PRODRUGS OF PHOSPHONOFORMATE - THE EFFECT OF PARASUBSTITUENTS ON THE PRODUCTS, KINETICS AND MECHANISM OF HYDROLYSIS OF DIBENZYL METHOXYCARBONYLPHOSPHONATE

The para-substituted analogues of dibenzyl methoxycarbonylphosphonate (1; X = N3, NO2, CF3) have been prepared in ca. 60% yield and their product and kinetic profiles of hydrolysis have been evaluated. Relative to the unsubstituted analogue 1 (X = H) which has a half-life of 64 min, the para-substituted triesters of phosphonoformate undergo rapid hydrolysis at pH 7.4 and 36.4-degrees-C with half-lives of 2.5 min (X = N3), 5.6 min (X = NO2) and 15 min (X = CF3). In contrast to 1 (X = H), which on hydrolysis gives ca. 30% C-P bond cleavage with dibenzyl phosphite formation, the parasubstituted analogues hydrolyse predominantly to the para-substituted benzyl methoxycarbonylphosphonate diesters (2). Triester 1 (X = NO2) hydrolyses to the diester 2 (X = NO2) with P-O bond cleavage, consistent with nucleophilic attack of water at phosphorus and identical to that observed for the unsubstituted analogue. In contrast, triester 1 (X = N3) hydrolyses to the diester 2 (X = N3) with C-O bond cleavage presumably via an intermediate with benzyl carbonium ion