Ketones and esters (formed when an acid reacts with an alcohol) are ubiquitous as pharmaceutical intermediates and widely used for the synthesis of drug molecules. However, both share a critical limitation: Generally, only two specific sites within their structure—the carbonyl carbon and the alpha position—are easily accessible to conventional chemical reactions. The remaining carbon sites are protected by stable carbon-hydrogen (C-H) bonds that don’t readily interact with catalysts. Thus, the C-H bonds make it difficult to modify ketones and esters.
Now, new work from chemists at Scripps Research showcases a novel method that simplifies and expands the use of ketones and esters without the need for additional chemical steps. By overcoming the resistance of ketones and esters to chemical modification, the research team’s breakthrough has implications for faster and more sustainable chemical production.
These findings are published in Nature in the paper, “β-C−H bond functionalization of ketones and esters by cationic Pd complexes.”
“Ketones are the bread and butter of chemical synthesis, which is the process of building new, complex molecules from simpler ones,” said Jin-Quan Yu, PhD, professor of chemistry at Scripps Research. “They’re foundational yet underutilized because certain reactive sites were essentially inaccessible until now. Esters are also crucial to drug development, making their efficient modification important for pharmaceutical innovation as well.”
This new approach for accessing ketones and esters builds on years of developing methods to transform traditionally unreactive bonds into useful chemical tools. For more than a decade, Yu has been at the forefront of C-H activation, a process that allows chemists to more easily break strong C-H bonds and reconfigure molecules in precise ways.
Despite ketones and esters playing a central role in synthesis, their low affinity for metal catalysts has long posed a challenge for chemists attempting to activate inert C-H bonds. “C-H bonds are incredibly strong, and the natural structure of ketones and esters makes it especially difficult to direct a catalyst to the desired site,” explained Yu.
Furthermore, their C-H bonds are very strong and resist transformation. This paradox has frustrated scientists for decades, forcing them to use cumbersome extra steps—like attaching chemical “directing groups”—to modify these molecules and guide catalysts to the right spot. But this approach added waste to the process.
Yu and his team solved this challenge by designing a unique catalyst system. At its heart is the monoprotected amino neutral amide ligand, which helps palladium—a common catalyst—bind to ketones and esters more effectively. Paired with the strong acid, tetrafluoroboric acid, this setup stabilizes the catalyst just long enough to break the C-H bonds in both ketones and esters, opening them up for modifications.
More specifically, they wrote, “Here we report diverse methyl β-C−H functionalizations, including intermolecular arylation, hydroxylation and intramolecular C(sp3)–H/C(sp2)–H coupling of ketones and carboxylic esters with a monoprotected amino neutral amide (MPANA) ligand.”
Using this approach, Yu and his team were able to induce chemical reactions (such as arylation and hydroxylation) that add key building blocks to molecules to make them more functional. Such modifications could streamline drug production and help with tailoring specialized chemical compounds, as they allow scientists to create more intricate and biologically relevant molecules—without the multistep processes typically required.
“This approach not only gives ketones and esters a new life in synthesis, but it also expands the possibilities for creating molecules with greater precision and functionality,” noted Yu.
Because this method streamlines the production of key pharmaceutical compounds, it makes the process quicker, cheaper, and more environmentally friendly. By simplifying ketone transformation, Yu’s approach reduces chemical waste and aligns with the broader push toward greener chemistry.
However, the impact of this research extends past the pharmaceutical industry. Beyond drug discovery, the findings have implications for materials science, agrochemicals, and the production of everyday items like plastics and solvents.
“Ketones are everywhere—from durable resins to the acetone in nail polish remover,” said Yu. “Similarly, esters are key ingredients in drugs like aspirin, as well as in fragrances, flavors, and even biodegradable plastics.”
Yu’s next goal is to adapt his new system to create chiral molecules—an essential step in producing many pharmaceutical products. “This method doesn’t just expand what we can do with ketones and esters,” said Yu. “It unlocks a new dimension of chemical synthesis, one that connects simpler materials to more complex, valuable structures.”
