Common Reaction Types in Heterocyclic Chemistry 13Halogenation
Five-membered aromatic heterocycles are suffi ciently reactive that the introduction of a halogen by electrophilic sub-
stitution can often be achieved using the halogen alone, that is without the Lewis acid catalyst usually required in ben-
zene chemistry. The indole example below illustrates both this intrinsically high reactivity towards electrophiles and
also selectivity over benzene ring substitution. On the other hand, six-membered nitrogen heterocycles are relatively
resistant to electrophilic substitution so halogenation of quinoline proceeds in the benzene ring.
Fluorine itself is highly reactive and diffi cult to handle, but several mild electrophilic fl uorinating agents are com-
mercially available, the most notable being various N-fl uoroamides (cf. N-bromo- and N-chlorosuccinimides) or
N-fl uoro-quaternary salts, for example NFSI and Selectfl uorTM.
Nitration
Here again, much milder conditions suffi ce for the substitution of fi ve-membered heterocycles than are required in
benzene chemistry. Also, many of the fi ve-membered heterocycles are not stable to the classical concentrated acidic
conditions. A device that can be used is the formation of the mixed anhydride of nitric acid and acetic acid, generated
by mixing acetic anhydride with nitric acid – this serves as a source of NO 2 via displacement of acetate.
Nucleophilic substitution of aromatic molecules
In benzene chemistry, nucleophilic substitution is the exception, rather than the rule. Again, a two-step sequence is
required: (i) addition of the nucleophile to a favoured carbon forming a non-aromatic, though delocalised, anion, then
(ii) loss of the substituent attached to that carbon, returning the system to an aromatic status. There must be a group
present to facilitate the addition of the nucleophile, that is the group must be capable of stabilising a negatively charged,
non-aromatic intermediate; in benzene chemistry this group is usually ortho- or para-nitro. Further, the substituent
that is ipso displaced must be capable of departing carrying a negative charge – normally halide. This type of transfor-
mation is generally referred to as an addition/elimination process.