As mentioned above, the pKa corresponding to the thiopurine core for these molecules lies between 7.7-7.87, which makes both 6MP and Aza exist as a mixture of neutral (67-75%) and deprotonated (25-33%) species at physiological pH. Moreover, prototropic tautomerism is well-known to exist in purine derivatives. Previous work on the prototropic tautomerization of neutral Aza in aqueous solution has shown that neutral Aza exists only as the N9(H) tautomer, while the deprotonated form of Aza cannot exhibit prototropic tautomerization. In the case 6MP, the prototropic tautomerization of the neutral species have been studied in deuterated-dimethylsulfoxide, deuterated-dimethylformamide, and deuteratedmethanol. The investigation demonstrated that the N7(H)-N1(H) is the predominant species of 6MP in these solvents. In order to determine which tautomer(s) is available in aqueous solution, the ground-state geometries of four tautomers of the neutral form of 6MP (i.e., N7(H)-