Abstract
ConspectusClassical education in organic chemistry and catalysis, not the least my own, has centered on two-electron transformations, from nucleophilic attack to oxidative addition. The focus on two-electron chemistry is well-founded, as this brand of chemistry has enabled incredible feats of synthesis, from the development of life-saving pharmaceuticals to the production of ubiquitous commodity chemicals. With that said, this approach is in many ways complementary to the approach of nature, where enzymes frequently make use of single-electron "radical" steps to achieve challenging reactions with exceptional selectivity, including light detection and C-H hydroxylation. While the power of radical elementary steps is undeniable, the fundamental understanding of─and ability to apply─these in catalysis remains underdeveloped, constraining the palette with which chemists can make new reactions.Motivation to remedy this traditional underemphasis on radical catalysis has been intensified by the runaway success of outer-sphere photoredox catalysis, not only confirming the versatility of radicals in anthropogenic catalysis but also teaching the value of robust and well-understood catalytic cycles for reaction design. Indeed, I would argue the success of outer-sphere photoredox catalysis has been fueled by strong fundamental understanding of its underlying radical elementary steps, with consideration of single-electron transfer (SET) energetics allowing new reactions to be designed de novo with enviable confidence. However, outer-sphere photoredox catalysis is an outlier in this regard, with other mechanistic approaches remaining underexplored.Our research group is part of a growing movement to expand the vocabulary of synthetic radical catalysis beyond the traditional outer-sphere photoredox SET manifold, assembling new cycles comprised of hydrogen atom transfer (HAT), light-induced homolysis (LIH), and radical ligand transfer (RLT) steps in new combinations to achieve challenging transformations. These efforts have been made possible by the ever-growing understanding of these radical elementary steps and discovery of catalyst systems with significant mechanistic flexibility, most recently iron/thiol (Fe/S) cocatalysis.In this Account, I will focus on our efforts applying HAT and LIH steps in Fe/S cocatalysis, sharing broad guidelines we have found helpful for using these steps and demonstrating how they can be combined to make new reactions using three case studies: radical hydrogenation (HAT + HAT), decarboxylative protonation (LIH + HAT), and alkene hydrofluoroalkylation (LIH + HAT, with an intervening radical alkene addition). These efforts have highlighted the importance of several key parameters, including bond dissociation energy (BDE) and radical polarity, and I hope our findings similarly provide a valuable framework to others designing new radical catalytic reactions.