Heterocycles with More than Two Heteroatoms: Higher Azoles (5-Membered) and Higher Azines (6-Membered) 1331,2,3-Triazoles are remarkably stable, considering that they contain three directly-linked nitrogens, and will generally
withstand temperatures greater than 150 °C. Tetrazoles usually are also surprisingly stable although tetrazole itself
(mp 158 °C, decomposes above180 °C) is classifi ed as an explosive, at least for shipping. The ring systems of these
azoles are very resistant to reduction.
Most of the relatively few known pentazoles (N-aryl derivatives) are unstable at room temperature – some are even said
to explode on reaching 10 °C.
Electrophilic substitution at carbon
The triazoles and tetrazole undergo electrophilic substitution under surprisingly mild conditions, considering the
electron-defi cient nature of the rings. Although some of these reactions on NH substrates are base-catalysed, and
therefore may proceed via the anion, N-alkyl compounds react similarly, so some mechanism other than that for
standard aromatic electrophilic substitution may be involved.
Nucleophilic substitution at carbon
Nucleophilic displacements occur with reasonable ease in N-alkylated compounds, that is, those lacking the acidic NH.
Sulfones are particularly good leaving groups for carbon nucleophiles.
N-Deprotonation and N-metallated triazoles and tetrazoles
N-Alkylation is one of the most important reactions of NH triazoles and tetrazoles, with control of regioselectivity being
a signifi cant problem, the proportions of regioisomers depending on substituents in the heterocyclic ring, the bulk of
the alkylating agent, and reaction conditions. The preparation of the pure regioisomers can be a signifi cant challenge.
Owing to their relatively high acidity, all these azoles can be readily alkylated in the presence of weak bases.
(Note: Many 1-substituted 1,2,3-triazoles and tetrazoles are actually readily available by direct ring synthesis, but the
2-substituted isomers are usually not accessible in this way and often depend on preparation via N-alkylation.)
1,2,3-Triazoles have some tendency to alkylate on N-2 but there is considerable variation in selectivity, although this
can often be controlled (by trial and error!) by choice of conditions, as exemplifi ed below.