34 Pyridines
Electrophilic substitution at carbon
The electronic structure of pyridine (page 5) involves mesomeric transfer of electron density from C-2(6) and C-4
to the nitrogen and this, combined with inductive withdrawal of electron density by the heteroatom, results in over-
all electron defi ciency at all carbons, but particularly at C-2(6) and C-4 (the - and -positions). Thus pyridine,
as an electron-defi cient aromatic compound, is intrinsically much less susceptible to electrophilic attack at carbon
than is benzene. Additionally, there is also a second, more important factor, in that attempted substitution with
all electrophiles initially generates N-substituted pyridinium species by addition of the electrophile (or a proton
in acidic conditions) to nitrogen, in which the normal polarisation is greatly enhanced, so that the possibility for
electrophilic attack at carbon is suppressed even more. Thus, substitution requires either attack by the electrophile
on a positively charged pyridinium ring or attack on a small concentration of the free pyridine in equilibrium with
the pyridinium species.
The regiochemistry of electrophilic substitution is a refl ection of the relatively higher destabilisation of intermediates
for- and -attack due to very unfavourable delocalisation of the positive charge onto nitrogen – this is avoided in the
intermediate for -attack.
When electrophilic substitutions of simple pyridines are successful, they require very vigorous conditions and proceed
only at C-3, which is the least deactivated position. A miniscule yield of 3-nitropyridine using the standard nitrating
mixture applied at an outrageously high temperature, and the vigorous conditions necessary to produce 3-bromopyri-
dine illustrate this well (a practical conversion of pyridines into 3-nitropyridines is described on page 37).
The Friedel–Crafts alkylation/acylation reaction for the introduction of carbon substituents, which is so important
in benzene chemistry, is not applicable at all to pyridines – pyridines form strongly bound complexes with the typi-
cal Lewis acid catalysts (e.g. AlCl 3 ), which totally resist electrophilic C-substitution. This propensity for the pyridine
nitrogen lone pair to interact with metal centres has been very widely exploited in coordination chemistry, particularly
where two such nitrogens can be brought to bear, for example in 2,2'-bipyridine or 1,10-phenanthroline. The structure
of one enantiomer of a typical complex, Ru(phen) 3 I 2 , is shown.