Concentration and basicity of histamine rotamers

Abstract

A method was developed and applied to determine the populations and site- and conformer-specific basicities of histamine rotamers in three distinct states of protonation. The method that has been developed also allows the determination of molecule- and position-specific standard gauche and trans¹H NMR coupling constants, and the subsequent rotamer analysis from NMR spin systems with a single observed coupling constant, introducing simplifying allowances of symmetry origin. Synthesis and NMR analysis of a reference histamine derivative have also been carried out. The trans rotamers of histamine were found to exist in 41, 38 and 50% in the neutral, monocationic and dicationic forms, respectively, providing quantitative, experimental evidence for the preferential thermodynamic properties of the trans species over the two enantiomeric, statistically favoured g conformers in any ionisation form. Quantification of the rotamer- and site-specific basicities resulted in increased amino and decreased imidazole basicities in the gauche rotamer, indicating the formation of intramolecular hydrogen bonds in the monocationic form.