Foundations of Organic Chemistry

DAVID R. DALTON received his Ph.D. in Organic Chemistry from the University of California, Los Angeles and is a Professor Emeritus at Temple University. He has held visiting professorships (1972-1973) at Israel Institute of Technology (Technion), Haifa, Israel; (1976-1977) Yale University, New Haven, Connecticut; (1988-1989) Bryn Mawr College, Bryn Mawr, Pennsylvania; and in 1992, he was the visiting master teacher in Residence, Clemson University, Clemson, South Carolina.

Prologue xix

Acknowledgments xxi

About the Companion Website xxiii

Part I Background 1

1. An Introduction to Structure and Bonding 5

A. The Sources of Carbon Compounds 5

I. How Do We Know a Material is Pure? 6

B. More About Hydrocarbons: Heats of Combustion and Reaction 9

I. Combustion: Heats of Reaction 9

C. On The Nature of the Chemical Bond 12

I. Ionic and Nonpolar Covalent Bonds 12

II. Polar Covalent Bonds: Mixing Orbitals and Molecular Orbitals 17

III. The Use of Orbital Hybridization and Molecular Orbitals 21

a. Summary Comment on Bonding Models 37

IV. Allotropes of Carbon 37

V. Combination of Ionic and Covalent Bonding 37

Notice to the Student 41

Problems 41

Notes and References 44

2. An Introduction to Spectroscopy and Selected Spectroscopic Methods in Organic Chemistry 49

A. General Introduction. The Electromagnetic Spectrum 49

B. X‐Ray Crystallography 51

C. Photon Spectroscopy 52

I. General Introduction 52

II. Ultraviolet and Visible Spectroscopy 54

III. Infrared Spectroscopy 56

IV. Raman Spectroscopy 58

V. Microwave Spectroscopy 58

VI. Magnetic Resonance Spectroscopy 59

a. Nuclear Magnetic Resonance (NMR) 59

1. The Chemical Shift 62

2. Multiplicity (The Coupling Constant: Spin–Spin Splitting) 65

3. The Integrated Area 66

4. Expansion of the Principle 67

5. NMR in Two Dimensions 69

6. Double Resonance 70

7. 13C, 19F, and 31P NMR Spectroscopy 72

b. Electron Spin Resonance (ESR) Spectroscopy or Electron Paramagnetic Resonance (EPR) Spectroscopy 74

D. Mass Spectrometry 75

I. Creation of Ions in the Mass Spectrometer: The Ionization Chamber 76

II. The Separation of Ions by Mass: The Mass Analyzer 76

III. Detecting the Ions 77

Problems 77

Notes and References 78

3. Structure: The Nomenclature of Hydrocarbons and the Shape of Things to Come 83

A. Introduction 83

B. Nomenclature and Spectroscopy 84

I. Alkanes in Two and Three Dimensions 84

a. Acyclic Alkanes 84

b. Cyclic Alkanes 89

II. Alkenes, Arenes, and Alkynes in Two and Three Dimensions 92

a. Alkenes 93

b. Arenes 97

c. Alkynes 102

C. Physical and Chemical Properties: Oxidation and Reduction of Hydrocarbons 104

I. The Concept of Homology 105

II. Oxidation and Reduction 105

a. Oxidation 105

b. Reduction 108

Problems 112

Notes and References 115

4. An Introduction to Dynamics 119

A. Introduction 119

B. Review of Some Energy Considerations 120

C. The Barrier Between Reactants and Products 121

D. More About the Transition State 123

E. Rotation About Sigma (Σ) Bonds in Acyclic Alkanes, Alkenes, Alkynes, and Alkyl‐Substituted Arenes 126

I. Alkanes 126

II. Alkenes, Alkynes, and Alkyl‐Substituted Arenes 129

F. Conformational Analysis of Medium‐Ring Cyclic Alkanes 131

G. The Conservation of Symmetry During Reactions 146

H. The Measurement of Chirality 156

I. The Wave Nature of Light 156

II. Plane‐Polarized Light and Handedness 157

III. Optical Rotatory Dispersion (ORD) and Circular Dichroism (CD) 160

Problems 162

Notes and References 165

5. Classes of Organic Compounds: A Survey Along with an Introduction to Solvents, Acids and Bases, and to More About Computational Chemistry 173

A. Introduction 173

B. General Characteristics of Functional Group Placement 175

C. The Functional Groups, Their Names, and Some Physical and Spectroscopic Properties 176

I. Hydrocarbons 176

a. Alkanes 176

b. Alkenes 176

c. Alkynes 178

d. Arenes 178

II. Alkyl and Aryl Halides 179

III. Alcohols and Phenols 183

IV. Ethers 190

V. Thiols, Thioethers, and Disulfides and Their Oxides 193

VI. Amines, Hydrazines, and Other Nitrogenous Materials 196

VII. Phosphines, Phosphonium Salts, and Other Phosphorus Derivatives 199

VIII. An Introduction to Organometallic Compounds 201

IX. Compounds Containing Unsaturated Functional Groups 204

a. Aldehydes 204

b. Ketones 210

c. Nitrogen, Sulfur, and Phosphorus Analogues of Aldehydes and Ketones 212

d. Carboxylic Acids 213

e. Carboxylic Acid Derivatives 217

1. Carboxylic Acid Halides (Acyl Halides) 218

2. Carboxylic Acid Anhydrides 219

3. Carboxylic Acid Esters and Lactones 221

4. Amides, Lactams, Imides, Hydroxamic Acids, and Ureas 227

5. Nitriles 236

D. An Introduction to Solvents 237

I. Protic and Aprotic Solvents 238

II. Polar and Nonpolar Solvents 238

III. Polarizability 239

IV. Choosing a Solvent 240

a. Solvents for Spectroscopy 240

1. Solvents for UV Spectroscopy 240

2. Solvents for IR and Raman Spectroscopy 240

3. Solvents for NMR Spectroscopy 240

b. Immiscible Liquids 241

c. Organic Compounds That Dissolve in Water 241

d. Phase Transfer Catalysts 242

E. Acids and Bases 242

I. Brønsted Acids and Bases 243

II. Lewis Acids and Bases 245

III. Hard and Soft Acids and Bases (HSAB) 248

F. Computational Methods 250

I. Molecular Mechanics 251

a. Stretching Energy Contribution (Estretch) 251

b. Bending Energy Contribution (Ebend) 251

c. Stretch‐Bend Energy Contribution (Estretch‐bend) 251

d. Van der Waals Energy Contribution (Evan der Waals) 252

e. Torsional Energy Contribution (Etorsional) 252

f. Dipole Interaction Energy and Dipole Moment Contribution (Edipole) 252

Problems 253

Notes and References 255

Part II Middleground 261

6. The Reactions of Hydrocarbons: Oxidation, Reduction, Substitution, Addition, Elimination, and Rearrangement 271

A. Introduction 271

B. Alkanes 271

I. Oxidation 271

II. Reduction 276

III. Substitution 276

IV. Rearrangement 280

C. Alkenes 280

I. Oxidation 280

II. Reduction 286

III. Addition 292

a. Electrophilic Addition 294

1. The Stereochemistry of Electrophilic Addition 295

2. The Regiochemistry of Electrophilic Addition 298

3. The Kinetics of Electrophilic Addition 311

4. Cationic Polymerization: Electrophilic Addition in the Absence of a Reactive Nucleophile 315

5. Electrophilic Addition to Dienes and Polyenes 317

6. Special Cases: The Oxo and Ritter Reactions 321

b. Nucleophilic Addition to Alkenes, Dienes, and Polyenes 323

c. Radical Addition to Alkenes, Dienes, and Polyenes 327

d. Intermolecular Cheletropic and Other Cycloaddition Reactions 329

IV. Substitution 340

V. Rearrangements 343

D. Alkynes 353

I. Oxidation 353

II. Reduction 354

III. Addition 355

a. Electrophilic Addition 356

b. Nucleophilic Addition to Alkynes and Conjugated Ene‐Ynes 362

c. Radical Addition to Alkynes 365

d. Intermolecular Cheletropic and Other Cycloaddition Reactions 365

E. Arenes and Aromaticity: Special Introduction 370

I. Oxidation 377

a. Oxidation of the Aromatic Ring 377

b. Oxidation of Alkyl Substituents on the Aromatic Ring 381

II. Reduction 382

III. Addition 384

IV. Substitution 385

a. Electrophilic Aromatic Substitution 386

b. Nucleophilic Aromatic Substitution 405

c. Free Radical Substitution 405

Problems 407

Notes and References 410

7. The Reactions of Alkyl, Alkenyl, and Aryl Halides: Oxidation, Reduction, Substitution, Addition, Elimination, and Rearrangement 423

A. Introduction 423

B. Fluorocarbons 426

I. Freons and Halons 427

II. Polymers of Highly Fluorinated Monomers 428

III. Use of Fluorocarbons to Carry Oxygen 428

C. Oxidation 428

D. Reduction of Alkyl, Alkenyl, and Aryl Halides 430

I. Dehalogenation and Reductions at Carbon 430

a. Hydrogenolysis 431

b. Substitution of Hydride for Halide 431

c. Radical Replacement of Halogen by Hydrogen 431

d. Reaction of Alkyl, Alkenyl, and Aryl Halides with Metals 433

1. Organomercurials 433

2. Organomagnesium Compounds (Grignard Reagents) 434

3. Alkyl, Alkenyl, and Aryl Lithium Reagents 437

II. Reductions at Halogen 439

E. Nucleophilic Substitution 440

I. Nucleophiles and Nucleophilicity 441

II. Substitution, Nucleophilic, Unimolecular (SN1) 442

a. The Kinetics 443

b. Electronegativity Differences 446

c. The Structure of the Alkyl Group 447

d. The Role of the Solvent 448

e. The Substrate Stereochemistry Attending the SN1 Reaction 449

III. Substitution, Nucleophilic, Bimolecular (SN2) 452

a. The Kinetics 454

b. The Stereochemistry Attending the SN2 457

c. The Nature of the Leaving Group 459

d. The Nature of the Nucleophile 459

e. The Nature of the Solvent 460

IV. The SN2′ Reaction 460

V. Nucleophilic Aromatic Substitution 460

a. The Elimination–Addition Pathway (Benzyne) 461

b. The Addition–Elimination Pathway (SNAr Substitution) 462

VI. Electrophilic Aromatic Substitution 463

VII. Substitution by Carbon 464

VIII. Photochemically Induced Substitution of Vinyl and Aryl Halides 468

F. Addition Reactions 468

I. Addition Reactions to Vinyl and Allyl Halides 469

G. Elimination Reactions of Alkyl and Alkenyl Halides 473

I. α‐Elimination (1,1‐Elimination) 474

a. α‐Elimination of HX (X = Cl, Br) from Alkyl and Alkenyl Halides 474

b. α‐Elimination of X2 (X = Cl) from Alkyl Dihalides 475

II. β‐Elimination (1,2‐Elimination) 475

a. β‐Elimination of HX (X = F, Cl, Br, I) from Alkyl and Alkenyl Halides 475

1. Elimination, Unimolecular (E1) 476

2. Elimination, Unimolecular, conjugate base (E1cb) 482

3. Elimination, Bimolecular (E2) 484

4. 1,2‐Elimination and the Primary Deuterium Isotope Effect 498

b. 1,2‐ or α,β‐Elimination of X2 (X = Cl, Br) from Alkyl and Alkenyl Dihalides 501

III. γ‐Elimination (1,3‐Elimination) and δ‐Elimination (1,4‐Elimination) 502

a. γ‐Elimination of HX (X = Cl, Br, I) from Alkyl and Alkenyl Halides 502

b. γ‐Elimination of X2 (X = Cl, Br, I) from Alkyl Halides 502

c. δ‐Elimination of X2 (X = Cl, Br, I) from Alkenyl Halides 503

H. Rearrangement Reactions of Alkyl and Alkenyl Halides 503

Problems 510

Notes and References 512

8. Part I. The Reactions of Alcohols, Enols, and Phenols: Oxidation, Reduction, Substitution, Addition, Elimination, and Rearrangement

Part II. Ethers

Part III. Selected Reactions of Alkyl and Aryl Thiols and Thioethers 523

Special Introduction 523

Part I. Alcohols, Enols, and Phenols 526

A. Acidity and Basicity 526

B. Oxidation of Alcohols, Enols, and Phenols 533

I. Introduction 533

II. Oxidation at the Hydroxyl‐Bearing Carbon 534

a. Chemical Oxidation of Alcohols 534

b. Biological Oxidation of Alcohols 547

III. Oxidation at Sites That Do Not Bear the Hydroxyl 549

a. Oxidation of Enols 549

b. Oxidation of Phenols 553

c. Oxidation at the Double Bond of Allylic Alcohols 555

C. Reduction of Alcohols, Enols, and Phenols 559

I. Reduction of Alcohols 559

II. Reduction of Enols and Phenols 560

D. Substitution Reactions of Alcohols, Enols, and Phenols 563

I. Introduction 563

II. Substitution Reactions of Alcohols, Enols, and Phenols at Oxygen 564

III. Substitution Reactions of Alcohols at Carbon 566

a. Formation of Alkyl Halides 566

b. Replacement of the Hydroxyl (–OH) Functional Group by Other Substituents 567

c. Replacement of the Hydroxyl (–OH) Functional Group by Carbon 571

1. An Example from Nature 571

IV. Substitution Reactions of Enols and Phenols at Carbon 572

a. Substitution at the Carbon‐Bearing Oxygen 572

b. Electrophilic Aromatic Substitution of Phenols 574

E. Addition Reactions of Alcohols, Enols, and Phenols 581

I. Introduction 581

II. Addition of the Oxygen of Alcohols to Carbon (with Loss of Hydrogen) 583

F. Elimination Reactions of Alcohols, Enols, and Phenols 599

I. Introduction 599

II. Acid‐Catalyzed Elimination of Water 601

III. Elimination from Derivatives of Alcohols 604

G. Rearrangement Reactions of Alcohols, Enols, and Phenols 614

I. Introduction 614

Part II. Ethers 624

A. Introduction 624

B. The Reactions of Ethers 625

Part III. Thiols, Thioethers, and Some Products of Their Oxidation 638

Problems 648

Notes and References 649

9. Part I. The Reactions of Aldehydes and Ketones : Oxidation, Reduction, Addition, Substitution, and Rearrangement

Part II. The Reactions of Carboxylic Acids and Their Derivatives: Oxidation, Reduction, Addition, Substitution, Elimination, and Rearrangement 667

Introduction 667

Part I. Aldehydes and Ketones 676

A. Oxidation of Aldehydes and Ketones 676

B. Reduction of Aldehydes and Ketones 687

I. Introduction 687

II. Reduction of Aldehydes and Ketones to Hydrocarbons 688

III. Reduction of Aldehydes and Ketones to Alcohols 688

C. Addition to Aldehydes and Ketones 700

I. Introduction 700

II. Photochemical Reactions of Aldehydes and Ketones 703

a. Nonconjugated Carbonyl Compounds 703

b. Conjugated Carbonyl Compounds 704

III. Thermal Electrocyclic and Related Reactions of Aldehydes and Ketones 706

a. Nonconjugated Carbonyl Compounds 706

b. Conjugated Carbonyl Compounds 710

c. The Carbonyl “Ene” Reaction 711

IV. Nucleophilic Addition Reactions Retaining the Carbonyl Oxygen 711

a. General Comments 711

b. Addition of H–X 713

c. Addition of Carbon Nucleophiles 715

1. Hydrogen Cyanide 715

2. Organometallic Reagents 716

3. The Aldol Reaction (Without Dehydration) 719

4. The Darzens Glycidic Ester Condensation 727

5. Epoxide Syntheses 728

V. Nucleophilic Addition Reactions with Loss of the Carbonyl Oxygen 734

a. General Comments 734

b. Formation of Acetals, Ketals, and Thioketals 735

c. Reaction of Aldehydes and Ketones with Nitrogen Nucleophiles 737

d. Replacement of the Carbonyl Oxygen by Halogen and Sulfur 746

e. Replacement of the Oxygen of the Carbonyl by Carbon 749

f. Addition to the Carbon Alpha (α) to the Carbonyl (C=O) 761

1. Halogenation 761

2. Alkylation 762

3. C-Alkylation Versus O-Alkylation 762

4. Regioselectivity 764

5. Stereoselectivity 768

6. Enamine-Assisted Alkylation of Ketones 768

D. Substitution Reactions Producing Aldehydes and Ketones 770

I. Introduction 770

II. Reimer–Tiemann Synthesis. 770

III. Gattermann–Koch (Friedel–Crafts) Formylation 770

IV. The Pauson–Khand Reaction 773

E. Rearrangement Reaction of Aldehydes and Ketones 773

I. Introduction 773

II. The Benzilic Acid Rearrangement 773

III. The Dienone–Phenol Rearrangement 775

IV. Anionic Rearrangements 776

Part II. Carboxylic Acids and Their Derivatives 778

A. General Introduction 778

B. Oxidation 780

C. Reduction 786

D. Substitution: Addition and Elimination 793

E. Additional Reactions and Rearrangements of Esters and β‐Dicarbonyl Compounds 840

Problems 848

Notes and References 853

10. Part I. The Reactions of Amines: Oxidation, Reduction, Addition, Substitution, and Rearrangement

Part II. Some Organophosphorus Chemistry

Part III. Some Organosilicon Chemistry 865

Part I. The Reactions of Amines: Introduction and Comments on the Synthesis of Amines 865

A. Oxidation of Amines 876

I. Oxygen and Peroxide Oxidation 876

II. Other Oxidizing Agents. 882

a. General 882

b. Oxidation by Halogen 884

c. Oxidation with Nitrous Acid 885

B. Reduction of Amines 886

C. Addition and Substitution Reactions of Amines with a General Introduction 889

D. Addition and Rearrangement Reactions of Amines 898

Part II. Some Organophosphorus Chemistry 915

Part III. Some Organosilicon Chemistry 921

Problems 934

Notes and References 935

Part III Foreground 941

11. An Introduction to Carbohydrates, Acetogenins, and Steroids 945

A. Introduction 945

B. The Calvin Cycle 945

C. Carbohydrates 955

I. Biosynthesis 955

II. Chemistry 955

III. Oligosaccharides 969

IV. Polysaccharides 972

D. Acetogenins 974

I. Acetyl Coenzyme A (CH3COS‐CoA) 974

II. Acetyl‐CoA (CH3CO‐SCoA) to Fatty Acids and Related Compounds 979

III. Isoprenoids: To Dimethylallyl Diphosphate and Beyond 983

a. Dimethylallyl Diphosphate from Acetyl Coenzyme A via Mevalonate 983

b. Dimethylallyl Diphosphate from Pyruvate and Glyceraldehyde 990

1. The 1‐Deoxy‐d‐xylulose 5‐Phosphate Pathway 990

c. Terpenes 991

d. Loose Ends 1019

1. Cannabinoid Biosynthesis 1019

2. Iridoids (Loganin and Secologanin) 1020

3. Shikimic Acid, Isoshikimic Acid, and Prephenic Acid 1021

4. The Citric Acid Cycle (or the Tricarboxylic Acid [TCA] Cycle or the Krebs Cycle) 1027

Problems 1034

Notes and References 1035

12. An Introduction to Amino Acids, Peptides and Proteins, Enzymes, and Coenzymes and Metabolic Processes 1045

A. Introduction 1045

B. Amino Acids 1050

I. Biosynthesis 1050

II. Synthesis 1080

C. Peptides and Proteins: Introduction 1103

I. Amino Acids from Peptides 1105

II. Peptides from Amino Acids: In Vivo 1113

III. Peptides from Amino Acids: In Vitro 1121

D. The Coenzymes 1129

I. Pyridoxal Phosphate 1129

II. Lipoic Acid 1132

III. Thiamine Diphosphate 1134

a. 4‐Amino‐5‐hydroxymethyl‐2‐methylpyrimidine 1134

b. 4‐Methyl‐5‐(2‐phosphonooxyethyl)thiazole 1135

c. 3‐[(4‐Amino‐2‐methylpyrimidin‐5‐yl)methyl]‐5‐(2‐diphosphoethyl)‐4‐methyl‐1,3‐thiazolium 1136

IV. Biotin 1140

V. Adenosine 1143

VI. Nicotinamide Adenine Dinucleotide 1149

VII. Coenzyme A (CoA‐SH) 1152

VIII. Flavin Adenine Dinucleotide 1157

IX. S‐Adenosylmethionine 1160

X. Tetrahydrofolate 1162

Notes and References 1168

13. An Introduction to Alkaloids and Some Other Heterocyclic Compounds 1179

A. Introduction 1179

B. Tropane Alkaloids 1181

I. Chemistry of Hyoscyamine 1181

II. Chemistry of Nicotine 1187

III. Biosynthesis of Hyoscyamine and Nicotine 1192

a. The Common Feature 1192

b. The Biosynthesis of Nicotine 1194

c. The Biosynthesis of Hyoscyamine 1194

d. The Biosynthesis of Tropic Acid 1196

C. Morphine (and Codeine and Thebaine) 1197

I. Chemistry of Morphine (and Codeine and Thebaine) 1197

II. The Biosynthesis of Morphine (and Codeine and Thebaine) 1212

III. The Synthesis of Morphine 1217

D. Vinblastine 1222

I. Chemistry of Vinblastine 1222

II. Biosynthesis of Vinblastine 1230

E. Caffeine 1233

I. Some History and the Synthesis of Caffeine 1233

II. Biosynthesis of Caffeine 1236

Notes and References 1242

14. Part I. On the Genetic Code: Unity and Diversity

Part II. The Tetrapyrrolic Cofactors and Other Metal–Organic Frameworks 1249

A. Introduction 1249

Part I. The Genetic Code 1249

Part II. Metal–Organic Frameworks 1250

Part I. On The Genetic Code: Unity and Diversity 1250

A. The Bases of Deoxyribonucleic Acid (Dna) and Ribonucleic Acid (RNA) 1250

I. Adenine (A) 1250

II. Guanine (G) 1251

III. Uracil (U) and Thymine (T) 1254

IV. Cytosine (C) 1255

B. Deoxynucleotides 1259

C. The Role of Phosphate 1262

D. The Sequencing of DNA 1265

E. Chemical Synthesis of DNA 1265

F. Modification to DNA 1269

I. Zinc Finger Nucleases (ZFNs) 1272

II. Transcription Activator‐Like Effector Nucleases (TALENs) 1272

III. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and Associated Enzymes (Cas) 1273

Part II. The Tetrapyrrolic Cofactors and Other Metal–Organic Frameworks 1274

A. Introduction to Metals in an Organic Framework 1274

B. Some Early Pyrrole Chemistry 1276

C. Current Biosynthetic Understanding 1281

Notes and References 1291

Epilogue 1297

Appendix I The Schrödinger Equation 1299

Appendix II The Literature 1303

Index 1305