5-Aminolevulinic Acid Tautomers: Theoretical Elucidation of pKa’s, Species Distribution and Dimerization Constants

Abstract

Abstract: 5-aminolevulinic acid (5-ALA) applications in medicine and agriculture face the challenge of stability. In aqueous solutions, concentration, pH, and temperature have an effect on the loss of activity. Computational chemistry helps to determine tautomerization, formation of derivatives and the stability, in different conditions, in a short time and reducing the cost of analysis. This work aimed to model the 5-ALA molecule and its tautomers in aqueous solution, determine its pKa and molar fractions at different pH, determine its thermodynamic and kinetic parameters, and predict the degree of dimerization under different conditions. Gaussian 16 program, Density Functional Theory, and the M05-2X functional were used to obtain the stationary state frequencies. From the difference in Gibbs free energy (ΔGs) between each acid/base conjugate, pKa values and molar fractions at different pH's were determined. Equilibrium constants were calculated from the ΔGr at different temperatures. Using data from the literature, the activation energy was optimized and the rate constants were obtained. A model was obtained to approximate the half-life, t0.5, and shelf-life, t0.9, values for 5-ALA solutions. pKa values obtained, 4.40 and 7.87, coincide with the potentiometric determinations reported in the literature. The thermodynamic and kinetics parameters calculated in this study correctly predict the percentage of 5-ALA dimerization at concentrations ≤ 0.075M (1.25%) and 15°C-50°C. This work integrates quantum chemistry and literature data to generate a model for the degree of decomposition of 5-ALA at different pH, temperature and concentration. It will be useful in applications in medicine, agriculture and other fields.