Radical Intermediates Research Articles

Photo‐Induced Difluoroethylation or Monofluoromethyl Sulfonylation of 2‐Amino Aryl Ethynes to Access Diverse Seven‐Membered N‐Heterocycles

AbstractA photo‐induced two/three‐component radical difluoroethylation or monofluoromethyl sulfonylation of 2‐amino aryl ethynes was smoothly finished, which gave a series of difluoroethyl or monofluoromethyl sulfonyl seven‐membered N‐heterocycles. The two radical systems featured simple/mild reaction conditions, good substrate scopes, and excellent E/Z selectivity. In addition, various radical intermediates were successfully detected by HRMS to explore the reaction process. Single‐crystal X‐ray diffraction and scaled‐up experiments examined the product scaffold and application of this cyclization system.

Programmable C−N Bond Formation through Radical‐Mediated Chemistry in Plasma‐Microdroplet Fusion

AbstractNon‐thermal plasma discharge produced in the wake of charged microdroplets is found to facilitate catalyst‐free radical mediated hydrazine cross‐coupling reactions without the use of external light source, heat, precious metal complex, or trapping agents. A plasma‐microdroplet fusion platform is utilized for introduction of hydrazine reagent that undergoes homolytic cleavage forming radical intermediate species. The non‐thermal plasma discharge that causes the cleavage originates from a chemically etched silica capillary. The coupling of the radical intermediates gives various products. Plasma‐microdroplet fusion occurs online in a programmable reaction platform allowing direct process optimization and product validation via mass spectrometry. The platform is applied herein with a variety of hydrazine substrates, enabling i) self‐coupling to form secondary amines with identical N‐substitutions, ii) cross‐coupling to afford secondary amine with different N‐substituents, iii) cross‐coupling followed by in situ dehydrogenation to give the corresponding aryl‐aldimines with two unique N‐substitutions, and iv) cascade heterocyclic carbazole derivatives formation. These unique reactions were made possible in the charged microdroplet environment through our ability to program conditions such as reagent concentration (i. e., flow rate), microdroplet reactivity (i. e., presence or absence of plasma), and reaction timescale (i. e., operational mode of the source). The selected program is implemented in a co‐axial spray format, which is found to be advantageous over the conventional one‐pot single emitter electrospray‐based microdroplet reactions.

Harnessing the Reactivity of Nitroarene Radical Anions to Create Quinoline N‐Oxides by Electrochemical Reductive Cyclization

AbstractElectrochemical reduction of 2‐allyl‐substituted nitroarenes using a simple, undivided electrochemical cell with non‐precious electrodes to generate nitroarene radical anions was developed. The nitroarene radical anion intermediates participate in 1,5‐hydrogen atom transfer reactions to construct quinoline N‐oxides bearing aryl‐, heteroaryl‐, alkenyl‐, benzyl‐, sulfonyl‐, or carboxyl groups.

Light-assisted functionalization of aryl radicals towards metal-free cross-coupling.

The many synthetic possibilities that arise when using radical intermediates, in place of their polar counterparts, make contemporary radical chemistry research an exhilarating field. The introduction of photocatalysis has helped tame aryl radicals, leading to a resurgence of interest in their chemistry, and an expansion of viable coupling partners and attainable transformations. These methods are more selective and safer than classical approaches, and they utilize new radical precursors. Given the importance of sustainability in current organic synthesis and our interest in light-assisted metal-free transformations, this Review focuses on recent advances in the use of aryl radicals in photoinduced cross-couplings that do not rely on metals for the crucial bond-forming event, and it is structured according to the key step that the aryl radicals engage in.

Long-Range Charge Transport in Molecular Wires.

Long-range charge transport (LRCT) in molecular wires is crucial for the advancement of molecular electronics but remains insufficiently understood due to complex transport mechanisms and their dependencies on molecular structure. While short-range charge transport is typically dominated by off-resonant tunneling, which decays exponentially with molecular length, recent studies have highlighted certain molecular structures that facilitate LRCT with minimal attenuation over several nanometers. This Perspective reviews the latest progress in understanding LRCT, focusing on chemical designs and mechanisms that enable this phenomenon. Key strategies include π-conjugation, redox-active centers, and stabilization of radical intermediates, which support LRCT through mechanisms such as coherent resonant tunneling or incoherent hopping. We discuss how the effects of molecular structure, length, and temperature influence charge transport, and highlight emerging techniques like the Seebeck effect for distinguishing between transport mechanisms. By clarifying the principles behind LRCT and outlining future challenges, this work aims to guide the design of molecular systems capable of sustaining efficient long-distance charge transport, thereby paving the way for practical applications in molecular electronics and beyond.

Nickel‐Catalyzed Reductive Cross‐Coupling of α–Trifluoromethylated Alkyl Electrophiles and Allylic Sulfones

AbstractFluorinated motifs are commonly found in drugs and agrochemicals. The inclusion of fluorine‐containing motifs in drug candidates during lead optimization has become a valuable strategy in pharmaceutical research and development. Significant research efforts have been dedicated to synthesizing molecules with a trifluoromethyl (CF3−) group on a stereogenic carbon. Herein, we disclose a mild and efficient nickel‐catalyzed reductive cross‐coupling between α–trifluoromethyl alkyl bromides and allylic sulfones, enabling the efficient synthesis of α–trifluoromethyl homoallylic alkanes. This reaction featuring base‐free, mild conditions, a broad substrate scope, and high functional group tolerance. The synthetic versatility of this approach is further underscored by its successful application in the late‐stage functionalization of a range of drug molecules. Our preliminary mechanistic study suggests that this allylation process operates through a radical intermediate.

α-Trifluoromethylated Quinolines as Safe and Storable PET-Donor for Radical Polymerizations.

In the quest for powerful, safe, and storable photoinduced-electron transfer (PET) donors, the attention is turned to the α-trihalomethylated amine moiety that is not studied in the context of PET-reductants. The thermal and photophysical properties of α-trifluoromethylated quinolines are thus studied and their reducing abilities evaluated as initiators of polymerization reactions. Polymers of high molecular weights are obtained through a radical polymerization process and the PET-donor can be stored within the monomer for several months without losing its efficiency. Mechanistic investigations, combining spectroscopic analysis and theoretical calculations, confirm the mode of activation of these electron donors and the generation of radical intermediates through single electron transfer.

Unusual and Persistent Free Radical Intermediate Production from 2-Pyridyl Ketones via UV Irradiation: A Direct ESR Study.

Aryl ketones are often used as photosensitizers and photoinitiators. Free radical intermediates have been suggested, but not confirmed, to be generated after photoirradiation. Here we found, unexpectedly, that a persistent radical was produced from di-2-pyridyl ketone after UV irradiation, which was detected by the direct ESR method. Interestingly, the persistent radical was very sensitive to oxygen and the pH of the reaction medium. A similar persistent radical was also observed from phenyl-2-pyridyl ketone, but not from 3-benzoylpyridine, 4-benzoylpyridine, and benzophenone, suggesting that the presence of a carbonyl group connected to the ortho-position of the pyridine ring is critical for such radical production. By complementary applications of ESR, HPLC, and ESI-Q-TOF-MS, the possible chemical structures of the persistent radical and final product were identified, and the possible underlying reaction mechanism was proposed. This represents the first report on UV-induced persistent radical generation from 2-pyridyl ketones, which should be of great significance for future studies.

Dication Disulfuranes as Photoactivatable Sources of Radical Organocatalysts.

The recent development of photoredox and energy transfer catalysis has led to a significant expansion of visible light-driven chemical transformations. These methods have demonstrated exceptional efficiency in converting a wide range of substrates into radical intermediates and generating open-shell catalytic species. However, the simplification of catalytic systems and the direct generation of highly reactive radical organocatalysts through direct visible light irradiation from stable precatalysts remains largely an unrealized goal. This challenge is mainly due to the limited availability of precatalysts that are responsive to visible light. Herein, we introduce a new class of bench-stable dicationic disulfuranes, which release highly reactive thiyl radicals upon blue light excitation. Spectroscopic and computational studies reveal that this reactivity arises from a combination of structural features and intermolecular interactions. This family of molecules has been employed to catalyze radical cascades previously incompatible with photoredox conditions, enabling the efficient formation of 1,2-dioxolanes and 1,3-hydroxyketones in excellent yields and short reaction times.

Dication Disulfuranes as Photoactivatable Sources of Radical Organocatalysts

The recent development of photoredox and energy transfer catalysis has led to a significant expansion of visible light‐driven chemical transformations. These methods have demonstrated exceptional efficiency in converting a wide range of substrates into radical intermediates and generating open‐shell catalytic species. However, the simplification of catalytic systems and the direct generation of highly reactive radical organocatalysts through direct visible light irradiation from stable precatalysts remains largely an unrealized goal. This challenge is mainly due to the limited availability of precatalysts that are responsive to visible light. Herein, we introduce a new class of bench‐stable dicationic disulfuranes, which release highly reactive thiyl radicals upon blue light excitation. Spectroscopic and computational studies reveal that this reactivity arises from a combination of structural features and intermolecular interactions. This family of molecules has been employed to catalyze radical cascades previously incompatible with photoredox conditions, enabling the efficient formation of 1,2‐dioxolanes and 1,3‐hydroxyketones in excellent yields and short reaction times.

A Modern Approach to Intermittent Illumination for the Characterization of Chain-Propagation in Photoredox Catalysis

Photoredox catalysis has become an invaluable tool for the construction of organic molecules, allowing for unparalleled control over radical intermediates enabled by the mild conditions achieved through visible-light activation of a photocatalyst. These reactions can be classified under two distinct mechanistic paradigms: closed photocatalytic cycles, and photoinitiated chain reactions. While optimization strategies for each of these classes of reaction differ significantly, organic chemists still lack a straightforward means for probing chain-propagation. In this work, we report a simple and accessible approach to performing intermittent illumination studies for characterizing chain reactions in photoredox catalysis. Using modern LED technologies to precisely control the rate of sample illumination, we were able to validate the presence or absence of product-forming chain reactions in four previously reported photoredox protocols. Furthermore, this technique also allows for the determination of chain-propagating lifetimes through a simple graphical analysis. Given the operational simplicity and ease of accessibility, we believe this intermittent illumination technique will be of great value to practitioners of the field moving forward.

Synthesis of Alkyl Bis(trifluoromethyl)carbinols via Fe-LMCT-Enabled Hydrobis(trifluoromethyl)carbinolation of Alkenes.

Bis(trifluoromethyl)carbinols are valuable pharmacophores, yet their synthesis is challenging, largely due to a scarcity of safe and effective bis(trifluoromethyl)carbinolation reagents. Here, we realized the hydrobis(trifluoromethyl)carbinolation of alkenes, utilizing stable and readily accessible 2,2-bis(trifluoromethyl)glycolic acid as a source of both the bis(trifluoromethyl)carbinol unit and a hydrogen atom. This process leverages a photoinduced Fe-LMCT-enabled radical decarboxylation process that generates a key bis(trifluoromethyl)carbinol radical intermediate. Our mild protocol facilitates the synthesis of a diverse range of alkyl bis(trifluoromethyl)carbinols, including structurally complex molecules with pharmaceutical relevance.

Electrochemical Deconstructive Methoxylation of Arylalcohols-A Synthetic and Mechanistic Investigation.

Herein, we report a mechanistic investigation of a recently developed electrochemical method for the deconstructive methoxylation of arylalcohols. A combination of synthetic, electroanalytical, and computational experiments have been performed to gain a deeper understanding of the reaction mechanism and the structural requirements for fragmentation to occur. It was found that 2-arylalcohols undergo anodic oxidation to form the corresponding aromatic radical cations, which fragment to form oxocarbenium ions and benzylic radical intermediates via mesolytic cleavage, with further anodic oxidation and trapping of the benzylic carbocation with methanol to generate the observed methyl ether products. It was also found that the electrochemical fragmentation of 2-arylalkanols is promoted by structural features that stabilize the oxocarbenium ions and/or benzylic radical intermediates formed upon mesolytic cleavage of the aromatic radical cations. With an enhanced understanding of the reaction mechanism and the structural features that promote fragmentation, it is anticipated that alternative electrosynthetic transformations will be developed that utilize this powerful, yet underdeveloped, mode of substrate activation.

Dual NHC/HAT‐Promoted Esterification to Access α‐Aryl Glycines

α‐Aryl glycines are among the more important carbonyl compounds, particularly as nonproteinogenic α‐amino acids present in many pharmacophores. As such, many strategies have been developed to access this motif, but direct carboxylation methods remain underdeveloped. Herein, we employ a dual NHC/HAT catalysis strategy to access 2‐azaallyl radicals, which subsequently couple with in situ generated ester azolium radical intermediates. Base‐mediated collapse of the ensuing tetrahedral intermediate liberates the NHC catalyst and benzophenone protected aryl glycine. This methodology was employed to esterify obtain a variety of aryl substituted glycine derivatives, as well as allylic and benzylic sites. Mechanistic studies reveal that this radical process operates under both oxidative and reductive quenching cycles, while preliminary experiments employing a chiral NHC and Lewis acid additive demonstrate modest enantioselectivity.

Antioxidants as adjuvant in cancer therapy: A systematic review

While cancer therapies can effectively remove malignant cells from the body, their efficacy is mostly limited to a number of harmful side effects. Antioxidant treatment is therefore frequently necessary to lessen these negative effects by lowering reactive species levels and minimizing chronic oxidative damage. Antioxidants have a crucial role in inhibiting the production of reactive nitrogen and oxygen species as well as their activities. Reviewing the role of antioxidants in the development or prevention of cancer was the goal of this study. It is thought that antioxidants can both prevent and treat different kinds of cancer. As of right now, cancer prevention and treatment have primarily involved consuming natural antioxidant substances. These are unquestionably cell-type- and Reactive Oxygen Species (ROS)-specific, as evidenced by alterations in gene expression, cellular activities, and mechanisms of cell death. By decreasing hydrogen donors or quenching singlet oxygen and postponing oxidative reactions in cancer cells that are actively developing, natural antioxidants eliminate an overabundance of free radical intermediates. The primary topics covered in this study are antioxidant categorization, metabolic regulation, and antioxidant involvement in cancer treatment.

Next‐Generation Time‐Resolved Electron Paramagnetic Resonance for Direct Visualizing Mechanisms in Radical Chemistry

AbstractRadical chemistry is an important research field that plays a vital role in life science, material science, and energy conversions. However, directly visualizing the transient open‐shell intermediates unambiguously in radical chemistry is a significant and long‐standing challenge. Recently, we have developed an innovative ultrawide single‐sideband phase‐sensitive detection (U‐PSD) time‐resolved electron paramagnetic resonance (TREPR) technique, which enables the characterization of diverse transient radical intermediates and mechanistic studies close to reaction conditions. In this brief review, we will offer an outline of the principles underlying our U‐PSD TREPR technique, and present examples highlighting the technique's ability to accurately characterize and track free radical intermediates in photocatalytic reactions.

Photo‐and Electrochemical Modification of Amino Acids, Peptides and Proteins through Cysteine: Recent Advances and Future Perspectives

AbstractChemical modification of peptides and proteins has emerged as an efficient strategy to study and manipulate the physical and chemical properties and biological functionalities of proteins. Among the 20 proteinogenic amino acids, cysteine is one of the most frequently targeted residues for chemical modification of peptides and proteins due to its unique thiol group and its relatively low natural abundance. Cysteine is able to partake in radical and atom‐, electron‐ and hydride‐transfer reactions taking the benefit of redox activity of thiol side chain. Recently, photo‐ and electrochemistry have emerged as influential methodologies for enabling novel transformations in organic synthesis. These two fields both involve the generation of radical intermediates through single electron transfer processes, which align well with the redox activity of cysteine residue. Furthermore, the mild and controllable features are suitable for solving the chemo‐ and regioselective problems of the existing bioconjugation strategies. Given the intrinsic benefits of photo‐ and electrochemical redox catalysis, the application of developing novel cysteine‐based bioconjugation methods is increasingly compelling. This review provides a comprehensive overview of recent advancements in photo‐ and electrochemical approaches for modifying cysteine amino acid residues, cysteine‐containing peptides, and proteins. The advantages of photo‐ and electrochemical redox catalysis and its applicability in developing novel biocompatible methods are discussed. Additionally, the current limitations of these methods and the challenges that need to be addressed in the future are also explored.

Unravelling the favorability of radical-directed xn-H2O dissociation at serine and threonine

Among tandem-mass-spectrometry approaches, radical-directed dissociation (RDD) is uniquely sensitive to molecular structure because the location and types of cleavage observed are dictated by radical migration propensities. Although the underlying chemistry for many RDD fragmentation pathways has been previously explained, xn-H2O fragment ions that occur exclusively at serine and threonine residues, have not been examined in detail. Creation of this fragment type inherently requires two dissociation events, one to lose water and another to cleave the peptide backbone. Double dissociations are typically disfavored relative to pathways requiring a single cleavage, yet xn-H2O fragment ions are abundant in RDD spectra. To understand why this fragmentation pathway is favorable, we used a combination of computational chemistry and experiments on peptides with a variety of covalent modifications. Our results explore the energetics, location, and migration of the radical in each step of the mechanism, revealing that favorability can be attributed to the stability of the required radical intermediates and access to low-energy pathways connecting them. Ultimately, the abundant nature of xn-H2O ions and the selectivity associated with their exclusive generation at Ser/Thr provides high value sequence information in RDD experiments.

Programmable C-N Bond Formation through Radical-Mediated Chemistry in Plasma-Microdroplet Fusion.

Non-thermal plasma discharge produced in the wake of charged microdroplets is found to facilitate catalyst-free radical mediated hydrazine cross-coupling reactions without the use of external light source, heat, precious metal complex, or trapping agents. A plasma-microdroplet fusion platform is utilized for introduction of hydrazine reagent that undergoes homolytic cleavage forming radical intermediate species. The non-thermal plasma discharge that causes the cleavage originates from a chemically etched silica capillary. The coupling of the radical intermediates gives various products. Plasma-microdroplet fusion occurs online in a programmable reaction platform allowing direct process optimization and product validation via mass spectrometry. The platform is applied herein with a variety of hydrazine substrates, enabling i) self-coupling to form secondary amines with identical N-substitutions, ii) cross-coupling to afford secondary amine with different N-substituents, iii) cross-coupling followed by in-situ dehydrogenation to give the corresponding aryl-aldimines with two unique N-substitutions, and iv) cascade heterocyclic carbazole derivatives formation. These unique reactions were made possible in the charged microdroplet environment through our ability to program conditions such as reagent concentration (i.e., flowrate), microdroplet reactivity (i.e., presence or absence of plasma), and reaction timescale (i.e., operational mode source). The selected program is implemented in a co-axial spray format.

Probing the Molecular Interactions of Electrochemically Reduced Vitamin B2 with CO2.

The electrochemical reduction of riboflavin (vitamin B2) in a dimethyl sulfoxide solvent was examined under a CO2 atmosphere and compared with results under an argon atmosphere. Variable-scan-rate cyclic voltammetry combined with controlled potential electrolysis (CPE) and analysis by UV-vis and EPR spectroscopies provided insights into the nature of interactions of reduced flavins with dissolved CO2. Reductive exhaustive CPE experiments under CO2 indicated an overall two-electron stoichiometry, compared to one-electron reduction under an argon atmosphere, due to the lowering of the formal one-electron reduction potential of the flavin radical anion to form the dianion, which can be rationalized by riboflavin-CO2 molecular interactions. UV-vis spectroscopic measurements confirmed complete chemical reversibility of the redox transformations over extended time scales. Digital simulation modeling of the voltammetric data enabled extraction of thermodynamic and kinetic parameters for the proposed mechanism, comprising multiple proton-coupled electron transfer steps, diamagnetic anions, radical anions, and neutral radical intermediates enroute to the fully reduced state, as well as evidence of a long-lived solution phase complex of the reduced riboflavin with CO2.