Pyridones, acidity electrophilic substitution

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... 

Electrochemical fluorination of pyridine in the presence of a source of fluoride ion gave 2-fluoropyridine in 22% yield (85M11). With xenon difluoride, pyridine formed 2-fluoropyridine (35%), 3-fluoropyridine (20%), and 2,6-difluoropyridine (11%) in a reaction unlikely to be a conventional electrophilic substitution. Xenon hexafluoride has also been used (76JFC179). With cesium fluoroxysulfate at room temperature in ether or chloroform, the major product was 2-fluoropyridine (61 and 47%, respectively). Some 2-chloropyridine was also formed in chloroform solution. In methanol the entire product was 2-methoxypyridine (90TL775). Fluorine, diluted with argon in acetic acid, gave a 42% yield of the 5-fluoro derivative of l-methyl-2-pyridone [82H( 17)429],... 

Hydroxypyridines undergo a variety of other electrophilic substitution reactions. Sulfonation of 2-pyridone with 10% oleum at 180° gave the 5-sulfonic acid.69 110 A-Methyl-2-pyridone is similarly sulfonated with chlorosulfonic acid. The action of fuming sulfuric acid gave a mixture of the 5-sulfonic acid and the 3,5-disulfonie acid. A nitro group at C-5 is said not to hinder the reaction, sulfonation at the... 

Electrophilic substitution at carbon can be effected much more readily with the three oxy-pyridines than with pyridine itself, and it occnrs ortho and para to the oxygen fnnction, as indicated below. Acid catalysed exchange of 4-pyridone in denterinm oxide, for example, gives 3,5-didenterio-4-pyridone, via C-protonation of the neutral pyridone. ... 

Activating substitutents, i.e. groups which can release electrons either inductively or mesomerically, make the electrophilic substitution of pyridine rings to which they are attached faster, for example 4-pyridone nitrates at the 3-position via the O-protonated salt. In order to understand the activation, it is helpful to view the species attacked as a (protonated) phenol-like substrate. Electrophilic attack on neutral pyridones is best visualised as attack on an enamide. Dimethoxypyridines also undergo nitration via their cations, but the balance is often delicate, for example 2-aminopyridine brominates at C-5, in acidic solution, via the free base. ... 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

---