Date: 22 September 2025 | Category: News
A Suzuki–Miyaura coupling previously optimised for a packed bed reactor (PBR) was shown to provide identical results in both static catalyst and dynamic, recirculating catalyst modes using a cascade of four linked continuous stirred-tank reactors (CSTRs) and the Vapourtec RS-300 system, Figure 1.[1] Use of CSTRs provides significantly increased flexibility for reaction optimisation over fixed bed reactors, as solid supports with different particle sizes may be utilised. The use of CSTRs also decouples reactor volume from catalytic loading, enabling evaluation of reactor volume in conjunction with a fixed catalyst quantity. Finally, the cascade arrangement provides better control of residence time distribution (RTD) and increased conversion compared to a single CSTR, as well as the flexibility to control reaction parameters (e.g. temperature, mixing) and the catalyst at each stage. For this Suzuki–Miyaura coupling, the optimised conditions resulted in high conversion and yield with a residence time of just 75 seconds, without impacting catalyst performance.
Figure 1: Vapourtec R-Series flow chemistry system with a series cascade of four CSTRs
Flow Chemistry – a Greener, flexible approach
Continuous flow systems offer many advantages to traditional batch-based processes, including higher efficiency, flexibility in modification of reaction parameters, safer operating conditions, reliable reproduction of conditions during scale-up, and improved environmental footprint. Flow systems can be adapted to perform in-line analysis, providing real-time reaction monitoring, and low-volume reactors enable smaller scale reactions to be performed during scoping experiments. This allows scientists to explore a wide range of reaction parameters in a short space of time, facilitating rapid reaction optimisation.
Cascades of CSTRs provide advantages over single CSTR vessels
CSTRs are designed to operate continuously, with reactants flowing in and products flowing out of the vessel at the same time, whilst providing excellent mixing to give uniform composition, temperature, and concentration throughout. A cascade of linked CSTRs provides several advantages over a single CSTR, including tighter residence time distribution – a measure of the duration that a reaction component stays within the reaction vessel – and reduced back mixing.
Both static and dynamic CSTR cascades produce high conversion with short residence time
Heterogenous catalysis is widely utilised in the chemical, pharmaceutical and energy industries, and the Suzuki–Miyaura cross-coupling is one of the most important examples.[2, 3] Application of flow chemistry to this reaction provides improved reaction efficiency as well as reduced environmental impact, making this an attractive approach.[4, 5]
A Suzuki–Miyaura coupling previously optimised for a PBR [1] was assessed for feasibility using a cascade approach with CSTRs.[6] Using the Vapourtec RS-300 platform with four CSTR Flow reactors, two alternative configurations were assessed.
- A static design using CSTRs fitted with fritted cups that allowed only the reaction liquid to flow through the four vessels linked in series. Using 20 mL total volume and conducting the reaction at 100 °C, full conversion was achieved with a residence time of only 75 seconds. This static setup was also operated for a total of 12 hours without any blockage of the inline filters.
- A dynamic configuration was also assessed, wherein the first three CSTRs had no inline filters and the heterogenous reaction mixture was passed through each reaction vessel in series. The 4th CSTR vessel was operated at lower RPM to allow the catalyst to settle and an additional outflow line enabled recirculation of the catalyst back into the 1st CSTR, Figure 2. The final CSTR was also fitted with an inline filter and connected to a back pressure regulator to allow liquid to pass and product to be collected with the fraction collector. This dynamic mode also produced full conversion when the catalyst was recirculated.
a) 
b)
Figure 2: a) Schematic of dynamic CSTR cascade; b) Conversion and yield over time. Images from [6]
Both the static and dynamic modes produced identical results to the previously optimised PBR, utilising short residence times to produce high conversion without degradation of catalyst performance.
Summary
The Vapourtec RS-300 system was successfully configured to run a cascade of CSTRs in both static and dynamic modes to produce full conversion of a model Suzuki–Miyaura cross-coupling that replicated optimised conditions using a PBR. The cascade CSTR approach offers significant benefits, including increased flexibility of reaction parameters as well as the ability to conduct optimisation reactions more quickly than using PBRs.
References
[1] Vapourtec Application Note 49, 2016. https://www.vapourtec.com/flow-chemistry-resource-centre/suzuki-coupling-with-siliacat-dpp-pd-heterogeneous-catalyst/
[2] Recent Developments in the Suzuki-Miyaura Reaction: 2010–2014. (I. Maluenda, O. Navarro, Molecules, 2015, 20, 5, 7528–7557). https://doi.org/10.3390/molecules20057528
[3] Suzuki–Miyaura cross coupling reaction: recent advancements in catalysis and organic synthesis. (B. S. Kadu, Catal. Sci. Technol., 2021, 11, 1186–1221). https://doi.org/10.1039/D0CY02059A
[4] Green and scalable procedure for extremely fast ligandless Suzuki–Miyaura cross-coupling reactions in aqueous IPA using solid-supported Pd in continuous flow. (C. Mateos, J. A. Rincón, B. Martín-Hidalgo, and J. Villanueva, Tetrahedron Lett., 2014, 55, 27, 3701–3705). https://doi.org/10.1016/J.TETLET.2014.05.010
[5] Flow Chemistry for Flowing Cross-Couplings: A Concise Overview. (A. Ilenia Alfano, S. Barone, M. Brindisi, Org. Proc. Res. Dev., 2025, 29, 281−298). https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.4c00457
[6] Vapourtec Application Note 79, 2023. https://www.vapourtec.com/flow-chemistry-resource-centre/application-note-79-suzuki-miyaura-coupling-using-cstrs-2/
Download application note 79: Suzuki-Miyaura coupling using cascade of CSTRs