Structure-Reactivity Correlation for the Hydrolysis of Phosphoramidate Monoanions

The structure-reactivity relationship which correlates the rate constants for the hydrolysis of phosphoramidate monoanions with the pK_aof the leaving amine is nonlinear. The inflection point in the data which occuss at pK_a≈ 8 is attributed to changes in the nonsteady-state zwitterion concentration which are directly proportional to the pK_aof the parent amine. The equilibrium favors the zwitterionic species in aqueous solution for those phosphoramidates whose second dissociation constant is greater than 7.2. On the basis of these data, a semiquantitative description of the transition state for nucleophilic attack on phosphoramidates is developed which features bond cleavage to the departing group as greatly exceeding bond formation to the incoming nucleophile. This finding in conjunction with data for O- and S-phosphate mon- and diesters suggests that penta-covalent intermediates probably do not occur on the reaction pathways for acyclic mon- and diester hydrolysis.