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C-H Activation

Catalyst persuades alcohols to offer a helping hand for C-H activation

Tailored ligand on palladium catalyst uses hydrogen bonding to orchestrate reaction

by Mark Peplow, special to C&EN
September 9, 2023 | A version of this story appeared in Volume 101, Issue 30

 

This is a scheme showing a palladium catalyst and ligand.

Organic molecules are peppered with carbon-hydrogen bonds, and chemists have built up a fantastic toolbox of methods to break these bonds and put more useful functional groups in their place. This strategy, known as C–H activation, offers a direct approach to modifying molecules that helps shorten synthetic sequences.

Jin-Quan Yu at Scripps Research in California and colleagues have now extended C–H activation to alcohols, potentially opening up more-efficient routes to make molecules for medicinal chemistry (Nature 2023, DOI: 10.1038/s41586-023-06485-8). “Alcohols are everywhere, they’re the number 1 most abundant substrate in nature,” Yu says. “So you could generate huge amounts of new scaffolds for drug discovery.”

Fundamentally, this is already an exciting breakthrough that nobody thought would be possible.
Jin-Quan Yu, Scripps Research in California

The challenge of C–H activation is not just to break this relatively inert bond but to target the specific C–H bond required for a synthesis. One of the most successful approaches uses a functional group within the substrate molecule as a directing group, to coordinate a metal catalyst such as palladium and hold it close to the correct C–H bond.

This works well for various groups, including amides and carboxylates, but alcohols have stubbornly refused to play ball. This is in part because an alcohol’s hydroxyl group can only bind weakly to palladium, and the complexes formed with the metal tend to be too flexible to offer a precise directing effect. As a result, there have been no previous examples of using alcohols as a directing group for the activation of saturated (sp3) C–H bonds.

This is a structure of hydrogen bonding stabilizes the reaction’s
transition state.
Hydrogen bonding stabilizes the reaction’s transition state.

Previously, researchers who wanted to do C–H activation in alcohols had to take a circuitous route: converting the hydroxyl into a different functional group, carrying out the activation, and then changing the functional group back into a hydroxyl.

To overcome these problems, the researchers teamed palladium with a ligand that could use hydrogen bonding to strengthen hydroxyl binding to the metal. This makes the resulting complex more rigid and lowers the energy of a key transition state.

“It’s a bit analogous to enzyme-to-substrate interactions—instead of having one strong bond, you have several weak ones,” says Manuel van Gemmeren at Kiel University, who works on C–H activation and peer-reviewed the work.

After screening various ligands, Yu’s team found that N-acyl sulfonamides were the most effective. Two nitrogen groups in the middle of the ligand bind firmly to palladium, while an oxygen atom in the sulfonamide group forms a hydrogen bond with the substrate’s hydroxyl. This arrangement holds the palladium in just the right position to break open a C–H bond located four carbon atoms away from the hydroxyl group—a process further assisted by another oxygen atom within the ligand.

The researchers tested their method on a range of alcohol substrates containing cyclobutyl (example shown) and benzyl units, which they coupled with various aryl iodides in moderate to high yields. These fairly simple alcohols are particularly well suited to the method, van Gemmeren says, and it will take more work to show that the reaction can tackle a broader range of alcohol substrates. “But I think this is the paper that everybody is going to use to build towards this improvement,” he adds.

Meanwhile, Yu’s team is already working to extend the method. “Fundamentally, this is already an exciting breakthrough that nobody thought would be possible,” he says. “But if we could take care of every alcohol, that would be truly amazing.”

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