The Thermodynamics of Phosphate versus Phosphorothioate EsterHydrolysis
Journal of Organic Chemistry
Phosphorothioate esters are phosphate esters in which one of the nonbridging oxygen atoms has been replaced by sulfur. In the comparative hydrolysis reactions of phosphorothioate and phosphate esters, the sulfur substitution accelerates the rates of the monoesters while slowing the rates of diesters and of triesters. Previously measured enthalpies and entropies of activation for the hydrolysis reactions of the monoesters, p-nitrophenyl phosphate and p-nitrophenyl phosphorothioate, were compared to the activation parameters measured herein for the diesters, ethyl p-nitrophenyl phosphate and ethyl p-nitrophenyl phosphorothioate, and the triesters, diethyl p-nitrophenyl phosphate and diethyl p-nitrophenyl phosphorothioate. A consistent trend of a greater ΔH⧧ for the phosphorothioate analogue was found in all three classes of ester. In the monoester case, a more positive ΔS⧧ arising from a mechanistic difference (DN + AN for the phosphorothioate versus ANDN for the phosphate) compensates, resulting in a lower ΔG⧧ for the phosphorothioate monoester. Spectroscopic investigations indicate there is no significant difference in bond order to the leaving group in phosphates, as compared to their phosphorothioate analogues, ruling this out as a contribution to the consistently higher enthalpies of activation.
J. Purcell and A. C. Hengge "The Thermodynamics of Phosphate versus Phosphorothioate Ester Hydrolysis." J. Org. Chem., 2005, 70 (21): 8437-8442.