Computational Insights into Nucleophilic Copper-Catalyzed Trifluoromethylation of Aryl Halides
Departament de Química Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain
Institut de Recerca de Química Teòrica i Computacional, Universitat de Barcelona, Diagonal 645, E-08028 Barcelona, Spain
ACS Catal., 2014, 4 (12), pp 4389–4397
DOI: 10.1021/cs500872m
Publication Date (Web): October 28, 2014
Copyright © 2014 American Chemical Society
*E-mail: jesus.jover@qi.ub.es.
Abstract
Nucleophilic copper-catalyzed trifluoromethylation of aryl halides is one of the most challenging reactions leading to fluorinated products.
Although aryl iodides can be easily transformed, catalytic reactions with aryl bromides and chlorides are much more difficult; however, 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. (Chem. Commun. 2009, (14), 1909–1911), 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 a significant impact on the reaction outcome that would allow the trifluoromethylation of the more challenging substrates.
The slow addition of trifluoromethyltrimethylsilane (CF3SiEt3) into the reaction mixture also seems to be a good strategy to catalytically functionalize aryl iodides and even activated bromides and chlorides.
Supporting Information
The following file is available free of charge on the ACS Publications website at DOI: 10.1021/cs500872m.
- Includes all computed free energies and optimized structures, along with alternative reaction pathways (PDF).
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