Kinetics and mechanism of isatin ring opening in aqueous binary mixtures of methanol and acetonitrile cosolvents

Article abstract of DOI:10.1002/(SICI)1097-4601(1998)30:7<463::AID-KIN2>3.0.CO;2-Q

Solvent effects on the kinetics of hydrolysis of isatin by sodium hydroxide have been investigated within the temperature range (30-55 °C) in methanol-water and acetonitrile-water media of varying solvent compositions up to 70% (v/v) of the organic solven

Full text of DOI:10.1002/(SICI)1097-4601(1998)30:7<463::AID-KIN2>3.0.CO;2-Q

Kinetics and Mechanism of
Isatin Ring Opening in
Aqueous Binary Mixtures of
Methanol and Acetonitrile
Cosolvents
A. M. ISMAIL, A. A. ZAGHLOUL
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
Received 10 March 1997; accepted 15 September 1997
ABSTRACT: Solvent effects on the kinetics of hydrolysis of isatin by sodium hydroxide have
been investigated within the temperature range (30–55ЊC) in methanol-water and acetonitrile-
water media of varying solvent compositions up to 70% (v/v) of the organic solvent component.
The thermodynamic activation parameters were calculated and discussed in terms of solvation
effects. The determined isokinetic temperatures, in both systems, revealed the existence of
compensation effect arising from strong solute-solvent interactions; log k was correlated with
both log [H2O] and the reciprocal of the dielectric constant. The first correlation was observed
to be linear while the second was nonlinear. Finally a mechanism for the isatin ring opening
was proposed, which accounts for the role and the effect of the solvent on the reaction rate.
᭧ 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 463–469, 1998
modynamic properties of the activated complex. In
this manner, an analysis of the solvent effect on the
mechanism of isatin ring opening by sodium hydrox-
ide can be made.
INTRODUCTION
Studies on the biological and chemical reactivity of
isatin and its derivatives have been extensively docu-
mented [1–6]. However, only a few studies on the
kinetics of isatin ring opening were reported [7–9].
The present work represents an extension of these
studies in which the kinetics of alkaline hydrolysis of
isatin were investigated in two different mixed solvent
systems namely; methanol-water and acetonitrile-
water, over a wide range of solvent compositions and
temperatures. These media provide a useful range of
dielectric constant and medium effects. Solvation phe-
nomena can be readily accounted for from the ther-
EXPERIMENTAL
Reagents
Isatin of B.D.H. quality was further purified by re-
crystallization from benzene (m.p. 200ЊC). NaOH so-
lution (B.D.H. grade, carbonate free) was standardized
against potassium hydrogen phthalate. The stock so-
lution (5 ϫ 10Ϫ2 M) was kept in a waxed automatic
microburette. Pure cosolvents (B.D.H., AnalaR) were
further purified as recommended [10,11]. The solvent-
water binary mixtures were prepared using double dis-
tilled water.
Correspondence to: A.A. Zaghloul
᭧ 1998 John Wiley & Sons, Inc.
CCC 0538-8066/98/070463-07

464
ISMAIL AND ZAGHLOUL
Spectrophotometric Measurements
The spectra of isatin in water and in MeOH9H2O,
ACN9H2O mixed solvents were recorded on a Pye
Unicam Sp 8–400 spectrophotometer at 25ЊC. The
maximum observed at 300 nm in all media, indicated
that neither methanol nor acetonitrile caused any shift
in the position of absorption. Solution of isatin in
sodium hydroxide, revealed a new maximum at
370 nm, indicating the formation of the product.
Kinetic Measurements
The rate of alkaline hydrolysis of isatin was carried
out by preparing equal volumes of isatin and the alkali
solution. The two solutions were kept in a thermostat
at the required temperature till the thermal equilibrium
was reached. The two solutions were then quickly and
thoroughly mixed. The initial concentrations of isatin
and sodium hydroxide after mixing were 3 ϫ 10Ϫ4 M
and 5 ϫ 10Ϫ3 M, respectively. The zero time was re-
corded and the rate of the reaction was then followed
spectrophotometrically in 1 cm cell using a thermos-
tatted Perkin Elmer (550 A) spectrophotometer (con-
trolled to Ϯ 0.05ЊC). The reaction was followed with
progress of time through the hyperchromic shift,
which occurred at 370 nm.
Figure 1 Variation of velocity constant with water con-
centration: (a) MeOH9H2O and (b) ACN9H2O.
RESULTS AND DISCUSSION
[H2O] correlation (Fig. 1) in which two linear portions
were obtained for each solvent system. These two lin-
ear portions were separated by a sharp boundary at
water concentrations of 39.81 and 37.15 mole/l in
methanol and acetonitrile systems, respectively. This
behavior indicates that the internal structure of the me-
dium suffers serious changes [12] on addition of sol-
vent and reflects the formation of two regions of dif-
ferent medium internal structure which explains their
different behavior towards hydrolysis. In the first re-
gion, which is the region of higher water concentra-
tion, the rate decreases, in both systems, with progres-
sive addition of solvent. This can be explained in terms
of three factors: (a) the decrease in water concentra-
tion; (b) the decrease in the fraction of the free water
molecules due to the fact that addition of solvent
causes the water tetrahedral structure to be gradually
broken by interposition of organic solvent molecules,
and hydrogen bonding between water molecules to be
replaced by the stronger hydrogen bonding between
water and solvent molecules; and (c) the increase of
the hydroxide ion affinity of the medium by the grad-
ual addition of solvent due to the increase in its pref-
erential solvation. The net result is that the rate de-
The rates of alkaline hydrolysis of isatin have been
measured in MeOH9H2O and ACN9H2O media of
different solvent compositions (0–Ϸ65 wt% of or-
ganic solvent component) within the temperature
range of 30–55ЊC. The obtained results fit the pseudo-
first-order rate equation, since the plots of
log Aϰ/Aϰ Ϫ At vs. time exhibited straight lines (over
nearly 90% of the reaction). The first-order rate con-
stants were calculated from the average of duplicate
determinations. The iso-composition activation energy
(Ec), activation energy which is quoted at a fixed wt%
of the organic solvent, was computed for each com-
position in both systems from the linear least-square
Arrhenius plots. Table I collects the obtained values
of the rate constants and the iso-composition activa-
tion energies at different experimental conditions. It is
readily seen from this table, that k is decreasing with
the progressive addition of methanol and over the
whole entire range of the composition, while in case
of ACN9H2O mixtures the trend of reaction rate is
showing a minimum at acetonitrile mole fraction of
0.25. This trend of reaction rates with solvent com-
position can also be observed in the light of log k–log

ISATIN RING OPENING
465
creases in both solvent systems. The slopes of the lines
in this region are 6.8 and 4.4 in methanol and aceton-
itrile systems, respectively.
ond region is Ϫ0.8 which means that the rate begins
to increase with increasing solvent concentration in-
dicating that the last two factors ((i) and (ii)) largely
predominate with the net result that the rate increases
in this particular region of solvent compositions. This
effect arises from the fact that in MeOH9H2O mix-
ture there is usually some enhancement of water struc-
ture when a small amount of organic cosolvent is
added to water, while the addition of larger quantities
disrupted the water structure [13]. Acetonitrile dis-
rupts water structure over the whole range of the com-
position and this shifts the cluster size distribution of
water to smaller configurations [14].
The thermodynamic activation parameters
⌬G#, ⌬H#, and ⌬S#, under different experimental con-
ditions, were calculated by applying the least-squares
procedures and are given in Table I together with their
standard deviations. Figures 2 and 3 represent the vari-
ation of these parameters with the mole fraction (X2)
of each organic solvent component at 25ЊC. The pro-
file of the curves obtained predicts that a compensation
effect may exist between ⌬H# and ⌬S#. It is seen that,
in each solvent system, both ⌬H# and ⌬S# curves pass
through one minimum and one broad maximum. In
In the second region, region of smaller water con-
centration, the decrease in reaction rate in MeOH9
H2O, with progressive addition of solvent becomes
less pronounced and the slope of the line decreases to
2.7. This small decrease in reaction rate may be due
to two factors: (i) on gradual addition of organic sol-
vent the tetrahedral structure of water has been largely
broken, further addition of solvent molecules, al-
though resulting in a decrease in water concentration,
will be hydrogen bonded with each other and will have
little effect on the free water molecules which prefer-
entially solvate the activated complex. Hence, the
availability of water molecules in this range of solvent
compositions is greater than that in the previous re-
gion; and (ii) the hydroxide ion affinity of the medium
is decreased since the water molecules associated with
the hydroxide ion are being gradually freed. These fac-
tors compensate part of the effect due to the decrease
in water concentration and the net decrease in rate be-
comes less than that in the previous range. In case of
ACN9H2O, the slope of the line obtained in the sec-
Table I First-Order Rate Constant 104 k (sϪ1) at Different Temperatures and Thermodynamic Data at 25ЊC for the
Alkaline Hydrolysis of Isatin by NaOH in ACN9H2O and MeOH9H2O Mixtures
MeOH ϩ H2O
Solvent wt%
Temp.
(ЊC)
0.00
8.08
16.52
25.33
34.52
44.20
54.30
64.89
40
45
50
55
33.1
40.5
49.1
59.3
8.79
12.0
14.1
16.6
7.91
10.5
13.0
14.4
3.57
5.60
7.18
9.80
2.07
2.65
3.68
4.72
0.959
1.23
1.59
1.92
0.546
0.863
1.25
0.354
0.541
0.811
1.27
104 k
1
(sϪ
)
1.80
Ec
1
(k J moleϪ
)
33.2 Ϯ 1.9
30.7 Ϯ 2.0
194 Ϯ 6
32.9 Ϯ 4.8
30.4 Ϯ 4.8
206 Ϯ 15
92 Ϯ 9
33.6 Ϯ 4.1
31.1 Ϯ 4.1
204 Ϯ 13
92 Ϯ 8
55.5 Ϯ 8.5
52.9 Ϯ 8.5
141 Ϯ 27
95 Ϯ 16
49.5 Ϯ 4.3
47.0 Ϯ 4.3
166 Ϯ 13
96 Ϯ 8
38.4 Ϯ 2.6
35.9 Ϯ 2.7
207 Ϯ 8
66.5 Ϯ 1.6
63.9 Ϯ 1.6
122 Ϯ 5
70.2 Ϯ 2.2
67.7 Ϯ 5.2
114 Ϯ 7
⌬H#a
Ϫ⌬S#b
⌬G#a
89 Ϯ 4
98 Ϯ 5
100 Ϯ 3
102 Ϯ 4
ACN ϩ H2O
Solvent wt%
Temp.
(ЊC)
0.00
7.99
16.35
25.10
34.20
43.89
53.98
64.60
30
35
40
45
21.7
26.9
33.1
40.5
10.6
13.8
17.7
22.7
7.90
10.5
13.8
18.0
5.34
6.88
8.79
11.1
4.41
5.72
7.37
9.41
4.81
5.92
7.25
8.81
4.96
6.38
8.12
10.3
6.40
8.45
11.1
14.4
104 k
1
(sϪ
)
Ec
1
(k J moleϪ
)
33.2 Ϯ 1.9
30.7 Ϯ 2.0
194 Ϯ 6
40.7 Ϯ 2.8
38.2 Ϯ 2.8
175 Ϯ 9
43.9 Ϯ 2.0
41.4 Ϯ 2.0
167 Ϯ 7
39.2 Ϯ 1.8
36.8 Ϯ 1.8
186 Ϯ 6
40.6 Ϯ 2.5
38.1 Ϯ 2.5
183 Ϯ 8
32.4 Ϯ 2.4
30.0 Ϯ 2.4
209 Ϯ 8
38.9 Ϯ 1.4
36.3 Ϯ 1.4
188 Ϯ 5
43.3 Ϯ 2.3
40.8 Ϯ 2.3
171 Ϯ 7
⌬H#a
Ϫ⌬S#b
⌬G#a
89 Ϯ 4
91 Ϯ 5
91 Ϯ 3
92 Ϯ 4
93 Ϯ 5
92 Ϯ 5
93 Ϯ 3
92 Ϯ 4
1
a kJ molϪ
.
b J molϪ degϪ
.
1
1

466
ISMAIL AND ZAGHLOUL
Figure 2 Dependence of the thermodynamic parameters of
activation on the composition of ACN9H2O mixtures.
Figure 3 Dependence of the thermodynamic parameters of
activation on the composition of MeOH9H2O mixtures.
MeOH9H2O medium the maximum and minimum
are at X2 ϭ 0.16–0.23 and X2 ϭ 0.3, respectively, in
the same region determined previously for MeOH-
water mixtures [15], while in case of ACN9H2O
medium the maximum is found to be at X2 ϭ
0.04–0.19 and the minimum at X2 ϭ 0.25 and, also,
in good agreement with previously reported results in
ACN9H2O mixtures [16]. The observation of these
extrema can be visualized in the light of change of
water structure [17,18] in the presence of the organic
solvent. This type of variation is associated with sol-
vent shell reorganization of the substrate in the initial
and transition states which contributes appreciably to
the overall activation enthalpy and entropy of the re-
action [19]. Moreover, the weak dependence of ⌬G#,
in both solvent systems, upon composition of the or-
ganic solvent can be attributed largely to the general
linear compensation between ⌬H# and ⌬S#. The non-
linear variation of ⌬S# with the mole fraction in both
systems is a criterion of specific solvation where the
random distribution of two solvent components is not
valid in the absence of strong hydrogen-bonding be-
tween water molecules and the organic solvent mole-
cules [20]. Furthermore, the highly negative ⌬S# val-
ues, Table I, support the formation of highly restricted
transition state. The strong electrostriction developed
in the activated state restricts the freedom of motion
of solvent molecules in the neighborhood of the acti-
vated species and causes loss of entropy.
The plot of ⌬H# vs. ⌬S#, for different solvent com-
positions at 25ЊC was found to be linear in both solvent
systems. The isokinetic temperature (␤) was computed
from the slopes of such plots. The ␤ values are 313
and 320 K for ACN9H2O and MeOH9H2O
mixtures, respectively, which are fairly close
to the experimental temperature range studied
(303–328 K) confirming the existence of compensa-
tion effect, where the solute-solvent interactions play
an important role [21].

ISATIN RING OPENING
467
Figure 4 Variation of log k with 1/D at 25ЊC.
The effect of dielectric constant on the hydrolysis
rate of isatin was investigated in the light of the cor-
relation of log k vs. the reciprocal of the dielectric
constant (D) whose values were interpolated from the
where ⌬GtЊ (Tr.) and ⌬GtЊ (In.) are the free energy of
transfer of the transition state and initial state, respec-
tively. Thus, deviation from linearity reflects the
greater solvation of the activated complex motion of
solvent molecules surrounding the activated species.
This is in quite agreement with the negative ⌬S# values
obtained in both solvent media.
˚
data of Akerlof [22] and Moreau [23]. It is clear from
Figure 4 which represents this correlation in both sol-
vent systems, that it is not linear in both cases. The
electrostatic treatment of reaction rate, on the basis of
point charge in a dielectric continuum suggested that
1
the plots of log k against DϪ , should be linear [24,25].
The failure of the simple electrostatic interpretation,
led to the conclusion that the nonelectrostatic part of
solvent effect overcomes the electrostatic part [24]. In
such cases, the differential solvation of the initial and
transition states is the controlling factor for changes in
the rate constant with the solvent composition. This
was shown from the extension of the equation of Laid-
ler and Landskroaner [26] which allowed for the
changes in solvent structure with varying solvent com-
position:
Proposed Reaction Mechanism
The reaction of isatin with sodium hydroxide in water
takes place through the cleavage of the amide bond
and formation of a ring-opened amino acid [9]. This
ring opening is reversible and acidification reforms
isatin. Changes in the UV spectrum with pH indicated
[9] that above pH 6 the ring-opened form predomi-
nates. Thus, according to this fact and in the light of
all considerations, taking care of in this study, a mech-
anism for the ring opening of isatin by sodium hy-
droxide is proposed which would account satisfacto-
rily for both water dependence and effect of solvent
on reaction rate. This mechanism is similar to that
proposed earlier [27] and may be outlined in the
form:
⌬GtЊ(Tr.) ϾϾ ⌬GtЊ(In.)
or
⌬GtЊ(In.) ϾϾ ⌬GtЊ(Tr.)

468
ISMAIL AND ZAGHLOUL
O
C
x1H2O
k2
k1
C␦ϩ
O
␦Ϫ ϩ x2H2O . . . . OH . . . . y2S ϩ nH2O
y1S
N
H
(I)
O
C
OϪ (x1 ϩ x2 ϩ n)H2O
OH (y1 ϩ y2 Ϫ n)S
nS ϩ
C
N
H
(T)
O
C
OH
k3
T ϩ H2O
C
O
ϩ OH ϩ (x1 ϩ x2 ϩ n)H2O ϩ (y1 ϩ y2 Ϫ n)S
slow
NH2
Assuming that a steady-state concentration is attained
ment with other proposed bimolecular mechanisms
in the mixed solvent for intermediate T,
[28,29] and support the above mechanism.
k1[I][OH][H2O]n
T ϭ
k2[S]n ϩ k3[H2O]
BIBLIOGRAPHY
and, the rate ϭ k3 [T] [H2O]
1. W. R. Romanchick and M. M. Joullie, Heterocycles, 9,
1631 (1978).
2. F. D. Popp and H. Pajouhesh, J. Pharm. Sci., 71, 1051
(1982).
k3k1[I][OH][H2O]n
ϩ1
T ϭ
k2[S]n ϩ k3[H2O]
3. M. G. Karp, Org. Prep. Proced. Int., 25, 481 (1993).
4. A. A. El-Gendy, N. A. Abdou, E. Z. Sarhan, H. A. El-
Banna, Alex. J. Pharm. Sci., 7, 99 (1993).
5. V. Srivastava, S. Sen, and R. Shekhar, Indian J. Chem.,
32B, 946 (1993).
k3 ϽϽ k2 and so, k3 [H2O] can be neglected in the de-
nominator, so;
ϩ1
k1k3 [I][OH][H2O]n
Rate ϭ
6. G. N. Mitra and S. S. Guhasircar, J. Indian Chem. Soc.,
32, 7 (1995).
k2
[S]n
7. A. M. Ismail, Alex. J. Pharm. Sci., 6, 67 (1992).
8. A. M. Ismail, I. M. Sidahmed and El-Sayed H. El-
Ashry, Alex. J. Pharm. Sci., 8, 211 (1994).
9. L. A. Casey, R. Galt and M. I. Page, J. Chem. Soc.
Perkin Trans., 2, 23 (1993).
10. A. D’Aprano and R. M. Fuoss, J. Phys. Chem., 73, 400
(1969).
11. A. I. Vogel, “A Text Book of Practical Organic Chem-
istry”, 3rd ed., Longmans, London (1971).
12. E. Tommila, M. Tulikainen, A. Viopio, Acta. Chem.
Scand., 9, 975 (1955).
ϩ
1
Thus, the rate varies directly with [H2O]n and in-
versely with [S]n and so the rate increases on increas-
ing water and decreasing solvent concentrations. And
since the rate of reaction ϭ kobs [Isatin]
ϩ1
k1k3 [OH][H2O]n
kobs
ϭ
k2
[S]n
where, kobs is the observed pseudo-first-order rate
constant. The values of Ec and the large negative ⌬S#
values obtained in our study are in excellent agree-
13. M. J. Blandamer and J. Burgess, Quat. Rev., 4, (1), 55
(1975).

ISATIN RING OPENING
469
˚
22. G. Akerlof¨, J. Amer. Chem. Soc., 54, 4125 (1932).
23. C. Moreau and G. Douheret, J. Chem. Thermody., 8,
403 (1976).
24. K. J. Laidler and P. A. Landskroener, Trans. Faraday
Soc., 52, 200 (1956).
25. E. S. Amis. Kinetics of Chemical Change in Solution,
Macmillan, New York, Chap. 5 and 9 (1949).
26. C. F. Wells, J. Chem. Soc., Far. Trans., 73, 1851 (1977).
27. C. F. Wells, Discuss. Faraday Soc. 39, 132 (1965).
28. M. M. Elsemongy, M. S. Abu Elamayam, M. N. H.
Moussa and M. M. Gouda, J. In. Chem. Soc., LII, 1130
(1975).
14. H. Talukdar and K. K. Kundu, J. Phys. Chem., 96, 970
(1992).
15. M. F. Amira, Sh.A. El-Shazley and A. A. Zaghloul, Int.
Conf. Coord. Chem., Greece, 545 (1986).
16. I. M. Sidahmed and A. M. Ismail, Trans. Met. Chem.,
12, 29 (1987).
17. H. B. Benetto and C. F. Caldin, J. Chem. Soc., A, 2191
(1971).
18. E. M. Arnette, W. G. Bentrade, J. J. Bruke and P. Dug-
gleby, J. Am. Chem. Soc., 87, 154 (1965).
19. A. C. Dash and N. Dash, In. J. Chem. Kinetics, 21, 101
(1989).
20. R. F. Hudson and B. J. Saville, J. Chem. Soc. 4114
(1955).
21. R. Lumry and S. Rajender, Biopolymers, 9, 1125 (1970).
29. M. M. Elsemongy, M. S. Abu Elamayam and M. N. H.
Moussa, Z. Phys. Chemie. Neue Folge, 95, 215
(1975).