Enzyme-inspired catalyst places chemicals in the right position to produce ethers

Inspired by enzymes, chemists at the University of Illinois at Urbana-Champaign have developed a catalyst to simplify the synthesis of ethers, key functional components of many drugs, foods, personal care products and other consumer goods. The catalyst places the two chemical ingredients in the right proximity and position to come together, avoiding the steps and quantities required in standard synthesis protocols.

Led by University of Illinois chemistry professor Christina White, the researchers published their findings in the journal Science.

“Ethers are very important molecules, present in everything, and our approach really simplifies the manufacturing process and allows us to make ethers that we couldn’t make before,” White said. “We’re always inspired by nature. Enzymes have shown us how we can do these reactions more efficiently, more simply and more effectively.”

The ideal combination of ingredients to make an ether is an alcohol and a hydrocarbon called an alkene, but they don’t react on their own when mixed, said graduate student Sven Kaster, the study’s first author. The classic protocol involves abstracting a proton from the alcohol, which makes it reactive but yields a cocktail of products from which the desired ether must be extracted. It also takes large quantities of ingredients to produce enough ether to be useful, which isn’t practical for complex, valuable compounds.

“We took a different approach to solving the problem,” Kaster said. “We didn’t want to activate the alcohol and we didn’t want to have to use large amounts of reaction partners.”

The researchers developed self-assembling small molecule catalysts containing palladium, a metal that can break the bond between carbon and hydrogen in an alkene to react with the alcohol. They called these catalysts SOX. However, making the alkenes reactive was not enough to produce the ethers the researchers sought.

They looked to biology for inspiration, studying how enzymes catalyze complex reactions in nature: by placing reaction partners close together and in the right orientation to react, White explained. They produced a version of the SOX catalyst, Sven-SOX, with a specific geometry and electronic properties so that the activated alkene and alcohol line up perfectly to produce the desired ethers.

“It’s like if two people wanted to hold hands, they had to be close to each other. But to do it comfortably, they also had to be facing the right direction,” White said. “We put those two functions together, proximity and position, and kind of built our own self-assembling ‘enzyme,’ but with simple components.”

The Sven-SOX catalyst worked across a broad spectrum of ether-generating reactions. The researchers produced more than 130 ethers, including complex and bulky ethers that were previously difficult to produce by other means.

“The main advantage of our approach is its generality. We can make many ethers that have never been made before and that may have new or useful functions,” Kaster said. “We can make ethers from very large, normally difficult-to-assemble components. Our reaction also occurs under very mild conditions, which allows us to tolerate very sensitive groups that would normally undergo reactions that we don’t want in the classical method. Another advantage is that we make these ethers more efficiently, using fewer materials and fewer steps. It’s a procedure that a middle schooler could follow.”

The researchers next plan to explore other small-molecule catalysts that could have enzyme-like characteristics to make other classes of chemicals. They will also continue to explore ether reactions and how to optimize them.

“This really highlights the importance of fundamental science and the ability of small molecules to act like an enzyme,” White said. “This work has shown us how to design such catalysts in the future and how to use the tools that enzymes use in nature. We want to incorporate this into the design of future catalysts to solve important problems in chemistry, medicine and industry.”