THE REACTIVITY OF AROMATIC AND HETEROCYCLIC DERIVATIVES OF HYDRAZINE . VІІ . THE ACID-BASE PROPERTIES OF SUBSTITUTED 5 , 7-DICHLORO-9-HYDRAZINE ACRIDINE

The reactivity of substituted 5,7-dichloro-9-hydrazine acridine that exhibit various pharmacological activity by studying acid-base equilibria in the ethanol-water binary solvent (50 Mol % ethanol) at 25°С using the method of potentiometric titration has been investigated. The values рК of the corresponding conjugate acids obtained for 7 compounds indicate that these compounds are very weak bases. Analysis of the impact of the nature and position of substituents in the heterocycle on the strength of the corresponding conjugate acids has shown that the acceptor substituents weaken basicity of 5,7-dichloro-9-hydrazine acridine, and donor substituents cause the opposite effect. The quantitative assessment of the influence of substituents in the molecule by the Hammett equation within the principle of linearity of free energies with convincing statistical parameters has shown a low sensitivity of the reaction centre to structural changes in the molecule of 5,7-dichloro-9-hydrazine acridine. Using the correlation equation and the value рКВН+ experimentally obtained for 1-СН3 substituent the σ-constant of this substituent: σ(1-СН3) = 0.056 has been determined. The Hammett correlation equation is used to predict the acid-base properties of substituted 5,7-dichloro-9-hydrazine acridines and the molecular design of more active pharmacophores.

The reactivity of substituted 5,7-dichloro-9-hydrazine acridine that exhibit various pharmacological activity by studying acid-base equilibria in the ethanol-water binary solvent (50 Mol % ethanol) at 25°С using the method of potentiometric titration has been investigated.The values рК of the corresponding conjugate acids obtained for 7 compounds indicate that these compounds are very weak bases.Analysis of the impact of the nature and position of substituents in the heterocycle on the strength of the corresponding conjugate acids has shown that the acceptor substituents weaken basicity of 5,7-dichloro-9-hydrazine acridine, and donor substituents cause the opposite effect.The quantitative assessment of the influence of substituents in the molecule by the Hammett equation within the principle of linearity of free energies with convincing statistical parameters has shown a low sensitivity of the reaction centre to structural changes in the molecule of 5,7-dichloro-9-hydrazine acridine.Using the correlation equation and the value рК ВН + experimentally obtained for 1-СН 3 substituent the σ-constant of this substituent: σ(1-СН 3 ) = 0.056 has been determined.The Hammett correlation equation is used to predict the acid-base properties of substituted 5,7-dichloro-9-hydrazine acridines and the molecular design of more active pharmacophores.Substituted 9-hydrazine acridines exhibit the antimicrobial, antihypoxic, analgesic activity [3,5,6,[9][10][11] and are precursors for the synthesis of their various derivatives with new pharmacological properties.Therefore, the study of their reactivity is of undoubted scientific and practical interest since it allows optimizing the ways of their synthesis and predicting the biological activity.

Materials and Methods
The synthesis of substituted 5,7-dichloro-9-hydrazine acridine (1-7) was carried out according to the method [11], their physicochemical parameters are shown in Table .The ionization constants of the compounds under research were determined by the method of potentiometric titration [1, 7,17] in the ethanol-water binary solvent (50 Mol % ethanol) at 25°С.These constants are given in Table .The study of acid-base equilibria was carried out by the method [8].The titrant was 0.01 M aqueous solution of HCl.The concentration of the titrated solutions was 0.005 Mol•dm -3 at the semineutralization point.Potentiometric titration was performed on an ЕВ-74 ionomer with glass (ESP-43-074) and silver-silver chloride electrodes at 25°С.The experiment was performed in triplicates and processed in accordance with the requirements of the SPhU [2].The correlation analysis was conducted by the method of mathematical statistics (the confidence probability -0.95) [2,8].
To prepare the mixed solvent the СО 2 -free bidistillate and ethanol were used.

Results and Discussion
The reactivity of substituted 5,7-dichloro-9-hydrazine acridine of this isostructural series was studied in reversible conditions.Ionization of NH-acids conjugated with substituted 5,7-dichloro-9-hydrazine acridine was studied according to the equation (Scheme).
The preliminary experiments have proven that on the рНf (V HCl ) plot there is only one point of intersection that coincides with the literature data [4, [12][13][14][15] about protonation of 9-hydrazine acridine only on the heterocyclic nitrogen.
The data in Table indicate that the compounds studied are very weak bases in contrast to substituted 9-aminoacridines [12].This suggests the lack of resonance stabilization of the cation of 9-hydrazine acridine due to the isolating effect of the imino group.The introduction of acceptor substituents increases the positive charge at the reaction centre, therefore, the strength of conjugate acids with the acceptor substituent (2-NO 2 , 4-NO 2 ) regularly increases compared to the unsubstituted acid (the strength of the corresponding base reduces).Donor substituents cause the opposite effect.
The quantitative assessment of the influence of substituents in the molecule of 5,7-dichloro-9-hydrazine acridine was carried out by the Hammett equation within the principle of linearity of free energies.
The reaction constant ρ in the equation is small by the absolute value (ρ = 0.72), and it indicates the low sensitivity of the reaction centre to structural changes in the molecule of 5,7-dichloro-9-hydrazine acridine.
It is interesting to note that the reaction constant ρ for substituted 5,7-dichloro-9-hydrazine acridine within the experimental error coincides with ρ for substituted 9-aminoacridine [16], it indicates a single mechanism of electronic effects of substituents on the reaction centre.CONCLUSIONS 1.The reactivity of substituted 5,7-dichloro-9-hydrazine acridine has been studied in reversible conditions by investigating acid-base equilibria of conjugate acids in the mixed ethanol-water solvent (50 Mol % ethanol) at 25°С.
2. The impact of the nature and position of substituents in the heterocycle on the strength of the corresponding conjugate acids has been analyzed.
3. It has been proven that the acceptor substituents weaken basicity of 5,7-dichloro-9-hydrazine acridine, and donor substituents cause the opposite effect.
4. The Hammett correlation equation with convincing statistical characteristics has been determined, it is used to predict the acid-base properties of substituted 5,7-dichloro-9-hydrazine acridines.