Table Of ContentBest Synthetic Methods
Organophosphorus (V) Chemistry
OTHER VOLUMES IN THE SERIES
Scriven: Pyridines: From Lab to Production, 2013
PetragnaniandStefani:TelluriuminOrganicSynthesis:Second,UpdatedandEnlargedEdition,2007
Gronowitz and Ho¨rnfeldt: Thiophenes, 2004
Brandsma: Synthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques, 2004
Osborn: Carbohydrates, 2003
Jones: Quaternary Ammonium Salts: Their Use in Phase-Transfer Catalysed Reactions, 2001
Varvoglis: Hypervalent Iodine in Organic Synthesis, 1997
Grimmett: Imidazole and Benzimidazole Synthesis, 1997
Wakefield: Organomagnesium Methods in Organic Synthesis, 1995
Metzner: Sulfur Reagents in Organic Synthesis, 1994
Pearson: Iron Compounds in Organic Synthesis, 1994
Petragnani: Tellurium in Organic Synthesis, 1994
Motherwell: Free Radical Chain Reactions in Organic Synthesis, 1991
Best Synthetic Methods:
ORGANOPHOSPHORUS (V)
CHEMISTRY
Co-authored and edited by
CHRISTOPHER M. TIMPERLEY
DSTL FELLOW (Chemistry)
DSTL PORTON DOWN
SALISBURY
WILTSHIRE
UNITED KINGDOM
AMSTERDAM(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON
NEWYORK(cid:129)OXFORD(cid:129)PARIS(cid:129)SANDIEGO
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CONTRIBUTORS
Nicholas Cooper
Detection Department, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury,
Wiltshire, SP4 0JQ, UK
Catherine Gomez
Normandie Univ, COBRA, UMR 6014 & FR 3038, UNIV Rouen, INSA Rouen, CNRS, 1 Rue
Tesnie`res, 76821 Mont-Saint-Aignan Cedex, France
Guoxiong Hua
EaStCHEM School of Chemistry, University of St Andrews, Fife, KY16 9ST, UK
Pierre-Yves Renard
Normandie Univ, COBRA, UMR 6014 & FR 3038, UNIV Rouen, INSA Rouen, CNRS, 1 Rue
Tesnie`res, 76821 Mont-Saint-Aignan Cedex, France
James Riches
Detection Department, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury,
Wiltshire, SP4 0JQ, UK
John Tattersall
Biomedical Sciences Department, Defence Science and Technology Laboratory (Dstl), Porton Down,
Salisbury, Wiltshire, SP4 0JQ, UK
Christopher M. Timperley
Detection Department, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury,
Wiltshire, SP4 0JQ, UK
Derek Woollins
EaStCHEM School of Chemistry, University of St Andrews, Fife, KY16 9ST, UK
xi
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
toharvest,andthediscoveryofnewreactionsislikelytorewardchemiststhatcannavigatethesubject
with agility.
Appointedin1995asahigherscientificofficerinthesyntheticchemistryteamattheChemicaland
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).
Iwassurprisedtofindnomoderntextbookthatcollatedsyntheticrecipestoallthestructuralpermu-
tationsofphosphorusdeterminedbyitsvalencyofthreeorfive.NolecturecourseintheUKtaught
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
foreignlanguages,oftenGermanorRussia(wheretraditionalschoolsoforganophosphoruschemistry
hadbeenfounded),andpartofthisIhadtohavetranslated.Idecidedtowriteabookonedaytofillthe
gapperceivedallthoseyearsago.Indoingso,ithasbeenmyambitiontoprovideresearcherswithan
easypointofentryintopracticalmethodsusedtoformandtransformorganiccompoundscontaining
aphosphorusatom.Thistaskhasbeenmadeeasierthroughcollaborationwithexpertco-authorswho
have brought together many methods hidden in the literature or dispersed across publications in
different languages.
ThisbookfollowstheBestSyntheticMethodsformat.Itcontainspracticalmethods,synthetictips
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,
sectionsalsoincludetoxicitydataandhistoricaldata.Thestyleandorderingofchaptersareintended
to allow researchers to move from one practical method to another to find new ways of charting
unexplored chemical space.
xiii
xiv Preface
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
intheinorganic-organicphosphorusdomain,stillgreater possibilitiesweretobeexpected.Hewrote
‘Evenifatthispresentmomentnospecialpossibilitiesareapparentyet,therewill,ofthatIamsure,be
a future for this subject surpassing even its great past’ (6).
EXEMPTION
Theauthorsandpublisherarenotresponsibleforaccidentsthatmayarisefrominappropriatehandling
oftoxicorganophosphoruscompoundsorfor unlawfuldisregardoftheChemicalWeaponsConven-
tion, which prohibits the synthesis of certain toxic organophosphorus substances and their precursor
chemicals.Readersshouldfamiliarisethemselveswiththislegalframeworkbeforeconductingresearch
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,
ChrisGreen,JohnJenner,RickHall,JohnHarrison,JimManthei,JamesMcGilly,DaanNoort,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
ScienceandTechnologyLaboratory(Dstl)fortheirsupport:JonathanLyle,SimonEarwicker,Rebecca
Hopkins,andDeanPayne.IalsowishtothankProf.VernonGibsonFRS(ChiefScientificAdvisorof
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.Idedicatethisbooktomyfather,whoboughtmeachemistrysetwhenIwasaboy,andwas
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 andbiology. Nature 2004,432, 824e828.
2. Paolini,G.V.;Shapland,R.H.B.;vanHoorn,W.P.;Mason,J.S.;Hopkins,A.L.Globalmappingofpharmacological
space. NatureBiotech.2006, 24,805e815.
Preface xv
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 BiologicalDefence atPortonDown1916e2000; HMSO:London, 2000.
5. ConventionontheProhibitionoftheDevelopment,Production,StockpilingandUseofChemicalWeaponsandontheirDestruction,
1994. Organisation for theProhibitionof Chemical Weapons (OPCW),The Hague,TheNetherlands.
6. Schrader,G.TheDevelopmentofNewInsecticidesandChemicalWarfareAgents.BritishIntelligenceObjectivesSubcommittee
(B.I.O.S.)FinalReportNo.714,ItemNo.8(presentedbyS.A.MumfordandE.A.Perren,PortonDownUK),HMSO:
London,1945;p.53.
11
CHAPTER
General Overview
Christopher M. Timperleya and John Tattersallb
aDetectionDepartment,DefenceScienceandTechnologyLaboratory(Dstl),PortonDown,Salisbury,Wiltshire,SP40JQ,UK
bBiomedicalSciencesDepartment,DefenceScienceandTechnologyLaboratory(Dstl),PortonDown,Salisbury,Wiltshire,SP40JQ,UK
1.1 INTRODUCTION
‘Fifteen’sforfitfulPhosphorus.
Ontheheadofeverymatch,
FromBostontotheBosphorus
Itflamesatjustascratch’(1)
Phosphorus(symbolP;atomicnumber15;atomicweight30.97;electronconfiguration1s22s22p63s23p3)
isanonmetallicelementbelongingtothesamegroupoftheperiodictableasnitrogen(GroupVa).Its
namemeans‘light-bearing’.AlthoughtheArabicalchemistsandParacelsus(1493e1541)(2)mayhave
hadaccesstophosphorus(3),thediscoveryoftheelementisattributedtothealchemistHennigBrand,
whoisolateditinHamburgin1669(4)fromdriedurine.Brandhandledtheelementcarelesslyandwas
surprisedtodiscover itshazardousnature,ashewroteinalettertoGottfriedWilhelmvonLiebnizon
30April1679:‘WheninthesedaysIhadsomeofthatveryfireinmyhandanddidnothingmorethan
blowonitwithmybreath,thefireigniteditselfasGodismywitness;theskinonmyhandwasburned
trulyintoahardenedstonesuchthatmychildrencriedanddeclaredthatitwashorribletowitness’(5).
Phosphorus exists in about 10 allotropes in three main catagories: white, red, and black. White
phosphorus, the most reactive form, is a soft waxy solid that glows in the dark (phosphoresces) and
(cid:1)
burnsincontactwithair,formingdensewhitefumesoftheoxide.Whitephosphorusmeltsat44 C
(cid:1)
and boils at 280 C. It has two allotropes: an alpha form of cubic crystal structure stable at ordinary
temperatures,andabetaformofhexagonalcrystalstructurestablebelow(cid:3)78(cid:1)C.Botharepoisonous.
(cid:1)
Exposuretosunlightorheat(250 C)convertswhitephosphorustored,whichdoesnotphosphoresce
origniteinair.Blackphosphorusformsuponsubjectingwhitephosphorustohighpressures.Itisflaky
like graphite and is the least reactive form. White phosphorus has beenused for military purposes to
producesmokesandasafillforgrenadesandincendiarymunitions.Redphosphorusisusedtoprepare
the striking surface for safety matches.
All naturally occurring phosphorus is present as the stable isotope phosphorus-31. Radioactive
phosphorus-32, a beta emitter, has a half-life of 14.3days and is a useful tracer for studying the life
cycles and metabolic processes of plants and animals (6).
1.2 NATURAL OCCURRENCE OF PHOSPHORUS
Inviewofitsreactivity,phosphorusisnotanelementoneexpectstofindfreeinnature,althoughtraces
havebeenreportedtooccurinsomemeteorites.Otherwise,phosphorusoccursincompoundsthatare
BestSyntheticMethods:ORGANOPHOSPHORUS(V)CHEMISTRY (cid:1)2015ElsevierLtd.
ISBN978-0-08-098212-0,http://dx.doi.org/10.1016/B978-0-08-098212-0.00001-7 Allrightsreserved. 1
2 ChristopherM.Timperley,JohnTattersall
widely distributed in many rocks, minerals, plants, and animals. Phosphorus normally ranks 12th in
most tables of abundance of the elements in the Earth’s crust: its average concentration approaches
0.12%byweightasphosphateionðPO3(cid:3)Þpresentinminerals.Over200speciesofphosphateminerals
4
arerecognised (7), all composed of tetrahedral PO units, and theyaregrouped into three categories
4
according to their origin:
1. Primary phosphates, crystallising from aqueous solution, occur in rocks of low silica
content, and include apatite Ca (F,Cl,OH)(PO ) , lithiophilite and triphylite Li(Fe,Mn)PO .
5 4 3 4
2. Secondaryphosphates,fromalterationofprimaryphosphatesatlowtemperaturesinthepresence
of water, often contain iron or manganese (II) or (III), and are usually brilliantly coloured.
Examples include strengite FePO $2H O and vivianite Fe (PO ) $8H O.
4 2 3 4 2 2
3. Rockphosphates,fromdepositionofbones,shellsanddiatoms,arepoorlycharacterisedbecauseof
their fine grain.
The main commercial source of phosphorus is phosphate rock (phosphorite, mostly fluorapatite
Ca (PO ) F) (8), which is rich in phosphates derived from various sources, including marine
5 4 3
invertebrates that secrete shells of calcium phosphate, and the bones and excrement of vertebrates.
Phosphoritedepositsareoftenassociatedwithsubsiding rock,suchascarbonaceousshaleandchert,
and may be up to 1m deep. Phosphorite also forms on stable planes of sandstone or shale. Typical
phosphorite beds contain 30% phosphorus pentoxide (P O ) and comprise the primary source of
2 5
material for most of the world’s production of phosphate fertilizers. Significant deposits of phos-
phorites are found in the USA (Idaho and California) and Peru (Sechura Desert) (9). Phosphate
mineralsarealsofoundinminesinCornwall(10)intheSouthWestofEnglandandinclude:bassetite
Fe(UO ) (PO ) $8H O; fluorapatite Ca (PO ) F; metatorbernite Cu(UO ) (PO ) $8H O; pseu-
2 2 4 2 2 5 4 3 2 2 4 2 2
domalachite Cu (PO ) (OH) ; pyromorphite Pb (PO ) Cl; and turquoise (var. Henwoodite)
5 4 2 4 5 4 3
CuAl (PO ) (OH) $4H O.
6 4 4 8 2
Phosphorus is a limiting mineral nutrient for plants (11). A large proportion of soil
phosphorus is bound tightly to soil particles or fixed as organophosphorus compounds (12)
and is relatively unavailable for plant uptake. Plant access to phosphate plays an important
role in global food security. However, the phosphorus in fertilizers is derived from rock phos-
phate, a nonrenewable resource that could be depleted in 50e100years (13), and this non-
sustainability has prompted interest in crops that require less soil phosphorus and produce
improved yields (14). The role of phosphorus in plants has featured in the novel The Periodic Table
by Primo Levi (15).
1.3 PRINCIPAL COMPOUNDS OF PHOSPHORUS
Phosphorus is used almost entirely in the form of compounds usually of oxidation state (cid:3)3, þ3
or þ5. It tends to prefer the þ5 state unlike nitrogen and other members of its group. Hydrogen
phosphide or phosphine gas (PH ) is produced by treating white phosphorus with hot water or
3
a strong base, or by the hydrolysis of a metal phosphide, and is of considerable economic
GeneralOverview 3
significance. It is employed as a starting material for the synthesis of various organophosphorus
compounds and as a doping agent for solid-state electronics components. Other important
phosphorus compounds include the oxides and acids. A large proportion of industrially produced
white phosphorus is burned to form P O that is obtained as a soft white powder or colourless
2 5
crystalline solid. It is often used in organic chemistry as a drying or condensing agent due to its
high affinity for water. Its controlled hydrolysis provides phosphoric acid (H PO ), which is
3 4
used industrially to produce salts containing the phosphate ðPO3(cid:3)Þ, hydrogen phosphate
4
ðHPO2(cid:3)Þ or dihydrogen phosphate ðH PO(cid:3)Þ ion. Such salts are used in baking, as abrasives
4 2 4
in toothpaste, and as additives in detergents. Calcium dihydrogen phosphate Ca(H PO ) e
2 4 2
known as ‘superphosphate’ e is prepared by the action of phosphoric acid on phosphate rock
and is the most widely employed phosphorus fertilizer. Phosphorus reacts with halogens to
produce various halides that are used to manufacture many organophosphorus chemicals. It also
reacts with sulfur to provide several sulfides that are used to make organic compounds and
matches.
Elemental phosphorus is obtained industrially by reduction of phosphate rock with silica and
carbon in an electric furnace (16). The furnace is charged continuously and the mixture heated to
1300e1400(cid:1)C, whereupon it transforms into calcium silicate slag, phosphorus vapour, and carbon
monoxide. The overall reaction proceeds as follows: Ca (PO ) þ3SiO þ5C/3CaSiO þ
3 4 2 2 3
0.5P þ5CO(17).Thevapour iscooledtocondensethephosphorustotheliquidandeventuallythe
4
solid,whichisstoredunderwatertopreventitfromigniting.Elementalphosphoruscanbepurifiedby
distillation (18).
Some industrial routes to key organophosphorus starting materials and reagents are shown in
Fig. 1.3.1. Treatment with sulfur provides phosphorus pentasulfide (P S , vapour: P S ). Molten
4 10 2 5
white phosphorus reacts with chlorine to give phosphorus trichloride (PCl ) and phosphorus
3
pentachloride (PCl ). During conversion to the former, phosphorus trichloride distills into
5
receivers and is redistilled with white phosphorus to remove any pentachloride. Oxidation of
phosphorus trichloride, controlled hydrolysis of phosphorus pentachloride, or treatment of it with
P O , gives phosphorus oxychloride (POCl ). Passage of phosphorus trichloride vapour over
2 5 3
(cid:1)
liquid sulfur of low viscosity at 140 C, in the presence of catalysts (e.g. charcoal), produces
continuously thiophosphoryl chloride (PSCl ). However, this method of preparation is
3
unsuitable for laboratory synthesis and other methods are preferred for small-scale production.
Alkylphosphonous dichlorides (RPCl ) can be prepared by several methods, such as heating
2
phosphorus trichloride vapour and an alkane to high temperature, whereupon hydrogen chloride
forms as the by-product. Physical properties for some organophosphorus compounds that are
commonly used as starting materials for synthetic campaigns appear in Table 1.3.1.
Thiophosphoric,phosphoric,andphosphonicacidesterchloridesareobtainedfromsequencesof
quite straightforward reactions and many simple derivatives are available commercially and used as
common starting materials. Chapters 2 to 6 cover many of the typical functional group intercon-
versionsthatcanbecarriedoutfromsuchmaterialsbyselectionofappropriateexperimentalmethods
and conditions.
