Oxidative dehalogenations

Xun L, E Topp, CS Orser (1992a) Confirmation of oxidative dehalogenation of pentachlorophenol by a Flavobacterium pentachlorophenol hydroxylase. J Bacterial 174 5745-5747. 

Aromatic hydroxylation Aliphatic hydroxylation AM Iydroxylalion N-, O-, 5-Dealkylation Deamination Sulfoxidation Af-Oxidation Dehalogenation... 

N-dealkylation, O-dealkylation, oxidative dehalogenation, and oxidation of aryl and alkyl methyl groups. 

Halogen dealkylation mimics O-dealkylation both in terms of mechanism and the commonality of the process. Virtually any drug that contains a carbon-hydrogen bond adjacent to a halogen atom will be subject to P450-catalyzed oxidative dehalogenation (Fig. 4.61). 

FIGURE 4.62 Oxidative dehalogenation of halothane to form areactive acid chloride intermediate and structures of other anesthetics that can form similar reactive metabolites. 

FIGURE 4.65 Mechanism of oxidative dehalogenation of an aryl halide. 

Oxidative dehalogenation of aromatic halogens should not occur because there is no hydrogen atom on the carbon involved however, it often does occur. One mechanism likely involves ipso addition as will be discussed later and as proposed for the dechlorination of pentachlorophenol (Fig. 4.65) (131). 

In contrast, the reactivity of trifluoroacetyl chloride, the reactive metabolite of halothane discussed in Chapter 4 under oxidative dehalogenation (Fig. 8.7), is due to the electron-withdrawing effect of the carbonyl and trifluoromethyl groups, which makes it very electrophilic, more reactive than most other molecules that have chloride as the leaving group (Fig. 8.7). 

Fig. 11.3. Comparison of a) hydrolytic dehalogenation and b) oxidative dehalogenation. The products of Reaction a (an alcohol) and Reaction b (a carbonyl) may be interconverted by de-hydrogenation/hydrogenation (Reaction c). When these products are a primary alcohol and an aldehyde, further oxidation to the acid is possible (Reaction c).

Another reaction of dehalogenation, the oxidative dehalogenation of haloalkyl groups, summarized in Fig. 11.3,b (Chapt. 8 in [50]), has also been observed in mammals and other organisms. Here, the haloalkane is oxidized by a cytochrome P450 enzyme to form a hydroxylated intermediate that loses HX to become a carbonyl derivative. The latter is then reduced by dehydrogenases to the corresponding alcohol (Fig. 11.3,c), or, when the carbonyl derivative is an aldehyde, oxidation to the acid can occur (Fig. 11.3,c). 

This reaction should not be confused with hydrolytic dehalogenation, despite apparent similarities [58] although both hydrolytic and oxidative dehalogenation routes may produce the alcohol and carbonyl derivatives, the product that is formed as the primary or secondary metabolite is different in the two pathways. Further, it is clear that the enzymes involved cannot be identical. 

The metabolism of 1,2,3-trichloropropane (11.27), an industrial solvent that undergoes biotransformation via dechlorination at C(l) and C(2) [60], is a clearer case of oxidative dehalogenation. Following incubation with human or rat liver microsomes, the compound was converted to 1,3-dichloroacetone (11.29), which could a priori be produced by oxidative dehalogenation (i. e., via 11.28) or by hydrolytic dehalogenation. In this study, evidence was found... 

Tris(2-chloroethyl) phosphate (11.30), a flame retardant, also undergoes monodehalogenation in rats and mice [61]. All evidence is compatible with oxidative dehalogenation to an intermediate aldehyde, which, in turn, accounts for the CNS toxicity of the compound. 

Non-microsomal oxidations may be subdivided into amine oxidation, alcohol and aldehyde oxidation, dehalogenation, purine oxidation, and aromatization. 

Oxidative dehalogenation. Halogen atoms may be removed from xenobiotics in an oxidative reaction catalyzed by cytochromes P-450. For example, the anesthetic halothane is metabolized to trifluoroacetic acid via several steps, which involves the insertion of an oxygen atom and the loss of chlorine and bromine (Fig. 4.28). This is the major metabolic pathway in man and is believed to be involved in the hepatotoxicity of the drug. Trifluoroacetyl chloride is thought to be the reactive intermediate (see chap. 7). 

Hales,D. B., Ho, B. Thompson,J. A. (1987). Inter-and intramolecular deuterium isotope effects on the cytochrome P-450-catalyzed oxidative dehalogenation of 1,1,2,2-tetrachloroethane. Biochemical and Biophysical Research Communications, 149, 319—25. 

Osborne RL, Raner GM, Hager LP, Dawson JH (2006) C.fumago Chloroperoxidase is also a Dehaloperoxidase Oxidative Dehalogenation of Halophenols. J Am Chem Soc 128 1036... 

Osborne RL, Coggins MK, Temer J, Dawson JH (2007) Caldariomycesfumago Chloroperoxidase Catalyzes the Oxidative Dehalogenation of Chlorophenols by a Mechanism Involving Two One-Electron Steps. J Am Chem Soc 129 14838... 

When Y = F in [Cu2(XYL—F)]2+ (19), neither hydroxylation nor F migration occurs and intact XYL—F ligand is recovered. The lack of reactivity may be ascribed to the presence of both a deactivated ring and a very strong C—F bond. We note that when Y = Cl, reasonable yields of copper complexes with oxidatively dehalogenated ligand are obtained [168,169] the reaction also requires an external reductant. 

Oxidative dehalogenation occurs when oxygen is added in place of a halogen atom, as shown by the following reaction ... 

The reactive electrophilic acyl and carbonyl compounds produced by oxidative dehalogenation may react with nucleophilic biological molecules such as DNA, proteins, lipids and carbohydrates to possibly form toxic metabolites. 

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