Radical Substitution Research Articles

Structure confirmation, reactivity, bacterial mutagenicity and quantification of 2,2,4-tribromo-5-hydroxycyclopent-4-ene-1,3-dione in drinking water.

The presence of two new disinfectant by-product (DBP) groups in the UK was recently shown using non-target analysis, halogenated-hydroxycyclopentenediones and halogenated-methanesulfonic acids. In this work, we confirmed the structure of 2,2,4-tribromo-5-hydroxycyclopent-4-ene-1,3-dione (TBHCD), and quantified it together with dibromomethanesulfonic acid at 122 ± 34 and 326 ± 157 ng L-1 on average in London's drinking water, respectively (n = 21). We found TBHCD to be photolabile and unstable in tap water and at alkaline pH. Furthermore, spectral and computational data for TBHCD and three other halogenated-hydroxycyclopentenediones indicated they could act as a source of radicals in water and in the body. Importantly, TBHCD was calculated to have a 14.5 kcal mol-1 lower C-Br bond dissociation enthalpy than the N-Br bond of N-bromosuccinimide, a common radical substitution reagent used in organic synthesis. TBHCD was mutagenic in Salmonella/microsome assays using strains TA98, TA100 and TA102. This work reveals the unique features, activity and toxicity of trihalogenated hydroxycyclopent-4-ene-1,3-diones, prompting a need to more comprehensively assess their risks.

Polar-Effect-Directed Control in Site-Selectivity of Radical Substitution Enables C-H Perfluoroalkylation of Coumarins.

A novel Ru-catalyzed protocol for C-7 selective C-H trifluoromethylation of coumarins in the presence of light is presented. This reaction undergoes a radical type nucleophilic substitution instead of a radical type electrophilic substitution owing to the benzocore activation as a result of lowering the lowest unoccupied molecular orbital (LUMO).

How does using an AR learning environment affect student learning of a radical substitution mechanism?

Abstract As the use of augmented reality (AR) in educational settings grows, it becomes increasingly important to understand how to use AR in classrooms. Here, we present an AR learning environment that we designed for teaching an organic chemistry reaction mechanism in high school chemistry classes. This new environment was tested in six tenth-grade chemistry classes (upper secondary) taught by five different teachers in three different schools over the course of five months and evaluated for effectiveness. Students completed knowledge tests before and after they used the AR learning environment to test their learning gain, and surveys to measure their acceptance of the technology, the cognitive load they experienced, and their attitude toward the use of AR to learn the mechanism for radical substitution. Analysis shows that the knowledge posttest scores were significantly higher than the pretest scores (p < 0.001), with a large effect size (r = 0.8). Student responses showed acceptance of the technology, experience of low extraneous cognitive load, and a positive attitude toward the use of AR to learn this reaction mechanism. These findings indicate that this AR learning environment can be used to teach the mechanism of radical substitution to tenth-grade students in introductory high school chemistry courses.

Hydroxyl radical-induced C1'-H abstraction reaction of different artificial nucleotides.

Recently, a few antiviral drugs viz Molnupiravir (EIDD-1931), Favipiravir, Ribavirin, Sofosbuvir, Galidesivir, and Remdesivir are shown to be beneficial against COVID-19 disease. These drugs bind to the viral RNA single strand to inhibit the virus genome replication. Similarly, recently, some artificial nucleotides, such as P, J, B, X, Z, V, S, and K were proposed to behave as potent antiviral candidates. However, their activity in the presence of the most reactive hydroxyl (OH) radical is not yet known. Here, the possibility of RNA strand break due to the OH radical-induced C1'-hydrogen (H) abstraction reaction of the above molecules (except Remdesivir) is studied in detail by considering their nucleotide conformation. The results are compared with those of the natural RNA nucleotides (G, C, A, and U). Due to low Gibbs barrier-free energy and high exothermicity,all these nucleotides (except Remdesivir) are prone to OH radical-inducedC1'-H abstraction reaction.As Remdesivir contains a C1'-CN bond,the OH radical substitution reactions at theCN and C1' siteswould likely liberate the catalytically important CN group, thereby downgrading its activity. Initially, the B3LYP-D3 dispersion-corrected density functional theory method and 6-31 + G* basis set were used to optimize all reactant, transition state, and product complexes in the implicit aqueous medium. Subsequently, the structures of these complexes were further optimized by using the ωB97X-D dispersion-corrected density functional theory method and cc-PVTZ basis set in the aqueous medium. The IEFPCM method was used to model the aqueous medium.

Strategies and Mechanisms of First-Row Transition Metal-Regulated Radical C-H Functionalization.

Radical C-H functionalization represents a useful means of streamlining synthetic routes by avoiding substrate preactivation and allowing access to target molecules in fewer steps. The first-row transition metals (Ti, V, Cr, Mn, Fe, Co, Ni, and Cu) are Earth-abundant and can be employed to regulate radical C-H functionalization. The use of such metals is desirable because of the diverse interaction modes between first-row transition metal complexes and radical species including radical addition to the metal center, radical addition to the ligand of metal complexes, radical substitution of the metal complexes, single-electron transfer between radicals and metal complexes, hydrogen atom transfer between radicals and metal complexes, and noncovalent interaction between the radicals and metal complexes. Such interactions could improve the reactivity, diversity, and selectivity of radical transformations to allow for more challenging radical C-H functionalization reactions. This review examines the achievements in this promising area over the past decade, with a focus on the state-of-the-art while also discussing existing limitations and the enormous potential of high-value radical C-H functionalization regulated by these metals. The aim is to provide the reader with a detailed account of the strategies and mechanisms associated with such functionalization.

Why •CF2H is nucleophilic but •CF3 is electrophilic in reactions with heterocycles

Radical substitution is a useful method to functionalize heterocycles, as in the venerable Minisci reaction. Empirically observed regiochemistries indicate that the CF2H radical has a nucleophilic character similar to alkyl radicals, but the CF3 radical is electrophilic. While the difference between •CH3 and •CF3 is well understood, the reason that one and two Fs make little difference but the third has a large effect is puzzling. DFT calculations with M06-2X both reproduce experimental selectivities and also lead to an explanation of this difference. Theoretical methods reveal how the F inductive withdrawal and conjugative donation alter radical properties, but only CF3 becomes decidedly electrophilic toward heterocycles. Here, we show a simple model to explain the radical orbital energy trends and resulting nucleophilicity or electrophilicity of fluorinated radicals.

A new radical initiation for the ring-opening polymerization of tetrahydrofuran with a radical substitution mechanism

A new radical-Lewis acid system has been discovered to achieve the ring-opening polymerization of tetrahydrofuran. Different types of reaction mechanisms were discovered for the initiation and polymerization processes. The proposed initiation mechanism was studied by MALDI-TOF and ESI-MS as a radical substitution mechanism and polymerization was a coordination-insertion mechanism. And polytetrahydrofuran with high molecular weight (Mn = 14.6 × 104 g mol−1) and narrow molecular weight distribution (PDI = 1.44) could be obtained.

Convergent abinitio analysis of the multi-channel HOBr + H reaction.

High-level potential energy surfaces for three reactions of hypobromous acid with atomic hydrogen were computed at the CCSDTQ/CBS//CCSDT(Q)/complete basis set level of theory. Focal point analysis was utilized to extrapolate energies and gradients for energetics and optimizations, respectively. The H attack at Br and subsequent Br-O cleavage were found to proceed barrierlessly. The slightly submerged transition state lies -0.2kcal mol-1 lower in energy than the reactants and produces OH and HBr. The two other studied reaction paths are the radical substitution to produce H2O and Br with a 4.0kcal mol-1 barrier and the abstraction at hydrogen to produce BrO and H2 with an 11.2kcal mol-1 barrier. The final product energies lie -37.2, -67.9, and -7.3kcal mol-1 lower in energy than reactants, HOBr + H, for the sets of products OH + HBr, H2O + Br, and H2 + BrO, respectively. Additive corrections computed for the final energetics, particularly the zero-point vibrational energies and spin-orbit corrections, significantly impacted the final stationary point energies, with corrections up to 6.2kcal mol-1.

P-NP mineralization, total nitrogen removal and toxicity reduction using an alternating-electroreduction-electrooxidation system

Electrochemical degradation has emerged as a sustainable technology for treating p-Nitrophenol (p-NP). However, most studies have focused only on electrochemical oxidation or electrochemical reduction, and limited research on alternating-electroreduction-electrooxidation system (AEES). The process of p-NP degradation in AEES system has not been understood. In this work, the effect of AEES on p-NP treatment was investigated by regulating the reduction and oxidation time ratios as well as the alternating cycles. The results indicated that the different modes had a significant effect on p-NP degradation rate and TN removal, while the effect on mineralization was limited. Obviously, the sequential reduction–oxidation system performed better than the sequential oxidation–reduction system, with p-NP degradation rates increasing by 34.2 % and 147.9 % over the oxidation and reduction modes alone, respectively. Moreover, an increase in the number of alternating cycles (R60O120 × 1 to R10O20 × 6) results in the improved mineralization from 84.4 % ± 2.1 % to 88.7 % ± 1.7 % and TN removal from 35.1 % ± 1.9 % to 46.6 % ± 2.1 %. The increased mineralization, decreased nitrogen compounds, and reduced complex by-products also contributed to 10.0 % ± 1.4 % reduction of acute toxicity. On the basis of intermediates identification, a degradation pathway for AEES including free radical substitution and ring opening process were proposed.

Cloning human Benchwarmer gene (BNCH) harboring E164K in vector pcDNA3.1 by site-directed mutagenesis method

Benchwarmer (BNCH) gene encodes an orphan transmembrane transporter belonging to the Major Facilitator Superfamily (MFS), facilitating the transport of ions, amino acids, simple sugars and recently lysolipids. The loss of BNCH function caused lethality in several animal models with neurodegeneration and senescence. At the cellular level, dysregulation of BNCH leads to adverse phenotypes of lysosome and also autophagy (i.e. dyshomeostasis, accumulation of carbohydrates and sphingolipids, and enlarged lysosome). However, the molecular function and ligand of BNCH protein remain to be unrevealed. This study aims to create a radical substitution change in human BNCH coding gene to knock out the protein functions. More specifically, lysine (K) was used to replace the glutamic acid residue 164 (E164K) which is conserved in many animals (fly, zebrafish, mouse and human) and this E164K mutation recapitulated BNCH mutant phenotype. In conclusion, BNCH harboring E164K (BNCH*) was successfully produced by site-directed mutagenesis and cloned into pcDNA.3.1 vector. The construct was transformed into E. coli OmniMAX and that provides a valuable cell assay to search for the molecular ligand of BNCH.

Divergent [2 + n] Heteroannulation of β-CF3-1,3-enynes with Alkyl Azides via Hydrogen Atom Transfer and Radical Substitution.

A copper-promoted divergent intermolecular [2 + n] heteroannulation of β-CF3-1,3-enynes with alkyl azides via alkyl radical-driven HAT and radical substitution (C-C bond formation) to form four- to ten-membered saturated N-heterocycles is developed. This method enables the aryl-induced or kinetically controlled site selective functionalization of the remote C(sp3)-H bonds at positions 2, 3, 4, 5, 6, 7, or 8 toward the nitrogen atom through triplet nitrene formation, radical addition across the C═C bond, HAT and radical substitution cascades, and features a broad substrate scope, excellent site selectivity, and facile late-stage derivatization of bioactive molecules. Initial deuterium-labeling and control experiments shed light on the reaction mechanism via nitrene formation and HAT.

Способы синтеза соединений фосфора R4PX, где Х  электроотрицательная группа

Based on the analysis of literature sources from the beginning of the 21st century to the present, various methods for obtaining phosphorus compounds of the general formula R4PX (X is an electronegative group) have been systematized and described. The present study is a continuation of classical research in the field of chemistry of organic phosphorus compounds in the Laboratory of Chemistry of Organoelement Compounds of South Ural State University. The prin-cipal attention is paid to synthesis methods for tetraorganylphosphonium derivatives based on radical redistribution reactions and substitution reactions, which are used to synthesize tetra-phenylphosphorus bromide and a series of alkyltriphenylphosphonium arenesulfonates, respec-tively. It has been shown that the single product of the interaction of triphenylphosphorus dibro-mide with pentaphenylphosphorus in a benzene solution (1 hour, 25 °C) is tetraphenylphosphoni-um bromide, isolated from the reaction mixture, yielding 92%. Tetraphenylphosphonium benzene-sulfonate has been obtained, yielding 90%, by a substitution reaction from tetraphenylphosphoni-um bromide and benzenesulfonic acid in water. Using a similar scheme, a series of alkyltri-phenylphosphonium arenesulfonates have been obtained with yields up to 92 %: [Ph3PC3H5-cyclo][OSO2Naft-1] (2), [Ph3PCH2СN][OSO2Mez)] (3), [Ph3PCH2СN][OSO2C6H3Сl2-2,5] ∙ ½MeOH (4), [Ph3PCH2OH][OSO2C6H3Сl2-2,5] ∙ H2O (5), [Ph3PEt][OSO2C6H3(NO2)2-2,4] (6), [Ph3P(СH2)2OH] [OSO2C6H3(NO2)2-2,4] (7), [Ph3P(С6H11-cyclo)] [OSO2C6H3(NO2)2-2,4] (8). The complex structures have been proved by IR spectroscopy and X-ray diffraction analysis (XRD). According to the XRD data, crystals of complexes 2–5 have ionic structure; they consist of tetraorganylphosphonium and arenesulfonate anions.

Synthesis of Fluoromethylated Chromones and Their Heteroatom Analogues via Sodium Fluoromethanesulfinate-Enabled Direct Fluoromethylation.

An array of biologically interesting tri/difluoromethylated chromones and their heteroatom analogues were conveniently synthesized from the reaction of chromones and their heteroatom analogues with CF3SO2Na or HCF2SO2Na in the presence of tert-butyl hydroperoxide under mild conditions. A mechanistic pathway involving the generation of the electrophilic tri/difluoromethyl radical, followed with the radical substitution of chromones and their heteroatom analogues, was postulated.

Plasmon-induced immobilization of xanthene chemosensors toward repurposing as SERS nanotags

Surface-enhanced Raman spectroscopy (SERS) has emerged as a powerful tool in biophysics, bioanalytical chemistry, and biomedicine due to its unique ability to monitor extracellular chemical activity using fiber optics and multiplexed detection, which are essential for the study of complex biological systems. However, the exceptionally limited choice of SERS nanotags has hindered the practical application of SERS sensing in the fields. Enormous efforts and time are needed to develop new nanotag lines from ab initio for different targeted analytes. This study is inspired by the extensive range of fluorescent chemosensors already in use for various applications and takes a pioneering step toward repurposing them as the SERS nanotags. More specifically, this study explores the potential of plasmon-induced aromatic radical substitution reaction to immobilize xanthene-based chemosensors onto plasmonic nanostructures using a chemical linker without pre-modifying the chemical structures of the chemosensors or compromising the functionality of their binding groups towards specific analytes. Using this proposed method, we immobilize two primary xanthene-based chemosensors and demonstrate their functionality as SERS chemosensors.

Recent Advances in the Synthesis of Fluoroalkylated Alkenes and Alkynes via Fluoroalkyl Radical Substitution Reactions

AbstractTrifluoromethylated alkenes and alkynes are versatile building blocks for organofluorine synthesis. In addition, (trifluoromethyl)alkene motifs are found in biofunctional molecules. Hence, their synthesis is an important research objective. Although trifluoromethylated alkenes and alkynes have been prepared using transition‐metal‐mediated coupling reactions, more environmentally benign processes that obviate the use of precious metal catalysts and/or harsh reaction conditions should be developed. This review outlines recent advances in the synthesis of fluoroalkylated alkenes and alkynes via fluoroalkyl radical substitution reactions.

Radical Substitution of Polyfluoroarenes and Heteroarenes Promoted by Photoredox Activation of Organozinc Iodides

AbstractAromatic compounds interact with organozinc reagents under photoredox conditions, leading to the substitution products. The reaction is performed under blue light irradiation via in situ generated organozinc reagents (Barbier conditions), which are oxidized by the photocatalyst, followed by radical attack at the aromatic substrate. The method works with polyfluorinated arenes, 2‐chlorobenzoxazoles, and 2‐sulfonyl‐substituted benzothiazole.

Photoredox-Catalyzed Radical-Radical Coupling of Potassium Trifluoroborates with Acyl Azoliums.

Potassium trifluoroborates have gained significant utility as coupling partners in organic synthesis, particularly in the Suzuki-Miyaura coupling reaction. Recently, they have also been used as radical precursors under oxidative conditions to generate carbon-centered radicals. These versatile reagents have found new applications in photoredox catalysis, including radical substitution, conjugate addition reactions, and transition metal dual catalysis. In addition, this photomediated redox neutral process has enabled radical-radical coupling with persistent radicals in the absence of a metal, and this process remains to be fully explored. In this study, we report the radical-radical coupling of benzylic potassium trifluoroborate salts with isolated acyl azolium triflates, which are persistent radical precursors. The reaction is catalyzed by an organic photocatalyst and forms isolable tertiary alcohol species. These compounds can be transformed into a range of substituted ketone products by simple treatment with a mild base.

Radical approaches to C-S bonds.

Organosulfur functionalities are ubiquitous in nature, pharmaceuticals, agrochemicals, materials and flavourants. Historically, these moieties were introduced almost exclusively using ionic chemistry; however, radical-based methods for the installation of sulfur-based functional groups have recently come to the fore. These radical methods have enabled their late-stage introduction into complex molecules, avoiding the need to preserve labile organosulfur moieties through multistep synthetic sequences. Here, we discuss homolytic C-S bond-forming processes, with a particular emphasis on radical substitution approaches to sulfide, disulfide and sulfinyl products, and the use of sulfur dioxide and its surrogates to build sulfonyl products. We also highlight the mechanistic considerations that we hope will guide further development of radical-based strategies compatible with the various organosulfur moieties that feature in modern chemistry.

Radical Cascade Reaction in Heterocyclic Synthesis: Formation of Bicyclic 2,3‐dihydrostannoles and Other Heterocyclic Compounds from Amide‐type 1,6‐Enyne Compounds

AbstractAmide‐type 1,6‐enyne compounds, readily available from unsaturated N‐Boc acyl amide and propargylic mesylate, underwent a radical cascade reaction upon treatment with Bu3SnH, giving bicyclic 2,3‐dihydrostannole lactams in good yields. Regioselectivity of the reaction depended on the presence or absence of alkyne substituents; alkyl‐substituted internal alkynes selectively gave 2,3‐dihydrostannoles in good yields, while terminal alkynes gave a mixture of piperidine and 2,3‐dihydrostannole. The reaction promoted the radical cascade process starting from the addition of tin radical to the alkenyl terminal followed by 5‐exo‐dig radical cyclization. The resulting vinyl radical attack the tin atom, and direct radical substitution progressed, giving bicyclic 2,3‐dihydrostannoles in good yields.

Reactivity and Mechanisms of Methane, Ethane, and Benzene C–H Amination with an Iodine(III) Bistriflimide Complex

The iodine(III) bistriflamide complex (C6F5)IIII(NTf2)2 in HNTf2 (bistriflimide acid; (CF3SO2)2NH) selectively aminates methane and ethane. At a 100 °C reaction with methane after 3 h, it resulted in the exclusive formation of MeNTf2 with a yield of approximately 40%. For ethane, at 100 °C in 2 h, a > 80% yield was found for a combination of monofunctionalized and difunctionalized amination products. In contrast to alkanes giving functionalized products, the reaction of (C6F5)IIII(NTf2)2 with benzene resulted in being stalled at (C6F5)IIII(Ph)(NTf2) with a <5% conversion to PhNTf2 even at 120 °C. PWPB95-D3(BJ) density functional theory calculations indicate that C–H activation is the lowest energy pathway to break the hydrocarbon bonds and is lower in energy than radical, electron-transfer, proton-coupled electron-transfer, or hydride substitution pathways. For methane, from the (C6F5)IIII(CH3)(NTf2) intermediate, there is a one-step amine functionalization mechanism that avoids a carbocation intermediate. For ethane, from the (C6F5)IIII(Et)(NTf2) intermediate, dynamics simulations suggest the possibility of a competitive two-step functionalization pathway that involves a short-lived carbocation intermediate. A reaction coordinate strain analysis provides a straightforward model for understanding the relative reactivity rates for alkyl versus aryl functionalization.