An Innovative Fluidic Technology For The Exploitation Of N₂O₃ In Organic Synthesis

Researchers from CiTOS - Center for Integrated Technology and Organic Synthesis ( MolSys Research Unit , Faculty of Sciences ) directed by Jean-Christophe Monbaliu have developed a microfluidic platform for the generation of anhydrous dinitrogen trioxide (N₂O₃ ) . N₂O₃ is a notoriously difficult nitrosating reagent to prepare and use. This project, funded by the FRS-FNRS as part of a Scientific Impulse Mandate, opens up new perspectives for the use of N₂O₃ for the preparation of organic molecules with high added value. The results of this study are now published in the journal Angewandte Chemie International Edition . This article is open access, and can be read online for free.

Small cyclic molecules containing nitrogen atoms (N -heterocycles) are common structures in biologically active compounds, especially molecules with a pharmaceutical purpose. Developing new methods for the incorporation of nitrogen into ring structures is therefore a timely and important goal for drug development. Among these methods, nitrosation is one of the most effective approaches for introducing nitrogen onto the backbone of organic molecules. Common nitrosation reagents are mainly salts and esters of nitrous acid (HNO₂), which are by-products of nitric oxide (NO). NO, best known as a pollutant associated with combustion engine exhaust, is also produced industrially on a large scale. The usual nitrosation reagents have a deleterious environmental impact.

Dinitrogen trioxide (N₂O₃) is a dark blue compound, acting as a powerful nitrosating agent. It can be prepared by reaction between NO and oxygen (O₂ ) under strictly controlled conditions and at low temperature, preferably in solution. N₂O₃ is not stable at room temperature: it equilibrates with several decomposition products (NO, NO₂ and N₂O₄ ), whose synthetic utility is much less. This instability is exacerbated when the N₂O₃ solution is surrounded by a gaseous atmosphere, making the concentration of N₂O₃ in the liquid phase extremely difficult to control. Consequently, the concrete applications of N₂O₃ in synthetic organic chemistry for the preparation of N -heterocycles are reduced to a trickle.

Stimulated by the unique reactivity of N₂O₃ and the possibility of preparing it from a common pollutant (NO), researchers from the CiTOS laboratory (Center for Integrated Technology and Organic Synthesis), directed by Jean-Christophe Monbaliu, have developed a concrete solution to allow its preparation and study under very controlled conditions. The research team relied on the inherent characteristics of micro- and mesofluidic reactors in order to design a unique technological response. " In the confined internal volume of micro- and mesofluidic reactors, the elimination of the gaseous phase is possible thanks to the operation in continuous flowexplains Yuesu Chen, first author and senior postdoctoral researcher affiliated with CiTOS. The precise combination of NO and O₂ in the presence of a suitable solvent forces the N₂O₃ to form directly in the liquid phase, thus avoiding any deleterious secondary reaction and decomposition in the gas phase. A reliable and robust chemical generator of N₂O₃ is therefore now available to the scientific community ”.

This N₂O₃ chemical generator feeds a downstream module for nitrosation reactions, allowing its direct use for the preparation of a wide variety of unique N-heterocycles, including benzotriazole and sydnone family molecules , two structures common to certain drugs. “This research has both practical and theoretical importance for the organic chemistry of nitrogen oxides and nitrosation reactions. It represents a significant breakthrough in the development of modular continuous-flow strategies for the preparation of high value-added N-heterocyclic compounds .This technological approach breaks with the state of the art: it quite simply makes the study and synthetic chemistry of N₂O₃ possible ,” comments Jean-Christophe Monbaliu.

The culmination of this project, funded by the FRS-FNRS . as part of Jean-Christophe Monbaliu's Scientific Impulse Mandate, is based on a multidisciplinary approach at the interface between organic chemistry, new process technologies and computational chemistry. This research is part of one of the priority areas of research at the CiTOS laboratory, with the ambition of chemical and technological innovation to tame unstable reagents.

Funding
FRS-FNRS (Scientific impulse mandate MIS F453020F, JCMM).