University researchers pioneer new reaction robotics

The prospects of making unexpected and groundbreaking chemical discoveries may have just received a huge boost, thanks to a method recently developed and successfully tested by University researchers.

The scientists have identified a technique to accomplish “accelerated serendipity” by using robotics to perform over 1,000 chemical reactions a day with molecules that have never before been combined. In a single day of trials, the team discovered a shortcut for producing pharmaceutical-like compounds that shaves weeks off the traditional process, the researchers reported.

“This is a very different way of approaching how we come up with valuable chemical reactions,” said chemistry professor and department chair David MacMillan, who was a senior researcher and co-author of the study.

The basis of the research was to combine new technology with a unique, rapid-reaction approach that could allow chemists to explore unheard-of and potentially important chemical combinations without devoting years to the pursuit, he explained.

The team was able to go beyond the traditional principle of simply combining molecules that one thinks will react, by instead taking molecules with no obvious reaction and looking for accidental reactivity — with the ultimate hope of stumbling upon a groundbreaking discovery.

To illustrate this principle, the scientists combined two molecules with no history of reacting to generate the type of functionality found in eight of the world’s top 100 pharmaceuticals, MacMillan said.

The reaction involved a nitrogen-based molecule called an amine that has a hydrogen and carbon pair, and a circle of atoms stabilized by their bonds, known as an aromatic ring.

This reaction mimics the behavior of molecules in the body and has proved useful in several medications, including antihistamines, decongestants and antidepressants.

“This is a very different way of approaching how we come up with valuable chemical reactions,” MacMillan said.

The team ran reactions once a day using a high-speed, automated reaction accelerator in Princeton’s Merck Center for Catalysis, combining molecules with no reported effect on each other.

This technique accomplishes more than just speeding up the discovery process: The researchers actually developed a unique framework for creating new materials and found better ways of producing existing ones, Massachusetts Institute of Technology chemistry professor Stephen Buchwald explained.

Importantly, however, “new” does not necessarily equal interesting or important, MacMillan said. His team searched for potential applications for each new reaction, a process that revealed the nitrogen-carbon molecule with the aromatic ring.

Get the best of the ‘Prince’ delivered straight to your inbox. Subscribe now »

“If we found this was one really valuable reaction, we wondered what others exist that we just don’t know about,” MacMillan said.

When envisioning the possibilities of this new project, MacMillan calculated that if, in a single day, he ran the equivalent of one reaction per day for three years — nearly 1,100 reactions — the odds favored a new discovery.

“To us that really proved the point of why you want serendipitous findings,” MacMillan said. “They present new knowledge, and based upon that new knowledge, you can invent.”

The research was published in a November issue of Science magazine and was supported by a grant from the National Institutes of Health as well as gifts from Merck, Amgen, Abbott and Bristol-Myers Squibb.

Co-authors included MacMillan, research associate Andrew McNally and chemistry graduate student Christopher Prier.