Computational Insights into Nucleophilic Copper-Catalyzed Trifluoromethylation of Aryl Halides

Abstract

Nucleophilic copper-catalyzed trifluoromethylation of aryl halides is one of the most challenging reactions leading to fluorinated products. While aryl iodides can be easily transformed, catalytic reactions with aryl bromides and chlorides are much more difficult; although some stoichiometric reactions using these substrates have been published. In this report the mechanism of the copper-catalyzed trifluoromethylation of aryl halides, based on the reaction developed by Amii et al. in 2009, has been explored with DFT calculations. The computed catalytic cycles allow the interpretation of the experimental observations; electron-poor substrates produce faster reactions because their oxidative addition barrier, the rate-limiting step of the reaction, is lower. The proposed mechanism for the trifluoromethylation reaction also explains why the reactivity greatly decreases for aryl bromide and chloride substrates. The results obtained have been employed to propose alternative strategies and catalyst modifications that could improve the trifluoromethylation reaction studied. These modifications, which have been evaluated computationally, indicate that varying the nucleophilic trifluoromethylating agent has significant impact on the reaction outcome that would allow the trifluoromethylation of the more challenging substrates. The slow addition of trifluoromethyltrimethylsilane (CF 3 SiEt 3 ) into the reaction mixture also seems to be a good strategy to catalytically functionalize aryl iodides and even activated bromides and chlorides.

Copper-Mediated C–X Functionalization of Aryl Halides

“…A significant advancement has been made in understanding the mechanism of copper-catalyzed trifluoromethylation of aryl halides. − In this direction, Jover utilized DFT studies to rationalize the mechanism of nucleophilic trifluoromethylation of the aryl halide developed by Amii and co-workers (Scheme ). The initial step in this mechanism is the formation of neutral (phen)­CuCF 3 ( 5 ) by the reaction of (phen)­CuI ( 5′ ) and KCF 3 derived from CF 3 SiEt 3 and KF. Notably, after the formation of 5 , the mechanism branched into two pathways.…”

A radical approach to the copper oxidative addition problem: Trifluoromethylation of bromoarenes

“…Such diminished catalytic reactivity in comparison to other well-known coupling reactions is ascribed to the C sp 2 –CF 3 reductive elimination step, a well-documented challenge for both palladium and nickel catalysts (17, 19, 20). In contrast, copper complexes have been shown to generally undergo facile C sp 2 –CF 3 reductive elimination (21, 22). This realization has propelled extensive research efforts to develop copper-catalyzed trifluoromethylation protocols with haloarenes.…”

A Mechanistic Insight into the Cu(II)‐Catalyzed C–N and C–O Coupling Reaction of Arylglyoxylic Acids with Isatins; A DFT Investigation

“…To check the reliability of the functional used throughout the paper we carried out single-point computations (including solvent effects) on the M06 optimized geometries using other functionals recommended to treat reactivity problems involving transition metals. [26][27][28][29] The same basis set (6-31+G(d) + LANL2DZ for copper) was employed. The results are reported in Appendix II.…”