Iron -mediated radical reaction

The scope of this chapter is based on the analogous one by Naso and Marchese published in 19831. Since the time of their review, the focus of work in this area has shifted somewhat, and sections have been added or omitted to reflect that focus. New sections covering chromium(II)-mediated reactions of halides and covering cobalt-mediated radical reactions of halides have been added. In view of the relatively mature nature of the areas, sections dealing with 7c-allylnickel complexes, iron oxyallyl cations and cyanation reactions have been omitted. 

Compared to iron(III), copper(ll), and especially manganese(III) and cerium(IV) other metals have found less application for the oxidative generation of radicals [1]. An exception is cobalt(III)-mediated radical reactions, based on the pioneering work of Iqbal et ah, which was recently reviewed [20] (see also Volume 1, Chapter 1.8). Some examples of oxidative couplings of silyl enol ethers 44 in the presence of silver(I) oxide were developed [21]. However, there is no advantage over copper(II)-mediated radical reactions, since the reagent is more expensive and the 1,4-diketones 45 are isolated in only moderate yield (Scheme 15). 

Iron(II) salts, usually in conjunction with catalytic amounts of copper(II) compounds, have also been used to mediate radical additions to dienes91,92. Radicals are initially generated in these cases by reductive cleavage of peroxyesters of hydroperoxides to yield, after rearrangement, alkyl radicals. Addition to dienes is then followed by oxidation of the allyl radical and trapping by solvent. Hydroperoxide 67, for example, is reduced by ferrous sulfate to acyclic radical 68, which adds to butadiene to form adduct radical 69. Oxidation of 69 by copper(H) and reaction of the resulting allyl cation 70 with methanol yield product 71 in 61% yield (equation 29). 

Iron-mediated generation of hydroxyl radical ( 0H) was monitored by the hypoxanthine-xanthine oxidase method as previously described (28). Formaldehyde produced by reaction of 0H with DMSO was determined spectrophotometrically by the Hantzsch reaction (29). 

Crich and Rumthao reported a new synthesis of carbazomycin B using a benzeneselenol-catalyzed, stannane-mediated addition of an aryl radical to the functionalized iodocarbamate 835, followed by cyclization and dehydrogenative aromatization (622). The iodocarbamate 835 required for the key radical reaction was obtained from the nitrophenol 784 (609) (see Scheme 5.85). lodination of 784, followed by acetylation, afforded 3,4-dimethyl-6-iodo-2-methoxy-5-nitrophenyl acetate 834. Reduction of 834 with iron and ferric chloride in acetic acid, followed by reaction with methyl chloroformate, led to the iodocarbamate 835. Reaction of 835 and diphenyl diselenide in refluxing benzene with tributyltin hydride and azobisisobutyronitrile (AIBN) gave the adduct 836 in 40% yield, along with 8% of the recovered substrate and 12% of the deiodinated carbamate 837. Treatment of 836 with phenylselenenyl bromide in dichloromethane afforded the phenylselenenyltetrahydrocarbazole 838. Oxidative... 

It should be emphasized that virmaUy all of the above discussion is based on biomimetic chemistry, where the Fe(II) source varies from salts such FeS04 to the more reactive FeCla-THaO as well as heme mimetics (TPP) and ester hematin variants. When heme models are used, since porphyrin alkylation is a favoured process, end-product distributions of products can be very different from when a free ferrous ion source is employed. Furthermore, solvent has been shown to have a profound effect on the rate of reaction and product distributions obtained in iron-mediated endoperoxide degradation. Thus all of these studies are truly only approximate models of the actual events within the malaria parasites. Future work is needed to correlate the results of biomimetic chemistry with the actual situation within the parasite. In general, most workers do accept the role of carbon-centred radicals in mediating the antimalarial activity of the endoperoxides, but the key information defining (a) the chemical mechanism by which these species alkylate proteins and (b) the basis for the high parasite selectivity remains to be unequivocally established. 

The transition metals, especially copper and iron ions, catalyse the formation of harmful hydroxyl radicals ( OH) from hydrogen peroxide (Haber-Weiss reaction). Because iron mediates oxidative damage, the substantial intracellular pool of free iron must be regulated by iron chelators, e.g. intracellular storage proteins such as ferritin. 

Hu and Yu reported an iron/macrocyclic polyamine-catalyzed reaction of arylboronic acids with a large excess of pyrrole or pyridine at 130°C tmder air (Eqs. 26 and 27) [63], based on their previous studies on iron-mediated reactions (initial report using a stoichiometric amount of iron [64]). Pyrrole derivatives were arylated at 2-position in good yield (Eq. 26), but when pyridine was used as a substrate, the catalyst turnover was poor and 2-arylpyridine was obtained together with a small amount of 3-aryl- and 4-arylpyridine (Eq. 27). Because a catalytic amotmt of a radical scavenger did not inhibit the reaction, the authors proposed an oxoiron complex as the active species to activate the ort/io-hydrogen of the heterocycle via o-bond metathesis and also performed a DPT analysis of the mechanism. A related iron-catalyzed reaction of aryl boronic acids with heteroarenes was reported by Singh and Vishwakarma [65]. 

Aluminium salts stimulated luminol-enhanced chemiluminescence production by human neutrophils (Stankovic and Mitrovic 1991). Kong et al. (1992) described an Al(lll) complex with O which was a stronger oxidant than 02 " itself and which may contribute to the adverse biological effects of Al(III). Aluminium can enhance hydroxyl radical production by iron, but it is not in itself capable of catalysing the generation of hydroxyl radical fi-om the Fenton or Haber-Weiss reactions (Gutteridge et al. 1985). Aluminium fadhtation of iron-mediated Upid peroxidation is dependent on substrate, pH (greater at pH 5.5 than 7.4), and alumi-... 

Humans Hydrogen peroxide has been used as an enema or as a cleaning agent for endoscopes and may cause mucosal damage when applied to the surface of the gut wall. Hydrogen peroxide enteritis can mimic an acute ulcerative, ischaemic or pseudomembranous colitis, and ranges from a reversible, clinically inapparent process to an acute, toxic fulminant colitis associated with perforation and death (Bilotta and Waye, 1989). It is conceivable that anecdotal reports of exacerbation of IBD by iron supplementation (Kawai et al. 1992) are mediated by hydroxyl radical production by the Fenton reaction. 

Indeed, when present in concentrations sufficient to overwhelm normal antioxidant defences, ROS may be the principal mediators of lung injury (Said and Foda, 1989). These species, arising from the sequential one-electron reductions of oxygen, include the superoxide anion radical, hydrogen peroxide, hypochlorous ions and the hydroxyl radical. The latter species is thought to be formed either from superoxide in the ptesence of iron ions (Haber-Weiss reaction Junod, 1986) or from hydrogen peroxide, also catalysed by ferric ions (Fenton catalysis Kennedy et al., 1989). 

Lipid peroxidation (see Fig. 17.2) is a chain reaction that can be attacked in many ways. The chain reaction can be inhibited by use of radical scavengers (chain termination). Initiation of the chain reaction can be blocked by either inhibiting synthesis. of reactive oxygen species (ROS) or by use of antioxidant enzymes like superoxide dismutase (SOD), complexes of SOD and catalase. Finally, agents that chelate iron can remove free iron and thus reduce Flaber-Weiss-mediated iron/oxygen injury. 

---