Organic Chemistry Organic Chemistry—online support Each chapter in this book is accompanied by a set of problems, which are available free of charge online. To access them visit the Online Resource Centre at www.oxfordtextbooks.co.uk/orc/clayden2e/ and enter the following: Username: clayden2e Password: compound 2069_Book.indb i 12/12/2011 8:21:29 PM This page intentionally left blank ORGANIC CHEMISTRY SECOND EDITION Jonathan Clayden Nick Greeves Stuart Warren University of Manchester University of Liverpool University of Cambridge 1 2069_Book.indb iii 12/12/2011 8:21:35 PM 1 Great Clarendon Street, Oxford OX2 6DP Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide in Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offi ces in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries Published in the United States by Oxford University Press Inc., New York © Jonathan Clayden, Nick Greeves, and Stuart Warren 2012 The moral rights of the authors have been asserted Crown Copyright material reproduced with the permission of the Controller, HMSO (under the terms of the Click Use licence.) Database right Oxford University Press (maker) First published 2001 All rights reserved. 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Ltd ISBN 978-0-19-927029-3 10 9 8 7 6 5 4 3 2 1 2069_Book.indb iv 12/12/2011 8:21:40 PM Brief contents Abbreviations xv Preface to the second edition xvii Organic chemistry and this book xix 1 What is organic chemistry? 1 2 Organic structures 15 3 Determining organic structures 43 4 Structure of molecules 80 5 Organic reactions 107 6 Nucleophilic addition to the carbonyl group 125 7 Delocalization and conjugation 141 8 Acidity, basicity, and pK 163 a 9 Using organometallic reagents to make C–C bonds 182 10 Nucleophilic substitution at the carbonyl group 197 11 Nucleophilic substitution at C=O with loss of carbonyl oxygen 222 12 Equilibria, rates, and mechanisms 240 13 1H NMR: Proton nuclear magnetic resonance 269 14 Stereochemistry 302 15 Nucleophilic substitution at saturated carbon 328 16 Conformational analysis 360 17 Elimination reactions 382 18 Review of spectroscopic methods 407 19 Electrophilic addition to alkenes 427 20 Formation and reactions of enols and enolates 449 21 Electrophilic aromatic substitution 471 22 Conjugate addition and nucleophilic aromatic substitution 498 23 Chemoselectivity and protecting groups 528 24 Regioselectivity 562 25 Alkylation of enolates 584 26 Reactions of enolates with carbonyl compounds: the aldol and Claisen reactions 614 27 Sulfur, silicon, and phosphorus in organic chemistry 656 28 Retrosynthetic analysis 694 29 Aromatic heterocycles 1: reactions 723 30 Aromatic heterocycles 2: synthesis 757 31 Saturated heterocycles and stereoelectronics 789 32 Stereoselectivity in cyclic molecules 825 2069_Book.indb v 12/12/2011 8:21:40 PM vi BRIEF CONTENTS 33 Diastereoselectivity 852 34 Pericyclic reactions 1: cycloadditions 877 35 Pericyclic reactions 2: sigmatropic and electrocyclic reactions 909 36 Participation, rearrangement, and fragmentation 931 37 Radical reactions 970 38 Synthesis and reactions of carbenes 1003 39 Determining reaction mechanisms 1029 40 Organometallic chemistry 1069 41 Asymmetric synthesis 1102 42 Organic chemistry of life 1134 43 Organic chemistry today 1169 Figure acknowledgements 1182 Periodic table of the elements 1184 Index 1187 2069_Book.indb vi 12/12/2011 8:21:41 PM Contents Abbreviations xv 4 Structure of molecules 80 Preface to the second edition xvii Introduction 80 Organic chemistry and this book xix Electrons occupy atomic orbitals 83 Molecular orbitals—diatomic molecules 88 1 What is organic chemistry? 1 Bonds between different atoms 95 Hybridization of atomic orbitals 99 Organic chemistry and you 1 Rotation and rigidity 105 Organic compounds 2 Conclusion 106 Organic chemistry and industry 6 Looking forward 106 Organic chemistry and the periodic table 11 Further reading 106 Organic chemistry and this book 13 Further reading 13 5 Organic reactions 107 22 Organic structures 15 Chemical reactions 107 Hydrocarbon frameworks and functional groups 16 Nucleophiles and electrophiles 111 Drawing molecules 17 Curly arrows represent reaction mechanisms 116 Hydrocarbon frameworks 22 Drawing your own mechanisms with curly arrows 120 Functional groups 27 Further reading 124 Carbon atoms carrying functional groups can be classifi ed by oxidation level 32 6 Nucleophilic addition to the Naming compounds 33 carbonyl group 125 What do chemists really call compounds? 36 Molecular orbitals explain the reactivity of the How should you name compounds? 40 carbonyl group 125 Further reading 42 Attack of cyanide on aldehydes and ketones 127 The angle of nucleophilic attack on aldehydes 3 Determining organic structures 43 and ketones 129 Introduction 43 Nucleophilic attack by ‘hydride’ on aldehydes and ketones 130 Mass spectrometry 46 Addition of organometallic reagents to aldehydes Mass spectrometry detects isotopes 48 and ketones 132 Atomic composition can be determined Addition of water to aldehydes and ketones 133 by high-resolution mass spectrometry 50 Hemiacetals from reaction of alcohols with aldehydes Nuclear magnetic resonance 52 and ketones 135 Regions of the 13C NMR spectrum 56 Ketones also form hemiacetals 137 Different ways of describing chemical shift 57 Acid and base catalysis of hemiacetal and A guided tour of the 13C NMR spectra of some hydrate formation 137 simple molecules 57 Bisulfi te addition compounds 138 The 1H NMR spectrum 59 Further reading 140 Infrared spectra 63 Mass spectra, NMR, and IR combined make quick 7 Delocalization and conjugation 141 identifi cation possible 72 Double bond equivalents help in the search for a structure 74 Introduction 141 Looking forward to Chapters 13 and 18 78 The structure of ethene (ethylene, CH=CH) 142 2 2 Further reading 78 Molecules with more than one C=C double bond 143 2069_Book.indb vii 12/12/2011 8:21:41 PM viii CONTENTS The conjugation of two ππ bonds 146 And to conclude... 220 UV and visible spectra 148 Further reading 220 The allyl system 150 Delocalization over three atoms is a common 11 Nucleophilic substitution at C=O with loss structural feature 154 of carbonyl oxygen 222 Aromaticity 156 Introduction 222 Further reading 162 Aldehydes can react with alcohols to form hemiacetals 223 Acetals are formed from aldehydes or ketones plus 8 Acidity, basicity, and pKa 163 alcohols in the presence of acid 224 Organic compounds are more soluble in water as ions 163 Amines react with carbonyl compounds 229 Acids, bases, and pK 165 Imines are the nitrogen analogues of a Acidity 165 carbonyl compounds 230 The defi nition of pK 168 Summary 238 a Constructing a pK scale 171 Further reading 239 a Nitrogen compounds as acids and bases 174 12 Equilibria, rates, and mechanisms 240 Substituents affect the pK 175 a Carbon acids 176 How far and how fast? 240 pK in action—the development of the How to make the equilibrium favour the a drug cimetidine 178 product you want 244 Lewis acids and bases 180 Entropy is important in determining equilibrium constants 246 Further reading 181 Equilibrium constants vary with temperature 248 9 Using organometallic reagents to make Introducing kinetics: how to make reactions go C–C bonds 182 faster and cleaner 250 Rate equations 257 Introduction 182 Catalysis in carbonyl substitution reactions 262 Organometallic compounds contain a carbon–metal bond 183 Kinetic versus thermodynamic products 264 Making organometallics 184 Summary of mechanisms from Chapters 6–12 266 Using organometallics to make organic molecules 189 Further reading 267 Oxidation of alcohols 194 13 1H NMR: Proton nuclear magnetic Looking forward 196 resonance 269 Further reading 196 The differences between carbon and proton NMR 269 10 Nucleophilic substitution at the Integration tells us the number of hydrogen atoms carbonyl group 197 in each peak 270 Regions of the proton NMR spectrum 272 The product of nucleophilic addition to a carbonyl group is not always a stable compound 197 Protons on saturated carbon atoms 272 Carboxylic acid derivatives 198 The alkene region and the benzene region 277 Why are the tetrahedral intermediates unstable? 200 The aldehyde region: unsaturated carbon bonded to oxygen 281 Not all carboxylic acid derivatives are equally reactive 205 Protons on heteroatoms have more variable shifts Acid catalysts increase the reactivity than protons on carbon 282 of a carbonyl group 207 Coupling in the proton NMR spectrum 285 Acid chlorides can be made from carboxylic acids using SOCl or PCl 214 To conclude 301 2 5 Making other compounds by substitution reactions Further reading 301 of acid derivatives 216 Making ketones from esters: the problem 216 14 Stereochemistry 302 Making ketones from esters: the solution 218 Some compounds can exist as a pair of mirror- To summarize... 220 image forms 302 2069_Book.indb viii 12/12/2011 8:21:42 PM CONTENTS ix Diastereoisomers are stereoisomers that are Anion-stabilizing groups allow another not enantiomers 311 mechanism—E1cB 399 Chiral compounds with no stereogenic centres 319 To conclude 404 Axes and centres of symmetry 320 Further reading 406 Separating enantiomers is called resolution 322 Further reading 327 18 Review of spectroscopic methods 407 There are three reasons for this chapter 407 15 Nucleophilic substitution at Spectroscopy and carbonyl chemistry 408 saturated carbon 328 Acid derivatives are best distinguished by infrared 411 Mechanisms for nucleophilic substitution 328 Small rings introduce strain inside the ring and How can we decide which mechanism (SN1 or SN2) higher s character outside it 412 will apply to a given organic compound? 332 Simple calculations of C=O stretching A closer look at the SN1 reaction 333 frequencies in IR spectra 413 A closer look at the SN2 reaction 340 NMR spectra of alkynes and small rings 414 Contrasts between SN1 and SN2 342 Proton NMR distinguishes axial and equatorial The leaving group in S 1 and S 2 reactions 347 protons in cyclohexanes 415 N N The nucleophile in S 1 reactions 352 Interactions between different nuclei can give N enormous coupling constants 415 The nucleophile in the S 2 reaction 353 N Identifying products spectroscopically 418 Nucleophiles and leaving groups compared 357 Tables 422 Looking forward: elimination and rearrangement reactions 358 Shifts in proton NMR are easier to calculate and more informative than those in carbon NMR 425 Further reading 359 Further reading 426 16 Conformational analysis 360 19 Electrophilic addition to alkenes 427 Bond rotation allows chains of atoms to adopt a number of conformations 360 Alkenes react with bromine 427 Conformation and confi guration 361 Oxidation of alkenes to form epoxides 429 Barriers to rotation 362 Electrophilic addition to unsymmetrical alkenes is Conformations of ethane 363 regioselective 433 Conformations of propane 365 Electrophilic addition to dienes 435 Conformations of butane 365 Unsymmetrical bromonium ions open regioselectively 436 Ring strain 366 Electrophilic additions to alkenes can be stereospecifi c 439 A closer look at cyclohexane 370 Adding two hydroxyl groups: dihydroxylation 442 Substituted cyclohexanes 374 Breaking a double bond completely: periodate To conclude... 381 cleavage and ozonolysis 443 Further reading 381 Adding one hydroxyl group: how to add water across a double bond 444 17 Elimination reactions 382 To conclude...a synopsis of electrophilic Substitution and elimination 382 addition reactions 447 How the nucleophile affects elimination versus Further reading 447 substitution 384 E1 and E2 mechanisms 386 20 Formation and reactions of enols Substrate structure may allow E1 388 and enolates 449 The role of the leaving group 390 Would you accept a mixture of compounds E1 reactions can be stereoselective 391 as a pure substance? 449 E2 eliminations have anti-periplanar Tautomerism: formation of enols by proton transfer 450 transition states 395 Why don’t simple aldehydes and ketones exist The regioselectivity of E2 eliminations 398 as enols? 451 2069_Book.indb ix 12/12/2011 8:21:42 PM