Degradation Mechanisms of 4,7-Dihydroxycoumarin Derivatives in Advanced Oxidation Processes: Experimental and Kinetic DFT Study

Abstract

Coumarins represent a broad class of compounds with pronounced pharmacological properties and therapeutic potential. The pursuit of the commercialization of these compounds requires the establishment of controlled and highly efficient degradation processes, such as advanced oxidation processes (AOPs). Application of this methodology necessitates a comprehensive understanding of the degradation mechanisms of these compounds. For this reason, possible reaction routes between HO^• and recently synthesized aminophenol 4,7-dihydroxycoumarin derivatives, as model systems, were examined using electron paramagnetic resonance (EPR) spectroscopy and a quantum mechanical approach (a QM-ORSA methodology) based on density functional theory (DFT). The EPR results indicated that all compounds had significantly reduced amounts of HO^• radicals present in the reaction system under physiological conditions. The kinetic DFT study showed that all investigated compounds reacted with HO^• via HAT/PCET and SPLET mechanisms. The estimated overall rate constants (k_overall) correlated with the EPR results satisfactorily. Unlike HO^• radicals, the newly formed radicals did not show (or showed negligible) activity towards biomolecule models representing biological targets. Inactivation of the formed radical species through the synergistic action of O₂/NO_x or the subsequent reaction with HO^• was thermodynamically favored. The ecotoxicity assessment of the starting compounds and oxidation products, formed in multistage reactions with O₂/NO_x and HO^•, indicated that the formed products showed lower acute and chronic toxicity effects on aquatic organisms than the starting compounds, which is a prerequisite for the application of AOPs procedures in the degradation of compounds.

Keywords: 4,7-dihydroxycoumarin; AOPs; DFT; EPR; QM−ORSA; hydroxyl radical; radical scavenging.

Figure 1

Structures of previously synthesized [21] aminophenol derivatives of 4,7−dihydroxycoumarin.

Figure 2

Structures of investigated molecular targets—constituents of important molecules: phospholipid bilayer, proteins, and nucleic acids.

Figure 3

The experimental EPR spectra of DEPMPO−HO^• in the presence (red line) and absence (black line) of the compounds (a) A₁–RH, (b) A₂–RH, and (c) A₃–RH.

Figure 4

Deprotonation process, estimated pK_a values, and molar fractions (f) of acid–base species of newly synthesized aminophenol derivatives of 4,7−dihydroxycoumarin (A₁RH to A₃RH) at physiological pH = 7.4.

Figure 5

Optimized geometries of investigated compounds in water at M06-2X/6-311++G(d,p) level of theory with carbon atom numbering scheme.

Figure 6

Optimized transition state geometries for radical adduct formation for A₂–RH and HO^• in water at M06-2X/6−311++G(d,p) level of theory.

Figure 7

Optimized geometries of selected radicals/radical cations of biomolecular target compounds in water at M06-2X/6-311++G(d,p) level of theory.

Figure 8

The proposed mechanism for the reaction between the formed radical species: A_n–R^• and O₂/NO (Ia, IIa, IIIa, IVa) and A_n–R^• and HO^• (Ib, IIb).

Figure 9

Optimized geometries of neutral final products P2 (top) and P4 (bottom) in water at M06−2X/6−311++G(d,p) level of theory.