Intramolecular general base catalysis in the hydrolysis of a phosphate diester. calculational guidance to a choice of mechanism

Notwithstanding its half-life of 70 years at 25 C, the spontaneous hydrolysis of the anion of di-2-pyridyl phosphate (DPP) is thousands of times faster (ca. 3000 at 100 C, over 10000-fold at 25 C) than expected for a diester with leaving groups of pK_a 9.09. The kinetic parameters do not permit a conclusive choice between five possible mechanisms considered, but the combination of kinetics and calculational evidence supports a single-step, concerted, S_N2(P) mechanism involving the attack of solvent water on phosphorus assisted by intramolecular catalysis by a (weakly basic) pyridine nitrogen acting as a general base. Catalysis is relatively efficient for this mechanism, with an estimated effective molarity (EM) of the general base of >15 M, consistent with the absence of catalysis by typical buffers. Further new results confirm that varying the nonleaving group has minimal effect on the rate of spontaneous diester hydrolysis, in striking contrast to the major effect on the corresponding reaction of triesters: though protonation of one nitrogen of DPP^- increases the rate of hydrolysis by 6 orders of magnitude, in line with expectation.