2-Pyridones tautomerism

The pyridine ring system may carry snbstituents, jnst as we have seen with benzene rings. We have enconn-tered a nnmber of snch derivatives in the previons section. Hydroxy or amino heterocycles, however, may sometimes exist in tautomeric forms. We have met the concept of tantomerism primarily with carbonyl componnds, and have seen the isomerization of keto and enol tantomers (see Section 10.1). In certain cases, e.g. 1,3-dicarbonyl componnds, the enol form is a major component of the eqnilibrinm mixtnre. In the example shown, liquid acetylacetone contains about 76% of the enol tautomer. 

2-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. 

So why can tautomerism occur with a hydroxypyri-dine It is because 2-pyridone and 4-pyridone still retain aromaticity, with the nitrogen atom donating its lone pair electrons to the aromatic sextet. This is more easily seen in the resonance structures, and shonld remind ns of the resonance stabilization in 

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. 

Like amides, 2- and 4-pyridones are also very weak bases, mnch weaker than amines. Like amides, they actnally protonate on oxygen rather than nitrogen (see Section 4.5.4). This fnrther emphasizes that the nitrogen lone pair is already in nse and not available for protonation. On the other hand, the N-H can readily be deprotonated pyridones are appreciably acidic abont 11). The conjngate base benefits from considerable resonance stabilization, both via 

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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... 

Clauson-Kaas and co-workers333 have carried out a different pyridine synthesis with acylfurans. 2-Acetylfuran (54) is first converted into the ketal (55). After electrolysis to 56, the pyridine-A-oxide (57) is formed via acid-catalyzed ring opening and treatment with hydroxylamine. A tautomeric pyridone form (58) (hydroxamic acid) has also been proposed334 ... 

Oxygen Substituents. The presence of oxygen or sulfur attached to the ring can affect the chemistry of those compounds through tautomerism. This phenomenon ia the pyridine series has been well studied and reviewed (38). An example of 2-pyridone—2-pyridinol tautomerism was shown ia equation 2, compound (16). 

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. 

Together with pyridones, the tautomerism of pyrazolones has been studied most intensely and serves as a model for other work on tautomerism (76AHC(Sl)l). 1-Substituted pyrazolin-5-ones (78) can exist in three tautomeric forms, classically known as CH (78a), (DH (78b) and NH (78c). In the vapour phase the CH tautomer predominates and in the solid state there is a strongly H-bonded mixture of OH and HN tautomers (Section 4.04.1.3.1). However, most studies of the tautomerism of pyrazolones correspond to the determination of equilibrium constants in solution (see Figure 20). 

Benzopyridodiazines, 3, 199-262 Benzo-2-pyridone tautomerism, 2, 346 Benzo-4-pyridone tautomerism, 2, 346 Benzopyridones acylation, 2, 352 alkylation, 2, 349 Benzopyrido[3,2-ii]pyrimidine reactions... 

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. 

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 )... 

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... 

A different type of tautomeric relationship exists between compounds of types 323 and 324. Both types of structure can be isolated, pyridones (324, Z = N—Me) and pyrones (324, Z = 0) being formed when 323 (Z = N—Me or 0) is heated with palladium on charcoal in ethylene glycol. Similar isomerizations in the quinol-4-one series have been reported."... 

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... 

Pyridones and other six membered compounds (functional tautomerism)... 

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). 

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). 

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). 

Recently, zero kinetic energy (ZEKE) photoelectron spectroscopy has been used to study the OH/NH tautomerism of 2-pyridone in the gas phase (95JPC8608). This work, which is expected to develop considerably, provides a wealth of information about that equilibrium for the states So, Sj, and Do (cation ground state). 

Katritzky and Taft were the first to use ICR proton affinities for tautomeric studies (76JA6048). This and work of Katritzky and Nibbering (77TL1777) discuss the tautomerism of pyridones and thiopyridones and conclude that ICR results are in agreement with previous studies of Beak (76JA171)—that in the gas phase the OH and SH tautomers predominate. The complicated case of 2-thiouracil (six aromatic tautomers) was studied by Katritzky and Eyler [89JCS(P2)1499] they conclude that the oxothioxo tautomer is the most stable. 

Katritzky et al. have studied, using pK measurements, the tautomerism of aza[10]annulenone (2-azabicyclo[4.4.1]undeca-4,6,8,10-tetraen-3-one) 68 (93H2483). Comparison of the pX s of 68 and of model compounds 69 and 70 suggests that 68a is the dominant tautomer pKr = -0.70).Tliis implies a significantly diminished preference for the oxy form in compound 68 compared to 2-pyridone pKr = -3.0). This result indicated that aza[10]-annulenones 68a and 70 should be viewed as 677-homoaromatic species. NMR spectra support this conclusion (93H2483). 

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. 

Tautomerism in 4,8-dioxygenated 1,5-naphthyridines 163 has been studied by UV speetroseopy in aqueous solution. Under these eonditions, the eompounds exist predominantly as the bis-pyridone tautomers 163a (78JOC1331). 

Kuzuya M., Noguchi A. The Nature of Substituent Effects on Tautomeric Equilibria of 2-Pyridones and Their Reactions Trends Org. Chem. 1991 2 73-92 Keywords chemo- and regiochemistry of Diels-Alder reactions with benzyne,... 

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