ERETIC2-Assisted NMR Determination of Acid Dissociation Constants (pKa) for Some Novel Coumarin-Substituted Benzimidazolium Salts.

Abstract

Coumarin and benzimidazole are widely preferred pharmacophores in drug design due to their broad spectrum of biological activities, and hybrid molecules formed by the combination of these two structures are thought to possess improved pharmacokinetic and pharmacodynamic properties. In this study, four coumarin-substituted benzimidazolium salts were synthesized, three of which are reported here for the first time. Structural characterization was performed using NMR spectroscopy, FTIR, and elemental analysis. To assess their acid-base properties, the pK_a values of all compounds were determined using three complementary approaches: a signal intensity-based NMR method (pK_aNMRI), classical potentiometric titration (pK_aPTS), and the ERETIC2-assisted quantitative NMR method (pK_aNMRE), which is applied for the first time in the literature for this purpose. Comparison of the obtained pK_a values showed that the pK_aNMRE method yielded values in the range of 10.7-11.4, the pK_aNMRI method provided values between 10.0 and 11.2, and the pK_aPTS method resulted in values ranging from 12.1 to 12.8. All compounds displayed intermediate acidity, attributed to the formation of resonance-stabilized anionic species upon deprotonation by tetrabutylammonium hydroxide. The consistency between the acidity rankings obtained by ERETIC2 and potentiometric titration highlights the robustness of combining advanced NMR-based quantification with classical techniques for reliable and comparative pK_a determination.