Single-electron Oxidation Research Articles

Functionalized Terthiophene as an Ambipolar Redox System: Structure, Spectroscopy, and Switchable Proton-Coupled Electron Transfer.

Organic redox systems that can undergo oxidative and reductive (ambipolar) electron transfer are elusive yet attractive for applications across synthetic chemistry and energy science. Specifically, the use of ambipolar redox systems in proton-coupled electron transfer (PCET) reactions is largely unexplored but could enable "switchable" reactivity wherein the uptake and release of hydrogen atoms are controlled using a redox stimulus. Here, we describe the synthesis and characterization of an ambipolar functionalized terthiophene (TTH) bearing methyl thioether and phosphine oxide groups that exhibits switchable PCET reactivity. Electrochemical studies established that the functionalized TTH can be reversibly oxidized and reduced, prompting the synthesis and characterization of cationic and anionic radicals on a single TTH platform. Combined structural, spectroscopic, and computational investigations revealed the influence of the methyl thioether and phosphine oxide moieties on the TTH electronic structure that results in the stabilization of both cationic and anionic radicals. Upon single-electron oxidation, the functionalized TTH serves as a hydrogen atom acceptor and undergoes PCET with 1,4-dihydroquinone to generate a TTH hydroxyphosphonium species. The process was found to be reversible upon single-electron reduction, with functionalized TTH acting as a hydrogen atom donor in a PCET reaction with 2,3-dimethylanthraquinone. The thermochemistry of the O-H bond formed and cleaved in functionalized TTH during the reaction sequence was investigated, revealing that a bond weakening of 30 kcal/mol underpins the switchable PCET reactivity. Overall, these studies provide an electrochemical, structural, spectroscopic, and thermochemical foundation for the use of ambipolarity to control PCET reactions in organic redox systems.

Electro-oxidative Deoxyfluorination of Arenes with NEt3·3HF.

This report describes the design, development, and optimization of an electrochemical deoxyfluorination of arenes using a tetrafluoropyridine-derived leaving group. NEt3·3HF serves as the fluoride source, and the reactions are conducted using either constant potential or constant current electrolysis in an undivided electrochemical cell. Mechanistic studies support a net oxidative pathway, in which initial single-electron oxidation generates a radical cation intermediate that is trapped by fluoride. The resulting radical undergoes a second oxidation reaction, followed by the loss of the leaving group to yield the fluoroarene product.

Visible‐Light‐Induced Tandem Cyclization of 1,7‐Enynes to Access Phenanthridin‐6(5H)‐Ones Using a Polydimethylsiloxane (PDMS) Based Microreactor

AbstractWe report an organophotoredox‐catalyzed visible‐light‐induced tandem cyclization of 1,7‐enynes with diaryliodoniumtriflates has been established leading to Phenanthridin‐6(5H)‐one derivatives under metal‐free conditions. This transformation is initiated by visible light induced aryl radical formation from diaryliodoniumtriflates, followed by its regioseletive addition to the acrylate moiety of 1,7‐enynes then undergoes intramolecular 6‐exo‐dig cascade radical annulation and which is terminated by single electron oxidation along with proton abstraction. This effective, sustainable and metal‐free protocol exhibits a broad substrate scope and excellent tolerability towards various functional groups in good to excellent yields. Further implementation of a batch protocol to continuous flow protocol utilizing polydimethylsiloxane (PDMS) based microreactor exhibits its efficiency.

Glycosylase Pretreatment with Chemical Labeling-Assisted HPLC-MS/MS: An Ultrasensitive and Reliable Strategy for Quantification of 8-Oxo-7,8-dihydro-2'-deoxyguanosine in Genomic DNA.

8-Oxo-7,8-dihydro-2'-deoxyguanosine (dOG), the dominant oxidative product of 2'-deoxyguanosine (dG) under high levels of reactive oxygen species, usually serves as a biomarker for oxidative stress and a risk assessment factor for various diseases. Due to the extremely low abundance of dOG and the susceptibility of dOG detection to the interference of spurious oxidation, research on related biological processes is limited by insufficient sensitivity and specificity. In this work, an ultrasensitive and reliable approach for genome-wide dOG quantification was developed through chemical labeling-assisted high-performance liquid chromatography-tandem mass spectrometry with the introduction of glycosylase pretreatment. Upon derivatization by a novel labeling reagent rhodamine B ethylenediamine, the detection sensitivity of dOG was enhanced by 100-fold, and the detection limit was as low as 25 amol, which was superior to those of reported mass spectrometry-based methods. Potassium ferricyanide, as a single-electron oxidant, was shown to possess strong selectivity for dOG versus dG, improving the labeling specificity and reducing the interference from dG. The spurious oxidation during sample pretreatment was systematically explored and minimized, and a control assay of glycosylase pretreatment was proposed to further improve the quantitative accuracy of dOG. Precise quantification of endogenous dOG in different cells was achieved with less than 500 ng of genomic DNA. This method was successfully applied to the assessment of the overall level of oxidative damage under the treatment of glycosylase inhibitors, potentially contributing to the exploration of the complex role of dOG in physiological status and disease phenotype.

Harnessing Photoredox and Weak Brønsted Base Dual Catalysis for Selective C(sp3)–H Bond Activation

AbstractVisible light photoredox and weak Brønsted base dual catalysis has emerged as a powerful and versatile tool in the activation of C(sp3)–H bonds under mild reaction conditions. This method allows for the selective functionalization of a wide range of substrates, including amines, sulfides, ethers, dithianes and dithiolanes, dioxolanes, and alkenes. By exploiting the increased acidity of C–H bonds following single electron oxidation, this strategy employing a dual catalyst facilitates various carbon–carbon bond-forming reactions, as well as selective rearrangements, with high efficiency and regioselectivity. This review highlights recent advancements in this field, emphasizing the underlying mechanisms and the broad applicability of these methodologies in organic synthesis.1 Introduction2 Activation of α-C(sp3)–H Bonds in N-, S-, and O-Containing Compounds for C–C Bond Formation3 Activation of Allylic C–H Bonds for C–C Bond Formation4 Photoredox and Base Dual Catalysis for Rearrangement Reactions5 Conclusion

Dehydrogenative Photoredox Catalyzed Synthesis of Indolyl Δ2‐Isoxazolines via a Formal C(sp3)–H Functionalization.

A dehydrogenative photoredox catalyzed formal C(sp3)‐H intramolecular cyclization of indolyl‐oximes to generate indolyl Δ2‐isoxazolines is reported. In contrast to the current state‐of‐the‐art, the reaction avoids the use of super stoichiometric chemical oxidants and high reaction temperatures and is proposed to operate via two sequential single electron oxidation events.

Single-Electron Oxidation Triggered by Visible-Light-Excited Enzymes for Asymmetric Biocatalysis.

By integrating enzymatic catalysis with photocatalysis, photoenzymatic catalysis emerges as a powerful strategy to enhance enzyme catalytic capabilities and provide superior stereocontrol in reactions involving reactive intermediates. Repurposing naturally occurring enzymes using visible light is among the most active directions of photoenzymatic catalysis. This Minireview focuses on a cutting-edge strategy in this direction, namely single-electron-oxidation-triggered non-natural biotransformations catalyzed by photoexcited enzymes. These straightforward transformations feature a unique radical mechanism initiated by single-electron oxidation, achieving redox-neutral non-natural C-C, C-O, and C-S bond formation, and expanding the chemical toolbox of enzymes. By highlighting recent advances in this field and emphasizing their catalytic mechanisms and synthetic potential, innovative approaches for photobiomanufacturing are anticipated.

Catalytic Enantioselective Hydrogen Atom Abstraction Enables the Asymmetric Oxidation of Meso Diols.

Desymmetrization of meso diols is an important strategy for the synthesis of chiral oxygen-containing building blocks. Oxidative desymmetrization is an important subclass, but existing methods are often constrained by the need for activated alcohol substrates. We disclose a conceptually distinct strategy toward oxidative diol desymmetrization that is enabled by catalytic enantioselective hydrogen atom abstraction. Following single electron oxidation of a cinchona alkaloid-derived catalyst, enantiodetermining hydrogen atom abstraction generates a desymmetrized ketyl radical intermediate which reacts with either DIAD or O2 before in situ elimination to form valuable hydroxyketone products. A range of cyclic and acyclic meso diols are competent, defining the absolute configuration of up to four stereocenters in a single operation. As well as providing rapid access to complex hydroxyketones, this work emphasizes the broad synthetic potential of harnessing hydrogen atom abstraction in an enantioselective manner.

Construction of Isochromanones via Hemin-Catalyzed Phenol-Enamine Oxidative Annulation.

We have developed a hemin-catalyzed biomimetic oxidative annulation of 2,3-dihydroxybenzoic acid with an array of cyclic enamines to form isochromanones in good to excellent yields and high regioselectivity. This formal [4+2] cycloaddition protocol showed high efficiency and remarkable functional group tolerance. Mechanistic studies indicate the involvement of a single-electron oxidation pathway. Preliminary biological investigations showed that isochromanones 3ag and 3ca exhibited antineoplastic activities against MCF-7 cell lines with IC50 values of 25.21 and 29.09 μM, respectively.

Biomimetic Dehydrogenative Intermolecular Formal Allylic Amidation of Branched α-Olefins.

Allylic amide moieties are commonly encountered in natural products and are privileged structures in pharmaceuticals and agrochemicals. Moreover, because allylic amide can be to converted into an array of high-value motifs, they have been widely employed in organic synthesis. However, the development of catalytic systems for intermolecular allylic amidation of olefins, particularly branched α-olefins, has proven to be challenging. Here, a biomimetic, synergistic catalytic method is reported that combines photoredox, cobalt, and Brønsted base catalysis for the synthesis of substituted allylic amides from branched α-olefins and simple imides without using oxidants. This low-cost, operationally simple method features a broad substrate scope and excellent functional group compatibility. Moreover, it is successfully used for the functionalization of several structurally complex molecules demonstrating the method's potential utility for medicinal chemistry applications. Mechanistic studies revealed that C(sp3)─N bond formation is mediated by a nitrogen-centered radical intermediate, which is generated via a sequence involving deprotonation and single-electron oxidation.

Gem-Difluorobicyclo[2.1.1]hexanes via Photochemical [2π + 2σ] Cycloaddition Initiated by Oxidative Activation of gem-Difluorodienes.

The incorporation of fluorine atoms into three-dimensional sp3-rich scaffolds represents an attractive tactic during bioisosteric evolution campaigns by endowing bioisosteric candidates with improved pharmacokinetic properties. Photo- or Lewis acid-mediated bicyclo[1.1.0]butane cycloaddition has offered an efficient approach for the construction of numerous regular bicyclo[n.1.1] scaffolds (n = 1-5) but remains a significant challenge to the synthesis of related 3D fluorinated scaffolds. Herein, we unveiled a photochemical single-electron oxidative strategy for gem-difluorodiene activation and subsequent [2π + 2σ] cycloaddition with bicyclo[1.1.0]butanes to provide a broad range of gem-difluorobicyclo[2.1.1]hexane scaffolds containing several post-transformable handles. A combination of experimental and computational mechanistic studies suggested that the conjugated π system of gem-difluorodiene plays important dual roles in promoting its preferential single-electron oxidation and stabilizing various radical-involved intermediates during the cyclization.

NaNH2 as a Nitrogen Source and Base to Synthesize Triarylamines from Aryl Halides Using Pd-Catalyzed C-N Coupling.

Triarylamines (TAAs) are excellent core structures for multifunctional materials. Reversible single-electron oxidation is the key to versatile applications. Synthesizing these from feedstock materials is inevitable. Here, we report the one-pot synthesis of TAAs from aryl halides and inexpensive NaNH2 as a nitrogen source and base (dual role). The Pd/Xantphos catalytic system shows excellent selectivity toward TAAs from aryl bromides without adding organic amines and an additional base. Various para substituents on the aryl ring show good functional group tolerance in the presence of NaNH2, resulting in moderate to excellent yield (20-91%). Even though the meta-substituted aryl bromides give TAA products in moderate to excellent yields (20-81%), the ortho substitution leads to only diarylamine products. TAAs from aryl chlorides can be achieved only by changing the ligand to Xphos. The mechanistic investigation suggests that three sequential C-N cross-coupling reactions give the TAA products in the presence of NaNH2. The photophysical and electrochemical properties of TAAs and corresponding radicals were tunable based on substitution patterns.

Photoredox-Catalyzed Markovnikov Hydroamination of Alkenes with Azoles.

A visible-light induced intermolecular hydroamination of alkenes with azoles is reported, delivering pharmaceutically valuable N-benzyl azoles in high yields with excellent Markovnikov selectivity. Mechanistic studies suggest that the process is initiated by the energy transfer of the excited photocatalyst with alkenes, followed by the single electron reduction, protonation, and subsequent single electron oxidation to afford the key alkyl carbocation intermediate. This protocol exhibits advantages of broad functional group tolerance, excellent atom economy, high efficiency, and mild reaction conditions.

Strain-Release-Driven Electrochemical Skeletal Rearrangement of Non-Biased Alkyl Cyclopropanes/Butanes.

Capitalizing the inherent strain energy within molecules, strain-release-driven reactions have been widely employed in organic synthesis. Small cycloalkanes like cyclopropanes and cyclobutanes, with their moderate ring strain, typically require dense functionalization to induce bias or distal activation of (hetero) aromatic rings via single-electron oxidation for relieving the tension. In this study, we present a pioneering direct activation of alkyl cyclopropanes/butanes through electrochemical oxidation. This approach not only showcases the potential for ring-opening of cyclopropane/butane under electrochemical conditions but also streamlines the synthesis of diverse oxazolines and oxazines. The applicability of our method is exemplified by its broad substrate scopes. Notably, the products derived from cyclobutanes undergo a formal ring contraction to cyclopropanes, introducing an intriguing aspect to our discoveries. These discoveries mark a significant advancement in strain-release-driven skeletal rearrangement reactions of moderately strained rings, offering sustainable and efficient synthetic pathways for future endeavours.

Organocatalyzed Carbonylation of Alkyl Halides Driven by Visible Light.

Herein, we describe a new strategy for the carbonylation of alkyl halides with different nucleophiles to generate valuable carbonyl derivatives under visible light irradiation. This method is mild, robust, highly selective, and proceeds under metal-free conditions to prepare a range of structurally diverse esters and amides in good to excellent yields. In addition, we highlight the application of this activation strategy for 13C isotopic incorporation. We propose that the reaction proceeds by a photoinduced reduction to afford carbon-centered radicals from alkyl halides, which undergo subsequent single electron-oxidation to form a carbocationic intermediate. Carbon monoxide is trapped by the carbocation to generate an acylium cation, which can be attacked by a series of nucleophiles to give a range of carbonyl products.

Asymmetric Synthesis of Dialkyl Carbinols by Ni-Catalyzed Reductive-Oxidative Relay of Distinct Alkenes.

Enantioenriched unsymmetric dialkyl carbinol derivatives are of importance in natural products, bioactive molecules, and functional organic materials. However, the catalytic asymmetric synthesis of dialkyl carbinol derivatives remains challenging due to the similar steric and electronic properties of two alkyl substituents. Herein, an unprecedented synthesis of chiral dialkyl carbinol ester derivatives from Ni-catalyzed reductive-oxidative relay cross-coupling of two alkenes is developed for the first time. The reaction features the use of enol esters and unactivated alkenes as two different alkyl equivalents to undergo head-to-tail and enantioselective alkyl-alkyl cross-coupling. The reaction undergoes two-electron reduction and single electron oxidation in the presence of both reductants and oxidants. The use of an allyl bromide as single electron acceptor is crucial for the success of this non-trivial asymmetric cross-coupling, providing a new reaction mode for asymmetric alkyl-alkyl bond-forming event in the absence of stoichiometric alkyl electrophiles.

Application of a laccase-catalyzed oxidative coupling for the removal and detoxification of typical flotation reagent salicylhydroxamic acid

Residual organic flotation reagents in mineral processing wastewater (MPW) can pose environmental hazards and hinder the sustainable development of the mining industry. Laccase as a versatile biocatalyst can eliminate various recalcitrant contaminants from the environment, but its potential applications for the removal and detoxification of organic flotation reagents have until now been overlooked. Herein, the influence of superparamagnetic immobilized laccase (SPM-IMLac) on the enzymatic removal of salicylhydroxamic acid (SHA), a typical mineral flotation reagent, as well as the mechanism of this process have been explored for the first time. The results indicated that SPM-IMLac can effectively remove SHA over a broad pH range and this process follows the pseudo-first-order reaction kinetics. A methodology which combined high resolution mass spectrometry (HRMS) and a solid phase extraction (SPE) technique revealed that SPM-IMLac could catalyze a single-electron oxidation of SHA to generate self/cross-oligomers via radical-driven C-C and/or C-O-C covalent coupling pathways. The Vibrio fischeri bioluminescence inhibition assay and a total organic carbon (TOC) analysis corroborated that the SHA transformation was accompanied by detoxification and by a reduction in TOC of the reaction solution, the extent of which correlated with the extent of the oxidative coupling. Moreover, SPM-IMLac could be easily recovered and reused, while keeping its high removal efficiency of SHA in the actual MPW matrices. This study not only provides fascinating insights into the transformation mechanisms and environmental fate of SHA mediated by SPM-IMLac, but it also exploits a viable and sustainable approach for the remediation of organic flotation reagents-contaminated MPW.

Photocatalytic Generation of Germyl Radicals from Digermanes Enabling the Hydro/Deuteriogermylation of Alkenes.

We have developed a visible-light-induced method to photolyze digermanes through single-electron oxidation using a photocatalyst, in contrast to direct excitation, to generate germyl radicals and achieve the hydro/deuteriogermylation of alkenes. This protocol allows the previously elusive incorporation of the small trimethylgermyl group and deuterium, metabolically stable bioisosteres of tert-butyl and hydrogen, respectively, making this approach attractive in not only organic synthesis but also medicinal chemistry.

A chiral hydrogen atom abstraction catalyst for the enantioselective epimerization of meso-diols.

Hydrogen atom abstraction is an important elementary chemical process but is very difficult to carry out enantioselectively. We have developed catalysts, readily derived from the Cinchona alkaloid family of natural products, which can achieve this by virtue of their chiral amine structure. The catalyst, following single-electron oxidation, desymmetrizes meso-diols by selectively abstracting a hydrogen atom from one carbon center, which then regains a hydrogen atom by abstraction from a thiol. This results in an enantioselective epimerization process, forming the chiral diastereomer with high enantiomeric excess. Cyclic and acyclic 1,2-diols are compatible, as are acyclic 1,3-diols. Additionally, we demonstrate the viability of combining our approach with carbon-carbon bond formation in Giese addition. Given the increasing number of synthetic methods involving hydrogen atom transfer steps, we anticipate that this work will have a broad impact in the field of enantioselective radical chemistry.

Cooperative NHC and Photoredox Catalyzed Radical Aminoacylation of Alkenes to Tetrahydropyridazines.

Tetrahydropyridazines constitute an important structural motif found in numerous natural products and pharmaceutical compounds. Herein, we report an aminoacylation reaction of alkenes that enables the synthesis of 1,4,5,6-tetrahydropyridazines through cooperative N-heterocyclic carbene (NHC) and photoredox catalysis. This approach involves the 6-endo-trig cyclization of N-centered hydrazonyl radicals, generated via single-electron oxidation of hydrazones, followed by a radical-radical coupling step. The mild process tolerates a wide range of common functional groups and affords a variety of tetrahydropyridazines in moderate to high yields. Preliminary investigations using chiral NHC catalysts demonstrate the potential of this protocol for asymmetric radical reactions.