Importance of Conformer Diversity over Quantity in COSMO-RS-Based LLE Predictions: A Case Study

Accurate phase equilibrium prediction is vital for chemical process design, particularly for challenging systems involving complex intermolecular interactions. This study examines how conformer selection and sigma profiles affect COSMO-RS predictions of liquid–liquid equilibria (LLE’s), using the tetrahydrofurfuryl alcohol (THFA)–methyl isobutyl ketone (MIBK)–water system as a case study. THFA’s conformational flexibility and the contrasting polarity of the two phases, make this system highly sensitive to conformer effects. Predictions were performed at two levels of theory: TZVP and TZVPD-FINE. The TZVP calculations failed to reproduce the experimentally observed LLE behavior, whereas the TZVPD-FINE calculations showed better agreement. This contrast arises because TZVP favors the lowest-energy, less-polar conformers, while TZVPD-FINE emphasizes more polar, hydrogen-bonding-capable conformers. Although the TZVPD-FINE prediction with the full conformer set clearly improves upon the TZVP result and reproduces the main experimental trends, it should be noted that the predicted organic-phase composition does not fully meet the agreement criterion adopted in this work, as MPDorg equals 5.27%, slightly above the 5% threshold. The prediction should therefore be regarded as near-threshold rather than fully successful, according to our own definition. This residual deviation may arise from several sources, such as experimental uncertainties in tie-line compositions or uncertainties in the predictions for phase compositions close to the plait point or critical solubility point. Single-conformer predictions showed, for the systems tested, that individual conformers could skew predictions and that only a representative conformer set yields reliable predictions. Comparative predictions for the case study investigated further indicated that predictive accuracy depends more on σ-profile diversity than on the number of conformers used. These findings highlight the importance of the conformer representation in COSMO-RS. For systems governed by subtle changes in interactions between phases of different polarity such as liquid–liquid equilibria, both aspects must be carefully considered to ensure predictive reliability. These insights increase understanding of COSMO-RS and might help toward its correct application in both academic and industrial contexts.