Robots and AI uncover unexpected pathway in classic 135-year-old chemical reaction

A 135-year-old chemical reaction, the Biginelli reaction, has revealed an unexpected pathway that may have remained hidden for decades. Scientists from the Institute for Basic Science (IBS) utilized an automated robotic platform to systematically map the vast reaction hyperspace of the Biginelli reaction, which has been studied since its inception in 1891.

By exploring 960 different sets of conditions, the researchers discovered a previously unknown branch of the reaction that produces complex bicyclic structures, unlike its conventional products. The newly identified pathway involves a pseudo-seven-component transformation, wherein seven starting molecules contribute to the formation of one complex product.

This discovery was made possible by combining robotic experimentation, large-scale reaction mapping, and chemical AI. The researchers then redesigned the synthesis using the newly reconstructed reaction network, producing a family of related molecules with intricate structures and unusual supramolecular behavior. Some of these compounds spontaneously assembled into larger structures depending on concentration and temperature, while others selectively bound metal ions, particularly barium and zinc, potentially enabling applications in selective metal sensing.

One compound exhibited an especially unusual form of chiral self-sorting, with molecules preferring to assemble with molecules of the same or opposite handedness based on the presence of metal ions. This zinc and barium ion-dependent chiral self-sorting behavior is extremely rare and could have significant implications for enantioselective sensing, responsive materials, and molecular recognition.

The study highlights the potential of using robotic experimentation and large-scale reaction mapping to uncover hidden pathways and discover entirely new chemistry, even in reactions that have been extensively studied for over a century.