Computational investigation on the structure-activity relationship of the biradical mechanism for monoamine oxidase.

Although a considerable amount of mechanistic data has accumulated in literature, the detailed mechanism for amine oxidation by monoamine oxidase is still controversial. The single electron transfer mechanism (SET) has been widely discussed, but not completely understood yet. In the present study, the modified SET mechanism, proposed by Silverman et al., was explored by quantum chemical calculations. The ONIOM method was applied with UDFT/B3LYP/6-31 + G(d,p) for the higher layer and with UHF/6-31G(d) for the lower layer. Isoalloxazin heterocyclic ring and benzylamine were employed in the calculations to represent flavin and the substrate, respectively. The substituents CH(3), OH, OCH(3), H, F, Cl, Br, CF(3) and NO(2) were incorporated at the para position of benzylamine to explore structure-activity relationships. The structures of the reactant complex, transition state and product complex were fully optimized. Activation energies and rate constants of all the reactions were calculated. The results obtained from the linear regression analysis showed that electron-donating groups at the para position of benzylamine increase the reaction rate. A linear but inverse correlation between the log of the calculated rate constants (log k) and the electronic parameter of the substituent was observed (R = 0.93). In accordance with this result, a relatively weak inverse correlation between the calculated log k and the experimental log k was obtained (R = 0.78). The results are contrary to the previous kinetic experiments and the computational study on the effect of p-substituents in the flavin reduction of MAO A by p-substituted benzylamine analogs. Therefore, they present negative evidence for the modeled biradical mechanism.

A DFT study on the mechanism of the annulation reaction of trichloronitroethylene with aniline in the synthesis of quinoxalinone-N-oxides.

The new annulation reaction of trichloronitroethylene with aniline results in the formation of a quinoxalinone-N-oxide derivative. The mechanism of this one-pot annulation reaction between trichloronitroethylene (TCNiE) and anilines has been extensively investigated with B3LYP/6-31+G** methodology. Five different paths (1-5) were proposed and modeled by using this method. These paths were compared in terms of the activation energies of their rate-determining steps and in regard to the experimental findings. Paths 3 and 5, proceeding via four-membered heterocyclic rings, were found to be the most plausible paths with activation energies of 32 and 29 kcal/mol for the rate-determining steps, respectively. The effects of substituent, solvent, temperature, and computational method on these steps were also investigated. The results showed that path 5 is the most plausible mechanism for the annulation reaction of trichloronitroethylene with aniline.