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