Tautomerism nicotinic acid

One interesting problem frequently recurring in heterocyclic chemistry, particularly with respect to nitrogen heterocycles, is tautomeric equilibria. Too many methods are available for the elucidation of equilibrium positions and tautomeric equilibrium constants (Kj) to adequately review the whole question here. However, the Hammett equation provides one independent method this method has the advantage that it can be used to predict the equilibrium position and to estimate the equilibrium constant, even in cases where the equilibrium position is so far to one side or the other that experimental determination of the concentration of the minor component is impossible. The entire method will be illustrated using nicotinic acid as an example but is, of course, completely general. 

In this section the synthesis of coumalic acid (92), representing the a(2)-pyrone system, is described. a-Pyrones readily undergo a simple lactone-amide transformation, and the conversion of coumalic acid into the tautomeric 6-hydroxy-nicotinic acid (93) provides a further illustration of the conversion of a six-membered oxygen heterocycle into the corresponding nitrogen system. 

It is remarkable that the intermediates in the conversion of hydroxyanthranilic acid to nicotinic acid are still not known with certainty. Intermediates A and B of diagram 21 are plausible suggestions, but no synthesis of either has been reported. Both are extremely unlikely to be stable in the free state, but should be obtainable as simple derivatives. In the free state Intermediate A, for example, might be expected to tautomerize to the imino acid, and hence give keto acid and ammonia, or it could cyclize to a piperazine or to quinolinic acid. Tautomerism through the imino acid would eliminate the necessity for a fumaric —> maleic isomerization. It is quite possible that spontaneous cyclization explains the prominent part quinolinic acid plays in work on hydroxyanthranilic-nicotinic conversion. If the latter occurred in the following.way ... 

Naphthalimide, methylation of, 255 Naphthols, tautomerism of, 5 Naphtho-r,2, 4,5-selenazoles, 350 Nicotinic acid derivatives, metal catalysts, action on, 183, 186 Nitrones, 84, 88, 92, 99... 

The individual ionization constants for pairs of tautomers and the constant for the equilibrium between them can be deduced from the experimentally determined ionization constants in another way. It will be seen (p. 156) that the effect of substituents on the basic strength of the pyridine nitrogen atom can be represented by the Hammett equation. Accordingly, the ionization constant for the NM form (T b) can be estimated from the Hammett substituent constant of the group — A H. Combined with the experimentally determined Ki this leads to estimates of the remaining quantities. In this way Jaffe 2 deduced that nicotinic and isonicotinic acids exist predominantly as zwitterions in aqueous solution. Similarly, Bryson s obtained the values pi B 5-0 and Kt = 0 78 for 3-hydroxypyridine (cf. Tables 5,10 and 5.12), Hammett correlations have been used in evaluating the tautomeric equilibria in a number of 2-arylsulphonamidopyridines . ... 

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