(101a) A Plug-and-Play Microreactor Platform for Small Volume Reaction Optimization

Applications of microsystem technology in organic synthesis are rapidly growing. There are several benefits of scaling down synthetic reactions to the microliter scale, such as extremely efficient mass and heat transport. Furthermore, temperatures can be controlled in a fast, accurate and reproducible way, enabling a higher selectivity in reactions. In addition, working with lower volumes is safer and more cost efficient.

To explore the possibilities of these new technologies, we started a collaboration with the Fraunhofer Institute for Microelectronic Systems in Duisburg (Germany) to jointly design and develop our own microreactor systems aimed at application in organic synthesis. This has resulted in a new plug-and-play automated microreactor system for chemical synthesis, which is currently routinely used by our group to perform approximately one hundred reactions per day in a single chip.

We have used this automated setup to study various catalytic reaction types such as selective protection of alcohol groups, biphasic Pd-catalyzed cross-coupling reactions (e.g. Sonogashira), oxidation reactions (e.g. Swern-Moffatt oxidations at room temperature), organocatalytic reactions (e.g. asymmetric Mannich reactions), but also biocatalytic reactions using crude cell lysates (e.g. enzymatic formation of cyanohydrins involving hydroxynitrile lyases). In all of these cases, minute amounts of catalyst and starting material were sufficient to generate a large number of data points allowing fast and efficient (i) reaction optimization, (ii) determination of scope and limitations of specific reactions, and (iii) determination of pH and temperature profiles of enzymatic reactions. In most cases, there appeared to be no significant differences between the continuous flow microscale setup and batchwise lab-scale experiments, implying that the automated microscale setup can be used to screen reaction conditions for subsequent synthetic application at large scale.