Advanced Organic Chemistry-Part A: Structure and Mechanisms

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Advanced Organic Chemistry

PART A: Structure and Mechanisms

PART B: Reactions and Synthesis

Author:

FRANCIS A. CAREY

and RICHARD J. SUNDBERG

University of Virginia

Charlottesville, Virginia

Advanced Organic Chemistry-Part A: Structure and Mechanisms

This Fifth Edition marks the beginning of the fourth decade that Advanced Organic

Chemistry has been available. As with the previous editions, the goal of this text is to

allow students to build on the foundation of introductory organic chemistry and attain

a level of knowledge and understanding that will permit them to comprehend much

of the material that appears in the contemporary chemical literature. There have been

major developments in organic chemistry in recent years, and these have had a major

influence in shaping this new edition to make it more useful to students, instructors,

and other readers

The expanding application of computational chemistry is reflected by amplified

discussion of this area, especially density function theory (DFT) calculations in

Chapter 1. Examples of computational studies are included in subsequent chapters

that deal with specific structures, reactions and properties. 

Chapter 2 discusses the

principles of both configuration and conformation, which were previously treated in

two separate chapters. The current emphasis on enantioselectivity, including development

of many enantioselective catalysts, prompted the expansion of the section on

stereoselective reactions to include examples of enantioselective reactions. Chapter 3,

which covers the application of thermodynamics and kinetics to organic chemistry,

has been reorganized to place emphasis on structural effects on stability and reactivity.

This chapter lays the groundwork for later chapters by considering stability effects on

carbocations, carbanions, radicals, and carbonyl compounds.

Chapters 4 to 7 review the basic substitution, addition, and elimination mechanisms,

as well as the fundamental chemistry of carbonyl compounds, including enols

and enolates. A section on of the control of regiochemistry and stereo- chemistry of

aldol reactions has been added to introduce the basic concepts of this important area. A

more complete treatment, with emphasis on synthetic applications, is given in Chapter

2 of Part B.

Chapter 8 deals with aromaticity and Chapter 9 with aromatic substitution, emphasizing

electrophilic aromatic substitution. Chapter 10 deals with concerted pericyclic

reactions, with the aromaticity of transition structures as a major theme. This part of

the text should help students solidify their appreciation of aromatic stabilization as a

fundamental concept in the chemistry of conjugated systems. Chapter 10 also considersthe important area of stereoselectivity of concerted pericyclic reactions. Instructors

may want to consider dealing with these three chapters directly after Chapter 3, and

we believe that is feasible

Chapters 11 and 12 deal, respectively, with free radicals and with photochemistry

and, accordingly, with the chemistry of molecules with unpaired electrons. The latter

chapter has been substantially updated to reflect the new level of understanding that

has come from ultrafast spectroscopy and computational studies.

As in the previous editions, a significant amount of specific information is

provided in tables and schemes. These data and examples serve to illustrate the issues

that have been addressed in the text. Instructors who want to achieve a broad coverage,

but without the level of detail found in the tables and schemes, may choose to advise

students to focus on the main text. In most cases, the essential points are clear from

the information and examples given in the text itself.

We have made an effort to reduce the duplication between Parts A and B. In

general, the discussion of basic mechanisms in Part B has been reduced by crossreferencing

the corresponding discussion in Part A. We have expanded the discussion

of specific reactions in Part A, especially in the area of enantioselectivity and enantioselective

catalysts.

We have made more extensive use of abbreviations than in the earlier editions.

In particular, EWG and ERG are used throughout both Parts A and B to designate

electron-withdrawing and electron-releasing substituents, respectively. The intent is

that the use of these terms will help students generalize the effect of certain substituents

such as C=O, C≡N, NO2, and RSO2 as electron withdrawing and R (alkyl) and RO

(alkoxy) as electron releasing. Correct use of this shorthand depends on a solid understanding

of the interplay between polar and resonance effects in overall substituent

effects. This matter is discussed in detail in Chapter 3 and many common functional

groups are classified.

Several areas have been treated as “Topics”. Some of the Topics discuss areas that

are still in a formative stage, such as the efforts to develop DFT parameters as quantitative

reactivity indices. Others, such as the role of carbocations in gasoline production, have

practical implications

We have also abstracted information from several published computational studies

to present three-dimensional images of reactants, intermediates, transition structures,

and products. This material, including exercises, is available at the publishers web site,

and students who want to see how the output of computations can be applied may want

to study it. The visual images may help toward an appreciation of some of the subtle

effects observed in enantioselective and other stereoselective reactions. As in previous

editions, each chapter has a number of problems drawn from the literature. A new

feature is solutions to these problems, which are also provided at the publisher’s

website at springer.com/carey-sundberg

Our goal is to present a broad and fairly detailed view of the core area of organic

reactivity. We have approached this goal by extensive use of both the primary and

review literature and the sources are referenced. Our hope is that the reader who

works through these chapters, problems, topics, and computational studies either in an

organized course or by self-study will be able to critically evaluate and use the current

literature in organic chemistry in the range of fields in which is applied, including

the pharmaceutical industry, agricultural chemicals, consumer products, petroleum

chemistry, and biotechnology. The companion volume, Part B, deals extensively with

organic synthesis and provides many more examples of specific reactions.

Introduction about Advanced Organic Chemistry-Part A: Structure and Mechanisms

This volume is intended for students who have completed the equivalent of a

two-semester introductory course in organic chemistry and wish to expand their understanding

of structure and reaction mechanisms in organic chemistry. The text assumes

basic knowledge of physical and inorganic chemistry at the advanced undergraduate

level.

Chapter 1 begins by reviewing the familiar Lewis approach to structure and

bonding. Lewis’s concept of electron pair bonds, as extended by adding the ideas of

hybridization and resonance, plus fundamental atomic properties such as electronegativity

and polarizability provide a solid foundation for qualitative descriptions of

trends in reactivity. In polar reactions, for example, the molecular properties of acidity,

basicity, nucleophilicity, and electrophilicity can all be related to information embodied

in Lewis structures. The chapter continues with the more quantitative descriptions of

molecular structure and properties that are obtained by quantum mechanical calculations.

Hückel, semiempirical, and ab initio molecular orbital (MO) calculations, as well

as density functional theory (DFT) are described and illustrated with examples. This

material is presented at a level sufficient for students to recognize the various methods

and their ranges of application. Computational methods can often provide insight

into reaction mechanisms by describing the structural features of intermediates and

transition structures. Another powerful aspect of computational methods is their ability

to represent electron density. Various methods of describing electron density, including

graphical representations, are outlined in this chapter and applied throughout the

remainder of the text. Chapter 2 explores the two structural levels of stereochemistry—

configuration and conformation. Molecular conformation is important in its own right,

but can also influence reactivity. The structural relationships between stereoisomers and

the origin and consequences of molecular chirality are discussed. After reviewing the

classical approach to resolving racemic mixtures, modern methods for chromatographic

separation and kinetic resolution are described. The chapter also explores how stereochemistry

affects reactivity with examples of diastereoselective and enantioselective

reactions, especially those involving addition to carbonyl groups. Much of today’s work

in organic chemistry focuses on enantioselective reagents and catalysts. The enantioselectivity

of these reagents usually involves rather small and sometimes subtle differences

in intermolecular interactions. Several of the best-understood enantioselective

reactions, including hydrogenation, epoxidation of allylic alcohols, and dihydroxylation

of alkenes are discussed. Chapter 3 provides examples of structure-stability relationships

derived from both experimental thermodynamics and computation. Most of the

chapter is about the effects of substituents on reaction rates and equilibria, how they are

measured, and what they tell us about reaction mechanisms. The electronic character of

the common functional groups is explored, as well as substituent effects on the stability

of carbocations, carbanions, radicals, and carbonyl addition intermediates. Other topics

in this chapter include the Hammett equation and related linear free-energy relationships,

catalysis, and solvent effects. Understanding how thermodynamic and kinetic

factors combine to influence reactivity and developing a sense of structural effects on

the energy of reactants, intermediates and transition structures render the outcome of

organic reactions more predictable.

Chapters 4 to 7 relate the patterns of addition, elimination, and substitution

reactions to the general principles developed in Chapters 1 to 3. A relatively small

number of reaction types account for a wide range of both simple and complex

reactions. The fundamental properties of carbocations, carbanions, and carbonyl

compounds determine the outcome of these reactions. Considerable information about

reactivity trends and stereoselectivity is presented, some of it in tables and schemes.

Although this material may seem overwhelming if viewed as individual pieces of information,

taken in the context of the general principles it fills in details and provides a

basis for recognizing the relative magnitude of various structural changes on reactivity.

The student should strive to develop a sufficiently broad perspective to generate an

intuitive sense of the effect of particular changes in structure

Chapter 4 begins the discussion of specific reaction types with an examination of

nucleophilic substitution. Key structural, kinetic, and stereochemical features of substitution

reactions are described and related to reaction mechanisms. The limiting mechanisms

SN 1 and SN 2 are presented, as are the “merged” and “borderline” variants. The

relationship between stereochemistry and mechanism is explored and specific examples

are given. Inversion is a virtually universal characteristic of the SN 2 mechanism,

whereas stereochemistry becomes much more dependent on the specific circumstances

for borderline and SN 1 mechanisms. The properties of carbocations, their role in

nucleophilic substitution, carbocation rearrangements, and the existence and relative

stability of bridged (nonclassical) carbocations are considered. The importance of

carbocations in many substitution reactions requires knowledge of their structure and

reactivity and the effect of substituents on stability. A fundamental characteristic of

carbocations is the tendency to rearrange to more stable structures. We consider the

mechanism of carbocation rearrangements, including the role of bridged ions. The case

of nonclassical carbocations, in which the bridged structure is the most stable form, is

also discussed.

Chapter 5 considers the relationship between mechanism and regio- and stereoselectivity.

The reactivity patterns of electrophiles such as protic acids, halogens,

sulfur and selenium electrophiles, mercuric ion, and borane and its derivatives are

explored and compared. These reactions differ in the extent to which they proceed

through discrete carbocations or bridged intermediates and this distinction can explain

variations in regio- and stereochemistry. This chapter also describes the E1, E2, and

E1cb mechanisms for elimination and the idea that these represent specific cases

within a continuum of mechanisms. The concept of the variable mechanism can

explain trends in reactivity and regiochemistry in elimination reactions.

Chapter 6

focuses on the fundamental properties and reactivity of carbon nucleophiles, including organometallic reagents, enolates, enols, and enamines. The mechanism of the aldol

addition is discussed. The acidity of hydrocarbons and functionalized molecules is

considered. Chapter 7 discusses the fundamental reactions of carbonyl groups. The

reactions considered include hydration, acetal formation, condensation with nitrogen

nucleophiles, and the range of substitution reactions that interconvert carboxylic acid

derivatives. The relative stability and reactivity of the carboxylic acid derivatives is

summarized and illustrated. The relationships described in Chapters 6 and 7 provide the

broad reactivity pattern of carbonyl compounds, which has been extensively developed

and is the basis of a rich synthetic methodology

Chapter 8 discusses the concept of aromaticity and explores the range of its applicability,

including annulenes, cyclic cations and anions, polycyclic hydrocarbons, and

heterocyclic aromatic compounds. The criteria of aromaticity and some of the methods

for its evaluation are illustrated. We also consider the antiaromaticity of cyclobutadiene

and related molecules. Chapter 9 explores the mechanisms of aromatic substitution

with an emphasis on electrophilic aromatic substitution. The general mechanism is

reviewed and the details of some of the more common reactions such as nitration,

halogenation, Friedel-Crafts alkylation, and acylation are explored. Patterns of position

and reactant selectivity are examined. Recent experimental and computational studies

that elucidate the role of aromatic radical cations generated by electron transfer in

electrophilic aromatic substitution are included, and the mechanisms for nucleophilic

aromatic substitution are summarized. Chapter 10 deals with concerted pericyclic

reactions, including cycloaddition, electrocyclic reactions, and sigmatropic rearrangements.

This chapter looks at how orbital symmetry influences reactivity and introduces

the idea of aromaticity in transition structures. These reactions provide interesting

examples of how stereochemistry and reactivity are determined by the structure of the

transition state. The role of Lewis acids in accelerating Diels-Alder reactions and the

use of chiral auxiliaries and catalysts to achieve enantioselectivity are explored.

Chapter 11 deals with free radicals and their reactions. Fundamental structural

concepts such as substituent effects on bond dissociation enthalpies (BDE) and radical

stability are key to understanding the mechanisms of radical reactions. The patterns of

stability and reactivity are illustrated by discussion of some of the absolute rate data

that are available for free radical reactions. The reaction types that are discussed include

halogenation and oxygenation, as well as addition reactions of hydrogen halides, carbon

radicals, and thiols. Group transfer reactions, rearrangements, and fragmentations are

also discussed.

Chapter 12 ventures into the realm of photochemistry, where structural concepts

are applied to following the path from initial excitation to the final reaction product.

Although this discussion involves comparison with some familiar intermediates,

especially radicals, and offers mechanisms to account for the reactions, photochemistry

introduces some new concepts of reaction dynamics. The excited states in photochemical

reactions traverse energy surfaces that have small barriers relative to most

thermal reactions. Because several excited states can be involved, the mechanism

of conversion between excited states is an important topic. The nature of conical

intersections, the transition points between excited state energy surfaces is examined.

Fundamental concepts of structure and its relationship to reactivity within the

context of organic chemistry are introduced in the first three chapters, and thereafter

the student should try to relate the structure and reactivity of the intermediates and

transition structures to these concepts. Critical consideration of bonding, stereochemistry,

and substituent effects should come into play in examining each of the basic

reactions. Computational studies frequently serve to focus on particular aspects of

the reaction mechanism. Many specific reactions are cited, both in the text and in

schemes and tables. The purpose of this specific information is to illustrate the broad

patterns of reactivity. As students study this material, the goal should be to look for the

underlying relationships in the broad reactivity patterns. Organic reactions occur by

a combination of a relatively few reaction types—substitution, addition, elimination,

and rearrangement. Reagents can generally be classified as electrophilic, nucleophilic,

or radical in character. By focusing on the fundamental character of reactants and

reagents, students can develop a familiarity with organic reactivity and organize the

vast amount of specific information on reactions.

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