Electrophilic Nitration of Azoles

The most widespread method of introducing nitro group in aromatic compounds, i.e., electrophilic substitution, is mainly used for the preparation of nitrodiazoles and benzazoles. The accumulation of pyridine nitrogen atoms in the cycle reduces the electrophilic substitution ability of compounds. Therefore, some indirect methods of introducing the nitro group are employed for the synthesis of triazole and tetrazole nitro derivatives. 

Larina and V. Lopyrev, Nitroazoles Synthesis, Structure and Applications, 

The ability of azoles to electrophilic substitution reactions is determined by the activity of reagents, the basicity of substrates, and the acidity of media. This caused some uncertainty in the interpretation of results and complicated a comparison of the reactivity of various azoles. The situation has changed after Katritzky and Johnson [1] have reported the criteria allowing, with a sufficient degree of reliance, the establishment in what form (base or conjugative acid) the compound reacts. The information on the mechanism of nitration of azoles was basically borrowed from the extensive literature on the nitration of aromatic hydrocarbons [2-8] therefore, we have found expedient to discuss briefly some works in this field. 

Nitration of aromatic compounds is an immensely important industrial process. The nitroaromatic compounds so produced are themselves widely utilized and act as chemical feedstocks for a great range of useful materials such as dyes, pharmaceuticals, perfumes, and plastics [6, 7], 

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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. 

The reader is directed to several excellent reviews for further details. Hassner and Fischer s general review of oxazoles covers both electrophilic aromatic substitution (EAS) reactions and addition reactions. Belen kii and Chuvylkin surveyed EAS reactions of oxazoles as part of a larger review for azoles. Larina and co-workers published two extensive reviews of nitration of azoles, including oxazoles. The articles cover kinetics and the mechanism of nitrations as well as the synthesis of nitroazoles via heterocyclization and ring transformations and direct methods of nitration. In light of these reviews, only a few selected examples of EAS reactions of oxazoles are described in this section. 

Electrophilic agents and nitrating reagents, in particular, can displace other functional groups apart from hydrogen. Such processes are usually called substitutive nitration or first example of nitric acid on 4-(4-tolylazo)-3,5-dimethylpyrazole led to the formation of 3,5-dimethyl-4-nitropyrazole [366] (Scheme 45). 

The only known C-substitutions in the heterocyclic rings of any benzo-azole are the 2-bromination of benzimidazole with A-bromosuccinimide, the 2-substimtion of benzothiazole with bromine at 450 °C ° and the 3-nitration of indazole." The general rnle is that electrophilic nitrations and halogenations can be achieved only in the benzene ring at the 5-, or 6- or 7-positions, for example 5-bromobenzimidazole can be obtained in high yield from the unsubstituted heterocycle." The efficient conversion of indazole into 3-iodoindazole" is achieved in the presence of base and probably involves iodination of the indazolyl anion (see 26.3). 

M.o. theory has had limited success in dealing with electrophilic substitution in the azoles. The performances of 7r-electron densities as indices of reactivity depends very markedly on the assumptions made in calculating them. - Localisation energies have been calculated for pyrazole and pyrazolium, and also an attempt has been made to take into account the electrostatic energy involved in bringing the electrophile up to the point of attack the model predicts correctly the orientation of nitration in pyrazolium. ... 

The general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should be consulted as some of the conclusions reported therein are germane to this discussion. Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation, etc.). Pyrazole cations, formed in strong acidic media, show a pronounced deactivation (nitration, sulfonation, Friedel-Crafts reactions, etc.). For the same reasons quaternary pyrazolium salts normally do not react with electrophiles. 

Like 1,3-azoles, due to the presence of a pyridine-like nitrogen atom in the ring, 1,2-azoles are also much less reactive towards electrophilic substitutions than furan, pyrrole or thiophene. However, 1,2-azoles undergo electrophilic substitutions under appropriate reaction conditions, and the main substitution takes place at the C-4 position, for example bromination of 1,2-azoles. Nitration and sulphonation of 1,2-azoles can also be carried out, but only under vigorous reaction conditions. 

The presence of three heteroatoms in the azole ring reduces its reactivity in electrophilic substitution reactions more. 1,2,3-Triazole itself could not be nitrated [240], An attempt to introduce a nitro group into the heterocyclic ring 1-phenyl- and 4-phenyl-... 

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