Heterolytic hydroxylation

Scheme 18.5 Heterolytic hydroxylation of phenol by TI—OOH species. (Adapted from Ref [47] Copyright 1991, with permission of Elsevier).

In the field of enzyme catalysis, heme-proteins such as cytochrome P450, for example, exhibit both types of 0-0 bond cleavages in organic hydroperoxides and peroxy acids (178). Heterolytic cleavage of HOOH/ROOH yields H20 or the corresponding alcohol, ROH and a ferryl-oxo intermediate (Scheme 4). Homolytic 0-0 bond cleavage results in the formation of a hydroxyl (HO ) or an alkoxyl (RO ) radical and an iron-bound hydroxyl radical. 

Fig. 9. Possible electron transfer mechanism for NOS utilizing a pterin radical. The oxy-complex in 2 is shown as the ferric (Fe +)-superoxide complex. The role of the pterin then is to donate an electron to the iron, thus giving the peroxy dianion in 3. The dianion is a potent base that abstracts a proton from the substrate, giving 4. The system is now set up for a peroxidase-like heterolytic cleavage of the 0-0 bond to give the active hydroxylating intermediate in 5 and, finally, the first product in 6.

Once the oxy complex is formed, a second electron transfer to the HO heme effectively reduces the oxy complex to the peroxide level. From this point many heme enzymes catalyze the heterolytic fission of the peroxide 0-0 bond, leaving behind the well known oxyferryl center, (Fe-0) +, characteristic of peroxidase compound 1 and similar to the active hydroxylating intermediate thought to operate in P450s. However, in HO the active oxidizing intermediate is peroxide. Peracids that form the (Fe-0) + intermediate do not support the HO reaction, whereas H2O2 addition to Fe + HO does support substrate hydroxylation 187, 188). EPR and ENDOR spectroscopy have been used to analyze the cryo-genically reduced oxy-HO complex 189). In these studies reduction of... 

Nitrobenzenes with an ortho or a para hydroxyl or amino function form an exceptional group of compounds in which the nitro function can readily be reduced to amino in alkaline solution. Heterolytic cleavage of the nitrogen-oxygen bond in the phenylliydroxylamine intermediate is promoted by any 2- or 4-substituent which can donate a lone pair of electrons. Further reduction steps then lead to the overall... 

Much of what is understood today about the influence of solvent on rates of oxidation reactions with hydrogen peroxide, alkyl hydroperoxides and peroxyacids can be attributed to the seminal studies by Edwards and his collaborators over thirty years ago " . They provided convincing experimental data that showed that a hydroxylic solvent (e.g. ROH) can participate in a cyclic transition state where a proton relay can in principle afford a neutral leaving group attending heterolytic 0-0 bond cleavage (equation 13). 

Although hydroxyl radical is commonly assumed to be the most toxic of the oxygen radicals (with little direct evidence), other direct reactions are more likely to be important for understanding the cytotoxicity of peroxynitrite. A second oxidative pathway involves the heterolytic cleavage of peroxynitrite to form a nitronium-like species (N02 ), which is catalyzed hy transition metals (Beckman et al., 1992). Low molecular weight metal complexes as well as metals bound in superoxide dismutase and other proteins catalyze the nitration of a wide range of phenolics, including tyrosine residues in most proteins (Beckman et al., 1992). 

The structural similarity of the catalytic domains of the enzymes of the AAH family, together with the identical reaction that they catalyze (i.e., hydroxylation of aromatic substrates) and the common dependency on BH4 and 02 (Section I), suggests that the mechanisms by which these enzymes operate are similar. It is assumed that the general AAH reaction mechanism follows a two-step reaction route in which a high-valent iron-oxo (FeIV=0) complex is formed in the first step, and that this intermediate is responsible for the hydroxylation of the aromatic amino acid substrate in the second step (15,26-28,50). The first step starts with 02 binding and activation and proceeds via a Fe-0-0-BH4 bridge and a subsequent heterolytic cleavage of the... 

The disproportionation of NO into N2O and surface nitrates was investigated for CoO-MgO and NiO-MgO solid solutions by IR and EPR techniques (379). The heterolytic dissociation of H2 on Co2+ and O2 pairs present at edges and steps of CoO-MgO cubes to generate hydride and hydroxyl species has been shown by IR spectroscopy (380). The decomposition of N2O was also investigated (356). 

The oxidized dimer, [Fe2(TPA)20(0Ac)]3+, 41, was shown to be an efficient catalyst for cyclohexane oxidation using tert-BuOOH as a source of oxygen (69). This catalyst reacts in CH3CN to yield cyclohexanol (9 equiv), cyclohexanone (11 equiv), and (tert-butylperoxy)cyclohexane (16 equiv) in 0.25 h at ambient temperatures and pressures under an inert atmosphere. The catalyst is not degraded during the catalytic reaction as determined by spectroscopic measurements and the fact that it can maintain its turnover efficiency with subsequent additions of oxidant. Solvent effects on product distribution were significant benzo-nitrile favored the hydroxylated products at the expense of (tert-butyl-peroxy)cyclohexane, whereas pyridine had the opposite effect. Addition of the two-electron oxidant trap, dimethyl sulfide, to the catalytic system completely suppressed the formation of cyclohexanol and cyclohexanone, but had no effect on the production of (tert-butylper-oxy)cyclohexane. These and other studies suggested that cyclohexanol and cyclohexanone must arise from an oxidant different from that responsible for the formation of (tert-butylperoxy)cyclohexane. Thus, two modes of tert-BuOOH decomposition were postulated a heterolytic... 

At physiological pH the protonated form of ONOO-, the peroxynitrous acid (ONOOH), is unstable and decomposes to nitrate (N03). ONOOH can also react directly with reductants or can decompose by homolytic dissociation to form nitrogen dioxide (N02) and hydroxyl radical (OH"), or can dissociate by a heterolytic mechanism to yield nitryl cation (NOj), which reacts with thiol, methionyl, tyro-syl, and tryptophanyl residues in proteins. 

Radiolysis has also been employed to generate the hydroxyl radical. However, because very energetic particles are used (x-rays, 7-rays, electron beams, etc.) aqueous solutions are used instead of hydrogen peroxide. Water molecules can be cleaved homolytically and heterolytically to produce three radical species hydroxyl radical, hydrated electron and hydrogen atom.30 A great many rate constants of hydroxyl radical with reductants, especially alcohols, have been measured using radiolysis combined with EPR or electronic spectroscopy.31... 

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