Structure of barbituric acids

The structure of barbituric acid was the subject of disagreement for many years, but since 195 2 (52BSB44) the trioxo formulation (57 R = H) has been accepted generally, along with the fact that barbituric acid loses a proton, first from carbon (anion) and subsequently from nitrogen (dianion). Barbital (5,5-diethylbarbituric acid) adopts a similar trioxo form (57 R = Et) (69AX(B)1978). 

Figure 6. Structure of barbituric acid dyes based on DACMA.

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). 

An experimental study of barbituric acid found one new polymorph where molecules in the asymmetric unit adopted two different conformations [10]. The conformational aspect was investigated through the use of ab initio calculations, which permitted the deduction that the new form found would have a lower lattice energy than would the known form. It was also found that many hypothetical structures characterized by a variety of hydrogen-bonding structures were possible, and so the combined theoretical and experimental studies indicated that a search for additional polymorphs might yield new crystal structures. 

Acylated derivatives of urea are referred to as ureides. Acylation of urea with a monoacid produces acyclic ureides, whereas diacylation with malonic acid (a diacid) yields the cyclic structure of barbiturates. The acyclic ureides carbromal and bromisoval, now outdated hypnotics, can be considered ring-opened analogues of the barbiturates to be examined in the next subsection. 

Although uracil possesses a structure very similar to that of barbituric acid, it is a much weaker acid (pKa 9.38) [368]. Also unlike barbituric acid, it is not... 

Urea may be recognised as a structural feature in the triketo form disconnection then reveals diethyl malonate as the other reagent. The synthesis of barbituric acid is therefore effected (Expt 8.36) by condensation of diethyl malonate with urea in the presence of sodium ethoxide. Barbituric acid undergoes nitration in the 5-position on treatment with fuming nitric acid, and reduction of the nitro derivative (98) yields 5-aminobarbituric acid (99) (uramil). 

The barbiturates are derivatives of barbituric acid and have the general structure given below. The nitrogen atom at position 1 may be methylated. Substitution of sulphur for oxygen at position 2 gives the thiobarbiturates. 

The electronic structure of barbiturates has also been investigated by spectropolarimetric methods.73-77 Circular dichroism (CD) spectra of a series of (S)-5-alkyl-5-(2 -pentyl)barbituric acids show three Cotton effects centered around 212, 240, and 260 nm, and the short-wavelength band is positive and has an opposite sign in relation to the longer wavelengths. However, in the case of (S)-5-(2 -pentyl)barbituric acid, the signs of all three Cotton effects are opposite to those of all the other derivatives. The solvent studies indicate that the 212- and 260-nm bands arise from the n - n and n - n transitions, respectively, but the 240-nm band is due to n - a or the second n - n transitions.74 An influence of concentration and ionization mode has not been observed. Similar assignment of three Cotton effects has been reported for (S)-5-alkyl-5-(2 -pentyl)-2-thiobarbituric acids.75... 

Uric acid, a purine derivative found mainly in the excrement of snakes and birds, has the molecular formula CsHnNiiOa- On nitric acid oxidation it breaks down to urea and a hydrated compound called alloxan of formula CijRaNaOit HaO. Alloxan is readily obtained by oxidation of barbituric acid. What is the probable structure of alloxan and uric acid Why is alloxan hydrated ... 

Barbiturates are derivatives of barbituric acid [67-52-7], whose structure is as follows ... 

This test identifies the substance to be examined as a non-nitrogen substituted barbiturate or thiobarbiturate. Barbiturates are a large group of structurally related compoxmds with anxiolytic and hypnotic effect. They are derivatives of barbituric acid (Figure 3.10.1) or thiobarbituric acid (Figure 3.10.2). 

The term barbiturate is by long usage considered synonymous with hypnotic agents . However, the salts of barbituric acid, and of many of its derivatives, have no observable hypnotic properties in most systems. A consideration of the non-hypnotic barbiturates is one of the main objectives of this section. For comparison, a short review of the structural requirements... 

Other mustard-substituted pyrimidines synthesised include benzylidine derivatives of barbituric acid [540] (C), cytosine and thiocytosine mustards [541] (Cl) and DL-willardiine mustard [542] (CII). No significant anticancer activity was found among these compounds. Compound (Cl) may actually have an ionic structure such as (CIII). 

A very profitable engagement of Fischer was the work on derivatives of malonic and barbituric esters. In 1902 the Professor of medicine, J. von Mering, whom Fischer had met in Strassburg, and who was working in Halle/Saale, visited Fischer in Berlin. He showed him a crystalline substance he had synthesized by the reaction of phosphorous oxichloride, urea and diethylmalonic acid. It seemed to be the diethyl ester of barbituric acid and he asked Fischer to confirm the constitution of this substance. Fischer found that the structure was different. With his nephew Alfred Dilthey he found two ways to obtain it. Mering tested diethylbarbituric acid and found that it was a very active soporific substance. Fischer himself used it successfully. Other derivatives of barbituric acid also showed hypnotic properties. Fischer and Mering published their results in January 1903.2 ... 

The barbituric acid derivatives, which have been known as hypnotic sedatives [136], were chosen as the first of the heterocycHc 1,3-dicarbonyl compounds for study because they consist of a cyclic diamide structure. The reaction of barbituric acid with 1,1-diphenylethene was conducted in acetic acid at room temperature in air using a catalytic amount of manganese(III) acetate. Surprisingly, solid products were easily obtained as a diastere-omixture, meso and racemic. Although the diastereomers could not be... 

The barbiturates, which include several important drugs used as sedatives (tranquilizers) and hypnotics (sleep-producers), are closely related to the pyrimidines. The structural formulas of barbituric acid and two of its derivatives are given below in these formulas the distribution of the hydrogen atoms between oxygen and nitrogen is uncertain, and... 

Two important papers by Gobetto et al. belong to this section. In the first one, the tautomerism of barbituric acid (33) was discussed (08CGD1454). In the solid state, the barbituric acid is well known to exist as two anhydrous forms (polymorph I and II, which differ in the HB network) and a dihydrate phase. They all display the trioxo structure 33a of Figure 7 shown by X-ray diffraction studies. In solution, on the contrary, the barbituric acid may exist as 11 possible structures (Figure 7) because of tautomeric equilibria. 

Figure 5. Crystalline substructures obtainable in 1 1 co-crystals of dmvatives of barbituric acid (B) and melamine (M). T = the number of B-M dimers that constitute a translational repeat unit along a tape (boxed) S = the number of tapes that constitute a translational repeat unit in a sheet 6 = the angle between tape axes in adjacent sheets. Tlie structures in this figure are representative examples of possible geometries and not an exhaustive list of all possible orientations of M andB.

Figure 4.10. Structure of sodium thiopental (left). This compound is a derivative of barbituric acid, a compound first prepared by von Baeyer as shown in Scheme 4.1. While barbituric acid itseif is devoid of physiological effects, many derivatives, such as phenobarbital (right), have an important history as drugs, as detailed in the text...

Barbituric acid can be considered as a cyclized malonic acid diamide (malonyl-urea). It is therefore a cyclic diketone that may be classified, in the sense of the compounds discussed in Section 12.6, as a coupling component with a methylene group activated by two carbonyl groups in the a- and a -positions. The reaction with arenediazonium salts was studied by Nesynov and Besprozvannaya (1971). These authors obtained coupling products (in good yield) that they considered to be arylhydrazones. Coupling with 4-(phenylazo)benzenediazonium chloride was studied by Chandra and Thosh (1991). The lH NMR spectra of these compounds are consistent with the arylhydrazone structure 12.68. 

These dyes are invariably monoazo compounds with the reactive system attached to the diazo component, owing to the ready availability of monosulphonated phenylenediamine intermediates. Pyrazolone couplers are most commonly used, as in structure 7.82 (where Z is the reactive grouping), and this is particularly the case for greenish yellow vinylsulphone dyes. Catalytic wet fading by phthalocyanine or triphenodioxazine blues is a characteristic weakness of azopyrazolone yellows (section 3.3.4). Pyridones (7.83), barbituric acid (7.84) and acetoacetarylide (7.85 Ar = aryl) coupling components are also represented in this sector, with the same type of diazo component to carry the reactive function. 

This subsection examines the hydrolytic stability of cyclic structures containing a ureido link. Schematically, ring closure can be achieved by N-alkylation or by /V-acylation of the second N-atom of the ureido moiety. The former results in the formation of, e.g., hydantoins and dihydropyrimidines. The latter ring closure leads to, e.g., barbituric acids. Taken together, cyclic ureides can also be regarded as ring structures that contain an imido function with an adjacent N-atom. We begin our discussion with the five-membered hydantoins, to continue with six-membered structures, namely dihydropyrimidines, barbituric acids, and xanthines. 

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. 

Fig. 2 Structure of D-glucuronic acid (38) and P-D-glycopyranosyl barbiturates obtained from hexoses or D-glucuronic acid...

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