Hydroxypyridine-pyridone tautomers

A.2.2.2 From equilibria. A study of equilibria can be used to estimate the relative contributions of aromaticity to equilibrating tautomers by relating their thermodynamic data to that of the corresponding saturated derivatives. This is illustrated by the relationship between the pyridine and pyridone tautomers shown in Scheme 8. In this way, 2-pyridone and 4-pyridone are calculated to be ca. 30 kj mol-1 less aromatic than the hydroxypyridines <2001CRV1421>. In the quinolones the difference in aromaticity between the two forms is less. The precise degree of aromatic character possessed by 2- and 4-pyranone is not settled various methods of estimation give different values. 

Evaluation of A jb by this method has been applied to the 2-pyridone and 4-pyridone tautomers systems using CNDO/2 wave functions. Three hydration sites were found for both 2-hydroxypyridine and 2-pyridone, yielding a net difference of 20 kJ mole-1 in favor of 2-pyridone. Three hydration sites were found for both 4-hydroxypyridine and 4-pyridone, resulting in A Ik = 17.2 kJ mole-1. The preferred hydration sites determined by this method are in complete agreement with those obtained by the supermolecule and OMTP methods (see Table VI). 

The kinetic energy release associated with the decomposition of metastable ions has been used to differentiate between the hydroxypyridines and their pyridone tautomers in the gas phase. The hydroxy forms were found to be favored for 2-hydroxypyridines (88JCS(P2)347). 

A direct substitution mechanism was indicated for the 2-pyridone catalysis of aminolysis of methyl acetate by methylamine." This mechanism is represented in Figure 7.9. It avoids a tetrahedral intermediate and describes a concerted displacement process that is facilitated by proton transfer involving 2-pyridone. Two very closely related TSs involving either the 2-hydroxypyridine or 2-pyridone tautomers were found. These TSs show extensive cleavage of the C-0 bond (2.0-2.2 A) and formation... 

The ligand 2,6-bis(2-pyridyl)pyridin-4(l//)-one (HOtpy) is particularly interesting. As the free ligand it exists as the pyridone tautomer, but co-ordination to a metal ion converts it to the 4-hydroxypyridine form (Figure 8). This behaves as a typical phenol, and is readily deprotonated under very mild conditions. 

Many heterocyclic compounds exist as mixtures of tautomers. For example, 2-hydroxypyridine exists in equilibrium with 2-pyridone. 

Compare energies of 2-hydroxypyridine and 2-pyridone to see which tautomer is preferred. Use equation (1) to calculate the equilibrium concentrations of the two at room temperature. 

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... 

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). 

For most simple phenols this equilibrium lies well to the side of the phenol, since only on that side is there aromaticity. For phenol itself, there is no evidence for the existence of the keto form. However, the keto form becomes important and may predominate (1) where certain groups, such as a second OH group or an N=0 group, are present (2) in systems of fused aromatic rings and (3) in heterocyclic systems. In many heterocyclic compounds in the liquid phase or in solution, the keto form is more stable, although in the vapor phase the positions of many of these equilibria are reversed. For example, in the equilibrium between 4-pyridone (118) and 4-hydroxypyridine (119), 118 is the only form detectable in ethanolic solution, while 119 predominates in the vapor phase. " In other heterocycles, the hydroxy-form predominates. 2-Hydroxypyridone (120) and pyridone-2-thiol (122) are in equilibrium with their tautomers, 121 and 123, respectively. In both cases, the most stable form is the hydroxy tautomer, 120 and 122. ... 

Tautomer conversion involves nonlocal structural editing, and substructural patterns must generally be defined more carefully. 2-Pyridones are consistently registered in the AstraZeneca database as their typically less stable 2-hydroxypyridine tautomers. The conversion can be carried out by first defining an atom type corresponding to a nonfused aromatic carbon atom. 

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... 

The synthesis of cis-1,4 polymers was also tried by e use of monomers with an s-cis conformation. The solid-state photopolymerization of pyridone derivatives, which is a six-membered cyclic diene amide and is a tautomer of 2-hydroxypyridine, was attempted [100]. Pyridones make hydrogen-bonded cocrystals with a carboxylic acid in the crystalline state. Because the cyclic structure fixes its s-cis conformation, if the polymerization proceeds, a cis-2,5 polymer would be obtained. Actually, however, the photopolymerization did not occur, contrary to our expectation, but [4-1-4] photodimerization proceeded when the carbon-to-carbon distance for the dimerization was small (less than 4 A) [101]. A closer stacking distance of the 2-pyridone moieties might be required for the topochemical polymerization of cychc diene monomers. 

Since the two tautomers - the hydroxypyridine 1A and the pyridone IB - equilibrate rapidly, mixing of two pyridone ligands with different donor sites would afford... 

Alkylation of hydroxyazines where reaction does not lead to quaternization is not considered. Molecules such as 4-pyridone usually exist largely as the carbonyl, but not as the 4-hydroxypyridine, tautomer in polar solvents8 [Eq. (1)]. Monoalkylation of the neutral species of such molecules can take place preferentially at either the annular nitrogen atom of the OH form or the oxygen atom of the N—H form in each case subsequent proton loss yields a neutral product. Dialkylation then gives rise to a cationic product, the second alkyl group being introduced at the other site. 

Polar solvents stabilize polar forms. In the vapor phase at equilibrium both 2- and 4-hydroxypyr-idines exist as such, rather than as the pyridones. 3-Hydroxypyridine, which in water is an approximate 1 1 mixture of OH and NH forms, also exists as the OH form in the vapor phase. However, 2- and 4-quinolinones remain dominantly in the NH (oxo) forms, even in the vapor phase. Hydrocarbon or other solvents of very low polarity would be expected to give results similar to those in the vapor phase, but intermolecular association by hydrogen bonding often leads to a considerably greater proportion of polar tautomers being present than would otherwise have been predicted. 

Experimental assessments of the concentration of the minor hydroxy tautomer of 2-pyridone and substituted derivatives in cyclohexane and acetonitrile solution may be carried out by the use of fluorescence spectroscopy (85JCS(P2)1423). For the parent compound, the pyridinol component in cyclohexane is estimated to be 4% and in acetonitrile 1.2% this preference for the hydroxy form in the former over the latter solvent is maintained over a fair range of variously substituted pyridones. Ab initio calculations (85JA7569) on 4-hydroxypyridine, the minor tautomer in aqueous solution, include 92 water molecules in the estimations, and thus give a very detailed picture of the solvated molecule, while the experimental technique of microwave spectroscopy not only gives an accurate estimation of the 2-hydroxypyridine / 2-pyridone ratio of 3 1 in the gas phase but also reveals that the former isomer is predominantly in the (Z)-form (80) and that both isomers are planar (93JPC46). 

Uncharged pyridines are resistant to hydroxide ion at usual temperatures. Pyridine itself reacts with hydroxide ions under extreme conditions (KOH-air, 300°C) to give 2-pyridone, the stable tautomer of 2-hydroxypyridine, which is formed by oxidation of the initial adduct. As is expected, this reaction is facilitated by electron-withdrawing groups and fused benzene rings quinoline and isoquinoline form... 

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... 

Hydroxylation of 111 gave mostly 3-hydroxypyridine (120) and lesser amounts of the isomeric tautomers 2- (121) and 4-pyridone (122).175 Because the oxidation was done under strongly acidic conditions, this appears to be an... 

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