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(N)2(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.

Activating water: important effects of non-leaving groups on the hydrolysis of phosphate triesters.

The high rate of spontaneous hydrolysis of tris-2-pyridyl phosphate (TPP) is explained by the activating effects of the non-leaving ("spectator") groups on P-OAr cleavage, and not by intramolecular catalysis. Previous work on phosphate-transfer reactions has concentrated on the contributions to reactivity of the nucleophile and the leaving group, but our results make clear that the effects of the non-leaving groups on phosphorus can be equally significant. Rate measurements for three series of phosphate triesters showed that sensitivities to the non-leaving groups are substantial for spontaneous hydrolysis reactions, although significantly smaller for reactions with good nucleophiles. There are clear differences between triaryl and dialkyl aryl triesters in sensitivities to leaving and non-leaving groups with the more reactive triaryl systems showing lower values for both ß(LG) and ß(NLG). Intramolecular catalysis of the hydrolysis of TPP by the neighbouring pyridine nitrogens is insignificant, primarily because of their low basicity.