Hydrolytic Mechanisms of Phosphoramidates of Aromatic Amino Acids

The pH-rate profile for the hydrolysis of o-carboxyphenyl phosphoramidate reveals intramolecular protonated carboxyl group interaction that serves to accelerate the rate of hydrolysis of the monoanionic and neutral species. Hydronium ion catalyzed hydrolysis of o-carboxyphenyl phosphoramidate also is more rapid than the reference compound, p-carboxyphenyl phosphoramidate. Solvolytic experiments in dioxane-water reveal the importance of the zwitterionic form in the hydrolysis of the various phosphoramidate species, in particular the neutral form. Product composition studies in alcohol-water mixtures (methanol, ethanol, 2-propanol, and t-butyl alcohol) reveal: (1) that the product composition in methanol-water (alkyl phosphate:orthophosphoric acid) is independent of the state of ionization of the phosphoramidate; (2) that the product composition is unaffected by the presence of the neighboring carboxyl group; (3) that the phosphorylating species exhibits a marked selectivity for alcohol rather than water; and (4) that steric factors in both substrate and alcohol affect the product composition obtained with the more branched alcohols. These results are discussed in terms of the metaphosphate hypothesis and a bimolecular alternative.