THE SIGNIFICANCE OF ELECTROSTATIC EFFECTS IN PHOSPHO-ESTER HYDROLYSIS

The detailed activation free energy profiles for alkaline hydrolysis of the methyl aminoethylenephosphonate (MNP) in vacuum and the changes upon solvation have been computed. The calculations predict that alkaline hydrolysis of MNP in solution proceeds via (OH)(-) attack opposite the ring oxygen instead of the nitrogen, in agreement with the concept of apicophilicity. The MNP + (OH)(-) solution reaction is predicted to yield a mixture of products, viz., inversion of configuration production from P-O endocyclic cleavage and retention of configuration products from P-O exocyclic cleavage and P-N endocyclic cleavage. Intramolecular charge-charge interactions between the hydroxyl and/or amide protons with neighboring atoms influence the position of the ring nitrogen relative to the ring oxygen in a TBP and facilitate endo- and exocyclic cleavage. There is no evidence of transition-state stereoelectronic effects controlling the MNP + (OH)(-) reaction pathway.