Preview Organic Chemistry by Marye Anne Fox James K. Whitesell (1994)

I

Marye Anne Fox

James K.Whitesell


A

B

B

Periodic Table of the Elements

i

Group

at

Key

IA

Q.
1

atomic mass

0079

12.011

electronegativity

2.2

2.5
2

[He]2s 2p

H

i

Hydrogen
6.941

901218

10

1

configuration

C

symbol

II

electronic

2

name

atomic

6

number

Carbon

5
2

[He^s

Li

3

Lithium

Be
Beryllium

22.98977

24.305

1.0

1.2

[Ne]3s

[Ne]3s

Na

4

11

2

Mg

VII

12

B

III

IV

VB

B

VI

VII

Sodium

Magnesium

39 0983

40.08

44.9559

47.88

50.9415

51.996

54.9380

55.847

0.9

1.0

1.2

1.3

1.5

1.6

1.6

1.6

[Ar]4s

[Ar]4s

JX

19

2

[Ar]3d4s

Ca

20

2

2

[Ar]3d 4s

SC

2

3

[Ar)3d 4s

Ti

21

22

2

5

5

V

23

Cr

24

Mn

1.7

[Ar^s

2

[Ar]3d 4s

(Ar]3d 4s

58.9332

25

2

Fe

7

[Ar]3d 4s

26

2

CO

Potassium

Calcium

Scandium

Titanium

Vanadium

Chromium

Manganese

Iron

Cobalt

85.4678

87.62

88.9059

91.22

92.9064

95.94

98.906

101.07

102.9055

0.9

1.0

1.1

1.2

1.2

1.3

1.4

1.4

[Krj5s

[Kr)5s

Rb

37

2

br

[Kr)4d5s

38

2

2

[Kr]4d 5s

Y

4

2

[Kr]4rf

ZA

39

40

6

5

[Kr]4d 5s

5s

Nb

41

[Kr]4c/

MO

42

1.5
e

7

5s

[Kr]4d 5s

[Kr]4d 5s

TC

43

RU

44

Rh

Rubidium

Strontium

Yttrium

Zirconium

Niobium

Molybdenum

Technetium

Ruthenium

Rhodium

132.9054

137.33

138.9055

178.49

180.9479

183.85

186.207

190.2

192.22

0.9

1.0

1.1

1

1.3

1.4

1.5

1.5

[Xe]6s

[Xe]6s-'

[Xe]5d6s

CS

55

Ba

14

2

[Xe]4r

La

56

2

57

2

5d 6s

,4

2

Hf

[Xe]4f~

72

3

5d 6s

Ta

2

73

K

[Xe]4/

4

5d 6s

W

Barium

Lanthanium

Hafnium

Tantalum

Tungsten

(223)

226.0254

227.0278

(261)

(262)

(263)

0.9

1.0

1.0

[Rn]7s

[RnRs

Fr

2

87

Ra

se

Radium

Francium

2

[Rn]5f"6d 7s

{Rr\$d7s*

tAC

89

[Rn]5f

4

6d 7s

5

5d 6s

Re

2

75

1.6
,4

[Xe]4f

OS

5dV

4

2

[Xe)4r'

76

Ir

77

Osmium

Iridium

157.25

2

Unnilpentium

Unnilhexium

140.12

140.9077

144.24

145

150.4

151.96

1.1

1.1

1.1

1.1

1.0

2

6

5d 6s

Rhenium

1.1

[XeHfts

45

Unqio4 Unpio5 Unhioe
Unnilquadium

Actinium

,4

2

[Xe]4/'

74

Cesium

4

2

27

3

[Xe)4f 6s

4

2

[Xe]4f 6s

5

2

[Xe]4/

6s

6

2

[Xe]4/

6s

2

1.1
7

[Xe]4/

6s

7

2

[Xe]4r

5d6s

2

*Lai

Ce
6

58

Pr

59

Nd

60

Pm

61

Sm

62

63

G(l

Praseodymium

Neodymium

Promethium

Samarium

Europium

232.0381

231.0359

238.029

237.0482

(244)

(243)

(247)

1.1

1.1

1.2

1.2

1.2

1.2

=1.2

2

[Rn)6d 7s

2

[Rnl'^ctfs

3

2

[Rn)5f 6cr7s

2

[Rn]5f6o7s

2

[RnjSr^s

2

Th
Thorium

90

Pa
Protactinium

91

U
Uranium

92

Np
Neptunium

93

PU
Plutonium

2

94

Am
Americium

64

Gadolinium

7

[RnJSrVs

t Actinides

7

EU

Cerium

[Rn]5r

95

6d7s

Cm
Curium

2

96

A

Noble

Gases

The elements shown

in color

commonly

are those that

4.0026

undergo bonding with carbon.
1s

2

He
III

A

IV

Helium

20.179

12.011

14.0067

15.9994

18.9984

2.5

3.1

3.5

4.1

2

[He]2s 2p

B

5

26.9815
1.5

2

[He]2s 2p

N

4

2

[He]2s 2p

O

7

.

F

.

30.97376

32.06

35.453

39.948

1.7

2.1

2.4

2.8

2

Si

H

2

3

[Ne]3s 3p

P

2

4

[Ne]3s 3p

D

,5

CI

16

Chloride

Argon
83.80

74.9216

78.96

79.904

1.8

1.8

1.7

1.8

2.0

2.2

2.5

2.7

[Ar]3d'°4s

[Ar]3d'°4s

28

CU

29

,0

[Ar)3d

Zll

30

2

4s 4p

VJcl

2

[Ar]3d'°4s

31

4p

Ge

2

[Ar]3d

32

Germanium

,0

AS

Nickel

Copper

Zinc

Gallium

106.4

107.868

112.41

114.82

,18.69

121.75

1.4

1.4

1.5

1.5

1.7

1.8

[Kr]4d'°

[Kr]4d

,0

Pd

46

5s

[Kr]4d

Ag

47

,0

5s

2

Cd

48

In

[Kr]4d'°5s 5p

49

2

3

[Ar]3d'°4s 4p

Sn

2

[Kr)4d

50

,0

4

Se

33

[Ar]3d'°4s

34

2

5s 5p

3

Sb

4p

Br

5

~5

[Ar]3d

,0

.Kr

127.60

126.9045

131.30

2.2
2

4

5s 5p

Te

[Kr]4d

,0

2

5s 5p

1

52

5

53

[Kr]4d

,0

Palladium

Silver

Cadmium

Indium

Tin

Antimony

Tellurium

Iodine

Xenon

196.9665

200.59

204.37

207.2

208.9804

(209)

(210)

(222)

1.4

1.5

1.4
14

4

9

5d 6s

Pt

[Xe]4r"

78

AU

[Xe]4f

79

5d'°6s

Hg

Tb

65

6s

2

Dy

ee

173.04

174.967

1.1

,2

2

HO

[Xe]4f 6s

67

2

Er

Holmium

Erbium

,3

[Xe]4f 6s

68

Tm

259

260

(257)

(258)

=1.2

=1.2

Bk
Berkelium

97

V^I
Californium

[Rn]5/"7s

98

2

ES
Einsteinium

[Rn]5f

99

,2

7s

Fm
Fermium

2

[Rn]5f'

100

3

7s

2

Mdioi
Mendelevium

4

[Rn]5/'

7s

NO
Nobelium

2

[Rn]5f

102

2

Lu
Lutetium

(254)

2

70

,4

Lr

[Xe]4/'

5d

At
Astatine

5d6s

Ytterbium

=1.2

7s

Yb

4

[Xe]4/'

Thulium

(251)

,0

2

[Xe]4f 6s

69

84

1.1
14

2

6p

PO

1.1

=1.2
[Rn]5f

83

168.9342

(247)

2

Bi

4

4

2

[Xe)4i" 5o"°6s

167.26

=1.2
[Rn]5f*7s

82

4

3

1.1

[Xe]4f""6s

Dysprosium

Terbium

Pb

2

1.1

1.1
,0

8,

,0

2

5s 5p

6

54

2.0

1.8
4

[Xe]4f 5d 6s 6p

164.9304

162.50

1.1

[Xe]4/

Tl

2

Polonium

158.9254
2

80

1.7
2

[Xe]4r5d'°6s 6p

Bismuth

Mercury

6s

2

6s 6p

[Xel4^' 5cf'

Lead

Gold

9

4

2

Thallium

Platinum

[Xe]4/

1.6

1.4
,4

,0

5d 6s

6

36

Xe

195.09

(Xe]4/

2

2.0
10

is

4s 4p

Krypton

[Kr]4d

51

2

Bromine

Selenium

Arsenic

2

2

[Kr]4d'°5s 5p

2

4s 4p

6

Ar

Sulfur

72.59

Ni

,7

Phosphorus

69.72
2

2

10

[Ne]3s 3p

Silicon

65.38

2

5

Aluminum

63.546
8

Ne

28.0855

[Ne]3s 3p

4

2

Neon

2

2

[He]2s 2p

Fluoride

58.70

[Ar]3d 4s

5

Oxygen

2

,3

3

Nitrogen

[Ne]3s 3p

Al

[He]2s 2p

,

Carbon

2

2

2

C

Boron

[Ne]3s 3p

MB

VII

10.81

2

IB

VIA

2.0
[He]2s 2p

1

VA

A

71

6d7s

2

103

Lawrencium

,0

6sV
85

,4

[Xe]4f

,0

2

5d 6s 6p

Rn
Radon

6

se



ORGANIC
CHEMISTRY


Reproduction of a woodblock print, in the authors' collection, from a book published in 1497 in Basel, Switzerland, depicting an alchemist (standing at the right) and
his two assistants, one working at the "fume hood" and
the other taking a sample from the cask. The alchemist is
holding a retort, an all-in-one distillation apparatus in
which the long snout serves as the condenser. (Another
retort

is

in use in the fume hood,

the floor.)

and a

third one

is

on

ORGANIC
CHEMISTRY

Marye Anne Fox
James K. Whitesell
The

University of Texas

Austin, Texas

Jones and Bartlett Publishers
Boston

London


Editorial, Sales,

Jones and

and Customer Service

Offices

Bartlett Publishers

One

Exeter Plaza
02116
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617-859-3900
800-832-0034

MA

Jones and Bartlett Publishers International
PO Box 1498

London

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England

©

1994 by Jones and Bartlett Publishers, Inc.
All rights reserved. No part of the material protected by this copyright notice
be reproduced or utilized in any form, electronic or mechanical, including

Copyright

may

photocopying, recording, or by any information storage and retrieval system,
without written permission from the copyright owner.

Library of Congress Cataloging-in-Publication Data
Fox,

Marye Anne, 1947Organic chemistry / Marye Anne Fox, James K. Whitesell.
cm.
p.
Includes bibliographical references and index.
ISBN 0-86720-207-6
2. Biochemistry.
1. Chemistry, Organic.

II.

I.

Whitesell,

James K.

Title.

QD251.2.F69
547— dc20

1994
93-43800

CIP

David E. Phanco
Developmental Editor: Patricia Zimmerman
Production Editor: Judy Songdahl
Manufacturing Buyer: Dana L. Cerrito

Acquisitions: Arthur C. Bartlett,

Design:

Nancy Blodget

Illustrations:

Typesetting:

Sarah Mittelstadt Bean
The Clarinda Company

Cover Design: Marshall Henrichs
Printing and Binding: Rand McNally
Cover Printing: John P. Pow Company

Cover: Opiate drugs such as morphine are effective in relieving pain because they
bind to the same site in the central nervous system as do the enkephalins. The image
on the cover is of crystals of an enkephalin, viewed between crossed polarizers so
as to bring out the vivid rainbow display of colors. (Photograph © Dr. Dennis

Kunkel/Phototake NYC)

Printed in the United States of America

10 9 8 7 6 5 4 3 2
98 97 96 95 94


Brief Contents

Bonding

Chapter

1

Structure and

Chapter

2

Alkenes, Arenes, and Alkynes

in Alkanes

1

21

Chapter

Functional Groups Containing Heteroatoms

Chapter

Chromatography and Spectroscopy

Chapter

Stereochemistry

Chapter

Understanding Organic Reactions

193

Chapter

Mechanisms of Organic Reactions

227

109

155

Chapter

8

Nucleophilic Substitutions at sp -Hybridized
Carbon

267

Chapter

9

Elimination Reactions

Chapter 10

Chapter 11

303

Electrophilic Addition to

Bonds

59

Carbon-Carbon Multiple

331

Electrophilic Substitution of Aromatic

Molecules

3 69

Chapter 12

Addition and Substitution by Heteroatomic
401
Nucleophiles at sp -Hybridized Carbon

Chapter 13

Addition and Substitution by Carbon Nucleophiles
451
sp -Hybridized Carbon

Chapter 14

Skeletal-Rearrangement Reactions

Chapter 15

Multistep Syntheses

505

Chapter 16

Polymeric Materials

541

Chapter 11

Structures and Reactions of Naturally Occurring

Compounds Containing Oxygen
Groups

581

477

Functional

at


vi

Brief Contents

Chapter 18

Structures and Reactions of Naturally Occurring

Compounds Containing Nitrogen
Groups

Functional

613

Chapter 19

Noncovalent Interactions and Molecular
651
Recognition

Chapter 20

Catalyzed Reactions

Chapter 21

Cofactors for Biological

Chapter 22

Energy Storage

Chapter 23

Molecular Basis for Drug Action

in

681

Redox Reactions

Organic Molecules

713

745
789


4

7

Contents

Preface

xxi

Acknowledgments

Chapter

xxv

1

Structure and

Bonding

1-1

Atomic Structure

1-2

sp*

1-3

Covalent Bonding

1-4

Ionic

1-5

Alkanes

in Alkanes

6

Hybridization at Carbon

Bonding

9
10

12

Sigma Bonding

13

Drawing Three-Dimensional

Cycloalkanes

Strain

1-7

Nomenclature

1-8

Alkane

16

1

18

22

Stability

Combustion

22
23

Heats of Formation

1-9

Physical Properties of Hydrocarbons
Conclusions

Review Problems

1

16

Structure and Formula

Ring

Structures

15

Structural Isomers

1-6

8

24

25

26

vu


viii

(

Contents

Chapter 2
Alkenes, Arenes, and Alkynes
2-1

Alkenes
sp

Pi

21

21

Hybridization

28

Bonding

29

Structures of Alkenes

30

Molecular Orbitals

34

Higher Alkenes
Isomerism

in

34

Alkenes

Nomenclature
Alkene

for

34

Alkenes

31

Stability

2-2

Dienes

2-3

Aromatic Hydrocarbons

42

Resonance Structures

43

44

45

Stability

Aromaticity and Hiickel's Rule

Alkynes
sp

51

51

Hybridization

52

Higher Alkynes

2-5

46

48

Arenes

2-4

21

Physical Properties of Hydrocarbons
55

Conclusions

of New Reactions

Summary

54

56

56

Review Problems

Chapter 3
Functional Groups Containing Heteroatoms
3-1

Compounds Containing
Ammonia
Amines

3-2

-Hybridized Nitrogen

sp

59

Moments

Amines

64

65

Solvation

Nucleophiles and Electrophiles

66

61

Cleavages

3-3

Arrow Pushing

3-4

Acidity and Basicity of Amines

3-5

Oxidation Levels

at

at

Nitrogen

77

s|>

Motion

69

69

-Hybridized Nitrogen

11

11

14

Compounds Containing
in an O-H Bond
77
Water

2

Nitrogen

Compounds Containing

Bonding

3-7

to Indicate Electronic

Compounds Containing
Double Bonding

3-6

62

63

Hydrogen Bonding

Bond

59

60

Polar Covalent Bonding in
Dipole

59

5|>-Hybridized Nitrogen: Triple
77

sp

3

-Hybridized Oxygen


6 7
Contents

Alcohols:

R

— OH

78

Homolytic Cleavages: Bond Energies and Radical Structure

C-OH Bonds:

Heterolytic Cleavage of

Formation

84

of Carbocations

Ordering Alcohol Reactivity by Class

85

Conjugation in Radicals and Cations

R— O — R

86

3-8

Ethers:

3-9

Carbonyl Compounds: R2
Carboxylic Acids and Derivatives

3-10
3-11

3-12

79

88

C=0

89
90

Compounds
94
Aromatic Compounds Containing Heteroatoms
Sulfur-containing

95

Heteroaromatic Molecules

98

Heteroatom-substituted Arenes

3-13

Alkyl Halides

3-14

Nomenclature
Conclusions

Summary

95

99

101
1

02

of New Reactions

Review Problems

1

105

05

Chapter 4

Chromatography and Spectroscopy
4-1

The Use of Physical

4-2

Chromatography

109

Properties to Establish Structure
111

Liquid Chromatography on Stationary Columns

Paper and Thin-Layer Chromatography

Gel Electrophoresis

Spectroscopy

115

11

118

Nuclear Magnetic Resonance Spectroscopy

119

135

Infrared Spectroscopy

140

and Visible Spectroscopy

Ultraviolet

112

11

Gas Chromatography

4-3

109

Mass Spectroscopy

147

151

Conclusions

Review Problems

152

Chapter 5
Stereochemistry
5-1

5-2

155

Geometric Isomerization: Rotation about Pi Bonds

Conformational Analysis: Rotation about Sigma

Bonds

159

Ethane

Butane
Gauche and

159
161

And Conformers

5-3

Cycloalkanes

5-4

Cyclohexanes
Cyclohexane

164

165
1

67

167

Monosubstituted Cyclohexanes

1

69

155

ix


(

"fontents

Multiply Substituted Cyclohexanes

Fused Six-membered Rings

Chirality

5-6

Absolute Configuration

5-7

Polarimetry

5-8

Designating Configuration

A

1

12

1

5-5

73

177

179
181
181

Single Center of Chirality

182

Multiple Centers of Chirality

Meso Compounds

184

Fischer Projections

185

5-9

Optical Activity in Allenes

5-10

Stereoisomerism
Conclusions

Summary

171

1

of New

186

Heteroatom Centers

at

88
190

Reactions

190

Review Problems

Chapter 6
Understanding Organic Reactions
6-1

6-2

Characterizing Transition States:

from Reaction

Relative Rates

6-4

Reactive Intermediates

198

Profiles

198

200

Carbenes

201

Radical Ions

6-6

Hammond

199

Carbanions

Thermodynamic

Factors

Enthalpy Effects

203

Entropy

The

193

196

6-3

6-5

193

Reaction Profiles (Energy Diagrams)
Postulate

187

Effects:

203

The Diels-Alder Reaction

Chemical Equilibria

205

206
206

Relating Free Energy to an Equilibrium Constant

207

Acid-Base Equilibria

Acidity: Quantitative Measure of Thermodynamic
Equilibria
208

209

Electronegativity

Bond

209

Energies

209

Inductive and Steric Effects

2i2

Hybridization Effects

Resonance

212

Effects

Enolate Anion Stability

214

215

Aromaticity

Thermodynamic Control

6-8

Kinetic and

6-9

Reaction Rates: Understanding Kinetics
Unimolecular Reactions
Bimolecular Reactions
Conclusions

Summary

222

222

of New Reactions

Review Problems

220

224

223

216
219


1

1

Contents

Chapter 7

Mechanisms of Organic Reactions
7-1

Classification

of Reactions

227

228

Addition Reactions
Elimination Reactions

228

Substitution Reactions

229
229

Condensation Reactions

230

Rearrangement Reactions

23

Isomerization Reactions

Oxidation and Reduction Reactions

7-2

227

Bond Making and Bond

23

Breaking:

Thermodynamic

232

Feasibility

Energy Changes

in

Energy Changes

in Heterolytic

Homolytic Reactions

233

Reactions

234

7-3

How

7-4

Mechanism of a Concerted Reaction: Concerted
Nucleophilic Substitution (S N 2)
239
Mechanism of Two Multistep Heterolytic Reactions:

7-5

to Study a

New

Organic Reaction

Electrophilic Addition

236

and Nucleophilic Substitution

244

(S N 1)

Electrophilic Addition of HC1 to an Alkene

245

Multistep Nucleophilic Substitution (S N 1): Hydrolysis of Alkyl

248

Bromides

7-6

Mechanism of a Multistep Homolytic Cleavage: Free
Radical Halogenation of Alkanes
251
Energetics of Homolytic Substitution in the Cholorination

252

of Ethane

Steps in a Radical

Chain Reaction

253

255

Relative Reactivity of Halogens

Regiocontrol in Homolytic Substitution

1-1

Synthetic Applications

260

260

Conclusions

Summary

251

of New Reactions

Review Problems

261

263

Chapter 8
Nucleophilic Substitutions at sp -Hybridized

Carbon

261

8-1

Review of Mechanisms of Nucleophilic Substitution

8-2

Functional-Group Transformations through S N 2
Reactions
270
Williamson Ether Synthesis

211

Reaction of Alkyl Halides with Nitrogen Nucleophiles
Phosphines

8-3

as

Nucleophiles

216

Preparation of Carbon Nucleophiles

277

Carbon Nucleophiles: Cyanide and Acetylide
277

5/>-Hybridized

Anions

213

261

xi


xii

Contents

2
sp -

3
and 5/) -Hybridized Carbon Nucleophiles: Organometallic
218
Reagents

Protonation

8-4

Reactivity of

283

Limitation

as a

Carbon Nucleophiles

in S N 2 Reactions

S N 2 Reactions by sp-Hybridized Carbon Nucleophiles
S N 2 Opening of Ethylene Oxide by Grignard Reagents

Alpha-Halogenation of Enolate Anions

286

Enolate Anion and Enamine Alkylation

288

Alkylation

8-5

284

285

Alkylation of Other Organometallics

Ester Enolate

284

285

289

Anion Alkylations

of Beta-Dicarbonyl Compounds

290

Synthetic Methods: Functional-Group Conversion

294

296

Conclusions

Summary of New

291

Reactions

300

Review Problems

Chapter 9
Elimination Reactions
9-1

303

Mechanistic Options for Eliminations

304

El versus E2 Elimination Reactions: Dehydrohalogenation
of Alkyl Halides
306
306

Regiochemistry

312

Leaving Groups

313

Nucleophiles
Stereochemistry

3 14

9-4

HX from Vinyl Halides
Elimination of HX from Aryl Halides

9-5

Dehydration of Alcohols

9-6

Elimination of

9-7

Oxidations of Alcohols

9-8

Oxidation of Hydrocarbons

9-9

Synthetic

9-3

Elimination of

319

320

321

2

Methods

322

325

326

326

Conclusions

Summary

X

31 6

of New Reactions

Review Problems

321

328

Chapter 10
Electrophilic Addition to

Multiple Bonds

Carbon-Carbon

331

10-1

Electrophilic Addition to Alkenes

10-2

Addition of

HX

333

Gas-Phase Reactivity

333

Solution-Phase Reactivity:

on

HX Addition

331

334

The

Effect of Water


Contents

336

Hydration

331

Regiochemistry

338

Addition to Dienes
Stereochemistry

339

Rearrangements

340

HX Addition to Alkynes
10-3

341

Reversing Markovnikov Regiochemistry
Radical Addition of HBr

344

341

Hydroboration-Oxidation

10-4

Other Electrophiles

349
349

Oxymercuration-Demercuration
Addition of

X2

351

355

Carbenes

356

Epoxidation

358

Ozonolysis
Carbocations

360

as Electrophiles

10-5

Radical Additions

10-6

Synthetic Methods

361

362

362

Conclusions

Summary

344

of New Reactions

363

365

Review Problems

Chapter 11
Electrophilic Substitution of Aromatic

Molecules
11-1

11-2

369

Mechanism of Electrophilic Aromatic Substitution
369
The Introduction of Groups by Electrophilic Aromatic
Substitution: Activated Electrophiles

Halogenation

311

3 12

313

Nitration

3 14

Sulfonation

374

Friedel-Crafts Alkylation
Friedel-Crafts Acylation

316

11-3

Reactions of Substituents and Side Chains

11-4

Substituent Effects

380

Electron Donors and Acceptors

An

318

382

Exception: Electrophilic Substitution of Halogen-substituted

Aromatics

386
389

Multiple Substituents

Using Substituent

Effects in Synthesis

on Poly cyclic Aromatic

11-5

Electrophilic Attack
Compounds
393

11-6

Synthetic Applications
Conclusions

Summary

395

396

of New Reactions

Review Problems

390

398

396

xiii


1

xiv

(

1

Contents

Chapter 12
Addition and Substitution by Heteroatomic
401
Nucleophiles at sp -Hybridized Carbon
12-1

Nucleophilic Addition to Carbonyl Groups

12-2

Complex Metal Hydride Reductions

404

404

Aldehydes and Ketones

406

Reduction of Derivatives of Carboxylic Acids

Compounds

Relative Reactivity of Carbonyl

toward Hydride Reducing Agents

408

12-3

Biological Hydride Reductions

12-4

Nonhydride Chemical Reductions

410

413

Dissolving-Metal Reductions

12-5

Anions

12-6

Addition of Oxygen Nucleophiles

Nucleophiles

415

Addition of Water: Hydrate Formation

Hydroxide Ion

as a

Nucleophile:

411

The Cannizzaro Reaction

Addition of Nitrogen Nucleophiles
Amines

419

423

423

426

Other Nitrogen Nucleophiles

12-8

411

420

Addition of Alcohols

12-7

410

410

Catalytic Hydrogenation

as

402

Nucleophilic Acyl Substitution of Carboxylic Acids
and Derivatives
427
Hydrolysis of Carboxylic Acid Derivatives

429

Interconversion of Carboxylic Acids and Esters
Transesterification

433

Amide

433

Hydrolysis

Substitution Reactions of Acid Chlorides

Reactions of Acid Anhydrides

434

436

Formation of Carboxylic Acids from Nitriles

12-9

Sulfonic Acid Derivatives

12-10

Phosphoric Acid Derivatives

12-11

Synthetic Applications

43

438

440

441

441

Conclusions

Summary

43

of New Reactions

Review Problems

444

446

Chapter 13
Addition and Substitution by Carbon Nucleophiles
at sp -Hybridized Carbon
451
Reaction of Carbon Nucleophiles with Carbonyl

Groups
Cyanide

452
452

Grignard Reagents

453

Organolithium Reagents

455


Contents

456

Conjugate Addition

The Wittig Reaction
13-2

459

Enolates and Enols as Nucleophiles:
Condensation
460
Base-catalyzed Condensation of Aldehydes

461

Acid-catalyzed Condensation of Aldehydes

463

Aldol Condensations of Ketones

464

465

Crossed Aldol Condensations

461

Intramolecular Aldol Condensation

13-3

The

Claisen Condensation

468
468

Base-induced Claisen Condensation

469

Crossed Claisen Condensations

470

Reformatsky Reaction

Dieckmann Condensation
13-4

The Aldol

470

Synthetic Applications
4 12

Conclusions

Summary

472

of New Reactions

413

415

Review Problems

Chapter 14
Skeletal-Rearrangement Reactions
14-1

Carbon-Carbon Rearrangements

A
14-2

Anionic Rearrangement

Pericyclic

481

Rearrangement: The Cope Rearrangement

Carbon-Nitrogen Rearrangements
The Beckmann Rearrangement
The Hofmann Rearrangement

14-3

481
489

Rearrangement: The Claisen Rearrangement

Synthetic Applications

493

494

500

Conclusions

Summary

491

492

Baeyer-Villiger Oxidation

A Pericyclic

482

481

Carbon-Oxygen Rearrangements
The

14-4

477

477

Cation Rearrangements

An

477

of New Reactions

Review Problems

501

502

Chapter 15
Multistep Syntheses

505

15-1

Grouping Chemical Reactions

15-2

Retrosynthetic Analysis: Working Backward

15-3

Complications: Reactions Requiring both Functional-Group
512
Transformation and Skeletal Construction

15-4

A

15-5

Selecting the Best Synthetic

15-6

Criteria for Evaluating Synthetic Efficiency

Multistep

Example

506
509

514

Route

51 1

519

xv

1

xvi

(

intents

15-7

"Real World" Examples: Functional-Group
Compatibility

15-8

522

Protecting Groups

521

521

Protecting Groups for Aldehydes and Ketones

529

Protecting Groups for Alcohols

529

Protecting Groups for Carboxylates
Protecting Groups for

15-9

Practical

530

Amines

Examples

532

532

Ibuprofen and Ketcprofen

535

Valium

53

Conclusions

Summary

of New Reactions

538

539

Review Problems

Chapter 16
Polymeric Materials

541

16-1

Linear and Branched Polymers

16-2

Types of Polymerization

545

16-3

Addition Polymerization

545

546

Radical Polymerization
Ionic Polymerization

543

541

551

Cross-Linking

Heteroatom-containing Addition Polymers

16-4

Condensation Polymers

556

556

Polyesters

551

Polysaccharides

560

Polyamides

561

Polypeptides

16-5

Extensively Cross Linked Polymers

16-6

Three-Dimensional Structure

564

561

561

Polypropylene

568

Polypeptides

Cellulose and Starch

515

516

Conclusions

Summary

553

of New Reactions

Review Problems

518

518

Chapter 11
Structures and Reactions of Naturally Occurring
Compounds Containing Oxygen Functional
Groups
581
17-1

Lipids
Fats

581

and Waxes

Saponification

Micelles

585

581

584


6

4 3

6

1

1

Contents

Membranes

Bilayer

581

590

Terpenes

594

Steroids

17-2

Terpene Biosynthesis

17-3

Carbohydrates

17-4

Classification

600

of Sugars

601

60 1

Trioses

602

Aldotetroses

602

Aldopentoses

604

Aldohexoses

606

Ketoses

17-5

595

Oligomeric Carbohydrates
609

Conclusions

Summary

607

of New Reactions

610

610

Review Problems

Chapter 18
Structures and Reactions of Naturally Occurring
Compounds Containing Nitrogen Functional
Groups
613
18-1

Methods for Forming Carbon-Nitrogen Bonds:
Review
61

A

Amines

614

Amides

61

Imines

615

Nucleophilic Addition to Imines

Mannich Condensation
Nitrile

61

61

611

Reduction

Beckmann Rearrangement of Oximes
18-2

Amino

Acids

619

Hydrophobic and Hydrophilic Properties
Acidic and Basic Properties

18-3

Peptides

18-4

Peptide Synthesis

62

62

Zwitterionic Character of Amino Acids

622

623

624

Merrifield Solid-Phase Peptide Synthesis

18-5

Alkaloids

18-6

Nucleic Acids

18-7

Aminocarbohydrates

18-8

Abiotic Synthesis

626

631

Adenine

634
638

639

640

Carbohydrates (Ribose)

18-9

618

644

Synthetic Methods for Preparing Nitrogen-containing

Compounds
Conclusions

Summary

645

646

of New Reactions

Review Problems

648

641

xvii


wiii

Contents

Chapter 19
Noncovalent Interactions and Molecular
651
Recognition
19-1

Nonpolar (Hydrophobic) Interactions

19-2

Polar Interactions: Dipole-Dipole Interactions

19-3

Polar Interactions:

651

19-5

Hydrogen Bonds
655
Polar Interactions: Metal-Heteroatom Bonds
Multiple Hydrogen Bonds in Two Dimensions

19-6

Genetic Coding, Reading, and Misreading

19-7

Molecular Recognition of Chiral Molecules

19-4

653

659

664

665
611

Three-Point Contacts Are Necessary for Chiral Recognition

674

Resolution

676

Biological Significance of Chirahty

677

Conclusions

678

Review Problems

Chapter 20
Catalyzed Reactions
20-1

671

681

General Concepts of Catalysis
683

Transition-State Stabilization
Effect of Solvation

682

on S N 2 Reactions

684

20-2

Avoiding Charge Separation in Multistep Reactions

20-3

Distinction between Catalysis and Induction

20-4

Base Catalysis

687

692

694

Intermolecular and Intramolecular Reactions

Compared

695

20-6

Transition-Metal Catalysis

20-7

Catalysis

by Enzymes

Enzyme-Substrate Binding
Catalysis

696
700
700

by the Enzyme Chymotrypsin

20-8

Enzymes and

20-9

Artificial

Chiral Recognition

701

704

Enzymes: Catalytic Antibodies

Conclusions

Review Problems

706

709
710

Chapter 21
Cofactors for Biological

Redox Reactions

713

21-1

Molecular Recognition

21-2

Recycling of Biological Reagents

21-3

Cofactors: Chemical Reagents for Biological
Transformations
716

21-4

Pyridoxamine Phosphate: Reductive Amination of AlphaKetoacids as a Route to Alpha-Amino acids
718

714

715


1

Contents

21-5

21-6

NADPH:

FADH

2:

Hydride Reduction of Beta-Ketoacids

Electron-Transfer Reduction of an Alpha, Beta-

Unsaturated Thiol Ester
21-7

Acetyl

723

CoA: Activation of Carboxylic Acids

Esters) toward Nucleophilic Attack

21-8

726

730

Tetrahydrofolic Acid: A One-Carbon Transfer Cofactor
for the Methylation of Nucleic Acids
736

74

Conclusions

Summary

of New Reactions

741

743

Review Problems

Chapter 22
Energy Storage in Organic Molecules
22-1

Reaction Energetics
Catalysis

745

745

748

749

Multistep Transformations

22-2

Complex Reaction Cycles

22-3

Energy Storage

in

Anhydrides

22-4

Energy Storage

in

Redox Reactions

22-5

Energy Storage

in Fatty

749

750

752

Acid Biosynthesis

Carbon— Carbon Bond Formation
Reduction

754

758

22-6

Energy Release

22-7

The Krebs Cycle

22-8

Controlling Heat Release

22-9

Energy Release from Carbohydrates through
Glycolysis

754

757

Synthesis of Longer Chains

in Fatty

Acid Degradation

759

760
767

769

Isomerization of Glucose to Fructose

22-10

Thiol

Mimicking Biological Activation with Reverse Polarity
Reagents

21-10

(as

724

Thiamine Pyrophosphate and Lipoic Acid: Decarboxylation
of Alpha-Ketoacids

21-9

72?

770

Cleavage of Fructose into Three-Carbon Fragments

772

Conversion of the Three-Carbon Fragments
Derivatives
776

Acid

into Acetic

Biological Reactions in Energy Storage and
Utilization
780
Conclusions

Review Problems

784

785

Chapter 23
Molecular Basis for Drug Action
23-1

Chemical Basis of Disease

23-2

Intact Biological Systems as

States

789
790

Chemical Factories

793

xix


xx

(

Contents

Modern Antacids

23-3

Beta-Blockers:

23-4

Beta-Phenethylamines: Peptide Mimics

23-5

Blocking Tetrahydrofolic Acid Synthesis

23-6

Antibiotics Affecting
across

Membranes

Membrane

194

Structure and Ion Balance

Disruption of Bacterial Cell Walls

23-8

Drugs Affecting Nucleic Acids Synthesis
810

Review Problems

Appendix

813

Glossary

Index

819
851

191

801

23-7

Conclusions

195

812

803

809


Preface

Each

year,

most of the thousands of students who

finish a first course in

organic chemistry clearly express their dissatisfaction with what they have

They convey their displeasure both vocally and, even more persuaby "voting with their feet" that is, by not enrolling in other
advanced science courses. Ask a typical group of such students what was
wrong with their course and you will hear the same answer that this query
draws from deans of medical schools, from educational psychologists who
specialize in the instruction of mathematics and science, from university
administrators, and even from many instructors of the courses: all say that a
learned.

—

sively,

typical organic chemistry text contains too

which

is

much

information,

excruciatingly detailed, disconnected from "real

life,"

much

of

irrelevant to

other parts of a technical or liberal education, and just plain boring.

Now,

even among the strongest students, many emerge from a year of organic
chemistry without a good picture of what a practicing organic chemist does.
Adopting a "less is more" philosophy for an introductory undergraduate course, we have tried in this text to address each of these common criticisms in an intellectually demanding year-long course.
».

First,

the content of this rigorous course

is

presented in less than a

thousand pages.
».

>

Second, the course is developed as a "story," with each chapter containing only those topics and reactions that are needed to understand
the intellectual roots of organic chemistry as it is currently practiced.
Third, specific examples are included at each stage to illustrate familiar,

concrete uses of the chemistry under discussion.
».

we

intended to enhance the student's
appreciation of the significance of chemistry in other science and preprofessional courses, in undergraduate research in a modern organic
chemistry laboratory, and in industrial and biomedical research.

And,

fourth, the story that

tell is

xxi