The Persistent Radical Effect: From Mechanistic Curiosity to Synthetic Tool

The Fischer–Ingold persistent radical effect (PRE) provides a simple conceptual framework to rationalize reactivities in systems involving two radicals with very different self‐reaction rate constants; in a limiting, but rather common case, one of these radicals is persistent at room temperature. In these cases, the cross‐coupling product is strongly favored. This contribution summarizes some of the work carried out at the University of Ottawa, where the PRE plays a key role in determining product distributions. Much of this work was inspired by the seminal contributions of Hanns Fischer.     

Photosensitized Intermolecular Carboimination of Alkenes through the Persistent Radical Effect

An intermolecular, two‐component vicinal carboimination of alkenes has been accomplished by energy transfer catalysis. Oxime esters of alkyl carboxylic acids were used as bifunctional reagents to generate both alkyl and iminyl radicals. Subsequently, addition of the alkyl radical to an alkene generates a transient radical for selective radical–radical cross‐coupling with the persistent iminyl radical. Furthermore, this process provides direct access to aliphatic primary amines and α‐amino acids by simple hydrolysis.     

Alkyl Carbon–Carbon Bond Formation by Nickel/Photoredox Cross‐Coupling

The union of photoredox and nickel catalysis has resulted in a renaissance in radical chemistry as well as in the use of nickel‐catalyzed transformations, specifically for carbon–carbon bond formation. Collectively, these advances address the longstanding challenge of late‐stage cross‐coupling of functionalized alkyl fragments. Empowered by the notion that photocatalytically generated alkyl radicals readily undergo capture by Ni complexes, wholly new feedstocks for cross‐coupling have been realized. Herein, we highlight recent developments in several types of alkyl cross‐couplings that are accessible exclusively through this approach.     

Photoredox Catalysis of Aromatic β‐Ketoesters for in Situ Production of Transient and Persistent Radicals for Organic Transformation

Radical formation is the initial step for conventional radical chemistry. Reported herein is a unified strategy to generate radicals in situ from aromatic β‐ketoesters by using a photocatalyst. Under visible‐light irradiation, a small amount of photocatalyst fac‐Ir(ppy)₃ generates a transient α‐carbonyl radical and persistent ketyl radical in situ. In contrast to the well‐established approaches, neither stoichiometric external oxidant nor reductant is required for this reaction. The synthetic utility is demonstrated by pinacol coupling of ketyl radicals and benzannulation of α‐carbonyl radicals with alkynes to give a series of highly substituted 1‐naphthols in good to excellent yields. The readily available photocatalyst, mild reaction conditions, broad substrate scope, and high functional‐group tolerance make this reaction a useful synthetic tool.     

Ru‐Catalyzed Dehydrogenative C−O Bond Formation with Anilines and Phenols

The Ru catalyzed cross‐dehydrogenative C?O bond formation between anilines and phenols is described and discussed. The exclusive C?O versus C?N bond‐formation selectivity, moreover in the absence of chelating–assisting directing groups and while leaving the N?H position untouched, is a remarkable feature of this metal‐catalyzed radical cross‐dehydrogenative coupling.     

New Radical Borylation Pathways for Organoboron Synthesis Enabled by Photoredox Catalysis

Radical borylation using N‐heterocyclic carbene (NHC)‐BH₃ complexes as boryl radical precursors has emerged as an important synthetic tool for organoboron assembly. However, the majority of reported methods are limited to reaction modes involving carbo‐ and/or hydroboration of specific alkenes and alkynes. Moreover, the generation of NHC‐boryl radicals relies principally on hydrogen atom abstraction with the aid of radical initiators. A distinct radical generation method is reported, as well as the reaction pathways of NHC‐boryl radicals enabled by photoredox catalysis. NHC‐boryl radicals are generated via a single‐electron oxidation and subsequently undergo cross‐coupling with the in‐situ‐generated radical anions to yield gem‐difluoroallylboronates. A photoredox‐catalyzed radical arylboration reaction of alkenes was achieved using cyanoarenes as arylating components from which elaborated organoborons were accessed. Mechanistic studies verified the oxidative formation of NHC‐boryl radicals through a single‐electron‐transfer pathway.     

Sulfur(IV)‐Mediated Unsymmetrical Heterocycle Cross‐Couplings

Despite the tremendous utilities of metal‐mediated cross‐couplings in modern organic chemistry, coupling reactions involving nitrogenous heteroarenes remain a challenging undertaking – coordination of Lewis basic atoms into metal centers often necessitate elevated temperature, high catalyst loading, etc. Herein, we report a sulfur (IV) mediated cross‐coupling amendable for the efficient synthesis of heteroaromatic substrates. Addition of heteroaryl nucleophiles to a simple, readily‐accessible alkyl sulfinyl (IV) chloride allows formation of a trigonal bipyramidal sulfurane intermediate. Reductive elimination therefrom provides bis‐heteroaryl products in a practical and efficient fashion.     

Semi‐heterogeneous Dual Nickel/Photocatalysis using Carbon Nitrides: Esterification of Carboxylic Acids with Aryl Halides

Cross‐coupling reactions mediated by dual nickel/photocatalysis are synthetically attractive but rely mainly on expensive, non‐recyclable noble‐metal complexes as photocatalysts. Heterogeneous semiconductors, which are commonly used for artificial photosynthesis and wastewater treatment, are a sustainable alternative. Graphitic carbon nitrides, a class of metal‐free polymers that can be easily prepared from bulk chemicals, are heterogeneous semiconductors with high potential for photocatalytic organic transformations. Here, we demonstrate that graphitic carbon nitrides in combination with nickel catalysis can induce selective C?O cross‐couplings of carboxylic acids with aryl halides, yielding the respective aryl esters in excellent yield and selectivity. The heterogeneous organic photocatalyst exhibits a broad substrate scope, is able to harvest green light, and can be recycled multiple times. In situ FTIR was used to track the reaction progress to study this transformation at different irradiation wavelengths and reaction scales.     

Photoredox Catalysis of Aromatic β-Ketoesters for in Situ Production of Transient and Persistent Radicals for Organic Transformation

Radical formation is the initial step for conventional radical chemistry. Reported herein is a unified strategy to generate radicals in situ from aromatic β-ketoesters by using a photocatalyst. Under visible-light irradiation, a small amount of photocatalyst fac-Ir(ppy)₃ generates a transient α-carbonyl radical and persistent ketyl radical in situ. In contrast to the well-established approaches, neither stoichiometric external oxidant nor reductant is required for this reaction. The synthetic utility is demonstrated by pinacol coupling of ketyl radicals and benzannulation of α-carbonyl radicals with alkynes to give a series of highly substituted 1-naphthols in good to excellent yields. The readily available photocatalyst, mild reaction conditions, broad substrate scope, and high functional-group tolerance make this reaction a useful synthetic tool.     

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.     

Tin-free radical alkoxyamine addition and isomerization reactions by using the persistent radical effect: variation of the alkoxyamine structure

Various C-centered radicals can efficiently be generated through thermal C-O-bond homolysis of alkoxyamines. This method is used to perform environmentally benign radical cyclization and intermolecular addition reactions. These alkoxyamine isomerizations and intermolecular carboaminoxylations are mediated by the persistent radical effect (PRE). In the paper, the effect of the variation of the alkoxyamine structure--in particular steric effects in the nitroxide moiety--on the outcome of the PRE mediated radical reactions will be discussed. Fourteen different nitroxides were used in the studies. It will be shown that reaction times can be shortened about 100 times upon careful tuning of the alkoxyamine structure. Activation energies for the C-O-bond homolysis of the various alkoxyamines are provided. The kinetic data are used to explain the reaction outcome of the PRE-mediated processes.     

Photochemical Reactions and Photoinduced Electron‐Transfer Processes in Liquids,Frozen Solutions,and Proteins as Studied by Multifrequency Time‐Resolved EPR Spectroscopy

In this overview, modern multifrequency EPR spectroscopy, in particular at high magnetic fields, is shown to provide detailed information about structure, motional dynamics, and spin chemistry of transient radicals and radical pairs occurring in photochemical reactions. Examples discussed comprise photochemical reactions in liquid solution and light‐initiated electron transfer processes both in biomimetic donor–acceptor model systems in frozen solution or liquid crystals and in natural photosynthetic‐reaction‐center protein complexes. The transient paramagnetic states exhibit characteristic electron polarization (CIDEP) effects. They contain valuable information about structure and dynamics of the transient reaction intermediates. Moreover, they are exploited for signal enhancement. Continuous‐wave (cw) and pulsed versions of time‐resolved high‐field EPR spectroscopy, such as cw‐transient‐EPR (TREPR) and pulsed‐electron‐spin‐echo (ESE) experiments, are compared with respect to their advantages and limitations for the specific system under study. For example, W‐band (95‐GHz) TREPR spectroscopy in conjunction with a continuous‐flow system for light‐generated short‐lived transient spin‐polarized radicals of organic photoinitiators in solution was performed with a time resolution of 10 ns. The increased Boltzmann polarization at high fields even allows detection of transient radicals without CIDEP effects. This enables one to determine initial radical polarization contributions as well as radical‐addition reaction constants. Another example of the power of combined X‐band and W‐band TREPR spectroscopy is given for the complex electron‐transfer and spin dynamics of covalently linked porphyrin–quinone as well as Watson–Crick base‐paired porphyrin–dinitrobenzene donor–acceptor biomimetic model systems. Furthermore, W‐band ESE experiments on the spin‐correlated coupled radical pair in reaction centers of the purple photosynthetic bacterium Rb. sphaeroides reveal details of distance and orientation of the pair partners in their charge‐separated transient state. The results are compared with those of the ground‐state P₈₆₅Q_A. The high orientation selectivity of high‐field EPR provides single‐crystal‐like information even from disordered frozen‐solution samples. The examples given demonstrate that high‐field EPR adds substantially to the capability of ‘classical’ spectroscopic and diffraction techniques for determining structure–dynamics–function relations of biochemical systems, since transient intermediates can be observed in real time in their working states on biologically relevant time scales.     

The Development of Bulky Palladium NHC Complexes for the Most-Challenging Cross-Coupling Reactions

Palladium‐catalyzed cross‐coupling reactions enable organic chemists to form C? C bonds in targeted positions and under mild conditions. Although phosphine ligands have been intensively researched, in the search for even better cross‐coupling catalysts attention has recently turned to the use of N‐heterocyclic carbene (NHC) ligands, which form a strong bond to the palladium center. PEPPSI (pyridine‐enhanced precatalyst preparation, stabilization, and initiation) palladium precatalysts with bulky NHC ligands have established themselves as successful alternatives to palladium phosphine complexes. This Review shows the success of these species in Suzuki–Miyaura, Negishi, and Stille–Migita cross‐couplings as well as in amination and sulfination reactions.     

Persistent Antimony‐ and Bismuth‐Centered Radicals in Solution

Stibinyl and bismuthinyl radicals are recognized as representative intermediates of antimony and bismuth compounds, but still elusive in the condensed phase. We successfully synthesized persistent stibinyl and bismuthinyl radicals in solution by facile dissociation of the corresponding dimers with bulky substituents. We characterized the radicals by NMR and UV/Vis spectroscopy and estimated the thermodynamic parameters for the dissociation equilibria. The radicals show n→p (HOMO→SOMO) transition bands at 497 nm (stibinyl) and 543 nm (bismuthinyl) in 3‐methylpentane and react with a stable nitroxyl radical to give the cross‐radical coupling products in good yields.     

Chemoselective Three-Component Geminal Cross Couplings of Dihaloalkanes with Cr Catalysis: Rapid Access to Tertiary and Quaternary Alkanes via a Metal–Carbene Intermediate

Geminal cross couplings using multiple components enable the formation of several different bonds at one site in the building of tertiary and quaternary alkanes. Nevertheless, there are remaining issues of concern—cleavage of two geminal bonds and control of selectivity present challenges. We report here the geminal cross couplings of three components by reactions of dihaloalkanes with organomagnesium and chlorosilanes or alkyl tosylates by Cr catalysis, affording the formation of geminal C−C/C−Si or C−C/C−C bonds in the creation of tertiary and quaternary alkanes. The geminal couplings are catalyzed by low-cost CrCl₂, enabling the sluggishness of competitive Kumada-type side couplings and homocouplings of Grignard reagents, in achieving high chemoselectivity. Experimental and theoretical studies indicate that two geminal C-halide bonds are continuously cleaved by Cr to afford a metal carbene intermediate, which couples with a Grignard reagent, followed by silylation, in the formation of geminal C−C and C−Si bonds via a novel inner-sphere radical coupling mechanism. These three-component geminal cross couplings are value-addition to the synthesis of commercial drugs and bioactive molecules in medicinal chemistry.     

Novel hyperbranched polymers synthesized via A3 + B(B′) approach by radical addition‐coupling polymerization

In this study, a novel application of radical addition‐coupling polymerization (RACP) for synthesis of hyperbranched polymers is reported. By Cu/PMDETA‐mediated RACP of 2‐methyl‐2‐nitrosopropane with trimethylolpropane tris(2‐bromopropionate) or a bromo‐ended 3‐arm PS macromonomer, two types of hyperbranched polymers with high degree of polymerization are synthesized under mild conditions, respectively. The chemical structures of the hyperbranched polymers are carefully characterized. By selective degradations of the ester groups and weak bonds of NO? C in the polymers, high degree of alternative connection of the two monomers in the synthesized polymers have been identified. Based on the experimental results, mechanism of formation of the hyperbranched polymer is proposed, which includes formation of carbon radicals from the tribromo monomer through single electron transfer, its capture by 2‐methyl‐2‐nitrosopropane that results in nitroxide radical, and cross‐coupling reaction of the nitroxide radical with other carbon radicals. Hyperbranched polymer can be formed in a step‐growth mode after multiple steps of such reactions. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 904–913     

A Pyridine–Pyridine Cross‐Coupling Reaction via Dearomatized Radical Intermediates

A pyridine–pyridine coupling reaction has been developed between pyridyl phosphonium salts and cyanopyridines using B₂pin₂ as an electron‐transfer reagent. Complete regio‐ and cross‐selectivity are observed when forming a range of valuable 2,4′‐bipyridines. Phosphonium salts were found to be the only viable radical precursors in this process, and mechanistic studies indicate that the process does not proceed through a Minisci‐type coupling involving a pyridyl radical. Instead, a radical–radical coupling process between a boryl phosphonium pyridyl radical and a boryl‐stabilized cyanopyridine radical explains the C?C bond‐forming step.     

Transmetalation in the Suzuki–Miyaura Coupling: The Fork in the Trail

The Suzuki–Miyaura coupling is one of the few transition‐metal‐catalyzed C? C bond‐forming reactions that have been used in applications ranging from discovery chemistry to manufacturing processes. Although coupling proceeds through the generic three‐stage ‘oxidative addition, transmetalation, reductive elimination’ sequence, there are a number of features that differentiate the Suzuki–Miyaura process from other transition‐metal‐catalyzed cross‐couplings. Most of these features are centered around, or are a consequence of, activation of the boron reagent for transmetalation through one or both of two distinct pathways. This review focuses on the evidence that has been presented for this ‘fork in the trail′, and the potential to apply such mechanistic insight to the design of reaction conditions.     

Kinetic analysis of the cross reaction between dithioester and alkoxyamine by a Monte Carlo simulation

A model reaction of dithioester and alkoxyamine is proposed to probe the reversible addition–fragmentation chain transfer (RAFT) process. The kinetics of the model reaction is analyzed and compared with that of pure alkoxyamine homolysis with a Monte Carlo simulation. Although the pure alkoxyamine obeys the law of persistent radical effect, the model reaction results in higher concentration of the persistent radical during the main period of the reaction. However, for a very fast RAFT process or a very low addition rate constant, the time dependence of the persistent radical concentration is quite close to that of pure alkoxyamine. Furthermore, the cross termination between the intermediate and alkyl radicals causes a retardation effect for the model reaction when the intermediate is relatively long‐lived. The Monte Carlo simulation indicates that it is feasible to measure the individual rate constants of the RAFT process, such as the rate constant of addition, with a large excess of alkoxyamine. In addition, the special feature of the system with different leaving groups in the alkoxyamine and dithioester is also discussed. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 374–387, 2007     

Cleavage of C(aryl)−CH3 Bonds in the Absence of Directing Groups under Transition Metal Free Conditions

Organic chemists now can construct carbon–carbon σ‐bonds selectively and sequentially, whereas methods for the selective cleavage of carbon–carbon σ‐bonds, especially for unreactive hydrocarbons, remain limited. Activation by ring strain, directing groups, or in the presence of a carbonyl or a cyano group is usually required. In this work, by using a sequential strategy site‐selective cleavage and borylation of C(aryl)?CH₃ bonds has been developed under directing group free and transition metal free conditions. Methyl groups of various arenes are selectively cleaved and replaced by boryl groups. Mechanistic analysis suggests that it proceeds by a sequential intermolecular oxidation and coupling of a transient aryl radical, generated by radical decarboxylation, involving a pyridine‐stabilized persistent boryl radical.