Heterocyclic Chemistry at a Glance, Second Edition. John A. Joule and Keith Mills.
© 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.
Introduction
The 1,2- and 1,3-azoles each contain a nitrogen in an environment analogous to that in pyridine, that is, an imine
nitrogen with a lone pair of electrons in an sp^2 orbital in the plane of the ring and not involved in the aromatic sextet.
Each also has another heteroatom in the environment of the nitrogen in pyrrole, the sulfur in thiophene, or the oxygen
in furan, with a pair of electrons in a p orbital orthogonal to the ring and part of the aromatic sextet. Consequently,
the chemical reactions of the azoles present a combination and mutual interaction of the types of reactivity typical of
pyridine on the one hand and of pyrrole, thiophene and furan on the other.
Electrophilic addition to N
The imine (pyridine-like) nitrogen has fi rst call on electrophiles. The azoles are basic and react with acids to form azo-
lium salts. The second heteroatom has a substantial effect on the basicities. Considering fi rst imidazole and pyrazole,
addition of a proton produces species in which the positive charge is shared equally between the two nitrogens – there
are two exactly equivalent resonance structures. Consequently, imidazole and pyrazole are the strongest bases in their
respective trios. Inductive withdrawal means that replacing the NH of imidazole and pyrazole with the more electron-
egative sulfur or oxygen reduces the basicity of the imine nitrogen. Additionally, the linking of one electronegative
atom directly to another further reduces basic strength, cf.NH 3 (pKaH 9.3) versus NH 2 NH 2 (7.9) versus NH 2 OH (5.8),
thus each 1,3-azole is a stronger base than its 1,2-counterpart.
The azoles react at the imine nitrogen with alkyl halides, pyrazole and imidazole the fastest in their trios, the sul-
fur-containing heterocycles faster than the oxygen-containing heterocycles and the 1,3-azoles much faster than the
1,2-azoles, that is, the relative nucleophilicities are similar to the relative basicities.