Ebook Modern physical organic chemistry

Ebook Modern physical organic chemistry has contents: Molecular structure and thermodynamics; reactivity, kinetics, and mechanisms; electronic structure: theory and applications. Ebook Modern physical organic chemistry has contents: Molecular structure and thermodynamics; reactivity, kinetics, and mechanisms; electronic structure: theory and applications.

Modern Physical Organic Chemistry Eric V Anslyn UNIVERSITY OF TEXAS , AUSTI N Dennis A Dougherty CALIFORNIA I NSTITUTE OF TECH NOLOGY University Science Books www u scibooks.com Uni versity Science Books www uscibooks.com Production Manager: Christine Taylor Manuscript Editor: John Murdzek Designer: Robert Ish i Illustrator: Lineworks Compositor: Wilsted & Taylor Publishing Services Printe r & Binder: Edwards Brothers, Inc This book is p rinted on acid-free paper Cop yright © 2006 by University Science Books Reprodu ction or transla tion of any part o f this work beyond tha t permitted by Section 107 or 108 of the 1976 Un ited Sta tes Copyright Act w ithout the permission of the copyrigh t owner is unlawful Requests for permission or furth er informatio n shou ld be addressed to the Permissions Department, University Science Books Library o f Congress Cataloging-in-Publica tion Data An slyn, Eric V., 1960Modern physical organic chemistry I Eric V Anslyn, Dennis A Dougherty p em In cludes bibliographi cal references and index ISBN 978-1-891389-31-3 (alk paper) C hem istry, Ph ysica l organic I Dou gher ty, Dennis A., 1952- II Title QD476.A57 2004 547' 13-d c22 2004049617 Printed in the United States of America 10 Abbreviated Contents PART I: Molecular Structure and Thermodynamics CHAPTER PART Introduction to Structure and Models of Bonding Strain and Stability 65 Solutions and Non-Covalent Binding Forces 145 Molecular Recognition and Supramolecular Chemistry 207 Acid-Base Chemistry 259 Stereochemistry 297 II: Reactivity, Kinetics, and Mechanisms CHAPTER PART III: CHAPTER 10 Energy Surfaces and Kinetic Analyses 355 Experiments Related to Thermodynamics and Kinetics 421 Catalysis 489 Organic Reaction Mechanisms, Part 1: Reactions Involving Additions and / or Eliminations 537 11 Organic Reaction Mechanisms, Part 2: Substitutions at Aliphatic Centers and Thermal Isomerizations / Rearrangements 627 12 Organotransition Metal Reaction Mechanisms and Catalysis 13 Organic Polymer and Materials Chemistry 753 705 Electronic Structure: Theory and Applications 14 15 16 17 APPENDIX Advanced Concepts in Electronic Structure Theory Thermal Pericyclic Reactions 877 Photochemistry 935 Electronic Organic Materials 1001 807 Conversion Factors and Other Useful Data 1047 Electrostatic Potential Surfaces for Representative Organic Molecules Group Orbitals of Common Functional Groups: Representative Examples Using Simple Molecules 1051 The Organic Structures of Biology 1057 Pushing Electrons 1061 Reaction Mechanism Nomenclature 1075 INDEX 1049 1079 v Contents 1.3.2 1.3.3 1.3.4 1.3.5 List of Highlights xix Preface xxiii Acknowledgments xxv A Note to the Instructor xxvii PART I MOLECULAR STRUCTURE AND THERMODYNAMICS 1.3.6 1.3.7 CHAPTER 1: Introduction to Structure and Models of Bonding 1.3.8 1.3.9 Intent and Purpose 1.1 A Review of Basic Bonding Concepts 1.1.1 Quantum Numbers and Atomic Orbitals 1.1.2 Electron Configurations and Electronic Diagrams 1.1.3 Lewis Structures 1.1.4 Formal Charge 1.1.5 VSEPR 1.1.6 Hybridization 1.1.7 A Hybrid Valence Bond / MolecularOrbital Model of Bonding 10 Creating Localized CJand n Bonds 11 1.1.8 Polar Covalent Bonding 12 Electronegativity 12 Electrostatic Potential Surfaces 14 Inductive Effects 15 Group Eiectronegativities 16 Hybridization Effects 17 1.1.9 Bond Dipoles, Molecular Dipoles, and Quadrupoles 17 Bond Dipoles 17 Molecular Dipole Moments 18 Molecular Quadrupole Moments 19 1.1.10 Resonance 20 1.1.11 Bond Lengths 22 1.1.12 Polarizability 24 1.1.13 Summary of Concepts Used for the Simplest Model of Bonding in Organic Structures 26 1.2 A More Modern Theory of Organic Bonding 26 1.2.1 Molecular Orbital Theory 27 1.2.2 A Method for QMOT 28 1.2.3 Methyl in Detail 29 Planar Methyl 29 The Walsh Diagram: Pyramidal Methyl 31 "Group Orbitals"for Pyramidal Methyl 32 Putting the Electrons In - The MH3 System 33 1.2.4 The CH2 Group in Detail 33 The Walsh Diagram and Group Orbitals 33 Putting the Electrons In- The MH System 33 1.3 Orbital Mixing-Building Larger Molecules 1.3.1 Using Group Orbitals to Make Ethane 36 35 Using Grou p Orbitals to Make Ethy lene 38 The Effects of Heteroatoms-Formaldehyde 40 Making More Complex Alkanes 43 Three More Examples of Building Larger Molecules from Group Orbitals 43 Propene 43 Methyl Chloride 45 Butadiene 46 Group Orbitals of Representative TI Systems: Benzene, Benzyl, and Allyl 46 Understanding Common Functional Groups as Perturbations of Allyl 49 The Three Center-Two Electron Bo nd 50 Summary of the Concepts Involved in Our Second Model of Bonding 51 1.4 Bonding and Structures of Reactive Intermediates 52 1.4.1 Carbocations 52 Carbenium Ions 53 Interplay with Carbonium Ions 54 Carbonium Ions 55 1.4.2 Carbanions 56 1.4.3 Radicals 57 1.4.4 Carbenes 58 1.5 A Very Quick Look at Organometallic and Inorganic Bonding 59 Summary and Outlook EXERCISES 61 62 FURTHER READING CHAPTER 2: 64 Strain and Stability Intent and Purpose 65 65 2.1 Thermochemistry of Stable Molecules 66 2.1.1 The Concepts of Internal Strain and Relative Stability 66 2.1.2 Types of Energy 68 Gibbs Free Energy 68 Enthalpy 69 Entropy 70 2.1.3 Bond Dissociation Energies 70 Using BDEs to Predict Exothermicity and Endothermicity 72 2.1.4 An Introduction to Potential Functions and Surfaces- Bond Stretches 73 Infrared Spectroscopy 77 2.1.5 Heats of Formation and Combustion 77 2.1.6 The Group Increment Method 79 2.1.7 Strain Energy 82 Vll Vlll CON TENTS 2.2 Thermoch emistry of Reactive Interm ediates 82 2.2.1 Stability vs Persistence 82 2.2.2 Radicals 83 BDEs as a Measure of Stability 83 Radical Persistence 84 Group Increments for Radicals 86 2.2.3 Carbocations 87 Hydride Ion Affinities as a Measure of Stability 87 Lifetimes ofCarbocations 90 2.2.4 Carbanions 91 2.2.5 Summary 91 Electrostatic Interactions 131 Hydrogen Bonding 131 The Parameterization 132 Heat of Formation and Strain Energy 132 2.6.2 General Commen ts on the Molecular Mechanics Method 133 2.6.3 Molecul ar Mech anics on Biomolecules and Unnatu ral Polymers-"Modeling" 135 2.6.4 Molecu lar Mech anics Studies of Reactions 136 2.3 Rela tionships Between Struc ture and Energe ticsBasic Conformationa l Analysis 92 2.3.1 Acyclic Systems-Torsiona l Poten tial Surfaces 92 Ethane 92 Butane- The Gauche Interaction 95 Barrier Height 97 Barrier Foldedness 97 Tetraalky!ethanes 98 The g+g- Pentane Interaction 99 Allylic(A 1•3) Strain 100 2.3.2 Basic Cyclic Systems 100 Cyclopropane 100 Cyc!obutane 100 Cyc!opentalle 101 Cyc!ohcxanc 102 Larger Rings- Transamwlar Effects 107 Group ln creme11t Corrections for Ring Systems 109 Ri11g Torsional Modes 109 Bicyc!ic Ring Systems 110 Cycloalkencs and Bredt's Rule 110 SuJmJtan; of Conformational Analysis and Its Connection to Strain 112 EXERCISES 2.4 Electronic Effects 112 2.4.1 Inte ractions Involving TI Systems Subs titution 011 Alkenes 112 112 Confor/1/atiolls of Substituted Alkenes 113 Conjugation 115 Aromaticity 116 Antiaromaticity, An Unu sual Des tabilizing Effect 117 NM R Chemical Shifts 118 Polycyclic Aromatic Hydrocarbons 119 Large Annulenes 119 2.4.2 Effects of Multiple Heteroatoms 120 Bond Le11gth Effects 120 Orbital Effects 120 2.5 Highly-Strai ned Molecul es 124 2.5 Long Bonds and Large Angles 124 2.5.2 Sma ll Rings 125 2.5.3 Very Large Rotation Barriers 127 2.6 Molecular Mechanics 128 2.6.1 The Molecular Mechanics Mod el 129 Bond Stretching 129 Angle Bending 130 Torsion 130 Nonbonded Interactions 130 Cross Terms 131 Summary and Outlook 137 138 FURT HER READI NG 143 CH A PT ER 3: Solu tions and Non-Covalent Binding Forces 145 Intent and Purpose 145 3.1 Solvent and Solution Properties 3.1.1 N ature Abh ors a Vacuum 146 3.1.2 Solvent Scales 146 Dielectric Constant 147 Other Solvent Scales 148 Heat of Vaporization 150 145 Surface Tension and Wetting 150 Water 151 1.3 Solubility 153 General Overview 153 Shape 154 Using the "Like-Dissolves-Like" Paradigm 3.1.4 Solute Mobility 155 Diffusion 155 Fick's Law of Diffusion 156 Correlation Times 156 3.1.5 The Thermodynamics of Solutions 157 Chemical Potential 158 The Thermodynamics of Reactions 160 Calculating t1H and flS o 162 154 3.2 Binding Forces 162 3.2.1 Ion Pairing Interacti ons 163 Salt Bridges 164 3.2.2 Electrosta tic In teractions In volving Dipoles 165 Ion-Dipole Interactions 165 A Simple Model of Tonic Solvation The Born Equation 166 Dipole-Dipole Interactions 168 3.2.3 Hydrogen Bon d ing 168 Geometries 169 Strengths of Normal Hydrogen Bonds 171 i Solvation Effects 171 ii Electronegativity Effects 172 iii Resonance Assisted Hydrogen Bonds 173 iv Polarization Enhanced Hydrogen Bonds 174 v Secondary Interactions in Hydrogen Bonding Systems 175 CONTE vi CoopemtivihJ in Hydrogen Bonds 175 Vibra tional Properties of Hydrogen Bonds 176 Short-Strong Hydrogen Bonds 177 3.2.4 '1T Effects 180 Cation-rc Interactions 181 Polar-rc Interactions 183 Aromatic-Aromatic Interactions (rc Stacking) 184 The Arene-Perfluoroarene Interaction 184 rr: Donor-Acceptor Interactions 186 3.2.5 Indu ced -D ipole Interactio ns 186 /on- Induced-Dipole Interactions 187 Dipole-Induced-Dipole Interactions 187 lndttced-Dipole-lnduced-Dipole Interactions 188 Sunnttarizing Monopole, Dipole, and Induced-Dipole Binding Forces 188 3.2.6 The Hyd ro phobic Effect 189 Aggregation of Orga nics 189 The Origin of the Hydro phobic Effect 192 3.3 Computational Mod eling of Solva tio n 3.3.1 Conti nuum Solva ti on Mod els 196 3.3.2 Expli cit Solva tionModel s 197 3.3.3 Monte Carlo (MC) Method s 198 3.3.4 Molecula r Dyn amics (MD) 199 3.3.5 Stati sti cal Perturbation Theory/ Free Energy Pe rturba tion 200 Sum mary and Outlook 194 Molecular Recognition via Hydrogen Bonding in Water 232 4.2.4 Molecular Recognition with a Large H ydrop hobic Component 234 Cyclodextrins 234 Cyclophanes 234 A Sum mary of the Hydrophobic Co mpoueut of Molecular Recognition in Water 238 4.2.5 Molecul ar Recognition with a La rge '1T Componen t 239 Ca tion-lf Interactions 239 Polar-lf and Related Effects 241 4.2.6 Summary 241 4.3 Supramolecul ar Chemistry 243 4.3 Supra molecular Assembl y of Complex Architectures 244 Self-Assembly via Coordination Compounds 244 Self-Assernbly via Hydrogen Bonding 245 4.3.2 Novel Supra molecul a r Architectu res-Cate nanes, Rotaxa nes, and Knots 246 Nano technology 248 4.3.3 Container Compo w1ds-Molecu les w ithin M olecules 249 Summary and Outlook EXERCISES 201 252 253 FU RT H ER READING EXERC IS ES TS 256 202 FURTH ER READING CHAPTER 4: 204 M olecular Recognition and Supramolecular Chemistry In tent and Purpose CHAPTERS: 207 Acid-Base Chemistry Intent a nd Purpose 259 259 207 5.1 Bro ns ted Acid-Base Chemistry 4.1 Th erm od ynamic Anal yses of Binding Phen omena 207 4.1.1 General Thermodynamics of Bind ing 5.2 Aqueous Solutions 261 5.2.1 pK 261 5.2.2 pH 262 5.2.3 The Leveli ng Effect 264 5.2.4 Acti vity vs Concentration 266 5.2.5 Acidi ty Fu nction s: Acidity Sca les fo r Hig hl y Con centrated Acidic Solutions 266 5.2.6 Super Acid s 270 208 The Relevance of the Standard State 210 The Influence of a Change in Hea t Capacity 212 Coopera tivity 213 En thalpy-En tropy Compensation 216 4.1.2 The Binding Isotherm 21 4.1.3 Ex perimental Methods 21 U V/Vis or Fluorescence Methods 220 NMRMethods 220 Isothermal Calorimetry 221 4.2 M ol ecular Recognition 222 4.2.1 Comple mentarity and Preorgan ization 5.3 Nonaqueous Sys tems 271 5.3.1 p K, Shi fts at Enzyme Acti ve Sites 273 5.3.2 Solu tion Phase vs C as Ph ase 273 224 Crowns, Cryptands, and Sphera nds -Molecular Recogn ition with a Large Ion-Dipole Component T·weezers and Clefts 228 4.2.2 Molecul ar Recognition w ith a La rge Ion Pairing Component 228 4.2.3 Mo lecul ar Recognition with a Large H ydrogen Bonding Componen t 230 Represen tative Structures 230 259 224 5.4 Predicting Acid Stre n gth in Solution 276 5.4 Me thods Used to Measure Wea k Acid Strength 5.4.2 Tw o Gu iding Princip les for Predi ctin g Rela ti ve Acidities 277 5.4.3 Electronega tivity and Inducti on 278 5.4.4 Reson an ce 278 5.4.5 Bo nd Stre ngth s 283 5.4.6 Electrostatic Effects 283 5.4.7 H ybridi za ti on 283 276 IX X CONTENTS 5.4.8 Aromaticity 284 5.4.9 Solvation 284 5.4.10 Cationic Organic Structu res 6.6.3 NonplanarGraphs 326 6.6.4 Achievements in Top ologica l and Supram olecular Stereochemistry 327 285 5.5 Acids and Bases of Biological Interest 285 6.7 Stereochemical Issues in Polymer Chemistry 331 5.6 Lewis Acids/Bases and Electrophiles/ Nucleophiles 288 5.6.1 The Concept of Hard and Soft Acids and Bases, Genera l Lessons for Lewis Acid-Base In teractions, and Relative Nucleophilicity and Electrophilicity 289 Summary and O utlook 292 EXERCISES 292 FURTHER READING 294 6.8 Stereochemical Issues in Chemical Biology 6.8.1 Th e Linkages of Proteins, N ucleic Acids, and Polysacch arides 333 Proteins 333 Nucleic Acids 334 Polysaccharides 334 6.8.2 Helicity 336 Syn thetic Helical Polymers 337 6.8.3 Th e Origin of Ch ira lity in Nature 339 6.9 Stereochemical Terminology CHAPTER 6: Stereochemistry 297 Summary and Outlook Intent and Pu rpose 297 EXER C ISES 6.1 Stereogenicity and Stereoisomerism 297 6.1.1 Basic Concepts and Term inology 298 Classic Terminology 299 More Modem Terminology 301 6.1.2 Stereochemical Descriptors 303 R,S System 304 E,Z System 304 o and L 304 Erythro and Tlneo 305 Helical Descriptors- M and P 305 Ent nnd Epi 306 FURT HER READI NG Using Descriptors to Compare Structures 340 344 344 350 PART II REACTIVITY, KINETICS, AND MECHANISMS 306 6.1.3 Di stin gu ishing Enan tiomers 306 Optical Activity nnd Chirality 309 Why is Plane Polarized Light Rotated by a Chirnl Medium? 309 Circular Dichroism 310 X-Ray Crystallography 310 6.2 Sym metry and Stereochemis try 311 6.2 Basic Symmetry Ope rations 311 6.2 Chirality and Symmetry 311 6.2.3 Symmetry Arguments 313 6.2 Focusing on Carbon 314 6.3 Top icity Relations h ips 315 6.3.1 Homotopic, Enantiotopic, and Diastereotopic 315 6.3.2 To pi city Descri ptors-Pro-R I Pro-S and Re I Si 316 6.3.3 Chirotopicity 317 6.4 Reac tion Stereochemis try: Stereoselectivity and Stereospecifi city 317 6.4.1 Simple Guidelines for Reaction Stereoch emis try 317 6.4.2 Stereospecific and Stereoselective Reactions 319 6.5 Symmetry and Time Scale 333 CHAPTER 7: Energy Surfaces and Kinetic Analyses 355 Intent and Purpose 355 7.1 Energy Surfaces and Related Concepts 7.1.1 Energy Surfaces 357 7.1.2 Reaction Coordinate Diagrams 359 7.1.3 What is the Nature of the Activa ted Complex/ Transition State? 362 7.1.4 Rates and Rate Constants 363 7.1.5 Reaction Order and Rate Laws 364 356 7.2 Transition State Theory (TST) and Related Topics 365 7.2.1 The Mathem ati cs of Transition State Theory 365 7.2.2 Relationship to the Arrhenius Rate Law 367 7.2.3 Boltzmann Distributions and Temp erature Dependence 368 7.2.4 Revisi ting "Wh at is the Na tu re of the Acti va ted Complex?" and Why Does TST Work? 369 7.2.5 Experimental Determinations of Activa tion Param eters and Arrhenius Parameters 370 7.2.6 Examples of Acti va tion Param eters and Their Interpretations 372 7.2.7 Is TST Com p letely Correct? The Dynamic Beh avior of Organic Reactive Intermedia tes 372 322 6.6 Topological and Supramolecular Stereochemistry 324 6.6.1 Loops and Kno ts 325 6.6.2 Topological Chirality 326 7.3 Postulates and Principles Related to Kinetic Analysis 374 7.3.1 The Hammond Postulate 374 7.3.2 The Reacti vity vs Selectivity Principle 377 CO 7.3.3 The Curtin-Hammett Principle 378 7.3.4 Microscopic Reversibility 379 7.3.5 Kinetic vs Thermodynamic Control 380 7.4 Kinetic Experiments 382 7.4.1 How Kinetic Experimen ts are Performed 382 7.4.2 Kinetic Analyses for Simple Mechan isms 384 First Order Kinetics 385 Second Order Kinetics 386 Pseudo-First Order Kinetics 387 Equilibriu111 Kinetics 388 Initial-Rate Kinetics 389 Tal111lating a Series ofConwton Kinetic Scenarios 7.5 Complex Reactions-Deciphering Mechanisms 7.5.1 Steady Sta te Kinetics 390 7.5.2 Using the SSA to Predict Changes in Kinetic Order 395 7.5.3 Saturation Kinetics 396 7.5.4 Prior Rap id Equilibria 397 8.1 8.1.4 389 390 7.6 Methods for Following Kinetics 397 7.6.1 Reactions w ith Half-Lives Greater than a Few Seconds 398 7.6.2 Fast Kinetics Techniques 398 Flow Techniques 399 Flash Photolysis 399 Pnlse Radio/ ysis 401 7.6.3 Re laxation Methods 401 7.6.4 Summary of Kinetic Analyses 402 7.7 Calculating Rate Constants 403 7.7.1 Marcus Theory 403 7.7.2 Marcus Theory Ap plied to Electron Transfer 405 7.8 Considering Multiple Reaction Coordinates 407 7.8.1 Variation in Tra nsition Sta te Stru ctures Across a Series of Re la ted Reactions-An Example Using Substitution Reactions 407 7.8.2 More O'Ferrall-Jencks Plots 409 7.8.3 Changes in Vibrational State Along the Reaction Coordinate-Relating the Third Coordinate to Entropy 412 Summary and Outlook EXERC ISES 413 413 FURTHER READING 417 CHAPTER 8: Experiments Related to Thermodynamics and Kinetics Intent and Purpose 8.1.5 8.1.6 421 421 8.1 Isotope Effects 421 8.1.1 The Experiment 422 8.1.2 The Origin of Primary Kinetic Isotope Effects 422 Reaction Coordinate Diagrams and Isotope Effects 424 8.1.7 8.1.8 TENTS Primary Kinetic Isotope Effects for Linear Transition States as a Function ofExothermicity and Endothermicity 425 Isotope Effects for Linear vs Non-Linear Transition States 428 The Origin of Secondary Kineti c Isotope Effects Hybridization Changes 429 Steric isotope Effects 430 Equilibrium Isotope Effects 432 Isotopic Perturbation of EqtlilibriumApplications to Carbocations 432 Tunne ling 435 Solve nt Isotope Effects 437 Fractionation Factors 437 Proton In ventories 438 Heavy Atom Isotope Effects 441 Summ ary 441 8.2 Substituent Effects 441 8.2.1 The Origin of Substituent Effects Field Effects 443 Indu ctive Effects 443 Resonance Effects 444 Polarizability Effects 444 Steric Effects 445 Solvation Effects 445 428 443 8.3 Hammett Plots-The Most Common LFER A General Method for Examining Changes in Charges During a Reaction 445 8.3.1 Sigma (cr) 445 8.3.2 Rho (p) 447 8.3.3 The Power of Hamme tt Plots for Deciphering Mechanisms 448 8.3.4 Dev iati on s from Linearity 449 8.3.5 Separa ting Resonance from Induction 451 8.4 Other Linear Free Energy Relationships 454 8.4.1 Steric and Polar Effects-Taft Parameters 454 8.4.2 Solvent Effects- Grun wa ld- Winstein Plots 455 8.4.3 Schleyer Ad aptation 457 8.4.4 Nucleophilicity and N ucleofuga ljty 458 Basicity/Acidity 459 Solvation 460 Polarizability, Basicity, and Solvationlnterplay 460 Shape 461 8.4.5 Swa in-Scott Parameters-Nucleophilicity Parameters 461 8.4.6 Ed wards and Ritchie Correlati ons 463 8.5 Acid-Base Related EffectsBnmsted Relationships 464 8.5.1 fJNu c 464 8.5.2 f3Lc 464 8.5.3 Acid-Base Ca talysis 466 8.6 Why Linear Free Energy Relationships Work? 466 8.6.1 Gene ral Mathematics ofLFERs 467 8.6.2 Conditions to Create an LFER 468 8.6.3 The Isokine tic or Isoequilibrium Temperature 469 Xl xii CONTE TS 8.6.4 Wh y does Enthalpy-Entropy Compensa tion Occur? 469 Steric Effects 470 Solvation 470 8.7 Summary of Linear Free Energy Relationships 8.8 Miscellaneous Experiments for Studying Mechanisms 471 8.8.1 Productldentifi cation 472 8.8.2 Changing the Reactant Stru cture to Divert or Trap a Proposed Intermediate 473 8.8.3 Trapping and Competition Experiments 474 8.8.4 Checking fo r a Common In termediate 475 8.8.5 Cross-Over Experiments 476 8.8.6 Stereochemical Analysis 476 8.8.7 Isotope Scrambling 477 8.8.8 Techniques to Stud y Radicals: Clocks and Traps 8.8.9 Direct Isolation and Characterization of an Intermediate 480 8.8.10 Transien t Spectroscopy 480 8.8.11 Stable Media 481 Summary and Outlook EXERCISES 9.4 Enzymatic Catalysis 523 9.4.1 Michaelis-MentenKinetics 523 9.4.2 The Meaning of KM, kcau and kcatf KM 524 9.4.3 Enzyme Active Sites 525 9.4.4 [S] vs KM-Reaction Coordina te Diagrams 9.4.5 Sup ramolecular Interactions 529 EXERCISES 489 530 535 CHAPTER 10: Organic Reaction Mechanisms, Part 1: Reactions Involving Additions and/or Eliminations 537 489 9.1 General Principles of Catalysis 490 9.1.1 Binding the Transition State Better th an the Gro und State 491 9.1.2 A Thermodynamic Cycle Ana lysis 493 9.1.3 A Spa tial Temporal Approach 494 9.2 Forms of Catalysis 495 9.2.1 "Binding" is Akin to So lvation 495 9.2.2 Proximity as a Binding Phenomenon 9.2.3 Electro philic Ca talysis 499 Electrostatic fnteractions 499 Me tal Jon Catalysis 500 9.2.4 Acid-Base Cata lysis 502 9.2.5 Nucleophili c Catalysis 502 9.2.6 Cova lent Catalysis 504 9.2.7 Strain and Distortion 505 9.2.8 Phase Transfer Catalysis 507 527 531 FURTHER READIN G 487 CHAPTER 9: Catalysis Intent and Purpose 478 Summary and Outlook 482 482 FURTHER READING 470 9.3.4 Concerted or Sequential General-AcidGeneral-Base Catalysis 515 9.3.5 The Bremsted Catalysis Law and Its Ramifications 516 A Linear Free Energy Relationship 516 The Meaning of a and /3 517 a+/3=1 518 Deviations from Linearity 519 9.3.6 Predicting General-Add or General-Base Catalysis 520 The Libido Rule 520 Potential Energy Surfaces Dictate General or Specific Catalysis 521 9.3.7 The Dynamics of Proton Transfers 522 Marcus Analysis 522 495 9.3 Brans ted Acid-Base Catalysis 507 9.3.1 SpecificCatal ysis 507 The Mathematics of Specific Catalysis 507 Kine tic Plots 510 9.3.2 General Catalysis 510 The Mathematics of General Catalysis 511 Kinetic Plots 512 9.3.3 A Kinetic Equi valency 514 Intent and Purpose 537 10.1 Predicting Organic Reactivity 538 10.1.1 A Useful Paradigm for Polar Reactions 539 Nucleophiles and Electrophiles 539 Lewis Acids and Lewis Bases 540 Donor-A cceptor Orbital Interactions 540 10.1.2 Predicting Radical Reactivity 541 10.1.3 In Preparation for the Follow ing Sections 541 -ADDITION REACTIONS- 542 10.2 Hydration of Carbonyl Structures 542 10.2.1 Acid-Base Catalysis 543 10.2.2 The Thermodynamics of the Formation of Geminal Diols and H emiacetals 544 10.3 Electrophilic Addition of Water to Alkenes and Alkynes: Hydration 545 10.3.1 Electron Pushing 546 10.3.2 Acid-Catalyzed Aqueous Hydration 546 10.3.3 Regiochemistry 546 10.3.4 Alkyne Hydrati on 547 10.4 Electrophilic Addition of Hydrogen Halides to Alkenes and Alkynes 548 10.4.1 Electron Pushing 548 474 C H A P TE R : EX PERIM E T S REL AT ED T O THERMO D YNAM I CS A N D K I NE TI CS 8.8.3 Trapping and Competition Experiments A common method for intermediate identification is trapping of the intermed iate w ith an added reagent Several radical traps exist (see Section 8.8.8), and many good nucleophiles make viable traps for transient electrophiles such as carbocations You should use your own chemical insight to devise traps for intermediates such as carbanions, carbenes, etc Reactive intermediates are short lived, though, so the trap mus t be very reactive to compete w ith the standard reaction path of the reactive intermediate Also, because the trapping reacti on will typically be bimolecular, high concentrations of trap will often be required Alternatively, the trap could be covalently tethered to the reactant, facili tating capture of the reacti ve intermediate A variant of a trapping experiment is a competition experiment In our analysis of kinetic experiments in Chapter 7, we said that steps beyond the te-determining step d o not affect the kinetics, and thus information about them cannot be obtained This lack of a kinetic dependence often lea ves a large portion of the mechanism invisible to kinetic analysis One way to probe chemical steps past the rate-limiting step is to u se competition experiments A competition experiment involves the addition of two or more reagents that compete for one or more intermediates It is a variant on the trapping expe rimen t, where now more th an one trap is used (Eq 8.68) The ratio of products derived from the different traps tells the ratio of rate constants for the reaction of the traps with the intermediate From this ratio, som e insight into the nature of the intermediate can be gained The experi ment is viable onl y w hen the trapping reaction is under kinetic control Reactant T~ Product Slow lntermediateT¢ (Eq 8.68) Product Connections Trapping a Phosphorane Legitimizes Its Existence Pentacoordinate species (phosphoranes) are proposed inte rmediates in the hyd ro lysis of RN A and DN A Before su ch species were well accep ted, chemists exa m ined the chemis try of phosphoeste rs s uch as i as mode l systems Compound i can cyclize to g ive phospho ne ii, although ii was never seen at room temperature However, upon adding acetyl chloride to a solution of i, both iii a nd iv a re isolated Trapping expe rime nts such as this o ne give good evide nce that ii is present in a solution of i, showing tha t phosphora nes are legitimate species an d possible inte rmedia tes in chemical reactions Sarma, R., Ram irez, F., McKeever, B., Nowako,vski, M., and Ma recck, j F "Crystal and Mo lecula r Structure of Phosphate Esters Crystal and Molecular Structure of o·Hyd roxyphenyl-o-phen ylenc l'hosphatl', (o-HO C, H,)(C.H,)PO, Equil ibrium Between Pe nta va lent and Tetrava lent Phos rus in So lutio ns." f A111 Clle111 Soc., 100,539 (1978) ii iv iii Phosphorane trapping 8.8 M IS CE LL AN EOU S E X PER IM E NT S FOR ST UDY I NG MECH AN IS MS 8.8.4 Checking for a Common Intermediate Often simil ar reactions p roceed v ia the sa me interm ediate For exampl e, th e SNl so lvolysis oft-bu tyl bromide and t-butyl iodide in wa ter would both be presum ed to proceed via th e t-b u tyl ca tion We co uld easily verify this conclusion by p erformin g a com petition ex p eriment w h ere the addition of two nucleophilic trap s would give two products resulting from th e sam e in termedia te in the sam e tio An y d evia tio n in p roducts and ratios would indicate d ifferent interm ed ia tes This is exactly the sam e cept that was u sed in our example of compe tition exp eriments, exce pt now we compare th e p roduct ratio fro m two different reac tan ts Connections Checking for a Common Intermediate in Rhodium-Catal yzed Allylic Alkylations A ve ry co mmon struc tu re in organ o me talli c trans form ation s is the TI-all y l complex (see Chap te r 12) Such a stru ctu re is a resonance hybrid of two for ms with rr and 'IT bond ch arac ter These struc tures are for med from all ylcarbonates a nd can un dergo a ttack by vario us ca rbon-based nucleo ph iles to g ive ex tended ally lic sys tems ? M rr· AIIyl complex o- o M M Individually know n as cr + rr complexes A rhod iu m-based sys te m that gives exce lle nt cont ro l of ste reoch emistry has recentl y been re po rted, and it w as show n by testi ng for a common intermedi ate tha t the p u tative allyl- Rh s pecies is in fact unsy mmetri ca l The expe riment cons isted of subjecting the unsymme tr ical secondary all ylic carbonates i and ii to reac ti on with ca talyti c Rh(PPh>h C l Convention al wi sdom predi cted the two would fo rm th e sa me TI-ally l comp lex iii lf so, com pound iii should give upo n reacti on w ith the nucleop hile the two prod ucts sh ow n in the sa me ratio regardless of w hether i or ii is the sta rtin g ma teri al Instead, the reacti ons of i and ii retained regioche mi stry, w ith the nu cleo phile in bo th cases attach ed to the ca rbon that possessed the leav in g grou p in the sta rting mate rial Hen ce, a co mm on inte rmedi a te such as iii is not form ed The a uth ors interpre ted thi s result to support d istinct rr + TI in te rmed iates ins tead of symm etri c TI-al Iyl complexes Eva ns, P A., a nd Ne lson, ) D " Conserva ti o n of Abso lute Con fi g ura tion in the Acycl ic Rh odium-Ca ta lyzed All y lic A lky la tio n Reaction: Ev id e nce for a n Eny l {rr + TI) Org ano rhod ium Inte rmedia te."/ Alii CII~111 Soc., 120, 5581 (1998) + i: R =Me, R2 = iPr ii: R1 = iPr, R2 = Me 97 3 97 ~ Rh iii Symm etrical rr -allyl intermediate 475 476 C HAPTER 8: EXPER I MENTS RELATED T O THERMODYNAM I CS AN D KINET I CS 8.8.5 Cross-Over Experiments A cross-over experiment is used to determine if a reactant breaks apart to form intermediates that are released to solution before they recombine to give product To accomplish this kind of experiment, we use two similar reactants, one that is labeled in some manner to distinguish it from the other The label can be a different substituent or an isotope; the more subtle the variation the better Consider a simple reaction in which A-Breacts to give C-D We want to know whether the A and B fragments, which give rise to C and D, respectively, are ever free in the flask The reactant (A-B) and its labeled variant (A*-B* in Eq 8.69) are mixed together, and we analyze the products No scrambling of the label ed and unlabeled portions of the reactant indicates no free intermediates to cross over between the two reactions (Eq 8.69) When intermediates are released to solu tion, scrambling can occur (Eq 8.70) However, sometim es the observation of no scrambling can still be consistent with frag mentation, where recombination of the intermediates occurs fa s ter than diffusion of the inte rmediates into bulk solution As always, a negative result should be interpreted with caution In favorable cases, however, a cross-over experiment gives us information about whether a reaction occurs by an intramolecular or intermolecular process (look at Section 12.2.3 for exa mples) (Eq 8.69) A-B +A *-B* - - C-D + C*-D* A-B + A*-B* 8.8.6 C-D+ C*-D* + C*-D +C-D* (Eq 8.70) Stereochemical Analysis Very often the existence of an intermediate and I or the nature of a reaction can be deciphered from an analys is of the stereochemical outcome of an ex periment This type of experiment is covered in all introductory organic chemistry textbooks when the SN2 a nd SN1 reactions are first introduced The observation of complete inversion of configuration in the product derived from an enantiomerically pure reactant is indicative of no inte rm edi a te and a concerted displacement of the leaving group by the nuc\eophile (Eq 8.71, SN2) On the other hand, complete or partial racemi zation is indica tive of a planar intermediate (Eq 8.72, SN1) This simple but elegant probe into the existence and nature of an intermediate can be ex tended to much more complicated reactions, and ste reochemica l analysis is one of the most powerfu I mechanisti c probes We give a biochemical example in the Connections highlight, and we will see many exampl es of stereoche mi cal analyses in subsequ ent ch apters ~ ~ NC G CH CN H20 e ~ CN + I ~ + I Heat / (Eq 8.71) e ~ (Eq 8.72) ~ ' OH OH Connections Pyranoside Hydrolysis by Lysozyme The hydrolysis of f3-pyranosid es by lysozyme occurs strictly with retention of configuration at the anomeric center, giving a f3-hemiacetal product To explain the retention, the following mechanism is postulated Protonation of the aglycon group (the leaving group attached to the anomeric center) by an enzyme carboxylic acid occurs duri.ng leaving group departure Either backside nucleophilic attack or ion pai ring with an enzy me ca rboxy late protects one face of the anomeri c ca rbo n from reaction with water Thus, replacement of the departin g saccharid e with water lead s to addition from the sa me face as the leavin g group, giving a double inversion and hence overall retenti on This s tudy is a cla ss ic case of exa mining the stereochemica l outcome of an enzyme-catalyzed reaction, p rovid ing support for a particular mechanisti c scenario 8 M IS CELLANE O U S EXP E R I MENTS FOR S TUDYING MECHA N I SMS o OH RO ~e ~ HO - Enz AcHN : ie 0~0 ;r Enz Q OH HO ~ HO HNAc OR Enz RO ~ OH.o· HO OH AcHN oy o Enz 8.8.7 Isotope Scrambling A related tool tha t ca n give u s insight into the involvement of symmetrica l interm ediates is isotope scra mblin g In this experiment one iso topically labels one portion of thereactant and checks to see where that label resides in the product The p osition of the label in the product can tell u s about the nature of the intermediate and / or whether dissocia tion has occurred to give a symmetrical interm edi ate The classic check for a tetrahedral interm ediate in an acyl transfer experim ent is a good example (see Section 10.17.2) For another example, consider the th erm al and photochemical Claisen rearrangements shown in Eqs 8.73 and 8.74 Labeling the terminal position of th e all yl group of the reactant and ana lyzing th e products gives insight into the nature of the intermediates Th e label cleanly migrates to only one place in the therm al rearrangement, suggesting a concerted mechanism with no free sy mmeh·ic allyl fragment (see Section 15.5.4) However, the photochemical rearrangement gives a 50:50 scrambling of the label on both ends of the allyl fragment, sugges ting the inter mediacy of a symmetric allyl fra gment somewhere during th e m echanism, where both ends can react equally D /'o (Eq 73) ~ # /'o - hv (Eq 8.74) + 477 478 CHAPTER : EXPER IM ENTS RELATED TO THER M ODY N AMIC S AND KINETI C S Connections Using Isotopic Scrambling to Distinguish Exocyclic vs Endocyclic Cleavage Pathways for a Pyranoside The h ydrol ysis of pyranosides is postulated to largely proceed via exocyclic cleavage to give a cyclic oxocarbenium ion (Pa th A) Yet, it has long been recognized that an alte rn a tive pathway is also possible-namely, endocyclic cleavage to give an acyclic oxoca rben ium ion (Path B) ln fact, molecular dynamics calcu latio ns have suggested th a t th e endocyclic pathway may be opera tive in enzym eca tal yzed processes In order to delineate the extent to whi ch this alternative pathway occurs in soluti on, an isotopic scrambling experi ment was performed OH Exocyclic cleavage OH R'O -r -( =~ HO ~ oR AcHN ~c'~ / R'0 -r - ( =·0 HO~ + AcHN PathA ROH Compound i creates intermediates that either lack an internal mirror plane (ii) or possess an inte rnal mirror plane (iii, where the symmetry is on ly broken due to de uterium incorporation) upon exocycl ic or endocycli c cleavage, respectively Analysis of whether the deuterium scram bles in the products leads to conclusions about the extent to whi ch exocycl ic or endocyclic cleavage occurs (see below) A lack of deuterium scramb ling in the products (iv and v) indicates exocycli c cleavage, a nd the observa ti on of de uterium scra mbling in the products ind ica tes endocyclic cleavage (iv, v, vi, and v ii) Using this method, it was discovered that approx imately 15% of the reaction proceeds v ia the cnd ocycl ic pathway, with the rest occurring by the exocycli c pathway Liras, J L., Lynch, V M., and Ansly n, E V "The Ra tio between Endocycli c and Exocyclic Cleavage of Py ranos idc Aceta Is is Depende nt upo n the Ano mer, the Temperature, the Agylco n Gro u p, and the Solvent " j A111 Chc111 Soc., 119, 8191-8200(1997) ~(j PathS ~ OH R'O -r - ( Endocycl ic cleavage =~H HO ~OR AcHN ~co, ·~oco, 0 iv v ~ H + OCD vi O OC0 0 v ii + iv + v D Both mechanisms are observed 8.8.8 Techniques to Study Radicals: Clocks and Traps Radica l clocks are one experimen tal technique that s received considerable use in th e ana lysis of radical reactions Most radical clocks in volve an intramolecular free radical rearrangement th at proceeds wi th a well-defined rate constant The prototype is the rearrangem e nt of 5-hexenyl radical to cyclopentylmethyl radical, which occurs with a unimolecular rate constant of 1.0 X 10 s- a t25 °C (Eg 8.75) The clock strategy is to embed a 5-hexenyl unit into the reactive sys tem of interest If a radi cal forms, and if its life time is comparable to or greater than 10-5 s, cyclopentylmeth yl-derived produ cts should form G· - (Eq 8.75) 8.8 MIS CEL LANEOU S EXPER I MENTS FOR STU DYING MECHANISMS Table8.7 Various Radical Clocks and Their Rate Constants for Rearrangements* Rate constant for rearrangement (s- 1}, 25 oc Clock lif·- v ~­ f ·····- Clock ···· ········ ·· ·-··· ·-···-· - r - & ~ &- - - - - - -r -1.3 10 - - - - - - - - · 1r · -· ····-· f -· 1~ ~ 59 i} N- 71 ~ C\ ~ ~ r 7.8 X Rate constant for rearrangement (s- 1) , 25 oc ~­ v v· Xo J 10 - +oA_ - 1.3 x 103 ! l R02C - - Ro 9.8 x 10 i 5.2 x 10 r, X 10· i I -1 ~: ~ (5-8) x 10 """ I Ar ~ I c 1\ • In order to s tudy the li fetimes of various radicals in new reactions, one requires several radical clocks with varying lifetimes Incorporation of these clocks into th e molecules under study is used both to show that radical intermediates or not exist, and if tl1ey do, their lifetimes relative to the clock Several free radical clocks with th eir rate constants for rearrangement are shown in Table 8.7 Such a coll ection has been termed an horlogerie, after a French term for a small shop that sell s clocks Seven orders of magnitude can be spanned by choosi ng the correct clocks Another tool for studying radicals is the use of a spin trap, in an experiment called spin trapping The addition of a free radical to a nitroso or nitrone group (the spin trap; see Eqs 8.76 and 8.77) creates a spin adduct The spin adduct is another radical, but it is typically a long lived radical that can often be studied using EPR spectroscopy The EPR spectrum can be informa tive about the structure of the radical that added - R'· R' N I R' N' R' (Eg 8.76) A nitroso R,e,o N R)lR A nitrone - R'· R ' / a· N R~R R' 10 11 (1-4) x 10 *G riller, D., a nd Ingold K U "F ree Radica l Clocks." Ace Che111 Res., 13,317 (1 980) Newkomb, M., and Toy, P H " Hypersensiti ve Radi ca l Probe' and the Mecha nisms of Cytochrome P450-Ca talyzed Hydroxylation Reacti ons." Ace Che111 Res., 33, 449 (2000) II 1.3 X 10 Ar w· -;-~L :::, ' 10 t p ~- ·A co I -+ + I I +o~ + X (Eg 8.77) 479 48Q CHAPTER 8: EXPER IMENTS RELATED T O THERMODYNAM I CS AND KINET I CS Connections Determination of 1,4-Biradical Lifetimes Using a Radical Clock The photolysis of ketones lea d s to reactions that we will ca ll Norrish type II in Chapter 16 The reaction involves carbonyl excitation followed b y hydrogen atom abstraction from a -y-carbon Imbedd ed carbon monox ide, in the form of an ester, placed between the ketone and the-ycarbon is known to accelerate the decay of the resulting 1,4-biradical by allowing a fragmentation pathway To ascertain the lifetime of the rad ical intermedia tes formed from the photolysis of the following a-ke to es ter, the incorporation of a radical cl ock was performed Upon photoly- sis, three products a re fo un d, one that results from no opening of the radical clock, and two that resu lt from the open ing Hence, the ring opening of the clock competes with the fragm entation As seen in Tab le 8.7, the radical clocks of this type open with rate constants near 108 In thjs particular case, the rate constant is 9.4 x ]Q7 s- 1• Hence, the lifetime fo r fragm entation of the kin ds of biradi ca l created upon photolysis of a-ketoesters is in the range of to ns Hu, S., and Neckers, D C " Lifetimes of the 1,4-Bira di ca l Derived from Alkyl Phcnylglyoxy late Triplets: An Estimation Us in g the Cyclop ropy lme th yl Rad ica l Clock." f Org Che111., 62,755-757 ( 1997) - OH hv ~ 0~ ""CH3 Using a radical clock to probe the mechanism 8.8.9 Direct Isolation and Characterization of an Intermediate If an intermediate is s table en ough to be isolated, then common spectroscopic a nd other characterization techni ques can be u sed to identify it However, we mu s t demons trate that under the established reaction conditi ons the isolated intermediate proceeds to the same produ cts as the reactants to be confident that it is an intermediate and not just a by-product Conversely, if one su sp ects that a certa in compound is an intermediate in a reaction, the suspected intermediate can be synthesized by an ind ependen t route and subjected to the experimental conditions of the reaction und er stud y If the correct product(s) is(are) produced, this gives good but n ot concl usive eviden ce (it m ay be coin ciden tal that they give the sa me product) that th e s tructure in question is an interm edia te If the proposed intermediate gives a different product, on the other hand, it is good eviden ce th at it is not an intermediate in the reaction under study 8.8.10 Transient Spectroscopy For short lived reactive intermediates, simple isolation and characterization is not an option, so we must resort to other techniques As we noted in Chapter 7, fast spectroscopy methods have allowed chemists to obtain real-time characterization of many types of reac- M IS C ELLA NE OU S EX P E RIM ENTS FOR S T U DYI NG M EC HANISMS Connections The Identification of Intermediates from a Catalytic Cycle Needs to be Interpreted with Care The mechanism of hydrogenation of alkenes using Wilkinson's ca talyst (i) is shown below The two other species outside the box have been either detected in, or isolated from, solutions undergoing catalysis (S = solven t) However, the actual catalytic cycle is given within the box The species outside the box were found to be too sl uggish to react as competent intermediates in the rapidly proceeding catalytic cycle Hence, they are simply by-products of some of the ca talytically active species Their accumulation actually slows the rate of the catalytic reaction This example shows that the identification of a detectable species in a catalytic system can lead to misinterpretations of the catalytic cycle Being able to detect an intermediate often means that it is stable, and therefore may not be active, especially in a catalytic system We must always show that the species are ki netically competent to participate in the cycle Halpern, ) " Mecha nism and Stereoselcctivity of Asy mmetric Hydroge· nation." Science, 217, 401 (1982) H Ph3P,,,, ,,,, PPh '·· Rh Cl., " PPh H2 I I Ph3P,,,, ,,,, H '· Rh ··· Cl , " PPh3 PPh sjj Ph 3P1,,, ,,,,S ··· Rh Cl., " PPh sjj H2 H H Ph3P,,,, H '·· Rh ··· Cl., " PPh3 Ph3P,,,, H '·· Rh ··· Cl , " PPh3 I ,, I s >==< I ,,,, I 1\ / Ph 3P,,, ,,,CI ,,, ,,,PPh '· Rh ···' '··· Rh ···' Ph 3P , " cl , " PPh3 ++ H H Hydrogenation mechanism tive intermediates Just as with isolating intermediates, we must demonstrate that the intermediate observed by the fast spectroscopy is indeed an intermediate involved in the m ech anism under study Furthermore, we should demonstrate that the spectroscopy is of the inte rm ediate we are proposing and not of som e other unknow n species These tw o proofs are often challenging, but careful experimental design can provide convincing support 8.8.11 Stable Media Another strategy for characterizing reactive intermediates that are short lived is to gene te them in an environment in which there are no available reaction paths If there is n o thing the reactive inte rmediate can do, it will persist There are two basic strategies The first, typified b y the stable ion media used so successfully to study carbocations, is to simply remove all possible species that could react with the reactive intermedia te For carbocations, this means removing all nucleophiles This approach is only viable if the reactive interm ediate cannot react with itself, either bimolecularly (dimerization) or unimolecularly (rearrangem ent) For example, because free radicals can u sually dimerize readily, there is no 481 482 C H APTER 8: EXPER I MENTS RELATED TO THERMODYNAM I CS AND K I NET I CS such thing as "stable radical media" However, radicals can be observed in a frozen matrix (see below) Still, when a stable medium can be found for a reactive intermedi a te, the full array of spectroscopic tools becomes ava ilable, including NMR, IR, UV I vis, etc For extremely reactive structures for which no stable fluid m edium can be envisioned, the technique of matrix isolation is useful This approach combines two features to make the reactive inte rmedi ate observable First, the reactive intermediate is genera ted in a solid (frozen) solvent 2-Methyltetra h ydrofuran forms a particularly u seful glass at low temperature The matrix suppresses all bimolecular reactions Often this is enough to stabili ze the intermediate, if the reactive intermediate has no unimolecu lar decomposition path ways For example, methyl radical is incredibl y reactive But, if it is genera ted locked in a rigid glass, there is rea ll y nothing it can It can't rearrange, and it isn't photoreactive Indeed , samples of meth yl rad ical in g lass are indefinitely stable a t room temperature This example highlights the di stinction be twee n stability and persistence given in Section 2.2.1 Mo re typicall y, hi ghly reactive inte rmediates also have unim olecular decomposition pathways that need to be suppressed For this purpose, matrix isolation experiments are typically carri ed out at ex tre mely low temperatures For example, temperatures as low as K are not uncommon Note that at th ese low temperah1res, inert gasses such as Ar are rigid so lid s, and they make perfect inert ma tri ces You should convince yourself th at at K a barrier as sm all as kcal I mol is comp letely insurmountable The matrix isolation methodology is technicall y demanding, and it is bes t suited to IR, UV I vi s, and EPR characteriza ti on Summary and Outlook Kinetics, isotope effects, lin ear free energy relationships, and th e varied experiments discussed in th e last section of this chapter make up the vast m ajority of the meth ods chemists use to d eciph er rea ction m echani sms The level at whi ch we discussed these techniques was aimed at se ttin g the s ta ge for a more de tail ed analysi s of man y of the common organic and organom e tallic reaction m echanisms By h avin g the chapters on experimen tal tool s behind us, we are ready to exa mine h ow these tool s are used to delineate the details of mechanisms However, man y organic reactions, as w ell as most biochemical reactions, are catalyzed We still need to und erstand catalysis before examining common organic mechanisms Therefore, we now examine general method s of catalysis (Chapter 9) After thi s, we look at the mech a nis ms of substituti o ns, e liminations, and additions (Chapters 10 and 11) Looki ng forward eve n further to Ch a pters 12 and 13, you will see the application of mechani sti c tools in organometa ll ic and polymerization reactions, respectively Therefore, you may consider Chapters a nd the " bread and butte r" o f classical physical organic chemis try, and the subsequent ch apters as the applica tions to classical and modern topics Exercises One eq uation often used to calculate kinetic iso tope e ffects is g ive n below Derive this equ a ti on For a C-H bond with a stre tching frequency of 3000 cm- 1, use the eq u a tion in Exercise to calculate the expected isotope effect a t298 K fora full bond homolysis Given the frequ encies of the o ut-of-pl ane bending modes in Figure 8.6, calcu late the maximum secondary isotope effect th at could ari se dur ing a reactio n with a C-H(D) bond tha t rehybridizes from sp3 to sp a t 298 K (Hint: Although Eq 8.2 was introduced in rela ti o n to stretching vibrations, it may also be used for bending v ibra tions.) From our discu s ion of fractionation factors, d e ri ve Eq 8.11 Here, assume two reactants and two products, each with only one exchangeable hydrogen Derive the Hamme tt equation in terms of te cons tants instead of equilibrium constants Use the discussion given in Section 8.6.1 as your guideline EXERCISES Ste ric effects are commonly d ominated by differences in entropy Taft parameters are domina ted by entropy until the steric effect becom es very la rge, and then en thalpy effects start to dominate the steric effects a Using an e ntropy- enthalpy compen sation analysis, explain why a linear free energy relationship for steric effects works at all b Explain h ow e ntropy-enthalpy compe nsa tion is involved in the Grunwald- Winstein LFER Consider a unimo lecular reactio n with an Arrhenius A value of 10 13 s- a nd E,, of 0.5 kca l/ mol What is the half-life of this s pecies at K? At K? Why is there such a large rate ch a nge in response to raising the te mperatu re only K? A major research area is the conside ration of the kinds of o rganic chemistry that might go o n in interstellar space It is possible that organic molecules formed in space could have been ca rried to earth on comets or meteorites, seeding prebiotic organic chemistry Also, the o rganics in space can be a s ignatu re of sta r formati on or collapse In interstellar organic chenustry, tunnelling is often g iven much m ore consideration tha n in conventional, te rrestrial chem ishy Why should this be so? 9.ln the Going Deeper highlight o n page 466 that discusses why a good leaving group can also be a good nu cleophile, we tie the answer to the principle of microscopic reversibility At fi rst glance, reading this highlight may lead one to believe that all good nucleophiles a re good leaving groups This is not true, however, because hydroxide is a better nucleophile than wa te r, but water is the better leaving g roup Use reaction coordinate diagrams to explain when a good nucleophile is a good leaving group and when a good nucleophile is a poor leaving group 10 Ex plai n why the relief of ring stra in or steric sh·ain in a n SN1 reaction ca n often lead to small111 values (reaction constants in Grunwald- Winstein plots) 11 In the nucleophilic addition to substituted alkenes, thep val ues are larger when the subs tituent is aryl than wh en the substituent is arylsulfonyl This is also true if there is a second aryl group (deno ted PhX) Why is this so? - Nuc~ 0~ Nuc: ~X H or PhX ~ vx ,,0 s H or PhX - Nuc~ -u Nuc: X 12 The acid-catalyzed hydrolysis of substituted ethy lbenzoates has a p value of 0.14, whereas the base-catalyzed hyd rolysis of the sa me series of compounds shows a p value of 2.19 Why is there such a difference? ~OEt x)l) 13 It is often stated that deuterium prefers the strongest b o nd This implies tha t one should use bond strengths (meaning bo nd dissociation e nergies) to predict wh ere deuterium will concentra te during a reactio n that is in eq uilibrium and where the de uterium changes positio ns between two bonds Ex plain what is not quite correct about thjs statement, and give an explanation of a be tter way to predict which bond d e ute rium would prefe r 14 Explain how one would experime nta lly perform a Hammett plot study for the following reaction Do you exp ect a positi ve or negativep value? Br f : Br Br A V-I# 15 How can one dis tinguish expe rime ntall y if the o rtho ester shown below hydrolyzes in acidic water by an SN1 or S, mechanism? There are actually two possible SN2 mechanis ms, but recall that an SN2 at a te rtiary carbon is u ncommon, and therefore this is not one of the two choices tha t we are trying to distinguish 483 484 CHAP T ER 8: EXPER IMENTS RELATED TO THER MODYNAMl SAND K I NET ICS 16 a Given that a primary carbocation is less stable than a tertiary carbocation, would you expect that a reaction that creates a primary cation would be more or less responsive to solvent polarity than a reaction that crea tes a tertiary cation? b ow give some reasons wh y them value for ethy!tosylate is less than the standard (t-butyl ch loride) on whjch this free energy relationship is based Does this experimental resu lt agree wi th your answer to part a of this question? 17 ln the following equilibrium the hydrogens (or deuteria) can be found in either terminal or bridging positions It is harder to break the bond(s) to the H or D when they a re bridging be tween the metals, and due to this, the reaction is slightly exothermic in the direction sh own (from left-to-right) because the hydrogens are bound more strongly B Bridging hydrogens A Terminal hydrogens a Is the equi librium constant for this reaction larger or sm aller when one has D instead of H? Consider the equilib ri um expression as K eq = [B] I [A] b Draw a reaction coordinate diagram showi ng the relative shapes of the potential wells for the Os-H(D) bonds in the reactants and products, and the proper zero point energy levels within these wells The Os-H bonds not brea k and form in sequential steps Use this diagra m to explain your answer to part a 18 In the following reactions substituent X was varied between electron donating and electron withdrawing If you u e the usual a values, you expect a positive or negative p value for each equilibrium? Should each reaction be more sensiti ve or less sensitive to the X substituent than benzoic acid? Explain your reasoning for each answer 0e dx NaOEI HOE! oY X C±b,H X ff xff He 19 State whether the following reactions w ill show a normal or inverse, primary or secondary, kjnetic isotope effect Explain your reasoning A B ~I rl N~ N H(D) H(D) lJ H(D) o 'o c :c AAo - (;'?' H(D) ~ 0/ H(D) A 20 The following isotope effects are found for the ozonolysis of various deuterium-substituted propenes What these isotope effects tell you a bout the mechanism ? r H(D) KIE = 0.88 (D)H != KIE = 0.88 EXERCISES 21 Two possible mechanisms for the Wittig rearrangement of benzyl e thers are shown below Path involves concerted intramolecular migration of CR3, whereas Path involves a heterolysis In either mechanism, the deprotonation step is ratedetermining How would you apply the fo llowing experiments to dis tinguish between the two mechan is ms: cross-over, trapping, and stereochem istry? 22 The treatmen t of ch lorobenzen e w ith potassium amide in liquid a mmonia results in the fo rmation of anili ne Propose four experime nts discussed in this cha pter, or others yo u ca n dev ise, tha t can be used to d istinguish between the two mechanisms given below e CI ~ e ~ /./ 23 The h ydrolysis of the followin g anhydrides gave the activation param eters listed W hat is the isokinetic temperature for this reaction? 0 x-d' ~ x Substituent Jl.H ~ (kcal/mol) Jl.st (eu) m -Methyl p-Methoxy m-Nitro p-Nitro 17.8 20.1 11.6 10.7 -31.4 - 27.8 - 38.8 - 40.5 24 The acid-catalyzed Beckmann rearrangement of oximes to ami des (see Chapter 11) has two possible rate-determining s teps, the first one in each path s hown below Expl ain how you would u se a Hammett p lot analysis to d istinguish these possibilities It may be helpful to know tha t the R group trans to the d ep a rting wa ter is the only one tha t migrates e c_:OH N Rdl_ R' N :OH Il l Path A eR c I R' e c_:O H2 N RQ R' R I Path B N :OH ec I R' 25 The relative rates of the SN1 reactions of the following two alkyl p-nitrobenzoates (PN B) are as shown over the arrows below The reason for the dramatic diffe rence in the rate of departure of the nitrobenzoate leaving groups is the stabilization fro m the alkene to form a non-classical carbocation (recall non-classical carboca tions from Chapters and 2) 485 486 C HAP TER 8: EXPER IMENTS RELATED TO THERMODYNAMICS AND KI NET ICS \:O(PNB) K 8 , O(PNB) 10" £() - A t _tJ a When p-anisyl is placed in the reactant as shown below, the 10 11 rate enhance ment by the double bo nd is reduced to o nly a factor of Explain why introdu ction of this substituent ch anges the relative reacti v ity from the example given above e MeO~ MeO~:O(PNB) ~ I ( o(PNB) ~ I e MeO W ~ k;NB) O(F b Thep values for the SNl reaction of the following compou11ds were measured u si n g 13* values Interpret these values in light ofthe information g iven above Do these p values support o r contradi ct the conclusions based upon the diffe ren ce in relative rates of the two comparisons given above? ~ k;NB ) XWO(F p=-5.17 p = - 2.30 c When Hand CF3 are the X groups s hown above, the relative tes of the SNl reaction of the no rbo rne ne structure com pared to the norborn a ne analog are 41 and 35,000, respecti vely Why are these re la ti ve rates higher than when X = OMe? d The d ata g iven in this pro ble m have led to the rule of increasing electron demand for the extent of ne ighboring grou p participa tion We will examine neighboring group participation in Chapter 11 Consider the a lke ne in the above reacta nts as a " neighboring g roup" that participates in the s tabiliza tion of the carbocation Use a ll the data presented above to make a gu ess as to what the rule of increasing e lectron demand must state 26 Draw two curves associated with proton in vento ry studies w here two protons a re " in fli ght" in the rate-determining step In the firs t case each proto n h as an associated isotope effect of 2, whi le in the second case one isotope effect is l.S and the other is 2.5 Using a proton inventory ana lysis, can you diffe re ntia te the two possibilities? 27 The followin g reaction is an example of the Baeyer-Villager oxidatio n (see Chapter 11; 111CPBA = 111-chloroperbenzoic acid) A heavy atom isotope effect for the ca rbo n labeled was found to be k 12 / k ~ = 1.048 What does this tell you abo ut the m echanis m (do not write the entire mechanism)? i fmCPBA 28 In general, how would you u se radical clocks to m easure the te constant for the following radical rearrangement? Give one s pecific example - * Ph~ R FURT H ER RE A D I NG 29 In a n SN2 reaction it is commonl y observed that f3Nuc va lues are large r for reactions with poorer leaving g roups Similarly, f3Lc values are larger for reac tions involving weaker nucleophil es Such interrelati onshi ps are ca lled Bema Hapothle effects (an acronym of chemists' names) Explain the inte rdepend e nce between f3Nuc and f3Lc for SN2 reactions Further Reading Isotope Effects Melande1~ L., and Saunders, W A., Jr (1980) Reactio11 Rates of Isotopic Molecules, John Wiley & Sons, New York Westheimcr, F H "The Magnitude of the Primary Kinetic Isotope Effect for Compounds of Hydrogen and De uterium " Chcm Rev., 61, 265 (1961) Bi gelei sen, J., and Wolfs berg, M "Theo re ti cal and Ex perimental Aspects of Isotope Effects in Chemical Kine tics." Adv Chem Phys., 1, 15 (1958) Collins, C J., and Bowman, N S (eds.), Isotope Effects in Che111ical Reactions, ACS Monograph 167, Van Nostrand Reinhold, New York, 1970 Shiner, V J , Jr in Isotope Effects in Chemical Reactions, C J Collins a nd S Bowman (eds.), Van Nostrand Reinhold, New York, 1970 Kresge, A J "Cor relation of Kinetic Isotope Effects with Free Energies of Rea ction." f Am Cl1e1n Soc., 102, 7797 (1980) Wiberg, K B "The Deuterium Isotope Effect." Chem Rev., 55, 713 (1955) Meland e r, L (1960).1 so tope Effects 11 Reactio11 Rates, Ronald Press, New York Linear vs Non-Linear Transition State More O'Ferrall, R A " Model Calcu lations of H ydrogen Isotope Effects for Non-linear Transition States." f Che111 Soc B, 785 (1970) Kwart, H., Wilk, K A., and Ch a tellie1~ D.J " Verification and Characteriza tion of the E2C Mechanism The Weak Base Cata lyzed Elimin ation Reaction of [3-Phe nyl e th y!." Org Che111., 48, 756 (1983) Vitale, A A., an d Sa n Filippo, ]., Jr "Four-Center Cyclic Transition States and Their Associated Deuterium Kinetic Iso tope Effects: Hydrogeno lysis of n-Octy llithium " ] Am Chem Soc., 104,7341 (1982) Anhede, B., and Be rgma n, N.-A "Transition-State Structure a nd the Temperature Dependence of the Kinetic Isotope Effect." f A111 Che111 Soc., 106,7634 (1984) Primary Isotope Effects Bell, R P., and Cox, B G "Primary Hydrogen Isotope Effects on the Rate of Ioni zation of Nitroethane in Mixtures of Water a nd Dimethyl Sulphoxide." J Chem Soc B, 783 (1971) More O'Ferrall, R A in Proton Transfer Reactio11 s, E Ca ldin and V Gold (ed s.), Chapman and Hall, London, 1975, p 201 Zero-Point Energy Huskey, W P "Contributions oflnternal Rotation to [3-Deuterium Isotope Effects." f Phys Chem., 96, 1263 (1992) Secondary Isotope Effects Halevi, E A " Second ary Isotope Effects." Frog Phys Org Che111., 1, 109 (1963) Sunko, D E., Hirsl-Starcev ic, S., Pollack, S K., and Hehre, W J " Hyperconjugation and Homohyperconjugation in the 1-Adamantyl Cation Qualitative Models for v-Deuterium Isotope Effects." ] Am Chem Soc., 101, 6163 (1979) Sunko, D E., and Hehre, W J "Secondary De uterium Isotope Effects on Reactions Proceeding Through Carboca tions." Frog Phys Org Che111., 14, 205 (1983) Saunders, W H., Jr in Investigation of Rates and Mechan isms of Reactions, 4th ed , C F Be rnasconi (ed.), John Wiley & Sons, New York, 1986, Vol VI, Part I, p 565 Bunce!, E., and Lee, C C (ed s.), Isotopes in Organic Chemis try, Elsevier, Amsterdam, 1987, Vol 487 488 C H A PT E R : EXPE RI ME TS R ELATED TO TH E RMODY NA MI C S A N D KI N ET ICS Tunneling Le wis, E S in Proton Transfer Reactions, E Caldin and V Gold (eds.), C hapman and Hal1, London, 1975, p 317 Sa unders, W H , Jr "Contribu tion of Tunnelm g to Seconda ry Isotope Effects in Proton-Transfer Reactions." ] Am Chem Soc., 106, 2223 (1984) Bell, R P (1980) The Tu11nel Effect in Chemistry, Chapm a n and Hall, London Cald in, E F "Tunneling in Proto n-Tra nsfe r Reactio ns in Solu tion." Chem Rev., 69, 135 (1969) Bell, R P (1960) The Proton in Chemistry, Methue n, Lon don Solvent Isotope Effects Sch owen, R L " Mech a nistic Deductions From Solvent Isotope Effects." Prog Phys Org Cllem., 9, 275 (1972) Albe ry, W J in Proton-Transfer Reactions, E Galdin a nd V Gold (ed s.), Cha pman Hall, Lo ndo n, 1975 Parker, A J " Rates of Bimolecu lar Substitution Reactio ns in Pro tic and D ipolar Solvents." Adv Phys Org Chenr., 5, 173 (1967) Parker, A J " Protic-Dipolar Ap rotic Solven t Effects o n Ra te of Bimolecu lar Reactions." Chem Rev., 69, (1969) Wadding ton, T C (1969) Non-Aqueous Solvents, Thomas elson, Londo n Kosower, E M (1968) An introduction to Physical Orga11ic Chemistry, John Wiley & Sons, New York, p 259 Mechanistic Analyses in General William s, A "The Diagnosis of Co ncerted O rganic Mech anisms." Chem Soc Rev., 93 (1994) Jencks, W P " A Primer fo r th e Be ma H apo thle An Empirical App roach to the Characterization of Changing Tra nsition-State Structures." Chem Rev., 85,511 (1985) Linear Free Energy Relationships Williams, A (2003) Free Energy Relatio11ships in Organic and Bio-Organic Chemistry, Royal Soc of Chem., Cambridge, England Hammett Plots Fuchs, R., a nd Lewis, E S in Investigation of Rates and Mechanisms ofReactioiiS, 3rd ed., E W Lew is (ed.), Wiley-Interscience, New York, 1974, pp 777-824 John on, C D (1973) The Hamrnett Equation, Cambridge Uni ve rsity Press, Ca mbrid ge, England Jaffe, H H " A Reexamina tio n of the Ha mme tt Equa tio n." Chern Rev., 53, 191 (1953) McDa niel, D H , a nd Brown, H C " An Extended Table of Hamme tt Substitue nt Constants Based o n the Ioni zatio n of Substituted Benzoic A cid " ] Org Chern , 23, 420 (1958) Solvent Ionizing Plots Ben tley, T W., a nd Llewe llyn, G "X Y Sca les of Solvent Ion izing Power." Prog Phys Org Chem , 17, 121 (1990) Bronsted Plots Bender, M L " Mech a nisms of Cata lysis of ucleophilic Reactions of Ca rboxylic Acid De rivatives." Chem Rev., 60, 53 (1960) Lewis, E W " Ra te-Equilibrium LFER Characte riza tio n of Transition Sta tes The Interpre ta tion of a." ] Phys Org Chem., 3, (1990) Enthalpy-Entropy Compensation Liu, L., Guo, Q -X " lsokine tic Re la tionshi p, lsoeg u ilibrium Relations h ip, and Entha lpy-Entropy Compe nsation " Che111 Rev., 101, 673-695 (2001) ... of physical organic chemistry and the intellectual approach to problems embodied by the discipline remain as relevant as ever to organic chemistry Therefore, a course in physical organic chemistry. .. biomolecules Organometallic chemistry traces its intellectual roots directly to physical organic chemistry, and the tools and conceptual framework of physical organic chemistry continue to permeate... reactivity in organic structures that is the field's hallmark continues, physical organic chemistry has expanded to encompass other disciplines In our opinion, physical organic chemistry is alive