Atom Transfer Research Articles

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.

Radical‐Driven Imine Hydrogenation Promoted by the Cooperativity of Nickel and a Redox‐Active Ligand

AbstractIn the case of N‐alkylation reaction via borrowing hydrogen (BH) methods, imine hydrogenation is one of the critical steps. Mechanistically, the majority of imine hydrogenation, either by dihydrogen gas or by alcohol in case of BH methods, follow two‐electron chemistry, where a metal‐hydride intermediate plays a pivotal role. Herein we demonstrate a completely complementary protocol, where the hydrogenation is governed by a radical pathway. Such a pathway is adopted from the redox active nature of the azophenolate ligand backbone. The facile and reversible 2e−/2H+, azo/hydrazo redox couple in a nickel catalyst helps in storing the hydrogen from alcohol dehydrogenation. An imine substrate is reduced by one‐electron from the azo motif with the assistance of the nickel center. The reduced imine drives a critical hydrogen atom transfer step from the hydrazo motif to conduct the hydrogenation. A set of kinetics experiments including Eyring analysis, radical inhibition experiment along with computational probation attest for the radical‐promoted hydrogenation mechanism.

C(sp3)−F Bond Activation by Lewis Base‐Boryl Radicals via Concerted Electron‐Fluoride Transfer

AbstractSelective C−F bond activation through a radical pathway in the presence of multiple C−H bonds remains a formidable challenge, owing to the extraordinarily strong bond strength of the C−F bond. By the aid of density functional theory calculations, we disclose an innovative concerted electron‐fluoride transfer mechanism, harnessing the unique reactivity of Lewis base‐boryl radicals to selectively activate the resilient C−F bonds in fluoroalkanes. This enables the direct abstraction of a fluorine atom and subsequent generation of an alkyl radical, thus expanding the boundaries of halogen atom transfer reactions.

Chemoselective Dehydrogenation and Hetero-Arylation of Amides via Radical Translocation Enabled by Photoexcited Triplet Ketone Catalysis.

We herein report the chemoselective dehydrogenation and heteroarylation of amides through photoexcited triplet ketone catalysis. Under mild reaction conditions, the generated aryl radical through the halogen atom transfer (XAT) process further undergoes an intramolecular 1,5-HAT event to generate an α-amido alkyl radical, which then intercepted with either cobalt or a reduced cyano arene radical leads to dehydrogenated and heteroarylated products, respectively, in good yields.

The Photodynamic Agent Designed by Involvement of Hydrogen Atom Transfer for Enhancing Photodynamic Therapy.

Although Type-I photodynamic therapy has attracted increasingly growing interest due to its reduced dependence on oxygen, the design of effective Type-I photosensitizers remains a challenge. In this work, we report a design strategy for Type-I photosensitizers by the involvement of hydrogen atom transfer (HAT). As a proof of concept, a HAT-involved Type-I PS, which simultaneously generates superoxide and carbon-centered radicals under light-irradiation, was synthesized. This photosensitizer is comprised of a fluorene-substituted BODIPY unit as an electron acceptor covalently linked with a triphenylamine moiety as an electron donor. Under light-irradiation, photo-induced intramolecular electron transfer occurs to generate the BODIPY anion radical and triphenylamine cation radical. The former transfers electrons to oxygen to generate O2 -⋅, while the latter loses a proton to produce a benzyl carbon-centered radical which is well characterized. The resulting carbon-centered radicals efficiently oxidize NADH by HAT reaction. This photosensitizer demonstrates remarkable photocytotoxicity even under hypoxic conditions, along with outstanding in vivo antitumor efficacy in mouse models bearing HeLa tumors. This work offers a novel strategy for the design of Type-I photosensitizers by involvement of HAT.

The Photodynamic Agent Designed by Involvement of Hydrogen Atom Transfer for Enhancing Photodynamic Therapy

AbstractAlthough Type‐I photodynamic therapy has attracted increasingly growing interest due to its reduced dependence on oxygen, the design of effective Type‐I photosensitizers remains a challenge. In this work, we report a design strategy for Type‐I photosensitizers by the involvement of hydrogen atom transfer (HAT). As a proof of concept, a HAT‐involved Type‐I PS, which simultaneously generates superoxide and carbon‐centered radicals under light‐irradiation, was synthesized. This photosensitizer is comprised of a fluorene‐substituted BODIPY unit as an electron acceptor covalently linked with a triphenylamine moiety as an electron donor. Under light‐irradiation, photo‐induced intramolecular electron transfer occurs to generate the BODIPY anion radical and triphenylamine cation radical. The former transfers electrons to oxygen to generate O2−⋅, while the latter loses a proton to produce a benzyl carbon‐centered radical which is well characterized. The resulting carbon‐centered radicals efficiently oxidize NADH by HAT reaction. This photosensitizer demonstrates remarkable photocytotoxicity even under hypoxic conditions, along with outstanding in vivo antitumor efficacy in mouse models bearing HeLa tumors. This work offers a novel strategy for the design of Type‐I photosensitizers by involvement of HAT.

Reassessing the Photochemical Upcycling of Polystyrene Using Acridinium Salts.

Approaches aimed at deconstructing PS by photocatalytic means struggle to generate high-energy species capable of cleaving the C-H and C-C bonds of PS. We show herein that 9-mesityl-10-methylacridinium perchlorate (MA) is capable of upcycling various grades of PS susbstrates into benzoic acid (BAc) up to 40%, with small proportions of acetophenone and formic acid, under visible light (456 nm) or through solar radiation. Time-resolved emission and absorption spectroscopy evidence that a reaction with oxygen is the primary photochemical step in oxygen-saturated solutions, accounting for 77% of the photons absorbed vs. 1% for the direct reaction with PS. These results suggest a mechanism in which MA-mediated photocycling of PS to BAc occurs through the abstraction of benzylic H atoms by reactive oxygen species generated by energy or electron transfer from the excited state of MA. Addition of triplet O2 to these radicals, followed by intra- or inter-molecular hydrogen atom transfer (HAT), generates C- or O-centered radicals then undergoing β-scission or hydroperoxide fragmentation. The formation of intermediate oligomers functionalized by terminal carbonyl groups is demonstrated by both infrared analysis and mass spectrometry. These oligomers undergo further photoinduced conversion in the absence of MA, as evidenced by size exclusion chromatography analysis.

Reassessing the Photochemical Upcycling of Polystyrene Using Acridinium Salts

Approaches aimed at deconstructing PS by photocatalytic means struggle to generate high‐energy species capable of cleaving the C‐H and C‐C bonds of PS. We show herein that 9‐mesityl‐10‐methylacridinium perchlorate (MA) is capable of upcycling various grades of PS susbstrates into benzoic acid (BAc) up to 40%, with small proportions of acetophenone and formic acid, under visible light (456 nm) or through solar radiation. Time‐resolved emission and absorption spectroscopy evidence that a reaction with oxygen is the primary photochemical step in oxygen‐saturated solutions, accounting for 77% of the photons absorbed vs. 1% for the direct reaction with PS. These results suggest a mechanism in which MA‐mediated photocycling of PS to BAc occurs through the abstraction of benzylic H atoms by reactive oxygen species generated by energy or electron transfer from the excited state of MA. Addition of triplet O2 to these radicals, followed by intra‐ or inter‐molecular hydrogen atom transfer (HAT), generates C‐ or O‐centered radicals then undergoing β‐scission or hydroperoxide fragmentation. The formation of intermediate oligomers functionalized by terminal carbonyl groups is demonstrated by both infrared analysis and mass spectrometry. These oligomers undergo further photoinduced conversion in the absence of MA, as evidenced by size exclusion chromatography analysis.

Photocatalytic Silylation of Aryl Alkynoates: Synthesis of Silylated Coumarins

AbstractHerein, we report the photocatalytic synthesis of 3‐silyl coumarins using hydrosilanes as the silyl radical source with aryl alkynoates. Readily prepared N‐aminopyridinium salts act as hydrogen atom transfer reagents for generating silyl radicals under photoredox catalysis. The reaction proceeds through a silyl radical addition to alkyne followed by radical cascade cyclization/migration with subsequent oxidation and aromatization to give the desired 3‐silyl coumarins in 34–89% yield.

Fe‐Catalyzed α‐C(sp3)−H Amination of N‐Heterocycles

AbstractNitrogen‐heterocycles are privileged structures in both marketed drugs and natural products. On the other hand, C−H amination reactions furnish unconventional and straightforward approaches for the construction of C−N bonds. Yet, most of the known methods rely on precious metal catalysts. Herein we report a site‐selective intermolecular C(sp3)−H amination of N‐heterocycles, catalyzed by inexpensive FeCl2, which allows the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C−H amination occurs site‐selectively in α‐position to the nitrogen atom, even when weaker C−H bonds are present, and furnishes Troc‐protected aminals or amidines. The method employs the N‐heterocycle as limiting reagent and is applicable to the late‐stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α‐aminated products and the application to a concise total synthesis of the reported structure for senobtusin. Mechanistic studies allowed to propose a plausible reaction mechanism involving a turnover‐limiting Fe‐nitrene generation followed by fast H atom transfer and radical rebound.

Cobalt-Hydride-Catalyzed Alkene-Carboxylate Transposition (ACT) of Allyl Carboxylates.

The alkene-carboxylate transposition (ACT) of allyl carboxylates is one of the most atom-economic and synthetically reliable transformations in organic chemistry, as allyl carboxylates are versatile synthetic intermediates. Classic ACT transformations, including [3,3]-sigmatropic rearrangement and transition metal-catalyzed allylic rearrangement, typically yield 1,2-alkene/1,3-acyloxy shifted products through a two-electron process. However, position-altered ACT to produce distinct 1,3-alkene/1,2-acyloxy shifted products remains elusive. Here, we report the first cobalt-hydride-catalyzed ACT of allyl carboxylates, enabling access to these unprecedented 1,3-alkene/1,2-acyloxy shifted products via a 1,2-radical migration (RaM) strategy. This transformation demonstrates broad functional group tolerance, is suitable for late-stage modification of complex molecules, and is amenable to gram-scale synthesis. It also expands the reaction profiles of both allyl carboxylates and cobalt catalysis. Preliminary experimental and computational studies suggest a mechanism involving metal-hydride hydrogen atom transfer (MHAT) and the 1,2-RaM process. This reaction is expected to serve as the basis for the development of versatile Co-H-catalyzed transformations of allyl carboxylates, generating a wide array of valuable building blocks for synthetic, medicinal, and materials chemistry.

Cu-Catalyzed Asymmetric Three-Component Radical Acylarylation of Vinylarenes with Aldehydes and Aryl Boronic Acids.

The direct use of readily available aldehydes as acyl radical precursors has facilitated diverse three-component acylative difunctionalization reactions of alkenes, offering a powerful route to synthesize β-branched ketones. However, asymmetric three-component acylative difunctionalization of alkenes with aldehydes still remains elusive. Here we report a copper-catalyzed asymmetric three-component radical acylarylation of vinylarenes with aldehydes and aryl boronic acids. This method begins with acyl radical formation from an aldehyde via hydrogen atom transfer. The acyl radical adds to the alkene, forming a new benzylic radical that then undergoes copper-catalyzed enantioselective arylation. A chiral binaphthyl-tethered bisoxazoline ligand is essential for achieving high stereocontrol. This strategy enables the direct synthesis of a range of synthetically valuable chiral β,β-diaryl ketones from aldehydes and vinylarenes.

B2(OH)4 and Et3N-BH3: A New Combination of Reagents for the Mild and Efficient Photoreduction of Nitro(hetero)arenes

AbstractAnilines are a common motif in many bioactive compounds and their production through the reduction of nitroarenes has become an essential method for their synthesis. We demonstrate that the combination of an amine-borane complex and hypoboric acid (tetrahydroxydiborane) under visible light irradiation can accomplish the reduction of nitroarenes to the corresponding anilines. Preliminary mechanistic studies suggest the generation of boryl radicals via a hydrogen atom transfer (HAT) step from the photoexcited nitroarene. Involvement of a parallel thermal pathway is demonstrated with the high reaction efficiency being partially attributed to both routes.

Dual Ce@g-C3N4-Photoredox/Chlorine Catalysis: Cross-Dehydrogenative Coupling of N-Heteroarenes and Alkanes/Ethers with H2 Evolution.

With Ce@g-C3N4 as a heterogeneous semiconductor photocatalyst, nBu4NCl as both a redox catalyst and a hydrogen atom transfer catalyst, the first example of semiheterogeneous photocatalytic cross-dehydrogenative coupling of N-heteroarenes and alkanes/ethers with H2 evolution was developed. Both a diverse array of high-value alkylated N-heteroarenes and clean H2 can be efficiently coproduced under sacrificial reagent- and chemical oxidant/reductant-free conditions. Combining both the reversible Ce4+/Ce3+ redox pair and the reversible Cl̅/Cl ̇ redox pair can considerably improve the photocatalytic efficiency.

Photoredox-Catalyzed Synthesis of 3,3-Difluoro-γ-lactams via 1,5-Hydrogen Atom Transfer-Involved Alkyne Difunctionalization and C-N Cleavage.

This manuscript describes the application of a 1,5-hydrogen atom transfer strategy in photoredox-catalyzed hydrodifluoroalkylation of alkynes. The approach utilizes a sequential cascade process of difluoroalkylation, 1,5-hydrogen atom transfer, C(sp3)-N cleavage, and intramolecular condensation cyclization to accomplish efficient [3 + 2] cycloaddition of readily available propargylamines with halodifluoroacetates (or halodifluoroacetamides). The reaction allows for the selective construction of polysubstituted 3,3-difluoro-γ-lactams with good functional group tolerance, and further transformations of the resulting 3,3-difluoro-γ-lactams into different building blocks are also accomplished.

Iron-Mediated Segment Coupling of Alkenols with Acceptors via C-C Radical Translocation and Remote Oxidative 1,5/6-Hydrogen Atom Transfer.

Iron-mediated segment coupling followed by oxidative 1,5/6-hydrogen atom transfer (HAT) for synthesis of ε-oxo alkene derivatives is developed. This transformation involved translocation of the radical from H-to-C-to-C-to-C followed by the oxidation under MHAT conditions providing rapid access to 1,6/1,7-keto functionalized esters/ketone/sulfones/phosphonates/arenes. The different outcomes of coupling with acceptors could be explained by bond dissociation energies (BDEs), and mechanistic insights were gained through control experiments, including deuterium labeling studies.

Catalytic Aldehyde-Alkyne Couplings Triggered by Ketyl Radicals.

A general and flexible platform for catalytic aldehyde-alkyne couplings triggered by ketyl radicals is described. This open-shell strategy necessitates only a catalytic quantity of a photoredox catalyst, along with Hünig's base (DIPEA) as a halogen atom transfer reagent. The reaction proceeds through sequential steps involving activation, halogen atom transfer, and radical addition. This carbonyl-alkyne coupling exhibits a wide substrate scope and functional group compatibility and has been successfully applied to the late-stage modification of complex architectures.

Modelling the Repair of Carbon-Centered Protein Radicals by Phenolic Antioxidants

Oxidative stress is a biological process that has been linked to many diseases, hence understanding how to prevent and repair it is essential to medicine. The thermodynamics and kinetics of the repair reactions of radically damaged leucine (a lateral chain in a simplified protein environment) by twenty phenolic antioxidants are studied at the M06-2X(SMD)/6-31++G(d,p) level of theory in water and pentyl ethanoate. The two repair mechanisms modelled are formal-hydrogen atom transfer (f-HAT) and single electron transfer (SET). Although all f-HAT reactions are thermodynamically favourable, only one of the phenols produced rate constants in the diffusion limit, exhibiting biological relevance. SET is not suspected to be an important repair pathway for the phenols studied. We show that the Bell–Evans–Polanyi principle, which relates thermodynamics and kinetics properties for a reaction, breaks down when comparing between the solvents, protein repair sites, and the phenolic antioxidants. While thermodynamic data can be used as valuable screening tools, the kinetic calculation of rate constants in solution is crucial for enhancing the biological relevance of theoretical studies.

C−H Alkylation of N‐Benzyl Anilines via Visible‐Light‐Driven 1,5‐Hydrogen Atom Transfer (1,5‐HAT) of Hydroxamic Acid Derivatives

AbstractHere we reported the photo‐catalyzed C−H alkylation of pyridyl‐substituted N‐benzyl anilines through nitrogen‐centred radical 1,5‐hydrogen atom transfer. A broad range of methylpyridyl‐substituted aniline and hydroxylamine acid derivatives were successfully transformed into the corresponding products in moderate yields without adding any base and metal. This protocol features mild reaction conditions, a broad range of substrates, remarkable functional group tolerance and simple operation procedure.

Ultrasound-Assisted Remote Benzylic C(sp3)-H Alkylation of N-Fluoroamides with Enol Silanes.

We have developed an ultrasound-assisted remote benzylic C(sp3)-H alkylation of N-fluorobenzamides with enol silanes; a series of β-aryl substituted propiophenones was generated in good to high yields. This reaction represents a formal C(sp3)-C(sp3) coupling and features simplicity, high efficiency, and wide substrate scope in a multiple-step sequential process, which involves N-F homolysis, 1,5-hydrogen atom transfer, benzylic radical addition, oxidation by copper(II) salt, and removal of the trimethylsilyl group. Also, DFT theoretical calculations and Marcus theory were employed to consolidate the proposed reaction mechanism.