Hazardous reactions made safer through flow technology

Nitration reactions are among the most hazardous in chemistry. In addition to their explosive nature, conventional nitrating agents are highly aggressive and poorly suited to sensitive bio-based molecules. Furfural, a key precursor for nitrofuran antibiotics, is a fragile biomass-derived compound. Traditional methods often lead to poor yields, inconsistent reproducibility, and significant safety risks.

To address these challenges, researchers from CiTOS (Center for Integrated Technology and Organic Synthesis) developed an automated continuous flow platform for the in situ generation and immediate use of acetyl nitrate -- a milder, more selective nitrating agent. This enables the rapid, scalable, and much safer synthesis of nitrofuran drug precursors.

"This platform combines advanced automation with practical simplicity," explains Prof. Jean-Christophe Monbaliu, Director of CiTOS. "It can be remotely operated by a single person and delivers high-quality results, representing a major step toward safer pharmaceutical manufacturing. In addition, we can produce multiple nitrofuran-based drugs using the same setup."

The process uses furfural, a compound derived from biomass and identified by the U.S. Department of Energy as a high-value bio-based molecule. It is transformed via nitration using acetyl nitrate within a series of interconnected flow modules equipped with real-time IR/UV analytical tools, temperature and pressure sensors, and an automated separation unit. "Acetyl nitrate is extremely dangerous when handled or stored," adds Loïc Bovy, PhD student and co-author of the study. "But by generating it in situ and consuming it instantly in flow, we eliminate the risk while maintaining full control."

The system was successfully tested on four antibacterial compounds listed by the World Health Organization, all produced in under five minutes with excellent purity and high yield. "This is not just a chemical process -- it offers a complete and open-access solution," says Hubert Hellwig, senior postdoctoral researcher and lead author of the study. "We designed custom modules, electronics, and control systems to make this platform safe, scalable, and reproducible -- and all data was made freely available."

With this automated continuous flow system developed at CiTOS, it is now possible to efficiently and safely produce key antibacterial drugs from biomass-derived furfural. By reducing the risks associated with nitration, this open-access solution paves the way toward a safer, more sustainable and more efficient pharmaceutical industry.