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New reagent could add trifluoromethyl groups to molecules from waste fluoroform

Optimized Lewis acid-base approach promises reduction in cost and waste of fluorinating chemicals

by Stephen K. Ritter
December 19, 2017

A reaction scheme depicts a new borazine-based trifluoromethylating reagent and some of the compounds it enables chemists to make.

University of Michigan chemists have developed a Lewis acid-base pair strategy to prepare and stabilize a versatile new reagent capable of adding trifluoromethyl groups to molecules. The method promises to expand on current synthetic strategies for making fluorinated pharmaceuticals and agrochemicals while lowering costs and reducing chemical waste.

Jacob B. Geri and Nathaniel K. Szymczak conducted a computational study and developed an acid-base affinity scale to help identify hexamethylborazine as the optimal Lewis acid—an electron-pair acceptor—to pair with trifluoromethyl anion as the Lewis base—an electron-pair donor. They carried out the study with the aim of deriving CF3 from fluoroform (CHF3), an industrial waste product and potent greenhouse gas, while also allowing for simple CF3 transfer from the acid-base pair to a range of inorganic and organic electrophilic reagents (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b05408).

Chemists have previously developed acid-base trifluoromethylating reagents, including the widely used trifluoromethyltrimethylsilane (TMSCF3). These reagents are a challenge to use, however, because CF3 is unstable and can decompose or irreversibly react with its Lewis acid partner to limit trifluoromethyl transfer.

The Michigan team found that hexamethylborazine paired with a potassium crown ether counterion provides a Lewis acidity sweet spot for maintaining CF3 stability—the combination allows reactions to take place at room temperature in just a few minutes, and the borazine is recyclable. Geri, Szymczak, and Michael M. Wade Wolfe report the ability to use the new reagent to functionalize carbonyls and imines and carry out nucleophilic aromatic substitutions. They can also prepare commonly used metal trifluoromethyl transfer reagents (Cu, Zn, Pd, Ag, Au) and synthesize commonly used nucleophilic (TMSCF3), radical (KSO2CF3), and electrophilic (iodonium-CF3) trifluoromethylation reagents starting from fluoroform instead of more expensive trifluoromethyl halides (Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201711316).

“Szymczak’s group has developed a very clever and thoughtful approach that exploits a Lewis acid-base combination with broad utility,” says Douglas W. Stephan of the University of Toronto, who specializes in reactive Lewis acid-base pair chemistry. “This has wide-reaching implications, and I expect rapid adoption of this strategy.”

Szymczak thinks the method could be applied to unstable anions other than CF3to promote nucleophilic reactions. Plus, he believes this is the first useful application of borazine as a reagent in any branch of synthetic chemistry. Chemical supplier Sigma-Aldrich is planning to offer hexamethylborazine and the trifluoromethyl reagent soon, he notes. “These results may be a game-changer for the synthetic community because the high cost and waste generation of existing trifluoromethylation reactions have limited progress,” Szymczak says.

“This new approach represents a significant advantage over previously used nucleophilic CF3-transfer reagents,” adds G. K. Surya Prakash of the University of Southern California, who codeveloped TMSCF3 as a trifluoromethylating reagent. Prakash applauds the Michigan team’s computational study to zero in on borazine. But he points out a few limitations to watch for, such as the high mass of the borazine reagent and the ability to easily recycle toxic borazine, which could pose challenges in industrial settings where TMSCF3 is already established. Despite those caveats, Prakash says the work “clearly can be expected to have a broad impact in the future.”


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