Intramolecular carboxylic group-assisted cleavage of N-(2-hydroxyphenyl)- phthalamic acid (7) and N-(2-methoxyphenyl)-phthalamic acid (8): Absence of intramolecular general acid catalysis due to 2-OH in 7

Article abstract of DOI:10.1002/kin.20203

The values of pseudo first-order rate constants (k_obs) for the cleavage of AM 2-hydroxyphenyl)phthalamic acid (7), obtained at 4.9 × 10^-2 M HCl, 35°C, and within CH₃CN content range 2-80% (v/v) in mixed aqueous solvent are smaller than k_obs for the cleavage of N-(2-methoxyphenyllphthalamic acid (8), obtained under almost similar experimental conditions, by nearly 1.5- to 2-fold. These observations show the absence of expected intramolecular general acid catalysis due to 2-OH group in 7. The values of k_obs for the cleavage of 7 and 8 decrease by more than 20-fold with the increase in the content of CH₃CN from 2 to 80-82% (v/v) in mixed aqueous solvent. The kinetic data reveal that in acidic aqueous cleavage of 7, N-cyclization (leading to the formation of imide) and O-cyclization (leading to the formation of phthalic anhydride) vary from ～10 to 15% and ～90 to 85%, respectively, with the increase in CH ₃CN content from 2 to 80% (v/v). Similar increase in CH₃CN content causes increase in N-cyclization from ～0 to 5% and decrease in O-cyclization from ～100 to 95% in the acidic aqueous cleavage of 8. Some speculative, yet conceivable, reasons for nearly 10 and 0% N-cyclization in the cleavage of respective 7 and 8 at low content of CH₃CN have been described.

Full text of DOI:10.1002/kin.20203

Intramolecular Carboxylic
Group-Assisted Cleavage
of N-(2-Hydroxyphenyl)-
phthalamic Acid (7) and
N-(2-Methoxyphenyl)-
phthalamic Acid (8):
Absence of Intramolecular
General Acid Catalysis
Due to 2-OH in 7
YOKE-LENG SIM, AZHAR ARIFFIN, M. NIYAZ KHAN
Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
Received 20 March 2006; revised 4 June 2006; accepted 4 June 2006
DOI 10.1002/kin.20203
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: The values of pseudo first-order rate constants (k ) for the cleavage of N-(2-
obs
−
2
◦
hydroxyphenyl)phthalamic acid (7), obtained at 4.9 × 10 M HCl, 35 C, and within CH CN con-
3
tent range 2–80% (v/v) in mixed aqueous solvent are smaller than k
for the cleavage of N-(2-
obs
methoxyphenyl)phthalamic acid (8), obtained under almost similar experimental conditions,
Correspondence to: M. N. Khan; e-mail: niyaz@um.edu.my.
Contract grant sponsor: National Scientific Research and Devel-
opment Council of Malaysia for IRPA.
Contract grant number: 09-02-03-0147.
Contract grant sponsor: Academy of Sciences Malaysia for
SAGA.
Contract grant number: 66-02-03-0039.
Contract grant sponsor: Malaysia Toray Science Foundation.
Contract grant number: 66-02-03-0030.
ꢀ
c 2006 Wiley Periodicals, Inc.

INTRAMOLECULAR CARBOXYLIC GROUP-ASSISTED CLEAVAGE
747
by nearly 1.5- to 2-fold. These observations show the absence of expected intramolecular gen-
eral acid catalysis due to 2-OH group in 7. The values of kobs for the cleavage of 7 and 8 decrease
by more than 20-fold with the increase in the content of CH CN from 2 to 80–82% (v/v) in mixed
3
aqueous solvent. The kinetic data reveal that in acidic aqueous cleavage of 7, N-cyclization
(leading to the formation of imide) and O-cyclization (leading to the formation of phthalic an-
hydride) vary from ∼10 to 15% and ∼90 to 85%, respectively, with the increase in CH CN content
3
from 2 to 80% (v/v). Similar increase in CH CN content causes increase in N-cyclization from
3
∼
0 to 5% and decrease in O-cyclization from ∼100 to 95% in the acidic aqueous cleavage of 8.
Some speculative, yet conceivable, reasons for nearly 10 and 0% N-cyclization in the cleavage
of respective 7 and 8 at low content of CH CN have been described. ꢀC 2006 Wiley Periodicals,
3
Inc. Int J Chem Kinet 38: 746–758, 2006
−
2
INTRODUCTION
in mixed H2O–CH3CN solvents at 4.9 × 10 M HCl.
The results and their probable explanations are de-
scribed in this article.
Since the appearance of classical paper of Bender on
intramolecular carboxylic group-assisted hydrolysis of
amide bond in phthalamic acid in 1957, a surge of in-
terest in this area of research can be seen in the lit-
erature, partly because the value of second-order rate
constant for the reaction of benzoic acid with phthala-
mic acid at pH 1–3 is almost zero, which shows that
the rate enhancement due to intramolecularity is ap-
proximately infinity [1]. Depending upon the reaction
conditions, the rate of these reactions have been found
to involve uncatalyzed, specific acid, and intermolecu-
largeneralacid–generalbase-catalyzedkinetictermsin
the rate law [2]. Pseudo first-order rate constants (kobs)
EXPERIMENTAL
Materials
−2
for the aqueous cleavage of 1 at 3.0 × 10 M HCl and
0% (v/v) CH3CN is nearly ∼10-fold larger than kobs
Synthesis of N-(2-Hydroxyphenyl)phthalimide 5.
Phthalic anhydride (4.90 g, 33.1 mmol) and o-
aminophenol (3.01 g, 40.5 mmol) were added into
a 50 mL round bottom flask containing 20.0 mL
of glacial acetic acid. The reaction mixture was re-
fluxed with stirring for 4 h, after which TLC indi-
cated the completion of the reaction. The reaction mix-
ture was allowed to cool to room temperature and
poured into distilled water. The resulting red precip-
itates were filtered and dried to give reddish brown
solid, 6.10 g (93.0%). Further purification by recrys-
tallization in boiled denaturated ethanol (95%) gives
fine crystals of N-(2-hydroxyphenyl)phthalimide (5),
2
for 2 under essentially similar reaction conditions [3].
These observations have been attributed to the internal
hydrogen bonding as shown in 3. Most of the studies
have been carried out in aqueous solvents containing
a very low content of organic co-solvent such as 1,4-
dioxane and acetonitrile. Thus, a rather limited num-
ber of systematic kinetic studies on the effects of mixed
aqueous–organic solvents on the rates of such reactions
led Granados and de Rossi [4] to conclude that pH and
co-solvent concentration are important factors that de-
termine the competition between N-cyclization (i.e.,
imide formation) and O-cyclization (i.e., anhydride
formation). Mixed aqueous–organic solvents consti-
tute, at least, partial model to the medium charac-
teristics to the micro reaction environment for mi-
cellar and many enzyme-catalyzed reactions [5]. We
have therefore been studying the effects of such sol-
vents on the rates of intramolecular reactions because
intramolecularity is an essential feature of most of
the enzyme-catalyzed reactions. Furthermore, in or-
der to discover whether there is an intramolecular gen-
eral acid (IGA) catalysis involving internal hydrogen
bonding as shown in 4, the rates of aqueous cleav-
age of N-(2-hydroxyphenyl)phthalamic acid and N-
◦
◦
4.90 g, 74.0%: m.p. 238–241 C (lit. 216 C) [6]; IR
−
1
ꢀ 3376 (OH), 1786, 1769, 1700 (C O) cm ; δH
(400 MHz, Acetone-d6) δ 6.96–7.00 (m, 1H, ArH),
7.04–7.06 (m, 1H, ArH), 7.30–7.35 (m, 2H, ArH),
7.87–7.94 (m, 4H, ArH(Pth)); δC (100 MHz,
Acetone-d6) δ 117.5 (ArCH), 120.3 (ArC N), 120.6
(ArCH), 123.9 (2ArCH(Pth)), 131.1 (ArCH), 131.2
(ArCH), 133.4 (ArC OH), 135.1 (2ArCH(Pth)), 154.9
(2ArC(Pth)), 167.9 (2C O).
Synthesis of N-(2-methoxyphenyl)phthalimide (6)
is described elsewhere [7]. All other chemicals used
were commercial products of highest available pu-
−
2
rity. Standard solutions of 5 (3.0 × 10 M) and 6
−
2
(2-methoxyphenyl)phthalamic acid have been studied
(1.0 × 10 M) were prepared in acetonitrile.
International Journal of Chemical Kinetics DOI 10.1002/kin

748
SIM, ARIFFIN, AND KHAN
Kinetic Measurements
Alkaline Hydrolysis of 5 and 6 in Mixed H2O–CH3CN
Solvents. The rates of alkaline hydrolysis of 5 and 6
were conveniently studied spectrophotometrically by
monitoring the disappearance of 5 at 300 nm and ap-
pearance of hydrolysis product of 6 at 290 nm and
◦
3
5 C. The details of the kinetic procedure are described
elsewhere [7,8]. Pseudo first-order rate constants (kobs)
were calculated from Eqs. (1) and (2) for alkaline hy-
drolysis of 5 and 6, respectively. In Eqs. (1) and (2),
Aobs is the observed absorbance, δapp (= δR − δP or
δP − δR, with δ representing molar extinction coeffi-
cient as well as R and P representing reactant and
product, respectively) is apparent molar extinction co-
efficient of reaction mixture, [X]0 is the initial concen-
tration of 5 or 6, A∞ = [X]0δP, and A0 = [X]0δR.
cyclization) as minor and major products [10–12] as
well as major and minor products [13]. In view of these
reports, the possible reaction paths in the cleavage of 7
and 8 at 4.9 × 10 M HCl may be expressed by Eq. (3)
−
2
k3
k1
k2
H2O + E ←− A −→ B −→ D
(3)
−
C
where A = 7 or 8, B = phthalic anhydride, C =
Aobs = δapp[X]0 exp(−kobst) + A∞
(1)
(2)
2
-hydroxyaniline or 2-methoxyaniline, D = phthalic
acid, and E = 5 or 6. The disappearance of A through
Aobs = δapp[X]0[1 − exp(−kobst)] + A0
reaction paths k1-step (i.e., O-cyclization) and k3-step
(
i.e., N-cyclization) may be resolved as follows.
The observed data (Aobs versus t) were found to fit to
Eqs. (1) and (2) up to >10 half-lives of the reactions for
both 5 and 6. The details of data analysis are described
elsewhere [9].
The estimated value of kobs for hydrolysis of N-
−
10 −1
−2
M
methylphthalimide is ∼3 × 10
s
at 3.0 × 10
HCl [14] and hence hydrolysis of E to give A within
4
9
.6 × 10 s (the maximum reaction time attained in the
present study at 80–82% (v/v) CH3CN) is considered to
be insignificant and consequently k3-step is an almost
irreversible step under such reaction conditions. The
values of kobs for hydrolysis of 7 and 8 (Table I) and
for hydrolysis of phthalic anhydride (Table II) show
that the reaction mixture should not contain B after a
reaction period of nearly 4–38 and ≥7 half-lives of the
reaction involving disappearance of A and B, respec-
tively. Thus, the final products of the aqueous cleavage
of 7 or 8 should be D, C, and E if both O-cyclization
and N-cyclization occur during the reaction. If Y rep-
resents fraction of O-cyclization, then
Hydrolysis of Phthalic Anhydride in Mixed H2O–
−2
◦
CH3CN Solvents at 4.9 × 10 M HCl and 35 C. The
rate of hydrolysis of phthalic anhydride (PAn) in acidic
mixed H2O–CH3CN solvents was studied by monitor-
ing the decrease in absorbance (Aobs) of the reaction
mixture at 280 and 285 nm as a function of reaction
time, t. The observed data (Aobs versus t), obtained for
several half-lives of the reaction, followed Eq. (1).
Aqueous Cleavage of N-(2-Hydroxyphenyl)phth-
alamic Acid (7) and N-(2-Methoxyphenyl)phthalamic
Acid (8) in Acidic Mixed H2O–CH3CN Solvents. In a
typical kinetic run, reaction mixture (4.8 mL) contain-
δ∞ = Y(δC + δD) + (1 − Y)δE
(4)
−
4
−3
ing 2.0 × 10 M 5 or 6 and 1.0 × 10 M NaOH, the
rate of cleavage of imide was allowed to progress for
where δ∞ = A∞/[X]0, with A∞ is the absorbance
of reaction mixture at reaction time t = ∞ and
>
100 half-lives for 5 and >15 half-lives for 6, respec-
−
4
tively. The reaction mixture was then made acidic by
adding 0.2 mL of 1.25 M HCl and the rate of cycliza-
tion of 7 and 8 were studied spectrophotometrically by
monitoring the disappearance of 7 at 280 nm and 8 at
[X]0 = 2.0 × 10 M (Table I), δC, δD, and δE repre-
sent molar extinction coefficients of C, D, and E, re-
spectively. The values of δC, δD, and δE were obtained
by using commercially available 2-hydroxyaniline, 2-
methoxyaniline, phthalic acid, and synthesized 5 and 6
and these results are summarized in Table III.
2
85 nm. The observed data revealed satisfactory fit to
Eq. (1) for reaction period covering 3–12 half-lives for
7
and 5–39 half-lives for 8.
The aqueous cleavage of mono N-substituted phtha-
The values of Y (Table III) show that in the acidic
aqueous cleavage of 7, N-cyclization varies from
∼10 to 15% with the increase in the CH3CN con-
tent from 2 to 80% (v/v). Similarly, the increase in the
CH3CN content from 2 to 82% (v/v) causes increase in
lamic acids in mild acidic medium revealed the forma-
tion of respective N-substituted phthalimides (through
N-cyclization) and phthalic anhydride (through O-
International Journal of Chemical Kinetics DOI 10.1002/kin

INTRAMOLECULAR CARBOXYLIC GROUP-ASSISTED CLEAVAGE
749
◦
a
Table I Values of kobs, δapp, and A∞ for Cleavage of 7 and 8 in Mixed H O–CH CN at 35 C
2
3
5
b
105kd
105k
e
10 kd
5
CH3CN
%, v/v)
10 k
δapp
δapp
−1 −1
obs
calcd
−1
obs
calcd
−1
−
1
−1 −1
nc (s
−1
(s
nc (s
(
(s
)
(M
s
)
A∞
)
)
(M
s
)
A∞
0.210 ± 0.006
0.214 ± 0.005 10 79.9
0.212 ± 0.005 52.2
)
f
f
f
f
f
f
2
1
1
2
2
3
3
4
4
5
5
6
6
7
7
8
8
66.9 ± 1.1 3405 ± 20 0.502 ± 0.004
51.6 ± 0.7 3480 ± 16 0.516 ± 0.003
5
6
68.4
49.2
120 ± 3
4900 ± 31
5318 ± 33
5621 ± 26
5522 ± 73
6085 ± 22
6205 ± 35
6321 ± 35
5
122
0
2
0
2
0
2
0
2
0
2
0
2
0
2
0
2
84.5 ± 1.5
54.3 ± 0.7
28.5 ± 1.1
21.4 ± 0.2
14.4 ± 0.2
10.2 ± 0.1
33.4 ± 0.6 3573 ± 25 0.527 ± 0.005
20.2 ± 0.3 3576 ± 19 0.540 ± 0.004
13.5 ± 0.2 3346 ± 17 0.597 ± 0.003
4
4
4
32.6
21.6
14.3
8
0.248 ± 0.013 39 34.2
0.217 ± 0.004 31 22.3
0.238 ± 0.007 17 14.6
0.229 ± 0.007 13 9.55
9.51 ± 0.16 3337 ± 24 0.623 ± 0.005 12 9.47
6.37 ± 0.07 3368 ± 16 0.600 ± 0.003
3.16 ± 0.06 3489 ± 26 0.579 ± 0.005
3.07 ± 0.06 3213 ± 26 0.609 ± 0.005
8
3
3
6.27
4.16
2.75
7.60 ± 0.10 6504 ± 50
0.235 ± 0.010
0.244 ± 0.003
8
8
6.24
6.60 ± 0.00 6402 ± 15
a
b
c
d
e
f
−4
[
k
7]
obs values for 7.
The reactions were carried out for n numbers of half-lives.
Calculated from Eq. (6) with the values of k and ꢀ listed in Table VII.
obs values for 8.
Error limits are standard deviations.
0
= [8]
0
= 2 × 10 M; [HCl] = 0.049 M, λ = 280 nm for 7 and λ = 285 nm for 8.
0
k
N-cyclization from ∼0 to 5% in the acidic aqueous
cleavage of 8. Unlike these observations, the forma-
tion of N-methylphthalimide in the cleavage of N-
methylphthalamic acid under almost similar experi-
mental conditions varies from ∼20 to ∼4% with the
increase in the content of CH3CN from 2 to 80% (v/v)
20% 1,4-dioxane, while N-phenylphthalamic acid did
not produce N-phenylphthalimide under the same
reaction conditions, but this imide was formed in
20% yield when the solvent contained 80% 1,4-
dioxane [12]. Nearly 80–100% formation of N-(2-
aminophenyl)phthalimide has been observed in the
cleavage of N-(2-aminophenyl)phthalamic acid at pH
[14]. However, it has been reported in the literature
◦
that N-(4-nitrophenyl)phthalamic acid produced N-(4-
range 0–6 and 60 C in aqueous solvent [13]. The es-
timated values of pseudo first-order rate constants for
◦
nitrophenyl)phthalimide when heated at 65.8 C and at
pH 4.42 in mixed H2O–1,4-dioxane solvent containing
pH-independent N-cyclization (kN) and O-cyclization
◦
a
Table II Values of kobs, δapp, and A∞ for Hydrolysis of Phthalic Anhydride in Mixed H O–CH CN at 35 C
2
3
4
b
b
104kc
(s
104k
(s
d
d
104kc
(s
CH3CN
%, v/v)
10 k
δ
δ
obs
app
s
calcd
−1
obs
app
−1 −1
calcd
−1
−
1
−1 −1
b
−1
d
(
(s
)
(M
)
A
)
)
(M
s
)
A
)
∞
∞
e
e
e
e
e
e
2
1
2
3
4
5
6
7
8
187 ± 1
705 ± 2
704 ± 3
674 ± 2
624 ± 3
530 ± 3
438 ± 5
0.242 ± 0.000 193 (192)
0.244 ± 0.000 119 (120)
176 ± 2
121 ± 2
907 ± 3
929 ± 4
928 ± 4
905 ± 4
877 ± 6
858 ± 6
846 ± 7
790 ± 3
0.197 ± 0.000 182 (180)
0.195 ± 0.001 112 (113)
0.192 ± 0.001 68.8 (71.0)
0.196 ± 0.001 42.3 (44.6)
0.185 ± 0.001 26.0 (28.0)
0.184 ± 0.001 16.0
2
2
2
2
2
2
2
2
132 ± 1
76.1 ± 0.7
41.4 ± 0.6
22.2 ± 0.4
12.5 ± 0.4
0.239 ± 0.000 73.0 (75.0) 74.8 ± 1.1
0.240 ± 0.001 44.9 (46.9) 40.2 ± 0.5
0.238 ± 0.001 27.6 (29.4) 20.4 ± 0.4
0.244 ± 0.001 17.0
0.245 ± 0.001 10.4
0.234 ± 0.001 6.42
0.244 ± 0.002 3.95
9.87 ± 0.16
5.14 ± 0.09
2.33 ± 0.02
5.40 ± 0.21 381 ± 5
2.57 ± 0.11 351 ± 5
0.711 ± 0.082 291 ± 12
0.179 ± 0.001 9.84
0.183 ± 0.001 6.06
0.813 ± 0.010 688 ± 4
0.208 ± 0.001 3.73
a
b
c
d
e
= 2 × 10−4 M and [HCl] = 0.049 M.
[
Phthalic anhydride]
0
λ = 280 nm.
Calculated from Eq. (6) with values of k
λ = 285 nm.
0
and ꢀ listed in Table VII.
Error limits are standard deviations.
International Journal of Chemical Kinetics DOI 10.1002/kin

750
SIM, ARIFFIN, AND KHAN
◦
a
Table III Values of δC, δD, δE, and δ∞ for Cleavage of 7 and 8 in Mixed H O–CH CN at 35 C
2
3
δC (M 1cm ) δD (M cm ) δE (M cm ) δ∞ (M cm
−
−1
−1
−1
−1
−1
−1
−1
)
h
i
CH3CN
%, v/v)
Y f
Y g
10 k1 10 k3 10 k1 10 k3
5
6
5
6
(
b
c
b
c
b
c
d
e
2
1000
105
1315
1210) (985)
1315
1315
1080 4460
2870
2510
1050
1070
1060
1240
1085
1190
1145
1175
1220
0.91 1.08 60.9 60.2 120
[0.87] [1.02] [58.2] [87.0] [120] [0]
0.91 47.0 46.4
0
j
j
k
k
k
k
k
k
(
1
1
0
2
1065
1065
4640
1080 4640
2580
2635
2700
2985
3115
3000
2895
3045
100
95
3015
3080
3105
3125
3170
3175
3190
3130
1.06
[0.87] [1.00] [44.9] [67.1] [84.5] [0]
0.90 30.1 33.4
84.5
0
(1220) (975)
2
2
0
2
1130
1130
1275 4800
1275
1030 4800
1.03
[0.87] [1.00] [29.1] [43.4] [54.3] [0]
0.91 18.4 18.2
54.3
0
(
(
(
(
(
(
(
1195) (960)
1275 4950
1275
1200) (980)
1270 5015
1270
1190) (925)
1245 5090
1245
1220) (920)
1200 5095
1200
1225) (895)
1215 5130
1215
1170) (915)
1210
1210
3
3
0
2
1200
1200
105
115
110
115
120
135
1020 4950
0.94
[0.88] [0.92] [17.8] [24.2] [26.2] [22.8]
0.82 11.1 24.3
26.8 17.1
4
4
0
2
1270
1270
1010 5015
1.02
[0.79] [0.98] [10.7] [28.4] [21.0] [4.30]
0.78 7.42 20.9
21.4
0
5
5
0
2
1320
1320
975 5090
0.95
[0.77] [0.93] [7.32] [21.9] [13.4] [10.1]
0.82 5.22 11.5
13.7 7.20
6
6
0
2
1335
1335
935 5095
0.96
[0.83] [0.94] [5.29] [10.8] [9.59] [6.12]
0.89 2.81 3.48
9.79 4.08
7
7
0
2
1400
1400
930 5130
0.94
7.14 4.56
[0.87] [0.94] [2.75] [4.11] [7.14] [4.56]
8
8
0
2
1430
1430
5130
970 5130
0.84
2.58 4.91
0.94
–
6.20 4.00
–
1220) (1040)
[0.84]
[2.58] [4.91]
–
a
b
c
d
e
f
D = phthalic acid.
λ = 280 nm, E = 5, and C = 2-hydroxyaniline.
λ = 285 nm, E = 6, and C = 2-methoxyaniline.
δ
∞
= A
= A
∞
/[7]
/[8]
0
with A values listed in Table IV.
∞
with A values listed in Table IV.
∞
δ
∞
∞
0
Y values calculated from Eq. (4) for 7.
g
h
i
Y values calculated from Eq. (4) for 8.
k
1
= Ykobs and k
= Ykobs and k
3
= kobs − k
1
for 7.
for 8.
k
1
3
= kobs − k
1
j
Values in parentheses were derived from the relationship δ
D
= A
∞
/[PAn]
0
∞
with A values listed in Table II.
k
D
These values are based upon parenthetical δ values.
(
kO) for a rather limited number of N-substituted ph-
of B and hence phthalic acid could be formed directly
from hydrolysis of 7 or 8. But this perception has been
ruled out on the basis as described elsewhere [14].
Reaction scheme shown by Eq. (3) can be reduced
to a two-step parallel reaction scheme that could pro-
duce either Eq. (1) or Eq. (2) provided k2 ꢁ k1 (or
arbitrarily k2/k1 > 10). The values of kobs in Table II
(kobs = k2) and in Table I (kobs = k1 + k3 or k1 if k3 ≈ 0)
show that k2/(k1 + k3) ≥ ∼10 at ≤70% (v/v) CH3CN
for the cleavage of 7 and at ≤42% (v/v) CH3CN for
the cleavage of 8. Thus, the observed data (Aobs versus
t) at 80% (v/v) CH3CN for the cleavage of 7 and at
>52% (v/v) CH3CN for the cleavage of 8 should fol-
low the reaction scheme shown by Eq. (3). It is evident
thalamic acids are summarized in Table IV.
Does the Cleavage of 7 and 8 in Acidic Mixed H2O–
CH3CN Solvents Involve the Formation of Phthalic
Anhydride (B)?. Indirect experimental detection of B
in the acidic aqueous cleavage of phthalamic acid was
achieved by an ingenious isotopic labeling technique
[
1] while direct experimental detection of B was ob-
tained by UV spectrophotometric technique by using
the typical reaction conditions where observed data
(
[
Aobs versus t) could not fit to either Eq. (1) or Eq. (2)
14–18]. A skeptic might argue that the fitting of the
observed data to Eq. (1) does not show the intermediacy
International Journal of Chemical Kinetics DOI 10.1002/kin

INTRAMOLECULAR CARBOXYLIC GROUP-ASSISTED CLEAVAGE
751
Table IV The Values of Pseudo First-Order Rate Constants for pH-Independent N-Cyclization (kN) and O-Cyclization
kO) for a Few N-Substituted Phthalamic Acids
(
6
−1
6
−1
2
-CO2HC6H4CONHR
Organic Co-solvent
10 kN (s
)
10 kO (s )
Reference
R = CH3
R = H
0
0
∼4.3
∼20.6
∼71.1
∼13.6
∼51
[11]
[11]
[2a]
[1]
[15]
[4]
[2h]
[3]
[18]
[18]
[4]
[12]
[2b]
[13]
[13]
[4]
∼0.22
R = CH3
R = H
2% (v/v) CH3CN
∼4.38
0
0
0
0
0
0
0
0
0
0
0
∼470
∼63.2
∼17000
∼230
2260
1470
∼545
∼273
∼727
∼1.5
–
R = adamantyl
R = pyrrodinyl
R = OCH3
4% (v/v) CH3CN
0
20% (v/v) CH3CN
20% (v/v) CH3CN
0% (v/v) CH3CN
4% (v/v) CH3CN
R = OH
1
R = C6H5
2
0% (v/v) 1,4-dioxane
0
0
0
0
ꢂ
R = 2 -NH2C6H4
∼16.8
∼27.8
ꢂ
ꢂ
R = 4 -NO2C6H4
4% (v/v) CH3CN
10% (v/v) 1,4-dioxane
0
2% (v/v) CH3CN
2% (v/v) CH3CN
0
0
∼29.6
R = 4 -MeOC6H4
604
[8]
[8]
0
61.0
0
1010
608
1200
ꢂ
ꢂ
R = 2 -HOC6H4(7)
This work
This work
R = 2 -MeOC6H4(8)
from Table III that k3 is negligible compared with k1
and hence k3 + k1 ≈ k1. The observed data under such
experimental conditions should follow Eq. (5), which
can be easily derived from Eq. (3).
calculated values of k1, k2, and A∞ are shown in
Table V. The fitting of observed data to Eq. (5) is
almost similar to the fitting of same observed data to
Eq. (1) as evident from the values of Aobs and Acalcd
summarized in Table V. Although the calculated values
of k1 and A∞ are almost similar (within the average
error of <6%) to the respective values of kobs and
A∞ calculated from Eq. (1), the calculated value of
δ2k1[X]0
Aobs = δ1[X]0 exp(−k1t) +
k2 − k1
×
[exp(−k1t) − exp(−k2t)] + A∞ (5)
−5 −1
s ) is significantly smaller than kobs
k2 (3.04 × 10
−
5
−1
(
= 7.62 × 10
s , Table II) for hydrolysis of phthalic
In Eq. (5), δ1 = δA − δC − δD, δ2 = δB − δD, and
A∞ = (δC + δD)[X]0. Equation (5) can be reduced to
Eq. (1) provided k2 ꢁ k1 or δB ≈ δD, i.e., δ2 ≈ 0. The
lowest values of k2/k1 are 2.3 for 7 and 1.2 for 8 at 82%
anhydride under similar experimental conditions. The
values of k and A were also calculated from Eq.
1
∞
1
−
5
−1
(5) by considering δ , δ , and k (= 7.62 × 10
2
2
s )
as known parameters and these calculated values of
k1 and A are also shown in Table V. Again the
(v/v) CH3CN and the values of δB/δD are 1.25 for 7
∞
and 1.80 for 8 at 82% (v/v) CH3CN. Thus, although the
values of A
at different t (Table V) remain almost
calcd
−
1
−1
)
value of k2/k1 is 2.3, the value of δ2 (= 300 M cm
unchanged compared to the corresponding Acalcd val-
−1
−1
is significantly smaller than δ1 (= 3620 M cm ) for
ues obtained from Eq. (5) by treating k as unknown
2
7
and consequently Eq. (5) should reduce to Eq. (1)
parameter.
under such conditions.
Although the observed data (Aobs versus t) were
found to fit to Eq. (1) perfectly despite the fact that
∞
The value of A (0.222) remains unchanged while
−
5
−1
s ) is decreased by only
the value of k (= 7.24 × 10
1
−
5
−1
∼3% compared to k (= 7.47 × 10
1
s ) obtained
−1
−1
−1
k2/k1 = 1.2, δ2 = 760 M cm , and δ1 = 6515 M
from Eq. (5) by treating k as unknown parameter.
2
−1
cm for the cleavage of 8 at 82% (v/v) CH3CN, an
These calculated data show that the contribution of
attempt has been made to fit the observed data at 82%
[k δ [X] /(k − k )][exp(−k t) − exp(−k t)] is in-
1
2
0
2
1
1
2
(v/v) CH3CN to Eq. (5). The nonlinear least-squares
significant compared to δ [X] exp(−k t) + A in
1
0
1
∞
technique was used to calculate k1, k2, and A∞ from
Eq. (5) considering δ1 and δ2 as known parameters.
The values of δ1 and δ2 were obtained from the ob-
served data summarized in Table III. The least-squares
Eq. (5), which is conceivable for the reason that
(δ + A /[X] )/[δ k /(k − k )] ≈ 2 and k /k ≈ 1.1
1
∞
0
2
1
2
1
2
1
and hence |exp(−k t) − exp(−k t)| should be a small
1
2
number.
International Journal of Chemical Kinetics DOI 10.1002/kin

752
SIM, ARIFFIN, AND KHAN
Table V Values of A
Versus t for the Cleavage of 8 at
Thus, in order to ease the complexity of the kinetics of
obs
a
8
2% (v/v) CH CN
the cleavage of 7 and 8 in mild acidic H O CH CN
3
2
3
solvents, it is desirable to study the rate of hydrolysis
of PAn under the reaction conditions in which the rate
of cleavage of 7 and 8 has been studied. A few kinetic
runs were carried out within the CH3CN content range
of 2–82% (v/v) at 4.9 × 10 M HCl, 35 C, and 280 nm
as well as 285 nm. The values of kobs, calculated from
Eq. (1) under these mixed H2O CH3CN solvents, are
summarized in Table II.
b
c
d
t (s)
Aobs
A
A
A
calcd
calcd
calcd
1
5
1
1
3
5
8
1
1
2
3
5
7
1
1
8
7
0
00
99
49
98
47
204
801
498
503
503
503
0,500
4,998
0,100
1.526
1.522
1.516
1.505
1.490
1.473
1.453
1.425
1.381
1.331
1.263
1.139
1.027
0.886
0.716
0.251
1.522
1.520
1.516
1.507
1.495
1.475
1.455
1.426
1.381
1.330
1.261
1.135
1.025
0.886
0.721
0.250
1.524
1.521
1.517
1.508
1.496
1.475
1.455
1.426
1.380
1.328
1.258
1.133
1.024
0.886
0.726
0.247
1.524
1.521
1.517
1.509
1.497
1.477
1.457
1.429
1.384
1.333
1.263
1.137
1.027
0.885
0.716
0.229
−2
◦
Effects of Mixed Acidic H O–CH CN
2
3
Solvents on the Rate of Cleavage of 7 and 8
Effects of mixed H2O CH3CN solvents on the rate of
−2
cleavage of 7 and 8 at 4.9 × 10 M HCl were studied
by carrying out a few kinetic runs at varying CH3CN
content ranging from 2 to 80% and from 2 to 82% (v/v),
respectively, in mixed aqueous solvents. The observed
data (Aobs versus t) fit to Eq. (1) and the least-squares
calculated values of kobs, δobs, and A∞ are summa-
rized in Table I. Nearly ≤2-fold larger values of kobs
for 8 than for 7 rule out the presence of IGA catal-
ysis as shown by 4 in the cleavage of 7 within the
a
= 2.0 × 10−4 M, [HCl] = 4.9 × 10−2 M, 35 C, and λ =
◦
[
8]
0
2
δ
7
85 nm.
b
Calculated from Eq. (1) with 10 kobs = 6.58 ± 0.03 s−1
5
,
−1
−1
app = 6402 ± 15 M cm , and A
∞
= 0.244 ± 0.003.
c
−1
−1
Calculated from Eq. (5) with δ
1
= 6515 M cm , δ
2
=
−
1
−1
5
−1
5
−1
60 M cm , 10 k
= 0.222 ± 0.002.
Calculated from Eq. (5) with δ
1
= 7.47 ± 0.06 s , 10 k
2
= 3.04 ± 0.33 s , and
A
∞
CH CN content range 2–80% (v/v) in mixed aqueous
3
d
−1
−1
1
= 6515 M cm , δ
2
=
solvent.
−
1
−1
5
−1
5
−1
760 M cm , 10 k
2
= 7.62 s , 10 k
1
= 7.24 ± 0.08 s , and
A
∞
= 0.222 ± 0.002.
DISCUSSION
RESULTS
Effects of Mixed H O–CH CN on k
obs
Mechanism for Alkaline Hydrolysis
of Phthalimide and N-Substituted
Phthalimides
2
3
for Alkaline Hydrolysis of 5 and 6
In order to know the time period in which the conver-
The most probable and conceivable mechanism for
sion of 5 and 6 to the respective hydrolysis products,
alkaline hydrolysis of N-substituted phthalimides is
7
and 8, was completed to almost 100% under mixed
shown in Scheme 1 where k -step is presumably rate-
determining step because of (i) the release of five-
1
H2O CH3CN solvents, a few kinetic runs were car-
ried out for the cleavage of 5 and 6 within CH3CN
content range from 2 to 90 and 2 to 96% (v/v), respec-
membered ring-strain energy in k -step, (ii) pK of
2
a
conjugate acids of leaving groups in k -step are lower
2
−
3
tively, inmixedaqueoussolventscontaining1.0 × 10
than that of H O (conjugate acid of leaving group in
2
−
3
◦
M or 2.0 × 10 M NaOH at 35 C. Pseudo first-
order rate constants at different content of CH3CN are
summarized in Table VI.
−
k 1-step) by more than 2pK units, and (iii) nitrogen
leaving group is better leaving group than the aryl ox-
ide leaving group of comparable proton basicity [19].
Effects of Mixed H O–CH CN on k
obs
Mechanism for Acidic Hydrolysis of
Phthalamic Acid and N-Substituted
Phthalamic Acids
2
3
for Hydrolysis of Phthalic Anhydride
at 4.9 × 10− M HCl
2
It has been established that mild acidic hydrolysis of
phthalamic acid, N-substituted phthalamic acids, and
structurallyrelatedcompoundsinvolves O-cyclization,
leading to the formation of PAn in case of phthalamic
acid and N-substituted phthalamic acids [1,3,8,14–18].
Unlike the mechanism of the N-cyclization in the
cleavage of phthalamic acid, N-substituted phthala-
mic acids, and related compounds, the mechanism
of O-cyclization in the cleavage of these compounds
has been well understood [1–4]. Recently, conceivable
International Journal of Chemical Kinetics DOI 10.1002/kin

INTRAMOLECULAR CARBOXYLIC GROUP-ASSISTED CLEAVAGE
753
◦
a
Table VI Values of kobs, δapp, and A∞ or A for Hydrolysis of 5 and 6 in Mixed H O–CH CN at 35 C
0
2
3
3
b
103kc
(s
103k
d
103kc
(s
CH3CN
%, v/v)
10 k
δapp
δapp
−1 −1
obs
calcd
−1
obs
calcd
−1
−
1
−1 −1
−1
(s
(
(s
)
(M
s
)
A∞
)
)
(M
s
)
A0
)
e
e
e
1
2
1
2
3
4
5
6
7
8
8
9
9
114 ± 2.53
2866 ± 111
1.358 ± 0.001 117 (118)
e
e
e
64.7 ± 0.35 2880 ± 15
0.538 ± 0.003
0.527 ± 0.003
0.498 ± 0.002
0.478 ± 0.002
0.462 ± 0.002
0.456 ± 0.003
0.460 ± 0.004
0.468 ± 0.013
64.6
43.1
26.0
15.7
9.44
5.69
0
0
0
0
0
0
0
0
5
0
6
108 ± 1.82
104 ± 1.84
87.8 ± 1.11
76.2 ± 1.49
65.6 ± 1.24
61.6 ± 0.80
59.0 ± 0.73
56.5 ± 0.74
59.7 ± 0.9
62.3 ± 1.1
2917 ± 58
2995 ± 59
2854 ± 39
3325 ± 73
3173 ± 44
3326 ± 43
3362 ± 40
3337 ± 43
3084 ± 38
3857 ± 46
1.382 ± 0.001 107 (109) 42.6 ± 0.27 3419 ± 15
1.384 ± 0.001 96.9 (98.3) 27.0 ± 0.10 4070 ± 8
1.366 ± 0.001 87.4 (87.3) 15.0 ± 0.08 4713 ± 9
1.374 ± 0.002 78.8 (76.2) 9.01 ± 0.05 5165 ± 10
1.361 ± 0.003 71.1 (64.8) 6.22 ± 0.06 5503 ± 19
1.363 ± 0.001
1.314 ± 0.001
1.334 ± 0.002
1.367 ± 0.002
1.311 ± 0.003
64.1
57.8
52.2
4.87 ± 0.07 5705 ± 26
3.86 ± 0.14 5779 ± 77
4.72 ± 0.37 5980 ± 172 0.494 ± 0.031
8.80 ± 0.05 6409 ± 41 0.434 ± 0.009
9.53 ± 0.66 6917 ± 49 0.564 ± 0.010
11.0 ± 0.3
7171 ± 27
0.598 ± 0.006
a
b
c
= 3 × 10 M, [NaOH] = 1.0 × 10−3 M, λ = 300 nm; [6]
−4
= 2 × 10−4 M, [NaOH] = 2.0 × 10−3 M, λ = 290 nm.
[
k
5]
0
0
obs values for 5.
0
Calculated from Eq. (6) with kinetic parameters, k and ꢀ, listed in Table VII and values in parentheses were calculated from Eq. (7) with
3
−n −1
10 k
w
= 3.37 M
s
, n = 0.89.
d
k
obs values for 6.
e
Error limits are standard deviations.
but purely speculative explanation for predominant O-
cyclization in the mild acidic aqueous cleavage of these
compounds has been published [14]. The mechanism
of O-cyclization clearly demonstrates that 9 is com-
pletelynonreactivewhile O-cyclizationoccursthrough
kO represent first-order rate constants for N-cyclization
and O-cyclization, respectively.
1
0 only in these reactions. Thus, any factor such as re-
action medium or substituents in the reactants, which
causes carboxylic hydrogen less acidic and conse-
quently less readily available for the progress of the
O-cyclization reaction, is expected to retard the rate of
this reaction. But if such a factor has either no effect or
rate-increasing effect or relatively less rate-decreasing
effect on the rate of N-cyclization reaction, then such a
factor would increase the value of kN/kO where kN and
Nearly 0, 10, and 92% (Table IV) N-cyclization in
the pH-independent cleavage of respective 8, 7, and
N-(2-aminophenyl)phthalamic acid (NAPH) may be
Scheme 1
International Journal of Chemical Kinetics DOI 10.1002/kin

754
SIM, ARIFFIN, AND KHAN
explained in view of the extent of internal hydrogen
14 is also expected to decrease kO compared to kO for
bonding as shown by 11–13. Since oxygen is more
PHbecausesuchinternalhydrogenbondingdiminishes
electronegative than nitrogen and ether oxygen is ex-
pected to be less hydrogen bond acceptor than phe-
nolic or alcoholic oxygen because ether oxygen lacks
the ability of hydrogen bond donor, the absolute mag-
nitude of negative charge density (|δ−|) on internally
hydrogen-bonded carboxylic oxygen should vary in the
order: (|δ−|) for 13 > (|δ−|) for 12 > (|δ−|) for 11.
Under such circumstances, the value of kO should be
expected to vary in the order: kO for 11 > kO for 12 > kO
for 13, which is in agreement with observed values of
kO as shown in Table IV. The nearly 400- and 800-fold
lower value of kO for NAPH than kO for, respectively, 7
and 8 shows that the internal hydrogen bonding effects
of 11–13 as well as polar and partial resonance effects
of substituents at 2-position in the aryl leaving group
the nucleophilicity of the internal nucleophilic COOH
of 7. The value of k is also affected by polar and par-
O
tial resonance effects of ortho-substituent in aryl leav-
5
−1
ing group. The values of k for PH (10 k = 72.7 s
O
O
)
5
−1
[2b] and 7 (10 k = 60.8 s , Table VI) are in agree-
O
ment with this prediction. Significantly higher value
(1.20–1.27 pK units) of pK of COOH group of NAPH
a
compared to that of PH shows the absence of inter-
nal hydrogen bonding similar to one in 14, which may
be attributed to larger electronegativity and hydrogen
bond donor ability of atom O than that of N.
A conceivable mechanism for O-cyclization of 7
and 8 in aqueous solvent is shown in Scheme 2. It is
well known that such reactions are catalyzed by both
specific and general acids. But at <0.05 M HCl and in
the absence of general acid, these catalyzed reaction
paths are ignored in Scheme 2. It is not easy to predict
the relative polarity of 7 or 8 and Int , but if Int is
∗
are important because the reported values of ρ and ρ
∗
for the respective plots of log kO versus σ and log kO
versusσ arenegative[2c,2d,12,15]. Theinternalhydro-
gen bonding in 11–13 is expected to decrease the Ka
1
1
more polar than 7 or 8, then the value of K is expected
f
(ionization constant) of COOH group and, thus, the ex-
to decrease with the decrease in the polarity of the
tent of internal hydrogen bonding in 11–13 may be seen
in the experimentally determined relative values of pKa
of COOH group in NAPH, 7, 8, and phthalanilic acid
mixed solvent, i.e., the decrease in the water content
of mixed H O–CH CN solvent. Similarly, the value
2
3
of K should decrease with the decrease in the content
T
(
PH). The structures 11–13 predict that ꢁpKa (= pKa
of H O because Int is apparently more polar than Int
1
2
2
for COOH in NAPH or 7 or 8 −pKa for COOH in PH)
(Scheme 2). The value of KT should also decrease
with the increase in the difference of pK (ꢁpK ) of
should vary in the order: ꢁpKa for NAPH > ꢁpKa for
a
a
−
7
> ꢁpKa for 8.
The reported values of the carboxylic pKa for NAPH
conjugate acid of basic site (C O ) and the acidic site
(C NH Ar ) of Int . The value of ꢁpK increases
+
2
2
a
(
6
4.43 by titrimetric methods, 4.49 by kinetic methods at
1.5 C) [13] and for PH (3.62 at 25.8 C) [2b] indicate
and consequently K decreases with the decrease in
T
◦
◦
pK of leaving group in k-step. But the decrease in the
a
that ꢁpKa = 1.20–1.27. The values of pKa of 7 and 8,
pK of leaving group in k-step increases the value of
a
◦
determined spectrophotometrically at 35 C, are 3.33
k. Thus, the value of kobs (= kK K ) is affected by the
T
f
and 3.57, respectively. Nearly 0.06 pK units higher
value of pKa of 8 than that of PH shows significant in-
ternal hydrogen bonding as shown in 11. The value of
pKa of 7 is lower than that of PH by ∼0.18 pK units,
which shows an extensive internal hydrogen bonding
as shown in 14. But the internal hydrogen bonding in
combined effect of mixed solvent on k, K , and K .
T
f
Effects of Mixed H O–CH CN on k for
2
3
obs
Alkaline Hydrolysis of 5 and 6
The values of kobs for alkaline hydrolysis of 5 show
a nonlinear decrease of ∼2-fold with increase in the
content of CH3CN from 2 to 80% (v/v) and further in-
crease in the content of CH3CN from 80 to 90% (v/v)
−
3
−3 −1
increased kobs from 56.5 × 10 to 62.3 × 10
s .
But the values of kobs for 6 decrease by 16-fold with
increase in the content of CH3CN from 2 to 70% (v/v)
International Journal of Chemical Kinetics DOI 10.1002/kin

INTRAMOLECULAR CARBOXYLIC GROUP-ASSISTED CLEAVAGE
755
Scheme 2
−
3
−1
s
followed by a significant increase from 3.86 × 10
N-(4-methoxyphenyl)phthalimide (Table VII). The
nearly 31% smaller value of kOH for 6 than
that for N-(4-methoxyphenyl)phthalimide and N-
phenylphthalimide cannot be explained in terms of
Hammett substituent constants, which are the func-
tion of polar and resonance interaction of substituent
with reaction site. A search of the literature reveals
that ionization constant (Ka) of 2-methoxybenzoic acid
is ∼2.5-fold larger than that of 4-methoxybenzoic
acid [21], and 2-methoxybenzoic acid is even stronger
acid than benzoic acid by 0.09 pK units [21,22].
These and related observations may be explained
by the proposal that steric hindrance between re-
action site and 2-OMe substituent causes a partial
change in co-planarity between benzene ring and re-
action site as well as substituent (2-OMe) and conse-
quently benzene ring or 2-OMe substituent acts like
an electron withdrawer due to predominant polar ef-
fect and electron donor due to partial resonance ef-
fect [23]. Thus, nearly 31% smaller value of kOH for
−
3
−1
to 11.0 × 10
s with the increase in CH3CN con-
tent from 70 to 96% (v/v) (Table VI). Although such
observations are not unusual in view of the reported
observations on the related reacting systems, they lack
quantitative explanation because of the lack of a perfect
and generaltheoreticalmodel. Itis customary to the sci-
entific advancement that when the observed data could
not be explained in terms of a theoretical model, an em-
pirical treatment of such data is generally considered
of some use, at least, in predicting the values of depen-
dent variable (such as kobs) at any value of independent
variable (such as % (v/v) content of organic co-solvent)
and sometimes an empirical treatment of observed data
forms the basis for the improvement in the existing
theoretical model. The values of kobs obtained within
CH3CN content range 2–80 and 2–50% (v/v) for alka-
line hydrolysis of 5 and 6, respectively, showed good
fit to the empirical Eq. (6), where X represents % (v/v)
content of CH3CN, k0 and ꢀ are empirical constants.
6
than kOH for N-(4-methoxyphenyl)phthalimide and
kobs = k0 exp(−ꢀX)
(6)
N-phenylphthalimide is due to predominant steric ef-
fect because steric and resonance effects of 2-OMe are
expected to decrease kOH while polar effect of 2-OMe
should increase kOH.
Nearly 2- and 16-fold decreases in kobs with increase
in the content of CH3CN from 2 to 70% (v/v) for re-
The magnitude of ꢀ is the measure of the rate-
inhibition susceptibility of the mixed aqueous–organic
solvents. The values of k0 and ꢀ, calculated from
Eq. (6) using the nonlinear least-squares technique,
are summarized in Table VII. The value of second-
order rate constant (kOH) for hydroxide ion-catalyzed
◦
spective alkaline hydrolysis of 5 and 6 at 35 C indicate
the occurrence of possible different mechanism in the
hydrolytic cleavage of 5 and 6. The rate of hydrolysis
of 5 and 6, carried out at different [NaOH] in aqueous
solvent containing 2% (v/v) CH3CN reveals that the
−
1
−1
hydrolysis of 6, 36.0 M
s
(=k0/[NaOH], where
the k0 value is calculated from Eq. (6)), is nearly 31%
−1
−1
) for alkaline hy-
smaller than kOH (= 52.0 M
s
drolysis of N-(4-methoxyphenyl)phthalimide [8] and
−
values of kobs for 5 are almost independent of [HO ]
−1
−1
s ) for alkaline hydrolysis of N-
kOH (= 51.0 M
−3
−3
within its range 1.0 × 10 –5.0 × 10 M while kobs
phenylphthalimide [20].
Similarly, the value of ꢀ for alkaline hydrol-
ysis of 6 is nearly 10% larger than that for
−
values for 6 increase linearly with [HO ] within its
−3
−3
range 1.0 × 10 –5.0 × 10 M [24]. These observa-
−3
tions show that the hydrolysis of 6 at 2.0 × 10
M
International Journal of Chemical Kinetics DOI 10.1002/kin

756
SIM, ARIFFIN, AND KHAN
Table VII Values of k and ꢀ, Calculated from Eq. (6), for Hydrolysis of Imides and Esters and Cyclization of
0
Phthalamic and N-Substituted Phthalamic Acids
3
−1
2
Solvent
Reaction
10 k0 (s
)
10 ꢀ
X Range (%, v/v)
k
H2O–CH3CN
H2O–CH3CN
H2O–CH3CN
H2O–CH3CN
H2O–CH3CN
5 −→ 7
119 ± 3
1.03 ± 0.07
5.06 ± 0.10
4.12 ± 0.13
4.26 ± 0.18
2–80
2–50
2–80
2–72
−
HO
k
6 −→ 8
71.5 ± 0.8
0.743 ± 0.014
1.33 ± 0.04
−
HO
k
7 −→ PAn + Am
+
H
k
8 −→ PAn + Am
+
k
H
PAn −→ Phthalic acid
λ = 280 nm
PAn −→ Phthalic acid
21.3 ± 0.8
21.0 ± 1.1
20.0 ± 0.7
19.8 ± 0.9
99.9 ± 4.4
4.86 ± 0.30
4.69 ± 0.42
4.86 ± 0.28
4.66 ± 0.36
4.51 ± 0.35
2–82
2–42
2–82
2–42
2–50
+
H
k
H2O–CH3CN
+
H
λ = 285 nm
k
H2O–CH3CN [8]
PT1 −→ NPA1
−
HO
k
H2O–1,4-dioxane [8]
H2O–1,4-dioxane [8]
H2O–CH3CN [10]
H2O–CH3CN [3]
PT1 −→ NPA1
108 ± 3
3.20 ± 0.27
5.13 ± 0.07
4.25 ± 1.9
2.91 ± 0.15
2–80
10–80
2–60
−
k
HO
NPA −→ PAn
1.01 ± 0.01
51.0 ± 1.9
106 ± 4
+
H
k
PT2 −→ NPA2
−
HO
k
PT3 −→ NPA3
10–80
−
HO
PT
acid.
1
= N-(4-methoxyphenyl)phthalimide; PT
2
= N-phenylphthalimide; PT
3
= N-methoxyphthalimide; NPA = N-substituted phthalamic
−
−
−
NaOH involves 6 and HO as the reactants. But the
is higher in HO than in TS. Nucleophilicity of the re-
actant (hydroxide ion) is expected to decrease with the
3
hydrolysis of 5 at 1.0 × 10 M NaOH may involve
−
+
−
either ionized 5 (S ) and H2O or nonionized 5 (SH)
increaseinthestabilityofsolvatedionpair(Na :HO ).
The increase in the content of CH3CN decreases the
dielectric constant of the mixed H2O–CH3CN reac-
tion medium which in turn increases the stability of
Na :HO andconsequentlydecreaseskobs value. How-
ever, at considerably high content of CH3CN, be-
cause of the insufficient of water molecules, acetoni-
trile molecules also enter into the solvation shell of the
−
and HO as the reactants. Nearly 2- and 16-fold de-
creases in kobs with increase in CH3CN content from
to 70% (v/v) in the respective hydrolysis of 5 and 6
2
−
3
+
−
show that the rate of hydrolysis of 5 at 1.0 × 10
M
−
NaOH is unlikely to involve SH and HO as the re-
actants in view of the following observations. The in-
crease in the content of CH3CN from 2 to 80% caused
a decrease in kobs for pH-independent hydrolysis of
phenyl salicylate [25] and phthalimide [26] by nearly
+
−
solvated ion pair (Na :HO ). Since CH3CN can pref-
erentially solvate only cations (Na ), the participation
+
2
- and 21-fold, respectively. The reactants in the pH-
of CH3CN molecules into the solvation shell of ion
pair is expected to decrease its stability because of the
asymmetric structural network of solvation shells of
independent hydrolysis of phenyl salicylate and phthal-
imide have been concluded to involve H2O and ionized
phenyl salicylate and HO and nonionized phthalim-
ide, respectively [27,28]. The charge density is appar-
entlysignificantlyhigherinHO thaninionizedphenyl
−
+
−
Na and HO ions. Thus, under such conditions, the
increase in the content of CH3CN should increase kobs
values.
−
−
3
salicylate or ionized 5.
The rate of hydrolysis of 5 at 1.0 × 10 M NaOH
involves H2O (= Nu in Scheme 1) as the reactant and
hencethedecreasein[H2O](i.e., increaseinthecontent
of CH3CN in mixed H2O–CH3CN solvent) is expected
to decrease kobs values. The values of kobs within the
CH3CN content range 2–50% (v/v) were found to fit
reasonably well to Eq. (7)
The nonlinear decrease in kobs for alkaline hydrol-
ysis of 6 with the increase in the content of CH3CN
may be explained qualitatively as follows. As con-
cluded earlier, k1-step is the rate-determining step for
the reactions following reaction mechanism shown in
Scheme 1. It is apparent that the reactant state is more
polar than transition state (TS) in k1-step for reac-
−
n
tion between 6 and HO because the charge density
kobs = kw[H2O]
(7)
International Journal of Chemical Kinetics DOI 10.1002/kin

INTRAMOLECULAR CARBOXYLIC GROUP-ASSISTED CLEAVAGE
757
where n represents the order of reaction with respect
to reactant H2O and kw is (n + 1)th order rate con-
stant of the reaction between H2O and ionized 5. The
least-squares calculated values of n and kw are 0.89 and
associated with the calculated values of k0 and ꢀ are
nearly the same and apparently satisfactory, the percent
negative residual errors [RE = 100(kobs − kcalcd)/kobs]
show a continuous increase with increase in CH3CN
content at 42% (v/v) and kcalcd value becomes ∼5-fold
larger than kobs value at 82% (v/v) CH3CN (Table II).
The values of kobs, obtained within CH3CN content
range of 2–42% (v/v), have been also used to calcu-
late k0 and ꢀ from Eq. (6) and these results are also
listed in Table VII. The values of k0 and ꢀ seem to be
almost insensitive to the choice of the observed data
range of 2–42 and 2–82% (v/v) CH3CN. The values
of kobs are comparable with the corresponding kobs val-
ues obtained by monitoring the absorbance range at
−
3
−n −1
s , respectively. The values of kcalcd,
3
.37 × 10
M
−3
−0.89
calculated from Eq. (7) with kw = 3.38 × 10
M
−
1
s
and n = 0.89, in Table VI, show the extent of relia-
bility of the data fit to Eq. (7). An attempt to fit the kobs
3
values to Eq. (7) with n = 1 resulted in 10 kw = 2.24 ±
−1
−1
s but the data fit did not appear as good as
0
.09 M
with n = 0.89.
The values of kobs at 60, 70, 80, and 90% (v/v)
CH3CN are larger by, respectively, 13.5, 30.1, 49.2,
and 75.1% compared to the corresponding kcalcd val-
ues obtained from Eq. (7) with n = 0.89. The values
of molar ratio [H2O]/[CH3CN] at 60, 70, 80, and 90%
−
4
310 nm with [PAn]0 = 2.0 × 10 M [10] and 218 nm
−
5
with [PAn]0 = 2.0 × 10 M [8].
(v/v) CH3CN are 1.9, 1.2, 0.7, and 0.3, respectively.
The nearly 260-fold decrease in kobs with the in-
crease in the content of CH3CN from 2 to 80% (v/v) has
been explained by a reaction mechanism as shown by
Eq. (8)
These observations show that the factor that causes
the increase in kobs with the increase in the content of
CH3CN becomes increasingly significant above 60%
(
v/v) CH3CN. The increase in kobs with increase in the
K
k
content of CH3CN may be explained in terms of the
concept of polarization of water molecules by CH3CN
molecules as shown by 15 [29]. The nucleophilicity of
the polarized water molecule 15 is expected to be sig-
nificantly increased compared to that of nonpolarized
water molecule or 16. Thus, as the content of CH3CN
in mixed aqueous solvent increases, the concentration
of 15 also increases, which in turn increases kobs. Thus,
the values of kobs are affected by, at least, two oppos-
ing effects, i.e., the effect of change of [H2O] and the
effect of polarization of water molecule by acetonitrile
molecule. It is interesting to note that the value of kw
PAn + nH2O ꢁꢀ C −→ Phthalic acid (8)
n1H2O
where K is the association constant and k is the rate
constant for the hydrolysis of complex (C) to phthalic
acid [10]. Although the decrease in kobs with increase
in acetonitrile content from 2 to 80% (v/v) at 310 nm
[
10] is almost similar to the corresponding decrease in
kobs at 218 [8], 280, and 285 nm (Table II), the decrease
in apparent molar absorptivity of the reaction mixture,
δapp (∼4.0-fold) at 310 nm is significantly larger than
those at 218 nm (∼1.1-fold) [8], 280 nm (∼2.4-fold),
and 285 nm (∼1.3-fold) (Table II). Rather low decrease
in δapp with increase in the content of CH3CN from 2 to
−3
−n −1
(
= 3.38 × 10
M s
with n = 0.89) is not signifi-
cantly different from second-order rate constant kMeOH
−3
−1 −1
◦
8
2% (v/v) at 280 and 285 nm does not allow one to cal-
(
= 2.15 × 10
M
s
at 30 C) [25] for the reaction
−
culate the values of n and K by using δapp as reported
elsewhere [10]. In order to explain the decrease in kobs
with increase in the content of CH3CN in terms of reac-
tion mechanism shown by Eq. (8), which contains four
unknown parameters (n, n1, k, K), it is preferable to
reduce the number of unknown parameters from 4 to 2
by calculating the values of n and K using δapp values
of MeOH with ionized phenyl salicylate (PS ), but the
−
value of kw is nearly 100-fold larger for 5 than for PS
[25].
[10].
Effect of Mixed H O–CH CN Solvents on
2
3
the Rate of Cleavage of 7 and 8
Effect of Mixed H O–CH CN Solvents on
kobs for Hydrolysis of Phthalic Anhydride
2
3
The increase in the content of CH3CN from 0 to 80 and
82% (v/v) in mixed aqueous solvent decreased pseudo
The values of kobs at different contents of CH3CN at
first-order rate constant (kobs) for hydrolytic cleavage of
7 and 8, respectively, by more than 20-fold (Table I).
The values of kobs for hydrolytic cleavage of N-(4-
methoxyphenyl)phthalamic acid decreased by nearly
2
80 and 285 nm were attempted to fit to Eq. (6) and the
nonlinear least-squares calculated values of k0 and ꢀ
arelistedinTableVII. Althoughthestandarddeviations
International Journal of Chemical Kinetics DOI 10.1002/kin

758
SIM, ARIFFIN, AND KHAN
1
3-fold under almost similar experimental conditions
4. Granados, A. M.; de Rossi, R. H. J Org Chem 2001, 66,
1548.
[8]. But the values of kobs for hydrolytic cleavages of
5
. Hol, P.; Streefland, L.; Blandamer, M. J.; Engberts,
J. B. F. N. J Chem Soc, Perkin Trans 2 1997, 485, and
references cited therein.
several N-alkylphthalamic acids remained either al-
most unchanged or varied mildly (≤4-fold) with the
increase in the content of CH3CN from 0 to 80% (v/v)
in mixed aqueous solvents [3,10,14,18].
6
7
8
. Prasad, C. S. N.; Varala, R. A.; Srinivas, R. Heterocycl
Commun 2002, 8(3), 281.
. Leng, S. Y.; Khan, M. N.; Ariffin, A. Mal J Sci 2004, 23,
1
75.
. Leng, S. Y.; Ariffin, A.; Khan, M. N. Int J Chem Kinet
004, 36, 316.
CONCLUSIONS
2
The cleavage of 7 and 8 in mixed CH3CN–H2O sol-
vents give major O-cyclization product (phthalic an-
hydride), ≥85% for 7 and ≥95% for 8, and minor
N-cyclization product (imide), ≤15% for 7 and ≤5%
for 8. The increase in CH3CN content from 2 to 80
and 82% (v/v) causes only minor variations in O-
cyclization product. The values of rate constants k1 (for
O-cyclization) decreases nonlinearly by ∼20-fold with
the increase in CH3CN content from 2 to 80% (v/v) for
both 7 and 8. Slightly lower values of k1 for 7 than k1 for
9. Khan, M. N. J Org Chem 1983, 48, 2046.
10. Khan, M. N. Indian J Chem Sect A 1993, 32, 387.
11. Brown, J.; Su, S. C. K.; Shafer, J. A. J Am Chem Soc
1
966, 88, 4468.
2. Hawkins, M. D. J Chem Soc, Perkin Trans 2 1976,
42.
3. Christopher, J. P. J Chem Soc, Perkin Trans 2 1997,
77.
4. Ariffin, A.; Khan, M. N. Bull Korean Chem Soc 2005,
6, 1037.
1
1
1
1
6
9
2
5. Blackburn, R. A. M.;Capon, B.;McRitchie, A. C. Bioorg
Chem 1977, 6, 71.
8
at varying contents of CH3CN in mixed aqueous sol-
vents rule out the presence of expected IGA catalysis
due to 2-OH group in 7.
16. Khan, M. N. Indian J Chem Sect A 1993, 32, 395.
17. Khan, M. N. J Org Chem 1996, 61, 8063.
18. Khan, M. N. J Phys Org Chem 1998, 11, 216.
1
9. Gresser, M. J.; Jencks, W. P. J Am Chem Soc 1977, 99,
6
963.
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1
International Journal of Chemical Kinetics DOI 10.1002/kin