Chemistry and creativity: 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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