The Solvation Shell of Small Solutes in Aqueous–Organic Solvent Mixtures and Its Implications for Reversed-Phase Liquid Chromatography

Reversed-phase liquid chromatography (RPLC) operates with water–organic solvent (W–OS) mobile phases where preferential solvation (PS) of solutes is likely. To investigate the relevance of the solute solvation shell in the mobile phase for RPLC retention, we combine data from molecular dynamics simulations of small, neutral solutes (six analytes and two dead time markers) in W–methanol (MeOH) and W–acetonitrile (ACN) mixtures with corresponding retention data obtained on an RPLC column over a wide range of W/OS ratios. Data derived from Kirkwood–Buff integrals show PS by the OS for analytes vs low or negative PS for dead time markers. W–ACN mixtures generate a higher amount of PS than W–MeOH mixtures, which contributes to the higher eluent strength of ACN in RPLC. Difference spatial distribution functions reveal anisotropic solvation shells with OS excess at hydrocarbon elements and W excess at functional groups, predicting that retention by the hydrophobic stationary phase is favored by hydrocarbon elements and limited by functional groups. Analysis of solute–solvent hydrogen bonds pinpoints the hydrogen-bond requirements toward W as the retention-limiting factor. The relation between the solute solvation shell and retention confirms the importance of W–OS and solute–W hydrogen bonding for RPLC retention