O- and p-nitroanisole

Anisole. The simultaneous (homolytic and nucleophilic) annihilations of AN+ as described by the time-resolved spectroscopic results lead to the distinctive mixtures of o- and p-nitroanisoles, in which the isomeric composition is strongly dependent on the nitrating reagent in the following way. 

The effect of an o-methyl substituent on the photosubstitution of o- and p-nitroanisole by hydroxide ions28 (equations 24-26) can be ascribed to both electronic and steric effects that determine the reactivity and selectivity. 

These quinone derivatives, by further reduction, can produce only arnidophenols. If the quinone formation is prevented from taking place, for instance by esterifying the hydroxyl-group, the normal reaction to azoxy-bodies occurs, o- and p-Nitroanisol pass smoothly into azoxy- or azo-derivatives. The acylizing of the amido-group in the case of o- and p-nitroamines hinders likewise the quinone, and. therewith the amine, formation. The azoxy-body is smoothly formed, thus ... 

When o-, m- and p-nitroanisole with 14C-labelled at the methoxy group were irradiated under identical conditions in methanol in the presence of sodium methoxide, only m-nitroanisole underwent methoxy exchange, with the limiting quantum yield (

labelled isotope experiments support a a complex intermediate and indicate an Sjv23Ar mechanism (direct substitution in the triplet state) for this reaction (equation 12) and for 4-nitroveratroles (equation 13). Further evidence from quenching and lifetime experiments also support a direct displacement SAr2Ar mechanism for the photosubstitution reaction of nitroaryl ethers with hydroxide ions13. 

The nitro group in the ortho position also gave a higher frequency. Thus for instance in the case of o-, m- and p- nitroanisoles the frequencies were 1352, 1347 and 1341 cm 1 respectively. In the case of m- and p- nitrophenol the frequencies were 1349 and 1339 cm 1 respectively. 

Problem 22 1 Describe exactly how you would go about separating a mixture of the three water-insoluble liquids, aniline (b.p. 184 ), n-butylbenzene (b.p. 183 ), and /f-valeric acid (b.p. 187 ), recovering each compound pure and in essentially quantitative yield. Do the same for a mixture of the three water-insoluble solids, p-toluidine, o-bromobenzoic acid, and p-nitroanisole. 

Figure 4. Reversal of decreased aniline hydroxylase, aminopyrine N-demethylase and p-nitroanisole O-demethytase activities in vitamin C deficient guinea pigs with ascorbic acid (15).

We may separate the solids p-toluidine,o-bromohenzoin acid, and p-nitroanisole in a way similar to the way we separated the liquids, the major difference is that the original mixture need not be dissolved in ether and can be treated directly. We remove the carboxylic acid (o-bromobenzoic acid) and the amine (p-toluidine) by converting them again to their water-soluble salts. The ether(p-nitroanisole) is too- weak a base to be protonated by the dilute acid. A flow scheme for this separation is ... 

Dealkylation 0-, N-, and S-Dealkylation. Probably the best known example of O-dealkylation is the demethylation of p-nitroanisole. Due to the ease with which the product, /t-nilrophcnol, can be measured, it is a frequently used substrate for the demonstration of CYP activity. The reaction likely proceeds through formation of an unstable methylol intermediate (Figure 7.5). 

R.E. Ebel, Hepatic microsomal p-nitroanisole O-demethylase, Effects of chlorde-cone or mirex induction in male and female rats. Biochem. Pharmacol. 33 559, 1984. 

Epoxidation and hydroxylation A-Dealkylation O-Dealkylation -Dealkylation -Oxidation A-Oxidation P-Oxidation Desulfuration Dehalogenation Nitro reduction Azo reduction Cytochrome P450 (CYP) Aflatoxin, aldrin, benzo[a]pyrene, bromobenzene, naphthalene Ethylmorphine, atrazine, dimethylnitrocarbamate, dimethylaniline p-Nitroanisole, chlorfenvinphos, codeine Methylmercaptan Thiobenzamide, phorate, endosulfan, methiocarb, chlorpromazine 2-Acetylaminofluorene Diethylphenylphosphine Parathion, fonofos, carbon disulfide CCLt, CllCb Nitrobenzene O-Aminoazotoluene Flavin-Containing Monooxygenase (FMO)... 

Reduction of 2-nitrochIorobenzene-4-sulfonic acid gives o-chlorometanilic acid which is used in making azo dyes. The real technical value of nitrochlorobenzene-sulfonic acid, however, lies in the ability of its chlorine atom to be replaced by various groups. For example, o-nitrophenol-p-sulfonic acid is obtained by treatment wiui sodium hydroxide, and this product, on reduction, yields o-aminophenol-p-sulfonic acid. An ogously, nitrochlorobenzenesulfonic acid gives o-nitroanisole-p-sulfonic acid by treatment with alcoholic methanol, and from this is obtained o-anisidine-p-sulfonic acid. The action of ammonia on nitrochlorobenzenesulfonic acid produces o-nitroaniline-p>sulfonic acid aniline and its derivatives produce o-nitrodiphenylamine-p Sulfonic acids (cf. Table II). 

The following yields were obtained by this method 1-nitronaphthalene 68 %, 2-nitronaphtha-lene 60%, p-nitrotoluene 69 %, p-nitroanisole 68 %, and o-nitrotoluene 61 %.172... 

All of these effects are observed when comparing the rates of various electrophilic aromatic substitution reactions. Activating substituents increase the rate of reaction relative to benzene. The rate of reaction for the nitration of anisole, for example, was 9.7 x 10 times faster than nitration of benzene. The reaction of anisole with nitric and sulfuric acids, gave 44% of o-nitroanisole, 56% of p-nitroanisole and < 1% of m-nitro-anisole.2 9 contrasts with reactions involving deactivating substituents, where selectivity for the meta -product is usually very good. Nitration of nitrobenzene, for example, gave 1,3-dinitrobenzene in 94% yield, with only 6% of the ortho product and < 1% of the para product. ... 

MOP induces mixed-function oxidase in mouse liver. This compound clearly induces p-nitroanisol-O-demethylase, but psoralen (2) and 4,2 ,8-trime ylpsoralen failed to induce the enzyme [251,252]. Since coumarins have phosphodiesterase inhibitory activity, it is expected that the intracellular level of cAMP increases after their administration. This situation might induce COH activity and CYP2A5 mRNA levels [253]. 

Figure 2. Microsomal -p-nitroanisole 0-demethylation. (C), Complete system containing 1.2mM pNA, O.lSmM NADP, 44mM pyrophosphate, 2.4mM nicotinamide, 6mM MgClt, 6mM G6P, 4 units/mL G6PDH, and 0.73 mg/mL microsomal protein in a final volume of 2.5 mL of O.IM sodium phosphate buffer, pH 7.4 (A), Pyrophosphate and nicotinamide deleted (B), Pyrophosphate deleted ...

I, 3-biscarbazolylpropane, o-nitroanisole, m-nitroanisole, p-nitroanisole, and tripheny-lamine. " ... 

Figure 9.9 Plots of log Po vs. log k for a series of 21 aromatic compounds. AC18 column was used with (a) methanol-water 50 50 (v/v), and (b) 0.05 M SDS with 2% 1-propanol. Compounds (1) benzyl alcohol, (2) benzaldehyde, (3) 2,4-dinitrophenol, (4) benzo-nitrile, (5) acetophenone, (6) nitrobenzene, (7) p-nitroanisole, (8) methylbenzoate, (9) anisole, (10) benzene, (11) toluene, (12) chlorobenzene, (13) bromobenzene, (14) ethylbenzene, (15) resorcinol, (16) catechol, (17) phenol, (18) p-nitrophenol, (19) o-chlorophenol, (20) o-bromophenol and (21) 2,4-dichlorophenol. Reprinted from Ref 15 with permission ofElsevier.

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