Modern Physical Organic Chemistry - University Science Books
Transcript of Modern Physical Organic Chemistry - University Science Books
Modern Physical Organic Chemistry
Modern Physical Organic Chemistry
Eric V. AnslynUniversity of Texas, Austin
Dennis A. DoughertyCalifornia Institute of Technology
University Science BooksSausalito, California
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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
Intent and Purpose 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
Summary and Outlook 137
EXERCISES 138FURTHER READING 143
CHAPTER 3: Solutions and Non-CovalentBinding Forces 145
Intent and Purpose 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
Summary and Outlook 201
EXERCISES 202FURTHER READING 204
CHAPTER 4: Molecular Recognition andSupramolecular Chemistry 207
Intent and Purpose 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
Summary and Outlook 252
EXERCISES 253FURTHER READING 256
CHAPTER 5: Acid–Base Chemistry 259
Intent and Purpose 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
Summary and Outlook 292
EXERCISES 292FURTHER READING 294
CHAPTER 6: Stereochemistry 297
Intent and Purpose 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
Summary and Outlook 340
EXERCISES 344FURTHER READING 350
PART IIReactivity, Kinetics, and Mechanisms
CHAPTER 7: Energy Surfaces andKinetic Analyses 355
Intent and Purpose 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
Summary and Outlook 413
EXERCISES 413FURTHER READING 417
CHAPTER 8: Experiments Related toThermodynamics and Kinetics 421
Intent and Purpose 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
Summary and Outlook 482
EXERCISES 482FURTHER READING 487
CHAPTER 9: Catalysis 489
Intent and Purpose 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
Summary and Outlook 530
EXERCISES 531FURTHER READING 535
CHAPTER 10: Organic Reaction Mechanisms,Part 1: Reactions Involving Additionsand/or Eliminations 537
Intent and Purpose 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
Summary and Outlook 617
EXERCISES 617FURTHER READING 624
CHAPTER 11: Organic Reaction Mechanisms,Part 2: Substitutions at AliphaticCenters and Thermal Isomerizations/Rearrangements 627
Intent and Purpose 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
Summary and Outlook 695
EXERCISES 695FURTHER READING 703
CHAPTER 12: Organotransition Metal ReactionMechanisms and Catalysis 705
Intent and Purpose 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
Summary and Outlook 747
EXERCISES 748FURTHER READING 750
CHAPTER 13: Organic Polymer andMaterials Chemistry 753
Intent and Purpose 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
Summary and Outlook 800
EXERCISES 801FURTHER READING 803
PART IIIELECTRONIC STRUCTURE:THEORY AND APPLICATIONS
CHAPTER 14: Advanced Concepts in ElectronicStructure Theory 807
Intent and Purpose 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
Summary and Outlook 868
EXERCISES 868FURTHER READING 875
xviiCONTENTS
CHAPTER 15: Thermal Pericyclic Reactions 877
Intent and Purpose 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
Summary and Outlook 928
EXERCISES 929FURTHER READING 933
CHAPTER 16: Photochemistry 935
Intent and Purpose 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
Summary and Outlook 993
EXERCISES 993FURTHER READING 999
CHAPTER 17: Electronic Organic Materials 1001
Intent and Purpose 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
Summary and Outlook 1041
EXERCISES 1042FURTHER READING 1044
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