Computational Study of the Trifluoromethyl Radical Donor Abilities of CF3 Sources

Organic compounds containing trifluoromethyl (CF3) group(s) are widely prevalent in biochemical and medicinal science. This is mainly due to the fact that the trifluoromethyl group often improves the metabolic stability and lipophilicity of biologically active compounds. The need of efficient methods for the incorporation of this group into target molecules has spurred research to discover new, practical CF3 sources. Among various CF3 sources, the radical trifluoromethylating reagents has provided a strong driving force for the discovery of the novel trifluoromethylation reactions, and contributed enormously to the efficient synthesis of various CF3-containing compounds. Although a wide variety of radical CF3 sources are now available to organic chemists, little attention has been paid to assess their trifluoromethyl radical donor abilities (TRDA). Moreover, the available radical reagents show a very rich and diverse reactivity. The establishment of an extensive scale to quantify their CF3 radical donating abilities should be of great value for both the rational design of novel reagents and the judicious selection of appropriate reagent to explore new radical reactions. Herein, we present a systematic computational study of the homolytic X-CF3 bond dissociation enthalpies of 35 radical trilluoromethylating reagents by using the SMD-M06-2X/[6-311+ +G(2df, 2p)-Def2-QZVPPD]//SMD-M06-2X/[6-31+G(d)-LANL2DZ] method. aiming to provide an energetic guide for estimating their trifluoromethyl radical donor abilities. A comprehensive TIMA scale was constructed, which covers a range from -21.5 to 95.2 kcal.mol(-1). The effects of the frequently used activators including single electron transfer reagents and halogen/chalcogen-bond donors on trifluoromethyl radical donor abilities were investigated. 'Ile results show that single electron transfer is the most efficient way to promote the CF3 radical release. We expect that the results of this study could be highly valuable for the mechanistic understanding and the rational design of novel CF3 sources and new radical trifluoromethylation reactions.