The Role of Amide-π Stacking in Resolving the DMF-Benzene Miscibility Paradox.

The complete miscibility of polar N,N-dimethylformamide (DMF) with nonpolar benzene (PhH) challenges the classic "like-dissolves-like" principle, highlighting the need for a molecular-level understanding. By synergistically combining multiple research methods, we identified amide-π interactions as the pivotal driving force of this miscibility. First-principles calculations revealed a near-parallel DMF-PhH alignment resembling biological motifs. Meanwhile, the interaction energy of this amide-π stacking was intermediate between those of PhH-PhH (π-π stacking) and water-water (hydrogen bonding) systems. Energy decomposition analysis quantitatively indicated the hybrid nature of amide-π interactions arising from a combination of correlation/dispersion and electrostatics forces. We further demonstrated this interaction's structural dominance and generality through statistical analysis of the Cambridge Structural Database. This work not only resolves the DMF-PhH miscibility paradox but also establishes amide-π interactions as a universal solvation mechanism, providing theoretical guidance for the rational solvent screening in synthetic chemistry.