Oxo−Hydroxy Tautomerism of 5-Fluorouracil:  Water-Assisted Proton Transfer

Abstract

Post-Hartree-Fock ab initio quantum chemical calculations were performed for 5-fluorouracil in the gas phase and in a three-water cluster. Full geometry optimizations of the 5-fluorouracil-water complexes were carried out at the MP2/6-31+G(d,p) level of theory. MP4/6-31+G(d,p)//MP2/6-31+G(d,p) and MP4/6-31++G(d,p)//MP2/6-31+G(d,p) single-point calculations were performed to obtain more accurate energies. In water solution, 5-fluorouracil exists mainly in the 2,4-dioxo form (A). We propose that the populations of the 2-hydroxy-4-oxo (B) and 4-hydroxy-2-oxo (D) tautomers are 1 x 10(-4)% and 3.9 x 10(-8)%, respectively, on the basis of the relative stabilities of the tautomers calculated at the MP4/6-31++G(d,p)//MP2/6-31+G(d,p) level of theory. A profound difference between isolated and hydrated 5-fluorouracil is noted for the height of the tautomerization barrier. In the absence of water, the process of proton transfer is very slow. The addition of water molecules decreases the barrier by 2.3 times, making the process much faster. The minimum energy path (MP2/6-31+G(d,p)) for water-assisted proton transfer in trihydrated 5-fluorouracil was followed. CNDO/S-CI calculations predict singlet pi-pi(*) electron transitions at 312 nm for B and at 318 nm for D. The fluorescence spectrum of 5-fluorouracil in water confirms the presence of the hydroxy tautomer.

Effect of hydration on the stability and tautomerisms of different isomers of uracil

“…12,13,24,25 These studies showed that water molecules decrease the activation energies of the proton transfers. 12,13,24,25 These studies showed that water molecules decrease the activation energies of the proton transfers.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Furthermore, some studies have been performed on the reactions of uracil and its interaction with other molecules. Many researchers have studied structures of different tautomers of uracil as well as their stability in the gas and solution phases.…”

Proton transfer at the carboxylic sites of amino acids: A single water molecule catalyzed process

“…In this work, the proton transfer A0 ↔ B0 [Scheme (c)] was investigated using ab initio methods. The previous studies on formamide and many other systems indicated that the water molecules around play an important role and assist the proton transfer processes 6, 15, 37–42. Here, the solvent effects on the present A0 ↔ B0 tautomerization processes were considered in two different ways: (a) Interactions with one and two discrete water molecules.…”

Spectroscopic and calorimetric studies of formation of the supramolecular complexes of PAMAM G5-NH2 and G5-OH dendrimers with 5-fluorouracil in aqueous solution

“…In chemical terms 5-fluorouracil is an aromatic compound, whose most stable tautomer in a neutral medium is the diketone form ( Fig. 1) (Marino et al, 1997;Markova et al, 2005Markova et al, , 2010Pavel et al, 2005;Yekeler and Ozbakır, 2001). In water it dissolves better (85.1 mM (Sloan et al, 2005), 96.9 mM (Singh, 2005), 138.2 mM (Szterner, 2008)) than in ethanol (<1 mM, (Kobayashi et al, 1998)).…”