14 Common Reaction Types in Heterocyclic Chemistry
In the context of heteroaromatic reactivity, the group that both encourages addition and accepts responsibility for the
negative charge in the intermediate is normally a ring imine (C=N) and halide is the group normally ipso displaced.
Typical conditions for replacement of halogen can be seen in the following examples.
Using strong nucleophiles, even hydrogen can be displaced in some cases. Addition to an unsubstituted imine carbon
occurs, giving a relatively stable dihydro intermediate. Further reaction with an oxidising agent may be required to
remove the H, leading to re-aromatisation.
Radical substitution of heterocycles
The Minisci reaction: addition of nucleophilic radicals
Although many reactions of (carbon) radicals with heterocycles are of only academic interest, one of these processes –
the Minisci reaction – is of signifi cant practical use with electron-defi cient heterocycles, most prominently pyridines
and quinolines, but also other systems that have an imine unit.
Although radicals are neutral species, they do have degrees of polarisation, and a number exhibit signifi cant nucle-
ophilic character and are capable of adding to heterocycles with imine units. As a ‘rule of thumb’, one can say that if the
notional removal of the lone electron from a radical would generate a particularly stabilised carbonium ion, then that
radical would be expected to be nucleophilic. This leads to an interesting, very useful, contrast with normal reactivity,
for example acyl radicals are very good nucleophiles, whereas acyl reagents are more usually encountered as acyl cati-
ons in the Friedel–Crafts reaction. Similarly, t-butyl radicals are much better nucleophiles than methyl radicals, in fact
methyl radicals are often used to generate other, more nucleophilic, radicals via H-abstraction.