Using sodium p-nitrophenyl methylphosphonate as a model for aged (dealkylated) phosphonylated cholinesterase, a study was made of its rate of reaction with various alkylating reagents containing nucleophilic groups.In DMF the alkylation rate ranged widely between a second-order rate constant, k2 = 190 M~l hr-1, at 25°, to no observable reaction in 96 hr at 60°c orresponding to k2 <0.02 M~l hr-1. Aqueous hydrolysis rates at pH 7.15, 25°, were determined for 20 of the mixed esters. The hydrolysis rates also varied extensively, with ii" ranging from 106 sec to less than 5 sec. The exceptionally rapid aqueous hydrolysis of several activated -bromo ketones strongly supports a mechanism involving attack by OHon the CO group. The first example of the intramolecular participation of an amide group in phosphonate hydrolysis by attack on P was observed in carbamoylmethyl p-nitrophenyl methylphosphonate. An exceptionally small rate ratio of 0.025 was found for the reaction of phenacyl methylsulfonate vs. phenacyl bromide with sodium p-nitrophenyl methylphosphonate in DMF. It is suggested that this ratio reflects steric interference in the reaction of the sulfonate and indicates that caution must be exercised in using the Hoffman method for estimating the position of the transition state on the reaction coordinate in SNs reactions. Finally, it was found that the spontaneous reactivation of phenacyl methylphosphonylated eel acetylcholinesterase occurs about 100 times more rapidly than that of the corresponding ethyl methylphosphonylated enzyme.

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The picrate of I was prepared by adding 0.10 g. of I to 5 ml. of a saturated solution of picric acid in chloroform, heating the mixture to boiling, and allowing it to cool slowly.The precipitate was collected, washed with a little chloro-form, and recrystallized from chloroform to give yellow needles melting at 199-200°( dec.

A novel and convenient method has been developed for the preparation of tris(hydroxymethyl) phosphine oxide (THPO) from tetrakis(hydroxymethy1) phosphonium chloride (THPC). The method consists essentially of oxidative deformylation of THPC with lead carbonate in n-propyl alcohol. The reaction is facilitated by azeotropic distillation of di-npropylformal and n-propyl alcohol.The reaction of THPC with lead carbonate as well as with lead oxide has been studied in detail in aqueous solution and in n-propyl alcohol. The reaction proceeds via the initial formation of tetrakis(hydroxymethy1) phosphonium hydroxide (THPOH) followed by deformylation to tris(hydroxymethy1) phosphine (THP). T H P then undergoes oxidation by air as well as by lead carbonate or oxide to THPO. If air is bubbled through the mixture a t elevated temperatures, atmospheric oxidation predominates with little or no oxidation by the lead compound.Depending upon the reaction conditions, a phosphonium hydroxide, a phosphine, or a phosphine oxide are products of the reaction of tetrakis(hydoxymethy1) phosphonium chloride with lead carbonate or oxide.For several years this laboratory has been engaged in the synthesis of phosphoruscontaining polymers in order to provide flame resistant and thermally stable end products. One of the starting materials for the introduction of phosphorus into the polymeric molecules was tetrakis(hydroxymethy1) phosphonium chloride, referred to as THPC.Although several polymers derived from T H P C have been reported (5, 6), we have found that in many instances phosphorus was not incorporated into the polymeric chains which are primarily formed by polycondensation reaetions of formaldehyde resulting from the degradation of THPC. These polymers, insufficiently characterized, possessed poor hydrolytic stability and fracture strength. By use of tris(hydroxymethy1) phosphine oxide (THPO) and its monobenzoylated derivative we were able to obtain polymers containing phosphorus in the polymeric chain which possessed markedly improved hydrolytic stability, fracture strength, flame resistance, etc. (3).A key problem which arose in the initial stages of work with THPO-derived polymers was the conversion of commercially available T H P C t o THPO. Methods previously described for this conversion required a number of tedious operations to isolate the product. In attempting to devise a better method for the synthesis of THPO from T H P C some interesting chemistry was uncovered involving not only the preparation of THPO but also the formation of tetrakis(hydroxymethy1) phosphonium hydroxide (THPOH) and tris(hydroxymethy1) phosphine (THP). This paper is concerned with a new synthesis of THPO from T H P C and with the properties and reactions of some of the intermediates.T H P C was reported (1,2) to react with aqueous sodium hydroxide a t room temperature or upon gentle heating below SO0 C to yield THPO with the evolution of one molecule of I hydrogen. On boiling, a second molecule of hydrogen is given off with the formation of the...