Frustrated radical pairs facilitate C–H activation

A radical new method has just been added to the C–H activation toolbox. In a new Nature paper, Song Lin and his group at Cornell University describe how frustrated radical pairs can make a handy team for activating C–H bonds on saturated carbon atoms (2023, DOI: 10.1038/s41586-023-06131-3). The reaction takes only half an hour, uses commercially available reagents, and opens up multiple functionalization options. “The simplicity of the system is really cool,” says Lin.

The researchers matched up hexamethyldisilazide (HMDS-), which can be oxidized to make a nitrogen-centered radical, and the well-known oxidant and radical trap 2,2,6,6-tetramethyl-1-oxo-piperidinium (TEMPO+). The two radicals are too bulky to annihilate each other—hence the frustrated moniker—so they turn their pent-up reactivity on other molecules.

Lin says his team initially set out simply to see what kinds of reactions the radical pair could accomplish, and they were delighted to find it worked for C–H activation.

The HMDS radical snatches a hydrogen atom from the molecule to be functionalized. That molecule then becomes a carbon-centered radical and gets trapped by the TEMPO radical. The resulting adduct has relatively weak C–O and N–O bonds, which opens up numerous possibilities for installing new functional groups.

The researchers found that it’s possible to influence which hydrogen gets plucked off of the moleculeby altering the size of the H-atom acceptor. A streamlined tert-butoxide radical can reach into crannies and pluck out tertiary hydrogens, while bulked-up hexaphenyldisilazide goes for less thermodynamically favored but easy-to-reach primary and secondary hydrogens.

In an email, Rebecca Melen of Cardiff University called the method “an elegant way of achieving selective C–H functionalization without using transition-metal catalysts.” She praised the study for advancing scientists’ understanding of radical species in C–H activation.

Lin says the next steps include further investigating the relationship between H-atom acceptor choice and selectivity and exploring other radical traps that can provide different functionalization options.