Phosphorylated hydroxylamine derivatives

Characteristic of these compounds is the P—O—N atom group. A typical example is 0,0-diethyl-0-[oxabicyclo-(2,2,1 )-hept-5-ene-2,3-dicarboximido] 

Because of its very low toxicity to warm-blooded anim s its broad range of insecticidal action and its strong initial effect, 0-(0,0-di yl-thiophosphoryl)-a-phenyl-a-hydroximinoacetonitrile (phoxim, 100) gained importance in recent years. Its oral LD50 for rats is 2500 mg/kg. It is prepared by phosphorylation of a-cyanobenzaldoxime (Lorenz et ai, 1965 Wybou and Hammann, 1968). 

Following the development of schradan (12) in 1941, discussed earlier under pyrophosphoric acid derivatives, it was only after an interval of more than two decades that other insecticides were developed with a phosphorus-nitrogen bond in the molecule. 

The revival of this type of compound was opened by tbe development of tri-amphos in 1960. Although it has a considerable insecticidal effect, it is used mainly as a fungicide, and is therefore discussed in the fungicides section. 

According to the original process of Addor (1962), phospholan is prepared by the reaction of ethylene-1,2-dithiol with cyanogen chloride, followed by the reaction of 2-imino-l,3-dithiolane (103) with diethyl phosphorochloridate. According to his later process (1970), N-(0,0-diethylphosphoryl) dithiocarbamate (104), obtained by the addition reaction of diethyl phosphoryl isothiocyanate and potassium hydrosulilde, is cyclised with ethylene bromide. 

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In subsequent years, much evidence has been adduced to support this mechanism. Alkaline phosphatase and, by analogy, other serine enzymes, are directly phosphorylated on serine serine phosphate is not an artifact (Kennedy and Koshland, 1957). In the presence of nitrophenyl acetate, chymotrypsin is acetylated on serine, and the resulting acetylchymotrypsin has been isolated (Balls and Aldrich, 1955 Balls and Wood, 1956). Similarly, the action of p-nitrophenyl pivalate gave rise to pivaloyl chymotrypsin, which could be crystallized (Balls et al., 1957). Neurath and workers showed that acetylchymotrypsin is hydrolyzed at pH 5.5, but that it is reversibly denatured by 8 M urea the denatured derivative is inert to hydrolysis and even to hydroxylamine, whereas the renatured protein, obtained by... 

A successful antidote to organophosphorus compounds must hydrolyze the enzyme-phosphoryl bond to release the acetylcholinesterase. The simplest compound that will do this is hydroxylamine. Unfortunately, hydroxylamine is toxic at the concentrations needed. However, derivatives can be prepared that work at much lower concentrations and can be used clinically. One such derivative is pyridine aldoxime methiodide (Fig. 8.7). In this derivative, the hydroxylamine group is fixed in position relative to the pyridine ring. The pyri-... 

Kinetic studies of the reaction between the a-nucleophile hydroxylamine and tri-2-pyridyl phosphate (TPP) (54) showed that an initial rapid reaction occurred via a general base-catalysed attack of TPP by the ammonia oxide tautomer of hydroxylamine TlgN -O to form a transient 0-phosphorylated derivative (55) (Scheme 19), which is trapped by the NH2OH in solution to generate diimide (56) and DPP (Scheme 20). 

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