Phosphorodiamidic fluorides

The reaction was found to be general and was extended to the preparation of a large range of phosphorodiamidic fluorides, e.g-from diethylamine, butylamine, methylaniline, benzylamine, cycfohexylamine, morpholine and piperidine. The method was patented. 

Many of these compounds were toxic for example, tetra-methyl phosphorodiamidic fluoride (dimethylaminofluorophos-phine oxide (VII)) had a l.c. 50 of 0-1 mg./l. Unlike the phosphorofluoridate esters, however, they were devoid of myotic action. 

About this time2 we also worked out the conditions for an alternative method for preparing phosphorodiamidic fluorides from phosphorus oxychloride. The principle of the method is given by the following equations ... 

We then decided to combine the toxicities of a phosphoro-fluoridic ester with that of a phosphorodiamidic fluoride in a hybrid molecule, and carried out the following synthesis in 1943 3... 

III) was very much less toxic than (II). This applied to subcutaneous as well as to inhalation experiments. By subcutaneous injection the l.d. 50 of (III) for mice was ca. 160 mg./kg. This close analogy between the two types of compound cannot, however, be pressed too far. The toxicities by subcutaneous injection into mice of other hitherto undescribed substituted phosphorodiamidic fluorides, are given on p. 89. 

In view of the rapid toxic action and myotic effect of the dialkyl phosphorofluoridates and of the high toxicity of some of the phosphorodiamidic fluorides, we prepared2 and examined a hybrid molecule containing the essential features of each type of compound. The first to be examined was ethyl phenyl-phosphoramidofluoridate (VII). One mol. of phosphorus oxy-dichlorofluoride was added to 1 mol. of ethyl alcohol, and the resulting ethyl phosphorofluoridochloridate (which it was not necessary to isolate) was treated with aniline. 

On subcutaneous injection into mice, (VII) had a l.d. 50 of 10 mg./kg., which was unexpectedly high in view of the reduction of toxicity caused by the phenyl group on both the phosphoro-fluoridates (p. 54) and the phosphorodiamidic fluorides (p. 87). 

Amitrole (i. e., a weakly basic pesticide) and the insecticide Dimefox (tetra-methyl phosphorodiamidic fluoride) have been shown to be adsorbed by HA through ionic bonding [17, 151-153]. The interaction between the cationic pesticide Chlorodimeform and SPHA was studied and, based on IR data, Maqueda et al. [154] indicated that an ion exchange bonding mechanism occurred. 

Previous investigations by Traylor and Westheimer26 and Crunden and Hudson27 had strongly supported the suggestion that the rapid alkaline reaction of phosphorodiamidic fluorides or chlorides and pyrophosphoramides which contain at least one amide hydrogen was by way of an anion derived from the amidate, viz. 

NTE is an integral membrane protein in neurons and some non-neural cell types of vertebrates [3,27,32] and its activity depends on lipid contents. It is present in all neurons, but is absent from glia [32], NTE can hydrolyze many esters of carboxylic acids. NTE is conveniently detected in vitro by its ability to catalyse OP-sensitive hydrolysis of an artificial substrate, phenyl valerate. Its activity is operationally defined as phenyl valerate hydrolysis resistant to inhibition by 0,0-diethyl-4-nitrophenyl phosphate (paraoxon, non-neuropathic) and sensitive to inhibition by NJ T-diisopropyl phosphorodiamidic fluoride (mipafox, neuropathic), determined under specified conditions [3]. Differential centrifugation of brain homogenates resulted in an enrichment of NTE in microsomal fractions containing elements of endoplasmic reticulum (ER), Goldgi, and plasma membrane [39],... 

The phosphorodiamidic fluorides also are activate in vivo. Dimefox is converted to an unstable active principle by microsomal enzyme activity, which may be prevented by p- iethylaminoethyl diphenylpropylacetate (SKF 525A), by 2,4-dinitrophenol, and by cyanide ions [46]. 

---