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

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.