Nitrogen-containing aromatic rings, known as aza-arenes, are common structural motifs in biologically active molecules. Hydrogenation of these rings can profoundly alter a compound’s chemical and biological properties, influencing reactivity, biological activity, and how a drug behaves in the body (pharmacokinetics). This makes such transformations highly valuable for medical chemistry: around 82% of FDA-approved small-molecule drugs contain at least one nitrogen-containing ring. Despite their importance, selectively hydrogenating aza-arenes has remained challenging. Their high aromatic stability, the presence of sensitive functional groups, and the harsh reaction conditions required by traditional methods often limit practical applications.

A research team led by Prof. Siegfried R. Waldvogel at the MPI CEC has now developed a simple and sustainable, and highly versatile electrochemical method to hydrogenate aza-arenes using water as a clean hydrogen source. Recently published in the Journal of the American Chemical Society, the approach operates under mild acidic conditions, at ambient temperature and pressure, and uses readily available nickel foam electrodes.

“Conventional hydrogenation often relies on high-pressure hydrogen gas and precious metal catalysts, which can be hazardous, expensive, and poorly compatible with complex molecues,” explains Prof. Waldvogel. “Our electrochemical method uses electricity to generate reactive hydrogen directly from water, offering a safer, greener, sustainable, and more scalable alternative.”

The researchers demonstrated the versatility of the method across a wide range of aza-arene substrates, including quinolines, isoquinolines, quinoxalines, pyridines, and protonated aza-arenes salts. Importantly, sensitive functional groups such as halides, hydroxyls, ethers, and amines were preserved, as were complex, drug-like molecular frameworks. The protocol also enables deuterium labeling, an important tool in pharmaceutical research and metabolism studies.

Notably, the team scaled the reaction up to 25 grams using a tailored flow reactor without loss of efficiency, showcasing the method’s industrial potential. Mechanistic studies suggest two complementary pathways: hydrogenation via chemisorbed hydrogen atoms on the cathode and direct electroreduction of protonated substrates, accounting for the method’s high selectivity and stereo-control.

“This work demonstrates how green electrochemistry can address long-standing challenges in synthetic chemistry,” adds first author Subhabrata Dutta. “It opens new opportunities for sustainable production of pharmaceutically relevant compounds while maintaining excellent yield, selectivity, and scalability.”

The method represents a significant step toward sustainable chemical synthesis, highlighting the growing role of electrochemical strategies in modern organic chemistry. The researchers anticipate that this approach will stimulate further developments in electrochemical hydrogenation and inspire broader adoption in both academic and industrial settings.

Reference:
Dutta, S.; Narobe, R.; Waldvogel, S. R. Electrochemical Hydrogenation of Aza-Arenes Using H₂O as the Hydrogen Source. J. Am. Chem. Soc. 2025, https://pubs.acs.org/doi/10.1021/jacs.5c21117