Acid-Base Equilibrium of 5,5,6-Trihydroxy-6-Methyldihydropyrimidine-2,4(1H,3H)-Dione in the Gas Phase and in Water

The first-stage acid-base equilibrium of 5,5,6-trihydroxy-6-methyldihydropyrimidine-2,4(1H,3H)-dione was studied for the first time in aqueous solutions. Its constant (pK_a1 = 9.23 ± 0.03) and thermodynamic parameters (ΔG₂₉₈ = 52 ± 1 kJ·mol^-1, ΔH = 83 ± 1 kJ·mol^-1, and ΔS₂₉₈ = 103 ± 4 J·mol^-1·K^-1) were determined by potentiometric titration. Computational analysis, including molecular dynamics (MD) simulations and quantum chemical calculations, was conducted to evaluate solvation effects and proton dissociation sites. MD simulations identified distinct solvation shells and interactions with water molecules, while quantum chemical calculations highlighted the primary deprotonation site. Fuzzy bond order (FBO) analysis and energy calculations of anionic forms corroborated these findings, demonstrating a strong correlation between the ΔE and FBO values. The research established the dissociation sequence for conformational - and -isomers of the title compound and validated the FBO method as an efficient tool for assessing dissociation processes in polybasic acids.