Development and Mechanistic Studies of Photocatalytic Functionalization of Aryl Halides: From Red Light Photocatalysis to Chromoselective Bond Activation

Abstract

Aromatic compounds are prevalent in various fields, spanning from cutting-edge pharmaceuticals to polymers and materials science. This underscores the ongoing demand for innovative approaches to disconnecting aromatic rings to push the boundaries of applied research further. Classic methods for arylation reactions rely on transition metal-based cross-coupling reactions where aryl halides are the most commonly used arene source. While effective, these approaches have inherent toxicity concerns, are operationally expensive, thus rendered unsustainable in many regards. Photoredox catalysis has emerged as a robust technique for developing new synthetic methodologies, offering selective activation of organic substrates under mild conditions through the use of open-shell intermediates via single electron transfer pathways. In this context, milder green and red-light mediated photocatalytic aryl halide functionalization and a detailed study on mechanistically less understood pathways are disclosed herein.The direct α-arylation of carbonyl compounds using aryl halides represents a powerful method to synthesize critical building blocks for diverse useful compounds. Numerous synthetic methods exist to forge C(sp2)-C(sp3) bonds, albeit mild and metal-free direct α-arylation of ketones has long been a challenging transformation. We have developed a green-light-mediated α-arylation of ketones via activation of a C(sp2)-X bond (X=I, Br, Cl) and an α-carbonyl C(sp3)-H bond in a single photocatalytic cycle. This approach is characterized by its mild reaction conditions, operational simplicity, and wide functional group tolerance. Importantly, the impressive outcome from multi-gram photocatalytic reaction underpins the strength of this method as a potentially practical and attractive approach for scale-up industrial purposes. The utility and scope of this reaction were further demonstrated by formal syntheses of several feedstock chemicals that are commercially expensive but are critical pharmaceutical synthons. In pursuit of further extension of photocatalytic aryl halide functionalization, chromoselective C(sp2)-X bond activation has been achieved in the organic helicenium (nPr-DMQA+) based photoredox catalysis. Consequently, control over chromoselective C(sp2)-X bond activation in multi-halogenated aromatics has been demonstrated. nPr-DMQA+ can only initiate halogen atom transfer (XAT) pathway under red-light irradiation to activate low energy accessible C(sp2)-I bonds. In contrast, blue-light irradiation initiates consecutive photoinduced electron transfer (conPET) to activate more challenging C(sp2)-Br bonds. Comparative reaction outcomes have been demonstrated in α-arylation of cyclic ketones with red and blue-lights. Furthermore, red-light-mediated selective C(sp2)-I bonds have been activated in iodobromoarenes keeping the bromo functional handle untouched. Finally, the strength of the chromoselective catalysis has been highlighted with two-fold functionalization using both photo to transition-metal and photo to photo-catalyzed transformations. From a mechanistic point of view, high energy blue-light can initiate an interesting yet less understood conPET pathway. In recent years, in-situ generated organic radicals have been used as highly potent photoinduced electron transfer (PET) agents resulting in catalytic systems as reducing as alkaline metals that can activate remarkably stable bonds. However, the transient nature of these doublet-state open-shell species has led to debatable mechanistic studies, hindering adoption and development. We have documented the use of an isolated and stable neutral organic radical as a highly photoreducing species with a reduction potential lower than – 3.4 V vs SCE. The isolated radical offers a unique platform to investigate the mechanism behind the photocatalytic activity of organic radicals. Our mechanistic study supports the involvement of solvated electrons formed by single electron transfer (SET) between the short-lived excited state organic radical and the solvent.