HYDROLYTIC STABILITY OF BENZYL DERIVATIVES OF BARBITURIC ACIDS

A. A. SHESTEROVA, A. G. PECHENKIN, N. I. SMETANNIKOV

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

In order to search for anticonvulsant agents and on the basis of previous studies [1], we synthesized a series of acyl derivatives of barbituric acids of the general formula:

\[ \begin{array}{c} \mathrm{C_2H_5{-}CO{-}NH} \\ \phantom{\mathrm{C_2H_5{-}}}\overset{6}{\phantom{CO}}\quad\overset{1}{\phantom{NH}}\ \backslash \\ \phantom{\mathrm{C_2H_5{-}}}\mathrm{C_5}\quad\overset{4}{\phantom{C}}\quad\overset{3}{\phantom{N}}\ \overset{2}{\phantom{C}}\quad \mathrm{C{-}X} \\ \mathrm{R_1{-}CO{-}N}\ /\ \\ \phantom{\mathrm{R_1{-}CO{-}}}| \\ \phantom{\mathrm{R_1{-}CO{-}}}\mathrm{R_2} \end{array} \]

where \(R_1\) is alkyl with \(C_2{-}C_5\), phenyl, benzoyl;
\(R_2\) is benzoyl, phenyl; \(X = O, H_2\).

It has been established that barbiturates that do not have substituents in positions 1 and 3 are resistant to various chemical effects. However, \(N\)-aryl barbiturates, when boiled in water, undergo hydrolysis at the 1–6 and 5–6 bonds with rupture of the ring [2]. It was of interest to study the relative hydrolytic stability of benzoyl derivatives of barbituric acids as a function of the structure of the substituents in position 5 and of the position of the acyl residue in the barbituric ring.

It is known that the hydrolytic stability of barbiturates increases when alcohol or glycerin is added to the barbiturate solution [2]. Therefore, to study the hydrolytic stability of the compounds obtained, we used an aqueous-alcoholic medium, assuming that under these conditions the acyl residue would be cleaved first of all. The course of the hydrolysis process was monitored by the change in electrical conductivity over time.

Experimental Part

To determine hydrolytic stability, six standard solutions were prepared, corresponding to a definite degree of hydrolysis (from 0 to 100%), by dissolving calculated amounts of the acyl derivative and the presumed hydrolysis products in aqueous alcohol. The resistance of the prepared solutions was measured, the specific electrical conductivity was calculated, and a calibration curve was constructed in coordinates of electrical conductivity–degree of hydrolysis in %. A solution of the acyl derivative was prepared at a concentration of 0.001 mol/l in an amount of 200 ml. Since the acyl derivatives are poorly soluble in water, the weighed portion of the substance was dissolved in alcohol (100 ml). The alcoholic solution was diluted—

water (bidistillate) to the mark and kept in a thermostat at 20°C until a constant volume was established. The solution thus prepared was transferred to a flask fitted with a reflux condenser and heated at 99°C. Every hour, a sample was taken from the previously cooled reaction flask. 10 ml of this sample was placed in a vessel for determining electrical conductivity, kept in a thermostat at 20°C. After 10 min, the resistance of the solution was measured and the specific electrical conductivity was calculated. Using a calibration graph, the hydrolysis curve was constructed in the coordinates time—degree of hydrolysis.

The hydrolysis reaction in an alcohol–water solution, as a result of the excess of solvent, is monomolecular. The hydrolysis rate constant was calculated from the equation for the rate constant of a first-order reaction. The constancy of the hydrolysis rate constants is proof that the given reaction belongs to first-order reactions. To determine the specific electrical conductivity, a circuit was used in which an audio generator ZG-10 served as the current source, and an EO-7 oscilloscope as the null indicator [3]. The experimental results are presented in Table 1 and in Fig. 1. As an example, Tables 2 and 3 give data on the hydrolysis of 5-ethyl-5-isobutyl-1(3)-benzoylbarbituric acid.

Table 1

Table 2

Measurement of the electrical conductivity of standard solutions

Table 3

Determination of the hydrolysis rate of 5-ethyl-5-isobutyl-1(3)-benzoylbarbituric acid

Fig. 1.

On the basis of the results obtained, the following conclusion may be drawn:

1. By the electrical-conductivity method, the relative hydrolytic stability of nine acyl derivatives of barbituric acids was determined.

2. It was established that the rate of hydrolysis of N-benzoyl derivatives of 5-ethyl-5-alkylbarbituric acids depends on the length and structure of the alkyl radical in position 5. The rate of hydrolysis of N-benzoylbarbiturates with alkyl radicals of normal structure is somewhat higher than that of barbiturates with alkyl radicals of branched structure. In terms of their effect on the rate of hydrolysis (in order of decreasing rate), the alkyl radicals may be arranged in the series propyl > butyl > amyl.

3. The benzoyl group located in position 5 is split off much more rapidly than that located in position 1 (3).

4. The rate of hydrolysis increases significantly when the C=O group in position 2 is replaced by a CH₂ group.

5. Replacement of the alkyl radical in N-benzoyl-5-ethyl-5-alkylbarbituric acids by phenyl leads to an increase in the rate of hydrolysis.

LITERATURE

1. L. P. Kulev, G. M. Stepnova, V. G. Stolyarchuk, O. N. Nechaeva, ZhOKh, 30, no. 4, 1385–1387 (1960).

2. R. Ya. Levina, F. K. Velichko, Uspekhi khimii, 8, 929–971 (1960).

3. N. K. Vorob’ev, V. A. Gol’shmidt et al., Practical Course in Physical Chemistry, Moscow, Izd. “Khimiya,” p. 256, 1964.