<scp>COSMO</scp>‐<scp>RS</scp> prediction, liquid–liquid equilibrium experiment and quantum chemical calculation to separate <i>n</i>‐hexane and <i>n</i>‐propanol azeotropic system with ionic liquids

Abstract BACKGROUND n ‐Hexane and n ‐propanol (NPA) are frequently used for drug synthesis. During the synthesis of fenbufen drug eutectic, n ‐hexane and NPA will form an azeotrope; separation of the azeotrope by conventional distillation techniques is extremely difficult. However, it can be achieved by liquid–liquid extraction. RESULTS In this study, the Conductor‐like Screening Model for Real Solvents (COSMO‐RS) was employed to screen ionic liquids (ILs) for separating the n ‐hexane–NPA azeotrope. The liquid–liquid equilibrium (LLE) data of the ternary n ‐hexane–NPA–IL systems were determined under atmospheric pressure at 303.15 K. The data were correlated using the non‐random two‐liquid model. The root‐mean‐square deviation and binary interaction parameters were acquired, and the parameters were validated using the ‘GMcal_TieLinesLL’ tool of the MATLAB program to meet the Gibbs stability criterion. Besides, quantum chemical calculations were conducted, including interaction energy, electrostatic potential analysis, independent gradient model based on Hirshfeld partition analysis and quantum theory of atoms in the molecule topological analysis. CONCLUSION LLE experiments showed the extraction efficiency of the ILs: Three ILs were identified as promising extractants: 1‐ethyl‐3‐methylimidazolium trifluoroacetate ([C 2 MIM][TFA]), 1‐butyl‐3‐methylimidazolium trifluoroacetate ([C 4 MIM][TFA]) and 1‐hexyl‐3‐methylimidazolium trifluoroacetate ([C 6 MIM][TFA]). Extraction performance follows the order [C 2 MIM][TFA] &gt; [C 4 MIM][TFA] &gt; [C 6 MIM][TFA]. Quantum chemical calculations demonstrated that ILs and NPA are more inclined to form hydrogen bonds. The process simulation was conducted using Aspen Plus V11. © 2025 Society of Chemical Industry (SCI).