110 1,2-Azoles and 1,3-Azoles
4-Halopyrazoles are accessible directly from the heterocycle, as are 4-bromoisothiazole and 4-bromoisoxazole, though
less effi ciently.
Electrophilic substitutions with carbon electrophiles, as in Friedel–Crafts processes, are virtually unknown in azole
chemistry except where there is a strong activating group already present. Electrophilic substitution takes place ortho
to an amino- or acylamino-substitutent.
Nucleophilic substitution of halogen
The 2-position in 1,3-azoles is formally analogous to the -positions of a pyridine and thus nucleophilic substitutions
of halide take place relatively easily, though most of the imidazole examples have N-1 blocked, that is, they do not have
an acidic hydrogen.
In principle, both 3- and 5-positions of an isothiazole are positions at which nucleophilic substitution is facilitated
by conjugation to the imine. In an interesting example, selective displacement of a 5-chloride occurs with the further
activation of an ortho nitrile substituent.
N-Deprotonation and N-metallated imidazoles and pyrazoles
Just as addition of a proton to pyrazole and imidazole generates symmetrical cations, and is therefore relatively
favoured, so the removal of an N-hydrogen generates symmetrical anions with two equivalent mesomeric forms, and
thus both imidazolyl and pyrazolyl anions are more stabilised than the pyrryl anion, that is, imidazole and pyrazole are
more acidic than pyrrole: imidazole pKa 14.2, pyrazole 14.2 and pyrrole 17.5.