Researchers at Hokkaido University have developed a new catalytic method to generate ketyl radicals from alkyl ketones, solving a long-standing challenge in organic chemistry. Using a computational screening tool, the team identified an effective ligand that prevents unwanted electron transfer, enabling cleaner and more reliable reactions. This breakthrough aids natural product synthesis and pharmaceutical development.
Chemists have long sought ways to harness ketones for forming chemical bonds, given their prevalence in organic molecules. A particularly stubborn hurdle has been the one-electron reduction of ketones to produce ketyl radicals, which serve as key intermediates in natural product synthesis and pharmaceutical research. While methods exist for aryl ketones, alkyl ketones—more common but harder to reduce—have resisted similar success.
A team of organic and computational chemists at the WPI-ICReDD institute at Hokkaido University addressed this issue with a photoexcited palladium catalysis strategy. Their work, published in the Journal of the American Chemical Society, demonstrates how light-activated palladium catalysts, paired with specific phosphine ligands, can now drive transformations of alkyl ketones.
In prior studies, the same palladium system worked for aryl ketones but failed for alkyl ones. Data showed that alkyl ketyl radicals formed momentarily, only to undergo back electron transfer (BET) to the palladium, reverting the material unchanged. To find a solution, the researchers employed the Virtual Ligand-Assisted Screening (VLAS) method, developed by Associate Professor Wataru Matsuoka and Professor Satoshi Maeda.
VLAS analyzed 38 phosphine ligands, generating a heat map of their electronic and steric properties to predict reactivity. This guided lab tests on three candidates, with tris(4-methoxyphenyl)phosphine (P(p-OMe-C6H4)3), labeled L4, proving most effective. It suppressed BET, allowing stable ketyl radical formation and high-yield reactions.
The authors, including Kosaku Tanaka, Ren Yamada, and Tsuyoshi Mita, note that this approach provides an accessible tool for chemists and highlights VLAS's role in accelerating reaction optimization. The study appears in volume 147, issue 43, with DOI: 10.1021/jacs.5c13115.