Advanced Practical Organic Chemistry

Dedicated to Professor Gi/bert Stork

In recognition ofthe skills and enthusiasmfor chemistry
gained in his laboratories
ADV ANCED PRACTICAL
ORGANIC CHEMISTRY

M.CASEY
J.LEONARD
B. LYGO
Department of Chemistry and Applied Chemistry
University of Salford
G. PROCTER
George Ramage Professor of Chemistry
University of Salford

Springer Science+Business Media, LLC

 © 1990 Springer Science+Business Media New York
First Published 1990
Originally published by Blackie and Son Ltd in 1990.

All rights reserved.

No part 01 this book may be reproduced,
stored in a retrieval system, or transmitted,
in any lorm or by any means,
electronic, mechanical, recording or otherwise
without prior permission 01 the Publishers

British Library Cataloguing in Publication Data

Advanced practical organie chemistry.

1. Organie chemistry. Laboratory techniques
I. Casey, M.
547' . 0028

ISBN 978-0-216-92796-4 ISBN 978-1-4899-6643-8 (eBook)

DOI 10.1007/978-1-4899-6643-8

For the USA, International Standard Book Number is

0-412-02461-6
 Preface

The preparation of organic compounds is central to many areas of scientific

research, from the most applied to the most academic, and is not limited to
ehemists. Any research which uses new organic chemicals, or those which
are not available commercially, will at some time require the synthesis of
such compounds.
This highly practical book, covering the most up-to-date techniques
commonly used in organic synthesis, is based on our experience of
establishing research groups in synthetic organic chemistry and our
association with some of the leading laboratories in the field. It is not
claimed to be a eomprehensive compilation of information to meet all
possible needs and circumstances; rather, the intention has been to provide
sufficient guidance to allow the researcher to carry out reactions under
conditions which offer the highest ehance of success.
The book is written for postgraduate and advanced level undergraduate
organie chemists and for chemists in industry, particularly those involved in
pharmaeeutical, agrochemical and other fine chemicals research. Biologists,
biochemists, genetie engineers, material scientists and polymer researchers
in university and industry will find the book a useful source of reference.
 Contents

1 General Introduction 1

2 Keeping records of laboratory work 3

2.1 Introduction 3
2.2 The laboratory notebook 3
2.2.1 Why keep a lab book? 3
2.2.2 How to write a lab book 4
2.2.3 Suggested notebook format 5
2.3 Keeping records of data 8
2.3.1 What type of data should be collected 8
2.3.2 Formats for data records 9

3 Equipping the laboratory and the bench 13

3.1 Introduction 13
3.2 Setting up the laboratory 13
3.3 Generallaboratory equipment 14
3.4 The individual bench 20
3.4.1 Routine glassware 20
3.4.2 Personal items 21
3.4.3 Specialized personal items 21

4 Purification and drying of solvents 28

4.1 Introduction 28
4.2 Purification of solvents 28
4.3 Drying agents 29
4.4 Drying of solvents 33
4.5 Solvent stills 39
viii Contents

5 Reagents: purification and handling 43

5.1 Introduction 43
5.2 Classification of reagents for handling 44
5.3 Techniques for obtaining pure and dry reagents 45
5.3.1 Purification and drying ofliquids 45
5.3.2 Purifying and drying solid reagents 48
5.4 Techniques for handling and measuring reagents 50
5.4.1 Storing liquid reagents or solvents under inert atmosphere 50
5.4.2 Bulk transfer of a liquid under inert atmosphere (cannulation) 51
5.4.3 Using cannulation techniques to transfer measured
volumes of liquid under inert atmosphere 54
5.4.4 Use of syringes for the transfer of reagents or solvents 57
5.4.5 Handling and weighing solids under inert atmosphere 64
5.5 Preparationof~omethane 70
5.5.1 Safety measures 71
5.5.2 Preparation of ~omethane (a dilute ethereal solution) 71
5.5.3 General procedure for esterification of carboxylic acids 73
5.5.4 Titration of diazomethane solutions 73

6 Gases 74
6.1 Introduction 74
6.2 Use of gas cylinders 74
6.3 Handling gases 77
6.4 Measurement of gases 79
6.5 Inert gases 84
6.6 Reagent gases 84

7 Vacuum pumps 88
7.1 Introduction 88
7.2 Low vacuum pumps 88
7.2.1 Water aspirators 88
7.2.2 House vacuum systems 89
7.2.3 Electric diaphragm pumps 89
7.3 High vacuum pumps 90
 Contents ix

7.3.1 Rotary oil pumps 90

7.3.2 Vapour diffusion pumps 92
7.4 Pressure measurement and regulation 92
7.4.1 Units ofpressure (vacuum) measurement 93

8 Carrying out the reaction 94

8.1 Introduction 94
8.2 Reactions with air sensitive reagents 95
8.2.1 Introduction 95
8.2.2 Preparing to carry out areaction under inert conditions 95
8.2.3 Drying and assembling glassware 96
8.2.4 Typical reaction set-ups using a double manifold 97
8.2.5 Basic procedure for inert atrnosphere reactions 98
8.2.6 Modifications to basic procedure 101
8.2.7 Use of baUoons for holding an inert atrnosphere 106
8.2.8 The use of a 'spaghetti' tubing manifold 108
8.3 Reaction monitoring 110
8.3.1 Thin layer chromatography 110
8.3.2 High performance liquid chromatography 117
8.3.3 Gas-liquid chromatography 121
8.4 Reactions at other than room temperature 125
8.4.1 Low temperature reactions 125
8.4.2 Reactions above room temperature 128
8.5 Driving equilibria 133
8.5.1 Dean and Stark traps 133
8.5.2 High pressure reactions 134
8.6 Agitation 135
8.6.1. Magnetic stirring 135
8.6.2. Mechanical stirrers 136
8.6.3. Mechanical shakers 139
8.6.4. Sonication 139

9 Working up the re action 141

9.1 Introduction 141

X Contents

9.2 Quenching the reaction 142

9.2.1 General comments 142
9.2.2 Strongly basic non-aqueous reactions 142
9.2.3 Neutral non-aqueous reactions 143
9.2.4 Strongly acidie non-aqueous reactions 144
9.2.5 Acidie or basic aqueous reactions 144
9.2.6 Liquid ammonia reactions 144
9.3 Isolation of the crude product 145
9.3.1 General comments 145
9.3.2 Very polar aprotic solvents 146
9.4 Purification 147
9.4.1 Crystallization 147
9.4.2 Distillation 155
9.4.3 Sublimation 164
9.5 Chromatographie purification of reaction product 166
9.5.1 Flash chromatography 166
9.5.2 Dry-column flash chromatography 176
9.5.3 Preparative tlc 178
9.5.4 Medium pressure liquid chromatography 178
9.5.5 Preparative hplc 185

10 Small scale reactions 188

10.1 Introduction 188
10.2 Reactions at or below room temperature 189
10.3 Reactions above room temperature 192
10.4 Reactions in nmr tubes 193
10.5 Purification of materials 194
10.5.1 Distillation 194
10.5.2 Crystallization 195
10.5.3 Chromatography 195

11 Large scale reactions 197

11.1 Introduction 197
11.2 Carrying out the reaction 198
 Contents xi

11.3 Purification of the products 200

12 Characterization 201
12.1 Introduction 201
12.2 Nmr 202
12.3 Ir 202
12.4 Uv 203
12.5 Mass spectra 203
12.6 M.p. and b.p. 204
12.7 Optical rotation 204
12.8 Microanalysis 205
12.9 Keeping the data 205

13 The chemical literature 207

13.1 The structure of the chemical information 207
13.1.1 Introduction 207
13.1.2 The structure of the literature 208
13.2 Some important sources of chemical information 208
13.2.1 Chemical Abstracts 209
13.2.2 Beilstein 210
13.2.3 Science Citation Index 211
13.2.4 Computer databases 212
13.3 How to fmd chemical information 213
13.3.1 How to do searches 213
13.3.2 How to find information on specific compounds 214
13.3.3 How to find information on classes of compounds 215
13.3.4 How to fmd information on synthetic methods 216
13.4 Current awareness 217

14 Special procedures 219

14.1 Introduction 219
14.2 Catalytic hydrogenation 219
14.3 Photolysis 222
14.4 Ozonolysis 223
xü Contents

14.5 Flash vacuum pyrolysis 224

14.6 Liquid ammonia reactions 224

15 'Trouble shooting'; 227

what to do when things don 't work

16 Example reactions 229

16.1 Preparation of n-butyllithium 229

16.2 Titration of n-butyllithium 230
16.3 Aldol reaction 231
16.4 Preparation of ethyl(triphenyl-phosphoranylidene)acetate 233
16.5 Claisen rearrangement 234
16.6 Hydrogenation of maleie acid 236

17 Safety 238
17.1 Safety is your primary responsibility 238
17.2 Safe working practice 239
17.3 Common hazards 239
17.4 Accident and emergency procedures 241
17.5 Bibliography 242

Appendices 243

Appendix 1. Properties of common solvents 243

Appendix 2. Properties of common gases 244
Appendix 3. Approximate pKa values for some common deprotonations 245
compared to some common bases
Appendix 4. Lewis acids 246
Appendix 5. Common reducing reagents 247
Appendix 6. Common oxidizing reagents 252

Index 257
 CHAPTER 1

General Introduction

The preparation of organic compounds is central to many areas of scientific

research, from the most applied to the most academic, and is not limited to
chemists alone. Any research which uses new organic chemicals, or those
which are not available commercially, will at some time require the
synthesis of such compounds. Accordingly the biologist, biochemist,
genetic engineer, materials scientist, and polymer researcher in university or
industry all might find themselves faced with the task of carrying out an
organic preparation, along with those involved in pharmaceutical,
agrochemical, and other fine chemicals research.
These scientists share with the new organic chemistry graduate student
a need to be able to carry out modern organic synthesis with confidence and
in such a way as to maximize the chance of success. The techniques,
methods, and reagents used in organic synthesis are numerous, and
increasing every year. Many of these demand particular conditions and care
at several stages of the process, and it is unrealistic to expect an
undergraduate course to prepare the chemist for all the situations which
might be met in the research laboratories. The non-specialist is even more
likely not to be conversant with most modern techniques and reagents.
Nevertheless, it is perfectly possible for both the non-specialist and the
graduate student beginning research in organic chemistry to carry out such
reactions with success, provided that the appropriate precautions are taken
and the proper experimental protocol is observed.
Much of this is common sense, given a knowledge of the properties of
the reagents being used, as most general techniques are relatively
straightforward. However, it is often very difficult for the beginner or non-
specialist to find the appropriate information.
2 General Introduction

At Salford, we found ourselves handing out to students beginning

research in organic chemistry a compilation of what we hoped was useful
information on the practical aspects of organic synthesis, based on the
authors' recent associations with some of the top synthetic organic research
laboratories. We have gathered this information together in this book, and
expanded it to cover some other areas, in the hope that it will be an aid to the
specialists and non-specialists alike. Of course most research groups will
have their own modifications and requirements, but on the whole the basic
principles will remain the same.
This book is intended to be a guide to carrying out the types of
reactions which are widely used in modern organic synthesis, and is
concerned with basic technique. It is not intended to be a comprehensive
survey of reagents and methods. A few representative procedures are
given, and the appendix contains some information on commonly used
reagents.
If we have achieved our aims, users of this book should be able to
approach their synthetic tasks with confidence. Organic synthesis is both
exciting and satisfying, and provides opportunity for real creativity. If our
book helps anyone along this particular path then our efforts will have been
worthwhile.
 CHAPTER 2

Keeping Records of Laboratory Work

2.1 Introduction
No matter how high the standard of experimental technique employed
during areaction, the results will be of litde use unless an accurate record is
kept of how that reaction was carried out and of the data obtained on the
product(s). Individuals or individual research groups will develop their
own style for recording experimental data, but no matter what format you
choose to follow, there are certain pieces ofvital information which should
always be included. In this section a format for keeping records of
experimental data will be suggested and although this need not be stricdy
adhered to, it will be used to point out the essential features which should be
included. It is suggested that records of experimental work and
experimental data be kept in two complementary forms: The lab notebook
should be a diary of experiments performed and should contain exact details
of how experiments were carried out; A data book or set of data sheets
should also be kept to record the physical data and preferred experimental
procedure for each individual compound which has been synthesized.

2.2 The la bora tory notebook

2.2.1 Why keep a lab book ?
Before any practical work is undertaken in the laboratory a sturdy hard-
backed lab notebook should be obtained and a standard format for keeping
the notebook should be decided upon. A good deal of thought should go
into the layout of the lab book. It should be stressed that a lab book is not a
4 Keeping Records ofLaboratory Work

fonnat for polished report writing, but a daily log of work carried out in the
lab. Some of the main reasons for keeping a lab book are:
1. In order that the exact procedure followed for areaction can be referred
to later. This can be very important even if the reaction was not
successful. For instance, after several attempts to bring about a
re action have failed, it is often possible to review what has been done
then carry out a more successful experiment.
2. It should be the main index point that will enable you to find
experimental, literature and spectroscopic data on any compound which
you have synthesized.
3. It is the main source of reference when you come to write reports,
papers, theses etc.
4. It is a chronological diary of the experiments carried out and thus it
should allow you to say exactly when a particular experiment was
carried out.
5 . In order that another worker can follow your work, it is very important
to use a lab book style which is easily understood by others.

2.2.2 H ow to write a lab book

One of the most important points about keeping a lab book is that it is kept
on the bench and written up as you perfonn the experiments. It is bad
practice to keep rough notes about experiments, then transfer the details to a
lab book later. This can cause many problems, for instance: the original
notes can be lost; even with the strongest will, the exact truth often becomes
distorted in transferring infonnation to the lab book and small facts which
may at the time seem unimportant are left out; it is also very easy to forget
to rewrite an experiment altogether, especially if the reaction failed, and this
can lead to much time wasting later. It is more important that the lab book
be an accurate record of the way an experiment was performed, than for it to
be in your neatest writing, although of course it should be legible.
An example of a fonnat that is effective for general synthetic chemistry
is outlined on page 6. This can be adjusted to personal needs but its
essential features, which are listed below, should be included in any format
chosen.
 Keeping Records of Laboratory Work 5

2.2.3 Suggested notebookJormat (Fig. 2.1)

1 . General layout
It is good practice to start each new experiment on the next free right
hand page of the notebook. This makes finding any particular
experiment easier.
2 . Experiment number
The experiment number is in the top right hand corner of the page and
this is very important since it is used to reference all the compounds
which are prepared. If a notebook with numbered pages is used, it is
common for the experiment number to be the number of the page on
which the experiment starts. The way in which the notebook is indexed
is open to personal preference. In this system a researcher's first book
is book A, then B,C,D etc. Figure 2.1 therefore shows experiment 23
of book A. Compounds isolated from this experiment all carry the
number A23, prefixed with the researchers initials (in this case BB).
When more than one product is isolated from areaction a suffix, a, b, C
etc. is added to the reference number, a being the spot running highest
on tlc, b the next, and so on. Thus, for this experiment two products
were isolated and these carry reference numbers BB A23a and BB
A23b. Using this system the origin of any synthetic sampie can be
deterrnined very quickly.
3. Thedate
It is important that the date is always included.
4. Areaction scheme indicating the proposed transformation
This is always included at the top of the page so that an individual
experiment is easily found. If the reaction proceeded as desired the
scheme is left intact, but if the desired product was not obtained it can
be crossed through in red to indicate this. If other products were also
obtained they can be added, again in a different colour ink if desired.
Thus, simply flicking through the lab book, looking at the schemes,
can quickly provide a good deal of information. Some people prefer to
write only the left-hand side of the equation until the experiment is
complete.
6 Keeping Records of Laboratory Work

9 March 2000 A23

st(OBO
H H

OH
5+(.0&
H OBn
NaBHiceCI3

MeOHlo'C
•
HO H OBn
BB21a mw=348 mw=350

Ref. J.-L. Luche. L. Rodriguez-Hahn and P. Crabbe. J. Chem. Soc .• Chem. Commun ..
1978.601

Substance Quant. Mol. wt. m.moles Equiv. Source

BBA21a 200mg 348 0.57 p.A21
NaBH4 27mg 38 0.71 2.84 Aldrich
CeCI3(0.4MIMeOH) 2ml 0.8 1.4
MeOH 25ml

Method:
The aldehyde (200mg) and CeCl3 solution 2ml) in MeOH (25mi). was cooled to
OOC. then treated with NaBH4 (27mg in MeOH. 8ml) .

TLC 10 min 30 min

~:1 PetlEtOAc ~:1 PetJEtOAc

0 88 0 80 - B B A23a (redJbrown - vanilin)

o 0 o 0 - B B A23b (blue - vanilin)

.. .. Rxn
SM
.. ..
SM
Je Je
Rxn
After 30 min tlc shows no SM. but two products. MeOH was evaporated. CH2Cl2
(30ml) added and the mixture washedwith 10% HCI (lOml)foliowed by satd. NaHC03 (3
X10ml). dried and evaporated. (210mg crude)

Flash chromatography using 9:1 (pet. etherlEtOAc) on 8g of silica provided:

H
BB A23a 27mg (12%)- NMR (BB28).
MS (BB19). IR (BB27) . Data sheet 6- ~OBn C2sH3004
looks like: MeO-{1;"\"" mw=394
OMa OBn

BB A23b 140 mg (69% yield) - NMR H

(BB29). MS (BB20). IR (BB28) • Data (i}-oBn
sheet 5 - OKfor:
HO~OBn
Comment:
Next time use aqueous solvent - may avoid ketal formation
Figure 2.1
 Keeping Records of Laboratory Work 7

5 . Literature references (if there are any)

6. Quantities
The quantities of each ingredient of the reaction are listed at the
beginning, together with the molecular weight, number of moles and
number of molar equivalents. It is very useful to have this information
available at a glance. Having the molecular weights on hand saves a
good deal of time when going on to other reactions and when looking at
mass spectra etc., but the real importance of this section is that the
values contained here are critical when evaluating the outcome of a
reaction, and you might want to adjust them in subsequent
modifications of the procedure.
7. The procedure
This should be an exact account of the practical procedure carried out,
inc1uding any spillages or other rnishaps. It can be quite brief and not
necessarily of publication standard, as long as it is understandable.
8. Reaction monitoring
Tlc is the most widely used method for reaction monitoring and it is
very important to include a full size representation of the tlc plate(s)
used, giving the development solvent and the stain used for
visualization. Tlc gives us a true feel for the re action and a good picture
of a tlc is worth many words when it comes to following a procedure.
In some cases hplc, gc, or other technique will be used to monitor the
progression of the reaction and again a representation of this should be
included. Some people find that it is more convenient to draw the tlcs
on the adjacent notebook page. (For more details about tlc, see Chapter
8)
9. Details 0/ work-up and purification 0/ the product(s)
For chromatography it is important to include the quantity and type of
adsorbent, and the solvent system used for elution. Some people also
like to inc1ude a tlc representation of the column fractions. If the
product is purified by crystallization, record the solvent used and the
m.p. If it is distilled describe the type of distillation set-up and record
the b.p. and pressure.
8 Keeping Records of Laboratory Wode

10. Cross references to the spectra and data book(sheet)

All compounds should be given reference numbers, as described
above, and these should be cross referenced with data book entries and
the reference numbers of the corresponding spectra. Indeed, many
people like to use the same number for the spectra. The yield of each
compound isolated should also be given and if possible its structure.
11. Finally include any concluding remarks about the reaction.

2.3 Keeping records of da ta

When it comes to writing reports, papers, and especially theses, one of the
most time consuming and tedious jobs is collecting together experimental
and spectroscopic data for compounds, and it can be very frustrating 10 find
that a particular piece of data has been mislaid or was never obtained. Also,
when the collecting of such data is left to the time of report writing, errors
can easily creep into spectral assignments. It is a much better practice to
collect data and make spectral assignments as your work progresses and
keep this infonnation stored in a standard fonnat.
Whenever a significant compound has been synthesized a data sheet or
data book page should be created for it. The fonnat of a data sheet can vary
according to personal preferences, but it should contain at least the
following pieces of infonnation:
1 . The structure and molecular fonnula of the compound
2. A procedure for the preparation of the compound, preferably in a style
suitable for publication.
3. An appropriate range of spectroscopic and chromatographic data which
is suffieient to characterize the compound. Full assignments of spectra
should be entered in the data sheets as soon as the information is obtained,
then when it comes to report writing most of the information required is on
hand.
4. Cross references to speetra and lab notebook
5. Literature references, if there are any

2.3.1 What types of data should be collected ?

There is now a plethora of speetroscopie and chromatographie teehniques
available for determining the structure and purity of organic eompounds and
 Keeping Records ofLaboratory Work 9

it is therefore impossible to give a hard and fast rule stating the type of data
which should be obtained on every compound. Because of the rapid
expansion in the variety of techniques available there is presently much
debate about what constitutes a rigorous structure and purity analysis.
Traditionally, microanalysis was held to be the single standard test to which
any new organic molecuIe was subjected, and in some instances you may
find that it is a mandatory requirement. This is often the case for patent
applications. However, many researchers now prefer to use a range of
spectroscopic and chromatographie techniques to determine the structure and
purity of their compounds, and each researcher or research group will be
biased towards the particular types of data they find appropriate to
characterize the type of compounds that they work with.
For each individual compound you should decide first of all how
rigorously it needs to be characterized, then decide upon the appropriate
techniques to do this. For known compounds structure proof is often trivial
and simple techniques such as mixed melting point should not be
overlooked. If you are working on a synthetic sequence where the
structures of some of your intermediates are wen established, it is not
always necessary to treat each individual compound as a compIete
unknown. This is especially true if the reaction which has been carried out
is a very simple one, such as the reduction of an aldehyde to a primary
alcohol. On the other hand, when a crucial reaction has been carried out you
should be very careful to choose a characterization technique which gives
you the structural information you require, unambiguously.

2.3 .2 Formats for data records

If you choose to keep a data book, it is a good idea to start each new entry
on the next free right hand page of the book. The data for some compounds
will not fill the space allocated, but it is best to allow a reasonable space,
because some compounds will require a large amount of spectroscopic data
for characterization.
Data sheets are an alternative to the data book. These can be of a
standardized design with spaces for each type of data to be filIed in. The
advantage of this system is that it is easy to see at a glance whether a
particular piece of data has been obtained for a compound. However, two
disadvantages of the fixed format data sheet are: it does not provide the
10 Keeping Records of Laboratory Wode

flexibility which is often required to record diverse types of data which may
be used to characterize a particular compound; and it tends to encourage the
mistaken idea that every compound requires the same characterization data.
The system we prefer for data records, is one which makes use of a micro
computer word processor. A standard format blank data sheet, as shown
be1ow, is kept on disk (Fig. 2.2).

DA TA SHEET

Chemical Name:

Scheme:

Lit. Refs:

Method:

Mol. Formula:
m.p.lb.p.: ·c
Tlc : Rf (pet. ether/ethyl acetate, )
[aP25 : (e =, CHC13)
1H nmr (MHz): ~
J3C nmr (MHz): ~
V max : em- 1
A. max : nm
mlz (NH4, CI):
Found M , ealc. for
Analysis: Found C%; H%; N%; 0%,
Calc. for CHNO = C%; H%; N%; 0%
Notebook:
Spectra:
Figure 2.2
When a new compound is synthesized a blank data sheet is modified
with the data of the compound and a data record is created which is tailored
to the needs of the particular compound. Any of the data types which are
inappropriate for characterization of a particular compound can be removed,
and any additional data types can be added if required. This is especially
 Keeping Records ofLaboratory Worlc 11

(±)-E xo,e xo -7,8- D ib enzyloxy -e xo -e is- bieyelo [3.3.0] -oet -2 -en -4-01-2-

m
earboxaldehyde

H OBn ..
a) Swem oxidn.

HO H OBn

Method:
To a stirred solution of oxalyl chloride (l00ml, 1.10mmol) in dry dichloromethane
(15ml) at -78°C, a solution of dimethylsulphoxide (200ml, 2.58mmol) in
dichloromethane (lml) was added dropwise. The reaction mixture was stirred for 5 min,
then epoxide (200mg, 0.55mmol) in dichloromethane (2ml) was added dropwise. The
resulting mixture was stirred for a further 20 min, then triethylamine (Iml, 7.61mmol)
was added. After 10 min at -78°C the mixture was allowed to warm to room temperature,
then poured into 2M HCI (30ml) and extracted with dichloromethane (2 x 30mI). The
extract was washed with saturated aqueous NaHC03 (4OmI), then dried, and the solvent
removed in vacuo.
The crude product was taken up in dichloromethane (15mi), 1,5-
diazabicyclo[5.4.0]undec-5-ene (167mg, 1.1 mmol) was added, and the mixture was stirred
at room temperature for 2h. The solution was then poured into 2M HCI (20mi), extracted
with dichloromethane (2 x 30mi), and washed with saturated aqueous NaHC03 (40m1),
then dried, and the solvent removed in vacuo. Tlc. examination of the cmde mixture
showed the presence of one major product. An analytical sampie of the hydroxy enal was
obtained by flash chromatography (1:1 pet. ether/ethyl acetate), yie1d, 80%.

Mol. Formula: C23H2404 (mw = 364)

Tlc: RfO.23 (uv-active; pet. ether/ethyl acetate, 1:1)
vmax.: 3600-3200,3075,3050,2750,1690 and 700cm- 1
mlz (FAB+. thioglycerol): 365 (M + 1,9.6%),364 (M+), 92 and 57 (100%)
Notebook: BBD45b
Spectra: nmr 257; ms 163; ir 250

1H nmr (300 MHz):

ö value Proton(s) Mult. J value/Hz (coupled proton)
9.73 H-lO s
7.5-7.15 Ar m
6.55 H-7 -t J = 1.0 (H-6) and 1.0 (H-9)
4.70 PhCfu m
4.50 H-6 dl J =1.5 (H-5) and 1.0 (H-7)
4.30 PhCfu m
3.80 H-1 dl J =4.5 (H-3) and 1.0 (H-9)
3.58 H-9 dH J = 8.0 (H-5), 1.0 (H-7) and 1.0 (H-1)
3.47 H-3 dH J = 11.0 (H-4b), 6.5 (H-4a) and 4.5 (H-1)
2.68 H-5 m J = 9.0 (H-4b), 8.0 (H-9), 1.5(H-4a) and 1.5 (H-6)
2.37 H-4b dH J =12.5 (H-4a), 11.0 (H-3) and 9.0 (H-5)
1.84 H-4a dH J = 12.5 (H-4b), 6.5 (H-3) and 1.5 (H-5)
1.65 OH bs
Figure 2.3
12 Keeping Records of Laboratory Work

useful for nmr data, which can be as simple as a list of 60MHz signals, or
could comprize a vast array of information from a high field FT instrument
such as, coupling constants, nOe's or 2D data. Once the data sheets have
been printed out they are kept in a ring file, to make a very flexible data
book. Similar non-computer based record systems can also be devised but
the advantage of using a computer is that the record can easily be updated at
any time. When designing our data sheet we decided upon a standard style
which we also use for experimental sections of reports and theses.
Therefore, if a researcher is conscientious about keeping data records up to
date the tedium is taken out of reporting results. Also, with only slight
modifications, the data record can become an experimental entry which fits
the style of any major journal. An example of a completed data record is
shown in Fig. 2.3. Notice that there are some quite detailed high field nmr
data which are represented in a table. The table is also a standard design and
provides a good way of presenting complex nmr data so that they can be
deciphered quickly.
 CHAPTER 3

Equipping the Laboratory and the Bench

3.1 Introduction

In this chapter we will describe generallaboratory and bench equipment

which we have found to be of great use when working with modern organic
chemical reactions.
Many modern procedures which have now become standard
methodology in organic chemistry require dry reaction conditions, and often
an inert atmosphere. This has had a dramatic effect on the way efficient
laboratory facilities are arranged. Not so long aga reactions involving
anhydrous, inert conditions were rare and it was expedient to arrange the
equipment for such procedures on a one-off basis. However, now that this
type of reaction is common place, it makes sense to set up the laboratory in
such a way that reactions under inert conditions can be carried out as a
matter of routine. This chapter is written with this principle in mind. Much
of the equipment introduced here will be discussed in more detail in
subsequent chapters.

3.2 Setting up the laboratory

The basic furniture provided in organic chemistry laboratories will vary

considerably from one establishment to another and clearly any advice given
in this chapter will have to be tailored to the facilities available. The ideal
layout of the lab is also a very subjective matter and the advice given here is
therefore not intended to be taken as gospel, but simply reflects the
experiences of the authors from various laboratories in which they have
worked.
14 Equipping the Laboratory and the Bench

When setting up the lab it is usual for some areas of bench space to be
set aside for communal apparatus, and other parts to be allocated as
individual benches. Clearly, the areas which are assigned as communal
bench space will depend on the amount and type of communal equipment
which is to be installed. In this chapter some pieces of equipment will be
identified as communal and others as part of the individual bench kit, but the
classification will vary from one laboratory to another. The distinction will
to some extent depend on the type of work being undertaken, but will also
depend on the budget and space available.
U nless alternative office space is provided, it is a good idea to have
some desk space in the lab where workers can read and write, away from
areas used for chemicals. Desk space may also be required for small
computers which are also becoming a common feature of the modem
organic chemistry lab. Drawers or filing cabinets are useful for the safe
storage of spectta and other paperwork, and a blackboard is an invaluable
laboratory aid.
The area which constitutes an individual'bench' will vary considerably
from one lab to another. In our view all procedures involving organic
chemicals should be carried out in an efficient fume cup board. This implies
that each full-time worker in an organic chemistry lab permanently requires
at least one mette of fume cupboard space. However, in practice it is often
the case, particularly in academic labs, that much less fume cupboard space
is actually provided, and fume cup boards may be communal. In this chapter
the term 'bench' will refer to the space occupied by an individual worker
and it will be assumed that this space incorporates an adequate area of fume
cupboard, where all reactions are carried out.

3.3 General laboratory equipment

In this section we describe the communal facilities that should be found in a
laboratory in which modem organic chemistry is undertaken. Careful
thought should go into the placing of communal equipment. It may be quite
reasonable to place unattended items such as a fridge or oven in an awkward
corner, but a piece of apparatus at which a person will be working should be
in a position where the operator has enough room to work without hindering
anybody else. Equipment such as stills, which are used regularly by all
 Equipping the Laboratory and the Bench 15

members of the lab, should be located so that they are easily accessible,
without causing a disturbance to anyone working elose by.
Rotary evaporators
Rotary evaporators are perhaps the most heavily used pieces of equipment in
an organic research lab. They should therefore be located conveniently
throughout the lab, or preferably, each worker should have his or her own
on the bench.
Fridge and/or jreezer
A fridge and/or freezer should be provided to store chemicals, and this
should never be used for food storage.
Glass drying oven(s)
Again these should be conveniently located.
Vacuumoven
This may be used infrequently, but is still a very valuable piece of
equipment.
Balances
A two place balance is indispensable and a four place balance needs to be
available for sma11 scale work. When locating these remember that they are
used frequently, by people carrying out careful work, so do not put them in
the way of others, also avoid drafts and vibrations.
Kugelrohr bulb to bulb distillation apparatus (e.g. Buchi)
This apparatus is invaluable when preparing relatively small quantities of
high-boiling liquids. It is relatively mobile and can be moved from bench to
bench and attached to various vacuum sourees. However, it is useful to
locate it near to a high vacuum pump, where it is normally used.
Vacuum pumps
Vacuum at various levels will be required around the lab. Each bench
should have a modest vacuum source available (about 20mmHg), and this
can be provided by a water aspirator, a house vacuum system or a small
diaphragm pump. This level of vacuum is sufficient for rotary evaporation
of most solvents, filtering under vacuum, distillation of relatively volatile
oils, and similar tasks. However, there are a variety of operations for which
a high vacuum pump is either preferable or necessary. These operations
16 Equipping the Laboratory and the Bench

include, removing last traces of solvent from small quantities of product,

disti1lation of high-boiling oils and providing vacuum for a double manifold
(described later). For most purposes a simple two stage rotary pump,
which will provide a vacuum of <1mm, is adequate. If sufficient resources
are available each bench should have a high vacuum pump, connected to a
double manifold, but in many labs vacuum pumps are considered to be
communal equipment. Whether or not pumps are used communally, it is a
good idea to reserve one pump for distillations, so that a reliable high
vacuum can always be obtained. This pump should be fitted with an
efficient trapping system (see Chapter 7) to avoid solvent contamination,
and can be either on a mobile trolley or in a fixed position, depending on the
bench and floor space available. A pump which is used for distillations only
does not require a manifold to be attached. It is useful to have a general
purpose communal pump, attached to a single manifold (Fig. 3.1), which
can be used for removing trace amounts of solvent, and for distillations.

/~ =t t..---t--,
W~
~ connected to
high vacuum
.....-,~ pump via traps
connected 10
vacuum gauge
high vacuum
stopcock
Figure 3.1

lnen gases
A constant supply of dry inert gas (usually argon or nitrogen) is now
essential in an organic chemistry lab. Some labs will have nitrogen or argon
on tap and this is ideal, provided there are enough outlets and the gas is dry.
However, in most labs gas is supplied from cylinders, which take up a lot
of space and are quite expensive to rent. It causes great inefficiency in a
modem lab if there are too few inert gas outlets, and it is therefore important
when setting up the lab to decide how many gas outlets are required. We
suggest that there should be at least one outlet for each person working in
the lab, plus one for each piece of apparatus (such as a still) which is kept
permanently under inert gas. This may suggest that the same number of
cylinders is required, but the cost of this is usually prohibitive and space can
also be a problem. One efficient way to use cylinders to service a large
number of permanent inert gas lines, is to fit them with multi-way needle
 Equipping the Laboratory and the Bench 17

valves (e.g. 3-way). These are available from gas line hardware suppliers at
a very modest cost and give several gas outlets for the price of one!
Having decided on the number of gas cylinders required these should
be positioned in the laboratory so that semi-permanent PVC (Tygon) tubing
lines can easily be taken to each bench and to each piece of apparatus
requiring a supply. Some of the apparatus commonly used in conjunction
with inert gases will be described below and in Chapters 6 and 8.
Solvent stills
Two basic types of solvent still are found in the lab, one is for distillation of
solvents for routine use and the other is for distillation of ultra-dry solvents
for carrying out reactions under dry conditions. Unless very high grade
solvents are purchased, most solvents used in the lab for reactions or
chromatography should be distilled. For solvents which are used regularly
it is best to set up permanent stills and some typical designs for these are
given in Chapter 4. Routine stills are usually quite large (up to 5 litres), and
so therefore take several bottles of solvent at a time. Permanent large scale
stills should normally be available for petroleum ether (usually the largest
still), ethyl acetate, methylene chloride and any other solvents, according to
your particular needs.
Some solvents, such as tetrahydrofuran and diethyl ether (there may be
others you require also) are frequently required in very dry form, and it is
inconvenient to set up a still each time a small quantity is required for a trial
reaction. The efficiency of an organic lab is therefore greatly enhanced by
having these dry solvents available 'on-tap' from permanent stills, which
provide very effective drying, and are kept under an inert atmosphere.
Modern designs for permanent stills used for these distillations are very
compact, and do not cause inconvenience (see Chapter 4). A permanent still
should be installed for any solvent which is used regularly in the lab. It is
also worth keeping aspare distillation apparatus on hand for occasions
when a less common dry solvent is required.
General distillation equipment
Apart from standard Quickfit equipment, labs should also have some one-
piece distillation kits, which provide more effective distillation. A short-
path distillation apparatus is very useful for low-holdup, high-throughput
18 Equipping the Laboratory and the Bench

distillations, particularly on a small scale. These can be made by a

glassblower, and one design is shown in Fig. 3.2.

~E

ABC D E F
Size 1 5.5crn 3.5cm 6crn 2crn B14 B14
Size 2 llcrn 3.5crn 13cm 3cm B24 B14

Figure 3.2

For fractional distillation a one-piece apparatus incorporating small

fractionating columns is useful, and again two sizes are frequently used
(Fig. 3.3; see also Chapters 5 and 9).
Generallaboratory glassware
In any lab there will be quite a number of pieces of glassware which it is
only practical to keep communally, this is especially true for large
equipment. However, the nature of this equipment will vary a good deal,
depending on the type of work being undertaken.
 Equipping the Laboratory and the Bench 19

TB

tA

Bl4or~
B24
1 Alternative take
off for direet
B14
(14/20)

eoupling with
vaeuum

A B C
Sizel 8em 3.5cm 13em
Size 2 18em 3.5cm 18cm

Figure 3.3

Chromatographie equipment
Tlc is by far the most widely used technique for rapid, routine reaction
monitoring and it is essential that the lab should have permanent facilities for
visualization of t1c plates. A range of solvent dips, an iodine tank and a
small uv lamp are usually all that is necessary (see Chapter 8).
More sophisticated chromatographie techniques are also finding much
wider application in organic chemistry labs, and both hp1c and capillary gc
instruments are now quite common-place. These techniques complement t1c
20 Equipping the Laboratory and the Bench

as analytical techniques and, although an initial investment of time is

necessary to leam how to use the instrumentation, this pays good dividends
in the long ron (see Chapters 8 and 9).

3.4 The individual bench

There are a variety of factors that influence the proportion of laboratory
equipment which is part of an individual bench set, and that which is
communal. In most acadernic research labs workers find it most convenient
to keep a more or less complete set of routine glassware as part of the bench
kit. The individual then looks after the set, replaces broken equipment, and
keeps it clean, so that any particular piece of equipment is available when
required. On the other hand, in an industriallab there is normally an
extensive range of communal routine glassware which is washed by lab
helpers, and there is little need for workers to keep a full set of bench
equipment. In either type of situation there are certain pieces of equipment
which individuals usually like to keep for personal use, including such
things as syringes and chromatography columns. Whether more specialized
or sophisticated equipment is communal or personal will depend, to some
extent, on how frequently it is used, and on the funds available. A list of
equipment which we find useful to keep as part of the bench set is given
below, with abrief description of some of the more specialized items.

3.4.1 Routine glassware

A typical bench set of routine glassware, excluding specialized equipment,
is given below.
Item Quantity

Adapter reduction B14 socket B24 cone 1

Adapter reduction BIO socket B 14 cone 1
Adapter tube B14 cone 1
Adapter expansion B24 socket B 14 cone 1
Adapter expansion B29 socket B24 cone 1
Beakers low fonn IOmI 2
Beakers low fonn 25ml 4
Beakers low fonn l00m1 4
Beakers low fonn 400ml 2
Cylinders measuring IOml 1
Cylinders measuring 25ml 1
Cylinders measuring 100ml 1
 Equipping the Laboratory and the Bench 21

Cylinders measuring (stoppered) l000m! 1

Funne!s filter 15.00cm 1
Funnels filter 7.5cm 1
Funne!s separating 250m! 1
Funnels separating 50m! 1
Funnels separating l000m! 1
F!ask conicall00ml 4
Flask conical 250ml 2
Flask conical 500m! 2
Flask round-bottom 10m! B14 socket 6
Flask round-bottom 50m! B14 socket 6
Flask round-bottom 100m! B24 socket 6
F!ask round-bottom 250m! B24 socket 3
F!ask round-bottom 500m! B24 socket 2
Flask round bottom lO00m! B24 socket 1

3.4.2 Personal items

There are certain items which individuals usually prefer to keep for their
own personal use, even when routine glassware is communal. Here is a list
of standard, commercially-available items which we think should be kept as
the bench kit:
Item Quantity

Spatu!as (various sizes)

Magnetic followers 25.00mm 4
Magnetic followers 12.5mm 4
Magnetic followers 25.00mm (oval) 1
Magnetic followers 50.00mm (oval) 1
Syringe need!es 6 inch S-S Luer fit 6
Syringe need!es 12 inch S-S Luer fit 6
Syringe with meta! Luer lock 2ml 2
Syringe with meta! Luer lock 5m! 2
Syringe with meta! Luer lock IOml 2
Luer lock tubing adapter 1
Thermometers -10 to 360'C 1
Thermometers -10 to IIO'C 1
Thermometers -100 to IO'C 1
Thermometers, quickfit B 14 -10 to 360'C 1
Pasteur pipettes 1 box
Via!s (1 & 5 dram) 1 box

3.4.3 Specialized personal items

There are so me specialized pieces of glassware which we find to be
extremely useful to have as part of the bench set and these will be briefly
22 Equipping the Laboratory and the Bench

described here, but for full details of how they are used see the appropriate
chapter.
The double manifold
P------------ 25cm--------------~
inert gas from cylinder
~ via bubbIer

from vacuum pump

-+ via trapping system

Figure 3.4
'"
2-way double
oblique tap - see Fig. 3.5

If you would like to carry out reactions under dry and/or inert
conditions as a matter of routine, the double manifold is perhaps the single
most useful item of equipment which will enable you to do this. We
recommend that this be a standard item of equipment, permanently fitted to
every individual bench and connected to the laboratory inert gas supply by
PVC (Tygon) tubing. The manifold consists of two glass barrels, one
evacuated and one filled with an inert gas. An outlet is supplied by either
barrel of the manifold via a two-way double oblique tap (see Figs. 3.4 and
3.5). Thus, at the turn of the tap, equipment connected to the manifold can
be alternately evacuated or filled with inert gas.

(a) tap switched to inert gas (b) tap switched to vacuum

Figure 3.5 Cross section through a double oblique tap
 Equipping the Laboratory and the Bench 23

A bubbier should be incorporated in the line from the cylinder which

feeds the inert gas barrel and it should have a built in anti suck-back valve to
avoid oil contaminating the manifold (Fig. 3.6).
to manifold +-- C:=:::;-;:=:=:::J +-- from inert gas
cylinder
2cm!

r
12cm
+-+- anti suck-back
valve

1
++--- oil

Figure 3.6
A rotary pump is normally connected to the vacuum barrel of the
manifold and a schematic diagram showing the complete set-up is shown in
Fig. 3.7.
PCV (Tygon) tubing
/
~===:==~==~==>=========~========~~r=~,+--inertgas
from cy linder
regulator

double
1
vacuum
tubing bubbIer
manifold
~vacuum

solvent tubing
traps

rotary pump
Figure 3.7
Although it is preferable for workers to have their own individual
manifold, in some labs this may not be possible, because of insufficient
fume cupboard space or lack of pumps. In this case, manifolds can be
treated as communal items of equipment, but discipline must be observed to
keep the manifold clean and avoid cross-contamination.
Another type of manifold which is useful for carrying out reactions
under inert atmosphere is the 'spaghetti tubing' manifold (Fig. 3.8). This is
24 Equipping the Laboratory and the Bench

a single barrel inert gas manifold, fitted with narrow bore Teflon tubing
outlets. Each outlet has a syringe needle attached which can be pushed
through a septum to provide an inert atmosphere within a flask. This type
of system is particularly useful for small scale work.

to bubbIer +- +- inert gas

+-- stopcock
(optional)

+-- syringe needle

(Luer fitting rernoved)

Figure 3.8
Full descriptions of how to use manifolds are given in Chapters 5 and
8.
Three-way Quickfit gas inlet T taps
A simple piece of equipment which is applicable to a variety of tasks is a 3-
way teflon tap connected to a Quickfit cone joint (Fig. 3.9).

2=~'~1 2=f'i
3.4 rnrn bore
stopcock
~ +- ~2~~40) 1.2 rnrn bore
stopcock
PTt +- B 14
(14/20)

Figure 3.9
These are so universally useful that we suggest you have at least three
of the B 14 size and two of the B24 size as part of your personal bench set.
They are particularly useful when used in conjunction with a double
manifold. With the inert gas from the manifold connected to the horizontal
inlet and the tap in position A (Fig. 3.10), areaction flask can be kept under
a slight positive inert gas press ure. If the gas flow is increased and the tap
is turned to position B, liquids can be introduced via the vertical inlet, whilst
maintaining an inert atmosphere (see Chapters 5 and 8 for more details).
 Equipping the Laboratory and the Bench 25

Another simple use is for connecting fIasks to a high vacuum system for
removal of last traces of solvent.

tap
position

position B position C

~r ~l-- ~l
flow through
tap

(a) (b) (c)

Figure 3.10

Filtering aids
Rapid filtration is often needed, and the speed of filtration is increased
dramatically by applying pressure or a vacuum. There are two types of one-
piece sintered funnels wh ich we find very useful, as shown in Fig. 3.11.
The parallel-sided type are constructed by fusing a circular sinter into the
appropriate diameter glass tubing, which is then joined to a cone joint and a
piece of narrow-bore tubing (about lOmm od). It is useful to have two or
three of these in the bench kit, ranging in diameters of between 1 and 10cm.
The larger ones are particularly valuable for filtering off drying agent,
leaving the the dried solution in a round-bottom fIask, from which solvent
can be evaporated directly. One or two of the smaller Hirsch-style funnels
are useful and these are more commonly used for filtering off crystals after
small-scale recrystallizations, the mother liquor being conveniently
deposited in a round-bottom fiasko These can be made starting from a
sintered funnel, but a glassblower can make them more cheaply by inserting
a circular sinter into a narrow tube, then forming the funnel from this.
Two other pieces of equipment of value as filtration aids are the Craig
tube (Fig. 3.12a, see Chapter 9), used for very small recrystallizations, and
a sintered funnel (Fig. 3.12b) for filtration under inert atmosphere (see
Chapter 5 for more details).
26 Equipping the Laboratory and the Bench

+ - - C-----+

A------+ 1D

"""""""'"
1
1·····1
E

1
A B C D E
size 1 5em 4em size 1 5em 5em 5.5em
size 2 7.5em 4em size 2 7.5em 7em 5.5em
size 3 lOem gem 5.5em
Figure 3.11

B14

i~ ~ I
(14/20)

12em
lOem '\. solid

1
glass

1
+- glass
tubing +--- porosity 3
sinter

+-- PI'FE

(a) Craig tuhe (b) inert atmosphere filter

Figure 3.12
 Equipping the Laboratory and the Bench 27

Glassware for chromatography

Flash chromatography (see Chapter 9) is probably the most effective method
available for rapid routine purification and separation of reaction products.
To gain expertise in flash chromatography it is asound idea to have a
familiar set of columns on hand, and it is useful to have a set of about five,
ranging in diameter from about 5mm to 50mm, as part of the bench kit (Fig.
3.13b). A convenient length for all columns is 25cm, except for those with
a very narrow bore, which can be shorter. Reservoirs will also be required
for flash chromatography, 250ml, 500ml, and 1 litte being useful sizes
(Fig.3.13c). Another useful item is a simple 'flash valve' (Fig. 3.13a) that
will limit the pressure applied to the column, thus making the operation safer
by reducing the possibility of column fracture. All this equipment is
described in more detail in Chapter 9.

+-824
(25/40)

+-B24

1
(25/40)

25cm

+-500ml

+-Teflon
stopcock

(a) flash valve (b) flash column (c) reservoir

Figure 3.13
 CHAPTER 4

Purification and Drying of Solvents

4.1 Introduction
The use of appropriately purified solvents is vital to the success of the
procedures for which they are used. It is important to note that the degree of
purity and dryness required depends on the intended application, so when
choosing a method from this chapter remember to pick one which is
appropriate for your purpose. Consult Appendix 1 for useful data about
commonly used organic solvents.
Remember that solvents are hazardous materials and
beware particularly of the flammability of the hydrocarbons
and ether, the toxicity of benzene, chloroform, and carbon
tetrachloride, and the possibility of peroxide contamination of
ethereal solvents.

4.2 Purification of solvents

The most commonly used grade of solvent is 'reagent grade' which typically
means 97-99% purity with small amounts of water and other volatile
impurities as listed in the specification. This is adequate for use in
extractions and in many chemical reactions. However, some applications
are more demanding and require either the use of commercial solvents of
higher purity, or the purification of commercially available products.
Notable examples inc1ude the following.
1 . Reactions involving strongly basic organometallic compounds, e.g.
Grignard reagents, organolithiums, and metal hydrides, require the use
of carefully dried solvents. Anhydrous solvents « 50ppm of water)
 Purification and Drying of Solvents 29

are available but they are more expensive and less reliable than solvents
dried by the techniques described below.
2. Solvents used for spectroscopy, especially nmr and uv, should be of
high purity. Many suppliers provide 'spectroscopic grade' solvents
which are particularly suitable for uv spectroscopy because ultraviolet
absorbing impurities have been removed.
3. Solvents used for chromatography should always be fractionally
distilled to ensure that non-volatile impurities are removed. Solvents
for hplc should be of high purity and again many suppliers provide
special'hplc grade' solvents, wh ich have been purified and filtered to
remove contaminants which might degrade hplc columns.
4. All applications involving quantitative analysis require the use of
'analytical grade' (typically >99.5% purity) solvents. It is good
practice in general to use high quality solvents for the purification of
your products, and it is particularly important to use pure solvents
when purifying sampies for microanalysis.
In most cases purification of a solvent simply involves drying and
distilling it, so the next sections are devoted to drying agents and methods
used for drying common solvents, and the final section contains
descriptions of typical continuous stills. Apart from water the only other
commonly encountered contaminant is peroxidic material formed by aerial
oxidation of ethereal solvents. Methods for dealing with these dangerous
impurities are described in the section on the purification of diethyl ether.

4.3 Drying agents

Drying agents fall into two broad categories, those used for preliminary
drying and the drying of extracts, and those used for rigorous drying. The
pre-drying agents are largely interchangeable with each other and the choice
is usually limited only by the chemical reactivity of some of the reagents.
Preliminary drying of solvents, prior to rigorous drying, is essential unless
the solvent already has a low « 0.1 %) water content. Of necessity the
reagents used for thorough drying are very reactive and they must be treated
with great care. In particular, it is important to make the right choice of
drying agent for the solvent in question, in order to avoid dangerous or
undesirable reactions between the solvent and the drying agent, and care
30 Purifieation and Drying of Solvents

must be taken to ensure the safe destruction and disposal of excess reagent
remaining in solvent residues.
When the solvent is to be distilled after standing over adesiccant, the
drying agent should be filtered off before distillation if it removes water
reversibly, e.g. by hydrate formation (MgS04, CaCI2), or by absorption
(molecular sieves). The solvent can be distilled without removal of the
desiccant in cases where water removal is irreversible (CaR2, P20s).
The recommendations in this and the following section are largely
based on the work of Burfield and Smithers et al. who have carried out
quantitative studies on the efficiency of drying agents for a wide range of
solvents. 1 Their work has supplanted earlier studies many of which are of
doubtful reliability. ether useful sources of information inc1ude Perrin and
Armareg02, and Riddick, Bunger, and Sakano.3
Alumina, Al203
Neutral or basic alumina of activity grade I is an efficient drying agent for
hydrocarbons, 5% w/v loading giving extremely dry solvents. It is also
useful for the purification of chloroform.
Barium oxide, BaO
The commercially available anhydrous product is an inexpensive drying
agent which is useful for amines and pyridines (30-50ppm after standing for
24h over 5% w/v). It is strongly basic and is ineffective for alcohols and
dipolar aprotic solvents.
Boric anhydride, Bz03
Recommended drying agent for acetone, and effective also for thorough
drying of acetonitrile.
1. (a) D.R Burfield, K.H. Lee, and RH. Smithers, J. Org. ehern., 1977,42, 3060; (b)
D.R Burfield, G.H. Gan, and RH. Smithers, J. Appl. ehern. Biotechnoi., 1978,
28, 23; (e) D.R Burfield and RH. Smithers, J. Org. ehern., 1978, 43, 3966; (d)
D.R Burfield and RH. Smithers, J. ehern. Technol. Biotechnoi., 1980, 30, 491; (e)
D.R Burfield and RH. Smithers, and A.S.C. Tan, J. Org. ehern., 1981,46,629;
(f) D.R. Burfield and RH. Smithers, J. ehern. Educ., 1982,59,703; (g) D.R
Burfield and RH. Smithers, J. Org. ehern., 1983,48,2420.
2. D.D. Perrin and W.L.F. Armarego, Purification o[Laboratory Chemieals, 3rd ed.,
Pergamon, Oxford, 1988.
3. J.A. Riddiek, W.B. Bunger, and T.K. Sakano, Organic Solvents. Physical Properties
and Methods o[ Purification, 4th ed., Wiley-Interscienee, New York, 1986.
 Purification and Drying of Solvents 31

Calcium chloride, CaCl2

Both the powder and pellet forms are effective for pre-drying hydrocarbons
and ethers. It reacts with acids, alcohols, amines, and some carbonyl
compounds.
Calcium hydride, CaH2
The reagent of choice for rigorous drying amines, pyridines, and HMP A,
and effective also for hydrocarbons, alcohols, ethers, and DMF. It is
available in powdered or granular form, the granular is preferable if it is to
be stored for any length of time. The granules should be crushed
immediately before use and residues should be destroyed by careful
addition of water (H2 evolution).
Calcium sulphate, CaS04
Available as 'Drierite', it is only suitable for drying organic extracts. The
blue self-indicating version should not be used to dry liquids because the
coloured compound may leach into the solvent.
Lithium aluminium hydride, LiAIH4
Although widely used for drying ethers, it is less effective than other
methods and is extremely dangerous.
Its use is strongly discouraged.
Magnesium, Mg
Recommended for methanol and ethanol.
Magnesium sulphate, MgS0 4
The monohydrate is fast acting and has a high capacity (forms a
heptahydrate), making it the desiccant of choice for organic extracts. It is
slightly acidic so care is required with very sensitive compounds. It is not
efficient enough to be useful for pre-drying.
Molecular sieves
These are sodium and calcium aluminosilicates which have cage-like crystal
lattice structures containing pores of various sizes, depending on their
constitution. They can absorb small molecules, such as water, which can fit
into the pores. The most commonly used types 3A, 4A, and 5A have pore
sizes of approximately 3Ä, 4Ä, and 5Ä respectively, and they are available
in bead or powder form. After activation at 250-320°C for a minimum of 3h
they are probably the most powerful desiccants available1(b). They can be
32 Purification and Drying of Solvents

stored in a desiccator or in an oven at >lOO·e for a few weeks but they are
rapidly hydrated in the air. If you are doubtful about the effectiveness of an
old batch, place a few beads in the palm of your hand and add a drop of
water - if the sieves are active you should feel a distinct1y exothermic
reaction. In most cases extremely dry solvent can be obtained simply by
batchwise drying over sieves, i.e. aIlowing the solvent to stand over 5%
w/v of sieves for 12h, decanting, adding a second batch of sieves etc.
Sieves absorb water reversibly so a solvent should always be decanted from
the sieves prior to distillation. 4A Beads are recommended for thorough
drying of amines, DMF, DMSO, and HMPA, and almost all rigorously
dried solvents are best stored over 5% w/v of 4A sieves. However,only
the 3A form is suitable for drying acetonitrile, methanol, and ethanol, and
higher alcohols require the use of powdered 3A sieves. They are not useful
for drying acetone because they cause self-condensation. Provided that they
are not discoloured, sieves can be reused by washing weIl with a volatile
organic solvent, allowing to dry, drying at lOO·C for several hours, and
then reactivating at 300·C.
Plwsphorus pentoxide, P20S
(Causes burns) Although a rapid and efficient desiccant its use is
limited by its high chemical reactivity. It reacts with alcohols, amines,
acids, and carbonyl compounds and causes significant decomposition of
HMPA, DMSO, and acetone. It is useful for drying acetonitrile and may be
used for hydrocarbons and ethers but is less convenient than other reagents.
It is often used in desiccators. It is best decomposed by careful portionwise
addition to ice-water followed by neutralization with base (do not add water
to P20s, the mixture may become so hot that the vessel could crack). It is
extremely efficient for drying gases and is available in a convenient form,
mixed with an inert support, so that it does not become syrupy.
Potassium hydroxide, KOH
(Causes burns) Freshly powdered KOH is a good drying agent for
amines and pyridines but is inferior to calcium hydride. It should not be
used with base sensitive solvents.
Sodium, Na
Sodium is widely used to dry hydrocarbons and ethers. It may be formed
into wire using a sodium press or used as granules by cutting the bars under
 Purification and Drying of Solvents 33

petroleum ether. It suffers from the disadvantage that the metal surface
rapidly becomes coated with an inert material so it should not be used unless
the solvent is pre-dried. Sodium reacts with benzophenone to give a dark
blue ketyl radical which is protonated by water to give colourless products.
Thus the sodium-benzophenone system is particularly convenient because it
is self-indicating, and it is the preferred reagent for rigorous drying of ether,
THF, DME, and other ethereal solvents. Sodium-potassium alloy has been
recommended because it is liquid and therefore its surface does not become
coated so easily, but this advantage is outweighed by the increased danger
resulting from the use of potassium. Sodium residues can be destroyed by
slow careful addition of ethanol until hydrogen evolution ceases. The
mixture should then be stirred weIl, to ensure that no coated lumps of
sodium remain, before carefully adding methanol. After leaving for several
hours the mixture should be stirred again to ensure that all of the sodium has
been consumed, and then the mixture should be added cautiously to a large
excess of water before disposal.
Sodium should never be added to chlorinated solvents
because a vigorous or explosive reaction could occur.
Sodium sulphate, Na2S04
Anhydrous sodium sulphate is a weak drying agent suitable only for drying
extracts. It is preferable to magnesium sulphate for drying very acid
sensitive compounds.

4.4 Drying of solvents

Solvents may be dried in individual batches using conventional distillation

apparatus (Chapter 9), but it is more convenient to dry common solvents
such as dichloromethane, ether, and THF in continuous stills (Section 4.5).
In either case the solvent must be protected from moisture using an inert
atmosphere (nitrogen or argon). Rigorously dried solvents must be stored
under an inert atmosphere and handled using syringe or cannula techniques
(Chapter 5).
Acetone
Acetone is completely miscible with water and its susceptibility to acid and
base catalysed self condensation makes it particularly difficult to dry. Good
results are obtained by drying over 3A sieves (10% w/v) overnight (any
34 Purification and Drying of Solvents

longer causes significant condensation), stirring over boric anhydride (5%

w/v) for 24h, and then distilling 1(c). Distillation after 24h over boric
anhydride or 6h over 3A sieves provides material which is adequate for
most purposes.

Aceticacid
(Causes bums) Acetic acid is very hygroscopic. It can be dried by
adding acetic anhydride (3% w/v) and distilling (b.p. 118°C). Reagent
grade acetic acid usually contains some acetaldehyde. If this is likely to
cause problems add chromium trioxide (2% w/v) as wen as acetic anhydride
before distilling, or use analytical grade material.

Acetonitrile
(Toxic) Preliminary drying is accomplished by stirring over potassium
carbonate for 24h. A further 24h over 3A sieve or boric anhydride gives
moderately dry solvent (- 5Oppm) but much better results are obtained by
stirring over phosphorus pentoxide (5% w/v) for 24h. and then distilling 1(a).
Drawbacks of this method are the formation of substantial quantities of
coloured residue, and the possibility that the product is contaminated with
traces of acidic impurities. If the acetonitrile is required for use with very
acid sensitive compounds it is best to redistil it from potassium carbonate.

Ammonia
Distil from the cylinder into a flask cooled to <-40°C and fitted with a dry-
ice condenser (Chapter 14). Add pieces of sodium until the dark blue colour
persists, and then distil the ammonia into your reaction vessel.

Benzene
(Carcinogenic) Benzene, like most hydrocarbons is very easy to dry.
No preliminary drying is required and several reagents will reduce the water
content to < Ippm. Alumina, calcium hydride, and 4A sieves (all 3% w/v
for 6h) are the most convenient drying agents and the benzene is then
distilled and stored over 4A sieves 1(a). Altematively benzene may be dried
over calcium hydride in a continuous still. Toluene may be dried in the
same way.
 Purification and Drying of Solvents 35

tert-Butanol
Reflux over calcium hydride (5% w/v) and distil onto powdered 3A
sieves 1(g). Other low molecular weight alcohols, but not methanol, can be
dried in this way.
Carbon disulphide
(Highly flammable, toxic) Distil (using a water bath) from calcium
chloride or phosphorus pentoxide (2% w/v). Do not use sodium or
potassium.
Carbon tetrachloride
(Carcinogenic) See chloroform.
Chlorobenzene
See dichloromethane
Chloroform
(Toxic) Perhaps the simplest procedure is to pass the chloroform through
a column of basic alumina (grade I, lOg per 14mi). This removes traces of
water and acid and also removes the ethanol which is present as astabiliser.
Carbon tetrachloride may be purified in the same way. Larger volumes of
either solvent can be dried with 4A sieves, or by distillation from
phosphorus pentoxide (3% w/v). Distilled chloroform should be stored in
the dark to prevent formation of phosgene.
Addition of sodium to chloroform or carbon tetrachloride
may cause an explosion. Chloroform mayaiso react
explosively with strong bases and with acetone.
Cyclohexane
See petroleum ether.
Decalin (decahydronaphthalene)
Decalin is very easy to dry but it forms peroxides on prolonged contact with
air so it is advisable to use a drying agent which will reduce the peroxides.
Reflux over sodium for 2h and distil onto 4A sieves. Tetralin should be
treated similarly.
l,2-Dichloroethane
See dichloromethane.
36 Purification and Drying of Solvents

Dichloromethane
Reflux over calcium hydride (5% w/v) and distil onto 4A molecular sieves.
Chlorobenzene and 1,2-dichloroethane can be dried in the same way.
Dichloromethane can be dried over calcium hydride in a continuous still.
Never add sodium or powerful bases to chlorinated
solvents - an explosion may occur. Reaction of azide saUs
with dichloromethane resuUs in the formation of explosive
azides.
Diethyl ether (ether)
(Flammable) Ether itself, along with the other commonly used ethereal
solvents, THF, DME, and dioxan, can contain substantial amounts of
peroxides formed by exposure to the air. These peroxides can cause
serious explosions. Test for the presence of peroxides by adding Iml
of the solvent to Iml of a 10% solution of sodium iodide in acetic acid. A
yellow colour indicates the presence of low concentrations of peroxides
whereas a brown colour indicates high concentrations. Low concentrations
of peroxides must be removed before further purification and a number of
methods have been suggested4 • One frequently recommended procedure is
to shake the solvent with concentrated aqueous ferrous sulphate. Ethers are
usually pre-dried over calcium chloride or sodium wire, and rigorously
dried over sodium-benzophenone. Careful preliminary drying is necessary
because all of these solvents can dissolve substantial quantities of water.
The pre-dried solvent is then placed in a reflux apparatus or a continuous
still and sodium pieces (1 % w/v) and benzophenone (0.2% w/v) are added.
The mixture is refluxed under an inert atmosphere until the deep blue colour
of the ketyl radical anion persists. The ether may then be collected or
distilled onto 4A sieves. This drying method also removes the peroxides
wh ich are a serious hazard when handling ethereal solvents. If a continuous
still is used it will be necessary to add more sodium and benzophenone
occasionally. Eventually the still will become very murky as the
benzophenone reduction products accumulate. If this happens, or if the blue
colour no longer persists, it is time to distil most of the solvent - do not distil
to dryness. The sodium residues may then be destroyed as described in
4. D.R. Burfield, J. Org. ehern., 1982,47,3821.
 Purification and Drying of Solvents 37

Seetion 4.3. Purified ethers are very susceptible to peroxide fonnation, so

they should be stored in dark bottles under an inert atmosphere, and they
should not be kept for more than a few weeks.
1,2-Dimethoxyethane (DME)
See diethyl ether.
Dimethylformamide (DMF)
Stir over calcium hydride or phosphorus pentoxide (5% w/v, overnight),
filter, and distil (56°C at 20mmHg) onto 3A sieves 1(c). If phosphorus
pentoxide is used a second distillation from potassium carbonate may be
necessary. Alternatively, sequentially dry over three batches of 3A sieves
(5% w/v, 12h ).
Dimethyl sulphoxide (DMSO)
Distil (75°C at 12mmHg) discarding the first 20% and sequentially dry with
two batches of 4A sieves (5% w/v, 12h)1(c). Store over 4A sieves.
Dioxan
See diethyl ether.
Ethanol
Distil absolute alcohol from magnesium (as described for methanol) onto 3A
molecular sieve powder or sequentially dry over two batches of 3A sieve
powder (5% w/v, 12h)1(g).
Ether
See diethyl ether.
Ethyl acetate
Distil from potassium carbonate onto 4A sieves.
Hexamethylphosphoric triamide (HMPA)
(Carcinogenic) HMPA is very difficult to dry and even when stored
over 4A sieves it needs to be dried afresh within a couple of weeks. Dry
HMPA can be obtained by distilling (89°C at 3mmHg) from calcium hydride
(10% w/v) onto 4A molecular sieve (20% w/v)l(c).
Hexane
See petroleum ether.
38 Purification and Drying of Solvents

Methanol
(Toxie) To dry llitre of methanol place magnesium turnings (5g) and
iodine (0.5g) in a 2 litre flask fitted with a reflux condenser and add
methanol (50ml). Warm the mixture until the iodine disappears, and if a
stream of bubbles (hydrogen) is not observed add more iodine (0.5g).
Continue heating until all of the magnesium has been consumed and then
add the remainder of the methanol. Reflux the mixture for 3h , distil
(bumping) onto 3A sieve beads (10% w/v), and allow to stand for at least
24h 1(g).
Nitromethane
Dry by standing over calcium chloride, filtering, and distilling onto
molecular sieves. Do not use phosphorus pentoxide.
Pentane
See petroleum ether.
Petroleum ether (petrol)
(Flammable) This confusing name is used for mixtures of aliphatic
hydrocarbons containing smaller amounts of aromatic compounds. It is
generally supplied as several fractions each having a 20'C boiling range (40-
60, 60-80 etc.). Alkane mixtures which do not contain aromatic compounds
are supplied as pentane, hexane, cyc10hexane etc. All of these solvents are
readily drled by distilling, and standing over activity grade I alumina (5%
w/v), or over 4A molecular sieves.
Pyridines
(Toxie) Distil from calcium hydride onto 4A molecular sieves 1(e).
Tetrahydrojuran (THF)
See diethyl ether.
Tetralin (tetrahydronaphthalene)
See decalin.
Toluene
See benzene.
Xylene
See benzene.
 Purification and Drying of Solvents 39

4.5 Solvent stiIIs

There are two main types of solvent still that are commonly employed in
organic research laboratories. One is the classical distillation set-up
consisting of distillation pot, still-head, thermometer, condenser, receiver-
adapter, and collection vessel. This arrangement is described in more detail

condenser_

collecting pot-

solvent
outlet

/
heating

'"
mantle

..A
~

Figure 4.1
40 Purification and Drying of SoIvents

in Chapter 9, and is used for the distillation of solvents that are either
required infrequently, or that can be stored without deterioration for long
periods of time. The other is a continuous still set-up that consists of a
distillation pot, collecting head, and condenser (see Fig. 4.1).
This type of still arrangement is used for solvents that are required on a
regular basis and the still system is usually left set up, although generally it
is only turned on when the solvent is required - it is not recommended that
any type of solvent still is left on unattendedfor prolonged periods oftime .
Continuous still systems typically have an upright arrangement that
takes up less space than the conventional still set-up and a collecting vessel
that is positioned between the still-pot and the condenser. The apparatus is
designed such that the distilling solvent is condensed and collects in a
collecting head. Once the collecting head is full the solvent simply
overflows back into the still pot, allowing continuous distillation without the
still boiling dry. The solvent can simply be drawn off from the collecting
head when required, or poured back into the still pot if not.

round-bottomed
flask

3-way tap

~
- collecting head

glass tube with

- male joint

Figure 4.2
 Purification and Drying of Solvents 41

A typical design for the continuous still collecting head is outlined in

Fig. 4.2, and can be simply constructed from a round-bottom flask, ground
glass cone, 2-way tap, and 3-way tap. The 2-way tap allows the solvent to
be withdrawn via syringe which is particularly convenient for anhydrous
solvents. The 3-way tap allows the solvent to be collected, drawn off, or
poured back into the distillation pot. Obviously the size of the still depends
upon the quantity of solvent required, however the still head should always
be smaller in capacity than the still pot, so as to avoid the possibility of the
still boiling dry.
When setting up a continuous still it is necessary to ensure that the
solvent condenser is efficient, usually a double walled condenser is required
(see Chapter 9), this is especially true for the lower boiling solvents. Also,
all ground glass joints should be fitted with teflon sleeves to ensure a good
seal, and prevent jamming. It is inadvisable to use grease on the joints since
this will be leached out by the hot solvent, contaminating the solvent and
causing the joints to stick. Similarly teflon taps are to be preferred over
glass taps in the collecting head.
If an inert atmosphere is required for the solvent distillation, as is often
the case for anhydrous solvents, then the continuous still system requires to
be connected to a nitrogen or argon line (see Chapter 8). It is important
when using such lines, you ensure that oil bubblers or similar devices do
not suck back when the still is cooling. This often happens as a result of the
gas volume of the still contracting as it cools, which creates a partial vacuum
in the system. It is simply remedied by turning up the flow rate of the inert
gas for the period whilst the still is cooling. It is also important that you do
not heat up the still system without some mechanism for allowing the
increase in gas volume to be released otherwise an explosion may result; this
is prevented by incorporating an oil bubbler in the gas line (see Chapter 8).
The design of collecting heads can vary, for instance they can also be
constructed using a conical flask instead of the round-bottom flask (Fig.
4.3a). Also, a more complex arrangement (Fig. 4.3b) incorporating a
condenser to cool the distillate (particularly useful for high boiling solvents)
is often used. This system also has the advantage of less ground glass
joints in the set-up, although this can make cleaning the still head more
difficult.
42 Purification and Drying of Solvents

(a) (b)
Figure 4.3
 CHAPTER 5

Reagents: Purification and Handling

5.1 Introduction
One of the key steps to becoming a successful practitioner of modern
organic chemistry is knowing how to handle and store air- and moisture-
sensitive reagents, with the certainty that they have not been contaminated.
This is a skill which takes some time to acquire and many people
unfortunately learn the hard way, after astring of failed reactions. An
efficient, successful organic chemist achieves good results rapidly, not by
cutting corners, but by rigidly observing strict working practices that allow
sensitive reagents to be used with confidence. The biggest waste of
research time sterns from employing reagents or procedures which you think
are 'OK'. It will usually take far more time to repeat areaction than it would
have taken to re-purify a suspect reagent before starting. Perhaps more
important than the time was ted by failed reactions, is the uncertainty which
is introduced by using suspect reagents. No matter how carefully the
outcome of an experimental reaction is quantified, in terms of yield,
stereoselectivity, by-products, etc., the data will be meaningless if there was
any uncertainty about the re action conditions or reagents.
Handling sensitive reagents confidently is not difficult once a few
standard techniques are learned and adhered to. In this chapter we will give
examples of simple general methods which can be employed to handle a
variety of reagents.
44 Reagents: Purification and Handling

5.2 Classification of reagents for handling

The methods used to handle a particular reagent will be dependent on the

properties of that reagent and you should be fully conversant with these
before you start work. If you are working with areagent and you are not
familiar with its properties, you should look them up, or consult someone
who is familiar with them, before you begin. This is very important, if you
are to use the reagent effectively, without causing a hazard to you and others
around you. Once you are conversant with the properties of a particular
reagent, the handling requirements are largely a matter of common sense.
For example, it is clearly unnecessary to rigorously exclude atmospheric
moisture from areagent which is to be reacted in aqueous solution, but it is
important if the reagent is pyrophoric! Most reagents fall into one of the
four categories below.
Stahle rum-toxie reagents
Reagents which are neither sensitive to the atmosphere nor toxic are
normally stored in ordinary bottles on the shelf and they are usually easy to
handle. However, if you are going to use this type of reagent for reactions
with air sensitive materials, they must also be dry and be stored with the
atmosphere excluded! It is no use setting up an anhydrous reaction very
carefully, then adding areagent straight from an unsealed bottle on the shelf.
Stahle reagents whieh are toxie or have an unpleasant odour
These should be treated in the same way as those in the previous category,
except that special precautions should be taken to avoid their escape into the
lab. They should always be used in a fume cup board and stored in a
ventilated storage cupboard.
Reagents whieh will deeompose on exposure to moisture or air
These reagents should always be stored in special containers, under a dry
inert atmosphere. Whenever they are used, they should be measured and
transferred using techniques which constantly maintain the inert atmosphere.
Some of these techniques will be described below.
Reagents whieh deeompose explosively or pyrophorieally on exposure to
moisture or air
These should be treated as above, but extra care should be taken, especially
when dealing with residues once the reaction is over.
 Reagents: Purification and Handling 45

5.3 Techniques for obtaining pure and dry reagents

Before using any organic reagent or starting material for areaction its purity
should be checked. It should not be taken for granted that areagent is pure
simply because it has been obtained from a commercial source. Indeed the
specification of many commercial compounds is much less than 100% and
this should always be checked. Even if the specified purity of the reagent is
high, at least one analytical check should also be carried out, such as tlc, gc
or nmr. This check is particularly important if you are attempting new
reactions. If the purity of the reagent is not up to the level required,
standard purification techniques (distillation, recrystallization,
chromatography, sublimation etc.) should be used to purify it (see Chapter 9
for more details).
Remember that any reagent which is to be used in areaction under inert
conditions with sensitive reagents, must also be dried very carejully!
Once you have gone to the trouble of purifying and drying areagent, it
is good practice to store it very carefully in order to keep it dry for future
use. This normally means storing it in a sealed container, under an inert
atmosphere. When you keep reagents in this way, you must be able to rely
on their purity and it is therefore best to keep them for your own personal
use. Remember that a person who has not gone to the trouble of purifying a
reagent is not likely to take good care ofyours!
In this section we will describe some typical techniques for purification
and drying of reagents. There are several other more specialized texts which
should be consulted if you need to purify other reagents. 1,2,3

5.3.1 Purification and drying ojliquids

For most liquids the method of choice for both purification and drying is
distillation. In many cases the liquid is either dried over a drying agent
before distillation or distilled from a drying agent (see also Chapter 4).
1. Purification of Laboratory Chemieals, 3rd ed., D.D. Perrin and W.L.F. Armarego,
Pergamon Press, Oxford, 1988.
2. Reagentsfor Organic Synthesis~ Vols. 1-13, Fieser and Fieser, Wiley, New York.
3. Organic Synthesis, Col. Vols. 1-6, Wiley, New York.
46 Reagents: Purification and Handling

Distillation under inert atmosphere at normal pressure

This technique is used to purify andlor dry most liquid reagents which boil
at less than about 150·C, at atmospheric pressure. Typically the liquid is
pre-dried by shaking over magnesium sulphate, then decanted onto a more
active drying agent, such as powdered calcium hydride, from which it is
distilled. 1t is important to make sure that the drying agent does not react
with the liquid. If you require a dry reagent, it is useless to carry out the
distillation in the atmosphere, and the process must be carried out under
argon (or nitrogen). For ease and reliability we suggest that a one-piece
distillation apparatus is used for this type of distillation, in conjunction with
a double manifold; the technique is fully described in Chapter 9, Section
9.4.2.
When the distillation is complete remove the collector, seal it quickly
with a septum and purge the bottle with inert gas. For compounds which
react with rubber, such as Lewis acids, a Teflon stopper should be used.
Some of the less sensitive reagents can simply be poured into areagent
bottle before it is sealed, provided this is done quickly. However, if the
reagent is particularly sensitive to air or moisture (such as a Lewis acid), a
cannulation technique should be used to transfer it. See Section 5.4.1 for
more details about storage and transfer of reagents under dry, inert
conditions. Whatever type of container is used for storage it is always
preferable that it be full, or nearly so.
Table 5.1
Reagent Drying agent b.p:C Comment
Methyl iodide CaCl2 before dist. 43 Very toxic! Wash with
Na2S203 or pour through
alumina ftrst to remove 12
Diisopropylamine dist. from CaR2 84
Triethylamine dist. from CaR2 89
lsobutyraldehyde CaS04 before dist. 62 readily oxidized
Titanium tetrachloride none 136 very reactive with moisture
Cyclohexene dist. from Na 83 wash first with NaRS03
to remove peroxides
Crotonaldehyde CaS04 before dist. 104 use vigreux
 Reagents: Purification and Handling 47

Distillation under reduced pressure

For liquids with a high boiling point, or which decompose on heating,
distillation under reduced pressure is the usual method of purification.
Again it is convenient and effective to use a one-piece distillation apparatus
in conjunction with a double manifold for this type of distillation. The
procedure is described in more in Chapter 9, Section 9.4.2.
When the distillation is complete the heat is turned off and the two-way
tap on the double manifold is slowly turned to the inert gas position. The
flask containing the distillate will then be conveniently under an inert
atmosphere and should be quickly removed and fitted with a tightly fitting
septum (see Section 5.4.1 for more details about storing and transferring
reagents under inert conditions).
Table 5.2

Reagent Drying agent b.p.oC/mm Comment

Dimethyl formamide MgS04 before dist. 76'/39 do not use CaH2 or other
basic drying agents
BF3·Et20 dist. from CaH2 67'/43 reacts with moisture
SnCl4 dist. from tin high vac. reacts with moisture
Et2AlCI dist. from NaCI 107'/25 heated nichrome spiral in
50cm column; Reacts
with air - spontaneously
flammable!
Et3Al none 130'/55 ibid.
Benzaldehyde MgS04 before dist. 62'/10 wash with Na2C03before
dist. Store over
0.1 % hydroquinone
Benzyl bromide MgS04 before dist. 85'/12 dist. in dark. lacrymator

Some special cases Jor drying oJ liquids

There are a number of liquid reagents which hydrolyse when they come in
contact with water and subsequently contain the hydrolysis product, which
is usually an acid. These reagents are distilled from a high-boiling amine, or
other base, so that any acidic impurity is removed. It is always important
that the distillation is carried out under inert atmosphere (or under reduced
48 Reagents: Purification and Handling

pressure) and the techniques are exactly as above. Some examples are given
in Table 5.3.
Table 5.3
Reagent Distil from b.p.oC Comment

Acetic anhydride quinoline 138 10:1 with quinoline

Acetyl chloride quinoline 52 10:1 with quinoline
Me3SiCI* quinoline 106 10:1 with quinoline
(Chloro trimethyJsilane)

*Another method for removing HCI from trimethylsilyl chloride (chlorotrimethyl

silane) is to add it to an equal volume of triethylamine in a centrifuge tube, sea1ed under
argon with a septum. After centrifuging, triethylamine hydrochloride forms asolid
precipitate and the liquid can be drawn off by syringe and used for most purposes as 50%
Me3SiCl.
Details about how to store and handle liquid reagents under dry and
inert conditions are given in Section 5.4.1.

5.3.2 Purifying and drying solid reagents

If the purity of the reagent is not up to the level required, standard solid
purification techniques (chromatography, recrystallization, sublimation)
should be used to purify it (see Chapter 9 for more details).
Remember that if asolid re agent is to be used in areaction under inert
conditions with sensitive reagents, it must be dried very carefully. For bulk
drying of solids an oven is often used (preferably a vacuum oven), or the
solid is placed in a vacuum desiccator over a drying agent (P205, H2S04,
etc.). If the reagent is to be stored, for future use in reactions under inert
conditions, it should be kept under argon (or nitrogen), in a sealed bottle, to
prevent exposure to moisture. Small quantities of solid can often be dried in
the reaction fIask, prior to the apparatus being set up. This is conveniently
done by connecting the dried fIask, containing the solid, to the double
manifold, evacuating under high vacuum for several hours, then introducing
argon (or nitrogen).
 Reagents: Purification and Handling 49

Purification of some common solid reagents

AIBN ( a, a'-Azobis(isobutyronitrile))
Recrystallize from ether and dry under vacuum, over P20S at room
temperature. Store under inert atmosphere, in the dark, at -10°C.
Para-toluenesulphonyl chloride
Para -toluenesulphonyl chloride often contains a considerable quantity of p-
toluenesulphonic acid. This can be removed by placing the reagent in the
thimble of a soxhlet apparatus containing dry petroleum ether. After several
hours of extraction under an inert atmosphere, the chloride will have
dissolved in the solvent and the unwanted acid will be left behind in the
soxhlet thimble. On cooling the solvent mixture, the acid chloride
crystallizes and can be collected by filtration. The purified material should
be stored under an inert atmosphere.
Copper(l) iodide (Jor the preparation of cuprate reagents)
Impure copper iodide is often slightly brown due to the presence of iodine
and copper(II) salts. It is very important that these contaminants are
removed and that the reagent is dried efficiently if it is to be used in the
preparation of copper-lithium reagents. This is accomplished by placing the
material in the thimble of a soxhlet apparatus and extracting with methylene
chloride for several hours (usually overnight) until no further colour is being
removed. The almost white reagent is then dried under vacuum and stored
under argon (or nitrogen) in a dark bottle, sealed with parafilm.
Magnesium (Jor Grignard reactions etc.)
Wash with ether, to remove grease from the surface of the metal, dry at
100°C under vacuum and cool in a desiccator. For a more active form of
magnesium, stir the turnings under nitrogen overnight. They will turn
almost black as the oxide coat is removed from the surface. The material
produced is very active and should be stored under inert atmosphere.
Zinc
Zinc is normally coated with oxide, which must be removed prior to use.
This can be done by stirring with 10% HCI for 2 min, then filtering and
washing with water, followed by acetone. The metal can then be vacuum-
dried and kept under an inert atmosphere prior to use.
50 Reagents: Purification and Handling

5.4 Techniques for handling and measuring reagents

Although extreme care must be taken to exclude air and moisture from
reagents kept under an inert atmosphere, once you become familiar with the
simple techniques outlined in this section, you should find them easy to use.
Bottles and flasks containing liquids or solutions sealed under an inert
atmosphere are widely used in modern organic chemistry. A knowledge of
the techniques required to manipulate such reagents, without allowing them
to come into contact with the atmosphere, is therefore essential.
When handling air sensitive reagents always think ahead, and design
the whole sequence of events you intend to follow so that air never comes
into contact with the reagent.
A method for titration of alkyllithium reagents is given in Chapter 16
and a method for titration of hydride reagents is given in Chapter 6.

5.4.1 Storing liquid reagents or solvents under an inert atmosphere

After drying and/or distillation, reagents or solvents can be stored, under
argon, in a bottle or flask sealed with a septum. There are also many other
commonly used reagents that are extremely reactive towards water and/or
oxygen and these are stored in the same way. Examples of such reagents
are: alkYllithium reagents; Grignard reagents; organoboranes; metal
hydrides; organoaluminium compounds and Lewis acids. Some of these are
available commercially and are delivered under inert atmosphere in sealed
bottles. Less common reagents may be prepared in the lab and then stored
for future use. The seals of the commercially supplied containers have a
limited life-span and if one is suspect it should be replaced with a rubber
septum. For Lewis acids, which often react with rubber, a Teflon stopper
can be used. For storing small quantities of liquid under inert atmosphere
'mininert valves' are very useful. These screw threaded bottle caps
incorporate Teflon valves through which a syringe needle can enter the
container. They provide a better seal than ordinary septa (see Section 5.4.4
for more detail on the use of mininert valves).
To change or fit a septum
Choose a septum which fits tightly into the neck of the bottle that you wish
to seal. Fit a new septum as quickly as possible, minimizing exposure of
the reagent to the atmosphere. As soon as the septum has been fitted purge
 Reagents: Purification and Handling 51

the container with argon (or nitrogen). This is done using a syringe needle
connected to an inert gas manifold by a Luer adapter. Another needle is
used as a vent as shown in Fig. 5.1a. The septum should be secured with
copper wire and for extra protection another septum of the same size,
without any needle holes in it, can be pulled over the first (Fig. 5.1 band c).
The second septum. is removed before syringing liquid from the bottle. For
long term storage, it is also a good idea to wrap parafilm around the septum,
especially if the bottle is to be stored in the fridge.
inert---+
gas second
septum

"- ~-""

(b) (c)

(a)
Figure 5.1
If the septum has been fitted properly and the reagent is used carefully,
according to the techniques below, it can be kept for many months and used
many times over.
If you need to use areagent which has been stored in a fridge or
freezer, always allow it to warm up to room temperature and remove any
condensation, before unsealing it.

5.4.2 Bulk transfer of a liquid under inert atmosphere (cannulation)

As a general rule, never attempt to remove liquidfrom a container which is
sealed under inert gas, unless you have pressurized the container with inert
gas first (Fig. 5.2a). Also, whenever you are using ground glass joints
connected under pressure always secure them with either plastic (bibby)
clips, elastic bands or springs.
52 Reagents: Purification and Handling

General principle of cannulation and gas pressure adjustments

Cannulation is a very general procedure for the transfer of a liquid from one
container to another whilst maintaining an inert atmosphere. The principle
of cannulation is very simple. A positive pressure is applied to the flask
from which the liquid is to be transferred. This pressure forces the liquid
out through a double ended needle (cannula) into the receiving flask (see
Fig. 5.3). In order for the liquid to flow, there must be some means by
which the gas in the receiving vessel can escape. The simplest way to allow
this to happen is to vent the receiving flask with a short needle passed
through the septum. It is good practice to connect the vent needle to a
bubbier to prevent suck back of air occurring.
It is is quite common that the flask into which you need to cannulate the
liquid is already part of an inert gas system and can not simply be vented.
In this ca se the pressure applied to the first flask must be higher than the
pressure in the receiving flask if the liquid is to flow and there must be some
means by which gas can escape from the receiving flask. All inert gas
systems should incorporate a bubbier (for example, see Fig. 3.7) and this
automatically provides a means of escape for gas which is displaced from
the receiving flask. To create a higher pressure in the delivery flask, the
inert gas inlet could, in principle, be connected directly to a cylinder outlet.
However, it is preferable to incorporate a bubbier into this line also. The
rate of flow of liquid during cannulation will be governed by the pressure in
this gas line and it can easily be controlled by restricting the vent of the
bubbier with a finger. For more precise control of pressure the vent can be
restricted by connecting a Rotaflow tap or needle valve to it (see Fig. 5.2).
General procedure for cannulation
The following procedure is a general method for transferring liquids by
cannulation and will be referred to in other seetions of the book.
1. Make sure the bottle or flask into which you are going to transfer the
reagent is thoroughly dry, fit a septum into the neck and purge with
inert gas as described in the previous section. If the container was oven
dried it is preferable to fit the septum whilst it is still hot and allow it to
cool as it is being purged with inert gas (Fig. 5.1 a).
2. When the bottle or flask is cool, make sure the septum is fitted tightly
and wire it on, then remove the vent before removing the argon line
 Reagents: Purification and Handling 53

(Fig.5.1b). The container now contains an inert atmosphere and is

ready for use.
3. Insert an inert gas line needle into the septum of the bottle or flask
containing the liquid to be transferred. If you are transferring liquid to
a flask that is already part of an inert gas system, a separate gas line
must be used to pressurize the bottle and a simple bubbler system is
recommended (Fig. 5.2a).

inert gas
from cylinder---+ c:::::::;-;::::c::::'-

restriet vent---+
with finger or
needle valve
to increase
press ure

--_ .......... _.... -

............
.......... - ........ .
-_ ... _...........
................ _-
(a) (b)
Figure S.2
4. Insert a double ended needle (cannula) into the bottle containing the
reagent, taking care not to push the needle below the surface of the
liquid. Check that the inert gas is flowing through the system and out
through the cannula (Fig. 5.2b).
5. Insert the other end of the cannula through the septum of the new bottle
or flask, then push the inlet end below the surface of the liquid in the
delivery flask. There should be no flow initially, because the receiving
container is sealed. Vent it by inserting a short needle through the
septum. The vent needle can be connected to a bubbler or an inert gas
system which incorporates a bubbier. If the liquid does not start to
flow, increase the press ure by restricting the vent of the inlet bubbier
using a finger, a septum or by connecting a needle valve (Fig. 5.3).
When argon is used it is normally safe to dispense with the bubbler
connected to the vent of the collecting flask.
54 Reagents: Purification and Handling

~vent to
inert gas bubbIer or
from cylinder--+ C::::::;:-;::::::::I:t:~ to inert gas
system that
restriet vent--+ incorporates
with fmger or a bubbIer
needle valve
to increase
pressure

_._ .. __ ....... _-
-_ ....... -_.
. . . . . . . . 0' ___ •
.....
:::::.'1;-::::.

Figure 5.3
6. When all the liquid has been transferred, first remove the vent needle,
then remove the cannula at the receiver end. The remainder of the
system can then be dismantled in any order, but remember to be very
careful with the residues, particularly if the liquid is toxic or reactive to
moisture.

5.4.3 Using cannulation techniques to transfer measured volumes of

liquid under inert atmosphere
The cannulation teehnique ean easily be adapted for measuring volumes of
liquid under inert atmosphere. It is mainly used for measuring quantities of
liquid that are too large to be conveniently handled by syringe (> 50ml), but
it is also suitable for measuring pre-cooled solutions without significant
warming. The cannulation technique is identical to that described in the
previous section, but an intermediary graduated container is used. The
graduated container can be a measuring cylinder with a neck that can be
fitted with a septum (Fig. 5.4a), or it can be a graduated Schlenk tube (Fig.
5.4b).
Dry the container and transfer the required quantity of liquid to it
according to the procedure described in Section 5.4.2.
Onee the required volume of liquid has been measured, remove the
needle from the storage bottle and insert it through the septum of a dry
receiving vessel that is filled with inert gas. Apply inert gas pressure to the
graduated cylinder and vent the receiving flask to deliver the liquid (Fig.
5.5, see also Chapter 8 for more details on setting up reactions).
 Reagents: Purification and Handling 55

--+ to bubbier
(or manifold) cannula inlet

i +- septum
+-stopcock
inert---+
gas
inert --+ fli.I-ft'I\)----.,.",..J
gas

............... __ ..
-- ---..........
.. ....... _........ -
_....
::_-::_-:;'::::-
-_ .. _--------
(b)
(a)
Figure 5.4
inert---+
gas

--+ to bubbier
(or manifold)

... =.....-
-_.=
Figure 5.5
If the liquid is being measured for addition to a reaetion flask, an
alternative proeedure is to use a graduated pressure equalizing dropping
funnel attaehed to the apparatus. The required quantity of liquid ean then be
eannulated into the dropping funnel direet1y.
56 Reagents: Purification and Handling

Types oj cannula
For most purposes cannulation can be carried out using an ordinary double
ended needle, bent to a suitable shape (Fig. 5.6a). A cannula made by
joining two long syringe needles to a Luer to Luer stopcock allows the flow
of liquid to be controlled (Fig. 5.6b). For tansferring large volumes of
liquid the 'flex-needle' (available from Aldrich Chemical Co.) is useful.
This is a jacketed Teflon tube with a wide-bore needle attached to either end
(Fig. 5.6c). It provides rapid liquid transfer, and a degree of insulation for
a cold reagent. The wide-bore needles of the flex-needle should not be
inserted through a new septum without first making a hole with anormal
gauge needle.

Luer to Luer
stopcock

long --+
needles Teflon inner
insulation tubing

+-- meta! needle

(a) (b) (c)

Figure 5.6
For small scale work all Teflon cannulas are very useful, and some
people prefer them to syringes. They are easily made by taking a piece of
narrow-bore (1.5mm) Teflon tubing, of a suitable length and cutting each
end at a shallow angle with a sharp razor blade or scalpel (Fig. 5.7).
Always be sure to make holes in the septa, using a metal needle, before
attempting to insert the Teflon cannula.
ends cut at an angle narrow-bore
using scalpel /Teflon tubing

~ ....:==:=:::::=---
Figure 5.7
 Reagents: Purification and Handling 57

5.4.4 Use of syringesfor the transfer ofreagents or solvents

Syringes are extremely useful for transferring small quantities (up to 50ml)
of air sensitive reagents or dry solvents from one bottle or flask to another.
There are a variety of syringe types and you need to appreciate wh ich type is
suitable for a particular application. It is most important to choose a syringe
of an appropriate size for the quantity ofliquid you need to transport. Using
a syringe with a volume much larger than you need will lead to inaccuracy
and using a syringe which is too small will waste time. For most purposes
the syringe should be equipped with a long needle (l0-20cm). This is
necessary in order to avoid any need to tip the reagent or solvent bottle when
syringing from it. When using syringes, the condition of septa should be
checked regularly. Their life can be extended by making sure that the needle
tips are kept sharp.
The skill of using syringes is of great importance to an organic chemist,
but, as with all skills, you will only become proficient after a certain amount
of practice. It is a good idea to have your own set of syringes which are
appropriate for the type of work in which you are engaged. They will be
some of your most frequently used tools so you should practice using them
and take great care of them.

Types of syringe

Micro syringes
Micro syringes are extremely useful for sm all scale synthetic work,
delivering small quantities of liquid accurately. Sizes ranging from 10111 to
Iml are common, but 100111 is perhaps the most useful size to have.
There are two general types ofmicro syringe, gas-tight and liquid-tight.
The liquid-tight syringes have matched glass bores and stainless steel
plungers, which should not be mixed-up (Fig. 5.8). Certain types of
reagent will corrode the steel plunger and cause ceasure if the syringe is not
c1eaned immediately after use. These are indeed delicate and quite expensive
items which should always be treated with great care (see later for care of
syringes).
58 Reagents: Purification and Handling

ndOu-uu-uuu-u--uu-uu--u-u-u--UI======~O
wrurT-rTT-j-TTTT-j-TT u
•

glass barrel matched metal plunger

------------~----o
screw-on needle
Figure S.8
Gas-tight micro syringes have Teflon tipped plungers, making them
more inert to chemical reagents (e.g. Lewis acids). The barrels and
plungers are also interchangeable and they are thus much more reliable than
the liquid-tight syringes. The drawback with gas tight syringes is that they
are more expensive (Fig. 5.9).

at------------------------------------------ ß--=======================================0
Mt --j --r -j --j --r -r -j --j ur· j UjU r· r·· U
glass barrel Teflon tipped plunger

screw-on needle
E·
Figure S.9
Both types of micro syringe are available with either fixed or removable
needles, but the type with removable needles are generally preferred.
Removable needles have the advantages that they can be replaced when
damaged or blocked and that different sizes can be fitted. Long needles for
micro syringes normally have to be ordered specially.
All-glass Luer syringes
These syringes range in size from Iml to lOOml, are generally quite cheap
and are the most commonly used type. Some glass syringes have matched
barrel and plunger and they can only be used as a pair, but most modern
syringes have interchangeable barrels and plungers. Syringes with
interchangeable parts will be marked as such and these are the preferred type
to use. They are adequate for most purposes, but should be c1eaned
immediately after use and treated carefully to avoid jamming.

~i---------.J
~ 1IIlilllllillillllllllllllllllllllllllllllllllljrD

glass plunger glass barrel

Figure S.10
 Reagents: Purification and Handling 59

Glass gas-tight Luer syringes

For most purposes these are the best type of syringe available. The barrel of
the syringe is made from glass and the plunger is made from metal or plastic
and has a separate Teflon tip (Fig. 5.11). Their main advantages over all-
glass syringes are that they are less prone to leakage and jamming. They are
very expensive, but all the components are replaceable, so they do last a
long time.
~ 1IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII}oJ

gl ass barrel

Figure 5.11

Plastic disposable syringes

Plastic syringes are cheap, hold a very good seal, they are quite accurate and
virtually unbreakable. They can be used many times over, but they do have
the drawback of being susceptible to attack from certain solvents. For this
reason they are most widely used transferring aqueous solutions, such as
aqueous hydrogen peroxide.
Syringe fittings
Miero syringes normally have one of two types of screw-on needle, as
shown in Figs. 5.8 and 5.9. The fittings of larger syringes are more
standard and are normally the Luer type. A Luer fitting is a joint produced
with a standard taper which matches the internal taper of a Luer syringe
needle. There are several types of Luer fitting (Fig. 5.12).
/"" locking sleeve
Luerlip- ~ ~
sleeIOrTef1~~ ~

Lucr lock meta! Luer gl ass Luer

Figure 5.12
The simplest fitting is the Luer glass tip, but these break very easily and
should be avoided. Metal Luer tips are more robust, but the needles tend to
work loose and for this reason Luer-lock syringes are preferred. These
have a slot into which the rim of the needle engages so that it can not come
loose. The most common fitting is the metal tip Luer-lock, but the best seal
of all is provided by the Teflon tip Luer-lock, normally found only on gas-
60 Reagents: Purification and Handling

tight syringes. In this case the Luer tip is Teflon and the locking sleeve is
meta!.
Syringe needles
Luer fitting syringe needles are available in a range of lengths and bore
diameters. The optimum bore diameter depends on the volume of liquid
being dispensed. As a rough guide we use 22 gauge needles for volumes of
less than Iml, 20 gauge for volumes between 1 to 5ml and 18 gauge for
larger quantities. Long needles are usually preferred for transferring liquids
by syringe, but short needles are useful as nitrogen inlets or vents.
Disposable needles with plastic shanks can also be used for this purpose.
/ " Bevel must be clean and sharp

~========================~
long all-metal needle for transferring liquid

"'===~
short disposable needle for introducing and venting inert gas
Figure 5.13
Most needles have a 12· bevel and this should be kept in good, sharp
condition so that minimal damage is caused when penetrating a septum. Flat
ended needles are sometimes useful for removing the last traces of liquid
from a container, but they should only be introduced through septa which
have previously been pierced by a sharp needle.
Cleaning and care 0/ syringes
Syringes and needles can give good service for long periods, but careful
treatment is required to prevent leakage and jamming. It is therefore very
important to clean syringes and needles immediately after use. Organic
liquids or solutions are generally quite easily removed, by simply flushing
with solvent. However, more care is required when a reactive reagent such
as butyllithium or titanium tetrachloride has been used. To c1ear such
reactive reagents the syringe should immediately be flushed several times
with the solvent in which the reagent is dissolved. Whatever the syringe has
been used for it should always be dismantled for final cleaning of the
individual components. If the syringe has been used for an alkyllithium or
any other strongly basic reagent, it should be washed with dilute Hel,
 Reagents: Purification and Handling 61

water, then acetone. After using an acidic reagent or a Lewis acid, the
components should be washed with dilute sodium hydroxide, water, then
acetone.
If a syringe has jammed or become contaminated with remnants of a
stubborn reagent, handle it carefully and do not use force to free the
plunger. This will almost certainly lead to the syringe being broken and you
may weIl end up with a cut hand also. One of the most reliable methods for
removing a contaminant from a syringe, or syringe needle, is to submerge it
in a solvent which will dissolve the contaminant and place it in an ultra sonic
cleaning bath for a few minutes. Sonication will often free syringes which
are completely jammed provided you choose the correct solvent. If you do
not know what is blocking the syringe try sequentially sonicating in the
following series of solvents; 10% Hel, then water, then dilute NaOH, then
water, then acetone, then methanol and finally methylene chloride.
How to handle a syringe
The type of reagent that you will need to deli ver by syringe is very often one
that has to be measured precisely in order for the reaction to be successful.
It is also likely to be a very corrosive reagent, such as butyllithium, which
you do not want to splash around the lab or spill onto your skin. So, before
attempting to use a syringe for transferring any reagent, practise using it first
by measuring solvent until you are confident that you can handle it safely.
You will often need to hold a syringe fuH of liquid in one hand whilst
performing another operation with the other hand. One way to do this is as
follows: fill the syringe with the required volume of liquid using both
hands; then place the syringe against the palm of one hand using the 3rd, 4th
and 5th fingers of the same hand to grip the barrel; carefully place the
forefinger around the plunger and against the end of the barrel to hold the
plunger firrnly in pla('e; the liquid can now be delivered by pressing the
plunger down using the thumb, and the other hand is completely free. This
method should be practised using solvent until your technique is good
enough to confidently transfer liquid without spillage.
Preparing a syringefor use
An appropriate clean syringe and needle should be chosen, dried in an oven,
then left to cool in a desiccator. Before using a syringe it should be purged
with argon (or nitrogen) and this is conveniently done by 'syringing out' the
62 Reagents: Purification and Handling

gas via a septum inlet attached to the inert gas system. This should be
repeated several times (Fig. 5.14). After purging with argon (or nitrogen)
the syringe can be kept for a short time before use if the tip of the needle is
inserted into a rubber stopper.
/ septum

glass or rubber tubing

~i---_liID====={g::::::::::;:33:::~~~::::::::::::::::::: + - - connected to inert gas system

~::::::::::::::::::::::::::::::::
Figure 5.14

Syringing liquidfrom a bottle or flask under inert atmosphere

Before attempting to syringe liquid from a bottle which is under an inert
atmosphere, make sure you have: an effective inert gas system with a needle
outlet; a dry syringe (and preferably aspare) prepared as described above;
and a receptacle, also under inert conditions, into which you are going to
transfer the liquid. The procedure outlined below should be practised with
solvent fIrst if you have not done it before.
1 . Pressurize the reagent container with an inert gas line using a syringe
needle attached via a tubing connector.
2. Carefully insert the needle of the syringe through the septum, holding
the syringe plunger in. Then very slowly fill the syringe by pulling the
plunger up (Fig. 5.15a). You should never fIll the syringe more than
about two-thirds capacity.
3. Tip the syringe upside down, bending the long needle. Slowly force
any excess reagent and bubbles back into the bottle until the exact
volume is indicated (Fig. 5.15b).
4. Holding the syringe barrel carefully in place with one hand, slowly
withdraw the needle from the septum using your other hand to control
it. Then, avoiding prolonged exposure to the atmosphere, quickly
insert the needle into the receptor.
5. Slowly deliver the measured volume into the receptor flask, which
should itself be connected to an inert gas system.
 Reagents: Purification and Handling 63

/ l o n g needle connection to
inert gas system

~inert
~
gas

--
measured-+
volume

_...
----- ------
._-- ..
_---------
...---_ ..... _...

_----
..... - --_ ...
------ --_ ......
---_ _------
_-_ ..

(a)
T (b) (c)

Figure 5.15

Syringing reagents which are extremely moisture sensitive

When a particularly moisture sensitive reagent is being transported by
syringe, simply exposing the tip of the syringe needle to the atmosphere
may cause problems. However, there is a very simple method for keeping
the syringe tip under inert atmosphere at all times. Take a short piece of dry
glass tubing (about 5cm long), insert a tight fitting septum in each end and
purge with inert gas. This provides a mobile inert gas capsule that can be
used to protect your syringe tip (Fig. 5.16a). The procedure for transferring
the liquid is exacdy as described above except for the following points:
1. When drawing the liquid out of the reagent container the syringe needle
is passed through both septa of the inert gas capsule (Fig. 5.16b).
2. After filling the syringe the end of the needle is pulled into the capsule
so that the tip is protected (Fig. 5.16c).
3. The capsule is pressed against the septum of the receiving flask and the
needle is pushed through both septa to deliver the liquid (Fig. 5. 16d).
64 Reagents: Purification and Handling

+-- inert

:H
·1:
gas

septum

glass

g gy tube syringe tip

enclosed in
capsule

~
--inert
~~ g gas

(a) (b) (c) (d)

Figure 5.16

Syringing jrom Mininert bottles

Mininert valves are too narrow for two syringe needles to pass through
them. It is therefore impossible for a container fitted with aMininert valve
to be pressurized from an inert gas system while syringing from it.
However, because the containers used with these valves are very small a
very simple alternative procedure can be used.
1. After flushing a syringe with inert gas fill it with slightly more gas than
the quantity of liquid you wish to syringe. (A gas-tight syringe is
preferred for this procedure).
2. Open the Mininert valve, push the syringe needle through and push the
plunger to pressurize the container with inert gas.
3 . With the needle below the surface of the liquid allow the syringe to fill
with liquid, under the pressure which you have introduced (never suck
liquid into the syringe as this will draw air into the system).
4. Bend the needle to invert the syringe, displace air bubbles and measure
the required volume of liquid.
5. Remove the needle from the container and deli ver the liquid as usual.

5.4.5 Handling and weighing solids under inert atmosphere

Manipulation of solid reagents under dry conditions tends to be somewhat
more awkward than handling liquids or solutions. However, there are two
 Reagents: Purification and Handling 6S

distinctly different problems which can be considered. Firstly, there is the

use of dry but unreactive solid reagents in reactions under inert conditions,
and this will be dealt with in Chapter 8. The other, and more significant
problem, is manipulation of very reactive solid reagents which may react
with moisture in the atmosphere. The only way to handle solids under
completely dry conditions is to use a glove box, which is a sophisticated and
relatively expensive piece of equipment. Fortunately most solid reagents
used in organic chemistry are not so reactive that absolute dryness is
required.
In cases where great accuracy is required, or where a particularly
reactive solid is to be handled, a glove bag can be used. This is essentially a
large, clear polythene bag, which can be sealed after equipment and reagents
have been placed in it. Inlets are provided for electricity cables, gas lines
etc. and glove inserts allow for the manipulation of the apparatus inside the
bag. After loading all the equipment and the reagent into the bag, it is
evacuated three times and filled with an inert gas (a double manifold can be
used for this purpose). Some skill is required to work within a glove bag
so, as usual when working under inert conditions, plan your work very
carefully making sure everything you require is on hand before you start. It
is also a good idea to practice working in the bag before you attempt the
'real thing'.
In the vast majority of cases, the reactive solids used in organic
synthesis can be handled relatively simply, without the need for a glove bag,
provided you master a few simple techniques, and you are careful and work
quickly. The most common moisture sensitive solids are metals (sodium,
lithium, potassium etc.) and metal hydrides (sodium hydride, potassium
hydride, lithium aluminium hydride etc.) and the most commonly
encountered problem is weighing. We have already seen that measuring
liquids under inert atmosphere is relatively simple and for this reason many
air-sensitive organic solids are sold in solution. In order to weigh asolid
without using a glove bag, a certain amount of exposure to the atmosphere
is inevitable, but this can be minimized, provided you are careful. When
carrying out areaction it is normally best if you can plan events so that any
air sensitive solid is added to the reaction flask before other reagents or
solvent (see Chapter 8 for more details).
66 Reagents: Purification and Handling

Weighing solid reactive metals

As usual, plan your work ahead and make sure you have a flask pre-dried
and under inert gas. The metal will normally be under paraffin oil and may
also have an oxide or hydroxide layer coating it. Both these impurities will
have to be removed before weighing the metal and this can be done using
the following sequence. Remember that reactive metals are
pyrophoric when they come into contact with moisture.
1. Place the metal into a beaker, covering it with oil, then cut some of it
into small pieces with a scalpel, removing any coating and leaving the
shiny surface exposed. H eavily coated potassium has been
known to detonate on cutting and should be discarded.
2. U sing a pair of forceps, quickly wash the oil from the metal chunks in a
second beaker containing dry hexane or pentane. Remove the chunks,
allowing the solvent to evaporate very briefly, and drop into a weighed
beaker of oil.
3. Once you have weighed the required quantity, remove the metal
chunks, wash again in the pet. ether, quickly add them to the reaction
flask and re-connect to the inert gas system.
4. When weighing is complete add an alcohol (e.g. ethanol) to the beakers
to neutralize any scraps of meta! before washing with water.

'\.~dry
oil
01 pet. ether
'\.~---- .. _.. _._
.....~
.:.:.:.:.:.:.:.:.:.:.:.:.: ----+'\.
'1
•••::":":" =:
•• '!":':
••• ..
-
:.::-:>i.:
1-:-::.::-:-:. ..rz:.:.:-:-:.:.::-:-:.:.::-:-1.:
.............
........... __ .
.... _--.....
._---_ .. -...._.--- ------------
............
------------ _.. - -.. __---
.... .. _-_......
.. - .. -
...............
..---- ..---
--_. .... --- ... _--_ ........-.
.. ............. ••••••I"'l . . . .
.. ..
balance
i) clean metal ii) wash üi) weigh into a beaker
andcut of oil, then re-wash
Figure 5.17

Handling metal and metal hydride dispersions

Finely divided metals and metal hydrides are very useful reagents and are
usually packed as dispersions in paraffin oil. The most common of these
reagents are sodium hydride, potassium hydride and lithium metal. Whilst
 Reagents: Purification and Handling 67

dispersed in the oil the reagents are moderately stable and ean be weighed
out quiekly in the atmosphere.
For some experiments the dispersion ean be used without separating
out the oil. To do this simply weight it into a pre-dried reaetion flask and
place it under inert atmosphere by sequentially evacuating, then purging the
flask with an inert gas. A 3-way Quickfit tap eonneeted to a double
manifold is ideal for this purpose.
There are various teehniques for removing the oil from a metal
dispersion. The simplest method is as follows:
1. Weigh the dispersion in a flask (do not forget to take the oil into
account) and plaee it under inert atmosphere. Use a double manifold
conneeted by a 3-way Quickfit tap ifpossible (Fig. 5.18a).
2. While maintaining a rapid flow of inert gas through the bubbier of the
inert gas system, open the 3-way tap and add some dry petroleum ether
using a syringe. Swirl the flask to dissolve the oil, then let it stand until
the metal has settled at the bottom (Fig. 5.18b).

inert gas

(a) (b) (c)

Figure 5.18
3. Draw off the petroleum ether earefully using a syringe (Fig. 5.18e).
Diseard the solvent earefully as it may eontain a small quantity of the
metal.
4. Repeat the washing process two more times.
5. The flask ean then be evaeuated to remove last traees of petroleum
ether, then re-weighed to determine the exact quantity of metal.
68 Reagents: Purification and Handling

Reaction solvents and other reagents can then be added directly to this
flask.
If you need to separate the oil from a quantity of metal dispersion
without placing it directly into areaction flask, the piece of apparatus shown
in Fig. 5.19 is very useful. A typical procedure is as follows:
1. After drying the filtration apparatus and cooling under a stream of inert
gas, quickly weigh into it slightly more than the required quantity of the
dispersion, loosely packed.
2. Add some dry petroleum ether to the apparatus and quickly connect a
Quickfit 3-way Teflon tap to the top.
3 . Open the stopcock at the bottom of the funnel and pressurize with inert
gas (Fig. 5.19a). The inert gas can be introduced from a simple line
wh ich incorporates a bubbler (see Fig. 5.2a). The vent of the bubbler
should be restricted to increase the pressure.

Pasteur
pipette

.- inert gas

.-dry
pet.ether

.- meta!
dispersion

.- porosity 3
sinter
.- stopcock

(a) (b)

Figure 5.19
4. Before the level of the solvent reaches the top of the dispersion, turn the
the 3-way tap so that argon is directed out of the vertical inlet as well as
 Reagents: Purification and Handling 69

into the funnel. Then add more solvent through the vent using a Pasteur
pipette (Fig. 5.19b).
5. Repeat the washing steps until solvent flows freely, indicating that all
the oil has been washed away, then elose the top and bottom stopcocks.
This procedure will leave you with finely divided metal or hydride,
under argon, and this can be kept for a few hours in the sealed apparatus
without deterioration. The fine powder will be very reactive and therefore
great care is required in handling it. For titration of metal hydrides see
Chapter6.
Weighing reactive powdered solids
The simple procedure given below can be used for most solids, other than
those which are extremely reactive with even the slightest amount of
moisture or air. Examples of reagents which can be weighed by this method
are: sodium hydride, potassium hydride, lithium metal, lithium aluminium
hydride, finely divided metals and metal hydrides (from dispersions). A
glove bag should be used for particularly reactive solids, or in cases where
extreme accuracy is required.
As always, plan ahead when handling reactive materials and make sure
you have a dry vessel, under inert atmosphere, into which you want to
weigh the powder.
1. Remove the receiving vessel from the inert gas system and place on a
balance pan under a stream of argon, provided by the simple set-up
shown in Fig. 5.20. Caution: argon is the prejerred inert gas jor this
procedure, but because it is heavier than air, make sure the jlask
remainsfilled through-out the weighing procedure.
2. Keep the top of the container holding the powdered metal under the
argon stream whilst removing it, and quickly weigh the required
amount into the flask. When weighing any finely powdered
reactive solid avoid sifting it through the air as this can
lead to a fire.
3. Re-connect the flask to the inert gas system (preferably a double
manifold, evacuate very carefully to avoid the power being disturbed,
then refill with inert gas.
4. Carefully neutralize remaining traces of the metal or hydride on the
apparatus using an alcohol.
70 Reagents: Purification and Handling

balance
Figure 5.20
The inverted fllter funnel technique described above reduces contact of
the reactive solid with moist air and thus lowers the chances of deterioration,
and also the risk of fire. In some instances the less reactive powders, such
as sodium hydride, can be safely weighed in the atmosphere if you are quick
and careful. However, it is recommend that an inert atmosphere blanket is
always used for weighing more reactive reagents, such as potassium
hydride.

5.5 Preparation of diazomethane

Diazomethane is an extremely valuable reagent which is very easy to prepare
and use. However, there are certain hazards associated with the compound
and its preparation that should be taken into account. The observance of a
few simple safety measures allow the reagent to be prepared and used with
confidence.
The single most valuable application of diazomethane is its reaction
with carboxylic acids to provide the equivalent methyl ester, under very mild
conditions. This and other reactions of the reagent have been weH
reviewed.4
4. T.R. Black, Aldrichimica Acta. 1983, 16, 3.
 Reagents: Purification and Handling 71

5.5.1 Sajety measures

There are two types of hazard associated with diazomethane; toxicity and
detonation. Since the reagent is agas, it can easily be inhaled causing
serious lung disorders and a cancer risk. The precursors to diazomethane
are also toxic and should also be treated with extreme care.
Diazomethane has been known to explode, initiators to detonation being
rough glass surfaces, alkali metals, certain drying agents such as calcium
sulphate, and strong light.
Fortunately, the risks highlighted can be circumvented by adhering to
the following simple safety measures.

1. Diazomethane should always be prepared and used in an

efficient fume cup board, behind a safety shield.
2. The detonation risk is chiefly associated with concentrated
solutions or neat diazomethane, and the risk is almost
completely avoided if it is always handled in dilute
solution. This also reduces the health hazard.
3. Never use diazomethane with ground glass joints or glass
apparatus with rough, broken edges and do not use anti
bumping chips.
4. If a dry solution is required use potassium hydroxide as
the drying agent.
5. A void strong light.
6. Do not store diazomethane, use it immediately and
neutralize any excess reagent with acetic acid.

5.5.2 Preparation oj diazomethane (a dilute ethereal solution)

'Clearfit' apparatus can be used to prepare diazomethane, but a cheaper
alternative is to have a simple one piece distillation apparatus made by a
glassblower. The set-up shown in Fig. 5.21 can be used to prepare
between 3 and 17mmol of diazomethane.
72 Reagents: Purification and Handling

rubber ~
stopper t
8em

\------~~100ml
flask

8em

i
Figure 5.21

Method 1
Dissolve KOH (1g) in water (2mi), dilute with 95% ethanol (8ml), and add
to the reaction flask. Cool the flask in an ice bath, then slowly add a
solution of Diazald (N-methyl-N-nitroso-p-toluenesuphonamide) in diethyl
ether (15mi), using a Pasteur pipette. When all the Diazald has been added,
stopper the neck of the flask, put the ice bath under the receiver and place a
warm water bath (about 65°C) under the re action flask. The yellow
diazomethane-ether mixture will start to distil out of the flask. Carry-on
distilling until all the yellow colour has disappeared from the reaction flask,
adding a further 5ml of diethyl ether if necessary. The yellow distillate
contains about 3.3mmol of diazomethane.
Method2
To produce 16.6mmol of diazomethane use 5g Diazald, 5g KOH, 8ml
water, 10ml ethanol and 50ml of diethyl ether. The procedure is similar, but
on this larger scale, add the Diazald solution slowly to the warm KOH
solution, while distilling off the diazomethane. A separating funnel (with a
PTFE stopcock) pushed through a rubber stopper can be used for the
addition.
 Reagents: Purification and Handling 73

5.5.3 General procedure for esterification of carboxylic acids

To an ice cooled solution of the carboxylic acid in ether or ethanol, add an
ethereal solution of diazomethane slowly, until gas evolution stops, and a
very pale yellow colour remains. Add just enough dilute acetic acid in ether
to remove the yellow colour, then evaporate the mixture and purify the
product as appropriate. For very acid-sensitive reactants the acetic acid
work-up can be omitted, and excess diazomethane removed by bubbling
nitrogen through the reaction mixture (in a good fume cupboard) until all the
yellow colour has disappeared.

5.5.4 Titration of diazomethane solutions

Add an aliquot of diazomethane solution to an accurately weighed, excess
quantity of benzoic acid in ether. Dilute the mixture with ether and titrate
with a standard alkali solution to calculate the quantity of acid remaining.
For more information on the uses of diazomethane see reference 4.
 CHAPTER 6

Gases

6 .1 Introduction
Many organic reactions require the use of gases, either inert gases which are
used to protect the reaction, or reagent gases which actually take part in the
reaction. Special experimental techniques are required for handling gases
and this chapter contains a summary of methods for the preparation,
handling and measurement of the more commonly encountered gases.
It must be emphasized at the outset that many gases are
very hazardous, either beeause they are toxie or beeause they
are supplied in eylinders whieh eontain eompressed gas at very
high pressures and, as a result, partieular attention must be
paid to safe praetiee in gas manipulation.

6.2 Use of gas cylinders

A large number of gases are commercially available and details about
individual gases are provided in Sections 6.5 and 6.6. The purpose of this
section is to describe safe methods for handling the containers in which
these gases are supplied. 1,2
Most gases are supplied in pressurized metal cylinders in sizes ranging
from about 50cm in diameter and 350cm tall (lecture bottles) to the familiar
size used for nitrogen (ca. O.25m diameter by 1.5m talI). Some gases with
higher boiling points are supplied at lower pressure in relatively light metal
cylinders. The fittings on the cylinders vary depending on the supplier and
1. Safe under Pressure, BOC Ltd, 1988.
2. Handbook ofCompressed Gases, Compressed Gas Association, Reinhold, 1981.
 Gases 75

on the gas hence it is very important to comply with the suppliers

instructions regarding fittings and accessories.

r - fitting for
"regulator spindle

- cylindcr valv. ~

Figure 6.1
Most cylinders are fitted with a unit containing an on-off valve, and an
outlet fitting (Fig. 6.1). This unit should never be tampered with.
The valve fitting is a weak point in the cylinder and might be dislodged or
weakened if the cylinder was dropped. Apart from releasing a potentially
dangerous gas this could allow the highly pressurized gas to vent
uncontrollably converting the cylinder into an extremely dangerous missile.
For this reason cylinders and lecture bottles should never
be allowed to stand unsupported.
They should always be securely c1amped to a bench or a wall. If they
have to be moved frequently they should be supported in a sturdy metal
frame, or in a trolley designed for this purpose. Cylinders should only be
moved in purpose designed trolleys and should always be treated with great
care.
Cylinders are generally pressurized to 175-200atm and the on/off
valves provide no more control than their name suggests so cylinders must
be fitted with a regulator to allow controlled delivery of the gas. The most
popular regulators are the two stage types shown in Fig. 6.2.
The regulators provide a constant outlet pressure which can be adjusted
to suit the particular application. These are often fitted with needle valves to
give control over the outlet flow rate. The procedure for fitting a regulator
to a cylinder is as follows:
1. Find the correct regulator for the gas in question. Different gas
cylinders have different fittings (to prevent the gas from coming into
76 Gases

output cylindcr
pressure
gauge

pressure
nccdlc adjusLing
valvc scrcw

Figure 6.2
contact with incompatible materials) so the appropriate regulator, fitted
with the correct threaded connector, must be used. (Consult supplier's
data for more detailed information). For safety reasons it is best to
choose a regulator which has a fairly low delivery pressure (~ 0-50
psi), unless a high output pressure is specifically required. (1atm =
1.01bar = 14.5psi (lbf/in2) = 1.03 kgf/cm2 = 760mmHg.)
2. Remove the protective cap from the cylinder fitting and ensure that the
fitting is clean and dry.
Never use grease or Teflon tape on cylinder fittings.
3. Screw the fitting onto the cylinder and tighten firmly. A poor fit
probably means that the regulator is not of the correct type. (Note that
some cylinders have 'left hand' threads.)
Never try to force the fitting.
4. Test for leaks by applying a little dilute soapy water, or a commercial
leak detection solution, around the joint.

The correct procedure for controlled delivery of the gas is as follows:

1. Turn the delivery pressure adjusting screw anticlockwise until it rotates
freely. The regulator is then closed.
2. Open the cylinder valve by slowly turning the spindie anticlockwise
with the recommended key, until the cylinder pressure gauge shows the
tank pressure. Do not open the valve any further.
3. Close the output needle valve.
 Gases 77

4. Turn the delivery pressure adjusting screw clockwise until the required
output pressure (typically lOpsi) is registered on the outlet pressure
gauge.
5. When the gas line is correcdy attached to the apparatus (see Section
6.2) open the needle valve slowly to obtain the desired flow rate.
When the gas is no longer required the flow should be shut off and the
cylinder closed by closing the regulator (rotate the pressure adjusting screw
anticlockwise) and then closing the cylinder valve. The cylinder valve
should always be shut when the gas is not in use.
Lecture botdes should also be fitted with a regulator and needle valve,
as specified by the manufacturer. The regulators are of two types, one for
corrosive and one for non-corrosive gases, and they require a Teflon or lead
washer. The procedures for using lecture botdes are the same as for larger
cylinders.
A number of gases are supplied in liquefied form at relatively low
pressures and these generally only require the use of a flow control valve.
The valves on these cylinders are generally fitted with a handwheel. Again
you should consult the supplier's technical data for information on the
correct fittings and handling procedures.

6.3 Handling gases

This section is concerned with general procedures for handling gases and
includes a discussion of apparatus and techniques for adding them to
reaction flasks,. The preparation and scrubbing of some common reagent
gases are described in Section 6.6. Methods for use of inert gases to protect
air sensitive reactions are detailed in Chapter 8. Hydrogenation, ozonolysis,
and liquid ammonia reactions are described in Chapter 14.
Two important principles must be borne in mind when carrying out a
reaction involving agas.
1. Apressure release device, such as an oil or mercury bubbier, must be
attached to the apparatus in order to prevent the possibility of a
dangerous pressure build-up.
2. Pressure fluctuations may result in the re action mixture being sucked
out of the reaction flask, so valves or traps must be placed in the gas
line.
78 Gases

Reactions involving toxic gases must be carried out in an

efficient fume hood.
A typical arrangement for the addition of agas to areaction flask is
shown in Fig. 6.3. The gas is supplied from a cylinder or is prepared in
another vessel and is supplied at a steady flow rate. It passes through an
appropriately sized trap, such as a Dreschel bottle or an empty bubbier,
before reaching the reaction flask. If apressure revers al occurred and the
contents of the flask were sucked back, the trap would prevent them from

C\ip ___ 10 furnc

hood

-trap

oil
"- rnercury friucd
disc reaction bubblcr
bubbIer flask

Figure 6.3
coming into contact with the cylinder or the reagents used to prepare the gas.
The gas can be bubbled into the solution via a needle or via a glass tube
fitted with a wide bore glass frit. Use of a frit gives better dispersion of the
gas but care should be taken that the frit does not become blocked by asolid
product.
It is important to pi ace an oil or mercury bubb1er between the gas
supply and the trap so that if the gas line is blocked the gas can be vented
safely. Obviously the depth of oil or mercury in the bubbier must be large
enough to ensure that the gas will pass through the reaction mixture rather
than venting from the bubbier. With the inclusion of a bubbier as a safety
device, it is advisable to put clips on all the ground glass joints, or to wrap
them securely with Teflon tape, so that the gas cannot leak from the
apparatus.
The type of tubing used in the line will be dictated by the nature of the
gas. Rubber or PVC tubing is convenient for non-corrosive, non-toxic
gases such as carbon dioxide but many reagent gases require the use of
 Gases 79

glass or resistant plastic tubing. Abrief guide to the chemical resistance of

some common tubing materials is provided below, and more detailed
information about specific products can be obtained from manufacturers.
Caution should be exercized when corrosive and toxic gases are used.
PVC (Tygon)
Flexible with low permeability but poor resistance to organic solvents and
acidic gases.
Polyethylene, polypropylene
Better resistance to solvents and acids than PVC but not suitable for
halogens.
Fluorocarbons (Teflon)
Poor flexibility, but excellent chemical resistance.
Natural rubber
High gas permeability and low chemical resistance.
Neoprene
Relatively good resistance to organic solvents and to acids.
Fluorocarbon rubber (Viton)
Expensive but good chemical resistance. Unsuitable for amines and
ammonia.
Gas which is not absorbed can escape via a bubbier. Small quantities
of non-toxic gases can be allowed to vent into an efficient fume-cupboard.
Toxic gases should be passed through a scrubbing system and suitable
procedures for various gases are described in Section 6.6. The bubbier also
provides a means of monitoring the rate of uptake of the gas, and the flow
rate should be adjusted so that very litde is vented. For relatively insoluble
gases, or for slow reactions, it may be necessary to stir or shake the reaction
fIasko

6.4 ~easurernent of gases

The addition of an accurately measured quantity of agas is sometimes
necessary, for example to obtain selective hydrogenation of a diene. Some
convenient and reasonably accurate methods for measuring gases are
described in this section.
80 Gases

Use of standardized solutions

If agas is soluble in a suitable solvent, and the concentration of the solution
can be detennined by a simple analytical technique, then accurately
measured quantities of the gas can be dispensed by using the appropriate
volume of the solution. For example solutions of the hydrogen halides in
various solvents can be detennined by simple acid/base titration and
solutions of chlorine in carbon tetrachloride can be detennined by addition
of excess potassium iodide and back titration with sodium thiosulphate.
Refer to textbooks of inorganic analysis for details of these methods.

Using gas-tight syringes

Commercially available gas-tight syringes provide the most convenient
method for dispensing small volumes of gases. A syringe fitted with an
on/offvalve and a needle (Fig. 6.4) is repeatedly filled with the gas and then
emptied again, to remove the air. 1t is then filled to the required volume
from agas stream, pressurized by a bubbier, and the valve is shut.

~f------I~J-_I'_I'I'_"'!L'I'_I'I'_I'I'I_'I'I_'I'I-'l'1'_1'1'_I'I'_I'I'---JI'I"~0Iir';:"
gas-tight valve With inert
syringe Lue~-lock gas line
fittmgs

Figure 6.4
Just before use, the valve is opened to purge the needle and allow the gas to
reach atmospheric pressure, and then the needle is inserted into the reaction
flask. If a sm all volume of gas is involved (less than 100ml) the reaction
vesse1 can be a sealed system and the gas can be added slowly from the
syringe. For larger volumes the reaction flask should be fitted with a
mercury bubbIer and the gas should be added at such a rate that gas does not
vent from the bubbler.
 Gases 81

Using agas burette

Gas burettes are most commonly used for low pressure hydrogenations, but
they can of course be used for delivering other gases thus providing an easy
method of dispensing accurately measured volumes. A simple gas burene
design is shown in Fig. 6.5. It is operated as follows:
1. Open the double oblique tap to the vent (fume hood), and the three-way
tap to the burette. Raise the levelling bulb to expel most of the gas from
the burette.
2. Turn the double oblique tap to the gas line, turn on the gas supply, and
fill the burette slowly, lowering the levelling bulb as the burette fills.
3. Repeat steps 1 and 2 twice more to ensure that all of the air has been
expelled. Then fill the burette to approximately 20% more than the
required volume.
4. Open the three-way tap to the line fitted with a needle, which can be
inserted into the reaction flask, and flush the tubing with gas. Turn off
the gas supply.

to fume hood -
gassupply -~
-? 'f=:3!(9;~:r:::==~
t
double -
oblique tap ==
=

levelling
bulb
to reaction

flexible
- - - tubing

Figure 6.5
82 Gases

5. Open the three-way tap to connect the burette to the line with the need1e,
thus allowing the gas to come to atmospheric pressure and giving the
the needle a final flush. Rapidly read the volume in the burette and
insert the need1e into the reaction flask.
6. Raise the levelling bulb slowly to keep a slight positive pressure of the
gas as the reaction proceeds. When the required volume has been
added, close the three-way tap. If the gas is hazardous flush the
apparatus with inert gas (steps 1-4) after use.
If gas burettes are used for a variety of different gases then some safety
points should be noted. The burette should be thoroughly flushed with inert
gas after each use. The tubing may need to be changed for use with
different gases, and the liquid in the reservoir may also need to be changed
depending on the application (aqueous copper sulphate, mercury, mineral
oil, and dibutyl phthalate are often used). The gas burette method is
particularly good for reactions in which the uptake of gas is slow. Gas
burettes are also used for measuring the volume of gas absorbed, or
evolved, in areaction. A useful application is the quantitative analysis of
hydride solutions by adding the hydride to an excess of protic or acidie
solvent, and measuring the volume of hydrogen evolved.3
The procedure for the analysis ofBH3.TIIF is illustrative.
1. Place 50 m1 of a 1:1 mixture of glycerol and water, and a stirring bar, in
a flask and seal it with a rubber septum. Connect to the gas burette
using a need1e as before.
2. Open the burette to the flask and add a few millilitres of hydride
solution to the flask in order to saturate the atmosphere with hydrogen.
3. Open the burette to the atmosphere and raise the levelling bulb to give a
reading of approximately zero. Note this reading.
4. Turn the three-way tap so that the burette is connected only to the flask.
Add an accurately measured volume of hydride solution, with rapid
stirring. The volume used should be sufficient to more than half fill the
gas burette you are using.
5. When hydrogen evolution has ceased, lower the levelling bulb so that
the liquid levels in the burette and the reservoir are equal, and read the
volume. Calculate the molarity using the following equation.
3. H.C. Brown, Organic Synthesis via Boranes, Wiley, New York, 1975.
 Gases 83

Molarity = (Pa-Ps)(273)(Vh-V a>

«760) (T) (22.4) (V a>

Pa = Atmospheric pressure (mmHg)
Ps = Vapour pressure of the solvent in the resevoir at tempo T
(mmHg)
Vh = Volume ofhydrogen evolved (ml)
Va = Volume ofhydride solution added (ml)
T = Temperature ("K)
This method should give an accuracy of better than ±5%.
6. Repeat the measurements until reproducible results are obtained.

By condensing the gas

Many gases (see Appendix 2) have relatively high boiling points so they can
easily be liquefied and measured in the liquid form. The gas is passed into a
vessel, which is then cooled to the appropriate temperature, as shown in
Fig. 6.6. The quantity of condensed gas can be measured by
to rcaction
or bubbier

+
gas - - ==~;::::r::::==~I====::---

mercury
bubbier
- - - - :.-- :::::. - - -
._-.-- - --
- - - - ......
:: .. t
suck-back
cold trap
bath

Figure 6.6
84 Gases

volume or by weight. When the required quantity has been condensed the
cylinder is closed and the reaction flask is attached to the safety trap. The
cooling bath is then removed and the gas allowed to distil into the reaction
vessel. The mercury bubbler and safety trap serve the usual functions.

Using a quantitative reaction

A specific quantity of gas can be added to areaction if the gas is prepared
using a chemical reaction of known yield. Methods and apparatus for
preparing some commonly used gases are described in Section 6.6 and
mention must also be made of an elegant gas generator devised by H.C.
Brown, which is described in detail elsewhere.3

6.5 Inert gases

Nitrogen and argon are by far the most commonly used inert gases and
techniques for conducting reactions under an inert atmosphere are described
in Chapter 8. Both N2 and Ar are available in various grades of purity and
usually gas of 99.995% purity can be used without further purification.
Attempted purification using conventional drying trains is generally counter-
productive. An easy method of checking whether your inert gas line is
absolutely dry is to place a flask containing some titanium tetrachloride on
the manifold. Evacuate carefully for a few seconds and then open to the
inert gas. If you see white fumes of titanium dioxide, you have a poor batch
of gas or a leak in your gas line. Effective gas purification systems are
described elsewhere. 4,5 Although it is more expensive, argon is superior to
nitrogen in two important respects. It is heavier than air and therefore
protects the contents of a flask more effectively, and it is completely inert
whereas nitrogen does react with some materials, the most commonly
encountered examples being lithium met al and some transition met al
complexes.

6.6 Reagent gases

It may occasionally be necessary to prepare agas, if a cylinder is not
available. Methods for the preparation (and scrubbing) of some simple
gases are provided in this section. Most of these preparations can be carried
out in the apparatus shown in Fig. 6.7.
 Gases 85

.-;:::r::::::::-::jJ.=:::I:~-;::::::C::== _ to trap and

Tcaction

Figure 6.7
The solution in the pressure-equalizing dropping funnel is added
slowly and cautiously to the reagent in the fiask, with stirring and
cooling if necessary. The gas then passes through a suck-back trap and on
to the reaction fiask, and any that is not absorbed passes through a scrubber.
As usual, there are two bubblers, the first to prevent pressure build-up and
the second to monitor the amount of gas which is not being absorbed. The
rate of addition of the reagents should be adjusted so that relatively little of
the gas escapes through the second bubbier. This bubbier also provides a
gas-tight seal to the atmosphere which protects the reaction fiask from the
reagent (often water) used in the scrubber. If a toxic gas is being generated,
the apparatus should be flushed with an inert gas before dismantling.
4. D.F. Shriver and M.A. Drezdzon, The Manipulation 0/ Air-Sensitive Compounds,
2nd ed., Wiley, New York, 1986.
5. AL Wayda and M.Y. Darensbourg Eds., Experimental Organometallic Chemistry,
A Practicum in Synthesis and Characterization, American Chemical Society,
Washington, 1987.
86 Gases

Various types of scrubber may be employed but the simplest method of

scrubbing relatively small quantities of water-soluble gases is to pass them
through water. Two simple devices for this purpose are shown below. The
first (Fig. 6.8(a)) is suitable only for small quantities of gas whereas the
second (Fig. 6.8(b)) is more appropriate for larger volumes.
gas

gas

L
H~h~;;ro==-- to drain

- ....... ..
-....................
............
..
::.....::..::..::::::: :::
......................
(a) (b)

Figure 6.8
Methods for preparing some common gases are described below (see
ref. 3 for other methods). The properties of these and other gases are listed
in Appendix 2. Many of these gases are very harmful and they should only
be handled in an efficient fume cup board, taking care to prevent leaks and to
scrub any excess gas.
Acetylene
Prepare by addition of water to calcium carbide and dry by passing through
a column of molecular sieves. Acetylene can explode spontaneously,
especially when pressurized. For this reason the gas should be generated
very cautiously, the generator should be cooled, and the gas line should be
fitted with a bubbier so that the pressure cannot rise above 15 psi. Dispose
by venting slowly in an efficient hood.
Carbon dioxide
The simplest method is to allow solid carbon dioxide to evaporate, and the
gas can be dried by passage over mo1ecular sieves. It can also be prepared
 Gases 87

by addition of dilute hydrochloric acid to calcium carbonate. Passage over

molecular sieves will remove any aqueous acid in the gas stream.
Carbon monoxide
Carbon monoxide is very toxic by inhalation: TLV 50ppm. Prepare by
slow addition of anhYdrous fonnic acid to concentrated sulphuric acid at 90-
100·C (frothing tends to be a problem). One millilitre of formic acid
generates 26.6 mmoles of gas. The CO is contaminated with small amounts
of carbon dioxide and sulphur dioxide which may be removed by passage
over potassium hydroxide or the commercial product Ascarite (sodium
hydroxide on silica). Dispose of carbon monoxide by slow venting in an
efficient hood.
Chlorine
Chlorine is extremely toxic and a powerful irritant: TLV 1ppm. Prepare by
slow addition of concentrated hydrochloric acid to potassium permanganate
(6.2ml of acid per gram of permanganate ), with occasional shaking. The
gas evolution slows as the reaction proceeds and warming is required to
complete the reaction; 1.12g of chlorine should be formed per gram of
permanganate but in our experience the yield is substantially lower than this.
Chlorine may be stored in solution in carbon tetrachloride. Dispose by
dissolving in water.
Diazomethane
See Chapter 5.
Hydrogen bromide
HBr is corrosive and toxic: TLV 3ppm. It can be prepared by slow
addition of bromine to purified tetralin, with stirring. The small amount of
bromine which passes over with the HBr can be removed by passing the gas
through a trap containing pure dry tetralin. Dispose by dissolving in water.
Hydrogen chloride
Hydrogen chloride is corrosive and toxic: TLV 5ppm. Prepare by adding
concentrated sulphuric acid to anhydrous ammonium chloride and dry by
passage over molecular sieves. Dispose by dissolving in water.
 CHAPTER 7

Vacuum Pumps

7.1 Introduction
There are a variety of tasks in organic chemistry which require provision of
a vacuum source. However, different tasks will require different levels of
vacuum and more than one type of vacuum source will be needed to service
all the requirements of the lab. We can split vacuum supplies loosely into
two categories: low vacuum, being 1-50mmHg and high vacuum being
below ImmHg. A low vacuum source is valuable for such tasks as vacuum
filtration, operation of rotary evaporators and vacuum distillation of
relatively volatile liquids. High vacuum is required for serving inert gas line
manifolds, vacuum distillations and drying solids by removing traces of
solvent or moisture from them.

7.2 Low vacuum pumps

7.2.1 Water aspirators

The water aspirator is probably the most common laboratory vacuum
source. It is normally possible to achieve a vacuum of about 1O-12mmHg
using a normal cold water supply, and this is adequate for many
requirements. The advantage of the water aspirator is that it is cheap, simple
to operate and fairly reliable. Its main disadvantage is that it is prone to
'suck-back', which can leave your apparatus full of water! This occurs if
the water pressure drops after a good vacuum has built up in the apparatus.
The same thing will happen if the tap is turned off while the system is still
under vacuum. For this reason the tap should always be kept full on, and
an air inlet should be provided by means of a 3-way tap. A simple trap
 Vacuum Pumps 89

should also be incorporated, which will give you some time to disconnect
the apparatus if suck-back occurs (Fig. 7.1). A water trap will not prevent
suck-back altogether and hence it is not advisable to leave apparatus
unattended while connected to an aspirator. Clearly, this type of pump is
not suitable for connecting to an inert gas manifold.

to apparatus +-- ~

3-way tap
/
(air inlet)

Water trap for aspirator

Figure 7.1
Other disadvantages of the water aspirator are that it is quite noisy and
uses a considerable volume of water if it is left on for prolonged periods.

7.2.2 House vacuum systems

Many large laboratory buildings have a large central vacuum pump which
serves a house vacuum system. There are great variations in the
effectiveness of such systems, depending on the type of pump employed,
the number of users and various other factors. A good house vacuum
system will pull about 50mmHg and can be very useful for driving rotary
evaporators, filtrations and simple vacuum distillations. The advantage of
the system is ease of use, but the vacuum can fluctuate quite considerably
depending on how many people are using it.

7.2.3 Electric diaphragm pumps

There are now a number of simple low-vacuum electric pumps available that
will produce a vacuum of about 12mmHg. Some of these pumps are
specially designed to withstand solvent vapours and are therefore suitable
for use with rotary evaporators. They are clearly an alternative to water
pumps and, although the initial capital expenditure is much higher, they
90 Vacuum Pumps

have several advantages: they are quiet, there are no problems of 'suck-
back' and they do not use vast quantities of water.
For some tasks very cheap and simple fishtank-type diaphragm pumps
are useful. These will produce a vacuum of about 300mmHg and can also
be used to provide compressed air for pressurizing chromatography
columns (see Chapter 9).

7.3 High vacuum pumps

7.3.1 Rotary oU pumps

Rotary oil pumps will provide a reliable vacuum down to about O.OlmmHg
(at the apparatus) and are thus one of the most valuable pieces of equipment
in the lab, being used for a wide variety of tasks. Ideally every research
worker should have hislher own high vacuum pump, but in many cases cost
prohibits this and pumps are shared. If a pump is shared, it is common to
have it mounted on a trolley which has all the ancillary devices (traps, gauge
etc.) mounted on it. Alternatively, a shared pump may be fixed in one
place, but attached to a communal manifold, distillation set-up or other piece
of apparatus. A good two-stage pump is suitable for most high vacuum
requirements in an organic chemistry lab.
Solvent traps
A high vacuum pump must be fitted with efficient solvent traps to prevent
the pump oil from becoming contaminated. The traps are simply cold finger
condensers incorporated into the vacuum line before it enters the pump. It is
preferable to have two traps which can be cooled by either liquid nitrogen,
or solid C02-acetone, but if only one trap is used solid C02-acetone will be
ineffective and liquid nitrogen must be used as the coolant. A typical design
for a trapping system is given in Fig. 7.2.
If the trapping system incorporates a cone joint, it can be connected
direct1y to a manifold such as that shown in Fig. 3.1 (Chapter 3).
Alternatively, a piece ofhigh vacuum tubing can be used to connect the traps
to a distillation apparatus, a double manifold (Fig. 3.4, Chapter 3), or any
other piece of equipment.
 Vacuum Pumps 91

+----16cm---+

cone joint
or tubing

""ne,,i~ 1 ' - B29 1

connected
to pump

18cm

Figure 7.2

Operating a high vacuum pump

Do not immerse the traps in liquid nitrogen unless they are
evaeuated, as this will eause liquid air to eondense. The result
0/ this ean be a violent explosion, eaused by re-vaporization or
by oxidations 0/ organie solvents ete.
Before switching the pump on check that the traps are empty. Then
with the 2-way tap elosed and the 3-way tap open between the pump and the
traps, but closed to the vent, turn the pump on. Next immerse the traps in
Dewars filled with liquid nitrogen and check the vacuum by connecting a
vacuum gauge to the 3-way tap. If the vacuum is satisfactory «lmm), the
2-way tap can be opened, to evacuate the apparatus which is connected to it.
The vacuum should then be checked again to make sure there are no leaks in
the system.
When you want to switch the pump off, elose the 2-way tap, turn the 3-
way tap to vent through the pump (not into the traps), then turn the pump
off. Remove the liquid nitrogen Dewars from the traps immediately after
switching the pump off and then vent air into the traps using the 3-way tap.
It is very important to vent the pump before turning it off otherwise pump
oil may suck back into the traps.
92 Vacuum Pumps

Care of high vacuum pumps

High vacuum pumps are very expensive items, but they will give very
reliable service for many years if they are treated properly. For an organic
chemist to work efficiently he/she must be able to rely on pumps working
properly and this will only be the case if they are treated with care. The
main reason for deterioration of vacuum pumps is contamination of the oil
with volatile organic compounds and acidie vapours such as Hel or HBr.
To avoid this problem, you should be very conscientious about keeping the
coolant well topped-up around the traps, and emptying them regularly. No
matter how careful you are, some solvent vapour will always find its way
into the pump, and for this reason the oil should be changed regularly, at
least once a month for a pump which is used every day.

7.3.2 Vapour diffusion pumps

Occasionally a distillation will require a higher vacuum than that produced
by a rotary pump. Higher vacuums are normally obtained by employing a
mercury or oil vapour diffusion pump, in conjunction with a rotary pump.
Oil vapour pumps are most commonly used today and various models are
now commercially available which will produce a vacuum of about
lO-SmmHg. These pumps are only used occasionally but it is very useful to
have one shared between a large group or section.

7.4 Pressure measurement and regulation

1t is very important to be able to measure the pressure in a vacuum system,
particularly when carrying out a distillation. For low vacuum measurement
a simple manometer, such as that shown in Fig. 7.3a, is commonly used
and the pressure is taken by subtracting the heights of the mercury levels.
Dial gauges are also useful for in-line measurements and they are
particularly valuable when used with rotary evaporators. For high vacuum
measurement a McLeod gauge, with a range of 1 to O.OOlmmHg, is most
commonly used (Fig. 7.3b). The gauge is rotated into the vertical position
to read the vacuum, but must be turned back to the horizontal position and
back again to vertical, in order to read a change in pressure. Electronic
Pirani gauges are also available for measuring high vacuum.
 Vacuum Pumps 93

Quite a common requirement is for a distillation pressure somewhat

higher than that delivered by the high vacuum pump. Achieving this is no
simple matter because a very accurate leak must be provided in order to
maintain a constant vacuum. There are various devices available, one of the
simplest being an accurate needle valve (such as an Edwards LV5) which
will be suitable for most distillation purposes.

mercury

prcssurc
gauge

mercury

(a) (b)

Figure 7.3

7.4.1 Units ofpressure (vacuum) measurement

There is often confusion about different units of pressure measurement, but
the way they relate to one another is quite simple. The most common units
are mm Hg, and Imm Hg is the same as 1Torr. The other common scale is
mbar which relates to atmospheric pressure, 1 bar = 1 atmosphere =
760mm. Thus:
Imbar = O.76mmHg = O.76Torr
 CHAPTER 8

Carrying Out The Reaction

8.1 Introduction
This is the most important single chapter in this book. In order to be certain
of the results of a particular experiment, and to ensure reproducibility, it is
important that the appropriate precautions are taken, and that proper
preparations are made. Many common organic reactions involve the use of
air sensitive reagents, which requires the reaction to be carried out under
inert, anhydrous conditions. These conditions are also used for reactions
which are sensitive to the presence of water. Indeed the majority of
reactions, although not requiring such conditions, will usually benefit from
being carried out in the absence of air and water. Accordingly most of this
chapter is concerned with the use of air sensitive reagents, since the same
basic techniques can be used for almost all types of reactions likely to be
encountered.
First of all, before attempting the reaction it is important to ensure that
you have the necessary glassware, apparatus, reagents, and experimental
procedure (including work up and a t1c system which will allow you to
follow the reaction). Do not forget to check on the safety aspects of the
chemicals (including solvents), of the likely reaction products, and of the
procedures which you will be using. As alluded to above, most reactions
will require monitoring of some kind (dc, gc, hp1c, etc.) and it is important
to ensure that your chosen system is suitable for the starting material, and
give some consideration as to where the expected product is likely to be
found (will the polarity increase or decrease on converting starting material
to product?). Make certain that you allow yourself plenty of time to
complete the reaction, or at least to monitor it in the early stages if it is likely
 Carrying Out The Reaction 95

to be a lengthy experiment. Finally it is most important that the reaction is

written up earefully as you go along, rather than writing it up 'properly' a
few days later for the reasons given in the seetion on keeping your
laboratory notebook. Remember, it is important to write up experiments
whieh have 'failed' as earefully as those whieh are sueeessful. If this is
done the reason for 'failure' might be apparent to you at a later stage, and in
any ease this detailed information is likely to be of real value to someone
following up your work.

8.2 Reactions with air sensitive reagents

8.2.1 lntroduction
Many eommonly used organie reagents are extremely reactive towards water
andlor oxygen. Some examples are: alkyllithium reagents, Grignard
reagents, organoboranes, metal hydrides, organoaluminium eompounds,
euprates, titanium tetraehloride, dry solvents, ete. Some of these reagents
are available eommercially and others are prepared in situ, in either ease they
are most eonveniently handled in solution. Although extreme eare must be
taken to exc1ude air and moisture when using these reagents, you should
find them easy to handle onee you beeome familiar with some simple
teehniques. General proeedures for handling air sensitive reagents are
deseribed in Chapter 5 and the appropriate parts of that ehapter should be
eonsulted in eonjunetion with this seetion.

822 Preparing to carry out areaction under inert conditions

If you already have permanent inert gas lines in the lab as suggested in
Chapter 3, then earrying out a reaetion under inert eonditions should be
routine. However, it is very important that you do not expose the reaetion
to the atmosphere at any stage. The teehniques for ensuring this beeome
seeond nature onee you gain experienee; but forward planning is always
essential so that everything is in the right plaee at the right time and under an
inert atmosphere. Therefore, before you start think very earefully about
how you intend to earry out eaeh operation of your reaetion sequenee, and
list the equipment you will need. All equipment needs to be dried and
eooled in advanee and it is partieularly important to have enough syringes
96 Carrying Out The Reaction

available. Indeed, you should always have some spare dry syringes in case
one gets jammed, contaminated or broken.

8.2.3 Drying and assembling glassware

It is assumed that the glassware has been c1eaned before use and it is also
important to check glassware, particularly flasks, for cracks and scratches
especially if the glassware is going to be evacuated. If you are in doubt as
to the safety of a particular item of glassware do not use it, and do not forget
to get it repaired by the glassblower or to dispose of it. Do not leave it
around for someone else to discover its weakness. Under normal
conditions glassware has a thin film of water adsorbed to its surfaces which
must be removed before moisture-sensitive reagents, dried solvents, or
starting materials are allowed to come into contact with it. There are two
basic methods for doing this. The first method is to heat the glassware in an
oven at a temperature above 125"C for at least 6h, then quickly assemble it
whilst hot and cool under a stream of dry inert gas. The second method is
to assemble the glassware, evacuate it by connecting it to a double
manifold/high vacuum pump, then heat the whole set-up with either a
bunsen or heat-gun. The two-way tap on the manifold is then switched so
that the apparatus fi1led with argon (or nitrogen) while it cools, leaving the
apparatus set up and ready for use. This procedure can save a good deal of
time but, because of the dangers involved in heating glassware under
vacuum, this procedure is best reservedfor small-scale reactions.
Glassware and normal syringes can be dried in an oven then cooled in a
desiccator over P20S or self-indicating silica gel, but it is not advisable to
heat microlitre syringes and these should be dried under vacuum in a
desiccator.
If you are going to use magnetic stirring, do not forget to inc1ude a
stirrer bar before the apparatus is assembled and before the drying procedure
is carried out, since the stirrer bar will also be covered in a film of moisture
and adding it later is likely to introduce air and moisture into the system.
It is not advisable to use grease for glassware assembly, sinee this will
eventually find its way into your reaction product. If you have to use it,
always use the minimum quantity possible and remove it carefully from the
joint immediately after the reaetion has been quenched. This ean be done
using a tissue dampened with chloroform or other halogenated solvent. It is
 Carrying Out The Reaction 97

important to do this before addition of an extraction solvent, or before

pouring the reaction mixture through the joint. Rather than use grease, it is
much better to use Teflon tape or sleeves, since these are at least as efficient,
do not contaminate your product, and in the case of sleeves they are
reusable. 1t is also advisable to seal the outside of the joint by wrapping
Teflon tape around to cover the 'join'. This will help to prevent any
condensation on the outside of the glassware from finding its way into the
reaction. Joint clips (e.g. Bibby clips) should be used on all accessible
joints.

8.2.4 Typical reaction set-ups using a double manifold

A double manifold (Fig. 8.1) is an extremely useful piece of apparatus,
especially for carrying out reactions under inert atmosphere and its
installation is described in more detail in Chapter 3. One barrel of the
manifold is connected to a high vacuum pump (or house vacuum system)
and another to a cylinder of dry inert gas. 1ts main advantage is that, simply
by turning the two-way tap on one of the outlets, any vessel connected to
that outlet can be switched instantaneously from vacuum to inert gas
atmosphere or vice versa. Several reactions can also be set up at once, the
only limit being the number of outlets. At the end of the argon (or nitrogen)
line there is a bubbier which prevents air from being sucked back into the
system, and provides a convenient means of monitoring the gas flow rate.

to bubbier - - inert gas

- to vacuum pump

"-.... double-oblique taps

Figure 8.1
98 Carrying Out The Reaction

A fast flow is used when filling a system, but once the reaction is set up,
one bubble every 5-10s is adequate. A piece of apparatus which is very
useful when used in conjunction with a double manifold is a Quickfit 3-way
tap, which is also described in more detail in Chapter 3.

8.25 Basic procedurejor inert atmosphere reactions

A typical simple re action set-up using a manifold is shown in Fig. 8.1 and
the following general procedure is applicable to a wide range of reactions.
However, this is only intended to be a general guide-line and can easily be
modified to suit various requirements. Some of these modifications are
discussed later in this chapter.
Before starting decide on the order for addition of reagents and if
possible arrange this so that any solid re agent is added first. If this is not
possible try to add the solid as a solution, using the technique described
later. If areagent really does have to be added as asolid, this can be done
successfully and again a method will be described to do this.
Make sure before you start that you have all the dry syringes, needles,
and any other ancillary items, and that you are familiar with the operation of
the manifold and the 3-way Quickfit tap.
1. Set up and dry the system
Connect the re action flask including stirrer bar to the manifold (Fig.
8.1), set the 2-way tap on the manifold and the 3-way tap on the
reaction flask (position A, Fig. 8.2a) so that the system is evacuated,

J: 1:
and heat the glassware with a heat gun (or bunsen) for 5min. Then,

~~riti~t
position A position B position C

flow .....gI> "" 5t= r ft=1

(a) (b) (c)

Figure 8.2 Flow through a 3-way tap relative to tap position.

 Carrying Out The Reaction 99

with inert gas flowing through the bubbier at a rapid rate, turn the
manifold tap slowly to introduce the inert gas. Keep an eye on the
bubbier while you are switching to the inert gas supply and operate the
tap carefully to avoid 'suck-back'. Finally leave the apparatus to cool.
2 . Add initial reactants
Solid reactants (or heavy gum oils) can be weighed into the reaction
flask at this stage. With the inert gas flow at a reasonably high level,
remove the flask from the system and quickly weigh the reagent into it
(for reactive solids see Chapter 5). Then re-attach the flask to the 3-
way tap and switch the manifold tap to evacuate. If there are traces of
solvent on the reactant these can be removed by leaving the fIask under
vacuum for an extended period, otherwise the 2-way tap can be
switched back to argon straight away leaving the reactant in the flask
under inert atmosphere.
3. Add solvent
The best way to add solvent to the system, and avoid breaking the inert
atmosphere, is to use a syringe. It is best to syringe the solvent straight
from the collecting head of a still, which is itself under inert atmosphere
(see Chapter 4), but the solvent might also be taken from a bottle or
fIask under inert atmosphere (see Chapter 5). In either case, once you
have a syringe loaded with solvent, open the 3-way tap to position B
(Fig. 8.2b), keeping an inert gas flow which is rapid enough to
maintain bubbling, and add the solvent. Then turn 3-way tap back to
position A (Fig. 8.2a) and reduce gas pressure to maintain steady
bubbling. For large scale reactions solvents can be added by
disconnecting the fIask, adding the solvent quickly and re-assembling,
but this inevitably leads to air entering the system. With higher boiling
solvents the air can be removed by sequentially partially evacuating and
refilling with inert gas several times, using the 2-way manifold tap.
4 . Cool the jlask
At this stage the reaction fIask can be immersed in a cooling bath and
stirred with a magnetic stirrer (see Chapter 8). Never cool a flask
be/are it is under the inert atmosphere as this causes moisture to
condense.
100 Carrying Out The Reaction

inert gas inert gas

from manifold from manifold

(a) (b) (c)

Figure 8.3

5. Add reagents
It is most commonly the reagents used in the reaction which are air
and/or moisture sensitive and they should be added with great care (see
Chapter 5 for more detail). After pressurizing the reagent container
with inert gas, syringe out the required quantity (Fig. 8.3a). Increase
the inert gas flow through the manifold so that rapid bubbling is
maintained as the 3-way tap is opened to position B, then insert the
syringe through the tap to deliver the reagent (Fig. 8.3b). When all the
re agent has been added turn the 3-way tap back to position A and
reduce the gas flow so that there is a bubble every few seconds (Fig.
8.3c). Any further reagents are added in the same way and the reaction
is left to proceed. To add a cooled reagent it is advisable to use a
cannula made out of Teflon tubing (see Chapter 5, Section 5.4.3 for
more detail).
6. Reaction monitoring
The reaction can easily be monitored by de, ge, ete. Again inerease the
inert gas flow through the manifold so that rapid bubbling is maintained
as the 3-way tap is opened to position B, then insert a drawn piece of
glass tubing or Pasteur pipette through the tap to remove a drop of the
mixture.
 Carrying Out The Reaction 101

7. Work-up
Once the reaction is complete it can be worked up as normal (see
Chapter 9). However, when there is the likelihood of residual reactive
reagents such as organometallics, be very careful when adding aqueous
solutions 1t is normally safer to keep the mixture under an inert
atmosphere whilst the solution is added.

8.2.6 Modifications to basic procedure

1. Reactions at elevated temperatures

When areaction needs to be heated or when there is any possibility that it
might be exothermic, a condenser should be incorporated into the reaction
set-up. Normal Liebig condensers have the water jacket next to the outer
surface and there is always the possibility of atmospheric moisture
condensing on the outside, running down to the ground glass joint, and
seeping into the re action flask. Teflon sleeved joints should prevent water
getting into the reaction vessel, but a better method is to use coil type-

..~~o gas
inert

Figure 8.4
102 Carrying Out The Reaction

condensers (Fig. 8.4) for reactions under inert conditions. Since the
cooling surfaces are inside the apparatus, the problem of outside
condensation is alleviated.
Typical set-ups for reactions which are to be heated are shown in Fig.
8.4. The procedure for carrying out the reaction is exactly as described in
the previous section, except that the reaction is heated instead of being
cooled. Reagents can be added through the 3-way tap, provided a syringe
with a long needle is used, or as an alternative a flask with a side arm fitted
with a septum can be used. Whilst the temperature of areaction is changing
the bubbIer of the system should be checked to make sure there is a constant
inert gas pressure.
2. Slow addition ofreagents and large scale work
When slow addition of an air-sensitive reagent is required it is best to
incorporate apressure equalizing addition funnel into the apparatus, and for

inert <J.~­ - mechanical stirrer

gas-<-
- septum

coiled condenser -

Figure 8.5
 Carrying Out The Reaction 103

large scale work this is always best. The apparatus can be set up with or
without a condenser, can be stirred either magnetically or mechanically. A
typical arrangement is shown in Fig. 8.5. Where very careful slow addition
is required, particular on a small scale, the use of a syringe pump is strongly
advised. These are mechanical devices which drive the plunger of a syringe
very slowly into the barrel.
mechanical
stirrer ~

inert
gas-

(a) Cooling apparatus under inert atmosphcre

inert
/gas

to bubbier
via manifold ____r--.,
• (inert gas
turned off)

- ~
(b) Filling droppingfunnel using cannula
Figure 8.6
To dry this larger, more elaborate set-up, it is best to oven-dry the
equipment first, assemble it hot and leave to cool under a stream of inert
gas. This can be done by connecting to inert gas from the manifold, with a
short needle through the septum acting as a vent (Fig. 8.6a). Once the
apparatus is cool reactants can be added as described above. A syringe can
be used to add small quantities of re agent to the addition funnel. For larger
quantities (>50mI) the cannulation technique described in Chapter 5 for bulk
transfer of liquids is best, and if the funnel is graduated the reagent can be
104 Carrying Out The Reaction

added straight from the re agent bottle (Fig. 8.6b). If a mechanical stirrer is
used a Teflon sealed guide should be used for the stirrer rod. The reaction
is carried out exact1y as before.

3. Addition 0/ areagent prepared separately, or 0/ asolid

reaction flask -

Figure 8.7
When asolid re agent is to be added to areaction set-up which is already
under inert conditions, it is best to add it in solution. To do this, weigh the
solid into a dry flask, fit the flask with a 3-way tap, connect to aseparate
outlet on the manifold, and evacuate. Then switch the manifold tap to
introduce inert gas, and with the gas flow high enough to maintain rapid
bubbling at the bubbier, open the 3-way tap to position Band syringe in the
required dry solvent. With the 3-way tap turned back to position A, the
solution is under inert atmosphere and can be kept indefinitely (Fig. 8.7).
To transfer the reagent, make sure that the inert gas flow is high enough to
maintain rapid bubbling whilst the 3-way tap on the reagent vessel is opened
to position B. Then syringe out the solution, turn the tap back to position
A, open the tap on the reaction flask to position Band add the reagent.
Alternatively, a cannula can be used to transfer the reagent (see below).
A similar procedure can be used when areagent has to be prepared
under inert conditions for use in the reaction. This is quite a common
occurrence, for example when a Grignard or alkyllithium reagent has to be
prepared, then added to areaction mixture. In this case the reaction flask
assembly is set up attached to one outlet of the manifold, while the reagent is
 Carrying Out The Reaction 105

prepared in an appropriate set-up at another outlet. The reagent can easily be

transferred to the reaction flask using a syringe.
For large scale transfers, or for the transfer of a pre-cooled solution, a
cannula can be used. To use a cannula, first fit the 3-way tap of the reagent
flask with a septum, turn the tap to the closed position and disconnect from

inert
gas

(a) (b)
Figure 8.8
the manifold. Then pressurize the flask with a separate inert gas supply,
turn the 3-way tap to position B, insert a cannula, and transfer the solution
either to the re action flask directly (Fig. 8.8a), or to an addition funnel (Fig.
8.8b).
For more information about cannulation and adjustment of inert gas
pressures see Chapter 5, Seetion 5.4.2.

4. Direct addition 0/ asolid to areaction under inert atmosphere

Although it is much easier to add solids in solution, on some occasions a
solid will have to be added direct1y. With the apparatus connected to a
manifold and with argon as the inert gas, the procedure is often quite
simple. Areaction flask with a stoppered side arm should be used and, after
first increasing the argon flow to give very rapid bubbling, the stopper can
be removed to add the solid reactant. If this procedure is used, great care
should be taken. The stopper should be removed for the minimum time
106 Carrying Out The Reaction

Figure 8.9
required to add the reagent, and you should make sure that it is not added at
a rate which might lead to the reaction going out of control. Alternatively,
an inverted funnel (see Chapter 5) can be used to blanket the apparatus with
an inert atmosphere to protect the reaction mixture.
There are alternative arrangements for adding sölids, but none are
universal. One method is to attach a bent tube containing the solid to the
side arm of the fIask, and twist the tube to allow the compound to pour into
the reaction fIask (Fig. 8.9).

8.2.7 Use of balloons for holding an inert atmosphere

Although we recommend using the double manifold techniques described
above, reactions can also be kept under inert atmosphere by using a balloon
filled with inert gas (Fig. 8.10). This can prove particularily useful if a
double manifold system is not available. To do this you ftrst ftll the balloon

_ _- - tubing - - - -
~!!!EJ

Figure 8.10
 Carrying Out The Reaction 107

with the inert gas from a cylinder, then attach it to the reaction system using
either a needle/septum or 3-way tap, taking care to ensure that there are no
leaks in the system.
In the case of the needle/septum attachment, any air contained in the
reaction tlask is then tlushed out by using another need1e to vent the system
(Fig. 8.11). After the reaction tlask has been thoroughly tlushed with the
inert gas, the extra needle is removed and the reaction tlask is ready for use.
The balloon keeps the whole system under a positive press ure of the inert
gas, and also allows liquid materials to be added to, or removed from, the
tlask via syringe insertion through the septum.

balloon filled
with inert gas---+-

needle allowing air

~ to be flushed out

Figure 8.11
Generally argon is preferred when using this technique because it is
more dense than air, and will fill the reaction tlask, pushing out any air more
effectively than would nitrogen. This technique can also be employed when
syringing air-sensitive materials from bottles or containers.
With the three-way tap attachment, a vacuum line can be connected
(Fig. 8.10). The system can then be purged by sequentially evacuating,
then filling with the inert gas from the balloon. This is a more effective
procedure than simply tlushing out the tlask and so both nitrogen and argon
can be used with this set-up. Liquid materials can then be added to the tlask
by syringe via the septum inlet as before.
Since balloons are perishable it is often advisable to use a 'double
balloon system'. This is simply two balloons, one inside the other,
allowing the inert atmosphere to be maintained even if one bursts.
108 Carrying Out The Reaction

How to make a balloon attachment

Balloon attachments are easily constructed as outlined in Fig. 8.12. First
the balloon (or double balloon) is pushed over a piece of rubber tubing
which is about the same diameter as the balloon neck. This is secured in
/ balloon (not inflated)

c==5~ . . c> . . ~
1!
rubber tubing 3
t ta
~'''''''"' ..._ -woy p

+needle

Figure 8.12
place using a piece of wire, elastic band, or parafilm. The open end of the
tubing can then be attached to a three-way tap, or to a needle-tubing adapter
and needle as shown. It is advisable to seal all joins with parafilm in order
to ensure that there are no leaks.
Setting up areaction
Once the balloon system has been constructed, the reaction system is simply
set up as outlined in Fig. 8.10.
If the reaction is to be heated, a condenser will need to be fitted, in this
case it may be necessary to use a two necked flask so that materials can be
added to the flask. In such cases the balloon should be placed at the top of
the condenser in order to prevent volatile liquids reaching it.
All joints should be sealed with Parafilm or Teflon tape, the latter being
especially useful if the system is to be heated (Parafilm melts!).

8.2.8 The use 0/ a 'spaghetti' tubing manifold

The main drawback with balloons is that they have a tendancy to burst and
this can have grave consequences, especially if you are working on a small
scale. A spaghetti manifold (Fig. 8.13) will provide a similar low pressure
inert gas source, but is much more reliable. It is particularly useful if you
need to set up several small sc ale reactions running in parallel to one
 Carrying Out The Reaction 109

another. This is often the case if you need to optimize the conditions for a
reaction.
+- inert gas

'-stopcock
(optional)

tubing

. - syringe needle
(Luer fitting rernoved)

Figure 8.13
The reaction is set up in exactly the same way as described in the
previous section for use of balloons. With either type of set-up a tlc sampie
can easily be removed by pushing a syringe needle through the septum then
inserting the tlc capillary through it. When using the 'spaghetti' manifold it
is often convenient to add reagents, or transfer them, by cannulation using a
Teflon cannula (Fig. 8.14, see also Chapter 5, Seetion 5.4.2).

syringe needle.-.
(vent)

Figure 8.14
110 Carrying Out The Reaction

8.3 Reaction monitoring

Most people who are new recruits to the research labs learned their basic
skills for carrying out reactions in an undergraduate laboratory. Inevitably,
most of the organic chemistry undertaken in these lab c1asses involves
following 'recipes', which have been well tried and tested. Therefore the
conditions and the time taken for the reactions to reach completion is well
established, and work-up can be carried out after apreset time.
Unfortunately, the idea that you can guess the time it takes for areaction to
reach completion is a very bad habit to carry over into a research
environment.
Every reaction you carry out should be monitored, and one of the first
things you should do before starting any reaction is to decide on a suitable
method for monitoring its progress. Even if you are following a literature
procedure, reaction monitoring is still essential and it will usually save you
time as well as giving you confidence about what is happening. Carrying
out areaction without monitoring its progress is like trying to thread a
needle with your eyes c1osed!
The simplest and most universal method of reaction monitoring is thin
layer chromatography (tlc) and this will be discussed first of all, but it is not
always the best or only method, and sometimes you may have to use a little
ingenuity to find an appropriate reaction monitoring technique.

8.3.1 Thin layer chromatography (tlc)

Tlc is a simple, but extremely powerful analytical too1. However it may take
a little time before your expertise reaches a consistently high level, since a
certain amount of intuition is always involved in choosing the appropriate
solvent system, spotting the correct amount of sampie, etc. Once you have
gained experience and confidence in the use of tlc, you will find it extremely
useful for a variety of purposes.
The main uses 0/ tlc
1 . Tlc is normally the simplest and quickest way to monitor areaction and
the reaction mixture should be chromatographed against starting
materials (and a co-spot). This allows you to follow how the reaction
is progressing, and to assess when is the best time to work it up. In all
 Carrying Out The Reaction 111

cases arecord of the tlc should be made in your lab book (see Chapter
2).
2. TIc can be used to indicate the identity of a compound, by comparing
the unknown sampie with a known material. In general each substance
is spotted separately and also together (co-spot). Caution should be
applied as co-running on tlc is not definitive proof of identity. Of
course, substances that do not co-run are definitely not the same.
3. TIc usually gives a good indication of the purity of a substance.
Diastereoisomers can usually (but not always), be distinguished.
4. For flash chromatography (see Chapter 9), tlc is first used to determine
the solvent system and quantity of silica required, and secondly to
monitor the column fractions.
Tlcplates
There are two main types of coating for tlc plates, silica and alumina. Silica
plates are most commonly used, they are slightly acidie and are suitable for
running a broad range of compounds. Most of the information in this
section refers directly to silica plates, but the same principles apply when
using alumina plates. Alumina plates are slightly basic and are quite
commonly used when a basic compound will not run very well on silica.
The most common tlc plates have either a glass or plastic backing
coated with a thin layer of silica, which contains a binding agent to keep it
bonded to the backing. Although tlc plates can be horne-made, most people
prefer to use commercial ones as they give very consistent results. For
analytical purposes plates with a O.25mm layer of silica are normally used.
They are available in a variety of sizes, although 5 x 20cm is probably the
most convenient size. The chromatographs are run along the 5cm length,
cut to an appropriate width. This normally gives adequate resolution, with a
very short running time. Plastic backed plates are sometimes cheaper and
can easily be cut into strips with scissors, but glass plates see m to give
better resolution and can be heated more vigorously for visualization
purposes.
To cut a glass tlc plate, place it face down on a clean piece of paper,
hold a ruler firmly along the proposed cut and draw a sharp diamond glass
cutter along the line once only. Then holding the plate with the forefinger
and thumb of each hand, on either side of the score line snap the plate along
112 Carrying Out The Reaction

the line. With practice, and a good glass cutter, you should be able to cut
plates down to about 1.5cm without ever spoiling them.
The proeedure for running a tle
1. Cut a tlc plate which is 5cm long, and wide enough so that about O.5cm
can be left between each spot (obviously the width of the plate is
dependant upon the number of spots to be run on it).
2. Make a tlc spotter by drawing out a Pasteur pipette or melting point tube
to about O.5mm using a micro burner. The spotter can be used many
times provided you wash it with clean solvent in between runs.
3. If the substance to be analysed is not already in solution, take it up in a
volatile solvent as a ca. 1-2% solution. A non-polar solvent is
preferable but methylene chloride is often used as a universal solvent
for tlc sampies. Reaction mixture solutions can be diluted down if
necessary, and with experience making sampies to a reasonable
strength becomes intuitive.
cover
I
,
tlc plate
tlc tank-
l
solvent front
tlc plate "
tlc spotter -----.... !
l ,,
j - filter paper
!

t
solvent
starting reaction
material mixture Ch) Cc)

co-spot

(a)
Figure 8.15
4. U sing the spotter, spot a small amount of each solution about O.5cm
from the bottom of the plate, leaving a similar distance between each
spot. The spots should be kept as small as possible, and you should
take care to make sure that each of the spots is the same distance from
the bottom of the plate (Fig. 8.15a).
 Carrying Out The Reaction 113

The absolute distance which a compound runs up a tlc plate is

extremely variable, depending on the exact conditions under which the
plate was run. 1t is therefore much more informative to run
comparative tlcs. When analysing areaction mixture, it should always
be run in comparison with the starting material and a mixed spot should
also be run. This is very important because it often enables you to
distinguish between compounds which run in almost identical
positions.
5. Place the plate upright in a tank lined with a filter paper and containing
the chosen solvent system (to a depth of ca. O.3cm as shown in Fig.
8.15b). Allow the solvent to creep up the tlc plate until it is ca. O.3cm
from the top, then remove it, and mark the level of the solvent front
(Fig. 8.15c). A 150mllipless beaker makes a convenient tlc tank and a
petri dish can be used as a cover.
Detecting the spots
The three general ways to visualize spots on tlc plates are listed below. Any
one or combination of these techniques can be used, but they should be
carried out in the order shown, as the first two techniques are non-
destructive.
1 . The plate can be viewed under a ultraviolet lamp to show any uv-active
spots.
2. The plate can be stained with iodine. This can be achieved rapidly, by
shaking the plate in a bottle containing silica and a few crystals of
iodine. The iodine will stain any compound that reacts with it and so is
especially good for visualizing unsaturated compounds. Most spots
show up within a few seconds, but the stain is not usually permanent.
3 . The plate can be treated with one of the reagents listed below and then
heated to stain the spots. The reagent can be sprayed onto the plates,
but this technique is quite hazardous and it is more effective for them to
be dipped in the reagent. To do this, first let the tlc solvent evaporate,
then holding the edge of the plate with tweezers, immerse the plate as
completely as possible in the stain and remove it quickly. Rest the edge
of the plate on a paper towel to absorb the excess stain before heating
carefully on a hot plate or with a heat gun, until the spots show. This
method is always permanent and so should be done last. When glass
114 Carrying Out The Reaction

plates are used the spots can sometimes be seen more c1earIy from the
glass side of the plate.

Stains U selcomments
Vanillin Good general reagent, gives a range of colours.
PMA Good general reagent, gives bIue-green spots.
Anisaldehyde Good general reagent, gives a range of colours.
Ceric suiphate Fairly general, gives a range of colours.
DNJ># Mainly for aldehydes and ketones, gives orange
spots.
Permanganate# MainIy for unsaturated compounds and
alcohoIs, gives yellow spots.

# - usually do not require heating.

Recipesjor visualization reagents.

Vanillin: vanillin (15g) in ethanol (250ml) + conc. H2 S04
(2.5ml)
PMA: phosphomolybdic acid (l2g) in ethanol (250mi).
Anisaldehyde: anisaldehyde (15g) in ethanol (250ml) + conc.
H 2S04 (2.5ml).
Ceric sulphate: 15% aqueous H 2S04 saturated with ceric sulphate.
DNP: 2,4-dinitrophenolhydrazine (12g) + conc. H 2 S04
(6OmI) + water (80m1) + ethanol (200ml).
Permanganate: KMn04 (3g) + K2 C03 (20g) + 5% aqueous NaOH
(5ml) + water (300m1).

Solvent systems and polarity

The distance which a compound travels up a tlc plate depends on two
factors, its polarity and that of the solvent. In the same solvent, the more
polar the compound, the more tightly it is bound to the silica (or alumina)
and the less it travels. There are some common trends, and with experience,
it is often possible to predict whether a product will be Iess or more polar
than the starting material. For exampie when a ketone, or ester is reduced,
the resultant alcohol is almost always significantly more polar, and a clean
transformation to a lower running spot will indicate a successful reaction. If
 Carrying Out The Reaction 115

the polarity of the solvent used for elution is increased the spots will move
further up the plate and the distance between the centres of the spots usually
increases, up to about half way up the plate. However, the spots also
become more defuse, the further they travel, so an Rf value of about 0.4 is
normally the optimum for analytical purposes.
The best tlc solvent system for a particular compound or mixture can
only be determined by trial and error. However it is good practice to stick to
a 'standard' solvent mixture, which can be used most of the time and you
are familiar with. The most widely used solvent mixtures are based on a
non-polar hydrocarbon, such as 40/60 petroleum ether or hexane, with a
polar constituent added in a proportion which gives a suitable polarity.
Probably the most popular 'universal' tlc system is petroleum ether - ethyl
acetate, the polarity of which is easily adjusted by changing the proportions
of the two solvents. If the compounds being analysed will not travel in
ethyl acetate mixtures, a more polar solvent such as ethanol is used as the
additive. On the other hand, if the compounds travel too far a less polar
additive such as petroleum ether is used.
The degree of separation between compounds will also vary according
to the solvent used, so if compounds do not separate or give poor separation
in one system, different systems should be tried. Where there are a number
a compounds in a mixture it may be best to use two or more different
systems, for resolving the polar and non-polar components.
Common tlc solvents fall ioto one of three categories based on polarity,
with smaller variations within each category.
Very polar solvent additives: methanol> ethanol> isopropanol

All much more polar than:

Moderately polar additives: acetonitrile > ethyl acetate> chloroform >
dichloromethane > diethyl ether> toluene
All much more polar than:
Non-polar solvents: cyclohexane, petroleum-ether, hexane,
pentane
Most solvent systems consist of one of the non-polar solvents together
with a solvent from one of the other c1asses. However, for very polar
compounds, one of the moderately polar solvents can be used as the less
116 Carrying Out The Reaction

polar constituent. An example of this is chloroform - methanol mixtures,

which are useful for highly hydroxylated compounds. The chlorinated
hydrocarbons are also commonly used as single components.
Rfvalues
The Rf value of a compound depends upon the conditions under which the
plate was run and is only accurate to about 20%, therefore it is best to
compare compounds on the same plate, and run a mixed spot. However, it
is useful to record the Rf value of a compound, remembering to quote the
solvent system.

Rf = Distance of centre of the spot from the baseline

Distance of solvent front from baseline
Multiple elutions
It is sometimes useful to elute a particular tlc plate several times and so
improve the separation of closely running spots. In practice this is done by
eluting the tlc plate as normal, removing it from the tlc tank and allowing the
solvent to evaporate from it, and then re-eluting the plate as before. Eluting
a plate n-times is effectively the same as running a plate n-times its length.
Running acidic or basic compounds
Acidic and basic compounds often streak up the tlc plate. However, they
will usually form distinct spots if, for acids a small amount of a carboxylic
acid (e.g. acetic acid) is added to the solvent system, and for bases a small
amount of amine (e.g. triethylamine) is added.
Running acid sensitive compounds
The silica on tlc plates is acidic in nature, and so compounds that are
sensitive to acid may weH decompose on dc. There are several ways of
getting around this problem, you can use alumina t1c plates (these suffer
from the disadvantage that resolution is generally not as good, and the plates
are basic in nature), or alternatively you can add a smaH amount of an amine
(usually ammonia or triethylamine) to the solvent mixture to neutralize the
acidic sites on the silica.
Checking for decomposition
Some organic compounds do decompose on silica to some extent, if you
suspect that this is happening you can check by running a two-dimensional
 Carrying Out The Reaction 117

plate. This is done by cutting a square plate (ca. 5cm x 5cm) and spotting
the compound in the bottom left-hand corner (ca. O.5cm from the bottom) as
shown in Fig. 8.16a. The plate is then eluted as nonnal to give the spots in
a line up the left-hand side of the plate. The plate is then removed from the
tlc tank and the solvent allowed to evaporate. It is then placed back in the
tank with the line of spots along the bottom, and re-eluted (Fig. 8.l6b).
decomposition

~.

elute
(a) (b) (c)

Figure 8.16
The result, if no decomposition is occurring will be the tlc running
diagonally across the square plate, however if decomposition is occurring,
the spot due to the unstable compound will show decomposition products
off-diagonal (Fig. 8.16c).
It is very useful to carry out this test before any fonn of preparative
chromatography, if you suspect that a compound may be labile on silica.

8.3.2 High performance liquid chromatography (hplc)

There is a broad range of hplc techniques, and many different types of
equipment. It is beyond the scope of this book to describe in great detail the
methods for operating the equipment. This seetion will therefore focus on
some of the ways that hplc can be used to aid the synthetic organic chemist.
Description 01 hplc
The general arrangement of an hplc system is fairly simple, as shown in
Fig. 8.17.
Solvent is pumped from a reservoir through a piston pump, which
controls the flow rate. From the pump the solvent passes through a pulse
damper, which removes some of the pulsing effect generated in the pump
118 Carrying Out The Reaction

injeclion valve
(sampIe being
loaded onlO loop)
pulse darnpcr
j / r······················_·_.. _··l
pump

I
= !~ '
-OOI"m~--~
filler c:::::J
a 0 a a
a a
·····················1 injcelion valve
(sam pIe ßowing
a 0
onlO column)

/
deleclOr sampIe out

i
chart recorder
Figure 8.17
and also acts as apressure regulator. In between the pulse damper and the
column there is an injection valve which allows the sampie to be introduced
into the solvent stream. In the 'load' mode the solvent by-passes a sampie
loop, into which the sampie is injected from a syringe. On switching to
'inject', the solvent stream is diverted through the load loop, introducing a
very accurately measured volume of the sample solution onto the column.
Components are separated on the hplc column in exactly the same way as
they would be on a tlc plate, the less polar compounds running faster and
coming through first. The effluent from the column passes into a detector
(usually an ultraviolet or refractive index) which produces a signal on the
chart recorder when a component is present.
The time at which the compound comes off the column is characteristic
of that particular material, and is referred to as the retention time.
The area under any peak on the chart recorder is proportional to the
quantity of that component and the method is therefore quantitative.
Uses 0/ analytical hplc
Finding a tlc system and running a sampie can be done very quickly and for
this reason tlc is the normal method of choice for routine reaction
monitoring. However, there are occasions when it is worth spending the
time to set up an hplc system for reaction monitoring, especially if, as in
many modern synthetic labs, you have a system close to hand. One reason
to use hplc is that the compounds in which you are interested do not separate
very weil on dc. The other common reason is that you require a quantitative
 Carrying Out The Reaction 119

technique. This may be the case if you are trying to optimize areaction to
maximize the quantity of one produet over another, and for this type of
extended study it is well worth the time it takes to set up the system. For
most synthetie purposes it is the relative, rather than the absolute
proportions of substances which are important, and if that is the case a
simple comparison of integrated peak areas may be all that is required. If
aeeurate quantification is needed, then a ealibration is required and this ean
be done using an intern al standard (see below).
Another common use of hplc is for identification of a compound by
comparison with a known substance. Under a specific set of conditions
(solvent, flow rate and quantity applied) any compound will have a specific
retention time and this can therefore be used as a characteristic of the
compound. However, just as a mixed spot should be always be run when
comparing substanees on tle, so with hplc a single enhanced peak should be
observed when the comparison substance and the unknown are injected as a
mixture. Again caution should be used, sinee a single peak is not absolute
proof that compounds are the same.
Preparative hplc is now beeoming widely used in organie ehemistry for
separating eompounds with very similar polarity (see Chapter 9 for more
details). Before committing all your material to a preparative column it is
always best to run a small quantity of the sample on an analytical eolumn, in
order to work out the best eonditions. Indeed, eolumns are produeed in
various sizes which are directly comparable with one another.
If you are monitoring a reaetion by hplc and you want to know the
identity of one or more of the products, you can often separate a few
milligrams from a few runs on the analytical column, wh ich is enough to get
a fuH range of speetral data. On simple hple systems this ean be done
manually by collecting the effluent from the column when the peak of
interest is coming off, and repeating several times. On more sophisticated
systems a fraction collector is often incorporated and in so me cases
injections can be made automatically, so that the system can be set up to
collect a particular peak or peaks over a large number of runs.
Several methods are now available for coupling an hplc system to a
mass spectrometer, so that a mass spectrum is produced for each peak thus
providing some structural information.
120 Carrying Out The Reaction

Quantitative analysis
For any type of detector each compound will have a different response, but
for a particular compound, the area under its peak is directly proportional to
the mass of material which produced the peak. If you are using a uv
detector to analyse two compounds which have the same chromophore and
extinction coefficients, then you can compare peak areas direct1y to
determine the proportions of each compound.
Since the peak area is proportional to the mass of a compound, it is
possible to take a known mass of a compound, make a standard solution
and inject specific quantities, to work out the proportionality constant.
However, a more accurate method of calibration is to use an internal
standard. To do this follow the procedure below:
1 . Choose as a standard a readily-available stable compound, with a
retention time away from the peaks of interest.
2. Make up at least three mixtures containing known quantities of the
standard and each of the compounds which are to be analysed.
3. Run the mixtures and measure the areas of each peak -
The mass of material under any peak, y, is:
My = ky x Areay
now, comparing the area under the standard peak with that under the
unknown:
My/M(std) = ky/k:(std) x Areay/Area(std)
Using this equation we can work out ky!k(std) which is a constant ky ,
known as the correction factor for compound y. Using data from each
of the runs, the average correction factor for each compound is
calculated.
4. Now if we want to calculate the quantity of a compound in a mixture,
the mixture is spiked with a known quantity of the standard and the
following equation is used:
My = ky/M(std) x Areay/Area(std)
Peakshape
For good quantitative results from analytical hplc (or gc, see below) you
should aim to produce chromatographs with symmetrical peaks. Tailing of
the peaks is usually caused by overloading and can thus be avoided by
 Carrying Out The Reaction 121

reducing the quantity of sample applied. If this does not solve the problem
and the tail of a component is long and drawn out, there may be an
incompatibility between the compound and the stationary phase, a problem
which is less easy to rectify.
Hplc can also be used for preparative separations and this is described
in Chapter 9.

8.3.3 Gas-liquid ehromatography (ge, gle, vpe)

Gas-liquid chromatography is becoming increasingly popular for reaction
monitoring and for analysis of reaction products. It can be used for the
analysis of any compounds which are volatile below about 300·C and
thermally stable. It is not the intention of this section to give a detailed
description of gc instrumentation, but simply to outline some of the uses of
the technique for reaction monitoring and related work.
Deseription of gas ehromatography
Gas chromatography is a very sensitive technique requiring only very small
amounts of sampie (1O-6g). A solution of about 1% is sufficient and a few
microlitres of this is injected into a heated injector block. A stream of carrier
gas, usually helium, passes through the injector and sweeps the vapours
produced onto the column, which is contained in an oven. The temperature
sampie injcction

~ flame ionization
injection port dctcctor

carrier gas ------ 1

(hClium)p=~liillr'F===O::::;::[::C;:==1i1 r--...,

amplifier

_ ovcn

Figure 8.18
122 Carrying Out The Reaction

of the oven can be accurately controlled and can either be kept constant or
increased at a specified rate. Separation of the components in gc is not
based on the principle of adsorption, as it is in liquid chromatography, but
on partition. A gc column is rather like an extremely effective distillation
colurnn with the relative volatility of the components being the main factor
which determines how quickly they travel through the column. The
stationary phase of the colurnn is a very high molecular weight, non-volatile
oil, which has a very large surface area (see below for more detail about
columns) and the gaseous components of the mixture are partitioned
between the oil and the carrier gas at different rates. Thus the components
are separated along the length of the column and emerge as discrete bands.
The gas stream passing out of the column enters a flame ionization detector
(FID) which produces an electric current when a compound is burned in the
its flame. The electric current is amplified to produce a peak on the chart
recorder. These detectors are very sensitive and the response produced is
proportional to the quantity of material being burned, thus the peak area is
proportional to the quantity of sample. As with hplc, the time taken for a
particular substance to reach the detector is characteristic of that substance,
and referred to as the retention time.
Types 0/ gc column
A gc colurnn must contain a liquid stationary phase with a large surface area,
which must be supported, so that it stays in the colurnn and the gas can pass
through it. Packed columns are the traditional type, they are made from
metal or glass coils, and have an internal diameter of about 2 to 4mm. The
stationary liquid phase is coated on particles of solid with which the column
is packed. There are a wide variety of stationary phases available ranging
from Apiezon greases, which are very non-polar to polyethylene glycols
which are very polar. With packed columns the choice of stationary phase
is often critical for good separation and a good deal of experimentation is
usually required before the best material is found.
The development of modern capillary columns has led to improved
resolution and has also simplified the process of running gcs considerably.
The columns are normally made from fused silica capillary with an inside
diameter of between 0.2 and 0.5mm, and are polymer coated. They have no
packing, but instead the liquid stationary phase is bonded to the inside wall
of the capillary, and this allows gas to flow very easily. Because of this the
 Carrying Out The Reaction 123

columns can be made much longer than packed columns (between 12 and
100m) and they are typically ten times as efficient. Capillary columns give
extremely high sensitivity and only a very small quantity of material is
required. For this reason the injector normally incorporates a 'splitter', so
that only a small portion of the sampIe injected actually enters the column.
The development of capillary columns has been largely responsible for
the increased use of gc for monitoring organic reactions and for product
analysis. The increased sensitivity of these columns is one important reason
for this, but the fact that they are very simple to set up and operate is
perhaps more significant. The type of stationary phase is not so critical as
with packed columns and the gas flow rate is essentially determined by the
column, so the instrument can be operated successfully with minimal prior
expertise. For most purposes relating to preparative organic chemistry it is
sufficient to rely on just two types of column, one non-polar (such as a
BP1) and one polar column (such as a BP20).
Uses of gc for reaction monitoring and product analysis
Capillary gc instruments are so simple to use that, provided there is one
c10se by, monitoring areaction by gc is almost as quick as running a dc. It
is common to turn to gc monitoring when dc does not provide resolution
between starting material and product or between one product and another.
Gc will usually separate components which co-run on dc. We also find that
some compounds, such as amines, which do not run very weIl on tlc, can
be analysed very easily by capillary gc.
Gc also provides quantitative analysis and is widely used for
determination of product ratios from diastereoselective reactions, down to
about 200:1. This makes it an ideal technique for optimization studies,
where a large number of small-scale reactions are carried out under different
conditions and product ratios are measured simply by syringing out a few
microlitres from each and then injecting into the gc instrument earlier.
For absolute quantitative studies the gc instrument can be calibrated in
exacdy the same way as described for the hplc instrument. Some people use
this technique to measure theoretical yields for reactions, although it is
always preferable that isolated yields are quoted.
The identity of a compound can often be determined by gc, if an
unknown has the same retention time, and co-runs with a known compound
when the two are injected as a mixture, but just as with tlc and hplc co-
124 Carrying Out The Reaction

running, caution should be exercised. A very powerful structure analysis

technique is gc mass specrometry (ge-ms) and when eapillary gc is used this
is a very simple and quick form of analysis. The mass speetrometer simply
aets as the deteetor, but as weH as providing a ehromatograph, a mass
speetrum of eaeh individual eomponent is obtained. Capillary ge-ms is a
very sensitive technique and mass speetroseopie data ean be obtained even
on very minor components of a mixture.
One example ofhow ge and ge-ms can be useful is shown in Fig. 8.19.
The first time this reaetion was earried out, tle analysis indieated that the
starting material had been eompletely transformed to a single product, whieh
ran as one spot in a number of solvent systems, but the produet did not
appear to be pure by IH nmr speetroseopy. When a ge-ms was run on the
reaetion produet, two eompounds (which ran together on tle) were separated
and easily distinguished as eompounds A and C. Also, 3% of isomerie
eompound B was identified and although this runs separately from A and C
on tle it had not been deteeted previously due to lack of sensitivity.

EtO~O
~ ~l~?+
.....-y~o
E t 0 ' ( ' A :0
° l..
...... "'>
+ I
0
+
0

A B c
Figure 8.19
Having diseovered the identity of the re action produets by ge-ms,
produet ratios for aseries of reaetion were obtained using simple ge and we
were thus able to find optimum eonditions for generation of eompound A.
In this seetion we have not endeavoured to give a eomprehensive
review of methods which ean be used for reaetion monitoring, but we have
deseribed the most universal and eommonly used modern teehniques.
Various other monitoring methods ean be devised for specifie reaetions.
For instanee ultraviolet (uv) speetroscopy ean be used if one strong
chromophore is being eonverted to another, but the disadvantage of
speetroseopic methods is that they do not indieate how many produets are
being produced. Nmr speetroseopy ean also be employed and this is
mentioned further in Chapter 10.
 Carrying Out The Reaction 125

8.4 Reactions at other than room temperature

In many cases it is necessary to carry out reactions at non-ambient
temperatures. U sually reactions that are exothermic or involve the
intermediacy of thermally-unstable species have to be carried out at low
temperatures, typically in the range o·e to -lOO·e. Similarly, reactions that
are endothermic or have high energies of activation have to be carried out at
higher temperatures, typically in the range 30·e to 180·e although in some
cases temperatures exceeding 300·e may be necessary. This section deals
with the techniques involved in such situations.

8.4.1 Low temperature reactions

]ow-tempcrature septum
thermometer
,/
inert
ga

coolant

lagged
bath ________ ~IM----r--:---t'I
~

Figure 8.20
Reactions are usually carried out below room temperature by placing the
reaction vessel in a cooling bath. In general this is done by placing a
cooling rnixture into a lagged bath, and then immersing the reaction vessel in
the cooling mixture to a depth that ensures the reaction contents are below
the level of coolant (Fig. 820). The temperature of the coolant can be
monitored by means of a low temperature thermometer' immersed in the
bath. It should be noted when carrying out reactions using cooling baths,
that the reaction itself may not be at the same temperature as the bath due to
exothermic processes taking place, so where possible the internal reaction
temperature should also be monitored. A particularly convenient way of
doing this is to use a digital low-temperature thermometer. These are
126 Canying Out The Reaction

hypodcrmic
probe -

incTl
gas
reacLion mixturc

Figure 8.21
commercially available, and most come with a hypodermic probe which can
be inserted into the reaction flask through a septum (Fig. 8.21). The
temperature can then be noted and the probe withdrawn. This is often a
much easier procedure than the more usual method of setting up the reaction
apparatus to inc1ude an internal thermometer, and is particularly useful for
small-scale set-ups where an internal thermometer cannot be used.
In general all low temperature reactions should be done under inert
atmosphere (nitrogen or argon) to avoid atmospheric moisture from being
condensed into the reaction mixture.
The three main types of cooling mixtures are described below:
i) lee-salt baths. Various salts or solvents can be mixed with crushed ice
to produce sub-zero temperatures. In practice, temperatures ranging
from o·e to -40·e can be obtained (see Table 8.1); however at the
lower temperatures the cooling mixture consists of granular ice-salt
partic1es with little or no liquid, and so this can result in poor thermal
contact with any vessel immersed in it. For the lower temperatures,
where careful temperature control is important, it is preferable to use a
liquid or slush coolant which has good thermal contact with any vessel
immersed in it.
 Carrying Out Tbe Reaction 127

Table 8.1: Ice-based cold baths 1

Additive Ratio (ice/additive) Temperature 'C

Water 1:1 o
NaCI 3:1 -8
Acetone 1:1 -10
CaCI 2·6Hp 4:5 -40

ii) Dry ice-solvent baths. Solid carbon dioxide (dry ice) is commercially
available as pellets or blocks, and forms very good cooling mixtures
when combined with a variety of organic solvents (see Table 8.2). In
practice the baths are prepared by adding the dry ice pellets carefully to
a bath containing the requisite solvent until the temperature required is
reached. The temperatures quoted in Table 8.2 refer to baths in which
an excess of dry ice is contained in the solvent. In this case cooling
mixtures ranging from -l5"C to -78'C can be achieved.

Table 8.2: Dry-ice cold baths2

Solvent Temperature 'C Solvent Temperature 'C

Ethylene glycol -15 Chloroform -61

Carbon tetrachloride -25 Ethanol -72
Heptan-3-one -38 Acetone -78
Acetonitrile -42

iii) Liquid nitrogen slush baths. Slush baths are made by adding liquid
nitrogen carefully to a solvent contained in the bath, with continuous
stirring (gi ass rod, not athermometer). The coolant should become the
consistency of ice-cream, and stirring should prevent any solidification.
Again a variety of different liquids can be used to give temperatures
ranging from 13'C to -196'C (see Table 8.3). Such cooling systems
can often be left for several hours if the cooling bath is well lagged,
however for longer periods (overnight) some form of mechanical
cooling is usually necessary. In such instances, the reaction vessel can
1. AJ. Gordon and R.A. Ford, "The Chemist's Companion", J. Wiley and Sons, New
York,1972.
2. A.M. Phillips and D.N. Hume, 1. ehern. Ed., 1968, 54, 664.
128 Carrying Out The Reaction

be placed in a refrigerator, or cooled by the use of a portable

commercial refrigeration unit.

Table 8.3: Liquid nitrogen slush baths 3

Solvent Temperature 'C Solvent Temperature 'C

p-Xylene 13 Chloroform -63

p-Dioxane 12 Isopropyl acetate -73
Cyclohexane 6 Butyl acetate -77
Formamide 2 Ethyl acetate -84
Aniline -6 2-Butanone -86
Diethylene glycol -10 Isopropanol -89
Cycloheptane -12 n-Propyl acetate -92
Benzyl alcohol -15 Hexane -94
0-Dichlorobenzene -18 Toluene -95
Carbon tetrachloride -23 Methanol -98
o-Xylene -29 Cyclohexene -104
m-Toluidine -32 lsooctane -107
Thiophene -38 Carbon disulphide -110
Acetonitrile -41 Ethanol -116
Chlorobenzene -45 Methyl cyclohexane -126
m-Xylene -47 n-Pentane -131
Benzyl acetate -52 Isopentane -160
n-Octane -56 Liquid nitrogen -196

8.4.2 Reactions above room temperature

1. Reactions in a sealed tube
Reactions above room temperature usually require modifications to the
standard equipment set-up. In some instances the reaction can be performed
in a sealed tube, usually made of thick-walled glass. The reaction mixture is
placed in the tube which is then sea1ed, placed in an oven and heated to the
appropriate temperature (Fig. 8.22). After the re action is complete, the tube
is coo1ed, opened and the contents removed. Such a technique is employed
when temperatures in excess of the solvent boiling point are required, or for
reactions involving extremely volatile compounds. This technique naturally
3. R.E. Rondeau, J. ehern. Eng. Data, 1966, 11, 124.
 Carrying Out The Reaction 129

scalcd
lhick-walled lUbe

- -
gl ass tube

~
rcaelion
mixlure

Figure 8.22
requires a high degree of skill, since heating leads to apressure build-up
inside the tube which can result in explosion if there are any flaws in the
seal.
Tcnon _ __
scrcw-lOp
oUllct 10 allow
cvacuation
O-ring seal -

thiek walled
glass lube

reaction
mixlure

Figure 8.23
An alternative to the all-glass sealed tube is to use areaction tube,
which consists of a thick-walled glass tube with a teflon screw seal at the
top (Fig. 8.23). This serves as a re-usable sealed tube apparatus, and
commercial versions of this apparatus are available. 1t also features a useful
side-arm that allows evacuation or purging with an inert gas prior to sealing
the tube.
130 Carrying Out The Reaction

2. Reactions involving the use 0/ a condenser

For most reactions above room temperature, an open system which does not
lead to a build-up of pressure is employed. This usually consists of a

inert
~!:>F'~gäS

- waterout

condenser-

waterin-

heating
bath

hotplate--

.-Ä
~

Figure 8.24
reaction vessel protected with a condenser (Fig. 8.24). The condenser is
used to prevent the evaporation of volatile materials (usually the solvent)
from the reaction mixture.
There are many different designs of condenser available, and the type
used depends upon the nature of the re action involved. The most common
designs of condenser are the Liebig condenser (Fig. 8.25a), the coiled
condenser (Fig. 8.25b), the double-jacketed coiled condenser (Fig. 8.25c),
and the cold-finger condenser (Fig. 8.25d). Other condensers available tend
to be simple modifications of these three types.
The Liebig condenser, the coiled condenser, and the double-jacketed
coiled condenser are similar in design and function. They are water-cooled
 Carrying Out The Reaction 131

via connection to a cold-water tap, in the case of the Liebig condenser the
water flows in at the bottom and flows out at the top giving a jacket of cold
water around the condenser stern and leading to a cold surface on the inside.
Any volatile materials in the reaction condense on the cold outer surface and

(a) (b) (c) (d)

Figure 8.25
run back into the reaction mixture. The coiled condenser functions in a
similar way only now the cold surface is on the inside of the condenser.
This can offer an advantage in particularly humid locations because there is
less tendency for atmospheric moisture to condense on the outside of the
condenser and run down over the reaction vessel. The double-jacketed
coiled condenser is also water-cooled, again water flows in at the bottom
and out at the top. This condenser design tends to be more efficient than the
other two because it provides a greater area of cold surface. Consequently it
is preferred when low boiling materials (:S; 40°C) are involved.
The cold-finger condenser is rather different from the above three. It is
cooled by either solid carbon dioxide / acetone (-78°C) or liquid nitrogen
(-196°C). The coolant is placed in the top of the condenser and more
coolant is added as required. This results in an extremely cold surface on
the inside of the condenser. Condensers of this type are usually employed
for reactions that involve solvents or components that boil at or below room
temperature (e.g. liquid ammonia, b.p. -33°C), although they can be used
for higher boiling materials as weIl.
132 Carrying Out The Reaction

3. Heating devices
As with low-temperature reactions, a common method of increasing the
temperature of areaction is to place the reaction flask in a bath (Fig. 8.23).
In this case the contents of the bath are then heated, usually using a hotplate.
inert

- waterout

condenser -

reaction

heating mantle

~ .-1===::::L-

~
~

Figure 8.26
There are four commonly employed heating baths; water, silicone oil,
Woods metal, flaked graphite, and sand. Water baths consist of a pyrex
glass container filled with water, and are used for reactions requiring
temperatures up to lOO·C. Silicone oll baths are similar in design but can be
used for temperatures up to about 180·C, although the maximum
temperature in this case depends upon the precise type of oil employed.
Woods metal is a commercially available alloy (50% Bi, 25% Pb, 12.5%
Sn, 12.5% Cd) that melts at 70·C. It has excellent thermal properties and so
is a safe material for use at quite high temperatures (up to 300°C). It is
normally used in a steel container, and again heated via a hot-plate device.
 Carrying Out The Reaction 133

Similarly, fIaked graphite and sand can be used in heating baths up to

300·C, although they cool slowly compared with the Woods metal.
Reactions can also be heated by an electric heating mantle (Fig. 8.26),
although in general this is less satisfactory since it is more difficult to control
the temperature of the mantle surface and excessive heating of the re action
flask can result. Because of this, where possible heating mantles should be
avoided for reactions below 100·C although they can be used if necessary.

8.5 Driving equilibria

A number of important organic reactions involve equilibria and do not give
good yields unless the equilibrium can be shifted to the product side. An
equilibrium can be driven to the right by using an excess of one of the
reactants, by continuously removing one of the products, or by chan ging the
temperature or the press ure at which the reaction is carried out. In most
cases use of excess reagent or removal of a product can be achieved
usingnormal apparatus and techniques. This section is concerned with two
methods which involve special apparatus; Dean and Stark traps, and high
pressure reactors.

85.1 Dean and Stark traps

Perhaps the most commonly encountered equilibrium reactions are those
involving water as a reactant or product. Driving such equilibria by using
excess water (e.g. hydrolysis reactions) is easy, but driving equilibria by
removing water (e.g. in ester or acetal formation) can be more difficult. An
excellent device for the continuous removal of water from areaction mixture
is the Dean and Stark trap (Fig. 8.27). The apparatus is assembled as
shown and the reaction is conducted in a solvent which forms an azeotrope
with water (almost invariably a hydrocarbon such as toluene). When the
mixture is heated the solvent/water azeotrope distils over and, on
condensing, is collected in the trap. The water then separates and the light
organic solvent fIows back into the reaction fIasko It is usually easy to
monitor the progress of the reaction either by recording the volume of water
produced or by waiting until the characteristically milky heterogeneous
azeotrope is no Ionger produced.
134 Carrying Out The Reaction

condenser-

Dean-Stark
trap -

- heating bath
.. --- --. - -
Figure 8.27 A Dean and Stark trap
A Dean and Stark trap can also be used to remove volatile alcohols,
such as methanol and ethanol, which are miscible with many organic
solvents. They can nevertheless be removed by placing sA molecular sieves
(Section 4.3) in the trap, in order to absorb the alcohol. An alternative is
use a Soxhlet extractor containing molecular sieves.
On a small scale, simply placing some activated sieves in the reaction
flask is a convenient means of removing water. This method is effective in
driving equilibria and is also used to promote reactions which are adversely
affected by water.

8.5.2 Highpressure reactions

A more esoteric technique is to carry out the reaction at very high pressures
(> lOkbar) , thus shifting the equilibrium to the side of the components which
have the smaller volume. Some transformation of the products must be
carried out as soon as they are removed from the reactor, in order to prevent
re-equilibration. Arecent review l gives an account of some applications of
high pressure techniques.
1. N.S. Isaacs and A.V. George, ehern. Br., 1987,23,47.
 Carrying Out The Reaction 135

8.6 Agitation
For homogeneous reaction systems at constant temperature, agitation is not
normally necessary. However, most reactions involve heterogeneous
reaction mixtures and so require some form of agitation to ensure efficient
mixing of the reactants. The most commonly used methods of agitation are
outlined in this section.

8.6.1 Magnetic stirring

Magnetic stirrer machines are commonly available and come in two general
types: either a simple stirring machine, or one that also incorporates a
hotplate for heating reaction systems (Fig. 8.28). They consist of a box
containing a motor that drives an electromagnet which spins horizontally.
Most magnetic stirrers have a flat top to allow cooling or heating baths (see
Section 4.6) to be placed on top. Agitation of the reaction mixture is
achieved by placing a magnetic stirrer bar (or folIower) in the reaction
mixture. The reaction vessel is then clamped over the top of the stirrer
machine in such a position as to allow the mixture to be stirred by magnetic
interaction of the folIower with the electromagnet in the stirrer machine.
Usually the rate of stirring can be adjusted using a control on the stirrer
machine.
hot-plate

speed contral
l )

,I
/ )
, ,
i
~
~
{} {}
"\ I." '
\/
speed + temperature
controls
Figure 8.28
The folIower consists of a magnet coated with an inert polymer, usually
Teflon or PVC, and come in a variety of shapes and sizes (Fig. 8.29) It is
important that the polymer coating does not react with any components in
the reaction mixture, and because of this Teflon is usually the preferred
coating. The size of the folIower is also important, it should be large
136 Carrying Out The Reaction

enough to stir the reaction mixture effectively but not so large that it will not
sit flat in the bottom of the reaction flask.

c___) ( ~ )
(a) (b) (c)

Figure 8.29 Magnetic followers: (a) bar; (b) octagonal; (c) egg-shaped
Because the follower is driven by a magnetic field and has no
mechanical connection with the stirrer machine, this method of agitation
does not require special modification of areaction apparatus.
Magnetic stirrer machines are probably the most commonly employed
method of agitation for organic reactions, but can become ineffective if
particularly viscous systems are encountered. They may also be ineffective
if the reaction vessel has to be placed inside another piece of apparatus such
as a heating mantle or large cooling bath. In such cases the extra apparatus
can effectively shield the re action flask from the magnetic field created by
the stirrer machine. Magnetic stirring can also be a problem for large scale
reactions (reaction volumes over one litre), and in such cases mechanical
stirring is a valuable alternative.

8.6.2 Mechanical stirrers

Mechanical stirring machines consist of an electric motor clamped above the
re action vessel, that rotates a vertical rod (usually glass, although it can be
steel or Teflon). A vane or paddle is attached to the bottom of this rod, and
it is this that is responsible for agitation of the reaction mixture (Fig. 8.30)
The rod and vane are usually detachable enabling different length rods and
different sized vanes to be used as appropriate. As with magnetic stirrer
machines, the rate of stirring can usually be adjusted by means of a control
on the motor. There are many different designs for the vane, the most
common being acrescent shaped piece of Teflon about 5mm thick. This has
a slot in it that·allows easy attachment to the glass rod (Fig. 8.31). In this
design the vane can be rotated about a horizontal axis and so can easily be
put through the narrow neck of a round-bottomed flask, then rotated into a
horizontal position ready for use.
 Carrying Out The Reaction 137

speed control
!

motor_

glass rod- - stand

stirrer guide-

Figure 8.30

glass rod

~
Teflon paddle glass rod
+ paddle

~+
\
slot to aJlow attachrnent
- ,/

to the glass rod

Figure 8.31
138 Carrying Out The Reaction

Because the mechanical stirrer requires a physical attachment to the

reaction flask, precautions have to be taken if the re action is to be carried out
under anhydrous conditions, or under an inert gas atmosphere. The usual
way of doing this is to use astirrer guide that allows the rod to enter the
reaction flask, but prevents atmospheric gases from doing so. These are
constructed from Teflon (Fig.8.32a), and provide a tight fit between a
ground glass joint and the glass rod. The tight seal around the rod is
achieved by means of an O-ring seal inside the stirrer guide, and a set-up of
this type should be good enough to withstand a vacuum of O.5-0.1mmHg
inside the reaction flask without leaking. Because the guide is constructed
entirely from Teflon it does not require lubrication.

~~~ - tightening nut

ground glass
-..,..::>C>CC><?'" - locking nut - stirrer guide

- Teflon joint ground gl ass

- joint

_ glassrod ground glass

rod

Figure 8.32
Such guides are necessarily expensive, and for many uses that do not
require rigorously controlled reaction conditions a glass guide can be
employed (Fig. 8.32b). This consists of a precision-ground glass tube
attached to anormal ground glass joint. In this case it is essential to use a
ground glass rod that forms a good fit with the tube. Oil lubrication is
required to allow the rod to rotate, and so this set-up is not suitable for
reactions above room temperature that involve volatile solvents which can
leach the lubricant into the reaction mixture.
Because mechanical stirrers use an electric motor mounted above the
reaction flask, there is a serious danger of sparks from the motor igniting
volatile flammable solvents. In such instances the use of mechanical stirrers
powered by compressed air is recommended.
 Carrying Out The Reaction 139

8.6.3 Mechanical shakers

reaction flask
~ counter balance
~ flask

Figure 8.33
Mechanical shakers come in many designs, and are simply motors that will
shake an attached reaction flask. The flask is usually clamped to the shaker
(Fig. 8.33), often with a counter-weight to balance the machine. This is a
useful device for reactions that involve vigorous mixing of two immiscible
liquids for prolonged periods of time, and can also be employed when
efficient mixing of agas and liquid are required (e.g. hydrogenation);
however, for most applications other methods of agitation are preferable.

8.6.4 Sonication

septum

----
_ ultrasonic
balh

Figure 8.34
140 Carrying Out The Reaction

Ultrasonic waves can also be employed as a means of agitation. This most

common arrangement is to use a simple ultrasonic bath, in which the
reaction vessel is placed (Fig. 8.34), although ultrasonic probes can also be
used and are often placed inside the reaction vessel (Fig. 8.35). The latter
arrangement is particularly desirable if precise control of the ultrasound
frequency is required, or if extern al control of the reaction temperature is
necessary. In both cases ultrasonic waves are generated inside the reaction
vessel, causing agitation of its contents. This technique is particularly
useful for reactions involving insoluble solids. The ultrasonic waves break
up the solids into very small particles facilitating solvolysis and reaction.
septum
............... :... : ultrasound generator
inert
gas
/
..--===1 I' I 'li I I I I I1

~
~

ultrasonie probe

Figure 8.35
 CHAPTER 9

Working Up The Reaction

9.1 Introduction
It is important to give some thought to the work up of the reaction before
you attempt it. There are several aspects which need to be considered which
will be dealt with here. First of all do make sure that the reaction has indeed
finished (by careful analysis using your chosen monitoring system). When
using tlc analysis it is sometimes difficult to judge by spotting the reaction
mixture directly on to the tlc plate. In these cases it is often possible to get a
more accurate assessment by withdrawing a small aliquot of reaction
mixture by syringe and adding it to a small vial containing a few drops each
of ether and aqueous ammonium chloride. Agitation followed by tlc of the
organic phase will often give clean, reliable tlc information. This technique
can also be used to screen alternative work up conditions, for example
adding to water or aqueous base rather than ammonium chloride solution, or
using other organic solvents in place of ether.
Having satisfied yourself that the reaction has run to completion, or that
it is time to end the experiment, the appropriate 'quench' is added to the
reaction mixture. Choice of this reagent can be very important in
determining the yield of desired product, and it is obviously vital to use a
reagent or procedure which is safe. Given that the product is expected to be
reasonably stable, which usually is the case, then the choice of procedure
for quenching the reaction is determined by the reagent(s) used in the
reaction. Clearly we cannot cover all possibilities in this chapter, but
general procedures wh ich should cover most of the situations that are likely
to be encountered are provided below. The classification is made on the
basis of the nature of the reaction mixture which is to be worked up.
142 Working Up The Reaction

9.2 Quenching the reaction

9.2.1 General comments
If the re action has been carried out under an inert atmosphere then it is
advisable to add the quench before exposing the reaction mixture to the air.
It is best added as you would add areagent, dropwise by syringe. If the
reaction was run at low temperature, then add the quench at this temperature
and allow to warm to room temperature slowly before opening to the air and
proceeding with the isolation of the product. If the reaction was run at
elevated temperature, allow to cool before adding the quench (still under the
inert atmosphere if used). If an exotherm is possible, ensure that the
reaction is cooled in a cooling bath (e.g. ice/water) if it is not already in a
low temperature bath, and that the quench is added very carefully (if the
scale of the reaction is such that an internal thermometer can be used, then
do so and keep a close eye on the internal temperature while quenching the
reaction).
These general comments apply to the following specific types of
reactions. Obviously if a known, fully described literature procedure is
being used, then follow the work up and isolation process exactly. Only
modify such a procedure if you encounter problems.

9.2.2 Strongly basic non-aqueous reactions

This is a common type of reaction, typical examples would include
alkylation using strong bases (e.g. BuLi, (i-PrhNLi), many organometallic
reagents (e.g. MeLi, Grignard reagents), hydride reducing agents (e.g.
LiAIH4, Na(EtOCH2CH20hAIH2), and cuprate reactions. The most
commonly used quench for this type of reaction is an excess of aqueous
ammonium chloride, added slowly, to protonate anions present and to
destroy excess or unreacted reagent. This can be added at low temperatures,
but if you are concerned about the aqueous solution freezing out (there is
usually no need to worry about this in our experience) then use acetic acid as
the quench. Make sure that enough is added to destroyali the reagent and to
protonate any anions which might be present, but do not add too much as it
can sometimes make isolation and purification of the product more difficult.
In the case of aluminium based reagents such as LiAIH4 and
(i-BuhAlH, alternative procedures are often used to attempt to avoid very
 Working Up The Reaction 143

fine precipitates which are difficult to filter and which can lead to emulsions.
One simple method which often gives good results is to add a saturated
aqueous solution of sodium sulphate dropwise with stirring (and cooling!),
until a very heavy precipitate is forrned (do not add excess solution just to
'make sure'). The supernatant can then be decanted and the solid extracted a
few times with the re action solvent, combining all the organics. (If you try
this, do not dispose of the solid until you are certain that you have obtained
a good recovery of material. It might be necessary to extract further to
obtain all of the product).

9.2.3 Neutral non-aqueous reactions

'Neutral' is taken to cover all reactions which involve neither strong base or
acid. Such a 'neutral' reaction might be in fact slightly acidic (e.g. acid-
catalysed ketalisation) or slightly basic (e.g. tosylation of an alcohol using
pyridine or triethylamine as the base). Clearlya great many reactions fall
into this category and in general the quench can be ammonium chloride
solution or water for mildly basic reactions, and dilute sodium hydrogen
carbonate for mildly acidic reactions.
If a fairly reactive reagent has been used then add the quench carefully
with cooling. For example if p-toluene sulphonyl chloride has been used to
prepare a tosylate, it is useful to add a relatively small volume of water and
stir for an hour or so to destroy any remaining sulphonyl chloride (be certain
to add at least enough to destroy all of the sulphonyl chloride which was
used). This will convert the chloride to the sulphonic acid (present as a salt
with the amine used in the reaction) which is easy to remove in the
subsequent extraction and purification.
As ever, it is important to be certain that your product is unlikely to be
sensitive to (or destroyed by) the quench. For example any reaction which
has been driven to completion by removal of water needs some thought. A
common example of this is acid-catalysed ketalisation. The product ketal is
likely to be sensitive to aqueous acid, so be sure to quench with plenty of
aqueous sodium hydrogen carbonate solution before proceeding with the
isolation.
144 Working Up The Reaction

9.2.4 Strongly acidic non-aqueous reactions

This type of reaction will usually involve the use of a strong Lewis acid
such as TiC4 or BF3.0Et2. It is important to be aware that the addition of
water to these reagents will be exotherrnic and usually liberates strong protic
acid. If the product is likely to be unaffected by the liberated acid, then
water can be used as a quench. It is often the case that the product will be
unstable towards this acid, or at least to contain functionality which will be
destroyed by acid, and in this case aqueous sodium bicarbonate or carbonate
can be used. If a non-aqueous quench is desired then a solution of gaseous
ammonia in the reaction solvent can be used. Quench these reactions
carefully, with cooling, and be aware that the metals used (Ti and Al
particularly) can give rise to insoluble precipitates and be prepared to deal
with the problems which these rnight cause (see below).

9.2.5 Acidic or basic aqueous reactions

To quench these reactions it is usually enough to neutralize with dilute acid
or base, but do consider the product which you wish to isolate. For
example if you are hydrolyzing an ester then no quench will be required, the
desired product will be isolated by the appropriate extraction procedure.

9.2.6 Liquid ammonia reactions

A number of synthetically useful reactions use this as solvent, and usually
involve either the use of, or generation of strongly basic species. The usual
quench for this type of reaction is to add (carejully) an excess solid
ammonium chloride, and allowing the ammonia to evaporate ifume
cupboard).
Conclusion
In conclusion, the correct quench for areaction is usually simple to
determine, given that adequate consideration is given to the reagents used
and the product expected. If you are at all unsure, then remove a small
quantity of the reaction mixture and add it to a via! containing a few drops of
both the quench and the reaction solvent and observe. Tlc analysis (or
whatever analytical technique was used to monitor the reaction) will be
useful in ensuring that all is weIl (or otherwise). It is better to 'waste' a little
product in this way than to lose it all by incorrect choice of quench.
 Working Up The Reaction 145

With the reaction successfully quenched, then the isolation of the cmde
product can be carried out, as outlined below.

9.3 Isolation of the erude produet

9.3.1 General comments

The usual isolation procedure involves partitioning the reaction mixture
between an organic solvent and water (or aqueous solutions). Before
carrying this out it is often useful to remove any solid which is present. It
can be particularly important to remove very fine particles, even if they are
present in a small amount, as these can lead to emulsions forming in
subsequent extractions. This is best achieved by dilution of the (quenched)
reaction mixture with the reaction solvent followed by vacuum filtration
through a Celite pad, made by packing Celite onto a sintered glass funnel
(with the vacuum on). Do wash the pad thoroughly with water, followed
by the solvent wh ich you are using since Celite can contain soluble
impurities. Simply filter the reaction mixture through this pad, and rinse
through two or three times to ensure compIete transfer of your product.
If your solvent has reasonabIe solubility in water then it is advisable to
remove most or all of it at this stage on a rotary evaporator. This is not
always necessary but omitting it can lead to losses of product to the aqueous
phase during extraction. The most commonly encountered examples of this
type of solvent are alcohols and tetrahydrofuran, and the problem gets
worse as the polarity of the product increases.
The reaction mixture can now be partitioned between water (or an
aqueous solution) and an organic solvent. Throughout the extraction
procedure do not discard any extract until you have made sure that you have
a good mass recovery (on weighing the cmde product). If a low recovery is
obtained the rest must be somewhere and it is likely that the product will be
in one of the extracts. For most reactions dichloromethane can be used or
diethyl ether if a solvent less den se than water is required. Dichloromethane
is much safer than ether so use it whenever possible. If a low recovery is
obtained with dichloromethane or ether, then simply extract the aqueous
layers (which you have kept!) with either chloroform or ethyl acetate. These
are more powerful solvents and will often extract polar compounds from
aqueous solutions. If this fails, try saturating the aqueous extracts with
146 Working Up The Reaction

sodium chloride and extracting again with chlorofonn or ethyl acetate.

Whenever you extract with an organic solvent use several portions rather
than one large one as this is much more efficient.
Occasionally you will encounter the problem of emulsions during
extraction. There is no universal solution to this, but a common cause is the
presence ofvery fine particles, which can be removed by fIltration through
Celite as described above. If this fails, try adding sodium chloride to the
aqueous, and try adding another organic solvent.

9.3.2 Very polar aprotic solvents

The most commonly encountered of these are dimethyl sulphoxide (DMSO)
and N,N-dimethylfonnamide (DMF). With these solvents it is often
possible to remove most if not all by adding the quenched reaction mixture
to a relatively large volume of water, and extracting this several times with
ether. The combined organics are then washed with more water. Any
remaining DMF or DMSO will need to be removed in further purification of
the crude product.
With the extractions completed the organic extract needs to be dried. A
lot of the dissolved water can be removed by extracting with saturated brine
and it is advisable to do this. The organic extract is then dried fully by
addition of either anhydrous magnesium or sodium sulphate and standing
for an hour or so (or less if you are in a hurry!), followed by vacuum
fIltration through a sintered glass funnel.
The solvent is now usually removed using a rotary evaporator, with the
final traces being removed using a high vacuum line. Beware when using
the high vacuum line, if your product is volatile it will 'disappear' into the
traps!
At this stage it is very useful (after weighingl) to examine the emde
product by ir, nmr, and tlc before proceeding with purification as this will
give you an idea as to the state of purity amongst other things. The rest of
this chapter is given over to methods for purification of the erude produet.
 Working Up The Reaction 147

9.4 Purification
When a product has been isolated from areaction the next step is to purify
it. The degree of purity required will depend on the use for which the
sampie is intended, a synthetic intermediate might only require rough
purification, whereas a product for elemental analysis would require
rigorous purification. This section describes the most important purification
techniques, crystallization, distillation, sublimation, and chromatography. It
is assumed that the reader is familiar with the basic principles of these
methods, so the emphasis is on more demanding applications such as the
purification of air-sensitive materials, and purifications on a micro-scale.

9.4.1 Crystallization
Simple recrystallization of an impure solid is a routine operation, which
nevertheless requires care and good judgement if good results are to be
obtained. The basic procedure can be broken down into six steps, which
are listed below, together with some tips on how to overcome common
problems.
1. Select a suitable solvent
Find a suitable solvent by carrying out small scale tests. Remember that
'like dissolves like'. The most commonly used solvents in order of
increasing polarity are petroleum ether, toluene, chloroform, acetone, ethyl
acetate, ethanol, and water. Chloroform and dichloromethane are rarely
useful on their own because they are good solvents for the great majority of
organic compounds. It is preferable to use a solvent with a boiling point in
excess of 60·C, but the b.p. should be at least lO·C lower than the m.p. of
the compound to be crystallized, in order to prevent the solute from 'oiling
out' of solution. In many cases a mixed solvent must be used, and
combinations of toluene, chloroform, or ethyl acetate, with the petroleum
ether fraction of similar boiling point are particularly usefu!. Consult
Appendix 1 for boiling points, polarity (dielectrlc constant), and toxicity of
common solvents.
2. Dissolve the compound in the minimum volume 0/ hot solvent
Remember that most organic solvents are extremely flammable
and that many produce very toxic vapour.
148 Working Up The Reaction

Place the crude compound (always keep a few 'seed' crystals) in a

conical flask fitted with a reflux condenser, add boiling chips and a small
portion of solvent, and heat in a water bath. Continue to add portions of
solvent at intervals until all of the crude has dissolved in the hotlrefluxing
solvent. If you are using a mixed solvent, dissolve the crude in a small
volume of the good solvent, heat to reflux, add the poor solvent in portions
until the compound just begins to precipitate (cloudiness), add a few drops
of the good solvent to redissolve the compound, and allow to cool.
When adding the solvent it is very easy to be misled into adding far too
much if the emde is contaminated with an insoluble material such as silica or
magnesium sulphate.
3. Filter the hot solution to remove insoluble impurities
This step is often problematic and should NOT be carried out unless an
unacceptable (use your judgement) amount of insoluble material is
suspended in the solution. The difficulty here is that the compound tends to
crystallize during the filtration so an excess of solvent (ca. 5%) should be
added, and the apparatus used for the filtration should be preheated to about
the boiling point of the solvent. U se a clean sintered funnel of porosity 2 or
3, or a Hirsch or Buchner funnel, and use the minimum suction needed to
draw the solution rapidly through the funnel.
If the solution is very dark andlor contains small amounts of tarry
impurities, allow it to cool for a few moments, add ca. 2% by weight of
decolorising charcoal, reflux for a few minutes, and filter off the charcoal.
Charcoal is very finely divided so it is essential to put a 1 cm layer of a filter
aid such as Celite on the funnel before filtering the suspension. Observe the
usual precautions for preventing crystallization in the funnel. Very dark or
tarry products should be chromatographed through a short (2-3cm) plug of
silica before attempted recrystallization.
4. Allow the solution to cool and the crystals to form
This is usually straightforward except when the material is very impure or
has a low m.p. « 40·C) in which case it sometimes precipitates as an oil. If
an oil forms it is best to reheat the solution and then to allow it to cool
slowly. Try scratching the flask with a glass rod or adding a few 'seed'
crystals to induce crystallization, and if this fails try adding some more
solvent so that precipitation occurs at a lower temperature.
 Working Up The Reaction 149

If nothing at all precipitates from the solution, try scratching with a

glass rod, seeding, or cooling the solution in ice-water. If all these faH,
stopper the flask and set it aside for a few days, patience is sometimes the
best policy.
5. Filter off and dry the crystals
When crystallization appears to be complete filter off the crystals using an
appropriately sized sintered glass funnel. It is very important to wash the
crystals carefully. As soon as all of the mother liquor has drained through
the funnel, remove the suction and pour some cold solvent over the crystals,
stirring them if necessary, in order to ensure that they are thoroughly
washed. Drain off the washing under suction and repeat once or twice
more.
After careful washing allow the crystals to dry briefly in the air and then
remove the last traces of solvent under vacuum, in a vacuum oven, in a
drying pistol, or on a vacuum line. Take care to protect your crystals
against accidental spillage or contamination. If they are placed in a dish, a
beaker, or a sample vial, cover with aluminium foH, sec ure with wire or an
elastic band, and punch a few small holes in the foH. If the crystals are in a
flask connected direct1y to a vacuum line, use a tubing adapter with a tap and
put a plug of glass wool in the upper neck of the adapter so that the crystals
are not blown about or contaminated with rubbish from the tubing, when the
air/inert gas is allowed in.
If a relatively high boiling solvent such as toluene was used for the
recrystallization it is essential to heat the sample under vacuum for several
hours to ensure that all of the solvent is removed.

Small scale crystallization

When sm all samples (less than 200mg) are to be recrystallized it is
particularly important to remove traces of insoluble material and to avoid
contarnination by dust, filter paper, etc. Thus it is essential to use carefully
c1eaned glassware and purified solvents, and to filter the hot solution. The
apparatus shown in Fig. 9.1 is convenient for small scale (5-200mg)
recrysta1lizations. Place the sample in the bulb and wash it with a few drops
of solvent. Heat the bulb in an oH bath or a water bath so that the solvent
refluxes up to the level of the sintered disco Add more solvent, in small
150 Working Up Tbe Reaction

portions, until the compound has dissolved. Remove the apparatus from the
bath, wipe the bulb to remove oll or water, and quickly fIlter the hot solution
into a clean receiver by pressurising the vessel using hand bellows or an
inert gas line. Filtering under pressure in this way avoids the problem of
unwanted crysta1lization, and reduces transfer losses.

Figure 9.1
The hot solution can be fIltered into a sma11 conical fiask, but on a scale
of l00mg or less, a Craig tube (Fig. 9.2) gives better recovery because it
allows the crystals to be recovered without another fIltration.

glass centrifuge
rod- tube ----

crystals

Craig
tube - mother
liquor ------oO~~

(a) (b)
Figure 9.2
Filter the hot solution into a suitably sized Craig tube and cover the tube
with aluminium foil while crystallization occurs. When crystallization is
complete fit the matching (a close fit is essential) glass rod into the Craig
tube and secure it tightly with a rubber band. Place the inverted assembly in
a centrifuge tube (Fig. 9.2b) and put the centrifuge tube (and a counter-
 Working Up The Reaction 151

balancing tube) in a centrifuge. Centrifuge for a few minutes to force the

mother liquor through the narrow gap into the centrifuge tube, and then
remove the Craig tube. Tap the tube to dislodge any crystals attached to the
neck, cover the tube with foil, and dry the crystals under vacuum.
If necessary the product can be recrystallized again in the same tube.
Dissolve in the minimum volume of hot solvent as usual. The neck of the
tube will act as a condenser but care is required, and the tube should be no
more than one third fuH in order to avoid losses due to splashing or frothing
of the refluxing solution. Cooling and centrifuging then gives another batch
of crystals. This process can be carried out several times with minimal
losses.

Crystallization at low temperature

Occasionally the most convenient method of purifying a low melting solid or
a thermally unstable liquid may be by low temperature crystallization. This
technique is attended by two important complications. First, cooling the
materials and apparatus below ambient temperature will cause condensation
to form. If the compound being crystallized is inert to water, and can be
easily dried, then the condensation is not a major problem and normal
recrystallization methods can be adopted particularly if drying tubes are used
to protect the solutions. A more satisfactory solution is to carry out the
crystallization under an inert atmosphere. The second difficulty is that of
keeping the solutions cold during the filtration and washing steps. This can
be achieved by using apparatus which can be immersed in ordinary cold
baths, by using specially built apparatus with integral jackets for holding
cooling solutions, or in small scale work by carrying out these steps very
rapidly.
A number of ingenious solutions to these technical problems have been
developed, but only a few methods which involve standard organic
laboratory glassware will be described here.
For medium to large scale crystallizations (~ 19) a set-up along the lines
shown in Fig. 9.3 may be used. The compound is dissolved in the
minimum volume of solvent at room temperature and is filtered into a two-
or three-necked pear shaped flask. The flask is then fitted with an inert gas
inlet and a thermometer adapter containing a filter stick connected to a
bubbler. With the filter stick held above the solution the flask is purged
152 Working Up The Reaction

with inert gas and placed in a cooling bath. It should be cooled slowly by
gradual addition of the cooling agent to the solvent. When crystallization is
complete the bubbler is disconnected and the filter stick is connected to an
appropriately sized receiver using chemically inert tubing (Teflon). The
filter stick is then lowered into the solution and the mother liquor is forced
through into the receiver using inert gas pressure. The thermometer adapter
will allow sufficient freedom of movement of the filter stick to pack the
crystals to the bottom of the flask and drain off the mother liquor
thoroughly. The crystals can then be washed by releasing the gas pressure
and adding small amounts of precooled solvent via the three-way tap, using
a cannula. The washings can then be removed using the filter stick as
before. The cooling bath can be removed and the crystals isolated and dried
in the usual way or the low temperature recrystallization can be repeated in
the same flask.

to bubbIer
t

flltcr
stick

cooling
balh -

Figure 9.3
The sintered disc of the filter stick should be of porosity 3 or larger in
order to avoid blockage. A convenient alternative to a filter stick is to use an
ordinary glass rod with filter paper wrapped round the end (Fig.
9.4b).Wrap some Teflon tape round the end of the tube, then carefully fold
filter paper over the end and sec ure it with wire. The Teflon tape will give a
better seal because the wire will sink into it. Another alternative, which is
 Working Up The Reaction 153

very useful on a smaller scale, it to use a septum with an inverted ne edle

through it (Fig. 9.4c). Again the end of the needle should be wrapped with
Teflon tape and covered with filter paper, which is then secured with wire.
The sharp end of the needle can be inserted into the receiving flask, thus
obviating the need for connecting tubing (Fig. 9.6). These devices are also
very useful for filtering re action mixtures under an inert atmosphere, as is
the filter flask described in Chapter 5 (Fig. 5.19).

, / glass tube~
_ _ Teflon tape

sintered
/ disk

---- filter paper""""'-

(a) (b) (c)

Figure 9.4
Small scale low temperature recrystallizations can be carried out in the
same device recommended for ordinary small scale work. The solution is
filtered into the flask and the apparatus is then purged with inert gas. The
outlet is sealed with a small septum and the flask immersed in a cold bath
almost up to the level of the sintered disk (Fig. 9.5).

inert
gas

cooling
bath - t&Ss:S:sS~~~~~

Figure 9.5
154 Working Up The Reaction

When crystallization is complete the outlet septum is removed, the

apparatus is removed from the cold bath and wiped dry, and the suspension
is filtered rapidly under inert gas pressure. On a small scale the solution will
not warm up significantly during the short time required to filter off the
crystals. The crystals can be washed with precooled solvent in the usual
way.

Crystallization 0/ air-sensitive compounds

Clearly the recrystallization of air and moisture sensitive compounds must
be carried out under an inert atmosphere. The tricldest step in this regard is
often the introduction of the crude solid into the recrystallization flask. It
may be possible to do this by transferring it very quickly in the air or using a
"blanket" of inert gas under a funnel (Fig. 5.20). For very sensitive
compounds the transfer of the solid must be carried out in a glove bag or a
glove box.
Once the solid has been placed in the flask the remaining problems are
similar to those described for low temperature recrystallizations under inert
atmosphere. Many methods for carrying out inert atmosphere
recrystallizations have been developed but organic chemists are rarely likely
to need anything more sophisticated than those described in the previous
section. Those methods involve inert atmosphere filtration using a filter
stick (Fig. 9.3) or a flask with an integral sintered disk (Fig. 9.5) and we
leave it to the reader to devize variations appropriate to his particular
problem. Figure 9.6 shows a typical set-up which could be used either for
filtration of the hot solution or for removal of the mother liquor from the
recrystallized product.
One particular problem which arises with air sensitive materials is that
they tend to be contaminated with small amounts of decomposition products
which can block filters. Also if a sintered disc is used it must be
scrupulously dry in order to prevent some hydrolysis occurring in the pores
of the disc, which will rapidly block the filter. For these reasons the filter
sticks made using filter paper are probably better than sintered discs, and at
least one dry filter should be kept at hand in case the first one is blocked.
 Working Up The Reaction 155

- inert gas

to
bubbier
t

Figure 9.6

9.4.2 Distillation
Distillation is the most useful method of purifying liquids. It is used
routinely for purifying solvents and reagents and, with care and the correct
apparatus, it can be used to separate liquids whose boiling points are less
than 5°C apart. We will assume that the reader is familiar with the
fundamentals of the theory and practice of distillation but it is appropriate to
begin by reiterating some basic safety rules.
1. Never heat a c10sed system.
2. Remember that most organic liquids are extremely flammable so great
care must be taken to ensure that the vapour does not come into contact
with flames, sources of sparks (electrical motors), or very hot surfaces
(hot plates).
3. Never allow a distillation pot to boil dry. The residues may ignite or
explode.
156 Working Up The Reaction

4. Beware of the possibility that ethers and hydrocarbons may be

contaminated with peroxides (Section 4.4).
5. Carry out a safety audit on the compound you plan to distil to check that
it is not thermally unstable. Some types of compounds, e.g. azides,
should never be distilled.

Simple distillation
The conventional apparatus for simple distillation is shown in Fig. 9.7. It is
only useful for distilling compounds from involatile residues, or for
separating liquids whose boiling points differ by at least SO·C. Moisture
can be excluded by attaching a drying tube to the vent or by connecting the
vent to an inert gas line. It is essential to add so me boiling chips, or better
to stir the liquid, in order to prevent bumping, especially if a finely divided
solid, such as a drying agent, is present.

_ ___ thermometer
/ thermometer adapter

/ stillhead

receiver
adapter
/

tirring bar

Figure 9.7
The flask should be heated in a water bath, or an oil bath, not with a
Bunsen burner or a heating mantle (Section 8.4.2). The temperature of the
bath should be increased slowly until distillation begins and then it should
be adjusted to give a steady rate of distillation. If the boiling point is high
 Working Up The Reaction 157

(> 150·C) the stillhead may need to be lagged with glass wool, and an air
condenser should be used rather than a water condenser.
For routine solvent distillation it is more convenient to use a compact
distillation apparatus such as that shown in Fig. 9.8. These can be bought,
or constructed in two or three convenient sizes to fit the common ground
glass joints.

solid
glass rod

Figure 9.8
If the distillation is being used to dry areagent, the process must be
carried out under an inert atmosphere. To do this, first of all dry all glass
apparatus in an oven, or with a heat gun under vacuum, and purge with
argon whilst cooling. This is most easily accomplished by connecting the
apparatus to a double manifoldlbubbler system (see Chapter 3). Although
Quickfit assemblies can be used, we prefer one piece type distillation
apparatus, as shown in Fig. 9.8 and Fig. 9.9b. When the glassware has
cooled, increase the argon fIow, quickly disconnect the distillation fIask,
add any drying agent required, a few anti-bumping granules, and the liquid
to be distilled, and reassemble the system. Heat the distillation fIask in an
oi! bath (do not carry out distillations using a heating mantIe) and collect the
distillate which comes over at the required temperature. When the
distillation is complete remove the collector and seal it quickly with a
septum. Most reagents can simply be poured into areagent bottle before
sealing, provided you are quick. However, if the reagent is particularly
sensitive to air or moisture a cannulation technique should be used to
transfer it (see Chapter 5). Whatever type of container is used for storage it
is always preferab1e that it be fuH or nearly so.
158 Working Up The Reaction

packing
material

vacuum
jacket
_ v.acuum
Jacket

packing
support

(a) (b) (c)

Figure 9.9

Fractional distillation
Separation of liquids whose boiling points are between SOC and 50·C apart
requires the use of an apparatus which gives better contact between the
vapour and liquid phases in the distillation column. Columns which do this
are called fractionating columns and the most common type, a Vigreux
column, is shown in Fig. 9.9. A 50cm long vacuumjacketed Vigreux (Fig.
9.9a) should allow reasonable separation of compounds which boil30-40·C
apart. The Vigreux assembly shown in Fig. 9.9b is less efficient but is
convenient for routine distillations and gives quite good results at reduced
pressure. The keys to getting good results from a fractional distillation are
to raise the temperature very gradually, and to collect the distillate very
slowly.
Efficient separation of compounds with a boiling point difference of 10-
30·C can be achieved using a long glass tube packed with glass rings or
helices, or for high efficiency, wire mesh rings (Fig. 9.9c). A description
of the technique for operating such columns is beyond the scope of this
 Working Up The Reaction 159

book. Two more sophisticated commercially available designs are the

'Spaltrohr' columns which consist of concentric grooved tubes, and
spinning band columns in which a rapidly spinning spiral band is fitted
inside the column. Both of these systems have low hold ups and give very
high efficiency so they can be used for the separation of small volumes (as
little as Iml) and for separating compounds with very similar boiling points
(as little as 3°C). Consult the manufacturer's manuals for operating
instructions for these devices.

400-::

700-::

600-':
300""
500-':

400~

200~
300-::

100~ 100-=

b.p. at reduced -: pressure in Torr

pressure ('C) ~
b.p. at 700 Torr CC)

0-=

Figure 9.10

Distillation under reduced pressure

Many compounds decompose when heated to their boiling points SO they
cannot be distilled at atmospheric pressure. In this situation it may be
possible to avoid thermal decomposition by carrying out the distillation at
reduced pressure. The reduction in the boiling point will depend on the
reduction in pressure and it can be estimated from a pressure-temperature
160 Working Up The Reaction

nomograph (Fig. 9.10). To find the approximate boiling point at any

pressure simply place a ruler on the centralline at the atmospheric boiling
point of the compound, pivot it to line up with the appropriate pressure
marking on the right-hand line, and read offthe predicted boiling point from
the left-hand line. You can also use the nomograph to find the b.p. at any
pressure if you know the b.p. at some other pressure, by first using the
known data to arrive at an estimate of the atmospheric boiling point. Note
that although pressure is usually measured in millimetres of mercury
(mmHg) it is often quoted in different units, especially Torr. Happily 1
Torr = ImmHg. Boiling points measured at reduced pressure may be
expressed in several ways, e.g. 5TC/25mmHg or b.p.25 57·C. As a very
rough guide a water pump (ca. 15mmHg) will give a 125"C reduction in
boiling point and an oil pump (ca. 0.1 mmHg) will give a reduction of 200-
250·C. A typical vacuum distillation apparatus is shown in Fig. 9.11.

-- Quickfit thermometer

stirring bar

Figure 9.11
The chief difference from the simple distillation apparatus is in the
design of the receiver adaptor. This must allow several fractions to be
 Working Up The Reaction 161

collected without needing to break the vacuum. The simplest design is the
'pig' type shown in Fig. 9.12a. When using a pig, remember to grease the
joint lightly so that the receiver can be rotated while under vacuum, and to
fix the receivers securely using clips.

inert
receiver gas

(a) (b)
Figure 9.12
The procedure for carrying out the distillation is as folIows.
1. Place the sample in the distillation flask (no more than two thirds full)
and add a stirring bar. Anti-bumping granules are not effective at
reduced pressure and so an alternative must be used. A very narrow
capillary which allows a slow stream of air or nitrogen bubbles to pass
through the solution is effective, but brisk stirring using a magnetic
folIower is much more convenient.
2. Assemble the (oven-dried) apparatus, putting a litde high vacuum grease
on each joint. Ensure that the receiver adapter and the collection flasks
are secured using clips, and connect the assembly to a vacuum pump.
One convenient method of doing this is to connect it to a vacuumlinert
gas double manifold (Chapter 3). The pump must be protected with a
cold finger trap and the line should contain a gauge for monitoring the
pressure (Chapter 7).
3. Stir the liquid rapidly and carefully open the apparatus to the vacuum.
Some bumping and frothing may occur as air and volatile components
are evacuated. Adjust the pressure to the required value by allowing
inert gas into the system via a needle valve.
162 Working Up The Reaction

4. Reat the flask slowly to drive off any volatile impurities and then to
distil the product. Monitor the stillhead temperature and collect a forerun
and a main fraction, which should distil at a fairly constant temperature.
Iffractionation is required you may have to collect severaHractions and
it is very important to distil the mixture slowly and steadily.
5. Stop the distillation when the level of liquid in the pot is running low, by
removing the hearing bath.
6. Isolate the apparatus from the vacuum and carefully fill with inert gas.
The flask containing the distillate is now under a dry, inert atmosphere
and should be quickly removed and fitted with a tightly fitting septum.
7. Switch off the pump and clean the cold trap.
APerkin triangle (Fig. 9.12b) is a more convenient device for
collecting fractions on a larger scale. It is operated as follows.
1. Attach a receiver and open both the apparatus and the receiver to the
vacuum using taps A and B. Open tap C and collect the forerun in the
receiver.
2. Close tap C so that the next fraction will collect in the bulb D, while
you are removing the receiver. Use tap B to allow inert gas/air into the
receiver, and then replace the receiver with a new one.
3. Close tap A to temporarily isolate the still. Evacuate the receiver by
opening tap B to the vacuum. Wait until the pressure has steadied,
open tap A, and then open tap C to allow the distillate to drain into the
new receiver.
4. Continue to collect fractions by repeating steps 3 and 4 as necessary.

Small seale distillation

The chief difficulty with small scale distillations is that a significant
proportion of the sampie may be lost in 'wetting' the surface of the column
and the condenser. This problem is reduced by using very compact
designs, but this reduces the efficiency of the columns thus making
fractionation impractical. Different apparatus designs, giving different
tradeoffs between recovery and efficiency, are available. A typical example,
featuring a short Vigreux and a rotary fraction collector, is shown in Fig.
9.13. Very small quantities can be distilled in a cold-finger sublimation
apparatus (Fig. 9.15). Spinning band and Spaltrohr columns combine high
 Working Up The Reaction 163

efficiency with low hold up so they provide an effective, if expensive,

solution to the problem of fractionation of small volumes (> 1ml).

- [0 vacuum

stirring bar

Figure 9.13
Another popular solution to these problems is the Buchi Kugelrohr
apparatus (Fig. 9.14). The key features of this system are (i) a horizontal
oven (made of glass or metal) with an iris c1osure, which heats the flasks
efficiently, (ii) short path distillation between aseries ofbulbs which can be
moved horizontally in and out of the oven, and (iii) a motor to rotate the
bulbs (optional). The Kugelrohr can be used to distil very sm all quantities
« lOOmg) and can be operated at high vacuum. A simple distillation is
carried out as folIows. Place the sampie in the end bulb using a Pasteur
pipette. If necessary wash the sampie into the bulb and then evaporate the
solvent on a rotary evaporator. Add two more bulbs and a straight length of
tubing, insert the tube in the motor assembly, and slide the end bulb into the
oven. Gently c10se the iris type seal gently onto the connecting joint. Set
the bulbs rotating (to prevent bumping and speed up the distillation), apply
the vacuum and raise the oven temperature gradually. When distillation is
complete allow the flasks to cool under an inert atmosphere and then remove
164 Working Up The Reaction

the bulbs from the apparatus and recover the distillate. Fractionation of
compounds with a 20-30°C boiling point difference can be achieved by
inserting all the bulbs except one into the oven, distilling the most volatile
component into that bulb, withdrawing the next bulb from the oven and
distilling the next fraction into that, and so on.

oven / support rod iris type

oven closure to
vacuum

"- motor
unit

sliding bar
control unit

Figure 9.14

9.4.3 Sublimation
Sublimation is an excellent method for purifying relatively volatile organic
solids on scales ranging from a few milligrams to tens of grams. At reduced
pressure many compounds, especially those of low polarity, have a
sufficiendy high vapour pressure that they can be sublimed, i.e. converted
directly from the solid phase into the vapour phase without melting.
Condensation of the vapour then gives purified solid product provided, as is
often the case, that the original impurities were much less volatile. Two
designs of sublimation apparatus are shown in Fig. 9.15. The larger
sublimator (Fig. 9.15a) consists of a tube with a side arm which is fitted
with a cold-finger condenser. It is used as follows. If the crude material is
asolid, powder it and place it in the bottom of the outer vessel. If it is waxy
or oily, wash it into the tube with a small amount of solvent, cover the side
arm with a septum, and remove the solvent on a rotary evaporator. Put
 Working Up The Reaction 165

some vacuum grease on the joint of the cold-finger condenser and fit it into
the sublimator (there should be a gap of approximately lcm between the
solid and the condenser). Evacuate the apparatus slowly to try to prevent
any spattering of the solid. Turn on the condenser water and slowly heat the
base of the sublimator. A fine mist of sublimed material on the condenser
indicates that sublimation is beginning and the temperature should then be
held fairly constant until the process is complete. At this stage the sublimed
product may be c1inging precariously to the cold finger so proceed with
great care. Turn off the water, carejully allow air/inert gas into the
sublimator, and very carejully remove the cold-finger. Scrape off the
product with a microspatula.

to
- wateT out vacuum
oven

- tovacuum

cold -finger
condenseT

I!,......!J..,..-- sublimate
crude
- cTude

(b)
Ca)

Figure 9.15
The simple glass tube shown in Fig. 9.l5b functions in a similar way
exeept that the water eondenser is omitted. Plaee the erude sampIe in a small
sampIe vial, put a plug of glass wool in the neck, and drop the vial into the
tube. Put a plug of glass wool in the neck of the tube and attach it to a
vacuum line. Evacuate carefully and heat the base of the tube gently in an
oil bath or in a custom designed metal block as shown. Proceed as before
and isolate the sublimed product by cutting the tube and scraping out the
solid.
166 Working Up The Reaction

9.5 Chromatographie purifieation of reaction produets

Chromatographie techniques for analysis and purifieation of reaction
products are probably the most universally important of all the skills in
which an organie chemist requires expertise!
Before attempting any of the chromatographie separation techniques
described in this seetion you will need to be confident about your ability in
running analytical tlc (see Chapter 8), as the two skills are very closely
interlinked. For routine separation and purifieation of reaction products,
some form of column chromatography is normally employed. Traditionally
long columns were filled with silica and a good head of solvent was used,
so that a flow was achieved by force of gravity. This method of
chromatography is very slow and the slow elution rate not only wastes time,
but also but leads to band dispersion. This reduces the resolution and often
leads to a large number of fractions which contain a mixture of compounds.
The technique has therefore become obsolete, and has been largely
superseded by flash chromatography.

9.5.1 Flash chromatography

Flash chromatography was introduced by Still, Khan and Mitra in 1978 1. It
has cut down the time taken for routine purification of re action mixtures
considerably and, perhaps more importantly, has provided the chemist with
a fast and simple technique for separating isomerie materials which have
similar polarities. It has become the standard method of purifieation in
many synthetic laboratories, with a resultant reduction in the time taken to
achieve many synthetic goals.
The key to the effectiveness of flash chromatography is that a
comparatively fine silica powder is used, with a relatively narrow particle
range (e.g. Merck C60, 40-63Ilm, type 9385 or May and Baker Sorbsil C60
40-60llm). This silica gives better surface contact, and therefore more
effective adsorption, than that previously used for gravity columns. The
press ure required to drive the solvent through increases the resolution by
cutting down band dispersion and considerably reduces the time required for
running the column.
There are some practical difficulties with the original published method
l. W.C. Still, M. Khan and, A. Mitra, J. Org. ehern .. 197843, 2923
 Working Up The Reaction 167

for running flash columns and modifications have therefore been introduced
over the years. These make the technique easier to carry out and somewhat
safer. This seetion will lead you through the basie steps for running a
modified version of flash chromatography whieh we find to be very
convenient and effective. Flash chromatography is a very powerful and
rapid technique for separation of organic compounds, but like all
chromatographie techniques you will only gain expertise by experience, and
these instructions can only be considered as guide-lines. Every separation is
different so do not be despondent if you have some failures at first. With
practice you should be able to acquire the skill and intuition required to get
good separation, even in the most difficult circumstances, every time, and
quickly!
Equipment required
The set-up originally described by Still requires the use of long columns, to
accommodate a reasonable supply of solvent, but these are diffieult to load
and need to be dismantled for addition of extra solvent during the run. We
therefore recommend the use of shorter columns plus areservoir. It is
important to have a familiar set of columns on hand and we suggest that you
have a set of about five columns, ranging in diameter from about 5mm to
50mm. A very convenient length for all columns is 25cm, except for those
with a very narrow bore, which can be shorter (Fig. 9.16). It is convenient
to standardize on a B24 (24/40) joint on the top of the column and a
glassblower can make reservoirs from a round-bottom flask and a male
joint. The 250ml reservoir is used more than any other, but it is also useful
to have 100ml, 500ml, and 1 litre sizes available.
We find that it is difficult to control the column pressure using a
Rotaflow valve as suggested in the original paper and this can be dangerous
if too much pressure is inadvertently applied. Two alternative methods are
used successfully in our labs. One of these is simply to use a rubber
bellows attached directly to a tubing inlet and apply enough pressure to give
the required flow rate. The only problem with this technique is that it is
difficult to keep the pressure constant, partieularly with large columns. An
alternative is to construct a simple pressure-release valve, such as that
shown in Fig. 9.17 and use this in conjunction with a compressed air
supply or nitrogen cylinder.
168 Working Up The Reaction

+-B24
(25/40)

25cm
1
+-500ml

+-Teflon
stopcock

(a) flash valve (b) flash column (c) reservoir

Figure 9.16
The glass part of the 'flash adapter' is made from a B24 joint and a
piece of 14mm i.d. heavy wall tubing. The valve is simply a septum, with
the skirt cut off, glued to a shaped metal (brass) plate.

-
l.4mm id.

V.. UI2cm
~
~
~
~
~
~
I
7cm
a..

I I
~ ~
§~
~ ~
~ ~
~ ~ §
~
~ 0 ~
~ § 4cm
§
12.5cm
~ ~ §
~
~
~ 1

Constuction of 'flash valve'

Figure 9.17
 Working Up TheReaction 169

The adapter should be constructed with the dimensions shown and

fitted with standard 4cm stainless steellab springs and it will then provide a
constant, safe pressure, which will give a suitable flow rate for all purposes.
It is also possible to use a small compressor, such as a fish tank pump, or
small diaphragn pump, to provide a suitable pressure source.
For analysis of the column fractions, have a tlc tank c10se at hand
containing an appropriate solvent, and several tlc plates, cut to about 4cm
wide.
For relatively sm all columns the most suitable way for collecting
fractions is in a rack of tubes and the best type of racks are those which hold
the tubes very c10se together (for example those supplied by
Gilson/Anachem for their fraction collectors). Using this type of rack, the
column flow can be changed from one tube to the next simply by moving
the whole rack. For large columns, conical flasks are often more convenient
for collecting fractions.

Procedurefor running aflash column

Safety note:
Silica dust is very toxic if inhaled, you should therefore
take precautions to avoid breathing it in and always handle it in
a fume cupboard. Large volumes of solvent are also used for
chromatography and you should take precautions to avoid
breathing in the vapours or exposing them to sparks.

1. Decide on the solvent system and on the quantity of silica

i) Run dcs to find a solvent system which will give a good separation of
the components of the mixture, and a Rr value of ca. 0.2-0.3 (usually
start with ethyl acetate - petroleum ether mixtures). If spots are running
c10se together an Rr value of 0.2-0.3 at the mid-point is normally
satisfactory, but if they are well separated, a solvent which puts the
lower spot at Rr 0.2-0.3 will usually work. If you know which spot
you are most interested in, try to bias your judgement towards this.
There are often irrelevant impurities which are either very polar or very
non-polar and these can be largely ignored.
170 Working Up The Reaction

1.0

0
Rf 0.5 0
0 0
0 0
0 0 0 0 0
0.0

Si0z/sample 20:1 30:1 50:1 100:1 50:1

ratio
1.0

O~
0
Rf 0.5
0
0 0 0 0 0
0
0 0
0
o X 0
0 S ~ o X 0
0.0

30:1 100:1 30:1 50:1 50:1

*spots marked x not required (grad. elution)

Figure 9.18

ii) You should try to use as little silica as possible since it is quite
expensive. Where the component you require is well separated from
other components, a ratio of ca. 20: 1 (silica:mixture) should be
sufficient. For more difficult separations up to 100: 1 ratio can be used
(with a ratio of 100: 1 spots that are touching on tlc should be separable
in the appropriate solvent system). As a rough guide some
representations of tIes are given in Fig. 9.18 which indicate a solvent
system which could be selected for separation of the mixture. Below
the drawings, an approximation of the relative quantity of silica
(compared to the sampIe) required to bring about separation is given.
 Working Up The Reaction 171

An important fact to remember for all chromatographie separations is

that the more spots there are in the mixture, the greater the ratio of silica
for each individual separation. Thus, you normally require less not
more silica to separate a 3 spot mixture, than for a 2 spot mixture
having similar separations. 1t is in this first step of the procedure that
the greatest skill and judgement is required and careful attention should
be paid to trial dc's. With experience, the appropriate column and
solvent to choose will become almost instinctive.

2. Choose and prepare the column

i) Weigh out the required quantity of silica in a conieal flask and make it
into a mobile slurry with some of the chosen solvent.
ü) Choose a column whieh will fill to about I8cm with the amount of
silica being used (it is useful to mark columns once you know how
much they hold).
ili) To plug the bottom of the column: roll a piece of cotton wool between
the fingers so that it is just wider than the column outlet; connect the
column to a low vacuum line with the tap c1osed; drop the cotton wool
ball to the bottom of the column, then open the tap. This is the most
reliable way to insert the plug.
iv) Mount the column vertically using a c1amp stand, pour about 8cm of the
solvent in and then carefully sprinkle a layer of fine sand (ca. Imm), to
cover the plug.
v) Very carejully add the silica slurry to the column, in small portions, via
a powder funnel. Between each portion, pressurize the column to pack
down the silica and remove excess solvent. Be carejul not to allow the
the solvent to drop below the level oj the top oj the silica.
vi) When all the silica has been loaded, leave a good head of solvent on top
of it and sprinkle in enough sand to cover the surface of the silica
evenly (ca. Imm). Then force the excess solvent through the column
until there is just a smalllayer left above the sand. There should now
be afiat layer of silica covered by a thin and even layer of sand.
172 Working Up The Reaction

Alternative inlet for

attachment to bellows
or low pressure pump

pasteur
pipette

cotton wocl --+ +-- sand

(a) loading the column (b) complete column set-up

Figure 9.19

Note:
The eolumn onee prepared ean be left for a very short time, but onee
you load the sampie the remaining steps should be earried out as swiftly
as possible, and the solvent flow should be eontinued without
interruption if possible, especially during the early stages of elution.
 Working Up The Reaction 173

Leaving the column standing with the sample loaded leads to band
dispersion and loss of resolution. So, before starting the remainder of
the procedure make sure you have everything that you will need to
hand, including plenty of solvent.
3. Load the sampIe
i) Dissolve the sample in the minimum amount of solvent, preferably the
same solvent that you intend to run the colurnn in (if this is not possible
as is often the case, dissolve the sampie in a small amount of
dichloromethane)t. Keep a tlc sample of the sampie mixture to
compare with the column fractions.
ü) Load the solution onto the top of the column, very carefully, using a
Pasteur pipette to drip it around the walls of the column, just above the
sand. Caution must be taken not to disturb the layer of sand. Repeat
the procedure using the minimum quantity of solvent to rinse any
remaining sample from the flask.
üi) Once all the solution has been added allow the level of liquid to drop so
that the top of the sand is just starting to dry.
4 . Add the solvent
i) Add the solvent to the top of the column, very carefully at first, again
using a Pasteur pipette to drip solvent around the walls of the column
just above the sand, and taking care not to disturb the sand. On ce a
head of solvent is present, more can be poured in carefully from a
beaker.
ü) Attach a solvent reservoir to the top of the column, secure it with elastic
bands (Bibby clips are not strong enough), and fill with solvent.
5. Run the column
i) Connect bellows or flash adapter to the top of the reservoir and secure
with elastic bands (your set-up should then look like the diagram
shown in Fig. 9.19).t
ii) Apply pressure to give a fast solvent flow rate and collect fractions
continuously. It is very important to maintain a fast flow rate through
t For some very non-polar compounds, even sm all quantities of methylene chloride
may cause elution problems and an alternative method of loading can be used. Thus, a
solution of the sampIe is added to a small amount of silica in a round bottom flask and
the mixture is evaporated to dryness. The dry impregnated silica is then added to the top
of the pre-packed column.
174 Working Up The Reaetion

the column - the solvent should run, rather than drip! A slow flow rate
eauses redueed resolution, NOT improved separation. tt The size of
fractions will depend mainly upon the size of the column and as a rough
guide, they should be in m1 about half the weight of silica (Le. for a
30g column you should collect ca.15m1 fractions). 1t is a myth that you
get less mixtures by collecting smaller fractions - the mixture simply
appears in more tubes and leads to a good deal of extra work! You may
feel safer collecting relatively small fractions at fIrst, but as you become
more experienced you will tend to collect larger fractions, and thus
considerably lower the amount of time you spend on chromatography.
Always be eareful not to let the eolumn run dry.
iii) Monitor the column fractions by running tlcs whilst the column is
running (5 or 6 spots per tlc plate is usually a convenient amount). You
should have time to apply a spot of the previous fraction to a tlc plate
whilst the present fraction is collecting.
6. Analyse tles and eombine fraetions
When all the compounds you are interested in have eluted, and you
have identified in which fractions they are, combine the fractions as
appropriate (keeping fractions that contain mixtures separate from those
containing pure materials). Remove the solvent from the combined
fractions on a rotary evaporator, and fInally remove the last traces of
solvent under high vacuum.
-
000

o
o
_ L..-_ _- - '

Figure 9.20 Typieal set of tles for a sueeessful eolumn

Gradient elution
When the components of a mixture run c10se together, a single solvent
system which gives the spots a tlc Rf of 0.2-0.3, will be effective.
However, when the spots are a long way apart, increasing the
solvent
tt Apressure of 7psi is reeommended in Still's original paper, but we tend to rely on
flow rate, rather than press ure.
 Working Up The Reaction 175

polarity as the column is running will save a good deal of time and solvent -
this is referred to as gradient elution. You should be confident with single
solvent chromatography before you attempt gradient elution, as it requires
quite a bit of experienced judgement. The procedure for doing this is:
1. Start running the column in a solvent which will give the highest
running spot an Rf of 0.2-0.3.
2. When tlc analysis indicates that this component is almost completely
off, change the solvent polarity to that which gives the second spot an
Rf of 0.3. In some cases you may need to change the solvent polarity
in steps.
3. Continue this process until all the spots that you require are off.

Recycling procedure for flash silica

Flash silica is quite expensive but if you can buy it in bulk (25kg at a time)
the cost will be reduced by nearly half. Another way to save money is to
recyc1e it, using the procedure given below. The material generated by this
method is very reliable.
1. Washing
Suspend lkg of silica in 1.5 litres of acetone, stir, then filter on a
Buchner funnel and wash with an additionalllitre of acetone, followed
by 2 litres of deionized water
2. Ignition
Place the silica in a Iarge crucible and dry at 120-140'C overnight.
Then heat in a muffle furnace at 500-600'C for 4h.
3. Coarse particle removal
After cooling, place the silica in a bucket containing about 5 Iitres of
deionized water. Mix the suspension thoroughly, avoiding vortexing,
and allow the mixture to settle for 30 s. Then carefully pour the top
50% of the mixture into a second bucket. Make the first bucket up to 5
litres, stir again, allow to settle for 30 sand again decant off the first
50% into the second bucket. Repeat this procedure twice further then
discard the remaining contents of the first bucket.
176 Working Up The Reaction

4. Fine partic/e removal

The second bucket should now contain about 10 litres of silica/water
mixture. Stir this thoroughly and allow it to settle for 4 min. Decant
off the first 50% carejully and discard it. Stir again, then allow to
settle for 4 min, decant off the first 50% and discard again. Repeat this
procedure twice more, after making up to 5 litres each time.
S . Activation
Filter the silica in a Buchner funnel then dry in an oven at 120-130°C
overnight. Recovery should be 650-800g.

9.5.2 Dry-columnjlash chromatography

This technique was developed by Harwood2 and can be used as an
alternative to flash chromatography. The apparatus simply consists of a
parallel-sided vacuum filter funnel, incorporating a porosity 3 sinter (see
Chapter 3) and a flask (Fig. 9.21).
~~~ +--- so lvent
+--- si lica

Figure 9.21

Method jor running the column

1. Column packing
Fill the funnel to the lip with tlc grade silica (e.g. Merck Kieselgel 60) and
tap gently, then apply suction from a water aspirator, pressing the silica
down starting at the circumference and working towards the centre.
Continue until a level and firm bed is obtained and mere is a head space for
2. L.M. Harwood, Aldrichimica Acta, 1985, 18, 25
 Working Up The Reaction 177

sample and solvent addition. The approximate funnel sizes, compared with
the quantity of sample to be applied, are given in Table 9.1.
Table 9.1
Funnel Funnel Weightof Weightof Fraction
Diameter(mm) Length(mm) Silica(g) Sample(mg) Size(ml)

30 45 15 15-500 10-15
40 50 30 500-2000 15-30
70 55 100 1000-5000 20-50

2. Pre-elution
Under vacuum, pre-elute the column with a solvent whieh will give a t1c Rf
of about 0.2 for the least polar constituent of the sampie. If the silica has
been packed correctly, the solvent should run down the column with a
horizontal front, but if it channels, the column should be sucked dry and re-
packed. Keep the surface of the silica covered with solvent while pre-
eluting until solvent starts collecting, then suck it dry.
3 . Loading the sampie
Load the sample as a solution, in the same solvent as used for pre-elution, in
an even layer onto the surface of the silica. Alternatively, if the sampie is
insoluble in the pre-elution solvent, it can be pre-adsorbed onto a small
quantity of silica (see Seetion 9.5.1, loading a flash column)) which is then
spread on the surface of the silica in the funnel.
4. Eluring the column
Sequentially add solvent fractions to the funnel according to the quantities
indieated in Table 9.1, sucking the silica dry in between each fraction, and
keeping fractions separate. For each successive fraction increase the solvent
polarity by increasing the proportion of the more polar solvent by about 5-
10% (e.g. from 50% EtOAc/50% petrol to 55% EtOAc, for a 10%
increase). Analyse the fractions by tlc to determine the locations of the
components of interest, but as a rough guide, the solvent mixture whieh
would give the compound a tlc Rf value of about 0.5 will probably elute it.
As with any chromatographie technique expertise will only come with
experience, but given that, you should be able to separate quite closely
running compounds quickly using this technique.
178 Working Up The Reaction

95.3 Preparative tle

Until quite recently preparative tlc was widely used for separating small
quantities of compounds of similar polarity, but the technique has largely
been superseded by the development of flash chromatography and hplc,
each of which can give better resolution. Thickly coated 'prep plates'
should definitely be considered a thing of the past, but some people still do
like to ron large (e.g. 20 x lOcm) analytical plates as prep plates, and about
10mg can be loaded onto this size plate.
A high degree of skill is required to draw a tlc dropper across a line at
the base of the plate, applying a very thin and even line of the sampie
solution, without damaging the silica. In between each application the
solvent is allowed to dry before a further application is made, and this
process is repeated until all the sampie has been loaded.
After ronning the plate (multiple elution is often required for good
separation), it is viewed under a uv lamp and the bands are marked with a
fine pencil (it is very difficult to use prep tlc for non-uv active compounds).
A sharp scalpel is used to cut the bands and scrape them carefully off the
plate and the compound is separated from the silica by washing through a
cotton-wool plug with a very small quantity of methanol. After evaporation
it is necessary to re-dissolve the compound in methylene chloride and filter
again to remove traces of silica.
Great skill is required to ron preparative tlcs effectively, and even then
the sampie obtained is often contaminated with significant quantities of
grease and tlc plate binding agent. Since there are now much beuer modem
small scale separation techniques available, we do not recommend
preparative tlc (see below for details of preparative hplc and Chapter 10 for
more on small scale flash chromatography).

95.4 Medium pressure liquid ehromatography (mple)

There are often times when quite difficult separations need to be performed
on a fairly large sc ale. Even if the mixture will separate by flash
chromatography, it may be prohibitively expensive, especially if it is a step
which needs to be carried out routinely. This is one occasion when mplc is
very useful. The resolution of mplc is somewhat better than flash
chromatography, but another important feature is that the columns are re-
 Working Up The Reaction 179

used many times, thus avoiding the expense of throwing away large
quantities of silica.

Setting up an mplc system

pulse dampcr injeclion valve

wilh prcssure incorporaling sampie Joop •
limiler ~ see Fig. 9.26 for flow diagram

pump ~ r--------, /

o 0 0 0

+- main
column

fraction
/ colleclOT

dmfrJ
.:-:- :.:.:- +- solvenl bolLle

MPLC scemalic diagram

,",\lVIIY VIIVUV YYYVV

Figure 9.22
The mplc system is essentially a simplified and much cheaper version
of an hplc set-up. At the heart of the system is any type of pump which will
operate at lOOpsi, with a controllable flow rate of up to lOOml/min. There
are a variety of moderately-priced pumps on the market, including one
produced by Buchi, which is especially designed for mplc. However, we
use a Gilson hplc pump, which has interchangeable flow heads. For mplc,
a lOOml head is fitted, but the same pump can also be used for either
analytical or preparative hplc, simply by changing the head. Since glass
columns are used for mplc it is important that apressure limiting valve is
fitted in-line, to prevent high pressure building up in the column, in the
event of a blockage. The valve should normally be set to cut off the pump at
about lOOpsi, but you should consult the instructions for your columns
before setting this.
180 Working Up The Reaction

All the pipework used in the mplc system is 3mm Teflon tubing, which
is very easily tailored to your needs. The tubing is connected to the various
components of the system by plastic screw ferules, which should only be
tightened finger tight. 1t is very easy to make up the tubing to suit your
needs, but you will need a flanging tool to fit the ferules onto the tube ends
(Fig. 9.23). The tubing can be connected using threaded plastic sleeves
(Fig. 9.24).
ferule

"'"
.z=J>. I.\\\\\\\\§ ..
hot flanging
tao 1
meta] flange
~ teflon rubing

Figure 9.23 Fitting a ferule to 3mm teflon tubing

~\\\\\\\·It:::===:=::::j .\\\\\\\~

+
rn·:~::;·:sZ~~:~;·~;·;:~ :·+tJ
Figure 9.24 Connecting 3mm tubing using a threaded sleeve
The sampie is introduced into the system via an injection valve, but this
is a much simpler and less expensive valve than that found in an hplc
system. We use a Rheodyne type 50 Teflon rotary valve, which will take a
flow rate of 100mIlmin (Fig. 9.25). The pump and the column are
connected to the red and white connectors respectively, whilst a sampie load
loop (see below) is fitted to the black and yellow connectors. A Luer fitting
is attached to the blue connector, which is where the sampie is introduced,
using a syringe. The green connector is a vent and should be positioned so
that effluent from it can be collected in a beaker or flask.
 Working Up The Reaetion 181

§l1I'IIIIAI:

sideview

black (to loop)

~~5=:~??'~~~~~. blue (to syringe inlet)
red (to pump) ~~~=F=#:;)

white (to column) ~~~}==~~~~~~=a~~1: yellow (to loop)

rearview

Figure 9.25 Rheodyne Type 50 mpIe injeetion valve

In the 'load' mode (anti-clockwise position), solvent from the pump
in1et (red) passes direct1y out into the column (white). In this mode the
sampie inlet (blue) is connected through the load loop (black and yellow) to
the vent (green). Thus with the solvent flow by-passing the load loop,
sampie can be injected from a syringe onto the loop, displacing any residual
solvent out of the vent.

g
pump 8 sampie
pump

loop

column
Anti-clockwise position Clockwise position -
- sampie loaded onto loop sampie flows onto column
by injection at port 6

Figure 9.26 Flow through mple injection valve

On switching the valve clockwise to the alternative 'inject' position, the
solvent stream is diverted through the load loop, introducing the sampie
onto the column (Fig. 9.26).
Load loops are made very simply by coiling a length of 3mm Teflon
tubing which holds the required volume and fitting ferules on either end -
10, 25 and 50 mlloops are useful sizes to make.
182 Working Up The Reaction

There are now several manufacturers of good quality glass mplc

columns. The ones we use are made by Buchi and we have found them to
be very effective. They are available in a wide variety of sizes and it is
convenient to have a selection, but if your budget is tight, just one large
column would be very useful. The colurnn we use most frequently is 50cm
long by 50mm wide and we can separate between 8 and 20g on this
depending on the separation. It is useful to have a smaH'scrubber' column
in front of the main column, which will prolong its usefullife. Each column
manufacturer will recommend a packing method, and Buchi supply a special
loader for their columns, which is very quick and simple to use, and packs
the silica dry under compressed air pressure.
There is a choice of silica available for mplc, but for most purposes
ordinary 'flash' (40-60llm) silica is used. It is surprising to find out how
much more effective this silica is under mplc conditions than under simple
flash conditions. A column packed with 15-20llm silica is more effective
for difficult separations but there is a lot to be said for sticking to only one,
or perhaps two types of silica and becoming familiar with their
characteristics. In most cases geuing a good separation is simply a matter of
choosing the appropriate size of column and the correct solvent. Other solid
phases can also be used on an mplc system alumina, ion exchange resin,
Sephadex.
The final piece of equipment which is more or less essential to an mplc
system is a fraction collector. Any kind of fraction collector will work, but
we use a Gilson computer controHed device, which is ideal for a variety of
purposes. For smaH scale work we coHect 20 ml fractions (Gilson number
22 rack), and for large scale we coHect 60 ml fractions (sintillation rack
number 24 with horne-made tubes to fit).
A uv or refractive index detector can also be incorporated into the
system, or the fractions can simply be analysed by tlc, as for flash
chromatography. If the conditions are kept constant the results from mplc
are very consistent, so if you wish to repeat separations of the same
mixture, it is very easy to predict which fractions will contain each
component.
 Working Up The Reaction 183

Procedure for using mplc

You will normally have had experience of flash chromatography before
attempting mplc, and the two are really quite similar except that the
relationship between tlc polarity and column solvent is slightly different.
Again there is no substitute for experience! The following list will guide
you through the essential steps.
1. Decide on column and solvent
A solvent which gives an Rf between 0.2-0.4 usually works best, and
the size of the column will depend on quantity and separation. As a
guide, we routinely resolve 8g quantities of a quite closely running
mixture on a 50 x 5cm column, but we have separated up to 20g if the
separation is very good. 1t is always best to rely on experience and for
this reason we keep a log of all the runs on the system, which inc1udes
tlc sketches, quantities, solvent system, flow rate, column information
and comments. Then when you are running something for the first
time, you can look back to find similar mixtures which have been
separated before and gain some idea of what to use for your sampie.
2 . Set up the system
Set the system up as described above, re-charging the scrubber column,
if one is fitted, and switch on to run solvent through the column. If the
column is newly packed, recycle the effluent from the column back into
the solvent reservoir and leave the instrument to equilibrate for at least
15 min. If the column already contains solvent, flush this off before
recycling. Also, set the injection valve so that solvent flows through
the load loop andflushes away any solvent which was in there! The
optimum flow rate is dependent on column diameter, but will also vary
with solvent, separation etc. The following figures are a rough guide:
about 20ml/min for a 25mm column; about 45ml/min for a 35mm
column; 75-85ml/min for a 50mm column and lOOml/min for anything
larger (see under preparative hplc for flow rate calculation). Having
chosen the flow rate, set the fraction collector to stop at each tube for an
appropriate time.
3 . SampIe preparation
Mplc is aseparation technique and not a clean-up technique, and since
the columns are re-used, any base-line material or inorganic solid
184 Working Up The Reaction

should be removed from the sampie before you start. This can be done
either by simple flltration or by flltration through a small pad of silica in
a short column. While the mp1c column is equilibrating, make up a
concentrated solution of the sampie in either the chosen solvent or in
methylene chloride.
4. Load the sample
Switch the injection valve to the 'load' position (Fig. 9.26, solvent by-
passing the loop). Using a good syringe with a flat-ended needle, draw
up the sampie, then invert the syringe and hold it with the needle
pointing upwards. Next draw in an air bubble of about Iml and
remove the needle from the syringe. Still holding the syringe in the
inverted position, carejully connect it to the Luer fitting on the injection
valve. Now turn the syringe the right way up and inject the sample
until all the solution and a very small bubble have entered the load loop.
To avoid a sudden pressure build-up as the sampie is injected, reduce
the flow rate by half, then switch the injection valve quickly. As the
sampie begins to enter the column, gradually turn the flow rate back up
and start the fraction collector.
5. Running the column
Whilst the column is running, collect dcs or use the detector to
determine which fractions contain the required components. Unless
you are using a refractive index detector, gradient elution is simply
achieved by gradually adding more polar solvent to the reservoir.
6. Finishing the run
Before you leave the system make sure all the components that were
loaded onto the column have been eluted and if necessary, run a more
polar solvent through to remove polar material. The column can be left
with a length of Teflon tubing attached between the ends to prevent it
drying out.
7. Regenerating columns
Sometimes a column will become contaminated with stubborn polar
material. 'Back-washing' some columns is possible, but this is not
necessarily the best way to treat them. It is better to run a polar solvent
through, such as methanol ( or even water), then gradually change the
 Working Up The Reaction 185

solvent back to a less polar system, through the sequence: water;

methanol; ethyl acetate; ethyl acetate/petrol; petrol.

955 Preparative hplc

Equipment required
A preparative hplc system has exactly the same components as an analytical
system, except that several features are larger (see Chapter 8). With some
systems, such as the Gilson, the pump head can simply be changed to
provide the higher flow rates required. The injection valve must also be the
large bore type (e.g. Rheodyne 7125) fitted with a large load loop (up to
5ml), and of course the columns are much larger. It is also useful, but not
essential, to have a fraction collector, and if this is microprocessor
controlled, it can be liked to the detector so that fractions are only collected
when a peak is being detected. There are now several extremely
sophisticated, computer-controlled systems available, which can be set to
inject sampies automatically and collect selected peaks into designated
flasks. Thus, large quantities of material can be separated over multiple
injections. However, for most research purposes the prime requirement is
for one-off separations.
The choice of detector can be quite critical. Uv detectors are very
sensitive but are of litde use if molecules without chromophores are being
separated. A refractive index detector is universally applicable but has the
drawback that gradient elution is virtually impossible.

Running a preparative hplc column

The sequence of events for running a preparative hplc column is almost the
same as that for mplc, as described above. However, there are a few
significant differences which should be taken into account, and will be
described here.
Care of hplc columns
First of all you should appreciate that preparative hplc should only be used
for separation of clean mixtures. Some other form of chromatography
should always have been carried out previously to remove any material
which is significantly more polar than the compounds to be separated and
any suspended solid should also be removed. Preparative hplc is a very
186 Working Up The Reaction

powerful technique and it is often possible to separate compounds which do

not separate on tlc. However, preparative hplc colurnns are extremely
expensive, and although they should last for a very long time, they can
easily be ruined by one thoughtless application. Tiny solid panicles will
damage a colurnn, and for this reason sampie solutions should be passed
through a fine filter directly before loading
Choice of column, solvent andflow rate
It is very difficult to draw a correlation between the behaviour of a mixture
on tlc and the way it runs on hp1c, and it is therefore preferable to carry out a
few analytical hplc runs to find an appropriate solvent system and determine
the quantity which can be separated. If you can use the identical type of
column for your analytical work this is of course ideal. There are now sets
of columns which run from micro analytical sizes through to large
preparative scale, and have uniform characteristics through the series. We
use 'Rainin Dynamax' colurnns which have a very sophisticated design and
give exceIlent results for preparative work. The biggest factor which leads
to loss of performance in hplc columns is the packing down of the solid
phase which occurs with constant use and causes voids, particularly at the
ends of the column. One of the features of Dynamax colurnns is that they
are fitted with a compression joint, which closes the voids and enables the
colurnns to perform weIl over extended periods of use. They can also be
fitted with integral scrubber units which extend the life of the main colurnn.
The sizes of the columns increase in regular steps and it is therefore
very easy to correlate between the smaller 'analytical' columns and the larger
'preparative' columns. In fact the column which we use for analytical work
is 4.5mm x 25cm, and would probably be viewed as a semi-prep colurnn by
an analytical chemist. However, it is very useful for method development,
as it takes only a few minutes to equilibrate and to run. Indeed, it can be
used as a small scale preparative column for quantities between about 5 and
40mg. For normal analytical hp1c the intention is to develop a method
which gives the best peak shape with good separation, and column
overloading is therefore to be avoided. On the other hand, a good
preparative method is one which will separate the components and allow
you to 'get away' with maximum overloading, peak shape being largely
irrelevant.
 Working Up The Reaction 187

For full-scale preparative work either a 22.5mm or a 45mm column is

nonnally used and it is easy to scale up to this size knowing the conditions
used for the smaller column. If the columns are the same length the scale-up
factor will depend on the area of the column surface, thus:-

Scale-up factor, F = Area(large col) = 1tR2(large) = !D!2)2(large)

Area(small col) 1tR2(small) (D!2)2(small)

Using these equation, the scale-up factor between the 4.5mm column
and the 22.5mm column is 22.35. and between the 22.5mm and the 45mm
it is 4. If the columns are not the same length then simply multiply the
factor by the proportionate length difference (for example going from a
4.5mm x 12.25cm column to a 22.5 x 25cm column the scale-up factor
would be 44.7). To work out the conditions for running the larger column
simply multiply the flow rate and the quantity loaded on the small column by
the scale-up factor and this should produce identical results on the large
column. As a rough guide a 4.5mm x 25cm column runs at about
O.75m1/min and can be loaded with 5-35mg; a 22.5mm x 25cm column runs
at about 16m1/min and can be loaded with lOO-800mg and a 45mm x 25cm
column runs at about 64mllmin and has a capacity of about 450mg to 3.2g.
Once you have worked out a good system for prep hplc the run times are
quite short, so that large amounts of material can be separated quite
conveniently by multiple runs.

Solvents for hplc

All solvents used for hplc must be very high grade and must be degassed
before use. Degassing can be achieved by bubbling helium through the
solvent via a gas diffuser, by standing the bottle of solvent in an ultrasonic
bath, or by stirring the solvent under vacuum. The solvent inlet line of the
hplc system should always incorporate a filter to prevent small particles
entering the system. Ethereal solvent mixtures are not very successful for
hplc work and in general it is nonnally best to use a system where the more
polar constituent is also the least volatile.
 CHAPTER 10

Small Scale Reactions

10.1 Introduction
For the purposes of this chapter we will define small scale reactions as those
involving re action mixture volumes of less than 5ml. When performing
organie reactions on this sc ale special problems arise, most notably:
1. Difficulties in measuring out small quantities of sensitive reagents.
2. Significant losses of material due to apparatus design.
3. Difficulties in excluding trace amounts of water from moisture-sensitive
reactions.
Whenever reactions are performed, material los ses are obtained as a
consequence of the above problems. Normally these los ses only account
for a few percent of the total material, however this percentage can increase
dramatically as the reaction sc ale decreases. For example if a moisture-
sensitive reaction was carried out on a one mole scale, it would take 18g of
water to completely stop the reaction occurring, however if the same
reaction is carried out on a O.1mmol sc ale, then only 1.8mg of water would
completely quench the reaction.
The problem of weighing out small quantities of sensitive reagents is
best solved by accurately weighing larger quantities, and making up
solutions in an inert solvent, ideally the reaction solvent. Since the molarity
of the solution is known, a quantitative aliquot of this solution can then be
added to the reaction mixture using a syringe. This effectively reduces the
problems of weighing out the material to those that exist in larger scale
reactions, and discussed in earlier chapters. As a general rule many of the
techniques used in setting up reactions discussed in the earlier chapters, can,
with care, be applied to small sc ale reactions. Indeed there are a wide
 Small Scale Reactions 189

variety of miniature chemical apparatus commercially available for just this

purpose.
This chapter will outline some of the more specialized techniques that
can be employed to alleviate the problems associated with small scale, and
that can be carried out without the requirement of relatively expensive
specialized glassware.

10.2 Reactions at or below room temperature

When carrying out small-scale reactions at or below room temperature it is
quite possible to use a conventional apparatus set-up. Most reactions are
carried out in round-bottomed flasks, which are available in sizes down to
lrnl. The main problems arise when you come to work up the reaction
mixture. If an aqueous or organic extraction is required, then the material
must be transferred to a separating funnel. This will inevitably lead to some
loss of material during the transfer, but this should be minimal. The main
problem arises from the fact that separating funnels rarely come in sizes
below lOml. In addition, because of their design there will always be some
loss of material in the apparatus itself. This is mainly because the re action
mixture necessarily comes into contact with a large surface area of
glassware, and retrieving material coated over this large area tends to be
difficult. A useful alternative for extractions involving 2ml or less is to use
a glass sampIe vial or small test-tube (Fig. 10.1). The reaction mixture can
be washed into the sampIe vial, and the extraction solvent added. The lid of
the vial is then put on, and the mixture shaken. Removal of the lid allows
any pressure build-up to be released. Particular care should be taken when
removing the lid to avoid spillage.
The required solvent layer is then removed using a Pasteur pipette.
Three or four extractions are usually sufficient to recover the majority of the
material. This technique is particularly straightforward for diethyl ether
extractions of aqueous solutions in which the ether layer is required, since it
can readily be pipetted from the top of the aqueous layer (Fig. 10.1). If you
require the lower solvent layer, this can be recovered either by pipetting
away the top layer, or by pipetting from the bottom of the vial. Because
efficient separation of the two phases is required, it is preferable to use a
190 Small Scale Reactions

sampIe vial

/ extraction

-
solvent
--:::--: ~

reaction
•: •: . :. -mixture

Pasteur pipette

:/

- or
- ... _

~~~~~~~ -
extracts

drying agent
""'"
Figure 10.1
tall, thin vial rather than a short, fat one. A second vial containing drying
agent can then be used to dry the extracts.
Removal of the drying agent is normally achieved by filtration of the
solvent mixture, and on a small scale this is best achieved using a Pasteur
pipette fitted with a cotton wool plug as the filtration apparatus (Fig. 10.2).
Once the solvent has been transferred into the filtration pipette, it can be
forced through the plug by applying pressure with a pipette teat.
Evaporation of the solvent in the normal way then yields the emde reaction
product. As stated earlier, material is inevitably lost with each transfer of
apparatus. 1t is possible to cut down the number of transfers by using the
sample vial as the reaction vessel. Very small magnetic fleas are now
commonly available, and will fit most small sample vials. Consequently,
with magnetic stirring, the vials can serve as small reaction vessels (Fig.
10.3). They are conveniently attached to the top of a magnetic stirrer
machine using plasticine.
 Small Scale Reactions 191

/
tcat-
---
Pasteur -:-
pipette

~
o
o
-
cotton wool -
plug -
riltered
Solulion

/
Figure 10.2
When capped, the vial is a sealed system, consequently this set-up is
only useful for small scale reactions at room temperature that do not involve
an increase or decrease in press ure inside the reaction vessel. For reactions
at low temperature, or those requiring a positive pressure of an inert gas
atmosphere, it is often more convenient to use a Pyrex test tube fitted with a
septum (Fig. 10.3). In all other respects the arrangement is the same and,
since Pyrex test tubes are available in a range of sizes, this apparatus can
inert gas
I
eap
j
!- septum
::;

-.;

sampie via1--

- test tube
reaclion
_____ mi)tlure~

=. __ magnelic
ficas - =
Figure 10.3 Use of sampie via! or test tube as areaction vessel
192 Small Scale Reactions

cope with a range of reaction volumes down to about O.2ml. Again the
reaction vessel can also be used for a subsequent extraction procedure
simply by replacing the septum with a bung.

10.3 Reactions above room temperature

Carrying out small scale reactions above room temperature, particularly
those involving solvent at reflux, is very difficult. The problems are
associated with preventing the evaporation of very sm all amounts of
solvent, and materiallosses in the apparatus. This is usually caused by
losses of material through ground-glass joint attachments of condensers to
the reaction fiask, and by inefficient condensation of the solvent vapour.
One solution is to use a sealed tube (see Chapter 8) as the reaction vessel,
and this is probably the equipment of choice for reactions involving volatile
solvents (:::; 50°C) on scales below Iml. For higher boiling solvents it is
possible to use a one-piece apparatus, incorporating an air condenser system
(Fig. 10.4). This apparatus can be conveniently constructed at the required
size from a piece of Pyrex tubing. The air condenser is adequate enough to
prevent the evaporation of higher boiling solvents (~100°C). Alternatively,

,
a one-piece apparatus incorporating a water condenser can also be used
inert gas
,
inert gas

_ - - septum _ __ : 11 i

air
condenser _ water
condenser

reaction mixt ure

~/~~
Figure 10.4 Small scale air condenser and water condenser systems.
 Small Scale Reactions 193

(Fig. 10.4). In this case the condenser system is more efficient, however
construction of the apparatus is correspondingly more complex. In both
cases the reflux apparatus can be easily constructed to allow re action
volumes down to about O.5m1.

10.4 Reactions in nmr tubes

In many cases it is necessary to monitor c10sely the progress of a sma11 scale
re action by methods other than tlc; one very useful alternative is nuc1ear
magnetic resonance (nmr). With larger scale reactions this is simply done
by removing an aliquot of the reaction mixture and recording its nmr
spectrum. Obviously this approach cannot be applied to reactions involving
relatively small quantities of material. The answer is to carry out the
reaction in an nmr tube. Both 5mm and lOmm diameter nmr tubes can
conveniently be used as reaction vessels (Fig. 10.5) in the same way as test-
tubes were employed in Section 10.2.
inert gas
J

septum_ iii

nmrtube- inert gas supply

must be removed
I
prior to running
the nmr spectrum

reaction
mix.ture~ -.

Figure 10.5
The reaction can then be monitored by recording the spectrum of the
reaction mixture direct1y. There are however several important points to
note when using nmr tubes as reaction vessels:
194 Small Scale Reactions

1. The reaction solvent should be chosen carefully to ensure that it does

not obscure the nmr region to be observed.
2. Magnetic stirring cannot be used because the magnetic flea in the nmr
tube would interact with the nmr field causing severe broadening of the
spectrum. Similarly the presence of paramagnetic material in the
reaction mixture will lead to broadening of the spectrum.
3. For high-quality nmr spectra to be recorded, the reaction mixture
should be homogeneous. The presence of solids in the reaction mixture
will lead to poorly resolved spectra.
As a general rule you should use the reaction solvent that is normally
employed for the type of reaction being carried out, however its deuterated
equivalent must be used if IH nmr spectra are to be observed. Agitation of
the reaction mixture is probably best achieved using sonication in an
ultrasonic bath (Chapter 8), although periodie shaking will often suffice.
If you require to carry out the reaction at elevated temperatures then it is
usually advisable to use a sealed nmr tube. Thick-walled nmr tubes are
commercially available if the reaction mixture is required to withstand
increased reaction pressures typical of those obtained in sealed tube
experiments.

10.5 Purification of materials

The purification of small quantities of materials (~ 50mg) also poses certain
problems. A number of simple techniques used are outlined below.

105.1 Distillation
By far the most convenient method of carrying out distillation on a small
sc ale is to use a Kugelrohr apparatus (see Chapter 9). In order to cut down
on los ses through ground glass joint connections it is often necessary to use
a one piece Kugelrohr bulb set (Fig. 10.6). This can be conveniently made
to the size required from a piece of Pyrex tubing.
After distillation is complete the apparatus is left to cool, and the
purified material recovered by cutting up the apparatus into three seetions
using a glass knife.
 Small Scale Reactions 195

G)()(j~
./'
erude sampIe 1

c ~
~
~

Figure 10.6

10.5.2 Crystallization
Crystallizations on a small scale are most conveniently carried out using a
Craig tube apparatus as described in Chapter 9.

10.5.3 Chromatography
All the normal chromatography techniques (see Chapter 9) can be used to
purify small quantities of material. Indeed preparative hplc and glc are often
more successful when small quantities of material are involved.
In the case of flash chromatography however, it is often impractical to
simply scale down the equipment. A useful alternative is to employ a
Pasteur pipette as the column. Such a column is easily constructed using a
pipette containing a cotton wool plug (Fig. 1O.7a). The pipette is then filled
with the required adsorbent (typically silica gel). The amount of adsorbent
used depends upon the quantity of cmde sampie to be purified, however it is
inadvisable to fill the pipette more than three-quarters full, otherwise there is
insufficient room for the solvent. Next, the eluting solvent is added to the
top of the column and allowed to run through the column under gravity.
More solvent is added to the top of the column as required. Once the
solvent starts to appear at the bottom of the column, pressure can be applied
196 Small Scale Reactions

using a pipette teat, forcing the solvent through at a faster rate. After about

lcal -

PaSleur pipette_

- solvenl

- ad,orbent
-adsorbent

cotton wool plug_

(a) (b)

Figure 10.7
two column-volumes of solvent have been passed through the silica it
should be ready for use. The sampie is applied to the top of the column in
the usual way and pressure is applied using a pipette te at. The main
difference between this arrangement and the more usual flash
chromatography set-up is that the pressure applied to the top of the colurnn
is not constant. The teat is constantly being removed to a110w the addition
of more solvent to the top of the column. Consequently the solvent is not
passing through the column at a constant rate. In most instances this does
not appear to significantly affect the separations achieved. If, however, this
proves to be a problem, a miniature chromatography column with solvent
reservoir can easily be constructed from Pyrex glass tubing (Fig. 1O.7b).
With a cotton wool plug in the bottom this can be used in exactly the same
way as the larger columns described in Chapter 9.
 CHAPTER 11

Large Scale Reactions

11.1 Introduction
This chapter deals briefly with some of the specialized techniques required
when working with larger scale reactions. For the purposes of this chapter
we will define a large scale reaction as one involving reaction volumes of
between 2 and 5 litres. Working on reaction volumes in excess of this
usually requires the use ofpilot-plant equipment and is beyond the scope of
this book.
When working on larger reaction volumes, several problems arise as a
consequence of the scale:
1. The use of syringes to add liquids to areaction becomes impractical if
you require to add volumes of more than 50m!.
2. Stirring the reaction mixtures can become a problem, because magnetic
stirrers become ineffective for volumes much above 1 litre.
3. Control of the reaction temperature becomes more difficult as the
reaction volume increases, because reaction mixtures will take much
longer to heat up or cool down.
4. Exothermic reactions can prove to be a major problem on a large scale
since they are prone to induction periods before reaction starts. After
the induction period, the reaction can heat up rapidly and, unless
extreme care is taken in these situations, the reaction can easily go out
of contro!. It is recommended that very careful monitoring of the
temperature is undertaken in such cases, and any addition of reagents
which may lead to an exothermic reaction is carried out slowly.
5. Purification of materials on a large scale is often less easily carried out.
198 Large Seale Reaetions

On the other hand, some problems that exist with smaller scale
reactions can be less troublesome when working on large scale. For
example, materiallosses that occur as a consequence of transferring the
material between pieces of equipment become insignificant. Moisture-
sensitive reactions are less of a problem because if traces of water get into
the reaction they will only affect a very small percentage of the reaction
mixture.

11.2 Carrying out the reaction

mechanical stirre T - o

dropping
Cunncl
inert gas - ............>===-

condcnser -

Figure 11.1
 Large Seale Reaetions 199

In most cases large versions of the standard laboratory equipment are

adequate. Agitation is almost always achieved using a mechanical stirrer
(see Chapter 8), since this is the only device powerful enough to stir large
reaction volumes efficiently. As already mentioned, syringes tend to be
useless for transferring large volumes of liquid and pressure-equalized
dropping funnels serve weH as their replacement. A typical set-up for a
large scale reflux is outlined in Fig. 11.1. The pressure-equalized dropping
funnel can be filied by removing the stopper and pouring in the required
material or, if the material is moisture sensitive, then it can be transferred

mechanical stirrer_

incJt gas

jackclcd dropping
funnel - - f + -
=

= I~I-+I-+- coolant
=

low lcmpcrawrc
thcnnomcLcr -

Figure 11.2
200 Large SeaIe Reaetions

into the dropping funnel via a cannula by replacing the stopper with a
septum.
If the solution to be added from the dropping funnel requires cooling
prior to addition it is possible to use a jacketed dropping funnel, with the
cooling mixture (e.g. dry-ice/acetone) placed in the jacket. This is a
common set-up encountered for low temperature reactions on larger scales
(Fig. 11.2).

11.3 Purification of the products

Many purification techniques are not practical when dealing with large
quantities of material. In general the most useful methods of purification
that can be applied to large quantities of material are recrystallization for
solids, and distillation or steam distillation for liquids. These techniques
have already been discussed in previous chapters. Chromatography should
be avoided if possible since it becomes a very expensive operation on large
scale, but if it is necessary, then medium pressure liquid chromatography
(mplc) as described in Chapter 9 is the method of choice.
 CHAPTER 12

Characterization

12.1 Introduction
This chapter deals with the type of physical data that are required for the
proper characterization of the purified product. No theory is discussed as
this is wen covered in other sources and, given good data, it is often
possible to find a colleague (for example) who will help out if you are
unable to interpret a spectrum. With inadequate data it will be difficult to be
certain of the structure and purity of your product, and it will certainly be
more difficult to interest the colleague referred to above!
It is important to acquire as much information as possible on your
product. It might be 'obvious' from the nmr that the structure is what you
think that it should be, but it is still necessary to record (at least) the ir and
mass spectra. These might simply confirm the nmr data, or they might raise
other structural possibilities.
The full set of routine physical data which could and, ideally, should be
obtained on a pure compound is as follows; ir, uv, high field nmr (IH and
13C), and low and high resolution mass spectra, m.p. or b.p.,
microanalysis (for a new compound). If the compound is optically active
then the optical rotation must be measured. Only mass spectroscopy and
microanalysis from this list are destructive techniques, but modern
techniques mean that only a small amount of material need be 'sacrificed'.
Some general points concerning these techniques and the sampie
requirements are given below.
202 Characterization

12.2 Nmr
Nowadays the IH nmr spectrum is often the first measurement taken. The
size of sample required depends on the type of spectrometer used. A
continuous wave machine operating at 90 MHz will need at least lOmg of a
normal organic compound, probably more. Pulsed Fourier transform
spectrometers require less, 5mg being anormal amount, and good spectra
can be obtained using much smaller quantities. Most spectra are measured
in deuteriochloroform (CDCI3) although other solvents will be required
from time to time. A typical solvent volume would be ca. 0.4-0.5ml in a
5mm tube. Routine measurement of the 13C nmr spectrum usually requires
more sample (25-50mg) but good spectra can be obtained on less, it simply
takes more time.
The solution used must be free ofparamagnetic metal ions (it usually is)
and particles (it usually is not). Filtration through a small wad of cotton
wool forced into a Pasteur pipette will usually remove sufficient particles to
allow a good spectrum to be obtained.
The high field 1H nmr spectrum will show up impurities containing
protons. Given that the compound has been purified, the most common
impurity peaks observed in the 1H nmr spectrum are those from the last
solvent used (for example, solvents used in crystallization or
chromatography). This should be avoided, and it is always possible unless
the boiling point of your product is close to the solvent (which it should not
be) or your product is a crystalline solvate (not that common). Thorough
exposure to high vacuum should suffice but some very viscous oils and
gums will 'hold on' to solvent due to the very slow rate of diffusion. If
warming in high vacuum fails to remove all solvent, and a 'clean' 1H nmr
spectrum cannot be obtained, then dissolve the sampIe in a small amount of
CDCl3 and evaporate. Repeat once or twice and most of the residual solvent
should be CDC13 rather than (say) ethyl acetate. This will improve matters,
but do not forget that your sampIe will still be impure on evaporation as it
will contain residual CDC13.

12.3 Ir

The sampIe again needs to be free of impurities and solvents for infrared
spectroscopy. There are various methods for sampIe preparation and which
 Characterization 203

you choose will depend largely on the type of compound. The amount
required is no more than a few milligrams. For a liquid sample the spectrum
can be obtained using a thin film obtained by compressing a small drop
between sodium chloride plates, or as a solution (usually in chloroform)
using solution cells. The spectra of solids can be recorded either as mulls
with a hydrocarbon ('Nujol', for example), or by mixing with KBr and
compressing to form a thin disko Which you use will depend upon the
facilities available, and often on the usual working practice of your
department.

12.4 Uv
Ultraviolet spectroscopy is only of use if your compound has a characteristic
chromophore. There is little point trying to measure weak bands which will
provide no information. However, it is of considerable value in several
areas of research; for example, natural product isolation, heteroaromatic
chernistry, porphyrin and related chemistry, and in the study of dyestuffs.
The amount of material required is usually very small (fractions of a
milligram) since the extinction coefficients are usually large. The sampie
must be as pure as possible and is dissolved in the solvent of choice (usually
spectroscopically pure ethanol). The concentration must be known
accurately before extinction coefficients can be calculated, and will vary
depending upon the type of chromophore. An estimate of the concentration
to use can be made if the extinction coefficients of compounds sirnilar to that
being studied are available. If this data is not available make up a solution
accurately and dilute it (accurately!) until a reasonable spectrum is obtained.

12.5 Mass spectra

There are three pieces of useful information which can be obtained from
mass spectroscopy; the molecular mass, composition, and the fragmentation
pattern of your compound. The accurate molecular mass is of primary
importance since this will confirm the composition of your compound.
Fragmentation information might be of value for supporting the proposed
structure, possibly by comparison with known compounds. The amount
required is minimal (a few milligrams at most), and the material should be
204 Characterization

reasonably pure. If you are unable to obtain good microanalytical data the
accurate mass measurement may provide an acceptable alternative.

12.6 M.p. and b.p.

These are usually straightforward. Always obtain a rough melting point
before attempting to make accurate measurements and it is often useful to
'calibrate' the apparatus by measuring a known (pure!) compound with a
similar m.p. to the product. If there is a significant discrepancy then a more
reliable apparatus must be used. Do not forget to get the inaccurate
apparatus repaired, and discard it if necessary The compound needs to be
pure and free from dust, and the temperature must be raised very slowly as
you near the melting point. If there is a range over which the compound
melts (there usually is) then record it; do not estimate an 'average' reading.
If a capillary tube is used, it is sometimes useful to examine the upper part
of the tube for sublimate or distilled decomposition products.
If you have distilled your product to isolate and purify it then you
should already have the information required for reporting the boiling point.
It is important to quote the range of temperature (if observed) over which the
compound distills, the pressure (measured as it is distilling), the vapour
temperature (if measured), and the bath temperature. All these will be useful
when you or anyone else come to repeat the work, and most of this
information will be required at some time for a publication, report, or thesis.

12.7 Optical rotation

If your product is, or should be, optically active then the specific rotation
will need to be measured and recorded. The precise value of this property is
dependent on the wavelength of the light used, solvent, concentration, and
temperature. Moreover, great care should be taken to exclude any by-
products from the reaction since, although these might be present in small
quantities, they might have very large rotations and make your
measurements quite misleading. Clearly then, it is important to be sure of
the purity of your product, and to make up the solution carefully and
accurately. If you are unsure then make a measurement using a known
compound before you try to measure the rotation of your product (assuming
that the specific rotation of your product is not known). Usually you will
 Characterization 205

use the sodium-D line and measure at ambient temperature, but be sure to
reeord the eoncentration, solvent, wavelength, and temperature along with
the actual value of the measured specific rotation. Oceasionally optieal
rotatory dispersion andlor cireular diehroism spectra will be required.
These measurements will usually made by specialists and the specifie
requirements for your particular type of compound are best discussed with
them.

12.8 Microanalysis

There are several schools of thought on this topic. Some maintain that all
new eompounds must be analysed, whereas others say that, with the
modem array of physical methods (high resolution nmr speetroseopy and
high resolution soft ionization mass speetroscopy, for example) the need for
eombustion analysis no longer exists. Many follow amiddie course and use
microanalysis for erystalline compounds which are available in sufficient
quantity, and high resolution mass spectrometrie measurements in all other
cases. The course you take will depend upon eircumstances (the
requirements of your supervisor or the department, for example).
1t goes without saying that the compound must be homogeneous and
free from dust, inorganics, ete. For solids, careful reerystallization using
pure, filtered solvents followed by equally eareful filtration will usually
suffice. For oils, distillation folllowed by sealing in an ampoule will
provide aeeeptable sampies. All the glassware involved must be clean and
dry including the ampoule. Solids must be dried in high vaeuum in a drying
pistol to remove traees of solvent, and submitted in clean, dry vials. 1t is
possible to obtain reasonable microanalytical data on oils wh ich cannot be
distilled by careful column chromatography using pure, distilled solvents
followed by thorough pumping down in high vaeuum.

12.9 Keeping the data

If you work for any length of time in the laboratory you will rapidly acquire
a large number of spectra. 1t is important that you keep these safe and in
proper order, with an unambiguous eross-referencing system so that you
(and anyone else) ean loeate the speetra or measurements whieh apply to the
product of a particular experiment (see Chapter 2 for detailed advice on
206 Characterization

this). Spectra are best kept in c1early labelled folders or binders of some
description, preferably ones which allow for removable attachment of the
spectra. The other data should be recorded in the laboratory notebook along
with the experimental write up. If data sheets are used then all the data
should be recorded on these as they are measured.
 CHAPTER 13

The Chemical Literature

13.1 The structure of the chemical literature

13.1.1 Introduction
Consulting the literature is an essential element of chernical research.
Whether you want to confirm the identity of your latest product, or check
the feasibility of an exciting new idea, it would be both unscientific and
counterproductive not to conduct a thorough literature search. Moreover, it
is vital to the success of your work to keep abreast of developments in
organic chemistry in general, and in your area in particular. The problem is
that finding chemical information and keeping in touch with current
developments are difficult and time consuming tasks.
We are the beneficiaries of almost one and a half centuries of research
in organic chemistry. The accumulated output of that effort is an enormous
body of data collected in a vast literature. 1t is estimated that over half a
million articles (papers, patents, books, etc.) are published each year and the
volume of publications will probably continue to rise. Searching such a
huge body of work is a formidable problem but it must be emphasized that
the time spent reading the literature is often more than repaid by the
experimental time saved as a result.
This chapter is intended as a practical guide to efficient searching of the
chemical literature; the main part is devoted to adescription of the most
important access routes to the primary literature, and a discussion of
methods of tackling some common types of literature search. The chapter
concludes with a section on methods of keeping in touch with the current
literature. The reader is referred to two recent texts for more detailed
information. 1,2
208 The Chemical Literature

13.1.2 The structure of the literature

Almost all chemical infonnation is originally published in research journals,
in patents, and in theses. These sources are called the primary literature and
the goal of most literature searches is to find the original reports containing
the required infonnation. There are thousands of journals which publish
papers on chemistry but in practice the great majority of papers which are of
interest to the organic research chemist appear in just a hundred or so of
these. This is still a dauntingly large body of infonnation but there are
several routes by which it can be searched and specific items of infonnation
located.
An important route, and one which is rapid and easy, is to tap the
chemical knowledge of your colleagues and supervisors. Many of the
people working around you are likely to be experts in their own fields.
Another route is to use the secondary literature. This comprises review
articles and books, in which the originalliterature has been organized and
summarized, and reference books in which particular kinds of data have
been collected together. Of course, finding the appropriate review or
handbock is a problem in itself. A third route is via indexes which give the
literature references for all of the infonnation on a given compound, or
procedure, or author etc. Prominent among these is Chemical Abstracts,
which contains short summaries of just about every paper published on a
chemical topic, as well as comprehensive indexes to these abstracts, and
hence to the original papers. Finally there are computer databases, which
offer unprecedented speed, reliability, and flexibility, but at a price!

13.2 Some important sources of chemical information

This section contains adescription of structure, strengths, and weaknesses
of four of the most important tools for locating infonnation in the primary
literature: Chemical Abstracts, Beilstein, the Science Citation Index, and
computer databases. It is followed by a complementary section on how to
carry out some specific kinds of searches.
1. Y. Wolman, Chemical Information. A Practical Guide to Utilization. 2nd ed., Wiley,
Chichester, 1988.
2. R.E. Maizell, How to Find Chemical Information. 2nd ed., Wiley, Chichester, 1987.
 The Chemical Literature 209

13.2.1 Chemical Abstracts

Chemical Abstracts (CA) consists of two main parts, abstracts of every
paper containing new chemical information, and indexes whieh provide
access to the abstracts and thence to the originalliterature. It is published
weekly and each issue contains a keyword index and an author index. The
weekly issues are collected in volumes covering a six month period (one
year, prior to 1962) and each volume contains author, chemieal substance,
formula, and general subject indexes. Every five years (ten years, prior to
1957) the indexes for the ten volumes are combined to give Collective
Indexes. These indexes are the single most important and comprehensive
information tool available to the chemist.
A search of Chemical Abstracts should begin with the appropriate index
of the most recent volume and should progress backwards through the other
volumes until the beginning of the period covered by the most recent
Collective Index (currently the 11th - 1981-1986), at which stage the
Collective Indexes are used to search the literature back to 1907. The most
useful indexes are the chemical substance, formula, and general subject
indexes and their use is described more fully in Section 13.3. Consulting
the indexes will, in the first instance, lead to references to the abstracts, not
directly to the literature. The references to the abstracts take the following
form: 90:108753h where 90 is the CA volume number and the abstract
number is 108753. Since 1967 abstracts have been numbered sequentially
in each volume. Prior to that the references were of the form 46:13761 a
where 46 is the volume number, 13761 is the column number, and the letter
a indicates that the abstract is at the top of the column. Earlier still, a
numerical superscript was used to indieate the position of the abstract in the
column. The letters R or P before an abstract number indieate that the
original work is a review or a patent, respectively.
The abstracts contain full bibliographie details ofthe original paper, and
a summary of the principal new findings reported in the paper. A glance at
the abstract will tell you if the original journal is likely to be accessible, what
language the paper is in, and most importandy it will give an indieation of
whether the paper really does contain the information you require.
Remember that many of the compounds described in the original paper will
not be mentioned in the abstract but will be contained in the indexes. If the
210 The Chemical Literature

abstract looks promising all that remains is to locate the journal and consult
the paper.
An Index Guide is published every eighteen months and contains
invaluable information on the use of the indexes and the system of
nomenclature used in CA. 1t is essential reading for serious users of
Chemical Abstracts. FinaUy, the Ring Systems Handbook and its
predecessors, the Ring Index and the Parent Compound Handbook, contain
information on ring and cage systems and gives the names under which ring
systems can be found in the Chemical Substance Index.
The great strengths of CA are that it provides comprehensive literature
coverage, and it has extensive indexes. However, the coverage of the
literature in the early years was not so rigorous, and Beilstein provides more
thorough coverage of the pre-1949 literature.

13.2.2 Beilstein
Beilstein's Handbuch der Organischen Chemie, or Beilstein for short, is a
huge (> 300 volumes) reference work which contains physical and chemical
data for over one and a half million compounds. The compounds are
organized according to a unique classification system and each volume
contains a subject (actually compound) index and a formula index.
Comprehensive literature coverage is attempted, so Beilstein contains
essentially all the compounds of a given class, which were prepared from
the beginning of organic chemistry to the date of publication of the most
recent volume covering that class of compounds. A considerable amount of
critically reviewed information, with references to the primary literature, is
provided for each compound. This data includes the molecular structure,
natural occurrence, methods of preparation, physical properties including
references to papers containing spectral data, and chemical properties.
The Handbook consists of the original series of 27 volumes (the
Hauptwork, H) and a number of supplementary series (Ergansingbande, EI,
EIl, etc.). Work on the supplements is constantly in progress. Coverage of
the literature up to 1959 has almost been completed, and some progress has
been made in bringing the coverage up to 1979. Cumulative indexes are
only available for the pre-1930 literature. 1t is relatively easy to find data for
any compound reported prior to 1930 by checking the cumulative formula
index (Volume 29 in three subvolumes) which will give the volume and
 The Chemical Literature 211

page numbers for the entries in H, EI and EIl. Compounds of the same
c1ass will appear in the same volume of each series (although some of the
volumes are now divided into several subvolumes). Thus if a compound is
located using the cumulative index it is a simple matter to locate references in
the later series, using the volume indexes for the same volume or using the
Beilstein System Number. If a compound is not contained in the cumulative
index it is best to try to identify whieh volume it should be contained in,
using the c1assification system. A free booklet explaining how to use the
Beilstein system is available from the publishers (Springer-Verlag).
Beilstein is the best and most comprehensive source of data for organic
compounds prepared before 1930 and it is not partieularly difficult to use.
Its major weakness is the lack of data and cumulative indexes for more
modern work.

13.2.3 Science Citation Index

Science Citation Index (SCI) is a combination of three indexes whieh
provide coverage of all the important publications in the physical sciences.
SCI is published every two months and is cumulated annually. There are
cumulative indexes covering the period 1945-1979. It inc1udes coverage of
all of the major chemistry journals.
1. The Source Index lists the bibliographie details for the publieations for
each author/organization.
2. The Permuterm Index is based on combinations of keywords in the
tides of the artieies published in the journals whieh are covered by SCI.
For example under the keyword 'epoxide' will be a list of other
keywords, such as 'stereoselective', whieh occur in association with
'epoxide'. For each pairing there is a list of authors names, and
looking these up in the Source Index wi11lead to the references for the
original work.
3. The Citation Index is a unique feature whieh allows you to search the
literature forward in time. The index entries are the names of the first
authors of each paper which was cited in any paper published during
the period covered by that issue. Its use is best illustrated with the aid
of an example. Suppose that a researcher found a paper published in
1980, by S. Smith et al., which contained some very interesting
results, and he wanted to know if any further relevant work had
212 The Chemical Litemture

appeared. He would consult the annual indexes ofthe SCI from 1980
onwarc!s. Each index contains an alphabetic list ofjirst authors names
and under S. Smith's name would be a chronological list of his/her
publications. Under the entry for the paper of interest to our researcher
there would be a list of papers, published during the period covered by
that index, which cited it. It is reasonable to assume that any workers
who followed up on the results in the Smith paper would have cited it
in their own publications. Thus the list of papers which cited the
original should include most of the work subsequently carried out in
that area. Hence if you fmd an important paper you can use SCI to get
a list of all the papers which subsequently referred to it. The drawback
is that many of the references you find will not be relevant to your
interest and there is no way of knowing which are relevant except by
consulting the Source Index, which gives the titles of the papers, or by
consulting the papers themselves.
The citation index is an extremely useful tool and we recommend that
you carry out a search for every key paper you come across. You can also
use it to find out who is referring to your own work.

I3 2.4 Computer databases

The development of computer databases over the last decade has brought
about a revolution in the way in which we search and store chemical
information. The advantages of online searching inc1ude much greater
speed, greater accuracy, and greater reliability. Some computer databases
inc1ude material which cannot otherwise be searched directly, e.g. the full
text of many major journals and reference books, and they generally contain
more information than is accessible at the majority of institutionallibraries.
The principal advantage is much greater flexibility and power in carrying out
searches. For example, it is possible to combine a number of searches in
one using logical operators (oxidation AND (alcohol OR aldehyde)). Even
more importantly it is possible to search for c1asses of compounds or
compounds containing some specific substructure, searches which were
almost impossible using printed indexes.
There are disadvantages too. Some databases do not include all of the
material available in conventional form; for example, much of the early
Chemical Abstracts is not available online. Another problem is that the
 The Chemical Litemture 213

software for online searching is relatively complex, so it is more difficult to

learn and, as a result, online searches by inexperienced users can be
unreliable. The increasing use of personal computers and graphical input
and output have made database searching much easier but a good
understanding of the software is still essential. Finally the cost of hardware,
software, consumables, and the searches themse1ves, can be considerable.
The most important chemical databases inc1ude CAS Online, CAS
React, Beilstein, ORAC, and REACCS. The online versions of CA and
Beilstein are incomplete but the searching facilities are so powerful that they
are indispensible. CAS React, ORAC and REACCS are databases of
organic reactions which are extremely useful in searching for precedents for
synthetic transformations. Many other databases are available so you
should ask at your library for a list of those accessible to you. It is not
possible to describe the operation of the databases here but you should get
some help from your librarians or your supervisor and leam how these very
powerful tools can help you.

13.3 How to find chemical information

13.3.1 How to do searches
The following are some basic mies for guidance in searching the literature.
1. Clearly define the goals of your search.
2. Discuss the problem with your colleagues and supervisors; they may
have some valuable expertise.
3. Decide which information sources to use.
4. Start with the current literature and work backwards, the recent
literature will contain references to earlier work.
5. When you find a key paper, check it carefully for references to relevant
earlier work, and also work forward in time by carrying out a Science
Citation Index search.
6. Keep a complete record of your search, noting all the sources you used
and the information you obtained (e.g.lists ofCA abstract numbers and
·their contents). This is invaluable if you have to carry out related
searches later. It is advisable to keep aseparate notebook for recording
your literature searches, the information you accumulate will build into
a very useful resource.
214 The Chemical Literature

13.3.2 How to find information on specijic compounds

The chief sources of data for particular compounds are Chemical Abstracts
and the numerous reference handbooks, inc1uding Beilstein. Information on
relatively simple compounds can often be obtained from handbooks such as
the following:
1 . The catalogues of major chemicals suppIiers.
2. CRC Handbook of Chemistry and Physics, R.C. Weast Ed., CRC
Press.
CRC Handbookfor Organic Compound Identification.
CRC Handbook of Data on Organic Compounds.
These sources contain physical and chemical data for a large number of
organic compounds.
3. The Dictionary of Organic Compounds, 5th ed. Chapman and Hall.
The Dictionary ofOrganometallic Compounds.
These multivolumed works quote physical properties and references to
the preparation and properties of about 75,000 compounds and many
derivatives. Both have name and formula indexes, kept up to date by
the pubIication of annual supplements. They are available onIine.
4. Several extensive collections of spectral data are available. The most
extensive of these are produced by Sadtler Research Laboratories and
cover ir, Raman, uv, IH nmr, l3C nmr, and mass spectra. The Aldrich
Chemical Company has produced three excellent collections of data: ir,
Fr-ir, and IH nmr.
For data on more complex structures it is usually necessary to turn to
Beilstein or CA. Beilstein is in fact a giant handbook containing data for all
organic compounds published in the timespan of the volumes which are
available. Its use is described in Section 13.2.2. The best way to find
specific compounds in Chemical Abstracts is to start with the F ormula
Index. The formulas are listed in order of increasing number of carbons,
then increasing number of hydrogens, and then increasing numbers of the
other elements in alphabeticalorder. U nder each formula is a list of names,
and for each substance there is a list of abstract numbers. It is best to scan
through the list of names to try to identify the compound you want and then,
armed with the correct CA name, use the Chemical Substance Index. The
Chemical Substance Index has the advantage that, for each substance, it
gives a list of keywords (isolation, preparation, etc.) followed by the
 The Chemical Literature 215

abstract numbers. The keyword list makes it much easier to identify which
abstracts are most likely to contain the information you require. With a little
experience you may prefer to use the Chemical Substance Index directly but
the complexities of nomenc1ature and indexing preclude any further
discussion here. Note that prior to the 9th Collective Index, the Chemical
Substance and General Subject Indexes were combined in the Subject
Index.

13.3.3 How to find information on classes of compounds

Finding information about a broader area, such as a class of compounds is
usually more difficult than finding data about a specific compound. It is
usually best to begin by consulting books on the area, and then progress to
more specialized monographs and reviews, before consulting the primary
literature.
Good starting places include Comprehensive Organic Chemistry,
Comprehensive Organometallic Chemistry and Comprehensive
Heterocyclic Chemistry (Pergamon Press), which are multivolume texts
giving a detailed overviews of the title areas. A much more detailed
treatment of many common classes of compounds is contained in the series
The Chemistry of the Functional Groups edited by S. Patai (Wiley). This
excellent series consists of over 30 volumes (in nearly 60 parts) each of
which contains reviews on all aspects of the chemistry of one particular
functional group. Other multivolume series inc1ude The Chemistry of
Heterocyclic Compounds - ASeries 0/ Monographs (Wiley) and Rodd's
Chemistry 0/ Carbon Compounds (Elsevier). In addition there are many
review series devoted to the chemistry of particular classes of compounds,
including the Specialist Periodical Reports published by the Royal Society
of Chemistry. See Section 13.3.4 for a list of sources of information on
synthetic methods for families of compounds.
Finding individual books or reviews is more difficult. A good starting
point is your library, glance along the shelves and consult the catalogue. A
more systematic method is to use Index of Reviews in Organic Chemistry
(Royal Society of Chemistry) or Index to Scientific Reviews (Institute for
Scientific Information) to locate books and reviews.
Manual searching of C hemical Abstracts is not a good method for
tackling this kind of search because the indexing policy means that very few
216 The Chemical Literature

articles will be cited under a general heading such as aldehydes. CAS

Online will usually give much better results because a wider range of subject
terms can be used in the search. If you are looking for information on a
highly specific structure type, a substructure search of CAS Online should
give essentially 100% recovery of the relevant references.

13.3.4 How to find information on synthetic methods

The reference books on the chemistry of classes of compounds which are
listed in Section 13.3.3 are good starting points in this case too.
Additionally there are several major works devoted specifically to synthetic
methods. Comprehensive Organic Synthesis (Pergamon), a ni ne volume
overview of the area, is due to be published in 1989. Other useful texts
include Compendium olOrganic Synthetic Methods (Wiley) and Survey 01
Organic Synthesis (C.A. Buehler and D.E. Pearson, Wiley), and no list
would be complete without the excellent Advanced Organic Chemistry,
Reactions, Mechanisms, and Structures by J. March (Wiley). Organic
Syntheses (Wiley) is a compilation of carefully checked procedures with
full experimental details and is an excellent source of representative synthetic
procedures. Numerous syntheses of natural products are reviewed in the
volumes of The Total Synthesis of Natural Products edited by Ap Simon
(Wiley). Organic Reactions (Wiley) is an ongoing series containing
reviews of specific reactions. A relatively new series called Best Synthetic
Methods (Academic Press) aims to present critical reviews of the preferred
methods for carrying out common transformations. Reagents for Organic
Synthesis (L.F. Fieser and M. Fieser, Wiley) is the best source of
information on the preparation, purification, and use, of reagents, whereas
Synthetic Reagents (S.S. Pizey, Wiley) provides detailed reviews of a
smaller number of particularly common reagents.
Two excellent series provide annual coverage of developments in
synthetic chemistry. Theilheimer's Synthetic Methods 01 Organic
Chemistry provides thorough coverage of the synthetic literature and is
organized according to a unique (and easily learned) system of classifying
the transformations taking place. Theilheimer is available online via the
Chemical Reactions Documentation Service (Derwent Publications Ltd.)
and REACCS (Molecular Design Ltd.). Annual Reports in Organic
 The Chemical Literature 217

Synthesis (Academic Press) is a weH organized coHection of representative

synthetic transformations and it is up to date and very easy to use.
ChemicaL Abstracts is not particularly useful for the same reasons as
outlined in Section 13.3.3. Again CAS Online is much better but the best
onIine sources are the databases of synthetic methods. Databases such as
ORAC, SYNLIB and REACCS contain tens of thousands of
transformations, chosen for their synthetic value. They can be searched
very easily using graphical input and output, and powerful software features
aHow you to perform highly specific searches which cannot be carried out in
any other way.

13.4 Current awareness

Keeping in touch with the current Iiterature is a difficult and time consuming
exercise but it is vital to your development as a chemist, and to the success
of your research. You should aim to read through at least 6-12 of the most
important journals in your field and the best way of doing this is to set aside
a specific period each week for reading the periodicals. You should also
scan the review journals (Angewandte Chemie,lnternational Edition in
English, Chemieal Society Reviews, Chemieal Reviews, Synthesis, and
Tetrahedron) and magazines such as Chemie al and Engineering News,
Chemistry and Industry and Chemistry in Britain.
As if this is not enough, there is still the problem of how to cover the
hundreds of other chemistry periodicals. The only practical method of
doing this is to use compilations of abstracts. You could read Chemical
Abstracts itself but this is too large and a much better choice is one or more
of the titles in the CA Seleets series, which only contain abstracts relating to
a particular area. However, wider Iiterature coverage is essential and a good
approach is to read one of the periodicals which abstracts new compounds
and reactions. M ethods olOrganie Synthesis (Royal Society of Chemistry)
and the more comprehensive Index C hemieus (Institute of Scientific
Information) are good examples of this genre.
All of this effort will be was ted if you do not keep good records of
what you have read. Building your own computer database is an
increasingly practical way of doing this but for now the simplest method is
to use a card file. Make arecord of each important paper on an index card.
218 The Chemical Literature

Inc1ude the bibliographie details and an abstract of the key results in the
paper. The pile of eards is not of much use unless it is properly filed.
Many filing systems, eaeh with its own strengths and weaknesses, can be
conceived but one possibility deserves special mention, at least as a starting
point. Annual Reports in Organic Synthesis (Seetion 13.3.4) is essentially
a eompilation of index eards in book form, and the systematic way in which
the material is organized could serve as a useful model for your system. As
time progresses you can modify this system to adapt it to your own interests
and requirements.
 CHAPTER 14

Special Procedures

14.1 Introduction
This section deals with some of the specialized procedures which might be
encountered. All the topics covered here have one thing in common, namely
that the particular type of apparatus used will vary from one laboratory to
another and accordingly detailed instructions will not be given here for any
one piece of apparatus. Representative systems are shown, and common
operating procedures discussed. Often there will be someone in the
department who is responsible for, or has particular expertise in, one of
these techniques. If this is the case then always consult this person before
you intend attempting the reaction.

14.2 Catalytic hydrogenation

Caution: Extreme care must be taken whenever hydrogen gas

and active catalysts are used. Observe loeal safety precautions
strict/y.
If you are unfamiliar with catalytic hydrogenation or with the particular
local apparatus, do find someone with experience of the apparatus and
technique, and familiarize yourself with the manipulations and precautions
before attempting the reaction.
The reduction of organie compounds using hydrogen and a catalyst is a
reaction which is often encountered. Most catalytic hydrogenations are
carried out at atmospheric pressure, and organic chemistry laboratories will
have their own 'atmospheric' hydrogenation apparatus. These consist of a
gas burette (or burettes) connected to a hydrogen supply, and to the reaction
220 Special Procedures

flask (see Section 6.3 for details of gas burettes). A typical arrangement is
shown in Fig. 14.1 and the operation is simple in principle. A volume of
hydrogen (more than the theoretical amount whenever possible) is
transferred to the burette, with the reaction vessel containing the solvent,
catalyst, and reactant, and the initial volume noted. The reaction is then
agitated (stirred or shaken) and the uptake of hydrogen monitored using the
burette. The detailed operation will depend upon the precise equipment
which is used, but a written step-by-step procedure should be available. It
is important to follow the procedure closely, and to consider the effect of
opening any tap before doing so.

to to to to
reaction gas bUTette manometer source
vessel ofhydrogen

to
waterpump
(or other source
ofvacuum)

Figure 14.1 Schematic diagram of an atmospheric hydrogenator

When filling the reaction flask, add the catalyst first, followed by the
solvent, and then your substrate. Addition of an active batch of catalyst to
solvent can cause fires. Do make sure that all air is removed from the
system by following the detailed procedure which applies to your particular
system, and when the reaction is over, ensure that as much residual
hydrogen is removed as possible; again, follow the procedure. Ensure that
a safety screen is used as much as possible throughout the whole operation.
Filtration of the reaction mixture must be done carefully. Filter through
a pad of Celite on a sintered glass funnel, but do not allow the catalyst to dry
out. Wash through with more solvent and dispose of the wet catalystiCelite
mixture properly. Most Iaboratories have a special bottle for catalyst
residues; use it. Numerous fires have resulted from wet catalyst residues
being placed in a waste bin, since the residue dries out in the air and ignites.
Do not attempt a catalytic hydrogenation until you know wh at to do with the
catalyst residue.
 Special Procedures 221

The above procedure is sometimes inconvenient for small sc ale work (it
depends upon the type of hydrogenation system available), and we often
resort to the use of a small balloon of hydrogen connected to the reaction via
a three-way tap, which is also connected to a manifold. This technique is
illustrated in Fig. 14.2.
Fill the balloon with hydrogen (several times to remove air) and connect
it to the fiasko Connect the three-way tap to the manifold, open to vacuum
(carefully) and then to the inert gas (Fig. 14.2a). Several cyc1es will be
required. Then turn the tap so as to isolate the system from the manifold,
and allow hydrogen to enter the fIask (Fig. 14.2b). The reaction can then be
monitored in the usual way. When the reaction is over, vent the excess
hydrogen from the balloon (sa/ely) to a fume cupboard (Fig. 14.2c).
Residual hydrogen can be removed from the system by the use of several
cyc1es of evacuation followed by admission of inert gas using the manifold
as above (Fig. 14.2a). All precautions re/erred to in the use 0/ the
atmospheric hydrogenator must be observed here 0/ course.

t :::··:~
\:iI·
i I

(a) (b) (e)

Figure 14.2 Small scale hydrogenation using a balloon

Medium- and high-pressure hydrogenations require specialized
equipment and great care. This equipment usually consists of a metal
reaction vessel and the appropriate 'plumbing' to allow its safe
pressurization with hydrogen. These reactions are potentially most
hazardous, and must be carried out under the c10se supervision of the
person who is responsible for the apparatus.
222 Special Procedures

14.3 Photolysis

Caution: Ultraviolet radiation is very damaging to the eyes and

skin.
The reactor must be properly screened. Wear special protective
goggles, or better still a face shield which offers protection against
ultraviolet radiation if the apparatus is to be adjusted (or samples taken)
while the lamp is on. When doing this also protect the hands with gloves
and make sure that no other areas of skin would be exposed to radiation in
the event of an accident. It is much safer to turn off the lamp when such
manipulations are being carried out.
Preparative photochemical reactions are usually carried out in an
immersion-weIl reactor, the usual design is shown in Fig. 14.3.
wircs 10
~owc,un it

coolir1g

L
.......-""\,·otc, OLll

/ 0'vclll to b.. bblc,

manifold

I-t-H---i--l'

solution or
substrate

....
..
.. ..

glas. f';t

Figure 14.3 Photochemical reactor

Air is removed from the solvent by bubbling nitrogen or argon up
through the solution via the sintered glass disko Ensure that the correct
choice of lamp has been made. Low pressure lamps emit most of their
radiation at 254nm, are low power (up to - 20W) and require a quartz
 Special Procedures 223

immersion weIl (not Pyrex). Most preparative reactions use the much
higher power (lOO-400W) medium pressure lamps, as these emit their
radiation over a much wider range (mainly at - 365nm with other bands at
both shorter and Ion ger wavelength). Occasionally a filter will be required
and it is important that the correct one is used (this will be specified in the
preparation being followed).
Reactions are usually run at fairly high dilution (up to - O.05M) and the
solvent should be pure and chosen with care. It must not decompose under
ultraviolet irradiation and should not absorb at the wavelength being used
for the reaction. Work up often involves no more than evaporation of the
solvent followed by purification.

14.4 Ozonolysis

Caution: Ozone is toxie, and ozonides potentially explosive.

Ozone is generated using a commercial ozonator (or ozonizer) which
can produce a concentration of up to 8% in oxygen, and which will be
available in most organic research establishments. The operation of these is
very simple providing that the instructions for the particular device are
followed carefully. Make sure that these are consulted before attempting the
reaction.
The compound to be ozonized is dissolved in the appropriate solvent,
and cooled to the desired temperature. Ozone is then passed through the
solution until no more starting material remains. For most purposes an
excess of ozone can be used. It can be difficult to avoid this, but an
indicator wh ich can be added to the solution to show you when there is free
ozone in the solution can sometimes be most valuable in avoiding over-
oxidation. 1
The work up depends upon the desired product, but will include a
reagent which reacts with the ozonide. This reagent is almost always added
in excess, and before any product isolation is attempted. Make sure that you
allow plenty of time for the ozonide to react, as isolation of ozonides is to be
avoided due to their potential for violent explosive decomposition. Once the
ozonide is fully reacted the reaction can be processed in the usual manner.
1. T. Veysoglu, L.A. Mitscher, and l.K. Swayze, Synthesis, 1980,807.
224 Special Procedures

14.5 Flash vacuum pyrolysis (fvp)

This technique is not often encountered in synthetic organic chemistry, but it
can prove invaluable in some circumstances. As with most of the topics in
this chapter, the exact type of apparatus used will depend on what is
available in your department. One simple (schematic) set up is shown in
nitrogen
inlet

_--1~~ ~
-
to vacuwn

t. ---- .._._.::_"::::::. .... -

................ vaCllum
pyro IYSIS oven
:::~.:

flask for
--- ---- guage
_ .. 0 ____ - . - - _ • • • _ ..

substrate ..................
:::::::,,":::::::::
.- ........
........ -._-.-.
_.. ----,,--
__ 0 .... ___ • • - - - - - - -

cold batb

...... __ ....................... _-
. . . . . . . . . . . _ ...... _ ................ 0 __ -

Figure 14.4 Schematic representation of an apparatus for FVP

Fig. 14.4. It is important to vaporize the substrate at the appropriate rate,
and to make sure that the thermolysis temperature is correct. If this
information is not available then some experimentation will inevitably have
to be carried out. A typical vaporization rate might be between 0.5 and 1.0g
per h.
As with all high vacuum work, care must be taken. After all of the
substrate has passed through the hot tube, turn off the furnace and allow to
cool to room temperature (still under vacuum). Then turn off the pump and
admit nitrogen to atmospheric pressure. Remove the traps to a fume
cup board and allow to warm to room temperature, and work up in the usual
way. If the desired product is unstable towards air, water, or is simply
very reactive, then a more sophisticated pyrolysis system might be required,
and more elaborate work up procedures used.

14.6 Liquid ammonia reactions

Caution: Ammonia is a powerful irritant, toxic, and the gas is
flammable. Conduct all reactions in an effident fume
cupboard and avoid all contact with the liquid.
 Special Procedures 225

Liquid ammonia (b.p. -330C) is a solvent which is not encountered

frequently, but which does have several important general uses, in particular
'dissolving metal' reductions ('Birch' type reductions) and most reactions
involving lithium amide or sodium amide as bases. Ammonia gas from a
cylinder is condensed direct1y into the flask (Fig. 14.5).

----+ [0 bubblcr

low tcmperalllrc----+
thermomeu~r

cooling halh

Figure 14.5
The apparatus is set up as in Fig. 14.5 and a rapid flow of ammonia is
used to flush out the system. A small volume of acetone (or ethanol) is
poured into the condenser, and solid carbon dioxide pellets are added (very
slowly atfirst) until the condenser is nearly full. The ammonia will begin to
condense, and when the required volume is obtained, the ammonia flow is
shut off and the gas inlet replaced by a septum or stopper. If undried
impure ammonia will suffice, and often it will, then the reaction is carried
out as normal. A cooling bath can be added if a long reaction time is
anticipated, or if a temperature below -33°C is required (see Chapter 8).
If dry liquid ammonia is needed this is usually obtained by distillation
off sodium. The appropriate volume of ammonia is condensed as above and
small pieces of sodium are added to produce a blue solution. The ammonia
can then be distilled using anormal distillation apparatus (Chapter 9) except
that the receiver (usually the reaction flask) is cooled in asolid carbon
226 Special Proccdurcs

dioxide/acetone cooling bath. The ammonia in the distillation flask must

remain blue throughout). The distillation apparatus is disconnected from the
receiver which is then fitted with a cold-finger condenser and the reaction
carried out as normal. The work up is usually simple. Solid ammonium
chloride is added carefully and the ammonia allowed to evaporate (Chapter
9). The product may then be isolated and purified in the usual way.
 CHAPTER 15

'Trouble Shooting':
What to do when things do not work

Do not despair - yet. ..

Some reactions will not work, for proper chemical reasons associated
with the substrate. These may or may not be 'obvious' (many things
become 'obvious' with hindsight). Do not jump to the conc1usion that you
have encountered such areaction. Before you can conc1ude that this is the
case a number of possibilities must be explored.
The fIrst and most obvious is to make sure that the starting material is
pure, dry, and free from solvents, and that it is indeed what you think it iso
A critical perusal of all the analytical and spectroscopic data will usually be
sufficient. If you have used several batches of starting material then do
make certain that the spectra which you check are from the batch which you
used in the failed reaction. If necessary, re-run the spectra to ensure that the
starting material has not partially decomposed, or picked up moisture.
Once you are certain that the problem does not lie with the starting
material, check the solvent. Many reactions will not work if the solvent is
not anhydrous; methods for obtaining anhydrous solvents are given in
Chapter 4. Tetrahydrofuran (THF) is very commonly used, and is usually
dried by distillation off sodium/benzophenone; however it is possible collect
wet THF from a bright blue distillation pot (which means that the solvent is
dry in this part of the still). This problem is encountered when a still head is
used to collect the solvent, but insufficient time has been allowed at reflux
before collection is commenced. One way to check this is to repeat the
reaction, but take a sample of the THF used (before introducing it into the
reaction flask) and add a litde sodium hydride (dispersion in oil) (care). If
immediate hydrogen evolution is observed, the solvent is wet. The remedy
228 'Trouble Shooting'

is to allow more time at reflux before collecting the solvent, if this does not
work the drying agents might need recharging.
Another source of water could be the inert gas which you are using;
make sure that the drying agent (if used) used is still working renew it if
necessary. Failing this, try the reaction under argon, which usually contains
much less moisture than nitrogen. Check the manifold and renew any
suspect tubing.
With pure starting materials, and anhydrous solvent and atmosphere,
the reagent(s) must be suspected. If it is possible to purify them, do so, and
make sure that you are handling them correct1y (see Chapter 5). Itwill not
be practical to purify some reagents, for example alkyllithiums, and in this
case the quality should be checked by titration where possible. It is unwise
to purchase areagent (from any source) and to take for granted the quoted
molarity and purity; even the most reputable suppliers are fallible and
occasionally make mistakes.
If starting material, reagents, solvent, and inert gas are all as they
should be then it might be you! You might be inadvertently carrying out the
re action in such a way that it will not work. For example, is the temperature
correct, is the concentration of reactant and reagent correct, is too much or
too little time being allowed at a particular stage? There are many
possibilities. To test this it is advisable to carry out the same reaction but
use a substrate which is known from the literature to react properly. If this
is successful, and your desired reaction is not then you have found a
reaction which does not work on your substrate, and alternative conditions
(different metal ions, different Lewis acid etc.) might be required. Above
all, if the reaction is an important one, do not give up; perhaps you could
take the opportunity to develop a new re agent or procedure which will
work!
 CHAPTER 16

Example Reactions

16.1 Preparation of n-butyllithiurn 1

Li
~CI

A dry, 250ml, round-bottomed flask fitted with Liebig condenser and a

septum is flushed with dry argon and the reaction vessel placed under a
positive pressure of argon (Fig. 16.1). Freshly cut lithium wire (5g,
O.71mol) is placed in the reaction flask, and dry hexanes (80ml) added to
the reaction flask via syringe. The reaction mixture is sonicated using an
ultrasonic bath. n-Butyl chloride (37ml, 0.35mol) in dry hexanes (50ml) is
added dropwise to the lithium suspension via syringe over aperiod of about
lOmin. Reaction begins after a short induction period (ca. 5-lOmin) causing
the reaction mixture to warm and producing a purple precipitate. The
reaction mixture is sonicated for a further 3h, and then filtered under an
argon atmosphere (see Chapter 9). The resulting n-butyllithium solution is
collected in a 250ml conical flask which is subsequently fitted with a
septum. The conical flask is flushed with argon such that the n-butyllithium
solution remains under an inert atmosphere. As long as the solution is
protected from atmospheric moisture and oxygen, it can be stored in the
conical flask until required for use. The molarity of the n-butyllithium
solution produced should be about 1.8M, and this can be checked by
titration (see Section 16.2).
1. H. Gilman, J.A. Beel, C.G. Brannen, M.W. Bullock, G.E. Dunn, and L.S. MiIler,
J. Am. ehern. Soc., 1949, 71, 1499.
230 Example Reactions

inert gas
~

septum -

condenser-

reaction flask

ultrasonic
- bath

Figure 16.1

16.2 Titration of n-butyllithium

~Li

Red-<>range
A dry, 2ml, round-bottomed flask or small Pyrex test tube fitted with a
magnetic stirrer bar and septum is flushed with argon, and then placed under
a positive pressure of argon (Fig. 16.2).
 Example Reactions 231

inert gas
~
septum - t:t1 (
GoQ):====~l 0

reaction mixture- 7:
e

( )
Figure 16.2
1,3-Diphenyl-2-propanone p-toluenesulphonylhydrazone (113 mg,
0.5mmol)2 is placed in the flask, and dry tetrahydrofuran (2ml) added via
syringe. The reaction mixture is stirred rapidly to dissolve the hydrazone,
and the n-butyllithium solution is added dropwise to the colourless solution
until the orange-red end-point is observed. At this point the volume of n-
butyllithium solution added is noted, and from this the molarity of the
solution is calculated using the following equation:

Molarity of n-butyllithium solution = Volume of solution used x 1000

In order to obtain an ace urate titre it is necessary to carry out this

titration at least three times and calculate the average of the results obtained.

16.3 Aldol reaction: preparation of 5-hydroxy-2,2-dimethyl-5-

phenylpentan-3-one 3

o o

xV'o
OH

~
1) LDA
2) Benzaldehyde

A dry, 100ml, round-bottomed flask fitted with septum and magnetic stirrer
2. For a discussion of the varoious titration methods see, J. Suffert, J. Org. Chern.,
1989, 54, 509.
3. H.O. House, D.S. Crumrine, AY. Teranishi, and H.D. OImstead, J. Am. Chern.
Soc., 1973, 95, 3310.
232 Example Reactions

septum

low tempcrature
lbcnnomctcr -
/
~~I!!}---.5 - argon

lagged balb -

~
~

Figure 16.3
bar is flushed with argon, then placed under a positive pressure of argon.
Anhydrous diisopropylamine (2.9ml, 20.8mmol) is added to the flask via
syringe, followed by dry diethyl ether (20mi). The reaction mixture is
cooled to _78°C using a dry ice-acetone cooling bath (Fig. 16.3). n-
butyllithium (11.6ml of a 1.8M solution in hexanes, 20.8mmol) added
dropwise via syringe to the stirred mixture. After addition of the n-butyl-
lithium is complete the reaction mixture is stirred for lOmin at -78°C
allowing complete formation of lithium diisopropylamide then a solution of
3,3-dimethylbutan-2-one (2Aml, 19.2mmol) in dry diethyl ether (5ml) is
added dropwise via syringe to the reaction mixture. After stirring at -78°C
for 10min, benzaldehyde (2Ag, 19.2mmol) is added and the mixture stirred
for a further 30min. The reaction is quenched by careful addition of 1M
hydrochloric acid (50ml), and the resulting mixture allowed to warm to
room temperature before being transferred to a 250ml separating funnel.
The mixture is extracted with diethyl ether (3x50ml) and the combined
etheral extracts washed with saturated aqueous sodium chloride solution
(50ml). The organic extracts are then dried over magnesium sulphate, and
the solvent removed on a rotary evaporator to give the crude product as an
oil. Kugelrohr distillation gives 5-hydroxy-2,2-dimethyl-5-phenylpentan-3-
 Example Reactions 233

one (3.2g, 80%) as a colourless oil (b.p. 86°C/0.07mmHg) which solidifies

on standing to give a colourless solid m.p. 22-23°C.

16.4 Preparation of ethyl(triphenylphosphoranylidene)

acetate 4

2. NaOH

A 2 litre, 3-necked, round-bottomed fIask, fitted with thermometer,

mechanical stirrer, and dropping funnel (Fig. 16.4) is charged with
triphenylphosphine (104.8g, O.4mol) and toluene (250mi). The solution is
stirred vigorously while ethyl bromoacetate (74.4g, O.4mol) is added
dropwise at a rate that maintains the reaction temperature at, or slightly
above, room temperature.After the addition is complete, the reaction mixture

nitrogen

mcchanical stilTCF--

dropping funncl

Ihermomctef-

rcaction mixture

Figure 16.4

4. R.W. Lang and H.-I. Hansen, Org. Synth .• 1984, 62, 202.
234 Example Reactions

is stirred at room temperature for 2h, then the colourless phosphonium salt
precipitate is filtered off, and washed first with cold toluene (250ml) and
then petroleum ether (l50ml). The cmde phosphonium salt is dissolved in
water (2 litres) , placed in aseparatory funnel, and further organic impurities
removed by washing with diethyl ether (2x400ml). The aqueous solution is
transferred to a 5 litre beaker, and 2% alcoholic phenolphthalein (10 drops)
added. The solution is cooled in an ice-water bath and stirred vigorously by
means of a glass rod as 2N aqueous sodium hydroxide is added slowly until
the pink end-point is reached. At this stage as much water as possible is
decanted from the precipitated phosphorane, then ethyl acetate (1.5litres) is
added. The resulting two phase mixture is transferred to a separating funnel
and the aqueous layer removed. The ethyl acetate solution is dried over
magnesium sulphate and evaporated on a rotary evaporator, to give ethyl
(triphenylphosphoranylidene)acetate (l22g, 88%) as a cream solid, m.p.
124-126°C.

16.5 Claisen rearrangement 5

~OH 1) (EtOhCCH3, H+
~ 2) KOH

A mixt ure of cinnamyl alcohol (3.3g, 25mmol), triethyl orthoacetate

(4.6ml, 25mmol) and hexanoic acid (2 drops) is placed in a 50ml, 2-necked,
round-bottomed flask equipped with athermometer, Dean-Stark trap, and
condenser (Fig. 16.5). The solution is heated in an oil bath, allowing the
ethanol produced to distil out of the reaction mixture and collect in the trap.
After 2h, the distillation of ethanol slows, and more hexanoic acid (l drop)
is added. Additional portions of hexanoic acid are added after 3 and 4h.
After 4.5h, at least 2ml of ethanol should have been collected, and tlc (25%
diethyl ether - 75% petroleum ether) should indicate complete consumption
of the cinnamyl alcohol. Over the 4.5h period the internal temperature rises
from 100°C to 166°C. The solution is then allowed to cool and a solution of
potassium hydroxide (2g, 35mmol) in water (3ml) and methanol (8m!) is
added. The Dean-Stark trap is replaced by a condenser and then the mixture
5. F. B. Gonzalez and P. A. Bartlett., Org. Synth .• 1985, 64, 175.
 Example Reactions 235

~~f.LJ-nitrogcn

condenser-

Dean-Stark
trap -

slirrer-hotplate- ~
~

Figure 16.5
is heated under reflux for 45min under nitrogen (Fig. 16.6). After the
alkaline solution has cooled to room temperature, water (3Oml) is added, the
mixture washed with diethyl ether (20ml) and then acidified with
concentrated hydrochloric acid. The acidic aqueous solution is extracted
with diethyl ether (3x20ml), and the extracts dried over magnesium
sulphate. Filtration and removal of the solvent on a rotary evaporator then
gives the crude product. Flash chromatography on silica gel (20% diethyl
ether - 80% petroleum ether) gives the purified 3-phenyl-4-pentenoic acid as
a pale yellow solid which can be recrystallized from petroleum ether (m.p.
44-46°C).
236 Example Reactions

~~EJ - nitrogen

eondenser -

_ _ _ _ _ _ _ _ _-: -: -: -: -: -: - oil baLh

.. --_ . .. -.. .. .... .
.. . . .. . .......
. . . .. . ..

slirrer-hotplate -

~
~

Figure 16.6

16.6 Hydrogenation of maleie acid6

H2, Ethanol
Pt02

A 50ml, round-bottomed flask fitted with a magnetic stirrer bar is charged

with maleie anhydride (2.32g, 20mmol) platinum oxide (2Omg), and ethanol
(30m1). The flask is fitted with a 3-way tap connected to a vacuum line, and
balloon fi1led with hydrogen (Fig. 16.7). The reaction flask is sequentially
evacuated and purged with hydrogen three times, and then Ieft under a slight
6. R. Adams and V. Voorhees, Org. Synth. Col .. 1932, 1, 61.
 Example Reactions 237

balloon filled
with hydrogen-

-t!~!f[] - attached to vacuum

reaction flask

A
'\;:;:;:I
Figure 16.7
positive pressure of hydrogen maintained by the balloon.
The reaction mixture is stirred at room temperature for 1h, the hydrogen
balloon removed, and the mixture filtered through a pad of silica gel (3g) to
remove the catalyst. The solvent is the removed on a rotary evaporator to
give a white solid which can be crystallized from about 2ml of boiling
water, to give succinic acid (2g, 84%), m.p. 187-189°C.
 CHAPTER 17

Safety

17.1 Safety is your primary responsibility

Chemicallaboratories are potentially dangerous workplaces and accidents in
the lab can have serious and tragic consequences. However, if you are
aware of potential hazards, and work with due care and attention to safety,
the risk of accidents is sm alL Some general guidelines for safety in the
laboratory are presented in this section. In addition to these principles you
must be familiar with the safety regulations in force in your area and the
rules and guidelines applied by the administrators of your laboratory.
Your supervisor has a responsibility to warn you of the dangers
associated with your work, and you should always consult him/her, or a
safety officer, if you are unsure about potential hazards. However, your
own safety, and that of your colleagues in the lab, is largely determined by
your work practices. Always work carefully, use your commonsense, and
abide by the safety regulations.
Some important general principles of safe practice are summarized in
the following roles
1. Work carejully, do not take risks.
This covers basic rules such as always wearing safety spectac1es, never
working alone, and working neatly and unhurriedIy.
2. Assess the possible hazards bejore carrying out areaction.
Find out about the dangers of handling unfamiliar chemicals or
apparatus and take note of any necessary precautions.
3. Know the accident and emergency procedures.
 SAFETY 239

It is vital to know what to do in case of an accident. This includes

being familiar with the fire fighting and first aid equipment, and knowing
how to get assistance from qualified personnel.

17.2 Safe working practice

It has been emphasized already that you should be familiar with the
regulations and codes of practice pertaining in your laboratory. We will not
discuss safety legislation here but some fundamental rules should be
stressed. Never work alone in a laboratory. Always wear suitable safety
spectacles and a non-flammable lab coat, and use other protection such as
gloves, face masks, or safety shields if there is a particular hazard. Never
eat, drink or smoke in a laboratory. Work at a safe steady pace, and keep
your bench and your lab clean and tidy. Familiarity breeds contempt, do not
allow yourself to get careless with everyday dan gers such as solvent
flammability. Familiarize yourself with the location and operation of the
safety equipment in your laboratory.
As regards specific hazards the chief rule is to carry out an assessment
of the dan gers involved before using an unfamiliar chemical or piece of
apparatus. Some of the commonest hazards are described in the next
section. Once you are aware of the possible dangers take all the necessary
precautions, and ensure that you know what to do if an accident does occur.
Store your chemicals in clearly labelled containers, and abide by the
regulations concerning storage of solvents and other hazardous materials.
Dispose of waste chemicals safely, according to the approved procedures
for your laboratory. Never pour organic compounds down the sink.

17.3 Common hazards

Always assess the risks involved before carrying out areaction. Extensive
compilations of information about the dangers posed by a large number of
compounds are available (see Bibliography). Consult these references and
your supervisor before using a compound or procedure which is new to
you. In some areas safety legislation makes it mandatory to conduct such a
safety audit, but even if it is not legally required, it should still be regarded
as an essential preliminary before doing areaction.
240 SAFETY

Remember to treat all compounds, especially new materials, with care.

Avoid breathing vapours and do not allow solids or solutions to get on your
skin. The majority of accidents are caused by a few common hazards.
Some of the most frequently encountered dangers are listed in Table 17.1
and you should be aware of all of these, and always take appropriate
precautions. Consult safety manuals and other Sections of this book for
more information. Throughout the book safety warnings are highlighted in
hold italic text.
Table 17.1
Common hazards in the chemicallaboratory

Source Hazard
Glassware Danger of cuts, leaks of harmful compounds
Solvents Most are extreme1y flammable
Benzene, halogenated solvents are toxic
Vacuum apparatus May implode violently
Pressure apparatus May explode violently
Gas cylinders May leak harmful gases or discharge violently
(Chapter6)
Strong acids Extremely corrosive
React violently with water, bases
May produce harmful vapours
Strong bases Extremely corrosive
React violently with acids, protic solvents
Strong oxidizing agents React violently with easily oxidizable compounds
such as organic solvents
Alkali metals React violently with water, protic solvents and
chlorinated solvents
Strong alkylating agents Extremely toxic

In addition to these general warnings you should be aware of the severe

hazards posed by some more specific families of compounds. The
compounds listed in Table 17.2 pose a severe risk of explosion and those in
Table 17.3 should be regarded as extremely toxic.
 SAFETY 241

Table 17.2
Explosion hazards

Acetylene and meta! acetylides

Alkali meta!s in contact with chlorinated solvents
Azides, both organic and inorganic
Diazo compounds and diazonium salts
Glass vacuum apparatus, e.g. Dewar flasks
Liquid oxygen and liquid air (formed by evaporation of liquid nitrogen)
Nitrates and polynitro compounds, e.g. TNT (trinitrotoluene)
Perchloric acid, perchlorates, and chlorates
Peroxides (formed in ethers and in alkenes on standing in air)

Table 17.3
Toxic and carcinogenic compounds

Compounds ofheavy meta!s (arsenic, mercury, lead, selenium, thallium)

Alkylating agents including methyl iodide, dimethyl sulphate (CARClNOGENIC)
Fluorine, chlorine and bromine
Hydrofluoric acid and meta! fluorides
Cyanides and hydrogen cyanide
Oxalic acid and its salts, oxalyl chloride
Aromatic amines and nitro compounds
Ozone
Hydrogen sulphide
Phosgene
Osmium tetroxide
Benzene, polycyclic aromatics (CARClNOGENIC)
Hexamethylphosphoric triamide (HMPA) (CARClNOGENIC)

17.4 Accident and emergency procedures

Regrettably accidents are still all too cornmon so it is vital that you know
what to do if an accident does occur. You must be familiar with the fire
fighting equipment in your lab (fire extinguishers, fIre blankets, sand
buckets) and you must know the procedures for summoning the fIre brigade
242 SAFETY

and for evacuating the building. In the ca se of injuries or exposure to

harmful chemicals you should know who to summon to administer first aid,
and how to get medical assistance. It is particularly important to know how
to get help outside of normal working hours. If you are using particularly
dangerous materials (such as cyanides) or equipment (such as high pressure
apparatus) you should know about the relevant emergency procedures and
take precautions such as having antidotes, protective equipment, or qualified
personnel at hand. In the aftermath of an accident it is very important that
you complete the required accident report forms, and take steps to avoid any
possibility of a repeat.
Ask yourse1f now: are you familiar with accident procedures? If not
you should not be working in the lab.

17.5 Bibliography

Guide to Safe Practices in Chemical Laboratories, Royal Society of

Chemistry, 1986.
Hazards in the Chemical Laboratory, 4th ed., L. Bretherick Ed., Royal
Society of Chemistry, 1986.
The Sigma-Aldrich Library ofChemical Safety Data, 2nd ed., R.E. Lenga
Ed., Sigma-Aldrich Corp., Milwaukee, 1987.
Dangerous Properties of Industrial Materials, 7th ed., N.!. Sax and R.J.
Lewis, Van Nostrand Reinhold Co., New York, 1988.
First Aid Manual for Chemical Accidents, M.J. Lefevre, Dowden
Hutchinson and Ross, Stroudsburg, 1980.
Safe Storage of Laboratory Chemieals, D.A. Pipitone, Wiley, New York,
1984.
Handbook of Laboratory Waste Disposal, MJ. Pitt and E. Pitt, Wiley, New
York,1985.
 Appendix 1 Properties of common solvents

B.p. M.p. I)IH 1)13C Preliminary Rigorous TLV

Solvent E Density drylng
CC) CC) (300MHz, CDCI3) (300MHz, CDCI 3) drying (ppm)

Acetic acid 118 17 6.19 1.049 2.08 s, 10-13 br s var 20.7, 177.6 Acetic anhydride Acetic anhydride 10
Acetone 56 -94 20.7 0.790 2.13 s 30.7, 206.5 3Asieve 3A sieve 1000
Acetonitrile 82 -46 36.2 0.777 1.97 s 1.7, 116.2 Potassium carbonate Phosphorus pentoxide 40
Benzene 80 5.5 2.28 0.879 7.37 s 128.3 Not necessary Calcium hydride 10

t-Butanol 82 25 3.49 0.850 1.24 s, 1.35 br s var 31.2, 69.2 Calcium hydride Calcium hydride
Carbon tetrachloride 76 -23 2.23 1.460 - 96.2 Alumina Phosphorus pentoxide 10
Chlorobenzene 132 -46 5.62 1.106 7.28 brm 126, 129, 130, 134 Not necessary Calci um hydride 75
Chloroform 62 -63 4.70 1.480 7.24 s 77.0 Alumina Phosphorus pentoxide 10

Dichloroethane 83 -35 10.4 1.235 3.71 s 44.4 Not necessary Calcium hydride 10
Dichloromethane 40 -97 8.9 1.325 5.28 s 53.4 Not necessary Calcium hydride 100
Diethyl ether 35 -116 4.34 0.714 1.18 t, 3.45 q 15.2, 65.8 Calcium chloride; Na SodiunVbenzophenone 400
Dimethoxyethane 83 -58 0.850 3.36 s, 3.51 s 59.0, 71.8 Calcium chloride; Na SodiunVbenzophenone g~
Dimethylformarnide 152 -61 36.7 0.945 2.81 s, 2.89 s, 7.94 s 31.4, 36.4, 162.4 Calcium hydride Phosphous pentoxide 10 ~
Dimethyl sulphoxide 189 18 49.0 1.101 2.62 s 40.6 Distillation 4A sieve
Dioxan 102 12 2.21 1.034 3.66 s 67.0 Calcium chloride: Na SodiunVbenzophenone 50
Ethanol 78 -114 24.3 0.785 1.18 t, 2.05 br s, 3.65q 18.3, 58.2 Magnesium 3A sieve 1000

Ethyl acetate 77 -84 6.02 0.900 1.22 t, 2.01 s, 4.09 q 14.1,20.9,60.3,171.0 Potassium carbonate 4A sieve 400
HMPA 235 7 1.030 2.59 d 36.8 Calcium hydride Calcium hydride
Methanol 64 -97 32.6 0.791 1.94 br s var, 3.42 s 50.5 Magnesium 3A sieve 200
Nitromethane 101 -28 38.6 1.137 4.33 s 62.4 Calcium chloride 4A sieve 100

Pyridine 116 -42 12.3 0.982 7.24 m, 7.63 m, 8.58 m 123.6, 135.8, 149.8 Calcium hydride Calcium hydride 5
Tetrahydrofuran 66 -65 18.5 0.805 1.82 m, 3.72 m 25.6, 67.9 Calcium chloride; Na SodiunVbenzophenone 200
Toluene 111 -95 2.38 0.867 2.32 s, 7.17 br s 21,125,128,129,138 Not necessary Calcium hydride ~OO

Water 100 0 78.5 1.000

~
w
 Appendix 2 Properties of common gases
t
Mol. Denslty Density Hazardous
Gas B.p.- M.p.b TLV' Notes
weigbt o( gas· of IIquld d propertles·
26.04 -84 1.109 As, Fl, Note g a. °c at 1atm
Acetylene
Ammonia 17.03 -33 -78 0.71 0.68 To, Co, Fl 25 b. oe
Argon 39.944 -189 -186 1.66 1,4 As c. g/l at 2QoC at 1atm
Boron trichloride 117.19 12.5 -107 4.85 To,Co
d. g/ml at b.p.
Baron trifluoride 67.81 -100 -127 3 1.59 To,Co 1
e. As = Asphyxiant
Carbon dioxide 44.01 -78 1.83 Co 5000 Co = Conosive
Carbon monoxide 28.01 -191 -207 1.16 0.79 To, Fl 50 Fl = Flammable
Chlorine 70.914 -34 -101 2.97 1.56 To,Co 1
Ox = Oxidising
Ethylene 28.05 -104 -170 1.17 0.57 Fl
Ethylene oxide 44.05 10.7 -112 1.82 0.88 To, Fl 5 To= Toxic
f. ppm ~
Fluorine 37.997 -188 -220 1.57 1.5 Fl,Co 1 g. Potenliallyexplosive ~
Helium 4.0026 -269 -272 0.17 0.12 As ~
when pressurised
Hydrogen 2.016 -253 0.08 0.07 Fl ~
Hydrogen bromide 80.917 -67 -87 3.34 2.16 To,Co 3
Hydrogen chloride 36.461 -85 -114 1.52 1.19 To,Co 5

Hydrogen fluoride 20.006 19.5 -83 0.94 To,Co 3

Hydrogen ~ulphide 34.08 -60 -85 1.43 1.0 To, Co, Fl 10
Isobutylene 56.11 -6.9 -140 2.39 0.63 Fl
Methanethiol 48.107 6 -121 2.14 0.89 To, Fl 0.5
Nitric oxide (NO) 30.006 -152 -164 1.24 1.27 To 25

Nitrogen 28.0134 -196 1.25 0.8 As

Nitrogen dioxide (NOV 46.0055 21 -9.3 3.3 1,45 To,Co 3
Oxygen 32.0 -183 -218 1.33 1.14 Ox
Phosgene 98.92 8.2 -128 4.1 1.41 To,Co 0.1
Sulphur dioxide 64.063 -10 -75 2.70 1.46 To,Co 2
 Appendix 3 Approximate * pK a values for some common deprotonations cf. some common bases

Rea2ent to be deprotonated pKa Bases pKa (of BH)

ArSH 7
RCH 2N02 9
RCOCH 2CN 9
RCOCH 2COR 9
RSH 10 Et3N 11
RCOCH 2C02R 11 Et2NH 11
RC02CH2C02R 13 ~
Cyclopentadiene 15 Na+-OH 16 9
RCH 2CHO 17 Na+ -OEt 18
~
~
RC=CH 25 K+ -OtBu 19
CH3COCH3 20
CH3C02Et 25 Na+-H 35
CH3CN 25 Na+-NH2 35
PhH 41 U+ -NiPr2 36
H2C=CHCH3 43
H2C= CH 2 44 U+ -nBu 50

------- - -
U+ -tBu - --
>50
*These figures are very approximate. A pKa difference of >4 between base and reagent will cause complete deprotonation.
~
U1
 Appendix 4 Lewis acids
~
Lewis acid Compatlble solvents Comments 0\

Aluminium trichloride Hydrocarbons, halogenated Slrong, widely used in Friedel-Crafts

Boron tribromide Hydrocarbons, halogenated Slrong, used to cleave ethers, acetals

Boron trichloride Hydrocarbons, halogenated Slrong, used to cleave ethers, acetals
Boron trifluoride etherate Many solvents Moderate, very versatile

DiethyWuminium chloride Hydrocarbons, halogenated Moderate, useful for proton-sensitive reactions

EthyWuminium dichloride Hydrocarbons, halogenated Moderate, useful for proton-sensitive reactions

Feme chloride Hydrocarbons, halogenated Moderate

Mercuric chloride Many solvents Weak, useful for cleaving C-S bonds

Lanthanide Many solvents Weak, useful for reactions involving sensitive

shift reagents dienes, ethers ::l
i
Magnesium bromide Hydrocarbons, halogenated Moderate [
Magnesium chloride.etherate Hydrocarbons, halogenated, ethers Moderate

Sil ver chloride Many solvents Moderate, used to generate carbonium ions
Sil ver triflate Many solvents Moderate, used to generate carbonium ions

Stannie chloride Hydrocarbons, haIogenated Slrong, very versatile

Titanium tetrachloride Hydrocarbons, halogenated Slrong, very versatile

Trimethylsilyl iodide Hydrocarbons, halogenated, MeCN Strong, used to cleave ethers, acetals, esters
Trimethylsilyl triflate Hydrocarbons, halogenated Strong, used with silylated reagents

Zinc bromide Hydrocarbons, halogenated Moderate, versatile

Zinc chloride Hydrocarbons, halogenated, ethers Moderate, versatile
~-
-----
 Appendix 5 Common reducing reagents

1. Hydride reducing agents

Reagent Typical solvents Temperature Functional groups
(OC) reduced
LiB14 Tetrahydrofuran o to RT ester ~ alcohol
Qithium borohydride) ketone ~ alcohol
aldehyde ~ alcohol

Li[Et3BH] (Superhydride) Tetrahydrofuran -78 to RT ester ~ alcohol

Qithium triethylborohydride) ketone ~ alcohol
aldehyde ~ alcohol
alkyl halide ~ alkane
epoxide ~ alcohol g~
Li[SBu3BH] (L-Selectride) Tetrahydrofuran -78 to RT ketone ~ alcohol [
Qithium tri-sec-butylborohydride) aldehyde ~ alcohol
alkyl halide ~ alkane

NaB14 Alcohols, ethers o toRT ketone ~ alcohol

(sodium borohydride) aldehyde ~ alcohol

Na[BH3CN] Alcohols, water, o toRT ketone ~ alcohol

(sodium cyanoborohydride) DMSO aldehyde ~ alcohol
alkyl halide ~ alkane
imine ~ amine

Na[BH(OAc)3] Aceticacid o toRT ketone ~ alcohol

I (sodium triacetoxyborohydride) aldehyde ~ alcohol ~
-.l
 ~
Appendix 5 cont'd 00

Reagent Typical solvents Temperature Functional groups

(OC) reduced
Zn(Bl4h Ethers OtoRT ketone -+ alcohol
(zinc borohydride) aldehyde -+ alcohol

nBu.tNBI4 Dichloromethane, OtoRT ketone -+ alcohol

(tetra-n-butylammonium borohydride) ethers aldehyde -+ alcohol

LiAIH4 Ethers -78 to RT ester -+ alcohol

(lithium aluminium hydride) ketone -+ alcohol
aldehyde -+ alcohol
alkyl halide -+ alkane
acetylene -+ trans alkene f
epoxide -+ alcohol r-
imine -+ amine
amide -+ amine

Li[(tBu0}JAlHJ Tetrnhydrofuran -78 acid chloride -+ aldehyde

(lithium tri-tert-butoxyaluminium RT ketone -+ alcohol
hydride) aldehyde -+ alcohol

Na[AIH2(OCH2CH2OCH3hJ (RED-AL) Ethers, toluene -78 to RT ester -+ alcohol

(sodium bis-[2-methoxyethoxyJ- ketone -+ alcohol
aluminium hydride) aldehyde -+ alcohol
alkyl halide -+ alkane
epoxide -+ alcohol
a.ß-unsaturated enone -+ allylic alcohol
 Appendix 5 cont'd

B2% Dichloromethane, -78 to RT carboxylic acid ~ alcohol

(diborane) tetrahydrofuran amide ~ amine
RT ketone ~ alcohol
aldehyde ~ alcohol

BH3S(CH3h Tetrahydrofuran, -78 to RT carboxylic acid ~ alcohol

(borane-dimethylsulphide complex) dimethyl sulphide RT amide ~ amine I
ketone ~ alcohol
aldehyde ~ alcohol

(SiahBH Tetrahydrofuran -78 to RT ketone ~ alcohol

~
(disiamylborane) aldehyde ~ alcohol g
lactone ~ lactol
ftf)l
AlH3 Ethers -78 to RT ester ~ alcohol
ketone ~ alcohol I
(alane)
aldehyde ~ alcohol
alkyl halide ~ alkane
epoxide ~ alcohol
lactone ~ cyclic ether

iBu2AlH (DIBAL) Dichloromethane, -78 ester ~ aldehyde

(Di-isobutylaluminium hydride) ethers, toluene lactone ~ lactol
amide ~ aldehyde
nitrile ~ aldehyde
-78 to RT ketone ~ alcohol
aldehyde ~ alcohol
~
a,ß-unsaturated ketone ~ allylic alcohol \0
acetylene ~ cis-alkene
 t->
U\
Appendix 5 cont'd o

2. Single electron transfer reducing agents

Reagent Typical Solvents Temperature Functional Groups
(OC) Reduced
Li/NH3 Liquid ammonia -78 a,ß-unsaturated ketone ~ ketone
(lithium in ammonia) -78 to -33 ketone ~ alcohol
aldehyde ~ alcohol
aryl ring ~ dihydroaryl ring

LiClOH8 Tetrahydrofuran -78 to RT sulphide ~ alkane

(lithium naphthalenide) sulphone ~ alkane
~
NaHg Methanol O-RT ketone ~ alcohol '§
(sodium amalgam) aldehyde ~ alcohol
- -
sulphone ~ alkane r-
3. Common hydrogenation catalysts
Catalyst Solvent Temperature H2 Pressure Functional Groups
("C) (bar) Reduced
Ni Alcohols, toluene 5 to 100 3-10 alkene ~ alkane
ketone ~ alcohol
aldehyde ~ alcohol

Pd/C Alcohols 5 to 50 1-5 aromatic nitto ~ aromatic amine

Alcohols, acetic acid 5 to 100 1-10 nitrile ~ amine
Toluene 5 to 100 1-10 acetylene ~ alkane
'-------- ,~- -~ ~- , .~ ~ ------
alkyl halide ~ alkane
 Appendix 5 cont'd

Alcohols, toluene 510100 3-10 alkene ~ alkane

Toluene 5010150 3-50 imines ~ amine
alkyl nitro ~ amine
Aceticacid epoxide ~ alcohol

Pd/B aS °4 Alcohols, toluene 51050 1-3 acetylene ~ cis alkene

PtfC Alcohols 5 to 50 1-5 aromatic nitro ~ aromatic amine

Alcohols, toluene 510100 3-10 olefin ~ alkane
ketone ~ alcohol
aldehyde ~ alcohol
a,ß-unsatura1ed ketone ~ alylic alcohol
Toluene 50 to 150 3-50 imines ~ amine

Rh/C Alcohols, toluene 5 to 100 3-10 olefin ~ alkane

Acetic acid, alcohols 50 to 150 3-50 aromatic ring ~ cyc10hexane
ketone ~ alcohol
,
aldehyde ~ alcohol

Rh/Al203 Alcohols 50 to 150 3-50 aromatic ring ~ cyc10hexane

N
VI
 tv
Ut
Appendix 6 Common oxidizing reagents tv

Reagent Typical Solvents Temperature Functional Groups

('C) Oxidized
Cr03fH2S04 (H2Ct04) Acetone; ether o toRT 2° a1cohol-+ ketone
(Jones reagent; chromic acid) 1° a1cohol-+ acid
aldehyde -+ a1cohol

Ct03.Pn (Collins reagent) Pyridine;dichloromethane OtoRT 2° a1cohol-+ ketone

1° a1cohol-+ aldehyde

PyH+Cr03Cl- (PCC) Dichloromethane; DMF OtoRT 2° a1cohol-+ ketone

(pyridinium chlorochromate) 1° a1cohol-+ aldehyde
~
::I

(PyH+)2Cr207 (pDC) Dichloromethane; DMF o toRT 2° a1cohol-+ ketone ~

(pyridinium dichromate) 1° a1cohol-+ aldehyde

Ag2C03/Celite (Fetizon's reagent) Hexane; benzene; RT, Reflux 2° a1cohol-+ ketone

(silver carbonate on Celite) chloroform diols-+lactones

MnÜ2 Hexane; benzene; 0, RT, Reflux selective for a1lylic

(manganese dioxide) dichloromethane or benzylic a1cohols-+
aldehydes or ketones

KMn°4 Often used in 0, RT, reflux Very powerful oxidant

(potassium permanganate) aqueous solution 2° a1cohol-+ ketone
- ----
1° a1cohol-+ acid
 Appendix 6 cont'd

KMn04 cont'd a1kene~ diol

sulphide~ sulphone
I
Ru04 Carbon tetrachloride/ RT cleaves a1kenes ~
acetonitrile/water carboxylic acids

AI(OR)3f'M~CO (Oppenauer oxidation) Acetone; RT 2° alcohol~ ketone

Al(OR)3/cyclohexanone toluene Reflux

Pb(OAc)4 Benzene; acetic acid; -78 to RT cleaves 1,2 diols ~

(lead tetraacetate) acetonitrile C=O compounds >
ketones~ ~
a-acetoxy-ketones
many other systems ~
also oxidized

DMSO/electrophilic reagent (EI.) -40 to RT 2° alcohol~ ketone

EI. = Dichloromethane 1° alcohol~ aldehyde
(COCl)2 (oxalyl chloride) !Et3N Dichloromethane
DCC (dicyclohexylcarbodiimide) Dichloromethane
(CF3COhO (trifluroacetic acid anhydride) Dichloromethane
Py.S03 (pyridine-sulphur trioxide) DMSO

N-Chlorosuccinimide (NCS)/M~S (DMS) Toluene -20 2° alcohol~ ketone

(N-Chlorosuccinimide/dimethyl sulphide 1° alcohol~ aldehyde
D:
Vl
 N
Appendix 6 cont'd ~

Reagent Typical Solvents Temperature Functional Groups

(OC) Oxidized
Os04/N-methylmorpholine-N-oxide (NMO) Acetone/water; RT alk:ene~ 1,2-diol
(osmium tetroxide/ t-butanol
N-methylmorpholine-N-oxide)

Os04/NaI°4 Ether/water; RT c1eaves alk:enes~

(osmium tetroxide/sodium periodate) dioxanlwater C=O compounds

m-Chloroperoxybenzoic acid (MCPBA) Dichloromethane -20 to RT alk:ene~ epoxide

sulphide~ sulphoxide/sulphone
~
Ti(OPri)4fBuOOH/tartrate ester (Sharpless Dichloromethane -20 enantioselective ~
oxidation) epoxidation of ~
(titanium isopropoxide/t-butyl hydroperoxide/ allylic alcohols
dialk:yl tartrate)

VO(acac)2fButo<:>H Dichloromethane -20 to RT a1lylic a1cohols~

(vanadyl acetylacetonate!t-butyl hydroperoxide) epoxides

H202/PhCH2(Me)3N+ OH- AIcohols o toRT a,ß-unsaturated C~

(hydrogen peroxide/benzyltrimethyl- epoxide
ammonium hydroxide)

PdCI2ICuCI2f02 (Wacker oxidation) Sulpholane/water RT to 100 terminal a1kenes~

(palladium chloride/cupflc chloride/oxygen) methyl ketones
 Appendix 6 cont'd

Pt/02 Acetone/water RT to 100 10 a1cohol~ acid

(platinum/oxygen) diol~lactone

°3 Dichloromethane; -78 to RT cleaves alkenes ~

(ozone) methanol car~nylcornJPOu~~

f
E

N
VI
VI
 Index
Accidents 241 safety 242
Aceticacid 34 synthetic chemistry 216
Acetic anhydride Boric anhydride, drying agent 30,34
drying agent 34 Boron trifluoride etherate 47
purification 48 lßutanol, drying 35
Acetone 33 nButyllithium
reaction with chloroform 35 preparation 229
Acetonitrile 34 titration 230
Acetyl chloride 48 use 231
Acetylene, preparation 86 Calcium chloride, drying agent 31,34,35
Air sensitive reagents Calcium hydride, drying agent 30-35
cannulation 51 Calcium sulphate, drying agent 31
setting up reactions 97 Cannula, cannulation 51,56,103
syringing 62,100 Capillary gc columns 122
Aldol reaction 231 Carbon dioxide, preparation 86-87
Alumina, drying agent 30,34 Carbon disulphide, drying 35
Ammonia 34,224 Carbon monoxide, preparation 87
Azeotrope 133 Carbon tetrachloride, drying 35
Azides, hazards 36 Celite 145
a,a'Azobis(isobuyronitrile), (AIBN) 49 Chemical abstracts 213-217
Balances 15 CA Selects 217
Balloons CAS OnIine 216,217
attachment 108 CAS REACT 213
for inert reactions 106 Chlorine, preparation 87
for hydrogenation 236 Chlorobenzene, drying 35
Barium oxide 30 Chloroform, drying 35
Bases, table 245 Chromatographic equipment 19
Beilstein 210,214 Chromatography
Benchkit 14,20 drycolumn 176
Benzene, drying 34 flash chromatography 27,166
Benzyl bromide 47 195,235
Bibby clips 97 gc 121-124
Boiling point 204 hplc 117,185
Books mplc 178
functional group chemistry 215 tlc 110
reference handbooks 215,216 Circular dichroism 205
258 Index

Claisen rearrangement 234 Detectors

Cold fmger condenser 131,165 uv 182,185
Collecting heads 40 refractive index 182,185
Column packing Diaphragm pump 89,169
dry column chromatography 176 Diazomethane
flash chromatography 171 esterification 73
Common reagents, table 46,47,48 preparation 70,71
Compressor, for chromatography 169 safety measures 71
Computer data records 10 titration 73
Condensers 1,2-Dichloroethane 35
~ 192 Diethylaluminium chloride 47
coiled 101,131 Diethyl ether
coldfmger 91,131,165 drying 36
double jacketed 131 peroxides 36
double walled 131 Düsopropylamine 46
for solvent stills 41 1,2-Dimethoxyethane, drying 37
Liebig 131,192,229 Dimethylformamide, drying 35
Cooling bath 125,199,232 Dimethyl sulphoxide 37,146
Cooling mixtures 126-128 Dioxan, drying 37
Copper{l) iodide 49 Distillation
Craig tube 25,26,150,195 equipment 17,155-157
Cmde product, isolation 145 fractional 158-159
Crystallization Kugelrohr 15,163,194,232
at low temperature 151 one-piece 17
of air-sensitive compounds 154 pressure!temperature nomograph 159
small scale 150 reduced pressure 47,159-162
technique 147 shortpath 17,157,158
Cyclohexane, drying 35 small scale 162-164
Cylinders, gas 74-77 solvents 39-42
Data book/data record solvent stills 39-42
completed example 12 under inertatmosphere 46,157
formats 10 Double manifold 23,23,97,104
keeping records 8 Dropping funnel 199;233
Dean and Stark trap 135,235 Dry column chromatography 176
Decalin, drying 35 Dry ice, solvent mixtures 127
Deuteriochloroform 204 Drying agents 29-33
 Index 259

Drying liquids 33-38,145 Fraction collecting 174,182

organie extracts 146 Fractional distillation 18
special cases 47 Fume cupboard 14
Drying ovens, for glassware 15,23 Funnels
Emulsions 143,145,146 for filtration under inert
Equipment atmosphere 25,26
bench set 20 Hirsch one piece sintered, 25
specialized items 21 Gas bubbIer 23,41,53,78,97
Ethanol, drying 37 Gas burette 81-83
Ethyl acetate, drying 35 Gases
Ethyltriphenylphosphoranylidene addition to reactions 78-79
acetate 233 bubbIers 23,41,53,78,97
Failed reactions 43,227-228 cylinders 74-77
Filtration gas burette 81-83
at 10w temperature 154 gas-tight syringes 59,80
Craig tube 25,26,150,195 handling 77-79
filter aids 25 inert 16,84
filter sticks 152,154 lecture bottles 77
of hot solutions 148,150 measurement 79-84
sm all scale 190 preparation 86-87
under inert atrnosphere 68,154 properties, table 244
Flame ionization detector (FID) 122 reagent gases 84-87
Flash adapter 168-169,172 regulators 75-76
Flash chromatography 166-176 scrubbing 86
columns 27 suck back traps 78
column loading 173 Ge (glc)
column preparation 171 capillary 121-124
column running 171 columns 122
equipment 167-169 correction factor 120
fraction size 174 gc-mass spectrometry 124
gradient elution 174 quantitative 123
reservoirs 27 splitter 123
silica 166,175 Glassware
solvent systems 169,170 assembling 96
Flash vacuum pyrolysis 224 chromatography 27
FolIower 135,136 drying 96
260 Index

general 18-20 table 247

routine 20-21 Hydrogen bromide, preparation 87
typical bench set 20-21 Hydrogen chloride, preparation 87
Glovebag 65 Hydrogenation
Glovebox 65 atmospheric hydrogenator 219
Grignard reagents 28 catalytic 219
Hazards catalysts 249
common 239 medium pressure 214
table 240 using a baIloon 236-237
with solvents 33-38 Ice-salt mixtures 126-127
Heating baths 132-133 Identification of compounds
Heating mantIes 132 b.p. 204
Hexamethylphosphoric triamide 37 gc 121-124
Hexane, drying 37 gc-ms 124
High vacuum system hplc 117-121
care 92 microanalysis 205
operation 91 m.p. 201,204
pressure measurement 92 optical rotation 204-205
traps 90-91 spectra 202-204
with manifold 97 Inert atmosphere
Hotplates 132,135 crystallization 154
Hplc 117-121 distillation 46,157
analytical 118 fIltration 154
care of columns 185 general 16-17,84
choice of columns 186-187 measuring liquids 55,103
correction factor 120 transfering liquids 51-57
detectors 185 Inert atmosphere reactions 95,109,191
equipment 117,185 addition of reactants 99
flowrates 186 addition of reagents 100
load loop 118 addition of solids 105-106
preparative 185-187 addition of solvents 99
quantitative 120 at elevated temperature 101-104,192
solvents 187 in nmr tubes 193
Hydrides large scale 102-104,198-199
quantitative analysis 82 slow addition to 102-104
reducing agents 31,142-143 tIc 109
 Index 261

weighing solids 66-70 Birch reductions 225

use of balloons 106-108 condensing 225
Inert gas 225
cylinders 16 reaction work-up 144
outlets 16-17 Liquid nitrogen-solvent mixtures 127-128
pressures 96 Liquids
purity 84 storing under inert atmosphere 50
sem i-permanent gas lines 17 distillation 46-48
use with solvent stills 41 purification and drying 33-38,45
Ir spectra 202-203 Magnesium 31-49
Isobutyraldehyde 46 Magnesium su1phate, drying agent 31
KBr disks, for ir 203 Magnetic stirrers 135-136
Kugelrohr apparatus 15,163,194,232 Manifo1d
Laboratory double 22,23,97,104
equipment 14-27 single 16
notebook 3-8 spaghetti 23-24,108-109
setting up 13 Manometer 92-93
Lewis acids 47,144 Mass spectra 203-204
table 246 McLeod gauge 92-93
Literature Mechanical shaker 139
computer databases 212 Mechanical stirrer 136-138,198-199,233
current awareness 217 Melting point 204
primary 208 Metal and metal hydride
references 8 dispersions, handling 66-69
reviews and books 216-218 Metal hydrides 31,142-143,247
searches 213 Methanol 38
searches for classes of Methyl iodide 46
compounds 215 Microana1ysis 205
searches for specific compounds 214 Microsyringe 57-58
searches for synthetic methods 216 Mininert valves 50,64
secondary 208 Mo1ecular sieves 31-32
structure 208 Mplc 178-185
Lithium aluminium hydride 31,142 columns 182
Lithium amide 225 ferrules 180
Lithium diisopropyl amide 231,232 flanging 180
Liquid ammonia 224 flow through injection valve 181
262 Index

flowrates 183 Pirani gauge 92

loadloops 181 Platinum oxide 236
procedure for running 183-184 Potassium hydroxide, drying agent 32
regenerating columns 184-185 Preparative hplc 185-187
sampie loading 181 Preparative tlc 178
silica 182 Pressure (vacuum) measurement 92-93
MulIs, ir 203 Pumps
Multiple elution, tlc 116 diaphragm 169
Needle valves, three-way 16-17 mplc 179
Nitrogen-solvent mixtures 127-128 vacuum 87-92
Nitromethane, drying 38 Pyridine, drying 38
Nmr Quantitative analysis
13Cspectra 202 bygc 123
following reactions 193-194 by hplc 120
IH spectra 202 Reactions
impurities in spectra 202 high temperature 101-102,128-133,
reporting data 10-12 192
N,N-Dimethylformamide 37,146 in nmr tubes 193-194
Notebook, Iaboratory 3-8 large scaIe 197-200
Oil bath 132,235 low temperature 125-128,189-192,
Oil bubbier 23,41,53,78,97 199-200
Optical rotation 204-5 small scale 187-196
Optical rotatory dispersion 205 Reaction monitoring
Organolithiums 28,229 gc 123-124
Organometallic reagents 42,47,50 hplc 118-119
Ozonolysis 223 nmr 193-194
Peak shape, hplc, gc 120-121 tlc 100,110-117
Pentane, drying 38 Reaction tube 129
Perkin triangle 161,162 Reagents
Peroxides air and moisture sensitive 51
detection, removal 36 gases 84-87
in decalin 35 handling and measuring 50-70
in ether 36 purity 45
Petroleum ether, drying 38 pyrophoric 44
Phosphorus pentoxide 32,37 specification 44
Photolysis 223 storage 44
 Index 263

Records flammability 28
of experimental data 8-11 for chromatography 29,169-170
of laboratory work 3-8 for crystallization 147
Refractive index detector 182,185 for spectroscopy 29
Retention time inert atmosphere distillation 41,46,
gc 122 157
hplc 118 peroxide contamination 29
Safety 238-242 properties 243
Sand bath 132 purification 28,29
Science Citation Index 211 stills 39-42
Sealed tuhe 128-129,194 toxicity 28
Septum 50-51 Solvent reservoir, for flash 167,168
Shaker 139 Solvent traps, for vacuum system 91
Sieves, molecular 31-32 Sonication 139,194,229
Silica Soxhlet extractor 49,134
for flash chromatography 166 Spaghetti manifold 108
quantity for flash 170 Spaltrohr columns 159,162
recycling 175-176 Specific rotation 204
safety 169 Spinning band columns 159
Silica/sample ratio, for flash 170 Stills
Sodium 33 one-piece 18,19,157,158
Sodium/benzophenone ketyl 33 solvent 39-42
Sodium chloride plates, ir 203 Stirring 135-138,190,199
Sodium-D line 205 Strong bases 142,246
Sodium/potassium a1loy 33 Structure determination 201-205
Sodium sulphate, drying agent 33 Sublimation apparatus 164,165
Solids Syringe fittings 59
air sensitive 66,69,154 Syringes 57-65
crystallization 61,147,154 care and c1eaning 60
handling and weighing 69 glass 58
purification and drying 48 gas-tight 59,80
Solvent handling 61
analytical grade 29 micro 57
anhydrous 28 plastic, disposable 59
distillation 39-42 preparation for use 61
drying 29,33 transfer of liquid under inert
264 Index

atmosphere 62 spectra 203

Taps Vacuum pumps 88-92
double oblique 22 electric diaphragm 89
threewayT 24,25,98 house system 89
Teflon tubing, for mplc 180 rotary oil pumps 90
Tetrahydrofuran, drying 38 vapour diffusion 92
Tetralin, drying 38 wateraspirator 88
Thermometers Vacuum sinter funnel 176
digital 126 Vials 190
low temperature 125 Vigreux columns 158,162
Tin tetrachloride 44 Vpc seegc
Titanium tetrachloride 47 Waterbath 131
TIc 19,110-117 Wood's meta1 132
checking decomposition 117 Work-up 142
detecting spots 113 Xylene, drying 38
for flash analysis 169,170,174
inert reaction monitoring 109
multiple elution 116
plates 111
preparative 178
procedure for running 112
recipes for staining reagents 114
Rfvalues 116
solvent polarity 114
spotter 102
Toluene, drying 38
p-Toluenesulphonyl chloride 49,143
Traps, for vacuum pumps 91
Triethylaluminium 47
Triethylamine 46
Trimethylsilyl chloride 48
Ultrasound 139,194,229
Ultraviolet radiation
detectors 182
in photolysis, 222-223
lamp for tlc viewing 178