Effects of mixed H2O-CH3CN solvents on the rate of hydrazinolysis of N-phenylphthalimide: Spectral and kinetic evidence for the occurrence of N-aminophthalimide on the reaction path

Article abstract of DOI:10.1002/kin.20057

Kinetic study on the cleavage of N-phenylphthalimide (NPhPT) in the presence of 0.05 M NH₂NH₂ and mixed H₂O-CH ₃CN solvents reveals the occurrence of reaction scheme B ← A → C →^-An C₁↑^E → F where A, B, C, C₁, An, E, and F represent NPhPT, 0-CO₂ ^-C₆H₄CONHC₆H₅, 0-CONHNH₂C₆H₄-CONHC₆H₅, N-aminophthalimide, aniline, 0-CO₂^-C₆H ₄CONHNH₂, and 0-CONHNH₂C₆H ₄-CONHNH₂, respectively. But, in the presence of either nonbuffered ≥0.20 M NH₂NH₂ or hydrazine buffer of pH～7.30-8.26 with total buffer concentration ([Buf]_T) of > 0.02 M, further conversion of F to 2,3-dihydrophthalazine-1,4-dione (DHPD) has been detected depending upon the length of the reaction time (t), the values of [Buf]_T, and pH. It has been shown that the rate of conversion of C₁ to F is much faster than that of C to C₁ which is much faster than that of F to DHPD. The reaction step A → C involves general base (GB) catalysis, while step C → C₁ seems to involve specific base-general acid (GA) and GB-GB catalysis.

Full text of DOI:10.1002/kin.20057

Effects of Mixed
H2O-CH3CN Solvents on the
Rate of Hydrazinolysis of
N-Phenylphthalimide:
Spectral and Kinetic
Evidence for the
Occurrence of
N-Aminophthalimide on the
Reaction Path
AZHAR ARIFFIN, SIM YOKE LENG, LAI CHWEE LAN, M. NIYAZ KHAN
Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
Received 11 March 2004; accepted 21 September 2004
DOI 10.1002/kin.20057
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: Kinetic study on the cleavage of N-phenylphthalimide (NPhPT) in the presence of
0.05 M NH2NH2 and mixed H2O-CH3CN solvents reveals the occurrence of reaction scheme
E
↑
−An
B ←− A −→ C −→ C1 −→ F
where A, B, C, C1, An, E, and F represent NPhPT, o-CO−2 C6H4CONHC6H5, o-CONHNH2C6H4-
CONHC6H5, N-aminophthalimide, aniline, o-CO−C6H4CONHNH2, and o-CONHNH2C6H4-
CONHNH2, respectively. But, in the presence of2 either nonbuffered ≥0.20 M NH2NH2 or
Correspondence to: M. Niyaz Khan; e-mail: niyaz@um.edu.my.
Contract grant sponsor: IRPA.
Contract grant number: 09-02-03-0147.
2005 Wiley Periodicals, Inc.
c
ꢀ

148
ARIFFIN ET AL.
hydrazine buffer of pH ∼ 7.30–8.26 with total buffer concentration ([Buf]T) of >0.02 M, fur-
ther conversion of F to 2,3-dihydrophthalazine-1,4-dione (DHPD) has been detected depending
upon the length of the reaction time (t), the values of [Buf]T, and pH. It has been shown that
the rate of conversion of C1 to F is much faster than that of C to C1 which is much faster than
that of F to DHPD. The reaction step A → C involves general base (GB) catalysꢀis, while step
C
C → C1 seems to involve specific base–general acid (GA) and GB-GB catalysis. 2005 Wiley
Periodicals, Inc. Int J Chem Kinet 37: 147–161, 2005
mixture was then allowed to cool to room temperature
and water (50.0 mL) was then added to the reaction
mixture. The resulting white precipitate was filtered
and washed with water (100 mL) to give a white solid.
Further purification by recrystallization in EtOAc-
hexane afforded a white crystalline solid (2.54 g, 82%),
mp 205–208◦C (lit. [4] 204–207◦C). δH (400 MHz,
CDCl3): 7.37–7.51 (5H, m, ArH), 7.76–7.95 (4H, m,
ArH); δC (100 MHz, CDCl3): 123.7(2ArCH), 126.5
(2ArCH), 128.0(2ArC), 129.1(2ArCH), 131.7 (ArC),
134.3(2ArCH), and 167.2(2C O). m/z (GCMS) 223
(M+, 100%). Stock solutions (0.01 M) of N-phenyl-
phthalimide (NPhPT) were prepared in acetonitrile.
INTRODUCTION
Synthesis of primary amines using Ing–Manske pro-
cedure involves the reaction of hydrazine with N-
substituted phthalimides [1]. Fine details of mecha-
nism(s) involved in these reactions are not understood
even at a rudimentary level. This led to the researchers,
interested in synthesis of primary amines, to follow
trial and error approach [2]. Mechanistic details of
this rather complex reaction have been studied kinet-
ically in aqueous solvents containing 1% v/v acetoni-
trile [3]. These kinetic data led to the qualitative con-
clusion for the occurrence of N-aminophthalimide as
an intermediate in the hydrazinolysis of phthalimide.
But the synthesis of primary amines with hydropho-
bic moieties using this procedure involves organic
or mixed aqueous-organic solvents. We therefore de-
cided to study the effects of mixed aqueous-acetonitrile
solvents on the rate of reaction of hydrazine with
N-phenylphthalimide (NPhPT). The observed results
and their probable explanations are described in this
manuscript.
Determination of Ionization Constant (Ka)
of DHPD
TheionizationconstantofDHPDwasdeterminedspec-
trophotometrically at 320 nm. The pH range 2.02–
10.00 was covered using buffer solutions of acetate
(0.1 M total buffer concentration), phosphate buffer
(0.1 M total buffer concentration), and carbonate buffer
(0.1 M total buffer concentration). Details of the pro-
cedure and calculation of Ka, δA−, and δAH (where
δA− and δAH represent molar extinction coefficient
of ionized and nonionized DHPD at 320 nm, respec-
tively) are described elsewhere [5]. The least squares
calculated respective values of Ka, δA−, and δAH are
(2.11 0.00) × 10−6 M, 5415 72 M−1 cm−1, and
1921 62 M−1 cm−1 at 30◦C in aqueous solvent con-
taining 0.5% v/v dimethylformamide. The values of
observed absorbance (Aobs) of aqueous mixture con-
taining 2 × 10−4 M DHPD and 0.5% v/v dimethylfor-
mamide at 320 nm and [NaOH] = 0.0, 0.001 M as well
as pH 10.0, 2.04 are 0.472, 1.087, 1.144, and 0.355,
respectively.
EXPERIMENTAL
Materials
N-Aminophthalimide (C1), 2,3-dihydrophthalazine-
1,4-dione (DHPD), hydrazine, and other chemicals
were obtained from commercial sources and were
of the highest commercially available purity. Be-
cause of the low solubility of DHPD in acetonitrile,
stock solution (0.04 M) of DHPD was prepared in
dimethylformamide. Stock solutions of sodium hy-
droxide were freshly prepared by diluting standard so-
lution of 5 M NaOH just before the start of kinetic
runs.
Kinetic Measurements
Synthesis of N-Phenylphthalimide
Rate of cleavage of N-phenylphthalimide (NPhPT)
in the presence of hydrazine and mixed aqueous-
acetonitrile solvents was studied spectrophotometri-
cally by monitoring the change in absorbance (Aobs
of the reaction mixture as a function of reaction time
Phthalic anhydride (2.04 g, 13.79 mmole) and aniline
(1.89 mL, 20.69 mmole) were added into a 50 mL
round-bottom flask containing 15.0 mL glacial acetic
acid. The reaction mixture was refluxed for 6 h. The
)

EFFECTS OF MIXED H2O-CH3CN SOLVENTS ON THE RATE OF HYDRAZINOLYSIS
149
(t) at 276 nm. The details of the experimental procedure
are same as described elsewhere [6].
results at 300 nm are available from the literature [3],
the values of these molar extinction coefficients were
also determined at 300 nm (Table I).
Product Characterization
RESULTS AND DISCUSSION
Inviewofthelargenumberofreportsonhydrazinolysis
of N-substituted phthalimides since Ing–Manske [1]
reported this reaction as an improved procedure in the
second step of Gabriel synthesis of primary amines, the
most obvious expected end products are phthalanilic
acid (minor product—due to hydrolysis), aniline, and
2,3-dihydrophthalazine-1,4-dione (DHPD) (major
products) [7]. Nearly 80% yield of product aniline
was obtained after stirring the mixed aqueous reaction
mixture containing NPhPT (1.03 g, 4.61 mmole) and
hydrazine hydrate (2.23 mL, 46.05 mmole) 50% v/v
CH3CN at room temperature for about 5.3 h [8].
In order to have a quantitative spectrophotometric
characterization of intermediate and end products of
hydrazinolysis of NPhPT in mixed water-acetonitrile
solvents, molar extinction coefficients NPhPT, o-
CO−2 C6H4CONHC6H5, o-CO2−C6H4CONHNH2,
C6H5NH2, N-aminophthalimide, and DHPD were
determined in 10–80% v/v at 276 nm. These results
are summarized in Table I. Since some of the related
Effect of Mixed H2O-CH3CN Solvents on
the Rate of Alkaline Hydrolysis of NPhPT
at 0.001 M NaOH and 35◦C
Effect of Mixed H2O-CH3CN solvents on the rate of
alkaline hydrolysis of NPhPT was studied by carrying
a few kinetic runs within the acetonitrile content range
10–80% v/v. Observed absorbance (Aobs) values at dif-
ferent reaction time (t) were found to follow Eq. (1)
Aobs = δapp[X]0[1 − exp(−kobst)] + A0
(1)
where A0 = Aobs at t = 0, [X]0 is the initial concentra-
tion of NPhPT, δapp is the apparent molar extinction co-
efficient of the reaction/product mixture, and kobs rep-
resents pseudo-first-order rate constant for the reaction
of HO− with NPhPT. The values of kobs, δapp, and A0
were calculated from Eq. (1) by the use of nonlinear
least squares technique, and these calculated results are
summarized in Table II.
Table I Values of A∞, and Molar Extinction Coefficients (δA, δB, δC1, δD, δE, and δAn) of Chemical Species Involved in
the Hydrazinolysis of NPhPT in Mixed H2O-CH3CN at 276 nma
−3
c
d
−3
10 δ
An
(M−1 cm−1
)
MS b
(% v/v)
10−3δA
(M−1 cm−1
10−3δB
(M−1 cm−1
10
δ
10−3δD
10−3δD
10−3δE
(M−1 cm−1
C1
A
)
)
(M−1 cm−1
)
(M−1 cm−1
)
(M−1 cm−1
)
)
∞
2
(2)
10
(10)
20
0.638
(0.131)
0.717
(0.154)
0.721
1.36
5.750
3.68
(4.61)
3.74
(4.62)
3.61
2.44
(5.50)
2.35
(5.34)
2.09
1.36
(2.03)
1.49
6.125
(0.95)
6.70
0.90
(2.24)
0.91
0.95
(0.00)
1.00
1.63
(0.25)
1.62
(20)
30
(0.152)
0.719
(2.04)
1.47
(1.12)
7.01
(2.20)
0.91
(4.78)
3.62
(5.12)
2.11
(0.02)
1.01
(0.33)
1.60
(30)
40
(0.173)
0.642
(2.04)
1.45
(1.28)
7.37
(2.14)
0.92
(4.99)
3.61
(4.91)
2.02
(0.00)
1.04
(0.41)
1.60
(40)
50
(0.226)
0.593
(1.93)
1.56
(1.43)
7.60
(2.08)
0.93
(4.73)
3.60
(5.06)
1.89
(0.01)
1.06
(0.49)
1.58
(50)
60
(0.245)
0.565
(1.94)
1.50
(1.57)
7.86
(2.00)
0.94
(4.74)
3.55
(4.56)
1.81
(0.02)
1.11
(0.72)
1.55
(60)
70
(0.294)
0.542
(1.85)
1.54
(1.71)
8.10
(1.93)
0.95
(4.80)
3.55
(4.56)
1.76
(0.17)
1.22
(0.73)
1.50
(70)
80
(0.394)
0.511
(1.86)
1.48
(1.92)
8.50
(1.86)
0.94
(5.03)
3.46
(4.26)
1.76
(0.26)
1.34
(0.75)
1.66
(80)
(0.413)
(1.88)
(2.24)
(1.76)
(4.83)
(4.07)
(0.03)
(1.04)
a [X]0 = 2 × 10−4 M (X = A, B, C1, D, E, and An) and values in parentheses stand at ꢀ = 300 nm, A = NPhPT, B = o-CO−2 C6H4CONHC6H5,
C1 = N-aminophthalimide, E = o-CO−2 C6H4CONHNH2, D = DHPD, and An = C6H5NH2.
b Unless otherwise noted MS = H2O-CH3CN.
c Mixed H2O-CH3CN solvent for each set of observations contains a constant content (2% v/v) of dimethylformamide (DMF).
d Mixed H2O-CH3CN solvent for each set of observations contains 0.001 M NaOH and a constant content (0.5% v/v) of dimethylformamide
(DMF).

150
ARIFFIN ET AL.
Table II Values of Kinetic Parameters, kobs, δapp, and A0 Calculated from Eq. (2) for Alkaline Hydrolysis of NPhPT in
Mixed H2O-CH3CN Solventa
c
MSb (% v/v)
103kobs (s−1
)
103kcalcd (s−1
)
δapp (M−1 cm−1
)
A0
10
20
30
40
50
60
70
70
80
80
33.0 0.4d
23.0 0.2
13.4 0.1
8.80 0.10
6.07 0.09
4.67 0.09
5.47 0.12
5.53 0.03
5.98 0.18
5.80 0.03
33.0
21.8
14.2
9.32
6.10
3.99
4301 33d
5218 23
5628 25
6076 27
6275 37
6518 42
6673 47
7004 13
6922 75
7345 14
0.365 0.007d
0.295 0.005
0.276 0.005
0.258 0.005
0.264 0.007
0.268 0.008
0.265 0.009
0.241 0.002
0.289 0.015
0.251 0.003
a [NPhPT]0 = 2 × 10−4 M, [NaOH] = 0.001 M, 35◦C. ꢀ = 276 nm.
b MS = H2O-CH3CN.
c Calculated from Eq. (2) as described in the text.
d Error limits are standard deviations.
The nonlinear decrease in kobs with the increase in
the content of acetonitrile in mixed H2O–CH3CN sol-
vents is expected one in view of similar results ob-
tained in several related addition–elimination reactions
at carbonyl carbon. The quantitative interpretation of
such observations is difficult due to lack of a perfect
theoretical model for such reactions. However, these
results may be explained qualitatively as follows. The
hydroxide ion-catalyzed hydrolysis of NPhPT is ex-
pected to involve hydroxide ion attack at carbonyl
carbon of imide as the rate-determining step. Nucle-
ophilicity of the reactant hydroxide ion is expected to
decrease with the increase in the stability of solvated
ion-pair (Na+:HO−). The increase in the organic co-
solvent (acetonitrile) decreases the dielectric constant
of the reaction medium which in turn increases the
stability of Na+:HO− and consequently decreases kobs
value. However, at considerably high content of or-
ganic cosolvent, because of the insufficient number of
water molecules, the organic cosolvent molecules also
enter into the solvation shell of Na+:HO−. Since ace-
tonitrile can preferentially solvate only cations (Na+),
the participation of organic cosolvent molecules into
the solvation shell of Na+:HO−is expected to decrease
its stability because of the asymmetric structural net-
work of solvation shells of Na+ and HO− ions. Thus,
under such conditions, the increase in the content of
organic cosolvent should increase kobs value. However,
the decrease in the dielectric constant with increasing
acetonitrile content is expected to increase the stability
of solvent separated ion-pair (Na+:HO−) and conse-
quently decreases the nucleophilicity of nucleophile,
HO−. Thus, the effect of preferential ion-solvation
by acetonitrile molecules and the effect of dielec-
tric constant of acetonitrile-water solvents on solvent
separated ion-pair (Na+:HO−) have opposite effect
on kobs
.
An empirical interpretation of such observations
may be considered of some use, at least in predict-
ing the rate constant value at any content of organic
cosolvent within the experimental range of the content
of organic cosolvent. The values of kobs were found to
fit to empirical Eq. (2)
kobs = k0 exp(−ꢀX)
(2)
where k0 and ꢀ are empirical constants and X stands
for acetonitrile content in mixed aqueous solvent. The
least squares calculated respective values of k0 and
ꢀ are (51.0 1.9) × 10−3 s−1 and (4.25 1.9) × 10−2
(% v/v)−1. The magnitude of ꢀ is the measure of the
ability of organic cosolvent to decrease the rate of
mixed water-organic cosolvent-mediated reaction.
Effect of Mixed H2O-CH3CN Solvents on
the Rate of Cleavage of NPhPT in the
Presence of 0.05 M NH2NH2
A few kinetic runs for hydrazinolysis of NPhPT were
carried out at 2 × 10−4 M NPhPT, 0.05 M NH2NH2,
and 35◦C under mixed water-acetonitrile solvent con-
taining acetonitrile content range 2–80% v/v. The plots
of Aobs versus t, as shown in Figs. 1 and 2 for these
kinetic runs, revealed the presence of a stable inter-
mediate that absorbs strongly compared to reactants
(NPhPT and NH2NH2) and end products at 276 nm.
The observed kinetic data (Aobs versus t), obtained at

EFFECTS OF MIXED H2O-CH3CN SOLVENTS ON THE RATE OF HYDRAZINOLYSIS
151
Figure 1 Plots showing the dependence of Aobs versus reaction time (t) for hydrazinolysis of NPhPT at 10% (ꢀ), 20% (ꢁ),
and 30% ( ) v/v CH CN. The solid lines are drawn through the calculated data points using Eq. (3) and parameters listed in
ꢂ
3
Table III.
Figure 2 Plots showing the dependence of Aobs versus reaction time (t) for hydrazinolysis of NPhPT at 40% (ꢀ), 50% ( ),
ꢂ
60% (ꢁ), 70% (×), and 80% ( ) v/v CH CN. The solid lines are drawn through the calculated data points using Eq. (5) and
◦
3
parameters listed in Table III.

152
ARIFFIN ET AL.
≤30% v/v CH3CN, were found to fit to Eq. (3)
φ1[X]0
the insignificant amount of DHPD during the reac-
tion time of ∼3000 s (= tmax at 2% v/v CH3CN
as mentioned in Table III). Molar extinction coeffi-
cients (δB) of B are significantly larger than those of
NPhPT, An, and DHPD at 276 nm within acetoni-
trile content range 10–80% v/v (Table I). These results
show that the strongly absorbing intermediate C, ex-
hibited by the maxima in the plots of Figs. 1 and 2,
is most likely o-CONHNH2C6H4CONHC6H5 because
this is an expected immediate product in the reaction
of NPhPT with hydrazine. It can be easily shown that
Eq. (4) can lead to Eq. (3) with φ1 = (δB − δA)k1ꢁ +
(δD + δAn − δA)k1, φ2 = (δC − δD − δAn)k1, (δ repre-
sents molar extinction coefficient) and k1obs = k1 + k1ꢁ .
The values of unknown parameters, k1obs, k2obs, φ1,
and φ2 were calculated from Eq. (3) by the use of non-
linear least squares technique considering A0 and [X]0
as known parameters [9]. The values of A0, at different
contents of acetonitrile, under kinetic conditions, were
obtained by the extrapolation of Aobs versus t plot to
t = 0. These results are summarized in Table III. The
reliability of the fit of observed data to Eq. (3) is ev-
ident from the plots of Fig. 1 where the solid lines
are drawn through the calculated data points and from
the standard deviations associated with the calculated
parameters, k1obs, k2obs, φ1, and φ2 (Table III).
Aobs = A0 +
[1 − exp(−k1obst)]
k1obs
φ2[X]0
+
[exp(−k1obst) − exp(−k2obst)]
)
(k2obs − k1obs
(3)
where A0 = Aobs at t = 0, [X]0 is the initial concentra-
tion of NPhPT, φ1 and φ2 are empirical constants, k1obs
and k2obs represent pseudo-first-order rate constants for
the following reaction steps:
k1ꢁ
k1
k2obs
B ←− A −→ C −→ D + An
(4)
where k1 + k1ꢁ = k1obs, A = NPhPT, B = o-CO−2 C6H4-
CONHC6H5, An = C6H5NH2, C and D, most likely,
stand for o-CONHNH2C6H4CONHC6H5 and DHPD,
respectively, (if N-aminophthalimide, C1 does not
form as an intermediate in the hydrazinolysis of
NPhPT). But, if the formation of DHPD does in-
volve C1 then D must stand for C1 and, under
the present reaction conditions, C1 should quickly
convert to o-CONHNH2C6H4CONHNH2 and o-
CO−2 C6H4CONHNH2. It may be noted that hydrazi-
nolysis of C1, as described latter in the text, shows
Table III Values of Kinetic Parameters, k1obs, k2obs, φ1, and φ2 Calculated from Eq. (3) for Hydrazinolysis of NPhPT in
Mixed H2O-CH3CN Solventa
MSb
(% v/v) A0
104k1obs
(s−1
104k2obs
(s−1
φ1
(M−1 cm−1 s−1) (M−1 cm−1 s−1) (M−1 cm−1
φ2
10−3δC
tmax
(s)
104k1
d
f
h
c
e
)
)
)
A
Y g
(s−1
)
∞
2i
0.240 229 2j
21.4 0.4j
46.0 0.4j
71.0 0.4j
6.69
0.641 2960 0.246
0.252k
173
10
20
30
40l
50l
60l
70l
80l
0.254 186
1
23.3 0.2
43.1 0.2
16.4 0.1
6.89 0.14
2.71 0.02
1.77 0.01
1.32 0.01
1.10 0.01
0.94 0.01
65.9 0.2
28.4 0.4
13.1 1.1
6.97 0.03
4.14 0.01
3.17 0.01
3.03 0.01
3.46 0.01
7.73
8.49
8.70
9.34
7.89
7.03
7.01
7.89
0.717 2999 0.310
0.721 2999 0.302
0.719 4998 0.272
0.642 7887 0.193
0.593 8448 0.161
0.565 8503 0.094
0.542 8939 0.054
128
48.4
21.5
10.4
7.89
7.26
7.07
7.08
0.250 69.4 0.7 20.0 0.3
0.252 29.5 0.6 15.4 0.5
0.222 12.9 0.01 12.9 0.01
0.217 9.41 0.03 9.41 0.03
0.235 8.01 0.04 8.01 0.04
0.247 7.47 0.03 7.47 0.03
0.245 7.08 0.03 7.08 0.03
0.511 10002
0m
a [NPhPT]0 = 2 × 10−4 M, [NH2NH2]T = 0.05 M, 35◦C. ꢀ = 276 nm.
b MS = H2O-CH3CN.
c Values of A0 were obtained from extrapolation of initial absorbance values to t = 0.
d δC = (φ2/k1) + δD + δAn
.
e
A
∞ = A0 + ([NPhPT]0φ1)/k1obs
.
f
tmax is the maximum reaction time attained in the kinetic run.
g Y = k1ꢁ /k1obs = [(φ1/k1obs) − (δD + δAn − δA)]/(δB − δD − δAn), where D stands for E and k1obs = k1 + k1ꢁ .
h k1 = (1 − Y)k1obs
.
i The value pH of the reaction mixture at ∼3000 s (≡t ) is 9.93 and the value of Aobs at ∼3000 s is 0.131.
∞
j Error limits are standard deviations.
k The value of Y was obtained from the relationship: Y = kOH10(pH − pKw)/k1obs with pH = 9.93, pKw = 13.84, and kOH = 47 M−1 s−1 (estimated
from observed data summarized in Table II) [1]. The parameters, k (where k = k1obs = k2obs), φ1, and φ2 were calculated from Eq. (5).
m Y value was slightly negative.

EFFECTS OF MIXED H2O-CH3CN SOLVENTS ON THE RATE OF HYDRAZINOLYSIS
153
The observed data, obtained within 40–80% v/v
CH3CN, did not fit to Eq. (3) because under such con-
ditions, k1obs ≈ k2obs. Reaction steps shown by Eq. (4)
can lead to kinetic Eq. (5) where k1obs = k2obs = k
that based upon the observed values of pH (= 9.93)
and kOH (=47 M−1 s−1), k1ꢁ /k1obs = 0.252. Further-
more, the observed value of A∞ = 0.131 at 300 nm
(Table I) is very much different from the calcu-
calcd
lated value (≥1.10) of A
= (= (δAn + δD)[X]0,
∞
where [X]0 = 2 × 10−4 M, δD = 5500 M−1 cm−1, and
δAn ≈ 250 M−1 cm−1 at 300 nm, Table I).
φ1[X]0
Aobs = A0 +
[1 − exp(−kt)]
k
The respective values of k1obs and k2obs decreased
nonlinearly ∼32-fold and ∼3-fold with increase in the
content of CH3CN from 2 to 80% v/v in mixed aque-
ous solvent (Table III). A quantitative explanation of
such solvent effects on k1obs and k2obs is difficult, at
least, for two reasons. (i) Both k1 and k2obs are the func-
tions of rate constants for different elementary steps be-
cause nucleophilic attack by NH2NH2 at carbonyl car-
bon of A in k1-step to produce C and by o-CONHNH2
at carbonyl carbon of C to produce F cannot be rate-
determining step. (ii) The lack of a perfect and flaw-
less theoretical model that could be used to explain
the effects of mixed aqueous-organic solvents on re-
action rates. Significantly, larger sensitivity of k1obs
compared to that of k2obs (Table III) to the mixed H2O-
CH3CNsolventmaybeattributedtobimolecularityand
monomolecularity of the reaction steps represented by
rate constants k1obs and k2obs, respectively. The values
of k1obs and k2obs at different contents of acetonitrile in
mixed H2O-CH3CN solvents were found to fit to em-
pirical Eq. (2). The least squares calculated respective
values of k0 and ꢀ (obtained by using rate constant
values within acetonitrile content range 2–60% v/v)
are (276 24) × 10−4 s−1 and (6.17 0.92) × 10−2
(% v/v)−1 for kobs = k1obs, and (24.9 1.4) × 10−4 s−1
+ φ2[X]0t exp(−kt)
(5)
The values of Aobs versus t at ≥40% v/v CH3CN
obeyed Eq. (5) as evident from the plots of Fig. 2
where solid lines are drawn through the calculated data
points. The unknown parameters, k, φ1, and φ2, were
calculated from Eq. (5) considering A0 and [X]0 as
known parameters [9]. These results are summarized
in Table III.
The relationships: φ1 = (δB − δA)k1ꢁ + (δD + δAn
−
δA)k1 and k1obs = k1 + k1ꢁ can lead to Eq. (6)
k1ꢁ /k1obs
= [(φ1/k1obs) − (δD + δAn − δA)]/(δB − δAn − δD)
(6)
where D stands for o-CO−2 C6H4CONHNH2 (E), if the
formation of DHPD occurs through the intermediate
N-aminophthalimide (because molar extinction coef-
ficients of N-aminophthalimide, E and presumably o-
CONHNH2C6H4CONHNH2, F, at 276 nm are nearly
same, Table I). The values of k1ꢁ /k1obs at different con-
tents of acetonitrile were calculated from Eq. (6) with
known values of φ1 and k1obs (Table III) as well as
δA, δB, δAn and δE (= δD) from Table I. These values
of k1ꢁ /k1obs are summarized in Table III. The value of
k1ꢁ /k1obs (= 0.246) at 2% v/v CH3CN is comparable
with the corresponding value of 0.252 obtained from
the relationship: k1ꢁ /k1obs = (kOH 10pH−pKw)/k1obs with
pH = 9.93, pKw = 13.84 [10], and kOH = 47 M−1 s−1
(estimated from observed data summarized in Table II).
The calculated values of k1ꢁ /k1obs were used to calculate
k1 from the relationship: k1 = [1 − (k1ꢁ /k1obs)]k1obs and
these k1 values are shown in Table III. The known val-
ues of φ2, k1, δAn, and δE (= δD) were used to calculate
δC from the relationship: δC = (φ2/k1) + δD + δAn and
these calculated values of δC at different contents of
acetonitrile are also shown in Table III which are con-
ceivable in view of the observed values of δB (Table I).
On the other hand, if one assumes that the for-
mation of DHPD does not occur through interme-
diate N-aminophthalimide then D stands for DHPD
and under such situation k1ꢁ /k1obs value, calculated
from Eq. (6), turned out to be −0.43 at 2% v/v
CH3CN which is inconceivable in view of the fact
and (1.67 0.18) × 10−2 (% v/v)−1 for kobs = k2obs
.
Effects of Hydrazine Buffers on the Rate
of Cleavage of NPhPT in Aqueous
Solvent Containing 2% v/v CH3CN
The use of buffer in mixed aqueous-organic cosol-
vent with relatively high contents of organic cosol-
vent is complicated by (i) the unreliability of the
pH measured by usual combined glass electrode and
(ii) the complex effects of mixed solvents on pKa of
acid component of the buffer. Because of this rea-
son, buffer solutions were not used in the study on
the effects of mixed H2O-CH3CN solvents on the
rate of hydrazinolysis of NPhPT. In order to study
the effects of total hydrazine buffer concentration,
[Buf]T (=[NH2NH2] + [NH2NH+3 ]), and pH on k1obs
and k2obs, a few kinetic runs were carried out within
the [Buf]T range ≥ 0.02 − ≤ 0.16 M at a constant pH
and 35◦C in aqueous solvent containing very low con-
tent of acetonitrile (2% v/v). The observed plots of
Aobs versus t, obtained at [Buf]T ≥ 0.12 M, pH 7.31,

154
ARIFFIN ET AL.
[Buf]T ≥ 0.08 M, pH 7.46, [Buf]T ≥ 0.06 M, pH 7.92
and [Buf]T ≥ 0.05 M, pH 8.25, were strictly biphasic
as evident from some representative typical plots of
Fig. 3; and observed data (Aobs versus t) were found
to fit to Eq. (3), and the least squares calculated values
of k1obs, k2obs, φ1, and φ2 are summarized in Table IV.
The reliability of the data fit to Eq. (3) is evident from a
few typical plots of Fig. 3 where solid lines are drawn
through the least squares calculated data points.
The plots of Aobs versus t at [Buf]T < 0.12 M,
pH 7.31, [Buf]T < 0.08 M, pH 7.46, [Buf]T < 0.06 M,
pH 7.92, and [Buf]T < 0.05 M, pH 8.25 revealed dou-
ble maxima (i.e. tetraphasic nature of plot) within the
reaction time (t) range of 20 −< 8000 s (Fig. 3). The
absorbance obtained at the minimum after second max-
imum of the plot of Aobs versus t (i.e. Aobs at t = 4470 s)
at [Buf]T = 0.04 M and pH 8.18, was found to increase
from 0.547 (at 35◦C) to 0.858 (at ambient tempera-
ture) with increase in t from 4470 s to 108 h. Simi-
lar observations were obtained at different values of
[Buf]T. These observations are summarized in Table V.
These observations show the presence of two interme-
diates and final product(s) that absorb significantly at
276 nm. Thus, the reaction scheme shown by Eq. (4)
for the cleavage of NPhPT in the presence of hydrazine
should be revised and represented by Eq. (7)
k1
k2
k3
k4
A −→ C −→ C1 −→ F −→ D
(7)
↓k1ꢁ
↓k3ꢁ
−An
B
E
where A = NPhPT, B = o-CO−2 C6H4CONHC6H5,
An = C6H5NH2; C, C1, E, F, and D, most likely, stand
for o-CONHNH2C6H4CONHC6H5, N-aminophthali-
mide, o-CO−2 C6H4CONHNH2, o-CONHNH2C6H4-
CONHNH2, and DHPD, respectively. It is evident from
Table I that B, C1, D, E, and An absorb significantly
at 276 nm. Molar extinction coefficients of C1 and E
are almost same at 276 nm (Table I). Molar extinction
coefficient of F is expected to be similar to that of E.
Thus, the observed biphasic plots (with no apparent
induction period), obtained at [NH2NH2] ≥ 0.03 M of
Figs. 1–3, show that, under such conditions, k3 ꢂ k2
and k4 ꢃ k3.
Figure 3 Plots showing the dependence of Aobs versus reaction time (t) for the cleavage of NPhPT in the presence of hydrazine
buffer (Buf) at pH 8.25 0.01, ionic strength 1.0 M and [Buf]T = 0.07 M for (ꢀ), [Buf]T = 0.06 M for (ꢁ), and [Buf]T = 0.05 M
for ( ). The solid lines are drawn through the calculated data points using Eq. (3) and parameters listed in Table IV. Plots with
ꢂ
dotted lines were drawn through the observed data points at pH 8.16 0.01, ionic strength 1.0 M and [Buf]T = 0.04 M for ( ),
◦
[Buf]T = 0.03 M for (+) and [Buf]T = 0.02 M for (×).

EFFECTS OF MIXED H2O-CH3CN SOLVENTS ON THE RATE OF HYDRAZINOLYSIS
155
Table IV Values of Kinetic Parameters, k1obs, k2obs, φ1, and φ2 Calculated from Eq. (3) for the Cleavage of NPhPT at
35◦C in the Presence of Hydrazine Buffera
103k1obs
(s−1
104k2obs
(s−1
φ1
φ2
tmax
(s)
b
e
[Buf]T
(M)
(M−1 cm−1 s−1
)
(M−1 cm−1 s−1
)
A
W f
c
d
pH
A0
)
)
∞
0.12
0.14
0.16
0.08
0.10
0.12
0.14
0.15
0.06
0.07
0.08
0.09
0.10
0.05
0.06
0.07
7.31 0.260
7.31 0.259
7.31 0.303
7.45 0.248
7.48 0.245
7.46 0.243
7.44 0.239
7.45 0.247
7.91 0.242
7.92 0.261
7.93 0.231
7.92 0.274
7.92 0.227
8.26 0.250
8.24 0.261
8.24 0.206
16.0 0.5g
19.5 0.9
23.0 0.8
12.9 0.2
16.7 0.3
22.7 0.5
28.5 0.5
33.1 0.6
17.0 0.3
20.2 0.4
24.1 0.6
31.6 1.3
34.3 0.6
19.7 0.5
24.4 0.5
35.4 1.3
6.35 0.67g
6.23 1.20
10.8 0.9
8.14 0.36
13.0 0.6
16.4 0.8
21.5 0.6
23.1 0.8
6.98 0.6
11.8 0.6
15.9 0.9
15.5 1.3
23.3 0.8
12.2 0.7
17.6 0.7
18.2 1.3
18.6 1.1g
17.7 3.5
24.2 1.5
16.9 0.4
22.1 0.5
30.2 0.9
42.8 0.9
50.2 1.1
19.2 1.4
28.4 0.7
33.2 1.1
38.2 2.3
47.3 1.0
26.5 0.8
30.9 0.8
52.6 2.4
29.8 1.3g
44.6 4.1
62.0 2.2
30.6 0.5
45.5 0.7
67.3 1.1
0.493 4841 1863
0.441 3343 2287
0.513 3062 2696
0.510 3956 2364
0.510 3682 2725
0.509 3570 2965
0.539 3553 3579
0.550 3312 3505
0.468 2974 2429
0.542 3730 2475
0.507 2814 2751
0.516 2845 2940
0.503 2780 3178
0.519 3618 2695
0.514 4550 3004
0.503 3296 2890
102
116
1
1
41.3 1.6
50.0 0.9
66.3 1.3
92.9 3.3
109
1
53.1 1.0
73.3 1.0
102
3
a [NPhPT]0 = 2 × 10−4 M, ionic strength 1.0 M (by NaCl), ꢀ = 276 nm, and reaction mixture for each kinetic run contains 2% v/v CH3CN.
b Total hydrazine buffer concentration ([Buf]T = [NH2NH2] + [NH2NH+3 ]).
c Values of A0 were obtained from extrapolation of initial absorbance values to t = 0.
d
A
∞ = A0 + ([NPhPT]0φ1)/k1obs
.
e tmax is the maximum reaction time attained in the kinetic run.
f
W = φ2/k1obs
.
g Error limits are standard deviations.
The values of A at different [Buf]T and pH, as
that the calculated value of A is entirely contributed
∞
∞
shown in Table IV, are comparable with the calculated
value of A {= 0.518, where A∞ = (δE + δAn)[X]0
with [X]0 =∞2 × 10−4 M} based upon the assumption
by the products C1, E, F, and An, δC1 ≈ δE ≈ δF and
[B] ≈ 0. The value of second-order rate constant, kOH
(=47 M−1 s−1 at 2% v/v CH3CN), for the reaction
of HO− with NPhPT, gives the values of k1/k1ꢁ of
>160 at pH < 8.26 and [Buf]T > 0.05 M, and thus
these results show that [B] ≈ 0 under the present ex-
perimental conditions. These results also predict that
[D] ≈ 0 under such conditions because δD/δE ≈ 3.9
(Table I).
SincethereportedendstableproductinIng–Manske
reaction [7] is DHPD, the most conceivable interme-
diate products C1 and F are N-aminophthalimide and
o-CONHNH2C6H4CONHNH2, respectively. This pos-
sibility is affirmed by studying the cleavage of authen-
tic N-aminophthalimide in the presence of hydrazine.
Four kinetic runs were carried out on hydrazinoly-
sis of N-aminophthalimide under the reaction condi-
tions used for the hydrazinolysis of NPhPT. The ob-
served data (Aobs versus t) are summarized in Table VI.
The values of Aobs at [Buf]T = 0.15 M and pH 7.46
showed a fast decrease followed by a very slow in-
crease with the increase in reaction time t. The ini-
tial fast decrease in Aobs with increase in t followed
Eq. (8)
Table V Values of Aobs at Different Reaction Time (t)
a
for Hydrazinolysis of NPhPT at Different [Buf]T
[Buf]T (M) pH 10−3tc (s) Aobs (276 nm) Aobs (300 nm)
b
0.02
8.16
4.94
76.0
156
4.10
122
4.47
389
3.62
389
4.55
406
8.09
434
0.574
0.608
0.699
0.557
0.699
0.547
0.807
0.542
0.823
0.525
0.847
0.518
0.858
0.167
0.181
0.244
0.173
0.288
0.177
0.441
0.174
0.530
0.177
0.606
0.201
0.653
0.03
0.04
0.05
0.06
0.07
8.15
8.18
8.26
8.24
8.24
a [NPhPT]0 = 2 × 10−4 M, ionic strength 1.0 M (by NaCl),
ꢀ = 276 nm and reaction mixture for each kinetic run contains 2%
v/v CH3CN.
b Total hydrazine buffer concentration ([Buf]T = [NH2NH2] +
[NH2NH+3 ]).
c Reaction time.
Aobs = δapp[X]0 exp(−k3obst) + A
(8)
∞

156
ARIFFIN ET AL.
Table VI Values of Aobs at Different Reaction Time (t) for the Reaction Mixture Containing N-Aminophthalimide and
Buffer/Nonbuffer Solutions of Hydrazinea
[Buf]T = 0.15 Mb
[NH2NH2] = 0.05 Mc
[NH2NH2] = 0.20 Md
[NH2NH2] = 0.50 Me
f
Time (s)
Aobs
Acalcd
Time (s)
Aobs
Time (s)
Aobs
Time (s)
Aobs
Acalcd
17
20
22
25
28
31
36
39
0.182
0.163
0.150
0.139
0.132
0.126
0.119
0.117
0.114
0.112
0.113
0.116
0.118
0.122
0.127
0.131
0.139
0.147
0.154
0.630
–
0.182g
0.162
0.151
0.140
0.131
0.126
0.119
0.117
123
303
543
0.066
0.061
0.056
0.052
0.050
0.044
0.043
0.043
0.042
0.043
0.044
0.047
0.050
0.051
0.081
0.196
44
133
189
322
389
455
511
710
966
0.054
0.067
0.074
0.090
0.098
0.105
0.110
0.129
0.148
0.167
0.193
0.221
0.228
0.230
0.235
0.240
0.247
0.252
0.259
0.264
0.363
0.450
0.424
63
123
303
423
663
0.090
0.116
0.182
0.229
0.304
0.367
0.456
0.542
0.594
0.651
0.681
0.701
0.717
0.724
0.719
0.730
0.749
0.702
0.690
–
0.093
0.117
0.186
0.227
0.301
0.363
0.452
0.534
0.597
0.662
0.695
0.711
0.720
0.723
0.724
0.724
0.724
603
1,083
1,443
1,803
6,423
7,683
11,704
13,384
15,424
17,704
19,924
94,082
431,460
903
1,323
1,863
2,463
3,543
4,683
5,943
7,743
10,143
12,724
15,784
19,804
22,504
257,580
∞
45
64
99
1,288
1,798
2,831
3,918
4,562
5,339
6,616
8,225
10,001
13,309
14,160
253,080
425,940
687,900
0.114h
0.116
0.118
0.121
0.127
0.130
0.139
0.147
0.155
0.630
0.633
200
300
500
799
1,000
1,512
1,994
2,492
157,260
∞
0.723
a [N-Aminophthalimide]0 = 2 × 10−4 M, 35◦C, ꢀ = 300 nm, and reaction mixture for each kinetic run contains 2% v/v CH3CN.
b Total hydrazine buffer concentration ([Buf]T = [NH2NH2] + [NH2NH+3 ]), pH 7.46, and ionic strength 1.0 M (by NaCl).
c Total nonbuffered hydrazine concentration and pH 9.72 at t = 55 h, pH 9.61 at t = 120 h.
d Total nonbuffered hydrazine concentration and pH 10.29 at t = 4.83 h.
e Total nonbuffered hydrazine concentration, pH 10.60 at t = 6.25 h and pH 10.39 at t = 71.6 h.
f
Calculated from Eq. (1) with kobs = k4obs = (6.68 0.18) × 10−4 s−1, δapp = 3292 34 M−1 cm−1, and A0 = 0.065 0.006.
g Calculated from Eq. (8) with 103 k3obs = 115 6 s−1, δapp = 2507 235 M−1 cm−1, and A∞ = 0.111 0.014.
h Calculated from Eq. (1) with 105 k4obs = 3.41 0.07 s−1 (where kobs ≡ k4obs), δapp = 2600 4 M−1 cm−1, and A0 = 0.113 0.004.
where all the symbols have their usual meanings. The
equilibrium in the reaction of cyclic imides with reac-
tive primary amines is very common [11]. The value
of second-order rate constant (kOH) for the reaction
of HO− with C1 is 54.2 M−1 s−1 and therefore the
value of k3ꢁ at pH 7.46 is ∼2.3 × 10−5 s−1. The value of
k3obs (=0.115 s−1) shows that k3ꢁ ꢃ (k3 + k−3) because
least squares calculated respective values of k3obs, δapp
,
and A are (115 6) × 10−3
s
−1, 2507 235 M−1
∞
cm−1, and 0.111 0.014. The final slow increase in
Aobs with increase in t fits to Eq. (1) with symbol
kobs changed to k4obs, and the least squares calculated
respective values of k4obs, δapp, and A0 are (3.41
k3obs = k3 + k and hence k3ꢁ can be neglected com-
−3
0.07) × 10−5
s
−1, 2600 4 M−1 cm−1, and 0.113
pared to k3obs. The value of k3obs/k4obs (= 3.37 × 103)
affirms the fast attainment of equilibrium between C1
and F. The values of A0 (= δapp[X]0 + A∞ = 0.612)
and A (= 0.111) gave k3/k ([(A0 − A ]/A ) as
0.004. The last observed value of Aobs was ob-
tained at t = 7.7 half-lives of the final phase of the
reaction.
∞
−3
∞
∞
The value of A (=0.111) shows the presence of
4.5 and this value coupled with k3obs (= k3 + k
)
−3
∞
an equilibrium between N-aminophthalimide (C1) and
equilibrium product (F) as expressed by Eq. (9). The
presence of such
yielded k3 and k−3 as 94.1 × 10−3 s−1 and 20.9 × 10−3
s
−1, respectively. The values of k3ꢁ (≈2.3 × 10−5 s−1
)
and k4 (= 3.4 × 10−5 s−1) give the values of fD = [D]/
{[E] + [D]} (= k4/(k3ꢁ + k4)) as 0.60. Since the pKa
of D is 5.68, D is expected to exist in almost com-
plete ionized form at pH 7.46. The values of molar
k3ꢁ
k3
k4
←−
E ←− C1
F −→ D
(9)
−→
k
−3

EFFECTS OF MIXED H2O-CH3CN SOLVENTS ON THE RATE OF HYDRAZINOLYSIS
157
extinction coefficients, δ, of D and E at 300 nm are
at 0.50 M NH2NH2 is due to decrease in the equilibrium
concentration of F with the decrease in [NH2NH2].
The observed data (Aobs versus t) for the kinetic
runs at [Buf]T < 0.12 M, pH 7.31, [Buf]T < 0.08 M,
pH 7.46, [Buf]T < 0.06 M, pH 7.92, and [Buf]T <
0.05 M, pH 8.25, where the plots of Aobs versus t re-
vealed double maxima (i.e. tetraphasic nature of the
plots) within the reaction time (t) range of 20–<8000 s
(Fig. 3), were attempted to fit to a rather more complex
kinetic equation derived from irreversible consecutive
reactions shown in Eq. (7). But the observed data could
not fit to such a kinetic equation partly because under
such conditions, reversible nature of k1-step and k3-
step cannot be kinetically ignored. The effectiveness
of reversibility of k1-step and k3-step is expected to
increase with the decrease in [Buf]T at a constant pH.
The values of W (= φ2/k1obs = δC − δE − δAn because
k1obs ≈ k1 under the present experimental conditions)
show a significant decrease with the decrease in [Buf]T
at all pH values except pH 8.25 (Table IV). Such a de-
crease in W is probably due to kinetically insignificant
(i) reversibility of k1-step and (ii) occurrence of k4-step.
But, since δD/δE = 3.9 and δC/δA = 4.9, the kinetically
insignificant presence of equilibrium concentrations of
A and C as well as the rate of formation of D within
the reaction period of ≤tmax (Table IV) will cause sig-
nificant apparent decrease in δC and increase in δE and
consequently this will decrease δC − δE − δAn, i.e. W.
The values of k1obs for hydrazinolysis of NPhPT at
different [Buf]T and at a constant pH (Table IV) were
found to fit to Eq. (10)
5500 and 0.0 M−1 cm−1, respectively (Table I).
These results show that the value of A [= ( fDδD +
∞
fEδE)[X]0, with [X]0 = 2 × 10−4 M, fD = 0.60,
fE = 0.40, δD = 5500 M−1 cm−1 and δE = 0.0] should
be equal to 0.660 which is not appreciably different
from the observed value of A∞ = 0.633 (Table VI).
These results support the conclusion that the formation
of D in the hydrazinolysis of NPhPT occurs via C1.
Three kinetic runs were carried out at 0.05, 0.2, and
0.5 M NH2NH2 in nonbuffered solutions. The values of
Aobs at different reaction time (t) monitored at 300 nm
for these kinetic runs are summarized in Table VI. For
the kinetic run at 0.05 M NH2NH2, the value of Aobs
dropped from a maximum (∼0.50) to a minimum value
(0.061) within 300 s (due to hydrazinolysis of C1) fol-
lowed by a slow decrease from 0.061 to 0.042 within
300–9660 s (due to hydrolysis of C1 after the attain-
ment of equilibrium between C1 and F). Further ex-
tremely slow increase in Aobs with the increase in re-
action time t beyond 9660 s is caused by the formation
of D from F. In view of this kinetic run, the values of
tmax (=2960 s) listed in Tables III and IV for the ki-
netic run at 2% v/v CH3CN correspond to the reaction
periods within which the formation of D is insignifi-
cant. Thus, this set of observation negates the forma-
tion of D in the hydrazinolysis of NPhPT without the
formation of C1 on the reaction path. It is highly un-
likely that the rate of formation of D from C is much
larger than that from F because the leaving ability of
C6H5NH− may not be better than that of NH2NH−.
This is evident from the values of pseudo-first-order
rate constants for alkaline hydrolysis and hydrazinol-
ysis of NPhPT and C1 under similar experimental
conditions.
2
k1obs = kun1[Buf]T + kca1[Buf]T
(10)
where kun1 and kca1 represent uncatalyzed second-order
It is interesting to note that the value of Aobs at
300 nm increased from a minimum (0.112) to a maxi-
mum (0.630) with the increase in reaction time t from
64 s to 157,260 s at [Buf]T = 0.15 M and pH 7.46 while
within nearly same reaction time, the value of Aobs
increased by only ∼0.06 absorbance unit at 0.05 M
NH2NH2 and pH 9.72 (Table VI). These observations
show that the rate of formation of D from F is highly
sensitive to general acid catalysis. Such catalysis has
been detected in the related cyclization reaction [12].
As expected, the values of k4 at 0.05 M NH2NH2 are
very sensitive to pH of the reaction medium. The val-
and catalyzed third-order rate constant, respectively.
1
1
Least squares calculated values of kun and kca at dif-
ferent pH are summarized in Table VII. The extent of
reliability of the fit of observed data to Eq. (10) may
be recognized from the standard deviations associated
with the calculated parameters and maximum per-
cent residual errors, RE [= 100(k1obs − kcalcd)/k1obs] as
shown in Table VII. However, even with low-standard
1
deviations and RE values, the calculated values of kun
1
and kca at pH 7.31 and 8.25 cannot be considered as
reliable because at these two pH values, these param-
eters were calculated from rather very low number of
data points (only three data points). The experimental
limitations, such as at high values of [Buf]T, the rate
of reaction became too fast to monitor conveniently
and at low values of [Buf]T, the kinetics of the reac-
tion became too complicated (plots with dotted lines in
Fig. 3), restricted to attain a rather low range of [Buf]T
at every pH.
ues of A , obtained at [Buf]T = 0.15 M and pH 7.46
∞
(for the second phase of the reaction) and 0.50 M
NH2NH2 and pH 10.60, revealed the formation of 58
and 60% D, respectively, and consequently ∼40% E.
The value of A (≈0.45), obtained at 0.20 M NH2NH2
∞
and pH 10.29, yielded ∼40% D. Thus, at t = t , the
∞
lower value of [D] at 0.2 M NH2NH2 compared to that

158
ARIFFIN ET AL.
1
1
Table VII Values of Kinetic Parameters, kun and kca Calculated from Eq. (10) for the Cleavage of NPhPT at 35◦C in
the Presence of Hydrazine Buffera
1
1
c
c
pH
102kun (M−1 s−1
)
kca (M−2 s−1
)
REb
kn (M−1 s−1
)
kgb (M−2 s−1
)
7.31 0.0d
7.46 0.02
7.92 0.01
8.25 0.01
10.3 0.3d
8.16 1.39
16.7 4.4
7.0 15.8
0.257 0.022d
0.901 0.107
1.83 0.52
0.5
4.6
5.4
−7.0
0.632
0.378
0.377
0.110
9.7
19.3
9.3
6.08 2.52
16.4
a Same as footnote a in Table IV.
b RE = 100(k1obs − kcalcd)/k1obs, where kcalcd stands for rate constant calculated from Eq. (10) using kinetic parameters listed in Table VII.
c kn = kun1/fb and kgb = kca1/fb2, where fb = Ka/(aH + Ka) with Ka representing ionization constant of conjugate acid of hydrazine
(pKa = 8.15).
d Error limits are standard deviations.
GA, and GB-HO− catalyses have been detected ki-
netically in cyclization of ethyl N-[o-(N-methyl-
N-hydroxycarbamoyl)benzoyl]carbamate to benzo-3-
methyl-2,3-oxazine-1,4-dione within the pH range
5.45–7.28 [14].
1
1
Thus, although the values of kun and kca are not
very reliable, the significant increase in kca with
increase in pH does show the occurrence of general
base catalysis. The values of nucleophilic second-order
rate constant (kn) and general base catalyzed third-
order rate constant (kgb) were calculated from the
1
respective relationships: kn = kun1/fb and kgb = kca
/
2
fb , where fb = Ka/(aH + Ka) with Ka representing
ionization constant of conjugate acid of hydrazine
(pKa = 8.15). The average value of kgb (=13.7 M−2
MECHANISTIC PROPOSAL
Based upon product(s) characterization studies, the
most obvious reaction steps in the hydrazinolysis of
phthalimide and N-substituted phthalimides are shown
in Scheme 1 [7]. But, probably, the intermediate B has
never been isolated or characterized by any chemical
means. The formation of RNH2 has been suggested
to take place through intermediate I1 [1]. The kinetic
study coupled with spectral characterization of prod-
ucts in the hydrazinolysis of phthalimide in aqueous
solvent containing 1% v/v CH3CN led to a mechanism
that is briefly shown in Scheme 2 [3]. This mechanism
negates the formation of I1 on the reaction paths of
these reactions under alkaline pH. Basic knowledge of
s
−1) may be compared with the corresponding
values of kgb for hydrazinolysis of phthalimide
(kgb = 22.4 M−2 s−1 at 30◦C) [3] and methylaminoly-
sis of phthalimide (kgb = 207 M−2 s−1 at 30◦C) [13].
The rate of uncatalyzed hydrazinolysis of phthalimide
was found to be negligible compared to that of general
base catalyzed one [3]. Significantly lower value of
kgb for NPhPT than that for phthalimide probably
made possible to detect kn (=0.374 M−1 s−1) in
the hydrazinolysis of NPhPT. The average value of
kn (=0.374 M−1 s−1) may be compared with the
corresponding kn (=0.323 M−1 s−1 at 30◦C) for
methylaminolysis of phthalimide [13].
1
acid–base chemistry predicts that k2 step should in-
The values of k2obs show nonlinear increase (i)
with increase in [Buf]T at a constant pH and (ii)
with increase in pH at a constant [Buf]T (Table IV).
These observations suggest the presence of specific
base (HO−), general base (GB), or kinetically equiv-
alent general acid (GA)-HO−, GB-HO−, and GB-
GB catalysis. But, unfortunately, data points are
not sufficient to analyze the occurrence of these
catalyses quantitatively. Recently, specific base, GB,
volve a reactive intermediate I2 because the terminal
nitrogen in hydrazine moiety of B is more basic than
the nitrogen next to carbonyl carbon (i.e. carboxamide
nitrogen). This conclusion/speculation is correct only
if k21 step involves noncatalyzed reaction with neutral
reactant. But mechanistically extensive and thoroughly
studied aqueous cleavages of phthalamides and re-
lated compounds under alkaline medium, i.e. high pH,
1
reveal that k2 step involves both specific and general
Scheme 1

EFFECTS OF MIXED H2O-CH3CN SOLVENTS ON THE RATE OF HYDRAZINOLYSIS
159
Scheme 2
base catalysis while rate of noncatalyzed reaction is
kinetically insignificant compared to catalyzed ones
[12].
tion of such a compound should depend largely on pKa
of leaving group. This fact is reflected from the ob-
served values of hydroxide ion-catalyzed second-order
rate constants (kOH) for cyclization of phthalamide
(kOH = 4.9 M−1 s−1) [23], N-piperidinylphthalamide
(kOH = 1.1 M−1 s−1) [24], o-(aminomethyl)benzamide
(kOH = 0.16 M−1 s−1) [25], and o-(hydroxymethyl)-
benzamide (kOH = 0.15 M−1 s−1) [19].
In view of well-recognized mechanistic aspects
[15–22] of cyclization reactions of the type shown
1
2
in Scheme 3, the reaction mechanism for k2 or k2
step may be shown in Scheme 4. It is evident from
4
4
Scheme 4a and Scheme 4b that Kiꢁ4 > Ki and K1
>
4
4
4
K2 andꢁ4therefore Ki K1 may not be very different
Although this study provides spectral and kinetic
evidence for the formation of N-aminophthalimide
during the hydrazinolysis of N-phenylphthalimide (A
or NPhPT), a serious skeptic might still argue that
terminal amino group rather than amide nitrogen of
o-CONHNH2 in C should act as nucleophile in its
cyclization as shown in Scheme 4a. This genuine
skepticism is based upon the facts that (i) terminal
amino group is more basic than amide nitrogen of o-
CONHNH2 in C and (ii) terminal amino group rather
than amide nitrogen of CONHNH2 group in semicar-
bazide acts as nucleophilic site in its reactivity toward
carbonyl carbon of esters and related compounds in
addition–elimination reactions. But the mechanism in-
volved in the cyclization of C is not strictly similar
to the mechanism involved in the reactions of semicar-
bazide with esters and related compounds. The reaction
mechanisms for cyclization of C, phthalamide, and o-
(aminomethyl)benzamide are expected to be same and
hence nearly 30-fold larger value of the rate constant
for the cyclization of phthalamide [23] compared to
that of o-(aminomethyl)benzamide [25] supports the
mechanism shown by Scheme 4b compared to the one
shown by Scheme 4a.
4
from Ki K2 and consequently the rate of cycliza-
Scheme 3

160
ARIFFIN ET AL.
Scheme 4
The kinetic data described in this manuscript are
2. (a) Barber, H. J.; Wragg, W. R. J Chem Soc 1947, 1331
and references cited therein; (b) Mosher, H. S. J Am
Chem Soc 1946, 68, 1565 and references cited therein.
3. Khan, M. N. J Org Chem 1995, 60, 4536.
4. Aldrich, Handbook of Fine Chemicals and Laboratory
Equipment, 2000–2001.
5. Khan, M. N. J Org Chem 1983, 48, 1046.
6. Khan, M. N. J Chem Soc, Perkin Trans 2, 1990, 435.
7. March, J. Advanced Organic Chemistry: Reactions,
Mechanisms and Structures, 2nd ed.; McGraw-Hill
Kogakusha, Tokyo, 1977, p. 388.
consistent with the mechanism shown by Scheme 2 for
hydrazinolysis of NPhPT. The rate of disappearance of
C1 at 0.026 M NH2NH2, pH 7.46 is more than 50-fold
larger than the rate of its formation from C at 0.05 M
NH2NH2, pH 9.9 and at ≥0.03 M NH2NH2 within the
pH range 7.30–8.25. The rate of formation of D from
F is ∼70-fold slower than the rate of formation of C1
from C at 0.15 M hydrazine buffer of pH 7.46. Thus,
it is apparent that k42 < k22 < k32 [NH2NH2] under the
experimental conditions of the observed data shown
in Tables III and IV. A qualitative approach was used
8. Unpublished observations.
9. Margenau, H.; Murphy, G. M. The Mathematics of
Physics and Chemistry, 2nd ed.; D. Van Nostrand,
Princeton, NJ, 1956, p. 517.
10. Ritchie, C. D.; Wright, D. J.; Huang, D.-S.; Kamego,
A. A. J Am Chem Soc 1975, 97, 1163.
11. (a) Khan, M. N. J Chem Soc, Perkin Trans 2 1988,
1129; (b) Khan, M. N. Int J Chem Kinet 1996, 28,
421.
2
to conclude that k42 < k22 < k3 [NH2NH2] in the hy-
drazinolysis of phthalimide [3]. It is evident from Table
2
IV that k1 -step involves general base (GB) catalysis
2
while k2 -step involves catalysis which may involve
specific base (HO−), GB/general acid (GA)-HO−, GB-
HO−, and GB-GB catalysis.
12. Khan, M. N. Indian J Chem Sect A 1991, 30, 777.
13. Khan, M. N.; Ohaygha, J. E. React Kinet Catal Lett 1996,
58, 97.
The authors thank IRPA for financial support.
14. Khan, M. N. Int J Chem Kinet 2003, 35, 427.
15. Hegarty, A. F.; Bruice, T. C. J Am Chem Soc 1970, 92,
6575.
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