Hydrogen Bonding Phase-Transfer Catalysis with Alkali Metal Fluorides and Beyond

Phase-transfer catalysis (PTC) is one of the most powerful catalytic manifolds for asymmetric synthesis. Chiral cationic or anionic PTC strategies have enabled a variety of transformations, yet studies on the use of insoluble inorganic salts as nucleophiles for the synthesis of enantioenriched molecules have remained elusive. A long-standing challenge is the development of methods for asymmetric carbon-fluorine bond formation from readily available and cost-effective alkali metal fluorides. In this Perspective, we describe how H-bond donors can provide a solution through fluoride binding. We use examples, primarily from our own research, to discuss how hydrogen bonding interactions impact fluoride reactivity and the role of H-bond donors as phase-transfer catalysts to bring solid-phase alkali metal fluorides in solution. These studies led to hydrogen bonding phase-transfer catalysis (HB-PTC), a new concept in PTC, originally crafted for alkali metal fluorides but offering opportunities beyond enantioselective fluorination. Looking ahead, the unlimited options that one can consider to diversify the H-bond donor, the inorganic salt, and the electrophile, herald a new era in phase-transfer catalysis. Whether abundant inorganic salts of lattice energy significantly higher than those studied to date could be considered as nucleophiles, e.g., CaF₂, remains an open question, with solutions that may be found through synergistic PTC catalysis or beyond PTC.