Molecular Insights into Two-Phase Systems of Water and Deep Eutectic Solvents Based on Menthol and Fatty Acids: A Combined COSMO-RS and Molecular Dynamics Study

The limited understanding of how fatty acid alkyl chain length influences the interfacial behavior and stability of menthol-based hydrophobic deep eutectic solvents (HDESs) in aqueous environments hinders their rational design for biphasic applications. This study integrates molecular dynamics (MD) simulations and COSMO-RS modeling to investigate the effect of fatty acid alkyl chain length (valeric acid, C5; enanthic acid, C7; pelargonic acid, C9) on the structural, interfacial, and dynamic properties of menthol-based hydrophobic deep eutectic solvents (HDESs) in aqueous environments. Our integrated approach reveals that increased hydrophobicity and steric hindrance of longer-chain fatty acids are the key mechanisms driving enhanced phase stability. COSMO-RS predicts increasing log K ow and decreasing water selectivity with chain length. MD validates these predictions through minimal water penetration, shorter FA–water hydrogen bond lifetimes (VAL: 1.9 ps; PEL: 0.8 ps), and more negative excess volume for MPEL. The stability factors confirm partial miscibility with stability order PEL > ENA > VAL. FA–water interaction energies become less negative with chain length, while menthol–PEL interactions strengthen upon hydration. Diffusion coefficients decrease with chain length, and distribution coefficients (D FAs /D water ) decline markedly for MPEL, confirming reduced mobility. The strong concordance between MD and COSMO-RS establishes a validated mechanistic framework linking alkyl chain length to HDES stability, enabling rational design of task-specific hydrophobic DESs for biphasic extraction, contaminant removal, and pharmaceutical processing.