2-Hydroxy-6-methyl-pyridines tautomerism

Table 11 summarizes the main results on the tautomerism of mono-hydroxy-, -mercapto-, -amino- and -methyl-azines and their benzo derivatives, in water. At first sight the equilibrium between 2-hydroxypyridine (71) and pyridin-2-one (72) is one between a benzenoid and a non-benzenoid molecule respectively (71a 72a). However, the pyridinone evidently... 

Pyridin-4-one, 1 -hydroxy-2,6-dimethyl-hydrogen-deuterium exchange reactions, 2, 196 Pyridin-4-one, 1-methyl-hydrogen-deuterium exchange, 2, 287 pK 2, 150 Pyridin-2-one imine tautomerism, 2, 158 Pyridin-2-one imine, 1-methyl-quaternization, 4, 503 Pyridin-4-one imine tautomerism, 2, 158 Pyridinone methides, 2, 331 tautomerism, 2, 158 Pyridinones acylation, 2, 352 alkylation, 2, 349 aromaticity, 2, 148 association... 

Pyrrolo[3,2-c]pyridine, 4-hydroxy-tautomerism, 4, 500 Pyrrolo[3,2-c]pyridine, 2,3,3-trimethyl-methylation, 4, 513 Pyrrolo[3,4-6]pyridine, 2-methyl-UV spectra, 4, 501 Pyrrolo[3,4-c]pyridine, 2-methyl-UV spectra, 4, 501 Pyrrolopyridines acylation, 4, 504 bromination, 4, 505 diazo coupling, 4, 506 NMR, 4, 498... 

In comparison with mercapto-, hydroxy-, and amino-pyridines, methylpyridines should show an even greater tendency to exist in the methyl form [instead of as pyridmethines (297)] than do the amino compounds to exist as such. If the methyl carbon atom carries an electron-withdrawing group, it might be expected that structures of type 297 would be stabilized. Fused benzo groups should also tend to stabilize the methine form, and tautomerism involving 298 has, in-... 

Finally, we note that Karelson et al. [295] have used the D02 model with small cavity radii to consider aqueous solvation effects on other tautomeric equilibria of substituted pyridines. In particular, they examined methyllmethylene, amino/imino, hydroxy/oxo, and mercapto/thiono substitution at the 2-, 3, and 4-positions of pyridine. They observed methyl/methylene equilibria to be only slightly perturbed by aqueous solvation. Amino/imino equilibria were slightly more perturbed, followed by hydroxy/oxo equilibria. Mercapto/thiono equilibria were very significantly affected by aqueous solvation Karelson et al. predicted pK shifts of up to 16 units. This sensitivity of the thiono group to solvation is also discussed in the next section. Overall, the tautomeric equilibria of 3- and 4-substituted pyridines were more sensitive to aqueous solvation than were those of 2-substituted pyridines. 

Table 11 summarizes the main results on the tautomerism of mono-hydroxy-, -mercapto-, -amino- and -methyl-azines and their benzo derivatives, in water. At first sight the equilibrium between 2-hydroxypyridine (71) and pyridin-2-one (72) is one between a benzenoid and a non-benzenoid molecule respectively (71a 72a). However, the pyridinone evidently has a continuous cyclic p- orbital system, containing six it- electrons, the usual aromatic count, if the carbonyl group contributes none. This assumption implies the formula (72b), from which by redistribution of electrons we arrive at (72c), which has the same benzenoid system as (71a). Further canonical forms (71b, 71c) can be drawn of (71) which correspond to the non-benzenoid forms of (72). The elusive property of aromaticity is therefore possessed by both tautomers, although not necessarily by both equally. When the carbonyl oxygen of (72) is replaced by less electronegative atoms, as in the imine tautomers of amino heterocycles, or the methylene tautomers of methyl derivatives, the tendency towards polarization in forms corresponding to (72b) and (72c) is considerably less, and the amino and methyl tautomers are therefore favoured in most instances. 

The PE spectra of hydroxy- and mercapto-pyridines have been examined, together with the model iV-alkyl and S- or O-alkyl compounds, to elucidate the tautomeric equilibria in the vapor phase (77JCS(P2)1652) (Section 2.04.4.2). Figure 21 and Table 13 show details of the PE spectra of l-methylpyridin-2-one, 2-methoxypyridine and the tautomeric mixture at equilibrium of pyridin-2-one and 2-hydroxypyridine. This indicates that there is approximately 25% of oxo form present once adjustment has been made for the expected influence of methylation, similar measurements reveal ca. 10% of the thione form in the mercapto-thione equilibrium. Other spectra indicate that 3- and 4-hydroxy- and 3- and 4-mercapto-pyridine exist in the vapor phase with less than 5% of the alternative tautomer present. 

Methylation of 6-chloro-4-hydroxy-3-methylisothiazolo[5,4-6]pyridine (200) with ethereal diazomethane for 13 h gave the 4-methoxy derivative (201) (93%) <90JCS(P1)1477>. None of the 7-methyl derivative was observed in the reaction, indicating that compound (200) exists almost exclusively as the 4-hydroxy tautomer and that the tautomeric 6-chloro-3-methylisothiazolo[5,4-6]pyridin-4-one (202) does not contribute significantly to the equilibrium. 

Among examples of lactam-lactim tautomerism pyridine derivatives 98a, 98b, and 100 have been proven to be pyridones on the basis of their IR spectra, whereas UV and IR spectra suggest the aminopyridine structure 101 (63BCJ633). Spectral data similarly confirm the existence of substance 31a (Scheme 57) in the 4-hydroxy-2-pyridone form rather than the 2,4-dihydroxypyridine form 234 (74BCJ1750). Consequently, its acetylation by acetic anhydride/pyridine at 130 °C or methylation yield N,0-disubstituted derivatives 235a and 235b, respectively. Acetylation at 100 °C, however, leads to 0,0 -disubstitution (236). 

A comprehensive theoretical smdy of some pyrazolones has been presented. The predicted tautomeric equilibrium constants of these compounds were found to be in good agreement with existing experimental data, indicating that the oxo tautomers are present in aqueous solution whereas, in the main, the hydroxy tautomers predominate in the gas phase. It has been shown that, in solution, the most abundant tautomer of both l-(2, 4 -dinitrophenyl)-3-methyl-2-pyrazolin-5-one and its 1-phenyl derivative is dependent on the solvent used, while an NMR study of a number of l(2)//-dihydropyrazolo[3,4-fc]pyridin-6-ones has revealed that they all exist as 2//-tautomers both in solution and in the solid state. DFT and ab initio calculations have been carried out to investigate the stability of different tautomers of 2-hydroxy- and 2,3-dihydroxy-pyrazine in the gas phase and in different media. The data obtained indicated that 2-hydroxypyrazine is more stable than its 2-keto tautomer in the gas phase, whereas in solution the stability order is reversed. For 2,3-dihydroxypyrazine it appears that the intramolecular hydrogen-bonded hydroxyoxo and the a-diketo tautomers are the most stable species at all theoretical levels in the gas phase. Both spectroscopic and theoretical studies of the tautomerism of 2,1,3-benzothiadiazinone 2,2-dioxides and other related fused heterocyclic amides have predicted that the keto form (415) is the most abundant tautomer in the gas phase, whereas the NH hydroxy form (416) is the preferred tautomer in solution and in the solid state. 

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... 

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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