Establishing Cation and Radical Donor Ability Scales of Electrophilic F, CF3, and SCF3 Transfer Reagents

Because of their unique biological, physical, and chemical properties, organofluorine compounds play an increasingly important role in numerous areas of chemistry and everyday life. However, although fluorine is the most abundant halogen in the earth's crust and ranks 13th in abundance among all elements, naturally occurring organofluorine compounds are rare. Consequently, there is a growing demand for the development of safe and efficient reagents and selective synthetic methodologies for the introduction of fluorine or fluorine-containing groups into organic compounds. A wide variety of shelf-stable electrophilic fluorinating and fluoroalkylating reagents have been developed in the past decades. Some of them have also been shown to act as radical sources. These versatile reagents have promoted revolutionary advances in synthetic fluorine chemistry. These developments of novel reagents and the choice of suitable reagents for new reactions have relied largely on the traditional trial-and-error approach because (i) structure-reactivity relationships and mechanisms of reactions of these reagents are sparse and (ii) the rules that govern the synthesis of non-fluorinated analogues cannot necessarily be transposed to fluorinated compounds ( Cahard , D. ; et al. Chem. Soc. Rev. 2014 , 43 , 135 ), since organic fluorine compounds often exhibit unusual properties. Over the past several years, our studies have aimed at establishing comprehensive cation and radical donor scales of electrophilic F, CF3, and SCF3 transfer reagents. We have also developed detailed structure-reactivity relationships. We used density functional theory calculations to systematically investigate the energies required to heterolytically cleave the Y-F/CF3/SCF3 bonds to donate electrophilic F/CF3/SCF3 groups. We found that these energies can be used as convenient indicators of the relative electrophilic fluorinating/trifluoromethylating/trifluoromethylthiolating strengths of these reagents. We have constructed the first comprehensive cation donor scales for electrophilic F, CF3, and SCF3 transfer reagents. In collaboration with Mayr group, we experimentally determined the electrophilicity parameters of SCF3 transfer reagents and demonstrated the importance of intrinsic barriers for predicting their kinetic reactivity. The recognition of the novel application of a few traditional electrophilic reagents as radical sources prompted us further to construct comprehensive radical donor scales of electrophilic F, CF3, and SCF3 transfer reagents. We identified a series of potential new radical F, CF3, and SCF3 donors. Single electron transfer was found to exhibit a substantial effect on activation of the Y-CF3/SCF3 bonds, significantly facilitating the release of CF3/SCF3 radicals. This Account summarizes computational and experimental accomplishments from our group and others to establish the missing links between structure and reactivity for these reagents. Our results pave the way toward the rational optimization, design, and prediction of novel electrophilic fluorinating and fluoroalkylating reagents and new reactions.