Barbituric acid, tautomerism

Less common are literature examples in which mechanochemical reaction was carried out at elevated temperature. Naimi-Jamal reported the heating of double-walled ball-mill beaker equipped with fittings for circulating water at 96°C (boiling water as circulant) [45]. One-pot solvent-free synthesis of pyrano[2,3-d]pyrimidine-2,4(lFf,3F0-diones 154 was achieved by simply ball milling a stioichiometric mixture of an aromatic aldehyde, malononitrile, and barbituric acid, without addition of solvent and catalyst (Scheme 2.53). Quantitative yields were obtained (Table 2.47) and products generally did not require purification, the solid products were just dried at 80°C in vacuum and recrystaUized, if necessary. Reaction presumably takes place by initial Knoevenagel condensation of aromatic aldehyde with malononitrile to afford the intermediate Michael acceptor, which subsequently reacts with barbituric acid. Tautomerization of Michael adduct is followed by intramolecular cyclocondensation and another tautomerization to afford pyrano[2,3-d]pyrimidine-2,4(177,37f)-diones 154. 

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). 

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. 

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... 

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. 

Barbituric acid like parabanic acid exhibits keto-enol tautomerism as illustrated below ... 

It has been adequately substantiated that the presence of 5, 5-disubstituted barbituric acid essentially comprises of three lactam moities which can be circumvented conveniently to pH dependent lactim-lactam tautomerization as given under ... 

Keto-enol tautomerism exists in parabenic acid and barbituric acid. Explain. 

The 5,5-disubstituted barbituric acid contains three lactam groups that can undergo pH dependent lactim-lactam tautomerization, as shown in Figure 19.5. 

Ultraviolet speotroscopic studies with 5,5-disubstituted barbituric acids (44) indicated that in aqueous solutions, the dominant forms are either the dioxo tautomeric form (i.e., monolaotam in alkaline medium) or the trioxo tautomerio form (barbituric acid structure in acid medium). The acidity of barbiturates in aqueous solution depends on the number of substituents attached to barbituric acid. The 5,5-disubstituted barbituric acids, 5,5-disubstituted thiobarbituric acids, and 1,5,5-trisubstituted barbituric acids are relatively weak acids, and salts of these barbiturates are easily formed by treatment with bases. The pKa of 5,5-disubstituted barbituric acids ranges from 7.1 to 8.1 (44). The 5,5-disubstituted barbiturio aoids can undergo a second ionization, having pKa values in the range of 11.7 to 1 2.7. The alkali metal salts of the barbiturates coupled with their highly lipophilic character will cause chemical incompatibility reactions (precipitation) when these compounds are mixed with acid salts of weakly basic amines. 

On the other hand, uracil exists as the dione and most of its reactions can be interpreted on this basis. Barbituric acid adopts a tricarbonyl tautomeric form. 

---