The Zinc- and Copper-Promoted Hydrolysis of Lactams.

The importance of the precise geometric orientation of a metal in metal promoted amide hydrolysis has been demonstrated. Large rate enhancements (10('3) - 10('6)) at neutral pH were found in zinc and copper complexes where the metal is forced to lie above the plane of an amide. For this study, lactams 1-{(6-dimethylaminomethyl)-2-pyridyl}methylhexahydro-1,4-diazepin-5-one 11 and 1-{(6-di(carboxymethyl)aminomethyl}-2-pyridyl}methylhexahydro-1,4-diazepin-5-one 12 were synthesized. Titrimetrically determined formation constants indicated that both 11 and 12 readily bind divalent metals (Cu('2+), Ni('2+), Zn('2+), Co('2+)). Thus, detailed investigations of the various metal complexes were possible over a wide range of pH. At 50(DEGREES)C, the Cu('2+)-promoted hydrolysis of 11 exhibited a strictly sigmoidal pH-rate profile. The rates increased commensurate with the ionization of metal-bound water molecule. A similar behavior was observed with the Zn('2+)-12 complex at 70(DEGREES)C. Both Cu('2+) and Zn('2+) greatly facilitate amide hydrolysis at pH 7. Compared to base hydrolysis of the lactams with no metal, a rate enhancement of 9 x 10('5) and 1.0 x 10('3) was observed with the Cu('2+)-11 and Zn('2+)-12 complexes, respectively. Activation parameters for the metal-promoted hydrolyses indicated that catalysis results from a substantial increase in (DELTA)S('(NOT=)). These observations are interpreted in terms of nucleophilic catalysis by a metal-hydroxo species in basic media. Concurrent carbonyl oxygen exchange accompanied base hydrolysis of 11. In contrast, significant oxygen-18 exchange was not observed during the Cu('2+)-promoted hydrolysis of 11. These results are considered in the context of the known stereoelectronic control in the cleavage of tetrahedral intermediates.PhDOrganic chemistryInorganic chemistryUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/158414/1/8125082.pd