Advanced Practical Organic Chemistry

Advanced Practical Organic Chemistry

Dedicated to Professor Gi/bert Stork In recognition ofthe skills and enthusiasmfor chemistry gained in his laboratories

ADV ANCED PRACTICAL ORGANIC CHEMISTRY M.CASEY J.LEONARD B. LYGO Department of Chemistry and Applied Chemistry University of Salford G. PROCTER George Ramage Professor of Chemistry University of Salford Springer Science+Business Media, LLC

1990 Springer Science+Business Media New York First Published 1990 Originally published by Blackie and Son Ltd in 1990. All rights reserved. No part 01 this book may be reproduced, stored in a retrieval system, or transmitted, in any lorm or by any means, electronic, mechanical, recording or otherwise without prior permission 01 the Publishers British Library Cataloguing in Publication Data Advanced practical organie chemistry. 1. Organie chemistry. Laboratory techniques I. Casey, M. 547'. 0028 ISBN 978-0-216-92796-4 ISBN 978-1-4899-6643-8 (ebook) DOI 10.1007/978-1-4899-6643-8 For the USA, International Standard Book Number is 0-412-02461-6

Preface The preparation of organic compounds is central to many areas of scientific research, from the most applied to the most academic, and is not limited to ehemists. Any research which uses new organic chemicals, or those which are not available commercially, will at some time require the synthesis of such compounds. This highly practical book, covering the most up-to-date techniques commonly used in organic synthesis, is based on our experience of establishing research groups in synthetic organic chemistry and our association with some of the leading laboratories in the field. It is not claimed to be a eomprehensive compilation of information to meet all possible needs and circumstances; rather, the intention has been to provide sufficient guidance to allow the researcher to carry out reactions under conditions which offer the highest ehance of success. The book is written for postgraduate and advanced level undergraduate organie chemists and for chemists in industry, particularly those involved in pharmaeeutical, agrochemical and other fine chemicals research. Biologists, biochemists, genetie engineers, material scientists and polymer researchers in university and industry will find the book a useful source of reference.

Contents 1 General Introduction 1 2 Keeping records of laboratory work 3 2.1 Introduction 3 2.2 The laboratory notebook 3 2.2.1 Why keep a lab book? 3 2.2.2 How to write a lab book 4 2.2.3 Suggested notebook format 5 2.3 Keeping records of data 8 2.3.1 What type of data should be collected 8 2.3.2 Formats for data records 9 3 Equipping the laboratory and the bench 13 3.1 Introduction 13 3.2 Setting up the laboratory 13 3.3 Generallaboratory equipment 14 3.4 The individual bench 20 3.4.1 Routine glassware 20 3.4.2 Personal items 21 3.4.3 Specialized personal items 21 4 Purification and drying of solvents 28 4.1 Introduction 28 4.2 Purification of solvents 28 4.3 Drying agents 29 4.4 Drying of solvents 33 4.5 Solvent stills 39

viii Contents 5 Reagents: purification and handling 43 5.1 Introduction 43 5.2 Classification of reagents for handling 44 5.3 Techniques for obtaining pure and dry reagents 45 5.3.1 Purification and drying ofliquids 45 5.3.2 Purifying and drying solid reagents 48 5.4 Techniques for handling and measuring reagents 50 5.4.1 Storing liquid reagents or solvents under inert atmosphere 50 5.4.2 Bulk transfer of a liquid under inert atmosphere (cannulation) 51 5.4.3 Using cannulation techniques to transfer measured volumes of liquid under inert atmosphere 54 5.4.4 Use of syringes for the transfer of reagents or solvents 57 5.4.5 Handling and weighing solids under inert atmosphere 64 5.5 Preparationof~omethane 70 5.5.1 Safety measures 71 5.5.2 Preparation of ~omethane (a dilute ethereal solution) 71 5.5.3 General procedure for esterification of carboxylic acids 73 5.5.4 Titration of diazomethane solutions 73 6 Gases 74 6.1 Introduction 74 6.2 Use of gas cylinders 74 6.3 Handling gases 77 6.4 Measurement of gases 79 6.5 Inert gases 84 6.6 Reagent gases 84 7 Vacuum pumps 88 7.1 Introduction 88 7.2 Low vacuum pumps 88 7.2.1 Water aspirators 88 7.2.2 House vacuum systems 89 7.2.3 Electric diaphragm pumps 89 7.3 High vacuum pumps 90

Contents ix 7.3.1 Rotary oil pumps 90 7.3.2 Vapour diffusion pumps 92 7.4 Pressure measurement and regulation 92 7.4.1 Units ofpressure (vacuum) measurement 93 8 Carrying out the reaction 94 8.1 Introduction 94 8.2 Reactions with air sensitive reagents 95 8.2.1 Introduction 95 8.2.2 Preparing to carry out areaction under inert conditions 95 8.2.3 Drying and assembling glassware 96 8.2.4 Typical reaction set-ups using a double manifold 97 8.2.5 Basic procedure for inert atrnosphere reactions 98 8.2.6 Modifications to basic procedure 101 8.2.7 Use of bauoons for holding an inert atrnosphere 106 8.2.8 The use of a 'spaghetti' tubing manifold 108 8.3 Reaction monitoring 110 8.3.1 Thin layer chromatography 110 8.3.2 High performance liquid chromatography 117 8.3.3 Gas-liquid chromatography 121 8.4 Reactions at other than room temperature 125 8.4.1 Low temperature reactions 125 8.4.2 Reactions above room temperature 128 8.5 Driving equilibria 133 8.5.1 Dean and Stark traps 133 8.5.2 High pressure reactions 134 8.6 Agitation 135 8.6.1. Magnetic stirring 135 8.6.2. Mechanical stirrers 136 8.6.3. Mechanical shakers 139 8.6.4. Sonication 139 9 Working up the re action 141 9.1 Introduction 141

X Contents 9.2 Quenching the reaction 142 9.2.1 General comments 142 9.2.2 Strongly basic non-aqueous reactions 142 9.2.3 Neutral non-aqueous reactions 143 9.2.4 Strongly acidie non-aqueous reactions 144 9.2.5 Acidie or basic aqueous reactions 144 9.2.6 Liquid ammonia reactions 144 9.3 Isolation of the crude product 145 9.3.1 General comments 145 9.3.2 Very polar aprotic solvents 146 9.4 Purification 147 9.4.1 Crystallization 147 9.4.2 Distillation 155 9.4.3 Sublimation 164 9.5 Chromatographie purification of reaction product 166 9.5.1 Flash chromatography 166 9.5.2 Dry-column flash chromatography 176 9.5.3 Preparative tlc 178 9.5.4 Medium pressure liquid chromatography 178 9.5.5 Preparative hplc 185 10 Small scale reactions 188 10.1 Introduction 188 10.2 Reactions at or below room temperature 189 10.3 Reactions above room temperature 192 10.4 Reactions in nmr tubes 193 10.5 Purification of materials 194 10.5.1 Distillation 194 10.5.2 Crystallization 195 10.5.3 Chromatography 195 11 Large scale reactions 197 11.1 Introduction 197 11.2 Carrying out the reaction 198

Contents xi 11.3 Purification of the products 200 12 Characterization 201 12.1 Introduction 201 12.2 Nmr 202 12.3 Ir 202 12.4 Uv 203 12.5 Mass spectra 203 12.6 M.p. and b.p. 204 12.7 Optical rotation 204 12.8 Microanalysis 205 12.9 Keeping the data 205 13 The chemical literature 207 13.1 The structure of the chemical information 207 13.1.1 Introduction 207 13.1.2 The structure of the literature 208 13.2 Some important sources of chemical information 208 13.2.1 Chemical Abstracts 209 13.2.2 Beilstein 210 13.2.3 Science Citation Index 211 13.2.4 Computer databases 212 13.3 How to fmd chemical information 213 13.3.1 How to do searches 213 13.3.2 How to find information on specific compounds 214 13.3.3 How to find information on classes of compounds 215 13.3.4 How to fmd information on synthetic methods 216 13.4 Current awareness 217 14 Special procedures 219 14.1 Introduction 219 14.2 Catalytic hydrogenation 219 14.3 Photolysis 222 14.4 Ozonolysis 223

xü Contents 14.5 Flash vacuum pyrolysis 14.6 Liquid ammonia reactions 224 224 15 'Trouble shooting'; 227 what to do when things don 't work 16 Example reactions 16.1 Preparation of n-butyllithium 16.2 Titration of n-butyllithium 16.3 Aldol reaction 16.4 Preparation of ethyl(triphenyl-phosphoranylidene)acetate 16.5 Claisen rearrangement 16.6 Hydrogenation of maleie acid 229 229 230 231 233 234 236 17 Safety 238 17.1 17.2 17.3 17.4 17.5 Safety is your primary responsibility Safe working practice Common hazards Accident and emergency procedures Bibliography 238 239 239 241 242 Appendices 243 Appendix 1. Properties of common solvents 243 Appendix 2. Properties of common gases 244 Appendix 3. Approximate pka values for some common deprotonations 245 compared to some common bases Appendix 4. Lewis acids 246 Appendix 5. Common reducing reagents 247 Appendix 6. Common oxidizing reagents 252 Index 257