Within the first two years of the 4-year project, much progress has been made in the experimental exploration of novel electrochemical processes for the pharmaceutical/fine chemical industry. In detail, a robust method for the electrochemical cyclopropanation was established, showing its application on an already promising chemical scope. Moreover, this methodology is a potential first step towards a fluorination methodology of high scientific interest by changing the carbon source. Further, electrochemical cross-coupling reactions for drug discovery purposes were developed addressing the enrichment of the Csp3 fraction of medicinal chemistry scaffolds. C(sp3)-H methylation, C(sp3)-C(sp3) cross coupling and C(sp2)-C(sp3) cross coupling reactions were successfully investigated and optimized via high-throughput experimentation (HTE). The HTE approach enables diverse and rapid library synthesis with minimal human intervention, significantly decreasing times and costs of development. Along the same lines, an autonomous self-optimization platform with a flow reactor, inline real-time analytical instrumentation and algorithm-based optimization was developed. The functionality and operability of this system was successfully tested with, for now, two non-electrochemical model reactions. Addressing electrooxidation chemistry, a reductive electrocatalytic pathway for the activation of oxygen by a manganese-based mediator was investigated. A comprehensive mechanistic study of this reaction was conducted, gaining valuable novel insights. The application of this electrocatalytic system was explored in non-aqueous media on various model compounds showing promising results in terms of efficiency and activity. Approaches for the electrooxidation of aromatic amines, especially targeting important synthetic intermediates for pharmaceuticals, were developed. Building on insights into the mechanism and into successful chemical synthesis, the focus is now on the electrochemical generation of the necessary superoxides, as well as the impact of the aqueous environment. Lastly, a method for the electrochemical production of diazo compounds from hydrazones in a non-aqueous electrolyte has been established, representing a target of high interest in the field of modular chemistry. The synthesis was successfully transferred onto micro flow reactor level, allowing for the safe generation of the highly reactive product circumventing accumulation and showing excellent yields on selected model substrates.
Making use of the interdisciplinary MiEl framework, a novel 1D-reaction model was built in COMSOL for this multistep electrochemical hydrazone oxidation reaction to diazo compounds, in order to unravel the underlying reaction mechanism. Moreover, a deep foundation on meso-scale lattice-Boltzmann methods was established to tackle the complexity of phase interphases and multi-step reactions overcoming limitations of regular coupled-physics tools for modelling.
Addressing new fabrication methods for cells, a fully PCB-based electrochemical micro flow cell with different flow channels was developed. A selection of surface finishes was successfully produced on the robust PCB FR4-material, making the device suitable for a variety of electrosynthetic applications. Further, the integration of temperature sensors and temperature controllers on ceramic-based PCBs was successfully shown, allowing easy monitoring and controlling of the reaction directly at the active site. Moreover, a custom-made flow cell was fabricated via additive manufacturing and 3D-printing, enabling locally resolved measurements of current density via PCB technology and sampling along the reaction channel for monitoring of the reaction progress.
Lastly, a framework was developed to conduct a comprehensive cost analysis for evaluating the economic feasibility and viability of novel synthesis routes in the pharmaceutical and fine chemical industries, and essential data was compiled. The feasibility of such an early-stage design and economic analysis tool was shown - for now, for the pharmaceutical model compound ibuprofen.
