Tautomeric forms and ionisation processes in xanthine and its N-methyl derivatives

Abstract

The n.m.r. chemical shifts of the 8-protons in xanthines with an unsubstituted imidazole ring (class a) and in 7-methylxanthines (class b) are very similar; however the 8-H signals for 9-methyl derivatives (class c) occur at higher field. Thus, in aqueous solution, members of class a must be essentially present as the N(7) H tautomers.

Methyl substituents in various positions may be distinguished by their n.m.r. signals; their δ values can be arranged in the following order: 7- > 9- > 3- > 1-methyl. The signals of individual N-methyl groups are influenced only slightly by introduction of additional alkyl substituents, with the exception of 3,9-dimethylxanthines, in the spectra of which both methyl signals are shifted to lower field because of steric interference.

U.v. spectra establish the order of anion formation in 7- and 9-methylxanthine as 3 → 1 and in 3-methylxanthine as 7 → 1. However, the displacement of the 8-H signals in the n.m.r. spectra of xanthine and its 1-methyl derivative suggests that their monoanions are tautomeric mixtures in which both the N (3) H and N (7) H groups participate in ionisation.

Cation formation is accompanied by a much larger displacement of the 8-H n.m.r. signal in class c than in class a or b.