Pyridines 35In contrast to what has been explained above, the presence of activating (electron-releasing) substituents such as amino
and hydroxyl (or the tautomeric pyridones – see page 41) allows standard electrophilic substitutions in a pyridine ring
to be carried out under relatively mild conditions. The usual ortho/para directing effects of these substituents operate
so that, for example, chlorination of 1-methyl-2-pyridone proceeds at the available positions ortho and para to the
oxygen. One may alternatively view electrophilic substitutions of pyridones as involving attack at the -position of the
enamine (or dienamine) units in these molecules – as suggested by the arrows on 4-pyridone below.
It is a curious fact, but with little theoretical rationale, that electrophilic substitutions of pyridines carrying an acti-
vating substituent at C-3, generally occur at C-2 rather than C-4/C-6, as exemplifi ed by the iodination and Mannich
substitution of 3-hydroxypyridine. This selectivity is also found in nucleophilic substitution of 3-substituted pyridines.
Nucleophilic substitution
Pyridine is susceptible to addition of nucleophiles at the - and -positions due to delocalisation of the negative charge
onto nitrogen in the intermediate anion thus produced. This process is very similar to the addition of nucleophiles to
the carbonyl carbon of a ketone or the -position of an ,-unsaturated (conjugated) ketone. In intermediates that
would result from nucleophilic addition at a -position, the nitrogen cannot directly assist the delocalisation.
Substitution of hydrogen
Simple pyridines react with strong nucleophiles such as sodium amide, or alkyl- or aryllithiums, under forcing condi-
tions, with elimination of hydrogen in the former case and lithium hydride in the latter, resulting in the formation of
2-amino-, 2-alkyl- or 2-arylpyridines, respectively. The intermediate 1,2-dihydropyridines from alkyl- and aryllithi-
ums can also be re-aromatised by oxidation – simply with air or oxygen. These nucleophilic substitutions of hydrogen
usually occur at C-2, probably because the reagents coordinate with the pyridine nitrogen in the relatively non-polar
conditions and then the nucleophile is delivered selectively to the -position by an intramolecular process.