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

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 CF3 center dot 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 CF3 center dot free radical concertedly. In the Cu-I-catalyzed trifluoromethylation of terminal olefins, Cu-I promotes the homo-cleavage of the F3C-I bond in 1 via SET to produce Cull species and CF3 center dot free radical. Then the CF3 center dot free radical attacks the olefin, leading to trifluoromethyl alkyl radical intermediate. Subsequently, the Cull 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 F3C-Cu-III species via oxidative addition, formation of allylic radical intermediate, were considered and excluded. (II) Mode-B, acting as a CF3+ 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 nudeophilic attack at the CF3 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 nudeophilicity determines the reaction mode of regent 1.