Sulfuric nitric acid mixture

Most synthetic camphor (43) is produced from camphene (13) made from a-piuene. The conversion to isobomyl acetate followed by saponification produces isobomeol (42) ia good yield. Although chemical oxidations of isobomeol with sulfuric/nitric acid mixtures, chromic acid, and others have been developed, catalytic dehydrogenation methods are more suitable on an iadustrial scale. A copper chromite catalyst is usually used to dehydrogenate isobomeol to camphor (171). Dehydrogenation has also been performed over catalysts such as ziac, iadium, gallium, and thallium (172). 

The existence of the nitronium ion in sulfuric-nitric acid mixtures was demonstrated both by cryoscopic measurements and by spectroscopy. An increase in the strong acid concentration increases the rate of reaction by shifting the equilibrium of step 1 to the right. Addition of a nitrate salt has the opposite effect by suppressing the preequilibrium dissociation of nitric acid. It is possible to prepare crystalline salts of nitronium ions, such as nitronium tetrafluoroborate. Solutions of these salts in organic solvents rapidly nitrate aromatic compounds. ... 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

Nitration with Nitric Acid or Sulfuric-Nitric Acid Mixture... 

At the same time the use of a sulfuric-nitric acid mixture leads to the 3,5-dinitro derivative [68], Analogically dinitro compounds with high yield (70-80%) are observed on the nitration of 4-methyl-, 4-cloropyrazole and polypyrazoles [71,73] (Scheme 7). 

When 1-methylpyrazole is heated for a long time with a sulfuric-nitric acid mixture, l-methyl-4-nitropyrazole and l-methyl-3,4-dinitropyrazole are formed in a ratio of 4 1. Here the dinitro derivative is formed as a result of further nitration of l-methyl-3-nitropyrazole [45] (Scheme 8). 

In some cases l-methyl-5-nitro- and l-methyl-3,5-dinitropyrazole can form as a result of deoxygenation [76], Nevetheless, the nitration of 2-benzylpyrazole 1-oxide by sulfuric-nitric acid mixture leads to 2-benzyl-3-nitropyrazole 1-oxide in quantitative yield. Further nitration takes place in the phenyl 4-position forming 3-nitro-2-(4-nitrobenzyl)pyrazole 1-oxide and then in the pyrazole 5-position to give 3,5-dinitro-2-(4-nitrobenzyl)pyrazole 1-oxide as the final product [77],... 

In spite of extensive investigations into the electrophilic substitution of imidazoles, no rational explanation has yet been found for certain features of the reaction [78], The nitration of imidazoles takes place exclusively at position 4 or 5. In reaction with the sulfuric-nitric acid mixture imidazole itself forms the 4(5)-nitro derivative [79-85], A large number of papers have been devoted to the production of 2-methyl-4(5)-nitroimidazole by the nitration of 2-methylimidazole [79, 82, 86-94], This is due to the fact that 2-methyl-4(5)-nitroimidazole is an important intermediate product in the synthesis of highly effective medical products (metronidazole, tinidazole, dimetridazole, etc.). 

In some cases the nitration is accompanied by oxidation of the side groups [122, 123], Thus, for example, depending on the conditions, 4(5)-hydroxym-ethylimidazole is converted by the action of the sulfuric-nitric acid mixture into the corresponding aldehyde [124-126], into 4(5)-imidazolecarboxylic acid [124, 125], or into 4(5)-nitro-5(4)-imidazolecarboxylic acid [122, 123] (Scheme 11). 

For many years it was not possible to introduce two nitro groups into the imidazole ring [159], By the use of a somewhat unusual nitration condition (by heating the substrate first with nitric add and then with the sulfuric-nitric acid mixture) it was possible to obtain 4,5-dinitroimidazole [79], The method has now also been used for the production of 4,5-dinitroimidazoles [84, 93, 160], It was also shown that C-polynitrobisimidazoles [79] and not /V-nitroimidazolcs, as considered earlier [161], are formed during the nitration of 2,2 -bisimidazole and its bromine derivatives. As already mentioned earlier, during the nitration of ethyl l-methylimidazole-2-carboxylate the 4,5-dinitro derivative was also isolated together with the other nitration products [128], Increase in the reaction time increases the amount of the dinitro derivative. 

The nitration of 1,4,5-trimethylimidazole 3-oxide with the sulfuric-nitric acid mixture leads to the 2-nitro derivative [76, 162], Both this compound and 1-meth-ylpyrazole 2-oxide enter into reaction in the form of the free base [76], The nitration of 2-aryl-1-hydroxyimidazole 3-oxides leads either to cleavage of the imidazole ring or to the formation of the 4-nitro or 4,5-dinitro derivatives, depending on the reaction conditions [162] (Scheme 15). 

Only the benzene ring is nitrated during the action of the sulfuric-nitric acid mixture on 3-phenylisoxazole. At the same time a mixture of nitric and acetic acids converts it into 3-phenyl-4-nitroisoxazole [176], Earlier Musante [177] isolated a... 

The kinetics of the nitration of 3-methyl-5-phenyl- and 5-methyl-3-phenylisoxazoles [183] and 5,5-dimethylisoxazole [184] were studied. During the nitration of 3,5-diphenylisoxazole by the sulfuric-nitric acid mixture only the phenyl group enters into the reaction [177, 185], In acetic anhydride, however, the main nitration product is 3,5-diphenyl-4-nitroisoxazole [185],... 

The action of the sulfuric-nitric acid mixture on isothiazole gives a high yield of the corresponding 4-nitro derivative [190, 192, 193] (Scheme 18). 

Only one example of the nitration of thiazoles at position 2 has been described the action of the sulfuric-nitric acid mixture on 4,5-dimethylthiazole gave 4,5-dimethyl-2-nitrothiazole [199],... 

The nitration of 2-phenylamino-4-phenylselenazole takes place in a more complicated way ([230], part 3). A very vigorous reaction with the formation of several nitration products is observed even with careful addition of this compound to the sulfuric-nitric acid mixture. It was possible to separate and partly to identify the products by column chromatography and thin-layer chromatography. The products from opening of the heterocycle were not detected (Scheme 30). 

It is not possible to introduce a nitro group into the 1,2,4-triazole ring by the action of the sulfuric-nitric acid mixture because of the disactivation of the cycle by two pyridine nitrogen atoms furthermore, their disactivation effect is aggravated by the heterocycle protonation in the acid medium. The only exception is the nitration of l,2,4-triazolon-5 [250-264], This is probably due to the specific electronic structure of the substrate (the azolone form) (Scheme 32). 

Table 2 The relative reactivity (F) of afkylthiazoles (compared with benzene, F = 1) in nitration (sulfuric-nitric acid mixture, 70°C)...

Fig. 3 The standardized constants for the nitration (k2°) of some heteroaromatic substrates by the sulfuric-nitric acid mixture...

In addition to the sulfuric-nitric acid mixture, acetylnitrate (or a mixture of acetic anhydride with nitric acid) is used quite widely for the introduction of a nitro group into the azole ring. Azoles not containing a pyrrole nitrogen atom are nitrated by acetylnitrate in the same way as by the sulfuric-nitric acid mixture. Data have been published on the nitration of isoxazoles [176,181-183,185,292,293] and thiazoles [203, 206, 215] by acetylnitrate. 1-Substituted pyrazoles [48, 61, 294-301], imidazoles [ 116,133, 302-305], and isoxazoles [306] are nitrated by the nitric acid-acetic anhydride system in the same way as by the sulfuric-nitric acid mixture. 

Aminothiazole is converted by the action of ethyl nitrate into the 5-nitro derivative [352], As already mentioned 2-phenyloxazole and 2-phenylthiazole are nitrated into benzene ring by the sulfuric-nitric acid mixture. At the same time their nitration under conditions excluding protonation of the azole ring (with the use of acetylnitrate or /V-nitropicolinium tetrafluoroborate as nitrating agent) leads to the 5-nitro derivatives [353] (Scheme 40). 

The nitration of thiazoles can also be conducted in organic solvents (e.g., dichlo-roethane) with a nitrating mixture consisting of trifluoromethanesulfonic acid, its anhydride, and potassium nitrate. Here the yields of the nitro derivatives are substantially higher than with the sulfuric-nitric acid mixture [361],... 

Ipso-nitration of 4-bromopyrazoles by the sulfuric-nitric acid mixture is approximately 100 times slower than normal nitration of the corresponding unsubstituted pyra-zoles [46], Substitutive nitration of 4-halogeno-l-alkylpyrazoles takes place in parallel with normal nitration at positions 3 and 5 of the heterocycle [46, 74] (Scheme 47). 

Parallel i/wo-ni (ration at position 4 and nitration at position 5 of the pyrazole ring were also observed during the action of the sulfuric-nitric acid mixture on 1,3-dim-ethyl-4-bromopyrazole [369], The released bromine cation partly brominates the initial reagent with the formation of l,3-dimethyl-4,5-dibromopyrazole. The latter is subsequently transformed into l,3-dimethyl-5-bromo-4-nitropyrazole (see the Scheme later). The nitration of l,3-dimethyl-4,5-dibromopyrazole leads to the formation of l,3-dimethyl-5-bromo-4-nitropyrazole and l,3-dimethyl-4-nitropyrazole [369] (Scheme 48). 

A convenient synthetic procedure for the preparation of 4-nitroiodopyrazoles (useful synthons) - nitrodeiodination of polyiodopyrazoles with sulfuric-nitric acid mixture - has been proposed [370] (Scheme 49). 

Dimethyl-4-halogenoisoxazoles also enter into substitutive nitration. Here, only the iodine derivatives react with the sulfuric-nitric acid mixture. Both the bromine and the chlorine derivatives react slowly with a mixture of acetic anhydride and nitric acid [169],... 

The nitration of 2-phenylindazole at 0°C with sulfuric-nitric acid mixture leads to 5-nitro-2-phenylindazole and 7-nitro-2-phenylindazole. These compounds have been identified using NMR spectroscopy [19]. In spite of the fact that the indazole positions 5 and 7 are most reactive with respect to electrophilic substitution [20] it is difficult to know beforehand the competition between the aromatic positions of the indazole ring (C-4, C-5, C-6, C-7) and the /V-phcnyl ring. 

The mechanism of the nitration of benzisoxazoles in sulfuric-nitric acid mixture has been studied with 3-methyl-l,2-benzisoxazole [121], It has been found that at a sulfuric acid concentration of about 80-90% the substrate reacts as a free base, and at a higher concentration the conjugated acid undergoes nitration. It is worth mentioning that in 1,2-benzisoxazole and its 3-methyl derivative the higher electron density is concentrated on the C-7 atom and in the case of charge-controlled reactions the nitration would lead to 7-nitro isomers. Since 5-nitro derivatives are formed, the process of nitration seems to be of orbital-controlled character [121],... 

Outline of Method. A sample is weighed into a beaker, dissolved in benzene 2-propanol, and burned in an oxy-hydrogen flame using a Wickbold combustion apparatus. The combustion products are collected in a 5% sulfuric-nitric acid mixture containing potassium permanganate. Prior to measurement, trapped mercuric salts are reduced to elemental mercury with tin (II) chloride. The mercury is then swept out of solution and measured by cold-vapor atomic absorption spectroscopy. 

Bozsai and Vastagh (54) determined primidone by polarography after nitrating it with a sulfuric-nitric acid mixture. The pher l group nitrates to form the 3 -nitrophenyl derivative (12), which is reducible at the dropping mercury electrode. The method was applied to tablets containing primidone, as well as to the raw material. The observed half-wave potential was -0.17 volt vs. the saturated calomel electrode. 

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