Effect of Phosphono Substituents on Acyl Transfer Reactions

Article abstract of DOI:10.1021/ja00410a033

The rate of release of p-nitrophenoxide from esters of phosphono-substituted carboxylic acids was examined as a function of pH(D), temperature, divalent metal ion (Mg²⁺ and Ca²⁺) concentration, and acyl acceptor (^-OH and the thiolate of N-acetylcysteine).The hydrolysis of p-nitrophenyl 3-phosphonopropionate involves intramolecular nucleophilic catalysis by the dianionic phosphono substituent (pK_a2(*) = 7.5) and is characterized by a first-order rate constant of 94 min^-1 at 37 deg C.A comparison of the rate constant of the unimolecular reaction with that of the corresponding bimolecular reaction (corrected for the inductive effect of the acyl substituent and for the phosphonate basicity) yields a rate constant ratio of k_uni/k_bi = 7(+/-6)*10³ M.The magnitude of this rate enhancement is similar to those of analogous intramolecular reactions (e.g., hydrolysis of mono-p-nitrophenyl succinate or of p-nitrophenyl 4-(N,N-dimethylamino)butyrate but, unlike these reactions, the rate acceleration resulting from intramolecular nucleophilic catalysis by the dianionic phosphono group is enthalpic in origin (Δ(*) ca. 8 kcal/mol).The entropy of activation for the intramolecular reaction is less favorable than that for the bimolecular reaction (Δ(*) ca. 9 eu).The alkaline hydrolysis and the thiolysis rates of p-nitrophenyl phosphonoacetate are accelerated over 100-fold by the association of Mg²⁺ or Ca²⁺ with the ester.This rate acceleration is attributed to the formation of a six-membered bidentate coordination complex between the divalent cation and the incipient tetrahedral intermediate.The metal-promoted acyl transfer reactions of p-nitrophenyl phosphonoacetate provide a convenient system for the quantitative assessment of the role of metal ions in the catalysis of aqueous reactions.