Chemical Reaction Engineering Principles of Continuous Flow Photoredox Catalysis

Chemical Reaction Engineering Principles of Continuous Flow Photoredox Catalysis   Eric G. Moschetta,^* Kaid Harper,^* Steven M. Richter, Steve J. Wittenberger   AbbVie, Inc. Process R&D, 1401 Sheridan Road North Chicago, IL 60064   ^*co-corresponding authors: eric.moschetta@abbvie.com, kaid.harper@abbvie.com               Scaling up complex organic syntheses via flow chemistry is becoming common in the pharmaceutical industry. Careful reaction engineering of continuous flow chemistries allows for increased throughputs of desired chemical products and clever solutions to common problems observed in large scale batch reactors, such as improved heat transfer in highly exothermic reactions. One area of recent interest in organic synthesis is photoredox catalysis, reactions that involve species being excited to high energy states by visible light to undergo single electron transfer events that lead to the desired product(s). These reactions frequently use ruthenium and iridium polypyridyl complexes as the catalysts because they have long-lived excited states and high redox potentials, allowing access to many reaction pathways.^[1] However, these precious metal catalysts would incur a large expense if such reactions are to be used at scale. As an alternative, various organic photocatalysts, such as Eosin Y and acridinium-based species, also possess high redox potentials and can facilitate other single electron transfer events that their transition metal counterparts cannot.^[2] The main disadvantage of these organic photocatalysts is their shorter excited state lifetimes. Organic photocatalysts have excited state lifetimes on the order of nanoseconds while transition metal photocatalysts often have observed excited state lifetimes on the order of microseconds. While synthetic organic chemists have made, and continue to make, significant advances in the synthetic utility of transition metal and organic photocatalysts alike, the universal challenge in applying photoredox catalysis in the pharmaceutical industry is scaling up such reactions for kilogram-level production. Photoredox catalysis, and photochemistry in general, is not a part of the traditional chemical reaction engineering paradigm. For example, chemical engineers have many tools and solutions available for reactions where heat and mass transfer limitations, mixing limitations, multi-phase chemistry, and chemoselectivity all present problems in scale up of continuous flow reactors. Over the last decade, the enormous increase in the interest and study of photoredox catalysis has led to a broad and diverse array of chemical transformations. As such, a platform for scalable photoredox chemistry should be as versatile as possible to accommodate the many types of photocatalysts, reactants, and chemistries that are already developed. Additionally, such reactors should include high intensity light sources to supply the reactor with high photon fluxes to allow operation under the intrinsic kinetics of the reaction. Most importantly, the ideal reactor should operate in continuous flow to maximize production. This study implements a new continuous flow reactor for several photoredox chemistries and compares the observed rates of reactions to those obtained from other known reactor configurations, in both batch and flow. The discussion emphasizes how and why this reactor configuration outperforms the other reactors using fundamental principles of chemical reaction engineering and physical chemistry. The discussion concludes with a demonstration of the scale-up potential of the continuous flow reactor and how this new reactor configuration may be used across the entire discipline of photoredox catalysis in organic synthesis.   References

[1]        C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013, 113, 5322-5363.

[2]        N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116, 10075-10166.   This abstract presentation was sponsored by AbbVie. AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the publication. All authors are AbbVie employees.