Self-optimization of Claisen Schmidt condensation on a microflow reaction system

The doctoral dissertation presents the development of an autonomous, self-optimizing microflow system, which was experimentally validated on the Claisen–Schmidt condensation between 2-methoxybenzaldehyde and acetone. The aim of the research was to develop a faster, more efficient and sustainable approach for the optimization of complex, multi-step reactions sensitive to process conditions. Due to the limitations of classical approaches (one parameter at a time, DoE), we designed an integrated system that combines flow chemistry, process analytical techniques (PAT) and artificial intelligence methods. The system is based on a microflow reactor with a FlowPlate reaction plate, two PAT technologies (in-line FTIR and off-line UPLC) and the multi-objective optimization algorithm TSEMO. The Python software, using DLL and OPC UA protocols, implements a master/slave architecture for connecting and controlling components, which allows for precise automated control of reaction conditions, detection of steady state and triggering of UPLC analyses. The model reaction proceeds in two stages, the second of which is kinetically limiting. We developed a two-step kinetic model that allows reliable predictions of reaction conditions and takes into account the temperature and concentration dependence of the formation of the intermediate (enone) and the final product (dienone). Despite the lower activation energy, the second step is limiting due to the lower pre-exponent, which requires precise control of the intermediate equilibrium. The system achieved rapid convergence to optimal conditions; the maximum dienone content was 69.1% (UPLC area %), with an average deviation of 7.5%. We validated the experimental results with model predictions and achieved agreement within ±10%, which confirms the reliability of the system. The results prove that complex chemical reactions can be controlled and optimized without manual control. The system is modular, scalable, enables easy integration of new devices and methods, shortens development time and reduces reagent consumption. Autonomy ensures faster search for optimal conditions, greater safety and reproducibility, which contributes to the digitalization of laboratories of the future. The innovation received a gold award from the Chamber of Commerce of Dolenjska and Bela Krajina.

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