5‐Fluorouracil solutions: NMR study of acid–base equilibrium in water and DMSO

A comprehensive analysis of solutions of 5‐fluorouracil (5FU) in water and an organic medium (dimethylsulfoxide, DMSO) was carried out using quantum chemical methods and nuclear magnetic resonance (NMR) spectroscopy. The details of anionic form generation in the solution of 5FU with an equimolar amount of potassium hydroxide were studied by ¹³С, ¹Н, ¹⁵N and ¹⁹F NMR. Interpretation of NMR spectral data was carried out using quantum chemical calculations at the TPSSTPSS/6‐311+G(d,p) level of theory. Specific solvation of 5FU and 1THF‐5FU was modeled in approximation using the five‐water cluster model and solvate complex including two DMSO molecules. It was established that in an alkaline medium in DMSO 5FU occurred mainly as a type of an anion with a deprotonation on N(1) position of a pyrimidine ring whereas in water alkaline solution—as a mixture of two anions with a deprotonation on N(1) and N(3) positions with a predominant content of the latter form. For the quantitative definition of the deprotonation forms of 5FU the technique based on the data of theoretical and experimental NMR ¹³C spectroscopy, tested on a model compound 1‐(tetrahydrofuranyl‐2)‐5‐fluoro‐pyrimidinedione‐2,4 (tegafur, THF‐5FU), was offered. The N(3) anion was found from spectral data to be more thermodynamically stable than the N(1) anion by 2.40 kJ mol^?1 (calculated value 2.24 kJ mol^?1) in an alkaline–water solution. Both alkaline–water and alkaline–DMSO solutions of THF‐5FU (THF‐5FU/KOH = 1/1) were characterized by the ratio of the equilibrium concentrations of the anion and diketo‐tautomer as 9:1 and 4.3:1, respectively. Copyright © 2014 John Wiley & Sons, Ltd.