N-Benzylnicotinamide and N-benzyl-1,4-dihydronicotinamide: useful models for NAD+ and NADH

Abstract

3-Aminocarbonyl-1-benzylpyridinium bromide (N-benzylnicotinamide, BNA), C13H13N2O+·Br−, (I), and 1-benzyl-1,4-dihydropyridine-3-carboxamide (N-benzyl-1,4-dihydronicotinamide, rBNA), C13H14N2O, (II), are valuable model compounds used to study the enzymatic cofactors NAD(P)+ and NAD(P)H. BNA was crystallized successfully and its structure determined for the first time, while a low-temperature high-resolution structure of rBNA was obtained. Together, these structures provide the most detailed view of the reactive portions of NAD(P)+ and NAD(P)H. The amide group in BNA is rotated 8.4 (4)° out of the plane of the pyridine ring, while the two rings display a dihedral angle of 70.48 (17)°. In the rBNA structure, the dihydropyridine ring is essentially planar, indicating significant delocalization of the formal double bonds, and the amide group is coplanar with the ring [dihedral angle = 4.35 (9)°]. This rBNA conformation may lower the transition-state energy of an ene reaction between a substrate double bond and the dihydropyridine ring. The transition state would involve one atom of the double bond binding to the carbon ortho to both the ring N atom and the amide substituent of the dihydropyridine ring, while the other end of the double bond accepts an H atom from the methylene group para to the N atom.