An old but simple and efficient method to elucidate the oxidation mechanism of NAD(P)H model 1-aryl-1,4-dihydronicotinamides by cations 2-methyl-5-nitroisoquinolium, tropylium, and xanthylium in aqueous solution

Cations 2-methyl-5-mitroisoquinplinium (IQ⁺), tropylium (T⁺), and xanthylium (Xn⁺) were treated by an NAD(P)H model 1-(p-substituted phenyl)-1.4-dihydronicotinamide series (1) in buffered aqueous solution to give the corresponding reduced products by accepting hydride. Effects of the 4-substituents of 1 on the reaction rates were investigated. Hammett's linear free energy relationship analysis on the three reactions of 1 provides the reaction constants of -0.48, -2.2, and -1.4 with IQ⁺, T⁺, and Xn⁺ as the hydride acceptors, respectively. Comparison of the present reactions with the reaction examples whose mechanisms are well-known, such as the reaction of 1 with a one-electron oxidant Fe(CN)₆^-3, shows that the active site of 1 in the oxidation with IQ⁺ is at the 4-position on the dihydropyridine ring but that the active site of 1 in the oxidations with T⁺ and Xn⁺ is at the 1-position, which is in agreement with the results from the Brønsted-type linear analysis and the relation studies of the logarithm of the second-order rate constants with the oxidation potentials of the hydride donors. According to the dependence of the reaction mechanism on the active site of 1, a conclusion can be made that the reaction of 1 with IQ⁺ proceeds by direct one-step hydride transfer mechanism, but the reactions of 1 with T⁺ and Xn⁺ would take place via multistep hydride transfer mechanism initiated by one-electron transfer.