Electrophilic aromatic substitution 1,3-azoles

In 1,2-type azole N-oxides, the 3- and 5-positions are activated toward electrophilic aromatic substitution since attack at these positions gives rise to intermediates 17 and 21 in which only one positive charge remains while attack at C4 would lead to an intermediate 19 with three charges (Scheme 4). 

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. 

The mechanisms of the electrophilic substitutions in the isoxazole nucleus have not yet been studied. They should not differ fundamentally from those usually accepted for the substitution of aromatic systems but the structural specificity of the isoxazole ring might give rise to some peculiarities, as recently specially discussed.One important point is that isoxazole shows a clearcut tendency to form coordination compounds. Just as pyridine and other azoles, isoxazoles coordinate with halogens and the salts of heavy metals, for example of cadmium,mercury,zinc. Such coordination... 

Leonid Belen kii was born in Moscow, and he graduated from M. V. Lomonosov Moscow State University in 1953 with Professor A. P. Terentiev as supervisor in organic chemistry. Since 1955, he has worked as junior, senior (since 1966), and leading scientist (since 1988) at N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, where he obtained his Ph.D. degree (1963) under the direction of Professor Ya. L. Gol dfarb and his Degree of Dr. Chem. Sci. (1974) and rank of Professor in Chemistry (1991). His scientific interests include all aspects of chemistry of heterocyclic and aromatic compounds, particularly electrophilic substitution in benzene, thiophene, furan, and azole series as well as organosulfur chemistry. 

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 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. 

Electrophilic substitution in the azoles is intermediate in facility between pyridine on the one hand and pyrroles, thiophenes and furans on the other the presence of the electron-withdrawing imine unit has an effect on the flve-membered aromatic heterocycles just as it does when incorporated into a six-membered aromatic framework, i.e. the comparison is like that between benzene and pyridine (Chapter 7). The order of reactivity - pyrrole > furan > thiophene - is echoed in the azoles, though the presence of the basic nitrogen complicates such comparisons. The regiochemistry of electrophilic attack can be rationalised nicely by comparing the character of the various ring positions - those that are activated in being flve-membered in character and those that are deactivated by their similarity to a- and y- positions in pyridine. 

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