Boosting Productivity in Scalable Continuous Grignard Reagent Formation via Model-Based Design of Experiments and Optimization

The continuous synthesis of reactive Grignard reagents poses a process engineering challenge due to the exothermic reaction, the tendency to form side products, and the dependence on various parameters (e.g., concentrations of halide and magnesium, temperature, residence time, reaction kinetics, reactor-specific variables). The benzylmagnesium bromide synthesis is prone to Wurtz coupling and serves as a benchmark synthesis for developing a numerical physical model of a lab-scale tubular flow reactor. The model is refined through an iterative, model-based Design of Experiments (DoE) approach, which then enables both process optimization and reactor scale-up. When applied at the laboratory scale, this DoE strategy reduces the number of required experiments while preserving the model accuracy. Ultimately, model-driven optimization leads to a demonstrated 2-fold increase in productivity in the pilot-scale reactor, all while maintaining safe operating conditions.