4-Pyridone tautomers

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... 

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). 

For ring systems that incorporate a pyridine ring, chemistry and reactivity of pyridone derivatives have been incorporated into Sections 10.06.5-10.06.9, wherever appropriate. For crystalline products, which represent most of the derivatives contained within this chapter, the compounds exist as the pyridone tautomer. 

Pyridone likewise reacts mainly as the neutral pyridone tautomer at pH <6 and via the conjugate anion at pH > 6, 4-methoxypyridine being unreactive by comparison over the whole pH range. Facile dibromination of 4-pyridone occurs because at most pH values the lower pKa of the monobromo derivative more than compensates for its intrinsically lower reactivity (83CJC2556). 

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). 

Pyridone derivatives themselves can be used for aza-annulation. The pyridone tautomers 446 and 447 underwent facile aza-annulation with 47 at ambient temperature (eq. 95).109 In the presence of NaOH, in which the anion was stabilized through conjugation with ester (446) or amide (447) functionality, reaction occurred immediately at ambient temperature to give 448 and 449. 

The same authors found that thieno[2,3-c - and - 3,2-c]pyridones (e.g., 58) yielded substitution products (59) when treated with hydrogen halides and hydrogen peroxide, or with nitric acid. The orientation of substitution and increased reactivity compared with the parent thieno-pyridine were ascribed to the +M effect of the hydroxy group in that tautomeric form however, it is clear that the same results would be expected from the pyridone tautomer. 

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. 

The dimethyl and diethyl esters of 2,6-di-a-pyridinyl- and 2,6-di-a-quinolinyl-4-hydroxy-3,5-pyridinedicarboxylic acids (XH-479)also exist in the solid state a conjugate chelates. 2,6-Diphenyl-4-pyridone, which does not possess the ortho-hydwxy ester structural feature of XEI-479, exists as the pyridone (XII-480) in the solid state and in solution. 3-Acetyl-4,6-dimethyl-2-pyridone (W-481) exists as the pyridone tautomer in methanol. Stabilization of the pyridinol form by hydrogen bonding does not occur. The infrared (KBr) and ultraviolet spectra (ethanol) of 3-hydroxy-2-pyridone are consistent with the pyridone structure (XII-482). ... 

Pyridone tautomers prob. predominate where feasible in this series. Entries are given under the dihydroxydipyridine names for ease of presentation. Cryst. Mp >300°. 

Pyridone tautomers prob. predominate in this series where appropriate. Off-white cryst. (2-propanol). Mp 189-192°. 

Both J(C-3,C-6) and j(C-5,C-6) were used successfully as probes to examine the keto-enol tautomerism in derivatives of 2-OH-pyridine 52 in solution, which is strongly dependent on the solvent s dielectric constant and type/position of the substitution [96], Experimental J values of the pyridine-pyridone tautomers were measured in natural abundance with the INADEQUATE technique, and theoretical values were computed at DFT level of theory considering the solvent by the SCRF-PCM model [96],... 

The compounds 2- (16) and 4-pyridone (38) undergo chlorination with phosphoms oxychloride however, 3-pyridinol (39) is not chlotinated similarly. The product from (38) is 4-chloropyridine [626-61-9]. The 2- (16) and 4-oxo (38) isomers behave like the keto form of the keto—enol tautomers, whereas the 3-oxo (39) isomer is largely phenolic-like, and fails to be chlotinated (38). 

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). 

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... 

---