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
This book is principally concerned with the chemistry of aromatic heterocycles, but there are many other heterocycles,
including those with three- and four-membered rings, that are not aromatic. We devote comparatively little space to
these because their reactions are very similar to those of acyclic analogues – the reactions of piperidine or pyrrolidine,
for example, are exactly like those of any secondary dialkylamine. Small-ring heterocycles (three- and four-membered)
have reactivities associated with relief of the strain inherent in their structures, when the ring is opened.
Some saturated heterocycles are widely used as solvents for organic reactions, notably tetrahydrofuran (THF) and
1,4-dioxane (often referred to simply as ‘dioxane’), which are inert, ethereal-type solvents. N-Methylpyrrolidone
(NMP) and sulfolane are useful dipolar aprotic solvents, with characteristics like those of dimethylformamide (DMF)
and dimethyl sulfoxide (DMSO). Saturated and partially unsaturated heterocycles occur widely as components of
natural product structures.
Three-membered rings
Aziridines, oxiranes and thiiranes are well-known stable compounds. Oxiranes (epoxides) and aziridines are widely-
used intermediates in general synthesis. 1H-Azirines only occur as reactive intermediates but 2H-azirines, by contrast,
are well-known stable compounds.
The pKaH of aziridine (7.98) shows it to be an appreciably weaker base than the four-membered azetidine (11.29). The
explanation is probably associated with the strain in the three-membered compound, meaning that the lone pair is
in an orbital with less p-character than a ‘normal’ sp^3 nitrogen orbital, and is therefore held more tightly. The rate of
pyramidal inversion of the saturated nitrogen in aziridines is very slow compared with simpler amines. This is because
there is a further increase in angle strain when the nitrogen rehybridises (→ sp^2 ) in the transition state for inversion.
The main chemical reactions of three-membered heterocycles are a direct consequence of the strain inherent in such
small rings, which, combined with the ability of the heteroatom to act as a leaving group, means that most of the chemical
proper ties involve ring-opening reactions. Most epoxide ring-openings occur by SN2 nucleophilic displacements at carbon
and a very wide range of carbanion and heteroatom nucleophiles have been shown to react in this way, including amines,