Abstract: In order to investigate the tautomerism of 5-fluorouracil (5-FU) induced by proton transfer, we describe a study of structural tautomer interconversion using density functional theory (DFT) calculations at B3LYP/6-311++G(d, p) level of the theory. Thirty-eight geometries including fifteen transition states with and without water molecule were studied. The calculated results indicate that there are two absolutely opposite regions in the vicinity of 5-FU. In one of the regions, water molecules can assist the tautomerism from 5-FU to its enol form (5-FU*), whereas in another region, water molecules can protect 5-FU from tautomerizing to 5-FU*. Furthermore, compared with the tautomerizing processes of uracil, the probability of 5-FU to tautomerize to its enol form is much higher. Based on such facts, the reason why 5-FU is an effective anticancer medicament but with some of toxicity is explained to some extent.

Key words: Density functional theory, 5-fluorouracil, Proton transfer, Tautomerism, Water