Effect of methyl substituents in the reactivity of methylxanthines.

The methylxanthines have attracted interest due to the changes on their biological activities and physicochemical properties in terms of the number and position of the methyl groups present in the xanthine moiety. We report a theoretical study of the influence of the methyl substituent in the basicity and reactivity of xanthine and its methylated derivatives. Our results provide that when the xanthine increases the number of methyl substituents, the gas phase basicity increases (reactivity to proton increases), and the global hardness decreases. The result is in agreement with the maximum hardness principle (MHP) that states, "at equilibrium, chemical systems are as hard as possible" (Pearson, R.G., J. Chem. Educ., 1987, 64, 561-567, and Parr R.G., Chattaraj P.K., J. Am. Chem. Soc. 1991, 113, 1854-1855). Graphical abstract Xanthine and its methyl derivatives.