Pyridones and Hydroxypyridines

In the consideration of the tautomerism of pyridines and azines there is usually little need to consider the transfer of hydrogen to a ring carbon atom. In other words, in the set of formulae (73)-(75) the non-aromatic form (75) is not significantly populated. However, there are exceptions in, for example, polyhydroxy-pyridines and -azines. 

the major area of consideration is tautomerism of the type between structures (73) and (74). Table 29 summarizes the main results on the tautomerism of mono-hydroxy-, -mercapto-, -amino- and -methyl-azines and their benzo derivatives for dilute solutions in water at ca. 20°C. 

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). 

The effects of substituents on the form of the substrate reacting is nicely shown by comparison of the rate profiles for 9.27 and 9.33. 4-Pyri-done (9.27) exchanges as the free base even at H0 -10, whereas for its 2,6-dimethyl derivative (9.33), the reaction takes place mainly via the conjugate acid at // -— 3.5. 1,2,6-Trimethyl-4-pyridone (9.35) shows the changeover at even lower acidity (H0 -— 2.7). At high acidity, 9.33, 9.35, and 4-methoxy-2,6-dimethylpyridine (9.36) all react at similar rates and show similar dependence of rate upon acidity. This indicates that all react as the conjugate acids of type 9.37, and excludes the unlikely alternative 9.38. [In [68JCS(B)866], curve C of Fig. 3 refers to 4-methoxy-2,6-dimeth-ylpyridine, and not as stated]. At lower acidity the similarity in rate persists for 9.33 and 9.35, but 9.36 is much less reactive. Hence, the 4-pyridone 9.33 reacts as such and not as the 4-hydroxypyridine tautomer. 

At high acidity, 2,6-dimethyl-l-hydroxy-4-pyridone (9.34) reacted as the conjugate acid [68JCS(B)866] with a rate similar to that of 4-methoxy-2,6-dimethylpyridine N-oxide, so both must then react as conjugate acids of the structure type 9.39. In the intermediate acidity range pD +1 to H0 -2.5, the rate-acidity profile slope was zero for 9.34, indicating reaction on a neutral form. Since 4-methoxy-2,6-dimethylpyridine N-oxide (9.40) was much less reactive, the neutral form reacting must be 9.34 and not 9.41. 

Acid-catalyzed exchange has not been established in pyridine JV-oxide itself. The exchange of a number of derivatives has been studied [64CI(L) 1576]. 3,5-Dimethylpyridine N-oxide (9.42) reacts as the free base at the 2(6)- and 4-positions giving a zero slope of the rate-acidity profile [67JCS(B) 1222] the 2- and 6-positions are slightly more reactive than the 4-position, as expected. In 2,4,6-trimethylpyridine N-oxide 

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The powerful 7V,7V-diethylcarbamate DMG serves admirably for the synthesis of substituted oxygenated pyridines. Thus, metalation of all isomeric pyridyl O-carbamates 317 with sec-BuLi/TMEDA followed by quench with numerous electrophiles affords diversely substituted products 318 in good to excellent yields (Scheme 96) (85JOC5436). Base-induced hydrolysis provides access to pyridones and hydroxypyridines. 

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 )... 

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). 

The direct bromination of 2-hydroxypyridine is regioselective at C-3 whereas chlorination is not. Qu6guiner has developed a halide exchange reaction. Heating 3-bromo-2-hydroxypyridine in pyridine hydrochloride at reflux gives 3-chloro-2-hydroxypyridine in good yield <96TL(37)6695>. The directed aminomethylation of 3-hydroxy-2(lH)-pyridones and 3-hydroxy-4(lfl)-pyridones has been studied <96T(52)1835>. 

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. 

Acylation of Hydroxypyridines, Pyridones and their Benzo Analogues 352... 

It is now well established that 2- and 4-pyridone and their benzo analogues exist predominantly in the oxo form, e.g. (101a), rather than the hydroxypyridine form, e.g. (101b) (76AHC(S1)84 63AHC(l)34l). The enaminone system NH—C=C—C=0 is considerably more stable than the alternative iminoenol system N=C—C=C—OH by a factor of... 

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. 

Meuwly, M., Muller, A. and Leutwyler. S. (2003) Energetics, dynamics and infrared spectra of the DNA base-pair analogue 2-pyridone 2-hydroxypyridine. Phys. Chem. Chem. Phys., 5, 2663-2672. 

Stable anions can be formed by the loss of a proton from /V-unsubstituted pyridones or hydroxypyridines. They are the pyridine analogues of phenolate anions and react very readily with electrophilic agents at N, O or ring carbon (see Section 3.2.1.8.4). 

Highly activated rings are hydroxylated by K2S208-FeS04 2-pyridone and 3-hydroxypyridine are both hydroxylated para to the substituent thus, each gives the same compound (5-hydroxy-2-pyridone). 2-Pyrimidinone affords the 5-hydroxy derivative. Addition of hydrogen peroxide to the... 

Hydroxypyridines (776) are both weak acids and bases and can therefore exist as zwitterions (777) (see Section 2.2.5.1). The zwitterions of 2- and 4-hydroxypyridines are known as 2- and 4-pyridones because of their uncharged canonical forms, e.g. (778) and (779). a- and y-Hydroxypyridines exist in aqueous solution very predominantly as the oxo or pyridone form. For a- and y-hydroxy-benzopyridines and -benzazines, the equilibrium favors the benzopyridone form still more, with the exception of 3-hydroxyisoquinoline. The reactivity of the pyridones and azinones is considered in Sections 3.2.3.7.2-4. 

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],... 

Alkylation of Hydroxypyridines, Pyridones, and their Benzo Derivatives 138... 

Neither pyridine nor pyridine /V-oxide can be alkylated or acylated (but see 67MI1(I62) for early reports]. 2-Pyridone and 3-hydroxypyridine can be carboxylated ortho and para to the hydroxy group under basic conditions (24CB1161 54CA1337i, 54JOC510). 

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. 

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