Handling of gaseous reagents for the preparation of high value-added chemicals under flow conditions

Abstract

Gas-liquid reactions are a common occurrence in organic synthesis, but are usually met with difficulties. These comprise the inefficiency of the gas-liquid mixing in reaction vessels, and the use of high pressures to increase the solubility of gaseous reagents. As a result, gas-liquid reactions are suffering from the limitation of mass transport and safety issues. To mitigate both hazards, continuous flow microreactor has emerged as an attractive technology due to its enhanced mixing efficiency, heat transfer and risk management capabilities. In this thesis, two distinct gaseous reagents, namely dinitrogen trioxide (N2O3) and carbon dioxide (CO2) are explored with flow technology. This work also relies on a subtle combination of both experimental and theoretical approaches to access insights on reaction mechanisms and inherent features. Firstly, the handling of N2O3 in flow, a strong and unstable nitrosative agent, is examined in the context of the preparation of sydnone and derivatives, a family of high added-value N-heterocycles. These N-heterocycles are typically synthesized from amino acid derivatives which undergo a N-nitrosative step, followed by a dehydrative cyclization step (cyclodehydration). The mechanistic pathway of the N-nitrosative reaction using N2O3 is studied in detail, allowing the rationalization of the inherent features of the reaction (such as the stoichiometric requirements). Then the optimization of the cyclodehydration in flow shows the inherent gains offered by flow processes compared to traditional batch reactions. Finally, the generation of N2O3, the N-nitrosative step and cyclodehydration reaction are concatenated in a one flow approach for the preparation of sydnone from N-phenylglycine. Secondly, the use of gaseous CO2, a quite unreactive C1 building block, is demonstrated with its reaction with bio-based glycidol to produce glycerol carbonate in flow. Glycerol carbonate is a high value-added target with expanding markets. After the optimization at the microfluidic scale, Barton’s base was identified as an effective homogeneous catalyst for the coupling of CO2 with biobased glycidol. The transposition of the optimized mesofluidic conditions in a pilot-scale reactor afforded an unprecedented daily productivity of 3.6 kg/day (E-factor = 4.7). Computational studies using density functional theory (DFT) provided key parameters of the reaction mechanism, such as the basicity of the catalyst, which is essential for a fast conversion of the epoxide substrate.