The area of catalysis of radical reactions has recently flourished. Various reaction conditions have been discovered and explained in terms of catalytic cycles. These cycles rarely stand alone as unique paths from substrates to products. Instead, most radical reactions have innate chains which form products without any catalyst. How do we know if a species added in "catalytic amounts" is a catalyst, an initiator, or something else? Herein we critically address both catalyst-free and catalytic radical reactions through the lens of radical chemistry. Basic principles of kinetics and thermodynamics are used to address problems of initiation, propagation, and inhibition of radical chains. The catalysis of radical reactions differs from other areas of catalysis. Whereas efficient innate chain reactions are difficult to catalyze because individual steps are fast, both inefficient chain processes and non-chain processes afford diverse opportunities for catalysis, as illustrated with selected examples.

Catalysis of Radical Reactions: A Radical Chemistry Perspective.

Synthesis of piperidines

The high utility of halogenated organic compounds has prompted the development of a vast number of transformations which install the carbon–halogen motif. Traditional routes to these building blocks have commonly involved multiple steps, harsh reaction conditions, and the use of stoichiometric and/or toxic reagents. In this regard, using transition metals to catalyze the synthesis of organohalides has become a mature field in itself, and applying these technologies has allowed for a decrease in the production of waste, higher levels of regio- and stereoselectivity, and the ability to produce enantioenriched target compounds. Furthermore, transition metals offer the distinct advantage of possessing a diverse spectrum of mechanistic possibilities which translate to the capability to apply new substrate classes and afford novel and difficult-to-access structures. This Review provides comprehensive coverage of modern transition metal-catalyzed syntheses of organohalides via a diverse array of mechanisms. Atte...

Modern Transition-Metal-Catalyzed Carbon–Halogen Bond Formation

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

ConspectusNumerous methods for transition metal catalyzed carbonylation reactions have been established. Examples that start from aryl, vinyl, allyl, and benzyl halides to give the corresponding carboxylic acid derivatives have all been well documented. In contrast, the corresponding alkyl halides often encounter difficulty. This is inherent to the relatively slow oxidative addition step onto the metal center and subsequent β-hydride elimination which causes isomerization of the alkyl metal species. Radical carbonylation reactions can override such problems of reactivity; however, carbonylation coupled to iodine atom transfer (atom transfer carbonylation), though useful, often suffers from a slow iodine atom transfer step that affects the outcome of the reaction. We found that atom transfer carbonylation of primary, secondary, and tertiary alkyl iodides was efficiently accelerated by the addition of a palladium catalyst under light irradiation. Stereochemical studies support a mechanistic pathway based on...

Carbonylation Reactions of Alkyl Iodides through the Interplay of Carbon Radicals and Pd Catalysts

Evidence that palladium(0)-promoted cyclizations of unsaturated α-iodocarbonyls occur by an atom transfer mechanism

Atom transfer cyclization reactions of α-iodo carbonyls

Synthesis of 2-spirocyclopropylglucose via condensation of erythrose with the lithium enolate of 2,6-di-tert=butyl-4-methylphenyl cyclopropanecarboxylate

The free radical isomerization of unsaturated α-iodo carbonyls to cyclic γ-iodo carbonyls is described. Iodine atom abstraction from the starting iodide by the cyclic radical is the key chain transfer step.

Atom Transfer Cyclization Reactions of α-Iodo Carbonyls.

Glyceraldehyde, erythrose, and threose are condensed with the enolate derived from cyclopropanecarboxylic acid BHT ester. The conversion of two diastereomeric products of this condensation into new 2-spirocyclopropyl-substituted aldopyranoses is described.

Synthesis of 2-Spirocyclopropylglucose via Condensation of Erythrose with the Lithium Enolate of 2,6-Di-tert-butyl-4-methylphenyl Cyclopropanecarboxylate.

Chi-Tai Chang

Papers

Evidence that palladium(0)-promoted cyclizations of unsaturated α-iodocarbonyls occur by an atom transfer mechanism

Atom transfer cyclization reactions of α-iodo carbonyls

Synthesis of 2-spirocyclopropylglucose via condensation of erythrose with the lithium enolate of 2,6-di-tert=butyl-4-methylphenyl cyclopropanecarboxylate

Atom Transfer Cyclization Reactions of α-Iodo Carbonyls.

Synthesis of 2-Spirocyclopropylglucose via Condensation of Erythrose with the Lithium Enolate of 2,6-Di-tert-butyl-4-methylphenyl Cyclopropanecarboxylate.