Pyridones are good substrates for nucleophilic substitution
المؤلف:
Jonathan Clayden , Nick Greeves , Stuart Warren
المصدر:
ORGANIC CHEMISTRY
الجزء والصفحة:
ص728-729
2025-07-13
387
Pyridones are good substrates for nucleophilic substitution
The starting materials for these nucleophilic substitutions (2- and 4-chloro- or methoxypyri dines) are themselves made by nucleophilic substitution on pyridones. If you were asked to propose how 2-methoxypyridine might be made, you would probably suggest, by analogy with the corresponding benzene compound, alkylation of a phenol. Let us look at this in detail.
The starting material for this reaction is a 2-hydroxypyridine that can tautomerize to an amide-like structure known as a pyridone by the shift of the acidic proton from oxygen to nitrogen. In the phenol series there is no doubt about which structure will be stable as the ketone is not aromatic; for the pyridine both structures are aromatic.
In fact, 2-hydroxypyridine prefers to exist as the ‘amide’ because that has the advantage of a strong C=O bond and is still aromatic. There are two electrons in each of the C=C double bonds and two also in the lone pair of electrons on the trigonal nitrogen atom of the amide. Delocalization of the lone pair in typical amide style makes the point clearer. Pyridones are easy to prepare and can be alkylated on oxygen as predicted by their structure. A more important reaction is the direct conversion to chloropyridines with POCl3. The reaction starts by attack of the oxygen atom at phosphorus to create a leaving group, followed by aromatic nucleophilic substitution. The overall effect is very similar to acyl chloride formation from a carboxylic acid.
The same reaction occurs with 4-pyridone, which is also delocalized in the same way and exists in the ‘amide’ form, but not with 3-hydroxypyridine, which exists in the ‘phenol’ form. Its only tautomer is a zwitterion but the pyridine nitrogen is too weak to remove a proton from the hydroxyl group.
●Pyridines undergo nucleophilic substitution Pyridines can undergo electrophilic substitution only if they are activated by electron-donating substituents (see next section) but they readily undergo nucleophilic substitution without any activation other than the ring nitrogen atom.
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