Introduction

There is excitement, adventure, and challenge, and there can be great art in
organic synthesis. These alone should be enough, and organic chemistry
will be sadder when none of its partitioners are responsive to these stimuli.
R. B. Woodward, 1956
The term organic synthesis means literally that its major goal is the construc-
tion of organic molecules. What for? From what? How? These are questions
that face both newcomers to this field as well as experienced professionals.
The answer to the question from what? seems more or less obvious - from
simpler molecules. From simpler usually means from more available. Avail-
able natural sources of organic compounds include carbon dioxide, raw organic
material from fossil sources (petroleum, gas, coal), and living organisms. Their
composition ultimately delineates the spectrum of compounds which can be
used as starting products for an organic synthesis. For example, a well known
material of our century, polyethylene, can be produced in multiton quantities
because its synthesis is easily achieved by the polymerization of a simple and
available raw product, ethylene. An enormously large area of industrial and
laboratory chemistry, dealing with aromatic compounds (polymers, dyes,
explosives, medical drugs, etc. ), is actually based upon the wide occurrence of
the common basic element of their structures, the benzene nucleus, in the large
number of aromatic hydrocarbons which are isolated during the regular
processing of coal and petroleum. Viscose and acetate fibers, nitrocellulose
materials and gun powder, and glucose also became industrial products because
they are obtained by simple chemical reactions from polysaccharides, the most
abundant class of organic compounds on Earth.
In the molecule of polyethylene or, for example, phenol, it is trivial to
recognize the structural elements corresponding to available natural precursors
and hence to elaborate a logistically simple scheme for the preparation of the
target products. However, in the majority of cases the well-trained eye of the
professional is required in order to identify the basic fragment(s) present in the
complex target molecule which can be derived from a suitable precursor(s). This
skill rests primarily in the ability to refer easily to the rich arsenal of synthetic
xv
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xvi In t r oduc t ion
methods, i.e. one should be able to answer the question how?. In considering
the latter question, however, it becomes clear that by no means can the problem
be reduced only to the availability of possible starting materials. For example, it
would be tempting to obtain acetic acid from the readily available gases
methane and carbon dioxide:
CH4 +COz -+ CH,COOH
On paper, this route seems to be quite reasonable, inasmuch as it involves
formally the simple combination of two molecules. In reality this preparation
cannot be achieved as indicated in such a straightforward way. Yet, as we will
see shortly, it is possible to elaborate indirect routes which will ultimately lead to
such a conversion. In fact, the power of modern organic synthesis has reached
the level when an organic chemist is able to prepare, at least in principle,
whatever you need from whatever you choose. However, this power is by no
means a magic wand to be employed arbitrarily at ones will. The might of
organic synthesis is based on the knowledge of rigorously established and rather
strict laws governing the course of chemical reactions which comprise the set of
the basic tools for doing a synthetic job. In every reaction there are formed and/
or cleaved some specific bonds between specific atoms. It is this very
specificity of the chosen transformations that enables chemists to predict and
control the overall results of synthetic operations. Thus the right choice among
the set of available reactions is of paramount importance in order to solve the
main tactical problem of organic synthesis: how to achieve a selective creation
or rupture of the required bond(s) in the assembled structure?
The assemblage of complex molecules from simple precursors most usually
involves a step-by-step protocol and thus the entire process is broken into
several separate steps, each one aimed at the creation of a particular bond(s)
present in the final molecule or, more often, in an intermediate precursor to be
employed at a later step(s) of the whole sequence. Only in special cases do these
sequential steps turn out to be of the same type, and thus the final goal can be
achieved as a result of a single operation (as is the case in the polymerization of
ethylene into polyethylene). More usually the pathway of a complex synthesis
includes a series of entirely different synthetic steps and realization of each step
may represent an independent chemical problem. Furthermore, as a rule, more
than one route might be envisaged for the preparation of a target compound
and each of the alternative pathways may include different reaction sequences
and starting materials. Therefore, in addition to the selection of suitable
precursors and reactions for the creation of the chosen bonds in the target
molecule, the synthetic chemist has to address a more general and often rather
troublesome strategic task, namely the elaboration of an optimal plan for the
entire synthesis.
In the rational planning of a synthesis, it is expedient to perform a mental
disconnection of the target molecule in order to arrive at the structure of the
nearest precursor(s) which can be converted into the required structure with the
help of known methods. Theoretically, one may start this disconnection
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Introduction xvii
procedure from any site of the target structure and then proceed retrosyntheti-
cally by applying the same procedure with any of the emerging precursors, thus
arriving eventually at readily available starting materials. Obviously it would
not be productive to undertake such an exhaustive search; the selection of a few
rational options among a multitude of thus generated alternative pathways
might be too formidable a task. In the elaboration of a synthetic strategy, one
should also never forget that even the well-established procedures may fail when
applied in a specific structural context and thus an otherwise chemically sound
synthetic plan may prove to be unworkable. If such a misfire occurs at the
initial steps of the synthetic sequence, at most only a few days or weeks are lost.
However, if it happens at the concluding step of a lengthy, for example, 40-step
synthesis, it might cost an entire year of work, as this failure would never be
found until the previous 39 steps were completed. Hence synthetic plans should
have the maximum flexibility, with the most risky synthetic operations shifted to
the earliest possible step of the entire sequence.
A number of criteria must be considered when making the final selection
between the options that emerge for the total synthesis of a given compound.
Among the most important are the length of the scheme (the fewer the steps, the
better) and anticipated yield at each step; the availability and price of starting
compounds and other materials, including solvents, catalysts and adsorbents;
the complexity of the equipment needed, etc. In order to make an adequate
assessment of all these, sometimes contradictory, requirements, one must have
both an in-depth knowledge of a rich arsenal of available synthetic methods and
a clear understanding of the ultimate goal of the whole endeavor. Here it is of
the utmost importance to address the question why should this synthesis be
undertaken?. In fact, a synthetic plan designed for industrial application may
appear nearly ideal from a purely chemical viewpoint, but nevertheless it might
be turned down as absolutely unacceptable owing to cost considerations or the
necessity of employing toxic or explosive materials or due to the problem
associated with hazardous wastes. On the other hand, application of a reaction
that requires an additional and rather meticulous elaboration of optimal
conditions (say a heterogeneous catalysis process) can hardly be recommended
as a procedure of choice for a laboratory synthesis. Yet this reaction might be
extremely promising for the chemical industry because the laborious prelimin-
ary investigation may pay off once the procedure has been finely tuned and
elaborated into a profitable large-scale process.
The question about the goals of organic synthesis reflects not only narrow
professional interests, but in fact ascends to a more global and important
problem regarding the destination and usefulness of pure science. Is it really
imperative to spend time and money pursuing the goals of pure science which
are not likely to bring immediate benefits to humanity in the foreseeable future?
The history of modern civilization is ripe with conclusive evidence attesting to
the pragmatic utility of even the most esoteric pursuits of scientific endeavor and
we need not repeat here the well-known reasoning underlying this assertion.
Nevertheless, the issue is never closed completely and the same questions keep
emerging with reference to this or that particular area of science. This apparent
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xviii Introduction
lack of understanding might be boring or even annoying for the scientists, who
always tend to believe in the intrinsic merits and unquestionable values of their
own pursuits. Yet, in our opinion, no researcher may feel free of the responsi-
bility to answer these legitimate doubts of the layman.
People that directly or indirectly provide financial support for the develop-
ment of science have the right to learn why we are so persistent in pursuing our
goals. Thus it should not be surprising that from time to time they will question
the expediency of some academic investigation that may appear as if conceived
with one sole purpose, namely to satisfy the scientists curiosity at the taxpayers
expense. When the discussion refers to synthetic studies directed at the
manufacturing of an artificial foodstuff, then such efforts are likely to get
approval almost without question (There is nothing more indisputable than
bread! - so says the Great Inquisitor in The Karamazov Brothers by
Dostoevsky). However, when professionals assess the ingenious synthesis of
chlorophyll (Woodward, 1960) as one of the benchmark achievements of
organic chemistry, the non-specialists may view this undertaking as, politely
speaking, dubious, since any green plant is capable of synthesizing chlorophyll
every summer in abundant amounts and without our assistance. Such a
perplexity is understandable and it should be clarified. Therefore we start our
book with the question why? in regards to the goals of organic synthesis.
This book refers almost exclusively to the laboratory and not industrial
organic syntheses, The former is much more diversified in its goals and methods,
but the fundamentals of both, of course, are the same. In the final analysis, any
industrial synthesis was conceived in the laboratory and differs from ordinary
bench chemistry only due to the necessity to satisfy a certain set of economical
and technical requirements.
This book is not aimed at the comprehensive coverage of the whole area of
organic synthesis. Our goal is to present the ideology and general principles and
approaches employed in this branch of organic chemistry. Therefore we had to
face a rather difficult task of making the choice of representative examples from
an almost innumerable multitude of synthetic studies. The selection of material
inevitably bears also the imprinting of the personal scientific interests and
experiences of the authors. Nevertheless, it seems to us that inasmuch as the
principles of modern organic synthesis bear a universal character, one can
almost arbitrarily choose illustrative examples from any area, whether it is the
chemistry of aliphatic or aromatic compounds, carbohydrates, organometallics,
acylic compounds, or polycyclics.
Organic synthesis is a rather peculiar area of intellectual activity, creative in
all its major aspects. Its methodology is based on both logistic and purely
heuristic (and not amenable to easy formalization) approaches. Likewise, the
immediate result of a synthesis might be not only finding the way to prepare a
natural compound, but also the creation of artificial objects which had never
existed before in Nature and may fortuitously exhibit an absolutely unexpected
set of properties. In this area are merged together such different qualities as a
rigorous scientific analysis of natural phenomena with its exact predictions, a
search for aesthetically appealing solutions, a deep knowledge of chemistry, and
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Introduction xix
an adroit feeling for compounds, almost an intuitive apprehension of their
behavior. That is why outstanding achievements of modern synthesis are often
perceived as marvellously created pieces of art, having their intrinsic beauty
fused with the expediency and laconism.
We attempted in this book to show not only the basic problems which are
dealt with by synthetic chemists, but also a meaning and creative function of
their activity. We fully apprehend the futility of attempts to describe our subject
in a way equally acceptable for all potential readers, from graduate students to
professional synthetic chemists. Nevertheless, it is still our hope that the former
will be able to grasp some insights about the appeals of our science while the
latter will not chastise us for oversimplification unavoidable in the presentation
of complicated problems within the limited volume of this book.
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Introduction xix
an adroit feeling for compounds, almost an intuitive apprehension of their
behavior. That is why outstanding achievements of modern synthesis are often
perceived as marvellously created pieces of art, having their intrinsic beauty
fused with the expediency and laconism.
We attempted in this book to show not only the basic problems which are
dealt with by synthetic chemists, but also a meaning and creative function of
their activity. We fully apprehend the futility of attempts to describe our subject
in a way equally acceptable for all potential readers, from graduate students to
professional synthetic chemists. Nevertheless, it is still our hope that the former
will be able to grasp some insights about the appeals of our science while the
latter will not chastise us for oversimplification unavoidable in the presentation
of complicated problems within the limited volume of this book.
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