Solvent interactions with N, N-dialkylnicotinamides and their effects on rotational barriers

Carbon-13 nuclear magnetic resonance techniques were employed to examine the effects of solvent environment on rotational barriers in a series of molecules structurally-related to the analeptic, nikethamide: N,N-dimethylnicotinamide, N,N-di-n-propylnicotinamide, and 1-nicotinoyl piperidine. Total bandshape analysis was performed for the exchanging alkyl carbon resonances of these compounds as a function of temperature in four solvent systems: D2O, CH3OD, CH3CH2OD and CDCl3. The rate constants for rotation about the amide bond obtained in this way were used to calculate free energy (delta G), enthalpy (delta H) and entropy (delta S) of activation parameters for this process. Our results indicate that rotational barriers are less affected by the nature of the alkyl chain attached to the amide nitrogen than by the size and polarity of the solvent molecules. Interpretation of the thermodynamic parameters in light of both nikethamide analogue structure and solvent type has further clarified the manner in which hydrogen bonding interactions between solvent molecules and the carbonyl oxygen of these analogues stabilize transition state conformers.