10 Common Reaction Types in Heterocyclic Chemistry
Table 3.1 Table of pKaH and pKa values of some typical heteroaromatic ring systems.
Note: The pKa values for the aromatic N-hydrogen heterocycles all fall within the range where, under aqueous basic conditions, they would be partly
or fully deprotonated.
Electrophilic substitution of aromatic molecules
The majority of heterocycles dealt with in this book are aromatic and so, as in benzene chemistry, they are subject to
substitution reactions with electrophiles – some less easily than benzene and some more easily. All electrophilic substi-
tutions of aromatic molecules proceed via a two-step sequence: (i) addition of the electrophile to a favoured carbon
forming a non-aromatic, though delocalised, cation, then (ii) loss of the proton attached to that carbon, returning the
system to an aromatic status. This is described as ipso substitution – the electrophile ends up on the same carbon as
the hydrogen that it displaces. Usually, the fi rst step is the slower (rate-determining) step, because an aromatic starting
molecule has to lose some delocalisation energy in forming the intermediate; the corollary is that the second step is fast
because the system is regaining aromaticity.
In the remaining chapters, chemical schemes that include electrophilic substitutions do not explicitly show the cationic
intermediate or the aromatising loss of a proton, but the two-step nature of the process must always be kept in mind.
Ipso displacement of groups other than hydrogen can also occur, for example of CO 2 H. In the present context the most
important examples are displacements of trialkylsilyl groups – indeed electrophilic ipso displacement of silicon is actu-
ally favoured over substitution of hydrogen so that trialkylsilyl groups can be used as blocking groups, to be removed
selectively by protonolysis (El H) when they have served their purpose, as in the scheme below (for a discussion
of C-metallation see pages 16–17).