Pyridine hydroxypyridine-pyridone tautomerism

A variety of spectroscopic evidence, notably UV-Vis spectroscopy, has been used to determine the tautomeric equilibria in substituted 2-hydroxypyridines <2002ARK198>. Electron-donating substituents favor the hydroxy-pyridine form, while electron-withdrawing substituents favor the pyridone form Hammett analysis of the substituent effects gives a p value of -4. The effect of solvent in this case is not as marked, with polarity being of greater significance than proticity. 

It was first necessary to define the species of the heterocycle entering into reaction under any particular set of conditions. For example, basic molecules such as pyridine could react as free base or conjugate acid, whereas a potentially tautomeric compound such as 4-pyridone could react as such, or in the other tautomeric form (4-hydroxypyridine), or as the conjugate acid or base. 

In an ab initio study of the tautomerism of 2- and 4-hydroxy-pyridines, 4,-hydroxypyridine was calculated to be 2.4 kcal/mol more stable than 4-pyridone. 2-Pyridone was calculated to be 0.3 kcal /mol more stable than 2-hydroxypyridine and this is in good agreement with experimental values obtained from tautomeric studies in the gas phase.61 A study of the bromination of the 2-pyridone/2-hydroxypyridine system has revealed that reaction occurs via the principal "one" tautomer at pH<6 and via the conjugate anion at pH>6. Attack on the "one occurs preferentially at the 3-position, whereas on the anion it probably occurs mainly at the 5-position. The facile formation of 3i5-dibromo-2-pyridone results from the comparable reactivity of the monobromopyridones at pH<1 and pH>4- Practical procedures have been reported for the preparation of 3-bromo-2-pyridone and... 

Pyridone 1 [pyridin-2(l//)-one] and 4-pyridone 2 [pyridin-4(l//)-one] are tautomeric with the corresponding 2- and 4-hydroxypyridines, respectively. 

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. 

Proton resonance spectroscopy has been used to study the tautomerism of 4-hydroxypyridine and its 1-oxide, with results in agreement with those obtained by other physical methods discussed here. Resonance spectroscopy also indicated that the cations of 4-hydroxypyridine, 1-methyl-4-pyridone and 4-methoxypyridine are of the type (32), that of 4-hydroxy-pyridine 1-oxide as (33), and that 2-pyridone cation is protonated on... 

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