Distorted amides as models for activated peptide N-C(O) Units. 3. Synthesis, hydrolytic profile, and molecular structure of 2,3,4,5-Tetrahydro-2-oxo-1,5-propanobenzazepine

Article abstract of DOI:10.1021/ja00015a033

A distorted amide (2,3,4,5-tetrahydro-2-oxo-1,5-propanobenzazepine (1d)) was synthesized and its structure determined by X-ray diffraction. The amidic unit of 1d is compared with that found in undistorted p-bromo-N,2-dimethylacetanilide (3b) and more distorted 2,3,4,5-tetrahydro-2-oxo-1,5-ethanobenzazepine (1b) and 3,4-dihydro-2-oxo-1,4-propanoquinoline (1c). The progressive distortion manifests itself in a lengthening of the N-C(O) bond, a slight shortening of the C=O bond, and a twisting about the N-C(O) unit with attendent rehybridization of the N from sp² to sp³ and a slight pyramidalization of the (N)(C)C=O unit. The hydrolysis of 1d in D₂O and H₂O is compared with those of N-methylacetanilide (3a), 1b, 1c, and 1a (3,4-dihydro-2-oxo-1,4-ethanoquinoline), the most distorted anilide in the series. In passing from 3a to 1a, the attack of OH^- is accelerated by roughly 7 orders of magnitude, while the acid-catalyzed hydrolysis is accelerated by 11 orders of magnitude. Based on the solvent kinetic isotope effects, pH/rate profiles, and activation parameters, a unified mechanism for H₃O⁺- and OH^--promoted hydrolysis of these anilides is proposed. The effect of varying [acetate] in catalyzing the hydrolysis of 1b and 1c in H₂O and D₂O as a function of pL was studied and analyzed in terms of a specific-acid/general-base process involving acetate-promoted delivery of L₂O on protonated amide.