How a Simple Molecular Handshake Is Solving Chemistry’s Toughest Radical Problem

Lausanne, Switzerland, Nishant Shrivastava :

Imagine trying to control a particle that exists for only a few billionths of a second. That is the daily reality of working with radicals, those fleeting, highly reactive molecular fragments that drive many chemical reactions. For decades, chemists have struggled to impose one critical property on these short lived species: handedness, or chirality. Now, a team at the École Polytechnique Fédérale de Lausanne (EPFL) has found a surprisingly elegant way to do it, and they did not build a complex new catalyst from scratch. Instead, they let two simple molecules assemble themselves.

Published in Nature on June 1, 2026, the study introduces a platform that achieves enantioselective hydrogen atom transfer (HAT) using a catalyst that forms on its own, right inside the reaction flask. The key players are chiral phosphoric acids, which are well known in the field, and 2-mercaptopyridines, which are commercially available and inexpensive. When mixed together, these components spontaneously arrange into a supramolecular complex through non covalent forces like hydrogen bonding and π–π stacking. This dynamic assembly then acts as a chiral relay, guiding the transfer of a hydrogen atom with remarkable precision.

What makes this approach so compelling is that it bypasses the traditional bottleneck of catalyst design. Normally, creating a new chiral catalyst requires months of synthesis, purification, and testing. Here, the chiral information is not built into the catalyst permanently. It is borrowed from the phosphoric acid and transmitted to the thiol through weak interactions. This means researchers can rapidly generate a library of chiral HAT catalysts simply by swapping one phosphoric acid for another, or by changing the mercaptopyridine derivative. The combinatorial space is vast, and the screening process becomes almost trivial.

The team demonstrated the power of this system by targeting 2-aryl pyrrolidines, a class of compounds that appears in many pharmaceuticals, including drugs for psychosis, depression, and inflammation. Using visible light and ambient temperature, they achieved enantiomeric excess values often exceeding 90 percent, even on substrates with multiple stereocenters. That level of control over radical intermediates is unprecedented in a system this simple.

Mechanistic studies using NMR spectroscopy and computational modeling confirmed that the active species is a well defined complex between the phosphoric acid and the thiol. The hydrogen bonded network stabilizes the transition state and dictates which face of the radical intermediate gets attacked. The result is a highly predictable stereochemical outcome, which is exactly what synthetic chemists need when designing routes to single enantiomer drugs.

Beyond pyrrolidines, the method proved effective for piperidines and azepanes, showing that the platform is not limited to one ring size. In many cases, the reaction enabled deracemization of racemic mixtures without requiring stoichiometric chiral auxiliaries or expensive metal catalysts. This positions the technology as a practical alternative to enzymatic resolution or transition metal catalyzed asymmetric hydrogenation, both of which have their own limitations in terms of substrate scope and operational complexity.

From a green chemistry perspective, the advantages are clear. The catalysts are generated on demand, eliminating the need to store or purify sensitive chiral intermediates. The reaction conditions are mild, relying only on visible light and room temperature. And because the building blocks are already commercially available, any well equipped laboratory can start using this method immediately. There is no barrier to entry, which is rare for a breakthrough in asymmetric catalysis.

What this work really highlights is a shift in thinking. Instead of designing ever more complex catalysts, the EPFL team asked a different question: What if the catalyst could assemble itself? The answer turned out to be not only possible but highly effective. It is a reminder that sometimes the most powerful solutions come from letting molecules do what they do naturally, with a little guidance from clever design.

Looking forward, the authors anticipate that this non covalent strategy will inspire a new generation of asymmetric radical reactions. The same principle could be extended to C–C, C–N, and C–O bond forming reactions, potentially opening up entirely new synthetic routes to complex molecules. For now, the immediate impact is clear: a simple, scalable, and sustainable way to control radical stereochemistry that was previously thought to be out of reach.

This is not just a technical achievement. It is a demonstration of how creative thinking and interdisciplinary collaboration can solve problems that have stumped the field for years. And it shows that the most elegant solutions often come from the simplest ideas.