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A Guide for the

Organic Experimentalist
Second Edition

H. J. E. Loewenthal
Israel Institute of Technology, Haifa

with a contribution from

E. Zass
Eidgenossische Technische Hochschule, Zurich


Chichester New York Brisbane Toronto Singapore

Aarau Frankfurt am Main Salzburg
First edition 1978, 1980 Heyden & Sons Ltd
Second edition 1990 by John Wiley & Sons Ltd, Chichester,
Ouo Salle Verlag GmbH & Co., Frankfurt am
Verlag Sauerliinder AG, Aarau

No part of this book may be reproduced by any means,

or transmined, or translated into a machine language
without the wrinen permission of the publisher.

library of Congress Cataloging-in-Publication Data:

Loewenthal, H.J. E.
A guide for the perplexed organic experimentalist / H.J .E.
Loewenthal, E. Zass - 2nd ed.
p. cm.
I. Chemistry, Organic-Laboratory manuals. I. Zass, E.
II. Title.
QD261.L63 1990
547' .0078-dc20 89-70711

British Library Cataloguing in Publication Data:

Loewenthal, H.J. E.
A guide for the perplexed organic experimentalist-2nd ed
I. Organic chemistry. Research
I. Title II. Zass, E.
ISBN O 471 91712 5

CIP-Titelaufnahme der Deutschen Bibliothek

Loewenthal, H.J. E.:
A guide for the perplexed organic experimentalist/ H.J.E.
Loewenthal ; E. Zass. - 2. ed. - Chichester ; New York ;
Brisbane ; Toronto ; Singapore : Wiley ; Aarau ; Frankfurt am
Main ; Salzburg ; Salle u. Sauerliinder, 1990
ISBN 3-7935-5542-9 (Salle u. Sauerliinder) Gb.
ISBN 0-471-91712-5 (Wiley) Gb.
NE: Zass, Engelbert:

WG: 30 DBN 90.012807.0 89.12.07

1846 mar V: Sauerliinder

Typeset in 10 on I 2pt Times by Mathematical Composition Seuers Ltd,

Salisbury, Wiltshire
Printed and bound in Great Britain by Biddies Lid., Guildford, Surrey
Contents *

Preface to First Edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

Preface to Second Edition . . . . . . . . . . . . . . . . . . . . . . . . . . ix

1 On Searching the Literature. The Important

Sources. Using Your Head .................... .

2 On Searching the Literature-Using the Computer

(and Your Head) to Retrieve Structures,
References, Reactions and Data Online . . . . . . . . . . 45
E. Zass

J Basic Safety Rules 83

4 Running Small-scale Reactions in the Research

Laboratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

5 Isolating and Purifying the Product . . . . . . . . . . . . . 121

6 Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 5

7 Which Base Should I Use? . .. .. .. . .. .. . .. .. . . .. 175

All chapters, excluding Chapter 2, by H. J. E. Loewenthal.


8 On Small-scale Distillation 195

9 On Hydrogenation-The Cinderella of the Organic

Chemist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

10 On Keeping it Clean .. .. .. .. .. .. .. . .. .. .. .. .. .. 213

11 Bottling Things Up .. . .. .. .. .. .. . .. .. .. .. .. .. .. 217

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Preface to First Edition

The perplexed organic experimentalist is in my experience the

beginning research student and (frequently) the post-doctoral
research worker. He is the one who early on discovers that he
has to stand on his own two feet, in the task of searching for
information on his subject and in all the practical aspects of his
work-and that means not only how to run a reaction but also
how to choose and acquire the tools and materials of his trade.
All too often it is not by choice that he finds himself in this
situation. His supervisor (or, more politely, his 'Senior Collab-
orator') was himself once a graduate student and post-doctoral
researcher. But in the majority of cases he has long since
abandoned the laboratory bench and is now busy with adminis-
tration, with writing and refereeing research grant applications
and scientific papers, and with teaching and thinking. In the
process he will have forgotten most of the practical knowledge
which he had to acquire painfully in his own day and will have
become unaware of later developments.
The average graduate student is ill-prepared for searching the
literature. Most practical textbooks will have done little to train
him to think for himself. Few prepare him for continuing
preparative work on a small scale, and fewer still for working
with sensitive reagents and under dry and anaerobic conditions.
None, so far as I know, do anything to assist him (or his super-
visor) to grapple with indifferent suppliers, manufacturers and

This small book attempts to fill some of the gaps, on the basis
that organic chemistry is an experimental science first and
foremost, and that in the final analysis-with all of modern
instrumentation and computerisation-it is the organic
chemist's brain and own two hands that are and will remain
indispensable. Hence there is little on instrumental
spectroscopic and analytical techniques and other special fields,
which are quite adequately dealt with elsewhere. The important
matter of safety is, with regret, touched upon only in brief; to
do proper justice to it would be beyond the scope of this book.
Workers in certain areas such as carbohydrates or peptides may
find comparatively little of special relevance to them. Others
will no doubt take exception to a number of statements in this
book. I shall be happy if their misgivings will induce them all
to write a similar book of their own.
I am indebted to many friends and colleagues for constructive
advice and criticism, and above all to Professor R. A. Raphael,
F.R.S. (University of Cambridge), for his encouragement and
great help, and to Professor 0. Jeger (Swiss Federal Institute of
Technology, Zurich) whose hospitality enabled me to get started
on this work.

January 1978 H.J. E. LOEWENTHAL
Pref ace to Second Edition

This edition was written for three good reasons. The first was
that the challenge expressed in the last but one paragraph of the
previous Preface has gone largely unanswered. The second is the
lamentable fact that in the 11 years since the appearance of
the first edition there has been little if any progress in training
the synthetic organic chemist in two essentials: finding the infor-
mation he really needs, and using his own two hands in doing
what distinguishes chemistry from the other sciences, viz.
creating the objects of its own study. The third reason was the
success of the first edition, and the publisher's suggestion to
write another one.
Much of the added material, and also some omissions, are
based on comments on the first edition, most of which were
favourable. A few quaint exceptions: the chemist, acting as
watchdog (or should one say watchbitch?) for a feminist organ-
isation, who succeeded in detecting evidence of male chauvinist
prejudice, and the Scandinavian critic who complained that
dispensing with a condenser in small-scale distillation and
instead cooling with an alcohol-soaked swab of cotton wool led
to inebriation and demoralisation in the laboratory.
It is a great pleasure to thank Dr E. Zass (Laboratory of
Organic Chemistry, ETH, Zurich) for the enthusiasm and great
ability with which he tackled the sisyphean task of writing about
use of the Computer in Information Retrieval. I am also
indebted to Dr J. Schreiber (ETH, Zurich) for a number of

expertly drawn illustrations. Finally, I wish to express my

sincere thanks to Prof. A. Eschenmoser (ETH, Zurich) and
Prof. C. W. Rees (Imperial College, London) for their
hospitality, and once again to Prof. R. A. Raphael (University
of Cambridge, UK) for fruitful discussions.

October 1989 H. J. E. LOEWENTHAL

On Searching the Literature.

The Important Sources.
Using Your Head

This chapter comes first because that is where it ought to be. No

serious programme of research, chemical or otherwise, is ever
embarked upon before a thorough investigation of the current
state of knowledge of the subject has been undertaken. In short,
looking for information is the very first thing you, the beginning
researcher, will be called upon to do in the vast majority of
cases, whether in an academic institution or in industry; and
more often than not you will be completely unprepared for that
The decade that has passed since the first edition of this book
appeared has seen an unprecedented explosion of the amount of
information published in organic chemistry and adjacent fields.
Fortunately, at the same time there has been an impressive
development of computer-aided means for retrieving that infor-
mation. Unfortunately, on the other hand, it is just this which
may delude you into thinking that from now on the computer
will do all your work searching the literature. There you would
be mistaken.
Chapter 2 will indeed guide you in how best to exploit modern
methods of information retrieval: from a number of, but by no
means all, important sources, and going back only for a limited

period of time as things stand at present. However, your most

important computer by far is the one at the top of your spine,
and against that, as you should constantly keep in mind, the
entire framework of modern information retrieval is no more
than a willing but stupid horse that will do the donkey work-if
you will pardon the expression. And that horse must be fed
properly, otherwise the consequences can be disastrous as well
as very expensive.
The following sections are meant to give you a purpose-
oriented brief overview of a number of the important currently
available sources of information, irrespective of whether they
happen to be 'online' at the time of writing or not, and then,
by a series of concrete examples, how to achieve the goal of
getting the fullest information by an integrated effort involving
their combined use.



A number of excellent books on the chemical literature have

appeared in recent years, 1 - 4 and if you want to specialise in this
field or at least feel the urge for some reason or other to acquire
a detailed and systematic expertise in it, you are indeed advised
to become well acquainted with one or two of these. However,
for you as an experimentalist, that is not so likely to be the case.
Here we should perhaps start with a few general rules which
will help you in the search for information. The finer points
which are described in greater detail in the books mentioned
above you will most likely pick up as you go along.
The first is the rule of Retrospectivity, or in other words, start
from the present and work backwards in time. Of course, this
may mean acting against ingrained habits and commonly
acquired behavioural patterns (in fact just as in learning how to
ski for the first time!), but it has a solid logical basis here. In
over 950Jo of all cases you are not the first to look for that spe-
cific item of information. Someone was there before you, and

he in turn will have discovered others who were there before

him. So why not benefit from the labours of your most imme-
diate predecessor, to begin with? In concrete terms this means
looking first at the latest available abstracts index, the most
recently available edition of a collective work such as Beilstein 's
Handbuch der Organischen Chemie (usually referred to simply
as Beilstein) (with which you will soon become acquainted) and
the most recently published review or monograph.
The second rule is: Keep your eyes open, browse, and note
down. You will soon discover that information which in the
long run will turn out to be much more useful will turn up by
the wayside rather than at the original destination. Many (per-
haps most) important lines of research and even important dis-
coveries have started in this way. But it will all be pretty useless
without your having a pen or pencil and some piece of paper
(even a bus ticket or sales slip will do), to write it down imme-
diately. The systematic filing and storage of the incidental infor-
mation you have thus picked up can and should come
afterwards, and more on that point later.
The third rule is to Know and also suspect. Never rest assured
that, having arrived at the desired information, your work is
done. Keep in mind the following possibilities: (a) it may be
inaccurate, (b) it may be incomplete and (c) it may be slanted,
not to say misleading. Possibility (a) is seldom deliberate. More
likely it is the result of sloppiness or the lack of means, or
both of these. For obvious reasons, the further you go back in
time the more likely you will encounter it. All the same, it is
remarkable how reproducible work last done in the non-
instrumentation age can turn out to be (although it sounds
ridiculous, one can get a kick out of finding that a compound
last prepared in 1865 still has the same melting point). Possi-
bility (b) is sometimes deliberate but more frequently due to
neglect, e.g. in not going far enough in trying out different
reaction conditions. Much of your own success will depend on
making up for that. Possibility (c) is deliberate by definition.
Scientists are generally honest, but even with them there is a dif-
ference between the truth, the whole truth and nothing but the

truth. One example might be the selective citation or non-

citation of the work of others, another 'forgetting' to state
whether the yield quoted is of isolated material or 'by GLC'.



The most frequent object of a literature search is to find out

whether a certain compound is known, how it is best prepared
and what its properties are or appear to be. Here in particular
you will end up at a point that will indicate where your own
work should start off.
Instead of giving systematic surveys, tables, schemes, etc.,
which analyse the most important sources and which you will
find in most of the excellent books cited above, the following
will briefly describe these sources and the most important prob-
lems and advantages associated with them, and leave the rest to
the Examples at the end of the chapter.

Chemical Abstracts
This is and remains the uniquely indispensable source of recent
information for this class of search object, perhaps less so for
others. 'Recent' here means 'since the appearance of the latest
relevant volume of Beilstein' (see below)-assuming your insti-
tution or place of work can still afford to subscribe to the latter.
It is to be hoped that your library has a section set aside solely
reserved for Chemical Abstracts and its perusal, which generally
involves consulting and moving around several heavy volumes
simultaneously, and that under no circumstances will any
volume ever leave that area except for binding-not even for
photocopying, to which there is not much point anyway.
The most important parts are the Indexes: the Collective
Indexes insofar as they have appeared and the semi-annual ones
if not. Before 1971 there was only one General Index; since then
this has been subdivided into the Chemical Substance Index and

the General Subject Index. The two other important ones are
the Formula Index and the Author Index. With the appearance
and binding of each new Collective Index all the preceding semi-
annual ones can safely be consigned to oblivion except perhaps
the Author Index-there may always be the time when you will
be looking for something published by so-and-so in the year X.

Chemical Substance Index

There are four main problems encountered by the beginning
researcher, those of nomenclature, of evaluating the entry, of
evaluating the abstract itself (now not all that significant!), and
last but not least evaluating the journal publication or other
source referred to.

Here the golden rule is be on guard all the time. If you think
that IUPAC nomenclature is now universally accepted, you are
mistaken; Chemical Abstracts form a little universe of their
own. Of course, the ever-increasing use of computer searching
and printing provides a good reason (not to say excuse), but
Chemical Abstracts do have some quirks which do not fit even
that kind of rationale. And what complicates matters most is
the way they have in the past changed their minds every couple
of years. If there is one indispensable advice to give, it is this:
use the Index Guide constantly. It is the one instrument that will
guide you through the many confusions, inconsistencies and
incongruities you will encounter.
The 'easy' way out of the nomenclature predicament usually
chosen by beginners is to look up the Formula Index. If you are
lucky you will have something like 20-30 isomers with the same
empirical formula to choose from and decide on one whose
name looks reasonably like that of the compound you are
looking for. If not, you will have over 100 to mull over. Prob-
ably you will soon come to the conclusion that one might as well
face the nomenclature problem head-on to start with.

Evaluating the Entry

This is where you can save a lot of time by using your powers
of deduction and occasionally intuition. Here one faces the fact
that hundreds of people are involved in pr~paring Chemical
Abstracts and that human nature and subjectivit~ _play their
part. However, there have been considerable improvements in
recent years. For example, 'preparation of ... ' now does refer
to where a compound was indeed prepared, quoting exper-
imental details; previously in many cases it referred to where
it just happened to turn up as a by-product in minute yield.
Entries such as 'carcinogenic activity of ... .', or 'in grape-
fruit seed' are not likely to reveal information about the com-
pound's 13 C NMR spectrum, whereas 'bond length in .. .'
might. Physical properties (e.g. melting or boiling points) are
not likely to turn up in entries referring to 'Raman spectrum
of .. .', but they might be given or at least the relevant literature
cited, in entries referring to 'magnetic susceptibility of ... '.
Entries such as 'oxidation of ... ', 'reaction with tributyltin
hydride' or 'N-protection of peptide end groups with .. .' were
once a safe bet that the source in question would describe or at
least cite the compound's synthesis; nowadays in all likelihood
you will find at best that the compound was obtained from the
Y.Z. Company and used as received. That is, unless the
researcher was on a limited budget-a matter on which the
Index is not likely to be informative.

Evaluating the Abstract and the Journal (or other source)

In this section, journals are mostly referred to by their common
Chemical Abstracts abbreviations as this is the form in which
answers to searches are obtained. In the good old days, an
abstract really was an abstract and gave enough detail to serve
in most cases as a substitute for the full publication. Those days
have gone and the abstract has become little more than another
shunting point en route to the original publication. Evaluation

is thus reduced to deciding which journal to look at first and

which to look at at all. If it happens to be in your own library
there is no problem. If not, as happens more and more these
days, the question arises of whether to take the next train or bus
to wherever publications such as Farmaco Ed. Sci., Khim.
Geterosikl. Soedin. or Sb. Pr. Pedagog. Fok. Ostrave Rada E
can be found. This should not even be contemplated unless you
know the language; and knowing someone who does and then
ordering a copy is not always a solution. There are few experi-
ences as frustrating as trying to translate an article in Yakugaku
Zasshi with the help of a Japanese Lecturer in Social
Economics. With Russian journals, however, an important but
still not widely known fact is that a number are now available
in English translation, such as J. Gen. Chem. USSR (Zh.
Obshch. Khim.) and J. Org. Chem. USSR (Zh. Org. Khim.).
An important point to ascertain is whether the journal is in
the form of a communication, and if so, in which journal. In
Angew. Chem. (including the International Edition in English),
Chem. Commun. or Chimia you are not likely to find much
experimental detail. There is more chance of that if it is in
Tetrahedron Lett., J. Org. Chem. or J. Am. Chem. Soc. As far
as the latter is concerned, you will soon find that certain authors
publish nothing but communications and only very rarely a full
paper. Here the prospect of ever getting fuller information is
not bright unless the Senior Author is willing to send it to you
after writing to him personally (and when you write, do not
forget to check whether there has been a change of address from
that given in the paper, lest you commit the unpardonable
offence of not knowing that he/she has moved to a more pres-
tigious institution or position>', And now even with full papers
there are more and more aggravating instances where exper-
imental detail will be sent to you as 'supplementary material'
only after you have sent a cheque for a trifling sum, for which
the bank may charge you more to process than it is worth.
The fact that a reference is to a journal which from its title
is not strictly in the organic chemistry field need not deter you.
Some of the best and most detailed information can turn up in
journals such as Agric. Biol. Chem., Phytochemistry and J.

Organomet. Chem., which cover adjacent fields in which the

majority of authors started off as organic chemists, and it is
only natural for them to try and demonstrate that they have not
lost their touch and expertise.
And now a few comments on where the abstract is of a
patent. This is a real problem when you are nowhere near a
Patent Library and where the abstract gives no worthwhile
detail. By and large it is definitely advisable to order a copy by
airmail or if possible Telex or Fax, assuming you have made
sure that the information in question has not been published in
a regular form, which does happen. Turning up one's nose
automatically at a patent is not justified; this author can recall
a number of cases in his experience where in the preparation of
a tricky kind of compound, following a patent and not a paper
in a 'reputable' journal led to success. Moreover, in many fields
of commercial importance only patents are published and you
then have no alternative. However, remember the bottom line
in connection with patents: they are written by people who first
and foremost are lawyers and not scientists and whose prime
objective is not publication of knowledge for its own sake (or
even the sake of their own personal advancement), but purely
the staking-out of a legal claim-and that usually by not giving
away more information than is absolutely necessary for that

Beilstein's Handbuch der Organischen Chemie

There is probably nothing to compare with this work in any
other branch of science and we organic chemists are unique in
benefiting from a compendium of its kind. While there are
increasing doubts for many of us on how much longer we can
afford it, we should make the fullest possible use of what there
is. The fact that it is written in German (up to the fourth supple-
ment) is no excuse at all for not doing so. There is plenty of
material 5 written in English, including a glossary of German
words used and their equivalent in English and French, to guide
you in using Beilstein, and most of it is available free on appli-

To summarise, Beilstein is organised into acyclic (Volumes

1-4), isocyclic (carbocyclic) (Volumes 5-16) and heterocyclic
parts (Volumes 17-27). There once were additional but now
unimportant volumes. In each volume the original version
(Hauptwerk, H) has been complimented by additional series
(Ergiinzungsbiinde, EI, Ell, EIII, EIV; from Volume 17
onwards the latter two are combined); and those four Comp-
lementary Series are now complete together with a Formula
Index and Subject Index. These cover all organic compounds on
which information had been published up to and including the
year 1959. That year is thus the cut-off date between Beilstein
and Chemical Abstracts as things stand at present, and hence on
the whole there is no need to look for a compound in the
Chemical Abstracts Indexes before the Collective Indexes for
the period 1957-1961. This is assuming, of course, that the
library to which you have access is fortunate in being up-to-date
in this respect. A new comprehensive General Index for all these
series including the original H is presently coming out. It is
probably very advisable to acquire this, even by libraries who
have recently given up on Beilstein for financial reasons,
because apart from giving a total picture of all that is known to
date it will indicate whether it is worth the trouble to seek out
more fortunate libraries which can still afford to subscribe.
A fifth supplementary series includes compounds on which
information had been published up to and including 1979, and
this is now in English; however, so far this applies only to
Volumes 17-19 and thus to heterocycles with one or two oxygen
The rule of retrospectivity applies also to Beilstein. Each
series refers back, with every compound, to the appropriate
page in previous series. An important auxiliary is the System
Number allotted to each compound and its homologous and
functional modifications. This continues unchanged throughout
all series and helps in locating the appropriate book (particu-
larly in later series where each 'Volume' is spread out over a
number of separate books).
The great advantage of compound searching in Beilstein
rather than Chemical Abstracts lies not only in the fact that you

get full details-far more even than in an old Chemical

Abstracts abstract-but that you also benefit from a critical atti-
tude: not everything reported is taken for granted and later
series never hesitate to correct errors in previous ones. Also, the
Indexes make far more allowances for variations in nomencla-
ture. Above all, Beilstein is ideal for browsing, to an extent
unthinkable of in the case of Chemical Abstracts and probably
never to be attainable in the foreseeable future in an online com-
puter search (see Chapter 2). What is meant here is exploiting
the fact that near the compound searched for one will find its
derivatives and homologues and, of course, their properties and
methods of preparation.
However, to get the most out of Beilstein, you must know the
system. Only then will you be able to decide whether an amide
or ester is to be found under the amine or alcohol or under the
acid, or to avoid the frustration caused by the fact that a com-
pound such as succinic anhydride is nowhere near succinic acid
but will be found in the volume marked 'Heterocycles, 10,
Mono- and Polyoxo Compounds'. However, the main point is
that there is a system and that it has remained practically
unchanged during the 75 years of the work's existence in its
present basic form.

Other. Minor, Sources of Value for Compound Searching

The Merck Index

This work, published for the last 100 years by the Merck Co.,
lists substances (both defined chemical compounds and others)
of mainly medical, pharmaceutical, biological and also general
industrial interest. The 10th edition (1983) lists exactly 10 000
substances arranged throughout by serial number. If the com-
pound you happen to be looking for is among those 10 000 you
are in luck because the information is presented very
thoroughly. What you will see are structure, IUPAC and
alternative names, generic and commercial brand names,
physical properties, therapeutic effect and/or general use, a rel-
evant recent literature citation or two, cross-indexes also giving

the Chemical Abstracts name, a Formula Index and one of

Organic Name Reactions, various tables, and incidentally also
with each compound its Chemical Abstracts Registry Number (a
very important item for Chapter 2). All in all, for a one-volume
work this is a real bargain.

Dictionary of Organic Compounds (Ed. J. Buckingham) 6

This successor to the former 'Heilbron' Dictionary is un-
doubtedly an improvement on its predecessor (albeit Chapter 2
will refer to this too as 'Heilbron', for convenience only). It has
so far appeared in five main and four supplementary volumes.
Compounds are still listed on a purely alphabetical basis, with
structures, physical properties (including those of simple deriva-
tives) and several relevant and comparatively recent literature
references (fortunately now indicating whether relating to syn-
thesis or to spectral properties). All compounds listed (and these
include trivial names and compounds of still unknown consti-
tution) are now given a running serial number which makes it
easier to use two additional Index volumes: one a cross-index of
alternative names, the other with a molecular formula index, a
'heteroatom' index (useful when searching for a group of com-
pounds containing, e.g., sulphur, gold or arsenic), and also a
Chemical Abstracts Registry Number Index (sec Chapter 2).
However, the basic weakness is and remains the alphabetical
arrangement (i.e. compounds are not grouped under some basic
structure), and thus it can by no means take the place of
Chemical Abstracts or Beilstein for a thorough compound
search. Also, it will take the experienced user less than five
minutes to find, or rather not find, at least half-a-dozen
perfectly ordinary and common compounds that are not listed
at all.



This is much more difficult because the search object is by nature

less well defined. If it is a name reaction (e.g. Reformatski,

Hell-Volhard-Zelinski), a standard and well documented

procedure (silylation, hydrogenation) or accepted concept
(neighbouring group participation, transannular reaction), the
task is relatively simple. It will become more and more difficult
as its designation becomes more elaborate and complex (e.g.
Michael-type intramolecular addition-cyclisation, gas chroma-
tography of silylated amino acids, effect of solvents on enoli-
There are two possible approaches to this problem. One is to
take into account that most such general search objects can
be expressed in a number of ways and that the abstractor's or
indexer's ideas on this will frequently be different from yours.
Much will depend on your ability to put yourself in his place;
and it is in any case a salutary and educational exercise first to
sit down and write a number of variations by which your prob-
lem can be formulated. But this means employing your intellec-
tual powers for more than merely changing the order of
keywords-any old computer can do that.
The second approach lies in examining how your problem can
be split into component parts, examining each separately and
then seeing how the results can be integrated. For example,
when studying the possibility of getting product B from starting
material A, possibly using a reaction such as R and a reagent
such as X, one can proceed as follows:
(a) look up every known review on R and see if the Tabular
Survey shows anything like A as starting point and like B as
(b) look up A in, for example, Beilstein and look up whether it
or homologues or derivatives have ever been subjected to a
similar reaction (an example of 'Beilstein-browsing');
(c) look up B in the same way and see whether it or similar
compounds have been obtained in a like manner;
(d) look up X in reference books devoted to reagents and see
whether its use has ever been associated with compounds
such as A or 8.
Naturally, whichever approach you embark on you will be

engaged in much toing and froing, trying to assemble, tie up

and disentangle bits of information from different sources. A
searcher engaged on this kind of task can usually be spotted by
the glazed and yet determined look in his eyes and by the way
he forgets appointments and fails to recognise even close
friends. What is practically certain is that in this kind of search
in particular he will come across a lot of unexpected and yet
potentially useful information by the wayside, but the ultimate
benefit from this, just as from the search for the initial object
itself, will depend entirely on the way in which the information
is noted down and ultimately filed away for future reference.
Here the rule of retrospectivity is particularly important. A
worker who has in the past used a compound in which you are
interested may well not have bothered to give a previous refer-
ence to it; but when it comes to a special type of reaction or
application of a particular concept, there he cannot get away
with ignoring his predecessors; they themselves or the Editor or
the referees will see to that.
We are dealing here with a type of literature search where the
number of potential sources of information is very large. What
the beginner needs is some guide to the most generally useful
ones, and to the problems of scope and limitations that must be
taken into account.

Theilheimer's Synthetic Methods of Organic Chemistry1a

Here is another unique compendium which, after getting used
to working with it, the organic experimentalist will soon decide
he cannot do without. What comes then is that he will hear how
much it costs, and he will be left wondering and worrying how
much longer the library he uses can afford to continue to sub-
scribe to it. Forty-three volumes have so far appeared, almost
one each year, and every fifth volume has a collective index. The
literature coverage and choice of examples leave no room for
complaint, even though occasionally showing a subjective slant.
Every example gives full structures (apparently the most 'cost-
intensive' item in this work) of starting materials, intermediates

and products, and brief details with references not only for the
example in question but also for other closely similar work. The
most important part is . the detailed and carefully cross-
referenced index. It is very rare to find one instance, for
example, where a reference for 'A, starting material for B' was
not matched by a corresponding one under 'B, from A'. The
index refers to the Example Number and not to the page. It also
lists reagents (inorganic and metal-organic always under the
metal or non-carbon element), name reactions and reaction
types. A special Guide for using this work has appeared. 7 b
There is a distinctive system and symbolism for division into
reaction classes which looks rather intimidating and tends to
frighten off the beginner, but mastering it is not really essential.
It is essential, however, to get acquainted with it if you intend
to exploit Theilheimer like Beilstein for browsing and getting
information by association, since it groups reactions of the
general type together. This, incidentally is another example (as
with Beilstein) where the fact that this work is now available for
online computer researching is of no consequence regarding
At the end of each volume there is a very important Table
which lists later supplementary references for examples given
in previous volumes. This must be used with some care. For
example, 'Vol. l.. .23, Vol. 28 ... 10' means that page 10 in
Volume 28 contains an example or other information which
complements example 23 in Volume I. Each volume is also
prefaced by an introduction which sums up special develop-
ments since the appearance of the previous one.
The binding of this work used to be terrible (for its price)-in
practically every library the author has been to, Volume 10 has
gone through a stage of complete disintegration, but since then
there has been considerable improvement in this regard.

Chemical Abstracts
Since the advent of the division of the original Subject Index
into the Chemical Substance Index and the General Subject

Index, the latter should by rights serve as an important means

for searching for reactions, methods and concepts. Very often
it does indeed-with some reservations. The number of head-
ings has increased enormously, but so has the number of
entries. Quite apart from making this hard on one's eyesight
and stamina, a lot of careful judgment has to be exercised, the
reason being, as mentioned before, an all-too-frequent differ-
ence of approach between you and the abstractor and indexer.
Here is one example:
The searcher may be looking for a method which specifically
effects meta-bromination of phenols. In Theilheimer, Index
of Collective Vol. 40, he will find: 'meta-bromination'-this
refers to Vol. 36, example 474. This refers to a paper by J. C.
Jaquesy et al., Chem. Commun. 110 (1980), which shows
that 4-alkyl and 2,6-dialkylphenols are brominated spe-
cifically in the meta position when dissolved in HF-SbFs
('super-acid'). Theilheimer also states: 'cf. Tetrahedron 37,
747 (1981)', meaning that there one will find additional infor-
mation. In Chemical Abstracts, on the other hand (General
Subject Index, Collective Vol. 1977-81) the following situ-
ation is encountered: under 'Phenols, Reactions' one will find
'bromination', but not 'meta' nor even 'regiospecific', but
one will find 'bromination of, in super-acid, mechanism of'
(93, 94918a), which is found to refer to the above Chem.
Commun. paper-however, there is no mention of 'meta' or
of the Tetrahedron paper. On the other hand, under
'bromination' one will find 'meta', but now this is qualified:
'of dimethylphenol and -anisole, in super acids', and this
refers only to 95, 80347t, which is the abstract of the Tetrahe-
dron paper.
This is the sort of thing that happens all the time in a search
of this kind in Chemical Abstracts, but that should not
necessarily put you off consulting it altogether. There are
enough instances where you will get information from that
source which is missing from, e.g., Thei/heimer, to make it
worth while.

Fieser and Fieser's Reagents for Organic Synthesis 8

This work, 14 volumes of which have appeared so far, delivers
far more than its title would suggest, since it is the work in
which to find important and up-to-date information by
browsing and association, but then only if it is read and not
merely used as a work of reference. This is why, in this author's
opinion, it is probably the best single investment an
experimental organic chemist can acquire at the present time. It
deals alphabetically with reagents used in organic chemistry,
their use with different substrates, how they are prepared or
where they can be bought, and in each volume reference is made
to the reagent's treatment in previous volumes. There is a
general index and, more important, an 'Index of Reagents
According to Types', which in effect is an index to reactions and
methods. The only snag lies in occasional and unexpected
changes in nomenclature from one volume to the next and even
in the same volume between the index and the text to which it
refers. But with a work like this it may even be a blessing in dis-
guise, since putting this straight m~y well put you on to more
unexpected gems of information by the wayside.

Methoden der Organischen Chemie (Houben-Wey!) 9

There is a lot that needs to be said about this elephantine work
(82 parts up to last counting!) which deals with classes of organic
compounds, their preparation and reactions. For the beginning
literature searcher it could perhaps best be summarised as fol-
lows: much of it is not easy to use, to put it mildly; some of it
is excellent and well worth making the effort of acquaintance.
Up to the most recent volumes one had first of all to decipher
the fine gold lettering on the back or what was left of it, guess
which of five or six volumes (all marked, for example 'oxygen
compounds') might possibly be the right one, admire a full-page
photograph of a Very Important Person, skip through 2-4
pages of miscellaneous forewords and prefaces and wade
through 14 pages or more of journal abbreviations before

getting to the nitty-gritty of a list of actual contents. Recent

volumes have done away with most of that nonsense, but now
one has to cope with fiendish new-style indexes that mention
actual compounds grouped under rather arbitrarily selected
basic structures but that are woefully short of listing more
general topics and concepts. As for the actual contents, some of
the newer volumes are superb (e.g. those on organometallic
compounds and the new supplementary volume on aldehydes),
others are just plain awful as far as level and coverage are con-
cerned. Altogether one gets the impression of a lack of a guiding
hand and of general principles of construction-in this respect
Houben-Wey/, although also a German work, is the antithesis
of Beilstein. No wonder this work is almost ignored outside
German-speaking countries, which in some ways is unfortunate.
The Examples given at the end of the chapter will serve to
amplify some of the comments made here.

Organic Reactions
This old-established series collecting reviews on 'name'
reactions and others of a well defined character is perhaps the
best known of its type. Each such review has sections discussing
mechanism, scope and limitations of the reaction discussed, but
the most important parts are the Tabular Surveys. Only a study
of these will answer the cardinal question in every case: how a
specific reaction will work within a particular molecular
environment and/or in the presence of other functional groups.
Most of the Tables have had a lot of work put into them and
this occasionally borders on the incredible, such as the two-
author review on the Aldo! Reaction (Volume 16), which lists a
total of 2359 references.
The total number of volumes has now reached 36, but it is
unlikely that you can consider any of the chapters published in
the first 20 volumes as constituting any guide at all to present
knowledge of the subject. For any subject dealt with in these
you are strongly advised to look for a more recent review (see
below, 'On Reviews in General') which in all likelihood you will

find. You may even find repeat reviews in Organic Reactions

themselves (e.g. Reformatski reaction, Fluorination). If you do
happen to work on a well defined reaction or in a field of well
documented current interest such as metallation, fluorination,
directed aldol condensations or use of alkynylaluminium com-
pounds, then your first step should be to take advantage of the
fact that there is a recent Organic Reactions chapter on the
subject and that the most recent references quoted there are by
authors who in all likelihqod are still active (see 'Searching by
Author') at the present time.

Comprehensive Organic Chemistry (Barton and Ollis) 10

The best overview of the state of organic chemistry as of the
beginning of the 1980s is probably given by this work, not least
because of the superb last Index Volume. This deals with the
following: Formulae, Subjects (both classes of compounds and
individual compounds mentioned), Authors, Reactions (in-
cluding references to the most important recent reviews) and
Reagents. The work as a whole thus supplements and even sup-
plants in many ways many of the compendia mentioned above,
at present-the question is, for how much longer?

Organic Syntheses
This well known collection has been left here until last for a
good reason, which applies particularly to the first five Collec-
tive Volumes. The very fact that it contains detailed and pains-
takingly checked directions for preparing specific compounds or
closely related ones, in itself performing a great service to
organic chemists as a whole, can be a psychological trap for the
beginning researcher. He is tempted to believe that directions
for preparing aromatic ketone A by a Friedel-Crafts reaction
can be applied verbatim to making another aromatic ketone B,
or that the same tools and procedures described for a reaction
on a molar scale are suitable for making a millimole. Fortu-
nately, the more recent issues take a wider view with each spe-
cific example, discuss scopes and limitations and tend to give

procedures which can serve as a general model and which in

many cases have not been published elsewhere.


The problem is that there are so many of them, and hence the
need first of all to look for a review, let alone the question of
how to consult and evaluate it. Fortunately, there are Indexes
of Reviews. At present the most comprehensive and up-to-date
index, not merely of reviews per se but of any publication that
might be construed as having review character, is the semi-
annual Index of Scientific Reviews published by the ISi (Insti-
tute for Scientific Information). This may not be found in many
libraries, but as part of a thorough literature search it is worth
going some distance to consult this work. Other such indexes
are that published by the Royal Society of Chemistry (RSC),
which has been updated several times in the past but not very
recently, and that appearing at the back of each issue of the per-
iodical Methods in Organic Synthesis, also published by the
RSC and which should be consulted on a routine basis. The
same kind of list used to appear periodically in issues of Journal
of Organic Chemistry, where it benefited in particular from an
accompanying keyword index; unfortunately, this has been dis-
A review is, of course, where someone else should have done
all the work of collecting information for your benefit. In prac-
tice this rarely turns out to be the case and it is necessary to
understand why, by knowing something of the circumstances
under which most reviews are written. To this end one could
divide reviews roughly into three categories. In the first are
those whose authors were required to cover a subject compre-
hensively up to the time of writing. Obvious examples are those
appearing in Organic Reactions and Chemical Reviews. Parts of
series such as The Chemistry of Functional Groups, 11 The
Chemistry of Heterocyclic Compounds 12 and Organic
Chemistry, a Series of Monographs 13 could also be considered
as belonging to this category.

The second group includes those reviews in which coverage of

a subject was done for a limited period of time. These can be
found in series such as Annual Reports and Specialist Periodical
Reports from the RSC (many of the latter now discontinued),
and in a large number of other series usually prefixed by
'Annual Reports ... ', 'Progress in ... ' or 'Fortschritte .. .'. In most
of these coverage of the literature is likely to be especially
thorough, at any rate for the period in question, because the
authors knew of their assiinment ahead of time and were thus
prepared for thorough and systematic scanning of the field.
That is why reviews of this kind, containing the most significant
earlier references, will probably give the best overall picture of
the present state of knowledge in any subject covered.
The third category are those where the author had been
working intensively in his field, had accumulated many litera-
ture data and had come to the conclusion that he had a contri-
bution to make (and/or saw an opportunity to enlarge his
publication list). It also includes those cases where he was con-
sidered by others to be a leader in his chosen or self-originated
field and was then invited to write a review with no strings
attached. Naturally you will find there particular emphasis on
the author's own contributions and on that previous work
which he considered to be most relevant (if not affirmative) to
his own. Such reviews will often be found in series such as
Accounts of Chemical Research, Chemical Society Reviews
(formerly Quarterly Reviews), Angewandte Chemie and in
journals such as Synthesis, Tetrahedron, Bulletin de la Societe
Chimique de France and Organic Preparations and Procedures.
What had best be said about a review of this type is that any one
in which references to the author's own work exceed lOOJo of the
total number should be treated with reserve.


Reactions, methods and concepts usually become associated

with the name of whoever has been considered to have contri-
buted most to these (sometimes unjustifiably so). Hence it
stands to reason that you can get more, and up-to-date, infor-

mation if you follow up his/her name in the literature, in par-

ticular if he/she is still alive and active. The Author Index of
Chemical Abstracts is the first place'to look, but first of all one
has to decide which name to look out for. There is the problem
of name duplication-you will be amazed to find how many
chemists there are around even bearing a name that is uncom-
mon; and even the customary request made of authors that they
supply at least two initials (whether they exist or not) does not
suffice to prevent confusion. But then when you have got the
right name there may be another problem. Until recently it was
not clear from a paper authored by, for instance, Pickles,
Chutney and Gherkin who was the senior author and hence the
main source of inspiration. You then found out that there were
20 entries for Chutney and only one for each of the others-
obviously Chutney was your man (or woman). This approach is
not quite foolproof: Chutney may by now be over 65 and
spending most of his/her time on committees or travelling from
one meeting to another, and it is now Pickles who is now pub-
lishing (or perishing) in a junior position. Quite likely it is
he/she who is now following up the original idea. Nowadays
journals require marking with an asterisk the author 'to whom
correspondence should be addressed'. In most cases this is
indeed the senior author unless he/she does not want to be
bothered by people asking for reprints-in most cases nowadays
such requests are motivated by getting the stamps on the enve-
lope rather than the learned material inside.
You will have noticed how this particular paragraph has been
careful about the sex problem. With ladies there is the addi-
tional problem of the change of name on marriage. For example,
perhaps you would like to follow up the organic chemist
who first published in 1948 under the name of M. Roberts.


Chemical Abstracts Key Word Index

Every weekly issue of Chemical Abstracts now contains this
index which alphabetically lists combinations of 'keywords',

which are taken from the titles of both the original publication
and from the abstract, for what the latter may be worth. These
keywords are assigned by the indexer and of course ignore
trivial words such as 'and', 'by', etc. For example, a publication
entitled 'Preparation of 3-Acyl Indoles. Triethyl Orthoacetate
and Trimethyl Orthobenzoate as Effective Acylating Agents' is
referenced in the Keyword Index by four entries as follows:
Indo/e-acylation orthoacetate orthobenzoate
Acj,lation-indole orthoacetate orthobenzoate
Orthoacetate-triethyl indole acylating agent
Orthobenzoate-trimethyl indole acylating agent
This index is by no means a vade mecum for following up
everything happening in the field in which you are interested.
For one thing it depends entirely on what the author(s) has
(have) chosen to put into the title and/or what the abstractor
had found fit to put into the abstract. For another it is often
incomplete. For instance, by rights in the example given above
there should have been another entry: Indole-3-acyl, etc., but
there is not. In other words, the Keyword Index should be
regarded as only one of the many devices you should use for
keeping up-to-date.

Science Citation Index

This is the collective name for a number of indexes published on
a periodical basis (usually quarterly) by the Institute of Scien-
tific Information (ISi), already mentioned as publisher of the
Index of Reviews. There are three main parts. The Source Index
lists alphabetically the names of authors and other sources who
have published in the period under review and gives the titles
and location of their publications. The Permuterm Index lists
'subjects' (see below) and enters the name of authors who have
published on them, indicating at the same time those who have
published more than once on the subject and those who have
published on them uniquely. This index should not be con-
sidered as equivalent to the Chemical Abstracts one-unlike in

the latter, the terms are arrived at by computer manipulation

only. However, for the practising organic chemist the most
important by far is the Citation Index.

Citation Index
In recent years it has been difficult, month by month or even
week by week, not to find any issue of a journal in organic
chemistry without some publication describing a synthetic
method or reagent, that does not lay claim to a superlative of
some sort: 'the best', 'the most direct', 'the most economical',
'the first time that...' or 'the only one that both... and .. .'.
More often than not our perplexed chemist will discover that
application to his case under the conditions cited gives either
zero or very low yields or leads to different results altogether.
The particular importance of the Citation Index in this situation
lies in the way it enables one to find out what other workers'
experience has been since the appearance of the original publi-
cation, especially as this index (which appears every 3 months)
is one of the most up-to-date secondary publications now
available. With older work, recent authors do show a tendency
not to cite, whether out of negligence, forgetfulness or from Jess
forgivable motives. With more recent publications they will do
so, wherever comment is appropriate, whether it be positive (i.e.
confirming the original finding), negative (reporting that it does
not work or works badly and then of course describing a better
method) or elaborative (where an improvement on the original
was worked out). This is where following Chemical Abstracts as
it appears weekly is of practically no use at all.
Citations in the Citation Index will appear under the firs/-
named author (regardless of his actual status!) and his initial(s),
followed by the year, the abbreviation of the journal, volume
number and page. It is therefore necessary to make a careful
note of each item, because with names like Smith and Jones or
with Japanese authors (even with two initials) duplication often
occurs, and the searcher may find himself pursuing a citer in
meteorology or pediatrics. Citers appear underneath in lighter

type, in alphabetical order with initials, name of publication,

etc., and the year at the end. Some insight into the significance
of the cited publications can be obtained just by counting the
number of citations in each year. An ever-increasing number
over, say, 5 years is a good omen.
The best way of examining each citing publication is to look
first at the references and then tracing the reference number in
the text. Footnotes should not be ignored-that is where some
people 'hide' the experimentally most valuable information.

Methods in Organic Synthesis

This monthly publication by the Royal Society of Chemistry is
a must for the beginning (and advanced) searcher and
researcher. Each issue abstracts articles from current journals
by giving authors, reference, structures of starting materials,
reagents and products, as well as summary of procedures, yields
and number of examples given, in other words anything of syn-
thetic interest. Most of the material is hand-drawn and photo-
graphically reproduced for economy and rapidity of publication
(when this publication first appeared it appeared to this author
to bear a curious resemblance to a privately issued previous one
by a number of graduate students at a certain well known uni-
versity in the USA!). Each issue has indexes .of authors, pro-
ducts, reactions, reagents and reactants and also a list of
currently issued reviews, books and conference proceedings.
Altogether this is a publication whose issues can and should be
routinely taken home overnight for rigorous and systematic


So far we have dwelt on the problem of how to get to the right

reference and journal. Now a few words on how to read jour-
nals, assuming it is concrete information in which you are
interested. To put things in a nutshell, there is in the end no
alternative to reading each journal as it comes in. This is

because the most significant information one may ever pick up

is that found incidentally and not from any keyword, index or
abstract: a casual reference, a chance remark or a fortuitous
experimental observation. However, strictly speaking this is
physically impossible. What one can suggest is some speed-
reading course or at least system or approach that will enable
the researcher to spot the 'horse' of facts, results and
experimental detail, rather than get held up by the 'cart' of
exposition and justification and pearls of wisdom after the fact.
In the following text, most journals are referred to by their
Chemical Abstracts abbreviations for brevity.
With Communications (Tetrahedron Lett., Chem. Commun.,
Synth. Commun., Angew. Chem. Int. Ed. Engl. and the back
parts of J. Am. Chem. Soc. and J. Org. Chem.), scanning the
list of contents is usually enough to bring all the important facts
to one's attention; full details will usually be absent. Perhaps
one more thing should be checked, though-footnotes, which is
where, as already pointed out, much important information
may be hidden, to be 'pulled out of the hat' when the question
of priority ever arises!
Full papers need .a different approach. Probably you will turn
first to those devoted entirely to organic chemistry: J. Org.
Chem., Tetrahedron, Synthesis, J. Med. Chem., J. Heterocycl.
Chem., J. Chem. Soc. Perkin Trans., Annalen, and the rel-
evant separate parts of Bull. Soc. Chim. Fr. and Acta Chem.
Scand. Other journals (Helv. Chim. Acta, Chem. Ber., Bull.
Chem. Soc. Jpn.) have an organic section in the Contents list
but not in the journal itself. A third group (notably J. Am.
Chem. Soc.) make no attempt to help the reader by any subdivi-
sion, perhaps in the (forlorn) hope of getting across the idea
that 'Chemistry is One'.
With full papers it will not do to rely on the title of the paper
or on the author list when making a choice on what to read.
Any really novel finding will most probably have been published
earlier in Communication form. But most importantly: a paper
on purines may contain details on the preparation of an impor-
tant /3-dicarbonyl intermediate, one on the mechanism of the

Claisen rearrangement may give valuable information on an

important organometallic reagent and one on carbohydrates on
how to open a sterically hindered epoxide by an organoc:opper
reagent. All such potentially valuable information will be lost to
you if you decide from the outset that purines, Claisen-type
rearrangements and sugars have nothing to do with your own
line of work; and of course it will equally be lost to you if you
rely on a Keyword Index.
So how do you 'go through' a journal from cover to cover?
By looking for the key items that will serve as a kind of anchor:
first and foremost structural formulae, reaction flow charts, and
conditions used. If every author would also give these priority,
his work would receive much more attention. Often this is not
easy because of an ever-increasing tendency to list compounds
under a basic structural formula with variations indicated as R,
R', R" etc.; n = I, 2, 3, etc.; this is not always the fault of the
author, but that of the Editor intent on saving money.
After having fixed these items in your mind you will be able
to plan in your mind the scanning of the Experimental section.
In this it is safe to assume that any author who has taken care
that his work is reliable and reproducible will have taken equal
pride in the way he describes the work. For example, the word
'treat' ('the solution was treated with .. .') is frequently con-
venient when the author has forgotten exactly how it was done.
Other dreadful examples of currently fashionable jargon that
often cover up sloppiness are 'exposed to .. .', 'subjection of
.. .', 'protocol' (look up the real meaning!), 'aged overnight',
and that great favourite ' - 78'. Opening statements such as
'General directions as described in Part X' may hide the fact
that they do not work in Part XI. Apart from this, General
Directions and Methods often contain valuable information on
techniques, preparation and purification of intermediates, sol-
vents and reagents that can easily be overlooked.
Only after this should you skim the main text for anything
that might be of further value rather than padding and
reasoning after the event. Should you encounter a statement

such as 'the presently described method is greatly superior to

previously reported ones', your first reaction should be to look
at the overall yield and efforts involved in reaching the final pro-
duct, and the effort and expense that go into the reagent used,
rather than only at the high-yield last step.
Statements such as 'Further work is continuing' or 'ad-
ditional results will be reported subsequently', once an implied
threat and 'keep off' notice, are now rarely more than an off-
hand promise honoured in the breach rather than in observance.


Perhaps you should not read this until after going through
Chapter 2. If you have, and are not entirely convinced that the
computer will be your constant companion and helpmeet in the
future, you should start a card index, to have it all 'at your
finger tips'. There should be a card for every possible topic, and
there should be cross-referencing cards pointing in all feasible
directions. You should always have a supply of cards with you;
envelopes or paper napkins get lost, mixed up or used for other
purposes. There is no need to use the customary stiff cards, slips
of ordinary paper cut to size will do just as well. In fact, if you
plan to be active for at least part of your 'active' life it would
pay to put the information on cut-to-size slips of thin air-mail
paper. In that way even an index containing 15 000-20 000 items
still weighs less for travelling than a small personal computer
with all the trimmings.
One could make suggestions on classification such as dividing
a card index into two main parts: functional groups on the one
hand, and reactions, methods and concepts on the other. But in
the end you will have to devise the system that suits you best,
and change or modify it as time goes on and experience is ac-
cumulated. Your card index is an extension of your memory
cells and should remain strictly your private domain. Never ever
lend your cards to anyone else.


1. References are given without authors, except where appro-
2. For journal abbreviations the reader should consult the
Chemical Abstracts Source Index.
3. References are given uniformly in the order: volume (if any),
page (year); and not necessarily as in Chemical Abstracts
where practice has changed over the years.

Example 1




Ibuprofen (antiinflammatory drug)

Information available on resolution into enantiomers, on a
possibly preparative scale.


IUPAC name: 2-(4' -Isobutylphenyl)propanoic acid

Chemical Abstracts Collective Index 1982-1986: nothing
under: propanoic acid, 2-(4' -isobutylphenyl), nor under:
propanoic acid, 2-phenyl; i.e. IUPAC name not used here!
Consultation of Index Guide and Merck Index: alternatives
(a) a-Methyl-4-(2-methylpropyl)benzeneacetic acid,

(b) p-lsobutyl hydratropic acid.

Index Guide: shows that (a) applies; hence looked for:
Benzeneacetic acid, o:-methyl-4-(2-methylpropyl)



Chemical Abstracts Collective Index 1982-1986

(R )- or resolution of, with chiral 0:1-acid
(S)-: glycoprotein column, 104: 230570f-
J. Liq. Chromat. 9, 621 (1986). Ref. l
( )-: resolution of, by gas chromato-
graphy, with amphetamine as
derivatizing agent, 105: 202672-J.
Chromatogr. 378, 125 (1986). Ref. 2
( )-: resolution of, by high-performance
liquid chromatography of
naphthylmethylamide deriv., 100:
l 26986c-J. Chromatogr. 284, 117
(1984). Ref. 3
( )- and resolution of, by HPLC: 104:
(R)- 174767m-Am. Lab. (Fairfield,
and (S)- Conn.) 18, 138 (1986). Ref. 4
105: 90672j-J. Chromatogr. 378
409 (1986). Ref. 5
()-and separation of diastereomers of, by
(R)- centrifugal TLC of phenylethylamide
and (S)-: derivs., 104: 230579r-J.
Chromatogr., 356, 341 (1986). Ref. 6
(R)-, chiral separation by HPLC on
(S)-: 0:1-acid glycoprotein-bonded
stationary phase, mobile phase and
pH effect on, 105: 232524p-J.
Chromatogr. 365, 73 (1986). Ref. 7
(R)- and separation of, from racemic mixture,

(S)-: 101: 203779n-J. Chromatogr. 299,

397 (1984). Ref 8

Chemical Abstracts Collective Index 1977-1981

( )-: resolution of diastereomers of, by
liquid chromatography following
derivatization with chiral reagents,
94: 53433r-Anal. Chim. Acta, 120,
187 (1980). Ref. 9
(S)-: (no entry), 95, P 683 le-US Patent
No. 4,209,638. Ref. 10

Chemical Abstracts Collective Index 1972-1976

( )-: nothing under 'separation' or
(R)- and preparation and metabolism of,
(S)-: isomeric inversion in relation to, 84:
l 15595z-J. Pharm. Sci. 65, 269
(l 976). Ref. 11

Chemical Abstracts Collective Index 1967-1971

No 'Benzeneacetic acid' in
Index-Change in nomenclature!
After consultation of later Index
Guides, previous name emerges as:
Hydratropic acid, p-Isobutyl.
Under this name: nothing on
'resolution', 'separation of isomers',
'separation of enantiomers'; and no
listing of (R) or (S).

Chemical Abstracts Collective Index 1962-1966

Again looked under: 'Hydratropic
acid, p-Isobutyl':
Only four references, two of them to
ethyl ester, no reference to 'enan-
tiomers', 'resolution', 'separation',

Chemical Abstracts Collective Index 1957-1961

No listing of any kind (tried various
nomenclature combinations, and also
Formula Index).


Established as belonging in Volume 9. Looked at Index of 4th

Supplementary, Volumes 9-11. Not listed under any of the
above nomenclature possibilities.


This example illustrates difficulties caused by nomenclature

changes, and different wordings of entry in the abstract Index
referring in effect to the same thing: 'resoln.' and 'sepn. of
diastereomers of. . .' for the racemate and 'sepn. of, from
isomer', 'chiral sepn. of' and 'sepn. of, from racemic mixture'
for the (R )- and (S)-enantiomers. Ref. 4 and Ref. 11: journal
unavailable. Refs. 1, 2, 5, 7, 8 and 9: the methods described
appear suitable for analytical purposes only. Refs. 3 and 6:
appear suitable for separations on a small preparative scale.
Ref. 10: the abstract indicates large scale separation of
diastereomeric salts and give an example for a related com-
pound on a kilogram scale; hence copy of this patent was

Example 2


CH1-CO-CH=CH-C02Me Method suitable for large-

scale preparation, as a
substrate for 1,4-addition
reactions (hence question of
, Z-geometry probably


IUPAC name: Methyl 4-oxopent-2-enoate

Looked up in Chemical Abstracts latest Index under:
2-Pentenoic acid, 4-oxo, methyl ester
-found to appear under this name.



Chemical Abstracts Collective Index 1982-1986

(E)-: 101: 718lle-J. Org. Chem. 49, 2857
(1984). Ref. 1
(E)-: 100: 209l43b-Liebigs Ann. Chem.
820 (1984). Ref 2
(E)-: 97: l09528g-Tetrahedron Lett. 23,
2013 (1982). Ref. 3
(E)-: 98: 2l5425b-Tetrahedron 38, 2377
(1982). Ref. 4
(E)- or
(Z)-: 103: 53729w-J. Org. Chem. 50,
2650 (1985). Ref 5
(Z)-: 101: 38ll4g-Synthesis 280 (1984). Ref 6

Interim Evaluation
Ref. 1: Compound obtained by sulphenylation-
desulphenylation; not likely to be of preparative
value as applied to a starting material.
Ref. 2: Compound obtained by cleavage of a
silyloxy cyclopropane, a method claimed to be of
general value for a, ,3-unsaturated r-keto esters,
but probably quite unsuitable economically for this
particular one.
Ref. 3: turns out to be Preliminary Communi-
cation for Ref. 2. Also refers to:
Chem. Ber. 96, 465 (1963). Ref 3a

Ref. 4: Compound turns up as one of several

products in one reaction, in 3.30'/o yield. Probably
Ref. 5: Describes a Michael annelation sequence
using this compound without giving details on it,
but refers to:
J. Org. Chem. 39, 2213 (1974). Ref. 5a
Ref. 6: Compound obtained by oxidative
cleavage of a methoxyfuran (but how easily is that
available?). Refers to Ref. 5a and also to:
J. Chem Soc. 1772 (1950). Ref. 6a
Ref. 3a: Compound obtained by a Wittig
reaction. Probably not suitable for large scale.
Ref. 5a: Describes the preparation of the ethyl
(not methyl) ester from ethyl levulinate (com-
mercially available, cheap) by bromination-
dehydrobromination. Gives b.p., spectral data
(n.m.r., i.r.). No mention of methyl ester. Worth
keeping in mind!
Ref. 6a: Compound obtained by semi-
hydrogenation of the corresponding acetylenic ester
which of course is quite difficult to prepare. Quite
unsuitable for large scale preparation!

Chemical Abstracts Collective Index 1977-1981

( )-: 87: l 18049x-Chem. Stosow. 21, 251
(1977). Ref 7
( )-: 95: 42965k-J. Org. Chem. 46, 3137
(1981). Ref 8
()- and 86: 154965f-J. Org. Chem. 42, 1256
(Z)-: (1977). Ref 9
()-: 86: 139930x-Chem. Ber. 110, 540
(1977). Ref 10
( )-: 94: 191203s-J. Org. Chem. 46, 1745
(1981). Ref. 11

Interim Evaluation
Ref. 7: Journal unavailable.
Ref. 8: Quotes Ref. Sa and gives m.p. of methyl
ester (59 C).
Ref. 9: Describes a four-step sequence via
acetals of both ()- and (Z)-isomers, with separ-
ation problems-unsuitable for preparative work.
Does give spectral data but no m.p.
Ref. 10: Gives n.m.r. spectrum of pure com-
pound and quotes for its preparation:
Liebigs Ann. Chem. 403, 150 (1914). Ref. lOa
Ref. 11: Compound made by hydrolysis (pyri-
dine hydrobromide perbromide) of corresponding
thioketal using a phase transfer catalyst; no details
on the product and no reference to method of
preparation of starting material.

Chemical Abstracts Collective Index 1972-1976

( )-: 76: P 72045k-Italian Patent 796,
247. Ref. 12
( )-: 81: 49233q-Chem. Ber. 107, 1509
(1974). Ref. 13
( )-: 81: 91744y-J. Org. Chem. 39, 2211
(1974). Ref. 14
( )-: 85: l 76776b-Canad. J. Chem. 54,
1998 (1976). Ref. 15
()-: 79: 11508la-Tetrahedron Lett. 14,
217 (1973). Ref. 16
( )-: 78: 3569p-Bull. Soc. Chim. Fr. 2817
(1972). Ref. 17

Interim Evaluation
Ref. 12: Method involves catalytic carbonylation using
Ni(C0)4-highly poisonous, inadvisable as laboratory
Ref. 13: Compound obtained by reaction of ester with

nitroenamine Uust how available in this case?), then cleavage

(Si02) of intermediate; final product obtained in 37% yield.
Looks rather unpromising.
Ref. 14: Same as Ref. 5a.
Ref. 15: Compound obtained as one of many in low yield.
Ref. 16: Compound obtained by selective ozonisation of a
diene ester. Claimed to be general for this type of compound,
but in this case at least the starting material is much less
accessible than the desired product.
Ref. 17: Compound obtained from methyl levulinate by
bromination-dehydrobromination. Details are given but no
yield. Ref. lOa is not cited. Quotes non-available dissertation.
Worth keeping in mind. Note: no reference in entry or
abstract to 'preparation'.

Chemical Abstracts Collective Index 1967-1971

(note: in this case no nomenclature change)
( )-: 67: 8l773n-Justus Liebigs Ann.
Chem. 106, 68 (1967). Ref. 18
( )-: 70: 6754lr-Khim. Geterotsik/.
Soedin 1131 (1968). Ref. 19
( )-: 71: l0l489n-Chim. Ind. (Milan) 51,
673 (1969). Ref. 20
( )-: 71: 8388u-Bu//. Chem. Soc. Jap.
42, 1098 (1969). Ref. 21
( )-: 69: 589l9x-Bu/l. Chem. Soc. lap.
41, 971 (1968). Ref. 22
( )-: 69: 105639t-Bu//. Chem. Soc. lap.
41, 2219 (1968). Ref. 23
()-: 67: 77715c-Bu//. Chem. Soc. lap.
40, 1512 (1967). Ref. 24

Interim Evaluation:
Ref. 18: Compound obtained by Wittig reaction-see
comment on Ref. 3a.
Ref. 19: Russian journal, unavailable, no English trans-

Ref. 20: Not much detail in abstract, journal unavailable,

probably identical with Ref. 12.
Refs. 21 and 22 (same research group): No detail on pre-
paration but quote Ref. IOa and give m.p. (58.5-60 C).
Ref. 23: Preliminary communication to Refs. 21 and 22, no
Ref. 24: No details on compound.

Chemical Abstracts Collective Index 1962-1966

( )-: 56: 5808b-Angew. Chem. 73, 620
(1961). Ref. 25
( )-: 58: 13788h-Ber. 96, 465 (1963). Ref. 26
( )-: 61: 628g-Collection Czech. Chem.
Commun. 29, 1380 (1964). Ref. 27
( )-: 63: P 13086c-Czech Patent 113,213. Ref. 28
trans-: 63: 6851b-Lantbrukshogskol. Ann.
30, 615 (1964). Ref. 29
( )-: 58: 11205g-Arkiv Kemi 20, 115
(1961). Ref. 30

Interim Evaluation
Refs. 25 and 26: Virtually identical to Ref. 3a.
Ref. 27: Compound prepared from a furan derivative by
bromination-dehydrobromination. Very good yield claimed,
but too many steps involved. Mentions bacteriostatic activity.
Refers to Ref. lOa, and also cites:
J. Amer. Chem. Soc. 72, 4304 (1950). Ref. 27a
Ref. 28: Apparently identical to Ref. 27.
Ref. 29: Journal (?) quite unavailable.
Ref. 30: Journal unavailable.
Ref. 27a: Compound obtained by Se02 dehydrogenation of
methyl levulinate-too expensive and also toxic; Ref. 1Oa is

Chemical Abstracts Collective Index 1957-1961

( )-: 53: 9094b-Comptes rend. 247, 665
(1958). Ref. 31

( )-: 52: 12197e-J. Pharmaco/. Exptl.

Therap. 122, 489 (1958). Ref. 32
( )-: 54: 270e-J. Amer. Chem. Soc. 81,
2075 (1959). Ref. 33
( )-: SS: 12279i-Arkiv Kemi 16, 181
(1960). Ref. 34
trans-: SS: 373e-Nature 187, 146 (1960). Ref. 35

Interim Evaluation
Refs. 31 and 32: Unavailable.
Ref. 33: Cites for parent acid:
J. Chem. Soc. 3500 (1950). Ref. 33a
Ref. 34: Unavailable.
Ref. 35: No experimental details given.
Ref. 33a: Compound obtained by
bromination-dehydrobromination (acid and ethyl
ester)-worth keeping in mind. Ref. IOa not cited.

Early Ref. lOa (cited by 4 out of 29 authors): by H. Pauly,

R. Gilmour and G. Will; the first paper describing the desired
methyl ester, m.p. 60 C, probably the -isomer, prepared by
bromination of levulinic acid, esterification of the bromo
acid, followed by dehydrobromination by sodium acetate-
acetic acid; overall yield claimed of the order of 70-75%.
Actually the main topic of this paper is an interesting
reaction in quite a different context: the cleavage of
o-nitrophenols by sulphuric acid to give aliphatic products
without carbon loss, a reaction restudied by Linstead and co-
workers in later years but since ignored. An immediate note
was made by the searcher.

Interim Conclusions
This intensive literature search for a comparatively simple
starting material is given here in full because it demonstrates
several points of general importance:
l. There has been a surfeit in recent years of publications that
claim to describe a generally valid synthesis of compounds

exemplified by the Search Object, but which may be quite

unsuitable for a particular one as far as number of steps,
availability of starting material and expense are concerned
(Refs. 1, 2, 3, 3a, 13, 16, 27). This is something which the
beginning searcher should be on particular guard against.
2. The abstract entry may be misleading; either it claims
'preparation' when the method has no preparative value
(Ref. 4), or it mentions no preparation when in fact the
paper describes a detailed procedure (Ref. 17).
3. A number of workers use the desired compound and quote
for its preparation another paper which in fact does not
describe it (Refs. 5, 6).
4. Less than one seventh of the authors of all publications
checked did their homework (or were sufficiently honest?)
and cited the original paper, Ref. lOa which describes the
most direct and economical procedure (or so it seems). Of
course this paper is quoted in:

Volume 3, 1st Supplementary, p. 255, which induced the
searcher to search for it in the 4th Supplementary. The original
Beilstein reference shows the compound to have System No,
282, which enables him to locate it in the third book of Volume
3, 4th Supplementary, p. 1723. Here there is little novel infor-
mation. However, by glancing through adjacent pages he found
detailed information on the preparation of homologues, such as
the one-step preparation of the 2-methyl acid from pyruvic acid
and acetone. Also, he found two papers which deal with the
configuration of the E- and Z-isomers:

J. Org. Chem. 33, 2708 (1968). Ref. 36

Helv. Chim. Acta 50, 798 (1967). Ref. 37

The latter paper gives details on the preparation of the parent

acid corresponding to the Search Object, by direct condensation
of acetone with glyoxylic acid (now commercially available)
using phosphoric acid, quoting a personal communication and

two unpublished dissertations. This shows up the value of

Beilstein-Browsing! The fact is that no one else in need of the
compound searched for had spotted Ref. 37.
Of course, with hindsight it may be argued that this finding
points to the need for searching not only for the methyl ester but
also for the acid and possibly other esters and derivatives but
that would have at least tripled the number of publications to
be examined, and it is a moot question whether it would have
led any sooner to the


The choice is now clear: either a three-step procedure from

levulinic acid (Ref. IOa), or a two-step one from glyoxylic acid
(Ref. 37). The following must be taken into account:
Pure levulinic acid: price $4.20 per g/mole.
Glyoxylic acid.H20 : price $12.51 per g/mole.
The overall yields are similar in both cases.

Example 3


Search for the Best Method for effecting the acetalization:

Ar-CO-C02Me -+ Ar-C-C02Me

Here all the regular known methods had failed, clearly because
of hindrance and deactivation of the ketone carbonyl group.
Some other, preferably irreversible process not dependent on
water removal, was required.



Last Collective Volume, No. 40, Index:
'Acetals: ... from alkoxysilanes'-this caught the searcher's
attention. This referred to Vol. 36, Example 219, citing the
work of Noyori's group:
T. Tsunoda, M. Suzuki and R. Noyori, Tetrahedron Lett. 21,
1357 (1980) based on the following sequence:

R-CO-R' + 2R"OSiMe3 -+ R-C-R' + Me3Si-O-SiMe3

The irreversibility of this reaction appears certain from the

fact that no water is involved and that a Si-0 bond is formed.
The above publication claims that trimethylsilyl triflate, a
'proton equivalent' (and a rather expensive one) is required as
essential catalyst.
However, following the published procedure exactly in the
above case gave low yields, with much starting material
Hence other workers' experience was searched for in:

under: Tsunoda, T.
80 Tetrahedron Lett. 21, 1357

The following citation distribution was found:

1980-1984: 14 times, i.e. 2.8 per year
1985: 3 times
1986: 10 times
1987: 12 times
i.e. steadily increasing interest.


After examining citing publications:

Most refer to acetalisation by glycols, i.e. using alkoxysilanes of
type Me1SiO-(CHR)n-OSiMe1. Some report negative results,
with the above and other methods of acetalisation. However,
one citing publication:
A.A. Ponaras and M.Y. Meah, Tetrahedron Lett. 27, 4953
reported that using Noyori's method in a related transfor-
mation, formation of a mono-enol ether from a 1,2-diketone,
the yield was strongly increased (Footnote 8) by using
triftuoromethanesulphonic acid (less expensive!) as catalyst
instead of the trimethylsilyl ester.
This modification was indeed found to lead to good yields in
the above reaction~

Example 4


Information on the action of alkali metals in liquid ammonia

on aryl sulphonamides.



The following search method was adopted:
In the Collective Indexes (Vols. 5, 10, 15, 20, 25, 30, 35 and
40) and the Indexes for Vols. 41, 42, and 43 the Volume and
Example numbers were searched for and noted down, for the
following topics:
'Sul phonic Acid Amides, starting material for .. .'
'Lithium/liq. ammonia'
'Sodium/liq. ammonia'
'Potassium/liq. ammonia'

and the list checked for possible convergence. This was found
in the case of Volume 9 (1955), Example No. 42, which referred
1. M. Swan and V. du Vigneaud, J. Amer. Chem. Soc. 76,
31 JO (1954).
According to this publication the N-tosyl protecting group
can be specifically removed in peptides by the action of sodium
in liquid ammonia, and working-up facilitated by adding an
exchange resin in the NHt form. This article refers to an earlier
V. du Vigneaud and 0. K. Behrens, J. Biol. Chem. 117, 27
However, no more recent examples could be found.

Chemical Abstracts Collective Subject Index 1947-1956
Under 'Sulphonamides': nothing relevant under 'cleavage
of', 'reaction of' or 'reaction products with'.
Chemical Abstracts Collective Subject Index 1957-1961 and
Under 'Sulphonamides' the following entries were found:
'cleavage', 'cleavage of arene', and 'cleavage/oxidn.-red. of',
but none of these related to the action of metals in liquid
Chemical Abstracts Collective Subject Index 1967-1971
Under 'Sulphonamides': entries for 'cleavage with radical
anions' and 'sodium naphthalene', but none with 'metals in
liquid ammonia'.
Chemical Abstracts Collective General Subject Index
Under 'Sulphonamides': nothing on metals in liquid
ammonia', but there is an entry on:
'reductive cleavage of, by sodium in hexametapol' : 80:
70194q-T. Cuvigny, M. Larcheveque, J. Organomet.
Chem. 64, 315 (1974).

In this publication: three references on metal-ammonia

cleavage of sulphonamides, including the above-mentioned
1937 du Vigneaud paper.
Chemical Abstracts Collective General Subject Indexes
1977-1981 and 1982-1986; Indexes for 1987 and 1988
No further relevant entries under 'Sulfonamides'.

At this point searcher recollects that there are two volumes of
Houben-Weyl on Synthesis of Peptides-Volumes 15/1 I and
15/ I II (1974). In the first of these the list of contents quotes
'Sulphonylschutzgruppen' (sulphonyl protective groups) on
p. 223. On p. 228 there is a thorough review by E. Wuensch on
the reductive cleavage ofi the aryl sulphonamido group using
sodium in liquid ammonia; and a detailed description of the
work of du Vigneaud and later researchers, including unpub-
lished work by J. Rudinger.
In the Special Subject Index of this volume, which is sup-
posed to list procedures, there is no word on 'Spaltung'
(cleavage), 'Abspaltung', 'Natrium', etc.


I. This is the kind of information that cannot be found directly

by perusal of the Thei/heimer Index or its Reaction Notation.
The method described is time-consuming, but it works; in
this instance even the most convinced manual searcher will
admit that this kind of labour is best performed by a com-
puter (or, for that matter, a student or secretary).
2. A search of this kind in Chemical Abstracts shows that while
a priori this sort of information should be more 'findable'
there because of the format of the General Subject Index,
this is not borne out in practice because of the subjectivity
of the indexer.
3. The example shows how important it is to be able to rephrase
the search object: one man's 'Aryl sulphonamide' is
another's 'N-tosyl peptide'.

4. There is always a good chance that Houben-Wey) has the

desired information. The problem is where to find it. A
recent (1985) volume in this series on hexavalent sulphur
compounds has a section on aryl sulphonamides, with only
very sketchy information on their preparation and nothing at
all on their reactions. On the other hand, in the same volume
there is a section by a different author on Sulphones, with
full details on both preparation and reactions, including
cleavage by metals in liquid ammonia. In the Indexes for that
same volume there is no mention at all of any of these
general subjects. The early Houben-Wey! volume on
sulphur compounds (Vol. 9) deals with: 'Sulphonamides,
Reductive Cleavage' on p. 631, but this mentions nothing of
the 1937 work of du Vigneaud and co-workers although the
book claims to 'cover the literature up to and including

On Searching the
Literature-Using the
Computer (and Your Head)
to Retrieve Structures,
References, Reactions and
Data Online
Engelbert Zass

In Chapter I, as illustrated by examples, you have seen what is

called manual searching for chemical information using printed
indexes. Now we come to the use of the computer to search
'online' in databases, the computer-readable equivalents of the
printed information sources. This modern approach is in many
ways a very powerful one, and it will enable you to do things
such as substructure searching which when attempted manually
would either take far too long or could not be done at all. It is
not only fast, but also generally very reliable. There are, of
course, disadvantages: new techniques and the use of new
equipment (terminals or personal computers) have to be mas-
tered and additional costs have to be paid. Above all, a search
utilising these modern methods must be prepared thoroughly

because present online database systems are 'dumb', they do

exactly what you tell them to do, no more and no less, and then
only with the appropriate commands. As with all present com-
puters, the word is GIGO-garbage in, garbage out!


During an online search, your terminal or personal computer is
connected via telecommunication equipment and international
communication networks with a large central computer system
that holds the information in machine-searchable form. The
questions you enter are searched there, and answers (literature
references, structures or data) will be immediately on display on
your terminal, although the central computer may be thousands
of miles away. You will then have to decide whether that answer
is sufficient. If not, then you have to modify the way your ques-
tion is phrased-broaden it or narrow it down, or change it
more fundamentally. Online searching is an interactive process,
a kind of (strictly formalised) dialogue between you and the
system. Your part of that 'dialogue' is entered at the terminal
(or personal computer) and consists of two types of entries:
system commands which tell the computer what to do (select a
database, search, display answers), and the search terms to look
for in the database. Depending on the kind of database you are
searching, these can be text such as keywords or author names,
numerical data or graphics (e.g. structural formulae). The com-
puter then looks for an exact match with your terms anywhere
in the database. As computers operate on a binary level, the
question is first internally translated into that represen-
tation-each single character of text and data is converted into
an internationally standardised 7-bit code (i.e. a sequence of
seven zeros and ones), structures are transformed from two-
dimensional formulae into a linear, textual representation 14
which can then be encoded in the same way. This 'working prin-
ciple' accounts for both the strength of online searching and for
the remarkable weakness of the systems currently used.
Searching by simply matching input with stored information is

done rapidly and reliably but on an entirely mechanical basis.

Everything depends on your input-the correct and appropriate
formulation of the question. This means that th~ question as
understood by you, the user, must first be phrased as a 'search
profile' in accord with the requirements of the database and the
computer system, and you can assume no 'understanding'. As
judged by your own capabilities as a chemist, the present online
search systems are complete idiots, albeit industrious idiots,
whatever else the vendors of online information might tell you!
Online retrieval of chemical and other information has
become possible through the interaction of three separate
developments: 15
l. A vailabi/ity of machine-readable information as a product
of the mechanisation of information processing in the produc-
tion of secondary (and more recently, primary) literature. In the
1960s organisations such as Chemical Abstracts Service (CAS)
and Biosciences Information Service (BIOSIS), which process
virtually the entire primary literature of their respective fields of
science, were swamped by the flood of primary publications.
Abstracting that wealth of information and producing the
indexes as necessary access tools by established methods became
too time consuming and expensive. That problem was solved by
computer-assisted mechanisation of the information processing,
from keeping track of incoming primary publications to the
final computerised typesetting of abstracts and indexes. 16 As the
magnetic tapes used for the typesetting contained all the infor-
mation within the printed publication in machine-readable
form, they at the same time laid the foundation for computer
databases with the same information. This brings up an impor-
tant point: apart from a few cases where databases are produced
per se and have no printed equivalent, the contents of a data-
base and the corresponding printed publication are virtually
identical. The significant difference, then, is in the access, first
in the method of access-fast mechanical searching instead of
manual look-up, and second the extent. Searching printed
sources is limited by the type of indexes available; within it, only
the first alphabetised heading of an index phrase can normally

be searched for directly. In databases, on the other hand, every

word or number is searchable, alone or in combination and
regardless of its position in the text.
Let us take an example to demonstrate this-suppose you are
looking for enaminoketones. In the Chemical Abstracts General
Subject Index you will find that a heading for that class of com-
pounds does not exist (all headings are taken from a controlled
vocabulary list, see below). As a consequence, you have to look
for the tens of thousands of index entries under the broader
heading 'Ketones' and scan them for 'enamino' somewhere in
the index phrase following that heading. Of course you have to
repeat this for the headings 'Amines' and 'Enamines' if you do
not want to miss relevant information. In the corresponding
online search, the computer scans every keyword in all index
entries in all the indexes for you, and not just the headings.
Keyword Indexes that are printed with the single issues are sear-
ched as well as all the titles; the first you cannot study manually
for anything except the current issues because they are usually
thrown away when the issues are bound, and the second is not
accessible because of lack of an appropriate printed index (you
cannot rely on every important term from the title to show up
in the indexing as well). There is a price to pay, however, for
this versatility: when you see any of the variants of 'enamino-
ketones' such as
enaminoketone (singular)
enamino ketone(s) (spelling variant, both singular and
ketone(s), enamino (inverted spelling as often used in
enaminone(s) (synonym)
you know that these refer to the same thing. On the other hand
the computer is just matching characters, not identifying
meanings! In an online search, all these grammatical or spelling
variants and synonyms must therefore be spelled out and
included in the search profile (in one of the latter examples, you
will see how this can be handled without excessive typing).

In author searches, the printed index refers directly only to

the first-named author. If you come across one of the scions of
chemistry who out of modesty (or possibly other motives) puts
his name at the end, you may have to check dozens of cross-
references in a manual search to find all his publications. Not
so in online searching; and you get it nicely printed out, too.
Author's addresses (institutions, companies) are not searchable
in the printed Chemical Abstracts (CA), and this is something
you might need in order to find the right Brown or Miller among
hundreds of others, particularly if you are not sure about his
first name or initials. Some caution is necessary, however; when
trying to limit papers by the late Robert B. Woodward to 'Har-
vard', which looks like a clear-cut case, you will miss out on
papers by him originating from the Woodward Research Insti-
tute in Basie. Other information only accessible by computer is
often useful for narrowing down searches: CA sections as broad
topics, year of publication, title of primary journal, language
and type of document. You may want to eliminate papers in
Japanese, or Russian, or patents, and it is easy to do that
online. However, you should not make a habit of eliminating
patents or foreign literature on a routine basis without at least
looking at the titles because that would be a sure way to miss
relevant information.
All this should have made clear by now that you can search
a lot more online than manually. But there is another price you
have to pay: there is no browsing online as with printed indexes,
no coming across useful information by accident (with very rare
exceptions, to be described later)-everything must be spelled
out and put in literally, and is searched for literally.
2. Organisations called 'hosts' providing computer hardware
and software to search large databases with millions of 'records'
(i.e. single entries such as literature references or structures)
rapidly and interactively. The tapes mentioned above which
hold the information in machine-readable form are not useful
as such for searching. Programs are needed that read this infor-
mation into the central processing unit of a computer and
manipulate it there. It is only since the early 1970s that advances

in technology have made it possible to search 'online' at a ter-

minal with the answers immediately available. This mode of
operation depends on time-sharing computer systems which
allow many users to search databases simultaneously, _and on
information s_torage devices with fast random access, i.e. mag-
netic disks instead of magnetic tapes. Such programs have been
developed by companies such as System Development Corpor-
ation (SDC) and Lockheed (later established as the DIALOG
Information Service) in the USA, initially financed by the US
Federal Government in ,relation to space- or defence-related
projects. In 1972 (Lockheed DIALOG 17 ) and 1973 (SDC
ORBIT, now ORBIT Search Service, a division of Maxwell
Online 18 ), these systems were made publicly available, first with
only a few databases, but by now as large 'information super-
markets' with hundreds of databases. 15
3. Large, reliable and not too expensive telecommunication
networks. The computer processing and storage power
necessary for operating large database systems has so far been
available only in centralised facilities. These must be accessible
to and utilised by a large number of people who are scattered
over a large area, because otherwise such an installation cannot
be run on an economic basis (most of the present hosts are com-
mercial profit-oriented organisations).
The technicalities involved in online searching such as instal-
ling a terminal or microcomputer for searching; signing a con-
tract with a host and establishing a telecommunication link with
the host's computer will not be discussed here. There are many
books and publications on that subject and on online searching
in general. 19 - 21 It is assumed that the user is provided with all
this through the institution he/she is working for and that this
deals also with administration and trouble-shooting. Here
we shall discuss only the intellectual or 'chemical' part of the
search-how to construct the search profile that goes into the
terminal. This is the most difficult part anyway and the one that
really determines the quality of the result. So far, only a few
publications have discussed online searching in chemistry in a
subject-oriented and yet generally applicable manner. 21 22



There are now more than 4000 publicly available online data-
bases, offered by several hundred hosts. Of course, only a
number of those are of importance for chemists. Normally, as
a casual user, you will not search on more than one host,
because another one means using another command language.
For example, for searching, the command is 'SELECT' in
DIALOG, 17 'SEARCH' in STN, 23 'FIND' in ORBIT 18 and
' ... SEARCH' in DAT A-STAR. 24 In fact, the problem is not as
bad as it looks because one needs literally only a handful of
commands for any system.
However, most people understandably refuse to learn to use
more than one host system. The question is then which host to
select; and in any case is there a good reason for searching in
more than one? 25 Cost is one selection criterion but not
necessarily the most important. For chemistry departments in
universities there is perhaps no real alternative to the host STN
(Scientific and Technical Network International), 23 run jointly
by CAS and two other organisations in Germany and Japan,
because several important databases are offered there at an
'academic rate' of only 15-20% of the regular price. Moreover,
it is only STN and the French host Telesystemes Questel/
DARC 26 that offer the CAS Registry structure database that is
needed for (sub)structure searches with structural formulae (see
below). Chemical Abstracts online literature searches are
available through all the important hosts, and whatever subtle
differences there are in the 'implementation' of that database
(that is, the way the information is stored and searchable in the
computer) are often unimportant or not meaningful to a non-
specialist. They do differ significantly, however, in the other
databases they offer and that could possibly be an important
factor in preferring one to another as the main system or for
using several hosts if you search databases other than CA.
Again, many chemists are reluctant to do that, but with more
and more interdisciplinary projects coming up straddling, for

example, chemistry/biology/biotechnology, it can be a grave

omission to stick to CA only and not utilise databases such as
BIOSIS (Biological Abstracts online), and SCISEARCH (Sci-
ence Citation Index online).
For example, an online literature search done in 1981 in the
host DIALOG about the Chinese plant Artemisia annua, which
contains natural products of potential pharmaceutical interest,
resulted in 30 references in CA (15 of these exclusively in that
database), 30 (18) in BIOSIS, 2 (0) in SCISEARCH (searching
keywords in the title only). and I (0) in the database IRL Life
Sciences Collection. Of the 15 references found exclusively in
CA and the 18 from BIOSIS, one could definitely be classified
as 'biological' and three as 'chemical', respectively. In other
searches of an interdisciplinary nature, the overlap between CA
and BIOSIS was around 50%, which means that having sear-
ched in only in one of these two you would miss about half of
all relevant publications! Incidentally, patent databases, hardly
ever searched by non-specialists, are an important source of
chemical information that should not be overlooked. 27
How do you find out which databases are available in your
field of interest, and which will provide you with the answer to
a particular question? Some hosts such as DIALOG 17
(Dialindex) and DAT A-STAR 24 (CROS) offer a 'master index'
of all their databases, where you can find out at a glance how
many references there are on your subject in several databases.
The search can then be restricted to those databases that look
the most promising. In order to find out which databases are
around for a given field on any host, you can consult published
guides-two of these 28 are available online on DIALOG and
DAT A-ST AR as 'databases of databases'.



The most important single source for this kind of chemical

information is, of course, Chemical Abstracts (CA). Its online

version covers the literature from 1967 onwards (i.e. since the
8th Collective Index period) to the present. Since 1965, the onset
of computerised structure registration at CAS, the corre-
sponding compound information has been stored in the CAS
Registry System, 29 which at present contains more than 10
million compounds. The hosts DIALOG, 17 ORBIT Search Ser-
vice 18 and DAT A-ST AR 24 hold only the nomenclature infor-
mation from that database, whereas Telesystemes Questel/
DARC 26 and STN 23 also offer structure search. Further, the
last host (the one that CAS is participating in!) exclusively offers
structures registered from the literature before 1965, and the
corresponding CAS abstracts numbers as access points to publi-
cations of that period in a file called CAOLD (see, Example 2
below). This 'Pre-1965 Registration Project' 29 b currently
extends back to the late 1950s (6th Collective Index); whether it
will go all the way back to 1920 as originally envisaged will
depend mainly on who will finance this expensive undertaking.
Even 'older' compounds, going right back to the beginnings
of organic chemistry, are covered by the Beilstein online data-
base, 30 which has been available since the end of 1988 from
STN, since October 1989 from DIALOG, and ORBIT Search
Service will have it soon. At the time of writing (July 1989), it
contained I. 7 million compounds, that is, all heterocyclic com-
pounds in the period 1830-1980 [i.e. the content of the printed
Beilstein Handbook, Vols 17-27 (H to EIV; cf. Chapter 1) as
well as the material for the 5th supplementary series (EV), as yet
mostly unpublished] and acyclic compounds for the period
1830-1959 (corresponding to the printed Vols 1-4 from H to
EIV). Further compounds are scheduled to be added soon,
bringing the database much more up-to-date than the printed
Handbook, but containing the wealth of data in concentrated
form for each compound that the Handbook is rightly famous
for. Online access to the information in Beilstein is much more
powerful than searching the printed Handbook. More than 300
types of data associated with organic compounds are searchable
(provided that they were reported in the primary literature, of
course), and the actual numerical values are searchable for more

than 60 of them. For example, you will be able to look for all
compounds having a red colour and a certain melting point
range, or for compounds with a certain substructure which
possess an optical rotation falling in a defined range and whose
H NMR spectra in CDCb have been reported.
This kind of data and spectra search has hardly been possible
so far. In CA, physical data are not searchable at all, and
spectra are indexed only if they constitute an essential part of
the publication and are not reported just routinely. Spectros-
copic databases, on the other hand, offer powerful means for
getting information of that kind. This can be on the basis of a
structure or a spectral data search, and include comparison,
simulation and interpretation of spectra. 31 Such databases are
an important tool for analytical chemists. Their usefulness in
general preparative organic chemistry, however, is limited by
the relatively small number of compounds in publicly available
databases. Only those for mass, IR and 13 C NMR spectra
contain a significant number, and even this is only about 100000
compounds at present.
When you search manually for a compound in the printed
CA, you have to know the systematic CA name for the index
period in question (cf. Example l in Chapter 1). In the CA data-
base, compounds are represented and searched for by the CAS
Registry Number instead. This is an arbitrarily assigned number
for each compound registered by CAS; it is not a structure code
of any kind. In contrast to the systematic name, it does not
change [at least not normally-except in the case of (re)assign-
ment of configuration or constitution] , it is short and it can be
validated automatically by the computer-the last digit is a
check-digit calculated from the other digits. You can find these
CAS Registry Numbers in

(a) CA Chemical Substance Indexes;

(b) the CA Index Guides (for compound trivial names);
(c) the Merck Index;
(d) 'Heilbron' (now edited by J. Buckingham as the Dictionary
of Organic Compounds 6 32 );

and even in the catalogues of major chemical suppliers. The

most comprehensive (and expensive) source is, of course, the
' CAS Registry File (file is an often used synonym for a database
or a part of it).

Example 1
In Example l, an online literature search in Chemical Abstracts
regarding the resolution of ibuprofen into enantiomers (cf.
Chapter l and Example 1 there) is shown. On the host STN 23
(and also other hosts), the online version of CA consists of two
files: the CAS Registry File with structures and nomenclature
for all compounds registered by CAS (we shall use that later)
and the CA File that we are going to use here, which contains
all bibliographic data, indexing and most of the abstracts (the
latter exclusively on STN) since 1967. The CAS Registry
Number needed was taken from the Merck Index; a CA Index
Guide or 'Heilbron' 6 32 would have served just as well in this
example. This number was then combined with appropriate
search terms to give the search profile shown in Fig. l(a) (under-
lined). The profile is preceded by S, the abbreviation for the
search command in STN. The following registry number
(15687-27-1) for ibuprofen and the keywords representing the
concept 'resolution' are linked by the 'proximity operator' (L).
This operator instructs the computer system to retrieve only
those 'records' (literature references with CA indexing) that
have both 'sides' of the operator (i.e. compound registry
number and keywords) in the same index entry, and therefore
in the correct context (you should remember here that all index
entries from the printed CA Substance Index are contained in
the database, with the important difference that systematic
names are replaced with the corresponding CAS Registry
Numbers-that is the reason why we need them in compound
searching online!). Without this limitation by proximity, refer-
ences that dealt with ibuprofen and the resolution of some other
compounds might be retrieved as 'false hits'. The concept 'res-
olution' must be expressed in several ways, using both

synonyms and different spellings (see the discussion about

'enaminoketone' above), and abbreviations such as 'sepn' that
CA uses extensively must be included for comprehensive
retrieval. In a manual search you could say that this happens
'automatically' because you understand the meaning of index
entries while scanning them, but the computer needs to be told
everything explicitly. In order to avoid too much typing, we use
a little help from the computer: the word stems are cut off
(truncated) at a significant point with a question mark. This
serves as a 'mask' for any number of any characters, and
here takes care of 'resolved'/'resolving', 'separation(s)'/
'separating'/'separated', etc. All variants are combined with the
Boolean logic operator OR and held together by parentheses in
what might be called a logical expression of the concept 'resol-
ution'. The terms in the search profile are searched one after
another, and the intermediate results [numbers of records in the
database containing the respective term, cf. Fig. l(a)) displayed
before the final result is computed as the specified logical combi-
nation. Generally, the capability to combine several concepts in
the same question by logical and/or proximity operators shown
in this example with 'ibuprofen' and 'resolution', that is, to
search multi-dimensionally, not one-dimensionally as in a
printed index, is one of the greatest strengths of online search-
The references retrieved in this way by the computer are
stored temporarily in a 'set' numbered LI. They can displayed
immediately with the (abbreviated) command 'D(isplay)' in dif-
ferent formats. For example, just a few titles to check the
relevance, the complete bibliographic data as in Fig. l(a), or
everything there is [format 'ALL', Fig. l(b)]. including
indexing and abstract (text, some including formulae from the
printed CA). As you can see in both Fig. 1(a) and 1(b ), the data
are displayed (and searchable) in data fields with the following

CAS Abstract Number


Corporate Source (company, institution)
SOurce (primary publication)
CAS Section Code
Document Type
CODEN (code for journal name)
ISSN (International Standard Serial Number)
Publication Year (of primary publication)
KeyWords (from printed CA issue Keyword Index)
Index Terms (from printed CA General Subject Index and
Chemical Substance Index, with CAS Registry Numbers
instead of CA names, index headings shown ranged left,
index modifications indented and in parentheses).

You pay for the time you are connected to the computer, the
searching you do and every single reference displayed; the more
information you get, the more it will cost you. The total outlay
for this search was of the order of DM20 ($12).
For an analysis of the indexing of the eleven references
retrieved, we displayed them in the format 'IND' (IT and KW
data fields): no less than six had been indexed with the abbrevi-
ation 'resoln'; one about 'high-resoln. gas chromatog.' was ob-
viously not relevant. Of the other five references retrieved with
'sepn.', only one containing the phrase 'enantiomeric sepn.' was
relevant. In a manual search in printed indexes, such 'ballast' is
of course weeded out in the search process. We could have
avoided the five irrelevant references here by the more specific
(and more complicated) profile '15687-27-1 (L) (resolution? or
resolv? or resoln or ((separat? or sepn) (L) (enantiomer? or
diastereomer? or isomer?)))'. The use of nested parentheses is
essential here as it is in mathematical expressions in order to
ensure the correct logic operation, i.e. sequence of execution of
the search profile [the (L) operator takes precedence normally
to OR, but expressions in parentheses are executed first] . In this

FILE 'CA' ENTERED AT 10:57:15 ON 08 APR 88

FILE !AST UPDATED: 1 APR 88 (880401/ED) VOL 108 ISS 14
1434 15687-27-1
6332 RESOLV?
14490 RESOLN
73897 SEPARAT?
89354 SEPN
s> p TI 1-'.l

TI Stereoalectronic model to explain the resolution of

enantiomeric ibuprofen amides on the Pirkle chiral stationary

TI High-performance liquid chromatographic assay of ketoprofen

enantiomers in human plasma and urine

Tl Qptical resolution and configuration o!

2-(4-dimethylvinylphenyl)propionic acid

=> .IL2

AN CA107(3):17130t
TI High-performance liquid chromatographic assay of ketoprofen
enantiomers in human plasma and urine
AU Foster, R. T.: Jamali, F.
CS Fae. Pharm. Pharm. Sci., Univ. Alberta
LO Eanonton, AB T6G 2N8, Can.
so J. Chromatogr., 416(2), 388-93
SC 1-1 (Pharmacology)
IS 0021-9673
PY 1987
IA Eng

Fig. l(a). Print-out from an online search for the resolution of

ibuprofen into enantiomers in the STN CA File (Example I; user input
underlined). Reproduced by permission of Chemical Abstracts Service,
a division of the American Chemical Society

AN CAl07(l6) :l4l2l0h
TI Stereoelectronic model to explain the resolution of enantiomeric
ibuprofen amides on the Pirkle chiral stationary phase
AU Nicoll-Griffith, D. A.
CS Dep. Pharmacol., Univ. Toronto
LO Toronto, ON MSS lA8, can.
SO J. Chromatogr., 402, 179-87
SC 64-3 (Pharmaceutical Analysis)
IS 0021-9673
PY 1987
LA Eng
.AB A chiral recognition model is proposed which incorporates the
electronic and steric interactions between amide derivs. of
ibuprofen and the (R)-N-(3,5-dinitrobenzoyl)phenylglycine-derived
Pirkle chiral stationary phase during HPLC. Based on this
rationale, amide derive of ibuprofen were prepd. from 4-
chloraniline, 4-bromoaniline, aniline, 4-methoxyaniline, and 1-
aminonaphthalene to improve the enantiomer sepn. over previously
reported results with this column. The amides prepd. gave sepn.
values of 1.16, l.l6, 1.19, l.21, and 1.23, resp. These high
sepn. values are consistent with the proposed model.
KW ibuprofen stereoisomer amide deriv HPLC; liq chromatog ibuprofen
stereoisomer amide deriv; review ibuprofen stereoisomer HPLC
IT Substituent constant
(of ibuprofen amides, HPLC resoln. in relation to)
IT Resolution
(of ibuprofen optical isomers, by HPLC)
IT 15687-27-lP 89269-77-2P 89269-79-4P ll0032-64-9P
110501-22-9P 110501-23-0P 110501-24-lP 110501-25-2P
(prepn. and stereoisomeric resoln. of, by HPLC)
IT 62-53-3, reactions l00-46-9, reactions 104-94-9 106-40-1
106-47-8, reactions 118-31-0 134-32-7
(reaction of, with ibuprofen)
IT 51146-56-6 51146-57-7
(resoln. of, by HPLCI
IT 15687-27-1
(stereoisomers of, HPLC reaoln. of)

Fig. l(b). Print-out from an online search for the resolution of

ibuprofen into enantiomers in the STN CA File (Example I; user input
underlined, search terms in bold). Reproduced by permission of
Chemical Abstracts Service, a division of the American Chemical

particular instance, however, the small number of irrelevant ref-

erences is not worth bothering about. In fact, it may actually be
dangerous to overspecify a profile because we do not really
know just how the staff at CAS might have indexed something.
In the present case only abbreviations had been used for
indexing the desired concept, but in general you would do best
not to rely on that and should include all possible variants you
can think of.
And now, since you have to take into account all the different
spellings, variants, abbreviations, acronyms and synonyms,
how do you find them? One route makes use of the interactive
nature of online searching by employing a first preliminary
search profile, displaying the titles of the references found and
then the indexing of a few of those deemed to be relevant. This
will show you how your concept was indexed at CAS and will
enable you to supplement search terms in your profile. Insofar
as complete retrieval is possible at all, this optimisation is essen-
tial even if the search profile seems near perfect, owing to the
vagaries of indexing. This online optimisation should actually
be preceded by a thorough offiine search profile preparation,
unless you want just a few references on a given topic, or you
(or your superiors) do not mind wasting a lot of money online.
Use your knowledge of the field, your imagination, your experi-
ence with CAS indexing and above all the search aids provided
to find terms describing your concept:

CA Index Guides for the headings (the controlled indexing

vocabulary of CAS) and for more general/more specific
terms from the Hierarchies of General Subject Headings in
the guides;
the printed CA General Subject Index Headings List which
contains all headings from the 9th to the 11th Collective
Index period;
the CA Natural Language Term List and the CA Rotated
Title Phrase List, both on microfiche, and covering the
most common 'uncontrolled' terms from index entries and
title phrases;
the list of CA Standard Abbreviations (provided without

charge on application), an important source of common

abbreviations and acronyms;
the appropriate edition of the manual Subject Coverage and
Arrangement of Abstracts by Sections in Chemical
Abstracts if you want to limit your searches by using CA

Perhaps this may put you off online searching altogether but
the use of all these aids is important for good results, and in any
event using them is also indispensable for a really good manual
search in the printed indexes. The fact that many chemists never
use them is not a convincing argument-probably in the end
they all find out the hard way what they had missed. Hence you
should make this extra effort to exploit fully online searching
with its greatly enhanced searchability (speed and access) and its
full interaction and optimisation potential. .
This is by no means all we can learn from Example 1. Another
problem to face is connected to the fact that the assignment of
a CAS Registry Number is specific in the extreme. There is not
just one number for ibuprofen (15687-27-1) used in the example,
but another one for the (R )-enantiomer (51146-57-7) and one
for the (S)-enantiomer [51146-56-6], and yet another for the
racemate (58560-75-1). Incidentally, all four are reported in
'Heilbron'. Moreover, a structure search for ibuprofen in the
CAS Registry File (see below) revealed a tetradeuterated deriv-
ative in addition to six different salts, and in addition 28
mixtures containing ibuprofen (obviously for pharmaceutical
purposes). All these 'compounds' have different numbers which
have to be used for retrieving their literature; you should even
include the trivial name 'ibuprofen' in addition to all these
registry numbers if you really wanted to retrieve everything. As
a general rule, for a compound with n diastereomers, you have
to expect more than n registry numbers-one for the racemate,
and one for the compound with no stereochemistry ascribed, and
additional ones for labelled derivatives, salts, polymers, etc. In
our example, ibuprofen [without stereochemistry (15687-27-1)]
had a total of 1447 references in the CA File, whereas the
number for the racemate (58560-75-1) retrieved only 26

references. However, if we augmented our profile with that

number, using the same keywords as above, we found another
13 references, all missed by the first approach, and all of these
were about resolution, except for a less relevant one dealing
with lanthanide shift reagents for NMR 'separation'. In other
words, had we taken account of relevant references only we
would have missed more than two thirds at the first go! This
should teach you to be careful not only with keywords, but also
with CAS Registry Numbers.
The above search was restricted to the period 1967-88. When
we now compare the results of this online search with the
manual search in Chapter I, we find that ref. IO (a preparatively
important patent) and ref. 11 were not retrieved here. These
were not indexed under the registry number of the racemate as
starting material but instead under those of the enantiomers, the
products of the resolution, and consequently the search should
also have included those. This unsatisfactory indexing situation
in connection with reactions is unfortunately not uncommon.
On the other hand, the online search retrieved four potentially
relevant references for 1967-86 that we had missed in the
printed indexes; these dealt mainly with HPLC separations.
What conclusions can we draw from this? It makes no sense to
do both manual and online searches; instead, one should take
extra care in preparing the search profile. For this an orien-
tational search in the printed CA is a good start.

Example 2
In Example 2, the preparation of methyl 4-oxopent-2-enoate,
the first thing that needs to be done is locate the CAS Registry
Numbers of the geometrical isomers. As these are less common
compounds, some of the 'easier' sources discussed in Example
l did not look promising here, so we looked for them in the
Registry File provided by STN. 23 There are two ways for
searching a single compound (exact structure): either by
drawing the structure at the terminal (as shown in the substruc-

ture search below), or via nomenclature. The latter is sometimes

faster, but less reliable (intrinsic problems connected with
nomenclature) and was the one chosen here. The 540 com-
pounds retrieved with the molecular formula ('S C6H803/MF')
were narrowed down by successively combining them (logical
operator AND) with the name fragments 'ester', 'oxo' and
'methyl' to 21 compounds. Instead of further reducing this by
ANDing' additional fragments, the Index Names were dis-
played (command 'DIN') for all 21 compounds, the three rel-
evant ones [ ( )- and (Z)-isomers of '2-pentenoic acid, 4-oxo-,
methyl ester' and one with no stereochemistry given) identified
in the name display, and their registry numbers transferred
by 'SELECT 16, 19,20' (answer numbers of the relevant com-
pounds) into a separate answer set L5 (all sets are numbered
consecutively by the computer during a search) for further proc-
essing. The CA File was entered, and with 'S L5/P' the litera-
ture about the preparation of any of the three isomers retrieved.
The 20 literature references since 1967 were then printed out
online in the 'BIB HIT' format which displays the bibliographic
data [cf. Fig. l(a)] and those index entries which contain any
of the three registry numbers we searched with. This format
makes it easy to decide which information is relevant and
permits also access to the primary literature. All publications
found were indeed relevant, and all but two had already been
retrieved in the manual search (Chapter I). From the latter refs.
5, 10, 17 and 21-24 were missed by the online search because
these were not appropriately indexed, and according to the
evaluation in Chapter I not relevant in a strict sense. The two
references missed by the manual search were the following: one
described the preparation of the desired compound by a Wittig
type reaction of Me02CCH=PPh3 with Me2NN=C(Me)CHO
(prepared from acetone and N,N-dimethylhydrazine, followed
by Se02 oxidation, 40% overall yield), followed by hydrolysis
(overall yield 91 %). The second described a 1,3-dipolar cycload-
dition of the trimethylsilyl nitronate of acetaldehyde (from
nitroethane in 640'/o yield) to methyl acrylate, after which the
product was converted into an isoxazolidine and the latter

cleaved reductively by Ti 3 +. The resulting a-hydroxy acid dehy-

drated to give the methyl pentenoate in only 200Jo overall yield.
In both publications the configuration had not been specified,
and registration by CAS had therefore been done with the
number for the 'isomer' without ascribed stereochemistry.
With the command 'S L5', 12 abstracts numbers from the
period before 1967 could be retrieved in the CAOLD File. You
cannot narrow it down to 'preparation' or other concepts,
because this file contains only abstract numbers and the corre-
sponding CAS Registry Numbers but no indexing (indexing for
that period is not available in machine-readable form, because
indexes before 1967 were composed and printed using more con-
ventional technology; see Introduction above).


What no doubt distinguishes chemical information from other

scientific information is the structural formula, the unique and
universal language of chemistry. Having to search for com-
pounds in printed indexes via systematic CA names is a nuisance
for chemists who are used to expressing their ideas in graphic
form. The detour via nomenclature becomes not just tedious
but impassable if you look not for a single defined compound
but for a whole group having a substructure in common. In the
printed index, compounds are arranged by names of parent
structures, assigned through giving a certain order of priority to
functional groups and/or rings. Small changes in such a parent
structure can thus lead to significant changes in nomenclature.
When searching for a substructure it is usually not possible or
not desirable to define all potential parents because that would
mean having to define the unknown part of the substructure as
In a simple search for all known IJ,1-unsaturated a-amino
acids, an analysis of the names of compounds retrieved via
substructure showed that there were 77 differently substituted

but-3-enoic acids, 69 compounds with a total of six different

parent names (e.g. norvaline), and 40 with 25 different ad-
ditional parent names. Such substructure searches are based on
the CAS Registry System 29 database which contains (in addition
to nomenclature) structures as computer-searchable connection
tables (lists of atoms and bonds) 14 29 Since 1981, the French
system DARC (via host Telesystemes Questel 26 ) and CAS
ONLINE (now via STN 23 ) by CAS themselves have made this
structure information accessible. 21 33 Unfortunately, only the
connectivity (topology) of compounds is stored in the connec-
tion tables at present, 29 c and hence stereochemistry (geometry)
is not generally searchable. Nonetheless, these systems are
capable of searching a file with more than ten million com-
pounds within usually a few minutes for almost any structure or
substructure entered-but it will cost you more than DMI 30
($80) per search (cf. the 'academic program' mentioned above).
(Sub)structures can be drawn at the terminal by a 'menu' or
by entering drawing commands in the STRUCTURE mode of
the Registry File in STN. The result of such a procedure is
shown for another example in Fig. 2(a). First, with the
command GRAPH, the skeleton was created, e.g. GRAPH R6
for the ring, GRA 3 C2 (at atom 3 chain of length 2) to become
later the sulphonamide group. At first by default, all atoms are
carbon and all bonds are undefined (i.e. any type). Therefore,
(re)definition of all non-carbon atoms (e.g. NODE 7 S, 9100),
and bond definition with the BOND command must follow. As
we do not have the time to go into all the details here, it suffices
to say that this is a fairly easy procedure. Now there are pro-
grams such as STN EXPRESS 34 available that allow you to do
the drawing offiine (i.e. when not connected to the computer
and therefore not paying connect time fees) on a personal com-
puter and give you some assistance with it. The computer draws
not only the structure based on the commands for the con-
venience of the user, it also generates a connection table
as a linear, machine-processable representation of it. In our
example, the first line of the table in Fig. 2(a) means that atom
1 ( = node in the graph) is a carbon atom, bound to atom 2 by


I _t 11
6 C"" ..

* ~ C TIONS-
2 C 3 ASE 1 ASE
3 C 7 CSE 4 FIDE 211SE
.. c 5 ASE 3 FIDE
5 C 6 ASE 4 ASE
6 C l RD 5 ASE
7 S llCD oco ecs
8 N 7 CS
9 0 7 CD
1111 0 7 CD
Fig. l(a). Graphic input for a substructure search in the STN Registry
File. Reproduced by permission of Chemical Abstracts Service, a div-
ision of the American Chemical Society.

a Ring Single Exact bond and to atom 6 by a Ring Double bond,

A closer look at the connection table in Fig. 2(a), however,
illustrates some of the problems that exist even with structure
searching. There are two different kinds of double bonds in the
figure: the one between atoms 3 and 4 is a localised double bond
(specified upon entry as 'Ring Double Exact', shown as such in
the connection table in Fig. 2(a), drawn with two solid lines),
while the double bond connecting atoms I and 6 is of a general
type, including both localised (double line) and 'normalised'
bonds (dotted line). Normalised bonds occur, for example, in
benzene; by defining the double bond 1-6 as 'Exact' like the
other, you would automatically, but probably unknowingly and
unintentionally, exclude all compounds with an anellated
benzene ring! By defining it as normalised as in benzene, you
would retrieve only such anellated compounds. The general


RN 1111S11&-~
lN Phos~
114-oxo-3-lto-~I >sul fmo..,11-2,,-.o,,clotwlCICll...-1"'\,ll l~lh
drmonoltrl!IIWnul- (lltl > -
MF C3e H28 N3 D4 p-s


Fig. 2(b). Print-out of a compound found with the substructure in Fig.
2(a) in the STN Registry File. Reproduced by permission of Chemical
Abstracts Service, a division of the American Chemical Society.

bond type is a good compromise here. A caveat is necessary:

'normalized' is not identical in meaning with the chemical term
'aromatic'; it is a formalised (computer-adequate!) definition
including all even-membered rings with alternating single and
double bonds-by that definition, cyclooctatetraene is 'norma-
lised', but pyrrole is not! Another, similar bond differentiation
is important in potentially 'tautomeric situations': tertiary sul-
phonamides (no hydrogen at the N) have localised, primary and
secondary amide normalised bonds-the general bond type here
again takes care of both cases. A carboxyl function has localised
bonds in an ester, but normalised bonds in the free acid. You
may not like these CAS bond conventions 29 d but for successful
searches, you need to know and apply them correctly. There is
yet another potential complication you must be aware of: the
nitrogen in Fig. 2(a) bears a 'Node SPECification Ring or
Chain'-every atom or bond not actually drawn in a ring is by

default assumed to be in a chain, and only there, unless you

explicitly define it otherwise as we did in Fig. 2(a). Unless you
take care of these definitions in the Registry File, you will miss
relevant compounds.
One of the 134 compounds retrieved with the substructure in
Fig. 2(a) from nine million in the Registry File (at that time) is
shown in Fig. 2(b). This particular one is from the 'Pre-1965
Registration Project' 29 b mentioned above, because it has
CAOLD in the SouRce field, and REFERENCES (only CAS
abstract numbers) in that file, but none in the CA File. The
other data fields in Fig. 2(b) contain the Registry Number, the
CAS Index Name, and the Molecular Formula of this com-
Substructure searching is particularly weII suited to demon-
strate the power of online searching. You can get fast and reli-
able answers to questions you would probably not have dreamt
of asking ten years ago within the context of the printed
sources. For example, suppose you are interested in aII
coumarin glycosides that have been isolated as natural products
since 1980. For this it is necessary first to translate 'coumarin
glycosides' into an acceptable substructure. This was done by
creating four different substructures, each containing the cou-
marin skeleton as one structure fragment and a second 'pentose'
or 'hexose' one in the cyclic or acyclic form, respectively-
this is unconnected to aIIow attachment at different points in the
coumarin ring (see Fig. 3). In order to retrieve all types
including desoxy sugars, only the C-1 oxygen at the 6- and

~ 0 Ao

Fig. 3. Structure fragments used to retrieve 'coumarin glycosides'


5-ring fragment, respectively, and the C-1 and C-4(5) oxygens in

the acyclic fragments were specified. A substructure search in
the Registry File with these four substructures combined with
the logical operator OR, limited to the period in question (this
is done by restricting the search to a range of CAS Registry
Numbers corresponding to the desired time period), gave 391
compounds. It was now necessary to identify all those isolated
from natural sources. There are two ways of doing this. One is
to print out all 169 literature references found for these com-
pounds subsequently in the CA File and check them manually
for 'isolation from natural sources'. This is reliable, . but
tedious. In this instance, you might not want to display them all
on the screen while online (as we did in the earlier examples) and
print them with a local printer attached to your terminal/per-
sonal computer, but enter a command to have them printed
offiine, i.e. with a laser printer at the computer facility, and
then mailed to you. This 'offiine printing' is usually a cheaper
alternative for large amounts of output, particularly structures
from a substructure search.
The other approach employs the computer, and for that one
must somehow specify 'natural products'. In a first approach to
this the numbered answer set from the substructure search (con-
taining the CAS Registry Numbers of all 391 compounds
retrieved in that search) in the CA File was linked with '(L)
(occur? or isolat? or isoln or extract? or identif? or formation?
or formed or forming or natural)'. This gave 17 literature refer-
ences. By entering the command 'SELECT HIT RN 1-17', the
computer now extracts only those registry numbers from the 17
references that were among the total of 391 from the previous
substructure search and that had been indexed with any of the
keywords in the search profile. These 30 registry numbers can
then be re-transferred ('crossover') to the Registry File and the
corresponding compounds be displayed there. This 'advanced'
example illustrates that CAS Registry Numbers are synonymous
with compounds and form the common link of both the CA
structure and literature files. It may happen, unfortunately, that
natural product isolation is not indexed with any of the
keywords used above, but rather as, e.g., 'from Apium

graveolens'. A check on the remaining compounds confirmed

that this kind of indexing was indeed used; and at the same time
that those relevant literature references were in the CA section
'Plant Biochemistry'. As a result of this finding and using the
same techniques-with section title instead of keywords-a
further 57 (!) naturally occurring coumarin glycosides were
retrieved. I do not know of any other way this could have been
done except by computer.
The same kind of search is simpler and more reliable in
Beilstein online. 30 Because this database is also available on
STN, 23 the input of the substructure is the same; you could
draw the structure in either the Beilstein or Registry file and
then use it for searching in both. In contrast to CA online (see
above) Beilstein online contains structure, data and literature
references in a single file, obviating transfers ('crossovers') like
those described above. The substructure described above
retrieved 403 coumarin glycosides in Beilstein for the period
1830-1979 (there is at present no way to limit the search to a
certain time period as was shown above for CA). The natural
products are conveniently selected by combining the answer set
with 'AND INP/FA', meaning Isolation from Natural
Product/Field Availability. This retrieves only those 46 com-
pounds that have a data field describing the isolation from
natural sources in their record. Likewise, any collection of
structures may be restricted to those having certain properties.
Narrowing dowri further with 'ORP/FA' (Optical Rotatory
Power), only 31 compounds remain. One of them is shown in
Fig. 4 with the relevant data. You may now display further data
present for that compound, or alternatively look them up in the
printed handbook using the reference shown in the SOurce data
field (meaning supplement 5 (EV), Vol. 18 in Fig. 4). This search
would not be possible in the printed Beilstein; it costs a total of
DM105 ($60), including the substructure search fee of DM90
($50) (academic institutions that subscribe to the Beilstein
Handbook get a 500fo reduction on the rates). With regard to the
costs involved, you should continue searching the printed Beils-
tein for all questions that can be solved there, such as data on
single fully defined compounds, provided your institution still


L8 ANSEi I IF 31
BAN IM:562 Bel \stein
l'F C15 Hiii C8
SV U.0.lllfron-7.l:lela.-glucosld
Al 324.29
SO 5-18
LN 1541 i 11&47

INP =~s~:
Isolation fro Nat,rol Product:
aepa, alen T

I. nlkab9-ld2e el al., Ch.... Nat.Coa,pd. <Engl.Transl.>, 8, <11172,
INP - As~lus falcatus
Fieference( s >:
1. ~~f~ Chn.Nat.Coo,pd. <Engl.Transl.), 8, <11172>, 235,
Oollcal AolalC!"'l,I P__.:
OAP -84. 5n dla
T111e: <aT~

Mci.lel: 5811.N m
I. nlkab9-ldze el al., Che.NCll.Coapd. <Engl.Transl.>, 8, <11172>,

Fig. 4. Coumarin glycoside retrieved from Beilstein online by a combi-

nation of substructure and data search. Reproduced by permission of

subscribes to the handbook. For chemists who have problems in

locating the volumes in which to find the desired compound, the
program SANDRA 3oa, 35 obviates the need to know the Beilstein



Example 3
Example 3, a method for effecting the acetalisation of a hin-
dered keto group in an cx-keto ester, poses a problem because

CA is compound, rather than reaction, oriented. A straightfor-

ward keyword search 36 gave 31 literature references in the STN
CA File, which were reduced to zero when further specified with
'hindered or hindrance'. By checking indexing and titles all
31 were found to be irrelevant. A substructure search in the
Registry File for all acyclic and cyclic ketals of ~-keto arylacetic
esters retrieved in April 1988 only 17 such compounds (out of
9 million!). Following this, 13 references were found concerning
their preparation. Most were judged not relevant in this context
(i.e. prepared by methods other than ketalisation) by checking
title, indexing and abstract. Out of the few more promising ones
looked up in the original publication one described the conver-
sion of 4-acetylaminophenylglyoxylic acid to the dimethyl acetal
with MeOH/H+, and a 1983 publication gave a general method
of ketalisation with MeOH/Me1SiCl-here phenylglyoxylic acid
reacted in 55070 yield. The latter reference cites the 1980 Noyori
paper found by a different approach in Chapter l, Example 3.
Fortunately many roads converge!
Since there are special printed sources for reaction infor-
mation (see Chapter 1), there are databases devoted solely to
reactions. The 'Chemical Reactions Documentation Service'
(CRDS) 37 produced by Derwent and exclusively available via the
host ORBIT Search Service 18 contains all information from
Theilheimer's Synthetic Methods of Organic Chemistry 7 a (see
Chapter 1) and the Journal of Synthetic Methods. The disadvan-
tage of this online-searchable file is the lack of graphics.
In order to meet the growing need for more and better re-
action information, CAS have been building a special reaction
database, CASREACT, which was made available (exclusively
on STN 23 ) in spring 1988. 38 This has no printed equivalent and
covers single- and multi-step reactions from ca 100 primary
journals in the CA organic chemistry sections since 1985,
constituting at present over 740000 reactions steps from ca
58 000 references, with an expected addition of more than
170 000 reactions annually. In this database, every reagent and
solvent is indexed and therefore searchable, whereas in CA they
were only indexed if new or used in a novel way. Reactions in

CASREACT are searched via compounds (i.e. their CAS

Registry Numbers) and their role (reactant, product, reagent,
etc.) in the reaction; retrieved are literature references con-
taining the reaction, not reactions themselves (see below); these
can be displayed graphically from the references found. In this
example, you therefore have to start with a substructure search
for the product in the Registry File. The search described above
was later (July 1989) repeated on a more general level, including
o:-keto acids as well as esters, to give an answer set L3 with 57
compounds. Only one of those was found to be present in
CASREACT, and the search 'S L4/PRO' (compound in L4 as
PROduct) retrieved only one reaction which was displayed and
found irrelevant: no ketalisation reaction (remember, we had
not specified the starting material 'side' of the reaction).
We now come to the commercially available in-house reaction
database systems REACCS, SYNLIB and ORAC 38 39 ). These
differ significantly from the hosts and databases discussed so
far. With these you buy the system package (reaction databases
and software for building and searching them) and run it on
your own DEC VAX minicomputer. There are no usage-
dependent costs as in 'classical' online searching; all you pay are
the expenses incurred in running the computer and fixed annual
licence and maintenance fees for databases and software. This
is very attractive for large chemical companies who not only do
a lot of searching, but want to build their own databases with
confidential company information. Although 'academic pro-
grams' for all three systems are offered, not many universities
have access so far to these excellent tools for training in both
computerised retrieval and chemical reactivity studies. Owing to
the special cost situation, access can be considerably more
liberal than with online databases. All three systems have a
graphic-oriented, menu-driven 'user interface', and are
definitely more 'user friendly' than the other databases
described here. 39 Our versions of REACCS and ORAC cur-
rently have stored about 130 000 and 40 000 reactions respect-
ively, so it was not really surprising to find nothing useful
concerning Example 3.

Example 4
In Example 4, where information on the action of alkali metals
in liquid ammonia on aryl sulphonamides was required, a key-
word search in the CA File again gave no relevant information,
and a substructure search is not feasible for this kind of prob-
lem with a very general and common substructure. In contrast,
REACCS and ORAC 39 both did provide potentially useful
answers. In these systems the search for reactions proceeds
basically by (sub)structures, plus their roles (as reactant, solvent,
etc.) in the reaction. It is also possible to search for data such
as yield and temperature, and with keywords. In REACCS, a
sulphonamide group was drawn on the screen easily and speedily
with a 'mouse' and the help of a menu and defined as reactant
substructure. The result from a menu-activated search for all
reactions with that reactant was combined with a second one for
all those having ammonia as solvent. Because the reactions
retrieved were specific enough, it was not even necessary to limit
further to alkali metals as reagents. A more 'advanced' (and
faster) query would have used keyboard commands instead of
the menus: with the sulphonamide group on the screen, entering
'SSS (substructure) AS REACTANT AND FORMULA:;: H3N
AS SOL VENT' does it all in one step. Either way, four reactions
were found in the Theilheimer File (46 305 reactions from
printed volumes 1-35; cf. Chapter 1), in all sodium was the
reducing agent (see Fig. 5). A search with the same query in the
Current Literature File with ca 25 000 reactions from the period
1983-88 gave another two reactions with lithium and potassium
as reagents. A similar search in ORAC retrieved six reactions
out of 40 000 in our present version of the database; one of these
is reproduced from the terminal screen in Fig. 6. You will notice
that this uncovered an unusual type of reaction-an example of
how even the idiot computer can come up with serendipitous
information in an online search, of the kind that in a manual
search might easily have fallen by the wayside!
Example 4 was later also tried in CASREACT. As stated
above, a substructure as common as the reactant 'aryl

A-> B
Eiclt !bin Build Secret,
Fl,..t NDt PNv
I t . List Tmle
Data n--
I u,-1 Plot Fa-9
Db Q.nwlt 112111 A
AaLlst lrl t.Llst Ch File
DeleW. Jrde<Llst List 4 A
l'N O
~ s:!, ~'

R A eo1-. o Pnil trr, Hel1,1 o,1e Acta, 3& p. n, um
c\:r'99 of l+-protcll"'il ~ Is
lh fol lculn; ..:"- frr alcli1,1e
r+-art:m.tzCN,1 I th HBr In 9 lac lal
-&s .
al :Ill C, N
e111 b C I ~ 11',1 catal\jtlcf

r~: 112111 11138 11 33 lEXT

Fig. 5. Reaction display for action of alkali metals in liquid ammonia

on aryl sulphonamides (Example 4) in the in-house reaction database
system REACCS (Theilheimer File). Reproduced by permission of
Molecular Design Ltd/S. Karger AG.

sulphonamide' cannot normally be run to completion within

system limits. This is possible, however, when the structures
are limited to those occurring in the CASREACT database
while searching in the Registry File by adding a code ('screen')
to the search profile with the substructure. The 3951(!) sulphon-
amides thus found in answer set L 7 were then crossed over
from the Registry File to CASREACT where 13 references
(not reactions!) were retrieved with the profile 'SL 7/RCT (L)
7664-41-7/SOL (L) (7439-93-2/RGT or 7440-23-5/RGT or
7440-09-7/RGT or 7440-17-7/RGT or 7440-46-2/RGT)'.
The registry numbers of the sulphonamides as ReaCTants are
in set L 7, the ones for the SOL vent ammonia and the possible
ReaGenTs Li, Na, K, Rb and Cs are each specified with their
role in the reaction; the (L) operator again ensures specificity by
retrieving only those reactions that have all the given partners

Mode: searchln

l of:& Ttrcitwdron ~tt., 1983, 24, 979.

9,irlthesls of enol trlflates.

l> LI NH3
f ~
0.:~~> TW" ~E THF -78'1C

~.f; -"lllC

One oth.,. -i> le. Eno l tr I f lat of ketone crld tr Ith\l l I 11,1 I
enol ethers can be slllarl1,1 generated, eMaples are gl~en.


Fig. 6. Reaction display for action of alkali metals in liquid ammonia

on aryl sulphonamides (Example 4) in the in-house reaction database
system ORAC. Reproduced by permission of ORAC Ltd.

in the same step and not in different steps of a multi-step

sequence. One of the reactions from ref. 10 is shown in Fig. 7.
It is possible to display (or print offiine, see above) all relevant
reactions (there are 26 out of 33 found here!), but it is usually
cheaper to print the references after checking just a few
reactions for usefulness. The dependence on a previous Registry
File substructure search (unless you look for reactions of single
compounds only) is a weakness of CASREACT, because then
you are often unable to answer general questions such as func-
tional group transformations. This fault is aggravated by the
fact that reacting bonds are marked in the display (see the aster-
isks on some bonds in Fig. 7), but cannot (yet) be searched for
as in REACCS or ORAC; 39 this sometimes results in many
irrelevant reactions. The total cost for Example 4 was DM370
($205), including DM205 ($115) for the one substructure search
(universities currently pay only 15 O'/o of the substructure search


Lii RNS~ER 11 OF 13
RX(3) OF & H >

Rt I
f:.N ff-H

71 1~l
7Et NE l
El El
H ~ I

RX<3> RCT H !127&7-87-3

PRO I Q&BS4-se-3
SOL u7&&4-41-7 NH3, 118-88-3 PhM
ROT 7441-23-S Na, 7&&4-41-7 NH3

Fig. 7. Reaction display for action of alkali metals in liquid ammonia

on arylsulphonamides (Example 4) in the reaction database
CASREACT (STN; search terms framed by n). Reproduced by per-
mission of Chemical Abstracts Service, a division or the American
Chemical Society.

fees, but they have to pay the full price for CASREACT itself).
The strength of CASREACT is its thorough coverage of organic
reactions (albeit only since 1985, see above); its annual increase
is of the same magnitude as the accumulated total of reactions
in all REACCS files! You should use it as a last resort if other
printed sources and databases discussed here and in Chapter 1
fail to produce the desired results.
Concept searching via keywords 40 is problematic for two
main reasons. First, when doing it online, as many spellings and
variants as one can think of have to be included in the search
profile, using search aids and print-out as described before. The
other difficulty has already been discussed in Chapter 1 and is
probably beyond solution. It is sometimes impossible to ascer-
tain the exact terms in which the indexer had described the

concept you are looking for, even with the help of search aids.
Worse still, he might not have indexed it at all, either because
he did not think it important or the author of the primary
publication did not. There is no point in discussing whether this
was done on purpose (e.g. routine spectroscopic data) or
In a search for the separation of enantiomers by capillary gas
chromatography, three relevant references were provided by the
chemist before the search, all of them dealing uniquely with that
subject. None of them had 'capillary' in the title or in the CA
indexing; using the term 'capillary' in the search profile gave
highly relevant articles, but obviously missing some; leaving it
out gave about ten times as many references but with most of
them about conventional gas chromatography and thus not rel-
evant. One of the characteristics of online searching is that it
shows up deficiencies not only in the search process but also in
the indexing. In a manual search in printed CA you would never
have noticed this problem, because there you cannot check how
a certain article was indexed by CAS.
A different keyword-independent approach to concept
searching is provided by the Science Citation Index (cf. Chapter
1) and its online version SCISEARCH, available from
DIALOG 17 and DATA-STAR. 24 This is based on later authors'
citations of 'prior art' in the appropriate context, whether posi-
tively (i.e. he used it himself with success) or negatively (he
found it did not work). Whether this is more reliable than
indexing is a matter for judgement. More about the application
of this method, as yet not utilised much by chemists, and the
ideas behind it can be found in the documentation by the
database producer, the Institute for Scientific Information, 41 or
by its founder, Eugene Garfield. 42 Apart from using a completely
different search principle, the Science Citation Index offers a
more interdisciplinary coverage, albeit at the price of a less com-
prehensive coverage of chemistry than that provided by CA.
In a search for applications of the 'Baldwin rules' for the
regioselectivity of ring closure reactions, 43 you will not get far
when using CA online and even less when searching manually.

By looking for that author's special terminology 'exo' and

'endo' with 'trig' or 'trigonal', you will miss out even on key
papers by Baldwin himself. On the other hand, on selecting the
general heading 'Ring Closure and Formation' with the
qualifications 'stereo' or 'regio' you will obtain a flood of refer-
ences. A citation search based on the first five Baldwin papers 43
gave a large number of relevant references. To narrow this
down, a 'co-citation' strategy was used, consisting of looking
only for publications which cited both of the first two Baldwin


Questions that can be well defined chemically, but are ill-defined
with respect to the capability (access points) and coverage of
information sources (see the CA search in Examples 3 and 4),
cause problems with both the online and the manual
approaches. Only experience and a certain amount of intuition
as demonstrated for these examples in Chapter 1 can help you
there. As a rule of thumb, the more general and/or less describ-
able your question is, the more likely it will be that you will need
several online 'sessions', with intermediate checking of the
indexing, consulting search aids and thus iteratively optimising
the search profile. Aiming at too much perfection can be
dangerous too, and often you will have to make do with some-
thing less than perfect. Sometimes a look at a library catalogue
for a good monograph is better than a lengthy and costly online
search. 44 On the other hand, do not let the computer tempt you
to do what is rightly called 'quick and dirty' searching.
Always be on your guard when you get zero answers. Often,
chemists with preconceived ideas ('you know, I am first in this
field, nobody has done anything like this before') run away
happily from the terminal after such an 'affirmative' result and
tell all their colleagues. It is convenient for them to forget that
a misspelled keyword, a false logical combination, a missing
space or one too many (very common, that!) might be respon-
sible for hiding what really is there all the time. Do not put all

your trust either in the computer or in yourself. True, it is easier

to find (or rather select) information by browsing through
explicit information in a printed index than to predefine and
first describe it in an abstract implicit way when preparing a
search profile. In the end, the latter is much faster, however,
and above all not subject to omissions caused by fatigue after
hours of reading small print. We have recently seen significant
improvements in search for data and reactions-Beilstein online
and CASREACT-and there is more to come. But today's
problems cannot wait for tomorrow's databases!
By way of a post mortem, let us return to Example I. Most
chemists with online search experience would have included all
four ibuprofen Registry Numbers right from the beginning to
get a result superior to that with the manual search. In Example
2, the online search was narrower and more precise in scope
than the manual search described in Chapter I. An online
search for all publications on the ()- and (Z)-isomers of the
pentenoic acid, with print-out of bibliographic data and rel-
evant index entries, would have given a more comprehensive
result. Perhaps, though, one should not make these compar-
isons, because they take no account of time and effort. What is
clear is that in substructure search online is far ahead, but one
can make out a case like that in other respects too-most
concept or compound class searches if there is no appropriate
heading in CA, or else one with a surfeit of examples like
'ketones'. The search for enaminoketones mentioned above is a
case in point; this and other examples have been described
elsewhere. 22 a' 448
Another point in favour of online searching: it is hard to
check on the thoroughness and validity of a manual search, par-
ticularly long after, because so many things are only implied,
intuitive and not recorded. A print-out of an online search, on
the other hand, is not only more presentable, but the entire pro-
cess-choice of keywords, inclusion of different spellings,
etc.-can be checked years after and if necessary repeated (I
leave it to your imagination to detect certain disadvantages in

Perhaps I have not convinced you entirely on the pros of

online searching, but if you now have second thoughts about
both pros and cons of either approach to searching the literature
the main purpose of this chapter will have been achieved.
So, to get started with online searching, ask experienced col-
leagues (if there are any around), read the relevant litera-
ture, 19 - 22 solicit information from hosts and database
producers (always with considerable scepticism toward their
claims!), and try it out yourself.

Basic Safety Rules

I. The moment you enter a laboratory where any work is

being done, whether by yourself or by others, put on Safety
Glasses. This should become a conditioned reflex. Perhaps
the best way to induce it is a system of on-the-spot fines
which everyone is entitled to collect; the proceeds to go to
some worthy cause like the coffee club.
2. At least once a day while in the laboratory stop and ask
yourself what you would do should an accident or fire occur
at that moment:
Where are the nearest eye-flushing device and safety
shower? Can you find your way there blind-folded? Do
they work? Check them yourself!
Where is the nearest fire-extinguisher? When was it last
checked, and by whom? Is the checker still around, to
accept responsibility, or has he 'checked out'?
Where is the nearest sand bucket? Does it contain sand
or cigarette butts? Your laboratory should be decidedly
out of bounds to smokers!
What emergency route is open to you from where you are
working? You should refuse point-blank to work in
any location from which there is only one way out.
Where is the nearest protective mask? The location of
these should be clearly marked-the most important
one is a smoke mask.
Are the gas cylinders secure? In an emergency it may be

necessary to move them away as quickly as possible,

hence it is best to have them secured on movable carts
rather than strapped or chained to the bench.
Where is the nearest gas main valve?
Which is the most direct route to a first-aid station?
What is the telephone number of the fire brigade?
3. Medical treatment. Few doctors have enough chemical or
toxicological knowledge to be able to judge which is the
best immediate treatm.ent for poisoning, burns or injuries
caused by a specific chemical. Many charts are av~ilable
which suggest the best course of action in common cases,
and these should be available at all times and shown to the
doctor or nurse. In most large hospitals there is now a
Poison Information Centre which can be reached at all
hours, and its telephone number should be prominently dis-
4. Do you always keep in mind that you can be held personally
accountable for the consequences of allowing children and
other unauthorised persons into the laboratory? That, inci-
dentally, includes pets!
5. Avoid working alone, and never work in the absence of
someone else in the vicinity who knows of your presence
and is within shouting distance.
6. Always tend to work in a hood. In addition, work behind
a safety screen if there is any element of risk. All organic
compounds should be regarded as toxic on principle. Rela-
tive toxicity values should not be relied upon; you have no
way of checking how much of each you inhale or handle
during any specific period. It is a part, and an essential
part, of the good experimental technique which you want to
acquire, not to handle or inhale any chemical you work
with. Also if you direct the work of anyone else, you are
probably required by law to be fully aware beforehand of
any risk involved!
7. Overnight reactions involving heating and/or reflux and/or
stirring should be done in a Night Room. This should have
a device cutting off electricity in case of interruption of the
water supply. Plastic rather than rubber tubing should be

used for water cooling. Wiring-on should be done with

care. Leave a securely fastened note with your name,
address and telephone number next to each experiment.
8. Disposal. It all depends on what is being disposed of, the
state of the plumbing, the location of your place of work
and the laws and regulations of your community and State.
There are plenty of books on the subject. Just one basic
point: whatever you want to throw away and whichever way
you decide to do it can have far-reaching legal and other
consequences for you personally, so be in the know! It is,
however, the primary responsibility of your supervisor and
of your administration to formulate clear and unambiguous
disposal instructions and to assume full responsibility.
9. Every laboratory should have posted on the outside a list
giving names, addresses and telephone numbers of people
to contact in case of fire, floods and similar occurrences.
10. Refrigerators and cold rooms. These may malfunction and
catch fire or explode at any time. It follows, by the laws of
probability, that this is more likely to happen outside
normal working hours which under normal circumstances
make up no more than ca 25% of the total time
(Yes-figure it out yourself! That should wake up those in
charge who tend to economise by pensioning off the
nightwatchman!). No open vessel should ever be placed
inside. To make certain, light bulbs should be taken out and
any other source of sparking should be eliminated.

With a few minor changes, these are the same ten command-
ments that appeared in the first edition of this book. Since then
there has been a flood, if not an orgy, of exhortation on the sub-
ject, some of it ridiculous, some of it self-contradictory, and
much of it exaggerated and thus counter-productive and in the
nature of overkill. The book has been criticised for devoting
'only three pages' to the subject. The author believes that for
the mature and reasonably experienced audience for which it is
written, whose main shortcoming is more likely to be forgetful-
ness than ignorance or recklessness, three pages is enough, pro-
vided that they are fully taken to heart.

Running Small-scale
Reactions in the Research


Building a Framework
On starting work, most likely you will be convinced that you
have far less space to work in than you had expected or hoped
for. The way to cope with this is to think carefully about how
to make the most of it. For example, from your undergraduate
days you were probably conditioned to expanding your
experimental set-up in a horizontal direction-now you should
think about doing things as far as possible going either up or
down. And even should you be so lucky as to have more space
than you bargained for, it will not take you long to discover the
advantage of compactness-or having as much as possible
within reach of two hands without having to walk more than 3 ft
in either direction.
Probably the best way to bring this about is to construct a
framework system. This applies to the regular workbench, and
even more to a hood ('fume cupboard' to the British), where
you should do as much of your work as possible for basic safety
reasons, and where inevitably proper space organisation is of
utmost importance.

) - _ ' -. b - - - - --------

Bench top
Fig. 1.

The arrangement shown schematically in Fig. 1 is based on

the author's own experience and circumstances to be varied
according to your own situation, preferences and vital statistics.
Suggested dimensions are: a= 20-25 cm and b = 15-25 cm.
Labelled components are (c) wire for holding flasks (e.g. chro-
matographic fractions), (d) beaker for holding pipettes, rods,
spatulae, etc., and (e) suitable place for rolls of Parafilm,
cleaning tissue or aluminium foil. One or two of the vertical
rods should be higher (say 1.8 m) than the others, for holding
fractionation set-ups or large chromatographic columns.
In a hood the main problem is corrosion. Even stainless-steel
rods and fittings are affected in the course of time. The use of
the glass-fibre composite rods now available should be con-
A feature worth incorporating on one of the vertical rods,
either on the extreme left or right, is shown enlarged for clarity
in Fig. 2. This is for apparatus which is permanently assembled
for frequent use, such as a rotary evaporator or a solvent distil-
lation set-up, and where the only variable factor is its height.
Very simply, the set-up is attached not to the vertical rod itself


- ~~~--=
~.r:J h
=r"S ~
====-=-~ c=
'"'r T.J
I :

-.,, I

. .

Fig. 2.

but to a metal tube which can slide up and down on the rod and
is held at the desired height by resting on a clamp. The fact that
the whole can be rotated sideways is usually an additional
The bottom feet attaching the vertical rods to the bench top
should be as small as possible to minimise interference with
apparatus. For this the usual support plates [Fig. 3(a)) should
be sawn down [Fig. 3(b)). One screw for attachment is
sufficient. For side attachment to the wall, however, the full
three-screw plates should be employed.
Cross-links between rods should not be lower than ca 40 cm
up from the bench. Interconnectors should be as small and
compact as possible [e.g. Fig. 4(a) and (b)). Figure 4(a) shows



Fig. 3. Fig. 4.

the type which if employed in a hood should be checked for cor-

rosion as often as possible, because once the internal screws are
stuck the connector as a whole cannot be removed.
Permanent or semi-permanent fixtures, such as safety flasks
en route to water-pump vacuum, towers for drying or purifying
gases or vacuum manifolds, should be attached as high on the
framework as possible so as to minimise interference with work
being done on the bench-top.
The standard framework systems which are available com-
mercially are in most cases unsuitable for preparative organic
chemistry. Their frame systems start some way up because in
the main they are meant for use by physical chemists.

Making a Multiple Inert Gas Trap (MIGT)

It is difficult to think of any organic reaction that runs better
when not conducted under an inert gas atmosphere. This usually
means nitrogen, but argon is preferable in every way. In many
laboratories one sees this problem 'solved' by an array of
colourful and sometimes grotesquely (not to say Rabelaisian)
shaped rubber balloons attached to apparatus (which is full of
air to begin with, the hope being that somehow the air will leak
out, but not the balloon's contents). This looks cheerful on
colour slides and takes one back to one's childhood. However.

this will not do. It is a sobering experience to consult a suitable

source of reference and find out just how permeable rubber is
to oxygen and in particular water vapour, especially the thin
variety used for toy balloons.
Figure 5 shows an apparatus that can be made by most glass-
blowers. Based on a simpler trap originally described by

Fig. S.

Johnson and Schneider,4' the version shown will allow you to

run several reactions under inert gas at the same time, or
alternatively to store one or more reaction systems or containers
with exclusion of oxygen and moisture, until used at a later
stage. The thick-walled capillary tube (2 mm i.d.) on the left
dips into a mercury reservoir (ca 10 mm head of mercury), and
has to be 85-95 cm high. This leads via a safety bulb to a ver-
tical manifold with three to five outlets, ending in a three-way
stopcock which will allow for either evacuation or admission of
inert gas. The mercury reservoir must have an outlet leading to
a hood. When evacuating, care must be taken to have open only
the outlet concerned, with the others closed. Since the apparatus
as a whole is rather fragile, the two vertical tubes are best con-
nected by one or two fused-on bridges and mounted (not too
tightly) on a wooden board.
The tubing connecting the outlets to reaction systems has to
be of the right sort. Unfortunately, what are called high-barrier
elastomers [poly(vinylidene chloride) or polyacrylonitrile co-
polymers] do not seem to be available in the form of flexible
tubing, and thickness may have to make up for inferior proper-
ties in other materials. Hence one has to compromise between
thick-walled polyethylene or natural rubber pressure tubing
(rather heavy) and rubber latex pressure tubing (much lighter
but expensive and deteriorates more rapidly).
There are four great advantages in using this apparatus as a
matter of routine: (a) the way it allows alternative evacuation
and filling with inert gas makes the absence of oxygen and
moisture almost certain and complete, (b) it allows the addition
of reactants and reagents against inert gas pressure, thus preven-
ting simultaneous entry of oxygen and moisture, (c) it saves on
inert gas because once the system is filled no more need be
passed in except when the internal pressure drops (as indicated
by a rise of the mercury column) and (d) with proper attention
(opening and closing the right stopcocks!) several reactions can
be run on this apparatus at the same time.
The whole set-up can form an integral part of the framework
system (Fig. l) and if so it should be on either the extreme right
or left.



The Basic Set-up

To a solution of M (516 mg, 1.1 mmol) in T (anhydrous, 6 ml)
was added under nitrogen a solution of N (115 mg, 1.25 mmol)
in T (anhydrous, 7 ml) dropwise and with rapid stirring during
0.5 h, keeping the temperature between x and y C, after which
(he whole was allowed. to reach room temperature during 1 h.
It was then heated under reflux for 1 h, after which it was
cooled and ice was added.
This is the kind of experimental procedure that you will see
routinely in almost every issue of any journal in organic chem-
istry. Not many beginning researchers, not all advanced ones,
and probably not many of those who actually write up these
procedures know exactly how best this is done. In most cases it
is not they who are entirely at fault, but it is because of the
absence of the right sort of equipment. For that one should
blame the manufacturers of scientific glassware.
In other words, your glassblower is someone whose friend-
ship you will do well to cultivate in the future.
The general set-up to use is shown in Fig. 6. Flask A is the
kind that will enable you to carry out small-scale reactions
volume-wise, and still be able to measure the temperature inside
the reaction mixture. The most useful sizes are of 50 and 100 ml
total volume. The former can be used down to 5 ml actual
volume, the latter up to 65 ml. These were formerly known as
sulphonation flasks and then available in much larger sizes.
Since the appearance of the first edition of this book they have
reappeared on the market, this time quaintly under the name
'European style'. The best joint sizes are BI 9 or 824 in the
centre and 814 at the sides. Bis an equilibrated addition funnel,
and such are available commercially in small sizes. The con-
denser (C) should be as short as possible-on this kind of scale
the amount of cooling surface needed is very small. D is a
drying tube connected to an outlet of the MIGT. G is the mag-
netic stirring motor (of the non-heating variety). H is not part

of the stirrer but in fact is a pile of thin plywood plates whose

removal or addition will cause the heating or cooling bath to be
raised or lowered. If there is a simpler way of 'keeping the tem-
perature between x and y C' without interrupting the magnetic

Fig. 6.

Note: The arrow in this and subsequent illustrations indicates points of

attachment to the multiple inert gas trap (MIGT)

stirring, I should like to know about it. NaturalJy this means

that there will be some distance between the motor and the bar
inside the flask, but the effective range is usualJy 5 cm and mag-
netic stirring is generalJy more steady at some distance than
close by.
With this set-up, and always when using an addition funnel,
one basic warning is needed: the stopcock should be well-
greased and it must not be clogged by grease. This is best
ensured by connecting the stopcock outlet briefly to vacuum.
There are few greater disasters than being all set to start, with
reagent, solvent and reactant in place, and then discovering the

What Size Flask to Use

As a general rule, the total contents (i.e. after everything has
been added) should never exceed 40% of the flask's volume.
There are two good main reasons:
I. forestalling eventualities, such as foam, the ever-lurking
enemy, and sudden exothermic events which can more easily
be brought under control when the flask is less full,
2. making it possible to do the working-up (Chapter 5) in the
reaction flask itself; for that you need additional volume.
When in doubt, and when you simply do not have the size to
fit the above, your golden rule should be that it is better to have
the flask too big than too small.

The Basic Procedure

The apparatus is connected to the MIGT as shown, with A and
B stoppered. If the thermometer is of the low-temperature type
it is best inserted later. The substrate may already be placed in
A and the reactant in B if they are not too volatile. Water-pump

vacuum is then applied via the MIGT; and using a Bunsen

burner or heat gun (also known as a hair dryer and much
cheaper under that name!) the apparatus is heated gently,
starting at the extreme ends including the addition funnel and
working towards the exit E. The desiccant in D should be heated
more strongly. The system is then allowed to cool and inert gas
is admitted.

Working at or Below Room Temperature Only

In such a case there is naturally no need for a condenser, and
a flask and adapter as shown in Fig. 7 greatly simplify matters.
The thermometer-cum-drying tube adapter offers the advantage
of an unobstructed view of the entire temperature scale. For
that reason it is particularly suitable for small-scale low-
temperature work, and a two-necked flask can be used.

Fig. 7.

Introducing Anhydrous Solvent (Tetrahydrofuran, Diethyl

Ether, Dioxane, Dichloromethane, etc.)
On a small scale these are best introduced directly into the re-
action flask against inert gas pressure via a small cylindrical ad-
dition funnel (previously flamed out) containing active alumina.
The latter is the usual grade I material which has been further
activated by heating in a high vacuum at 300 C (metal bath)
and thereafter stored in small bottles with a rubber-stoppered
narrow neck. The arrangement as a whole is illustrated in Fig.
8. The funnel outlet should be drawn to a fine point so that no
water vapour can get in between additions. Naturally it will also
serve to introduce solvent into the addition funnel (B) (Fig. 6)
to dissolve the reactant.

Fig. 8.

The amount of alumina should be of the order of 0.4-1 g per

10 ml of solvent in the case of tetrahydrofuran, acetonitrile, 1,2-
dimethoxyethane or dioxane, and less than half that with diethyl
ether or dichloromethane. The alumina will of course retain any
stabiliser (such as butylated hydroxytoluene) which is usually
added to ethereal solvents.



Fig. 9.

On a really small scale, and when a small enough equilibrated

addition funnel is not available, the procedure shown in Fig. 9
is a useful variant. The addend is first dissolved in a small pear-
shaped two-necked flask, and then drawn up into a delivery
pipette connected to the pipette filler via a capillary stopcock
[Fig. 9(a)] . The filled pipette plus stopcock (now closed) is then
inserted into the reaction flask, the stopcock is attached to the
MIGT and the contents are added dropwise to the reaction
mixture by cautious opening of the stopcock [Fig. 9(b)].

Heating and Cooling

With a bath like F in Fig. 6, the handiest way of heating is by
means of a small single-coil immersion heater connected to a
variable resistance [Fig. lO(a)] which may incorporate a ther-
mostat device. These may have to be home-made; the commer-
cially available ones [Fig. lO(b)] are suitable only on a larger
As for cooling media, there are many possibilities, ranging
from ice-water to various solvents cooled by dry-ice or liquid
nitrogen (liquid air should not be used for safety reasons). A
large list of suitable combinations is given in The Chemist's
Companion, 46 all involving solid C0 2 or liquid nitrogen and a
slush of the liquid in equilibrium with the frozen material. Some
cautionary remarks are appropriate here. The temperature
quoted is always the very minimum attainable, and inside the

Fig. 10.

flask it will always be 5-10 C above that, even when disregar-

ding any possible reaction isotherm. Thus the effective tempera-
ture for C02 + CC4 is - 15 C and not - 24 C, that for
chloroform and liquid N2 is - 50 C and not - 64 C (just fine
for reactions in dimethylformamide which would always be
frozen if what the tables say were true). And as for that ubiqui-
tous piece of fiction, ' - 78 C', the lowest effective temperature
attainable with solid C0 2 and any solvent liquid above - 90 C
and remaining reasonably fluid (methanol, isopropanol,
acetone, ethyl acetate, etc.) is ca - 70 C. If a lower tempera-
ture is really required with such solvents, or where a reaction
isotherm has to be kept in check, this is best achieved by ju-
dicious addition of liquid N2 to the solvent-C02 combination.
Incidentally, another excellent solvent to add to that list is tert-
butyl methyl ether (TBME), discussed elsewhere in this book; it
does not become viscous above the freezing point, is not hygro-
scopic, is easily dryable for re-use and is stable (no peroxides!);
all this in addition to the fact that it is now among the cheapest
of all organic solvents.
When a low temperature has to be sustained for any length
of time it is necessary to use an insulated bath. The shallow
Dewar flasks now on the market are expensive and easily prone
to breakage. Also, their height and the metal enclosure used for
protection will make it difficult to use magnetic stirring. A
simple and most inexpensive alternative is illustrated in Fig. 11.
The two nestling dishes are of glass, or better still of polypropy-
lene or polycarbonate, the type you can usually find in various
sizes in kitchenware stores or even supermarkets. The space
between them is best filled with polyurethane foam using the

Fig. 11.

two-liquid combination or spray now commercially available

(when doing this the dishes have to be separated by some spacer,
with a weight on the upper one otherwise it will float up while
the foam is forming). After hardening, the excess foam is cut off
and the exposed rim protected by epoxy adhesive.

Other Means of Adding Reactant or Reagent

When a sensitive reagent solution, such as an alkyl lithium or
Grignard reagent, has to be added in small amounts, there is no
point in first transferring it to an addition funnel. Instead (and
this really applies to all dropwise additions of liquids in small-
scale work), it is worth constructing an addition burette as
shown in Fig. 12. The capillary outlet of this (i.d. l mm) has a
length of ca 10 cm, which allows for filling as shown in Fig. 13
from a storage bottle, keeping the latter under a gentle stream
of inert gas. Here the advantages of the MIGT come to the fore:
the various outlets serve at the same time for this and for con-
nection to the reaction system, and also to the top of the
addition burette while the reagent is being added so as to
equalise pressure. Such addition burettes can be of 5, 10 or
25 ml total capacity.

When a Reagent is Best Added as a Solid

When the addend is a non-hygroscopic solid and is reasonably
stable, it may be of advantage to add it in small portions rather
than in solution. This will keep the total volume to a minimum
(desirable in all but unimolecular reactions) and will prevent
complications with a hygroscopic solvent such as tetrahydro-
furan (THF).
This is also advisable where prior preparation of a solution
involves some risk, such as with lithium aluminium hydride
(inverse addition) or aluminium chloride. Here the reagent is
quickly weighed out in a stoppered vial and kept there between
additions. The rate of addition should be monitored by fol-
lowing the temperature of the reaction mixture-if there is no

Fig. 12. Fig. 13.

change it usually means that the temperature is too low (and

reagent concentration may build up towards an uncontrollably
exothermic reaction), and it should be raised before further
additions are made.

When a Reagent is Best Added in Solution

Many sensitive reagents can be bought in solid form, particu-

larly bases such as sodium methoxide, potassium tert-butoxide

and lithium isopropylamide. However, these are usually pre-
pared in solution to begin with and then the solvent is removed
under circumstances over which you have no control. If you
prepare such solutions yourself you know what you have, and
can in most cases standardise them and dispense them by
volume which is faster and surer than weighing out. A typical
example is sodium methoxide in methanol (up to 4 M concentra-
tion). If the reagent will be needed in solid form after all, it will
be possible to remove the solvent, either in vacuo or as an azeo-
In other cases the reagent, although available in its original
state, is so reactive that it is more practical and safer to have
and add it in solution. Examples are all alkylaluminium reagents
and diethylzinc (best kept in toluene or heptane or, even better,
cyclohexane), titanium tetrachloride, tin(IV) chloride, the boron
halides and bromine (best in dichloromethane or carbon tetra-
chloride). Such solutions are best made by rapidly adding a
roughly known volume to a weighed volumetric flask, weighing
again and then diluting to the mark with the dry solvent. The
same procedure should be used when having to add a catalytic
amount of a sensitive reagent (transition metal complexes,
crown ethers, BFretherate, zinc chloride); dosage by volume is
more reliable.
Frequently such solutions can be bought but you should do
so only if the contents are known in terms of molarity. All too
often suppliers still give content on a percentage basis without
even giving the specific gravity (and then add insult to injury by
warning you not to expose the contents!).
When there is just no alternative but to weigh out accurately
the reactant which is the sensitive one (typical example: sub-
limed potassium tert-butoxide), the course to follow is roughly
and quickly to weigh out in a tared container first on, e.g. a
digital balance, then to weigh accurately with the container
closed, and then adjust the quantities of all other reactants

Concerning Magnetic Stirring

The choice of the right kind of stirring bar can be crucial. Prob-
lems usually arise when the medium is viscous and/or inhomo-
geneous. Then, and always when you are not sure what is going
to happen to the consistency of the reaction mixture in the
course of a reaction, it is advisable to use a bar which is short
and compact and thus has maximum torque. Two such versions
are shown in Fig. 14(a) and (b). Both have what is important,
namely a pivoting point, although that shown in Fig. 14(a) has
one which is usually removable, which can cause trouble when
it happens in the middle of a reaction. The second type
(' American football') is now obtainable in small sizes (length
down to 10 mm), the 16 mm size is perfectly suitable for
volumes up to 100 ml. The one shown in Fig. 14(c) should be
avoided; it is good only for beakers.
Above all, one should aim for steady rather than rapid stir-
ring. This will avoid losses due to splashing, and can usually be
ensured by finding the right position and height above the stir-
ring motor.
Frequently it is advantageous to stir a heating bath, both to
prevent local overheating and to help along the bar in the flask.
For this you need something that will take up as little space as
possible. The best solution is the common paper-clip, the inside
of which is slightly bent upward [Fig. 14(d)].

(al le)
c[p c=::::)

Fig. 14.

On the Importance of Being Temperature-Wise

The paucity of the right kind of small-scale glassware leads to
a situation where, let us face it, most researchers do not actually
measure temperatures inside a reaction, at any rate low tem-
peratures. That is the real origin of' - 78 C'. That situation is
most undesirable and leads to virtual irreproducibility of

experimental results in many cases. Moreover, there is the basic

fact that the most significant indicator of whether a reaction
occurs on adding A to B is a change in temperature.
The problem is not just that of suitable glassware. There is a
well known extension of 'Murphy's law' which states that the
part of the scale of the thermometer which is crucial to the
experiment is the one hidden behind the stopper. If only more
thermometers were made (and used) with scales that begin well
above the bulb and which are corrected for a reasonable (say
1 cm) immersion instead of the usual 7-10 cm! From all the
information available to this author, such desirable changes
would make little difference to the price. Other aggravations:
scales which become invisible owing to leaching out of the pig-
ment, and bulbs of ridiculous sizes and shapes. One way to
solve most of these problems is to use the dial-type stainless-
steel thermometers now available for the laboratory (and not
just for the roast in the oven!), for use up to 250 C or even
higher, and even more conveniently down to - 100 C. Their
accuracy may not be that high (usually 2 C), but in most
instances that is enough for synthetic work. That, and their
relatively high price, are more than compensated for by their
specific advantages: resistance to breakage, the very small space
occupied by their business end and their readability.
As for thermometers of the regular kind and in particular the
alcohol-filled type, do remember to store them upright at all
times. Whatever the manufacturers may tell you, a broken
thread cannot be reconnected in most cases.

Concerning Drying Tubes

You can definitely do without the sort shown in Fig. 15(a) unless
you are the sloppy type who forgets to turn on the cooling water
in the condenser. This kind breaks easily and is awkward to
connect to the MIGT. The straight [Fig. 15(b)J or sturdy curved
[Fig. 15(c)] types are the ones to use. The best desiccant is silica
gel of the self-indicating type, and a supply of this and the
drying tubes themselves should be kept in an oven about

-~ '

la) (b)
~ !cl

Fig. 15.

Fig. 16.

100 C. The condenser-cum-drying tube shown in Fig. 16 is a

useful piece of glassware so long as you remember that the
cooling surface is limited.

Concerning Connection Adapters

More often than not you have no choice but to use bits of ap-
paratus with different joint sizes, so that connection adapters
have to be employed. That means elongating your set-up and
increasing the internal surface and total weight, all of which are
undesirable. A simple way to avoid this or at least cut it down
to a minimum is to substitute the Teflon rings shown in Fig. 17,
machined inside and outside on a lathe to the requisite dimen-
sions. If this is done well they can even hold a moderate
vacuum. The only snag is sometimes taking them out again, but
this problem can be surmounted by using the contraption shown
in Fig. 18, which is known as a 'reverse hammer' by dentists,


Flg.17. Fig. 18.


who use it to remove old crowns. The way to use it in this

instance is to hold the stem (below the 'hammer') in one hand,
place the bottom hook below the Teflon ring, and sharply push
the 'hammer' up to the top plate with the other hand. These
rings, of course, only solve the problem of reducing, and not
of enlarging, adapters.

Coping with Other Experimental Procedures

The viscous reaction mixture was stirred at 80 C for 1 h, after
which it was cooled in an ice-bath and decomposed with ice.
Here one cannot avoid the use of an overhead mechanical
stirrer as shown in Fig. 19. A Lubriseal joint in the centre neck
is highly recommended; it should be lubricated by applying to
the top a drop of silicone oil (not grease). Here you can see
again the advantage of the special type reaction flask, in the way
it allows a thermometer to reach far down even in such a case.

Fig. 19.

When the above procedure is followed to the point of ice

cooling, then the reaction mixture will become much too viscous
for stirring. One should raise the stirrer above the reaction
mixture before cooling, and then stir the ice above so that
decomposition can proceed downward. This applies, for
example, to a polyphosphoric acid acylation or to a
Friedel-Crafts reaction.
The clear solution thus obtained was then transferred under
inert gas pressure to an addition funnel (or three-necked flask,
or storage bottle, or onto dry-ice).
This is where a twice-bent tube of the kind illustrated in
Fig. 20 should be used. The lower end is wider and filled with
glass-wool in case filtration is necessary. The rubber stopper has
two holes, closing one of which with one's finger creates the
internal pressure needed for transfer. Before doing this the tube

Fig. 20.

should be raised to allow flushing with inert gas beforehand,

and for this the tube should be lubricated slightly with silicone
grease. Also, it is usually necessary to push the magnetic stirring
bar aside to allow the tube to pass right to the bottom.
There is little advantage to using a double-ended needle or
cannula. In the device shown here you can at least see what is
happening, especially if there is a blockage.
The solution was heated under reflux for 2 h, after which it
was concentrated by distillation to one third its volume.
Earlier, the desirability of going up instead of sideways was
mentioned. The adapter shown (Fig. 21) is fitted between the
reaction flask and condenser. The small joint is for a thermo-
meter if needed. The bore of the stopcock has to be wide enough
to allow exit of air (or rather inert gas) and thus entry of distil-
Naturally, this adapter is useful in any situation where solvent
is first heated under reflux (e.g. over calcium hydride for
drying), and then distilled.
To a suspension of sodium hydride (from 0.62 g of oil
suspension, 12.9 mmol) in anhydrous THF (6 ml) there was
added ....

Fig. 21.

Fig. 22.

Proceed as follows:
I. Flame-out and cool as described before.
2. Introduce the weighed amount of sodium hydride and
enough pentane to cover it.
3. Stir for 1-2 min and then allow to settle with the flask tilted
to one side [Fig. 22(a)].
4. Carefully tilt the flask to the other side and withdraw the
pentane by pipette (against inert gas pressure) [Fig. 22(b)J.
5. Repeat this washing twice more, and then add dry THF as
The same procedure should be used with potassium hydride.
There in particular the washings must be carefully neutralised
by adding isopropanol, otherwise a fire will inevitably occur
later. Incidentally, as will be pointed out in another context,
complete removal of the protecting oil can be checked for by
allowing a drop of the washings to evaporate on the ground
glass of the flask joint-if anything is left, it will show up imme-
The solution was then heated under reflux under a Dean-
Stark trap ....
The object is to remove water in the course of the reaction,
and in small-scale work (IO mmol water= 0.18 ml) the commer-

' I a)

Fig. 23.

cially available Dean-Stark traps [Fig. 23(a)) are ridiculous.

The adapter shown in Fig. 23(b), placed between the reaction
flask and the condenser, is not only more appropriately sized
but really does its job of removing water completely by the bed
of molecular sieves. These can be activated in situ during the
flaming-out process, and for this that part of the apparatus has
to be heated more strongly.
The crystalline solid which was formed was filtered off under
nitrogen, dried in a high vacuum and stored under nitrogen
below O C.
This is where our standard set-up will allow you to simplify
matters. Against inert gas pressure the supernatant liquid is
withdrawn by capillary pipette, after which more of the same
anhydrous solvent is added by the standard procedure. After
stirring, the solvent is again withdrawn. This is, of course, on
the assumption that the product is indeed insoluble in that sol-
vent, otherwise another one has to be chosen, or the entire oper-
ation performed in a cooling bath. When the washing process
is complete (little or no residue on evaporation on the joint), the
flask is stoppered and, with gentle stirring, vacuum (water

pump) is carefully applied. Inert gas is then re-admitted and as

rapidly as possible the condenser is replaced by a stopcock [Fig.
24(a)] , through which high vacuum is applied through the
MIGT. After the material is judged to be dry, inert gas pressure
is again applied, the flask is tilted and opened, and through the
centre neck with the aid of a bent spatula the solid is broken up
[Fig. 24(b)J and scraped into a bottle or vial. The latter is best
closed with a rubber stopper, or a screw cap additionally closed
with Parafilm.
X gas is passed into the stirred solution below O C until pre-
cipitation of the product appears to be complete.
The most frequent problem here is clogging of the gas inlet
tube, and some way has to be found to clear passage through
it at frequent intervals. In Fig. 25 this function is performed by
the thermometer, which is supposed to be there anyway. This is
held inside the T-type inlet tube by a slightly lubricated sleeve
of latex pressure tubing; a similar sleeve holds the inlet tube in
the flask neck. The keyword here is flexibility-of course you
can buy an inlet tube with a standard joint, but what are the
chances that it will always immerse to the right depth in every

ta) (b)

Fig. 24.

Fig. 25.



And now a few words on that ever-green topic. Figures 26(a)

and (b) show arrangements that have been suggested recently
for conducting a reaction under an inert atmosphere. In Fig.
26(a) inert gas is passed in at the top of the condenser, to bubble
out again a short distance above through a gas bubbler. It seems
that whoever thought this up lives in hope that in the course of
time the inert gas will somehow find its way by diffusion into the
reaction mixture below. Or perhaps he had resigned himself to
the fact that part of his reagent, that which will be decomposed
by the oxygen originally present, is expendable? In the second
arrangement, that shown in Fig. 26(b), inert gas is passed into
an inlet in the stirrer joint just above the reaction mixture, and
exits, once again, through the top bubbler. Here the question is

Fig. 26.

merely just how much time will pass until all the solvent has dis-
Both of these versions are, of course, also wasteful on inert
gas. Another question to be asked is, 'where does the thermo-
meter go?' With that kind of flask, with its time-hallowed
shape, even if one neck were free, the thermometer would either
be broken by the stirrer or else would measure the temperature

Fig. 27.

in the empty vortex caused by the stirring action. Flasks of the

type shown in Fig. 27, which are commercially available, do in
principle solve that problem, but only down to a 500 ml size.
For anything smaller there would be no room for the clamp
holding the centre neck. Hence there is really no alternative to
the type of flask shown in Fig. 6 when working on a small scale.


The apparatus routinely used for this purpose is as suggested in

Fig. 28. The special solid carbon dioxide condenser should be of
a size which is commensurate with the flask used and may have
to be made specially. The drying tube for such reactions should
contain sodium or potassium hydroxide pellets, and never silica
or calcium chloride. Connection to the MIGT and the flaming-
out procedure, with the substrate in the flask, and also intro-
duction of anhydrous solvent (usually THF or diethyl ether) is
as previously described. Cooling medium (methanol or acetone)
is then placed both in the bath and in the condenser and, after
adding solid carbon dioxide and/or liquid nitrogen to both,
ammonia is passed in until condensed to the desired volume
(mark on the flask before the whole is assembled!). For drying
the ammonia it has always been found sufficient to pass it
through two towers in series, the first containing sodium hydr-
oxide pellets and the second calcium oxide lumps and finally a

Fig. 28.

layer of granular calcium hydride. The emerging ammonia is at

least as dry as that distilled from sodium in another flask. Direct
pouring in from a cylinder is decidedly not advisable, as one
might be tempted to do when working with larger quantities, the
condensation of which may admittedly take some time. The
moment the ammonia cylinder is closed inert gas pressure must
be applied, and maintained throughout if and when a protic
solvent and of course the metal used for reduction are added.
At the end of the reaction the flask may be opened to the
atmosphere and the ammonia allowed to evaporate over-
night-in a hood, of course. It is preferable, however, to
remove both the ammonia and the solvent (usually THF, water-
miscible and hence lowering the yield on isolation unless

removed anyway) in vacuo, naturally using a water pump. At

the beginning of this care must be taken to avoid 'boiling over'.
The completion of this process is best indicated by the fact that
the inside temperature has reached ambient; cautious warming
with Juke-warm water is permissible but has to be monitored, as
the bulb of the low-temperature thermometer may burst.
Teflon magnetic stirring bars used in such reactions inevitably
turn black. The way to make them white again is to cover them
with 30% hydrogen peroxide in a beaker and then add an equal
volume of 20% sodium hydroxide. A vigorous reaction occurs,
and this is best done in a hood. However, if in this way enough
Teflon is lost for the magnet to show through, it is best to
discard the stirring bar.


For many years this meant the use of sealed tubes, with all the
bother and risks involved, except if a small-size autoclave with
a small-enough glass liner was available. More recently, with
improvements in glass technology, simpler solutions have
appeared on the market, and three examples are shown in
Fig. 29(a), 47 (b) 48 and (c). 49 Such tubes are available in sizes of
between 50 and 350 ml total volume .

(al (bl (cl
Fig. 29.

It is difficult, and indeed inadvisable, to give any guidance as

to how much pressure any of these can withstand-so much
depends on imperfections in the glass, which can include even
outside scratches. What must be stressed are some basic safety
1. No such tube should ever be more than one third full.
2. While being heated in a liquid bath (never in a heating
mantle!) the entire length must be completely surrounded by
a section of heavy iron piping which is open at both ends so
that the force of the explosion, if any, is directed up and
down and never sideways.
3. No tube should ever be opened until the bath has completely
cooled; and there should be additional cooling in case one of
the products of the reaction has a vapour pressure higher
than that of any of the initial components of the reaction
4. Before even starting you should look up the vapour pressure
of the most volatile component of the mixture at the tem-
perature to which the tube will be heated, so that you know
what you are up against.

Isolating and Purifying the



Capillary Pipettes
Earlier, stress was laid on choosing a reaction flask of a size
appropriate not only for conducting a small-scale reaction
safely but also for doing the working-up at the end. The
indispensable tool for this is the capillary pipette. This will
mean that except in very special circumstances, a separating
funnel is an item which you can put into storage.
Such pipettes can be straight [Fig. I (a)] or curved to get into
awkward corners [Fig. l(b)] or really contorted (e.g. for getting
the contents out of a Kugelrohr bulb) [Fig. l(c)]. Their basic
use in the working-up process is as illustrated in Fig. 2 (here
illustrating the advantage of using an extraction solvent heavier
than water; see below). Two such pipettes can serve for really
small-scale filtration (for example, into a flask sitting on a
steam-bath prior to recrystallisation) (Fig. 3).
The adjective 'disposable' with which such pipettes (and a
good many other items!) are sold need not concern you. Im
mediately after use each pipette should be placed (with the thin
end up) in a chromic acid cleaning bath-for this a polypropy-
lene 500 ml measuring cylinder will do very nicely. Here the

(a) (b)

J,"ig. 1.

Fig. 2. Fig. 3.

Fig. 4.

pipettes rest on a round PVC disk perforated with small holes

for drainage, which can be lifted by an attached PVC stem (Fig.
4). When all the cleaning solution has drained down it is no
trouble to take them out with tweezers and wash and dry them
for re-use.

Some Basic Caveats and Rules

It is in the working-up process where probably the greatest
number of avoidable mistakes are made by the beginning

researcher. The reason is not only the half-hearted if not sloppy

way the topic is taught to the beginning student but also the
manner it is airily glossed over in the literature by standard
phrases such as 'the customary working-up ... ', 'isolation by
extraction (or trituration) .. .' or 'chromatography of the crude
product gave .. .'. Another case in point is 'the mixture was
poured into water'.
You should always approach with scepticism anything written
in an Experimental section about the final state of a reaction,
more often than not by someone who did not do the work him-
self. For instance, how often does one encounter the above sen-
tence in connection with a Friedel-Crafts reaction or
Claisen-type condensation, only to find that this is ludicrously
impossible to carry out.

Rule Number One

Whenever a reaction set-up is disconnected for working-up, the
first thing to do is remove grease from joints. This is best done
by wiping them several times with tissue paper lightly soaked in
carbon tetrachloride; for narrow openings a pair of tweezers
should be employed. It is difficult to overemphasise this point;
no extraction solvent should ever be added before this is done.
Silicone grease has many advantages over other types but it has
a pernicious habit of creeping into one's product unless
removed first thing, as witness the characteristic broad band at
1050-1100 cm - I in the infrared spectrum of so many beginners'
preparations. It may also find its way into the glassware itself,
a point which experienced glassblowers faced with a repair job
never tire of making.

Rule Number Two

Before extraction, water-soluble solvents used in the reaction
must be removed at the rotary evaporator. This most frequently
means tetrahydrofuran, less so methanol or ethanol. Adding
some water (and acidification if needed) beforehand will expe-

dite this, particularly if the crude product can be induced to

crystallise by seeding at some stage.
This is the proper occasion for a dire warning: never ever
leave the evaporation process unattended! The chances are that
at some stage a change in surface tension will lead to sudden
foaming and resulting loss of product. The only thing that can
possibly avoid this is to immerse the flask as deeply as possible
in the water-bath.
With high-boiling solvents such as ethylene glycol,
dimethylformamide or dimethyl sulphoxide, prior removal is
not easy, but it often pays to get rid of as much as possible in
a high vacuum.

Using the Right Extraction Solvent

This is no problem when the product's properties are known,
but that is not so in most cases and it may be advisable to make
some tests first on a micro-scale. The fact that it may separate
as an oil does not mean that a convenient low-boiling but medi-
ocre solvent such as diethyl ether can confidently be used. All
too often it is on adding this that at least part of the product
may crystallise out and cannot be redissolved. In such a case
there is at least the added advantage of working-up in the
reaction flask that you can remove such a solvent at the rotary
evaporator and then try another one.
If at all possible solvents heavier than water should be used
for extraction, such as dichloromethane or chloroform. One
good reason is evident from Fig. 2. Another is economy. It is
an instructive demonstration for any beginner to show him two
conical separating funnels or round-bottomed flasks, each con-
taining 100 ml of water, and then add 50 ml of diethyl ether to
one and 50 ml of chloroform to the other. Further, the dis-
solving power of such solvents for difficult products (such as di-
carboxylic acids and other polyfunctional compounds) can
increase dramatically on adding up to lOOJo of tetrahydrofuran.
This 'synergistic' phenomenon is not uncommon; mixtures of
solvents (diethyl ether-benzene, chloroform-ethyl acetate) are

often better than the sum of their constituents. When using such
mixtures one must naturally ensure that the mixture is definitely
either heavier or lighter than water.
Taking a thin-layer chromatogram of the crude product at as
early a stage as possible is advisable, because this can give a
good indication not only of what happened in the reaction but
also what the first purification steps should be. Moreover, while
this is running you can get on with the working-up process
itself. To facilitate this you should get into the habit of using an
amount of solvent (having found the right one) to give a stand-
ard concentration of product. For example, 10% (w/v) is just
right for a 1 >- (I) micropipette and the average silica TLC plate,
5% for one of 2 I capacity, and so forth. There is obviously no
problem in taking a sample when the extraction solvent is on
top. If a solvent heavier than water is used then the sample can
still be taken by drawing up a small amount in the capillary
pipette and then applying a drop to the cleaned and drained
micropipette-that is enough to fill it.
The amount of water used should be minimal but must take
into account the solubility of inorganic salts finally present. For
example, when sodium dihydrogenphosphate is used for acidifi-
cation of a reaction mixture, the salts produced have a low solu-
bility particularly when lithium ion is present, and this must be
thought of in advance.
Further extractions and washings are best done using a con-
secutive series of Erlenmeyer flasks. And never ever throw the
last layer away until you are sure that you have the entire pro-
duct! You may find that you have some salting-out to do to
extract the total product: use sodium chloride with neutral and
basic solutions and ammonium sulphate for acidic solutions.

Snags Frequently Encountered

Some Carboxylic Acids and Eno/s May Form Insoluble Salts

When this is discovered (often too late), it can be disastrous for
a systematic and quantitative working-up process, more so

because the resulting mess is often difficult to filter. When this

type of product is expected it is best to make a preliminary
micro-scale test. The solution of the problem, if there is any, lies
in a change in cation (from sodium to potassium or lithium and
occasionally ammonium). If this is of no avail it will be best to
separate the bulk of the polar material from the total crude by
crystallisation and then doing a proper work-up on the mother

The Acidic or Enolic Product is not Extracted Suffrciently by

This happens with tertiary and hindered carboxy!ic acids and
with hindered phenols. The solution lies in lowering the polarity
of the organic phase, e.g. by substituting benzene or toluene for
diethyl ether, or adding hexane as much as possible without
causing oiling-out of product. The same principle obviously
applies to extraction of a weakly basic amine with mineral acid,
where incidentally another phenomenon must be taken into
account: salts of many higher molecular weight amines can be
appreciably soluble in non-polar solvents.

Aqueous Alkaline Solutions of Organic Acids (or Acidic

Solutions of Organic Bases) Tend to Dissolve Neutral
Organic Material
Such solutions should be back-extracted at least twice to be on
the safe side, and the extracts added to the neutral portions.

This common problem can be associated with any one or more
of the above. The trouble is that every case is different. What
should be tried are: (a) filtration of the whole under moderate
suction through a reasonably wide bed of Celite or
Filtercel-the culprit may be a minute amount of amorphous
solid from an impurity in one of the reagents; (b) cautiously dis-
solving a neutral electrolyte (NaCl, Na2S04) in the aqueous

phase; (c) adding a more polar solvent (diethyl ether, ethyl

acetate or even some methanol) to the organic phase; and (d)
most important of all, patience and waiting.

The layer Boundary Cannot be Seen

This of course can happen with very messy and dark reaction
products. Here each portion of extract must be carefully
examined in the capillary pipette against a strong light, which
may take a long time. Sometimes the problem can be solved by
deliberately adding a white inert solid which will float at the

Dealing with the Extract

Solvents such as diethyl ether and ethyl acetate are never dried
completely by either sodium sulphate or magnesium sulphate.
Extracts in these solvents should be given a final wash with satu-
rated sodium chloride solution, in order to reduce the amount
of water still further, dried and then, before final solvent
removal, a higher boiling or azeotroping solvent should be
added. For this carbon tetrachloride is best, particularly when,
as is usually the case, the crude product is to be examined by
infrared or NMR spectroscopy.
Filtration of the dried product solution should be into a flask
with an opaque and not clear (KPV) ground joint. Complete
transfer of product by washing through with solvent is clearly
shown up on this by allowing a drop of filtrate to evaporate on
it. Even a trace of product can be seen in this way. This is also
the case when using polypropylene instead of glass funnels;
besides, their light weight will help to prevent toppling-over of
the flask.
This is the stage at which some preliminary purification could
be considered, in case the TLC examination of the crude re-
action product indicates a highly polar and most likely highly
coloured impurity. The first thing to try is to pass the dried
extract through a short column of a neutral adsorbent such as
Table 1. Solubility of inorganic salts in organic solvents-comparative data (weight loss per hour on Soxhlet
extraction with refluxing solvent)*

Saltt Methanol 960Jo Ethanol Abs. ethanol Acetone Ethyl acetate

Na2C03 0.3 g IOmg 4mg 0 0

NaHCOJ 0.8 g 15 mg 15 mg 0 0
K2C03 4.3 g 50mg 50mg 0 0
Na2S04 5 mg 0 0 0 0
K2S04 0 0 0 0 0
NaCl 1.2 g 0.15 g 70 mg 0 0
KC! 0.7 g 0.1 g 70mg 0 0
Na Br VS ca 7 g 30 mg 0
Nal VS vs VS VS 2.3 g
Kl VS vs vs 3.3 g IOmg
KNOJ 0.35 g 0.2 g SO mg 9-12 mg 0
KCI03 0.17 g 70mg 30mg 6-11 mg 0
KCI04 0.2 g 70mg 40mg 0.25 g 6mg
NH4C( s 0.5 g 1.9 g 0 0
H3803 VS VS VS ca 2 g 0.1-0.2 g
vs, Very soluble; s, soluble.
t No weight loss of any of above with benzene, light petroleum, carbon tetrachloride, carbon disulphide, chloroform or diethyl
ether (except with the last: H1B01, 0.15 g).


Florisil. The amount of the latter should be about the same in

weight as that of the product, and once the extract has passed
through the column further washing should be effected with a
more polar solvent, until later washings, evaporated separately,
are shown to contain little or no product. Another action to
consider is Kugelrohr distillation (see Chapter 8, p. 200).
If the product is highly water-soluble, then the only options
open are either continuous extraction, or complete evaporation
followed by extraction of the residue with an organic solvent.
The former means having to find an apparatus that 'happens'
to be of the right size for the volume of solution to be extracted,
and for that either you have to be just lucky, or else it means
further concentration or dilution. As for the second possibility,
it is not generally realised that many inorganic salts can be ap-
preciably soluble in some organic solvents; Table 1, based on
data found in the literature, so gives some semi-quantitative and
comparable figures to enable you to choose the appropriate sol-

(al lb) le)

Fig. S.

Solvent Removal
The rotatory evaporator has by now become an indispensable
item of equipment. Together with the apparatus itself, the
manufacturer will probably supply a mongrel-shaped flask
which you are invited to use for all your evaporations large and
small. One day you will no doubt find some use for it. What he
does not usually supply, and what you really need, is a suitable
adapter to guard against splashing and sudden ebullition leading
to loss and contamination of both your product and of the
apparatus. Suitable adapters are shown in Fig. S(a) and (b). The
latter will almost completely prevent contamination of the
apparatus but, unlike the former, it will be more difficult to
return solution back into the flask unless a curved capillary
pipette is used. Such return is naturally almost impossible in
another version where the tube inside the bulb is bent [Fig.


Today's young researcher finds it difficult to grasp that there

was a time when this technique just did not exist. Yes, chemists
did somehow manage without it, they did find out somehow if
anything happened in a reaction and how many products were
formed, etc. It was a lot more difficult then, but then they
worked a lot harder in those days!
Unfortunately, books on the subject still either cater for the
advanced technician working in a specific field of compounds of
mainly commercial and pharmaceutical interest (hence the sub-
division into topics such as 'essential oils', 'alkaloids', 'lipids'
and 'medicinal substances', (?!) or else go deeply into the
theoretical side which will not in most cases help you with syn-
thetic work.

The Tools
You had best cut your own plates. For that you need a good

glass cutter, not necessarily a diamond one. The type with small
cutting wheels (usually six in a circle) needs to be grasped at the
right angle. Some people never get the hang of it-if you are one
of those, let a colleague do it for you.
The commercially available 20 x 20 cm plates (silica or
alumina with a fluorescent material added) should be cut into
two unequal halves, one 9 cm and the other 11 cm wide. Each
half is then scratched at 15-25 mm intervals but the individual
plates are not already broken off to begin with because you
cannot foretell what total width of plate you will require in each
case in the future. A 15 mm wide plate can accommodate two
spottings and one of 25 mm is good for four spottings, whereas
in examination of fractions from column chromatography you
will need room for eight or even more and thus a plate
50-70 mm wide will be required. Important: For cutting the
plates should be placed, with the uncoated side up, on a large
sheet of filter paper. Any other type of paper, especially with
print on it, may 'transfer' chemicals with which it has been
treated, with disastrous consequences.
The 11 cm high plates are for more accurate work and where
multiple development (see below) is to be used; the shorter ones
are for routine work, e.g. with mixtures of substances of more
widely differing polarity such as in fractions from column chro-
The above remarks apply to the more commonly used glass
plates. With plates on a flexible base it probably pays to obtain
the ready-cut microscope slide-sized ones, because cutting up
larger sizes by yourself with a pair of scissors can create prob-
lems (crumbly edges and hence uneven ascent of the solvent
Alumina plates are more sensitive than silica plates to crum-
bling, mechanical damage and deterioration from the atmos-
phere in the course of time; hence it is best not to cut down
more of the larger plates than are needed in the immediate
For spotting, the commercially available micropipettes, of 1,
2 or 5 }.. size should be used, because uniformity in spotting is

Fig. 6.

very important and you can never achieve this by relying on

home-made capillaries. These micropipettes are another item
sold as 'disposable' whereas in fact they are not. With one or
two applications of a drop of solvent, followed by drainage on
a filter paper, they are as good as new, at least until they become
An old ruler, notched at regular (say 6 mm) intervals and pro-
vided at each end with 2 mm thick support spacers (see Fig. 6)
should do nicely as a spotting template. The long notch along
the centre is for preparative plates (see below).
Development jars are best if they have a narrow rectangular
shape. Most of the commercially available ones are too large
and moreover made of pressed glass and thus not sufficiently
transparent (a matter of importance with alumina plates, on
which it is not easy to follow ascent of the solvent front). Hence
one has to fall back on using either tall, narrow, spoutless
beakers (Berzelius type) or suitable household jam, jelly or pre-
serve jars. They must have as flat a bottom and as wide an
opening as possible. Perhaps next time at the supermarket you
should gently steer whoever is in charge of the shopping towards
those brands which will meet with these requirements; and do
not forget to take a tape measure with you. Any such vessel
must have a uniform rim for covering with a watch-glass or
Petri dish.

Development of the Plate

The development vessel must be kept saturated with solvent
vapour at all times. This can be ensured by lining at least on one
side with a strip of filter paper and shaking the whole frequently
(not, of course, while a side is being developed!).
The best elution solvent combination is a pair mutually mis-

cible, differing appreciably in polarity but little in vapour

pressure. Suitable pairs can be chosen from solvents such as
cyclohexane, ethyl acetate, carbon tetrachloride, acetone,
chloroform and hexane. Bottles containing such mixtures in dif-
ferent proportions should be kept ready for use. Frequently a
pair containing diethyl ether may give better resolution but
cannot be kept for long (enrichment by the higher boiling
partner, peroxide formation), and should be used only in a
tightly closed vessel.
TLC of carboxylic acids and other highly polar compounds
usually results in streaks and otherwise poorly resolved spots.
What works well in such cases is a mixture of a non-polar
solvent with a small amount of acetic or formic acid. For
example, diisopropyl ether and acetic acid in ratios ranging
from 99: I to 90: 10 on silica plates can give well defined spots
with carboxylic acids of higher molecular weight. Such mixtures
must be kept in tightly closed vessels, preferably under argon
(danger of peroxide formation).
Multiple development is a technique which in effect increases
the height of the TLC plate, although this does not mean that
in practice the same effect is obtained by a plate 50 cm in height.
Find out which solvent combination (say ethyl acetate-cyclo-
hexane, 1:3) gives an RF value of ca 0.4-0.5 after one develop-
ment. Then use a combination which doubles the relative
amount of the non-polar component (i.e. to I :6), and develop
the plate in this .three or four times, drying lightly but not
completely after each development. In this way greatly
improved resolution will be obtained.
On the whole there is little sense in recording RF values for
future use unless with reference to a standard substance run on
the same plate at the same time, because they can differ greatly
from day to day depending on atmospheric conditions (tem-
perature and humidity).

This depends very much on the chemical nature of the

substance(s) on the palte and, since this may differ a great deal
between the components of a mixture, one should never rely on
one method of visualisation alone. Fluorescence quenching
observed on examination under UV light is restricted to
substances with chromophoric groups, and the intensity of the
spots observed will differ according to the nature of
these-groups and of course components having no such groups
will hardly show up at all. Staining by iodine double bonds and
very strong with compounds containing isolated double bonds
and very weak with those containing aromatic rings (which, of
course, show strongly under UV light). Compounds that have
only functional groups such as ester, carboxylic acid or nitrile
can hardly be discerned by either method. Hence, in order to get
a complete picture, the first examination should be under UV
light, with a note made of the findings, then in an iodine vapour
chamber, and, to make quite sure, another plate should be
treated after drying with a desctructive agent such as sulphuric
acid and/or acidic cerium(IV) sulphate (an exhaustive list is
given in most books on the subject). Only then can you come
to some conclusion regarding relative amounts of products.

Following a Reaction by TLC

This is one of the most useful applications of the technique and
probably the mildest and most convenient tool available when
trying to optimise reaction conditions (solvent, time, tempera-
ture, relative proportions of reactants) by trial experiments. Gas
chromatography (GC) does have the advantage of giving a
quantitative picture (although under the dubious assumption
that on direct injection of a reaction mixture the course of the
reaction is frozen), but it takes rar less time to find a suitable
TLC solvent and plate than to establish the right GC column
filling, oven temperature and flow-rate. The third alternative, of
using spectroscopic methods (IR, NMR) means having to allow
for interference by solvent and other components of the mix-
Indeed, when planning reaction conditions, TLC follow-up

should be one of the factors to be kept in mind. This means

choosing a suitable concentration and taking into account the
nature of the solvent. A high-boiling solvent will usually inter-
fere in that it is difficult to dry off completely on the plate, and
will drag spots along with it, resulting in a dreadful smear.
Dimethylformamide, dimethyl sulphoxide and hexamethyl-
phosphorotriamide are specific offenders in this regard. Some-
times this can be corrected for by changing the nature of the
plate, for example from silica to alumina. This may be essential
anyway when, for example, the course of an acid-catalysed
reaction is being followed. Here only alumina plates which
instantly neutralise the catalyst will give a true picture. On silica
the reaction can proceed further on the plate itself, and at a rate
significantly faster than in the reaction mixture. Other cases
where one has to think ahead are where one or more compo-
nents are present not in the free state but, say, as enolates.
Sometimes instant protonation occurs on the (water-containing)
silica plate which solves the problem; in others it may be
necessary to submit a drop of the reaction mixture to a micro-
work-up in a micro-centrifuge tube.
Above all, you should remember that the picture you actually
get when trying to gauge the progress of a reaction is that of the
contents of the capillary at the moment of application to the
TLC plate (and of what happens on the plate subsequently).
Statements such as 'the reaction mixture was kept at - 40 C
until TLC showed reaction to be complete' are complete non-
sense unless your laboratory is somewhere in Siberia in the
middle of January in an open field. If you should follow such
a procedure, naturally keeping the temperature as low as poss-
ible during work-up, you will most likely discover that nothing
at all has happened. All that is even more likely when following
such a reaction by GC.

Other Considerations
TLC can help you determine to what extent a product or
product mixture is sufficiently stable to survive protracted

purification by column chromatography or high-performance

liquid chromatography (HPLC). Instability is not sufficiently
indicated by one TLC development or even two. What you
should do, if instability is suspected, is to make one develop-
ment, leave the plate overnight (best under argon in a desic-
cator), and then do another development the following
morning. Compare the result with that of two developments
done one after the other.
Always keep on hand TLC samples from every significant
experimental run-starting material, intermediate stages and
crude product-until your project has come to a conclusion
either in the form of writing up for publication or by being
irrevocably abandoned. You can be sure there will be a time
when you will wish you had not thrown that sample down the
sink .... Obviously that is what should be done with leftover or
recovered sample solutions from spectroscopic examination.
They are best kept for that purpose in 1 dram screw-capped
vials which take up little space but are yet large enough to carry
a legible label or serial number.

Preparative Thin-Layer Chromatography

In many places this technique is being superseded by either
HPLC or by the 'Chromatotron' which is simply a clever,
speeded-up (and expensive) version of preparative TLC. How-
ever, that brings to mind the very advantage of the older tech-
nique. The fact that a preparative plate can take up to 2 h for
development and needs no attention whatever during that time
means that you can kill two birds with one stone: separate a
mixture and do something else of a constructive nature at the
same time.
The problem, however, is that of visualisation. When the
product has chromophoric groups there is no problem except if
by any chance there are additional products not in that cat-
egory. When the components are coloured in the visible region
one is often tempted to preserve the plate for posterity as the
dernier cri in post-impressionist painting. When there are no

chromophoric groups there are only two possible solutions. One

is to run a single spot of the mixture on the plate alongside the
streak of the bulk of the product (see Fig. 6, where there are two
holes, one each side, for that purpose) and expose this to a spray
or to iodine vapour while keeping the bulk portion of the plate
covered. This is on the assumption that all the main zones will
be parallel to the spots, which is true only if the plate is of the
highest quality and the product main solution is applied with an
automatic streaking or dropping device. The other way out of
the dilemma is to divide the plate arbitrarily into a large number
of sections, extract each separately and subject all extracts to
analytical TLC systematically.
An important thing to remember is that adsorbed compounds
are very sensitive to air oxidation and more so at higher tem-
perature. Hence, when subjecting preparative plates to multiple
development, in-between drying should be done as quickly as
possible and never to complete dryness.
Elution of scraped-off sections is best done by Soxhlet ex-
traction. The thimble should be as small as possible in order to
economise on the amount of solvent needed; dead space can be
filled up by clean glass beads. Many extraction solvents may
slightly dissolve or otherwise carry over traces of the adsorbent;
hence the solution after concentration should be filtered through
a very small 'column' inside a capillary pipette (cf. Fig. 3).


Columns and Adsorbents

As is well known, for a given amount of adsorbent, columns of
smaller diameter effect better separation but have lower capacity
and are slower to develop. As the diameter of the column is
increased these properties are reversed. A compromise solution
that has received comparatively little attention is that of the
multibore column 51 as shown in Fig. 7. None of these are
available commercially, but construction by a glassblower is not



Fig. 7.

much of a problem. In these the diameter of each portion is in

the ratio of ca 1.4: l to the adjoining one.
These columns are appreciably better at separation than the
ordinary ones with uniform diameter. Moreover, there is sur-
prisingly little difference in flow-rate with different amounts of
adsorbent. A column such as those shown, with lengths of sec-
tions of 12, 12 and 13 cm and outer diameters of 1.2, 1.7 and
2.4 cm, respectively, can serve for quantities of between 5 and
40 g of silica; when using 'gradient elution' (see below), the
amount of adsorbent necessary for an average good separation
rarely has to be greater than 15 g per gram of substrate. This
should be compared with the 50-100-fold quantity required in

'flash chromatography', si moreover, the claim advanced for the

latter technique that the adsorbent can be used many times over
is not often borne out by actual experience. When working in
a hot climate the use of a water-jacketed column [Fig. 7(b)]
may become imperative, and may be good policy in general,
since exothermic adsorption of a substrate is the most common
cause of 'cracking' of a column.
There is no practical alternative to Teflon stopcocks for chro-
matographic columns, certainly for your peace of mind when a
separation has to be interrupted even for going to lunch. Glass
stopcocks cannot be greased for obvious reasons, and even the
use of spherical joints and interruption of flow by inclining the
socket portion upward does not guarantee against leakage.
Adsorbents should be obtained only from well established
firms who have a reputation to keep up-this is one of those
items which you cannot 'purify'. When purchased they should
be of activity I. A quick way to test for this SJ is the yellow
colour which should appear on shaking with a I% solution of
chlorotriphenylmethane in benzene, which is absent if more
than 0.50!o water is present. However, for actual use in chroma-
tography they have to be deactivated in a specific manner, by
mixing with the specified amount of water. The best way to do
this is a closed jar on a ball-mill (without the balls), or in a large
flask attached firmly and in a nearly horizontal position to a
rotary evaporator (without applying vacuum). In both cases a
speed of not more than I rev. s - 1 should be used, and 2 h is
usually sufficient. A fluorescent indicator can be incorporated at
the same time, and for adsorbents to be impregnated with silver
nitrates 4 (for separation of olefins) the latter can be dissolved in
the water used for deactivation.
The way to fill a column depends on the adsorbent. In the
case of silica and Florisil these should be slurried in hexane in
an amount sufficient to pour most if not all the suspension into
the column in one go. For alumina it is best to add this in a fine
stream from a separating funnel with a non-greased stopcock
into the column containing at least 3 ml solvent per gram of
adsorbent used. Only after that should the hexane be replaced

gradually by the initial solvent mixture (if more polar) used. In

all cases the column should be perfectly vertical and vibrated by
hand or with an electric vibrator to encourage even settling. The
most critical portion of the column is the very top. Its homo-
geneity and levelness will predetermine whether the zones will
elute in sequence or not. For this reason it is inadvisable to
disturb this layer such as by adding another layer of sand.
Everything depends on how carefully the substrate solution is
added by capillary pipette down the sides while there is still a
sufficient head of solvent. Any resinous material which might
clog the top layer should have been removed by the preliminary

Elution Order and Choice of Adsorbent

Roughly, and in general, functional groups in an organic com-
pound contribute to its retention in the following order: halide
< hydrocarbon < olefin < ether < nitro < ketone < carbox-
ylic ester < aldehyde < amine < tertiary amide < secondary
amide, Jactone < alcohol, primary amide < phenol < carbox-
ylic acid.
On silica amines may be more strongly retained than is
indicated. Another general factor is the relative proportion of
the functional and the non-functional part of the molecule. For
example, a butyl ester is Jess strongly adsorbed than the cor-
responding methyl ester, and a neopentyl glycol acetal less than
the dimethyl acetal. A mixture of olefinic alcohols is separated
much better after conversion into the corresponding acetates or
methoxymethyl ethers, in particular when using silver nitrate-
impregnated adsorbent. Often, such functional modification
can be planned both to facilitate separation and as part of the
synthetic pathway, e.g. ketone --+ mixture of acetals with chiral
glycol --+ chromatographic separation of diastereomers and res-
olution --+ halogenation of acetal. As a general principle, the
functional group which is the most polar one should be
modified to give a less retentive group.
Silica and to a lesser extent alumina are now the most com-

monly employed adsorbents; the last IO years have seen a great

improvement in the quality and variety (activity, mesh size, etc.)
over those encountered in the past. However, one keeps coming
across examples in the literature 55 of decomposition of com-
pounds on these adsorbents, and of solving the problem by use
of Florisil, a naturally occurring magnesium silicate, which, for
example, is found not to cause epimerisation next to a carbonyl
group, or opening of a sensitive epoxide ring. Indeed, specially
prepared magnesium silicate for chromatography, although
very expensive, can be greatly superior- in the separation of
difficult to separate compounds whether sensitive to decompo-
sition or not.

Elution Solvents
Many books show a table of elutropic order of solvents, 56 with
some differences apparent from one book to another. It must be
remembered that this holds in any case only for absolutely pure
solvents. Traces of ethanol (as stabiliser) in either diethyl ether
or chloroform may strongly modify the position of these
solvents in the elutropic series. Further, for accurate and repro-
ducible work it may be necessary to use solvents which are 'iso-
tonic' with regard to the adsorbent, i.e. which contain a
requisite amount of water, 57 otherwise desorption of water
from the adsorbent which had been used for deactivation may
occur at certain eluent compositions and lead to a sudden and
sometimes drastic change in activity.
The best course of action is to choose a mixture of two sol-
vents which differ widely in boiling point (which also makes
recovery easier) and differ fairly widely in polarity, with the less
polar one preferably of higher boiling point. An excellent pair
is dichloromethane-hexane with increasing proportions of the
former, followed by dichloromethane-chloroform (containing
ca I "lo ethanol for stabilisation-the commercial grade). The
procedure to follow is to start by dissolving the mixture of pro-
ducts in ca 2 ml/g- 1 of dichloromethane, then add hexane up to
beginning turbidity, and to use that combination as the starting

eluent. If the components to be separated are of relatively non-

polar nature as evidenced by the TLC plate, then elution should
be continued with a fairly large amount of the same solvent
combination, or one can even go back to a less polar eluent, i.e.
containing relatively more hexane; if not, then one can go over
to gradually increasing the proportion of dichloromethane, with
more graduality on approaching the 1: l ratio. The gradual
increase of the more polar solvent can be automated by devices
ensuring 'gradient elution' 58 in which the proportion of solvents
is made to vary continuously and not step-by-step. Hexane, in
this connection, refers to what are commonly termed 'hexanes',
or light petroleum of b.p. 50-70 C. Acetone should be avoided
because of its possible reactivity on the adsorbent, with itself
and possibly with the substrate, and even ethyl acetate, which
is an excellent component solvent for TLC, may cause compli-
cations in chromatography such as transesterification of esters.

Fraction Collection
The feast of gadgeteering in this connection has now ended,
except in certain modifications of the chromatographic tech-
nique. This is because it is feasible only when fractions are col-
lected in test-tubes, from which evaporation of solvent is
difficult and necessitates transfer to a flask. This has meant that
anyone religiously monitoring fractions by TLC has been
wasting a lot of time and TLC plates on fractions containing
nothing at all. It is better to see as soon as possible whether any-
thing is coming off the column, and that means collecting in
flasks. These should be of 50, 100 and 250 ml capacity, depen-
ding on the scale of material used; those without a standard
joint cost only half to one third of the variety with such a joint.
They should be wired, with a ring and/or hook so as to enable
them to be hung on a wire (see Chapter 4, Fig. l, item c), and
evaporation on a rotary evaporator can be done by a suitable
adapter which is attached to the flask by means of a section of
thick rubber latex tubing (probably best as far as resistance to
solvent attack is concerned) as shown in Fig. 8. When evapor-

Fig. 8.

ation shows that material has been eluted, solvent is added

(more if crystallisation indicates a more or less homogeneous
fraction, less if a mixture of products is suspected), and a TLC
sample can be taken by lowering the micropipette in its appli-
cator using a long pair of forceps.

Carboxylic Acids
Column chromatography of carboxylic acids is a problem
because they tend to smear with the usual eluents just as they
do on a TLC plate unless a non-polar eluent containing 1-5%
of either formic or acetic acid is used. That means that on
evaporation of fractions these addends are left and would either
have to be removed in vacuo or azeotropically with toluene.
Another remedy would appear to be to use adsorbents pre-
viously treated with methanol. 59 There is, however, a different

method of 'fractionation' of carboxylic acids, that of fractional

the crude mixture (e.g. 20 mmol) dissolved in a solvent such
as tert-butyl methyl ether is shaken with small portions (say
4 ml) of 30Jo sodium hydrogencarbonate and each extract is
back-extracted with more solvent. Each consecutive extract is
acidified separately. When the amount of product obtained
decreases, one should proceed to 60Jo sodium hydrogen-
carbonate, then to lOOJo, then to 30Jo sodium carbonate and so
forth, up to reaching 50Jo sodium hydroxide. Each acidified
fraction can be examined separately by TLC. This method
has given excellent results with both highly coloured impure
products which could not be purified by Kugelrohr distil-
lation, and even with mixtures of different acids.


This is where the men are separated from the boys and where
organic chemistry is not a science at all. It was said of Adolf von
Baeyer that his success was in large measure due to his large
beard harbouring seeds of every compound he ever made.
Beards are indeed again in fashion-unfortunately that does not
seem to have contributed to the experimental skill of the average
young organic chemist. In fact, in many research groups there
appears to prevail an attitude of disdain towards the crystalline
compound-all that seems to matter is the 400 MHz NMR spec-
trum. The fact that both matter soon dawns on whoever
emerges into the real world.

Which Solvent Should I Use?

At the outset a distinction must be made between getting a com-
pound crystalline, and recrystallising it. Rarely is a given solvent
suitable for both.
The former requires a good solvent (at any rate, to start with)
for the gum or oil which you want to crystallise (assuming that

TLC and/or GC shows it to be a single compound), one which

itself has a low freezing point and low viscosity right through its
liquid range, and high volatility. A prime example is diethyl
ether, followed closely by terr-butyl methyl ether. That is for
active attempts at crystallisation, which means cooling the con-
centrated solution right down to - 100 C, and scratching all
the time while the solution is warming up. The scratching
should be done not with a glass rod but with a micro-spatula,
because with that you can get around bends, and it is at the
bend of a round-bottomed, flask, where the round portion.. ends
and the straight part begins, and where the glass is roughened
by previous scratching, that crystallisation usually begins.
The passive approach to crystallisation is to dissolve the gum
in a good solvent, add some 'bad' solvent, such as hexane, and
leave the flask open during the weekend. That may sound
shocking, but it usually works. Slow evaporation, together with
nucleation by dust, can work hand in hand. Leaving the flask
in the refrigerator not only prevents both, but leads to greater
viscosity of the medium. Of course, these remarks apply only to
compounds in which instability (to temperature and oxygen) is
not suspected; if so, it would be best to leave the compound dis-
solved in the minimum amount of diethyl ether in the freezer.

Solvents for Recrystallisation

Here again there are two main categories: (1) Single-solvent
recrystallisation and (2) recrystallisation by a solvent pair (and
occasionally trio).
For ( 1), the single solvent must exhibit as steep a solu-
bility-temperature gradient as possible. Of course this depends
to a large extent on the solute, but there are many solvents
which in principle are bad ones in that respect. Often it takes
some time to find the right one for any given compound, which
is the reason why most first attempts at recrystallisation are by
approach (2), dissolving in a low-boiling solvent which is a good
one (e.g. dichloromethane), and replacing it by a high-boiling
bad solvent (e.g. hexane or cyclohexane).

Perhaps it might be best to give a brief overview, based on

some years of the author's experience, of the most common sol-
vents used for recrystallisation, and what kinds of compounds
they are good for, in rough order of their polarity:

Hexane, cyclohexane, heptane: as single solvents for com-

pounds of moderate polarity (alcohols, aldehydes, ketones,
amines, esters, nitrites, acyl chlorides), of m.p. 50-80,
80-100 and 100-120 C, respectively.
Diisopropyl ether: an excellent single solvent for the above
and compounds of greater polarity (e.g. unsaturated
ketones) of m.p. below 80 C, where the use of hexane may
cause 'oiling out'; may need cooling to O C or even below
to give maximum recovery. Must be tested frequently for
Benzene: a bad solvent for single-solvent recrystallisation,
mainly because crystallisation in it is slow and it is more
viscous. Also suspected to be a carcinogen-it should be
used as little as possible; it is banned in many labora-
Toluene: better than benzene because it is higher boiling and
considered to be non-toxic (at time of writing this section!).
Good as a single solvent for compounds of higher polarity
(carboxylic acids, amides, lactones, polyfunctionals, e.g.
hydroxyketones, ketonitriles) of higher m.p. (above 150
Carbon tetrachloride: often a surprisingly good single solvent
for compounds of higher polarity (sulphonyl chlorides,
unsaturated ketones and unsaturated aldehydes, alcohols)
of m.p. below 100 C; good for decolorisation by charcoal.
Disadvantages: crystallisation may be slow, product swims
on top and hence removal of mother liquor by pipette may
be difficult. May need cooling and addition of hexane to
ensure maximum recovery with low-melting solutes.
Diethyl ether, tert-butyl methyl ether: rarely suitable as single
recrystallisation solvents, and then only by using the range
- 30 C (freezer temperature) to + 30 C.

Dichloromethane, chloroform: too good solvents to be suita-

ble for single-solvent recrystallisation, but the ideal first
components for solvent-pair recrystallisation. A less good
solvent but higher boiling is: 1,2-dichloroethane.
Trichloroethylene is probably toxic.
Tetrahydrofuran: a special case. An excellent solvent in
particular for polar polyfunctional compounds, particu-
larly dicarboxylic acids, keto acids of m.p. above 150 C
(owing to solvation). Rarely good as a single solvent, but
excellent as the first cpmponent in a solvent pair for such
compounds, e.g. in THF-toluene or THF-cyclohex"'ane.
Acetone: As for THF in many respects, but often unsuitable
because of its reactivity. Much better as a solvent, although
not for single-solvent recrystallisation, because it is higher
boiling, is butan-2-one (ethyl methyl ketone).
Ethyl acetate: Often surprisingly good as single-solvent
recrystallisation candidate for moderately polar com-
pounds of m.p. 100-150 C. Excellent as the first compo-
nent in solvent pair such as ethyl acetate-cyclohexane,
especially for fractional crystallisation. Has to be used with
caution for recrystallising compounds containing ester
groups because of possible transesterification.
Methanol: For non-polar compounds (hydrocarbons, olefins,
aromatics, nitro compounds, halides) as a single solvent,
sometimes the only one feasible for compounds in which
the non-polar part is predominant (e.g. steroids). If neces-
sary, and for higher-melting compounds of that type, as the
second component in solvent-pair crystallisation (e.g.
diethyl ether-methanol, dichloromethane-methanol).
Good also for low-temperature recrystallisation of more
polar compounds (ketones, aldehydes, enones) because it
retains coloured and polar impurities; provided crystals
formed are such that the mother liquor can be removed by
Ethanol, isopropanol: as for methanol, although less polar as
solvents, particularly isopropanol. More viscous than
methanol and hence crystallisation is slower. lsopropanol is

a good compromise recrystallisation solvent for high-

melting polar compounds containing coloured impurities.
Pyridine, dimethy/formamide, nitromethane: often the sol-
vents of last resort in cases of high-melting insoluble com-
pounds of whatever intrinsic polarity.
Acetic acid: good as a single recrystallisation solvent for
other carboxylic acids of high m.p. and also, surprisingly
for relatively non-polar compounds of m.p. 100-150 QC.

Proper Tools and Technique for Recrystallisation

When finally collecting your product for recrystallisation, after
chromatography or other methods of purification such as
Kugelrohr distillation or sublimation, the size of the flask used
should bear a reasonable relationship to the total amount. For
instance, 25 mg should never be in a flask of over 10 ml capa-
city. And before recrystallisation, never forget to keep a seed
crystal (e.g. from one of the chromatographic fractions).
From the list of solvents for recrystallisation given above it
can be seen that the majority boil below 100 QC, i.e. can be used
on a steam-bath, which is also the safest way of heating. The
trouble with steam-baths is the concentric metal rings used.
They are either too small or too large for the round-bottomed
or Erlenmeyer flask. The best way to deal with this (and some
other) problems is to use Neoprene rubber filter cones
(Fig. 9) in a manner for which they were not originally intended
(see Fig. 10). These are available with upper diameters from 70

Fig. 9. Fig. 10.


down to 22 mm, and are thus suitable for round-bottomed and

Erlenmeyer flasks of up to 100 ml capacity. Their use provides
not only for greater flexibility in the use of steam-bath rings but
also a steady place for the flask to stand (or sit). Moreover, if
you want to reduce the amount of steam heating (for reasons of
excessive foaming, etc.), all you have to do is place another
smaller filter cone inside the original one.
Recrystallisation of small amounts is most conveniently (and
cheaply) done in jointless round-bottomed flasks of the type
shown in Fig. 11 and of 10-25 ml capacity. These when ordered
in bulk should cost no more than $2-3. Hot filtration is best
done using small funnels whose angle is ca 45 and not the usual
'regulation' 60, and the stem should be fairly wide (Fig. 12) to
allow solvent vapour from the flask on the steam-bath to rise
and dissolve material which has crystallised on the filter paper.

Fig. 11.

Fig. 12. Fig. 13.


Incidentally, cotton-wool should never be used for filtration; it

always contains some fat or grease.
Another consideration when choosing a crystallisation sol-
vent, although one which cannot be planned in advance, is
whether the crystals formed are sufficiently compact to allow
removal of mother liquor with a capillary pipette. It is worth
spending some effort on finding such a solvent, because filtra-
tion on a small scale always leads to losses. This is particularly
true of low-temperature recrystallisation, when both solvent
removal and washing with additional solvent must be done
while the flask (after standing in the freezer compartment) is
immersed in a dry-ice-carbon tetrachloride bath. On this point,
a low-temperature recrystallisation should be done in stages,
first at room temperature, then in the main refrigerator com-
partment ( + 4 C), and only subsequently in the freezer com-
partment. This should also help in obtaining compact crystals.
Drying crystals in a flask can be done either as shown in
Fig. 13 (illustrating another use for the rubber filter cones, this
time the small sizes), or (and this applies to Erlenmeyer flasks
which should never be thus evacuated) in a vacuum desiccator.
In that case the neck should be covered with aluminium foil held
in place with a rubber band and punctured by a needle in several
places. That will prevent the crystals from jumping out as the
last remaining traces of solvent come off.

Fractional Crystallisation
It would be a disaster if this were to become a forgotten art.
Imagine getting a crystalline mixture, with a melting range of
10-20 C, say of diastereomers as shown by the NMR spec-
trum, whose TLC behaviour shows that there is almost no hope
of separation by chromatographic methods, or that if there is a
slight hope it will only come about by a lengthy procedure, espe-
cially if quantities of 1 g or more are involved. Are you going
to leave it at that ('an inseparable mixture was obtained'), or are
you willing to have a go at another method, even if it is one
practised for over 200 years? If the latter, then look at Fig. 14,


Crystallize from enough
solvent to separate less
than 35% of mixture

Mother liquor; Crystals;

concentrate to recrystallize
2/3 volume

Mother liquor; Crystals, mother

liquor; Crystals;
concentrate to
heat together to recrystallize
2/3 volume

Crystals, mother Crystals.mother

Mother liquor;
liquor; liquor; Crystals;
concentrate to
heat together to heat together to recrystallize
2/3 volume
dissolve dissolve

Fig. 14.

which shows the general scheme to be followed. It is a leisurely

process, and one which rarely harms the product.
The sequence shown is interrupted at any stage where melting
point determination or spectroscopic evidence shows that a pure
product has been separated. Any 'unpartnered' mother liquors
left as a result should then be combined to start the process
afresh, with seeding where appropriate.
There are a few rules for this game which must be observed:
(a) Cleanliness must be ensured. Solvents must be absolutely
pure. Mother liquor removal and washing of crystals by
pipette only! No boiling stones!
(b) Use only a single solvent, or a pair with similar vapour
pressures. No hygroscopic or peroxide-forming solvents!

(c) Careful judgment must be employed to decide when to

proceed to the next stage. Close examination of crystals is
of help.
(d) Resist the temptation to pick up the flask while crystallis-
ation is progressing! Let forming crystals lie!

Beware of Explosive Crystallisation

Notwithstanding the last injunction, some attention must be
drawn to the fact that the process of crystallisation can be very
exothermic. This can cause a disaster, particularly when a
solvent pair is used for recrystallisation-the mixture may boil
right out of the flask. Hence: have an ice-water bath handy just
in case, and once again: Never leave unattended!
Once melting point determination and spectroscopic evidence
has established the purity of your compound, almost all of it
can be transferred to a suitably sized vial. Whatever sticks to the
side of the flask and cannot be scratched out can still be made
use of as a TLC sample: simply add a few drops of a solvent
such as 1,2-dichloroethane, place on a steam-bath, allow the
rising and condensing vapour to dissolve and wash down the
material and, after cooling, transfer to a small vial by capillary


'Which solvent did you use?'

[ Standard question, conveniently asked on waking up after
(almost) any organic chemistry lecture J


Solvents as a group usually constitute the biggest single item in

the budget of a research group, especially where much chroma-
tographic work is done and even where provision for partial
recovery is made.
The figures in Table 1 should be an eye-opener regarding the
enormous difference in cost between solvents purchased in bulk
and in individual glass bottles. They refer to the annual con-
sumption of 11 common solvents by a department of a well
known European university.
As to the obvious question of whether a difference such as
this would not cover at least six times the annual salary of
someone solely engaged on distilling bulk solvents, that is
clearly not the direct concern of you, the individual researcher.
It does, however, constitute one good reason why you should
either distil solvents yourself or rely solely on locally distilled
material. The other good reason is that you know what you are
working with. On the matter of purity of solvents there can be
no compromise. Any glass bottle from a manufacturer desig-
nated 'analytical grade' or 'puriss' is bound to pass through

Table 1. Cost of solvents purchased in bulk and in individual 2.5 litre bottles

Annual consumption Cost in bulk Cost in bottles

Solvent (litres) (SWF) (SWF)

Acetone 15000 16950 105000

Diethyl ether 7000 21140 210000
Ethanol 3000 3450 24000
Benzene 100 247 2000
Chloroform 400 2048 32000
Ethyl acetate 2000 3400 32000
Hexane 4600 7360 82800
Methanol I 000 740 4500
Light petroleum (b.p. 60-90 C) 100 133 1600
Tetrahydrofuran 10 142 200
Toluene 400 480 7 360
Total 65190 509460
Difference 442270 (681.SOJo)

some weak link in a chain, e.g. the man who cleaned the bottles
that morning or the one who was in charge of the filling
unit-and you were not there at the time. Of course, any repu-
table firm will apologise handsomely if there is any reason for
complaint and will pay full compensation for the defective
bottle, but that will not be any consolation for what may be
weeks of work and other expensive reactants wasted.


Any arrangement for routine distillation of solvents should

ideally answer to the following requirements:
(I) it should be one fixed in position and yet allow for the easy
switch-over from one solvent to another;
(2) it should be in a safe location; and
(3) since that means usually a hood, and since hood space is
always at a premium, it should be constructed so as to take
up as little usable space as possible.
Figure l shows an apparatus, planned by Dr J. Schreiber
(ETH, Zurich), which was designed with these criteria in mind.
The dimensions are in millimetres. The condenser C is mounted
high up on the wall in the centre of the hood. It is connected
by linking tubes to the distillation flask A at one side of the
hood, and to the receiving vessel B at the other end. The impor-
tant point is that all connecting joints are spherical, allowing for
maximum flexibility in both position and size of A and B and
making disconnection of both these an easy matter. Position 1
is for distillation from A to B while position 2 is for reflux from
the condenser back into A via the right-angled tube. If one
forgets to change B in time it will simply fill up and solvent will
reflux back into A. The little extension D serves to create an air
cushion inside B which will prevent spillage on subsequent
change of receiver in such a case. Naturally, all these dimen-
sions, and in particular the lateral ones, should be adjusted in
accord with your local ones-as you can see the ones given are

Fig. 1.

for a hood at least 1.5 m wide. The result is, of course, that the
entire space between A and B is free for additional apparatus.

Anhydrous Solvent Distillation

In almost every research laboratory nowadays there is a need
for an arrangement or device which will allow continuous
refluxing over a drying agent, and at the same time withdrawal
of such dried solvent in a desired amount and whenever needed,

I ,

(al (b)

Fig. 2.

and all this preferably while under an inert atmosphere. Figure

2(a) and (b) show two such designs of apparatus.
In both the top of the condenser is connected to an inert gas
manifold such as Chapter 4, Fig. 5. In the first, simpler version,
solvent can be withdrawn by syringe, through the wide Teflon
stopcock A, from the 500 ml capacity intermediate collector
with stopcock B closed. When the latter is open the dry solvent
will circulate continuously from the distilling flask at the

bottom. In the second, more sophisticated apparatus, solvent

withdrawal is possible either through the stopcock C or by
direct run-out from the three-way stopcock D. The cylindrical
form of the collector E allows for easy calibration of volume in
terms of ml cm - I; for example, when the outer diameter of the
cooling finger is 12 mm and the inner diameter of E is 52 mm,
then the scale is 20 ml cm - 1 Use of the thermometer socket is,
of course, optional.


Table 2, based on the author's experience, has withstood the

test of time. It is meant to reconcile some of the conflicting
advice encountered on the subject of solvent purification, drying
and storage, and it takes into account the comparatively high
state of purity now shown by many commercially supplied sol-
vents even when purchased in bulk and described as being of
'practical' or even 'technical' grade.
A number of points must be stressed. First, most hydro-
carbon (and halocarbon) solvents can be dried as thoroughly as
by any other means by azeotropic water removal, which means
distilling off between 50Jo and 250Jo of the total and thus drying
not just the solvent but also the containing vessel (the author's
own criterion is the lack of reaction with sodium hydride sus-
pension). It follows that in many reactions where anhydrous
conditions are essential the inclusion of an inert hydrocar-
bon-preferably toluene or cyclohexane-as part of the solvent
system should be considered.
Second, the use of extruded sodium wire for drying solvents,
especially diethyl ether, is a still persisting pernicious practice
which should be stamped out once and for all. Its drying ca-
pacity is limited to start with and ceases immediately on forma-
tion of the adhering layer of sodium hydroxide. Wherever this
is still practised it is a major cause of fires.
Third, a few comments on molecular sieves. Their use is now
routinely advocated and is probably most generally effective.

However, it is often not sufficiently realised that this type of

material must be freshly activated, usually by heating to
300-350 C (metal bath) in a high vacuum. Either this is done
immediately before use, or else the activated material should be
stored under totally anhydrous conditions (e.g. like activated
alumina in bottles with a very narrow opening stoppered by a
rubber stopper). Many suppliers do not trouble to supply this in
the proper kind of container, and thus newly supplied material
must nearly always be subjected to this activation.
Now to the special problems posed by solvents such as tetra-
hydrofuran, 1,2-dimethoxyethane and dioxane. Tetrahydro-
furan as now supplied by reputable suppliers is good enough as
is for direct drying, either by passing through activated alumina
(Chapter 4, p. 97) or, for larger amounts in an apparatus such
as illustrated in Fig. 2. If of more doubtful origin, it must be
treated with the same amount of suspicion as the other two sol-
vents. That means first testing for the presence of peroxides and
taking steps for their removal; in this connection you should be
warned that the potassium iodide-starch test strips are not
absolutely reliable. After that, pre-drying is usually required
(see Table 2).
A few special remarks should be devoted to tert-butyl methyl
ether. This is now the cheapest available organic solvent, a
secret reasonably well kept by firms not especially keen to lose
on sales of other solvents. The reasons for the low price is that
it is now made on a relatively enormous scale as a gasoline addi-
tive in place of the banned tetraethyllead. For that reason, the
cheapest supply is directly from one of the large petroleum
processing firms. For the organic chemist, in considering it as a
solvent for general extraction and chromatographic purposes
there are other considerable advantages: (i) the negligible tend-
ency for peroxide formation, (ii) its boiling point (55-56 C),
which is higher than that of diethyl ether yet still low enough for
easy removal by distillation, a special advantage in summer
or in warm climates, and (iii) its lower mutual miscibility with
water. It is possibly inferior to diethyl ether and tetrahydro-
furan for use with Grignard or other organometallic reagents,
Table 2. Purification, drying and storage of common solvents

Boiling point
(acceptable Further drying and
Solvent range, C) Preliminary purification purification Recommended storage

Pentane 36 (2-3) Wash several times with Rarely necessary; if so by

Hexane 69 (2-5.) cone. sulphuric acid to azeotropic water removal
Cyclohexane 80.7 ()) remove olelins if necessary,
Other alkanes wash with water, dry over Up to 500 ml in glass-
CaClz, collect after wet stoppered bottles; above
forerun that and for long periods
in dark screw-capped
Benzenet 80.1 (0.5) Dry over CaClz, Boil off from or redistil into bottles. No sense in
Toluenet 110.6 ()) refractionate, reject first reaction flask, rejecting first keeping over molecular
Xylenes 144.5 (ortho) 5-10% of wet forerun 5V/o (see text) sieves
139 (meta)
138.3 (para)

Dichloromethane 40 (I) Wash with water, dry over Redistil from P20s; on small As above, but chloroform
Chloroform 61.2 (0.5) CaCI,, redistil, collect after scale and in special cases for longer periods in
Carbon 5% wet forerun pass through alumina (basic, tightly closed full bottles
tetrachloride 76.8 (0.5) act. I) directly into reaction and in darkness.
1,2- flask
Dichloroethane 83.5 (I)
Diethyl ether 34.5 (I) Test for peroxide; if positive Small amounts: pass through Best in cool, dark place in
Diisopropyl ether 68.5 (I) wash with 5870 up to 10 wt 87o alumina nearly full screw-lidded
rert-Butyl methyl metabisulphite soln, then (basic act. I); with larger metal cans. For long
ether 55 (I) with sat. NaCl; dry over amounts best to use absolute periods seal with Para film f
CaCii; distil (but not over diethyl ether from cans
cone. HzSO.)

Tetrahydrofuran 65.5 (0.5) Distil from potassium under In dry plastic-insert screw-
1,2-Dimethoxy Stand overnight over KOH, argon (see text), small capped 100 ml bottles over
ethane (glyme) 84 (I) decant, test for peroxide; if amounts pass directly into basic active alumina under
positive stir with up to flamed-out reaction flask argon. For long periods
0.4870 wt 810 NaBH. through alumina (basic act. seal with Parafilm; dioxane
overnight, add CaH2, I) best kept frozen in
fractionate but not to refrigerator (but watch out
Dioxane 101.5 (I) dryness Distil from sodium under for burst bottles!)
(m.p. 11-12) argon (see text)

Carbon 46.5 (I) Redistil in hood from small Shake with small amount of Don't! Avoid leaving
disulphide amount of phosphorus mercury, redistil from around laboratory
pentoxide; use only water phosphorus pentoxide
bath heated by steam

Ethyl acetate 77.1 (0.5) Fractionate from up to 5 wt

Methyl acetate 57 (I) Dry over active Caso. 87o of acetic anhydride
Over activated molecular
(Sikkon) and/or anhydr.
sieves SA in tightly closed
Other esters K2C01, decant, distil Refractionate
boiling 0
below 100 C
(continued) '
Table 2. (continued)
Boiling point -?
(acceptable Further drying and
Solvent range, C) Preliminary purification purification Recommended storage

Acetonitrile 81.5 (0.5) Predry over MgSO,, I lhen Fractionate from P20s. Over activated molecular
over anhydr. K2C03, Small amounts: pass through sieves JA, best in 100 ml
decant, distil from CaH2 alumina (basic act. I) dated bottles
directly into reaction vessel

Acetone 56.2 (0.5) Distil over 2 C range, dry Over rreshly activated
over anhydr. Caso,, If used for oxidation molecular sieves JA
decant, redistil reactions reflux over suffi-
cient KMnO, to retain violet
Butan-2-one 79.5 (0.5) Fractionate off water azeo- colour, distil, dry, frac- Over freshly activated
tropc (b.p. 73.5 C), dry tionate. Very pure via Nat molecular sieves SA
this and remainder addition compound
separately as for acetone

Methanol 64.5 (0.5) Simple fractionation now

usually sufficient even with
bulk grade
Predried material redistillcd In small boules over
Ethanol 78.J (0.5) From 'rectified spirit' (950Jo) from CaH2, best directly freshly activated molecular
most economically by reflux into reaction vessel sieves JA
and distillation from Cao
(at least 1.5 times amount
needed to bind water pre-
lsopropanol 82.5 (0.5) Fractionate, collect after
water azeotrope (b.p.
80.3 C), dry latter as for
ethanol Predried material redistilled In small bottles over
from CaH2, best directly freshly activated molecular
n-Propanol and 97.2 (0.5) Fractionate, collect after into reaction vessel sieves 3A
higher alcohols aqueous azeotrope forerun

tert-Butanol 82.5 (0.5) Water azeotrope, b.p. As for previous alcohols but As for previous alcohols;
(m.p. 25.8) 79.9 C. Treat as for care needed in distillation- bottles best kept in warm
isopropanol solid may block condenser! place during cool season to
save bother of 'thawing

Ethylene glycol, 198, 68-70/4 Fractionate in vacuo, collect Refractionate after Best in 100 ml plastic
higher glycols mm Hg aher 5-IOOJo forerun. High dissolving up to I wt-'lo of insert screw-capped bottles
108-110/28 latent heat of vaporisation! sodium (very hygroscopic!), larger
mmHg (2) amounts only over large
excess of molecular sieves

Nitromethane 101.3 Ol I Dry over CaCh, decant, Refractionate from Over molecular sieves 4A
Nitroethane 115 fractionate molecular sieves 4A

Table 2. (continued) -
Boiling point
(acceptable Further drying and
Solvent range, C) Preliminary purification purification Recommended storage

Formic acid IOI (I) Fractionate, best under

(m.p. 8.3) reduced pressure. Can be
dried further by reflux and
On prepurified material
distillation from phthalic
freeze completely, allow to
anhydride. Water azeotrope
thaw to extent or 10-20970,
has b.p. 107 C (22.5970 In screw-capped bottles
decant (all while protected
from moisture), use
Acetic acid 118 (0.5) Refractionate after adding
(m.p. 16.6) up to 5 970 acetic anhydride
and up to 2970 Cr01

Pyridine 115.5 (0.5) Ir very crude dry over Reflux with CaO, Bao or In tightly closed dated
Methylpyridines KOH, decant, fractionate very active basic alumina, bottles over molecular
refractionate sieves SA

N, N-Dimethyl- 153, 42/ IO Fractionate in vacuo, Stir overnight with CaO, Best over freshly activated
formamide1 mm Hg, rejecting first and last 1007o. BaO or alumina (basic act. molecular sieves in small
N,N-Dimethyl- 55/20 Avoid distilling at I), then refractionate in dated bottles. With larger
acetarnide mmHg; (I) atmospheric pressure vacuo amounts (above 500 ml)
N-Methyl- 166, the amount of sieves
pyrrolidone 58-59/ 11 should be large to take up
mmHg, moisture introduced on
frequent opening
mmHg; (1)
mm Hg;
mmHg; (I)

Dimethyl 190, 50/3 Fractionate in vacuo, Stir with CaH 2 overnight, Best over freshly activated
sulphoxide mmHg, rejecting first and last 100/o. then fractionate from CaH2 molecular sieves in small
72/12 A void distilling at in vacuo. Can be further dated bottles. With larger
mmHg, atmospheric pressure purified by partial freezing if amounts (above 500 ml)
84-85/22 dry the amount of sieves
mmHg; should be large to take up
(I), m.p. moisture introduced on
18.5 frequent opening

Hexamethyl 235, 68-70/1 Stir for 1 h with CaH 2 at In small (50 ml) plastic
phosphoric- mm Hg, 100 C under reduced insert screw-capped bottles
triamide 115/ 15 pressure, then refractionate under argon and over
mmHg; in vacuo activated molecular sieves
126/30 IJX or over oil-free NaH
mm Hg; if available.
(1), m.p. 7

Cheaper 'hexane fraction'.

t Assumed free of sulphur compounds such as thiophene.
t Can be stabilised or restabilised by adding up to 0.001 'lo of a dihydric phenol.

May frequenrly be supplied in s1a1e of purity inferior 10 !hat claimed; purification calls for exrra care.
I May be encountered in pan as low-boiling azeotropc with water.
1 Reported to be light-sensitive; probably best kept in dark bollles at all times. '

although there are indications of its superiority to these two in

heteroatom-facilitated metallation. Recently, there have been
signs that at least in part, its place as a gasoline additive may
be taken by tert-butyl ethyl ether, a solvent with probably the
same advantages but with a higher boiling point. The one great
disadvantage of both is, of course, their instability to strong
Tetrahydrofuran now clearly holds pride of place as the best
solvent for nucleophilic reactions, so much so that deciding to
use it has become something of a kneejerk reaction. It is advis-
able, however, that where its solvation power is inherently of no
importance or possibly even detrimental, other ethereal or even
non-polar hydrocarbons should be tried. Much the same pre-
eminence is occupied now by dichloromethane for electrophilic
reactions. This is entirely understandable, in view of its stabi-
lity, its excellent solvent power for Lewis acids of all kinds,
simple and complex, and its low boiling point. It has also
become fashionable for certain types of nucleophilic reactions,
although here its reputation has suffered recently. 59 a

Dipolar Aprotic Solvents

These have undoubtedly advanced synthetic organic chemistry a
great deal. 60 Table 3 summarises some useful information on
the most important of these, much of it available only in
brochures and other commercial literature.
Their chief drawback is the difficulty of getting rid of them
once they have served their purpose. This applies particularly to
hexamethylphosphorictriamide (HMPT A) and to the same
extent to various substitutes for this that have been suggested
recently, in view of the presumed toxicity of that solvent. Prac-
tically every month sees the publication of yet another example
of how various reactions proceed under milder conditions, or in
better yield, or proceed at all when using this or a similar sol-
vent, but on closer examination one often finds that the
substrates have been carefully chosen so as to make isolation of
the product a simple matter, e.g. the product is non-polar and
Table 3. Dipolar aprotic solvents-some useful data

Propcr1y N,N-Oime1hylformamidc 61 acetamidc 61 N-Me1hylpyrrolidone 62 Dimethyl sulphoxide 61 . . Hexamethylphosphoriclriamide 6 '66

Melting -61 -20 -24.5 18.6 7

point (C)
Oielcciric 36.7 37.8 32.3 48.9 30
Basicity, I.JO 1.34 2.03
as ~om
Some (in g per 100 ml al 25 C): More than 10'7o at (in g per 100 ml at 25 C): (in g per JOO ml al 25 C):
selected AgCI > 16.5, 25 C: (NH,l,S, Kl 20, KNO, 10, NH;CI 4.4, AgNO,
solubilities CuCl,.2H,O> 14.7, Pb(OAC),, PbCI,, S, KNO, 2, AgNO, 130, 33.3, CuSO, 13.7,
CuSO, 1.7, KCN 0.2, KMnO,, KCNS, Nal 30, NaNO, 20, NaCl 0.78, KCI 0.2,
KCNO 0.11, KCNS ZnCI,. NaNO, 20, ZnCI, 30, NaNO, 8.8, Na,SO,
17, K,Fe(CN)o < 0.05, KF: 307, at Cul I, Cu8r 2 I, LiBr 0.1
Kl> 23.6, KMnO, > 190-200C 31.4, LiNO, 10,
16.5 LiCIO, 31.S

~om= om - 6, where om is the chemical shirt of chloroform in the solvent at infinite dilution and 6 is !hat of chloroform in an inert solvent

Table 4. Some important azeotropes 0

Methylcyclo- Carbon
Hexane Heptane Benzene Cyclohexane hexane Toluene tetrachloride
69* 98.4 80.1 81.4 100.3 110.6 76.8

Methanol 50 59.1 57.5 54 59.3 63.8 55.7

64.65* (30)t (51.5) (39.1) (38) (54) (69) (21.6)
Ethanol 58.7 70.9 68.2 64.8 72.1 76.7 65
78.5 (21) (49) (32.4) (31.3) (47) (68) (16)
n-Propanol 65.6 87.5 77.1 74.3 86.3 92.6 73.4
97.2 (4) (36) (17) (20) (35) (50) (18)
Isopropanol 62.7 76.4 71.9 69.4 77.6 80.6 68.6
82.3 (23) (50) (33) (32) (53) (69) (28)
n-Butanol - 94 - 79.8 95 105.5 76.55
117.7 (18) (9) (20) (32) (2.5)
sec-Butanol 67.2 88.1 78.5 76 89.9 95.3 74
99.5 (8) (37) (15) (18) (41) (55) (8)
tert-Butanol 63.7 78 74 71.3 78.8 - 71.1
82.8 (22) (62) (36.6) (37) (66) (17)
tert-Amyl - - 80 78.5 92 100.5
alcohol (15) (16) (40) (56)
Acetone 50 56 - 53 - - 56
56.5 (59) (89.5) (67) (88.5)
Butan-2-one 64 77 78.2 71.0 77.7 - 73.8
79.6 (29) (73) (45) (52.5) (80) (29)
Tetrahydro- 63
furan 65.5 (53)
Acetonitrile 57 69.4 73 62.2 71.1 81.1 65
81.6 (25) (44) (34) (33) (51) (78) (44)
Nitromethane 62 80 79.1 70.2 81 96.5 71
101 (18) (35) (14) (28) (39.5) (55) (17)
Dioxane - 92 - 79.5 93.7
101.5 (44) (25) (45)
Pyridine - - - - - 110.1
I 15.3 (20)
Methyl 51.7 57 - 55
acetate 57. I (60) (96) (83)
Ethyl 65 - - 72.8 - - 74.8
acetate 77. I (38) (54) (43)
Dimethyl 67 82.3 - - - - 75.75
carbonate 90.5 (20) (61) (12)
Acetic acid 68.2 95 79.6 79.7 96.3 104 76
118.1 (6) (17) (2) (2) (31) (32) (1.5)
Formic acid 60.6 78.2 71 70.7 80.2 86 66.65
100.7 (28) (56.5) (31) (30) (46.5) (50) (8.5)
Water 61.6 79.2 69.2 69.56 81 84.1 66
100.0 (5.6) (12.9) (8.83) (8.4) (13.5) (4)

Figures not in parentheses refer to boiling point in C.

t Figures in parentheses refer to approximate percentage by weight of polar solvent in each azeotrope.

- .I

hence isolable with a hydrocarbon solvent such as pentane, not

to speak of cases where on looking just a little closer one dis-
covers that the product was not actually isolated at all but that
results and yields were arrived at by GC or spectroscopic
examination alone. When the method is applied to more
complex cases one usually finds that product isolation is a lot
more difficult.
Another solvent in that category which deserves more atten-
tion than it currently enjoys is sulpholane (tetrahydrothiophene
l, I-dioxide) and its 3-methyl homologue, both commercially
available. These have been found to be superior in reactions
such as SN2 displacement with fluoride ion, 67 palladium-
catalysed oxidation of olefins 68 and the formation of sulphonyl
chlorides from sulphonates. 69
With all these solvents one should first investigate whether the
use of a very minimum say (2-3 mmol per mmole of substrate),
together with a more easily removable solvent (diethyl ether,
tetrahydrofuran, toluene) will not give just as good results.
Often there is no need even for enough to give a homogeneous
mixture. When the product is acidic, HMPT A can be removed
almost quantitatively by extraction of the alkaline solution with
a chlorinated solvent such as chloroform, 66 and where the
product is neutral it should be extracted with, e.g., toluene, and
the HMPT A removed destructively by several washes with 3 M
hydrochloric acid. In any case, the best policy when using
dipolar aprotic solvents is to work the product up using
only hydrocarbons (toluene if not hexane or cyclohexane) for

The Importance of Azeotropes

Many organic reactions are equilibrium reactions in which the
yield of the desired product can be enhanced by removing one
of the products (water, an alcohol or some other low-boiling
material) from the system, and this is best achieved by the use
of an inert reaction solvent which can do so as an azeotrope.
This principle is likewise important when freeing a product from

traces of a high-boiling contaminant, and when recrystallising

from a mixture of solvents. A reference book such as the ACS
Monograph on the subject ' 0 should be available to every
research group; for the sake of convenience, Table 4 lists azeo-
tropes formed by inert solvents with the most commonly
encountered polar solvents or reactants.
From this it is easy to see, for instance, that the only way to
remove traces of pyridine is with toluene, that formic acid is
removed azeotropically much more easily than acetic acid and
that ethyl acetate-cyclohexane or ethyl acetate-carbon tetra-
chloride are suitable solvent pairs for TLC and fractional crys-

Which Base Should I Use?


So much of synthetic organic chemistry nowadays involves

deprotonation that it is not surprising that this is one of the
questions most frequently asked by the perplexed organic
When you need a base it means usually that you have to
remove a proton, most frequently from a carbon atom, but the
question can be just as pertinent if it has to be removed from
oxygen, nitrogen or sulphur. The major, although not the only,
factor is the acidity of the substrate. Table I 71 constitutes a
rough guide, adapted to the most common types of carbon
substrates, and the most frequently used Brnnsted bases.
Put in a nutshell, the base appearing on the right should be
able to deprotonate to an appreciable extent the type of
substrate above it on the left, and the higher above the better.
The fact that often this is not the case, and also need not be the
case, can be due to a number of reasons.

Posslblllties of Shifting the Equilibrium

All deprotonations are fundamentally equilibrium reactions,
and an unfavourable equilibrium (i.e. one established between
a base on the right and a substrate on the same level or below
it) can be shifted to a favourable one, if by some means one of
Table 1. C- H and N-H acidities and commonly used bases (in
dimethyl sulphoxide solution) (protons affected in italics)

Typical substrates for deprotonation pX- Commonly used bases

Cyano ester NC-CHR-C02R' 9

3-Keto esters R "CO-CHR-C02R'
Dinitriles R-CH(CNh
1,3-Diketones [ II
Malonic esters R -CH(C02R 'h 13

Acid halides R - CH2COCI

CH=CH, [ 16
Cyclopentadiene I / CH2
Aldehydes R-R'CH-CHO 19

Esters R -CHR' -C02R"
Nitriles R-CHR' -CN Sodium methoxide
Ketones R-CHR'-COR" Sodium isopropoxide
Amides, primary
R-CHR'-CONH2 27 Potassium tert-butoxide
Lithium hexamethyldisilylazide
Amides R-CHR' -CONR"2
Acetylenes R-C=CH ( 28
Sulphones R-CHR' -S02R"
Triarylalkanes Ar3CH 31 Triphenylmethylsodium

Sulphoxides R-CHR' -SOR" Sodium dimethylsulphoxide
Thioacetals RS-CHR' -SR"
Diarylalkanes Ar2CHR
Dialkylamines R2NH lithium diisopropylamide
(Hydrogen H- H) 36' Sodium hydride
Potassium hydride

Arylalkanes Ar-CHR' R"

Vinylalkanes -CH=CH-CHR
Alkenes -CH=CH- (: Phenyllithium

Thioethers RS-CHR' R"

( 48
Alkanes, primary R-CH1 so n-Butyllithium
Alkanes, secondary R -CH2- R' sec-Butyllithium

pK values or conjugate base (ler1 column) or conju1a1e acid (riaht column).


the primary products is removed from the system. For example,

sodium methoxide is a bad base, equilibrium-wise, for efficiently
removing a proton from methyl acetate; but if the resulting
enolate reacts with the carbonyl group of a non-deprotonated
ester molecule and as a result a much less basic 3-oxo ester
enolate is formed, the overall reaction will go to completion,
especially if the solvent is diethyl ether, in which the enolate salt
formed is insoluble and thus leaves the equilibrium system.
Another example is how such a weak base as 5 % sodium car-
bonate (not even mentioned in Table 1) can deprotonate at the
a-carbon next to one of the carbonyls in a 1,5-diketone, even
though this can proceed only to a minute extent at equilibrium,
for the reason that the subsequent aldol cyclisation gives a very
stable product (a cyclopentenone).
Another approach of considerable practical importance is
through removal of one of the primary products by distillation,
such as, again using sodium methoxide, removal of methanol
formed in the form of an azeotrope (see Chapter 6, Table 4)
with a co-solvent such as benzene or toluene. The same can
apply to the stronger base potassium tert-butoxide. This works
particularly well when the first-formed enolate is expected to
react in situ with the carbonyl of a non-enolisable second reac-
tant. An example of this is the reaction between a ketone and
dimethyl carbonate to form a 3-keto ester. Dimethyl carbonate,
incidentally, itself forms an azeotrope with methanol, so it can
serve well as both solvent and reactant.
Actually for many such reactants sodium or potassium
hydride is used. Theoretically these are much stronger bases and
also the ideal 'irreversible' ones since here equilibrium is shifted
by the irrevocable exit of hydrogen from the system. However,
in most cases, because of their insolubility, they do not start to
react until a trace of alcohol is present. In effect this means that
one is actually using an alkoxide base, albeit one continuously
generated as reaction proceeds and in effect under irreversible

Choice of Base to Avoid Sida Reactions on the Substrate

Many of the common strong bases cannot be used under all
circumstances, for the simple reason that they can also act as
nucleophiles. This means most alkyllithium reagents, and even
more so other organometallics such as Grignard reagents, and
other types of bases such as sodium or lithium amides. In many
cases this can be circumvented by increasing the steric bulk of
the anionic part of the base, e.g. lithium diisopropylamide and
hexamethyldisilylazide instead of unsubstituted amides or those
substituted by less hindered alkyl groups. Another example is
the use of isopropylmagnesium halides, which can act as effi-
cient bases in many instances 72 73 where a less-hindered Grig-
nard reagent would function exclusively as a nucleophile.
Added advantages here are that this reagent is stable in tetrahy-
drofuran and available commercially and that the magnesium
can act as additional driving force by chelating with the pro-
duct. 74 Among organolithium compounds there is the example
of mesityllithium 75 76 instead of phenyllithium as a non-
nucleophilic base; this is also probably stronger than the ubiqui-
tous lithium diisopropylamide with the added advantage of
avoiding a problem generally overlooked with the latter, namely
the formation of an amine as byproduct. Such introduction of
hindrance may actually increase basicity to some extent; for
example, whereas sodium phenoxide is an ineffective base, the
2,6-di-tert-butyl 77 and the 2,4,6-trimethyl 78 homologues are not
only highly non-nucleophilic but also stronger as bases.

Choice of Base and Conditions to Avoid Sida Reactions of

the Substrate
Here are meant instances where a partially deprotonated
substrate may as a nucleophile react with still protonated
material, for example the undesirable self-condensation of an
aldehyde, ketone or ester. The way to avoid this is three-fold:
(a) doing the deprotonation at as low a temperature as possible,
and (b) using as strong and as non-nucleophilic a base as poss-

ible and (c) adding the substrate to the base and not the other
way around as is customary.
An important requirement is therefore that the base be
soluble at that low temperature, which accounts for the
popularity of lithium diisopropylamide and other amide bases
of both high molecular weight and degree of hindrance. It is
possible that if one goes down to - 100 C (and can find a
solvent system suitable at that temperature), then by following
the above principles a strong and ordinarily nucleophilic base
such as n-butyllithium could be used as base alone.
Incidentally, this may well be another instance where adding
a substrate as a solid in small portions, i.e. with none ever in
solution in excess, could be of advantage.

The Role of the Solvent and of Chelating Agents; Making

Strong Bases as Strong as They Should Be
The advent of the polar aprotic solvents N,N-dimethyl-
formamide (DMF), dimethyl sulphoxide (DMSO) and hex-
amethylphosphorictriamide (HMPT A) has made a considerable
impact on carbanion and other anion chemistry and such sol-
vents are described in detail elsewhere (see Chapter 6, p. 168).
Briefly, their function is in solvating the cation and/or non-
solvating the anion, thus making this and also the deprotonated
intermediate more soluble and more reactive. Compared with
hydroxylic solvents, reaction rate differences of up to 10 14 are
known; with the common ethereal solvents they are of the order
of 'only' 10 2 -10 3 , which is still impressive, however.
Nonetheless, there are snags when using such solvents with
strong bases. DMSO is itself acidic and will form the 'dimsyl'
anion, which is both a weaker base and also a nucleophilic one
compared with the initial deprotonator; DMF has a carbonyl
group subsceptible to nucleophiles; HMPT A is attacked simi-
larly and moreover has to live down its notoriety as a strongly
suspected carcinogen. Hence the usefulness of these solvents is
restricted to weaker bases, such as potassium tert-butoxide in
DMSO, or to completely non-nucleophilic ones, such as sodium

hydride in DMF. In the latter there is the added advantage that

alkyl halides are practically inert to that base even in that sol-
vent, hence deprotonation can be done in their presence with in
situ alkylation of the substrate as formed.
To a certain though lesser extent, this effect is observed with
ethereal solvents, and there are differences between different
compounds, although not to the same extent. Thus, the
increasing order of effectiveness appears to be diethyl ether <
tetrahydrofuran < dintethoxyethane (glyme) < (2,2' -
bismethoxy)diethyl ether (diglyme), i.e. following the increasing
number of oxygen atoms in the molecule. Unfortunately, this is
also the order of increasing sensitivity to attack of strong base
on the solvent itself. 79 As a result, tetrahydrofuran is the com-
promise solvent of choice for many such reactions, and substi-
tuted tetrahydrofurans appear to be more stable to strong
bases. 80
More recently, advantage is increasingly being taken of
another development which allows us to have the best of both
worlds: the use of chelating addends such as tetramethyl-
ethylenediamine (TMEDA) and of crown ethers. These can
effect cation solvation on a more or less stoichiometric and even
catalytic level, and thus make it possible to use strong bases in
solvents which are completely inert but also completely non-
solvating and thus ordinarily useless (e.g. saturated hydro-
carbons). Thus, n-butyllithium with one equivalent of TMEDA
in cyclohexane can deprotonate anything with a pKa of less than
50, including hydrogen itself (a good way of making highly re-
active lithium hydride! 81 ). What happens here in addition to
cation solvation is the breaking-up of aggregation of molecules
of the organometallic. It is this kind of factor that ordinarily
makes them Jess strong bases than they ought to be on a pKa
basis. Thus, n-butyllithium in hydrocarbons cannot deprotonate
the methyl group in toluene, although it should according to
Table I; it will do so after adding TMEDA.
It must be kept in mind that the n-butyllithium-TMEDA
combination will attack a solvent such as tetrahydrofuran even
more readily than the organometallic alone, hence it should be

prepared, and the substrate added, at as low a temperature as

possible (below - 70 C at any rate). 82
These addends can show considerable specificity for the
cation used. TMEDA and 14-crown-4 are mainly for lithium, 83
15-crown-5 for sodium 84 85 and 18-crown-6 for potassium. 86
Their enhancing effect applies even to the insoluble hydrides of
sodium and potassium, for example when extremely hindered
alcohols have to be converted into the alkoxides.

Effect of Changing the Cation

This can have a marked effect but may introduce practical
difficulties. On going from lithium to sodium and then pot-
assium, the ionic character and hence reactivity generally
increase, but at the same time solubility decreases. Thus
butylsodium is more difficult to produce and use, but more reac-
tive than butyllithium. This difficulty can apparently be over-
come by adding potassium or sodium butoxide to either an
alkyllithium 87 or a lithium dialkylamide, 88 although there is still
controversy as to whether the resulting extremely strong and
non-nucleophilic bases formed are in fact the alkylpotassium or
-sodium. Striking differences have been found not only in the
base strength but also the direction of deprotonation of the dif-
ferent hexamethylsilylazides, 89 which can be prepared directly
by displacement from the corresponding unsubstituted amides
or hydrides. 90 In the case of the metal hydrides, where solubility
being non-existent is not an issue, reactivity differences are
extreme. 90

Double Deprotonatlon - Dianlons and Polyanions

This is a greatly expanding subject, a fuller discussion of which
is outside the scope of this chapter, and in any case there are a
number of reviews. 91 From a practical point of view, it has been
found desirable in most cases where a proton can be detached
at two or more sites with a view to reaction at the most basic
site, to use different bases for each site in sequence. This will

reduce the chances that the stronger base used for the Jess acidic
site will complicate matters by acting as a nucleophile.
Thus, with ethyl acetoacetate the C-3 anion is formed with
non-nucleophilic sodium hydride, followed by deprotonation at
C-5 with n-butyllithium. 92 The same applies to dianions from
carboxylic acids, 93 olefinic non-conjugated ketones, 94
9 96
phosphonates s and imides. The use of an addend such as
TMEDA in such cases appears to be beneficial or even
essential. 97


This is now undoubtedly the most widely used organometallic
reagent, and one of the most frequently used strong bases. It is
usually available in hexane solution in concentrations ranging
from 1.0 to 2.5 M. However, in the author's experience it
appears that for this and other alkyllithium reagents cyclo-
hexane is the preferred hydrocarbon solvent. n-Butyllithium is
also available at a lower price per gram-mole in high concentra-


Fig. 1.

tion, 9-10 M in hexane. Such solutions are far too viscous for
dispensing, for example, by syringe and, after some investment
in the necessary safety precautions (liberal blanketing of the
entire operation with dry argon), it is a good idea to transfer
each bottle under argon pressure into a flask large enough to
allow dilution with high-quality cyclohexane to a concentration
of 2-2.5 M. It can then be transferred to small (50ml capacity)
bottles. For both these operations the devices shown in Fig. 1
can be used: in Fig. 1(a) the stopper has a third hole, closing of
which with one's finger creates the internal pressure for trans-
fer; in Fig. l(b) there is a small hole in the T-tube for the same
purpose. At the above concentration, and provided the bottles
are of the screw-cap closure variety and additionally sealed with
Parafilm and kept in the refrigerator in a closed metal tin, such
solutions can be kept for a prolonged period (1-2 years)
without deterioration. Each bottle, after removal from the
refrigerator, should be allowed first to reach room temperature,
otherwise moisture will enter on opening. The precipitate
formed on longer standing is lithium hydride, owing to attack
on the solvent. This may take a long time to settle, particularly
in solutions of still high concentration. It is probably respon-
sible for anomalous results reported in certain cases (e.g. forma-
tion of lithium organocuprates) even where the titre of the
solution (see below) was satisfactory. Misgivings regarding poss-
ible crystallising-out of cyclohexane at low temperatures have
not been borne out.


This presents a stability problem. It should be bought only in

cyclohexane or isopentane-cyclohexane solution and if possible
during the winter months. Even at 5 C the rate of decompo-
sition (as shown by formation of lithium hydride) is by no
means negligible. However, there is little doubt that it is an even
stronger base than n-butyllithium. Similar problems are met
with in tert-butyllithium, exacerbated by the fact that it is
commercially available only in pentane solution, is much more

spontaneously flammable on contact with air, and much more

difficult to handle in a warm climate.

Here is one organometallic that is indefinitely stable at room
temperature in a particular solvent. The trouble is that the
solvent is diethyl ether. Like n-butyllithium it is not stable in
tetrahydrofuran, and it is insoluble in hydrocarbon solvents.
Were it not for these facts, being much less nucleophilic it
would have taken the place of butyllithium a long time ago.
Once again, dispensing this reagent accurately is difficult except
in a cold climate.
Recently it has been offered commercially as a tetrahydro-
furan complex in cumene, 98 which looks like going to another
extreme solvent-wise.

Other Organollthlum Compounds. Preparation

There are not too many other organolithium reagents generally
available commercially, and you might find it worthwhile to
prepare some which look promising, such as cyclohexyl- or
cyclopentyllithium. When doing so, and in any reaction
involving Group I and II metals, it has been found advan-
tageous to immerse in the upper part of the reaction mixture
half of a razor blade of the old-fashioned variety tied by copper
wire to a Teflon rod (see Fig. 2), in such a way that the cutting
edge faces against the direction of stirring, thus scratching the
metal particles and exposing fresh surfaces continuously. The
suggestion has been made that pieces of broken glass be added
for that purpose. That does not appear to be good advice, for
two reasons: it does not do the flask and in particular the ther-
mometer much good, and since lithium always swims on the top
and the broken glass sits at the bottom one would have to stir
really hard-and that will really chew up everything! The
lithium should be of the kind containing ca 2% of sodium; if
this is not specified it should not be used for that purpose. Inci-

Fig. 2.

dentally, whereas sodium and potassium can be purified by

cautious melting under an inert solvent, when the globules of
the metal will separate from impurities such as the
hydroxide, 99 100 this unfortunately does not apply to lithium. It
needs a much higher temperature for melting and when it does
there is no such separation from impurities. It can, however, be
purified by subjection to ultrasound whilst in (or rather on)
toluene; surface dross will separate then and sink to the bottom.

Lithium Diisopropylamide
This widely used base is generally prepared by adding the calcu-
lated amount of n-butyllithium to a solution of diiso-
propylamine (distilled from calcium hydride) in tetrahydrofuran
or diethyl ether. It is difficult nowadays to find an issue of a
journal devoted to organic chemistry where this is not men-
tioned at least half-a-dozen times. It is natural to look for some
way of making a stock solution, but there are problems here.
This base also decomposes ethereal solvents at room tempera-

ture at an appreciable rate, and when prepared in hexane it may

come out of solution at the wrong moment especially at con-
centrations greater than 1 M. Substitution by benzene or
toluene can correct that, but often there are good reasons for
not having an aromatic solvent present. However, there is a way
of making a reasonably stable solution (ca 1.5 M) in a
cyclohexane-tetrahydrofuran mixture, directly from lithium
metal with isoprene as hydrogen acceptor (the resulting 2-
methylpropene rarely interferes afterwards):
In a 500 ml three-necked flask attached via drying tube to the
multiple inert gas trap (see Chapter 4, Fig. 5) and containing
a magnetic stirring bar is placed 110 ml of cyclohexane, IO ml
of which is then distilled out in an inert gas stream to ensure
dryness of the remainder. After cooling to room temperature
there are added, in order, dry diisopropylamine (63 ml), dry
tetrahydrofuran (35 ml), freshly cut lithium (3.1 g, excess),
isoprene (freshly distilled, 21 ml) and the razor blade shown
in Fig. 2. The whole is stirred at 20 2 C (occasional cooling
may be needed) for at least 12 h (if left overnight the flask
should be left in an insulated bath containing plenty of ice).
The resulting solution (some lithium must be left over) is
transferred by inert gas pressure (see Fig. l) into 50 ml
storage bottles which are tightly sealed with Parafilm and kept
in the refrigerator until needed. Once a bottle has been
opened, even with inert gas introduction, it will deteriorate
rapidly. The exact content can be determined by the method
of Watson and Eastham 103 (see below) using 2,2' -
biquinolinyl as indicator.

Other Metal Dialkylamides

Another generally useful reagent based on lithium is the hexa-
methyldisilylazide, usually prepared from butyllithium and the
corresponding amine. Presumably a stock solution of this can
also be made directly from lithium metal as described above,
although in lower concentration. One advantage of this base

seems to lie in its lower nucleophilicity and that of the amine

liberated (as well as rapid cleavage of the latter on aqueous
work-up). It is often stated to be more selective than lithium
diisopropylamide, but probably the main reason for that is that
it is significantly less basic by several orders of magnitude. 101 It
has been suggested that bases of intermediate strength could be
prepared from N-silylated primary amines. 102
Other such bases prepared from, e.g. dicyclohexyl, or tert-
butylcyclohexyl- or isopropylcyclohexylamine or from 2,2,6,6-
tetramethylpiperidine (for details see ref. 8) have been used
where they have specific advantages; here the higher molecular
weight amine liberated may complicate working-up.
A base of this type distinguished by exceptional stability over
long periods (more than 2 years) at room temperature is sodium
hexamethyldisilylazide, which can be prepared in toluene from
sodium hydride as follows:
Freshly distilled hexamethyldisilylazane is added to an excess
(15-20%) of hexane-washed sodium hydride suspension in
dry toluene in an amount calculated to lead to a 0. 7-0.9 M
solution; the suspension is heated under reflux for at least
24 h. After cooling, the excess of sodium hydride is allowed
to settle and the supernatant solution transferred to bottles
which are tightly sealed and kept at room temperature (in
winter some material may crystallise out but will redissolve on
gentle warming).

Titration of C-Li and N-Li Bases

The methods suggested in recent years fall roughly into two
categories: the first involves titration of the base against a
weighed stoichiometric amount of a reagent, itself dissolved in
a solvent whose dryness has to be assured, which forms a di-
anion the appearance of the intense colour of which indicates
the end-point. The other utilises the formation of an intensely
coloured complex between the base and a small amount of an
indicator, the colour of which is discharged at the end-point by

titration with a standard solution of an acid or alcohol. The

latter is, of course, much more convenient, particularly the
method of Watson and Eastham, 103 where the indicator can be
one of a number of heterocyclic compounds whose common
feature is two nitrogen atoms in a 1,4-relationship. These form
coloured charge-transfer complexes with many organometallics,
and the choice between them (e.g. o-phenanthroline, 2,2' -
dipyridyl, 2,2 1 diquinolinyl) may depend on the base and on per-
sonal preferences as to colour. As titrant standard solutions of
sec-butanol or menthol in toluene or xylene can be used. An
advantage of this method is that it works also with amide bases
and with Grignard reagents, but it gives best results when the
solvent is at least in part hydrocarbon (which makes it easy to
achieve dry conditions by azeotroping). The indicator may also
be used in a reaction mixture; here the amount of base needed
until appearance of colour is an indication of the dryness of the
solvent. This does not work so well with tetrahydrofuran, in
which case a better indicator is the intense blue dianion colour
formed with N-benzylbenzamide. 104

Alkoxide Bases
Solid sodium methoxide is a good base for many large-scale
reactions, but the commercially available material should
always be regarded with suspicion. It should be freely soluble in
anhydrous methanol with no more than a trace of precipitate
(sodium carbonate). Far too often it is still supplied in polyethy-
lene containers, which are far more pervious to water vapour
and carbon dioxide than is generally known. The same remarks
apply to potassium tert-butoxide, with the additional problem
that it is not easy to ascertain how much is unsolvated and how
much the alcoholate. The only way to make sure is to sublime
it in a high vacuum. Figure 3 shows a large test-tube adapted for
this purpose; its diameter is just less than that of a Kugelrohr
oven; the rubber stopper and stopcock have to ftt precisely to
assure the highest possible vacuum (0.05 mmHg or better)
which will allow sublimation below 200 C. After opening, best

G_-------~- Fig. 3.

in a dry-box with the tube kept carefully horizontal, the

material is carefully and rapidly scraped out using a sharp
spatula with a bent tip into a rubber-stoppered bottle.
Sodium tert-amyl oxide is soluble in aromatic hydrocarbons
such as toluene. The solution is easily prepared by heating under
reflux for 12 h a known amount of the anhydrous alcohol in
toluene with a 300Jo excess of sodium, which remains melted and
reactive throughout. This must be done with strict exclusion of
both moisture and oxygen, to which the solution is particularly
sensitive. The subsequent transfer is best done into bottles of no
more than 25 ml capacity unless a large amount is required
immediately. Also, if the concentration is greater than ca 1.4 M
it may crystallise out, and hence this reagent is best kept in a
warm place (30-35 C). The corresponding potassium alkoxide
appears to be much more soluble 105 106 (up to 2.1 M even under
refrigeration); here benzene may be used since its boiling point
is above the melting point of the metal.

Metal Hydrides
Sodium hydride, usually supplied oil-coated, presents few prob-
lems except that the effective real concentration is nearly always
less than claimed. To be on the safe side, a weighed amount
should be added to isopropanol followed by addition of water
and titration with standard acid. Also, after prolonged stand-
ing, material at the top of the bottle tends to differ from that
at the bottom and occasional vigorous mixing is recommended.
Potassium hydride is much more difficult to handle because
manufacturers have still not found a way to supply it in a form
similar to sodium hydride. The material always settles out as a
sludge in the oil whose specific gravity and other properties are
never revealed. There seems to be no choice other than vigor-

ously shaking the suspension, immediately withdrawing it by

volume, assuming a specific gravity of 0.90 in case of material
claimed to be '200Jo', and then washing it through the pipette
with hexane into the reaction flask (the pipette should be of
polypropylene with the tip cut back to give an opening of
2 mm). However, to obtain more reliable results it is necessary
to use a tared reaction flask with a stopcock, dry the introduced
material after washings in vacuo, admit dry argon and weigh
Lithium hydride is generally available only as the unprotected
solid whose effective content is both uncertain and difficult to
determine except gasometrically. In practice, an excess of up to
500Jo is used which, because of its relative inertness, rarely
causes problems.

Radical Anion Bases

Alkali metals react with polycyclic aromatic hydrocarbons, in
particular naphthalene, in solvents such as tetrahydrofuran or
dimethoxyethane to give deeply coloured solutions, which are
stable at room temperature and which contain the radical anion
of the hydrocarbon. Since this is one of the easiest ways to
prepare an organometallic, and certainly the cheapest when con-
sidering sodium and naphthalene, the question has often been
raised of whether such species could function as non-
nucleophilic bases for proton abstraction pure and simple. The
answer is 'yes, with reservations.' As a proton base the naphtha-
lene radical anion has been estimated to have a pK value of ca
33, and as such it has served in the deprotonation of substrates
such as ketones, aldehydes, nitriles and acetylenes and in the
formation of dianions from carboxylic acids and acetylenic
alcohols, i.e. all species more acidic than diarylalkanes in Table
I. The subject has been reviewed in some detail. 107 However, in
many cases the yields (of products of subsequent reactions with
electrophiles) have been far from impressive, and this is prob-
ably due, at least in part, to complications arising out of the
electronic nature of the reagent. Also, in all such reactions there

is the practical problem of having to remove the polycyclic such

as naphthalene, and its own transformation products such as
dihydro products and dimers, usually by chromatography. One
advantage of these reagents is that they are 'self-indicating'
because of their intense colour.
More recently, the dual electronic nature of the species has
been utilised in synthesis for the formation of carbanionic inter-
mediates through reductive cleavage of carbon-sulphur
bonds 108 109 and carbon-halogen bonds. 110 The latter has been
shown to have particular value where formation of organo-
lithium compounds directly from the halide and lithium metal
leads to low yields, and a detailed examination has shown that
instead of naphthalene the best results are obtained with 4,4' -
di-tert-butyldiphenyl, 110 a hydrocarbon which is now easily
available as the product of a standard student exercise. 111 For
solving the problem of subsequent working-up, the suggestion
has been made of using 1-dimethylaminonaphthalene instead of
naphthalene, making it possible to remove the spent reagent by
acid extraction. However, the radical anion in this case has to
be prepared and used below - 40 C. 112


It would be difficult to discuss such bases in the same way as

with Brensted bases used specifically for C-deprotonation. They
are weaker and have been used for direct C-deprotonation to a
much lesser extent. Instead, they are used in a wide variety of
reactions where specificity is more important than mere base
strength. This can take the form of, e.g., specific interaction
with the substrate (such as hydrogen bonding in elimination re-
actions) or specifically unstable and active intermediate forma-
tion (e.g. acylation).
Table 2, compiled for 15 important nitrogen bases, is
intended to give some idea of the extent to which they have been
used in 18 types of reactions of general importance. Since many
of these are done on a large scale and with at least stoichio-
Table 2. Amine bases (amines, amidines, guanidines): Relative frequency of use in various reactions N

Amines (cost per gram-mo! in parentheses):

A: s-collidine (4.50) I: hexamethyldisilazane (12)
8: l,S-diazabicyclo[4,3,0J non-S-ene, DBN (27) J: N-methylmorpholine (2.5)
C: 1,4-diazabicyclo (2,2,2] octane, DABCO (8.40) K: pyridine ( I. 77)
D: l,8-diazabicyclo[S,4,0)undec-7-ene, DBU (22) L: 4-pyrrolidinopyridine (458)
E: N,N-diethylaniline (1.60) M: 1,1,3,3-tetramethylguanidine (13)
F: diisopropylethylamine (12) N: 2,2,6,6-tetramethylpiperidine (114)
G: 4-dimethylaminopyridine, DMAP (33) 0: triethylamine (0.83)
H: N,N-dimethylaniline (0.83)

Reaction type/
reagent A B c D E F G H I J K L M N 0
0-Acylation (e.g.
by anhydride
or halide) + + #' ++ + +r + ++
0-Alkylation (e.g.
tritylation +++ ++' +
0-Silylation + +++ + ++ +
N-Acylation (e.g.
BOC formation) + + + ++ +++
ation ++ ++ + + # ++' + +++ ++.
Other {3-
eliminations + + +
Acid scavenger + + ++ + + ++ + +++ +++
Esterification (acid
and halide or
sulphate) ++ ++ ++' + ++' +
Ester cleavage ( {J-
keto ester,
malonate) + II +
Macrolactonisation + ++
Macrolactamisation + ++
Michael or other
addition + + ++ +
Reactive methylene
condensation + + + ++ ++ ++
Reactive methylene
alkylation + ++ +++ ++
Reactive methylene
acylation + ++' +
Dehydration with
sulphonyl halide + +i +
Wittig reaction,
formation of
ylide + +
Peptide coupling ++' + ++ + ++j

+, Used occasionally; + +, used frequently; + + +, used very frequently; II, reagent of choice.
causes aldol condensation at a-position of a,/l-unsalurated ketones with aldehydes.
'Advantages of high b.p.
Hydrochloride non-hygroscopic, easily filtered.
Used in kctene formation from a-haloacyl halides.
'Active in catalytic amounts, for review see E. F. Scriven, Chem. Soc. Rev., 12, 129 (1983).
I Does not cause racemisation.

Selective reaction.
'Can catalyse formation even of isopropyl esters from isopropyl halides. \C)
i Hydrochloride insoluble; product isolated from filtrate. .....

metric amounts, Table 2 also contains data on their relative cost

(which is approximate and in Swiss francs or German marks for
convenience only), a factor often overlooked in a group of rea-
gents where this factor can differ from one reagent to another
by two orders of magnitude.

On Small-scale Distillation


When one considers the glassware encountered in most labora-

tories and offered by the great majority of glassware manufac-
turers, one is struck by the lack of suitable apparatus for
fractional distillation of quantities of between 1 and 15 ml. This
range is, of course, between that commonly dealt with by
preparative gas chromatography and that encountered in the
teaching laboratory.
For very accurate work there are spinning band columns, and
micro and semimicro versions are commercially available. How-
ever, they are expensive and their repair is a task which even
experienced glassblowers are reluctant to undertake. Most
experienced workers solve this problem on an ad hoc basis by
asking the glassblower to make up a suitable apparatus for a
particular distillation at hand, after which it is usually relegated
to a distant corner and its existence kept a dark secret.
The main problem in fractionation on this scale lies in loss of
material, caused by (a) insufficient immersion of the stillpot, (b)
too long a distillation path and flooding caused by too many
bends and joints and resulting constriction, (c) excessive
hold-up due to inappropriate column filling and (d) further loss
of distillate on the way out caused by impeded outflow,
unnecessary use of a condenser or use of one with an excessive
internal surface.

Several years of experience in the author's laboratory has

established the overall advantages of the type of distillation
flask shown in Fig. I. A set of three, with bulbs of IO, 25 and

Fig. 1.

50 ml capacity and the other dimensions sized appropriately,

should cover most amounts commonly encountered. The jacket
into which the flask is fused (low enough so that magnetic stir-
ring of contents is possible) serves two purposes: to protect the
column from draughts, and to make it possible to add more
heating medium up to the very top, in the case of very high
boiling materials. The outlet tube can be straight at the usual
60-75 angle, or bent down again, finally parallel to the jacket
in order to benefit from the two possibilities of connection to
the fraction collector shown in Fig. 3. For the latter purpose it
is necessary that the dimensions of the flask from the joint out-
wards be standard.
With these flasks the temperature gradient between that of the
heating medium and the distillation temperature rarely exceeds
5 C, except of course with liquids of exceptionally high heats
of vaporisation.
The column filling is of the twisted wire gauze type, 113 which
gives separations much superior to those with the usual Vigreux
type of column. It may not be as good as a packed column, but
in contrast to the latter the hold-up and consequent loss of
material are very small. Above all, it can be made very easily
from metal gauze (nickel-chrome or stainless steel) and a pair
of identical pliers. A strip of gauze of length 1.5 times the length

Fig. 2.

of the column and of width equal to the column's inner

diameter plus two additional wire strands is cut, using scissors.
The two additional strands are then stripped off and the resul-
ting bare cross-strands bent down parallel to the strip. The latter
should then slide easily into the column; if not, then one or two
additional strands have to be removed. Portions of the strip
(0.5-1 cm distant) are then held by the two pliers, one of which
is then turned 90 to the other and the two are pressed
together-this is repeated all along the strip. The procedure and
the finished product are illustrated in Fig. 2. In practice, the
latter rarely looks that good but that should not worry you
unduly. .
Such a filling is slowly attacked by, e.g., acyl and allyl hal-
ides, but it is so inexpensive and easy to make that this is hardly
a deterrent.
The fraction collector shown in Fig. 3 is designed for both

Fig. 3.

versions of the flask; in either case the vacant socket joint is

used for vacuum take-off. As can be seen, it consists of two
halves connected by a flange or 0-ring joint. The former must,
of course, be well greased and protected from heat. The lower
half contains a ground-in turnkey on whose upper square end
rests a shallow circular metal tray with rim, by means of a
hollow square tube. The latter can be packed with internal
spacers to permit variation in height. On the tray rimless vials
of various sizes can be arranged circularly and kept in place
either using a clock mainspring or by means of a suitably sized
vial in the middle. Usually up to eight vials can be accommo-
dated. The whole assembly is best supported by a support plate
or movable platform ('lab-jack').
As for the absence of a condenser: very little cooling is
usually needed on this scale and at the speed suitable for good
fractionation. A piece of cotton-wool soaked in methanol or

Fig. 4.

acetone placed on the outlet tube is usually sufficient; if not,

then one can place a piece of dry-ice on top of that.
Other than that there is the possibility of modifying the top
part of the flask shown in Fig. l in order to take advantage of
one of the commercially available micro distillation heads with
condenser and 'cow'-type fraction collector. The latter usually
takes only four receivers, but with a very experienced glass-
blower it can be modified to take more (see Fig. 4).
The proper way to fill the distillation flask is to take out the
column filling, place it with the heating medium on a steam-
bath, add the material for distillation, if necessary diluted with
diethyl ether or dichloromethane, and then evaporate the
transfer solvents in a partial vacuum. At the end of the distil-
lation, while still hot, a suitable solvent can be added to dissolve
the residue, which can then be withdrawn using a long capillary
pipette. In this way, emptying out the heat medium each time
can be avoided.

The exceedingly useful and versatile Kugelrohr (for some inex-
plicable reason Kilgelrohr to the Americans) oven should by
now be in standard use even in undergraduate laboratories. It
can be employed for distillation and sublimation of amounts
ranging from 5 mg to over 30 g (see below). It is the fastest and
most convenient way to purify preliminarily even the most
messy looking product, provided of course that the desired part
is thermally stable.
Bulbs connected by standard joints (Fig. 5) are now in general
use. When using them it must be remembered that grease,

Fig. S.

Fig. 6.

especially when hot and subjected to vacuum, may flow in and

contaminate the product-hence only the upper wider part of
the joint should be greased. If grease has to be avoided
altogether, then the arrangement of connected bulbs (Fig. 6)
should be employed. Incidentally, with both receiver arrange-
ments some degree of fractionation can be achieved by first
immersing the whole up to the last bulb in the oven, and with-
drawing to the next in line as the temperature increases. When
the amount to be distilled is large (more than one third of the
distilling bulb's volume) it is essential to incline the whole
arrangement at first and then bring it to level as distillation pro-
ceeds. Cooling is best done, once again, by a swab of cotton-
wool soaked with methanol or acetone, but there is a device on
the market (which your or your workshop's fertile imagination
should not find difficult to reproduce) where the open end of a
metal tube presses against the bulb from below, this tube con-
taining pieces of ice, a perforated metal plate and a spring.
After the bulbs have been detached at the end of the distil-
lation the contents, if liquid, can be withdrawn using a twice-
bent capillary pipette (Fig. 7), or, if they have to be
recrystallised, placed on an Erlenmeyer or round-bottomed
flask with solvent on a steam-bath so that the contents are
washed in by the rising solvent vapour and condensate (Fig. 8),
with cooling by a piece of dry-ice at the point marked by an
Most commercial Kugelrohr ovens now have an arrangement
that ensures oscillation or even rotation during distillation, so as
to avoid bumping and splashing. This is useful to have, of
course, if you can afford the extra amount that it will cost, but
in most cases boiling stones or glass-wool and very carefully
controlled heating will do just as well.

Fig. 7. Fig. 8.

v 0

Fig. 9. Fig. 10.

Fig. 11.

An arrangement which allows Kugelrohr distillation directly

into a specimen vial, and has thus proved to be a great asset
both in convenience and in saving money on flasks which are of
an order of magnitude more expensive, is shown in Fig. 9. Here
joint A leads to the flask in the Kugelrohr oven (not shown). S
is a B24 stopper and the diameter of tube C is in accord. T is
the vacuum outlet. The specimen vial V has in this case a capa-
city of 14 ml, but of course the arrangement can be used for
smaller vials as shown in Fig. 10, using a piece of cork or rubber
tubing cut to size as a spacer. The length of the inlet tube as
shown suffices for methanol-soaked cotton-wool swab cooling if
required; by careful use of a micro Bunsen burner the last traces
of a viscous liquid can be transferred. Amounts of the order of
100-200 mg have thus been transferred with a recovery of
If the vacuum is applied via a Johnson multiple outlet trap
(Chapter 4, Fig. 5), then in the case of air-sensitive distillates
argon instead of air can be admitted after the distillation, and
withdrawal and capping of the vial can be done in the inert gas
stream. Naturally this device can be constructed in larger size
(with a 834 stopper) and using a larger range of vial sizes.
When really large amounts have to be distilled by the
Kugelrohr oven, arrangements such as that in Fig. 11 can be
used. Here the size of the distilling vessel is limited only by the
dimensions of the oven.

On Hydrogenation-The
Cinderella of the Organic

It is difficult to understand the unpopularity of hydrogenation,

other than the frequent absence of suitable apparatus. It is one
of the cleanest synthetic operations, and sooner or later you will
have to do one anyway, so why not plan to do it properly.
Except for very special cases, two basic set-ups are needed:
one for doing hydrogenation at atmospheric pressure, for small
amounts, in the 0.1-100 mmol range, and where hydrogen
uptake needs to be measured accurately; and the other for
medium-pressure (1-5 atm), for amounts generally ranging
from 0.05 to I mo!, although in principle it is possible to use the
commercially available apparatus (see below) for either larger or
smaller amounts.


A number of gas burettes, B, C, D (recommended: one of

25 ml, one of 100 ml and one of 500 ml capacity) are connected
with each other, and on one side with the three-way stopcock A,
A' [which are inlets for vacuum (water pump) and source of
hydrogen] and on the other with items R, M and S as shown in


Fig. 1.

Fig. I. The standard, necessarily high quality, joints J can be

either the standard conical type making for tighter connections
but also inflexibility, or the spherical type for greater flexibility
but at the expense of more likely leaking. In either case they
should be held together with suitable clamps (not shown). B, C
and D each have their own reservoir of appropriate size
attached; these should be filled with ca 2% copper sulphate sol-
ution, which will prevent algal growth over longer periods. R is
a safety reservoir preventing the spill-over of burette liquid, M
is a mercury-filled manometer and S is a female joint consti-
tuting the business end to which the hydrogenation flask is
This is shown in greater detail in Fig. 2. It is of the shape
advocated earlier for reaction flasks, to facilitate rapid and
steady magnetic stirring, and is of one piece, connected to reser-
voir F via a stopcock (carefully greased). It should be noted that

Fig. 2.

this apparatus, in contrast to similar ones in common use, com-

pletely avoids the use of rubber tubing, the usual source of
leakage in a system where no leakage whatever should occur.
The detailed procedure is as follows. The hydrogenation flask
containing the catalyst and just enough solvent to cover it is
attached to S. With stopcocks leading to B, C and D closed, the
system is evacuated via A, causing the mercury in M to rise. The
stopcock of the chosen burette is then very carefully opened to
raise the liquid just to stopcock level and thus expel all air, after
which it is closed again. A is then closed, and hydrogen

admitted via A' until M shows the system to be at atmospheric

pressure. This process of evacuation and hydrogen admission is
repeated to make sure there is no air in the system. Finally,
during hydrogen admission and with M showing slight excess
pressure in the system, the stopcock of the chosen burette is
opened and hydrogen allowed in to slightly more than the
required volume, after which A and A' are closed. The system
is now under hydrogen entirely, and magnetic stirring is started
to prehydrogenate the catalyst.
When this appears to be complete (cessation of uptake), stir-
ring is stopped and the reservoir of the burette lowered to create
a partial vacuum. The solution to be hydrogenated is placed in
F and its stopcock is very carefully opened to run in the solution
except for the last drop (so no air will get in). It is then washed
in completely with small amounts of solvent using the same pro-
cedure. Stirring is then resumed for the hydrogenation proper.
When this is complete, all the hydrogen is pumped out after
closing the burette stopcock, and then air is admitted, the flask
disconnected, the suspension filtered and the solvent removed to
isolate the product.


With the advent of modern active catalysts, it is very rare that

really high pressures are still needed for catalytic hydrogen-
ation. The kind of apparatus that will allow doing so at up to
5 atm and, more importantly, for larger amounts, with little
attention necessary during the process, is exemplified by that
shown in Fig. 3(a), manufactured by Parr Instrument Co. 114
A thick-walled glass bottle [Fig. 3(b)] inside a protective per-
forated metal cylinder is connected via a rubber stopcock (kept
in place by a cross-piece and two thumbscrews), and by a flex-
ible and pressure-tight plastic or metal tube to a main hydrogen
reservoir (of 4 I capacity) which is filled via a stopcock to the
right of Fig. 3(a). The glass bottle (of 500 or 200 ml capacity)
can be shaken to and fro for agitation. There are two pressure


I tt'
I I):.'f

(b) Bottle clamp for above apparatus with guard screen removed.

Fig. 3. Reproduced by permission of the Parr Instrument Company.


gauges (still marked in lb/sq. in!), one showing the pressure

inside the main reservoir and the other inside the glass bottle.
It should be remembered that I atm equals ca 14.7 lb/sq. in,
and that the reservoir and bottle should never be filled to more
than ca 63 lb/sq. in. The procedure here is to clamp the bottle
containing catalyst and substrate in solution (never tightening
the screws to more than finger pressure) and evacuate the bottle
only through a two-way tap (not shown); this allows entry of
hydrogen from the reservoir in its second position. This evacua-
tion-hydrogen admission.cycle must be repeated at least twice.
With large amounts the bottle is then shaken with the connec-
tion to the reservoir open. A pressure drop of ca 8.5 lb (right-
hand gauge) corresponds to uptake of 0.1 mo! of hydrogen.
When hydrogenating smaller amounts it is preferable to use the
smaller 200 ml bottle and shake with the reservoir connection
closed. Uptake can then be calculated from the pressure drop on
the bottle gauge using the expression

Pressure drop at NTP (lb/

= f ~ x millimole H2 absorbed
ree vo ume

where the free volume is the volume of the bottle and con-
necting tube less the volume of the solution contained therein in
millilitres. For very accurate work the uptake of catalyst and
solvent must be determined by a blank experiment.
The most frequent source of leakage in this apparatus is
where the flexible tube enters the glass bottle via a one-holed
stopper. It is futile to use laboratory-made stoppers, and only
those supplied with the apparatus should be used.
At the end of the hydrogenation the connection to the reser-
voir should be opened briefly so that the inrush of hydrogen will
return solution which has found its way into the plastic con-
necting tube, otherwise it will end up in the stopcock block
where material will crystallise out and cause a mess by blocking
the system-cleaning that out is a special kind of aggravation.
Vacuum is then applied to remove all the hydrogen; this should

be prolonged even with the solvent partly evaporating otherwise

hydrogen will remain adsorbed and may cause an explosion
when the system is opened to air.


At the beginning of this chapter it was said that hydrogenation

is a clean reaction. That depends, of course, on how cleanly you
start it, and that means solvent, catalyst and above all substrate.
A melting point is not necessarily the criterion for the presence
or absence of impurities which can act as catalyst poisons. If at
all possible the substrate material should be redistilled or sub-
limed. If it results from a sequence which at any stage involved
sulphur or selenium intermediates or reagents, it should be
stirred in solution with silver powder or, better, passed through
a column of an adsorbent containing ca 10% silver powder.
When Lindlar catalyst is used (which is partly poisoned to start
with), it has been found of great advantage to pass the substrate
solution through a column of purified calcium carbonate. 115 A
hydrogenation which because of suspected poisoning takes days
for completion either shows uptake because of leakage or
because it is incomplete, or both. It is far better to stop, filter,
use pure fresh catalyst or else purify the substrate!
The reactivity of a catalyst will decrease in proportion to how
many times the bottle of commercially procured material has
been opened, by how many people (whose personal habits
cannot be followed) and over what period of time. In view of
this, the range of platinum metal catalysts in the hydroxide
form, whose preparation has been described by Pearlman, 116 is
highly recommended. They are non-pyrophoric and stable
almost indefinitely. They must be pre-reduced immediately
before use, which of course makes them always more active
than the commercial product.
Catalyst recovery is a subject much like the weather-many
people talk about it but few ever do anything about catalyst resi-
dues. Few if any books on catalytic hydrogenation ever bring up

the subject, probably in the knowledge that the amount of

credit you will get from a supplier for returning them is nil
unless industrial quantities are involved. Nonetheless, you
should not throw away residues (probably bad for the environ-
ment too!), but recover them yourself when having nothing
better to do. You may have to work out a procedure by your-
self, though.
When carrying out a hydrogenation there is in most cases no
need to have all the star.ting material in solution, since the
product is generally much more soluble. Following this principle
will often greatly increase the scale on which a hydrogenation
can be conducted.

On Keeping It Clean

The fanatically tidy laboratory is more likely than not one

where little work gets done, so if you are the type that gets
things done you do not have to feel too guilty if there is a bit
of a mess so long as it does not affect your results. That, of
course, means fanatically clean equipment.
It should become an automatic habit to clean glassware pre-
liminarily after use by dissolving out residues, before washing
out with water-based detergents, none of which is capable of
shifting most organic tars, whether this is attempted manually
or in a machine. This is the best use to which to put recovered
solvent mixtures, such as from a rotary evaporator.
Drying of glassware is preferably done in an oven, if there is
room for all. If not, it has to be allowed to drain. The cus-
tomary pegboard has disadvantages which are obvious with
many types of item. A much better installation for the purpose
is a horizontal drying rack (Fig. 1), which incorporates a frame-
work of thin plastic-covered rods forming square or rectangular
openings of various sizes. Here there is no contact with the
inside of the vessel, and this is suitable not only for flasks but
also for funnels, dishes and flat objects.
Although it is supposed to show up better in photographs
when dirty, the necessity for clean glassware, especially in small-
scale work, is rarely questioned. But when it comes to porcelain
ware, 'what the eye does not see, the heart does not grieve over'.


\. '

Fig. 1.

If at any time you feel like letting off steam by breaking some-
thing, choose a Buchner funnel-the result can be very instruc-
tive. One should make it a habit, automatically, to dissolve
material and wash through a Hirsch or Buchner funnel into the
vessel holding the mother liquor, and to make quite sure all such
porcelain ware should be immersed in chromic acid at regular
A necessary but messy item in any laboratory is stopcock
grease. The idea of dispensing it from a plastic syringe (without
the needle), best of 10 ml size, 117 is an excellent one, but only
if this syringe is hung up in the way shown in Fig. 2, otherwise
the weight of the plunger will slowly but surely deliver the grease
where it is not wanted. For this one merely has to put two blobs
of epoxy adhesive where shown, to hold the wiring in place.
And now to a more delicate observation. In many institutions
the demand for cleaning tissue reaches alarming dimensions, at
which point it becomes clear that it is being used for purposes
best described as non-scientific. I now suggest a reasonable and

Fig. 2.

far more economic alternative: toilet paper. In principle it is

exactly the same. You will soon get over the psychological
block: and if the secretarial staff do not, so much the better.

Bottling Things Up

It is astonishing how often even experienced researchers, after

devoting much thought and effort to the preparation of a pure
product, become careless and thoughtless when it comes to
bottling and storing it. The same still goes for manufacturers
and suppliers, although with them there have been a good many
improvements in the last few years.
With a few exceptions, which will be mentioned below, the
glass bottle or vial is still the best receptacle. It does not
necessarily have to be round-square and rectangular bottles
are easy to come by and are better for storage where space is at
a premium (e.g. in a refrigerator). Colour is another factor.
Many organic compounds are sensitive to light and a lot of
organic photochemical research has started by looking for those
bottles on the shelf which show a colour change on the side
facing the window-hence brown is preferable to colourless.
However, the crucial problem is that of the type of closure to
be used. The only completely satisfactory closure is that of the
sealed tube and ampoule, but one can safely assume that this
will be ruled out as impracticable in most cases.


These are definitely out, except for routinely used solvents on

the laboratory bench where easy and rapid access is desirable,

(al (bl (c)

Fig. 1.
and for acids such as hydrochloric, sulphuric and acetic acid. In
such cases, preference should be given to stoppers as shown in
Fig. l(a), which will keep the dust out, and not to the type
shown in Fig. I (b). The same consideration should apply to
solvent dropping bottles (usually of 50-60 ml capacity), where
the type shown in Fig. l(c) is superior.
In almost all other cases glass-stoppered bottles should be
given a wide berth. With volatile materials they offer little resist-
ance to loss by evaporation and virtually none to entry of water
vapour and air. With most inorganic solutions, especially if
alkaline, evaporation or reaction with oxygen or carbon dioxide
will cause 'freezing' of the stopper, which often cannot be
removed. That means having to throw away the bottle, a two-
fold problem: one a waste of money and effort invested, the
other of disposal without causing immediate or potential harm
to others.
All these considerations apply equally to the use of glass
stoppers in reaction set-ups where there is another good reason:
sudden development of pressure within a reaction system, a
common enough occurrence, can convert a glass stopper into a
dangerous projectile.


These are still the best type on the whole, but much depends on
what is inside the screw cap, i.e. the part that will be in direct
contact with the substance inside. A mere cardboard or cork
pad offers very little protection, neither from the outside in
(water vapour, air) nor from the inside out (attack by contents
on the plastic screw cap and beyond that on the label and on the
surroundings). Many such pads have a plastic coating which will
be found to dissolve in many organic liquids. An additional
layer of aluminium foil offers little improvement.
Much better are screw caps with an inner cone of polyethy-
lene or polypropylene [e.g. Fig. 2(a) and (b), with the latter
preferred] or a cushion made of a Teflon-rubber laminate [Fig.
2(c)]. These are fully effective only with bottles whose rim is
smooth and uniform and will press snugly under pressure of the
screwed-home cap against the elastomer used. This type of
closure is essential with contents such as solutions of organome-
tallics, volatile amines (a particularly troublesome class of com-
pounds), acyl halides and most Lewis acids such as boron
trifluoride etherate, tin(IV) chloride, titanium tetrachloride
(neat or in solution) and boron halides in solution. With other
compounds, such as organoaluminium or organozinc com-
pounds, even such screw caps are not satisfactory over longer
periods, and such compounds should be left in the cylinders in
which they are usually supplied and withdrawn only to the
extent to which they are immediately used, or else for dilution
by a suitable solvent-such solutions are usually less aggressive.
For storage over longer periods, additional sealing with
Parafilm is recommended. To cut down on loss by evaporation

F1 (al
l\71 (bl
I 1 (cl
Fig. 2.

and spoilage even further, the bottles should be placed in a

closed metal can, especially in a refrigerator where safety is an
additional requirement.


With these there is the advantage of no risk of breakage. They

are satisfactory for most inorganic substances and solutions and
in fact much superior to glass for concentrated alkaline sol-
utions. Further, they are cheap. They can be used for organic
substances provided that these are not affected by moisture,
carbon dioxide or oxygen, to which polyethylene is much more
permeable than generally realised. Another undesirable prop-
erty of polyethylene to be on guard against over longer periods
of time is deterioration by light and heat. It becomes brittle and
cracks and large containers, e.g. containing distilled water, have
been known to burst without prior warning.
There are some organic compounds which are known to
suffer decomposition catalysed by impurities usually present on
glass surfaces, such as alkyl chloroformates and solutions of
diazomethane. Here storage in polyethylene bottles seems to be
the only, although not completely satisfactory, solution.



These are where most of your products will end up, hence a
good deal of thought should be devoted to this topic, depending
on the properties of the stored substance.
In the author's experience, the best general type of vial for the
storage of small amounts is the glass vial closed by a polyethy-
lene stopper. The tall type [Fig. 3(a)] is to be preferred to the
squat type [Fig. 3(b)], as there is less exposure of the stopper.
The ribbed open-bottom type of stopper [Fig. 4(a)] provides

t al (bl
Fig. 3.

~ (bl
Fig. 4.

more reliable complete closure than the smooth 'solid' (actually

hollow) type [Fig. 4(b)J. Such vials can be used for both solids
and liquids, although in the latter case storage should be upright
just to be on the safe side. Here too additional Parafilm sealing
will augment protection.
As for screw-capped vials, the same problems as with screw-
capped bottles are encountered, only more so because with these
the cardboard or cork pad is still standard. For special cases it
is possible to cut a suitable liner from silicone rubber sheeting
using a very sharp cork borer-provided you can find one of
just the right diameter.
Vials with closure of the 'snap-cap' type (Fig. 5) are con-

Fig. S.

venient for easy access, but strictly only for innocuous solid
materials and for purely temporary storage.
Now to vials with a septum closure for withdrawal by syringe,
a reasonable variety of which are on the market. With all these
there is just no getting around the fact that there is as yet no
known elastomer which is impermeable and chemically and
mechanically indifferent to all types of organic materials, and
certainly not once it has been punctured. A Teflon liner does
give extra protection, but that too only up to the point of first
puncture. Hence the use of such vials should be restricted to
cases where withdrawal by syringe only is envisaged, and then
only for a limited time after first withdrawal; certainly not for
long-time storage per se. Many such vials containing expensive
volatile materials, closed by a septum held by a crimped metal
closure, have been encountered which on arrival were com-
pletely empty-witness to the permeability of the type of
material used.
Occasionally one encounters storage problems even on a
small scale which need special treatment. A case in point is
osmium tetraoxide. This usually comes in 1 g sealed ampoules,
but is now used mainly in catalytic amounts ( l 0-100 mg) only.
Hence, once such an ampoule had been opened the question
arose of what to do with the rest of this highly volatile, very
expensive and very toxic material. The solution lay in preparing
a vial with a specially machined Teflon plug which alone
prevented leakage (always easily shown up with this compound
by the blackening of the surroundings).


These are not suitable for storing your products. The fact that
so many chemicals are now commercially supplied in cans, often
of the snap-open beer can type, is for reasons of economy and
safety in transit only. In fact, once such a can has been opened
it is highly desirable to transfer the contents immediately to a
glass container. The plastic lid usually supplied for subsequent
closure should not be relied upon. This advice applies particu-
larly to substances such as lithium aluminium hydride, sodium
borohydride and hydrides of sodium, calcium and lithium. It
does not apply to alkali metals supplied under mineral oil. For
safety's sake these should remain in the screw-capped metal
container in which they should usually arrive.
Naturally, none of these comments apply where the can is
marked 'Bottle Inside' and where this is indeed found to be


For the synthetic organic chemist there are few aggravations to

equal the bottle which has lost its label, or where the writing has
become illegible through chemical attack or fading by light.
The most lasting inscription is that made by old-fashioned
black ink. Electronic typewriting (based on carbon black) and
the ordinary graphite pencil come a close second. Very few of
the inks used in ball and felt pens are vapour- and light-fast.
However, using the right type of ink is not enough. The label
should be protected by a lacquer-type spray-the best is the type
used for electrical insulation. Adhesive tape should never be
used. It deteriorates in the course of time and the writing may
diffuse into it and simply 'disappear'.
Special care should be taken with bottles kept in a freezer
compartment, because the process of defrosting will detach
almost any label. Hence, when the time comes, each bottle

should be taken out and allowed to defrost separately. An ad-

ditional safeguard to forestall disaster is to tie an additional
label on to the neck of the bottle. With vials, the small size of
the label makes loss almost inevitable, and a good habit to
acquire is to use a long label, somewhat longer than the vial's
circumference, and allow the ends to stick together.


Many every-day goods and articles now come packaged sealed

in polyethylene sheeting, and it should be pointed out that with
the availability, at a reasonable price, of heat sealers (Fig. 6)

Fig. 6.

8 12

D Fig. 7.

anybody can get into the act. Sealing of chemicals in polyethy-

lene bags is a quick and convenient way of storage for limited
periods, at any rate for reasonably stable compounds. More-
over, as far as solids are concerned, for dispatch of samples by
mail this is by far the best way. Such samples should be sealed-
in as illustrated in Fig. 7, with one compartment for the sample
and one for the label, and the whole should be attached by
adhesive tape, not stapled, to the letter.
One can think of a number of items in the laboratory which
are used or used up intermittently and need to be protected from
dust, excessive humidity or corrosion, such as preparative TLC
plates, syringes, small lecture bottle gas cylinders, special
gas regulators and special metal fittings. All such items can
conveniently be protected by sealing in polyethylene enclosures.

1. R. Bottle, Use of the Chemical Literature, 3rd Edn, Butterworths,

London, 1979.
2. M. Muecke, Die Chemische Literatur, Verlag Chemie, Weinheim,
3. H. Skolnik, The Literature Matrix of Chemistry, Wiley, New
York, 1982.
4. Y. Wolman, Chemical Information, Wiley, New York, 1983.
5. E. g., Beilstein Dictionary for Users of the Beilstein Handbook of
Organic Compounds, Springer, Berlin, Heidelberg, New York;
apply to Beilstein Institut fiir Literatur der Organischen Chemie,
Frankfurt/Main, FRG.
6. J. Buckingham (Ed.), Dictionary of Organic Compounds, 5th
Edn, Chapman and Hall, London, 1982.
7. (a) W. Theilheimer, Synthetic Methods of Organic Chemistry,
Karger, Basie, London, New York, Sidney; (b) A. F. Finch and
P. R. Mitchell, Thei/heimer's Synthetic Methods of Organic
Chemistry. A Guide for Users, Karger, Basie.
8. L. F. Fieser and M. Fieser, Reagents for Organic Synthesis,
Wiley, New York, Vols 1-13 (from 1967).
9. E. Muller and 0. Bayer (Eds), Methoden der Organischen Chemie
(Houben-Wey/), 4th Edn, Georg Thieme Verlag, Stuttgart.
10. D. Barton and W. D. Ollis, Comprehensive Organic Chemistry,
Pergamon Press, Oxford, New York, 1979.
11. S. Patai (Ed.), The Chemistry of Functional Groups,
Wiley-Interscience, Chichester, New York, Sydney.
12. A. Weissberger and E. C. Taylor (Eds), The Chemistry of
Heterocyclic Compounds, Wiley, New York, Chichester.
13. A. T. Bourquist (Ed.), Organic Chemistry, A Series of Mono-
graphs, Academic Press, New York.

14. J. Ash, P. Chubb, S. Ward, S. Welford and P. Willett, Com-

munication, Storage and Retrieval of Chemical Information,
Ellis Horwood, Chichester, 1985.
15. M. L. Neufeld and M. Cornog, J. Am. Soc. Inf. Sci. 37, 183
16. F. A. Tate, Chem. Eng. News 45(4), 78 (1967); 53(24), 30 (1975).
17. DIALOG Information Services Inc., 3460 Hillview Ave., Palo
Alto, CA 94304, USA (for USA); Learned Informa-
tion/DIALOG, Woodside, Hinksey Hill, Oxford OXl SAU, UK
(for Europe).
18. ORBIT Search Service, Achilles House, Western Ave., London
W3 OUA, UK; 8000 Westpark Drive., McLean, VA 22102, USA.
19. C. J. Armstrong and J. A. Large (Eds), Manual of Online Search
Strategies, G. K. Hall, Boston, 1988.
20. S. P. Harter, Online Information Retrieval. Concepts, Principles,
and Techniques, Academic Press, New York, 1986; C. L.
Borgman, D. Moghdam and P. K. Corbett, Effective Online
Searching. A Basic Text, Marcel Dekker, New York, 1984; R. E.
Hoover (Ed.), Online Search Strategies, Knowledge Industries
Publications, White Plains, NY, 1982; C. T. Meadow and P.
Cochrane, Basics of Online Searching, Wiley, New York, 1981;
W. M. Henry, J. A. Leigh, L. A. Tedd and P. W. Williams,
Online Searching. An Introduction, Butterworths, London, 1980.
21. H. R. Pichler, Online-Recherchen fur Chemiker, VCH,
Weinheim, 1986.
22. (a) E. Zass, Computer als Hilfsmittel fiir die
Informationsversorgung-Online-Literatur- und Struktur-
Recherchen, in E. Ziegler (Ed.), Computer in der Chemie,
2nd Edn, Springer, Heidelberg, 1985, p. 24; (b) P. Hassanaly and
H.J. M. Dou, Online access to chemical information, in G. Vernin
and M. Chanon (Eds), Computer Aids to Chemistry, Ellis
Horwood, Chichester, 1986; Y. Wolman, Chemical Information.
A Practical Guide to Utilization, 2nd Edn, Wiley, Chichester,
1988; H. Schulz, From CA to CAS Online, VCH, Weinheim,
1988; ref. 19, Ch. 4.
23. STN International, c/o FIZ Karlsruhe, P.O. Box 2465, D-7500
Karlsruhe 1, FRO (for Europe); c/o Chemical Abstracts Service,
2540 Olentangy River Road, P.O. Box 3012, Columbus, OH
43202, USA (for USA); c/o Japan Information Center of Science
and Technology, C.P.0. Box 1478, Tokyo 100, Japan (for
24. DATA-STAR, Plaza Suite, 114 Jermyn St, London, SWlY 6HJ,
UK; D-S Marketing Inc., Suite 110, 485 Devon Park Dr., Wayne,
PA 19087, USA.

25. E.g. T. Novak, World Pat. Inf 9, 222 (1987); T. Novak, Online
Inf 10, 353 (1986).
26. Telesystemes Questel, 83-85 Bd. Vincent Auriol, F-75013 Paris,
France; Questel Inc., 5201 Leesburg Pike, Suite 603, Falls
Church, VA 22041, USA.
27. S. M. Kaback, J. Chem. Inf Comput. Sci. 24, 159 (1984); S. M.
Kaback, Database 10(5), 17 (1987); J. van der Drift, World Pat.
Inf 8, 243 (1986); E. M. D. Smith World Pat. Inf 10, 11 (1988);
articles in World Pat. Inf. 7, issue 1 (1985).
28. Directory of Online Databases, Cuadra Associates, Santa Monica,
CA, 1979-; M. E. Williams, L. Lannom and C. G. Robins (Eds),
Computer-Readable Databases. A Directory and Data Source-
book, North-Holland, Amsterdam, 1985-.
29. (a) P. G. Dittmar, R. E. Stobaugh and C. E. Watson, J. Chem.
Inf. Comput. Sci. 16, 111 (1976); R. E. Stobaugh, J. Chem. Inf.
Comput. Sci. 28 180 (1988); (b) K. A. Hamill, R. D. Nelson, G.
G. vander Stouw and R. E. Stobaugh, J. Chem. Inf. Comput. Sci.
28, 175 (1988); (c) J.E. Blackwood, P. M. Elliot, R. E. Stobaugh
and C. E. Watson, J. Chem. Inf. Comput. Sci. 17, 3 (1977); (d)
J. Mockus and R.E. Stobaugh, J. Chem. Inf. Comput. Sci. 20,
18 (1980).
30. (a) S. R. Heller, Database 10(4), 47 (1987); (b) C. Jochum, World
Pat. Inf. 9, 147 (1987): Online Searching on STN. Beilstein Work-
shop Manual. Springer, New York, 1989; S. R. Heller and G. W.
A. Milne, Online Searching on STN. Beilstein Reference Manual,
Springer, New York, 1989.
31. J. Zupan (Ed.), Computer-Supported Spectroscopic Databases,
Ellis Horwood, Chichester, 1986; W. Bremser, Nachr. Chem.
Tech. Lab. 31, 456 (1983); G. H. Wood, J. R. Rodgers and S. R.
Gough, J. Chem. Inf. Comput. Sci. 29, 118 (1989).
32. J. Buckingham, Chem tech 15, 674 (1985).
33. R. Attias, J. Chem. Inf. Comput. Sci. 23, 102 (1983); P. G.
Dittmar, N. A. Farmer, W. Fisanick, R. C. Haines and J.
Mockus, J. Chem. Inf. Comput. Sci. 23, 93 (1983); A.B. Wagner,
Online Rev. 10, 173 (1986).
34. Y. Wolman, J. Chem. Inf. Comput. Sci. 29, 42 (1989); Y. Wol-
man, Online Inf. 12, 203 (1988).
35. A. J. Lawson, in W. A. Warr (Ed.), Graphics for Chemical Struc-
tures (ACS Symp. Ser., No. 341), American Chemical Society,
Washington, DC, 1987, p. 80; Y. Wolman, J. Chem. Inf. Com-
put. Sci. 27, 144 (1987).
36. A. J. Beach, H. F. Dabek, Jr, and N. L. Hosansky, J. Chem.
Inf. Comput. Sci. 19, 149 (1979).
37. A. F. Finch, J. Chem. Inf. Comput. Sci. 26, 17 (1986).

38. P. Willett (Ed.), Modern Approaches to Chemical Reaction

Searching, Gower, Aldershot, 1986.
39. E. Zass and S. Muller, Chimia 40, 38 (1986); A. J. Kos and G.
Grethe, Nachr. Chem. Tech. Lab. 35, 586 (1987); A. Deroulede,
Inf. Chim. 289, 143 (1987); J. H. Borkent, F. Oukes and J. H.
Noordik, J. Chem. Inf. Comput. Sci. 28, 148 (1988).
40. B. Charton, J. Chem. Inf. Comput. Sci. 17, 45 (1977).
41. Institute for Scientific Information, 3501 Market St., Philadelphia
PA 19104, USA (for USA); 132 High St., Uxbridge, Middlesex
UBS IDP, UK (for Europe).
42. E. Garfield, J. Chem. Inf. Comput. Sci. 25, 170 (1985); E.
Garfield, Citation Indexing, Wiley, New York, 1979.
43. J.E. Baldwin, J. Chem. Soc., Chem. Commun. 734 (1976); J.E.
Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman and R.
C. Thomas, J. Chem. Soc., Chem. Commun. 736 (1976), J. E.
Baldwin and J. A. Reiss, J. Chem. Soc., Chem. Commun. 77
(1977); J. E. Baldwin and L. I. Kruse, J. Chem. Soc., Chem.
Commun. 233 (1977); J.E. Baldwin, R. C. Thomas, L. Kruse and
L. Silberman, J. Org. Chem. 42, 3846 (1974).
44. E. Akaho, A. Bandai and M. Fuji J. Chem. Inf. Comput Sci. 26,
59 (1986); R. E. Buntrock, J. Chem. Inf. Comput. Sci. 24, 54
44. (a) E. Zass, Naturwissenschaften 69, 276 (1982); E. Zass, Nachr.
Chem. Tech. Lab. 32, 424 (1984); G. Naber, Database 8(1), 20
45. W. S. Johnson and W. P. Schneider, Organic Syntheses, Coll.
Vol. 4, Wiley, New York, 1963, p. 132.
46. A. J. Gordon and R. A. Ford, The Chemist's Companion, Wiley,
New York, 1972, p. 375.
47. Ace Glass Inc., 1430 Northwest Boulevard, Vineland, NJ 08360,
48. Fisher & Porter Inc., Lab Crest Division, Warminster, PA 18974,
49. Lab Glass Inc., P.O. Box 610, Vineland, NJ 08360, USA.
50. H. Schneider, Fresenius Z. Anal. Chem. 135, 191 (1952).
51. G. A. Fisher and J. A. Kabara, Anal. Biochem. 9, 303 (1964).
52. W. C. Still, M. Kahn and A. J. Mitra, J. Org. Chem. f3, 2923
53. G. Hesse, Chromatographisches Praktikum, Akademische
Verlagsgesellschaft, Frankfurt, 1968, p. 34.
54. R. Breslow, S. Baldwin, T. Flechtnet, P. Kalicky, S. Lin and W.
Washburn, J. Am. Chem. Soc. 95, 3259 (1973).
55. J. Wolinsky, J. A. Thorstenson and T. A. Killinger, J. Org.
Chem. 43, 875 (1978).

56. Ref. 46, p. 375.

57. Ref. 53, p. 35; Woelm AG. Information Sheet No. 20.
58. A.H. Gordon and J.E. Eastoe, Practical Chromatographic Tech-
niques, Newnes, London, 1964, pp. 51, 82; Ref. 53, p. 42.
59. G.T. Chapman, D.W. Mathieson and V.P. Arya, J. Chem. Soc.
4013 (1963).
59. (a) D. F. Mccomsey, R. G. Stanzione and L. Scott, J. Org.
Chem. 52, 1857 (1982).
60. A. J. Parker, Adv. Org. Chem. S, 1 (1965).
61. E. I. Du Pont De Nemours & Co. Inc., Wilmington, DE 19898,
62. GAF Corp., Calvert City, USA.
63. Crown Zellerbach, Chemical Products Div., Camas, WA 98007,
64. D. Martin and H. G. Hauthal, Dimethyl Su[foxide, Van Nostrand
Reinhold, Wokingham, 1971.
65. Pierrefitte-Auby, 92202 Neuilly-sur-Seine, France.
66. H. Norman!, Angew. Chem., Int. Ed. Engl. 6, !046 (1967).
67. J. H. Clark, A. J. Hyde and D. K. Smith, J. Chem. Soc., Chem.
Commun. 79 (1986).
68. D. R. Fahey and E. A. Zuech, J. Org. Chem. 39 3276 (1974).
69. S. Fujita, Synthesis 423 (1982).
70. L. H. Horsley, Azeotropic Data Ill, American Chemical Society,
Washington, DC, 1973.
71. F. G. Bordwell, personal communication to A. Beck and D.
72. G. E. Wilson and A. Hess, J. Org. Chem. 45, 2766 (1980).
73. H. E. Zimmerman, F. X. Albrecht and M. J. Haire, J. Am.
Chem. Soc. 97, 3726 (1975).
74. R. E. Ireland and J. A. Marshall, J. Amer. Chem. Soc. 81, 2907
75. A. K. Beck, M. S. Hoekstra and D. Seebach, Tetrahedron Lett.
18, 1187 (1977).
76. D. L. Comins and D. H. LaMunyon, Tetrahedron Lett. 29, 773
77. H. Namba and H. C. Brown, J. Am. Chem. Soc. 92, 5790 (1970).
78. E. J. Corey and R. N. K. Chen, J. Org. Chem. 38, 4086 (1973).
79. J. J. Fitt and H. W. Gschwend, J. Org. Chem. 49, 209 (1984).
80. G. H. Posner, M. Weitzberg and S. Jew, Synth. Commun. 611
(1987); R. Lehmann and M. Schlosser, Tetrahedron Lett. 25, 745
81. R. Pi, T. Friedl, P. v. R. Schleyer, P. Klusener and L. Brandsma,
J. Org. Chem. 52, 4299 (1987).
82. P. Beak and K. D. Wilson, J. Org. Chem. 52, 218 (1987).

83. I.E. Kopka, M.A. Novak and M. W. Rathke, Synth. Commun.

27, (1986); A. B. Smith, III, and R. M. Scarborough, Tetrahedron
Lett. 19, 1649 (1978).
84. R. C. Cookson and R. L. Crumbie, Tetrahedron Lett. 26, 3377
85. R. Baker and R. J. Sims, Synthesis, 117 (1981); 83 (1988).
86. T. F. Braish and P. L. Fuchs, Synth. Commun. 111 (1986).
87. M. Schlosser and S. Strunk, Tetrahedron Lett. 25, 741 (1984).
88. R. Ranger, H. Hugel, W. Wykypiel and D. Seebach, Chem. Ber.
111, 2630 (1978); S. Raucher and G. A. Koolpe, J. Org. Chem. 43,
3794 (1978).
89. G. Stork and R. K. Hoekman, J. Am. Chem. Soc. 95, 2016
90. C. A. Brown, J. Org. Chem. 39, 3913 (1974).
91. E. M. Kaiser, J. D. Petty and P. L. A. Knutson, Synthesis 509
92. S. L. Huckin and L. Weiler, Tetrahedron Lett. 13, 2405 (1972).
93. A. G. M. Barett, S. V. Attwood, G. Richardson and H. D. A.
Walche, J. Org. Chem. 51, 4840 (1986).
94. M. Pohmakotr and D. Seebach, Tetrahedron Lett. 20, 2272
95. P.A. Grieco and R. S. Finkelhor, J. Org. Chem. 38, 2909 (1973).
96. 0. E. Seitz, F. E. Gianchelli and J. L. Neumeyer, Synth. Com-
mun., 367 (1977).
97. N. S. Narasimhan and R. Ammanamanchi, J. Org. Chem. 48,
3945 (1983).
98. Product Bulletin D-518, Lithium Corporation of America, 1988.
99. D. E. Pearson and 0. D. Keating, J. Org. Chem. 28, 1557 (1963);
C.H. de Puy, G. F. Morris, J. S. Smith and R. J. Smet, J. Am.
Chem. Soc. 87, 2421 (1965).
100. L. F. Fieser and M. Fieser, Reagents for Organic Synthesis, Vol.
I, Wiley, New York, 1967, p. 1022.
IOI. R. R. Fraser and T. S. Mansour, J. Org. Chem. 49, 3442 (1984).
102. R.R. Fraser and T. S. Mansour, J. Org. Chem. 50, 3232 (1985).
103. S. C. Watson and J. F. Eastham, J. Organomet. Chem. 9, 165
104. A. N. Tishler and M. H. Tishler, Aldrichim. Acta 11, 20 (1978).
105. J.P. Schmit, M. Piraux and J. F. Pilette, J. Org. Chem. 40, 1585
106. S. R. Schow and T. C. McMorris, 44, 3760 (1979).
107. N. L. Holy, Chem Rev. 74, 243 (1974).
108. T. Cohen and M. Bhupathy, Chem. Rev. 89, 152 (1989).
109. G. Stork and S. D. Rychnovsky, J. Am. Chem. Soc., 109, 1565
(1987); C. Ruecker, Tetrahedron Lett. 25, 4)49 (1984).

110. P. K. Freeman and L. L. Hutchinson, J. Org. Chem. 45, 1924

(1980); S. Brandaenge, 0. Dahlemann, B. Lindquist, A. Mahlen
and L. Moerch, Acta Chem. Scand. Ser. B 38, 837 (1984).
111. D. A. Horne, J. Chem. Educ. 60, 246 (1983).
112. T. Cohen and J. R. Matz, Synth. Commun. 311 (1980).
113. J. R. Bower and L. M. Cooke, Ind. Eng. Chem . Anal. Ed., 15,
290 (1943); E. Krell, Handbook of Laboratory Distillation, 2nd
Edn, Elsevier, Amsterdam, 1963, p. 367.
114. Parr Instrument Co., 211 53rd St., Moline, IL. 61265, USA.
115. D. Becker, personal communication.
116. W. M. Pearlman, Tetrahedron Lett. 8, 1663 (1967).
117. J. H. Saugier, A/drichim. Acta 17, 2 (1984).

Abbreviations 55, 56, 57, 60 Surette, addition IOI

Academic Rates (databases, n-Butyllithium 182ff
etc.) 51, 70, 73, 76 sec-Butyllithium 183
Acidities, C-H and N-H 176 tert-Butyllithium 183
Adapters, connecting, Teflon tert-Butyl methyl ether 100,
107 161, 168
Addition, of reactants 94, 97,
98, 102 Carboxylic acids, separation
Adsorbents, in chromatography 126, 145
138, 140 TLC 134
Amine bases 19lff Catalysts, hydrogenation 211
Ammonia, liquid, reactions in CA 4, 49, 52ff, 54, 55, 62
116 Author Index 5
Angewandte Chemie 7 Chemical Substance Index 5
Annual Reports (RSC) 20 Collective Index 29ff
Author Search 20, 48, 49 compound names 54, 57, 63,
Azeotropic mixtures l 70ff, 172 64
file 55, 58, 61, 63, 68, 69,
Balloons, rubber 90 72, 74
Bases 175fT Formula Index S
Beilstein (Beilstein 's Handbuch Index Guides S, 54, 55, 60
der Organischen Chemie) index headings 47ff, 57, 60
3, 8tT, 38, 53, 70 indexing 48, 54, 55, 57, 60,
Beilstein-browsing 39 62, 63, 69, 77, 79
Beilstein System Number 9 keyword index 21
Biological Abstracts, see BIOSIS CAOLD 53, 64, 68
BIOSIS 47, 52 CA Printed Indexes 48, 54, SS,
Boolean Operator, see Operator 57, 64
Bottles 217fT Registry File 55, 61, 62, 65ff,
Browsing 39, 49, 80 72, 73, 75

CASREACT 72, 73, 74ff of solvents 155

CAS Registry Number 54, SStT, Crimped metal closures 222
61, 62, 63, 64, 69, 73, 75, Crown ethers 181
80 Crystallisation 145
Registry system SI, 53, 65 fractional 1S 1
CA sections 49, 61, 70, 72 solvents 145
Chemical Abstracts, see also CA
Chemical Abstracts, for methods DARC 53, 65
and concept search 14ff Database 45, 47, 49, SOff, 52,
Chemical Abstracts Service 54, 72, 73
(CAS) 47, 51, 53ff, 65, 72 Data field 56ff, 67ff, 70
Chemical Communications 7 Data search 53, 54, 70, 74
Chemical Reactions DATA-STAR 52
Documentation Service 72 Derwent 72
Chimia 7 DIALOG 50, 51, 52, 53, 78
Chromatography, carboxylic Dianions, formation 181
acids 144 Dictionary of Organic
column l 38ff Compounds ('Heilbron')
columns, multibore 139 ll,54ff,61
elution 142 Display format 56, 57, 63
flash 139 Di-tert-butyldiphenyl 191
fraction collecting 143 1,2-Dimethoxyethane 180
gradient elution 142 Dimethylformamide 179
thin-layer, see TLC Dimethyl sulphoxide 179
Chromatotron 137 Disposal 85
Citation Index 23fT, 40 Distillation 195ff
Citation Search 78ff Distillation, columns 197
Cleavage, reductive 191 fractional 195
Code 46, 75 into specimen vials 202
Commands 46, SI, SS, 56, 63, Kugelrohr 200
65, 69, 74 of solvents 157
Communications 25
Compound search 4, 48, 52ff,
64, 80 Elution order 141
Comprehensive Organic Elutotropic order, of solvents
Chemistry 18 142
Concentration, of solutions 110 Emulsions 127
Concept search SSff, 60, 64, Extraction 125
77ff, 80 Extraction purification 128
Connection table 65, 66
Cooling 99, 100, 199 File 53, 55
Cooling baths 100 Filter cones, rubber 149
Cost, of computer search S1, Fire precautions 83
57, 65, 70, 73, 76 Flaming-out 95

Flasks, reaction 94, 96, 97, Keywords 48, 52ff, 57, 62, 69,
115, 116 72, 74, 77, 78, 79, 80
Florisil, as adsorbent 147 Kugelrohr distillation 130, 200
Foam, foaming 95, 125
Fraction collection 143, 198, Labelling 223
200 Literature search 51 ff, 55, 63,
Frameworks 87, 88 70, 72
Fume cupboard, see Hood Lithium diisopropylamide 178,
Gas chromatography 135 Lithium hexamethyldisilylazide
Gas cylinders 84 178, 187
Gases, introduction of 113, 114 Lithium hydride 190
Glassware, cleaning and drying
213 Manual searching 45, 47, 49,
Grease removal 124 54, 56, 57, 61, 62, 63, 74,
Grease, stopcock 124, 215 78, 79, 80
Medical treatment 84
Heating 99 Merck Index 10, 28, 54ff
Heilbron, see Dictionary of Mesityllithium 178
Organic Compounds Methods in Organic Synthesis
Hexamethylphosphoric triamide (RSC) 19, 24
. 168, 172, 179 'Minus 78 degrees' 26, 100, 104
Hood 84, 87 Methods, reactions, concepts,
Host 49, 50ff, 53, 65, 72, 73, searching for 11, 71
81 Methyllithium 184
Houben-Wey/ (Methoden der Multiple inert gas trap (MIGT)
Organischen Chemie) 16, 90ff
43, 44
Hydrogenation, 205ff Nomenclature 5, 53, 55, 63, 64,
atmospheric pressure 205 65
catalysts 211
medium pressure 208
Operator, Boolean logical 56,
63, 69, 70
Indexes 45, 4 7, 49, 52, 56, 57 Operator, proximity 55, 69, 75
Isopropylmagnesium halides, as ORAC 73, 74, 76
bases 178 ORBIT Search Service (Maxwell
Online) 50, 51, 53, 72
Jargon, in scientific Online I, 45
publications 26 Organic Reactions 17
Journal of the American Organic Syntheses 18
Chemical Society 7 Organising information 27ff
Journal of Organic Chemistry Organo-aluminium compounds
7 103, 219

Organolithium compounds, Reviews, Index of Scientific

preparation 184 (ISi) 19
Osmium tetraoxide 222 Rotary evaporators 124, 130
Overnight reactions 84 Russian literature 7

Patents 8, 49, 52 Safety glasses 83

Personal computer 46, 65, 69 SANDRA 71
Pipettes capillary 121ff Scanning journals 24ff
cleaning 123 Science Citation Index (IS/) 22,
Poison Information Centres 84 52, 78
Polyethylene containers 220 SCISEARCH 52
packaging 224 Screwcap closures 219
Polyurethane foam JOI Search I, 45, 46, 48, 49, 79
Potassium tert-butoxide 177, Search aids 60, 77, 79
188 Search profile 47, 50, 55, 56ff,
Potassium hydride 111, 177, 60, 62, 69, 75, 77, 78, 79,
189 80
Pressure reactions 118 Search terms 46, 50
Primary literature 47, 53, 63 Searching for methods,
Protective masks 83 reactions, concepts 11,
Purification, preliminary 128 71 ff
Secondary literature, 47
Radical anion bases 190 Separation, water, azeotropic
REACCS 73, 74, 75 111, 112
Reactions, following course by Sodium tert-amyloxide 189
TLC 135 Sodium hydride 110, 177, 179,
methods, concepts, literature 189
search for, 11, 71 ff Sodium methoxide 103, 188
small scale 93ff Solid products, isolation 113
under inert atmosphere 93ff Solubilities, of inorganic
how not to run 114 compounds in organic
Reagents for Organic Synthesis solvents 129
(Fieser and Fieser) 16 Solvents, anhydrous 97
Reagents, in solution 103 cost 155
organometallic 103 dipolar aprotic 128ff
Records 49, 55, 56, 70 distillation 157 IT
Recrystallisation I 49ff extraction 125
Reductions, metal-ammonia for crystallisation 145ff
116 individual 160ff
Refrigerators, cold rooms, 85 purification l 62ff
storage in 85, 223 Spectra, literature search for 54
Retrospectivity 2, 13 Steam bath support, for flasks
Reviews (general) 19 149

Stirring, magnetic 95, 104 TLC plates, alumina 136

mechanical 108 for following low temperature
STN 51, 53, 55, 58ff, 62, 65, reactions 136
70, 72, 77 for following reactions,
STN EXPRESS 65 general 135
Stoppers, ground glass 217 development 133
Structure search 51, 53, 54, 61, multiple development 133
62, 66 TLC, preparative 137
Substructure search 45, 51, 54, samples 153
641T, 72, 73, 74, 76, 80 spotting 132
Sulpholane 172 stability determination by 136
SYNLIB 73 visualisation 134, 137
Synonyms 48, 56, 60 Toxicity, of organic compounds
Transfer, of reagents, reactants
Telecommunication 46, 50 98, I02, I09, 182
Telesystemes Questel 51, 53, 65 Triangulation (recrystallisation)
Temperature measurement 151
104ff Truncation 56
Terminal 46, 49, 50, 65, 69, 74 Tubes, drying 105ff, 116
Tetrahedron letters 7 Tubing, elastomer 92
Tetrahydrofuran 161, 168, 180
Tetramethylethanediamine Vials, specimen 220
(TMEDA) 180, 182 distillation into 202
Theilheimer (Synthetic Methods Visualisation, of TLC plates
of Organic Chemistry) 134, 137
13ff, 40, 41, 72, 74
Thermometers IOS ff Water separation, azeotropic,
Titration, of C-Li and N-Li small-scale 112
bases I 87ff Working-up 95, 121
TLC 126, 131ff problems I 26ff