Distorted Amides as Models for Activated Peptide N-C=O Units Produced during Enzyme-Catalyzed acyl Transfer Reactions. 1. The Mechanism of Hydrolysis of 3,4-Dihydro-2-oxo-1,4-ethanoquinoline and 2,3,4,5-Tetrahydro-2-oxo-1,5-ethanobenzazepine

Article abstract of DOI:10.1021/jo00364a012

A series of four substituted benzoquinuclidones (6-X-3,4-dihydro-2-oxo-1,4-ethanoquinoline, X = H, CH3, OCH3, Cl) (3a-d) and the next higher homologue <2,3,4,5-tetrahydro-2-oxo-1,5-ethanobenzazepine (5)> were synthesized and their hydrolyses studied.These are considered as models for the putative distorted amide N-C=O unit in the Michaelis complex produced during enzyme-catalyzed hydrolyses of peptides.Compound 3, with an sp³-like N having complete orthogonality of the N lone pair and C=O ?-bond, hydrolyzes rapidly at all pH values and shows a pH/rate profile consisting of H2O attack on an N-protonated species, as well as H2O and OH^- attack on the neutral species.Strong general base catalysis of H2O attack is observed in the OH^- domain.Acetate and formate give curved buffer plots consistent with superimposed general catalysis in the acid domain.Amide 5, in which the N is also sp³ hybridized and the N-C=O dihedral angle is 30-35 deg, shows a pH/rate profile consisting of H2O attack on an O-protonated species and OH^- attack on the neutral with a minimum at pH 7.0; no H2O attack on the neutral is observed and general base catalysis is not observed in the OH^- domain.However, buffer catalysis is observed for 5 at pH values <7. 18O-exchange experiments show that in Na18OH/H218O, 3 and 5 produce carboxylates containing only one 18O, indicating that the tetrahedral intermediates are not reversibly produced in base.Also, 50percent 18O-enriched 5, when partially hydrolyzed at pH 10.1 and recovered, shows no loss of 18O.However, in the acid domain, recovered 18O-enriched amide when hydrolyzed in H216O is shown to incorporate 16O for both 3 and 5 such that the tetrahedral intermediate is formed reversibly for both amides.The 18O-exchange results are discussed in terms of the Deslongchamps' stereoelectronic theory.