Nitration with benzoyl nitrate

Indole can be nitrated with benzoyl nitrate at low temperatures to give 3-nitroindole. More vigorous conditions can be used for the nitration of 2-methylindole because of its resistance to acid-catalyzed polymerization. In nitric acid alone it is converted into the 3-nitro derivative, but in a mixture of concentrated nitric and sulfuric acids 2-methyl-5-nitroindole (47) is formed. In sulfuric acid, 2-methylindole is completely protonated. Thus it is probable that it is the conjugate acid which is undergoing nitration. 3,3-Dialkyl-3H-indolium salts similarly nitrate at the 5-position. The para directing ability of the immonium group in a benzenoid context is illustrated by the para nitration of the conjugate acid of benzylideneaniline (48). 

Friedel-Crafts acylation of benzene with benzoyl chloride (CgH5CCl) (j) Nitration of the product from part (1)... 

When nitration of pyridazine iV-oxides is carried out with acyl nitrates (prepared in situ from acyl chlorides and silver nitrate) the reaction takes place at the /3-position relative to the iV-oxide group. Under these circumstances only mononitro derivatives are formed. For example, nitration of pyridazine 1-oxide with acetyl nitrate yields 3-nitropyridazine 1-oxide (17%) and 5-nitropyridazine 1-oxide (0.8%), whereas with benzoyl nitrate a better yield of 5-nitropyridazine 1-oxide is obtained. 

Dimethylpyridazine 1,2-dioxide gives the 4-nitro derivative in good yield with nitric acid, while with benzoyl nitrate the yield is considerably lower. 

Both 4-nitrocinnoline 1-oxide and the 5-nitro isomer give 4,5-dinitrocinnoline 1-oxide when treated with fuming nitric and sulfuric acids. Cinnoline 1-oxide also reacts with benzoyl chloride/silver nitrate to give 3-nitrocinnoline 1-oxide in 71% yield. 

Nitration of cinnoline 2-oxide takes a different course. With nitric and sulfuric acids or with potassium nitrate and sulfuric acid a mixture of 8-nitrocinnoline 2-oxide, 6-nitrocinno-line 2-oxide and 5-nitrocinnoline 2-oxide is obtained, while with benzoyl nitrate in chloroform only a low yield (1.5%) of the 5-nitro derivative is obtained. 

The nitration of l,2,5-selenadiazolo[3,4-/] quinoline 77 with benzoyl nitrate affords the 8-nitro derivative 78, whereas methylation with methyl iodide or methyl sulfate afforded the corresponding 6-pyridinium methiodide 79 or methosulfate 80, respectively (Scheme 29). The pyridinium salt 80 was submitted to oxidation with potassium hexacyanoferrate and provided 7-oxo-6,7-dihydro derivative 81 or, by reaction of pyridinium salt 79 with phenylmagnesium bromide, the 7-phenyl-6,7-dihydro derivative 82. Nucleophilic substitution of the methiodide 79 with potassium cyanide resulted in the formation of 9-cyano-6,9-dihydroderivative 83, which can be oxidized by iodine to 9-cyano-l,2,5-selenadiazolo [3,4-/]quinoline methiodide 84. All the reactions proceeded in moderate yields (81IJC648). 

The partial rate factors for dibenzofuran relative to a benzene position, for protodetritiation, protodetrimethylsilyIation, nitration with nitric acid in acetic anhydride, and benzoylation with benzoyl chloride and aluminum chloride in nitrobenzene at 15°C are shown in Table VII along with the relevant values for diphenyl ether, It is seen that by introducing the biphenyl bond in diphenyl ether the reactivity is lowered at both the positions ortho (4-) and para (2-) to the oxygen of dibenzofuran. This lowering of reactivity has been attributed to the fact that the 2- and 4-positions, as... 

Nitration of pyridines in other than nitric or sulfuric acids is of little interest here because either no reaction or N-nitration takes place (see Section 2.05.2.10). However, pyridine 1-oxide is considerably more reactive and treatment with benzoyl nitrate ultimately leads to the 3-nitro derivative (Scheme 25) (60CPB28). Annelation of a benzene ring bestows greater reactivity on the 3-position in quinoline, compared with pyridine, and reaction with nitric acid in acetic anhydride furnishes the 3-nitro derivative (ca. 6%) (Scheme 26). This isomer has also been obtained, again at low yield (6-10%), by treatment of quinoline with tetranitratotitanium(IV) in carbon tetrachloride (74JCS(P1)1751>. Nitration of benzo analogues of pyridine occurs much more readily in the benzene ring, and Chapter 2.06 should be consulted for these reactions. 

Nitration of hydroxypropiophenone (7-1) followed by conversion of the phenol to its methyl ether by means of methyl iodide provides the intermediate (7-2) the nitro group is then reduced to the corresponding amine (7-3) by catalytic reduction. The newly introduced amine is then replaced by a nitrile group by successive conversion to the diazonium salt by means of nitrous acid followed by treatment with cuprous cyanide (7-4). Reaction with aluminum chloride removes the methyl ether to afford the ortho acylphenol (7-5). This is converted to the chromone (7-6) as above by reaction with benzoyl chloride and sodium benzoate. The nitrile is next hydrolyzed to the carboxylic acid (7-7) by means of sulfuric acid. The acid is then converted to its acid chloride by means of thionyl chloride and that treated with 2-(A -piperidyl)ethanol (7-8). There is thus obtained flavoxate (7-9) [8], a muscle relaxant whose name reflects its flavone nucleus. 

Reaction of pyridine 1-oxide with benzoyl nitrate leads to the 3-nitro derivative the postulated mechanism is shown in Scheme 10. 

Nitration of monosubstituted aromatics, toluene in particular, has been extensively studied using zeolites in order to direct the reaction towards the formation of the desired para-isomer. Toluene has been nitrated para-selectively with benzoyl nitrate over zeolite catalysts.[14,15] For example, when mordenite is used as a catalyst, MNTs are formed in almost quantitative yields, giving 67 % of the para-isomer in 10 min, but tetrachloromethane is required as solvent. However, the main problems associated with the use of benzoyl nitrate are handling difficulties due to its sensitivity toward decomposition, and the tendency toward detonation upon contact with rough surfaces. Nagy et a/.[19 21] reported the nitration of benzene, chlorobenzene, toluene and o-xylene with benzoyl nitrate in the presence of an amorphous aluminosilicate, as well as with zeolites HY and ZSM-11, in hexane as a... 

Benzoyl nitrate C6H5C00N02 (prepared by reacting silver nitrate with benzoyl chloride) can in certain cases be a useful nitrating agent (Francis [181]). For example, thiophene is nitrated with this compound in theoretical yield, while if conventional methods are used, only a low yield is obtained and this only with great difficulty. 

Use of nitric acidracetic anhydride gives an 80% yield of nitrothio-phenes the 2- 3-product ratio was 6.2 with benzoyl nitrate, which also gave a small secondary inverse isotope effect (kT/kH = 1.14)... 

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