ON THE INTERMOLECULAR INTERACTION OF CERTAIN BARBITURIC ACID DERIVATIVES WITH NITROPHENOLS

A. A. Shesterova, L. P. Petrenko, A. P. Izakenaite,
A. G. Pechenkin, N. D. Strelnikova

(Presented by the scientific-methodological seminar of the Faculty of Chemical Technology)

The literature contains data on the complex-forming ability of barbituric acid derivatives (Veronal, Luminal, Benzonal, etc.) with p-nitrophenol [1]. Information is given on the correlation between physiological activity (anticonvulsant and hypnotic action) and the values of the equilibrium constants of these preparations with p-nitrophenol, chosen as a model reagent in reactions of intermolecular interaction.

In the present work we investigated the above-mentioned regularity for a broader series of barbituric acid derivatives synthesized by us, and studied the influence of the chemical structure of these substances on the strength of their intermolecular interaction with p-nitrophenol. The barbituric acid derivatives synthesized by us have the following general structural formula:

\[ \begin{array}{c} \begin{array}{ccccc} & & R_3 & & \\ & & | & & \\ R_1 & \backslash & & CO{-}N & \backslash \\ & & C^5 & & CO \\ R_2 & / & & CO{-}N & / \\ & & & | & \\ & & & R_4 & \end{array} \end{array} \]

Study of the complex-formation reaction between p-nitrophenol and barbiturates was carried out spectrophotometrically on an SF-4A instrument at a temperature of 21–22°C. Absolute methyl alcohol and 96% ethyl alcohol were used as solvents. The equilibrium constants were calculated by the Nagakura method [2]. Good agreement was obtained for the equilibrium constants determined by this method,

with the data obtained by the Hammick–Wardley method, modified by V. D. Gol'tsev [3]. This makes it possible to consider that, upon interaction of barbiturates with p-nitrophenol, complexes of composition 1:1 are formed. The calculation results were statistically processed and are given in Table 1.

Table 1

* — data of [1];
** — increase in optical density

In the investigation of the electronic absorption spectra of solutions of p-nitrophenol in water and in 96% ethyl alcohol, it was found that, in contrast to other absolute alcohols of normal and branched structure, in these solvents a band at 390 appears in the spectrum of p-nitrophenol. The intensity of this band depends on the concentration of p-nitrophenol and on the water content in the ethyl alcohol. We assume that in solutions of p-nitrophenol in 96% ethyl alcohol competing reactions take place (scheme a, b and Fig. 1. [1]). The appearance of a new band (390 mμ) in the visible region of the spectrum can be explained by ionization of the intermolecular compound that is formed.

Andrews and Keefer [4] explain the appearance of new bands in the visible region of the spectrum during the interaction of symmetrical trinitrobenzene with aliphatic amines also by the formation of the ionic form of the nitro compound, and point out that the polarity of the solvent has a great influence on the degree of dissociation of such complex compounds.

In the investigation of the electronic absorption spectra of p-nitrophenol in nonpolar and slightly polar solvents (absolute alcohols of normal and branched structure, chloroform), we did not observe the 390 mμ band.

In studying the interaction of p-nitrophenol with barbiturates in methyl and 96% ethyl alcohols, a decrease in the inten-

sity of the long-wavelength band of p-nitrophenol (390 mμ). Barbiturates are optically transparent in this region of the spectrum. Such a decrease in the intensity of the 390 mμ band can be explained by the interaction of barbiturates with p-nitrophenol, with formation of a weakly ionized complex (scheme c, Fig. 1).

Fig. 1. Schemes of interaction of nitrophenols with barbiturates

a)

\[ \text{\(p\)-nitrophenol}\cdots \mathrm{OH_2} \rightleftharpoons [\text{\(p\)-nitrophenolate}]^{-} + \mathrm{H_3O}^{+} \]

b)

\[ \text{\(p\)-nitrophenol}\cdots \mathrm{OHC_2H_5} \rightleftharpoons [\text{\(p\)-nitrophenolate}]^{-} + \mathrm{OH_2C_2H_5}^{+} \]

c)

\[ [\text{\(p\)-nitrophenolate}]^{-} + \mathrm{OH_2C_2H_5}^{+} + \mathrm{O{=}C{=}B} \longrightarrow \text{\(p\)-nitrophenol}\cdots \mathrm{O{=}C{=}B} + \mathrm{C_2H_5OH} \]

d)

\[ [\text{2,6-dibromo-4-nitrophenolate}]^{-} + \mathrm{OH_2CH_3}^{+} + \mathrm{O{=}C{=}B} \rightleftharpoons \text{2,6-dibromo-4-nitrophenol}\cdots \mathrm{O{=}C{=}B} - \mathrm{CH_3OH} \rightleftharpoons [\text{2,6-dibromo-4-nitrophenolate}]^{-} + \mathrm{HO{=}C{=}B}^{+} \]

\[ \mathrm{O{=}C{=}B} \quad \text{(general formula of the barbiturate taken in the experiment)} \]

We believe that the degree of ionization of the complexes studied is affected both by the structure of the barbiturates and by the structure of the nitrophenols. Thus, when barbiturates (Table 1, preparations 14, 15) interact with p-nitrophenol, an increase in the intensity of the 390 mμ band is observed, which indicates stronger ionization of these complex compounds.

To clarify the influence of the structure of nitrophenols on the ionization of complex compounds of nitrophenols with barbiturates, electronic absorption spectra were recorded for reaction and additive mixtures of 2,6-dibromo-4-nitrophenol with veronal and luminal in methyl and 96% ethyl alcohols (Fig. 2). The choice of 2,6-dibromo-4-nitrophenol as the second model reagent was not accidental. The literature [5] contains data showing that introduction of substituents of the first order in the 2,6 positions of p-nitrosophenol weakens the O—H bond in molecules of such phenols. Our previous studies [6] showed that such a

effect is exerted by the introduction of substituents into the 2,6 position of p-nitrophenol on proton mobility in these molecules, which, undoubtedly, may promote easier ionization of complexes of dihalogenonitrophenols with barbiturates.

Fig. 1. Electronic absorption spectra: 1 — p-nitrophenol in methanol, \(C_{\mathrm{n}} = 1 \cdot 10^{-3}\) mole/l, \(l = 1\) cm; 2 — p-nitrophenol + veronal in methanol, \(CH = 1 \cdot 10^{-3}\) mole/l, \(C_{\mathrm{l}} = 1 \cdot 10^{-1}\) mole/l, \(l = 1\) cm; 3 — p-nitrophenol + luminal in methanol, \(C_{\mathrm{n}} = 1 \cdot 10^{-3}\) mole/l, \(C_{\mathrm{v}} = 1 \cdot 10^{-1}\) mole/l, \(l = 1\) cm.

From Fig. 2 it is evident that, when 2,6-dibromo-4-nitrophenol is examined in methyl alcohol, a band appears at 390 mµ, indicating the formation of the ionic form of this nitrophenol (Fig. 2 and scheme г). The absorption intensity of this band in 2,6-dibromo-4-nitrophenol in 96% ethyl alcohol is 2–3 times higher than in absolute methyl alcohol, which, apparently, is explained by the stronger competing influence of water molecules and the formation of a more dissociated complex between water and this nitrophenol. Upon interaction of barbiturates with 2,6-dibromo-4-nitrophenol in methyl alcohol, an increase occurs in the optical density of the 390 mµ band, which confirms the assumptions stated above that the complex compounds formed are in the ionized state.

For a quantitative assessment of the strength of intermolecular interaction as a function of the structure of the barbiturates, we carried out, as indicated above, a calculation of the equilibrium constants of p-nitrophenol with barbiturates in 96% ethyl alcohol.

From the data obtained (Table 1), the following conclusion can be drawn on this question:

1. The length of the second alkyl radical in position 5 in 5-ethylbarbituric acids does not have a significant effect on the donor-

...the ability of the carbonyl groups of barbiturates, but radicals of branched structure somewhat reduce the ability of these compounds to form complexes.

Fig. 2. Electronic absorption spectra:
1 — 2,6-dibromo-4-nitrophenol (2,6 DBNP) in chloroform, $C = 1 \cdot 10^{-3}$ mol/l; 2 — 2,6 DBNP in methyl alcohol, $C = 1 \cdot 10^{-3}$ mol/l; 3 — 2,6 DBNP $C = 1 \cdot 10^{-3}$ + luminal, $c = 1 \cdot 10^{-1}$ mol/l; 4 — 2,6 DBNP in ethyl alcohol, $c = 1 \cdot 10^{-3}$ mol/l; 5 — 2,6 DBNP $c = 1 \cdot 10^{-3}$ + luminal $c = 1 \cdot 10^{-1}$

1. Introduction of a phenyl radical into position 5 instead of one of the alkyl radicals leads to an increase in complex-forming ability (compare preparations 1 and 9, 8 and 13 in Table 1).

2. Introduction of a benzoyl residue into position 1 (3) significantly increases the complex-forming ability of these compounds with p-nitrophenol in comparison with barbiturates unsubstituted in this position.

REFERENCES

1. N. D. Strelnikova. Dissertation, Tomsk (1966).
2. S. Nagakura. J. Amer. Chem. Soc., 76, 3070 (1954).
3. V. D. Gol’tsev, N. D. Strelnikova et al. In: “Organic Complex Compounds,” Tomsk (1965).
4. L. Andrews, R. Keefer. “Organic Complex Compounds,” Moscow (1967).
5. V. V. Ershov, G. N. Nikiforov. Uspekhi khimii, 11, 1953 (1966).
6. L. P. Petrenko, N. D. Strelnikova et al. Izvestiya TPI (in press).