General Reaction Mode of Hypervalent Iodine Trifluoromethylation Reagent: A Density Functional Theory Study

Abstract

The mechanisms of trifluoromethylation with hypervalent iodine trifluoromethylation reagent (Togni’s reagent 1 ) have been comprehensively studied by density functional theory (DFT) calculations. The results show that there are two general reaction modes for reagent 1: (I) Mode-A, acting as a CF 3 • free radical source . When one-electron reductants are available in the reaction system, such as Cu I, Fe II, TEMPONa, or electron-rich lithium enolate, 1 will be reduced via single-electron transfer (SET) and give out CF 3 • free radical concertedly. In the Cu I -catalyzed trifluoromethylation of terminal olefins, Cu I promotes the homo -cleavage of the F 3 C–I bond in 1 via SET to produce Cu II species and CF 3 • free radical. Then the CF 3 • free radical attacks the olefin, leading to trifluoromethyl alkyl radical intermediate. Subsequently, the Cu II species act as a one-electron oxidant oxidizing the alkyl radical to carbocation intermediate, and the following deprotonation leads to the final product. Other mechanisms, such as formation of F 3 C–Cu III species via oxidative addition, formation of allylic radical intermediate, were considered and excluded. (II) Mode-B, acting as a CF 3 + cation source . 1 can be activated by a Lewis acid such as Zn II and becomes more inclined to undergo an S N 2 type nucleophilic attack at the CF 3 group by nucleophiles (pentanol in this work). For substrates studied in this paper, such as the lithium enolate, pentanol, and sodium 2,4,6-trimethylphenolate, the competition between their reducibility and nucleophilicity determines the reaction mode of regent 1 .