Trichloromethyl radical, carbon tetrachloride

Degradation of carbon tetrachloride by photochemical, x-ray, or ultrasonic energy produces the trichloromethyl free radical which on dimeri2ation gives hexachloroethane. Chloroform under strong x-ray irradiation also gives the trichloromethyl radical intermediate and hexachloroethane as final product. 

On the other hand, microsomes may also directly oxidize or reduce various substrates. As already mentioned, microsomal oxidation of carbon tetrachloride results in the formation of trichloromethyl free radical and the initiation of lipid peroxidation. The effect of carbon tetrachloride on microsomes has been widely studied in connection with its cytotoxic activity in humans and animals. It has been shown that CCI4 is reduced by cytochrome P-450. For example, by the use of spin-trapping technique, Albani et al. [38] demonstrated the formation of the CCI3 radical in rat liver microsomal fractions and in vivo in rats. McCay et al. [39] found that carbon tetrachloride metabolism to CC13 by rat liver accompanied by the formation of lipid dienyl and lipid peroxydienyl radicals. The incubation of carbon tetrachloride with liver cells resulted in the formation of the C02 free radical (identified as the PBN-CO2 radical spin adduct) in addition to trichoromethyl radical [40]. It was found that glutathione rather than dioxygen is needed for the formation of this additional free radical. The formation of trichloromethyl radical caused the inactivation of hepatic microsomal calcium pump [41]. 

A similar reaction of 1,5-cyclooctadiene with trichloromethyl radicals, produced from carbon tetrachloride and dibenzoyl peroxide, leads to 2-chloro-6-trichloromethylbicyclo-[3.3.0]octane (94), with chloroform and dibenzoyl peroxide the analogue 95 is obtained and iV-t-butylfonnamide affords compound 96 (equation 57)62,63. 

The metabolism of carbon tetrachloride proceeds via cytochrome P-450-dependent dehalogenation (Sipes et al. 1977). The first step involves cleavage of one carbon-chlorine bond to yield Cl- and a trichloromethyl free radical, which is then oxidized to the unstable intermediate trichloromethanol, the precursor of phosgene. Hydrolytic dechlorination of phosgene yields C02 and HC1 (Shah et al. 1979). Although there are similarities in the metabolism of chloroform and carbon tetrachloride, metabolic activation of chloroform produces primarily phosgene, whereas the level of phosgene production from... 

Carbon tetrachloride is a solvent that is chemically inert, highly resistant to oxidation, but biologically toxic. Despite its chemical stability, P450 is able to convert carbon tetrachloride to several reactive species. Reduced P450 transfers an electron to chloride leading to the elimination of a chloride anion and the generation of the reactive trichloromethyl radical (10). Trichloromethyl radical can undergo a second one-electron reduction to... 

FIGURE 5.5 P450-mediated reduction of carbon tetrachloride and subsequent reactions of the trichloromethyl radical. 

A one-electron reduction of the bond between an aliphatic carbon and a halogen leads to a halogen anion and a carbon-free radical. A good example is the reduction of carbon tetrachloride as discussed earlier in this chapter. The first product in the reduction is the trichloromethyl-free radical. Carbon-centered radicals are not very reactive with biological molecules, but they react very rapidly with molecular oxygen (a diradical) to form a peroxy-free radical (Fig. 5.15), which is quite toxic (10). 

Laser flash photolysis at wavelengths within the charge-transfer absorption bands of 2,2,6,6-tetramethylpiperidine-./V-oxyl (TEMPO) and carbon tetrachloride yields theoxoam-monium chloride of TEMPO 291 (Xmax = 460 nm) and the trichloromethyl radical in an essentially instantaneous 18 ps) process152. The primary photochemical reaction is an electron transfer from TEMPO to carbon tetrachloride followed by immediate decomposition of the carbon tetrachloride anion radical to chloride and trichloromethyl radical (equation 140). The laser flash photolysis of TEMPO and of other nitroxides in a variety of halogenated solvents have confirmed the generality of these photoreactions152. 

The reaction of superoxide ion with carbon tetrachloride is important for olefin epoxidations. This reaction includes the formation of the trichloromethyl peroxide radical Oj" + CCI4 —> Cl + CI3COO. The trichloromethyl peroxide radicals formed oxidize electron-rich olefins. The latter gives the corresponding epoxides. This peroxide radical is a stronger oxidizing agent than the superoxide ion itself (Yamamoto et al. 1986). 

Irradiation of diazo 21d in carbon tetrachloride gave, in addition to 72 (R = Me) and 73, the 3-chloro-3-trichloromethyl-l-methyloxindole (76a) (64JOC3577). Since the photolysis in carbon tetrachloride under comparable conditions produces, in the primary step, CCI3 radicals and chlorine atoms (63JOC3442), in the formation of 76a and probably in the reaction with oxygen to give 74, the carbene 71 shows biradical properties in the... 

Finally, chain transfer is undesirable except when it is used intentionally to limit molecular weight by adding good chain transfer agents such as carbon tetrachloride. Here transfer of a chlorine atom limits the size of one chain and at the same time initiates formation of a new chain by the trichloromethyl radical. Instead of (3), (3), (3), etc., we get (3), (3), (7), (8), (3), (3), (7), (8), etc., with a lower average chain length. 

Administration of hyperbaric oxygen following exposure to carbon tetrachloride improved survival from 31 to 96% in rats (Ellenhorn and Barceloux 1988). Hyperbaric oxygen has also been used in treating overdoses of carbon tetrachloride in humans and may correct regional tissue hypoxia and damage, as well as inhibit the P-450-dependent reductive dehalogentation of carbon tetrachloride to the metabolically active acute trichloromethyl radical in the liver. However, the effectiveness of this method has not been established in humans (Burkhart et al. 1991 Ellenhorn and Barceloux 1988). 

Dose and duration dependence of free radical generation during carbon tetrachloride metabolism in the endoplasmic reticulum relation between trichloromethyl radical formation and lipid radical format on. 

Methods for Determining Biomarkers of Exposure and Effect. Covalent adducts between reactive carbon tetrachloride metabolites (e.g., the trichloromethyl radical) and cellular proteins, lipids and nucleic acids are known to occur, but at present these can only be measured using radiolabeled carbon tetrachloride. Development of immunological or other methods to detect such adducts in humans exposed to carbon tetrachloride could be of value in estimating past exposures to carbon tetrachloride. 

Lai EK, McCay PB, Noguchi T, et al. 1979. In wVo spin-trapping of trichloromethyl radicals formed from Carbon tetrachloride. Biochem Pharmacol 28 2231-2235. 

Noguchi T, Fong K-L, Lai EK, et al. 1982a. Specificity of a phenobarbital- induced cytochrome P-450 for metabolism of carbon tetrachloride to the trichloromethyl radical. Biochem Pharmacol 31 615- 624. 

Poyer JL, Floyd RA, McCay PB, etal. 1978. Spin-trapping of the trichloromethyl radical produced during enzymic NADPH oxidation in the presence of carbon tetrachloride or bromotrichloromethane. Biochim Biophys Acta 539 402- 409. 

Tezuka M, Ishii S, Okada S. 1991a. Chromium (III) decreases carbon tetrachloride-originated trichloromethyl radical in mice. J Inorganic Biochem 44 261-265. 

Homolytic cleavage of covalent bonds is an alternative means of generating free radicals. This may be assisted by the addition of an electron as in the case of carbon tetrachloride activation. The electron may be donated by cytochrome P-450, allowing the loss of chloride ion and the production of a trichloromethyl radical (Fig. 4.7). This can initiate other radical reactions by reacting with oxygen or unsaturated lipids. 

The cytochrome P-450 destroyed may be a specific isoenzyme, as is the case with carbon tetrachloride and allylisopropylacetamide (Table 5.28). Indeed, with carbon tetrachloride the isoenzyme destroyed is the one, which is responsible for the metabolic activation (CYP1A2). With allylisopropylacetamide, it is the phenobarbital-inducible form of the enzyme, which is preferentially destroyed as can be seen from Table 5.25. It seems that it is the heme moiety, which is destroyed by the formation of covalent adducts between the reactive metabolite, such as the trichloromethyl radical formed from carbon tetrachloride (see chap. 7), and the porphyrin ring. 

Carbon tetrachloride causes centrilobular liver necrosis and steatosis after acute exposure, and liver cirrhosis, liver tumors, and kidney damage after chronic administration. The mechanism underlying the acute toxicity to the liver involves metabolic activation by cytochrome P-450 to yield a free radical (trichloromethyl free radical). This reacts with unsaturated fatty acids in the membranes of organelles and leads to toxic products of lipid peroxidation including malondialdehyde and hydroxynonenal. This results in hepatocyte necrosis and inhibition of various metabolic processes including protein synthesis. The latter leads to steatosis as a result of inhibition of the synthesis of lipoproteins required for triglyceride export. 

Diphenyl-4//-pyran (151a R = Ph) undergoes a free-radical chain process with trichloromethyl radicals generated from carbon tetrachloride, affording pyrylium radical cation 378a353 (see Eq. 19). 

Primary alkyl chlorides are fairly stable to fluorine displacement. When fluonnated, 1-chloropropane is converted to 1-chloroheptafluoropropane and 1-chloro-2-methylbutane produces 39% l-chlorononafluoro-2-methylbutane and 19% perfluoro-2-methylbutane. Secondary and tertiary alkyl chlorides can undergo 1,2-chlonne shifts to afford perfluormated primary alkyl chlorides 2-Chloro-2-methylpropane gives l-chlorononafluoro-2-methylpropane, and three products are obtained by the fluonnation of 3-chloropentane [3] (equation 1). Aerosol fluonna-tion of dichloromethane produces dichlorodifluoromethane which is isolated in 98% purity [4] (equation 2). If the molecule contains only carbon and halogens, the picture is different. Molecular beam analysis has shown that the reaction of fluorine with carbon tetrachloride, lodotrichloromethane, or bromotrichloromethane proceeds first by abstraction of halogen to form a trichloromethyl radical [5]... 

The metabolism of carbon tetrachloride (a chemical solvent that was formerly in common use) attracts attention as well. Its bioactivation appears to involve consecutive one-electron reduction and the formation of chloride ion and the trichloromethyl radical. The latter radical then reacts with oxygen, giving rise to an oxygenated radical and, eventually, to highly toxic phosgene (Mico Pohl 1983). Scheme 3-70 (below) describes these reactions ... 

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