Acidity Determination by Spectroscopic and Modeling Methods in Monohydroxy- and Dihydroxy-Substituted Coumarins.

Abstract

We report the pKa values for 15 mono- and disubstituted hydroxycoumarins determined using UV-vis absorbance spectroscopy and computational methods. Six of these values, including the pKa of 5-hydroxycoumarin, are reported for the first time. While the primary focus is on the effects of hydroxyl substitution on the benzene ring, we also examine how a 4-methyl substituent may influence acidity in a subset of four coumarin pairs. The experimental results are supported by two kinds of density functional theory calculations. Time-dependent DFT (TD-DFT) models of the UV-vis spectra show strong agreement with experimental observations of 30 species and facilitate spectral interpretation. In addition, pKa values are predicted through a thermodynamic-cycle calculation that combines gas-phase Gibbs free energies with solvation free energies. This computational method accurately reproduces pKa values for a training set (mean absolute error, MAE = 0.37) and yields predictions for the full experimental data set (MAE = 0.65). Together, the experimental and computational results provide a comprehensive view of the structure-acidity relationships in a diverse series of simple hydroxycoumarins.