Hydroxylation, aromatic

Aromatic hydroxylation is most commonly used for the detection of OH. However, the primary OH adducts must be oxidized to yield the final product(s). Disproportionation reactions produce these compounds usually only in very low yields. For this reason, an oxidant is required. Although oxygen may serve as an oxidant, the yields are not quantitative because of side reactions (Chap. 8). The addition of a one-electron oxidant, for example Fe(CN)63, may overcome this problem (Volkert and Schulte-Frohlinde 1968 Bhatia and Schuler 1974 Madha-van and Schuler 1980 Buxton et al. 1986), but in certain cases an even stronger oxidant such as IrCl62- maybe required (Fang et al. 1996). 

It was mentioned above that in aromatic hydroxylation an oxidant is required, and the product yields vary considerably with the oxidant used (for the reason why 02 does not serve as a typical one-electron oxidant, see Chap. 8). A typical example is the formation of tyrosines from phenylalanine (Table 3.4). Their yields are especially low in the absence of an oxidant, since dimerization usually dominates over disproportionation in these systems. The determination of the products is usually done by either HPLC or GC/MS after trimethylsilylation, and the proteins have to be hydrolyzed prior to analysis. Attention has been drawn to the fact that in vivo cytochrome P-450 enzymes hydroxylate phenylalanine to p-tyrosine (Bailey et al. 1997). 

The terephthalate system follows the same principle. It has the advantage that the main product, 2-hydroxyterephthalate, is the only product which fluoresces and thus can be easily detected, even at low concentrations. Details of the mechanism have been elucidated (Fang et al. 1996). Hydroxyl radicals [fc( OH + terephthalate) = 3 x 109 dm3 mol-1 s 1] react preferentially (85%) at the 2-position [reaction (48)]. The resulting OH adduct is much more difficult to oxidize than many other hydroxycyclohexadienyl radicals (Chap. 6), and the more powerful oxidant IrCl62- is required for a quantitative oxidation [reaction (45)]. With O2 as the oxidant [reactions (46)-(50)], the yield of 2-hydroxyterephthalate is only 

side reactions [reactions (49) and (50)] are the reason for its lower yields (Chap. 8). The detection limit of the fluorescing 2-hydroxyterephthalate has been given as 5 x 10 8 mol dm-3 (Saran and Summer 2000). 

Since OH is strongly electrophilic, the OH group directs OH into its ortho- and para-positions [reactions (51)—(53)]. One of the ortho-positions is occupied by the somewhat bulky carboxylate group which renders reaction (51) less likely than reaction (52). An addition to the meta-position can be largely neglected. Upon oxidation of the OH-adduct radicals, cyclohexadienones are formed [reactions (54)-(56)] which either decarboxylate [reaction (57)] or rearrange into the corresponding phenols [reactions (58) and (59) e.g., Bausch et al. 1976]. Product yields from hydroxybenzoic acids are compiled in Table 3.5 from salicylic acid in Table 3.6. 

Endogenous or exogenous aromatic compounds such as phenols and phenolic acids react extremely rapidly with OH radicals to form a mixture of hydroxylated products (Halliwell et /., 1988). Indeed, aromatic hydroxylation serves as an efiective method for evaluating OH radical activity both in vitro (Moorhouse et al., 1985 Grootveld and Halliwell, 1986a) and in vivo (Grootveld and Halliwell, 1986b). 

If an aromatic compound reacts with an OH radical to form a specific set of hydroxylated products that can be accurately identified and quantified in biological samples, and one or more of these products are not identical to naturally occurring hydroxylated species, i.e. not produced by normal metabolic processes, then the identification of these unnatural products can be used to monitor OH radical activity therein. This is likely to be the case if the aromatic detector molecule is present at the sites of OH radical generation at concentrations sufficient to compete with any other molecules that might scavenge OH radical. 

There is a very wide range of aromatic compounds present in living systems, e.g. the amino acids phenylalanine and tyrosine, and catecholamines such as norepinephrine. Although these speciesi are very useful for in vitro investigations of OH radical generation, their applicability as suitable aromatic detector molecules for OH radical in vivo largely depends on their concentration (i.e. their ability to compete with alternative 

TAG-CH3 and TAG-CH2-, acyl chain terminal-CH3 and bulk (-CH2-)n groups, respectively, of fatty acids (predominantly triacylglycerols) associated with chylomicron- and very low-density lipoprotein (VLDL) Thr, threonine-CHs Val, valine-CHs. The asterisk In spectrum (b) denotes a radiolytically-generated 2.74 p.p.m. 

The intense water signal and the broad protein resonances were suppressed by a combination of continuous secondary Irradiation at the water frequency and the Hahn spin-echo sequence (0[90 x-t-180 y-t-collect]). 

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I-Naphthylamine readily diazotizes and couples to aromatic hydroxylic or basic compounds. It was thus used as a first component in a number of important monoazo dyes, but its use has been severely curtailed because of its potent carcinogenicity. It sulphonates to give naphthionic acid (l-naphthylamine-4-sul-phonic acid). 

H2O2 in the presence of HE/BE acts as an effective and economical reagent for aromatic hydroxylation (163). Hydroxylations of phenols and amines in similar high acidity media are very effective (163). Xylenes were hydroxylated by bis(trimethylsilyl) peroxide and AlCl in poor yields (164). 

Dmg metaboHsm may also produce toxic materials. Thus, the aromatic hydroxylation of hydrocarbons such as ben2pyrene produces the highly reactive and carcinogenic 1,2-epoxides. 

Zavitsas et al. added terms for the extent of hemiformal and paraformaldehyde formation. Hemiformal formation slows the methylolation reaction as does the presence of paraformaldehyde. They report that only monomeric methylene glycol appears to methylolate. They point out that the terms for the two polyoxy-methylene species partially cancel one another, as depolymerization of paraformaldehyde naturally occurs while hemiformal formation is increasing due to methylolation. They observe that hemiformals form only on the methylolphenol hydroxyls and not on the aromatic hydroxyl. They calculate that the average number of methoxy groups involved in each of the hemiformals is about two in addition to the original methylol. There is no selectivity for ortho versus para positions in hemiformal formation. 

It would not be unreasonable to suggest that the dipole moment of the phenolic system has a negative skew toward the aromatic hydroxyl and that the electronic repulsion of these groups in an ortho-ortho situation greatly reduces the likelihood... 

Removal of one of the aromatic hydroxyl groups gives an agent similar to epinephrine in its effects but with longer dura-... 

The isomer of isoproterenol in which both aromatic hydroxyl groups are situated meta to the side chain also exhibits bron-chiodilating activity. Oxidation of 3,5-dimethoxyacetophenone by means of selenium dioxide affords the glyoxal derivative (15). Treatment of the aldehyde with isopropylamine in the presence of... 

Replacement of the aromatic hydroxyl groups in isoproterenol by chlorine again causes a marked shift in biologic activity. 

Aromatic nitroso compounds usually are considered to be intermediates in the hydrogenation of a nitroaromatic compound to the aromatic hydroxyl-amine or amine. However, nitroso compounds do not accumulate in these reductions, suggesting that they are reduced more easily than are nitro compounds. Catalysts effective for the nitro group should also be effective for nitroso. 

About half of the dissolved organic carbon may appear in humic or fulvic acids. These are high-molecular weight organic compounds of a composition which is somewhat uncertain. They contain aromatic hydroxyl and carboxyl groups which have the ability to bind to metal ions. Rivers and estuaries typically contain 10 mg/liter of acid with an exchange capacity of 5-10 mmol/g, mainly due to carboxylic... 

Figure 18.2 Representative receiver operator curves to demonstrate the leave n out validation of K-PLS classification models (metabolite formed or not formed) derived with approximately 300 molecules and over 60 descriptors. The diagonal line represents random. The horizontal axis represents the percentage of false positives and the vertical axis the percentage of false negatives in each case. a. Al-dealkylation. b. O-dealkylation. c. Aromatic hydroxylation. d. Aliphatic hydroxylation. e. O-glucuronidation. f. O-sulfation. Data generated in collaboration with Dr. Mark Embrechts (Rensselaer Polytechnic Institute).

Borodina Y, Rudik A, Filimonov D, Kharchevnikova N, Dmitriev A, Blinova V, et al. A new statistical approach to predicting aromatic hydroxylation sites. Comparison with model-based approaches. J Chem Inf Comput Sci 2004 44 1998-2009. 

Smith RV, Erhardt PW, Leslie SW. Microsomal O-demethylation, A-demethyl-ation and aromatic hydroxylation in the presence of bisulfite and dithiothreitol. Res Commun Chem Path Pharmacol 1975 12 181-4. 

AROMATICS HYDROXYLATION WITH NITROUS OXIDE 2.1. Discovering zeolite catalysts... 

Acronycine 0 0CH3 Cunninghamella echinulata NRRL 3655 Cunninghamella bainieri ATCC 9244 Aromatic hydroxylation [25]... 

Smith RV, Rosazza JP (1974) Microbial models of mammalian metabolism. Aromatic hydroxylation. Arch Biochem Biophys 161(2) 551-558... 

Other dialdehydes, keto aldehydes, hydroxyl aldehydes, ortho-substituted aromatic dialdehydes, and ortho-substituted aromatic hydroxyl aldehydes have been claimed to be active in a similar way [459]. 

Kaur, H., Fagerheim, L, Grootveld, M., Puppo, A. and Halliwell, B. (1988). Aromatic hydroxylation of phenylalanine as an assay for hydroxyl radicals application to activated human neutrophils and to the haem protein leghaemoglobin. Anal. Biochem. 172, 360-367. 

A relatively stable QM is produced by initial P450-catalyzed aromatic hydroxylation of the SERM tamoxifen to yield 4-hydroxytamoxifen, followed by a cytochrome P450-catalyzed direct two-electron oxidation (Scheme 10.9).7 58 This QM is extremely long lived at physiological pH and temperature (tl/2 3 h, Table 10.2),59 most likely... 

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

Encapsulated Cu—chlorophthalocyanines oxidize hexane at C-l using 02 and at C-2 using H202 as oxidants. The dimeric structure of copper acetate is intact when it is incorporated into the zeolite. This is a regioselective aromatic hydroxylation catalyst, which mimics the specificity of the monooxygenase enzyme tyrosinase.82,89 Zeolite NaY catalysts made with a tetranuclear Cu(II) complex were synthesized and characterized.90... 

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