ARCHIEHOODAND WILLYLANGE
4956
[CONTRIBUTION PROM THE
DEPARTMENT OF CHEMISTRY
Vol. 72
OF THE UNIVERSITY OF CINCINNATI]
Esters of Monofluorophosphoric Acid' BY 'ARCHIE HOOD^ AND WILLY LANGE3
As would be expected from the above equation, The neutral dialkyl esters of monofluorophosphoric acid, (RO)zPOF, and in particular the the highest yields of neutral esters of monofluorodiisopropyl ester, DFP, have become of interest phosphoric acid, (RO)zPOF, were obtained from since Adrian, Kilby and Kilby* discovered the neutral tetra-esters of pyrophosphoric acid, or extreme toxicity of these esters and shortly there- in other words in the case in which n is zero. after found the toxicity to be the result of a pro- As a matter of fact, the synthesis of diethyl was found to be nearly nounced cholinesterase inhibitory p ~ w e r . ~ monofluorophosphate !~ Lange and v. Krueger6 first synthesized dialkyl quantitative according to the equation in the monofluorophosphates by means of the reaction reaction of a slight excess of anhydrous hydrogen of alkyl iodides with silver monofluorophosphate, fluoride with tetraethyl pyrophosphate at or and they noted the pronounced effects of these below room temperature. Although quantitaneutral esters on the human organism. LAIC- tive experimental results were not obtained with Combie, Saunders, and a group of co-workers' polyphosphates containing three or more phoslater developed practical methods for producing phorus atoms, since no such esters were available the esters, and in particular diisopropyl mono- as relatively pure individual compounds, experifluorophosphate, by methods involving the use of mental evidence showed that with increasing either phosphoryl fluorodichloride, or dialkyl chain length of the polyphosphoric acid ester esters of monochlorophosphoric acid as essential there was a corresponding increase in the prointermediates. portion of monoalkyl monofluorophosphate, (H0)Possible medical applications of diisopropyl (RO)POF, formed and a decrease in yields of monofluorophosphate, as discussed recently by dialkyl monofluorophosphate and dialkyl orthoWood,8 have stimulated an interest in obtaining phosphate. As expected, therefore, best yields readily water-soluble derivatives of alkyl esters of of the half-esters of monofluorophosphoric acid monofluorophosphoric acid, containing the group- were obtained when the starting material was ing -(RO)POF, for physiological tests and possible the metaphosphate, which is believed to be a complex mixture of long-chain polyphosphate medical application. The present study was initiated with the aim esters with an average molecular weight sufof producing certain acidic half-esters of mono- ficiently great that the over-all effect of the endfluorophosphoric acid, (HO) (RO)POF, which groups of the chain is practically negligible. Although best yields, on the basis of phosphorus would be water-soluble as such or in the form of their alkali salts. A method was developed for recovered as the half-ester, were obtained with producing these half-esters, as well as the corre- metaphosphates, the use of a symmetrical pyrosponding neutral esters, by a reaction i k s t r a t e d phosphoric acid diester was found to be more convenient because of the easier separation of the by the equation reaction products
+ (?z + 1)HF --+ OR
OR 0 I1
RO- P--OH OR Orthophosphoric acid ester
OR 0 1;
4- TZ F -P-OH OK Acidic halfester of monoAuorophosphoric acid
0
0
II
,,
OK
OR
EIO-Pp- -0--P-OH
+ HI' --+ 0
I/
4- F-P--OR
0
(1 'i
OK Neutral ester of monofluorophosphoric acid
(1) A portion of a thesis by A. Hood. submitted t o the Faculty of the Graduate School of Arts and Sciences, University of Cincinnati, in partial fulfillment of the requirements for the degree of Doc' tor of Philosophy, June, 1948. (2) T h e Shell Oil Company, Houston, Texas. (3) The Procter and Gamble Company, Cincinnati 17, Ohio. (4) E. D. Adrian. vi'. Feldberg and B. A. Kilby, B y i t . J . Pharmacol., 2, 66 (1947). ( 5 ) H. McCombie and A. C. Saunders, Neture, 161, 776 (194lji. (8) W. Lange and G . v. Krueger, Bcr., 66, 1598 (1932). (7) H . McCombie and R . C.Saunders, S a f u r e , lST, 287 ( 1 4 $ A i (8) .I, R K o o < l , C . h ~ r 7 9 . ( ' o v r s . I . 2, 5'0.3 , 6 , i l (1948).
I1
110-P-OH I
OR
0
It + F-P-OH
(2)
I
OR
Reaction Mechanism.-The mechanism of the reaction seems t o be essentially one of successive hydrofluorolysis of the P-0-P bridges of the polyphosphate chain, proceeding successively from one end of the chain to the other, with one phosphorus atom being split off a t a time as a n ester of (H0)zPOF. If the chain were broken in a random fashion, rather than in successive steps from one end to the other, the resulting product would contain considerable and equimolar amounts of dialkyl monofluorophosphate and xnonoalkyl orthophosphate, but this is found not to be t h e C ~ S C .
Nov., 1950
ESTERS OF ~IONOFLUOROPHOSPHORIC ACID
Half-esters of Monofluorophosphoric Acid and Their Salts.-The low-molecular-weight monoalkyl esters of monofluorophosphoric acid are much like the corresponding orthophosphoric acid diesters, (ROZ)(HO)PO, in a number of their physical properties and likewise with respect to salt formation. The great solubility of their salts in general and their thermal instability a t elevated temperatures make preparation in high purity quite difficult. As yet the most satisfactory means of purification is repeated molecular distillation. Salts of the half-esters are quite stable to hydrolysis in neutral or slightly alkaline solutions. Although these salts might be expected to be excellent water-soluble cholinesterase inhibitors, by analogy with the strongly inhibitory, insoluble neutral esters, Fitch@has shown recently that the salts exhibit only weakly inhibitory power. A solution of the alkali salts was effective in preventing the growth of Aspergillus niger and Aspergillus flavus in the agar cup-plate test using Czapek-Dox agar cultures. A 0.1% solution of the alkali salts gave in this test a zone of complete inhibition 12 to 23 mm. in diameter and a zone of partial inhibition 31 to 4'7 mm. in diameter. In the zone of partial inhibition no pigment was produced by A . niger. Very little effect, however, was obtained in any medium when the salts were added to cultures of yeast or bacteria. Work is in progress on the reaction of hydrogen fluoride with polyphosphates, such as adenosine triphosphate, which are carriers of energy-rich phosphate bonds of importance in the enzymic transfer of phosphate radicals between molecules.
Experimental Materials and Apparatus.-The various polyphosphates used in this study were furnished by the Victor Chemical \\'arks, Chicago Heights, Illinois. Anhydrous hydrogen fluoride (HF) was distilled into the reaction vessel from a Harshaw Chemical Company cylinder. Platinum bottles of 100-ml. capacity were used as reaction vessels, but distillations were performed in glass. Methods of Analysis.--Phosphorus was determined by precipitation as magnesium ammonium phosphate after removal of fluoride.1° The Rowley and Churchill'* modification of the Willard and Winter12 method was used in tlctermiiiation of fluorine. General Procedure.-The polyphosphoric acid ester was :dried in small portions to a small excess of liquid anhytlrous hydroogen fluoride in a platinum bottle cooled to ahout -40 Additions of the ester were always performed rapidly to ensure minimum exposure of the reactants to atmospheric moisture, and as soon as the platinum stopper was in place again, the contents were agitated by shaking. Continued cooling was necessary to maintain a reaction temperature below 0' because of the great heat of reaction. The final product was allowed to reach room temperature before removing the excess of hydrogen fluo-
.
(9) H. M. Fitch, Department of Therapeutics, N. Y. UniversityBellevue Medical Center, private communication. (10) W. Lange, Bcr., 88, 786 (1929). (11) R. J. Rowley and H. V. Churchill, Ind. Eng. Chew., Artal. E d . , 9, 551 (1937). (12) H. H. Willard and 0. B. Winter,
