New palladium-catalysed reaction selectively breaks stable hydrogen–carbon bonds in ethers and ketones

Palladium has already proven its effectiveness in a number of processes, including cross-coupling reactions and carbon–hydrogen bond activation. Until recently, however, modifying stable organic compounds such as ketones and simple ethers with palladium remained a serious scientific challenge. A recent study by chemists at Scripps Research, published in the Nature journal, has demonstrated a breakthrough solution to this problem. This opens up the prospect of developing more sustainable and cost-effective methods for synthesising medicinal compounds.

Ketones and ethers are fundamental classes of organic compounds that are widely used in synthesising molecules with high biological activity.

Ketones contain a carbonyl group connected to two hydrocarbon radicals (general formula: R₁−CO−R₂), while simple ethers include an ether group consisting of an oxygen atom connected to two organic radicals (general formula: R−O−R′). The main limitation of their use, however, is that chemical reactions occur primarily in two parts of the molecule: the carbonyl carbon and the alpha position. The remaining carbon fragments are chemically inert due to the strength of the carbon–hydrogen bonds.

Researchers Yi-Hao Li, Nikita Chekshin, Yilin Lu and Jin-Quan Yu at Scripps Research have proposed a solution to this problem by developing a method for activating C(sp³)−H and C(sp²)−H bonds in ketones and ethers using a palladium catalyst. In their experiment, they used a combination of a palladium complex, a monoprotected amine neutral amide ligand, and tetrafluoroboric acid (HBF₄). This combination enabled the selective cleavage of stable carbon−hydrogen bonds, facilitating reactions such as arylation, hydroxylation and intramolecular C(sp³)−H/C(sp²)−H coupling.

This development is of great practical importance for optimising synthetic processes in the pharmaceutical industry. The proposed method reduces dependence on traditional multi-stage production processes by minimising the number of reaction stages and byproduct formation. This improves economic efficiency and reduces the environmental impact. One possible application of this technology is reducing the production cost of common drugs such as acetylsalicylic acid (aspirin), which could transform approaches to the mass production of medicines.

This new method of carbon−hydrogen bond activation catalysed by a complex palladium compound is a significant step forward in synthetic chemistry and pharmaceuticals. It expands the possibilities for working with chemically inert compounds and makes the production of medicinal substances more efficient, sustainable and economically viable.

Source: https://phys.org/news/2025-01-chemists-potential-ketone-ester-molecules.html