Trichloromethyl Radical Research Articles

Deciphering Molecular Mechanisms of Carbon Tetrachloride- Induced Hepatotoxicity: A Brief Systematic Review.

The liver plays a critical role in metabolic processes, making it vulnerable to injury. Researchers often study carbon tetrachloride (CCl4)-induced hepatotoxicity in model organisms because it closely resembles human liver damage. This toxicity occurs due to the activation of various cytochromes, including CYP2E1, CYP2B1, CYP2B2, and possibly CYP3A, which produce the trichloromethyl radical (CCl3*). CCl3* can attach to biological molecules such as lipids, proteins, and nucleic acids, impairing lipid metabolism and leading to fatty degeneration. It can also combine with DNA to initiate hepatic carcinogenesis. When exposed to oxygen, CCl3* generates more reactive CCl3OO*, which leads to lipid peroxidation and membrane damage. At the molecular level, CCl4 induces the release of several inflammatory cytokines, including TNF-α and NO, which can either help or harm hepatotoxicity through cellular apoptosis. TGF-β contributes to fibrogenesis, while IL-6 and IL-10 aid in recovery by minimizing anti-apoptotic activity and directing cells toward regeneration. To prevent liver damage, different interventions can be employed, such as antioxidants, mitogenic agents, and the maintenance of calcium sequestration. Drugs that prevent CCl4- induced cytotoxicity and proliferation or enhance CYP450 activity may offer a protective response against hepatic carcinoma.

Visible-Light-Driven C-H Imidation of Arenes and Heteroarenes by a Phosphonium Ylide Organophotoredox Catalyst: Application to C-H Functionalization of Alkenes.

Phosphonium ylide catalysis through an oxidative quenching cycle has been developed for visible-light-driven C-H imidation of arenes and heteroarenes. The present protocol could be applied not only to trihalomethylative lactonization reactions involving trifluoromethyl, trichloromethyl, and tribromomethyl radicals but also to the first example of an organophotoredox-catalyzed imidative lactonization reaction involving a nitrogen-centered electrophilic radical species.

Trichloromethyl‐Radical‐Initiated Three‐Component Reaction of Alkenes with CHCl3 and Quinoxalinones

AbstractAn iron(II)‐catalyzed three‐component reaction was developed for the construction of trichloromethylated 3‐benzylquinoxalin‐2(1H)‐ones. This reaction was conducted through the trichloromethylation of alkenes with quinoxalin‐2(1H)‐ones using commercially available chloroform as trichloromethyl radical source, which provided a convenient approach toward trichloromethylated 3‐benzylquinoxalin‐2(1H)‐ones.magnified image

Effects of Medicinal Plants on Carbon Tetrachloride-Induced Liver Injury: A Review

The liver is the primary organ for metabolizing and eliminating foreign chemicals. When liver cells are exposed to large concentrations of dangerous substances, hepatocyte malfunction, membrane damage, and degradation may occur. Another chemical that can harm the liver is carbon tetrachloride (CCl4). CCl4 is converted into trichloromethyl radical [CCl3]- by several cytochrome P450 isoforms. [CCl3]- subsequently reacts with oxygen to generate trichloromethyl peroxyl radical [CCl3OO]- and induce lipid peroxidation in cell membranes. In this study, the mechanism by which a variety of recently identified medicinal plants display hepatoprotective activity against CCl4-induced liver injury is investigated. We find that animal models have been used in investigations of plant extracts. Herbal plants largely protect against CCl4-induced hepatotoxicity because their phytochemicals have an inhibitory nature. The antioxidant properties of phytochemicals can halt lipid oxidation and restrict the production of free radicals by inhibiting microsomal enzymes. They can also help liver cells in their fight against CCl4-induced inflammation by strengthening and fortifying them. The effectiveness of various herbs that are hepatoprotective and are thus plausible candidates for use in medicine must be confirmed. Experiments using entire plant extracts should be replaced with tests that pinpoint the active ingredients and assess the extracts’ effect on a variety of liver cell lines.

Chemical Composition of Various Nepeta cataria Plant Organs' Methanol Extracts Associated with In Vivo Hepatoprotective and Antigenotoxic Features as well as Molecular Modeling Investigations.

This report summarizes the chemical composition analysis of Nepeta cataria L. flower, leaf, and stem methanol extracts (FME, LME, SME, respectively) as well as their hepatoprotective and antigenotoxic features in vivo and in silico. Herein, Wistar rat liver intoxication with CCl4 resulted in the generation of trichloromethyl and trichloromethylperoxy radicals, causing lipid peroxidation within the hepatocyte membranes (viz. hepatotoxicity), as well as the subsequent formation of aberrant rDNA adducts and consequent double-strand break (namely genotoxicity). Examined FME, LME, and SME administered orally to Wistar rats before the injection of CCl4 exerted the most notable pharmacological properties in the concentrations of 200, 100, and 50 mg/kg of body weight, respectively. Thus, the extracts’ hepatoprotective features were determined by monitoring the catalytic activities of enzymes and the concentrations of reactive oxidative species, modulating the liver redox status. Furthermore, the necrosis of hepatocytes was assessed by means of catalytic activities of liver toxicity markers. The extracts’ antigenotoxic features were quantified using the comet assay. Distinct pharmacological property features may be attributed to quercitrin (8406.31 μg/g), chlorogenic acid (1647.32 μg/g), and quinic acid (536.11 μg/g), found within the FME, rosmarinic acid (1056.14 μg/g), and chlorogenic acid (648.52 μg/g), occurring within the LME, and chlorogenic acid (1408.43 μg/g), the most abundant in SME. Hence, the plant’s secondary metabolites were individually administered similar to extracts, upon which their pharmacology in vivo was elucidated in silico by means of the structure-based studies within rat catalase, as a redox marker, and rat topoisomerase IIα, an enzyme catalyzing the rat DNA double-strand break. Conclusively, the examined N. cataria extracts in specified concentrations could be used in clinical therapy for the prevention of toxin-induced liver diseases.

Radical Polychloromethylation/Cyclization of Unactivated Alkenes: Access to Polychloromethyl‐Substituted Ring‐Fused Quinazolinones

AbstractA radical di‐ and trichloromethylation/cyclization of unactivated alkenes was developed with commercially available dichloromethane and chloroform as di‐and trichloromethyl radical sources under metal‐free conditions. Variously substituted di‐ and trichloromethylated pyrrolo‐ and piperidino‐quinazolinones were obtained in 47–94% yields. Additionally, dibromomethylation/cyclization was also achieved under standard conditions when CH2Br2 was utilized. Moreover, the obtained dichloromethylated product can be transformed into 1′H‐spiro[cyclopropane‐1,3′‐pyrrolo[2,1‐b]quinazolin]‐9′(2′H)‐one after treating by KOH.magnified image

Metal-free polychloromethyl radical-initiated cyclization of unactivated N-allylindoles towards pyrrolo[1,2-a]indoles.

A metal-free polychloromethyl radical-initiated cyclization of unactivated alkenes was developed using CH2Cl2 and CHCl3 as the di- and trichloromethyl radical sources. Variously substituted N-allyl-indoles were successfully transformed into the corresponding C2-(di- and trichloromethyl) pyrrolo[1,2-a]indoles in moderate to good yields. This reaction has a broad substrate scope and good functional group tolerance. Dibromomethylated products can also be obtained using CH2Br2 under standard conditions.

Functionalized β,β-dichloroenones and β,β-dibromoenones as versatile building blocks: Synthesis and transformations

An efficient one-step synthesis of functionalized β,β-dichloroenones and β,β-dibromoenones was achieved via the Fe-catalyzed radical induced reaction between silyl enol ethers and carbon tetrachloride, bromotrichloromethane or carbon tetrabromide in moderate to good yields. This reaction proceeds through addition of the trichloromethyl or tribromomethyl radical group to the CC bond of the silyl enol ethers and subsequent base-induced elimination under mild conditions.

Radical Relay Trichloromethylacylation of Alkenes through N-Heterocyclic Carbene Catalysis.

N-Heterocyclic carbene catalysis enabling vicinal trichloromethylacylation of alkenes using tetrachloromethane and aldehydes has been developed. The reaction involves single electron transfer from the enolate form of the Breslow intermediate to tetrachloromethane to generate the persistent Breslow intermediate-derived ketyl radical and a transient trichloromethyl radical. After radical addition of the trichloromethyl radical to an alkene, the prolonged alkyl radical is preferentially captured by the ketyl radical over tetrachloromethane leading to the atom transfer radical addition product.

Trichloromethylative Olefin Cycloamination by Photoredox Catalysis

AbstractThe trichloromethyl group is an important functionality. It is a useful synthetic moiety and appears in the structures of natural and biologically active compounds; hence, developing synthetic methods for its introduction into structural motifs is an important objective. Herein, we report an efficient chemistry for the trichloromethylations and cycloaminations of olefin. These reactions are realized in a single step and triggered by the addition of the trichloromethyl radical, generated from bromotrichloromethane by photoredox catalysis, to a double bond, with the resulting intermediate trapped through intramolecular reaction with an amino group. This process facilitates the construction of N‐heterocycles having trichloromethyl units and tetrasubstituted carbons from simple compounds under mild conditions.

Toxicity of carbon tetrachloride, free radicals and role of antioxidants

Several chemicals, including environmental toxicants and clinically useful drugs, cause severe cellular damage to different organs of our body through metabolic activation to highly reactive substances such as free radicals. Carbon tetrachloride is an organic compound of which chemical formula is CCl₄. CCl4 is strong toxic in the kidney, testicle, brain, heart, lung, other tissues, and particularly in the liver. CCl4 is a powerful hepatoxic, nephrotoxic and prooxidant agent which is widely used to induce hepatotoxicity in experimental animals and to create hepatocellular carcinoma, hepatic fibrosis/cirrhosis and liver injury, chemical hepatitis model, renal failure model, and nephrotoxicity model in recent years. The damage-causing mechanism of CCl4 in tissues can be explained as oxidative damage caused by lipid peroxidation which starts after the conversion of CCl4 to free radicals of highly toxic trichloromethyl radicals (•CCl₃) and trichloromethyl peroxyl radical (•CCl₃O2) via cytochrome P450 enzyme. Complete disruption of lipids (i.e.,peroxidation) is the hallmark of oxidative damage. Free radicals are structures that contain one or more unpaired electrons in atomic or molecular orbitals. These toxic free radicals induce a chain reaction and lipid peroxidation in membrane-like structures rich in phospholipids, such as mitochondria and endoplasmic reticulum. CCl4-induced lipid peroxidation is the cause of oxidative stress, mitochondrial stress, endoplasmic reticulum stress. Free radicals trigger many biological processes, such as apoptosis, necrosis, ferroptosis and autophagy. Recent researches state that the way to reduce or eliminate these CCl4-induced negative effects is the antioxidants originated from natural sources. For normal physiological function, there must be a balance between free radicals and antioxidants. If this balance is in favor of free radicals, various pathological conditions occur. Free radicals play a role in various pathological conditions including Pulmonary disease, ischemia / reperfusion rheumatological diseases, autoimmune disorders, cardiovascular diseases, cancer, kidney diseases, hypertension, eye diseases, neurological disorders, diabetes and aging. Free radicals are antagonized by antioxidants and quenched. Antioxidants do not only remove free radicals, but they also have anti-inflammatory, anti-allergic, antithrombotic, antiviral, and anti-carcinogenic activities. Antioxidants contain high phenol compounds and antioxidants have relatively low side effects compared to synthetic drugs. The antioxidants investigated in CCI4 toxicity are usually antioxidants from plants and are promising because of their rich resources and low side effects. Data were investigated using PubMed, EBSCO, Embase, Web of Science, DOAJ, Scopus and Google Scholar, Carbon tetrachloride, carbon tetrachloride-induced toxicity, oxidative stress, and free radical keywords. This study aims to enlighten the damage-causing mechanism created by free radicals which are produced by CCl4 on tissues/cells and to discuss the role of antioxidants in theprevention of tissue/cell damage. In the future, Antioxidants can be used as a therapeutic strategy to strengthen effective treatment against substances with high toxicity such as CCl4 and increase the antioxidant capacity of cells.

Estimation of the infl uence of cytochrome P450 induction on carbon tetrachloride genotoxicity in vitro

Introduction. One of the stages of the pathogenesis of the toxic eff ect of carbon tetrachloride is the formation of compounds of reactive oxygen species with DNA, leading to the modifi cation of nitrogenous bases. The frequency of formation of nucleotides modifi ed by nitrogenous bases correlates with the number of single-and double-chain breaks of deoxyribonucleic acid (DNA) molecules. The initiator of the formation of active forms of oxygen and lipid peroxidation in liver cells upon receipt of carbon tetrachloride is a trichloromethyl radical formed during biotransformation by microsomal enzymes of cytochrome P450.The aim of the study was to analyze the changes in the genotoxicity of carbon tetrachloride in hepatocytes at normal and increased activity of cytochrome P450 caused by the infl uence of an inductor (sovol).Materials and methods. Evaluation of genotoxicity is performed by the method of DNA-comets aft er gavage with carbon tetrachloride culture of mouse hepatocytes МН22а in 96-well microplates without the induction of cytochrome P450 and chemical induction of cytochrome P450 by sovol. Determination of DNA content in comet tail (%), comet tail length (μm) and tail moment was performed in ImageJ 1.48. Statistical analysis of the results was performed in the program SPSS Statistics 21.Results: Experimental data on the genotoxic eff ect of carbon tetrachloride on hepatocytes of the MN–22A cell line without induction of cytochrome P450 and chemical induction of cytochrome P450 by sovol are presented. It was found that 0.5 mm solution of carbon tetrachloride in 1 hour aft er addition to the culture medium is genotoxic for hepatocytes MH–22a without the use of sovol (p<0.001). Th e lack of determined using the method of DNA-comet signs of genotoxicity of 5 mm carbon tetrachloride (p>0.05) in the culture medium, probably due to the transition of the cells into a state of parametros. Genotoxic eff ect is not detected by DNA comet aft er 3 and 24 hours of incubation of hepatocytes MN–22A with 0.5 and 5 mm solutions of carbon tetrachloride without preincubation with sovol (p>0.05), which may indicate repair of the damage. Aft er 72 hours of preliminary incubation of hepatocytes with sovol and the followin g four-hour cell priming with 2.5 mm tetrachloromethane solution, higher values of the parameters of DNA comets are observed than when seeding with tetrachloromethane without incubation with sovol (p<0.05).Conclusions: According to the results of the study 72 hours of cytochrome P450 induction by sovol increases the genotoxicity of carbon tetrachloride in vitro, compared with 24 h of inductor exposure, which may indirectly indicate a higher level of formed reactive oxygen species caused by increased activity of cytochrome P450 enzymes.

Visible-Light-Driven Chlorotrifluoromethylative and Chlorotrichloromethylative Cyclizations of Enynes.

Described herein is a visible-light-driven chlorotrifluoromethylative and chlorotrichloromethylative cyclization reaction to synthesize chlorotrifluoromethylated and chlorotrichloromethylated cyclic compounds. Visible-light photochemistry was utilized to generate trifluoromethyl and trichloromethyl radicals and trigger radical addition/cyclization/chlorination sequences. The use of terminal alkene-derived enynes enables the regioselective and stereoselective synthesis of chlorotrifluoromethylated and chlorotrichloromethylated pyrrolidines, piperidines, and cyclopentanes.

Theoretical studies of hydrogen abstraction from H2X and CH3XH (X = O, S) by trichloromethyl radicals.

We have theoretically investigated the hydrogen abstraction reactions of H2O, H2S, CH3OH, and CH3SH by the CCl3 radical, which is of interest in atmospheric chemistry research. In this study, mechanistic and kinetic analyses for the title reactions have been performed at the W1 and the CCSD(T)/cc-pVTZ//M06-2X/cc-pVTZ level. Standard Gibbs free energies for all reaction channels at the W1 level with ZPE corrections were also calculated. Intrinsic Reaction Coordinate (IRC) calculations were performed to verify the connectivity of all the transition states with the reactants and products. All rate coefficients are computed by conventional transition state theory (CTST) with the zero-curvature tunneling (ZCT) and also Wigner's tunneling (W) correction in the temperature range from 200 K to 2000 K. The rate coefficients for each reaction channel are also evaluated by canonical variational transition state theory (CVT) with the small-curvature tunneling correction method (SCT) in the same temperature range. Three-parameter Arrhenius expressions have been obtained by fitting to the computed rate coefficients of all abstraction channels between 200 and 2000 K. The branching ratios for these reactions have been determined. This study provides the first theoretical and kinetic determination of the CCl3 rate coefficient for reactions with H2O, H2S, CH3OH, and CH3SH over a large temperature range.

Combustion and Pyrolysis Kinetics of Chloropicrin.

Chloropicrin (CCl3NO2) is widely used in agriculture as a pesticide, weed-killer, fungicide or nematicide. It has also been used as a chemical agent during World War I. The precise understanding of its combustion chemistry for destruction processes or in the event of accidental fire of stored reserves is a major safety issue. A detailed chemical kinetic model for the combustion and pyrolysis of chloropicrin is proposed for the first time. A large number of thermo-kinetic parameters were calculated using quantum chemistry and reaction rate theory. The model was validated against experimental pyrolysis data available in the literature. It was shown that the degradation of chloropicrin is ruled by the breaking of the C-N bond followed by the oxidation of the trichloromethyl radical by NO2 through the formation of the adduct CCl3ONO, which can decompose to NO, chlorine atom, and phosgene. Phosgene is much more stable than chloropicrin and its decomposition starts at much higher temperatures. Combustion and pyrolysis simulations were also compared and demonstrated that the addition of oxygen has very little effect on the reactivity or product distribution due to the absence of hydrogen atoms in chloropicrin.

Ellagic acid impedes carbontetrachloride-induced liver damage in rats through suppression of NF-kB, Bcl-2 and regulating Nrf-2 and caspase pathway.

The use of natural antioxidants instead of conventional treatments is considered effective and safe alternative therapy for hepatotoxicity. Ellagic acid (EA) is a strong antioxidant matter having protecting effect particularly on the liver. Hepatotoxic compounds can cause very heavy damage. Among these chemical hepatotoxins, CCl4 are responsible for the trichloromethyl radical resulting from biotransformation of the liver. The aim of this study was to examine whether EA plays a protective role against to liver damage induced with carbon tetrachloride (CCl4) in rats. In this study, 36 male wistar albino (n = 36, 8 weeks old) rats were used. The rats were distributed into 4 groups, and 9 rats involved in each group. The groups were: (i) Control Group: Fed with standard diet; (ii) EA Group: Fed with standard diet + EA; (iii) CCl4 Group: Fed with standard diet + CCl4; (iv) CCl4 + EA Group: Fed with standard diet + CCl4 + EA. After 8 weeks, the rats were decapitated and the liver tissue were examined. As a result; EA application created a significant difference (p < 0.05) on caspase-3, bcl-2, NF-kB and Nrf-2 expression in the CCl4 + EA group in comparison to CCl4 group. Caspase-3 and Nrf-2 expression levels were increased in the CCl4 + EA group in comparison to CCl4 group, but bcl-2 and NF-kB expression levels were decreased. In TUNEL assay examinations, apoptotic index ratio was decreased in the CCl4 + EA group in comparison to CCl4 group. These results show that EA reduce liver damage ratio at wistar albino rats and also these results suggest that ellagic acid may be a potentially protective drug against to liver damage in future.

Characterization of Neutral Radicals from a Dissociative Electron Attachment Process.

Despite decades of gas-phase studies on dissociative electron attachment (DEA) to various molecules, as yet there has been no direct detection and characterization of the neutral radical species produced by this process. In this study, we performed stepwise electron spectroscopy to directly measure and characterize the neutrals produced upon zero-electron-energy DEA to the model molecule, carbon tetrachloride (CCl_{4}). We observed the direct yield of the trichloromethyl radical (CCl_{3}^{·}) formed by DEA to CCl_{4} and measured the appearance energies of all the other neutral species. By combining these experimental findings with high-level quantum chemical calculations, we performed a complete analysis of both the DEA to CCl_{4} and the subsequent electron-impact ionization of CCl_{3}^{·}. This work paves the way toward a complete experimental characterization of DEA processes, which will lead to a better understanding of the low-energy electron-induced formation of radical species.

Decomposition of Strong Carboxylic Acids Redox Catalyzed By Carboxylate Ions; Chemical Grafting of Carbon Surfaces

In mixtures of trichloroacetate ion and trichloroacetic acid in acetonitrile, trichloromethyl radicals are produced as a result of the redox reaction between the acid and its conjugated base. The reaction follows a loop mechanism in which the trichloroacetic acid is slowly consumed by proton reduction while the trichloroacetate ion is oxidized like in an electrochemical Kolbe reaction [1]. The hydroquinone-trichloroacetate complex was a good sensor of this unexpected self-decarboxylation redox reaction [2]. According to the conceptual framework of this reaction, the acid-base mixture was also tested but using the compounds derived from 4-nitrophenylacetic acid. The reaction ocurrs also in this system, however, when a glassy carbon electrode was present in the reaction solution, the grafting of nitrobenzyl groups on the surface was detected, whereas 4-nitrotoluene was detected as the product of a paralel reaction in solution. Therefore, the reaction represent an alternative to the covalent modification of carbon substrates without electrochemical induction.[1] Drochss P. Valencia, Pablo D. Astudillo, Annia Galano, Felipe J. González, Org. & Biomol. Chem., 2013, 11, 318-325 [2] Pablo D. Astudillo, Annia Galano, Jorge Tiburcio, Felipe J. González, J. Electroanal. Chem., 2007, 604, 57-64 Figure 1

Copper-Catalyzed Transformation of Hydrazones into Halogenated Azabutadienes, Versatile Building Blocks for Organic Synthesis

A one-step copper-catalyzed reaction of aldehyde-derived N-substituted hydrazones with CCl4 resulted in efficient synthesis of 4,4-dichloro-1,2-diazabuta-1,3-dienes. It was proven that this C–C bond-forming cascade reaction operates via an addition of trichloromethyl radical to the C═N bond of hydrazone followed by a base-induced elimination of HCl. The reaction was found to be very general, as diverse hydrazones possessing various aromatic groups at N-site, as well as aromatic, aliphatic, and heterocyclic substituents at C-site, are capable partners for coupling with a wide range of polyhalogenated compounds (CCl3Br, CBr4, CCl3CN, CCl3COOEt, CCl3CF3, CBr3CF3) to produce a family of functionalized 1,2-diazabuta-1,3-dienes. It was demonstrated that the prepared heterodienes are highly versatile building blocks for straightforward assembly of various valuable acyclic and heterocyclic molecules.

Determining chemospecificity in reactions with chain transfer agent and corresponding radical via evaluation of molecular weight dependency of apparent comonomer reactivity ratios: free-radical copolymerization of vinyl acetate and dibutyl maleate

Performing copolymerization with two different conditions leading to different molecular weights allows us to determine trichloromethyl radical reactivity towards comonomers.