Study of the Hydrolytic Stability of Antipyrilamides of Aromatic Acids
Abstract Generated abstract
This study examines the acid hydrolysis of antipyrylamides of substituted aromatic acids, motivated by the possibility that hydrolytic stability may influence their reported anti-inflammatory and antipyretic activity. Hydrolysis was measured in hydrochloric acid aqueous or aqueous-alcoholic media at 99°C by determining the formation of 4-aminoantipyrine colorimetrically, and rate constants were calculated using first-order kinetic treatment. The results indicate that polar substituent effects in the phenyl ring have little influence on hydrolysis rate, while ortho substituents markedly slow cleavage, a fatty acyl group accelerates hydrolysis, and alcohol in the medium inhibits the reaction. The authors suggest an acid-catalyzed AAc2-type mechanism under the conditions studied and report no observed correlation between hydrolysis rate and pharmacological activity.
Full Text
STUDY OF THE HYDROLYTIC STABILITY OF ANTIPYRYLAMIDES OF AROMATIC ACIDS
E. V. Schmidt, G. M. Stepnova
(Presented by the Scientific-Methodological Seminar of the Faculty of Chemical Technology)
It is known that, for certain medicinal substances of the complex ester and amide type, the reaction of their hydrolytic cleavage constitutes a necessary stage in the mechanism of action. The physiological activity of such compounds is sometimes correlated with their reactivity [1, 2].
Previously we synthesized a series of antipyrylamides of aromatic acids [3, 4]. Pharmacological tests showed that these compounds possess anti-inflammatory and antipyretic activity. Certain relationships were established between the structure of the antipyrylamides and their physiological activity [5].
Assuming that the anti-inflammatory and antipyretic activity of antipyrylamides may depend on their differing hydrolytic stability, we studied the rate of acid hydrolysis of a series of antipyrylamides of substituted aromatic acids. For comparison, the hydrolysis of the antipyrylamide of stearic acid was also carried out.
Hydrolysis of an accurately weighed portion of antipyrylamide was carried out in a 0.1 N aqueous-alcoholic solution of hydrochloric acid in a thermostat at 99°C. The percentage of hydrolysis was determined by periodic measurement of the concentration of 4-aminoantipyrine formed as a result of the reaction, photoelectrocolorimetrically, using the color reaction with ferric chloride.
Processing of the kinetic results was carried out by the integral method. The hydrolysis rate constant was calculated from the formula for first-order reactions. The experimental results are given in Table 1. As can be seen from Table 1, the polar nature of substituents in the phenyl radical of benzanthipyrylamides does not substantially affect the rate of their hydrolytic cleavage; however, a sharp slowing of the reaction is caused by the presence of substituents near the reaction center (ortho effect). Acceleration of the hydrolysis reaction is observed for the antipyrylamide with a fatty acyl group in the molecule. Addition of alcohol to the reaction medium noticeably inhibits hydrolysis.
The results obtained make it possible to suggest that, under the selected conditions, the acid hydrolysis of antipyrylamides proceeds by the \(A_{\mathrm{Ac}}2\) mechanism (according to the notation system for mechanisms of C. K. Ingold), which, as is known, is characterized by analogous features [6, 7].
When the anti-inflammatory and antipyretic activity of antipyrylamides was compared with the rate of their hydrolysis, no relationship was found.
Table 1
| No. | Antipyrilamide | Average hydrolysis constant, \(10^3\ \mathrm{min}^{-1}\) |
|---|---|---|
| 1 | of 3,5-dinitrobenzoic acid | 1.79 |
| 2 | of 3-fluorobenzoic acid | 2.92 |
| 3 | of 3-fluorobenzoic acid* | 4.92 |
| 4 | of 2-chlorobenzoic acid | 0.368 |
| 5 | of 4-bromobenzoic acid | 2.95 |
| 6 | of 3-iodobenzoic acid | 2.78 |
| 7 | of 2-iodobenzoic acid | 0.158 |
| 8 | of 3-toluic acid | 2.71 |
| 9 | of 4-aminobenzoic acid | 2.40 |
| 10 | of stearic acid | 13.45 |
* Hydrolysis was carried out in a 0.1 N aqueous solution of hydrochloric acid.
Conclusions
-
The hydrolysis reaction of nine antipyrilamides of carboxylic acids in a hydrochloric acid aqueous–alcoholic medium at 99°C has been studied.
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The relationship between the structure of the antipyrilamides and the rate of their hydrolytic cleavage has been discussed. An assumption has been put forward concerning the probable mechanism of hydrolysis under the experimental conditions.
References
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- N. S. Dobychina. Izv. TPI, 151, 88, 1966.
- G. M. Stepnova, E. V. Shmidt. Izv. vuzov SSSR—Khimiya i khim. tekhnologiya, 8, 3, 520, 1965.
- G. M. Stepnova, E. V. Shmidt. ZhVKhO im. D. I. Mendeleeva, 10, 3, 358, 1965.
- A. S. Saratnikov, G. M. Stepnova, E. V. Shmidt et al. Izv. Sib. otd. AN SSSR (biological-medical series), 12, 3, 84, 1965.
- K. K. Ingold. Mechanisms of Reactions and the Structure of Organic Compounds, IIL, Moscow, 605, 1959.
- K. Laidler. Kinetics of Organic Reactions. Mir Publishers, Moscow, 18, 1966.