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Isomers and conformational barriers of gas-phase nicotine, nornicotine, and their protonated forms.

We report extensive conformational searches of the gas-phase neutral nicotine, nornicotine, and their protonated analogs and the pathways and barriers for the interconversion between their various isomers that are based on ab initio second-order Møller-Plesset perturbation (MP2) electronic structure calculations. Initial searches were performed with the 6-31G(d,p), and the energetics of the most important structures were further refined from geometry optimizations with the larger aug-cc-pVTZ basis set. On the basis of the calculated free energies at T = 298 K for the gas-phase molecules, neutral nicotine has two dominant trans conformers, whereas neutral nornicotine is a mixture of several conformers. For nicotine, the protonation on both the pyridine and the pyrrolidine sites is energetically competitive, whereas nornicotine prefers protonation on the pyridine nitrogen. The protonated form of nicotine is mainly a mixture of two pyridine-protonated trans conformers and two pyrrolidine-protonated trans conformers, whereas the protonated form of nornicotine is a mixture of four pyridine-protonated trans conformers. Nornicotine is conformationally more flexible than nicotine; however, it is less protonated at the biologically important pyrrolidine nitrogen site. The lowest energy isomers for each case were found to interconvert via low (<6 kcal/mol) rotational barriers around the pyridine-pyrrolidine bond. These barriers are much lower than previous estimates based on lower levels of theory obtained without relaxation of the structure along the path. Nicotine was found to bind more strongly to tryptophan (Trp) than nornicotine, a finding that is consistent with nicotine's enhanced affinity in the nicotinic acetylcholide receptor.