N-centered Radicals Research Articles

N-Carbazolyl π-Radical and Its Antiaromatic Nitrenium Ion: A Threshold Photoelectron Spectroscopic Study.

Understanding the structure and properties of heterocyclic radicals and their cations is crucial for elucidating reaction mechanisms as they serve as versatile synthetic intermediates. In this work, the N-carbazolyl radical 1 was generated via pyrolysis and characterized using photoion mass-selected threshold photoelectron spectroscopy coupled with tunable vacuum-ultraviolet synchrotron radiation. The N-centered radical 1 is classified as a π-radical (2B1), with the unpaired electron found to be delocalized over the central five-membered ring of the carbazole. Adiabatic ionization energies corresponding to the transition from radical 1 to its singlet 1+(1A1) and triplet 1+(3B2) cations were determined to be 7.70 ± 0.03 and 8.14 ± 0.03 eV, respectively. The antiaromatic nitrenium ion 1+ exhibits a singlet ground state with an experimental singlet-triplet energy gap (ΔES-T) of -0.44 eV (10.1 kcal/mol), in very good agreement with theory. N-centered radicals are found to have a higher ionization energy than their C-centered analogues due to stabilization of the singly occupied molecular orbital.

Photoinduced Asymmetric Alkene Aminohetarylation with Chiral Sulfoximine Reagents.

Given the pivotal role of β-(het)arylethylamine moiety in bioactive molecules, the direct amino(het)arylation of alkenes occupies a privileged position in the construction of (het)arylethylamine derivatives. Herein we devise chiral sulfoximines as novel bifunctional reagents which exhibit remarkable efficiency in the challenging asymmetric alkene aminohetarylation reaction, particularly in terms of reactivity and stereo-control. The chiral reagents can be conveniently accessed in gram scale, and efficiently generate N-centered radicals under mild photochemical conditions. The transformation proceeds through enantioselective 1,4-hetaryl migration, ensuring precise chirality transfer from sulfur- to carbon-centers, rendering wide applicability to both aromatic and aliphatic alkenes. Furthermore, the method is straightforward to operate and does not require transition metals or photosensitizers, making it an attractive and practical option.

1,3-Difunctionalization of [1.1.1]propellane through iron-hydride catalyzed hydropyridylation

Current methodologies for the functionalization of [1.1.1]propellane primarily focus on achieving 1, 3-difunctionalized bicyclo[1.1.1]pentane or ring-opened cyclobutane moiety. Herein, we report an innovative approach for the 1, 3-difunctionalization of [1.1.1]propellane, enabling access to a diverse range of highly functionalized cyclobutanes via nucleophilic attack followed by ring opening and iron-hydride hydrogen atom transfer. To enable this method, we developed an efficient iron-catalyzed hydropyridylation of various alkenes for C − H alkylation of pyridines at the C4 position, eliminating the need for stoichiometric quantities of oxidants or reductants. Mechanistic investigations reveal that the resulting N-centered radical serves as an effective oxidizing agent, facilitating single-electron transfer oxidation of the reduced iron catalyst. This process efficiently sustains the catalytic cycle, offering significant advantages for substrates with oxidatively sensitive functionalities that are generally incompatible with alternative approaches. The strategy presented herein is not only mechanistically compelling but also demonstrates broad versatility, highlighting its potential for late-stage functionalization.

EDA Complex-Promoted Cascade Cyclization of Alkynes Enabling the Rapid Assembly of 3-Sulfonylindoles and Vinyl Sulfone Oxindoles.

Herein, we disclose a photoinduced radical cascade cyclization of alkynes with sulfinates via a novel EDA complex for the synthesis of various 3-sulfonylindoles and vinyl sulfone oxindoles, which are crucial motifs in medicinal and biological chemistry. The reaction proceeds under mild, photocatalyst- and transition-metal-free conditions, featuring operational simplicity, broad substrate scope, and easy scalability. Mechanistic studies reveal that the reaction is initiated with a photoinduced intermolecular charge transfer from sulfinates to N-sulfonamides, generating a sulfonyl radical followed by an N-centered radical, thus enabling the cascade cyclization process.

Organic Synthesis Away from Equilibrium: Contrathermodynamic Transformations Enabled by Excited-State Electron Transfer.

ConspectusChemists have long been inspired by biological photosynthesis, wherein a series of excited-state electron transfer (ET) events facilitate the conversion of low energy starting materials such as H2O and CO2 into higher energy products in the form of carbohydrates and O2. While this model for utilizing light-driven charge transfer to drive catalytic reactions thermodynamically "uphill" has been extensively adapted for small molecule activation, molecular machines, photoswitches, and solar fuel chemistry, its application in organic synthesis has been less systematically developed. However, the potential benefits of these approaches are significant, both in enabling transformations that cannot be readily achieved using conventional thermal chemistry and in accessing distinct selectivity regimes that are uniquely enabled by excited-state mechanisms. In this Account, we present work from our group that highlights the ability of visible light photoredox catalysis to drive useful organic transformations away from their equilibrium positions, addressing a number of long-standing synthetic challenges.We first discuss how excited-state ET enabled the first general methods for the catalytic anti-Markovnikov hydroamination of unactivated alkenes with alkyl amines. In these reactions, an excited-state iridium(III) photocatalyst reversibly oxidizes secondary amine substrates to their corresponding aminium radical cations (ARCs). These electrophilic N-centered radicals can then react with olefins to furnish valuable tertiary amine products with complete anti-Markovnikov regioselectivity. Notably, some of these products are less thermodynamically stable than their corresponding amine and alkene starting materials. We next present a strategy for light-driven C-C bond cleavage within various aliphatic alcohols mediated by homolytic activation of alcohol O-H bonds by excited-state proton-coupled electron transfer (PCET). The resulting alkoxy radical intermediates then undergo C-C β-scission to ultimately provide isomeric linear carbonyl products that are often higher in energy than their cyclic alcohol precursors. Applications of this chemistry for the light-driven depolymerization of lignin biomass, commercial phenoxy resin, hydroxylated polyolefin derivatives, and thermoset polymers are presented as well. We then describe a method for the contrathermodynamic positional isomerization of highly substituted olefins by means of cooperative photoredox and chromium(II) catalysis. In this work, generation of an allylchromium(III) species that can undergo highly regioselective in situ protodemetalation enables access to a less substituted and thermodynamically less stable positional isomer. Product selectivity in this reaction is determined by the large differential in oxidation potentials between differently substituted olefin isomers. Lastly, we discuss a light-driven deracemization reaction developed in collaboration with the Miller group, wherein a racemic urea substrate undergoes spontaneous optical enrichment upon visible light irradiation in the presence of an iridium(III) chromophore, a chiral Brønsted base, and a chiral peptide thiol. Excellent levels of enantioselectivity are achieved via sequential and synergistic proton transfer (PT) and H atom transfer (HAT) steps. Taken together, these examples highlight the ability of excited-state ET events to enable access to nonequilibrium product distributions across a wide range of catalytic, redox-neutral transformations in which photons are the only stoichiometric reagents.

Sulfonamide-directed site-selective functionalization of unactivated C(sp3)−H enabled by photocatalytic sequential electron/proton transfer

The generation of alkyl radical from C(sp3)−H substrates via hydrogen atom abstraction represents a desirable yet underexplored strategy in alkylation reaction since involving common concerns remain adequately unaddressed, such as the harsh reaction conditions, limited substrate scope, and the employment of noble metal- or photo-catalysts and stoichiometric oxidants. Here, we utilize the synergistic strategy of photoredox and hydrogen atom transfer (HAT) catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers with broad reaction scope, high functional group compatibility, and operational simplicity. A combination of validation experiments and density functional theory reveals that the N-centered radicals, generated from free N − H bond in a stepwise electron/proton transfer event, are the key intermediates that enable an intramolecular 1,5-HAT or intermolecular HAT process for nucleophilic carbon-centered radicals formation to achieve heteroarylation, alkylation, amination, cyanation, azidation, trifluoromethylthiolation, halogenation and deuteration. The practical value of this protocol is further demonstrated by the gram-scale synthesis and the late-stage functionalization of natural products and drug derivatives.

β-Phenethylamine Synthesis: N-Pyridinium Aziridines as Latent Dual Electrophiles.

β-Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N-pyridinium aziridines as latent dual electrophiles for the synthesis of β-phenethylamines. Bromide-promoted ring opening generates β-halopyridinium amines. Selective Ni-catalyzed C-C cross-coupling between organozinc nucleophiles and the benzylic C-Br electrophile affords a diverse family of β-functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni-catalyzed reductive N-N bond activation within the β-functionalized phenethylaminopyridinium salts furnishes the products of formal olefin carboamination. Other reductive N-N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N-centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of β-phenethylamines and significantly expand the utility of N-pyridinium aziridines as linchpins in chemical synthesis.

Organo-Photocatalytic Anti-Markovnikov Hydroamidation of Alkenes with Sulfonyl Azides: A Combined Experimental and Computational Study.

The construction of C(sp3)-N bonds via direct N-centered radical addition with olefins under benign conditions is a desirable but challenging strategy. Herein, we describe an organo-photocatalytic approach to achieve anti-Markovnikov alkene hydroamidation with sulfonyl azides in a highly efficient manner under transition-metal-free and mild conditions. A broad range of substrates, including both activated and unactivated alkenes, are suitable for this protocol, providing a convenient and practical method to construct sulfonylamide derivatives. A synergistic experimental and computational mechanistic study suggests that the additive, Hantzsch ester (HE), might undergo a triplet-triplet energy transfer manner to achieve photosensitization by the organo-photocatalyst under visible light irradiation. Next, the resulted triplet excited state 3HE* could lead to a homolytic cleavage of C4-H bond, which triggers a straightforward H-atom transfer (HAT) style in converting sulfonyl azide to the corresponding key amidyl radical. Subsequently, the addition of the amidyl radical to alkene followed by HAT from p-toluenethiol could proceed to afford the desired anti-Markovnikov hydroamidation product. It is worth noting that mechanistic pathway bifurcation could be possible for this reaction. A feasible radical chain propagation mechanistic pathway is also proposed to rationalize the high efficiency of this reaction.

Nickel-Photoredox-Catalyzed Stereoconvergent Coupling of Alkenyl Halides and Nitrogen-Containing Heterocycles.

Nitrogen-containing heterocycles possessing N-alkenyl substituents are an important structural motif. However, the synthetic methods reported thus far cannot selectively synthesize the Z stereoisomer on the basis of the stereochemistry of the substituted alkenes. Herein, we report the stereoconvergent coupling of heterocycles and alkenyl halides consisting of a mixture of E/Z stereoisomers, which selectively afforded the thermodynamically less stable Z-coupling product. Mechanistic studies suggest that a nickel photoredox catalyst facilitates the formation of N-centered heteroarene radicals.

Treatment of emerging pyrrolizidine alkaloids in drinking water by UV/persulfate process: Kinetics, energy efficiency and degradation pathway

Pyrrolizidine alkaloids (PAs), recognized as a group of toxic secondary metabolites, have raised growing concerns in recent years due to their potential high toxicity. However, studies on the degradation of PAs in drinking water treatments have yet to be conducted. Herein, the treatment of Heliotrine (HEL) and N-oxide (HELNO), two dominant PAs detected in the treated drinking water, are analyzed for the first time. The UV/peroxydisulfate (UV/PDS) process was demonstrated to be efficient in the degradation of PAs, achieving almost complete removal of HEL and HELNO in 30 min. SO4•− plays a dominant role in the system, with second-order rate constants of 2.3 × 109 M−1 s−1 and 1.0 × 109 M−1 s−1 for HEL and HELNO, respectively. Based on the steady-state kinetic models, the effect of influence factors, including PDS dosage, initial pollutant concentration, pH, dissolved organic matter (DOM), and chloride (Cl−), were evaluated. Acidic conditions were proven to be favorable for PA degradations, primarily contributed to the minimized quenching effect of OH− and phosphate on SO4•−. The inhibitory effect of DOM on radical quenching significantly overweighted the promotion effect of the generated excited triplet DOM (3DOM*), resulting in a diminished degradation efficiency. The pronounced inhibition of Cl− could be attributed to the conversion of SO4•− to OH•, involving the formation of reactive chlorine species. The UV/PDS treatment was suggested economical in the removal of PAs as a post-filtration and before-chlorination treatment through electrical energy per order (EE/O) calculation. Finally, reasonable degradation pathways of HEL and HELNO reacted with SO4•− were proposed, involving the initial one-electron oxidation of HEL/HELNO by SO4•− radical, and further reactions (e.g., hydroxylation, pyrrolidine ring-cleavage and self-coupling) of the formed N-centered cation radicals.

Sulfonamides as N-Centered Radical Precursors for C-N Coupling Reactions To Generate Amidines.

Nitrogen-centered radicals (NCRs) are valuable intermediates for the construction of C-N bonds. Traditional methods for the generation of NCRs employ toxic radical initiators, transition metal catalysts, photocatalysts, or organometallic reagents. Herein, we report a novel strategy for the generation of NCRs toward the construction of C-N bonds under transition-metal-free conditions. Thus, super-electron-donor (SED) 2-azaallyl anions undergo single-electron transfer (SET) with sulfonamides, forming aminyl radicals (R2N•, R = alkyl) and culminating in the generation of amidines bearing various functional groups (33 examples, up to 96% yield). Broad substrate scope and gram-scale telescoped preparation demonstrate the practicality of this method. Radical clock and electron paramagnetic resonance (EPR) experiments support the proposed radical coupling pathway between the generated N-centered radical and the C-centered 2-azaallyl radical.

Remote Radical Azidation of Unactivated C(sp3)-H Bonds in Sulfamoyl Azides.

An efficient method for remote radical C(sp3)-H azidation at unactivated sites is described. C-H functionalization proceeds via intramolecular 1,5-hydrogen atom transfer to N-centered radicals that are generated via azido group transfer and/or fragmentation. The readily installed sulfamoyl azide serves as both an amidyl radical precursor and an azido source. This reaction features excellent site selectivity for tertiary, secondary, primary, and benzylic C(sp3)-H bonds and exhibits broad functional group compatibility.

Regioselective Rearrangement of Nitrogen- and Carbon-Centered Radical Intermediates in the Hofmann-Löffler-Freytag Reaction.

The Hofmann-Löffler-Freytag (HLF) reaction serves as a late-stage functionalization technique for generating pyrrolidine heterocyclic ring systems. Contemporary HLF protocols utilize in situ halogenated sulfonamides as precursors in the radical-mediated rearrangement cycle. Despite its well-established reaction mechanism, experiments toward the detection of radical intermediates using EPR techniques have only recently been attempted. However, the obtained spectra lack the distinct features of the N-centered radicals expected for the employed reactants. This paper presents phenylbutylnitrone spin-trapped C-centered and N-centered radicals, generated via light irradiation from N-halogen-tosyl-sulfonamide derivatives and detected using EPR spectroscopy. NMR spectroscopy and DFT calculations are used to explain the observed regioselectivity of the HLF reaction.

Harnessing the Potential of Electron Donor-Acceptor Complexes and N-Centered Radicals: Expanding the Frontiers of Isoquinoline Derivative Synthesis.

Research on synthesizing nitrogen-containing heterocyclic scaffolds is important because these structures are commonly found in Nature, such as in the alkaloids' family. In our study, we propose a new method to synthesize the isoquinoline core using an electron donor-acceptor (EDA) complex strategy. Our mechanistic investigations have confirmed that our synthesis process operates through an EDA mechanism, which is not extensively discussed in the literature, particularly regarding its applications on alkynyl substrates. This EDA strategy has proven to be a simple and straightforward way to produce isoquinoline scaffolds and their derivatives without the need for metal catalysts.

Site-Selective Electrochemical Arene C-H Amination.

Here we present the discovery and development of a highly selective aromatic C-H amination reaction. This electrochemical strategy involves a cathodic reduction process that generates highly electrophilic dicationic N-centered radicals that can efficiently engage in aromatic C-H functionalization and channel the regioselectivity of the aromatic substitution. The nitrogen-radical cation-pi interaction with arenes used throughout nature leads to a charge transfer mechanism, with subsequent aromatic C-N bond formation. This electrochemical process generates aryl DABCOnium salts in excellent yields and regioselectivities (single regioisomer in most cases). The scope of the reaction on arene is broad where various functionalities such as aryl halides (bromides, chlorides, fluorides), carbonyls (ketones, esters, imides), sulfonamides, and heteroarenes (pyridines, bipyridines, and terpyridines) are well tolerated. Moreover, we disclose the synthetic utility of the aryl DABCOnium salt adducts leading to the direct access of diverse aryl piperazines and the chemoselective cleavage of the exocyclic aryl C(sp2)-N bond over electrophilic C(sp3)-N+ bonds via photoredox catalysis to afford synthetically useful aryl radicals that can engage in aryl C-C and C-P bond formation.

Designing unimolecular photoinitiator by installing NHPI esters along the TX backbone for acrylate photopolymerization and their applications in coatings and 3D printing

Developing efficient and long wavelength sensitive unimolecular photoinitiators (PIs) is still facing a great challenge. In this work, a series of thioxanthone-based N-hydroxyphthalimide esters (TX-NHPIEs) were synthesized by installing NHPIEs along the TX backbone and characterized. The investigated TX-NHPIEs have a 60 nm redshift and demonstrate sterling initiating efficiency for free radical photopolymerization (FRP) under LED@450 nm light irradiation compared with the commercialized isopropylthioxanthone (ITX). Real-time 1Hnuclear magnetic resonance (1H NMR), electron spin resonance (ESR), decarboxylation and gas chromatograph-mass spectrometer (GC–MS) experiments and density functional theory (DFT) reveal that TX-NHPIEs can generate one alkyl radical and one N-centered iminyl radical, which can initiate FRP directly and indirectly, respectively. In other words, TX-NHPIEs absorb one photon and can generate two active radicals, which break through the limitations of common PIs. TX-NHPIE-Cpe demonstrates the highest initiating efficiency, and its application in coatings and 3D printing was also studied, indicating TX-NHPIEs have broad potential applications in photopolymerization processes.

A general alkene aminoarylation enabled by N-centred radical reactivity of sulfinamides.

Arylethylamines are popular structural elements in bioactive molecules but are often made through a linear series of synthetic steps. A modular protocol to assemble arylethylamines from alkenes in one step would represent a useful advance in discovery chemistry, though current limitations preclude a generally applicable method. In this work we disclose an aminoarylation of alkenes using aryl sulfinamide reagents as bifunctional amine and arene donors. This reaction features excellent regioselectivity and diastereoselectivity on a variety of activated and unactivated substrates. Using a weakly oxidizing photocatalyst, a nitrogen radical is generated under mild conditions and adds to an alkene to form a new C-N bond. A desulfinylative aryl migration event known as a Smiles-Truce rearrangement follows to form a new C-C bond. In this manner, arylethylamines can be rapidly assembled from abundant alkene feedstocks. Moreover, chiral information from the sulfinamide can be transferred via rearrangement to a new carbon stereocentre in the product, thus advancing the development of traceless asymmetric alkene difunctionalization.

Photocatalyst-free regioselective sulfonamidation of N-(2-hydroxyaryl)amides in visible-light.

In this work, we report a regioselective sulfonamidation of N-(2-hydroxyaryl)amides with iminoiodinanes and iodine in visible light at room temperature. The method does not require a strong oxidant, metal or photocatalyst and enables direct functionalization of a C-H bond to a C-N bond. Mechanistic investigations suggest in situ generation of an N-centered radical from N,N-diiodo-sulfonamide by homolytic N-I bond cleavage followed by its site-specific addition to N-(2-hydroxyaryl)amides to furnish para-sulfonamide derivatives.

Nickel-Catalyzed Reductive 1,2-Alkylarylation of Alkenes via a 1,5-Hydrogen Atom Transfer (HAT) Cascade

N-centered radicals mediated remote C(sp3)–H functionalization via HAT processes have been successfully applied in the difunctionalization of alkenes, serving as an elegant and robust method to convert readily available alkenes...

Photoredox catalyzed reductive trifluoromethylation of imines via a radical umpolung strategy.

Visible light-induced radical umpolung chemistry is utilized to synthesize trifluoromethylated unnatural α-amino acid and amine derivatives. This approach utilizes photoredox catalysis to perform a single-electron-transfer reduction of imines generating a N-centred radical that eventually migrates to the C-centre followed by a radical-radical cross-coupling to deliver reductive trifluoromethylation products.