Transition State Differences in Hydrolysis Reactions of Alkyl versus Aryl Phosphate Monoester Monoanions

Although aryl phosphates have been the subject of numerous experimental studies, far less
data bearing on the mechanism and transition states for alkyl phosphate reactions have been presented.
Except for esters with very good leaving groups such as 2,4-dinitrophenol, the monoanion of phosphate
esters is more reactive than the dianion. Several mechanisms have been proposed for the hydrolysis of
the monoanion species. 18O kinetic isotope effects in the nonbridging oxygen atoms and in the P−O(R)
ester bond, and solvent deuterium isotope effects, have been measured for the hydrolysis of m-nitrobenzyl
phosphate. The results rule out a proposed mechanism in which the phosphoryl group deprotonates water
and then undergoes attack by hydroxide. The results are most consistent with a preequilibrium proton
transfer from the phosphoryl group to the ester oxygen atom, followed by rate-limiting P−O bond fission,
as originally proposed by Kirby and co-workers in 1967. The transition state for m-nitrobenzyl phosphate
(leaving group pKa 14.9) exhibits much less P−O bond fission than the reaction of the more labile
p-nitrophenyl phosphate (leaving group pKa = 7.14). This seemingly anti-Hammond behavior results from
weakening of the P−O(R) ester bond resulting from protonation, an effect which calculations have shown
is much more pronounced for aryl phosphates than for alkyl ones.