The chemistry partnership has led to a new approach to putting carbon dioxide to good – and even healthy – use: by electrosynthesizing it into a series of organic molecules critical to pharmaceutical research.
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During the approach, the team made a new discovery. They could make two completely different products, both of which are valuable in medicinal chemistry, by changing the type of electrochemical reactor.
The study was published in the journal Nature on January 5, 2023. Postdoctoral researchers Peng Yu and Wen Zhang, as well as Guo-Quan Sun of Sichuan University in China, co-authored the paper.
The Cornell group, led by Song Lin, a professor of chemistry and chemical biology in the College of Arts and Sciences, had previously combined simple carbon molecules to create complex compounds using the electrochemical process, eliminating the need for precious metals or other catalysts to accelerate the chemical reaction.
The researchers narrowed their focus for the new initiative to pyridine, the second most common heterocycle among FDA-approved drugs. Heterocycles are organic compounds in which the atoms of the molecules are linked in ring structures, one of which is not carbon. These structural units are known as “pharmacophores” because they are often found in medicinally active substances. They are also widely found in agrochemicals.
The researchers wanted to create carboxylated pyridines, which are pyridines with carbon dioxide attached to them. The addition of carbon dioxide to a pyridine ring has the advantage of altering the function of the molecule and ultimately assisting it in binding to certain targets such as proteins. However, the two molecules are not natural companions. Pyridine is a reactive molecule while carbon dioxide is an inert gas.
“There are very few ways to directly introduce carbon dioxide into pyridine. Current methods have very serious limitations,” added Lin, co-senior author of the paper along with Da-Gang Yu of Sichuan University.
Lin’s lab successfully synthesized carboxylated pyridines by combining their skills in electrochemistry with Yu’s group’s expertise in the use of carbon dioxide in organic synthesis.
Electrochemistry gives you that lever to pull up the potential that’s enough to activate even some of the most inert molecules. That’s how we managed to achieve this reaction.
Song Lin, Professor of Chemistry and Chemical Biology, College of Arts and Sciences, Cornell University
While performing the electrosynthesis, the researchers made an accidental discovery. An electrochemical reaction is usually carried out in one of two ways by chemists: either in an undivided electrochemical cell (where the anode and cathode that supply the electric current are in the same solution) or in a divided electrochemical cell (where the cathode and anode are separated by a porous separator that blocks large organic molecules but allows ions to pass through). Although one strategy is more effective than the other, both generate the same product.
Lin’s group found that the transition from a divided to an undivided cell allowed them to selectively attach the carbon dioxide molecule to different sites on the pyridine ring, resulting in two different products: C4-carboxylation in the undivided cell and C5-carboxylation in the divided cell.
This is the first time we found that by simply changing the cell, what we call an electrochemical reactor, you completely change the product. I think that this mechanistic understanding of why it happened will allow us to continue to apply the same strategy to other molecules, not just pyridines, and perhaps make other molecules in this selective but controlled way. I think this is a general principle that can be generalized to other systems.
Song Lin, Professor of Chemistry and Chemical Biology, College of Arts and Sciences, Cornell University
Although the project’s method of using carbon dioxide won’t solve the world’s climate change problem, Lin said, “it’s a small step toward using excess carbon dioxide in a beneficial way.”
Co-authors of the study include postdoctoral researcher Yi Wang and doctoral student Zhipeng Lu; and researchers from Sichuan University.
The National Institute of General Medical Sciences, Eli Lilly, Cornell and the Sloan Foundation funded the research.
Journal reference
Sun, G.-Q., et al. (2023) Electrochemical reactor dictates site selectivity in N-heteroarene carboxylation. Nature. doi.org/10.1038/s41586-022-05667-0.
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