1- Hydroxy-2-pyridone, tautomerism

Hydroxy-, Hydroxyall l-, and Aminoall lpyridines. A full discussion of the tautomerism occurring in heterocycles with oxygen and sulfur substituents has been pubUshed (38). Equation 2 shows the tautomerism expected in 2-pyridone (16) and 4-pyridone (38). 

As discussed in Section 4.01.5.2, hydroxyl derivatives of azoles (e.g. 463, 465, 467) are tautomeric with either or both of (i) aromatic carbonyl forms (e.g. 464,468) (as in pyridones), and (ii) alternative non-aromatic carbonyl forms (e.g. 466, 469). In the hydroxy enolic form (e.g. 463, 465, 467) the reactivity of these compounds toward electrophilic reagents is greater than that of the parent heterocycles these are analogs of phenol. 

The importance of ring size holds also for tautomerism of -pyrrol-5-ones and. d -dihydro-6-pyridones. While the former compounds behave as cyclic 1-methyl-2-alkyl-2-hydroxy-5-pyrrolidones 179) (76) [or, on distillation, as the dehydrated l-methyl-2-alkyl-J -pyrrolones (77)], the latter compounds exist as acyclic N-methylamides of 8-oxo-acids (78) [as shown by infrared spectroscopy (/80)j. The dehydration of 78 during distillation to form l-methyl-2-alkyl-. -dihydro-6-pyridones (79) is achieved only with difficulty. 

In their acidity, basicity, and the directive influence exerted on electrophilic substitution reactions in benzenoid nuclei, acylamino groups show properties which are intermediate between those of free amino and hydroxyl groups, and, therefore, it is at first surprising to find that the tautomeric behavior of acylaminopyridines closely resembles that of the aminopyridines instead of being intermediate between that of the amino- and hydroxy-pyridines. The basicities of the acylaminopyridines are, indeed, closer to those of the methoxy-pyridines than to those of the aminopyridines, the position of the tautomeric equilibrium being determined by the fact that the acyl-iminopyridones are strong bases like the iminopyridones and unlike the pyridones themselves. Thus, relative to the conversion of an... 

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). 

We do not discuss in detail the cases of tautomerism of heterocycles embedded in supramolecular structures, such as crown ethers, cryptands, and heterophanes, because such tautomerism is similar in most aspects to that displayed by the analogous monocyclic heterocycles. We concentrate here on modifications that can be induced by the macrocyclic cavity. Tire so-called proton-ionizable crown ethers have been discussed in several comprehensive reviews by Bradshaw et al. [90H665 96CSC(1)35 97ACR338, 97JIP221J. Tire compounds considered include tautomerizable compounds such as 4(5)-substituted imidazoles 1///4//-1,2,4-triazoles 3-hydroxy-pyridines and 4-pyridones. 

One other, perhaps even more dramatic and common example concerns compounds like 2 and 4 hydroxy- and amino-pyridines. These compounds exhibit tautomeric behaviour and tend to exist in solution as the corresponding pyridone and imine. This reduces the familiar pyridine-like properties of the ring system, accentuating the effects of these substituents (in terms of induced chemical shifts) and at the same time, radically increasing the expected couplings 2 -3 couplings. 

Hydroxy- and 4-hydroxy-pyridines are in equilibrium with their tautomeric amide structures containing a carbonyl. These tautomers are called 2-pyridone and 4-pyridone respectively. This type of tautomerism does not occur with the corresponding benzene derivative phenol, since it would destroy the stabilization conferred by aromaticity. 

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. 

Hydroxy pyridine 1-oxides are also tautomeric the 4-isomer exists in about equal amounts of forms (783) and (784). 4-Hydroxy-pyrones and -pyridones exhibit a different type of tautomerism the a-one (e.g. 785) structure is favored relative to the y-one structure. (3-Hydroxy-4-pyrones such as kojic acid (786) show phenolic properties (CHEC 3.28, Scheme 30). a- and 3-Hydroxy cations (e.g. 787) are the conjugate acids of pyridones and pyrones and are considered in the next section. 

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. 

The tautomeric 6-hydroxy-7-azaindole shows a shift to longer wavelength, which is characteristic of 2-hydroxypyridine as the neutral molecule or of l-methyl-2-pyridone. The degree of tauto-merization is solvent-dependent, and Yakhontov et have determined the lactam/lactim R = Me) ratio from the position of... 

In a review article (91H(32)127) the concept of heterocyclic aromaticity has been presented, summarized, and applied to discussion of tautomerism for a series of hydroxy-substituted azines. Later, the tautomerism of 2(l/7)-pyridone, 2(177)-pyrimidone, 2(177)-pyrazinone, 4-pyrimidone, and 3(277)-pyridazinone in low-temperature inert gas matrices has been investigated by means of IR spectroscopy. It was found that the relative stability of the oxo and hydroxy tautomers of these compounds depends in a systematic way on the relative position of the lactam group and the second nitrogen atom in the ring (92JPC6250). 

Measuring the intensity of the OH and NH stretching vibrations in the IR spectra of 2-hydroxypyridine in the range from 428 to 533 K in the gas phase allowed for determination of AH and AS for the equilibrium. The oxo-hydroxy tautomeric ratio in Ar or N2 matrices has been estimated as 1 2.80 and 1 2.99, respectively. A similar ratio of tautomers has been observed also in the gas phase (92JPC1562). IR has also been used as a quantitative tool to determine the association of pyridone dimer (96MI1). 

The concentration dependence of FTIR and UV spectra of 2-hydroxypyridine and its 6-chloro analog was measured in chloroform and CCI4 in order to elucidate their tautomeric equilibrium and determine the association constants (96MI1). For unsubstituted 2-hydroxypyridine, the hydroxy monomer or dimer was not detected in both solvents, and the equilibrium existed exclusively between oxo monomer and dimer. In contrast, for 6-chloro-2-pyridone both monomeric hydroxy (about 72%) and oxo (about 28%) forms were observed in chloroform. Increase in the substrate concentration led to decrease in the content of the monomeric species in favor of relevant dimers. In CC14, 6-chloro-2-hydroxypyridine was found to exist mainly in hydroxy monomer hydroxy dimer equilibrium. 

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). 

The substituent effect on the tautomeric equilibrium in solution has been studied using experimental pKa values and UV spectra (in water at 20 °C) of several 4(177)-pyridones and their N- and O-fixed derivatives. It was concluded that most of the factors affecting the tautomerism of 4(l/7)-pyridones are due to the electronic effect, including steric effect, of the substituents in the 2-position. Thus, the proportion of the hydroxy form increases on introduction of an electron-withdrawing group into the 2-position. For example, 5-methoxy-4(l/7)-pyridones with a methyl, hydroxymethyl, and methoxymethyl groups in the 2-position exist essentially in the pyridone form however, 2-methoxycarbonyl-substituted derivative exists as a mixture of hydroxy and oxo form in water (77BCJ710). The effect of substituents in the 3-position... 

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