Efficient Intramolecular General Acid Catalysis of Nucleophilic Attack on a Phosphodiester

摘要

The hydrolysis of methyl 8-dimethylamino-1-naphthyl phosphate 4 and its reactions with a representative range of nucleophiles are catalyzed by the dimethylammonium group at acidic pH with rate accelerations of the order of 10~6.The reaction persists up to pH 7 because the strong intramolecular hydrogen bond,which is the key to efficient general acid catalysis,is present also in the reactant.The sensitivity to the basicity of the nucleophile (Bronsted beta_(nuc) = 0.29) lies between values measured previously for mono- and triesters.The comparisons suggest that general acid catalyzed reactions of phosphate mono-or diesters with strongly basic oxyanion nucleophiles (like those derived from a serine oxygen or a bound water molecule in an enzyme active site) will be fastest when their negative charges are neutralized by protonation.Reactions with NH_2OH and its N-methylated derivatives show an apparent a-effect,but NH_2-OMe reacts no faster than a primary amine of similar basicity.It is suggested that the reaction involving NH_2OH as an oxygen nucleophile proceeds through the pre-equilibrium formation of the tautomer H_3N~+-O~-as the active nucleophile: ab initio calculations support this idea.