Julian West and his team at Rice University have developed a method for attaching electron-rich alkyl groups to electron-rich double bonds using, effectively, a polarity bait and switch (Nat. Catal. 2026, DOI: 10.1038/s41929-026-01600-0). In keeping with the West group’s commitment to accessible and green chemistry, the reaction relies on inexpensive reagents and commercially available acid precursors.
West calls the reaction “a culmination of everything we learned” since the group began working on iron-and-sulfur photocatalysis. “The team was led toward this project basically by every discovery that we made.”
Julian West and his team used their new hydroalkylation method to shorten the synthesis of a G protein coupled receptor agonist (right) from 8 steps to just 3.
In 2022 the team published a method for removing carboxyl groups from molecules. The natural extension of that work was to react the radical formed during the decarboxylation with an alkene to forge a new carbon-carbon linkage. But the electron-rich nature of carbon-carbon double bonds meant that it was easiest to start with carboxylic acid pieces bearing electron-withdrawing groups such as fluorine.
All the while, West says, he and his team contemplated how they might expand the chemistry to less-electron-deficient alkyl radicals.
The deceptively simple solution to the problem was to use malonic acids, which have two carboxyl groups. Removing one of them gives a radical intermediate with an electron-withdrawing carboxyl group, which can be deleted after it’s fulfilled its purpose of giving the radical the correct polarity to react with the alkene.
“Electron-rich radicals don’t really like to react with electron-rich alkenes, and he’s figured out a way to essentially trick the system,” says Jon A. Tunge of the University of Kansas, who was not involved in the work. Tunge called the new reaction “a clever strategy” that advances synthetic chemistry both conceptually and practically.
West says optimizing the reaction was a challenge because it’s a complex catalytic cycle that has to happen twice—once for the coupling and again for the final decarboxylation. “Finding out the conditions to get both of those steps to not only happen but to happen efficiently took a lot of time,” he says.
In some cases, the researchers had to pause the reaction to wash out excess propionic acid side products to get a good yield, West says. But the method avoids the common reactivity limitations of traditional organometallic cross-coupling, such as the need for stoichiometric reductants, as well as the price tag and toxicity of palladium.
The researchers used their polarity-switching strategy to add methyl and ethyl groups, other small saturated carbon groups, and single fluorine atoms to a variety of alkene partners. They also figured out how to stop the reaction before the second decarboxylation step to get bespoke carboxylic acids.
Elias Picazo, an organic chemist at the University of Southern California who also was not involved in the work, says he likes how the carboxylic acid fulfills multiple roles in the reaction. “[It] activates, steers selectivity, and then gets removed.”
Having conquered additions of electron-donating and electron-withdrawing groups to alkenes, West says he would like to start exploring the realm of radical-cascade chemistry next. “Can we start to use that one bond formation as a single step in a cascade to build up something bigger?”
