Mass Transfer in Flow Chemistry

One of the key benefits of flow chemistry is its superior mass transfer capabilities, which are crucial for multiphase reactions. The review highlights the photocatalytic Giese-type alkylation of gaseous hydrocarbons as an example. In flow reactors, the increased pressure forces gases into the liquid phase, enabling efficient activation of gaseous components. This technique is advantageous for flash chemistry, which requires ultra-fast reactions, and in the synthesis of complex pharmaceuticals like Verubecestat (Alzheimer’s disease), where efficient mixing in flow reactors enhances selectivity and yield.

Heat Transfer Advantages

Flow reactors’ microchannels provide a high area-to-volume ratio, leading to better heat transfer. This allows for precise temperature control and safer handling of exothermic reactions. The synthesis of diaryliodonium salts and Grignard reagents are prime examples where flow chemistry’s improved heat transfer results in higher yields, better safety, and scalability compared to batch processes. Flow reactors enable reactions under isothermal and superheated conditions, offering significant advantages over traditional methods.

Streamlining Multi-Step Synthesis

Flow chemistry excels in multi-step synthesis by integrating multiple reactions into a continuous process. This integration reduces the need for intermediate purification, significantly improving efficiency. The continuous synthesis of the antibiotic Linezolid and the kilogram-scale production of Prexasertib monolactate monohydrate exemplify flow chemistry’s potential. These processes demonstrate enhanced efficiency, safety, and scalability, showcasing the method’s promise in pharmaceutical manufacturing.

Innovations in Photochemistry

Flow chemistry’s coupling with photochemistry overcomes challenges such as light absorption limitations in batch reactors. Flow reactors ensure uniform light intensity, reducing reaction times and side-product formation. For instance, decatungstate-photocatalyzed amination of C(sp³)–H bonds in flow reactors achieves high productivity and efficiency. Other applications include modular allylation of unactivated C(sp³)–H bonds and various photocatalytic transformations, illustrating the versatility and power of flow photochemistry.

Electrochemistry in Flow Systems

Flow chemistry is particularly beneficial for electrochemical reactions due to its ability to manage the precise conditions required for these processes. Continuous flow reactors facilitate better electrode contact and efficient electron transfer, leading to higher reaction efficiencies and yields. The integration of electrochemistry in flow systems opens up new avenues for green and sustainable synthesis, enabling novel transformations that are difficult to achieve in batch processes.

Safety and Scalability

– Safety: Flow chemistry improves safety by minimizing the volume of hazardous materials and providing better control over reaction conditions. This is crucial for reactions involving toxic or unstable intermediates.

– Scalability: The continuous nature of flow processes allows for easy scaling from laboratory to industrial production without significant modifications. This scalability is a key advantage for pharmaceutical manufacturing and other high-demand industries.

High-Throughput Experimentation and Automation

Flow chemistry is well-suited for high-throughput experimentation (HTE) and automation, facilitating rapid screening of reaction conditions and optimization.

– High-Throughput Experimentation: Allows the simultaneous testing of multiple reactions under varying conditions, significantly speeding up the discovery and development process.

– Automation: Automated flow systems enhance reproducibility and efficiency by precisely controlling reaction parameters and reducing human error.

Conclusion

Flow chemistry provides significant advantages in mass and heat transfer, multi-step synthesis, photochemistry, electrochemistry, safety, scalability, high-throughput experimentation, and automation. Recent advancements have made it more accessible, leading to its increased adoption in synthetic organic chemistry. This review offers valuable guidelines for using continuous-flow reactors, aiding researchers in leveraging flow chemistry for efficient and scalable synthesis.

Authors’ Contributions and Affiliations

– Luca Capaldo: MSCA postdoctoral researcher specializing in photocatalyzed hydrogen atom transfer.

– Zhenghui Wen: Postdoctoral researcher focused on green, scalable photochemistry in flow.

– Timothy Noël: Professor and Chair of Flow Chemistry, Editor-in-Chief of the Journal of Flow Chemistry.

For a detailed exploration, refer to the original article: A field guide to flow chemistry for synthetic organic chemists