SOME ASPECTS OF THE ORGANIC CHEMISTRY OF DERIVATIVES OF PHOSPHORUS OXYACIDS By F. R. ATHERTON B.Sc. M.Sc. PH.D. (RESEARCH DEPARTMENW ROCHE PRODUCTS LIMITED WELWYN GARDEN CITY) THE only naturally occurring organic derivatives of phosphorus are the esters and amides of phosphoric acid and the esters of polyphosphoric acids these compounds being present in the living organism as structural units co-enzymes and enzyme substrates. During the present century numerous compounds of these types have been isolated and identified thus enabling the establishment of the r81e played by phosphorus-containing materia.ls and in particular the elucidation of the pattern of carbohydrate metabolism. It is now known that the phosphate residues introduced into metabolites serve not only to facilitate breakdown? but also as prospective carriers of energy metabolic processes being so designed as to accumulate the energy of individual stages in " energy-rich " phosphate bonds.These '' energy- rich" phosphate bonds are distinguished by the large amount of energy liberated by bond-fission (ca. 11,000 cals.) in comparison with fission for a normal phosphoric ester (ca. 3000 cals.). The types of compounds possess- ing such bonds are those containing the linkages carboxyl-P enol-P N-P and P-0-P. The first two types are formed in metabolic processes by reactions which occur with little energy change but involve a redistribution of the energy of the molecules so that a considerable part becomes associated with the phosphate bonds. The other types which are con- cerned with the storage and utilisation of phosphate bond-energy do not arise directly but are the result of trans-phosphorylations.Enzymes acting as catalysts in these and other biological processes have in many cases been found to possess co-enzyme components which are phosphorus- containing materials. Since compounds of phosphorus occur ubiquitously and play such varied dies in the living organism it is only to be expected that related types of compounds would possess physiological activity. Indeed research during the war-years led to the discovery of phosphorus compounds of extreme toxicity which act by inhibiting choline-esterase the enzyme which hydrolyses acetylcholine. The difference between a toxic compound and one with therapeutic action being of degree and not of type it is likely that many new drugs will be found among phosphorus compounds.There is already some evidence that this is the case. Much of the present interest in the organic compounds of phosphorus lies in the development of methods for the synthesis of the more complex naturally-occurring derivatives of phosphoric acid and the search for compounds with physiological activity. It is however by no means restricted to these aspects for in addition to the many interesting theoretical points connected with their chemistry the patent literature indicates the most diverse uses for phosphorus compounds. 146 ATHERTON PHOSPHORUS OXYACID DERIVATIVES 147 The present article deals only with certain aspects of the chemistry of the substituted acids esters and chlorides of phosphorus. As the available space doesnot permit a full discussion of all classes of compounds con- taining these groupings the subject-matter presents some of the reactions characteristic of the individual types of groupings.The nomenclature used is that recently put forward by the Chemical Society in which compounds are derived by the replacement of hydrogen in the following parent acids HO*PH2 (HO )2PH HO *PO -H2 (HO),PO*H Phoephinous Phosphinio Phosphonous Phosphonic acid. acid. acid. acid. In American usage the terms phosphinic and phosphonous are inverted. 1. Hydroxy-compounds of Quinquevalent Phosphorus Compounds containing the characteristic grouping ‘PO*OH exhibit / well-marked acidic properties forming stable salts with both inorganic and organic bases. The most important reactions of the group are the replace- ment of the hydroxyl by halogen and its conversion into esters.(a) Formation of Halides.-This reaction does not seem yet to have been widely employed chiefly because many halides are more easily obtained by other methods. It is most likely to be of use for those compounds which do not contain ester groups. The reaction can be effected by treating the acid with phosphorus pentachloride under mild conditions ‘POeOH + PCl -+ >OCl + HCl + POCI In this manner alkylphosphonic and dialkylphosphonous acids have been converted into the corresponding chlorides. The above reaction proved less successful when applied to dibenzyl hydrogen phosphate,2 but in this case conversion has been achieved by the action of thionyl chloride on the potassium salt 3 (C,H,-CH,*O),PO*OK + SOCI -.+ (C,H,*CH2*O),PO-C1 + KC1 + SO ( 6 ) Formation of Esters.-The direct esterification of acids derived from phosphorus with alcohols though one of the earliest known reactions 4s 6 can be accomplished only under drastic conditions and has little application.On the other hand the formation of esters by the reaction of halides with silver salts has been so widely employed as to merit no further mention. Among the other methods of producing esters from the acids are the reactions occurring with diazo-compounds and olefin oxides. (i) Reaction with substituted diazomethanes. Diazomethane and sub- stituted diazomethanes react smoothly to give the corresponding esters. / 1A. W. Hofmann Ber. 1873 6 306. SA. Deutsch and 0. Ferno Ncctupe 1945 156 604. 4 T. J. Pelouze Anmkn 1833 6 129. =L. Zervas Naturwhs. 1939 27 317.5 J. yon Liebig ibid. p. 149. 148 QUARTERLY REVIEWS Phosphorous acid which contains only two true acid groups gives the corresponding diesters 6~ 'I BRR'CN + (HO),PHO -+ (RR'CH*O),PHO + ZN whilst phosphoric acid has been preferentially monosubstituted 8 RaCHN + HO*PO(OH) -+ R*CH,*O*PO(OH) + N Fully substituted phosphoric esters have been obtained by the action of diazoalkanes on monoesters and die~ters.~ (ii) Reaction with o l e h oxides. The oxide ring in olefin oxides can be opened by the acids of phosphorus to produce hydroxyalkyl esters. In order to effect mono-substitution of phosphoric acid 0. Bailly 10 treated disodium hydrogen phosphate with glycidol to give the disodium salt of a-glycerol phosphate /O\ CH,-CH-CH,*OH + HO*PO( ON&) + OH*CH,*CH( OH)*CH2*O*PO*( ON&) Other workers have treated olefin oxides with free phosphoric acid to get partial 11 l2 or complete sub~titution.~~ The hydroxyl groups of the products may react further with excess of olefin 0xide.13 As would be expected phosphorous acid gives only diesters,l3 e.g./"\ (HO),PHO + BCH,-GH + ( OH*CH,*CH,*O),PH*O Olefin imines undergo analogous reactions 139 l4 as do olefin sulphides.13 (c) Formation of Amides.-Amide formation from oxyacids of phos- Dianilinodithiophosphonous acid phorus and amines has not been reported. however reacts at high temperatures with aniline 15 (C6H5NH),*Ps*SH + C,H5*NH -+ (C,H,NH),PS + H2S ( d ) Formation of Anhydrides.-(i) With carboxylic acids. Monoacyl phosphates may be prepared by the action of acyl chlorides on monosilver phosphate 16* l7 R-COC1 + AgO.PO(OH) -+ R*CO*O*PO(OH) + AgCl or of a keten on excess of phosphoric acid 18 e.g.CH :CO + HO*PO(OH) -+ CH,*CO*O*PO(OH),e The dibenzyl esters of acyl phosphates are similarly prepared from dibenzyl hydrogen phosphate.l8. l9 * F. C. Pallazo and F. Maggiacomo Gaxzetta 1908 38 11 115. 7 F. R. Atherton H. T. Howard and A. R. Todd J. 1948 1106. * T. Reichstein and W. Schindler Helv. Chim. Acta 1940 23 669. BE. Muller A. Langerbeck and W. Riedel 2. physiol. Chem. 1944 281 29. 10 Ann. Chirn. 1916 6 133. 11F. Zetzche and F. Aeschlimann Helv. Chim. Acta 1926 9 708. l*E. Eiderbenz and M. Depner Arch. Pharm. 1942 280 227. 18 C. E. Adams and B. M. Shoemaker U.S.P. 2,372,244. 1 4 H. N. Chiistensen J. Biol. Chem. 1940 135 399. 1sA. C. Buck J. D. Bartleson and H. P. Lankelma J.Amer. Chem. Soc. 1948 17 A. L. Lehninger ibid. 1946 162 333. 1eR. Bentley J. Amer. Chm. Soc. 1948 70 2183. 1eF. Lynen Ber. 1940 73 367. 70 744. 16F. Lipmann and L. C. Tuttle J. Biol. Chem. 1944 153 571. ATHERTON PHOSPHORUS OXYACID DERIVATIVES 149 (ii) With acids of phosphorus. Polyphosphoric esters may be syn- thesised by condensation of the silver salt of an acid with a phosphorus halide. Thus chlorophosphonic esters react with the silver salt of a diester of phosphoric acid 2o to give the substituted pyrophosphate 0 0 + AgCl ""\f ?/OR RO 0 0 OR + P-0-P OR' / \ \Pf + \I?/ RO / \ RO ' 'Cl Ago OR' and with the silver salts of triesters of pyrophosphoric acid to give the substituted triphosphate' 21 0 0 0 0 0 ""\f t L O R + \P' -+ P-0-P-0-P ""\t f/ OR 0 OR P-0-P OAg C1 ' \OR R'O OR OR / \ R'O 2.Hydroxy-compounds of Tervalent Phosphorus The compounds which might, from their mode of synthesis be expected to be hydroxy-derivatives of tervalent phosphorus are not acidic and do not form stable salts although the hydrogen may be replaced by alkali metals. Their reactions which have been mainly studied with diesters of phosphorous acid are best interpreted as those of the tautomeric form The most important of these reactions are those occurring with halogens and halogen-containing materials. ( a ) Formation of Halogenophosphonates.4hlorophosphonates are formed from dialkyl 22* 23 and diaralkyl 24 phosphites by the action of chlorine a t low temperatures RO 0 RO 0 \I?' +HCl RO / \Cl / \ RO H or of sulphuryl chloride at room temperature 7 RO 0 RO 0 \Pf +HCl +so GI / \ RO / \H RO 2O J.Baddiley and A. R. Todd J. 1947 648. *1 J. Baddiley A. M. Michelson and A. R. Todd Nature 1948 161 761. 2aH. McCombie B. C. Saunders and G. J. Stacey J . 1945 380. **H. G. Cook H. McCombie and B. C. Saunders ibid. p. 873. %4F. R. Atherton H. T. Openshaw and A. R. Todd ibid. p. 382. 150 QUARTERLY REVIEWS Although the intermediate product cannot be isolated chlorination almost certainly takes place in the reaction which occurs when diesters of phos- phorous acid are treated with a polychlorinated hydrocarbon and an amine,25* 26 e-g- RO 0 RO 0 \I?/ +CHCl c1 / \ RO / \ RO H RO 0 R’ RO 0 -+ \/. + HCl / \ \Pf +HN / \ R’ RO NR’R” c1 / \ RO The formation of bromophosphonates can be effected by the action of bromine on diaralkyl phosphites 27 but iodine does not give iodophos- phonates,28 probably because the hydrogen iodide reducing the iodo p hosp hona t e .RO H RO 0 \PP \ / / 4 p +I + I / \ RO RO 0 (b) Formation of Phosphonates.-The sodium produced is capable of + HI derivatives of dialkyl phosphites which may be produced by the action of metallic sodium or sodium ethoxide react with halogen compounds when heated with them under reflux for several hours in an inert solvent to form phosphonates RO 0 RO 0 R‘ / \ RO / RO m a This reaction originally observed with ethyl iodide,29 has been extended to many other alkyl halidesY3O aralkyl halides,31 halogeno-carboxylic esters,32* 33 cyanoalkyl halide~,~3 and diaryl- arylalkyl- and dialkyl-arsine halides.34 It is of no use when applied to trialkyl- and triaryl-tin halides35 and proceeds only very poorly with dialkyltin ~lihalides.3~ Abnormal reactions occur a5 F.R. Atherton H. T. Openshaw and A. R. Todd J. 1945 660. asF. R. Atherton and A. R. Todd J. 1947 674. 27F. R. Atherton F. Bergel A. Cohen J. W. Haworth H. T. Openshaw and zsH. McCombie B. C. Saunders and G. J. Stacey J. 1945 921. zBA. Michaelis and T. Becker Ber. 1897 30 1003. 3oG. M. Kosolapoff J. Amer. Chem. Soc. 1945 67 1180. 311dern ibid. p. 2259. 3aP. Nylen Ber. 1924 57 1023. 3(L G. Kamai and 0. N. Belorossova Bull. Acd. Sci. U.R.S.S. Classe sci. chim. 35 B. A. Arbusov and A. N. Pudovick J. Gen. Chem. Russia 1947 17 21 58. s6B. A. Arbusov and N. P. Grechkin ibid. p. 2166. A. R. Todd B.P. 593,480. 331dern ibid. 1926 59 1119. 1947 191. ATHERTON PHOSPHORUS OXYACID DERIVATIVES 151 when the halogen is " positive " ; thus the reaction of ethyl bromomalonate and sodium dibutyl phosphite 37 gives tetraethyl ethanetetracarboxylate.Although no explanation has been published it would appear that the ethyl bromomalonate halogenates the sodium derivative i.e. RO 0 C0,Et RO 0 C0,Et / \ -+ \Pf +Na}CH / \ + Br*CH C0,Et Br / \ RO \P7 C0,Et / RO p a and further reaction then occurs among the components of the reaction mixture leading to the desired product tetraethyl ethanetetracarboxylate and probably tetrabutyl hypophosphate. This would account for the high phosphorus content of the phosphorus-containing fraction which was observed. An abnormal reaction also takes place with 9-chloroacridine to give acridme. s* 3. Esters of QuinquevaIent Phosphorus These esters can be converted into the acids by acid or alkaline hydrolysis or in the case of phenyl and benzyl esters by hydrogenolysis.The aryl esters are comparatively inert and will not be considered here. The most interesting reactions of the alkyl and aralkyl esters which are in many respects similar to esters derived from the sulphur acids are alkylation and the reactions they undergo in the presence of phosphorus halides. (a) Alblating Properties.-Although in published work at the present time these properties have been demonstrated only with esters of phosphoric acid they are not restricted to these compounds. (i) Alkylation of phenols. The alkylation of phenols by alkyl phosphates was first demonstrated 50 years ago when A. Morel 39 observed the production of phenetole in the reactions of triphenyl and diphenyl ethyl phosphate with sodium ethoxide e.g.(PhO),PO + 3EtONa -+ (EtO),PO*ONa + ZPhONa + PhOEt This reaction undoubtedly proceeds by a trans-esterification followed by alkylation of the phenoxide by an ethyl phosphate. It has been shown more recently 40 that trialkyl phosphates will alkylate phenols and that not all of the alkyl groups are utilised. At temperatures over 160° high-boiling alcohols are converted into their methyl ethers by trimethyl p h ~ s p h a t e ~ ~ whilst in addition to trans-esterification ether formation has been observed when trialkyl phosphates react with sodium b ~ t o x i d e . ~ ~ (EtO),PO + BuONa + (EtO),PO*ONa + BuOEt (ii) Alkylation of alcohols. (iii) Alkylation of amines. At high temperatures many trialkyl phos- 37 G. M. Xosolapoff J . Amer. Chm.SOC. 1946 68 1103. 3s1dem ibid. 1947 69 1002. 40C. R. NoIler and G. R. Dutton J . Amer. Chern. Soc. 1933 55 424. 41 A. D. F. Toy ibid. 1944 66 499. e2W. H. C. Rueggeberg and J Cbemaok ibid. 1948 70 1802. 39 Compt. rend. 1899 128 507. 152 QUARTERLY REVIEWS phates convert arylamines into the tertiary aminesY43 all three alkyl groups being utilised in the reaction 3NH& + 2(RO),PO -+ 3NArR + 2H,P04 Triisopropyl phosphate however gives only the secondary amine. 4-Ethyl- morpholine is produced by the action of triethyl phosphate on morpholine a t 150°.42 It should be emphasised that as with dialkyl sulphates there is con- siderable difference in the alkylating powers of successive groups the neutral esters being far more powerful alkylators than the salts produced by the primary alkylation.The aralkyl esters of phosphates and pyrophosphates are as would be expected considerably more powerful alkylating agents than albyl esters-with tertiary amines they form quaternary salts under comparatively mild conditions. These properties have been used to achieve the selective debenzylation necessary for the synthesis of the biologically important adenosine tri- phosphate.21 / \ +/ \ / \ / \ PO*O*CH,Ph + N- -+ PO*O-{CHzPh*N- (b) Interchange Reactions with Phosphorus Halides.-(i) Direct replace- ment. On heating with phosphorus pentachloride ester groups may be replaced directly by chlorine. When this reaction is applied to a dialkyl alkylphosphonate,44 either one or both of the ester groups may be replaced. 0 0 0 t/”’ or -P L O R -+ -P -P t/”” OR \ CI \ c1 \ (ii) Redistribution.It has been observed that trialkyl phosphates react when warmed with phosphorus oxychloride. Thus W. Gerrard 45 demon- strated the successive replacement of the butyloxy-groups in tributyl phosphate the extent of the replacement being dependent on the excess of phosphorus oxychloride present. (BuO),PO + POCI --+ (BuO),POCl or BuO*POCl Since the reaction will not be discussed elsewhere it is relevant to point out that similar redistributions occur with trialkyl phosphites and phosphorus trichl0ride.4~ (c) EIimination Reactions with Phosphom Halides.-Those compounds which contain both a halogen and an ester group are capable of eliminating the alkyl halide and forming a polymeric compound J. K. BilImann A. Radike and B. W. Mundy J . Amer. Chem. SOC. 1942 84 44 M. I.Habachnik and P. A. Roasiiekaya BulI. Acad. Sci. U.R.S.S. C b s e sci. 2977. c h h . 1946 615. ‘ 6 J . 1940 1464. ATHERTON PHOSPHORUS OXYACID DERIVATIVES 7 0 + [-P-O]n + RCI -P f/OR I I c1 \ 153 The reaction probably occurs in many of the thermal decompositions observed with compounds of this type. In thermal decompositions of the ethyl dial kylaminoc hlor o p hosp honi t e s which occur a t about 1 50 O the phosphorus compounds produced have been shown to be cyclic t r i m e r ~ . ~ ~ 0 0 T -+ [R,N-P-O-] + 3EtC1 7 7 3R,N*P I OEt \ This type of reaction may also be brought about by the action of tertiary bases at room temperature. Thus 4-methylmorpholine reacts with dibenzyl chlorophosphonate to give a high yield of the quaternary salt with benzyl chloride the other product presumably being benzyl metaphosphate.' (CH,Ph*O),POCl -j.[CHzPh.O*PO,]z + CHzPhCl There is also evidence that the reaction can occur between dissimilar molecules as the new insecticide tihe so-called " hexaethyl tetraphosphate " which is prepared by the action of phosphorus oxychloride on triethyl phosphate is now known to be a mixture of ethyl metaphosphate and tetraethyl pyrophosphate. G. M. Kosolapoff 47 has suggested rather a com- plex mechanism for this reaction although the formation of the products is simply explained by an initial redistribution reaction to form diethyl chlorophosphonate which could then undergo an elimination reaction either with itself to give ethyl metaphosphate or with triethyl phosphate to give tetraethyl pyrophosphate. 4. Esters of Tervdent Phosphorus The most characteristic reactions of this class of compounds occur in the presence of halogens or halogen-containing materials and result in a change of valency.(a) Action of Halogens.-Halogens react at low temperatures to split out alkyl halides and effect the reaction 0 In this manner trialkyl phosphites are converted into dialkyl chlorophos- phonates by chlorine 22 4 5 3 48 dialkyl bromophosphonates by bromine,4* dialkyl iodophosphonates by iodine 28 and dialkyl cyanophosphonates by 40 A. Michaelis Annakn 1902 826 129. r8 H. Wichelhaus AnnizZen Suppl. 1867 6 266. 47 Science 1948 108 486. 154 QUARTERLY REVIEWS the pseudo-halogen cyanogen iodide. 49 Diethyl chlorophosphinate reacts with chlorine to give ethyl dichloroph~sphonite.~~ (EtO),PCl + C1 + EtO*POCl + EtCl Although of little practical importance the conversion of alkyl dichloro- phosphinites into phosphorus oxyhalides and alkyl halides by the action of halogens 489 50 shows the generality of the reaction still further.The action of bromine on 1 1 1-trifluoro-2-propyl dibromophosphinite 51 is interesting in that these materials give an additive compound in the cold which decomposes on warming partly into its components and partly in the usual manner. CF CF3 CF3 \ / CHBr + POBr \ / CH*O*PBr + Br =J CH*O*PBr + \ / CH3 (b) Action of Halides.-Many halogeno-compounds react with tervalent compounds of phosphorus containing an alkoxy-group in accordance with the equation CH3 CH3 0 P-OR+XY -+ \pi’ +RX \ / / \ Y This reaction which usually occurs on heating but may sometimes take place on mixing the components is known as the Arbusov reaction.It has been demonstrated with a variety of types of tervalent esters but does not appear to occur if the phosphorus atom is halogen-substituted. Alkyl halides react with trialkyl phosphites to give dialkyl alkylphos- phonates ,52 dial k yl arylphosp hinat e s to give alky 1 ar ylal kylphosphoni t es 53 and alkyl diarylphosphinites to give diarylalkylphosphine oxides. 53 The ethyl esters of bisdialkylaminophosphinous acids also undergo the reaction,46 but in thiskinstance an unstable adduct may be isolated which eliminates alkyl halide on standing e.g. (R@),P*OEf + Me1 -.+ [(R2N),P<M]1 + (R,N),Pf + EtI Moreover the reaction is not restricted to the oxygen esters since alkyl diarylthiophosphinites form diarylalkylphosphine sulphides when treated with alkyl halides 54 Ar,P*SR + RI -+ Ar,R*PS + RI OR 0 Me \ ~ ~~~~ 4s B.C. Saunders G. J. Stacey F. Wild and I. G. E. Wilding J . 1948 699. 50N. l\denschutkin Anmkn 1866 139 343. 5rF. Swarts Bull. SOC. chim. Belg. 1929 38 99. 5aA. Arbusov J . Rum. Phys. Chem. SOC. 1906 38 687. 531dem ibid. 1910 42 396. sp Idem <bid. p. 549. ATHERTON PHOSPHORUS OXYACID DERIVATIVES 155 It has been shown that the reaction occurs with a wide variety of halogen- containing compounds. Thus trialkyl phosphites have been treated success- fully with polyhalogenoalkanes 38 49 55 halogenocarboxylic esters,56 aralkyl halides 31 49 57 halogen derivatives of heterocyclic halides of disubstituted ar~ines,3~ trialkyltin halides 35 dialkyltin dihalides and alkyltin trihalides.36 Acid chlorides such as acetyl chloride and benzoyl chloride react readily even at room temperature to give esters of acylphosphonic acids.58 The above reactions are undoubtedly typical of the corresponding aralkyl esters. 5. Chlorides of Quinquevalent Phosphorus Compounds of this type exhibit most of the characteristic properties of normal acid chlorides. They are decomposed by water to give the corre- sponding acids with varying ease and exhibit the usual formation of esters and amides and replacement reactions of the halogens. (a) Ester Formation-(i) With sodium alkoxides. The reaction takes place smoothly alkyl dichlorophosphine dialkylaminodichloro- phosphine oxides 46 and aryl dichlorophosphonites 59 undergoing replacement of both halogens and bisdialkylaminochlorophosphine oxides 46 and diary1 chlorophosphonates 59 replacement of the one halogen atom.A r ~ l - ~ o alkyl-,61 and anilino-dichlorophosphine oxides 62 and aryl dichlorophosphonites 63 usually react with both halogens but it has been shown that when quinoline is used as the tertiary base it is possible to achieve selective replacement of one chlorine in phenyl dichloropho~phonite.~~ Diary1 63 and diaralkyl73 24 chlorophosphonates and dianilinochlorophosphine oxide 62 react satisfac- torily and removal of the protecting groups from the products may be achieved to yield pure monosubstituted phosphoric esters. (b) Replacement Reactions.-(i) By amino-groups. All types of com- pounds containing halogen atoms may be caused to react successfully with amines to give the corresponding amino-derivatives. A.Michaelis 4~ gives a wide range of examples of both complete and partial substitution. Alkyl dichlorophosphonites,65~ e6 dialkyl chlorophos- phonates 66 dial k y laminodichlor o - and bis dial k ylamino - c hlor o - p hosp hin e (ii) In the presence of organic tertiary bases. (ii) By fluorine. 55A. J. Arbusov and N. P. Kuschkowa J . Gen. Chem. Rwaia 1936 6 283. 56A. Arbusov and A. Dunin J . Rws. Phys. Chem. SOC. 1914 46 295. 67 B. P. Lugovkin and B. A. Arbusov Doklady Akad. Nauk. S.S.S.R. 1948,59,1301. M. I. Kabachnik and P. A. Rossiiskaya Bull. Acad. Sci. U.R.S.S. Classe sci. chim. 1945 364. 59 A. Morel Bull. Soc. chim. 1899 [iii] 21 491. 6o A. D. F. Toy J . Amer. Chem. SOC. 1948 70 186. 61 M. I. Kabachnik P. A. Rossiiskaya and N. N. Novikova Bull. A d . Sci. U.R.S.S. 62 F. Zetzche and W.Buttiker Ber. 1940 73 47. 63 P. Brig1 and H. Miiller {bid. 1939 72 2121. 64E. Baer and M. Kates J . Amer. Chem. SOC. 1948 70 1394. 6 5 B. C. Saunders and G. J. Stacey J . 1948 695. Classe sci. chirn. 1947 97 B.I.O.S. Final Report No. 714 Item 8, 156 QUARTERLY REVIEWS oxides and sulphides 66 are converted into the corresponding fluoro-com- pounds by the action of sodium fluoride in an inert solvent 0 0 4 3. \I \I P-Cl + NaF + P-F fNaCl The complete and partial fluorination of ethyl dichlorothiophosphonite may be accomplished by the action of antimony trifl~oride.~’ (iii) By the thiocyanato-group. Dialkyl chlorophosphonates 49 react with potassium thiocyanate to give dialkyl thiocyanatophosphonates. The reac- tion of diethylamino-dichlorophosphine oxide 46 with silver thiocyanate is said to give a thiocyanato-derivative though from general experience it would not be surprising if this were actually an isothiocyanato-compound.The action of an alcoholic solution of potas- sium cyanide on diethylaminodichlorophosphine oxide 46 gives simultaneous replacement by the cyano-group and esterification (iv) By the cyano-group. 0 LCN Et,N*POCl + Et,N*P OEt \ Diethyl chlorophosphonate however reacts poorly with potassium cyanide.49 (v) By acyloxy-groups. Dialkylaminodichlorophosphine oxides react with the sodium salts of carboxylic acids to replace both halogens,66 but when the reaction is carried out in alcoholic solutions an ester group is also . introduced. 0 0 t/OR’ R,N*P --+ R,N*P 0.OC.R” \ c1 \ ( c ) Reaction with diazoa1kanes.-Although only one observation of this type of reaction has been made to date namely that a dialkyl fluorophos- phonate reacts with diazomethane to give the fluoromethylphosphonate,49 RO 0 RO 0 \Pf + CH,N -+ + NB CH,F / \ F RO / \ RO it is very probable that this will prove to be a general reaction applicable to all types of halides.67 H. S . Booth D. R. Martin and F. E. Kendall J . Amer. Chern. Xoc. 1948,70,2523. ATHERTON PHOSPHORUS OIZI?ACfD DERIVATIVES 157 6. Chlorides of Tervdent Phosphorus Compounds of this type are as would be expected very similar in many respects to the corresponding quinquevalent compounds giving esters with sodium alkoxides or alcohols in the presence of tertiary bases and under- going replacement of the halogen by amino- and other groupings. These reactions of the compounds will not therefore be discussed further although it is relevant to point out that irregularities are more.likely to occur in this series.Thus whilst diphenylchlorophosphine reacts normally with most sodium alkoxides to give the corresponding esters sodium methoxide and benzyloxide give the phosphine 0xide,~3 e.g. PPh,C1 + NaOMe + PPh,MeO + NaCl Reactions peculiar to this class of compound are those which they undergo with carbonyl compounds and olefin oxides. (a) Reaction with Carbons1 Compoun&Although earlier workers had found that mixtures of phosphorus trichloride and carbonyl compounds gave a-hydroxy-phosphonic acids when treated with water our knowledge of this type of reaction is largely due to the studies of J. B. Conant and his co-workers. The initial reaction of phosphorus trichloride with carbonyl compounds was found to be reversible,6** G9 giving an additive product which reacted more readily with acetic acid or anhydride than did phosphorus trichloride.In this way it was possible to disturb the equilibrium and make the reaction proceed virtually to completion. The mechanism of the reaction is postu- lated by these workers as an extension of valency of the phosphorus tri- chloride 0 PCI \ / \ &o +PCl + c- \ / / as had already been suggested,'O followed by a disturbance of the equilibrium by interaction of the intermediate with acetic anhydride (or acid) e.g. 0 PCI + Ac,O C- \ / \ / Hydrolysis of the reaction mixture 0 0 \ / \ P / + c--- P-Cl + 2AcC1 would then give the hydroxy-phosphonic acid OH 0 0 0 C- P-CI \ / \ P / \I t/OH + c-P OH / \ 68 J.B. Conant and A. D. Macdonald ibid. 1920 42 2337. 70 A. Michaelis and A. Fleming Ber. 1901 34 1291. J. B. Conant A. D. Mscdonald and A. McB. h e y {bid. 1921 43 1928. 158 QUARTERLY REVIEWS Similar reactions occur with phenyldichlor~phosphine,~~ diphenylchloro- ph~sphine,~~ phenyl and alkyl dichlorophosphinites and diphenyl chloro- ph~sphinate.~~ The general overall reaction may therefore be expressed OH 0 \I 7 C=O +Cl-PRR’ -+ C-PRR’ \ / / When ap-unsaturated ketones are treated with phosphorus tri- The production of this class of compounds is postulated to occur in a similar manner the initial addition being of the 1 4-type 75 the product is a p-keto-phosphonic acid. CHR-CH*CO.R’ + PCl + CHR-CH=CR’ I 0 I C1,P to give an adduct which then reacts with acetic anhydride (or acid).On hydrolysis the enol-phosphorus link is severed to give the /?-keto-phosphonic acid CHR-CH=CR’ CHR*CH,*CO OR’ I -+ //OH 0 OtP O I \P OH / \ Cl Here again similar reactions occur with phenyldi~hlorophosphine,7~ T7 diphenyl~hlorophosphine~7 phenyl dichlorophosphinite and diphenyl chloro- ph~sphinate,~~ the general reaction therefore being CHR==CH*COR’ + PR”R”’C1 + CHR-CH,*CO*R’ I 0 CPRNR”’ Although the overall reactions as described above are correct the mechanisms are very probably incorrect? since other experiments 7* suggest that the initial reaction between phosphorus trichloride and benzaldehyde is a more conventional type of addition. Ph*CHO + PCl + CHPhCl*O*PCl A further point against the above mechanisms is that the reaction can be carried out successfully with alkyl dichlorophosphinites which would necessitate the production of an intermediate compound with an alkoxy- group and a halogen on a phosphorus atom with five substituents.71A. Michselis Annalen 1896 293 222. 7% J. B. Conant J. B. S. Braverman and R. E. Hussey J . Amer. Chem. SOC. 1923. 79 J. B. Conant V. H. Wallingford and S. S. Gandheker ibid. p. 762. 74 J. B. Conant ibid. 1917 39 2679. 75 J. B. Conant and A. A. Cook {bid. 1920 42 830. 76 J. B. Conant and S. M. Pollack ibid. 1921 43 1665. 77 J. B. Conant A. H. Bump and H. S. Holt ibid. p. 1677. 78F. R. Atherton and A. R. Todd unpublished. 45 165. ATHERTON PHOSPHORUS OXYACID DERIVATIVES 159 (b) Reaction with Olefin Oxides.-Although halides of quinqevalent phosphorus compounds do not react with olefin oxides in the absence of hydrogen halide tervalent compounds react very readily to form esters e.g.0 /-\ \ P-Cl + CH,-CH2 + P-O*CH,*CH2CI \ / / In this way ethylene oxide reacts with diphenyl chlorophosphinate and phenyl dichlorophosphinite to give triesters of phosphorous a~id.7~ With phos- phorus trichloride ethylene oxide reacts progressively to give 2-chloroethyl dic hlor o phosp hinite di - (2 - chlor oe t h yl) c hlor op hos phinat e and tri - (2 - chlor o - ethyl) phosphite 8o ; propylene oxide behaves similarly.78 It is hoped that the above review will serve to give an insight into the chemical behaviour of the more common types of phosphorus compounds. The material represents however only one facet of the organic chemistry of phosphorus of which the pioneer A. Michaelis is quoted by G Schrader 8* as having written “ 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.’’ 7sM. I. Kabachnik Bull. Acad. Sci. U.R.S.S. C h s e sci. china. 1947 631. M. I. Kabachnik and P. A. Rossiiskaya Bull. Acad. Sci. U.R.S.S. Classe sci. china. 1946 295. L