Dissociation constants of substituted aryl azo barbituric and thiobarbituric acids

Article abstract of DOI:10.1524/zpch.2001.215.4.531

The acid dissociation constants of 5-(substituted phenylazo) barbituric and thiobarbituric acids were determined in aqueous media and in 25%-75% (v/v) ethanol-water and dioxanewater mixtures potentiometrically in the temperature range 25-40°C, in presence

Full text of DOI:10.1524/zpch.2001.215.4.531

Zeitschrift für Physikalische Chemie, 215, 4, 531–542 (2001)
by Oldenbourg Wissenschaftsverlag, München
Dissociation Constants of Substituted Aryl Azo
Barbituric and Thiobarbituric Acids
2
1
By Mamdouh S. Masoud1, , Ahmed K. Ghonaim , Rabah H. Ahmed ,
∗
Ahmed A. Mahmoud1 and Alaa E. Ali3
1
Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt
Physics & Chemistry Department, Faculty of Education (Damanhour), Alexandria
2
3
University, Egypt
(Received January 3, 2000; in revised form March 1, 2000)
Dissociation Constant / Azo Compounds / Pyrimidines / Potentiometry /
Thermodynamic Parameters
The acid dissociation constants of 5-(substituted phenylazo) barbituric and thiobarbituric
acids were determined in aqueous media and in 25%–75% ( ) ethanol–water and dioxane–
water mixtures potentiometrically in the temperature range 25–40 ◦C, in presence of 0 5 M
KCl. The values of the enthalpy change ∆H (kJmol−1), entropy change ∆S (J K−1 mol−1
)
and the free energy change ∆G (kJ mol−1) of these compounds were evaluated at 25 ◦C. The
data were explained from the electronic character of the substituent.
1. Introduction
N-Heterocyclic compounds containing amide linkage are widely used in
medicine, principally as hypnotic drugs and produce depressive effects on the
central nervous system [1]. The therapeutic applications of barbituric and thio-
barbituric acids are reported [2, 3]. Most of the pyrimidines are with antimicro-
bial, anti-inflammatory and antitumoral activities [2, 3]. Guanidine or its salts
is treated with barbituric and thiobarbituric acids or their derivatives to give
guanidine barbiturate and thiobarbiturate which are used as fire proofing agents
for plastics, polyamides, polyurethane or polyacrylonitrile [4]. Serum lipid per-
oxidation was measured by thiobarbituric acid reactive material method during
physical exercise of different duration [5]. Azo compounds are concerned with
a number of important biological reactions such as protein synthesis inhibition
cytostatic, carcinogenesis, azo reduction mono-amine oxidase inhibition muta-
genic, immunochemical affinity labeling, nitrogen fixation and act as alkylating
*
Corresponding author. E-mail: drmsmasoud@yahoo.com

532
M. S. Masoud et al.
agents with carcinogenic properties where they induce tumors in rats [6–8] and
possess inhibitory effects on the biosynthesis of DNA, RNA and proteins [9].
In our laboratory, Masoud et al. [10–46] published a series of papers to throw
light on the chemistry of azo pyrimidine compounds and their complexes.
The 5-(substituted phenylazo) barbituric and thiobarbituric acids are studied
through this paper. The main purpose is three-folds:
(i) evaluation of the acid dissociation constants potentiometrically in 25%–
75% ( ) ethanol–water and dioxane–water mixtures,
(ii) explanation of the mechanism of dissociation from solvation and aquation
views,
(iii) evaluation of the thermodynamic parameters. The data are discussed from
the electronic character of the substituent and the nature of the hydrogen
bond views.
2. Experimental
Barbituric(I) and thiobarbituric acids(II) were obtained from BDH. Dyestuff
chromogenic azo barbituric and thiobarbituric acids (III, IV) were prepared
by the usual diazotization process [47]. The corresponding amines (0 1 mole)
were dissolved in 0 2 mole HCl and 25 ml distilled water. The hydrochloride
compounds were diazotized below 5 ◦C with 0 1 mole NaNO2 solution and
20 ml distilled water. The diazonium chlorides were coupled with an alkaline
solution (0 1 mole NaOH) of barbituric and thiobarbituric acids. The crude
dyes were filtered and were crystallized from ethanol. The analytical data done
at the Central Laboratory, Faculty of Science, Alexandria University, Egypt, are
given in Table 1.

Dissociation Constants of Substituted Aryl Azo Barbituric and Thiobarbituric Acids 533
Table 1. Analytical data for 5-(substituted phenylazo) barbituric and thiobarbituric acids*.
Compound
Colour
% Calculated
(% Found)
H
C
N
5-(Phenylazo)
barbituric acid
Yellowish green
Yellow
3.4
(3.1)
51.7
(51.5)
24.1
(23.8)
5-(Phenylazo)
3.2
48.4
22.6
thiobarbituric acid
(3.0)
(48.6)
(22.8)
5-(m-Tolylazo)
barbituric acid
Orange
4.0
(3.8)
53.7
(53.3)
22.8
(23.0)
5-(m-Chloro phenylazo)
barbituric acid
Orange
2.6
(2.5)
45.0
(44.9)
21.0
(21.2)
5-(p-Chloro phenylazo)
barbituric acid
Yellow
2.6
(2.8)
45.0
(44.8)
21.0
(20.8)
5-(p-Carboxy phenylazo)
barbituric acid
Yellow
2.9
(3.0)
47.8
(47.5)
20.3
(20.2)
5-(o-Chloro phenylazo)
thiobarbituric acid
Brown
2.5
(2.4)
42.5
(42.2)
19.8
(20.0)
5-(m-Chloro phenylazo)
thiobarbituric acid
Yellowish brown
Yellow
2.5
(2.3)
42.5
(42.3)
19.8
(19.5)
5-(p-Carboxy phenylazo)
2.7
45.2
19.2
thiobarbituric acid
(2.6)
(45.0)
(19.0)
* m.p for all compounds 300 ◦C
Acidity and stability constants were determined by using acid-base titration
technique. A standard 10−2 M KOH solution was prepared in CO2 free distilled
water. 0 5 M KCl was used as a supporting electrolyte. A stream of purified
nitrogen gas was passed through the solution during the whole titration. BDH
spectroscopic quality solvents (dioxane and ethanol) were used. The correc-
tion factor, , for measuring the pH values in different dioxane–water and
ethanol–water concentration was calculated [48]. The values are −0 1 in the
dioxane–water solvents in the concentration ranges 25%–50% and +0 3 in
75% concentration. These values are 0.05 and +0 2 in ethanol–water media,
respectively. The dissociation constants of the organic compounds were deter-
mined by introducing 50 ml10−3 M of the organic compound into the titration
cell in presence of 5 ml 0 5 M KCl solution and different %’s ( ) of ethanol–
water at different temperatures (25–45 ◦C). The same experiment was done in
presence of different %’s ( ) of dioxane–water at 25 ◦C. Cole Palmer pH-
meter model 60648 was used. The electrode system was calibrated before and
after each titration using standard buffers of pH’s 4.01 and 9.14. The titrations
were carried out in 150 ml thermostated cell. The cell compartment was kept
constant at the desired temperature using a thermostat model U10.

534
M. S. Masoud et al.
3. Results and discussion
The potentiometric measurements depend on the evaluation of the average
number of protons associated with the ligand [49], n . This was determined at
¯
A
different pH’s using the simplified following equation [11].
Vt N◦
n = Y −
(1)
¯
A
◦
V CL
◦
Where Vt denotes the volume of alkali required to reach a given pH on the titra-
tion curve, V is the initial volume of the ligand, N◦ is the alkali concentration,
◦
CL◦ is the total concentration of the ligand and Y is the number of displaceable
hydrogen atoms in the ligand. The dissociation constants are obtained by plot-
ting n against pH for the free ligands which gave two pK’s values at n = 0 5
¯
¯
A
A
and 1.5. The data are collected in Tables 2–5. The point-wise method [50] gave
almost same values with 0.02 deviation.
The following points are recorded:
1. The pK values of barbituric and thiobarbituric acids are increased with
increasing the % of the co-solvent ethanol in ethanol–water mixture and
also with increasing the % of dioxane in dioxane–water mixture. Mean-
while, the values of pK for barbituric acid in the dioxane media are higher
than that in the presence of the ethanolic media. The high polarity of
ethanol facilitates the ionization of H+ leading to a relative decrease in
the pK values. In dioxane–water mixtures, increasing the dioxane % leads
to increase the extent of intramolecular hydrogen bonding, retarding the
ionization of H+ leading to increase the pK values. For thiobarbituric
acid, the pK values in 25% and 35% dioxane–water mixtures are lower
than those in the presence of the same concentration of ethanol–water
mixtures.
2. The compounds with o-, m- and p-chloro groups of the entitled se-
ries are with higher pK’s values while the p-carboxy derivatives have
lower pK’s values probably due to that the carboxy group in the p-
position can act as an electron acceptor rather than electron donor [51].
The electronegativity property of the substituent is a major factor for
controlling the behaviour of these compounds. The pK values of 5-
(substituted phenylazo) barbituric and thiobarbituric acids in presence
of 75% ( ) dioxane–water media are relatively higher than that in
presence of 75% ( ) ethanol–water media due to the high polar-
ity of ethanol that facilitates the ionization of H+ leading to increase
in the pK values. 5-(p-carboxy phenylazo) derivatives of both bar-
bituric and thiobarbituric acids gave three pK values in 75% (
)
dioxane–water media while and two pK values in 75% ( ) ethanol–

Dissociation Constants of Substituted Aryl Azo Barbituric and Thiobarbituric Acids 535
water media, Tables 4, 5. The scheme of ionization is represented as
follows:
4. Thermodynamic parameters of ionization
The ∆G, ∆H and ∆S values are evaluated in the temperature range 25–45 ◦C,
Tables 2–5. The equation K = A e−∆H RT is applied for studying the effect of
temperature on the pK’s values. Plotting the pK values versus 1 T, straight
lines are obtained with a slope of ∆H 2 3R, from which the ∆H values
(kJ mol−1) are computed. The free energy values ∆G (kJ mol−1) are calcu-
lated using the equation ∆G = 2 3RT pK. The ∆S (J K−1 mol−1) values are
calculated from the relation ∆G = ∆H − T∆S. In general, the pK values
are decreased with increasing temperature. The values of ∆H based on pK1
and pK2 values for barbituric acid are independent on the %’s of ethanol–
water mixture. The sequence of ∆H values for the barbituric acid compounds
based on the pK values decreases in the following order: m-Cl
H
p-Cl
∼
m-CH3 p-COOH. Thus, the ∆H values of the barbituric acid compounds de-
=
pend on the electronic requirements of the substituent. The values are increased
with increasing electron-withdrawal property. The order of the ∆H values
∼
based on pK values is as follows: H p-Cl m-Cl m-CH3 p-COOH,
i.e. increased with increasing electron withdrawal property. The sequence of
=
2
∆H values for the series of thiobarbituric acid compounds computed from
pK1 is as follows: m-Cl o-Cl
H
p-COOH. However, those values based
on pK2 are as follows: o-Cl m-Cl p-COOH H. On the other hand, the
∆H values for the series of thiobarbituric acid compounds depend on the elec-
tronic character of the substituents rather than the steric hindrance of the group.
The intramolecular hydrogen bonding gives rise to a positive entropy change
whereas the hydrogen bonding to solvent leads to a higher degree of solvent or-
dering with a negative entropy change [52]. The ∆S values for barbituric acid
in different %’s of ethanol–water mixture and for 5-(substituted phenylazo)
barbituric acid in 75% ethanol–water media are attributed to the predominant
presence of intermolecular hydrogen bonding. The same conclusions are ob-
tained for thiobarbituric acid in different %’s of ethanol–water mixture and for
5-(substituted phenylazo) thiobarbituric acid in 75% ethanol–water media. The
+∆S for barbituric and thiobarbituric acids in aqueous media and 50% (
)
ethanol–water proved the presence of both intramolecular and intermolecular
hydrogen bonding [53].

536
M. S. Masoud et al.

Dissociation Constants of Substituted Aryl Azo Barbituric and Thiobarbituric Acids 537

538
M. S. Masoud et al.

Dissociation Constants of Substituted Aryl Azo Barbituric and Thiobarbituric Acids 539

540
M. S. Masoud et al.
In the following, the effect of ethanol and dioxane solvents on the be-
haviour of such compounds is explained from another view. Assume that the j
factor, representing a solvent-transfer number characteristic of the tested chem-
ical reaction, can be attributed to the transfer of the solvent. The following
relation is tested [54, 55].
j log[S]+log K* −log K = −∆Gt 2 303RT − W log [H2O]s [S]
+ j log[H2O]
Where log[H2O]s [S] = X ; j log[S]+log K* −log K = Y
[S] and ∆G represent the solvent concentration and the free energy, respec-
tively. [H2O], [H2O]s are the concentration of water, and that of the co-solvent
molecule. Y is plotted against X. Trail values of j = 1 2 3 4
are used to
find values of W for the gradients of Y vs. X. Fig. 1 is taken as a representative
example. Table 6 includes the slopes of the X–Y relation to give the values for
water in the molecules (W). The obtained data may throw light on the role of
aquation and solvation during the course of dissociation. For barbituric acid in
different %’s of ethanol–water mixtures, the W values for j = 1 and j = 2 at
temperatures from 25–45 ◦C are higher than that of j values to pinpoint more
aquation by increasing the temperature. The values of W are smaller than that
of j = 3 and j = 4 which suggests more solvation. In the temperature range
from 35–45 ◦C, the values of W for different values of j from 1 to 4 are nearly
constant which means that the aquation process is independent on tempera-
ture. For barbituric acid in different %’s of ethanol–water mixtures at 25 ◦C,
the W values are greater than that the values of j which suggest more aqua-
tion. For thiobarbituric acid in different %’s of ethanol–water, the W values
are higher than that of j which suggests more aquation. As a result, the ef-
fect of solvent is of major importance in aquation and solvation during the
dissociation.
Fig. 1. X–Y relationship for pK1 and pK2 of barbituric acid in different %’s of ethanol–
water at 25 ◦C.

Dissociation Constants of Substituted Aryl Azo Barbituric and Thiobarbituric Acids 541
Table 6. Values of (W) in ethanol–water at (25–45 ◦C) and in dioxane–water at 25 ◦C for
different values of ( j).
Temperatures
Barbituric acid
Thiobarbituric acid
j = 1
j = 2
j = 3
j = 4
3.13
2.92
3.05
3.02
3.00
j = 1
0.80
0.78
0.71
j = 2
1.29
1.27
1.25
j = 3 j = 4
25 ◦C
30 ◦C
35 ◦C
40 ◦C
45 ◦C
1.67
2.08
2.60
1.80
2.29
(1.65) (2.03) (2.48)
1.56
(1.67)
1.98
2.05
2.02
2.03
2.40
2.56
2.53
2.54
1.78
1.56
(1.52)
1.53
(1.74)
1.54
dioxane–water
at 25 ◦C
3.14
3.63
(4.17) (4.66) (3.06) (3.55) (4.06) (4.55)
Values in parentheses are for pK2.
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