modern physical organic chemistry

Modern Physical Organic Chemistry


Eric V. AnslynUniversity of Texas, Austin

Dennis A. DoughertyCalifornia Institute of Technology

University Science BooksSausalito, California

University Science Bookswww.uscibooks.com

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Copyright� 2005 byUniversity Science Books

Reproduction or translation of any part of this work beyond that permitted bySection 107 or 108 of the 1976United States Copyright Act without the permissionof the copyright owner is unlawful. Requests for permission or further informationshould be addressed to the Permissions Department, University Science Books.

Library of Congress Cataloging-in-PublicationData

Ansyln, 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 2004547�.13—dc22

2004049617

Printed in theUnited States of America09 08 07 06 05 10 9 8 7 6 5 4 3 2 1

v

Abbreviated Contents

part I: Molecular Structure and Thermodynamics

chapter 1. Introduction to Structure andModels of Bonding 32. Strain and Stability 653. Solutions andNon-Covalent Binding Forces 1454. Molecular Recognition and Supramolecular Chemistry 2075. Acid–Base Chemistry 2596. Stereochemistry 297

part II: Reactivity, Kinetics, andMechanisms

chapter 7. Energy Surfaces andKinetic Analyses 3558. Experiments Related to Thermodynamics andKinetics 4219. Catalysis 48910. Organic ReactionMechanisms, Part 1:Reactions InvolvingAdditions and/or Eliminations 537

11. Organic ReactionMechanisms, Part 2:Substitutions at Aliphatic Centers and ThermalIsomerizations/Rearrangements 627

12. OrganotransitionMetal ReactionMechanisms andCatalysis 705Intent and Purpose 705

13. Organic Polymer andMaterials Chemistry 753

part III: Electronic Structure: Theory andApplications

chapter 14. Advanced Concepts in Electronic Structure Theory 80715. Thermal Pericyclic Reactions 87716. Photochemistry17. Electronic OrganicMaterials 1001

appendix 1. Conversion Factors andOther Useful Data 00002. Electrostatic Potential Surfaces for Representative OrganicMolecules 00003. GroupOrbitals of Common Functional Groups:Representative Examples Using SimpleMolecules 0000

4. TheOrganic Structures of Biology 00005. Pushing Electrons 00006. ReactionMechanismNomenclature 0000

vii

Contents

List of Highlights 00Preface 00Acknowledgments 00A Note to the Instructor 00

PART IMOLECULAR STRUCTURE ANDTHERMODYNAMICS

CHAPTER 1: Introduction to Structure andModels of Bonding 3

Intent and Purpose 3

1.1 A Review of Basic Bonding Concepts 41.1.1 QuantumNumbers andAtomic Orbitals 41.1.2 Electron Configurations and Electronic Diagrams 51.1.3 Lewis Structures 61.1.4 Formal Charge 61.1.5 VSEPR 71.1.6 Hybridization 81.1.7 AHybrid Valence Bond/Molecular Orbital

Model of Bonding 10Creating Localized s and p Bonds 11

1.1.8 Polar Covalent Bonding 12Electronegativity 12Electrostatic Potential Surfaces 14Inductive Effects 15Group ElectronegativitiesHybridization Effects

1.1.9 BondDipoles,Molecular Dipoles,andQuadrupoles 17BondDipoles 17Molecular DipoleMoments 18Molecular QuadrupoleMoments 19

1.1.10 Resonance 201.1.11 Bond Lengths 221.1.12 Polarizability 241.1.13 Summary of Concepts Used for the Simplest

Model of Bonding inOrganic Structures 26

1.2 A More Modern Theory of Organic Bonding 261.2.1 Molecular Orbital Theory 271.2.2 AMethod for QMOT 281.2.3 Methyl in Detail 29

PlanarMethyl 29TheWalsh Diagram: PyramidalMethyl 31‘‘GroupOrbitals’’ for PyramidalMethyl 32Putting the Electrons In—TheMH3 System 33

1.2.4 The CH2Group inDetail 33TheWalsh Diagram and GroupOrbitals 33Putting the Electrons In—TheMH2 System 33

1.3 Orbital Mixing—Building Larger Molecules 351.3.1 UsingGroupOrbitals toMake Ethane 36

1.3.2 UsingGroupOrbitals toMake Ethylene 381.3.3 The Effects of Heteroatoms—Formaldehyde 401.3.4 MakingMore ComplexAlkanes 431.3.5 ThreeMore Examples of Building Larger

Molecules fromGroupOrbitals 43Propene 43Methyl Chloride 45Butadiene 46

1.3.6 GroupOrbitals of Representative� Systems:Benzene, Benzyl, andAllyl 46

1.3.7 Understanding Common FunctionalGroups as Perturbations of Allyl 49

1.3.8 The Three Center–Two Electron Bond 501.3.9 Summary of the Concepts Involved in

Our SecondModel of Bonding 51

1.4 Bonding and Structures of Reactive Intermediates 521.4.1 Carbocations 52

Carbenium Ions 53Interplay with Carbonium Ions 54Carbonium Ions 55

1.4.2 Carbanions 561.4.3 Radicals 571.4.4 Carbenes 58

1.5 A Very Quick Look at Organometallicand Inorganic Bonding 59

Summary and Outlook 61

EXERCISES 62FURTHER READING 64

CHAPTER 2: Strain and Stability 65


2.1 Thermochemistry of Stable Molecules 662.1.1 The Concepts of Internal Strain

and Relative Stability 662.1.2 Types of Energy 68

Gibbs Free Energy 68Enthalpy 69Entropy 70

2.1.3 BondDissociation Energies 70Using BDEs to Predict Exothermicityand Endothermicity 72

2.1.4 An Introduction to Potential Functionsand Surfaces—Bond Stretches 73Infrared Spectroscopy 77

2.1.5 Heats of Formation andCombustion 772.1.6 TheGroup IncrementMethod 792.1.7 Strain Energy 82

viii CONTENTS

2.2 Thermochemistry of Reactive Intermediates 822.2.1 Stability vs. Persistence 822.2.2 Radicals 83

BDEs as aMeasure of Stability 83Radical Persistence 84Group Increments for Radicals 86

2.2.3 Carbocations 87Hydride Ion Affinities as aMeasure of Stability 87Lifetimes of Carbocations 90

2.2.4 Carbanions 912.2.5 Summary 91

2.3 Relationships Between Structure and Energetics—Basic Conformational Analysis 92

2.3.1 Acyclic Systems—Torsional Potential Surfaces 92Ethane 92Butane—The Gauche Interaction 95Barrier Height 97Barrier Foldedness 97Tetraalkylethanes 98The g+g– Pentane Interaction 99Allylic (A1,3) Strain 100

2.3.2 Basic Cyclic Systems 100Cyclopropane 100Cyclobutane 100Cyclopentane 101Cyclohexane 102Larger Rings—Transannular Effects 107Group Increment Corrections for Ring Systems 109Ring TorsionalModes 109Bicyclic Ring Systems 110Cycloalkenes and Bredt’s Rule 110Summary of Conformational Analysis andIts Connection to Strain 112

2.4 Electronic Effects 1122.4.1 Interactions Involving� Systems 112

Substitution on Alkenes 112Conformations of Substituted Alkenes 113Conjugation 115Aromaticity 116Antiaromaticity, AnUnusual Destabilizing Effect 117NMRChemical Shifts 118Polycyclic Aromatic Hydrocarbons 119Large Annulenes 119

2.4.2 Effects ofMultipleHeteroatoms 120Bond Length Effects 120Orbital Effects 120

2.5 Highly-Strained Molecules 1242.5.1 Long Bonds and LargeAngles 1242.5.2 Small Rings 1252.5.3 Very Large Rotation Barriers 127

2.6 Molecular Mechanics 1282.6.1 TheMolecularMechanicsModel 129

Bond Stretching 129Angle Bending 130Torsion 130Nonbonded Interactions 130Cross Terms 131

Electrostatic Interactions 131Hydrogen Bonding 131The Parameterization 132Heat of Formation and Strain Energy 132

2.6.2 General Comments on theMolecularMechanicsMethod 133

2.6.3 MolecularMechanics on Biomolecules andUnnatural Polymers—‘‘Modeling’’ 135

2.6.4 MolecularMechanics Studies of Reactions 136



CHAPTER 3: Solutions and Non-CovalentBinding Forces 145


3.1 Solvent and Solution Properties 1453.1.1 Nature Abhors a Vacuum 1463.1.2 Solvent Scales 146

Dielectric Constant 147Other Solvent Scales 148Heat of Vaporization 150Surface Tension andWetting 150Water 151

3.1.3 Solubility 153General Overview 153Shape 154Using the ‘‘Like-Dissolves-Like’’ Paradigm 154

3.1.4 SoluteMobility 155Diffusion 155Fick’s Law of Diffusion 156Correlation Times 156

3.1.5 The Thermodynamics of Solutions 160Chemical Potential 158The Thermodynamics of Reactions 160Calculating�H� and�S� 162

3.2 Binding Forces 1623.2.1 Ion Pairing Interactions 163

Salt Bridges 1643.2.2 Electrostatic Interactions InvolvingDipoles 165

Ion–Dipole Interactions 165ASimpleModel of Ionic Solvation—The Born Equation 166Dipole–Dipole Interactions 168

3.2.3 Hydrogen Bonding 168Geometries 169Strengths of Normal Hydrogen Bonds 171i. Solvation Effects 171ii. Electronegativity Effects 172iii. Resonance Assisted Hydrogen Bonds 173iv. Polarization Enhanced Hydrogen Bonds 174v. Secondary Interactions in HydrogenBonding Systems 175

ixCONTENTS

vi. Cooperativity in Hydrogen Bonds 175Vibrational Properties of Hydrogen Bonds 176Short–StrongHydrogen Bonds 177

3.2.4 � Effects 180Cation–p Interactions 181Polar–p Interactions 183Aromatic–Aromatic Interactions (p Stacking) 184The Arene–Perfluoroarene Interaction 184pDonor–Acceptor Interactions 186

3.2.5 Induced-Dipole Interactions 186Ion–Induced-Dipole Interactions 187Dipole–Induced-Dipole Interactions 187Induced-Dipole–Induced-Dipole Interactions 188SummarizingMonopole, Dipole, andInduced-Dipole Binding Forces 188

3.2.6 TheHydrophobic Effect 189Aggregation of Organics 189The Origin of the Hydrophobic Effect 192

3.3 Computational Modeling of Solvation 1943.3.1 Continuum SolvationModels 1963.3.2 Explicit SolvationModels 1973.3.3 Monte Carlo (MC)Methods 1983.3.4 Molecular Dynamics (MD) 1993.3.5 Statistical Perturbation Theory/

Free Energy Perturbation 200



CHAPTER 4: Molecular Recognition andSupramolecular Chemistry 207


4.1 Thermodynamic Analyses of BindingPhenomena 207

4.1.1 General Thermodynamics of Binding 208The Relevance of the Standard State 210The Influence of a Change in Heat Capacity 212Cooperativity 213Enthalpy–Entropy Compensation 216

4.1.2 The Binding Isotherm 2164.1.3 ExperimentalMethods 219

UV/Vis or FluorescenceMethods 220NMRMethods 220Isothermal Calorimetry 221

4.2 Molecular Recognition 2224.2.1 Complementarity and Preorganization 224

Crowns, Cryptands, and Spherands—MolecularRecognition with a Large Ion–Dipole Component 224Tweezers and Clefts 228

4.2.2 Molecular Recognitionwith a LargeIon Pairing Component 228

4.2.3 Molecular Recognitionwith a LargeHydrogenBonding Component 230Representative Structures 230

Molecular Recognition via HydrogenBonding inWater 232

4.2.4 Molecular Recognitionwith a LargeHydrophobic Component 234Cyclodextrins 234Cyclophanes 234ASummary of the Hydrophobic ComponentofMolecular Recognition inWater 238

4.2.5 Molecular Recognitionwith a Large�Component 239Cation–p Interactions 239Polar–p and Related Effects 241

4.2.6 Summary 241

4.3 Supramolecular Chemistry 2434.3.1 Supramolecular Assembly of Complex

Architectures 244Self-Assembly via Coordination Compounds 244Self-Assembly via Hydrogen Bonding 245

4.3.2 Novel Supramolecular Architectures—Catenanes,Rotaxanes, andKnots 246Nanotechnology 248

4.3.3 Container Compounds—MoleculeswithinMolecules 249



CHAPTER 5: Acid–Base Chemistry 259


5.1 Brønsted Acid–Base Chemistry 259

5.2 Aqueous Solutions 2615.2.1 pKa 2615.2.2 pH 2625.2.3 The Leveling Effect 2645.2.4 Activity vs. Concentration 2665.2.5 Acidity Functions: Acidity Scales forHighly

ConcentratedAcidic Solutions 2665.2.6 Super Acids 270

5.3 Nonaqueous Systems 2715.3.1 pKa Shifts at EnzymeActive Sites 2735.3.2 Solution Phase vs. Gas Phase 273

5.4 Predicting Acid Strength in Solution 2765.4.1 MethodsUsed toMeasureWeakAcid Strength 2765.4.2 TwoGuiding Principles for Predicting

Relative Acidities 2775.4.3 Electronegativity and Induction 2785.4.4 Resonance 2785.4.5 Bond Strengths 2835.4.6 Electrostatic Effects 2835.4.7 Hybridization 283

x CONTENTS

5.4.8 Aromaticity 2845.4.9 Solvation 2845.4.10 Cationic Organic Structures 285

5.5 Acids and Bases of Biological Interest 285

5.6 Lewis Acids/Bases and Electrophiles/Nucleophiles 288

5.6.1 The Concept of Hard and Soft Acids and Bases, GeneralLessons for Lewis Acid–Base Interactions, and RelativeNucleophilicity and Electrophilicity 289



CHAPTER 6: Stereochemistry 297


6.1 Stereogenicity and Stereoisomerism 2976.1.1 Basic Concepts and Terminology 298

Classic Terminology 299MoreModern Terminology 301

6.1.2 Stereochemical Descriptors 303R,S System 304E,Z System 304d and l 304Erythro and Threo 305Helical Descriptors—Mand P 305Ent and Epi 306UsingDescriptors to Compare Structures 306

6.1.3 Distinguishing Enantiomers 306Optical Activity and Chirality 309Why is Plane Polarized Light Rotatedby a ChiralMedium? 309Circular Dichroism 310X-Ray Crystallography 310

6.2 Symmetry and Stereochemistry 3116.2.1 Basic SymmetryOperations 3116.2.2 Chirality and Symmetry 3116.2.3 SymmetryArguments 3136.2.4 Focusing onCarbon 314

6.3 Topicity Relationships 3156.3.1 Homotopic, Enantiotopic, andDiastereotopic 3156.3.2 Topicity Descriptors—Pro-R/Pro-S andRe/Si 3166.3.3 Chirotopicity 317

6.4 Reaction Stereochemistry: Stereoselectivityand Stereospecificity 317

6.4.1 Simple Guidelines for Reaction Stereochemistry 3176.4.2 Stereospecific and Stereoselective Reactions 319

6.5 Symmetry and Time Scale 322

6.6 Topological and Supramolecular Stereochemistry 3246.6.1 Loops andKnots 3256.6.2 Topological Chirality 326

6.6.3 Nonplanar Graphs 3266.6.4 Achievements in Topological and Supramolecular

Stereochemistry 327

6.7 Stereochemical Issues in Polymer Chemistry 331

6.8 Stereochemical Issues in Chemical Biology 3336.8.1 The Linkages of Proteins, Nucleic Acids,

and Polysaccharides 333Proteins 333Nucleic Acids 334Polysaccharides 334

6.8.2 Helicity 336Synthetic Helical Polymers 337

6.8.3 TheOrigin of Chirality inNature 339

6.9 Stereochemical Terminology 340



PART IIReactivity, Kinetics, and Mechanisms

CHAPTER 7: Energy Surfaces andKinetic Analyses 355


7.1 Energy Surfaces and Related Concepts 3567.1.1 Energy Surfaces 3577.1.2 Reaction Coordinate Diagrams 3597.1.3 What is theNature of the Activated

Complex/Transition State? 3627.1.4 Rates and Rate Constants 3637.1.5 ReactionOrder and Rate Laws 3647.2 Transition State Theory (TST) and Related Topics 3657.2.1 TheMathematics of Transition State Theory 3657.2.2 Relationship to theArrhenius Rate Law 3677.2.3 BoltzmannDistributions and Temperature

Dependence 3687.2.4 Revisiting ‘‘What is theNature of the Activated

Complex?’’ andWhyDoes TSTWork? 3697.2.5 Experimental Determinations of Activation Parameters

andArrhenius Parameters 3707.2.6 Examples of Activation Parameters and

Their Interpretations 3727.2.7 Is TSTCompletely Correct? TheDynamic Behavior

of Organic Reactive Intermediates 372

7.3 Postulates and Principles Relatedto Kinetic Analysis 374

7.3.1 TheHammond Postulate 3747.3.2 The Reactivity vs. Selectivity Principle 3777.3.3 The Curtin–Hammett Principle 3787.3.4 Microscopic Reversibility 3797.3.5 Kinetic vs. Thermodynamic Control 380

xiCONTENTS

7.4 Kinetic Experiments 3827.4.1 HowKinetics Experiments are Performed 3827.4.2 Kinetic Analyses for SimpleMechanisms 384

First Order Kinetics 385SecondOrder Kinetics 386Pseudo-First Order Kinetics 387EquilibriumKinetics 388Initial-Rate Kinetics 389Tabulating a Series of Common Kinetic Scenarios 389

7.5 Complex Reactions—Deciphering Mechanisms 3907.5.1 Steady State Kinetics 3907.5.2 Using the SSA to Predict Changes

in Kinetic Order 3957.5.3 Saturation Kinetics 3967.5.4 Prior Rapid Equilibria 397

7.6 Methods for Following Kinetics 3977.6.1 ReactionswithHalf-Lives Greater

than a Few Seconds 3987.6.2 Fast Kinetics Techniques 398

Flow Techniques 399Flash Photolysis 399Pulse Radiolysis 401

7.6.3 RelaxationMethods 4017.6.4 Summary of Kinetic Analyses 402

7.7 Calculating Rate Constants 4037.7.1 Marcus Theory 4037.7.2 Marcus TheoryApplied to Electron Transfer 405

7.8 Considering Multiple Reaction Coordinates 4077.8.1 Variation in Transition State Structures Across

a Series of Related Reactions—AnExampleUsing Substitution Reactions 407

7.8.2 MoreO’Ferrall–Jencks Plots 4097.8.3 Changes in Vibrational State Along the Reaction

Coordinate—Relating the Third Coordinateto Entropy 412



CHAPTER 8: Experiments Related toThermodynamics and Kinetics 421


8.1 Isotope Effects 4218.1.1 The Experiment 4228.1.2 TheOrigin of Primary Kinetic Isotope Effects 422

Reaction Coordinate Diagrams and Isotope Effects 424Primary Kinetic Isotope Effects for LinearTransition States as a Function of Exothermicityand Endothermicity 425Isotope Effects for Linear vs. Non-LinearTransition States 428

8.1.3 TheOrigin of Secondary Kinetic Isotope Effects 428Hybridization Changes 429Steric Isotope Effects 430

8.1.4 Equilibrium Isotope Effects 432Isotopic Perturbation of Equilibrium—Applications to Carbocations 432

8.1.5 Tunneling 4358.1.6 Solvent Isotope Effects 437

Fractionation Factors 437Proton Inventories 438

8.1.7 HeavyAtom Isotope Effects 4418.1.8 Summary 441

8.2 Substituent Effects 4418.2.1 TheOrigin of Substituent Effects 443

Field Effects 443Inductive Effects 443Resonance Effects 444Polarizability Effects 444Steric Effects 445Solvation Effects 445

8.3 Hammett Plots—The Most Common LFER.A General Method for Examining Changesin Charges During a Reaction 445

8.3.1 Sigma (s) 4458.3.2 Rho (r) 4478.3.3 The Power of Hammett Plots for

DecipheringMechanisms 4488.3.4 Deviations fromLinearity 4498.3.5 Separating Resonance from Induction 451

8.4 Other Linear Free Energy Relationships 4548.4.1 Steric and Polar Effects—Taft Parameters 4548.4.2 Solvent Effects—Grunwald–Winstein Plots 4558.4.3 Schleyer Adaptation 4578.4.4 Nucleophilicity andNucleofugality 458

Basicity/Acidity 459Solvation 460Polarizability, Basicity, and Solvation Interplay 460Shape 461

8.4.5 Swain–Scott Parameters—NucleophilicityParameters 461

8.4.6 Edwards and Ritchie Correlations 463

8.5 Acid–Base Related Effects—Brønsted Relationships 464

8.5.1 bNuc 4648.5.2 bLG 4648.5.3 Acid–Base Catalysis 466

8.6 Why do Linear Free Energy Relationships Work? 4668.6.1 GeneralMathematics of LFERs 4678.6.2 Conditions to Create an LFER 4688.6.3 The Isokinetic or IsoequilibriumTemperature 4698.6.4 Why does Enthalpy–Entropy

CompensationOccur? 469Steric Effects 470Solvation 470

8.7 Summary of Linear Free Energy Relationships 470

xii CONTENTS

8.8 Miscellaneous Experiments forStudying Mechanisms 471

8.8.1 Product Identification 4728.8.2 Changing the Reactant Structure to Divert

or Trap a Proposed Intermediate 4738.8.3 Trapping andCompetition Experiments 4748.8.4 Checking for a Common Intermediate 4758.8.5 Cross-Over Experiments 4768.8.6 Stereochemical Analysis 4768.8.7 Isotope Scrambling 4778.8.8 Techniques to Study Radicals: Clocks and Traps 4788.8.9 Direct Isolation andCharacterization

of an Intermediate 4808.8.10 Transient Spectroscopy 4808.8.11 StableMedia 481



CHAPTER 9: Catalysis 489


9.1 General Principles of Catalysis 4909.1.1 Binding the Transition State Better

than the Ground State 4919.1.2 A Thermodynamic Cycle Analysis 4939.1.3 A Spatial Temporal Approach 494

9.2 Forms of Catalysis 4959.2.1 ‘‘Binding’’ is Akin to Solvation 4959.2.2 Proximity as a Binding Phenomenon 4959.2.3 Electrophilic Catalysis 499

Electrostatic Interactions 499Metal Ion Catalysis 500

9.2.4 Acid–Base Catalysis 5029.2.5 Nucleophilic Catalysis 5029.2.6 Covalent Catalysis 5049.2.7 Strain andDistortion 5059.2.8 Phase Transfer Catalysis 507

9.3 Brønsted Acid–Base Catalysis 5079.3.1 Specific Catalysis 507

TheMathematics of Specific Catalysis 507Kinetic Plots 510

9.3.2 General Catalysis 510TheMathematics of General Catalysis 511Kinetic Plots 512

9.3.3 AKinetic Equivalency 5149.3.4 Concerted or Sequential General-Acid–

General-Base Catalysis 5159.3.5 The Brønsted Catalysis Law

and Its Ramifications 516ALinear Free Energy Relationship 516TheMeaning of a and b 517a + b = 1 518Deviations from Linearity 519

9.3.6 PredictingGeneral-Acid orGeneral-Base Catalysis 520The Libido Rule 520Potential Energy Surfaces DictateGeneral or Specific Catalysis 521

9.3.7 TheDynamics of Proton Transfers 522Marcus Analysis 522

9.4 Enzymatic Catalysis 5239.4.1 Michaelis–Menten Kinetics 5239.4.2 TheMeaning ofKM, kcat, and kcat/KM 5249.4.3 EnzymeActive Sites 5259.4.4 [S] vs.KM—Reaction Coordinate Diagrams 5279.4.5 Supramolecular Interactions 529



CHAPTER 10: Organic Reaction Mechanisms,Part 1: Reactions Involving Additionsand/or Eliminations 537


10.1 Predicting Organic Reactivity 53810.1.1 AUseful Paradigm for Polar Reactions 539

Nucleophiles and Electrophiles 539Lewis Acids and Lewis Bases 540Donor–Acceptor Orbital Interactions 540

10.1.2 Predicting Radical Reactivity 54110.1.3 In Preparation for the Following Sections 541

—ADDITION REACTIONS— 542

10.2 Hydration of Carbonyl Structures 54210.2.1 Acid–Base Catalysis 54310.2.2 The Thermodynamics of the Formation

of Geminal Diols andHemiacetals 544

10.3 Electrophilic Addition of Water to Alkenesand Alkynes: Hydration 545

10.3.1 Electron Pushing 54610.3.2 Acid-CatalyzedAqueousHydration 54610.3.3 Regiochemistry 54610.3.4 AlkyneHydration 547

10.4 Electrophilic Addition of Hydrogen Halidesto Alkenes and Alkynes 548

10.4.1 Electron Pushing 54810.4.2 Experimental Observations Related to

Regiochemistry and Stereochemistry 54810.4.3 Addition toAlkynes 551

10.5 Electrophilic Addition of Halogensto Alkenes 551

10.5.1 Electron Pushing 54810.5.2 Stereochemistry 552

xiiiCONTENTS

10.5.3 Other Evidence Supporting a �Complex 55210.5.4 Mechanistic Variants 55310.5.5 Addition toAlkynes 554

10.6 Hydroboration 55410.6.1 Electron Pushing 55510.6.2 Experimental Observations 555

10.7 Epoxidation 55510.7.1 Electron Pushing 55610.7.2 Experimental Observations 556

10.8 Nucleophilic Additions toCarbonyl Compounds 556

10.8.1 Electron Pushing for a FewNucleophilicAdditions 557

10.8.2 Experimental Observations forCyanohydrin Formation 559

10.8.3 Experimental Observations forGrignard Reactions 560

10.8.4 Experimental Observations inLAHReductions 561

10.8.5 Orbital Considerations 561The Burgi–Dunitz Angle 561OrbitalMixing 562

10.8.6 Conformational Effects in Additionsto Carbonyl Compounds 562

10.8.7 Stereochemistry of Nucleophilic Additions 563

10.9 Nucleophilic Additions to Olefins 56710.9.1 Electron Pushing 56710.9.2 Experimental Observations 56710.9.3 Regiochemistry of Addition 56710.9.4 Baldwin’s Rules 568

10.10 Radical Additions to UnsaturatedSystems 569

10.10.1 Electron Pushing for Radical Additions 56910.10.2 Radical Initiators 57010.10.3 Chain Transfer vs. Polymerization 57110.10.4 Termination 57110.10.5 Regiochemistry of Radical Additions 572

10.11 Carbene Additions and Insertions 57210.11.1 Electron Pushing for Carbene Reactions 57410.11.2 CarbeneGeneration 57410.11.3 Experimental Observations for

Carbene Reactions 575

—ELIMINATIONS— 576

10.12 Eliminations to Form Carbonyls or ‘‘Carbonyl-Like’’Intermediates 577

10.12.1 Electron Pushing 57710.12.2 Stereochemical and Isotope

Labeling Evidence 57710.12.3 Catalysis of theHydrolysis of Acetals 57810.12.4 Stereoelectronic Effects 57910.12.5 CrO3Oxidation—The Jones Reagent 580

Electron Pushing 580AFew Experimental Observations 581

10.13 Elimination Reactions for Aliphatic Systems—Formation of Alkenes 581

10.13.1 Electron Pushing andDefinitions 58110.13.2 Some Experimental Observations

for E2 and E1 Reactions 58210.13.3 Contrasting Elimination and Substitution 53810.13.4 Another Possibility—E1cB 58410.13.5 Kinetics and Experimental Observations

for E1cB 58410.13.6 Contrasting E2, E1, and E1cB 58610.13.7 Regiochemistry of Eliminations 58810.13.8 Stereochemistry of Eliminations—

Orbital Considerations 59010.13.9 Dehydration 592

Electron Pushing 592OtherMechanistic Possibilities 594

10.13.10 Thermal Eliminations 594

10.14 Eliminations from Radical Intermediates 596

—COMBINING ADDITION AND ELIMINATIONREACTIONS (SUBSTITUTIONS AT sp2 CENTERS)— 596

10.15 The Addition of Nitrogen Nucleophilesto Carbonyl Structures, Followedby Elimination 597

10.15.1 Electron Pushing 59810.15.2 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 60010.17.1 General Electron-Pushing Schemes 60010.17.2 Isotope Scrambling 60110.17.3 Predicting the Site of Cleavage for

Acyl Transfers fromEsters 60210.17.4 Catalysis 602

10.18 Electrophilic Aromatic Substitution 60710.18.1 Electron Pushing for Electrophilic

Aromatic Substitutions 60710.18.2 Kinetics and Isotope Effects 60810.18.3 Intermediate Complexes 60810.18.4 Regiochemistry and Relative Rates of

Aromatic Substitution 609

10.19 Nucleophilic Aromatic Substitution 61110.19.1 Electron Pushing forNucleophilic

Aromatic Substitution 61110.19.2 Experimental Observations 611

10.20 Reactions Involving Benzyne 61210.20.1 Electron Pushing for Benzyne Reactions 61210.20.2 Experimental Observations 61310.20.3 Substituent Effects 613

10.21 The SRN1 Reaction on Aromatic Rings 61510.21.1 Electron Pushing 61510.21.2 A FewExperimental Observations 615

xiv CONTENTS

10.22 Radical Aromatic Substitutions 61510.22.1 Electron Pushing 61510.22.2 Isotope Effects 61610.22.3 Regiochemistry 616



CHAPTER 11: Organic Reaction Mechanisms,Part 2: Substitutions at AliphaticCenters and Thermal Isomerizations/Rearrangements 627


—SUBSTITUTION aTO A CARBONYL CENTER:ENOL AND ENOLATE CHEMISTRY— 627

11.1 Tautomerization 62811.1.1 Electron Pushing for Keto–Enol

Tautomerizations 62811.1.2 The Thermodynamics of Enol Formation 62811.1.3 Catalysis of Enolizations 62911.1.4 Kinetic vs. Thermodynamic Control

in Enolate and Enol Formation 629

11.2 a-Halogenation 63111.2.1 Electron Pushing 63111.2.2 A FewExperimental Observations 631

11.3 a-Alkylations 63211.3.1 Electron Pushing 63211.3.2 Stereochemistry: Conformational Effects 633

11.4 The Aldol Reaction 63411.4.1 Electron Pushing 63411.4.2 Conformational Effects on theAldol Reaction 634

—SUBSTITUTIONS ON ALIPHATIC CENTERS— 637

11.5 Nucleophilic Aliphatic Substitution Reactions 63711.5.1 SN2 and SN1 Electron-Pushing Examples 63711.5.2 Kinetics 63811.5.3 Competition Experiments and Product Analyses 63911.5.4 Stereochemistry 64011.5.5 Orbital Considerations 64311.5.6 Solvent Effects 64311.5.7 Isotope Effect Data 64611.5.8 AnOverall Picture of SN2 and SN1 Reactions 64611.5.9 Structure–Function Correlations

with theNucleophile 64811.5.10 Structure–Function Correlations

with the LeavingGroup 65111.5.11 Structure–Function Correlations

with the RGroup 651Effect of the R Group Structure on SN2 Reactions 651Effect of the R Group Structure on SN1 Reactions 653

11.5.12 Carbocation Rearrangements 65611.5.13 Anchimeric Assistance in SN1 Reactions 659

11.5.14 SN1 Reactions InvolvingNon-ClassicalCarbocations 661Norbornyl Cation 662Cyclopropyl Carbinyl Carbocation 664

11.5.15 Summary of Carbocation Stabilizationin Various Reactions 667

11.5.16 The Interplay Between Substitutionand Elimination 667

11.6 Substitution, Radical, Nucleophilic 66811.6.1 The SET Reaction—Electron Pushing 66811.6.2 TheNature of the Intermediate

in an SETMechanism 66911.6.3 Radical Rearrangements as Evidence 66911.6.4 Structure–Function Correlations

with the LeavingGroup 67011.6.5 The SRN1 Reaction—Electron Pushing 670

11.7 Radical Aliphatic Substitutions 67111.7.1 Electron Pushing 67111.7.2 Heats of Reaction 67111.7.3 Regiochemistry of Free Radical

Halogenation 67111.7.4 Autoxidation: Addition of O2

into C–HBonds 673Electron Pushing for Autoxidation 673

—ISOMERIZATIONS AND REARRANGEMENTS— 674

11.8 Migrations to Electrophilic Carbons 67411.8.1 Electron Pushing for the

Pinacol Rearrangement 67511.8.2 Electron Pushing in the Benzilic Acid

Rearrangement 67511.8.3 MigratoryAptitudes in the Pinacol

Rearrangement 67511.8.4 Stereoelectronic and Stereochemical Considerations

in the Pinacol Rearrangement 67611.8.5 A FewExperimental Observations for the Benzilic

Acid Rearrangement 678

11.9 Migrations to Electrophilic Heteroatoms 67811.9.1 Electron Pushing in the Beckmann

Rearrangement 67811.9.2 Electron Pushing for theHofmann

Rearrangement 67811.9.3 Electron Pushing for the Schmidt

Rearrangement 68011.9.4 Electron Pushing for the Baeyer–Villiger

Oxidation 68011.9.5 A FewExperimental Observations for the

Beckmann Rearrangement 68011.9.6 A FewExperimental Observations for the

Schmidt Rearrangement 68111.9.7 A FewExperimental Observations for the

Baeyer–Villiger Oxidation 681

11.10 The Favorskii Rearrangement and OtherCarbanion Rearrangements 682

11.10.1 Electron Pushing 68211.10.2 Other Carbanion Rearrangements 683

xvCONTENTS

11.11 Rearrangements Involving Radicals 68311.11.1 Hydrogen Shifts 68311.11.2 Aryl andVinyl Shifts 68411.11.3 Ring-Opening Reactions 685

11.12 Rearrangements and IsomerizationsInvolving Biradicals 685

11.12.1 Electron Pushing Involving Biradicals 68511.12.2 Tetramethylene 68711.12.3 Trimethylene 68911.12.4 Trimethylenemethane 693



CHAPTER 12: Organotransition Metal ReactionMechanisms and Catalysis 705


12.1 The Basics of Organometallic Complexes 70512.1.1 Electron Counting andOxidation State 706

Electron Counting 706Oxidation State 708d Electron Count 708Ambiguities 708

12.1.2 The 18-Electron Rule 71012.1.3 StandardGeometries 71012.1.4 Terminology 71112.1.5 Electron PushingwithOrganometallic

Structures 71112.1.6 dOrbital Splitting Patterns 71212.1.7 Stabilizing Reactive Ligands 713

12.2 Common Organometallic Reactions 71412.2.1 Ligand Exchange Reactions 714

Reaction Types 714Kinetics 716Structure–Function Relationships with theMetal 716Structure–Function Relationshipswith the Ligand 716Substitutions of Other Ligands 717

12.2.2 Oxidative Addition 717Stereochemistry of theMetal Complex 718Kinetics 718Stereochemistry of the R Group 719Structure–Function Relationship for the RGroup 720Structure–Function Relationships for the Ligands 720Oxidative Addition at sp2 Centers 721Summary of theMechanisms for OxidativeAddition 721

12.2.3 Reductive Elimination 724Structure–Function Relationship for theRGroup and the Ligands 724Stereochemistry at theMetal Center 725OtherMechanisms 725Summary of theMechanisms forReductive Elimination 726

12.2.4 �- and �-Eliminations 727General Trends for a- and b-Eliminations 727Kinetics 728Stereochemistry of b-Hydride Elimination 729

12.2.5 Migratory Insertions 729Kinetics 730Studies to Decipher theMechanism ofMigratoryInsertion Involving CO 730Other Stereochemical Considerations 732

12.2.6 Electrophilic Addition to Ligands 733Reaction Types 733CommonMechanismsDeduced FromStereochemical Analyses 734

12.2.7 Nucleophilic Addition to Ligands 734Reaction Types 735Stereochemical and Regiochemical Analyses 735

12.3 Combining the Individual Reactions into OverallTransformations and Cycles 737

12.3.1 TheNature of Organometallic Catalysis—Change inMechanism 738

12.3.2 TheMonsantoAcetic Acid Synthesis 73812.3.3 Hydroformylation 73912.3.4 TheWater-Gas Shift Reaction 74012.3.5 OlefinOxidation—TheWacker Process 74112.3.6 PalladiumCoupling Reactions 74212.3.7 Allylic Alkylation 74312.3.8 OlefinMetathesis 744



CHAPTER 13: Organic Polymer andMaterials Chemistry 753


13.1 Structural Issues in Materials Chemistry 75413.1.1 MolecularWeight Analysis of Polymers 754

Number Average andWeight AverageMolecularWeights—Mn andMw 754

13.1.2 Thermal Transitions—Thermoplasticsand Elastomers 757

13.1.3 Basic Polymer Topologies 75913.1.4 Polymer–Polymer Phase Behavior 76013.1.5 Polymer Processing 76213.1.6 Novel Topologies—Dendrimers and

Hyperbranched Polymers 763Dendrimers 763Hyperbranched Polymers 768

13.1.7 Liquid Crystals 76913.1.8 Fullerenes andCarbonNanotubes 775

13.2 Common Polymerization Mechanisms 77913.2.1 General Issues 77913.2.2 Polymerization Kinetics 782

Step-Growth Kinetics 782

xvi CONTENTS

Free-Radical Chain Polymerization 783Living Polymerizations 785Thermodynamics of Polymerizations 787

13.2.3 Condensation Polymerization 78813.2.4 Radical Polymerization 79113.2.5 Anionic Polymerization 79313.2.6 Cationic Polymerization 79413.2.7 Ziegler–Natta and Related Polymerizations 794

Single-Site Catalysts 79613.2.8 Ring-Opening Polymerization 79713.2.9 Group Transfer Polymerization (GTP) 799



PART IIIELECTRONIC STRUCTURE:THEORY AND APPLICATIONS

CHAPTER 14: Advanced Concepts in ElectronicStructure Theory 807


14.1 Introductory Quantum Mechanics 80814.1.1 TheNature ofWavefunctions 80814.1.2 The Schrodinger Equation 80914.1.3 TheHamiltonian 80914.1.4 TheNature of the�2 Operator 81114.1.5 WhyDo Bonds Form? 812

14.2 Calculational Methods—Solving the SchrodingerEquation for Complex Systems 815

14.2.1 Ab InitioMolecular Orbital Theory 815Born–Oppenheimer Approximation 815The Orbital Approximation 815Spin 816The Pauli Principle andDeterminantalWave Functions 816The Hartree–Fock Equation andthe Variational Theorem 818SCF Theory 821Linear Combination of Atomic Orbitals—Molecular Orbitals (LCAO–MO) 821Common Basis Sets—Modeling Atomic Orbitals 822Extension BeyondHF—Correlation Energy 824Solvation 825General Considerations 825Summary 826

14.2.2 Secular Determinants—ABridge BetweenAb Initio,Semi-Empirical/Approximate, and PerturbationalMolecular Orbital TheoryMethods 828The ‘‘Two-OrbitalMixing Problem’’ 829

Writing the Secular Equations andDeterminantfor AnyMolecule 832

14.2.3 Semi-Empirical andApproximateMethods 833Neglect of Differential Overlap(NDO)Methods 833i. CNDO, INDO, PNDO (C =Complete,I = Intermediate, P = Partial) 834ii. The Semi-EmpiricalMethods:MNDO, AM1, and PM3 834Extended Huckel Theory (EHT) 834HuckelMolecular Orbital Theory (HMOT) 835

14.2.4 SomeGeneral Comments on ComputationalQuantumMechanics 835

14.2.5 AnAlternative: Density FunctionalTheory (DFT) 836

14.3 A Brief Overview of the Implementationand Results of HMOT 837

14.3.1 ImplementingHuckel Theory 83814.3.2 HMOT of Cyclic� Systems 84014.3.3 HMOT of Linear� Systems 84114.3.4 AlternateHydrocarbons 842

14.4 Perturbation Theory—Orbital Mixing Rules 84414.4.1 Mixing of Degenerate Orbitals—

First-Order Perturbations 84514.4.2 Mixing ofNon-Degenerate Orbitals—

Second-Order Perturbations 845

14.5 Some Topics in Organic Chemistry forWhich Molecular Orbital Theory LendsImportant Insights 846

14.5.1 Arenes: Aromaticity andAntiaromaticity 84614.5.2 Cyclopropane andCyclopropylcarbinyl—

WalshOrbitals 848The Cyclic Three-OrbitalMixing Problem 849TheMOs of Cyclopropane 850

14.5.3 PlanarMethane 85314.5.4 Through-BondCoupling 85414.5.5 Unique Bonding Capabilities of Carbocations—

Non-Classical Ions andHypervalent Carbon 855Transition State Structure Calculations 856Application of TheseMethods to Carbocations 857NMREffects in Carbocations 857The Norbornyl Cation 858

14.5.6 Spin Preferences 859TwoWeakly Interacting Electrons:H2 vs. Atomic C 859

14.6 Organometallic Complexes 86214.6.1 GroupOrbitals forMetals 86314.6.2 The Isolobal Analogy 86614.6.3 Using the GroupOrbitals to Construct

Organometallic Complexes 867



xviiCONTENTS

CHAPTER 15: Thermal Pericyclic Reactions 877


15.1 Background 878

15.2 A Detailed Analysis of Two SimpleCycloadditions 878

15.2.1 Orbital SymmetryDiagrams 879[2+2] 879[4+2] 881

15.2.2 State CorrelationDiagrams 883[2+2] 883[4+2] 886

15.2.3 FrontierMolecular Orbital(FMO) Theory 888Contrasting the [2+2] and [4+2] 888

15.2.4 Aromatic Transition StateTheory/Topology 889

15.2.5 TheGeneralizedOrbitalSymmetry Rule 890

15.2.6 SomeComments on ‘‘Forbidden’’ and‘‘Allowed’’ Reactions 892

15.2.7 Photochemical Pericyclic Reactions 89215.2.8 Summary of the VariousMethods 893

15.3 Cycloadditions 89315.3.1 AnAllowedGeometry for [2+2]

Cycloadditions 89415.3.2 Summarizing Cycloadditions 89515.3.3 General Experimental Observations 89515.3.4 Stereochemistry and Regiochemistry

of the Diels–Alder Reaction 896AnOrbital Approach to PredictingRegiochemistry 896The Endo Effect 899

15.3.5 Experimental Observations for[2+2] Cycloadditions 901

15.3.6 Experimental Observations for1,3-Dipolar Cycloadditions 901

15.3.7 Retrocycloadditions 902

15.4 Electrocyclic Reactions 90315.4.1 Terminology 90315.4.2 Theoretical Analyses 90415.4.3 Experimental Observations:

Stereochemistry 90615.4.4 Torquoselectivity 908

15.5 Sigmatropic Rearrangements 91015.5.1 Theory 91115.5.2 Experimental Observations: A Focus on

Stereochemistry 91315.5.3 TheMechanism of the

Cope Rearrangement 91615.5.4 The Claisen Rearrangement 921

Uses in Synthesis 921Mechanistic Studies 923

15.5.5 The Ene Reaction 924

15.6 Cheletropic Reactions 92415.6.1 Theoretical Analyses 92615.6.2 CarbeneAdditions 927

15.7 In Summary—Applying the Rules 928



CHAPTER 16: Photochemistry 935


16.1 Photophysical Processes—The Jablonski Diagram 936

16.1.1 Electromagnetic Radiation 936Multiple Energy Surfaces Exist 937

16.1.2 Absorption 93916.1.3 Radiationless Vibrational Relaxation 94416.1.4 Fluorescence 94516.1.5 Internal Conversion (IC) 94916.1.6 IntersystemCrossing (ISC) 95016.1.7 Phosphorescence 95116.1.8 QuantumYield 95216.1.9 Summary of Photophysical Processes 952

16.2 Bimolecular Photophysical Processes 95316.2.1 General Considerations 95316.2.2 Quenching, Excimers, and Exciplexes 953

Quenching 954Excimers and Exciplexes 954Photoinduced Electron Transfer 955

16.2.3 Energy Transfer I. TheDexterMechanism—Sensitization 956

16.2.4 Energy Transfer II. The ForsterMechanism 95816.2.5 FRET 96016.2.6 Energy Pooling 96216.2.7 AnOverview of Bimolecular Photophysical

Processes 962

16.3 Photochemical Reactions 96216.3.1 Theoretical Considerations—Funnels 962

Diabatic Photoreactions 963OtherMechanisms 964

16.3.2 Acid–Base Chemistry 96516.3.3 Olefin Isomerization 96516.3.4 Reversal of Pericyclic Selection Rules 96816.3.5 Photocycloaddition Reactions 970

MakingHighly Strained Ring Systems 973Breaking Aromaticity 974

16.3.6 TheDi-�-Methane Rearrangement 97416.3.7 Carbonyls Part I: TheNorrish I Reaction 97616.3.8 Carbonyls Part II: Photoreduction and

theNorrish II Reaction 97816.3.9 Nitrobenzyl Photochemistry: ‘‘Caged’’

Compounds 980

xviii CONTENTS

16.3.10 Elimination ofN2: Azo Compounds, DiazoCompounds, Diazirines, andAzides 981Azoalkanes (1,2-Diazenes) 981Diazo Compounds andDiazirines 982Azides 983

16.4 Chemiluminescence 98516.4.1 Potential Energy Surface for a

Chemiluminescent Reaction 98516.4.2 Typical Chemiluminescent Reactions 98616.4.3 Dioxetane Thermolysis 987

16.5 Singlet Oxygen 989



CHAPTER 17: Electronic Organic Materials 1001


17.1 Theory 100117.1.1 Infinite� Systems—An Introduction

to Band Structures 100217.1.2 The Peierls Distortion 100917.1.3 Doping 1011

17.2 Conducting Polymers 101617.2.1 Conductivity 101617.2.2 Polyacetylene 101717.2.3 Polyarenes and Polyarenevinylenes 101817.2.4 Polyaniline 1021

17.3 Organic Magnetic Materials 102217.3.1 Magnetism 102317.3.2 TheMolecular Approach toOrganicMagnetic

Materials 102417.3.3 The PolymerApproach toOrganicMagnetic

Materials—VeryHigh-SpinOrganicMolecules 1027

17.4 Superconductivity 103017.4.1 OrganicMetals/SyntheticMetals 1032

17.5 Non-Linear Optics (NLO) 1033

17.6 Photoresists 103617.6.1 Photolithography 103617.6.2 Negative Photoresists 103717.6.3 Positive Photoresists 1038



APPENDIX 1: Conversion Factors and OtherUseful Data 1047

APPENDIX 2: Electrostatic Potential Surfaces forRepresentative Organic Molecules 1049

APPENDIX 3: Group Orbitals of Common FunctionalGroups: Representative Examples UsingSimple Molecules 1051

APPENDIX 4: The Organic Structures of Biology 1057

APPENDIX 5: Pushing Electrons 1061

A5.1 The Rudiments of Pushing Electrons 1061A5.2 Electron Sources and Sinks for

Two-Electron Flow 1062A5.3 How toDenote Resonance 1064A5.4 Common Electron-Pushing Errors 1065

BackwardsArrowPushing 1065Not EnoughArrows 1065Losing Track of theOctet Rule 1066Losing Track ofHydrogens and Lone Pairs 1066Not Using the Proper Source 1067MixedMediaMistakes 1067TooManyArrows—Short Cuts 1067

A5.5 Complex Reactions—Drawing a ChemicallyReasonableMechanism 1068

A5.6 TwoCase Studies of PredictingReactionMechanisms 1069

A5.7 Pushing Electrons for Radical Reactions 1071Practice Problems for Pushing Electrons 1073

APPENDIX 6: Reaction Mechanism Nomenclature 1075

Index 1079

xix

List of Highlights

CHAPTER 1HowRealistic are Formal Charges? 7NMRCoupling Constants 10Scaling Electrostatic Surface Potentials 151-Fluorobutane 16Particle in a Box 21Resonance in the PeptideAmide Bond? 23A Brief Look at Symmetry and SymmetryOperations 29CH5

+—Not Really aWell-Defined Structure 55Pyramidal Inversion: NH3 vs. PH3 57Stable Carbenes 59

CHAPTER 2Entropy Changes During Cyclization Reactions 71AConsequence of High Bond Strength:

TheHydroxyl Radical in Biology 73TheHalf-Life forHomolysis of Ethane

at RoomTemperature 73The Probability of FindingAtoms at Particular

Separations 75HowDoWeKnowThat n� 0 isMost Relevant

for Bond Stretches at T� 298 K? 76Potential Surfaces for Bond BendingMotions 78HowBig is 3 kcal/mol? 93Shouldn’t TorsionalMotions beQuantized? 94TheGeometry of Radicals 96DifferingMagnitudes of Energy Values in Thermodynamics

andKinetics 100‘‘Sugar Pucker’’ inNucleic Acids 102AlternativeMeasurements of Steric Size 104TheUse ofAValues in a Conformational Analysis

Study for the Determination of IntramolecularHydrogen Bond Strength 105

TheNMRTime Scale 106Ring Fusion—Steroids 108AConformational Effect on theMaterial Properties

of Poly(3-Alkylthiophenes) 116Cyclopropenyl Cation 117Cyclopropenyl Anion 118Porphyrins 119Protein Disulfide Linkages 123From StrainedMolecules toMolecular Rods 126Cubane Explosives? 126Molecular Gears 128

CHAPTER 3TheUse of Solvent Scales to Direct Diels–Alder

Reactions 149TheUse ofWetting and the Capillary Action

Force to Drive the Self-Assembly ofMacroscopic Objects 151

The Solvent Packing Coefficient andthe 55% Solution 152

Solvation CanAffect Equilibria 155A van’t Hoff Analysis of the Formation of a

Stable Carbene 163

The Strength of a Buried Salt Bridge 165TheAngular Dependence of Dipole–Dipole Interactions—

The ‘‘Magic Angle’’ 168AnUnusual Hydrogen BondAcceptor 169Evidence forWeakDirectionality Considerations 170Intramolecular Hydrogen Bonds are Best

for Nine-Membered Rings 170Solvent Scales andHydrogen Bonds 172The Extent of Resonance can be Correlatedwith

Hydrogen Bond Length 174CooperativeHydrogen Bonding in Saccharides 175HowMuch is aHydrogen Bond in an �-HelixWorth? 176Proton Sponges 179The Relevance of Low-Barrier Hydrogen Bonds

to Enzymatic Catalysis 179�-Peptide Foldamers 180ACation–� Interaction at theNicotine Receptor 183The Polar Nature of BenzeneAffects Acidities

in a PredictableManner 184Use of the Arene–Perfluorarene Interaction in the

Design of Solid State Structures 185Donor–Acceptor Driven Folding 187TheHydrophobic Effect and Protein Folding 194More Foldamers: FoldingDriven by

Solvophobic Effects 195CalculatingDrug Binding Energies by SPT 201

CHAPTER 4TheUnits of Binding Constants 209Cooperativity in Drug Receptor Interactions 215TheHill Equation andCooperativity in

Protein–Ligand Interactions 219The Benisi–Hildebrand Plot 221How areHeat Changes Related to Enthalpy? 223Using theHelical Structure of Peptides and the

Complexation Power of Crowns to CreateanArtificial Transmembrane Channel 226

Preorganization and the Salt Bridge 229AClear Case of EntropyDriven Electrostatic

Complexation 229Salt Bridges Evaluated byNon-Biological Systems 230DoesHydrogen BondingReally Play a Role in

DNAStrand Recognition? 233Calixarenes—Important Building Blocks forMolecular

Recognition and Supramolecular Chemistry 238Aromatics at Biological Binding Sites 239Combining the Cation–� Effect andCrown Ethers 240A Thermodynamic Cycle to Determine the Strength

of a Polar–� Interaction 242MolecularMechanics/Modeling andMolecular

Recognition 243Biotin/Avidin: AMolecular Recognition/

Self-Assembly Tool fromNature 249Taming Cyclobutadiene—ARemarkable Use of

Supramolecular Chemistry 251

xx LIST OF HIGHLIGHTS

CHAPTER 5Using a pH Indicator to Sense Species Other

Than theHydronium Ion 264Realistic Titrations inWater 265An ExtremelyAcidicMedium is FormedDuring

Photo-Initiated Cationic Polymerization inPhotolithography 269

Super Acids Used toActivateHydrocarbons 270The Intrinsic Acidity Increase of a CarbonAcid

by Coordination of BF3 276Direct Observation of Cytosine ProtonationDuring

TripleHelix Formation 287A Shift of the Acidity of anN–HBond inWater Due to

the Proximity of anAmmonium orMetal Cation 288TheNotion of Superelectrophiles Produced by

Super Acids 289

CHAPTER 6Stereoisomerism andConnectivity 300Total Synthesis of anAntibiotic with a Staggering

Number of Stereocenters 303TheDescriptors for the AminoAcids Can Lead

to Confusion 307Chiral Shift Reagents 308C2 Ligands inAsymmetric Synthesis 313Enzymatic Reactions,Molecular Imprints, and

Enantiotopic Discrimination 320Biological Knots—DNAand Proteins 325Polypropylene Structure and theMass of the Universe 331Controlling Polymer Tacticity—TheMetallocenes 332CDUsed toDistinguish �-Helices from �-Sheets 335Creating Chiral Phosphates for Use asMechanistic

Probes 335AMolecular Helix Created fromHighly Twisted

Building Blocks 338

CHAPTER 7Single-Molecule Kinetics 360Using theArrhenius Equation to DetermineDifferences

in Activation Parameters for TwoCompetingPathways 371

Curvature in an Eyring Plot is Used as Evidence for anEnzymeConformational Change in the Catalysisof the Cleavage of the Co–C Bond of Vitamin B12 371

Where TSTMay be Insufficient 374The Transition States for SN1 Reactions 377Comparing Reactivity to Selectivity in Free Radical

Halogenation 378Using the Curtin–Hammett Principle to Predict the

Stereochemistry of anAddition Reaction 379Applying the Principle ofMicroscopic Reversibility

to Phosphate Ester Chemistry 380Kinetic vs. Thermodynamic Enolates 382Molecularity vs.Mechanism. Cyclization Reactions and

EffectiveMolarity 384First Order Kinetics: Delineating Between aUnimolecular

and a Bimolecular Reaction of Cyclopentyne andDienes 386

TheObservation of SecondOrder Kinetics to Support aMultistepDisplacementMechanism for aVitaminAnalog 387

Pseudo-First Order Kinetics: Revisiting theCyclopentyne Example 388

ZeroOrder Kinetics 393AnOrganometallic Example of Using the SSA

toDelineateMechanisms 395Saturation Kinetics ThatWe Take for Granted—

SN1 Reactions 397Prior Equilibrium in an SN1 Reaction 398Femtochemisty: Direct Characterization of

Transition States 400‘‘Seeing’’ Transition States Part II: The Role of

Computation 401TheUse of Pulse Radiolysis toMeasure the pKas

of Protonated Ketyl Anions 402Discovery of theMarcus Inverted Region 406Using aMoreO’Ferrall–Jencks Plot in Catalysis 00

CHAPTER 8TheUse of Primary Kinetic Isotope Effects to Probe

theMechanism of Aliphatic Hydroxylation byIron(III) Porphyrins 425

An Example of Changes in the Isotope Effect with VaryingReaction Free Energies 428

TheUse of an Inverse Isotope Effect to Delineate anEnzymeMechanism 431

An IngeniousMethod forMeasuring Very SmallIsotope Effects 432

An Example of Tunneling in a Common SyntheticOrganic Reaction 436

Using Fractionation Factors to Characterize Very StrongHydrogen Bonds 439

TheUse of a Proton Inventory to Explore theMechanismof Ribonuclease Catalysis 440

A Substituent Effect Study toDecipher the Reasonfor theHigh Stability of Collagen 444

Using aHammett Plot to Explore the Behavior of aCatalytic Antibody 450

An Example of a Change inMechanism in a SolvolysisReaction StudiedUsing �+ 452

A Swain–Lupton Correlation for Tungsten-Bipyridine-CatalyzedAllylic Alkylation 453

Using Taft Parameters to Understand the Structuresof Cobaloximes; Vitamin B12Mimics 455

TheUse of the SchleyerMethod toDetermine the Extent ofNucleophilic Assistance in the Solvolysis of ArylvinylTosylates 459

TheUse of Swain–Scott Parameters to DeterminetheMechanism of SomeAcetal SubstitutionReactions 459

ATPHydrolysis—How bLG and bNuc ValuesHaveGivenInsight into Transition State Structures 465

HowCan SomeGroups be BothGoodNucleophiles andGood LeavingGroups? 466

An Example of anUnexpected Product 472Designing aMethod toDivert the Intermediate 473Trapping a Phosphorane Legitimizes its Existence 474Checking for a Common Intermediate in Rhodium-

CatalyzedAllylic Alkylations 475PyranosideHydrolysis by Lysozyme 476Using Isotopic Scrambling to Distinguish Exocyclic vs.

Endocyclic Cleavage Pathways for a Pyranoside 478

xxiLIST OF HIGHLIGHTS

Determination of 1,4-Biradical LifetimesUsinga Radical Clock 480

The Identification of Intermediates from aCatalytic CycleNeeds to be Interpretedwith Care 481

CHAPTER 9TheApplication of Figure 9.4 to Enzymes 494High Proximity Leads to the Isolation of a Tetrahedral

Intermediate 498TheNotion of ‘‘Near Attack Conformations’’ 499Toward anArtificial Acetylcholinesterase 501Metal andHydrogen Bonding PromotedHydrolysis

of 2�,3�-cAMP 502Nucleophilic Catalysis of Electrophilic Reactions 503Organocatalysis 505Lysozyme 506AModel for General-Acid–General-Base Catalysis 514Anomalous Brønsted Values 519Artificial Enzymes: Cyclodextrins Lead theWay 530

CHAPTER 10Cyclic Forms of Saccharides andConcerted Proton

Transfers 545Squalene to Lanosterol 550Mechanisms of Asymmetric Epoxidation Reactions 558Nature’s Hydride ReducingAgent 566The Captodative Effect 573Stereoelectronics in anAcyl TransferModel 579The SwernOxidation 580Gas Phase Eliminations 588Using the Curtin–Hammett Principle 593Aconitase—AnEnzyme that Catalyzes Dehydration

and Rehydration 595Enzymatic Acyl Transfers I: The Catalytic Triad 604Enzymatic Acyl Transfers II: Zn(II) Catalysis 605EnzymeMimics for Acyl Transfers 606Peptide Synthesis—OptimizingAcyl Transfer 606

CHAPTER 11Enolate Aggregation 631Control of Stereochemistry in Enolate Reactions 636Gas Phase SN2 Reactions—AStarkDifference inMechanism

from Solution 641A Potential Kinetic Quandary 642Contact Ion Pairs vs. Solvent-Separated Ion Pairs 647An Enzymatic SN2 Reaction: Haloalkane

Dehydrogenase 649TheMeaning of bLG Values 651Carbocation Rearrangements in Rings 658Anchimeric Assistance inWar 660Further Examples of Hypervalent Carbon 666Brominations UsingN-Bromosuccinimide 673An Enzymatic Analog to the Benzilic Acid Rearrangement:

Acetohydroxy-Acid Isomeroreductase 677

CHAPTER 12BondingModels 709Electrophilic Aliphatic Substitutions (SE2 and SE1) 715C–HActivation, Part 1 722C–HActivation, Part 2 723

The Sandmeyer Reaction 726Olefin SlippageDuringNucleophilic Addition to

Alkenes 737Pd(0) Coupling Reactions inOrganic Synthesis 742Stereocontrol at Every Step inAsymmetric Allylic

Alkylations 745Cyclic Rings PossessingOver 100,000 Carbons! 747

CHAPTER 13MonodisperseMaterials Prepared Biosynthetically 756AnAnalysis of Dispersity andMolecularWeight 757AMeltingAnalysis 759Protein FoldingModeled by a Two-State Polymer

Phase Transition 762Dendrimers, Fractals, Neurons, and Trees 769Lyotropic Liquid Crystals: From Soap Scum to

BiologicalMembranes 774Organic Surfaces: Self-AssemblingMonolayers and

Langmuir–Blodgett Films 778Free-Radical Living Polymerizations 787Lycra/Spandex 790Radical Copolymerization—Not as Random

as YouMight Think 792PMMA—One Polymerwith a Remarkable Range

of Uses 793Living Polymers for Better Running Shoes 795Using 13CNMRSpectroscopy to Evaluate Polymer

Stereochemistry 797

CHAPTER 14TheHydrogenAtom 811Methane—Molecular Orbitals or Discrete Single

Bondswith sp3 Hybrids? 827Koopmans’ Theorem—AConnection BetweenAb Initio

Calculations and Experiment 828AMatrix Approach to SettingUp the LCAOMethod 832Through-BondCoupling and Spin Preferences 861Cyclobutadiene at the Two-Electron Level of Theory 862

CHAPTER 15SymmetryDoesMatter 887AllowedOrganometallic [2�2] Cycloadditions 895Semi-Empirical vs.Ab Initio Treatments of Pericyclic

Transition States 900Electrocyclization in Cancer Therapeutics 910FluxionalMolecules 913ARemarkable Substituent Effect: TheOxy-Cope

Rearrangement 921A Biological Claisen Rearrangement—TheChorismate

Mutase Reaction 922Hydrophobic Effects in Pericyclic Reactions 923Pericyclic Reactions of Radical Cations 925

CHAPTER 16Excited StateWavefunctions 937Physical Properties of Excited States 944The Sensitivity of Fluorescence—GoodNews and

BadNews 946GFP Part I: Nature’s Fluorophore 947Isosbestic Points—Hallmarks of One-to-One Stoichiometric

Conversions 949

xxii L IST OF HIGHLIGHTS

The ‘‘Free Rotor’’ or ‘‘Loose Bolt’’ Effect onQuantumYields 953

Single-Molecule FRET 961Trans-Cyclohexene? 967Retinal and Rhodopsin—The Photochemistry

of Vision 968Photochromism 969UVDamage of DNA—A [2�2] Photoreaction 971Using Photochemistry to Generate Reactive Intermediates:

Strategies Fast and Slow 983

Photoaffinity Labeling—APowerful Tool forChemical Biology 984

Light Sticks 987GFP Part II: Aequorin 989Photodynamic Therapy 991

CHAPTER 17Solitons in Polyacetylene 1015Scanning ProbeMicroscopy 1040Soft Lithography 1041

xxiii

Preface

The twentieth century saw the birth of physical organic chemistry—the study of the inter-relationships between structure and reactivity in organicmolecules—and thedisciplinema-tured to a brilliant and vibrant field. Some would argue that the last century also saw thenear death of the field.Undeniably, physical organic chemistry has had somedifficult times.There is a perception by some that chemists thoroughly understand organic reactivity andthat there are no important problems left. This view ignores the fact that while the rigoroustreatment of structure and reactivity in organic structures that is the field’s hallmark contin-ues, physical organic chemistry has expanded to encompass other disciplines.In our opinion, physical organic chemistry is alive and well in the early twenty-first

century. New life has been breathed into the field because it has embraced newer chemicaldisciplines, such as bioorganic, organometallic, materials, and supramolecular chemistries.Bioorganic chemistry is, to a considerable extent, physical organic chemistry on proteins,nucleic acids, oligosaccharides, andother biomolecules.Organometallic chemistry traces itsintellectual roots directly to physical organic chemistry, and the tools and conceptual frame-workof physical organic chemistry continue topermeate thefield. Similarly, studies ofpoly-mers and other materials challenge chemists with problems that benefit directly from thetechniques of physical organic chemistry. Finally, advances in supramolecular chemistry re-sult from a deeper understanding of the physical organic chemistry of intermolecular inter-actions. These newer disciplines have given physical organic chemists fertile ground inwhich to study the interrelationships of structure and reactivity. Yet, even while these newfields have been developing, remarkable advances in our understanding of basic organicchemical reactivity have continued to appear, exploiting classical physical organic tools anddeveloping newer experimental and computational techniques. These new techniques haveallowed the investigation of reaction mechanisms with amazing time resolution, the directcharacterizationof classically elusivemolecules suchas cyclobutadiene, andhighlydetailedand accurate computational evaluation of problems in reactivity. Importantly, the tech-niques of physical organic chemistry and the intellectual approach to problems embodiedby thediscipline remainas relevant as ever to organic chemistry. Therefore, a course inphys-ical organic chemistrywill be essential for students for the foreseeable future.This book is meant to capture the state of the art of physical organic chemistry in the

early twenty-first century, and, within the best of our ability, to presentmaterial that will re-main relevant as thefield evolves in the future. For some time it hasbeen true that if a studentopens a physical organic chemistry textbook to a random page, the odds are good that he orshe will see very interesting chemistry, but chemistry that does not represent an area of sig-nificant current research activity. We seek to rectify that situation with this text. A studentmust know the fundamentals, such as the essence of structure and bonding in organic mol-ecules, the nature of the basic reactive intermediates, and organic reaction mechanisms.However, students should also have an appreciation of the current issues and challenges inthe field, so that when they inspect themodern literature theywill have the necessary back-ground to read andunderstand current research efforts. Therefore,while treating the funda-mentals, we havewherever possible chosen examples andhighlights frommodern researchareas. Further, we have incorporated chapters focused upon several of the modern disci-plines that benefit from a physical organic approach. From our perspective, a protein, elec-trically conductive polymer, or organometallic complex should be as relevant to a course inphysical organic chemistry as are small rings, annulenes, or nonclassical ions.We recognize that this is a delicate balancing act. A course in physical organic chemistry

xxiv PREFACE

cannot also be a course in bioorganic or materials chemistry. However, a physical organicchemistry class shouldnot be ahistory course, either.Weenvision this text as appropriate formany different kinds of courses, depending on which topics the instructor chooses to em-phasize. In addition,we hope the bookwill be the first source a researcher approacheswhenconfronted with a new term or concept in the primary literature, and that the text will pro-vide a valuable introduction to the topic. Ultimately, we hope to have produced a text thatwill provide the fundamental principles and techniques of physical organic chemistry,while also instilling a sense of excitement about the varied research areas impacted by thisbrilliant and vibrant field.

Eric V. AnslynNormanHackerman ProfessorUniversity Distinguished Teaching ProfessorUniversity of Texas, Austin

Dennis A. DoughertyGeorgeGrantHoag Professor of ChemistryCalifornia Institute of Technology

xxv

Acknowledgments

Many individuals have contributed to the creation of this textbook in various ways, in-cluding offeringmoral support, contributing artwork, andproviding extensive feedback onsome or all of the text.We especially thank the following for numerous and varied contribu-tions: Bob Bergman,Wes Borden, AkinDavulcu, Francois Diederich, Samuel Gellman, Rob-ertHanes,KenHouk,AnthonyKirby, JohnLavigne,CharlesLieber, ShawnMcCleskey,KurtMislow, Jeffrey Moore, Charles Perrin, Larry Scott, John Sherman, Timothy Snowden, Su-zanne Tobey, Nick Turro, GrantWillson, and SherylWiskur.Avery special thanks goes toMichael Sponsler,whowrote the accompanying Solutions

Manual for the exercises given in each chapter. He read each chapter in detail, andmade nu-merous valuable suggestions and contributions.Producing this text has been extraordinarily complicated, andwe thank: Bob Ishi for an

inspired design; TomWebster for dedicated efforts on the artwork; Christine Taylor for or-chestrating the entire process and proddingwhen appropriate; JohnMurdzek for insightfulediting; Jane Ellis for stepping up at the right times; and Bruce Armbruster for enthusiasticsupport throughout the project.Finally, it takes a pair of very understandingwives to put upwith a six-yearwritingpro-

cess.We thankRoxannaAnslyn andEllenDougherty for their remarkable patience and end-less support.

xxvii

ANote to the Instructor

Our intent has been to produce a textbook that could be covered in a one-year course inphysical organic chemistry. The order of chapters reflects what we feel is a sensible order ofmaterial for a one-year course, althoughother sequenceswould also be quite viable. In addi-tion, we recognize that at many institutions only one semester, or one to two quarters, isdevoted to this topic. In these cases, the instructor will need to pick and choose among thechapters and even sectionswithin chapters. There aremanypossible variations, and each in-structorwill likely have a different preferred sequence, butwemake a few suggestions here.In our experience, coveringChapters 1–2, 5–8, selectedportions of 9–11, and then 14–16,

creates a course that is doable in one extremely fast-moving semester. Alternatively, if or-ganic reaction mechanisms are covered in another class, dropping Chapters 10 and 11 fromthis order makes a very manageable one-semester course. Either alternative gives a fairlyclassical approach to the field, but instills the excitement of modern research areas throughouruse of ‘‘highlights’’ (seebelow).WehavedesignedChapters 9, 10, 11, 12, and 15 for an ex-haustive, one-semester course on thermal chemical reaction mechanisms. In any sequence,mixing inChapters 3, 4, 12, 13, and 17whenever possible, basedupon the interest and exper-tise of the instructor, should enhance the course considerably. A course that emphasizesstructure and theory more than reactivity could involve Chapters 1–6, 13, 14, and 17 (pre-sumably not in that order). Finally, several opportunities for special topics courses or partsof courses are available: computational chemistry,Chapters 2 and14; supramolecular chem-istry, Chapters 3, 4, and parts of 6;materials chemistry, Chapters 13, 17, and perhaps parts of4; theoretical organic chemistry, Chapters 1, 14–17; and so on.One of thewayswe bringmodern topics to the forefront in this book is through provid-

ing twokinds of highlights: ‘‘GoingDeeper’’ and ‘‘Connections.’’These are integral parts of thetextbook that the students should not skip when reading the chapters (it is probably important totell the students this). The GoingDeeper highlights often expand upon an area, or point outwhat we feel is a particularly interesting sidelight on the topic at hand. The Connectionshighlights are used to tie the topic at hand to a modern discipline, or to show how the topicbeing discussed can be put into practice. We also note that many of the highlights make ex-cellent starting points for a five- to ten-page paper for the student towrite.As noted in the Preface, one goal of this text is to serve as a reference when a student or

professor is reading the primary literature and comes across unfamiliar terms, such as ‘‘den-drimer’’ or ‘‘photoresist.’’ However, given the breadth of topics addressed, we fully recog-nize that at some points the book reads like a ‘‘topics’’ book, without a truly in-depth analy-sis of agiven subject. Further,many topics in amore classical physical organic text have beengiven less coverage herein. Therefore,many instructorsmaywant to consult the primary lit-erature and go into more detail on selected topics of special interest to them.We believe wehave given enough references at the end of each chapter to enable the instructor to expandany topic. Given the remarkable literature-searching capabilities now available tomost stu-dents, we have chosen to emphasize review articles in the references, rather than exhaus-tively citing the primary literature.We view this book as a ‘‘living’’ text, sincewe know that physical organic chemistrywill

continue to evolve and extend into new disciplines as chemistry tackles new and variedproblems. We intend to keep the text current by adding new highlights as appropriate, andperhaps additional chapters as new fields come to benefit from physical organic chemistry.We would appreciate instructors sending us suggestions for future topics to cover, alongwith particularly informative examples we can use as highlights. We cannot promise that

xxviii A NOTE TO THE INSTRUCTOR

they will all be incorporated, but this literature will help us to keep a broad perspective onwhere the field ismoving.Given the magnitude and scope of this project, we are sure that some unclear presenta-

tions, misrepresentations, and even outright errors have crept in. We welcome correctionsand comments on these issues fromour colleagues around theworld.Manydifficult choiceshad to bemade over the six years it took to create this text, and no doubt the selection of top-ics is biasedbyourownperceptions and interests.Weapologize in advance to anyof our col-leagueswho feel their work is not properly represented, and againwelcome suggestions.Wewish you the best of luck in using this textbook.

modern physical organic chemistry

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