3CN N

Ts 62 (93)c

8 N Ts PhCN N

NTsC6Cl4H4

TsCu(OTf)2

Ts Cu(OTf)2Ph

NCu(OTf)2

55 56 57 58

Cs2CO3 DMF60 - 100

OH R3R4

R1 R1 R1R2R2R2

MeCN reflux

Cs2CO3 DMF74 - 95

MeCN reflux

by Bi(OTf)3

R2Y(OTf)3 5 mol

CH3CN rt

selectivity overall

good yields

AgOTfa

Isolated yields

Conclusions

Introduction

more complex

have to be found

comparative studies

be ICl gt I2 gt Br2

ketones

Δλ pK Δλ pK

GaBr3 66 -057 91 -061

GaCl3 63 -057 89 -051

ZnBr2 37 -052 48 -051

ZnCl2 39 -052 50 -039

BF3 59 +063 90 +251

Base rarr

Br2(g) - -144 +004 +0226 Cl2(g) - - +44 +165

Base rarr

-benzene

Naphalen

ICl 054 151 227 139 I2 015 031 135 025

Br2 011 023 - -

techniques

Order Method Ref

gtgt SiF4 ~ CrF3

ArH+MFn+1-

complex

Salt formation 100

spectroscopy

formation

the parameter

Ž = Z rk2 ndash 77Xz + 80 (8)

rk = ionic radius

bond strength)

IR spectroscopy

X in base

acetate

Δν (cm-1)

- ΔHf

(kcal mol-1)

F 119 317

Cl 176 395 (379)9

Br 191 445 (435)9

were solid samples

stoichiometry

BF3 156 1 1

PhSnCl3 150 1 1

ZnCl2 120 1 1

SnBr4 157 2 1

ZnBr2 118 2 1

SnCl4 158 2 1

GaCl3 157 1 1

BCl3 640 100 752 100 790 100

AlCl3 518 81 640 85 672 85

i-C4H9CCl2 500 78 511 68 536 68

BiCl3a 480 75 - - - -

TiCl4 - - 526 70 600 76

InCl3b 410 64 - - - -

BF3 391 61 458 61 498 63

SnCl4 - - 384 51 - -

SnBr4c 256 40 00 0 - 0

(i-C4H9)2BCl 252 40 00 0 00 -

AsCl3 110 11 - - - 0

SnI4 00 0 - - 00 0

SiCl4 00 0 00 0 00 0

GeCl4 00 0 00 0 00 0

PCl3 00 0 00 0 00 0

C5H9O3P C6H9O3P

Figure 17 Figure 18

crotonaldehydea

H1 H2 H3 H4 C1 C2 C3 C4

BBr3 011 093 149 051

BCl3 -065 085 135 049 68 -37 317 43

SbCl5 017 078 132 048 69 -40 276 37

AlCl3 -020 076 123 047

EtAlCl2bc -020 077 125 047

BF3 -027 074 117 044 83 -33 261 31

EtAlCl2bcd -017 067 115 038

Et3Al2Cl3b -015 069 114 039

TiCl4 003 060 103 036

Et2AlClbc -015 055 091 030 94 -20 201 23

SnC4 -002 050 087 029 78 -28 192 23

opposite direction

adducts

Acid ΔνC=O pK

BF3 156 -113

PhSnCl3 150 -114

ZnCl2 120 -148

SnBr4 157 -155

ZnBr2 118 -172

SnCl4 158 -266

GaCl3 157 lt-40

AsCl3 ca -

080 ca 63 ca 80 - - - -

SbCl3 -176 58 801 ca 74 - - -

BF3 -293 850 930 815 -186 72 ca 96

ZnBr2 -294 870 860 800 -217 148 890

ZnCl2 -294 870 558 802 -217 148 892

GaBr3 -340 2510 960 864 -249 310 1010

GaCl3 - - - - -253 340 1012

calculated

oxide as the base

acids125

acidity (Table 132)

Lewis acidity

that of Childs116

Conclusions

complex formation85

are being used

be addressed

reagents

OSiMe3Ln(OTf)3THF

CH2O aq Ph OH

Yield ()

100 mol 20 mol

1 La(OTf)3 90 23 88

2 Pr(OTf)3 92 40 80

3 Nd(OTf)3 74 6 89

4 Sm(OTf)3 92 51 91

5 Eu(OTf)3 92 28 93

6 Gd(OTf)3 92 20 79

7 Dy(OTf)3 89 20 85

8 Ho(OTf)3 91 38 86

9 Er(OTf)3 90 44 83

10 Yb(OTf)3 94 5 94

OSime3

THFH2O (41) rt 20h

NO3- and SO4

reactions136

PhCOH + Ph

OSiMe3

OH OMXn (02eq)

H2OTHF (91)rt 12 h

1 A 51 OSime3

2 B 74

3 C 79

5 HCOCH2OH H2O C 80

TBDMSO

BnO OO

TBDMSO

Sn InCl3

H2O rtR1

OH OH+

Isomer

(antisyn)b

7 C6H11CHO CO2Et

Br Sn InCl3 H2O (15 h) 65 6832

SnBrR InCl3H2O

R InCl2 +

InCl265 66 67

R InCl266

InCl2RH

reactions occur

Michael additions

+Yb(OTf)3

Yb(OTf)3

Other reactions

1 15 TfOH 7723 92

2 5 Bi(O2CCF3)3 7723 77

3 1 Bi(OTf)3 7228 94

4 5 Bi(OTf)3 8614 84

comparative reasons

H2N NH2

REtO2C

MeO CHOMeO

M(NTf2)norM(OTf)n

water rt 24 h

1 Ni(NTf2)2 59 65c 40d

3 Cu(NTf2)2 65 70c 62d

4 Cu(OTf)2 lt10b

5 Zn(NTf2)2 8

6 Yb(NTf2)3 88 90c

7 Yb(OTf)3 lt5b

4 Ni(NTf2)2 HCl 71

1 CH3CO2H (47) lt5

2 CF3CO2H (023) 56

3 HCl (-23) lt5

4 HNTf2 (12) 33

5 CH3SO2H (-12) lt5

15 Conclusions

16 References

Y 1929

1927 pp 60 and 116

Pa 1941

Easton Pa 1944

New York NY 1946

Mulliken papers)

London 1969

York 1973

Eur J 2008 14 3056

2003 68 9340

Sci 1999 71 1941

63 8478

Chem 2005 3 4129

Am Chem Soc 1965 88 986

2008 49 3814

Chem Ser 1968 72 265

1961 65 123

37 4629

132 Li C J Chem Rev 2005 105 3095

38 3465

Lett 2008 2289

Stark trap1

orthoester

HR+ C O

RH O R

H OO R

H + OH RH

O R HC O

Hemiacetal

oxonium cation

HR O R

HR OR H

H ROH2+

R2R1R2RO

reagent

the alcohol

Bacd Yield ()

Caef Yield ()

MeO OMe

H3CO 21

88g 97h 75 g (90)

EtO OEt

H3CO 22

67g 90h 72 g (80)

76 88 gt98i

79 90 gt98i

MeO OMe

O2N 25

97 94h 82g (94)h

EtO OEt

O2N 26

92 91h 57g (75)h

Bacd Yield ()

Caef Yield ()

MeO OMe

NO2 27

57 96 95

EtO OEt

NO2 28

64 92 gt98i

92 99 gt98i

72 93 96

11 OMeMeO

90 96 gt98i

12 OEtEtO

85 96 gt98i

78 74g gt98i

81 73g gt98i

Green Chemistry

not happen again11

destruction

bull Other

use of solvents

Yield () adf

MeO OMe

96 63 98 92

EtO OEt

83h 75 89 92

MeO OMe

94hj 0 92 73 (92)i

EtO OEt

77 0 0 75 (82)i

MeO OMe

80 33 77 90

EtO OEt

83 33 80 93

OMe 222

86 0 gt98k 96

OEt 223

74 0 82 92

formed

Run Yield ()abc

1 gt98

2 gt98

24 Deprotections

96 yield

OOOMeMeO

0 oC 15 h96

5 mol Al(OTf)3

MeO OMe

H3CO 21

MeO OMe

O2N 25

O N2 55

EtO OEt

Acetal Product

In(OTf)3

Hf(OTf)4

Cu(OTf)2

Ca(OTf)2

MeO OMe

21 H3CO

100 100 100 21

MeO OMe

O2N 25

O N2 89 100 18 15

EtO OEt

100 100 43 19

Acetal Product

Al(OTf)3

In(OTf)3

Hf(OTf)4

No Cat

MeO OMe

H3CO 21

100 100 100 100

MeO OMe

O2N 25

O N2 100a 100a 100a 100a

OMeMeO

O16 22 26 0

EtO OEt

100 100 100 68

O OMeR R

Acetal Product

Al(OTf)3

In(OTf)3

Hf(OTf)4

Sc(OTf)3

No Cat

MeO OMe

H3CO 21

100 100 100 100 97

MeO OMe

O2N 25

O N2 100a 100a 100a 100a 100a

EtO OEt

100 100 100 100 75

Silyl ethers

OH OTBDMS

224 (78)

15 eq Pyridine

OTBDMS

225 (80)

15 eq Pyridine

20 eq TBDMSCl

of 1 mol TfOH

reaction

Yield ()a

OTBDMS

Yield ()a

OTBDMS

O OROH

conditions23

overall efficiency

Yield ()

+O MeOH

OMeO+ H+

211 entry 1 and 2)

TBDMSO

OO 229

OTBDMS

TBDMSO

231 Yield ()

TBDMSO

O Yield ()

Yield ()

TBDMSO

OTBDMS

OMe 232

Yield ()

OTBDMS

O Yield ()

OTBDMS

faster reaction

OTBDMS

OMe Yield ()

OTBDMS

O Yield ()

OTBDMS

Al(OTf)3 82 18 0

Sc(OTf)3 91 9 0

In(OTf)3 94 6 0

Cu(OTf)2 gt98 0 0

Ca(OTf)2 gt98 0 0

29 Conclusions

210 References

R S J Org Chem 2002 67 5202

Ed 2008 47 560

Carb Res 2008 343 1814

New York 1991 31

Chapter 3

31 Introduction

M+n + H2O M OHH

solvents more fully

ROH + SO2 + RN

2I- I2 + 2e-

[alkylsulfite salt]

ammonium salt

mg of water

content8

Reading

Hydranal

Std Mass

content

1 0401 72

2 0391 80

3 0386 75

4 0390 74

5 0391 75

6 0411 77

7 0381 76

8 0375 80

9 0370 70

10 0391 75

Average 75 ppm

Std dev 03 ppm

RSD 39

Solvents

Residual water

contenta (ppm)

Std dev ppm RSD ()

DCM 4103 6 224 120 536 THF 2815 6 1078 066 062

acceptable limits

sieves9

Solvent

Residual water

contenta (ppm)

Std dev ppm

RSD ()

Experiment number

Residual water

contenta (ppm)

Std dev (ppm)

RSD ()

1 2836 6 1140 429 376

2 2650 6 440 066 150

repeatable

352 Drying reagents

36 The alcohols

sieves (5 wv)

Time (h) n

Average sample

weighta (g)

Residual water

content (ppm)

Std dev

24 6 2672 753 074 098 24 6 2621 789 067 085 24 6 2557 777 062 080 48 6 2488 452 055 122 48 6 2571 489 047 096 48 6 2612 464 082 177 72 6 2612 329 041 125 72 6 2488 343 040 117 72 6 2612 354 049 138

5 days 6 2523 257 124 482 5 days 6 2584 266 120 451

sieves (10 wv)

Time (h)

Residual water

content (ppm)

Std dev (ppm)

24 6 2688 407 093 229 24 6 2619 392 059 151 24 6 2624 419 041 098 48 6 2561 268 071 265 48 6 2508 293 071 242 48 6 2502 322 087 270 72 6 2612 224 042 188 72 6 2592 236 084 356 72 6 2505 263 063 240

5 days 6 2589 166 057 343 5 days 6 2573 182 058 319 5 days 6 2606 199 168 844

sieves (20 wv)

Time (h) n

Residual water

content (ppm)

Std dev

(ppm) RSD ()

24 6 2509 280 057 204 24 6 2609 292 042 144 24 6 2634 290 031 107 48 6 2496 211 046 218 48 6 2605 239 038 159 48 6 2556 244 087 357 72 6 2591 176 051 290 72 6 2541 188 055 293 72 6 2610 212 088 415

5 days 6 2575 97 099 1021 5 days 6 2542 104 049 471

(5 wv)

Time (h) n

Residual water

content (ppm)

Std dev

(ppm) RSD

24 6 2699 2511 181 072 24 6 2637 2703 166 061 24 6 2662 2664 250 094 48 6 2648 1021 075 073 48 6 2639 1064 074 070 48 6 2633 1110 055 050 72 6 2664 549 093 169 72 6 2639 541 059 109 72 6 2639 563 123 218

5 days 6 2635 144 051 354 5 days 6 2631 141 049 348 5 days 6 2659 149 015 101

(10 wv)

Time (h) n

Residual water

content (ppm)

Std dev ppm

RSD ()

24 6 2668 1894 153 081 24 6 2666 1792 081 045 24 6 2638 1896 050 026 48 6 2645 678 051 075 48 6 2637 695 064 092 48 6 2640 712 058 081 72 6 2642 351 107 305 72 6 2624 359 073 203 72 6 2616 397 118 297

5 days 6 2611 114 113 991 5 days 6 2658 130 076 585 5 days 6 2619 124 089 718

(20 wv)

Time (h)

Residual water

content (ppm)

Std dev ppm

RSD ()

24 6 2639 1186 058 049 24 6 2641 1190 109 092 24 6 2630 1218 037 030 48 6 2643 231 076 329 48 6 2639 243 055 226 48 6 2666 277 079 285 72 6 2604 190 028 147 72 6 2612 194 056 289 72 6 2608 231 061 264

5 days 6 2651 69 035 507 5 days 6 2612 81 035 432

5 days 6 2599 95 050 526

acceptable

powder

Average sample

weight (g) n

Residual water

contenta (ppm)

Std dev ppm

RSD ()

Methanol KOH (10 wv) 24 2525 6 318 081 255

Methanol KOH (10 wv) 24 2555 6 339 099 292

Methanol KOH (10 wv) 24 2606 6 337 093 276

Ethanol KOH (10 wv) 24 2856 6 259 074 286

Ethanol KOH (10 wv) 24 2760 6 284 053 187

Ethanol KOH (10 wv) 24 2640 6 250 056 225

37 Acetonitrile

Desiccant Time (h)

Residual water

contenta (ppm)

Std dev ppm

RSD ()

24 2628 6 40 065 1606 48 2626 6 18 050 2841 72 - 6 ltdlb - -

24 2643 6 05 041 8367

48 - 6 ltdlb - -

10 (wv) -c 2966 6 61 062 1015

10 (wv) -c 2924 6 49 015 306

10 (wv) -c 2826 6 68 037 537

titrations

Residual water

contenta (ppm)

Std dev ppm

RSD ()

(20 wv)

Time (h) n

Residual water

content (ppm)

Std dev (ppm)

RSD ()

24 6 3029 152 029 191 24 6 3027 143 012 084 24 6 3007 146 036 247 48 6 3034 59 021 356 48 6 3000 60 021 350 48 6 2998 64 010 156 72 6 2970 43 005 116 72 6 3016 42 018 429 72 6 2907 38 010 263

Fischer titration

Residual water

contenta (ppm)

Std dev ppm

RSD ()

repeatable

39 Discussion

310 Conclusions

38 References

Oxford 1963 682

41 Introduction

acidity6

literature

H3C CH3

CH3H3CN

CH3H3C

H3C CH3

CH3H3C

5 mol Bi(OTf)3 H2OH

Ph NH2

O NH OPh

41 42 43 44

Water 7 h

OTES OBz

OTES OH

Bz2O CH2CN

10 mol Sc(OTf)3

SO2PhBz2O CH3CN

OH O Ph

O3 eq Bz2O

Conversion

1 Yb(OTf)3 99 15 11

2 Bi(OTf)3 40 15 8

3 In(OTf)3 34 15 3

4 Sc(OTf)3 63 15 2

5 Cu(OTf)2 3 - -

6 Sc(OTf)3 63 5 6

OHHOHO

TfOH (005 eq) 10 min 84

OHHOHO

In(OTf)3 (005 eq) 1 h 99

OHHOHO

In(OTf)3 (005 eq)

With DTMP 24 h 11

OHH2NHO

In(OTf)3 (005 eq)

1 h NR

OHH2NHO

+ In(OTf)3

OIn(OTf)2H2N

+ HOTf

n(H2O)YbO

431 Introduction

OH H H

Enolate

OSiMe3+ R3 C R4

Lewis acid

OSiMe3 O

+MXn 02eq

THFH2O (91)12 h rt413 414 415

proceed no further

product

La(OTf)3 80

Ce(OTf)3 81

Pr(OTf)3 83

Nd(OTf)3 78

Sm(OTf)3 85

Eu(OTf)3 88

Gd(OTf)3 90

Tb(OTf)3 81

Dy(OTf)3 85

Ho(OTf)3 89

Er(OTf)3 86

Tm(OTf)3 85

Yb(OTf)3 92

Lu(OTf)3 84

Yield ()a

Hydrolysis of

Silyl ether

(silyl ether)

La(OTf)3 92 (80)b 8 0

InCl3 89 (68)b 3 8

CuCl2 86 (25)b 11 3

LiCl 6 (-)b 7 77

ScCl3 59 (70) 41 -

Er(OTf)3 56 (86)b 6 38

GaCl3 28 (-)b 56 16

ZnCl2 22 (10)b 0 78

AlCl3 0 (0)b 100 0

Cu(OTf)2 96 4 0

Sc(OTf)3 94 6 0

Y(OTf)3 89 11 0

Zn(OTf)2 77 2 21

Ca(OTf)2 42 28 30

In(OTf)3 41 59 0

Al(OTf)3 21 79 0

Zr(OTf)4 0 100 0

Hf(OTf)4 0 100 0

Li(OTf) 0 11 89

TiCl4 0 100 0

TiCl4 -098 100 TfOH 034 100

Y(OTf)3 445 6 Cu(OTf)2 464 4 Zn(OTf)2 540 2

LiCl 830 7 LiOTf 889 11

In(OTf)3 277 59 400 InCl3 432 6 400 ScCl3 254 41 430

Sc(OTf)3 275 6 430 CuCl2 408 11 753

ZnCl2 549 0 896 Ca(OTf)2 607 28 1285

LiCl 830 7 1364 LiOTf 889 11 1364 TfOH 034 100

rate constant

OSiMe3

PhCHO TiCl4 CH2Cl2

TiCl3Cl -Me3SiCl

Me PhPhPh

ClCl Cl

Me PhPhPh

catalytic cycle

THF H2O (91)

La(OTf)3 92 35 Y(OTf)3 89 83

788764755

Lewis Acid

Δδ H aldehyde

Δδ Ortho

protons

Δδ Para

protons

Δδ Meta

protons 1001 788 764 755

Sc(OTf)3 -0033a 0109 0108 0044

ScCl3 0054 0093 009 0029

In(OTf)3 -0015a 016 016 007

proceed (Figure45)

OSiMe3

M(OTf)3

phenomena

of ligands

Water 79

Acetonitrile 375

Methanol 315

Ethanol 242

Acetone 22

Chlorobenzene 56

Tetrahydrofuran 76

Ether 45

Benzene 23

Pentane 18

M3+M OTfTfO

OTf M OTf M OTF

Quadruplet

OTf M OTfTriplet

solvents

+-+- +-+- etc)32

Et3N + CH3Iδ δ

Solvent Dielectric

Hexane 20 1

MSn OH

+ MSn-1

+ S eq 42

MnXm-1

ion-pair formation

415)34

M+n + H2O M(H2O)x

M(H2O)x-1OH+n-1

Broslashnsted acid

particular

conditions

Lewis acid

Without

Yield ()

La(OTf)3 92 0 0

Sc(OTf)3 96 79 50

InCl3 89 99 0

Cu(OTf)2 94 65 0

N+ ROH

Lewis acid pH in

THFH2O (91)

pH in THFH2O

(91) and 15 eq

46 Summary

Retinyl acetate

CH2+ HO

triflate

Retinyl acetate +

hydrolysis

non- polar solvents

-OTf416

BA OTf-

Al(OTf)3

BA =Al(OTf)3K

5 mL of DCM

(Table 416)

Retinyl acetate +

Mr = 42544 F000 = 884

V = 17580 (2) Aring3 T = 296 (2) K

Lewis acid

Reaction Yield ()a

Reactions +200 uL

ScCl3 0 21 InCl3 50 53 TfOH 31 31

p-xylenea

Metal triflate

Yield ()b

4 mL p-xylene

Yield ()b

2 mL p-xylene

spectroscopy

systemsa

Lewis Acid 10 mol

Yield ()b

Cumene 16 mL 48 h

Yield ()b

Anisole 16 mL 24 h

Yield ()b

Toluene 16 mL 48 h

Zr(OTf)4 71 gt 95 66 Al(OTf)3 47 gt95 77

Metal Triflate

bottle

was 60

Hf(OTf)4)

attention

49 Conclusions

modified

410 References

M J Carb Res 2008 343 2814

68 9340

M J Carb Res 2008 343 2814

1994 188

1998 39 1641

1997 613

Chem Soc 2008 131 6342

2008 49 2384

Winston 1959

Chapter 5

51 Introduction

triflates

Crotonaldehyde

signala

Croton

aldehyde

Δ δ on

addition

Al(OTf)3

Δ δ on

addition

Δ δ on

addition

Sc(OTf)3

Δ δ on

addition

Δ δ on

addition

In(OTf)3

Δ δ on

addition

H-1 947 -026 -016 -025 003 -006 -007

H-2 610 054 013 044 045 030 027

H-3 687 093 023 093 071 050 043

Lewis acids

signala

Croton

aldehyde

Δ δ on

addition

Al(OTf)3

Δ δ on

addition

Δ δ on

addition

Sc(OTf)3

Δ δ on

addition

Δ δ on

addition

In(OTf)3

Δ δ on

addition

C-1 1941 111 04 116 175 04 29

C-2 1348 -20 05 -14 -15 03 -02

C-3 1544 219 02 221 1752 04 45

C3C2 C1

NMR signala

Trans-

cinnamaldehyde

δ ppm

Hf(OTf)4 003 005 13 -02 12

Sc(OTf)3 -016 -002 24 01 25

In(OTf)3 -0171 0047 17 00 16

Ca(OTf)2 -0074 0014 04 -04 02

Zn(OTf)2 -005 0038 29 03 26

Y(OTf)3 -0048 0145 31 03 33

Zr(OTf)4 -0107 004 23 -07 24

Al(OTf)3 -0076 0032 09 00 09

Lewis acids

Phosphorus NMR

thermodynamic data

Phosphorus compound

δ uncomplexeda

Δ δ on addition

of Al(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of In(OTf)3

(OTf)3M

NMR signal

Croton aldehyde

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

18 aH-1 947 -027 -022 -015 -008

H-2 687 045 014 026 014

H-3 610 100 083 057 024

CH3 201 028 023 014 005

NMR signal

Croton aldehyde

Δ δ on addition

of In(OTf)3

Δ δ on addition

of In(OTf)3

Δ δ on addition

of In(OTf)3

Δ δ on addition

of InOTf)3

18 aH-1 947 -009 -008 -007 -006

H-2 687 027 019 010 008

H-3 610 049 037 021 017

solvent to solvent

A = εbc 1

(Figure 58)9

(Figure 59)

complex

the probes

Lewis Acid

laboratory

method was sought

may be obtained

[bmim][OTf]

acid coordination

LiOTf 14422 22 -a

Ca(OTf)2 14424 24 -a

Zn(OTf)2 14520 120 -a

Cu(OTf)2 14530 130 -a

Ba(OTf)2 14610 210 -a

LiCl 14860 460 -a

ScCl3 14870 470 -a

InCl3 14890 490 -a

metal salts

activity

Table 58

14694 14694 14694 14694

144428 14463 14463 14463

the Lewis acids

55 Conclusions

References

Int Ed 2008 47 560

Main conclusions

identified

Future research

expensive triflates

Chapter 6

611 Chromatography

prior to use

63 Melting Points

uncorrected

64 Chemical methods

Chapter 2

MeO OMe

Yield 97 yellow oil

Obtained = 1510753

EtO OEt

Yield 90 yellow oil

Obtained = 1650910

Obtained = 1569867

Obtained = 1690416

MeO OMe

(ortho) 491 (2 x OCH3) 258 (CH3)

Obtained = 1960593

EtO OEt

Yield 92 yellow oil

(CH3) 151 (OCH3)

Obtained = 1940811

MeO OMe

(C3) 1280 (C5) 1241 (C4) 997 (acetal) 544 (2 x OCH3)

Obtained = 1660498

EtO OEt

1241 (C4) 983 (acetal) 634 (2 x OCH2) 150 (2 x CH3)

Obtained = 1800655

Ph OMe

x OCH3)

Obtained = 1470805

Ph OEt

Obtained = 1610960

Obtained = 1711741

Obtained = 1851902

(C3 and C5) 263 (C4) 257 (C4 and C6)

Obtained = 1271099

Obtained = 1411275

Yield 98White solid

Obtained = 1921147

MeO OMe

(ortho) 1031 (CH) 526 (OCH3)

Obtained = 1210445

EtO OEt

Obtained = 1350807

MeO OMe

Obtained = 1510755

EtO OEt

(OCH2CH3)

Obtained = 1791067

(C4) 228 (C3 C5)

Obtained = 1130967

2H H2 H6) 147 (m 2H H3 H5) 137 (m 1H H4) 115 (t 6H J =

(C4) 230 (C3 C5) 156 (2 x CH2CH3)

Obtained = 1281196

Obtained = 1110465

Obtained = 1250597

OTBDMS

(C(CH3)3 -54 (OSi(CH3)2)

Obtained = 1790887

OTBDMS

Obtained = 2289670

was used

(C5) 254 (C4) 194 (C3)

Obtained = 1220727

mp 566ndash584

1138 (para) 965 (acetal) 620 (C2) 302 (C5) 251 (C4) 186 (C3)

Obtained = 179521

618 (C2) 540 (HCequivCCH2) 301 (C3) 252 (C3) 252 (C4) 190

Obtained = 850646

1262 (C2) 1207 (C6) 1100 (C5) 554 (OCH3) 255 (C(CH3)3) 184

(C(CH3)3 -46 (OSi(CH3)2)

Obtained = 2090629

OTBDMS

Yield 90 yellow oil

1215 (C5 C6) 1202 (C3) 256 (C(CH3)3) 163 (C(CH3)3 -43

(OSi(CH3)2)

Obtained = 1790523

TBDMSO

OTBDMS

120 (C6) 1010 (acetal) 538 (2 x OCH3) 263 (C(CH3)3) 192

(C(CH3)3 -40 (OSi(CH3)2)

Obtained = 2250946

Chapter 3

i=1(xi - μ)2

Eq 1 RSD = ( x) x 100σ Eq 2

x = sample mean

data see appendix A

Chapter 4

To make LDA

10 minutes

chromatography

OSiMe3

Obtained = 1340732

Obtained = 2250946

(CH2CH3)

Obtained = 2880755

6410 Crystal data

Mr = 42544 F000 = 884

λ = 071073 Aring

V = 17580 (2) Aring3 T = 296 (2) K

Data collection

CCD area detector

T = 296(2) K θmax = 280deg

Refinement

Fourier map

neighbouring sites

wR(F2) = 0137 w = 1[σ2(Fo

2) + (00834P)2]

S = 098 (Δσ)max = 2220

706 (s 1H H2) 706 (d 2H J = 18 H4 H5) 577 (d 1H J = 15 Hz

1330 (C6) 1307 (C5) 1300 (C6) 1283 (C10 and C12) 1282 (C11)

1275 (C2) 1265 (C9 and C13) 1146 (C14) 210 (C16) 196 (C15)

Obtained = 2081240

Chapter 5

at 25 degC

NMR spectroscopy

11 01 mmol 01 mmol

12 01 mmol 02 mmol

14 01 mmol 04 mmol

18 01 mmol 08 mmol

65 References

Chem Soc 2006 128 5930

60 4037

1 2765 CL 95

2 2874 1015 3 2874 1025 4 2749 1018 5 2868 1019 6 2761 1013

Average 2815 1018

1 2933 1171 2 2780 1189 3 2806 1132 4 2951 1071 5 2867 1116 6 2838 1161

Average 2863 1140

1 2638 441 2 2656 435 3 2648 441 4 2675 449 5 2639 431 6 2641 446

Average 2650 440

1 2673 432 2 2702 422 3 2698 421 4 2657 434 5 2712 420 6 2668 436

Average 2685 428

1 2840 276 2 2795 290 3 2917 291 4 2647 272 5 2730 267 6 2762 271

Average 2782 278

1 3000 593 2 2906 572 3 2860 560 4 2880 520 5 2853 578 6 2800 550

Average 2883 562

1 2973 807 2 2960 CL 95

3 2965 824 4 3005 824 5 2993 837 6 2987 834

Average 2981 825

1 2900 1066 2 2942 1057 3 2735 1097 4 2902 1009 5 2854 1025 6 2894 1090

Average 2871 1057

1 2981 909 2 2821 896 3 2921 864 4 2922 866 5 2932 939 6 2848 889

Average 2904 894

1 2857 742 2 2889 763 3 2806 747 4 2838 712 5 2821 774 6 3027 739

Average 2873 746

1 2952 618 2 2959 597 3 2888 649 4 2933 598 5 2860 550 6 2987 560

Average 2930 595

1 2937 730 2 2872 716 3 2920 688 4 2903 646 5 2915 659 6 2933 702

Average 2913 690

1 2939 606 2 2953 624 3 2975 630 4 2967 613 5 2825 575 6 2901 603

1 3112 156 2 2998 151 3 3100 149 4 2976 153 5 2987 148 6 3001 153

1 3101 145 2 2964 143 3 2899 142 4 3112 CL 95

5 3103 143 6 2981 142

Average 3027 143

1 2899 146 2 2976 140 3 2988 147 4 2978 143 5 3100 149 6 3102 149

Average 3007 146

1 3004 59 2 2987 57 3 3003 58 4 3067 57 5 3076 61 6 3064 62

Average 3034 59

1 3044 61 2 2988 59 3 3000 58 4 2991 62 5 2989 62 6 2988 57

Average 3000 60

1 3014 63 2 2994 64 3 2983 61 4 2997 63 5 2996 62 6 3004 62

1 2864 43 2 2990 43 3 2999 44 4 2988 CL 95

5 3009 44 6 2968 43

Average 2970 43

1 3074 41 2 2998 41 3 2995 42 4 3031 45 5 3006 43 6 2994 40

Average 3016 42

1 3014 39 2 2918 38 3 2990 37 4 3011 37 5 3029 39 6 2948 39

Average 2985 38

1 3004 55 2 3100 56 3 2713 54 4 2985 57 5 3005 56 6 3001 55

Average 2968 56

1 2934 49 2 2991 48 3 2997 48 4 2990 47 5 3010 CL 95

6 3084 46 Average 3001 48

1 2948 54 2 2789 53 3 2994 54 4 2783 55 5 2956 53 6 2973 56

1 2568 1427 2 2371 1436 3 2666 1426 4 2559 1407 5 2598 1418 6 2554 1407

Average 2553 1420

1 2646 45 2 2634 45 3 2574 38 4 2631 46 5 2645 40 6 2638 29

Average 2628 40

1 2604 19 2 2645 16 3 2673 26 4 2536 20 5 2645 13 6 2655 12

Average 2626 18

1 2652 12 2 2584 01 3 2652 02 4 2653 07 5 2657 02 6 2660 04

Average 2643 05

1 2963 69 2 2991 66 3 2953 58 4 2960 64 5 2965 56 6 2964 54

Average 2966 61

1 2913 CL = 95

2 2951 49 3 2923 51 4 2940 49 5 2925 50 6 2894 47

Average 2924 49

1 2943 67 2 2911 65 3 2863 73 4 2440 69 5 2895 64 6 2904 72

1 2563 1748 2 2576 1746 3 2603 1757 4 2590 1749 5 2594 1754 6 2613 1755

Average 2590 1751

1 2689 758 2 2625 740 3 2664 751 4 2674 CL 95

5 2678 761 6 2702 756

Average 2672 753

1 2643 794 2 2598 786 3 2586 787 4 2633 798 5 2644 779 6 2635 792

Average 2621 789

1 2584 779 2 2552 768 3 2621 774 4 2556 781 5 2529 CL 95

6 2497 785 Average 2557 777

1 2703 417 2 2671 394 3 2712 409 4 2654 412 5 2648 398 6 2739 414

Average 2688 407

1 2568 398 2 2633 387 3 2574 397 4 2632 CL 95

5 2695 396 6 2613 386

Average 2619 393

1 2598 420 2 2648 418 3 2653 417 4 2589 424 5 2655 421 6 2599 412

Average 2624 419

1 2589 288 2 2498 273 3 2534 279 4 2477 284 5 2490 CL 95

6 2465 274 Average 2509 279

1 2541 292 2 2653 289 3 2666 287 4 2579 294 5 2534 299 6 2683 291

Average 2609 292

1 2695 293 2 2653 291 3 2648 288 4 2589 290 5 2648 293 6 2568 285

Average 2634 290

1 2529 462 2 2428 447 3 2484 451 4 2437 453 5 2590 448 6 2459 449

Average 2488 452

1 2491 493 2 2623 486 3 2626 489 4 2489 482 5 2564 495 6 2633 489

Average 2571 489

1 2615 463 2 2613 459 3 2608 470 4 2619 474 5 2558 467 6 2658 451

Average 2612 464

1 2575 275 2 2573 266 3 2640 268 4 2530 278 5 2458 264 6 2590 259

Average 2561 268

1 2530 283 2 2528 294 3 2530 285 4 2447 301 5 2550 CL 95

6 2463 298 Average 2508 292

1 2451 313 2 2500 324 3 2506 324 4 2519 334 5 2504 329 6 2533 312

Average 2502 323

1 2549 203 2 2428 211 3 2514 213 4 2437 216 5 2627 209 6 2419 213

1 2675 243 2 2423 236 3 2608 243 4 2630 234 5 2671 238 6 2620 241

1 2560 256 2 2508 247 3 2570 234 4 2457 246 5 2650 249 6 2593 234

Average 2556 244

1 2615 324 2 2613 327 3 2608 332 4 2619 335 5 2558 326 6 2658 330

Average 2612 329

1 2529 339 2 2428 342 3 2484 347 4 2437 337 5 2590 346 6 2459 345

Average 2488 343

1 2615 349 2 2613 358 3 2608 356 4 2619 CL 95

5 2558 359 6 2658 354

Average 2612 355

1 2655 221 2 2550 232 3 2608 225 4 2618 224 5 2614 221 6 2626 222

1 2645 CL 95

2 2633 236 3 2540 245 4 2540 246 5 2538 224 6 2658 231

1 2479 257 2 2428 264 3 2474 267 4 2537 254 5 2640 271 6 2471 263

Average 2505 263

1 2590 174 2 2570 180 3 2658 CL 95

4 2519 169 5 2598 183 6 2610 173

Average 2591 176

1 2539 184 2 2628 193 3 2464 191 4 2447 CL 95

5 2540 195 6 2629 183

Average 2541 189

1 2651 205 2 2450 211 3 2668 204 4 2678 224 5 2684 205 6 2526 221

Average 2610 212

1 2539 253 2 2628 243 3 2534 262 4 2417 274 5 2560 264 6 2459 243

Average 2523 257

1 2675 269 2 2560 274 3 2517 243 4 2606 273 5 2526 CL 95

6 2622 261 Average 2584 264

1 2460 274 2 2410 264 3 2584 289 4 2447 271 5 2580 264 6 2489 273

Average 2495 273

1 2574 167 2 2613 159 3 2588 173 4 2569 160 5 2608 164 6 2579 171

Average 2589 166

1 2489 189 2 2588 173 3 2524 183 4 2697 CL 95

5 2578 179 6 2559 183

Average 2573 181

1 2570 193 2 2590 187 3 2628 183 4 2620 194 5 2588 206 6 2638 229

Average 2606 199

1 2420 115 2 2590 96 3 2640 95 4 2669 89 5 2638 101 6 2490 88

Average 2575 97

1 2559 103 2 2478 107 3 2624 99 4 2497 111 5 2620 CL 95

6 2471 98 Average 2542 104

1 2641 124 2 2540 127 3 2596 104 4 2602 118 5 2606 99 6 2634 115

Average 2603 115

1 2569 305 2 2548 312 3 2489 325 4 2548 316 5 2450 324 6 2548 324

Average 2525 318

1 2459 354 2 2657 334 3 2658 341 4 2549 342 5 2459 324 6 2548 341

Average 2555 339

1 2658 331 2 2642 324 3 2548 335 4 2548 342 5 2658 339 6 2549 351

Average 2600 337

Methanol from MgI2

1 2660 545 2 2385 537 3 2693 540 4 2683 531 5 2531 530 6 2667 533

1 2650 14291 2 2537 14327 3 2618 14306 4 2653 14218 5 2673 14263 6 2598 14292

Average 2622 14283

1 2701 2516 2 2694 2486 3 2698 2508 4 2704 2496 5 2699 2523 6 2700 2536

Average 2699 2511

1 2655 2676 2 2596 2715 3 2626 2705 4 2572 2691 5 2684 CL 95

6 2691 2720 Average 2637 2701

1 2658 2651 2 2645 2671 3 2632 2644 4 2651 2712 5 2671 2656 6 2713 2652

Average 2662 2664

1 2661 CL 95

2 2664 1882 3 2678 1887 4 2674 1892 5 2659 1891 6 2670 1887

Average 2668 1888

1 2665 1804 2 2650 1793 3 2638 1795 4 2659 1781 5 2675 1785 6 2709 1793

Average 2666 1792

1 2653 1904 2 2592 1899 3 2629 1895 4 2576 1889 5 2687 1896 6 2693 1895

Average 2638 1896

1 2651 1183 2 2689 1185 3 2628 1191 4 2581 1195 5 2685 CL 95

6 2597 1184 Average 2639 1188

1 2647 1206 2 2591 1193 3 2629 1196 4 2579 1189 5 2695 CL 95

6 2705 1184 Average 2641 1194

1 2661 1214 2 2647 1216 3 2539 1220 4 2657 1221 5 2672 1215 6 2604 1223

Average 2630 1218

1 2643 CL 95

2 2692 1020 3 2639 1018 4 2586 1016 5 2693 1024 6 2633 1014

Average 2648 1018

1 2695 1065 2 2650 1076 3 2643 1065 4 2659 1054 5 2575 1059 6 2609 1063

1 2651 1107 2 2724 1106 3 2668 1113 4 2634 1111 5 2509 1119 6 2610 1104

Average 2633 1110

1 2541 672 2 2667 678 3 2648 679 4 2694 682 5 2649 685 6 2669 673

Average 2645 678

1 2666 694 2 2525 696 3 2636 689 4 2653 CL 95

5 2701 687 6 2643 703

1 2652 710 2 2591 717 3 2633 703 4 2579 719 5 2693 709 6 2693 713

Average 2640 712

1 2671 242 2 2644 229 3 2622 227 4 2654 231 5 2659 220 6 2610 237

Average 2643 231

1 2681 245 2 2634 249 3 2618 246 4 2634 236 5 2629 247 6 2640 237

1 2666 267 2 2649 270 3 2636 281 4 2659 279 5 2680 276 6 2708 289

1 2661 532 2 2652 558 3 2634 553 4 2657 556 5 2680 548 6 2702 549

Average 2664 549

1 2646 541 2 2595 539 3 2632 537 4 2577 546 5 2690 548 6 2694 532

Average 2639 541

1 2652 569 2 2627 577 3 2666 574 4 2648 549 5 2609 CL 95

6 2630 549 Average 2639 564

1 2651 367 2 2592 339 3 2635 342 4 2586 346 5 2690 CL 95

6 2699 357 Average 2642 350

1 2647 368 2 2600 365 3 2639 352 4 2574 350 5 2689 362 6 2593 356

1 2663 387 2 2653 395 3 2538 397 4 2658 402 5 2585 417 6 2599 384

1 2649 190 2 2522 189 3 2634 187 4 2526 192 5 2683 194 6 2611 187

Average 2604 190

1 2655 189 2 2550 196 3 2608 197 4 2618 185 5 2614 196 6 2626 CL 95

Average 2612 193

1 2648 224 2 2556 226 3 2663 240 4 2524 231 5 2643 236 6 2612 229

Average 2608 231

1 2569 139 2 2668 138 3 2584 144 4 2637 152 5 2690 146 6 2659 142

Average 2635 144

1 2591 133 2 2623 142 3 2726 146 4 2589 140 5 2664 139 6 2593 146

Average 2631 141

1 2641 148 2 2643 151 3 2706 147 4 2649 150 5 2704 149 6 2613 148

Average 2659 149

1 2529 120 2 2618 128 3 2614 119 4 2607 113 5 2660 103 6 2639 CL 95

Average 2611 117

1 2631 136 2 2663 125 3 2716 125 4 2609 139 5 2744 120 6 2583 135

Average 2658 130

1 2581 134 2 2653 131 3 2676 124 4 2549 110 5 2714 128 6 2543 118

Average 2619 124

1 2687 75 2 2655 69 3 2680 68 4 2659 64 5 2615 70 6 2609 69

Average 2651 69

1 2496 81 2 2589 76 3 2620 80 4 2680 79 5 2677 85 6 2609 85

1 2541 92 2 2593 95 3 2663 87 4 2527 CL 95

5 2648 94 6 2619 97

Average 2599 93

1 2875 257 2 2975 249 3 2896 258 4 2846 260 5 2758 272 6 2785 258

Average 2856 259

1 2587 278 2 2846 291 3 2874 286 4 2795 CL 95

5 2876 279 6 2579 284

Average 2760 284

1 2579 251 2 2858 254 3 2548 254 4 2479 252 5 2797 249 6 2579 239

1 4167 263 2 4146 230 3 4154 222 4 4079 205 5 3923 226 6 4151 237

Average 4103 231

1 4393 01 2 4172 02 3 4405 02 4 4183 00 5 4285 01 6 4168 02

1 4198 15 2 4206 09 3 4149 09 4 4168 14 5 4286 15 6 4295 CL = 95

Average 4217 13

DCM dried over CaH2

1 4206 147 2 4357 121 3 3871 129 4 4215 114 5 4347 121 6 3927 140

Average 4154 129

Front page



Faculty of Science



June 2009

Table of Contents

Synopsis

Abbreviations

Figures and schemes

Chapter 1

Chapter 2

Chapter 3_12099

Chapter 4

Chapter 5


Chapter 6

Appendix A


Chapter 6

alcohols

65 References 242

observed

solvents

Abbreviations

Aring angstrom

Bn benzyl

Bu butyl

C coulomb

CL confidence level

CPL ε-caprolactone

Cy cyclohexyl

d doublet

DCM dichloromethane

DHP dihydropyran

DL detection limit

Eq equivalents

EtOH ethanol

Et3N triethylamine

h hour

IR infrared

i-Pr iso-propyl

mp melting point

MeOH methanol

Me methyl

OAc acetate

PDI polydispersity

Ph phenyl

q quartet

rt room temperature

s singlet

t triplet

t-Bu tert-butyl

TES triethylsilyl

THF tetrahydrofuran

THP tetrahydropyran

TMS trimethylsilyl

thesis)

VL valerolactone

wrt with respect to

Scheme

Figure Heading Page

alcohols 29

by Bi(OTf)3 41

Figure 110

values 61

formaldehyde 65

Scheme 130

by InCl3 69

and urea 73

Scheme

Figure Heading Page

bromophenol 98

Scheme

Figure Heading Page

over time 122

over time 124

Scheme

Figure Heading Page

by water 153

organic solvent 161

nucleophile 164

Figure 49

of the solutions

Figure 412

counterion 176

Scheme

Figure Heading Page

triflate 195

to Lewis acid 201

List of tables

Table Heading Page

Table 13

different additives

with In(OTf)3 25

Table 117

Ga(OTf)3

bases at 28 degC 54

one 57

(9-fluorenone) 62

Ln(OTf)3 65

aldehydes 70

Table 139

Table Heading Page

ketones 85

ketones 86

ketones 90

the substrate 92

metal triflates 94

Al(OTf)3 102

triflates 105

Table Heading Page

standard 115

SilicaSodium 118

Table 315

alumina

Table Heading Page

mixture 150

solvents 161

DTBMP 164

without DTBMP 164

carbocation 167

pyridine 178

Table Heading Page

Table 51

Table 52

Table 53

Chapter 1

Introduction

system theories5

a proton acceptor

equation 3

ψ ψ ψAB = a 0 (AB) + b 1 (A-B+) (3)

ψ1 (A-B

β 01 EoSo1( )_ 2

E1_ Eo( )

EAB = Eo_

equation 5)

Σ ΣΔΕ β_ qsqt

Conclusions

reaction mixtures

amounts

(see Chapter 4)

OAcMeOOC O

OMeOOC

BnO OAc

O(OTf)3M

Lanthanide Reaction

Yb(OTf)3 180 70

Eu(OTf)3 90 85

Sm(OTf)3 90 92

AcOAcOAcO

AcOAcO

AcO COOMe

OAc Nd(OTf)3

MeOH rt 4 h

Nd(OTf)3

MeOH rt 4 h

AcOAcO

AcO COOMe

metal triflates

Starting

material Product

Yb(OTf)3a

Yield ()

Eu(OTf)3a

Yield ()

Sm(OTf)3a

Yield ()

Nd(OTf)3a

Yield ()

AcOAcAcOAcOAcO H

OAcOAcO

85 81 85 81

OAcAcOAcO

AcO CH2OAc

AcOAcO

AcO CH2OAc

68 78 82 82

OAcAcOAcOcO

CH2OAc

AcOAcOAcO

CH2OAc

61 62 79 81

HAcOAcOAcO

CH2OAc

AcOAcOAcO

CH2OAc

67 62 67 68

OIn (10 eq)

THFH2O 40 oC 20h

+ TIPS CF2

215 16 17 18

1 H2OTHF (41) 11 - 206

2 H2OTHF (41) 11 - 3112

3 H2OTHF (41) 11 - 257

4 Satd NH4Cl(aq)THF (41) 11 - 204

7 H2OTHF (41) 22 - 298

8 H2OTHF (41) 33 - 364

9 H2OTHF (41) 11 Sc(OTf)3 424

10 H2OTHF (41) 11 Er(OTf)3 647

11 H2OTHF (41) 11 Eu(OTf)3 788

12 H2OTHF (41) 11 Tb(OTf)3 7610

13 H2OTHF (41) 11 Sm(OTf)3 489

14 H2OTHF (41) 11 Y(OTf)3 4713

BrF + R

H2OTHF (41) 40 oC 20h

1 TIPS Ph 68

2 TES Ph 72

3 TMSb Ph 41

(18 scheme 14)

In (reducing agent)

examples

OHHO CO2Me

+Lewis acid

CH2Cl2 or CH3NO2

HO CO2Me

naphthyl)ethanol

(2-naphthyl)ethanol

mol Time h Yield ()

1a TiCl4 100 1 6

2a BF3OEt2 100 1 96

3a BF3OEt2 10 1 6

4b La(OTf)3 1 05 99

5b La(OTf)3 01 1 98

6b La(OTf)3 001 24 93

7b La(OTf)3 1 15c 98

8b Yb(OTf)3 1 033 96

OHHO CO2R

+1 mol La(OTf)3

HO CO2R

R25 26 27

CH3NO2

alcohols

1 H Me 15 min 99

2 OSiR3a Me 2 h 93

3 OAc Me 6 h 95

4 OBn Me 14 h 97

1 H Me Hf 5 min 89

3 H Me Sc 15 min 99

4 H Me Yb 25 min 99

5 H Bn La 25 h 99

6 H t-Bu La 19 h 59

a TfOH 3 mol

Nucleophile

Olefin

Triflate

H2OOHAr

Triflate Ar O Ar

Products

Ar = Ph

Ar = 2-naphthyl

process5758

2 mol M(OTf)x

toluene 25 oCO

of n-BnOH

Mol Time (h)

1 CPL 0 4 gt99 6900

2 CPL 2 23 gt99 3500

3 CPL 5 2 gt99 2400

4 CPL 10 2 gt99 1600

5 VL 0 15 96 4300

6 VL 2 1 95 2900

7 VL 5 1 97 1900

1 Sc [BF4]- 2 d 0 -

2 Y [BF4]- 7 d 29 500

3 La [BF4]- 2 d 29 300

4 Ceb [BF4]- 6 d 32 600

5 Nd [BF4]- 6 d 30 500

6 Eu [BF4]- 2 d 0 -

7 Gd [BF4]- 5 d 30 600

8 Yb [BF4]- 4 d 27 500

9 Lu [BF4]- 3 d 26 500

10 Sc [PF6]- 42 80 2500

11 Y [PF6]- 53 83 2800

12 La [PF6]- 46 100 3700

13 Ceb [PF6]- 47 100 3500

14 Nd [PF6]- 35 100 2700

15 Eu [PF6]- 49 100 2400

16 Gd [PF6]- 48 100 3400

17 Yb [PF6]- 48 43 1600

18 Lu [PF6]- 47 100 4400

19 Sc [SbF6]- 30 87 900

20 Y [SbF6]- 48 99 1800

21 La [SbF6]- 42 100 1800

22 Ceb [SbF6]- 29 100 1700

23 Nd [SbF6]- 43 100 1700

24 Eu [SbF6]- 48 4 1500

25 Gd [SbF6]- 29 100 2500

26 Yb [SbF6]- 48 82 1400

Sc(OTf)3

O(TfO)3Sc

OSc(OTf)3

Sc(OTf)3

Propagation

monomer mechanism

R NH2+

001 molYb(OTf)3

yields

Indium triflate

AcOAcO

OHHOHO

OAcAcOAcO

OHHOHO

OAcAcOAcO

AcOH3C

OH HO O

OAcOAc

OAc AcO 97

OAcAcOAcO

OHHOHO

OAcAcOAcO

OHHOHO

OHAcHNHO

OAcAcHNAcO

ether and THF

O+ SnBu2

2 H3C OH

Ph10 mol M(OTf)3

Solvent rt 12h

respectively

diallyldibuyltin

a Isolated yields

O+ SnBu2

2 R2 OH

R110 mol M(OTf)3

Entry R1 R2 Yield

1 Ph CH3 95

2 p-FC6H4 CH3 81

3 p-ClC6H4 CH3 75

4 p-BrC6H4 CH3 86

5 p-NO2C6H4 CH3 66

6 m-BrC6H4 CH3 93

7 m-CF3C6H4 CH3 90

8 p-MeC6H4 CH3 58

9 p-NH2C6H5 CH3 -

10 Ph Ph 42

14 CH2CH2CH3 CH3 45

15 CH2CH(CH3)2 CH3 27

16 p-MeOC6H4 H 80

a Isolated yields

In(OTf)3

O(TfO)2In

SnBu2OTf

OBu2Sn

Aluminium triflate

aluminium triflate

Al(OTf)3

NOAl(OTf)3

Yield ()

2 N OH

(CH2Cl)2

82 (11)

Al(OTf)338

various alcohols

Entry Product

1 39 R = Me 0 1 8 94

2 39 R = Et 94 95 -a -a

3 39 R = nPr 93 97 92 (4)b -a

4 39 R= iPr 91 92 -a -a

5 39 R = 2-Bu -a 14 97 96 (4)b

6 39 R = tBu -a 77 77 -a

-a 41 (34)b -a -a

-a 31 (24)b -a -a

-a 55 88 -a

-a 21 42 62

-a -a 89 -a

OCH2CH3

OHOCH2CH2CH3

OHOCH(CH3)2

OHOCH2CH2CH2CH3

EtOHAl(OTf)3 R

position

(Table 115)

aminesa

Product Yield ()

Al(OTf)3

Yield ()

Al(OTf)3

Yield ()

10 mol

Al(OTf)3

48 75b -

45 80b -

14 - 43c

31 (31)cd

- 35 (34)cd

regioisomer

Product Yield ()

Al(OTf)3

Yield ()

Al(OTf)3 OH

Gallium triflate

O O5 mol Ga(OTf)3

solvent

Ga(OTf)3

Entry Product Time

5 gt99

360 90

10 gt99

O 10 gt99

240 90

OO 10 98

(OTf)3Ga

Ga(OTf)3

H2N NH2

(OTf)3Ga

+ NH4OAcNH

NHCatalyst

ammonium acetate

NH4OAc or R3NH2 N

NCatalyst

R2CHOR1 R3

Ga(OTf)3

Entry R1 R2

NH4OAc

1 H p-(CH3)C6H4 NH4OAc 50 86

2 H 24-(OCH3)2C6H3 NH4OAc 45 90

3 H p-(N(CH3)2)C6H4 NH4OAc 35 88

5 H m-(F)C6H4 NH4OAc 50 85

7 H o-(NO2)C6H4 NH4OAc 70 71

8 H p-(NO2)C6H4 NH4OAc 60 73

13 Cl p-(F)C6H4 NH4OAc 55 83

15 H p-(OH)C6H4 sBuNH2 55 83

16 H p-(Cl)C6H4 nBuNH2 50 89

17 H p-(NO2)C6H4 nPrNH2 50 87

Entry R1 R2 Time

1 H p-(CH3)C6H4 50 84

2 H C6H4 55 83

3 H 24-(OCH3)2C6H3 50 89

4 H 34-(CH2O2)C6H3 55 84

5 H p-(N(CH3)2)C6H4 55 87

6 H p-(OH)C6H4 50 92

7 H m-(F)C6H4 55 84

8 H m-(Cl)C6H4 55 86

9 H p-(Cl)C6H4 55 89

10 H m-(NO2)C6H4 70 82

11 H p-(NO2)C6H4 65 81

12 H 2-Furyl 55 80

DMSO as a solvent

NH4OAc

CO2 NH2

RCHOGa(OTf)3

Ga(OTf)3

2 Ga(OTf)3N

48 49 50

51 52 53

(Ga(OTf)3)

Other triflates

RCN Cu(OTf)2

65 oC 30 min N

82 (91)c

NPh CH3

NPh Ph

(C6H4)Me-4

(C6H4)Me-4 PhCN N N

(C6H4)Me-4

CH3CN N N

(C6H4)Cl-4

PhCN N N

(C6H4)Cl-4

7 N Ts CH3CN N

Ts 62 (93)c

8 N Ts PhCN N

NTsC6Cl4H4

TsCu(OTf)2

Ts Cu(OTf)2Ph

NCu(OTf)2

55 56 57 58

Cs2CO3 DMF60 - 100

OH R3R4

R1 R1 R1R2R2R2

MeCN reflux

Cs2CO3 DMF74 - 95

MeCN reflux

by Bi(OTf)3

R2Y(OTf)3 5 mol

CH3CN rt

selectivity overall

good yields

AgOTfa

Isolated yields

Conclusions

Introduction

more complex

have to be found

comparative studies

be ICl gt I2 gt Br2

ketones

Δλ pK Δλ pK

GaBr3 66 -057 91 -061

GaCl3 63 -057 89 -051

ZnBr2 37 -052 48 -051

ZnCl2 39 -052 50 -039

BF3 59 +063 90 +251

Base rarr

Br2(g) - -144 +004 +0226 Cl2(g) - - +44 +165

Base rarr

-benzene

Naphalen

ICl 054 151 227 139 I2 015 031 135 025

Br2 011 023 - -

techniques

Order Method Ref

gtgt SiF4 ~ CrF3

ArH+MFn+1-

complex

Salt formation 100

spectroscopy

formation

the parameter

Ž = Z rk2 ndash 77Xz + 80 (8)

rk = ionic radius

bond strength)

IR spectroscopy

X in base

acetate

Δν (cm-1)

- ΔHf

(kcal mol-1)

F 119 317

Cl 176 395 (379)9

Br 191 445 (435)9

were solid samples

stoichiometry

BF3 156 1 1

PhSnCl3 150 1 1

ZnCl2 120 1 1

SnBr4 157 2 1

ZnBr2 118 2 1

SnCl4 158 2 1

GaCl3 157 1 1

BCl3 640 100 752 100 790 100

AlCl3 518 81 640 85 672 85

i-C4H9CCl2 500 78 511 68 536 68

BiCl3a 480 75 - - - -

TiCl4 - - 526 70 600 76

InCl3b 410 64 - - - -

BF3 391 61 458 61 498 63

SnCl4 - - 384 51 - -

SnBr4c 256 40 00 0 - 0

(i-C4H9)2BCl 252 40 00 0 00 -

AsCl3 110 11 - - - 0

SnI4 00 0 - - 00 0

SiCl4 00 0 00 0 00 0

GeCl4 00 0 00 0 00 0

PCl3 00 0 00 0 00 0

C5H9O3P C6H9O3P

Figure 17 Figure 18

crotonaldehydea

H1 H2 H3 H4 C1 C2 C3 C4

BBr3 011 093 149 051

BCl3 -065 085 135 049 68 -37 317 43

SbCl5 017 078 132 048 69 -40 276 37

AlCl3 -020 076 123 047

EtAlCl2bc -020 077 125 047

BF3 -027 074 117 044 83 -33 261 31

EtAlCl2bcd -017 067 115 038

Et3Al2Cl3b -015 069 114 039

TiCl4 003 060 103 036

Et2AlClbc -015 055 091 030 94 -20 201 23

SnC4 -002 050 087 029 78 -28 192 23

opposite direction

adducts

Acid ΔνC=O pK

BF3 156 -113

PhSnCl3 150 -114

ZnCl2 120 -148

SnBr4 157 -155

ZnBr2 118 -172

SnCl4 158 -266

GaCl3 157 lt-40

AsCl3 ca -

080 ca 63 ca 80 - - - -

SbCl3 -176 58 801 ca 74 - - -

BF3 -293 850 930 815 -186 72 ca 96

ZnBr2 -294 870 860 800 -217 148 890

ZnCl2 -294 870 558 802 -217 148 892

GaBr3 -340 2510 960 864 -249 310 1010

GaCl3 - - - - -253 340 1012

calculated

oxide as the base

acids125

acidity (Table 132)

Lewis acidity

that of Childs116

Conclusions

complex formation85

are being used

be addressed

reagents

OSiMe3Ln(OTf)3THF

CH2O aq Ph OH

Yield ()

100 mol 20 mol

1 La(OTf)3 90 23 88

2 Pr(OTf)3 92 40 80

3 Nd(OTf)3 74 6 89

4 Sm(OTf)3 92 51 91

5 Eu(OTf)3 92 28 93

6 Gd(OTf)3 92 20 79

7 Dy(OTf)3 89 20 85

8 Ho(OTf)3 91 38 86

9 Er(OTf)3 90 44 83

10 Yb(OTf)3 94 5 94

OSime3

THFH2O (41) rt 20h

NO3- and SO4

reactions136

PhCOH + Ph

OSiMe3

OH OMXn (02eq)

H2OTHF (91)rt 12 h

1 A 51 OSime3

2 B 74

3 C 79

5 HCOCH2OH H2O C 80

TBDMSO

BnO OO

TBDMSO

Sn InCl3

H2O rtR1

OH OH+

Isomer

(antisyn)b

7 C6H11CHO CO2Et

Br Sn InCl3 H2O (15 h) 65 6832

SnBrR InCl3H2O

R InCl2 +

InCl265 66 67

R InCl266

InCl2RH

reactions occur

Michael additions

+Yb(OTf)3

Yb(OTf)3

Other reactions

1 15 TfOH 7723 92

2 5 Bi(O2CCF3)3 7723 77

3 1 Bi(OTf)3 7228 94

4 5 Bi(OTf)3 8614 84

comparative reasons

H2N NH2

REtO2C

MeO CHOMeO

M(NTf2)norM(OTf)n

water rt 24 h

1 Ni(NTf2)2 59 65c 40d

3 Cu(NTf2)2 65 70c 62d

4 Cu(OTf)2 lt10b

5 Zn(NTf2)2 8

6 Yb(NTf2)3 88 90c

7 Yb(OTf)3 lt5b

4 Ni(NTf2)2 HCl 71

1 CH3CO2H (47) lt5

2 CF3CO2H (023) 56

3 HCl (-23) lt5

4 HNTf2 (12) 33

5 CH3SO2H (-12) lt5

15 Conclusions

16 References

Y 1929

1927 pp 60 and 116

Pa 1941

Easton Pa 1944

New York NY 1946

Mulliken papers)

London 1969

York 1973

Eur J 2008 14 3056

2003 68 9340

Sci 1999 71 1941

63 8478

Chem 2005 3 4129

Am Chem Soc 1965 88 986

2008 49 3814

Chem Ser 1968 72 265

1961 65 123

37 4629

132 Li C J Chem Rev 2005 105 3095

38 3465

Lett 2008 2289

Stark trap1

orthoester

HR+ C O

RH O R

H OO R

H + OH RH

O R HC O

Hemiacetal

oxonium cation

HR O R

HR OR H

H ROH2+

R2R1R2RO

reagent

the alcohol

Bacd Yield ()

Caef Yield ()

MeO OMe

H3CO 21

88g 97h 75 g (90)

EtO OEt

H3CO 22

67g 90h 72 g (80)

76 88 gt98i

79 90 gt98i

MeO OMe

O2N 25

97 94h 82g (94)h

EtO OEt

O2N 26

92 91h 57g (75)h

Bacd Yield ()

Caef Yield ()

MeO OMe

NO2 27

57 96 95

EtO OEt

NO2 28

64 92 gt98i

92 99 gt98i

72 93 96

11 OMeMeO

90 96 gt98i

12 OEtEtO

85 96 gt98i

78 74g gt98i

81 73g gt98i

Green Chemistry

not happen again11

destruction

bull Other

use of solvents

Yield () adf

MeO OMe

96 63 98 92

EtO OEt

83h 75 89 92

MeO OMe

94hj 0 92 73 (92)i

EtO OEt

77 0 0 75 (82)i

MeO OMe

80 33 77 90

EtO OEt

83 33 80 93

OMe 222

86 0 gt98k 96

OEt 223

74 0 82 92

formed

Run Yield ()abc

1 gt98

2 gt98

24 Deprotections

96 yield

OOOMeMeO

0 oC 15 h96

5 mol Al(OTf)3

MeO OMe

H3CO 21

MeO OMe

O2N 25

O N2 55

EtO OEt

Acetal Product

In(OTf)3

Hf(OTf)4

Cu(OTf)2

Ca(OTf)2

MeO OMe

21 H3CO

100 100 100 21

MeO OMe

O2N 25

O N2 89 100 18 15

EtO OEt

100 100 43 19

Acetal Product

Al(OTf)3

In(OTf)3

Hf(OTf)4

No Cat

MeO OMe

H3CO 21

100 100 100 100

MeO OMe

O2N 25

O N2 100a 100a 100a 100a

OMeMeO

O16 22 26 0

EtO OEt

100 100 100 68

O OMeR R

Acetal Product

Al(OTf)3

In(OTf)3

Hf(OTf)4

Sc(OTf)3

No Cat

MeO OMe

H3CO 21

100 100 100 100 97

MeO OMe

O2N 25

O N2 100a 100a 100a 100a 100a

EtO OEt

100 100 100 100 75

Silyl ethers

OH OTBDMS

224 (78)

15 eq Pyridine

OTBDMS

225 (80)

15 eq Pyridine

20 eq TBDMSCl

of 1 mol TfOH

reaction

Yield ()a

OTBDMS

Yield ()a

OTBDMS

O OROH

conditions23

overall efficiency

Yield ()

+O MeOH

OMeO+ H+

211 entry 1 and 2)

TBDMSO

OO 229

OTBDMS

TBDMSO

231 Yield ()

TBDMSO

O Yield ()

Yield ()

TBDMSO

OTBDMS

OMe 232

Yield ()

OTBDMS

O Yield ()

OTBDMS

faster reaction

OTBDMS

OMe Yield ()

OTBDMS

O Yield ()

OTBDMS

Al(OTf)3 82 18 0

Sc(OTf)3 91 9 0

In(OTf)3 94 6 0

Cu(OTf)2 gt98 0 0

Ca(OTf)2 gt98 0 0

29 Conclusions

210 References

R S J Org Chem 2002 67 5202

Ed 2008 47 560

Carb Res 2008 343 1814

New York 1991 31

Chapter 3

31 Introduction

M+n + H2O M OHH

solvents more fully

ROH + SO2 + RN

2I- I2 + 2e-

[alkylsulfite salt]

ammonium salt

mg of water

content8

Reading

Hydranal

Std Mass

content

1 0401 72

2 0391 80

3 0386 75

4 0390 74

5 0391 75

6 0411 77

7 0381 76

8 0375 80

9 0370 70

10 0391 75

Average 75 ppm

Std dev 03 ppm

RSD 39

Solvents

Residual water

contenta (ppm)

Std dev ppm RSD ()

DCM 4103 6 224 120 536 THF 2815 6 1078 066 062

acceptable limits

sieves9

Solvent

Residual water

contenta (ppm)

Std dev ppm

RSD ()

Experiment number

Residual water

contenta (ppm)

Std dev (ppm)

RSD ()

1 2836 6 1140 429 376

2 2650 6 440 066 150

repeatable

352 Drying reagents

36 The alcohols

sieves (5 wv)

Time (h) n

Average sample

weighta (g)

Residual water

content (ppm)

Std dev

24 6 2672 753 074 098 24 6 2621 789 067 085 24 6 2557 777 062 080 48 6 2488 452 055 122 48 6 2571 489 047 096 48 6 2612 464 082 177 72 6 2612 329 041 125 72 6 2488 343 040 117 72 6 2612 354 049 138

5 days 6 2523 257 124 482 5 days 6 2584 266 120 451

sieves (10 wv)

Time (h)

Residual water

content (ppm)

Std dev (ppm)

24 6 2688 407 093 229 24 6 2619 392 059 151 24 6 2624 419 041 098 48 6 2561 268 071 265 48 6 2508 293 071 242 48 6 2502 322 087 270 72 6 2612 224 042 188 72 6 2592 236 084 356 72 6 2505 263 063 240

5 days 6 2589 166 057 343 5 days 6 2573 182 058 319 5 days 6 2606 199 168 844

sieves (20 wv)

Time (h) n

Residual water

content (ppm)

Std dev

(ppm) RSD ()

24 6 2509 280 057 204 24 6 2609 292 042 144 24 6 2634 290 031 107 48 6 2496 211 046 218 48 6 2605 239 038 159 48 6 2556 244 087 357 72 6 2591 176 051 290 72 6 2541 188 055 293 72 6 2610 212 088 415

5 days 6 2575 97 099 1021 5 days 6 2542 104 049 471

(5 wv)

Time (h) n

Residual water

content (ppm)

Std dev

(ppm) RSD

24 6 2699 2511 181 072 24 6 2637 2703 166 061 24 6 2662 2664 250 094 48 6 2648 1021 075 073 48 6 2639 1064 074 070 48 6 2633 1110 055 050 72 6 2664 549 093 169 72 6 2639 541 059 109 72 6 2639 563 123 218

5 days 6 2635 144 051 354 5 days 6 2631 141 049 348 5 days 6 2659 149 015 101

(10 wv)

Time (h) n

Residual water

content (ppm)

Std dev ppm

RSD ()

24 6 2668 1894 153 081 24 6 2666 1792 081 045 24 6 2638 1896 050 026 48 6 2645 678 051 075 48 6 2637 695 064 092 48 6 2640 712 058 081 72 6 2642 351 107 305 72 6 2624 359 073 203 72 6 2616 397 118 297

5 days 6 2611 114 113 991 5 days 6 2658 130 076 585 5 days 6 2619 124 089 718

(20 wv)

Time (h)

Residual water

content (ppm)

Std dev ppm

RSD ()

24 6 2639 1186 058 049 24 6 2641 1190 109 092 24 6 2630 1218 037 030 48 6 2643 231 076 329 48 6 2639 243 055 226 48 6 2666 277 079 285 72 6 2604 190 028 147 72 6 2612 194 056 289 72 6 2608 231 061 264

5 days 6 2651 69 035 507 5 days 6 2612 81 035 432

5 days 6 2599 95 050 526

acceptable

powder

Average sample

weight (g) n

Residual water

contenta (ppm)

Std dev ppm

RSD ()

Methanol KOH (10 wv) 24 2525 6 318 081 255

Methanol KOH (10 wv) 24 2555 6 339 099 292

Methanol KOH (10 wv) 24 2606 6 337 093 276

Ethanol KOH (10 wv) 24 2856 6 259 074 286

Ethanol KOH (10 wv) 24 2760 6 284 053 187

Ethanol KOH (10 wv) 24 2640 6 250 056 225

37 Acetonitrile

Desiccant Time (h)

Residual water

contenta (ppm)

Std dev ppm

RSD ()

24 2628 6 40 065 1606 48 2626 6 18 050 2841 72 - 6 ltdlb - -

24 2643 6 05 041 8367

48 - 6 ltdlb - -

10 (wv) -c 2966 6 61 062 1015

10 (wv) -c 2924 6 49 015 306

10 (wv) -c 2826 6 68 037 537

titrations

Residual water

contenta (ppm)

Std dev ppm

RSD ()

(20 wv)

Time (h) n

Residual water

content (ppm)

Std dev (ppm)

RSD ()

24 6 3029 152 029 191 24 6 3027 143 012 084 24 6 3007 146 036 247 48 6 3034 59 021 356 48 6 3000 60 021 350 48 6 2998 64 010 156 72 6 2970 43 005 116 72 6 3016 42 018 429 72 6 2907 38 010 263

Fischer titration

Residual water

contenta (ppm)

Std dev ppm

RSD ()

repeatable

39 Discussion

310 Conclusions

38 References

Oxford 1963 682

41 Introduction

acidity6

literature

H3C CH3

CH3H3CN

CH3H3C

H3C CH3

CH3H3C

5 mol Bi(OTf)3 H2OH

Ph NH2

O NH OPh

41 42 43 44

Water 7 h

OTES OBz

OTES OH

Bz2O CH2CN

10 mol Sc(OTf)3

SO2PhBz2O CH3CN

OH O Ph

O3 eq Bz2O

Conversion

1 Yb(OTf)3 99 15 11

2 Bi(OTf)3 40 15 8

3 In(OTf)3 34 15 3

4 Sc(OTf)3 63 15 2

5 Cu(OTf)2 3 - -

6 Sc(OTf)3 63 5 6

OHHOHO

TfOH (005 eq) 10 min 84

OHHOHO

In(OTf)3 (005 eq) 1 h 99

OHHOHO

In(OTf)3 (005 eq)

With DTMP 24 h 11

OHH2NHO

In(OTf)3 (005 eq)

1 h NR

OHH2NHO

+ In(OTf)3

OIn(OTf)2H2N

+ HOTf

n(H2O)YbO

431 Introduction

OH H H

Enolate

OSiMe3+ R3 C R4

Lewis acid

OSiMe3 O

+MXn 02eq

THFH2O (91)12 h rt413 414 415

proceed no further

product

La(OTf)3 80

Ce(OTf)3 81

Pr(OTf)3 83

Nd(OTf)3 78

Sm(OTf)3 85

Eu(OTf)3 88

Gd(OTf)3 90

Tb(OTf)3 81

Dy(OTf)3 85

Ho(OTf)3 89

Er(OTf)3 86

Tm(OTf)3 85

Yb(OTf)3 92

Lu(OTf)3 84

Yield ()a

Hydrolysis of

Silyl ether

(silyl ether)

La(OTf)3 92 (80)b 8 0

InCl3 89 (68)b 3 8

CuCl2 86 (25)b 11 3

LiCl 6 (-)b 7 77

ScCl3 59 (70) 41 -

Er(OTf)3 56 (86)b 6 38

GaCl3 28 (-)b 56 16

ZnCl2 22 (10)b 0 78

AlCl3 0 (0)b 100 0

Cu(OTf)2 96 4 0

Sc(OTf)3 94 6 0

Y(OTf)3 89 11 0

Zn(OTf)2 77 2 21

Ca(OTf)2 42 28 30

In(OTf)3 41 59 0

Al(OTf)3 21 79 0

Zr(OTf)4 0 100 0

Hf(OTf)4 0 100 0

Li(OTf) 0 11 89

TiCl4 0 100 0

TiCl4 -098 100 TfOH 034 100

Y(OTf)3 445 6 Cu(OTf)2 464 4 Zn(OTf)2 540 2

LiCl 830 7 LiOTf 889 11

In(OTf)3 277 59 400 InCl3 432 6 400 ScCl3 254 41 430

Sc(OTf)3 275 6 430 CuCl2 408 11 753

ZnCl2 549 0 896 Ca(OTf)2 607 28 1285

LiCl 830 7 1364 LiOTf 889 11 1364 TfOH 034 100

rate constant

OSiMe3

PhCHO TiCl4 CH2Cl2

TiCl3Cl -Me3SiCl

Me PhPhPh

ClCl Cl

Me PhPhPh

catalytic cycle

THF H2O (91)

La(OTf)3 92 35 Y(OTf)3 89 83

788764755

Lewis Acid

Δδ H aldehyde

Δδ Ortho

protons

Δδ Para

protons

Δδ Meta

protons 1001 788 764 755

Sc(OTf)3 -0033a 0109 0108 0044

ScCl3 0054 0093 009 0029

In(OTf)3 -0015a 016 016 007

proceed (Figure45)

OSiMe3

M(OTf)3

phenomena

of ligands

Water 79

Acetonitrile 375

Methanol 315

Ethanol 242

Acetone 22

Chlorobenzene 56

Tetrahydrofuran 76

Ether 45

Benzene 23

Pentane 18

M3+M OTfTfO

OTf M OTf M OTF

Quadruplet

OTf M OTfTriplet

solvents

+-+- +-+- etc)32

Et3N + CH3Iδ δ

Solvent Dielectric

Hexane 20 1

MSn OH

+ MSn-1

+ S eq 42

MnXm-1

ion-pair formation

415)34

M+n + H2O M(H2O)x

M(H2O)x-1OH+n-1

Broslashnsted acid

particular

conditions

Lewis acid

Without

Yield ()

La(OTf)3 92 0 0

Sc(OTf)3 96 79 50

InCl3 89 99 0

Cu(OTf)2 94 65 0

N+ ROH

Lewis acid pH in

THFH2O (91)

pH in THFH2O

(91) and 15 eq

46 Summary

Retinyl acetate

CH2+ HO

triflate

Retinyl acetate +

hydrolysis

non- polar solvents

-OTf416

BA OTf-

Al(OTf)3

BA =Al(OTf)3K

5 mL of DCM

(Table 416)

Retinyl acetate +

Mr = 42544 F000 = 884

V = 17580 (2) Aring3 T = 296 (2) K

Lewis acid

Reaction Yield ()a

Reactions +200 uL

ScCl3 0 21 InCl3 50 53 TfOH 31 31

p-xylenea

Metal triflate

Yield ()b

4 mL p-xylene

Yield ()b

2 mL p-xylene

spectroscopy

systemsa

Lewis Acid 10 mol

Yield ()b

Cumene 16 mL 48 h

Yield ()b

Anisole 16 mL 24 h

Yield ()b

Toluene 16 mL 48 h

Zr(OTf)4 71 gt 95 66 Al(OTf)3 47 gt95 77

Metal Triflate

bottle

was 60

Hf(OTf)4)

attention

49 Conclusions

modified

410 References

M J Carb Res 2008 343 2814

68 9340

M J Carb Res 2008 343 2814

1994 188

1998 39 1641

1997 613

Chem Soc 2008 131 6342

2008 49 2384

Winston 1959

Chapter 5

51 Introduction

triflates

Crotonaldehyde

signala

Croton

aldehyde

Δ δ on

addition

Al(OTf)3

Δ δ on

addition

Δ δ on

addition

Sc(OTf)3

Δ δ on

addition

Δ δ on

addition

In(OTf)3

Δ δ on

addition

H-1 947 -026 -016 -025 003 -006 -007

H-2 610 054 013 044 045 030 027

H-3 687 093 023 093 071 050 043

Lewis acids

signala

Croton

aldehyde

Δ δ on

addition

Al(OTf)3

Δ δ on

addition

Δ δ on

addition

Sc(OTf)3

Δ δ on

addition

Δ δ on

addition

In(OTf)3

Δ δ on

addition

C-1 1941 111 04 116 175 04 29

C-2 1348 -20 05 -14 -15 03 -02

C-3 1544 219 02 221 1752 04 45

C3C2 C1

NMR signala

Trans-

cinnamaldehyde

δ ppm

Hf(OTf)4 003 005 13 -02 12

Sc(OTf)3 -016 -002 24 01 25

In(OTf)3 -0171 0047 17 00 16

Ca(OTf)2 -0074 0014 04 -04 02

Zn(OTf)2 -005 0038 29 03 26

Y(OTf)3 -0048 0145 31 03 33

Zr(OTf)4 -0107 004 23 -07 24

Al(OTf)3 -0076 0032 09 00 09

Lewis acids

Phosphorus NMR

thermodynamic data

Phosphorus compound

δ uncomplexeda

Δ δ on addition

of Al(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of In(OTf)3

(OTf)3M

NMR signal

Croton aldehyde

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

Δ δ on addition

of Sc(OTf)3

18 aH-1 947 -027 -022 -015 -008

H-2 687 045 014 026 014

H-3 610 100 083 057 024

CH3 201 028 023 014 005

NMR signal

Croton aldehyde

Δ δ on addition

of In(OTf)3

Δ δ on addition

of In(OTf)3

Δ δ on addition

of In(OTf)3

Δ δ on addition

of InOTf)3

18 aH-1 947 -009 -008 -007 -006

H-2 687 027 019 010 008

H-3 610 049 037 021 017

solvent to solvent

A = εbc 1

(Figure 58)9

(Figure 59)

complex

the probes

Lewis Acid

laboratory

method was sought

may be obtained

[bmim][OTf]

acid coordination

LiOTf 14422 22 -a

Ca(OTf)2 14424 24 -a

Zn(OTf)2 14520 120 -a

Cu(OTf)2 14530 130 -a

Ba(OTf)2 14610 210 -a

LiCl 14860 460 -a

ScCl3 14870 470 -a

InCl3 14890 490 -a

metal salts

activity

Table 58

14694 14694 14694 14694

144428 14463 14463 14463

the Lewis acids

55 Conclusions

References

Int Ed 2008 47 560

Main conclusions

identified

Future research

expensive triflates

Chapter 6

611 Chromatography

prior to use

63 Melting Points

uncorrected

64 Chemical methods

Chapter 2

MeO OMe

Yield 97 yellow oil

Obtained = 1510753

EtO OEt

Yield 90 yellow oil

Obtained = 1650910

Obtained = 1569867

Obtained = 1690416

MeO OMe

(ortho) 491 (2 x OCH3) 258 (CH3)

Obtained = 1960593

EtO OEt

Yield 92 yellow oil

(CH3) 151 (OCH3)

Obtained = 1940811

MeO OMe

(C3) 1280 (C5) 1241 (C4) 997 (acetal) 544 (2 x OCH3)

Obtained = 1660498

EtO OEt

1241 (C4) 983 (acetal) 634 (2 x OCH2) 150 (2 x CH3)

Obtained = 1800655

Ph OMe

x OCH3)

Obtained = 1470805

Ph OEt

Obtained = 1610960

Obtained = 1711741

Obtained = 1851902

(C3 and C5) 263 (C4) 257 (C4 and C6)

Obtained = 1271099

Obtained = 1411275

Yield 98White solid

Obtained = 1921147

MeO OMe

(ortho) 1031 (CH) 526 (OCH3)

Obtained = 1210445

EtO OEt

Obtained = 1350807

MeO OMe

Obtained = 1510755

EtO OEt

(OCH2CH3)

Obtained = 1791067

(C4) 228 (C3 C5)

Obtained = 1130967

2H H2 H6) 147 (m 2H H3 H5) 137 (m 1H H4) 115 (t 6H J =

(C4) 230 (C3 C5) 156 (2 x CH2CH3)

Obtained = 1281196

Obtained = 1110465

Obtained = 1250597

OTBDMS

(C(CH3)3 -54 (OSi(CH3)2)

Obtained = 1790887

OTBDMS

Obtained = 2289670

was used

(C5) 254 (C4) 194 (C3)

Obtained = 1220727

mp 566ndash584

1138 (para) 965 (acetal) 620 (C2) 302 (C5) 251 (C4) 186 (C3)

Obtained = 179521

618 (C2) 540 (HCequivCCH2) 301 (C3) 252 (C3) 252 (C4) 190

Obtained = 850646

1262 (C2) 1207 (C6) 1100 (C5) 554 (OCH3) 255 (C(CH3)3) 184

(C(CH3)3 -46 (OSi(CH3)2)

Obtained = 2090629

OTBDMS

Yield 90 yellow oil

1215 (C5 C6) 1202 (C3) 256 (C(CH3)3) 163 (C(CH3)3 -43

(OSi(CH3)2)

Obtained = 1790523

TBDMSO

OTBDMS

120 (C6) 1010 (acetal) 538 (2 x OCH3) 263 (C(CH3)3) 192

(C(CH3)3 -40 (OSi(CH3)2)

Obtained = 2250946

Chapter 3

i=1(xi - μ)2

Eq 1 RSD = ( x) x 100σ Eq 2

x = sample mean

data see appendix A

Chapter 4

To make LDA

10 minutes

chromatography

OSiMe3

Obtained = 1340732

Obtained = 2250946

(CH2CH3)

Obtained = 2880755

6410 Crystal data

Mr = 42544 F000 = 884

λ = 071073 Aring

V = 17580 (2) Aring3 T = 296 (2) K

Data collection

CCD area detector

T = 296(2) K θmax = 280deg

Refinement

Fourier map

neighbouring sites

wR(F2) = 0137 w = 1[σ2(Fo

2) + (00834P)2]

S = 098 (Δσ)max = 2220

706 (s 1H H2) 706 (d 2H J = 18 H4 H5) 577 (d 1H J = 15 Hz

1330 (C6) 1307 (C5) 1300 (C6) 1283 (C10 and C12) 1282 (C11)

1275 (C2) 1265 (C9 and C13) 1146 (C14) 210 (C16) 196 (C15)

Obtained = 2081240

Chapter 5

at 25 degC

NMR spectroscopy

11 01 mmol 01 mmol

12 01 mmol 02 mmol

14 01 mmol 04 mmol

18 01 mmol 08 mmol

65 References

Chem Soc 2006 128 5930

60 4037

1 2765 CL 95

2 2874 1015 3 2874 1025 4 2749 1018 5 2868 1019 6 2761 1013

Average 2815 1018

1 2933 1171 2 2780 1189 3 2806 1132 4 2951 1071 5 2867 1116 6 2838 1161

Average 2863 1140

1 2638 441 2 2656 435 3 2648 441 4 2675 449 5 2639 431 6 2641 446

Average 2650 440

1 2673 432 2 2702 422 3 2698 421 4 2657 434 5 2712 420 6 2668 436

Average 2685 428

1 2840 276 2 2795 290 3 2917 291 4 2647 272 5 2730 267 6 2762 271

Average 2782 278

1 3000 593 2 2906 572 3 2860 560 4 2880 520 5 2853 578 6 2800 550

Average 2883 562

1 2973 807 2 2960 CL 95

3 2965 824 4 3005 824 5 2993 837 6 2987 834

Average 2981 825

1 2900 1066 2 2942 1057 3 2735 1097 4 2902 1009 5 2854 1025 6 2894 1090

Average 2871 1057

1 2981 909 2 2821 896 3 2921 864 4 2922 866 5 2932 939 6 2848 889

Average 2904 894

1 2857 742 2 2889 763 3 2806 747 4 2838 712 5 2821 774 6 3027 739

Average 2873 746

1 2952 618 2 2959 597 3 2888 649 4 2933 598 5 2860 550 6 2987 560

Average 2930 595

1 2937 730 2 2872 716 3 2920 688 4 2903 646 5 2915 659 6 2933 702

Average 2913 690

1 2939 606 2 2953 624 3 2975 630 4 2967 613 5 2825 575 6 2901 603

1 3112 156 2 2998 151 3 3100 149 4 2976 153 5 2987 148 6 3001 153

1 3101 145 2 2964 143 3 2899 142 4 3112 CL 95

5 3103 143 6 2981 142

Average 3027 143

1 2899 146 2 2976 140 3 2988 147 4 2978 143 5 3100 149 6 3102 149

Average 3007 146

1 3004 59 2 2987 57 3 3003 58 4 3067 57 5 3076 61 6 3064 62

Average 3034 59

1 3044 61 2 2988 59 3 3000 58 4 2991 62 5 2989 62 6 2988 57

Average 3000 60

1 3014 63 2 2994 64 3 2983 61 4 2997 63 5 2996 62 6 3004 62

1 2864 43 2 2990 43 3 2999 44 4 2988 CL 95

5 3009 44 6 2968 43

Average 2970 43

1 3074 41 2 2998 41 3 2995 42 4 3031 45 5 3006 43 6 2994 40

Average 3016 42

1 3014 39 2 2918 38 3 2990 37 4 3011 37 5 3029 39 6 2948 39

Average 2985 38

1 3004 55 2 3100 56 3 2713 54 4 2985 57 5 3005 56 6 3001 55

Average 2968 56

1 2934 49 2 2991 48 3 2997 48 4 2990 47 5 3010 CL 95

6 3084 46 Average 3001 48

1 2948 54 2 2789 53 3 2994 54 4 2783 55 5 2956 53 6 2973 56

1 2568 1427 2 2371 1436 3 2666 1426 4 2559 1407 5 2598 1418 6 2554 1407

Average 2553 1420

1 2646 45 2 2634 45 3 2574 38 4 2631 46 5 2645 40 6 2638 29

Average 2628 40

1 2604 19 2 2645 16 3 2673 26 4 2536 20 5 2645 13 6 2655 12

Average 2626 18

1 2652 12 2 2584 01 3 2652 02 4 2653 07 5 2657 02 6 2660 04

Average 2643 05

1 2963 69 2 2991 66 3 2953 58 4 2960 64 5 2965 56 6 2964 54

Average 2966 61

1 2913 CL = 95

2 2951 49 3 2923 51 4 2940 49 5 2925 50 6 2894 47

Average 2924 49

1 2943 67 2 2911 65 3 2863 73 4 2440 69 5 2895 64 6 2904 72

1 2563 1748 2 2576 1746 3 2603 1757 4 2590 1749 5 2594 1754 6 2613 1755

Average 2590 1751

1 2689 758 2 2625 740 3 2664 751 4 2674 CL 95

5 2678 761 6 2702 756

Average 2672 753

1 2643 794 2 2598 786 3 2586 787 4 2633 798 5 2644 779 6 2635 792

Average 2621 789

1 2584 779 2 2552 768 3 2621 774 4 2556 781 5 2529 CL 95

6 2497 785 Average 2557 777

1 2703 417 2 2671 394 3 2712 409 4 2654 412 5 2648 398 6 2739 414

Average 2688 407

1 2568 398 2 2633 387 3 2574 397 4 2632 CL 95

5 2695 396 6 2613 386

Average 2619 393

1 2598 420 2 2648 418 3 2653 417 4 2589 424 5 2655 421 6 2599 412

Average 2624 419

1 2589 288 2 2498 273 3 2534 279 4 2477 284 5 2490 CL 95

6 2465 274 Average 2509 279

1 2541 292 2 2653 289 3 2666 287 4 2579 294 5 2534 299 6 2683 291

Average 2609 292

1 2695 293 2 2653 291 3 2648 288 4 2589 290 5 2648 293 6 2568 285

Average 2634 290

1 2529 462 2 2428 447 3 2484 451 4 2437 453 5 2590 448 6 2459 449

Average 2488 452

1 2491 493 2 2623 486 3 2626 489 4 2489 482 5 2564 495 6 2633 489

Average 2571 489

1 2615 463 2 2613 459 3 2608 470 4 2619 474 5 2558 467 6 2658 451

Average 2612 464

1 2575 275 2 2573 266 3 2640 268 4 2530 278 5 2458 264 6 2590 259

Average 2561 268

1 2530 283 2 2528 294 3 2530 285 4 2447 301 5 2550 CL 95

6 2463 298 Average 2508 292

1 2451 313 2 2500 324 3 2506 324 4 2519 334 5 2504 329 6 2533 312

Average 2502 323

1 2549 203 2 2428 211 3 2514 213 4 2437 216 5 2627 209 6 2419 213

1 2675 243 2 2423 236 3 2608 243 4 2630 234 5 2671 238 6 2620 241

1 2560 256 2 2508 247 3 2570 234 4 2457 246 5 2650 249 6 2593 234

Average 2556 244

1 2615 324 2 2613 327 3 2608 332 4 2619 335 5 2558 326 6 2658 330

Average 2612 329

1 2529 339 2 2428 342 3 2484 347 4 2437 337 5 2590 346 6 2459 345

Average 2488 343

1 2615 349 2 2613 358 3 2608 356 4 2619 CL 95

5 2558 359 6 2658 354

Average 2612 355

1 2655 221 2 2550 232 3 2608 225 4 2618 224 5 2614 221 6 2626 222

1 2645 CL 95

2 2633 236 3 2540 245 4 2540 246 5 2538 224 6 2658 231

1 2479 257 2 2428 264 3 2474 267 4 2537 254 5 2640 271 6 2471 263

Average 2505 263

1 2590 174 2 2570 180 3 2658 CL 95

4 2519 169 5 2598 183 6 2610 173

Average 2591 176

1 2539 184 2 2628 193 3 2464 191 4 2447 CL 95

5 2540 195 6 2629 183

Average 2541 189

1 2651 205 2 2450 211 3 2668 204 4 2678 224 5 2684 205 6 2526 221

Average 2610 212

1 2539 253 2 2628 243 3 2534 262 4 2417 274 5 2560 264 6 2459 243

Average 2523 257

1 2675 269 2 2560 274 3 2517 243 4 2606 273 5 2526 CL 95

6 2622 261 Average 2584 264

1 2460 274 2 2410 264 3 2584 289 4 2447 271 5 2580 264 6 2489 273

Average 2495 273

1 2574 167 2 2613 159 3 2588 173 4 2569 160 5 2608 164 6 2579 171

Average 2589 166

1 2489 189 2 2588 173 3 2524 183 4 2697 CL 95

5 2578 179 6 2559 183

Average 2573 181

1 2570 193 2 2590 187 3 2628 183 4 2620 194 5 2588 206 6 2638 229

Average 2606 199

1 2420 115 2 2590 96 3 2640 95 4 2669 89 5 2638 101 6 2490 88

Average 2575 97

1 2559 103 2 2478 107 3 2624 99 4 2497 111 5 2620 CL 95

6 2471 98 Average 2542 104

1 2641 124 2 2540 127 3 2596 104 4 2602 118 5 2606 99 6 2634 115

Average 2603 115

1 2569 305 2 2548 312 3 2489 325 4 2548 316 5 2450 324 6 2548 324

Average 2525 318

1 2459 354 2 2657 334 3 2658 341 4 2549 342 5 2459 324 6 2548 341

Average 2555 339

1 2658 331 2 2642 324 3 2548 335 4 2548 342 5 2658 339 6 2549 351

Average 2600 337

Methanol from MgI2

1 2660 545 2 2385 537 3 2693 540 4 2683 531 5 2531 530 6 2667 533

1 2650 14291 2 2537 14327 3 2618 14306 4 2653 14218 5 2673 14263 6 2598 14292

Average 2622 14283

1 2701 2516 2 2694 2486 3 2698 2508 4 2704 2496 5 2699 2523 6 2700 2536

Average 2699 2511

1 2655 2676 2 2596 2715 3 2626 2705 4 2572 2691 5 2684 CL 95

6 2691 2720 Average 2637 2701

1 2658 2651 2 2645 2671 3 2632 2644 4 2651 2712 5 2671 2656 6 2713 2652

Average 2662 2664

1 2661 CL 95

2 2664 1882 3 2678 1887 4 2674 1892 5 2659 1891 6 2670 1887

Average 2668 1888

1 2665 1804 2 2650 1793 3 2638 1795 4 2659 1781 5 2675 1785 6 2709 1793

Average 2666 1792

1 2653 1904 2 2592 1899 3 2629 1895 4 2576 1889 5 2687 1896 6 2693 1895

Average 2638 1896

1 2651 1183 2 2689 1185 3 2628 1191 4 2581 1195 5 2685 CL 95

6 2597 1184 Average 2639 1188

1 2647 1206 2 2591 1193 3 2629 1196 4 2579 1189 5 2695 CL 95

6 2705 1184 Average 2641 1194

1 2661 1214 2 2647 1216 3 2539 1220 4 2657 1221 5 2672 1215 6 2604 1223

Average 2630 1218

1 2643 CL 95

2 2692 1020 3 2639 1018 4 2586 1016 5 2693 1024 6 2633 1014

Average 2648 1018

1 2695 1065 2 2650 1076 3 2643 1065 4 2659 1054 5 2575 1059 6 2609 1063

1 2651 1107 2 2724 1106 3 2668 1113 4 2634 1111 5 2509 1119 6 2610 1104

Average 2633 1110

1 2541 672 2 2667 678 3 2648 679 4 2694 682 5 2649 685 6 2669 673

Average 2645 678

1 2666 694 2 2525 696 3 2636 689 4 2653 CL 95

5 2701 687 6 2643 703

1 2652 710 2 2591 717 3 2633 703 4 2579 719 5 2693 709 6 2693 713

Average 2640 712

1 2671 242 2 2644 229 3 2622 227 4 2654 231 5 2659 220 6 2610 237

Average 2643 231

1 2681 245 2 2634 249 3 2618 246 4 2634 236 5 2629 247 6 2640 237

1 2666 267 2 2649 270 3 2636 281 4 2659 279 5 2680 276 6 2708 289

1 2661 532 2 2652 558 3 2634 553 4 2657 556 5 2680 548 6 2702 549

Average 2664 549

1 2646 541 2 2595 539 3 2632 537 4 2577 546 5 2690 548 6 2694 532

Average 2639 541

1 2652 569 2 2627 577 3 2666 574 4 2648 549 5 2609 CL 95

6 2630 549 Average 2639 564

1 2651 367 2 2592 339 3 2635 342 4 2586 346 5 2690 CL 95

6 2699 357 Average 2642 350

1 2647 368 2 2600 365 3 2639 352 4 2574 350 5 2689 362 6 2593 356

1 2663 387 2 2653 395 3 2538 397 4 2658 402 5 2585 417 6 2599 384

1 2649 190 2 2522 189 3 2634 187 4 2526 192 5 2683 194 6 2611 187

Average 2604 190

1 2655 189 2 2550 196 3 2608 197 4 2618 185 5 2614 196 6 2626 CL 95

Average 2612 193

1 2648 224 2 2556 226 3 2663 240 4 2524 231 5 2643 236 6 2612 229

Average 2608 231

1 2569 139 2 2668 138 3 2584 144 4 2637 152 5 2690 146 6 2659 142

Average 2635 144

1 2591 133 2 2623 142 3 2726 146 4 2589 140 5 2664 139 6 2593 146

Average 2631 141

1 2641 148 2 2643 151 3 2706 147 4 2649 150 5 2704 149 6 2613 148

Average 2659 149

1 2529 120 2 2618 128 3 2614 119 4 2607 113 5 2660 103 6 2639 CL 95

Average 2611 117

1 2631 136 2 2663 125 3 2716 125 4 2609 139 5 2744 120 6 2583 135

Average 2658 130

1 2581 134 2 2653 131 3 2676 124 4 2549 110 5 2714 128 6 2543 118

Average 2619 124

1 2687 75 2 2655 69 3 2680 68 4 2659 64 5 2615 70 6 2609 69

Average 2651 69

1 2496 81 2 2589 76 3 2620 80 4 2680 79 5 2677 85 6 2609 85

1 2541 92 2 2593 95 3 2663 87 4 2527 CL 95

5 2648 94 6 2619 97

Average 2599 93

1 2875 257 2 2975 249 3 2896 258 4 2846 260 5 2758 272 6 2785 258

Average 2856 259

1 2587 278 2 2846 291 3 2874 286 4 2795 CL 95

5 2876 279 6 2579 284

Average 2760 284

1 2579 251 2 2858 254 3 2548 254 4 2479 252 5 2797 249 6 2579 239

1 4167 263 2 4146 230 3 4154 222 4 4079 205 5 3923 226 6 4151 237

Average 4103 231

1 4393 01 2 4172 02 3 4405 02 4 4183 00 5 4285 01 6 4168 02

1 4198 15 2 4206 09 3 4149 09 4 4168 14 5 4286 15 6 4295 CL = 95

Average 4217 13

DCM dried over CaH2

1 4206 147 2 4357 121 3 3871 129 4 4215 114 5 4347 121 6 3927 140

Average 4154 129

Front page



Faculty of Science



June 2009

Table of Contents

Synopsis

Abbreviations

Figures and schemes

Chapter 1

Chapter 2

Chapter 3_12099

Chapter 4

Chapter 5


Chapter 6

Appendix A


Documents

Metal triflate catalysed organic transformations