Effects of mixed aqueous-organic solvents on the rate of intramolecular carboxylic group-catalyzed cleavage of N-(4′-Methoxyphenyl -phthalamic acid

Article abstract of DOI:10.1002/kin.20003

Kinetic study on the cleavage of N-(4′-methoxyphenyl)phthalamic acid (NMPPAH) in mixed H₂O-CH₃CN and H₂O-1,4-dioxan solvents containing 0.05 M HCI reveals the formation of phthalic anhydride (PAn)/phthalic acid (PA) as the sole or major product. Pseudo first-order rate constants (κ₁) for the conversion of NMPPAH to PAn decrease nonlinearly from 60.4 × 10^-5 to 2.64 × 10^-5 s^-1 with the increase in the contents of 1,4-dioxan from 10 to 80% v/v in mixed aqueous solvents. The rate of cleavage of NMPPAH in mixed H₂O-CH₃CN solvents at ≥50% v/v CH₃CN follows an irreversible consecutive reaction path: NMPPAH _→^κ1 PAn _→^κ2 PA. The values of κ₁ are larger in H₂O-CH₃CN than in H₂O-1,4-dioxan solvents.

Full text of DOI:10.1002/kin.20003

Effects of Mixed
Aqueous-Organic Solvents
on the Rate of
Intramolecular Carboxylic
Group-Catalyzed Cleavage
of N-(4ꢀ-Methoxyphenyl)-
phthalamic Acid
SIM YOKE LENG, AZHAR ARIFFIN, M. NIYAZ KHAN
Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
Received 14 May 2003; accepted 21 January 2004
DOI 10.1002/kin.20003
ABSTRACT: Kinetic study on the cleavage of N-(4ꢀ-methoxyphenyl)phthalamic acid (NMPPAH)
in mixed H2O-CH3CN and H2O-1,4-dioxan solvents containing 0.05 M HCl reveals the for-
mation of phthalic anhydride (PAn)/phthalic acid (PA) as the sole or major product. Pseudo
first-order rate constants (k1) for the conversion of NMPPAH to PAn decrease nonlinearly
from 60.4 × 10−5 to 2.64 × 10−5 s−1 with the increase in the contents of 1,4-dioxan from
10 to 80% v/v in mixed aqueous solvents. The rate of cleavage of NMPPAH in mixed H2O-
CH3CN solvents at ≥50% v/v CH3CN follows an irreversible consecutive reaction path:
k1
k2
NMPPAH
PAn
PA. The values of k1 are larger in H2O-CH3CN than in H2O-1,4-dioxan
−→
−→
solvents. ꢁ 2004 Wiley Periodicals, Inc. Int J Chem Kinet 36: 316–325, 2004
C
sence and presence (20%) of N-phenylphthalimide
INTRODUCTION
in the cleavage of N-phenylphthalamic acid at 20
and 80% v/v 1,4-dioxan, respectively [2]. Hydrolytic
cleavage of N-(4ꢀ-nitrophenyl)phthalamic acid pro-
duced detectable and nondetectable amount of N-
(4ꢀ-nitrophenyl)phthalimide in acidic aqueous sol-
vents containing 20% v/v 1,4-dioxan [2] and 4%
v/v acetonitrile [3], respectively. Nearly 20% for-
mation of N-methylphthalimide has been reported
in the cleavage of N-methylphthalamic acid in
pure aqueous solvent under acidic pH [4]. In the
aqueous cleavage of N-(o-carboxybenzoyl)-L-leucine,
Efficient intramolecular carboxyl group catalyzed hy-
drolysis of amide bond has been found in many re-
lated reactions [1]. Hawkins studied the cleavage of
many N-aryl substituted phthalamic acids in acidic
mixed aqueous-1,4-dioxan solvent and found the ab-
Correspondence to: Niyaz Khan; e-mail: niyaz@um.edu.my.
Contract grant sponsor: IRPA.
Contract grant number: 09-02-03-0147.
2004 Wiley Periodicals, Inc.
c
ꢁ

EFFECTS OF MIXED AQUEOUS-ORGANIC SOLVENTS
317
of N-(4ꢀ-methoxyphenyl)phthalimide (NMPPT) was
prepared in acetonitrile.
∼<10% imide formation is reported at [HCl] <1.0 M
and 50◦C [5]. Perry reported the formation of
N-(2ꢀ-aminophenyl)phthalimide (between ∼80 and
∼100% yields) in the cleavage of N-(2ꢀ-aminophenyl)-
phthalamic acid under dilute aqueous acids in the pH
range 0–6 [6]. Recently, Wu and coworkers studied
modeling the reaction mechanisms of the imide for-
mation in an N-(o-carboxybenzoyl)-L-amino acid [7].
These rather limited number of reports on acid hydrol-
ysis of substituted phthalamic acids where both anhy-
drideandimideformationoccurred, arenotsufficientto
draw any convincing conclusion on competitive imide
and anhydride formation in these reactions. Studies on
the effects of mixed aqueous-organic solvents on the
rates of these reactions are rare. Such studies, apart
from their intrinsic worth, are partial model to the mi-
cro reaction environment for many enzyme-catalyzed
reactions. The two organic solvents, acetonitrile and
1,4-dioxan, were selected simply because these are
the most common water miscible aprotic organic sol-
vents and some kinetic data on closely related reac-
tions are available in these solvents. We decided to
study the effects of mixed H2O-CH3CN and H2O-1,4-
dioxan solvents on the hydrolytic cleavage of N-(4ꢀ-
methoxyphenyl)phthalamic acid where 4ꢀ-OCH3 is a
powerful electron-donating group. The observed re-
sults and their probable explanations are described in
this paper.
Kinetic Measurements
Alkaline Hydrolysis of N-(4ꢀ-Methoxyphenyl)-
phthalimide (NMPPT). The UV spectra of NMPPT
and its alkaline hydrolysis product, N-(4ꢀ-methoxy-
phenyl)phthalamate ion (NMPPA−), in mixed water-
acetonitrile and water-1,4-dioxan solvents revealed
suitable wavelengths for kinetic measurements as
225 and 300 nm for monitoring the disappearance
of NMPPT in the acetonitrile content range 2–30%
v/v and appearance of NMPPA− in the acetonitrile
content range 40–80% v/v, respectively, as a function
of reaction time. Similarly, UV spectra of NMPPT and
NMPPA− revealed 285 nm as suitable wavelength to
monitor the appearance of NMPPA− as a function of
reaction time in mixed aqueous-1,4-dioxan solvents.
Details of the kinetic procedure are same as described
elsewhere [8].
Pseudo first-order rate constants (kobs) for alkaline
hydrolysis of NMPPT were calculated from Eq. (1)
(where disappearance of NMPPT was monitored as
a function of reaction time, t) or Eq. (2) (where ap-
pearance of NMPPA− was monitored as a function of
reaction time, t).
Aobs = δapp[X]0 exp(−kobs t) + A
Aobs = δapp[X]0 [1 − exp(−kobs t)] + A0
(1)
(2)
∞
EXPERIMENTAL
Materials
In Eqs. (1) and (2), Aobs is the observed absorbance,
−
−
δapp (= δNMPPT − δNMPPA or δNMPPA − δNMPPT, with
δ representing molar extinction coefficient) is apparent
molar extinction coefficient, [X]0 is the initial concen-
Synthesis of N-(4-Methoxyphenyl)phthalimide. Ph-
thalic anhydride (1.84 g, 12.36 mmoles) and p-
anisidine (1.01 g, 8.24 mmoles) were added into a
50 ml round bottom flask containing 10.0 ml glacial
acetic acid. The reaction mixture was refluxed for 5 h
after which TLC indicated the completion of the re-
action. The mixture was then allowed to cool slowly
to room temperature. The resulting yellow precipi-
tates were filtered through sintered glass and dried to
give 1.86 g (89%) yellowish solid. Further purifica-
tion by recrystallization in 95% ethanol afforded a yel-
low crystalline solid (1.34 g, 64%). mp: 167–171◦C.
δH (400 MHz, CDCl3): 3.83 (3H, s, -OCH3), 6.99–
7.01 (2H, d J 9, ArH), 7.30–7.33 (2H, d J 9, ArH),
7.75–7.77 (2H, m, ArH), and 7.90–7.94 (2H, m, ArH);
δC (100 MHz, CDCl3): 55.5 (OCH3), 114.5 (ArCH),
123.7 (ArCH), 124.2 (ArC), 127.9 (ArCH), 131.8
(ArC), 131.8 (ArCH), 134.3 (ArCH), 159.2 (ArC-
OMe), and 167.6 (C O).
−
tration of NMPPT, A∞ = [X]0 δNMPPA , and A0 = [X]0
δNMPPT. The reactions were generally carried out for re-
action period of more than 6–7 halflives. Details of the
data analysis have been described elsewhere [8].
Aqueous Cleavage of N-(4ꢀ-Methoxyphenyl)phthala-
mic Acid (NMPPAH) in Acidic Mixed Aqueous-
OrganicSolvents. TheUVspectraofNMPPAHandits
aqueous cleavage products, obtained in mixed water-
acetonitrile and water-1,4-dioxan solvents containing
different contents of organic cosolvents at 0.05 M
HCl revealed suitable wavelengths as 218 and 250 nm
to monitor the rate of appearance of products and
disappearance of reactant (NMPPAH) in the acetoni-
trile content range 50–80% v/v and in the 1,4-dioxan
range of 10–80% v/v, respectively. Kinetic runs at
<50% v/v CH3CN could produce insignificant ab-
sorbance changes (∼≤0.050 absorbance unit) within
All other chemicals used were commercial products
of highest available purity. Standard solution (0.01 M)

318
LENG, ARIFFIN, AND KHAN
the reasonable length of reaction period (≥890 s to
≤107340 s) and consequently observed data (Aobs ver-
sus t) could not fit either Eq. (2) or Eq. (3). Details of the
kinetic procedure are same as described elsewhere [8].
The observed data (Aobs versus t), obtained at ≥50%
v/v CH3CN, for the cleavage of NMPPAH in mixed
H2O-CH3CN solvents were found to fit to Eq. (3)
PAn and CH3CN) and 250 nm (for reaction mixture
containing 4 × 10−5 M PAn and 1,4-dioxan) as a func-
tion of reaction time (t). The observed data (Aobs versus
t) followed Eq. (1). Details of the data analysis have
been described elsewhere [8].
RESULTS AND DISCUSSION
k
1obsδ1app[X]0
Aobs
=
[exp(−k1obs t) − exp(−k2obs t)]
k2obs − k1obs
+ δ2app[X]0[1 − exp(−k1obs t)] + A0
Effects of Mixed H2O-CH3CN and H2O-
1,4-Dioxan Solvents on the Rate of
Alkaline Hydrolysis of NMPPT
(3)
where k1obs, k2obs are pseudo first-order rate con-
In order to know the time period in which the conver-
sion of NMPPT to NMPPA− was completed to almost
100% under mixed H2O-OS (OS = CH3CN and 1,4-
dioxan) solvents, a few kinetic runs were carried out
within CH3CN content range of 2–80% v/v in mixed
aqueous solvents containing 0.002 M NaOH at 35◦C.
Similar observations were obtained in mixed H2O-1,4-
dioxan solvents. Pseudo first-order rate constants, ob-
tained under these mixed water-organic solvents, are
summarized in Table I. Nearly 10- and 9-fold nonlinear
decreaseinkobs withincreaseinCH3CNand1,4-dioxan
contents from 2 to 70 and 10 to 80% v/v, respectively,
are usual but difficult to explain quantitatively with any
theoretical model. However, an empirical treatment of
such data may be considered of some use, at least, in
k1obs
k2obs
stants for the reaction of the type: R
I
P ,
2
−→ −→
1
A0 = Aobs at t = 0 as well as δ1app a−ndP1 δ2app repre-
sent apparent molar extinction coefficients of reaction
components.
The rate of cleavage of NMPPAH, studied spec-
trophotometrically in mixed water-1,4-dioxan solvents
(1,4-dioxan content range 10–80% v/v), followed
pseudo first-order rate law and pseudo first-order rate
constants were calculated from Eq. (1). The absorbance
changes between the first and the last observed values
of Aobs forallkineticrunsarewithintherangeof0.283–
0.388.
Hydrolysis of Phthalic Anhydride (PAn) in Mixed
Aqueous-Organic Solvents at 0.05 M HCl and 35◦C.
The rate of hydrolysis of PAn was studied by monitor-
ingthedecreaseintheabsorbanceofreactionmixtureat
predicting the value of dependent variable (such as kobs
)
atanyvalueof independent variable(such as%v/vcon-
tent of OS). The values of kobs, obtained within CH3CN
content range 2–50% v/v and 1,4-dioxan content range
218 nm (for reaction mixture containing 2 × 10−5
M
Table I Values of kobs for Alkaline Hydrolysis of NMPPT in Mixed Water-Acetonitrile and Water-1,4-Dioxana
b
c
d
f
c
d
MS1
103 kobs
(s−1
103 kcald
(s−1
tmax
(s)
MS1
103kobs
(s−1
103kcald
(s−1
tmax
(s)
e
e
(% v/v)
)
)
ꢀAobs
(% v/v)
)
)
ꢀAobs
2g
88.2 0.6h
70.5 0.2
37.9 0.1
25.1 0.1
14.7 0.1
10.7 0.1
9.72 0.04
8.53 0.03
12.8 0.0
91.3
63.7
40.6
25.8
16.5
10.5
90
500
1160
1112
787
777
790
782
791
0.174
0.289
0.457
0.619
0.141
0.180
0.206
0.246
0.244
10
20
30
40
50
60
70
80
83.3 0.7h
48.1 0.3
44.0 0.2
29.4 0.1
22.9 0.1
17.1 0.1
13.2 0.1
9.70 0.07
78.7
57.1
41.5
30.1
21.9
15.9
11.5
815
1154
1158
1196
1196
1173
1162
1150
0.070
0.151
0.162
0.266
0.333
0.384
0.463
0.461
10
20
30
40i
50
60
70
80
8.39
a[NMPPT]0 = 1 × 10−4 M, [NaOH] = 0.002 M, 35◦C.
bMS1 = H2O-CH3CN.
cCalculated from Eq. (3) as described in the text.
dMaximum reaction time attained in the kinetic run.
t(max)
t(first)
t(first)
t(max)
eꢀAobs = |Aobs
− Aobs
| where Aobs
and Aobs
represent first and last observed value of Aobs, respectively.
f
MS1 = H2O-1,4-dioxan and λ = 285 nm.
gλ = 225 nm.
hError limits are standard deviations.
i λ = 300 nm.

EFFECTS OF MIXED AQUEOUS-ORGANIC SOLVENTS
319
10–80% v/v, showed good fit to empirical Eq. (4)
kobs = k0 exp(−ꢁX)
or 1,4-dioxan) may be explained qualitatively in terms
of the stability of solvated ion-pair (Na+:HO−). 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 of the organic co-
solvent (acetonitrile and 1,4-dioxan) decreases the di-
electric constant of the reaction medium which in turn
increases the stability of solvated ion-pair (Na+:HO−)
and consequently decreases kobs value. However, at
considerably high content of organic cosolvent, be-
cause of the insufficient number of water molecules,
the organic cosolvent molecules also enter into the sal-
vation shell of the solvated ion-pair (Na+:HO−). Since
acetonitrile and 1,4-dioxan can preferentially solvate
only cations (Na+), the participation of organic co-
solvent molecules into the salvation shell of ion-pair
(Na+:HO−) is expected to decrease its stability because
of the asymmetric structural network of salvation shells
of Na+ and HO− ions. Thus, under such conditions, the
increase in the content of organic cosolvent should in-
crease kobs value.
(4)
where X represents % v/v content of OS, k0 and ꢁ are
empirical constants. The magnitude of ꢁ is the mea-
sure of the rate-inhibition susceptibility of the mixed
aqueous organic solvents. The nonlinear least squares
calculated respective values of k0 and ꢁ are (99.9
4.4) × 10−3 s−1 and (4.51 0.35) × 10−2 (% v/v)−1
for OS = CH3CN and (108 3) × 10−3 s−1 and (3.20
0.27) × 10−2 (% v/v)−1 for OS = 1,4-dioxan. It
is interesting to note that the values of kobs at differ-
ent contents of CH3CN show a minimum at 70% v/v
CH3CN. Such minima have been observed in the re-
lated reactions in mixed aqueous-organic solvents and
have been attributed to a variety of factors [2]. The val-
ues of k0 (0.099 s−1 and 0.108 s−1) give the average
value of second-order rate constant (kOH) for hydrox-
ide ion-catalyzed hydrolysis of NMPPT as 52 M−1 s−1
which is nearly 2-fold larger than kOH (= 26 M−1 s−1
at 30◦C [9]) for phthalimide.
Mixed aqueous-acetonitrile and aqueous-1,4-
dioxan solvents are characterized as typically
nonaqueous (TNA) and typically aqueous (TA)
solution, respectively. These mixed solutions display
some different characteristic solution properties [10].
Although it is difficult to assess, even qualitatively,
different degree of effects of these solvents on kobs
due to different nature of these solvents (TA and
TNA), different values of ꢁ for water-acetonitrile and
water-1,4-dioxan solvents are conceivable. In view
of the present and related observations, a probable
mechanism for alkaline hydrolysis of N-substituted
phthalimides is shown in Scheme 1 where k1 – step
is concluded as the rate-determining step in mixed
aqueous solvent containing ≤2% v/v acetonitrile [11].
Generally, the change in solvent from pure water to
mixed water-organic cosolvent does not change the
reaction mechanism of a reaction and present data are
not sufficient to determine if there is a mechanistic
change with the change in the composition of mixed
aqueous-organic solvents.
Nearly 2-fold larger value of kOH for NMPPT than
for phthalimide in nearly pure water solvent cannot be
explained in terms of polar effect of substituent in leav-
ing group because the value of σH∗ (= 0.49 [12,13]) is
almost similar to σ4∗-MeOC6H4 = 0.52 [12]. But the val-
ues of kOH for a few N-alkyl substituted phthalimides
and phthalimide correlate reasonably well with Taft
0
equation (i.e. log kOH = log kOH + ρ∗σ∗), with Taft
0
reaction constant ρ∗ = 1.03 and intercept log kOH
=
1.04 M−1 s−1 [14]. It is quite possible that kOH values
of N-aryl substituted phthalimides might fit to Ham-
mett equation instead of Taft equation because the reso-
nance interaction between substituent and reaction site
in these reactions (especially with 4-substituted aryl
groups) cannot be ignored.
Hydrolysis of Phthalic Anhydride (PAn)
in Mixed Aqueous-Organic Solvents
Containing 0.05 M HCl
It is well established that the acidic hydrolysis of ph-
thalamic and N-substituted phthalamic acids involves
PAn as an intermediate [8,15,16]. Thus, in order to
The nonlinear decrease of kobs values with the in-
crease in the contents of organic cosolvent (acetonitrile
Scheme 1

320
LENG, ARIFFIN, AND KHAN
Table II Values of kobs, δapp, and A for Hydrolysis of PAn in Mixed Water-Acetonitrile and Water-1,4-Dioxana
∞
105 kobs
(s−1
10
(M−1 cm−1
δ
105 kcald MS1
(s−1
(% v/v)
105 kobs
( s−1
10
(M−1 cm−1
105 kcald
( s−1
b
−4
c
d
−3
δ
app
c
MS1
app
(% v/v)
)
)
A
)
)
)
A
)
∞
∞
2
10
20
30
40
50
60
70
80
1717 4e 2.39 0.01e 0.150 0.000e
1280
776
402
211
100
7
4
4
4
1
2.51 0.01 0.153 0.001
2.50 0.01 0.197 0.001
2.59 0.01 0.159 0.001
2.55 0.02 0.197 0.002
2.65 0.01 0.189 0.001
1300
726
405
226
126
70.6
39.4
22.0
10 1522 27e 1.67 0.01e 0.097 0.003e 1620
20 1220 36 1.71 0.02 0.106 0.001
1050
684
444
288
187
121
79.0
30
40
50
60
70
80
701 20 1.80 0.02 0.081 0.001
454 14 1.99 0.02 0.122 0.001
238 12 2.24 0.04 0.080 0.001
96.3 2.0 2.31 0.02 0.081 0.001
37.1 1.0 2.49 0.05 0.097 0.002
20.7 2.0 1.91 0.07 0.116 0.002
57.6 0.8 2.57 0.02 0.238 0.001
25.8 0.2 2.50 0.01 0.253 0.001
8.60 0.1 2.38 0.01 0.206 0.003
a [PAn]0 = 2 × 10−5 M, [HCl] = 0.05 M, 35◦C.
b MS1 = H2O-CH3CN and λ = 218 nm.
c Calculated from Eq. (4) as described in the text.
d MS1 = H2O-1,4-dioxan and λ = 250 nm.
e Error limits are standard deviations.
ease the complexity of the kinetics of the cleavage of
NMPPAH in acidic aqueous-organic solvents, it is de-
sirable to study the rate of hydrolysis of PAn under
the reaction conditions in which the rate of cleavage
of NMPPAH has been studied. Kinetic runs were car-
ried out within acetonitrile content range of 10–80%
v/v in mixed aqueous solvents containing 0.05 M HCl
at 35◦C. Similar observations were attempted in mixed
water-1,4-dioxan solvents. Pseudo first-order rate con-
stants (kobs), calculated from Eq. (1) under these mixed
water-organic solvents, are summarized in Table II.
These rate constants showed good fit to Eq. (4) and
nonlinear least squares calculated values of k0 and ꢁ
are (23.3 0.8) × 10−3 s−1 and (5.83 0.21) × 10−2
(% v/v)−1 for H2O-CH3CN and (25.0 2.3) × 10−3
cyclization) as major product [2,4–6]. In view of these
reports, expected reaction paths in the cleavage of
NMPPAH at 0.05 M HCl may be shown by Eq. (5)
k1
k1
k2
←−−−−−−−−−
−−−−−−−−→
−−−−−−−−→
B
A
C
D
(5)
−H2O
-Anis
where A, B, C, D, and Anis stand for NMPPAH,
NMPPT, phthalic anhydride, phthalic acid, and 4-
anisidine, respectively. The values of kobs (≡ k2) for
acidic hydrolysis of C decrease from 128 × 10−4
to 8.6 × 10−5 s−1 and from 152 × 10−4 to 27 ×
10−5 s−1 with the increase in the content of CH3CN
and 1,4-dioxan from 10 to 80% v/v (Table II), respec-
tively. But the values of k1 for a few N-substituted
phthalamic acids have been found to be considerably
less sensitive to the concentrations of organic cosol-
vents in mixed acidic aqueous solutions. The values of
k2/k1 vary from >1 to <1 with increase in the con-
tents of CH3CN from 2 to 80% v/v in mixed aque-
ous solvents for a few N-substituted phthalamic acids
[8a,18,19]. Thus, it seems unlikely for the rate of
cleavage of A to obey first-order rate law within the
whole range of CH3CN and 1,4-dioxan content unless
k2 ꢂ k1 or δC ≈ δD where δ represents molar extinc-
tion coefficient. If δC ≈ δD = δ then Eq. (5) can lead
s
−1 and (4.32 0.45) × 10−2 (% v/v)−1 for H2O-1,4-
dioxan. The values of kobs (Table II) are comparable
with the corresponding kobs values obtained by moni-
toring the absorbance change at 310 nm with [PAn]0 =
0.002 M [17]. These observations show that the values
of kobs for the hydrolysis of PAn in acidic medium are
independent of the initial concentrations of PAn and
the choice of wavelength for monitoring the rate of re-
action. The mechanistic details of the effects of these
aqueous-organic mixed solvents on kobs are described
elsewhere [17].
to Eqs. (1) and (2) with kobs = k1 + k−1, A = {(δD +
∞
Effects of Mixed Acidic H2O-1,4-Dioxan
and H2O-CH3CN Solvents on the Rate
of Cleavage of NMPPAH
δAnis)k1 + δBk−1}[X]0/(k1 + k−1), δapp = {(δA − δD −
δAnis)k1 + (δA − δB)k−1}/(k1 + k−1) or δapp = {(δD +
δAnis − δA)k1 + (δB − δA)k−1}/(k1 + k−1) and A0 =
δA[X]0.
Acidic aqueous cleavage of a few mono N-substituted
phthalamic acids revealed the formation of N-
substituted phthalimides (through N-cyclization) as
minor products and phthalic anhydride (through O-
The observed data (Aobs versus t), obtained at
250 nm in mixed water-1,4-dioxan solvents, obeyed
strictly first-order rate law i.e. Eq. (1). The calculated

EFFECTS OF MIXED AQUEOUS-ORGANIC SOLVENTS
321
Table III Values of kobs for Cleavage of NMPPAH in Mixed Water-Acetonitrile and Water-1,4-Dioxana
105k1obs
(s−1
105k2obs
(s−1
MS1
105kobs
(s−1
105kcald
10
b
c
d
−3
t
max
(s)
e
MS1
(% v/v )
)
)
(% v/v)
)
(s−1
)
10
20
30
40
50
60
70
80
10
20
30
40
50
60
70
80
60.4 0.4 f
36.4 0.1
21.7 0.1
12.7 0.2
7.27 0.07
4.58 0.05
3.15 0.04
2.64 0.06
60.4
36.2
21.7
13.0
7.76
4.64
2.78
1.66
9.80
10.31
11.89
9.65
154.5
154.5
154.5
154.5
18.8 1.4 f
15.4 1.1
8.64 0.20
8.01 0.08
136 12 f
61.2 4.7
25.8 0.6
9.39 0.10
a [HCl] = 0.05 M, 35◦C.
b MS1 = H2O-CH3CN, [NMPPAH]0 = 2 × 10−5 M and λ = 218 nm and values of k1obs and k2obs were calculated from Eq. (3).
c MS1 = H2O-1,4-dioxan, [NMPPAH]0 = 4 × 10−5 M and λ = 250 nm and values of kobs were calculated from Eq. (1).
d Calculated from Eq. (4) with 105 k0 = 101 s−1 and 102ꢁ = 5.15 (% v/v)−1
.
e Maximum reaction time attained in the kinetic run.
f
Error limits are standard deviations.
values of kobs at different contents of 1,4-dioxan are
summarized in Table III. These observations predict
that either k2 ꢂ k1 or δC ≈ δD under such conditions.
The values of k2/kobs vary from ∼10 to 250 with the
decrease in the content of 1,4-dioxan from 80 to 10%
v/v in mixed aqueous solvents (Tables II and III). The
values of δA, δB, δC, δD, and δAnis, obtained under
such conditions as shown in Table IV, show that δC ≈
δAnis)k1 + (δA − δB)k−1}/(k1 + k−1) or δapp = {(δD +
δAnis − δA)k1 + (δB − δA)k−1}/(k1 + k−1) showed the
absence of NMPPT within 1,4-dioxan range 10–80%
v/v. The possibility that imide (NMPPT) formed dur-
ing the cleavage of NMPPAH might have hydrolyzed
back to NMPPAH in a relatively fast step may be ruled
out for the following reasons. The value of second-
order rate constant (kH+) for acid-catalyzed hydrolysis
of phthalimide is 9.83 × 10−5 M−1 s−1 at 100◦C in
pure water solvent [20] and this value of kH+ may be
2δD. The values of A , A0, δapp, δA, δB, δC, δD, and
∞
δAnis (Table IV) and relationships: A∞ = {(δD + δAnis
)
k1 + δB k−1}[X]0/(k1 + k−1) and δapp = {(δA − δD −
used to estimate pseudo first-order rate constant (kobs
)
Table IV Values of A , A , δapp, δA, δB, δC, δD, and δ
for Cleavage of NMPPAH in Mixed Water-Acetonitrile and
Anis
∞
0
Water-1,4-Dioxana
−3
−3
δ
Anis
MSb
(% v/v)
(10
δ
)
10−3 δA
(M−1 cm−1
10−4 δB
(M−1 cm−1
10−3 δC
(M−1 cm−1
10−3 δD
(M−1 cm−1
10
app
A0 (A
)
(M−1 cm−1
)
)
)
)
)
(M−1 cm−1
)
∞
10
(10)
20
(20)
30
(30)
40
(40)
50
(50)
60
(60)
70
(70)
80
(80)
0.265
(0.084)
0.300
(0.054)
0.292
(0.035)
0.377
(0.046)
0.296
(0.070)
0.292
(0.095)
0.279
(0.099)
0.297
(0.137)
13.3
(11.1)
15.0
(10.7)
14.6
(10.6)
18.9
(11.2)
16.8
(11.5)
16.1
(12.0)
17.4
(11.4)
18.2
(12.6)
4.05
(1.34)
4.21
(1.40)
4.33
(1.49)
4.32
(1.51)
4.40
(1.56)
4.27
(1.66)
4.34
(1.63)
4.37
(1.64)
32.7
(4.10)
34.8
(4.35)
33.9
(3.83)
35.3
(5.02)
36.0
(4.22)
37.6
(4.32)
37.6
(4.90)
34.1
7.70
(2.18)
7.55
(2.50)
8.15
(2.00)
8.60
(2.15)
8.95
(2.00)
8.75
(2.05)
9.60
(2.18)
9.95
(2.23)
8.35
(0.35)
10.0
(0.45)
8.70
(0.40)
9.80
(0.43)
10.1
(0.40)
9.90
(0.25)
10.1
(0.30)
11.7
(0.48)
(8.94)
(9.36)
(9.72)
(10.05)
(9.74)
(9.64)
(8.95)
(9.19)
(4.80)
a Parenthesized values stand for H2O-1,4-dioxan solvent, M [HCl] = 0.05 M, λ = 250 nm, A = NMPPAH, B = NMPPT, C = phthalic
anhydride, D = phthalic acid, Anis = 4-methoxyaniline, and [A]0 = [B]0 = [C]0 = [D]0 = [Anis]0 = 4 × 10−5 M.
b MS = H2O-CH3CN, λ = 218 nm and [A]0 = [B]0 = [C]0 = [D]0 = [Anis]0 = 2 × 10−5 M.

322
LENG, ARIFFIN, AND KHAN
as 1.1 × 10−9 s−1 at 0.05 M HCl and 35◦C. Thus, it
seems that the fraction of NMPPT hydrolyzed within
10–100 h is 4 × 10−5–4 × 10−4. The value of kH+ for
NMPPT may not be significantly different from that
for phthalimide. Thus the observed facts, k2/kobs > 10,
least squares calculated respective values of k1 and A0
are(3.23 0.01) × 10−5 s−1 and0.455 0.001at70%
v/v and (2.28 0.11) × 10−5 s−1 and 0.502 0.003 at
80% v/v 1,4-dioxan. The calculated values of k1 and A0
are almost similar to the corresponding values of kobs
and A0 (= A∞ + δapp [X]0) calculated from Eq. (1).
The residual errors (= Aobs i − Acald i where Aobs i and
Acald i represent respective observed and calculated val-
ues of absorbance at the reaction time ti), obtained from
the fitting of observed data to Eq. (1) and Eq. (3) are al-
most same as evident from the values of Aobs and Acalcd
summarized in Table V. These data show that the contri-
bution of [k1obsδ1app[X]0/(k2obs − k1obs)][exp(−k1obs t)
− exp(−k2obst)] is insignificant compared to δ2app[X]0
[1 − exp(−k1obst)] + A0 in Eq. (3) which is conceiv-
δC ≈ 2δD, and k ≈ 0, show that kobs = k1 in view of
−1
Eq. (5).
Although the observed data (Aobs versus reaction
time t) were found to fit to Eq. (1) perfectly despite
the fact that δC/δD ≈ 2 (Table IV), an attempt has been
made to fit the observed data at 70 and 80% v/v 1,4-
dioxan to Eq. (3) which can be derived from Eq. (5)
with k = 0, k1obs = k1, k2obs = k2, δ1app = δC − δD,
−1
δ2app = δD + δAnis − δA, and A0 = δA[X]0. Values of
k1 and A0 were calculated from Eq. (3) considering
δ1app, δ2app, and k2 as known parameters. The values
of k2, δ1app, and δ2app were obtained experimentally
from the data summarized in Tables II and IV. The
able for the reason that |δ2app|/[k1obsδ1app/(k2obs
−
k1obs)] = 35 and 42 at 70 and 80% v/v 1,4-dioxan,
respectively.
Table V Values of kobs for Alkaline Hydrolysis of NMPPT in Mixed Water-1,4-Dioxana
1,4-Dioxan
70% v/v
80% v/v
b
c
d
e
Time (s)
Aobs
Acalcd
Acalcd
Time (s)
Aobs
Acalcd
Acalcd
80
503
0.456
0.451
0.445
0.439
0.434
0.427
0.417
0.408
0.398
0.389
0.381
0.375
0.367
0.361
0.351
0.100
0.455
0.450
0.445
0.439
0.434
0.428
0.417
0.408
0.399
0.389
0.381
0.376
0.368
0.360
0.349
0.100
0.454
0.450
0.446
0.441
0.436
0.430
0.420
0.410
0.400
0.391
0.382
0.376
0.367
0.359
0.347
0.090
60
120
180
720
1260
1560
1980
2460
3600
3900
4800
6480
8400
10080
12600
19800
31080
38160
72540
88140
99360
120600
154500
0.508
0.505
0.504
0.496
0.490
0.488
0.485
0.479
0.471
0.468
0.461
0.448
0.433
0.419
0.400
0.363
0.302
0.269
0.185
0.168
0.163
0.153
0.150
0.505
0.505
0.504
0.499
0.491
0.490
0.487
0.482
0.472
0.469
0.462
0.447
0.432
0.419
0.401
0.355
0.298
0.271
0.191
0.173
0.164
0.152
0.143
0.502
0.502
0.501
0.497
0.494
0.492
0.488
0.485
0.476
0.474
0.467
0.455
0.440
0.428
0.411
0.365
0.306
0.277
0.185
0.161
0.149
0.133
0.119
1005
1541
2084
2660
3745
4710
5708
6713
7638
8295
9259
10224
11611
154500
a [NMPPAH]0 = 4 × 10−5 M, [HCl] = 0.05 M, 35◦C and λ = 250 nm.
b Calculated from Eq. (1) with 105 kobs = 3.04 0.02 s−1, δapp = 8976 24 M−1 cm−1 and A = 0.097 0.001.
∞
c Calculated from Eq. (3) with δ1app = 2720 M−1 cm−1, δ2app = −9190 M−1 cm−1, 105 k2obs = 37 s−1, 105 k1obs = 3.23 0.01 s−1, and
A0 = 0.455 0.001.
d Calculated from Eq. (1) with 105 kobs = 2.64 0.06 s−1, δapp = 9193 61 M−1 cm−1, and A = 0.137 0.003.
∞
e Calculated from Eq. (3) with δ1app = 2570 M−1 cm−1, δ2app = −9890 M−1 cm−1, 105 k2obs = 27 s−1, 105 k1obs = 2.28 0.11 s−1, and
A0 = 0.502 0.003.

EFFECTS OF MIXED AQUEOUS-ORGANIC SOLVENTS
323
Figure 1 Plots of absorbance (Aobs) at 218 nm against reaction time (s) for a mixed aqueous solutions of NMPPAH (2 ×
10−5 M) in 50, 60, 70, and 80% v/v CH3CN, 0.05 M HCl at 35◦C. The solid lines are drawn through the calculated data points
using Eq. (3) and parameters, k1obs (= k1), k2obs (= k2), A0, δ1app (= δC − δD) and δ2app (= δD + δAnis − δA), listed/calculated
from data summarized in Tables III and IV.
tion period of 40 h at 35◦C is ∼6 × 10−4. It is therefore
The observed data (Aobs versus t), obtained in
mixed H2O-CH3CN solvent at ≥50% v/v CH3CN and
218 nm, were found to fit to Eq. (3) which can be de-
rived from Eq. (5) with k1obs = k1 + k−1, k2obs = k2,
δ1app = δC − δD, δ2app = {(δD + δAnis − δA)k1 + (δB −
δA)k−1}/(k1 + k−1), and A0 = δA[X]0. Kinetic runs at
50, 60, 70, and 80% v/v CH3CN were carried out for
reaction periods of ∼21–40 h. But the values of Aobs
remained unchanged within the reaction period of 13–
21 h at 50, 12–24 h at 60, 14–23 h at 70, and 23–40 h at
80% v/v CH3CN (Fig. 1). This shows that these reac-
tions were completed within <23 h. The average values
apparent that k−1 is negligible compared to k1 or simply
−1
k
≈ 0 under the present experimental conditions and
consequently k1obs = k1, k2obs = k2, δ1app = δC − δD,
and δ2app = δD + δAnis − δA. Values of k1, k2, and A0
were calculated from Eq. (3) considering δ1app and δ2app
as known parameters whose values were obtained ex-
perimentally (Table IV). The calculated values of k1
and k2 are summarized in Table III and those of A0
are shown in Table IV. The reliability of the fit of the
observed data to Eq. (3) is evident from the plots of
Fig. 1 where solid lines are drawn through the calcu-
lated data points. The values of k2 may be compared
with the corresponding values of kobs obtained in the
study on the rate of hydrolysis of PAn (= C) (Table II).
However, the calculated values of k1 and k2 at 50%
v/v CH3CN may not be considered as very reliable be-
cause of considerably low value of ꢀAobs (= 0.054,
Table III).
of Aobs (= A ) within the reaction period of 13–21 h,
∞
12–24 h, 14–23 h, and 23–40 h are 0.330
0.001,
0.326 0.002, 0.323 0.002, and 0.363 0.002 at
50, 60, 70, and 80% v/v CH3CN, respectively. These
values of A show the presence of D and Anis only un-
∞
der these conditions. The values of δB are nearly 2-fold
larger than the corresponding values of the sum of δAnis
and δD (Table IV). This shows that even the presence of
10% B could have caused significantly larger values of
The value of k1 (= kobs = 3.64 × 10−4 s−1
,
Table III) for O-cyclization of NMPPAH at 20% v/v
1,4-dioxan may be compared with the corresponding
value of 3.54 × 10−4 s−1 estimated from the reported
A
compared to observed ones (A = 0.323–0.363)
∞
∞
because the fraction of hydrolyzed B within the reac-

324
LENG, ARIFFIN, AND KHAN
value at 65.8◦C [2]. The values of k1 decrease
nonlinearly from 60.4 × 10−5 to 3.15 × 10−5 s−1
with the increase in 1,4-dioxan from 10 to 70% v/v.
Similar but less pronounced decrease in kobs was
obtained in O-cyclization of N-phenylphthalamic acid
under similar solvent system at 65.8◦C [2]. Nearly
20-fold change in k1 with the change in 1,4-dioxan
content from 10 to 70% v/v is very different from
∼2- to 3-fold change in k1 for phthalamic and N-alkyl
substituted phthalamic acids [5,17], obtained under
almost similar conditions. The values of k1 at different
contents of 1,4-dioxan fit to Eq. (4) and the nonlinear
least-squares calculated values of k0 (= k10) and ꢁ
are 105 k0 = 101 1 s−1 and 102ꢁ = 5.13 0.07 (%
v/v)−1, respectively.
The effects of mixed aqueous-organic cosolvents
on k1 may be explained qualitatively in terms of con-
ceivable mechanism for O-cyclization of NMPPAH as
showninScheme2wherek-stepistherate-determining
step. It is well known that such reactions are cat-
alyzed by both specific and general acids in the pres-
enceofconsiderablyhighconcentrationsoftheseacids.
But at 0.05 M HCl and in the absence of general
acid, these catalyzed reaction paths are ignored in
Scheme 2.
The value of equilibrium constant, Kf, is expected to
decrease with the decrease in the polarity of the solvent,
i.e., the increase in the content of organic cosolvent be-
cause the formation of neutral reactive intermediate,
Int1, occurs through a transition state or a more reac-
tive intermediate, Int2 [2,3], which is more polar than
the reactant state. Similarly, the value of KT should also
decrease with the decrease in the content of water in
mixed aqueous solvent because Int3 is more polar than
Int1. However, the same solvent effect increases the
value of k because the transition state in k-step is ap-
parently less polar than the reactant state (Int3). Since
k1 = kKfKT, therefore mixed solvent effect on k1 de-
pends upon its effect on k, Kf, and KT.
The values of k1 at ≥60% v/v CH3CN are ∼3-fold
larger than the corresponding k1 values obtained at
≥60%v/v1,4-dioxan(TableIII). Butpseudo first-order
rate constants for alkaline hydrolysis of NMPPT, ob-
tained within 30–70% v/v content range of CH3CN are
∼1.5- to 2-fold smaller than the corresponding kobs val-
ues for 1,4-dioxan (Table I). Such characteristic effects
of mixed H2O-1,4-dioxan and H2O-CH3CN solvents
on k1 for NMPPAH and N-alkyl substituted phthalamic
acids are interesting but difficult to explain quantita-
tively. However, a qualitative explanation may be given
in terms of different reaction mechanisms (Schemes 1
and 2) as well as typically aqueous (TA) and typically
nonaqueous (TNA) nature of mixed water-1,4-dioxan
and water-acetonitrile solvent, respectively. The for-
mation of Int2 from Int1 (Scheme 2) involves water
molecule-mediated 1,3-proton transfer and unlike 1,4-
dioxan molecules, acetonitrile molecules breakdown
long range three-dimensional structural network of wa-
ter (a characteristic feature of TNA solutions [10]).
Thus, there are more water molecules to mediate 1,3-
proton transfer in water-acetonitrile solvent than in
water-1,4-dioxan solvent, especially at rather low con-
tent of water. Such characteristics of mixed aqueous
solvent might cause KT larger in water-acetonitrile than
in water-1,4-dioxan solvent.
The value of k1 (≡ k10) for NMPPAH (105 k10
= 101 s−1) shows rather larger intrinsic reactivity of
N-aryl substituted phthalamic acids than that of N-
alkyl substituted phthalamic acids because the reported
values of k10 for N-methylphthalamic acid, N,N-
dimethylphthalamic acid, N-acetylphthalamic acid,
and phthalamic acid are 2.8 × 10−5 s−1 at 37◦C [4], 100
× 10−5 s−1 at 35◦C [8a], 77 × 10−5 s−1 at 100◦C [4],
and 9.2 × 10−5 s−1 at 37◦C [4], 24 × 10−5 s−1 at 47.2◦C
[15], 100 × 10−5 s−1 at 48◦C [12], respectively, while
σ∗4-MeOC6H4 = 0.52 [12], σ∗Me = 0 [15], σ∗MeCO = 1.65
Scheme 2
[13], σ∗ = 0.49 [12,13] and 0.16 [21]. Similarly, the
H
values of k1 at 70% v/v CH3CN (105 k1 = 8.64 s−1
)
and 70% 1,4-dioxan (105 k1 = 3.15 s−1) for NMPPAH

EFFECTS OF MIXED AQUEOUS-ORGANIC SOLVENTS
325
are significantly smaller than that for phthalamic acid
(105 k1 = 20.2 s−1 [8b]). These results may be at-
tributed to the possibility that while the reactivity of
N-alkyl substituted phthalamic acids is affected by po-
lar and steric effects, the reactivity of N-aryl substituted
phthalamic acids is expected to be influenced by polar
and resonance effects.
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Franks, F. (Ed.); Plenum Press: New York, 1979; Vol. 6,
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