1.2- Azoles electrophilic substitution

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. ... 

Electrophilic substitution occurs readily in Af-phenyl groups, e.g. 1-phenyI-pyrazoIes, -imidazoles and -pyrazolinones are all nitrated and halogenated at the para position. The aryl group is attacked preferentially when the reactions are carried out in strongly acidic media, where the azole ring is protonated. 

Imidazo[ 1,2-e]thiazoles biological activity, 6, 1024 reactions, 6, 1041 synthesis, 6, 1048 Imidazo[2, l-6]thiazoles electrophilic substitution, 6, 979 synthesis, 6, 992, 993, 1010, 1018 Imidazo[3,l-6]thiazoles synthesis, 6, 986 Imidazo[5,l-6]thi azoles biological activity, 6, 1024 synthesis, 6, 1017 Imidazo[2,l-6]thiazolium chloride synthesis, 6, 1013... 

It should be expected that the orientation and rate of electrophilic substitution in the isoxazole nucleus would be affected by both hetero atoms. Because of the electron-accepting effect of the nitrogen atom, electrophilic substitution of the isoxazole nucleus should proceed less readily than in the case of benzene and should occur essentially at the position jS to the nitrogen atom, just as in pyridine and other azoles. Simultaneously the electron-donating oxygen atom should facilitate such reactions in isoxazole as compared with the substitution in pyridine. These predictions are confirmed by the available experimental evidence. 

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... 

Imidazole is a n-electron-excessive heterocycle. Electrophilic substitution normally occurs at C(4) or C(5), whereas nucleophilic substitution takes place at C(2). The order of reactivity for electrophilic substitution for azoles is ... 

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. 

Like other 7r-excessive heterocycles9 (e.g., azoles), the main reactions of azapentalenes are electrophilic substitutions at electron-rich centers (nitrogen or carbon atoms) in the molecule. 

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. 

The presence of a pyridine-like nitrogen in the 1,2-azoles makes them markedly less reactive towards electrophilic substitution than furan, pyrrole, and thiophene. (The same effect was noted for the 1,3-azoles in Chapter 3.) Nevertheless, electrophilic substitution is known in 1,2-azoles, occurring principally at the C4 position. This selectivity is reminiscent of pyridine chemistry where the position meta to the electronegative nitrogen atom is the least deactivated (see Chapter 5). 

Nevertheless, this collection of heterocycles does share certain characteristics. The trend we have seen of decreasing tendency towards electrophilic substitution on going from furan, pyrrole, and thiophene to the azoles is continued into these series. The presence of additional pyridine-like nitrogen atoms renders these systems particularly electron-deficient, and electrophilic substitution is of little importance. 

So far little information is available on electrophilic substitution reactions these are mainly expected to occur in the azine ring when activated by electron-releasing substituents. Nucleophilic substitution reactions, however, occur readily in either ring. The N—S bond may be cleaved by nucleophilic attack at sulfur and this may be the preferential reaction path in some cases. The N—S bond may also be cleaved as a result of proton abstraction from the azole ring. 

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. 

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-... 

Although Fricdel-Crafts alkylations and acylations will not take place with imidazoles (Lewis acid catalysts deactivate the azole), it is possible to introduce some acyl and aroyl groups at C-2 by what is essentially an electrophilic substitution reaction. The conditions used arc modified Schotten-Baumann conditions in which an acyl or aroyl halide reacts with a 1-substituted imidazole in acetonitrile solution in the presence of triethylamine [15-17]. 

In the application of theoretical studies to the azole field many of these have attempted to achieve comparisons within the range of azole molecules. Thus, calculations of electron densities, dipole moments, and energies of formation give values that reflect the decrease in azole stability as the number of nitrogen atoms increase. ° Good correlations between a and total electron densities and and chemical shifts have been obtained. " Calculations (SCF) of n-electron distributions for the ground state of imidazole do not take into account the tautomeric equivalence of the 4-and 5-positions, but predict the order of electrophilic substitution as 5 > 2 > 4242,243 Various other quantum-mechanical calculations have... 

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