1,2-Azoles and 1,3-Azoles 109Electrophilic substitution at C
In the sense that the azoles have a fi ve-membered heteroaromatic system, one might anticipate easy electrophilic
C-substitution, as in pyrrole, for example. However, the imine nitrogen inductively withdraws electrons and reduces
markedly the ability of these heterocycles to undergo electrophilic C-substitution compared with pyrrole, thiophene and
furan. A second important generalisation is that the 1,2-azoles are substantially less reactive than their 1,3-counterparts,
to the extent that some simple substitutions do not occur at all. Overall, the utility of electrophilic C-substitutions in
azole manipulation is distinctly less than for pyrrole, thiophene and furan.
The gradation of reactivity is well illustrated by nitrations. Imidazole undergoes normal nitration at room temperature
whereas thiazole itself is untouched by nitric acid–oleum at 160 °C. 2-Methylthiazole can however be nitrated, though
requiring a higher reaction temperature than does imidazole. Oxazoles do not undergo nitration. The orientation of
attack on 2-methylthiazole is signifi cant: both 4- and 5-substituted products are formed but with the latter predomi-
nating. Note that the isolation of 4-nitroimidazole from nitration of imidazole does not necessarily imply that attack is
at C-4 since in 4(5)-nitroimidazole the tautomeric equilibrium lies almost completely on the side of the 4-isomer. Each
of the 1,2-azoles can be nitrated, at C-4. It is important to remember, in making comparisons, that although pyrazole
and imidazole are more reactive than other azoles, they are also more basic, and in the strongly acidic media of typical
nitrating mixtures, there is a much smaller concentration of the neutral heterocycle available for attack and, depending
on conditions, the substitution may actually take place on the salt.
A comparable pattern of reactivity applies in halogenations: imidazole is brominated so easily that 2,4,
5-tribromoimidazole is formed without a catalyst and probably by a special mechanism in which the 2-bromine
is introduced as bromide anion. The 2- and 5-halogens can be easily reductively removed. The thiazole system
requires the activation of a 2-methyl to permit formation of 5-bromo-2-methylthiazole; oxazole has not been
directly halogenated.