Barbiturates tautomerism

Barbituric acid — see also Pyrimidine-2,4,6-trione, perhydro-acidic pK, 3, 60 bromination, 3, 70 fluorination, 3, 70 structure, 3, 68 tautomerism, 2, 27 in thermography, 1, 392 Barbituric acid, iV-alkyl-chlorination, 3, 70 Barbituric acid, 5-aminomethylene-synthesis, 3, 524 Barbituric acid, 5-arylidene-pyridopyrimidines from, 3, 227 Barbituric acid, 1,3-dicyclohexyl-synthesis, 3, 113 Barbituric acid, 2-thio-sensitizing dye... 

Early investigators adduced various kinds of chemical evidence in support of a monohydroxy-dioxo structure for barbituric acid (112) (a) reaction with diazomethane afforded a mono-O-methyl deriva- iye,i59,i6o barbituric acid and its 5-alkyl derivatives are much stronger acids than the 5,5-dialkyl derivatives, and (c) the 5-bromo and 5,5-dibromo derivatives have different chemical properties. - The early physical evidence also appeared to substantiate the monoenol structure, this formulation having been suggested for barbituric acid in 1926 on the basis of its ultraviolet spectrum and again in 1934, In the 1940 s, ultraviolet spectroscopic studies led to the suggestion of other monohydroxy and dihydroxy structures for barbituric acid, whereas its monoanion was assigned structure 113 (a clear distinction between ionization and tautomerism was not made in these papers). 

A thiazole derivative that incorporates a fragment of the amphetamine molecule shows some CNS stimulant activity more specifically, the compound antagonizes the depression caused by overdoses of barbiturates and narcotics. Reaction of benzalde-hyde with sodium cyanide and benzenesulfonyl chloride gives the toluenesulfony1 ester of the cyanohydrin (141). Reaction of this with thiourea leads directly to aminophenazole (143) It is probable the reaction proceeds by displacement of the tosylate by the thiourea sulfur to give 142 addition of the amino group to the nitrile followed by tautomerization affords the observed product. ... 

A particular mechanism of barbiturate ring opening has been observed for some barbiturates hydroxylated on the side-chain. The mechanism and relevance of this tautomeric lactam-lactone equilibrium are discussed in Chapt. 11. 

Apart from tautomerism between identical structures, NMR can also be used to investigate tautomeric equilibria between states of different energy. Thus it can be shown that barbituric acid exists as a urea derivative and is only formally a pyrimidine derivative. 

Compounds of type (460) can aromatize by isomerization [(460) — (461), Y = CHR, NR]. In a few cases such tautomerism is reversible barbituric acid (462) exists mainly in the trioxo form whereas its anion is aromatic. 

Barbituric acid (83), which is formally 2,4,6-trihydroxyprimidine, is extensively tautomeric (p. 1175). The barbiturate drugs are derivatives of the triketo form. Piperazine-2,5-dione (84) is a diamide based upon the pyrazine ring system. 

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. 

Theoretically, the purine- and pyrimidine-based nucleic acid constituents and the barbiturates have the potential to occur in several tautomeric forms of the keto/ enol and amino/imino type where the aromatic character of the six-membered pyrimidine ring is fully or, as in the barbiturates, partially retained, as illustrated in Fig. 15.4. In these molecular species, which are all feasible on the basis of organic chemical considerations, the hydrogen-bonding donor/acceptor properties of the functional amino, imino, enol and keto groups vary considerably, being donor in one form and acceptor in the other. 

Pulse radiolysis studies using optical detection suggested the main species in equilibrium to be the ot-aminoalkyl radical (31) and the A -protonated ot-aminoalkyl radical (32) whereas results from ESR studies were indicative of protonation at the a-carbon site to form the iV-centered radical cation (30). A subsequent study showed that these results could be attributed to kinetic and thermodynamic factors [84]. Thus iV-protonation resulting in the formation of 32 is kinetically favored and is hence observed in the short time-scales involved in pulse-radiolysis systems. In the longer times involved in ESR measurements the thermodynamically more stable N-centered radical cation will be observed. The pA a of 30 and 32 were estimated as 8.0 and 3.6 by use of pulse radiolysis [84]. Using the equation for similar keto enol tautomerism of barbituric acid [97], the ratio of 30/32 was estimated to be 10 /10 = 10", indicating the N-centered radical (30) to be the predominant protonated species. 

Both hydrogen atoms at the 5 position of barbituric acid must be replaced. This may be b ause if one hydrogen is available at position S, tautomerization to a highly acidic trihydroxypyrimidine (pK 4) can occur. Consequently, the compound is largely in the anionic form at physiological pHs. with little nonionic lipid-soluble compound available to cross the blood-brain barrier. 

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... 

Phenytoin and barbiturates display tautomerism of the imine-imide type, as shown in Figure 3.16. The predominant tautomer is the imide form, although some older textbooks list the structure of the drug as the minor tautomer. 

Barbituric acids, 5-ylidene derivatives of 83WCH479. Dihydropyrimidines, synthesis, structure, tautomerism of 86H(24)1433, Hydrazinopyrimidines, advances in chemistry of 82KGS579. 

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-... 

The imide hydrogen atoms in barbituric acids take part in tautomerism (Section II,A) so that the alkylation of these compounds leads to a mixture of N- and O-alkyl derivatives. Levina thoroughly discussed the N-alkylation.4... 

In the solid (crystalline) form the barbituric acid exists in the triketo or lactam form. In aqueous solution tautomerism to the enolic lactim occurs the enolic hydroxyl (at C-2) is acidic acid and is ionized according to the particular drug s pKa (e.g., pentobarbital = 8.0, phenobarbital = 7.5). Titrating such a solution with a stoichiometric equivalent of base such as NaOH will convert the lactam quantitatively to the barbiturate s sodium salt, which can be isolated. Many barbiturates are commercially produced both in the lactam and in the sodium enolate salt form. Of course, the salts are water soluble and thus are used to formulate injectable dosage forms including those for IV anesthetic use. 

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