N-Oxidation, N-methylation and N-conjugation reactions of nicotine

Abstract

N-Oxidation, N-methylation and N-conjugation reactions of nicotine are metabolic transformations that result in the formation of the corresponding quaternary ammonium product, which is usually more polar in nature and more water soluble than the parent base. In these reactions, the generation of a positively charged tetrahedral nitrogen centre represents a higher oxidation state, hence such metabolic transformations can be considered collectively as N-oxidation reactions (Damani, 1985). In the case of nicotine, two tertiary amino centres are present in the molecule, thus allowing two possible sites of oxidation. The relative basicities of these nitrogen centres are somewhat different, i.e., pKa (pyridino N) = 3.04, pKa (pyrrolidino N) = 7.84. The pyridino moiety contains an aromatic azaheterocyclic nitrogen which is considerably less basic than the pyrrolidino nitrogen, due to the effect of sp² hybridization on base strength, since as the ‘s’ character of an orbital increases, the electrons in that orbital are bound more tightly to the nucleus. In this respect, the regiospecificity of N-oxidation is an important consideration, especially as it relates to the structural and chemical features of the nicotine molecule, and the active site chemistry of the metabolizing enzymes involved. In addition, the presence of a chiral centre at C-2’ of the nicotine molecule introduces the interesting possibility of diastereo-meric metabolic products resulting from N-1’-oxidation reactions.