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Synthesis

How to add a carbonyl to a molecule using carbon monoxide and light

Palladium-catalyzed reaction makes acid chlorides, amides, esters, and ketones from both alkyl and aryl halides

by Bethany Halford
April 16, 2020 | APPEARED IN VOLUME 98, ISSUE 15

 

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Carbonyls (C=O groups) are popular reactive handles. But carbonylation reactions, which create these useful groups by appending carbon monoxide to aryl halides or alkyl halides with the help of a metal catalyst, tend to work with only a few types of molecules. So even though it’s possible to make ibuprofen on an industrial scale using carbonylation, the reaction isn’t a common tool.

But that could change, thanks to a discovery by McGill University chemists Bruce A. Arndtsen, Gerardo M. Torres, and Yi Liu. These researchers found that by shining blue light on a palladium-catalyzed carbonylation, they could make the reaction work with many types of aryl halides and alkyl halides. The transformation can be used to make acid chlorides, amides (example shown), esters, and ketones, motifs found in or en route to a large number of pharmaceuticals (Science 2020, DOI: 10.1126/science.aba5901).

Ilhyong Ryu, a chemist at Osaka Prefecture University who studies catalysis, says this reaction is “amazing” because it is a simple system that works with many different substrates. “It’s like carbonylation in automatic mode without the need to change gears,” he says. “It is also striking to see that acid chlorides can be synthesized by their system. Acid chlorides have been a difficult class of carbonyl compounds to prepare by carbonylation chemistry.”

It is also striking to see that acid chlorides can be synthesized by their system. Acid chlorides have been a difficult class of carbonyl compounds to prepare by carbonylation chemistry.
Ilhyong Ryu, Osaka Prefecture University

Arndtsen says the group discovered the reaction while trying to use photoredox catalysis to make acid chlorides via carbonylation. “When we started looking more closely, we realized the photoredox catalyst was doing nothing.” Instead, he says, the blue light itself was doing the work, by exciting two stages of the catalytic cycle—a radical-induced oxidative addition and a radical-induced reductive elimination.

“Catalysis is a lot about balancing,” Arndtsen explains. “Anything you do to help one side of the catalytic cycle oftentimes hurts the other side.” But the blue light helps drive both sides, striking a balance that’s otherwise difficult, if not impossible. “By using light to drive both, you can start to do hard steps in both directions, and that’s what adds a lot of the generality here.”

Vladimir Gevorgyan, a chemist at the University of Texas at Dallas who has used light to spur palladium-catalyzed oxidative addition reactions, says that the McGill group’s reaction is “a highly useful method for mild and general carbonylative functionalization of organic halides, dramatically broadening the boundaries of this important methodology.” He adds that the approach could also be used with other cross-coupling reactions.

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