Aminolysis of isatin and N-acetyl isatin in acetonitrile and mixed acetonitrile-water solvents

Article abstract of DOI:10.14233/ajchem.2014.16968

The reactions of N-acetyl isatin and N-propionyl isatin with morpholine, piperazine and diethylamine in acetonitrile underwent nucleophilic substitution reactions at the amide linkage with ring opening process to give N-[2-(2-amino-2-oxo-acetyl)phenyl]ace

Full text of DOI:10.14233/ajchem.2014.16968

Asian Journal of Chemistry; Vol. 26, No. 23 (2014), 8029-8038
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16968
Aminolysis of Isatin and N-Acetyl Isatin in Acetonitrile and Mixed Acetonitrile-Water Solvents
1
1
1
1,3,4,*
MAHMOUD F. IBRAHIM , ASMA A.A. AL-KAREWI , SHERINE N. KHATTAB , EZZAT A. HAMED1,2,* and AYMAN EL-FAHAM
1Department of Chemistry, Faculty of Science, Alexandria University, Ibrahimia 21321, P.O. Box 426, Alexandria, Egypt
2Department of Chemistry, Faculty of Science, Beirut Arab University, Beiurt, Lebanon
3Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, 11451 Riyadh, Kingdom of Saudi Arabia
4Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain
*Corresponding authors: Tel: +961 71244851; E-mail: ezzatah2@hotmail.com (E. A. Hamed);
Fax: +2 03 5771399; Tel.: +2 0122 3140924; E-mail: aymanel_faham@hotmail.com (A. El-Faham)
Received: 31 December 2013;
Accepted: 17 June 2014;
Published online: 15 November 2014;
AJC-16288
The reactions of N-acetyl isatin and N-propionyl isatin with morpholine, piperazine and diethylamine in acetonitrile underwent nucleophilic
substitution reactions at the amide linkage with ring opening process to give N-[2-(2-amino-2-oxo-acetyl)phenyl]acetamide derivatives
and N-[2-(2-amino-2-oxoacetyl)phenyl]propionamide derivatives, respectively. The rate constants of the titled reactions were studied
spectrophotometerically in pure acetonitrile and acetonitrile-water mixed solvent. The reactions in pure acetonitrile obeyed third order
kinetics. The activation parameters suggest that the mechanism of the reaction proceeds by parallel specific base and dimer mechanisms
depending on temperature and the nature of amine. The reaction of isatin with piperazine in acetonitrile-water mixed solvent passes
through formation of solvated intermediate which in turn gives zwitterionic ion intermediate that leads to the final product in a slow step.
The nonlinear plots of log kN versus 1/D of the binary solvent as well as the plot of log kN versus XH2O, indicate a specific solvation. The
plot of log kN versus log [H2O] gives the number of water molecules (n) contaminated in the transition state. The inversely proportional
correlation between EN and log kA values agrees with the formation of solvated zwitterionic (tetrahedral) intermediates in the rate
T
determined step. The application of multiparameter approach of α, β and π* indicates that the rate of the reaction is influenced by both
specific and nonspecific solute-solvent interactions.
Keywords: Isatin, N-acetyl isatin, Kinetics, Morpholine, Piperazine, Diethylamine.
The two carbonyl groups of isatin showed different beha-
viour toward nucleophilic reagents. This is because the 2-
carbonyl group has considerable amide character, thus redu-
cing its electrophilic properties. While conjugation of the lone
pair electrons on nitrogen through the benzene ring with 3-
carbonyl group is not favored because it destroys the aroma-
ticity of the benzene ring.
INTRODUCTION
Isatin derivatives were precursors for synthesis of different
heterocyclic compounds1. They exhibit broad spectrum of
biological activities such as antiviral, antibacterial, antibiotic,
antitumor, antipyretic, antispasmodic and anesthetic2-7 and
were also successfully used in the treatment of hyperplasia8.
Isatin was also used as calorimetric reagent for quantitative
determination of proline in maize and wheat9. It is further
employed as an inhibitor for glucose in flux into human
erythrocytes10.
On this basis, selective addition at C-3 should be possible.
It is well known that carbonyl (C-2) and (C-3) undergo
nucleophilic attack to form the tetrahedral intermediate12-21. The
tetrahedral intermediate from C-3 gains a proton and the result
is addition. The tetrahedral intermediate from C-2 attack ejects
C6H5-N-R and the result is substitution. The ease with which
C6H5N-R is lost depends on its basicity i.e. the weaker the base,
the better the leaving group. But in case of the nucleophilic attack
at C-3 to undergo substitution, the leaving group would have to
be C6H5NR-C=O which is hardly formed and accordingly C-3
addition almost always takes place instead, Scheme-I.
Reactivity of isatin and isatin derivatives: Isatin 1 is an
orange solid which upon dissolution in water of pH > 11 forms
a deep-violet colour and it does not preclude reaction at C-3
probably due to formation of highly conjugated anion 2
(Fig. 1). The violet colour is not formed with N-acetyl isatins
presumably due to the absence of the hydrogen atom of the
N-H group. The formation of yellow colouration is due alkaline
hydrolysis of the isatin to the ring-opened amino acid. This
ring opening is reversible and acidification reforms isatin11.
Most reactions of hydroxide ion and secondary amine with
isatin and N-alkyl isatins in aqueous cosolvents underwent

8030 Ibrahim et al.
Asian J. Chem.
O
O
the amine leaving group. These requirements are met in isatin
1 and its derivatives 3, 4 (Fig. 2) with activating α-carbonyl
group and stabilizing the expelled amine anion. Other factors
which affected the rate of ring opening of isatins are the nature
of the nucleophile, the solvato-chromic parameters of the
solvent, as well as the pH of the medium11.
O
O
N
H
N
1
2
Fig. 1. Structure of isatin 1 and its conjugated anion 2
O
O
O
N
R
O
O
O
Nu
Nu: OH, 2°-amines
N
O
O
Nu
C
N
N
R
R
O
R
3, R = CH3
4, R = CH2CH3
O
O
Fig. 2. N-acetyl isatin 3 and N-propionyl isatin 4
O
Nu
O
It has been reported that the aminolysis of amides such as
isatin and N-substituted isatins can proceed by two mecha-
nisms, depending on the basicity of the amine, the nature of
C
Nu
N
N
R
R
the leaving group and the solvent used, Scheme-III2-11,31,32
.
O
O
O
O
a
O
Nu
k
1
+
NH
R
HN
O
k
-1
N
R
HN
N
R
Am, -H+
kAm
Scheme-I: Nucleophilic attack at carbonyl (C-2) and (C-3)
b
Zwitterionic intermediate
nucleophilic substitution reactions at the amide linkage with
ring opening process22-27. Whereas the reaction of isatin and
N-alkyl isatins with reagents such as HCN, sodium bisulfate,
hydroxylamine, phenyl hydrazine and primary amines were
reported28-30, Scheme-II. On the other hand, the rate and
mechanism of ring opening of isatin 1 and N-substituted isatins
3, 4 showed great dependence on the water molecules present
O
O
k
2
O
O
N
R
N
N
NH3
Tetrahedral
intermediate
R
O
O
N
in the reaction mixture22-27
.
k
3
NH
O
R
Scheme-III: Two possible mechanisms of aminolysis of isatin and
N-substituted isatins
NuH
O
N
R
The nucleophilic acetyl substitution mechanism in pure
acetonitrile can proceed by a concerted mechanism (Scheme-
III, pathway b), or a stepwise mechanism in which the rate
determining step is the formation of a tetrahedral intermediate
or the proton transfer process (kAm) or may be the expulsion
of the leaving group (Scheme-III, pathway a). An alternative
process is the dimer mechanism.
Addition-
OH-, 2o-amine
Ar-NH-NH2
elimination =
Acyl substitution
R-NH2
Ar-NH2
condensation
O
N
O
Isatin can undergo keto-enol tautomerism and the enol
form is stabilized by hydrogen bonding with the oxygen of
the adjacent carbonyl group 5 (Fig. 3). This stability does not
exist in case of the N-substituted isatins in the ground state
and consequently the reactivity towards nucleophiles must
increase compared to isatin itself. Furthermore, the dipole-
dipole repulsion in the α-diketo form of N-substituted isatins
is reduced by enolization33 and thus their reactivity toward
nucleophile is increased.
O
Nu
NH
N
R
R
Scheme-II: Reaction of isatin and N-alkyl isatins with different nucleophiles
Accordingly, in isatin the two important aspects which
facilitate the C-N bond fission are the activation of the carbonyl
group C-2 towards nucleophilic attack and the stabilization of

Vol. 26, No. 23 (2014)
Aminolysis of Isatin and N-Acetyl Isatin in Acetonitrile and Mixed Acetonitrile-Water Solvents 8031
1857), IR (KBr, νmax, cm-1): 3304 (NH), 1697 (C=O), 1651
(C=O). 1H NMR (CDCl3): δ 2.28 (s, 3H, CH3), 3.38 (t, 2H, J =
4.5 Hz, CH2), 3.68 (t, 2H, J = 4.5 Hz, CH2), 3.82 (m, 4H,
O
H
O
2CH2), 7.17 (t, 1H, J = 8.4 Hz, Ar-H), 7.63-7.71 (m, 2H, Ar-
H), 8.81 (d, 1H, J = 8.4 Hz, Ar-H), 11.25 (s, 1H, NH, D2O
exchangeable). Elemental analysis Calcd for C14H6N2O4: C,
N
5
Fig. 3. Enol form of isatin is stabilized by hydrogen bonding
60.86; H, 5.84; N, 10.14 %. Found:C, 60.43; H, 5.51; N, 10.49 %.
N-[2-{2-Oxo-2-(piperazin-1-yl)acetyl}phenyl]acet-
amide (6b): The product was obtained as yellow powder (0.13
g; 86.7 % yield) (m.p. 57-58 °C); UV (CH3CN): λmax = 348
nm (ε = 1979), IR (KBr, νmax, cm-1): 3438 (NH), 1692 (C=O),
According to the previous introduction, the reactivity of
reaction centers in isatin and N-substituted derivatives (C-2
and C-3) as well as the mechanism depend on nature of the
nucleophile, necessity of water, type of N-substituent and the
properties of pure or binary solvents (water + organic solvent).
The aim of this study is to investigate the effect of solvato-
chromic parameters on rate and mechanism for the reaction
of piperazine with isatin in several acetnitrile-water mixed
solvents. Furthermore, the effect of N-acetyl and N-propionyl
substituent in isatin on rate and mechanism for their reactions
with morpholine, piperazine and diethylamine in pure aceto-
nitrile was studied.
1
1649 (C=O), 1588.67 (C=O). H NMR (CDCl3): δ 2.30 (s,
3H, CH3), 2.83-2.94 (m, 2H, CH2), 2.97-3.01 (m, 2H, CH2),
3.33 (t, 2H, J = 5.4 Hz, CH2), 3.76 (t, 2H, J = 5.4 Hz, CH2),
5.47 (s, 1H. NH, D2O exchangeable), 7.13-7.18 (m, 1H, Ar-
H), 7.62-7.70 (m, 2H, Ar-H), 8.80 (d, 1H, J = 8.1 Hz, Ar-H),
11.28 (s, 1H, NH, D2O exchangeable). Elemental analysis
Calcd for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26 %. Found:
C, 61.41; H, 6.51; N, 15.61 %.
2-(2-Acetamidophenyl)-N,N-diethyl-2-oxoacetamide
(6c): The product was obtained as brown powder (0.2 g; 89.3
% yield) (m.p. 60-61 °C); UV (CH3CN): λmax = 306 nm (ε =
2321), IR (KBr, νmax, cm-1): 3435 (NH), 1639 (C=O), 1531
EXPERIMENTAL
Acetonitrile was obtained from PROLABO, BDH and
were used without further purification. Morpholine, piperazine
and diethylamine were obtained from Aldrich and were
distilled before use. Melting points were determined with a
Mel-Temp apparatus and are uncorrected. The UV spectra were
carried out on a 160-A UV-visible recording spectrophotometer
Shimadzu. Infrared spectra (IR) were recorded on a Perkin-
Elmer 1600 series fourier transform instrument as KBr pellets.
Nuclear magnetic resonance spectra (1H NMR spectra) were
recorded on a JOEL 500 MHz spectrometer with chemical
shift values reported in δ units (ppm) relative to an internal
standard. Elemental analyses were performed on Perkin-Elmer
2400 elemental analyzer and the values found were within
0.3 % of the theoretical values. Follow-up of the reactions
and checks of the purity of the compounds was done by TLC
on silica gel-protected aluminum sheets (Type 60 GF254,
Merck) and the spots were detected by exposure to UV-lamp
at λmax = 254 nm for a few seconds. The compounds were
named using chem. Draw ultra version 11, Cambridge soft
Corporation.
1
(C=O), 1451.27 (C=O). H NMR (CDCl3): δ 1.35-1.40 (m,
6H, 2 CH3), 2.24 (s, 3H, CH3), 3.00 (q, 4H, J = 7.2 Hz, 2 CH2),
7.05 (t, 1H, J = 7.8 Hz, Ar-H), 7.35 (t, J = 7.8 Hz, H, Ar-H),
7.89 (d, 1H, J = 7.8 Hz, Ar-H), 8.72 (d, 1H, J = 7.8 Hz, Ar-H),
11.50 (s, 1H, NH, D2O exchangeable). Elemental analysis
Calcd for C14H18N2O3: C, 64.10; H, 6.92; N, 10.68 %. Found:
C, 64.39; H, 6.67; N, 10.53 %.
Preparation of N-[2-(2-amino-2-oxo-acetyl)phenyl]-
propionamide derivatives (7): A solution (10 mL) of 1-pro-
pionylindoline-2,3-dione (4) (0.406 g, 2 mmol) and (4 mmol)
of the respective secondary amines (morpholine, piperazine,
diethylamine in acetonitrile was stirred for 3 h. The organic
solvent was evaporated under vacuum. The crude products in
case of morpholine and diethyl amine were dissolved and
diluted with CH2Cl2 (50 mL), the organic phase was collected
and washed with 5 % citric acid (30 mL) twice and saturated
aqueous NaCl (30 mL), dried over anhydrous Na2SO4 and then
filtered and the solvent was then removed on a rotary
evaporator. The residue was further recrystallized from ethanol.
In case of piperazine the crude product was directly
recrystallized from ethanol. The purity was checked by TLC
(1:1 ethyacetate: n-hexane).
Synthesis of N-[2-(2-amino-2-oxoacetyl)phenyl]aceta-
mide derivatives (6): A solution (10 mL) of 1-acetylindoline-
2,3-dione (3) (0.378 g, 2 mmol) and (4 mmol) of the respective
secondary amine (morpholine, piperazine, diethylamine) in
acetonitrile was stirred for 3 h. The organic solvent was evapo-
rated under vacuum. The crude products in case of morpholine
and diethyl amine were dissolved diluted with CH2Cl2 (50 mL),
the organic phase was collected and washed with 5 % citric
acid (30 mL) twice and saturated aqueous NaCl (30 mL), dried
over anhydrous Na2SO4 and then filtered and the solvent was
then removed on a rotary evaporator. The residue was further
recrystallized from ethanol. In case of piperazine the crude
product was directly recrystallized from ethanol. The purity
was checked by TLC (1:1 ethyacetate: n-hexane).
N-[2-(2-Morpholino-2-oxoacetyl)phenyl]propionamide
(7a): The product was obtained as orange powder (0.11 g;
78.6 % yield) (m.p. 95-96 °C); UV (CH3CN): λmax = 336 nm
(ε = 2318), IR (KBr, νmax, cm-1): 3274 (NH), 1705 (C=O),
1
1651 (C=O). H NMR (CDCl3): δ 1.30 (t, 3H, J = 7.5 Hz,
CH3), 2.52 (q, 2H, J = 7.5 Hz, CH2), 3.38 (t, 2H, J = 4.5 Hz,
CH2), 3.68 (t, 2H, J = 4.5 Hz, CH2), 3.81 (m, 2H, 2CH2), 7.16
(t, 1H, J = 7.5 Hz, Ar-H), 7.63-7.70 (m, 2H, Ar-H), 8.84 (d,
1H, J = 8.1 Hz, Ar-H), 11.27 (s, 1H, NH, D2O exchangeable).
Elemental analysis Calcd for C15H18N2O4: C, 62.06; H, 6.25;
N, 9.65 %. Found: C, 62.37; H, 5.97; N, 9.26 %.
N-[2-(2-Morpholino-2-oxoacetyl)phenyl]acetamide
(6a): The product was obtained as beige powder (0.12 g; 82.2
% yield) (m.p. 115-116 °C); UV (CH3CN): λmax = 347 nm (ε =
N-[2-{2-Oxo-2-(piperazin-1-yl)acetyl}phenyl]propion-
amide (7b): The product was obtained as yellow powder (0.12
g; 85.7 % yield) (m.p. 103-104 °C); UV (CH3CN): λmax = 346

8032 Ibrahim et al.
Asian J. Chem.
nm (ε = 1116), IR (KBr, νmax, cm-1): 3524 (NH), 3303 (NH),
where A0, At and A∞ are the values of absorbance at zero time,
time t and at the end of the reaction, respectively. The A∞ for
each run was taken as the experimentally determined values
and kΨ is the pseudo-first-order rate constant.
1
1706 (C=O), 1639 (C=O). H NMR (CDCl3): δ 1.30 (t, 3H,
J = 7.2 Hz, CH3), 2.52 (q, 2H, J = 7.2 Hz, CH2), 2.86 (t, 2H,
J = 5.4 Hz, CH2), 2.95-3.01 (m, 2H, CH2), 3.33 (t, 2H, J = 5.4
Hz, CH2), 3.76 (t, 2H, J = 5.4, 2CH2), 5.46 (s, 1H, NH), 7.15
(t, 1H, J = 8.4 Hz, Ar-H), 7.62-7.70 (m, 2H, Ar-H), 8.83 (d,
1H, J = 8.4 Hz, Ar-H), 11.31 (s, 1H, NH, D2O exchangeable).
Elemental analysis Calcd for C15H19N3O3: C, 62.27; H, 6.62;
N, 14.52 %. Found: C, 61.87; H, 6.31; N, 14.90 %.
The plots of kΨ against amine concentrations give scattered
correlation. While the plots of kΨ values against the square
amine concentrations gave good straight lines with negligible
intercepts and correlation coefficient r = 0.99 for 6a-c and
7a-c. Generally, six different amine concentrations were used
to calculate third-order rate constants k3 L2 mol-1 s-1, i.e. the
kinetic and mechanism depends on two amine molecules. The
k3 L2 mol-1 s-1 values for the aminolysis of N-acetyl isatin (3)
and N-propionyl isatin (4) were determined (Table-1).
Reaction of piperazine with isatin 1 in water-acetonitrile
at 25 °C: The study examines the effect of the solvatochromic
parameters of the water-acetonitrile mixed solvent on rate and
mechanism. The reaction of isatin 1 with piperazine in five
ratio of water-acetonitrile mixed solvent proceeded with
quantitative formation of isatamide 1-(2-aminophenyl)-2-
(piperazin-1-yl)ethane-1,2-dione (8). The isolation of this
product indicates that the reaction under investigation
undergoes nucleophilic acetyl substitution at C-2.All reactions
studied in this part obeyed pseudo-first-order kinetics under
excess piperazine. Pseudo-first-order rate constants (kΨ) were
calculated from the average of duplicate determinations using
eqn. 2.
N-[2-{2-(Diethylamino)-2-oxoacetyl}phenyl]propion-
amide (7c): The product was obtained as orange powder (0.23
g; 85.2 % yield) (m.p. 72-73 °C); UV (CH3CN): λmax = 345
nm (ε = 1575), IR (KBr, νmax, cm-1): 3458 (NH), 1705 (C=O),
1
1641 (C=O). H NMR (CDCl3): δ 1.18 (t, 3H, J = 7.2 Hz,
CH3), 1.28-1.33 (m, 6H, 2CH3), 2.52 (q, 2H, J = 7.2 Hz, CH2),
3.25 (q, 2H, J = 7.5 Hz, CH2), 3.57 (q, 2H, J = 7.5, CH2), 7.13
(t, 1H, J = 7.8 Hz, Ar-H), 7.60-7.65 (m, 2H, Ar-H), 8.81 (d,
1H, J = 9.3 Hz, Ar-H), 11.35 (s, 1H, NH, D2O exchangeable).
Elemental analysis Calcd for C16H21NO3: C, 69.79; H, 7.69;
N, 5.09 %. Found: C, 70.20; H, 7.33; N, 5.44 %.
Preparation of 1-(2-aminophenyl)-2-(piperazin-1-
yl)ethane-1,2-dione (8): A solution (10 mL) of indoline-2,3-
dione (1) (0.294 g, 2 mmol) and (4 mmol) of piperazine, in
acetonitrile was stirred for 3 h. The organic solvent was evapo-
rated under vacuum. The crude product was directly recrysta-
llized from MeOH/EtOAc. The purity was checked by TLC
(1:1 ethyacetate: n-hexane). The product was obtained as brown
powder (0.26 g; 83.9 % yield) (m.p. 180-181 °C); UV (CH3CN):
λmax = 367 nm (ε = 411), IR (KBr, νmax, cm-1): 3437 (NH),
ln (A∞-At) = -kΨ + c
(2)
The second order rate constants (kN) were obtained from
dividing the average kΨ value by the corresponding piperazine
concentration.
1
2852 (NH), 1712 (C=O), 1623 (C=O). H NMR (CDCl3): δ
2.91 (s, 1H, NH, D2O exchangeable), 3.37-3.50 (m, 4H, 2CH2),
3.77-3.90 (m, 4H, 2CH2), 6.37 (m, 2H, NH2, D2O exchan-
geable), 6.66-6.73 (m, 2H, Ar-H), 7.33-7.46 (m, 2H, Ar-H).
Elemental analysis Calcd for C12H15N3O2: C, 61.79; H, 6.48;
N, 18.01 %. Found: C, 62.08; H, 6.14; N, 17.76 %.
RESULTS AND DISCUSSION
Preparation of 2-(2-acetamidophenyl)-2-oxoacetamide
derivatives (6a-c) and N-[2-(2-amino-2-oxoacetyl)phenyl]-
propionamide derivatives (7a-c): The reactions of 3 and 4
with morpholine, piperazine and diethylamine in pure aceto-
nitrile at room temperatures undergo nucleophilic acetyl ring
opening process and gave N-[2-(2-amino-2-oxoacetyl)phenyl]-
acetamide derivatives (6a-c) and N-[2-(2-amino-2-oxoacetyl)-
phenyl]propionamide derivatives (7a-c), respectively. Also,
carrying out these reactions at 50 °C, gave the same substitution
products 6a-c and 7a-c without complications or side products,
Scheme-IV. Elemental analysis, IR and 1H NMR spectroscopy
were used to confirm the structure of 6a-c and 7a-c compounds.
Kinetic measurements
Reaction of N-acetyl isatin (3) and N-propionyl isatin
(4) with morpholine (Mo), piperazine (pipz) and diethyl-
amine (DEA) in pure acetonitrile (AN): The kinetics of N-
acetyl isatin (2) and N-propionyl isatin (3) with morpholine
(Mo), piperazine (Pipz) and diethylamine (DEA) in pure
acetonitrile (AN) was measured spectrophotometrically using
a shimadzu (UV-160A) spectrophotometer in conjunction with
a shimadzu thermo bath (TB-85). Temperature control (
0.1 °C) was attained by circulating water through cell compart-
ments. The kinetic runs were carried out at five temperatures
(25-45 °C) in the same solvents and the absorbance variation
with time were recorded at wavelength λ = 336, 337 and 325
nm. by following the appearance of products of the reaction
depending on the nature of the amine. All reactions were
carried out under pseudo-first-order conditions, with various
concentrations of amine ranges from 1 × 10-1 to 4 × 10-2 M
and final concentration of substrates 3, 4 (1 × 10-4 mol dm-3)
were used. The pseudo-first-order rate constants kΨ were
estimated by applying equation
O
R2
N
O
R2
ACN
R3
O
HN
R3
O
N
NH
O
R1
R2,R3=morpholinyl
R2, R3=piperazinyl
R2= R3= Et
R1
3, R1= Me
4, R1= Et
O
6a, R1 = Me, R2,R3=morpholinyl
, R1 = Me, R2, R3=piperazinyl
6b
6c, R1 = Me, R2= R3=Et
1 = Et, R2,R3=morpholinyl
7a,
R
7b, R1 = Et, R2, R3=piperazinyl
7c, R1 = Et, R2= R3= Et
−kψ t
Scheme-IV: Reactions of N-acetyl isatin (3) and N-propionyl isatin (4) with
morpholine, piperazine and diethylamine in acetonitrile
log (A∞-At) =
+ log (A0-A∞)
(1)
2.303

Vol. 26, No. 23 (2014)
Aminolysis of Isatin and N-Acetyl Isatin in Acetonitrile and Mixed Acetonitrile-Water Solvents 8033
Preparation of 1-(2-aminophenyl)-2-(piperazin-1-
yl)ethane-1,2-dione (8): The reaction of isatin [indole-2,3-
dione] 1 with piperazine in all ratios of acetonitrile-water mixed
solvent proceeded with quantitative formation of isatamide 1-
(2-aminophenyl)-2-(piperazin-1-yl)ethane-1,2-dione (8) at
25 °C (Scheme-V). Elemental analysis, IR and 1H NMR spectro-
scopy were used to confirm the structure of compound 8.
metrically by following the appearance of products 6a-c and
7a-c at λ = 336, 337 and 325 nm, respectively.All the reactions
obeyed pseudo-first order kinetic over 85 % of the reaction.
The plots of kΨ values against the square amine concentrations
gave good straight lines with negligible intercepts and corre-
lation coefficient r = 0.99 for 6a-c and 7a-c. Generally, six
different amine concentrations were used to calculate third-
order rate constants k3 L2 mol-1 s-1, i.e. the kinetic and mecha-
nism depends on two amine molecules. The k3 L2 mol-1 s-1
values for the aminolysis of N-acetyl isatin (3) and N-propionyl
isatin (4) are summarized in Table-1.
O
NH
O
H
N
N
ACN/H2O
25 oC
O
N
H
N
H
O
NH2
TABLE-1
THIRD ORDER RATE CONSTANTS k3 L2 mol-1 s-1 AND
ACTIVATION PARAMETER VALUES FOR THE AMINOLYSIS
OF N-ACETYL ISATIN (3) AND N-PROPIONYL ISATIN (4) IN
PURE ACETONITRILE
piperazine
1
8
Scheme-V: Reaction of isatin [indole-2,3-dione] 1 with piperazine
The effective atomic charges calculated with usage of
Mulliken method ( B3LYP) for the compounds 1 and 3 shows
that the carbonyl carbon C-2 is more positively charged in N-
acetyl isatin than that in isatin itself (Fig. 4). Thus the electro-
philic centre in compounds 3 and 4 is only the amide group
C-2 which it supported from the isolation and identification
of the same reaction products 6a-c and 7a-c at room tempe-
rature and at 50 °C.
k3 (L2 mol-1 s-1)
N-Acetyl isatin (3)
T (oC) Amine
Morpholine
42.62
Piperazine
22.94
18.50
14.83
-
Diethylamine
450.27
517.64
601.56
19.58
25
30
59.28
35
82.29
∆H# (KJ mol-1)
-∆S# (J K-1)
40
47.68
53.73
-
128.47
450.88
347.44
-59.97
63.72
12.24
10.17
-28.96
125.56
O
O
45
∆H# (KJ mol-1)
-∆S# (J K-1)
49.39
-38.97
3
3
81.86
64.52
2
2
O
O
k3 (L2 mol-1 s-1)
1
N
1
N
N-Propionyl isatin (4)
T (oC) Amine
10
H
C
Morpholine
43.53
Piperazine
11.06
9.38
Diethylamine
H3C
O
25
30
487.93
599.83
727.19
27.73
1
3
61.88
Fig. 4. Structure of isatin and N-acetyl isatin
35
86.55
8.07
∆H# (KJ mol-1)
-∆S# (J K-1)
40
49.97
-
Kinetic study: It is reported that hydrolysis and aminolysis
of isatin and its derivatives in water and aquo-organic solvents
proceeded through ring opening process at the amide linkage24-27
45.84
-
99.69
39.52
6.91
545.74
408.56
-44.35
51.23
.
45
∆H# (KJ mol-1)
-∆S# (J K-1)
20.13
5.99
-116.24
156.64
-21.58
157.74
This process showed great dependence on water and the pH
of the medium11. However, reaction of cyclic secondary amines
with isatin under deanstark condition in toluene or benzene
as solvents gave for example 9 and 10 in modest yields
(Fig. 5)34.
When the reactions of compounds 3 and 4 with morpho-
line, piperazine and diethylamine are running in acetonitrile
containing slight amount of water not exceeds 1 %, the kinetic
measurement cannot be followed spectrophotometrically.
Inspection of the kinetic data presented in Table-1,
suggests that the rate of reactions of compound 3 and 4 with
morpholine, piperazine and diethylamine obeyed third-order
kinetics i.e. catalyzed process.
X
X
N
N
O
(i) The third-order rate constants (k3 L2 mol-1 s-1) for the
reactions of compounds 3 and 4 with morpholine and
diethylamine increased with increasing temperature from 25
to 35 °C. Then a decrease in rate constant with raising tem-
perature from 35 to 45 °C is observed i.e. convex log kN-1/T
shape is observed. While the reaction rate constants of
compounds 3 and 4 with piperazine in pure acetonitrile is
continuously decreased by raising temperature from 25 to 45
°C i.e. negative temperature are observed for the reactions of
3 and 4 with morpholine and diethylamine in the temperature
N
H
9, X= CH2
10, X= O
Fig. 5. Products obtained from the reaction of cyclic secondary amines
with isatin in toluene or benzene
Kinetic and mechanism of the reaction of N-acetyl
isatin (2) and N-propionyl isatin (3) with morpholine (Mo),
piperazine (pipz) and diethylamine (DEA) in pure aceto-
nitrile (AN): The kinetic studies were measured spectrophoto-

8034 Ibrahim et al.
Asian J. Chem.
range 35-45 °C and with piperazine in the temperature range
25-45 °C.
temperature range 40 to 45 °C are decreased with ∆H# = -38.97,
∆H# = -59.97 KJ mol-1 and ∆H# = -116.24, ∆H# = -44.35 KJ
mol-1 for the reaction of compounds 3 and 4 with morpholine
and diethylamine respectively (Table-1). The ∆S# values are
highly negative than those in the range 25° to 35 °C. This
point out that the transition state involved in the rate deter-
mining step is more organized and has different structure below
35 °C.
(ii) The reactivity of morpholine and diethylamine towards
compound 3 increases as the basicity of this amine increased
i.e. rate constant increases from 42.62 to 450.27 L2 mol-1 s-1 as
the pKa of the conjugate acid of the amine increases from 8.33
(H2O) for morpholine to 10.73 (H2O) for diethylamine at 25 °C.
Similarly, the rate constant k3 L2 mol-1 s-1 for the reaction of
compound 4 increases from 43.53 for morpholine to 487.93
L2 mol-1 s-1 for diethylamine. The pKa of piperazine (5.73 in
H2O) is smaller than that of diethylamine and morpholine and
accordingly the reactions of compounds 3 and 4 with pipera-
zine are slower than those with diethylamine and morpholine.
Table-1 shows that the rate constant values are in harmony
with the pKa of the amines used.
(v) The reaction rates for compounds 3 and 4 with pipera-
zine in acetonitrile are decreased by raising temperature from
25 to 45 °C with ∆S# = -125.58 and -157.74 JK-1 and negative
∆H# = -28.96 and -21.56 KJ mol-1, respectively. A behaviour
different from the reactions of compound 3 and 4 with
morpholine and diethylamine in pure acetonitrile at the same
range of temperature 25 to 45 °C.
(iii) Piperazine shows a continuous decrease in rate constant
by raising temperature while diethylamine and morpholine
show an increase by increasing temperature from 25 to 35 °C
followed by a decrease in rate constant on increasing tempe-
rature from 40 to 45 °C. This suggests that the reactions of
compounds 3 and 4 with diethylamine and morpholine can
proceed by a mechanism differs from that of the reaction the
same substrates with piperazine.
Kinetic data shows that the ∆H# values (large positive
values) for the reactions of 3 and 4 with morpholine and
diethylamine at 25-35 °C are completely different compared
to the negative values of enthalpy at temperature higher than
35 °C and those for the reaction of 3 and 4 with piperazine in
the temperature range 25 to 45 °C. The entropy of activation
values is variably negative and ranging between -51.23 to
156.64 JK-1 and depending on the temperature as well as the
nature of amines. The negative values of ∆S# as well as the
large difference in the ∆S# values with raising temperatures
indicate more organi-sations of the involved transition states.
This suggests that the reaction of compounds 3 and 4 with the
titled amines proceeded by different and/or by parallel mecha-
nisms. Accordingly, the well known mechanisms of amides
with amines, Scheme-VI pathway (a) specific base (SB)
mechanism and pathway (b) dimer mechanism are postulated
(iv) The reaction mechanism in the temperature range
25 to 35 °C is constant for the reactions of morpholine and
diethylamine with compounds 3 and 4 with ∆H# = 47.68, ∆H#
= 19.58 and ∆H# = 49.63 KJ mole-1, ∆H# = 27.92 KJ mol-1,
respectively, While the ∆S# of reaction is negative with -53.70,
-128.47 and -45.84, -99.69, respectively. The negative ∆S#
values suggest a great degree of organization of the activated
complex before the final products. The reaction rates in the
NH
+
O
O
O
a
O
O
NH
k1
k2
k-2
N
H
N
O
H
N
b
HN
k-1
N
N
N
dimer
12
11
R
O
R
O
R
O
k3
k-4
k4
O
O
N
H
+
H2N
N
O
k5
H
O
O
N
N
N
13
R
O
R
O
O
N
N
O
O
N
O
O
NH
R
R
Scheme-VI: Mechanism for the reaction of 3 and 4 with morpholine, piperazine and diethylamine in pure acetonitrile

Vol. 26, No. 23 (2014)
Aminolysis of Isatin and N-Acetyl Isatin in Acetonitrile and Mixed Acetonitrile-Water Solvents 8035
to explain the previous results. The switch from specific base
mechanism to a dimer could occur at the point of formation of
the amine dimer. This switching may depend on the nature of
amine, type of the leaving group, the nature of the medium as
well as the temperature. The concept, of the change of the specific
base process to the dimer mechanism or vice versa, completely
or partially, is presumably consistent with our kinetic data.
Above suggestion is supported by the inability to measure
the rate of reactions of compounds 3 (R = COCH3) and 4 (R =
COCH2CH3) on addition of a slight amount of water to aceto-
nitrile, even the same reaction products 6a-c and 7a-c are
isolated either in pure acetonitrile or in mixed CH3CN-H2O.
This points out that the mechanism shown in Scheme-VI (i.e.
depends greatly on water molecules) is completely rejected in
pure acetonitrile.
with morpholine, piperazine and diethylamine in pure
acetonitrile is the summation of the two pathway reactions:
specific base and dimer mechanisms, eqn. 3.
dP
= k3[12]+ k5[13]
(3)
dt
The dimer process, at temperature 25 to 35 °C, k4 >>>
K1k2, for the reaction of 3 and 4 with morpholine and diethyl-
amine, is omitted. While their reaction rates at the temperature
range of 35 to 45 °C, may occur by two parallel mechanisms
in which the predominant dimer process reflect a decrease in
the over rate constant.
kN = K1k2[Am] + k4[Am]
(4)
The continuous decrease of rate constants over the entire
range of temperature for the reactions of 3 and 4 with pipera-
zine is presumably due to the difference in its stereochemical
structure or its ability to dimerize in dipolar solvents.
Reaction of piperazine with isatin 1 in water-aceto-
nitrile at 25 °C: The second order rate constants (kN) were
obtained from dividing the average kψ value by the correspon-
ding piperazine concentration (Table-2).
The reported decrease in association constant, K4, with
increasing temperature35 is presumably a reasonable expla-
nation for the apparently surprising negative temperature effect.
This lead us to postulate that the increase in rate for the proton
transfer process with increasing temperature, would be
compensated by a shift to a specific base (SB) mechanism. While
the observed decrease in rate constant on raising temperature
is presumably due to the shift of the reaction towards the slow
dimer pathway.
It was also reported that all isatin reactions with amines
in various water-organic solvent were not catalyzed by a secon-
dary amine and the reaction kinetic obeyed second-order
process. The reaction of isatin with piperazine in water takes
place through the cleavage of the amide bond and the formation
of a ring-opened amino acid11. Thus, according to the previous
facts, a mechanism for the ring opening of isatin by piperazine
is proposed which would account satisfactorily for both the
water dependence and the effect of solvent on reaction rate
(Scheme-VII)11.
Kinetic results and activation parameters for the reactions
of compounds 3 and 4 with morpholine and diethylamine
agreed with the specific base catalyzes process in the tempe-
rature range from 25 to 35 °C (Scheme-VI). In contrast, the
higher negative entropy values and the negative enthalpy at
the temperature range from 35 to 45 °C may indicate a minor
specific catalyses process and a predominant dimer mecha-
nism. This may be due to a decrease in the rate constants with
raising temperature. The change of N-substituent from N-acetyl
to N-propionyl does not show a change in mechanism at both
ranges of temperatures from 25 to 35 °C and between 35 to
45 °C.
Accordingly, the kinetic law obeyed in the present reaction
is given by eqns. 5 and 6.
Rate = kψ [isatin] [piperazine]
kobs = kN [piperazine]
(5)
(6)
A mixed specific base catalyzes process and dimer
mechanism for the reaction of 3 with piperazine are responsible
for the continuous decrease in rate by raising the temperature.
This is presumably due to the increase of piperazine dimeri-
zation. The shift in the reaction process to the dimer mechanism
in a slow process reflects a decrease in the overall rate constants
(Table-1). Similarly, compound 4 with N-pro-pionyl group
reacts by the same mixed mechanisms. The negative enthalpy
values corroborates that the dimer process is much slower than
the specific base process.
Therefore, the reaction is suggested to proceed through
solvated intermediate 14 that gives zwitterionic ion 15, which
in turn leads to the final product in a slow step. Therefore, the
stability of the zwitterionic intermediate 15 determines the
rate constants of the reaction, Scheme-VII.
The kinetic expression is derived with reference to the
mechanism in Scheme-VII on the basis of the steady-state
assumption, where the term Am symbolizes piperazine and S
symbolizes acetonitrile. The differential rate equation for the
product P is given by eqn. 7:
The kinetic expression is derived with reference to the
mechanism in Scheme-VI on the basis of the steady-state
assumption. The total rate equation for the reaction of 3 and 4
dP
= rate = k2[15][H2O]
(7)
dt
TABLE-2
SECOND ORDER RATE CONSTANTS (L mol-1 s-1) FOR THE REACTION OF ISATIN WITH
PIPERAZINE IN FIVE RATIOS OF ACETONITRILE-WATER MIXED SOLVENT AT 25 °Ca
N
ET
XCH
102 kN (L mol-1 s-1)
1/D
H2O
α
β
π*
CN
3
0.000
0.047
0.158
0.201
0.226
1.95
1.35
0.60
0.45
0.30
0.013
0.013
0.015
0.016
0.017
1.00
0.93
0.84
-
1.13
1.03
0.91
-
0.47
0.59
0.61
-
1.14
1.10
1.01
-
55.47
50.00
38.82
35.56
33.34
0.81
0.89
0.59
0.97
a[Isatin] = 10-4, [piperazine] = 0.2 M

8036 Ibrahim et al.
Asian J. Chem.
O
O
X1H2O
(X1+ X2 +n) H2O
O
k
1
C
O
+ X2H2O .....AmH .....Y2S + n H2O
C
nS
+
AmH
k
(Y1 + Y2 - n) S
N
H
-1
Y1S
N
H
14
Solvated isatin by Water-AN
Solvated Zwitterionic intermediate
15
O
Am
k
2
15
+ H2O
+
(X1 + X2 + n) H2O + (Y1 + Y2 - n) S
slow
O
NH2
Scheme-VII: Mechanism for the reaction of amine with isatin 1 in H2O-CH3CN mixed solvent
where kψ is the pseudo first-order rate constant (see kinetic
measurement part).
The formation of kN yields
is not linear for the reaction of isatin with piperazine. The
failure of the simple electrostatic interpretation points out that
the non electrostatic part of the solvent is predominated and
the changes in rate constants depend on the mixed solvent
compositions46. Thus, the activated complex is solvated by the
polar part of the mixed solvent.
kψ
kN =
= Kk2[H2O]n
(8)
[Am]
where K is the equilibrium constant of step 1 and kN is the
apparent second-order rate constant. The decrease in the rate
of reaction on progressive addition of the organic cosolvent
may be attributed to the decrease in the equilibrium constant
(K) of step 1, which shift the equilibrium to the left leading
to the decrease in concentration of 15 and consequently
decreasing the rate of the reaction. Similar behaviour has been
observed on adding of water to the organic solvent for the
hydrolysis and aminolysis of isatins30-36. The complete
stopping the reaction in pure acetonitrile indicates that
water molecules must be necessary for completion the
The plot of log kN versus XH2O in 100-70 % water is linear
(gradient = 0.14, R2 = 0.97) and shows a decrease in rates on
going from water to acetonitrile. This is because the water
structure remains more or less intact to the acetonitrile mole-
cules without disrupting the water structure24. Therefore, the
intermediate 15 is preferentially solvated by H2O and indicating
that the reaction rate is probably associated with small specific
solvation of the medium as observed from the low gradient
value (0.14).
The plot of log kN versus log [H2O] gives good straight
line (Fig. 6). It shows that the rate decreases linearly with
progressive addition of acetonitrile. The slope is equal to n =
3.50 and it reflects not only the number of water molecules
contaminated in the transition state but also indicates that
acetonitrile does not change the internal structure of the medium
on addition of organic solvent36. However, some reactions
showed that (n) value decreases or increases when [H2O]
increases depending on the type of reaction37.
reaction30-36
.
The selection of mole fractions was based on the fact that
the applied solvatochromic parameters were available in the
lileratures36. This solvatochromic parameters represent solute-
solvent interactions (called empirical scales), such as norma-
N
lized polarity (ET ), dipolarity-polarizability (π*), hydrogen
bond donor (HBD) (α) and hydrogen bond acceptor (HBA)
(β) ability. These parameters have been used to explain
variations of the reaction rate by modifying the reaction
media36. The solvent effect on a typical property is described
by a general correlation model, which gives simultaneous
calculation of the contributions of non-specific solute-solvent
interaction (such as polarity and polarisability) and specific
solute-solvent interactions (such as electron donor-acceptor
and hydrogen-bond donor-acceptor abilities)37-39. Some of the
factors that affect the reaction rates are the general medium
effect and the intersolute effects40-45
.
Fig. 6. Plot showing the correlation between log kN and log [H2O] for the
reaction of isatin with piperazine for five ratios of CH3CN-H2O
mixed solvent
Solvent-reactivity correlation: The reaction of isatin with
piperazine is studied in varying mole fractions of H2O in
CH3CN with a view to understand the effect of preferential
solvation on the rate constants of the reaction. Such mixtures
are very useful for studying solvent effects upon reactions since
the properties can be adjusted continuously by changing the
composition of the mixture. The variation of log kN with 1/D
Correlation between rate constant kN and preferential
solvation EN value: The linear plot36 of log kN versus EN
T
T
values for the reaction of isatin with piperazine in same ratios
of CH3CN-H2O mixed solvent is shown in Fig. 7.

Vol. 26, No. 23 (2014)
Aminolysis of Isatin and N-Acetyl Isatin in Acetonitrile and Mixed Acetonitrile-Water Solvents 8037
1.6
1.4
1.2
1
uniparameter regression suggests that the hydrogen bond donor
effect of the mixed solvent retards the formation of intermediate
15. The negative sign of the coefficient β term for uniparameter
regression and the increase of β parameter suggests specific
interaction between the reactants and the solvent, via hydrogen-
bonding acceptor properties, is more than that between the
0.8
0.6
0.4
0.2
0
y = 4.0691x - 2.7226
R2 = 0.9388
0.75
0.8
0.85
0.9
0.95
1
1.05
intermediate 15 and the solvent. This also leads to a decrease
in rate constants, Table-2. The high coefficient value of π*
term for uniparameter regression and the decrease in π* term
by progressive addition of CH3CN suggests that the non-
specific interaction between the intermediate 15 and the
solvent, via electrostatic interactions, is more than that between
the reactants and the solvent. This also explains the decrease
in rate constant by increase of CH3CN content.
N
ET
Fig. 7. Plot showing the correlation between log kN and ETN for the reaction
of isatin with piperazine for five ratios of CH3CN-H2O mixed solvent
Table-2 and Fig. 7, show that EN values are inversely
proportional with XCH CN i.e. kN values decreases by progressive
T
3
addition of CH3CN, so it seems that intermediate 15 is
preferentially solvated by water. This is based on the ground
that when CH3CN molecules are gradually added, it breaks
down the self-associated structure of water and prevents
structured water molecules to solvate intermediate 15. These
properties of both solvents agree well with formation of 14
and 15 intermediates in the rate determining step, where the
effect of medium is specific and consistent with the decrease
in the dielectric constant of the medium, Table-2.
TABLE-3
SOLVENT-REACTIVITY CORRELATIONS (ISATIN
WITH PIPERAZINE IN CH3CN-H2O MIXED SOLVENT)
Equation
log kN = -5.76 + 4.12 EN
r = 0.97
r = 0.95
r = 0.96
r = 0.99
r = 0.99
r = 0.99
r = 0.98
r = 0.99
s
s
s
s
s
s
s
s
0.11
0.14
0.33
0.06
0.08
0.02
0.12
0.10
T
log kN= -5.16 + 3.12α
log kN = 0.14-3.92β
log kN = -6.97 + 4.63π*
log kN = -8.05 + 2.06β + 5.37 EN
log kN = -7.41-10.10α + 17.13 EN
Solvent-reactivity correlations: In order to determine
the incidence of each type of solvent properties on the kinetics
of the reaction, a linear free energy relationship (LFER)
correlation based on Kamlet, Abboud and Taft47,48, hypothesis
was applied. In this respect the solvatochromic approach which
defines three parameters: π*, α and β (with the addition of
others when the need arose), to evaluate the different solvent
effects, was highly successful in describing the solvent effects
on the rates of reactions. When the property studied refers to a
single solute in multiple solvents, the general equation is
usually expressed as eqn. 947.
T
T
log kN = -8.06 + 4.47α + 2.76β
log kN = -4.98-4.20 α-2.36β + 8.01π*
n = 5 ratios of CH3CN–H2O, r = correlation coefficient, s = standard
deviation
It is found that most dual parameters correlations (β and
EN ) and (β and α) gave satisfactory results. The positive coeffi-
T
cient values indicates the progressive addition of CH3CN
retards the formation of the intermediate 15 and consequently
a decrease in rate constant is observed. When the dual ENT and
α-parameters are used in the regression, a negative coefficient
for α-parameter and positive ENT are observed. This point out
that the preferential solvation is more pronounced and the α-
parameter stabilizes the reactants more than the intermediate.
The application of multiparameter approach of α, β and π* is
more pronounced than uni and dual parameter model because
it explains most properties of pure or mixed solvents. This
approach shows that the α, β parameters give negative coeffi-
cients meaning that both hydrogen bond donor and hydrogen
bond acceptor effects predominantly solvate the reactants.
While the contribution of π* parameter has high positive coeffi-
cient suggesting that non-specific solvation of the intermediate
15 is predominated. The rate of the reaction is influenced by
both specific and nonspecific solute-solvent interactions. The
percentage contributions of α, β and π* parameters indicate
that the non-specific solvation is approximately equivalent to
the specific solvation.
log kA = constant + sπ* +αβ + ba
(9)
This solvatochromic solvent effect equation has been
probably the most widely used one in the analysis of solvent
effect49-52. Eqn. 9 can be applied on the single or multiparameter
correlation between the log kN of the reaction and the solvato-
chromic parameters of the media. The data derived from these
correlations are presented in Table-3. Multiparameter regre-
ssion can be usually used, because combination of some of
the solvent properties can shed light on their effects on the
rate coefficient and mechanism. Scheme-VI shows that rate
constants depends on the solvation of isatin 14, the intermediate
15 and CH3CN-H2O composition.
Single-parameter correlations of log kN versus ETN in all
composition of the solvent represent a linear result and
indicates that the second-order rate coefficient of the reactions
decreases with the decrease in the value of this parameter,
Table-3. This points out that the intermediate has zwitterionic
properties and the reaction is preferentially facilitated by
progress addition of water. This suggestion is supported from
the higher coefficient values of ENT obtained from the single
and dual parameter correlations compared to those of α and β
parameters.
Conclusion
The reactions of N-acetyl isatin and N-propionyl isatin
with morpholine, piperazine and diethylamine in acetonitrile
at room temperatures gave N-[2-(2-amino-2-oxo-acetyl)-
phenyl]acetamide derivatives (6a-c) and N-[2-(2-amino-2-
oxoacetyl)phenyl]propionamide derivatives (7a-c) respec-
tively. The activation parameters suggest that the mechanism
It is observed that the decrease in α-parameters by
decreasing H2O content shows decrease in rate, Table-2. In
addition, the positive sign of the coefficient α term for

8038 Ibrahim et al.
Asian J. Chem.
17. K. Hori, A. Kamimura, K. Ando, M. Mizumura and Y. Ihara, Tetrahe-
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of the reaction proceeds by parallel specific base and dimer
mechanisms depending on temperature. The reaction of isatin
with piperazine in various CH3CN-H2O mixed solvents gives
zwitterionic ion intermediate which in turn leads to the final
product in a slow step. The nonlinear plots of log kN versus
1/D as well as the plot of log kN versus XH2O, indicate a specific
solvation. The plot of log kN versus log [H2O] gives the number
of water molecules (n) contaminated in the transition state.
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(tetrahedral) intermediates in the rate determined step. It is
found that most dual parameters correlations (β and ENT, α
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interactions of the solvent is slightly preferable compared to
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