The acid-base properties of 2-(benzoylamino)(1-R-2-oxoindolin-3-ylidene)acetic acids

Abstract

Aim. To study the acid-base properties of derivatives of 2-(benzoylamino)(1-R-2-oxoindolin-3-ylidene)acetic acid substituted by the location 1 of oxoindolin fragment. Results and discussion. The compounds studied are weak acids, their strength decreases with the elongation of the alkyl fragment in a heterocyclic nitrogen atom due to the extinction of the inductive effect. The reaction center (carboxyl group) has low sensitivity to the influence of substituents, and it may be due to the location distance of the substituents, as well as disturbance of coplanarity between the reaction center and the bicyclic fragment of the molecule. The ionization constants of a series of 2-(benzoylamino)(1-R-2-oxoindolin-3-ylidene)acetic acids have been set; the compounds studied are weak acids, their strength regularly decreases with replacement of the hydrogen atom at the heterocyclic nitrogen atom with methyl fragment, while the elongation of the alkyl fragment has little effect on their dissociation. The dependence of the ionization process on the nature of the substituents according to the Hammeth equation is quantified and it is shown that the reaction center (carboxyl group) has a small sensitivity to the influence of the substituents, which can be related both to the distance of the substituents location and to the violation of the coplanarity between the reaction center and the bicyclic fragment of the molecule. The small value of the ionization constant is consistent with the data of the (2Z)-(benzoylamino)(1-methyl-2-oxoindolin-3-ylidene)acetic acid stereostructure. Experimental part. The acid-base properties of 2-(benzoylamino)(2-oxoindolin-3-ylidene)acetic acid derivatives was studied by the method of potentiometric titration on an EV-74 ionomer with a glass indicator electrode (ESP 43-074) and a saturated silver chloride (EVP-1) reference electrode at 298 К within three analytical runs. A mixture of 1,4-dioxane–water (60:40, v/v) was used as a solvent. The structure of the molecule of (2Z)-(benzoylamino)(1-methyl-2-oxoindolin-3-ylidene)acetic acid was determined by X-ray diffraction analysis. Conclusions. The reactivity of the series of 2-(benzoylamino)(1-R-2-oxoindolin-3-ylidene)acetic acid has been investigated by studying the acid-base equilibria. Their ionization constants have been determined and the influence of alkyl radicals at the heterocycle nitrogen atom on the acid-base properties has been analyzed; the low sensitivity of the reaction center to the influence of substituents has been proved. The correlation equation pKa – f(σ) obtained has reliable statistical characteristics and can be used for QSAR analysis of active pharmacophores of this isostructural series.

Keywords

• ionization constant
• acid-base properties
• (2-oxoindolin-3-ylidene)acetic acid
• x-ray diffraction analysis