Spectroscopic investigations into the acid–base properties of nicotine at different temperatures

Abstract

Electronic circular dichroism (ECD) spectrometric titration methodology was used to determine the acid ionisation constants (pK_a) of (S)-(−)-nicotine. Thermostatically controlled instrumentation allowed measurements to be conducted between 20 and 40 °C and the changes in pK_a with temperature were characterised. The methodology was robust, precise and could be utilised for other chiral chromogenic compounds. We believe this article is the first report of the use of chiroptical spectroscopy to characterise the acid–base properties of a small bio-active molecule, and the technique could become the method of choice for defining these attributes in similar molecules. For (S)-(−)-nicotine the two pK_a values were found to be 2.96 and 8.07 at 20 °C, 2.85 and 7.89 at 25 °C, 2.84 and 7.83 at 30 °C and 2.74 and 7.57 at 40 °C. Using the van't Hoff relationship the pK_a of the pyrrolidyl ionisation at 37 °C was calculated as 7.65. Changes in the ionisation status of nicotine with temperature are of interest to investigators studying the attributes of nicotine derived from the human use of oral tobacco products. The reversibility of UV and ECD spectra of nicotine with temperature between 10 and 87 °C was demonstrated for both enantiomers. Additionally there was good evidence that at pH 9.5 nicotine underwent conformational change, and the transition mid-point occurred at 49.7 and 49.4 °C for (S) and (R)-nicotine respectively.