Ketones appear throughout organic molecules, which is why chemists are desirous to create latest reactions that reap the benefits of them when forming chemical bonds. One response that has remained especially difficult is the one-electron reduction of ketones needed to generate ketyl radicals. These radicals are highly useful intermediates in natural product synthesis and pharmaceutical research, but most available techniques are designed for aryl ketones relatively than simpler alkyl ketones. Although alkyl ketones are much more common, also they are naturally harder to scale back than their aryl counterparts. With this challenge in mind, a team of organic and computational chemists at WPI-ICReDD at Hokkaido University has developed a catalytic strategy that finally enables the formation of alkyl ketyl radicals. The study appears within the Journal of the American Chemical Society and is obtainable open access.
In earlier work, WPI-ICReDD scientists showed that a palladium catalyst paired with phosphine ligands could drive light-activated (response activated by shining light) transformations of aryl ketones, but the identical system didn’t work for alkyl ketones. Their data indicated that alkyl ketyl radicals did form briefly. Nonetheless, these radicals immediately returned an electron to the palladium center, a phenomenon generally known as back electron transfer (BET), before any useful response could proceed. Because of this, the starting material remained unchanged.
Just like traditional palladium-based catalysis, the behavior of photoexcited palladium catalysts is very depending on the phosphine ligand attached to the metal. The team suspected that selecting the right ligand might unlock reactivity with alkyl ketones. The issue was scale: hundreds of phosphine ligands exist, and experimentally screening them for an unfamiliar response could be slow, labor-intensive, and generate unnecessary chemical waste.
To beat these limitations, the researchers turned to computational chemistry to narrow down the sphere of candidate ligands. They used the Virtual Ligand-Assisted Screening (VLAS) approach developed by Associate Professor Wataru Matsuoka and Professor Satoshi Maeda at WPI-ICReDD. Applying VLAS to 38 phosphine ligands, the strategy produced a heat map that predicted how well each ligand might promote the specified reactivity by analyzing electronic and steric properties.
Guided by these predictions, the team chosen three ligands for laboratory testing and ultimately identified L4 as probably the most effective option — tris(4-methoxyphenyl)phosphine (P(p-OMe-C6H4)3). This ligand successfully suppressed BET, allowing alkyl ketones to generate ketyl radicals and take part in high-yield transformations.
The resulting method provides chemists with an accessible approach to work with alkyl ketyl radicals and demonstrates how VLAS can rapidly guide the event and optimization of recent chemical reactions.