Mechanistic Investigation into Photoredox Catalysis

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Project Summary: The area of photoredox catalysis has witnessed explosive growth over the past decade and has been established as a central pillar of modern-day organic synthesis. Fundamental to these methods is the use of an organic dye or an organometallic complex as a photocatalyst that is activated by visible-light to trigger a single electron transfer event that generates a highly reactive open- shell radical intermediate. Furthermore, these photoredox events can be coupled with two-electron organocatalysis and traditional transition-metal catalysis to enable novel bond-formations. Detailed mechanistic understanding of these intricate catalytic cycles has emerged at a significantly diminished pace compared to new reaction discovery. This has impacted the translation of these new technologies to industrial settings for the synthesis of high-value pharmaceuticals. The lack of atomistic details of the key-bond forming events has also slowed the development of catalytic asymmetric versions of these reactions. We propose to apply a suite of robust physical organic techniques to address this significant deficiency in this important area of contemporary catalysis. In particular, this proposal outlines both experimental and theoretical approaches that probe the transition state geometry of rate- and stereo- determining steps of some important reactions in photoredox catalysis. Our proposed investigations will complement the current state-of-the-art mechanistic studies of photocatalytic reactions, which focuses on the identification and reactivity of the radical intermediates. The main tool in our proposed investigations is the experimental determination of 2H and 13C kinetic isotope effects under synthetically relevant conditions followed by interpretation of these experiments using high-level theoretical techniques. We expect this collaborative approach between experiment and theory to yield information that will either enhance or provide new insights into the existing mechanistic understanding of these reactions. We focus our efforts on two important classes of reactions enabled by photoredox catalysis – C– H bond functionalization and alkene functionalization. This choice is based on the fact that these two classes of reactions generate new chiral centers. However, since catalytic asymmetric versions of these reactions have been slow to emerge, we believe that our studies will provide an important blueprint for the rational design and optimization of strategies to deliver enantio-enriched products. More importantly, we expect the results from our investigations to establish experiment-validated transition state analysis as a routine tool in the mechanistic description of photoredox catalysis.