Physical organic chemistry

Physical organic chemistry Second edition Neil S. Isaacs

Foreword to first edition Foreword to second edition Symbols and abbreviations Mechanistic designations vi i ix xxvi i xxvii r Models of chemical bonding 1 1.1 Covalency and molecular structure 1 1.1.1 The valence bond (VB) model 2 1.1.2 The molecular orbital (MO) model 3 1.2 Approximate molecular orbital theory 3 1.2.1 The Hückel molecular orbital (HMO) method 4 1.2.2 Properties of Hückel molecular orbitals 1 3 1.2.3 The relationship between MO and VB models 2 6 1.2.4 Advanced MO methods 2 7 1.3 Properties of covalent bonds 3 1 1.3.1 Bond lengths 3 1 1.3.2 Interbond angles 3 4 1.3.3 Force constants 3 5 1.3.4 Bond and molecular dipole moments 36 1.3.5 Molecular and bond polarizabilities 39 1.3.6 Bond dissociation enthalpies (BDE) 4 3 1.3.7 Group additivities to bond enthalpies 4 5 1.4 Intermolecular forces 54 1.4.1 Electrostatic forces 54 1.4.2 Ion-pairs 5 8 1.4.3 Short-range intermolecular forces 6 3 1.4.4 The hydrogen bond 6 7 1.4.5 Charge-transfer complexes 74 1.4.6 Crowns, cryptates, calixarenes and cyclodextrins 7 6

s Kinetics and thermodynamics 8 7 2.1 Enthalpy 8 8 2.1.1 Endothermic reactions 90 2.2 Entropy 90 2.3 The Gibbs function, G 92 2.4 Factors that contribute to entropy 94 2.5 Chemical equilibrium 9 6 2.6 Some useful thermodynamic relationships 9 8 2.6.1 Temperature dependence 99 2.7 The application of thermodynamics to rate processes 100 2.7.1 Activation 100 2.7.2 The potential energy surface 10 1 2.7.3 The transition state model 104 2.8 Properties of the transition state 105 2.8.1 Activation parameters 105 2.8.2 Heat capacity of activation 106 2.8.3 Variation of rate with pressure 107 2.9 The uses of activation parameters 10 8 2.9.1 The empirical treatment of rates of simpl e irreversible reactions 10 8 2.9.2 The rate-determining step 11 1 2.9.3 Relative rates 11 2 2.9.4 Entropies and volumes of reaction 11 3 2.9.5 The isokinetic relationship 11 6 2.10 The location of the transition state 11 8 2.10.1 The Hammond Postulate 11 8 2.10.2 Reactivity and selectivity 12 1 2.10.3 Kinetic and thermodynamic control of products 12 2 2.10.4 The principle of least motion 12 3 2.10.5 The principle of microscopic reversibility 124 2.10.6 Limitations of the transition-state theory 12 5 3 Reagents and reaction mechanisms 12 9 3.1 Polar and radical pathways 129 3.1.1 Polar reactions 130 3.1.2 Nucleophiles 13 1 3.1.3 Electrophiles 13 2 3.1.4 Radicals 132 3.1.5 Reactivity 133 3.2 A classification of fundamental reaction types 133 3.2.1 Bond formation and bond breaking 134 3.2.2 Transfer reactions 13 4 3.2.3 Elimination (E) and addition (Ad) 136

3.2.4 Pericyclic reactions 136 3.2.5 Oxidations and reductions 137 3.3 Reaction mechanism 138 3.3.1 The advantages of synchronous reactions 138 3.4 Electron supply and demand 139. 3.5 Transition-state properties and structural change 140 4 Correlation of structure pith reactivity 146 4.1 Electronic demands 146 4.2 The Hammett equation 149 4.3 Substituent constants a 15 1 4.4 Theories of substituent effects 15 1 4.4.1 The resonance effect 15 3 4.4.2 The inductive effect 15 5 4.5 Interpretation of a-values 156 4.5.1 Unshared-pair (n) substituents, -7C 15 7 4.5.2 Alkyl groups 15 8 4.5.3 Electron-withdrawing groups, -2 160 4.5.4 Cationic centres 160 4.6 Reaction constants, p 16 1 4.7 Deviations from the Hammett equation 16 1 4.7.1 Random deviations 16 3 4.7.2 Mechanistic change '16 3 4.7.3 Enhanced resonance 164 4.7.4 Variable resonance interactions 16 8 4.8 Dual-parameter correlations : the flowering of LFER 170 4.8.1 Inductive substituent constants 17 1 4.8.2 The Taft model 17 1 4.8.3 Other chemical model systems : modern o and QR scales 17 5 4.9 Molecular orbital considerations 183 4.10 Cross-interaction terms 186 4.10.1 The sign of p;; 187 f Solvent effects 193 5.1 The structure of liquids 194 5.2 Solutions 195 5.3 Solvation 19 8 5.3.1 Polarity - 19 9 5.3.2 Polarizability 199

5.3.3 Hydrogen bonding 19 9 5.3.4 Donor-acceptor interactions 19 9 5.4 Thermodynamic measures of solvation 20 0 5.4.1 Free energies of solution and transfer functions 20 2 5.4.2 Activities of solutes 20 2 5.4.3 `Solvation' in the gas phase 20 4 5.5' The effects of solvation on reaction rates and equilibria 20 5 5.5.1 Solvent effects on rates 20 7 5.6 Empirical indexes of solvation 20 8 5.6.1 Scales based on physical properties 20 8 5.6.2 Scales based on solvent-sensitive reaction rates 214 5.6.3 Scales based on spectroscopic properties 21 6 5.6.4 Scales for specific solvation 220 5.7 Relationships between empirical solvation scales 22 3 5.8 The use of solvation scales in mechanistic studies 22 3 5.8.1 Multiparameter solvation analysis 22 6 6 Acids and bases, electrophiles and nucleophiles 23 5 6.1 Acid-base dissociation 23 5 6.2 The strengths of oxygen and nitrogen acids 23 7 6.2.1 The effect of pressure on acid-base dissociation 24 0 6.2.2 The interpretation of KA 24 0 6.3 Linear free-energy relationships 24 2 6.4 Rates of proton transfers 24 3 6.5 Structural effects on amine protonation 24 3 6.5.1 Linear free-energy relationships 24 5 6.6 Acidities of carbon acids 24 6 6.6.1 The measurement of weak acidity 24 8 6.7 Factors that influence carbon acidity 24 9 6.7.1 Electronic effects of adjacent - R and - I groups 24 9 6.7.2 Stabilization by d-orbitals 250 6.7.3 s-character of carbon hybridization 250 6.7.4 Aromaticity 25 1 6.8 Rates of ionization of carbon acids 252 6.9 Gas-phase acidity and basicity 25 5 6.10 Theories of proton transfer 257 6.11 Highly acidic and highly basic solutions 25 9 6.11.1 Highly acidic solutions 260 6.11.2 Highly basic media 265 6.12 Nucleophilicity and electrophilicity 265 6.12.1 Measurement of nucleophilicity : nucleophilicit y and basicity 266

6.12.2 Hard and soft acids and bases : frontier orbita l interactions 26 7 6.12.3 Nucleophilicity scales 27 0 6.12.4 The relationship between nucleophilicity an d nucleofugacity 27 4 6.12.5 The `a-effect' 27 6 6.12.6 Ambident nucleophiles 27 7 6.13 The measurement of electrophilicity 28 0 6.14 Brr nsted relationships in nucleophilic reactions 28 0 6.15 The Leffler index 28 2 Kinetic isotope effects 28 7 7.1 Isotopic substitution 28 7 7.2 Theory of isotope effects : the primary effect 28 8 7.3 Transition-state geometry 29 5 7.4 Secondary kinetic isotope effects 29 6 7.4.1 `Inductive' and `steric ' isotope effects 30 1 7.5 Heavy atom isotope effects 30 2 7.6 The tunnel effect 30 4 7.7 Solvent isotope effects 30 7 7.7.1 Fractionation factors 30 8 7.7.2 Solvent isotope effects in mixed isotopic solvents : the proton inventory technique 310 7.7.3 Examples of solvent isotope effects 31 2 8 Steric and conformational properties 319 8.1 The origins of steric strain 31 9 8.2 Examples of steric effects upon reactions 32 2 8.2.1 Ortho effects 32 2 8.2.2 F-strain effects 32 4 8.2.3 Bond-angle strain 32 5 8.2.4 Steric inhibition of resonance 32 6 8.2.5 Steric acceleration 32 7 8.2.6 Steric enhancement of resonance 32 8 8.2.7 Calculation of steric effects : the molecula r mechanics method 32 8 8.3 Measurement of steric effects upon rates 33 1 8.3.1 The Taft-Ingold hypothesis 332

8.3.2 Other steric parameters 33 3 8.3.3 Examples of steric LFER 33 7 8.4 Conformational barriers to bond rotation 33 8 8.4.1 Spectroscopic detection of individual conformers 34 1 8.4.2 Acyclic compounds 34 2 8.4.3 Cyclic compounds 34 6 8.5 Rotations about partial double bonds 350 8.5.1 Inversion at Group V elements 35 1 8.6 Chemical consequences of conformational isomerism : the Winstein-Holness-Curtin-Hammett principle 352 9 Homogeneous catalysis 36 9 9.1 Acid and base catalysis 369 9.1.1 Specific and general catalysis 37 1 9.1.2 Mechanisms of acid catalysis 374 9.1.3 Methods of distinguishing between Al and A 2 reactions 37 6 9.1.4 Linear free-energy relationships ; the Brenste d Catalysis Law 37 9 9.1.5 Interpretation of the Brensted coefficients 38 1 9.1.6 Nucleophilic catalysis 38 4 9.1.7 Potential-energy surfaces for proton transfers 38 5 9.1.8 Solvent isotope effects 38 9 9.1.9 Electrophilic catalysis 39 0 9.2 The mechanisms of some catalysed reactions 39 2 9.2.1 Substitutions a- to a carbonyl group 39 2 9.2.2 Keto-enol equilibria 39 4 9.2.3 Hydrolyses of acetals, ketals, orthoesters and related compounds 39 7 9.2.4 Dehydration of aldehyde hydrates and related compounds 39 8 9.2.5 The formation of oximes, semicarbazones and hydrazones 39 8 9.2.6 Decarboxylation 399 9.2.7 Acid-catalysed alkene-alcohol interchange 400 9.2.8 Some acid-catalysed rearrangements 40 1 9.2.9 Rate-limiting proton transfers 40 7 9.3 Catalysis by non-covalent binding 409 9.3.1 Host-guest interactions 41 1

to Substitution reactions at carbon 41 8 10.1 Substitutions at saturated carbon 418 10.1.1 Nucleophilic substitution (S N 2) 41 8 10.1.2 The bimolecular reaction, S N 2 422 10.1.3 Solvolytic reactions-the S N 1 spectrum 43 3 10.1.4 Measurement of solvent participation 43 5 10.1.5 Kinetic isotope effects 438 10.1.6 The structures of intermediates in S N1 reactions 440 10.1.7 The phenomenon of `return' 442 10.1.8 Rearrangement criteria for return 443 10.1.9 The `special' salt effect : an ion exchange in an ion-pair 445 10.1.10 Structural effects upon ionization 447 10.1.11 Leaving-group effects 449 10.1.12 Bridgehead systems 45 1 10.1.13 Linear free-energy relationships 45 1 10.1.14 Intramolecular assistance in ionization 45 5 10.1.15 Activation parameters 45 7 10.1.16 The S N 1 reactions 46 0 10.1.17 Aliphatic S N 2 reactions in the gas phase 46 1 10.2 Electrophilic substitutions at saturated carbon 46 3 10.2.1 The S E 1 mechanism 46 3 10.2.2 The S E2 mechanism 46 4 10.2.3 Electrophilic substitution via enolization 46 8 10.3 Nucleophilic displacements at a vinyl carbon 46 9 10.4 Electrophilic displacements at an aromatic carbon 47 3 10.4.1 Timing of bond-breaking and making 47 4 10.4.2 The general mechanism for electrophili c aromatic substitution 47 5 10.4.3 The nature of the electrophilic reagents 47 7 10.4.4 Kinetic isotope effects 48 1 10.4.5 Kinetics of S E 2-Ar reactions 48 1 10.4.6 Structural effects on rates 48 5 10.4.7 The ortho-para selectivity ratio, so, n = (2fo/fp) 49 1 10.4.8 The nature of the intermediate 49 3 10.4.9 Ipso attack 49 5 10.4.10 The MO interpretation of aromatic reactivity 49 5 10.5 Nucleophilic substitution at an aromatic centre 49 8 10.5.1 The addition-elimination pathwa y (S NAr-Ad, E) 49 8 10.5.2 The unimolecular mechanism 50 3 10.5.3 The aryne mechanism (E-Ad) 504 10.5.4 Nucleophilic substitution via ring opening : the S N(ANRORC) route 506 10.6 Nucleophilic substitutions at carbonyl carbon 507 10.6.1 Basic hydrolysis of carboxylic esters 511

10.6.2 Acidic hydrolysis of esters 51 9 10.6.3 Stereoelectronic factors in the decomposition of the tetrahedral intermediate 52 1 10.6.4 Other mechanisms for ester hydrolysis 52 2 10.6.5 Hydrolysis of amides, acyl halides and anhydrides 52 9 10.6.6 Properties of tetrahedral intermediates 53 3 10.6.7 Nucleophilic catalysis in carbonyl substitutions 53 6 Problems it Elimination reactions 55 1 11.1 Base-promoted eliminations in solution 55 1 11.1.1 Kinetic criteria of mechanisms 55 5 11.1.2 Structural effects on rates of elimination 55 6 11.1.3 Kinetic isotope effects 56 2 11.1.4 Variation of the base-solvent system 56 6 11.1.5 Competition between elimination an d substitution 56 8 11.1.6 Orientation in product formation 572 11.1.7 Stereochemistry of E2 reactions 574 11.1.8 Frontier orbital considerations 579 11.1.9 Elcb reactions -579 11.1.10 Ester hydrolysis by the Elcb mechanism 58 1 11.2 Intramolecular pyrolytic eliminations (the E ; reactions) 58 1 11.2.1 Ester pyrolysis 582 11.2.2 The Chugaev reaction 58 5 11.2.3 Amine oxide, sulphoxide and selenoxid e pyrolyses 58 6 11.2.4 Pyrolysis of alkyl halides 58 7 11.3 a-eliminations 58 8 11.4 Oxidative eliminations 58 9 11.4.1 Oxidations of alcohols by chromium (VI) 590 11.4.2 The Moffatt oxidation 59 2 12 Polar addition reactions 599 12.1 Electrophilic additions to alkenes 600 12.1.1 Kinetics 600 12.1.2 Effect of structure 602 12.1.3 Isotope effects 607

12.1.4 Orientation and stereochemistry 60 8 12.1.5 The nature of the intermediates in Ad E reactions 61 0 12.2 Miscellaneous additions 61 3 12.2.1 Hydroboration 61 3 12.2.2 Addition with ring closure ; halolactonization 61 7 12.2.3 Addition of carbocations 61 7 12.2.4 Additions to dienes, alkynes and allenes 61 8 12.3 Nucleophilic additions to multiple bonds 62 0 12.3.1 Michael addition 62 1 12.3.2 Carbonyl additions 62 2 12.3.3 Additions to heterocumulenes 62 9 12.4 Frontier orbital considerations 63 1 12.5 Vinyl substitution via addition/elimination 63 2 12.5.1 Examples 63 4 12.5.2 Stereochemistry 63 6 Problems 13 Intramolecular reactions 643 13.1 Neighbouring-group participation 64 3 13.1.1 The scope of neighbouring-group effects 64 6 13.1.2 Methods for recognizing neighbouring-group participation 64 6 13.1.3 The kinetic criterion 646 13.1.4 Linear free-energy relationships 650 13.1.5 Kinetic isotope effects 654 13.1.6 Solvent effects 654 13.1.7 Participation in carbonyl reactions 65 6 13.1.8 The stereochemical criterion 65 8 13.1.9 The rearrangement criterion 660 13.1.10 Factors influencing neighbouring-group participation 662 13.1.11 Observation and isolation of cycli c intermediates 667 13.1.12 a- and z-participation : the question of nonclassical ions 670 13.2 Enzymic reactions 678 13.2.1 The structures of enzymes 67 8 13.2.2 A model for enzyme action 680 13.2.3 Mechanisms of some enzyme-catalysed reactions 684 13.2.4 Enzymes that use cofactors 690 13.2.5 Enzyme model systems 69 3

r Perigclic reactions 70 1 14.1 Classification of pericyclic reactions 70 1 14.2 The theory of pericyclic reactions 70 2 14.2.1 Conservation of orbital symmetry : correlation diagrams 70 3 14.2.2 The frontier orbital concept 70 5 14.2.3 The aromaticity concept 70 7 14.2.4 Suprafacial and antarafacial geometries 70 7 14.3 Thermal cycloadditions : their scope and characteristics 70 9 14.3.1 The Diels-Alder reaction 71 1 14.3.2 Stereo- and regiospecificity in Diels-Alde r reactions 71 5 14.3.3 Retro Diels-Alder reactions 72 1 14.3.4 The nature of the Diels-Alder transition state 72 3 14.3.5 Related six-electron cycloadditions 72 5 14.4 Thermal (2 + 2) cycloadditions 72 7 14.4.1 Cycloadditions of cumulenes 72 8 14.4.2 Two-step cycloadditions 73 2 14.4.3 (2 + 2) Cycloreversions 73 4 14.5 1,3-Dipolar cycloadditions 73 6 14.6 Electrocyclic reactions 740 14.7 Cheletropic reactions 742 14.8 Sigmatropic reactions 748 14.8.1 Concertedness in sigmatropic rearrangements 75 1 14.9 Acid catalysis of the Diels-Alder reaction 75 3 rj Reactions via free radicals 767 15.1 The generation of radicals 767 15.1.1 Primary processes 76 8 15.1.2 Secondary routes 772 15.2 The detection of radicals 773 15.2.1 Direct observation 77 3 15,2.2 Indirect methods 779 15.2.3 By chemical characteristics 784 15.3 Reactions of radicals 78 8 15.3.1 Radical coupling 78 8 15.3.2 Displacement (abstraction, transfer) reactions 790 15.3.3 Additions to 7c-systems 79 3 15.3.4 Fragmentation of radicals 79 7 15.3.5 Radical rearrangements 79 8 15.3.6 Radical cyclization reactions 80 1 15.3.7 Linear free-energy relationships 804 15.3.8 Electron transfer reactions 806

15.4 Factors influencing the reactivities of radicals 810 15.4.1 Radical stability 81 1 15.4.2 Polar influences 81 4 15.4.3 Solvent effects on radical reactions 81 7 15.4.4 Steric effects in radical reactions 81 7 15.4.5 Frontier-orbital considerations 82 1 15.5 The stereochemistry of radicals 82 4 r6 Organic photochemistry 83 7 16.1 Excited electronic states 83 7 16.1.1 Absorption of light by molecules 83 7 16.1.2 Vertical and horizontal excitation 83 8 16.1.3 Spin multiplicity: singlet and triplet states 83 9 16.1.4 Sensitization and quenching 840 16.1.5 Techniques of photochemistry 844 16.2 Photochemistry of the carbon-carbon double bond 844 16.2.1 Geometrical isomerization 84 4 16.2.2 Photochemical pericyclic reactions 84 6 16.2.3 The di-rr-methane rearrangement 85 1 16.2.4 Photoadditions to alkenes 85 2 16.3 Photoreactions of carbonyl compounds 85 3 16.3.1 Carbon-carbon bond cleavage 854 16.3.2 Cycloadditions 85 6 16.4 Photochemistry of aromatic compounds 85 7 16.4.1 Photosubstitutions at the aromatic ring 85 8 16.4.2 The photo-fries rearrangement 85 9 16.4.3 Valence isomerization 859 16.4.4 Photocycloadditions 86 1 16.4.5 Photo-oxidations with oxygen 864 Index 871