Two-in-one reagent combines fluoroalkylation with being click ready

A new bifunctional reagent allows chemists to install a fluoroalkyl group while simultaneously attaching an azide click handle.¹

Click chemistry is a powerful and efficient approach to preparing complex molecules through selective and high yielding reactions that work with many different types of substrates. The classic version combines an azide and an alkyne. However, before chemists can perform such reactions, the molecules they want to join must first have the appropriate functional groups.

Now, a team led by Petr Beier at the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences has designed a bifunctional reagent that installs an azide-containing fluoroalkyl fragment onto a broad range of molecules – including arenes, heteroarenes, thiols and alkenes – leaving them ready for further functionalisation through click chemistry. The fluoroalkyl group offers the additional benefit of potentially improving properties such as metabolic stability, bioavailability and membrane permeability in bioactive compounds.

The reagent, sodium 2-azido-1,1,2,2-tetrafluoroethanesulfinate, can be prepared in a single step from three inexpensive feedstocks: tetrafluoroethylene, sodium azide and sulfur dioxide.

‘We wanted the reagent to combine a free-radical precursor, enabling radical addition reactions, with an azido group that could subsequently be used for click chemistry,’ explains Beier.

In 2013, Phil Baran’s group at Scripps Research in La Jolla, California, US, reported a bifunctional reagent for attaching azidoalkyl chains onto heteroaromatics so that they could then be attached to monoclonal antibodies through a click reaction.² However, that reagent was more complex to prepare. Beier says his team’s reagent ‘combines the two functionalities in a more readily accessible structure’.

As a proof of concept, Beier’s team used their reagent to attach a coumarin-based fluorescent probe to the monoclonal antibody trastuzumab, which is used to treat breast and stomach cancers. Beier envisions wide applications in medicinal chemistry for their new reagent: ‘We would like to explore the use of our reagent for peptide or DNA derivatisation, where it could be used to introduce a range of functional modifications’.

‘We would like to develop conditions, or modify the reagent itself, so that the free radical could be generated using visible light without the need of external oxidant, which can lead to oxidative stress of biological systems. This could make the chemistry even more attractive in applications in life sciences,’ says Bier.

The group’s research highlights the important role that bifunctional reagents will likely play in the future of synthetic chemistry. As Beier explains, ‘bifunctional and multifunctional reagents are increasingly being used not only in synthetic chemistry, but also in material science, biochemistry and the life sciences’.

For David O’Hagan, an organofluorine expert at the University of St Andrews, UK, the connector-like function of the dual ended reagent ‘is rare for a single reagent’. He says ‘it should inspire others to broaden the concept’.