6-Substituted 2-hydroxypyridines tautomerism

Substitution of hydroxy groups into a pyridinone constitutes a special case, because now alternative tautomeric structures can arise. Glutaconamide, for example, can exist in any of five structures (179), (180), (181), (182) and (183), of which the first three predominate. Again, the situation has been admirably discussed previously (76AHC(Sl)7l), as has the tautomeric situation in 3-hydroxypyridines (184) and (185) and in 3-hydroxypyridine... 

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. 

A comparison of the 1H and 13C NMR spectra for a series of N- and 0-acyl substituted 2-hydroxypyridines allows unambiguous distinction between isomeric N-and/or O-substituted derivatives on the basis of 13C chemical shifts and, thus, use of this method as a tool for tautomeric equilibrium studies (84T4067). H- H coupling constants are used to determine the major tautomeric structure in 2( 1 //)-pyridone/2-hydroxypyridine equilibrium (83JST(94)163). 

The tautomeric equilibrium in solution could be shifted by changes in the physical conditions or by additives increasing the medium polarity or complexing with the tautomeric substrate. For example, the equilibrium constant KT — (oxo)/(hydroxy) for unsubstituted 2-hydroxypyridine interconversion in supercritical fluids (1,1-di-fluoroethane at 403 K) increases 4-fold for a pressure increase of 40 bar and, thus, can be adjusted over a continuum from gas-phase values to those encountered in polar solvents isothermally over a relatively small pressure change (89JPC4297). An increase in the temperature of a substituted 2-pyridone in aq. THF shifts the equilibrium toward the hydroxy form (02MI198). 

Hydroxypyridine (201) itself possesses latent 1,3-dipolar character because of tautomerism involving 1-protiopyridinium 3-oxide (202). Aprotic diazotization of anthranilic acid in the presence of 201 gives two heterocyclic products [196 (20%) and 203 (23%)] which were isolated in separate experiments run under almost identical conditions.103,105 Formation of the bis-adduct 196 must involve cycloaddition of benzyne to 202 and N-phenylation and there is some evidence from related additions to 2//-phthalazin-1 -one (208) that the steps occur in this order.3 7b Formation of the isocoumarin structure 203 apparently involves electrophilic substitution of 201 by the benzyne precursor 5, followed by lactonization. From 3-hydroxy-6-methylpyridine compounds analogous to 196 and 203 were also obtained (10 and 29%, respectively). 3-Hydroxyquinoline afforded only the corresponding isocoumarin 204 (20%) whereas 4-hydroxyisoquinoline gave 4-phenoxyisoquinoline (12%) and the bis-adduct 205 (12%) with benzyne.103,105... 

Next, the substituent effect on the tautomeric preference should be considered. For example, ortho-derivatives of pyridine with substituents which have an acidic proton may participate in prototropic tautomerism (Scheme 12 2002A(11)198). Stabihty of the particular tautomeric form depends on an additional substituent and intermolecular H-bonding (Scheme 13). Moreover, tautomeric preferences can be changed by a solvent. For 6-X substituted 2-hydroxypyridines, the tautomeric equihbrium is stron y affected by substituents which can change the Tt-electron structure of fragments involved in the prototropy. For example, it was found that 2-hydroxy-6-chloro-and 2-hydroxy-6-methoxy-pyridines exist mainly in the aromatic form a... 

In an Initio study of the tautomerism of 2- and -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.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 3f5-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 3,5-dibromo-2-pyridone Cycloaddition of 2-substituted pyridinium betaines with unsymmetrical alkenes gives products of mixed orientation for example, treatment of (40) with methyl... 

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