Assessment of isolated electronic effects on conformation. NMR analysis of nicotine and related compounds and ab initio studies of model compounds

The influence of electronegative substituents on the N′-methyl group of nicotine upon the conformation of the pyrrolidine ring has been evaluated by the exact analysis of the high field 1H NMR spectra of nicotine (1),N′-ethylnornicotine (2), N′-(2,2-difluoroethyl)-nornicotine (3) and N′-(2,2,2-trifluoroethyl) nornicotine (4). The vicinal coupling constants for the pyrrolidine ring of 1–4 remain nearly constant, suggesting that as the electronegativity of the N′-methyl substituent increases, only very small changes are seen for the C3′—C4′—C5′—N′ and the C2′—C3′—C4′—C5′ dihedral angles. Substitution on the N′-methyl group appears to have little effect on the orientation of the pyridyl ring with respect to the pyrrolidine ring. Ab initio calculations have been performed on the analogous 2-substituted diethylamines (diethylamine, N-ethyl-2-fluoroethylamine, N-ethyl-2,2-difluoroamine, and N-ehtyl-2,2,2-trifluoroethylamine) which constitute substructure models of 1–4. These calculations confirm the NMR results in that they both indicate little, if any, effects on the rotational barriers and conformational energy profiles as a function of number of fluorine atoms.