Modern Physical Organic Chemistry
`
`Eric V. Anslyn
`
`UNIVERSITY OF TEXAS, AUSTIN
`
`Dennis A. Dougherty
`CALIFORNIA INSTITUTE OF TECHNOLOGY
`
`University Science Books
`Sausalito, California
`
`ALL 2089
`PROLLENIUM V. ALLERGAN
`IPR2019-01505 et al.
`
`

`

`University Science Books
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`Copyright© 2006 by University Science Books
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`
`Library of Congress Cataloging-in-Publication Data
`
`Anslyn, Eric V., 1960-
`Modern physical organic chemistry/ Eric V. Anslyn, Dennis A. Dougherty.
`p.cm.
`Includes bibliographical references and index.
`ISBN 1-891389-31-9 {alk. paper)
`1. Chemistry, Physical organic.
`
`I. Dougherty, Dennis A., 1952-
`
`II. Title.
`
`QD476.A57 2004
`547' .13-dc22
`
`2004049617
`
`Printed in the United States of America
`10 9 8 7 6 5 4 3 2
`
`

`

`xix
`
`Li t of High light
`Preface xxiii
`xxv
`Acknowledgme nt
`A ote to the In tru ctor xxvii
`
`PARTI
`MOLECULAR STRUCTURE AND
`THERMODY AMICS
`
`HAPTER 1: Introduction to Structure and
`Models of Bonding 3
`
`Intent and Purpo e 1
`
`1.1 A Review of Ba ic Bonding Concepts 4
`1.J. l Quantum umbers and Atomic Orbitals 4
`1.1 .2 Electron on figurations and Electronic Diagrams 5
`1.1.3 Lewis Structures 6
`1.1.4 Formal
`'harge 6
`1.15 VSEPR 7
`1.1.6 l lybndization 8
`1.1.7 A llybrid Valen e Bond /Molecular Orbital
`Model of Bonding 10
`Crmtins l.ornfr;:ed arwd ,c Bonds 11
`1.1.8 Polar ovalent Bonding 12
`Ucctronesatrz,rfy 12
`£.'lectrostatic Potenlial Surfaces 14
`Inductive Efji·cts 15
`Group Electronesativitres 16
`I lybridiwticm EffC'Cts 17
`1.1.9 Bond Dipoles, Mole ularDipoles,
`and Quadrupoles 17
`Bond D1poh•s 17
`Molernlar Dipole Moments 1
`MoiC'rnlar Quadrupole Moments 19
`1.1.10 Resonance 20
`1.1.11 Bond Lengths 22
`1.1.12 Polarizability 24
`1.1 .13 Summary of oncepts Used for the Simplest
`Model ofBonding in
`rganic tructur
`26
`
`1.2 A More Modern Theory of Organic Bonding 26
`1.2.1 Molecular Orbital Theory 27
`1.2.2 A Method for QMOT 2
`1.2.3 Methyl in D •tail 29
`Planar Met/111/ 29
`Tire Walsh 6iasrn111: Pyramidal Methyl 31
`"Group Orbitals"for Pyramidal Methyl 32
`Put tins tire Ell'Ctrons /11 - Tire MH 3 System 33
`1.2.4 The
`·11 7 Group in Detail 33
`Tire Walsh Diasrn111 and Group Orbitals 33
`Puttins tire f.lectrons /11 - The MH 1 System 33
`
`1.3 Orbital Mi ing-Building Larger Molecules 35
`1.1.1
`singC,roupOrbitalstoMakeEthane 36
`
`Contents
`
`1.3.2 Using Group Orbitals to Make Ethylene 38
`1.3.3 The Effects of Heteroatoms-Formaldehyde 40
`1.3.4 Making More Complex Alkanes 43
`1.3.5 Three More Examples of Building Larger
`Molecules from Group Orbitals 43
`Propene 43
`Methyl Chloride 45
`Butadiene 46
`1.3.6 Group Orbitals of Representative TI Systems:
`Benzene, Benzyl, and Allyl 46
`1.3.7 Understanding Common Functional
`Groups as Perturba tions of Ally l 49
`1.3.8 The Thr e Center-Two Electron Bond 50
`1.3.9 Summary of the Concepts Involved in
`Our Second Model of Bondi ng 51
`
`1.4 Bonding and Structures of Reactive Intermediates 52
`1.4.1 Carbocations 52
`Carbenium Ions 53
`Interplay with Cnrbonium Ions 54
`Carboniu11r Ions 55
`arbanions 56
`1.4.2
`1.4.3 Radica ls 57
`1.4.4 Ca rbenes 58
`
`1.5 A Very Quick Look at Organometallic
`and Inorganic Bonding 59
`
`Summary and Outlook 61
`
`EXERCISES 62
`FU RTHER READING 64
`
`CHAPTER 2: Strain and Stability 65
`
`Intent and Purpose 65
`
`2.1 Thermochemistry of Stable Molecules 66
`2.1.1 The Concepts oflnternal Strain
`and Relative Stability 66
`2.1.2 Types of Energy 68
`Gibbs free Energy 68
`Enthalpy 69
`Entropy 70
`2.1.3 Bond Dissociation Energies 70
`Using 80£s to Predict Exothermicity
`and Endothemricity 72
`2.1.4 An Introduction to Potential Functions
`and Surfaces-Bond Stretches 73
`Infrared Spectroscopy 77
`2.1.5 H ats of Formation and Combustion 77
`2.1.6 The Group Increment Method 79
`2.1.7 Strain Energy 82
`
`Vll
`
`

`

`Vlll
`
`CONTENTS
`
`2.2 Thermochemistry of Reactive Intermediates 82
`2.2.1 Stability vs. Persistence 82
`2.2.2 Radicals 83
`BDEsasaMeasureofStability 83
`Radical Persistence 84
`Group Increments for Radicals 86
`2.2.3 Carbocations 87
`Hydride Ion Affinities as a Measure of Stability 87
`Lifetimes of Carbocations 90
`2.2.4 Ca rbanions 91
`2.2.5 Summary 91
`
`2.3 Relationships Between Structure and Energetics(cid:173)
`Basic Conformational Analysis 92
`2.3.1 Acyclic Systems-Torsional Potential Surfaces 92
`Ethane 92
`Butane - The Gauche [nteraction 95
`Barrier Height 97
`Barrier Foldedness 97
`Tetraalkylethanes 98
`The g+g-Pentane Interaction 99
`Allylic (A 1.3) Strain 100
`2.3.2 Basic Cyclic Systems 100
`Cyclopropane 100
`Cyclobutane 100
`Cyclopentane 101
`Cyclohexane 102
`Larger Rings - Transannular Effects 107
`Group Increment Corrections for Ring Systems 109
`Ring Torsional Modes 109
`Bicyclic Ring Systems 110
`Cycloalkenes and Bredt's Rule 110
`Summary of Conformational Analysis and
`Its Connection to Strain 112
`
`2.4 Electronic Effects 112
`2.4.1 Interactions Involving 'IT Systems 112
`Substitution on Alkenes 112
`Conformations of Substituted Alkenes 113
`Conjugation 115
`Aromaticity 116
`Antiaromaticity, An Unusual Destabilizing Effect 117
`NMR Chemical Shifts 118
`Polycyclic Aromatic Hydrocarbons 119
`Large Annulenes 119
`2.4.2 Effects of Multiple Heteroa toms 120
`Bond Length Effects 120
`Orbital Effects 120
`
`2.5 Highly-Strained Molecules 124
`2.5.1 Long Bonds and Large Angles 124
`2.5.2 Small Rings 125
`2.5.3 Very Large Rota tion Barriers 127
`
`2.6 Molecular Mechanics 128
`2.6.1 The Molecular Mechani cs Model 129
`Bond Stretching 129
`Angle Bending 130
`Torsion 130
`Nonbonded Interactions 130
`Cross Terms 131
`
`Electrostatic Interactions 131
`Hydrogen Bonding 131
`The Parameterization 132
`Heat of Formation and Strain Energy 132
`2.6.2 General Comments on the Molecular
`Mechanics Method 133
`2.6.3 Molecular Mechanics on Biomolecules and
`Unnatural Polymers-"Modeling" 135
`2.6.4 Molecular Mechanics Studies of Reactions 136
`
`Summary and Outlook 137
`
`EXERCISES 138
`FURTHER REA DING 143
`
`CHAPTE R 3: Solutions and Non-Covalent
`Binding Forces 145
`
`Intent and Purpose 145
`
`3.1 Solvent and Solution Properties 145
`3.1.1 Nature Abhors a Vacuum 146
`3.1.2 SolventScalcs 146
`Dielectric Co11sta11 t 147
`Otlier Solvent Scales 148
`Heat of Vaporization 150
`Surface Tension and Wetting 150
`Water 151
`3.1.3 Solu bility 153
`General Overview 153
`Shape 154
`Using tlie "Like-Dissolves-Like" Paradi:,:111 154
`3.1.4 Solute Mobility 155
`Diffusion 155
`Fick's Law of Diffusion 156
`Correlation Times 156
`3.1.5 TheThermodynami csofSolutions 157
`Chemical Potential 158
`The Thermodynamics of Reactions 160
`Calrnlating !:lH 0 and ~S
`162
`
`3.2 Binding Forces 162
`3.2.1 Ion Pairing Interactions 163
`Salt Bridges 164
`3.2.2 Electrostatic Interactions In volving Dipoles 165
`Ion- Dipole Interactions 165
`A Simple Model of Tonic So/vat ion -
`The Bom Equation 166
`Dipole- Dipole Interactions 168
`3.2.3 Hydrogen Bonding 168
`Geometries 169
`Strengths of Normal Hydrogen Bonds
`i. Solvation Effects 171
`ii. [lectronegativity Effecb 172
`iii. Resonance Assisted Hydrogen Bonds 173
`iv. Polarization Enhanced Hydrogen Bonds 174
`v. Seco11darv /11teractio11s in Hydrogen
`Bonding Systems 175
`
`171
`
`

`

`0 TENTS
`
`IX
`
`tii. Cooperativity in Hydrogen Bonds 175
`Vibrational Properties of Hydroge11 Bonds 176
`S/rort-Stro11g Hydroge11 Bonds 177
`3.2.4 'TT Effects 1 0
`Catw11-Jr lnteractions 181
`Polar-Jr Interactions 1 3
`Aromatic-Aromatic Interactions (Jr Stacking) 184
`The Arene-Pcrjluoroarenc Interaction 1 4
`Jr Donor-Acceptor lntcractio11s 1 6
`3.2.5 Induced-Dipole Interactions 1 6
`Jon-lnd11ced-D1pole lntcractio11s 187
`Dipolc-lnd11ccd-D1pole lntcractions
`l 7
`/11d11ced-Dipole- /11d11ced-Dipole Interactions 1
`S11111mari::.111g Monopole, Dipole, a11d
`Induced-Dipole B111ding Forces 18
`3.2.6 The I lydrophobic ·ffect 1 9
`Aggregatio11 ofOrga111cs 189
`The Origin of the Hydrophobic Effect 192
`
`omputational Modeling of olvation 194
`3.3
`ontmuum olvat1on Models 196
`3.1.1
`::u.2 Lxpli it ohation Models 197
`3.3.3 Monte arlo (
`) Methods 19
`3.3.4 Mol cular Dynami s (MD) 199
`3.3.5 • tatist1cal P 'rturbation Theory/
`Pree Lnergy Perturbation 200
`
`ummary and Outlook 201
`
`202
`l RUSE
`l
`f RTJ f[R RE D ING 204
`
`Molecular Recognition via Hydrogen
`Bonding in Water 232
`4.2.4 Molecular Recognition with a Large
`Hydrophobic Component 234
`Cyclodextrins 234
`Cyclophanes 234
`A Summary of the Hydrophobic Component
`of Molecular Recognition in Water 238
`4.2.5 Molecular Recognition with a Large 'TT
`Component 239
`Cation-,r Interactions 239
`Polar-,r and Related Effects 241
`4.2.6 Summary 241
`
`4.3 Supramolecular Chemistry 243
`4.3.1 Supramolecu lar Assembly of Complex
`Architectu res 244
`Self-Assembly via Coordination Compounds 244
`Self-Assembly via Hydrogen Bonding 245
`ovel Supramolecular Architectures-Catenanes,
`Rotaxane , and Knots 246
`Nanotechnology 248
`4.3.3 ontainer Compounds-Molecules within
`Molecules 249
`
`4.3.2
`
`Summary and Outlook 252
`
`EXER ISES 253
`FURTHER REA DI C 256
`
`II PT R 4: Molecular Recognition and
`upramolecular Chemi try 207
`
`Intent and Purpo e 207
`
`4.1 Thermodynamic Analy e of Binding
`Phenomena 207
`4.1.1 C.enl'ral Thermodynami s ofBindi ng 20
`The Reh7.>ann' of the Standard
`fate 210
`The !11j111e11ce of a Change in Heat Capacity 212
`Cooperativity 213
`E11t/ralp11 Entropy Co111pcnsatio11 216
`4.1.2 The Binding Isotherm 216
`4.1.3 Exp •rimenta l Methods 219
`UV/Vis or F/11oresm1ce Met/rods 220
`MR Met/rods 220
`Isothermal Calonmctry 221
`
`CHAPTER 5: Acid- Base Chemistry 259
`
`Intent and Purpose 259
`
`5.1 Bronsted Acid- Base Chemistry 259
`
`5.2 Aqueous Solutions 261
`5.2.1 pK, 261
`5.2.2 pH 262
`5.2.3 The Leveling Effect 264
`5.2.4 Activity vs. Concentration 266
`5.2.5 Acidity Functions: Acidity Scale for Highly
`oncentrated Acid ic Solu tions 266
`5.2.6 Super Acids 270
`
`5.3 Nonaqueous Systems 271
`5.3.1 pK, Shifts at Enzyme Active Sites 273
`5.3.2 Solution Phase v . Gas Phase 273
`
`4.2 Molecular Recognition 222
`4 2.1
`omplem •ntarity and Preorganization 224
`Crowns, Cryptands, and pherands-Molccular
`Rccag111t1011 withal argc /011 Dipole Component 224
`Tll>cczcr, and Chjts 228
`ole ular Re ognition with a Large
`Ion Pairing ompon nt 22
`4.2.3 Mol cular Recognition wi th a Larg Hyd rogen
`Bonding omponent 230
`Rcprcscntatn•c tructures 230
`
`4.2.2
`
`5.4 Predicting Acid Strength in Solution 276
`5.4.1 Meth d Used to Measur Weak Acid Strength 276
`5.4.2 Two Guiding Principle· for Predicti ng
`Relative Acid ities 277
`5.4.3 Electronegativity and Induction 278
`5.4.4 Re onance 278
`5.4.5 Bond Strengths 283
`5.4.6 Electrosta tic Effects 283
`5.4.7 Hybridization 283
`
`

`

`X
`
`CONTE TS
`
`5.4.8 Aromaticity 284
`5.4.9 Solvation 284
`5.4.10 Cationic Organic Structures 285
`
`6.6.3 Nonplanar Graphs 326
`6.6.4 Achievements in Topological and Supramolecular
`Stereochemistry 327
`
`5.5 Acids and Bases of Biological Interest 285
`
`6.7 Stereochemical Issues in Polymer Chemistry 331
`
`5.6 Lewis Acids/Bases and Electrophiles/
`Nucleophiles 288
`5.6.1 The Concept of Hard and Soft Acids and Bases, General
`Lessons for Lewis Acid-Base Interactions, and Relative
`Nucleophilicity and Electrophilicity 289
`
`Summary and Outlook 292
`
`EXERCISES 292
`FURTHER READING 294
`
`CHAPTER 6: Stereochemistry 297
`
`Intent and Purpose 297
`
`6.1 Stereogenicity and Stereoisomerism 297
`6.1.l Basic Concepts and Terminology 298
`Classic Terminology 299
`More Modern Terminology 301
`6.1.2 Stereochemical Descriptors 303
`R,S System 304
`E,Z System 304
`oand L 304
`Erythro and Threo 305
`Helical Descriptors-Mand P 305
`Ent and Epi 306
`Using Descriptors to Compare Structures 306
`6.1.3 Distinguishing Enantiomers 306
`Optical Activity and Chirality 309
`Why is Plane Polarized Light Rotated
`by a Chiral Medium? 309
`Circular Dichroism 310
`X-Ray Crystallography 310
`
`6.2 Symmetry and Stereochemistry 311
`6.2.1 Basic Symmetry Operations 311
`6.2.2 Chirality and Symmetry 311
`6.2.3 Symmetry Arguments 313
`6.2.4 Focusing on Carbon 314
`
`6.3 Topicity Relationships 315
`6.3.1 Homotopic, Enantiotopic, and Diastereotopic 315
`6.3.2 Topi city Descriptors-Pro-R /Pro-Sand Re/ Si 316
`6.3.3 Chirotopicity 317
`
`6.4 Reaction Stereochemistry: Stereoselectivity
`and Stereospecificity 317
`6.4.l Simple Guidelines for Reaction Stereochemistry 317
`6.4.2 Stereospecific and Stereoselective Reactions 319
`
`6.5 Symmetry and Time Scale 322
`
`6.8 Stereochemical Issues in Chemical Biology 333
`6.8.l The Linkages of Proteins, Nucleic Acids,
`and Polysaccharides 333
`Proteins 333
`Nucleic Acids 334
`Polysaccharides 334
`6.8.2 Helicity 336
`Synthetic Helical Polymers 337
`6.8.3 The Origin of Chirality in ature 339
`
`6.9 Stereochemical Terminology 340
`
`Summary and Outlook 344
`
`EXERCISES 344
`FURTHER READING 350
`
`PARTII
`REACTIVITY, KINETICS, AND
`MECHANISMS
`
`CHAPTER 7: Energy Surfaces and
`Kinetic Analyses 355
`
`Intent and Purpose 355
`
`7.1 Energy Surfaces and Related Concepts 356
`7.1.1 Energy Surfaces 357
`7.1.2 Reaction Coordinate Diagrams 359
`7.1.3 What is the Nature of the Activated
`Complex/Transition State? 362
`7.1.4 Rates and Rate Constants 363
`7.1.5 Reaction Order and Rate Laws 364
`
`7.2 Transition State Theory (TST) and Related Topics 365
`7.2.l The Mathematics of Transition State Th ory 365
`7.2.2 Relationship to the Arrhenius Rate Law 367
`7.2.3 Boltzmann Distributions and Temperature
`Dependence 368
`7.2.4 Revisiting "What is the Nature of the Activated
`Complex?" and Why Does TST Work? 369
`7.2.5 Experimental Determinations of Activation Parameters
`and Arrhenius Parameters 370
`7.2.6 Examples of Activation Parameters and
`Their Interpretations 372
`7.2.7 Is TST Completely orrect? The Dynamic Behavior
`of Organic Reactive Intermediates 372
`
`6.6 Topological and Supramolecular Stereochemistry 324
`6.6.1 Loops and Knots 325
`6.6.2 Topological Chirality 326
`
`7.3 Postulates and Principles Related
`to Kinetic Analysis 374
`7.3.l The Hammond Postulate 374
`7.3.2 The Reactivity vs. Selectivity Principle 377
`
`

`

`CONTENTS
`
`XI
`
`7.3.3 The Curtin-Hammett Principle 378
`7.3.4 Microscopic Reversibility 379
`7.3.5 Kinetic vs. Thermodynamic Control 380
`
`7.4 Kinetic Experiments 382
`7.4.1 How Kinetic Experiments are Performed 382
`7.4.2 Kinetic Analyse., for Simple Mechanisms 384
`r m,t Order K111etics 385
`Seco11d Order Kinetic, 3 6
`Pse11do-First Order Ki11etics 387
`Eq11ili/1ri11111 Ki11etics 388
`/11itial-Rate Kinetic:, 389
`Tal11tl11tins 11 Series ofC0111111011 Kinetic Scenarios 389
`
`7.5 Complex Reactions-Deciphering Mechanisms 390
`7.5.1 Steady State Kinetic:-, 390
`7.5.2 u ... ing the SSA to Predict Changes
`111 Kinetic Order 395
`7.5.3 Saturation Kinetics 396
`7.5.4 Prior Rapid Equilibria 397
`
`7.6 Methods for Following Kinetics 397
`7.6.1 Reactions with Half-Lives Greater
`than a few Seconds 398
`7.6.2 f.ast Kinetics Techniques 398
`l fou, 1cch111q11e~ 399
`flash Photolysis 399
`Pube Radiolysi~ 401
`7.61 Relaxation Ml'thods 401
`7.6.4 Summary of Kinetic Analyses 402
`
`alculating Rate Constants 403
`7.7
`7.7.1 Marcus Thl'or, 40.1
`7.7.2 Marcus Theory Applied to Electron Transfer 405
`
`on idering Multiple Reaction Coordinates 407
`7.8
`7.8.1 Variation in Tr,m.,ition State Structures Across
`a Series of Related Rcacltons- An Example
`Ustng Subs ti tu tion React10ns 407
`7.8 2 More OTerrall Jencks Plots 409
`7.8.3 Change.., in Vibrational State Along the Reaction
`Coordinate Relating the Third oordinate
`to Entropy 412
`
`ummary and Outlook 413
`
`[X[R ISES 411
`fURTIIER R[ADI G 417
`
`CHAPTER 8: Experiments Related to
`Thermodynamics and Kinetics 421
`
`Intent and Purpose 421
`
`8.1 I otope Effects 421
`8.1 1 The Experiment 422
`8.1.2 The Origin of Primary Kineticlsotope Effects 422
`Reactio11 Coordi1111te Di11srm11s 1111d Isotope
`Effects 424
`
`Primary Kinetic Isotope Effects for Linear
`Transition States as a F11nctio11 of Exothermicity
`and Endothermicity 425
`Isotope Effects for Linear vs. Non-Linear
`Transition States 428
`8.1.3 The Origin of Secondary Kinetic Isotope Effects 428
`Hybridization Changes 429
`Steric Isotope Effects 430
`8.1.4 Equilibrium Isotope Effects 432
`Isotopic Pert11rbatio11 of Equilibrium(cid:173)
`Applications to Carbocations 432
`8.1.5 Tunneling 435
`8.1.6 Solvent Isotope Effects 437
`Fractionation Factors 437
`Proton Inventories 438
`8.1.7 Heavy Atom Isotope Effects 441
`8.1.8 Summary 441
`
`8.2 Substituent Effects 441
`8.2.1 The Origin of Substituent Effects 443
`Field Effects 443
`Inductive Effects 443
`Reso11a11ce Effects 444
`Polarizability Effects 444
`Steric Effects 445
`Salvation Effects 445
`
`8.3 Hammett Plots-The Most Common LFER.
`A General Method for Examining Changes
`in Charges During a Reaction 445
`8.3.1 Sigma (a) 445
`8.3.2 Rho (p) 447
`8.3.3 The Power of Hammett Plots for
`Deciphering Mechanisms 448
`8.3.4 Deviations from Linearity 449
`8.3.S Separating Resonance from Induction 451
`
`8.4 Other Linear Free Energy Relationships 454
`8.4.1 Steric and Polar Effects-Taft Parameters 454
`8.4.2 Solvent Effects-Grunwald-Winstein Plots 455
`8.4.3 Schleyer Adaptation 457
`8.4.4
`ucleophilicity and Nucleofugality 458
`Basicity/Acidity 459
`Solvatio11 460
`Polarizability, Basicity, and Salvation Interplay 460
`Shape 461
`8.4.5 Swain-Scott Parameters- ucleophilicity
`Parameters 461
`8.4.6 Edwards and Ritchie Correlations 463
`
`8.5 Acid-Base Related Effects-
`Bronsted Relationships 464
`8.5.1 /3r-.u, 464
`8.5.2 /31 (, 464
`8.5.3 Acid-Base Catalysis 466
`
`8.6 Why do Linear Free Energy Relationships Work? 466
`8.6.1 General Mathematics of LFERs 467
`8.6.2 Conditions to Create an LFER 468
`8.6.3 The Isokinetic or lsoequilibrium Temperature 469
`
`

`

`Xll
`
`CONTENTS
`
`8.6.4 Why does Enthalpy-Entropy
`Compensation Occur? 469
`Steric Effects 470
`Solvation 470
`
`8.7 Summary of Linear Free Energy Relationships 470
`
`8.8 Miscellaneous Experiments for
`Studying Mechanisms 471
`8.8.1 Product Identification 472
`8.8.2 Changing the Reactant Structure to Divert
`or Trap a Proposed Intermediate 473
`8.8.3 Trapping and Competition Experiments 474
`8.8.4 Checking for a Common Intermediate 475
`8.8.5 Cross-Over Experiments 476
`8.8.6 Stereochemical Analysis 476
`8.8.7 Isotope Scrambling 477
`8.8.8 Techniques to Study Radica ls: Clocks and Traps 478
`8.8.9 Direct Isolation and Characterization
`of an Intermediate 480
`8.8.10 TransientSpectroscopy 480
`8.8.11 Stable Media 481
`
`9.3.4 Concerted or Sequential General-Acid(cid:173)
`General-Base Catalysis 515
`9.3.5 The Brnnsted Catalysis Law
`and Its Ramifications 516
`A Linear Free Energy Relationship 516
`TheMeaningofaandfl 517
`a+fl=1 518
`Deviations from Linearity 519
`9.3.6 Predicting General-Acid or
`General-Base Catalysis 520
`The Libido Rule 520
`Potential Energy Surface;. Dictate
`General or Specific Catalysis 521
`9.3.7 The Dynamics of Proton Transfers 522
`Marrns Analysis 522
`
`9.4 Enzymatic Catalysis 523
`9.4.1 Michaelis Men ten Kinetics 523
`9.4.2 The Meaning of K'l.1, k,.1, and kc.,J K,1 524
`9.4.3 Enzyme Active Sites 525
`9.4.4 [SJ vs. KM-Reaction Coordinate Diagrams 527
`9.4.5 Supramolecular Interactions 529
`
`Summary and Outlook 482
`
`EXERCISES 482
`FURTHER REA DI NG 487
`
`Summary and Outlook 530
`
`EXE RCISES 531
`FURTHER READING 535
`
`CHAPTER 9: Catalysis 489
`
`Intent and Purpose 489
`
`9.1 General Principles of Catalysis 490
`9.1.1 Binding the Transition State Better
`than the Ground State 491
`9.1.2 A Thermodynamic Cycle Ana lysis 493
`9.1.3 A Spa tial Temporal Approach 494
`
`9.2 Forms of Catalysis 495
`9.2.1 "Binding" is Akin to Solvation 495
`9.2.2 Proximity as a Binding Phenomenon 495
`9.2.3 Electrophilic Catalysis 499
`Electrostatic Interactions 499
`Metal Ton Catalysis 500
`9.2.4 Acid-Base Catalysis 502
`9.2.5 Nucleophilic Catalysis 502
`9.2.6 Covalent Catalysis 504
`9.2.7 Strain and Distortion 505
`9.2.8 Phase Transfer Catalysis 507
`
`9.3 Brnnsted Acid- Base Catalysis 507
`9.3.1 Specific Catalysis 507
`The Mathematics of Specific Catalysis 507
`Kinetic Plots 510
`9.3.2 General Catalysis 510
`The Mathematics of General Catalysis 511
`Kinetic Plots 512
`9.3.3 A Kinetic Equivalency 514
`
`CHAPTER 10: Organic Reaction Mechanisms,
`Part 1: Reactions Involving Additions
`and/or Eliminations 537
`
`Intent and Purpose 537
`
`10.1 Predicting Organic Reactivity 538
`10.1.1 A Useful Paradigm for Polar Reaction'> 539
`Nucleophiles and Electrophiles 539
`Le1.1.1is Acids and Ll'1.ois Bases 540
`Donor- Acceptor Orbital Interactions 540
`10.1.2 Predicting Radical Reactivity 541
`10.1.3 In Prepa ration for the following Section., 541
`
`- ADDITION REACTIONS- 542
`10.2 Hydration of Carbonyl Structures 542
`10.2.1 Acid-Base Cata lysis 543
`10.2.2 The Thermodynamics of the Formation
`of Geminal Diols and f Iemiacetals 544
`
`10.3 Electrophilic Addition of Water to Alkenes
`and Alkynes: Hydration 545
`10.3.1 Electron Pushing 546
`10.3.2 Acid-Catalyzed Aqueous J !yd ration 546
`10.3.3 Regiochemistry 546
`10.3.4 Alkyne Hydration 547
`
`10.4 Electrophilic Addition of Hydrogen Halides
`to Alkenes and Alkynes 548
`10.4.1 Electron Pu'ihing 548
`
`

`

`C.0 TE TS
`
`Xlll
`
`10.4.2 E perimental Observations Related to
`Regiochcmistry and tereochemistry 548
`10.4.3 Addition to Alkynes 551
`
`10.5 Electrophilic Addition of Halogens
`to Alkene
`551
`10.5.1 I:lcdron Pushing 551
`10.5.2 StL•rcochemistry 552
`10.5.3 Other Ev1dcnc~ Supporting arr Complex 552
`10.5.4 Mechanistic Variants 553
`10.5.5 Addition to Alk.ynes
`,54
`
`10.6 Hydroboration 554
`10.6.1 Elt•ctron Pu..,hing 555
`10.6.2 E pcrimental Observations 555
`
`10.7 poxidation 555
`10.7.1 Electron Pushing 556
`10.7.2 fapL•rimL•ntal Observations 556
`
`10.8
`
`ucleophilic Addition to
`Carbonyl ompound
`S56
`10.8.1 [ lcctron Pushing for a Few ucleophilic
`Additions 557
`10.8.2 E perimL•ntal bservalions for
`yanohydrin Formation 559
`10.8.3 E. pcrimental Observations for
`Crignard RL•actions 560
`10.8.4 E perimental Observations in
`I.Al I Reductions 561
`,61
`10.8.5 Orbital Considerations
`The 81irgi- D1111itz Angle 561
`Orbital Mni11g 562
`10.8.6 onformational Effects in Additions
`to Carbony 1 Compounds 562
`10.8.7 ">tL•reoch •nw,try of ucleophihc Additions 563
`
`uclcophilic ddition to Olefins 567
`10.9
`l(l 9 1 [ lectron Pushing 567
`10.9.2 E pcrimental Observations 567
`10.9.3 RL•giochem1strv of Addition 567
`10.9.4 Baldwin's Rules 568
`
`10.10 Radical Additions to Unsaturated
`y tern
`569
`10.10.1 Llectron Pw,hing for Radical Additions 569
`10.10.2 Radical Initiators 570
`10.10.3 Chain Transfer vs. Polymerization 571
`10.10.4 TL•rmination 571
`l 0.10.5 Reg1ochemistry of Radical Addition
`
`572
`
`arbene Additions and Insertions 572
`10.11
`10.11 l flectron Pushing for arbene Reactions 574
`10.11.2 Carbene eneration 574
`10.11 1 r perimental Observations for
`C.arbene RL•,Kbons 575
`
`10.12.2 Stereochemical and Isotope
`Labeling Evidence 577
`10.12.3 Catalysis of the Hydrolysis of Acetals 578
`10.12.4 Stereoelectronic Effects 579
`10.12.5 Cr03 Oxidation-The Jones Reagent 580
`Electron Pushing 580
`A Few Experimental Observations 581
`
`10.13 Elimination Reactions for Aliphatic Systems(cid:173)
`Formation of Alkenes 581
`10.13.1 Electron Pushing and Definitions 581
`10.13.2 Some Experimental Observations
`for E2 and El Reactions 582
`10.13.3 Contrasting Elimination
`and Substitution 583
`10.13.4 Another Possibility-E1cB 584
`10.13.5 Kinetics and Experimental Observations
`for ElcB 584
`10.13.6 Contrasting E2, El, and E1cB 586
`10.13.7 Regiochemistry of Eliminations 588
`10.13.8 Stereochemistry of Eliminations-
`Orbital onsiderations 590
`10.13.9 Dehydration 592
`Electron Pushing 592
`Other Mechanistic Possibilities 594
`10.13.10 Thermal Eliminations 594
`
`10.14 Eliminations from Radical Intermediates 596
`
`-COMBI ING ADDITIO A D ELIMINATIO
`REACTIONS (SUBSTITUTIONS AT sp2 CENTERS)- 596
`10.15 The Addition of Nitrogen Nucleophiles
`to Carbonyl Structures, Followed
`by Elimination 597
`10.15.1 Electron Pushing 598
`10.15.2 Acid-Base Catalysis 598
`
`10.16 The Addition of Carbon Nucleophiles,
`Followed by Elimination-
`The Wittig Reaction 599
`10.16.1 Electron Pushing 600
`
`10.17 Acyl Transfers 600
`10.17.1 General Electron-Pushing Schemes 600
`10.17.2 IsotopeScrambling 601
`10.17.3 Predicting the Site of Cleavage for
`Acy! Transfers from Esters 602
`atalysis 602
`
`10.17.4
`
`10.18 Electrophilic Aromatic Substitution 607
`10.18.1 Electron Pushing for Electrophilic
`AromaticSubstitutions 607
`10.18.2 Kinetics and Isotope Effects 608
`10.18.3 Intermediate Complexes 608
`10.18.4 Regiochemistry and Relative Rates of
`Aromatic Substitution 609
`
`576
`-CLIMI ATIO
`-
`10.12
`· limination to Form Carbonyl or "Carbonyl-Like"
`Intermediate
`577
`10.12.1 Electron Pushing 577
`
`10.19 Nucleophilic Aromatic Substitution 611
`10.19.1 Electron Pushing for ucleophilic
`Aromatic Substitution 611
`10.19.2 Experimental Observations 611
`
`

`

`XIV
`
`CONTENTS
`
`10.20 Reactions Involving Benzyne 612
`10.20.1 Electron Pushing for Benzyne Reactions 612
`10.20.2 Experimental Observa tions 613
`10.20.3 Substituent Effects 613
`
`10.21 The SR 1 Reaction on Aromatic Rings 615
`10.21.l Electron Pushing 615
`10.21.2 A Few Experimental Observations 615
`
`10.22 Radical Aromatic Substitutions 615
`10.22.1 Electron Pushing 615
`10.22.2 Isotope Effects 616
`10.22.3 Regiochemistry 616
`
`Summary and Outlook 617
`
`EXERCISES 617
`FURTH ER REA DING 624
`
`11.5.9 Structure-Function Correlations
`with the ucleophile 648
`11.5.10 Structure-Function Correlations
`with the Leaving Group 651
`11.5.11 Structure-Function Correlations
`with the R Group 651
`Effect of the R Group Structure 011 SN2 Reactions 651
`Effect of the R Group Structure 011 S..,1 Reactions 653
`11.5.12 CarbocationRearrangements 656
`11.5.13 Anchimeric Assistance in S,,.1 Reactions 659
`11.5.14 S. 1 Reactions Involving on-
`lassical
`Carbocations 661
`Norbornyl Cation 662
`Cyclopropyl Carbinyl Carbocatio11 664
`11.5.15 Summary of Carbocation Stabilization
`in Various Reactions 667
`11.5.16 The Interplay Between Substitution
`and Elimination 667
`
`CHAPTER 11: Organic Reaction Mechanisms,
`Part 2: Substitutions at Aliphatic
`Centers and Thermal Isomerizations/
`Rearrangements 627
`
`Intent and Purpose 627
`
`- SUBSTITUTION u TO A CARBONYL CENTER:
`627
`ENOL AND ENOLATE CH EMISTRY-
`11.1 Tautomerization 628
`11.1.l Electron Pushing for Keto-Eno!
`Tautomerizations 628
`11.1.2 The Thermodynamics ofEnol Formation 628
`11.1.3 Catalysis ofEnolizations 629
`11.1.4 Kinetic vs. Thermodynamic Control
`in Enola te and Enol Formation 629
`
`11.2 a-Halogenation 631
`11.2.1 Electron Pushing 631
`11.2.2 A Few Experimenta l Observations 631
`
`11.3 a-Alkylations 632
`11.3.1 Electron Pushing 632
`11.3.2 Stereochemistry: Conformational Effects 633
`
`11.4 The Aldol Reaction 634
`11.4.1 Electron Pushing 634
`11.4.2 Conformational Effects on the Aldo] Reaction 634
`
`- SUBSTITUTIONS ON ALIPHATIC CENTERS- 637
`11.5 Nucleophilic Aliphatic Substitution Reactions 637
`11.5.1 S 2 and SNl Electron-Pushing Examples 637
`11.5.2 Kinetics 638
`11.5.3 Competition Experimen ts and Product Analyses 639
`11.5.4 Stereochemistry 640
`11.5.5 Orbital Considerations 643
`11.5.6 Solvent Effects 643
`11.5.7 Isotope Effect Data 646
`11.5.8 An Overall Picture ofSN2 and SNl Reactions 646
`
`11.6 Substitution, Radica l, Nucleophilic 668
`11.6.1 The SET Reaction-Electron Pushing 668
`11.6.2 The Nature of the Intermediate
`in an SET Mechanism 669
`11.6.3 Radical Rearrangements as Evidence 669
`11.6.4 Structure-Function orrelations
`with the Leaving Group 670
`11.6.5 The SRN1 Reaction Electron Pushing 670
`
`11.7 Radical Aliphatic Substitutions 671
`11.7.1 Electron Pushing 671
`11.7.2 Heats of Reaction 671
`11.7.3 Regiochemistry of Free Radical
`Halogenation 671
`11.7.4 Autoxidation: Addition of02
`into C-H Bonds 673
`Electron Pushing for Autoxidalion 673
`
`- ISOM ERI ZATIONS AN D REARRA CEMENTS- 674
`11.8 Migrations to Electrophilic Carbons 674
`11.8.1 Electron Pushing for the
`Pinacol Rearrangement 675
`11.8.2 Electron Pushing in the Benzilic Acid
`Rearrangement 675
`11.8.3 Migratory Aptitudes in the Pinacol
`Rearrangement 675
`11.8.4 Stereoelectronic and Ster ochemical onsiderations
`in the Pinacol Rearrangement 676
`11.8.5 A Few Experimental Observations for the Benzilic
`Acid Rearrangement 678
`
`11.9 Migrations to Electrophilic Heteroatoms 678
`11.9.1 Electron Pushing in the Beckmann
`Rearrangement 678
`11.9.2 Electron Pushing for the Hofmann
`Rearrangement 679
`11.9.3 Electron Pushing for the chmidt
`Rearrangement 680
`11.9.4 Electron Pushing for the Baeyer-Villiger
`Oxidation 680
`11.9.5 A Few Experimental Observations for the
`Beckmann Rearrangement 680
`
`

`

`CONTEI\JTS
`
`xv
`
`11.9.6 A Few Experimental bservations for the
`hmidt Rearrangement 6 1
`11.9.7 A Few Experimental bs •rvations for the
`Baeyer-Villiger xidation 6 1
`
`11.10 The Favor kii Rearrangement and Other
`arbanion Rearrangement
`682
`11.10.1 Llectron Pushmg 682
`11.10.2
`ther arbanion Rearrangements 6 3
`
`11.11 Rearrangements Involving Radicals 6 3
`11.11 1 Hydrogen hifts 6 3
`11.1 l 2 Ary) and
`inyl hifts 6 4
`11.11 1 Ring• pening Rea tions 6 5
`
`11.12 Rearrangement and I omerization
`Involving Bi radical
`685
`I 1.12.1 L lectron Pushing Involving Bi radicals 686
`11.12.2 ·1,tramethvlene 6 7
`11.12.3 lrimcthyl~nc 689
`11.12.4 'Jrimethylcn •methane 693
`
`ummary and Outlook 695
`
`695
`ISL
`L UR
`f RTllrR R[ DI G 703
`
`H rr R 12: Organotran ition Metal Reaction
`Mechani m and ataly is 705
`
`Intent and Purpo e 705
`
`12.1 Th Ba ic of Organometallic omplexes 705
`12.1.1 I lcctron ounting and x1dc1tion
`late 706
`Ueclrm1 Ca1111ting 706
`Oxidation State 708
`d Uectron Co1111t 708
`A111big11itie, 708
`12.1.2 Th • 1 -[ le tron Ruic 710
`12.1.3
`tandard C, omctnes 710
`12.1.4 Tcrminolog)-
`711
`12.1.5 Electron Pushing with
`Stnictur>s 711
`12.1.6 dOrbital plitting Patterns 712
`12.1.7 Stabilizing Reactive Ligands 713
`
`rganometallic
`
`Structure-Function Relationships
`for the Ligands 720
`Oxidative Addition at sp2 Centers 721
`Summary of the Mechanisms for Oxidative
`Addition 721
`12.2.3 Reductive Elimination 724
`Structure-Function Relationship for the
`R Group and the Ligands 724
`Stereoc/zemistry nt the Metal Ce11ter 725
`Other Mechanisms 725
`Summary of the Mechanis111s for
`Reductive Elimination 726
`12.2.4 o:- and [3-Eliminations 727
`General Trends for a- nnd /3-Eli111i11ations 727
`Kinetics 728
`Stereoche111istry of {3-Hydride Elimi11ntion 729
`12.2.5 Migratory Insertions 729
`Kinetics 730
`Studies to Decipher the Mechanism of Migratory
`lnsertio11 /11volving CO 730
`Other Stereoche111icnl Considerations 732
`12.2.6 Electrophilic Addition to Ligands 733
`Reaction Types 733
`Common Mechanisms Deduced from
`Stereoc/1e111icnl Analyses 734
`ucleophilic Addition to Ligands 734
`Reaction Types 735
`Stereochemical and Rcgiochemicnl A11alyses 735
`
`12.2.7
`
`12.3 Combining the Individual Reactions into Overall
`Transformations and Cycles 737
`12.3.1 The atureofOrganometallic ataly is-
`hange in Mechanism 738
`12.3.2 The Mon anto Acetic Acid Synthesis 738
`12.3.3 Hydroformylation 739
`12.3.4 Th Water-Gas Shift Reaction 740
`12.3.5 OlefinOxidation-Th WackerProcess 741
`12.3.6 Palladium oupling Reactions 742
`12.3.7 Allylic Alkylation 743
`12.3.8 Olefin Metathesis 744
`
`Summary and Outlook 747
`
`EXERCI ES 748
`FURTHER READ! G 750
`
`12.2
`12 2.1
`
`12.2.2
`
`ommon Organometallic Reactions 714
`l igand Exchange Reactions 714
`Rmctio11 Type~ 714
`Kint'lic~ 716
`tr11ct11re-F1111ctian Rclation~/11ps with the Mein/ 716
`trnct11rc-F1111ction Rclntio11ships
`with the Ligand 716
`11/1stit11tions of Other Ligands 717
`. idativeAddition 717
`Staeocl,emiMry of the Mein/ Co111plex 71
`Kinetic~ 718
`tcreoc/1e1111stry of t/1e R Gro11p 719
`lr11rl11re-F11nctio11 Rdnlic111shipfor the R Group 720
`
`CHAPTER 13: Organic Polymer and
`Materials Chemistry 753
`
`Intent and Purpose 753
`
`13.1 Structural Issues in Materials Chemistry 754
`13. 1.1 Molecular Weight Analysis of Polymer
`754
`Number Average nnd Weight Average Molernlnr
`Weights-M,, and M11• 754
`13.1.2 Thermal Transitions-Thermoplastics
`and Elastomers 757
`13.1.3 Basic Polym r Topologi s 759
`
`

`

`xvi
`
`CONTENTS
`
`13.1.4 Polymer-Polymer Phase Behavior 760
`13.1.5 Polymer Processing 762
`13.1.6 Novel Topologies-Dendrimers and
`Hyperbranched Polymers 763
`Dendrimers 763
`Hy