On the Complexation of Esters of 8-Hydroxyquinoline and Its Derivatives with Salts of Heavy Metals

L. P. Kulev, L. I. Aristov

8-Hydroxyquinoline was discovered by the Russian scientist Lyubavin in 1869 [1]. 8-Hydroxyquinoline itself and its substituted derivatives are widely used in analytical chemistry as complex-forming precipitants for the quantitative determination of magnesium, zinc, copper, aluminum, and other cations [2].

Some derivatives of 8-hydroxyquinoline, such as, for example, the compound of 8-hydroxyquinoline with sulfuric acid (“quinosol”), are used as antiseptics; 8-hydroxy-7-iodo-5-quinolinesulfonic acid (“yatren”) and 5-chloro-7-iodo-8-hydroxyquinoline (“vioform”) are used to combat protozoa—the causative agents of amoebic dysentery, leishmaniases, and piroplasmoses.

In 1944 Albert and Rubbo [3] put forward the supposition that the antibacterial activity of 8-hydroxyquinoline is explained by its ability to form intracomplex compounds with metals that are components of the enzymatic systems of microbes.

G. N. Pershin [4] points out that shifting the hydroxyl group in the 8-hydroxyquinoline molecule to another position leads to the destruction of the antiseptic activity of this compound.

It was also observed that gram-positive bacteria subjected to lethal concentrations of quinosol revived again when cobalt salts were added to the medium, while gram-negative bacteria did so when zinc and copper salts were added.

Altman and Kruk [5] established that 8-hydroxyquinoline pyrophosphate markedly activates preparations of succinoxidase from horse heart; the authors explain this by the ability of 8-hydroxyquinoline to remove heavy metals from the reaction medium.

The enzyme is completely deprived of activity upon the addition of copper or zinc, but regains it in the presence of 8-hydroxyquinoline.

Sorkin and Rose [6] studied the effect of substances with an oxine-like grouping on antitubercular activity in the presence of copper ions. They established that the activity of these compounds was stronger in the presence of copper ions than the simple sum of the concentrations of these substances, which the authors explain by a complexation reaction.

Wishing to test the validity of the hypothesis put forward by Albert and Rubbo, M. N. Shchukina and N. V. Savitskaya [7] synthesized a series of esters of 8-hydroxyquinoline and its derivatives. The compounds obtained by the authors, in experiments on animals, exhibited pronounced antibacterial activity and also inhibited the iron-containing enzyme phenol oxidase, despite the fact that they did not contain free hydroxyl groups necessary for the formation of intracomplex salts with metals.

Thus, the hypothesis of Albert and Rubbo concerning the mechanism of the antibacterial activity of 8-hydroxyquinoline and similar compounds was called into question.

It seems to us that 8-hydroxyquinoline should not completely lose its antibacterial activity if the hydrogen of the hydroxyl group of this compound is replaced by radicals.

The point is that in the compounds obtained a very active complex-forming agent is retained—the nitrogen of the heterocycle. This is confirmed by the fact that pyridine and quinoline very readily form complexes with the most diverse substances, including salts of heavy metals, through the nitrogen atom. It is true that, with the disappearance of the hydrogen of the hydroxyl group in 8-hydroxyquinoline, the compound loses the ability to form inner complexes with salts of heavy metals; however, this by no means signifies that it is altogether deprived of the conditions necessary for the formation of complexes of another type. On the contrary, esters of 8-hydroxyquinoline should have a more strongly basic character than 8-hydroxyquinoline itself, i.e., they will possess a property that promotes enhancement of the complex-forming ability of amines.

In this case, the mechanism of action of esters of 8-hydroxyquinoline on metal-containing systems of microbes and protozoa may be represented by the following scheme:

\[ \begin{aligned} \text{8-hydroxyquinoline ester} + \mathrm{Me\text{-}enzyme} \;\longrightarrow\; \text{8-hydroxyquinoline ester}\,N\cdots \mathrm{Me\text{-}enzyme} \end{aligned} \]

Proceeding from the above, we obtained the butyl esters of 8-hydroxyquinoline and 5,7-dibromo-8-hydroxyquinoline and, by a colorimetric method, studied their interaction with salts of copper and iron. When alcoholic solutions of esters of 8-hydroxyquinoline and alcoholic solutions of salts of copper and iron are mixed, intensely colored solutions are formed. The color of these solutions, in hue and intensity, differs sharply from the corresponding color of solutions of 8-hydroxyquinoline and 5,7-dibromo-8-hydroxyquinoline with the given salts, which indicates a different mechanism of interaction of the esters with salts of heavy metals.

Experimental Part

1. The butyl esters were obtained by the method described in the article by M. N. Shukina and N. V. Savitskaya [7]. The starting substances had the following melting points: butyl ester of 8-hydroxyquinoline, m.p. 47–48°C; butyl ester of 5,7-dibromo-8-hydroxyquinoline, m.p. 62°C.

2. Colorimetric studies were carried out on an FEK-M photocolorimeter by interaction of 0.01 M alcoholic solutions of the esters and 0.01 M alcoholic solutions of salts of copper and iron.

Butyl ester of dibromo-8-hydroxyquinoline—copper sulfate, cuvette 10 ml, blue light filter, dilution alcoholic.

It is evident from the table that at a molar ratio of 1:1 the greatest light absorption is obtained.

Butyl ester of 8-hydroxyquinoline—ferric chloride, cuvette 10 ml, blue light filter

From the tabular data it is evident that, at a ratio of the reacting substances of 1:1, the greatest light absorption is obtained.

Preparation of complex compounds

a) Complex salt of the butyl ester of 8-hydroxyquinoline with copper nitrate

0.5 g of the butyl ester is dissolved in methyl alcohol, and a solution of 0.442 g of copper nitrate in methyl alcohol is added to the hot solution. The solution becomes green. After heating for 30–40 minutes, the contents are transferred to a crystallizer and left to stand in a vacuum desiccator. Green crystals, m.p. 115–118°.

b) Complex salt of the butyl ester of dibromo-8-hydroxyquinoline with copper sulfate

To a hot solution of 0.509 g of the butyl ester in methyl alcohol is added 0.352 g of a solution of the copper salt. After brief heating, the contents are transferred to a vacuum desiccator. Yellow leaflets, m.p. 55°.

Conclusions

1. The interaction of butyl esters of 8-hydroxyquinoline and 5,7-dibromo-8-hydroxyquinoline with copper and iron salts has been studied colorimetrically. It has been shown that, at equimolecular ratios of these esters and salts, complex compounds are formed.

2. Complexes of the esters with copper salt have been obtained.

3. On the basis of literature and experimental data, considerations have been put forward concerning the mechanism of the antibacterial action of oxine-like compounds.

LITERATURE

1. Lyubavina, Vest., 2, 400, 1889.
2. Berg R., Application of 8-hydroxyquinoline in analytical chemistry, Moscow, 1957.
3. Albert, Rubbo and Goldacre, Brit. J., 28, 69, 1947.
4. Perrin G. N., The influence of chemotherapeutic substances on bacterial enzymes, Moscow, Medgiz, 1952.
5. Altman, Klug, Zh. Russ. Fiz.-Khim. O-va, Chemistry, 2, 663, 1953.
6. Corkin, Ross et al., Chemistry and Chemical Technology, 5, 145, 1952.
7. Shukina M. N., Savitskaya N. V., ZhOKh, 22, 1218, 1952.

CORRECTIONS AND MISPRINTS

Izv. TPI, vol. 102.