PREDIÇÃO TEÓRICA DOS VALORES DE PKA PARA DERIVADOS DE ANILINAS E AMINAS APLICANDO MODELOS CONTÍNUOS DE SOLVATAÇÃO

Abstract

Several methodologies have been extensively studied and used for the theoretical calculation of pKa in simple and complex systems aiming the most diverse applications in science, specially in pharmacology, considering that this is one of the most fundamental physicochemical properties in the development of new drugs. Among the most recent computational methods of pKa prediction, emerge the application of first principles calculations for the species involved in the protons transfer reaction directly in solution, avoiding the necessity of the thermodynamic cycle (TC), the approach is named direct method. In this work the direct method, using DFT and continuum solvation methods, were applied to predict the pKa values for a series of primary, secondary and tertiary amine derivatives, as well as a set of ortho/para substituted anilines and two commercial drugs which have nitrogen functions, paracetamol and sulfadiazine. The selected structures were optimized in the neutral and protonated forms, using DFT with the hybrid functional B3LYP and the set of basic functions 6-31+G(d, p), in aqueous solution applying the SMD solvation model. The substituent and the structure effect on the pKa values were analyzed. The experimental data were compared with the results obtained, to verify the method accuracy. The results obtained for the amine derivatives showed deviations less than two pKa units, the errors for the anilines derivatives and the drug molecules were around 3-5 pKa units in compare to the experimental values. These results suggest that the combination of direct method with the theory level B3LYP/6-31+G(d,p):SMD was not able to predict pKa with acceptable accuracy for complexes molecules. However, the method was efficient to predict the pKa for amines molecules and in both systems, it was possible to make a direct relation of the pKa values and the substituents effect on the property.