Jones M., Fleming S.A. Organic Chemistry

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xix

Helium 5

Methane 60

Ethylene: A Plant Hormone 106

Strychnine 172

Thalidomide 180

Carboranes: Weird Bonding 217

Synthetic diamonds 219

Ajoene 252

Malic Acid 274

Cholesterol Formation 358

Ethyl Alcohol 400

Pyrethrins 456

Radical inhibitors as food preservatives 484

Vitamin E 505

Vitamin A and vision 533

Bombykol 534

The birth-control pill 562

Vanillin 582

Carcinogens 605

Carcinogenesis 614

Aniline 648

Magnetic resonance imaging (MRI) 713

Maitotoxin 745

Civetone 769

Salicylic Acid 838

Nylon and polyesters 852

Fats, oils, soaps, and detergents 862

Velcro 898

Eat Your Broccoli! 921

Anticancer drugs 980

Palytoxin 1009

Chorismate to Prephenate:

A Biological Cope Rearrangement 1063

Mustard Gas 1089

Sugar Substitutes 1164

Cellulose and starch 1168

Canavanine: An Unusual Amino Acid 1177

DNA and RNA 1211

Selected Applications

xxi

Organic Reaction Animations

Bimolecular nucleophilic substitution: S

2 267

Halide formation 285

Unimolecular nucleophilic substitution: S

1 289

Unimolecular elimination: E1 298

Bimolecular elimination: E2 301

Hofmann elimination 308

Acetylide addition 312

Intramolecular S

2 316

2 with cyanide 344

Alkene hydrohalogenation 365

Alkene hydration 381

Alkene polymerization 385

Carbocation rearrangement E1 389

Alkene hydroboration 390

Alkene halogenation 414

Stabilized alkene halogenation 417

Halohydrin formation 418

Alkene epoxidation 424

Basic epoxide ring opening 426

Acidic epoxide ring opening 427

Dihydroxylation of alkenes 443

Radical alkene hydrohalogenation 485

Alkane halogenation 494

1,2-Hydrohalogenation of dienes 534

1,4-Hydrohalogenation of dienes 534

Diels–Alder reaction 544

Benzylic oxidation 613

Friedel–Crafts acylation 644

Arene halogenation 670

Nucleophilic aromatic substitution 674

Benzyne formation 681

Carbonyl hydration 775

Acetal formation 786

Imine formation 792

Grignard reaction 801

Carbonyl reduction 802

Alcohol oxidation 804

Cleavage of vicinal diols 807

Wittig reaction 812

Fischer esterification 841

Acid chloride formation 854

Acid chloride aminolysis 854

Acid chloride aminolysis 889

Ester hydrolysis 895

Nitrile hydrolysis 904

Baeyer–Villiger reaction 907

Enol halogenation 947

Decarboxylation 960

Malonate alkylation 962

Aldol condensation 965

Michael addition 976

Mixed aldol condensation 983

Claisen condensation 987

Cope rearrangement 1063

Intramolecular S

2 1081

Most students in our organic chemistry courses are not chemistry majors. We wrote

this book for anyone who wants a broad yet modern introduction to the subject. We

stress general principles because it is impossible to memorize all the details of this

vast subject. We want students to learn to make connections and to apply a set of

broad organizing principles in order to make the material more manageable and

understandable.

The Fourth Edition

Quite a bit has changed from the third to the fourth edition. New coauthor Steven

Fleming brought his experience with this book and with his students to this revi-

sion.Developmental editor Irene Nunes read the third edition from the student per-

spective and made extensive comments.Irene helped us identify places where we may

have assumed knowledge some students would not have or where we could further

clarify a point or figure.We made substantial changes that will benefit students using

this book.

The voice of the book remains the same. It is personal, and talks directly to the

student not only about the material at hand, but also about the “how and why” of

organic chemistry. We think it is much easier to enjoy, and learn, organic chemistry

if a strong focus on “Where are we and why are we here?” and “What is the best

way to do this?”is maintained. On occasion, we try to help students through a tough

part of the subject by pointing out that it is tough and then suggesting ways to deal

with it. Everyone who has taught this subject knows there are such places—when

we talk to students ourselves, we try to use our experi-

ence to help students succeed, even when we know the

going is likely to be difficult for some,and the book tries

to do the same thing.

Every chapter begins with a Preview section in

which the coming chapter is outlined. At the end of the

Preview, we describe the Essential Skills and Details

students will need for the chapter. At exam time, stu-

dents can use these sections as guides for study and

review.

Organic chemistry is a highly visual subject. Organic

chemists think by constructing mental pictures of mol-

ecules and communicate with each other by drawing pic-

tures. This book favors series of figures over long

discussions in the text. The text serves to point out the

changes in successive figures. Color is used to highlight

xxiii

Preface to the Fourth Edition

ESSENTIAL SKILLS AND DETAILS

1. Sidedness and Handedness. You have the broad outlines of structure under control

now—acyclic alkanes, alkenes, and alkynes have appeared, as have rings. Now we come

to the details, to stereochemistry. “Sidedness”—cis/trans isomerism—is augmented by

questions of chirality—“handedness.”Learning to see one level deeper into three-

dimensionality is the next critical skill.

2. Difference.The topic of difference and how difference is determined arises in this

chapter. The details may be nuts and bolts, and, indeed, any way that you work out to

do the job will be just fine, but there is no avoiding the seriousness of the question.

When are two atoms the same (in exactly the same environment) or different (not in

the same environment)? This question gets to the heart of structure and is much

tougher to answer than it seems. By all means, concentrate on this point. This chapter

will help you out by introducing a method—an algorithm for determining whether or

not two atoms are in different environments. It is well worth knowing how it works.

3. There is no way out—the (R) and (S) priority system must be learned.

4. Words—Jargon.This chapter is filled with jargon: Be certain that you learn the

difference between enantiomers and diastereomers. Learn also what “stereogenic,”

“chiral,” “racemic,” and “meso”mean.

change and often to track the fates of atoms and groups in reactions. We have used

text bubbles to show important steps in a process or to note an important point.

One factor that can make organic chemistry difficult is that new language must

be learned. Organic chemists talk to each other using many different conventions

and at least some of that language must be learned or communication is impossi-

ble. In addition to general treatments of nomenclature at the beginning of many

chapters, we have incorporated numerous Convention Alerts in which aspects of

the language that chemists use are highlighted.

Throughout the book, reference is made to the connection between organic

chemistry and the world of biology. Almost every chapter has a section devoted to

the biological relevance of new reactions discussed.We have also added Applications

Boxes to illustrate the relevance of the subject to students’ lives.

xxiv PREFACE TO THE FOURTH EDITION

CONVENTION ALERT

3-Hydroxy-3-methylglutaryl

(or HMG)

Mevalonic acid

Cholesterol

CoA

HMG-CoA

reductase

rate-limiting

step

many

steps

–

O OH

O O

–

H H

–

CHOLESTEROL FORMATION

Sometimes, our well-being depends on interfering with

an enzyme-mediated rate acceleration. Cholesterol (p. 121)

is formed in the body by a lengthy process in which the

thioester A is reduced to mevalonic acid, which is then

converted in a series of reactions into cholesterol.

Controlling cholesterol levels in the body is an important

part of healthy living. Recent advances in medicinal and

organic chemistry have allowed the development of the

“statin” drugs (i.e., atorvastatin, fluvastatin, lovastatin, pravas-

tatin, simvastatin, and rosuvastatin), which act to reduce the

level of “unhealthy” low-density lipoprotein (LDL) choles-

terol. Examples of a healthy artery and a partially clogged

artery, which can result from high levels of LDL cholesterol,

are shown below. The benefit of taking a statin drug is a sig-

nificant reduction in the risk of heart attacks and strokes.

The statins function by inhibiting the enzyme HMG-

CoA reductase, which is involved in the rate-limiting or

slowest step in the formation of mevalonic acid, and hence

cholesterol. Without the enzyme, the reduction to mevalonic

acid in the body is much too slow. We have learned about

hydride reagents (p. 315), and we do have biological hydride

sources. You will meet one, NADH, in Chapter 16. But simply

mixing this “natural” hydride reagent with the HMG-CoA

thioester A results in no reaction. However, HMG-CoA

reductase can bring the hydride source and the thioester A

together in a fashion that allows the reaction to occur. The

energy barrier for the reaction is lowered, and mevalonic acid

is formed and goes on to make cholesterol.The statins inter-

fere with the reduction by inhibiting the enzyme necessary—

no reduction, no cholesterol!

810 S

It can be a great help to be shown profitable (and

unprofitable) approaches to problem solving, and the

number of Problem Solving sections has greatly

increased in the fourth edition. Although there is no

substitute for a thorough understanding of the ma-

terial, our subject is an experience-intensive one, and

by definition students are short on that commodity.

There are many moments in organic chemistry

when it is important to take stock of where we are.

Summary sections have been incorporated into every

chapter. Here the narrative is broken and the reader is brought up to date on the

important points of the previous topic.These summaries serve as excellent “reminder

and review” sections when a student is studying for an exam.

Each chapter ends with a summary of New Concepts, Key Terms,new

Reactions, Mechanisms, and Tools,new Syntheses, and Common Errors.These

sections recapitulate and reinforce the material of the chapter, and serve as excellent

study tools.

We incorporate unsolved problems in two ways.There are many such problems

scattered throughout the text and more problems, of all degrees of difficulty, are found

at the end of each chapter. They range from drill exercises and simple examples,

designed to emphasize important skills and illustrate techniques, to sophisticated,

challenging problems. In those last cases, we are careful to provide hints and refer-

ences to material useful for the solution. All these problems are solved in the Study

Guide, which does much more than provide a bare-bones answer. It, along with the

new Problem Solving sections in the fourth edition, tries to show students prob-

lem-solving techniques that will help them solve future problems. There are also

many solved problems in the text, each designed to reinforce a point just made.

The fourth edition contains many new problems including ones that require the

use of the Organic Reactions Animations software.

Highlights of the Content and Organizational Changes

in the Fourth Edition

The fourth edition has:

• A much more complete discussion of resonance in Chapter 1. This change is in

response to a request by reviewers who felt this central theme should be presented

as early as possible. We agree. Understanding resonance structures is critical, and

early coverage provides a strong foundation. The student will have a chance to

review the topic in Chapter 9.

• A reorganization of Chapter 15. The new outline emphasizes important topics in

NMR spectroscopy. Also, the chapter was modified so that it is even more movable

than it was in the third edition, in case the instructor wants to present spectroscopy

early in the first semester. We believe spectroscopy is a topic that should be taught

early. Students can use the tools (UV, IR, NMR, MS) to help understand symme-

try, resonance, electronegativity, aromaticity, acidity, and reactivity of molecules.

Spectroscopy is an important tool to link structure and activity.

• Enolates discussed as a single topic in Chapter 19. Earlier editions of this text had

the enolate topic covered in two chapters separated by a chapter on carboxylic acids.

Because enolates of aldehydes, ketones, esters, and carboxylic acids all share similar

PREFACE TO THE FOURTH EDITION xxv

PROBLEM SOLVING

Whenever you see the word “rate” in a problem, or when you see words such as

“faster” that talk about rates, you are very likely to have to answer the question by

drawing the transition state for the reaction. Remember that the rate of a

reaction is determined by ΔG

‡

, the energy difference between starting material

and the transition state, and not by the energy difference between starting

material and product. You need a pull-down menu that says, “Think about the

transition state” when the word “rate” appears in a problem.

reactions, we have combined them into one chapter. It is the chemistry of carban-

ions formed by deprotonating the carbon alpha to a carbonyl that sews this chapter

together. Students will benefit from this unified approach to enolate chemistry.

• New structures and topics in the carbohydrate chapter, Chapter 22. This chapter

was rewritten in an attempt to provide more current carbohydrate material. Many

instructors do not cover carbohydrates in their organic chemistry course, but those

who do will find both the historical Fischer proof and modern synthetic methods

presented in this chapter. We have drawn most of the carbohydrates as chair struc-

tures so that students can recognize and remember why glucose is the most com-

mon carbohydrate.

• Special Topics in most chapters (except Chapters 7, 20, 21, and 23). This material

deals with logical extensions and applications of related subjects. Instructors who

choose to move through the chapters more quickly may opt to leave these sections

out of lecture material. We hope students will read the Special Topic sections. The

material is provided because we believe it is important, but we recognize that it is

not critical.

• A substantially increased use of the terms electrophile and nucleophile throughout the

text. There is a unifying theme that the interaction between Lewis acids (elec-

trophiles) and Lewis bases (nucleophiles) in organic chemistry is stabilizing. In

orbital terms, that statement simply means that the interaction between a filled and

empty orbital is stabilizing. The text has a focus on this principle and the frequent

use of these terms will help direct the student to see their significance.

• More end-of-chapter problems. Over 100 new problems have been added in this

edition. The added problems are not the mind-numbing sort; these are practice

problems that will give the student more experience and confidence with the sub-

ject. Organic Reaction Animations (ORA) problems have also been added. These

questions will help the student connect the ORA visualizations with the principles

being discussed in the chapter.

Overall Organization

To understand atoms and molecules one must first think sensibly about electrons,

and for that we need to explore a bit of what quantum mechanics tells us.That does

not mean we will all have to become mathematicians. Far from it. Our discussion

here will be purely qualitative,since we need only grasp qualitatively what the math-

ematicians have to say to us. Qualitative molecular orbital theory is not too compli-

cated a subject for students, and requires no mathematics. Yet, this simple theory is

amazingly powerful in its ability to rationalize and, especially, to predict structure

and reactivity. The abbreviated tutorial in Chapter 1 on qualitative applications of

molecular orbital theory is likely to be new to students. This material is important,

as it enables us to emphasize explanations throughout the rest of the book.Not only

are traditional subjects such as aromaticity and conjugation (Chapters 12–14) more

accessible with the background of Chapter 1,but explanations for the essential, build-

ing-block reactions of organic chemistry (Chapters 7 and 9, for example) become

possible. There is, after all, no essential difference between the classic statement

“Lewis acids react with Lewis bases”and the idea that the interaction of a filled and

empty orbital is stabilizing.The latter formulation allows all sorts of seemingly dis-

parate reactions to be gathered together—unified—in a very useful way. (For exam-

ple, a hydride shift and the S

1 reaction become partners in a unified theory rather

than two wildly different reactions that must be memorized in all their detail.)

xxvi PREFACE TO THE FOURTH EDITION

The language that makes both the macro scale and the micro scale accessible to

us is mathematics.Although we need not do the mathematical operations ourselves,

we do need to appreciate some of the things that quantum mechanics has to say to

us. Chapter 1 also focuses strongly on Lewis structures—pictorial representations

of atoms and ions. The ability to write good Lewis structures easily and to deter-

mine the locations of charges in molecules with ease is an essential skill. This skill

is part of the language of chemistry and will be as important in Chapter 23 as it is

in Chapter 1.

After the introductory chapter comes a sequence of four chapters devoted large-

ly to aspects of structure (Chapters 2–5). Here the details of the archetypal struc-

tures of organic chemistry are introduced. Hybridization appears,and the wonderful

three-dimensionality of the subject begins to grow in. Some functional groups are

introduced,and stereochemistry is dealt with in depth.A particularly vexing and fun-

damental question concerns what makes two atoms or molecules the same or dif-

ferent. The fourth edition includes a preview of NMR spectroscopy in Chapter 2.

This section is not detailed—it is only an introduction—but it allows a real discus-

sion of that elusive question of “difference.” It also allows reinforcement through a

series of new problems introduced throughout the first half of the book.

In Chapter 3, the addition of HX molecules to alkenes allows an introduction

to synthesis, as well as a discussion of selectivity, catalysis, and reaction mechanism

in general.

After the series of “structure” chapters comes Chapter 6 on alcohols, amines,

halides, and the properties of solvents. This chapter functions as a lead in to a dis-

cussion of several building-block reactions, the S

2, S

1, E2, and E1 reactions.

Chapter 7 is one of the key chapters, and the reactions discussed here—substi-

tution and elimination—serve as reference points throughout the book; they are fun-

damental reactions to which we return over and over in later chapters in order to

make analogies.

Once we have these basic reference reactions under control, a general discussion

of the role of energetics—kinetics and thermodynamics—becomes appropriate

(Chapter 8). Chapters 9 and 10 introduce other building-block reactions, and other

functional groups, in the context of an expansion of the earlier discussion of addi-

tion reactions in Chapter 3. Even at these early stages we introduce the biological

applications of organic chemistry. For example, in the chapters devoted to the struc-

ture of alkanes, and, especially, alkenes, biorelevant examples appear. These do not

obscure the essential information of the chapters, however. They are kept as exam-

ples, potential extensions, and applications of what we have learned at this point.

Later on in the book their role is expanded, with whole chapters (Chapters 22 and

23) devoted to biological topics.

The basic reactions of the middle chapters (Chapters 7–14) provide a founda-

tion for the chemistry of carbonyl compounds, the subject of a series of chapters in

the second half of the book (Chapters 16–19).

Chapter 15, set in the midst of this run of chapters, is devoted to spectroscopy.

Sections of earlier chapters have already dealt with parts of this subject in an intro-

ductory way (Chapter 2 for NMR, Chapter 12 for UV/vis). So, in order to allow

flexible usage of this chapter, we have tried to make this chapter freestanding.

To make an analogy to the study of a language, in the first sequence of reaction

chapters (Chapters 7, 9, and 10) we write sentences constructed from the vocabu-

lary and grammar developed in the early, structural chapters. We will go on in later

chapters in the book to more complicated mechanisms and molecules, and to write

PREFACE TO THE FOURTH EDITION xxvii

whole paragraphs and even short essays in organic chemistry. Some of those essays

are contained in the Special Topics chapters toward the end of the book (Chapters

20–23) in which biological chemistry and physical-organic chemistry are further

explored with the material of the early chapters as a foundation.

Flexibility. There is no consensus on the precise order in which to take up many

subjects in organic chemistry. This book makes different decisions possible. For

example, as already pointed out, the spectroscopy chapter is largely freestanding.

Traditionally, it comes where it is here, roughly at the midpoint of the book. But

cogent arguments can be made that spectroscopy should be introduced earlier, and

that is possible, if one is willing to pay the price of delaying the serious discussion

of chemical reactions one more chapter.

The last few chapters explicitly constitute a series of Special Topics. No one real-

ly hopes to finish everything in an organic textbook in one year, and this book pro-

vides a number of choices. One might emphasize biological aspects of our science,

for example,and Chapters 22 and 23 provide an opportunity to do this.Alternatively,

a more physical approach would see the exciting chemistry of Chapters 20 and 21

as more appropriate.

Instructor Resources

• PowerPoint slides, available at wwnorton.com/nrl. Both lecture slides and slides

containing textbook art are available for download from the instructor site. Lecture

slides include questions for classroom response systems (also known as clickers).

• Transparency set, with approximately 150 key figures from the text.

• Test Bank (Tim Minger, Mesa Community College). New to the fourth edition,

the Test Bank contains 1,150 questions from which to choose.Questions are organ-

ized by chapter section, and each question is ranked by difficulty and type.The Test

Bank is available as a printed book, in Word RTF, in PDF, and in ExamView

Assessment Suite.

Student Resources

• Study Guide/Solutions Manual (Maitland Jones, Jr., New York University; Henry L.

Gingrich, Princeton University; Steven A. Fleming,Temple University).Written by

the textbook authors, this guide provides students with fully worked solutions to all

unworked problems that appear in the text. In addition to the solutions presented

for each specific problem, the authors present good problem-solving strategies for

solving organic chemistry problems in general.

• StudySpace, available at wwnorton.com/studyspace. This free and open Web site

is available to all students. StudySpace includes more than 350 interactive, 3-D

molecules from the text (formerly hosted on Norton’s Orgo3D Web site). These

structures were made in Chem3D and can be manipulated in space and viewed in

several ways (ball-and-stick, space-filling, etc.). In addition, there is a short writeup

and usually a few questions (and answers!) for most of the molecules.

StudySpace will house two review features from the text: Essential Skills and

Details and Convention Alerts. The site will also provide links to the ebook and

SmartWork.

• SmartWork: an online tutorial and homework program for organic chemistry,

available at wwnorton.com/smartwork. SmartWork is the most intuitive online

tutorial and homework-management system available for organic chemistry. Powerful

xxviii PREFACE TO THE FOURTH EDITION

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