Harken back to your early days in organic chemistry class and you’ll recall learning how SN1 and SN2 substitution reactions transform carbon–halogen bonds. Chemists have now figured out a way to use that single C–X substitution handle to make 1,2-disubstituted products. The reaction creates molecular complexity quickly and constructs scaffolds not previously imagined from alkyl halides (Science 2026, DOI: 10.1126/science.aef0766).
The reaction discovery was serendipitous, says University at Buffalo’s Patricia Z. Musacchio, who led the research effort with Binghamton University’s Jennifer S. Hirschi. The origins of the discovery came when Mrinmoy Das, a postdoctoral researcher in Musacchio’s lab, found an unexpected difunctionalized product while running a photoredox-triggered hydrogen-atom transfer reaction.
“At first I wasn’t very excited about it,” Musacchio says. She thought it was just a riff on some chemistry they’d already published. But Das went back to the lab and proved to her that the disubstituted product was coming from one central mechanistic intermediate, instead of being produced by two distinct reactions occurring back-to-back in the reaction vial. This piqued Musacchio’s interest, and she reached out to Hirschi to help figure out the mechanism.
The simplest explanation was that the reaction was a substitution reaction going through a halonium intermediate. “But none of those were working on a computational surface,” Hirschi says.
Instead, computational studies from Hirschi’s group indicate that a concerted reaction takes place. When the hydrogen-atom transfer occurs, the homobenzylic halide undergoes heterolytic cleavage to generate a styrene radical cation, in what’s called a spin-center shift process. A nucleophile can then attack the cation portion, leaving behind a benzylic radical that gets oxidized to a benzylic carbocation, which then reacts with another nucleophile.
“I think this is just a really cool way to redefine how people are using alkyl halides in synthesis.”
The cosolvent 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) plays a key role in pulling the halide off. Organic chemists talk about HFIP having a sort of magical quality, Musacchio says. “You just throw it in, and you get something very different from the standard sweep of solvents.”
If the chemists use certain reaction partners, they can isolate benzylic bromide and chloride compounds where the halide has shuttled from the homobenzylic position to the benzylic position.
Zachary K. Wickens, a synthetic organic chemist at the University of Wisconsin–Madison, says in an email, “It’s rare that we find a way to take a classic reaction like substitution of an alkyl halide and totally reinvent it. But that’s exactly what the authors report here.”
Wickens points out that substitution of an alkyl halide is typically a straightforward functional group interconversion. But Musacchio and Hirschi’s work shows a way to shuttle the halide over by a carbon rather than displacing it from the molecule. “This gives us super versatile building blocks since the halide product can then be substituted by a distinct second nucleophile,” he says.
Bernd Giese, an expert in radical reactions at the University of Fribourg, says that the formation of a styrene radical cation by hydrogen-atom transfer is new but also limits the reaction to homobenzylic halides. But, he says, this reaction could be further developed to expand the substrate scope.
Musacchio and Hirschi say that’s one area they’re working on now. The current work creates “fertile ground for developing a ton more transformations,” Musacchio says. “I think this is just a really cool way to redefine how people are using alkyl halides in synthesis. It’s not just for substitution chemistry.”
