Radical Addition Reactions Research Articles

N‐Oxyl Radicals in Oxidative C−O Coupling: Free‐Radical Hydrogen Substitution and Addition to C=C Bonds

AbstractN‐oxyl radicals occupy an important place in free‐radical oxidative CH‐functionalization being one of the most efficient redox‐organocatalysts for hydrogen atom abstraction (HAT). Their applications include aerobic radical chain autoxidation, CH‐functionalization with the formation of carbon‐carbon and carbon‐heteroatom bonds. The persistent nature of N‐oxyl radicals combined with their high reactivity in HAT results in their unique dual chemistry: the same radical can both propagate radical chain reaction (at low N‐oxyl concentrations) and effectively “terminate” carbon‐centered radicals (at higher N‐oxyl concentrations). The latter case opens a new synthetic application area of N‐oxyl radicals, in which they act as both hydrogen abstracting species and O‐reagents for cross‐coupling with carbon‐centered radicals thus produced. Apart from the C−H bond cleavage, reactive N‐oxyl radicals have been extensively used recently in C=C double bond functionalization via radical addition reactions. In this review, both free‐radical CH‐functionalization reactions with the introduction of N‐oxyl fragments and alkene difunctionalizations by N‐oxyls are covered with emphasis on the relationship between reaction conditions and selectivity.

Copper‐Catalyzed Carboamination of Unactivated Alkenes to Synthesize β‐Lactams with Trichloroacetonitrile

ABSTRACTβ‐Lactams, as nitrogen‐containing heterocycles with distinctive biological activities, have made significant contributions to the treatment of infectious diseases. This study which used inexpensive copper salts as catalysts, trichloroacetonitrile as a radical precursor, and potassium carbonate as base offers a concise route for the synthesis of β‐lactam compounds substituted with potentially pharmacologically active dichloroacetyl moieties. Preliminary mechanistic studies indicate that unactivated alkenes undergo sequential intermolecular radical addition and intramolecular amidation reactions. The copper salts undergo catalytic cycles involving Cu(I)/Cu(II)/Cu(III) species.

Stereodivergent atom transfer radical addition of α-functionalized alkyl iodides to alkynes: a strategy for selective synthesis of both E- and Z-iodoalkenes.

The geometrical control of atom transfer radical addition (ATRA) reactions to alkynes poses significant challenges. Herein, we present a uniform solution by developing a stereodivergent synthetic method for both isomers of the resulting alkene products, starting from the same materials. The synthesis of the thermodynamically more stable isomer utilizes the strategy of uphill catalysis while the accumulation of the less stable isomer is facilitated by a manganese-catalyzed iodo-abstraction/radical rebound process, taking advantage of its reversibility. Various substituted alkyl iodides can be used to provide easy access to both isomers of iodoalkene products with valuable functional groups such as CF3, CF2H, CN, ester, or amide at the allylic position.

Recent Advances in Visible‐Light‐Mediated Synthesis of Phosphorylated Heterocycles

Organophosphorus compounds, especially phosphorylated heterocycles, are gaining increasing attention in the fields of materials science, pharmaceuticals, and agrochemistry due to their excellent biological activities. Consequently, the exploration of green and efficient methods for the synthesis of phosphorylated heterocycles has garnered significant interest from organic chemists. In recent years, visible light‐induced photoredox‐catalyzed organic synthesis has made substantial progress in the field of phosphorylation reaction since its eco‐friendly and mild conditions. This review summarizes the advance of the past five years in the visible‐light‐mediated synthesis of phosphorylated heterocycles using phosphine oxides as precursors through P‐centered radical addition, cross‐couping, and cyclization reactions.

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis.

Isocyanide is a promising synthetic reagent not only as a one-carbon homologation reagent but also as a nitrogen source for nitrogen-containing molecules. Because of their isoelectronic structure with carbon monoxide, isocyanides also react with nucleophiles, electrophiles, carbon radicals, and transition metal reagents, and are widely used in organic synthesis. On the other hand, the use of isocyanides in reactions with heteroatom radicals is limited. However, the reaction of isocyanides with heteroatom radicals is a promising synthetic tool for the construction of nitrogen-containing organic molecules modified with a variety of heteroatoms. In this Perspective, we review the addition and cyclization reactions of heteroatom radicals with isocyanides and discuss the synthetic prospects of the reaction of isocyanides with heteroatom radicals.

Access to β‐Lactam Sulfonamides from Sulfamoyl Chlorides via Photoredox Catalyzed C−S Bond Formation

AbstractSulfonyl chlorides are a synthetically attractive source of sulfonyl radicals in photoredox catalysis and are useful precursors in the synthesis of sulfones. Sulfamoyl chlorides, on the other hand, remain poorly represented despite their similar potential. In this study, N‐chlorosulfonylated β‐lactams were prepared from readily available precursors and utilized in an atom transfer radical addition (ATRA) reaction with a variety of olefins, producing β‐lactam sulfonamides in 49–95% yields. β‐Lactams fused to a dihydro‐1,2‐thiazine ring which closely resemble carbacephems, a widely used class of antibiotics, were also synthesized by an intra‐molecular ATRA reaction. This methodology enables the preparation of β‐lactam sulfonamides, a class of compounds that are of great interest in pharmacology.

A Modular Dual-Catalytic Aryl-Chlorination of Alkenes.

Alkyl chlorides are a class of versatile building blocks widely used to generate C(sp3)-rich scaffolds through transformation such as nucleophilic substitution, radical addition reactions and metal-catalyzed cross-coupling processes. Despite their utility in the synthesis of high-value functional molecules, distinct methods for the preparation of alkyl chlorides are underrepresented. Here, we report a visible-light-mediated dual catalysis strategy for the modular synthesis of highly functionalized and structurally diverse arylated chloroalkanes via the coupling of diaryliodonium salts, alkenes and potassium chloride. A distinctive aspect of this transformation is a ligand-design-driven approach for the development of a copper(II)-based atom-transfer catalyst that enables the aryl-chlorination of electron-poor alkenes, complementing its iron(III)-based counterpart that accommodates non-activated aliphatic alkenes and styrene derivatives. The complementarity of the two dual catalytic systems allows the efficient aryl-chlorination of alkenes bearing different stereo-electronic properties and a broad range of functional groups, maximizing the structural diversity of the 1-aryl, 2-chloroalkane products.

A Modular Dual‐Catalytic Aryl‐Chlorination of Alkenes

AbstractAlkyl chlorides are a class of versatile building blocks widely used to generate C(sp3)‐rich scaffolds through transformation such as nucleophilic substitution, radical addition reactions and metal‐catalyzed cross‐coupling processes. Despite their utility in the synthesis of high‐value functional molecules, distinct methods for the preparation of alkyl chlorides are underrepresented. Here, we report a visible‐light‐mediated dual catalysis strategy for the modular synthesis of highly functionalized and structurally diverse arylated chloroalkanes via the coupling of diaryliodonium salts, alkenes and potassium chloride. A distinctive aspect of this transformation is a ligand‐design‐driven approach for the development of a copper(II)‐based atom‐transfer catalyst that enables the aryl‐chlorination of electron‐poor alkenes, complementing its iron(III)‐based counterpart that accommodates non‐activated aliphatic alkenes and styrene derivatives. The complementarity of the two dual catalytic systems allows the efficient aryl‐chlorination of alkenes bearing different stereo‐electronic properties and a broad range of functional groups, maximizing the structural diversity of the 1‐aryl, 2‐chloroalkane products.

Synthesis of 2,3-Dihydrobenzofurans via a Photochemical Gold-Mediated Atom Transfer Radical Addition Reaction.

A light-mediated cyclization reaction initiated by an atom transfer radical addition (ATRA) of haloalkanes onto alkenes was exploited for the synthesis of functionalized dihydrobenzofurans. Initial investigation indicated that the dimeric gold catalyst [Au2(μ-dppm)2Cl2] can effectively be used for intermolecular ATRA reactions. Further, the reactivity was applied in a cascade-like cyclization for the preparation of dihydrobenzofuran derivatives. With the presented photochemical approach, the functionalization can be achieved directly from ortho-allylphenols in yields of up to 96% under mild conditions.

Environmental fate of phenobarbital in water: Homogeneous and non-homogeneous environment

In aqueous environments, phenobarbital (PB) undergoes degradation mediated by hydroxyl radicals (HO·) and sulfate radicals (SO4·−). In this study, a theoretical approach was used to investigate the oxidation of phenobarbital triggered by HO·/SO4·− in different dissociated forms of PB at different pH values, as well as the adsorption mechanism of phenobarbital on the silica surface and the non-homogeneous reaction with HO·. Our study confirms three primary reaction models for PB degradation: radical addition, hydrogen abstraction, and single electron transfer reactions. Thermodynamic and kinetic calculations show that the reaction of PB with HO· is the main degradation pathway compared to the reaction of SO4−. At the C5 and C6 positions, HO·-addition and H-abstraction from H6 and H7 are competitive mechanisms. However, in non-homogeneous environments, HO·-addition at C5 becomes the dominant pathway. Our work identifies the primary products of these degradation reactions. At a temperature of 298 K, the total rate constants for the degradation reactions of HO· with PB neutral molecules and anions were determined to be 2.06 M−1 s−1 and 4.11 × 107 M−1 s−1, respectively. In a non-homogeneous reaction with HO·, the total rate constant is 4.47 × 1010 M−1 s−1. Despite degradation, the majority of these products retain their potential to impact aquatic organisms. In particular, compounds such as 5-ethyl-5-hydroxypyrimidine-2,4,6(1H,3H,5H)-trione, 5-(1-hydroxyethyl)-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione, and 5-acetyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione have a greater toxic effect on green algae. The findings underscore the need for future research to consider the environmental implications and ecotoxicity of PB. Such consideration is crucial for a comprehensive understanding of the long-term environmental impact of pharmaceutical residues in aquatic ecosystems.

Spatially confined radical addition reaction in the sub-nanometer scaled interlayers of electrochemically expanded graphene sheets

Here we report a spatially confined radical addition reaction which occurs in the sub-nanometer scaled interlayers of the expanded graphene sheets during the electrochemical exfoliation processes of graphite. Due to its chemical stability, challenge remains to functionalize graphene simultaneously during the preparation processes. To this, we use tetrachloroaluminate (AlCl4−) as the co-intercalation anions together with sulfate (SO42−) for the electrochemical exfoliation of graphite. We revealed the extremely irreversible intercalation of AlCl4− ions in graphite layers and the generation of C–Cl bonds during electrolysis. Chlorine and oxygen were homogeneously distributed on the basal plane of the obtained graphene, and the controlled functionalization was achieved by tuning the concentration of AlCl4− anions in the electrolyte solution, indicating the spatially confined chlorine addition reaction occurring between the sub-nanometer interlayers of expanded graphite. Furthermore, the chlorine and oxygen hybrid-substituted graphene exhibited excellent electrocatalytic performance for oxygen reduction reaction. This work demonstrates an innovative radical addition reaction in the confined space at nanometer or subnanometer scale and, meanwhile, provides a direct functionalization of graphene during the electrochemical exfoliation of graphite.

Investigation on the steam gasification mechanism of different chars using isotopic tracing method

Gasification can provide syn-gas for consequent chemical production from carbon resources. The control of CO2 emission produced from gasification calls for the lower temperature and the more biomass char for the feed compared with traditional gasification, and the mechanism for steam gasification of different chars is more important. The gasification behaviors of four biomass chars and four coal chars are studied. The mechanism is probed using H216O/H218O period step tracing method coupled with various solid-state analyses on char structures. The increment of intermediates with increasing conversion demonstrate other slow step exists during gasification, and the solid state spectra of chars after and before gasification demonstrates that the condensation of poly-aromatic clusters in chars occurs accompanied with gasification. The addition reactions of radicals generated from gasifying agents and unsaturated carbon bonds C = C in chars is the slower step during gasification and enhancing the addition of radicals to unsaturated C = C bonds may be helpful for the higher gasification rate.

Photoinduced Tandem C−O Bond Reduction/Ketyl Radical Addition Reactions of α‐Keto‐N,O‐Acetals Enabled by Proton‐Coupled Electron Transfer

AbstractThe C10a‐acetoxylated tetrahydroazepino[1,2‐a]indole‐6,11‐diones are a class of tricyclic oxindoles that feature an α‐keto‐N,O‐acetal substructure, rendering them highly susceptible to SET reduction followed by fragmentation. In protic medium, they undergo a PCET‐assisted two‐step reduction including an interposed C−O bond cleavage that can be initiated photocatalytically as well as by cathodic reduction, and which generates nucleophilic ketyl radicals. In the presence of acrylonitrile and DIPEA as additional reactants, the photoinduced reaction unfolds as a tandem C−O bond reduction/ketyl radical conjugate addition, to furnish C10a‐reduced, C11‐cyanoethyl‐substituted tricyclic azepino‐[1,2‐a]indole derivatives with high stereoselectivity.

Characteristic reactivity of 3-acetamido-5-acetylfuran under oxidation conditions

Abstract Chitin is an abundant nitrogen-containing biomass and a major derivative is 3-acetamido-5-acetylfuran (3A5AF). The oxidation of 3A5AF could produce 3-acetamido-5-carboxyfuran (3A5CF), which is a promising monomer for producing nitrogen-containing polymers. However, the conversion of 3A5AF into 3A5CF is actually difficult. The present study clarifies the characteristic reactivity of 3A5AF under typical oxidation reaction conditions. Specifically, corresponding benzene derivatives or acetylfuran are transformed into carboxylic acids, but 3A5AF cannot. Then, density functional theory calculations indicate that 3A5AF facilitates the radical addition reaction on the furan ring instead of the oxidation of the C-acetyl group. In addition to the low aromaticity of furan, the acetamido group stabilizes the radical adduct by orbital interactions. Finally, we provide a potential methodology to decrease the reactivity of the furan ring in 3A5AF.

Easy functionalization of carbon nano-onions with disulfides and their use as recyclable heterogeneous organocatalysts

A facile functionalization of carbon nano-onions (CNO), through an atom economical one-step process, with a series of different generation (2.0, 2.5, and 3.0G) poly(amidoamine) (PAMAM) dendrimers with a cystamine core and endowed with either methyl ester or amino groups in the periphery has been reported. The radical addition reaction onto CNO surface, after the homolytic rupture of the S–S bond of cystamine, afforded CNO-PAMAM hybrids, which were extensively characterized using various analytical and spectroscopic techniques such as thermogravimetric analysis (TGA), attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, solid state 13C NMR, Raman, X-ray photoelectron spectroscopy (XPS), dynamic light scattering (DLS) and zeta potential (ZP). Morphological and textural properties were also investigated by high-resolution transmission electron microscopy (HRTEM) analysis and N2 adsorption/desorption isotherms. Furthermore, the presence and availability of –NH2 groups has been demonstrated by applying the functionalized CNO with PAMAM 2.0G and 3.0G as heterogeneous and recyclable organocatalysts in the one-pot three-component synthesis of 2-amino-4H-chromene derivatives.

Theoretical studies on the kinetics and mechanism of hydroxyl radical reaction with quinclorac and quinmerac herbicides in aqueous media

AbstractThe kinetic and mechanistic studies for the reaction of hydroxyl radical with two quinoline based herbicides, namely, quinclorac and quinmerac has been performed using various computational methods in aqueous media. Geometry optimizations were performed using Density Functional Theory (DFT) methods including water as the solvent. Local reactivity parameters of these herbicides towards the •OH radical are predicted using condensed Fukui function. Single point energies of various species were calculated using double hybrid method, namely, B2PLYP–D for better accuracy. The pKa values for these acid based herbicides allow them to exist in deprotonated form in aqueous condition. Hence, the calculations are also performed for the deprotonated or the anionic form apart from the neutral species. Individual rate coefficients for •OH radical addition reaction with each carbon atoms were evaluated using conventional transition state theory using one–dimensional tunneling corrections. The solvent effect on reaction is implemented through Collins–Kimball formulations. Both the approaches, namely, the Fukui index and individual rate constant determination confirms that the most reactive site for the •OH radical addition in these two herbicide is the carbon atom attached to the COOH group. The total rate constant for the •OH radical reaction with both neutral and anionic forms of these two herbicides are relatively high and equal to its diffusion‐limit value. Evaluation of the ecotoxicities of the parent herbicides and their OH adducts is estimated using the structure–activity relationship concept.

Visible-light-catalyzed synthesis of amino alcohols from N,N-dimethylaniline and aryl aldehyde

Abstract Herein, we describe a direct radical addition reaction of aryl aldehyde and N, N-dimethylaniline using iridium complex as photocatalyst to form amino alcohols under mild conditions, offering a convenient and sustainable methodology. The reaction could be easily scaled up through continuous flow reaction with high yield. A series of amino alcohol compounds were synthesized with iridium complex as photocatalyst. The reaction could be scaled up with continuous flow reaction. The reaction mechanism has been investigated with the aid of density functional theory (DFT) calculations.

Spatially Confined Radical Addition Reaction for Electrochemical Synthesis of Carboxylated Graphene and its Applications in Water Desalination and Splitting.

Due to the chemical stability of graphene, synthesis of carboxylated graphene still remains challenging during the electrochemical exfoliation of graphite. In this work, a spatially confined radical addition reaction which occurs in the sub-nanometer scaled interlayers of the expanded graphene sheets for the electrochemical synthesis of highly stable carboxylated graphene is reported. Here, formate anions act as both intercalation ions and co-reactant acid for the confinement of electro-generated carboxylic radical (●COOH) in the sub-nanometer scaled interlayers, which facilitates the radical addition reaction on graphene sheets. The controllable carboxylation of graphene is realized by tuning the concentration of formate anions in the electrolyte solution. The high crystallinity of the obtained product indicates the occurrence of spatially confined ●COOH addition reaction between the sub-nanometer interlayers of expanded graphite. In addition, the carboxylated graphene have been used for water desalination and hydrogen/oxygen reduction reaction. Therefore, this work provides a new method for the in situ preparation of functionalized graphene through the electrolysis and its applications in water desalination and hydrogen/oxygen reduction reactions.

Halogen-Bonding-Enabled Photoinduced Atom Transfer Radical Addition/Cyclization Reaction Leading to Tricyclic Heterocycles.

Atom transfer radical addition (ATRA) reactions are crucial for the dual functionalization of unsaturated hydrocarbons. Radical generation, pivotal in ATRA, has seen advancements from thermal to photochemical methods. Recent focus on halogen-bonding-based radical generation, including our group's innovative photochemical approach, offers cost-effective alternatives to transition-metal-dependent photocatalysts. This eliminates the need for high-energy UV light, enhancing the efficiency with noncovalent interactions.

Photodriven Radical-Polar Crossover Cyclization Strategy: Synthesis of Pyrazolo[1,5-a]pyridines from Diazo Compounds.

This work demonstrates the synthesis of a variety of perfluoroalkyl heterocycles via a visible-light-driven radical-polar crossover cyclization strategy. In this process, single-electron reduction/SNV-type/cyclization sequences follow the radical addition reaction of a diazoester, which differs from the current role of diazoesters as radical precursors/acceptors. This transformation demonstrates excellent functional group compatibility and allows for the modification of many bioactive molecules with diazoesters. Such a reaction could represent a novel approach to the photochemical transformation of diazo compounds.