Mechanistic aspects of oxidation of N‐substituted 5H‐dibenz[c,e]azepines by aldehyde oxidase

Abstract

5H‐Dibenz[c,e]azepine (2) and its N‐ethyl and N‐(2‐ethoxyethyl) analogues 3 and 4 were prepared and evaluated as substrates for aldehyde oxidase. Quaternization of 2 with ethyl iodide furnished 3, while 4 was prepared by lithium aluminum hydride reduction of N‐(2‐ethoxy)ethyldiphenimide followed by mercuric acetate oxidation of the resultant amine 6. The rates of oxidation of 2 and 3 were similar, suggesting a lack of selectivity by the enzyme for the respective imine and iminium functional groups in these compounds. The rate of oxidation of 3 decreased with increasing pH while the extent of “hydration” of this substrate increased over a similar pH range, signifying a preference by the enzyme for 3 over its carbinolamine equilibrium partner. Experiments with deuterium labelled analogues of 2 and 3 indicated that azomethine hydrogen loss from these substrates during enzymatic oxidation was not rate determining. Thus 5H‐dibenz[c,e]azepine‐5,5,7‐d3 (7), prepared by lithium aluminum deuteride reduction of diphenimide (5), and its N‐ethyl analogue 8, had respective enzymatic oxidation rates which did not differ from those of their non‐deuterated counterparts.