Visible light-driven photoredox catalysis has taken on a significant role in industrial chemistry by enabling challenging bond disconnections, as well as advancing chemical sustainability efforts. The increased industrial application of photochemical synthesis underscores the demand for new technologies that enable rapid reaction discovery as well as efficient process scale-up. In recent years, high-throughput experimentation (HTE) strategies have provided chemists with the ability to run orders of magnitude more experiments while leveraging big data informatic approaches for reaction design and optimization. While many of these methods have been applied towards non-photochemical catalytic systems (e.g. Pd-catalyzed cross-coupling reactions), current HTE technology have not been able to address the specific needs and challenges of optimizing photochemical reactions, while providing a platform for their efficient scale-up. Given the Stephenson lab’s long-standing interest in photocatalytic reaction development and continuous flow, as well as the Kennedy’s lab’s expertise in designing droplet microfluidics-based analytical methods, we saw a unique opportunity to join forces in leveraging droplet microfluidics for photochemical reaction discovery.
Under the support of the 2018 American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable Grant, we set out to develop a continuous flow system that would allow us to screen individual photochemical reactions in nanoliter-sized droplets. Following reaction irradiation, we performed characterization with electrospray ionization mass spectrometry (ESI-MS). From a material efficiency standpoint, we were drawn to the ability to perform reactions on picomole scales, which further reduces material consumption compared to well plate-based screens. By integrating droplet sample format and ESI-MS, we created a versatile platform for rapidly identifying “hit” conditions within a photochemical reaction screen.
Our first goal for this project was to demonstrate proof-of-concept for performing photoredox reactions in nanoliter droplet format and subsequent ESI-MS analysis. We were excited to see successful product formation in our first photochemical droplet reactions involving the radical trifluoromethylation of several commercially available Pfizer drug compounds. We then set out to develop an in-droplet flow setup that could enable us to perform screens of 100-200 reaction droplets per incubation period. Upon designing an oscillatory reactor that gave us the flexibility of varying reaction residence times, we performed a photoredox alkene aminoarylation screen using 100 different substrate combinations. Among the 100 different new products that we could generate, we were able to identify 37 hit conditions. Selecting 9 of these 37 hits, we successfully performed flow scale-up and isolation of 7 out of 9 new compounds. It is also noteworthy that ESI-MS analysis provided us with analysis throughputs of 3 seconds per sample, and we were able to characterize all 350 samples (triplicate reactions with appropriate controls) within 19 mins. This study lays the groundwork for using droplet microfluidics in the high-throughput discovery of new photochemical reactions, and we hope that the development of automation and data processing tools can further enhance the robustness and utility of this system! We invite you to read the full article, now published in Nature Communications.