Approaching Flow Chemistry: A Tutorial

Flow chemistry has revolutionized chemical synthesis by offering precise control over reaction conditions and enabling reproducibility across a wide range of chemical processes. This article serves as a summary of the tutorial review published by Mara Guidi, Peter H. Seeberger, and Kerry Gilmore in Chem. Soc. Rev., 2020, 49, 8910-8932.

• Mara Guidi was a PhD student in the Biomolecular Systems department at the Max Planck Institute of Colloids and Interfaces in Potsdam, Germany, supervised by Prof. Seeberger. Her research focuses on flow chemistry and the development of automated platforms for organic synthesis.
• Peter H. Seeberger studied chemistry in Erlangen, Germany, and completed his PhD in biochemistry in Boulder, Colorado. He established an independent research program at MIT and later held positions at ETH Zurich before becoming Director at the Max Planck Institute in Potsdam and a Professor at the Free University Berlin. His research spans glycosciences from chemistry to immunology and includes significant contributions to flow chemistry.
• Kerry Gilmore, born in Brewster, Massachusetts, in 1984, earned his PhD from Florida State University in 2012 and conducted postdoctoral research at the Max Planck Institute of Colloids and Interfaces. He leads the Continuous Chemical Systems team, focusing on advancing small molecule synthesis methodologies and understanding reactivity fundamentals. In 2020, he joined the University of Connecticut as an Assistant Professor in the Chemistry department.

Introduction to Flow Chemistry, Modular Approach and CAS

Flow chemistry modules are designed to maintain stable reaction conditions while reagents flow continuously through the system. Unlike traditional batch methods, flow chemistry ensures reproducibility and efficiency by controlling factors such as temperature, pressure, and reagent concentration throughout the reaction. This approach not only enhances safety but also broadens the scope of accessible chemical transformations.

A fundamental aspect of flow chemistry is its modular design, categorized into transformers and generators. Transformers facilitate specific transformations, such as functional group modifications, whereas generators produce reactive intermediates like radicals or ions. These modules are designed to be versatile, accommodating various starting materials and reagents without compromising the desired chemical outcome.

One of the most significant advantages of flow chemistry is its capability to telescope modules, linking multiple operations in a continuous process. This approach minimizes purification steps and waste, thereby enhancing efficiency and yield. Conceptualizing flow modules within a Chemical Assembly System (CAS) allows researchers to target core structural motifs efficiently. CAS facilitates the rapid synthesis of compound libraries and derivatives by reconfiguring modules to suit different synthetic pathways.

Successful implementation of flow chemistry hinges on comprehensive knowledge of reactor design, reaction kinetics, and the interplay between reagents and conditions. Key parameters such as flow rates, reactor size, and solvent compatibility are critical for process optimization and scalability. Advanced techniques like inline analytics provide real-time data, enabling precise monitoring and optimization of reaction parameters. 

Contact us at sales@manetco.be to learn more.

Transformers in Flow Chemistry: Advancing Modular Functional Group Transformations

Organic chemistry's evolution into flow systems has paralleled traditional batch processes, now enhancing reproducibility and selectivity through flow modules categorized as transformers. These transformers, designed for versatile and substrate-independent functional group modifications, exemplify the synergy between reagent types, environmental conditions, and equipment setups essential for reproducible chemical transformations.

Organic chemistry traditionally categorizes transformations into functional groups, and similarly, flow modules are classified based on their capability to induce specific reactions reproducibly. These modules leverage reagent compatibility, equipment availability, and manage byproduct generation, ensuring efficient and adaptable chemical modifications independent of starting materials.

Oxidation Modules

Flow systems have streamlined oxidation reactions, addressing challenges associated with hazardous, flammable, or explosive reagents. Two main categories dominate flow oxidation modules: gas-liquid systems employing molecular oxygen and liquid-liquid systems with soluble oxidants.

Gas-Liquid Oxidation with Molecular Oxygen

Molecular oxygen serves as an ideal, environmentally friendly oxidant, although its use in batch processes is hindered by safety concerns and poor gas solubility. In flow, these issues are mitigated through precise control and enhanced mixing, typically facilitated by:

• Utilizing a T-mixer setup, oxygen gas is mixed with liquid reagents, creating biphasic systems ideal for reactions such as benzylic oxidations catalyzed by iron(III) chloride.
• Employing a tube-in-tube reactor, this setup pioneered by the Ley group efficiently delivers oxygen into solutions, exemplified by the anti-Markovnikov Wacker oxidation converting styrenes to arylacetaldehydes.

Liquid Phase Oxidations

For safer and simpler operation, monophasic liquid-phase oxidation modules avoid handling gases altogether. These setups utilize T-mixers to combine reagents like KMnO4 or other oxidants directly with substrates, minimizing issues such as precipitate formation through innovative solutions like ultrasonic baths.

• A straightforward setup utilizing liquid-phase oxidants combined with effective mixing strategies, essential for oxidations like alcohol to carboxylic acid conversions.

Reductions Modules

Flow chemistry excels in reduction processes, offering enhanced safety and control over traditional batch methods. Reduction modules utilize either gaseous hydrogen or soluble reductants, adapting similar setups from oxidation modules for efficiency and reproducibility.

Hydrogenation and Reduction Modules

Reductions in flow benefit from pressurization and precise catalyst control, improving selectivity and yield. Key examples include:

• Incorporating hydrogen gas through a tube-in-tube reactor system, combined with heterogeneous catalysts like palladium on carbon, facilitates efficient hydrogenations such as cinnamate reductions.
• Utilizing in-situ generated hydrogen via electrolysis, this module offers enhanced safety and flexibility, enabling reductions from nitro groups to amines using various catalyst cartridges.
• Demonstrating the capability for homogeneous reductions, this setup controls the challenging reduction of esters to aldehydes using diisobutylaluminum hydride (DIBALH) under cryogenic conditions with exceptional selectivity.

Olefination Reactions

Flow protocols for olefination reactions utilize adaptable setups for reactions like Wittig, Knoevenagel, and Horner-Wadsworth-Emmons couplings, highlighting the efficiency of flow conditions in reducing reaction times and enhancing yields.

• Featuring specialized packed bed reactors like the PASSFlow setup for Horner-Wadsworth-Emmons olefinations, combining catalysis and purification in a single module.

Huisgen Cycloadditions

Cycloadditions like the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) benefit from continuous flow conditions, enhancing safety and efficiency through controlled mixing and inline purification.

• Utilizing a copper coil reactor for in-situ catalysis of CuAAC reactions, offering robust performance without additional catalysts.

These examples underscore the transformative impact of flow chemistry in organic synthesis, emphasizing modular design principles to address diverse chemical transformations efficiently and reproducibly. As flow chemistry continues to evolve, these modules represent a paradigm shift in synthetic methodologies, promising continued advancements in chemical synthesis and application.

Exploring the Frontier of Flow Chemistry: Generators for On-Demand Reactive Intermediates

In the realm of organic synthesis, the concept of generating reactive intermediates in situ and on-demand has revolutionized the efficiency, safety, and scope of chemical reactions. This paradigm shift is exemplified by the innovative use of generators within flow chemistry systems, where precise control over reaction conditions and intermediates leads to enhanced synthetic capabilities.

Carbocations: Unstable but Accessible

Carbocations, fleeting positively charged intermediates, are notoriously difficult to isolate but crucial for many organic transformations. The "cation flow method," pioneered by the Yoshida group, illustrates a groundbreaking approach to continuously generate iminium ions via electrochemical oxidation. This method, utilizing a dual-feed system with supporting electrolytes and a sacrificial proton source, allows for inline monitoring and selective trapping with nucleophiles, thus bypassing traditional isolation challenges.

Benzyne: Bridging Isolated Intermediates

Benzyne, an intermediate straddling carbocations and anions, presents unique synthetic challenges. In flow systems, benzyne is efficiently generated from 1,2-dihalobenzenes through lithiation and subsequent trapping reactions. The modular setup includes precise temperature control across three zones, enabling sequential reactions with various nucleophiles and electrophiles to yield diverse o-disubstituted benzenes.

Carbanions: Harnessing Reactive Power

Organometallic compounds like aryllithium species are pivotal in organic synthesis but demand careful control due to their reactivity. Flow systems provide a solution by facilitating the in-situ generation of aryllithium species from o-haloaryl precursors. This setup, employing microtube reactors and T-shaped micromixers under cryogenic conditions, achieves precise trapping of organolithium intermediates before side reactions occur, expanding the repertoire of accessible organic molecules.

Radicals: Taming Unpaired Electrons

Carbon-centered radicals, characterized by unpaired electrons, are highly reactive species essential for diverse synthetic pathways. Flow systems simplify their generation via two-step processes involving alkyl iodides and hydrogen peroxide. This controlled environment ensures selective trapping with suitable partners, thereby enabling intricate carbon-carbon bond formations.

Diazo Compounds: Harnessing Instability

Diazo compounds, known for their synthetic versatility but also hazardous nature, are effectively managed in flow systems. Different generators for diazomethane exemplify this, such as membrane reactors facilitating safe in situ generation and subsequent reactions with various reagents to yield methyl esters, diazo ketones, and homologated products.

Phosgene: Controlled Toxicity

Phosgene, a toxic yet indispensable reagent in organic synthesis, finds application in flow chemistry through a two-stage setup. This approach allows for the continuous generation and immediate consumption of phosgene, facilitating safe synthesis of acid chlorides and telescoped reactions to produce amides without environmental exposure to phosgene gas.

Singlet Oxygen: Green Reactivity

Singlet oxygen, an unstable and highly reactive species, is generated continuously in flow reactors using photoreactors driven by medium pressure mercury lamps. This setup, employing oxygen and photosensitizers, facilitates a wide range of oxidative transformations, from heteroatom oxidations to cycloadditions, underscoring its versatility and environmental benefits.

The integration of generators within flow chemistry platforms represents a transformative approach in modern organic synthesis. By enabling precise control over the generation and utilization of reactive intermediates, these systems not only enhance synthetic efficiency and product diversity but also mitigate safety risks associated with hazardous reagents. As research continues to innovate within this field, the potential for generators to expand the frontiers of synthetic chemistry remains promising, paving the way for greener, safer, and more efficient chemical processes.

In summary, generators in flow chemistry exemplify a convergence of innovation, safety, and efficiency, heralding a new era in organic synthesis.

Chemical Assembly Systems (CAS): Expanding Synthetic Potential in Flow Chemistry

In the realm of chemical synthesis, the evolution towards more efficient and flexible methodologies has been driven by the adoption of flow chemistry. This approach not only enhances reproducibility but also integrates diverse chemical transformations into modular systems known as Chemical Assembly Systems (CAS). These systems, reminiscent of assembly lines in manufacturing, offer unparalleled control over reaction sequences and product outcomes through the strategic combination of generators and transformers.

CAS represents a paradigm shift in synthetic chemistry, where the focus shifts from synthesizing specific target molecules to creating libraries of compounds with diverse functionalities. This is achieved by modularizing chemical transformations into discrete units, each capable of performing specific reactions under controlled conditions.

The core concept of CAS lies in its modular design, which comprises generators and transformers. Generators initiate specific reactions, such as the formation of reactive intermediates or key functional groups, while transformers modify these intermediates into desired products through subsequent reactions. The order and combination of these modules can be adjusted to synthesize a variety of compounds from a common set of starting materials.

Example CAS Applications

1. Artemisinin Derivatives: An exemplary CAS targeting antimalarial compounds demonstrates the versatility of the system. By coupling a singlet oxygen generator with a reduction module, artemisinin derivatives are synthesized through a sequence of transformations, offering flexibility in the final product by altering the last-step reagent.
2. Divergence from Imines: Using singlet oxygen as a generator, this CAS exemplifies the divergence into multiple compound classes from a common intermediate. By choosing different modules (e.g., high temperature reactors or carbon dioxide gas), α-aminonitriles can be directed towards various functional groups, illustrating the modular adaptability of CAS.
3. Automated CAS Platforms: Advancements in automation have further streamlined CAS operations. Automated systems utilize robotic arms to assemble and connect modules, enabling precise control over reaction conditions and sequence. This automation not only accelerates synthesis but also enhances reproducibility and safety.

The future of CAS lies in its integration with advanced technologies such as artificial intelligence (AI) for synthesis planning and optimization. AI-driven platforms can suggest optimal module combinations based on vast databases of reactions, thereby accelerating the discovery of new chemical entities and reducing reliance on manual intervention.

Conclusion

In conclusion, Chemical Assembly Systems represent a revolutionary approach to chemical synthesis, enabling the creation of compound libraries with diverse functionalities through modular, reproducible processes. As flow chemistry continues to evolve, these systems promise to expand the boundaries of synthetic chemistry by facilitating the rapid development of novel molecules and pharmaceuticals. With ongoing advancements in automation and AI, the future holds immense potential for CAS to become a cornerstone of modern chemical discovery and development.

By harnessing the power of modular design and automation, CAS not only enhances the efficiency of chemical synthesis but also opens new avenues for exploring chemical space and accelerating drug discovery efforts. As we look ahead, the continued refinement and adoption of CAS promise to revolutionize the way we approach chemical synthesis, making complex molecular design more accessible and transformative than ever before.

https://pubs.rsc.org/en/content/articlehtml/2020/cs/c9cs00832b

This is a summary of the article: Mara Guidi, Peter H. Seeberger, and Kerry Gilmore. "How to approach flow chemistry." Chem. Soc. Rev., 2020, 49, 8910-8932. DOI: 10.1039/C9CS00832B.