A symmetrical model for the self-association of xanthines in aqueous solution

Abstract

The self-association of caffeine, 7-ethyl-, 7-propyl-, and 7-butyl-theophylline, theophylline, 1,3-diethylxanthine, and 3-isobutyl-1-methylxanthine in aqueous solution was explored in this study. Detailed analyses of all the proton shifts in CDCl₃ and D₂O solutions were undertaken, measuring both concentration- and temperature-dependence. Operative factors determining the chemical shift values include solvent-structuring effects, polarizability capacities, and hydrogen bonding involving water bridges. Evidence is given to support a symmetric mode of association induced by hydrophobic interaction and hydrophilic hydration between contiguous groups. The chemical shifts of theophylline and two of its analogues were measured in D₂O, CD₃OD, and CDCl₃ solutions. Only in CD₃OD did the shifts show different trends which were interpreted on the basis of the solvation capacity of CD₃OD and steric hindrance to the specific solvation.