Multiparameter kinetic analysis of alkaline hydrolysis of a series of aryl diphenylphosphinothioates: models for P=S neurotoxins

Abstract

Alkaline hydrolysis of a series of X-substituted-phenyl diphenylphosphinothioates (2a-i) in 80 mol%/20 mol% DMSO at 25.0 +/- 0.1 degrees C has been studied kinetically and assessed through a multiparameter approach. Substrates 2a to 2i are approximately 12 to 22 times less reactive than their P=O analogues 1a to 1i (ie, the thio effect). The Bronsted-type plot for the reactions of 2a to 2i is linear with beta(lg) =-0.43, consistent with a concerted mechanism. Hammett plots correlated with sigma degrees and sigma(-) constants also support a concerted mechanism; the Yukawa-Tsuno plot results in an excellent linear correlation with rho(X) = 1.26 and r = 0.30, indicating that expulsion of the leaving group occurs in the rate-determining step (RDS). The Delta H double dagger value increases from 10.5 to 11.7 and 13.9 kcal/mol as substituent X in the leaving group changes from 3,4-(NO2)(2) to 4-NO2 and H, in turn, while T Delta double dagger remains constant at -6.0 kcal/mol. The strong dependence of Delta H double dagger on the electronic nature of substituent X also indicates that the leaving group departs in the RDS. The reaction mechanism and origin of the thio effect are discussed by comparison of the current kinetic results with those reported for the reactions of 1a to 1i. The results suggest that for useful OP neurotoxins the mechanism of abiotic hydrolysis is concerted (with varying degrees of asynchronicity) when the substrate bears good leaving groups.