Unraveling Alcohol\nAdditive Effects on Hypervalent\nIodine(III)-Catalyzed Asymmetric Phenolic Dearomatization: Ligand\nSubstitution and Low-Barrier Hydrogen Bonds

Despite the widespread use of hexafluoropropanol (HFIP)\nas a “magic”\nsolvent or additive in organic synthesis, its fundamental mechanisms\nlag far behind. This study presents mechanistic insights into the\npuzzling alcohol additive effects observed in Ishihara’s conformationally\nflexible C2-symmetric iodoarene-catalyzed asymmetric phenolic dearomatization\nthrough density functional theory calculations. The results reveal\nthat due to the “booster effect” of fluorinated alcohols,\nHFIP assembles a trimeric hydrogen bond cluster that displaces a ligand\nfrom the active iodine(III) catalyst and forms a low-barrier hydrogen\nbond with the substrate, which significantly enhances the oxidizing\npower of the iodine(III) center, thus facilitating the dearomatization\nof electron-deficient phenols. Conversely, methanol is found to promote\nthe dearomatization of electron-rich phenols via a formally similar\nyet distinct mechanism, thus highlighting the unique role of HFIP\nas an additive. The insights gained from this investigation advance\nour molecular-level understanding of the synergistic interactions\nbetween catalysts and additives, potentially guiding the design of\ncatalytic systems that exploit these effects for broader applications.