Toward Divergent Compound Library Synthesis by Cascaded, Heterogeneous Catalysis in Continuous-Flow Microfluidic Reactors

For the identification of novel compounds, the development of effective laboratory procedures in synthetic chemistry is crucial, especially in the field of drug discovery, where the cost-effective design and synthesis of therapeutic candidates are essential. To accommodate the rising need for complex chemicals and materials, innovative technologies, such as miniature flow microreactors, have been developed recently. These microreactors are an excellent tool for multistep reactions and thorough reaction screens because they can provide precise and responsive control over homogeneous reaction conditions and boost space-time yield in comparison to batch reactors.
Collaborating with IBM Research Zurich, wall-coated flow microreactors were used to provide the groundwork for a self-optimizing reaction screening device on a microfluidic chip used for divergent compound library synthesis through cascaded heterogeneous catalysis. The envisioned microreactors comprise several interconnected compartments, each hosting a certain heterogeneous organocatalyst that has been immobilized as a monolayer on the surface. With the design of multiple reactor types and the creation of a modular manufacturing technique employing microfabrication, the utility of wall-coated flow microreactors was examined. Sulfur-linked organocatalysts were anchored to the reactor as self-assembled monolayers (SAMs) on the microchannel surfaces metalized with a thin gold coating.
The wall-coated microreactors were developed using novel azide-functionalized organocatalysts in batch or in solid-phase synthesis to form SAMs. The most successful catalytic reaction was the hydrolysis of benzaldehyde dimethyl acetal (BDMA), with a significantly higher conversion rate than the control value. In addition, this thesis investigated the use of packed-bed microfluidic reactors, establishing an efficient procedure for carrying out solid-phase synthesis of pyrrolidinyl-tetrazole-functionalized beads. The feasibility of heterogeneous catalysis in packed-bed microreactors was successfully investigated. Overall, the development of wall-coated and packed-bed microfluidic reactors holds excellent potential for the synthesis of complex molecules and materials, and the work presented in this thesis provides an important foundation for further research in this field.