Rapid determination of activation parameters with the ReactALL™

Introduction

In chemical reaction analysis, parallel reactor setups are essential for rapidly assessing reaction conditions such as temperature, which affects both the reaction rate and selectivity. In SNAr reactions, where a nucleophile displaces a leaving group on an electron-deficient aromatic ring, these setups allow for the efficient collection of data across multiple conditions, facilitating the determination of critical kinetic parameters like activation energy.

The ReactALL™ system, with its five independently controlled reactors, is designed for such applications, enabling temperature-dependent kinetics and multidimensional kinetic evaluations across concentration and reagents.

Experimental

Hawkins et al. [1] conducted experiments to evaluate the SNAr reaction between 2,4-difluorobenzonitrile and 1-phenylpiperazine using the ReactALL system. Two sets of experiments were performed. The first set varied the temperature (32 - 80 ºC) while maintaining a fixed reactant concentration of 0.20 M, and the second set varied the reactant concentrations at a constant temperature of 56 ºC. The stoichiometry of the nucleophile, electrophile, and base was maintained at a 1:1.1:2 ratio in acetonitrile. Aliquots were periodically sampled, quenched with acetic anhydride, and analyzed using UPLC-MS.

Results

The ReactALL system provided reliable concentration vs. time plots, allowing for the determination of initial rates of 1-phenylpiperazine consumption at different temperatures, as shown in Figure 1a. These rates were decomposed into component rate constants for two regioisomeric products, Para-1 and Ortho-1. The reaction showed a strong preference for the formation of the Para-1 product over Ortho-1, with a selectivity ratio of approximately 7:1, largely independent of temperature and concentration. The kinetic analysis revealed that the reaction is first-order in both electrophile and nucleophile, but zeroth-order in the base. The Eyring analysis yielded activation enthalpies of 9.7 kcal/mol and 10.2 kcal/mol for Para-1 and Ortho-1, respectively, with notable differences in activation entropies, as given in Table 1.

Conclusion

The ReactALL system enabled a rapid determination of activation parameters for the SNAr reaction. The system’s automation and independent temperature control proved essential for collecting high-quality kinetic data. These results highlight the utility of ReactALL in optimizing reaction conditions for industrial applications. The study also suggests that strategies beyond simple base promotion, such as alternative catalysis or solvent effects, may be necessary to modulate regioselectivity in similar reactions.

References

[1] 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.