Fluorinated azides click to make triazoles

With the help of new fluorinating reagents, a team led by Zsófia E. Blastik and Petr Beier of the Czech Academy of Sciences has devised a versatile fluorinated version of copper-catalyzed click chemistry. The approach overcomes some previous difficulties with preparing suitable fluorinated reagents for click reactions and opens the door to broader use of click chemistry, which has become invaluable to chemical biology and materials science.

The new chemistry hinges on the ability to make azidoperfluoroalkanes. Azidotrifluoromethane (CF₃N₃) has been known for some time, but its best reported synthesis starting from CF₃I requires cumbersome handling of toxic and corrosive CF₃NO, N₂H₄, and Cl₂ gases—an approach that has limited CF₃N₃’s applications. Beier’s group alternatively attempted using electrophilic CF₃I with sodium azide (NaN₃) as a nucleophile, but the reaction didn’t work. Instead, the team found that CF₃N₃ and its previously unknown longer chain analogs can be prepared more conveniently from CF₃Si(CH₃)₃ and related nucleophiles and sulfonyl azide electrophiles. In effect, the researchers flipped the polarity of the reaction’s constituents (Angew. Chem. Int. Ed. 2016, DOI: 10.1002/anie.201609715).

The reported azidoperfluoroalkanes undergo copper-catalyzed azide-alkyne cycloadditions, also known as click reactions, leading to N-perfluoroalkyl triazoles as underexplored building blocks, Beier says. “In fact, azidoperfluoroalkanes are more reactive in the click reaction with alkynes than nonfluorinated alkyl azides.”

“A reminder emerging out of this paper by Beier and colleagues is that, if you want to build a bond by a polar mechanism, there are always two options,” says Andrei K. Yudin of the University of Toronto, who focuses on the chemistry of heterocyclic compounds. “It is a good idea to reverse the polarity of components if one path is problematic. As a result, they have developed an efficient entry into azidoperfluoro­alkanes.”

CORRECTION: On Jan. 9, 2017, this story was updated to correct one of the starting reagents in the reaction scheme. It should be C₈F₁₇Si(CH₃)₃ rather than C₈H₁₇Si(CH_{3)3 as originally stated.}