High-speed circulation microflow synthesis facilitating practical large-scale heterogeneous photocatalysis

doi:10.21203/rs.3.rs-2990313/v1

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High-speed circulation microflow synthesis facilitating practical large-scale heterogeneous photocatalysis

https://doi.org/10.21203/rs.3.rs-2990313/v1

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Although continuous-flow synthesis using microtubing reactors has provided a wealth of opportunities for photochemical synthesis and has proven particularly beneficial in scaling up processes, handling solids and slow reactions remains major hurdles that have hampered its broad application. Here, we present a solution to these issues by changing the continuous-flow mode to a high-speed circulation-flow mode. The high flow rate set in a circulation microflow reactor overcomes solid sedimentation to prevent clogging and improve mixing efficiency. We successfully conducted 100 g-scale C-N and C-S cross-couplings using a heterogeneous photocatalyst and a nickel catalyst in the microflow reactor that significantly outperformed conventional batch reactors. The photocatalyst was recycled and reused 10 times to achieve kg-scale synthesis without obvious deactivation. Even though the reaction occurred in batch mode, semi-continuous production was achieved via automated feeding and collection, and a photo-promoted gas/liquid/solid three-phase trifluoromethylation reaction was employed to produce the drug trifluridine on a kg scale. Our study suggests that a circulation flow reactor with high flow speed will become a crucial tool in the synthetic chemist’s toolbox, owing to its simple infrastructure, ease of operation and automation, significant efficiency improvement compared to conventional batch reactors, scalability, improved safety and tolerance of solids.

Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology

Physical sciences/Chemistry/Photochemistry/Photocatalysis

Physical sciences/Chemistry/Catalysis/Heterogeneous catalysis

In the last decade, photocatalysis has undergone significant exponential development, and photo-harvesting catalysts have opened up tremendous opportunities for assembling molecules in a mild, green, and effective manner. These catalysts can promote various mechanisms such as single-electron transfer (SET)¹, energy transfer², or hydrogen atom transfer (HAT)^3,4 to access reactive open-shell species or pump to energy uphill intermediates. While conventional batch photochemical reactors remain the first choice for developing new reactions due to their low cost and ease of screening, operation, and reaction monitoring, continuous-flow reactors are gaining increasing attention for scaling up photochemical reactions as a result of the Beer‒Lambert law^5,6. The fact that only the proximal area (e.g., within 2 mm) of the vessel wall can be irradiated effectively with visible light makes it difficult to employ a dimension-enlarging strategy for scaling up reactions in conventional batch reactors⁷. In contrast, a continuous microflow reactor can achieve uniform and effective light irradiation with narrow-diameter tubing or microchannels. Other advantages of the continuous microflow reactors include improved mass/heat transfer, enhanced safety, precise control of reaction parameters, excellent reproducibility, and ease of scaling up^8,9, which enable faster reactions and lower photocatalyst loadings.

Although continuous-flow reactors offer significant advantages, slow reactions that require extended reactor lengths can pose challenges due to the increased risks of pressure drops, clogging, and infrastructure complications. Furthermore, heterogeneous photocatalysis in a continuous-flow reactor remains a challenging task (Fig. 1). In this context, various advanced flow technologies have been designed to overcome the limitations posed by solid photocatalysts (Supplementary Fig. 7)¹⁰. Although packed-bed reactors are commonly utilized for heterogeneous catalysis, the opacity of solid photocatalysts restricts their usage to capillary reactors¹¹ or premodified glass bead-supported photocatalysts (Supplementary Fig. 7a)^12,13. Continuous stirred tank reactors (CSTRs) have been applied to heterogeneous photocatalysis to achieve gram-scale syntheses¹⁴, but they exhibit poor residence time distributions (RTDs), particularly for large vessels (Supplementary Fig.7b). Oscillatory flow reactors offer a promising technology for heterogeneous photocatalysis, even for slow reactions¹⁵. Gram- to hundred-gram-scale syntheses have been demonstrated with these systems (Supplementary Fig. 7c)¹⁶. However, a compromise between efficient particle suspension and a narrow RTD has to be achieved through optimization. Other methods include a gas‒liquid-solid system used to assemble serial microbatch reactors¹⁷(Supplementary Fig.7d) and a rotor-stator spinning disk reactor¹⁸ (Supplementary Fig. 7e). However, only gram-scale production was obtained with the former method, and the latter setup for photo-involved processes was limited by the irradiated area and has only been demonstrated for heterogeneous photodegradation of an organic dye to date. Most of the developed reactors yielded low production rates with short residence times due to limited reactor volumes. Furthermore, most of these reactors require specialized equipment investments and are difficult to customize on demand. Therefore, a general, simple, customizable and easily scalable system that is effective for heterogeneous photocatalysis remains an unmet but highly desirable need.

Circulation flow reactors, which immobilize photocatalysts for wastewater treatment and waste degradation, have been subject to theoretical investigation and experimental validation at a small scale^19-22. Although there are sporadic reports of utilization in fine chemical syntheses^23-27 and natural product syntheses²⁸, their advantages have not yet been widely recognized within the synthetic community. In contrast to continuous-flow reactors, which halt the reaction at the outlet, circulation flow reactors recirculate the reaction mixture back to the reaction reservoir, allowing it to reenter the reactor until the reaction reaches completion. They maintain all the benefits associated with microtube reactors, including excellent light penetration, improved mass and heat transfer, and enhanced safety. More importantly, we envisioned that the use of circulation flow reactors for conducting reactions offers several advantages over continuous-flow reactors. First, the reaction occurs in batch mode, and the reaction time is not restricted to the reactor volume; thus, it can be performed for as long as necessary, enabling the performance of slow reactions in flow mode. Even though the reaction scale may be somewhat limited by the tubing volume, we can easily introduce new sets of reagents and starting materials into the reservoir to start another batch and achieve semi-continuous production via automated feeding and collection. The compact and modular design of the system lends itself to scaling up through a numbering-up strategy. Second, as the time now is not limited to the reactor volume, the flow can be operated at elevated velocities that can overcome issues related to solid sedimentation and clogging²⁹. This allows for effective heterogeneous photocatalysis in flow, while also facilitating improve mass and heat transfer for greater efficiency of the reaction.

We herein demonstrate successful applications of high-speed circulation flow reactors to heterogeneous photocatalysis at the kilogram scale. Based on our preliminary results, we anticipate that these reactors will become an essential tool in the chemist's repertoire, especially for conducting slow reactions or those involving solids. By enabling a wider range of synthetic methods to be performed in flow, even at a large scale and in an automated fashion, these reactors hold tremendous potential for advancing the field of chemistry.

Investigation of high-speed circulation flow reactors for heterogeneous photocatalysis. Compared to homogeneous photocatalysis, heterogeneous photocatalysis is an underexplored field in organic synthesis, especially with respect to scaling up³⁰. Polymeric carbon nitrides (PCNs) are among the most appealing heterogeneous catalysts for photocatalysis and have undergone significant development during the past decade due to their metal-free and inexpensive characteristics, tunable bandgaps, and excellent chemical and photostabilitities^31,32. In this study, we investigated the feasibility of heterogeneous photocatalysis in a flow process using nickel/mesoporous graphitic carbon nitride (mpg-CN) photo-mediated C−N coupling reported by König^33,34, which is an industrially significant dual catalytic reaction for achieving ligand-free Buchwald-Hartwig type C−N coupling under ambient conditions³⁵. However, initial attempts to perform the reaction in a capillary packed with mpg-CN (with particle diameters ranging from 1–3 µm, Supplementary Fig. 2), yielded a very low product yield, with significant Ni-black contamination after just an hour of flow operation, thus blocking light penetration (Supplementary Fig. 8a). Furthermore, introducing argon gas to flow a gas‒liquid−solid suspension to mimic a serial microbatch reactor proved to be ineffective, with less than 5% conversion achieved due to the short residence time. Reducing the flow rate to increase the residence time to 5 h only gave small improvement to 12% conversion and 7% yield (Supplementary Fig. 8b). We then focused our efforts on utilizing the circulation flow reactor.

A custom-designed circulation flow system was assembled as a proof-of-concept for a study, comprising a reagent reservoir, peristaltic pump, perfluoroalkoxyalkane (PFA) tubing coil, and multiple sets of 64 W light-emitting diode (LED) (Supplementary Fig. 9). The study aimed to investigate the impact of different flow rates to overcome the challenge of solid deposition. At a 10-gram scale, the substrates were first mixed with 5% w/w mpg-CN and 5 mol% NiCl₂⋅glyme in 100 mL of DMA to create a slurry. The slurry was continuously pumped at variable flow rates using a peristaltic pump and directed to the PFA tubing reactor (outer diameter (O.D.) = 6.4 mm, inner diameter (I.D.) = 4.8 mm, volume (V) = 90 mL). The reactor was irradiated by 9 sets of 64 W LEDs (Supplementary Fig. 9c). The reaction mixture was recirculated to the original reservoir until the reaction was completed.

To ensure optimal irradiation of most of the solution in the tubing coil, the tubing reactor volume was kept constant at 90 mL. The results indicated that at a flow rate of 20 mL/min, the flow was interrupted after 2 hours of reaction due to clogging, resulting in only 35% conversion (refer to Fig. 2a). However, when the flow rate was raised to 30 mL/min, full conversion was achieved in 12 hours, despite partial aggregation of the mpg-CN in the tubing reactor. At a flow rate of 40 mL/min, complete conversion was accomplished in just 8 hours, and aggregation was entirely prevented. Higher flow rates (80 and 120 mL/min) resulted in smooth flow processes, but no further acceleration of the reaction rate was observed. Therefore, circulation with a high flow rate proved effective in overcoming solid sedimentation and preventing clogging.

The I.D. of the tubing utilized in the circulation flow reactor was identified as a crucial parameter affecting several important factors such as production capacity, mixing efficiency, and light penetration and uniformity. To assess the effect of tubing size on the reaction, the experiment was repeated in the circulation flow reactor at a flow rate of 80 mL/min using three different tubing sizes with I.D. values of 1.6 mm, 3.2 mm, and 4.8 mm, as depicted in Fig. 2b. The results revealed that comparable conversions and yields were attained with the different tubing sizes, provided no clogging occurred.

Subsequently, the concentration and catalyst loading were explored (Fig. 2c and Supplementary Fig. 9c). It was found that a lower catalyst loading of 2.5% w/w mpg-CN and 2.5 mol% NiCl₂⋅glyme at a concentration of 10 g/100 mL yielded satisfactory results in the circulation flow reactor. Moreover, it was observed that the number of 64 W LED lamps could be reduced from 9 to 5 without compromising the reactivity (Fig. 2d). However, a decrease in the number of lamps to 3 or 4 was observed to lead to a noticeable decline in the reaction efficiency.

Scaling up of heterogeneous photocatalytic C−N, C−S, and C−C couplings. After demonstrating the viability of heterogeneous photocatalysis in high-speed circulation flow syntheses, we scaled up the C−N coupling model to 100 g to showcase its practical synthetic applications. This was achieved using a circulation flow rate of 400 mL/min in a microtubing reactor with a volume of 850 mL (Supplementary Fig. 10). Full conversion was attained in 8 h (Fig. 3a, left), with yields comparable to that of the 10-g scale reaction. Remarkably, conducting the same-scale reaction in a conventional batch reactor (Supplementary Fig. 13) only yielded 30% conversion after 12 h, underscoring the circulation flow reactor's tenfold greater efficiency than the batch reactor. Moreover, the heterogeneous mpg-CN photocatalyst was recovered via simple filtration and washing and sustained its catalytic capacity for at least ten cycles of the C−N coupling reaction (Supplementary Figs. 11 and 12), enabling kilogram-scale synthesis with the same batch of photocatalyst (Fig. 3a, right).

To demonstrate the broad utility of the high-speed circulation flow reactor, the same reactor was used in a 100-g scale heterogeneous photocatalytic C−S coupling³¹ to produce a precursor for the drug molecule bipenamol (Fig. 3b). As expected, the high-speed circulation flow exhibited significantly higher reaction rates compared to conventional batch synthesis due to enhanced light irradiation and excellent mixing efficiency. Furthermore, the circulation flow reactor was easily reconfigured for gas/liquid/solid triphasic photocatalytic oxidative trifluoromethylation³³ by introducing another peristaltic pump for the delivery of air. This modification led to the production of 57.3 grams of the isolated drug trifluridine (Fig. 3c and Supplementary Fig. 14). Notably, the reactions run in the circulation flow reactor consistently showed significantly improved efficiencies compared to those of the conventional batch reactor.

Enabling kilogram-scale semi-continuous production in an automated fashion. The transition from manual to automated chemical synthesis offers numerous benefits, such as enhanced efficiency, cost-effectiveness, on-demand production^36–39, and improved reproducibility in processes adhering to good manufacturing practice (GMP)^40,41. However, the adoption of conventional batch reactors for automation necessitates the use of sophisticated control systems and significant investments in specialized infrastructure^42–44. Continuous flow processing offers a promising and easy alternative for automation due to its continuous nature and ease of automating unit operations^45–47. Nonetheless, the incompatibility of solids limits the range of viable reaction patterns.

We envisioned that the high-speed circulation flow system would serve as an excellent platform for automated syntheses, inheriting the merits of continuous microflow reactors while addressing challenges related to solid clogging. Although the reactions occur in batch mode, semi-continuous production can be simply achieved through automated feeding and collection, controlled by pumps and valves. To demonstrate its feasibility, the 100-g Minisci-type trifluoromethylation circulation flow system was further equipped with a reagent feeding container, a solvent feeding container, a product collecting bottle, a waste collection bottle, a jacket-condenser and an additional set of valves and pumps. Automation was implemented through the use of Python programming, which enabled the precise control of pumps and valves to specify the paths of air, solvent, and slurry (Figs. 4b and 4c). Automated production for 210 h using irradiation with 425 nm LED light and 1 kg of starting materials afforded the product trifluridine in an overall 43.2% yield (Fig. 4a). Consistent results were obtained across ten batches of circulation flow synthesis (Section 7.4 in the Supplementary Information). Moreover, the absence of clogging throughout the entire reaction process demonstrated the robustness of the system. The catalyst could be recovered and reused. These results clearly indicate the potential for scalable on-demand production of value-added compounds using this simple yet highly efficient platform.

We demonstrated the successful implementation of 100 g-scale C−N, C−S, and C−C cross-couplings via heterogeneous photocatalysis using a custom-built high-speed circulation flow reactor, which significantly outperforms conventional batch reactors. The photocatalyst can be recycled and reused at least 10 times. A kilogram-scale gas/liquid/solid three-phase photochemical synthesis was achieved with an automated and continuous 210 h process to give trifluridine in an overall 43.2% yield. The high-speed circulation flow reactor represents an overlooked technology that holds great potential for enhancing the synthetic community's ability to leverage heterogeneous photocatalysis on a scalable platform. The high-speed circulation flow reactor promises to become a critical component in supplementing existing reaction setups owing to its simple infrastructure, ease of operation, and excellent efficiencies for mixing, heating, and light irradiation. In addition, the system overcomes clogging issues, facilitates effective slow reactions, enables scale up, and achieves automation. Ongoing research on this technology has revealed its capability to perform smoothly and effectively even with an excess amount of solid reagents (Supplementary Fig. 22), thereby expanding the range of chemical syntheses in flow and providing chemists with a convenient and automated platform.

High-speed circulation flow synthesis for C−N and C−S couplings. The solvent, additives and mpg-CN were successively added to a Duran® screwed bottle. Under stirring, the resulting slurry was bubbled with argon gas sufficiently, and the substrates and the nickel catalyst were added. The slurry mixture was subjected to ultrasonication for 10 min and then connected to the tubing of the circulation flow reactor (Supplementary Fig. 9 or Supplementary Fig. 10). The pump was started with the set flow rate. When the tubing was filled with the reaction mixture, air cooling and water cooling were switched on. Then, all LEDs were turned on. The reaction was monitored via GC analysis by following the method described in Supplementary Section 5 and Supplementary Section 6. When the GC analysis indicated full conversion, the reaction mixture was subjected to the posttreatment procedure described in Supplementary Section 6 to furnish the desired products.

Manual operation of circulation flow synthesis for the trifluoromethylation reaction. DMSO, 2’-deoxyuridine, CF₃SO₂Na, and mpg-CN were added to a Duran® screwed bottle. The resulting mixture was ultrasonicated for 10 min and then connected to the tubing of the circulation flow reactor (Supplementary Fig. 14). Two pumps were started simultaneously with set flow rates. The air cooling and the water cooling were switched on. When the slurry had flowed back to the bottle, all LED lights were turned on. The reaction process was monitored via HPLC analysis by following the method described in Supplementary Section 6. When the HPLC analysis indicated full conversion, the reaction mixture was subjected to the posttreatment procedure described in Supplementary Section 6 to furnish the desired product.

Kilo-gram scale automated execution of the trifluoromethylation reaction. The automated circulation flow reactor was assembled as illustrated in Supplementary Fig. 16, and it consisted of two peristaltic pumps, two four-port selection valves, PFA tubing (V = 1300 mL), and a computer serving as the control station. The reaction material was prepared as in the manual operation, and the feeding bottle was fed again after swab-off. The automated operation was performed as depicted in Supplementary Fig. 19 for 10 batches (210-hour continuous running) to enable a kilogram-scale synthesis.

Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. The Python code for the automated synthesis of trifluridine described in this study is available at https://github.com/nus-automated-flow-system/Automated-circulated-flow

Acknowledgements

We are grateful for the financial support provided by Pharma Innovation Programme Singapore (A*STAR, SERC A19B3a0014), Pfizer (A-8000004-00-00), the Agency for Science, Technology and Research (A*STAR) under its AME IRG Grant (Project No. A20E5c0096), the Prime Minister’s Office of Singapore under its NRF-CRP Programme (NRF-CRP25-2020RS-0002), and the NUS (Chongqing) Research Institute. The authors would like to thank Prof. Shunsuke Chiba (NTU), Prof. Edwin K. L. Yeow (NTU), Patrick O’Neill (Pfizer), Srinivas Reddy Dubbaka (Pfizer), Joel M. Hawkins (Pfizer), Thomas Knauber (Pfizer), François Lévesque (Merck), Lee Edwards (GSK), and Jean-Philippe Krieger (Syngenta) for helpful discussion.

Author contributions

C.L. and J.W. conceived and designed the investigations. C.L., L.S., J.X. and M.W. performed the experiments. J.W., C.L., L.S. and J.X. analysed the experimental data. Q.L. and L.C. prepared the mpg-CN catalyst and performed its characterization. W.C., Y.Z. and T.W.T. performed the programming for automated control. J.W., C.L., S.A.K., J.X., Z.L. wrote the manuscript with input from all authors. All of the authors have approved the final version of the manuscript.

Competing interests

J.W., C.L. and M.W. are inventors on a Provisional Patent Application 10202251278Y filed by the National University of Singapore, which covers heterogeneous photocatalysis based on high-speed circulation flow reactors. The authors declare no other competing interests.

Additional information

Supplementary Information is available for this paper at

Correspondence and requests for materials should be addressed to Jie Wu.

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Yes there is potential Competing Interest. J.W., C.L. and M.W. are inventors on a Provisional Patent Application 10202251278Y filed by the National University of Singapore, which covers heterogeneous photocatalysis based on high-speed circulation flow reactors. The authors declare no other competing interests.

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