Essentials Of Organic Chemistry - Paul M. Dewick

Essentials of Organic Chemistry Essentials of Organic Chemistry For students of pharmacy, medicinal chemistry and biological chemistry Paul M Dewick School of Pharmacy University of Nottingham, UK Copyright  2006 John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England Telephone (+44) 1243 779777 Email (for orders and customer service enquiries): cs-books@wiley.co.uk Visit our Home Page on www.wiley.com Reprinted with corrections June 2006 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, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1T 4LP, UK, without the permission in writing of the Publisher Requests to the Publisher should be addressed to the Permissions Department, John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England, or emailed to permreq@wiley.co.uk, or faxed to (+44) 1243 770620 Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners The Publisher is not associated with any product or vendor mentioned in this book This publication is designed to provide accurate and authoritative information in regard to the subject matter covered It is sold on the understanding that the Publisher is not engaged in rendering professional services If professional advice or other expert assistance is required, the services of a competent professional should be sought Other Wiley Editorial Offices John Wiley & Sons Inc., 111 River Street, Hoboken, NJ 07030, USA Jossey-Bass, 989 Market Street, San Francisco, CA 94103-1741, USA Wiley-VCH Verlag GmbH, Boschstr 12, D-69469 Weinheim, Germany John Wiley & Sons Australia Ltd, 42 McDougall Street, Milton, Queensland 4064, Australia John Wiley & Sons (Asia) Pte Ltd, Clementi Loop #02-01, Jin Xing Distripark, Singapore 129809 John Wiley & Sons Canada Ltd, 6045 Freemont Blvd, Mississauga, ONT, L5R 4J3, Canada Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books Proudly sourced and uploaded by [StormRG] Kickass Torrents | TPB | ET | h33t British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN-13: 978-0-470-01665-7 (HB) 978-0-470-01666-4 (PB) ISBN-10: 0-470-01665-5 (HB) 0-470-01666-3 (PB) Contents Preface Molecular representations and nomenclature 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 xiii Molecular representations Partial structures Functional groups Systematic nomenclature Common groups and abbreviations Common, non-systematic names Trivial names for complex structures Acronyms Pronunciation Atomic structure and bonding 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Atomic structure Bonding and valency Atomic orbitals Electronic configurations Ionic bonding Covalent bonding 2.6.1 Molecular orbitals: σ and π bonds 2.6.2 Hybrid orbitals in carbon 2.6.3 Hybrid orbitals in oxygen and nitrogen Bond polarity Conjugation Aromaticity 2.9.1 Benzene 2.9.2 Cyclooctatetraene 2.9.3 Hăuckels rule 2.9.4 Kekule structures 2.9.5 Aromaticity and ring currents 1 14 15 15 15 16 19 19 19 20 23 23 24 24 26 33 35 37 41 41 42 42 44 44 vi CONTENTS 2.10 2.11 2.12 Stereochemistry 3.1 3.2 3.3 3.4 3.5 2.9.6 Aromatic heterocycles 2.9.7 Fused rings Resonance structures and curly arrows Hydrogen bonding Molecular models Hybridization and bond angles Stereoisomers Conformational isomers 3.3.1 Conformations of acyclic compounds 3.3.2 Conformations of cyclic compounds Configurational isomers 3.4.1 Optical isomers: chirality and optical activity 3.4.2 Cahn–Ingold–Prelog system to describe configuration at chiral centres 3.4.3 Geometric isomers 3.4.4 Configurational isomers with several chiral centres 3.4.5 Meso compounds 3.4.6 Chirality without chiral centres 3.4.7 Prochirality 3.4.8 Separation of enantiomers: resolution 3.4.9 Fischer projections 3.4.10 D and L configurations Polycyclic systems 3.5.1 Spiro systems 3.5.2 Fused ring systems 3.5.3 Bridged ring systems Acids and bases 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 Acid–base equilibria Acidity and pKa values Electronic and structural features that influence acidity 4.3.1 Electronegativity 4.3.2 Bond energies 4.3.3 Inductive effects 4.3.4 Hybridization effects 4.3.5 Resonance/delocalization effects Basicity Electronic and structural features that influence basicity 4.5.1 Electronegativity 4.5.2 Inductive effects 4.5.3 Hybridization effects 4.5.4 Resonance/delocalization effects Basicity of nitrogen heterocycles Polyfunctional acids and bases pH The Henderson–Hasselbalch equation 44 44 45 49 51 55 55 56 57 57 60 73 73 80 83 85 90 92 94 99 100 103 106 106 107 116 121 121 122 125 125 125 125 128 129 135 136 136 137 138 139 143 144 146 149 vii CONTENTS 4.10 4.11 Reaction mechanisms 5.1 5.2 5.3 5.4 5.5 5.6 Ionic reactions 5.1.1 Bond polarity 5.1.2 Nucleophiles, electrophiles, and leaving groups Radical reactions Reaction kinetics and mechanism Intermediates and transition states Types of reaction Arrows Nucleophilic reactions: nucleophilic substitution 6.1 6.2 6.3 6.4 Buffers Using pKa values 4.11.1 Predicting acid–base interactions 4.11.2 Isotopic labelling using basic reagents 4.11.3 Amphoteric compounds: amino acids 4.11.4 pKa and drug absorption The SN reaction: bimolecular nucleophilic substitution 6.1.1 The effect of substituents 6.1.2 Nucleophiles: nucleophilicity and basicity 6.1.3 Solvent effects 6.1.4 Leaving groups 6.1.5 SN reactions in cyclic systems The SN reaction: unimolecular nucleophilic substitution 6.2.1 The effect of substituents 6.2.2 SN reactions in cyclic systems 6.2.3 SN or SN 2? Nucleophilic substitution reactions 6.3.1 Halide as a nucleophile: alkyl halides 6.3.2 Oxygen and sulfur as nucleophiles: ethers, esters, thioethers, epoxides 6.3.3 Nitrogen as a nucleophile: ammonium salts, amines 6.3.4 Carbon as a nucleophile: nitriles, Grignard reagents, acetylides 6.3.5 Hydride as nucleophile: lithium aluminium hydride and sodium borohydride reductions 6.3.6 Formation of cyclic compounds Competing reactions: eliminations and rearrangements 6.4.1 Elimination reactions 6.4.2 Carbocation rearrangement reactions Nucleophilic reactions of carbonyl groups 7.1 7.2 7.3 7.4 Nucleophilic addition to carbonyl groups: aldehydes and ketones 7.1.1 Aldehydes are more reactive than ketones 7.1.2 Nucleophiles and leaving groups: reversible addition reactions Oxygen as a nucleophile: hemiacetals, hemiketals, acetals and ketals Water as a nucleophile: hydrates Sulfur as a nucleophile: hemithioacetals, hemithioketals, thioacetals and thioketals 152 155 155 157 159 164 167 167 170 171 171 173 173 174 175 183 183 184 185 187 188 190 191 193 195 195 198 198 198 201 204 205 206 206 207 214 221 221 222 223 224 234 235 viii CONTENTS 7.5 7.6 7.7 7.8 7.9 7.10 7.11 7.12 7.13 Electrophilic reactions 8.1 8.2 8.3 8.4 Hydride as a nucleophile: reduction of aldehydes and ketones, lithium aluminium hydride and sodium borohydride Carbon as a nucleophile 7.6.1 Cyanide: cyanohydrins 7.6.2 Organometallics: Grignard reagents and acetylides Nitrogen as a nucleophile: imines and enamines 7.7.1 Imines 7.7.2 Enamines Nucleophilic substitution on carbonyl groups: carboxylic acid derivatives Oxygen and sulfur as nucleophiles: esters and carboxylic acids 7.9.1 Alcohols: ester formation 7.9.2 Water: hydrolysis of carboxylic acid derivatives 7.9.3 Thiols: thioacids and thioesters Nitrogen as a nucleophile: amides Hydride as a nucleophile: reduction of carboxylic acid derivatives Carbon as a nucleophile: Grignard reagents Nucleophilic substitution on derivatives of sulfuric and phosphoric acids 7.13.1 Sulfuric acid derivatives 7.13.2 Phosphoric acid derivatives Electrophilic addition to unsaturated carbon 8.1.1 Addition of hydrogen halides to alkenes 8.1.2 Addition of halogens to alkenes 8.1.3 Electrophilic additions to alkynes 8.1.4 Carbocation rearrangements Electrophilic addition to conjugated systems Carbocations as electrophiles Electrophilic aromatic substitution 8.4.1 Electrophilic alkylations: Friedel–Crafts reactions 8.4.2 Electrophilic acylations: Friedel–Crafts reactions 8.4.3 Effect of substituents on electrophilic aromatic substitution 8.4.4 Electrophilic substitution on polycyclic aromatic compounds Radical reactions 9.1 9.2 9.3 9.4 9.5 9.6 Formation of radicals Structure and stability of radicals Radical substitution reactions: halogenation 9.3.1 Stereochemistry of radical reactions 9.3.2 Allylic and benzylic substitution: halogenation reactions Radical addition reactions: addition of HBr to alkenes 9.4.1 Radical addition of HBr to conjugated dienes 9.4.2 Radical polymerization of alkenes 9.4.3 Addition of hydrogen to alkenes and alkynes: catalytic hydrogenation Radical addition of oxygen: autoxidation reactions Phenolic oxidative coupling 235 238 238 240 242 242 247 248 252 252 256 261 262 267 271 272 272 275 283 283 284 286 292 296 296 299 304 306 308 309 315 319 319 321 322 325 325 328 330 331 332 333 340 ... ketones O but-2-yl 3-phenylpropanoate 4,4-dimethylcyclohexa-2,5-dienone N H CHO 2-ethyl-4-ethylamino-2-methylbutanal 2-ethyl-2-methyl-5-azaheptanal O O 2 OH 3-phenylpropanoic acid HO 2-butanol •... ester (ester) -oic anhydride O O C O C alkyl -oate alkoxylcarbonyl- (or carbalkoxy-) -oyl halide haloalkanoyl- -amide carbamoyl- -nitrile (or -onitrile) cyano- -al formyl- -one -oxo- CO2R O Acyl... this book is available from the British Library ISBN-13: 97 8-0 -4 7 0-0 166 5-7 (HB) 97 8-0 -4 7 0-0 166 6-4 (PB) ISBN-10: 0-4 7 0-0 166 5-5 (HB) 0-4 7 0-0 166 6-3 (PB) Contents Preface Molecular representations