Phosphate Ester Hydrolysis

This chapter examines recent evidence for and against two chemically distinct mechanisms with two chemically distinct intermediates in the hydrolyses of phosphate esters. The first mechanism for a hydrolysis reaction at phosphorus is a nucleophilic or associative displacement of the leaving group. This mechanism is analogous to S_N2 displacement reactions at tetrahedral carbon and is often referred to as the “S_N2(P) mechanism.” The second mechanism for a hydrolysis reaction at phosphorus involves the initial dissociative loss of the leaving group to generate the metaphosphate anion. This reactive species is then captured by the nucleophile. This mechanism is analogous to S_N1 displacement reactions at tetrahedral carbon and is often referred to as the “S_N1(P) mechanism.” Depending on the stability (lifetime) of the metaphosphate anion, the leaving group could have time to separate from the anion and be replaced by solvent so that it would be symmetrically solvated. Then, either of two solvent molecules could react with the metaphosphate anion to generate the hydrolysis product. If the mechanism were truly this dissociative, the stereochemical consequence of the S_N1(P) reaction would be racemization. If the metaphosphate anion were so reactive that it would react with solvent as soon as the bond to the leaving group had been broken, the stereochemical consequence would be the inversion of configuration; this variation of the S_N1(P) mechanism has been termed “preassociative.”