Self-Association of Nicotinamide in Aqueous-Solution: N.M.R. Studies of Nicotinamide and the Mono- and Di-methyl-Substituted Amide Analogs

Abstract

The concentration-dependent self-association of nicotinamide in solution has been studied by ¹H and ¹³C n.m.r. spectroscopy, attendant relaxation time measurements, and osmometric techniques. N-Methylnicotinamide and N,N- dimethylnicotinamide were also studied to evaluate the role of the amide group in the association process. The osmometric studies indicated that the dimethyl -substituted analogue underwent little (if any) self-association, whereas nicotinamide and N- methylnicotinamide did self-associate. The concentration-dependent ¹H and ¹³C chemical shift profiles of nicotinamide and the monosubstituted analogue indicated that the association involved the amide group and did not occur through stacking of the pyridine rings. Spin lattice relaxation (T₁) studies indicated that the T₁( ortho C)/T₁( para C) ratio of nicotinamide decreased with increasing concentration, and that loss of a preferred axis of rotation had occurred due to formation of a large associated species. The T₁ ratios of either substituted amide analogue were not concentration-dependent. The extent of self-association of the monosubstituted derivative was insufficient to affect the measured T₁ ratios. These data indicate that the self-association of nicotinamide in aqueous solution occurs primarily through interamide hydrogen bonding.