Green Chemistry: : A Textbook [1 ed.] 9781783320097, 9781842657539

Citation preview

V.K. Ahluwalia

a Alpha Science International Ltd. Oxford, U.K.

Green Chemistry A Textbook 568 pgs.

V.K. Ahluwalia Honorary Visiting Professor B.R. Ambedkar Centre for Biomedical Research University of Delhi Delhi Copyright © 2013 ALPHA SCIENCE INTERNATIONAL LTD. 7200 The Quorum, Oxford Business Park North Garsington Road, Oxford OX4 2JZ, U.K.

www.alphasci.com All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the publisher. ISBN 978-1-84265-753-9 E-ISBN 978-1-78332-009-7 Printed in India

Preface

Green Chemistry is environmentally benign chemical synthesis. Its objective is to eliminate or reduce pollution by preventing the generation of hazardous byproducts or substances. Green synthesis is achieved by following the twelve principles of green chemistry as suggested by Paul T. Anatas and John C. Warner. Green chemistry, in fact, is the pressing need of all nation. The book is divided into seven parts. The introduction to green chemistry is discussed in Part 1 (Chapter 1). Part 2 deals with organic synthesis in benign solvents like water, supercritical carbon dioxide, ionic liquids, polyethylene glycol and its solutions and fluorous solvents. All these are discussed in chapters 2 to 6. Organic synthesis in solid state forms the subject matter of Part 3 (Chapter 7). Part 4 deals with the use of alternative energy process in chemical synthesis. The energy sources include microwave (Chapter 8), ultrasound (Chapter 9) and photo induced organic synthesis (Chapter 10). Organic synthesis using green reagents have been discussed in Part 5 (Chapter 11). The reagents discussed include oxygen, singlet oxygen, ozone, hydrogen peroxide, dioxiranes, dimethyl carbonate and a number of polymer supported reagents. The use of green catalyst are discussed in Part 6). The green catalysts include phase transfer catalysts (Chapter 12), crown ethers (Chapter 13), biocatalyst (Chapter 14) and polymer supported catalyst (Chapter 15). Finally some examples of green synthesis using basic principles of green chemistry are given in Part 7 (Chapter 16). Green chemistry is the requirement of all undergraduate, Postgraduate and M Phil students of all Universities and Colleges. Besides, it is also included as course content in Engineering colleges and Environmental Studies. Most important is that all industrial establishments dealing with organic chemicals, green chemistry is an asset. It is hoped that this comprehensive book will be of immense use to all concerned. The author takes the opportunity of expressing his thanks to Mr. N. K. Mehra of Narosa Publishing House for letting him use the material already published in other books published by him (Narosa Publishing House) and also for the help rendered in the publication of this book.

V.K. Ahluwalia

Contents

Preface

v Part I

Introduction

1. IntroducƟon 1.1 1.2

Principles of Green Chemistry Explanation of the Twelve Principles of Green Chemistry 1.2.1 It is better to prevent waste than to treat or clean up waste after it is formed 1.2.2 Synthetic methods should be designed to maximise the incorporation of all the starting materials in the process into the final product 1.2.3 Whenever practicable, synthetic methologies should be designed to use and generate substances that possess little or no toxicity to human health and environment 1.2.4 Chemical products should be designed to preserve efficacy of function while reducing toxicity 1.2.5 The use of auxiliary substances (solvents, separation agents etc.) should be made unnecessary wherever possible, and when used, innocuous 1.2.6 Energy requirements should be recognised for their environmental and economic impacts and should be minimised 1.2.7 A raw material or feed stock should be renewable rather than depleting whenever technically and economically practical

1.3 1.4 1.4 1.4 1.5

1.7

1.8 1.8

1.9 1.9

viii Contents 1.2.8

1.3

Unnecessary derivatisation (blocking group, protection and deprotection, temporary modification of physical/chemical processes) should be avoided whereever possible 1.2.9 Catalytic reagents (as selective as possible) are superior to stoichiometric reagents 1.2.10 Chemical products should be so designed so that at the end of their function they do not persist in the environment and instead break down into innocuous degradation products 1.2.11 Analytical methodologies need to be further developed to allow real-time, in process monitoring and control prior to the formation of hazardous substances 1.2.12 Substances and the form of a substance used in a chemical process should be chosen so as to minimise the potential for chemical accidents, including releases, explosion and fires How to Plan a Green Synthesis 1.3.1 The synthetic methods should be such that all the starting materials be converted into the final product 1.3.2 Unnecessary derivation (blocking group, protection and deprotection) should be avoided whenever possible 1.3.3 Use an environmentally benign solvent 1.3.4 The requirement of energy should be minimised to a bare minimum Use of catalyst 1.3.5 1.3.6 Use of polymer supported substrates or polymer supported reagents

Part II

1.9 1.10

1.10

1.10

1.11 1.11 1.11 1.12 1.13 1.14 1.16

Organic Synthesis in Benign Green Solvents

2. Organic Synthesis in Water 2.1 2.2

1.9

Introduction Reactions in Water 2.2.1 Pericyclic reactions 2.2.2 Claisen rearrangement 2.2.3 Wittig–Horner reaction 2.2.4 Michael reaction 2.2.5 Aldol condensation 2.2.6 Knoevenagel reaction 2.2.7 Pinacol coupling 2.2.8 Benzoin condensation

2.3 2.3 2.5 2.6 2.12 2.12 2.14 2.15 2.17 2.19 2.20

Contents

2.3

2.2.9 Claisen–Schmidt condensation 2.2.10 Heck reaction 2.2.11 Strecker synthesis 2.2.12 Wurtz reaction 2.2.13 Oxidations 2.2.14 Reductions 2.2.15 Electrochemical synthesis 2.2.16 Weiss–Cook reaction 2.2.17 Mannich type reactions 2.2.18 Conversion of o-nitrochalcones into quinolines and indoles 2.2.19 Synthesis of octadienols 2.2.20 Carbon-carbon bond formations in aqueous media 2.2.21 Coupling of indoles with 1, 4-benzoquinones in water Conclusion References

3. Organic Synthesis in SupercriƟcal Carbon Dioxide 3.1

3.2 3.3

ix

2.21 2.22 2.25 2.26 2.26 2.38 2.48 2.50 2.50 2.52 2.52 2.53 2.63 2.63 2.64

3.1

Historical Development 3.1 Properties of Carbon Dioxide 3.1 Phase Diagram for Carbon Dioxide 3.1 3.2 Use of Supercritical Carbon Dioxide (SC-CO2) for Dry Cleaning Use of Supercritical Carbon Dioxide (SC-CO2) as Solvent for Organic Reactions 3.4 3.3.1 Asymmetric catalyst using supercritical carbon dioxide 3.4 3.3.2 Supercritical polymerisations 3.5 3.3.3 Free radical bromination 3.5 3.3.4 Hydrocarbon functionalisation 3.5 3.3.5 Diels–Alder reaction 3.7 3.3.6 Kolbe–Schmitt synthesis 3.9 3.3.7 Bromination: Displacement of a chlorinated aromatics 3.9 3.3.7a Polymerisations 3.9 3.3.8 Freidel–Crafts Reaction 3.10 3.11 3.3.10 Hydrogenation in SC – CO2 3.14 3.3.11 Hydroformylation in SC – CO2 3.14 3.3.12 Oxidations in SC – CO2 3.18 3.3.13 Radical reactions in SC – CO2 3.3.14 Acid–catalysed reactions 3.19 3.3.15 Coupling reactions 3.21

x Contents 3.3.16 3.3.17 3.3.18

3.4

Stereochemical control in reactions using SC – CO2 Photochemical reactions in SC – CO2 Formation of silica nanoparticles using SC – CO2 and water in oil microemulsions 3.3.19 Miscellaneous applications Conclusion References

4. Organic Synthesis using Ionic Liquids 4.1 4.2 4.3 4.4

4.5

4.6

4.7

Introduction Types of Ionic Liquids Preparation of Ionic Liquids 4.3.1 Typical preparation routes for ionic liquids Selection of a Suitable Ionic Liquid for a Particular Reaction 4.4.1 The Baylis–Hillman reaction in ionic liquids The Knoevenagel Condensation 4.4.2 4.4.3 Claisen–Schmidt condensation 4.4.4 The Horner–Wadsworth–Emmons reaction in ionic liquids Synthetic Applications 4.5.1 Alkylation 4.5.2 Allylation 4.5.3 Oxidations 4.5.4 Hydrogenations 4.5.5 Carbon-carbon bond forming reactions Task-specific Ionic Liquids (TSILs) 4.6.1 Brønsted acidic ionic liquids 4.6.2 Brønsted-basic ionic liquids Other Application of Ionic Liquids 4.7.1 Conversion of epoxides to halohydrins 4.7.2 Conversion of oxiranes (epoxides) into thiiranes 4.7.3 Thiocyanation of alkyl halides 4.7.4 Synthesis of cyclic carbonates 4.7.5 Biginelli reaction 4.7.6 Synthesis of 3-acetyl-5-[(z)-arylmethylidene] 1, 3-thiazolidine-2, 4-diones 4.7.7 Synthesis of symmetric urea derivatives 4.7.8 Synthesis of homoallylic amines

3.23 3.26 3.27 3.27 3.34 3.34

4.1 4.1 4.2 4.3 4.4 4.4 4.5 4.6 4.7 4.8 4.9 4.9 4.10 4.10 4.13 4.14 4.21 4.22 4.25 4.25 4.25 4.26 4.27 4.27 4.27 4.27 4.28 4.28

Contents

Conjugate addition of thiols to a, b-unsaturated ketones Nucleophilic displacement reactions Bromination of alkynes Electrophilic nitration of aromatics Carbon-oxygen bond formation Synthesis of 1-acetylnaphthalene Synthesis of tonalid and traseolide Selective hydrogenation of aromatic compounds Alkylation of indole and 2-naphthol Methylene insertion reactions Cycloaddition of carbon dioxide to propylene oxide catalysed by ionic liquids 4.7.20 Epoxidation of electrophilic alkenes in ionic liquids 4.7.21 Oxidation benzylic alcohols to carbonyl compounds with KMnO4 in ionic liquids Biotransformations in Ionic Liquids 4.8.1 Synthesis of Z-aspartame 4.8.2 Conversion of 1, 3-dicyanobenzene to 3-cyanobenzamide and 3-cyanobenzoic acid 4.8.3 Transesterification reactions 4.8.4 Ammoniolysis of carboxylic acids 4.8.5 Synthesis of epoxides 4.8.6 Synthesis of geranyl acetate 4.8.7 Transesterification of glucose and L-ascorbic acid 4.8.8 Enantioselective hydrolysis of a prochiral malonic ester 4.8.9 Enantroselective esterification of ibuprofen and 2-substituted propanoic acids 4.8.10 Enantioselective aminolysis of methyl mandelate Conclusion References

4.7.9 4.7.10 4.7.11 4.7.12 4.7.13 4.7.14 4.7.15 4.7.16 4.7.17 4.7.18 4.7.19

4.8

4.9

5. Organic Synthesis using Polyethylene Glycol and its SoluƟons 5.1 5.2 5.3

Introduction Characteristics of PEG Use of PEG in Organic Reactions 5.3.1 Substitution reactions 5.3.2 Oxidation reactions

xi

4.28 4.29 4.29 4.29 4.30 4.30 4.30 4.30 4.31 4.31 4.32 4.32 4.33 4.34 4.34 4.34 4.35 4.36 4.36 4.37 4.37 4.38 4.38 4.39 4.39 4.39

5.1 5.1 5.1 5.2 5.2 5.4

xii Contents

5.4

5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12 5.13 5.14 5.15 5.16

5.3.3 Reduction Reactions PEG as Phase-Transfer Catalyst (PTC) 5.4.1 Williamson Ether synthesis 5.4.2 Substitution reactions using PEGs as PTC 5.4.3 Oxidation reactions using PEG as PTC 5.4.4 Reductions using PEG as PTC L-Proline Catalysed Asymmetric Aldol Reactions L-Proline Catalysed Asymmetric Transfer Aldol Reaction Asymmetric Dihydroxylation of Olefins Regioselective Heck Reaction Baylis–Hillman Reaction Suzuki Cross-Coupling Reaction in PEG Synthesis of Azo Compounds Using PEG Oxidation of Cyclohexene to Adipic Acid in Polyethyleneglycol based Aqueous Biphasic System Using Sodium Tungstate and Hydrogen Peroxide Enzymatic Reactions Synthesis of 2-amino-2-chromenes Decarboxylation of Cinnamic Acid Conclusion References

6. Organic Synthesis using Fluorous Solvents 6.1 6.2 6.3 6.4 6.5 6.6

Introduction Characterstics of Perfluorous Liquids Phase Switching Perfluorinated Catalysts Some Application of Fluorous Phase Techniques Conclusion References

Part III

5.20 5.21 5.22 5.22 5.22

6.1 6.1 6.1 6.3 6.4 6.4 6.9 6.9

Organic Synthesis in Solid State

7. Organic Synthesis in Solid State 7.1 7.2

5.5 5.6 5.6 5.7 5.9 5.9 5.10 5.12 5.13 5.14 5.15 5.17 5.17 5.20

Introduction Solid State Reactions at Room Temperature 7.2.1 Aldol condensation 7.2.2 Grignard reaction 7.2.3 Reformatsky reaction

7.3 7.3 7.3 7.3 7.5 7.5

Contents

7.3

7.4

7.5

7.6

7.2.4 Synthesis of quinoxaline derivatives 7.2.5 Synthesis of b-keto sulfones from ketones 7.2.6 Synthesis of a-Tosyloxy b-keto sulfones 7.2.7 Synthesis of 1-aryl-4-methyl-1, 2, 4-trizolo [4, 3-a] quinoxalines Solid State Reactions on Heating 7.3.1 Oxidation of hydroxylated aldehydes and ketones to hydroxylated phenols using urea-hydrogen peroxide adduct (UHP) 7.3.2 Oxidation of nitriles to amides using UHP 7.3.3 Selective oxidation of sulfides to sulfoxides or sulfones using UHP 7.3.4 Oxidation of nitrogen heterocycles to N-oxides using UHP Solid State Reactions using Solid Support 7.4.1 Protection and deprotection reactions 7.4.2 Oxidations 7.4.3 Reductions 7.4.4 Rearrangement reactions 7.4.5 Isomerisation reactions 7.4.6 Condensation reactions 7.4.7 Synthesis of heterocyclic compounds Miscellaneous Reactions 7.5.1 A single step conversion of aryl aldehydes to aromatic nitriles 7.5.2 Synthesis of anhydrides from dicarboxylic acids 7.5.2a Side chain nitration of styrene to b-nitrostyrene 7.5.3 Oxidative coupling of b-napthols 7.5.4 Methylenation of 3, 4-dihydroxybenzaldehyde 7.5.5 Michael addition 7.5.6 Synthesis of bridgehead nitrogen heterocyclic compounds 7.5.7 Organometallic reactions (reactions involving C-C bond formation) 7.5.8 Aromatic substitution 7.5.9 Pericyclic reactions 7.5.10 Alkylations 7.5.11 Condensations 7.5.12 Reactions involving silicon reagents 7.5.13 Synthesis of aspirin Conclusion References

xiii 7.5 7.6 7.8 7.9 7.9 7.9 7.14 7.15 7.16 7.17 7.17 7.26 7.32 7.36 7.37 7.38 7.42 7.55 7.55 7.56 7.56 7.57 7.57 7.58 7.59 7.60 7.62 7.62 7.64 7.65 7.68 7.69 7.69 7.70

xiv Contents

Part IV

Use of Alternate Energy Processes in Chemical Synthesis

8. Microwave Assisted Organic Synthesis 8.1 8.2

8.3

Introduction Microwave Assisted Reactions in Water 8.2.1 Hofmann elimanation 8.2.2 Hydrolysis of benzyl chloride 8.2.3 Hydrolysis of benzamide 8.2.4 Hydrolysis of n-phenyl benzamide 8.2.5 Hydrolysis of methyl benzoate to benzoic acid (saponification) 8.2.6 Oxidation of toluene 8.2.7 Coupling of amines with halides 8.2.8 N-heterocylisations Microwave Wave Assisted Reactions in Organic Solvents 8.3.1 Esterification: Reaction of carboxylic acid and alcohol 8.3.2 Reaction of carboxylic acid and benzyl ethers using microwave in presence of Ln Br3 (Ln = La, Nd, Sm, Dy, Er) 8.3.3 Fries rearrangement 8.3.4 Diels–Alder reaction 8.3.5 Claisen rearrangement 8.3.6 Cycloaddition reaction between fulvenes and some alkenes and alkynes. Synthesis of polycyclic ring systems 8.3.7 Knoevenagel condensation 8.3.8 Baylis–Hillman reaction 8.3.9 Orthoester–Claisen rearrangement 8.3.10 Synthesis of 4-aryl-3, 4-dihydropyrimidine 2(IH) ones 8.3.11 Synthesis of b-lactams 8.3.12 Cycloaddition reactions 8.3.13 Synthesis of benzodiazepin-2-ones 8.3.14 Aromatic substitution reactions 8.3.15 Catalytic hydrogenation 8.3.16 Synthesis of chalcones 8.3.17 Decarboxylations 8.3.18 C-alkylation of active methylene group 8.3.19 Methanolysis of oligosaccharides 8.3.20 Preparation of unsaturated pyranosides 8.3.21 Ferrier rearrangement

8.3 8.3 8.6 8.6 8.6 8.7 8.7 8.8 8.8 8.8 8.8 8.9 8.9 8.10 8.10 8.10 8.11 8.12 8.12 8.13 8.13 8.13 8.14 8.14 8.15 8.16 8.16 8.17 8.17 8.18 8.18 8.18 8.19

Contents

8.3.22 8.3.23 8.3.24 8.3.25 8.3.26

8.4 8.5

Synthesis of jusminaldehyde Receminzation of (–)-vincadifformine to the (+)-isomer Synthesis of 1, 2-dimethyl-3-hydroxy-pyrid-4-one Synthesis of isopropylidene glycerol Synthesis of isotopically labelled (11C) diethyl oxalate and (11C) oxalic acid 8.3.27 Stereoselective addition of 2-aminothiophenol to glycidic esters 8.3.28 Development and application of a continuous microwave reactor (CMR) for organic synthesis using solvents 8.3.29 Pericyclic reactions 8.3.30 Cyclisation reactions 8.3.31 Oxidation 8.3.32 Synthesis of alkenes 8.3.33 Preparation of ferrocenyl oxime 8.3.34 Synthesis of ethers 8.3.35 Carbohydrates 8.3.36 Radical reactions Microwave Associated Reactions in Solid State Conclusion References

9. Ultrasound Assisted Organic Synthesis 9.1

9.2

9.3

Introduction 9.1.1 Instrumentation 9.1.2 The physical aspects 9.1.3 Types of sonochemical reaction Homogeneous Sonochemical Reactions 9.2.1 Curtius rearrangement 9.2.2 Sulphur extrusion from 1, 3, 4-thiadiazines 9.2.3 Isomerisation of maleic acid to fumaric acid 9.2.4 Organometallic reactions 9.2.5 Oxidations 9.2.6 Solvolysis and hydrolysis 9.2.7 Addition reactions Heterogeneous Liquid-Liquid Reactions 9.3.1 Esterification 9.3.2 Saponification

xv 8.20 8.20 8.20 8.21 8.21 8.22 8.22 8.24 8.27 8.28 8.28 8.28 8.29 8.29 8.29 8.30 8.30 8.30

9.1 9.1 9.1 9.3 9.4 9.4 9.5 9.5 9.5 9.6 9.8 9.8 9.9 9.13 9.13 9.15

xvi Contents

9.4

9.5

9.6

9.3.3 Hydrolysis/Solvolysis 9.3.4 Substitutions 9.3.5 Additions Heterogeneous Solid-Liquid Reactions 9.4.1 Alkylations 9.4.2 Oxidations 9.4.3 Reductions 9.4.4 Hydroboration 9.4.5 Hydrosilation and hydroalkylation 9.4.6 Coupling reactions 9.4.7 Dichlorocarbene 9.4.8 Some ultrasonically induced organic reactions Miscellaneous Sonochemical Reactions 9.5.1 Potassium superoxide 9.5.2 Sonolysis of Fe(CO)5 9.5.3 Oxymercuration of olefins: synthesis of a-terpinol 9.5.4 Activation of Nickel powder 9.5.5 Ultrasonically dispersed potassium 9.5.6 Organometallic compounds 9.5.7 Synthesis of aldehydes from halides 9.5.8 Sonochemical methylenation of alkenes and carbonyl compounds 9.5.9 Sodiumphenylselenide 9.5.10 Arylamides 9.5.11 Spiroketones 9.5.12 b-Keto-thinoesters 9.5.13 Dehalogenation 9.5.14 Thioamides 9.5.15 Catalysis Conclusion References

10. Photo Induced Organic Synthesis 10.1 10.2

Introduction Photochemical Reactions 10.2.1 Photolysis of benzophenone 10.2.2 Photochemical reactions of olefins

9.15 9.16 9.19 9.21 9.22 9.24 9.26 9.29 9.29 9.30 9.32 9.33 9.38 9.38 9.39 9.40 9.41 9.41 9.42 9.45 9.46 9.47 9.47 9.48 9.48 9.48 9.51 9.51 9.51 9.51

10.1 10.1 10.2 10.3 10.3

Contents

10.3

10.4

10.5

10.6

Principal Industrial Applications of Photochemistry 10.3.1 Free radical chlorination 10.3.2 Free radical sulfochlorination 10.3.3 Photochemical sulfoxidation 10.3.4 Photonitrosation 10.3.5 Photochemical synthesis of vitamin D and related compounds 10.3.6 Photo-oxygenation 10.3.7 The Barton reaction Miscellaneous Photochemical Reactions 10.4.1 Photochemical conversion of a-pinene into trans-pinocarveol using singlet oxygen 10.4.2 Photoirradiation of dibenzoyldiazomethane in presence of amino acid 10.4.3 Photochemical aromatic substitution 10.4.4 Synthesis of dydrogesterone Miscellaneous Applications 10.5.1 Arndt–Eistert synthesis 10.5.2 1, 4-Napthoquinone photomer 10.5.3 9-Phenyl phenanthrene Conclusion References

Part V

10.11 10.11 10.12 10.13 10.13 10.14 10.16 10.19 10.20 10.20 10.20 10.20 10.21 10.22 10.22 10.22 10.22 10.23 10.23

Organic Synthesis using Green Reagents

11. Organic Synthesis using Green Reagents 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8

xvii

Oxygen Singlet Oxygen Ozone Hydrogen peroxide Dioxiranes Peroxy Acids Dimethylcarbonate Polymer Supported Reagents 11.8.1 Poly-n-bromosuccinimide (PNBS) 11.8.2 Polymeric organotin dihydride reagent 11.8.3 Polystyrene carbodiimide 11.8.4 Polymer supported trisubstituted phosphine dichloride 11.8.5 Polystyrene anhydride

11.3 11.3 11.5 11.6 11.7 11.7 11.10 11.10 11.10 11.11 11.11 11.12 11.12 11.14

xviii Contents

11.9

11.8.6 Polymeric sulfonazide 11.8.7 Polymeric Wittig reagent 11.8.8 Polystyrene sulphide 11.8.9 Polymer supported peptide coupling agent EEDQ 11.8.10 Polymer supported peracid 11.8.11 Polymer supported chromic acid 11.8.12 Polymeric S-chloro sulfonium chloride Conclusion References

Part VI

Organic Synthesis using Green Catalysts

12. Organic Synthesis using Phase Transfer Catalysts 12.1 12.2 12.3 12.4 12.5

12.6 12.7

11.14 11.14 11.16 11.17 11.17 11.18 11.18 11.19 11.19

Introduction Mechanism of PTC Reaction Types of Phase Transfer Catalysts Advantages of Phase Transfer Catalysts Applications of Phase Transfer Catalysis in Organic Synthesis 12.5.1 Nitriles from alkyl halides 12.5.2 Benzoyl cyanides from benzoyl chlorides 12.5.3 Alkyl fluorides from alkyl halides 12.5.4 Alcohols from alkyl halides 12.5.5 Azides from alkyl halides 12.5.6 Sodium alkyl sulphonates from alkyl halides 12.5.7 Alkyl nitrates, thiocyanates, cyanides and p-toluene sulphonates from alkyl halides 12.5.8 Aryl ethers/thioethers 12.5.9 Esterification 12.5.10 Dihalocarbenes 12.5.11 Elimination Reactions Cobalt Carbonyl Catalysed Carbonylation of Aryl and Vinyl Halides by Phase Transfer Catalyst Alkylations 12.7.1 C-Alkylation of activated nitriles 12.7.2 C-Alkylation of oxindol 12.7.3 C-Alkylation of 2, 6-dimethyl pyridine 12.7.4 Alkylation of esters and keto esters

12.3 12.3 12.4 12.5 12.6 12.6 12.6 12.7 12.7 12.8 12.9 12.9 12.9 12.10 12.11 12.12 12.18 12.20 12.21 12.21 12.22 12.22 12.23

Contents

12.8 12.9 12.10 12.11 12.12 12.13 12.14 12.15

12.16 12.17

12.7.5 Alkylation of ketones 12.7.6 Alkylation of aldehydes 12.7.7 N-Alkylations 12.7.8 S-alkylations 12.7.9 Alkylation of mercaptans and thiophenols Benzion Condensation Darzen’s Reaction Michael Reaction Williamson Ether Synthesis The Wittig Reaction The Wittig–Horner Reaction Sulphur Ylids Heterocyclic Compounds 12.15.1 3-Arylcoumarins 12.15.2 Flavones 12.15.3 3-Aryl-2H-1, 4-benzoxazines 12.15.4 2-Aroylbenzofurans 12.15.5 1, 3-Benzoxathioles 12.15.6 Dihydropyrans 12.15.7 1, 4-Benzoxazines 12.15.8 Hydantoin derivatives 12.15.9 Piperazine-2, 5-Diones 12.15.10 Thietanes 12.15.11 N-Aryl-2-cyanoaziridines 12.15.12 1-Arylbenzimidazolines 12.15.13 Benzofurazan-1-oxides 12.15.14 Piperazinones 12.15.15 Thiazoles 12.15.16 5-Thiacyclohexane carboxaldehyde 12.15.17 Hydroxybutenolides 12.15.18 Pyrroles 12.15.19 Triazines 12.15.20 Fused naphthoquinone derivatives -Lactams Oxidation 12.17.1 Permanganate oxidation 12.17.2 Chromate oxidation

xix

12.23 12.24 12.25 12.27 12.28 12.28 12.29 12.30 12.30 12.31 12.32 12.33 12.33 12.33 12.34 12.34 12.34 12.36 12.36 12.36 12.37 12.37 12.37 12.38 12.38 12.38 12.38 12.38 12.39 12.39 12.39 12.39 12.40 12.40 12.41 12.41 12.42

xx Contents 12.17.3 Hypochlorite oxidation 12.17.4 Osmium tetroxide (or ruthenium tetroxide) with periodic acid oxidation 12.17.5 Potassium ferricyanide oxidation 12.17.6 Air oxidations 12.17.7 Peroxides 12.18 Reduction 12.18.1 Hydride reductions 12.18.2 Reduction by diborane 12.18.3 Formamidine sulfinic acids 12.19 Miscellaneous Reactions 12.19 Conclusion References

13. Organic Synthesis using Crown-ethers 13.1 13.2 13.3 13.4

13.5 13.6

Introduction Nomenclature Special Features Synthetic Applications 13.4.1 Esterification 13.4.2 Saponification 13.4.3 Anhydride formation 13.4.4 Potassium permanganate oxidation 13.4.5 Aromatic substitution reactions 13.4.6 Elimination reactions 13.4.7 Displacement reactions 13.4.8 Generation of carbenes 13.4.9 Superoxide anion 13.4.10 Alkylations 13.4.11 Other applications Cation Deactivation Conclusion References

14. Organic Synthesis using Biocatalysts 14.1 14.2 14.3

Introduction Biochemical (Microbial) Oxidations Biochemical (Microbial) Reductions

12.43 12.43 12.44 12.45 12.45 12.46 12.46 12.46 12.47 12.47 12.49 12.49

13.1 13.1 13.1 13.1 13.4 13.4 13.4 13.5 13.5 13.6 13.7 13.7 13.9 13.10 13.10 13.13 13.15 13.15 13.16

14.1 14.1 14.4 14.12

xxi

Contents

14.4

14.5

Enzymes Catalysed Hydrolytic Processes 14.4.1 Enantioselective hydrolysis of meso diesters 14.4.2 Hydrolysis of N-acylamino acids 14.4.3 Miscellaneous applications of enzymes Conclusion References

15. Organic Synthesis using Polymer Supported Catalysts 15.1 15.2

15.3

15.1

Introduction Polymer Supported Catalysts 15.2.1 Polymer bound anhydrous aluminium chloride 15.2.2 Polymeric super acid catalyst 15.2.3 Polystyrene metalloporphyrin 15.2.4 Polymer supported photosensitizers 15.2.5 Polymer supported phase transfer catalysts 15.2.6 Polymer supported crown ethers Conclusion References

Part VII

15.1 15.1 15.1 15.2 15.2 15.2 15.2 15.4 15.5 15.5

Some Examples of Green Synthesis using Basic Principles of Green Chemistry

16. Some Examples of Synthesis Involving Basic Principles of Green Chemistry 16.1 16.2

14.15 14.15 14.16 14.17 14.18 14.19

Introduction Some examples of green synthesis 16.2.1 Synthesis of adipic acid 16.2.2 Synthesis of adiponitrile 16.2.3 Synthesis of ibuprofen 16.2.4 Synthesis of methyl methacrylate 16.2.5 Synthesis of sebacic acid 16.2.6 Synthesis of polyaspartate 16.2.7 Synthesis of alcohols 16.2.8 Alkylation of reactive methylene compounds 16.2.9 Synthesis of 2-aroylbenzofurans 16.2.10 Synthesis of aromatic nitriles 16.2.11 Synthesis of a-tosyloxy b-ketosulfones 16.2.12 Synthesis of quinoxalines

16.3 16.3 16.3 16.3 16.4 16.4 16.4 16.6 16.7 16.7 16.8 16.8 16.8 16.9 16.9

xxii Contents 16.2.13 Synthesis of cyclohexane oxime 16.2.14 Synthesis of lauryllactam 16.2.15 Synthesis of 1-octanol 16.2.16 Synthesis of 6-APA 16.2.17 Synthesis of 1-acetylnaphthalene 16.2.18 Synthesis of 11a-hydroxy progesterone 16.2.19 Synthesis of 3-phenylcatechol 16.2.20 Synthesis of prednisolone References Index

16.9 16.9 16.9 16.10 16.10 16.11 16.11 16.12 16.12 I.1–I.7

Part I Introduction

1

Introduction

Chemistry has played a vital role for chemical manufacturing industries, which produce products on which we depend enormously. Some of these include: • Antibiotics, drugs and numerous other medicines required for the treatment of various ailments. In fact, these products are life saving. • Polymers. These include plastics (used in various forms for day to day use) and synthetic fibres (like nylon, rayon, polyester, etc., which are also used is dress materials, for making curtains, etc.). • Agrochemicals. These include fertilizers, pesticides, etc., which are essential for increasing the quality and quantity of crops. • Synthetic fuels are essential for the generation of energy, essential for our needs. • Synthetic Dyes are necessary to give pleasing colours to fabrics for day to day use. All these advances, particularly the drugs, medicines and antibiotics have resulted in increasing the average life expectancy from 47 years in 1900 to 80 years in 2010. The quality of life became pleasant due to the discovery of cosmetics, dyes and plastics, etc. All the above developments had advise side effects. The hazardous chemicals used in various manufacturing units, excess agrochemicals used for farming and the byproducts of various industries led to the pollution of the environment (including land, water and the atmosphere). The disposal of the hazardous waste created problems. The situation due to the pollution, etc., became so acute that various governments in most of the countries made laws to minimise the pollution. This resulted in the beginning of Green Chemistry. Green Chemistry is defined as environmentally benign chemical synthesis. Its objective is to eliminate or reduce pollution by preventing the generation of hazardous byproducts or substances. Chemists all over the world have been trying to develop benign (green) synthesis of not only of new products but also develop green synthesis also for existing chemicals.

1.4 Green Chemistry The objective of Green Chemistry can be achieved by bringing about changes in the chemistry curriculum at the secondary school level, colleges and universities. This will help to have the desired effect in educating students at all levels about Green Chemistry.

1.1

PRINCIPLES OF GREEN CHEMISTRY

Green synthesis can be conveniently achieved by following the twelve principles of Green Chemistry as suggested by Paul T. Anastas and John C. Warner, (Green Chemistry, Theory and Practice, Oxford University Press, New York, 1988). 1. It is better to prevent waste than to treat or clean up waste after it is formed. 2. Synthetic methods should be designed to maximise the incorporation of all materials used in the process into the final product. 3. Wherever practicable, synthetic methodologies should be designed to use and generate substances that possess little or no toxicity to human health and the environment. 4. Chemical products should be designed to preserve efficacy of function while reducing toxicity. 5. The use of auxiliary substances (solvents, separation agents, etc.) should be made unnecessary whenever possible and, when used, innocuous. 6. Energy requirements should be recognised for their environmental and economic impacts and should be minimised. Synthetic methods should be conducted at ambient temperature and pressure. 7. A raw material or feedstock should be renewable rather than depleting whenever technically and economically practical. 8. Unnecessary derivatisation (blocking group, protection/deprotection, temporary modification of physical/chemical processes) should be avoided whenever possible. 9. Catalytic reagents (as selective as possible) are superior to stoichiometric reagents. 10. Chemical products should be designed so that at the end of their function they do not persist in the environment and instead break down into innocuous degradation products. 11. Analytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances. 12. Substances and the form of a substance used in a chemical process should be chosen so as to minimise the potential for chemical accidents, including releases, explosions, and fires.

1.2

EXPLANATION OF THE TWELVE PRINCIPLES OF GREEN CHEMISTRY

1.2.1 It is Better to Prevent Waste than to Treat or Clean up Waste after it is Formed Any synthesis should be designed and carried out in such a way so that the waste or byproduct formation is minimum; it is however, best if the byproducts or to wastes are not generated. In fact,

Introduction

1.5

the overall cost of production is much more if the cost of treatment and disposal of waste is added to the overall cost. The waste is also obtained in case the starting materials and regents are not fully utilised. The unreacted starting materials may or may not be hazardous. It is most appropriate to follow the principle ‘Prevention is better than cure’. The waste or the byproducts, if formed are discharged into the environment and are responsible for pollution.

1.2.2 Synthetic Methods Should be Designed to Maximise the Incorporation of all the Starting Materials in the Process into the Final Product It is normally believe that if one mole of a starting material gives one mole to the product, the yield is 100%. However, such a synthesis may generate byproducts or waste, which is not visible. Though such a synthesis is 100% (as per the yield mentioned above), it is not considered to be a green synthesis. For example, Hofmann Elimination reaction, Witting reaction and Grignard reaction may proceed with 100% yield but they do not take into account the large amounts of byproducts produced. Some examples are given below:

1.6 Green Chemistry The extent of incorporation of the starting material into the product is by the following formula [R.A. Sheldon, Chem. Ind. (London), 1992, 903] F.W of atoms utilised % Atom economy = _________________________________ × 100 F.W of the reactants used in the reaction The calculation of the atom economy will be well understood by considering some of the common reactions like addition reactions, rearrangement reactions, substitution reactions and elimination reactions, which we generally come across in organic synthesis. (a) Addition Reactions Consider the bromination of 1-butene.

In the above reaction, all the atoms of starting materials (1-butene and bromine) are incorporated into the final product (1, 2-dibromobutane). So the reaction is 100% atom economical reaction. In a similar way cycloaddition reaction (Diels-Alder reaction) of butadiene and ethyne and addition of hydrogen to olefins are 100% atom economical reactions.

(b) Rearrangement Reactions In rearrangement reaction, there is rearrangement of atoms.

The rearrangement reaction like addition reactions is also 100% atom economical, since all the atoms in the reactant are incorporated into the product. (c) Substitution Reactions In substitution reactions, one atom (or group of atom) is replaced by another atom (or group of atoms). This reaction is less atom-economical than the addition or rearrangement reaction, since the atom that is replaced is not utilised in the final desired product. A typical example of a substitution reaction is the reaction of ethyl propionate with methyl amine.

Introduction

1.7

As seen, in the above substitution reaction besides one hydrogen atom of the amine, the leaving group (OCH2 CH3) is also not utilised is the desired N-methyl propamide. The remaining atoms of the reactants are incorporated into the final product. The total of atomic weights of the atoms of the reactants that are incorporated is 87.120 g/mol, and the total molecular weight of the reagent used is 133.189 g/mol. Thus a molecular weight of 46.069 g/mol (133.189-87.120) are not utilised in the reaction (see table below). Reagent

Unutilised Formula FW (g/mol)

FW

Formula

FW (g/mol)

C5H10O2

102.132

C3H5O

57.057

C2H5O

CH4N

30.049

H

C4H9NO

87.120

C2H6O

CH5N Total

Utilised

Formula

C6H15NO2

31.057 133.189

45.061 1.008 46.069

87.106 Therefore the percentage economy for this reaction is _______ × 100 = 65.41% 133.189

(d) Elimination Reactions In an elimination reaction, two atoms or group of atoms are lost from the substrate to form a p bond. An example of such a reaction is the Hoffmann elimination reaction as given below:

In the above elimination reaction, two group that are lost from the reaction are not present in the final desired product and so the elimination reaction is not very atom-economical. The percentage atom economy is 35.30%

1.2.3 Whenever Practicable, Synthetic Methologies Should be Designed to use and Generate Substances that Possess Little or no Toxicity to Human Health and Environment It is extremely important, in the context of Green Chemistry not to use any hazardous starting material. It is also equally important to make sure that no hazardous byproducts are generated in

1.8 Green Chemistry any synthetic procedure. Such chemicals are not only toxic to the workers but also produce harmful effects in the environment. The workers using such chemicals should use protective clothing and respirators. The disposal of hazardous chemicals also adds to the overall cost of production. Sometimes, there is more risk involved in case the controls fail. Green Chemistry, in fact, offers scientific options so that such situations be avoided.

1.2.4 Chemical Products Should be Designed to Preserve Efficacy of Function While Reducing Toxicity The chemicals synthesised (e.g., drugs, etc.) should not only be safe to handle but also should not have toxic effects. An example of a drug having toxic effects is thalidomide, which was used (1963) to reduce the effect of morning sickness during pregnancy. It was subsequently found that this drug ‘thalidomide’ was the cause of serious birth defects in children born to women taking this drug. This drug was banned and withdrawn. Due to this, strict regulations were enacted to test all new drugs for their toxic effects. However, in case of thalidomide it was found that it is a chiral drug and exists in two enantiomeric forms. One of the enantiomers (the right handed molecule) had the desired effect of reducing the effect of morning sickness and the other enantiomer (which was also present in the drug in equal amount) was the cause of birth defects. Subsequently thalidomide was approved under strict regulations for serious complications in case of leprosy patients. It in now possible to design safer chemicals due to development and advancement of technology. In fact, the molecular structure can be appropriately manupulated to have the descred effect.

1.2.5

The Use of Auxiliary Substances (Solvents, Separation Agents, etc.) Should be Made Unnecessary Wherever Possible, and When Used, Innocuous

A number of solvents, having excellent solvent properties have been tradiationally used for organic reactions. These solvents are mostly volatile organic solvents and include methylene chloride, chloroform, perchloroethylene, carbon tetrachloride, benzene and other aromatic hydrocarbons. However, it has been found that the halogenated solvents and also benzene are believed to be suspected human carcinogens. Some of the solvents have also hazardous effect on the environment. An example is that of chlorofluorocarbons (CFCs), which were used as cleaning solvents, blowing agents and as refrigerants. It is now well known that the CFCs are responsible for depletion of the ozone layer; this has serious health effects on humans. In view of the above, it is necessary to use benign solvents called green solvents. Some of the green solvent are water, super critical carbon dioxide, ionic liquids, polyethylene glycol and its solutions and fluorous solvents. This aspect forms the subject matter of a subsequent section. Besides using green solvents the pathway for a reaction should be such that there no need for purification or separation. A typical procedure involves the use of polymer supported substrates or reagents. These have been discussed subsequently. Using such procedures, the energy requirements is also kept to a minimum.

Introduction

1.9

1.2.6 Energy Requirements Should be Recognised for their Environmental and Economic Impacts and Should be Minimised For all chemical reactions, energy is required. The requirement of energy should be kept to a minimum. As an example, the reactants are dissolved in a suitable solvent (at times by heating) and the reaction mixture is heated in order the reaction to go to completion. It should be ascertained that for the reaction to go to completion, the heating should be done for minimum time (this can be ascertained by techniques like TLC); this ensures the use of minimum energy for the reaction. The energy requirement can also be reduced and kept to a minimum by using a suitable catalyst, which are known to reduce the amount of energy needed for a reaction. The energy to a reaction can be supplied by microwave heating and or sonication. Photochemical activation can also be used for supplying energy to a chemical reaction. This aspect forms the subject matter of a subsequent section.

1.2.7 A Raw Material or Feed Stock Should be Renewable Rather than Depleting Whenever Technically and Economically Practical The starting materials can be obtained from renewable and non-renewable sources. An example of a non-renewable source is petroleum oil which is the source of petrochemicals. It is well known that the petroleum oil formation take million of years from animal and vegetable remains. On the other hand, an example of renewable starting material are agriculture products. These, however, cannot be obtained in continuous supply due to reasons like failure of crops due to short rain falls, etc. Some other examples of renewable starting materials are carbon dioxide (which can be obtained from natural sources or synthetic process) and methane (obtained from natural sources such as natural gas, marsh gas, etc.).

1.2.8

Unnecessary Derivatisation (Blocking Group, Protection and Deprotection, Temporary Modification of Physical/Chemical Processes) Should be Avoided Wherever Possible

It is sometimes necessary, in organic synthesis to protect a particular group so that the reaction can proceed in the desired direction. The protecting group is useful to solve a chemoselectivity problem. The reagent used for protection of a particular group should be added in stoichiometric amount. After the completion of the reagent, the protecting group is deprotecled to get the desired product. Though protection and deprotection of groups are necessary in certain cases, but it increases the number of steps in organic synthesis. Also the reagents used for protection and deprotection ultimately form wastes. As far as possible, the steps of protection and deprotection should be avoided.

1.2.9 Catalytic Reagents (as Selective as Possible) are Superior to Stoichiometric Reagents In a large number of cases, it is found that all the starting materials are not consumed and the reaction does not go to completion. The unreacted starting materials form wastes. It is known that catalysts

1.10 Green Chemistry (wherever available) facilitate the transformation without being consumed. The catalysts are known to be selective in their action. A typical example is the reduction of a triple bond to double bond by palladised barium sulfate. Different types of catalysts are available. Examples include phase transfer catalysts, biocatalysts, etc. A discussion on these form the subject matter of a subsequent section.

1.2.10 Chemical Products Should be so Designed so that at the end of their Function they do not Persist in the Environment and Instead Break Down into Innocuous Degradation Products An important aspect of Green Chemistry is that the products of a reaction should not be persistent chemicals but should be biodegradable. The persistent chemical are non biodegradable and remain in the environment in the same form for long periods of time. These persistent chemicals (which may be toxic) are taken up by plants and various animal species. In fact, they bioaccumulate in animal systems. This is very harmful not only for the concerned species but also harmful to the humans who consume such plants and animals species (like fish, meat producing animals). Plastics and some pesticides are known to be non-biodegradable. DDT was the first pesticide, which bioaccumulated in animals species and found their way into human system resulting in serious health problems. It should be made sure that the synthetic products should be biodegradable. Introduction of certain groups and other features in a molecule makes it biodegradable. Groups which are susceptible to hydrolysis, photolysis or other cleavage make the product biodegradable. It should also be ascertained that the product of biodegradation should not be toxic to the environment. Plastics are known to be non-biodegradable. However, with the advancement of knowledge, it is now possible to make biodegradable plastics particularly for making garbage bags, etc.

1.2.11 Analytical Methodologies Need to be Further Developed to Allow Real-time, in Process Monitoring and Control Prior to the Formation of Hazardous Substances The advancement of knowledge has led to the development of methodologies, which not only minimise but also prevent the generation of hazardous substances in any chemical process. It is necessary to have reliable sensors, monitors and analytical techniques in order to assess the hazards that may be present in a process stream. It is thus possible to monitor a chemical process for the generation of hazardous byproducts and also prevent any accident which may occur.

1.2.12 Substances and the form of a Substance used in a Chemical Process Should be Chosen so as to Minimise the Potential for Chemical Accidents, Including Releases, Explosion and Fires Adequate precautions must be taken to avoid the occurrence of accidents including releases, explosions and fires in chemical industries. The episodes in Bhopal (India) and Seveso (Italy) and many others are responsible for the deaths and disability of thousands of people. In some cases, people are disabled for the rest of their lives as happened in the episode at Bhopal.

Introduction

1.11

The use of volatile organic solvents in chemicals industries has also resulted in fires and explosions.

1.3

HOW TO PLAN A GREEN SYNTHESIS

While planning a green synthesis, following points should be kept in mind.

1.3.1 The Synthetic Methods Should be Such that all the Starting Materials be Converted into the Final Product In a chemical reaction, there should be maximum incorporation of the reactants into the final product. This means that a reaction should be a 100% atom economical. Not all reactions are 100% atom economical. As already stated (Section 1.2.2) addition reactions and rearrangement reactions are 100% atom economical. However, substitution reactions and elimination reactions are about 60-65% and 30-35% atom economical. The latter two types of reaction involve formation of wastes (see also Section 1.2.2).

1.3.2

Unnecessary Derivation (Blocking Group Protection/Deprotection) Should be Avoided Whenever Possible

The use of protecting group (blocking group) is also a factor in the atom economy of a reaction. Though sometimes it is necessary to use protecting groups particularly to solve a chemoselectivity problem, these should be added to the reaction mixture in stoichiometric amount and then removed after completion of the reaction. As an example the reaction of methyl cyclohexanone-2 carboxylate with Grignard reagent in order to get the required product, it is necessary to use 1, 2-ethanediol to protect the keto group from reacting with the Grignard reagent.

1.12 Green Chemistry Another example of protection is the conversion of m-aminobenzonitrile into m-aminobenzaldehyde. In this case, the amino group has to be protected by benzylation. This is followed by Stevens reaction and final deprotection.

1.3.3 Use an Environmentally Benign Solvent A number of solvents like methylene chloride, chloroform, perchloroethylene (PCE), carbon tetrachloride and aromatic hydrocarbons (like benzene, toluene, etc.) are generally used in reactions due to their excellent solvent properties. It is, however known that the halogenated solvents (like CH2Cl2, CHCl3, PCE, CCl4, etc.) have been identified as suspected human carcinogens. Besides, these solvents are responsible for environmental pollution particularly destroying the ozone layer leading to the formation of ozone hole. The solvents which are responsible for destroying the ozone layer also include, chlorofluorocarbons (CFCs) In view of the above it is necessary to carry out the reaction in environmentally benign solvents like water, super critical carbon dioxide, ionic liquids and polyethylene glycol. The use of water as a solvent for organic reaction has been known to people till about the mid of twentieth century. Water is the cheapest solvent available and its use does not cause problems of pollution, which is a major concern in using volatile organic solvents. According to C&E News of September 3, 2007, it is recommended that in case organic solvents fail, try water. Water has been used as such as a solvent in a number of reactions. It has also been used as super critical water (or in Near Water [NCW] Region). The critical temperature of super critical water is 374°C and 22.1 MPa. Due to its unique physical and chemical properties that are quite different than those of ambient water, it has been used as a medium for organic reactions. The near critical water region is described as 250-300° at pressure 100-80 bar [For more details about organic reactions in super critical or near water (NCW) region, see V.K. Ahluwalia and R.S. Varma, Green Solvents for Organic Synthesis, Narosa Publishing House, 2009, Chapter 2 and the references cited there in]. Besides this, microwave assisted organic reactions and biocatalytic reactions have also been performed in water.

Introduction

1.13

Super critical carbon dioxide has also been used as a solvent in organic reaction. Carbon dioxide, as we know can exist in different states depending on the temperature and pressure of its surrounding. If we increase the pressure, CO2 becomes liquid; at this point (– 56°C and 5.1 atm), CO2 exist simultaneously as gas, liquid and solid. However, at 31°C and 73 atm. CO2 exists as super critical fluid. In super critical state, CO2 has a viscosity similar to that of a gas and density similar to that of a liquid. The solvent properties of SC-CO2 (e.g. dielectric constant, solubility parameters, viscosity and density) can be altered or charged in a manner not possible with conventional solvents via manupulation of temperature and pressure. The properties of SC-CO2 are intermediate between that of liquid and gas [For more details about super critical CO2, see V.K. Ahluwalia and R.S. Varma, Green Solvents for Organic Synthesis, Narosa Publishing House, 2009, Chapter 5 and the references cited there in]. Ionic liquids are emerging as novel replacement for volatile organic solvents used traditionally as industrial solvents. These reduce the volatility, environmental and human health are safety concerns that are experienced by exposure to organic solvents. Ionic liquids are made up of at least two components which can be varied (the cation and anion). These are liquid at ambient temperature and are colourless, have low viscosity and can be easily handled. In fact, these have attractive properties as a solvent. The solvent can be designed with a particular end use in mind or to possess particular set of properties. Hence these are also known as ‘designer solvents’. Properties such as melting point, viscosity, density and hydrophobicity can be varied by simple changes to the structure of ions. These can be recycled and this leads to a reduction of the cost of the process. The reactions are often quicker and easy to carry out than in conventional organic solvents. These are used to enhance activity, selectivity and stability of transition metal catalyst. The ionic liquids have virtually no vapour pressure and posses good thermal stability [For more details about ionic liquids, see V.K. Ahluwalia and R.S. Varma, Green Solvents for Organic Synthesis, Narosa Publishing House, 2009, Chapter 7 and the references cited there in]. Polyethylene glycol (PEG) and its solutions are believed to be a green reaction medium of the future. Polyethylene glycol, PEG, HO-(CH2 CH2O)n-H, is available in a variety of molecular weights. A special characteristics of PEG is that it has low flammability and is biodegradable. It is stable to acid, base and high temperatures and can be recovered and recycled. It has been used as a solvent for a number of organic reactions [For more details about PEG, see V.K. Ahluwalia and R.S. Varma, Green Solvents for Organic Synthesis, Narosa Publishing House, 2009, Chapter 8 and the references cited there in].

1.3.4 The Requirement of Energy Should be Minimised to a Bare Minimum It is well known that energy is required for any chemical reaction. This requirement should be kept to a bare minimum. For example, if the starting materials and reagents are soluble in a particular solvent, the reaction mixture has to be refluxed for completion of a reaction. It should be kept in mind, that the time required for completion of the reaction should be minimum, so that minimum amount of energy is required. It is, however known that use of a catalyst is beneficial for lowering the requirement of energy for a reaction.

1.14 Green Chemistry In case, the final product has to be purified by crystallisation, distillation, etc., energy is required. The chemical process should be so designed that there is no need for purification or separation. It is now well known the energy requirement can be kept bare minimum by using microwaves sonication or photoactivation. Among the important tools for organic synthesis, microwaves as alternative source of energy is being used for organic reactions. The household and industrial microwave oven, operate at a fixed frequency at 2.45 GHz. It is believed that microwave reactions involve absorption of electromagnetic waves by polar molecules (non-polar molecules are inert to microwaves). When molecules with permanent dipole are subjected to an electric field, they become aligned and as the field oscillates their orientation changes and this rapid reorientation provides intense internal heating. In fact, the main difference between microwave and classical heating is that microwave heating is associated in core and homogeneous heating, whereas in classical heating the heat transfer takes place by preheated molecules. Some of the common solvents that are used in MW ovens include formamide, methanol, ethanol, chlorobenzene, ethylene glycol, dioxane and diglyme. The microwave reactions can be performed in water, organic solvents or even in solid state [For more details about microwaves, see V.K. Ahluwalia and R.S. Varma, Alternate Energy Processes in Chemical Synthesis, Narosa Publishing House, 2008, Chapters 1 and 2 and the references cited there in]. Ultrasound is increasingly used for chemical synthesis. The term ‘Sonochemistry’ is used to describe the effect of ultrasound waves to chemical reactivity. A generally accepted theoretical interpretation is based on the phenomenon of cavitation. The creation of bubbles in a liquid medium, which collapse with the liberation of considerable energy [For more details about ultrasound and its applications in organic synthesis, see V.K. Ahluwalia and R.S. Varma, Alternate Energy Processes in Chemical Synthesis, Narosa Publishing House, 2008, Chapters 6 to 10 and the references cited there in]. Photochemical reactions occur by the absorption of electromagnetic radiations to produce electronically excited molecules which give the product of the reactions. The photochemical reactions are highly stereospecific and have been used for the synthesis of highly strained thermodynamically unstable compounds. The photochemical reactions are used in modern synthetic chemistry and lead to products which are inaccessible by thermal reactions [For more details about photoinduced reaction, see V.K. Ahluwalia and R.S. Varma, Alternate Energy Processes in Chemical Synthesis, Narosa Publishing House, 2008, Chapter 15 and the references cited there in].

1.3.5 Use of Catalyst Catalysts are known to facilitate chemical transformations, which are effected in much short time, consuming less energy and giving good yields. An advantage is that the catalysts are not consumed in the reaction and can often be recycled. Even in those case, where no reaction occurs usually, the reaction becomes feasible. An example of this type is the hydration of alkynes to give aldehydes or ketones. The catalysts have also been used for selective reduction of a triple bond to a double bond.

Introduction

1.15

Another type of catalysts, which are commonly used for reactions which give low yields (or the reaction does not take place) are the phase transfer catalysts (PTC). The phase transfer catalysts are ionic substances, usually quaternary ammonium salts, where the size of the hydrocarbon group in the cation is large enough to confer solubility of the salt in organic solvents (the cations must be highly lipophilic). In fact, the PTC reactions describe a methodology for accelerating reactions between water insoluble organic compounds and water soluble reactants, e.g. reaction of an organic halide with sodium cyanide. The PTC transfers the anion of the reactant from the aqueous phase to the organic phase. A typical example of a PTC reaction is the conversion of 1-chlorooctane into 1-cyanooctane using a small quantity of an appropriate PTC.

Another example is the oxidation of toluene which KMnO4 in presence of crown ether in much better yields.

The crown ethers are a family of cyclic polyethers and like PTC and can be used in a number of transformations. A typical example of a crown ethers is dicyclohexyl [18] crown-6 [For more details about PTC and Crown ethers, see V.K. Ahluwalia and R. Aggarwal, Organic Synthesis, Special Techniques, Narosa Publishing House, 2006, Chapters 1 and 2 and the references cited there in].

1.16 Green Chemistry Besides the points mentioned above, the following should be kept in mind for planning a green synthesis. • The nature of the waste products (or byproducts) should not be toxic or environmentally harmful. • Whenever possible, the synthetic methodologies should be designed in such a way that the products or byproducts generated should possess no toxicity to human health and environment. • The raw materials should be renewable rather than depleting, whenever technically and economically practicable.

1.3.6 Use of Polymer Supported Substrates or Polymer Supported Reagents In the conventional organic synthesis the substrate is treated with a reagent and the formed product is isolated from the reaction mixture by procedures involving extraction, precipitation, distillation, crystallisation and chromatographic procedure. However, use of polymer supported substrates or polymer supported reagents simplifies the procedure (N.K. Mathur, C.K. Narang, R.E. Williams, Polymers as Aids in Organic Chemistry, Academic Press, New York, 1980). Advantages of using polymer supported substrates or reagents • The reaction can be carried out easily and the isolation of product becomes easier. • The purification of the product is simplified. • Polymer supported reactions can be carried out, cleanly, rapidly and in high yields under mild conditions. • After isolation of the polymer supported product, the polymer support is cleaved to get the final desired product. There are three types of polymer supported organic synthesis. Type 1 In this type of synthesis, the organic substrate is covalently bonded to the polymer support and then reacted with the reagent, catalyst, etc. The formed product remains bounded to the polymer support. The product can be isolated by hydrolysis. Various steps involved are given below (the most widely used polymer is polystyrene).

Introduction

1.17

Type 2 In this type of synthesis, the reagent is linked to a polymeric material, which is then reacted with the substrate. After the reaction is over, the polymer support reagent is removed by filtration (and can be reused). The desired product is isolated from the reaction mixture. Various steps involved are given below:

Type 3 This is a polymer supported catalytic reaction. In this type of reaction, conventional catalysts, which are normally used in the homogeneous phase is linked to a polymer support and used in this form to catalyse the reaction [For more details about polymer supported organic synthesis, see V.K. Ahluwalia and R. Aggarwal, Organic Synthesis Special Techniques, Norosa Publishing House, 2006, Chapter 5 and the reference cited there in].

Part II Organic Synthesis in Benign Green Solvents

2 2.1

Organic Synthesis in Water

INTRODUCTION

The use of water – as a solvent for carrying out organic reactions – was not known to people till about the mid of the twentieth century. Solvents which are normally used are extremely harmful. For example, benzene–a commonly used solvent is known to cause or promote cancer in humans and other animals. Certain other aromatic hydrocarbons like toluene can damage the brain and may have adverse effects on speech, vision or cause liver and kidney problems. Halogenated solvents commonly used, e.g. methylene chloride, chloroform, polychloroethylene and carbon tetrachloride have been identified as suspected human carcinogens. Besides, the halogenated solvents, being volatile, rise to the stratospheric region, where they get converted into chlorine free radicals by the action of UV light from the sun. The chlorine free radicals are responsible for depletion of ozone layer. Similarly, CFCs (Chlorofluorocarbons) used till the twentieth century as cleaning solvents, blowing agents for molded plastics, and for refrigeration are responsible for the depletion of the ozone layer. In view of the environmental pollutions caused by organic solvents, scientists all over the world are carrying out the experiments in aqueous phase. There are many potential advantages of carrying out reactions using water as a solvent. • Water is comparatively a cheaper solvent available. Water, can be used as a solvent to make chemical reactions economical. • Unlike organic solvents, which are inflammable, potentially explosive, mutagenic and/or carcinogenic, water is free of all these disadvantages and is a safe solvent. • Water-soluble substances can be used directly. This will be particularly useful in carbohydrate, protein and fermentation chemistry. • In large industrial process, the products can be isolated by simple phase separation. Also, it is easier to control the reaction temperature, since water has one of the largest heat capacities of all substances.

2.4 Green Chemistry • The use of water as solvent may not cause problems of pollution, which is a major concern in using volatile organic solvents. • Water can be readily recycled. The structure of water is very well known. It has two sigma bonds; two lone pair H 104.5° H of electrons on oxygen and a bond angle of 104.5°. Water, as we know exists in three basic forms – vapour, liquid and solid. The relationship between these three forms of water is described by pressure-volume-temperature phase diagram (Fig. 2.1).

Pressure

760 mm

Normal Freezing point

Solid

Normal boiling point

Liquid Vapour

458 mm

Triple point

0° 0.01° Temperature

Fig. 2.1

100°

Phase diagram for water

The principal physical properties1,2 of water are described below: The peak density of water is at 3.98°C; the density decreases as the temperature falls to 0°C. It is for this reason that ice is lighter than water and floats. This phenomenon insulates the deeper water from the cold temperature and prevents it from freezing. The density of water also decreases when the temperatured exceeds 3.98°C. It reaches the same density of ice at about 70°C. The viscosity of water also changes with temperature. Infact the decrease in viscosity is inversely proportional to the rise in temperature. This is because the number of hydrogen bonds binding the molecules together decrease when the temperature rises. The viscosity of water affects the movement of solute in water and also the sedimentation rate of suspended solids. The specific heat of water is highest as compared to other substances. The high value of specific heat of water is due to the great heat capacity of the water mass. This implies that rapid changes of ambient temperatures result in slow changes in water temperature. This effect is important for aquatic organisms. In large-scale industrial processes, this effect is advantageous to control the temperature both for endo – and – exothermic reactions. Water has one of the highest surface tension of all liquids. For example, the surface tension of ethanol at 20°C is 22 mN/m, while that of water is 72.75 mN/m. The surface tension of water decreases with temperature. Also the surface tension of water decreases by the addition of surface – active agents (surfactants), such as detergents.

Organic Synthesis in Water

2.5

217.7

Critical point Liquid Solid

Supercritical fluid

Pressure (atm)

Many substances are soluble in water. However, the solubility is dependent on the temperature. For example, the solubility of gases like oxygen, nitrogen and carbon dioxide in water decreases with rise in temperature. There are, however, some gases like helium in which the solubility increases with increase in temperature. In case of solids, the solubility of AgNO3 increases with increases in temperature but for NaCl, there is only a slight increase in solubility with rise in temperature. The influence of temperature on the solubility is dependent on heat of solution of a substance, which is the heat emitted or absorbed during the dissolution of one mole of a substance in one litre of water. Polar compounds are compounds that iosize are readily soluble in water. Such compounds are said to be hydrophilic. On the other hand, hydrophobic substances have very low solubility in water. Ordinary water behaves very differently under high temperature and high pressure3. Thus the electrolytic conductance of aqueous solutions increases with increase in pressure. This effect is more pronounced at lower temperatures. For all other solvents, the electrical conductivity of solutions decreases with increase in pressure. This unusual behaviour of water is due to its peculiar associative properties4. Thermal expansion causes liquid water to become less dense as the temperature decreases. Also the liquid vapour density increases as the pressure rises. For example, the density of water varies from 1.0 g/cm3 at room temperature to 0.7 g/cm3 at about 300°C. The densities of the two phases become identical at the critical point. At this point the two phases become a single fluid called supercritical fluid. The water density at this point is only 0.3 g/cm3. The phase diagram of water around the super critical region is given in Fig. 2.2.

Vapour Temperature (°C) 274.0

Fig. 2.2

Phase diagram of water around the super critical region

In the chemical reactions given here water is used as a solvent.

2.2

REACTIONS IN WATER

Following are some of the reactions which have been carried out in aqueous medium.

2.6 Green Chemistry

2.2.1 Pericyclic Reactions 2.2.1.1 Diels–Alder reaction Diels–Alder reaction5 is one of the most important procedures used to form cyclic structures. It is a [4 + 2] cycloaddition reaction between a conjugated diene (4p-electron system) and a compound having a double or triple bond called the dienophile (2p-electron system) to form an adduct. In this reaction, the two components are either heated alone or in an inert solvent (Scheme 2.1). + Butadiene

Ethene

Cyclohexene

Ethyne

Cyclohexa 1, 4-deine

+ Butadiene

Scheme 2.1

The Diels–Alder reaction in aqueous media was first carried out in the beginning of the nineteenth century6. Thus, furan reacted with maleic anhydride in hot water to give the adduct (Scheme 2.2). Maleic anhydride hot water

O

COOH O

H2O

+

COOH

RT

Furan

COOH Maleic acid

Adduct

COOH

Scheme 2.2

In the above reaction, the product obtained was a diacid (Scheme 2.2) showing that the reaction proceeded via the formation of maleic acid from maleic anhydride. Similarly Diels–Alder reaction of cyclopentadiene with N-Sec. Butyl maleimide gave quantitative yield of the adduct (Scheme 2.3)7.

Scheme 2.3

Organic Synthesis in Water

2.7

Using water as a solvent also affect the stereoselectivity of some Diels–Alder reactions8. It has been found that at low concentrations, where both the components were completely dissolved, the reaction of cyclopentadiene with butenone gave (Scheme 2.4) a 21.4 ratio of endo/exo products when they were stirred at 0.15 M concentration in water, compared to only a 3.85 ratio in excess cyclopentadiene and a 8.5 ratio in ethanol as the solvent. An aqueous detergent solution had no effect on the product ratio. The sterochemical changes could be explained by the need to minimise the transition – state surface area in water solution favouring the more compact endo stereochemistry. The results are also in agreement will the effect of polar media on the ratio9.

Scheme 2.4

Water-induced selectivity was also observed8 in the reaction of cyclopentadiene with dimethyl maleate or methyl acrylate (Schemes 2.5 and 2.6). In the above cases, both the diene and dienophile are poorly soluble and are present as a separate phase, the influence of water on the selectivity is marked. CO2Me H2O

+

Cyclopentadiene

CO2Me

RT

CO2Me Dimethyl maleate

Endo + exo

Scheme 2.5

Scheme 2.6

CO2Me

2.8 Green Chemistry Diels-Alder reaction of cyclopentadiene with acrylonitrile proceeded10 in a similar way (Scheme 2.7) giving quantitative yield of the adduct. CN +

Cyclopentadiene

[4 + 2]

CN

H2O, RT

Acrylo nitrile

endo + exo

Scheme 2.7

The reaction between hydroxymethylanthracene and N-ethylmaleimide was also studied. It was found that in water at 45°, the second order rate constant in water was over 200 times larger than in acetonitrile (Scheme 2.8). In this case, the b-cyclodextrin became an inhibitor. A slight deactivation was also observed with a salting in salt solution, such as guanidine chloride in aqueous solution.

Scheme 2.8

An important feature of the Diels-Alder reaction is the use of Lewis acids for the activation of the substrate. Though most Lewis acids are deactivited or decomposed in water, it has been found11 that [Ti(Cp*)2 (H2O)2]2+ is air stable, water tolerant Diels-Alder catalyst. Other water stable catalysts are12 scandium triflate [Sc(OTf)3] and Lanthanide triflates [Ln(OTf)3]2. As an example, following cyclisation reaction (Scheme 2.9) has been reported13 in an aqueous solution containing 0.010 M Cu(NO3)2 is 250,000 times faster than in acetonitrile and is 1,000 times faster than that in water alone. Other salts such as Co2+, Ni2+, Zn2+ also catalyse the reaction, but are not as reactive as Cu2+. The reaction is also catalysed by bovine serum albumin14.

2.2.1.2 Hetero-Diels-Alder reactions Hetero-Diels-Alder reactions with nitrogen or oxygen containing dienophiles are of special interest for the synthesis15 of hetero cyclic compounds. The first example of Hetero-Diels-Alder reaction with nitrogen-containing dienophiles in aqueous medium was reported16 in 1985. In this method,

2.9

Organic Synthesis in Water

O O2N

N

NO2

+ O N

Scheme 2.9

simple iminium salts, generated in situ under Mannich – like conditions, reacted with dienes in water to give Aza-Diels–Alder reaction products (Scheme 2.10); this has potential for the synthesis of alkaloids (Table 2.1)

Scheme 2.10 Table 2.1 Aza-Diels-Alder reactions in aqueous medium Diene

Amine + Carbonyl Compound

Product

Yield (%)

BnNH2 ◊HCl + HCHO

41 NBn

BnNH2 ◊HCl + HCHO

NBn

BnNH2◊HCl + HCHO

BnNH2 ◊HCl + HCHO

69

59

NBn

62

Contd...

2.10 Green Chemistry Contd...

BnNH2 ◊HCl + HCHO

49

MeNH2 ◊HCl + HCHO

82 NMe

NH4 ◊HCl + HCHO

44 NH.HCl

NH4◊HCl + HCHO

NH.HCl

40

Me

BnNH2 ◊HCl + MeCHO

47 NBn

Data taken from reference 16

The intra molecular Aza-Diels–Alder reaction occurs17 similarly in aqueous media. These reactions lead to the formation of fused ring systems (Scheme 2.11) with bridge head nitrogen; such a structure is characteristics of many alkaloids. C-Acyl iminium ions also react18 similarly with cyclopentadienes (Table 2.2). Retro Aza-Diel–Alder reactions also occurred readily in water19. For example 2-azanorbornenes undergo acid-catalysed Retro-Diels–Alder catalysed in water (Scheme 2.12). A large number of Retro-Diels-Alder reaction have also been reported20. Due to the convenience of conducting Diels–Alder and related reactions in aqueous phase, this methodology has found a number of applications in pharmaceutical industry.

Organic Synthesis in Water

2.11

Scheme 2.11 Table 2.2

Aza-Diels-Alder reaction of cyclopentadienes with C-Acyl iminium ions

Substrates

Amine

C6H5COCHO

CH3NH2 ◊HCl

CH3COCHO

NH4Cl

CH3COCHO

CH3NH2 ◊HCl

CH3COCHO

BnNH2◊HCl

Product

Yield (%)

COC6H5

82

NCH3 COCH3

84

NH COCH3 NCH3 COCH3

67

65

NBn

HOOCCHO

CH3NH2

COOH

86 NCH3

Data taken from Reference 18.

2.12 Green Chemistry

Scheme 2.12

2.2.2 Claisen Rearrangement Allyl phenyl ether on heating to 200°C undergo intramolecular reaction called Claisen rearrangement. Both the aliphatic and aromatic Claisen rearrangement involve a 3, 3-sigmatropic shift22. There are reviews providing usefulness of this rearrangement reaction23. It is found that polar solvents have been known to increase24 the rate of the Claisen rearrangement reaction. Subsequently, it was observed that Claisen rearrangement reaction are accelerated on going from non polar to aqueous solvents25. The first reported use of water in promoting Claisen rearrangement was in 1970. The first example of the use of pure water for Claisen rearrangement of chorismic acid is given26 in Scheme 2.13. COOH

HOOC H2O

O

D O

COOH

O

COOH

HO Chorismic acid

OH

Scheme 2.13

An aliphatic Claisen rearrangement, a [3, 3]-sigmatropic rearrangement of an allyl vinyl ether in water give27 the aldehyde (Scheme 2.14).

Scheme 2.14

The corresponding ester also underwent similar rearrangement. Similarly, both allyl vinyl ether and 2-hept 3, 5-dienyl-vinyl ether underwent 3, 3-shift. The best results were obtained in 2/1 methanol water; the rates were about 40 times than those in acetone solvent28.

2.2.3 Wittig–Horner Reaction The Wittig reaction29 has been used for the preparation of olefins from alkylidene phosphoranes (ylids) and carbonyl compounds (Scheme 2.15).

Organic Synthesis in Water

2.13

Scheme 2.15

In the above reaction the ylide in unstable and is generated in situ. A modification of the above reaction, known as the Wittig-Horner reaction or Horner– Wadsworth–Emmons reaction uses phosphonate esters. Thus, the reaction of ethyl bromoacetate with triphenylphosphite gives the phosphonate ester, which on reaction with cyclohexanone in presence of base (NaH) gives a, b-unsaturated ester, ethyl cyclohexylidineacetate in 70% yield (Scheme 2.16).

Scheme 2.16

The above reaction is sometimes performed in an organic/water biphase system30, 31. In the above reaction (Scheme 2.16) in place of strong base like NaH, a PTC can be used in aq. NaOH with good results. In the above reaction (Scheme 2.16) the base used is NaH or any other strong base. It has been found that the reaction proceeds with a much weaker base, such as K2CO3 or KHCO3. Even compounds with base and acid sensitive functional groups can be used directly. In a typical example, under such condition b-dimethylhydrazoneacetaldehyde can be obtained efficiently32. Recently33 water has been demonstrated to be an effective medium for the Wittig reaction employing stablised ylides and aldehydes. Inspite of the poor solubility of the reactants good

2.14 Green Chemistry chemical yields ranging from 80 to 98% and high E-selectivites (up to 99%) are achieved. Typical examples of Wittig reaction are given below (Scheme 2.17). CHO

O CO2CH3

+ Ph3P OCH3

OCH3

CHO

O

H2O 20°, 1 hr 81%

H2O

+ Ph3P OCH3

OCH3

CO2CH3

20°, 2 hr 88%

Scheme 2.17

2.2.4 Michael Reaction The reaction34 between an a, b-unsaturated carbonyl compound and a compound with an active methylene group (e.g. malonic ester, acetoacetic ester, cyanoacetic ester, nitroparaffins, etc.) in presence of a base, e.g. sodium ethoxide or a secondary amine (usually piperidine) is known as Michael Reaction34. The first successful report of Michael Reaction in aqueous medium was the reaction of 2-Methylcyclopentane-1, 3-dione with vinyl ketone in water to give adduct without the uses of a basic catalyst (pH > 7). The adduct further cyclises to give a 5-6 fused ring system (Scheme 2.18)35.

Scheme 2.18

In this reaction (Scheme 2.18), use of water as a solvent gave pure compound in better yields compared to reaction in methanol in presence of a base. Michael Reaction of 2-methyl-cyclohexane-1, 3-dione with methyl vinyl ketone give optically pure Wieland-Miescher Ketone (Scheme 2.19)36. Use of acrolein in place of methyl vinyl ketone in the above reaction gave an adduct (Scheme 2.20) which was used for the synthesis of 13-a-methyl-14a-hydroxysteroid37. The rate of above Michael addition (Scheme 2.20) was enhanced by the addition of ytterbium triflate [yb(OTf)3].

2.15

Organic Synthesis in Water

CH3 O

O O Hydroquinone H2O

+

70-80° C, 4 hr ~ 100%

O

O

O Methyl vinyl Ketone

2-Methyl cyclohexane 1,3-dione

O D-(+) Proline DMSO, RT 6 days, 82%

O Wieland-Miescher Ketone

Scheme 2.19 O

O H +

H2O

H

RT 100%

O O 2-Methyl cyclopentane 1,3-dione

O

13-a-Methyl14-a-hydroxysteroid

O

Acrolein

Scheme 2.20 NO2 CH3NO2 + Nitromethane

40°, 32 hr H2O 100%

O Methyl vinyl ketone

+

O2N O A

O

O (4:1)

B

Scheme 2.21

The Michael addition of nitromethane to methyl vinyl ketone in water (in the absence of a catalyst) gave 4 : 1 mixture of adducts (A and B) (Scheme 2.21)38. Use of methyl alcohol as a solvent (in place of H2O) gave 1 : 1 mixture of A and B. The above reaction is unsuccessful in neat condition or in solvents like THF, PhMe, etc., in the absence of a catalyst.

2.2.5 Aldol Condensation The aldol condensation is one of the most important carbon-carbon bond forming reactions in organic synthesis. The conventional aldol condensation involve reversible self-addition of aldehydes

2.16 Green Chemistry containing a a-hydrogen atoms; the formed b-hydroxy aldehydes undergo dehydration to give a, b-unsaturated aldehydes. This has been extensively reviewed39. The reaction can occur either between two identical or different aldehydes, two identical or different ketones and an aldehyde and a ketone. Mukaiyama Reaction40, a stereoselective aldol condensation consists in the reaction of an silyl enol ether of 3-pentanone with an aldehyde (2-methyl-butanal) in presence of TiCl4 to yield an aldol product, Manicone, an alarm pheromone (Scheme 2.22)41.

OSiMe3 +

H2O

TiCl4

H

O

CH3

Cl

O 2-methyl butanal

Silyl enol ether of 3-pentanone

O Ti Cl

O

Cl

Manicone

Scheme 2.22

The above reactions are carried out in organic solvents. The first water-promoted aldol reaction of silyl enol ethers with aldehydes was first reported in 1986 (Scheme 2.23)42. OSiMe3

O

OH

O

H2O

+ R3 R1

R4

R2

R4

23-70%

R1

R2 R3

Scheme 2.23

The above reactions however, took several days for completion, probably because water serves as a weak Lewis acid. The addition of a stronger Lewis acid (e.g. lanthanide triflate) greatly improved the yield and rate of such reactions (Scheme 2.24)43. OSiMe3

O

OH

O

Yb(OTf)3

+ R¢ H

H

R¢¢

R¢¢

THF/H2O(2:1) RT, 3-12 hr

R¢ 77-98%

Scheme 2.24

Organic Synthesis in Water

2.17

It has been found that the dehydration of the alcohols can be avoided in presence of complexes of Zn with aminoesters or aminoalcohols44. Using the above method, vinyl ketones (Scheme 2.25) can be obtained by the reaction of 2-alkly-1, 3-diketones with aqueous formaldehyde (formalin) using 6-10 M aqueous potassium carbonate as base followed by the cleavage of the intermediate with base45. O

O 30% aq. HCHO

R¢

R1

R¢¢

O R1

K2CO3, H2O

R¢ O

O

R¢¢

R¢¢ R¢ O Vinyl ketone

Scheme 2.25

The reaction of several silyl enol ethers with commercial formaldehyde solution catalysed by yb(OTf)3 gave good yields (80 to 90%) of the products obtained 46, 47. In all the above reactions the catalyst could be recovered and used repetitively. The above methodology has been extensively reviewed 48. The reaction of isophorone with benzaldehyde in water gives only vinylogous aldol product but with low conversion. However, in presence of CTACl, the condensation product, (E)-benzylideneisophorone, is obtained in 80% yield. Use of tetrabutylammonium chloride (TBACl) gives a mixture of addition and condensation products (Scheme 2.26)49. O

O PhCHO

O OH

NaOH, RT, 4 hr

+

Ph

Ph

Isophorone Water only

24%

—

CTACI

—

80%

TBACl

27%

58%

Scheme 2.26

2.2.6 Knoevenagel Reaction It involves the condensation of aldehydes or ketones, with active methylene compounds (especially malonic ester) in presence of a weak base like ammonia or amine (primary or secondary)50, 51. However, when condensation is carried out in presence of pyridine as a base, decarboxylation usually occurs during the condensation. This is known as Doebner modification52. Some examples are given (Scheme 2.27).

2.18 Green Chemistry CH3CHO

+

Acetaldehyde

CH2(COOH)2

Base

C(COOH)2

CH3CH

Malonic acid

– CO2

CH3CH CHCOOH Crotonic acid C6H5CHO

+

Pyridine

CH2(COOC2H5)2 Benzene

(1) Hydrolysis (2) H3O

C6H5CH

+

C(COOH)2

D –CO2

C6H5CH

C(COOC2H5)2

C6H5CH CHCOOH Cinnamic acid

Scheme 2.27

The Knoevenagel reaction between o-hydroxy aldehydes and malononitriles in water at room temperature in the heterogeneous aqueous alkaline medium gave a-hydroxybenzylidene malononitriles, which are converted directly to 3-cyanocoumarins by acidification and heating (Scheme 2.28)53. O CN CN

H R

+ CN

–

OH RT

CN –+

R

CN

H

90°

R O

OH

OH

O

75-95%

R = H, OH, OMe

Scheme 2.28

Similarly, substituted acetonitriles (Scheme 2.28) gave the corresponding 3-substituted coumarins in 66-98% yields (Scheme 2.29). O C

R R

H +

H2O

CN OH

O 66-98%

O

R = CN, CO2Et, NO2, Ph, 2-Py

Scheme 2.29

In case of phenylacetonitrile, a catalytic amount of CTABr (0.1 mole/equiv) is used. The above reaction gives better yields in aqueous medium compared to in ethanol. The reaction of benzaldehyde with acetonitrile does not occus in water; however it requires the presence of catalytic amount of CTACl to give high yields of the corresponding arylcinnamonitriles (Scheme 2.30)50.

Organic Synthesis in Water

CTACl; NaOH

ArCH2CN + PhCHO

RT, 0.5-9 hr

Ar = Ph, p-NO2C6H4, PhSO2

Ph

2.19

CN

H

Ar 85-90%

Scheme 2.30

Knoevenagel-type addition product can be obtained by the reaction of acrylic derivatives in presence of a 1, 4-diazabicyclo [2.2.2] octane (DABCO) (Scheme 2.31)54.

Scheme 2.31

2.2.7 Pinacol Coupling Ketones on reaction with Mg/benzene give 1, 2-diols (pinacols). Thus, under these conditions acetone give pinacol (Scheme 2.32). CH3 CH3

O (1) Mg/benzene, D

CH3 — C — CH3

(2) H2O

Acetone

CH3 — C — C — CH3 OH OH Pinacol

Scheme 2.32

This is known as pinacol coupling. The use of Zn-Cu couple to couple unsaturated aldehydes to pinacols was recorded as early as 189255. Subsequently chromium and vanadium56 and some ammonical-TiCl3 57 based reducing agents were used. It has been found58 that pinacol coupling takes place in aromatic ketones and aldehydes in aqueous media in presence of Ti(III), under basic conditions. However, in presence of acids, only the substrates (aromatic ketones and aldehydes) having electron withdrawing group like CN, CHO, COMe, COOH, COOMe, pyridyl (activating groups) only underwent pinacol coupling59 (Scheme 3.33). Excess of the substrate was necessary as solvent for non-activated carbonyl compounds60. a, b-unsaturated carbonyl compound and acetone undergo coupling reaction61 using a Zn-Cu couple and ultrasound in an aqueous acetone suspension (Scheme 3.34)61.

2.20 Green Chemistry O TiCl3-H2O, H

R2

R1

+

HO R1

THF, RT, 1-7 hr

OH C

C

R2

R1 R2

61-75%

R1 = Ph, 2-Py R2 = CN, CO2Me

Scheme 2.33 O O

+

Zn/Cu, H2O

OH OH

85%

Scheme 2.34

The coupling of aldimines to give vicinal diamines (Scheme 2.35) by indium in aqueous ethanol in presence of a small amount of ammonium chloride (which accelerates the reaction)62 gave the coupled product. Ar2HN

NAr2

NHAr2

In–H2O–EtOH

Ar1

NH4Cl~100%

H

Ar1

Ar1 H

H

Scheme 2.35

2.2.8 Benzoin Condensation The reaction of aromatic aldehydes with sodium or potassium cyanide, usually in an aqueous ethanolic solution give a-hydroxy ketones (benzoins) (Scheme 2.36)63. This reaction is known as Benzoin condensation. H

O

OH

C

C

–

CN , D

2Ph

C

O

EtOH, H2O

Ph

Ph

H Benzaldehyde

Benzoin

Scheme 2.36

The mechanism of Benzoin condensation is given in Scheme 2.37 The Benzoin condensation of aldehydes are strongly catalysed by a PTC (quaternary ammonium cyanide in a two phase system)64. In a similar way, acyloin condensation are easily effected by

Organic Synthesis in Water

O ArCHO

CN

–

OH

–

ArCHO

Ar — C –

Ar — C — H

CN

CN HO

O

2.21

–

O

Ar — C — C — Ar

OH

Ar — C — C — Ar

CN H

H

Scheme 2.37

stirring aliphatic or aromatic aldehydes with a quaternary catalyst (PTC), N-laurylthiazolium bromide in aqueous phosphate buffer at room temperature65. The aromatic aldehydes reacted in a short time (about 5 min). However, aliphatic aldehydes require longer time (5-10 hrs) for completion. Mixed a-hydroxyketones are abtained66 from the benzoin condensation of mixture of aromatic and aliphatic aldehydes. On the basis of extensive work, Breslow found that the Benzoin condensation in aqueous media using inorganic salts (e.g. LiCl) is about 200 times faster than in ethanol (without any salts)67. The addition of g-cyclodextrin also accelerates the reaction, whereas the addition of b-cyclodextrin inhibits the condensation.

2.2.9 Claisen–Schmidt Condensation The condensation of aromatic aldehydes (without a-hydrogen) with an aliphatic aldehyde or ketone (having a-hydrogen) in presence of a relatively strong base (hydroxide or alkoxide) to form a, b-unsaturated aldehyde or a ketone (Scheme 2.38)68 is known as Claisen–Schmidt Condensation. C6H5CHO +

CH3CHO

NaOH

C6H5CH = CHCHO Cinnamaldehyde

C6H5COCH3 +

C6H5CHO

NaOH EtOH

C6H5COCH = CHC6H5 Benzalacetophenone (chalcone)

Scheme 2.38

Mukaiyama reaction69,70, a related reaction involves the reaction of silyl enol ether of the ketone with an aldehyde in an organic solvent in presence of TiCl4 (Scheme 2.39) (see also Scheme 2.22). It has been shown71 that the trimethyl silyl enol ether of cyclohexanone react with benzaldehyde in water in presence of TiCl4 in heterogeneous phase at room temperature and atmospheric pressure (Scheme 2.40) to give the products.

2.22 Green Chemistry

OSi(CH3)3 +

TiCl4

H

O CH3 Cl

O

Ti Cl

O Cl

H2O

O

Manicone (an alarm pheromone)

Scheme 2.39 O

CHO

OSiMe3

+ Trimethyl silyl enolether of cyclohexanone

H

OH

OH H

TiCl4 82%

O

+ Syn 1

:

Anti 3

Scheme 2.40

Better yields are obtained under sonication conditions. The reaction is favoured by an electronwithdrawing subsituent in the pra position of the phenyl ring in benzaldehyde. Flavanols are obtained by Claisen-Schmidt reaction of acetophenones with aromatic aldehydes in presence of cationic surfactants such as cetylammonium compounds, CTACl, CTABr, (CTA)2SO4 and CTAOH in mild alkaine conditions give chalcones, which on cyclisation give flavanols (Scheme 2.41). The reaction of cyclohexanone with benzaldehyde in water gives high yield of a 1 : 1 threoerythro mixture of the ketone. However in presence of CTACl, the bis-condensation product in obtained quantitatively (Scheme 2.42)72.

2.2.10 Heck Reaction The coupling of an alkene with a halide or triflate in the presence of Pd(O) catalyst to form a new alkene is known as Heck Reaction (Scheme 2.43). Heck Reactions uses mild base such as Et3N or anions like OH –, –OCOCH3, CO32–, etc. Some other applications of Heck Reaction are also given (Scheme 2.44).

Organic Synthesis in Water O

2.23

O Ar

Surfactant NaOH

+ ArCHO RT, 0.3-16 hr, 61-94%

R1

R

R1

R Chalcone

R = H, OH, OMe R1 = H, OMe Ar = X-C6H5 (X = H, p–Cl, p–NMe2, m–NO2)

80°C R = OH 20 min H2O2 O OH

O 70% Flavanol

R1

Ar

Scheme 2.41 O

O

OH

O

O

Ph

PhCHO, RT

Ph

Ph +

Ph

+

NaOH, 3 hr

Water only with CTACl

91% —

9% —

— 100%

Scheme 2.42 H

R Pd(O) base

RX + R1

+ HX R1

R = aryl, vinyl or alkyl group without b-hydrogens on 3 a sp carbon atom X = halide or triflate (OSO2CF3)

Scheme 2.43

Traditionally for carrying out the Heck reactions, anhydrous polar solvents (e.g. DMF and MeCN) and tert. amines as bases are used. Recently, it has been found that the Heck reaction can proceed very well in aqueous medium. Infact, the role of water in the Heck reaction, as well as in other reactions catalysed by Pd(O) in presence of phosphine ligands is: (i) transformation of catalyst precursor into Pd(O) species and

2.24 Green Chemistry Ph Pd(OAc)2/Ph3P

+

PhCl

NEt3, 80°C

Ph CO2H

CO2H Ph

Pd(OAc)2/Ph3P

+

NEt3, 100°C

Ph

Br

Pd(OAc)2

Br + S

N

100°C, 96 hr

S

Scheme 2.44

(ii) the generation of zero-valent palladium species capable of oxidative addition by oxidation of phosphine ligands by the Pd(II) catalyst precursor can be affected by water content of the reaction mixture. It has been found that the Heck reaction can be accomplished under mild conditions using PTC conditions73 with inorganic carbonates as bases at room temperature. It has been shown that the Heck reaction can also be carried out in water and aqueous organic solvents, catalysed by simple palladium salts in presence of inorganic bases like K2CO3, Na2CO3, NaHCO3, KOH, etc.74 An interesting application of the Heck reaction is the synthesis of cinnamic acid from of aryl halides and acrylic acid (Scheme 2.45).

Scheme 2.45

Use of acrylonitrile in place of acrylic acid in this method (Scheme 2.45) yield the corresponding cinnamonitriles. The product obtained in Heck reactions are almost exclusively (E) isomers. However, the reaction of acrylonitrile give a mixture of (E) and (Z) isomers with ratio 3 : 1, close to that observed under conventional anhydrous conditions 75. The Heck reaction can also be performed under milder condition by addition of acetate ion as given in (Scheme 2.46).

Organic Synthesis in Water HO2C

X

HO2C

CO2H

PdCl2, H2O

CO2H

+

2.25

K2CO3, 80°C, 2 hr (97%) K2CO3, KOAc, 50°C, 1 hr (98%)

Scheme 2.46

A large number of other application of the Heck reaction have been described in literature76. The Heck reaction has also been performed in ionic liquids (see Chapter 4, Section 4.5.5).

2.2.11 Strecker Synthesis The reaction of an aldehyde with ammonia followed by reaction with HCN gives a-aminonitrile intermediates, which on hydrolysis gives a-amino acid. This reaction is known as Strecker Synthesis of amino acids (Scheme 2.47)77. NH2 PhCH2CHO

NH3/HCN

NH2 +

PhCH2CH — CN

H3O

PhCH2CH — COOH

Scheme 2.47

The a-aminonitrile can also be obtained by the treatment of aldehyde with HCN followed by reaction of the formed cyanohydrin with ammonia. This method is known as Erlenmeyer modification 78. A more convenient route is to treat the aldehyde in one step with ammonium chloride and sodium cyanide (this mixture is equivalent to ammonium cyanide, which in turn dissociates into ammonia and HCN). This procedure is referred to as the Zelinsky-Stadnikoff modification79. The final step is the hydrolysis of the intermediate a-aminonitrile under acidic or basic conditions. Using Strecker Synthesis, disodium iminodiacetate (DSIDA) an intermediate for the manufacture of Monsantos’ Roundup (herbicide) was synthesised 80. In the above procedure hydrogen cyanide, a hazardous chemical is used and this requires special handling to minimise the risk to workers and the environment. An alternative synthesis of DSIDA was developed by Monsanto; this is a green synthesis. 2NaOH

NH3 + 2CH2O + 2HCN

NC

N H

CN

NaO2C

N H DSIDA

Strecker Synthesis of DSIDA HO

HO N H Diethanolamine

2NaOH Cu catalyst

NaO2C

N H DSIDA

Alternative Synthesis of DSIDA

CO2Na + 4H2

CO2Na

2.26 Green Chemistry The new method avoids the uses of HCN and CH2O and is safer to operate.

2.2.12 Wurtz Reaction Coupling of alkyl halides with sodium in dry ether to give hydrocarbon81 is known as Wurtz Reaction (Scheme 2.48). Na

CH3CH2CH2Br

CH3(CH2)4CH3

ether

Propyl bromide

Hexane

Scheme 2.48

It has been shown82 that the Wurtz coupling can be achieved by Zn/H2O (Scheme 2.49). I

Cl

Zn/H2O

Cl

Cl

Scheme 2.49

2.2.13 Oxidations It is one of the most widely investigated process in organic chemistry. A large number of reactions involving oxidations are used in laboratory and also in industries. A number of oxidizing agents with different substrates have been described83. Oxidations have been known to be carried out in aqueous medium for a very long time. The oxidation of arenes with KMnO4 in aqueous alkaline medium is well known 84. The yields are however considerably increased by using KMnO4 in presence of a phase transfer catalyst particularly in the oxidation of toluene. Another environment-friendly oxidant is the use of H2O2 in water; in this case water is formed as a secondary product. In the present unit, some recent oxidations by chemical reagents in aqueous media are described. Enzymatic oxidations have also been known to occur in water. However, this subject will be discussed in a separate section. Following are some of the important oxidations in water.

2.2.13.1 Epoxidation Peracids react with alkenes to give stable three-membered rings containing oxygen atom, called epoxides or oxiranes (Scheme 2.50). O C + O C Alkene

H

O

O

C Peracid

C O + R — C — OH R

C Epoxide (Oxirane)

Scheme 2.50

Organic Synthesis in Water

2.27

The reaction takes place in nonpolar solvents such as dichloromethane and benzene. The above epoxidations are stereoselective and takes place by syn addition to the double bond. As the cis alkene gives only cis epoxide and trans alkene gives trans epoxide, the reaction is concerted, i.e. the one step mechanism retains the stereochemistry of the starting alkenes. Simple alkenes can be epoxidised85 with m-chloroperoxybenzoic acid in aqueous NaHCO3 at room temperature to yield epoxides in good yield. A number of alkenes like cyclopentene, cyclohexene, cycloheptene, cyclooctene, methyl cyclohexene and (+)-3-carene have been epoxidized with MCPA at 20° in 30 min to give 90-95% epoxide. Styrene could be epoxidized at 20°C (1 hr), a-Methylstyrene and trans-a-methylstyrene could be epoxidized at 0°C in 1 hr. In aqueous medium, the reaction occurs in heterogeneous phase, but this does not effect the reactivity, which sometimes is higher than in homogenous organic phase. For direct epoxidation of simple alkenes the peroxide must be activated (Scheme 2.51). This is done in buffered aqueous tetrahydrofuran (THF), 50% H2O2 activated by stoichiometic amounts of organophosphorus anhydride. H2O2/(Ph2PO)2O; K2CO3 THF-H2O, –5°C; 20 hr

Alkene

O

Epoxide 60-100%

Scheme 2.51

Using this procedure a variety of alkenes could be epoxidized 86. The epoxidation of electrondeficient olefins can be achieved with H2O2 in presence of sodium tungstate as a catalyst87. The epoxidation of alkene has also been effected with other oxidizing reagents such as PhlO4, NaClO, O2, H2O2, KHSO5, etc., in aqueous medium in presence of metalloporphyrins88. Epoxidation of alkenes on a large scale is generally carried out by using hydrogen peroxide, peracetic acid or t-butyl hydroperoxide (TBHP) 89. A safe and cheap method for epoxidation has been developed 90. It consist in using nascent oxygen generated by electrolysis of water at room temperature by using Pd black as an anode. Using this procedure cyclohexene could be epoxidized in good yield. In this illustration, water is used as a reaction medium as well as reagent. Allyl alcohols could be epoxidised regioselectively in presence of other C = C bonds by using monoperphthalic acid (MPPA) in presence of cetyltrimethyl ammonium hydroxide (CTAOH) (Scheme 2.52)91. MPPA

OH

H2O/CTAOH 92%

Scheme 2.52

OH O

2.28 Green Chemistry Epoxidation takes place at different double bonds in the terpenoids, viz., geraniol (I), nerol (II), farnesol (III) and linalool (IV) with MPPA by carrying out the reaction at different pH. 3 2

3

CH2OH

2

OH

H

2

CH2OH

3 6

CH2OH

6 7

10

2

1 6

11

7

Geraniol I

7

Nerol II

Farnesol III

Linalol IV

2, 3-Epoxidation takes place in I, II and III with MPPA in aqueous medium at pH 12.5 and in about 90% yields92. In I, II and IV 6, 7-epoxidation takes place in aqueous medium at pH 8.3 (60-90% yields). The 10, 11-epoxidation takes place at pH 12 (88% yield). In case of linalool (IV), 1, 2-epoxidation does not take place. It is appropriate to state that 6, 7-epoxidation of geraniol (I) has been reported earlier with t-C4H9OOH/VO (acac)2 in benzene (refluxing) and 2, 3-epoxidation achieved by using m-chloroperbenzoic acid93. Epoxidation of a, b-unsaturated carbonyl compounds could be accomplished94, 95 by using sodium perborate (SPB) in water at pH 8 to give the epoxide (Scheme 2.53). O R1

COMe

R2

H

SPB, 57-80°C H2O-THF or H2O-dioxane

R1

COMe

R2

H 65-100%

R1 = H, Me R2 = Me, Ph O

O SPB, 75°C, 19 hr

O

.H2O-dioxane

91%

Scheme 2.53

The epoxidation of a, b-unsaturated carbonyl compounds with hydrogen peroxide under basic biphase condition, known as the Weitz-Scheffer epoxidation (Scheme 2.54) 96 is a convenient and efficient method for producing the epoxides. The new procedure (Scheme 2.54) has been used for the epoxidation of a number of a,b-unsaturated aldehydes, ketones, nitriles, esters and sulfones, etc.

Organic Synthesis in Water

– OH

–

HOO +

HOO

–

O

–

O

2.29

O

O

Scheme 2.54

The epoxidation of a, b-unsaturated carboxylic acid can be achieved with H2O2 in presence of Na2WO4 at pH 5.8-6.8 (Scheme 2.55). O R1

CO2H

R2

R3

Na2WO4/H2O2 pH 5.8-6.8; 60-65°C 1.5-3 hr

R1

CO2H

R2

R3

R1, R2, R3 = H, Me, Br

Scheme 2.55

The above reaction is known as Payne’s reaction97 using the modified procedure of sharpless98. The epoxidation of a, b-unsaturated carboxylic acids can also be achieved by using ozone acetone system and buffering the reaction with NaHCO399 in 75-80% yield. Epoxidation of fumaric acid can be achieved in quantitative yield100 by using ozone in water at neutral pH. The epoxidation of chalcones proceed very well101 with NaOCl (commercially available) in water suspension101 in presence of a PTC hexadecyltrimethylammonium bromide in excellent yields (50-100%) (Scheme 2.56). +

R1

R2

O Chalcone R1 = R2 = H R1 = p-Br; R2 = H R1 = H; R2 = p-Br R1 = m-Me; R2 = H R1 = p-Cl; R2 = H

–

C16H33NMe3Br NaOCl/H2O 10 hr to 2 days

R1

O

O Chalcone epoxide R1 = p-MeO; R2 = H R1 = p-Me; R2 = H R1 = H; R2 = p-Me R1 = R2 = p-Cl R1 = R2 = p-Me

Scheme 2.56

R2

2.30 Green Chemistry 2.2.13.2 Dihydroxylation In case of alkens, one can get either syn-or anti-dihydroxylation. syn-dihydroxylation syn-dihydroxylation of alkenes is achieved by treatment with dilute KMnO4 in presence of alkenes (Scheme 2.57). In fact the change in purple colour is the basis for the presence of double bond and this is known as Baeyer’s test for unsaturation. This method is used for syn-hydroxylation of oleic acid and norbornene (Scheme 2.58). C

C

dil. aq. KMnO4

HO

OH C

C

NaOH

Scheme 2.57

Scheme 2.58

A large number of other examples of syn-dihydroxylation of alkenes have been reported in the literature. Subsequently osmium tetraoxide in dry organic solvents 102 was used for syn-dihydroxylation of alkenes. The reaction is performed in presence of chlorate salts as the primary oxidant in presence of catalytic amount at OsO4. The epoxidation is carried out in H2O-THF solvent (Scheme 2.59). It is found that Ag or Ba chlorate give better yields. HO2C

CO2H

OsO4, NaClO3 THF-H2O, 98%

HO2C HO

CO2H OH

Scheme 2.59

The syn-dihydroxylation of alkenes can also be carried out by hydrogen peroxide in presence of catalytic amount of OsO4103. By this method allyl alcohol is quantitatively hydroxylated in water (Scheme 2.60)104.

Organic Synthesis in Water

2.31

OH OH

OsO4, H2O2

HO

OH

H2O, 100%

1,1,3-Trihydroxy propane (glycerol)

Allyl alcohol

Scheme 2.60

Following are given some other methods used for syn-dihydroxylation of alkenes: (i) Osmium-tetroxide-tertiary amine N-oxide system 105 has been used in aqueous acetone. (ii) K3Fe(CN)6 in presence of K2CO3 in aqueous or tertiary butyl alcohol has been used for the osmium-catalysed dihydroxylation of alkenes (Scheme 2.61) 106. Using this method even alkene having low reactivity or hindered alkenes could be hydroxylated. OH OH

OsO4,/ K3Fe(CN)6

HO OH

K2CO3/aq. t-BuOH

88%

Scheme 2.61

syn-hydroxylation of olefins has also been carried out with KMnO4 solution using a PTC catalyst under alkaline conditions. Thus cyclooctene gives107 50% yield of cis 1, 2-cyclooctane diol compared to an yield of about 7% by the classical technique, (Scheme 2.62).

Scheme 2.62

anti-dihydroxylation of alkenes Hydrogen peroxide in presence of tungsten oxide (WO3) or selenium dioxide (SeO2) give anti-dihydroxylation products, (Scheme 2.63) 108. R1

R2

WO3(50-70°C)

HO R1

R3

R4

H2O2

R3

Scheme 2.63

R2

R4 OH

2.32 Green Chemistry The above is known as the sharpless dihydroxylation procedure. Different types of alkenes can be transformed to diols with high enantiomeric-excess – this is known as asymmetric dihydroxylation and it has a number of synthetic applications. A one pot procedure for the antihydroxylation of the carbon-carbon double bond can be achieved as shown below, (Scheme 2.64)108a

OH (1) H2O2, MCPBA, 20°C, 0.5-8 hr +

(2) H , 20-100°C, 1-10 hr

OH 75-95%

Scheme 2.64

2.2.13.3 Miscellaneous oxidations in aqueous medium Alkenes The oxidation of alkenes with aqueous solution of KMnO4 in presence of a phase transfer catalyst (e.g. CH3(CH2)15N+(CH3)3Cl–) gives 79% yield of the carboxylic acid. Some examples are given below, (Scheme 2.65) aq. KMnO4

CH3(CH2)5CH = CH2

+

–

CH3(CH2)15N(CH3)3Cl

1-octene

O

KMnO4/H2O Dicyclohexano-18-crown-6

a-Pinene

CH3(CH2)4CH2COOH Heptanoic acid

CO2H cis-pinonic acid

Scheme 2.65

Another example is the oxidation of n-octane to 1-octanol (Scheme 2.66) using Pseudomonas oleovorans109. This procedure is used for the industrial production of 1-octanol (>98% pure)110. Pseudomonas

CH3(CH2)6CH3

oleovorans H2O

n-Octane

CH3(CH2)6CH2OH 1-Octanol

Scheme 2.66

Alkynes Alkynes on oxidation with KMnO4 in aqueous medium give a mixture of carboxylic acids. Some examples are given below, (Scheme 2.67)

Organic Synthesis in Water

R

C

C

R¢ + 4[O]

KMnO4

RCOOH + R¢COOH O

CH3(CH2)7C

C(CH2)7COOH alk. KMnO4

aq. KMnO4 pH 7.5

2.33

O

CH3(CH2)7 — C — C — (CH2)7 — COOH

CH3(CH2)7COOH + HOOC(CH2)7COOH

Scheme 2.67

2.2.13.4 Oxidation of aromatic side chains and aromatic ring system Some examples are given below, (Scheme 2.68)

Scheme 2.68

2.2.13.5 Oxidation of aldehydes and ketones A number of procedures are available for the oxidation of aldehydes to the corresponding carboxylic acids in aqueous and organic media 111. Aromatic aldehydes can be conveniently oxidized by aqueous performic acid obtained by addition of H2O2 to HCOOH at low temperature (0-4°C)112. The hetroaromatic aldehydes like formyl pyridines, formyl quinolines and formylazaindoles can also be oxidised by the above procedure to the corresponding carboxylic acids; in this procedure, the formation of N-oxides is avoided. Chemoselective oxidation of formyl group in presence of other oxidisable groups can be carried out in aqueous media in presence of a surfactant. Thus, 4-(methylthio)benzaldehyde is quantitatively oxidised to 4-(methylthio) benzoic acid with TBHP in a basic aqueous medium in presence of cetyltrimethylammonium sulfate113. Aromatic aldehydes having hydroxyl group in ortho or para position to the formyl groups can be oxidised with alkaline H2O2 (Dakin reaction) in low yields114. However this reaction has been carried out in high yields using sodium percarbonate (SPC; Na2CO3, 1.5 H2O2) in H2O-THF under

2.34 Green Chemistry ultrasonic irradiation115. Using this procedure, following aldehydes have been oxidised in good yields: o-hydroxybenzaldehyde; p-hydroxybenzaldehyde; 2-hydroxy-4-methoxybenzaldehyde, 2-hydroxy-3-methoxybenzaldehyde and 3-methoxy-4-hydroxybenzaldehyde. The Baeyer-Villiger oxidation116 is used for the conversion of ketones into the corresponding esters (Scheme 2.69). Usually the conversion is effected by peracids in organic solvents. This reaction has been carried out satisfactorily in aqueous heterogeneous medium using MCPBA at room temperature117. Some examples are given (Scheme 2.70). COCH3

OCOCH3 PhCOOOH, CHCl3 25°C Phenylacetate

Acetophenone

Scheme 2.69 R R

O

MCPBA, 20°C

O

H2O, 1 hr

O R = Me, t-Bu

R

95%

COMe

MCPBA, 80°C H2O, 0.5-1.5 hr

R = H, Cl, OMe

R

OCOMe

70-90%

Scheme 2.70

Using the above procedure even unreactive ketones can also be oxidised (Scheme 2.71) 118. O

O MCPBA, 80°C H2O, 3 hr

O

27%

Scheme 2.71

Some Baeyer-Villiger oxidation of ketones with m-chloroperbenzoic acid proceed much faster at room temperature in the solid state119. The yields obtained in solid state are much better than in CHCl3. Some representative examples are given as follows (Scheme 2.72).

Organic Synthesis in Water

2.35

Scheme 2.72

2.2.13.6 Oxidation of amines into nitro compounds Alkaline KMnO4 oxidises tertiary alkyl amines into nitro compounds (Scheme 2.73)120.

C

–

NH2 + 2MnO 4

30°C MgSO4

Tertiary alkyl amine

C

NO2

85%

Scheme 2.73

Primary and secondary alkyl amines remain unaffected under above conditions. Aromatic amines containing a carboxylic or alcoholic groups can also be oxidised to nitro compounds by oxone (potassium hydrogen peroxymonosulfate triple salt, 2KHSO3, KHSO4, K2SO4) in 20-50% aqueous acetone at 18° C in 73-84% yield 121.

2.36 Green Chemistry Aminopyridine N-oxides are obtained under acidic conditions in organic solvent and usually requires protection of the amino group122. It has now been possible to obtain N-oxide in good yield from aminopyridine directly by using oxone in water under neutral or basic conditions at room temperature 123. The selectivity of the reaction depends on the position of the amino group.

2.2.13.7 Oxidation of nitro compounds into carbonyl compounds Primary and secondary nitro compounds can be oxidised into the corresponding carbonyl compounds by alkaline KMnO4 (Scheme 2.74).

Scheme 2.74

2.2.13.8 Oxidation of nitriles Oxidation of nitriles into amides was first reported in 1986124 by heating the nitrile with alcoholic KOH (Scheme 2.75). Ph

Ph CN

CONH2

alc. KOH (20%) reflux 5 hr

Ph

N

NH2

Ph

2-Amino-3-cycano4,6-diphenylpyridine

N

NH2

2-Amino-3-carbamoyl4,6-diphenylpyridine

Scheme 2.75

The conversion of nitriles into amides can also be carried out under a variety of conditions in presence of metal catalyst 125. A convenient method using urea-hydrogen peroxide adduct (UHP, H2NCONH2, H2O2) in presence of catalystic amount of K2CO3 in water-acetone at room temperature (Scheme 2.76) has been developed 126. R—CN

UHP, K2CO3, H2O2 H2O-actone, R.T.

R—CONH2

Scheme 2.76

Using the above procedure following nitriles have been converted into corresponding amides in 85-95% yield: benzonitrile, methyl cyanide and chloromethyl cyanide.

Organic Synthesis in Water

2.37

Nitrlies can also be converted into amides by reacting with sodium perborate (SPB; NaBO3, nH2O, n = 1 to 4) in aqueous media such as H2O-MeOH 127, H2O-acetone 128 and H2Odioxan129. An interesting application of this reaction is the synthesis of quinazolin-4-(3H)-ones130 (Scheme 2.77). NHCOR1

R1

N SPB H2O-dioxane, 24 hr

NH

CN O 25-67%

R1 = Me, Ph, NMe2

Scheme 2.77

The quinazolin-4-(3H)-ones are interesting systems to build pharmaceutical compounds. The CN group of 4-(methylthio) benzonitrile is quantitatively and selectively oxidised131 to amides by tertiary butyl hydroperoxide (TBHP) in strong alkaline aqueous medium in presence of cetyltrimethylammonium sulfate [(CTA)2SO4] (Scheme 2.78). TBHP does not oxidise the CN group at pH 7 (even at 100°C), however in the absence of (CTA)2SO4, only the methylsulfenyl group is oxidised to methylsulfinyl. But under basic conditions, TBHP converts both groups into amide and sulfonyl groups, respectively (Scheme 2.78).

Scheme 2.78

2.2.13.9 Oxidation of sulfides A number of reagents (e.g. H2O2/acetic acid) are available for the oxidation of sulfides to sulfoxides and sulfones. On a large scale, an oxidant like oxone in aqueous acetone, buffered to pH 7.8-8.0 with sodium bicarbonate is used132. This procedure is environmentally benin. In this case, the formation of the oxidation products, viz., sulfoxides or sulfones depend on the equivalent of oxone used, temperature and reaction time. In aqueous medium at pH 6-7 (buffered with phosphate), the reaction is very fast and excellent conversions to sulfoxides and sulfones are obtained133. Another cheaply available industrial chemical, sodium perborate (SPB) in aqueous methanolic sodium hydroxide oxidises sulfides to sulfones in very good yield134. Sulfide can also be oxidised to

2.38 Green Chemistry sulfoxides exclusively by using commercial 70% aqueous TBHP in water in the heterogeneous phase at 20-70°C 135. Using this procedure some of the sulfides like Et2S, PhSMe, PhSPh, p-OHC6H4SMe can be oxidised quantitatively to the corresponding sulfoxides at 20°C. The SMe group of 4-(methylthio)benzaldehyde can be selectively oxidised to the sulfinyl group in water at 70°C at pH 7 with tertiary butyl hydroperoxide (TBHP) (Scheme 2.79)136. Under strong basic conditions both the CHO and SMe groups are oxidised to – COOH and –SO2Me, respectively. By using MCPBA under basic conditions, oxidation of – CHO group is prevented and SMe group is oxidised to SO2Me in good yield. OHC

TBHP pH > 7

H2O, 70°C 5 hr

OHC

SOMe

SMe

TBHP pH 13

H2O, 70°C 2 hr

HO2C

100%

SO2Me 100%

MCPBA H2O, 1-3°C 2 hr pH > 13

OHC

SO2Me 98%

Scheme 2.79

2.2.13.10 Oxidations with hypochlorite Hypochlorite is a well documented oxidising agent in the haloform reaction for the oxidation of methyl ketones to carboxylic acids. It has been found137 that the hypochlorite anion can be transferred into organic solutions by PTC (quaternary cations). Some of the applications of this technique are given as follows (Scheme 2.80).

2.2.13.11 Oxidation with ferricyanide 1, 2-Disubstituted hydrazines are oxidised by K3Fe(CN)6 in presence 2, 4, 6-triphenyl phenol (TPP) as a PTC in NaOH138. The product obtained is 1, 2-disubstituted azo compounds (Scheme 2.81). Besides what has been mentioned above, a number of oxidations can be performed in aqueous phase in the presence of a phase transfer catalyst.

2.2.14 Reductions Introduction Like oxidation, reduction of organic molecules has played an important role in organic synthesis. A number of reducing agents with different substrates have been described 139. During the last decade there has been considerable progress with respect to the types of bonds which can be reduced and also with respect to regio and stereo-selectivity of the reduction processes. Till some

Organic Synthesis in Water

C6H5CH2OH + NaOCl (aq.)

+ – Bu4NX

C6H5CHO 76%

CH2Cl2 (solvent) 75 min

RCH2OH +NaOCl

+ – Bu4NX Slow reaction

2.39

(RCHO)

RCO2H

Aliphatic alcohol

OH + NaOCl

+ – Bu4NX EtOAc (solvent) 1.2 hr

Cycloheptanol

C6H5CH — NH2 + NaOCl CH3 a-Methyl benzylamine n-C7H15CH2NH2 + NaOCl 1-Octylamine

+ – Bu4NX EtOAc (solvent) 1.4 hr

+ – Bu4NX EtOAc (solvent) 0.5 hr

O Cycloheptanone (89%)

C6H5COCH3 98%

n-C7H15CN 1-Cyanoheptane (60%)

Scheme 2.80 RNHNHR + K3Fe(CN)6

TPP NaOH

RN = NR 63-98%

Scheme 2.81

time back the only reducing agent which could be used in aqueous medium is sodium borohydride. From the point of view of industrial application, reduction in aqueous medium is very important. The hydride reductions which at one time seemed impossible to be carried out in aqueous medium have now been accomplished by the development of a number of water-soluble catalysts which give higher yields and selectivities. Even the hydrogenation of aromatic compounds is now possible in aqueous media. In the present unit, some examples of a few novel reduction performed in aqueous medium are described. Enzymatic reduction have also been known to occur in water. However, this subject will be discussed in a separate section. Some important reductions in aqueous media are given as follows:

2.2.14.1 Reductions of carbon-carbon double bonds Alkenes can be reduced to the corresponding saturated compounds (e.g. alkanes) by PtO2/H2, Pd/H2, Raney Ni/H2 or diimide.

2.40 Green Chemistry The reduction of carbon-carbon double bonds by the use of water soluble hydrogenation catalyst is possible 140. Thus, hydrogenation of 2-acetamidoacrylates with hydrogen at room temperature in water in the presence of water soluble chiral Rh(I) and Ru(II) complexes with (R)-BINAP (SO3Na) [BINAP is 2, 2¢-bis (diphenylphosphino-1, 1¢-binaphthyl) (Scheme 2.82)141.

Scheme 2.82

Ruthenium complexes are found to be more stable than the corresponding rhodium analogue; the ‘ee’ of the final reduced product is found to be 68-88%. The carbon-carbon double bond of a, b-unsaturated carbonyl compounds can be reduced by using Zn/NiCl2 (9 : 1) in 2-methoxyethanol (ME)-water system (Scheme 2.83)142. Sonication increases the yield. O

O Zn/NiCl2(9:1) ME-H2O, 30°C, 2 hr

CO2Et

CO2Et 86%

Scheme 2.83

The above procedure (Scheme 2.83) has been used to selectively reduce (–) – carvone to (+) dihydrocarvone and carvotanacetone by variation of experimental conditions (Scheme 2.84)143. Carvone was earlier reduced to dihydrocarvone by using homogeneous hydrogenation technique with hydridochlorotris (triphenyl phosphine) ruthenium (Ph3P)3 RuClH 144. Reduction of 3, 8-nonadienoic acid (a compound containing an terminal as well as an internal double bond) gives different products depending on the reaction conditions145. Thus, half hydrogenation of 3, 8-nonadienoic acid in anhyd. benzene with RhCl[P(p-tolyl)3]3 gives major amount

Organic Synthesis in Water

O

O Zn/NiCl2

+

ME-H2O, 30°C, 2 hr

(-)-Carvone

2.41

(+)-Dihydro carvone

Carvotanacetone

Scheme 2.84

(66%) of 3-nonenoic acid (A). However, addition of equal amount of water to the reaction medium gives an inversion of selectivity giving 8-nonenoic acid as the major product (85%). The use of aqueous KOH retards the hydrogenation rate (Scheme 2.85).

Scheme 2.85

The carbon-carbon double bonds can also be reduced by samarium diiodide-H2O system 146. Chemoselective hydrogenation of an unsaturated aldehyde by transition metal catalysed process 147 (Scheme 2.86) has been reported.

2.2.14.2 Reduction of carbon-carbon triple bonds The carbon-carbon triple bonds (e.g. alkynes) on catalytic hydrogenation gives the completely reduced product, viz., alkanes. Alkynes can also be reduced partially to give Z-alkenes by palladium calcium carbonate catalyst which has been deactivated (partially poisoned) by the addition of lead acetate (Lindlar catalyst) or Pd-BaSO4 deactivated by quinoline. Lindars catalyst is less active and the reduction is more selective. Some examples are given (Scheme 2.87). Disubstituted alkynes (which are electron deficient) can be reduced with water soluble monosulfonated and trisulfonated triphenylphosphine (Scheme 2.88)148.

2.42 Green Chemistry Ru/tpps (1/10) H2(20 bar), 80°C toluene/H2O(1:1) pH 7

OH 100% Conversion Selectivity 99%

O Ru/tpps (1/10) H2(20 bar), 80°C toluene/H2O(1:1)

O 90% Conversion Selectivity 95%

Scheme 2.86

Scheme 2.87

Ph — C

Ph2P(m-C6H4-SO3Na), 1.2 eq.

Ph

H2O, RT 5 min

H

COMe Ph + H H 70%

C — COMe Ph2P(m-C6H4-SO3Na), 0.9 eq.

Ph

H2O, RT 3 min

H

H COMe 30%

H COMe

Scheme 2.88

In the above reaction (Scheme 2.88), the water acts both as a solvent as well as a reactant, and the amount of phosphine controls the cis/trans ratio of the formed alkenes since it catalyses the cistrans olefin isomerisation.

2.2.14.3 Reduction of Carbonyl Compounds Carbonyl compounds can be reduced by a variety of reagents. Some of the common reagents are Na-C2H5OH, PtO2/H2, LAH, NaBH4, Na2BH3CN, HCO2H/EtMgBr, (Et2O)SiH.Me, B2H6149. Some of the more common reductions using NaBH4 are given (Scheme 2.89).

Organic Synthesis in Water

C6H5CHO O

NaBH4/MeOH

2.43

C6H5CH2OH

NaBH4/MeOH

OH

O

OH NaBH4/MeOH

C

NO2CH2CH2CH2CHO Cl3CCH(OH)2 OHC

CO2Et

NaBH4/EtOH

NO2CH2CH2CH2CH2OH

NaBH4/H2O

Cl3CCH2OH

NaBH4/EtOH

HOH2C

NO2

CO2Et

NO2 CHO

NaBH4/MeOH

CH2OH

Scheme 2.89

Using sodium borohydride in aqueous medium, 2-alkylresorcinols have been prepared (Scheme 2.90) 150. HO

MeO2CO

OH

OCO2Me

ClCO2Me THF

C

C

R 92-95%

O R = Me, Ph

MeO2CO

R

O

OH

NaBH4 THF-H2O 0°C, 0.5-3 hr

CH2

R

54-80%

Scheme 2.90

The reduction of carbonyl compounds in water has been carried out by a number of reagents under mild conditions. The most frequently used reagent is sodium borohydride, which can also be used using phase-transfer catalysts 151 or inverse phase transfer catalyst152 in a two phase medium in the presence of surfactants. The carbonyl compounds can be reduced quantitatively regio- and stereo-selectively by NaBH4 at room temperature in aqueous solution containing glycosidic amphiphiles like methyl-b-D-

2.44 Green Chemistry glactoside, dodecanoyl-b-D-maltoside, sucrose, etc 153. By using this procedure, a, b-unsaturated ketones give 1, 2-reduction product (corresponding allylic alcohols) and cyclohexanones give the more stable alcohol. Reduction of ketones with NaBH4 also proceeds in the solid state154. In this procedure a mixture of powdered ketone and 10-fold molar amount of NaBH4 is kept in a dry box at room temperature with occasional mixing and grinding for five days to give the reduced product. Following ketones were reduced by this procedure (Scheme 2.91). NaBH4

Ph2CO

NaBH4

trans PhCH = CHCOPh

Ph2CHOH 100%

Trans PhCH = CHCHPh +

OH

PhCH2CH2CHPh OH (1:1) Yield 100% COMe

CH(OH)Me NaBH4

(50%) PhCHCOPh

NaBH4

PhCHCHPh

OH

HO OH Meso (62%)

t

Bu

O

NaBH4

t

Bu

OH (92%)

Scheme 2.91

Enantioselective hydrogenation of b-ketoesters has been carried out by using a ruthenium catalyst derived from (R, R) – 1, 2-bis (trans –2, 5-diisopropylphospholano) ethane [(R, R) –i-PrPEE- Ru] to give b-hydroxy esters with high conversion and high ee (Scheme 2.92) 155.

Organic Synthesis in Water

2.45

Scheme 2.92

The reduction of aldehydes like benzaldehyde and p-tolualdehyde with Raney Ni in 10% aqueous NaOH give the corresponding benzyl alcohols in 17-80% yields156 along with the corresponding carboxylic acids as byproducts, which arise by Cannizzaro reaction. However, in aqueous NaHCO3 under sonication conditions give the corresponding alcohols in good yields. Another interesting reagent used for reduction of carbonyl compounds is cadmium chloridemagnesium in H2O-THF system (Scheme 2.93)157. OH OCOCHMe2

O

OH

CdCl2-Mg H2O-THF

OCOCHMe2

RT, 15 min, 85% HO

O

O O

O

Scheme 2.93

Certain other reagents include samarium iodide in aqueous THF158, sodium dithionite in aqueous DMF 159, sodium sulfide in presence of polyethylene glycol160 and metallic zinc along with nickel chloride161. Using the latter reagent (Zn/NiCl2), a, b-unsaturated carbonyl compounds can be very easily reduced under ultrasound conditions162 (Scheme 2.94).

Scheme 2.94

2.46 Green Chemistry Ketones can also be reduced in an aqueous medium by SmI2-H2O163 (Scheme 2.95) PhCH2 O PhCH2

1) SmI2-H2O

PhCH2

THF, room temperature 10 min 2) Quenching in HCl

PhCH2

CHOH 94%

Scheme 9.95

2.2.14.4 Reduction of aromatic ring The hydrogenation of benzenoids to cyclohexane derivatives is a very useful process. Aromatic hydrocarbons require drastic conditions for reduction (for example PtO2/H2/CH3COOH; Raney Ni/H2/Pr/D, Rh-Al2O3/H2). It is now possible to effect the reduction of aromatic ring in aqueous medium at 50 atm of H2 and at room temperature with ruthenium trichloride stabilised by trioctylamine (RuCl3/TOA)164. One such example is given (Scheme 2.96). O

O R1

R2

RuCl3/TOA, H2 MeOH-H2O, RT, 1.2-10 hr

R1 R2 80-90% cis-trans 6:15

R1 = OMe, CO2Me R2 = H, Me, NH2

Scheme 2.96

In the above procedure (Scheme 2.96) the rate of the reaction is 10–12 times the rate in organic solvents and in the aqueous medium, in comparison to cis, the trans isomer is the major product. The hetercyclic compounds, like pyridine, 2-phenylpyridine and 3-methylpyridine can be reduced to the corresponding hexahydro product by Sm-20% HCl in 90-95% yields 165. However in the reduction of 4-aminopyridine by the above procedure, the 4-amino group is eliminated giving piperidine as the major product (60%). The heterocyclic compounds can also be reduced in 7094% yield by SmI2-H2O system at 0°C for 2.5 hr166. Using this method 2-amino–, 2-chloro–, and 2-cyano-pyridine on reduction give piperidine, the substituent groups are eliminated.

2.1.14.5 Miscellaneous reactions (i) Reductive removal of halogen from a-halocarbonyl compounds in aqueous medium can be effected by using sodium dithionite 167, zinc168, chromous sulfate169 and sodium iodide170. (ii) 2, 3-Epoxyallyl halides can be transformed readily into allylic alcohol (Scheme 2.97) using zinc-copper couple in H2O under sonication. (iii) Reductive dehalogenation in aryl halides can be effected in aqueous alkaline media in presence of PdCl2 with NaH2PO2 as a hydrogen source (Scheme 2.98) 171.

Organic Synthesis in Water R2 R1

R4 R 5 X

O

Zn(Cu) EtOH/H2O

R1

R2

R4

HO

R3

2.47

R5 R3 89-94%

Scheme 2.97 R

R PdCl2; NaH2PO2; NaOH

Cl

50-70 °C, 6-8 hr

15-94%

Scheme 2.98

The above procedure (Scheme 2.98) does not work in case of nitrogen containing heterocyclic compounds and the yield in case of m-substituted aryl halides is low. However, m-bromobenzoic acid can be debrominated to give benzoic acid in 90% yield by uing water soluble tris [3-(2-methoxyethoxy)propyl]stannane in presence of 4, 4¢-azobis (4-cyanovaleric acid) (ACVA) or sunlamp as initiator in aqueous NaHCO3172. Above debromination can also be effected by using [bis (potassium propanoate)n (hydroxystannate)], which in presence of NaBH4 and ACVA affords reductions and free radical cyclisation of aryl and alkenyl bromides (Scheme 2.99). CO2H

COOH (OH)nSn(CH2CH2CO2K)2 NaBH4, ACV A, KOH, 90°C

Br 90% EtO

EtO

O Br

(OH)nSn(CH2CH2CO2K)2

OR

O

NaBH4, ACV A, KOH, 90°C

OR 62%

Scheme 2.99

The hydrogenolysis of halopyridines can be effected with 15% aqueous TiCl4 in presence of acetic acid 173. Aqueous titanium trichloride quantitatively removes cyano group from cyanopyridines. Reductive dehalogenation is also catalysed by SmI2.

2.48 Green Chemistry (iv) Groups like azide, sulfoxide, disulphide, activated C = C bond and nitroxide can be reduced by using sodium hydrogen telluride (NaTeH) (Prepared in situ by the reaction of tellurium powder with aqueous ethanolic solution of NaBH4) 174. (v) Groups like aldehydes, ketones, olefins, nitroxides and azides are reduced by sodium hypophosphite buffer solution 175. (vi) Vinyl sulfones are stereospecifically reduced to the corresponding olefins with sodium dithionite in aqueous medium (Scheme 2.100) 176. RSO2 R¢

R¢¢

R¢

R¢¢

Na2S2O4 52-88%

R¢ RSO2

R¢

R¢¢

R¢¢

Scheme 2.100

(vii) Diarly and dialkyl sulfides can be reduced by triphenylphosphine in aqueous solvents (Scheme 2.101) 177. RS — SR + Ph3P:

H2O

+ RS — PPh3

RSH + Ph3P = O

Scheme 2.101

2.2.15 Electrochemical Synthesis Introduction The well known Kolbe reactions involving the oxidation of carboxylic acids to give decarboxylated coupling products (alkanes) is the earliest electrochemical synthesis. At present, the electrochemical synthesis has become an independent discipline. A large number of organic reactions (synthesis) have been achieved by this technique using water as solvent, though organic solvents have also been used. However, there is a distinct advantage in using aqueous solutions over organic solvents 178. The electrochemical synthesis are of two types: anodic oxidative processes and cathodic reductive processes. During anodic oxidative processes, the organic compounds are oxidised. The nature of the product of anodic oxidation depends on the solvent used, pH of the medium and oxidation potential.

Organic Synthesis in Water

2.49

In cathodic reductive processes, the cathode of electrolysis provide an electron source for the reduction of organic compounds. Generally the rate of reduction increase with the acidity of the medium. Electroreduction of unsaturated compounds in water or aqueous-organic mixtures give reduced products-this process in equivalent to catalytic hydrogenation. An electrochemical process uses a anode made of metal that resists oxidation, such as lead, nickel or most frequently platinum. The anode is usually in the shape of a cylinder made of a wire guage. The usual electrolytes are dilute sulphuric acid or sodium methoxide prepared in situ from methanol and sodium. The direct current voltage is 3-100 V, the current density is 10-20 A/dm3, and the temperature of the medium is 20-80°C. Electrochemical reactions are practically as diverse as non-electrochemical reactions. Thus, the combination of electrochemical reactions with catalysts (electrochemical catalytic process), enzymatic chemistry (electroenzymatic reactions) are quite common. Following are some representative examples of electrochemical synthesis:

2.2.15.1 Synthesis of adiponitrile Adiponitrile is used as an important raw material for preparing hexamethylene diamine and adipic acid, which are used for the manufacture of Nylon-66. It is obtained commercially by the electroreductive coupling of acrylonitrile. By this process about 90% of adiponitrile is obtained179. In this process a concentrated solution of certain quaternary ammonium salts (QASs), such as tetraethylammonium-p-toluene sulfonate is used together with lead or mercury cathode (Scheme 2.102). 2e

–

CN + 2H2O QASs

NC

+ 2OH CN

Acrylonitrile

–

Scheme 2.102

Another route for its preparation of adiponitrile is the selective hydrocyanation of butadiene catalysed by Ni(O)/triarylphosphite complexes (Scheme 2.103) 180. HCN

HCN CN

NC CN

Ni(O)

Butadiene

Adipointrile

Scheme 2.103

2.2.15.2 Synthesis of sebacic acid Sebacic acid is an important intermediate in the manufacture of polyamide resins. It was obtained earlier on a large scale by saponification of castor oil181. It is now obtained by electrochemical process involving the following three steps (Scheme 2.104)

2.50 Green Chemistry CH3OH

HO2C — (CH2)4CO2H CH3O2C(CH2)4CO2H esterification Adipic acid Monomethyl ester of adipic Electrolysis 55°C

Hydrolysis

CH3O2C(CH2)8CO2CH3 Dimethyl ester of sebacic acid

HO2C(CH2)8CO2H Sebacic acid

Scheme 2.104

In the above process, anodic coupling of the monomethyl ester of adipic acid takes place. The electrolyte is a 20% aqueous solution of monomethyl adipate, neutralised with sodium hydroxide. The anode is platinum-plated with titanium and cathode is of steel 182.

2.2.15.3 Miscellaneous electrochemical reactions (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix) (x) (xi) (xii) (xiii)

Reduction of glucose for the manufacture of sorbitol and mannitol 183. Reduction of phthalic acid to the corresponding dihydrophthalic acid184. Coupling of acetone to yield pinacol 185. Oxidation of 1, 4-butynediol to acetylene dicarboxylic acid 186. Oxidation of furfural to maltol 187. Epoxidation of alkenes 188. Conversion of alkenes into ketones 189. Oxidation of aromatic rings and side chains to carboxylic acids 190. Oxidation of primary alcohols to carboxylic acids 191. Oxidation of secondary alcohols to ketones 192. Oxidation of vicinal diols to carboxylic acids 193. Hydroxylation or dehydrogenative coupling of phenols 194. Kolbe synthesis of hydrocarbons 195.

2.2.16 Weiss–Cook Reaction The reaction of dimethyl 3-oxoglutarate with glyoxal in aqueous acidic solution gives [3.3.0] octane, 3, 7-dione-2, 4, 6, 8-tetracarboxylate; which on acid catalysed hydrolysis followed by decarboxylation gives cis-bicyclo [3.3.0] octane-3, 7-dione (Scheme 2.105)196. The reaction is believed to involve a double Knoevenagal reaction.

2.2.17 Mannich Type Reactions Compounds containing at least one active hydrogen atom (ketones, nitroalkanes, b-ketoesters, b-cyano ester) condense with formaldehyde and 1° or 2° amine or ammonia (in the form of HCl salt) to give the product known as mannich base (Scheme 2.106) 197.

Organic Synthesis in Water MeO2C MeO2C

H

H2O, H

H

MeO2C Dimethyl 3oxoglutarate

H

O

+

O

CO2Me

2.51

+

O

(1) hydrolysis

O

(2) -CO2

O

O

O MeO2C

Glyoxal

H

CO2Me

cis-bicyclo [3.3.0] octane-3,7-dione

MeO2C H

CO2Me

CO2Me

HO

O

MeO2C

MeO2C

O

O

O CO2Me MeO2C

CO2Me a,b-unsaturated g-hydroxycyclopentenone

Scheme 2.105 O

O

O

+ – C6H5 — C — CH3 + H — C — H + (CH3)2NH2Cl Acetophenone

Formaldehyde

+ – C6H5 — C — CH2 CH2 NH(CH3)2 Cl + H2O b-N, N-Dimethylamino ketone (HCl salt)

Dimethylamine hydrochloride

Scheme 2.106

Modification using preformed iminium salts and imines has been developed. The imines react with enolate (especially trimethylsilyl ethers) to give b-amino ketones 198. The general scheme for the synthesis of b-aminoketones is given in Scheme 2.107. 2

R

2

N

3

+

R

5

R

1

H Imines

NH Yb(OTf)3 (5 mol %) CH2Cl2, 0°C

4

R

R

OSiMe3

R

1

5

R

R 3

R Sily enolate

Scheme 2.107

O

4

R

b-amino ketone (60-95%)

2.52 Green Chemistry Imines and amines also reacts with Vinyl ethers in presence of catalytic amount of Yb(OTf)3 to give corresponding b-amino ketones (Scheme 2.108) 199. 2

R

NH

OMe 1

Yb(OTf)3 (10 mole %)

2

R CHO + R NH2 +

5

1

R

THF-H2O (9:1)

R

O R

2

60-95% b-amino ketones

Scheme 2.108

The above reaction was also used for the synthesis of b-amino esters from aldehydes using Yb(OTf)3 as catalyst (Scheme 2.109) 200. 2

R

NH 3

R 1

2

R CHO + R NH2 +

4

R

OSiMe Yb(OTf) (5-10 mole %) 3 5

R

O

1

R

3

4

R

CH2Cl2, RT in presence of MgSO4

R

5

R

b-amino ketones (75-90%)

Scheme 2.109

2.2.18 Conversion of o-nitrochalcones into Quinolines and Indoles Reduction of o-nitrochalcone under WGSR conditions 201 followed by the cyclisation give the formation of quinolines and indoles (Scheme 2.110)202. O Ar

Ar CO(30 bar), Ru2(CO)12

+

EtOH-H2O, 170°C

N

NO2 o-Nitrochalcones

Quinolines

Ar

N H Indoles

Scheme 2.110

2.2.19 Synthesis of Octadienols The isomerisation of butadiene in aqueous medium gives octadienols (Scheme 2.111) 203.

Scheme 2.111

O

Organic Synthesis in Water

2.53

2.2.20 Carbon-carbon Bond Formations in Aqueous Media Carbon-Carbon bond formations and functional group transformation are the two basic types of reactions for organic synthesis 204. Carbon-Carbon bond formation is the essence of organic synthesis. It provides the foundation for the generation of complicated organic compounds from simple molecules.

2.2.20.1 Reactions of alkanes Alkanes are generally considered unreactive in conventional organic chemistry. However, under drastic conditions, alkanes are known to react. It has now been possible to carry out some reactions of alkanes in aqueous conditions205. Thus, it is possible to couple methane with CO to generate acetic and in aqueous conditions using several catalysis206 (Scheme 2.112).

Scheme 2.112

Direct alkynylation of an sp3-hybridized C-H bond adjacent to nitrogen could be effected by tert.butyl hydroperoxide in presence of copper catalyst (Scheme 2.113) 207. Ar

N

+ H

R

CuBr (5 mol %), H2O tBuOOH (1.0-1.2 eq) 100°, 3 hr

Ar — N R

Scheme 2.113

Carbon-Carbon bond formation via carbene insertion into an alkane C-H bond is possible in aqueous media under photolytic conditions 208.

2.2.20.2 Reactions of alkenes Alkenes and its derivatives are known to undergo cationic polymerisation in aqueous media 209. Also, the reaction of simple olefins with aldehydes in the presence of acid catalyst is known as ‘Prins reaction’210; in this reaction a mixture of carbon-carbon bond formation product is obtained211. A direct formation of tetrahydropyranol derivative has been reported212 in water using a cerium-salt catalysed cyclisation in aqueous ionic liquids (Scheme 2.114).

Scheme 2.114

2.54 Green Chemistry The yield of the tetrahydropyranol (Scheme 2.114) improved 213 by using the Amberlite 1R-120 plus resin. A related reaction involving alkene-imine coupling proceeds well in water-THF. This reaction is used in the asymmetric synthesis of pipecolic acid derivatives214 (Scheme 2.115). The radical addition of 2-iodoalkanamide or 2-iodoalkanoic acid to alkenols using water soluble radical initiator yielded g-lactones 215 (Scheme 2.116). The reaction of ethyl diazoacetate and olefins proceeded well in aqueous media using Rh(II) carboxylates. This is a convenient procedure for cyclopropanation. In situ generation of ethyl diazoacetate and cyclopropanation also proceeded well216 (Scheme 2.117). O

OH

O

OH

OH H

Ph

OHC — CHO

NH

Ph

Ph

N

N

H2O — THF, 72%

OH

Scheme 2.115

O

O I H2N

OH

+

OH

O

Radical initator H2O, 75°, 95%

O

CN Radical initator HO

N

N CN

O

OH

Scheme 2.116

Scheme 2.117

The addition of activated alkenes to unactivated alkynes resulted in Alder-ene products using a ruthenium catalyst 217 (Scheme 2.118).

Organic Synthesis in Water

2.55

Scheme 2.118

2.2.20.3 Reactions of alkynes Terminal alkenes could be dimerised to give mixture of diynes in moderate yield218 (Scheme 2.119). Although such coupling are mainly catalysed by copper, other transition metal catalysts also work.

Scheme 2.119

Such dimerisation of terminal alkynes is known as the Glasar coupling or the Eglinton coupling. It was found that using a catalytic amount of Pd(OAc)2 and triphenylphosphine in dichloroethane resulted in a high yield of homocoupling of terminal alkynes 219. Terminal alkynes coupled with 2-iodoaniline or 2-iodophenol to give the corresponding indoles or benzofurans in good yield 220 (Scheme 2.120). I +

CH2CH2OH

OH

10% Pd/C, PPh3, CuI (S) Prolinol, H2O 80°, 85%

CH2CH2OH O

Scheme 2.120

An efficient coupling of acetylene with aryl halides in a mixture of acetonitrile and water (Scheme 2.121) has been reported221. I + H X

H

[Pd]/TEA CH3CN/H2O rt

X

X

Scheme 2.121

Terminal alkynes have been reported to couple with acid chlorides; the reaction is catalysed by PdCl2(PPh3)2/CuI along with a catalytic amount of sodium lauryl sulfate as the surfactant and K2CO3 as the base; the coupled product are ynones (Scheme 2.122) 222.

2.56 Green Chemistry O 1

+ R

R

O

Cal. Pd(PPh3)2Cl2/CuI Surfactant, H2O

Cl

R R¢

Scheme 2.122

A direct addition of terminal alkynes to aldehydes in water by using a ruthenium – indium bicatalyst system has been reported 223 (Scheme 2.123). OH 1

R CHO + H — C

2

C—R

Cat◊RuCl3, Cat◊In(OAc)3, amine 1

60-90°, H2O

R

2

R 27-94% of yield

Scheme 2.123

Terminal alkynes reacted with aldehydes and amines under suitable conditions to give 224 propargylamines (Scheme 2.124). Ar HN 1

2

R CHO + ArNH2 + R

cat CuBr, cat RuCl3 60°-90°, H2O

1

R

2

R 27-46%

Scheme 2.124

Terminal alkynes could be added to activated alkynes in water without the competition of the homocoupling of the terminal alkynes 225 (Scheme 2.125).

Scheme 2.125

A simple and highly efficient Pd-catalysed addition of a terminal alkynes to a C C double bond such as a conjugated enone, either in water or in acetone in air (Scheme 2.126) has also been reported 225.

Organic Synthesis in Water

2.57

O O R

+

R¢

R¢

[Pd] in H2O or acetone air atmophere

R

Scheme 2.126

Hydration of terminal alkynes is catalysed by Ru(II) complexes in presence of phosphine ligands to yield the anti-Markovnikov addition of water. In this reaction aldehydes with only a small amount of ketone are obtained 226 (Scheme 2.127). 10 mol % [RuCl2(C6H5) {PPh2(C6F6)}]

Ph

+

3PPh2(C6F5). H2O

17.3%

8.0%

O

O Ph

+ Ph

H 65%

7.0%

Scheme 2.127

Nucleophilic addition of H2O to alkynes is found to take place in presence of Au(I) catalysed procedure, to form the corresponding carbonyl compounds in high yields 227 (Scheme 2.128). O n-C4H9

+ H2O

C(Ph3P) AuCH3]. H2SO4 H2O, MeOH, 99%

n-C4H9

Scheme 2.128

The above procedure is a valuable alternative to the Wacker oxidation. Alkynes are hydrocarboxylated with HCO2H in presence of Pd(OAc)2 and a phosphine ligand (100-110°, 120 psi of CO gas pressure) to give the corresponding unsaturated carboxylic acids (Scheme 2.129)228 R

+ H2O

R

Pd(OAc)2, PPh3, dppb CO, HCO2H

R +

H O2 C

CO2H (A)

(B)

Scheme 2.129

In the above hydrocarboxylation reaction, the regioselectivity is approximately 90 : 10 in favour of (A) (when R is Ph or a straight chain alkyl). However, when R is tert-butyl, (B) is favoured and is the exclusive product when R is Me3Si.

2.58 Green Chemistry Reductive carbonylation of alkynes can be effected229 in presence of palladium iodide catalyst along with KI and H2O (Scheme 2.130); the products obtained are 3-alkyl- or 3-aryl substituted furan –2(5H) – ones. Carbonylation of terminal acetylens in water in presence rhodium carbonyl gives 230 g-lactones (Scheme 2.131). An efficient and steroselective hydrosilation of terminal alkynes was developed using ambient conditions of air, water and room temperature by using Pt(DVDS)-P as catalyst 231 (Scheme 2.132).

+ CO + H2O

PdI2, KI H2O/dioxane 65%

O

O

Scheme 2.130 R R

H2O, CO Rh6(CO)16, TEA 60-99%

R +

O

O

O

O

Scheme 2.131 SiEt3 C5H11

+ Et3SiH

Pt(DVDS)-P H2O, 97%

C5H11 trans

Pt(DVDS)P =

N

PPh2 PPh2

Scheme 2.132

The above hydrosilation proceeds much faster in water than under neat conditions 232. Cyclopentenone derivatives are obtained by the Pauson-Khand reaction; the reaction was conducted in aqueous media and promoted by a small amount of 1, 2-dimethyloxyethene or water 233. An intramolecular Pauson-Khand reaction in water was carried out in water using aqueous colloidal cobalt-nanoparticles as catalyst234 (Scheme 2.133).

Organic Synthesis in Water

2.59

Scheme 2.133

Some other cyclisation reactions of terminal alkynes have also been described 205.

2.2.20.4 Reactions of aromatic compounds Carbon-Carbon bond formation via the electrophilic substitution of aromatic hydrogens proceeded under aqueous conditions. The well known example is the Friedel-Crafts-type reactions. Thus, various indole derivatives reacted with equimolar amounts of 3% aqueous CH2O and 33% aqueous Me2NH at 70-75° in 96% ethanol to give Mannich-type products 235. A lanthanide catalised reaction of indole with benzaldehyde was reported in ethanol-water system236 (Scheme 2.134). Ph cat, Ln (OTf)3 EtOH-H2O Ph CHO

N H

N H

N H

Scheme 2.134

The reaction of N-methylindole and N-methylpyrole via Friedel-Crafts reaction with OCHCO2Et in aqueous medium yielded substituted indoles and pyrroles; it was not necessary to use any metal catalyst237 (Scheme 2.135). OH 1

R

O +

2

R

N

H

1

IM NaH2PO4-Na2HPO4

CO2Et

CO2Et

R

2

R

N H

Me

Scheme 2.135

Friedel-Crafts reaction of aromatic compounds with methyl trifluoropyruvate in water yielded 238 various a-hydroxy esters (Scheme 2.136). Benzene can be oxidised by Pd(OAc)2/molydo phosphoric acid/AcOH-H2O(2 : 1) to give239 biphenyl by oxidative dimerisation with 100% selectivity and 19% yield under the conditions of 130°, 10 atom and 4 hr (Scheme 2.137).

2.60 Green Chemistry

Scheme 2.136 Pd(OAc)2.co catalyst, O2

+

OH +

OAc

AcOH. (–H2O), 130°, 4 hr

Scheme 2. 137

The use of water as solvent influences the chemoselectivity in photochemical substitution reactions. Thus, the photochemical aromatic substitution of fluorine by the cyano group in orthofluoroanisole gives mainly the hydroxylation product; the same reaction with para fluoroanisole generates the cyanation product preferentially 240 (Scheme 2.138).

Scheme 2.138

2.2.20.5 Reactions of carbonyl compounds Some of the common reactions of carbonyl compounds which have already been discussed are Aldol condensation (Scetion 2.2.5), Knoevenagel Reaction (Section 2.2.6), Pinacol Coupling (Section 2.2.7) and Benzoin condensation (Section 2.2.8). Besides these Reformatsky-type reactions have been conducted in aqueous phase. Thus, aromatic aldehydes reacted with an a-bromo ester in water mediated by zinc in low yields 241. Also, the reaction of bromoacetates is greatly enhanced by catalytic amounts benzoyl peroxide or per acids and give satisfactory yields with aromatic aldehydes (Scheme 2.139).

Organic Synthesis in Water

OEt

RCHO + Br O

HO H Zn (BzO)2O

2.61

O OEt

R

Scheme 2.139

A radical chain mechanism indicated by electron abstraction from organometallic Retormatsky reagent has been proposed 242. The reaction of aldehydes or ketones with allyl bromide in presence of stirred slurry of activated Zinc dust in 95% ethanol at 78° give243 the allylation product. The reaction can also be conducted in aqueous medium244 (Scheme 2.140). O Zn 95% EtOH or H2O/THF

+ Ph

H

Br

HO Ph 66%

Scheme 2.140

The above reaction could also be mediated by other metals like Sn, In, B, Si, Ga, Mg, Mn, Bi, etc.

2.2.20.6 Reactions of , -unsaturated carbonyl compounds A typical reaction of a, b-unsaturated carbonyl compounds is the well known Michael addition (See Section 2.2.4). CH – CN) with aldehydes in presence of The reaction between activated olefins (e.g. CH2 tertiary amines generates useful compounds 245 (Scheme 2.141); the reaction is known as BaylisHillman Reaction. Ph CN + PhCHO

OH

DABCO

CN

Scheme 2.141

A significant increase in the reactivity has been observed246 when the reaction is conducted in water. The addition of lithium or sodium chloride increases the reactivity. An important reaction of acrylonitrile is its electro reductive coupling to adiponitrile. The reaction was conducted 247 in the presence of certain quaternary ammonium salts (QAS), such as tetraethylammonium-p-toluenesulfonate, with lead or mercury cathodes (Scheme 2.142). 2

CN + 2H2O

2e

–

NC –

CN + 2 OH

Scheme 2.142

2.62 Green Chemistry 2.2.20.7 Reactions of organic halides The most important reaction of organic halides are the coupling reactions. These include Wurtz-type coupling (See section 2.2.12) and Ullmann-type coupling 248 (Scheme 2.143).

Scheme 2.143

The reactions between aryl (or alkenyl) halides and alkenes in the presence of catalytic amount of a palladium compound to give substitution of the halides by the alkenyl group is referred to as the Heck Coupling reaction. Both inter and intramolecular Heck Reactions have been performed in aqueous media 249. Palladium catalysed reactions of aryl halides with acrylic acid or acrylonitrile yielded the corresponding coupled product in high yield in presence of a base in water 250 (Scheme 2.144). Ar – X +

E

Pd(OAc)2(1 mol%), H2O NaHCO3|K2CO3|80-100° 87-97%

E Ar

E = COOH or CN

Scheme 2.144

The above procedure (Scheme 2.144) provides a convenient method for the synthesis of substituted cinnamic acids and cinnamonitriles. The cross-coupling reaction of alkenyl and aryl halides with organo borane derivatives in presence of a palladium catalyst and a base is known as Suzuki coupling. It is generally carried out in an organic/aqueous mixed solvent (Scheme 2.145) 251.

Scheme 2.145

The coupling of alkenyl and arylhalides with organostannanes in presence of a palladium catalyst is known as the Stille reaction 252. Thus, a coupling in aqueous ethanol gave high yield of the coupled product, which hydrolysed in situ (Scheme 2.146).

2.63

Organic Synthesis in Water

Biaryls are obtained in good yield by reaction of diphenyldifluorosilane or diphenyldiethoxysilane with aryl halides in aqueous DMF at 120° in presence of KF and catalyst amount PdCl2 (Scheme 2.147) 253. Besides what has been stated above the reactions of C = N, C – N and C ∫ N compounds are also useful for carbon-carbon bond formation205. OMe N

OMe

Bu3Sn EtO

N OMe I

N

Pd(OAc)2, NaHCO3 H2O/EtOH (1:1) n-Bu4NCl 25°, 5 hr.

N OMe O

Me

Scheme 2.146

Ar Br + Ph2SiF2

2 mol% PdCl2 DMF-H2O, 120° KF

Ar-Ph + [PhSiF3]

Scheme 2.147

2.2.21 Coupling of Indoles with 1, 4-benzoquinones in Water An efficient direct coupling of indole compounds with 1, 4-benzoquinones in water in the absence of any catalyst, organic co solvents or additives gave 254 the corresponding products in excellent yield (Scheme 2.148). O 5

R O 3

R

R

5

3

R H2O rt

+ N 4

R

R

1

5

2

R

R

O

5

R O

R

4

N R

2

R

1

Scheme 2.148

Some other reactions like photochemical reactions and reactions using biocatalysts have also been perfomed in water. These form the subject matter of subsequent sections.

2.3

CONCLUSION

Due to the environmental concerns caused by pollution of volatile organic solvents, attempts have been made to use alternative solvents which may be environmentally benin. Of the various solvents which can be used as alternative solvents, water is the best choice. The advantage of using water

2.64 Green Chemistry as a solvent is its cost, safety (it is non-inflammable and is devoid of any carcinogenic effect) and simple operation. Water is being recognised as a medium for promoting old and new reactions. In fact a large numbers of organic reactions, which have been conventially performed using volatile organic solvents can be performed in water. Most importantly, completely new reactions have been discovered by using water as a solvent. A special advantage is that organic synthesis in water can significantly reduce the number of steps when designed properly. The use of water as a medium for organic reactions will provide economical, health and environmental benefits. According to C & E News (Sept 3, 2007), ‘When organics fail, try water’

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Organic Synthesis in Water

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203. D.M. Roundhill and S. Ganguly, Organometallics, 1993, 12, 4825; E. Monflier, P. Bourdauducq, J.L. Courturier, J. Kervennel and A. Mortreux, Appl. Catal. A – Gen., 1995, 131, 167. 204. E.J. Corey and X.M. Cheng, The logic of Chemical Synthesis, John Willy & Sons, New York, 1989 205. C.J. Li, Chem. Rev., 2005, 3095 and the references cited therein. 206. M. lin and A. Sen. Nature, 1994, 368, 613; G.V. Nizova, G.B. Shulpin, G.V. Suss – Fink and S. Stanislas, Chem. Commun., 1998, 1885; M. Asadullah, Y. Taniguchi, T. Kitamura and Y. Fujiwara, Appl. Organomet. Chem. 1998, 12, 277. 207. Z.P. Li, and C. Li, J. Am Chem. Soc. 2004, 126, 1181; Z. P. Li and C. Li, Org, Lett., 2004, 6, 4997. For a review, see, S. Doye – Angew. Chem. Int. Ed. 2001, 40, 3351. 208. U.H. Brinker, R. Buchkremer, M. Kolodzierjczyk, R. Kupler, M. Rosenberg, M.D. Poliks, M. Orlando and M.L. Gross, Angew. Chem. Int. Ed. Engl. 1993, 32, 1344; S.A. Keibaugh, Biochemistry, 1983, 22, 5063. 209. For a review, see, V. B. Kazansky, Catal. Today, 202, 73, 127. 210. H.J. Prins, Chem. Weekbl; 1919, 16, 1072. For a review see D.R. Adams and S.P. Bhatnagar, Synthesis, 1977, 661. 211. P.R. Stapp, J. Org. Chem., 1970, 35, 2419. 212. C.C.K. Keh, V.V. Namboodri, R.S. Varma and C.J. Li, Tetrahedron Lett., 2002, 43, 4993. 213. C.C.K. Keh and C.J. Li, Green Chem., 2003, 5, 80. 214. C. Agami, F. Couty, M. Poursoulis and J. Vaissermann, Tetrahedron, 1992, 48, 431. 215. H. Yorimitsu, K. Wakabayashi, H. Shinokubo and K. Oshima, Tetrahedron Lett; 1999, 40, 519. 216. S. Iwasa, F. Takezawa, Y. Tuchiya and H. Nishiyama, Chem. Commun., 2001, 59; R.P. Wurtz and A.B. Charette, Org. Lett., 2002, 4, 4531. 217. B.M. Trost, A.F. Indolese, T.J.J. Mullar and B. Treptow, J. Am. Chem. Soc. 1995, 117, 615. 218. C. Amatore, E. Blart, J.P. Genet, A. Jutand, S. Lemaire-Andoire and M. Savignac, J. Org. Chem., 1995, 60, 6829. 219. B.M. Trost, C. Chan and G. Ruhter, J. Am. Chem. Soc., 1987, 109, 3486. 220. M. Pal, V. Subramanian and K.R. Yeleswarapu, Tetrahedron Lett; 2003, 44, 8221; Y. Uozumi and Y. Kobayasi, Hetrocycles, 2003, 59, 71; B. Liang, M. Dai, J. Chen. and Z. Yang, Org. Chem; 2005, 70, 391. 221. C.J. Li, D.L. Chen and C.W. Costello. Org. Res. Process Dev; 1997, I, 315. 222. L. Chen and C.J. Li. Org. Lett., 2004, 6, 3151. 223. C. M. Wci and C.J. Li, Green Chem, 2002, 4, 39. 224. C.J. Li and C.M. Wei, Chem. Commun., 2002, 268. 225. L. Chen and C.J. Li, Tetrahedron Lett., 204, 45, 2771. 226. M. Tokumaga and Y, Wakatsuki, Angew. Chem. Int. Edn. 1998, 37, 2867. 227. E. Mizushima, K. Sato, T. Hayashi and M. Tanka. Angew. Chem. Int. Ed; 2002, 41, 4563. 228. D. Zargarian and H, Alper, Organometallics, 1993, 12, 712. 229. R. Gabriele, G. Salerno, M. Costa and G.P. Chiusoli, Tetrahedron Lett; 1999, 40, 989. 230. T. Joh, H. Nagata and S. Takahashi. Chem. Lett; 1992, 1305. 231. W. Wu and C.J. Li. Chem. Commun; 2003, 1668.

2.72 Green Chemistry 232. H. Kinoshita, T. Nakamura, H. Kakiya, H. Shinokubo, S. Matsubara and K. Oshima, Organic Lett; 2001, 3, 2521. 233. T. Sugihara and T.M. Yamaguchi, Synlett, 1998, 1384; T, Sugihara, M. Yamaguchi and M. Nishizawa, Chemistry, 2001, 7, 1589. 234. S.U. Son, S.I. Lee, Y.K. Chung, S.W. Kim and T. Hyeon, Organic Lett; 2002, 4, 277. 235. J. Thesing and P. Binger, Chem. Ber; 1957, 90, 1419. 236. D. Chen, L. Yu and P.G, Wang, Tetrahedron Lett; 1996, 37, 4467. 237. W. Zhuang and K.A. Jorgensen, Chem. Commun; 2002, 1336. 238. R. Ding, H.B. Zhang, Y.J. Chen, L. Liu, D. Wang and C. – J. Li, Synlett, 2004, 555. 239. M. Okamoto, M. Watanabe and T, Yamaji, Organomet. Chem., 2002, 664, 59; H.A. Burton and I.V. Kozhevnikov, Mol. Catal A: Chem. 2002, 185, 285; T. Jintou, H. Taniguchi and Y. Fujeward, Chem. Lett; 1987, 1865. 240. J.H. Liu and R.G. Weiss, J. Org. Chem; 1985, 50, 3655. 241. T.H. Chan, C.J. Li, M.C. Lee and Z.Y. Wci, Can. J. Chem; 1994, 72, 1181. 242. L.W. Bieber, I.M. Malvestiti and E.C. Stroch, J. Org. Chem; 1997, 62, 9061. 243. T.A. Killinger, N.A. Boughton, T.A. Runge and J.J. Wolinsky, J. Organometallic Chem., 1977, 124, 131. 244. C. Petricr and J.L. Luche, J. Org. Chem. 1985, 50, 910; C. Einhorn and J. L. Luche, J. Organomet. Chem., 1987, 322, 177; C. Petrier, J. Einhorn and J.L. Luchi, Tetrahedron Lett., 1985, 26, 1449. 245. For a review, see, D. Basavaiah, P.D. Rao and R.S. Hyman, Tetrahedron, 1996, 52, 8001. 246. J. Auge, N. Lubin and A. Lubineau, Tetrahedron Lett; 1994, 35, 7947. 247. M.M. Baizer and D.E. Danly, Chem. Tech; 1980, 10(3), 161. 248. D.V. Davydov and I.P. Beletskaya, Russ. Chem. Bull; 1995, 44, 1139. 249. For a review, see, R.F. heck, Acc. Chem. Res.; 1979, 12, 146. 250. N.A. Bumagin, P. More and I.P. Beletskaya, J. Organomet. Chem; 1989, 371, 397; N. A. Bumagin, V.V. Bykov, L.I. Sukhomlinova, T.P. Tolstaya and I.P. Beletskaya, J. Organomet. Chem. 1995, 486, 259. 251. For a review, see N. Miyaura and A. Suzuk, Chem. Rev, 1995, 95, 2451; T.A. Bryson, J.M. Gibson, J.J. Stewart, H. Voegtle, A. Tiwari, J.H. Dawson, W. Marley and B. Harmon, Green Chem, 2003, 5, 177. 252. A. Herrbach, A. Marinetti, O. Baudoin, D. Guenard and F. Gueritte, J. Org. Chem; 2003, 68, 4897. 253. H. Zhang and D. Davis, Organometallics, 1993, 12, 1499; A.I. Roshchin, N.A. Bumagin and I.P. Beletskaya, Dokl, Chem; 1994, 334, 47. 254. H.-B. Zhang, L, Liu, Y.-J. Chen, D, Wang and C.-j. Li, Eur. J. Org. Chem; 2006, 869.

3 3.1

Organic Synthesis in Supercritical Carbon Dioxide

HISTORICAL DEVELOPMENT

Till the early sixteenth century carbon dioxide CO2 was not known to people. It was in 1823 when Faraday introduced the existence of various liquefied gases including CO2. Gore1 in 1961 gave the process of preparing liquid CO2. However, most work on using carbon dioxide as a solvent for extraction of natural products dates from 1960.

Properties of Carbon Dioxide Carbon dioxide can exist as a solid, liquid or gas. The gas phase is very familiar and needs no further comment. The solid phase is frequently used for cooling applications and is sold as ‘DryIce’. At atmospheric temperature and pressure, the solid transforms directly to the gas without passing through the liquid phase. However under certain conditions (e.g. compression of the gas or heating of solid CO2 under pressure), liquid carbon dioxide can be formed. At the triple point all three phases are in equilibrium. The critical point is of considerable interest for CO2 as the critical temperature (31°C) lies close to ambient temperature. The critical temperature for a substance is that temperature above which it is impossible to liquify the gas no matter what pressure is applied. Hence 31°C is the upper limit for extraction using liquid carbon dioxide. The lower limit is theorically –56° but there are problems with running an extractor at such low temperatures.

Phase Diagram for Carbon Dioxide As already stated CO2 can exist in different states depending on the temperature and pressure of its surroundings. A phase diagram provides a graphic representation to the states of CO2 under various pressures and temperatures (Fig. 3.1).

3.2 Green Chemistry SC-CO2 B

Pressure

Liquid Solid

Gas A

Temperature

Fig. 3.1 Phase diagram of CO2 (Figure in not to scale)

However, if we increase pressure, CO2 becomes liquid; at this point (–56°C and 5.1 atm), CO2 exists as gas, liquid and solid simultaneously. At point B (31°C and 73 atm) CO2 exists as super critical fluid. In the supercritical state, CO2 has a viscosity similar to that of a gas and density similar to that of a liquid. The present discussion on the uses and applications of supercritical carbon dioxide is divided into following two heads. (1) Use of supercritical carbon dioxide for dry cleaning. (2) Use of supercritical carbon dioxide as solvent for organic reactions.

3.2 USE OF SUPERCRITICAL CARBON DIOXIDE SC CO2 FOR DRY CLEANING Articles of clothing made from fabrics cannot be washed in water and require a dry – cleaning process. In fact, the term dry cleaning is somewhat misleading, because a liquid solvent is actually used for removing dirt and stains. Most of the drycleaners use the solvent perchloroethylene, or PERC. Cl

Cl

Cl

Cl

Perchloroethylene

Disposal of perchloroethylene, a suspected carcinogen, can contaminate ground water. Besides this, PERC when released into the atmosphere rises to the stratosphere region, where it gets decomposed into chlorine radical by the action of UV rays of the sun. The chlorine radicals, as we know are responsible for depleting the ozone layer.

Organic Synthesis in Supercritical Carbon Dioxide uv rays

PERC •

O3 + C l •

3.3

•

Cl O2 + ClO

•

•

ClO + O

Cl + O2

Net result O3 + O

2O2

The environmental problems associated with drycleaning clothes and the rising costs of complying with environmental laws have encouraged search for alternative methods. One such approach uses liquid or super critical carbon dioxide (CO2) as the cleaning solvent. Joseph M. De Simone of the universals of North Carolina and North Carolina state university and cofounder of Micell Technologies has developed polymers that acts as surfactants so that liquid CO2 can be used more effectively as a drycleaning solvent. Though carbon dioxide (a non polar molecule) dissolves non-polar substances – most greases and oils (from cloths) turn out to be very insoluble in CO2. However, the new surfactants increase the solubility of oils and grease in CO2, in much the same way that soaps increase the solubility of non-polar substances in water. This makes CO2 a more effective cleaning agent. The surfactant developed by De Simone is a polymer composed of ‘CO2 – philic’ segments (which are attracted to CO2) and ‘CO2 – phobic’ segments (which are not attracted to CO2)

The ‘CO2 – phobic’ segment can be made lipophilic (attracted to fats, oils and grease) or hydrophilic (attracted to water). When this polymer is placed in a medium of supercritical or liquid CO2, it assembles into a micelle structure. The “CO2 – philic” segments surrounds or encase the “CO2 – phobic” segments. The miscelle structure can encase materials such as greases and oil in the inner “CO2 – phobic” area of the miscille structure and allow them to be washed away by the CO2 solvent. The Micell Technologies have produced dry – cleaning machines that use liquid CO2 and a surfactant to dry – clean clothes, potentially replacing the environmentally harmful PERC. [For more details on use pf liquid CO2 for dry – cleaning see Introduction to Green Chemistry, American Chemical Society (2002)].

3.4 Green Chemistry

3.3 USE OF SUPERCRITICAL CARBON DIOXIDE SC CO2 AS SOLVENT FOR ORGANIC REACTIONS There are a number of advantages associated with the use of supercritical carbon dioxide (SC – CO2) as a solvent for organic reactions. • CO2 is non – toxic and environmentally benign2. • Solvent properties of SC – CO2 (e.g. dielectric constant, solubility parameter, viscosity and density) can be dramatically altered or changed is a manner not possible with conventional solvents – via manipulation of temperature and pressure3,4. • The properties of SC – CO2 are intermediate between that of a liquid and gas. Some of the important application on the use of super critical carbon dioxide are given. The author apologizes in advance to anyone who believes their contributions have been omitted.

3.3.1 Asymmetric Catalyst using Supercritical Carbon Dioxide It has been found4a that asymmetric catalytic reductions, particularly hydrogenations and hydrogen transfer reactions can be carried out in supercritical carbon dioxide with selectivities comparable or superior to those observed in conventional organic solvent (Scheme 3.1) O

O

P Rh P

OCH3

R

O

HN

OCH3

R

O

HN

H2/CO2[sc]

CH3

CH3 Et

Et

P P

P

P Et

Et

Scheme 3.1

It has been found4 that asymmetric hydrogen transfer reductions of enamides using ruthenium catalysts proceeds with enantioselectivities that exceed those in conventional solvents. The success of the asymmetric catalytic reductions in CO2 is due to the several unique properties of CO2 including tunable solvent strength, gas miscibility, high diffusivity and ease of separation. The problem arising due to insolubility of salts has been overcome by using lipophilic anions, particularly tetrakis [3, 5-bis (trifluoromethyl) – phenyl] borate (BARF). This discovery has been useful for the synthesis of wide range of speciality chemicals like pharmaceuticals and agrochemicals.

Organic Synthesis in Supercritical Carbon Dioxide

3.5

3.3.2 Supercritical Polymerisations Supercritical CO2 has been used in place of less acceptable organic chemicals5 for polymerisations. As has already been stated, supercritical CO2 is mixed with a surfactant in order to enhance the solubility for large, hydrocarbon-based molecules. One such polymerisation is described below (Scheme 3.2). O O O + CO2

Catalyst

R O

O

+ O

O

n

R

R

Scheme 3.2

This supercritical CO2 containing a surfactant has been described as ‘Soapy CO2’. Various types of polymers have been synthesised5a using SC – CO2.

3.3.3 Free Radical Bromination Free radical bromination can be performed 6 in supercritical CO2, where selectivity and yield are not compromised. Thus free radical bromination of toluene in super critical CO2 using bromine as a brominating agent gives a mixture of benzyl bromide (>70%) and 4 – bromotoluene. However when N – bromosuccinimide was used in super critical CO2 quantitative yield of benzylbromide was obtained (Scheme 3.3). CH2Br

Benzyl bromide 100%

hv 400 NBS CO2(SC) 139 bar AlBN 4 hr

CH3

hv 40° Br2

CO2(SC) 252 bar K2CO3 Toluene 5 min

CH2Br

CH3

+

Benzyl bromide > 70%

Br p-Bromotoluene (minor)

Scheme 3.3

Some other radical reactions in SC – CO2 have been discussed subsequently in a separate section.

3.3.4 Hydrocarbon Functionalisation As already stated supercritical CO2 is proving to be a suitable solvent for free radical reactions. Towards this end, a new chemical process has been developed6 which results in concomitant hydrocarbon functionalisation.

3.6 Green Chemistry Z

Z

R Br + RH Z = H, P, CO2 Et, CN; R = H, CH3

+ H — Br

The suggested mechanism6 of this reaction is the free radical chain process (Scheme 3.4) Z

Z Br

Br

R

R• + Z

Z R

Br

R

Br• + R — H

+ Br•

H — Br + R•

Scheme 3.4

As seen, the key intermediate in this process is bromine atom, which abstracts (with high selectivity) a hydrogen atom from a hydrocarbon (typically an alkylaromatic such as toluene or cumene). The resulting benzyl radical subsequently adds to a double bond of an allyl bromide (CH2 = C(Z)) CH2Br; where Z = Ph, CO2R or (N). The resulting radical adduct completes the chain by undergoing b – cleavage to eliminate bromine atom. The reaction requires a free radical initiator such as benzyoyl peroxide or di-t-butyl peroxide. This reaction achieves hydrocarbon functionalisation and C – C bond formation, while avoiding the use of strong bases. Since Br is the chain carrier, hydrogen abstraction proceeds with high selectivity (i.e. only the weakest C – H bond in the hydrocarbon is susceptible to attack). This reaction can be carried out in SC – CO2 as a reaction solvent. Overall yields in this reaction are excellent (Table 3.1). Table 3.1 Reaction of Alkylaromatics with substituted allyl bromides R

R

Z

Br

R

Z

Yield (%)

H

H

33

H

Ph

82

CH3

Ph

100

H

CO2Et

47

CH3

CO2Et

48

H

CN

66

CH3

CN

80

Data taken from Reference 7

Z

Organic Synthesis in Supercritical Carbon Dioxide

3.7

3.3.5 Diels–Alder Reaction A typical reaction for carbon–carbon bond formation is the well-known Diels–Alder reaction. Following Diels–Alder reactions have been reported 8. (a) Diels–Alder reaction of isoprene and methylacrylate to produce para and meta isomers (Scheme 3.5)

Scheme 3.5

The above Diels–Alder reaction was also examined by other workers9-11 but the ratio of the products obtained were different. It was believed8 that the experiments9-11 were conducted in a two phase region rather than in a homogenous supercritical phase. (b) Diels–Alder reaction of 2-t-butyl-1, 3-butadiene and methyl acrylate to produce8 para and meta products (Scheme 3.6)

Scheme 3.6

(c) Diels–Alder reaction of 2-trmethylsiloxybutadiene with methyl acrylate to give para and meta products (Scheme 3.7)

Scheme 3.7

3.8 Green Chemistry In the above reaction little variation in regioselectivity was observed relative to normal Diels–Alder synthesis. (d) Diels–Alder reaction of isoprene and nitroethylene to give8 para and meta products (Scheme 3.8).

Scheme 3.8

(e) Diels–Alder reaction of cyclopentadiene and ethyl acrylate derivative to produce 12 endoexo isomer product (Scheme 3.9).

+ W

W W Cyclopentadine

W = COMe, CN or CO2Me

endo (1)

exo (2)

Scheme 3.9

In Diel-Alder reactions, the most important results have been recorded in presence of Lewis acid catalyst such as Scandium trifluoromethane sulfonate, optimium selectivity (endo/exo ratio) was observed around the critical point of the reaction mixture (Scheme 3.9a) 12a.

Scheme 3.9a

An aza-Diels-Alder reaction of Danishefsky’s diene with an imine in presence of scandium perfluoroalkanesulfonate [Se(OSO2C8F17)3] in SC-CO2 gave the aza-Diels-Alder adduct in 99% yield (Scheme 3.9b)12b. Silica gel has also been reported12c to be an efficient catalyst for Diel–Alder reaction in SC-CO2 (Scheme 3.9b).

Organic Synthesis in Supercritical Carbon Dioxide

3.9

Scheme 3.9b

3.3.6 Kolbe–Schmitt Synthesis This is a direct carboxylation reaction in supercritical CO213, 14. One of the isomers (o-hydroxy benzoic acid) leads to the production of aspirin. The ortho-and para selectivity between isomers of hydroxy benzoic acids are of particular interest (Scheme 3.10). OH

OH

OH COOH

(1) SC CO2, base (2) H

+

+

COOH para

ortho

Phenol

Scheme 3.10

3.3.7 Bromination: Displacement of a Chlorinated Aromatics Phase transfer catalysed reaction of benzyl chloride with potassium bromide in presence of PTC catalyst in supercritical CO2 gives 15, 16 benzyl bromide (Scheme 3.11). CH2Cl

CH2Br

+ KBr

PTC in SC.CO2

+ KCl

50°, 3000 psi Benzyl chloride

Benzyl bromede

PTC is tetra-n-heptammonium bromide or 18-crown-6

Scheme 3.11

3.3.7A Polymerisations A disadvantage in using supercritical CO2 as a replacement solvent in the low solubilities of many common reagents and reactants in CO2. The solvating ability of high density CO2 (Supercritical or liquid) is often compared to that of non-polar organic solvents such as hexane. It has been found 17

3.10 Green Chemistry that use of water in supercritical CO2 considerably enhances the solubility of organics. Thus the following polymerisation has been achieved18 (Scheme 3.12). CH2

CH

CN

C

O

(CH3)2 C

O

CN

(CH2

CH) C

N N C(CH3)2 AlBN in CO2

O

59.4°, 207 bar, 48 hr.

CH2

(CF2)6

O

CF3

CH2

(CF2)6

CF3

Scheme 3.12

3.3.8 Freidel–Crafts Reaction Using Friedal-Crafts reaction following transformation has been achieved 19 in SC – CO2. (Scheme 3.13). COCH3

+ CH3COCl

AlCl3 in CO2

COCH3 +

Naphthalene

Scheme 3.13

Freidel–Crafts alkylation of aromatics has been performed in supercritical fluids (SCF) media 19a. Thus, alkylation of mesitylene in SC – propane (Tc = 91.9°, Pc = 46.0 bar), which acted both as solvent and alkylating agent (Scheme 3.13a). A mixture of three products, viz., mono –, di and trialkylated products was obtained in 25 per cent, 6 per cent, minor respectively. The selectivity is much improved if SC – CO2 is used as the reaction medium with propan-2-ol as alkylating agent. At a molar ratio of mesitylene to propane – 2 – ol 2 : 1, a pressure of 200 bar, catalyst temperature of 250° and a flow rate of 0.60g/min, the mono alkylated product was obtained as the only product with a conversion of 42%.

Scheme 3.13a

Organic Synthesis in Supercritical Carbon Dioxide

3.11

3.3.10 Hydrogenation in SC – CO2 Hydrogen is soluble in SC – CO2. The ability of SC – CO2 is to bring together hydrogen, substrates and catalysts in a single homogenation reactions over conventional processes. The hydrogenation of alkenes in SC – CO2 is of great industrial importance20, 21. Hydrogenation of acetophenone has been achieved using a polysiloxane supported palladium catalyst 22. In fact by adjusting the reaction temperature and hydrogen concentration, the product obtained can be adjusted. Thus at 90° using 2 – equivalents of hydrogen the corresponding alcohol (14.1) is produced in 90% yield. However at 300° and the hydrogen ratio of 6 : 1 the fully saturated product (Ethyl cyclohexane, 14.2) is produced with > 95% yields. At intermediate temperature of 200°, product (14.3) and (14.4) are obtained, the actual ratio depends on the concentration of hydrogen used (Scheme 3.14).

Scheme 3.14

The selective hydrogenation (as in Scheme 3.14) has been achieved 23 in a number of organic compounds including aromatic and aliphatic alcohols, aldehydes, ketones, nitro-compounds, amines, oximes, olefins and acetylenes. Dehydroisophytol, a propargylic alcohol could be reduced to the corresponding alkenol, isophytol (Scheme 3.15) by using the glassy alloy, Pd81 Si19 supported on Pd/SiO2 as catalyst 24. It has been shown that Pd81Si19 exhibited more than 50 times higher turnover frequency than a conventional silica-supported palladium catalyst under similar conditions. Selectivity to isophytol was 100% at low conversion and declined to 77% at about 70% conversion due to over hydrogenation. The combined application of a glassy Palladium – Silicon alloy together with SC – CO2 is promising for this type of Lindlar reactions. Hydrogenation of maleic anhydride with hydrogen in presence of Pd/Al2O3 using SC – CO2 as solvent at 200° gives g-butyolactone (GBL) (Scheme 3.16) 25.

3.12 Green Chemistry

Dehydroisophytol HO

H2

Isophytol HO H2 Dihydroisophytol HO

Scheme 3.15 O

O 1 mole of Pd/Al2O3 O + H2

O 12 MPa SC-CO2, 200°

O Maleic anhydride

GBL

Scheme 3.16

The g-butyolactone is one of the most valuable alternatives to the environmentally harmful chlorinated solvents, which have been widely used in the polymer and paint industry 26. The above procedure (Scheme 3.16) does not involve the use of hazardous materials. The asymmetric hydrogenation of ethyl pyruvate give (R) – ethyl lactate (Scheme 3.17) 27 using a heterogeneous catalyst system. In this case, the enantioselectivity is derived from a chiral cinchonidine modifier which is absorbed on the surface of supported platinum. However, there was a strong catalyst deactivation in the enantioselective hydrogenation in SC – CO2 due to CO poisoning of the Pt following the reduction CO2 to CO on the catalyst surface. This problem was overcome by using SC ethane. O

Me

OH O Et + H2

O Ethyl pyruvate

5% Pt/Al2O3 cinchonidine SC-ethane 60 bar, 50°C

O

Me

Et O (R)–ethyllactate

Scheme 3.17

Organic Synthesis in Supercritical Carbon Dioxide

3.13

The enantioselective hydrogenation of prochiral a-enamidies in SC – CO2 using a catanoic rhodium species (A), which incorporates the chiral bidentate DuPHOS ligand (B) and tetrakis bis (trifluoromethyl) phenyl borate (BARF) counter ion (C) (Scheme 3.18) gives very high enantioselectivities with low catalyst loading (0.2 mol %) and comparable to those achieved in conventional solvents (methanol, hexane) 28.

Scheme 3.18

The asymmetric hydrogenation of b, b-disubstituted enamide (19.1) under similar condition gave the valine derivative (19.2) (Scheme 3.19) 27 in 85% ee.

Scheme 3.19

Hydrogenation of Tiglic acid gives (S) 2-methyl butanoic acid in 99% yield with an 81% ee (Scheme 3.20) catalysed by ruthenium complex (D) containing the partially hydrogenated BINAP ligand which increased solubility in SC – CO2 over the fully aromatic version29. This conversion and selectivity is comparable to the best obtained in conventional organic solvent. Enantroselective hydrogenation of prochiral imines (21.1) ulitised the cationic iridium (I) complexes with chiral phosphinodihydrooxazole modified with perfluoroalkyl groups for increased CO2 – philicity 30. The product obtained was (R) – N – phenyl – 1 – phenylethylamine (21.2) in quantitative yield with an 81 per cent i.e. using 0.078 mol % of catalyst (Scheme 3.21).

3.14 Green Chemistry

Me

Ph2 P

O O Ru

P Ph2

O O Me

(D) H

COOH

COOH

D

+ H2 Me

Me

30 bar

scCO2 50°C 175 bar

Me

Me

Tiglic acid

Scheme 3.20

Scheme 3.21

3.3.11 Hydroformylation in SC – CO2 Hydroformylation of styrene with hydrogen and carbon monoxide using Rh (CO2) (acac) and (R1S) – BINAPHOS (E) as ligand in dense phase CO2 31,32 gave at 60° (with CO2 density of 0.48 g/ml, close to the critical density) the branced product (A) in major amount along with minor achiral regioisomer (B) (Scheme 3.22). Though acrylates are amongst the least reactive olefins towards hydroformylation, but in SC – CO2, the reaction is rapid and regoselective (Scheme 3.23) 33. In this case the catalyst used is [Rh(acac) (CO)2] and the fluoroalkylated phosphine ligand P(p – C6H4C6F13)3.

3.3.12 Oxidations in SC – CO2 The high solubility of oxygen in SC – CO2 offers rate benefits for oxidations as in the case of hydrogenation and hydroformylation. This medium (i.e., oxygen dissolved in SC – CO2) is particularly useful for the oxidation of weakly polar, water insoluble alcohols, due to the low polarity of SC – CO2. Oxidation of alcohols to carbonyl compounds in SC – CO2 has been shown

Organic Synthesis in Supercritical Carbon Dioxide

3.15

O PPh2 O P O

(E)

(CH2)2C6F13 O

R O

P

R=– O

(F) H

O H

Styrene

H2 20bar, CO 20 bar 0.1 mol % Rh(CO)2(acac) E or F SCCO2 60°C 0.48-0.85g/ml

O

Me +

(A)

(B)

Scheme 3.22 CHO CO2R

CO/H2

OHC CO2R

Rh-L, solvent

+ CO2R

Scheme 3.23

to proceed with high selectivity at a high rate 34. The oxidations were performed in a continuous fixed-bed reactor over a promoted noble metal catalyst (4% Pd, 1% Pt, 5% Bi/C). Primary alcohols could be converted to aldehydes using the above procedure. Benzyl alcohol and related substrates could be oxidised to the corresponding aldehydes with > 99% selectivity. For transition metal catalysed epoxidations with oxygen, an aldehyde was used as a sacrificial oxygen transfer agent. Such reactions occur efficiently 35 in SC – CO2. Expoxidation of internal double bond could be achieved without the addition of metal catalyst. Thus, there is quantitative conversion of cis – cyclooctene into expoxycyclooctane (99% ee) (Scheme 3.24). In this case use

3.16 Green Chemistry of 2-propinaldehyde gave better results. Under similar conditions, cyclohexene and trans-3-hexene were quantitatively converted to epoxy cyclohexane (91% selectivity) and trans-3-epoxyhexane (> 99% selectivity) respectively (Scheme 3.24).

Scheme 3.24

The above epoxidations (Scheme 3.24) is catalysed by the stainless steel reactor which is expected to facililate the initial formation of acylperoxy radicals, allowing the oxidation to occur via a non-catalytic radical path way. Epoxidation of alkenes has also been effected36 in SC – CO2 using tert-butyl hydroperoxide (TBHP) and catalytic Mo(CO)6. It has been reported 36 that trans diols are formed by using aqueous TBHP solution (70 wt %). However, if anhydrous decane solutions of TBHP are used then the epoxide was formed. Cis-alkenes are found to react much faster than the trans-alkenes. Cyclooctene gave quantitative conversion to the epoxide. However, trans-2-heptene or trans-stilbene did not react. A number of allylic alcohols were epoxidised with aq. TBHP in SC – CO2 using a salen catalyst37 (G). Good diastereoselectivity for the erythro product was observed for alkenes with secondary alcohols (Scheme 3.25).

Scheme 3.25

Organic Synthesis in Supercritical Carbon Dioxide

3.17

Oxidations have also been carried out in liquid CO2 as the solvent38. Thus epoxidation of allylic alcohols by anhydrous TBHP and catalytic oxovanadium (V) tri (isopropoxide) was effected in liquid CO2 at 25°. Using titanium (IV) tetra (isopropoxide) and a chiral diisopropyl-L-tartrate (DIPT) ligand, the sharpless asymmetric oxidation of allylic alcohols was also shown to be effective at 0° in liquid CO2 (Scheme 3.26).

Scheme 3.26

Sulfides could be oxidised to sulfoxides by TBHP as the oxidant and AmberlystTM 15 as a hetrogeneous acid catalyst 39. Using this procedure, diastereoselective sulfoxidation of cystein derivative (27.1) in SC – CO2 was achieved40 giving the anti – diasteromer (27.2) as the sole product (Scheme 3.27). Oxidation in conventional solvents (toluene and dichloromethane) showed no diastereoselectivity.

Scheme 3.27

An interesting epoxidation reagant is peroxycarbonic acid, which is obtained48 in situ from H2O2 and CO2. Thus the epoxidation of cyclohexene and 3-cyclohexe-1-carboxylate sodium salt in biphasic system comprising of a SC – CO2/olefins phase and an aqueous H2O2 phase to yield the corresponding epoxides and diols (Scheme 3.28). The yield of the epoxide was improved by the addition of DMF to increase the aqueous solubility of the olefins, suggesting that epoxidation occurs in the aqueous phase. Epoxidation of 3-cyclohexen-1-carboxylate sodium salt gave 89% yield of the epoxide. This show the utility of this process for use for water-soluble alkenes.

3.18 Green Chemistry

CO2 Organic/Fluid Phase

Cyclohexene

Aq. H2O2 Phase O CO2 + H2O2

C HO

OOH

peroxy carbonic acid O

HO

C

+O HO

HO

+ OOH

Scheme 3.28

H2O2 has also been used as a primary oxidant for olefin epoxidation in SC – CO2 using managanese 5, 10, 15, 20-tetrakis (2¢, 6¢-dichlorophenyl) porphyrinate as catalyst and hexafluoroacetone hydrate (HFAH) as CO catalyst in the presence of 4-t-butyl pyridine42.

3.3.13 Radical Reactions in SC – CO2 SC – CO2 offer potential benefits for radical processes. This is because SC – CO2 is a low density fluid with low viscosity resulting in high rates of diffusion. Thus, SC – CO2 is a good medium 43 for free radical carbonylation of organic halides to ketones or aldehydes (Scheme 3.29). Using a silane mediated carbonylation of an alkyl halide, alkene and CO using AIBN initiator gave yields comparable to those obtained in benzene44.

Scheme 3.29

Bromo adamantane could be reduced to adamantane (initiated by AIBN) under SC – CO2 conditions (Scheme 3.30) 45. Using the above procedure (Scheme 3.30), steroidal bromides, iodides and selenides with (1) and (2) also gave the corresponding reduced products in high yields (85-95%).

Organic Synthesis in Supercritical Carbon Dioxide

3.19

Scheme 3.30

Another radical reaction involved reduction of 1, 1-diphenyl-6-bromo-1-hexene (31.1) with tri (perfluoro hexylethyl) tin hydride (2) gave the 5-exo product (31.2) in 87% yield (Scheme 3.31). Similar reduction of aryl iodide (31.3) with (2) gave the cyclised product (31.4) in quantitative yield (Scheme 3.31).

Scheme 3.31

3.3.14 Acid–Catalysed Reactions The acid-catalysed reactions involving dehydration of alcohols in SC – CO2 was investigated46. Thus, dehydration of 1, 4-butandiol gave THF (Scheme 3.32). R

OH HO

Acid-Deloxan SC CO2

150-200°, 100 bar 1,4-Butandiol

+ H 2O O THF

Scheme 3.32

3.20 Green Chemistry A number of Lewis acid catalysed alkylation reactions have been conducted in SC – CO2; these are aided by the addition of poly(ethylene glycol) (PEG) derivatives. This includes the Mannich and aldol reactions of silyl enolates with aldehydes and imines in SC – CO2 (Scheme 3.33)12b,47. In these reactions, PEGs act as surfactants and form collodial dispersions in SC – CO2, manifested as emulsions, and can be shown to accelerate reactions. In the case of scandium catalysed aldol reactions of silyl enolates with aldehydes, poly (ethylene glycol) dimethyl ether [PEG (OMe)2, average MW = 500] was found to be more effective than PEG itself 47. Bn

Bn N

OSiMe3

+ Ph

H

OMe

SC-CO2 (10-25 MPa) 50°, 3 hr

3

R

2

+

4

R

H

6

7

8

–1

PEG. 400 (4gL )

5

R

SC-CO2 (10-25 MPa) 50°, 3 hr

5

1

R

R

3

R

OH 2

R + H

1

R

O

OSi R R R Yb(OTF)3 (5 mol %)

O

R

OMe

Ph

NH

N R

O

R

2

R

1

NH

Yb(OTf)3 (5 mol %) –1 PEG. 400 (4gL )

5

6

OSiR R R 4

R

7

Sc(OTf)3 (5 mol %) –1 PEG (OMe)2 500 (2gL ) SC-CO2 (8MPa) 50°, 3 hr

4

R

O 4

1

R

R

2

R

3

R

Scheme 3.33

An alternative additive, 1-dodecycloxy-4-heptadecafluorooctylbenzene was reported 48 to work as an efficient surfactant to accelerate aldol, Mannich and Friedel-Crafts alkylation of indoles in SC – CO2 (Scheme 3.34). The additive incorporated a CO2 – philic unit (perfluoroalkyl chain), and a lipophilic unit (alkyl chain) in the same molecule.

Scheme 3.34

Organic Synthesis in Supercritical Carbon Dioxide

3.21

3.3.15 Coupling Reactions A number of palladium catalysed coupling reactions have been reported 39 in SC – CO2. The main problem in these coupling reactions in the low solubility of phosphine ligands (e.g. PPh3) [which is generally used in conjugation with palladium catalyst such as Pd (OAc)2] in SC – CO2. This draw back in overcome by using a fluorinated phosphine ligand (X), to give a palladium complex which dramatically increased solubility 49. Two other fluoxinated phosphine ligands (y and z) are also shown below (Scheme 3.35). F CF3

F 3C

Ph

F

F

F F

F

P C6F13

C6F13

F3C

CF3 F

P

F

P

F

F F

F

(x) F CF3

CF3 (y)

F

F (z)

Scheme 3.35

Thus, the Heck reactions between iodobenzene and methyl acrylate (Scheme 3.36) catalysed by Pd (OAc)2 in presence of fluorous ligand (X) gave a much better yield (92%) of methyl cinnamate than reported in conventional solvent.

Scheme 3.36

Examples of other intermolecular Heck reactions, Suzuki and Sonogashira couplings were also reported 50 giving better yields as compared to those obtained in conventional organic solvents. Heck and Still coupling reactions have also been reported in SC – CO2 using the fluorinated ligands (y) and (z). Still coupling mediated by fluorous tagged phosphines (PTP – I and PTP – II) has been achieved 51 (Scheme 3.37) in SC – CO2 using (nBu)4NCl as catalyst.

3.22 Green Chemistry

PdCl2

P C8F17

C8F17H2CH2C

P

PdCl2

3

3 2

2

PTP-I

PTP-II O

MeO

SnBu3

MeO

O

Pd cat. (2 mol%)

Br +

SC CO2, (nBu)4NCl

O

O

Scheme 3.37

Pd-catalysed biaryl formation by the homocoupling of iodobenzene in SC – CO2 has also been achieved (Scheme 3.38) 52.

I

2 mol% Pd(OCOCF3)2 or Pd(OAc)2 4 mol% tris(2-furyl) phosphine and or 50 mol % TBAB DIPEA, 75°C, 15 hrs 11.0 MPa SCCO2 or solvent

Scheme 3.38

Heck reactions have also been carried out using water-soluble catalysts in SC – CO2/water biphasic system 53. Thus the coupling of iodobenzene with butyl acrylate in SC – CO2 was performed using Pd(OAc)2 and triphenylphosphinetrisulfonate sodium salt (TPPTSS) (Scheme 3.39).

Scheme 3.39

Enhanced selectivity in the Mizoroki-Heck arylation reaction of ethylene has been observed in a SC – CO2 – liquid bibhasic system (Scheme 3.40) 54. The product obtained is exclusively the styrene derivative. Arx +

PdCl2[P(OC6H5)3]2 base, SC-CO2

Scheme 3.40

Ar

Organic Synthesis in Supercritical Carbon Dioxide

3.23

The palladium catalysed carbonylation of 2-iodobenzyl alcohol in supercritical mixture of CO2 (20MPa) and CO (1MPa) (Scheme 3.40a) 44, 55 in presence of palladium complex PdCl2[P(OEt)3]2 and triethylamine gave phthalide. O I

Pd cat, NEt3

OH

CO, SC-CO2 100-130°

O

2-Iodobenzyl alcohol

Scheme 3.40a

Wacker reaction of oct-1-ene in SC – CO2 using methanol as cosolvent and PdCl2/CuCl2 as catalyst in presence of oxygen gives the ketone in 91% yield (Scheme 3.41) 56.

Scheme 3.41

3.3.16 Stereochemical Control in Reactions using SC – CO2 An important feature during development of new reactions is to allow a high degree of stereochemical control during formation of the product. Some reactions like Sc(OTf)3 – catalysed Diel-Alder Reaction of n-Butyl acrylate with cyclopentadiene in SC – CO2 (see Section 3.3.5) and oxidation reactions have already been discussed (Section 3.3.12). A typical reaction in which stereochemical control is observed by using SC – CO2 is the well known Henry reaction, which is useful carbon-carbon bond forming raection giving highly functionalised products of considerably synthetic utility57. In the Henary reaction of p-cyanobenzaldehyde with 1-nirtopropane in SC – CO2 in presence of Et3N, the product obtained 58 was the syn isomer; a mixture of syn and anti isomer is obtained in conventional Henary reaction (Scheme 3.42). One of the best reactions to illustrate the potential for stereoselectivity is asymmetric cyclopropanation (Scheme 3.43) 59. Thus, the reaction of styrene and ethyl diazoacetate give transcyclopropane (Scheme 3.43).

The Morita-Baylis-Hillman reaction in SC – CO2 The Morita-Baylis-Hillman (MBH) reaction is a very useful C-C bond forming reaction, whose products are particularly versatile synthetically as they contain a high degree of functionality 60. A simple MBH reaction of p-nitrobenzaldehyde or p-cyanobenzaldehyde with methyl acrylate in

3.24 Green Chemistry O Et3N, 40°C, 24 h CO2 pressure

+ NO2 NC OH

OH NO2 +

NO2 NC

+

NO2

NC

NC

anti

Syn

Scheme 3.42 Me

Me

O

n-Bu O

N

O

O

N

N

1

n-Bu

n-Bu

O

O N

n-Bu

N 2

O

O

O

O

EtOCH2C O

CH2COEt O

Et2NCH2C O

CH2CNEt2 O

N

N

3

N

N

4

5

Ligand 1-5, Cu(OTf)2

+

SC CO2, 35°C

Ph

N

+ Ph

CO2Et

N2

+ Ph

EtO2C

CO2Et CO2Et

Scheme 3.43

SC – CO2 with the commonly used 1, 4-diazabicyclo [2.2.2] octane (DABCO) as catalyst61 is shown in Scheme 3.44.

Organic Synthesis in Supercritical Carbon Dioxide O

O H

OH O

+ R

methyl acrylate

3.25

O

DABCO 50°, SC CO2 24 hr

R

Meso

p-Nitrobenzaldehyde R = NO2 p-Cyanobenzaldehyde R = CN

N

N DABCO

Scheme 3.44

It was found that in general, the reaction proceeded normally and gave conversions better than those in comparable solution-phase reactions. It was, however, found that occasionally, unanticipated byproducts were formed to varying degree after prolonged reaction times. These were identified as symmetrical dimers of the initial MBH reaction products (Scheme 3.45). O

O

X

X O

+ X

O

DABCO 50°, SC CO2 72 hr

O OMe

O

O O

O O

OMe O O

O OMe

O X

Meso

OMe O

X

C2 symmetry

Scheme 3.45

The above dimerisation (Scheme 3.45) was novel, but it was of limited synthetic utility. Synthesis of unsymmetrical ethers by getting the initial MBH products to react with another alcohol will be more useful. Thus, the reaction of an aldehyde with methyl acrylate and appropriately substituted benzyl alcohol in SC – CO2 gave the formation of unsymmetrical ether (Scheme 3.46). In this reactions only alcohols which are sparingly soluble in SC – CO2 (e.g. p-nitrobenzyl alcohol) gave very good yield 43, 61.

Scheme 3.46

3.26 Green Chemistry In the above procedure (Scheme 3.46), SC – CO2 soluble alcohols can be used by carrying out neat MBH reaction under an atmosphere of supercritical CO2, i.e., just gaseous CO2 above the neat reaction 43. Thus unsymmetrical ethers were obtained in 67% yield from allyl alcohol, methylacrylate and p-nitrobenzaldehyde (Scheme 3.47). Using unreactive aldehyde like benzaldehyde in the above reaction gave 58% yield of the product.

Scheme 3.47

3.3.17 Photochemical Reactions in SC – CO2 The photo-induced addition of aldehydes to a, b-unsaturated carboxyl compounds is an effective, ‘environmentally benign’ method for the synthesis of 2-acyl-1, 4-hydroquinone (Scheme 3.48). The process has been improved by using SC – CO2 in place of the usual solvent benzene. Higher yields are obtained at high CO2 pressures or by the addition of 5% t-butyl alcohol as co-solvent. The reaction was mediated by using benzophenone 62. O

+ RCHO

hv SC-CO2 benzophenone t-Butyl alcohol (Co Solvent)

O R = Ph or CH2CH2CH3 p-Benzoquinone

OH COR

OH 2-Acyl-1,4-hydroquinone

Scheme 3.48

In a similar way, benzophenone mediated photochemical reaction of 2-cyclohexen-1-one with acetaldehyde give 3-acetyl cyclohexanone (Scheme 3.49).

Scheme 3.49

Organic Synthesis in Supercritical Carbon Dioxide

3.27

3.3.18 Formation of Silica Nanoparticles using SC – CO2 and Water in Oil Microemulsions Silica particles are well known for their excellent abrasive, optical, electrical and thermal properties. They are also used as catalysts or catalyst supports, insulating materials, stiffening or binding agents for fibrous or granular materials and polishing and antisticking or antisoiling agents 63. Encapsulated silica particles also find applications in cosmetics64, drug delivery, paints and coating of surfaces 65. A large number of methods have been used for the preparation of silica nano-particles. A novel method for the precipitation of silica nanoparticles is by using66 supercritical CO2, in which SC – CO2 acts both as the solvent and as a reactant. A water-in-oil microemulsion of an aqueous sodium silicate solution in n-heptane or isooctane is injected into SC – CO2 using a micronozzle; this results in the formation of small droplets. In facts, SC – CO2 rapidly extracts the solvent from the droplets and reacts with the exposed surfactant-supported aqueous sodium silicate reverse micelles, forming silica nanoparticles and sodium carbonate and water (Scheme 3.50). 2NaOH. SiO2 + CO2 (in n-heptane)

Na2CO3 + 2SiO2 + H2O

Scheme 3.50

The precipitated silica nanoparticles are washed with water and the surfactant and sodium carbonate free particles are obtained using ultrafiltration. By this procedure silica nanoparticles having sizes in the range 20-800 nm are obtained. In fact, silica nanoparticles of adjustable size can be produced using supercritical or gaseous CO2.

3.3.19 Miscellaneous Applications 3.3.19.1 Synthesis of 2-pyrones The coupling of two alkyne molecules with CO2 in the presence of nickel gives 2-pyrones. In SC – CO2, a catalyst generated from Ni(cod)2 and 1, 4-diphenyl phosphino butane [Ph2 P(CH2)4 PPh2] combines with 3-hexyne and CO2 to form tetraethyl-2-pyrone (Scheme 3.51) 67,68.

Scheme 3.51

3.3.19.2 Pauson–Khand reaction The CO-cyclisation of an alkyne with an alkene and carbon monoxide leading to the formation of cyclopentanones is known as Pauson–Khand reaction; it is carried out in SC – CO2 using dicobalt

3.28 Green Chemistry octacarbonyl as catalyst 69. Thus, the intramolecular reaction of enyne gave 85% of cyclised product (Scheme 3.52).

Scheme 3.52

The above reaction was also successful for a number of substituted enynes. An intermolecular Pauson-Khand reaction was shown to occur with phenyl acetylene coupled to an excess of norbornadiene to give the exo product in 87% yield (Scheme 3.53). O

+ Phenyl acetylene

+ CO

3 mol% Co2(CO)8

Ph

SC-CO2 180 bar, 88°

Nonbornadiene

exo product only

Scheme 3.53

3.3.19.3 Hydroboration of styrene The rhodium catalysed hydroboration of styrene with catecholborane (HbCat), rhodium catalyst precursor (A) and phosphorous ligand (B) gave a quantitative conversion in SC – CO2 (Scheme 3.54) 70. The catalytic reaction is homogeneous and exhibits higher rates and regioselectivity compared with the equivalent reaction performed in perfluoromethylcyclohexane or THF solvents. Bcat

+ CO OMe

1 eq. HB cat 2% (A) and 4% (B) SC CO2 40°, 2800 psi, 5 hr.

A = (hfacac) Rh (cyclooctene)2 B = cy2P(CH2CH2C6H13)

Scheme 3.54

OMe

Organic Synthesis in Supercritical Carbon Dioxide

3.29

3.3.19.4 Carbamate synthesis The reaction of potassium carbonate and an ammonium salt catalyst with a number of primary and secondary aliphatic as well as aromatic amines reacted with butyl chloride in SC – CO2 to gives the corresponding carbamate in 72-90% yield (Scheme 3.55) 71.

Scheme 3.55

In the above synthesis (Scheme 3.55) SC – CO2 acted as the reaction media and carbonyl source for the production of carbamates from amines. Use of potassium phosphate in place of potassium carbonate demonstrated that the carbonyl source was CO2 and not the carbonate. This novel procedure is an attractive catalytic one-pot alternative to the use of phosgene in unethane synthesis. In a related process, Vinyl carbamates were synthesised using SC – CO2, secondary amines and terminal alkynes in pressure of Ru catalyst (A) (Scheme 3.56) 72. O Ph — C

CH + HNEt2

Phenyl acetylene

SC-CO2 Ru catalyst (A)

Diethyl amine (2° amine)

Et2N

O

CHPh

Vinyl Carbamate

Scheme 3.56

3.3.19.5 The Baylis–Hillman reaction The Balis-Hillman reaction has been carried out in SC – CO2 and gives better conversion and reaction rates as compared to solution phase reactions (Scheme 3.57)73. In case, the reaction is carried out in presence of an alcohol, the major product is an ether resulting from a 3-component coupling reaction, which occurs only in presence of SC – CO2.

3.3.19.6 Synthesis of methyl formate and N, N-dimethylformamide The hydrogenation of CO2 under super critical conditions in the presence of methanol and dimethylamine has resulted in a very efficient synthesis of methylformate 74 and N, N- dimethylformamide75 (Scheme 3.58).

3.3.19.7 Electrochemical carboxylation of organic halides using SC – CO2: Synthesis of ibuprofen Electrochemical carboxylation of an benzylic chloride is prompted under super critical condition – the halogen is converted into COOH. This procedure is applied to the synthesis of Ibuprofin (Scheme 3.59)76.

3.30 Green Chemistry

Scheme 3.57

Scheme 3.58 Cl

CO2H + SC-CO2 (80 bar)

Pt/Mg electrode (3F/mol) + – (C4H9)4 N BF4 (5m mol) 2

25 mA/cm , 40°

55% yield Ibuprofin

Scheme 3.59

Organic Synthesis in Supercritical Carbon Dioxide

3.31

3.3.19.8 Biotransformations in SC – CO2 A large numbers of examples exist in literature 39 using enzymatic catalysis in SC – CO2 and performing reactions involving hydrolysis, oxidations, esterifications and trans-esterification reactions. Hydrolytic formation of p-nitrophenol from disodium p-nitrophenylphosphate has been achieved 77 by the enzyme alkaline phosphatase EC 3.1.3.1 in SC – CO2 at 35° and 100 bar, with a 0.1 vol. % of water concentration. The kinectic resolution of racemic 3-(4-methoxyphenyl) glycidic acid methyl ester by immobilised Mucor miehei liphase (Lipozyme 1M 20) in SC – CO2 (Scheme 3.60) 78 at a conversion of 53% after 5 hr. O O

Me O Lipozyme 1M2O, 0.5 Vol % water SC-CO2 40°, 130 bar

MeO

O

O

O

O

Me O

OH + MeO

MeO

Scheme 3.60

Transesterification of N-acetyl -1-phenlalanine chloroethyl ester with ethanol catalysed by Subitism Carlsberg (Scheme 3.61) 79 gave quantitative conversion after 45 min with 2.5 vol % ethanol in SC – CO2.

Scheme 3.61

The Lipid – Coated b-D-galactosidase (LCE) (prepared from Bacillus circulans) 80 effected trans acetalisation of 1-O-p- nitrophenyl-b-D-galactopyranoside with 5-phenylpentan-1-ol in SC – CO2 (40°, 150 bar). The reaction was 25 fold faster in SC – CO2 tham in isopropyl ether producing the trans acetalisation product after 3 hrs. (Scheme 3.62).

3.32 Green Chemistry OH

OH NO2

O

HO OH

(CH2)5OH

O

LCE

+

OH 1-O-p-nitrophenyl -b-D-galactopyranoside

O — (CH2)5OH

HO OH

O

SC-CO2 400, 150 bar

OH 5-Phenylpentan-1-ol

Scheme 3.62

The enzymatic esterification of lauric acid with glyceride at 40° using an alternative LCE prepared from Rhizopus delemar, proceeded much faster in SC – CO2 (200 bar) than in benzene at atmospheric pressure (Scheme 3.63) 81. In SC – CO2 di and tri-glycerides were produced in 90% yield after 3 hrs. OCOC11H23 C11H23COOH + Lauric acid

OH OH

OCOC11H23 LCE SC-CO2 40°, 200 bar

OCOC11H23 OH

OCOC11H23 +

OCOC11H23 OCOC11H23

Scheme 3.63

The rate of esterification of n-valeric acid with citronellol in SC – CO2 at 35° using the enzyme Cyclindracea lipase (CCL) showed a dramatic pressure dependence around critical pressure (Scheme 3.64) 82. It was believed that the mechanism of this esterification in SC – CO2 involved CO2 interaction with and activating the enzymes in a Lewis acidic manner.

Scheme 3.64

In a similar way cylindracea lipase (CCL) catalysed esterification of oleic acid with citronellol in SC – CO2 gave 3, 7-dimethyl-6-octenyl ester (Scheme 3.65). The stereochemistry exhibited a similar pressure dependence as in the case of n-valeric acid. Kinectic resolution of 1-phenylethanol with Vinyl acetate in SC – CO2 (Scheme 3.66) using Novozym (EC 3.1.1.3) from canadida antarcitica B gave 83 (R)-1-phenylethylacetate (> 99% ee, 50% conversion). A related resolution of 1-(p-chlorophenyl)-2, 2, 2-trifluoroethanol under similar conditions has also been reported 84.

Organic Synthesis in Supercritical Carbon Dioxide

3.33

CCL n

Oct

(CH2)7 COOH +

OH

Citronellol

Oleic acid R

SC-CO2 35° 7-24.5 MPa

O n

R = Oct

O

(CH2)7

Scheme 3.65

Scheme 3.66

A enentioselective acetylation of a number of racemic alcohols, e.g. trans-3-penten-2-ol using an immobilised lipase (Pseudomonas sp. from Aman op) in SC – CO2 has been reported 85 (Scheme 3.67). There was 50% conversion after 250 min at 40° compared with the rate in toluene where PF6– > BF 4– ª NO 3– > NTF2.

4.2

TYPES OF IONIC LIQUIDS

Ionic liquids consist of a salt where one or both the ions are large, and the cation has a low degree of symmetry. These factors tend to reduce the lattice energy of the crystalline form of the salt, and hence lower the melting point16. Ionic liquids come in two main categories, namely, (i) Simple salts (made of a single anion and cation) For example, [EtNH3]+ [NO3]– is a simple salt. (ii) Binary ionic liquid (salts where equilibrium is involved). For example mixtures of aluminium (III) chloride and 1, 3-dialkylimidazolium chloride (a binary ionic liquid system). It contained several different ionic species, and their properties and melting point depend upon the mole fraction of aluminum (III) chloride and 1, 3-dialkylimidazolium chloride present.

Organic Synthesis using Ionic Liquids

4.3

4.3

PREPARATION OF IONIC LIQUIDS

Ionic liquids mainly comprise organic cations such as tetraalkylammonium17, tetraalkylphosphonium18, trialkylsulphonium19, N-alkylpyidinum20, 1, 3,-dialkylimidazolium21, N, N-dialkylpyrrolidinum22, N-alkylthiazolium23, N-alkyloxazolium24, N, N-dialkylpyrazolium25 and N, N-dialkytriazolium26 (Fig. 4.1).

Fig. 4.1 Different type of organic cations in ionic liquids

The common anions which result in neutral and stoichometric ionic liquids are: BF 4–, PF6–, SbF 6– , ZnCl 3–, CuCl 2– , SnCl 3– , N(CF3SO2)2– , N(C2F5SO2)2– , C(CF3SO2)3–, CF3CO2– , CF3SO3– and MeSO 3–. There is another class of polynuclear anions such as Al2Cl 7–, Al3Cl 10–, AuCl 7–, Fe2Cl 7– and – ; the latter type of polynuclear anions are air and water sensitive. Sb2F 11

4.4 Green Chemistry In order to be liquid at room temperature, the cation should preferably be unsymmetrical, e.g. R1 and R2 should be different alkyl groups in the dialkyimidazolium cation. The melting point is also influenced by the nature of the anion. The hydrophilicity/lipophilicity of ionic liquid can be modified by a suitable choice of anion, [bmin]BF4, (bmin – 1 butyl –3- methylimidiazolium) is completely miscible with water while the PF6 salt is largely immiscible with water. The lipophilicity of dialkylimidazolium salts or other ionic liquids can also be increased by increasing the length of the alkyl groups. Room temperature ionic liquids are prepared by direct quaterisation of the appropriate amines or phosphines27. The aliphatic quaternary ammonium cations are prepared from alkylammonium halides which are commercially available or they can be prepared simply by the reaction of the appropriate halogenoalkane and amine. The anions are oxidation resistant anions such as CIO –4 , BF–4 or PF 6–. The asymmetric amide anion (CF3SO2 – N – COCF3)– has an excellent ability to lower both melting point and viscosity of room temperature ionic liquids, combining with small aliphatic cations.

4.3.1 Typical Preparation Routes for Ionic Liquids The most commonly and widely used method for the preparation of ionic liquid in metatheses of a halide salt of the organic cation with a group 1 or ammonium salt containing the desired anion. Scheme 4.1 describes the routes for the preparation of some typical ionic liquid27. Recently some new categories of ionic liquids have been prepared. These include ionic liquid based or polyammonium halide salt (can be synthesis by replacing the halide ion with phosphate ion28. Other ionic liquids with dicyanamide anion29 and C2-symmrtrical imidazolium cations30 and even deplex DNA31 anions have also been prepared.

4.4

SELECTION OF A SUITABLE IONIC LIQUID FOR A PARTICULAR REACTION

Not all type of ionic liquids are suitable for all type of reaction. To give an example, imidazolium based ionic liquid should not be used with bases. This can be understood by the following reactions (Scheme 4.1). N RCl

N

+

NaBF4

–

N Cl

N

N

+

–

N

R

R KPF6

AlCl3

N

+

BF4

–

N AlCl4 R

Scheme 4.1

N

+

–

N

PF4 R

Organic Synthesis using Ionic Liquids

4.4.1

4.5

The Baylis–Hillman Reaction in Ionic Liquids

This reaction generally involves a tertiary amine catalysed coupling between the a-position of an activated alkene with an aldehyde (Scheme 4.2)32. Though a number of 3° amines have been used for the above reaction, the base of choice is diazabicyclo [2. 2. 2] octane (DABCO). OH 3° amine

+ R

X

X

O

R

H X = electron withdrawing group

Scheme 4.2

Though the Baylis–Hillman reaction is 100% atom economical, it suffers from slow reaction rates often requiring several days for completion. Attempts to accelerate the reaction by using ultrasound33, microwave irradiation34 and the use of Lewis acids34 were unsuccessful. It is believed that the Baylis-Hillman reaction proceeds via an addition-elimination mechanism; the formed zwitterionic species such as (A) attacks the aldehyde to give the product (Scheme 4.3).

Scheme 4.3

The Baylis–Hillman reaction between benzaldehyde and methyl acrylate in the ionic liquid [bmim] [PF6] was found to be 33 times faster than the reaction in CH3CN, although only moderate yield of the desired produced was obtained (Scheme 4.4)35. OH

O

OCH3

PhCHO + O

DABCO [bmim][PF6] 24 h

OCH3

Ph 65%

Scheme 4.4

It was, however, found36 that under basic reaction conditions, the aldehyde was being consumed in a side reaction with the imidazolium cation. This accounts for low yields and also demonstrated that ionic liquids are not always inert solvents37. It was shown that the acidic nature of the C(2) hydrogen of the imidazolium cation was responsible for the side reaction (Scheme 4.5).

4.6 Green Chemistry

Scheme 4.5

On the basis of the results obtained it was concluded35 that caution must be exercised when using ionic liquids from one reaction for another; in such a case mixture of products were obtained. In order to overcome the problem of low yields due to formation of side reaction product (because of the acidity of C(2) imidazolium cation), ionic liquids substituted at the 2-position were used38. It was found38 that the Baylis-Hillman reaction between a variety of aldehydes and methyl acrylate proceeded smoothly in the ionic liquid [bmmin][PF6], in contrast to results obtained with [bmin][PF6] (Scheme 4.6). OH OCH3 2 eq DABCO

RCHO +

IL 24 h, rt

O OCH3

R

O 2 eq

Scheme 4.6

4.4.2 The Knoevenagel Condensation The Knoevenagel condensation reaction of benzaldehyde with malonoitrile in presence of KOH dissolved in [bmim][PF6] gave39 only low yield of the styrene product (Scheme 4.7) O + Ph

H

NC

CN

KOH/CH3CH2OH [bmim][PF6] rt

CN Ph CN

Scheme 4.7

Organic Synthesis using Ionic Liquids

4.7

The low yield in the above Knoevenagel condensation was due to the solubility to the formed product (styrene derivative) in the ionic liquid. The yield improved as the substrate concentration was increased and also as the ionic liquid was reused. The ionic liquid could be reused up to five times without the need of additional base. Kneovenagel condensation can also be carried out by using chloroaluminate ionic liquids40, which have a variable Lewis acidity such as 1-butyl-3-methylimidazolium chloroaluminate [bmim] Cl. AlCl3, X(AlCl3) = 0.67, were X is the mole fraction and 1-butyl pyridinium chloroaluminate [bpy]Cl. AlCl3, X(AlCl3) = 0.67. Ionic liquids work as Lewis acid catalyst and solvent in the Kneovenagel condensation of substituted benzaldehydes with diethyl malonate to gives benzylidene malonate, which subsequently undergo Michael addition with diethyl malonate (Scheme 4.8). The extent of the Michael product vary with the Lewis acidity and the molar proportion of the ionic liquids.

Scheme 4.8

4.4.3 Claisen–Schmidt Condensation As in the case of Knoevenagel condensation (Scheme 4.7) low yields were also obtained in the Claisen–Schmidt condensation between acetophenone and benzaldehyde (Scheme 4.9). However, in this case, ethyl benzoate was obtained as a byproduct and the base was depleted after two cycles of reuse of the ionic liquid. O

O

O NaOH/CH3CH2OH

+ Ph

H

Ph

CH3

[bmim][PF6] 40°C

Ph

+ PhCOOCH2CH3 Ph

Scheme 4.9

In the reaction of the ionic liquid with the base in the absence of the substrates, the base was being consumed by reaction with imidiazolium cation. This reaction was more pronounced at elevated temperature and so it was less of a problem in catalytic Knoevenagel condensation, which was carried out at room temperature. It was also shown on the basis of controlled experiments, that the source of ethyl group was sodium ethoxide and not ethanol.

4.8 Green Chemistry On the basis of the results obtained it was concluded that imidazolium ionic liquid are suitable under basic condition, only in a few reactions and precaution must be taken when reactions are carried out using these ionic liquids in conjunction with bases especially at higher temperatures.

4.4.4 The Horner–Wadsworth–Emmons Reaction in Ionic Liquids The Horner-Wadsworth-Emmons reaction between aldehydes and phosphonoacetates in both [emim][BF4] and [emin][PF6] gave low yield of either of the products (Scheme 4.10)41. The low yields are due to incompatibility of imidazolium–based ionic liquids with the strongly basic reaction conditions.

RCHO + (EtO)2P(O)CHFCO2Et

R

F

H

CO2Et

K2CO3 or DBU

R

CO2Et

H

F

+

[emin][BF4] or [emin][PF6]

Scheme 4.10

The yield of the product increased considerably if the reaction be carried out in the ioic liquids 8-ethyl – 1, 8- diazabicyclo [5, 4, 0] –7-undecene trifluoromethane sulfonate (A) and 8- methyl –1, 8- diazabicyclo [5, 4, 0] –7-undecene trifluoromethane sulfonate (B) (Scheme 4.11). Et

Me

N

–

CF3SO3

+

N

–

CF3SO3

+

N

N

(A)

(B)

Scheme 4.11

In vew of the incompatibility of imidazolium based ionic liquid under basic conditions (partriularly at elevoteel temperature) attempts have been make to develop ionic liquids for use under such conditions. An imidazolinium based ionic liquid containing a phenyl group at the C (2) position [cation = [mPhmim] has been developed42.

Thus, the Baylis-Hillman reaction between methyl acrylate and a variety of aromatic aldehyles using DABCO or quinuclidinol as the base was successfully carried out in these ionic liquids.

Organic Synthesis using Ionic Liquids

4.9

Ionic liquid[mPh mim][Tf2N] was also shown to be a suitable solvent for Grignard reaction (Scheme 4.12). It was shown that the ionic liquid did not undergo any deprotonation under the reaction conditions.

Scheme 4.12

Another phosphonium-based ionic liquid such as tetradecyl (trihexyl) phosphorium chloride for use under strongly basic conditions43 is given below. R P R

X

+

–

1

R R

X = Br, Cl, Tf2N

The inertness of the above ionic liquid towards reaction with bases is primarily due to the difficulty in accessing the acidic hydrogen.

4.5

SYNTHETIC APPLICATIONS

4.5.1 Alkylation The alkylation of isobutene with 2-butene to give isooctane, which can be converted to a methoxyether for use as a fuel additive to increase octane number, is a commercially important reaction. Traitionally used catalysts for the reaction are HF or H2SO4 which are non green processes because of cooling and preparation problems, high operating costs and safety aspects. The use of ionic liquid [bmim] CI/AlCl3 give44 high alkylation quality and simple product separation. The alkylation of benzene with long chain alkenes or halogenated alkanes to produce liner alkylbenzenes is also of commercial importance. The traditional catalyst is HF or AlCI3(catalyst/ olefin mole ratio = 5/20). Acidic ionic liquids have been used as catalysts in a ratio as low as about 0.004 with very high conversion45. An efficient alkylation of the ambident nucleophiles, indole and 2-naphthol has been carried out with simple alkyl halides at room temperature in [bmin]PF6 using solid KOH to give exclusively N-alkyated and O-alkylated products respectively46. The alkylation of active methylene compounds is an important reaction for formation of C-C bonds. A room temperature ionic liquid, N-butylpyridinium tetrafluoroborate [bpy][BF4] has been used as recyclable solvent for the alkylation of Meldrum’s acid47 with various alkyl halides at

4.10 Green Chemistry 60-70°C in presence of triethylamine as base, exclusively dialkylated products are obtained (Scheme 4.13) O O

O + RCH2X

O

Et3N, [bpy][BF4]

O

60 – 70°C

O

O

CH2R CH2R O

Scheme 4.13

4.5.2 Allylation The palladium (O) catyzed allylation of methylene compound by 1, 3-diphenylallyl acetate in [bmin] BF4 proceeds smoothly with easy recycling of catalyst and solvent48. In ionic liquids, the stabilised intermediate may be generated in situ and is a “greener” alternative to conventional process where volatile organic solvents are frequently employed and catalyst reuse is difficult to implement.

4.5.3 Oxidations 4.5.3.1 Oxidation of alkyl groups A number of transition metal-catalysed oxidation reactions have been performed in lowmelting imidazolium and pyridinium ionic liquids. Thus ethyl benzene could be oxidised by bis (acetylacetonato) nickel immoblised in the ionic liquid [bmim][PF6] at atmospheric presure49. This catalyst system is an important alternative to the heterogeneous catalyst presently used.

4.5.3.2 Oxidation of aldehydes A number of aromatic aldehydes have been oxidised to the corresponding carboxylic acids using bis (acetyacetonato) nickel (II) immobilised in [bmim][BF6] and oxygen at atmospheric pressure (Scheme 4.14)50 R

CHO

Ni(acac)2,O2 [bmim][PF6]

R

COOH

Scheme 4.14

4.5.3.3 Oxidation of alcohols Oxidation of alcohols to the corresponding aldehydes and ketones is an important functional group transformation in organic synthesis. Thus benzyl alcohol could be oxidised selectively to benzaldehyde in dry ionic liquids using Pb(OAc)2 as a catalyst and O2 as oxidant51. Selective oxidation of a series of substituted benzyl alcohols was carried out in a room temp. ionic liquid, cyclic hexaalkyl guanidium cation (prepared as given in Scheme 4.15) with sodium hypochlorite as an oxidant52.

Organic Synthesis using Ionic Liquids Bu O N

Bu N

N

POCl3

N

N

MeI

+ N

N

4.11

Bu I

+

–

KPF6

N

N

PF6

–

N

[nBuNH2]

Scheme 4.15

The classical oxidation of alcohols promoted by tetra-N-propylammonium perruthenate has also been carried out in tetraethylammonium bromide or [bmim][BF4]53. In this case the ionic liquid was used to remove or extract excess MnO2 and other associated impurities from the oxidation of codeine methyl ether to thebaine (Scheme 4.16)54. MeO

MeO

MnO2

O

O

[bmim][BF4]

N

N

Me

Me

MeO

MeO

Codeine methyl ether

Thebaine

Scheme 4.16

The selective oxidation of primary and secondary benzlyic alcohol with KMnO4 in ionic give carbonyl compounds.

4.5.3.4 Oxidation of oximes A efficient and eco-friendly method for the chemoselective oxidative cleavage of oximes with H2O2 catalysed by phosphotungstic acid in ionic liquid at room temperature to generate the corresponding carbonyl compound in excellent yield has been developed (Scheme 4.17)13. R R¢

N — OH

H2O2[H3PW12O40/RT]

R

[bmim][Br] or [bmim][BF4]

R¢

O

Scheme 4.17

4.5.3.5 Oxidation of olefins Epoxidation Alkenes and allylic alcohols could be oxidised to the corresponding epoxides in high yield55, using a room temperature ionic liquid as the solvent, methyltrioxorhenium (MTO) as the catalyst and urea-

4.12 Green Chemistry hydrogen peroxide (UHP) as the oxidant, both of which were completely soluble in [bmim] [PF6] (giving a homogeneous solvent). Epoxidation of olefins with NaOCI using Jacobsen’s chiral Mn(III) salen immobilised in a [bmim][PF6] catalyst is an efficient and recyclable method for asymmetric epoxidation56 (Scheme 4.18). In ionic solvent, the reaction proceeds via the formation of high valent manganeseoxo active intermediate, which was otherwise undetecatable in organic solvent57.

Scheme 4.18

Room temperature based catalysed epoxidation of electrophilic alkenes with H2O2 in ionic liquids as solvent has been disussed subsequently. Asymmetric dihydroxylation of olefins Osmium catalysts have been used in asymmetric dihydroxylation reactions of olefins. The high cost and toxicity of, and contamination of the product with the osmium catalyst, however, restrict the use of the asymmetric dihyroxylation reaction in industry. This problem is now overcome by making use of ionic liquids. The reaction is carried out either in biphasic [bmim][PF6]/ water or monophasic [bmim] [PF6]/tert. butanol system. Both procedures were applied to substrates using the chiral ligands. This method allows the recycling and reuse of the osmium ligand catalyst. The use of the supercritical carbon dioxide extraction helped in minimising the osmium leaching from the room remperature ionic liquid phase13. Oxidative carbonylation of amines Oxidative carbonylation of amines to produce phenyl carbamate and diphenyl urea has normally been achieved by alkali metal containing selenium compounds as effective catalyst58. The main disadvantage in this reaction is the difficulty in separating the product and the catalyst from the reaction mixture. This problem was solved by preparing ionic liquids containing anionic selenium species; these were found to show a high activity59 for the carbonylation of aniline, at temperatures as low as 40°.

Organic Synthesis using Ionic Liquids

4.13

R O

N +

Se — OMe N

O

Me Selenium-anion based imidazolium ionic liquid

Wacker-type oxidation reactions Wacker-type oxidation reaction have been performed by PdCl2 immobilised in [bmim][BF4] and [bmim][PF6] using H2O2 as the oxidant (Scheme 4.19)60. O PdCl2|H2O2|60° [bmin][PF6]

Scheme 4.19

4.5.4 Hydrogenations Butene-1 on hydrogenation using ionic equids such as [bmim][BF4], [bmim][PF6] and [bmim] [SbF6] as solvent and using Wilkinson’s catalyst (Scheme 4.20)61 – 63 gave the reduced product. H2, [Rh(nbd)(PPh3)2] [bmin] [X] –

–

–

X = BF 4, PF 6, Sb F 6, nbd = norboranadeine

Scheme 4.20

The product obtained being not miscible with the ionic catalyst solution could be removed from the reaction mixture by simple decantation and the recovered ionic catalyst solvent was reused several times without any significant change in catalyst activity and selectivity. A stereoselective ruthenium-catalysed hydrogenation of sorbic acide to cis–3-hexanoic acid was carried out in [bmim][PF6]/MTBE (MTBE = methyl t-butyl ether) system (Scheme 4.21)64. COOH

H2, [Ru]-cat

COOH

[bmin][PF6]/MTBE

Sorbic acid

cis-3-hexanoic acid

Scheme 4.21

4.14 Green Chemistry Hydrogenation of ethy acetoactate with the ammonium salt of 4. 4¢- and 5, 5¢-Rudiam BINAP in ionic liquids based on 1, 3-dialkyl imidazolium, N-alkylpyidinium and tetralkyl phosphonium cations occurred with moderate ee’s (Scheme 4.22)65 O

O

OH

O

H2(40 bar) catalyst

OEt

OEt

IL

Scheme 4.22

The 1L allowed the catalyst to be recycled with an increased in ee with recycle number. Halonitrobenzenes on hydrogenation with 5% Pt/C, Pd/C or Raney nickel catalyst to the corresponding haloanilines could be achieved in [BF4] – and [PF6]– 1, 3-dialkylimidazolium based ionic liquids (Scheme 4.23)66. NO2

NH2

X

H2/catalyst

X

IL

Scheme 4.23

The reaction of aliphatic and aromatic aldehydes with trialkylborane generally requires reaction temperature in excers of approx 150°. Ionic liquids like [b mim] [BF4] and [e mim][PF6] can be used in trialkylborane reduction of aldehydes with enhanced rate at low temperature67. The organic products can be easily removed from the ionic liquid via extraction and the ionic liquid can be reused with no reduction in yield.

4.5.5

Carbon-carbon Bond Forming Reactions

Carbon-carbon bond formation is extremely important for synthetic organic chemist. Some of the carbon-carbon bond forming reactions like the Baylis–Hillman reaction (Section 4.4.1). Knoevenagel condensation (Section 4.4.2) and the Horner-Wadsworth-Emmons reaction (Section 4.4.4) have already been discussed. Following are some of the other important carbon-carbon bond forming reactions.

Heck reaction The carbon-carbon coupling of an aryl or alkenyl halide with an olefin is known as the Heak reaction (Scheme 4.24) H + RX

Pd(O) ligand

Scheme 4.24

R + HX

Organic Synthesis using Ionic Liquids

4.15

Interst in the Heck reaction is due to versatility of the reaction and the relatively mild reaction condition used. In fact, Heck reaction has received a great attention in organic synthesis and in the manufacture of fine chemicals,68, 69. It has been found that the Heck reaction with less reactive halides (bromides and chlorides) require the use of phosphine liquids to stabilise the active palladium species. A drawback of the Heck reaction is that the palladium catalyst cannot be recovered and reused. Use of ionic liquids provide a convenient medium for the Heck reaction and also allows recycling of the catalyst70. In the Heck reaction of iodobenzene with ethylacrylate in both N-hexylpyidinium, (C6py) and N, N-dialkylimidazolium based ionic liquid (Scheme 4.25), higher yields were obtained in the former ionic liquid then the corresponding reaction in the imidazolium salts. O

O

I +

Iodobenzene

OEt

Pd(OAc)2

OEt

ionic liquid Et3N

Ethyl acrylate

trans-ethyl cinnamate 99%

Scheme 4.25

The low yield in imidazolium ionic liquid is due to the formation of carbene which reacts with palladium to form a mixture of palladium carbene complex. The Heck reaction was also carried out by the reaction of aryl halides with acrylates as well as with styrene in presence of Pd (OAc)2 in the ionic liquids [bmin] [BF4] and [b mim][Br] (Scheme 4.26)71

Scheme 4.26

4.16 Green Chemistry Better conversion and selectivity was noted in reactions carried out in [b mim][Br]. However in both ionic liquids a homogeneous yellow solution was initially obtained, which was followed by slow precipitation of palladium black. The low yield in case of [bmim] [BF4] was due to the formation of carbene intermediate which complexes with palladium to give a mixture of palladium carbene complex. It was suggested71 that the active catalyst in the Heck reaction is a palladium nanoparticle generated in situ from palladium-carbene species. It has also been shown72 that solution of ammonium stabilised Pd clusters are useful catalyst for the Heck reaction. Thus, the Heck reaction between iodobenzene and n-butyl acrylate in the presence of [N8.8.8.8] [Br] stabilised 3nm Pd clusters to afford n-butyl cinnamate (Scheme 4.27).

Scheme 4.27

Friedel-craft reaction Friedel Craft alkylation and acylation are of great commercial importance. The conventional calayst in Friedel Craft reaction is AlCl3 which gives rise to disposal and byproduct problems. The use of ionic liquid [e mim] Cl-AlCl3 in place of solid AlCl3 enhances the reaction rates and selectivity73 – 79 and also it a solvent for the reaction. These reaction worked efficiently giving the slereoelectronically favoured products. In acetyation reaction of naphthalene, the major product was the thermodynamically, unfavoured 1- isomer. Friedel Craft alkylation of aromatic compounds with alkenes using Sc (OTf)3 – ionic liquid system giving the benefits of simple procedure, easy recovery and reuse of catalyst, contributing to the development of environmentally benign and waste free process80.

Diels-alder reaction The great usefulness of Diels-Alder reaction lies in its high yield and high stereospecificity. Use of ionic liquids such as [bmim][BF4], [bmin][ClO4], [emin][CF3SO3] and [emin][PF6] for Diels-Alder reaction between cyclopentadiene and methyl acrylate result in rate enhancement, high yields and strong endoseclectivities (Scheme 4.28)81,82.

Aldol condensation The self-condensation reaction of propanal to form 2-methylpent 2-enal has been carried out in non-coordinating imidazolium ionic liquid83. The reaction proceeded through an aldol intermediate and produced unsat’d aldehyde under the reaction condition (Scheme 4.29). In aldol condensation highest product selectivity was found for [bmim][PF6].

Organic Synthesis using Ionic Liquids

+

H

H

H

COOMe

4.17

Ionic liquid

cyclopentadiene

+ COOMe COOMe

Scheme 4.28

Scheme 4.29

The proline-catalysed asymmetric direct aldol reaction of different aromatic aldehydes with acetone and other ketones in the ionic liquid [bmim][PF6] gave good yield of the aldol product with reasonable enantioselectivies (Scheme 4.30)84.

Scheme 4.30

Wittig reaction The Wittig reaction is the most popular method for C = C bond formation with high stereo control. The ionic liquid [bmim][PF4] has been used as a solvent medium to carry out Wittig reaction using stabilised ylides allowing easier separation of the alkene from Ph3PO and also recycling of the solvent85. In the Wittig reaction using ionic liquid the E-steroselectivity was observed as in the case of organic solvents.

4.18 Green Chemistry Suzuki coupling reaction Palladium catalysted coupling between aryl halides or aryl trifaltes and aryl boronic acids is a convenient method to generate biaryls86 and is known as Suzuki coupling reaction. The Suzuki coupling using a Pd catalyst in an ionic liquid as the solvent has been reported87, 88 to give an excellent yield and turnover numbers at room temperature (Scheme 4.31).

Scheme 4.31

It was shown89 that 1, 3-bis-(2, 4, 6-trimethylphenyl) imidazol-2-ylidene (A) catalysed the coupling raction between 4-chlorotoluene and phenyl boronic acid in dioxane at 80°. Since imidazol2-ylidene carbenes are not very stable to air and moisture, the carbene ligand was generated in situ from the salt (A) using Cs2CO3 as the base (Scheme 4.32). The results suggested the involvement of N-heterocyclic carbene in Suzuki coupling.

Scheme 4.32

The Suzuki coupling reaction has also been carried out under mild conditions in an ionic liquid with methanol as a co solvent (necessary to solubilise the phenylboronic acid) using ultrasound90 Scheme 4.33. In the above reaction (Scheme 4.33) there was formation of inactive Pd black; this prevented the recycling of the catalyst. This problem was overcome by synthesing a Pd-biscarbene complex (B), which was used as a catalyst for the Suzuki coupling using only methanol under sonochemical conditions.

Organic Synthesis using Ionic Liquids

R

X

+

B(OH)2

Halobenzenes R = H, Cl, OCH3, CH3, NO2 X = Br, Cl, I

IL, 30°

))))

4.19

R

Phenyl boronic acid

Substituted biphenyls

2+

n-Bu

n-Bu

N

N –

2 BF4

Pd N n-Bu

N (B)

n-Bu

Scheme 4.33

Still coupling reaction The still coupling reaction is one of the most widely used in the preparation of a variety of materials including polyarenes and diaryl and aromatic carbonyl compounds91. As in the case of Suzuki coupling reaction, in case of Still coupling reaction also there is problem of the expense of the catalyst and the need for expensive and/or toxic ligands. It has been found92 that use of palladium complexes immobilized in ionic liquid offer great advantage over the classical organic solvent used for Stille coupling reactions. A large number of stille coupling reactions with Pd(0) or Pd(II)catalyst procursors associated with Ph3 As in the presence of CuI of has been developed in [b mim][BF4] (Scheme 4.33a)92.

Scheme 4.33a

Negishi cross coupling reaction The Negishi cross coupling reaction of organozinc reagents has been achieved in 1-butyl-2,3dimethylimidazolium tetrafluoroborate ([bmim][BF4]) ionic liquid using a novel phosphine (C) prepared by the reaction of PPh2Cl with [b mim][PF4] and is catalysed by palladium93.

4.20 Green Chemistry –

BF 6 N

N

Me

nBu PPh2 (C)

Better yields (70-92%) were obtained using different types of substrates; the fastest reaction was observed for aryl iodides. An additional advantage in Negishi cross coupling reaction is that ionic phase could be recycled thrice. However the yield of the product decreased in each cycle.

The Trost–Tsuji Coupling Reaction This coupling reaction involved nucleophilic allylic substitution and is catalysed by Pd(0) complexes and is a convenient method to form C-C-bonds in organic synthesis. This reaction has also been preformol in ionic liquid using Pd(OAc)2 – PPh3 / K2CO2 in [bmim] [BF4]94 and PdCl2 – TPPTS(TPPTS = triphenyl phosphine trisulphonate sodium salt) in [bmim][Cl]/cyclohexene95 respectively (Scheme 4.34). OCO2Et

+

COMe PdCl2|TPPTS CO2Et

[bmin][Cl]| MeCy

COMe CO2Et

Scheme 4.34

Sakuai reaction a, b-Unsaturated ketones undergo the Sakuai reaction with allytrimethylsilane in presence of InCl3 using, [C4mim] [PF6] or [C4 mim][BF4]as solvent (Scheme 4.35)96.

Scheme 4.35

Henry reaction Nitroalkanes having a-hydrogen atom undergo aldol type reaction with carbonyl compound to give b-hydroxy nitro compounds. This reaction known as Henry reaction97, can be accelerated in chloroalumimate ionic liquids98. The tetra methyl guanidine (trifluoroacetate and lactate) –based ionic liquids was reported as a recyclable catalyst for Henry reaction to produce 2-nitroalcohols (Scheme 4.36)99.

Organic Synthesis using Ionic Liquids O R1

+ NO2 R2

R3

O 2N

OH

R1

R2 R3

4.21

Scheme 4.36

Stetter reaction The reaction of aldehydes and olefins to give 1, 4-dicarbonyls is known as Stetter reaction. It is now possible to carry out the reaction in ionic liquid using Et3N as catalyst (Scheme 4.37)100.

Scheme 4.37

Sonogashira Reaction Copper and ligand free Sonogashira reaction catalysed by Pd(0) nanoparticles proceed under ultrasound irradiation in ionic liquid [bbmim][BF4] (Scheme 4.38)101

Scheme 4.38

4.6

TASK SPECIFIC IONIC LIQUIDS TSILs

An increasing number of ionic liquids are being designed with a specific activity in mind. These task-specific ionic liquids (TSILs) serve the dual role of catalyst and reaction medium. These are of

4.22 Green Chemistry two types, viz.. Brønsted-acidic ionic liquids and Brønsted-basic ionic liquids. Besides the above two types of TSILs, we come across another type which is Lewis acid ionic liquids such as [cation] [Cl–/AlCl3]

4.6.1 Brønsted Acidic Ionic Liquids An early example of a Brønsted acidic ionic liquid102 is ethyl ammonium nitrate. Subsequently acidic ionic liquids [I and II) containing an alkane sulfonic acid group covalently attached to the ionic liquid cation103 were designed.

The ionic liquid (I) is a viscous liquid at room temperature while (II) is a glass-like material which becomes liquid at about 80°. These task- specific Brønsted acids exhibited behaviour of typical ionic liquid. Neither of the compound (I or II) fumed or exhibited any observable vapour pressure. It has been shown that these ionic liquids (I or II) are not mere mixture of a strong acid with dissolved zwitterions. The TSIL(II) has been used to effect a number of transformations like esterification, ether formation and the pinacol-pinacolne rearrangement (Scheme 4.39).

Scheme 4.39

It should be noted that in contrast to the results using (II), although the conversion of 1-octanol to dioctyl ether with p-TsOH gave a better yield, but more byproducts formed. Typically, the pinacol-pinacolone rearrangement is carried out using H2SO4 or H3PO4 as catalyst. The advantage of using (II) as a catalyst for the pinacol rearrangement is that the product (Pinacolone) could be directly distilled from the reaction mixture.

Organic Synthesis using Ionic Liquids

4.23

Esterification of a variety of aliphatic acids with olefins using the ionic liquid (III) has been carried out104. R

SO3H N

+

N –

CF3SO 3 R = Me, Et, n-Bu, n-Hex (III)

Using 3equiv. of the olefin in the ionic liquid (III, R = hex) (Scheme 4.40) best results were obtained104.

Scheme 4.40

In the above reaction (Scheme 4.40), the ester product being insoluble in the ionic liquid was separated by decantation. The excess olefin was extracted from the ionic liquid using toluene and the ionic liquid was reused after drying under vacuum at 80°. A large number of Brønsted –acidic ionic liquids have been synthesised36. A number of substituted coumarins have been synthesised via the Pechmann condensation using a Brønsted-acidic ionic liquid as both catalyst and solvent (Scheme 4.41)105.

Scheme 4.41

4.24 Green Chemistry Caprolactam is prepared on the industrial scale by the Beckmann rearrangement of cyclohexanone oxime using corrosive oleum, which has to be neutralised using NH4OH; this procedure produces large amount of (NH4)2 SO4 as a byproduct. The Beckmann rearrangement of cyclohexanone oxime has been carried out in ionic liquid that served the role of a catalyst and also reaction medium106. The main problem in using acidic ionic liquid is that the caprolactam product (being basic in nature) combines with the ionic liquid making the product separation impossible. It is found106 that the use of caprolactam based ionic liquid coupled with a dynamic exchange between the caprolactam product and the ionic liquid permitted facile product isolation. Better yields were obtained when the product was isolated by chromatography. Another useful product 3, 4-dihyropyrimidine-2(1 H) ones could be synithesised by the reaction of aromatic or aliphatic aldehydes with ethyl acetoacetate and urea at room temperature in the Brønsted acid ionic liquid [Hbim][BF4] using sonication (Scheme 4.42)107. O O

O

O

X

H3C

OEt Ethyl acetoacetate

[Hbim] [BF4], )))

+

+ R

H

30°, 40-90 min

H 2N

Aldehyde

NH2

Urea deriv. X = 0, S

R

EtO H 3C

NH N H

X

3,4-Dihydropyrimidine -2(IH) ones

Scheme 4.42

The same Brønsted acidic ionic liquid [Hbim][BF4] has also been used107 for the synthesis of b-enaminones (Scheme 4.43).

Scheme 4.43

A number of alcohols have been tetrahydropyranylated using Brønsted-acidic ionic liquids (Scheme 4.44)108. Ionic liquid RT

ROH +

RO

O

Scheme 4.44

O

Organic Synthesis using Ionic Liquids

4.25

4.6.2 Brønsted-basic Ionic Liquids A typical example of Brønsted-basic ionic liquid is [bmim][OH]. It is used as a catalyst and reaction medium for Michael addition. This ionic liquid provides an efficient and convenient procedure for Michael addition of active methylene compound to conjugated alkenes in one step without requiring any other catalyst or an organic solvent109. Thus, different types of active methylene compounds underwent Michael addition with a number of a-b-unsaturated ketones, carboxylic esters and nitriles by this procedure to yield the corresponding adducts (IV) or (V) in good yield (Scheme 4.45)109.

Scheme 4.45

The same ionic liquid, [bmim] [OH] was used110 as catalyst as well as reaction medium for the Markovnikov addition of N-hetrocycles to vinyl ethers, yielding the product under mild conditions (Scheme 4.46).

Scheme 4.46

4.7

OTHER APPLICATION OF IONIC LIQUIDS

4.7.1 Conversion of Epoxides to Halohydrins Typically, the conversion of epoxides to halohydrins is carried out using HX or hypohalite water, which often results in the generation of byproducts. It is now possible to carry out the conversion with ionic liquids, such as (VI) (Scheme 4.47)111. Using the above method (Scheme 4.47), following epoxides could be converted into the corresponding halohydrins (Scheme 4.47a).

4.26 Green Chemistry OH O R¢

R

[AC min] X (1.5 eq) 60-65°

R¢

R X

X = Cl, Br, I [Acmin] X =

N

+

N

COOH – X

(VI)

Scheme 4.47 O

O

O

O

CO2Et

Cl ( )5

Ph

O

EtO2C

O CO2CH3

Scheme 4.47(a)

However, trans stilbene epoxide did not yield the corresponding halohydrim. In this case, the epoxide underwent a rearrangement to give deoxybenzoin (Scheme 4.48). O

O Ph

1L (VI) 60-65°

Ph Ph

Ph Trans stilbene epoxide

Deoxybenzoin

Scheme 4.48

4.7.2 Conversion of Oxiranes (Epoxides) into Thiiranes Oxiranes (epoxides) could be converted into thiiranes by reacting with potassium thiocyanate in [bmim] [PF6]-H2O (2 : 1) solvent system at room temperature to produce the corresponding thiiranes in good yields (Scheme 4.49)112.

Scheme 4.49

Organic Synthesis using Ionic Liquids

4.27

4.7.3 Thiocyanation of Alkyl Halides Alkyl halides on treatment with ionic liquid [bmim][SCN] could be converted into alkyl thiocyantes at room temperature (Scheme 4.50)113. In this case the ionic liquid acted as both solvent and reactant. The ionic liquid was regenerated by the reaction of [bmim] [X] with KSCN. O R1

O X + [bmin] [SCN] (1.2 equiv)

RT

SCN + [bmin] [X]

R1

or

or 2

R2X

R SCN yield 80-96% KSCN (1.5 equiv)

1

R = C6H5, 4-BrC6H4, 4-ClC6H4, 4Me C6H4, 2-thenyl 2

R = C6H5CH2, HOC2H4, HOOCC3H6, X = Cl, Br

Scheme 4.50

4.7.4 Synthesis of Cyclic Carbonates The reaction of epoxide with carbon dioxide in tetrahaloindate (III) based ionic liquids generated cyclic carbonates (Scheme 4.51)114. O O R

+ CO2

0.5 Mol% [cat][InX3Y]

O

O

120°, 100 psi, 1 hr

Cat = imidazolium, phosphonium, ammonium, pyridinium X = Cl, Br, I ; y = Cl, Br

R

Scheme 4.51

These thermally stable ionic liquids were synthesis by the microwave promoted reaction of indium chloride, In X3, with a variety of ionic liquids.

4.7.5

Biginelli Reaction

Ionic liquids like [bmim] [PF4] and [b mim] [PF6] have used as catalysts for the Biginelli reaction under solvent free conditions (Scheme 4.52)115

4.7.6

Synthesis of 3-Acetyl-5-[(z)-Arylmethylidene] 1, 3-Thiazolidine-2, 4-Diones

The title compounds exhibit various biological and pharmaceutical activities and also are an important class of synthetic intermediates in organic synthesis116,117. A one pot synthesis of the title compounds has been deseribed using ioinc liquids as the solvent (Scheme 4.53)118.

4.28 Green Chemistry

Scheme 4.52 O

O NH + RX

Ar CHO + S

Et3N

H

[bmin][PF6]

Ar

R

N S

O

O

Scheme 4.53

4.7.7 Synthesis of Symmetric Urea Derivatives N, N-disubstituted urea derivatives are important chemicals and are mainly manufactured by the reaction of phosgene on amines. An effective process for the direct synthesis and separation of symmetric urea derivatives in good yield from amines by using CO2 in ionic liquid has been developed119. In this synthesis, the recyclable catalytic system consisted of an ionic liquid [bmim] [BF4], [bmim] [PF6] and [bmim] [Cl] and base CsOH.

4.7.8 Synthesis of Homoallylic Amines Homoallylic amines are prepared from imines (which are derived in situ from aldehydes and amines) by nucleophilic addition with allylbutyl stannate in the ionic liquid [bmim] [BF4]. The products are obtained in high yields with high selectivity120. This method is particularly useful for acid sensitive aldehydes.

4.7.9 Conjugate Addition of Thiols to , -unsaturated Ketones The a, b-unsaturated ketones underwent addition with thiols in [bmim] [PF6] / H2O solvent system (2:1) to afford the corresponding Michael adducts in high yield and with excellent 1, 4-selectivity under mild and neutral conditions (Scheme 4.54)121 O

O

+ RSH

[bmin][PF6]/H2O (2:1) RT

( )n

( )n n = 1, 2

Scheme 4.54

SR

Organic Synthesis using Ionic Liquids

4.29

The use of ionic liquid in the above reaction helped to avoid the acid or base catayst for this conversion.

4.7.10 Nucleophilic Displacement Reactions Nucleophilic displacement reaction are often carried out using phase transfer catalyst (PTC) to facilitate the reaction between the organic reactants and the inoganic salts that provide the nucleophile. However, conventional PTC uses environmentally undesirable organic solvent like methylene chloride or o-dichlorobenzene. Ionic liquids because of their bulky organic cations are well suited for the type of reaction for which PTC is effective122. Thus, nucleophilic fluorination of 2-(3-methanesulphonyloxypropyl) naphthalene with metal fluorides (e.g. KF.) in ionic liquid [bmim] [BF4] gives the corresponding substitution product123, 124(Scheme 4.55). OMe

F

KF, 100° MeCN (5% H2O) [bmin][BF4]

Scheme 4.55

The above reaction in MeCN at 100° hardly gave any produce even after 24hr., where as the same reaction in [bmim] [BF4] was completed in 2 hr. The addition of water eliminated the formation of undesired alkene.

4.7.11 Bromination of Alkynes Arylalkynes on bromination with bromime in [bmim] [Br] gave the anti addition product, (Scheme 4.56) reaction following a second order rate law. However in [bmim] [PF6] mixture of syn and anti addition products were obtained and the reaction followed a second or third order rate law, depending on the structure of alkyne and the concentration of Br2125. R

R¢

Br2

R

Br

[bmin] [Br] or [bmin] [BF6]

Br

R¢

Scheme 4.56

4.7.12 Electrophilic Nitration of Aromatics Electrophilic nitration of aromatics is a fundamental reaction, whose products are key organic intermediates or energetic material. The major problem with the existing process is disposal and regeneration of the used acids. The use of ionic liquids based on [emim] and [bmim] cations126, is a useful alternative to calssical nitration route due to easier product isolation and the recovery of the ionic liquid solvent, and because it avoids problems associated with neutralisation of large quantities of strong acid.

4.30 Green Chemistry

4.7.13 Carbon-Oxygen Bond Formation The synthesis of diaryl ethers from aryl halides and phenols in presence of base, catalysed by CuCI immobilised in [bmim] [BF4] (Scheme 4.57) produces high yield13 of the diaryl ethers as compared to those obtained in conventional solvent as DMF. OH

X O R +

R¢

CuCl, base

R¢

[bmin] [BF4]

R

Scheme 4.57

4.7.14 Synthesis of 1-Acetylnaphthalene Acetylation of naphthaline in chloroaluminate ionic liquid gives 89% of 1-acetyl naphthalene (Scheme 4.58)127. O CH3COCl [emin]Cl-AlCl3(X = 0.67) 5 min, 0°

Naphthalene

1-Acetyl naphthalene (89%)

Scheme 4.58

4.7.15 Synthesis of Tonalid and Traseolide Tonalid (5-acetyl-1, 1, 2, 6-tetramethyl-3-isopropylindane) and Traseolide (6-acetyl-1, 1, 2, 4, 4, 7-hexamethyltetralin), both commercially important fragrance molecules have been synthesised by the acctylation of 1, 1, 2, 6-tetramethyl-3-isoproplindane and 1, 1, 2, 4, 4, 7-hexamethyl tetralin in the ionic liquid [emin]Cl–AlCl3(X = 0.76) (Scheme 4.59)127. The chloroaluminate (III) ionic liquids are powerful Lewis acids and are prepared128 by mixing the appropriate organic halide salt with aluminum (III) chloride, the two solids melt on mixing to form the ionic liquid. The synthesis needs inert atmosphere.

4.7.16 Selective Hydrogenation of Aromatic Compounds Polycyclic aromatic hydrocarbon are soluble in chloroaluminate (III) ionic liquids to form highly coloured paramagnetic solution129. The addition of a reducing agent like an electropositive metal and a proton source results in selective hydrogenation of aromatic compounds. Thus perylene and anthracene can be reduced to perhydroperylene and perhydroanthracene at room temperature; only the thermodynamically more stable isomer of the product is obtained130. The procedure contrasts with catalytic hydrogenation reaction which need high temperature and pressure and expensive

Organic Synthesis using Ionic Liquids

4.31

Scheme 4.59

platinum oxide catalyst and generally gives a mixture of products131. By monitoring carefully the reduction in the ionic liquids, a number intermediates can be isolated and the sequence of reaction in the reduction process can be determind (Scheme 4.60).

[emin] Cl-AlCl3 (X = 0.67) Zn|HCl(g)

Anthralene

H

H H Perhydroanthracene (90%)

Scheme 4.60

4.7.17 Alkylation of Indole and 2 Naphthol Indole and 2-napthol undergo alkylation on the nitrogen and oxygen atoms, respectively , on treatment with a haloalkane and base (usually NaOH or KOH) in [bmim] [PF6]132. The main advantage of using ionic liquid is that the products of the reaction can be extracted by an organic solvent such as toluene, leaving behind the ionic liquid. The byproduct of the reaction is sodium or potassium halide; this can be extracted with water and the ionic liquid can be used again.

4.7.18 Methylene Insertion Reactions Methylene insertion reactions can be carried out in ionic liquids such as [bmin] [PF6] or [bmin] [PF4]. Thus the reaction of naphthalene 2-aldehyde with sulfonium ylids (prepared by the reaction

4.32 Green Chemistry of alkyl halides with sulfides) gives the methylene insertion product (Scheme 4.61)128. The reaction works equally well with preformed sulfonium salts. Alternatively, dialkyl sulfides and methyl iodide can be used. O

O +

H

+

[I]

S

–

[bmin] [PF6] KOH

+ KI

Preformed or generated in situ

Scheme 4.61

By using a chiral sulfide such as 2R, 5S-tetrahydrothiophene, it is possible to carry out asymmetric methylene insertion reaction. In this case, the product (stilbene oxide) obtained can be extracted from the reaction mixture with solvent. The byproduct (potassium halide) can be extracted from the ionic liquid with water. The ionic liquid containing the chiral catalyst is dried and reused133 (Scheme 4.62). O

O H

Benzaldehyde

Br [bmin] [PF6] KOH

+

Benzyl bromide

Stilbene oxide S

Scheme 4.62

4.7.19 Cycloaddition of Carbon Dioxide to Propylene Oxide Catalysed by Ionic Liquids Cycloaddition of CO2 to propylene oxide to give five membered cyclic carbonate using ionic liquids based on [bmim]+ and [bpy]+. It is found133a that the ionic liquid [bmim] [BF4] is to best catalytic medium for the reaction. The resulting cyclic carbonate can be separated from the ionic liquid by simple distillation, and the ionic liquid catalyst can be reused.

4.7.20 Epoxidation of Electrophilic Alkenes in Ionic Liquids A efficient procedure for epoxidation of electrophilic alkens in ionic liquids, [bmim] [PF6], [Bmim] [PF4] as solvent by using aqueous solution of H2O2 in the presence of basic catalyst has been reported (Scheme 4.63)134.

Organic Synthesis using Ionic Liquids O

4.33

O + H2O + NaOH

Ionic liquid 250° 2-5 min

O

Scheme 4.63

Using the above procedure, following alkenes were converted into epoxodes,

O

O

O

O

O

O

4.7.21 Oxidation Benzylic Alcohols to Carbonyl Compounds with KMnO4 in Ionic Liquids The oxidation of benzyl alcohol with KMnO4 in 1-butyl -3-methylimidazolium tetrafluoroborate [bmim] [BF4] ionic liquid at room temperature gave benzaldehyde in 90% yield in 1 hr (Scheme 4.64)135. C6H5CH2OH

KMnO4 [bmin][BF4] 1 hr. R.T.

C6H5CHO 90%

Scheme 4.64

Following alcohols were oxidised CH2OH

R2 R1

R1 H OCH3 Cl NO2 CH3 OCH3

R2 H H H H H OCH3

4.34 Green Chemistry R3 R2 R1

N

R3 H H CH2OH

R2 H CH2OH H

R1 CH2OH H H

OH H 3C

OH

CH3

OH HO O

4.8

BIOTRANSFORMATIONS IN IONIC LIQUIDS

Most of the enzymes tolerate aquous ionic liquid mixtures as the reaction medium. In fact, there is hardly an ionic liquid that is not tolerated by an enzyme. The general impression is that the ionic liquids are tolerated to higher concentrations than water miscible molecular solvents. In ionic liquids activites of the enzymes are comparable or higher than those observed in conventional solvents. Also, enhanced thermal and operational stabilities have been observed. Regio and or enantioselectives have also been observed in many cases. The retention of the activity of enzymes in ionic liquids present a very promising green alternative to organic solvent for enzyme catalysed reactions. Following are given some of the important biotransformations in ionic liquid.

4.8.1 Synthesis of Z-Aspartame Z-Aspartame, a precursor to the artificial sweetener, aspartame, has been synthesised by the reaction of carbobezoxy-L-asparate and L-phenylalanine methyl ester. Z is a protecting group that is later removed. By using [bmim] [PF6] containing 5 per cent by volume of the water. The reaction is catalysed by thermolysin, a proteolytic enzyme (Scheme 4.65)136. The yield was 95 per cent which is similar to that reported for enzymatic aspartame synthesis in organic solvent with low water content. The enzyme, thermolysin exhibited excellent stability in the ionic liquid.

4.8.2 Conversion of 1, 3-Dicyanobenzene to 3-Cyanobenzamide and 3-Cyanobenzoic Acid The reaction of 1, 3-dicyanobenzene with nitrile hydratase from Rhodocococus 313 give 3-cyanobenzamide and 3-cyanobenzoic acid. The transformation137 was carried out in biphasic water-[bmim] [PF6] system. It is found that the enzyme is not active in [bmim] [PF6] and the ionic liquid serves only as a reservoir for the substrate. The Rhodococcus R312 remains in the aqueous phase, where the reaction takes place; the ionic liquid only dissolved concentrations of substrate above the aqueous solubility limit, which then partitions into the aqueous phase.

Organic Synthesis using Ionic Liquids

4.35

Scheme 4.65

4.8.3 Transesterification Reactions Transesterification could be carried out using candida antarctica lipase B(CaLB) either as free enzyme (SP525) or in an immobilised form (NOVOZYM 435) in ionic liquid [bmim] [BF4] or [bmim] [PF6] in the absence of added water138 (Scheme 4.66). 1

2

R CO2Et + R OH

Cal. B [bmin][PF6] or [bmin][BF4] 40°

1

2

R CO2R + EtOH

Scheme 4.66

Transesterification at N acetyl-L-phenyl alanine ethyl ester with 1-propanol in [bmim] [PF6] and 1-octyl-3-methylimidazolium hexafluorophosphate [Omim] [PF6 ] could be carried out using a-chymotrypsin-catalysed enzyme139 (Scheme 4.67). O

O Me

NH

a-Chymotypsin

Me

NH

OEt Ionic liquid, PrOH O

OPr O

Scheme 4.67

4.36 Green Chemistry In the above transesterification, the presence of certain amount at water was necessary. The transesterification activity of a-chymotypsin in [Omim] [PF6] increased by co-lyophilisation with polyethylene glycol (PEG). The transesterification of ethyl butanate with butan-1-ol in ionic liquid [bmim] [BF4] or [bmim] [PF6] gave good yield138 of butyl butanoate with supported CALB (Scheme 4.68). O

O OEt

CALB.(lipase) + nBuOH [bmin][PF6]

OBu

Scheme 4.68

The transesterification of 2-hydroxymethyl-1,4-benzodioxane using vinyl acetate (Scheme 4.69) is catalysed by lipases in [bmim] [PF6] and [bmim] ]BF4] ionic liquids140

Scheme 4.69

4.8.4 Ammoniolysis of Carboxylic Acids Ammoniolysion of carboxylic acid, e.g. Octanoic acid with ammonia in presence of NOVOZYM 435 at 40° in [bmim] [BF4] proceeded138 to completion in 4 days (Scheme 4.70). OH CALB + NH3 O

[Bmin][BF4] 40°, 4 days

NH2 O

Scheme 4.70

4.8.5 Synthesis of Epoxides Peroxycarboxylic acids are commonly used for the preparation of epoxides. However, increasing restritions with respect to their handling, transport and storage are prohibitive factors for its use as an industrial chemical. It has been shown141 that it is feasible to generate peroxy carboxylic acid by lipase-catalysted perhydrolysis of the corresponding carboxylic acids. It is now possible to perform this reaction in an ionic liquid138. Thus epoxidation of cyclohexene by peroctanoic acid, generated in situ by Novozym435 catalysed reaction of octanoic acid by commonly available 60 per cent aqueous H2O2 in [bmim] [BF4]. The product obtained is cyclohexane epoxide in 83 per cent yield in 24hr. (Scheme 4.71).

Organic Synthesis using Ionic Liquids

Ionic liquid

O

Cyclohexene

Epoxide O

O CH3(CH2)6COOH Peroctanoic acid

H 2O

4.37

CH3(CH2)6COH Octanoic acid

H 2O 2

Enzyme

Scheme 4.71

4.8.6 Synthesis of Geranyl Acetate Geranyl acetate, the natural fragrance is produced by the esterification of commonly available geraniol (3, 7-dimethyl-2, 6-octadien-1-ol). The esterification is done in presence of a lipase, immobilised CaLB (Novozym 435) in [BMIm] [PF6] (Scheme 4.72)142. CH3

CH3

O O

OH

CH3

CH3COOH CaL.B Ionic liquid

H3C

CH3

H 3C

Geraniol

CH3 Geranyl acetate

Scheme 4.72

4.8.7 Transesterification of Glucose and L-Ascorbic Acid The CaLB-catalysed esterfication of glucose with vinyl acetate in the ionic liquid [EMIm] [BF4] was completely selective. The synthesis of long chain fatty acid esters of carbohydrates is more demanding due to their potential useful and fully green nonionic surfactants. Though glucose did not react with vinyl laurate in pure ionic liquid but in biphasic tert-butyl alcohol-[BMIm] [PF6], glucose could be acetylated by the vinyl esters of C12 – C16 fatty acids. Best results were obtained with CaLB143. The esterification of glucose with palmitic acid has been effected in tert-butyl alcohol [BMIm] [PE6] medium144, the latter estrificatione is important in industrial context. L-Ascorbic acid could be esterified with palmitic acid in presence of cal B, in [BMIm] [BF4] and other similarly related ionic liquids (Scheme 4.73)145, 146.

4.38 Green Chemistry

Scheme 4.73

4.8.8 Enantioselective Hydrolysis of a Prochiral Malonic Ester The enantioselective hydrolysis of a prochiral malonic ester in presence of pig liver esterase (PLE) in presence of trace amount of ionic liquids gave the carboxlic acid. Addition of 10% of a cosolvent like isopropyl alcohol improved the yields (Scheme 4.74)147.

COOCH3 CH3

H2O PEL

COOCH3 OH COOH

COOCH3

Scheme 4.74

4.8.9

Enantroselective Esterification of Ibuprofen and 2-Substituted Propanoic Acids

The esterification of ibuprofen with propyl alcohol into the (S)-ester in the presence of CrL took place with modest enantioselectivity (E = 13) when the reaction was carried out in isooctane. However the enantroselectivity increased to 24 in [ BMIm] [PF6] (Scheme 4.75)148, 149.

Scheme 4.75

Organic Synthesis using Ionic Liquids

4.39

4.8.10 Enantioselective Aminolysis of Methyl Mandelate Enantioselective aminolysis of methyl mandelate with CaLB in conventional media will modest E ratios, which became near quantitative when 20% [BMIm] [BF4] was added to the medium150 (Scheme 4.76). OH

OH

H N

OCH3 n C4H9 NH2

O

Ca LB, 35° Ionic liquid

Methyl mandelate

C4H9 O

(R)

Scheme 4.76

It was found150 that changing the medium from tert-butyl alcohol to chloroform switched the enantiomeric preference of CaLB from ( R) into S. The above biotransformations have been catalysed with lipases and Estereses in ionic liquid medium. However, a number biotransformations can be catalysed by Proteases and Redox enzyme systems.

4.9

CONCLUSION

Since the properties and behaviour of ionic liquids can be adjusted to suit an individual reaction type, they can truly be described as designer solvents. There are a very large number of simple and complex ionic liquids which can be synthesised. However, selecting the best system for a particular process is a real problem and challenge. The ionic liquids have huge potential for the various pharmaceutical industries, since its use makes the process green. A large number of synthetic applications of ionic liquids have been described. Ionic liquids have obvious potential as reaction media for biotransformations of highly polar substances, such as (poly) saccharides, which cannot be performed in water due to equilibrium limitations. During the recent few years there has been an increasing number of reports concerning application of ionic liquids as solvent for different polymensation processes.

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Organic Synthesis using Ionic Liquids

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103. A. Cole, J.L. Jensen, I. Ntai, K.L.T. Tran, K.J. Weaver, D.C. Forbes and J.H. Davis, J. Am. Chem. Soc, 2002, 124, 5962. 104. Y. Gu, F. Shi and Y.J. Deng, J. Mol. Catal. A: Chem. 2004, 212, 71. 105. Y. Gu, J. Zhang, Z. Duan and Y. Deng. Adv. Syth. Catal. 2005, 347, 512. 106. S. Guo, Z. Du, S. Zhang, D. Li, Z. Li, and Y. Deng. Green Chem. 2006, 8, 296. 107. A.R. Gholap, N.S. Chakor , T. Daniel, R.J. Lahoti and K.V. Srinivasan, J. Mol. Catal, A: Chem. 2006, 245, 37. 108. Z. Duan, Y. Gu and Y. Deng. Synth. Commun. 2005, 35, 1939. 109. B.C. Ranu and S. Banerjee, Org. Lett, 2005, 7, 3049. 110. J.-M. Xu, K.-B. Liu, W.-B. Wu, C. Qian, Q. Wu and X-F Lin, J. Org. Chem, 2006, 71, 3991. 111. B.C. Ranu and S. Banerjee, J. Org. Chem., 2005, 70, 4517. 112. J.S. Yadav, B.V.S. Reddy, C.R. Reddy and K. Rajasekhar, J. Org. Chem, 2003, 68, 2525. 113. A. Kamal and G. Chouhan, Tetrahedron Lett, 2005, 46, 1489. 114. Y.J. Kim and R.S. Varma, J. Org. Chem, 2005, 70, 7882. 115. J. Penj and Y. Deng, Tetrahedron Lett, 2001, 42, 5917. 116. E.B. Grant, D. Guiadeen, E.Z. Baum and B.D. Foleno, Biorg. Med. Chem. Lett, 2000, 10, 2179. 117. R.G. Giles, N.J. Lewis, J.K. Quick, M.J. Sasse, M.W.J. Urquhart and L. Youssef, Tetrahedron, 2000, 56, 4531. 118. D.-H. Yang, Z.-C. Chen, S.-Y. Chen and Q.-G. Zheng, Synthesis, 2003, 12, 1891. 119. F. Shi, Y. Deng, T. SiMa, J. Peng, Y. Gu and B. Qiau, Angew. Chem.Int Ed. 2003, 42, 3257. 120. J.S. Yadav , B.V.S. Reddy and A.K. Raju, Synthesis, 2003, 6, 6883. 121. J.S. Yadav, B.V.S. Reddy and G. Baishya, J. Org. Chem, 2003, 68, 7098. 122. C. Wheeler, K.N. West, C.L. Liotta, C.A. Eckert, Chem. Commun. 2001, 887. 123. D.W. Kim, C.E. Soong and C.Y.J. Chi, Am. Chem. Soc, 2002, 124, 10278. 124. M.R.C. Gerstenberger and A. Hass, Angew. Chem. Int. Ed. 1981, 20, 647. 125. C. Chippl, V. Conte, Pioraccini. Eur. J. Org. Chem, 2002, 2831. 126. K.K. Laali and V.S. Gettwert, J. Org. Chem. 2001, 66, 55. 127. C.J. Adams, M.J. Earle, G. Roberts and K.R. Seddon, Chem. Commun 1998, 2097. 128. M.J. Earle and K.K. Seddon, Pure Appl. Chem. 2000, 72, 1391 and the references cited there in. 129. P. Tarakeshwar, J.Y. Lee and S. Kim, J. Phys. Chem. A 1998, 102, 2253. 130. C.J. Adams, M.J. Earle and K.R. Seddon, Chem. Commun, 1999, 1043. 131. D.K. Dalling and D.M. Grant, J. Am. Chem. Soc, 1974, 96, 1827. 132. M.J. Earle, P.B. McCormac and K. R. Seddon, Chem. Commun, 1998, 2245. 133. M.R. Bell, T.E. Dambra, V. Kumar, M.A. Eissenstat, J.L. Herrmann, J.R. Wetzel, D. Rosi, R.E. Philion, S.J. Daum. D.J. Hlasta, R.K. Kullnig, J.H. Ackerman, D.R. Haubrich, D.A. Luttinger, E.R. Baiziman, M.S. Miller and J. Ward, J. Med. Chem. 1991, 34, 1099.

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5 5.1

Organic Synthesis using Polyethylene Glycol and its Solutions

INTRODUCTION

In The development of non-hazardous solvents is one of the several goals of Green Chemistry1. There are many advantages of replacing volatile organic compounds (VOCs) with water or various types of aqueous solutions. The most obvious advantages are low cost, reduced flammability, reduced toxicity and the most important are reduced environmental risk due to discharge of the various by products. The most commonly used VOC solvent alternatives include, water, super critical fluids and ionic liquids. The low solubility of organic reactants and their intermediates is the main limitations to the widespread use of water as a reaction solvent. It has been found that polyethylene glycol (PEG) solutions are a better alternative2. It is believed2 that polyethylene glycol may prove to be a green reaction medium of the future.

5.2

CHARACTERISTICS OF PEG

Polyethylene glycol, PEG, HO – (CH2CH2O)n – H, is available in a variety of molecular weights (200 to tens of thousands). At ambient temperature PEG – water solution and hygroscopic polymer is a colourness viscous liquid of molecular weight < 600 and a waxy white solid of molecular weight > 8003. The numerical designation of PEG indicates the number of average molecular weight (e.g. PEG – 2000). Liquid PEG is miscible with water in all proportions and solid PEG is highly soluble in water. For example, PEG – 2000 is soluble to the extent of 60% in water at 20°. Lower molecular weight PEG can be used as solvents with or without the addition of water. PEG has a number of benign characteristics, which are useful in bioseparations 4. According to US FDA, PEG is recognised as safe and is approved for internal consumption 5, 6. PEG is very weakly immunogenic, a factor due to which it is used by the drug companies7-10. Aqueous solutions of PEG are biocompatible and are used in tissue culture media for the preservation 4 of organs.

5.2 Green Chemistry The low molecular weight PEGs (unlike VOCs) are non-volatile. The requirement of industry standard for selection of alternative solvents to VOC’s are met, since the vapour density for low molecular weight PEG is greater than 1 relative to air according to available MS DS data11. Another advantage of PEG is that it has low flammability and is biodegradable. Besides, PEG is stable to acid, base and high temperature12 -15. Also PEG is not effected by O2, H2O2, high oxidation systems 16 and NaBH4 reduction system17, 18. However, partial oxidation of PEG terminal – CH2OH group to COOH may occur in such systems as H2O2 – Na2WO413. PEG can also be recovered from aqueous solution by extraction with a suitable solvent or by distillation of water or solvent19. Due to this PEG can be recovered and recycled.

5.3

USE OF PEG IN ORGANIC REACTIONS

PEG has been successfully used in a number of organic reactions. Following are given some of such reactions.

5.3.1 Substitution Reactions Following are given some examples of substitution reactions performed using liquid PEG as the solvent. (i) The reaction of alkyl halides of the type RCH2Br with nucleophiles like CH3COO –, I – and CN – in PEG 400 give20 the corresponding substituted products (Scheme 5.1).

Scheme 5.1

(ii) Potassium thioacetate in PEG – 400 has been used as a nucleophilic reagant to substitute alkyl halides of the type R1– CHXR2 to give 21 the products in 92-98% yield (Scheme 5.2). R1

CHX

R2

–

+ CH3COS

PEG-400

R1

CH

R2

SCOCH3

R1 = C6H5, C7H15, C9H10 R2 = H, CH3 X = Cl, Br, I

Scheme 5.2

(iii) The reaction of tert.butyl chloride with H2O in PEG-300 gives 22 tert.butyl alcohol (Scheme 5.3).

Organic Synthesis using Polyethylene Glycol and its Solutions

(CH3)3 CCl + H2O

PEG-300

5.3

(CH3)3 COH

Scheme 5.3

(iv) The reaction of 1-chloro-2-methylpropene with H2O in PEG-425 gave 23 a mixture of alcohols (Scheme 5.4).

Scheme 5.4

(v) The Diel-Alder reaction of 2, 3-dimethyl – 1, 3-butadiene with acrolein gave 22 the adduct in good yield (Scheme 5.5). CH2 CH3

C

+ CH2

CH3

C

CH

PEG 300

CHO

H3C H3C

CHO

CH2 2,3-Dimethyl 1,3-butadiene

Adduct

Acrolein

Scheme 5.5

In the above reaction, the yield was 14 fold in comparison to the reaction carried out in methanol. However, The Diel-Alder reaction of 2, 3-dimethy-1, 3-butadiene with nitroso-benzene in PEG-300 showed a 3.3 fold increase compared to the same reaction in dichloro-methane. (vi) The diazotisation of aryl amines followed by Sandmeyer reaction gave halogeno arenes and cyanoarenes. The reaction could be carried out even in 10 mM dilute substrate and is comparable with these reactions in various organic solvents (e.g. Xylene, DMSO and THF) giving high yields only in high concentrations of the substrate (≥ 73 mm)24. The usual aqueous Sandmeyer reaction reported in organic synthesis gave very poor yields 24 (Scheme 5.6).

Scheme 5.6

5.4 Green Chemistry (vii) Heck coupling reaction could be performed using molten liquid PEG – 2000 at 80°. The yield of the product was good 25; the reaction rate, yield and regio and stereo selectivies in this solvent system are comparable with the conventional organic solvents like DMF, DMSO, CH3CN or ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate. In this case, the recyclability of both PEG-2000 and Pd(OAc)2 could be achieved by ether extraction of the product. The higher yield can also be obtained after four subsequent experiments (Scheme 5.7).

Scheme 5.7

The Heck coupling reaction form the subject matter of a subsequent section (see Section 5.8)

5.3.2 Oxidation Reactions Some of the oxidation reactions conducted in PEG-200 and PEG-400 are given below: (i) Oxidation of Benzyl Bromide. K2Cr2O7 is soluble in PEG-400 and can oxidise benzyl bromide to benzaldehyde in good yield 19 (Scheme 5.8).

Scheme 5.8

The above oxidation is similar to the reaction of Na2Cr2O7 in hexamethyl phosphoramide (HMPA) and Crown ether using the same substrate. (ii) Dihydroxylation of olefins. Using PEG-400 as solvent and osmium tetraoxide as catalyst 26 gives high yield of diols (Scheme 5.9).

Scheme 5.9

In the above reaction, the PEG-400 and OsO4 could be recused by extraction of the product diols using ether. More than 90% yield was obtained even after five cycles. Also, the reaction was suitable for asymmetric dihydroxylation (Sharpless reaction) with high yields and good enantioselectivity. This oxidation procedures forms the subject matter of a subsequent section.

Organic Synthesis using Polyethylene Glycol and its Solutions

5.5

5.3.3 Reduction Reactions (i) In PEG-400, carbonyl compounds could be reduced by NaBH4 more conveniently and efficiently than by the slow reaction in THF 19 (Scheme 5.10). CH3COC6H13 + NaBH4

PEG-400

CH3CHOH C6H13

Scheme 5.10

(ii) The reduction of alkyl and aryl esters to the corresponding alcohol by NaBH4 in PEG-400 was enhanced. These alkyl and aryl esters are considered inert towards reduction in other organic solvents 27 (Scheme 5.11). R COOR¢ + NaBH4 R = alkyl, aryl R¢ = CH3, C2H5

PEG-400

R

CH2OH

Scheme 5.11

(iii) The reduction of halides of the type R-CHX-R¢ by NaBH4 in PEG-400 is comparable 28 to that in other polar protic solvents like DMSO, HMPA and DMF (Scheme 5.12). R

CHX

R¢

+ NaBH4

PEG-400

R

CH2

R¢

R=alkyl, aryl X=Cl, Br, I R¢ =H, CH3, C4H9

Scheme 5.12

(iv) The reduction of acyl chloride can be conveniently effected in PEG-400 as a substitute for inert solvent dioxane28 (Scheme 5.13). R

COCl

+ NaBH4

PEG-400

R

COH

R = C6H5, p-BrC6H4

Scheme 5.13

(v) The partial reduction of triple bonds in alkynes to cis-olefins has been achieved 29 by Lindlar’s catalyst, Pd-CaCO3 poisoned with PbO in presence of PEG-400. The PEG and the catalyst could be used a number of times (3-5) without loss of activity or yield. (vi) Hydrogenation of styrene is possible 30 using waxy solid PEG-900 at 155 bar pressure in SC – CO2 at 40°. The RhCl (PPh3) – catalysed hydrogenation of styrene to ethyl benzene in PEG – 900 at 155 bar, 55° in SC – CO2 was conducted as a homogeneous catalyst reaction.

5.6 Green Chemistry Ethyl benzene could be extracted into SC – CO2 and the catalyst containing PEG phase was reused 30 (Scheme 5.14). C6H5CH = CH2 + H2

PEG-900

C6H5CH2CH3

RhCl(PPh)3

Styrene

Ethyl benzene

Scheme 5.14

5.4

PEG AS PHASE TRANSFER CATALYST PTC

It is well known that PTCs are used to transport an aqueous reagent into an organic phase in an activated state, so that the reaction can proceed due to bringing the aqueous reagent and the organic substrate together 15. PEG has the ability to serve as a PTC because the polyethylene oxide chain can form complexes with metal cations similar to Crown ethers31. In order to maintain electroneutrality, such PEG – metal cation complexes must bring an equivalent anion into the organic phase. In this way, the anion is made available for reaction with organic substrates. A number of factors affect phase catalytic activity. These include PEG molecular weight, chain end effects and the nature of the associated cations and anions. PEGs are used as PTCs in a number of commercial processes to replace expensive and environmentally-harmful PTCs31-35. Of the commonly used PTCs, lintar PEGs are much cheaper than analogous macrocyclic Crown ethers and Cryptands36. PEGs are also comparatively more stable at high temperature upto 150-200° and show higher stability to acidic and basic conditions than quaternary onium salts 15. Following are given some of the examples in which PEGs have been used as Phase Transfer Catalysts.

5.4.1

Williamson Ether Synthesis

Williamson Ether synthesis is an important nucleophilic substitution reaction (SN2) and involves the synthesis of ether using alkyl halides and an alkoxide in an alcoholic solution (Scheme 5.15). R

OH + R¢X

PEG

R

O

R¢

Scheme 5.15

The yield of decan-1-ol during etherification in using PEG-2000 as PTC is 84%, which is comparable to that found by using 18-Crown-6 and higher than 72% yield found using kryptofix 222 (cryptand)37 - 39 (Scheme 5.16). C10H21OH + C4H9X

PEG - 300–2000

X = Cl, Br, I

Scheme 5.16

C10H21

O

C4H9

Organic Synthesis using Polyethylene Glycol and its Solutions

5.7

The crown ethers and cryptand are expensive and may constitute toxins or irritants 37.

5.4.2 Substitution Reactions using PEGs as PTC PEGs have been used as PTC in nucleophilic substitution reactions. The common anionic nucleophilic reagents which have been used are hydroxides, halides, sulfides, cyanides, cyanamides, carboxylates, etc. Thus, the synthesis of 1, 4-phenylenedioxydiacetic acids and aryl 1,4-phenylenedioxydiacetate has been achieved40 by using PEG-400 as PTC in good yields under mild conditions (Scheme 5.17).

Scheme 5.17

PEG as PTC has been employed in a SC – CO2 solvent to convert benzyl chloride with potassium cyanide to form phenylacetonitrile, although the yield is lower than a similar reaction using tetraheptylammonium cyanide. However, use of PEG as PTC is a beginning of a low cost, green reaction process 41 (Scheme 5.18). C6H5CH2Cl + KCN

PEG/SC-CO2

Benzyl chloride

C6H5CH2CN Phenyl acetonitrile

Scheme 5.18

Use of potassium sulphocyanide in the above reaction gives the corresponding sulphocyanide (Scheme 5.19).

5.8 Green Chemistry C6H5CH2Cl + KSCN

PEG/SC-CO2

C6H5

CH2SCN

Scheme 5.19

The reaction of mono and di-halobenzenes with alkoxide ions give 42 monoalkybenzenes (Scheme 5.20).

Scheme 5.20

In the above reaction, it is found that the yield of the product increased with primary, secondary and tertiary alkoxide ion and high molecular weight PEG was more effective than low molecular weight PEG . The synthesis of o-chlorobenzoylthiocyanate from 2-chlorobenzoyl chloride and ammonium thiocyanate using PEG-400 as PTC has been achieved (Scheme 5.21).

Scheme 5.21

The above synthesis is more effective than most quaternary ammonium salts and Crown ethers42a. n-Alkylations of different types of amines by alkyl halides using PEG-350 methyl ether has been effected (Scheme 5.22). R

NH2 + R¢I

PEG-350 methyl ether

R

NH

R¢

Scheme 5.22

The above N-alkylation is enhanced in presence of ultrasound 43. In all these reactions the cost of PEG is an important factor44.

Organic Synthesis using Polyethylene Glycol and its Solutions

5.9

5.4.3 Oxidation Reactions using PEG as PTC PEG has been used with success in many oxidation reactions. Thus benzylalcohol on oxidation with potassium hypochloride in PEG-6000 and ethyl acetate yields45 benzaldehyde (Scheme 5.23). PEG-6000/CH3COOC2H5

C6H5CH2OH + KOCl Benzyl alcohol

C6H5CHO Benzaldehyde

Scheme 5.23

The cobalt catalysed carbonylation of benzyl halides using PEG-400 proved to be much cheaper than that using quaternary ammonium salts or Crown ethers 46 (Scheme 5.24). R

C6H4 X = Cl or Br

CH2X

Air/Co2(CO)8 PEG-400 2–CH3 C4H9OH

R

C6H4

CHO

Scheme 5.24

Ultrasound assisted base catalysed oxidation of alkylnitrobenzene using PEG as PTC gave47 p-nitro benzoic acid (Scheme 5.25).

O2N

CH3

PEG-400|C6H5CH3|KOH

O2

p-Nitrotoluene

O2N

COOH

p-Nitrobenzoic acid

Scheme 5.25

Iodoarenes and Iodoalkanes on oxidation with oxygen in PEG-400 and inexpensive CoCl2 in KCN – BF3 ◊Et2O – FeCl2 gave 48 carboxylic acids. The reaction conditions in the above oxidation are milder compared to the use of a platinum catalyst48 (Scheme 5.26).

Scheme 5.26

Oxidation of diphenyl methane with oxygen and PEG-6000 gave 49 benzophenone.

5.4.4 Reductions using PEG as PTC The reduction of ketones and aldehydes can be effected17, 18,50 with PEG and NaBH4 and PEGNaBH4 complexes (Scheme 5.27).

5.10 Green Chemistry R COR¢

+ NaBH4

PEG-400/C6H6

R CH (OH) R¢

R = C6H5, C6H5CH2 R¢= CH3, C6H5

Scheme 5.27

It is found that free PEG can catalyse 50 reduction of ketones by NaBH4. However, PEG – NaBH4 derivative can selectively reduce aldehydes in the presence of ketones without concurrent reduction of ketone group17. PEG-6000 in benzene is found to be more effective than using Crown ether or quaternary ammonium salts for base catalysed autoxidation of picoline 17. The conversion of aldehydes to homologous acids by a simple two step process using PEG is considered more practical than the usual conversion of p-anisaldehyde to p-methoxyphenylacetic acid 51 (Scheme 5.28). CH3O

CHO

Air/Pd PEG-400/NaOH

CH3O

CH2COOH

p-Methoxy phenylacetic acid

Anisaldehyde

Scheme 5.28

5.5

L PROLINE CATALYSED ASYMMETRIC ALDOL REACTIONS

Aldol condensation is known to be very effective in C-C bond forming process and is used widely in organic synthesis. Usually aldehydes containing a-hydrogen atom undergo aldol condensation to give b-hydroxy aldehydes called aldol (Scheme 5.29).

Scheme 5.29

Aldol condensation is also known to take place between an aldehyde and a ketone. In this reaction called crossed aldol condensation or Claisen–Schmidt reaction, the formed aldol undergoes elimination of water to give the product (Scheme 5.30).

Scheme 5.30

Organic Synthesis using Polyethylene Glycol and its Solutions

5.11

Asymmetric version of aldol condensation52 - 58 has been utilised for enantioselective C-bond forming. This is the prime objective in organic synthesis. Such reactions have also been attempted using a recyclable ionic liquid as solvent59, buffered aqueous media or aqueous micelles61. L-Proline catalysed direct asymmetric aldol reaction of acetone with various aromatic and aliphatic aldehydes in PEG-400 has been reported 62 to give asymmetric aldol products (Scheme 5.31). OH

O H

R

O

L-Proline (10 mole%) acetone (4 eq.) PEG, 30 min

R Aldol product (asymmetric) yield 80-90% ee 60-70%

Aldehydes R = H; 2-NO2, 3-NO2, 4-NO2, 4-Br, 2Cl, 5-NO2

Scheme 5.31

The aliphatic aldehydes, isobutyraldehyde and cyclohexane carboxaldehyde have also been used as substractes 62 and asymmetric aldol products obtained in 90 and 65% yield respectively. Also high enantioselectivity (about 84%) was obtained for the reaction of isobutyraldehyde with acetone (Scheme 5.32). OH

O

CHO Proline, acetone PEG 120 min

Isobutyraldehyde

Aldol product 90% yield (84% ee) OH

O

CHO L Proline, acetone PEG, 180 min

Aldol product 60% yield

Cyclohexane carboxaldehyde

Scheme 5.32

The above asymmetric aldol reactions are green reactions 62, since PEG (a biologically compatible product) is used as a solvent, which is much cheaper ($ 43/kg) compared io ionic liquids ($ 1200-2400/kg) and L-proline is required in small concentration. Besides the catalyst, solvent can be recycled for about ten runs without losing any of the characteristics.

5.12 Green Chemistry

5.6

L PROLINE CATALYSED ASYMMETRIC TRANSFER ALDOL REACTION

Transfer aldol reaction involves the reaction of aldehydes with diacetone alcohol (as a source of ketone, acetone) in presence of alkoxides. In these reactions Aldol-Tischeno reaction in competitive to get mono protected 1, 3-diols and in a few cases normal products were observed 63. It has now been possible to use62 L-Proline as catalyst for asymmetric transfer aldol reaction. Thus, the reaction of 4-nitrobenzaldehyde and diacetone alcohol in the presence of L-Proline (30 mole %) in DMSO afforded the corresponding b-hydroxy ketone in 86% yield and 71% ee. No difference in yield was observed even after increasing the concentration of catalyst to 100 mole %. Using PEG – 400 as the solvent only lowered the yield and ee compared to the standard solvent (DMSO) (Scheme 5.33). The reaction conditions were mild enough to avoid the formation of Tischeno-Addol product (A). O C

OH H

O2N

L-Prolene (30 mol%) Diacetone alcohol (2 eq) DMSO, r.t

O

O2N Aldol product

4-Nitrobenzaldehyde

O HO

O NO2

NO2 (A) (Aldol-Tischeno product)

Scheme 5.33

In a similar way various other aldehydes such as 3-nitrobenzaldehyde, 4-bromobenzaldehyde, 2-chloro-5-nitrobenzaldehyde and 2-chlorobenzaldehyde on subjecting to this transformation gave the corresponding aldol products up to 88% yield and ee’s up to 71%. Transfer aldol reaction between simple benzaldehyde and diacetone alcohol gave the corresponding b-keto ester in 50% yield and 57% ee. In the case of anisaldehyde, the aldol product was obtained only after 5 days at room temperature with 48% ee and 40% yield along with the dehydrated aldol condensation product. Amongst aliphatic aldehydes, isobutyraldehyde gave aldol product in 80% yield and 84% ee and cyclohexane carboxaldehyde gave the aldol product in 90% yield with 86% ee. A plausiable reaction mechanism involving a cyclic transition state (re-facial attack of aldehyde to proline derivative) where a retro aldol and aldol reactions are initated by the same catalyst has been proposed 62.

Organic Synthesis using Polyethylene Glycol and its Solutions

5.7

5.13

ASYMMETRIC DIHYDROXYLATION OF OLEFINS

Conventionally vicinal diols are prepared 64 by the dihydroxylation of olefins using catalytic amount at OsO4. Even though the vicinal diols are used in pharmaceuticals and fine chemicals65, the cost, toxicity 66 and contamination of the product with osmium restricts its use in industry. Asymmetric dihydroxylation of olefins has been carried out26 using catalytic amount of osmium tetraoxide and PEG-400. The ligand is efficiently recovered and recycled with good enantioselectivity. Thus, dihydroxylation of styrene and a-methyl styrene using OsO4 (0.5 mol %) in PEG (400 MW) using N-methyl morpholine (NMO, 1.3 eq.) as the reoxidant give 94% and 97% respectively of the diols (Scheme 5.34). R

R

OH OH

OsO4 (0.5 mol%) PEG (400 MW), 2 hr NMO (1.3 eq)

Styrene R = H a-Methylstyrene R = Me

Diol Diol

R=H 94% R = CH3 97%

Scheme 5. 34

Other olefins, for example, trans-stilbene produced 1, 2-diphenyl-1, 2-ethane diol in 95% yield. Electron deficient olefins, viz., trans-ethylcinnamate and ethyl 4-methoxy cinnamate produced diols in 93 and 92% yield respectively (Scheme 5.35). OH OsO4 (0.5 mol%)

OH

PEG 400, 2 hr NMO (1.3 eq)

trans stilbene

1,2-Diphenyl-1,2-ethane diol (95%) OH

O OEt

OsO4 (0.5 mol%)

OEt OH

PEG 400, 2 hr NMO (1.3 eq)

R Trans ethyl cinnamate

O

R R= H

92-93%

4-Methoxy trans ethylcinnamate R = OMe Scheme 5.35

Some other olefins which produced diols on oxidation with OsO4/PEG/NMO are given below (Scheme 5.36).

5.14 Green Chemistry OH OH

OsO4|PEG|NMO 3 hr

OH OsO4|PEG|NMO 3 hr

OH Cyclohexene OsO4|PEG|NMO 3 hr

OH OH

Scheme 5.36

In all the above cases, the catalyst and PEG were recovered and recycled. The asymmetric dihydroxylation of olefins according to the Sharpless procedure took longer time (up to 24 hr).

5.8

REGIOSELECTIVE HECK REACTION

PEG having molecular weight 2000 (or lower) has been used 25 as an efficient reaction medium for Pd – catalysed C – C bond formations, namely the Heck reaction67,68. This transformation 25 is more rapid and high yielding; the catalyst is easily recycled with high efficiency. The stereo – and regioselectives are also different from those with conventional solvents and ionic liquids69. Thus, the reaction of bromobenzene with ethyl acrylate (both substrates 1 : 1), Pd(OAc)2 (3 mol %) and TEA (1 equiv) in PEG 2000 at 80° for 8 hr gave the clean formation of ethyl cinnamate in 90% yield and 90% purity. However, the reaction of bromobenzene with styrene gave exclusively trans stilbene in 93% yield. Interesting results were obtained by the reaction of bromobenzene with n – butylvinyl ether; in this case there is clean formation of butyl styryl ether with exclusive attack of aryl palladium species at the b-carbon of butyl vinyl ether (Scheme 5.37). The results obtained are different than when the reaction was performed in ionic liquids 69. However, when the reaction was performed in conventional solvents (DMF, DMSO, CH3CN) mixture of products were obtained in varying ratios70. Thus, PEG is unique is obtaining a single regioisomer with good diastereoselection (80/20 E/Z). The Heck reaction of 4-bromoanisole with all the three olefins, vig. ethyl acrylate, styrene and n-butyl vinyl ether gave excellent regio and stereoselectivies of 4-methoxy ethyl cinnamate (E : Z 91), 4-methoxy stilbene (E:Z 85) and 1-(2-butoxy-(E)-1-ethenyl-4-methoxybenzene (butyl p-bromostyryl ether) (E:Z/70:30) respectively. The Heck reaction of 4-chlorobromobenzene with butyl vinyl ether, there is exclusive formation of E-geometrical olefin. On the basis of the results obtained it was concluded25 that electronic factors in the aryl system control the geometry of the olefins to a certain extent; the other olefines, viz., styrene and ethyl acrylate behaved normally.

Organic Synthesis using Polyethylene Glycol and its Solutions

5.15

CO2Et CO2Et

+

ethyl acrylate

(E)

CO2Et (Z)

Ethyl cinnamate

Br

E : Z = 90

Ph Pd(OAc)2 (3 mol%) TEA(1 equiv) PEG 2000|80°|8 hr

Ph Styrene

+ (E) Stilbene

Ph (Z) E : Z = 93

OBu OBu

+

n-Butyl vinyl ether

(E)

OBu (Z) E : Z (80 : 20)

1-(2-Butoxy-(E)-1-ethenyl) benzene (Butyl styryl ether)

Scheme 5.37

The Heck reaction of 3, 4-methylenedioxy bromo benzene with butyl vinyl ether yielded a single regioisomer (b-attack) with 75% diastereoselectivity of the E isomer. In all the cases cited above, no additional PTC was added as was required in earlier reports71. In fact PEG besides being an efficient solvent medium, also acted as a PTC for smooth C-C bond formation.

5.9

BAYLIS HILLMAN REACTION

Baylis–Hillman reaction 72 involves the reaction of an aldehyde and electron deficient olefins resulting in a new C-C bond formation. The products obtained are used as synthons for other synthesis73. The main drawback is low yields of the products, requirement of high concentration of catalyst and long reaction times (sometimes up to a week for less than 50% conversion). It is found that the reaction is also inert to enones, a, b-substituted aldehydes and hindered aldehydes. PEG-400 has been used74 as a rapid and recyclable reaction medium for the Baylis-Hillman reaction [using the conventional basic catalyst DABCO (20 mole %)] between unreactive aldehydes and activated olefins. Thus, the reaction of benzaldehyde with ethyl acrylate and DABCO (20 mol %) in PEG 400 at room temperature for 2 hr gave the Baylis-Hillmann product in 92% yield. Similar reaction of benzaldehyde with acrylonitrile or methyl vinyl ketone and DABCO in PEG gave similar products (Scheme 5.38).

5.16 Green Chemistry

Scheme 5.38

The above procedure represents an improvement on earlier methods with respect to reaction time, concn., catalyst and yields. 4-Nitrobenzaldehyde reacted with ethyl acrylate and acetonitrile giving the expected product in 90% and 93% respectively after 2 hr. 4-Fluorobenzaldehyde reacted much faster forming the expected product in 4 hr; the same reaction took over 60 hr. using triethylamine (Scheme 5.39). O

OH H

CO2Et + DABCO + PEG 400 + CH2 = CHCO2Et

R

R

4-Nitrobenzaldehyde R = NO2 4-Fluorobenzaldehyde R = F

89-96%

Scheme 5.39

Some other aldehydes like 2-chloro-5-nitrobenzaldehyde, 2-furaldehyde and 2-thiophenecarboxaldehyde showed similar results. However, the yield was considerably reduced for the reaction between 4-methoxybenzaldehyde and ethylacrylate. Aliphatic aldehydes like 3-phenylCHO) also proponal (C6H5CH2CH2CHO), isobutyraldehyde ((CH3)2 CHCHO) and hexanal ( underwent the Baylis-Hillman reaction with activated olefins (viz., acrylonitrile and ethyl acrylate) in 75%, 86% and 80% yields respectively. Also formaldehyde and trans-cinnamaldehyde reacted with acrylates in PEG to provide good yields of the expected products.

Organic Synthesis using Polyethylene Glycol and its Solutions

5.17

The Baylis-Hillman reaction (as described above) is one of the very few reactions where in there is 100% atom economy.

5.10

SUZUKI CROSS COUPLING REACTION IN PEG

The palladium catalysed carbon-carbon coupling reaction of organoboron compounds with aromatic aldehydes in presence of a base provides 75 a mild method for the synthesis of various substituted biaryl76. The reaction, known as suzuki reaction has gained prominance due to availability of functionally substituted boronic acids, which are environmentally safer than most organometallics77. The biaryl formed in this reaction are important as pharmacophores in a number of biologically active molecules 78. The method 75 involves the reactions of substituted aromatic bromides/ iodides and aromatic boronic acids in PEG-400 as reaction medium in presence of potassium fluoride as a base. The reaction was conducted in a microwave oven for 50 sec. The yield of the biarys was 55-81% (Scheme 5.40).

Scheme 5.40

Among the aromatic halides, iodo and bromo compounds were found to be more reactive than the corresponding chloride. In this reaction, the formation of a small amount (< 5%) of symmetrical biaryls occurs due to the self-coupling of boronic acids79. The aliphatic halides, 1-butyl iodide, did not undergo reaction under the above conditions. The reaction, however, could be conducted in 15 min using an oil bath (100°) with similar yields. It is generally found that the use of microwave oven is very convenient and clean. The microwave approach could be adapted for the parallel synthesis to generate a library of compounds 80. The synthesis of biaryls (74-92% yield) by the Suzuki coupling reaction was conducted75 using a variety of aromatic halides (as given below) and reacting with 4-tolylboronic acid (Scheme 5.40a). The Suzuki reaction of bromobenzene was conducted with a variety of substituted boronic acids (given below) (Scheme 5.40b). It was found that the yield of the biaryls increased by the presence of electron withdrawing substituents.

5.11

SYNTHESIS OF AZO COMPOUNDS USING PEG

Azo compounds are known to be utilised as dyes, analytical reagents and as materials for non-linear optics and for storage optic information in laser dishes 81. These are found to possen photoelectric

5.18 Green Chemistry

Scheme 5.40(a)

Scheme 5.40(b)

properties82 and have played a significant role in the development of mechanistic and synthetic organic chemistry83. A number of methods have been used84 for the synthesis of azo compounds. In most of the methods evolution of large amounts of nitrogen oxide causes air pollution; also control of the reaction temperature is a major cost factor in industrialised manufacturing. A green route for the synthesis of azo compounds has been developed85. It absorps NO2 in PEG-400 to form an adduct PEG NO2. The absorption efficiency of NO2 (determined by GriessSaltzan method86) was found to about 97%. The concentration of NO2 in PEG was found to be 10.53 mmol; this was determined by reacting the adduct (PEG NO2) with excess of aqueous sodium hydroxide and then back titrating with hydrochloric acid87. The resulting absorbent product, proved to be a very efficient, clean and moderate oxidant (Scheme 5.41). PEG + NO2

PEG. NO2

Scheme 5.41

Organic Synthesis using Polyethylene Glycol and its Solutions

5.19

The absorbent product (PEG NO2) can convert hydrazo derivatives to the corresponding azo compounds. The spent PEG can be recovered and recycled after the oxidation process (Scheme 5.42).

Scheme 5.42

This is a convenient method of transformation of –NH–NH– to –N = N– by PEG NO2. Following are some more examples of transformation of other substrates into N = N compounds (Scheme 5.43). R — NHCONHNH — R¢ R p-FC6H4m-ClC6H4 p-ClC6H4 p-BrC6H4 p-MeC6H4-

PEG. NO2 25 min

R–NH CON = N – R 80–95%

1

R¢ C6H5 p-Me C6H4 C6H5 C6H5 C6H5

Scheme 5.43

Two other examples of compounds containing NH – NH in a heterocyclic rings are as follows. (Scheme 5.44) O H

N N

H

O R + PEG NO2

20-25 min

N

R N N N O

O R = NO2, OMe

R = NO2, OMe

Scheme 5.44

The above procedure brings together a new form of NO2 capture by PEG-400 and the application of the formed PEG NO2 as an oxidant for the oxidation of hydrazo derivatives to the corresponding azo compounds.

5.20 Green Chemistry

5.12

OXIDATION OF CYCLOHEXENE TO ADIPIC ACID IN POLYETHYLENE GLYCOL BASED AQUEOUS BIPHASIC SYSTEM USING SODIUM TUNGSTATE AND HYDROGEN PEROXIDE

Adipic acid is an important intermediate in the manufacture of nylon-66. At present, most industrial adipic acid production uses nitric acid oxidation of cyclohexanol or cyclohexene or both 88. In these processes, the emission of N2O is a considerable source of NOx environmental pollution. Environmentally benign oxidation methods were developed; these were based on catalytic oxidation of cyclohexene with concentrated aqueous hydrogen peroxide. Subsequently the effectiveness of catalytic oxidation of cyclohexene with hydrogen peroxide and sodium tungstate in the presence of [CH3(nC8H17)3N]HSO4 as a PTC was described89. Adipic acid was also synthesised by direct oxidation of cyclohexene with H2O2 over peroxytungstateorganic complex catalyst90. An elegant, environmentally benin synthesis of Adipic acid from cyclohexene in polyethylene glycol based aqueous biphasic system using sodium tungstate and hydrogen peroxide has been reported91 (Scheme 5.45).

+ 4H2O2

Na2WO4 PEG/NaHSO4

Cyclohexene

COOH COOH

+ 4H2O

Adipic acid

Scheme 5.45

Both PEG and PEG/salt ABS can be considered as potentially important green solvent systems with markedly reduced hazards to health compared to many aqueous/organic biphasic systems incorporating volatile organic components 92. In fact PEG/NaHSO4 was found 93 to be the only ABS in which the reaction took place.

5.13

ENZYMATIC REACTIONS

A number of important enzymes catalysed bioman hydrolyses and biosynthesis, including process applicable to cellulose, antibiotics, starch have been conducted in PEG aqueous two phase systems. Following are some of the important conversions. (i) In the bioconversion of cellulose to ethanol, the enzymes for hydrolysis and enzyme recycling constitute the major portion of the cost. Thus, cellulose is converted into glucose by the enzymes Endo-b-glucanase and Exo-b-glucanase using PEG-40000 and 200000 and Dextrin (Scheme 5.46) 94 – 99. PEG-40,000; 200000 Dextran

Cellulose + Endo-b-glucanase (C6H10O5)

4

(MW = 1,4,11,50,200 ¥ 10 )

Exo-bO-glucanase

Scheme 5.46

Glucose (C6H12O6)

Organic Synthesis using Polyethylene Glycol and its Solutions

5.21

(ii) The conversion of starch or native starch to glucose has been accomplished 99 – 102 using the enzymes a-amylase; glucoamylase and Amyloglucosidase in PEG-6000, 20000 and Dextran (M.W. = 5.7 ¥ 104). A continuous stream of glucose could be produced and PEG, Dextran and the starch degrading enzymes could be recycled (Scheme 5.47). PEG-6000, 20000

Starch + a-Amylase; Glucoamylase; or Amyloglucosidase Native starch

4

Maltose

+ glucose

Dextran (M.W. = 5-7 ¥ 10 )

Scheme 5.47

(iii) Cephalexin has been synthesised 103, 104 in ABS by using penicillen G acylase (PGA) as catalyst and 7-amino-deacetoxicephalosoporanic acid (7-ADCA) and phenyl glycine methyl ester (PGME) as substrate (Scheme 5.48). A yield of 60% of cephalexin was obtained in ABS compared to 21% in an entirety aqueous single phase reaction103. PEG-400 MgSO4

7-Amino-deacetoxicephalosp oranic acid (7-ADCA) Phenyl glycine methyl ester (PGM)

+ Penicillin G acylase

Cephalexin

Scheme 5.48

5.14

SYNTHESIS OF 2 AMINO 2 CHROMENES

2-Amino-2-chromenes were synthesised by a nano-sized magnesium oxide catalysed three component condensation reaction of aldehyde, malononitrile and a-naphthol in PEG-H2O. The chromenes were obtained in high yields at room temperature (Scheme 5.49). The attractive feature of this protocol are the simple experimental procedure, use of benign reaction solvents, cost effectiveness, the recyclability of catalyst and its adaptability for the synthesis of diverse set of 2-amino-2-chromenes 105.

Scheme 5.49

5.22 Green Chemistry

5.15

DECARBOXYLATION OF CINNAMIC ACID

Decarboxylation of substituted a-phenyl cinnamic acid derivatives has been achieved 106 using catalytic amount of methylimidazole and aqueous NaHCO3 in PEG under MW irradiation to give the corresponding para/ortho hydroxylated (E) stilbenes in a mild and efficient manner (Scheme 5.50).

aq. NaHCO3 Cat.

COOH Me OC O

methylimidazole PEG, MW

OMe

Me CO O OMe

a-Phenyl Substituted cinnamic acid derivatives

para/ortho hydroxylated (E) stilbenes

Scheme 5.50

The critical role of water in the above reaction in facilitating the decarboxylation imparts an interesting facet to the synthetic utility of water (PEG – H2O) mediated organic transformations. This procedure provides a clean alternative to the hitherto indispensable multistep approaches involving toxic quinoline and a copper salt combination as the common decarboxylating agent 106. It may be appropriate to mention here that decarboxylations has also been achieved using SC – H2O without any catalyst.

5.16

CONCLUSION

Polyethylene glycol (PEG) and its aqueous solutions have been used in many different types of reaction systems. The special feature of PEGs is their low toxicity, low volatility and biodegradability and relatively low cost as a bulk commodity chemical. Also, aqueous PEG solutions are good substitutes for expensive and often toxic PTCs. PEG finds use in substitution reactions, oxidation and reduction reactions. As PTC, the PEG’s have been used in Williamson ether synthesis and oxidation reduction reactions. PEG’s have also been used in L-Proline catalysed asymmetric aldol condensation. It is also used in asymmetric dihydroxylation of olefins. Regioselective Heck reaction, Baylis-Hillman reaction, Suzuki cross coupling reaction and catalytic transfer hydrogenation reaction to PEG-bound substrates have also been reported. Besides, PEG has also been used for absorbing NO2; the adduct finds application for conversion of –NH–NH– group to –N = N– group. The conversion cyclohexene to adipic acid is worth mentioning. Finally PEG has been used in a number of enzymatic transformations.

References 1. P.T. Anastas, in Clean Solvents, Alternative media for chemical reactions and Processing. ed. M.A. Abraham and L. Moens, ACS Symposium series 819, American Chemical Society, Washington DC., 2002, P. I.

Organic Synthesis using Polyethylene Glycol and its Solutions

5.23

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66. 67.

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Organic Synthesis using Polyethylene Glycol and its Solutions

5.27

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6 6.1

Organic Synthesis using Fluorous Solvents

INTRODUCTION

Fluorinated compounds and solvents are useful tools in synthetic organic chemistry 1. It was only in 1994 that the concept of fluorous biphasic system (FBS) and fluorous biphasic catalysis (FBC) was invented2. It is based on reagents or catalysts having perfluorated carbons chains, which are soluble in perfluorated solvents as FC – 72 (a mixture of perfluorohexanes). At ambient temperature, the perflouroalkanes are very less soluble in common organic solvents resulting in the formation of biphasic mixtures. At elevated temperatures, the biphase heterogeneous mixtures becomes monophasic and a clear solution is obtained. For carrying out a reaction, the organic substrate is dissolved in an organic solvent (e.g. toluene or dichloromethane) and the fluoro-tagged catalyst or reagents dissolved in perfluoroalkanes added. At elevated temperatures the biphasic heterogeneous mixture becomes monophasic permitting the reaction to take place. After the reaction has taken place (as indicated by TLC), the resultant liquid is cooled when the two phase are again formed. The formed product of the reaction is in the organic phase and is recovered by decantation of the upper organic phase. The catalyst remains in the lower fluorous phase and can be reused. In this procedure, the reaction time can be regulated by change of temperature. This procedume is knoun as fluorius phase technigue. The FBS technique can be compared with solid phase organic synthesis (SPOC, Scheme 6.1), which is generally used in pharmaceutical industry. Both the FBS technique and the SPOC technique offer similar opportunities for the separation of product/catalyst. However, The FBS technique seems to offer advantages over reaction on solid support. The FBS procedure is depected in Scheme 6.2.

6.2

CHARACTERSTICS OF PERFLUOROUS LIQUIDS

Most of the common perfluorous liquids, especially perfluoroalkanes, perfluoroethers and perfluoroamines 3 exhibit unique characteristics. This makes them convenient alternatives to

6.2 Green Chemistry

Scheme 6.1 SPOC-technique

Perflorotag

+ Subtrate

Cleavage

Perflorotag

Perflorotag — Subtrate

Perflorotag — Product

Workup

FBS reaction in liquid Phase; reagent

Perflorotag — Product + reagent

+ Product (separated by extraction)

Scheme 6.2 FBS-technique

conventional organic solvents. Thus, the perfluoro liquids are inert against chemical treatment; this permits reactions under drastic conditions whenever necessary4. The boiling points of perfluorous liquids is dependent on their molar mass and so a broad range is possible. As an example, the boiling points of fluorous alkanes are usually lower than the corresponding alkanes; this is attributed to decreased Van der Waals interactions. The density of perfluorous alkanes is higher than water and most other organic molecules. The perfluorous alkanes are commercially available; these also contain isomers and small amounts of their homologous. Gases like oxygen, carbon dioxide and hydrogen are highly soluble in perfluorocarbons. At one time, the perflourocarbons were investigated as blood transfusion survogates5. However, due to high volatility and risk of embolism, this area of research was curtailed. The perfluorous organic compounds are mostly used in electrical power industry as dielectric liquids and in the pharmaceutical industry as additives 6. Perfluorinated molecules show excellent solubilities in perfluorous solvents and also in supercritical CO2(SC – CO2)7. As already stated, the solubility of perfluorous liquids in organic solvents is temperature dependent. At ambient temperature, most of the combinations of an organic and a fluorous solvent are biphasic and at higher temperature they become monophasic; lowering of the temperature will result in reformation of the biphasic system. Following are some commonly used and commercially available perfluorinated solvents8,9: perfluorohexane (C6F14), perfluoroheptane (C7F16), perfluoromethylcyclohexane (C7F14), perfluorodecalin (C10F18) and perfluorotributylamine (C12F27N). Their m.p’s are of the order –87°, –78°, –45°, –10° and –50° respectively. Their boiling points are of the order 75°, 82°, 72°, 142° and 173° respectively. They are all heavier than water (density 1g/cm3). Their densities are of the order 1.68, 1.73, 1.79, 1.95 and 1.88 respectively).

Organic Synthesis using Fluorous Solvents

6.3

The following are the various solvent systems9 used along with the temperature at which they exist in 1 and 2 phases. Solvent system (ratio 1 : 1)

No. of phases

Temperature (°C)

Perfluoro (methyl cyclohexane)

2

– 16

CF3C6F11/pentane

1

r.t.

CF3C6F11/Diethylether

2 1

0 r.t.

CF3C6F11/hexane

2 1

0 r.t.

CF3C6F11/CCl4

2 1

r.t. > 27

CF3C6F11/CHCl3

2 1

r.t. >50

Perfluorodecalin/toluene

2 1

r.t. 64

CF3C6F11/benzene

2 1

r.t. >85

CF3C6F11/toluene

2 1

r.t. >89

CF3C6F11/chlorobenzene

2 1

r.t. > 127

Data taken from reference 9

6.3

PHASE SWITCHING

While planning any reaction involving fluorous technique, it is most important to think about the removal of the covalently bound fluorous tag from the desired product. The method chosen should not effect the organic moiety chemically. This is called phase switching. For this mild and efficient procedures are required. One such method, commonly used is Fluorous Reversed Phase Silica Gel Aided Work Up Procedure (FRPSG) 10, 11. In this procedure, interactions between the perfluoroalkyl chains on the surface of the gel and the fluorous ponytail of the labelled molecules lead to a retardation-the principle-which could be applied to purification of a single compound or isolation of various molecules with fluorous tags of different length by HPLC (fluorous mixture synthesis, Scheme 6.3)12-16. For filtration and extraction, organic solvent of variable polarity are applied, decreasing the polarity from polar (water, acetonitrile) via a polar organic to fluorous eluting the perfluorous tagged substance as the final fraction. This procedure was applied 12-16 to isolate perfluoro-allyl compounds, products of radical allylations of perfluoroalkyl iodides (Scheme 6.4) 17.

6.4 Green Chemistry

Scheme 6.3

Scheme 6.4

6.4

PERFLUORINATED CATALYSTS

A number of perfluorinated catalysts involving transition metals have been developed for use in organic synthesis involving fluorous phase techniques. Some of such catalysts are given in 1Scheme 6.4a.

6.5

SOME APPLICATION OF FLUOROUS PHASE TECHNIQUES 1. Palladium-catalysed carbon-carbon cross-coupling reactions such as Heck, Stille, Suzuki, Negishi and Sonogashira reactions18-22 were carried out under fluorous conditions. In all these cases there is already elucidated advantage of product isolation and catalyst recovery. Now, reaction kits for Pd-catalysed carbon-carbon cross-coupling reactions in FBS are commercially available. These kits have been developed by Schneider and Bannwarth, Fluka company Lid, Buchs, Switzerland. 2. Friedel-crafts acylation was carried out in FBS applying lanthanide methides 23, 24 and nonfluorous zinc chloride was used as Friedel-Crafts catalyst in perfluorotriethylamine, which replaced highly toxic sym. tetrachloroethane25. 3. Enantioselective alkylation of benzaldehyde in presence of chiral binaphthols and arylzincthiolates 26 - 28 was carried out. 4. Some other applications of Fluorous Phase Techniques are given, (Scheme 6.5). 5. The reaction of an aldehyde with grignard reagent using fluorous phase technique give secondary alcohol (Scheme 6.6). The grignard reaction was worked up by double triphasic

Organic Synthesis using Fluorous Solvents

6.5

H P(CH2CH2C6F13)3

(C6F13H2CH2C)3 P — Rh

P(CH2CH2C6F13)3

CO

C8F17H2CH2C

[B] 3

(C6F13H2CH2C)3 P

P

2 PdCl2

L M = Rh, Ir, Ni L = P(CH2CH2C6H13)3.CO.Cl

M

C7F15 O

O M = Ni, Pd

M O F15C7

[C]

P(CH2CH2C6F13)3

Cl F15C7

[A]

[D]

O C7F15

Scheme 6.4(a)

(fluorous/organic/aqueous) extraction comprising first a fluorous scavenging reaction of the alcohol followed by a cleavage of the perfluoro moiety by addition of CsF. Various stages/steps are shown in Scheme 6.6. In this procedure, recycling of the fluorous tag is not possible; this is a major disadvantage in this case. 6. Synthesis of tetrazoles: The reaction of perfluoro stannane linked azido with cyanides gave tetrazoles (Scheme 6.7) 29. 7. N-Alkylation of primary and secondary amines can be achieved by reacting with excess of alkyl bromides 30, 31 (Scheme 6.8). 8. Stille coupling has been achieved (Scheme 6.9) with perfluoro-tagged tin compounds 32, 33. 9. 3H-Quinazoline-4-ones were prepared by an Aza–Wittig reaction using fluorous triphenylphosphine (Scheme 6.10) 34, 35. 10. Mitsunobu reaction The reaction of 3,5-dinitrobenzoic acid with ethanol in presence of perfluorinated Mitsunobu reagents 36 11.1 and 11.2 gave the corresponding ester in 92% yield. The reagents (11.1 and 11.2) are helpful for removal of triphenylphosphine oxide (11.3) and hydrazide (11.4) byproducts after the reaction (Scheme 6.11) 36, 37. These could be completely

6.6 Green Chemistry

Scheme 6.5

Scheme 6.6

Organic Synthesis using Fluorous Solvents

Scheme 6.7 R org 1) Base reaction 1) C6F13CH2CH2SH 3) FRPSG Filtration

R N — H + R¢¢

R¢¢

N R¢

Br

R¢ 1° or 2° Amine

Fluorous R¢¢

Alkyl bromide

Scheme 6.8

Scheme 6.9

S

C6H13

6.7

6.8 Green Chemistry

Scheme 6.10

Scheme 6.11

Organic Synthesis using Fluorous Solvents

6.9

retained on FRPSG after filtration, while the non-fluorous products directly eluted. The original reagents could be regenerated by treatment with AlH3 and Br2. 11. Synthesis of perfluoroalkyl sulfides and sulfoxides. Perfluoroalkyl sulfides (12.1) and sulfoxides (12.2) were synthesised 38 (Scheme 6.12)

Scheme 6.12

Using the sulfoxide (12.2), a number of 1° and 2° alcohols could be converted to the corresponding aldehydes and ketones.

6.6

CONCLUSION

Perfluorinated hydrocarbons are found to be unique solvents with interesting applications in organic synthesis. Due to their immisicibility with water and most common organic solvents, they represent a third liquid phase – the perfluorous phase. The high solubility of oxygen in the perfluorinated hydrocarbons permits some selective and efficient oxidation reactions under mild conditions. The individual components of the reaction mixtures which bear perfluoroalkyl substituents of sufficient size and number, can be selectively extracted into fluorous phase. This is the basis of the so-called fluorous synthesis.

References 1. D. Clarke, M.A. Ali, A.A. Cliford, A. Parratt, P. Rose, D. Schwinn, W. Bannwarth and C.M. Rayner, Current Topics in Medicinal Chemistry, 2004, 4, 729. 2. I.T. Horvath and J.R. Abai, Science, 1994, 266, 72. 3. P.L. Nostro, Adv. Colloid Interface Sci., 1995, 56, 245. 4. W. Keim, M. Vogt, P. Wasserscheid and B. Driessen-Holscher, J., Mol. Catalysis A. Chemical, 1999, 139, 171. 5. T.H. Maigh, Science, 1979, 206, 205; J.G. Riess and M.L. Blanc, Pure Appl. Chem., 1982, 54, 2383. 6. G. Sandford, Phil. Trans. R. Soc. London. A, 2000, 358, 455. 7. T. Osswald, S. Schneider, S. Wang, W. Bannwarth and W. Stille, Tetrahedron Lett., 2001, 42, 2965; S. Kainz, D. Koch, W. Baimann and W. Leitner, Angew. Chem. Int. Ed., 1997, 36, 1628. 8. B. Betzemeier and P. Kochil, Top. Curr. Chem., 1999, 206, 61. 9. L.P. Barthel-Rosa and J.A. Gladysz, Coord. Chem. Rev., 1999, Pages 190, 587. 10. C.C. Tzschucke, C. Markert, H. Glatz and W. Bannwarth, Angew. Chem. Int. Ed., 2002, 41, 4500. 11. S. Kainz, Z. Luo, D.P. Curran and W. Leithner, Synthesis, 1998, 1425.

6.10 Green Chemistry 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

D.P. Curran and Z. Luo, J. Am. Chem. Soc., 1999, 121, 9069. Q. Zhang, Z. Luo and D.P. Curran, J. Org. Chem., 2000, 65, 8866. D.P. Curran and S. Hadida, J. Am. Chem. Soc., 1996, 118, 2531. D.P. Curran and T. Oderaotoshi, Tetrahedron, 2001, 57, 5243. Z. Luo, Q. Zhang, Y. Oderaotoshi and D.P. Curran, Science, 2001, 291, 1766. I. Ryu, S. Kreimerman, T. Niguma, S. Minakata, M. Somatsu, Z. Lou and D.P. Curran, Tetrahedron Lett., 2001, 42, 947. J. Monineau, G. Pozzi, S. Quici and D. Sinou, Tetrahedron Lett., 1999, 40, 7683. B. Betzemeier and P. Knochel, Angew. Chem. Int. Edn., 1997, 36, 2623. S. Schneider and W. Bannwarth, Angew. Chem. Int. Edn., 2000, 39, 4142. S. Schneider and W. Bannwarth, Helv. Chim. Acta, 2001, 84, 735. C. Markert and W. Bannwarth, Hel. Chim, Acta, 2002, 85, 1877. A.G.M. Barrett, D.C. Braddock, D. Catterick, D. Chadwick, J.P. Henschke and R.M. Mckinnell, Synlett, 2000, 847. K. Mikami, Y. Mikami, Y. Matsumoto, J. Nishikido, F. Yamamoto and H. Nakajima, Tetrahedron Lett., 2001, 42, 289. T. Kitazume, J. Fluorine Chem., 2000, 105, 265. H. Kleijn, E. Rijnberg, J.T.B.H. Jastrzebski and G.V. Koten, Org. Lett., 1999, I, 853. Y. Nakanura, S. Tekeuchi, Y. Ohgo and D.P. Curran, Tetrahedron, 2000, 56, 351. Y. Tian and K.S. Chan, Tetrahedron Lett., 2000, 41, 8813. D.P. Curran, Angew. Chem. Int. Ed., 1998, 37, 1175. M.W. Creswell, G.L. Bolton, G. Hodges and M. Meppen, Tetrahedron, 1998, 54, 3983. B. Linclau, A.K. Singh and D.P. Curran, J. Org. Chem., 1999, 64, 2835. M. Hoshino, P. Degenkolb and D.P. Curran, J. Org. Chem., 1997, 62, 8341. J.K. Still, Angew. Chem. Int. Ed. Engl., 1986, 25, 508. P. Molina and M.J. Vilaplane, Synthesis, 1994, 1197. S. Barthemy, S. Schneider and W. Bannwarth, Tetrahedron Lett., 2002, 43, 807. S. Dandapani and D.P. Curran, Tetrahedron, 2002, 58, 3855. O. Mitsunobu, M. Yamada and T. Mukaiyama, Bull. Chem. Soc. Jpn., 1967, 40, 935. D. Crich and S. Neelamkavi, Tetrahedron, 2002, 58, 3865.

Part III Organic Synthesis in Solid State

7

Organic Synthesis in Solid State

7.1 INTRODUCTION Performing organic reactions in solid state (generally known as solventless reactions) are, no doubt, the best alternative in the context of Green Chemistry. Such reactions are easy to operate and are cheaper alternatives and there is no worry of environmental pollution. Such reactions can be conducted in the following ways: Solid state reactions at room temperature, Solid state reactions on heating and solid state reactions using solid support.

7.2 SOLID STATE REACTIONS AT ROOM TEMPERATURE 7.2.1 Aldol Condensa on The aldol condensation of lithium enolate of methyl 3, 3-dimethylbutanoate with aromatic aldehyde gives1 8:92 mixture of syn and anti products in 70% yield (Scheme 7.1) The above reaction (Scheme 7.1) is carried out by mixing freshly ground mixture of the starting materials in vacuum for 3 days at room temperature. In the absence of any solvent, some aldol condensations proceed2 more efficiently and stereoselectively. In this procedure, appropriate aldehyde and ketone and NaOH is ground in a pestle and mortar at room temperature for 5 min. The product obtained is the corresponding chalcone. In this method, the initially formed aldol dehydrates easily to the chalcone in the absence of a solvent (Scheme 7.2). The use of alcohol as a solvent in the above method using conventional procedure gives only the aldol in poor yields (10-25%). The only exception was the reaction of benzaldehyde and acetophenone (solid state reaction), which gave aldol in 10 percent yield.

7.4 Green Chemistry

Scheme 7.1

Scheme 7.2

Using the above method, following chalcones were prepared: Ar ¢

Ar

Reaction time (mm)

yield (aldol)

% yield of Chalcone

Ph

Ph

30

10

–

p-Me C6H4–

Ph

5

–

97

p-Me C6H4–

p-Me C6H4–

5

–

99

p-Cl C6H4–

Ph

5

–

98

p-Cl C6H4–

p-Me C6H4–

10

–

79

p-Cl C6H4–

p-Br C6H4–

10

–

81

p-Br C6H4–

10

–

91

O H2C O

Organic Synthesis in Solid State

7.5

7.2.2 Grignard Reac on The results obtained by carrying out the usual grignard reaction (the reaction is carried out by mixing ketone and powdered grignard reagent, obtained by evaporating the solution of the grignard reagent, prepared as usual, in vacuo) in solid state gives more of the reduced product of the ketone than the alcohol (Scheme 7.3).

Scheme 7.3

Following results are obtained. Grignard reagent RMgX

% products obtained in solid state

R

X

(A)

(B)

Me

I

No reaction

Et

Br

30

31

iPr

Br

2

20

Ph

Br

59

–

7.2.3 Reformatsky Reac on Treatment of aromatic aldehydes with ethy1 bromoacetate and Zn-NH4Cl in the solid state gives4 the corresponding Reformatsky reaction product (Scheme 7.4).

Scheme 7.4

7.2.4 Synthesis of Quinoxaline Deriva ves Quinoxaline and their derivatives are widely used in many fields, as curatorial intermediates, bacteriocides and insecticides5. Many synthetic methods for these heltrocyclic compounds have been reported5,6. These procedures use catalysts and/or some special techniques6. Many of these methods

7.6 Green Chemistry are associated with a number of shortcomings such as long reaction times, expensive reagents, harsh conditions, low-product yields, formation of side products and difficulties in the recovery and reusability of the catalysts. An efficient synthesis of potential 1, 4-dihydro-quinoxaline-2, 3-diones has been reported7 in a one-pot reaction at room temperature from substituted o-phenylene diamines and oxalic acid under solvent-free conditions by a simple grinding method at room temperature with unsurpassed atom economy. (Scheme 7.5)

Scheme 7.5

Green Synthesis of quinoxaline derivatives A

B

Time(h)

Product obtained yield(%)

H

H

0.5

98

H

NO2

3

82

H

Cl

2

87

H

Me

1

95

H

n-Pr

1

95

H

Ph

0.5

96

Cl

Cl

5

76

The yield refer to isolated products. Data taken from reference 7.

7.2.5 Synthesis of -keto Sulfones from Ketones In organic synthesis, b-keto sulfones are an important class of compounds8. A number of useful compounds have been prepared using b-keto sulfones as intermediates. Some of such compounds include olefins9, disubstituted acetylenes9. vinyl sulfones10, allenes11 and polyfunctional 4H-pyrans12. b-keto sulfones are also precursors for optically active b-hydroxy sulfones13. b-keto sulfones are found to posses fungicidal activity14. b-keto sulfones are normally synthesised by the oxidation of b-keto-sulfides15, reaction of sulfonyl chlorides with silyl enol ethers16, reaction of diazo sulfones with aldehydes17, alkylation of arene sulfinate salts with a-haloketones18, acylation of alkyl sulfones, reaction of alkyl sulfones with N-acylbenzotriazoles19 and the reaction of sulfonyl chloride with arylacetylenes20. These procedures require toxic substrates, multi step synthesis and more reactions time and the yields are moderate.

Organic Synthesis in Solid State

7.7

A one pot synthesis21 of b-keto sulfones involve the condensation of ketones with relatively benign [hydroxyl (tosyloxy) Iodo] benzene and sodium arene sulfinates in the presence of a phase transfer catalyst (tetrabutyl ammonium bromide, T BAB) and sodium benzene sulfinate, Intimate grinding of the above reaction mixture gave the b-keto sulfones in high yields (Scheme 7.6).

Scheme 7.6

Using the above procedure, following b-keto sulfones were prepared (Table 7.1). Table 7.1 Synthesis of b-keto sulfones from ketones using hydroxy (tosyloxy) iodobenzene Entry

Substrate

Product

O

Time (min)

O

Yield (%)

O S O

1

O

7

91

8

92

5

87

5

89

O

O

S O

2 CH3 O

O

O S O

3 Cl

Cl O

O

O S O

4 Cl

Cl

CH3

Contd..

7.8 Green Chemistry Contd.. Entry

Substrate

Time (min) Yieldb (%)

Product O

O

O S O

5

8

88

7

90

6

84

5

85

6

82

7

81

H3C

H3C O

O

O S O

6 H3C

CH3

H3C O O

7

O S O

H3C CH3

H3C

O

S O

H3C

O

O

8 H3C

CH3

CH3 O

O S O

9

O

O S O

10 O Note: Data taken from reference 21

7.2.6 Synthesis of -Tosyloxy -keto Sulfones a-Tosyloxy b-keto sulfones are potentially very useful precursors in organic synthesis, particularly for heterocyclic compounds22. Most of the reported procedures23 for a-functionalisation of b-keto sulfones required longer reaction times under refluxing conditions and give the required products

Organic Synthesis in Solid State

7.9

in moderate yields. A simple procedure for the synthesis of a-tosyloxy b-keto sulfones consists in grinding together a neat mixture of a-benzenesulfonyl-acetopheone and [hydroxy (tosyloxy) iodo] benzene [H.T.I.B., commonly known as Koser’s reagent] at room temperature using a pestle and mortor. Within, 5 min, the reaction gave the required a-tosyloxybenzenesulfonyl-acetophenone in 94% yield via the formation of a eutectic semi-liquid phase (Scheme 7.7).

Scheme 7.7

Using this procedure, following a-tosyoloxy b-keto sulfones were synthesised23 (Table 7.2).

7.2.7 Synthesis of 1-aryl-4-methyl-1, 2, 4-trizolo [4, 3-a] Quinoxalines Triazoles, an important class of heterocyclic compounds, particularly the 1, 2, 4-triazole nucleus is an integral part of therapeutically interesting compounds which display antibacterial, CNS stimulative, sedative, antifungal and antitumor activities24. 1, 2, 4-Triazoles were earlier synthesised by the condensation of 2-hydroxyquinoxaline with carboxylic acids at elevated temperature25, 1, 3-dipolar cycloaddition reaction of aromatic nitriles in presence of strong base followed by hydrogen elimination26, photolysis of trizole-3-thiones27 and oxidation of arylhydrazones28. Most of these methods involve multistep harsh reaction conditions, toxic reagents and require longer reaction times. 1-Aryl-4-methyl-1, 2, 4-trizolo [4, 3-a] quinoxalines have been synthesised29 by mixing (in a pestle mortar) of arenecarbaldehyde 3-methylquinoxalin-2-yl-hydrazones with iodobenzene diacetate (Scheme 7.8) The above oxidative conversion involves a through mixing of the substrate with iodobenzene at room temperature (slightly warming in some cases) via an exothermic reaction. Hydrazone derivatives containing an electron-donoting group undergo ready conversion without warming. Following 1-aryl-4-methyl-1, 2, 4-triazolo [4, 3-a] quinoxalines were obtained by this procedure (Table 7.3). A plausible pathway for this transformation is given in (Scheme 7.9).

7.3 SOLID STATE REACTIONS ON HEATING These reactions are conducted by heating the reactants in an oil bath or water bath

7.3.1 Oxida on of Hydroxylated Aldehydes and Ketones to Hydroxylated Phenols using Urea-hydrogen Peroxide Adduct (UHP) In organic synthesis, phenols and their derivatives are extensively used. The conversion of hydroxylated benzaldehydes to hyroxylated phenols has been achieved using alkaline hydrogen

5

4

3

2

1

Entry

Cl

Me

O

O

O

O

O

O

S

S

S

O

b-keto sulfones

O

O

Me

Cl

Me

O O

O

O

O

OTs

S

O

O

S

OTs

S

O

O

S

O

OTs

O

S

OTs

O

Product

OTs

O

Table 7.2 Synthesis of a-tosyloxy b-keto sulfones using [hydroxyl(tosyloxy) iodo] benzene

O

O

Me

Me

5

5

6

9

7

Time (min)

Contd..

90

90

94

92

94

Yield (%)

7.10 Green Chemistry

Cl

Me

Me

O

O

O

O

O

S

O

S

S

O

O

O

O

Note: Data taken from reference 23.

9

8

7

6

Contd..

O

S

O

Me

Me

Me Cl

Me

Me

O

O

S

O

O

O S

O

S

OTs

O

OTs

OTs

O

OTs

O

O

O

S

O

Me

Me

Me

5

4

10

5

88

85

72

86

Organic Synthesis in Solid State

7.11

7.12 Green Chemistry

Scheme 7.8 Table 7.3 Synthesis of some 1-aryl-4-methyl-1, 2, 4-triazole [4, 3-a] quinoxalines Entry

Ar

2a

mp/°C

Yield (%)

205–206 (203)

65

2b

CH3

212–213

76

2c

Cl

220–222

75

2d

OCH3

186–187

74

168–187

72

258–260

69

2e OCH3 CH3

2f

N CH3

*Unoptimised yields are for the isolated products. Data taken from reference 29.

Organic Synthesis in Solid State

7.13

Scheme 7.9

peroxide30, although other oxidants such as peroxybenzoic acid31 and peroxyacetic acid32 have also been frequently used. However, solid-state oxidation of hydroxylated benzaldehydes with ureahydrogenperoxide adduct is superior alternative in terms of shorter reaction time, cleaner product formation and ease of manipulation (Table 7.4). Table 7.4 Solid-state Oxidation of Aldehydes and Ketones using UHP Entry

Startin Material

Reaction condition

Product

Time (°C)

Time

Per cent Yield

55

1.5h

85

85

20 min

80

3

55

3h

83

4

85

7 min

87

CHO

OH

1 OH

OH

CHO

OH

2 OH

OH

Contd..

7.14 Green Chemistry Contd.. OH

COCH3

5 OH

1h

86

85

1h

80

85

25 min

83

85

45 min

80

85

20 min

95

OH

6

CHO

OH

7 O2N

85

OH

O2N

CHO

OH OH

8 MeO

MeO CHO

COOH

9

Data taken from reference 33.

7.3.2 Oxida on of Nitriles to Amides using UHP The hydrolysis of nitriles is generally used for the preparation of carboxylic acid amides. Usual methods for the hydration of nitriles involve the use of strong mineral acids34, although some metals35 and their oxides36 and complexes37 have also been used for the conversion of carbonitriles to amides. Some other reagents like titanium tetrachloride in acetic acid38, potassium fluoride, on alumina39, potassium hydroxide in tertiary butyl alcohol40 sodium percarbonate in aqueous methanol41 and some hydroxylamine derivatives42 have also been used. The alkaline hydrolysis is not used, since it gives carboxylic acids. The base catalysed hydrolysis of nitriles was originally used by Rdziscewski, but it worked with aromatic nitriles, and the reaction gave only dismal yields in case of aliphatic nitriles43. Hydrogen peroxide in dimethyl sulfoxide44 or under phase transfer conditions45 has also been used. Many of these methods suffer from disadvantages of selectivity, longer reaction time and the use of hazardous reagents. Eco-friendly hydrolysis of nitriles to amides has been achieved using UHP under solvent free conditions33 (Table 7.5).

Organic Synthesis in Solid State

7.15

Table 7.5 Solid-State Oxidation of Nitriles to amides using UHP Startin Material

Product

CH2CN

Reaction condition Time (°C)

Time

Yield Per cent

85

1h

80

85

1.5 h

85

CH2CONH2

CN

CONH2

Data taken from reference 33.

7.3.3 Selec ve Oxida on of Sulfides to Sulfoxides or Sulfones using UHP Selective oxidation of sulfides to sulfoxides or sulfones is a challenging task for synthetic organic chemist. Some of the oxidants that have been used for this conversion include hydrogen peroxide46, chromic acid47, nitric acid48, manganese dioxide47, ozone49, peracids50, selenium dioxide51, sodium periodate52, hypervalent iodine reagents53, sodium perborate54 and dinitrogen tetroxide55, Most of these procedures suffer from drawbacks like extended period of time, using corrosive acids, hazardous peracids and toxic metallic compounds. A safer, viable protocol for the oxidation of sulfides to sulfoxides or sulfones is to use ureahydrogen peroxide adduct (UHP) under solvent free conditions33 (Table 7.6). Table 7.6 Solid-State Oxidation of Sulfides using UHP Entry

Startin Material

Product

SMe

Reaction condition

Yield Per cent

Time (°C)

Time

85

15 min

80

85

1h

87

SOMe

1

SMe

SOMe

2

3

[CH3 (CH2)3]2S

[CH3(CH2)3]2SO

85

10 min

85

4

[CH3(CH2)3]2S

[CH3(CH2)3]2SO2

85

45 min

90

S

85

7 min

87

5

S

O

Contd..

7.16 Green Chemistry Contd.. O

6

S

85

1h

88

85

30 min

87

85

2h

90

O

7

CH2)2S

CH2)2SO2

8

Data taken from reference 33.

On the basis of the results obtained, it is seen that oxidation of sulfides to sulfoxides (entries 1, 3, 5 and 7) and sulfones (entries 2, 4, 6, 8) are summarised in Table 7.6 above.

7.3.4 Oxida on of Nitrogen Heterocycles to N-oxides using UHP Using UHP, nitrogen heterocyclic compounds could be oxidised to the corresponding N-oxides33 (Table 7.7). Table 7.7 Solid-State Oxidation of Nitrogen heterocycles to N-Oxides using UHP Entry

Startin Material

Product

N+

1 N

Reaction condition

Yield Per cent

Time (°C)

Time

85

45 min

87

85

45 min

92

O– N

N

2 N

N+ O–

Data taken from reference 33.

The reactions (7.31 to 7.34) described have been conducted by slight warming of the reactants. It is, however, believed that all these reactions could be carried out using microwave irradiation for few seconds to few minutes.

Organic Synthesis in Solid State

7.17

7.4 SOLID STATE REACTIONS USING SOLID SUPPORT In these reactions, the reactants are dissolved in a suitable solvent like water, alcohol, methylene chloride, etc., and the solution stirred with a suitable adsorbent or solid support like silica gel, alumina or phyllosilicate (Mn+–montmorillonite). After stirring the solvent is removed in vacuo and the dried solid support on which the reactants have been adsorbed are used for carrying out the reaction under microwave irradiation. Most of the reactions in solid state are performed in open glass containers (test tubes, beakers and round bottomed flasks) using neat reactants under solvent free conditions in an unmodified household MW oven. Some of the supporting reagents, viz. clay supported iron (III) nitrate (Clayfen) and copper (II) nitrate (Claytop) are prepared by literature procedures56. Some of the important applications of solid support synthesis are given below:

7.4.1 Protec on and Deprotec on Reac ons Protection and deprotection are important steps for the preparation of monomer building blocks, fine chemicals and synthesis for pharmaceuticals. These reactions often involve the use of acidic, basic or hazardous reagents and toxic metal salts57. The solid support technique (MW-accelerated) provides an alternative to the conventional reactions.

7.4.1.1 Forma on of acetals and diaxolanes The acetals of 1-galacto-1, 4-lactone could be prepared58 in excellent yields by absorbing the lactone and the aldehyde on montmorillonite K-10 or KSF clay followed by heating the reaction mixture in a MW oven. (Scheme 7.10).

Scheme 7.10

In a similar way, thioacetals are prepared from active methylene compounds that are adsorbed on KF-alumina, admixed with methanesulphonothioate59 (Scheme 7.11). R1 CH2

Methanesulphonothioate Alumina-KF MW

R2 R1

R2

R1 C R2

CO2R, CN, Ph, PO (OEt)2

Scheme 7.11

SMe

SMe

7.18 Green Chemistry Alkylation of reactive methylene group can be conveniently achieved in a microwave oven60, 61 using tetrabutyl ammonium chloride (TBAC) as PTC without solvent (Scheme 7.12).

Scheme 7.12

In a similar way62 alkylation of ethyl mercapto acetate can be achieved (Scheme 7.12a).

Scheme 7.12 a

Aldehydes and ketones can be protected as acetals and dioxolanes using orthoformates, 1, 2-ethylene dithiol or 2, 2-dimethyl-1, 3-dioxolane62. This acid catalysed reaction proceeds in presence of p-toluenesulfonic acid (PTSA) or KSF clay under solvent-free conditions (Scheme 7.13). The yields obtained are better than that obtained using conventional heating mode (oil bath). R1 C

O

+

R2

HO

MW, 10-30 min

HO

KSF or PTSA

R1

O

R2

O

Scheme 7.13

7.4.1.2 N-alkyla on reac ons A number of N-alkylation reactions have been reported in solvent free conditions using phase transfer catalysts such as tetrabutylammonium bromide (TBAB) under microwave irradiation conditions. Using this procedures, N-alkylation of phthalimides63 (Scheme 7.14) or its potassium salt64 (Scheme 7.15), carbazole65 (Scheme 7.16) azaheterocycles66 (Scheme 7.17) including pyriolidino[60] fullerenes67 (Scheme 7.18) have been carried out using K2CO3/KOH and TBAB. O

O NH

+

RX

K2CO3, TBAB

N

MW, 4-10 min

O

O

Phathalimide

49-95%

Scheme 7.14

R

Organic Synthesis in Solid State O

7.19

O NK

CH3(CH2)7 Br/TBAB

N(CH2)7 CH3

Support, MW

O

O

Pot. phathalimide

Scheme 7.15

Scheme 7.16 Z

Y NH + RX

Cl, Br, l: TBAB X C, N Y, Z

K2CO3/KOH, TBAB

Z

Y

MW, 1-10 min 58-95% Tetrabutylammonium bromide

NR

Scheme 7.17 Ph NH

Ph MW, 10 min K2CO3, TBAB RBr

NR

Scheme 7.18

N-alkylation also proceed smoothly under microwave condition. Thus, irradiation of a mixture of saccharin and alkyl halide give the N-alkylated product68 in good yield (Scheme 7.19).

Scheme 7.19

7.20 Green Chemistry 7.4.1.3 Deacetyla on Aldehydes66, phenols65 and alcohols are protected by acetylation. After the reaction, the deacetylation of the acetate is carried out usually under acidic or basic conditions; the process takes long time and the yields are low. Use of microwave irradiation reduces the time of deacetylation and the yields are good. Some examples are given in (Scheme 7.20).

Scheme 7.20

As seen (Scheme 7.20) the selectivity of these deacetylation reaction is achieved by simply adjusting the time of irradiation. A similar deacetylation reaction has been reported69 using zeolites, wher in 1, 1-diacetate undergo deprotection under microwave irradiation under solvent free conditions (Scheme 7.21).

Scheme 7.21

7.4.1.4 Debenzyla on of carboxylic esters The carboxylic function is generally protected by the benzyl protecting group. After the reaction sequence, the deprotection of benzyl ester is carried out to using potassium carbonate69, Aluminium chloride70, Na-NH371, etc. Most of the procedures give moderate yields and a longer reaction time is required. The microwave irradiation procedure72 is completed in 3-10 min and yields are high (89-92%) (Scheme 7.22).

Organic Synthesis in Solid State

CO2CH2C6H5

R

R

Acidic Alumina mw, 7 min

R

7.21

CO2H

H or CH3

Scheme 7.22

The solven-free debenzylation of ester (Some more cases are given in Scheme 7.23) paves the way73 for the cleavage of the 9-fluorenylmethoxycarbonyl (Fmoc) group that can be extended to protected amines by changing the surface characteristic of the solid support. The cleavage of N-protected moieties require the use of basic alumina and irradiation time of 12–13 min at ª 130140°C.

[a, time in parentheses refer to deprotection in an oil bath at the same temp.] Scheme 7.23

This approach finds application in peptide bond formation that may eliminate the use of the irritating and corrosive chemicals with trifluoroacetic acid (TFA) and piperidine, as has been demonstrated for the deprotection of N-boc group (Scheme 7.24).

7.22 Green Chemistry R1 N

mw

O t

R

Bu

R1

Lewis acid

O

NH R

Scheme 7.24

7.4.1.5 Selec ve cleavage of N-tert-butoxycarbonyl Group The cleavage of the N-tert-butoxycarbonyl (Nboc) group can be readily achieved in presence of aluminium chloride ‘droped’ natural alumina upon exposure to microwave irradiation74 (Scheme 7.24).

7.4.1.6 Desilyla on reac ons Tert-Butyldimethylsilyl (TBDMS) ether derivatives of different type of alcohols can be deprotected to regenerate the corresponding hydroxyl compounds on alumina surface under MW irradiation conditions75 (Scheme 7.25). This approach circumvents the use of corrosive fluoride ions that are normally employed for cleaving of such silyl protecting groups.

7.4.1.7 Dethioacetaliza on reac ons Thioacetals and thioketals of aldehydes and ketones can normally be deprotected using toxic heavy metals such as Hg2+, Ag2+, Ti4+, Cd2+, Tl3+ or reagents like benzeneseleninic anhydride76. It is now possible to accomplish the dethiocetisation in high yield in solid state using clayfen65 (Scheme 7.26).

7.4.1.8 Deoxima on reac ons Oximes have been used as protecting groups for carbonyl compounds owing to their hydrolytic stability. The oximes were earlier deoximated by reagents like Raney nickel, pyridinium chlorochromate, pyridinium chlorochromate-H2O2, triethylammonium cholochromate, dinitrogen tetroxide, H2O2 over titanium silicalite-1, zirconium sulfophenyl phosphonate and bismuth chloride76. The solvent-free deprotection of protected carbonyl compounds has been effected using relatively benign ammonium persulfate on silca76 (Scheme 7.27). In the above procedure, neat oximes are mixed with a solid supported reagent and the contents are irradiated in a MW oven at full power to regenerate free adehydes and ketones. The surface of the support plays a critical role since the same reagent on a clay surface yields predominantly the Bechmann rearrangement products (i.e. the amides)77. Ketoximes could be deoximated78 with sodium periodate imprignated with moist silca gel. Aldoximes are not affected by this procedure (Scheme 7.28).

7.4.1.9 Cleavage of semicarbazones and phenyldrazones The semicarbazones and phenylhydrazones could be cleaved to regenerate the correspoinding carbonyl compounds by using ammonium persulphate impregnated on montmorillonite K10 clay (Scheme 7.29).

Organic Synthesis in Solid State

7.23

Scheme 7.25

The above cleavage (Scheme 7.29) could be achieved in minutes by the microwave exposure compared to 1-3 hr for completion in the Ultrasound promoted reaction.

7.4.1.10 Dethiocarbonyla on Dethiocarbonylations have normally been effected80 with a number of reagents like trifluoroacetic anhydride, CuCl/MeOH/NaOH, tetrabutylammonium hydrogen sulfate/NaOH, clay/ferric nitrate, NOBF, bromate and iodide solutions, alkaline, H2O2, sodium peroxide, bases like KOBu, thiophosgene, DMSO, trimethyloxonium fluoroborate, tellurium based oxidants, photochemical transformations,

7.24 Green Chemistry

Scheme 7.26

Scheme 7.27 R2

R2 C

N

OH

Wet NalO4

Silica C

MW, 1-2.5 min R1

R1

(68-93%) R1

Ph. p-ClC6H8. p-BrC6H4, p-MeOC6H4, p-NH2C6H4 : R2

R1

Ph : R2

Ph : R1

n-Bu; R2

Et; R1

R2

Scheme 7.28

Scheme 7.29

CH3

O

Organic Synthesis in Solid State

7.25

dimethyl selenoxide, benzeneselenic anhydride, benzoyl peroxide, halogen-catalysed alkoxides under PTC conditions NaNO2/HCl, Hg (OAc)2, SOCl2/CaO and singet oxygen. These reagents are often toxic and required longer reaction times and are tedious procedures. Dethiocarbonylation has been accomplished79 under solvent free conditions using clayfen or clayan (Scheme 7.30 and Scheme 7.31). S

O Clayfen or Clayan

R1

R1

90(60sec), 92-95(82-87)% R

R R1

Me, R

H, R1

Ph, R

H, Br, Me

Scheme 7.30 O

X

O

X

Clayfen or Clayan 120(90)s, 88-91(82-86) % X1

X1 S

O X

Ph, p-MeC6H4, p-MeO C6H4, X1 X

Ph, p-MeC6H4, X1

H

OMe

Scheme 7.31

7.4.1.11 Thiono on Reac ons: Synthesis of Thioketones, Thioamides, Thioesters and Thioflavonoids Conventionally the conversion of carbonyl compounds to the corresponding thioanalogues involve the reaction of the substrates with phosphorous pentasulphide under basic conditions, hydrogen sulfide in presence of acid or Lawesson’s reagent. In MW approach, no acidic or basic media is used. The carbonyl compounds are mixed with neat Lawesson’s reagent (0.5 equiv.) and irradiated with MW under solvent free condition. Using this approach, the conversion of ketones, flavones, isoflavones, lactones, amides and esters to the corresponding thioanalogues could be achieved (Scheme 7.32) in high yields. This eco-friendly approach avoids the use of dry hydrocarbon solvents like benzene, xylene, triethylamine or pyridine that are conventionally used80.

7.4.1.12 Saponifica on of Esters Hindered esters which take 5 hr under classical heating with alkali can be easily saponified under microwave condition81 using KOH-Aliquat (Scheme 7.33).

7.26 Green Chemistry

Scheme 7.32

Scheme 7.33

7.4.2 Oxida ons A number of conventional oxidising agents have been used82 for various types of oxidations. These include peracids, peroxides, manganese dioxide (MnO2), potassium permanganate (KMnO4) and potassium dichromate. These reagents have their own limitations in terms of toxicity, workup and associated waste disposal problems. A number of metal-based reagents have also been used in organic synthesis. Such reagents are toxic, have cumbersome properties and have potential danger (ignition or explosion) in handling of their complexes and difficulties encountered in the isolation of required products and waste disposal. However, the introduction of metallic reagents on solid support have overcome some of these problems and provided an attractive alternative in organic synthesis due to selectivity and ease of manuplation. Also, the immobilation of metals on the surface avoids their leaching into of environment.

Organic Synthesis in Solid State

7.27

7.4.2.1 Oxida on of alcohols (a) Using Clayfen A facile method has been developed for the oxidation of alcohols to carbonyl compound using montmorillonitre K10 clay supported iron (III) nitrate, (Clayfen) in solvent free conditions. The process is accelerated many folds by using MW irradiation83. The above oxidation presumably proceed via the nitrosonium ion intermediate. In this oxidation, no carboxylic acids are formed in the oxidation of alcohols. Using clayfen [Iron (III) nitrate] in solid state and in amounts that are half that used earlier84, it has been possible to synthesise carbonyl compounds from alcohol in high yields (Scheme 7.34)83.

Scheme 7.34

(b) Using Activated MnO2-Silica Carbonyl compounds have been obtained84 in good yield using 35% MnO2 ‘doped’ silica gel under MW irradiation conditions. By this procedures, benzyl alcohols are selectively oxidised to carbonyl compounds (Scheme 7.35).

Scheme 7.35

7.28 Green Chemistry (c) Using Chromium Trioxide Supported on Wet Alumina The use of chromium reagents in the oxidations is limited to toxicity of chromium, preparation of its various complexes (with acetic anhydride or pyridine) and crumbersome workup procedures. Chromium Oxide (Cr O3) immobilised in pre-moistened alumina is very efficient for the oxidation of alcohols to carbonyl compounds by simple mixing85 (Scheme 7.36). This oxidation is clean and does not involve any over oxidations to carboxylic acids. R2 CH

OH

CrO3

moist Al2O3

R2 C

MW, 40 S

R1

O

R1

R1

Ph, p-MeC6H4, p-MeOC6H4, p-NO2C6H4 ; R2

R1

Ph; R2

Me, Ph, Ph CO, R1

R2

H

,

Scheme 7.36

Using the above procedure, acyclic a-nitro ketones are obtained in one-pot operation utilising in situ oxidation of the nitroalkanols with premoistened alumina supported chromium trioxide86. (d) Using Iodobenzene Diacetate (IBD) “Doped” Alumina Alcohols and phenols have earlier been oxidised with iodoxy benzene, o-Iodoxybenzoic acid(1BX), bis (trifuoroacetoxy) iodobenzene (BTI) and Dess-Martin periodinane. Most of these reactions are conducted in high boiling DMSO and toxic acetonitrile media. Further, IBX has been reported to be explosive on heavy impact and heating over 200°C. It has been found that oxidation of a alcohols to carbonyl compound occurs rapidly with alumina-supported IBD under solvent free conditions and MW irradiations in quantitative yields87 (Scheme 7.37) R2

R2 MW, 1-3 Min CH

OH

C

IBD/Netural alumina

R1

O

R1

Scheme 7.37

It is interesting to note that 1, 2-benzenedimethanol undergoes cylisation to afford 1(3H)isobenzofuranone.

Organic Synthesis in Solid State

7.29

7.4.2.2 Oxida on of alkanes, bromides, carboxylic acids, cyanides and amines to carbonyl compounds Copper (II) nitrate impregnated on K10 clay (Claycop)-hydrogen peroxide is an effective reagent for the oxidations of a variety of substractes like alkanes, bromides, carboxylic acids, cyanides and amines to carbonyl compounds (Scheme 7.38) in excellent yields88.

Scheme 7.38

It may be appropriate to mention that earlier similar oxidations, were carried out by using copper (II) nitrate and hydrogen per oxide (eq. 1). …(1) 2Cu (NO2)2 + H2O2 + H2O Æ 2CuO2H + 4HNO3 However, in this case neutralisation of the reagent was necessary by KHCO3 to maintain a PH ª 5. In the procedure mentioned above in Scheme 7.38 in which claycop-H2O2 was used (mw irradiation) it was not necessary to maintain the pH of the reaction mixture.

7.4.2.3 Oxida on of -hydroxyketones to 1, 2-diketones For the oxidation of a-hydroxyketones to 1, 2-diketones, a number of reagents have been used89. They include nitric acid, Fehling’s solution, Thallium (III) nitrate, ytterbium (III) nitrate, clayfen and ammonium chlorochromate-alumina. Most of these reagents suffer from drawbacks, such as use of corrosive acids and toxic metallic compounds that generate undesirable waste materials. Recently solid support systems, copper (II) sulfate-alumina90 or oxone®-wet alumina90 under the influence of microwaves (Scheme 7.39) have been used for oxidation of a-hydroxyketones to 1, 2-diketones.

Scheme 7.39

7.30 Green Chemistry The above oxidative procedure (Scheme 7.39) is useful for the oxidation of only a-hydroxy Ketones. Primary alcohols as benzyl alcohol and secondary alcohols, e.g. 1-phenylpropan-1-o1 undergro only limited oxidative conversion which is of little practical utility. Mixed benzylic/ aliphatic a-hyroxypropiophenoe gives the corresponding vicinal diketone89.

7.4.2.4 Oxida on of sulfides to sulfoxides and sulfones Generally sulfides are oxidised to sulfoxides under strenuous conditions using strong oxidants like nitric and, hydrogen peroxide, chromic acid, paracids and periodate90. This oxidation can be conveniently carried out with desired selectivity to either sulfoxides or sulfones, using silica ‘doped’ with 10% sodium periodate under reduced power and reaction time (pulsed techniques)90. So a much reduced amount of the active oxidising agent is required which is safer and easier to handle (Scheme 7.40).

Scheme 7.40

An industrial application of the above procedure (Scheme 7.40) is that various refractory thiophenes that are often not reductively removed by conventional refining processes can be oxidised under the above conditions, e.g. benzothiphenes are oxidised to the corresponding sulfoxides and sulfones using ultrasonic and microwave irradiation respectively, in the presence of NaIO4-Silica90. A special feature of the above procedure is its applicability to long chain fatty sulfides which are insoluble in most solvents and are consequently difficult to oxidise. Selective oxidation of alkyl, ary1 and cyclic sulfides to the corresponding sulfoxides can be achieved by the solid reagent system iodobenzene diacetate (IBD)-alumina upon microwave activation (Scheme 7.41)91. In a solid state reaction with clayfen, a variety of alkyl, aryl and cyclic sulfoxides are easily oxidised to the corresponding sulfoxides in high yield upon microwave thermolysis92.

Organic Synthesis in Solid State

7.31

Scheme 7.41

7.4.2.5 Oxida on of enamines b, b-Disubstituted enamines on oxidation with KMnO4-Al2O3 in domestic (255 W, 82°C) as well as in focused (330 W, 140°C) microwave ovens under solvent free conditions give93 the carbonyl compounds. Use of focused (330W, 140°C) microwave oven gave better yields (Scheme 7.42). In the reactions conducted in an oil bath at 140°C, no ketone formation was observed. O

O N

R1

Al2O3/KMnO4

O

MW H

R1

N + O

H

R2

R2

Scheme 7.42

7.4.2.6 Oxida on of arenes KMnO4, impregnated alumina oxidises arenes to ketones within 10-30 min in solvent free conditions using focused microwaves (Scheme 7.43). KMnO4 on alumina MW O

Scheme 7.43

7.4.2.7 Aroma sa on A highly efficient aromatisation process has been achieved93a using microwave irradiation as shown below in (Scheme 7.44). It has been shown that if an electron denoting substituent is present at position 4, oxidation can proceed with concomitant dealkylation. It has also been shown that in contrast with conventionally promoted dihydropyridine oxidation, 4-alkyl substituted dihydropyridines give a mixture of products93b on the oxidation as shown in (Scheme 7.45).

7.32 Green Chemistry O

O

EtO

O OEt

HNO3, Bentonitc, MW, 1 min, 98.6%

O

EtO

OEt

N

N

H

H

Scheme 7.44

Scheme 7.45

7.4.3 Reductions 7.4.3.1 Sodium borohydride reduc on of carbonyl compounds to alcohols Sodium borohydride (NaBH4), a relatively inexpensive material has been widely used as a reducing agent because of its compatibility with protic solvents. The solid state reduction of Ketones has also been achieved by mixing the reactants with NaBH4 and keeping the mixture in a dry box for 5days. The major disadvantage in the heterogeneous reduction with NaBH4 is that the use of the solvent slows down the reaction rate while the time required in solid state reduction is too long (5 days) for it to be of any practical utility94. The reduction of carbonyl compounds with alumina supported NaBH4 using microwaves proceeds satisfactorily. The process involves94 mixing of carbonyl with (10%) NaBH4-alumina in the solid state and irradiating the mixture in a MW oven for 0.5-2 min (Scheme 7.46).

Scheme 7.46

Organic Synthesis in Solid State

7.33

The chemoselectivity of reduction with NaBH4 is evident from the reduction of trans cinnamaldehyde (Cinnamaldehyde/NaBH4-alumina 1 : 1 mol equivalent) when the olefinic moiety remains intact and only the CHO group is reduced. The rate of the reaction improves in the presence of moisture and the reaction does not proceed in the absence of alumina. The alumina support can be reused for subsequent reduction, repeatedly by mixing with fresh NaBH4 without any loss in activity. This process has been utilised for the MWenhanced solid state deuteration reactions using sodium borodeuteride impregnated alumina94.

7.4.3.2 Reduc ve amina on of carbonyl compounds Reductive amination of carbonyl compounds has been effected by sodium eyanoborohydride95, sodium triacetoxyborohydride96 or NaBH4 coupled with sulfuric acid97. These reagents involve the use of corrosive acids and result in waste generation. The environmentally benign methods developed earlier98, 99 have been extended to a Solvent-free reductive amination of carbonyl compounds using wet montmorillonite K10 clay supported sodium borohydride that is facilated by MW irradiation (Scheme 7.47)100.

Scheme 7.47

The solid-state reductive amination of carbonyl compounds on various inorganic solid supports such as alumina, clay, silica, etc. and especially a K10 clay surface rapidly affords secondary and tertiary amines100. Clay behaves as a Lewis acid and also provides water from its interlayers thus enhancing the reducing ability of NaBH4.

7.4.3.3 Reduc on of carbonyl compounds with aluminium alkoxides The reduction of carbonyl compounds with isopropyl alcohol and alumina is very well known101. It has now been possible to carry out the above reduction without any solvent under microwave irradiation conditions102 (Scheme 7.48). R1

CH3 C

R2

O

+

CH OH CH3

Aluminum alkoxide MW

Scheme 7.48

R1

CH3 CH OH

R2

+

C CH3

O

7.34 Green Chemistry 7.4.3.4 Solid state crossed Cannizzaro reac on The well known Cannizzaro reaction is the disproportionation of an aldehyde to an equimolar mixture of primary alcohol and carboxylic acid103, 104 and is restricted to aldehydes which lack the a-hydrogens. This oxidation-reduction reaction is generally conducted under strongly basic conditions and has the inherent disadvantage of the lower yields of the desired products105, 106. After the discovery of Li AlH4 in 1946, the popularity of Cannizzaro reaction in synthetic organic chemistry was lost. The crossed cannizzaro reaction105 using a scavenger and cheap paraformaldehyde provided improved yields of alcohol prior to the introduction of hydride reducing agent. This reaction is normally conducted in solution phase. It does not proceed under solventless MW-irradiation conditions using alumina surface with calcium hydroxide or in presence of strong base like NaOH. The solid state crossed Cannizzaro reaction has been found to proceed very well107 on barium hydroxide [Ba (OH)2.8H2O] surface upon mv irradiation (Scheme 7.49) using an aldehydes (which is free of a hydrogen) and formaldehyde.

Scheme 7.49

The table below gives the results obtained in case of a number of aldehydes. Product Distribution in Solvent-free Crossed Cannizzaro Reaction using Barium Hydroxide via Microwave as well as Classical Conditions. Entry

Startin Material

Reaction condition MW (min.) Oil bath (min.)

% Yield

Other

Alcohol

Acid

CHO

1

0.5

10

99 (98)

01 (02)

00 (00)

0.5

10

94 (95)

05 (o4)

01 (01)

0.5

15

83 (85)

16 (14)

01 (01)

CHO

2 Cl CHO

3 Br

Contd..

Organic Synthesis in Solid State

7.35

Contd.. CHO

0.5

12

85 (88)

14 (11)

01 (01)

0.25

10

80 (90)

20 (01)

00 (00)

6

2.0

60

83 (83)

13 (11)

04 (06)

7

2.0

37

80 (85)

10 (10)

10 (05)

1.5

15

80 (85)

19 (10)

05 (05)

1.0

180

85 (86)

10 (10)

05 (04)

2.0

240

83 (85)

09 (06)

08 (06)

1.5

40

82 (80)

15 (15)

03 (05)

4 F CHO

5 F

CHO

8

CHO OH

9 OH CHO

10 CHO O

11 O

Contd..

7.36 Green Chemistry Contd..

12

13 N

2.0

35

97 (97)

0.3 (0.3)

00 (00)

0.5

06

97 (99)

03 (01)

00 (00)

CHO

a. The relative amounts of product information are determined by GC-MS analysis and the results in the parentheses refer to the corresponding yields obtained using oil bath; the products exhibited physical and spectral properties (NMR and IR spectra) in accord with the assigned structures. Data taken from reference107.

7.4.4 Rearrangement Reac ons 7.4.4.1 Pinacol-pinacolone rearrangement Solventless pinacol-pinacolone rearrangement using microwave irradiation108 has been reported. The process involves the irradiation of the diols with Al3+ montmorillonite K10 clay for 15 min to give the rearrangement products in good yields (Scheme 7.50). These results are comparable to conventional heating is an oil bath wherein the reaction takes too long (15 hr). OH

OH

3+ Al – Montmorillonite

O

MW, 15 min, (98-99%)

Scheme 7.50

7.4.4.2 Ring expansion An efficient ring expansion transformation is described109 under solventless conditions (Scheme 7.51). This procedure is superior than the reaction conducted in conventional methanolic solution.

Scheme 7.51

7.4.4.3 Backmann rearrangement Usually, Beckmann rearrangement of oximes of ketones are converted into anilides by heating with acidic reagents like PCl5, HCOOH, SOCl2, etc. However, a solid-state microwave assisted Beckmann Rearrangement has been reported110,111. In this method, oxime of a kelone is mixed with

Organic Synthesis in Solid State

7.37

montmorillonite K10 clay in dry media and mixture irradiated for 7 min. in a microwave oven to give the corresponding anilide in 91% yield (Scheme 7.52).

Scheme 7.52

7.4.4.4 Benzil-benzilic acid rearrangement Usually, the above rearrangement has been carried out by heating benzil and alkali metal hydroxides in aqueous organic solvent. It is found that rearrangement proceeds more efficiently and faster in solid state112 and it takes 0.1 to 6 hr for completion and the yields are 70-93%. The Benzil-Benzilic acid rearrangement could be conducted in solid state by MW irradiation113 reducing considerably the time of the reaction and good yield (Scheme 7.53).

Scheme 7.53

Some other examples of rearrangement reactions include Fries Rearrangement on K10 clay that affords a mixture of ortho and para products114; Fries rearrangement that leads to the formation of flavonones115 and thia-Fries rearrangement of arylsufonates using aluminium trichloride and zinc chloride on silica gel116.

7.4.5 Isomerisa on Reac ons 7.4.5.1 Octylthiocyanate-octylisothiocynate isomerisa on Octylbromide undergoes thicyanation reaction117 with potassium thiocyanide, KSCN in presence of MW. The formed octylthiocyanates undergo further isomerisation to yield117 isothiocyanates under mw irradiation (Scheme 7.54).

7.38 Green Chemistry

Scheme 7.54

7.4.5.2 Eugenol isoeugenol isomerisa on Isoeugenol, an important compound used in flavour industries to manufacture vanillin, is obtained by base catalysed MW assisted isomerisation of naturally occurring eugenol under solvent free conditions in presence of potassium tert-butoxide and a catalytic amount of phase transfer reagent117a (Scheme 7.55).

Scheme 7.55

7.4.6 Condensa on Reac ons 7.4.6.1 Knoevenagel condensa on Knoevenagel condensation of aldehydes with creatinine takes place under solvent free reaction conditions at 160-170° using focused MW irradiation118 (Scheme 7.56).

Scheme 7.56

Organic Synthesis in Solid State

7.39

Similarly, the knoevenagel condensation of 5-nitro furaldehyde with active methylene compounds under MW irradiation using K10 and ZnCl2 as catalyst give 5-nitro furfurylidines119 (Scheme 7.57). CO2 Et

K10 ZnCl2

+ O

O2N

CO2 Et

MV CO2 Et

CHO

O2N

O

CH

C CO2 Et

Scheme 7.57

The classical Pechmann approach for the synthesis of coumarins via the MW assisted reaction120 has been extended to solvent-free system involving Knoevenagel condensation of salicylaldehydes with a variety of ethyl acetate derivatives under basic conditions (piperidine) to afford coumarins (Scheme 7.58). CHO

R2

R2

Piperidine

+ OH

R

CO2 Et

MV O

R

O

R1

R1

Scheme 7.58

7.4.6.2 Wi ng olefina on reac ons Stable phosphorous ylides undergo Wittig reaction with Ketones in the absence of solvent on MW irradiation to give improved yields when compared to conventional heating procedures121. The preparation of several phosphonium salts has been reported using a domestic MW oven wherein the reaction of neat triphenyl phosphine with organic halides show remarkable rate enhancement in a pressurised vessel122 (Scheme 7.59).

Scheme 7.59

7.40 Green Chemistry 7.4.6.3 Synthesis of imines, enamines, nitroalkenes and n-sulfonylimines, hydrazones and amides The conventational preparation of the titile compounds involve the azeotropic removal of water from the condensation reaction intermediates that are generally catalysed by p-toluene sulfonic acid, titanium (IV) chloride or montmorillonite K10 clay. The use of a Dean Starks apparatus is an essential requirement that necessatiates the use of large excess of aromatic hydrocarbons such as benzene or toluene for azeotropic water removal. Imines and enamines have been synthesised via the reaction of primary and secondary amines with aldehydes and ketones respectively. (Schemes 7.60 and 7.61 respectively). Using MW expediated dehydration reactions using montmorillonite K10 clay98 or Envirocat reagent99, EPZG®.

Scheme 7.60

Clay catalysed solvent free MW synthesis of imines

Scheme 7.61 Clay catalysed solvent free MW synthesis of enamines

Organic Synthesis in Solid State

7.41

In both the above synthesis, the generation of polar transition state intermediates that couple to microwave is mainly responsible for rapid imine- or enamine forming reactions. The use of a MW oven at lower power levels or intermittent heating has been used to prevent loss of low boiling reactants98, 99. , -Unsaturated Nitroalkenes have been prepared by the well known Henry reaction involving the condensation of nitroalkanes with carbonyl compounds under MV irradiation in presence of catalytic amounts of ammonium acetate123, thus avoiding the use of large excess of polluting nitrohydrocarbons usually employed in these reactions (Scheme 7.62).

Scheme 7.62

MW-expediated Synthesis of unsaturated nitroalkenes

A number of functional groups such as nitroalkenes, N-substituted hydroxylamines, amines, ketones oximes and a-substituted oximes and ketones124-26 could be prepared from a, b-unsaturated nitroalkenes. N-sulfonylimines have been synthesised by a one pot reaction involving MW heating of alkehydes with sulfonamides using relatively benign reagents, calcium carbonate and montmorillonile K10 clay127(Scheme 7.63). R1

R1

CHO R

+

Where R R2

N

SO2

CaCO3/clay/CH(OMe)3

R

MW, 30 – 70 min

H2N SO2

R2

CH

R2

H, Me, COOMe, Cl; R1

H, OMe, OCOMe, Br;

H, OMe, OCOMe

Scheme 7.63

One pot solvent free MW preparation of N-sulfonylimines

The formation of hydrazone derivatives have been achieved in toluene128. Further the reaction of hydrazone with alkali (KOH) accomplishes Wolff-Kichner reduction that proceeds in good yield under MW irradiation conditions129. Recently, it has been shown that a solvent-free and catalyst free reaction of hydrazines with carbonyl compounds in possible upon MW irradiation in

7.42 Green Chemistry household MW oven (Scheme 7.64)130. The reaction is completed below the melting points of the two reactants possibly via the formation of a eutectic131.

Scheme 7.64

MW assisted Synthesis of hydrazones

Amids have been synthesised by a solid-state synthesis by the reaction of non-enolisable esters and amines in a household MW oven using potassium tert-butoxide132 (Scheme 7.65). O R COOR1

+

2

H2NR

t Bu OK MW

R

C

NHR

2

Scheme 7.65

7.4.7 Synthesis of Heterocyclic Compounds 7.4.7.1 Aziridines Aziridines have been synthesised by a unique method using focused microwave approach under solvent free conditions, where it is observed that the elimination predominates over the Michael addition under MW irradiation unlike classical heating under the same conditions (Scheme 7.66)133.

Scheme 7.66

7.4.2 Benzimidazoles Benzimidazoles are prepared rapidly by condensation reaction of ortho-esters with o-phenylenediamines in presence of KSF clay under either refluxing conditions in toluene or solvent-free conditions using focused microwave irradiation (Scheme 7.67)134.

Organic Synthesis in Solid State H2N

EtO EtO

C

H

N KSF MWl

+

EtO

7.43

H2N

N H

Scheme 7.67

4-Alkylidine-1H-imidazol-5 (4H) ones are obtained in good to excellent yield by 1, 3-dipolar cycloaddition, in solvent free conditions under focused microwaves from an activated imidate and aldehydes in the presence of catalytic amounts of anhydrous acetic acid (Scheme 7.68)135. Me Me N EtO

CO OMe

+

R CHO

N

MeCO2H MWl

N MeOOC

Scheme 7.68

An expediations solvent-free synthesis of pyrazolino/iminopyrimidino/thiooxopyrimido imidazoline derivatives from oxazolones on solid support using microwave has been described. The reaction time was brought down from hours to minutes as compared to conventional heating (Scheme 7.69)136. A general method for solid phase synthesis of N-arylated benzimidazoles, imidazoles, triazoles and pyrazoles has been demonstrated utilising copper (II) mediated coupling of aryl boronic acid under MMI136 (Scheme 7.70).

7.4.7.3 Pyrazoles Pyrazoles are synthesised by a one pot reaction involving cyclocondensation of diarylnitrilimines with alkynes and disubstituted alkenes using irradiation with microwaves137. In this synthesis, the nitrilimine was generated in situ (Scheme 7.71).

7.4.7.4 Pyrroles A simple synthesis of a tetraphyrrolic macrocycle under dry media conditions with microwave activation was performed. Pyrrole and benzaldehyle adsorbed on silica gel afforded tetrahydroporphyrin within 10 min, where as conventional heating needed 24 hr (Scheme 7.72)137a. Synthesis of substituted pyrrole over silica gel under MW irradiation has also been reported (Scheme 7.73)137a.

7.4.7.5 Azoles Oxazolines are readily prepared from carboxylic acids and a, a, a-tri (hydroxymethyl) methylamine under MWI (Scheme 7.74)138.

7.44 Green Chemistry

Scheme 7.69

Scheme 7.70

Organic Synthesis in Solid State

Scheme 7.71

H

O

+

NH

Silica gel MWl

Scheme 7.72

Scheme 7.73

N

N

NH

N

7.45

7.46 Green Chemistry OH R CO OH

+

H2 NC (CH2 OH)3

O

MWl , 2–5 min 80 – 95 %

R

N OH

Scheme 7.74

1, 3-Dipolar cycloaddition of N-methyl-C-Phenylnitrones to methyl acrylate yield isoxazolidines on MW irradiation in presence of solid supports (silica gel, alumina) (Scheme 7.75)139. CH3 H Ph

+ N

CH3 + O

–

Ph

MWl COOCH3

CH3

N

Ph O

H3C OOC

O

+ H3C OOC

CH3 Ph +

N

CH3

N

Ph O

+ CO OCH3

N O CO OCH3

Scheme 7.75

The solid supported synthesis of azoles and diazines using K2CO3 as a solid support has been reported140 (Scheme 7.76). This novel technique involves aqueous work up.

Scheme 7.76

Organic Synthesis in Solid State

7.47

1, 2, 4-Oxadiazoles are obtained in good yield by the reaction of amidoximes with isopropenyl acetate in presence of KSF clay under MWI (Scheme 7.77)141.

Scheme 7.77

The 1, 2, 4-oxindiazoles were also obtained141 by MWI from o-acylamidoximes absorbed on alumina (Scheme 7.78).

Scheme 7.78

7.4.7.6 Isoxazoles Reaction of aromatic aldehydes with phenyl nitromethane under microwave irradiation (MWI) on basic alumina afforded excellint yields (90-96%) of isoxazoles within 2-3 minutes (Scheme 7.79)141a.

Scheme 7.79

7.4.7.7 Thiazoles Synthesis of thiazole (a group of pharmacologically important compounds) and their derivatives is generally accomplished by a-haloketones142 or a-tosyloxyketones143 and thiourea under acidic conditions. However, these methods often involve longer reaction times and suffer from the requirement of the use of lachrymatory a-haloketones and hazardous reagents that generate a waste stream of spent solvent. A rapid solvent-free approach to thiazoles is by simple mixing of thiamides with a-tosyloxykekone in a clay catalysed reaction that accelerated by MW irradiation144 (Scheme 7.80).

7.48 Green Chemistry O OTS

S R

C

NH2

+

K 10 clay MW

R1 R 4–Cl C6H4

R1 H, Cl, Me, OMe

4–MeO C6H4

H, Cl, Me, OMe

R1

N S

R

Scheme 7.80

7.4.7.8 Pyridines Microwave irradiation of aldehydes and b-ketoesters and urea in presence of silica gel gave 1, 4-dihydropyridines (Scheme 7.81)145.

Scheme 7.81

7.4.7.9 Quinolines KSF clay catalysed Friedlander condensation of 2-aminoaldehydes or ketones with carbonyl compounds containing a-methylene group has been achieved in solvent free conditions under MWI to give polycyclic quinoline derivative (Scheme 7.82)146.

Scheme 7.82

In an alumina supported synthesis of antibacterial quinolines using microwaves where in the reaction time, was brought down from hours to seconds with improved yields as compared to the conventional heating (Scheme 7.83)147.

Organic Synthesis in Solid State

7.49

Scheme 7.83

7.4.7.10 Quinolones, quinolinones and quinazolines Cyclisation of readily available 2¢-aminochalkones using montmorillonite K10 clay under MWI conditions, gave 2-aryl-1, 2, 3, 4-tetrahydro-4-quinolones which are valuable precursors for medicinally important quinalones (Scheme 7.84)148.

Scheme 7.84

2, 3-Disubstituted quinoxalines have been synthesised from the aryl or alkyl acyloins and o-phenylenediamine under MW irradiation for 3-6 min (Scheme 7.85)149. O

NH2 +

R

C

OH CH

R

NH2 R

Alkyl or aryl

Scheme 7.85

N

R

N

R

MW

7.50 Green Chemistry 7.4.7.11 4-Aminoquinazolines 4-Aminoquinazolines have been synthesised in good yields in a MW oven starting from cyanoaromatics and anthranilonilonitriles in the presence of 10% t-BuOH150. One-pot MW-enhanced synthesis of selective glycine-site NMPA receptor antagonists, 3-aryl-4-hydroxyquinolin-2(IH)ones have been developed via the amidation of malonic ester derivatives with anilines followed by subsequent cyclisation of the intermediate, malondianilides (Scheme 7.86)151.

Scheme 7.86

7.4.7.12 Pyrimidines A one pot sythesis of pyrano [2, 3-d] pyrimidines from thiobarbituric acids under MW irradiation has been reported. A significant reduction in time and yield enhancement was observed (Scheme 7.87)152. R N

S R

N O

R O

CH3 C(OEt)3 C6 H5CONH CH2 COOH Basic alumina MWl

N

S

O

O

N NHCOC6H5

R O

CH3

Scheme 7.87

Pyrimidino [1, 6-a] benzimidazoles (Scheme 7.88) and 2, 3-dihydroimidazo [1, 2-c] pyrimidines (Scheme 7.89) have been synthesised153 under focused microwave irradiation.

Scheme 7.88

Organic Synthesis in Solid State

7.51

R H N

O

EtO N

C

R2

R1 H

R1

N H

N

MWl 15 min

+ R

N

N R2

Scheme 7.89

An efficient synthesis of benzopyranopyrimidenes using three different solid supports viz., acidic alumina montmorillonite, silica gel has been carried out. The products were obtained with improved yields as compared to conventional heating (Scheme 7.90)154. O

O

O

O +

OH

R CHO X

O

H2N C NH2 Acidic solid support O

O R

HN

NH X

Scheme 7.90

7.4.7.13 Oxadiazines Condensation of N, N¢-dimethyl urea, paraformaldehyde and primary amines using montmorillonite K10 clay in dry media under microwave irradiation lead to the formation of triazones. However, condensation of N, N¢-dimethyl urea and paraformaldehyde supported on montmorillonite K10 using MWI gave 4-Oxo-Oxadiazinones (Scheme 7.91)154a.

7.4.7.14 Thiadiazepines An environmentally benign synthesis of 1, 2, 4-triazolo [3, 4-b]-1, 3, 4-thiadiazepenes from substituted triazoles and chalkones on basic alumina under MW irradiation has been achieved (Scheme 7.92)155.

7.52 Green Chemistry O O (CH2O)n

+ Me HN

NHMe

MeN

Montmorillonite

N Me

K 10, MWl O

R NH2 Montmorillonite K 10

MWl

O Me

N

Me

N N R

Scheme 7.91 N C6H4

H N

C

N

R

N

SH

NH2

Basic alumina MWl

CH

+ O

C C6H4

N

R1

X

R

N

S H

HN

C6H4 R1 C6H4 X

H

Scheme 7.92

7.4.7.15  -Lactams An efficient and rapid synthesis of a number of b-lactams has been described156 under MW irradiation. Further in closed Teflon vessels using KF and phase transfer catalyst (PTC), b-lactams have been synthesised in few minutes from ketene silyl acetal and aldimines (Scheme 7.93)157.

Scheme 7.93

N-(4-Hydoxycyclohexyl)-3-mercapto/cyano-4-aryl-azetidine-2 ones have been synthesised from N-(4-hyrdroxycyclohexyl)-arylaldimine by reacting with ethyl a-mercapto/a-cyanoacetate on basic alumina under microwave irradiation (Scheme 7.94), where in not only the reaction time was

Organic Synthesis in Solid State

7.53

brought down from hours to minutes in comparison to conventional heating but also the yields were improved158.

Scheme 7.94

Deacylation of cephalosporins, a growing class of b-lactam antibiotics, has been investigated using enzymatic and microwave activated solid phase techniques. The deacylation was achieved in less time with better yields (Scheme 7.95)159.

Scheme 7.95

Reaction of 7-amino-3 [5¢-methyl-1¢, 3¢, 4¢-thiadiazole-2¢-ylthiomethyl] cephalosporanic acid with heterocyclic amines using alumina under microwave irradiation afforded new cephalosporin analogs in shorter reaction time with improved yield as compared to conventional heating (Scheme 7.96)160. H2N

S

N

CH3

S

O COOH

+

MWl Basic alumina

S N

O C O

N

S N N S

N

R

N

S

N

H2N

N

N H

CH3 R

S

CH3, C6H5, C9H19, C11H23, 3-pyridinyl, 4-ClC6H4

Scheme 7.96

N

H2N S

R

.

7.54 Green Chemistry An environmentally friendly safe method developed for the preparation of 3-carbomoyl cephalosporin derivatives such as cefuroxime uses o-transcarbomylase, an enzyme of microbial origin for the conversion of 3-hydroxyfunction to the desired 3-carbomyl group. This new synthesis replaces the conventional chemical route, which employs hazardous isocyanates such as dichlorophosphenyl isocyanate or chlorosulfinyl isocyanate to achieve the same conversion (Scheme 7.97)160a. H

H

H

H

S R

S

HN OH

N

o — Trans Carbomylase

R

HN

O

NH2

N O O

O

OR1

O R R1

OR1

H, alyl group H or carboxyl protecting group

Scheme 7.97

7.4.7.16 Furans Naturally occurring, pharmacologically important 2-aroylbenzofuran are easily obtained under basic solvent-free conditions from a-toyloxyketones and salicylaldehydes in the presence of potassium fluoride doped alumina using MW irradiation (Scheme 7.98)161.

Scheme 7.98

7.4.7.17 Flavones Flavonoids are a class of naturally occurring phenolic compounds widely distributed in the plant kingdom, the most abundant being the flavones. Members of this class are known for a wide variety of biological activities and have been useful in the treatment of various diseases. Flavones have been prepared by a variety of methods such as Allan Robinson synthesis and synthesis from chalkones via intramolecular Writtig strategy162. The most common approach, however, involves the Bakervenkatraman rearrangement, where in o-hydroxyacetophenone is benzoylated to form the benzoyl ester followed by treatment with base (pyridine/KOH) to effect an acyl group migration, forming a 1, 3-diketone162. The diketone formed in then cyclised under strong acidic conditions using H2SO4 and acetic acid to give the flavones.

Organic Synthesis in Solid State

7.55

A solvent free synthesis of flavones involves the microwave irradiation of o-hydroxydibenzoylmethanes adsorbed on montmorillonite K10 clay for 1-1.5 min (Scheme 7.99)162.

Scheme 7.99

7.4.7.18 Isoflavan-3-enes Isoflavan-3-enes posses the chromene nucleus and are well known oestrogens. Several derivatives of these oxygen heterocycles have attracted the attention of medical chemists163-165. Several methods are available for the synthesis of chromene derivatives. The MW approach has been extended to a one pot synthesis of 2-aminosubstituted isoflavan-3-enes that involves the generation of the enamine derivative in situ followed by reaction with salicylaldehydes in the same vessel (Scheme 7.100)166-168.

Scheme 7.100

7.5 MISCELLANEOUS REACTIONS 7.5.1 A Single Step Conversion of Aryl Aldehydes to Aroma c Nitriles The conversion of aldehydes to the corresponding nitriles is an important transformation169. In most of the cases the aldoxime is first prepared and subsequently dehydrated using a

7.56 Green Chemistry wide variety of reagents like O, N-bis (trifluoroacetyl) or trifluoroacetohydroximic acid170, chloramines/base171, (H2SO4/SiO2)172, p-chlorophenyl chlorothioformate/pyridine173, triethylamine/ dialkyl hydrogen phosphinates174, TiCl4/pyridine175, triethylamine/phosphonitrilic chloride176 and 1, 1¢-dicarbonylbiimidazoles177. These methods involve dehydration of oxime which is a time demanding process for one pot reactions178. It is found that aldehydes are rapidly converted into nitriles in good yield (89-90%) with hydroxylamine hydrochloride supported on montmorillonite K10 clay in the absence of solvent179,180. The above mentioned reaction is a general one as exemplified by a variety of aldehydes (Scheme 7.101) that undergo this facile conversion to afford high yield of the corresponding nitriles (89-90%) within a short MW irradiation179,180. O R1

C

H

K10 Clay — NH2 OH. HCl Microwave 1 – 1.5 min

R2

R1

C

N

R2 89 – 95%

R1

H; R2

R1

R2

H, OH, Br, Me, OMe, NO2 OMe

Scheme 7.101

7.5.2 Synthesis of Anhydrides from Dicarboxylic Acids Dicarboxylic acids can be converted into anhydrides (Scheme 7.102) in the presence of isopropenyl acetate (which acts as a water scavenger) under microwave irradiation181 using montmorilloniteKSF. The driving force is the formation of acetone. COOH

OCOCH3 Montmorillonite

O

KSF O

mw COOH

O

Scheme 7.102

The method is rapid and convenient and avoids using corrosive reagents like CH3 COCl, SOCl2, (CH3 CO)2O.

7.5.2a Side Chain Nitra on of Styrene to -nitrostyrene A facile solid state synthesis of b-nitrostyrene from readily available feedstock, styrene and its substituted derivatives using inexpensive ‘doped’ clay reagents, Clayfen and clayan (Scheme 7.103)

Organic Synthesis in Solid State

7.57

has been described182. In this procedure, the neat reagent, styrene and clayfen or clayan are mixed in a glass container and the solid mixture heated in an oil bath (~ 100-110°C, 15 min) or irradiated in a microwave oven (~ 100-110°, 3 min). In the latter case, intermittent warming for 30s intervals to maintain temperature below 60-70° gives good results. The major product is b-nitrostyrene. NO2 CHO Clayfen or Clayan +

MW or at bath R Where R

R

R

Major

Minor

H, Cl, CH3, OCH3

Scheme 7.103

In case the reaction is conducted in solution phase, polymeric products are formed.

7.5.3 Oxida ve Coupling of -napthols b-Napthols undergo self coupling reaction in presence of iron (III) chloride, FeCl36H2O under focused microwave irradiation in solvent free conditions (Scheme 7.104)183. R

R OH

MW R

OH

FeCl3 6H2O

R

R

OH

R (40 –95%)

Scheme 7.104

7.5.4 Methylena on of 3, 4-dihydroxybenzaldehyde Methylenation of 3, 4-dihydroxybenzaldehyde takes place rapidly in presence of a phase transfer catalyst on a benign calcium carbonate surface. In this case, the bonding of the vicinal hydroxyl groups is low thereby enhancing the reaction with the alkylating agent under solvent-free microwave irradiation (Scheme 7.105)184.

7.58 Green Chemistry

Scheme 7.105

7.5.5 Michael Addi on A number of 2¢-hydroxy, 4¢, 6¢-dimethylchalcones undergo a solid state intramolecular Michael type addition to yield185 the corresponding flavanones (Scheme 7.106). Me

O

Me

OH

R

R

50 – 60° Solid, MWl

Me

O

Me

O

2¢ Hydroxy-4¢ , 6¢-dimethylchalcones

5, 7-dimethyl flavanones

H, Cl or Br

R

Scheme 7.106

The Michael addition of chalcone to 2-phenylcyclohexanone under PTC conditions186 gave 2, 6-disubstituted cyclohexanone derivatives in high disteroselectivity (99% ee) (Scheme 7.107). O

O

Ph +

2-Phenyl cyclohexanone

COPh Ph

K O Bu

t

Ph

Ph

H

O Ph

n-Bu4 NBr, MW 99% ee

Chalcone

Scheme 7.107

An interesting example in the solvent free Michael addition reaction of nitromethane to chalcone in the presence of alumina under microwave conditions that gives the adduct in 90% yield (Scheme 7.108)187.

Scheme 7.108

Organic Synthesis in Solid State

7.59

7.5.6 Synthesis of Bridgehead Nitrogen Heterocyclic Compounds Microwave assisted synthesis of bridgehead nitrogen heterocycles has been achieved. Thus, pyrimidimo [1, 6-a] benzimidazoles are synthesised from N-acylimidates and activated 2-benzimidazoles (Scheme 7.109)188.

Scheme 7.109

In a similar way MW irradiation of N-acylimidates and imidazoline ketene aminals give 2, 3-dihydroimidazo -1, 2-c] pyrimidines (Scheme 7.110)189. R H N

O C2H5 O R2

N

Where R1, R2

C

R1

+ N H

alkyl, R

H R

CN, CO2Et

R1

N

MW N

N R2

Scheme 7.110

Microwave-accelerated synthesis of the corresponding bridgehead heterocycles gets completed in a short time by the reaction of a-tosyloxyketones with ethylenethioureas (Scheme 7.111)190. In the conventional heating in an oil bath the reaction remains incomplete190, 191.

Scheme 7.111

7.60 Green Chemistry Pyrazolo [3, 4-b] quinolines and pyrazolo [3, 4-c] pyrazoles have been synthesised using MW irradiation from b-chlorovinylaldehydes and hydrazines in presence of p-toluene sulfonic acid (p-Ts OH) (Scheme 7.112)192. R1

CHO

R1

p-TsOH

N RNHNH2 MW

Cl

N

N

N

R H, Me, Cl, and R

Where R1

H, Ph

(78 – 79%)

Scheme 7.112

Imidazo [1, 2-a] pyridines, imidazo [1, 2-a] pyrazines and imidazo [1, 2-a] pyridimenes are obtained under solvent free condition using MW irradiation193 by the ugi reaction. The procedure consist in mixing aldehydes (aliphatic, aromatic and vinylic) and the corresponding 2-aminopyridine, pyrazine or pyrimidine in presence of catalystic amount of clay (50 mg) to generate the iminium intermediate. Subsequently isocyanate (aliphatic, aromatic or cyclic) is added to the same container and the reactants are further exposed to MW to afford the corresponding imidazo [1, 2-a] pyridines, imidazo [1, 2-a] pyrazines and imidazole [1, 2-a] pyrimidines respectively (Scheme 7.113). R

NH2 R R1

CHO

N +

NC

X X X

X

Microwave

y

Clay

R1

N H

N N

X y

y C C, y N N, y C

Scheme 7.113

7.5.7 Organometallic Reac ons (Reac ons Involving C-C Bond Forma on) C-C Bond forming reactions, viz., Suzuki, Heck and Stille reactions194-196 are found to be transitionmetal catalysed MW assisted reactions. Suzuki cross coupling of aryl halides with arylboronic acid (Suzuki cross coupling reaction) using PdCl2, KF and poly ethylene glycol (PEG) take place under microwave irradiation to give biaryls. This environmentally friendly process offers easy access to biarlys194 (Scheme 7.114). HO Br

+

B HO

PdCl2, KF, MW PEG – 400

Scheme 7.114

Organic Synthesis in Solid State

7.61

In the above protocol, the catalyst can be recyled195. Recently, a ligand free palladium-catalyused Suzuki reaction has been reported in water196, which uses low palladium loadings (0.4 mol%). The original molybedenum-catalysed asymmetric allylic alkylation developed by Trost et al. has now been transformed into a fast and efficient reaction under non-inert conditions using MW acceleration197. This modification has enabled the reaction to be performed in one-step employing stable precatalyst [Mo(CO)6] in low concentration and under air-stable environment. The scope of the flourous stille coupling with respect to both the tin and triflate/halide components has been extended using the MW protocol that gets completed in 2 minute compared to 1 day in the conventional thermal reaction198. A number of reactions have been described earlier in solution phase chemistry mostly palladium catalysed reactions of aryl halides and olefins199 for C-C bond formation reactions200. Palladium acetate is the commonly used catalyst, although other palladium complexes have also been used. A solvent free Heck reaction has been conducted in excellent yields using a household MW oven and palladium acetate as catalyst and triethylamine as base (Scheme 7.115)201. The reaction takes much shorter time compared to classical heating methods.

Scheme 7.115

A MW-assisted palladium catalysed coupling of heteroaryl and aryl boronic acids with iodo and bromo-substituted benzoic acids, anchored on Tenta Gel has been achieved202. An environmentally friendly Suzuki cross-coupling reaction has been developed which uses small amounts of recyclable polyethylene glycol (PEG) as the reaction medium and palladium chloride as catalyst195. A solventfree Suzuki coupling has also been reported on palladium-doped alumina in the presence of potassium fluoride as a base203, which has been extended to Sonogashira coupling reaction. In the latter case terminal alkynes are coupled with aryl or alkenyl iodides on palladium-doped alumina in the presence of triphenyl phosphine and iodide (Scheme 7.116)204.

Scheme 7.116

Intramolecular hydroacylation of 1-alkenes with aldehydes is a greener alternative to classical approach using homogeneous catalyst in toluene. The reaction is a general reaction and uses Rh(I) complex (Wilkinson catalyst) under solvent-free conditions and there is considerable rate enhancement of polar transition intermediates205.

7.62 Green Chemistry

7.5.8 Aroma c Subs tu on b-Carbolines have been synthesised via a Graebe-Ullmann reaction. The reaction involved206 microwave irradiation of benzotriazole and chloropyridines in the absence of solvent in presence of pyrophosporic acid. The formed product (2) is obtained in 13-16 minutes (Scheme 7.117). Attempts to support the reactants on silica gel or montmorillonite gave only moderate yield of the intermediate pyridyl benzotriazole (1). If the reaction is carried out under thermal condition without Microwaves, the required product (2) is obtained in similar yields but required much longer reaction times. R

N N

R

R

N

N

N H

Cl

R

R

N H2PO7, MW

MW

R

R N

N N

R ll

N

R

(2)

(1)

Scheme 7.117

Bisnaphthols have been prepared in moderate to good yields by microwave irradiationn of dry solid reagents, FeCl3. 6H2O and the appropriate naphthol in a resonance cavity.

7.5.9 Pericyclic Reac ons Some Pericyclic reactions have been discussed in Chapter 8 (Section 8.3.29) under microwave irradiation. An intra molecular Diels-Alder reactions has been reported by adsorbing the furan derivative (1) on silica gel, saturating with water and irradiating with microwaves. Cycloadducts (2) and (3) were obtained in 64% yields207. In this reaction (Scheme 7.118). water is crucial for the success of this transformation, acts as a source of heat, accelerates the cycloaddition by the hydrophobic effect and favours the hemiacetalketone equilibrium. Conventional thermolysis of the Furan (1) gives poor yields of cycloaddition due to substantial decomposition.

Scheme 7.118

Organic Synthesis in Solid State

7.63

Methyl nitroacetate and dimethyl acetylene dicarboxylate in presence of acid (SiO2 or molecular sieve) in an open vessel on microwave irradiation gave the cycloadduct in moderate to good yield208 (Scheme 7.119).

Scheme 7.119

Cycloheten-3-ol (1) on microwave irradiation with triethyl orthoacetate and KSF clay in DMF underwent ortho-ester claisen rearrangement to give the rearranged product (2) in good yield209 (Scheme 7.120). Under the conventional conditions in which propionic acid was used as a catalyst (as oppose to KSF clay), the reaction required 12.5 hours heating to give a 68% yield of the product (2). OH CH3C(CEt)3, KSF clay, DMF CO2Et

MW 9 min, 100% (1)

(2)

Scheme 7.120

Fishcher Indole Synthesis has be carried out210 using cyclohexanone and phenyl hydrazine in presence of montmorillonite KSF clay (Scheme 7.121). Using ‘dry conditions’ for a closely related cyclisation gave only traces of the product211.

Scheme 7.121

Montmorillonite clays has also been used for other organic transformations including [2, 3] sigmatropic rearrangements. Thus, adsorption of 3-methyl but-2-en-1-ol (1) onto KSF clay followed by microwave irradiation for 5 minutes give the rearranged product (2) (Scheme 7.122) in 75% yield212. When the reaction was carried out by conventional heating at 135°C for 5 min no product could be isolated.

7.64 Green Chemistry

Scheme 7.122

A number of other sigmatropic rearrangements can be carried out by adsorption of the substrates on y zeolites. Two of such rearrangements213 are given in Scheme 7.123.

Scheme 7.123

7.5.10 Alkyla ons Alkylation of carboxylic acids has been carried out using microwaves. Thus, potassium acetate and octyl bromide give the alkylated product in good yield using microwave irradiation214 (Scheme 7.124).

Scheme 7.124

On larger scale (up to 0.1 mole) the above alkylation could be carried out by irradiation in open vessels. An alternative procedure involving alkylation of carboxylic acids with alkyl halides in presence of phase transfer catalyst (PTC) has been developed. It gives yields of esters with 10 minutes irradiation. Thus, the reaction of hexanoic acid with benzyl bromide and PTC in a sealed tube gives the ester in good yield (72%)215. Sulfones have been prepared by microwave assisted alkylation of sodium phenylsulphinate. Thus, irradiation of a mixture of the sulphinate and benzyl halide adsorbed onto alumina gave the desired sulfone in 40-99% yield216 (Scheme 7.125).

Organic Synthesis in Solid State

7.65

Scheme 7.125

Allyldiphenylphosphine oxide has been obtained via phosphinic allylation. Though the reaction proceeds satisfactority by stirring the neat reagents at room temperature overnight, but the reaction time can be reduced to 1-3 minutes using microwave irradiation (Scheme 7.126)217.

Scheme 7.126

Active methylene groups can be alkylated using microwave irradiation. Thus, treatment of phenylsulphonylacetate with alkyl halide in presence of potassium carbonate and phase transfer catalyst leads to the alkylated product (Scheme 7.127) in good yield after 2-3 minutes of microwave irradiation218. Bu K2CO3 PTC, BuBr, MW, 3 min, 83% PhSO2

CO2Et

PhSO2

CO2Et

Scheme 7.127

7.5.11 Condensa ons Following are given some condensation reactions of importance. Condensation of cyclohexane 1, 2-dicarboxylic acid to the corresponding anhydride has been reported219 (Scheme 7.128). O CO2H

KSF or p-TSA, MW, 3–4 min, 72–94% O

CO2H

OAc O

Scheme 7.128

Active methylene compounds have been condensed with aldehydes using microwaves. Thus, condensation of 5-nitro-2-furaldehyde with active methylenes (like ethyl cyanoacetate) was achieved in high yields by adsorption of the reagents on the Lewis acid K10, ZnCl2 and irradiation220 with microwaves (Scheme 7.129).

7.66 Green Chemistry CN EtO2C OHC

K10, ZnCl2

MW, 1 min, 84%

NO2

O

CN

EO2C

NO2

O

Scheme 7.129

A closely related condensation was carried out on Al2O3-KF as examplified in the following (Scheme 7.130)221.

Scheme 7.130

Pyrimido [1, 6-a] benzimidazoles have been synthesised by microwave cyclocondensation approach. Thus, irradiation of neat benzimidazole (1) and n-acylimidate (2) is an open vessel in a microwave oven gave a good yield of the benzimidazole (3) (Scheme 7.131). The reaction involves a conjugate addition-elimination, condensation sequence. The use of open vessel permits the vaporization of ethanol and water produced in the reaction222. O

MW, 30 min, open vessel, 86%

N

N

N EtO

N H

(2)

CO2Me

N CO2Me N (3)

(1)

Scheme 7.131

Enaminoketones are obtained223 by the microwave irradiation of a b-diketone with an amine as exemplified in (Scheme 7.132). O

O H

Me

N

MW, 3 min, SiO2 open vessel

O

Ph Me

Ph

N

(1)

Scheme 7.132

Organic Synthesis in Solid State

7.67

The above procedure involves supporting the reagents on silica gel or clay K10. If in some cases the reaction is carried out in a sealed vessel the amide is formed as illustrated in Scheme 7.133. It is believed that in closed vessel the water of condensation hydrolyses the emioketone [(1), Scheme7.132] to give the product, (Scheme 7.133). O

O N

H Me

90%

Me

O

MW, 12 min, SiO2 closed vessel

N

+

O (1)

Scheme 7.133

Microwave assisted condensation has also been used to prepare heterobicyles as shown below in Scheme 7.134. Thus, irradiation of the diamine (1) with Ketoester (2) leads to the formation of the product (3) in 86% yield. The reaction was performed by supporting the reagents on the alumina followed by irradiation in an open vessel224.

Scheme 7.134

An industrially important raw material anthraquinone has been prepared225 by the use of microwaves. Thus, the microwave assisted acid catalyst cyclodehydration of benzophenone o-carboxylic acid (1) could be achieved using the same batch of catalyst without reduction in yields (12 reactions) (Scheme 7.135). Using conventional heating the yield was around 50% after four reactions using the batch of catalyst. O

O Acidic clay, MW

CO2H O (1)

Scheme 7.135

An interesting application of microwave assisted cyclocondensation is in the preparation of tetrapyrrole as shown in Scheme 7.136. Although the yield is about 10%, the isolation and purification of the product is simple226.

7.68 Green Chemistry

Scheme 7.136

7.5.12 Reac ons Involving Silicon Reagents The reaction of silyl ketene actals with imines under microwave condition227 give the addition product (1) (Scheme 7.137). It is of great advantage to absorb the reagents on K10 montmorillonite clay.

Scheme 7.137

When the above reaction (Scheme 7.137) is carried out by mixing neat reagents with 18-crown-6 and irradiation is a closed vessel, b-lactams (1) are isolated in good yield (Scheme 7.138).

Scheme 7.138

Silyl-Reformatsky process has been developed using silicon containing nucleophile. It has been found that a range of both supported and unsupported reaction conditions (alkali metal fluorides/ Al2O3, MgO or clay) can be used to prepare useful addition products as shown below228, 229 (Scheme 7.139).

Organic Synthesis in Solid State

7.69

Scheme 7.139

7.5.13 Synthesis of Aspirin Asprinin is a single drug which is produced and used in maximum amount on a global scale. It is conventially prepared from salicylic acid and acetic anhydride in presence of small amount of sulphuric or phosphoric acid (about 30 min. heating at 85-95°). About 4M equiv. of acetic anhydride are required for each mole of salicylic acid. Only one mole of acetic anhydride is the reactant and the rest is a reaction medium. After the reaction, excess acetic anhydride is hydrolysed by ice water to acetic acid. Using microwave technique230, aspirin preparation requires a beaker with a loose cover. Salicylic acid and slight excess of acetic anhydride is used, no acid catalyst is needed. When 2–20g of salicylic acid is used, the reaction time is 90 seconds at high microwave power (800–1000W). Ice-water added to the reaction mixture to destroy excess acetic anhydride and to separate aspirin. It is filtered and recrystallised from isopopyl alcohol (Scheme 7.140). OH

O CO CH3

COOH

COOH +

Salicylic acid

CH3 CO O COCH3

MW

+

90 Sec

Acetic Anhydride

CH3COOH

Aspirin

Scheme 7.140

Several hundred grams of salicylic acid can be used; the reaction mixture, which is a paste is spread out in a uniform layer in an inexpensive glasses plate or baking disk. Reaction time is 8-10 minutes in a microwave oven.

7.6 CONCLUSION Organic reactions in solid state or solventless reaction are the best in the context of Green Chemistry. It avoids the use of volatile organic solvents which is one of the main problems associated with pollution of the environment. Some of the reactions like aldol condensation, Grigrard reaction and Reformatsky reaction can be conducted just at room temperatures by grinding the reactants. In certain case the reagents have be heated. A large number of reactions are performed in solid state by using solid support and microwave irradiation.

7.70 Green Chemistry

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7.76 Green Chemistry 180. R.S. Varma, K.P. Naicker, D. Kumar, R. Dahiya and P.J. Liesen, J. Microwave Power Electromag. Energy, 1999, 34, 113. 181. D. Villemin, B. Labiad and A. Loupy, Synthetic Commun., 1993, 23(4), 419. 182. R.S. Varma, K.P. Naicker and P.J. Liesen, Tetrahedron Lett., 1998, 39, 3977. 183. D. Villemin and F. Sauvaget, Synlett., 1994, 435. 184. A. Vass, J. Toth and E. Pallai-Varsanyi, OR, 19, presented at international conf. in microwave chem., Prague, Czech Republic, Sep. 6-11, 1998. 185. B. Satish, K. Panneersel-Vam, D. Zacharids and G.R. Desivaju, J. Chem, Soc. Perkin Tran., 1995, 2, 325. 186. E. Diez-Barra, A. de la Hoz, S. Merino and P. Sanchez-Verdu, Tetrahedron Lett., 1997, 38, 2359. 187. A. Boruah, M. Boruah, D. Prajapati and J.S. Sandhu, Chem. Lett., 1997, 965. 188. M. Rahmouni, A. Derdour, J.-P. Bazureau and J. Hamelin, Tetrahedron Lett., 1994, 35, 4563. 189. M. Rahmouni, A. Derdour, J.-P. Bazureau and J. Hamelin, Synth. Commun. 1996, 453. 190. R.S. Varma, J. Heterocyclic, Chem. 1999, 36, 1565. 191. R.S. Varma, D. Kumar and J.P. Liesen, J. Chem. Res., Perkin Trans. I, 1999, 4093. 192. S. Paul, M. Gupta, R. Gupta and A. Loupy, Tetrahedron Lett., 2001, 42, 3827. 193. R.S. Varma and D. Kumar, Tetrahedron Lett., 1999, 40, 7665. 194. M. Larhed and A. Hallberg, J. Org. Chem., 1996, 61, 9582. 195. V.V. Namboodiri and R.S. Varma, Green Chem., 2001, 3, 146. 196. N.E. Leadbeater and M. Marco, Org. Lett., 2002, 4, 2973. 197. N.-F.K. Kaiser, U. Bremberg, M. Larhed, C. Moberg and A. Hallberg, Angew Chem. Int. Ed. Engl., 2000, 39, 3596. 198. M. Larhed, M. Hoshino, S. Hadida, D.P. Curran and A. Hallberg, J. Org. Chem., 1972, 62, 5583. 199. R.F. Heck, Org. React., 1982, 27, 345. 200. R.S. Varma, K.P. Naicker and P.J. Liesen, Tetrahedron Lett., 1999, 40, 2075. 201. A.D. Oritz, P. Prieto and E. Vazquez, Synlett., 1997, 269. 202. M. Larhed, G. Linderberg and A. Hallberg, Tetrahedron Lett., 1996, 378, 8219. 203. G.W. Kabalka, R.M. Pagni, V.V. Namboodri and C.M. Hair, Green Chem., 2000, 2, 120. 204. G.W. Kabalka, L. Wang, V.V. Namboodri and S. Chatti, Tetrahedron Lett. 2000, 41, 5151. 205. C.-H. Juss, J.-H. Chring, D.-Y. Lee, A. Loupy and S. Chatti, Tetrahedron Lett., 2001, 42, 4803. 206. A. Mohna, J.I. Vaguero, J.I. Garefa and J. Alvarez-Builla, Tetrahedron Lett., 1993, 34, 2673. 207. W.B. Wang and E.J. Roskamp, Tetrahedron Lett., 1992, 33, 7631. 208. H. Tonaux, H. Klein, F. Texier-Boullet and J. Hamelin, J. Chem. Research(S), 1994, 116. 209. G.B. Jones, R.S. Hurber and S. Chau, Tetrahedron, 1993, 49, 369; R.S. Hurber, G.B. Jones, J. Org Chem. 1992, 57, 5778. 210. D. Villemin, B. Labiad and Y. Ouhilal, Chem & Ind., 1989, 607. 211. R.A. Abramovitch and A. Bulman, Synlett., 1992, 795. 212. A.B. Alloum, B. Labiad and D. Villemin, J. Chem. Soc., Chem. Commun. 1989, 386. 213. J. Ipaktschi and M. Bruck, Chem. Ber., 1990, 123, 1591. 214. G. Bram, A. Loupy, M. Majdoub, E. Gutierrez and E. Ruiz-Hitzky, Tetrahedron, 1990, 46, 5167.

Organic Synthesis in Solid State

215. 216. 217. 218. 219. 220. 221.

222. 223. 224. 225. 226. 227. 228. 229. 230.

7.77

Y. Yuncheng and J. Yulin, Synth. Commun., 22, 3109. D. Villemin and A.B. Alloum, Synth. Commun., 1990, 20, 925. R.J. Giguere and B. Herberich, Synth. Commun., 1991, 21, 2197. W. Yuliang and J. Yaozhong, Synth. Commun., 1992, 22, 2287. D. Villemin, B. Labiad and A. Loupy, Synth. Commun., 1993, 23, 419. D. Villemin, B. Martin, J. Chem. Research(S), 1994, 416. D. Villemin and A.B. Alloum, Synth. Commun., 1990, 20, 3325; D. Villemin and B. Labiad, Synth. Commun., 1990, 20, 3207; D. Villemin and B. Labiad, Synth. Commun., 1990, 20, 3213; D. Villemin and B. Labiad, Synth. Commun., 1990, 20, 3333. M. Rahmouni, A. Derdour, J.P. Bazureau, and J. Hamelin, Tetrahedron, Lett., 1994, 35, 4563. B. Rechsteiner, F. Texier-Boullet and J. Hamelin, Tetrahedron Lett., 1993, 34, 5071. J.F. Pilard, B. Klien, F. Texier-Boullet and J. Hamelin, Synlett., 1992, 219. G. Bram, A. Loupy M. Majdaub and A. Petit, Chem. & Ind., 1991, 396. A. Petit, A. Loupy, Ph Maillard and M. Momenteau, Synth. Commun., 1992, 22, 1137. F. Texier-Boullet, P. Latouche and J. Hamelin, Tetrahedron Lett., 1993, 34, 2123. R. Latouche, F. Texier-Boullet and J. Hamelin, Bull. Soc. Chem. Fr., 1993, 130, 535. R. Latouche, F. Texier-Boullet and J. Hamelin, Tetrahedron Lett., 1991, 32, 1179. A.K. Bose, B.K. Banik, N. Lavlnskaia, M. Jayraman and M.S. Manhas, Chemtech, Sept. 1977, 18.

Part IV Use of Alternate Energy Processes in Chemical Synthesis

8 8.1

Microwave Assisted Organic Synthesis

INTRODUCTION

In the new millennium, Industrial Chemistry is adopting the concept of Green Chemistry to meet the scientific challenges of protecting human health and environment while maintaining commercial viability. A most important aspect is the replacement of volatile organic solvents from the reaction medium with possible substitutions by nonvolatile or recyclable alternatives, Among the emerging important tools the use of microwaves (MW) as alternative source of energy is becoming an alternative especially under the solvent free conditins1-4. The dramatic increase in the number of publications, books5, 6 and a growing amounts of patent literature7-16 speaks well for microwave enhanced chemical synthesis. Microwave ovens normally have wave lengths between 1 cm and 1 m (frequencies of 30 GHz to 300 Hz). These are similar to frequencies of radar and telecommunications. In order to avoid any interference with this systems, the frequency of radiation that can be emitted by household and industrial microwave oven is regulated, most of these appliance operate at a fixed frequency at 2.45 GHz. Microwave (MW) energy has been used17 for heating food materials for almost half a century. Microwaves are now commonly used for heating purpose. The mechanism of how energy is given to substance which is subjected to microwave irradiation is complex. It is believed that microwave reactions involve selective absorption of electromagnetic waves by polar molecules, non-polar molecules are inert to microwaves. When molecules with a permanent dipole are subjected to an electric field, they became aligned and as the field oscillates their orientation changes, this rapid reorientation provides intense internal heating. The main difference between classical heating and microwave heating, lies in core and homogeneous heating associated with microwaves, whereas classical heating is all about heat transfer by preheated molecules.

8.4 Green Chemistry The preferred reaction-vessel for microwave induced organic reaction, is a tall beaker (particularly for small scale preparations in the laboratory), loosely covered and the capacity of the beaker should be much greater than the volume of the reaction mixture. Alternatively, Teflon and polystyrene container can be used18,19. These materials are transparent to microwaves. Metallic containers should not be used as reaction vessels, as it gets heated soon due to preferential absorption and reflection of rays. In microwave induced organic reactions, the reaction can be carried out in a solvent medium or on a solid support in which no solvent is used. For reactions in a solvent medium, the choice of the solvent is very important2, 3. The solvent to be used must have a dipole moment so as to absorb microwaves and a boiling point at least 20–30° higher that the desired reaction temperature. An excellent solvent in a domestic microwave oven is N, N-dimethyl formamide (DMF) (b.p. 160°, e = 36.7). This solvent can retain water formed in a reaction, thus obviating the need for water separation. Some other solvents of choice are given in the table below: Some Common Solvents for use in M. W Ovens Solvent Formamide Methanol Ethanol

b.p.

Dielectric constant (e)

216

11.1

65

32.7

78

24.6

Chlorobenzene

214

5.6

1, 2-Dichlorobenzene

180

1.53

1, 2, 4-Trichlorobenzene

214

1.57

1, 2-Dichloroethane

83

10.19

Ethylene glycol

196

37.7

Dioxane

101

2.20

Diglyme

162

7.0

Triglyme

216

1.42

Hydrocarbon solvents, for example, hexane (e = 1.9), benzene (e = 2.3), toluence (e = 2.4) and xylene are unsuitable because of less dipole moment, and also because these solvent absorb microwave radiations poorly. However, addition of small amounts of alcohol or water in these solvents can lead to dramatic coupling effects. Liquids which do not have dipole moment cannot be heated by microwaves. By the addition of a small amount of a dipolar liquid to a miscible non-polar liquid, the mixture will rapidly achieve a uniform temperature under irradiation. Microwaves may be considered as a more efficient source of heating than conventional heating (steam or oil heating), since the energy is directly imparted to the reaction medium rather than through the walls of a reaction vessel. In fact, the rapid heating capacity of the microwave leads to a considerable saving in dissolution of the reaction time. The smaller volume of the solvent required contributes to saving in cost and diminishes the waste disposal problems20-21.

Microwave Assisted Organic Synthesis

8.5

Microwave procedures are limited22 by the presence of solvents which reach their boiling points within a very short time (~ 1 min) of exposure to microwave. Consequently, high pressures are developed, leading to damage to the vessel material or the microwave oven itself and may occasionally lead to explosion. Well designed microwave ovens are now available. Consideration of safety aspects coupled with the limitations of the solvents imposed by microwave heating, has led to many reactions being carried out in water or more commonly under solvent free conditions. It is believed that due to high polarity and non-volatility, ionic liquids (Chapter 4) might be ideal for carrying out high temperature reactions efficiently, since temperatures of over 200°C can be readily attainable. Microwave procedures now find potential useful application in chemical technology. These include acceleration of chemical reactions23-35; in this explosive growth has been witnessed, where in chemical reactions are accelerated because of selective absorption of MW energy by polar molecules, non-polar molecules being inert to MW dielectric loss36. As has already been stated, initially the chemical experiments with microwave heating used high dielectric solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) where the rate enhancements are now believed to be due to rapid superheating of the polar solvents and pressure effects14. However the development of high pressure, and the use of specialised sealed vessels are some of the challenges in these solution-phase reactions, which in part, have been addressed by newly introduced commercial MW instruments with precise temperature and pressure control. The latest developments in such newer instruments had attracted the attention of several chemical companies and their heighthened interest has become obvious as exemplified recently in the application of microwaves in combinatorial chemistry that rapidly generates a library of potentially useful chemical entities22. According to report published37 in science and technology (chemical and engineering news) microwaves are used in a number of industrial processes including meat tempering, beacon cooking, potato chips drying, rubber vulcanisation and drying of pharmaceutical compounds. The premise of micro waves attracted more than 320 scientists, engineers and others from 23 countries. Since microwave easily penetrate materials (with the exception of metals), they can be directly and uniformly absorbed throughout the entire volume of an object, causing it to heat up evenly and rapidly. This capability has opened new opportunities in chemistry, material science, and other areas. According to Ajay K. Bose, of Stevens Institute of Technology in Hoboken, N.J. a pharmaceutical company had a problem. During the course of developing a new drug, the chemists in the company had to synthesise an intermediate using a reaction that required four days of heating in an oil bath. This procedure besides consuming more time led to the loss of product in the form of degradation products. Professor Bose, a consultant to the company (Wyeth-Ayerst Research at Pearl River, N.Y.), suggested replacing the oil bath with microwave heating. With the aid of computer-controlled microwave oven that was able to maintain a constant reaction temperature, the intermediate was produced in four hours, with only a small amount of degradation product. According to Bose, microwave assisted chemistry could be a boon to the pharmaceutical, biotechnology and other industries. It is an environmentally friendly technology since it can reduce or eliminate the use of

8.6 Green Chemistry solvents. Reactants can simply be mixed together with little or no solvent. Since products often are produced in purer form with microwaves, use of solvents and chromatographic methods in purification can also be reduced. It is interesting to note that peptide hydrolysis using conventional heating has to be run overnight in a sealed tube containing hydrochloric acid. The advantage of microwave heating shortened the reaction time to 15 minutes. The hydrolysis can also be carried out in open vessels inside an ordinary microwave oven. Using this procedure, Bose et al. effected complete hydrolysis of di, tri and tetrapeptide in 3 to 15 minutes using saturated barium hydroxide solution in open flask inside an ordinary mircrowave oven. To prevent the volatile reagents from boiling off, the researchers devised a make shift reflux condenser which was placed on the top at the reaction flask. The condenser contained dry ice, liquid nitrogen or ordinary ice in the water socket of the condenser. Rajinder S. Varma38, a scientist while working at Sam Houstan State University in Hurntsville, Texas and Houstan Advanced Research Centre in the Woodlands Taxas, has found ways to perform organic transformations rapidly using catalyst under solvent free ‘dry’ conditions. According to Varma, it is the easiest possible way to run a reaction-just mix the neat reactants together with some catalyst (if possible) and heat them in a microwave for a few minutes, Varma believes that using microwave energy under solvent free conditions will lead to new procedures for conducting cleaner and efficient chemical transformations. This technology could aid pollution abatement efforts aimed at destroying hazardous wastes in the environment. Contaminated solids could be treated with catalysts (which are inexpensive) and microwaves to destroy toxic compounds. Broadly speaking the organic synthesis using microwaves can be grouped in the following three categories: • Microwave assisted reactions in water; • Microwave assisted reactions in organic solvents; • Microwave assisted reactions in solid state. Only a limited representative description of each category is given, since, excellent review articles are available14–16, 22.

8.2

MICROWAVE ASSISTED REACTIONS IN WATER

Following are given some microwave assisted organic reactions in water.

8.2.1 Hofmann elimanation In this method, normally quarternary ammonium salts are heated at high temperature and the yield of the product is low. However, use of microwave irradiation in water-chloroform system gives highyielding synthesis of a thermally unstable Hofmann elimination product (Scheme 8.1).

8.2.2 Hydrolysis of Benzyl Chloride Hydrolysis of benzyl chloride with water in microwave over gives39 97% yield of benzyl alcohol in 2 min (Scheme 8.2). The usual hydrolysis by usual heating takes about 35 min.

Microwave Assisted Organic Synthesis O

8.7

O + –

NR3 l

Water/CHCl3 mw, 1 min

OEt

OEt

Scheme 8.1 CH2OH

CH2Cl

+ H2O

mw 2 min

Benzyl chloride

Benzyl alcohol (97%)

Scheme 8.2

8.2.3 Hydrolysis of Benzamide The usual hydrolysis of benzamide takes 1 hr. However, under microwave, the hydrolysis is completed40 in 7 min giving 99% yield of benzoic acid (Scheme 8.3). CONH2

COOH

20%H2SO4 mw, 7 min Benzoic acid (99%)

Benzamide

Scheme 8.3

8.2.4 Hydrolysis of N-phenyl Benzamide N-Phenyl benzamide on heating with 20% H2SO7 in an microwave oven for 12 min gives40 74% yield of benzoic acid (Scheme 8.4). The conventional heating procedure takes 18 hrs. CONHC6H5

COOH

20% H2SO4 mw, 12 min N-Phenylbenzamide

Scheme 8.4

Benzoic acid (74%)

8.8 Green Chemistry

8.2.5 Hydrolysis of Methyl Benzoate to Benzoic Acid (Saponification) Saponification of methyl benzoate in aqueous sodium hydroxide under microwave irradiation (2.4 min) gives41 84% yield of benzoic acid (Scheme 8.5). COOCH3

COOH

aq. NaOH mw, 2.5 min Methyl benzoate

Benzoic acid (84%)

Scheme 8.5

8.2.6 Oxidation of Toluene Oxidation of toluene with KMnO4 under normal condition of refluxing takes 10-12 hr compared to reaction in microwave conditions41,42, which takes only 5 min. and the yield is 40% (Scheme 8.6). CH3

COOH

[0] aq. KMnO4 + aq. KOH mw, 5 min Benzoic acid (40%)

Toluene

Scheme 8.6

8.2.7 Coupling of Amines with Halides Amines on heating in microwaves with alkyl halides with NaOH/H2O gives43 the corresponding N-alkyl derivatives (Scheme 8.7). R1

R1 R

X + H

mw R H2O/NaOH

N

N

R2

R2

R = alkyl, aryl X = Cl, Br, l

R1 = H, alkyl, aryl R2 = alkyl, allyl

Scheme 8.7

8.2.8 N-heterocylisations Microwaves assisted N-heterocyclisation in aqueous media has been achieved44 using an aromatic amine and dihalide of the type X (CH2)nX in presence of K2CO3 (Scheme 8.8).

Microwave Assisted Organic Synthesis

NH2 + X (CH2)n X

K2CO3/H2O mw

R

N

8.9

(CH2)n

R R = H, CH3, CH2CH3, Br, COCH3, COOCH2 CH3 X = Br, I, OTs; n = 3, 4, 5, 6

Scheme 8.8

A typical example44 of N-hetercyclisation is given in Scheme 8.9. H N

N NH2 + Br

R

Br

Base/H2O

N N

MW R

N H

+ R

Scheme 8.9

8.3

MICROWAVE WAVE ASSISTED REACTIONS IN ORGANIC SOLVENTS

This section includes those microwave induced reactions in which one or both the reactants (if liquid) act as solvent and also those reactions in which organic solvent is used to assist the reaction.

8.3.1 Esterification: Reaction of Carboxylic Acid and Alcohol A mixture of a carboxylic acid (e.g. benzoic acid) and an alcohol (e.g. n-propanol) on heating in a microwave oven for 6 min in presence of catalytic amount of sulphuric acid gives39, 40, 42 the corresponding ester (e.g. propylbenzoate) (Scheme 8.10).

Scheme 8.10

Carboxylic esters have also been prepared by a tribromolanthanoid mediated reaction (see Section 8.3.2). Using microwave irradiation, it has also been possible to esterify hindered acids which are difficult to esterify under usual conditions. Thus, mesiotic acid can be esterified with isopropyl

8.10 Green Chemistry alcohol using microwave irradiation in presence of catalytic amount of sulphuric acid. The product obtained is isopropyl mesitoate (Scheme 8.11) in 56% yield. O

O OH

i

H2SO4’/Pr OH

O

MW Mesoitic acid

Isoproyl mesitoate (56%)

Scheme 8.11

8.3.2 Reaction of Carboxylic Acid and Benzyl Ethers Using Microwave in Presence of Ln Br3 (Ln = La, Nd, Sm, Dy, Er) The reaction of benzyl ethers and carboxylic acids catalysed by Ln Br3 (Ln = La, Nd, Sm, Ey, Ed) due to its weak lewis acid acid character, with microwave irradiation yeilds45 esters (Scheme 8.12). The reaction is carried out without solvent and esterification in complete in 2 minutes. However, when the reaction of benzyl n-butyl ether with acetic acid is carried out with conventional heating (118°, 10 hr) only 42% yield of benzyl acetate is formed even in presence of Nd Br3 in a sealed tube. Thus, heating in microwave oven affords better results. CH2O CH2CH2CH2CH3

+ CH3COOH Benzyl n-butyl ether

CH2OCOCH3 Ln Br3

+ Butyl alcohol

Ln = La, Nd, Sm, Dy, Er mw, 2 min Benzyl acetate

Acetic acid

Scheme 8.12

8.3.3 Fries Rearrangement Fries rearrangement is used for the preparation of phenolic ketones and is usually carried out by heating a mixture of substracte (e.g. p-cresyl acetate), aluminium chloride and chlorobenzene. There is considerable rate enhancement of Fries rearrangement by commercial microwave ovens over conventional methods. The reaction mixture on heating in a sealed tube in a microwave oven for 2 min gives46 85% yield to the product (Scheme 8.13).

8.3.4 Diels-Alder Reaction The reaction involves 1, 4-addition of an alkene (e.g. maleic anhydride) to a conjugated diene (e.g. anthracene) to form an adduct of six membered ring. Under usual condition47, the reaction requires

8.11

Microwave Assisted Organic Synthesis

Scheme 8.13

a refluxing time of 90 min. However, under microwave irridation48, 49 diglyme is used as a solvent and 80% yield of the adduct is obtained in 90 sec (Scheme 8.14). H

O

+

O

Diglyme mw, 90 Sec

O

H

O Anthracene

O

O

Adduct (80%)

Maleic anhydride

Scheme 8.14

In a similar way anthracene reacts with dimethylfumerate within 10 min in p-xylene to afford50 87% yield (Scheme 8.15) where as conventional heating conditions give only 67% yield in 5 hr. CO2Me COOMe mw, 10 Min p-xylene

+

CO2Me

MeOOC Anthracene

Dimethyl fumerate

Adduct

Scheme 8.15

8.3.5 Claisen Rearrangement Claisen rearrangement of allyl ether in the absence of solvent under conventional thermolysis provides a good yield of product within a short period of time51. The same rearrangement using microwaves in presence of N-methylformamide affords 87% of the product (Scheme 8.16).

8.12 Green Chemistry

Scheme 8.16

The ortho-claisen rearrangement of allyl phenyl ether has been achieved in aqueous media when 2-allylphenol is obtained51a exclusively after 10 min of irradiation (Scheme 8.17).

Scheme 8.17

8.3.6 Cycloaddition Reaction between Fulvenes and Some Alkenes and Alkynes: Synthesis of Polycyclic Ring Systems A number of polycyclic ring systems found in isobarbatene and alcyoptersin have been synthesised52 by cycloaddition reaction between fulvenes and some alkenes and alkynes. Such reactions conducted in benzene and DMSO do not occur under conventional thermolytic conditions.

8.3.7 Knoevenagel Condensation The Knoevenagel condensation reaction involving active methylene compounds and carbonyl groups for the synthesis of alkenes has been reported53 using MW irradiation (Scheme 8.18). The reactions are conducted in open vessels that lead to the efficient removal of water, thus circumventing the use of Dean-Stark apparatus. H

CN

O

mv 1.5 min

+ H

CN

Malanonitrile

H

Ph

Piperidine

Benzaldehyde

Scheme 8.18

Ph

CN

H

CN

Alkene (90%)

Microwave Assisted Organic Synthesis

8.13

8.3.8 Baylis–Hillman Reaction Baylis-Hillman reaction for alkene functionalisation is accelerated by altering reaction conditions such as pressure, temperature or using ultrasound. The use of MV irradiation improved54 the yield as well as reduction in time. The reaction of benzaldehyde with methyl crotonate in presence of DABCO leads to the required product in good yield in 10 minutes (Scheme 8.19). CO2Me

H

OH C

O

+ Benzaldehyde

CO2Me

DABCO MW, 10 min

Methylcrotanate

Scheme 8.19

8.3.9 Orthoester–Claisen Rearrangement The conventional procedure consist in heating a mixture of allyl alcohol, triethyl orthoacetate and propanoic acid in a sealed tube for 48 hr. However, under microwave condition55, a mixture of allyl alcohol, triethyl orthoacetate and propanoic acid in dry dimethyl formamide is heated in microwave oven for 10 min. The product (Scheme 8.20) is obtained in 83% yield.

Scheme 8.20

8.3.10

Synthesis of 4-Aryl-3, 4-Dihydropyrimidine 2(IH) Ones

A mixture of b-ketoesters, aryl halides and ammonium hydroxide-ethanol on heating in a microwave oven gave the corresponding 4-aryl-3, 4-dihydropyrimidine 2(1H) ones (Scheme 8.21)56-58.

8.14 Green Chemistry

Cl Cl

NH2OH/Et OH

O

O

RO2C

O

CO2R

OR

N

Me

Me

H

Scheme 8.21

8.3.11 Synthesis of -lactams Enantiomerically pure b-lactams have been prepared59 using MW irridation (Scheme 8.22). O

O CH2Ph

O

O

N

MW Bn OCH2COCl, Et3N

O

N

MW HCO2NH4, Pd/C O

BnO

NCH2Ph

CH2Ph

O

O

OH

Scheme 8.22

Using the procedure 25g of b-lactam could be easily prepared. Stereoselective outcome of the reaction under MW or classical conditions is different when tetraehorophythaloyl glycine chloride is reacted59a with an amine. There is exclusive formation of trans isomer of b-lactam under mw irradiation conditions. Variable amounts of cis and trans isomers of b-lactams are obtained under classical conditions (Scheme 8.23). H Et3N, CH2Cl2 TC PN

COCl

MW, RCH

N

NR

H

H

TCP

R

+

H

N

TCP

R

N O

O Trans

Tetrachlorophthaloyl glycine chloride

N Cis

Scheme 8.23

8.3.12 Cycloaddition Reactions Some cycloaddition reaction in xylene or dibutyl ether60 have been carried out and rate of the reaction is found to be much faster under MV irradiation conditions (Scheme 8.24). The acceleration

Microwave Assisted Organic Synthesis

8.15

is more in a polar solvents that show weak dielectric losses. It is believed60, 61 that this may be due to change in entropy of the system. O O MW Bu2O or xylene

+

Scheme 8.24

The cycloaddition reaction between cyclopentadiene and methyl acrylate (Scheme 8.25) under MV irradiation does not affect the endo/exo selectivity62. The observed difference could be explained by the fact that the reaction under MW irradiation occur at higher temperatures than those under conventional refluxing conditions. Other investigators63, 64 have also concluded that the reaction rates are identical in the presence or absence of mw irradiation, the final yield is dependent on the temperature and not on the mode of heating. CH2 +

CH CO2CH3

Cyclopentadiene

MW CH3OH

+ CO2CH3 CO2CH3

Methyl acrylate

Scheme 8.25

8.3.13 Synthesis of Benzodiazepin-2-ones MW irradiation of o-phenylene diamines and b-ketoesters in xylene gave65 benzodiazepin-2-ones (Scheme 8.26). NH2

R O O Et O

b-Ketoester

R

N Xylene MW, 10 min

+ NH2

N

O

H Benzodiazepin-2-ones

o-Phenylene diamine

Scheme 8.26

8.16 Green Chemistry The above reaction does not proceed on classical mode of heating. Other diazepines have also been prepared under the influence of microwaves66.

8.3.14 Aromatic Substitution Reactions Aromatic substitution reactions can be conveniently performed (Scheme 8.27) in presence of small amount of PTC under microwave irradiation; Under microwave the rate of the reaction is considerably enhanced (144-240 fold). Thus, p-chloronitrobenzene on treatment with sodium hydroxide in alcohol in presence of PTC under microwave irradiation give67 p-ethoxynitrobenzene (Scheme 8.27). NO2

NO2 MW NaOH, PTC, EtOH

Cl

OEt

p-Chloronitro benzene

p-Ethoxynitrobenzene

Scheme 8.27

The efficiency of aluminium catalysed Friedel-crafts germylation of benzene and toluene is enhanced by microwave irradiation. Thus germylation of benzene using standard reflux condition provides the substituted product (1) in 20% yield after 24 hrs. A slight improvement in the yield could be achieved using microwave irradiation. Two hours MW irradiation gave67a the product (1) in 25% yield (Scheme 8.28). GeCl3

H

GeCl4 +

AlCl3, MW

+ HCl (1)

Scheme 8.28

8.3.15 Catalytic Hydrogenation Benzaldehyde on reduction using RuHCl (CO) (PPh3)3 in presence of formic acid under microwave irradiation gave68 benzyl alcohol in 7 min (conventional refluxing 3 hr) (Scheme 8.29). Microwave-assisted hydrogenation of substituted b-lactams using Raneynickel or Pd/C have also been reported69. This reaction (Scheme 8.30) is particularly useful on a large scale.

Microwave Assisted Organic Synthesis

8.17

CH2OH

CHO

+ HCO2H Benzaldehyde

MW, 7 min Ru HCl (CO) (PPh3)3

Formic acid

Benzyl alcohol

Scheme 8.29

Scheme 8.30

8.3.16 Synthesis of Chalcones Microwaves have been used for the synthesis70 of chalkones and related enones. Considerable rate enhancement is observed bringing down the reaction time from hours to minutes in improved yield (Scheme 8.31).

R

+

OHC Ar

COCH3

EtOH Cat, Na OH 30 Sec-2Min

R

Ar

O (90 – 100%)

Scheme 8.31

8.3.17 Decarboxylations Microwave irradiation expediates71 the decarboxylation reaction in presence of phase transfer catalyst (Scheme 8.32).

8.18 Green Chemistry H

CO2Et

Ph

CO2Et

Bu4NBr, H2O, LiBr

H

CO2Et

MW, 10 min

H

Ph (90%)

Scheme 8.32

Conventional decarboxylation of carboxylic acid involves refluxing in quinoline in presence of copper chromite and the yields are low. However, in presence of microwaves72, decarboxylation takes place in much shorter time as illustrated in Scheme 8.33.

Scheme 8.33

8.3.18 C-alkylation of Active Methylene Group Phase transfer catalysts promote MW assisted C-alkylation of active methylene computed73 (Scheme 8.34).

Scheme 8.34

There is good selectivity for monoalkylated product (Scheme 8.34). The reaction can be carried out in toluene to ensure efficient mixing of the reagents.

8.3.19 Methanolysis of Oligosaccharides Methanolysis of oligosaccharides by MV irradiation leads to products with anomeric inversion74 (Scheme 8.35).

8.3.20 Preparation of Unsaturated Pyranosides MW-irradiation of tosylate or mesylate derivatives of disaccharides leads to improved yield of unsaturated pyranosides75 (Scheme 8.36) in comparison to classical heating.

Microwave Assisted Organic Synthesis

8.19

Scheme 8.35 O DMF, Zn, Nal

O Ph

O MsO

Ph

O O

O

MW OMs

OMe

OMe

Scheme 8.36

8.3.21 Ferrier Rearrangement The reaction of tri-O-acetyl D-glucals with phenols in sealed vessels (with MW thermolysis) leads to the formation76 of Ferrier rearrangement products in good yield (Scheme 8.37), compared to classical heating methods.

Scheme 8.37

8.20 Green Chemistry Montmorillonite K10 is known to catalyse Ferrier rearrangement of tri-O-acetyl-D-glucal with different alcohols and phenols in open vessels with high a-selectivity and without the formation of d-deoxy-D-lyxohexapyranoside77.

8.3.22 Synthesis of Jusminaldehyde A convenient synthesis of Jusminaldehyde (1) was achieved in 82% yield if benzaldehyde is reacted with n-heptanal in presence of a PTC catalyst and MW irradiation78 (Scheme 8.38). CHO

Ph CH3(CH2)5CHO

CHO

C6H13

KOH, PTC, MW, 1 min, PhCHO 100%

C5H11

C5H11 (1)

(2)

Scheme 8.38

The desired product (1) (82%) and selt condensation product (2) (18%) were obtained.

8.3.23 Receminsation of (–)-vincadifformine to the (+)-isomer A complete recemisation of (–)-vincadifformine has been achieved79 under MW irradiation in DMF (Scheme 8.39). The reaction involves two consecutive Diels-Alder cycloreversion and cycloaddition steps. The formed (+) isomer is useful in the preparation of pharmacologically important alkaloid vicamine. Under classical condition, there is significant amount of decomposition. N

N

H

H

DMF, H2O MW, 20 min N H

N H

CO2CH3

(–)-Vincadifformine

CO2CH3

(+)-isomer

Scheme 8.39

8.3.24 Synthesis of 1, 2-dimethyl-3-hydroxy-pyrid-4-one The reaction of 3-hydroxy-2-methyl-4-pyrone with aqueous methyl amine under MW irradiation condition gives80 1, 2-dimethyl-3-hydroxy-pyrid-4-one (65%) (Scheme 8.40). In contrast, under classical heating, the yield was only 50% after 6 hr.

Microwave Assisted Organic Synthesis

8.21

CH3 O

N +

CH3NH2

MW 1.3 min

OH

OH

O

O

3-Hydroxy-2-methyl 4-pyrone

1,2-Dimethyl-3-hydroxypyrid-4-one

Scheme 8.40

8.3.25 Synthesis of Isopropylidene Glycerol A solution of glycerol in acetone in presence of p-toluenesulfonic acid catalyst on mw irradiation give80 isopropylidene glycerol (Scheme 8.41).

Scheme 8.41

8.3.26 Synthesis of Isotopically Labelled (11C) Diethyl Oxalate and (11C) Oxalic Acid Diethyl oxalate and oxalic acid, both isotopically labelled (11C) have been prepared81 as given in Scheme 8.42. O

O 11

MeO

Cl

CN,

PTC

MW, 5Min

MeO

O 11

CN

O HCl (g) MW, 1/4 min

HO

11

OH

O

Scheme 8.42

HCl(g) EtOH MW, 1/4min

EtO

11 O

OEt

8.22 Green Chemistry An interesting application is the preparation of isotopically labelled drugs of short half life (11C, t = 20 min, 122I = 3.6 min and 18F, t1/2 = 100 min). The procedure is successful in terms of reduction in reaction time by a factor of 20 and in doubling the radioactivity to the final product82.

8.3.27 Stereoselective Addition of 2-aminothiophenol to Glycidic Esters The addition of 2-aminothiophenol to glycidic esters is highly stereoselective under MW irradiation conditions83. Using solvent polarity, the cis: trans ratio can be modified. Aprotic solvents favour cis isomer while protic solvents favour trans isomer. In a polar solvents however, gradual increase in power level leads to an increase in proportion of trans isomer (Scheme 8.43).

Scheme 8.43

8.3.28 Development and Application of a Continuous Microwave Reactor (CMR) for Organic Synthesis using Solvents A continuous microwave reactor (CMR) has been developed for use on a laboratory scale84. It operates by passing a reaction mixture through a pressurised, microwave-transparent coil that is held in microwave cavity85. It has been used to conduct organic synthesis routinely, rapidly and safely in a range of solvents, under pressure (up to 1400 Kpa) and at temperatures up to 200°C. A number of reactions have been carried out using CMR. These reactions included nuclephilic substitution, addition, esterification, transesterification, acetalisation, amidation, decarboxylation, and elimination. Some other reactions which could be performed by CMR include Michael addition, Hofmann degradation, Williamsons ether synthesis and the Mannich, Frinkestein, Baylis-Hillman and Knoevenagel reactions. Table 1 gives a number of reactions which have been performed in the solvents and with the reactants listed. It is possible to conduct reaction in volatile solvents in the CMR at temperatures up to 100° higher than the boiling point of the solvent at atmospheric pressure. These conditions have given accelerated reactions, in reduced reaction time (up to 3 orders of magnitude) when compared with literature conditions. It has been shown that at least for homogeneous reaction-mixtures, the rate enchancements are due to the elevated temperatures rather than from any specific “microwave effect”86, 87.

Microwave Assisted Organic Synthesis

8.23

Some Examples in Solvents Reactants (Nature of the reaction)

Mean Press. (K pa)

Time min.

Product

152-5

1200

1.3

i-Pr OAc

2. 2, 4, 6-Trime thyl benzoic acid + Me OH/H+ (esterification)

148-59

1250

3. 2, 4, 6-Trimethylbenzoic acid + i –PrOH/H+

155-64

1300

4. PhCOOMe + 5% Aq. NaOH (hydrolysis)

166-8

5. Glycerol in Me2CO/H+

1. HOAc + i – PrOH/H+ (esterification)

Temp. (°C)

Yield Reference % 98

88

4a × 1.3 methyl 2, 4, 6 trimethyl benzoate

83

89

4 × 1.6

isopropyl 2, 4, 6-trimetyl benzoate

81

86, 90

700

1.0

Ph COOH

100

91

132-5

1175

1.2

2, 2-dimethyl-1, 384 dioxalane-4-methanol

92

6. Ph COOEt + MeOH/H+ (transesterification)

145-50

1050

4 × 1.4

Ph COOMe

46

—

7. Paraformaldehyde in 3% aqueous HCl (De Polymerisation)

160-70

1100

1.2

aqueous HCHO

100

93

8. Benzophenone + NH2OH. HCl in pyridine/EtOH (Oxime formation)

164

500

1.5

benzophenone oxime 93

91

9. Ph Me in aqueous KMnO4 + K OH

180

1050

1.3

Ph COOH

41

91, 94

10. Bu Cl + Na OPh in Me OH (Williamson ether synthesis)

144-7

1000

1.5

Bu OPh

67

95

11. p-Chlorobenzaldehyde in EtOH/H+ (acetalisation)

142-4

950

1.4

p-chlorobenzaldehyde 59 diethyl acetal

96

158-64

950

1.5

Methyl 2-(hydroxymethyl) arcylate

30

97

13. Bu Cl in NaI/Me2 CO (Finkelstein reaction)

150

1000

1.5

Bu I

36

98

14. s-BuCl in NaI/Me2CO (Finkelstein reaction)

145

950

5 × 1.5

sBuI

5

160-2

200

1.3

1, 2-dimethyl-3hydroxy pyrid-4 one

12. Methyl acrylate in aqueous HCHO/DABCO (Michael addition)

15. 3-Hydroxy-2-methy4-pyrone in 25% aqueous MeNH2

65

88, 98 99

Contd...

8.24 Green Chemistry Contd... 16. Indole in Me NH2/aqueous HCHO

160-70

700

1.2

Gramine

97

88

164-5

350

1.4

5-methylfurfuryldimethylamine

48

93

164

500

1.5

Citronelladoxime

82

91,100

19. Citronellaldoxime + chloramine T in EtOH

128-33

800

1.5

3, 3, 6-Trimethyl3, 3a, 4, 5, 6, 7 hexahydro-2, 1-benzisoxazole

78

101

20. Carvone + IM aqueous H2SO4 with emulsifier

165-75

740

4 × 1.5

Carvacrol

32

102

21. Furfural in diethyl malonate/pyridene (Knoevengel reaction)

165

1200

1.6

2-Furanacrylic acid

18

103

180-90

400

1.0

Ph CO CH2 CH2 NMe2

29

88

90-95

100

1.6

Ph COCH = CH2

96

88

180

550

1.0

benzofuran

24

104

95

730

1.7

Ph CH = CH2 (75%) + 84 Ph CH2 CH2 OMe (9%)

17. 2-Metylfuran in Me2NH/ aqueous HCHO 18. Citronellal + NH2OH in pyridine + EtOH

22. PhCOMe in Me2 NH/HCHO 23. [Ph COCH2 CH2NMe3]+I– in H2O (Hofmann degradation) 24. 2-Formyl phenoxyacetic acid in Ac2O/HOAc with NaOAc 25. Ph CH2 CH2 Br in Na OMe/Me OH

138-45 1100 60 × 1.8 Ph CH2 CH2 OMe 38 26. Ph CH2 CH2 Br in Me OH a The integer refers to the number of passes of the reaction mixutre through the microwave zone.

105, 106 107

8.3.29 Pericyclic Reactions Some pericyclic reactions like Diels-Alder and Claisen rearrangements have already been discussed (see section 8.3.4 and 8.3.5). Some more pericyclic reactions are discussed in this section. 1, 4-Hexadience condenses in presence of MW with demethyl acetylene dicarboxylate to give50 the adduct 82% yield (Scheme 8.44). Claisen rearrangement of the Ketene acetal derived the alcohol A gives107 83% yield in 10 min as compared to 48 hr in a sealed tube (Scheme 8.45). Hetro-Diels-Alder reaction108 involving cydoaddition of diene (1) with dienophile (2) and MW irradiation gave two products in good yield, whereas under conventional heating no product could be isolated after 4 hr at 140° (Scheme 8.46).

Microwave Assisted Organic Synthesis

8.25

Scheme 8.44 TEOA, CH3CH2CO2H, DMF, OH

CO2Et

MW, Open vessel, 10 min, 83%

A

Scheme 8.45

Scheme 8.46

Fisher Cyclisation109 involving [3, 3] sigmatropic rearrangement of cyclohexanone phenyl hydrazone gave 100% yield of the cyclised product (Scheme 8.47). N NH

+

MV, H c.a. 100%

Ph N H

Scheme 8.47

The above reaction was carried out by irradiation of the hydrazone in formic acid in a Parr bomb. Cycloreversion of (1) to secodine intermediate (2) furnishes110 (3) via (4 + 2) cycloaddition. The reaction takes place less efficiently under conventional heating. The optimum conditions requires microwave irradiation in DMF for 20 minutes (Scheme 8.48). Microwave assisted intramolecular Diels Alder Reaction111 is a Key step in the synthesis of (+) Longifolene (Scheme 8.49). Morphinan analogues have been prepared112 by utilising microwave assisted reactions. Thus, the reaction of thebanine derivative (1) with methyl Vinyl Ketone is simplified and requires reduced

8.26 Green Chemistry

Scheme 8.48

Scheme 8.49

reaction times, the products obtained are the cycloadducts (2) and (3). Subsequently, microwave assisted demethylation procedure yielded the target molecule (4) in reasonable yield (Scheme 8.50).

Scheme 8.50

Microwave Assisted Organic Synthesis

8.27

8.3.30 Cyclisation Reactions Microwave assisted reactions have been used to improve different types of cyclisation reactions. Thus, in Hantzch-1, 4-dihydropyridine synthesis113, reduced reaction times and improved yields are associated with this procedure as shown in Scheme 8.51 by the reaction of o-chlorobenzaldehyde and b-ketoesters.

Cl

O

O

Cl CO2R

RO2C

MW Control (%, time sec) (%, time hr) 55, 4 44,24.

OR O

NH4OH/EtOH N

Me

Me

H

Scheme 8.51

Novel four membered oxazoborolidines have been obtained114 using highly efficient microwave assisted cyclisation reaction (Scheme 8.52). The transformation (Scheme 8.52) using literature procedure required 24 hours refluxing (82%). However, microwave irradiation reduced the reaction time to 15 minutes with an improvement in yield.

Scheme 8.52

Microwaves have been utilised in the synthesis of (Fe) substituted heteroaromatic systems115. Thus, the reaction of ferrocenyl substituted acrylaldehyde (1) with the appropriate ester (2) gave the heterocyclic compound (3) in good yield (Scheme 8.53). R R

CHO MW, 1:2Et3N:DMF, 2 min

X X

O Fe

Cl

Fe

XH

X

OR R¢ (1)

(2)

(3)

Scheme 8.53

R¢

S, R¢ O, R¢

H, 87% H, 35%

8.28 Green Chemistry

8.3.31 Oxidation Oxidation of toluene with KMnO4 has also been achieved under microwave conditions116 (Scheme 8.54). The reaction gives 40% yield after 5 minutes of microwave irradiation.

Scheme 8.54

8.3.32 Synthesis of Alkenes Alkenes are obtained in a simple way by Knoevenagel condensation of active methylenes with carbonyl groups as given below (Scheme 8.55). H

CN +

H

Ph

O

Ph

CN

H

CN

Piperidine, MW, 1.5 min, 90%

H

CN

Scheme 8.55

Oxidation reactions are carried out in open vessels from which water is vapourised, thus, avoiding the requirement of a Dean-stark apparatus. The formed alkene is isolated and purified by washing with solvent or by short path distillation117. The synthesis of Jusminaldehyde, an alkene has already been reported (See Section 8.3.22).

8.3.33 Preparation of Ferrocenyl Oxime In contrast to conventionally heated reactions, the microwave assisted reaction give118 only the thermodynamically stable isomer (Scheme 8.56). O

Fe

NOH

NH2OH.HCl, EtOH;Pyr MW, 20 sec, 97%

Scheme 8.56

Fe

Microwave Assisted Organic Synthesis

8.29

8.3.34 Synthesis of Ethers The effects of microwave irradiation on phase transfer assisted ether synthesis was explored119. In the examples investigated the effect was useful, leading to much shorter reaction time and better yields. Thus, the reaction of benzyl chloride with ethanol signicificantly accelerated using microwaves (Scheme 8.57). CH3CH2OH, PTC, MW Cl

MW Control (%, time min) (%, time min) 85, 5 66, 1440 OEt

Scheme 8.57

8.3.35 Carbohydrates Unsaturated pyranosides have been prepared by microwave assisted Tipson-Cohen reaction. Thus, irradiation of a mixture of mesylates or tosylates with sodium iodide and zinc dust in DMF with microwaves led in general to improved yields120 and reduced reaction times as compared to more conventional heating conditions (Scheme 8.58).

Scheme 8.58

1, 6-Anhydroglucose has been prepared121 from (1-4)-D-glucans by the microwave irradiation of starch (Scheme 8.59).

Scheme 8.59

The simplicity of the procedure (Scheme 8.59) makes it an alternative method for the production of the desired product in small amounts, though the yields are low (C. 0.5 to 2%).

8.3.36 Radical Reactions TBTH mediated reduction of b-lactams have been developed122 as shown in Scheme 8.60.

8.30 Green Chemistry Br

H

Br

S

Br

Bu3SnH, AIBN, THF, MW

H S

H

N

N O

O

CO2H

CO2H

Scheme 8.60

8.4

MICROWAVE ASSOCIATED REACTIONS IN SOLID STATE

These have already discussed in chapter 7, Sections, 7.2, 7.3 and 7.4.

8.5

CONCLUSION

Use of microwaves for heating purposes in organic reactions saves energy. Using microwave assisted organic synthesis is useful for conducting a number of organic reactions in water and also in organic solvents. Besides, microwaves also find application in hydrolysis, oxidation and substitution reactions.

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Microwave Assisted Organic Synthesis

8.31

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8.32 Green Chemistry 26. R.S. Varma, in Microwaves in Organic Synthesis, A. Loupy (Ed.) Chapter 6, pp 181-218, Viley-VCH, Weinheim (2002). 27. R.S. Varma in Microwaves: Theory and Application in Material Processing IV, D.E. Clark, W.H. Sutton and D.A. Lewis, (Eds.) pp. 357-.365, American Ceramic Society, Westerville, Ohio, (1997). 28. R.A. Abramovich, Org. Prep. Proc. Int., 23, 683(1991). 29. S. Caddick, Tetrahedron, 51, 10403 (1995). 30. F. Langa, P. de la Cruz, A. de la Hoz, A. Diaz-Ortiz and E. Diez-Barra, Contemp. Org. Chem., 4, 373(1997). 31. (a) R.S. Varma, Tetrahedron, 58, 1235(2002). (b) U. Pillai, E. Sahle-Demessie and R.S. Varma, J. Mat. Chem., 12, 3199(2002). 32. P. Lindstrom, J. Tiernery, B. Wathey and J. Westman, Tetrahedron, 57, 9225 (2001). 33. R.S. Varma. Pure Appl. Chem., 73, 193(2001). 34. (a) L. Perreux, A. Loupy, Tetrahedron, 57, 9199 (2001). (b) A. Loupy, A. Petit, J. Hamelin, F. Texier-Boullet, P. Jacquault and D. Mathe, Synthesis, 1213 (1998). 35. (a) C. Gabriel, S. Gabriel, E.H. Grant, B.S.J. Halstead and D.M.P. Mingos, Chem, Soc. Rev., 27, 213(1998). (b) A. Stadler, S. Pichler, G. Horeis and C.O. Kappe, Tetrahedron, 58, 3177 (2002). 36. G.A. Strohmeier and C.O. Kappe, J. Comb. Chem., 4, 154 (2002). 37. Ron Dagani, C & EN News Washington, 26 Feb. 1997, p. 26. 38. Present address: Clean Process Branch, National Risk Management Res. Lab., U.S. Environmental Protection Agency, 26, West MIK Drive, M.S. 443, Cincinnati, OH, 45268 USA. 39. R.N. Gedye, W. Rank and K.C. Westaway, Can. J. Chem., 1991, 69, 706. 40. R.N. Gedye, F.E. Smith and K.C. Westaway, Can. J. Chem., 1988, 66, 17. 41. R.N. Gedye, W. Rank and K.C. Westaway, Can. J. Chem., 1988, 66, 700. 42. R.N. Gedye, F. Smith. K. Westaway, H. Ali, L. Baldisera, Laberge and Rousell, Tetrahedron Lett., 1986, 26, 279. 43. Y. Ju and R.S. Varma, Green Chem., 2004, 6, 219. 44. Y. Ju, R.S. Varma Org. Lett., 2005, 7, 2409; Y. Ju, R.S. Varma, Tetrahedron Lett., 2005, 46, 6011; Y. Ju, R.S. Varma, J. Org. Chem., 2006, 71, 135-141. 45. J. Yulin, Y. Yuncheng, Synthetic Commun., 1994, 24(7) 105. 46. V. Sridar and V.S. Sundara Rao, Indian J. Chem., 1994, 33B, 184. 47. O.C. Dermer and J. King, J. Am. Chem. Soc., 1941, 63, 3232. 48. S.S. Bari, A.K. Bose, A.G. Chaudhary, M.S., Manhas, V.S. Raju and E.W. Robb, J. Chem., Ed., 1992, 69(11), 938. 49. R.J. Giguere, T.L. Bray and S.M. Duncan, Tetrahedron Lett., 1986, 27(41), 4945. 50. R.J. Giguere, A.M. Namen, B.D. Klopez, A. Arepally, D.E. Ramos, G. Majetich and I. Defauw, Tetrahedron Lett. 1987, 28, 6553. 51. R.J. Giguere, A.M. Namen, O. Lopez, A. Arepally, D.E. Ramos, G. Majetich and J. Dafauw, Tetrahedron Lett., 1987, 28, 6553.

Microwave Assisted Organic Synthesis

52. 53. 54. 55. 56. 57. 58. 59.

8.33

(a) K.D. Raner, C.R. Strauss, R.W. Trainer and J.S. Thern, J. Org. Chem., 1995, 60, 2456. B.-C. Hong, Y.-J, Shr, J.-H. Liao, Org. Lett., 2002, 4, 663. S.A. Ayoubi, F. Texier-Boullet and J. Hamelin, Synthesis, 1994, 258. M.K. Kundu, S.B. Mukherjee, N. Balu, R. Padmakumar and S.V. Bhal, Synlett., 1994, 444. A. Srikrishna and S. Nagaraju, J. Chem. Soc. Perkin Trans. I. 1992, 311. A. Alajarin, J.J. Vaquero, J.L. Garcia Navio and J. Alverezbuilla, Synlett, 1992, 297. C.O. Kappe, D. Kumar and R.S. Varma, Synthesis, 1999, 1799. A Stadler and C.O. Kappe, J. Comb. Chem., 2001, 3, 624. B.K. Banik, M.S. Manhas, Z. Kalruza, K.J. Barakat, and A.K. Bose, Tetrahedron Lett., 1992, 33, 3603.

(a) A.K. Bose, B.K. Banik and M.S. Manhas, Tetrahedron Lett., 1995, 36, 213. 60. J. Borlon, P. Giboreau, S. Lateuvre and C. Merchand, Tetrahedron Lett., 1991, 32, 2363. 61. T.J. Mason and J.P. Lorimer, Sonochemistry, Theory, Applications and Uses of Ultrasound in Chemistry, Ellis Horwood, Chichester, 1988. 62. R.N. Gedye, W. Rank and K.C. Westaway, Can J. Chem., 1991, 69, 706. 63. S.D. Pollington, Y. Bond, R.B. Monyes, D.A. Whan, J.P. Candlin and J.R. Jennings, J. Org. Chem., 1991, 56, 1313. 64. (a) K.D. Raner and C.R. Strauss, J. Org. Chem., 1992, 22, 6231. (b) D. Constable, K. Raner, P. Somlo and C. Strauss, J. Microwave Power Electromagnetic Energy, 1992, 27, 195. 65. K. Bougrin, A.K. Bennani, S.F. Tetouani and M. Soufiaoui, Tetrahedron Lett., 1994, 35, 8373. 66. A.C.S. Reddy, P.S. Rao and R.V. Venkataraman, Tetrahedron Lett., 1996, 37, 2843.

67. Y. Yuncheng, G. Dabin and J. Yulin Synth. Commun. 1992, 22, 2117. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81.

(a) Y. Yuncheng, G. Dabin and J. Yulin, Synth. Commun., 1992, 22, 2117. E.M. Gordon, D.C. Gaba, K.A. Jebber and D.M. Zackarias Organometallics, 1993, 12, 5020. A.K. Bose, B.K. Banik, K.J. Barakat and M.S. Manhas Synlett., 1993, 575. G. Optiz and E. Tempel, Liebigs Ann. Chem., 1966, 699, 68. A. Loupy, P. Pigeon, M. Ramdani and P. Jacquault, J. Chem., Res.(S), 1993, 36. G.B. Jones and B.J. Chapman, J. Org. Chem., 1993, 58, 5558. D. Runhua, W. Yuliong and J. Yaozhong. Synth., Commun., 1994, 24, 111 and 1917. M. Chang, H.V. Meyers, K. Nakanishi, M. Ojika, J.H. Park, M.H. Park, R. Takeda, J.T. Vazquez and W.T. Wiesler, Pune Appl. Chem., 1989, 61, 1193. L.H.B. Baptistella, A.Z. Onaga and E.A.M. Godoj, Tetrahedron Lett., 1993, 34, 8407. S. Sowmya and K.K. Balasubramanian, Synth. Commun., 1994, 24, 2097. B. Shanmugasundaram, A.K. Bose and K.K. Balasubramanian, Tetrahedron Lett., 2002, 43, 6797. D. Abenhaim, C.P. Nagoc Son, A. Loupy and N. Ba Hiep, Synth. Commun., 1994, 24, 1199. S. Takano, T. Kijima, S. Satoh and K. Ogasawara, Chem. Lett., 1989, 87. T. Cablewski, A.F. Faux and R. Strauss, J. Org. Chem., 1994, 59, 3408. J.O. Thorell, S. Stone-Elander and N. Elander, J. Labelled Compd. Radiopharm, 1993, 33, 995.

8.34 Green Chemistry 82. D.R. Huang, S.M. Moerlein, L. Lang and M.J. Welch, J. Chem. Soc. Chem. Commun., 1987, 1799. 83. J.A. Vega,. S. Cueto, A. Ramos, J.J. Vaquero, J.L. Garcia-Navio, J. Alvarez-Builla and J.J. Ezquerra, Tetrahedron Lett., 1996, 37, 6413. 84. T. Cablewski, A.F. Faux and C.R. Strauss, J. Org. Chem., 1994, 59, 3408-3412. 85. C.R. Strauss, A.F. Faux, International Patent Application PCT/AU 89/00437, 1989.; CMR was presented in part at the RACI Organic Division, National Conference, Tounsville, 1989, and at ACS Pacifichem’89 Conference, Honolulu, 1980. 86. K.D. Raner and C.R. Strauss, J. Org. Chem., 1992, 57, 6231. 87. K.D. Raner, C.R. Straus, F. Vyskoc and I. Mokbel, J. Org. Chem., 1993, 58, 950. 88. B.S. Furnis, A.J. Hannaford, V. Rogers, F.W. G. Smith and A.R. Tatchell, Vogel’s Textbook of Practical Organic Chemistry., 4th Ed., Longman, New York 1978. 89. M.S. Newman, J. Am. Chem. Soc., 1941, 63, 2431. 90. D. Constable, K. Raner, P. Somblo, and C. Strauss, Journal of Microwave Power and Electromagnetic Energy, 1992, 26, 195. 91. R.N. Gedye, F.E. Smith and K.C. Westaway, Can. J. Chem., 1988, 66, 17. 92. M. Ranoll, M.S. Newman, Organic Synthesis; E.C. Horning(Ed.); John Wiley and Sons, New York, Collect Vol. III, p. 502. 93. Reagents Chemicals American Chemical Society Specification 5th ed; American Chemical Society, Washington DC, 1974, p. 274. 94. R. Gedge, F. Smith, K. Westaway, H. Ali, L. Baldisera, L. Laberge and J. Rousell, Tetrahedron Lett., 1986, 27, 279. 95. S.T. Chen, S.-H. Chiou and K.T. Wang, J. Chem. Commun., 1990, 807. 96. J.M. Sayer, and W.P. Jencks, J. Am Chem. Soc., 1977, 99, 465. 97. S.H. Kusefoglu, A.O. Kress and L.J. Mathias, Macromolecules, 1987, 20, 2326. 98. W.K.R. Musgrave, Rodds Chemistry of Carbon Compounds, S. Coffeg, (Ed.); Elsevier Amsterdam, 1964, Vol 1A, p. 482. 99. G.J. Kontoghiorges and I. Sheppard, Inorg. Chem. Acta, 1987, 136, L11. 100. D. Agigoni and O. Jegar, Helv. Chim. Acta, 1954, 37, 881. 101. A. Hasanar and K.L.M. Rai, Synthesis, 1989, 57. 102. A. Sattar, R. Ahmad and S.A. Khan, Pak. J. Sci. Res., 1980, 23, 177. 103. S. Rajgopalan, and P.V. Raman, Organic Synthesis, E. Horning (Ed.), John Willy, New York, 1955; Collect Vol. III, p. 425. 104. A.W. Burgatahler and L.R. Worden, Organic synthesis, H.R. Baumgarian, (Ed.), John Wiley, New York, 1973; collect. Vol. V, p. 251. 105. Sh Mamedov, D.N. Zh, Obsheh Khim, 1962, 32, 1427; Chem. Abstr., 1963, 58, 4453e. 106. V.K. Bhaleroa, B.S. Nanjundiah, H.R. Sonawana and P.M. Nair, Tetrahedron, 1986, 42, 1987. 107. A. Srikrishna and S. Nagaraju, J. Chem., Soc. Perkin Trans I, 1992, 311. 108. A. Stamboule, M. Chastrettee and M. Soufiaoui, Tetrahedron, Lett., 1991, 32, 1723. 109. R.A. Abramovitch and A. Bulman, Synlett, 1992, 795. 110. S. Takano, A. Kijima, T. Sugihara, S. Sathoh and K. Ogasawara, Chem. Lett., 1989, 87.

Microwave Assisted Organic Synthesis

8.35

111. B. Lei, A.G. Fallis, J. Am. Chem. Soc.,1990, 112, 4609; B. Lei, A.G. Fallis, J. Org. Chem., 1993, 58, 2186. 112. J.T.M. Linders, J.P. Kokje, M. Overand, T.S. Lie, and L. Maat, Rec., Trav. Chim. Pays-Bas, 1988, 107, 449. 113. R. Alajarin, J.J. Vaquero, J.L. Garefa Novfo and J. Alvarez-Builla, Synlett, 1992, 297. 114. A.V. Rama Rao, M.K. Gujar and V. Kaiwar, Tetrahedron Assmm., 1992, 3, 859. 115. M. Puciova, P. Ertl and S. Toma, Collect. Czech. Chem. Commun., 1994, 59, 175. 116. R. Gedye, F. Smith, K. Westaway, A. Humera, L. Baldisera and L.R. Laberge, Tetrahedron Lett., 1986, 26, 279. 117. S.A. Ayoubi, F. Texier-Boullet and J. Hamelin, Synthesis, 1994, 258. 118. M. Puciova and S. Toma, Collect., Czech. Chem. Commun., 1992, 57, 2407. 119. G.B. Jones, and B.J. Chapman, J. Org. Chem., 1993, 58, 5558. 120. L.H.B. Baptistella, A.Z. Neto, H. Onaga and E.A.M. Godoi, Tetrahedron Lett., 1993, 34, 8407. 121. A.J.J. Sraahof, H. Van Bekkum, A.P.G. Kieboom Rect. Trav. Chem. Pays-Bas, 1988, 107, 647; M. Ubukuta, R. Kimura, H. Isono, C.C. Nelson, J.M. Gregson and J.A. MeCloskey, J. Org. Chem., 1992, 57, 6392. 122. A.K. Bose, M.S. Manhas, M. Ghosh, M. Shah, V.S. Raju, S.S. Bari, S.N. Newaz, B.K. Banik, A.G. Chaudhary and K.J. Karakat, J. Org. Chem., 1991, 56, 6968.

9 9.1

Ultrasound Assisted Organic Synthesis

INTRODUCTION

Ultrasound has been used in the service of mankind since 1950. It is more familiar in the context of animal communications (bats, dog whistles, etc.), medical diagnosis (foetal scanning), materials testing (Flow detection), under-water ranging (depth gauges) and cleaning ultrasonic baths. The name ultrasound is given to sound waves having frequencies higher than those to which the human ear can respond (i.e. > 16 KHz) (Hz = Hertz = cycles per second). It is considered to lie between 5 MHz (for gases) and 500 MHz (for liquids and solids). For many years ultrasound has found a variety to uses in engineering, science and medicine. However, its application to chemistry has received attention only in the recent past. A large number of publications have appeared in the past few years which describe various application of ultrasound to chemical synthesis. The term ‘sonochemistry’ is used to describe the effect of ultrasonic sound waves to chemical reactivity. A number of reviews on the chemical applications of ultrasound have been published1–7.

9.1.1 Instrumentation The Instrumentation for the generation of ultrasound requires an ultrasonic transducer, a device by which electrical or mechanical energy can be converted into sound energy. The most commonly used are the electromechanical transducers which convert energy into sound—they are most commonly based on piezo-electric effect. The piezo-electric effect is the production of a potential difference across opposite faces of a crystal of a material when it is subjected to sudden compression and is found in some crystalline materials like quartz. The inverse effect is produced when a rapidly alternating potential is placed across the faces of piezo-electric crystal. This will induce dimentional changes in the crystal and thus generate vibrational (sound) energy1–4.

9.2 Green Chemistry The ultrasonic equipments are normally of four types2 as explained below: (i) Whistle Reactor is a mechanical transducer device and is predominantly used for homogenisation and emulsification. (ii) Ultrasonic Cleaning Bath is the most accessible and simplest instruments available. In this, the amount of power reaching the ‘reaction’ immersed in the bath is not readily quantifiable because it will depend on the size of the bath and the type of the reaction vessel. Also, the temperature control is not easy in this system. A drawback in this system is that they do not all operate at the same frequency, and so do not give reproducible results. (iii) Direct Immersion Sonic Horn is the most efficient method of transmitting ultrasonic energy into a reaction. In this case, an ultrasonic probe is placed directly in the reacting system and such a equipment is used for biological cell disruption. The advantage of such a system is that much higher ultrasonic powers can be used since energy losses during the transfer of ultrasound through the bath media and reaction vessel walls are eliminated. These devices can be tuned to give optimum performance in the reaction mixture over a range of powers. However, in such a system there are difficulties of temperature control and operation at fixed frequency. Direct sonication results also in generation of radical species by the action of the probe tip in the solvent. (iv) The Cup Horn was originally designed for all disruption, but is more controllable than a cleaning bath in terms of power and temperature and less drastic in action than a sonic horn. Such a system allows more quantitative and reproducible studies. The frequency is fixed and the power is tuneable. Two commonly used ultrasound instruments as in the figures below:

Ultrasound Assisted Organic Synthesis

9.3

9.1.2 The Physical Aspects2 Ultrasound being a sound wave is transmitted through any substance, solid, liquid or gas, which posses elastic properties. When transmitted through a medium, it produces alternate compression and rarefraction (stretching cycle of waves). The use of ultrasound may be divided into two areas. First, low amplitude (high frequency) propagation, which is concerned with the effect of the medium on the wave. Generally speaking, the low amplitude waves are used to measure the velocity and absorption coefficient of the wave in the medium. Secondly, high energy (low frequency) propagation, which is concerned with the effect of the wave in the medium. Examples of the second type are ultrasonic cleaning, drilling, soldering, emulsification in chemical processes, etc. These processes are the result of either the mechanical agitation caused by the wave or are of consequence of cavitation (tiny bubbles) produced in the liquid. It is only after the understanding of the phenomenon of cavitation with significant development in the transducer design that a rapid expansion in the application of ultrasound to chemical processes occurred. It is the subsequent fate of some of the cativation bubbles, as they oscillate in the applied sinusoidal acoustic field, which is the origin of sonchemical effects. There are two forms of cativation—stable and transient. The stable cavities are those which oscillate, often nonlinearly, about some equilibrium size—such bubbles have an existence of many cycles. These are also capable of being transformed into transient cavities. The transient cavities, on the other hand, generally exist for less than a single acoustic cycle during which time they expand to at least double their initial size before collapsing violently into smaller bubbles generating high energies the bubbles involving pressures of hundreds of atmospheres and temperature of thousands of degrees. An estimate of temperature and pressures involved in the final phase of the implosion of a bubble containing nitrogen in water at ambient temperature (20°) and ambient pressure (1 bar), gives 4200 K and 975 bar. It is the existence of these very high temperatures within bubble that have formed the basis for the radical production and sonoluminescene. On the other hand, the release of pressure as a shock wave is a factor which has been used to account for increased chemical reactivity (due to increased molecular collision) and polymer degradation. The mechanical and chemical effects of the collapsing bubble will be felt in two distinct regions (a) within the bubble itself, which can be thought of as a high temperature and pressure microreactor. It is the existence of these very high temperatures within the bubble that has formed the basis for the radical production (homogeneous sonochemistry) and sonoluminiscence, and (b) in the immediate vicinity of the bubble where shock wave is produced in collapse as a result of release of pressure. This shock wave is believed to account for increased chemical reactivity due to increased molecular collisions (heterogeneous sonochemistry). The phenomenon of cavitation is dependent upon local environment and is effected by change in frequency, solvent, system vapour pressure and hence temperature, external pressure, etc. The types of ultrasound which are used in chemistry are basically divided into ‘Power Ultrasound’ between 20 and 100 KHz, which is used for cleaning, plastic welding and to affect chemical reactivity, and ‘High Frequency Ultrasound’ in the range 2-10 MHz, which is used in metal scanning, chemical analysis, in the study of relaxation phenomena, etc. The first type, i.e. power

9.4 Green Chemistry ultrasound provides a form of energy for the modification of chemical reactivity which is different from the normally used, i.e. light and pressure and it is this type which is of interest to synthetic chemists.

9.1.3 Types of Sonochemical Reaction The synthetic chemist is mainly concerned with reactions in solution. The effect of ultrasound on various reactions is summarised in the following types of reactions. Homogeneous Reactions The chemical effects of ultrasound on liquids have been studied for many years. If water is sonicated, cavitation induces the homolytic cleavage of water—the primary products are H2 and H2O2; other high-energy intermidiates, viz., HO2•, H•, OH• and e– (aq) have been suggested. This could have been an interesting synthetic method for generation of hydrogen, but it is not so. The formation of ammonia by the sonification of aqueous solution of nitrogen and hydrogen is worth mentioning. The main problem in non-aqueous sonochemistry is that organic solvents have high vapour pressure and, therefore, low temperatures are required to achieve cavitation. Heterogeneous Liquid-Liquid Reactions The use of phase transfer catalysts in organic aqueous biphasic system is well known to catalyse these reactions. However, ultrasound is much more effective in these reactions because ultrasonic waves generate extremely fine emulsions which result in very large interfacial contact areas between the liquid—the result is a dramatic increase in the reactivity between species dissolved in the separate liquids and, therefore, should react much faster than the conventional phase-transfer conditions. In some cases, it has been found that a combination of sonication and PTC has a better overall effect than either of the two techniques alone. Heterogeneous Solid-Liquid Reactions These are of two types: Type I—those in which the solid serves as one of the reagents, and is consumed during the reaction. The type II are those in which the solid often a metal functions either as a catalyst or is consumed. The Type I reactions have been used with success to improve yields—this is due to the dispersing and microstreaming effects of ultrasound. In type II reactions, the cavitational erosion is the major effect which is observed when ultrasonic waves propagate towards, or in the vicinity of a solid. The erosion of the metal follows the sequence Pb > Mg > Zn > Cu. Alkali metals have been submitted to sonochemical conditions in a variety of reactions.

9.2

HOMOGENEOUS SONOCHEMICAL REACTIONS

It has already been stated3 that cavitation induces the homolytic cleavage of water and that the primary products are H2O, H2O2 and other high energy intermediates like HO2•, H•, OH• and e– (aq). More complicated mixtures, containing formaldehyde, hydrogen cyanide, imidazole, etc. result from the irradiation of N2, H2 and CO molecules in water8. Following are given some of the interesting homogeneous sonochemical reactions:

Ultrasound Assisted Organic Synthesis

9.5

9.2.1 Curtius Rearrangement The cavitational explanation (given above) involved the spontaneous evolution of an exicitied species. A curtius rearrangement is the oldest example. Thus benzoyl azide on sonication in benzene solution undergoes Curtius rearrangement to give phenylisocyanate. Though the rate of formation is much higher than under stirring, the yield is low9 (Scheme 9.1).

Scheme 9.1

9.2.2 Sulphur Extrusion from 1, 3, 4-Thiadiazines 1, 3, 4-Thiadiazines on sonication in a solvent (ethanol)-sulphur extrusion occurs with a low energy cleaning bath as the ultrasound source10 (Scheme 9.2).

Scheme 9.2

9.2.3 Isomerisation of Maleic Acid to Fumaric Acid This is the most interesting example under homogeneous sonochemical reaction. The isomerisation takes place in presence of bromine or alkyl bromide11. The mechanism involves sonolysis of bromine molecule to the bromine radical (Scheme 9.3).

Scheme 9.3

9.6 Green Chemistry

9.2.4 Organometallic Reactions 9.2.4.1 Isomerisation of alkenes Sonolysis of iron pentacarbonyl in presence of alkene give the isomerised alkene (Scheme 9.4)12. Fe(CO)5 (cat)

Scheme 9.4

It is believed that ironpentacarbonyl on sonication gives Fe3(CO)12; the yield varies depending on the solvent. Heptane gives the best result

Fe(CO)5

heptane

Fe3(CO)12 82%

The rate of isomerisation of alkene is 105 higher than in the reaction performed on thermal or photlytic pathway. Similar observations have been made from various metal carbonyl complexes13.

9.2.4.2 Annulation The reaction of cyclopentene with appropriate organometallic complex (1) on sonication14 in toluene for 3 hr gave the annulated cyclopentene (2) in 49% yield. Under thermal conditions the yield was 42% (Scheme 9.5). toluene 110° , 36 hr

Ph

O

42%

Co(CO)3 H Co(CO)3

Ph Cyclopentene toluene 3h,

(1)

49%

(2)

Scheme 9.5

Using chiral ligand in the organometallic complex (1) leads to the expected cyclopentenone (2) on sonication15 (Scheme 9.6). The snonchemical ligand displacement can also be involved in as alkynone hydration reaction16 (Scheme 9.7).

Ultrasound Assisted Organic Synthesis

9.7

Scheme 9.6 O

O

1

PdCl2(CH3CN)2/CH3CN

2

R

R

2

1

R

R

O

H2O, r.t, 10 hr

Scheme 9.7

9.2.4.3 Grignard reagents Magnesium on sonication can be activated. This activated magnesium finds applications17, 18, 19 in the synthesis of Grignard reagents without the use of activators in ether in common laboratory cleaning bath (Scheme 9.8). R

X + Mg

ether

RMgX (90%)

Scheme 9.8

A number of Grignard reagents have been prepared19 from olefins, e.g., chlorodiene as shown below (Scheme 9.9). Mg* +

MgCl Cl

Scheme 9.9

Similarly, n-propyl, n-butyl and phenyl lithium are prepared17, 19 in > 90% yield by the reaction of appropriate bromide with lithium wire; sec- and tert-alkyl bromides require longer period of sonication (Scheme 9.10).

9.8 Green Chemistry

R

X + Li

R Li (90%)

Scheme 9.10

9.2.5 Oxidations The oxidising properties of ultrasound by the generation of hydroxyl radicals has been studied. During sonication sufficient concentration of hydroxyl radicals is not obtained and so this procedure is not synthetically useful. It is found that passing oxygen gas in solution to promote oxidation of aldehydes20 or sugars21 is advantageous. It is believed that these reactions involve the sonochemical ‘exitation’ of the oxygen molecule. An interesting example of such oxidations promoted by homogeneous sonication is in the preparation of nitroxyl radicals (1) from hindered piperazines (2) (Scheme 9.11). No reaction occurs under stirring22.

Scheme 9.11

9.2.6 Solvolysis and Hydrolysis Solvolysis of tert butyl chloride in aqueous ethanol takes place23 (Scheme 9.12). Rate enhancement of ~2 were observed using a clearing bath.

Scheme 9.12

It is believed that local electrical phenomena raise the ground state energy of the tert-butyl chloride, making the bond breaking easier. There is rate enhancement of hydrolysis of p-nitrobenzoates24 in acetonitrile (at pH8) on sonication (Scheme 9.13).

Ultrasound Assisted Organic Synthesis

9.9

Scheme 9.13

9.2.7 Addition Reactions 9.2.7.1 Diels-Alder reaction Diels-Alder Reaction is facilitated by sonication. Thus, the addition of dimethylacetylene dicarboxylate to furan derivatives in water at 22–45°C gives quantitative yield of the adduct (Scheme 9.14). O CO2Me

O

H2O, +

X

X

22 – 45°C

CO2Me CO2Me

CO2Me Y

99 – 100%

Y

Scheme 9.14

The Diels-Alder cycloaddition of various dienes (mostly belonging to 1-vinyl cyclohexenes) with o-quinone proceeds very well25 under ultrasound conditions to give the expected adducts in 59% yield (Scheme 9.15) compared to 30% under normal reaction conditions. Better results are obtained by sonication of the neat mixture, and the presence of solvent is detrimental.

9.2.7.2 1, 3-Dipolar cycloaddition Sonication influences 1, 3-dipolar cycloadditions. Thus nitrones (1) add to olefins (2) in excellent yields26, in times shorter by a factor of 20–40 with comparison to the silent reaction (Scheme 9.16).

9.10 Green Chemistry

Diel Alder reaction of (1) and (2) (R1 = H, R2 = H, R3 = H) Solvent

Conditions

Time (h)

Yield (3)

(4)

benzene

reflux

2

30

15

benzene

11 K bar

2

58

9

none

))))

2

59

7

Scheme 9.15 Ph R

N

Ar

Ph

Toluene

+

R

100°C

N O

O (1)

(2) Ar

Ar

Conditions

Ph Ph

))))

4-CI C6H4 4-CI C6H4

)))) Scheme 9.16

Time (h)

Yield %

34

80

1

81

24

75

1

75

Ultrasound Assisted Organic Synthesis

9.11

9.2.7.3 Strecker reaction The Strecker synthesis of aminonitriles takes place using sonication27 (Scheme 9.17).

Scheme 9.17

A modified strecker synthesis for preparation of a-aminonitriles in excellent yield consists of the adsorption of the reagents on the surface of the catalyst before the reaction (Scheme 9.18).

Scheme 9.18

In an homiogeneous acetic acid solution, a cyclic amine Ketone undergoes easy strecker synthesis27 (Scheme 9.19). H3CO

H3CO KCN/RNH2/AcOH N

H3CO

N

25 – 30hr, R = H, Ph, PhCH2CH2

H3CO

O

NC

NHR

90 – 100%

Scheme 9.19

Basic catalysed addition of thiourea to ferrocenyl chalkones (1) give excellent yields of the product (2), when run under sonication. The thermal process gives mixtures which cannot be separated due to instability of the compounds28 (Scheme 9.20):

Scheme 9.20

9.12 Green Chemistry The addition29 of magnesium or titanium phenolate (1) to aldehyde (2) by sonication using dichloromethane as the solvent. In this case, the stereoselectivity is sensitive to sonication (Scheme 9.21).

Mx

Conditions

Yield (%)

Mg Br

(3)

(4)

27

5

Mg Br

))))

64

6

Ti (OPr-i)3

))))

8

68

Scheme 9.21

9.2.7.4 Electrophilic addition Besides the nucleophilic addition reaction discussed, the only example of an electrophilic addition is found30 with the intramolecular aminomercuration of a carbopenam precursor (Scheme 9.22).

Scheme 9.22

9.2.7.5 [2 + 2] Cycloaddition reactions The 2 + 2 cycloaddition of dichloroketene (generated in situ) to alkenes is also improved by ultrasound31 (Scheme 9.23).

Scheme 9.23

Ultrasound Assisted Organic Synthesis

9.13

9.2.7.6 Cycloaddition reactions An interesting application of the cycloaddition reaction is the cyclopropanation32. In this reaction, sonochemically activated Zn is used. The yield is 91% compared to 51% by the normal route. Ultrasonic source is a cleaning bath (50 KHz) (Scheme 9.24).

Scheme 9.24

The method has several advantages and can also be scaled up33. Highly hindered bicyclo [3.2.1] oct-6-en-3-ones are easily obtained34 by zinc promoted cycloaddition of a, a-dibromo ketones to 1, 3-dienes. There is, however, no reaction in the absence of ultrasound (Scheme 9.25).

Scheme 9.25

9.3

HETEROGENEOUS LIQUID LIQUID REACTIONS

Ultrasound is much effective in heterogeneous liquid-liquid reactions. This is because ultrasound waves generate extremely fine emulsions, which result in very large interfacial contact areas between the liquids. This results in a dramatic increase in the reactivity between the species dissolved in separate liquids and, therefore react much faster than even the conventional phase-transfer conditions. However, it has been found that a combination of sonication and PTC gives a better overall effect than either of the two techniques. Following are described some of the important heterogeneous liquid-liquid reactions.

9.3.1 Esterification The esterification of carboxylic acids is a widely studied reversible reaction35. The esterification is generally carried out in the presence of catalysts like sulphuric acid, p-toluenesulphonic acid, tosyl chloride, polyphosphate ester, dicyclohexylcarbodiimide, graphite phosphate. The reaction requires longer time, and yields are generally low. A simple procedure for the esterification of a variety of carboxylic acids with different alcohols at ambient temperature using ultrasound has been reported36. (Scheme 9.26).

9.14 Green Chemistry

RCOOH + R' OH

H2SO4, R.T.

RCOOR'

Scheme 9.26

Low intensity ultrasound (cleaning bath) has also been used37 for esterification. (Scheme 9.27) KOH, PEG RCO2H + R'X X

RCO2R'

Cl, Br, l

Scheme 9.27

Using the reaction of carboxylic acid with alcohol (Scheme 9.26) following esters have been prepared36. RCOOH

ROH

Time (hrs)

Isolated Yields (%)

Benzoic Acid

Methanol

3

95

Benzoic Acid

Ethanol

3

89

Benzoic Acid

1-Propanol

4

91

Benzoic Acid

2-Propanol

5

88

Benzoic Acid

t-Butanol

5

46

p-Chlorobenzoic acid m-Chlorobenzoic acid p-Nitrobenzoic acid p- Hydroxybenzoic acid

Methanol Methanol Methanol Methanol

5 5 4 4

79 88 76 81

Salicyclic acid

Methanol

7

79

Cinnamic acid

Methanol

7

96

p-Anisic acid

Methanol

5

92

Phenylacetic acid

Methanol

1.5

93

Phenylacetic acid

Ethanol

1.5

93

Phenylacetic acid

1-Propanol

2

90

Phenylacetic acid

2-Propanol

4

87

Phenylacetic acid

1-Butanol

2

86

Phenylacetic acid

t-Butanol

5

57

Stearic acid

Methanol

2.5

90

Stearic acid

Ethanol

4

92

Oleic acid

Methanol

4

91 Contd...

Ultrasound Assisted Organic Synthesis

9.15

Contd...

Palmitic acid

Methanol

2

87

Succinic acid

Methanol

4

93

Oxalic acid

Methanol

4

79

Fumaric acid

Methanol

4

92

Maleic acid

Methanol

3.5

86

9.3.2 Saponification Ester hydrolysis is frequently effected under aggressive conditions. It can, however, be conducted under milder conditions when sonication is used38. The rate increase is attributed to the emulsifying effect. Thus, methyl-2, 4-dimethylbenzoate on saponification (20 KHz), gives 2, 4-dimethylbenzoic acid in 94% compared to 15% yield by normal process of heating with aqueous alkali (90 min) (Scheme 9.28).

Scheme 9.28

Ultrasonically (20 KHz) induced rate enhancements for the hydrolysis of a number of 4-nitrophenyl esters of a number of aliphatic carboxylic acids has been reported38,39. Saponification of commercially important substances such as glycerides, rape seed oil and wool waxes is greatly accelerated by sonication37.

9.3.3 Hydrolysis/Solvolysis Solvolysis of tert-butyl chloride in aqueous alcohol has been studied40 using sound waves. There is rate enhancement of ~2 using a cleaning bath. However, use of a probe generator raised the acceleration value to ~2 at 10° (Scheme 9.29).

Scheme 9.29

Basic hydrolysis of nitriles to carboxylic acids is also greatly improved by sonication41 (Scheme 9.30).

9.16 Green Chemistry –

HO /H2O ArCN

ArCOOH

Scheme 9.30

Using this procedure, benzoic acid is obtained40 in 33% yield compared to 15% yield by the usual procedure from the corresponding nitrile in 10 hr. Similarly, b-naphthoic acid is obtained in 90% yield compared to 63% yield by the usual procedure in 6 hrs. An interesting hydrolysis catalysed by ultrasound involves the synthesis of a Milbemycin D fragment (1)42 (Scheme 9.31). In this double hydrolysis followed by acetalisation, the role of sonic waves is unclear, but is essential. O

OH 30% of HClO4/CH2Cl2

MeO

MeO

20 min, OMe MeO O

+

O O

O

O (1) 50%

O 13%

Scheme 9.31

9.3.4 Substitutions An interestingly useful example is that of Finkelstein exchange reaction by which an w-bromofatty acid is transformed to its123I-analogue43 (Scheme 9.32). This radioisotope has short life and is expensive. The usual method makes use of temperatures up to 180°; This is inconvenient due to thermal instability of the product and also because it requires anhydrous conditions. On the contrary, sonication in a cleaning bath leads to a fast reaction (20 min) with quantitative yield.

Scheme 9.32

Ultrasound Assisted Organic Synthesis

9.17

The Friedel–Crafts acylation of aromatics is facilitated44 by ultrasound (Scheme 9.33).

Scheme 9.33

An application45 of the Friedel–Crafts reaction is used in the carbon-carbon bond formation. Excellent yield (75%) is obtained in sonochemical reaction (Scheme 9.34).

Scheme 9.34

Halides can be converted into cyanides. Thus, the reaction of benzyl bromide in toluene with potassium cyanide is catalysed by alumina on sonication to give46 the substitution product, viz., benzyl cyanide in 76% yield. In this case, the formation of the Friedel-Craft acylation product is not observed. Without the use of ultrasound 83% of the Friedel-Craft product is obtained. A probable explanation36 involves ultrasonic dispersion of potassium cyanide on the alumina surface which decreases the Friedel-Craft activity while promoting the nucleophilic displacement of CN– on its surface (Scheme 9.35). Aromatic acyl cyanides are obtained from the corresponding acyl chloride by treatment with potassium cyanide in acetonitrile at 50° and subjecting it to sonication even in the absence of phase transfer condition47. In the absence of ultrasound, the reaction is facilitated by the presence of traces of water but proceeds slowly (Scheme 9.36). The synthesis of azides from primary alkyl halides and aqueous sodium azide is also faciliated48 by ultrasound (Scheme 9.37). The alkyl bromides on sonication with KSCN in the presence of a quaternary ammonium salt gives the corresponding sulphocyanide in 62% yield compared to 43% yield under usual procedures (Scheme 9.38).

9.18 Green Chemistry

Scheme 9.35

Scheme 9.36

Scheme 9.37 Br

+

–

SCN 62%

KSCN/H2O/Bu4N Br , RT, 6hr

Scheme 9.38

Following the same principle, allylic and propargylic halides undergo an easy substitution with aqueous sodium azide48 (Scheme 9.39). Cl

NaN3/H2O, r.t,

N3

88%

Scheme 9.39

Alkylation of thiocarbonic acid salts (1) has also been achieved using sonication49 (Scheme 9.40).

Ultrasound Assisted Organic Synthesis

SNa N—S

CH3(CH2)2Cl/H2O, 40°

O

N—

9.19

SPr O

(1)

Scheme 9.40

The above illustration (Scheme 9.40) particularly useful due to thermal sensitivity of the starting material.

9.3.5 Additions Sodium azide adds on to several alkanoate esters (1). A satisfactory selectivity is obtained under sonication50 (Scheme 9.41).

Scheme 9.41

A hydroformylation has been developed for the synthesis of aldehydes from olefins. Thus, 1-hexene and water containing a soluble rhodium catalyst on sonication under a stream of carbon monoxide and hydrogen. A mixture of heptanal (1) 2-methylhexanal (2) is obtained with a rate 2-3 times higher than without ultrasound (Scheme 9.42)51, 52.

Scheme 9.42

Hydrocyanation of an aromatic aldehyde with sodium cyanide and benzene sulphonyl chloride in toluene/H2O (sonication) takes place to give 94% yield of cyanohydrin sulfonate ester. Without sonication, the yield is 40% (Scheme 9.43)53.

9.20 Green Chemistry NaCN/ PhSO2Cl toluene/H2O OSO2Ph

94% PhO

PhO

CHO

CN

Scheme 9.43

1, 4-Addition to a, b-unsaturated carbonyl compounds is traditionally54 carried out by organo copper reagents. However, significant improvements in yields, rates and ease of experimental technique is observed55 when the organo copper compounds are generated by sonication (bath 50 KHz) of copper (I) compounds, organic halides, and lithium sand in diethyl ether-THF at 0°, are allowed to react with a-enones (Scheme 9.44).

+

Li, Cu, Et2O O + RBr

C – Cu

THF, R

H3 O

O

R (R = n – Bu 89%)

Scheme 9.44

Similarly, arylzinc compounds are generated ultrasonically56 (cleaning bath); these are also excellent reagents for 1, 4-addition to a-enones and a-enals in presence of catalytic amount of Ni (acac)2 (Scheme 9.45).

Scheme 9.45

The allylic bromide adds regioselectively57 in the presence of zinc-silver couple to various aldehydes and ketones except benzophenone. Sonication increases the yield by about 50% and in one-third of time in comparison to a refluxed reaction. However, using magnesium instead of Zn-Ag reverses the regioselectivity (Scheme 9.46). Trifluoromethylation is possible58 by the sonification of ketones with perfluoroalkyl halides (Scheme 9.47). Methylenation of carbonyl group requires complex reagents. It can now be accomplished easily by the Simmons-Smith reagent (Zn/CH2I2) with sonification59 (Scheme 9.48).

Ultrasound Assisted Organic Synthesis

9.21

Scheme 9.46

Scheme 9.47 1

1

R

R

C 2

R

O

CH2l2/Zn/THF RT,

C

CH2

2

R

Scheme 9.48

The reaction is generally applicable to aldehydes, and not to ketones, with benzaldehyde (R = Ph; R2 = H), the yield is 70% in 20 min. 1

9.4

HETEROGENEOUS SOLID LIQUID REACTIONS

As already stated heterogeneous solid-liquid reactions are of two types. In Type I, solid serve as one of the reagents and is consumed during the reaction. In Types II reactions, the cavitational erosion is the major effect which is observed when ultrasonic waves propagate towards, or in the vicinity of a solid. Following are given some of the interesting heterogeneous solid-liquid reactions.

9.22 Green Chemistry

9.4.1 Alkylations 9.4.1.1 N-Alkylation Secondary amines can be N-alkylated under sonication in the presence of a phase transfer reagent, polyethylene glycol monomethyl ether was necessary. Thus, benzopyrrole on methylation with methyl iodide in toluene in the presence of potassium hydroxide and PTC gives the corresponding N-methyl product in 65% yield. However, under normal conditions (20°, 5 hr.) the yield is 60% (Scheme 9.49).

Scheme 9.49

Similarly, diphenylamine on sonication with benzyl bromide gives60 98% yield of the corresponding N-benzylated product in 1 hr, compared to 70% in 48 hr under normal conditions (reflux) (Scheme 9.50).

Scheme 9.50

In the absence of PTC, the reaction does not take place under sonication. This indicates that the increase in reactivity is not simply a matter of interfacial contact area. N-Alkylation of crown compounds can be effected61 conveniently under sonication (Scheme 9.51). H

Me Mel/solid KOH/toluene R.T., 8h,

N O

O

N O

O

N

N

H

Me 92%

Scheme 9.51

Ultrasound Assisted Organic Synthesis

9.23

9.4.1.2 C-Alkylation C-Alkylation of isoquinoline derivatives has been effected62 by sonication using PTC as catalyst (Scheme 9.52).

Scheme 9.52

Alkylation of thiocarbamic acid salts has been carried out under sonication63. This procedure is found to be advantageous because of the thermal sensitivity of the starting material. Without sonication the reaction is very much slow (Scheme 9.53).

Scheme 9.53

9.4.1.3 O-Alkylation Primary alcohols on sonication64 with benzyl bromide in the presence of silver oxide gives 72% yield of the O-benzylated product. Under normal conditions without sonication the reaction yield is low with poor reproducibility (Scheme 9.54). OH

OH OH

CO2Me

Ag2O/PhCH2Br

Ph

O

CO2Me

THF, 10°,

Scheme 9.54

Similarly, ether formation of a phenol group in 5-hydroxychromone is quantitative when sonicated with a probe generator65 (Scheme 9.55).

9.24 Green Chemistry

K2CO3 O

O

N

CO2Et

RX O

CH3

CO2Et

65°, 0.5 – 15 hr, )))) HO

OR

O

O

Scheme 9.55

Low intensity ultrasound (cleaning beth) has beneficial effects in the synthesis of ethers. Thus, ethyl phenyl ether is obtained66 in 80% yield on sonication compared to 44% in stirred control reaction (Scheme 9.56). C2H5OH

+

C6H5X

KOH, PEG ))))

C2H5OC6H5 80%

Scheme 9.56

In the above O-alkylation (Scheme 9.55), potassium carbonate is broken into small particles in N-methylpyrrolidone solvent which liberates high energy by cavitation. The same effect explains the high yield67 of diethyl carbonate by the sonochemical modification of the reaction of ethyl bromide with potassium carbonate.

9.4.1.4 S-Alkylation Arylthiols, aralkylthiols and alkanethiols can be alkylated68 in presence of K2CO3/DMF at ambient temperature (Scheme 9.57). RSH

+

R¢ X

K2CO3/DMF

RSR¢

))))

Scheme 9.57

The reaction is accelerated68 under sonication.

9.4.2 Oxidations In the case of oxidations, the usual inorganic reagents require water as a cosolvent, which can make the reaction less efficient and also make the work-up procedure difficult. Solid potassium permanganate can be used to oxidise alcohols in benzene or hexane suspension under sonication69 (Scheme 9.58).

Ultrasound Assisted Organic Synthesis 1

R

2

R

9.25

1

H C

KMnO4 hexane or benzene

R

r.t. ))))

R

OH

2

C

O

Scheme 9.58

It has been shown that in case of oxidation of octan-2-ol (R1 = C6H13; R2 = H) the corresponding ketone is obtained in 92.8% yield (5 hr) compared to 2% yield by mechanical stirring. Similarly cyclohexanol gives 53% yield of cyclohexanone by oxidation under sonication (5 hr) compared to 4% yield under usual conditions. In a similar way, oxidation of cinnamyl aldehyde under sonification gives 82% of cinnamic acid (3 hr) compared to 4% under usual conditions. R¢

R2

CH3(CH2)5

CH3

CH3(CH2)5

CH3

Conditions

Time (hr)

Yield (%)

5

2

))))

5

92

5

4

))))

5

53

3

4

3

82

– (CH2)5 – – (CH2)5 – PhCH=CH

H

PhCH=CH

H

))))

It has shown70 that crystalline manganese dioxide, which is of low reactivity, is activated upon sonification. Thus, sonication of cinnamyl alcohol, geraniol or 1-phenylethanol with MnO2 gives the corresponding aldehydes. In these oxidations pentane, hexane or octane is used as solvent — best result are obtained by using a less volatile medium (octane) (Scheme 9.59).

Time (min) pentane 10 15 20

Yield(%) of cinnamaldehyde hexane

23 32 44

actane

28 35 51

46 63 73

Scheme 9.59

The role of solvent in MnO2 oxidation is also clear from the following example (Scheme 9.60). OH

MnO2, 30°, ))))

CHO

Contd...

9.26 Green Chemistry Contd...

Time (min)

Yield(%) of aldehyde in Solvent pentane

hexane

60

19

55

75

34

67

90

48

80

Scheme 9.60

A number of benzylic halides have been oxidised71 with aqueous sodiumhypochlorite72 at ambient temperature on ultrasonic irradiation. The oxidations are believed to be proceeding via benzylic hypohalides (Scheme 9.61). ArRCHX

ArRCHOCl

+

NaOCl

+

NaOCl

CH3CN, RT )))) CH3CN, RT ))))

ArRCHOCl

ArRCO

Scheme 9.61

The above method has also been used for the oxidation of mesylates, tosylates, amines, oximes and alcohols.

9.4.3 Reductions Sonication plays an important role73 in the reactivity of platinum, palladium and rhodium black. Thus, formic acid and palladium on carbon are an efficient couple for the hydrogenation74 of a wide range of alkenes at room temperature in the presence of low intensity ultrasonic fields (cleaning bath, 50 KHz) (Scheme 9.62). Pd/C, HCO2H, 20° 1 hr, ))))

Scheme 9.62

Similarly, hydrazine-palladium on carbon couple is also useful for the hydrogenation of alkenes in ethanol at room temperature using an ultrasonic bath75. A commercially useful example of a sonochemically enhanced catalytic reaction is the ultrasonic hydrogenation of soyabean oil76. This has considerable advantage over the currently used batch methods which require much longer reaction times. Sonication has also been used76 for the hydrogenolysis of benzyl ethers with H2/Pd – C in methanol in the presence of acetic acid. Introduction of deuterium with Raney nickel in sugar derivatives77 and p-bromoacetophenone78 has been achieved (Scheme 9.63).

Ultrasound Assisted Organic Synthesis

9.27

Scheme 9.63

In the last case, a mixture of mono, di- and tri-deuterated compounds is obtained without sonication. Sonication also increases the activation of nickel power79 which, in turn, has been used for reduction of alkenes. Catalytically, active nickel can be obtained by sonochemical reduction of its salts such as chloride with zinc power. It has been shown that under these conditions the excess of metallic zinc is activated and reduces the water present in the medium producing hydrogen gas80. In this way, not only the catalyst but also the reagent is produced in situ with maximal efficiency and safety. This process has been used for the reduction of carbon-carbon double bonds in a, b-unsaturated carbonyl compounds which is reduced much faster than the carbonyl group. The variation in the conditions, especially the pH permits81 the selective reduction of C = C in preference to C = 0 (Scheme 9.64).

9.4.3.1 Reduction of carbonyl group Sonication82 has also been used to reduce carbonyl groups. Thus, camphor on sonication in tetrahydrofuran yields a mixture of endo and exo borneol in the same ratio as by using the metal in ammonia solution (Scheme 9.65). The endo product is obtained in 73, 68 or 42% by the use of Li, Na or K as the metal in the above reduction. Carbonyl groups with less negative redox potential such as quinones or a-diketones can be reduced on sonication with zinc in presence of trimethyl-chlorosilane83. In this case, tetrahydrofuran is found to be superior than diethyl ether. The Clemmensen reduction can also be carried out by sonication in improved yields84.

9.4.3.2 Reduction of aromatic rings Reduction of aromatic rings has been investigated only in a very limited case. For example, N-protected indole on sonication in the presence of lithium and trimethylchlorosilane undergoes a clean reduction to give the dihydrocompound (Scheme 9.66). Extension of this process to other aromatic rings, followed by benzoquinone oxidation of the dihydro intermediate, provides a satisfactory method for ring silation85, 86.

9.28 Green Chemistry O

O Zn

NiCl2 (9 : 1)/ EtOH

H2O (1:1)

RT, 2.5 hr., )))) 97% (In the absence of ultrasound the reaction takes 48 hrs.)

Zn

NiCl2 (9 : 1)/ EtOH

H2O (1 : 1)

O

R.T., 3 hr, )))) O 95%

Zn

NiCl2 (9 : 1)/ EtOH

H2O (1 : 1)

O

pH8, R.T., 1.5 hr, )))) 95%

Scheme 9.64

Scheme 9.65

Scheme 9.66

Ultrasound Assisted Organic Synthesis

9.29

Aromatic halides, which are known to be reluctant towards reduction by hydrides, undergo a substitution by hydride with excellent yields in dimethoxyethane (DME) solution87 (Scheme 9.67).

Scheme 9.67

9.4.4 Hydroboration Hydroboration is considerably enhanced88 by low intensity ultrasound, especially in heterogeneous systems. Thus, tricyclohexylborane is obtained in 1 hr by the reaction of cyclohexene with BH3. SMe2; this traditionally requires 24 hrs at 25° (Scheme 9.68). BH3SMe2

B 3

THF 1 hr, )))) (50 KHz, 150 W)

Scheme 9.68

Thus, sonication is shown to provide an interesting alternative and to provide excellent yields in short periods. The products obtained are stable under ultrasonic irradiation, even those with boronhalogen bond. Even chiral reagent can be obtained conveniently from a-pinene and 9-Borobicyclo [3.3.1] nonane (9-BBN) (Scheme 9.69).

Scheme 9.69

In the above two cases the normal preparations take 5 hrs.

9.4.5 Hydrosilation and Hydroalkylation Hydrosilation of alkenes can be achieved89, 90 in presence of platinum-carbon catalyst in an ultrasonic cleaning bath at much lower temperature 30° than is used for without sonication. Similarly,

9.30 Green Chemistry hydroperfluoroalkylation of alkynes is achieved sonically with perfluoroalkylcuprates (generated in situ by the reaction of perfluoroalkyl halides (Rf) with zinc and copper (I) iodide) in THF. The reaction is regiospecific. Similar results are obtained91 for perfluoroalkylation of dienes catalysed by Cp2 TiCl2 (Scheme 9.70).

Scheme 9.70

An interesting application of hydroalkylation is the preparation of dienes92 by the reaction of sonochemically generated highly functionalised allyl zinc intermediates with alkynes (Scheme 9.71). R R Br R¢ — C

CH

+

Zn, THF, )))) R

– CO2 alkyl, -PO (alkyl)2

R¢

Scheme 9.71

9.4.6 Coupling Reactions Sonication is effective in promoting90, 93 the homocoupling of organometallic intermediates obtained by the reaction of alkyl, aryl or vinyl halides with lithium wire in THF (ultrasonic bath, 117 W, 50 KHz). No reaction takes place in the absence of ultrasound (Scheme 9.72).

Br

Li, THF, ))))

Scheme 9.72

Similarly, coupling of benzyl halides in the presence of copper or nickel powder generated by lithium reduction of the corresponding halides in the presence of ultrasound gives high yields94 of dibenzyl (Scheme 9.73).

Ultrasound Assisted Organic Synthesis

9.31

Scheme 9.73

In the classical Ullmann coupling, copper has to be reacted at high temperature. On sonication, this requirement is modified as activation occurs by reducing the size of the metal powder95. Breakage of the particles brings in contact with the reactive solutions a fresh surface, the reactivity of which is not hindered by the usual oxide layer. Thus, sonication96 of o-iodonitrobenzene with copper powder in the presence of DMF at 60° gives 70% yield of the product in 95 min (Scheme 9.74).

Scheme 9.74

Sonication of aryl sulphonates in presence of in situ generated nickel (0) complex is an interesting Ullmann type coupling97. This method works best for triflates (R = CF3). However, for tosylates (R = 4 – CH3C6H4) the yields are low (Scheme 9.75). ArOSO2R

+

Ni (O)

)))) DMF 60°

Ar2

)))) DMF NlCl2/Zn, PPh3, Nal

Scheme 9.75

This process is proved to be of interest in the case of the formation of silicon-silicon bonds. Various chlorosilanes can be coupled by sonication in the presence of lithium98. The highly hindered tetramesityldisilane is prepared in good yield from dichlorodimethylsilane using lithium under sonication99 (Scheme 9.76).

9.32 Green Chemistry CH3 Li/THF 20min, ))))

R2SiCl2

R2 Si

SiR2 ; R

H3C CH3

Scheme 9.76

Cross coupling reactions91, 100, 101 of perfluoroalkylzinc reagents with vinyl, allyl or aryl halides can be achieved using a cleaning bath (35–45 KHz) (Scheme 9.77). X Rf RfX

+

Rf

CF3

RfX

+

R¢

Zn, Pd° ))))

R¢

Br

R¢

Zn, Pd (OAc)2 ))))

R¢

Rf

Scheme 9.77

Lithium dialkphosphides obtained by cleavage of Li-C bond in THF in the presence of low intensity ultrasound (cleaning bath) readily couple with alkyl halides to give102, 103 phosphonanes (Scheme 9.78).

Scheme 9.78

9.4.7 Dichlorocarbene Dichlorocarbene can be generated by the direct reaction104 between powdered sodium hydroxide and chloroform by sonication. The procedure is simple and efficient, and avoids the use of phase transfer catalyst. The generated dichlorocarbene in situ undergoes addition reaction to alkenes. Thus, the sonication of styrene with solid sodium hydroxide and chloroform by stirring gives 96% yield of the adduct in 1 hr. However, the yield is reduced to 38% (20 hr stirring only) and 31% (16 hr stirring only) (Scheme 9.79). In a similar way 2-methyl hexane-1 adds to dichlorocarbene (Scheme 9.80).

Ultrasound Assisted Organic Synthesis

9.33

Scheme 9.79 Cl Cl Solid NaOH/CHCl3 rt. 1 h. ))))

Scheme 9.80

9.4.8 Some Ultrasonically Induced Organic Reactions 9.4.8.1

Bouveault reaction

Organolithium reagents are obtained by sonication of aryl halides with lithium with low ultrasonic intensity. Their application in the Bouveault reaction has resulted in higher yields of product aldehydes than the traditional methods105 (Scheme 9.81).

Scheme 9.81

In non-ultrasonic Bouveault reaction, which suffers from numerous side reactions, the method is improved when DMF is replaced by more elaborate and expensive formamide, Me2NCH2CH2N (Me) CHO. A simplification of this method is by sonication of any aryl halide and amide with excess lithium for 15 min followed by dropwise addition of 1-bromobutane, sonification for 30 min more gives the o-substituted aldehydes (Scheme 9.82). X

CHO +

DMF

(1) Excess Li )))), 15 min (2) n-C4H9 Br )))), 30 min

CH2CH2CH2CH3 79%

Scheme 9.82

Use of iodomethane in place of n-butyl bromide in the above reaction gives o-tolualdehyde106.

9.34 Green Chemistry 9.4.8.2 Cannizzarro reaction The Cannizzarro Reaction under heterogeneous conditions catalysed by barium hydroxide is considerably accelerated by low intensity ultrasound (cleaning bath). The yields are 100% after 10 min, whereas no reaction is observed during this period without the use of ultrasound107 (Scheme 9.83). Ba(OH)2, EtOH

CHO

CH2OH

)))), 10 min

+

CO2H

Scheme 9.83

9.4.8.3 Strecker synthesis (See Section 9.2.7.3)

9.4.8.4 The Reformatsky reaction The Reformatsky reaction under sonication gives excellent yields with respect to more traditional methods, e.g., those employing activated zinc or trimethylborate as a cosolvent108. In the solution procedure it is necessary to activate the metal with iodine and to run the reaction in dioxane. Under optimal conditions quantitative yield of b-hydroxyester is obtained (Scheme 9.84). 1

R R

C

O

2

R

1

H; R

2

1

R

BrCH2 CO2 Et/Zn/l2 Dioxane, RT, 5 – 30 min, )))) 1

2

Ph or (CH2)2 CH3; R — R

2

R

CO2Et OH

— (CH2)4 —

Scheme 9.84

Application of Reformatsky reaction to Schiffs bases under sonication gives better results at room temperature in dioxane to give b-lactams. However, this modification is not of general applicability109 (Scheme 9.85).

Scheme 9.85

The Reformatsky reaction with nitriles leads to the formation of imines which readily hydrolyse to the ketones. This has made available keto-g-butyrolactones in fair yields110 (Scheme 9.86).

Ultrasound Assisted Organic Synthesis

CN 1

OSiMe3 R

1

R

H

CO2Et

CH3, Ph; R

2

))))

2

R

Zn/THF, RT, 2hr,

+

R

F

O

2

F

9.35

1

R

O

O

H, CH3

Scheme 9.86

9.4.8.5 The Barbier reaction of carbonyl compounds The reaction of a ketones with an organometallic reagent (obtained in situ) to give the corresponding alcohol is known as the Barbier reaction. It is to be noted that the same products are also obtained by using a ketone and a Grignard reagent, which is obtained separately. Thus, the Barbier reaction offers time-saving and also the possibility of utilising organometallics which are unstable. The main disadvantage is that in the normal Barbier reaction only reactive alkyl halides can be used. This difficulty is overcome if the reaction is carried out by sonication111. The reaction is carried out in tetrahydrofuran and even imperfectly dried alkyl halides give excellent yield of the expected alcohol by reaction with lithium and various aldehydes and ketones. Even reactive halides, e.g., allyl or benzyl halides which generally give Wurtz coupling can also be used. Some examples are given below (Scheme 9.87). R

1

3

O

C 2

R X/Li/THF RT, 10 – 15 min, ))))

R

3

R

2

R

1

R

OH

(70 – 100%) O

BuBr/Li/THF

OH

RT, 15 min, )))) 90%

Scheme 9.87

A synthetic intermediate in the synthesis of sesquiterpene is obtained by a sonochemical Barbier reaction112 (Scheme 9.88). OH

O Br/Li/THF RT, 45 min, ))))

Scheme 9.88

9.36 Green Chemistry A total synthesis of pentalenic acid has been achieved by the reaction of dimethyl-cyclopentenone with 5-bromo-1-hexene and lithium with sonication113 (Scheme 9.89). O

OH Br Li/Et2O, ))))

Scheme 9.89

Benzylhalides can also be used in Barbier reaction. It is to be noted that there is no Wurtz type coupling114,115 (Scheme 9.90). O

Cl

OH

/Li/Et2O

C

0°, 30 min, )))) 75%

Scheme 9.90

Chloromethyllithium is an unstable reagent. It is obtained in situ by the reaction of chlorobromomethane by sonication116 with lithium in tetrahaydrofuran. This reagent reacts with ketones to give epoxides in high yields. The aldehydes, however, give exposides or chlorohydrins (Scheme 9.91). 1

R

C

O

2

R

1

CH2BrCl/Li/THF

R

– 20°, 20 min, ))))

R

1

O

R +

2

OH Cl

2

R

Scheme 9.91

With benzaldehyde the chlorohydrins is obtained in 90% yield. However, with phenyl amyl ketone (R1 = Ph; R2 = n – (CH2)5) the epoxide is obtained in 91% yield.

9.4.8.6 Dieckmann cyclisation On sonication potassium is easily transformed to a silvery blue suspension in toluene. The ultrasonically dispersed potassium effects Dieckmann and Thorpe-Ziegler cyclisations under favourable conditions117 (Scheme 9.92). O

O OEt

CO2Et

Ultrasonically dispersed K Toluene. RT, 5 min

CO2Et

83%

Scheme 9.92

Ultrasound Assisted Organic Synthesis

9.37

Similarly, ultrasonically dispersed sodium is also obtained in toluene and can be used in various reactions.

9.4.8.7 Cyclocondensations A number of condensation reactions have been carried out on sonication. Thus, the yield of the condensation product of o-hydroxybenzaldehydes with b-nitrostyrene derivatives using basic alumina catalyst is considerably increased on sonication118. This is a convenient one pot route for the synthesis of 3-nitro-2H-chromenes (Scheme 9.93).

OH

O

Al2O3

+

))))

CHO

NO2 O2N

Scheme 9.93

The rate of aldol dimerisation of ketones catalysed by basic alumina is also increased by sonication119 (Scheme 9.94).

O

O Al2O3, 80°, 24 hr ))))

Scheme 9.94

9.4.8.8 Carbohydrates-formation of acetals and benzylidene derivatives of alkylglycopyranosides Many syntheses in carbohydrate series start with the formation of acetals (isopropylidene, cyclohexlidene, benzylidene derivatives) with a view to protect the hydroxyl groups and rendering the compounds soluble in organic media. The catalysts used normally are strong protic acids, e.g., sulphuric acid, perchloric acid, but the reaction is often slow and undesired products including tar are formed on prolonged reaction time. Sonication119, 120 permits the reaction time to be considerably shortened and better yields. Thus, the two vicinal hydroxyl groups in glucose can be protected by treatment with acetone or cyclopentanone on sonication in the presence of concentrated sulphuric acid at room temperature in 60–75% yields compared to 5–10% yield without sonication (Scheme 9.95). Similarly, the benzylidene derivatives of alkyl glycopyranoside are achieved121 on sonication. Initially, benzaldehyde is made to react with fused zinc chloride under sonication to give the

9.38 Green Chemistry 1

R

HO HO

1

C O OH

O/H2SO4/RT

2

2

R

R

1

R or, 1 R

OH OH

R

2

R

2

R

O O OH

O

CH3

O

2

O

(CH2)5

1

R R

Scheme 9.95

complex catalyst. Subsequent reaction with methylglycopyranoside and sonication, the benzylidene derivative is obtained (Scheme 9.96). HO

O O R1 OH

OH

R2

PhCHO/ZnCl2 RT, 0.6 hr, ))))

OH H

OH R1

H; R2

OMe

R1

OMe

H; R2

O R1

Ph O

R2 OH

Scheme 9.96

9.5

MISCELLANEOUS SONOCHEMICAL REACTIONS

Following are given some miscellaneous applications of ultrasound.

9.5.1 Potassium Superoxide It is used in the preparation122 of anion of acetonitrile. The formed anion condenses with various aldehydes (Scheme 9.97).

Scheme 9.97

Ultrasound Assisted Organic Synthesis

9.39

9.5.2 Sonolysis of Fe(CO)5 Sonolysis of Fe(CO)5 in hydrocarbon solvent (heptane) gives123, 124 results which are different both from the thermal and photochemical methods. The thermolysis of Fe(CO)5 above 100° gives mainly finely divided iron. However, Ultraviolet photolysis gives Fe2(CO)9 via the reaction of the intermediate, Fe(CO)4 with Fe(CO)5. On the other hand, sonolysis yields Fe3(CO)12. Use of heptane as solvent gives > 82% yield on sonication. The formation of Fe3(CO)12 during sonication is considered to arise from the coordinatively unsaturated species Fe(CO)3 (Scheme 9.98).

Scheme 9.98

Fe2(CO)9 has been used under sonication for a number of synthesis125. Thus, diiron nonacarbonyl [Fe2(CO)9] on sonication at –20°C in hexane suspension with anthracene readily forms the compound (1) (Scheme 9.99). It is not possible to obtain (1) by other chemical methods126.

Scheme 9.99

The same starting material [Fe2(CO)9] on reaction with Vinyl epoxides (1) under sonication gave allyl tricarbonyliron lactone (2), which are precursors to various heterocyclic compounds127 (Scheme 9.100). The reaction is easily conducted in inert solvents like benzene. In this solvent nonsonocical procedure there is no reaction (Scheme 9.100).

9.40 Green Chemistry O Benzene 0.5 – 5 hr., )))) Fe2 (CO)9

+

O

Fe(CO)3

40 – 76% R

R (1)

(2) b-or g lactones, lactams

Scheme 9.100

Using dienes in place of the monoepoxides also gives rise to a convenient synthesis of n4-diene tricarbonyl iron complexes127. Thus, from y-(pseudo) ionone, a reaction occurs to give 72% yield of a complex (1) and a small amount of (2) (Scheme 9.101). Isomerisation of (1) to (2) is possible by prolonged sonication.

Scheme 9.101

9.5.3 Oxymercuration of Olefins: Synthesis of -Terpinol Oxymercuration of olefins is a very well known reaction to form carbon-oxygen bonds. Generally it is performed with mercuric acetate or trifluoroacetate. Since other salts of mercury are not easily available. It has now been shown that almost any mercuric salt can be prepared from mercuric oxide and an organic acid under sonication128. It is possible that the salt preparation and the oxymercuration step can be carried out in a one pot reaction under sonication and excellent yields are obtained. Thus, limonene on sonication with mercuric acetate in THF–H2O gives 80% yield of a-terpinol (Scheme 9.102).

Hg (OAc)2 THF-H2O (1 : 1) ))))

OH a-terpinol

Limonene

Scheme 9.102

Ultrasound Assisted Organic Synthesis

Regent Hg(OA)2 HgO/t-BuCO2H HgO/C7H15 CO2H

9.41

Conditions

Time (min.)

Yield (%)

rt))) rt)))

30 7 5

48 80 80

9.5.4 Activation of Nickel Powder Nickel powder can be activated129 by sonication in octane medium. The activity of sonicated nickel powder increases by a factor of ~103. Using this technique, alkenes can be rapidly transformed to alkanes (Scheme 9.103).

Scheme 9.103

The use of sonochemically activated nickel power can offer interesting advantages over the classical Raney Nickel Catalyst. For making activated nickel powder, it should be sonicated in octane for about 1 hour.

9.5.5 Ultrasonically Dispersed Potassium On sonication potassium is easily transformed to a silvery blue suspension in toluene and that ultrasonically dispersed potassium is used in Dieckmann and Thorpe-Zieglar cyclisations under favourable conditions. Sodium needs xylene to be dispersed (solvent effect)130. Ultrasonically dispersed sodium has not been used in synthesis. However, ultrasonically dispersed potassium finds a number of synthetic applications. Ultrasonically dispersed potassium effects reduction of sulphur-carbon bonds in cyclic sulfone (1)131. This procedure provides excellent yields of open chain sulfones (2) and (3) after methylation of the intermediate (Scheme 9.104). Ultrasonically dispresed K, toluene, 0°C, 0.5 – 4 hr. )))) S O2

MeO2S

(ii) Mel, r.t.

+ (2) 82%

MeO2S (3) 8%

(1)

Scheme 9.104

In a similar way, the 3-sulfene (1) gives the dienes (2) and (3) with a satisfactory stereoselectivity132 (Scheme 9.105).

9.42 Green Chemistry

Scheme 9.105

Cyclopentadienyl iron couple (1) could also be synthesised in 10 min using the above technique (Scheme 9.106)133. The classical method takes 7 days.

Scheme 9.106

9.5.6 Organometallic Compounds The most common organometallic compounds are that of magnesium, commonly known as Grignard Reagents. These are best prepared by sonication.

9.5.6.1 Organolithium compounds Organo lithium compounds, viz., isopropenyl lithium was conveniently prepared under sonication134. Organo lithium compounds are frequently used in synthesis and make use of primary, secondary or tertiary butyllithium. Since these reagents can be conveniently prepared by sonication, their preparation and in situ reaction was successfully conducted in the presence of variety of substrates. One of the more important is diisopropylamine, which by metalation yields highly useful lithium diisopropylamide (LDA). This new ultrasonic method permits a quite direct and rapid preparation of LDA in high yield (92%) in the solvent needed for further use. In General tetrahydrofuran is used (Scheme 9.107).

Scheme 9.107

It has also been shown that the preparation of LDA in a discrete step can be unnecessary, as shown with the generation of isobutyric acid dianion. Some other metalation examples are given in (Scheme 9.108).

Ultrasound Assisted Organic Synthesis

9.43

Scheme 9.108

9.5.6.2 Organoaluminium compounds Organoaluminium Compounds were also obtained by sonication. Thus, tris (1-methyl-2-butenyl dialuminium tribromide132(1) was first prepared135 (Scheme 9.109). Al2 Br3

)))) Br

+ Al

3 (1)

Scheme 9.109

The method was extended for the preparation of trimethyl dialuminium triiodide (Scheme 9.110)136. Excellent yield (96%) is obtained in 3 hr by sonication at room temperature. The silent process (2 hr room temperature) gave no positive results. The reaction product can be transformed to trimethylaluminium by reaction with triethylaluminium. Sonochemically this process is accomplished in 2.5 hr at room temperature, while at 100° and 6.5 hr are necessary to obtain the same yield by a silent process (Scheme 9.110).

Scheme 9.110

9.44 Green Chemistry 9.5.6.3 Organo zinc and palladium compounds Allylic derivatives of zinc (1)137 and Palladium (2)138 can also be prepared by a direct sonochemical reaction from the metal (Scheme 9.111).

Scheme 9.111

Organozinc compounds are obtained in high yields by transmetalation, utilising an organic halide and lithium (in some cases magnesium) which undergoes instantaneously a metal exchange with zinc chloride presence in situ139. Scheme 9.112 describes the preparation of diaryl zinc using an aryl halide.

Br

Li/ZnBr2/Et2O

Zn

r.t., 30 min, )))) 2

Scheme 9.112

The above reaction could be carried out in cleaning bath140. On the other hand, dialkyl compounds require the use of the much more energetic probe generator141. The exact reason for this is not clear. The reagents, thus obtained seem to be interesting auxiliaries in synthesis, since they add smoothly to a-enones, in cases where the more popular copper derivatives are unsuccessful. b-Cuparenoal (1)142 and polycyclic compounds (2)143 were prepared in excellent yields (Scheme 9.113).

9.5.6.4 Synthesis of trialkyl boranes Trialkyl boranes are prepared in high yield by formation of a Grignard reagent followed by in situ transmetalation with borontrifluoride etherate144. A similar preparation of triethylborane can also be achieved by sonication of bromoethane with aluminium triethyl borate145 (Scheme 9.114).

Ultrasound Assisted Organic Synthesis

O Zn

9.45

O Ni(acac)2

+

76%

2 (1) H

H 1. Zn (CH3)2/ Ni (acac)2 2. Me3 SiCl/ El3N

O

O

Me3SiO

)))) 90%

O

O

O (2)

Scheme 9.113

Scheme 9.114

9.5.7 Synthesis of Aldehydes from Halides Various halides on sonication with lithium, dimethylformamide in THF give 76–80% yield of the corresponding aldehydes146 (Scheme 9.115). RX R alkyl, aryl, benzyl

Li/DMF/THF

LiO

r.t. 10 – 40 min ))))

R

Scheme 9.115

H NMe2

R CHO 76 – 80%

9.46 Green Chemistry

9.5.8 Sonochemical Methylenation of Alkenes and Carbonyl Compounds Methylenation of alkenes with CH2I2 in presence of zinc is referred to as Simmons Smith Cyclopropanation. One case has already been referred to in Section 9.2.7.6. It is possible to use low grade zinc (‘mossy’ zinc), with high yields and reproductibility147. It is possible to carryout the reaction on a large scale in specially designed apparatus148. This method has been slightly modified to be run with dibromo methane, much cheaper than the diiodo analogue149. Some illustrations of sonochemical methylenation using CH2I2 and CH2Br2 are given in Scheme 9.116.

Scheme 9.116

As seen, in the case of cyclopropanation of dimethyl maleate, the reaction catalysed with cobalt chloride is stereoselective, which is not the case with nickel chloride150. Methylenation of carbonyl group, which frequently requires complex reagents, can be easily accomplished by the Simmons-Smith reagent (Zn/CH2I2) with sonication151 (Scheme 9.117). This reaction, however, does not seem to be general, as the procedure cannot be applied to Ketones in high yields.

Ultrasound Assisted Organic Synthesis

9.47

Contd...

R1

CH2l2/Zn/THF, rt. ))))

O

R2

R1 R2

R1

R2

Time (min.)

Ph

H

20

70

I-naphthyl

H

120

54

(CH2)2CH3

H

20

71

60

18

–(CH2)3–

Yield (%)

Scheme 9.117

9.5.9 Sodiumphenylselenide The useful reagent sodiumphenylselenide is obtained152 by the reductive cleavage of diphenylselenide with sodium. It is obtained as a colloidal suspension on sonication. Its reactivity with various substrates, viz., halides, tosylates, epoxides, etc., is much higher than that of a conventionally prepared salt (Scheme 9.118). O PhSeSePh

Na/THF RT, ))))

OTs

PhSeNa

O SePh 93%

Scheme 9.118

9.5.10

Arylamides

Aryhalides on treatment with alkyl isocyanates in presence of alkali metals and magnesium under sonochemical Barbier conditions give secondary arylamides153 (Scheme 9.119).

ArX

+

RNCO

M, THF ))))

ArC

NR + – M O

H 2O

NHR Ar C O

Scheme 9.119

The intermediates are obtained in good yield when M = Mg and can be ortholithiated when M = Na; the ortho lithiated intermediates react with a wide range of electrophiles to give ortho substituted arylamides (Scheme 9.120).

9.48 Green Chemistry – + NRNa

NHR

Br +

C RNCO

2Na ))))

O

(1) RLi

O

(2) E E

Scheme 9.120

9.5.11 Spiroketones The synthesis of spiroketones from cycloalkanones has been effected successfully in excellent yield154 by sonication with appropriate alkyl halides in presence of potassium tert butoxide in benzene (Scheme 9.121).

Scheme 9.121

9.5.12 β-Keto-thinoesters Cyclohexanone can easily be converted155 into enolate by sonication with sodium hydride in tetrahydrofuran in 75% yield compared to 18% under normal reactions. Subsequent sonication of the enolate with trithiodicarbonate gave the b-ketothinoester (Scheme 9.122).

Scheme 9.122

9.5.13 Dehalogenation a, a¢-Dibromoorthoxylene in dioxane on treatment with zinc in the presence of ultrasonic irradiation gives a o-xylylene intermediate (1) which readily adds on to a dienophile giving high yield of the adducts156. In the absence of dienophile, polymer and a dimer is formed in 10% yield. However, only the dimer is obtained by the reaction of a, a¢-Dibromoorthoxylene with 1 equivalent lithium in ultrasonic bath157 (Scheme 9.123).

Ultrasound Assisted Organic Synthesis

9.49

Dimer O Br

O O

Zn, ))))

O

Br O

(1)

O Adduct

CO2Et

CO2Et

Adduct

Scheme 9.123

The o-xylydene intermediate (1) obtained in Scheme 9.123 can be trapped in situ by the dienophile present in the medium. Excellent yields of (2) were obtained (Scheme 9.124)158. It is noteworthy that the course of the reaction is completely different when lithium is used instead of zinc (Scheme 9.124)157. Z Z

Zn/dioxane 67 – 90%

r.t, 10 – 15h. )))) (1)

(2)

Br Br

Li/THF

Br

))))

Li

Scheme 9.124

Gem-Dihalogenocyclopropanes can be dehalogenated on sonication in presence of lithium, sodium or magnesium in tetrahydrofuran (but not pentane). This shows the importance of solvent in sonochemical reactions159 (Scheme 9.125).

9.50 Green Chemistry

Br

Li or Mg

Br

)))), THF 10 – 20 min

R Li or Mg

C

R—C H

)))), THF

CH2

Br Br

Br

Br

Li, THF

Br

Br

))))

C

C

Scheme 9.125

6-Bromopenicillinate esters can be debrominated160 with zinc in dioxane under ultrasonic irradiation. This method is efficient, clean and cheap than employing the usual debrominating agents Bu3SnH or Pd –C/H2 (Scheme 9.126). Reductive dehalogenation of aryl halides with nickel (II) chloride and zinc in aqueous HMPA is facilitated by low intensity ultrasound161. Alternatively, lithium aluminium hydride can also be used162. In the latter case, the yield is 97% in 5 hr from bromobenzene compared to only 21% in 24 hr under non-ultrasonic conditions (Scheme 9.127). S

Br

S (1) Zn, Dioxane, )))) Me

(2) aq. NH4Cl

N

O

Me O

Me

N Me H

CO2R

CO2R

Scheme 9.126

X X

Cl, Br, l

NiCl2, Zn, HMPA, H2O, 60°, )))) or LiAlH4, 1,2-dimethoxyethane 35°, ))))

Scheme 9.127

Ultrasound Assisted Organic Synthesis

9.51

9.5.14 Thioamides The rate of preparation of thioamides by the reaction of the respective amide with P4S10 in dry tetrahydrofuran is enhanced by using ultrasonic irradiation163. This method has additional advantage of requiring 1–1.5 aquiv. of P4S10 rather than large excess used in the traditional method (Scheme 9.128). R2NCOMe

P4S10 THF ))))

R2NCSMe

Scheme 9.128

9.5.15 Catalysis The ultrasonic field produces fine dispersions and cavitation phenomena give rise to clean surfaces containing an increased number of dislocations, which are widely considered to be the active sites in catalysis164.

9.6

CONCLUSION

It has been the constant endeavour of synthetic organic chemists to find out newer and better methods for various organic transformations. Though newer reagents are discovered very frequently, these are often costly or difficult to prepare and most of them have limited applications. Search for readily available inexpensive materials which can be used as potential reagents and employment of newer techniques is an important part of this activity. Ultrasound has numerous applications in engineering, science and medicine. Recently it has been found as a useful technique in organic synthesis. It can dramatically effect the rates of chemical reactions and a large number of organic transformations have been studied. Ultrasound is an important tool in organic synthesis. However, this area is still wide open for investigations.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

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Ultrasound Assisted Organic Synthesis

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48. H. Priebe, Acta. Chem. Second. Ser B. 1984, 38, 895. 49. R.B. Valitov, R.N. Galiakhmetov, R.N. Kurochkin, and M.A. Morgules, Russ. J. Phys. Chem., 1985, 59, 1782. 50. H. Priebe, Acta. Chem. Scand. Ser. B, 1987, 1341, 640. 51. B. Cornils, H. Bahrmann, W. Lipps and W. KonKol, Eu. Pat. Appl. E.P. 173219 (C1CO7C45/50); C.A., 1986, 105, 81168. 52. B. Cornils, H. Bahrmann, W. Lipps and W. KonKol, German Patent 3511428 (C1. CO6C47/02) (1987); C.A., 1988, 108, 21493. 53. S.Kawada and T. Kurokawa, Japanese patent JP62, 106, 07387, 106, 073 (C1CO7C1143/68) (1987), C.A., 1988, 108, 21493. 54. G.H. Posner, Org. React. (NY), 1972, 19, 1. 55. J.L. Lunche, C. Petrier, A.L. Gemal and N. Zirk, J. Org. Chem., 1982, 47, 3805. 56. J.C.S. Barboza, C. Petrier and J.L. Luchl, Tetrahedron Lett., 1985, 26, 829. 57. H. Tso, T. Chou and S.Hung, J. Chem. Soc. Chem. Commun., 1987, 1552. 58. T. Kitazume and N. Ishikawa, Chemistry Lett., 1981, 1679. 59. J. Yamashita, Y. Inou, Kando and H. Hashimoto, Bull. Chem. Soc. Japan, 1984, 57, 2335. 60. R.S. Davidson, A.M. Palel, A. Safdar and D. Thornthwaite, Tetrahedron Lett., 1983, 24, 5907. 61. J. Jurczak and R. Ostaszewki, Tetrahedron Lett., 1988, 29, 959. 62. J. Ezgerra and J. Alvorez-Builla, J. Chem. Soc. Chem. Commun., 1984, 54. 63. P.B. Valitov, R.N. Galiakhmetov, A.K. Kurochkin and M.A. Margulis, Russian J. Phys. Chem., 1985, 59, 1782. 64. R.D. Walkup and R.T. Cunningham, Tetrahedron Lett., 1987, 28, 4019. 65. T.J. Mason, J.P. Lorimer, A.T. Turner and A.R. Harris, J. Chem. Res.(S), 1988, 80. 66. R.S. Davidson, A. Safdar, J.D. Spencer and D.W. Lewis, Ultrasonics, 1987, 25, 35. 67. T. Fujinami, S. Sato and S. Sakai, Chemistry Lett., 1981, 749. 68. J.M. Khurana and P.K. Sahoo, Syn. Commun., 1992, 1691. 69. J. Yamawaki, S. Sumi, T. Ando and T. Hanafusa, Chemistry Lett., 1983, 379. 70. T. Kimura, M. Fujita and T. Ando, Chemistry Lett., 1988, 137. 71. J.M. Khurana, P.K. Sahoo, S.S. Titus and G.C. Maikap, Synth. Commun., 1990, 1357. 72. Sekera and Marvel, J. Am. Chem. Soc., 1933, 55, 345; A Text Book of Practical Organic Chemistry, A.I. Vogel, IV Edn., Longman, N.Y., 1907, p. 605. 73. A.W. Maltsev, Russ. J. Phys. Chem., 1976, 50, 995. 74. J. Jurczak and R. Ostaszewki, Tetrahedron Lett., 1988, 57, 2335. 75. D.H. Shin and B.H. Han, Bull. Korean Chem. Soc., 1985, 6, 247. 76. K.J. Moulton, S.Koritala and E.N. Frankel, J.Am. Oil Chem. Soc., 1983, 60, 1257. 77. E.A. Cioffi and J.H. Prestegard, Tetrahedron Lett., 1986, 27, 415. 78. M.Jashiro, M. Nokayama, Y. Nakamura, A. Aoki, K. Takigawa, I. Meada, I. Tago and M. Yoshida, Jap. Pat. JP 61.53, 28886, 53, 228 (1986); CA, 1986, 105, 133517. 79. K.S. Suslick and D.J. Casadonte, J. Am. Chem. Soc., 1987, 109, 3459. 80. C. Petrier and J.L. Luchi, Tetrahedron Lett., 1989, 28, 2347.

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Ultrasound Assisted Organic Synthesis

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B.C. Barot, D.W. Sullins and E. Eisenbraum, Synth. Commun., 1984, 14, 397. S. Akiya and S. Okui, J. Pharm. Soc. Japan, 1951, 71, 182. C. Chittendin and J.L. Luche, Carbohydrate Res., 1986, 155, 258. K. Shibata, H. Kondo, K. Urano and M. Matsumi, Chemistry Express, 1987, 2, 117 and 169. K.S. Suslick, P.F. Schubert and J.W. Grodale, J. Am. Chem. Soc., 1981, 103, 7324. K.S. Suslick, J.W. Goodale, P.F. Schubert and H.H. Wang, J. Am. Chem. Soc., 1983, 105, 5783. A.M. Horton, D.M. Hollinshead and S.V. Ley, Tetrahedron, 1984, 40, 1737. M.J. Begley, S.G. Puntambekar and A.H. Wrigit, J. Chem. Soc. Chem. Commun., 1987, 1251. S.Y. Ley, C.M.R. Low and A.D. White, J. Organomet. Chem., 1986, 302, C13. J. Einhorn, C. Einhorn and J. –L. Luche, Synthesis, 1989, 798. K.S. Suslick and D.J. Casadonte, J. Am. Chem. Soc., 1987, 109, 3459. J.L. Luche, C. Petrier and C. Dupuy, Tetrahedron Lett., 1985, 26, 753. T. Chou and M. You, Tetrahedron Lett., 1985, 26, 4495. T. Chou and M. You, J. Org. Chem., 1987, 52, 2224. C. Roger, P. Marseille, C. Salus, J.R. Hamon and C.J. Lapinte, Organomet. Chem., 1987, 336, C13. D.D. Sternbach, J.W. Hughes, D.F. Burdi and B.A. Banks, J. Am. Chem. Soc., 1985, 107, 2149. A.V. Kuchin, R.A. Nurushev and G.A. Tolstikov, Zh. Obshch. Khim, 1983, 53, 2519; C.A. 1984, 100, 103426. P. Yang, K. Liou and Y. Lin, J. Organometal. Chem., 1986. 307. 273. P. Knochel and J.F. Normant, Tetrahedron Lett., 1984, 25, 1475. Y. Inou, J. Yamashita and H. Hashimoto, Synthesis, 1984, 244. C. Petrier, J.C. de Souza-Barboza, C. Dupuy and J. –L. Luche, J. Org. Chem., 1985, 30, 5761. J. –L. Luche, C. Petrier J.P. Lansard and A.E. Greene, J. Org. Chem., 1983, 48, 3837. C. Petrier, J. –L. Luche and C. Dupuy, Tetrahedron Lett., 1984, 25, 3463. A.E. Greene, J.P. Lansard, J. –L. Luche and C. Petrier, J. Org. Chem., 1984, 49, 931. A.B. Smith and T.L. Leenay, Tetrahedron Lett., 1988, 29, 2787. H.C. Broun and U.S. Racheria, Tetrahedron Lett., 1985, 26, 4311. K. Liou, P. Yang and Y. Lin., J. Organometal. Chem., 1985, 294, 145. C. Petrier, A.L. Gemal and J. –L. Luche, Tetrahedron Lett., 1982, 23, 3361. O. Rapic and S. Vogt, Tetrahedron Lett., 1982, 23, 2729. O. Rapic, P.G. Lee and N. Giger, Org. Prep. Proc. Int., 1984, 16, 25. E.C. Friedrich, J.M. Domek and R.Y. Pong, J. Org. Chem., 1985, 50, 4640. X. Xu, Z. Li, Y. Na and G. Liu, Yingyong Huaxue, 1987, 4, 73; C.A 1988, 109, 54337. J. Yamashita, Y. Inoue, T. Kondo and H. Hashimoto, Bull. Chem. Soc. Japan, 1984, 57, 2335. S.V. Ley and J. –L. Luchi, Tetrahedron Lett., 1986, 27, 501. J. Einhorn and J. –L. Luchi, Tetrahedron Lett., 1986, 27, 5363. T. Fujita, S. Watanabe, M. Sakamoto and H. Mashimoto, Chem.. Ind. (London), 1986, 427. M.A. Palominos, R. Rodriguez and J.C. Vega, Chemistry Let., 1986, 1251. B.H. Han and P. Boudjouk, J. Org. Chem., 1982, 47, 751.

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10 10.1

Photo Induced Organic Synthesis

INTRODUCTION

We have known that for any chemical reaction or chemical transformation, certain amount of energy, known as activation energy has to be supplied to the molecules of the reactants. Besides direct heating, as already discussed, this energy can be supplied by microwaves or by ultrasound, commonly called sonication. However, it is sometimes possible to carry out a reaction by direct mixing of the reactants in the solid state or by slight warming. Alternatively, the energy for a chemical reaction can be supplied photochemically. This involves absorption of electromagnetic radiation in the visible or ultraviolet region. Under these conditions, a molecule absorbs a quantum of light, the energy of which depends on the frequency of the radiation as expressed by the equation c E = hv = h __ l where h is the Plank’s constant and c is the velocity of light. This energy is greater than the bond dissociation energy of a carbon-carbon s bond (347 kJ mol–1). Unlike thermal reaction, in photochemical reactions the absorption of light raises an individual molecule to an excited electronic state. In fact, the selective excitation of individual molecules is a special character of photochemical reactions. The chemistry of the excited molecules (in photochemical reactions) is quite different from the chemistry of the molecules in the ground state (in thermal reactions), even though the total energy supplied thermally is much more than what is introduced in photochemical process. Photochemical reactions, as we will see subsequently, have been used for synthesising highly strained, thermodynamically unstable compounds. Also, the photochemical reactions are highly stereospecific. The products obtained by thermal and photochemical process normally differ in stereochemistry.

10.2 Green Chemistry Photochemical reactions occur by absorption of electromagnetic radiation to produce electronically excited states. It is the electronically excited molecules which gives the product of reactions. The process of raising molecules from ground state of minimum energy to an excited state of higher energy is called excitation. Excitation in the rotational, vibrational or electronic energy levels of molecules result from absorption in microwave, infrared and ultraviolet region of the electromagnetic spectrum. The effects of various kinds of radiation on the molecules is given below: Type of radiation increasing energy

Effect on absorbing molecules

Ultraviolet, Visible

Electronic excitation

Infared Microwaves and Radiowaves

Vibrational excitation Rotational

The ultraviolet radiation causes high energy electronic transitions in molecules. The resulting photo excited species can relax (react) via a variety of pathways. Traditionally, most photo reactions have been performed with UV lamp sources. The electronic excitation is of great importance in organic photochemistry, although, it is also accompanied by increase in vibrational and rotational energies. A chemical reaction produces an electronically excited species which emits a photon in order to reach to ground state, the phenomenon is known as chemiluminescence. When these type of reactions are encountered in biological system, the phenomenon is known as bioluminescence. The chemiluminescence is a rare phenomenon. An example of chemiluminescence is given below: NO + O3 Æ NO*2 + O2 NO2* Æ NO2 + hv (l = 600 – 2800 nm) On the basis of what has been stated so far it can be said that thermal reactions occur through higher vibrational levels of the ground state, whereas, photochemical reactions take place through electronic excited states (singlet or triplet). Thermal reactions require less energy (63–209 kJ mol–1). So light-induced or photochemical reactions are comparatively high energy processes. In photochemical reactions the light energy is absorbed by the reactants at room temperature (or even below room temperature). In case photochemical reactions lead to polymeric products due to high concentration of substrate, in such cases low concentration of substrate is used.

10.2

PHOTOCHEMICAL REACTIONS

The importance of photochemical reactions can hardly be overemphasised, these are an important tool in modern synthetic chemistry and lead to products virtually inaccessible by thermal reactions and proceed along the excited-state pathway. The earliest known photochemical natural reaction is the photosynthesis of sugars by plants using sun-light, CO2 and H2O in presence of chlorophyll. Some examples of common photochemical reactions are given below:

Photo Induced Organic Synthesis

10.3

10.2.1 Photolysis of Benzophenone Photolysis of benzophenone (in sunlight) in presence of an alcoholic solvent (preferably isopropyl alcohol) gives benzopinacol in quantum yield unity (Scheme 10.1)

Scheme 10.1

It is well known that benzophenone by reduction with zinc and acetic acid gives benzopinacol. The photolysis reaction of benzophenone is known as photoreductive dimerisation. The coupling reaction of benzophenone to benzopinacol is more efficient when the hydrogen donor is benzhydrol, the reduction product of the carbonyl compound (benzophenone) (Scheme 10.2)

Scheme 10.2

10.2.2 Photochemical Reactions of Olefins In case of olefins, photochemical reactions involves two types of electronic absorption (i) sÆp* excitation (requires more energy and is available only from light of wavelength lower than 150 nm and so it is difficult to achieve under usual experimental conditions) and (ii) pÆp* excitation (requires the absorption of light of about 180–210 nm for nonconjugated olefins and above 220 nm for conjugated olefins). Most of the photochemical reactions of olefins involve pÆp* excitation. The initial excitation generally occurs with no change in multiplicity and so a first singlet excited state is obtained. Also, this transition (pÆp*) is symmetry allowed. The singlet excited states of olefins have less tendency for intersystem crossing and are capable of initiating many photochemical reactions. However, the T1 states of olefins are generated conveniently by intermolecular energy transfer from a triplet donor to an olefin molecule. The photochemistry of singlet excited state of an olefin differs from that of its triplet state.

10.2.2.1 Isomerisation of olefins On irradiation with UV light, olefins undergo isomerisation. This can be effected by irradiation of the olefin as such or in presence a sensitizer and it may take place through a singlet or triplet excited state.

10.4 Green Chemistry In simple olefins, E-isomers absorbs energy more effectively and at a slightly different wavelength than the Z-isomer. Usually, an E-isomer is partially converted into its thermodynamically less stable Z-isomer. An example is the interconversion of fumaric and maleic acids (Scheme 10.3).

Scheme 10.3

In presence of a sensitizer, many olefins are excited to a common triplet state which then decays at different rates of the E & Z-isomers. The ratio of the products formed depends on the substrate and sensitizer triplet energies as well as the nature of the alkene. A most commonly studied is the photoisomerisation of stilbene (discussed in detail below).

10.2.2.2 Photoisomerisation of cis and trans-stibene Olefins are known to exhibit geometrical isomerism. The photochemical cis-trans isomerisation of stilbenes (1, 2-diphenylethenes) provides the simplest case of light-induced geometrical isomerisation. It is found that irradiation of trans stilbene in hexane in UV light results in the formation of the cisisomer. After some time the cis-trans ratio becomes constant and does not change if irradiation is continued. This condition is called a photostationary state and is also reached on irradiation of the cis isomer. The equilibrium favours the formation of thermodynamically less stable cis form. The trans-stilbene gives the cis- and trans-isomers in relative amounts of 10: 1 (Scheme 10.4). H H

H

hn H cis-stibene

trans-stibene l

max(e) = 295 nm (16300)

l

max(e)

= 276 nm (2280)

Scheme 10.4

10.2.2.3 Photochemical cycloaddition reactions 1, 2 and 1, 4-Cycloadditions occur photochemically with or without sensitizers. Examples of both 1, 2 and 1, 4-cycloadditions are given (Scheme 10.5).

Photo Induced Organic Synthesis

H2C

CH2

H2C

CH2

hn

CH2

CH2 [2 + 2 Cycloaddition]

CH2

CH2

hn

+

10.5

[4 + 2 Cycloaddition]

Scheme 10.5

Photochemical cycloaddition of olefins give four-membered ring is a synthetically useful process. One familiar example is the dimerisation of cyclopentenone on irradiation with light in dichloromethane to give a mixture of ‘head to head’ and head to tail’ dimers. These dimmers may be formed via an excimer (excited dimer) derived from the (pÆp*) cyclopentenone and a molecule of ground state cyclopentenone (Scheme 10.6). O

2

O

O

hn

+

CH2Cl2

Cyclopentenone

O

Head-to- head dimer

Head-to- tail dimer O

Scheme 10.6

The photocyclisation could also proceed in an intramolecular fashion as shown below (Scheme 10.7).

Scheme 10.7

A very interesting photochemical cycloaddition reaction is the addition of carbonyl compounds to olefins to yield oxetanes (oxa-cyclobutanes) (Scheme 10.8). This reaction is known as Paterno–Büchi reaction. For example, photocycloaddition of butyraldehyde to 2-methyl-2-butene yields mixture of 2, 3, 3-trimethyl-4-propyloxetane and 2, 2, 3-trimethyl-4-propyloxetane (Scheme 10.9).

10.6 Green Chemistry

Scheme 10.8

Scheme 10.9

The Paterno-Büchi reaction normally occurs by the cycloaddition of the triplet state of the carbonyl compound with the ground state of an alkene. The photocycloaddition of benzophenone with cis- and trans-2-butene gives the same mixture of cis- and trans-oxetanes. This shows that the reaction is not stereospecific. The lack of stereochemical discrimination clearly shows that the reaction is not concerted and the ring is formed in two stages (Scheme 10.10).

C

O+

C

C

O+

H C

H

CH3

H

CH3

Ph

hn

C

H

Ph

Ph

CH3

CH3

Ph

C

Ph hn

CH3

O

Ph

CH3

Scheme 10.10

CH3

Ph

CH3

O

Ph (Major)

(Minor)

Photo Induced Organic Synthesis

10.7

The formation of mixture in both the cases (i.e. reaction of benzophenone with cis- and trans-2-butene) indicates that the time lag before the final spin-inversion is more than enough for rotation to occur about single bonds. Examples of photochemical addition of alkene and alkynes with benzene are given below (Scheme 10.11).

Scheme 10.11

1, 2-Cycloaddition of alkyne with benzene gives strained cyclobutene, which undergoes a spontaneous electrocyclic ring-opening reaction (Scheme 10.12). H

COOMe

COOMe

hn

+

COOMe COOMe

COOMe

H

COOMe

Scheme 10.12

10.8 Green Chemistry The cycloaddition could also proceed in an intermolecular fashion. For example, irradiation of trans, trans-1, 4-dimethyl-1, 3-butadiene undergoes ring closure to give cis-3, 4-dimethyl cyclobutene (Scheme 10.13).

hn

Scheme 10.13

Similarly, trans, trans-1, 6-dimethyl-1, 3, 5-hexatriene cyclises to give trans-5, 6-dimethylcyclohexadiene (Scheme 10.14). hn

Scheme 10.14

Both the reactions are concerted and are electrocyclic type pericyclic reactions. The intramolecular photocyclisation reaction of 1, 3-cyclooctadiene gives bicyclo [4 · 2 · 0] oct-7-ene (Scheme 10.15). hn

Scheme 10.15

10.2.2.4 Photoinduced substitution of aromatic compounds Photoexcitation1 of aqueous solution of 4-methoxy-1-nitronaphthalene (A) containing CN– ions results in the formation of 4-methoxy-1-naphthalene carbonitrile (B) (Scheme 10.16). NO2

CN hn CN

OCH3 (A)

OCH3 (B)

Scheme 10.16

Photo Induced Organic Synthesis

10.9

When the above photo-reaction was conducted in presence of CTAC micelles there was a large enhancement in the quantum yield [CTAC = hexadecyl (trimethyl) ammonium chloride].

10.2.2.5 The photorearrangement of 4-nitrophenyl-nitromethane Photorearrangement of 4-nitrophenyl nitromethane (A) into 4-nitrobenzaldehyde (B) was found to be much more efficient in a cationic detergent (CTAC) than in basic ethanol/water solution (Scheme 10.17)2.

Scheme 10.17

10.2.2.6 Photodecarbonylation of unsymmetrical dibenzyl ketones Photodecarbonylation of unsysmmetrical dibenzyl ketones of the type A–CO–B in homogeneous solution occurs via a free radical mechanism to produce 1, 2-diarylethanes in quantitative yield3. The products AA, AB, and BB are formed in 25, 50 and 25% yields respectively. However, photolysis of A–CO–B in micelle containing solutions of CTAC results in selective formation4 of AB. The yield of AB relative to (AA + BB) is dependent upon CTAC concentration. As in the case of dibenzyl ketones, photolysis of benzyl phenylacetate undergoes a more regioselective decarboxylation in potassium dodecanoate solution than that observed in homogeneous solution (e.g. in isopropanol) (Scheme 10.18)5.

10.2.2.7 Photochemical reactions in solid state There are few reports of photochemical reactions in the solid state: (i) Cinnamic acid (single crystal) on photoirradiation gives6 truxillic acid (Scheme 10.19).

10.10 Green Chemistry

Scheme 10.18

hn soild HOOC

COOH COOH

HOOC

Cinnamic acid (single cyrstal)

Truxillic acid (single cyrstal)

Scheme 10.19

The photodimerisation of cinnamic acid can be controlled by irradiation of its double salts with certain diamines in the solid states. Thus, the double salt crystal of cinnamic acid and o-diaminocyclohexane gave on irradiation in the solid state, b-truxinic acid as the major product7 (Scheme 10.20).

Photo Induced Organic Synthesis

10.11

Scheme 10.20

10.3

PRINCIPAL INDUSTRIAL APPLICATIONS OF PHOTOCHEMISTRY

Most of the industrial applications of photochemistry are so far in the fields of free-radical chlorination, sulfochlorination, sulfoxidation and nitrosation. In addition, the photochemical reactions are being used on an increasing scale for the synthesis of vitamins, drugs and fragrances.

10.3.1 Free Radical Chlorination The most important application of photochemical synthesis is in the area of radical chain reactions. The first industrial scale polychlorination8 was recorded in 1940’s. An example of industrial chlorination in externally irradiated glass tube was described by Philips corporation9, viz., the production of monochloroalkanes from a C11–14 n-paraffin cut only 15 mole % of chlorine was introduced in the photochemical reactor tube. Formation of undesired dichloro compounds is avoided by stopping the reaction at an overall conversion to 30%. Optimum yield is obtained at temperature < 40°C. hv

RCl + HCl RH + Cl2 RH = mixture of n-alkanes The chloroalkanes find use for alkylation of benzene to give alkylbenzenes, which are starting materials for alkylbenzene sulfonates10, an important class of detergents (Scheme 10.21). R

RCl +

SO3Na

R

Scheme 10.21

Photochemical chlorination of benzene to produce hexachlorocyclohexane (Scheme 10.22). Cl Cl

Cl

Cl

hn Cl2

Cl Cl

Cl Cl

Scheme 10.22

Cl Cl Lindane

Cl

Cl

10.12 Green Chemistry The photoaddition of chlorine to benzene serves for the production of g-isomer of hexachlorocyclohexane, a versatile insecticide marketed as Lindane or Gammexane (g-BHC). The yield of 15%, however is very modest. The photochlorination of toluene to benzyl chloride, benzylidene dichloride and benzotrichloride, is a very well known procedure (Scheme 10.23). hn C6H5CH3

Cl2

C6H5CH2Cl

hn Cl2

C6H5CHCl2

hn Cl2

C6H5CCl3

Scheme 10.23

Mixtures of the first two, viz., benzyl chloride and benzylidene dichloride is produced in specially designed photoreactors at 80–110°C. Benzyl chloride is also obtained by purely thermal chlorination of toluene and is mainly converted into benzyl alcohol, a well known fragrance. It is also used in the synthesis of drugs, disinfectants, and emulsifiers. On hydrolysis or preferably on reaction with benzoic acid, benzylidene dichloride yields benzaldehyde; in the later case a valuable intermediate, benzoyl chloride is also obtained (Scheme 10.24). C6H5CHCl2 + C6H5COOH

C6H5CHO + C6H5COCl + HCl

Scheme 10.24

Benzotrichloride is a valuable intermediate for dyes of the triphenylmethane, xanthene, and anthraquinone series and also for plant protection agents.

10.3.2 Free Radical Sulfochlorination Photochemical sulfochlorination of paraffins is of great industrial importance10 – 14. In sulfochlorination the function of light is for the formation of chlorine atoms from chlorine. The sulfonyl chloride group is distributed almost randomly over all the C atoms of hydrocarbon chain15 (Scheme 10.25). RH + SO2 + Cl2

hn

RSO2Cl + HCl

RH = Mixture of n-alkanes

Scheme 10.25

In sulfochlorination process, di- and poly-sulfonyl chloride (having undesirable properties) are also formed. So the reaction must be stopped at conversion of 30 to 50%, yields of 80 to 90% are then obtained. Industrial sulfochlorination has been reviewed by Lindner16. The alkylsulfonyl chlorides, thus produced are hydrolysed by caustic soda to give water-soluble alkanesulfonates, which are mainly used as emulsifiers for polymerisations10 (Scheme 10.26).

Scheme 10.26

Photo Induced Organic Synthesis

10.13

Due to contamination of di- and poly-sulfonyl chlorides, the above process (Scheme 10.26) is not suitable for the manufacture of RSO2Na, since it cannot be obtained in a pure state on industrial scale. So these type of alkenesulfonides are now not used in detergent manufacture17, 18. The reaction of alkanesulfonyl chlorides with ammonia gives sulfonamides (Scheme 10.27), which are used as textile auxilliaries17. The sulfonamides further react with chloacetic acid to give a mixture of sulfonylaminoacetic acids (Scheme 10.27). These type of compounds serve as emulsifiers and as anticorrosion agents for mineral oils17, 19. RSO2Cl

NH3

RSO2NH2

Cl CH2 CO2H NaOH

RSO2NHCH2CO2H

Scheme 10.27

10.3.3 Photochemical Sulfoxidation A convenient synthesis of alkanesulfonates is by sulfoxidation process. In this procedure, oxygen serves as an oxidising agent instead of chlorine used earlier (Scheme 10.28).

Scheme 10.28

The above procedure is used for Industrial preparation alkanesulfonates10, 20, 21. In the above procedure (Scheme-10.28), the primary sulfoxidation product is peroxysulfonic acid, which is trapped by water before it can undergo radical decomposition (Scheme 10.29). RSO2OOH + H2O + SO2

RSO3H + H2SO4

Scheme 10.29

10.3.4 Photonitrosation Light induced reaction of nitrosyl chloride with cyclohexane gives cyclohexane oxime, which is a starting material for the synthesis of caprolactam, the monomer of nylon 6 (Scheme 10.30).

Scheme 10.30

10.14 Green Chemistry A Japanese chemical company Toray finally decided to conduct the photochemical synthesis of caprolactam in a large production plant22. Another industrial application of photonitrosation is the manufacture of lauryllactam, which is a starting material for the production of Nylon 12. In this procedure, cyclododecane, [which is obtained from butadiene in two steps (Scheme 10.31)] is converted into the oxime by nitrosyl chloride in high yield. The oxime on reaction with acid gives lauryllactam23, the monomer of nyclon-12 (Scheme 10.31). H2

hn

3

NOCl Butadiene

Cyclododecane

H2SO4

Nylon 12 N

NOH

O

H Oxime

Lauryllactam

Scheme 10.31

Lauryllactam, due to its low density and low absorption of water, is used for a number of special purposes like production of dimensionally stable plastic components (automobile construction) and for the plastic coating of metals24. The photochemical lauryllactam was developed by ATO in france, who fabricated a 8000 t/a capacity plant25.

10.3.5 Photochemical Synthesis of Vitamin D and Related Compounds 10.3.5.1 Vitamin D2 One of the earliest non-radical industrial photoreactions is the synthesis of Vitamin D (commonly known as Vitamin D2) from ergosterol (Scheme 10.32).

10.3.5.2 Vitamin D3 Interest is now a days focussed mainly on Vitamin D3, which unlike Vitamin D2, is also active in poultry. Most of the Vitamin D3 now produced is not used to prevent or cure rickets (as Vitamin D2) in children but instead it is used as an additive in animal nutrition. Vitamin D3 is produced by photoirradiation of 7-dehydrocholesterol, which is obtained from cholestrol in a 4 step synthesis26. On irradiation, 7-dehydrocholesterol undergoes ring opening leading to the formation of previtamin D3, which on heating to 50–80°C gives thermodynamically

Photo Induced Organic Synthesis

10.15

Sheme 10.32

more stable vitamin D3 (Scheme 10.33). The irradiation of 7-dehydrocholesterol is carried out in dilute solutions (about 1%). Ethanol or ether serves as solvent26, 27.

10.3.5.3 Hydroxy derivatives of vitamin D3 It has been established28 that it is not Vitamin D3 which is responsible for regulating calcium metabolism. A metabolite formed in liver and kidney, 1a, 25-dihydroxyvitamin D3 is in fact responsible for regulating calcium metabolism (Scheme 10.34). 1a-Hydroxy Vitamin D3, which is as active as 1a, 25-dihydroxy Vitamin D3 is easier to produce. The intermediate (diacetate) required for the synthesis of 1a-hydroxy Vitamin D3 is obtained29, 30 in six steps from cholesterol. Photochemical ring opening of the starting diacetate gives previtamin D3 derivative, which on thermal heating gave29, 30 the diacetoxy vitamin D3. Final alkaline hydrolysis gave 1a-hydroxy Vitamin D331 (Scheme 10.35).

10.3.5.3 Photoisomerisation of vitamin A acetate The Wittig synthesis of Vitamin A acetate by BASF32 as industrial procedure gave a mixture of two stereoisomers, viz., all trans (A) and the 11-cis form (B). Out of the two isomers, only the all trans isomer (A) is used in pharmaceutical and animal feeds. A very convenient photochemical method has been developed by BASF33 for converting 11cis-(B) into all-trans-vitamin A acetate (A). The procedure consist in irradiating the stereoisomeric

10.16 Green Chemistry

hn

HO

HO Previtamin D3

7- Dehydrocholesterol

H2C D HO Vitamin D3

Scheme 10.33

Scheme 10.34

mixture with visible light in presence of a sensitizer such as chlorophyll or tetraphenylporphinatozinc (Scheme 10.36).

10.3.6 Photo-oxygenation During photo-oxygenation it is the singlet oxygen which is the reactive species. The most important method for the generation of singlet oxygen is the photoexcitation of the ground state of molecular oxygen in presence of a sensitizer (e.g. rose bengal). The formed hydroperoxide can be reduced to the alcohol.

Photo Induced Organic Synthesis

10.17

Scheme 10.35

Scheme 10.36

10.3.6.1 Rose oxide A most promising field for industrial photochemistry is the synthesis of fragrances. Thus, photo-oxygenation of citronellol (1) with rose bengal as sensitizer gives a mixture of two isomeric

10.18 Green Chemistry hydropexoxides34, which on reduction with sulphite give the corresponding alcohols (2) and (3). The major product (3) undergoes allylic rearrangement to (4) in acid solution. Final cyclisation of (4) gives rose oxide (5). Small scale production of rose oxide is being conducted at the Firmenich and Dragoeo companies (Scheme 10.37).

Scheme 10.37

10.3.6.2 Ascaridole Another example of photo-oxidation is the reaction of a-terpinene with singlet oxygen in presence of a sensitizer to give ascaridole. Though it was used earlier35 an fragrancy, but it is no longer used due to toxicity of this anthelmintic (Scheme 10.38).

1

O2

a-terpinene

Ascaridole

Scheme 10.38

Photo Induced Organic Synthesis

10.19

10.3.7 The Barton Reaction The reaction, discovered by D.H.R. Barton36 is used for the production of tritium-labelled aldosterone (1), which is used as a medical diagnostic aid. The reaction involves photochemical reaction of nitrite of pregnane (2) to give the C-18-oxime (3), which on heating gives the nitrone37 (4). The nitrone can be converted in a series of conventional steps into 1, 2-didehydroaldosterone acetate (5). This yields the radioactively labelled aldosterone (1) by catalytic tritiation and subsequent hydrolysis38. Various steps involved are shown in Scheme 10.39. The American company New Englaand Nuclear produces (1) in a small scale for use as a medial diagnostic aid.

Scheme 10.39

10.20 Green Chemistry

10.4

MISCELLANEOUS PHOTOCHEMICAL REACTIONS

10.4.1 Photochemical Conversion of -pinene into Trans-pinocarveol Using Singlet Oxygen (Scheme 10.40).

Scheme 10.40

10.4.2

Photoirradiation of Dibenzoyldiazomethane in Presence of Amino Acid39 (Scheme 10.41)

Scheme 10.41

10.4.3 Photochemical Aromatic Substitution Irradiation of o-fluoroanisole in presence of aqueous potassium cyanide gives catechol monomethylether as the major product. However, irradiation of p-fluoroanisole in presence of aqueous potassium cyanide solution gives p-cycnoanisole as the major product40 (Scheme 10.42). In the case of o-fluoroanisol, the hydrogen bonding between water and the methoxy group was attributed to the hydroxylation reaction. The effect of such a hydrogen bonding on the product distribution is much less in the latter case.

Photo Induced Organic Synthesis OCH3

OCH3 F

OCH3 CN

hn, KCN

10.21

OH +

H2O

major OCH3

OCH3 hn, KCN

OCH3

+

H2O

F

CN

OH

major

Scheme 10.42

10.4.4 Synthesis of Dydrogesterone Irradiation of pregnadiene derivative (1) gives the retrosteroid (2), which is cleaved by alcoholic HCl to form dydrogesterone (3)41 (a sex hormone) (Scheme 10.43).

Scheme 10.43

10.22 Green Chemistry

10.5

MISCELLANEOUS APPLICATIONS

10.5.1 Arndt–Eistert Synthesis Photochemical reaction of a-naphthoyl chloride with diazomethane in presence of methanol gives methyl a-naphthyl acetate (Scheme 10.44)42.

Scheme 10.44

10.5.2 1, 4-Napthoquinone Photomer Photochemical reaction of 1, 4-naphtoquinone in benzene solution by irradiation with UV light gives 1, 4-naphthoquinone dimer (Scheme 10.45).

Scheme 10.45

10.5.3 9-Phenyl Phenanthrene It is obtained by irradiation of triphenyl ethylene in cyclohexane in presence of iodine using a photochemical reactor (Scheme 10.46).

Scheme 10.46

Photo Induced Organic Synthesis

10.6

10.23

CONCLUSION

Photochemical transformations are the best green reactions, since no other byproducts which can go into the environment are formed. It is useful for a large number of organic synthesis including industrial scale preparations.

References 1. R.R. Hautala and R.L. Letsinger, J. org., Chem., 1991, 36, 3762. 2. K. Yamada, K. Shigehiro, T. Kujozuka and H. Lida, Bull. Chem., Soc. Jpn., 1978, 51, 2447. 3. P.S. Engel, J. Am. Chem. Soc., 1970, 92, 6074; W.K. Robins, R.H. Eastman, J. Am. Chem. Soc., 1970, 92, 6077; G. Quinkert, K. Opitz, W.W. Wiresdorf and J. Weinlich, Tetrahedron Lett., 1963, 1863. 4. N.J. Turro and W.R. Cherry, J. Am. Chem. Soc., 1978, 100, 7432. 5. P.de Mago, unpublished results. 6. V. Ramamurthy, Ed., Photochemistry of Organized and Constraint Media, VCH, Weinheimn, Germany, 1991; CRC Handbook of Organic photochemistry and photobiology, W.H. Horspool (Ed.), CRC Press, Boca Raton, Fl., 1995. 7. Y. Ilo, B. Borecka, J. Trotter and J.R. Scheffer, Tetrahedron Lett., 1995, 36, 6083; Y. ITo, B. Borecka, G. Olovasson, J. Trotter and J.R. Scheffer, Tetrahedron Lett., 1995, 36, 6087; Y. Ito and B. Olovasson, J. Chem. Soc. Perkin trans I, 1997, 127. 8. W.T. Anderson Jr., Ind. Eng. Chem., 1947, 39, 844; W.H. Shearon Jr; H.E. Hall and J.E. Steven Jr., Ind. Eng. Chem., 1949, 41, 1812. 9. T. Hutson, Jr., and R.S. Logan, Chem. Eng. Prog., 1972, 68(5), 76. 10. F. Broich, Fette and Scifen, Anstrichm, 1970, 17, 22. 11. L.J. Governate and J.T. Clarke, Chem. Eng. Prog., 1956, 52(7), 281. 12. H.G. Haring and H.W. Knol, Chem. Process Eng. 1964, 45, 560, 619, 690. 13. K.A. Lipper in: Ullmamns Encykiopodie der technischen Chemie, 4th Edn., Verlage Chemie, Weinheim, 1975, Vol. 9,525. 14. H.I. Jaschek, Chem. –Zig., 1969, 93, 655. 15. F. Asinger, Ber. Dtsch. Chem. Ges., 1944, 77, 191. 16. K. Lindner, Tenside, Textihilfsmittel, Waschrohstoffe. Wissenschafil, Verlagsges, Stuttgart, 1964, Vol. 1, p. 705. 17. See ref. 31. p. 717. 18. H. Schuller in: Ullmanns Encklopadie der Technichem. Chemi., 3rd Edn., Urban and Schwarzenberg, Muchehon, vol. 16, p. 724. 19. F. Asinger, Die Petro chemische Industrie. A. Kademie-Verlag, Berlin, 1971, p. 731. 20. L. Orthner, Angew. Chem., 1950, 62, 302; R. Graf. Justus Liebigs Ann. Chem., 1952, 50, 578. 21. C. Beermann, Eur. Chem. News, Normal Paraffins Supplement, Dec. 2, 1966, p. 36; H. Hartig, ChemZtg, 1975, 99, 179. 22. P. Turner, Inf. Chins, 1970, 9, (5, 6) 51; P. Hurine, P.E. Turner, Chem. Process Eng., 1967 (11), 96; Y. Ito, Y. Hara, DAS I 1962, 468, 737, Toray. 23. Inf. Chin, 1970, 8, (3, 4), 47.

10.24 Green Chemistry 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

Eur. Chem. News, March 29, 1947, p. 18. Chem. Ind (Dusseldorf), 1975, 27, 735. J. Fragner: Vitamine, Gustav Fisher Verlag, Jena 1964, Vol. I, p. 613. S.B. Greenbawm in Kirk-Othmer: Encyclopedia of Chemical Technology, 2nd Edn. Interscience, New York, 1970, Vol. 21, p. 549. M.F. Hollick, E.J. Semmier, H.K. Schnoes and H.F. DeLuca, Science, 1973, 180, 190. D.H.R. Barton, R.H. Hesse, M.M. Pechet and E. Rizzardo, J. Am. Chem. Soc., 1973, 95, 2748; N. Müller, DOS 2 400189, BASF Ag. A. Fürst, L. Labler, W. Muer and K. –A. Pfoertner, Helv. Chin. Acta, 1973, 56, 1708. Eur. Chem. News, August 22/29, 1975. W. Reif, H. Grassner, Chem.-Ing. Tech., 1973, 45, 646; H. Pommer, Angew. Chem., 1977; 89, 437; Angew. Chem. Int. Ed. Engl., 1977, 16, 423. M. Fischer and W.W. Weirsdorff, A. Nürrenbach, D. Horn, F. Feichimayr, DBP 2210800 BASF AG. G. Ohloff, E. Klein and G.O. Schenck, Angew. Chem., 1961, 73, 578. G.O. Schenck, Dechema-Monographien, 1955, 24, 105. M. Akthar, Adv. Photochem., 1964, 2, 263. D.H.R. Barton, N.K. Basu, M.J. Day, R.H. Hesse, N.M. Pechet and A.N. Starrat, J. Chem., Soc. Perkin Trans. I, 1975, 2243. K.R. Laumas, M. Gut, J. Org. Chem., 1962, 22, 314; D.H.R. Barton and Beaton, J. Am. Chem. Soc., 1961, 83, 4083. K. Nakatani, J. Shirai, R. Tamaki, and I. Saito, Tetrahedron Lett., 1995, 36, 5363. J.H. Liu and R.G. Weiss, J. Org. Chem., 1985, 50, 3655. O.A. de Bruin, H.F.L. Schöler, J.N. Walop, Philips Tech. Rundsch, 1967, 28(3, 4), 72; M.P. Rappoldt and T.R. Rix, Trav. Chim. Pays-Bas, 1971, 90, 27. A.B. Smith, Chem. Common, 1974, 695.

Part V Organic Synthesis using Green Reagents

11

Organic Synthesis using Green Reagents

A reagent is considered to be green it is not harmful to the environment. Some of such reagents are given below.

11.1

OXYGEN

The ordinary oxygen is known as ground-state oxygen (triplet oxygen) having two electrons with parallel spins. It behaves like a diradical and is paramagnetic

[ .O:O. ] Though ordinary oxygen is not used as such. A classical example is the auto oxidation of benzaldehyde to benzoic acid and the well known photosynthesis, in which it is used along with carbondioxide in presence of sun light and chlorophyll. However, oxygen is used for various oxidations in presence of certain catalatysts. This procedure is called catalytic oxidation and is useful for the industrial preparations of a number of important products. Some of these are given below: (i) Manufacture of formaldehyde by the controlled oxidation of methane

(ii) Manufacture of methyl alcohol by oxidation of methane

11.4 Green Chemistry (iii) Manufacture of a acetaldehyde by oxidation of ethylene.

(iv) Oxidation of toluene, naphthalene, o-xylene and furfural to important products

(v) Manufacture of maleic acid by oxidation of benzene followed by hydrolysis

(vi) Manufacture of chlorine (Deacon process)

Organic Synthesis using Green Reagents

11.5

(vii) Manufacture of nitric acid (Birkeland–Eyde process)

(viii) Manufacture of sulfuric acid (contact process)

11.2

SINGLET OXYGEN

It is the excited state of oxygen and has two odd electrons possessing anti parallel spins. [ .O:O. ] It is formed from oxygen gas by the irradiation with ultraviolet light in presence of sensitizers like benzophenone, methylene blue, rose bengal, etc. It can also be generated by the oxidation of hydrogen peroxide with sodium hypochlorite or alkaline solution of bromine.

Some of the important reactions in which singlet oxygen is used are given below: (i) Coversion of alkenes into hydroperoxides

The hydroperoxides on reduction give alcohols (ii) Conversion of conjugated dienes into endooxides (Diels Alder Reaction) (eq. 1) (iii) Conversion of alkenes into epoxides (eq. 2) (iv) Conversion of secondary alcohols to ketones (eq. 3) (v) Conversion of tertiary amines to secondary amine (eq. 4)

11.6 Green Chemistry

(eq. 1)

(eq. 2)

(eq. 3)

(eq. 4)

11.3

OZONE

Ozone, a blue gas [O = O – O:] or dark blue liquid and is used in a mixture with oxygen (which contains 2.3% ozone). It is generally prepared by passing oxygen through a silent electric discharge The most important application of ozone is in the ozonolysis of an alkene to give ozonide, which can be cleaved by Zn-H2O to give aldehydes or with H2O2 to give carboxylic acid and an aldehyde. The overall reaction of an alkene with ozone is given below:

This procedure is used for the structure elucidation of alkenes. An important reaction of ozone is the conversion cyclohexene into hexanedial.

Organic Synthesis using Green Reagents

11.4

11.7

HYDROGEN PEROXIDE

It is commercially available. Following are given some of the reaction in which hydrogen peroxide is used (i) Oxidation of hydroxy aldehydes to hydroxy compounds (–CHO or –COR Æ OH) (Dakins oxidation)

(ii) Conversion of carboxylic acids to per acids

(iii) Hydrogen peroxide reacts with alkyl boranes, nitriles, primary, secondary and tertiary amines to give various products as given below (eq. 5 to 9). Aromatic amins are oxidised to nitrocompounds (eq. 9a) (iv) Hydrogen peroxide, oxidises thiols to disulphides, which subsequently give sulfonic acids (eq. 10) (v) Diethyl sulfides are oxidised to the corresponding sulfoxides or sulfones depending on the concentration of H2O2 (eq. 11) (vi) Hydroxylation of alkenes takes place to give epoxides, syn hydroxylation or anti hydroxylation depending on the reaction conditions. (eq. 12) (vii) Hydrogenperoxide on treatment with urea gives urea-hydrogenperoxide complex (UHP), which is used for solid state oxidations of hydroxylated aldehydes and ketones to dihydroxy compounds, nitriles to amides, nitrogen heterocyles to N-oxides (For details see chapter 7. sections 7.3.1, 7.3.2 and 7.3.3).

11.5

DIOXIRANES

These are prepared from acetone or other aliphatic ketones by reaction with oxone (eq. 13)

11.8 Green Chemistry

(eq. 5) (eq. 6)

(eq. 7)

(eq. 8)

(eq. 9)

Aromatic amines are oxidised to nitrocompounds (eq. 9a) (eq. 9a)

(eq. 10)

(eq. 11)

(eq. 12)

Organic Synthesis using Green Reagents

11.9

(eq. 13)

Dioxiranes are used for epoxidations

Primary and secondary amines react as shown below:

11.10 Green Chemistry

11.6

PEROXY ACIDS

A number of peroxy acids are known (R CO3H; R = H, CH3, C6H5, p-NO2 C6H4 etc.) These are prepared in situ from the appropriate carboxylic acid and hydrogen peroxide. RCOOH + H2O2

RCO3H

+ H2O

These are mostly used for epoxidations C

C

+

RCO3H

C

C O

The epoxides are important intermediaties for the synthesis of diols.

11.7

DIMETHYLCARBONATE

Normally methylations are carried act with methyl halides or dimethyl sulfate, which are toxic chemicals. Such synthesis are undersirable in to context of green synthesis Dimethyl carbonate is a selective methylating agent1. It is useful for the methylation of active methylene compounds. Thus, aryl acetonitriles on reaction with dimethy carbonate in presence of potassium carbonate gives the corresponding methylated compound.

Reference 1. P. Tudo, F. Trotta and G. Morglio, J. Org. Chem., 1987, 52, 1300; P. Tudo, F. Trotta, G. Morglio and F. Ligoritti, Ind. Eng. Chem Res., 1998, 27, 1565.

11.8

POLYMER SUPPORTED REAGENTS

In the conventional organic synthesis, the substrate is reacted with a reagent and the product formed is isolated from the reaction mixture by procedures like extraction, precipitation, distillation, sublimation or chromatographic steps. Thus, the isolation procedure involves one or more steps. However, by using polymer supported reagent1, the isolation procedure involves only filtration and the reagent (polymer supported) is obtained as the solid product and can be reused. The various steps involved are (Scheme 11.1). A wide range of polymers are available for the preparation of polymer supported reagents. However, polystyrere is the most widely used polymer. Following is given a briet account of some polymer supported reagents and their typical uses.

Organic Synthesis using Green Reagents

11.11

Scheme 11.1

11.8.1 Poly-n-bromosuccinimide (PNBS) It is obtained by adding bromine to a suspension of polymaleimide polymer in aqueous sodium hydroxide solution. The polymaleimide is obtained by free radical polymerisation of maleimide in presence of 2.5 to 5% divinyl benzene (Scheme 11.2).

O

N

O

Br n (PNBS)

Scheme 11.2

PNBS is a novel and an efficient polymer based brominating agent and is used as benzylic and allylic brominating agent. Thus cumene on bromination2, 3 with PNBS in carbon tetrachloride gave a, b, b¢-tribromocumene as the major product. However, bromination with NBS gives a-b-dibromo cumene and a-bromocumene (Scheme 11.3).

11.8.2 Polymeric Organotin Dihydride Reagent The versality and selectivity of organotin hydride in well known. Use of insoluble polymer supported organotin dihydride reagent has the advantage of a typical polymeric reagent, ease of operation and reaction work up and avoidance of toxic vapours which are characteristic of the hydride. This reagent is useful4 for the conversion of aldehydes and ketones to alcohols in 80 to 90% yield and reduction of halides to hydrocarbons. The use of organotin hydrde for the reduction of alkyl and aryl halides in the presence of other functional group is in general superior to lithium aluminium hydride. In fact, this can be used for the selective reduction of only one functional group of a symmetrical difunctional aldehyde (tere-phthaldehyde). The reagent is prepared4 as follows (Scheme 11.4).

11.12 Green Chemistry

Scheme 11.3

11.8.3 Polystyrene Carbodiimide It is used for the conversion of acids (e g, acetic acid, stearic acid and glutaric acid) into their anhydrides in quantitative yields6. The anhydrides are obtained from the reaction mixture by filtration and evaporation of the filtrate. Polystyene carbodiimide is also useful6 for the Moffatt oxidation of alcohols to aldehydes and ketones. Using this procedure, even the labile prostaglandin intermediate (A) is converted into the desired aldehydes (B) (Scheme 11.5). In the above procedure (Scheme 11.5) the product formed is free from contamination of ureas, a major problem in the purification of the product. The polystyrene carbodiimide is prepared as given in (Scheme 11.6)6.

11.8.4 Polymer Supported Trisubstituted Phosphine Dichloride It is useful for the following transformations (Scheme 11.7). The reagent, polymer supported trisubstituted phosphine dichloride is obtained7 as follows (Scheme 11.8).

Organic Synthesis using Green Reagents

Scheme 11.4

Scheme 11.5

11.13

11.14 Green Chemistry

Scheme 11.6

Scheme 11.7

11.8.5 Polystyrene Anhydride It is obtained8,9 from polystyrene bearing carboxylic acid (Scheme 11.9). The reagent converts aniline into benzanilide and ethyl alcohol into ethyl benzoate.

11.8.6 Polymeric Sulfonazide It is useful for the transfer of diazo group to b-carbonyl compounds (Scheme 11.10)10. The reagent is prepared10 as follows (Scheme 11.11).

11.8.7 Polymeric Wittig Reagent Polymeric Wittig Reagent for the well known Witting Reaction is synthesised as given in (Scheme 11.12).

Organic Synthesis using Green Reagents

Scheme 11.8

Scheme 11.9

Scheme 11.10

Scheme 11.11

11.15

11.16 Green Chemistry

Scheme 11.12

A typical example of Wittig Reaction is the reacton of acetophenone with appropriately substituted polymeric Wittig reagent gave to 2-Phenl-2-hexane. A number of carbonyl compound have been reacted12-14 with polymeric Wittig reagent.

11.8.8 Polystyrene Sulfide It is prepared11 as given in (Scheme 11.13).

Scheme 11.13

This reagent (polystyrene sulphide)is used for lengthening of chain of alkyl iodides in good yield (Scheme 11.14).

Scheme 11.14

Organic Synthesis using Green Reagents

11.17

11.8.9 Polymer Supported Peptide Coupling Agent EEDQ Ethyl-1, 2-dihydro-2-ethoxy-1-quinolinecarboxylate (EEDQ) is an inexpensive reagent used for peptide bond formation with no reacemisation. This reagent is now used as polymer supported EEDQ. It is prepared15 by the incorporation of quinoline nucleus on to a suitable polymeric material by the free radical initated polymerisation of 6-isopropylquinoline, styrene and divinylbenzene (2: 3: 1.08) in benzene solution. The resulting polymer is converted into active reagent with ethylchloroformate, triethylamine and ethanol in methylene chloride overnight (Scheme 11.15).

Scheme 11.15

11.8.10 Polymer Supported Peracid It is used for epoxidations of olefins in good yields15,16. The required reagent is prepared as given below15 (Scheme 11.16).

Scheme 11.16

11.18 Green Chemistry Alternatively, Polymers supported peracid can also be obtained from polystyrene acid chloride (Scheme 11.17)15 or from polystyrene aldehyle (Scheme 11.18)11,15.

Scheme 11.17

Scheme 11.18

11.8.11 Polymer Supported Chromic Acid It is commercially available in the form Amberlyst A-26, HCrO–4 and is used to oxidise primary and secondary alcohols to carbonyl compounds17 and also allylic and benzylic halides to aldehydes and ketones18.

11.8.12 Polymeric S-chloro Sulfonium Chloride It is prepared19 from polystyrene methyl sulphide by treatment with chlorine in presence of triethylamine and is used as a selective oxidant for alcohols19 (Scheme 11.19).

Organic Synthesis using Green Reagents

11.19

Scheme 11.19

11.9

CONCLUSION

The green reagents are the best choice (if available) for organic synthesis/transformations in the context of Green Chemistry.

References 1. V.K. Ahluwalia and Renu Aggarwal, Organic synthesis, Special Techniques, Second Edition, Narosa, Publishing House, New Delhi, 2006, chapter 5, Page 150-194 and the references cited there in. 2. C. Yaroslavsky, A. Patchornik and E. Katchalski, Tetrahedron Lett., 1970, 3629. 3. C. Yaroslavsky, A. Patchornik and E. Katchalski, Israel J. Chem., 1970, 37. 4. N.M. Weinshenker, G.A. Crosby and J.Y. Wong J. Org. Chem., 1975, 40(13), 1966. 5. H.O. House and J.W. Blaker, J. Org. Chem., 1958, 23, 334. 6. N.M. Weinshenker and C.M. Shen, Tetrahedron Lett., 1972, 3281. 7. H.M. Relles and R.W. Schluenz, J. Am. Chem. Soc., 1974, 96, 6469. 8. M.B. Shambhu and G.A. Digenis, Tetrahedron Lett., 1973, 1627. 9. R.L. Letsinger, M.J. Kornet, V. Mahadevan and M.J. Jernia, J. Am. Chem. Soc., 1964, 86, 5163. 10. W.R. Roush, D. Feitler and J. Rebek, Tetrahedron Lett., 1974, 1391. 11. M.J. Farvall and J.M.J. Frechet, J. Org. Chem., 1976, 41, 3877. 12. W. Heitz and R. Michels, Angew. Chem. Int. Ed., 1972, 11, 298. 13. S.V. Mckinley, Jr. and J.W. Rakshys, J. Chem. Soc. Chem. Commun., 1972, 134. 14. F. Camps, J. Castells, J. Font and F. Vela, Tetrahedron Lett., 1971, 1715. 15. J.M.J. Frechet and K.E. Haque, Macromolecules, 1975, 8, 130. 16. C.R. Harrison and P. Hodge, J. Chem. Soc. Chem. Commun., 1974, 1009. 17. G. Cainelli, G. Cardillo, M. Orena and S. Sandri, J. Am. Chem. Soc., 1976, 98, 6737. 18. G. Cainelli, M. Orena and S. Sandri, Tetrahedron Lett., 1976, 3985. 19. G.A. Crossby, N.M. Weinshenker and H.S. Un, J. Am. Chem. Soc., 1975, 97, 2232.

Part VI Organic Synthesis using Green Catalysts

12 12.1

Organic Synthesis using Phase Transfer Catalysts

INTRODUCTION

In organic reactions difficulties are often encountered if the organic compound is soluble in an organic solvent and the reagent in water, then the two will react very slowly and the reaction proceeds only at the interface where these two solutions are in contact. The result is very slow or negligible reaction. The rate of reaction, however, can be increased by stirring the solution which depends upon the rate of stirring. Generally due to the low solubility of the organic compound in water and the low solubility of the regent in organic solvent, the rate of the reaction is very slow. This problem can, however, be overcome by using aprotic polar solvent, which solvate the cation—the result is that the anions are free. But such solvents are expensive and their removal is difficult. Examples of such solvents are, dimethyl sulfoxide (DMSO), dimethylformamide (HCONMe2), etc. In many reactions, e.g. Wittig, very strong bases are required, and the use of strong bases creates many other problems and side reactions take place. These problems can be overcome by using a catalyst, which is soluble in water as well as the organic solvents. Such catalysts are known as Phase Transfer Catalysts. The Phase Transfer Catalysts are ionic substances, usually quaternary ammonium salts, where the size of the hydrocarbon group in the cation is large enough to confer good solubility of the salt in organic solvents; in other words, the cation must be highly lipophilic. In general, the PTC reaction describes a methodology for accelerating reaction between water insoluble organic compounds and water soluble reactants, e.g. the reaction of an organic halide with sodium cyanide. The basic function of the catalyst is to transfer the anion and reacting salt from the aqueous phase to the organic one. The power of the phase transfer catalysts lies in the fact that it minimises the two important deactivating forces, viz., solvation and ion pairing. Following three factors play important role in the successful use of phase transfer catalyst reaction:

12.4 Green Chemistry (i) Influence of solvent Solvent should be aprotic and immiscible with water to avoid strong interactions with the ion pairs. Protic solvents will solvate the anions strongly and will lead to poor reactivity. (ii) Influence of cation The larger the number of carbon atoms around the central N atom in the PTC, the better is the lipophillicity of the catalyst. For example, N(CH3)4+ Cl– is a poor catalyst as compared to NBu4+Cl–. (iii) Salt effects Addition of sodium hydroxide and potassium carbonate increases the extraction coefficient many times and thus increases the rate of reaction.

12.2

MECHANISM OF PTC REACTION

The mechanism by which nucleophillic reactivity is enhanced by PTC depends on the solvent effect. The conditions for phase transfer involve the use of two-phase system. The organic substance is dissolved in a water-insoluble organic solvent, such as a hydrocarbon or a halogenated hydrocarbon. The ionic nucleophiles even with vigorous stirring and mixing will show little tendency to react since the nucleophile and the substrate remain separated in the aqueous and organic phase respectively. The situation changes when a PTC is added. The alkyl groups of PTC are sufficiently large enough to confer solubility in the organic phase, the PTC carries nucleophile from the aqueous phase into the organic phase (to maintain electro-neutrality) and the result is that the reaction proceeds satisfactorily in good yield. The general principle of this technique and the concepts behind it are better understood by the following example. Heating and stirring a mixture of 1-chlorooctane for several days with sodium cynide give practically no yield of 1-cyanooctane. But if a small quantity of an appropriate salt (PTC) is added, the product is formed in about 2 hrs. Thus, CH3 (CH2)6 CH2 Cl

NaCN, H2O, decane CH3 (CH2)15 P+ (n – Bu)3 Br– D 105°, 2 hr

CH3 (CH2)6 CH2CN 95%

The above reaction does not take place in the absence of catalyst because the CN– ions cannot cross the interface between the two phases, except in very low concentration. The reason is that Na+ ions are solvated by water, and this solvation energy would not be present in organic phase. Thus, CN– ions cannot cross without the Na+ ions because that would destroy the electrical neutrality of each phase. In contrast to Na+ ions, the quaternary ammonium and phosphonium ions with suffeciently large R groups are poorly solvated in water, and prefer organic solvents. If a small quantity of such a salt is added, three equilibrias set up. These are represented as: The Na+ ions remain in aqueous phase since they cannot pass into organic phase. The Q+ ions do cross the interface and carry the anion with them. At the beginning of the reaction, the chief anion present in aqueous phase is CN–. This gets carried to the organic phase (equilibrium 1) where it reacts with R¢Cl to produce R¢CN and Cl– then gets carried into the aqueous phase (equilibrium 2). Equilibrium 3 takes place entirely in the aqueous phase; it allows Q+CN– to be regenerated. The equilibria are normally reached much faster than the actual reaction 4 and so the latter is the rate determining step.

Organic Synthesis using Phase Transfer Catalysts

Organic phase

+

4

–

Q CN + R¢Cl

+

+

12.3

2 –

+

3

–

Q CN + Na Cl Q

+

–

R¢CN + Q Cl

1 Aqueous phase

12.5

+

R4N or R4P

+

–

+

–

Na CN + Q Cl

+

TYPES OF PHASE TRANSFER CATALYSTS

Phase transfer catalysts used are quaternary ‘onium’ salts such as ammonium, phosphonium, antimonium and tertiary sulphonium salts. However, in practice, only a limited number of ammonium and phosphonium salts are widely used. The more common phase transfer catalysts are commercially available. Some of the PTC’s normally used are: (i) Aliquat 336: CH3 (C8H17)3 Cl– Methyl trioctylammonium chloride (ii) Benzyl trimethylammonium chloride or bromide (TMBA) (CH3)3 CH2 C6H5 X– (X = Cl or Br) (iii) Benzyl triethylammonium chloride or bromide (TEBA) (C2 H5)3 CH2 C6 H5 X– (X = Cl or Br) (iv) Tetra-n-butylammonium chloride, bromide, chlorate or hydroxide (n – Bu)4 X– (X = Cl, Br, ClO4, OH) (v) Cetyl trimethylammonium chloride or bromide (CTMAB for bromide) (CH3)3 (CH2)15 CH3 X– (X = Cl or Br) (vi) Tetra n-pentyl, tetra n-hexyl and trioctyl propyl ammonium chloride or bromide (C5 H11)4 X–, (C6 H13)4 X–, (C8 H17)3 C3 H7 X– (X = Cl or Br) (vii) Benzyl tributylammonium chloride C6 H5 CH2 (n – C4 H9)3 Cl– (viii) Benzyl triphenyl phosphonium iodide C6 H5 CH2 (C6 H5)3 P+ I– Quaternary phosphonium salts are more expensive than the quanternary ammonium salts, but they do have an advantage of being more thermally stable than the corresponding ammonium salts. Alternatively, it is sometimes advantageous to use an agent which can complex an alkali metals cation, solvate it and provide a lipophilic anions which can be solvated by the organic medium. One such catalysts most widely used is the crown ethers. These are discussed in detail in Chapter 13. Phase transfer catalyst bonded to polymeric matric are also known. These are discussed in Chapter 15.

12.6 Green Chemistry

12.4

ADVANTAGES OF PHASE TRANSFER CATALYSTS

It is now well established that the PTC reactions have considerable advantages over the conventional procedures. The PTC reactions (i) Do not require vigorous conditions and the reactions are fast. (ii) Do not require expensive aprotic solvents. (iii) Do not require high temperatures; the reactions usually occur at low temperature. (iv) There is no need for anhydrous conditions since water is used as one of the phases. (v) With the help of PTC, the anion is available in organic solvent and so its nucleophilicity increases. (vi) In many cases the work up procedure is easier (vii) Many reactions which require strong base like alkoxide, sodamide, sodium hydride, etc., can proceed by even OH– as it becomes strongly nucleophilic in the presence of PTC. (viii) Almost all reactions can be carried out by PTC except those which are sensitive to water. (ix) Some special advantages in the use of PTC are: The reactions that do not otherwise proceed can be made to proceed in good yields. Modification of selectivity and modification of product ratio, e.g. O vs C alkylations are also possible. Higher yields through the suppression of side reactions is possible by the use of PTC.

12.5

APPLICATIONS OF PHASE TRANSFER CATALYSIS IN ORGANIC SYNTHESIS

It has already been mentioned that phase transfer catalysis can be used in numerous types of reactions due to its advantages over other conventional procedures. Some of the important applications are given below.

12.5.1 Nitriles from Alkyl Halides It has already been stated that 1-chlorooctane does not react with sodium cyanide under a variety of conditions, viz., stirring and heating for long time. However, if a small quantity of a phase transfer catalyst1 is used, the reaction goes to completion in about 2 hrs. It is found that quanternary ammonium or phosphonium salts and crown ethers and cryptates effectively catalyse the aqueous phase sodium or potassium cyanide with organic phase alkyl halides to yield nitriles. Thus,

Following are given some examples of the conversion of alkyl halides into the corresponding cyanides1,2

Organic Synthesis using Phase Transfer Catalysts

12.7

12.5.2 Benzoyl Cyanides from Benzoyl Chlorides Carboxylic acid chlorides on reaction with aqueous solution of sodium cyanide in presence of Bu4 X– gives3 the corresponding benzoyl cyanides. Thus, O C6H5C Cl + NaCN org. aq.

+ – Bu4NX

O C6H5C

CN + NaCl

The yield (60-70%) are comparable to previously reported method by the reaction of acid chlorides with either silver cyanide4 or cuprous cyanide5. The low yields are due to competing dimer formation as shown below:

12.5.3 Alkyl Fluorides from Alkyl Halides Alkyl fluorides can be obtained by the displacement of halide, viz., alkyl chloride or bromide with fluorine using a phase transfer catalyst and potassium fluoride. Thus,

The procedure is far superior to conventional methods6, 7 using anhydrous potassium fluoride and high boiling polar solvents. The utility of the PTC method is illustrated by the following example8.

12.8 Green Chemistry 12.5.3.1 Radioactive halides (alkyl halides having

36

Cl)

The techniques used is the exchange of an halide, e.g. chloride with bromide or iodide using PTC. Thus, R

Cl + (PTC)

Br

R

Br + (PTC)

Cl

For obtaining labelled alkyl halides, the appropriate alkyl chloride is reacted with labelled sodium chloride (Na36Cl) in presence of a PTC9. PTC

36

R

Cl + Na Cl

R

36

Cl + NaCl

12.5.4 Alcohols from Alkyl Halides The displacement of halogen by hydroxyl group under PTC conditions is difficult due to several factors: (i) Hydroxide ion is highly hydrated compared to chloride or bromide ion and so tends to be poorly transferred into the organic phase.

The concentration of OH– in the aqueous phase should be high to maintain a high proportion of catalyst in the active Q+OH– form. (ii) The quaternary ammonium hydroxides are thermally unstable. These are stable only up to 50-60°. Even the tetraalkyl salts on mixing with strong sodium hydroxide solution are even less stable and decompose at room temperature. (iii) Once the alcohol is formed, it is readily converted to an alkoxide resulting in the formation of ethers. (iv) Formation of elimination products, e.g. –

1

C8H17Br

OH PTC

CH3(CH2)5CH

CH2

On the basis of systematic study10, it is found that 1-bromooctane can be converted into the corresponding alcohol in 90-100% yields by using (n – C4H9)4 N+OH–, C16H33 (C2H5)3 N+OH– or (C8H17)3 C2H5N+OH– as PTC. The reaction is conducted at 80° for 48 hrs. It is reported11 that the displacement of halogen by hydroxyl group is best accomplished by the use of ‘betanine’ quaternary salts, R3N+CH2CO2–; these exhibit 10-50-fold greater activity than ordinary tetraalkylammonium salts in the reaction of 1-haloalkanes with aqueous sodium hydroxide. The greater activity is most likely due to rapid carboxylate displacement, followed by anion exchange and hydrolysis. Thus,

Organic Synthesis using Phase Transfer Catalysts

12.9

The betanine catalyst is particulary effective for the conversion11 of 1, 4-dibromobutane to tetrahydrofuran.

12.5.5 Azides from Alkyl Halides Alkyl azides can be prepared by treatment of the appropriate halide with azide ion. Alternatively, diazonium salts can be converted to aryl azides by the addition of sodium azides to the acidic diazonium salt solution12, 13. Under mild conditions, the choroaldehydes in an heterocyclic moiety react with sodium azides in dimethyl sulfoxide to give14 high yields of the corresponding azides. Thus,

het

O

POCl3/DMF

CHO Cl

NaN3 DMSO 20 – 70° 1 – 5 hr

CHO N3

The formyl azides are important intermediates for organic synthesis. It has been found that phase transfer catalysts have also been used15, 16 for the conversion of alkyl halides into azides. The utility of this technique is illustrated by the reaction of 3-methyl-5chloro-1H-pyrazol-4-carboxaldehyde into 3-methyl-5-azido-1H-pyrazole-4-carboxaldehyde17 by treatment with salium azide in DMSO in presence of tetrabutylammonium hydrogen sulfate (stirring at 45-50° for 1.5 hr).

12.5.6 Sodium Alkyl Sulfonates from Alkyl Halides Sodium alkyl sulfonates are obtained by the phase transfer catalysed displacement18 of alkyl halides with sodium bisulfite. +

RCl

+ Na2SO3

R4N X

–

RSO3Na

+

NaCl

Thus, the reaction of benzyl chloride with sodium bisulfite in aqueous medium in presence of (C2H5)4 N+Cl– (2.hr at 100°) gives 98% yield of the corresponding sodium alkyl sulfonate, C6H5CH2SO3Na.

12.5.7 Alkyl Nitrates, Thiocyanates, Cyanides and p-toluene Sulfonates from Alkyl Halides Alkyl nitrates are obtained19 by the phase transfer catalysed displacement of alkyl halides with sodium nitrite.

12.10 Green Chemistry

Similarly, the alkyl bromides on reaction with sodium thicyanate (NaSCN), sodium cyanate (NaCNO) and sodium p-toluene sulfonate (NaO2 SC6H4 p-CH3) in the presence of quaternary ammonium nitrates gave the corresponding thiocyanates2, 20, cyanataes21 and p-toluene sulfonates22 respectively.

12.5.8

Aryl Ethers/Thioethers

Aryl ethers are obtained by the reaction of phenols in strong aqueous sodium hydroxide in presence of a PTC viz., C6H5CH2 (C4H9)3 N+Cl– and an alkylating agent. The reaction is carried out in a suitable solvent, viz., methylene chloride. ArOH

+

RX

PTC NaOH

ArOR

In this reaction, either alkyl halide or sulfate ester can be used as alkylating agent. The PTC method is of special interest23 in the methylation of nitrophenols (o-, m-, and p) with methyl iodide (about 80% yield) since these phenols are alkylated only by special techniques. Also compounds containing o-dihydroxy group can be methylenated24 with methylene bromide in 70-80% yield. The aryl ethers are obtained by vigorously stirring a mixture of phenol, aqueous sodium hydroxide (1.5 times the phenol), alkylating agent (excess, 2-3 times of the phenol) and benzyl tributyl ammonium bromide (catalytic amount) in dichloromethane for 3-10 hr at room temperature. The organic layer is separated, washed with ammonia solution (2%) and then with sodium hydroxide solution (2N), saturated sodium chloride, dried and solvent removed by distillation. The PTC method can also be applied for the alkylation of chelatd hydroxyl groups, e.g., salicylaldehyde. Heteroanalogs of biphenyl ethers have been prepared using25 PTC. This method has been made use of in the preparation of some agrochemicals from 3-(or 5-) nitro-2-chloropyridine and a series of substituted phenols in 70-90% yield. Thus, Y

OH +

N

Cl

Y NaOH, H2O TBAS

R

N

O R

Organic Synthesis using Phase Transfer Catalysts

12.11

Aryl ethers have also been prepared26 by introducing b-adrengic blocking moiety in a 2-chloro3-cyanopyridine. This reaction has been extended to other aliphatic alcohols, using liquid-liquid and solid-liquid conditions. HO

CN

N

CN

O

+

Aliquat

N — C(CH3)3

Cl

O

N Ph

H

O

N — C(CH3)3

Ph

H

Heteroaryl thioethers have been prepared by treating thiophenol with chloro and bromo heterocycles under PTC conditions27, 28. With 5-nitro-2-chloropyridine, bipyridyl sulfide is obtained28 in high yield by disubstitution with Na2S. Thus, O2N

+

+

QX

Na2S

–

O2N

NO2

Cl

N

S

N

N

Dialkyl sulfides are obtained29 in excellent yields from alkyl halides and sodium sulfide using the PTC technique.

The reaction is carried out by half the molar equivalent of sodium sulfide at about 70° for about 40 hr.

12.5.9 Esterification Carboxylic acids can be esterified30,31 with alkyl halides in the presence of triethylamine. In this case, the PTC is obtained in situ by the reaction of triethylamine and alkyl halide. Thus, Et3N

+

R¢CO2Na

+

–

RX

Et3N RX

Alkyl halide

(PTC, Generated in situ)

+

RX

Carboxylic Alkyl acid as sod. halide salt (aq. soln)

PTC

R¢CO2R

+

Ester

NaX

12.12 Green Chemistry In the above esterification the alkyl halides must be highly reactive, viz., benzyl chloride, which rapidly form the quaternary salts. Alternatively, the quaternary ammonium or phosphonium salt can be directly used32 in the esterification of carboxylic acid with alkyl halides.

12.5.10 Dihalocarbenes Dihalocarbenes are synthetically useful intermediatres33-35, and are normally generated by the action of a base on chloroform. These reactions usually require anhydrous conditions, since in aqueous solution the dichlorocarbene may undergo hydrolysis. Thus,

That the generated dichlorocarbene undergo hydrolysis in aqueous medium is supported by the fact that addition of chloroform to a mixture of cyclohexene and aqueous sodium hydroxide (25%) gives36 less than 5% yield (based on chloroform) of the addition product, viz., 2, 2-dichlorobicyclo (4, 1, 0) heptane. However, use of sodium ethoxide or potassium tert. butoxide in anhydrous solvent, the addition product is obtained37 in 60-70% yield. It is now found that the use of a phase transfer catalyst (e.g., benzyltriethylammonium chloride) the addition product is obtained in 60-70% yield. Thus,

No catalyst +

CHCl3

+

NaOH aq.

Cl Cl 0.5%

PTC Cl Cl 60 – 70%

+

CHCl3

NaOEt or pot. t-butoxide anhyd. solvent

Cl Cl 60 – 70%

The remarkable increase in yield of the addition product by the use PTC is because CCl2 is transferred to the organic phase (as soon as it is generated) and reacts with cyclohexene than with water. The dichlorocarbene, thus, generated in situ by the PTC method has been used for a number of synthetic purposes. These reactions include addition to C = C, C = N bonds, insertion into C – H and N – H bonds, reactions with primary amines to yield isocyanides, etc. These are discussed below:

12.5.10.1 Addition to olefins The addition of dichlorcarbene to olefin in illustrated by the addition of CCl2 to styrene38

Organic Synthesis using Phase Transfer Catalysts

12.13

12.5.10.2 Addition to C == N bonds of Schiff ’s bases Dihalocarbene generated by the PTC catalyst adds on to the C = N of Schiff’s bases to give39,40 the corresponding dichloroaziridine derivative. Thus, Cl R

+

R CH

C6H5CH2N Et3Cl

N

Cl

–

CH

CHCI3, NaOH

N

R

R

With electron donor substituents, the products obtained are unstable and hydrolyse39 during the reaction. Thus, O

Cl Cl

Cl C

Ar — CH — N — Ar

Ar — CH Cl

C N — Ar

H2O

Ar — CH Cl

N — Ar H

10.5.10.3 Insertion into C—H bonds Dichlorocarbene generated by the PTC method undergoes insertion reactions into C – H bonds. The reaction with adamantanes41 and tetrahydrofuran42 is given below:

12.14 Green Chemistry 12.5.10.4 Reaction with hydrazine: Formation of diazomethane Dichlorocarbene generated by the PTC method reacts with hydrazine and gives43, 44 diazomethane. Thus, NH2NH2

+

CHCl3

+

NaOH

PTC Ether or CH2Cl2

CH2N2 in ether or CH2Cl2

In this reaction, lower yields (35%) are obtained by using sodium hydroxide and tetrabutylammonium hydroxide.

12.5.10.5 Reaction with primary amines, synthesis of isonitriles (phase transfer Hofmann carbylamine reaction) Dichorocarbene generated by the PTC method reacts45 with primary amines to yield isonitriles. Thus,

The yields from this technique are favourable with those from the less convenient two-step46,47 process i.e., conversion of an amine to its formamide derivative followed by its dehydration to isonitrile.

12.5.10.6 Reaction with secondary amines: Formation of formamides The reaction of secondary amines with dichlorocarbene (generated by the PTC method) give48, 49 N, N-disubstituted formamides. Thus,

R NH R¢

+

CHCl3

+

NaOH aq.

+ – C6H5CH2NEt3Cl

O R N — CH (85%) R¢

R, R¢ = ethyl, 2-butyl, cyclohexyl, allyl

12.5.10.7 Reaction with tertiary amines Bridgehead tertiary amines on reaction with chloroform and aqueous sodium hydroxide in presence of C6H5CH2 Et3Cl– results50 in elimination of carbon bridge. Thus,

Organic Synthesis using Phase Transfer Catalysts N + N

Ph

12.15

+ – C6H5CH2NEt 3Cl

2CHCl3

aq. NaOH

Ph

O

– CCl2

CHCl2

+

N

N

– N — CCl2

+

Ph O

H N — CHO

+

+

N — CHCl2

Ph

Ph

O

Ph

N — CHO

Ph O

Ph 23%

12.5.10.8 Reaction with amides, thiomides, aldoximes and amidines: Preparation of nitriles Dichlorocarbene generated by the PTC technique reacts with amides51, thioamides51, aldoximes51 and amidines52 and give the corresponding nitriles. Thus,

However, substituted ureas give51 the corresponding cyanamides. Thus, R2NCONH2

+

CHCl3

+

NaOH aq.

+ – C6H5CH2NEt3Cl

The formation of nitriles from amides is shown below:

R2NCN

12.16 Green Chemistry The utilits of the PTC procedure is illustrated by the conversion51 of benzamide into benzonitrile.

10.5.10.9 Reaction with heterocyclic compounds Substituted indoles53 react with haloform in presence of aqueous sodium hydroxide and a phase transfer catalyst resulting in ring expansion leading to the formation of quinolines. Thus,

This ring expansion technique has also been applied54 to a variety of heterocyclic compounds55. In some heterocyclic compounds, ring contraction has been reported. The reaction of 2, 2, 6, 6-tetramethyl-piperin-4-one with dichlorocarbene gave56, 57 an unexpected formation of a pyrrolidin2-one in almost quantitative yield. Thus, O

H3C H3C

N H

CH3 + CH3

CHCl3

TEBA

H3C H3C

+ N H

H3C

C

O

H3C

O

An interesting deamination of naphthalene-1, 4-imine with PTC generated dichlorocarbene has been reported58. X1

+ N

N

X2 + CHCl3 X3 X4

NaOH, H2O TEBA

– CCl2

X1 X2 + CH3NCCl2 X3 X4

Organic Synthesis using Phase Transfer Catalysts

12.17

Similar reaction takes place58 with anthracene-9, 10-imine.

12.5.10.10 Reaction with Alcohols Alcohols on reaction with dichlorocarbene generated in a phase transfer catalysed system gave59 good yield of chlorides. Thus, ROH

+

CHCl3

+

NaOH aq.

+ – C6H5CH2NEt3Cl

RCl

+

NaCl

+

H2 O

In case of steroidal alcohols, the OH is replaced with Cl with retention of configuration60.

12.5.10.11 Reaction with aldehydes Aromatic aldehydes react with chloroform and aqueous sodium hydroxide in the presence of a phase transfer catalyst to give61 mandelic acids. Thus,

R — CH — O

The reaction involves addition of : CCl2 to the carbonyl compound giving the product which on alkaline hydrolysis gives the observed product.

, Cl

Cl

The above reaction is temperature dependent and is best carried out at 56°. At lower temperature62 a-trichlorocarbinols are obtained. However, at moderately high temperature, carboxylic acids are the main products63. Thus,

12.5.10.12 Vinylidene carbenes Dimethylvinylidene carbenes can be generated64 from 3-chloro-3-methyl-1-butyne with base under vigorously anhydrous conditions. These add on to olefins in situ to give dimethyl vinylidenecylopropanes. Thus,

12.18 Green Chemistry

(CH3)2C — C

Base Anhyd. conditions

CH

Cl

(CH3)2C

C

C

RCH

CHR

R — CH — CH — R C C C H3C

CH3

It is found that the phase transfer technique with aqueous sodium hydroxide gives better yields and is much more convenient65.

12.5.10.13 Vinyl carbenes Vinyl carbenes are normally obtained66 by the reaction of strong bases with N-nitrosoacetylaminomethyl substituted carbionols. Thus, OH

NO

R R¢

C — CH2N — COCH3

Base

R C

C

R¢

It is found that the above reaction proceeds well in the presence of phase transfer catalyst and aq. Sodium hydroxide solution. These highly reactive vinyl carbenes add on to the olefins, aldehydes, ketones, azides, thiocyanate, iodide and triphenyl phosphate. Many of the products obtained by this technique are difficult to prepare by other methods (Scheme 12.1).

12.5.10.14 Carbethoxynitrines Carbethoxynitrines can be generated67 under PTC conditions; addition to alkenes gives aziridines. (Scheme 12.2)

12.5.10.15 Dichlorooxiranes Relatively stable dichlorooxiranes have been obtained68 by the reaction of chloroform with a sterically hindered carbonyl group. (Scheme 12.3)

12.5.11 Elimination Reactions 12.5.12.1 Dehydrohalogenation Phase transfer catalysts have been used69 for elimination reactions of alkyl halides with aqueous sodium hydroxide. (Scheme 12.4)

Organic Synthesis using Phase Transfer Catalysts

Scheme 12.1

Scheme 12.2

Scheme 12.3

12.19

12.20 Green Chemistry PTC

RCH — CH2R¢

RCH

CHR¢

Br

Scheme 12.4

12.5.12.2 Elimination of vic-dibromoalkanes vic-Dibromoalkanes can be neatly debrominated70 to the corresponding olefin by a simple phase transfer catalysed process using sodium thiosulphate with a catalytic amount of sodium iodide. Thus, +

RCH — CH — R¢ Br

+

Na2S2O3

–

C16H33Bu3P Br Nal

RCH

CHR¢

Br

Elimination of vic-dibromoalkanes can also be effected by procedure given below71. Ph — C

C — Ph

PhC

C — Ph

Br Br Ph — C

C—H

(75%) PhC

Br Br CH3

C

C—H

Br Br

12.6

CH (87%)

CH3

C

C—H (77%)

COBALT CARBONYL CATALYSED CARBONYLATION OF ARYL AND VINYL HALIDES BY PHASE TRANSFER CATALYST

The phase transfer catalysed cobalt carbonyl catalysed carbonylation of aryl and vinyl bromides has been carried out72 under photostimulation. By this procedure aryl halides can be converted into the corresponding carboxylic acids. The PTC used is tetrabutylammonium bromide. The reaction is carried out72 by simply stirring the reaction mixture consisting of aryl halide, benzene, sodium hydroxide (5N), tetrabutylammonium bromide, Co2CO8 under a slow steam of carbon monoxide in a Pyrex flask irradiated by 350 nm ultraviolet lamps in a photochemical reactor. Heating is achieved by means of a 100 W tungsten lamp placed under the reaction flask. The yields are generally quantitative. Thus,

Organic Synthesis using Phase Transfer Catalysts

12.21

The reaction is widely applicable with aryl bromides. Carbonylation does not occur with chlorobenzene. The method is also applicable to vinyl bromides. In place of 350 nm ultraviolet lamp, the irradiation can also be achieved73 by a commercial sun lamp.

12.7

ALKYLATIONS

12.7.1 C-Alkylation of Activated Nitriles Use of phase transfer catalysis permits experimental simplification for a variety of alkylations. The methods for the alkylation of nitriles have been reviewed74. These procedures generally involve the use of dangerous and expensive condensing agents, viz., sodium amide, metal hydrides, triphenyl methide, potassium tertiary butoxide, etc., and involve the use of anhydrous organic solvents or liquid ammonia. Due to the high selectivity75 of phase transfer catalyst, it is used for the synthesis of monoalkyl derivatives of nitriles. Thus, C6H5CH2CN

+

C2H5Cl

+

NaOH (aq.)

+ – C2H5CH2N (C2H5)3Cl

C6H5CHCN

+

NaCl

C2H5

The above technique is useful for most type of alkylation except those with simple esters or other easily hydrolysed functional group. In such cases, the ion pair extraction techniques is preferred. It involves several steps and requires a full molar quantity of quarternary ammonium bisulphate rather than a catalytic amount; all steps are carried out in the same pot. The steps involved are given below:

In many cases of alkylations both mono and dialkylated products are possible. Thus,

12.22 Green Chemistry It has been observed experimentally that malononitrile gives exclusively dialkylated products, whereas phenyl acetonitrile gives predominantly monoalkylated products with simple alkyl halides (ethyl or butyl halides), but dialkylated products with highly reactive alkyl halides (benzyl, allyl, etc.) The usefulness of the PTC method is demonstrated by the preparation of 2-phenyl butyronitrile and 2-phenyl-2-vinylbutyronitrile76.

12.7.2 C-Alkylation of Oxindol Oxindol reacts77 at position 3 with 2 mole of alkyl halide and a cycloaddition with an a, w-dihalide. Thus, (CH2)n–1 O

+

TEBA

Br (CH2)nBr

O

N

N

R

R

N-Benzoyl-1, 2-dihydroisoquinaldenitrile can be alkylated in the presence of sodium hydroxide and TEBA. Alkaline hydrolysis of the alkylated product gives isoquinoline derivatives, which are starting materials for the synthesis of alkaloids. Thus, H

CN

R

N — COC6H5

+

CN N — COC6H5

NaOH (50%) TEBA

RX

12.7.3 C-Alkylation of 2, 6-Dimethyl Pyridine Pyridine cannot be alkylated in carbons bonded to positions 2, 4 and 6 unless nitrogen atom is first quaternised. After C-alkylation78 by PTC, the nitrogen atom is dequaternised by 4-methylthiophenol to yield the free pyridine base. Thus, CH3I TBAI H3C

+ N CH3I

CH3 –

p — CH3C6H4SH H3C

HC

+ N

H3C CH3I

CH –

CH3 CH3

H3C H3C

HC

N

CH

CH3 CH3

Organic Synthesis using Phase Transfer Catalysts

12.23

12.7.4 Alkylation of Esters and Keto Esters Alkylation of esters like diethyl malonate or ethyl acetoacetate under PTC condition is not successful due to rapid ester hydrolysis. This problem has been overcome by the use79 of tert-butyl esters. Use of quaternary ammonium hydroxides in the form of ion exchange resins catalyses80 the alkylation of ethyl malonate, ethyl cyanoacetate and cyanoacetamide with a variety of alkyl halides in good yield. In this procedure the anion exchange resin is converted into the hydroxide form by using aqueous sodium hydroxide. The formed hydroxide resin is treated with alkylhalide and the active methylene compound (diethyl malonate) dissolved in ethanol at room temperature (equimolar resin hydroxide is used). A convenient method81 for the alkylation of acetoacetate consists in the treatment of a suspension of sodio salt of methyl acetoacetate with alkyl halide, viz., benzyl chloride in an organic phase in presence of a PTC (R4 Cl–). Thus, + – NaCH3COCHCO2CH3

+

C6H5CH2Cl Organic phase solvent

+ – R4NCl

CH3COCH — CO2CH3

+

NaCl

CH2C6H5 90%

This gives 90% carbon alkylation; there is no detectable oxygen alkylation. Ion pair extractive technique82 has been used in a single step for obtaining79 high yield of alkylated malonic, acetoacetic and benzoyl malonic esters. Thus,

(a small amount of O-alkylated product (2-3%) is also obtained). In this procedure, the tetrabutylammonium hydroxide (0.2 mole in 75 ml water) is added to a cooled solution of NaOH (0.2 mol in 75 ml H2O). The mixture is added to a stirred solution of methyl acetoacetate (0.1 mole) and alkyl iodide (0.2 mole) in chloroform (75 ml). The reaction is exothermic and becomes neutral after 5-10 min. The chloroform layer is separated and evaporated. The residue is treated with ether to separate tetrabutylammonium iodide. The ether solution is evaporated and the product is purified by distillation. b-Keto esters or nitriles on condensation with carbon disulphide in presence of PTC followed by treatment with alkyl halides give83 the corresponding thioacetal derivatives (Scheme 12.5).

12.7.5 Alkylation of Ketones Activated ketones, i.e. having an aromatic substituent at the a- CH2 group can be alkylated84-86 using phase transfer catalysed systems (Scheme 12.6).

12.24 Green Chemistry

(Scheme 12.5) C6H5CH2COCH3

+

RX

+

NaOH aq.

+ – C6H5CH2NEt3Cl

C6H5CHCOCH3 R

(Scheme 12.6)

In this case (Scheme 12.6) reactive alkylating agents, e.g., benzyl or allyl chloride give dialkylation products. Also, cyclic activated ketones, e.g. 1-acenaphthone or 2-tetralone yield disubstituted products regardless of the alkylating agents. Crown ethers have been used for the alkylation of ketones (see Chapter 13).

12.7.6 Alkylation of Aldehydes Aldehydes containing only an a-hydrogen atom, such as isobutraldehyde can be alkylated87 with alkyl halides in presence of 50% aqueous sodium hydroxide and catalytic amount of tetrabutylammonium ions. Thus,

(CH3)2CHCHO

+

RX

+

NaOH aq.

+ – Bu4NY

CH3 R — C — CHO CH3

In the above reaction, the alkyl halide used must be active, e.g., allyl chloride, benzyl chloride, etc. However, with less active alkylating agent, the base catalysed condensation of the aldehyde taken place leading to the formation of condensation products. This effect can be minimised by dropwise addition of isobutyraldehyde-alkyl chloride solution to mixture of aqueous sodium hydroxide, benzene and the PTC at 70°. The utility of this technique is illustrated by the following example87.

Organic Synthesis using Phase Transfer Catalysts

12.25

12.7.7 N-Alkylations Aziridines cannot be easily alkylated under conventional conditions due to rapid decompositions to open chain compounds. It has been shown88 that the alkylation of aziridine can be carried out quantitatively under PTC conditions. Thus,

In a similar fashion, N-alkylation of pyrrole under conventional conditions, C-alkylation also occur at positions 2 & 3. Under PTC conditions, N-Benzylated compound was the major product89. The ratio of N-alkylation versus C-alkylation of pyrrole and other heterocyclic compounds increased considerably if the alkylation is carried out90 with t-BuOK in presence of 18-crown-6 and diethyl ether (for use of crown ethers for N-alkylation, see Chapter 13). N-Alkylation of indoles gave91 intermediates of substituted tryptamines by PTC procedure. Thus,

Carbazole can also be N-alkylated91, 92 N-Alkylation of b-lactams has also been reported93 as a step in the synthesis of nocardicin. Thus, H (H3C)3COCHN +

O

H3CO

CH — CO2C(CH3)3

NH

Br

O H OCH3

(H3C)3COCHN O

N O

CH CO2C(CH3)3

TEBA

12.26 Green Chemistry 1, 4-Dihydropyridine derivatives have been N-alkylated under PTC conditions94 in good yield. Thus, 2

3

R

2

R

NC

CN

+

–

(CH3)2(PhCH2)(C12H25)N Br

4

+ R

RX

1

1

NC R

R

N H

3

R

R

CN 1

1

R

N 4

R

Alkylation of imidazole derivatives has been studied95-97 in detail under PTC conditions. Such compounds can be selectively98 N-alkylated. An specific example of N-alkylation of dichloroimidazole has been reported99. Thus, CH3

CH3 COCH2Cl +

N CH2Cl

HN Cl

CH3

N

COCH2Cl

PTC

N CH2 — N

Cl

N

CH3 Cl

Cl

18-Crown-6 catalyst has also been used for N-alkylation of benzimidazoles, in this case two isomers are obtained100. Thus, R¢ R

N

R +

N H

R ¢X

N

18-Crown-6

R

N

+ N

N

R¢

Alkylation of purines and pyrimidines in THF using tetrabutylammonium fluoride (TBAF) at room temperature has been reported101. Uracil, cytosine and adenine give mainly 1, 3-dialkylation. Michael-type reactions, with weakly basic heterocyclic amines, e.g., pyridazinones can be accomplished102 by the use of PTC. Thus,

Phase transfer glycosidation of pyrimidine derivatives has also been accomplished103, 104 in the synthesis of a potential interferon inductor intermediate. Thus,

Organic Synthesis using Phase Transfer Catalysts OCH3

OCH3 Br O

N

OR

N H

N

RO

N

TEBA

+ H3CS

12.27

H3CS

OR

N O

RO

N OR

OR

In case of adenine, 9-isomer is most important due to its applications in most pharmaceutical preparations. Normally alkylation105, 106 gives a mixture of 3- and 9-alkylated products. Use of PTC (viz., methyltricaprylammonium chloride) gives high yields and a high reaction selectivity of the preferred 9-isomer, Thus, NH2

NH2 N

N

+ N

N H

C6H5CH2Cl

NaOH +

N

N

–

QX

N

N CH2C6H5

9-Isomer

12.7.8 S-alkylations S-Alkylated products are obtained in major amount by the alkylation of S, N-nuclephilic heterocycles. However, in some cases N-alkylation follows S-alkylation to give N, S-dialkylated products. Thus methylation of 1-methyl-2-thioxo-2, 3-dihydroimidazole with methyl iodide gives S-alkylated product in 55% yield. On the other hand, with unsubstituted 2-thioxo-2, 3-dihydroimidazole, N, S-dialkylation is observed107. Thus,

12.28 Green Chemistry The reaction108 of benzothiazole-2-thiones, 2-pyridinethiones and 2-quinolinethiones with chlorobromomethane under PTC conditions gave the corresponding 2-chloromethylthioheterocycles. Thus,

S-Alkylation of pyrimidine derivatives has also been reported109. Also S-alkylation of 2-thiopyridine and 2-thiobenzoxazolone has been described110a; only S-alkylated products are obtained. Alkylation of D4-thiazoline-2-thione, thiazolidine-2-thione and benzothiazoline-2-thione have been achieved using phase transfer technique27.

Alkylation and acylation of thioacridone is difficult since the acridine thioether and thioesters formed undergo hydrolysis in alkyline condition. This difficulty has been overcome by the use of PTC110b. This prevents the hydrolysis and the products are obtained110b in 90-98% yield.

12.7.9 Alkylation of Mercaptans and Thiophenols Mercaptans can be alkylated with alkyl halides in the presence of quaternary ammonium salts to give the alkyl sulfides in 70-75% yield.

Thiophenol can be alkylated with methyl iodide, ethyl bromide, dimethyl sulfate and 1 – C8H17 Br to give109, 111 the alkyl derivatives.

12.8

BENZION CONDENSATION

Certain aldehydes on treatment with cyanide ion yield the condensation products called benzoins and the reaction is known as Benzoin condensation. Thus,

Organic Synthesis using Phase Transfer Catalysts 2RCHO

+

KCN

12.29

R — CH — C — R OH

O

This reaction can be accomplished only for aromatic aldehydes though not for all of them112. It is found that benzoin condensations of aldehydes are strongly catalysed by quaternary ammonium cyanide in a two phase system113. In a similar way, acyloin condensations are easily effected by stirring aliphatic or aromatic aldehydes with a quaternary catalyst114, N-laurylthiazolium bromide in aqueous phosphate buffer at room temperature. It is found that aromatic aldehydes reacted in a short time (about 5 minutes). However, aliphatic aldehydes required longer time (5-10 hrs) for completion. Mixtures of aliphatic aryl aromatic aldehydes give115 mixed a-hydroxy ketones.

12.9

DARZEN’S REACTION

The reaction of chloroacetonitrile with aldehydes and unsymmetrical ketones in alkali solution in presence of benzyl triethlammonium chloride give the glycidic esters. Darzen’s reaction consists in the condensation of aldehydes and ketones in presence of base to give a, b-epoxy ester called glycidic esters. Thus,

In case of simple aldehydes or aromatic ketones, the base used is lithium bis (trimethyl silyl amide [LiN (SiMe3)2] and the reaction performed in THF at – 78°. Darzen reaction has also been carried out with a-halo nitriles, allylic and benzylic halides. The use of phase transfer catalyst has made Darzen’s reaction very simple and the yields are 70-80%. Thus, the reaction of chloroacetonitrile with aldehydes and usymmetrical ketones in alkali in presence of benzyl triethyl ammonium chloride gives the corresponding epoxides. + – C6H5CH2NEt3Cl

R R¢

C

O

+

ClCH2CN

+

NaOH aq.

R R¢

C — CH — CN O

With aldehydes and unsymmetrical ketones both possible stereoisomers are obtained. However, with more acidic ketones, e.g., phenylacetone, the ketone carbanion is formed rather than from the nitrile, leading to alkylation of the ketone. Thus, +

C6H5CH2COCH3

+

ClCH2CN

+

NaOH aq.

QX

–

C6H5CHCOCH3 CH2CN

12.30 Green Chemistry With aromatic aldenydes, crown ethers have been used for the Darzen’s reaction (see Chapter 13). The usefulness of PTC in Darzen’s reaction is shown by the preparation 116 of 1-oxaspiro-[2, 5]-octane-2-carbonitrile.

12.10

MICHAEL REACTION

The reaction of a, b-unsaturated carbonyl compound with compounds containing reactive methylene group in presence of a basic to give an addition product is known as Michael reaction. This is the nuclephilic addition of carbanions to a, b-unsaturated compounds. Thus,

The reaction117 of active nitriles to acetylenes can be catalysed by addition of a quaternary ammonium chloride. Thus,

12.11

WILLIAMSON ETHER SYNTHESIS

The phase transfer technique provides a simple and convenient method for conducting Williamson ether synthesis. It is found84, 118 that use of excess alcohol or excess alkyl halide, lower temperature and larger alcohol (e.g. C8H17OH) give higher yields of ether. Thus,

Organic Synthesis using Phase Transfer Catalysts

C8H17OH

+

C4H9Cl

PTC NaOH Soln

C8H17OC4H9

+

12.31

C8H17OC8H17 by-product

Use of five fold excess of aqueous sodium hydroxide (50%) over alcohol, excess of alkyl chloride (also used as solvent) and tetrabutylammonium bisulfate (1-5 mole) is catalyst at 25-70° gave118 optimum yields of ether. Primary alcohols require longer time or greater amount of catalyst. Although dimethyl sulfate does not react with most alcohols in the presence of aqueous sodium hydroxide or even by the use of alkali metal alkoxides, the reaction proceeds easily119 with tetrabutylammomium salts as catalyst. Activated alcohols and primary alcohols give high yields of ethers but secondary alcohols react very slowly and tertiary alcohols do not react at all. The reaction is conducted by stirring a solution of the alcohol in petroleum ether and aqueous sodium hydroxide (50%, 2-2.5 times of the alcohol) for 30 min. The mixture is treated dropwise with dimethyl sulfate (slight excess compared to alcohol) at 40° and stirred for 2.5-3 hr. The mixture is treated with concentrated aqueous ammonia and stirred for 30 min more at room temperature and is poured into water, organic phase separated, washed with water, dried (sodium sulfate) and distilled. Ethers from phenols are obtained by using crown ethers as PTC (See Chapter 13).

12.12

THE WITTIG REACTION

The Wittig reaction120 consists in the reaction between a phosphorane or phosphonium ylid and an aldehyde or a ketone–the products obtained are an alkene and phosphine oxide. Thus,

This reaction provides a means of introducing C = C in place of C = O. It has been shown121-123 that phase transfer catalyst, viz., alkyltriphenyl-phosphonium salts react with aqueous sodium hydroxide to generate ylides, which combine with organic phase aldehydes to produce olefins. Thus,

The yield of olefin increases123 with the increase in concentration of alkali upto a maximum and then decreases. The yield depends on the alkyl group attached to the triphenylphosphonium salt. The quaternary phosphonium salts are better than the quaternary ammonium salts. The PTC catalysed Wittig reaction is limited to only aldehydes. No olefin is obtained from ketones. In spite of this limitation the method is very convenient and useful for the preparation of a variety of olefins of the type RCH = CHR¢.

12.32 Green Chemistry In certain cases, the phosphonium halides on treatment with aqueous sodium hydroxide give directly the crystalline phosphonium ylides124. Such stable crystalline ylides are also obtained when the phosphonium salts contain a COOCH3125 or a CHO126 rather than a cyano group.

12.13

THE WITTIG HORNER REACTION

In the Wittig-Horner reaction which is a modification of Wittig reaction, the readily available O

phosphine oxide Ph2P — CH2R is used. Its lithio derivative is made to react with aldehydes and ketones to yield a-hydroxy phosphine oxides, which on treatment with sodium hydride smoothly eliminate water to give the corresponding alkene. The step is stereospecific, erythro hydroxyl phosphine oxide gives the Z-alkene and the threo compound gives the E-alkene by preferential syn elimination. Various steps involved are given below:

The phase transfer catalysed Wittig-Horner reaction using aqueous sodium hydroxide and either tetraalkylammonium salts or crown ethers as catalyst has been explored for the synthesis of olefins. Thus,

Organic Synthesis using Phase Transfer Catalysts

12.33

It has been shown127 that with aldehydes, the reaction may be carried out without a typical phase transfer catalyst, suggesting that the starting phosphonates are themselves able to catalyse two-phase reaction. Halomethylpyridines have also been used in the Horner-Wittig reaction under phase transfer conditions128. Thus,

+ N

P(OCH2CH3)3

CH2X

N

CH2P(OCH2CH3)2 O

RCHO TBAI N

12.14

CH

CHR

SULPHUR YLIDS

The sulphur ylids are generally obtained from commercially available dimethyl-sulfonium salts by deprotonation. These sulphur ylids on reaction with aldehydes or ketones give the corresponding oxiranes. Thus,

It is found129 that trimethylsulfonium iodide directly reacts with aldehydes in the presence of aqueous sodium hydroxide and a phase transfer catalyst (1-5 mole % tetrabutylammonium iodide) and gives 2-phenyl oxirane in good yield. Thus,

12.15

HETEROCYCLIC COMPOUNDS

12.15.1 3-Arylcoumarins 3-Aryl coumarins are being increasingly used130 as optical brighteners. These were earlier obtained131-133 in low yield and required anhydrous conditions. These have now been obtained in excellent yield and purity by the use of a phase transfer catalyst in presence of aqueous potassium

12.34 Green Chemistry carbonate by the reaction of o-hydroxycarbonyl compound with phenylacetyl chloride. The useflness of this method is illustrated by the synthesis of 4, 6-dimethyl 3-phenylcumarin134, 135.

12.15.2 Flavones Flavones are an important class of natural products. These have been synthesised earlier by a number of methods136-139. In most of the methods, the yield is low and the work-up procedure difficult. These have now been obtained in excellent yield (90%) by the reaction of an appropriate o-hydroxyacetophenone with an appropriately substituted benzoyl chloride in benzene solution with a phase tranfer catalyst in presence of alkali (sodium hydroxide or sodium carbonate) followed by cyclisation of the formed o-hydroxydibenzoylmethanes (Baker-Venkataraman synthesis) with p-toluene sulfonic acid. The utility of the procedure is illustrated by the synthesis of flavone140 (Scheme 12.7).

12.15.3

3-Aryl-2H-1, 4-benzoxazines

3-Aryl-2H-1, 4-benzoxazines are known for their ani-inflammatory activity. These were prepared earlier in low yields.141-143 These have now been obtained134 by the condensation of an 2-aminophenol with phenacyl bromide in presence of a phase transfer catalyst in the presence of aqueous potassium carbonate (Scheme 12.8). The utility of this method is illustrated by the following example, involving synthesis of 3-(p-mthoxphenyl)-2H-1, 4-benzoxine134 (Scheme 12.9).

12.15.4 2-Aroylbenzofurans 2-Aroylbenzofurans are of considerable interest because of their pharmacological and estrigenic properties.144, 145 These were prepared earlier146,147 in low yields and have now been obtanied by the reaction of an o-hydroxyacetophenone and phenacyl bromide in the presence of PTC in aqucous potassium carbonate solution (Scheme 12.10).

Organic Synthesis using Phase Transfer Catalysts

12.35

Scheme 12.7 O

OH +

R

C6H5COCH2Br

PTC aq K2CO2

R

NH2

N

C6H5

O

CO

Scheme 12.8

Scheme 12.9 R¢ OH +

R

COCH3

COCH2Br R¢

PTC aq, K2CO3

R

CH3

Scheme 12.10

The usefulness of this method is illustrated by the following example134 (Scheme 12.11).

12.36 Green Chemistry

Scheme 12.11

12.15.5 1, 3-Benzoxathioles These are obtained148 from 2-hydroxy thiophenols under biphasic conditions. The yields are better than those obtained by using DMSO. (Scheme 12.12) OH

O +

CH2Br2

SH

S

Scheme 12.12

12.15.6 Dihydropyrans Dihydropyrans are obtained149a from cyclic enolates on reaction with 1, 3-dibromopropane in the presence of aliquat and sodium hydroxide. Thus, O

O +

Br (CH2)3Br

NaOH Aliquat

Similarly, a, .w-dibromoalkanes react150, with 2-thioxoimidazoline.

The 2-thioxobenzimidazoles react in a similar fashion. Aryl and benzo-substituents increase the acidity of the NH and facilitate the conversion to the corresponding anion.

12.15.7 1, 4-Benzoxazines Benzoxazines are obtained151 by the reaction of an N-benzoylaminophenol with 1, 2-dibromoethane, using solid sodium hydroxide and mixture of acetonitrile and methylene chloride as solvent in presence of aliquat. Thus,

Organic Synthesis using Phase Transfer Catalysts

12.37

Unsubstituted o-aminophenols do not undergo the reaction:

12.15.8 Hydantoin Derivatives Hydantoin derivatives are prepared152 using PTC. The yield is quantitative compared to the same reaction carried out in dimethyoxyethane (DME). Thus,

12.15.9 Piperazine-2, 5-Diones Piperazine-2, 5-Diones are synthesised153, 154 by the PTC cyclisation of a-halocarboxamides. Thus, 1

R 1

R CH(X) — CO — NHR

2

NaOH, H2O TEBA

2

R —N O

O N—R

2

1

R

12.15.10 Thietanes These are prepared155 very conveniently by the reaction of 1, 3-dihaloalkanes with sodium sulfide in presence of a suitable PTC. Thus,

12.38 Green Chemistry

12.15.11

N-Aryl-2-cyanoaziridines

N-Aryl-2-cyanoaziridines are prepared156 by the reaction of aromatic amines with 2-chloro-2propenenitrile in the presence of cupric acetate and acetic acid. The intermediate open chain compound is cyclised under PTC conditions. Thus,

ArNH2

12.15.12

+

CH2

CClCN

CN

CN

Cu(OAc)2

CH2Cl2

ArNHCH2CH

AcOH

+

Ar — N

–

QX NaOH

Cl

1-Arylbenzimidazolines

These are obtained157 by the cyclisation of carbanilides, using a biphasic medium. Thus, O

R¢

HN

NHCONH

N

+ – Bu4NCl

R¢

R

R

12.15.13 Benzofurazan-1-oxides Benzofurazan-1-oxides are obtained158 from o-nitroaniline derivatives by PTC procedure. Thus,

12.15.14 Piperazinones These are obtained by a general method159 using quaternary ammonium salts as catalysts. Thus, O RNHCH2CH2NHR

+

CH3 — C — CH3

CHCl3 +– QCl

R—N

N—R CH3

O

CH3

12.15.15 Thiazoles Substituted thaizoles are obtained160 by the action of tosylmethyl isocyanide161 and carbon disulphide in the presence of phase transfer catalyst and alkyl or acyl halide. Thus,

Organic Synthesis using Phase Transfer Catalysts

12.39

12.15.16 5-Thiacyclohexane carboxaldehyde 5-Thiacyclohexanecarboxaldehyde is obtained162 by the condensation of 3-thioacetoxybutanal with acrolin under PTC conditions. Thus,

OHCCH2CH(SAc)CH3

+

CH2

CHO

+ – Bu4NI

CH — CHO

TBAI S

12.15.17 Hydroxybutenolides A regiospecific synthesis of hydroxybutenolides has been carried out163 using carbonyl catalysed carbonylation of alkynes using PTC. Thus,

12.15.18 Pyrroles These are obtained164 by the reaction of cinnamonitrile with N-benzylidenebenzylamine in presence of a solvent and a PTC. Thus,

12.15.19 Triazines Triazines are abtained165 by the reaction of KOCN with an alkyl chloride. The reaction involves the trimerisation of alkyl isocyanate intermediate formed in liquid-liquid PTC. Thus, R +

RCl

+

KOCN

–

N

O

O

QX

N

N—R

R O

12.40 Green Chemistry

12.15.20 Fused Naphthoquinone Derivatives Condensation166 of 2, 3-dichloronaphthoquinones with ambident compounds having N-N, N-O or N-S nucleophilic centres under PTC conditions give the corresponding fused napthoquinone derivative. Thus, O O HOCH2CH(NH2)CH3 O Cl

CH3

N H

O O

Cl N

O

NH2

N N

O

In the above synthesis, the concentration of the catalyst is less than 2-5 mole % of the reagent. The concentration of the reactive intermediates does not exceed that of the catalyst. Thus, the PTC conditions mimic those of high-dilution technique, and are particularly favourable for cyclisation reaction.

12.16

LACTAMS

A novel method for the synthesis of b-lactams using PTC procedure starting from b-amino acids has been reported167. The reaction involves the esterification of the carboxylic acid, the formed product undergoes cyclisation. Thus,

a-Methylene-b-lactams are obtained 168 in good yield from 3-bromo-2bromomethylpropionamides by an internal N-alkylation of the amide followed by elimination. Thus, H2C BrCH2CH(CH2Br)CONHR

O

NaOH, H2O, CCl4 +

–

C5H11Et3N Br

N—R

Organic Synthesis using Phase Transfer Catalysts

12.41

Monocyclic b-lactams have been prepared 169-170 in good yield by cyclisation of BrCH2CH2CONHR with solid potassium hydroxide in methylene chloride in the presence of TBAB as a phase transfer catalyst. Thus,

Cyclic sulphonium salt (preformed can also be used as starting materials for the synthesis171 of b-lactams under PTC condition. Thus, Ph CH2 O CH3 — C — CNHCH2Ph

+

S

PhSCl

H3C O

KOH, H2O TBAB, C6H6

C NHCH2Ph

12.17

SPh

O

H3C O

N — CH2Ph

OXIDATION

Of the variety of reagents available for the oxidation of organic compounds, the most widely used are potassium permangante and derivatives of hexavalent chromium.

12.17.1 Permanganate Oxidation Permanganate, a derivative of heptavalent manganese, is a very powerful oxidant. Its reactivity depends to a greater extent on whether it is used under acid, neutral or basic conditions. In acidic solution, it is reduced to divalent manganese II ion. Mn2+ with net transfer of five electrons (Mn VII–Mn II), while in basic or neutral medium manganese dioxide is usually formed, corresponding to a three electron change (Mn VII–Mn IV). Permanganate is generally used in aqueous solution and this restricts its usefulness since many organic compounds are not soluble in water and only a few organic solvents are resistant to the action of the reagent. Solutions in acetic acid, 1-butanol or dry acetone or pyridine can sometimes be employed. It is found that oxidation with solutions of permanganate can be effected in presence of phase transfer catalyst (e.g., tetraalkyl ammonium or phosphonium salts). The permanganate anion strongly associates172, 173 with quanternary cations and is readily extracted into organic solvents by these reagents. The Q+MnO4– reacts much faster in organic solvents. A very small amount of PTC is sufficient to transfer all permanganate from aqueous to the organic phase. The permanganate ion transferred into an organic phase oxidises173, 174 olefins, alcohols, nitroalkanes, nitriles and 1, 3, 5-trimethylbenzene. The solution of potassium permanganate in benzene, thus, obtained by the action of quaternary salt to a suspension of benzene and potassium permanganate in water is known173 as ‘purple benzene’. The benzene solution can be separated and used for oxidations under anhydrous conditions. More

12.42 Green Chemistry conveniently, the two phase system can be used directly requiring only catalytic amount of PTC to maintain a concentration of permanganate in the organic phase. The phase transfer catalysts generally used for permanganate oxidations are tricaprylmethylammonium chloride (TCMA) (Aliquat 336), triphenyl methylarosonium bromide (TPMAB), tridodecylamine (TDA), benzyltriethylammonium chloride (BTEAC), tetrabutylammonium bromide (TBAB) and hexadecylbenzyldimethyl ammonium chloride (HBDM). It has been shown that triphenylmethylarsonium permanganate could be readily prepared175 in chloroform solution simply by shaking the arsonium bromide solution with aqueous permanganate (i.e. the ion pair extraction technique) and could be used as an organic phase oxidant. PTC does not oxidize, t-butanol, benzene, toluene, ethyl acetate, diethyl ether, acetone or 4-hexanone. The Q+MnO4– behaves like permanganate in neutral solution, being reduced in the presence of the suitable reductant to insoluble manganese dioxide. The formation of MnO2 is prevented by the addition of pyrophosphoric acid to the aqueous solution. The nature of the oxidation depends on the pH of the aqueous solution. Thus, under alkaline conditions cyclooctene gives176 50% yield of cis-1, 2-cyclooctane diol compared to an yield of about 7% by the classical technique.

It has been shown174 that oxidation of 1-alkenes gives not only the expected carboxylic acid, but also the next lower one. Thus,

Crown ethers have also been used for permanganate oxidations (see Chapter 13). The utility of the PTC technique is illustrated by the oxidation173 of stilbene to benzoic acid. A solution of potassium permanganate in water (1: 10) (a suspension can be used) is added with stirring to benzene, tetrabutylammonium bromide and stilbene. The mixture is stirred (2-3 hr) and worked up by addition of sodium bisulphite, acidification, separation and drying organic layer and evaporation. Benzoic acid is obtained in 95% yield.

12.17.2 Chromate Oxidation Chromic acid, a derivative of hexavalent chromium is one of the most versatile of the known oxidising agents. It reacts with almost all types of oxidisable groups. The reactions can be controlled to yield mainly one product and for this reason chromic acid oxidation is a useful process in synthesis.

Organic Synthesis using Phase Transfer Catalysts

12.43

Chromium(VI) oxide may be used in solutions in acetic anhydride, t-butanol or in pyridine. In these solutions the reactive species present are chromyl acetate, t-butyl chromate(VI) and the pyridinechromium VI oxide complex. Not much work has been done on the use of phase transferred chromate ions as oxidants for organic compounds. It has been shown177-179 that quaternary bichromate salts in organic media are of low oxidising power but have high selectivity. A commercial resin, Amberlyst A-26 can be converted into the HCrO4– form by stirring the chloride form of the resin (35 g) into a solution of CrO3 (15 g) in water (100 ml). The resin so obtained (3.8 mole of CrO3 per g of resin) is stable at room temperature for several weeks. The resin so obtained has been used for the oxidation of alcohol178, benzylic or allylic halides179 in various refluxing solvents (like hexane, benzene, chloroform, THF) and gives the corresponding aldehydes or ketones in high yields. In these oxidation carboxylic acids are not obtained. The dichromate anion Cr2O72– as compared to HCrO4– is difficult to transfer into organic solution. It has been shown that the commercially available quaternary salt ADOGEN 464 [a mixture of trialkyl (C6–10) methyl ammonium chloride] is effective for the transfer of dichromate into methylene chloride, chloroform, carbon tetrachloride and benzene using powdered potassium dichromate. These solutions are stable for several days and in the absence of acids are mild oxidants. Alcohols like benzyl alcohol, 1-phenylethanol, cinnamyl alcohol, cyclodecanol give180 good yields of the corresponding aldehydes.

12.17.3 Hypochlorite Oxidation Hypohalite is a well known oxidising agent in the haloform reaction. Thus, methyl ketones are oxidised smoothyl by means of hypohalite in the haloform reaction. Besides being commonly used to detect these ketones, this reaction is often useful in synthesis, hypochlorite having the special advantage of not attacking C-C double bonds. CH3 CH

C — C — CH3

KOCl

H

CH3

C

C — COOH

+

CHCl3

O

It has been shown180 that hypochlorite anions can be transferred into organic solutions by quaternary cations. This technique has been used for the preparation of aldehydes from benzyl alcohols, carboxylic acids from aliphatic alcohols, ketones from secondary alcohols and amines and nitriles from primary aliphatic amines in 70-80% yields (Scheme 12.13).

12.17.4 Osmium Tetroxide (Or Ruthenium Tetroxide) with Periodic Acid Oxidation Osmium tetroxide (catalytic amount) and periodate has been used181 for the oxidation of olefins to the aldehydes via the formation of 1, 2-diols. In homogeneous solutions, hydrogen peroxide

12.44 Green Chemistry

Scheme 12.13

in t-butanol and acetone have been used182-183 as oxidants. Heterogeneous systems involving chlorate184, hypochlorite185, ferricyanide186 and periodate187 have also been used. RCH = CHR¢ + OsO4 + NaIO4 Æ RCHO + R¢CHO Quaternary ammonium salts or trialkylamines are used188 as phase transfer catalysts for heterogeneous osmium catalysed olefin oxidation with periodic acid. Ruthenium tetroxide like osmium tetroxide is expensive and is used in catalytic amount with cheaper oxidising agnets like HIO4, MnO4–, BrO3–, Cl2, OCl– to maintain Ru in the RuO4 state. Quaternary ammonium and phosphonium salts are used188 as phase transfer catalyst for the oxidation of olefins to carboxylic acids. In these reactions, aldehydes can be obtained as major products if the reaction be carefully controlled.

12.17.5 Potassium Ferricyanide Oxidation 1, 2-Disubstituted hydrazines on oxidation with potassium ferricyanide in presence of 2, 4, 6-triphenylphenol (as PTC) in presence of sodium hydroxide give191 1, 2-disubstituted azo compounds. Thus,

Organic Synthesis using Phase Transfer Catalysts

RNHNHR¢

+

K3Fe(CN)6

TPP NaOH

12.45

RN NR 63-98%

The phenolic compound (TPP) acts as catalyst by transfer to the aqueous phase as anions which are oxidised to triaryphenoxyl radicals; these move into the organic phase where they dehydrogenate the hydrazine and simultaneously regenerate the triarylphenol. Thus, O

–

Ar

O Ar

Ar

OH Ar

Ar

K3Fe(CN)6

RNHNH2

aq phase

org. phase

Ar

Ar NaOH

Ar +

RN

NR

Ar

12.17.6 Air Oxidations A phase transfer technique for the simple oxidation of fluorene to fluorenone using benzene as the solvent and air as oxidant. The oxidation is conducted188 by striring fluorene, tricaprylmethylammonium chloride, benzene and sodium hydroxide solution (33%) using a magnetic stirrer. Usual work up given 55-70% fluorenone.

18-Crown-6 with solid KOH can also be used with similar results.

12.17.7 Peroxides Phase transfer catalysts transfer the peroxide anions to the organic phase as salts of percarboxylic acids. However, in this form, these are very weak oxidants. This has been made use192 of for the PTC oxidation of hydrazones to diazo compounds in high yields. In this oxidation the pH has to be maintained at 10. Iodine is found to be effective co-catalyst at a level 10–4 mole per mole of hydrazone.

(C6H5)2C NNH2 in CH2Cl2

+

CH3CO3H

+ NaOH (aq.)

+ – (C8H17)3NC3H7Cl 12(co – catalyst) 0°, 45 min

(C6H5)2C N 85%

N

12.46 Green Chemistry

12.18

REDUCTION

12.18.1 Hydride Reductions Tetraalkylammonium borohydrides193, 194 have been used as reducing agents in systems having special solubility problems. These salts transfer the BH4– anion from an aqueous solution to organic phase; the reduction rate is increased. The rate is still slow and inconvenient for preparative purposes. It has been found that the quaternary salts having a hydroxyl group on the b-carbon are superior catalysts for borohydride reductions. The tetraalkylammonium borohydrides are generally obtained in situ by the action of tetraalkylammonium halides with sodium borohydride in aqueous medium. In general the compound is reduced in organic solvent (viz., benzene) with potassium or sodium borohydride, water and the appropriate tetraalkylammonium halide (stirring at room temperature) for 0.5-7 hr. Following quaternary salt catalysts are used:

(-) N-Dodecyl-N, N-dimethyl ephedrinium bromide (catalyst B) has been used195 for the reduction of aldehydes and ketones. Tetraalkylammonium cyanoborohydrides prepared by the ion extraction technique have highly selective reducing activity in homogeneous solution196. Crown ethers have also been used for sodium borohydride reductions (see Chapter 13).

12.18.2 Reduction by Diborane It has already been stated that borohydride anion can be easily transferred into methylene chloride solution by ion pair extraction technique with tetrabutylammonium bisulphate. It has been found194

Organic Synthesis using Phase Transfer Catalysts

12.47

that the borohydride solutions in methylene chloride on treatment with simple alkyl halides, viz., methyl iodide, ethyl bromide or 1, 2-dichloroethane liberates diborane which can be used for usual reductions and hydroboration reactions. The diborane solutions may also be used for the usual olefin hydroboration reaction, followed by oxidation of the resulting adduct with aqueous hydrogen peroxide (30%) to give alcohols.

12.18.3 Formamidine Sulfinic Acids Formamidine sulfinic agent is a strong reducing agent and can be prepared197 by the oxidation of thiourea with hydrogen peroxide. NH H2N — C — NH2

+

H2O2

+ H2N

O C—S

H2N

S

H2N

OH

O C—S O

–

This reducing agent can be transferred198 by quaternary ammonium salts into organic solutions for reaction with organic substrates. Disulphides can be reduced to thiols in 60-90% yields.

12.19

MISCELLANEOUS REACTIONS

(i) Oxidation of substituted, 1, 2, 3-triazolines by potassium permanganate under PTC conditions gives199 5-substituted 1, 2, 3-triazoles. R2 N H R1

N N

R2 KMnO4 TBACl

N R1

N N

(ii) An improved method for the preparation of 3-diazoindoles using PTC has been described200. Thus, the indole derivatives react in position 3 because of the ambident reactivity of the molecule. Yields are 75-90% when R is aryl or heteroaryl.

12.48 Green Chemistry (iii) Preparation of xanthone and thioxanthone by molecular oxygen using PTC has been reported201. Thus, O

+

O2

CTEACl

X X

X

O or S

(iv) Cyclic acetals from vicinal diols and methylene chloride using PTC have been prepared202. This method is of special interest in carbohydrate chemistry where these acetals are usually obtained under acidic conditions by the reaction of the diol with an aldehyde. Thus, H RCH(OH)CH(OH)R¢

+

NaOH

CH2Cl2

+

–

H

R — C — C — R¢

Q Cl

O

O CH2

The PTC method has also been successfully applied203 to unreactive trans b-diols and cis-bdiols. Thus, O OCH3

(C6H5)3CO

+ OH

NaOH TBAB

CH2Cl2

O OCH3

(C6H5)3CO

OH

O

O CH2

Styrene Derivatives 2-Methylbenzoxazole and 2-methylbenzothiazole on condensation with aldehyde in presence of a phase transfer catalyst yield204 the corresponding styrene derivative. The intermediate carbinol can be isolated depending on the reaction conditions. Thus, X

+ ArCHO N X

X

CH3 TEBA

CH2 — CH N

Ar

X

CH2

OH N

CH Ar

O, S

Polymer supported phase transfer catalysts have distint advantage compared to unsupported PTC (For details see Section 15.2.5)

Organic Synthesis using Phase Transfer Catalysts

12.19

12.49

CONCLUSION

The phase transfer catalyst and related techniques have gained wide applications in organic synthesis. It offers extremely convenient conditions for a variety of reactions. Most of such reactions were carried out under traditional conditions, but PTC usually increases the yields and purity of the products and provides a much simpler procedures for the reactions and for the isolation of the products. There are also many reactions that do not proceed satisfactorily unless conducted under PTC conditions. Though PTC is not a universal methodology, nevertheless it is very versatile, the scope of applications is tremendous and when used it offers many advantages.

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Organic Synthesis using Phase Transfer Catalysts

61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74.

75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94.

12.51

A. Merz, Synthesis, 1974, 724. A. Merz and R. Tomohogh, Ber., 1977, 110, 96. P. Kuhl, M. Muhlstadt and J. Graefe, Synthesis, 1976, 825. H.D. Hartzler, J. Am. Chem. Soc., 1961, 83, 4990 and 4997; J. Org. Chem., 1964, 29, 1311. G.F. Hennison, J.J. Sheehan and D.E. Maloney, J. Am. Chem. Soc., 1950, 72, 3542; G.F. Hennison and A.P. Boisselle, J. Org. Chem., 1961, 26, 725. M.S. Newman et al., J. Org. Chem., 1972, 37, 3220; 1973, 38 547 and 2438; 1974, 39, 761 and 1186. M. Seno, T. Nambo and H. Kisi, J. Org. Chem., 1978, 43, 3345. H. Greuter, T. Winkler and D. Bellus, Helv. Chim. Acta, 1970, 62, 1375. For reviews, see E.V. Dehmlow, Angew. Chem. Int. Ed. Engl. 1977, 16, 493; W.B. Weber and G.W. Gokel, “Phase Transfer Catalysis in organic synthesis”, Springer-Verlag, Berlin, 1977. D. Landini, S. Quici and F. Rolla, Synthesis, 1975, 397. A. Gorgues and A. Le Cog, Tetrahedron Lett., 1976, 4723. J.J. Brunet, C. Sidot and P. Caubere, Tetrahedron Lett., 1981, 1013. J.J. Brunet, C. Sidot and P. Caubere, J. Org. Chem., 1983, 48, 1166. A.C.Cope, H.L. Holmes nd H.O. House, Org. React., 1957, 9, 107; M. Makosza, Wiad. Chem., 1967, 21, 1, (Chem. Abster., 1967, 67, 53161 t); M. Makosza, Wiad Chem., 1969, 23, 759. Chem. Abstr., 1969, 70, 96065u. M. Makosza, Tetrahedron, 1968, 24, 175. M. Makosza and B. Seradin, Rocz., Chem., 1965, 39, 7223, 1401, 1559, 1805 (Chem. Abstr., 1966, 64, 1295h, 17474g, 17475c, 17475j. M. Makosza and M. Fedorynski, Roct. Chem., 1971, 45, 1861. L.S. Hart, C.R. Killen and K.J. Naunders, J. Chem. Soc. Chem. Commun., 1979, 24. A. Joncyk, M. Ludiwikow and M. Makosza, Rocz., Chem., 1973, 89, 47. S. Shimo and S. Wakamatsu, J. Org. Chem., 1963, 28 504. H.D. Durst and L. Liebeskind, J. Org. Chem., 1974, 39, 3271. A. Brandston and U. Junggren, Tetrahedron Lett., 1972, 473. L. Dalgaard, L. Jensen and S.O. Lawesson, Tetrahedron, 1974, 30, 93. J. Jarrouse, C.R. Hebd, Scances Acad. Sci. Ser. C, 1951, 232, 1424. J. Jonczyk, B. Serafin and M. Makosza, Roz. Chem., 1971, 45, 1027. J. Joncyzk, B. Serafin and E. Skulimowska, Rocz. Chem., 1971, 45, 2097. H. Dietl and K.C. Brannock, Tetrahedron Lett., 1973, 1273. M. Maurette, A. Lopez, R. Martino and A. Lattes, C.R. Acad. Sci. Ser. C. 1976, 282, 599. A. Jonczyk and M. Makosza, Rocz. Chem., 1975, 49, 1203. W.C. Guida and J. Mathre, J. Org. Chem., 1978, 45, 3172. S.O. De Silva and V. Snieckus, Can. J. Chem., 1978, 56, 1621. H. Nishi, H. Kohno and T. Kano, Bull. Chem. Soc. Japan, 1981, 54, 1897. P.G. Mattingly and M.J. Miller, J. Org. Chem., 1981, 46, 1557. J. Palecek and J. Kuthan, Synthesis, 1976, 550.

12.52 Green Chemistry 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110.

111. 112. 113. 114. 115. 116. 117. 118. 119. 120.

121. 122. 123. 124. 125. 126. 127. 128.

H. Galous, I. Bergerat, C.C. Farnous and M. Micocque, Synthesis, 1982, 1163. J. Flguero, M. Espada, D. Mathieu and R. Phan Tan Liu, Ann. Quim., 1979, 729. P.V. Dehmlow and M. Fissel, J. Chem. Res., Synop, 1978, 310. H. Dou and J. Metzger, Bull. Soc. Chem. Fr. 1976, 1861. K. Eichen, W. Rohwomd, F. Linhart, Ger. Offen, 2830, 764(1980), to BASF. I.J. Mathias and D. Bukett, Tetrahedron Lett., 1970, 4709. K.K. Ogilvie, S.J. Beacage and M.F. Gillen, Tetrahedron Lett., 1978, 1663. T. Yamada and M. Ohki, Synthesis, 1981, 631. H.D. Winkeler and F. Neela, Chem, Ber., 1980, 113, 2069. F. Seela and D. Hasseimann, Chem. Ber., 1980, 113, 1180. L. Lindblom and M. Elander, Pharm, Technol, 1980, 59. I. Shinkai, M.C. Vanderzwan, F.W. Hartner, R.A. Reamer, R.J. Tull and I.M. Weinstock, J. Heterocycl. Chem., 1981, 18, 197. A. Mahamoud, J.P. Galy, E.J. Vincent and J. Barbe, Synthesis, 1981, 917. C.T. Goralski and G.A. Burk, J. Org. Chem., 1977, 42, 3094. D. Nasipuri, S. Banerjee, B.V. Alaka and N.P. Daw, Synthesis, 1980, 850. (a) H. Dou, P. Hassanaly, J. Kister and J. Metzger, Phosphones Sulfur, 1977, 3, 335. (b) J.P. Galy, E.J. Vincent, A.M. Caly, J. Barbe and J. Elguero, Bull. Soc. Chim. Belg., 1981, 90, 947. A.W. Harriott and D. Picker, Synthesis, 1975, 447. For a review, see Ide and Buck, Org. React. 1948, 4, 269-304. J. Solodar, Tetrahedron Lett., 1971, 287. W. Tagaki and H. Hara, J. Chem. Soc. Commun., 1973, 891. (a) H. Stetter and G. Dambkes, Synthesis, 1977, 403. A. Jonczyk, M. Fedorynski and M. Makosza, Tetrahedron Lett., 1972, 2395. M. Makosza, Tetrahedron Lett., 1966, 5489. H.H. Freeman and R.A. Dubois, Tetrahedron Lett., 1975, 3251. A. Merz, Angew Chem. Int. Ed. Engl., 1973, 12, 846. For a general Treatise, see Cadogan; Organophosphorus reagents in organic synthesis, Academic Press, N.Y., 1970; For a monograph see Johnson, “Ylid Chemistry”, Academic Press, N.Y., 1966, Reviews-Bestmann and Vostrowsky, Top Curr. Chem., 1983, 109, 85, 164. G. Markl and A. Merz, Synthesis, 1975, 295. S. Hung and I. Stemmler, Tetrahedron Lett., 1974, 3151. W. Tagaki, I. Inouse, Y. Yano and T. Okonogi, Tetrahedron Lett., 1974, 2587. P.D. Croce, J. Chem, Soc., Perkin Trans I, 1976, 619. F. Bohlmann and C. Zdero, Ber., 1973, 106, 3779. M.J. Berenquer, J. Castello, J. Fermandez and R.M. Galard, Tetrahedron Lett., 1971, 493. M. Mikolajczyk, S. Grzejszczk, W. Midura and A. Zatorki, Synthesis, 1976, 396. C. Pilchucki, Synthesis, 1974, 869.

Organic Synthesis using Phase Transfer Catalysts

129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162.

12.53

A. Merz and G. Marki, Angew, Chem. Int. Ed. Engl., 1973, 12, 845. A. Dorlars, C.W. Schellhammer and J. Schroeder, Angew Chem. Internat. Edit., 1975, 14. 665. P. Pulla Rao and G. Srimannarayanna, Synthesis, 1981, 11, 887. Ogliabloro, Gazz. Chem. Itial., 1879, 9, 478. T.R. Seshadri and S. Varadarajan, J. Sci. Ind. Res., 1952, Sect. B, 11, 48; Proc. Indian Acad. Sci., 1952, Sect. A, 35, 75. G. Sabitha and A.V. Subba Rao, Synth. Communication, 1987, 17(3), 341. V.K. Ahluwalia and C.H. Khanduri, Indian J. Chem., 1989 28B, 599. J. Allan and R. Robinson, J. Chem. Soc., 1924, 125, 2192. W. Baker, J. Chem. Soc., 1933, 1381. H.S. Mahal and K. Venkataraman, Curr. Sci., 1933, 4, 214. V.N. Gupta and T.R. Seshadri, J. Sci. Ind. Res(India), Section B, 1957, 16, 116. V.K. Ahluwalia et. al unpublished results. D.R. Sridhar, C.V. Reddy Sastry, O.P. Bansal and R. Pulla Rao, Indian J. Chem., 1983, 22b, 297; 1981, 11, 912. P. Battistoni, P. Bram and G. Fava, Synthesis, 1979, 220. F. Chioccara, E. Ponsiglione, G. Prola and R.H. Thomson, Tetrahedron, 1976, 32 2033. N.P. Buu-Hoi in Less Heterocyles Oxygen Collog. Int. CNRS, Paris, 1957, p. 121. E. Bisagni, N.P. Buu-Hoi and R. Roger, J. Chem. Soc., 1955, 3693. R. Stoermer et al., Ber., 192, 57, 72. M. Ghelardin, F. Russo and V. Pestellini, Bull. Chem. Farm., 1970, 109, 48; C.A., 1970, 73, 1459r, 24801v. S. Cibiddu, A. Maccioni and M. Secei, Synthesis, 1976, 797. (a) A. Jonezyk, G. Gullaumet and B. Loubinous, Rocz. Chem., 1971, 45, 1259. H. Dou, P. Ludwikow, P. Hassanaly, J. Kister and I. Metzger, J. Heterocycl. Chem., 1980, 17, 393. G. Coudert, G. Guillaumet and B. Loubinous, Synthesis, 1979, 541. K. Kieckononowiecz, A. Zefi, M. Mikolajozyk, A. Zaboraki, J. Karolak and M.W. Wiscaorek, Tetrahedron, 1981, 37, 408. T. Okawara, Y. Nogachi, T. Matsuda and M. Furukawa, Chem. Lett., 1981, 2, 185. T. Okawara, Y. Matsuda and M. Furukawa, Chem. Pharm. Bull., 1982, 30 1225. M. Lancaster and J.H. Smith, Synthesis, 1982, 582. S. Apparan, A. Kumar, H. Ila and H. Junjapa, Synthesis, 1981, 623. British Patent, 1,576,386 (1980). M. Fah, U.S. Patent (Ciba Geiby), 4, 185, 018 (1980). J.T. Lal, U.S. Patent, 4, 297, 496 (1981) (to Goodrich Co.), J. Org. Chem., 1980, 45, 754; Synthesis, 1981, 40; Synthesis, 1982, 71. M. Van Leusen and J. Wildeman, Synthesis, 1977, 501. M. Van Leusen, and Leact. Heterocycl. Chem., 1980, S111, 5, Suppl. issue of J. Heterocycl. Chem., 17. J.M. Melntosh and H. Khalil, J. Org. Chem., 1977, 42, 2123.

12.54 Green Chemistry 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199.

H. Alper, J.K. Currie and H. des Abbayes, J.C.S. Chem. Commun., 1978, 311. V. Dryansk, K. Popandova and C. Ivanov, Tetrahedron Lett., 1979, 443. K.F. Zenner and H. Appel, Ger. Offen, 2, 126, 296 (1972). A.K. Flahatel, A. Sultan and G. Vernin, Heterocycles, 1982, 10, 333. M. Makosza and T. Goetzen, Rocz. Chem., 1972, 46, 1239. S.R. Fletcher and I.T. Kos, J.C.S. Chem. Commun., 1978, 903. H. Takahata, Y. Ohnishi and Y. Yamazaki, Heterocycles, 1980, 14, 467. H. Takahata, Y. Ohnishi and Y. Yamazaki, Chem. Pharm. Bull., 1981, 20, 1063. M. Ihran and K. Fukumoto, Heterocycles, 1982, 19, 1435. W.A. Gibson and R.A. White, Anal. Chim. Acta, 1955, 12, 413. A.W. Herriott and D. Picker, Tetrahedron Lett., 1974, 1511. A.P. Krapcho, J.R. Larsen and J.M. Eldridge, J. Org. Chem., 1971, 42, 3749. N.A. Gibson and J.W. Hosking, Aust, J. Chem. 1965, 18, 123. W.B. Weber and J.P. Shepherd Tetrahedron Lett., 1972, 4907. I.A. Shevtshuk, T.N. Simonova, Ukr. Khim, Zr., 1964, 30 983. G. Cainelli, G. Cardillo, M. Orena and S. Sandri, J. Am. Chem. Soc., 1976, 98, 6737. G. Cardillo, G. Giamecian and S. Sandri, Tetrahedron Lett., 1976, 3985. G.A. Lee and H.H. Freedman, Tetrahedron Lett., 1976, 1641. F.D. Gunstone, Adv. Org. Chem., 1960, 1, 103. N.A. Milas and S. Sussman, J. Am. Chem. Soc., 1936, 58, 1302; 1937, 59, 2345. J.W. Cook and R. Schoental, J. Chem. Soc., 1950. 47. G. Braun, J. Am. Chem. Soc., 1929, 51, 228. R.W. Cummins (to FMS Corporation), U.S. Patent, 3, 846, 478 (1974). J.S. Mayell, Ind. Eng. Chem., Prod. Res. Dev., 1968, 7, 129. R. Pappo, D.S. Allen, R.U. Lemieux and W.S. Johnson, J. Org. Chem., 1956, 21, 478. Charles M. Starks and Charles Liotta, Phase Transfer Catalysts Principles and Techniques, Academic Press, Inc, NY, p. 310. J.L. Courtney and K.F. Swansborough, Rev. Pure Appl. Chem., 1972, 22, 47. KA. Keblys and M. Dubeck (to Ethyl Corpn), U.S. Patent, 3, 409, 649 (1968). K. Dimroth and W. Tuncher, Synthesis, 1977, 339. J.R. Adamson, R. Bywood, D.T. Eastlick, G. Gallagler, D. Walker and E.M. Wilson, J. Chem. Soc. Perkin Trans., 1975, 2050. E.A. Sullivan and A.A. Hinckley, J. Org. Chem., 1962, 27, 3731. A. Barandstom, U. Janggren and B. Lamm, Tetrahedron Lett., 1972, 3173. S. Colonna and R. Fornasier, Synthesis, 1975, 531. R.O. Hutchins and D. Kandasamy, J. Am. Chem. Soc., 1973, 95, 6131. E.E. Reid, Org. Chem. Bivalent Sulf, 1963, 5, 39. G. Borgogono, S. Colonna and R. Fornasier, Synthesis, 1975, 529. P.K. Kabada, Synthesis, 1978, 694.

Organic Synthesis using Phase Transfer Catalysts

200. 201. 202. 203. 204.

A. Gonzalez and C. Galvez, Synthesis, 1982, 741. E. Alnen, G. Bottacio and V. Carletti, Tetrahedron Lett., 1977, 2117. P. Dicesare and B. Gross, Carbohydr. Res., 1976, 48, 271. K.S. Kim and W.A. Szarek, Synthesis, 1978, 48. V. Dryanaka and C. Ivonov, Tetrahedron Lett., 1975, 3519.

12.55

13 13.1

Organic Synthesis using Crown-ethers

INTRODUCTION

The crown ethers are a family of cyclic polyethers. These are large ring compounds containing several oxygen atoms—usually a regular pattern. Some typical examples are (Scheme 13.1). The first number designates the ring size, and the second number designates the number of oxygen atoms in the ring. In place of oxygen other heteroatoms like sulphur and and nitrogen may also be present. If S is the heteroatom, these are called thia crown ethers, and if N is the hetero atom, these are called aza crown ethers (Scheme 13.2). Bicyclic and cycles of higher order are called cryptands and the corresponding metal complexes are called crypates (Scheme 13.3).

13.2

NOMENCLATURE

The crown ethers are designated as per IUPAC nomenclature and also by short names (Pedersen’s crown nomenclature). These are also represented by notations. Some typical examples are given below (Scheme 13.4).

13.3

SPECIAL FEATURES

It is found that in presence of crown ethers, viz., dicyclohexyl [18] crown-6, sodium hydroxide dissolves more than expected amount and systematic experimentation shows that dicyclohexyl [18] crown-6 forms a stable alkali and alkaline earth metal cation compledxes which are soluble in organic solvents. The alkali metal complexation is one of the crown ethers most important property. The [18] crown-6 molecule is shaped like a doughnut having a cavity in the middle. Facing into the cavity are oxygen atoms and facing outside are twelve CH2 groups. There is thus hydrophobic interior and lipophilic exterior. The cavity in [18] Crown – 6 has a diameter of 2.7 A°. Here K+

13.2 Green Chemistry

Scheme 13.1

S

NH

HN

NH

HN

S S

Thia crown ethers

Aza crown ethers Scheme 13.2

Organic Synthesis using Crown-ethers

O

O O

N O

O

O

O

Cryptands

O

+ M O

N

N

O

13.3

N

O O

Cryptates

Scheme 13.3

Scheme 13.4

ions, having a diameter 2.66 Å just fits into the cavity of crown, where it is held by unshared pair of electrons on the six oxygen atoms. Because of such close fit, K+ is bound very tightly. The crown ether is just not a solvent. It holds the K+ by some ion-dipole forces just as a solvent but the forces are much stronger here. Lipophilic exterior

O O

O K

+

O

O O

13.4 Green Chemistry

13.4

SYNTHETIC APPLICATIONS

The development of crown ether chemistry parallels the development of phase transfer catalysts (Chapter 12). The crown complex, e.g., 18-crown-6-K+ is like tetraalkyl ammonium cation in the sense that the charged species has a large hydrophobic surface. An anion paired with it in nonpolar solution is activated because the anion is poorly solvated either by the cation or by solvent. The activated anion has tremendous synthetic applications. The advantage in the case of crown ethers is that many of the reactions can be done under homogeneous conditions because crown compounds are easily soluble in organic phase. Below is described a brief account of some of the applications of crown ethers.

13.4.1 Esterification Crown ethers have been used for esterifications. Thus p-bromophenacyl esters have been prepared1 in 92% yields by the reaction of p-bromophenacyl bromide with potassium salt of a carboxylic acid using 18-crown-6 as the solubilising agent (Scheme 13.5).

Scheme 13.5

The phenancyl esters of fatty acids are also obtained2, crown ethers as catalysts.

3

in quantitative yields using

13.4.2 Saponification Normally saponification is carried out with potassium hydroxide. The main problem arises due to the insolubility of potassium hydroxide in organic solvents like toluene. Using the hydrophobic and hydrocarbon soluble macrocyclic derivative, viz, dicyclohexyl-18-crown-6, it has been shown that potassium hydroxide is soluble in toluene. The special application4 of this observation is the hydrolysis of sterically hindered esters by using potassium hydroxide complex in toluene (Scheme 13.6).

Scheme 13.6

Organic Synthesis using Crown-ethers

13.5

13.4.3 Anhydride Formation A facile synthesis of anhydride has been described by the reaction of potassium or sodium salts of carboxylic acids with activating halides (ethyl chloroformate, cyanuric chloride and benzyl chloroformate) in acetonitrile in the presence of 18-crown-6 (Scheme 13.7). O O

O OH

O

+ Cl

C

C R

C

+

OC2H5

C O

R

K — Crown R CH3CN room temp. 1.5 hr

Scheme 13.7

Using this procedure, cinnamic acid, p-nitrobenzoic acid, benzoic acid, acetic acid and propionic acid are converted into their anhydrides (the molar ratio of activating halide to salt is 1 : 2). However, use of molar ratio of activating halide to salt as 2 : 1 gives mixed anhydrides. Thus benzoic acid in presence of benzyl chloroformate (1 : 2) gave benzoic-ethylcarbonic mixed anhydride and p-nitrobenzoic acid in presence of ethyl chloroformate (1 : 2) gave p-nitrobenzoic-ethylcarbonic mixed anhydride.

13.4.4 Potassium Permanganate Oxidation Of the wide variety of agents available for oxidation of organic compounds, probably the most widely used is potassium permanganate, a derivative of hexavalent manganese is a powerful oxidant. Its reactivity depends to a greater extent on whether it is used under acidic, neutral or basic conditions. Permanganate is generally used in aqueous solution and this restricts its usefulness since not many compounds are sufficiently soluble in water and only a few organic solvents are resistant to oxidising action of the reagent. Some of such solvents are acetic acid, t-butanol, dry acetone and pyridine. Alternatively, oxidation with aqueous solution of permanganate can be effected in presence of a crown ether, dicyclohexano-18-crown-6, forms a permanganate complex (Scheme 13.8). Under these conditions, permanganate becomes soluble in benzene and the resulting solutions are excellent reagents for oxidation of a variety of organic substrate in organic solvents. O O

O O

O KMnO4

O

O

O +

K O

O

O O –

MnO4

Scheme 13.8

13.6 Green Chemistry Using this procedure, substituted catechols can be converted into the corresponding o-quinones in high yield (Scheme 13.9). Only 1 equivalent of MnO–4 is required for this reaction.

Scheme 13.9

The potassium permamganate solubilise in benzene by dicyclohexyl-18-Crown-6 has been used5 for the oxidation of trans-stilbene, benzyl alcohol, toluene and benzaldehyde into benzoic acid in quantitative yield at 25°. Oxidation of a-pinene with potassium permanganate in presence of crown ether gives5 pinonic acid in 90% yield (Scheme 13.10). Similar oxidation of b-pinene clearly cleaved the double bond and converted into cis-pinonic acid. O KMnO4, C6H6

COOH

Dicyclohexano [18] crown-6 25° a-Pinene

Pinonic acid

Scheme 13.10

13.4.5 Aromatic Substitution Reactions It is possible to effect nucleophilic substitution reactions on systems which had earlier proved resistant. This, 1, 2-dichlorobenzene undergoes substitution with methoxide to give6 only 2-methoxychlorobenzene (2-chloroanisole). In this case, the meta isomer is not obtained suggesting that a nucleophilic aromatic substitution had occurred. However, formation of meta isomer would have suggested a benzyne mechanism (Scheme 13.11).

Scheme 13.11

Two additional examples6 are the substitution of 2-chloropyridine by 1, 6-dihydroxyhexane in 60% yield and substitution of a more electron rich ring undergoes methoxide substitution in excellent yield using 18-crown-6 as catalyst (Scheme 13.12).

Organic Synthesis using Crown-ethers

13.7

Scheme 13.12

13.4.6 Elimination Reactions The ability of crown ethers to enhance the rate or alter the course of a reaction is both interesting and important6. This is illustrated as shown below (Scheme 13.13). H

Ph

Ph

t

KO Bu 50° TsO H Dicyclohexano [18] crown-6 no crown ether present

Ph +

syn-elimination 30% 91%

anti-elimination 70% 9%

Scheme 13.13

13.4.7 Displacement Reactions The ability of the crown ethers for displacement reaction is enormous even in those cases where there is a great possibility of elimination reaction taking place. Thus, in the reaction6 of 4-bromocyclohexenone with potassium acetate in presence of crown ether, displacement of bromide with acetate takes place (Scheme 13.14). However, in this case if elimination of HBr had occurred instead of substitution, cyclohexadienone would from and this would immediately rearrange to a phenol. Though the driving force for elimination seems great, substitution occurs.

Scheme 13.14

13.8 Green Chemistry The displacement of a halide by cyanide has been carried out in excellent yields by the use of phase transfer catalysts (see Chapter 12). Catalysis by 18-Crown-6 of the reaction of solid potassium cyanide with halide in acetonitrile has been studied7 using a variety of chlorides and bromides. With primary bromides, yields are high and the reactions times are 15-30 hrs at reflux (83°). Interestingly, in this system chlorides are more reactive than bromides and have reaction time of about 2 hrs. Secondary halides react considerably more slowly and the yield drops to 50-60% due to competing elimination. Tertiary halides do not react successfully since elimination process dominates. By the use of crown ethers, benzyl chloride, p-nitrobenzyl chloride, p-chlorobenzyl chloride and 3, 4-dimethoxy-benzyl chloride can be converted8 into the corresponding nitrile in 85-90% yield. An excellent example of the utility of these nonaqueous conditions is the preparation of trimethyl silyl cyanide from the hydrolytically sensitive trimethylsilyl chloride (Scheme 13.15).

Scheme 13.15

Crown ethers have also been used for nucleophilic displacement of chloride by cyanide at hindered positions. Thus, the reaction of 2-chloro-2-methylcyclohexanone with potassium cyanide in acetonitrile in presence of 18-Crown-6 gives excellent yield of the cyanide at room temperature. However if the reaction is conducted at reflux temperatures, Favorskii rearrangement occurs to give the five membered compound in high yield (Scheme 13.16).

Scheme 13.16

Similar reaction of 2-chloro-4-methylcyclohexanone proceeds smoothly to produce simple displacement product (Scheme 13.17). Sulfonyl chlorides are also readily converted9 to the corresponding fluorides by 18-crown-6 catalysed phase transfer exchange (Scheme 13.18).

Organic Synthesis using Crown-ethers

13.9

Scheme 13.17

Scheme 13.18

13.4.8 Generation of Carbenes It has already been stated (Chapter 12) that elimination from chloroform and other haloalkanes give carbenes in presence of phase transfer catalyst and aqueous alkali. The generation of phenylbromocarbene and phenylchloro carbenes from the corresponding a, a-dihalotoluene using potassium t-butoxide and 18-crown-6 as catalyst has been reported10. Under these conditions the usual addition reactions are observed with typical alkenes. The carbenes generated under these conditions are “free”. The potassium cation would be expected to be strongly solvated by the crown ether and therefore would not participate in the carbene generating step (Scheme 13.19). X CH

X

X

CH +

–

K t – O Bu [18] crown-6

Br or Cl

Free carbene

Scheme 13.19

Dicyclohexyl-18crown-6 has also been used11 to convert cyclohexene and trans-stilbene to the respective gem-dihalocyclopropanes in 30-70% yield by treatment with aqueous sodium hydroxide (50%) and chloroform or bromoform at 40°. Dibenzo-18-crown-6 has also been used12 as liquid-liquid phase tranfer catayst in the generation of carbenes (Scheme 13.20). Cl CH2

CH X

X + HCCl3

50% NaOH aq. dibenzo [18] crown-6

Ph, CN

X X X

Scheme 13.20

Cl

Ph 87% CN 40%

13.10 Green Chemistry An excellent application of the above is the preparation13 of diazomethane (Scheme 13.21). The method consists in the application of Hofmann carbylamine reaction to form diazomethane by reaction of hydrazine with dichlorocarbene followed by rearrangement. The procedure consists in heating (water bath) a mixture of potassium hydroxide (1.4 mole), water (20 ml), chloroform (0.4 mole), ether (200 ml), 18-crown-6 (0.8 m mole) and hydrazine hydrate (85%, 0.2 mole). The usual precautions of preparation of diazomethane are taken. Diazomethane is obtained in 50% yield by this procedure.

Scheme 13.21

13.4.9 Superoxide Anion Superoxide radical anion is readily available from commercial sources in the form of cheap potassium superoxide (KO2) or sodium superoxide (NaO2). Its use has been limited for synthetic transformations due to the solubility problem associated with the K+ and Na+ salts. Crown ethers, viz., 18-crown-6, dicyclohexyl-18-crown-6 and dibenzo-18-crown-6 have been used to dissolve solutions of naked superoxide on treatment with primary and secondary alkyl bromides form dialkyl peoxides as the major products (40-80%). The reaction is believed to proceed as follows (Scheme 13.22).

Scheme 13.22

On the basis of detailed studies15 it has been concluded that the sum total of three steps as per calculations proceeded with a 94% retention of configuration. Use of crown ethers has provided16 a simple means of converting bromides to alcohols (Scheme 13.23). In each case, 4 equiv. of KO2 and 2 equiv. of crown ether were employed. A typical application16 of superoxide anion is the oxidative dimerisation (Scheme 13.24). The nucleophilicity KO2 has been used6 to provide selectivity in hydrolysis reactions (Scheme 13.25). An additionl-induced rearrangement has been reported. When tropone is treated with KO2 and 18-crown-6 in DMSO solution, a 46% yield of salicylaldehyde is obtained (Scheme 13.26).

13.4.10 Alkylations O-Alkylations Potassium carbonate is used most widely to scavenge protons. Crown ethers enhance their solubility as well as reactivity. A good example is the conversion of phenol into benzyl phenyl ether in quantitative yield by using K2CO3 and a catalytic amount of 18-crown-6.

Organic Synthesis using Crown-ethers

13.11

Scheme 13.23 H N H3C

CH3 N H

KO2

CH3

[18]-crown-6 THF

N H

Scheme 13.24 OTs COOCH3 C5H11 OTHP

OTHP

KO2 Crown OH COOH C5H11 OTHP

Scheme 13.25

OTHP

13.12 Green Chemistry O CHO DMSO, KO2 [18]-crown-6 OH Tropone

Scheme 13.26

C-Alkylations Dibenzo-18-crown-6 has been used as a liquid-liquid phase transfer catalyst in the generation and reaction of carbanions. The addition of crown (1 mole %) to the two-phase system consisting of an organic phase and a concentrated aqueous sodium hydroxide phase results in carbanionic sodium species which are soluble in the organic phase where they undergo transformation17. Some of the alkylation reactions are given in (Scheme 13.27).

Scheme 13.27

It has been shown18 that many aldehydes and ketones condense with acetonitrile in presence of solid potassium hydroxide, aided by the use of 18-crown 6 as a catalyst. In case acetonitrile is used as a solvent which with poorly enolisable carbonyl compounds give good yield of unsaturated nitriles (Scheme 13.28).

Organic Synthesis using Crown-ethers

R C

O

R¢

+ CH3CN

[18]-crown-6

R

KOH

R¢

C

13.13

CHCN

Scheme 13.28

Similarly, phenylacetone can be alkylated19 with n-butyl bromide (1.2 mole) in 50% aqueous sodium hydroxide in presence of dicyclohexyl-18-crown-6 or [2.2.2] cryptate in better than 90% yield (Scheme 13.29).

Scheme 13.29

N-Alkylations The N-Alkylation of pyrrole and indole has been carried out20 in the presence of crown ether. The indolyl anion also behaves as an ambident nucleophile; alkylation occurs21 at nitrogen at C-3 (Scheme 13.30).

Scheme 13.30

13.4.11 Other Applications Crown ethers have numerous other applications in organic synthesis. Some of these are given below:

13.4.11.1 Photocyanation Photocyanation is carried out successfully with potassium cyanide in presence of hv and crown ethers (Scheme 13.31).

13.4.11.2 Resolution of racemic mixtures Chiral crown ethers have been used22 for the resolution of racemic mixtures. These have been used to separate mixtures of enantiomeric alkyl and arylammonioum ions by formation of diastereomeric complexes. The separation is often simplified by the fact that one diasteromer may form much more rapidly than the other.

13.14 Green Chemistry KCN hn CE

CN

CN KCN hn CE

Scheme 13.31

13.4.11.3 Acetylation of secondary amines in presence of primary amine (A useful method of separation) Secondary amines can be acetylated in the presence of a primary amine by conversion to their salts and addition of 18-crown-6. The crown ether complexes the primary ammonium salts, preventing its acetylation, while the secondary ammonium salts do not fit into the cavity of the crown and are to be acetylated.

13.4.11.4 Benzoin condensation Benzoin condensation can be carried out with either potassium cyanide/neat aromatic aldehyde or solid potassium cyanide/aldehyde dissolved in benzene or acetonitrile at 25-60° using 18-crown-6 or dibenzo-18-crown-6 as catalyst.

13.4.11.5 Heterocyclisation Cycloaddition of arylphosphines, arylarsines and dialkylstannanes with acetylene derivatives in the presence of [18] crown-6 and benzene results23 in the formation of heterocyclohexa-2.5-dines (Scheme 13.32).

Scheme 13.32

This method is superior to the conventional free radical method (benzene, AIBN) or to the method employing a strong base (BuLi, THF or NaNH2, NH3).

13.4.11.6 Synthesis of furanones Furanones have been prepared24 by the reaction of carboxylates with bromoaldehydes (Scheme 13.33). The first step of the reaction is an esterification of the potassium phenyl acetate followed by intramolecular addition of a carbanion to the aldehyde and final elimination.

Organic Synthesis using Crown-ethers

13.15

Scheme 13.33

13.5

CATION DEACTIVATION

The reamarkable ability of a crown ether to solvate a cation and, thus, active an anion has been considerably amplified. However, the complementary process of deactivation6 of cation is also possible in a few cases. This is illustrated by the following examples. The reduction of cyclohexanone in tetrahydrofuran with lithium aluminium hydride is very well known to give cyclohexanol. However, if a stoichiometric amount (relative to Li+) of [2.1.1] cryptat is added to the reaction mixture no reduction takes place. Lithium aluminium hydride is obviously a powerful reducting agent but requires coordination of lithium to the carboxy in order for hydride delivery to be effective (Scheme 13.34).

O O

N

O

O

N

O No cyclohexanol formed LiAIH4, THF

Scheme 13.34

Another reaction6 that involves hydride transfer is Cannazzirro reaction. When a crown either is added to an otherwise successful cannazzirro reaction, the metal ion is competitively complexed and the yield of the Cannazzirro reaction suffers. Polymer supported crown ethers have district advantage over usual crown eithers (For details see section 15.2.6).

13.6

CONCLUSION

The material presented indicates that the use of crown ether provides an excellent method for organic synthesis. The most important application is in superoxide chemistry.

13.16 Green Chemistry

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

H.D. Durst, Tetrahedron Lett., 1974, 2421. H.D. Durst, M. Milano, E.J. Kihta, S.A. Connelly and E. Grushka, Anal. Chem., 1975, 47, 1797. E. Grushka, H.D. Durst and E.J. Kihta, J. Chromatogra., 1975, 112, 673. C.J. Pedersen, J. Am. Chem. Soc., 1967, 89, 2485, 7017; 1970, 92, 386, 391. D. Sam and H.E. Simmons, J. Am. Chem. Soc., 1972, 94, 4024. G. Gokel, Crown ethers & Cryptands Monograph, Royal Society of Chemistry, Cambridge, 1991. A.L. Friedman and H. Shechter, J. Org. Chem., 1960, 25, 877: R.A. Similey and C. Arnole, J. Org. Chem., 1960, 25, 257; C.L. Liotta, F.L. Cook and C.W. Bowers, J. Org. Chem., 1974, 39, 3416. J.W. Zubrick, B.L. Dunbar and H.C. Durst. Tetrahedron Lett, 1975, 71. T.A. Bianchi and L.A. Catt, J. Org. Chem. 1977, 42, 2031. E.V. Dehmlov and Schonefeld, Liebigs Ann., 1971, 744, 42. R.R. Kostikov and A.P. Molchanov, Zh. Org. Khim., 1975, 11, 1767. M. Makosza and M. Ludwikow, Angew Chem. Int. Ed. Engl. 1974, 13, 665. D.T. Sepp, K.V. Scherer and W.B. Weber, Tetrahedron Lett., 1974, 2983. J.S. Valentine and A.B. Curtis, J. Am. chem..Soc., 1975, 97, 224. R.A. Johnson and E.S. Widy, J. Org. Chem., 1975, 40, 1680. E.J. Corey, K.C. Nicolaou, M. Shibaski, Y. Machida and C.S. Shines Tetrahedron Letty., 1975, 37, 3183. M. Makosza and M. Ludwikow, Angew. Chem. Int. Ed. Engl, 1974, 13, 655. G.W. Gokel, S.A. Di Base and B.A. Lipiska, Tetrahedran Lett., 1976, 3495. M. Cinquini, F. Montanori and P. Tundo, Chem, Commun., 1974, 878. E. Santaniello, C. Farachi and P. Pouti, Synthesis, 1970, 617. J. Sundherg, The Chemistry of Indols, Academic Press, New York, 1970. Kyba, Koga, Sousa, Siegel and Cram, J. Am. Chem. Soc., 1973, 95, 2642: Sogah and Cram, J. Am. Chem. Soc., 1970, 101, 3035. For review, see Stoddart, Prog. Macrocyclic. Chem., 1981, 2. 173. G. Market. H. Baier and R. Liebl, Synthesis, 1977, 842.

24. A. Pawda and D. Dehn, J. Org. Chem., 1975, 40, 3139.

14 14.1

Organic Synthesis using Biocatalysts

INTRODUCTION

Enzymes are known as biocatalysts. These are proteins that act as biological catalysts, i.e. these alter the rates of biochemical reactions without undergoing any permanent change in themselves. These have a high degree of specificity besides high efficiency on rates of reactions. In nature, enzymes help million of chemical reactions to occur at extraordinary speeds and under moderate conditions. In the absence of enzymes most chemical reactions that maintain a living organism would occur only under very drastic conditions, e.g. at a temperature of the order of 100° or above which would ‘kill’ the fragile cell. At normal body temperatures, these reactions would often proceed at an extremely slow rate. For example, the dissociation of carbonic acid into CO2 and H2O takes place in the lungs, proceeds only at a rate of about 107 mol dm–3 S–1 at room temperature in a test tube. On the other hand, in the cells, the enzyme carbonic anhydrase accelerates the reaction by more than a million times. Carbonic anhydrase

H2CO3 CO2 + H2O In a similar way, a single molecule of enzyme, catalyses the decomposition of about 107 molecules of H2O2, a toxic byproduct of metabolism, in one second. A comparison of the rates of the catalysed and uncatalysed reactions give an idea of the capability of the enzymes. For example: 2H2O2 2H2O2

Catalyst

Fe2+

2H2O + O2

K295 = 3.5 ¥ 107

2H2O + O2

K295 = 5.6

The most important conversions in the context of green chemistry is with the help of enzymes. Enzymes are also referred to as biocatalyst and the transformation are referred to as biocatalytic conversion. Enzymes are now easily available and are an important tool in organic

14.2 Green Chemistry synthesis. The earliest biocatalytic conversion known to mankind is the manufacture of ethyl alcohol from molasses, the mother liquor left after the crystallisation of cane sugar from concentrated cane juice. This transformation is brought about by the enzyme ‘invertase’ which converts sucrose into glucose and fructose and finally by the enzyme zymase which converts glucose and fructose into ethyl alcohol. It is well known that most of the antibiotics have been prepared using enzymes (enzymatic fermentation). The biocatalytic conversions have many advantages in relevance to green chemistry. Some of these are given below: • Most of the reactions are performed in aqueous medium at ambient temperature and pressure. • The biocatalytic conversions normally involve only one step. • Protection and deprotection of functional groups is not necessary. • The reactions are fast reactions. • The conversions are stereospecific. One of the most common examples is the biocatalytic conversions of Penicillin into 6-APA by the enzyme ‘Penacylase’ (one step process). However, the chemical conversion requires a number of steps (Scheme 14.1). H N

H

O

(1) Me3SiCl (2) PCl5/CH2Cl2 PhN Me2

H S N

O Penicillin G

N Cl

H

CO2H

H H2N

S

Penacylase H2O, 37°

H

H S

(1) n-BuOH; 40°C (2) H2O; 0°C

N O

N O

CO2H

6APA

CO2H

Scheme 14.1

A special advantage of the biochemical reactions is that they are chemoselective, regioselective and stereoselective. Also, some of the biochemical conversions are generally not possible by conventional chemical means. Two such examples in heterocyclic compounds are given in (Scheme 14.2)1. A number of diverse reactions are possible by biocatalytic processes, which are catalysed by enzymes. The major six classes of enzymes and the type of reactions they catalyse are discussed below:

Organic Synthesis using Biocatalysts CO2H

14.3

CO2H O2

N

Achromobacter xylosoclans

HO

N yield > 90%

CO2H

O2 P.obeovorans

N

N

Scheme 14.2

1. Oxidoreductases: These enzymes catalyse oxidation-reduction reactions. This class includes oxidases (direct oxidation with molecular oxygen) and dehydrogenases (which catalyse the removal of hydrogen from one substrate and pass it on to a second substrate). 2. Transferases: These enzymes catalyse the transfer of various functional groups, e.g. transaminase. 3. Hydrolases: This group of enzymes catalyse hydrolytic reactions, e.g. penteases (proteins), esterases (esters), etc. 4. Lyases: These are of two types, one which catalyses addition to double bond and the other which catalyses removal of groups and leaves double bond. Both addition and eliminations of small molecules are on sp3-hybridized carbon. 5. Isomerases: These catalyse various types of isomerisation, e.g. racemases, epimerases, etc. 6. Ligases: These catalyse the formation or cleavage of sp3-hybridized carbon. As already stated, the enzymes are specific in their action. This specificity of enzymes may be manifested in one of the three ways: (i) An enzymes may catalyse a particular type of reaction, e.g. esterases hydrolyses only esters. Such enzymes are called reaction specific. Alternatively, an enzyme may be specific for a particular class of compounds. These enzymes are referred to as substrate specific, e.g. urease hydrolyse only urea and phosphatases hydrolyse only phosphate esters. (ii) An enzyme may exhibit kinetic specificity. For example, esterases hydrolyse all esters but at different rates. (iii) An enzymes may be stereospecific. For example, maltase hydrolyses a-glycosides but not b-glycosides. On the other hand emulsin hydrolyses the b-glycosides but not the a-glycosides. It should be noted that a given enzyme could exhibit more than one specificites.

14.4 Green Chemistry

14.2

BIOCHEMICAL MICROBIAL OXIDATIONS

The oxidations accomplished by enzymes or microorganisms excel in regiospecificity, stereospecificity and enantioselectivity. The optical purity (enantiomeric excess) is usually very high nearing 100%. An unbelievable large number of enzymatic (or microbial) oxidations have been accomplished. Two important enzymatic oxidations have been very well known since early times. One is the conversion of alcohol into acetic acid by bacterium acetic in presence of air (the process is now known as quick-vinegar process) (Scheme 14.3) and the second one is the conversion of sucrose into ethyl alcohol by yeast (Scheme 14.4) (this process is used for the manufacture of ethyl alcohol). In a similar way, lactose can be converted into lactic acid (Scheme 14.5). The above enzymatic oxidations are referred to as fermentation. Bacterium acetic

CH3CH2OH + O2

CH3COOH + H2O

Ethyl alcohol

Acetic acid

Scheme 14.3

Invertase

C12H22O11 + H2O

yeast

Glucose & fructose

Sucrose C6H12O6

2C6H12O6

Invertase yeast

2C2H5OH + 2CO2 Ethyl alcohol

Scheme 14.4

C12H22O11 + H2O

Invertase yeast

Lactose

4CH3CH(OH)COOH Lactic acid

Scheme 14.5

Microbial oxidations occur under mild conditions, usually around 70° C and in dilute solution. They are slow and often take days. Considerable amount of work has been reported in the hydroxylation of aromatic rings. Thus, benzene on oxidation with Pseudomonas putida in presence of oxygen gives the cis-diol (Scheme 14.6) 2. The cis-diol obtained could be converted by four steps into 1, 2, 3, 4-tetrahydroxy compound, conduritol-F3 and by five steps into the hexahydroxy compound, pinitol, an antidiabetic agent (Scheme 14.6)4.

Organic Synthesis using Biocatalysts

14.5

OH Pseudomonas putida

O2 OH Benzene

cis-3,5-cyclohexdiene-1,2-diol (cis diol) 5 steps 4 steps OH

OH

HO

OH

HO

OH

HO

OH

OH Conduritol-F

OH Pinitol

Scheme 14.6

However, Micrococuus spheroids like organism converts benzene into trans, trans-muconic acid (Scheme 14.7) 5. CO2H

Micrococus spheroids like organism

Benzene CO2H trans, trans-Muconic acid

Scheme 14.7

In a similar way, toluene, halogensubstituted benzenes, halogensubstituted toluene gave the corresponding cis diols (Scheme 14.8) 6. X

X OH Pseudomonas putida

OH R R = H; X-Cl, Br, I, F R = CH3; X = Cl, Br, I, F R = CH3; X = H

Scheme 14.8

R

14.6 Green Chemistry The cis-diol obtained from chlorobenzene is converted into 2, 3-isopropylidene – L-ribose-glactone in four steps (Scheme 14.9) 7.

Scheme 14.9

Enzymatic conversion of ketones to esters is commonly encountered in microbial degradation 8. A typical transformation in the enzymatic Baeyer-Villiger oxidation, which converts cyclohexanone into the lactone (Scheme 14.10) using a purified cyclohexanone oxygenase enzyme9, 10. O

O Cyclohexanone oxygenase. FAD

+

O + NADP+ + H2O

NADPH, O2

Lactone

Cyclohexanone

Scheme 14.10

This enzymes also converts phenylactaldehyde into phenylacetic acid in 65% yield. Similarly, 4-methylcyclohexanone can be converted into the corresponding lactone (Scheme 14.11) in 80% yield 11 with > 98% ee with cyclohexanone oxygenase, obtained from Acineto bacter. O

O Cyclohexanone oxygenase NADPH, O2

O

Glucose-6-phosphate

Me Lactone

Me 4-Methylcyclohexanone

Scheme 14.11

In case of steroids, many different positions can be hydroxylated by different microorganisms, and usually, only one diastereomer is formed. From achiral molecules, optically active compounds are generated.

Organic Synthesis using Biocatalysts

14.7

A number of microbial reagents have been used for successful oxidation of steroids, isoprenoids, alkaloids, hydrocarbons and other type of molecules. A number of reviews and monographs are available 12. Here are given few cases which offer synthetic utility because they can afford excellent yield or they give single product that is inaccessible by other methods. Following are some typical microbial oxidations: (1) Progestesone can be converted by several microorganism 13 particularly Rhizopus nigrioans and Aspergillus ochraceus into 11a-hydroxyprogesterone. This is a commercial method of manufacturing of 11a-hydroxyprogesterone as raw material for medicinally important steriods (Scheme 14.12). (2) Hydroxylation of 9b-10a-pregna – 4, 6-diene-3, 20-dione to give the corresponding 16a-hydroxy derivative by Sepedonuim ampullosporium14. This reaction has been carried out in 81% yield on a kilogram scale (Scheme 14.13).

Scheme 14.12

Scheme 14.13

(3) Oxidation of oesterone by Gibberella fujikuroi gives 15 75% yield of 15a-hydroxy-oesterone (Scheme 14.14).

14.8 Green Chemistry O

O

H 3C

H3C

Gibberella fujikuroi

OH HO 15a-Hydroxy oestrone

Oestrone

Scheme 14.14

(4) Hydroxylation of the cholesterol by Mycobacterium sp. gives 16 cholest – 4 – en – 3 – one (Scheme 14.15). H3C

H3C Mycobacterium sp.

HO

O Cholesterol

Cholest-4-en-3-one

Scheme 14.15

(5) Allylic oxidation of 17-methyltestosterone by Gibberalla saubinetti gives 17 the corresponding 6b-hydroxy product (Scheme 14.16).

Scheme 14.16

(6) Baeyer-Villiger oxidations of steroids are accomplished biochemically. Thus, 19-Nortestosterone on treatment with Aspergilus tamarii gives 70% yield of 19-Nortestololactone 18. Progresterone and testosterone are converted into D|-dehydrotestololactone by

Organic Synthesis using Biocatalysts

14.9

fermentation with cyclindrocarpon radicicola19. Testololactone is obtained from progesterone by oxidation with Penicillium chrysogenum and from 4-androstene-3, 17-dione by treatment with penicillium lilacinum (Scheme 14.17)20.

Scheme 14.17

Sometimes, a single enzyme is capable of many oxidations. Some examples are: (i) Cyclohexanone oxygenase from Acinotobactor strain NCIB 9871 in presence of NADH (reduced nicotinamide adenine dinuleotide) coverts aldehydes into esters (Baeyer-Villiger reaction); phenylboronic acids into phenols; sulfides into optically active sulfoxides; and selenides into selenoxides (Scheme 14.18) 21. (ii) Horse liver dehydrogenase oxidises primary alcohols to acids (esters)22 and secondary alcohols to ketones 23 (Scheme 14.19). (iii) Horseradish peroxidase catalyses dehydrogenative coupling 24 and oxidation of phenol to quinones 25 (Scheme 14.20). (iv) Mushroom polyphenol oxidase hydroxylates phenols and oxidises them to quinones 26 (Scheme 14.21). Besides the above, there are a number of other examples involving the use of enzymes in oxidations 27. (v) Some important transformations (oxidations) of diols with horse liver alcohol– dehydrogenase (LHADH) using NAD are given in Table 14.1.

14.10 Green Chemistry

C6H5CH2CHO

Cyclohexanone oxygenase

Phenyl acetaldehyde

C6H5CH2COCH3

C6H5CH2CO2H + HCOOCH2C6H5 + C6H5CH2OH Phenylacetic acid (65%)

Cyclohexanone oxygenase

Benzylformate (12%)

Benzyl alcohol (23%)

C6H5CH2OCOCH3

+

O2, Enz-FAD, NADPH, H

Phenylacetone

Benzyl acetate O

(CH3)3C

Cyclohexanone oxygenase

S

S

(CH3)3C

4-tertbutyl Thiacyclohexane

cis

O

S

+ (CH3)3C Sulfoxides

O

Trans

O

Cyclohexanone oxygenase

C6H5SeCH3 Methyl phenyl selenide

(Acinetobacter sp.)

C6H5SeCH3 or C6H5SeCH3 Selenoxide

O Selenone

Cyclohexanone oxygenase

C6H5B(OH)2 Phenyl boronic acid

from acinetobacter strain NCIB 9781

C6H5OH phenol

Scheme 14.18 CH2OH Horse liver alcohol

O

dehydrogenase pH9, 20°C

CH2OH 72-77%

O

Horse liver

(±)-trans-3-methycyclohexanol

alcohol dehydrogenate

(–)–(S)–3–methylcyclohexanone 50% yield ee 100%

Horse liver

(±)-cis-3-methycyclohexanol

alcohol dehydrogenate

Scheme 14.19

(+)–(S)–3–methylcyclopentanone 55% yield ee 96%

Organic Synthesis using Biocatalysts

Scheme 14.20 Cl

Cl OH

Mushroom polyphenol oxidase

o-Chlorophenol

HO

OH 62%

Scheme 14.21

14.11

14.12 Green Chemistry Table 14.1 Substrate

Product

HO

O

OH

Ref.

100

28

100

28

100

28

100

29

96

30

O

S

OH

ee(%)

O

S OH

HO

O

O

OH

OH

OH

OH

14.3

OH

OH

OH

HO

O

O

OH

O

BIOCHEMICAL MICROBIAL REDUCTIONS

Like enzymatic oxidations, the enzymatic reductions are straightforward and highly stereoselective. Prelog was the first to study the reduction of carbonyl compounds with a number of enzymatic systems. For example, reduction of ketones with curvularia fulcata gave predictable stereochemical induction based on the groups present (large and small) in the keto group. This is known as Prelog’s rule 31. According to this rule, if the steric difference between large (L) and small (S) groups attached to the carbonyl group is large enough, the enzymes deliver hydrogen from the less hindered face to give the corresponding alcohol. O

HO

H

Enzyme

L

S

L

S

Organic Synthesis using Biocatalysts

14.13

Two most common enzymatic systems are yeast alcohol dehydrogenase (YAD) and horse liver alcohol dehydrogenase (HLADH). The selectivity observed with these enzymes is determined by non-bonded interaction of subtrate and enzymes in the hydrogen transfer transition state 31. Baker’s yeast (Saccharomyces cerevisiae) is a very common ‘reagent’ and it selectively reduces b-ketoesters and b-diketones. Thus, reduction of ethylacetoacetate with Baker’s yeast gave the (S) – alcohol. On the other hand, reduction of ethyl b-ketovalerate gave the (R) – alcohol (Scheme 14.22). It was shown that the selectivity of reduction changed from (S) selectivity with small chain esters to (R) selectivity with long chain esters32. The (S)-alcohol obtained above (Scheme 14.22) is used in the Mori’s synthesis of (S) – (+) – sulcatol 33.

Scheme 14.22

The selectivity of reduction is illustrated by the observation that 2-butanone is reduced by Thermoanaerobium brockii which gave the (R)-alcohol (2-butanol) in 12% yield and 48% ee, but the large ketones are reduced to the (S)-alcohol (85% yield and 96% ee, S)34, (Scheme 14.23). The above examples illustrate the enantioselectivity of the reduction and that selectivity depends on the size and nature of the groups around carbonyl. The (S)-alcohol obtained above (Scheme 14.23) is used in the Mori’s synthesis of (S)–(+) sulcatol33. There are a number of synthetic applications of the use of Baker’s yeast. Thus, reduction of the b-ketoester (Scheme 14.24) gave 71% yield of the alcohol, which was used in the Hoffmann’s synthesis of the cigarette beetle34a. The selectively of all these reactions is in consistent with the (S)-selectivity as predicted by Prelog’s rule. It is found that 1, 3 – diketones are normally reduced to b-ketoalcohol. Thus, 2, 4-hexanedione gave quantitatively (S)-5-hydroxy-3-hexanone (90% ee)35. The reduction of ethyl acetoacetate with Aspergillus niger gives 98% of a 75:21 mixtures favouring (R)-alcohol. This is an contrast to the formation of (S)-alcohol with Baker’s yeast or geotrichum candidum 36.

14.14 Green Chemistry

Scheme 14.23 OH

O CO2Et

CO2Et

Baker's yeast

S

S (S)-Alcohol

Scheme 14.24

Baker’s yeast reduces simple ketones37 as shown by the selective reduction of the ketonic moiety on the side cahin of the cyclopentadione to the (R)-alcohol (Scheme 14.25). The formed (R)-alcohol is used in the synthesis is norgestral 38. O

O

Me

Me

Me

Me

Baker's yeast

HO

O O

H O (R)-Alcohol

Scheme 14.25

Geranial on reduction with Baker’s yeast gave (R)-citronellol. However reduction of the Z isomer (neral) gave a 6:4 R:S mixture probably due to isomerisation of the double bond in neral prior to the delivery of hydrogen 39.

Miscellaneous Reductions Asymetric reduction of carbonyl compounds and production of isotopically labelled species has been achieved. A system based on deuterated formate and formate dehydrogenase provides the

Organic Synthesis using Biocatalysts

14.15

best system for the introduction of deuterium through nicotinamide-cofactor catalysed process40 (Table 14.2). Table 14.2 Substrate

Enzyme (cofactor)

Product (ee%)

Ref.

O T C

RO

T

HLADH (NADH)

MeO

RO

OH

H

H

OH

O

O HLADH (NADH)

42

(100%)

H

H HO

D

F3C

H (>97%)

O HLADH (NADH)

D

F3C

41

(100%)

MeO

O

H

43

OH Cl

O Cl

–

L-LDH (NaDH)

CO2

CO2–

44

(98%)

HLADH = Horse liver alcohol dehydrogenase L-LDH = L-lactic dehydrogenase

14.4

ENZYMES CATALYSED HYDROLYTIC PROCESSES

As already stated enzymes have great potential as catalysts for use in synthetic organic chemistry. The applications of enzymes in synthesis have been so far limited to relatively small number of large scale hydrolytic processes used in industry and to a large number of small scale synthesis of products used in research. Following are some of the applications of enzymes in hydrolytic processes.

14.4.1 Enantioselective Hydrolysis of Meso Diesters Pig liver esterase has been used for the enantioselective hydrolysis of the following meso substrates (Table 14.3). The enantioselective hydrolysis of the following have been achieved by hog pancreatic lipase (Scheme 14.26) 51.

14.16 Green Chemistry Table 14.3 Substrate

Product

ee(%)

Ref.

77

45

96

46, 47

100

48, 49, 50

O

O O O

O O

CO2Me CO2Me

1

CO2H CO2Me

CO2Me

CO2H

CO2Me

CO2Me

2

R

1

R

MeO2C

2

R

CO2Me

R

MeO2C

CO2H

R1 = OH, CH3, H, PhCH2OCONH R2 = CH3, H, CH2Ph, NO2, C6H5, CHMe2, cyclohexyl

CH3

CH3

AcO

CH3

CH3 OAc

AcO

OH ee 95%

CH3 AcO

CH3

CH3

CH3 OAc

HO

OAc ee 90%

Scheme 14.26

14.4.2 Hydrolysis of N-acylamino Acids The hydrolytic enzymes ‘amidases’ are useful for the hydrolysis of N-acylamino acids for the synthesis of amino acids and in the formation of amino bonds in polypeptides and proteins. In fact, this method is used in is the resolution of amino acids 52 (Scheme 14.27). O

R N H

O –

CO2

R

R

Acylase

N H

Scheme 14.27

– CO2

+ H2N

– CO2

14.17

Organic Synthesis using Biocatalysts

Some other applications in use of amidases are also given (Table 14.4): Table 14.4 Substrate 2

3

R

R Protease

+

H N

4

H2N

CO2

R HN

2

R –

1

Ref.

CO2R

O

4

CO2R R

3

53

O Ph

H N

S N

O

H2N – Penicillase PhCH2CO2 +

S N

O – CO2

–

CO2

NH2

NH2 OMe H2N O

54, 55

H N

S

S

Ph

+

O

OAcCyhalosporin

N

Acylase

CO2H

O O

OAc

N CO2H

14.4.3 Miscellaneous Applications of Enzymes (a) A number of commercial applications of Isomerases and Lyases are recorded. For example, glycosidases are used in large quantity in conversion of corn starch to glucose56 and glucose isomerase catalyses the equilibration of glucose and fructose 57. (b) Aspartic acid is prepared by addition of ammonia to fumaric acid in a reaction catalysed by aspartase 58. (c) Malic acid is obtained by hydration of fumaric acid by the enzyme fumarase 59. (d) Enantioselective condensation of HCN with aldehydes is catalysed by cyanohydrolases from several sources 60. (e) S-adenosylhomocysteine (or analogues) can be synthesised from homocysteine and adenosine (or analogues) by adenosylhomocysteine hydrolase 61. (f) Ester groups at Sn – 1 and Sn – 2 positions of glycerol moiety can be hydrolysed by phospholipases A1 and A2 respectively62. (g) L-Phenylalanine synthesised by addition of isotopivally labelled ammonia to cinnamic acid cataysed by phenylalanine ammonia lyase 63.

14.18 Green Chemistry (h) Using hydrolytic deaminations, L-citraline, L-arginine has been prepared on a large scale 64. (i) Acrylamine has been synthesised from acrylonitrile by nitrile hydratases 65. (j) D–, L– and mesotartaric acids have been synthesised by using epoxidehydrolases as shown as follow 66 (Scheme 14.28). (k) The synthesis of 5-phospho – D-ribosyl – 1-pyrophosphate, a key intermediate in the bi synthesis of nucleotide has been achieved67. (l) Enzymatic transformations have also been performed in green solvents like Ionic liquids68, supercritical carbon dioxide68, polyethylene glycol68 and fluoran solvents68. It has also been possible to perform emzyme catalysed reactions using microwaves68.

Scheme 14.28

14.5

CONCLUSION

The most important conversions in the context of green chemistry is with the help of enzymes. Most of the enzymatic reactions are conducted in aqueous medium at ambient temperature and pressure. Generally the biocatalytic conversion involves only one step. The reactions are fast and the conversions and stereospecific.

Organic Synthesis using Biocatalysts

14.19

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

9. 10. 11. 12.

13. 14. 15. 16. 17. 18. 19. 20. 21.

A. Kiener, CHEMTECH, September 1995, pp. 31-35. L.M. Shirley and S.C. Taylor, J. Chem. Soc. Chem. Commun., 1983, 954. S.V. Ley and A.J. Redgrave, J. Synlett., 1990, 393. S.V. Ley, F. Sternferd and S. Taylor, Tetrahedron Lett., 1987, 28, 225. A. Kleinzeller and Z. Fenel, Chem. Listy, 1952, 46, 300; Chem. Abstr., 1953, 47, 4290. D.T. Gibson, J.R. Koch, C.L. Schuld and R.E. Kallio, Biochemistry, 1968, 7, 3795; D.T. Gibson, M. Hansley, H. Yoshioka and T.J. Mabry, Biochemistry, 1970, 9, 1626. T. Hudlicky and J.D. Price, Synlett, 1990, 159; T. Hudlicky, H. Lund, J.D. Price and F. Rulin, Tetrahedron Lett., 1989, 30, 4053. C.J. Sih and J.P. Rosazza in Applications of Biochemical Systems in Organic Chemistry; J.B. Jones, C.J. Sih and D. Perlman, Eds, Wiley, New York, 1976; Part II, pp. 100-102; G.S. Fanken and R.A. Johnson, Chemical Oxidations with Microorganisms, Marcel Dekker, New York, 1972, pp. 157-164. C.C. Ryerson, D.P. Ballou and C. Walsh, Biochemistry, 1982, 21, 2644; N.A. Donoghu, D.B. Norris and P.W. Trudgill, Eur, J. Biochem., 1976, 63, 175. B.P. Branchand and C.T. Walsh, J. Am. Chem. Soc., 1985, 107, 2153. J.D. Blck and M.J. Taschner, J. Am. Chem. Soc., 1988, 110, 6892. Ch. Tamm, Angew. Chem., 1962, 74, 225; Angew. Chem. Int., Ed 1962, 1, 78; D. Perlan (ed.), Fermentation Advances, Academic, New York, 1969; K. Kieslich, Synthesis, 1969, 120; W. Charney and H.L. Herzog, Microbial Transformations of Steroids, Academic, New York 1967; A. Capek, O. Hanc and M. Tadra, Microbial Transformations of Steroids, Academia, Prague, 1966; M. Raynaud, Ph. Daste, F. Grossin, J.F. Biellmann and R. Wennig. Ann. Inst., Pasteur, 1960, 115, 731; H. Tizuka and A. Naqito, Microbial Transformation of Steroids and Alkaloids, University Park Press, State College, Pennsylvania, 1967; J.B. Davis, Petroleum Microbiology, Elsevier, Amsterdam, 1967; C. Ralledge, Chem. Ind., 1970, 843; L. Wallen, F.H. Stodola and R.W. Jacksom, Type Reactions in Fermentation Chemistry, U.S. Department of Agriculture, 1959, pp, 185-189; D.W. Ribbins, Ann, Rept. Chem. Soc., London, 1965, 62, 445; W.C. Evans, Ann. Rept. Chem. Soc., London, 1956, 53, 279; O. Hayashi and M. Noyaki, Science, 1969, 164, 338; D.T. Gibson, Science, 1968, 161, 1093; Grunther S. Fonken and Roy A. Johnson, Chemical Oxidations with Microorganism, Mercel Dekker, New York, 1972. D.H. Peterson and H.C. Murray, J. Am. Chem. Soc., 1952, 174, 1871; H.C. Murray and D.H. Peterson, U.S. Patent, 2, 602, 769 (July 8, 1952). W.F. Vander Waard, D. Vander Sijde and J. de Flines, Trans. Chim., 1966, 85, 712. P. Crabbe and C. Cassas Campillo, U.S. Patent, 3, 375, 175 (March 26, 1968). I.I. Zaretskaya, L.M. Kogan, O.B. Tikhomirova, Jr., D. Sis, N.S. Wulfon, V.I. Zareksu, V.G. Zaikin, G.K. Skrybin and I.V. Torgov, Tetrahedron Lett., 1968, 24, 1595. J. Ureaht, E. Vischer and A. Wettstein, Helv. Chim. Acta, 1996, 43, 1077. J.T. McCurdy and R.D. Garrett, J. Org. Chem., 1968, 33, 660. F.J. Fried, R.W. Thoma and A. Klingsberg, J. Am. Chem. Soc., 1953, 75, 5764. R.L. Prairie and P. Talalay, Biochemistry, 1963, 2, 203. B.P. Branchaud and C.T. Walsh, J. Am. Chem. Soc., 1985, 107, 2153.

14.20 Green Chemistry 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 34a. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52.

J.B. Jones and I.J. Jokovac, Org. Synth., 1984, 63, 10. J. Grunwald, B. Wirz, M.P. Scollar and A.M. Klibanov, J. Am. Chem. Soc., 1986, 108, 6732. A. Brossi, A. Ramel, J. O’Brien and S. Teitel, Chem. Pharm. Bull., 1973, 21, 1839. B.C. Saunders and B.P. Stark, Tetrahedron, 1967, 23, 1867. R.Z. Kazandjian and A.M. Klibanov, J. Am. Chem. Soc., 1985, 107, 5448. Milos Hudlicky, Oxidations in Organic Chemistry, ACS Monograph 186, American Chemical Society, Washington DC, 1990. G.S.Y. Ng., L.C. Yuan, I.J. Jakovac and J.B. Jones, Tetrahedron, 1984, 40, 1235. J.B. Jones and I.J. Jakovac, Can. J. Chem., 1982, 60, 19. J.B. Jones, Methods Enzymol, 1976, 44, 831. V. Prelog, Pure Appl. Chem., 1964, 9, 119. B. Zhou, A.S. Gopalan, F. van Middlesworth, W.R. Shiej and C.J. Sih, J. Am. Chem. Soc., 1983, 105, 5925. K. Mori, Tetrahedron, 1981, 37, 1314. E. Kienam, E.K. Hafeli, K.K. Seth and R. Lamed, J. Am. Chem. Soc., 1986, 108, 162. R.W. Hoffman, W. Helbig and W. Landner, Tetrahedron Letters, 1982, 23, 3479. J. Bolte, J.G. Gourey and H. Veschambre, Tetrahedron Lett., 1986, 27, 4051. R. Bernardi, R. Cardillo and D. Ghiringhelli, J. Chem. Soc. Chem. Commun., 1984, 460. J.K. Lieser, Synth. Commun., 1982, 13, 765. W.H. Zhou, D.Z. Hung, O.C. Deng, Z.P. Zhuang and Z.O. Wang, Nat. Prd. Proc. Sino-Am. Symp., 1980, 299; Chem. Abstr., 1983, 88, 198545w. M. Bostmembrum-Desrut, G. Dauphin, A. Kergomard, M.F. Renard and H. Veschambre, Tetrahedron., 1985, 41, 3679. C.H. Wong and G.M. Whitesides, J. Am. Chem. Soc., 1983, 105, 5012. A.R. Battershy, P.W. Sheldrake, J. Staunton and D.C. Williams, J. Chem. Soc. Perkin Trans., 1976, 1, 1056. D.R. Dodds and J.B. Jones. J. Chem. Soc. Chem. Commun., 1982, 1080. C.H. Wong and G.M. Whitesides, J. Am. Chem. Soc., 1983, 105, 5012. B.C. Hirschbein and G.M. Whitesides, J. Am. Chem. Soc. 1982, 104, 4458. Y. Ito., T. Shibata, M. Arita, H. Sawai and M. Ohno., J. Am. Chem. Soc., 1981, 103, 6739. H.J. Gais and K.L. Lukas, Angew. Chem., 1984, 96, 140; Angew. Chem. Int. Ed. Engl., 1984, 23, 142. S. Kobayashi, K. Kamiyama, T. Limori and M. Ohno, Tetrahedron Lett., 1984, 23, 2557. F.C. Huang, L.F.H. Lee, R.S.D. Mittal, P.R. Ravi Kumar, J.A. Chan and C.J. Sih, J. Am. Chem. Soc., 1975, 97, 4144; C.H. Chervenka and P.E. Wilson, J. Biol. Chem., 1956, 222, 635. Y.F. Wang, T. Izawa, S. Kabayski and M. Ohno., J. Am. Chem. Soc., 1982, 104, 6465. C.J. Francis, J.B. Jones, J. Chem. Soc. Chem. Commun., 1984, 579. Y.F. Wang, C.S. Chen, G. Girdaukas and C.J. Sih., J. Am. Chem. Soc., 1984, 106, 3695. I. Chibata, Immobilized Enzymes – Research and Development, Halsted Press, New York, 1978; Y. Izumi, I. Chibata and T. Itoh, Angew. Chem., 1978, 90, 187; Angew. Chem. Int. Ed., Engl., 1978, 17, 176.

Organic Synthesis using Biocatalysts

14.21

53. H.D. Jakubki, P. Kuhl and A. Konnecke, Angew. Chem., 1985(97); Angew Chem. Int. Ed. Engl., 1985, 24, 85. 54. B.J. Abbott, Adv. Appl. Microbiol, 1976, 20, 203. 55. D.L. Regan, M.D. Dunnill and M.D. Lilly, Biotechnol. Bioeng., 1974, 16, 333. 56. H.M. Walton, J.E. Eastman and A.E. Staly, Biotechnol. Bioeng., 1973, 447; J.H. Wilson and M.D. Lilly, Biotechnol. Biology, 1969, 11, 349; J.J. Marshall and W.J. Whelan, Chem. Ind., London, 1971, 25, 701; C. Gruesbeck and H. F. Rase, Ind. End. Chem. Proc. Res. Dev., 1972, 11, 74. 57. H.H. Weetall, Process Biochem, 1975, 10, 3; H.H. Weetall, W.P. Vann, W.H. Pitcher, Jr., D.D. Lee, Y. Y. Lee et al, Methods Enzymol, 1976, 44, 776; G.W. Strandberg and K.L. Similey. Appl. Microbiol., 1971, 21, 588; N.B. Havewala and W.H. Pitcher, Ir., Enzyme Engg., 1974, 2, 315; N.H. Mermelstein, Food Technol, Chicago, 1975, 29, 20. 58. T. Tosa, T. Sato, T. Mori, Y. Matuo and I. Chibata, Biotechnol. Biology, 1973, 15, 69. 59. K. Yamamoto, T. Tosa, K. Yamashita and I. Chibata, Eur. J. Appl. Microbiol, 1976, 3, 169. 60. W. Becker and E. Pteil, J. Am. Chem. Soc., 1966, 88, 4299. 61. B. Chabannes, A. Garib, L. Cronenberger and H. Pacheco, Prep, Biochem., 1983, 12, 395; R.C. Knudsen and I. Yall, J. Bacteriol, 1972, 112, 569; S.K. Shapiro and D.J. Ehninger, Anal. Biochem., 1966, 15, 323 62. G. Rao, H.O.O. Schmid, K.R. Reddy and J.G. White, Biochem. Biphys. Acta., 1982, 715, 205; H. Eibi, Angew. Chem. Int. Ed. Eng., 1984, 23 257 (a review). 63. A. R. Battersby, Chem. Ber., 1984, 20, 611. 64. Y. Izumi, I. Chibata and T. Itoh, Ang. Chem. Int. Ed. Engl., 1978, 17, 176. 65. Y. Asano, T. Yasunda, Y. Tani and H. Yamada, Agric. Biol. Chem., 1982, 46, 1183. 66. M. Ohno, Ferment, Ind. Tokyo, 1979, 37, 836; H. Sato, Jap. Patent 75 140 684, Japan Kokai; Chem Abstr., 1975, 84, 149212; R.H. Allen, W.B. Jakoby, J. Biol. Chem., 1969, 244, 2078. 67. A. Gross, O. Abril, J.M. Lewis, S. Geresh and G.M. Whitesides J. Am. Chem. Soc., 1983, 205, 7428. 68. V.K. Ahluwalia, Enzymes for Green Organic Synthesis, Narosa Publishing House, New Delhi, 2010, Pages 6.1-6.30 and the references cited there in.

15 15.1

Organic Synthesis using Polymer Supported Catalysts

INTRODUCTION

The advantage of using polymer supported substrates or reagents has been stated earlier (see section 1.3.6 and 11.8). Besides, these an organic reaction can also be performed by using polymer supported catalyst in those reactions where catalysts are required. The advantage of using polymer supported catalysts is that after the reaction, the unused catalyst can be recovered and used again.

15.2

POLYMER SUPPORTED CATALYSTS

Following are given some of the polymer supported catalysts commonly used.

15.2.1 Polymer Bound Anhydrous Aluminium Chloride It is prepared as follows (Scheme 15.1)

Scheme 15.1

The polymer bound anhydrous AlCl3 can be used for the formation of ethers from alcohol An example1 is given below (Scheme 15.2). Polystyrene-AlCl3 is a useful catalyst for synthetic reaction which require both a dehydrating agent and a lewis acid. Thus, acetals are obtained by the reactions of aldehyde, alcohol and polymericAlCl3 in anhydrous benzene in better yield.

15.2 Green Chemistry

Scheme 15.2

Polymenic-AlCl3 is also an effective catalyst2 for the hydrolysis of acetals, e.g., heating the diethyl acetal of o-Chlorobenzaldehyde with polymeric-AlCl3 in benzene-methanol-water (2:6:1) for 17.5 hr. yield is 61%.

15.2.2 Polymeric Super Acid Catalyst It is obtained3-5 by binding aluminium chloride to sulfonated polystyrene. By using this polymeric catalyst, cracking and isomerisation of n-hexane is possible at 357° at atmospheric pressure, which was carried out earlier in the presence of lewis acid at higher temperature and pressure.

15.2.3 Polystyrene Metalloporphyrin It is an effective catalyst6 for the oxidation of thiols to disulficles.

15.2.4 Polymer Supported Photosensitizers Photosensitizers are used in organic synthesis by supplying molecular oxygen. The various dyestuffs used as photosensitizers include Rose-Bengal, eosin-y, fluorescein etc. However, these dyestuffs have some limitations as given below: • The solvents that can be used for the reaction are limited. • The dye bleaches, in case the reaction is carried out for longer times. • The dye can sometimes react will the substractes or with the products. • The separation of the final product from the reaction mixture is diffcult. The above limitations can be overcome by using photosensitizers bound to Merrifield type resin via an ester bond7,8. It is obtained as shown below (Scheme 15.3).

15.2.5 Polymer Supported Phase Transfer Catalysts Phase Transfer catalysts have been widly used in organic synthesis (see Chapter 12). It is found that the reaction rates are slow due to difficulty in bringing the reacting species in contact with catalytic site. This difficulty has been overcome by using a long chain to bing the catalyst to the polymer matrix. The advantage of using polymer supported PTC is that by simple filtration from the reaction mixture, the recycling of the catalyst is possible. Some of the reactions involving polymer supported PTC are given below:

Organic Synthesis using Polymer Supported Catalysts

Scheme 15.3

15.2.5.1 Displacement reactions

9-11

Substitution of bromo by cyano, iodo and thiophenoxide (Scheme 15.4)

+

Scheme 15.4

The P —PTC used is P —(CH2)6 P (n-C4-H9)3 Br–

15.2.5.2 Alkylation10 Synthesis of 3-phenyl-2-heptanone (Scheme 15.5)

Scheme 15.5

15.3

15.4 Green Chemistry 15.2.5.3 Oxidation12 Dimethyl polyethylene glycol solubilises KMnO4 in benzene or methylene chloride and can be used as a PTC for KMnO4 oxidation. It oxidies terminal alkenes to the corresponding carboxylic acids with one carbon less, while nonterminal alkenes give diones, diols, Ketols and carboxylic acids. The required polymer supported PTC are obtained as follows (Scheme 15.6).

Scheme 15.6

15.2.6 Polymer Supported Crown Ethers Crown ethers have been used in organic synthesis (see Chapter 13). However use of polymer supported crown ethers give better yields and the recovered catalyst can be reused. A typical Polymer supported crown ether is synthesised9 as given below (Scheme 15.7):

Organic Synthesis using Polymer Supported Catalysts

15.5

Scheme 15.7

15.3

CONCLUSION

Polymer supported catalyst have distinct advantage over usual cataslysts in isolation of pure products and recycling of the polymer supported catalysts.

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

D.C. Neckers, D.A. Kooistra and G.W. Green J. Am. Chem. Soc., 1972, 9284. E.C. Blossey, L.M. Turner and D.C. Neckers, J. Org. Chem., 1975, 40, 959. V.L. Magnotta and B.C. Gates, J. Polym. Sci. Polym. Chem. Ed., 1977, 15, 1341. V.L. Magnotta, B.C. Gates and G.C.A. Schuit, J. Chem. Soc. Chem. Commun., 1976, 342. V.L. Magnotta and B.C. Gates, J. Catal., 1977, 46, 266. L.D. Rollmann, J. Am. Chem. Soc., 1975, 97, 2132. E.C. Blossey, D.C. Neckers, A.L. Thayes and A.B. Schapp, J. Am. Chem. Soc., 1973, 95, 5820. A.P. Schapp, A.L. Thayer, E.C. Blossey and D.C. Neckers, J. Am. Chem. Soc., 1975, 97, 3741. M. Cinouini, S. Colonna, H. Moliniari and F. Montanari, J. Chem. Soc. Chem. Commun., 1976, 394. 10. P. Tudo, synthesis, 1978, 315. 11. P. Tudo, J. Chem. Soc. Chem. Commun., 1977, 641. 12. D. G. Lee and V.S. Chang, J. Org. Chem, 1978, 43(8), 1532.

Part VII Some Examples of Green Synthesis using Basic Principles of Green Chemistry

16 16.1

Some Examples of Synthesis Involving Basic Principles of Green Chemistry

INTRODUCTION

It has already been stated (Chapter 1) that most of the chemical synthesis (whether in laboratory or industry) release harmful gaseous products and other byproducts, which are responsible for the pollution of the environment. In order to prevent these, the basic principles of green chemistry (as stated in section 1.1.) should invariably be followed. In any chemical synthesis special efforts should be made to keep into account the atom economy, i.e., there should be maximum incorporation of the reactants and reagents into the formed product. It is, of course, best to perform a reaction in water or in solid state or if necessary to use a organic solvent. One should use green solvent like ionic liquid, super critical carbon dioxide, polyethylene glycol etc, which are environmentally benign. Special care should be taken to use minimum amount energy and that the energy be provided by microwaves, sonication or photoactivation. It is equally important to use catalyst (whenever necessary) and to use reagents which are environmentally benign.

16.2

SOME EXAMPLES OF GREEN SYNTHESIS

Following are given some typical examples of green synthesis.

16.2.1 Synthesis of Adipic Acid Adipic acid is an important intermediate for the manufacture of Nylon 66. It is required in large quantifies (about 1 billion kg per year). So far, most industrial preparation produces adipic and involving nitric acid oxidation of cyclohaxanol or cyclohexene or both1. In these processes there is considerable emission of oxides of nitrogen, which cause environmental pollution. An elegant, environmentally benin synthesis2 of adipic acid from cyclohexene in polyethylene glycol based on aqueous biphasic system using sodium tungstate and hydrogen peroxide (Scheme 16.1)

16.4 Green Chemistry

Seheme 16.1

The above synthesis is cost effective and with the additional advantage is the recyclability of the catalyst.

16.2.2 Synthesis of Adiponitrile It is an important raw material for the synthesis of hexamethylene diamine and adipic acid required for the synthesis of Nylon 66. It is synthesised by the electroreductive coupling3 of acrylonitrile. In this procedure a concentrated solution of certain quaternary ammonium salts (QASs), such as tremethylammium-ptoluenesulfonate is used together with lead or mercury cathode (Scheme 16.2).

Scheme 16.2

16.2.3 Synthesis of Ibuprofen Ibuprofen is used in large quantities for making drugs used mostly an analgesics (pain killers). On an average, 30 million pounds of ibuprofen is used per year worldwide. It was earlier synthesised by a proess developed by Boots company of England (U.S. Patent, 3, 385, 886; 1960) as shown below using a six step synthetic procedure (Scheme 16.3). In the above synthesis large quantities of waste products are formed, which creates disposal problems. Also, the overall atom economy is 40%. Subsequently BHC company developed a greener synthesis4 of ibuprofen consisting of only three steps (Scheme 16.4). In the above synthesis only small amounts of waste is generated and the atom economy is 77%.

16.2.4

Synthesis of Methyl Methacrylate

Methyl methacrylate is a monomer used for the manufacture a thermoplastic polymer, poly (methyl methacrylate). It was earlier synthesised using stoichiometric amounts of hydrogen cyanide and sulfuric acid5 (Scheme 16.5) and had 47% atom economy.

Some Examples of Synthesis Involving Basic Principles of Green Chemistry

Scheme 16.3 Synthesis of Ibuprofen (Boots company, 1960)

Scheme 16.4 Green synthesis of Ibuprofen (BHC company)

16.5

16.6 Green Chemistry

Scheme 16.5 Earlier synthesis of methyl methacrylale (47% atom ecomomy)

Subsequently, a green synthesis of methyl methacrylate was developed (Scheme 16.6), which is 100% atom economical

Scheme 16.6 Green synthesis of methyl methacrylate (100% atom economy)

16.2.5 Synthesis of Sebacic Acid Sebasic acid is an important intermediate for the manufacture of polymide resin. A typical example is the manufacture of Nylon 610 by the condensation polymerisation of hexamethylene diamine (C6 monomer) and sebasic acid (C10 monomer) (Scheme 16.7)

Scheme 16.7

Sebasic acid was obtained on a large scale by the saponification of castor oil. It is now obtained by a electrochemical process involving the following steps (Scheme 16.8)6

Scheme 16.8

Some Examples of Synthesis Involving Basic Principles of Green Chemistry

16.7

In the above synthesis, anodic coupling of the monomethyl ester of adipic acid takes place. The electrolyte is a 20% aqueous solution of monomethyl adipate, neutralised with sodium hydroxide. The anode is platinum-plated with titanium and cathode is of steel6.

16.2.6 Synthesis of Polyaspartate Polyaspartate, a biodegradable polymes is used as a scale inhibitor, dispersing agent and for inhibition of corrosion. It also finds use in agriculture as a nutrient uptake enhancer7. It is obtainted8 by the condensation of aspartic acid followed by alkaline hydrolysis of the formed polysuccinimide (Scheme 16.9).

Scheme 16.9 Donlar corporation synthesis of polyaspartate

The hydrolysis of poly succinimide takes place at two position as shown in the Scheme 16.9.

16.2.7 Synthesis of Alcohols A green synthesis of alcohols involves solid state crossed cannizzaro reaction. The procedure9 consist in heating an aldehyde (which does not have a free a-hydrogen with barium hydroxide [Ba(OH)2. 8H2O] with paraformaldehyde in a MW Owen (Scheme 16.10). Using this method, a large number of aromatic aldehydes including heterocyclic aldehydes could be converted into the corresponding alcohols.

Scheme 16.10

16.8 Green Chemistry

16.2.8 Alkylation of Reactive Methylene Compounds Compounds containing reactive methylene group can be alkylated10-12 by heating with alkyl halide in presence of potassium hydroxide-potassium carbonate and a phase transfer catalyst (tetrabutyl ammonium chloride, TBAC) without any solvent (Scheme 16.11).

Scheme 16.11

16.2.9 Synthesis of 2-aroylbenzofurans Naturally occuming, pharmacologically important 2-aroylbenxofurans are syntheyed13 under solvent free conditions from a-toyloxyketones and salicyaldehydes in presence of potassium fluoride doped alumina under MW irradiation (Scheme 16.12).

Scheme 16.12

16.2.10 Synthesis of Aromatic Nitriles A single step conversion14,15 of aryl aldehydes to aromatic nitriles is effected by microwave irradiation of the aldehyde in presence of K10 clay-NH2OH.HCl (Schme 16.13). O C R

C H K10 Clay

NH2OH.HCl

MW , 1-1.5 min

P 89 – 95%

Scheme 16.13

N

Some Examples of Synthesis Involving Basic Principles of Green Chemistry

16.9

16.2.11 Synthesis of -Tosyloxy -Ketosulfones a-Tosyloxy b-Ketosulfones are potentially very useful precursors in organic synthesis, particularly for heterocyclic compounds16. A green procedure17 for their synthesis consist in grinding together a neat mixture of a-benzene sulfonyl-actophenone and [hydroxyl (tosyloxy) iodo] benzene [H.T.B] at room temperature using a pestle and mortar (Scheme 16.14).

Scheme 16.14

16.2.12 Synthesis of Quinoxalines Quinoxalines and their derivatives are used as curatorial intermediates, bacteriocides and insecticides18. These compounds are synthesised19 in a one pot reaction at room temperature from substituted o-phenylene diamine and oxalic acid under solvent free conditions by simple grinding at room temperature (Scheme 16.15). This is a green synthesis involving 100% atom economy.

Scheme 16.15

16.2.13 Synthesis of Cyclohexane Oxime Cyclohexane oxime is an important intermediate for the synthesis of caprolactam, the monomer of nylon 6. It is obtained20 by photoirradiation of cyclohexane with nitrosyl chloride (Scheme 16.16).

16.2.14

Synthesis of Lauryllactam

Lauryllactam, the monomer of nylon 12 is obtained21 by the photoirradiation of cyclododecane with nitrosyl chloride, followed by treatment of the formed oxime with acid (Scheme 16.17).

16.2.15 Synthesis of 1-Octanol 1-Octanol is obtained on industrial scale by the oxidation of n-octane using the enzyme Psuedomonas oleovorans22 (Scheme 16.18).

16.10 Green Chemistry

Scheme 16.16

Scheme 16.17

Scheme 16.18

16.2.16 Synthesis of 6-APA 6-APA is the most important intermediate required for the synthesis of semi-synthetic penicillins. It is obtained from Penicillin G by biocatalytic conversion using the enzyme Penacylase (Scheme 16.19).

16.2.17 Synthesis of 1-acetylnaphthalene Normally Friedel crasfs reaction of naphthalene with acetyl chloride in presence of anhydrous AlCl3 gives the 2-acetyl naphthalene. However, acetylation of naphthalene in choroaluminate ionic liquids gives23 89% of the thermodynamically unfavoured 1-isomer (Scheme 16.20).

Some Examples of Synthesis Involving Basic Principles of Green Chemistry

16.11

Scheme 16.19

Scheme 16.20

16.2.18 Synthesis of 11 -Hydroxy progesterone 11a-Hydroxy progesterone is an essential intermediate for the synthesis of medicinally important steroids. It is manufactured24 from progesterone by treatment with the enzyme Aspergillus ochraceus (Scheme 16.21).

Scheme 16.21

16.2.19 Synthesis of 3-phenylcatechol Catechols are important building blocks for chemicals and pharmaceutical industries. Chemical procedures are difficult. However, these can be obtained biochemically. Thus 3-phenyl catatechol is prepared25 as follows (Scheme 16.22).

16.12 Green Chemistry

Scheme 16.22

16.2.20 Synthesis of Prednisolone Prednisolone, a cortisone analog, used as a drug against rheumatoid arthritis is obtained on a commercial scale as shown below (Scheme 16.23)

Scheme 16.23

References 1. D.D. Davis and D.R. Kemp, Adipic acid in Kirk-Othmer Encyclopedia of Chemical Technology, J.L. Kroschwiz and M. Howe-Grant Eds, Willy, New York, 1991, Vol 1, P. 466. 2. Y. Deng, Z. Ma, K. Wang and J. Chen, Clean synthesis of adipic acid by direct oxidation of cyclohexene with H2O2 over peroxytungstate-organic complex catalysts, Green Chem. 1999, 1, 275. 3. D.E. Danly and C.J.H. King in Organic Electrochemistry, 3rd ed, H. Lund and M.M. Baizer, eds, Marcel Dekkar, New york, 1991; M.M. Baizer and D.E. Danly, Chemtech, 1980, 10(3), 161. 4. U.S. Patents, 4,981,995 and 5, 068, 448; 1991.

Some Examples of Synthesis Involving Basic Principles of Green Chemistry

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

16.13

Tropchiev, Pavlov, Chem. Abstr., 1953, 47, 8002h; Domingue et al, J. Chem. Ed., 1952, 29, 446. T. Isoya, R. Kakuta and C. Kawamura, U.S. Patent 3, 896, 611(1975)-Asahi Kasu. A.P. Wheeler and L.P. Koskan, Mat. Res. Soc. Sympn. Proc. 1993, 292, 277. Paul T. Anastas and John C. Warner, Green Chemistry, Theory and Practice, Oxford University Press, Newyork, 1998. R.S. Varma, K.P. Naicker and P.J. Liesen, Tetrahedran Lett, 1998, 39, 8437. D. Ruhua, W. Guliang and J. Yao, Synth. Commun, 1994, 24(i), 111. D. Ruhua, W. Yuliang and Y. Yaozhong, Synth. Commun, 1994, 24(13), 1917. B. Perio, M.J. Dozias, P. Jacquanult and J. Hamilin, Tetrahedron Lett, 1997, 38, 7867. R.S. Varma, R.K. Saini and D. Kumar J. Chem. Res.(S), 1998, 348. R.S. Varma and K.P. Naicker, Molecules on line, 1998, 2, 94. R.S. Varma, K.P. Naicker, D. Kumar, R. Dahiya and P.J. Liesen, J. Microwave Power Electromag. Energy, 1999, 34, 113. K.F. Koser, A.G. Relenyl, A.N. Kalos, L. Rebrovic and R.H. Wettach, J. Org. Chem.., 1982, 47, 2487; R.M.Moriaty, R.K. Vaid and G.F. Roser, Synlett., 1990, 365. Dalip Kumar, M. Swapna Sundaree, G. Patel, V.S. Rao and R.S. Varma, Tetrahedron Lett., 2006, 47, 8239 and the references cited there in. M.G. Moloney, Nat. Prod. Rep., 2002, 19, 597. H. Thakuria and G. Das, J. Chem. Soc., 2006, 118, 425. P. Turner, Inf. Chins, 1970, 9(5, 6), 51; P. Hurine, P.E. Turner, Chem. Process Eng., 1967, (11), 96; Y. Ito, Y. Hara, DASI 1962, 468, 737, Torary. Inf. Chim., 1970, 8(3, 4), 47. R.G. Mathys, O.M. Kuts and B. Withott, J. Chem. Tech. Bioeng, 1998, 71, 315. C.J. Adams, M.J. Earle, G. Roberts and K.R. Seddon, Chem. Commun., 1998, 2097. D.H. Peterson and H.C. Murray, J. Am. Chem. Soc., 1952, 174, 1871; H.C. Murray and D.H. Peterson, U.S. Patent 2,602,769 (July 9, 1952). H-P.E. Kohler, D. Staubkohler and D.D. Focht, Appl. Environ. Microbology, 1988, 54, 2683. K. Mosbach and P.O. Larsson, Biotechnol. Bioeng., 1970, 13, 19.

Index

A 1-Acetylnaphthalene 4.30, 16.10 Activated MNO2-Silica 7.27 Activation of Nickel Powder 9.41 Addition Reactions 1.6, 9.9 Additions 9.19 Adipic Acid 5.20, 16.3 Adiponitrile 2.49, 16.4 Air Oxidations 12.45 Alcohols 12.8, 16.7 Aldehydes 12.24 Aldol Condensation 2.15, 2.60, 5.13, 9.22 Aldol-Tischeno Reaction 5.12 Aliphatic Claisen Rearrangement 2.12 C-Alkylations 9.23, 12.21, 13.12 Alkylation 4.9 Alkylation of Reactive Methylene Compounds 16.8 Alkylations 7.64 S-Alkylations 9.24, 12.27 Alkyl Fluorides 12.7 Alkyl Nitrates 12.9 Allylation 4.10 4-Aminoquinazolines 7.50

Ammoniolysis 4.36 Annulation 9.6 Anti Dihydroxylation of Alkenes 2.31 Aromatic Substitution 13.6 Aromatisation 7.31 2-Aroylbenzofurans 16.8, 12.34 Arylamides 9.47 Aryl Ethers 12.10 3-Aryl-2H-1, 4-Benzoxazines 12.34 1-Arylbenzimidazolines 12.38 3-Arylcoumarins 12.33 Z-Aspartame 4.34 Aspirin 7.69 Asymmetric Aldol Reactions 5.10 Asymmetric Dihydroxylation 2.32, 4.12 Asymmetric Transfer Aldol Reaction 5.12 Atom economy 1.6 6-APA 16.10 Aza Crown Ethers 13.1, 13.2 Aza-Diels-Alder Reaction 2.9 Azides 12.9 Aziridines 7.42 Azo compounds 5.17 Azoles 7.43

I.2 Index B Backmann Rearrangement 7.36 Baeyer’s Test 2.30 Baeyer-Villiger Oxidation 2.34 Balis-Hillman Reaction 3.29 Barbier Reaction 9.35 Baylis-Hillman Reaction 2.61, 4.5 Benzil-Benzilic Acid Rearrangement 7.37 Benzimidazoles 7.42 Benzion Condensation 12.28 Benzofurane-1-Oxides 12.38 Benzoin Condensation 2.20, 2.60, 13.14 1, 3-Benzoxathioles 12.36 1, 4-Benzoxazines 12.36 Benzoyl Cyanides 12.7 Biginelli Reaction 4.27 Biocatalysts 14.1 Biochemical (Microbial) Oxidations 14.4 Biochemical (Microbial) Reductions 14.12 Biotransformations 3.29 Birkeland Iyde Process 11.5 b-Keto Sulfones 7.6 b-Lactams 7.52 b-Nitrostyrene 7.56 Bouveault Reaction 9.33 Bridgenhead Nitrogen Heterocyclic Compounds 7.59 Bromination 3.9 Brønsted Acidic Ionic Liquids 4.22 C Cannizzarro Reaction 9.34 Caprolactam 4.24 Carbamate Synthesis 3.28 Carbenes 13.9 Carbethoxynitrines 12.18 Carbon Dioxide 3.1 Carbonylation 12.20

Catalysis 7.34, 9.51 Chlorides 12.17 Chromate Oxidation 12.42 Claisen Rearrangement 2.12 Claisen-Schmidt Condensation 2.21, 4.7 Clayfen 7.27 Clemmensen Reduction 9.27 Condensations 7.65 Coupling Reactions 3.21 Crossed Cannizzaro Reaction 7.34 Crown Ethers 13.1 Crypates 13.1 Cryptands 13.1, 13.3 Cryptates 13.3 Curtius Rearrangement 9.5 3-Cyanobenzamide 4.34 3-Cyanobenzoic Acid 4.34 Cyclic Carbonates 4.27 [2 + 2] Cycloaddition Reactions 9.12 Cycloaddition Reactions 9.13 Cyclocondensations 9.37 Cyclohexance Oxime 16.9

D Dakins Oxidation 11.7 Darzen’s Reaction 12.29 Debenzylation 7.20 Decarboxylation 5.22 Decetylation 7.20 Decon Process 11.4 Dehalogenation 9.48 Dehydrohalogenation 12.18 Dehydroisophytos 3.12 Deoximation Reactions 7.22 Designer Solvents 4.1 Desilylation Reactions 7.22 Dethioacetalization 7.22

Index

Dethiocarbonylation 7.23 Diazomethane 12.14 Dichlorocarbene 9.32 Dichlorooxiranes 12.18 Dieckmann Cyclisation 9.36 Diels-Alder Reaction 2.6, 3.7, 4.16, 5.3 Dihalocarbenes 12.12 Dihydroisophytol 3.12 Dihydropyrans 12.36 Syn-Dihydroxylation 2.30 Diimide 2.39 1, 2-Diketones 7.29 2, 6-Dimethyl Pyridine 12.22 Dimethylcarbonate 11.10 Dioxiranes 11.7 1, 3-Dipolar Cycloaddition 9.9 Displacement Reactions 13.7, 15.3 Doebner Modification 2.17 E Eglinton Coupling 2.55 Electrochemical Carboxylation 3.29 Electrochemical Synthesis 1.12, 2.48 Electrophilic Addition 9.12 Elimination Reactions 1.7, 13.7 Enamines 7.31 Enantioselective Aminolysis 2.50, 4.39 Enantioselective Hydrolysis 4.38 Enantioselective Hydrolysis of Meso Diesters 14.15 Enantroselective Esterification 4.38 Environmentally Benign Solvent 1.12 Enzymatic Baeyer-Villiger Oxidation 14.6 Enzymatic Reactions 5.20 Enzymes 14.1 Enzymes Catalysed Hydrolytic Processes 14.15 Epoxidation 2.26 Epoxides 4.36 Esterification 9.13 Eugenol 7.38

I.3

F Favorskii Rearrangement 13.8 Fermentation 14.4 Finkelstein Exchange Reaction 9.16 Fishcher Indole Synthesis 7.63 Fisher Cyclisation 8.25 Flavones 7.54 Formamides 12.14 Formamidine Sulfinic Acids 12.47 Free Radical Bromination 3.5 Freidel-Crafts Reaction 3.10, 4.16 Friedel-Crafts Acylation 9.17 Friedlander Condensation 7.48 Fries Rearrangement 7.37 Furanones 13.14 Furans 7.54 G Geranyl Acetate 4.37 Glasar Coupling 2.55 Graebe-Ullmann Reaction 7.62 Green Chemistry 1.4 Green Synthesis 1.4 , 1.11 Grignard Reaction 1.5, 7.5 Grignard Reagents 9.7 H Halohydrins 4.25 Heck Coupling Reaction 2.62 Heck Reactions 2.22, 2.24, 3.21, 3.22, 4.14, 5.14, 7.61 Henry Reaction 3.23, 4.20 Heterocyclisation 13.14 Hetero-Diels-Alder Reactions 2.8 Hoffmann Elimination 1.5 Hoffmann Elimination Reaction 1.7 Hofmann Carbylamine Reaction 13.10 Homoallylic Amines 4.28 Horner-Wadsworth-Emmons reaction 2.13, 4.8 Hydantoin Derivatives 12.37

I.4 Index Hydride Reductions 12.46 Hydroalkylation 9.29 Hydroboration 9.29 Hydrocyanation 9.19 Hydroformylation 3.14, 9.19 Hydrogenations 3.11, 4.13 Hydrogen Peroxide 11.7 Hydrolases 14.3 Hydrolysis 9.8 Hydrolysis of N-acylamino Acids 14.16 Hydrosilation 9.29 11a-Hydroxy Progesterone 16.11 Syn-Hydroxylation 2.30 Hydroxybutenolides 12.39 Hypochlorite Oxidation 12.43 I Ibuprofen 16.4 Indoles 2.52 Intramolecular Diels Alder Reaction 8.25 Inverse Phase Transfer Catalyst 2.43 Iodobenzene Diacetate (IBD) 7.28 Ionic liquids 1.13 Isoeugenol 7.38 Isoflavan-3-Enes 7.55 Isomerases 14.3 Isomerisation 9.5 Isomerisation Reactions 7.37 Isophytol 3.12 Isoxazoles 7.47 K Ketones 12.23 a-Keto-Thinoesters 9.48 Knoevenagel Condensation 4.6 Knoevenagel Reaction 2.17, 2.60 Kolbe-Schmitt Synthesis 3.9 Kolbe Synthesis 2.50 Koser’s Reagent 7.9

L L-Ascorbic Acid 4.37 Lauryllactam 16.9 Lawesson’s Reagent 7.25 Ligases 14.3 Lindlar Catalyst 2.41 Lindlar Reactions 3.11 Longifolene 8.25 Lyases 14.3 M Maltol 2.50 Mandelic Acids 12.17 Mannich-Type Products 2.59 Mannich Type Reactions 2.50 Markovnikov Addition 4.25 Mercaptans 12.28 Methylenation 7.57 Methylene Insertion Reactions 4.31 Methyl Methoacrylate 16.4 Michael Addition 4.25, 7.58 Michael Reaction 2.14 Mizoroki-Heck Arylation Reaction 3.22 Moffatt Oxidation 11.12 Morita-Baylis-Hillman Reaction 3.23 Mukaiyama Reaction 2.16, 2.21 N N-Alkylations 7.18, 9.22, 12.25, 13.13 Nanoparticles 3.27 N-Aryl-2-Cyanoaziridines 12.38 Negishi Cross Coupling Reaction 4.19 Nitriles 12.6, 12.15, 16.8 N-Sulfonylimines 7.41 O O-Alkylations 9.23, 13.10 Octadienols 2.52 1-Octanol 16.9

Index

Organoaluminium Compounds 9.43 Organolithium Compounds 9.42 Organometallic Compounds 9.42 Organometallic Reactions 9.6 Organozinc Compounds 9.44 Ortho-Ester Claisen Rearrangement 7.63 Osmium Tetroxide 12.43 Ostwalds Process 11.5 Oxadiazines 7.51 Oxidation 12.41, 15.4 Oxidation Reactions 5.9 Oxidations 2.26 Oxidative Carbonylation 4.12 Oxidative Coupling 7.57 N-Oxides 7.16 Oxidoreductases 14.3 Oxindol 12.22 Oxone 2.35 Oxygen 11.3 Oxymercuration 9.40 Ozone 11.6 P Palladium Compounds 9.44 Pauson-Khand Reaction 2.58, 3.27 Payne’s Reaction 2.29 Pechmann Condensation 4.23 PEG as Phase-Transfer Catalyst 5.6 Pericyclic Reactions 2.6, 2.19 Permanganate Oxidation 12.41 Peroxides 12.45 Peroxycarbonic Acid 3.17 Phase transfer Catalysts 2.43, 12.3 Phase Transfer Hofmann Carbylamine Reaction 12.14 3-Phenylcatechol 16.11 Photochemical Reactions 1.14, 3.26 Photocyanation 13.13 Pinacol 2.50

I.5

Pinacol Coupling 2.19, 11.18 Pinacol-Pinacolone Rearrangement 4.22, 7.36 Piperazine-2, 5-Diones 12.37 Piperazinones 12.38 Polyaspartate 16.7 Polyethylene Glycol 1.13 Polymer Bound Anhydrous Aluminiuon Chloride 15.1 Polymeric Organotin Dihydride Reagent 11.11 Polymeric S-chloro Sulfonium Chloride 11.10, 11.18 Polymeric Sulfonazide 11.14 Polymeric Super Acid Catalyst 15.2 Polymeric Wittig Reagent 11.14 Polymerisations 3.9, 3.34 Polymer Supported Catalysts 15.1 Polymer Supported Catalytic Reaction 1.17 Polymer Supported Chromic Acid 11.18 Polymer Supported Crown Ethers 15.4 Polymer Supported Peptide Coupling Agent EEDQ 11.17 Polymer Supported Peracid 11.17 Polymer Supported Phase Transfer Catalysts 15.2 Polymer Supported Photosensitizers 15.2 Polymer Supported Reagents 1.16 Polymer Supported Substrates 1.16 Polymer Supported Trisubstituted Phosphine Dichloride 11.12 Poly-N-bromosuccinimide (PNBS) 11.11 Polystyrene Anhydride 11.14 Polystyrene Carbodiimide 11.12 Polystyrene Metalloporphyrin 15.2 Polystyrene Sulfide 11.16 Potassium Ferricyanide Oxidation 12.44 Potassium Permanganate Oxidation 13.5 Potassium Superoxide 9.38 Prednisolone 16.12 Prelog’s Rule 14.12 Prins Reaction 2.53

I.6 Index Psuedomonas Oleovorans 2.32 Pyrazoles 7.43 Pyridines 7.48 Pyrimidines 7.50 2-Pyrones 3.27 Pyrroles 7.43 Q Quick-Vinegar Process 14.4 Quinolines 2.52, 12.16 Quinolones 7.49 Quinoxaline Derivatives 7.5 Quinoxalines 7.49, 16.9 R Radical Reactions 3.18 Radioactive Halides 12.8 Rearrangement Reactions 1.6 Reduction 12.46 Reduction by Diborane 12.46 Reduction Reactions 5.5 Reductions 5.9 Reductive Amination 7.33 Reformatsky Reaction 7.5, 9.34 Resolution 13.13 Retro Aza-Diel-Alder Reactions 2.10 Ring Expansion 7.36 S Sakuai Reaction 4.20 Sandmeyer Reaction 5.3 Saponification 7.25, 3.21, 13.4 Sebacic Acid 2.49, 16.6 Selective Hydrogenation 4.30 Sharpless Asymmetric Oxidation 3.17 Sharpless Reaction 5.4 Silica Nanoparticles 3.27 Silicon Reagents 7.68

Silyl-Reformatsky Process 7.68 Simmons Smith Cyclopropanation 9.46 Simmons-Smith Reagent 9.20 Singlet Oxygen 11.5 Sodium Alkyl Sulphonates 12.9 Sodium Borohydride 7.32 Sodiumphenylselenide 9.47 Solid State Crossed Cannizzaro Reaction 16.7 Solvolysis 9.8 Sonochemical Barbier Reaction 9.35 Sonochemistry 1.14, 9.1 Sonogashira Coupling Reaction 7.61 Sonogashira Reaction 4.21 Sonolysis of Fe(CO)5 9.39 Spiroketones 9.48 Stetter Reaction 4.21 Still Coupling 3.21 Still Coupling Reactions 3.21, 4.19 Stille Reaction 2.62 Strecker Reaction 9.9 Strecker Synthesis 2.25, 9.34 Styrene 3.28 Substitution Reactions 1.6 Substitutions 9.16 Sulfones 7.30 Sulfoxides 7.30 Sulfonates 12.9 Sulphur Extrusion 9.5 Sulphur Ylids 12.33 Super Critical Carbon Dioxide 1.13, 3.2 Supercritical Polymerisations 3.5 Superoxide Anion 13.10 Suzuki Coupling 2.62 Suzuki Coupling Reaction 4.18 Suzuki Cross Coupling 7.60 Suzuki Cross-Coupling Reaction 5.17, 7.60, 7.61 Symmetric Urea Derivatives 4.28

Index

T Task-Specific Ionic Liquids 4.21 a-Terpinol 9.40 The Reformatsky Reaction 9.34 Thia Crown Ethers 13.1, 13.2 5-Thiacyclohexane Carboxaldehyde 12.39 Thiadiazepines 7.51 Thia-Fries Rearrangement 7.37 Thiazoles 7.47 Thietanes 12.37 Thiiranes 4.26 Thioamides 9.51 Thiocyanates 12.9 Thiocyanation 4.27 Thioethers 12.10 Thionotion Reactions 7.25 Thiophenols 12.28 Todalid 4.30 a-Tosyloxy b-keto Sulfones 7.8, 16.9 p-Toluene 12.9 Transesterification 3.31 Transfer Aldol Reaction 5.12 Transferases 14.3 Transmetalation 9.44 Traseolide 4.30 Trialkyl Boranes 9.44 Triazines 12.39 Trost-Tsuji Coupling Reaction 4.20

U Ullmann Coupling 9.31 a, b-Unsaturated Nitroalkenes 7.41 Ultrasonically Dispersed Potassium 9.41 Ultrasound 1.14, 9.1 Urea-Hydrogen Peroxide Adduct (UHP) 7.9 V Vinyl Carbenes 12.18 Vinylidene Carbenes 12.17 W Wacker Reaction 3.23 Wacker-Type Oxidation 4.13 Water 1.12 Weiss-Cook Reaction 2.50 Weitz-Scheffer Epoxidation 2.28 Wieland-Miescher Ketone 2.14 Wilkinson Catalyst 7.61 Williamson Ether Synthesis 5.6, 12.30 Wittig-Horner Reaction 2.12, 12.32 Wittig Reaction 2.12, 12.31 Witting Olefination Reactions 7.39 Witting Reaction 1.5 Wolff-Kichner Reduction 7.41 Wurtz Coupling 2.26 Wurtz Reaction 2.26 Z Zelinsky-Stadnikoff Modification 2.25

I.7