The Persistent Radical Effect in Organic Synthesis

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.     

Anharmonic thermochemistry of cyclopentadiene derivatives

This paper focuses on the thermochemistry of some derivatives of cyclopenta‐1,3‐diene, namely, 5‐methylcyclopenta‐1,3‐diene, 5‐ethylcyclopenta‐1,3‐diene, 5‐formylcyclopenta‐1,3‐diene, 5‐methylcyclopenta‐1,3‐diene‐1‐yl radical, 5‐ethylcyclopenta‐1,3‐diene‐1‐yl radical, 5‐carbonylcyclopenta‐1,3‐diene radical, 1‐formylcyclopenta‐2,4‐diene‐1‐yl radical, 5‐methylenecyclopenta‐1,3‐diene radical, 5‐ethylidenecyclopenta‐1,3‐diene radical, and 3,6‐dimethylenecyclohexa‐1,4‐diene. Several different chemistries of these compounds are of interest in combustion modeling. Here, we present gas‐phase thermochemical properties for the above cited species, which are, except for 3,6‐dimethylenecyclohexa‐1,4‐diene, previously unknown. These were obtained from corrected (using bond additivity corrections) high‐level ab initio quantum chemistry calculations validated with well‐known compounds including cyclopentane, cyclopentene, cyclopenta‐1,3‐diene, and cyclopentadienyl radical. Heat capacities and entropies have been corrected for anharmonic molecular motions, in particular for internal rotations. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 453–463, 2003     

Tautomerization and Dissociation of Molecular Peptide Radical Cations

Radical‐mediated dissociations of peptide radical cations have intriguing unimolecular gas phase chemistry, with cleavages of almost every bond of the peptide backbone and amino acid side chains in a competitive and apparently “stochastic” manner. Challenges of unraveling mechanistic details are related to complex tautomerizations prior to dissociations. Recent conjunctions of experimental and theoretical investigations have revealed the existence of non‐interconvertible isobaric tautomers with a variety of radical‐site‐specific initial structures, generated from dissociative electron transfer of ternary metal‐ligand‐peptide complexes. Their reactivity is influenced by the tautomerization barriers, perturbing the nature, location, or number of radical and charge site(s), which also determine the energetics and dynamics of the subsequent radical‐mediated dissociatons. The competitive radical‐ and charge‐induced dissociations are extremely dependent on charge density. Charge sequesting can reduce the charge densities on the peptide backbone and hence enhance the flexibility of structural rearrangement. Analysing the structures of precursors, intermediates and products has led to the discovery of many novel radical migration prior to peptide backbone and/or side chain fragmentations. Upon these successes, scientists will be able to build peptide cationic analogues/tautomers having a variety of well‐defined radical sites.     

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.     

Snowballing Radical Generation Leads to Ultrahigh Molecular Weight Polymers

Styrene is the classical monomer obeying zero‐one kinetics in radical emulsion polymerization. Accordingly, particles that are less than 100 nm in diameter contain either one or no growing radical(s). We describe a unique photoinitiated polymerization reaction accelerated by snowballing radical generation in a continuous flow reactor. Even in comparison to classical emulsion polymerization, these unprecedented snowballing reactions are rapid and high‐yielding, with each particle simultaneously containing more than one growing radical. This is a consequence of photoinitiator incorporation into the nascent polymer backbone and repeated radical generation upon photo‐irradiation.     

Tandem Anionic oxy‐Cope Rearrangement/Oxygenation Reactions as a Versatile Method for Approaching Diverse Scaffolds

Tandem anionic oxy‐Cope rearrangement/radical oxygenation reactions provide δ,?‐unsaturated α‐(aminoxy) carbonyl compounds, which serve as convenient precursors to diverse compound classes. Functionalized carbocycles are accessible by very rare all‐carbon 5‐endo‐trig cyclizations, but also common 5‐exo‐trig radical cyclizations, based on the persistent radical effect. The tandem reactions can be further extended by highly diastereoselective allylation or reduction steps to give complex scaffolds.     

An Alkenyl Boronate as a Monomer for Radical Polymerizations: Boron as a Guide for Chain Growth and as a Replaceable Side Chain for Post‐Polymerization Transformation

The ability of isopropenyl boronate pinacol ester to serve as a monomer in radical polymerizations was established and exploited for the synthesis of polymers that are difficult to access using other polymerization techniques. Although the monomer exhibits an α‐methyl‐substituted unconjugated structure, which is usually unfavorable for radical propagation, both free and controlled radical polymerizations smoothly afford the corresponding polymers. A density‐functional‐theory‐based investigation revealed that the boron atom moderately stabilizes the radical species, which leads to the suppression of the degradative chain transfer to the α‐methyl groups, and thus guides the reaction towards the radical polymerization. The boronyl pendants, which are directly attached to the polymer backbone, can be replaced with ‐OH or ‐NH₂ to yield poly(α‐methyl vinyl amine) or poly(α‐methyl vinyl alcohol), which has been inaccessible by conventional synthetic methods.     

Synthesis of Multivalent Organotellurium Chain‐Transfer Agents by Post‐modification and Their Applications in Living Radical Polymerization

Functionalized or multivalent organotellurium chain‐transfer agents (CTAs) for living radical polymerization were synthesized by post‐modification, which involved the condensation between a carboxylic‐acid‐functionalized CTA and various amines in excellent yields without affecting the reactive tellurium moiety. The CTAs exhibited high synthetic versatility for radical polymerization and gave structurally well‐controlled polymers, such as multiarmed polymers, from various monomers. Because all new CTAs are easily available on a large scale by simple purification, the current method significantly facilitates macromolecular engineering based on organotellurium‐mediated radical polymerization (TERP).     

Iodinated (Perfluoro)alkyl Quinoxalines by Atom Transfer Radical Addition Using ortho‐Diisocyanoarenes as Radical Acceptors

A simple method for the preparation of functionalized quinoxalines is reported. Starting from readily accessible ortho‐diisocyanoarenes and (perfluoro)alkyl iodides, the quinoxaline core is constructed during (perfluoro)alkylation by atom transfer radical addition (ATRA), resulting in 2‐iodo‐3‐(perfluoro)alkylquinoxalines. The radical cascades are readily initiated either with visible light or by using α,α′‐azobisisobutyronitrile (AIBN). The heteroarene products are obtained in high yields (up to 94 %), and the method can be readily scaled up. Useful follow‐up chemistry documents the value of the novel radical quinoxaline synthesis.     

Strategies for generating peptide radical cations via ion/ion reactions

Several approaches for the generation of peptide radical cations using ion/ion reactions coupled with either collision induced dissociation (CID) or ultraviolet photo dissociation (UVPD) are described here. Ion/ion reactions are used to generate electrostatic or covalent complexes comprised of a peptide and a radical reagent. The radical site of the reagent can be generated multiple ways. Reagents containing a carbon–iodine (C―I) bond are subjected to UVPD with 266‐nm photons, which selectively cleaves the C―I bond homolytically. Alternatively, reagents containing azo functionalities are collisionally activated to yield radical sites on either side of the azo group. Both of these methods generate an initial radical site on the reagent, which then abstracts a hydrogen from the peptide while the peptide and reagent are held together by either electrostatic interactions or a covalent linkage. These methods are demonstrated via ion/ion reactions between the model peptide RARARAA (doubly protonated) and various distonic anionic radical reagents. The radical site abstracts a hydrogen atom from the peptide, while the charge site abstracts a proton. The net result is the conversion of a doubly protonated peptide to a peptide radical cation. The peptide radical cations have been fragmented via CID and the resulting product ion mass spectra are compared to the control CID spectrum of the singly protonated, even‐electron species. This work is then extended to bradykinin, a more broadly studied peptide, for comparison with other radical peptide generation methods. The work presented here provides novel methods for generating peptide radical cations in the gas phase through ion/ion reaction complexes that do not require modification of the peptide in solution or generation of non‐covalent complexes in the electrospray process. Copyright © 2015 John Wiley & Sons, Ltd.     

Carbon‐Centered Radical Addition to OC of Amides or Esters as a Route to CO Bond Formations

Among various types of radical reactions, the addition of carbon radicals to unsaturated bonds is a powerful tool for constructing new chemical bonds, in which the typical applied unsaturated substrates include alkenes, alkynes and imines. Carbonyl is perhaps the most common unsaturated group in nature. This work demonstrates a novel C?O bond formation through carbon‐centered radical addition to the carbonyl oxygen of amide or ester, in which amide and ester groups are easily activated through the radical process. EPR spectroscopy and radical clock experiments support the radical process for this transformation, and density functional theory (DFT) calculations support the possibility of carbon‐centered radical addition to the carbonyl oxygen of amides or esters.     

Recent advances in the syntheses of radical‐containing macromolecules

Tailor‐made polymers containing specific chemical functionalities have ushered in a number of emerging fields in polymer science. In most of these next‐generation applications the focus of the community has centered upon closed‐shell macromolecules. Conversely, macromolecules containing stable radical sites have been less studied despite the promise of this evolving class of polymers. In particular, radical‐containing macromolecules have shown great potential in magnetic, energy storage, and biomedical applications. Here, the progress regarding the syntheses of open‐shell containing polymers are reviewed in two distinct subclasses. In the first, the syntheses of radical polymers (i.e., materials composed of non‐conjugated macromolecular backbones and with open‐shell units present on the polymer pendant sites) are described. In the second, polyradical (i.e., macromolecules containing stabilized radical sites either within the macromolecular backbone or those containing radical sites that are stabilized through a large degree of conjugation) synthetic schemes are presented. Thus, the state‐of‐the‐art in open‐shell macromolecular syntheses will be reported and future means by which to advance the current archetype will be discussed. By detailing the synthetic pathways possible for, and the inherent synthetic limitations of, the creation of these functional polymers, the community will be able to extend the bounds of the radical‐containing macromolecular paradigm. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1875–1894     

Transfer Hydrosilylation

Transfer hydrogenation is without question a common technology in industry and academia. Unlike its countless varieties, conceptually related transfer hydrosilylations had essentially been unreported until the recent development of a radical and an ionic variant. The new methods are both based on a silicon‐substituted cyclohexa‐1,4‐diene and hinge on the aromatization of the corresponding cyclohexadienyl radical and cation intermediates, respectively, concomitant with homo‐ or heterolytic fission of the Si? C bond. Both the radical and ionic transfer hydrosilylation are brought into context with one other in this Minireview, and early insight into the possibility of transfer hydrosilylation is included. Although the current state‐of‐the‐art is certainly still limited, the recent advances have already revealed the promising potential of transfer hydrosilylation.     

Olefin Isomerization via Radical‐Ion Pairs in Triplet States Studied by Chemically Induced Dynamic Nuclear Polarization (CIDNP)

Geometric isomerizations of olefins following photoinduced electron transfer (PET) are classified according to the relative energetic positions of the radical‐ion pairs and the reactant triplets. Each class exhibits characteristic CIDNP (chemically induced dynamic nuclear polarization) effects, for which typical examples are presented. Time‐resolved CIDNP experiments on the system triphenylamine/fumarodinitrile (= (2E)‐but‐2‐enedinitrile), where formation of the olefin triplet is impossible, show that there is also no isomerization of the olefin radical anion. With triisopropylamine or fumarodinitrile as the reaction partner for 4,4′‐dimethoxystilbene (= 1,1′‐[(1E)‐ethane‐1,2‐diyl]bis[4‐methoxybenzene]), both oxidative and reductive quenching give almost mirror‐image CIDNP spectra because of the pairing theorem; reverse electron transfer of the triplet radical‐ion pairs populates the stilbene triplet only, which then isomerizes. With anethole (= 1‐methoxy‐4‐(prop‐1‐enyl)benzene; M), the competition between electron return of triplet pairs to give either M + ³X or ³M + X was studied by using a second isomerizable olefin (diethyl fumarate (= diethyl (2E)‐but‐2‐enedioate) or cinnamonitrile (= (2E)‐3‐phenylprop‐2‐enenitrile)) as the reaction partner X. Classes can be changed by employing PET sensitization. With ACN (anthracene‐9‐carbonitrile) as the sensitizer, anethole does not produce any directly observable polarizations, but a substitution of ACN^.? by the radical anion of 1,4‐benzoquinone (= cyclohexa‐2,5‐diene‐1,4‐dione) or fumarodinitrile within the lifetime of the spin‐correlated radical‐ion pairs leads to very strong CIDNP signals that reflect the effects of both pairs.     

Unprecedented Acid‐Promoted Polymerization and Gelation of Acrylamide: A Serendipitous Discovery

Dilute acid polymerizes degassed, aqueous acrylamide with concomitant gelation, without the need for added free radical initiator or cross‐linking agent. This reaction is accelerated by sonication or UV irradiation, but inhibited by adventitious oxygen or the addition of a free radical inhibitor, suggesting an acid‐accelerated free radical process. The resulting hydrogels are thixotropic in nature and partially disrupted by the addition of chaotropic agents, indicating the importance of hydrogen bonding to the 3D network. This discovery was made while trying to prepare pectin‐polyacrylamide hydrogels. We observed that pectin initiated the gelation of acrylamide, but only if the aqueous pectin samples had a pH lower than ca. 5.     

Alkene 1,2‐Difunctionalization by Radical Alkenyl Migration

Transition‐metal‐free radical α‐perfluoroalkylation with the accompanying vicinal β‐alkenylation of unactivated alkenes is presented. These radical cascades proceed by means of 1,4‐ or 1,5‐alkenyl migration by electron catalysis on readily accessed allylic alcohols. The reactions comprise a regioselective perfluoroalkyl radical addition with subsequent alkenyl migration and concomitant deprotonation to generate a ketyl radical anion that sustains the chain as a single‐electron‐transfer reducing reagent.     

Molecule‐Induced Radical Formation (MIRF) Reactions—A Reappraisal

Radical chain reactions are commonly initiated through the thermal or photochemical activation of purpose‐built initiators, through photochemical activation of substrates, or through well‐designed redox processes. Where radicals come from in the absence of these initiation strategies is much less obvious and are often assumed to derive from unknown impurities. In this situation, molecule‐induced radical formation (MIRF) reactions should be considered as well‐defined alternative initiation modes. In the most general definition of MIRF reactions, two closed‐shell molecules react to give a radical pair or biradical. The exact nature of this transformation depends on the σ‐ or π‐bonds involved in the MIRF process, and this Minireview specifically focuses on reactions that transform two σ‐bonds into two radicals and a closed‐shell product molecule.     

Hydrogen Transfer in SAM‐Mediated Enzymatic Radical Reactions

S‐Adenosylmethionine (SAM) plays an essential role in a variety of enzyme‐mediated radical reactions. One‐electron reduction of SAM is currently believed to generate the C5′‐desoxyadenosyl radical, which subsequently abstracts a hydrogen atom from the actual substrate in a catalytic or a non‐catalytic fashion. Using a combination of theoretical and experimental bond dissociation energy (BDE) data, the energetics of these radical processes have now been quantified. SAM‐derived radicals are found to react with their respective substrates in an exothermic fashion in enzymes using SAM in a stoichiometric (non‐catalytic) way. In contrast, the catalytic use of SAM appears to be linked to a sequence of moderately endothermic and exothermic reaction steps. The use of SAM in spore photoproduct lyase (SPL) appears to fit neither of these general categories and appears to constitute the first example of a SAM‐initiated radical reaction propagated independently of the cofactor.     

Formation and decay of the ABTS derived radical cation: A comparison of different preparation procedures

Bleaching of a preformed solution of the blue‐green radical cation 2,2′‐azinobis (3‐ethylbenzothizoline‐6‐sulfonic acid) (ABTS^+·) has been extensively used to evaluate the antioxidant capacity of complex mixtures and individual compounds. The reaction of the preformed radical with free‐radical scavengers can be easily monitored by following the decay of the sample absorbance at 734 nm. The ABTS radical cation can be prepared employing different oxidants. Results obtained using MnO₂ as oxidant show that the presence of manganese ions increases the rate of [ABTS]^+· autobleaching in a concentration‐dependent manner. The radicals can also be obtained by oxidizing ABTS with 2,2^′‐azobis(2‐amidinopropane)hydrochloride (AAPH) or peroxodisulfate (PDS). The oxidation by AAPH takes place with a large activation energy and a low reaction order in ABTS. The data support a mechanism in which the homolysis of AAPH is the rate‐limiting step, followed by the reaction of ABTS with the peroxyl radicals produced after the azocompound thermolysis. On the other hand, the low activation energy measured employing PDS, as well as the kinetic law, are compatible with the occurrence of a bimolecular reaction between the oxidant and ABTS. Regarding the use of ABTS‐based methodologies for the evaluation of free radical scavengers, radical cations obtained employing AAPH as oxidant can be used only at low temperatures, conditions where further decomposition of the remaining AAPH is minimized. The best results are obtained with ABTS derived radicals generated in the reaction of PDS with an ABTS/PDS concentration ratio equal (or higher) to two. However, even with radicals prepared by this procedure, stoichiometric coefficients considerably larger than two are obtained for the consumption of the radical cation employing tryptophane or p‐terbutylphenol as reductants. This casts doubts on the use of ABTS‐based procedures for the estimation of antioxidant capacities. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 34: 659–665, 2002