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

Abstract

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.

Ferrocenoyl‐Substituted Pyrimidine Nucleobases: An Experimental and Computational Study of Regioselective Acylation of Uracil, Thymine, and 5‐Fluorouracil

“…This is in line with the recent NMR study on 5-FU and its N 1 -analogues. [16] However, according to NMR analysis of the reaction mixture (the small inset in Figure 3) we are confident that the regioselectivity in the reaction between 5-FU and FcCOCl follows the same pattern as that described for uracil and thymine.…”

Microhydration of Deprotonated Nucleobases

“…This result is supported by the reaction field calculations with the isodensity polarizable continuum (IPC) model, with the equilibrium constant ratio, K eq (N1) / K eq (N3) = 5 × 10 4 . In the case of 5F U , the N1 – / N3 – anion fraction ratio in aqueous alkaline solution was found to be 0.61 [ 60 ]. The N3 – anion, if formed in aqueous solution, in the gas phase can isomerize to N1 – in the presence of neutral nucleobase [ 20 ].…”

“…The N3 – anion, if formed in aqueous solution, in the gas phase can isomerize to N1 – in the presence of neutral nucleobase [ 20 ]. According to the in vacuo ab initio calculations, the N1 – anion of [ U -H] – is more stable than N3 – by 58.5 kJ/mol [ 59 ]; for [5F U -H] – this difference is 49.9 kJ/mol [ 60 ]. The energy barrier (185.4 kJ/mol) calculated [ 61 ] for the uracil N1 – —> N3 – conversion is too high to be overcome at thermal energies in our instrument.…”

A theoretical quantitative estimation of acidity of uracil and its derivatives through the pKa values

“…However, the measurement of acidity is sometimes very difficult, especially when dealing with a mixture of isomers that are difficult to separate, for example, highly labile tautomeric forms. Additionally, different schemes are known for the theoretical estimation of the p K a vlues of uracils . Such a diversity of works is due to the ongoing development of computational methods of quantum chemistry, providing novel opportunities for more accurate assessment of p K a .…”

“…Abdrakhimova and co‐authors carried out a comprehensive analysis of solutions of halouracils in water and organic media Dimethylsulfoxide (DMSO) in a number of works using quantum chemical methods and Nuclear magnetic resonance (NMR) spectroscopy. They found that in an alkaline medium in DMSO, for fluorouracil, an anion with deprotonation in the N1 position of the pyrimidine ring was formed, whereas in water and in an alkaline solution it was a mixture of two anions with deprotonation on N1 and N3 positions with a predominant content of the latter.…”