This Perspective illustrates the defining characteristics of free radical chemistry, beginning with its rich and storied history. Studies from our laboratory are discussed along with recent developments emanating from others in this burgeoning area. The practicality and chemoselectivity of radical reactions enable rapid access to molecules of relevance to drug discovery, agrochemistry, material science, and other disciplines. Thus, these reactive intermediates possess inherent translational potential, as they can be widely used to expedite scientific endeavors for the betterment of humankind.

Radicals: Reactive Intermediates with Translational Potential

Conventional methods for carrying out carbon–hydrogen functionalization and carbon–nitrogen bond formation are typically conducted at elevated temperatures, and rely on expensive catalysts as well as the use of stoichiometric, and perhaps toxic, oxidants. In this regard, electrochemical synthesis has recently been recognized as a sustainable and scalable strategy for the construction of challenging carbon–carbon and carbon–heteroatom bonds. Here, electrosynthesis has proven to be an environmentally benign, highly effective and versatile platform for achieving a wide range of nonclassical bond disconnections via generation of radical intermediates under mild reaction conditions. This review provides an overview on the use of anodic electrochemical methods for expediting the development of carbon–hydrogen functionalization and carbon–nitrogen bond formation strategies. Emphasis is placed on methodology development and mechanistic insight and aims to provide inspiration for future synthetic applications in the field of electrosynthesis.

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Electrochemical strategies for C-H functionalization and C-N bond formation.

A method for five- and six-membered heterocycle formation by palladium-catalyzed C-H/N-H coupling is presented. The method employs a picolinamide directing group, PhI(OAc)(2) oxidant, and toluene solvent at 80-120 °C. Cyclization is effective for sp(2) as well as aliphatic and benzylic sp(3) C-H bonds.

Heterocycle synthesis via direct C-H/N-H coupling.

Radical-radical couplings are mostly nearly diffusion-controlled processes. Therefore, the selective cross-coupling of two different radicals is challenging and not a synthetically valuable transformation. However, if the radicals have different lifetimes and if they are generated at equal rates, cross-coupling will become the dominant process. This high cross-selectivity is based on a kinetic phenomenon called the persistent radical effect (PRE). In this Review, an explanation of the PRE supported by simulations of simple model systems is provided. Radical stabilities are discussed within the context of their lifetimes, and various examples of PRE-mediated radical-radical couplings in synthesis are summarized. It is shown that the PRE is not restricted to the coupling of a persistent with a transient radical. If one coupling partner is longer-lived than the other transient radical, the PRE operates and high cross-selectivity is achieved. This important point expands the scope of PRE-mediated radical chemistry. The Review is divided into two parts, namely 1) the coupling of persistent or longer-lived organic radicals and 2) "radical-metal crossover reactions"; here, metal-centered radical species and more generally longer-lived transition-metal complexes that are able to react with radicals are discussed-a field that has flourished recently.

The Persistent Radical Effect in Organic Synthesis

The persistent radical effect (PRE) is a principle that explains the highly selective cross-coupling between a persistent and a transient radical when both species are formed at equal rates. In this paper, the concept of the PRE is briefly discussed. Applications of the PRE in different reactions such as Co-mediated radical addition and cyclization reactions, Kharasch reactions catalyzed by transition metals, the Barton reaction, and our nitroxide-mediated tin-free radical cyclizations are presented. Some future perspectives for the PRE in organic synthesis are also provided.

The persistent radical effect in organic synthesis.

Remote intramolecular free radical functionalizations: An update

Hydride-promoted demethylation of methyl phenyl ethers

Remote Intramolecular Free Radical Functionalizations: An Update

Solutions of L-Selectride or SuperHydride in refluxing THF efficiently deprotect methyl phenyl ethers. L-Selectride is the more effective reagent, while electron-poor arenes work best. Unlike other hydride sources, these reagents permit ether cleavage without the reduction of aryl halides.

Karen Wheless

Papers

Remote intramolecular free radical functionalizations: An update

Hydride-promoted demethylation of methyl phenyl ethers

Remote Intramolecular Free Radical Functionalizations: An Update

Hydride‐Promoted Demethylation of Methyl Phenyl Ethers.