Mechanistic Insights Into Ultrasound-Assisted Plant Stilbenes Sustainable Extraction Using Hydrophilic NADES: A Case Study of Cajaninstilbene Acid With Integrated NMR, COSMO-RS, and MD Simulation

Stilbenes are bioactive phytochemicals with notable health benefits, yet their extraction is hindered by hydrophobicity and reliance on toxic solvents. This study introduces a green, sustainable approach for stilbene extraction using hydrophilic natural deep eutectic solvents (NADES), with cajaninstilbene acid (CSA) from pigeon pea ( Cajanus cajan ) as the model compound. After screening, the optimal NADES and ultrasound-assisted extraction conditions were identified, achieving a predicted CSA yield of 0.832 mg/g. The method demonstrated excellent reusability and sustainability. Spectroscopic analyses (ATR-FTIR, 1 H NMR, 1 3 C NMR, 2D NOESY), COSMO-RS, and molecular dynamics (MD) simulations revealed that NADES-4 forms a hydrogen-bonded supramolecular structure involving betaine, glycerol, and water. MD simulations further clarified the thermodynamics and synergistic non-covalent interactions driving CSA solubilization. These findings provide mechanistic insights into NADES-based stilbene extraction and support the development of eco-friendly technologies for plant resource utilization.