Preface_2015_Best-Synthetic-Methods

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PREFACE
The total chemical space of carbon-based molecules that can be prepared given enough ingenuity
comprises more than 1060 small organic molecules and an even greater number of larger entities (1).
So far, only a tiny proportion of these have been prepared and screened for useful properties, such
as biological activity (2), and this drives chemists to develop novel reactions that can unlock new
territories of chemical space. Methods of rapid generation of skeleton and decoration diversity are
therefore in demand. Synthetic chemistry is a young science compared to mathematics and
astronomy, for example, and has grown exponentially powerful over the last 150 years, yet many
of the named reactions of organophosphorus chemistry were discovered a long time ago. For this
reason organophosphorus chemistry might be considered an unfertile field, yet there is much left
to harvest, and the discovery of new reactions is likely to reward chemists that can navigate the subject
with agility.
Appointed in 1995 as a higher scientific officer in the synthetic chemistry team at the Chemical and
Biological Defence Establishment, Porton Down, United Kingdom (3,4), under the direction of Dr
Robin Black, I was set the challenge of learning organophosphorus chemistry for the first time. I
needed to know about organophosphorus nerve agents to conduct defensive studies such as the
synthesis of environmental degradation products and metabolites (in preparation for ratification of
the Chemical Weapons Convention (5) that necessitated robust synthetic and analytical methods).
I was surprised to find no modern textbook that collated synthetic recipes to all the structural permu-
tations of phosphorus determined by its valency of three or five. No lecture course in the UK taught
synthetic phosphorus chemistry in adequate detail. I had to learn the subject by studying research
papers spanning the early days of the subject to those of the present, and supplement this with over
10 years of practical experience in the laboratory. Much of the primary literature was published in
foreign languages, often German or Russia (where traditional schools of organophosphorus chemistry
had been founded), and part of this I had to have translated. I decided towrite a book one day to fill the
gap perceived all those years ago. In doing so, it has been my ambition to provide researchers with an
easy point of entry into practical methods used to form and transform organic compounds containing
a phosphorus atom. This task has been made easier through collaboration with expert co-authors who
have brought together many methods hidden in the literature or dispersed across publications in
different languages.
This book follows the Best Synthetic Methods format. It contains practical methods, synthetic tips
and short-cuts to form phosphorus (V) compounds, including phosphonyl, phosphoryl and various
organophosphate species containing one or more sulfur or selenium atoms. Wherever relevant,
sections also include toxicity data and historical data. The style and ordering of chapters are intended
to allow researchers to move from one practical method to another to find new ways of charting
unexplored chemical space.
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To conclude this preface, I cannot beat the words of Gerhard Schrader, a master of organophos-
phorus chemistry; ‘I cannot close without recalling the German chemist August Michaelis whose
long years (1847e1916) of careful investigation created the framework of the organic chemistry of
phosphorus. Without this basic work I could not have been successful’. Michaelis had foreseen that
in the inorganic-organic phosphorus domain, still greater possibilities were to be expected. He wrote
‘Even if at this present moment no special possibilities are apparent yet, there will, of that I am sure, be
a future for this subject surpassing even its great past’ (6).
EXEMPTION
The authors and publisher are not responsible for accidents that may arise from inappropriate handling
of toxic organophosphorus compounds or for unlawful disregard of the Chemical Weapons Conven-
tion, which prohibits the synthesis of certain toxic organophosphorus substances and their precursor
chemicals. Readers should familiarise themselves with this legal framework before conducting research
in organophosphorus chemistry by accessing it through the website of the Organisation for the
Prohibition of Chemical Weapons (OPCW) (www.opcw.org).
ACKNOWLEDGEMENTS
Organophosphorus chemistry is a complex subject, especially within chemical defence, and I have
learned much through working with talented colleagues and friends: Herb Aaron, Eric Banks, Andy
Bell, Robin Black, Mike Bird, Gradon Carter, Matt Chinn, Steve Eley, Fred Berg, Parker Ferguson,
Chris Green, John Jenner, Rick Hall, John Harrison, Jim Manthei, James McGilly, Daan Noort, Rob-
ert Read, Helen Rice, Paul Rice, Mark Sambrook, Mark Sandford, Andy Smith, Horst Thiermann,
David Upshall, Peter Watts, Franz Worek, and Colin Willis. My thanks go to all co-authors e their
scholarship and professionalism has been an inspiration e and to senior management at the Defence
Science and Technology Laboratory (Dstl) for their support: Jonathan Lyle, Simon Earwicker, Rebecca
Hopkins, and Dean Payne. I also wish to thank Prof. Vernon Gibson FRS (Chief Scientific Advisor of
the UK Ministry of Defence) for his encouragement. I am grateful to the Elsevier Science team of
Adrian Shell, Louisa Hutchins, Katey Birtcher and Poulouse Joseph for their enthusiasm and help.
I thank my wife, Helen, and our sons, Edward and Jonny, and family, for their patience and
support. I dedicate this book to my father, who bought me a chemistry set when I was a boy, and was
diagnosed with cancer while I was writing this book.
Chris Timperley
Fellow (Chemistry), Defence Science and Technology Laboratory (Dstl), Porton Down, UK.
REFERENCES
1. Dobson, M. Chemical space and biology. Nature 2004, 432, 824e828.
2. Paolini, G. V.; Shapland, R. H. B.; van Hoorn, W. P.; Mason, J. S.; Hopkins, A. L. Global mapping of pharmacological
space. Nature Biotech. 2006, 24, 805e815.
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http://www.opcw.org
3. Carter, G. B. Porton Down e 75 Years of Chemical and Biological Defence; Her Majesty’s Stationery Office (HMSO):
London, 1992.
4. Carter, G. B. Chemical and Biological Defence at Porton Down 1916e2000; HMSO: London, 2000.
5. Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction,
1994. Organisation for the Prohibition of Chemical Weapons (OPCW), The Hague, The Netherlands.
6. Schrader, G. The Development of New Insecticides and Chemical Warfare Agents. British Intelligence Objectives Subcommittee
(B.I.O.S.) Final Report No. 714, Item No. 8 (presented by S. A. Mumford and E. A. Perren, Porton Down UK), HMSO:
London, 1945; p. 53.
Preface xv
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