A chiral electrochemical sensor for detecting the enantiomeric ratio of mandelic acid and studying the enantioselective mechanism

The precise determination of enantiomeric purity for mandelic acid ( D/L -MA), a chiral drug precursor, is crucial for the synthesis efficiency and efficacy of related chiral pharmaceuticals. High-performance liquid chromatography (HPLC) currently serves as a mainstream method for enantiomeric purity analysis, yet it suffers from some limitations, such as complicated sample pretreatment, long analysis cycles, and dependency on specialized equipment and operators. In this study, an electrochemical detection platform based on L -cysteine-stabilized gold nanoprobes was constructed, enabling effective analysis of MA enantiomer ratios. The sensor showed good selectivity for MA over its analogs. It also exhibited favorable enantioselectivity for D/L -MA, with a selectivity coefficient ( K D − MA / L − MA ) of 4.3. The limit of detection (LOD) for D -MA was determined to be 0.023 μM. Furthermore, this method showed good quantitative precision for real enantiomer mixtures at different ratio; the relative error is less than 5.4 % compared to reference measurements by HPLC. Density functional theory (DFT) calculations further reveal that the binding energy difference between L -MA and D -MA with the sensing interface reaches 34.9 kcal/mol (−7.3 kcal/mol vs. −42.2 kcal/mol). This stereospecific interaction regulates interfacial electron transfer kinetics to achieve enantiomeric discrimination. This study provides an electrochemical strategy integrating experimental and theoretical analyses for the purity assessment of chiral drug precursors, demonstrating the application potential in chiral drug synthesis and pharmaceutical quality control.