Quantum Chemistry based Simulation of Enantioseparation on Cyclodextrin‐ and Polysaccharide‐based Chiral Stationary Phases

We assess the capability of modern quantum chemical methods to simulate enantioseparation on chiral stationary phases (CSPs) in high‐performance liquid chromatography (HPLC) by comparing calculated and experimental elution orders (EEOs). Compared to previous studies, this work utilizes more accurate state‐of‐the‐art density functional theory (DFT) methods combined with automated computational workflows. The proposed approach employs molecular docking, conformer sampling, and DFT refinement for final ensemble‐based association free energy calculations of two diastereomeric complexes. Ten drug‐type molecules were considered on two common CSPs for which various molecular models were investigated. While the association free energies of the strongest binding motifs were rather system‐depended ranging from about −9 kcal/mol to 29 kcal/mol, the differences between the two enantiomers were always only a few kcal/mol, sometimes even below 1 kcal/mol. Despite these small differences, correct determination of EEOs for all tested cyclodextrin‐based CSP systems was achieved. Even for more flexible polysaccharide‐based CSPs, the workflow yielded correct EEO results in 90% of the tested cases provided that a sufficiently large cut‐out of the CSP material consisting of about 150 atoms was considered as model. Due to the latter constraint, the method remains computationally expensive, requiring further research for improving practical application in, e.g., screening studies.