2-Pyridone-2-hydroxypyridine tautomerization

Chou. P.-T, Wie, C.-Y. and Hung, F.-T. (1997) Conjugated dual hydrogen bonds mediating 2-pyridone/2-hydroxypyridine tautomerism. J. Phys. Chem. B, 101, 9119-9126. 

Pyridones and other six-membered compounds (functional tautomerism). The pyridone /hydroxypyridine tautomerism (76AHCS1, p. 87), especially 2-pyridone (15a)/2-hydroxypyridine (15b), has received more attention from theoreticians than any other example of tautomerism, probably in part because it is a simple model for biologically important molecules such as thymine, cytosine, and uracil (Scheme 8). 

Gas-phase studies where relevant tautomeric compounds are described are ihore scarce, but include uracil, thymine, and adenine [97CPL(269)39]. In the case of the 2-pyridone/hydroxypyridine equilibrium, the intensity of the OH and NH stretching vibrations was measured for eight temperatures in the range from 428 to 533 K in the gas phase. This allows determination otAH and AS for the equilibrium (92JPC1562). 

Repeat your analysis for tautomeric equilibria between 4-hydroxypyridine and 4-pyridone, 2-hydroxypyrimidine and 2-pyrimidone and 4-hydroxypyrimidine and 4-pyrimidone. For each, identify the favored (lower-energy) tautomer, and then use equation (1) to calculate the ratio of tautomers present at equilibrium. Point out any major differences among the four systems and rationalize what you observe. (Hint Compare dipole moments and electrostatic potential maps of the two pyridones and the two pyrimidones. How are these related to molecular stability )... 

It is well accepted that tautomerism relates to the equilibrium between two or more different tautomers e.g., it corresponds to determining if the structure of a compound is, for instance, a pyridone or an hydroxypyridine. The kinetic aspects are often neglected and when the tautomeric equilibrium constant, Kt, is equal to 1 (e.g., for imidazole), the problem may seem... 

Work under this classification (76AHCS1, p. 31) continues to be sparse. Heat-of-solution data provide a useful method for estimating A// for tautomeric processes in nonaqueous solvents, as was illustrated in the case of 2-pyridone 15a/2-hydroxypyridine 15b equilibrium (76TL2685). Heats of dehydration of 4-hydroxypyrazolines into pyrazoles and 5-hydroxyisoxazolines... 

Uracil, thymine, and cytosine have been studied using this technique (89JA2308 and references therein). For uracil and thymine, the dioxo tautomer predominates in the case of cytosine (70), three tautomers were detected, 70a, 70b, and 70c, the last one being the least abundant. The gas-phase tautomeric equilibrium of 2-pyridone 15a and 2-hydroxypyridine 15b has been studied by MW spectroscopy (93JPC46) using both a conventional spectrometer and a jet-cooled millimeter-wave spectrometer. The relative abundances are 3 1 in favor of the hydroxy form 15b, which exists in the Z conformation shown (Scheme 23). 

In a recent review [83], the present authors discussed the tautomeric equilibria of 2-hydroxypyridine/2-pyridone and the 5-(2//)-isoxazolone system in considerable detail, focusing on the application of several different continuum solvation models. The following presentation will be somewhat more broad in terms of the different equilibria discussed and will not recapitulate all of the analysis previously presented for the above two systems. 

Note, however, that we cannot get the same type of tautomerism with 3-hydroxypyridine. In polar solvents, 3-hydroxypyridine may adopt a dipolar zwitterionic form. This may look analogous to the previous structure, but appreciate that there is a difference. With 3-hydroxypyridine, the zwitterion is a major contribntor, and arises simply from acid-base properties (see Section 4.11.3). The hydroxyl gronp acts as an acid, losing a proton, and the nitrogen acts as a base, gaining a proton. The structure from 2-pyridone is a minor resonance form that helps to explain charge distribntion the compound is almost entirely 2-pyridone. 

We have seen that 2- and 4-hydroxypyridines exist primarily in their tautomeric amide-like pyridone forms (see Section 11.4.3). This preference over the phenolic tautomer was related to these compounds still retaining their aromatic character, with further stabilization from the carbonyl group. 3-Hydroxypyridine cannot benefit from this additional stabilization. In contrast, 2-aminopyridine and 4-aminopyridine exist almost entirely as the amino... 

Hydroxy- and 4-hydroxypyridines are in tautomeric equilibrium with isomers bearing a carbonyl group (Scheme 2.22). These are called 2- and 4-pyridones, respectively. The pyridone forms are favoured in ionic solvents and also in the solid state. 

The coordination behavior as well as the tautomerization equilibria of the new pyridone ligands was studied in detail by NMR and computational methods. For all three the data obtained strongly support a pseudo-bidentate hydroxypyridine-pyridone binding mode. 

The equilibrium constant for a tautomeric interconversion is simply the ratio of the mole fractions of the two forms for example, the ratio of enol to oxo forms of acetone12 in water at 25°C is 6.0 x 10 9, while that for isobutyraldehyde is 1.3 x ICE4. The ratio of 2-hydroxypyridine to 2-pyridone is about 10 3 in water but increases to 0.6 in a hydrocarbon solvent and to 2.5 in the vapor phase.13 14 The ratio of dipolar ion to uncharged pyridoxine (Eq. 2-5) is 4 at 25°C in water.15 The ratios of tautomers B, C, and D to the tautomer A of uracil (Eq. 2-4) are small, but it is difficult to measure them quantitatively.16 These tautomeric ratios are defined for given overall states of protonation (see Eq. 6-82). The constants are independent of pH but will change if the overall state of protonation of the molecule is changed. They may also be altered by... 

Selenium dioxide as a dehydrogenation reagent2 is capable of aromatizing the resulting nng to a 2-hydroxypyridine, which is present largely in its tautomeric form as pyridone 14 This product is not isolated, but is insLead immediately reacted further. 

The 2- or 4-hydroxypyridines [(81) and (82)] are tautomeric and in solution exist preferentially in the corresponding pyridone forms. Their synthesis from the corresponding pyrones by a heteroatom exchange reaction is possible. 

The tautomerism of 2-pyridones 25 that are favored over 2-hydroxypyridines 24 (and conversely, 2-aminopyridines 26 that are favored over 2-imino-derivatives 27) plays a central role in the chemistry and biochemistry of all azines [146-148], A comparison between A-methyl-2-pyridone and 2-methoxypyridine shows that the magnetic susceptibility of the former is about 20% greater than that of the latter [149],... 

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. 

Different tautomeric species (e.g., 6-chloro-2-pyridone/6-chloro-2-hydroxypyridine). 

Hydroxypyridines. Of the three hydroxypyridine isomers, 3-hydroxypyridine may behave as a phenolic compound, while in 2- and 4-hydroxypyridines the contribution of the corresponding tautomeric pyridones becomes important, as indicated by a great difference in their acidity between the 3-isomer (pK.d = 8.7) and the 2- and 4-isomers (pA7, = 11.6 and 11.1, respectively). Thus, the hydrogenation of 2-hydroxypyridine usually stops at 2-piperidone, a... 

Hydroxypyridine fV-oxides are also tautomeric the 4-isomer exists in about equal amounts of forms 812 and 813. In 4-hydroxypyrones and -pyridones, the -one (e.g., 814) structure is favored relative to the -one. -Hydroxy-4-pyrones such as kojic acid 815 show phenolic properties. - and -Hydroxy cations (e.g., 816) are the conjugate acids of pyridones and pyrones and are considered in the next section. 

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