Theoretical studies on the hydride transfer between 1-methyl-1,4-dihydronicotinamide and its corresponding pyridinium salt

Abstract

MNDO and AMI studies were performed to investigate the degenerate hydride transfer reaction between 1-methyl-l,4-dihydronicotinamide and the 1-methylnicotinamide cation, a model system for a novel brain-targeted delivery system and for the NAD + (ai) NADH interconversion. Four initial approach vectors were selected. These involved an endo orientation in which the carbamoyl groups are syn with respect to one another (cis H S- re ), an endo orientation with the carbamoyl groups anti (cis H S-si), an exo configuration with the carbamoyl groups syn (trans H S- re ) and an exo configuration with the carbamoyl groups anti (trans H S- re ). The cis H S- re approach generated the transition state with the lowest energy. The optimized structure indicated that a linear hydride transfer occurred. A more detailed study examined the cis H S- re approach from a 100A separation to the transition state. The data indicated the formation of an intermediate induced dipole-charge complex which altered the trajectory of the two species. Closer approach yielded the transition state. The energy of activation for this reaction was calculated to be 30.7 kcal mol using the MNDO approximation and 9.3 kcal mol usihg the AMI method. Finally, while the linear transition state was found to be the most stable conformation, bending of the C-H-C bond by ± 30° only modestly increased (3–4 kcal mol ) the energy of the system.