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ORGANIC
CHEMISTRY
An Acid–Base Approach


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ORGANIC
CHEMISTRY
An Acid–Base Approach

M I C H A E L

B. SMITH

Boca Raton London New York

CRC Press is an imprint of the
Taylor & Francis Group, an informa business


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Preface.................................................................xi
Acknowledgments............................................ xv

The Author.......................................................xvii
Chapter 1: Introduction.................................... 1
1.1
1.2

A Brief History of Organic Chemistry
The Variety and Beauty of Organic Molecules

Chapter 2: Why Is an Acid–Base
Theme Important?............................................ 19
2.1
2.2
2.3
2.4
2.5
2.6
2.7

Acids and Bases in General Chemistry
Acids and Bases in Organic Chemistry
How Are the Two Acid–Base
Definitions Related?
Acid and Base Strength
Lewis Acids and Lewis Bases
Why Is Acid–Base Chemistry a Theme
for Organic Chemistry?
Biological Relevance

Chapter 3: Bonding.......................................... 45
3.1

3.2
3.3
3.4
3.5
3.6
3.7
3.8

The Elements
What Is a Chemical Bond? Ionic versus Covalent
The Covalent Carbon–Carbon Bond
Molecular Orbitals
Tetrahedral Carbons and sp3 Hybridization
How Strong Is a Covalent
Bond? Bond Dissociation Energy
Polarized Covalent σ-Bonds
Biological Relevance

Chapter 4: Alkanes, Isomers, and an
Introduction to Nomenclature....................... 87
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8

The Fundamental Structure of

Alkanes Based on the sp3 Hybrid Model
Millions of Hydrocarbons: Alkanes
Combustion Analysis and Empirical Formulas
The Acid or Base Properties of Alkanes
Isomers
Naming Millions of Isomers:
Rules of Nomenclature. The
IUPAC Rules of Nomenclature
Rings Made of Carbon. Cyclic Compounds
Biological Relevance

Chapter 5: Functional Groups..................... 121
5.1
5.2
5.3
5.4
5.5

Introducing a Functional Group: Alkenes
Another Hydrocarbon Functional Group: Alkynes
Hydrocarbons with Several Multiple Bonds
Reactivity of Polarized Covalent σ-Bonds
Formal Charge
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Organic Chemistry: An Acid-Base Approach
5.6
5.7
5.8
5.9
5.10
5.11

Heteroatom Functional Groups
Acid–Base Properties of Functional Groups
Polarity and Intermolecular Forces
Functional Groups with Polarized π-Bonds
Benzene: A Special Cyclic Hydrocarbon
Biological Relevance

Chapter 6: Acids, Bases, Nucleophiles, and Electrophiles................... 191
6.1
6.2
6.3
6.4
6.5
6.6
6.7
6.8

Acid–Base Equilibria
Polarized Hydrogen–Heteroatom Bonds: Acidic Units
Factors That Influence the Strength of a Brønsted–Lowry Acid

Organic Bases
Lewis Acids and Lewis Bases
A Positive Carbon Atom Can Accept Electrons
Nucleophiles
Biological Relevance

Chapter 7: Chemical Reactions, Bond Energy, and Kinetics.............. 249
7.1
7.2
7.3
7.4
7.5
7.6
7.7
7.8
7.9
7.10
7.11
7.12
7.13

A Chemical Reaction
Bond Dissociation Enthalpy and Reactions
Transition States
Reactive Intermediates
Free Energy. Influence of Enthalpy and Entropy
Energetics. Starting Materials, Transition States, Intermediates,
and Products on a Reaction Curve
Competing Reactions
Mechanisms

Why Does a Chemical Reaction Occur? Defining a “Reactive” Center
Reversible Chemical Reactions
Kinetics
No Reaction
Biological Relevance

Chapter 8: Rotamers and Conformation.................................................. 295
8.1
8.2
8.3
8.4
8.5
8.6
8.7
8.8
8.9
8.10

Rotamers
Longer Chain Alkanes: Increased Torsional Strain
Conformations of Alkenes and Alkynes: Introducing π-Bonds
Influence of Heteroatoms on the Rotamer Population
Cyclic Alkanes
Substituted Cyclohexanes
Larger Rings
Cyclic Alkenes
Introducing Heteroatoms into a Ring
Biological Relevance

Chapter 9: Stereoisomers: Chirality, Enantiomers,

and Diastereomers.......................................................................................... 353
9.1
9.2
9.3
9.4
9.5

Stereogenic Carbons and Stereoisomers
Specific Rotation: A Physical Property
Absolute Configuration (R and S Nomenclature)
Alkenes
Diastereomers


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Contents
9.6
9.7
9.8
9.9

Stereogenic Centers in Cyclic Molecules
Stereogenic Centers in Complex Molecules
Optical Resolution
Biological Relevance

Chapter 10: Acid–Base Reactions of π-Bonds.......................................... 415

10.1
10.2
10.3
10.4
10.5

Alkenes and Acid–Base Chemistry
Carbocation Intermediates
Alkenes React with Weak Acids in the Presence of an Acid Catalyst
Alkenes React as Lewis Bases
Alkenes React as Lewis Bases with Electrophilic Oxygen.
Oxidation of Alkenes to Oxiranes
10.6 Alkynes React as Brønsted–Lowry Bases or Lewis Bases
10.7 Reactions That Are Not Formally Acid–Base Reactions
10.8 Non-ionic Reactions: Radical Intermediates and Alkene Polymerization
10.9 Synthetic Transformations
10.10 Biological Relevance

Chapter 11: Nucleophiles: Lewis Base-Like Reactions
at sp3 Carbon.................................................................................................. 503
11.1 Alkyl Halides, Sulfonate Esters, and the Electrophilic C–X Bond
11.2 Nucleophiles and Bimolecular Substitution (the SN2 Reaction)
11.3 Functional Group Transformations via the SN2 Reaction
11.4 A Tertiary Halide Reacts with a Nucleophile When the Solvent Is Water
11.5 Carbocation Rearrangements
11.6 Solvolysis Reactions of Alkyl Halides
11.7 Preparation of Halides and Sulfonate Esters by Substitution Reactions
11.8 Reactions of Ethers
11.9 Free Radical Halogenation of Alkanes
11.10 Applications to Synthesis

11.11 Biological Relevance

Chapter 12: Base-Induced Elimination Reactions................................. 583
12.1
12.2
12.3
12.4
12.5
12.6
12.7
12.8
12.9

Bimolecular Elimination
Stereochemical Consequences of the E2 Reaction
The E2 Reaction in Cyclic Molecules
Unimolecular Elimination
Intramolecular Elimination
1,3 Elimination: Decarboxylation
Elimination Reactions of Vinyl Halides: Formation of Alkynes
Elimination Functional Group Exchanges
Biological Relevance

Chapter 13: Substitution and Elimination Reactions Can Compete......621
13.1
13.2
13.3
13.4
13.5
13.6

13.7

A Few Simplifying Assumptions
Protic versus Aprotic and Water
Nucleophilic Strength versus Base Strength
The Nature of the Halide
What about Secondary Halides?
Strength and Limitations of the Simplifying Assumptions
When Do the Assumptions Fail?


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Organic Chemistry: An Acid-Base Approach

Chapter 14: Spectroscopic Methods of Identification........................... 641
14.1
14.2
14.3
14.4
14.5
14.6
14.7

Light and Energy
Mass Spectrometry
Infrared Spectroscopy
Nuclear Magnetic Resonance Spectroscopy

The Structure of an Unknown Molecule May Be Determined
Carbon-13 NMR Spectroscopy: Counting the Carbons
Biological Relevance

Chapter 15: Organometallic Reagents...................................................... 741
15.1
15.2
15.3
15.4
15.5
15.6
15.7
15.8

Introducing Magnesium into a Molecule
Reaction of Aryl and Vinyl Halides with Magnesium
Grignard Reagents Are Bases
Grignard Reagents Are Poor Nucleophiles with Alkyl Halides
Organolithium Reagents
Organocuprates
Organometallic Disconnections
Biological Relevance

Chapter 16: Carbonyl Compounds: Structure,
Nomenclature, Reactivity....................................................................................769
16.1 The Carbonyl Group
16.2 Aldehydes and Ketones. Nomenclature
16.3 Chemical Reactivity of Ketones and Aldehydes
16.4 Carboxylic Acids. Nomenclature and Properties
16.5 Dicarboxylic Acids

16.6 Dicarboxylic Acids Have Two pKa Values
16.7 Carboxylic Acid Derivatives. Nomenclature and Properties
16.8 Acyl Substitution with Carboxylic Acid Derivatives
16.9 Sulfonic Acids
16.10 Biological Relevance

Chapter 17: Oxidation................................................................................... 811
17.1
17.2
17.3
17.4
17.5
17.6

Defining an Oxidation
Oxidation of Alcohols with Chromium(VI)
Oxidation of Alkenes
Oxidative Cleavage
Summary of Functional Group Exchanges
Biological Relevance

Chapter 18: Reactions of Aldehydes and Ketones.................................. 843
18.1
18.2
18.3
18.4
18.5
18.6
18.7
18.8

18.9

Chemical Reactivity of the Carbonyl Group
Reversible versus Irreversible Acyl Addition
Reaction of Aldehydes or Ketones with Strong Nucleophiles
Organometallic Reagents Are Nucleophiles
Water: A Weak Nucleophile That Gives Reversible Acyl Addition
Alcohols: Neutral Nucleophiles That Give Reactive Products
Amines Are Nucleophiles That React to Give Imines or Enamines
Carbon–Carbon Bond-Forming Reactions and Functional Group Modification
Biological Relevance


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ix

Contents

Chapter 19: Reduction................................................................................. 905
19.1
19.2
19.3
19.4
19.5
19.6

Defining a Reduction
Hydrides as Reducing Agents
Catalytic Hydrogenation

Dissolving Metal Reductions
Summary of Functional Group Exchanges
Biological Relevance

Chapter 20: Carboxylic Acid Derivatives and Acyl Substitution....... 943
20.1 Chemical Reactivity of Carboxylic Acid Derivatives
20.2 Acyl Substitution. Acid Derivatives React with Water: Hydrolysis
20.3 Preparation of Acid Chlorides
20.4 Preparation of Acid Anhydrides
20.5 Preparation of Esters
20.6 Amides
20.7 The Reaction of Carboxylic Acid Derivatives with Carbon Nucleophiles
20.8 Reaction of Organometallics with Other Electrophilic “Carbonyl” Molecules
20.9 Dicarboxylic Acid Derivatives
20.10 Baeyer–Villiger Oxidation
20.11 Sulfonic Acid Derivatives
20.12 Sulfate Esters and Phosphate Esters
20.13 Nitriles Are Carboxylic Acid Derivatives
20.14 Carbon–Carbon Bond-Forming Reactions and Functional
Group Exchanges of Acid Derivatives
20.15 Biological Relevance

Chapter 21: Aromatic Compounds and Benzene Derivatives............ 1027
21.1 Benzene and Aromaticity
21.2 Functionalized Benzene Derivatives and a New Nomenclature System
21.3 Electrophilic Aromatic Substitution
21.4 Disubstituted Benzene Derivatives
21.5 Polysubstituted Benzene Derivatives
21.6 Reduction of Aromatic Compounds
21.7 Aromaticity in Monocyclic Molecules Other Than Benzene

21.8 Polynuclear Aromatic Hydrocarbons
21.9 Aromatic Amines and Diazonium Salts
21.10 Nucleophilic Aromatic Substitution
21.11 Aromatic Disconnections and Functional Group Exchange Reactions
21.12 Synthesis of Aromatic Compounds
21.13 Biological Relevance

Chapter 22: Enolate Anions: Acyl Addition and Acyl Substitution...... 1119
22.1 Aldehydes and Ketones Are Weak Acids
22.2 Enolate Anions Are Nucleophiles. The Aldol Condensation
22.3 Non-Nucleophilic Bases
22.4 Enolate Anions from Unsymmetrical Ketones
22.5 Dehydration of Aldol Products
22.6 The Intramolecular Aldol Condensation
22.7 Ester Enolates
22.8 Decarboxylation
22.9 Enolate Alkylation
22.10 Phosphorus Ylids and the Wittig Reaction
22.11 Many New Synthetic Possibilities
22.12 Biological Relevance


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Organic Chemistry: An Acid-Base Approach

Chapter 23: Difunctional Molecules: Dienes and Conjugated
Carbonyl Compounds................................................................................. 1193

23.1
23.2
23.3
23.4
23.5
23.6
23.7

Conjugated Dienes
Conjugated Carbonyl Compounds
Detecting Conjugation: Ultraviolet Spectroscopy
Reactions of Conjugated π-Bonds
Polymers from Conjugated Molecules
Synthetic Possibilities
Biological Relevance

Chapter 24: Difunctional Molecules: Pericyclic Reactions................ 1241
24.1
24.2
24.3
24.4
24.5
24.6

Frontier Molecular Orbitals: HOMOs and LUMOs
Reactivity of Dienes and Alkenes
Selectivity
Sigmatropic Rearrangements
Review of Synthetic Transformations
Biological Relevance


Chapter 25: Disconnections and Synthesis........................................... 1271
25.1
25.2
25.3
25.4

What Is Synthesis?
Specifying a Starting Material for a Given Target
The Starting Material Is Unknown
Disconnection of Molecules with Problematic Structural Features

Chapter 26: Heteroaromatic Compounds.............................................. 1313
26.1
26.2
26.3
26.4
26.5
26.6
26.7
26.8

Nitrogen in an Aromatic Ring
Oxygen and Sulfur in an Aromatic Ring
Substitution Reactions in Heterocyclic Aromatic Compounds
Reduced Forms of Heterocycles
Heteroaromatic Compounds with More Than One Ring
Aromatic Substitution Reactions of Polycyclic Heterocycles
Synthesis of Heterocycles
Biological Relevance


Chapter 27: Multifunctional Compounds: Amino Acids and Peptides......1353
27.1
27.2
27.3
27.4
27.5
27.6

A Review of Reactions That Form Amines
Reactions of Amines
Difunctional Molecules: Amino Acids
Biological Relevance. Peptides Are Polyamides of Amino Acid Residues
Biological Relevance. Proteins and Enzymes Are Polypeptides
New Synthetic Methodology

Chapter 28: Multifunctional Compounds: Carbohydrates................. 1421
28.1
28.2
28.3
28.4
28.5

Polyhydroxy Carbonyl Compounds
Biological Relevance. Oligosaccharides and Polysaccharides
Reactions of Carbohydrates
Synthesis of Carbohydrates
Biological Relevance. Nucleosides and Nucleotides
(Heterocycles Combined with Sugars)
28.6 Biological Relevance. Polynucleotides

28.7 Synthesis of Polynucleotides

Index............................................................................................................... 1481


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Perhaps the most common fable about organic
chemistry is the one often heard in the first few
days of the course: Organic chemistry is a memorization course. Memorize what you need and
regurgitate it on the test and you will pass. This
assessment is wrong on so many levels that it
serves as a starting point to describe this book.
One reason for the fable is that it may be difficult to ascertain a fundamental theme that ties
organic chemistry together. The other issue is the
fact that organic chemistry builds from the first
day to the last and is not compartmentalized. For
this reason, a theme is even more important.
Is there a common, underlying theme for
organic chemistry that allows one to understand it
rather than simply memorize? In this book, acids
and bases provide the theme. It is important to
understand the relationships among functional
groups. How are they similar and what structural
motifs make them react differently? What is the
relationship between structure and chemical reactivity? These questions point to understanding
not only the chemical reactions that populate an
organic chemistry book, but also the mechanisms
used to describe those reactions.
The theme of this book is the premise that

many if not most reactions in organic chemistry
can be explained by variations of fundamental
acid–base chemistry concepts. Moreover, the individual steps in many important mechanisms rely
on acid–base reactions. The ability to see these
relationships makes understanding organic chemistry easier and, perhaps more importantly, allows
one to make predictions about reactivity when
memory fails.
Apart from the acid–base theme, this book
uses several techniques to assist students in their
studies. A list of concepts that the student should
know before reading the chapter is listed at the
beginning of virtually every chapter. A list of
concepts that should be known after the chapter
is completed is also provided at the beginning of
most chapters. Each chapter concludes with this
same list of the concepts that should now have
been learned, and a correlation of each concept
with the homework problems is provided. The
xi

Preface


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xii

Organic Chemistry: An Acid-Base Approach

intent is to help identify concepts that need work apart from those that are

readily understood.
Each chapter has a number of embedded problems. They will help the student
think about the concept and possibly review something from a previous chapter
that is pertinent, with the goal of better understanding that section. The answers
to these problems are provided at the end of each chapter. Regular homework
problems are given with the intention of offering help in understanding the concepts in the chapter. For additional material and a solutions manual, please see
the book Web site ( />Experimental details are provided for key reactions to introduce the reaction. The point is to show that the experiment shows a result and then we try to
understand that result in the context of the structural features of the reactive
species. Mechanisms are given as part of the discussion of key reactions. The
mechanism is discussed in most cases first as a walk-through of the reaction to
understand how the transformation occurred, and then structures for the walkthrough are provided that constitute the mechanism. Many of these mechanistic steps will involve acid–base reactions—both Brønsted–Lowry and Lewis.
The book begins with an introduction to organic chemistry that describes
what it is as well as individuals who have contributed to building organic
chemistry as a scientific discipline. Chapter 2 provides a bridge between the
acid–base discussions in a typical general chemistry book and those in this
organic chemistry book. An understanding of bonding is critical to understanding the structure of organic molecules; this is provided in Chapter 3, followed
by Chapter 4 with an introduction to alkanes, the basic structure of organic
molecules, and the fundamental rules of nomenclature. Chapter 5 introduces
the concept of functional groups as well as several important functional groups
that appear in organic molecules. This chapter includes an extension of the
basic nomenclature rules to include functional groups.
Chapter 6 returns to the acid–base theme to give a direct correlation
between acid–base reactions and organic chemical reactions that involve the
functional groups just introduced in Chapter 5. Chapter 7 extends the acid–
base concept of equilibrium reactions to discuss bond energetics and kinetics.
Rotation about single covalent bonds leads to different orientations of atoms
and groups within a molecule, known as conformations; this is presented in
Chapter 8. Chapter 9 introduces the concept of chirality and the relationship
between chirality and structure.
Chapter 10 introduces the acid–base chemistry of molecules that contain the

C=C and C≡C functional groups. Related reactions that do not fall under the
acid–base category are also presented. Chapter 11 uses nucleophiles, which are
loosely categorized as specialized Lewis bases, in reactions with alkyl halides.
These are substitution reactions. Chapter 12 shows the acid–base reaction of
alkyl halides that leads to alkenes (an elimination reaction), and Chapter 13
ties Chapters 11 and 12 together with a series of simplifying assumptions that
allows one to make predictions concerning the major product.
Chapter 14 introduces methods used to identify the structure of organic
molecules: mass spectrometry, infrared spectroscopy, and nuclear magnetic


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Preface

xiii

resonance spectroscopy. This chapter is in the middle of the book, but it may
be presented in either semester, and homework problems associated with this
chapter are incorporated throughout. All homework problems requiring the
information in Chapter 14 are clearly marked and segregated from the other
problems. Therefore, this chapter may be introduced in either semester and the
associated homework problems can be easily found.
Chapter 15 provides a brief introduction to commonly used organic molecules
that also have a carbon–metal bond—organometallics. Chapter 16 introduces
the fundamental characteristics of molecules that contain the carbon functional
group, along with a review of the nomenclature of carbonyl-containing molecules.
Carbonyl compounds are often prepared by oxidation reactions, and several key
oxidation reactions are discussed in Chapter 17. Oxidation reactions of a few
other functional groups are included. Chapter 18 elaborates the chemical reactions of the carbonyl-containing molecules known as aldehydes and ketones. This

chemistry is dominated by the acyl addition reaction introduced in Chapter 16.
Chapter 19 in effect continues the chemistry of carbonyls by introducing
reduction reactions. Carbonyl-containing molecules, as well as molecules that
contain other functional groups, may be reduced to different functional groups,
and such reactions are discussed in this chapter. Chapter 20 continues carbonyl chemistry by discussing chemical reactions of the carboxylic acid derivatives introduced in Chapter 16, with a focus on acyl substitution reactions.
Chapter 21 discusses the concept of aromaticity as well as the nomenclature
and the specialized chemical reactions of aromatic compounds such as benzene
and its derivatives. This chapter comes late in the book, with the notion that
the chemistry of aliphatic compounds is simply used more often. The acid–
base theme is continued with the recognition that the fundamental substitution chemistry associated with benzene derivatives may be explained by the
reaction of aromatic rings as Lewis bases or nucleophiles with electrophilic
reagents. The reactions of benzene derivatives with strong bases and good
nucleophiles are also presented.
Chapter 22 returns to carbonyl chemistry and a discussion of the acid–
base properties of carbonyl compounds. The proton on the α-carbon (directly
attached to the carbonyl) is slightly acidic and removal with a suitable base
leads to an enolate anion. Enolate anions react as nucleophiles in aliphatic
substitution, acyl addition, and acyl substitution reactions.
Chapter 23 begins a discussion of multifunctional molecules that will
conclude the book and, in many courses, may be considered as special topic
material, beginning with simple conjugated dienes and conjugated carbonyl
compounds. Ultraviolet spectroscopy is discussed in the context of identifying
conjugated compounds. Chapter 24 continues this discussion with pericyclic
reactions that involve dienes and other multifunctional compounds. Chapter 25
is a stand-alone chapter to introduce the retrosynthetic approach to synthesis. It is presented as part of the discussion on multifunctional molecules, but
it may be taught at any point in the course. As with spectroscopy, synthesis
problems are clearly marked homework problems in several chapters and are
segregated from the other problems so that they are easily found.



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Organic Chemistry: An Acid-Base Approach

The book concludes with three chapters that involve multifunctional molecules. Heterocycles are introduced in Chapter 26, with nomenclature and structure as well some elementary chemical reactions of heterocyclic compounds.
Amino acids and peptides are discussed in Chapter 27 and carbohydrates and
nucleic acids are discussed in Chapter 28. These last three chapters are, arguably, the most important to biological chemistry.
This book constitutes an important introduction to organic chemistry. The
reactions and mechanisms contained herein describe its most fundamental
concepts, which are used in industry, biological chemistry and biochemistry, molecular biology, and pharmacy. These concepts constitute the fundamental basis of life processes, which means that they are pertinent to the
study of medicine. For that reason, most chapters end with a brief section
that describes biological applications for each concept. The last two chapters
(27 and 28) have more than one section that discusses biological applications
because these molecules make up the proteins, enzymes, cellular structure,
and DNA and RNA found in living systems. It is hoped that this course will
provide the skills to go to the next level of study using this fundamental
understanding of acids and bases applied to organic transformations and
organic molecules.


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There are many people to thank for a book such
as this one. First, let me thank my students,
whose enthusiasm and interest have pushed me
to develop better ways to communicate and better
ways to describe organic chemistry. I thank my
colleagues in the organic chemistry community,

particularly the synthetic organic community,
for allowing me to keep my knowledge and skills
honed over the years.
In addition, myriad discussions with my
colleagues have helped me to become a better
organic chemist and be better able to communicate that knowledge. I particularly want to
thank Spencer Knapp (Rutgers University) and
John D’Angelo (Alfred University) for providing
most helpful reviews of this manuscript. I thank
George Majetich (University of Georgia), Fred
Luzzio (University of Louisville), and Tyson Miller
(University of Connecticut) for discussions over the
years that helped me to crystallize certain aspects
of this book, particularly the acid–base theme and
how to present it.
All structures and reactions were drawn
using ChemBioDraw Ultra, v. 11.0.1 I thank
CambridgeSoft, Inc. for a gift of this software.
All 3-D drawings and molecular models were prepared using Spartan06 software, v.1.0.1. I thank
Warren Hehre, Sean Ohlinger, and Wavefunction,
Inc. for the gift of this software.
I thank my editor, Lance Wobus of Taylor &
Francis, for giving me the opportunity to write
this book and working with me over these many
months. His support, vision, and ability to solve
the inevitable issues that arise in such a project have been essential for getting this book into
print. I also thank Dr. Fiona Macdonald for her
support in getting this book off the ground and
David Fausel and Judith Simon for their excellent work in converting the manuscript to the
finished book. I also want to thank Jim Smith,

who was instrumental to this project in its early
days. I thank Warren Hehre (Wavefunction, Inc.),

xv

Acknowledgments


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xvi

Organic Chemistry: An Acid-Base Approach

who introduced me to Lance Wobus and who has provided many discussions
over the years that helped me in writing the book.
Finally, I thank my wife, Sarah, and my son, Steven, for their support and
encouragement over the years. That support has helped more than can be
properly expressed in words.


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Michael B. Smith is professor of chemistry in
the Department of Chemistry at the University
of Connecticut at Storrs. His research interests
focus on the identification of bioactive lipids from
the dental pathogen Porphyromonas gingivalis,
exploration of the use of conducting polymers as
a reaction medium for chemical transformations,

development of fluorescent probes for the detection
of cancerous tumors, and the synthesis of phenanthridone alkaloids. He is the author of volumes
6–12 of the Compendium of Organic Synthetic
Methods and author of the fifth and sixth editions
and upcoming seventh edition of March’s Advanced
Organic Chemistry. He is also the author of the first
and second editions and upcoming third edition of
the graduate level textbook Organic Synthesis, as
well as several monographs.
Dr. Smith received his PhD in organic chemistry from Purdue University in 1977, a BS in
chemistry from Virginia Polytechnic Institute in
1969, and an AA from Ferrum College in 1967.
Postdoctoral work at the Cancer Research Institute
at Arizona State University and at Massachusetts
Institute of Technology preceded his appointment
at the University of Connecticut.

xvii

The
Author


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1

Introduction
Congratulations, you are taking organic chemistry! It is likely that you are a science major, in a
class of students with a wide range of interests
and career choices. Why is organic chemistry
important? The answer lies in the fact that every
aspect of life—mammalian and nonmammalian as
well as plant and microscopic life—involves organic
chemistry. In addition, many of the products used
every day (pharmaceuticals, plastics, clothing,
etc.) involve organic molecules. Organic chemistry
holds a central place in chemical studies because
its fundamental principles and its applications
touch virtually all other disciplines. Several years
ago, a T-shirt at an American Chemical Society
meeting in Dallas sported the logo “Chemistry:
The Science of Everything.” Organic chemistry is
certainly an important player in that science.
Most organic chemistry textbooks have a brief
section to describe how organic chemistry developed as a science. I was a graduate student when
I first read an organic chemistry book that presented some historical facts as part of the normal
presentation of facts. The book was Louis Fieser’s
(United States; 1899–1977) Advanced Organic
Chemistry.1 This book gave a perspective to my
studies and helped me to understand many of the
concepts better. I believe that putting a subject
into its proper context makes it easier to understand, so I am introducing an abbreviated history
of organic chemistry as the beginning to this book.
I will include material from Fieser’s book and

also from a book on the history of chemistry by
Leicester.2 It is important to remember the great
organic chemists of the past, not only because their
work is used today but also because it influences
the way that we understand chemistry.

1


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Organic Chemistry: An Acid–Base Approach

1.1  A Brief History of Organic Chemistry
Humans have used practical applications of chemistry for thousands of years.
The discovery and use of folk medicines, the development of metallurgical techniques, and the use of natural dyes are simple examples. For most of history,
humans were able to use simple chemicals or a complex mixture of chemicals
without actually understanding the science behind them. Organic chemistry
became a defined science (the chemistry of carbon compounds) in the nineteenth century, but organic compounds have been known and used for millennia. Plants have been “milked,” cut, boiled, and eaten for thousands of years
as folk medicine remedies, particularly in Africa, China, India, and South
America. Modern science has determined that many of these plants contain
organic chemicals with effective medical uses, and indeed many of our modern medicines are simply purified components of these plants or derivatives of
them made by chemists.
OCH3

CH3

CH3

H
N

H
N
OH
1

CH3

OH

H
CH3
CH3
2

The bark of the Cinchona tree has been chewed for years to treat symptoms of malaria, and it was later discovered that this bark contains quinine
(1), which is a modern medicine. Ancient Egyptians ate roasted ox liver in the
belief that it improved night vision. Later it was discovered that ox liver is rich
in vitamin A (2), a chemical important for maintaining healthy eyesight. An
ancient antipyretic treatment (this means that it lowers a fever) involved chewing willow bark, and it was later discovered that this bark contained the glycoside salicin (3), a derivative of salicylic acid (4a). Eventually, chemists learned
how to make new organic molecules rather than simply isolating and using
those that were found in nature, although isolation from nature remains an
important source of new compounds.
In the mid-nineteenth century a new compound was synthesized (chemically prepared from other chemicals) called acetylsalicylic acid (4b; better
known as aspirin), and it was found to be well tolerated by patients as an
effective analgesic (this means that it reduces some types of pain). These few
examples are meant to represent the thousands of folk medicine remedies
that have led to important medical discoveries. All of these involve organic

compounds.


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3

Introduction
HO
O

OH
O

HO

OH

OH
RO

HO
H

O

O
4a R = H

3


4b R =

CH3

Plants have provided humans with many organic chemicals or mixtures of
chemicals that are useful for purposes other than medicine. Ethyl alcohol (5) has
been produced by fermentation of grains and fruits and consumed for thousands
of years in various forms, including a beer consumed by ancient Egyptians. The
symbols (1–5) used to represent the chemicals require some explanation, and
ethyl alcohol is a simple example. Each “line” is a chemical bond. Therefore, C–C
is a carbon–carbon bond and “–” is used as a shorthand notation to represent
that bond. The symbol C–N is a carbon–nitrogen bond, C–O is a carbon–oxygen
bond, and O–H is an oxygen–hydrogen bond. In 5, –OH represents –O–H. Each
intersection of bonds, such as [ ], is a carbon atom. Various groups may be
attached to these carbon atoms (OH, NH2, CH3, etc.). This notation, called line
notation, is used to draw most of the chemical structures in this book.
⦧

H

H

H

C

C

H


H

OH
O

H

5

Line notation uses one line for each bond, so C=C indicates two bonds
between the carbon atoms (a carbon–carbon double bond), and C=O indicates
two bonds between carbon and oxygen (a carbon–oxygen double bond). Similarly,
C≡C represents three bonds between the two carbon atoms, a carbon–carbon
triple bond. Many molecules have double and triple bonds. Examples are compounds 1–4, as well as compounds 6 and 7.
Line notation is used for simple compounds such as 5; however, as shown in
structures 1–3, it is applicable to very complicated structures. In ancient India,
in Java, and in Guatemala certain plants provided a deep blue substance used to
color clothing. In recent times, the main constituent was found to be indigo (6).
The ancient Phoenicians used an extract from a snail (Murex brandaris) found
off the coast of Tyre (a city in modern-day Lebanon) to color cloth. It was a beautiful and very expensive dye called Tyrian purple. This dye was so prized that
Roman emperors used it to color their clothing, and for many years no one else
was permitted to wear this color (hence the term “born to the purple”). The actual
structure of the organic chemical Tyrian purple is 7. Note that the only difference
between indigo and Tyrian purple is the presence of two bromine atoms in the latter. Structural differences that on the surface appear to be minor can lead to significant changes in the physical properties of organic compounds, such as color.


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4


Organic Chemistry: An Acid–Base Approach

Organic chemicals have also been used in an unethical manner. The plant
Atropa belladonna (deadly nightshade) has been used for centuries as a poison.
The plant extract is a deadly, but the “poison” isolated, found to be atropine (8)
is not produced by the plant, but produced from a natural alkaloid by the acidbase extraction procedure used for isolation.
O

H

O

H

Br

N

N

N

N
H

Br
H

O

6

O
7

These few examples show that organic chemicals are important to humans
and have been for a very long time. For most of this time, however, the actual
chemical structure of these compounds was unknown. Indeed, the fact that the
chemicals were discrete molecules was unknown. It was known that a multitude of materials could be obtained from natural sources, primarily from living
organisms. This knowledge sparked a curiosity that eventually led to modern
organic chemistry as a science. In the following paragraphs, a few of the chemists who advanced organic chemistry as a science are introduced.
••
N

O

CH3

OH
HOOC

COOH

H

H
COOH

HOOC
OH


COOH

OH
8

O

9
O

10

O

H
N

N

O
N

N
H

H
11

OH


As pointed out earlier, natural materials have been used for many years.
It was not until the eighteenth century that people began to look for specific
chemicals in these natural materials. One of the first to report discrete chemicals was Carl Wilhelm Scheele (Sweden; 1742–1786), who isolated acidic components from grapes and lemons by forming precipitates with calcium or lead
salts, and then added mineral acids to obtain the actual compounds. The compound from grapes is now known to be tartaric acid (9) and that from lemon is
now known to be citric acid (10). Scheele also isolated uric acid (11) from urine.
Friedrich W. Sertürner (Germany; 1783–1841) isolated a compound from
opium extracts in 1805 that is now known to be morphine (12). In 1815, Michel
E. Chevreul (France; 1786–1889) isolated a material from skeletal muscle now
known to be creatine (13), which has been used as a dietary supplement despite
the observation that it can cause kidney damage and muscle cramping. He also
elucidated the structure of simple soaps, which are metal salts of fatty acids (14)
and gave the name butyric acid (15) to the carboxylic acid found in rancid butter.
In 1818–1820, Pierre J. Pelletier (France; 1788–1842) and Joseph
Caventou (France; 1795–1877) isolated a poisonous compound from Saint


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5

Introduction

Ignatius’ beans (S. ignatii) that they called an alkaloid (an alkali-like base)
now known to be strychnine (16; found in the seeds of the nux vomica tree
[S. nux-vomica] and also from related plants of the genus Strychnost). Alkaloids
are a large group of diverse compounds that contain nitrogen and are primarily
found in plants. Although difficult to define because of their structural diversity, alkaloids are commonly assumed to be basic nitrogenous compounds of
plant origin that are physiologically active. The practice of isolating specific
compounds (now known to be organic compounds) from natural sources continues today. Such compounds are called “natural products.”

O

HO

H-N

H 3C

O
H
HO

H

H

N

NH2
N

H3C(H2C)16

N
O–Na+

14

H


H
O

O

OH

O

CH3

12

H

N
OH

13

O

15

H

H

16


Clearly, an early task in organic chemistry was to isolate pure compounds from
natural sources and then attempt to identify them. Initially, the compounds were
purified (usually by crystallization) and characterized as to their physical properties (melting point, boiling point, solubility in water, etc.). It was not until much
later (mid- to late nineteenth century and even into the early twentieth century)
that the structures of most of these compounds were known absolutely. Justus
Liebig (Germany; 1803–1873) perfected the science of analysis of organic compounds, based on the early work of Antoine Lavoisier (France; 1743–1794).
Late in the eighteenth century, Lavoisier made a monumental contribution
to the science of chemistry that was important to understanding organic chemistry. He used the discovery that air was composed mainly of oxygen (O2) and
nitrogen (N2) and burned natural materials in air. He discovered that carbon in
the burned material was converted to carbon dioxide (CO2) and that hydrogen
in the material was converted to water (HOH). By trapping and weighing the
carbon dioxide and the water, he was able to calculate the percentage of carbon and hydrogen in molecules, which led to a determination of the empirical
formula. Because we now know that organic molecules are composed mainly
of carbon and hydrogen, this elemental analysis procedure was and is an
invaluable tool for determining the structure of organic molecules.
H
H

N+
H

H –O
17

C

N

O


HEAT
NH2

18

NH2

In 1807, a Swedish chemist named Jöns J. von Berzelius (Sweden; 1779–
1848) described the substances obtained from living organisms as organic
compounds, and he proposed that they were composed of only a few selected


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6

Organic Chemistry: An Acid–Base Approach

elements, including carbon and hydrogen. Because all organic compounds
known at that time had been isolated as products of “life processes” from living organisms (hence the term organic), Berzelius and Charles F. Gerhardt
(France; 1816–1856) described what was known as the vital force theory. This
theory subscribed to the notion that “all organic compounds can arise with
the operation of vital force inherent to living cells.” The vital force theory was
widely believed at the time.
In 1828 Friedrich Wöhler (Germany; 1800–1882) synthesized (prepared
from other chemicals) the organic molecule urea (18) from chemicals that had
not been obtained from living sources. When he heated ammonium cyanate
(17), the product was urea (18). Urea is a component of urine and also a component of bird droppings that have been used for centuries as fertilizer. This
work, along with that of others, was contrary to the vital force theory because
it showed that an organic compound could be produced from a “nonliving” system. However, it was not until Pierre-Eugene-Marcellin Berthelot (France;

1827–1907) showed that all classes of organic compounds could be synthesized
that the vital force theory finally disappeared.
Synthesis of organic molecules (preparation of a more complex organic compound from more structurally simple compounds in several chemical steps) began
in the mid-nineteenth century, and many compounds were prepared. Hermann
Kolbe (Germany; 1818–1884) prepared ethane (CH3CH3) by electrolysis of potassium acetate (CH3CO2 –K+) and Sir Edward Frankland (England; 1825–1899)
prepared butane (CH3CH2CH2CH3) from iodoethane (CH3CH2I) and zinc (Zn).
Charles A. Wurtz (France; 1817–1884) discovered amines in 1849, and August
W. von Hofmann (Germany/England; 1818–1892) prepared many amines as
well as ammonium salts by an acid–base reaction of the amine with a mineral
acid. Amines are compounds containing nitrogen. Conceptually, they are carbon
derivatives of ammonia. This means that a thought experiment can replace a
hydrogen atom in NH3 with a carbon group to give C–NH2, which is an amine.
At about the same time, Alexander W. Williamson (England; 1824–1904)
showed how ethers (ethers contain the C–O–C linkage) could be prepared from
the potassium salt of an alcohol (an alcohol contains a C–O–H unit). The potassium salt is the conjugate base of that alcohol, C–O –K+, and the oxygen atom
of that species reacts with an alkyl halide, which contains a C–X bond. In this
representation, X is a halogen and alkyl is the term used for a unit containing
carbons and hydrogen atoms. The nomenclature for all of these compounds will
be described in Chapters 3 and 4.
CH3

NH2

N

N

19

N


H

O

OH

+

CH3

OH

O
20

21