Associative versus dissociative mechanisms of phosphate monoester hydrolysis:: On the interpretation of activation entropies

Phosphate monoester and anhydride hydrolysis is ubiquitous in biology, being involved in, amongst other things, signal transduction, energy production, and the regulation of protein function. Therefore, this reaction has understandably been the focus of intensive research. Nevertheless, the precise mechanism by which phosphate monoester hydrolysis proceeds remains controversial. Traditionally, it has been assumed and frequently implied that a near-zero activation entropy is indicative of a dissociative pathway. Herein, we examine free-energy surfaces for the hydrolysis of the methyl phosphate dianion and the methyl pyrophosphate trianion in aqueous solution. In both cases, the reaction can proceed through either compact or expansive concerted (A(N)D(N)) transition states, with fairly similar barriers. We have evaluated the activation entropies for each transition state and demonstrate that both associative and dissociative transition states have near-zero entropies of activation that are in good agreement with experimental values. Therefore, we believe that the activation entropy alone is not a useful diagnostic tool, as it depends not only on bond orders at the transition state, but also on other issues that include (but are not limited to) steric factors determining the configurational volumes available to reactants during the reaction, solvation and desolvation effects that may be associated with charge redistribution upon approaching the transition state and entropy changes associated with intramolecular degrees of freedom as the transition state is approached.