1. THE BASICS: Bonding and Molecular Structure .................. 1
Molecular Graphic: Glycine, an organic molecule found
in space ..................................................... 1
1.1. Organic Chemistry and Life ............................. 2
1.2. The Structural Theory of Organic Chemistry ............. 3
1.3. Isomers: The Importance of Structural Formulas ......... 4
1.4. Chemical Bonds: The Octet Rule ......................... 5
1.5. Writing Lewis Structures ............................... 7
1.6. Exceptions to the Octet Rule ........................... 9
1.7. Formal Charge ......................................... 10
1.8. Resonance Theory ...................................... 13
1.9. Quantum Mechanics and Atomic Structure ................ 18
1.10. Atomic Orbitals and Electron Configuration ............ 20
1.11. Molecular Orbitals .................................... 21
1.12. The Structure of Methane and Ethane: sp3
Hybridization ......................................... 24
THE CHEMISTRY OF Calculated Molecular Models:
Electron Density Surfaces ............................. 28
1.13. The Structure of Ethene (Ethylene): sp2
Hybridization ......................................... 28
1.14. The Structure of Ethyne (Acetylene): sp
Hybridization ......................................... 33
1.15. A Summary of Important Concepts that Come from
Quantum Mechanics ..................................... 35
1.16. Molecular Geometry: The Valence Shell Electron Pair
Repulsion Model ....................................... 36
1.17. Representation of Structural Formulas ................. 39
1.18. Applications of Basic Principles ...................... 44
2. REPRESENTATIVE CARBON COMPOUNDS: Functional Groups,
Intermolecular Forces, and Infrared (IR) Spectroscopy ....... 51
Structure and Function: Organic Chemistry, Nanotechnology
and Bioengineering / Molecular Graphic: A molecular
template for bone growth .................................... 51
2.1. Carbon-Carbon Covalent Bonds .......................... 52
2.2. Hydrocarbons: Representative Alkanes, Alkenes,
Alkynes, and Aromatic Compounds ....................... 52
2.3. Polar Covalent Bonds .................................. 55
THE CHEMISTRY OF Calculated Molecular Models:
Maps of Electrostatic Potential ....................... 56
2.4. Polar and Nonpolar Molecules .......................... 56
2.5. Functional Groups ..................................... 59
2.6. Alkyl Halides or Haloalkanes .......................... 60
2.7. Alcohols .............................................. 61
2.8. Ethers ................................................ 63
2.9. Amines ................................................ 63
2.10. Aldehydes and Ketones ................................. 65
2.11. Carboxylic Acids, Esters, and Amides .................. 65
2.12. Nitriles .............................................. 67
2.13. Summary of Important Families of Organic Compounds .... 68
2.14. Physical Properties and Molecular Structure ........... 68
2.15. Summary of Attractive Electric Forces ................. 75
THE CHEMISTRY OF Organic Templates Engineered
to Mimic Bone Growth .................................. 75
2.16. Infrared Spectroscopy: An Instrumental Method for
Detecting Functional Groups ........................... 76
2.17. Applications of Basic Principles ...................... 84
3. AN INTRODUCTION TO ORGANIC REACTIONS AND THEIR
MECHANISMS: Acids and Bases ................................. 91
Shuttling the Protons / Molecular Graphic: Diamox,
a drug that prevents altitude sickness ...................... 91
3.1. Reactions and Their Mechanisms ........................ 92
3.2. Acid-Base Reactions ................................... 94
THE CHEMISTRY OF HOMOs and LUMOs in Reactions ......... 97
3.3. Heterolysis of Bonds to Carbon: Carbocations and
Carbanions ............................................ 97
3.4. The Use of Curved Arrows in Illustrating Reactions .... 98
3.5. The Strength of Acids and Bases: Ka and pKa .......... 100
3.6. Predicting the Outcome of Acid-Base Reactions ........ 103
3.7. The Relationship between Structure and Acidity ....... 105
3.8. Energy Changes ....................................... 108
3.9. The Relationship between the Equilibrium Constant
and the Standard Free-Energy Change, ΔG0 ............. 110
3.10. The Acidity of Carboxylic Acids ...................... 111
3.11. The Effect of the Solvent on Acidity ................. 115
3.12. Organic Compounds as Bases ........................... 116
3.13. A Mechanism for an Organic Reaction .................. 117
THE CHEMISTRY OF Carbonic Anhydrase ................. 118
3.14. Acids and Bases in Nonaqueous Solutions .............. 119
3.15. Acid-Base Reactions and the Synthesis of Deuterium-
and Tritium-Labeled Compounds ........................ 120
3.16. Applications of Basic Principles ..................... 121
4. NOMENCLATURE AND CONFORMATIONS OF ALKANES AND
CYCLOALKANES ............................................... 129
To Be Flexible or Inflexible - Molecular Structure
Makes the Difference / Molecular Graphic: A portion
of the structure of diamond, an exceptionally rigid
molecule ................................................... 129
4.1. Introduction to Alkanes and Cycloalkanes ............. 130
THE CHEMiSTRY OF Petroleum Refining ................. 130
4.2. Shapes of Alkanes .................................... 132
4.3. IUPAC Nomenclature of Alkanes, Alkyl Halides, and
Alcohols ............................................. 134
4.4. Nomenclature of Cycloalkanes ......................... 141
4.5. Nomenclature of Alkenes and Cycloalkenes ............. 143
4.6. Nomenclature of Alkynes .............................. 145
4.7. Physical Properties of Alkanes and Cycloalkanes ...... 146
THE CHEMISTRY OF Pheromones: Communication
by Means of Chemicals ................................ 148
4.8. Sigma Bonds and Bond Rotation ........................ 148
4.9. Conformational Analysis of Butane .................... 151
4.10. The Relative Stabilities of Cycloalkanes: Ring
Strain ............................................... 153
4.11. The Origin of Ring Strain in Cyclopropane and
Cyclobutane: Angle Strain and Torsional Strain ....... 155
4.12. Conformations of Cyclohexane ......................... 156
THE CHEMISTRY OF Nanoscale Motors and
Molecular Switches ................................... 159
4.13. Substituted Cyclohexanes: Axial and Equatorial
Hydrogen Atoms ....................................... 160
4.14. Disubstituted Cycloalkanes: Cis-Trans Isomerism ...... 163
4.15. Bicyclic and Polycyclic Alkanes ...................... 166
THE CHEMISTRY OF Elemental Carbon ................... 167
4.16. Chemical Reactions of Alkanes ........................ 168
4.17. Synthesis of Alkanes and Cycloalkanes ................ 168
4.18. Structural Information from Molecular Formulas and
the Index of Hydrogen Deficiency ..................... 169
4.19. 13C NMR Spectroscopy - A Practical Introduction ...... 171
4.20. Applications of Basic Principles ..................... 175
5. STEREOCHEMISTRY: Chiral Molecules .......................... 181
The Handedness of Life /Molecular Graphic: The mirror
image stereoisomers of alanine, a chiral amino acid ........ 181
5.1. The Biological Significance of Chirality ............. 182
5.2. Isomerism: Constitutional Isomers and
Stereoisomers ........................................ 183
5.3. Enantiomers and Chiral Molecules ..................... 184
5.4. More about the Biological Importance of Chirality .... 187
5.5. Historical Origin of Stereochemistry ................. 188
5.6. Tests for Chirality: Planes of Symmetry .............. 189
5.7. Nomenclature of Enantiomers: The R,S-System .......... 190
5.8. Properties of Enantiomers: Optical Activity .......... 194
5.9. The Origin of Optical Activity ....................... 198
5.10. The Synthesis of Chiral Molecules .................... 200
5.11. Chiral Drugs ......................................... 202
THE CHEMISTRY OF Selective Binding of Drug
Enantiomers to Left- and Right-Handed Coiled DNA ..... 203
5.12. Molecules with More than One Chirality Center ........ 203
5.13. Fischer Projection Formulas .......................... 207
5.14. Stereoisomerism of Cyclic Compounds .................. 209
5.15. Relating Configurations through Reactions in Which
No Bonds to the Chirality Center Are Broken .......... 211
5.16. Separation of Enantiomers: Resolution ................ 213
5.17. Compounds with Chirality Centers Other than Carbon ... 214
5.18. Chiral Molecules that Do Not Possess a Chirality
Center ............................................... 215
6. IONIC REACTIONS: Nucleophilic Substitution and
Elimination Reactions of Alkyl Halides ..................... 221
Breaking Bacterial Cell Walls with Organic Chemistry /
Molecular Graphic: Lysozyme ................................ 221
6.1. Organic Halides ...................................... 222
6.2. Nucleophilic Substitution Reactions .................. 224
6.3. Nucleophiles ......................................... 224
6.4. Leaving Groups ....................................... 225
6.5. Kinetics of a Nucleophilic Substitution Reaction:
An SN2 Reaction ...................................... 226
6.6. A Mechanism for the SN2 Reaction ..................... 227
6.7. Transition State Theory: Free-Energy Diagrams ........ 228
6.8. The Stereochemistry of SN2 Reactions ................. 231
THE CHEMISTRY OF Lysozyme ........................... 234
6.9. The Reaction of tert-Butyl Chloride with Hydroxide
Ion: An SN1 Reaction ................................. 235
6.10. A Mechanism for the SN21 Reaction .................... 236
6.11. Carbocations ......................................... 237
6.12. The Stereochemistry of SN1 Reactions ................. 239
6.13. Factors Affecting the Rates of SN1 and SN2
Reactions ............................................ 241
6.14. Organic Synthesis: Functional Group Transformations
Using SN2 Reactions .................................. 250
THE CHEMISTRY OF Biological Methylation:
A Biological Nucleophilic Substitution Reaction ...... 251
6.15. Elimination Reactions of Alkyl Halides ............... 253
6.16. The E2 Reaction ...................................... 255
6.17. The E1 Reaction ...................................... 256
6.18. Substitution versus Elimination ...................... 257
6.19. Overall Summary ...................................... 260
7. ALKENES AND ALKYNES I: Properties and Synthesis.
Elimination Reactions of Alkyl Halides ..................... 269
Cell Membrane Fluidity / Molecular Graphic: cis-9-
Octadecenoic acid, an unsaturated fatty acid
incorporated into cell membrane phospholipids .............. 269
7.1. Introduction ......................................... 270
7.2. The (E)-(Z) System for Designating Alkene
Diastereomers ........................................ 270
7.3. Relative Stabilities of Alkenes ...................... 272
7.4. Cycloalkenes ......................................... 274
7.5. Synthesis of Alkenes via Elimination Reactions ....... 274
7.6. Dehydrohalogenation of Alkyl Halides ................. 275
7.7. Acid-Catalyzed Dehydration of Alcohols ............... 280
7.8. Carbocation Stability and the Occurrence of
Molecular Rearrangements ............................. 285
7.9. Synthesis of Alkynes by Elimination Reactions ........ 288
7.10. The Acidity of Terminal Alkynes ...................... 290
7.11. Replacement of the Acetylenic Hydrogen Atom of
Terminal Alkynes ..................................... 290
7.12. Alkylation of Alkynide Anions: Some General
Principles of Structure and Reactivity Illustrated ... 292
7.13. Hydrogenation of Alkenes ............................. 292
THE CHEMISTRY OF Hydrogenation in the
Food Industry ........................................ 293
7.14. Hydrogenation: The Function of the Catalyst .......... 294
THE CHEMISTRY OF Homogeneous Asymmetric Catalytic
Hydrogenation: Examples Involving L-DOPA,
(S)-Naproxen, and Aspartame .......................... 295
7.15. Hydrogenation of Alkynes ............................. 297
7.16. An Introduction to Organic Synthesis ................. 298
THE CHEMISTRY OF From the Inorganic to
the Organic .......................................... 302
8. ALKENES AND ALKYNES II: Addition Reactions ................. 311
The Sea: A Treasury of Biologically Active Natural
Products / Molecular Graphic: Dactylyne, a halogenated
marine natural product ..................................... 311
8.1. Introduction: Addition to Alkenes .................... 312
8.2. Electrophilic Addition of Hydrogen Halides to
Alkenes: Mechanism and Markovnikov's Rule ............ 314
8.3. Stereochemistry of the Ionic Addition to an Alkene ... 319
8.4. Addition of Sulfuric Acid to Alkenes ................. 320
8.5. Addition of Water to Alkenes: Acid-Catalyzed
Hydration ............................................ 321
8.6. Alcohols from Alkenes through Oxymercuration-
Demercuration: Markovnikov Addition .................. 323
8.7. Alcohols from Alkenes through Hydroboration-
Oxidation: Anti-Markovnikov Syn Hydration ............ 326
8.8. Hydroboration: Synthesis of Alkylboranes ............. 326
8.9. Oxidation and Hydrolysis of Alkyboranes .............. 329
8.10. Summary of Alkene Hydration Methods .................. 331
8.11. Protonolysis of Alkyboranes .......................... 331
8.12. Electrophilic Addition of Bromine and Chlorine to
Alkenes .............................................. 332
8.13. Stereochemistry of the Addition of Halogens to
Alkenes .............................................. 334
8.14. Halohydrin Formation ................................. 337
8.15. Divalent Carbon Compounds: Carbenes .................. 338
8.16. Oxidations of Alkenes: Syn 1,2-Dihydroxylation ....... 340
THE CHEMISTRY OF Catalytic Asymmetric
Dihydroxylation ...................................... 342
8.17. Oxidative Cleavage of Alkenes ........................ 343
8.18. Electrophilic Addition of Bromine and Chlorine to
Alkynes .............................................. 345
8.19. Addition of Hydrogen Halides to Alkynes .............. 346
8.20. Oxidative Cleavage of Alkynes ........................ 347
8.21. Synthetic Strategies Revisited ....................... 347
THE CHEMISTRY OF Cholesterol Biosynthesis:
Elegant and Familiar Reactions in Nature ............. 350
9. NUCLEAR MAGNETIC RESONANCE AND MASS SPECTROMETRY:
Tools for Structure Determination .......................... 363
A Thermos of Liquid Helium / Molecular Graphic:
1-chloro-2-propanol ........................................ 363
9.1. Introduction ......................................... 364
9.2. Nuclear Magnetic Resonance (NMR) Spectroscopy ........ 364
9.3. Interpreting Proton NMR Spectra ...................... 369
9.4. Nuclear Spin: The Origin of the Signal ............... 371
9.5. Detecting the Signal: Fourier Transform NMR
Spectrometers ........................................ 373
9.6. Shielding and Deshielding of Protons ................. 374
9.7. The Chemical Shift ................................... 376
9.8. Chemical Shift Equivalent and Nonequivalent
Protons .............................................. 377
9.9. Signal Splitting: Spin-Spin Coupling ................. 379
9.10. Proton NMR Spectra and Rate Processes ................ 388
9.11. Carbon-13 NMR Spectroscopy ........................... 390
9.12. Two-Dimensional (2D) NMR Techniques .................. 396
THE CHEMISTRY OF Magnetic Resonance Imaging
in Medicine .......................................... 399
9.13. An Introduction to Mass Spectrometry ................. 399
9.14. Formation of Ions: Electron Impact Ionization ........ 400
9.15. Depicting the Molecular Ion .......................... 400
9.16. Fragmentation ........................................ 401
9.17. Determination of Molecular Formulas and Molecular
Weights .............................................. 407
9.18. Mass Spectrometer Instrument Designs ................. 412
9.19. GC/MS Analysis ....................................... 415
9.20. Mass Spectrometry of Biomolecules .................... 416
10.RADICAL REACTIONS .......................................... 427
Radicals in Biology, Medicine, and Industry / Molecular
Graphic: Nitric oxide and Cialis® .......................... 427
10.1. Introduction ......................................... 428
10.2. Homolytic Bond Dissociation Energies ................. 429
10.3. The Reactions of Alkanes with Halogens ............... 433
10.4. Chlorination of Methane: Mechanism of Reaction ....... 435
10.5. Chlorination of Methane: Energy Changes .............. 437
10.6. Halogenation of Higher Alkanes ....................... 443
10.7. The Geometry of Alkyl Radicals ....................... 446
10.8. Reactions that Generate Tetrahedral Chirality
Centers .............................................. 446
10.9. Radical Addition to Alkenes: The Anti-Markovnikov
Addition of Hydrogen Bromide ......................... 449
10.10.Radical Polymerization of Alkenes: Chain-Growth
Polymers ............................................. 451
10.11.Other Important Radical Reactions .................... 455
THE CHEMISTRY OF Calicheamicin λ11: A Radical
Device for Slicing the Backbone of DNA ............... 456
THE CHEMISTRY OF Antioxidants ....................... 458
THE CHEMISTRY OF Ozone Depletion and
Chlorofluorocarbons (CFCs) ........................... 459
SPECIAL TOPIC A: CHAIN-GROWTH POLYMERS ..................... 464
11.ALCOHOLS AND ETHERS ........................................ 469
Molecular Hosts / Molecular Graphic: Monensin sodium
salt, an antibiotic that transports ions across cell
membranes .................................................. 469
11.1. Structure and Nomenclature ........................... 470
11.2. Physical Properties of Alcohols and Ethers ........... 472
11.3. Important Alcohols and Ethers ........................ 474
11.4. Synthesis of Alcohols from Alkenes ................... 476
11.5. Reactions of Alcohols ................................ 478
11.6. Alcohols as Acids .................................... 479
11.7. Conversion of Alcohols into Alkyl Halides ............ 480
11.8. Alkyl Halides from the Reaction of Alcohols with
Hydrogen Halides ..................................... 480
11.9. Alkyl Halides from the Reaction of Alcohols with
PBr3 or SOCl2 ........................................ 483
11.10.Tosylates, Mesylates, and Triflates: Leaving Group
Derivatives of Alcohols .............................. 484
THE CHEMISTRY OF Alkyl Phosphates ................... 487
11.11.Synthesis of Ethers .................................. 487
11.12.Reactions of Ethers .................................. 492
11.13.Epoxides ............................................. 493
THE CHEMISTRY OF The Sharpless Asymmetric
Epoxidation .......................................... 494
11.14.Reactions of Epoxides ................................ 496
THE CHEMISTRY OF Epoxides, Carcinogens, and
Biological Oxidation ................................. 498
11.15.Anti 1,2-Dihydroxylation of Alkenes via Epoxides ..... 500
THE CHEMISTRY OF Environmentally Friendly Alkene
Oxidation Methods .................................... 502
11.16.Crown Ethers: Nudeophilic Substitution Reactions in
Relatively Nonpolar Aprotic Solvents by Phase-
Transfer Catalysis ................................... 503
11.17.Summary of Reactions of Alkenes, Alcohols, and
Ethers ............................................... 506
12.ALCOHOLS FROM CARBONYL COMPOUNDS: Oxidation-Reduction
and Organometallic Compounds ............................... 513
The Two Aspects of the Coenzyme NADH / Molecular
Graphic: Nicotinamide (niacin) ............................. 513
12.1. Introduction ......................................... 514
12.2. Oxidation-Reduction Reactions in Organic Chemistry ... 515
12.3. Alcohols by Reduction of Carbonyl Compounds .......... 517
THE CHEMISTRY OF Alcohol Dehydrogenase .............. 519
THE CHEMISTRY OF Stereoselective Reductions of
Carbonyl Groups ...................................... 520
12.4. Oxidation of Alcohols ................................ 521
12.5. Organometallic Compounds ............................. 526
12.6. Preparation of Organolithium and Organomagnesium
Compounds ............................................ 526
12.7. Reactions of Organolithium and Organomagnesium
Compounds ............................................ 528
12.8. Alcohols from Grignard Reagents ...................... 531
12.9. Protecting Groups .................................... 539
FIRST REVIEW PROBLEM SET ...................................... 546
13.CONJUGATED UNSATURATED SYSTEMS ............................. 550
Molecules with the Nobel Prize in Their Synthetic
Lineage /Molecular Graphic: Morphine, the synthesis
of which involved the Diels-Alder reaction ................. 550
13.1. Introduction ......................................... 551
13.2. Allylic Substitution and the Allyl Radical ........... 551
THE CHEMISTRY OF Allylic Bromination ................ 554
13.3. The Stability of the Allyl Radical ................... 555
13.4. The Allyl Cation ..................................... 558
13.5. Summary of Rules for Resonance ....................... 559
13.6. Alkadienes and Polyunsaturated Hydrocarbons .......... 563
13.7. 1,3-Butadiene: Electron Derealization ................ 564
13.8. The Stability of Conjugated Dienes ................... 566
13.9. Ultraviolet-Visible Spectroscopy ..................... 568
THE CHEMISTRY OF The Photochemistry of Vision ....... 573
13.10.Electrophilic Attack on Conjugated Dienes:
1,4 Addition ......................................... 576
13.11.The Diels-Alder Reaction: A 1,4-Cycloaddition
Reaction of Dienes ................................... 580
THE CHEMISTRY OF Asymmetric and Intramolecular
Diels-Alder Reactions ................................ 586
14.AROMATIC COMPOUNDS ......................................... 595
Green Chemistry / Molecular Graphic: Benzene, parent
molecule in the family of aromatic compounds ............... 595
14.1. Aromatic Compounds: Why the Name? .................... 596
14.2. Nomenclature of Benzene Derivatives .................. 597
14.3. Reactions of Benzene ................................. 599
14.4. The Kekule Structure for Benzene ..................... 600
14.5. The Stability of Benzene ............................. 601
14.6. Modern Theories of the Structure of Benzene .......... 602
14.7. Huckel's Rule: The 4n + 2ir Electron Rule ............ 605
14.8. Other Aromatic Compounds ............................. 613
THE CHEMISTRY OF Nanotubes .......................... 616
14.9. Heterocylic Aromatic Compounds ....................... 617
14.10.Aromatic Compounds in Biochemistry ................... 618
14.11.Spectroscopy of Aromatic Compounds ................... 620
THE CHEMISTRY OF Sunscreens (Catching the Sun's
Rays and What Happens to Them) ....................... 624
15.REACTIONS OF AROMATIC COMPOUNDS ............................ 636
Biosynthesis of Thyroxine: Aromatic Substitution
Involving Iodine / Molecular Graphic: Thyroxine,
an aromatic iodine-containing hormone associated
with regulation of metabolic rate .......................... 636
15.1. Electrophilic Aromatic Substitution Reactions ........ 637
15.2. A General Mechanism for Electrophilic Aromatic
Substitution: Arenium Ions ........................... 837
15.3. Halogenation of Benzene .............................. 640
15.4. Nitration of Benzene ................................. 641
15.5. Sulfonation of Benzene ............................... 642
15.6. Friedel-Crafts Alkylation ............................ 643
15.7. Friedel-Crafts Acylation ............................. 645
15.8. Limitations of Friedel-Crafts Reactions .............. 647
15.9. Synthetic Applications of Friedel-Crafts
Acylations: The Clemmensen Reduction ................. 649
15.10.Effect of Substituents on Reactivity and
Orientation .......................................... 650
15.11.Theory of Substituent Effects on Electrophilic
Aromatic Substitution ................................ 653
THE CHEMISTRY OF Iodine Incorporation in Thyroxine
Biosynthesis ......................................... 662
15.12.Reactions of the Side Chain of Alkylbenzenes ......... 664
THE CHEMISTRY OF Industrial Styrene Synthesis ....... 665
15.13.Alkenylbenzenes ...................................... 668
15.14.Synthetic Applications ............................... 670
15.15.Allylic and Benzylic Halides in Nucleophilic
Substitution Reactions ............................... 674
15.16.Reduction of Aromatic Compounds ...................... 676
16.ALDEHYDES AND KETONES I: Nucleophilic Addition to
the Carbonyl Group ......................................... 686
A Very Versatile Vitamin, Pyridoxine (Vitamin B6) /
Molecular Graphic: Pyridoxal phosphate (Vitamin B6) ........ 686
16.1. Introduction ......................................... 687
16.2. Nomenclature of Aldehydes and Ketones ................ 687
16.3. Physical Properties .................................. 689
THE CHEMISTRY OF Aldehydes and Ketones
in Perfumes .......................................... 690
16.4. Synthesis of Aldehydes ............................... 690
16.5. Synthesis of Ketones ................................. 694
16.6. Nucleophilic Addition to the Carbon-Oxygen
Double Bond .......................................... 696
16.7. The Addition of Alcohols: Hemiacetals and Acetals .... 699
16.8. The Addition of Primary and Secondary Amines ......... 706
THE CHEMISTRY OF Pyridoxal Phosphate ................ 708
16.9. The Addition of Hydrogen Cyanide ..................... 710
16.10.The Addition of Ylides: The Wittig Reaction .......... 711
16.11.Oxydation of Aldehydes ............................... 715
16.12.Chemical Analyses for Aldehydes and Ketones .......... 715
16.13.Spectroscopic Properties of Aldehydes and Ketones .... 716
16.14.Summary of Aldehyde and Ketone Addition Reactions .... 719
17.ALDEHYDES AND KETONES II: Enols and Enolates ............... 732
TIM (Those Phosphate Isomerase) Recycles Carbon via an
Enol / Molecular Graphic: Glyceraldehyde-3-phosphate,
a key intermediate in metabolic energy production .......... 732
17.1. The Acidity of the a Hydrogens of Carbonyl
Compounds: Enolate Anions ............................ 733
17.2. Keto and Enol Tautomers .............................. 735
17.3. Reactions via Enols and Enolate Anions ............... 736
17.4. The Aldol Reaction: The Addition of Enolate Anions to
Aldehydes and Ketones ................................ 742
THE CHEMISTRY OF A Retro-Aldol Reaction in
Glycolysis—Dividing Assets to Double the ATP Yield ... 745
17.5. Crossed Aldol Reactions .............................. 747
17.6. Cyclizations via Aldol Condensations ................. 752
17.7. Lithium Enolates ..................................... 754
THE CHEMISTRY OF Silyl Enol Ethers .................. 758
17.8. α-Selenation: A Synthesis of α,β-Unsaturated Carbonyl
Compounds ............................................ 759
17.9. Additions to α,β-Unsaturated Aldehydes and Ketones ... 760
THE CHEMfSTRY OF Calicheamicin λ11 Activation for
Cleavage of DNA ...................................... 763
17.10.Summary of Enolate Chemistry ......................... 764
18.CARBOXYLIC ACIDS AND THEIR DERIVATIVES: Nucleophilic
Addition-Elimination at the Acyl Carbon .................... 778
A Common Bond / Molecular Graphic: A portion of nylon
6,6, a polyamide ........................................... 778
18.1. Introduction ......................................... 779
18.2. Nomenclature and Physical Properties ................. 779
18.3. Preparation of Carboxylic Acids ...................... 789
18.4. Nucleophilic Addition-Elimination at the Acyl
Carbon ............................................... 791
18.5. Acyl Chlorides ....................................... 794
18.6. Carboxylic Acid Anhydrides ........................... 795
18.7. Esters ............................................... 797
18.8. Amides ............................................... 802
THE CHEMISTRY OF Penicillins ........................ 809
18.9. Derivatives of Carbonic Acid ......................... 810
18.10.Decarboxylation of Carboxylic Acids .................. 812
THE CHEMISTRY OF Thiamine ........................... 813
18.11.Chemical Tests for Acyl Compounds .................... 815
SPECIAL TOPIC B: STEP-GROWTH POLYMERS ......................... 830
19.SYNTHESIS AND REACTIONS OF β-DICARBONYL COMPOUNDS:
More Chemistry of Enolates ................................. 840
Imposters / Molecular Graphic: 5-Fluorouracil, an enzyme
inhibitor that has anticancer activity by masquerading
as a natural substrate ..................................... 840
19.1. Introduction ......................................... 841
19.2. The Claisen Condensation: The Synthesis of β-Keto
Esters ............................................... 842
19.3. The Acetoacetic Ester Synthesis: Synthesis of
Methyl Ketones (Substituted Acetones) ................ 847
19.4. The Malonic Ester Synthesis: Synthesis of
Substituted Acetic Acids ............................. 853
19.5. Further Reactions of Active Hydrogen Compounds ....... 857
19.6. Direct Alkylation of Esters and Nitriles ............. 858
19.7. Alkylation of 1,3-Dithianes .......................... 858
19.8. The Knoevenagel Condensation ......................... 860
19.9. Michael Additions .................................... 860
19.10.The Mannich Reaction ................................. 862
THE CHEMISTRY OF A Suicide Enzyme Substrate .......... 863
19.11.Synthesis of Enamines: Stork Enamine Reactions ....... 864
THE CHEMISTRY OF Antibody-Catalyzed Aldol
Condensations ........................................ 866
19.12.Barbiturates ......................................... 867
SPECIAL TOPIC C: THIOLS, SULFUR YLIDES, AND DISULFIDES ........ 881
SPECIAL TOPIC D: THIOL ESTERS AND LIPID BIOSYNTHESIS .......... 886
20.AMINES ..................................................... 899
Neurotoxins and Neurotransmitters / Molecular Graphic:
Histrionicotoxin, a paralyzing neurotoxin from certain
poison dart frogs .......................................... 899
20.1. Nomenclature ......................................... 900
20.2. Physical Properties and Structure of Amines .......... 902
20.3. Basicity of Amines: Amine Salts ...................... 903
THE CHEMISTRY OF ... HPLC Resolution of
Enantiomers .......................................... 910
THE CHEMISTRY OF Biologically Important Amines ...... 910
20.4. Preparation of Amines ................................ 912
20.5. Reactions of Amines .................................. 919
20.6. Reactions of Amines with Nitrous Acid ................ 921
THE CHEMISTRY OF N-Nitrosoamines .................... 922
20.7. Replacement Reactions of Arenediazonium Salts ........ 923
20.8. Coupling Reactions of Arenediazonium Salts ........... 926
20.9. Reactions of Amines with Sulfonyl Chlorides .......... 929
THE CHEMISTRY OF ... Chemotherapy and Sulfa Drugs .... 930
20.10.Synthesis of Sulfa Drugs ............................. 933
20.11.Analysis of Amines ................................... 934
20.12.Eliminations Involving Ammonium Compounds ............ 935
SPECIAL TOPIC E: ALKALOIDS .................................... 949
21.PHENOLS AND ARYL HALIDES: Nucleophilic Aromatic
Substitution ............................................... 954
A Silver Chalice /Molecular Graphic: 4-tert-
Butylcalix[4]arene, a chalice-shaped molecule .............. 954
21.1. Structure and Nomenclature of Phenols ................ 955
21.2. Naturally Occurring Phenols .......................... 956
21.3. Physical Properties of Phenols ....................... 957
21.4. Synthesis of Phenols ................................. 957
THE CHEMISTRY OF Polyketide Anticancer Antibiotic
Biosynthesis ......................................... 958
21.5. Reactions of Phenols as Acids ........................ 961
21.6. Other Reactions of the O—H Group of Phenols .......... 963
21.7. Cleavage of Alkyl Aryl Ethers ........................ 964
21.8. Reactions of the Benzene Ring of Phenols ............. 964
21.9. The Claisen Rearrangement ............................ 967
21.10.Quinones ............................................. 968
21.11.Aryl Halides and Nucleophilic Aromatic
Substitution ......................................... 969
THE CHEMISTRY OF The Bombardier Beetle's Noxious
Spray ................................................ 970
THE CHEMISTRY OF Bacterial Dehalogenation of a PCB
Derivative ........................................... 972
21.12.Spectroscopic Analysis of Phenols and Aryl Halides ... 977
SECOND REVIEW PROBLEM SET ..................................... 986
SPECIAL TOPIC F: ARYL HALIDES: THEIR USES ..................... 992
SPECIAL TOPIC G: ELECTROCYCLIC AND CYCLOADDITION REACTIONS .... 995
SPECIAL TOPIC H: TRANSITION METAL ORGANOMETALLIC COMPOUNDS ... 1008
22.CARBOHYDRATES ............................................. 1020
Carbohydrate Recognition in Healing and Disease /
Molecular Graphic: Sialyl lewisx, a carbohydrate that
is important in the recognition and healing of
traumatized tissue ........................................ 1020
22.1. Introduction ........................................ 1021
22.2. Monosaccharides ..................................... 1023
22.3. Mutarotation ........................................ 1028
22.4. Glycoside Formation ................................. 1029
22.5. Other Reactions of Monosaccharides .................. 1032
22.6. Oxidation Reactions of Monosaccharides .............. 1035
22.7. Reduction of Monosaccharides: Alditols .............. 1040
22.8. Reactions of Monosaccharides with Phenylhydrazine:
Osazones ............................................ 1041
22.9. Synthesis and Degradation of Monosaccharides ........ 1042
22.10.The d Family of Aldoses ............................. 1044
22.11.Fischer's Proof of the Configuration of
D-(+)-Glucose ....................................... 1044
THE CHEMISTRY OF Stereoselective Synthesis of All
the L-Aldohexoses ................................... 1047
22.12.Disaccharides ....................................... 1049
THE CHEMISTRY OF Artificial Sweeteners
(How Sweet It Is) ................................... 1052
22.13.Polysaccharides ..................................... 1053
THE CHEMISTRY OF Oligosaccharide Synthesis on
a Solid Support — The Glycal Assembly Approach ...... 1057
22.14.Other Biologically Important Sugars ................. 1059
22.15.Sugars that Contain Nitrogen ........................ 1059
22.16.Glycolipids and Glycoproteins of the Cell Surface:
Cell Recognition and the Immune System .............. 1061
THE CHEMISTRY OF Vaccines Against Cancer ........... 1063
22.17.Carbohydrate Antibiotics ............................ 1064
23.LIPIDS .................................................... 1073
Insulation for Nerves / Molecular Graphic:
A sphingomyelin molecule, found myelin sheath
membranes ................................................. 1073
23.1. Introduction ........................................ 1074
23.2. Fatty Acids and Triacylglycerols .................... 1075
THE CHEMISTRY OF Olestra and Other Fat
Substitutes ......................................... 1078
THE CHEMISTRY OF Self-Assembled Monolayers—Lipids
in Materials Science and Bioengineering ............. 1082
23.3. Terpenes and Terpenoids ............................. 1083
23.4. Steroids ............................................ 1087
23.5. Prostaglandins ...................................... 1095
23.6. Phospholipids and Cell Membranes .................... 1097
THE CHEMiSTRY OF STEALTH® Liposomes for Drug
Delivery ............................................ 1099
23.7. Waxes ............................................... 1100
24.AMINO ACIDS AND PROTEINS .................................. 1107
Catalytic Antibodies: Designer Catalysts / Molecular
Graphic: A synthetic Diels-Alderase catalytic antibody
with a bound hapten ....................................... 1107
24.1. Introduction ........................................ 1108
24.2. Amino Acids ......................................... 1109
24.3. Synthesis of ct-Amino Acids ......................... 1115
24.4. Polypeptides and Proteins ........................... 1119
24.5. Primary Structure of Polypeptides and Proteins ...... 1122
24.6. Examples of Polypeptide and Protein Primary
Structure ........................................... 1126
THE CHEMiSTRY OF Sickle-Cell Anemia ................ 1128
24.7. Polypeptide and Protein Synthesis ................... 1129
24.8. Secondary, Tertiary, and Quaternary Structure
of Proteins ......................................... 1135
24.9. Introduction to Enzymes ............................. 1140
24.10.Lysozyme: Mode of Action of an Enzyme ............... 1141
24.11.Serine Proteases .................................... 1145
24.12.Hemoglobin: A Conjugated Protein .................... 1148
THE CHEMISTRY OF Some Catalytic Antibodies ......... 1148
24.13.Purification and Analysis of Polypeptides
and Proteins ........................................ 1150
24.14.Proteomics .......................................... 1152
25.NUCLEIC ACIDS AND PROTEIN SYNTHESIS ....................... 1158
Tools for Finding Families / Molecular Graphic:
A cytosine-guanine base pair .............................. 1158
25.1. Introduction ........................................ 1159
25.2. Nucleotides and Nucleosides ......................... 1160
25.3. Laboratory Synthesis of Nucleosides and
Nucleotides ......................................... 1163
25.4. Deoxyribonucleic Acid: DNA .......................... 1166
25.5. RNA and Protein Synthesis ........................... 1173
25.6. Determining the Base Sequence of DNA: The
Chain-Terminating (Dideoxynucleotide) Method ........ 1180
25.7. Laboratory Synthesis of Oligonucleotides ............ 1184
25.8. The Polymerase Chain Reaction ....................... 1184
25.9. Sequencing of the Human Genome: An Instruction
Book for the Molecules of Life ...................... 1188
ANSWERS TO SELECTED PROBLEMS .................................. A-1
GLOSSARY ...................................................... G-1
PHOTO CREDITS ................................................. C-1
INDEX ......................................................... I-1
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