Structure and Reactivity in Organic Chemistry

Mark G. MoloneyChemistry Research Laboratory, University of Oxford and St Peter’s College, Oxford.

“The author's approach is methodical and clever in that he brings relevance to protecting group chemistry under each class of reactions.” (CHOICE) "It will serve as a good reference source for any course that deals with physical organic chemistry." (CHOICE, January 2009)"An extremely well thought out and well presented book that achieves the author’s stated aims and deserves to be on any practising organic chemist’s shelf." (The Higher Education Academy Physical Sciences Centre, December 2008)"This book will be extremely useful as a guide to the essentials of modern organic chemistry, provided that you have a very good knowledge of organic chemistry or an excellent teacher to guide you through it." (Angewandte Chemie International Edition, December 22, 2008)

• Preface xi1 Bonding 11.1 Atomic structure 11.1.1 The chemical bond 11.1.2 The periodic table 11.1.3 Valence electrons 31.1.4 Lewis structures 31.1.5 Conventions for drawing structures 51.1.6 Atomic orbital theory 61.1.7 Molecular orbital theory 71.2 Covalent bonding 101.2.1 Bonding in hydrocarbons 111.2.2 Bonding in compounds containing heteroatoms 121.2.3 Bonding in common functional groups 121.2.4 Electronic effects 141.2.5 Steric effects 181.2.6 Stereoelectronic effects 181.2.7 Double bond equivalents 202 Structure 212.1 Configuration 212.1.1 Geometrical isomerism 222.1.2 Optical isomerism 232.1.3 Representations of stereoisomers 252.1.4 Molecules with one stereogenic centre 272.1.5 Molecules with more than one stereogenic centre 272.1.6 Molecules with more than one stereogenic centre which are not optically active 282.1.7 Optically active molecules without stereogenic centres: molecular asymmetry 292.1.8 Asymmetric heteroatoms 302.2 Conformation 312.2.1 Representation of conformers 312.2.2 Open-chain compounds 312.2.3 Ring compounds 332.3 Summary of stereochemical relationships 392.4 Naturally occurring chiral compounds 392.5 Asymmetric synthesis 412.5.1 Enantioselective synthesis 412.5.2 Diastereoselective synthesis 432.5.3 Methods for the determination of enantiomeric purity 433 Reactivity 473.1 Thermodynamics 473.1.1 Gibbs free energy 473.1.2 Enthalpy 483.1.3 Entropy 503.1.4 Chemical equilibrium 523.2 Kinetics 543.2.1 Rates of reaction 543.2.2 Reactions with competing steps 573.2.3 Overcoming activation energy barriers 583.3 Reaction mechanism 603.3.1 What is reactivity? 603.3.2 Lewis acids and bases: ‘philicity’ 603.3.3 Polarisability effects: Hard–Soft Acid–Base theory 613.3.4 Curly (‘curved’) arrows 633.4 Classes of reaction mechanism 663.4.1 Polar mechanisms 663.4.2 Radical mechanisms 673.4.3 Pericyclic mechanisms 673.4.4 Ligand coupling reaction mechanisms 673.5 Principle of microscopic reversibility 683.6 Selectivity of reactions 693.7 Solvents in organic chemistry 713.8 Redox reactions in organic chemistry 724 Intermediates 774.1 Carbocations 774.1.1 Structure 774.1.2 Factors stabilising carbocations 774.1.3 Generation of carbocations 814.1.4 Rearrangements of carbocations 824.2 Carbanions 824.2.1 Structure 824.2.2 Carbanions derived from simple alkanes 844.2.3 Factors stabilising carbanions 854.3 Carbanions with covalent character 884.3.1 Grignard reagents (RMgX) 884.3.2 Organolithium reagents (RLi) 894.3.3 Organocadmium reagents 894.4 Radicals 904.4.1 Structure 904.4.2 Factors stabilising radicals 904.4.3 Generation of radicals 924.5 Carbenes 944.5.1 Stability and structure 944.5.2 Generation of carbenes 954.6 Benzynes 964.6.1 Stability and structure 964.6.2 Generation of benzynes 974.7 Ketenes 984.7.1 Stability and structure 984.7.2 Generation of ketenes 985 Acidity and Basicity 995.1 Lowry–Brønsted Acid–Base theory 995.2 Organic acidity 1005.2.1 Organic acids 1005.3 Organic basicity 1115.3.1 Organic bases 1126 Nucleophilic Substitution 1176.1 The S N 1 reaction 1176.1.1 Factors affecting the S N 1 reaction 1186.2 The S N 2 reaction 1236.2.1 Factors enhancing the S N 2 reaction 1246.3 Synthetic applications of nucleophilic substitution reactions 1286.3.1 Protecting-group chemistry 1286.3.2 Stereocontrolled alkylation reactions 1317 Addition Reactions 1397.1 Electrophilic addition reactions 1397.1.1 Addition of halogens 1397.1.2 Addition of hydrogen halides 1417.1.3 Addition of hydrogen halides to conjugated dienes 1437.1.4 Addition of diborane (hydroboration) 1437.1.5 Addition of hydrogen 1477.1.6 Addition of oxygen 1487.1.7 Addition of carbon 1537.2 Nucleophilic addition reactions 1537.2.1 Irreversible nucleophilic addition 1547.2.2 Irreversible nucleophilic conjugate addition 1597.2.3 Reversible nucleophilic addition 1607.3 Additions to electron-deficient alkenes 1657.4 Additions of ketenes 1657.5 Synthetic applications 1668 Elimination Reactions 1698.1 Eliminations 1698.1.1 E 1 reactions 1698.1.2 E 1 CB reactions 1698.1.3 E 2 reactions 1708.1.4 Eliminations leading to isomeric products 1738.1.5 Competition between substitution and elimination 1758.1.6 The leaving group 1768.2 Oxidation processes 1788.3 Eliminations leading to carbenes and nitrenes 1818.4 Eliminations of phosphorus 1828.5 Eliminations of sulfur and selenium 1828.6 Eliminations in protecting-group chemistry 1849 Aromatic Substitution 1899.1 Aromaticity 1899.1.1 Benzene 1899.1.2 Heteroaromatics 1899.2 Reactions 1919.2.1 Acidity and basicity 1919.2.2 Electrophilic aromatic substitution 1919.2.3 Orientation effects in electrophilic aromatic substitution (S E Ar) 2029.2.4 o-Lithiation 2059.2.5 Nucleophilic aromatic substitution 2069.2.6 Arene chromium tricarbonyl complexes 21110 Sequential Addition and Elimination Reactions 21310.1 Addition–elimination reactions 21310.1.1 Addition of hydride 22010.1.2 Addition of heteroatom nucleophiles 22110.1.3 Addition of carbon nucleophiles 22210.1.4 Addition of phosphorus nucleophiles 22510.2 Addition–elimination reactions in conjugated systems 23010.3 Addition–elimination reactions in heterocyclic systems 23010.4 Addition–elimination reactions in ring-closing metathesis 23110.5 Addition–elimination reactions in deprotections 23411 Radical Reactions 23711.1 Generation 23711.2 Reactions 23711.2.1 Termination 23711.2.2 Propagation 23811.2.3 Substitution 23911.2.4 Addition reactions 24211.2.5 Fragmentation 24911.2.6 Rearrangement 25011.3 Synthetic utility 25512 Ligand Coupling Reactions 26312.1 Palladium-mediated couplings 26312.1.1 Palladium-mediated coupling processes 26412.1.2 Heck coupling 27112.1.3 Allylic coupling processes 27312.2 Ligand coupling processes mediated by other elements 27512.2.1 Copper 27612.2.2 Magnesium 27712.2.3 Lead 27913 Pericyclic Reactions 28313.1 Molecular orbitals and the FMO approach 28313.2 Pericyclic reactions 28413.2.1 Electrocyclic reactions 28513.2.2 Cycloaddition reactions 28713.2.3 Sigmatropic reactions 29313.3 Synthetic applications of pericyclic reactions 296Index 303