The Pyridinium-Dihydropyridine System. Reduction Potentials and the Mechanism of Oxidation of 1,4-Dihydropyridines by a Shiff Base

Article abstract of DOI:10.1021/ja00367a026

As a model system for the glutamate dehydrogenase catalyzed reductive amination of α-ketoglutarate we have studied the reduction of a Shiff base, Δ¹-pyrroline-2-carboxylic acid, by a series of 14 N-1 and C-3 substituted 1,4-dihydropyridines, including NMNH, NADH, and NADPH.The reversible electrode potentials of eight of the dihydropyridines, all dihydronicotinamides, have also been determined.The reduction reaction has the following characteristics: (a) it is first order in protonated Schiff base (zwitterionic form) and first order in the dihydropyridine, (b) there is a small deuterium isotope effect when the C-4 position of the dihydropyridine is deuterated (1.20-1.57 at 25 deg C), (c) there is a direct transfer of hydrogen from C-4 of the dihydropyridine to C-2 of the pyrroline, (d) the rates for seven N-1 substituted dihydronicotinamides are correlated satisfactorily with ?^* giving ρ^* = -1.98 (H2O) and -1.79 (aqueous methanol), there being only a modest difference in rates in these two solvents, (e) there is a good correlation between the rates of reduction by the dihydronicotinamides and the E⁰ values of the reversible two-electron dihydropyridine-pyridinium couple, the effect being 31.0 mV per logarithmic unit of rate, (f) there is a close correlation between the rates of reduction of pyrroline and of flavin by the dihydropyridines, and (g) the enthalpy and entropy of activation for the rate-controlling step in the reduction by 1-benzyl-1,4-dihydronicotinamide are 15.7 kcal mol^-1 and -7.6 eu.We believe that direct hydride transfer has taken place to produce proline in a single step and it can be inferred that the transition state closely resembles products in structure.The similarity between pyrroline and flavin reduction suggests that the latter reaction may also be a direct hydride transfer.