Quantum-Chemical Calculation-Based Entrainer Screening and Mechanistic Elucidation for Different Separation Sequences

Current computer-aided molecular design for entrainer screening often ignores microscopic mechanisms. This work integrates intermolecular interaction energy with process economics for systematic screening and mechanistic analysis, demonstrated on methanol/methyl propionate (MeOH/MP). Separation sequences are classified as MeOH-first or MP-first based on interaction strengths. Interaction energy differences ranked [BMIM][NTf2] best for MeOH-first and [MMIM][DMP] best for MP-first. Total annual cost (TAC) comparison confirmed [MMIM][DMP] as the optimal entrainer (7.376 × 105 $·Y1–). Mechanistic analysis shows entrainers with lone pairs disrupt the azeotrope via hydrogen bonding; MP-first involves electrostatic and dispersion interactions, while MeOH-first relies mainly on dispersion. Validation against isovolatility curves and σ-profiles shows agreement with TAC and isovolatility, whereas σ-profiles fail to rank entrainers correctly.