Ground-State pKa and Physicochemical Characterization of Resveratrone as a pH-Responsive Organic Fluorophore

Abstract

Elucidating acid dissociation constants (pKa) is essential for organic molecules, particularly for tentative drug candidates and biocompatible fluorescent probes, as pKa values determine the predominant ionic species and fluorescence properties in physiological environments. Consequently, accurate pKa determination is critical for designing new drug candidates and biosensors. In this study, we determined the ground-state pKa values of resveratrone, a photoproduct characterized by high fluorescence quantum yield, biocompatibility, and photodynamic therapy capability. To determine these unknown pKa values, we employed a dual approach combining experimental and computational methods. pH-dependent spectroscopy data acquired over a pH range of 5.87–12.05 were analyzed by singular value decomposition, which simultaneously deconvolutes all contributing spectral species and correctly accounts for the overlapping deprotonation equilibria inherent to a diprotic system. This approach yielded macroscopic pKa values of 7.81 (pKa1) and 10.97 (pKa2). These experimental values were validated through density functional theory calculations employing quantitative structure-property relationships and benchmarked against structurally analogous compounds. Notably, the proximity of pKa1 to physiological pH establishes resveratrone as an ideal candidate for pH-responsive applications, as it undergoes ionization state transitions accompanied by distinct spectral changes in cellular environments. The determined pKa values establish fundamental physicochemical properties that enable rational design of resveratrone-based fluorescent probes for pH sensing and pH-responsive drug delivery systems. This work provides an essential foundation for translating resveratrone from a photophysical entity into a functional biomedical tool.