Unraveling Alcohol Additive Effects on Hypervalent Iodine(III)-Catalyzed Asymmetric Phenolic Dearomatization: Ligand Substitution and Low-Barrier Hydrogen Bonds

Abstract

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