Organic synthesis

ORGANIC
SYNTHESIS
THIRD EDITION

MICHAEL B. SMITH
UNIVERSITY OF CONNECTICUT


ORGANIC SYNTHESIS, Third EDITION
Published by Academic Press, An Imprint of Elsevier Inc. All rights reserved. No part of this publication may
be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without
the prior written consent of Michael B. Smith or Warren Hehre, including, but not limited to, in any network
or other electronic storage or transmission, or broadcast for distance learning.
Some ancillaries, including electronic and print components, may not be available to
customers outside the United States.
This book is printed on acid-free paper.
1 2 3 4 5 6 7 8 9 0 KGP/KGP 0 9 8 7 6 5 4 3 2 1
ISBN-13: 978-1-890661-40-3
ISBN-10: 1-890661-40-6
Lead production supervisor: Pamela Ohsan
Cover designer: Pamela Ohsan
Printer: R R Donnelley
Cover image: The photo on the front cover shows the Atomium in Brussels, Belgium. The photo was taken by
Michael Smith.
Library of Congress Cataloging-in-Publication Data
Smith, Michael B., 1946 Oct. 17
Organic synthesis / Michael B. Smith. — 3rd ed.
p.
cm.
Includes bibliographical references and index.
ISBN 978-1-890661-40-3 (acid-free paper)

1. Organic compounds—Synthesis. I. Title.


About the Author
PROFESSOR MICHAEL B. SMITH was born in Detroit, Michigan in 1946 and moved to Madison Heights,

Virginia in 1957, where he attended high school. He received an A.A. from Ferrum College
in 1967 and a B.S. in chemistry from Virginia Polytechnic Institute in 1969. After working
for three years at the Newport News Shipbuilding and Dry Dock Co. in Newport News VA as
an analytical chemist, he entered graduate school at Purdue University. He received a Ph.D.
in Organic chemistry in 1977, under the auspices of Professor Joe Wolinsky. Professor Smith
spent one year as a faculty research associate at the Arizona State University with Professor
G. Robert Pettit, working on the isolation of cytotoxic principles from plants and sponges. He
spent a second year of postdoctoral work with Professor Sidney M. Hecht at the Massachusetts
Institute of Technology, working on the synthesis of bleomycin A2. Professor Smith moved to
the University of Connecticut in 1979, where he is currently professor of chemistry. In 1986
he spent a sabbatical leave in the laboratories of Professor Leon Ghosez, at the Université
Catholique de Louvain in Louvain-la-Neuve, Belgium, as a visiting professor.
Professor Smith’s research interests focus on (1) the synthesis and structure-proof of bioactive
lipids obtained from the human dental pathogen Porphyromonas gingivalis. The initial work
will be extended to study the structure-biological activity relationships of these compounds.
(2) A systematic study of the influence of conductivity-enhancing dopants on conducting
polymers, and a green-chemistry study of chemical reactions mediated by conducting polymers
in a neutral, two-phase system. (3) The development of chemical probes that targets and allows
fluorescent imaging of cancerous hypoxic tumors.
In addition to this research, Professor Smith is the author of the 5th and 6th editions of March’s
Advanced Organic Chemistry and editor of the Compendium of Organic Synthetic Methods,
Volumes 6-12. He is the author of Organic Chemistry: Two Semesters, in it’s second edition,
which is an outline of undergraduate organic chemistry to be used as a study guide for the
first organic course. He has authored a research monograph entitled Synthesis of Non-alpha

Amino Acids. He is also the author of an undergraduate textbook in organic chemistry entitled
Organic Chemistry. An Acid-Base Approach.

About the Author

iii


Preface to the 3rd edition
The new edition of Organic Synthesis has been revised and rewritten from front to back. I
want to thank all who used the book in its first and second editions. The book has been out
of print for several years, but the collaboration of Warren Hehre and Wavefunction, Inc. made
the third edition possible. It is the same graduate level textbook past users are familiar with,
with two major exceptions. First, the book has been revised and updated. Second, molecular
modeling problems are included in a manner that is not obtrusive to the theme of understanding
reactions and synthesis. More than 60 molecular modeling problems are incorporated into
various discussions, spread throughout 11 of the 13 reactions-synthesis oriented chapters.
These are intended for the SpartanModel program, which can be purchased from Wavefunction.
SpartanModel will allow the reader to manipulate each model and, in most cases, change or
create model compounds of interest to the reader. It is our belief that the selected molecular
m\ odeling problems will offer new insights into certain aspects of chemical reactivity, confirmational analysis, and stereoselectivity.
Updated examples are used throughout the new edition when possible, and new material is
added that make this edition reflect current synthetic methodology. The text has been modified
in countless places to improve readability and pedagogy. This new edition contains references
taken from more than 6100 journal articles, books, and monographs. Of these references,
more than 950 are new to this edition, all taken from the literature after 2002. More than
600 updated or new reactions have been added. There are several entirely new sections that
discuss topics missing from the 2nd edition. These include SN2 type reactions with epoxides; the
Burgess Reagent; functional group rearrangements (Beckmann, Schmidt, Curtius, Hofmann,
Lossen); Oxidation of allylic carbon with ruthenium compounds; A comparison of LUMOmapping with the Cram model and Felkin-Anh models in chapter 4; Electrocyclic reactions;

[2.3]-sigmatropic rearrangement (Wittig rearrangement); consolidation of C–C bond forming
reactions of carbocations and nucleophiles into a new section.
Homework in each chapter has been extensively revised. There are more than 800 homework
problems, and more than 300 of the homework problems are new. Most of the homework
problems do not contain leading references for the answers. The answers to all problems from
chapters 1-9, and 11-13 are available in an on-line Student Solutions Manual for this book. As
in previous edition, a few leading references are provided for the synthesis problems in chapter
10. Although answers are given for homework that relates to all other chapters, in chapter
10 most problems do not have answers. The student is encouraged to discuss any synthetic
problem with their instructor.

Preface to the 3rd Edition

ix


With the exception of scanned figures, all drawings in this book were prepared using ChemDraw,
provided by CambridgeSoft, and all 3D graphics are rendered with Spartan, provided by
Wavefunction, Inc. I thank both organizations for providing the software that made this project
possible.
I express my gratitude to all of those who were kind enough to go through the first and second
editions and supply me with comments, corrections, and suggestions.
For this new edition, special thanks and gratitude are given to Warren Hehre. Not only did he
design the molecular modeling problems, but provided the solutions to the problems and the
software. Warren also helped me think about certain aspects of organic synthesis in a
different way because of the modeling, and I believe this has greatly improved the book
and the approaches presented in the book. Special thanks are also given to Ms. Pamela Ohsan,
who converted the entire book into publishable form. Without her extraordinary efforts, this
third edition would not be possible.
Finally, I thank my students, who have provided the inspiration over the years for this book.

They have also been my best sounding board, allowing me to test new ideas and organize
the text as it now appears. I thank my friends and colleagues who have provided countless
suggestions and encouragement over the years, particularly Spencer Knapp (Rutgers), George
Majetich (Georgia), Frederick Luzzio (Louisville), and Phil Garner (Washington State). You
have all helped more than you can possibly know, and I am most grateful.
A special thanks to my wife Sarah and son Steven, whose patience and understanding made
the work possible.
If there are errors, corrections, and suggestions, please let me know by Email or normal post.
Any errors will be posted at />Thank you again. I hope this new edition is useful to you in your studies.

University of Connecticut
Department of Chemistry
55 N. Eagleville Road
Storrs, Connecticut 06269-3060
Email:
Fax: (860) 486-2981
Homepage: />
Preface to the 3rd Edition

x

Michael B. Smith
Storrs, Connecticut
April, 2010


Preface to the 1st edition. Why I wrote this book!
A reactions oriented course is a staple of most graduate organic programs, and synthesis is
taught either as a part of that course or as a special topic. Ideally, the incoming student is an
organic major, who has a good working knowledge of basic reactions, stereochemistry and

conformational principles. In fact, however, many (often most) of the students in a first year
graduate level organic course have deficiencies in their undergraduate work, are not organic
majors and are not synthetically inclined. Does one simply tell the student to “go away and read
about it,” giving a list of references, or does one take class time to fill in the deficits? The first
option works well for highly motivated students with a good background, less well for those
with a modest background. In many cases, the students spend so much time catching up that
it is difficult to focus them on the cutting edge material we all want to teach. If one exercises
the second option of filling in all the deficits, one never gets to the cutting edge material. This
is especially punishing to the outstanding students and to the organic majors. a compromise
would provide the student with a reliable and readily available source for background material
that could be used as needed. The instructor could then feel comfortable that the proper
foundations have been laid and push on to more interesting areas of organic chemistry.
Unfortunately, such a source of background material either is lacking altogether or consists of
several books and dozens of review articles. I believe my teaching experience at UConn as just
described is rather typical, with a mix of non-organic majors, outstanding and well-motivated
students, and many students with weak backgrounds who have the potential to go on to useful
and productive careers if time is taken to help them. Over the years I have assigned what
books were available in an attempt to address these problems, but found that “graduate level
textbooks” left much to be desired. I assembled a large reading list and mountains of handouts
and spent half of my life making up problems that would give my students a reasonable chance
at practicing the principles we were discussing. I came to the conclusion that a single textbook
was needed that would give me the flexibility I craved to present the course I wanted to teach,
but yet would give the students the background they needed to succeed. As I tried different
things in the classroom, I solicited the opinions of the graduate students who took the course and
tried to develop an approach that worked for them and allowed me to present the information
I wanted. The result is this book. I hope that it is readable, provides background information,
and also provides the research oriented information that is important for graduate organic
students. I also hope it will be of benefit to instructors who face the same challenges I do. I
hope this book will be a useful tool to the synthetic community and to graduate level education.
From talks with many people I know that courses for which this book is targeted can be for

either one or two semesters. The course can focus only on functional groups, only on making
carbon-carbon bonds, on some combination of both (like my course), or only on synthesis.
Preface to the 1st Edition. Why I wrote this book!

xi


I have tried to organize the book in such a way that one is not a slave to its organization.
Every chapter is internally cross-referenced. If the course is to focus upon making carboncarbon bonds, for example, there are unavoidable references to oxidation reagents, reducing
agents, stereochemical principles, etc. When such a reaction or principle appears, the section
and chapter where it is discussed elsewhere in the book is given “in line” so the student can
easily find it. It is impossible to write each chapter so it will stand alone, but the chapters are
reasonably independent in their presentations. I have organized the book so that functional
groups are discussed in the first few chapters and carbon-carbon bond formation reactions
are discussed in later chapters, making it easier to use the one book for two different courses
or for a combination course. The middle chapters are used for review and to help the student
make the transitions from functional group manipulations to applying reactions and principles
and thence to actually building molecules. I believe that a course devoted to making carboncarbon bonds could begin with chapter 8, knowing that all pertinent peripheral material is in
the book and readily available to the student. The ultimate goal of the book is to cut down on
the mountains of handouts, provide homework to give the student proper practice, give many
literature citations to tell the student exactly where to find more information, and allow the
instructor to devote time to their particular focus.
This book obviously encompasses a wide range of organic chemistry. Is there a theme? Should
there be? The beautiful and elegant total syntheses of interesting and important molecules
published by synthetic organic chemists inspired me to become an organic chemist, and I
believe that synthesis focuses attention on the problems of organic chemistry in a unique
way. To solve a synthetic problem, all elements of organic chemistry must be brought to
bear: reactions, mechanism, stereochemistry, conformational control, and strategy. Synthesis
therefore brings a perspective on all aspects of organic chemistry and provides a theme for
understanding it. The theme of this book is therefore the presentation of reactions in the context

of organic synthesis. Wherever possible, examples of a given reaction, process, or strategy are
taken from a published total synthesis. The disconnection approach is presented in the first
chapter, and as each new functional group transform and carbon-carbon bond forming reaction
is discussed, the retrosynthetic analysis (the disconnect products for that reaction) is given. An
entire chapter (chapter 10) is devoted to synthetic strategies, and chapter 14 provides examples
of first year students’ first syntheses. I believe that this theme is a reasonable and useful device
for presenting advanced organic chemistry.
The text is fully referenced to facilitate further study, and (where feasible) the principal
researcher who did the work is mentioned by name, so the student can follow that person’s
work in the literature and gain even more insight into a given area. As far as it is known to
me, the pioneering work of the great chemists of the past has been referenced. Many of the
“named reactions” are no longer referenced in journals, but when they are first mentioned in
this book, the original references are given. I believe the early work should not be lost to a new
generation of students.

Preface to the 1st Edition. Why I wrote this book!

xii


In many cases I have used 3-D drawings to help illustrate stereochemical arguments for a given
process. I give the structure of each reagent cited in the text, where that reagent is mentioned,
so a beginning student does not have to stop and figure it out. This is probably unnecessary for
many students, but it is there if needed.
This is a reaction oriented book, but an attempt is made to give brief mechanistic discussions
when appropriate. In addition, some physical organic chemistry is included to try to answer the
obvious if unasked questions: why does that alkyl group move, why does that bond break, why
is that steric interaction greater than the other one, or why is that reaction diastereoselective?
Most of all, a student needs to practice. Chapters 1-13 have end-of chapter problems that range
from those requiring simple answers based on statements within the text to complex problems

taken from research literature. In a large number of cases literature citations are provided so
answers can be found.
The first part of the book (chapters 1-4) is a review of functional group transforms and basic
principles: retrosynthesis, stereochemistry, and conformations. Basic organic reactions are
covered, including substitution reactions, addition reactions, elimination reactions, acid/base
chemistry, oxidation and reduction. The first two chapters are very loosely organized along the
lines of an undergraduate book for presenting the functional group reactions (basic principles,
substitution, elimination, addition, acyl addition, aromatic chemistry). Chapter 1 begins with
the disconnection approach. I have found that this focuses the students’ attention on which
reactions they can actually apply and instantly shows them why it is important to have a larger
arsenal of reactions to solve a synthetic problem. This has been better than any other device I
have tried and that is why it is placed first. Most of the students I see come into our program
deficient in their understanding of stereochemistry and conformational control, and so those
topics are presented next. Some of this information is remedial material and where unneeded can
be skipped, but it is there for those who need it (even if they will not admit that they do). Chapter
2 presents a mini-review of undergraduate organic chemistry reactions and also introduces some
modern reactions and applications. Chapter 3 is on oxidation and chapter 4 is on reduction.
Each chapter covers areas that are woefully under-emphasized in undergraduate textbooks.
Chapter 5 covers hydroboration, an area that is discussed in several books and reviews. I thought
it useful to combine this material into a tightly focused presentation which (1) introduces several
novel functional group transforms that appear nowhere else and (2) gives a useful review of
many topics introduced in chapters 1-4. Chapter 6 reviews the basic principles that chemists
use to control a reaction rather than be controlled by it. It shows the techniques chemists use
to “fix” the stereochemistry, if possible, when the reaction does not do what it is supposed
to. It shows how stereochemical principles guide a synthesis. An alternative would be to
separate stereochemistry into a chapter that discusses all stereochemical principles. However,
the theme is synthesis, and stereochemical considerations are as important a part of a synthesis
as the reagents being chosen. For that reason, stereochemistry is presented with the reactions

Preface to the 1st Edition. Why I wrote this book!

xiii


in each chapter. Chapter 6 simply ties together the basic principles. This chapter also includes
the basics of ring-forming reactions. Chapter 7 completes the first part of the book and gives
a brief overview of what protecting groups are and when to use them.
The last half of the book focuses on making carbon-carbon bonds. It is organized fundamentally
by the disconnection approach. In Chapter 1, breaking a carbon-carbon bond generated a
disconnect product that was labeled as Cd (a nucleophilic species), Ca (an electrophilic species),
or Cradical (a radical intermediate). In some cases, multiple bonds were disconnected, and many
of these disconnections involved pericyclic reactions to reassemble the target. the nucleophilic
regents that are equivalent to Cd disconnect products are covered in Chapters 8 and 9, with the
very important enolate anion chemistry separated into Chapter 9. Chapter 10 presents various
synthetic strategies that a student may apply to a given synthetic problem. This information
needs to be introduced as soon as possible, but until the student “knows some chemistry”, it
cannot really be applied. Placement of synthetic strategies after functional group transforms
and nucleophilic methods for making carbon-carbon bonds is a reasonable compromise.
Chapter 11 introduces the important Diels-Alder cyclization, as well as dipolar cycloadditions
and sigmatropic rearrangements that are critically important to synthesis. Chapter 12 explores
electrophilic carbons (Ca), including organometallics that generally react with nucleophilic
species. Chapter 13 introduces radical and carbene chemistry. Chapter 14 is included to give
the student a taste of a first time student proposal and some of the common mistakes. The point
is not to reiterate the chemistry but to show how strategic shortsightedness, poor drawings,
and deficiencies in overall presentation can influence how the proposal is viewed. It is mainly
intended to show some common mistakes and also some good things to do in presenting a
synthesis. It is not meant to supersede the detailed discussions of how and why a completed
elegant synthesis is done but to assist the first-time student in preparing a proposal.
The goal of this work is to produce a graduate level textbook, and it does not assume that a
student should already know the information, before the course. I hope that it will be useful to

students and to the synthetic community. Every effort has been made to keep the manuscript
error-free. Where there are errors, I take full responsibility and encourage those who find them
to contact me directly, at the address given below, with corrections. Suggestions for improving
the text, including additions and general comments about the book are also welcome. My goal
is to incorporate such changes in future editions of this work. If anyone wishes to contribute
homework problems to future editions, please send them to me and I will, of course, give full
credit for any I use.
I must begin my “thank yous” with the graduate students at UConn, who inspired this work
and worked with me through several years to develop the pedagogy of the text. I must also
thank Dr. Chris Lipinski and Dr. David Burnett of Pfizer Central Research (Groton, CT) who
organized a reactions/synthesis course for their research assistants. This allowed me to test
this book upon an “outside” and highly trained audience. I am indebted to them for their

Preface to the 1st Edition. Why I wrote this book!

xiv


suggestions and their help.
There are many other people to thank. Professor Janet Carlson (Macalester College) reviewed
a primeval version of this book and made many useful comments. Professors Al Sneden and
Suzanne Ruder (Virginia Commonwealth University) classroom tested an early version of this
text and both made many comments and suggestions that assisted me in putting together the
final form of this book. Of the early reviewers of this book, I would particularly like to thank
Professor Brad Mundy (Colby College) and Professor Marye Anne Fox (University of Texas,
Austin), who made insightful and highly useful suggestions that were important for shaping
the focus of the book.
Along the way, many people have helped me with portions or sections of the book. Professor
Barry Sharpless (Scripps) reviewed the oxidation chapter and also provided many useful
insights into his asymmetric epoxidation procedures. Dr. Peter Wuts (Upjohn) was kind

enough to review the protecting group chapter (chapter 7) and helped me focus it in the proper
way. Professor Ken Houk (UCLA), Professor Stephen Hanessian (Université de Montréal),
Professor Larry Weiler (U. of British Columbia), Professor James Hendrickson (Brandeis),
Professor Tomas Hudlicky (U. Florida), and Professor Michael Taschner (U. of Akron) reviewed
portions of work that applied to their areas of research and I am grateful for their help.
Several people provided original copies of figures or useful reprints or comments. These
include Professor Dieter Seebach (ETH), Professor Paul Williard (Brown), Professor E.J. Corey
(Harvard), Dr. Frank Urban (Pfizer Central Research), Professor Rene Barone (Université de
Marseilles), and Professor Wilhelm Meier (Essen).
Two professors reviewed portions of the final manuscript and not only pointed out errors but
made enormously helpful suggestions that were important for completing the book: Professor
Fred Ziegler (Yale) and Professor Douglass Taber (U. of Delaware). I thank both of them very
much.
There were many other people who reviewed portions of the book and their reviews were
very important in shaping my own perception of the book, what was needed and what needed
to be changed. These include: Professor Winfield M. Baldwin, Jr. (U. of Georgia), Professor
Albert W. Burgstahler (U. of Kansas), Professor George B. Clemens (Bowling Green State
University), Professor Ishan Erden (San Francisco State University), Professor Raymond C.
Fort, Jr. (U. of Maine), Professor John F. Helling (U. of Florida), Professor R. Daniel Little (U.
of California), Professor Gary W. Morrow (U. of Dayton), Professor Michael Rathke (Michigan
State University), Professor Bryan W. Roberts (U. of Pennsylvania), Professor James E. Van
Verth (Canisius College), Professor Frederick G. West (U. of Utah), and Professor Kang Zhao
(New York University). I thank all of them.
I must also thank the many people who have indulged me at meetings, at Gordon conferences,
and as visitors to UConn and who discussed their thoughts, needs, and wants in graduate level

Preface to the 1st Edition. Why I wrote this book!

xv

education. These discussions helped shape the way I put the book together.
Finally, but by no means last in my thoughts, I am indebted to Professors Joe Wolinsky and
Jim Brewster of Purdue University. Their dedication and skill taught me how to teach. Thank
you!
I particularly want to thank my wife Sarah and son Steven. They endured the many days and
nights of my being in the library and the endless hours on the computer with patience and
understanding. My family provided the love, the help, and the fulfillment required for me to
keep going and helped me to put this project into its proper perspective. They helped me in
ways that are too numerous to mention. I thank them and I dedicate this work to them.
Michael B. Smith

Preface to the 1st Edition. Why I wrote this book!

xvi


Introducing SpartanModel
SpartanModel is a virtual model kit, designed to provide students of organic chemistry information about
st
molecular structure, stability and properties. In the simplest of terms, SpartanModel is the 21 century
equivalent of “plastic models” used by students of previous generations. Both provide the means to move from
the two-dimensional drawings of molecules to accurate three-dimensional portrayals. However, SpartanModel
offers a number of significant advantages over plastic models.
The first advantage is that SpartanModel overcomes the fact that a plastic
model kit contains only a limited number of “parts”, perhaps ten or twenty
“carbon atoms” and a much smaller number of nitrogen and oxygen atoms.
Therefore, only relatively small molecules can be constructed. More
importantly, a shortage of parts means that a molecule needs to be disassembled
before another molecule can be assembled. This makes it impossible, or in the

best circumstances, unnecessarily difficult, to compare the structures of
different molecules. SpartanModel is unbounded, and molecules with dozens or
even hundreds of atoms can be accommodated. Comparisons between different
molecules can easily be made.
A related shortcoming of plastic model kits is that they are able to show off just a
single aspect of molecular structure, most commonly, the connections (bonds)
between atoms. Plastic models that depict overall size and shape are available,
but need to be purchased and used separately. On the other hand, models made
with SpartanModel may be portrayed either to emphasize bonding or to convey
information about a molecule’s overall size and shape. A further disadvantage is
that plastic models “show” but do not “tell” us about important aspects of
molecular structure, for example, about the volume that a molecule requires or its
surface area. SpartanModel provides both a visual image as well as numerical
values for these quantities. Of even greater practical value, SpartanModel
assigns and displays R/S chirality, both for simple molecules where the rules are
relatively easy to apply as well as for complex molecules where even an “expert”
would be challenged.
Neither SpartanModel nor a plastic model kit is able to build proteins. However,
SpartanModel seamlessly connects to the on-line Protein Data Bank1 (PDB),
providing access to >77,000 protein and biomolecule experimental structures. A
PDB entry is automatically retrieved given its identifier, and displayed as a
“ribbon model” to emphasize the secondary structure. The model may be
manipulated enabling detailed visual inspection.

1.

H.M. Berman, K. Henrick, H. Nakamura, Nat. Struct. Bio., 10 (12), 980 (2003).

Introducing SpartanModel

xvii


The second advantage is that the structures obtained by SpartanModel are not based on the fixed dimensions of
the “parts” as they are with plastic models, but rather result from application of quantum mechanics. This means
that SpartanModel is actually a predictive tool, not merely one following empirical rules. It can be used to
explore chemistry.
The third advantage is that the information provided by
SpartanModel is not restricted to molecular structure as it is with
plastic models. Energies, atomic charges and dipole moments,
molecular orbitals and orbital energies as well as electrostatic
potential maps may be obtained for any molecule. In addition,
heats of formation and infrared spectra for approximately 6000
molecules obtained from high-quality quantum chemical
calculations (beyond those provided in SpartanModel) are
available from a database included with and accessed from
SpartanModel. The availability of energies (as well as selected
heats of formation) allows the most stable isomer to be identified
and specification of a reaction as endothermic or exothermic.
Calculated energies may also be employed to assign the lowestenergy conformation of a molecule and to examine the likelihood
that other conformers will be present. The infrared database
provides realistic spectra and allows association of individual
features in the spectrum with vibrational motions of specific
groups of atoms.
In short, while there is utility in the use of plastic model kits, plastic models are severely restricted in terms of
the complexity of what can be built, the accuracy of the presentations and in what information they are able to
provide.
Some may argue that plastic models are “tried and tested”, and that an electronic model kit is unfamiliar or
intimidating. We suspect that the vast majority of students will have the opposite perspective. After all, today’s
students have grown up with computers and expect to use them during their college education. In the final

analysis, the choice is not between plastic and computer-based models, but whether or not models have
something to offer in a chemist’s education. We think that they do.

Introducing SpartanModel

xviii


GETTING STARTED WITH SpartanModel
The easiest way to learn how to use SpartanModel is to spend an hour to complete the set of tutorials that are provided
with the software. They cover both the use of the program and the interpretation of the quantities that result. Start with
Basic Operations, which shows how to manipulate molecules, query molecular properties, display molecular orbitals and
electrostatic potential maps and draw infrared spectra. Building molecules and performing quantum chemical calculations
are not illustrated, but deferred to Acrylonitrile. This tutorial should be completed next. The remainder of the tutorials
can be completed in any order. Camphor and Androsterone illustrate construction of successively more complex organic
molecules. The first of these provides another example of displaying an infrared spectrum, and both tutorials illustrate the
identification and assignment of chiral (R/S) centers. Acetic Acid Dimer shows how a molecular complex may be
assembled and its binding energy calculated. 1,3-Butadiene and trans-Cyclooctene show how energy comparisons
among molecules are made. The first involves different conformers of the same molecule and shows how the
conformation of a molecule can be changed. The second involves different stereoisomers. 2-Methylpropene and
Comparing Acid Strengths illustrate comparisons of molecular orbitals and electrostatic potential maps for different
molecules. Finally, Hemoglobin shows how to access the Protein Databank (PDB). A part of this tutorial requires that the
user be connected to the internet.

PROBLEMS KEYED TO ORGANIC SYNTHESIS
A set of ~60 problems, accessible under Problems in the Welcome screen, has been keyed to the 3rd edition of Organic
Synthesis. Many of the problems are made up of text (html) files only, opening up a “blank screen” in SpartanModel.
However, some of the problems include materials that cannot be generated with SpartanModel and have been prepared
using the full Spartan program. These include problems involving transition states and those using LUMO maps and local
ionization potential maps. These materials are “read only” and while the models may be examined and manipulated and

measurements taken, they may not be altered.
The instructor is free to make additional tutorials and problems using Spartan, and to add these to the existing collections.
Instructions are provided under Adding Tutorials and Problems under the Help menu.

TECHNICAL OVERVIEW OF SpartanModel
SpartanModel may be viewed in terms of its components: a molecule builder including a molecular mechanics based
scheme for preliminary structure refinement, a real-time quantum chemical engine and two databases.
2

3

SpartanModel’s builder uses atomic fragments (for example, sp, sp and sp carbon fragments), functional groups (for
example, amide and carbonyl groups) and rings (for example, cyclohexane and benzene). Some molecules can be made in
just one or two steps (“mouse clicks”), while most others require fewer than ten steps. For example, fewer than 20 steps
are required to build the steroid androsterone, the most complicated molecule provided in a tutorial that accompanies
SpartanModel. Once constructed, molecules can be displayed as to depict bonding (as with most types of plastic models)
or overall size and shape (so-called space-filling or CPK models). Associated with the builder is a simple “molecular
mechanics” procedure to provide a refined geometry as well as measurement tools for bond distances and angles,
volumes, surface areas and polar surface areas (of space-filling models) and for assignment of R/S chirality.

The quantum chemical engine provided in SpartanModel may be used to obtain the geometries and properties
of the vast majority of molecules encountered in elementary organic chemistry. The desire for open-endedness

Introducing SpartanModel

xix


(any “reasonable size” molecule may be calculated) together with practical concerns, requires use of a very
simple quantum chemical model. The procedure used in SpartanModel involves two quantum chemical steps

and is preceded by a molecular mechanics2 step to ensure a reasonable starting geometry. The first quantum
chemical step is calculation of geometry using the PM33 semi-empirical model and the second step is
calculation of the energy and wavefunction at this geometry using the Hartree-Fock 3-21G4 model. The
resulting wavefunction is used for calculation of the dipole moment and atomic charges and (if requested)
graphical displays of the molecular orbitals and electrostatic potential map. PM3 geometry calculations and 321G energy calculations for molecules comprising up to 30-40 heavy (non-hydrogen) atoms are likely to require
less than one minute on a present day Windows or Macintosh computer.
The quantum chemical calculations in SpartanModel properly account for geometry and provide a sound basis
for graphical displays of molecular orbitals and electrostatic potential maps. They also provide a qualitatively
accurate account of the energies of most types of chemical reactions as well as conformational energy
differences. Heats of formation for ~6000 molecules obtained from the T15 thermochemical recipe and included
in a database can be used to supplement calculated energies where higher accuracy may be necessary. T1 has
been shown to reproduce experimental heats of formation with an rms error of ~8 kJ/mol.
The second database contains infrared spectra for ~6000 molecules obtained from the EDF26/
6-31G* density functional model, adjusted to account for known systematic errors and for finite temperature.
The resulting spectra are visually and quantitatively very similar to observed infrared spectra. Vibrational
modes associated with individual lines in the spectrum may be “animated”.

2.
3.
4.

5.
6.

T.A. Halgren, J. Computational Chem., 17, 490 (1996).
J.J.P. Stewart, J. Computational Chem., 10, 209 (1989).
J.S. Binkley, J.A. Pople and W.J. Hehre, J. Am. Chem. Soc., 102, 939 (1980); W.J. Pietro, M.M. Francl, W.J.
Hehre, D.J. DeFrees, J.A. Pople and J.S. Binkley, ibid., 104, 5039, (1982). For a review and assessment
of techniques and computational methods, see: A Guide to Molecular Mechanics and Quantum Chemical
Calculations, Wavefunction, Inc., Irvine, CA, USA (2003).

W.S. Ohlinger, P.E. Klunzinger, B.J. Deppmeier, W.J. Hehre, J. Phys. Chem. A., 113 10, 2165 (2009).
R.D. Adamson, P.M.W. Gill, and J.A. Pople, Chem. Phys. Lett., 284, 6, (1998).

Introducing SpartanModel

xx


THIS BOOK IS DEDICATED TO:
MY WIFE SARAH
AND
MY SON STEVEN


Common Abbreviations
Other, less common abbreviations are given in the text when the term is used.
Ac

Acetyl

Acac
AIBN
All
Am
aq
Ax

Acetylacetonate
azo-bis-isobutyronitrile
Allyl

Amyl
Aqueous
Axial

B

Me

–CH2(CH2)3CH3

9-Borabicyclo[3.3.1]nonylboryl

9-BBN
BINAP
Bn

9-Borabicyclo[3.3.1]nonane
2R,3S-2,2’-bis-(diphenylphosphino)-1,1’-binapthyl
Benzyl

Boc

t-Butoxycarbonyl

Bpy (Bipy)
Bu
Bz
CAM
CAN
ccat

2,2’-Bipyridyl
n-Butyl
Benzoyl
Carboxamidomethyl
Ceric ammonium nitrate
CycloCatalytic

Cbz

Carbobenzyloxy

chap
Chirald

Chapter(s)

Common Abbreviations

O

2S,3R-(+)-4-dimethylamino-1,2-diphenyl-3methylbutan-2-ol

xxii

–CH2Ph
O
Ot-Bu

–CH2CH2CH2CH3

(NH4)2Ce(NO3)6

O
OCH2 Ph


CIP
COD
COT
Cp
CSA
CTAB

Cahn–Ingold-Prelog
1,5-Cyclooctadienyl
1,3,5-cyclooctatrienyl
Cyclopentadienyl
Camphorsulfonic acid
Cetyltrimethylammonium bromide

Cy (c-C6H11)

Cyclohexyl

°C
2D
3D
DABCO
d

dba
DBE
DBN
DBU
DCC
DCE
DDQ
% de
DEA
DEAD
DET
DHP
DIBAL-H
Diphos (dppe)
Diphos-4 (dppb)
DIPT
DMAP
DME

Temperature in Degrees Centigrade
Two-dimensional
Three-dimensional
1,4-Diazabicyclo[2.2.2]octane
Day(s)
Dibenzylidene acetone
1,2-Dibromoethane
1,5-Diazabicyclo[4.3.0]non-5-ene
1,8-Diazabicyclo[5.4.0]undec-7-ene
1,3-Dicyclohexylcarbodiimide
1,2-Dichloroethane

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
% Diasteromeric excess
Diethylamine
Diethylazodicarboxylate
Diethyl tartrate
Dihydropyran
Diisobutylaluminum hydride
1,2-bis-(Diphenylphosphino)ethane
1,4-bis-(Diphenylphosphino)butane
Diisopropyl tartrate
4-Dimethylaminopyridine
Dimethoxyethane

DMF

N,N’-Dimethylformamide

DMS

Dimethyl sulfide

C16H33NMe3+ Br–

BrCH2CH2Br

c-C6H11-N=C=N-c-C6H11
ClCH2CH2Cl

HN(CH2CH3)2
EtO2C-N=NCO2Et

(Me2CHCH2)2AlH
Ph2PCH2CH2PPh2
Ph2P(CH2)4PPh2

MeOCH2CH2OMe
O
H

NMe2

Common Abbreviations

xxiii


DMSO
dppb
dppe
dppf
dppp
dvb
e–
EA
% ee
EE
Et
EDA
EDTA
Equiv

ESR
FMN
FMO
fod
Fp
FVP
GC
gl
FVP
GC
gl
h
hν
1,5-HD
HMPA
HMPT
1
H NMR
HOMO
HPLC
HSAB
Common Abbreviations

Dimethyl sulfoxide
1,4-bis-(Diphenylphosphino)butane
1,2-bis-(Diphenylphosphino)ethane
bis-(Diphenylphosphino)ferrocene
1,3-bis-(Diphenylphosphino)propane
Divinylbenzene
Electrolysis

Electron affinity
% Enantiomeric excess
1-Ethoxyethoxy
Ethyl
Ethylenediamine
Ethylenediaminetetraacetic acid
Equivalent(s)
Electron Spin Resonance Spectroscopy
Flavin mononucleotide
Frontier Molecular Orbital
tris-(6,6,7,7,8,8,8)-Heptafluoro-2,2-dimethyl-3,5octanedionate
Cyclopentadienyl-bis-carbonyl iron
Flash Vacuum Pyrolysis
Gas chromatography
Glacial
Flash Vacuum Pyrolysis
Gas chromatography
Glacial
Hour (hours)
Irradiation with light
1,5-Hexadienyl
Hexamethylphosphoramide
Hexamethylphosphorus triamide
Proton Nuclear Magnetic Resonance Spectroscopy
Highest occupied molecular orbital
High performance liquid chromatography
Hard/Soft Acid/Base
xxiv

Ph2P(CH2)4PPh2

Ph2PCH2CH2PPh2
Ph2P(CH2)3PPh2

EtO(Me)CH-CH2CH3
H2NCH2CH2NH2

(Me2N)3P=O
(Me2N)3P


IP
i-Pr
IR
LICA (LIPCA)
LDA
LHMDS
LTMP
LUMO
MCPBA
Me
MEM
Mes
min
MOM
Ms
MS
MTM
MVK
NAD
NADP

Napth
NBD
NBS
NCS
NIS
Ni(R)
NMO
Nu (Nuc)
OBs
Oxone
P

PCC
PDC
PEG

or

Ionization potential
Isopropyl
Infrared spectroscopy
Lithium cyclohexylisopropylamide
Lithium diisopropylamide
Lithium hexamethyl disilazide
Lithium 2,2,6,6-tetramethylpiperidide
Lowest unoccupied molecular orbital
meta-Chloroperoxybenzoic acid
Methyl
β−Methoxyethoxymethyl
Mesityl

minutes
Methoxymethyl
Methanesulfonyl
Molecular Sieves (3Å or 4Å)
Methylthiomethyl
Methyl vinyl ketone
Nicotinamide adenine dinucleotide
Sodium triphosphopyridine nucleotide
Napthyl (C10H8)
Norbornadiene
N-Bromosuccinimide
N-Chlorosuccinimide
N-Iodosuccinimide
Raney nickel
N-Methylmorpholine N-oxide
Nucleophile
O-Benzenesulfonate
2 KHSO5•KHSO4•K2SO4

-CH(Me)2

LiN(i-Pr)2
LiN(SiMe3)2

-CH3 or Me
MeOCH2CH2OCH22,4,6-tri-Me-C6H2
MeOCH2MeSO2-

MeSCH2-

Polymeric backbone
Pyridinium chlorochromate
Pyridinium dichromate
Polyethylene glycol
Common Abbreviations

xxv


Ph

Phenyl

PhH
PhMe
Phth

Benzene
Toluene
Phthaloyl

Pip

Piperidino

PPA
PPTS
Pr

Polyphosphoric acid

para-Toluenesulfonic acid
n-Propyl

-CH2CH2CH3

Py

Pyridine

N

Quant
Red-Al
RT
sBu
sBuLi
s
sec
SEM
SET
Siamyl
(Sia)2BH
TASF

Quantitative yield
[(MeOCH2CH2O)2AlH2]Na
Room temperature
CH3CH2CH(CH3)
sec-Butyl
CH3CH2CH(Li)CH3

sec-Butyllithium
seconds
sections(s)
2-(trimethylsilyl)ethoxymethyl
Single electron transfer
(CH3)2CHCH(CH3)sec-Isoamyl
Disiamylborane
tris-(Diethylamino)sulfonium difluorotrimethyl
silicate

TBAF
TBDMS
TBHP (t-BuOOH)
t-Bu
TEBA
TEMPO
TFA
TFAA
Tf (OTf)

Tetrabutylammonium fluoride
t-Butyldimethylsilyl
t-Butylhydroperoxide
tert-Butyl
Triethylbenzylammonium
Tetramethylpiperidinyloxy free radical
Trifluoroacetic acid
Trifluoroacetic anhydride
Triflate

Common Abbreviations

xxvi

N

n-Bu4N+ F–
t-BuMe2Si
Me3COOH
-CMe3
Bn(Et3)3N+
CF3COOH
(CF3CO)2O
-SO2CF3 (-OSO2CF3)


ThexBH2
THF
THP
TMEDA
TMS
TMP
Tol
TPAP
Tr
TRIS
Ts(Tos)
UV
Xc

Thexylborane (tert-hexylborane)
Tetrahydrofuran
Tetrahydropyran
Tetramethylethylenediamine
Trimethylsilyl
2,2,6,6-Tetramethylpiperidine
Tolyl
Tetrapropylperruthenate
Trityl
Triisopropylphenylsulfonyl
Tosyl = p-Toluenesulfonyl
Ultraviolet spectroscopy
Chiral auxiliary

Me2NCH2CH2NMe2
-Si(CH3)3
4-(Me)C6H4
-CPh3
4-(Me)C6H4SO2

Common Abbreviations

xxvii


chapter

1.1.

1

Retrosynthesis, Stereochemistry, and Conformations

IntRoduCtIon

Where does one begin a book that will introduce and discuss hundreds of chemical reactions?
To synthesize a complex organic molecule many reactions must be used, and the strategy
used for that synthesis must consider not only the type of reaction but also the mechanism of
that reaction. We begin with a brief introduction to synthetic planning. A full discussion of
strategies for total synthesis will be introduced in chapter 10, but surveying the fundamental
approach can help one understand how reactions are categorized.
The total synthesis of complex natural products usually demands a thorough knowledge of
reactions that form carbon-carbon bonds as well as those that change one functional group into
another. Examination of many syntheses of both large and small molecules, reveals that building
up a carbon skeleton by carbon-carbon bond forming reactions is rarely done successfully
unless all aspects of chemical reactivity, functional group interactions, conformations, and
stereochemistry are well understood. The largest number of actual chemical reactions that
appear in a synthesis do not make carbon-carbon bonds but rather manipulate functional
groups.
OH

KOH , EtOH
1

Br

2

3

O

CrO3
4

Changing one functional group into another is defined as a functional group interchange
(FGI). Simple examples are the loss of H and Br from 2-bromo-2-methylpentane (1) to form
2-methyl-2-pentene (2), or oxidizing the alcohol unit in 2-pentanol (3) to the carbonyl unit in
2-pentanone (4). Contrast these reactions with a reaction that brings reactive fragments together
to form a new bond between two carbon atoms, such as the condensation of two molecules
of butanal (5) under basic conditions to give 6, which is known as the aldol condensation.
The aldol condensation forms a carbon-carbon bond but before such a reaction can occur one
usually must incorporate or change key functional groups. This observation is an important
reason that more functional group exchange reactions are typically required, relative to carboncarbon bond forming reactions. Several different functional groups may also be structural
units of the molecule being synthesized.

chapter 1

1


Nowadays, the relationship of two molecules in a synthesis is commonly shown using a device
known as a transform, defined by Corey and co-workers1 as: “the exact reverse of a synthetic
reaction to a target structure”. The target structure is the final molecule one is attempting
to prepare. The synthetic transformation that converts butanal (5) to hydroxy-aldehyde 6 via
the aldol condensation (see sec. 9.4.A) is an example. The transform for this synthetic step
is, therefore, 6 ⇒ 5. Inspection of 6 and 5 reveals that mentally breaking the highlighted
bond (bond a) in 6 (represented by the squiggly line) leads to disconnect fragments 5 and 7
and in this process bond a is said to be disconnected. An elementary disconnection approach
quickly becomes an integral part of how one thinks about molecules. The focus here, however,

is on how to put molecules together. How does the disconnection approach assist us in this
endeavor? Understanding why bond a is important comes from a thorough knowledge of the
chemical properties of compound 6. When we disconnect bond a, we eventually want to make
that bond by a chemical reaction. To understand the molecular characteristics of 6 that led us
to disconnect bond a, we must understand the chemical reactions required to form that bond.
CHO transform
a
HO

HO

6

where

5
•

•

7
indicates a
disconnection

CHO

5

synthesis
1. NaOEt , EtOH

reflux
CHO
2. H3O+

CHO
HO

6

Pentanoic acid (8) is a simple target that
a
OH
CO2H
illustrates the approach. Disconnection
9
8
of the carbon-carbon bond marked a
X + "CO H"
2
leads to 1-butanol (9) as the precursor
10
(the starting material). Analysis of the
targeted carboxylic acid as well as the product alcohol shows a change in oxidation state, and
a one-carbon extension of the carbon chain. Of the four carbon-carbon bonds in target 8,
bond a must be used to attach the carbonyl to the starting material 9. Disconnection of bond
a leads to the simplified structure 10 and the CO2H (carboxyl) fragment, which is not a real
molecule. These two structures are termed disconnect products but 10 contains an unspecified
X group, that must be a reactive functional group and could be hydroxyl (as in 9). In addition,
the carboxyl fragment shown does not exist and a synthetic equivalent of the disconnect
product that is a real molecule must be found. In other words, to complete any reaction a real

molecule or reagent must be used who reaction generates the disconnect fragment directly.
Alternatively, a surrogate can be used to give a product that can be converted to the fragment.
For example, in the disconnection C–NH2 to C and NH2, ammonia reacts with an alkyl halide
to give an amine, but there are problems with over-alkylation. The NH3 is the direct equivalent
1.

Corey, E.J.; Cheng, X. The Logic of Chemical Synthesis, Wiley-Interscience, NY, 1989.

chapter 1

2


of NH2. To overcome such problems, the phthalimide anion reacts with an alkyl halide to give
the phthalimide, and subsequent reaction with hydrazine liberates the amine. Phthalimide is
a surrogate for NH2, used to circumvent problems with the ammonia reaction. In the case of
8, we require a COOH surrogate, since COOH is not a real molecule. It is known that carbon
dioxide (CO2) reacts with Grignard reagents (10, where X = MgBr) to give a carboxylic acid
after hydrolysis of the resulting carboxylate salt in a second step. Therefore, the disconnection
shown is a viable process since we know a chemical reaction to make that bond. Working
backward in this manner is termed retrosynthetic analysis or retrosynthesis, defined by
Corey as “a problem-solving technique for transforming the structure of a synthetic target
molecule to a sequence of progressively simple materials along a pathway which ultimately
leads to a simple or commercially available starting material for chemical synthesis”.2
8

a
CO2H

C≡N:

Br

9

OH

Based on our retrosynthetic analysis, one solution to this synthetic problem is to use the
reaction of cyanide ion with primary halides via second order nucleophilic substitution (SN2,
see sec. 2.6.A), to generate a nitrile. The cyano unit is readily hydrolyzed to an acid. Is
there an alternative? The answer is yes via a Grignard reaction with carbon dioxide (sec.
8.4.C.iv), but this strategy requires that alcohol 9 be converted to an alkyl halide and then to
the corresponding Grignard reagent. Subsequent reaction with carbon dioxide and hydrolysis
will give 8. Formation of an alkyl halide from an alcohol is a functional group interchange
(FGI) reaction (see sec. 2.8.A), as is conversion of the halide to a nitrile and the nitrile to an
acid. The retrosynthesis effectively describes the reactions necessary for the real synthesis
starting from 8, but reagents must be added to complete the synthesis. Determining the key
bond for disconnection in the target led to the conclusion that the synthesis required a carboncarbon bond forming reaction as well as FGI reactions. Thinking about the synthesis and
disconnections led us to analyze and understand the reactions that must be used.
It is important to point out that rarely does one take a retrosynthetic analysis and use the exact
reverse track with simple reagents to synthesize the target. For mono-functional molecules
this approach often works, but for molecules with multiple functionality, particularly complex
natural products, the idea of doing a retrosynthetic analysis and simply providing reagents to
convert the starting material to the target is very naïve. There are usually steps that simply do
not work using available reagents or those suggested by literature precedent, and the reactions
may give poor yields or the wrong stereochemistry. There are unanticipated interactions of
functional groups and unexpected requirements for protecting groups. In short, the approach
shown here is a beginning, intended to get you to think about how to pull molecules apart,
what reactions may be appropriate to put them together again, and to think about strategies
2.

Reference 1, p 6.

chapter 1

3