STUDY OF COMPLEXATION REACTIONS OF SOME BARBITURIC ACID DERIVATIVES

B. V. TRONOV, N. D. STRELNIKOVA

Amides of carboxylic acids have a mixed type of reactivity. On the one hand, they exhibit electron-donor properties due to the unshared electron pair of the nitrogen atom; on the other hand, they must sometimes react as electron acceptors, especially in the tautomeric form with a hydroxyl group.

This dual type of reactivity makes the class of amides especially interesting for elucidating the regularities of the mutual influence of atoms in molecules, since the predominance of basic or acidic properties in the amide group depends to a greater degree on the composition and structure of the entire molecule.

For those representatives of the class of amides that are used as medicinal preparations, the nature of their physiological action must undoubtedly be connected with their acid–base properties.

In our work, the type of reactivity of organic compounds is determined by studying complexation reactions [6]. In the study of medicinal substances, such a method of work is also of interest because the very action of medicinal substances on the organism undoubtedly, in many cases, depends on their capacity for complexation. First, the action of a medicinal preparation may begin with its complexation with substances that are part of the organism of the patient himself, or with substances that are part of the microorganisms that caused the disease. Second, some preparations act better not in the free state, but in the form of their complexes with certain compounds, since in complexes they may possess properties different from those they have by themselves. This, one may suppose, explains the successful use in medicine of certain complex preparations.

Among recent works relating to this question one may note, for example, the investigations carried out by N. A. Predtechenskaya [2] and A. N. Tomaskin [1] on compounds of ascorbic acid with alkaloids and other medicinal substances. It was found that compounds of ascorbic acid often exert a stronger physiological action than the acid itself. The latter, in turn, can enhance the pharmacological action of medicinal substances bound to it. The compounds discussed in the cited article are undoubtedly complex compounds. In some cases, of course, there may also occur a combined physiological action of medicinal preparations without chemical interaction between them.

In the present work we have studied the complexation of derivatives of barbituric acid, namely luminal, veronal, and ethylisoamylbarbituric acid, the sodium salt of which is barbamyl. The second components of the systems studied were representatives of various organic compounds, including the barbiturates themselves.

Experimental Part

The systems selected were studied by the method of thermal analysis. The preparation, isolation, and verification of the purity of the compounds under study were carried out by various generally accepted methods, the same as in previous works in this area [3, 4, 6, 7].

A total of 93 binary systems were studied. Veronal gave eutectics of varied composition and depth with phenol, pyrocatechol, hydroquinone, naphthols, guaiacol, thymol, para-toluidine, benzidine, diphenylamine, naphthylamine, thiourea, benzamide, acetanilide, acetonaphthalide, benzoic, salicylic, and adipic acids, phenacetin, pyramidon, antipyrine, phenyl ester of salicylic acid, and ethylisoamylbarbituric acid. On the melting curves it was possible to detect a maximum for veronal with urea of composition 1:1, with urethane 1:1, and with luminal of the same composition (Fig. 1, curves 1, 2, 3, respectively), and a hidden maximum with acetamide and acetylsalicylic acid.

Fig. 1.

Eutectics were also found in most systems containing ethylisoamylbarbituric acid with phenol, pyrocatechol, hydroquinone, naphthols, guaiacol, thymol, diphenylamine, naphthylamines, urethane, acetamide, benzamide, acetanilide, benzoic, salicylic, and adipic acids, phenacetin, pyramidon, aspirin, salol, and veronal.

Melting curves could not be constructed in systems containing ethylisoamylbarbituric acid with resorcinol and with antipyrine; neither seeding nor vigorous stirring was able to induce crystallization; the melts, after many months of storage, continued to remain glass-like. Breaks in the melting curves were obtained with benzidine and [[unclear: compound name]], and a low maximum in the system with luminal (Fig. 2, curve 4).

The most effective proved to be binary systems containing ethylphenylbarbituric acid. Chemical interaction was found with hydroquinone, benzidine (Fig. 2, curve 1), diphenylamine (Fig. 2, curve 2), and with naphthylamines—a compound of composition 1:1; with carbamide, thiocarbamide, and urethane (Fig. 2, curves 3, 4, 5, respectively); and with pyramidon (Fig. 2, curve 6). The luminal–pyramidon system was studied by N. A. Figurovsky and V. M. Bashilova [8], who found a eutectic in it. However, in these authors’ work certain points deviate sharply from the curve shown. Our measurements show that these deviations correspond precisely to the composition of the complex compounds formed. Luminal with veronal, which is of special interest, and ethyl-isoamylbarbituric acid gave a maximum at the composition 1:1 (Fig. 1, curve 3, and Fig. 2, curve 7). Glassy solutions were obtained for ethylphenylbarbituric acid with resorcinol, with carbamide in the region of high luminal content, with antipyrine and salipyrine. In the remaining systems studied, ethylphenylbarbituric acid gave only eutectics.

Fig. 2.

Discussion of the Results

The complex-formation reaction is due primarily to electrostatic attraction between the positive nucleus of one of the atoms belonging to the acidic component of the complex (electron acceptor) and the unshared electron pair of the other, basic component (electron donor). The reactivity of acids and bases is usually assessed from the corresponding constants of electrolytic dissociation. However, one cannot always expect a direct dependence between the activity of a given substance in the formation of complexes and its dissociation constant. In the process of electrolytic dissociation the solvent, usually water, participates, and this process consists of two parts:

formation of a complex with water and dissociation of this complex.

The electrolytic dissociation constant directly characterizes only the second stage of this process and is only indirectly connected with the first. Moreover, the first stage itself, that is, the formation of the complex, depends not only on the distribution of charges in the molecule, expressed by the polarity of the substance, but also on polarizability, that is, on the ability of this molecule to change the distribution of charges (or, as is more often said, the distribution of electron density) under the influence of various conditions, for example, under the influence of the reagent acting upon it. Thus water (dipole moment \(1.84 \cdot 10^{-18}\) degree) has a higher polarity than ammonia (dipole moment \(1.46 \cdot 10^{-18}\)), but ammonia is polarized more readily than water. This explains the different behavior of water and ammonia toward salts of different metals. Salts with cations having an 8-electron outer shell, characteristic of atoms of inert gases, more readily give crystalline hydrates, since they are less readily polarized and polarize more weakly (both vary depending on the structure in parallel); here the greater polarity of the water molecules is of decisive importance. Salts with cations having an 18-electron outer shell more readily form crystalline ammoniates; their cations are more readily polarized and polarize more strongly. Hence calcium salts combine more readily with water; silver or copper salts, with ammonia.

The indicated regularity also extends to organic compounds. Thus, judging by its dissociation constant (\(K = 1.18 \cdot 10^{-9}\)), p-toluidine is a stronger base than benzidine (\(9.3 \cdot 10^{-10}\)), diphenylamine (\(7.6 \cdot 10^{-14}\)), alpha-naphthylamine (\(8.36 \cdot 10^{-11}\)), and beta-naphthylamine (\(1.29 \cdot 10^{-13}\)), but in determining the degree of dissociation we are dealing with water. However, in complex-formation reactions with nitro compounds [6], toluidine proves to be the least active; apparently the nitro compounds themselves are readily polarized and more strongly polarize the other component of the system, while amines with two benzene rings are more capable of polarization than aniline or toluidine, which have one benzene ring.

Taking into account both factors—polarity and polarizability—in discussing the results of the present work, we find that in systems with amines the barbiturates undoubtedly must exhibit acid electron-acceptor properties. If, of the amines taken, benzidine, diphenylamine, and naphthylamine, rather than p-toluidine, prove to be more active, this means that polarizability, and not polarization, should be considered the decisive condition here.

Phenols, judging by their dissociation constants, have considerably weaker acidic properties than barbituric acid and the derivatives of it that we used. For barbituric acid \(K = 9.8 \cdot 10^{-5}\); for diethylbarbituric acid \(K = 3.7 \cdot 10^{-8}\); the constant of ethyl-isoamylbarbituric acid is close to the constant of diethylbarbituric acid, while ethylphenylbarbituric acid, in terms of the magnitude of its dissociation constant, approaches barbituric acid. Phenol has \(K = 1.28 \cdot 10^{-10}\), pyrocatechol \(1.4 \cdot 10^{-9}\), resorcinol \(1.55 \cdot 10^{-10}\), hydroquinone \(4.5 \cdot 10^{-11}\). Hence barbiturates with phenols must also function as electron acceptors, and phenols as electron donors. This is in full agreement with the fact that, in complex formation with barbiturates, hydroquinone showed the greatest activity, possessing the weakest acidic, i.e., one must think, the strongest basic properties. The more acidic—phenol and pyrocatechol,

and, all the more so, the naphthols with dissociation constants \(2 \cdot 10^{-4}\) and \(6 \cdot 10^{-5}\) gave negative results.

For the barbiturates themselves it was noted that luminal, undoubtedly possessing stronger acidic properties than veronal and barbamyl, combines with hydroquinone, whereas the latter two do not react. An analogous phenomenon was also observed in systems with diphenylamine, with two naphthylamines, and also with thiocarbamide and partly with carbamide and urethane.

Carbonic acids, as well as benzamide, acetanilide, and acetonaphthalide, gave negative results with all barbiturates; on the melting curve of phenacetin—luminal an inflection was found. A weak chemical interaction was noted for acetamide with veronal, but not with luminal and barbamyl. The same was also observed for acetylsalicylic acid.

With pyramidone and antipyrine, which have more basic properties, pronounced complex formation was noted for luminal and, finally, the barbituric-acid derivatives among themselves—namely luminal with veronal—also enter into a complex-formation reaction.

Conclusions

1. Ninety systems were studied by the method of thermal analysis; these systems included derivatives of barbituric acid (luminal, veronal, and ethylisoamylbarbituric acid) and other organic compounds, namely phenols, carbonic acids, amines, and amides.

2. Ten complex compounds were found, and in 6 systems a weaker chemical interaction was detected.

3. Considerations are offered concerning the dependence of the ability of the compounds studied to undergo complex formation on their composition and structure, and also concerning the connection between complex formation and pharmacological action.

LITERATURE

1. Pomaskina A. N. Proceedings of the Conference of Physiologists, Biochemists, and Pharmacologists, Tomsk, 114, 1957.

2. Predtechenskaya N. A. Abstracts of Reports of the Scientific Conference of Physiologists, Biochemists, and Pharmacologists, Tomsk, 74, 1957.

3. Strelnikova N. D. Izv. Tomsk Polytechnic Institute, 77, 154–163, 1953.

4. Strelnikova N. D. ZhOKh 26, 1863, 1956.

5. Tronov B. V., Kulesh L. P. Izv. Tomsk Polytechnic Institute 61, 85–87, Tomsk, 1948.

6. Tronov B. V., Strelnikova N. D. Izv. Tomsk Polytechnic Institute 71, 63–99, Tomsk, 1952.

7. Tronov B. V., Strelnikova N. D. Izv. Tomsk Polytechnic Institute 83, 98–101, Tomsk, 1955.

8. Figurovskii N. A., Bashilova B. M. Aptechnoe delo, No. 2, 5–10, 1957.