Preview Organic Chemistry Principles and Mechanisms by Joel Karty (2014)

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Joel M Karty Elon University

Organic Chemistry

Principles and Mechanisms

b

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W W Norton & Company has been independent since its founding in 1923, when William Warder Norton and Mary D Herter Norton first published lectures delivered at the People’s Institute, the adult education division of New York City’s Cooper Union The firm soon expanded its program beyond the Institute, publishing books by celebrated academics from America and abroad By mid-century, the two major pillars of Norton’s publishing program—trade books and college texts—were firmly established In the 1950s, the Norton family transferred control of the company to its employees, and today—with a staff of four hundred and a comparable number of trade, college, and professional titles published each year—W W Norton & Company stands as the largest and oldest publishing house owned wholly by its employees.

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To Pnut, Fafa, and Jakers

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About the Author

JOEL KARTY earned his B.S in chemistry at the University of Puget Sound and his Ph.D at Stanford University He joined the faculty of Elon University in 2001, where

he currently holds the rank of associate professor He teaches primarily the organic chemistry sequence and also teaches general chemistry In the summer, Joel teaches at the Summer Medical and Dental Education Program through the Duke University medical center His research interests include investigating the roles of resonance and inductive effects in fundamental chemical systems and studying the mechanism of pattern formation in Liesegang reactions He has written a very successful student

supplement, Get Ready for Organic Chemistry, Second Edition (formerly called The

Nuts and Bolts of Organic Chemistry).

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Brief Contents

1 Atomic and Molecular Structure 1

Nomenclature 1 Introduction: The Basic

System for Naming Simple Organic Compounds:

Alkanes, Cycloalkanes, Haloalkanes, Nitroalkanes,

and Ethers 54

2 Three-Dimensional Geometry, Intermolecular

Interactions, and Physical Properties 76

3 Orbital Interactions 1: Hybridization and

Two-Center Molecular Orbitals 128

Nomenclature 2 Naming Alkenes, Alkynes, and

Stereochemistry: R and S Configurations

about Tetrahedral Stereocenters and Z and E

Configurations about Double Bonds 276

6 The Proton Transfer Reaction: An Introduction

to Mechanisms, Thermodynamics, and Charge

Nomenclature 4 Naming Compounds with

Common Functional Groups: Alcohols, Amines,

Ketones, Aldehydes, Carboxylic Acids, Acid Halides,

Acid Anhydrides, Nitriles, and Esters 398

8 An Introduction to Multistep Mechanisms: SN1

and E1 Reactions 420

9 Nucleophilic Substitution and Elimination

Reactions 1: Competition among SN2, SN1, E2, and

E1 Reactions 466

10 Nucleophilic Substitution and Elimination

Reactions 2: Reactions That Are Useful for

13 Organic Synthesis 1: Beginning Concepts 645

14 Orbital Interactions 2: Extended ě Systems, Conjugation, and Aromaticity 676

15 Structure Determination 1: Ultraviolet-Visible and Infrared Spectroscopies 715

16 Structure Determination 2: Nuclear Magnetic Resonance Spectroscopy and Mass Spectrometry 757

17 Nucleophilic Addition to Polar ě Bonds 1: Addition of Strong Nucleophiles 815

18 Nucleophilic Addition to Polar ě Bonds 2: Addition of Weak Nucleophiles and Acid and Base Catalysis 861

19 Organic Synthesis 2: Intermediate Topics

of Synthesis Design, and Useful Reduction and Oxidation Reactions 919

20 Nucleophilic Addition–Elimination Reactions 1: The General Mechanism Involving Strong

Nucleophiles 962

21 Nucleophilic Addition–Elimination Reactions 2: Weak Nucleophiles 1006

22 Electrophilic Aromatic Substitution 1:

Substitution on Benzene; Useful Accompanying Reactions 1065

23 Electrophilic Aromatic Substitution 2:

Substitution Involving Mono- and Disubstituted Benzene and Other Aromatic Rings 1104

24 The Diels–Alder Reaction and Other Pericyclic Reactions 1154

25 Reactions Involving Free Radicals 1199

Interchapter 2 Fragmentation Pathways in Mass Spectrometry 1245

26 Polymers 1255

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1.1 What Is Organic Chemistry? 2

1.2 Why Carbon? 3

1.3 Atomic Structure and Ground State Electron Configurations 4

1.4 The Covalent Bond: Bond Energy and Bond Length 8

1.5 Lewis Dot Structures and the Octet Rule 12

1.6 Strategies for Success: Drawing Lewis Dot Structures Quickly 15

1.7 Electronegativity, Polar Covalent Bonds, and Bond Dipoles 16

1.8 Ionic Bonds 18

1.9 Assigning Electrons to Atoms in Molecules:

Formal Charge and Oxidation State 20

1.10 Resonance Theory 22

1.11 Strategies for Success: Drawing All Resonance Structures 26

1.12 Shorthand Notations 32

1.13 An Overview of Organic Compounds: Functional Groups 35

1.14 Wrapping Up and Looking Ahead 39

The Organic Chemistry of Biomolecules

1.15 An Introduction to Proteins, Carbohydrates, and Nucleic Acids:

Fundamental Building Blocks and Functional Groups 39

Chapter Summary and Key Terms 47

Problems 47

Contents

1

Introduction: The Basic System for

Naming Simple Organic Compounds

Alkanes, Cycloalkanes, Haloalkanes, Nitroalkanes,

N1.3 Trivial Names and Common Alkyl Substituents 68

N1.4 Substituents Other Than Alkyl Groups: Naming Haloalkanes,

Nitroalkanes, and Ethers 71

List of Interest Boxes xxvii

List of Mechanisms xxix

Preface xxxiii

Nomenclature

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2.3 Strategies for Success: The Molecular Modeling Kit 83

2.4 Net Molecular Dipoles and Dipole Moments 84

2.5 Physical Properties, Functional Groups, and Intermolecular Interactions 87

2.6 Melting Points, Boiling Points, and Intermolecular Interactions 89

2.7 Solubility 98

2.8 Strategies for Success: Ranking Boiling Points and Solubilities of Structurally Similar Compounds 103

2.9 Protic and Aprotic Solvents 106

2.10 Soaps and Detergents 109

2.12 An Introduction to Lipids 114

Problems 121

Orbital Interactions 1

Hybridization and Two-Center Molecular Orbitals 128

3.1 Atomic Orbitals and the Wave Nature of Electrons 129

3.2 Interaction between Orbitals: Constructive and Destructive Interference 132

3.3 An Introduction to Molecular Orbital Theory and σ Bonds:

An Example with H2 134

3.4 Hybridized Atomic Orbitals 137

3.5 Valence Bond Theory and Other Orbitals of σ Symmetry: An Example with Ethane (H3CiCH3) 143

3.6 An Introduction to π Bonds: An Example with Ethene (H2CwCH2) 145

3.7 Nonbonding Orbitals: An Example with Formaldehyde (H2CwO) 148

3.8 Triple Bonds: An Example with Ethyne (HC{CH) 149

3.9 Bond Rotation about Single and Double Bonds: Cis–Trans Isomerism 151

3.10 Strategies for Success: Molecular Models and Extended Geometry

about Single and Double Bonds 154

3.11 Hybridization, Bond Characteristics, and Effective Electronegativity 155

Problems 159

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N2.1 Alkenes and Alkynes 163

N2.2 Benzene and Benzene Derivatives 170

Isomerism 1

Conformational and Constitutional Isomers 176

4.1 Isomerism: A Relationship 177

4.2 Conformational Isomers: Rotational Conformations, Newman

Projections, and Dihedral Angles 177

4.3 Conformational Isomers: Energy Changes and Conformational

Analysis 180

4.4 Conformational Isomers: Cyclic Alkanes and Ring Strain 185

4.5 Conformational Isomers: The Most Stable Conformations of

Cyclohexane, Cyclopentane, Cyclobutane, and Cyclopropane 189

4.6 Conformational Isomers: Cyclopentane, Cyclohexane, Pseudorotation,

and Chair Flips 192

4.7 Strategies for Success: Drawing Chair Conformations of Cyclohexane 196

4.8 Conformational Isomers: Monosubstituted Cyclohexane 197

4.9 Conformational Isomers: Disubstituted Cyclohexanes, Cis and Trans

Isomers, and Haworth Projections 201

4.10 Strategies for Success: Molecular Modeling Kits and Chair Flips 203

4.11 Constitutional Isomerism: Identifying Constitutional Isomers 203

4.12 Constitutional Isomers: Index of Hydrogen Deficiency (Degree

of Unsaturation) 206

4.13 Strategies for Success: Drawing All Constitutional Isomers of a Given

Formula 209

4.15 Constitutional Isomers and Biomolecules: Amino Acids

and Monosaccharides 213

4.16 Saturation and Unsaturation in Fats and Oils 215

Problems 217

Isomerism 2

Chirality, Enantiomers, and Diastereomers 224

5.1 Defining Configurational Isomers,

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5.3 Strategies for Success: Drawing Mirror Images 228

5.4 Chirality 230

5.5 Diastereomers 242

5.6 Fischer Projections and Stereochemistry 246

5.7 Strategies for Success: Converting between Fischer Projections and

Zigzag Conformations 248

5.8 Physical and Chemical Properties of Isomers 251

5.9 Stability of Double Bonds and Chemical Properties of Isomers 255

5.10 Separating Configurational Isomers 257

5.11 Optical Activity 258

5.13 The Chirality of Biomolecules 263

5.14 The D/L System for Classifying Monosaccharides and Amino Acids 264

5.15 The D Family of Aldoses 266

Problems 268

Nomenclature

Considerations of Stereochemistry

R and S Configurations about Tetrahedral Stereocenters

and Z and E Configurations about Double Bonds 276

N3.1 Priority of Substituents and Stereochemical Configurations at

Tetrahedral Centers: R/S Designations 276

N3.2 Stereochemical Configurations of Alkenes: Z/E Designations 289

The Proton Transfer Reaction

An Introduction to Mechanisms, Thermodynamics, and Charge Stability 295

6.1 An Introduction to Reaction Mechanisms: The Proton Transfer Reaction

and Curved Arrow Notation 296

6.2 Chemical Equilibrium and the Equilibrium Constant, Keq 298

6.3 Thermodynamics and Gibbs Free Energy 308

6.4 Strategies for Success: Functional Groups and Acidity 310

6.5 Relative Strengths of Charged and Uncharged Acids: The Reactivity

of Charged Species 312

6.6 Relative Acidities of Protons on Atoms with Like Charges 314

6.7 Strategies for Success: Ranking Acid and Base Strengths—

The Relative Importance of Effects on Charge 329

6.8 Strategies for Success: Determining Relative Contributions by

Resonance Structures 333

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Contents / xv

1

6.10 The Structure of Amino Acids in Solution as a Function

of pH 336

6.11 Electrophoresis and Isoelectric Focusing 339

7.2 Bimolecular Nucleophilic Substitution (SN2) Steps 356

7.3 Bond-Formation (Coordination) and Bond-Breaking

(Heterolysis) Steps 359

7.4 Bimolecular Elimination (E2) Steps 361

7.5 Nucleophilic Addition and Nucleophile Elimination Steps 362

7.6 Electrophilic Addition and Electrophile Elimination Steps 365

7.7 Carbocation Rearrangements: 1,2-Hydride Shifts and 1,2-Alkyl

Shifts 368

7.8 The Driving Force for Chemical Reactions 370

7.9 Keto–Enol Tautomerization 373

Problems 379

Interchapter

Molecular Orbital Theory and

IC1.1 An Overview of Frontier Molecular Orbital Theory 388

IC1.2 Proton Transfer Steps 390

IC1.3 Bimolecular Nucleophilic Substitution (SN2) Steps 391

IC1.4 Bond-Formation (Coordination) and Bond-Breaking

(Heterolysis) Steps 392

IC1.5 Bimolecular Elimination (E2) Steps 393

IC1.6 Nucleophilic Addition and Nucleophile Elimination Steps 395

IC1.7 Electrophilic Addition and Electrophile Elimination Steps 396

IC1.8 Carbocation Rearrangements 397

Problems 397

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N4.1 The Basic System for Naming Carboxylic Acids, Acid Anydrides,

Esters, Acid Chlorides, Amides, Nitriles, Aldehydes, Ketones, Alcohols, and Amines 398

N4.2 Substituents in Compounds with Functional Groups That Call for a

Suffix 403

N4.3 Naming Compounds That Have an Alkene or Alkyne Group as Well as a

Functional Group That Calls for a Suffix 406

N4.4 Stereochemistry and Functional Groups That Require a Suffix 408

N4.5 The Hierarchy of Functional Groups 410

N4.6 Trivial Names Involving Functional Groups That Call for a Suffix 412

An Introduction to Multistep Mechanisms

SN1 and E1 Reactions 420

8.1 The Unimolecular Nucleophilic Substitution (SN1) Reaction 421

8.2 The Unimolecular Elimination (E1) Reaction 425

8.3 Direct Experimental Evidence for Reaction Mechanisms 427

8.4 The Kinetics of SN2, SN1, E2, and E1 Reactions 427

8.5 Stereochemistry of Nucleophilic Substitution and Elimination

Reactions 433

8.6 Proton Transfers and Carbocation Rearrangements as Part of Multistep

Mechanisms: The Reasonableness of a Mechanism 446

Problems 457

Nucleophilic Substitution and Elimination Reactions 1

Competition among SN2, SN1, E2, and E1 Reactions 466

9.1 The Competition among SN2, SN1, E2, and E1 Reactions 467

9.2 Rate-Determining Steps Revisited: Simplified Pictures of the SN2, SN1,

E2, and E1 Reactions 469

9.3 Factor 1: Strength of the Attacking Species 471

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Contents / xvii

9.4 Factor 2: Concentration of the Attacking Species 480

9.5 Factor 3: Leaving Group Ability 482

9.6 Factor 4: Type of Carbon Bonded to the Leaving Group 487

9.7 Factor 5: Solvent Effects 493

9.8 Factor 6: Heat 498

9.9 Predicting the Outcome of Nucleophilic Substitution and Elimination

Reactions 499

9.10 Regioselectivity in Elimination Reactions: Zaitsev’s Rule 504

9.11 Intermolecular Reactions versus Intramolecular Cyclizations 507

9.12 Kinetic Control, Thermodynamic Control, and Reversibility 508

9.14 Nucleophilic Substitution Reactions and Monosaccharides:

The Formation and Hydrolysis of Glycosides 512

Reaction Tables 516

Nucleophilic Substitution and

Elimination Reactions 2

Reactions That Are Useful for Synthesis 524

10.1 Nucleophilic Substitution: Converting Alcohols to Alkyl Halides Using

PBr3 and PCl3 525

10.2 Nucleophilic Substitution: Alkylation of Ammonia and Amines 529

10.3 Nucleophilic Substitution: Alkylation of α Carbons 531

10.4 Nucleophilic Substitution: Halogenation of α Carbons 536

10.5 Nucleophilic Substitution: Diazomethane Formation of Methyl

Esters 541

10.6 Nucleophilic Substitution: Formation of Ethers and Epoxides 543

10.7 Nucleophilic Substitution: Epoxides and Oxetanes as

Substrates 547

10.8 Elimination: Generating Alkynes via Elimination Reactions 555

10.9 Elimination: Hofmann Elimination 558

Reaction Tables 562

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xviii / Contents

Nonpolar ě Bonds 1

Addition of a Brønsted Acid 570

11.1 The General Electrophilic Addition Mechanism: Addition of a Strong

Brønsted Acid to an Alkene 571

11.2 Benzene Rings Do Not Readily Undergo Electrophilic Addition

of Brønsted Acids 574

11.3 Regiochemistry: Production of the More Stable Carbocation

and Markovnikov’s Rule 575

11.4 Carbocation Rearrangements 579

11.5 Stereochemistry 581

11.6 Addition of a Weak Acid: Acid Catalysis 583

11.7 Electrophilic Addition of a Strong Brønsted Acid to an Alkyne 585

11.8 Acid-Catalyzed Hydration of an Alkyne: Synthesis of a Ketone 589

11.9 Electrophilic Addition of a Brønsted Acid to a Conjugated Diene:

1,2-Addition and 1,4-Addition 592

11.10 Kinetic versus Thermodynamic Control in Electrophilic Addition

to a Conjugated Diene 595

11.12 Terpene Biosynthesis: Carbocation Chemistry in Nature 598

Reaction Table 604

Electrophilic Addition to Nonpolar ě Bonds 2

Reactions Involving Cyclic Transition States 610

12.1 Electrophilic Addition via a Three-Membered Ring:

The General Mechanism 611

12.2 Electrophilic Addition of Carbenes: Formation of Cyclopropane Rings 613

12.3 Electrophilic Addition Involving Molecular Halogens: Synthesis

of 1,2-Dihalides and Halohydrins 616

12.4 Oxymercuration–Reduction: Addition of Water 623

12.5 Epoxide Formation Using Peroxyacids 627

12.6 Hydroboration–Oxidation: Anti-Markovnikov Syn Addition of Water to an

Alkene 630

12.7 Hydroboration–Oxidation of Alkynes 637

Reaction Tables 639

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13.1 Writing the Reactions of an Organic Synthesis 646

13.2 Cataloging Reactions: Functional Group Transformations and

Carbon–Carbon Bond Formation/Breaking Reactions 650

13.3 Retrosynthetic Analysis: Thinking Backward to Go Forward 652

13.4 Synthetic Traps 656

13.5 Choice of the Solvent 662

13.6 Considerations of Stereochemistry in Synthesis 664

13.7 Percent Yield 668

14.3 Aromaticity and Hückel’s Rules 688

14.4 The MO Picture of Benzene: Why It’s Aromatic 692

14.5 The MO Picture of Cyclobutadiene: Why It’s Antiaromatic 694

14.6 Aromaticity in Larger Rings: [n]Annulenes 697

14.7 Aromaticity and Multiple Rings 698

14.8 Heterocyclic Aromatic Compounds 699

14.9 Aromatic Ions 700

14.10 Strategies for Success: Counting ě Systems and ě Electrons Using

the Lewis Structure 701

14.12 Aromaticity and DNA 706

Problems 709

Structure Determination 1

Ultraviolet-Visible and Infrared

Spectroscopies 715

15.1 An Overview of Ultraviolet-Visible Spectroscopy 716

15.2 The UV-Vis Spectrum: Photon Absorption and

Electron Transitions 718

15.3 Effects of Structure on lmax 721

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xx / Contents

15.4 IR Spectroscopy 726

15.5 A Closer Look at Some Important Absorption Bands 734

15.6 Structure Elucidation Using IR Spectroscopy 744

16.2 Nuclear Spin and the NMR Signal 759

16.3 Shielding, Chemical Distinction, and the Number of NMR Signals 761

16.4 Strategies for Success: The Chemical Distinction Test and Molecular

16.10 Splitting of the Signal by Spin–Spin Coupling: The N + 1 Rule 776

16.11 Coupling Constants and Spectral Resolution 780

16.12 Complex Signal Splitting 784

16.13 13C NMR Spectroscopy 787

16.14 DEPT 13C NMR Spectroscopy 791

16.15 Structure Elucidation Using NMR Spectroscopy 793

16.16 Mass Spectrometry: An Overview 797

16.17 Features of a Mass Spectrum: Fragmentation 798

16.18 Isotope Effects: M + 1 and M + 2 Peaks 800

16.19 Determining a Molecular Formula from the Mass Spectrum 803

Problems 806

Nucleophilic Addition to Polar ě Bonds 1

Addition of Strong Nucleophiles 815

17.1 An Overview of the General Mechanism: Addition of Strong

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Contents / xxi

17.4 Sodium Hydride: A Strong Base but a Poor Nucleophile 825

17.5 Reactions of Organometallic Compounds: Alkyllithium Reagents and

Grignard Reagents 827

17.6 Limitations of Alkyllithium and Grignard Reagents 830

17.7 Wittig Reagents and the Wittig Reaction: Synthesis of Alkenes 831

17.8 Generating Wittig Reagents 833

17.9 Sulfonium Ylides: Formation of Epoxides 835

17.10 Direct Addition versus Conjugate Addition 837

17.11 Lithium Dialkylcuprates and the Selectivity of Organometallic

Reaction Tables 852

Problems 854

Weak Nucleophiles and Acid and Base Catalysis 861

18.1 Addition of Weak Nucleophiles: Acid and Base Catalysis 862

18.2 Formation and Hydrolysis Reactions Involving Acetals, Imines,

Enamines, and Nitriles 869

18.3 The Wolff–Kishner Reduction 877

18.4 Enolate Nucleophiles: Aldol and Aldol-Type Additions 879

18.5 Aldol Condensations 882

18.6 Aldol Reactions Involving Ketones 884

18.7 Crossed Aldol Reactions 886

18.8 Intramolecular Aldol Reactions 891

18.9 Aldol Additions Involving Nitriles and Nitroalkanes 894

18.10 The Robinson Annulation 896

18.11 Organic Synthesis: Aldol Reactions in Synthesis 898

18.12 Organic Synthesis: Imagining an Alternate Target Molecule in a

Retrosynthetic Analysis 900

18.14 Ring Opening and Closing of Monosaccharides; Mutarotation 902

Reaction Tables 907

Problems 909

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Organic Synthesis 2

Intermediate Topics in Synthesis Design, and Useful Reduction and Oxidation Reactions 919

19.1 Umpolung in Organic Synthesis: Forming Bonds between Carbon Atoms

Initially Bearing Like Charge; Making Organometallic Reagents 920

19.2 Relative Positioning of Functional Groups in Carbon–Carbon

Bond-Formation Reactions 923

19.3 Reactions That Remove a Functional Group Entirely from

a Molecule: Reductions of CwO to CH2 927

19.4 Avoiding Synthetic Traps: Selective Reagents

and Protecting Groups 931

19.5 Catalytic Hydrogenation 941

19.6 Oxidations of Alcohols and Aldehydes 947

Reaction Table 954

Problems 955

Nucleophilic Addition–Elimination Reactions 1

The General Mechanism Involving Strong Nucleophiles 962

20.1 An Introduction to Nucleophilic Addition–Elimination Reactions:

Base-Promoted Transesterification 963

20.2 Reaction of an Ester with Hydroxide (Saponification) and the Reverse

Reaction 968

20.3 Acyl Substitution Involving Other Carboxylic Acid Derivatives: The

Thermodynamics of Acyl Substitution 971

20.4 Carboxylic Acids from Amides; the Gabriel Synthesis of Primary

Amines 975

20.5 Haloform Reactions 979

20.6 Hydride Reducing Agents: Sodium Borohydride (NaBH4) and Lithium

Aluminum Hydride (LiAlH4) 982

20.7 Specialized Reducing Agents: Diisobutylaluminum Hydride (DIBAH)

and Lithium Tri-tert-butoxyaluminum Hydride 990

20.8 Organometallic Reagents 993

Reaction Tables 998

Problems 1000

Nucleophilic Addition–Elimination Reactions 2

Weak Nucleophiles 1006

21.1 The General Nucleophilic Addition–Elimination Mechanism Involving

Weak Nucleophiles: Alcoholysis and Hydrolysis of Acid Chlorides 1007

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Contents / xxiii

21.2 Relative Reactivities of Acid Derivatives: Rates of Hydrolysis 1010

21.3 Aminolysis of Acid Derivatives 1014

21.4 Synthesis of Acid Halides: Getting to the Top of the Stability Ladder 1016

21.5 The Hell–Volhard–Zelinsky Reaction: Synthesizing α-Bromo

Carboxylic Acids 1019

21.6 Sulfonyl Chlorides: Synthesis of Mesylates, Tosylates, and Triflates 1021

21.7 Base and Acid Catalysis in Nucleophilic Addition–Elimination

Reactions 1023

21.8 Baeyer–Villiger Oxidations 1028

21.9 Claisen Condensations 1030

21.10 Organic Synthesis: Decarboxylation, the Malonic Ester Synthesis,

and the Acetoacetic Ester Synthesis 1040

21.11 Organic Synthesis: Protecting Carboxylic Acids and Amines 1044

21.13 Determining a Protein’s Primary Structure via Amino Acid

Sequencing: Edman Degradation 1046

21.14 Synthesis of Peptides 1049

Reaction Tables 1053

Problems 1055

Electrophilic Aromatic Substitution 1

Substitution on Benzene; Useful Accompanying

22.8 Organic Synthesis: Considerations of Carbocation Rearrangements

and the Synthesis of Primary Alkylbenzenes 1084

22.9 Organic Synthesis: Common Reactions Used in Conjunction

with Electrophilic Aromatic Substitution Reactions 1085

Problems 1096

Electrophilic Aromatic Substitution 2

Substitution on Mono- and Disubstituted Benzene and

Other Aromatic Rings 1104

23.1 Regiochemistry of Electrophilic Aromatic Substitution: Identifying

Ortho/Para and Meta Directors 1105

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xxiv / Contents

25

23.2 Nitration of Phenol: Why Is a Hydroxyl Group an

Ortho/Para Director? 1107

23.3 Nitration of Toluene: Why Is CH3 an Ortho/Para Director? 1110

23.4 Nitration of Nitrobenzene: Why Is NO2 a Meta Director? 1112

23.5 The Activation and Deactivation of Benzene toward Electrophilic

Aromatic Substitution 1114

23.6 The Impacts of Substituent Effects on the Outcomes of Electrophilic

Aromatic Substitution Reactions 1118

23.7 The Impact of Reaction Conditions on Substituent Effects 1121

23.8 Electrophilic Aromatic Substitution on Disubstituted Benzenes 1123

23.9 Electrophilic Aromatic Substitution Involving Aromatic Rings Other

Than Benzene 1126

23.10 Nucleophilic Aromatic Substitution Mechanisms 1130

23.11 Organic Synthesis: Considerations of Regiochemistry; Attaching

Groups in the Correct Order 1135

23.12 Organic Synthesis: Interconverting Ortho/Para and

Meta Directors 1137

23.13 Organic Synthesis: Considerations of Protecting Groups 1139

Reaction Table 1143

Problems 1144

The Diels–Alder Reaction and

24.1 Curved Arrow Notation and Examples 1155

24.2 Conformation of the Diene 1159

24.3 Substituent Effects on the Driving Force 1162

24.4 Stereochemistry of Diels–Alder Reactions 1163

24.5 Regiochemistry of Diels–Alder Reactions 1168

24.6 The Reversibility of Diels–Alder Reactions; the Retro Diels–Alder

Reaction 1171

24.7 Syn Dihydroxylation of Alkenes and Alkynes Using OsO4 or KMnO4 1173

24.8 Oxidative Cleavage of Alkenes and Alkynes 1175

24.9 Organic Synthesis: The Diels–Alder Reaction in Synthesis 1181

24.10 A Molecular Orbital Picture of the Diels–Alder Reaction 1182

Problems 1191

25.1 Homolysis: Curved Arrow Notation and Radical Initiators 1200

25.2 Structure and Stability of Alkyl Radicals 1205

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Contents / xxv

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25.3 Common Elementary Steps That Free Radicals Undergo 1210

25.4 Radical Halogenation of Alkanes: Synthesis of Alkyl Halides 1213

25.5 Radical Addition of HBr: Anti-Markovnikov Addition 1226

25.6 Stereochemistry of Free-Radical Halogenation and HBr Addition 1228

25.7 Dissolving Metal Reductions: Hydrogenation of Alkenes and Alkynes 1229

25.8 Organic Synthesis: Radical Reactions in Synthesis 1234

IC2.2 Alkenes and Aromatic Compounds 1248

IC2.3 Alkyl Halides, Amines, Ethers, and Alcohols 1250

IC2.4 Carbonyl-Containing Compounds 1253

26.1 Polystyrene: A Synthetic Polymer 1256

26.2 General Aspects of Polymers 1266

26.3 Other Polymerization Reactions 1275

26.4 Chemical Reactions after Polymerization 1280

26.5 Properties of Polymers 1285

26.6 Uses of Polymers: The Relationship between Structure and Function in

Materials for Food Storage 1291

26.7 Degradation and Depolymerization 1294

26.8 Biological Macromolecules 1296

Problems 1304

Appendix A Values of Ka and pKa for Various Acids A-1

Appendix B Characteristic Reactivities of Particular Functional Groups A-4

Appendix C Reactions That Alter the Carbon Skeleton A-9

Appendix D Synthesizing Particular Functional Groups via Functional Group

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xxvii

List of Interest Boxes

Chemistry with Chicken Wire 5

Turning an Inorganic Surface into an Organic Surface 11

Room Temperature Ionic Liquids 97

Enzyme Active Sites: The Lock-and-Key Model 107

Phase Transfer Catalysts 112

Caution: Hydrofluoric Acid Is a Weak Acid 307

Superacids: How Strong Can an Acid Be? 328

“Watching” a Bond Break 369

Sugar Transformers 376

Phosphorylation: An Enzyme’s On/Off Switch 445

Using Proton Transfer Reactions to Discover New Drugs 452

Rotaxanes: Exploiting Steric Hindrance 493

You Can’t Always Want What You Get: How an Enzyme Can Manipulate

the Reactivity of a Substrate 497

DNA Alkylation: Cancer Causing and Cancer Curing 554

Mechanically Generated Acid and Self-Healing Polymers 561

Electrophilic Addition and Laser Printers 579

Kinetic Control, Thermodynamic Control, and Mad Cow Disease 598

Halogenated Metabolites: True Sea Treasures 623

Benzo[a]pyrene: Smoking, Epoxidation, and Cancer 631

Conjugated Linoleic Acids 689

Benzene and Molecular Transistors 696

The Chemistry of Vision 725

IR Spectroscopy and the Search for Extraterrestrial Life 744

Magnetic Resonance Imaging 787

Mass Spectrometry, CSI, and ER 805

NADH as a Biological Hydride Reducing Agent 825

Michael Addition in the Fight against Cancer 842

Hypoglycemia and Aldol Reactions 891

Protecting Groups in DNA Synthesis 940

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xxviii / List of Interest Boxes

Chromic Acid Oxidation and the Breathalyzer Test 951Biodiesel and Transesterification 967

The Stability Ladder in Biochemical Systems 974Biological Claisen Condensations 1039

Aromatic Sulfonation: Antibiotics and Detergents 1083Sodium Nitrite and Foods: Preventing Botulism but Causing Cancer? 1091

Iodized Salt and Electrophilic Aromatic Substitution 11102,4,6-Trinitrotoluene (TNT) 1119

Biological Diels–Alder Reactions 1158Ethene, KMnO4, and Fruit Ripening 1180Halogenated Alkanes and the Ozone Layer 1218Free Radicals in the Body: Lipid Peroxidation and Vitamin E 1225Stereochemistry, Polypropylene, and the Nobel Prize 1274

What Happens to Recycled Plastic? 1296

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xxix

List of Mechanisms

General SN2 mechanism (Equation 8-1) 421

General SN1 mechanism (Equation 8-2) 421

General E2 mechanism (Equation 8-4) 425

General E1 mechanism (Equation 8-5) 425

SN2 mechanism under basic conditions (Equation 8-28) 447

SN1 mechanism under acidic conditions (Equation 8-31) 449

SN1 mechanism with a carbocation rearrangement

(Equation 8-38) 454

Competition among SN2, SN1, E2, and E1 mechanisms

(Equations 9-1 through 9-4) 468

Acid-catalyzed dehydration of an alcohol (Equation 9-26) 486

Solvolysis of an alkyl halide (Equations 9-38 and 9-39) 502

Acid-catalyzed glycoside formation of a sugar (Equation 9-54) 513

Acid-catalyzed bromination of an alcohol (Equation 10-2) 525

PBr3 bromination of an alcohol (Equation 10-8) 527

Alkylation of an amine (Equation 10-13) 530

Alkylation of an α carbon of a ketone or aldehyde

Diazomethane formation of a methyl ester (Equation 10-33) 542

Williamson ether synthesis (Equation 10-36) 544

Formation of a cyclic ether from a haloalcohol under basic conditions

Trang 30

Acid-catalyzed hydration of an alkene (Equation 11-16) 584Addition of a Brønsted acid to an alkyne to produce a vinyl halide (Equation 11-18) 586

Addition of a Brønsted acid to an alkyne to produce a geminal dihalide (Equation 11-21) 587

Acid-catalyzed hydration of an alkyne (Equation 11-23) 590Addition of a Brønsted acid to a conjugated diene

(Equation 11-28) 592Addition of carbene to an alkene (Equation 12-5) 614Addition of dichlorocarbene to an alkene (Equation 12-7) 615Addition of a molecular halogen to an alkene (Equation 12-9) 617Addition of HOX to a symmetric alkene (Equation 12-17) 620Addition of HOX to an unsymmetric alkene (Equation 12-19) 622Oxymercuration–reduction of an alkene (Equation 12-22) 624Epoxidation of an alkene using a peroxyacid (Equation 12-32) 628Hydroboration of an alkene (Equation 12-35) 632

Oxidation of a trialkylborane (Equation 12-39) 635Generic addition of a strong nucleophile to a ě polar bond (Equation 17-1) 817

Simplified picture of the NaBH4 reduction of a ketone (Equation 17-5) 822

More accurate picture of the NaBH4 reduction of a ketone (Equation 17-6) 822

Alkyllithium reaction involving a ketone (Equation 17-17) 828Grignard reaction involving a nitrile (Equation 17-18) 828Wittig reaction (Equation 17-22) 832

Generating a Wittig reagent (Equation 17-25) 833Generating a sulfonium ylide (Equation 17-28) 835Epoxidation of a ketone involving a sulfonium ylide (Equation 17-30) 836

Direct addition of a nucleophile to a conjugated aldehyde (Equation 17-31) 838

Conjugate addition of a nucleophile to a conjugated aldehyde (Equation 17-32) 838

Uncatalyzed nucleophilic addition of a weak nucleophile to a ketone (Equation 18-3) 863

Base-catalyzed nucleophilic addition of a weak nucleophile to a ketone (Equation 18-4) 863

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List of Mechanisms / xxxi

Acid-catalyzed nucleophilic addition of a weak nucleophile to a ketone

(Equation 18-5) 864

Addition of HCN to a ketone (Equation 18-7) 866

Conjugate addition of a weak nucleophile to a conjugated ketone

(Equation 18-10) 868

Acid-catalyzed formation of an acetal (Equation 18-13) 870

Acid-catalyzed formation of an imine (Equation 18-19) 873

Acid-catalyzed hydrolysis of a nitrile (Equation 18-25) 876

Base-catalyzed hydrolysis of a nitrile (Equation 18-26) 877

Wolff–Kishner reduction of a ketone (Equation 18-28) 878

Self-aldol addition involving an aldehyde (Equation 18-30) 880

Dehydration of an aldol product under basic conditions: An E1cb

mechanism (Equation 18-32) 883

Dehydration of an aldol product under acidic conditions

Self-aldol addition involving a ketone (Equation 18-37) 885

Aldol condensation forming a ring (Equation 18-47) 892

Ring formation in a monosaccharide (Equation 18-67) 903

Catalytic hydrogenation of an alkene (Figure 19-2) 942

Chromic acid oxidation of a secondary alcohol (Equation 19-33) 948

Base-promoted transesterification (Equation 20-2) 964

Saponification: Conversion of an ester into a carboxylate anion

(Equation 20-4) 968

Esterification of an acid chloride under basic conditions

(Equation 20-7) 971

Hydrolysis of an amide under basic conditions (Equation 20-11) 975

Gabriel synthesis of a primary amine (Equation 20-13) 977

Haloform reaction (Equation 20-16) 980

NaBH4 reduction of an acid chloride to a primary alcohol

LiAlH4 reduction of a carboxylic acid to a primary alcohol

LiAlH4 reduction of an amide to an amine (Equation 20-26) 988

Reduction of an acid chloride to an aldehyde using LiAlH(O-t-Bu)3

Aminolysis of an acid chloride (Equation 21-9) 1014

SOCl2 conversion of a carboxylic acid to an acid chloride

(Equation 21-14) 1017

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xxxii / List of Mechanisms

Sulfonation of an alcohol (Equation 21-21) 1021Base-catalyzed transesterification (Equation 21-25) 1023Acid-catalyzed transesterification (Equation 21-29) 1025Amide hydrolysis under acidic conditions (Equation 21-33) 1027Baeyer–Villiger oxidation (Equation 21-35) 1029

Claisen condensation (Equation 21-37) 1031Decarboxylation of a β-keto ester (Equation 21-49) 1041Amide formation via dicyclohexylcarbodiimide coupling (Equation 21-56) 1049

General mechanism of electrophilic aromatic substitution on benzene (Equation 22-4) 1067

Bromination of benzene (Equation 22-8) 1070Friedel–Crafts alkylation of benzene (Equation 22-12) 1072Friedel–Crafts alkylation of benzene involving a carbocation rearrangement (Equation 22-16) 1075

Friedel–Crafts acylation of benzene (Equation 22-20) 1078Nitration of benzene (Equation 22-22) 1081

Sulfonation of benzene (Equation 22-24) 1082Diazotization of benzene (Equation 22-32) 1090General mechanism for electrophilic aromatic substitution on napthalene (Equation 23-28) 1127

General mechanism for electrophilic aromatic substitution on pyrrole (Equation 23-31) 1128

General mechanism for electrophilic aromatic substitution on pyridine (Equation 23-32) 1129

Nucleophilic aromatic substitution on benzene, via nucleophilic addition–elimination (Equation 23-34) 1130

Nucleophilic aromatic substitution on benzene, via a benzyne intermediate (Equation 23-39) 1133

Diels–Alder reaction (Equation 24-2) 1155Syn dihydroxylation of an alkene involving OsO4(Equation 24-31) 1173

Oxidative cleavage of an alkene involving KMnO4(Equation 24-37) 1176

Oxidative cleavage of cis-1,2-diol involving periodate

(Equation 24-41) 1178Ozonolysis of an alkene (Equation 24-45) 1179Radical chlorination of an alkane (Equations 25-18 through 25-20) 1214–16

Production of Br2 from N-bromosuccinimide (Equation 25-28) 1224

Radical addition of HBr to an alkene (Equation 25-33) 1226Radical hydrogenation of an alkyne via dissolving metal reduction (Equation 25-41) 1231

Birch reduction of benzene (Equation 25-45) 1233Free-radical polymerization (Equations 26-4 through 26-8) 1259–62

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More Than an Emphasis on Mechanisms:

Organized by Mechanism

During my first year of teaching organic chemistry, I taught what I have come to

learn is a traditional approach I organized the course the way that most textbooks are

organized, with reactions pulled together according to the functional groups involved

Moreover, because I wanted my students to understand and not just memorize the

material, I emphasized mechanisms very heavily Despite my best efforts, the

major-ity of my students struggled with even the basics of mechanisms and, consequently,

turned to flashcards as their primary study tool They tried to memorize their way

through the course, which made matters worse

My goal in writing this book was to solve the problem of memorization by

group-ing reactions accordgroup-ing to similarities in their mechanisms Thus, while the content

of this book is the same as in other mainstream textbooks, the different organization

establishes a coherent story of chemical reactivity The story begins with molecular

structure and energetics, and then guides students into reaction mechanisms with a

few transitional chapters Thereafter, students study how and why reactions take place

as they do, focusing on one type of mechanism at a time Ultimately, students learn

how to intuitively use reactions in synthesis

As mechanisms are central to the story of the book, students are naturally deterred

from overlooking them Students are made to feel more comfortable with

mecha-nisms, and are clearly shown how the material builds from one chapter to the next,

providing the foundation for understanding mechanisms in later chapters

Conse-quently, early in the course, students naturally embrace mechanisms as a learning

tool, which I believe is vital to their success throughout the entire course and later—

including on admission exams such as the MCAT

Advantages of a Mechanistic Organization

In terms of student success, an organization by mechanism type offers two main

ad-vantages over the traditional organization by functional group First, it allows students

to focus more on reaction mechanisms within each chapter This is because, once

stu-dents are introduced to a particular reaction type, they get to apply those mechanisms

across various functional groups For example, after learning nucleophilic substitution

reactions, students see that the mechanism applies to alkyl halides, alcohols, ethers,

ketones, aldehydes, amines, and carboxylic acids Second, as students begin to see the

mechanistic patterns that unfold in one chapter, they will develop a better toolbox of

mechanisms to draw upon in subsequent chapters Students will therefore be better

able to predict what will happen and why

An organization by functional group, on the other hand, makes it very difficult for

students to recognize patterns because each functional group chapter presents

disjoint-ed pieces of information relatdisjoint-ed to that functional group A functional group chapter

discusses aspects of nomenclature, physical properties, synthesis, and spectroscopy in

addition to new reactions and mechanisms As a result, students find themselves

over-whelmed and most will see no option but to memorize Specifically, they will memorize

what they perceive to be most important—predicting products of reactions—and will

typically ignore, or give short shrift to, fundamental concepts and mechanisms

xxxiii

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xxxiv / Preface

I have now taught organic chemistry using a mechanistic organization for nearly

a decade, during which time I have seen student performance and outlook improve dramatically.1 I believe it all begins with students having a better handle on concepts and reactions early on In my experience, the greatest motivator for students to put

forth effort is the feeling of understanding the material—the feeling of being in control

over the material Students who feel that they “get” it are vastly more motivated to put

in an even greater effort The better understanding that a mechanistic organization affords students at the outset, therefore, paves the way for their success throughout the entire course

Details about the OrganizationThe book is divided into three major parts:

Part I: Atomic and molecular structure

■ Chapter 1: Atomic structure, Lewis structures and the covalent bond, and resonance theory, culminating in an introduction to functional groups

■ Chapter 2: Aspects of three-dimensional geometry and its impacts on intermolecular forces

■ Chapter 3: Structure in terms of hybridization and molecular orbital (MO) theory

■ Chapters 4 and 5: Isomerism in its entirety, including constitutional isomerism, conformational isomerism, and stereoisomerism

Part II: Developing a toolbox for working with mechanisms

■ Chapters 6 and 7: Ten elementary steps of mechanisms are examined

■ Chapter 8: Beginnings of multistep mechanisms using SN1 and E1 reactions as examples

Part II provides a transition into Part III, which deals more intently with reactions.Part III: Major reaction types

■ Chapters 9 and 10: Nucleophilic substitution and elimination

■ Chapters 11 and 12: Electrophilic addition

■ Chapters 17 and 18: Nucleophilic addition

■ Chapters 20 and 21: Nucleophilic addition–elimination

■ Chapters 22 and 23: Electrophilic aromatic substitution

■ Chapter 24: Diels–Alder reactions and other pericyclic reactions

■ Chapter 25: Radical reactions

■ Chapter 26: Polymerization Notice that several of these chapters come in pairs The first chapter in each pair is used to introduce key ideas about the reaction/mechanism and the second chapter explores the reaction/mechanism to greater depth and breadth

Interspersed in Part III are chapters dealing with synthesis (Chapters 13 and 19), conjugation and aromaticity (Chapter 14), and spectroscopy (Chapters 15 and 16) The spectroscopy chapters are self contained and can be taught earlier, at the instruc-tor’s discretion

Another major structural component of the book pertains to nomenclature Nomenclature is separated out from the main chapters, in four relatively short units Each unit focuses on specific rules of nomenclature, as opposed to specific functional groups With each new nomenclature unit, new rules are introduced, which increases the complexity of the material discussed These units can be covered in lecture or easily assigned for self study

1 Bowman, B G.; Karty, J M.; Gooch, G “Teaching a Modified Hendrickson, Cram and Hammond Curriculum in Organic

Chemistry.” J Chem Ed 2007, 84, 1209.

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Preface / xxxv

Use the box provided to draw the product suggested by the faulty curved arrow notation in the following chemical equation What is unacceptable about the product you drew?

+

HO H Cl

–

7.10 Draw the S N 2 step that would occur between C 6 H 5 CH 2 I and CH 3 SNa.

 Which species is the nucleophile? Which is the substrate? What do we do with the metal atom? Which species is tron rich? Electron poor?

elec-C 6 H 5 CH 2 I will behave as the substrate because it possesses as I , a good leaving group that departs as I 2 The

conjugate acid of I 2, HI , is a very strong acid CH 3 SNa has a metal atom that can be treated as a spectator ion and thus ignored The nucleophile is therefore CH 3 S In an S N 2 step, a curved arrow is drawn from the lone pair of electrons on the electron-rich S atom to the electron-poor C atom bonded to I A second curved arrow must be drawn to indicate that the

Ci I bond is broken (otherwise that C would have five bonds).

δ +

+

+ S

Finally, the application of MOs toward chemical reactions is separated from the

main reaction chapters, and is presented, instead, as an optional, self-contained

inter-chapter This interchapter appears just after Chapter 7, the overview of the 10 most

common elementary steps Each elementary step from Chapter 7 is revisited from the

perspective of MO theory—more specifically, frontier MO theory Because this

inter-chapter is optional, inter-chapters later in the book do not rely on coverage of this material

A Better Tool for Students

While the organization provides a coherent story, other aspects of the book make it an

excellent learning tool for students

Extended coverage of general chemistry topics The early chapters provide

ex-tended coverage of a variety of general chemistry topics This is deliberate because I

believe most students need a review of several of these topics upon entering organic

chemistry For example, I have found that most students do not have a firm grasp of

Lewis structures, intermolecular forces, and equilibria and thermodynamics Rather

than assume that students will dive into their general chemistry textbook to review

these topics, I have provided this additional material, with an organic focus, as a

con-venient student resource Instructors can tailor their in-class coverage of this material

as they deem necessary

Strategies for Success In addition to reviewing important general chemistry

top-ics, I have provided Strategies for Success sections to help students build specific skills

they need in this course For example, Chapter 1 provides strategies for drawing all

resonance structures of a given species, and sections in Chapters 2 and 3 are devoted

to the importance of molecular modeling kits in working with the three-dimensional

aspects of molecules and also with the different rotational characteristics of σ and π

bonds In Chapter 4, students are shown how to draw chair conformations and how

to draw all constitutional isomers of a given formula Chapter 5 provides help with

drawing mirror images of molecules One Strategies for Success section in Chapter

6 helps students estimate pKa values and another helps students rank acid and base

strengths based only on their Lewis structures In Chapter 14, I include a section that

shows students how to use the Lewis structure to assess conjugation and aromaticity,

and Chapter 16 has a section that teaches students the chemical distinction test for

nuclear magnetic resonance

Your Turn exercises Getting students to read

active-ly can be challenging, so I wrote the Your Turns in each

chapter to motivate this type of behavior Your Turns are

basic exercises that ask students to either answer a

ques-tion, look something up in a table from a previous

chap-ter, construct a molecule using a model kit, use a table in

the chapter, or interact with art in a figure or data in a

plot In addition to getting students active when they read, these exercises are intended

to be “reality checks” for students as they read Your Turns should be used as indicators

to students as to whether they understand what they have just read If they cannot

solve/answer a Your Turn exercise easily, students should interpret this as a signal

that they need to either reread the previous section(s) or seek help Short answers to

all Your Turns are provided in the back of the book and

complete solutions to these exercises are provided in the

Study Guide and Solutions Manual

Consistent and effective problem-solving approach

Helping students become expert problem-solvers, in

this course and beyond, is one of my major goals I have

developed the Solved Problems in the book to train

students how to think as they approach a problem On

average, there are seven Solved Problems per chapter and

each one is broken down into two parts: Think and Solve

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xxxvi / Preface

In the Think part, students are provided a handful of questions that I want them to be

asking as they approach the problem In the Solve part, those questions are answered and the problem is solved This mirrors the strategy I use to help students during office

hours, and we have used these same steps for every problem in the Solutions Manual

that accompanies the book

Another excellent training tool is SmartWork, Norton’s online tutorial and work system SmartWork allows students to practice their problem-solving skills and receive hints and answer-specific feedback that reinforce what students see in the book

home-Developing a toolbox of mechanisms Understanding the common elementary

steps that make up mechanisms is a crucial part of solving organic chemistry lems The elementary steps introduced in Chapters 6 and 7 effectively provide students

prob-a toolbox for working comfortprob-ably with mechprob-anisms lprob-ater on Moreover, students will find that many reactions they encounter throughout the course have mechanisms that comprise just these steps This makes it more transparent to students how seemingly different reactions can, in fact, be very closely related—through the mechanism

Separating nomenclature As I discussed earlier, nomenclature is presented in

four separate units, interspersed between chapters in the first half of the book These units are self-contained and they can be covered where they are located in the textbook

or any point after One of the main reasons for presenting nomenclature separately is that it helps minimize distractions A second reason for separate coverage of nomen-clature is that nomenclature is among the most straightforward topics students will encounter Naming a molecule requires memorizing certain rules and then practicing applying those rules This is something that students are quite comfortable with, so instructors have the option of holding students accountable for learning nomenclature

on their own or covering it in class

Biochemistry and MCAT 2015 Most organic chemistry students are biology

ma-jors and/or are seeking a career in a health profession They appreciate seeing how

organ-ic chemistry relates to their interests and look for ways in whorgan-ich this course will prepare them for the admissions exams (such as the MCAT) that may determine their future Rather than relegating biochemistry to the end of the book, I have placed the Organic Chemistry of Biomolecules in self-contained sections at the ends of several chapters, beginning with Chapter 1 The topics chosen for these sections cover many

of the topics outlined in the MCAT 2015 Preview Guide, which means that the

Organic Chemistry of Biomolecules sections are not in addition to what students are expected to know for the MCAT; they are topics that students should know for the test

In even the earliest of chapters, students have the tools to start learning aspects of this traditional biochemistry coverage More importantly, these sections provide reinforce-

ment of topics In each biomolecules section, the material is linked directly back to concepts encountered earlier in the chapter.These Organic Chemistry of Biomolecules sections are both optional and flexible Instructors can decide to cover only a few

of these topics or none at all, and can do so either as they appear

in the book or as special topics at the end of the second semester

A range of interesting applications In addition to the

Or-ganic Chemistry of Biomolecules sections, most chapters have two special interest boxes These boxes apply a concept in the chapter

to a discovery or process that students can relate to In addition to reinforcing concepts from the chapter, these boxes are intended

to provide meaning to what students are learning, and to motivate

students to dig deeper

A focus on synthesis Synthesis problems represent one of the

greatest challenges undergraduates face in this course Not only must students have a command of the reactions they have learned, but they must also be able to think critically to find the right com-bination of those reactions that will transform the starting mate-

Proton transfer reactions are among the simplest of reactions, but they can be a powerful tool

in our never-ending quest to discover new drugs The key, as we learned here in Chapter 8, is

that proton transfer reactions tend to be quite fast, and there are several mildly acidic protons

throughout the structure of a protein, both in the amide groups that make up the protein’s

back-bone and in the side groups of certain amino acids If a protein is dissolved in deuterated water

(D 2 O), these protons can exchange with the D atoms of the solvent via simple proton transfer

reactions The rate of this H/D exchange can be monitored with mass spectrometry (see

Chapter 16), because the atomic mass of D is greater than that of H

How can this help us discover new drugs? The answer lies in the fact that drugs are typically

designed to bind to target proteins that are in their folded state, as shown below A potentially

viable drug, therefore, will help keep the protein folded, preventing D 2 O from exchanging with

protons on the interior of the protein Overall, then, the rate of H/D exchange will be slowed.

A drug bound to a protein stabilizes

the protein in its folded state.

H/D exchange

D 2 O

H D This technique is especially attractive because it requires only picomole amounts of protein, can

be carried out even in the presence of impurities, and can be automated As many as 10,000

potential drugs can be tested in a single day!

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Preface / xxxvii

rial into the desired compound I provide a thorough introduction to organic synthesis

in two chapters—Chapters 13 and 19 Chapter 13 discusses introductory topics in

synthesis, including the basics of retrosynthetic analysis and the idea of cataloging

reactions according to what they accomplish Chapter 19 presents more challenging

topics in synthesis, such as the use of protecting groups and how to place functional

groups strategically within a carbon backbone Therefore, whereas Chapter 13 ought

to be covered by most mainstream classes, instructors can choose to cover only certain

sections of Chapter 19 or skip it entirely

I have found that treating synthesis in dedicated chapters makes it more

mean-ingful to students When I taught synthesis under a traditional functional group

or-ganization, it became a distraction to the reactions that students are simultaneously

learning I also found that students often associated a synthetic strategy only with the

functional group for which it was introduced For example, when the idea of

protect-ing groups is introduced in the ketones/aldehydes chapter of a textbook

tradition-ally organized by functional group, students tend to associate protecting groups with

ketones/aldehydes only My dedicated synthesis chapters help students focus on

syn-thesis without compromising their focus on reactions Furthermore, synsyn-thesis

strate-gies are discussed more holistically, so students can appreciate them in a much broader

context rather than being applicable to a single functional group

Optional interchapter on the application of MO theory toward reactions

Under an organization according to functional group, the roles of MOs in chemical

reactions typically appear integrated into several different functional group chapters

For example, the role of orbitals in an SN2 reaction is typically integrated in an alkyl

halides chapter, and the role of orbitals in a nucleophilic addition reaction is typically

integrated into the ketones/aldehydes chapter For instructors who do not teach this

aspect of MOs in their course, these discussions can represent distractions and are

potentially counterproductive to student learning

Presenting this material together in an optional interchapter, as I have done in

this book, offers two main advantages to students One is that it removes a

poten-tial distraction from the main reaction chapters and, being optional, instructors have

the choice of not covering it at all Another advantage comes from the fact that the

MO pictures of all 10 common elementary steps appear together in the interchapter

Therefore, instructors who wish to cover this interchapter can expect their students

to come away with a better understanding of the bigger picture of MO theory as it

pertains to chemical reactions

Acknowledgments

There are many people who have been a part of or impacted by my work on this

text-book, and my gratitude for all of them is immense First and foremost, however, I must

acknowledge my family—Valerie, Joshua, and Jacob When I began work on this book,

Joshua wasn’t even walking; now he’s 11 and Jacob is 9 It has been a long and

ardu-ous endeavor But it is also one that has been worthwhile and has helped shape who I

am today Thank you for your love and support and for standing by me the entire way

I must also acknowledge my parents, Alec and Maraline, who instilled in me the

importance of academics and the love of learning My thanks goes out to them

espe-cially for the numerous sacrifices they made so that I could have the best in education

and the best in life

I owe a lot to my brothers and sister, too—Ben, Kevin, and Sarah Those sibling

rivalries we had growing up certainly brought out the best in me More recently, thank

you for tolerating me throughout this process

Thanks must also go to my colleagues in the chemistry department here at Elon,

for your support and understanding of how important this book has become I

es-pecially must acknowledge Gene and Marcia Gooch Gene was initially part of this

project but died tragically in a bicycle accident

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xxxviii / Preface

To my teachers through the years, thank you for your wisdom and ment, as well as your friendship Jack Howard, you got me started in chemistry in high school, and I still remember when you said: “I’m not a smart man, but I do know how

encourage-to convert units.” John Hanson and Bill Dasher, you “showed me the way” in organic chemistry, and Ken Rousslang, you taught me to appreciate the finer details in physi-cal chemistry and turned me on to the world of research Tim Hoyt, thank you for being the “Wiz” that you are And to John Brauman, it is because of you that I can truly call myself a scientist

My students deserve a lot of credit, too Even though I am the teacher cally), I continue to learn from my students year in and year out Thank you, especially, for being guinea pigs at times, giving me the chance to learn how to become a better teacher

(techni-To Maureen Cullins, thank you for letting me be creative It was in my first year teaching at the Summer Medical and Dental Education Program that I “discovered” a better way to teach organic chemistry, and you have always been one of my biggest fans

A tremendous amount of thanks goes to the many members of the Norton team Erik Fahlgren, thank you for believing in me, and for taking on this project with

as much passion as I have given it Your balance of optimism and critique has truly brought the book to a whole new level of quality John Murdzek, your help through the developmental editing process has been priceless, and your humor has helped me keep things in perspective Renee Cotton and Christine D’Antonio, I continue to be amazed with your attention to detail and ability to stay on top of things Jane Miller,

I appreciate the hours you have spent researching photos and bearing with me when things are not precisely to my liking And to Stacy Loyal, I admire the work you’ve done in marketing this book Changing a paradigm that’s over half a century old is no small task Kudos to you

A special thanks to Steve Pruett and Marie Melzer Steve, your patience with me and with this book has been incredible, and your insights have been tremendously appreciated Thank you, in particular, for your commitment through it all Marie, I ap-preciate your help creating the Your Turn answers at the end of the book and greatly value the energy and the insight that you have brought to the Study Guide and Solu-tions Manual

Finally, I am indebted to the many class-testers and reviewers, whose feedback has been invaluable in the evolution of this book I am especially grateful to Larry

French, Laurie Witucki, and Steve Miller, who accuracy-checked the entire book A

tremendous—and tremendously important—undertaking, indeed!

California State University–Los AngelesCatawba College

Catawba Valley Community CollegeDePauw University

Des Moines Area Community CollegeEastern Mennonite University

Elon UniversityJefferson Technical and Community College

Lakeland College

Luther CollegeMalcolm X CollegePasadena City College

St Catherine University SUNY—PotsdamTexas Lutheran UniversityUniversity of Minnesota–MorrisUniversity of Tennessee–KnoxvilleUpper Iowa University

Wake Forest UniversityAdopters of the Preliminary Edition

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Preface / xxxix

Reviewers

Robert Allen, Arkansas Tech University

Herman Ammon, University of

Maryland

Carolyn Anderson, Calvin College

Aaron Aponick, University of Florida

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Jared Ashcroft, Pasadena City College

Athar Ata, University of Winnipeg

Jovica Badjic, Ohio State University

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Brad Chamberlain, Luther College

Robert Coleman, Ohio State University

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Lorraine Deck, University of New Mexico

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Seth Elsheimer, University of Central

Florida

Eric Finney, University of Washington

Andrew Frazer, University of Central

Florida

Larry French, St Lawrence University

Gregory Friestad, University of Iowa

Brian Frink, Lakeland College

Anne Gorden, Auburn University

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State University

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Robert Grossman, University of Kentucky

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Philip Hultin, University of Manitoba

Kevin Jantzi, Valparaiso University

Amanda Jones, Wake Forest UniversityJeff Jones, Washington State UniversityPaul Jones, Wake Forest UniversityRobert Kane, Baylor UniversityArif Karim, Austin Community CollegeSteven Kass, University of MinnesotaStephen Kawai, Concordia UniversityValerie Keller, University of ChicagoMark Keranen, University of Tennessee–

KnoxvilleKristopher Keuseman, Mount Mercy College

Angela King, Wake Forest UniversityJesudoss Kingston, Iowa State UniversityFrancis Klein, Creighton UniversityJeremy Klosterman, Bowling Green State University

Dalila Kovacs, Grand Valley State University

Jason Locklin, University of GeorgiaBrian Long, University of Tennessee–

KnoxvilleClaudia Lucero, California State University–SacramentoDavid Madar, Arizona State University–

PolytechnicKirk Manfredi, University of Northern Iowa

Eric Masson, Ohio UniversityAnita Mattson, Ohio State UniversityGerald Mattson, University of Central Florida

Jimmy Mays, University of Tennessee–

KnoxvilleAlison McCurdy, California State University–Los Angeles

Dominic McGrath, University of ArizonaMark McMills, Ohio University

Marie Melzer, Old Dominion UniversityOgnjen Miljanic, University of HoustonJustin Miller, Hobart and William Smith Colleges

Stephen Miller, University of FloridaBarbora Morra, University of TorontoJoseph O’Connor, University of California–San DiegoJames Parise, University of Notre DameNoel Paul, Ohio State UniversityJames Poole, Ball State UniversityChristine Pruis, Arizona State University

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xl / Preface

Additional Resources

For Students

Study Guide and Solutions Manual

by Joel Karty, Elon University, and Marie Melzer, Old Dominion UniversityWritten by two dedicated teachers, this guide provides students with fully worked solu-tions to all unworked problems in the text Every solution follows the Think/Solve for-mat used in the textbook, so the approach to problem-solving is modeled consistently

SmartWork

Created by chemistry educators, SmartWork is the most intuitive online tutorial and homework system available for organic chemistry A powerful engine supports and grades an unparalleled range of problems written for Karty’s text, including numerous

arrow-pushing problems Every problem in SmartWork has hints and answer-specific

feedback to coach students and provide the help they need, when they need it lems in SmartWork link directly to the appropriate page in the electronic version of Karty’s text so students have an instant reference and are prompted to read

Prob-Instructors can draw from Norton’s bank of more than 2000 high-quality, tested problems, or use our innovative authoring tools to easily modify existing prob-lems or write new ones Instructors can sort problems by learning goal and create assignments to assess any learning goals, concepts, or skills that they choose

class-The Karty SmartWork course also features:

■ An expert author team The organic SmartWork course was authored by instructors

who teach at a diverse group of schools: Arizona State University, Florida State versity, Brigham Young University, and Mesa Community College The authors have translated their experience in teaching such a diverse student population by creating

Uni-a librUni-ary of problems thUni-at will Uni-appeUni-al to instructors Uni-at Uni-all schools

Harold Rogers, California State University–Fullerton

Sheryl Rummel, Pennsylvania State University

Nicholas Salzameda, California State University, Fullerton

Adrian Schwan, University of GuelphColleen Scott, Southern Illinois University–CarbondaleSergei Dzyuba, Texas Christian UniversityAlan Shusterman, Reed College

Joseph Simard, University of New EnglandChad Snyder, Western Kentucky UniversityJohn Sorensen, University of ManitobaLevi Stanley, Iowa State UniversityLaurie Starkey, California State University–Pomona

Tracy Thompson, Alverno CollegeNathan Tice, Butler UniversityJohn Tomlinson, Wake Forest University

Melissa VanAlstine-Parris, Adelphi University

Nanine Van Draanen, California Polytechnic State University–San Luis Obispo

Quin Wang, University of South CarolinaDon Warner, Boise State UniversityHaim Weizman, University of California–San Diego

Lisa Whalen, University of New MexicoJames Wilson, University of MiamiLaurie Witucki, Grand Valley State University

James Wollack, St Catherine UniversityAndrei Yudin, University of TorontoMichael Zagorski, Case Western Reserve University

Rui Zhang, Western Kentucky UniversityRegina Zibuck, Wayne State UniversityEugene Zubarev, Rice UniversityJames Zubricky, University of Toledo

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