New Opportunities For Organic Synthesis In Superhot Micro/Mesofluidic Conditions

The fruit of research from the Center for Integrated Technology and Organic Synthesis (CiTOS) demonstrates the opportunities offered by micro/mesofluidic technologies to explore new reaction spaces. By playing on the compression of the spatiotemporal framework of processes thanks to the unique properties of fluidic technologies, the horizons of increased productivity and discovery of new reaction pathways are broadening. This guide is now published in the journal Accounts of Chemical Research , and is available in open access.

L Micro/mesofluidic reactor technology (also known as continuous flow technology) has demonstrated enormous potential to rethink traditional chemistry pathways, but it still faces many challenges. Indeed, micro/mesofluidic reactors operate in a very different spatiotemporal framework than conventional macroscopic batch reactor technologies. As discussed in a previous article , reaction timing is a critical parameter to ensure the viability of large-scale continuous flow processes. While batch processes can easily accommodate slow reactions over extended periods (from minutes to days), micro/mesofluidic reactors are typically designed for much shorter reaction times (ideally less than a minute, but they can reasonably handle reactions down to about fifteen minutes to maintain economic viability at production scales).

This time constraint is significant, as many reactions require longer periods to reach high conversions, which is a major barrier to widespread adoption of micro/mesofluidic technologies. For example, a second-order reaction (1 M) in water with an activation enthalpy of 9.8 kcal/mol and an activation entropy of -0.0456 kcal/mol requires five days to reach complete conversion at room temperature. At reflux (100 °C), this same reaction undergoes a significant acceleration. Even at 35 times faster, it will still take more than 3 hours for this reaction to complete at reflux, making it still unsuitable for micro/mesofluidic technology. Conventional batch processes typically operate in the solvent boiling limit. This limit provides an upper limit on the reaction temperature, and requires changing the solvent to reach higher temperatures. This last point, although now routine, introduces additional drawbacks: the choice of solvent is restricted to the boiling point, to the detriment of reaction compatibility, solubility, selectivity, cost and toxicity.

Superhot approaches in micro/mesofluidic reactors leverage the advantages of this technology by operating above the boiling points of solvents to improve reaction rates, increase productivity and safety, while aligning with sustainability goals. Returning to our example, the same reaction under superhot conditions in a micro/mesofluidic reactor at 200 °C in water would see its rate increased 713 times, and would be completed in ten minutes. Like a magician, superhot approaches in micro/mesofluidic reactors defy conventional wisdom, compressing the spatiotemporal framework of processes and making slow reactions suitable for micro/mesofluidic technology.

"Despite its considerable advantages, accessing superhot conditions in micro/mesofluidic reactors is complex and resource-intensive, especially for beginners," explains Jean-Christophe Monbaliu, Director of CiTOS. " In this Account, we provide a concise overview of superhot chemistry in micro/mesofluidic reactors , including key concepts, reactor options, and strategic adoption methods based on experimental design, microwave preliminary testing, kinetic data collection, and quantum mechanics. Our goal is to guide the exploration of these vast chemical spaces and accelerate the adoption of these innovative techniques. We also highlight recent examples from our lab and other leading contributors. This Account also illustrates how this concept has become a foundation for our WEL-T research project "Intelligent flow systems for advanced chemical manufacturing."