Route scouting in heterogeneous reactions with the ReactALL™

Introduction

Heterogeneous solid-liquid reactions are vital in industries like pharmaceuticals and fine chemicals, where understanding reaction time profiles is key to optimizing conditions, ensuring quality, and maximizing yield. However, accurately monitoring these reactions is challenging due to sampling and mixing complexities. Optimizing such processes also requires evaluating parameters like stoichiometry, addition order, timing, and mixing mode.

This application note presents research by Hawkins et al. [1], which compares the performance of the ReactALL system in a heterogeneous amine alkylation reaction to that of a commercial reactor and a vial stirred with a magnetic stir bar.

Experimental

The study involved the N-methylation of 1-phenylpiperazine with methyl p-toluenesulfonate using potassium carbonate in 2 methyltetrahydrofuran. The reaction was monitored in three different reactor setups: a commercial overhead stirrer, a vial with magnetic stirring, and the ReactALL system. The experiment involved sequentially charging a reactor vial with reagents, maintaining a constant temperature of 25 ºC with continuous stirring at 500 rpm. The reaction was initiated by adding methyl p-toluenesulfonate, with automated sampling programmed using a quench solution and diluent for analysis.

Results

The ReactALL demonstrated precise control and consistent mixing, particularly in suspending solid potassium carbonate throughout the reaction. The time profiles revealed a significant difference between magnetic and overhead stirring methods, with the overhead stirring reactors stalling at 50% conversion, while magnetic stirring allowed further progress (Figure 1a). However, ReactALL showed a consistent conversion pattern similar to the commercial reactor, with added benefits of automated sampling and accurate chemoselectivity measurements (Figure 1b).

Additionally, Hawkins et al. evaluated the effect of grinding potassium carbonate on the reaction's time profile. A 16 mL vial was charged with potassium carbonate and 2-methyltetrahydrofuran, stirred at room temperature for 24 hours, then combined with additional reagents and stirred at 25 °C. After adding methyl p-toluenesulfonate to start the reaction, automated sampling was performed. The results showed that the reaction using ground potassium carbonate closely matched those obtained with magnetic stirring in the ReactALL system, as shown in Figure 2.

Conclusion

The ReactALL system proved to be an effective tool for route scouting in heterogeneous reactions, offering reliable sampling and mixing. Its ability to replicate scale-relevant conditions while providing real-time data makes it an asset in optimizing reaction parameters, improving decision-making in process development and scaling.

References

Hawkins, J. M., Pfisterer, D. M., Algera, R. F., & Monfette, S. (2024). The ReactALL Platform: Experimental Data and Case Studies. Organic Process Research & Development. https://doi.org/10.1021/acs.oprd.4c00210

Data and figures are adapted with permission from Org. Process Res. Dev. 2024, 28, 9, 3637–3644. Copyright © 2024 American Chemical Society.