Making tools

Watson’s lab develops catalysts for reactions in organic chemistry. These catalysts are the molecular “tools” that take simple molecules and bring them together to create more complex molecules that chemists use in a wide variety of applications.

In this work, Watson’s group created a new method to make chiral phosphines for use in transition metal catalysis, a traditionally understudied class of ligands as the process for creating reactions was complicated. The team brought together two non-identical aryl halide molecules to create 35 chiral biaryl mono-phosphine ligands. The ligands are the tools that will be used in other reactions.

“The class that we access in this new reaction are phenomenally important and widely used, but there aren’t that many of them available because they’ve been really hard to make,” Watson said.

The new method also gives chemists the ability to control exactly which functions the ligands can carry out, which was exceptional. The combination will give chemists “exquisite” control over any subsequent reactions, which will impact the way end products are created.

This is especially important when developing medications, as compounds that have similar bonds and connections between atoms can have different impacts within the human body. Having the ability to selectively make certain compounds is critical in creating more effective drugs that have fewer side effects.

“The molecules we make will ultimately allow for faster development of medicines, or even allow the creation of medicines we couldn’t make before,” said Catherine Mudd, a doctoral student in Watson’s lab. “If we can make better medicines faster we can get it to the people who need it quicker.” 

Raphael Kim, who received his doctorate at UD in 2023 and is now a postdoctoral student at Emory University, was the lead researcher on the project. He said creating the selectivity was the hardest part of the project and took more than a year.

“There were a lot of frustrations involved and it was a really difficult task,” he said. “There were times when I thought I wouldn't be able to find conditions to be able to make this process work, but thankfully, through perseverance and with the help of my colleagues, we were able to find the right conditions.”

“This project was my first introduction into graduate school and taught me a ton about what it means to be an organic chemist,” said Lebogang Kgoadi, also a doctoral student with Watson’s lab. “The skills I learned from this project are going to allow me to be even more effective as a chemist and as a mentor in the lab.”

Blue Hen Phosphines

The team named the new phosphine ligands after UD-related people and places, including SueJPhos for Sue James. There are UDPhos, HenPhos, BRLPhos for Brown Lab, and GlennPhos for Glenn Yap, the department’s crystallographer. Watson’s dog Pearly, the lab’s unofficial mascot, has her own ligand too.

“We thought it would be a cool way to pay homage to all of these people who are the unsung heroes of the department. None of this happens without the amazing staff that work in our department, and who oversee the operations of many of the facilities that enable science not only for the chemists and biochemists on campus, but for a significant portion of the research on campus,” Watson said.

Watson says ‘time will tell” whether there is interest in the new method but it could be used in fields such as agrichemicals and possibly electronics, in addition to pharmaceuticals.

“This idea of being able to take two things that in principle should have identical reactivity and to figure out how to get them to selectively pair up, and to be able to control which functions the products can do is a question a lot of people have shied away from because it’s been challenging,” Watson said.

“It was really high risk, and it may not have worked. But it ultimately did work out, which is really gratifying and opens up a ton of new research questions that we are currently following up on,” he said.