Transient Radical Research Articles

Room-Temperature Cu(II) Radical-Triggered Alkyne C-H Activation.

A dimeric Cu(II) complex [Cu(II)2L2(μ2-Cl)Cl] (1) built from an asymmetric tridentate ligand (2-(((2-aminocyclohexyl)imino)methyl)-4,6-di-tert-butylphenol) and weakly coordinating anions has been synthesized and structurally characterized. In dichloromethane solution, 1 exists in a monomeric [Cu(II)LCl] (1′) (85%)–dimeric (1) (15%) equilibrium, and cyclic voltammetry (CV) and electron paramagnetic resonance (EPR) studies indicate structural stability and redox retention. Addition of phenylacetylene to the CH2Cl2 solution populates 1′ and leads to the formation of a transient radical species. Theoretical studies support this notion and show that the radical initiates an alkyne C–H bond activation process via a four-membered ring (Cu(II)–O···H–Calkyne) intermediate. This unusual C–H activation method is applicable for the efficient synthesis of propargylamines, without additives, within 16 h, at low loadings and in noncoordinating solvents including late-stage functionalization of important bioactive molecules. Single-crystal X-ray diffraction studies, postcatalysis, confirmed the framework’s stability and showed that the metal center preserves its oxidation state. The scope and limitations of this unconventional protocol are discussed.

Development of the Peripheral Functionalization Chemistry of meso-Free Corroles.

In contrast to the extensive development of the meso-functionalization of porphyrins, that of corroles had rarely been explored until the development of practical synthetic methods for meso-free corroles in 2015. The ready availability of meso-free corroles opened up meso-functionalization chemistry of corroles, giving rise to successful synthesis of various meso-substituted corroles such as meso-halogen, meso-nitro, meso-amino, meso-oxo, and meso-iminocorroles as well as meso-meso-linked corrole dimers and corrole tapes. In some cases, 2NH corroles exist as stable or transient radical species. The impact of meso-functionalization on the structures, electronic properties, optical characteristics, and aromaticity of corroles are highlighted in this Minireview.

Quasi-Free Electron-Mediated Radiation Sensitization by C5-Halopyrimidines.

Substitution of the thymidine moiety in DNA by C5-substituted halogenated thymidine analogues causes significant augmentation of radiation damage in living cells. However, the molecular pathway involved in such radiosensitization process has not been clearly elucidated to date in solution at room temperature. So far, low-energy electrons (LEEs; 0-20 eV) under vacuum condition and solvated electrons (esol-) in solution are shown to produce the σ-type C5-centered pyrimidine base radical through dissociative electron attachment involving carbon-halogen bond breakage. Formation of this σ-type radical and its subsequent reactions are proposed to cause cellular radiosensitization. Here, we report time-resolved measurements at room temperature, showing that a radiation-produced quasi-free electron (eqf-) in solution promptly breaks the C5-halogen bond in halopyrimidines forming the σ-type C5 radical via an excited transient anion radical. These results demonstrate the importance of ultrafast reactions of eqf-, which are extremely important in chemistry, physics, and biology, including tumor radiochemotherapy.

Radical Relay Trichloromethylacylation of Alkenes through N-Heterocyclic Carbene Catalysis.

N-Heterocyclic carbene catalysis enabling vicinal trichloromethylacylation of alkenes using tetrachloromethane and aldehydes has been developed. The reaction involves single electron transfer from the enolate form of the Breslow intermediate to tetrachloromethane to generate the persistent Breslow intermediate-derived ketyl radical and a transient trichloromethyl radical. After radical addition of the trichloromethyl radical to an alkene, the prolonged alkyl radical is preferentially captured by the ketyl radical over tetrachloromethane leading to the atom transfer radical addition product.

Mass-independent fractionation of oxygen isotopes during thermal decomposition of divalent metal carbonates: Crystallographic influence, potential mechanism and cosmochemical significance

Few physical or chemical processes defy well-established laws of mass-dependent isotopic fractionation. A surprising example, discovered two decades ago, is that thermal decomposition of calcium and magnesium carbonate minerals (conducted in vacuo, to minimise back-reaction and isotopic exchange) causes the oxygen triple-isotope compositions of the resulting solid oxide and CO2 to fit on parallel mass-dependent fractionation lines in ln(1 + δ17O) versus ln(1 + δ18O) space, with anomalous depletion of 17O in the solid and equivalent enrichment of 17O in the CO2. By investigating the thermal decomposition of other natural divalent metal carbonates and one synthetic example, under similar conditions, we find that the unusual isotope effect occurs in all cases and that the magnitude of the anomaly (Δ′17O) seems to depend on the room temperature crystallographic structure of the carbonate. A lower cation coordination number (as associated with smaller cation radius) correlates with a Δ′17O value closer to zero. Local symmetry considerations may therefore be influential. Relative to a reference fractionation line of slope 0.524 and passing through VSMOW, solid oxides produced by thermal decomposition of orthorhombic carbonates were characterised by Δ′17O = −0.367 ± 0.004‰ (standard error). The comparable figure from rhombohedral examples was −0.317 ± 0.010‰, whereas from the sole monoclinic (synthesised) specimen it was −0.219 ± 0.011‰. The numerical values are, to some extent, dependent on details of the experimental procedure. We discuss potential origins of the isotopic anomaly, including the possibility of hyperfine coupling between 17O nuclei and unpaired electrons of transient radicals (the ‘magnetic isotope effect’). A new mechanism based on the latter process is proposed. The associated transition state is compatible with that suggested by recent quantum chemical and kinetic studies of the thermal decompositions of calcite and magnesite. An earlier suggestion based on the magnetic isotope effect is shown to be incompatible with the generation of a 17O anomaly, regardless of the identity of the carbonate. We cannot exclude the possibility that a Fermi resonance between states leading to dissociation may additionally affect the magnitude of Δ′17O in some cases. Our findings have cosmochemical implications, with thermal processing of carbonates providing a potential mechanism for the mass-independent fractionation of oxygen isotopes in protoplanetary systems.

Synergistic dynamics of photoionization and photoinduced electron transfer probed by laser flash photolysis and ultrafast fluorescence spectroscopy.

Photoionization (PI) and photoinduced electron transfer (PET) dynamics of coumarin 450 (C450) in micelles were investigated in the time domains of micro to femtoseconds using steady-state and time-resolved absorption and fluorescence spectroscopy. The PI of C450 occurs inside the micelles leads to the formation of C450 cation radical (CR) and hydrated electron, which is characterized by the respective transient absorption. The PI of C450 is monophotonic in nature and the yield is dependent on the charge of the micelles. The observation of amine CR in the transient absorption confirms the PET from amine to the excited state of C450 in micelles, which results in the quenching of both fluorescence intensity and lifetime. The decrease in femtosecond fluorescent decay of C450 and the absence of transient C450 radical anion in the presence of amine implies that the concerted ultrafast PET promoted PI and PET to the C450 CR-electron pair. The decrease in the time constant for the formation of relaxed state in the presence of amines is due to the ultrafast PET to the C450 CR-electron pair, which prevents the formation of a relaxed state through recombination at a longer time scale. In the present investigation, the recombination dynamics of the CR-electron pair is justified as one of the origins of the slow solvation in micelles. The influence of amine concentration on the decay of C450 CR indicates ET reaction between C450 CR and amine, which is further confirmed by the bleach recovery of C450 ground state in the presence of amine.

Radical 1,4-Aryl Migration Enabled Remote Cross-Electrophile Coupling of α-Amino-β-Bromo Acid Esters with Aryl Bromides.

We report an unprecedented, efficient nickel-catalysed radical relay for the remote cross-electrophile coupling of β-bromo-α-benzylamino acid esters with aryl bromides via 1,4-aryl migration/arylation cascades. β-Bromo-α-benzylamino acid esters are considered as unique molecular scaffolds allowing for aryl migration reactions, which are conceptually novel variants for the radical Truce-Smiles rearrangement. This reaction enables the formation of two new C(sp3 )-C(sp2 ) bonds using a bench-stable Ni/bipyridine/Zn system featuring a broad substrate scope and excellent diastereoselectivity, which provides an effective platform for the remote aryl group migration and arylation of amino acid esters via redox-neutral C(sp3 )-C(sp2 ) bond cleavage. Mechanistically, this cascade reaction is accomplished by combining two powerful catalytic cycles consisting of a cross-electrophile coupling and radical 1,4-aryl migration through the generation of C(sp3 )-centred radical intermediates from the homolysis of C(sp3 )-Br bonds and the switching of the transient alkyl radical into a robust α-aminoalkyl radical.

Radical 1,4‐Aryl Migration Enabled Remote Cross‐Electrophile Coupling of α‐Amino‐β‐Bromo Acid Esters with Aryl Bromides

AbstractWe report an unprecedented, efficient nickel‐catalysed radical relay for the remote cross‐electrophile coupling of β‐bromo‐α‐benzylamino acid esters with aryl bromides via 1,4‐aryl migration/arylation cascades. β‐Bromo‐α‐benzylamino acid esters are considered as unique molecular scaffolds allowing for aryl migration reactions, which are conceptually novel variants for the radical Truce–Smiles rearrangement. This reaction enables the formation of two new C(sp3)−C(sp2) bonds using a bench‐stable Ni/bipyridine/Zn system featuring a broad substrate scope and excellent diastereoselectivity, which provides an effective platform for the remote aryl group migration and arylation of amino acid esters via redox‐neutral C(sp3)−C(sp2) bond cleavage. Mechanistically, this cascade reaction is accomplished by combining two powerful catalytic cycles consisting of a cross‐electrophile coupling and radical 1,4‐aryl migration through the generation of C(sp3)‐centred radical intermediates from the homolysis of C(sp3)−Br bonds and the switching of the transient alkyl radical into a robust α‐aminoalkyl radical.

Visible-Light-Induced Dearomatization of Indoles/Pyrroles with Vinylcyclopropanes: Expedient Synthesis of Structurally Diverse Polycyclic Indolines/Pyrrolines

Visible-light-induced cycloaddition reactions initiated via energy-transfer processes have recently evolved as powerful methods for the construction of strained cyclic molecules that are not easily accessed using known ground-state synthetic methods. Particularly, the reactions initiated by the excitation of aromatic rings provide an alternative solution to the direct transformations of aromatic feedstocks under the scheme of dearomatization. Vinylcyclopropanes (VCPs) are well-known reagents in radical clock experiments, working as a probe to detect transient radical intermediates. However, the synthetic applications in this regard still remain limited due to uncontrollable selectivities. Herein, we report visible-light-induced dearomatization of indole- or pyrrole-tethered VCPs, in which several competitive reaction pathways, including [5 + 2], [2 + 2], interrupted [5 + 2], and [5 + 4] cycloadditions, can be well regulated by engineering substrate structures and tuning reaction conditions. The reaction mechanism has been explored by combined experimental and computational investigations. These reactions provide a convenient method to synthesize structurally diverse polycyclic molecules with high efficiency and good selectivity.

Origin of sonocatalytic activity of fluorescent carbon dots

Although ultrasound-induced reactive oxygen species (ROS) have believed to be primary intermediates for the realization of sonodynamic therapy and sonocatalytic reactions, the mechanism of ROS production under ultrasound has not been well clarified till now. Here we discovered that ultrasound cavitation can break up oxygen-containing groups on the surface of carbon dots (CDs) to generate ROS, giving rise to a novel mechanism different from as-reported those. The bond cleavage of oxygen-containing groups contribute transient oxygen free radicals (•O−) that involve in the subsequent formation of ROS by quickly reacting with hydrogen ions and water, thereby leading to a twice higher sonocatalytic activity of CDs than TiO2. Moreover, the sonosensitizer function of CDs can be tuned by pH values of the surrounding environment that determine the generation and evolution reaction of oxygen free radicals under ultrasound irradiation. This finding paves a new way to design multifunctional sonosensitizers and utilize them in various fields.

1,3-Alkyl Transposition in Allylic Alcohols Enabled by Proton-Coupled Electron Transfer.

A method is described for the isomerization of acyclic allylic alcohols into β-functionalized ketones via 1,3-alkyl transposition. This reaction proceeds via light-driven proton-coupled electron transfer (PCET) activation of the O-H bond in the allylic alcohol substrate, followed by C-C β-scission of the resulting alkoxy radical. The transient alkyl radical and enone acceptor generated in the scission event subsequently recombine via radical conjugate addition to deliver β-functionalized ketone products. A variety of allylic alcohol substrates bearing alkyl and acyl migratory groups were successfully accommodated. Insights from mechanistic studies led to a modified reaction protocol that improves reaction performance for challenging substrates.

1,3‐Alkyl Transposition in Allylic Alcohols Enabled by Proton‐Coupled Electron Transfer

AbstractA method is described for the isomerization of acyclic allylic alcohols into β‐functionalized ketones via 1,3‐alkyl transposition. This reaction proceeds via light‐driven proton‐coupled electron transfer (PCET) activation of the O−H bond in the allylic alcohol substrate, followed by C−C β‐scission of the resulting alkoxy radical. The transient alkyl radical and enone acceptor generated in the scission event subsequently recombine via radical conjugate addition to deliver β‐functionalized ketone products. A variety of allylic alcohol substrates bearing alkyl and acyl migratory groups were successfully accommodated. Insights from mechanistic studies led to a modified reaction protocol that improves reaction performance for challenging substrates.

A Novel Stoichio-Kinetic Model for the DPPH• Assay: The Importance of the Side Reaction and Application to Complex Mixtures.

The 2,2-diphenyl-1-picrylhydrazyl (DPPH•) assay is widely used to determine the antioxidant activity of food products and extracts. However, the common DPPH• protocol uses a two-point measurement and does not give information about the kinetics of the reaction. A novel stoichio-kinetic model applied in this study monitors the consumption of DPPH• by common antioxidants following the second order reaction. The fitting of such decay yields the rate constant k1, which describes the main reaction between antioxidants and DPPH•, and the rate constant k2, which is attributed to a slower side reaction considering the products generated between the transient radicals (AO•) and another molecule of DPPH•. The model was first applied to antioxidant standards. Sinapic acid, Trolox and ascorbic and chlorogenic acids did not show any side reaction. Instead gallic, ferulic and caffeic acids achieved the best fitting with k2. The products of the side reaction for these compounds were confirmed and identified with high-resolution mass spectrometry. Finally, the kinetic model was applied to evaluate the antioxidant activity of eight herbal extracts. This study suggests a new kinetic approach to standardize the common DPPH• assay for the determination of antioxidant activity.

Cover Feature: Exploiting Transient Radical Cations as Brønsted Acids for Allylic C–H Heteroarylation of Enol Silyl Ethers (Chem. Eur. J. 36/2021)

The reaction pathways of transient radical species are difficult to control, like the soap bubbles in the wind depicted in the cover image. Yet, these short-lived intermediates, when one encounters another, readily assemble into a united structure, as two bubbles fuse into a bigger single bubble. The enol silyl ether-derived radical cations with a highly acidic allylic proton facilitates the single-electron reduction of cyanopyridines via protonation. The resulting two radical intermediates successively engage in the radical−radical coupling to produce heteroarylated enol silyl ethers. More information can be found in the Communication by T. Ooi et al. (DOI: 10.1002/chem.202101352).

Exploiting Transient Radical Cations as Brønsted Acids for Allylic C-H Heteroarylation of Enol Silyl Ethers.

Intermediary radical cations, generated through single-electron oxidation of enol silyl ethers by excited Ir-based photocatalysts, can be exploited as Brønsted acids for the activation of heteroarylcyanides. This strategy enables the direct allylic C-H heteroarylation of enol silyl ethers under visible-light irradiation.

Retraction Note: Endoperoxide formation by an α-ketoglutarate-dependent mononuclear non-haem iron enzyme.

The X-ray crystal structures of FtmOx1, the first known α-ketoglutarate-dependent mononuclear non-haem iron enzyme that can catalyse an endoperoxide formation reaction, are presented, along with further biochemical analyses which reveal the catalytic versatility of mononuclear non-haem iron enzymes, and help to unravel the mechanisms of endoperoxide biosyntheses. Verruculogen, a non-ribosomal peptide produced by various Aspergillus and Penicillium strains, contains an unusual and highly reactive endoperoxide (R-O-O-R) functional group that is generated from fumitremorgin B by the mononuclear non-haem iron enzyme FtmOx1. Pinghua Liu and colleagues report the X-ray crystal structures of FtmOx1 alone and in the presence of fumitremorgen B or α-ketoglutarate. Together with further biochemical analyses, these structures reveal the catalytic versatility of mononuclear non-haem iron enzymes, and help to unravel the mechanisms of endoperoxide biosyntheses. Verruculogen, a non-ribosomal peptide produced by various Aspergillus and Penicillium strains, contains an unusual and highly reactive endoperoxide (R-O-O-R) functional group that is generated from fumitremorgin B by the mononuclear non-haem iron enzyme FtmOx1. Pinghua Liu and colleagues report the X-ray crystal structures of FtmOx1 alone and in the presence of fumitremorgen B or α-ketoglutarate. Together with further biochemical analyses, these structures reveal the catalytic versatility of mononuclear non-haem iron enzymes, and help to unravel the mechanisms of endoperoxide biosyntheses. Many peroxy-containing secondary metabolites1,2 have been isolated and shown to provide beneficial effects to human health3,4,5. Yet, the mechanisms of most endoperoxide biosyntheses are not well understood. Although endoperoxides have been suggested as key reaction intermediates in several cases6,7,8, the only well-characterized endoperoxide biosynthetic enzyme is prostaglandin H synthase, a haem-containing enzyme9. Fumitremorgin B endoperoxidase (FtmOx1) from Aspergillus fumigatus is the first reported α-ketoglutarate-dependent mononuclear non-haem iron enzyme that can catalyse an endoperoxide formation reaction10,11,12. To elucidate the mechanistic details for this unique chemical transformation, we report the X-ray crystal structures of FtmOx1 and the binary complexes it forms with either the co-substrate (α-ketoglutarate) or the substrate (fumitremorgin B). Uniquely, after α-ketoglutarate has bound to the mononuclear iron centre in a bidentate fashion, the remaining open site for oxygen binding and activation is shielded from the substrate or the solvent by a tyrosine residue (Y224). Upon replacing Y224 with alanine or phenylalanine, the FtmOx1 catalysis diverts from endoperoxide formation to the more commonly observed hydroxylation. Subsequent characterizations by a combination of stopped-flow optical absorption spectroscopy and freeze-quench electron paramagnetic resonance spectroscopy support the presence of transient radical species in FtmOx1 catalysis. Our results help to unravel the novel mechanism for this endoperoxide formation reaction.

Synthesis of Sterically Hindered α-Hydroxycarbonyls through Radical-Radical Coupling.

We describe a synthetic approach to sterically hindered α-hydroxy carbonyl compounds through radical-radical coupling. An organic photoredox catalysis reaction converts an aliphatic carboxylic acid and α-ketocarbonyl to a transient alkyl radical and a persistent ketyl radical, respectively, which couple selectively based on the persistent radical effect. This protocol allows the use of primary, secondary, and tertiary aliphatic carboxylic acids to introduce various alkyl substituents onto ketone moieties of α-ketocarbonyls under mild reaction conditions.

Revisiting magnetic field effects in homogeneous medium and bio-mimicking environments with emphasis on acridine derivatives

A weak external magnetic field, very close to the hyperfine interactions of the system, can acts as a tool to monitor spin dynamics and assess distance between the components of the spin-correlated transient radical pair or radical ion pair (RIP). The present review focuses on the magnetic field effect (MFE) on the photo-induced electron-transfer (PET) reactions among acridine derivatives and classical as well as biological electron acceptor or donor moieties, which produce spin-correlated RIPs, in homogeneous solvents, heterogeneous micellar media and in biological nanocavities of proteins. Although a confined medium is preferred to observe prominent MFE, yet unanticipated MFE on PET between acridine derivatives [Acridone (AD) and Acridine Yellow (AY)] and classical electron donors is obtained even in homogeneous medium when it consists of impurities like water molecules. In a comparative study of interaction of another acridine derivative, Proflavin (PF+) with two electron donors which are amines of aromatic nature, MFE on PET reveal that the bulk and the structure of the electron donor govern the mechanism as well as the spin dynamics of PET. While studying interaction of PF+ with a different amine which is aliphatic in nature, MFE on PET implies that it is the nature of the solvent matrix which determines the spin dynamics of PET. The cause of discrepancy in the experimental and calculated values of B1/2 for 9-amino acridine – methyl viologen system has been delineated. Apart from micellar medium, prominent MFE on PET is also observed while studying the interaction of PF+, AY and AD with tryptophan residues present in the nanocavities of serum albumins since the inter-radical distance within primary geminate RIP is enough to make exchange interaction negligible.

Photoinduced emissive naphthalenediimide radical anion in the confinement of cucurbituril nanocavity; in situ generation of gold nanoparticles

Supramolecularly assembled building blocks, especially those based on π stacked organic or inorganic redox active materials have found encouraging applications in recent years due to their electron-accepting nature and easy structural manipulations. In this regard, by employing various spectroscopic, thermodynamic and imaging measurements we establish the generation, stabilization and in situ reaction of a novel supramolecularly supported emissive radical anions through host–guest interaction of N, Ń-bis[2-(2-aminoethyl)benzimidazolyl] naphthalene diimide (BzNDI) with Cucubit[n]uril (CB7 and CB8) macrocycles in aqueous medium. While the CB7 and CB8 hosts revealed distinct interactions with the BzNDI, the CB8 complexation displayed a novel excimer emission band in the 523 nm region, which originated from dimeric inclusion of BzNDI dyes in to the larger CB8 cavity. These CB7/CB8 stabilized BzNDI complexes undergo photoinduced electron transfer process to generate respective radical anions. These transient radical anions held in the cucurbituril nanocavities displayed characteristic emission spectra in the visible region and longer lived (τav ~ 6.5 ns) radical excited states and the radical anions are found to be reversible to their parent complex under ambient condition in ~1–2 h. This dynamic stability window of the radical anions has been used for the in situ reduction of Au3+ to generate stable AuNPs. It is noteworthy that this chemistry was not observed with BzNDI in the absence of CB7/CB8 host interaction. We foresee that the demonstrated stimuli responsive supramolecular approach has the potential for the controlled assembly of smart materials, radical polymerization, molecular electronics and other gated radical induced reactions.

Selective Oxidation of Transient Organic Radicals in the Presence of Gold Nanoparticles.

The ability of gold nanoparticles (AuNPs) to catalyze reactions involving radicals is poorly studied. However, AuNPs are used in applications where chemical reactions involving transient radicals occur. Herein, we investigate AuNPs’ catalytic effect on 2-propanol oxidation and acetanilide hydroxylation in aqueous solutions under ionizing radiation at room temperature. In both cases, the presence of AuNPs led to selective oxidation of organic radicals, significantly changing the products’ composition and ratio. Based on these observations, we stress how AuNPs’ catalytic activity can affect the correctness of reactive oxygen species concentration determination utilizing organic dyes. We also provide a discussion on the role of AuNPs’ catalytic activity in the radiosensitization effect actively studied for radiotherapy.