In Partnership with the NIH: The Chirik Lab and Organic Synthesis

The functionalization of carbon–hydrogen (C-H) bonds so crucial to catalysis is a complex chemical process with many challenges. Improving its efficiency has huge ramifications for medicines, energy needs, and the sustainability of the nation’s products and technologies.

That goal has been at the heart of the Paul Chirik Lab’s nearly decade-long partnership with the National Institutes of Health (NIH). The funding seeks to enhance routes to C–H functionalization that advance organic synthesis.

This functionalization allows chemists to convert a specific C-H bond in a molecule—typically unreactive and useless to catalysis—into a more useful bond without undergoing numerous chemical steps. One of the biggest sustainability savings for a chemist is the elimination of steps in the lab that take time, reduce yield, generate waste, and cost more.

Chirik says the NIH partnership has been essential to his lab’s work.

“Great research costs money. It requires resources. The biggest resource we have is the support of the researchers – our postdocs and graduate students. You have to have people in the lab doing these experiments, making these molecules, making these discoveries,” says Chirik, the Edwards S. Sanford Professor of Chemistry. “Our partnership with the NIH allows us to attract the greatest scientists from around the country and around the world into our labs to do this work. Without it, it couldn’t be done.”

What is “functionalization”?

Carbon-hydrogen (C–H) bonds are the most ubiquitous linkages in organic molecules and in every drug molecule and intermediate. In order to do chemistry with them—and it would be a great loss not to because they have enormous catalytic potential—scientists must break these bonds to functionalize them. But breaking them is extremely difficult and choosing one C–H bond in a sea of others is daunting. Researchers working with this longstanding challenge not only have to find ways to break these bonds but also to break them selectively, so that only a portion of the molecular structure is involved.

Enter the Chirik Lab.

In order to expand the application of metal catalysis into organic synthesis, the Chirik Lab finds ways to selectively break bonds using metal catalysts, finding the right catalyst for any given situation.

“Say you have four bonds in a molecule and the synthetic chemist wants to target one C-H bond over the other three, and the difference between those four is very, very small,” says Chirik. “So now the catalyst comes into play. How does it know to go after only the bond you want? Because that’s what you need to advance organic synthesis.”

Getting away from precious metals

Chemists typically rely on precious metals like rhodium, iridium, and palladium as catalysts to spur functionalization. This is problematic because these metals are rare, expensive, and difficult to mine and separate. These reactions are also often “aselective,” reacting with every C-H bond in sight. So the Chirik Lab investigates the use of Earth-abundant metals like iron and cobalt as catalysts, drawing on their selectivity for a more efficient process.

“There’s an inherent property of the metal showing that the atomic properties of the cobalt allow it to be more selective,” said Chirik. “So it’s not only that this is more Earth-abundant or cheaper, but that it’s performance in terms of selectivity is hard to match by the precious metals.”

Why is this useful?

One of the key deliverables for the Chirik-NIH partnership is predictability. Researchers’ investigations over the years have allowed them to tell stakeholders—a synthetic chemist, a drug company making consumer medicines—exactly which catalyst to use to break a specific bond. This saves research steps, money, and energy along with expanding the range of molecules that can be used in discovery chemistry.

The result is better, more efficient medicines through predictability. Working with a biopharmaceutical firm, for example, the Chirik Lab can now say, if you want this bond broken, use this particular Earth-abundant catalyst; if you want that bond broken, use another. And so on.

In partnership with the NIH

“All of this sounds very cool, but you have to demonstrate it. You have to prove that the chemistry works, and you need people to do that in the lab. That’s where the NIH comes in,” said Chirik. “They give you the resources and then you assemble a team on and watch it blow up into something really impactful.

“The NIH is the Cadillac of funding. When you write an NIH grant, you know it’s going to go to a study section and that study section will have the premier scientists in your area, which helps you write a proposal that’s going to address really important problems related to human health,” says Chirik.

“When I look back at what we’ve done with the NIH support, we’ve developed a whole new class of catalysts,” he adds. “So now we’re starting to move away from cobalt into iron, which has its own exciting chemistry. We’ve accomplished a ton, but we need to see what else we can do.”

Some select C-H functionalization papers

The Chirik Lab/NIH partnership has yielded some groundbreaking papers over the last few years. Here are a few examples:

Shimozono, A. M.; Roque, J. B.; Li, H.; Zhang, T.; Lin, R.; Chirik, P. J. “Alkene borylation-hydrogenation enables highly active, site-selective cobalt-catalyzed borylation.” J. Am. Chem. Soc. 2025, 147, 26437-26445.

Li, H.; Cramer, H. H.; Roque, J. B.; Odena, C.; Shimozono, A.; Chirik, P. J. “The role of boron reagents in determining the site-selectivity of pyridine(dicarbene) cobalt-catalyzed C–H borylation of fluorinated arenes.” J. Am. Chem. Soc. 2025, 147, 14163-14173.

Roque, J. B.; Shimozono, A. M.; Pabst, T. P.; Hierlmeier, G.; Peterson, P. O.; Chirik, P. J. “Kinetic and thermodynamic control of C(sp2)–H activation enable site-selective borylation.” Science 2023, 382, 1165-1170.