Académique Documents
Professionnel Documents
Culture Documents
Perplexed
Organic Experimentalist
Second Edition
H. J. E. Loewenthal
Israel Institute of Technology, Haifa
E. Zass
Eidgenossische Technische Hochschule, Zurich
SALLE + SAUERLANDER
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
Main
Verlag Sauerliinder AG, Aarau
6 Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 5
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
~
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Preface to First Edition
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.
Haifa,
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
x PREFACE TO SECOND EDITION
Haifa,
October 1989 H. J. E. LOEWENTHAL
1
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
ON SEARCHING THE LITERATURE. THE IMPORTANT SOURCES 5
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.
Nomenclature
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.
6 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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
'browsability'.
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
ON SEARCHING THE LITERATURE. THE IMPORTANT SOURCES 15
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
18 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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
ON SEARCHING THE LITERATURE. THE IMPORTANT SOURCES 19
ON REVIEWS IN GENERAL
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-
continued.
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.
20 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
SEARCHING BY AUTHOR
KEEPING UP-TO-DATE
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.
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
24 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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.
28 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
Notes:
1. References are given without authors, except where appro-
priate.
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
SEARCH OBJECT
CH3
bH
D
CH2
I
CH
'co2H
/\
HiC CHi
NOMENCLATURE
SEARCH RESULTS
CHEMICAL ABSTRACTS
BEILSTEIN HANDBUCH
CONCLUSIONS
Example 2
SEARCH OBJECT
NOMENCLATURE
SEARCH RE SUL TS
CHEMICAL ABSTRACTS
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
ON SEARCHING THE LITERATURE. THE IMPORTANT SOURCES 33
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.
Interim Evaluation
Ref. 12: Method involves catalytic carbonylation using
Ni(C0)4-highly poisonous, inadvisable as laboratory
method.
Ref. 13: Compound obtained by reaction of ester with
ON SEARCHING THE LITERATURE. THE IMPORTANT SOURCES 35
Interim Evaluation:
Ref. 18: Compound obtained by Wittig reaction-see
comment on Ref. 3a.
Ref. 19: Russian journal, unavailable, no English trans-
lation.
36 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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
cited.
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.
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
38 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
BEILSTEIN HANDBUCH
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:
CONCLUSION
Example 3
SEARCH OBJECT
OMe
I
Ar-CO-C02Me -+ Ar-C-C02Me
I
OMe
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.
40 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
SEARCH RESULTS
OR"
I
R-CO-R' + 2R"OSiMe3 -+ R-C-R' + Me3Si-O-SiMe3
I
OR"
CITATION INDEX
under: Tsunoda, T.
80 Tetrahedron Lett. 21, 1357
CONCLUSION
Example 4
SEARCH OBJECT
SEARCH RESULTS
and the list checked for possible convergence. This was found
in the case of Volume 9 (1955), Example No. 42, which referred
to:
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
paper:
V. du Vigneaud and 0. K. Behrens, J. Biol. Chem. 117, 27
(1937).
However, no more recent examples could be found.
CHEMICAL ABSTRACTS
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
1962-1966
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
ammonia.
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
1972-1977
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).
ON SEARCHING THE LITERATURE. THE IMPORTANT SOURCES 43
HOUBEN-WEYL'S METHODEN
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.
On Searching the
Literature-Using the
Computer (and Your Head)
to Retrieve Structures,
References, Reactions and
Data Online
Engelbert Zass
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
52 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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
54 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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
1
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
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
56 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
AUthor
Corporate Source (company, institution)
LOcation
SOurce (primary publication)
CAS Section Code
Document Type
CODEN (code for journal name)
ISSN (International Standard Serial Number)
Publication Year (of primary publication)
LAnguage
ABstract
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
->~
=> .IL2
LB ANSWER l OF 1
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)
DT J
CO JOCRAM
IS 0021-9673
PY 1987
IA Eng
Ll ANSWER l OF ll
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)
OT J
CO JOCRAH
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)
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
62 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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-
ON SEARCHING THE LITERATURE-USING THE COMPUTER 63
SUBSTRUCTURE SEARCHING
STN I NTERNATICNI..
l(~~:
I _t 11
6 C"" ..
5
NODE ATTRIBUTES:
NSPEC I S AC FIT 8
GRAPH ATTFIIIIU'TES:
FIINO<S> ME ISOLATED Ofl EMBEDDED
HUl1BEFI OF NODES IS 11
* ~ C TIONS-
NOD $','M NOD/BON NOD/BON NODIIION
1C 2ASE 6RD
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
3 CSE
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.
STN llffEANATIOlft.
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
SA CACLD
~
~ 0 Ao
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~:
J:Y:-ca'I
Isolation fro Nat,rol Product:
"'"
aepa, alen T
u:
I. nlkab9-ld2e el al., Ch.... Nat.Coa,pd. <Engl.Transl.>, 8, <11172,
CDDEN: ~NCAB
INP - As~lus falcatus
Fieference( s >:
1. ~~f~ Chn.Nat.Coo,pd. <Engl.Transl.), 8, <11172>, 235,
2fl
Oollcal AolalC!"'l,I P__.:
OAP -84. 5n dla
T111e: <aT~
~~enc=t
Mci.lel: 5811.N m
C.l
I. nlkab9-ldze el al., Che.NCll.Coapd. <Engl.Transl.>, 8, <11172>,
PJ COOEN: OINCA8
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
72 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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
ON SEARCHING THE LITERATURE-USING THE COMPUTER 75
Helo
A-> B
Eiclt !bin Build Secret,
Fl,..t NDt PNv
I t . List Tmle
Data n--
I u,-1 Plot Fa-9
Ref-List
Mn.:
Db Q.nwlt 112111 A
AaLlst lrl t.Llst Ch File
DeleW. Jrde<Llst List 4 A
....
'Qo
l'N O
Na<JI)
~ s:!, ~'
<-r\)ro
(l~ld)
~
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
Mode: searchln
l> LI NH3
f ~
0.:~~> TW" ~E THF -78'1C
~.f; -"lllC
8111
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.
NEXT BACK SKIP KEEP STOP KEYS PLOT SITE UIELI HELP
f::.N-.P=N---S02--o
Rt I
NEl
I
El
f:.N ff-H
'-PNEl
71 1~l
7Et NE l
I
El El
(3)
H ~ I
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
78 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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
erroneously.
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.
ON SEARCHING THE LITERATURE-USING THE COMPUTER 79
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.
4
Running Small-scale
Reactions in the Research
Laboratory
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.
88 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
) - _ ' -. b - - - - --------
Bench top
Fig. 1.
1
I I
I I
I I
I I
c
- ~~~--=
~.r:J h
=r"S ~
====-=-~ c=
'"'r T.J
I :
I I
I I
I I
I
I
,,.
I
-.,, I
c,r.:.
. .
-<:;,~~:
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
advantage.
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
90 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENT AUST
la)~
(bl
Fig. 3. Fig. 4.
Fig. S.
92 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
Fig. 6.
Flaming-out
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
96 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
Fig. 7.
SMALL-SCALE REACTIONS IN THE RESEARCH LABORATORY 97
Fig. 8.
98 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
(b)
;;
(al
Fig. 9.
SMALL-SCALE REACTIONS IN THE RESEARCH LABORATORY 99
Fig. 10.
100 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
Fig. 11.
SMALL-SCALE REACTIONS IN THE RESEARCH LABORATORY 101
(al le)
c[p c=::::)
Fig. 14.
-~ '
la) (b)
~ !cl
Fig. 15.
Fig. 16.
SMALL-SCALE REACTIONS IN THE RESEARCH LABORATORY 107
-8
Fig. 19.
SMALL-SCALE REACTIONS IN THE RESEARCH LABORATORY 109
Fig. 20.
110 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
Fig. 21.
SMALL-SCALE REACTIONS IN THE RESEARCH LABORATORY 111
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
previously.
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-
diately.
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-
112 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
I
' I a)
Fig. 23.
(b)
ta) (b)
Fig. 24.
114 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
Fig. 25.
Fig. 26.
merely just how much time will pass until all the solvent has dis-
appeared.
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
] 16 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
Fig. 27.
Fig. 28.
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.
SMALL-SCALE REACTIONS IN THE RESEARCH LABO RA TORY 119
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
122 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
(a) (b)
J,"ig. 1.
Fig. 2. Fig. 3.
ISOLA TING AND PURIFYING THE PRODUCT 123
Fig. 4.
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.
Emulsions
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
128 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
'
130 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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.
S(c)J.
THIN-LAYER CHROMATOGRAPHY
The Tools
You had best cut your own plates. For that you need a good
132 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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-
matography.
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
front).
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
future.
For spotting, the commercially available micropipettes, of 1,
2 or 5 }.. size should be used, because uniformity in spotting is
ISOLATING AND PURIFYING THE PRODUCT 133
Fig. 6.
Visualisation
This depends very much on the chemical nature of the
ISOLA TING AND PURIFYING THE PRODUCT 135
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.
Other Considerations
TLC can help you determine to what extent a product or
product mixture is sufficiently stable to survive protracted
ISOLATING AND PURIFYING THE PRODUCT 137
COLUMN CHROMATOGRAPHY
:1
~Ii
Ii
!I
1I
Ii
Fig. 7.
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
ISOLATING AND PURIFYING THE PRODUCT 143
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-
144 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
Fig. 8.
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
145
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.
Fig. 11.
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,
152 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
MIXTURE
+
Crystallize from enough
solvent to separate less
than 35% of mixture
Fig. 14.
Solvents
ECONOMICS
Table 1. Cost of solvents purchased in bulk and in individual 2.5 litre bottles
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.
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.
I ,
(al (b)
Fig. 2.
Boiling point
(acceptable Further drying and
Solvent range, C) Preliminary purification purification Recommended storage
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
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
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
out'
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
(continued)
-'
v,
Table 2. (continued) -
OI
OI
Boiling point
(acceptable Further drying and
0
Solvent range, C) Preliminary purification purification Recommended storage
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
63/18
mmHg; (1)
202,
78-79/10
mm Hg;
%-97/24
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
-
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. '
-.i
168 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
N,N-Oime1hyl-
Propcr1y N,N-Oime1hylformamidc 61 acetamidc 61 N-Me1hylpyrrolidone 62 Dimethyl sulphoxide 61 . . Hexamethylphosphoriclriamide 6 '66
~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
(cyclohexane).
-'
l,O
.....
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
-
- .I
172 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
["
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
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.
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
n-Butyllithium
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-
(a)
(b)
Fig. 1.
WHICH BASE SHOULD I USE? 183
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.
sec-Butyllithium
Methyllithium
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.
Fig. 2.
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-
186 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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
WHICH BASE SHOULD I USE? 189
G_-------~- Fig. 3.
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-
190 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
Amine
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) + + + ++ +++
Dehydrohalogen-
ation ++ ++ + + # ++' + +++ ++.
Other {3-
eliminations + + +
Acid scavenger + + ++ + + ++ + +++ +++
Esterification (acid
and halide or
sulphate) ++ ++ ++' + ++' +
Ester cleavage ( {J-
keto ester,
malonate) + II +
Macrolactonisation + ++
Macrolactamisation + ++
Michael or other
conjugative
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. .....
194 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
On Small-scale Distillation
FRACTIONAL DISTILLATION
Fig. 1.
ON SMALL-SCALE DISTILLATION 197
Fig. 2.
198 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENT AUST
Fig. 3.
ON SMALL-SCALE DISTILLATION 199
Fig. 4.
200 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENT AUST
KUGELROHR DISTILLATION
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.
ON SMALL-SCALE DISTILLATION 201
Fig. 6.
Fig. 7. Fig. 8.
v 0
c
s
D
Fig. 9. Fig. 10.
ON SMALL-SCALE DISTILLATION 203
Fig. 11.
On Hydrogenation-The
Cinderella of the Organic
Experimentalist
J J J
Fig. 1.
Fig. 2.
(a)
/
I
/
I tt'
I
I I):.'f
(b) Bottle clamp for above apparatus with guard screen removed.
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
ON HYDROGENATION 211
On Keeping It Clean
\'
I
\. '
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
intervals.
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
ON KEEPING IT CLEAN 215
Fig. 2.
Bottling Things Up
GROUND-GLASS STOPPERS
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.
BOITLING THINGS UP 219
SCREW-CAP CLOSURES
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.
220 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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
BOTTLING THINGS UP 221
t al (bl
Fig. 3.
(al
~ (bl
Fig. 4.
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).
BOTTLING THINGS UP 223
METAL CANS
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
true!
LABELLING
POLYETHYLENE PACKAGING
Fig. 6.
Vitamin
8 12
D Fig. 7.
BOTTLING THINGS UP 225
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.
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37. A. F. Finch, J. Chem. Inf. Comput. Sci. 26, 17 (1986).
230 A GUIDE FOR THE PERPLEXED ORGANIC EXPERIMENTALIST
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,
185
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
238 INDEX