CARBOXYL-GROUP PARTICIPATION IN PHOSPHOROTHIOATE HYDROLYSIS . HYDROLYSIS OF S-(2-CARBOXYPHENYL)PHOSPHOROTHIOATE

The rates of hydrolysis of S-(2-carboxyphenyl)phosphorothioate have been measured in H2O and D2O as a function of pH at 35°. The pH-rate profile has a maximum occurring close topH4. Theortho-carboxyl-substituted derivative hydrolyzes 5.0 times faster than the para derivative at the rate maximum and 6.3 times faster in 5.90 M HCl where the compounds are predominantly in the neutral form. A plot of log Kobsd for hydrolysis in 5.90 M HC1 vs. the pKa of the thiol leaving group for a series of S-(4-substituted phenyl)phosphorothioates is linear with a slope of -0.06, but the point for the ortAo-carboxyl-substituted compound deviates markedly (+1.10 log units). A plot of log k for hydrolysis of the monoanionic species of the series of S-monoaryl phosphorothioates vs. the pK. of the leaving group is also linear with a slope of 0.08, but the point of o-COOH again shows a positive deviation. The value of KH/KD is 1.7 for hydrolysis of the neutral species of the o-COOH derivative and 2.1 for the monoanion. Thus, the ortho-carboxyl group is accelerating the reactions of the neutral and monoionized species with possible mechanisms involving partially rate-determining protonation of sulfur. The D2O solvent isotope effect for hydrolysis of the dianion of S-(2-carboxyphenyl)phosphorothioate is near unity (KH/KD = 1.2), consistent with either preequilibrium zwitterion formation with protonated sulfur or intramolecular nucleophilic catalysis by the carboxylate anion. The presence of an acyl phosphate intermediate which would be formed by nucleophilic attack could not, however, be demonstrated by the hydroxamic acid method. Steric facilitation of the neutral and monoanion reactions is produced by a bulky ortho substituent since in both reactions the 2-isopropyl derivative hydrolyzes faster than the unsubstituted compound. The rate of hydrolysis of S-(2-isopropylphenyl)- phosphorothioate dianion, however, was quite slow. © 1969, American Chemical Society. All rights reserved.