5- -substituted-barbituric acids tautomerism

This type of tautomerism occurs by a proton transfer and transforms a substituted azine, e.g., 170, into an isomer with exocyclic conjugation, e.g., 171. Transfer of a proton to a ring carbon atom, e.g., 172, is rarer, due to loss of aromaticity, but can occur in polyhydroxyazines (e.g., barbituric acid 173). Tautomerism in six-membered heterocycles has been reviewed <2006AHC(91)1>. Table 31 summarizes the tautomeric equilibria of monosubstituted azines and their benzo derivatives for dilute solutions in water at ca. 20 °C. 

The pharmacological activity of barbiturates is also influenced by their acidity, which is attributed to the lactam-lactim tautomer-ism that can occur in all derivatives in which at least one of the ring nitrogens is unsubstituted keto-enol tautomerism also takes place in 5-unsubstituted or mono-substituted compounds (Equation 5.17). Barbiturates must have acidity within certain limits to possess hypnotic activity (156). For example, barbituric acid (Ri, R2, R3, R4 = H), which has a pifa of 4.1 and is >99% dissociated at physiological pH, and the neutral N, iV -disubstituted compound (Ri, R2, R3 = Et, R4 = Ph) that is completely undissociated, are devoid of hypnotic... 

The tautomerism of barbituric acid and its derivatives has been briefly discussed in a review on this class of compounds (85AHC(38)229). Eleven tautomers are possible for unsubstituted barbituric acid 162. The position of the tautomeric equilibrium 162a 162b for unsubstituted barbituric acid and its N- and 5-substituted deriv-... 

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