SYNTHESIS AND HYDROLYTIC LABILITY OF ALPHA-PHENOXYACETAMIDES CONTAINING HYDROXY-GROUPS IN THE N-ALKYL RESIDUE

Secondary and tertiary amides of 3,5-bis[[(2,3 -dihydroxypropyl)amino] carbonyl]phenoxyacetic acid bearing hydroxy groups in positions beta ( beta-OH) and gamma (gamma-OH) relative to the acetamide nitrogen atom have been synthesised. Such amides easily undergo cleavage of the acet amide bond in water at neutral pH. Hydrolysis rate constants for a ser ies of such amides and protonation constants for the corresponding lea ving amines were determined. No simple correlation between the two par ameters could be found. A study of the dependence of these parameters on the structural features of the substrates, such as the presence of an N-methyl group and number of beta-OH and gamma-OH groups, was carri ed out. All these features lead to enhancement of the amide hydrolysis rate and a synergistic effect is operative when both N-methyl and bet a-OH groups are contained in the substrate. Presence of a methyl group increases the basicity of amines whereas beta-OH and gamma-OH groups have the opposite effect. Mechanistic speculations seem to indicate th at the abnormal lability of the acetamide bond is due to protic-like c atalysis by an intramolecular OH .... N hydrogen bond.