JOHN LEONARD
BARRY LYGO
GARRY PROCTER
ADVANCED
PRACTICAL
ORGANIC
CHEMISTRY
THIRD EDITION
ISBN-13: 978-1-4398-6097-7
9 781 4 3 9 860 9 7 7
9 0 0 0 0
K12806
CHEMISTRY
Any research that uses new organic chemicals or ones that are not commercially
available will at some time require the synthesis of such compounds. Therefore,
organic synthesis is important in many areas of both applied and academic
research, from chemistry to biology, biochemistry, and materials science. The
third edition of a bestseller, Advanced Practical Organic Chemistry is a
guide that explains the basic techniques of organic chemistry, presenting the
necessary information for readers to carry out widely used modern organic
synthesis reactions.
This book is written for advanced undergraduate and graduate students as well
as industrial organic chemists, particularly those involved in pharmaceutical,
agrochemical, and other areas of ne chemical research. It provides the novice
or nonspecialist with the often difcult-to-nd information on reagent properties
needed to perform general techniques. With over 80 years of combined experience
training and developing organic research chemists in industry and academia,
the authors offer sufcient guidance for researchers to perform reactions under
conditions that give the highest chance of success, including the appropriate
precautions to take and proper experimental protocols. The text also covers
the following topics:
•
Record keeping and equipment
•
Solvent purication and reagent preparation
•
Using gases and working with vacuum pumps
•
Purication, including crystallization and distillation
•
Small-scale and large-scale reactions
•
Characterization, including NMR spectra, melting point
and boiling point, and microanalysis
•
Efcient ways to nd information in the chemical literature
With fully updated text and newly drawn gures, the third edition provides
a powerful tool for building knowledge on the most up-to-date techniques
commonly used in organic synthesis.
ADVANCED PRACTICAL ORGANIC CHEMISTRY
LEONARD
LYG O
PROCTER
K12806_Cover_mech.indd 1 11/28/12 1:03 PM
AdvAnced
PrActicAl
OrgAnic
chemistry
Third EdiT ion
CRC Press is an imprint of the
Taylor & Francis Group, an informa business
Boca Raton London New York
John Leonard
Barry Lygo
garry Procter
AdvAnced
PrActicAl
OrgAnic
chemistry
Third EdiT ion
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2013 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Version Date: 20130109
International Standard Book Number-13: 978-1-4665-9354-1 (eBook - PDF)
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v© 2010 Taylor & Francis Group, LLC
Contents
List of Figures ................................................................................................. xiii
List of Tables ....................................................................................................xxi
Preface ............................................................................................................ xxiii
Authors ............................................................................................................xxv
Chapter 1 General introduction .................................................................. 1
Chapter 2 Safety ............................................................................................. 3
2.1 Safety is your primary responsibility ................................................... 3
2.2 Safe working practice .............................................................................. 4
2.3 Safety risk assessments ........................................................................... 4
2.4 Common hazards .................................................................................... 5
2.4.1 Injuries caused by use of laboratory
equipment and apparatus ........................................................5
2.4.2 Toxicological and other hazards caused
bychemicalexposure ................................................................5
2.4.3 Chemical explosion and re hazards .....................................6
2.5 Accident and emergency procedures ................................................. 10
Bibliography ...................................................................................................... 10
Chapter 3 Keeping records of laboratory work ..................................... 13
3.1 Introduction ............................................................................................ 13
3.2 The laboratory notebook ....................................................................... 13
3.2.1 Why keep a lab book? ............................................................. 13
3.2.2 Laboratory records, experimental validity, and
intellectual property ............................................................... 14
3.2.3 How to write a lab book: Paper or electronic ...................... 15
3.2.4 Paper lab notebook: Suggested lab notebook format ......... 17
3.2.5 Electronic laboratory notebooks ............................................ 20
3.3 Keeping records of data ........................................................................ 21
3.3.1 Purity, structure determination, and characterization ...... 22
3.3.2 What types of data should be collected? ..............................22
3.3.3 Organizing your data records ............................................... 27
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3.4 Some tips on report and thesis preparation ...................................... 29
3.4.1 Sections of a report or thesis .................................................. 31
3.4.2 Planning a report or thesis ..................................................... 31
3.4.3 Writing the report or thesis ....................................................33
Bibliography ...................................................................................................... 40
Chapter 4 Equipping the laboratory and the bench ............................. 41
4.1 Introduction ............................................................................................ 41
4.2 Setting up the laboratory ...................................................................... 41
4.3 General laboratory equipment .............................................................42
4.3.1 Rotary evaporators .................................................................. 42
4.3.2 Refrigerator and/or freezer .................................................... 42
4.3.3 Glass-drying ovens ................................................................. 42
4.3.4 Vacuum oven ............................................................................43
4.3.5 Balances .....................................................................................43
4.3.6 Kugelrohr bulb-to-bulb distillation apparatus ...................43
4.3.7 Vacuum pumps ........................................................................ 43
4.3.8 Inert gases ................................................................................. 44
4.3.9 Solvent stills ..............................................................................45
4.3.10 General distillation equipment ..............................................46
4.3.11 Large laboratory glassware .................................................... 47
4.3.12 Reaction monitoring ................................................................ 48
4.4 The individual bench ............................................................................ 48
4.4.1 Routine glassware ................................................................... 49
4.4.2 Additional personal items ......................................................50
4.4.3 Specialized personal items ..................................................... 50
4.4.3.1 Double manifold .....................................................50
4.4.3.2 Three-way Quickt gas inlet T taps ..................... 53
4.4.3.3 Filtration aids ...........................................................54
4.4.3.4 Glassware for chromatography ............................ 56
4.5 Equipment for parallel experiments ................................................... 58
4.5.1 Simple reactor blocks that attach to magnetic
stirrerhot plates ....................................................................... 59
4.5.2 Stand-alone reaction tube blocks...........................................60
4.5.3 Automated weighing systems ............................................... 60
4.5.4 Automated parallel dosing and sampling systems ............ 61
4.6 Equipment for controlled experimentation ....................................... 61
4.6.1 Jacketed vessels ........................................................................ 61
4.6.2 Circulating heater-chillers...................................................... 62
4.6.3 Peltier heater-chillers ..............................................................63
4.6.4 Syringe pumps ......................................................................... 63
4.6.5 Automated reaction control systems ....................................63
4.6.6 All-in-one controlled reactor and calorimeter systems .....63
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Chapter 5 Purication and drying of solvents ...................................... 65
5.1 Introduction ............................................................................................ 65
5.2 Purication of solvents ......................................................................... 65
5.3 Drying agents ......................................................................................... 66
5.3.1 Alumina, Al
2
O
3
........................................................................ 67
5.3.2 Barium oxide, BaO ................................................................... 67
5.3.3 Boric anhydride, B
2
O
3
.............................................................. 67
5.3.4 Calcium chloride, CaCl
2
.......................................................... 67
5.3.5 Calcium hydride, CaH
2
........................................................... 68
5.3.6 Calcium sulfate, CaSO
4
........................................................... 68
5.3.7 Lithium aluminum hydride, LiAlH
4
..................................... 68
5.3.8 Magnesium, Mg ....................................................................... 68
5.3.9 Magnesium sulfate, MgSO
4
.................................................... 68
5.3.10 Molecular sieves ....................................................................... 68
5.3.11 Phosphorus pentoxide, P
2
O
5
................................................... 69
5.3.12 Potassium hydroxide, KOH .................................................... 69
5.3.13 Sodium, Na ............................................................................... 69
5.3.14 Sodium sulfate, Na
2
SO
4
.......................................................... 70
5.4 Drying of solvents ................................................................................. 70
5.4.1 Solvent drying towers ............................................................. 70
5.4.2 Solvent stills .............................................................................. 71
5.4.3 Procedures for purifying and drying
common solvents ..................................................................... 74
5.4.4 Karl Fisher analysis of water content .................................... 79
References ......................................................................................................... 79
Chapter 6 Reagents: Preparation, purication, and handling ........... 81
6.1 Introduction ............................................................................................ 81
6.2 Classication of reagents for handling ............................................... 81
6.3 Techniques for obtaining pure and dry reagents ............................. 82
6.3.1 Purication and drying of liquids ........................................83
6.3.2 Purifying and drying solid reagents .................................... 85
6.4 Techniques for handling and measuring reagents ........................... 87
6.4.1 Storing liquid reagents or solvents under an
inertatmosphere ...................................................................... 87
6.4.2 Bulk transfer of a liquid under inert
atmosphere(cannulation) ....................................................... 89
6.4.3 Using cannulation techniques to transfer measured
volumes of liquid under inert atmosphere .......................... 91
6.4.4 Use of syringes for the transfer of reagents or
solvents ...................................................................................... 94
6.4.5 Handling and weighing solids under
inert atmosphere .................................................................... 102
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6.5 Preparation and titration ofsimple organometallic
reagentsand lithium amide bases .................................................... 107
6.5.1 General considerations ......................................................... 107
6.5.2 Preparation of Grignard reagents
(e.g.,phenylmagnesium bromide) ....................................... 109
6.5.3 Titration of Grignard reagents ............................................. 109
6.5.4 Preparation of organolithium reagents
(e.g.,n-butyllithium) ...............................................................110
6.5.5 Titration of organolithium reagents
(e.g., n-butyllithium) ...............................................................111
6.5.6 Preparation of lithium amide bases (e.g., lithium
diisopropylamide) ................................................................. 112
6.6 Preparation of diazomethane .............................................................113
6.6.1 Safety measures ......................................................................113
6.6.2 Preparation of diazomethane (a dilute ethereal
solution) ....................................................................................113
6.6.3 General procedure for esterication of
carboxylic acids .......................................................................115
6.6.4 Titration of diazomethane solutions ....................................115
References ........................................................................................................115
Chapter 7 Gases .......................................................................................... 117
7.1 Introduction ...........................................................................................117
7.2 Use of gas cylinders ..............................................................................117
7.2.1 Fitting and using a pressure regulator on
a gas cylinder...........................................................................118
7.3 Handling gases .................................................................................... 120
7.4 Measurement of gases ......................................................................... 122
7.4.1 Measurement of a gas using a standardized
solution .................................................................................... 122
7.4.2 Measurement of a gas using a gas-tight syringe .............. 123
7.4.3 Measurement of a gas using a gas burette ......................... 123
7.4.4 Quantitative analysis of hydride solutions
usingagasburette ................................................................ 125
7.4.5 Measurement of a gas by condensation ............................. 126
7.4.6 Measurement of a gas using a quantitative
reaction .................................................................................... 126
7.5 Inert gases ............................................................................................. 127
7.6 Reagent gases ....................................................................................... 127
7.6.1 Gas scrubbers ......................................................................... 128
7.6.2 Methods for preparing some commonly
used gases ............................................................................... 128
References ....................................................................................................... 130
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© 2010 Taylor & Francis Group, LLC
Chapter 8 Vacuum pumps ........................................................................131
8.1 Introduction .......................................................................................... 131
8.2 House vacuum systems (low vacuum) ............................................. 131
8.3 Medium vacuum pumps .................................................................... 131
8.3.1 Water aspirators ..................................................................... 131
8.3.2 Electric diaphragm pumps ................................................... 132
8.4 High vacuum pumps .......................................................................... 133
8.4.1 Rotary oil pumps ................................................................... 133
8.4.2 Vapor diffusion pumps ......................................................... 134
8.5 Pressure measurement and regulation ............................................ 135
8.5.1 Units of pressure (vacuum) measurement ......................... 136
Chapter 9 Carrying out the reaction ...................................................... 137
9.1 Introduction .......................................................................................... 137
9.2 Reactions with air-sensitive reagents ............................................... 138
9.2.1 Introduction ............................................................................ 138
9.2.2 Preparing to carry out a reaction under
inert conditions ...................................................................... 138
9.2.3 Drying and assembling glassware ...................................... 139
9.2.4 Typical reaction setups using a double manifold ............. 140
9.2.5 Basic procedure for inert atmosphere reactions ................ 140
9.2.6 Modications to basic procedure ........................................ 144
9.2.7 Use of balloons for holding an inert atmosphere ............. 149
9.2.8 Use of a “spaghetti” tubing manifold ................................. 152
9.3 Reaction monitoring ............................................................................ 153
9.3.1 Thin layer chromatography ................................................. 153
9.3.2 High performance liquid chromatography ....................... 160
9.3.3 Gas–liquid chromatography (GC, GLC, VPC) ................... 164
9.3.4 NMR .........................................................................................167
9.4 Reactions at other than room temperature .......................................167
9.4.1 Low-temperature reactions .................................................. 168
9.4.2 Reactions above room temperature .................................... 170
9.5 Driving equilibria ................................................................................ 177
9.5.1 Dean–Stark traps ................................................................... 177
9.5.2 High-pressure reactions ....................................................... 178
9.6 Agitation ............................................................................................... 178
9.6.1 Magnetic stirring ................................................................... 179
9.6.2 Mechanical stirrers ................................................................ 180
9.6.3 Mechanical shakers and vortexers ...................................... 182
9.6.4 Sonication ................................................................................ 183
9.7 Use of controlled reactor systems ...................................................... 184
9.7.1 Jacketed vessels ...................................................................... 185
9.7.2 Parallel reactors ...................................................................... 186
References ....................................................................................................... 189
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Chapter 10 Working up the reaction ........................................................191
10.1 Introduction .......................................................................................... 191
10.2 Quenching the reaction ...................................................................... 191
10.2.1 Strongly basic nonaqueous reactions .................................. 192
10.2.2 Near neutral nonaqueous reactions .................................... 192
10.2.3 Strongly acidic nonaqueous reactions ................................ 193
10.2.4 Nonaqueous reactions involving Al(III) reagents ............. 193
10.2.5 Reactions involving oxidizing mixtures that may
contain peroxide residues ..................................................... 195
10.2.6 Acidic or basic aqueous reactions ....................................... 195
10.2.7 Liquid ammonia reactions ................................................... 195
10.2.8 Reactions involving homogeneoustransition
metalcatalysts ........................................................................ 197
10.3 Isolation of the crude product ............................................................ 198
10.3.1 Typical isolation from an aqueous work-up ...................... 199
10.3.2 Isolation from a reaction involving nonvolatile polar
aprotic solvents ...................................................................... 203
10.3.3 Using an acid/base aqueous work-up to separate
neutralorganics from amines .............................................. 203
10.3.4 Using an acid/base aqueous work-up to separate
neutral organics from carboxylic acids .............................. 204
10.3.5 Nonaqueous work-ups .......................................................... 205
10.3.6 Work-ups using scavenger resins ........................................ 206
10.3.7 Use of scavengers to remove heavy metal
residues ................................................................................... 207
10.4 Data that need to be collected on the crude product
prior to purication ............................................................................. 208
Chapter 11 Purication ...............................................................................209
11.1 Introduction ..........................................................................................209
11.2 Crystallization ...................................................................................... 209
11.2.1 Simple crystallization............................................................209
11.2.2 Small-scale crystallization .................................................... 212
11.2.3 Crystallization at low temperatures ....................................214
11.2.4 Crystallization of air-sensitive compounds ....................... 217
11.3 Distillation ............................................................................................ 218
11.3.1 Simple distillation .................................................................. 218
11.3.2 Distillation under an inert atmosphere ..............................220
11.3.3 Fractional distillation ............................................................ 221
11.3.4 Distillation under reduced pressure ...................................223
11.3.5 Small-scale distillation .......................................................... 226
11.4 Sublimation ........................................................................................... 228
11.5 Flash chromatography ........................................................................ 229
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11.5.1 Equipment required for ash chromatography ................ 230
11.5.2 Procedure for running a ash column ............................... 232
11.5.3 Recycling silica for ash chromatography ......................... 239
11.6 Dry-column ash chromatography .................................................. 240
11.7 Preparative TLC ................................................................................... 241
11.8 Medium pressure and prepacked chromatography systems........ 242
11.9 Preparative HPLC ................................................................................ 245
11.9.1 Equipment required .............................................................. 245
11.9.2 Running a preparative HPLC separation ........................... 246
References ....................................................................................................... 248
Chapter 12 Small-scale reactions ..............................................................249
12.1 Introduction .......................................................................................... 249
12.2 Reactions at or below room temperature ......................................... 250
12.3 Reactions above room temperature .................................................. 252
12.4 Reactions in NMR tubes .....................................................................253
12.5 Purication of materials ..................................................................... 255
12.5.1 Distillation .............................................................................. 255
12.5.2 Crystallization ........................................................................ 255
12.5.3 Chromatography .................................................................... 255
Chapter 13 Large-scale reactions .............................................................. 259
13.1 Introduction .......................................................................................... 259
13.2 Carrying out the reaction ................................................................... 261
13.2.1 Using standard laboratory equipment ............................... 261
13.2.2 Using a jacketed vessel ......................................................... 261
13.3 Work-up and product isolation .......................................................... 263
13.4 Purication of the products ............................................................... 266
Chapter 14 Special procedures .................................................................. 267
14.1 Introduction .......................................................................................... 267
14.2 Catalytic hydrogenation ..................................................................... 267
14.3 Photolysis .............................................................................................. 270
14.4 Ozonolysis............................................................................................. 272
14.5 Flash vacuum pyrolysis (FVP) ........................................................... 273
14.6 Liquid ammonia reactions ..................................................................274
14.7 Microwave reactions ........................................................................... 275
References ....................................................................................................... 276
Chapter 15 Characterization ......................................................................277
15.1 Introduction .......................................................................................... 277
15.2 NMR spectra ........................................................................................277
15.3 IR spectra .............................................................................................. 280
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15.4 UV spectroscopy .................................................................................. 280
15.5 Mass spectrometry .............................................................................. 281
15.6 Melting point (m.p.) and boiling point (b.p.) .................................... 281
15.7 Optical rotation .................................................................................... 281
15.8 Microanalysis ....................................................................................... 282
15.9 Keeping the data .................................................................................. 283
Chapter 16 Troubleshooting: What to do when things
don’t work .................................................................................285
Chapter 17 The chemical literature ..........................................................289
17.1 Structure of the chemical literature .................................................. 289
17.2 Some important paper-based sources of
chemical information .......................................................................... 290
17.2.1 Chemical Abstracts ...................................................................290
17.2.2 Beilstein .................................................................................... 291
17.2.3 Science Citation Index (paper copy) .................................... 292
17.3 Some important electronic-based sources of chemical
information ........................................................................................... 294
17.3.1 SciFinder ................................................................................. 295
17.3.2 Reaxys ..................................................................................... 295
17.3.3 Web of Science and SCOPUS ............................................... 295
17.3.4 Cambridge Structural Database (CSD) ............................... 296
17.3.5 The World Wide Web ............................................................ 296
17.4 How to nd chemical information .................................................... 296
17.4.1 How to do searches ............................................................... 296
17.4.2 How to nd information on specic compounds ............. 297
17.4.3 How to nd information on classes of compounds ......... 297
17.4.4 How to nd information on synthetic methods ............... 298
17.5 Current awareness ............................................................................... 298
References ....................................................................................................... 299
Appendix 1: Properties of common solvents ............................................. 301
Appendix 2: Properties of common gases ..................................................305
Appendix 3: Approximate pK
a
values for some common
reagentsversus common bases .............................................309
Appendix 4: Common Bronsted acids .........................................................311
Appendix 5: Common Lewis acids ............................................................. 313
Appendix 6: Common reducing reagents .................................................. 315
Appendix 7: Common oxidizing reagents .................................................. 319
xiii© 2010 Taylor & Francis Group, LLC
List of Figures
Figure 3.1 An example of a lab notebook entry .....................................16
Figure 3.2 An example of a xed-format data sheet .............................. 28
Figure 3.3 A exible format data sheet (word processor le) ............... 29
Figure 3.4 A completed data sheet ........................................................... 30
Figure 3.5 Tabulated experimental data for inclusion in a thesis ........ 39
Figure 3.6 An example of a journal-specic experimental
procedure ..................................................................................40
Figure 4.1 Single manifold ........................................................................44
Figure 4.2 One-piece distillation apparatus............................................46
Figure 4.3 One-piece distillation apparatus incorporating a
fractionating column ............................................................... 47
Figure 4.4 Double manifold ...................................................................... 51
Figure 4.5 Cross section of a double-oblique tap ................................... 51
Figure 4.6 A simple bubbler design ......................................................... 52
Figure 4.7 Double manifold connected to a vacuum line and
aninert gas supply ................................................................... 52
Figure 4.8 Spaghetti tubing manifold ...................................................... 53
Figure 4.9 Three-way taps ......................................................................... 54
Figure 4.10 Using a three-way tap .............................................................54
Figure 4.11 One-piece sintered lter funnels ........................................... 55
Figure 4.12 Small-scale recrystallization apparatus ................................ 56
Figure 4.13 Inert atmosphere ltration apparatus ................................... 57
Figure 4.14 Flash chromatography column .............................................. 58
xiv List of Figures
© 2010 Taylor & Francis Group, LLC
Figure 4.15 Jacketed vessel and lid ............................................................ 61
Figure 4.16 A syringe pump ....................................................................... 62
Figure 5.1 Solvent drying towers .............................................................71
Figure 5.2 A continuous solvent still ....................................................... 72
Figure 5.3 Design of how to construct a continuous solvent
still collecting head .................................................................. 73
Figure 5.4 Alternative designs for solvent still collecting heads ......... 75
Figure 6.1 Preparing a vessel for storage of air- or moisture-
sensitive reagents .....................................................................88
Figure 6.2 Setting up a system for bulk transfer of a liquid
under inert atmosphere ........................................................... 89
Figure 6.3 Bulk transfer of a liquid under inert atmosphere ............... 90
Figure 6.4 Measuring large volumes of liquid under inert
atmosphere using either (a) a measuring cylinder
or (b) a Schlenk tube ................................................................ 92
Figure 6.5 Bulk transfer of measured volumes of liquid under
inert atmosphere ...................................................................... 92
Figure 6.6 Different types of cannula ...................................................... 93
Figure 6.7 Making an all-PTFE cannula .................................................. 93
Figure 6.8 Liquid-tight syringe ................................................................. 95
Figure 6.9 Gas-tight microsyringe ........................................................... 97
Figure 6.10 All-glass Luer syringes............................................................97
Figure 6.11 Gas-tight Luer syringe ............................................................. 96
Figure 6.12 Luer syringe ttings ................................................................ 96
Figure 6.13 Luer tting syringe needles .................................................... 97
Figure 6.14 Flushing a syringe with inert gas .......................................... 99
Figure 6.15 Transferring an air- or moisture-sensitive liquid
bysyringe ..................................................................................99
Figure 6.16 Maintaining inert atmosphere around a syringe
needle tip ................................................................................. 100
Figure 6.17 Weighing a moisture-sensitive metal.................................. 103
Figure 6.18 Removing oil from a metal dispersion (small-scale) ........ 104
xvList of Figures
© 2010 Taylor & Francis Group, LLC
Figure 6.19 Removing oil from a metal dispersion (large-scale) ......... 105
Figure 6.20 Using an inverted lter funnel to provide an argon
blanket ..................................................................................... 107
Figure 6.21 Two apparatus setups for the preparation of
organometallics ...................................................................... 108
Figure 6.22 Formation of a Grignard reagent ......................................... 109
Figure 6.23 Formation of an organolithium reagent ..............................110
Figure 6.24 Titration of an organolithium reagent..................................111
Figure 6.25 Preparation of LDA ................................................................ 112
Figure 6.26 Apparatus for preparing diazomethane solution ..............114
Figure 7.1 Gas cylinder head unit ...........................................................118
Figure 7.2 Gas cylinder regulator plus three-way needle valve
outlet .........................................................................................119
Figure 7.3 Typical arrangement for the addition of a gas to a
reaction ask ........................................................................... 121
Figure 7.4 Setup for dispensing gases via a gas-tight syringe........... 123
Figure 7.5 Gas burette setup ................................................................... 124
Figure 7.6 Measurement of a gas by condensation .............................. 126
Figure 7.7 Gas generator setup ............................................................... 128
Figure 7.8 Gas scrubber setup ................................................................ 129
Figure 8.1 Water trap for use with water aspirators ............................ 132
Figure 8.2 Cold-nger condenser solvent trap setup for high
vacuum pumps ....................................................................... 133
Figure 8.3 Figure showing (a) a mercury manometer and (b) a
McLeod gauge ........................................................................ 135
Figure 9.1 Reaction ask attached to a double manifold .................... 140
Figure 9.2 Flow through a three-way tap relative to tap
position inert gas ows ..........................................................141
Figure 9.3 Adding air- or moisture-sensitive liquids to a
reaction ask ........................................................................... 142
Figure 9.4 Typical setups for inert atmosphere reactions that
are to be heated....................................................................... 144
xvi List of Figures
© 2010 Taylor & Francis Group, LLC
Figure 9.5 Larger-scale apparatus for inert atmosphere reactions .... 146
Figure 9.6 Setting up larger-scale apparatus for inert
atmosphere reactions. ............................................................ 147
Figure 9.7 Using a double manifold ....................................................... 148
Figure 9.8 Transferring liquids via cannula ......................................... 148
Figure 9.9 Using a solid addition tube ................................................... 149
Figure 9.10 Using a balloon to maintain an inert atmosphere............. 150
Figure 9.11 Using a balloon to ush a ask with inert gas ................... 151
Figure 9.12 Attaching a balloon to a needle or three-way tap ............. 152
Figure 9.13 Using a spaghetti tube manifold ......................................... 152
Figure 9.14 Taking a TLC sample from a reaction under inert
atmosphere .............................................................................. 156
Figure 9.15 Running a TLC ....................................................................... 157
Figure 9.16 Running a two-dimensional TLC ........................................ 160
Figure 9.17 A typical analytical HPLC setup ..........................................161
Figure 9.18 Schematic of the injection port in load (a) and inject
(b) positions ..............................................................................162
Figure 9.19 A typical GC setup ................................................................ 165
Figure 9.20 Organolithium addition ........................................................ 166
Figure 9.21 Using a cooling bath .............................................................. 168
Figure 9.22 Monitoring internal temperature using a digital
thermometer ........................................................................... 169
Figure 9.23 A simple sealed tube (Carius tube) ..................................... 171
Figure 9.24 A reaction tube ....................................................................... 172
Figure 9.25 A typical setup for performing a reaction at reux .......... 173
Figure 9.26 Different types of condensers ...............................................174
Figure 9.27 Using an aluminum heating block ...................................... 175
Figure 9.28 Using a heating mantle ..........................................................176
Figure 9.29 Using a Dean–Stark trap ....................................................... 178
Figure 9.30 Magnetic stirrer machines .................................................... 179
xviiList of Figures
© 2010 Taylor & Francis Group, LLC
Figure 9.31 Magnetic followers ................................................................. 180
Figure 9.32 Using a mechanical stirrer .................................................... 181
Figure 9.33 Attaching a PTFE paddle ...................................................... 181
Figure 9.34 Apparatus for attaching a stirrer rod to a
reaction ask ........................................................................... 182
Figure 9.35 Mechanical shaker ................................................................. 183
Figure 9.36 Performing a reaction in an ultrasonic cleaning bath ...... 184
Figure 9.37 Using an ultrasonic probe ..................................................... 184
Figure 10.1 Soxhlet apparatus ................................................................... 194
Figure 10.2 Soxhlet extraction ................................................................... 196
Figure 10.3 Example of a Pd-mediated coupling ................................... 197
Figure 10.4 Filtration through Celite
®
to remove insoluble solids ...... 199
Figure 10.5 Using a separating funnel.....................................................200
Figure 10.6 Continuous liquid–liquid extraction using a
Hershberg–Wolfe apparatus ................................................. 202
Figure 10.7 Amine formation .................................................................... 203
Figure 10.8 Using an acid/base work-up to purify an amine ..............204
Figure 10.9 Carboxylic acid formation .................................................... 205
Figure 10.10 Using a base/acid work-up to purify a
carboxylic acid ........................................................................ 205
Figure 10.11 Filtration through layered reagents to remove
by-products ............................................................................. 206
Figure 11.1 Apparatus for small-scale recrystallization ....................... 213
Figure 11.2 Using a Craig tube ................................................................. 213
Figure 11.3 Recrystallization under an inert atmosphere .................... 215
Figure 11.4 Different designs of the lter stick ...................................... 215
Figure 11.5 Using a lter stick made from a syringe needle .................216
Figure 11.6 Low-temperature recrystallization ...................................... 217
Figure 11.7 Standard distillation apparatus ........................................... 219
Figure 11.8 One-piece distillation apparatus.......................................... 220
xviii List of Figures
© 2010 Taylor & Francis Group, LLC
Figure 11.9 Fractionating columns ........................................................... 221
Figure 11.10 One-piece Vigreux distillation apparatus .......................... 222
Figure 11.11 A temperature/pressure nomograph .................................. 223
Figure 11.12 Figure showing (a) pig and (b) Perkin triangle
apparatus ................................................................................. 224
Figure 11.13 Small-scale fractional distillation ........................................ 226
Figure 11.14 Kugelrohr apparatus .............................................................. 227
Figure 11.15 Sublimation apparatus ..........................................................228
Figure 11.16 Flash chromatography column and solvent reservoir ...... 231
Figure 11.17 Construction of a ash valve ................................................ 232
Figure 11.18 Determination of silica:sample ratios for ash
chromatography ..................................................................... 233
Figure 11.19 Running a ash column ........................................................ 236
Figure 11.20 The TLCs of an ideal set of fractions from a
successful column .................................................................. 238
Figure 11.21 Dry-column chromatography .............................................. 240
Figure 11.22 A simple MPLC system ......................................................... 243
Figure 11.23 Using ferrule and Luer connections .................................... 244
Figure 11.24 Flow through an MPLC injection valve .............................. 245
Figure 12.1 Small-scale Work-up in a sample vial ................................. 250
Figure 12.2 Small-scale ltration using a plugged Pasteur pipette ..... 251
Figure 12.3 Use of sample vial or small test tube as a
reaction vessel ......................................................................... 252
Figure 12.4 Small-scale air condenser and water condenser
systems .................................................................................... 253
Figure 12.5 Reactions in NMR tubes .......................................................254
Figure 12.6 One-piece Kugelrohr bulb set .............................................. 255
Figure 12.7 Small-scale ash chromatography ......................................256
Figure 13.1 Large-scale reaction setup (heat) ......................................... 262
Figure 13.2 Large-scale reaction setup (cool) .......................................... 263
xixList of Figures
© 2010 Taylor & Francis Group, LLC
Figure 13.3 Large-scale reaction—jacketed vessel with syringe
pump (cold) ............................................................................. 264
Figure 13.4 Large-scale reaction—jacketed vessel (heated) .................265
Figure 14.1 Schematic diagram of an atmospheric hydrogenator ....... 268
Figure 14.2 Small-scale hydrogenation using a balloon ....................... 270
Figure 14.3 Three components of an immersion well
photochemical apparatus ...................................................... 271
Figure 14.4 Assembled immersion well photochemical apparatus .... 272
Figure 14.5 Schematic representation of an apparatus for FVP ........... 273
Figure 14.6 Liquid ammonia reaction ......................................................274
Figure 14.7 Common microwave reaction setups .................................. 275
xxi© 2010 Taylor & Francis Group, LLC
List of Tables
Table 2.1 Common Hazards with Apparatus in the Chemical
Laboratory ................................................................................... 6
Table 2.2 Common Chemical Exposure Hazards .................................. 7
Table 2.3 Common Pyrophoric Hazards ................................................. 8
Table 2.4 Common Functional Groups with Chemical
Explosion Hazards .....................................................................9
Table 3.1 Suggested Key Phrases for a Standard
Experimental Method .............................................................38
Table 4.1 A Typical Set of Routine Glassware for Synthetic
Organic Chemistry ..................................................................49
Table 4.2 Standard, Commercially Available Items That
Should Be Included in an Individual Bench Kit ..................50
Table 6.1 Examples of Reagents That Should Be Distilled
under an InertAtmosphere .................................................... 84
Table 6.2 Examples of Reagents That Can Be Distilled under
Reduced Pressure ..................................................................... 85
Table 6.3 Examples of Reagents That Can Be Distilled from
Quinoline ..................................................................................85
Table 9.1 TLC Stains ............................................................................... 158
Table 9.2 Recipes for TLC Stains .......................................................... 158
Table 9.3 Ice-Based Cold Baths ............................................................. 170
Table 9.4 Dry Ice Cold Baths ................................................................. 170
Table 9.5 Liquid Nitrogen Slush Baths ................................................ 171
xxii List of Tables
© 2010 Taylor & Francis Group, LLC
Table 10.1 Properties of Commonly Used Extraction Solvents .......... 200
Table 10.2 Examples of Functionalized Silica Gel Scavengers ........... 206
Table 10.3 Commonly Used Functionality in Scavenger Resins ....... 207
Table 11.1 Funnel Sizes for Dry-Column Chromatography ............... 241
Table 15.1 Commonly Used NMR Experiments .................................. 278
Table A6.1 Hydride reducing agents ...................................................... 315
Table A6.2 Single electron transfer reducing agents ............................ 317
Table A6.3 Common hydrogenation catalysts ........................................318
xxiii© 2010 Taylor & Francis Group, LLC
Preface
The preparation of organic compounds is central to many areas of scien-
tic research, from the most applied to the most academic, and is not limi-
ted to chemists. Any research that uses new organic chemicals, or those
that are not available commercially, will at some time require the synthe-
sis 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 estab-
lishing research groups in synthetic organic chemistry and our associa-
tion with some of the leading laboratories in the eld. It is not claimed to
be a comprehensive compilation of information to meet all possible needs
and circumstances; rather, the intention has been to provide sufcient
guidance to allow the researcher to carry out reactions under conditions
that offer the highest chance of success.
The book is written for postgraduate and advanced level undergrad-
uate organic chemists and for chemists in industry, particularly those
involved in pharmaceutical, agrochemical, and other ne chemicals
research. Biologists, biochemists, genetic engineers, material scientists,
and polymer researchers in academia and industry will nd the book a
useful source of reference.
xxv© 2010 Taylor & Francis Group, LLC
Authors
John Leonard is currently a principal scientist at AstraZeneca Pharma-
ceuticals, where he is primarily involved with synthetic route design
and development activities. Prior to this, he was a professor of organic
chemistry at the University of Salford (U.K.).
Garry Procter is a professor and director of teaching in the School of
Chemistry at The University of Manchester (U.K.), and before this he was
director of undergraduate laboratories in the Department of Chemistry
and Chemical Biology at Harvard University.
Barry Lygo is currently professor of chemistry at the University of
Nottingham (U.K.), working in the eld of asymmetric catalysis and
synthesis.
1© 2010 Taylor & Francis Group, LLC
chapter one
General introduction
The preparation of organic compounds is central to many areas of sci-
entic research, from the most applied to the most “academic,” and is
not limited to chemists. Any research that uses new organic chemicals,
or those that 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 a univer-
sity or industry all might nd themselves faced with the task of carrying
out an organic preparation, along with those involved in pharmaceutical,
agrochemical, and other ne chemicals research.
These scientists share with the new organic chemistry graduate
student a need to be able to carry out modern organic synthesis with con-
dence and in such a way as to maximize the chance of success. The tech-
niques, 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 that
might be met in research laboratories. The nonspecialist is even more
likely not to be conversant with most modern techniques and reagents.
Nevertheless, it is perfectly possible for both the nonspecialist 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 knowledge of the properties of
the reagents being used, as most general techniques are relatively straight-
forward. However, it is often very difcult for the beginner or nonspecial-
ist to nd the appropriate information.
All three of us were fortunate enough to gain our initial training in
top synthetic organic research laboratories around the world and we have
subsequently acquired over 80 years combined experience in the training
and development of organic research chemists in industry and academia.
The knowledge that we have gained over this time is gathered together
in this book, in the hope that it will be an aid to the specialist and the
nonspecialist alike. Of course, most research groups will have their own
modications and requirements, but on the whole, the basic principles
will remain the same.
2 Advanced practical organic chemistry
© 2010 Taylor & Francis Group, LLC
This book is intended to be a guide to carry out the types of reac-
tions that are widely used in modern organic synthesis and is concerned
with basic techniques. It is not intended to be a comprehensive survey of
reagents and methods, but the appendices do contain 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 condence. 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.
3© 2010 Taylor & Francis Group, LLC
chapter two
Safety
2.1 Safety is your primary responsibility
Chemical laboratories are potentially dangerous workplaces and accidents
in the laboratory 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 small. Some general guidelines for safety
in the laboratory are presented in this section. In addition to these prin-
ciples, 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, ora
safety ofcer, if you are unsure about potential hazards. However, your
own safety, and that of your colleagues in the laboratory, is largely deter-
mined by your work practices. Always work carefully, use your common
sense, and abide by the safety regulations.
Some important general principles of safe practice are summarized in
the following rules:
1. Do your background reading and assessment of hazards rst.
Look for methods that involve the least hazardous reagents and
techniques.
2. Assess all the possible hazards before carrying out a reaction. Pay
particular attention to nding out about the dangers of handling
unfamiliar chemicals, apparatuses, or procedures and make sure
that any necessary precautions are in place before starting the
experiment.
3. Work carefully—do not take risks. This covers basic rules such as
always wearing safety spectacles and protective clothing, not work-
ing alone, and working neatly and unhurriedly.
4. Know the accident and emergency procedures. It is vital to know
what to do in case of an accident. This includes being familiar with
the reghting and rst aid equipment and knowing how to get
assistance from qualied personnel.
4 Advanced practical organic chemistry
© 2010 Taylor & Francis Group, LLC
2.2 Safe working practice
It has been emphasized already that you should be familiar with the regu-
lations and codes of practice pertaining to your laboratory. All labora-
tories should work with fundamental safety principles, which form the
“basis of safety,” and you should make sure that you and the people that
work around you are familiar with these. We will not discuss safety leg-
islation here but some fundamental universal rules should be stressed.
Never work alone in a laboratory, unless special safety arrangements have
been put in place to comply with local regulations. Always wear suitable
safety spectacles and an appropriate laboratory coat and use other pro-
tective equipment such as gloves, face masks, or safety shields if there is
a particular hazard or local requirement. Never eat, drink, or smoke in
a laboratory. Work at a safe, steady pace and keep your bench and your
laboratory clean and tidy. Familiarity breeds contempt; do not allow your-
self to get careless with everyday dangers such as solvent ammability.
Familiarize yourself with the location and operation of the safety equip-
ment in your laboratory.
As regards specic hazards, the chief rule is to carry out a full assess-
ment of the dangers involved before using an unfamiliar chemical or
piece of apparatus. Some of the most common hazards are described in
Section2.3. Once you are aware of the possible dangers, take all the neces-
sary precautions and ensure that you know what to do if an accident or
spillage occurs.
Store your chemicals in clearly labeled 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.
2.3 Safety risk assessments
Always assess the risks involved before carrying out a reaction. It is good
practice to carry out a systematic risk assessment for any new experiment
that you intend to carry out, reviewing the hazards associated with the
chemicals being used as well as the equipment and experimental pro-
cedure. In most 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 starting a reaction. If you are
aware that a procedure might carry some risks, consider alternative ways
of performing the experiment. Look for methods that involve the least
hazardous reagents and techniques. Assess all the possible hazards asso-
ciated with the reactions that you are planning to carry out as well as the
chemicals you are using before carrying out a reaction. As wellas toxico-
logical issues, make sure that you are aware of any signicant exotherms
5Chapter two: Safety
© 2010 Taylor & Francis Group, LLC
associated with the reaction and thermal instability issues associated with
your chemicals. This is particularly important when you work on a larger
scale. Remember that procedures other than chemical reactions can also
be hazardous! Unstable compounds (see discussion in Section 2.4.3) can
explode spontaneously when heated, for example, for the purpose of dis-
tillation or drying. Some of the worst personal accidents have been caused
by applying mechanical energy to unstable compounds, for example, by
grinding. Pay particular attention to nding out about the dangers of han-
dling unfamiliar chemicals or apparatuses and make sure that any neces-
sary precautions are in place before starting the experiment. Hazardous
material and reactions can often be handled with complete safety when
appropriate procedures are followed, but careful experimental design
may be required.
2.4 Common hazards
Each experiment will have its own set of risks that should be taken into
account, but a range of the more common general risks associated with
carrying out chemical reactions are described in the following sections.
2.4.1 Injuries caused by use of laboratory
equipment and apparatus
A high proportion of accidents in the laboratory occur when handling
glassware. Hand injuries are perhaps the most common of injuries and
can be serious. Many accidents occur when connecting rubber tubing to
glassware, and inexperienced workers are particularly prone to such inju-
ries, so learn from more experienced colleagues how to carry out such
tasks safely. Stabbing injuries, when using Pasteur pipettes and syringes,
are also common and can have dangerous consequences. Also pay atten-
tion to the condition of glassware and in particular check asks for star
cracks. Some general hazards are listed in Table 2.1, but there are also
many other types of equipment in modern laboratories that have particu-
lar associated hazards.
2.4.2 Toxicological and other hazards caused
by chemical exposure
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 pro-
cedure that is new to you. Most chemicals are supplied with an exten-
sive range of safety data, and these should examined before using any
