Persistent Menthol Hydrogen-Bonding Networks Govern the Structure and Hydration of a Hydrophobic Natural Deep Eutectic Solvent: Insights from NMR and Molecular Dynamics Simulations of the Camphor–Menthol System

Abstract Natural deep eutectic solvents (NADES) based on monoterpenoids have emerged as promising hydrophobic, biodegradable media. Despite their widespread use, the molecular interactions governing the formation and hydration behavior of camphor–menthol NADES remain insufficiently understood. Here, we combine 1H NMR spectroscopy and molecular dynamics (MD) simulations to elucidate the supramolecular structure of a camphor:menthol (1:1) eutectic liquid and its aqueous mixtures. NMR results reveal a persistent hydrogen-bonding network dominated by menthol–menthol interactions, consistent with slow exchange on the NMR time scale. MD simulations confirm that menthol–menthol self-aggregation provides the primary stabilization, with weaker camphor–menthol interactions. Upon adding water, the menthol OH resonance shifts and loses splitting, but water retains a distinct resonance, indicating minimal proton exchange and a reduced extent of water–water hydrogen bonding. Hydration produces microheterogeneous structures consistent with the presence of small, weakly hydrogen-bonded water-rich clusters rather than uniformly solvating the NADES. At higher water loadings, macroscopic phase separation occurs while NADES domains retain structural integrity. These results establish a unified molecular picture for hydrophobic NADES and provide design principles for tailoring their hydration behavior.