Nitration, of azoles

Much of the work on nitration of azoles has concerned the phenyl derivatives. These substitute in the phenyl ring at positions that depend on the reaction conditions and the relationship of the phenyl ring to the heteroatoms. Preferential nitration in the phenyl ring does not necessarily mean that the azole is intrinsically less reactive than benzene, because the phenyl ring may be strongly activated by one of the heteroatoms whereas the azole is relatively weakly activated by the phenyl group. The combination of bond-order effects and relationship to the heteroatom means that the preferred sites of substitution are as shown by arrows in structures 7.37-7.42. The effect of protonation is discussed later. 

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. 

Kinetics and Mechanism of Nitration of Azoles by Sulfuric-Nitric Acid Mixture... 

Determination of the mechanism of nitration of azoles is complicated by the fact that they can be nitrated both in the free form and in the protonated form. The kinetics of the nitration of azoles in media with various acidities is therefore compared with the kinetics of the nitration of related model compounds known to exist in the form of ions (e.g., the quaternary salt of the investigated azole). If nitration takes place through the protonated form, the rate initially increases with increase in the acidity on account of the increase in the concentration of the nitronium ion. After reaching a maximum the rate then remains almost unchanged or decreases slightly. 

The kinetics and mechanism of the nitration of azoles have been studied in a fan-amount of detail [56-60, 64, 70, 75, 76, 184, 193, 205, 207, 208, 210, 211, 251, 282-287], The reactivity of various mono- and dialkylthiazoles compared with benzene was studied by the competing nitration method (Table 2) [207],... 

Similar results were obtained during the nitration of 2-methoxythiazole [289], Katritzky et al. proposed the use of so-called standardized rate constants (k2°), obtained during the nitration of various aromatic heterocycles by nitric acid in 75% sulfuric acid at 25°C (H0 - 6.6) [59], These constants make it possible to compare quantitatively the reactivity of various types of heterocyclic compounds in nitration. The calculated standardized rate constants for the nitration of azoles are given in Table 4. 

Table 4 Standardized rate constants for the nitration of azoles... 

During the nitration of azoles with an unsubstituted pyrrole heteroatom under these conditions it is often possible to isolate the A-nitroazoles. Thus, with acetylnitrate in glacial acetic acid it was possible to obtain A-nitropyrazoles [63,307-317], A-nitro-1,2,4-triazoles [318, 319], and A-nitro-1,2,4-triazolon-5 [264] (Scheme 33). 

The kinetics of the nitration of azoles by acetylnitrate has not been studied systematically. Mention has only been made of the complex nature of the reaction kinetics and the low yield of the nitration products, which hinders correct interpretation of the results [56],... 

Table 5 Nitration of azoles with HN03/(CF3C0)20...

For a long time it was considered that the only method for the production of /V-nitroazoles was the nitration of azoles with acetylnitrate. Comparatively recently it was found that 4,4-dibromo-4//-pyrazoles form 3,5-disubstituted 4-bromo-l-ni-tropyrazoles with the complex of silver nitrate and trimethyl phosfite. 4-Bromopyrazole derivatives are formed as impurities [595] (Scheme 116). 

Therefore, in spite of the great number of studies devoted to the nitration of azoles, the interest in this issue has never waned. This is mainly because many nitroazoles are of great practical value. Mechanistic aspects of the Further extensive research of the kinetics and mechanism of the nitration of azoles, especially with novel nitrating agents, is desired. It should be expected that the (V-nitropyrazoles will find ever increasing use as nitrating agents. 

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. 

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