Effect of the microhydration on the tautomerism in the anticarcinogenic drug 5-fluorouracil and relationships with other 5-haloderivatives

• The six tautomers of 5-FU were determined and optimized at different levels.
• The first hydration shell 5-FU-(H2O)10 was calculated in the five most stable tautomers.
• The hydration causes a reordering of the stability order of the tautomers.
• The CP corrected interaction and formation energies were calculated.

The 5-fluorouracil (in short 5-FU) mutagenicity was investigated in the isolated state and in the hydrated form through an exhaustive quantum-chemical analysis. The most optimum tautomers of 5-FU were optimized and analyzed. Six of them were related to those of uracils molecule, with the same stability order. The effect of the halogen substitution in position 5 on the uracil ring in the stability of the different tautomers was analyzed. Solvent effects were considered using a variable number (1–10) of explicit water molecules surrounding 5-FU in order to simulate the first hydration shell. More than 100 cluster structures with water were analyzed. A comparative analysis in the different tautomers of the hydration effect on the molecular structure and energetics was carried out. For cases where literature data are available, the computed values were in good agreement with previous experimental and theoretical studies. Depending on the nature of the tautomers, cyclic, distributed, or clustered structures were formed. The deformation and interaction counterpoise (CP)-corrected energies between 5-FU and water molecules were determined. The maximum interaction was found in the enol form T2. The microhydrated environment stabilized remarkably the enol forms T3 and T5 (present in the corresponding nucleoside) more than the canonical keto T1, although this one continues being the most stable. Several relationships with 5-XU derivatives (X = F, Cl, Br, I) between the relative energy of tautomer T2 and the geometric parameters/atomic charges were underlined.