Scientists have long viewed ketones (a crucial class of chemicals) and esters (compounds created when an acid and an alcohol react) as hidden treasure troves of potential. Commonly found as intermediates in pharmaceuticals, ketones and esters play a significant role in the creation of drug molecules. However, they both possess a major limitation: Typically, only two particular sites in their structure—the carbonyl carbon and the alpha position—are readily available for traditional chemical reactions. The other carbon sites are shielded by robust carbon-hydrogen (C-H) bonds that resist interactions with catalysts—agents that facilitate chemical reactions and help researchers modify molecular structures. As a result, altering ketones and esters has been quite challenging. Fortunately, chemists at Scripps Research have discovered a method to unlock the hidden potential of these molecules.
Scientists have long viewed ketones (a crucial class of chemicals) and esters (compounds created when an acid and an alcohol react) as hidden treasure troves of potential. Commonly found as intermediates in pharmaceuticals, ketones and esters play a significant role in the creation of drug molecules. However, they both possess a major limitation: Typically, only two particular sites in their structure—the carbonyl carbon and the alpha position—are readily available for traditional chemical reactions. The other carbon sites are shielded by robust carbon-hydrogen (C-H) bonds that resist interactions with catalysts—agents that facilitate chemical reactions and help researchers modify molecular structures. As a result, altering ketones and esters has been quite challenging. Fortunately, chemists at Scripps Research have discovered a method to unlock the hidden potential of these molecules.
Their research, published in Nature on January 8, presents an innovative technique that simplifies and broadens the application of ketones and esters without needing extra chemical reactions. By overcoming the challenges posed by ketones and esters regarding chemical modification, this breakthrough from the research team has promising implications for faster and more sustainable chemical manufacturing.
“Ketones are integral to chemical synthesis, which involves constructing complex molecules from simpler building blocks,” mentions senior author Jin-Quan Yu, PhD, the Frank and Bertha Hupp Professor of Chemistry and the Bristol Myers Squibb Endowed Chair in Chemistry at Scripps Research. “They are essential but have been underused due to the previous inaccessibility of certain reactive sites. Esters are also vital for drug development, making efficient modification essential for innovation in pharmaceuticals.”
This new strategy for exploiting ketones and esters builds upon years of work focused on converting traditionally unresponsive bonds into valuable chemical tools. For over a decade, Yu has led the way in C-H activation, a technique that enables chemists to more easily break robust C-H bonds and reconfigure molecules accurately. By leveraging specific catalysts, researchers can “activate” these bonds, allowing for the addition of new atoms or groups to molecules.
Yu’s lab has previously developed techniques to unlock similar bonds in acids, alcohols, and amines, three other significant chemical categories crucial to drug synthesis. This recent advancement concerning ketones—and, to a lesser extent, esters—represents a significant milestone in extending this influential approach to all essential classes of organic compounds.
Despite the central role of ketones and esters in synthesis, their weak interactions with metal catalysts have historically made it challenging for chemists to activate inactive C-H bonds.
“C-H bonds are extraordinarily robust, and the inherent structure of ketones and esters complicates the targeting of catalysts to the desired site,” explains Yu.
Due to their low affinity for metal, ketones and esters tend not to bond effectively with catalysts. Additionally, their strong C-H bonds resist change. This dilemma has vexed scientists for years, compelling them to employ cumbersome additional steps—such as attaching chemical “directing groups”—to modify these molecules and direct catalysts to the appropriate location. Unfortunately, this method added unnecessary waste to the overall process.
Yu and his team met this challenge with an innovative catalyst system. Central to this system is a specially designed molecule known as the monoprotected amino neutral amide ligand, which enhances the ability of palladium—a common catalyst—to attach to ketones and esters more efficiently. When paired with a robust acid called tetrafluoroboric acid, this setup stabilizes the catalyst just long enough to break the C-H bonds in both ketones and esters, facilitating modifications.
Utilizing this technique, Yu and his team successfully prompted chemical reactions (like arylation and hydroxylation) that introduce essential building blocks to molecules, enhancing their functionality. These modifications could expedite drug manufacturing and aid in customizing specialized chemical compounds aimed at creating more complex and biologically relevant molecules—without relying on the traditionally lengthy multistep processes.
“This method not only revitalizes ketones and esters in synthesis but also broadens the scope for crafting molecules with heightened precision and functionality,” asserts Yu.
By streamlining the production process of crucial pharmaceutical compounds, this method makes it faster, more cost-effective, and environmentally sustainable. Yu’s approach simplifies the transformation of ketones, minimizes chemical waste, and aligns with the greater movement towards greener chemistry.
However, the significance of this research reaches beyond the pharmaceutical realm. The findings hold importance for materials science, agrochemicals, and even the production of everyday products like plastics and solvents.
“Ketones are ubiquitous—from robust resins to acetone in nail polish remover,” states Yu. “In the same vein, esters are fundamental constituents in drugs like aspirin, as well as in fragrances, flavors, and even biodegradable plastics.”
Yu’s upcoming goal is to modify his new system to synthesize chiral molecules (compounds made from the same elements but arranged as mirror images)—a crucial milestone in the production of various pharmaceutical items.
“This method expands the potential of what we can achieve with ketones and esters,” highlights Yu. “It opens up a new realm of chemical synthesis, linking simpler materials to more intricate and valuable structures.”
Co-authors of the study titled “β-C−H bond functionalization of ketones and esters by cationic Pd complexes” include Yi-Hao Li, Nikita Chekshin, and Yilin Lu from Scripps Research.
This research was funded by the National Institute of General Medical Sciences (grant 2R01GM084019).
