Integrated DFT and Cyclic Voltammetry Approach for Screening Redox-Active Knoevenagel Adducts with Potential...

In this study, a combined quantum-chemical and electrochemical approach was employed to evaluate synthesized Knoevenagel adducts as potential antioxidant candidates. Molecular geometries were optimized at the B3LYP/6-31 + G-(d,p) level, and electronic descriptors, including highest occupied molecular orbital, lowest unoccupied molecular orbital, energy gap, ionization potential (IP), single-electron transfer (SET), and molecular electrostatic potential (MEP) maps, were obtained from single-point calculations at the B3LYP/6-311++G-(2d,2p) level. Analysis of the MEP maps together with the frontier molecular orbitals enabled the identification of electron-rich and electron-deficient regions and helped rationalize the preferred redox-active sites involved in electron-transfer-based antioxidant screening. The theoretical results showed that dopamine, used as the reference compound, exhibited the lowest IP among the analyzed molecules. Among the Knoevenagel adducts, compound 6 showed the most favorable profile, with an IP of 182.92 kcal mol^-1 and a SET value of 4.92 kcal mol^-1. A series of Knoevenagel adducts (1-6) was synthesized by microwave-assisted condensation of cyanoacetic acid with aromatic aldehyde derivatives in the presence of KOH, affording yields of 71-85%. Structural elucidation was performed by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy. For compounds 5 and 6, FTIR spectra confirmed the characteristic CN stretching bands at 2223 and 2221 cm^-1, respectively, as well as CO absorptions at 1687 and 1716 cm^-1; compound 6 additionally showed bands consistent with methoxy substitution. Electrochemical validation was performed by cyclic voltammetry using graphite/epoxy composite electrodes chemically modified with compounds 5 and 6. The 6/GRAPHITE/EPOXY electrode exhibited the highest redox response, with anodic and cathodic peak currents of 59.25 and -40.37 μA, respectively, indicating more efficient electron transfer than the 5/GRAPHITE/EPOXY and unmodified electrodes. Overall, the results demonstrate that the integration of DFT-based screening with cyclic voltammetry is an effective strategy for identifying redox-active Knoevenagel derivatives with potential antioxidant applicability.