A failed laboratory experiment has led to an unexpected discovery that could change the way medicines are designed and manufactured. An international team of researchers, including Prof. Max García-Melchor, Group Leader of the Atomistic and Molecular Modelling for Catalysis group at CIC energiGUNE and Ikerbasque Research Professor, has helped develop a new light-driven chemical reaction that enables complex drug molecules to be modified more efficiently and sustainably.
The work, published in Nature Synthesis, describes a reaction the team calls “anti-Friedel–Crafts”, a new way to form carbon–carbon bonds—one of the most fundamental processes in organic chemistry—under mild conditions and without relying on precious metal catalysts or toxic reagents.
The research was led by the University of Cambridge, with contributions from researchers at Trinity College Dublin, CIC energiGUNE, and the pharmaceutical company AstraZeneca.
In traditional chemistry, Friedel–Crafts reactions rely on strong chemicals or metal catalysts under harsh experimental conditions. As a result, these reactions can typically only be used in the early stages of drug synthesis, meaning that scientists must subsequently perform many additional chemical steps to rebuild the final molecule.
The new approach developed by the international team reverses that pattern, allowing drug molecules to be modified at the final stages of development.
Instead of using heavy metal catalysts, the reaction is powered by light from an LED lamp at room temperature. Once activated, it triggers a self-sustaining chain process that forms new carbon–carbon bonds under mild conditions and without toxic or expensive chemicals.
In practical terms, this means chemists can introduce targeted modifications to complex molecules without dismantling and rebuilding them from scratch—a process that can otherwise take months.
The reaction is highly selective, meaning it can modify one specific part of a molecule without disturbing other sensitive regions, what chemists refer to as high functional-group tolerance. This is particularly important in drug development, where even small structural changes can significantly affect how well a medicine works, how it behaves in the body, or what side effects it may cause.
By reducing the number of steps required in chemical synthesis, the method could also lower energy consumption, reduce toxic chemical waste, and accelerate the development of new medicines.
The study combines experimental chemistry with advanced theoretical modelling and artificial intelligence tools to understand the reaction mechanism and predict where the reaction is likely to occur on complex molecules, helping guide future experiments and accelerate the exploration of new drug candidates. These theoretical insights were led by Prof. Max García-Melchor and his team at CIC energiGUNE, working in close collaboration with Trinity College Dublin.
“Understanding why this reaction works and predicting where it can occur on complex molecules required combining experimental chemistry with advanced computational modelling,” explains Prof. Max García-Melchor. “Our work helps reveal the mechanism behind this transformation and shows how theory and machine learning can guide the discovery and development of new chemical reactions.”
A discovery that emerged from a control experiment
The breakthrough emerged unexpectedly during a control experiment. Researchers had been testing a photocatalyst when they removed it as part of the control test and discovered that the reaction worked just as well—and in some cases even better—without it.
What initially appeared to be an experimental mistake ultimately revealed a new chemical mechanism. Throughout the history of science, some of the most important discoveries—from penicillin to X-rays—have also arisen from unexpected observations.
In this case, what seemed to be a failed experiment revealed a new chemical tool with the potential to transform how medicines are designed and manufactured, with significant implications for a pharmaceutical industry increasingly seeking more efficient and sustainable production processes.
