Kinetics and mechanism of the general base-catalyzed hydrolysis of N-hydroxyphthalimide

Article abstract of DOI:10.1007/s00706-013-0990-y

The kinetics and mechanism of hydrolysis of N-hydroxyphthalimide in the presence of various buffers (dichloroacetic acid, chloroacetic acid, glycine, sodium formate, sodium acetate, N-(2-morpholinoethane)sulfonic acid, and tris(hydroxymethyl)aminomethane) were studied at 50 C and an ionic strength of 1.0 M. The second-order rate constants k _b for the buffer-catalyzed hydrolysis of N-hydroxyphthalimide were found to conform to the Bronsted equation logk _b = C + β pK _a. A plot of pK _a versus k _b for the data obtained in the buffers and H₂O (covering a pK _a range of -1.74 to 8.33) was constructed, and the data were fitted with a straight line that had a slope (β) of 0.29 ± 0.05 and an intercept (C) of -5.19 ± 0.20.

Full text of DOI:10.1007/s00706-013-0990-y

Monatsh Chem (2013) 144:1299–1305
DOI 10.1007/s00706-013-0990-y
ORIGINAL PAPER
Kinetics and mechanism of the general base-catalyzed hydrolysis
of N-hydroxyphthalimide
•
W. Hamdah W. Ahmad Yoke-Leng Sim
•
M. Niyaz Khan
Received: 24 January 2013 / Accepted: 31 March 2013 / Published online: 8 May 2013
Ó Springer-Verlag Wien 2013
Abstract The kinetics and mechanism of hydrolysis of
N-hydroxyphthalimide in the presence of various buffers
(dichloroacetic acid, chloroacetic acid, glycine, sodium
formate, sodium acetate, N-(2-morpholinoethane)sulfonic
acid, and tris(hydroxymethyl)aminomethane) were studied
at 50 °C and an ionic strength of 1.0 M. The second-order
rate constants kb for the buffer-catalyzed hydrolysis of
N-hydroxyphthalimide were found to conform to the
Brønsted equation logkb = C ? b pKa. A plot of pKa
versus kb for the data obtained in the buffers and H2O
(covering a pKa range of -1.74 to 8.33) was constructed,
and the data were fitted with a straight line that had a slope
(b) of 0.29 0.05 and an intercept (C) of -5.19 0.20.
N-substituted phthalimides have been published, reports on
the hydrolysis of imides in acidic media and at neutral pH
are very rare. The water-promoted hydrolysis, or neutral
hydrolysis, of unactivated imides and amides is very slow,
and in most cases undetectable [2]. The reported pseudo-
first-order rate constants (k0) for the uncatalyzed hydrolysis
of five-membered ring imides and acyclic amides are on
the order of 10-6 to 10-8 and 10-9 to 10-12 s-1, respec-
tively, at 35 °C (which correspond to half-lives (t1/2) of
8–800 days and 22–2.2 9 104 years, respectively) [3–5].
The mechanisms of these reactions, especially when
general acid and general base (GA-GB) catalysis are
involved, are also miraculous inimitable and are not yet
fully understood [6–8]. The occurrence of intramolecular
GB assistance was noted for the pH-independent hydrolysis
of N-(o-hydroxymethyl)phthalimide [4].
Keywords Kinetics ꢀ Buffer catalysis ꢀ
N-hydroxyphthalimide ꢀ Hydrolysis ꢀ Mechanism
Kinetic studies of such slow reactions (t1/2 of more than
a few days) have not been attractive to researchers because
they are associated with some unavoidable experimental
complications [9]. An enzyme’s efficiency can be esti-
mated quantitatively once the rate constant for the
analogous uncatalyzed reaction has been determined
[10–12]. Recently, it was suggested that the cleavage of a
certain atypical peptide bond might occur through the
formation of an acyclic imide bond [13]. Thus, studies
involving inter- and intramolecular GA-GB-assisted
hydrolysis of imides and amides are considered to be very
important, given the expectation that the results of such
studies could be applied to gain a deeper understanding of
enzyme-catalyzed reactions [14]. In work described in the
present paper, which is a continuation of our mechanistic
studies of inter- and intramolecular GA-GB catalysis in the
cleavage of imide and amide bonds, we investigated the
effect of [HCl], [NaOH], and [buffers] on the rate of
hydrolysis of N-hydroxyphthalimide (1). The results
Introduction
Amide (i.e., peptide) bonds are the ‘‘glue’’ that hold pro-
teins—and thus living systems—together. The hydrolysis
of imides or amides is therefore frequently used as a model
to investigate the cleavage of peptide bonds [1]. Although
numerous reports on the hydrolysis of phthalimide and
W. H. W. Ahmad ꢀ M. Niyaz Khan (&)
Department of Chemistry, Faculty of Science, University
of Malaya, 50603 Kuala Lumpur, Malaysia
e-mail: niyaz@um.edu.my
Y.-L. Sim
Department of Chemical Science, Faculty of Science,
Tunku Abdul Rahman University (UTAR), 31900 Kampar,
Perak, Malaysia
123

1300
W. H. W. Ahmad et al.
obtained and their probable mechanistic explanation(s) are
discussed in this manuscript.
Eq. (1) by setting k000 ¼ 0. The fit of the data to Eq. (1) is
evidently reliable, considering the standard deviations of
the calculated parameters and the values of kcalcd shown in
Table 1.
Results and discussion
Effect of the total concentration of buffer, [Buf]T,
Effects of [HCl] and [NaOH] on the pseudo-first-order
on kobs at 50 °C
rate constant (kobs) for the hydrolysis of 1
A series of kinetic runs were carried at different pH values
in solutions of various buffer-forming compounds/salts
[mono- and dichloroacetic acids (ClAcA and Cl2AcA),
glycine (Gly), sodium formate (ForNa), sodium acetate
(AcNa), N-(2-morpholinoethane)sulfonic acid (MES), and
tris(hydroxymethyl)aminomethane (TRIS)]. The values of
A few kinetic runs were carried out within the [HCl] range
0.01–1.0 M at a constant ionic strength of 1.0 M (main-
tained by NaCl) at 50 °C. The values of kobs were found to
fit well to Eq. (1), where k0 and kH represent the pH-
independent and H?-catalyzed rate constants for the
hydrolysis of 1. The values of kobs at different [HCl] are
shown in Table 1. These data were fitted to Eq. (1) with
least-squares-calculated values of k0 and kH of
k
obs obtained at a constant pH but different values of [Buf]T
(the total buffer concentration) were found to fit reasonably
well to Eq. (2):
37.4 0.9 9 10-6 s-1 and 98.6 1.0 9 10-6 M-1 s-1
,
kobs ¼ k0 þ kap ½BufꢁT;
ð2Þ
b
respectively.
where k0 is the [Buf]T-independent first-order rate constant,
kbap is the [Buf]T-dependent second-order rate constant for
the hydrolytic cleavage of 1, and [Buf]T = [B] ? [BH?],
where B and BH? represent free base and protonated base
(i.e., conjugate acid), respectively. The values of k0 and kbap
were calculated from Eq. (2) using the linear least-squares
technique. The calculated values of k0 and kbap at different
pH values for different buffers are summarized in Table 2.
The fit of the observed data (kobs) vs. [Buf]T to Eq. (2) is
clearly reliable given the standard deviations associated
with the calculated parameters, k0 and kbap, and given the
plots shown in Fig. 1 for typical MES buffers, where solid
lines can easily be drawn through the least-squares-calcu-
lated rate constants (kcalcd).
kobs ¼ k0 þ kH ½HCLꢁ:
ð1Þ
Similarly, a few kinetic runs were carried out within the
[NaOH] range 1.5 9 10-3 to 7.0 9 10-3 M at a constant
ionic strength of 1.0 M and 50 °C. The kobs values at
different [NaOH], as shown in Table 1, were found to fit to
Eq. (1) when k0, kH, and HCl were replaced with k000; kO00 H
,
and NaOH, respectively. The least-squares calculated
-1
values of k000 and k were -19.2 2.0 9 10-4
s
and
00
OH
3.30 0.06 M-1 s-1, respectively. The symbol k is the
00
OH
second-order rate constant for the reaction of HO- with
ionized 1 (i.e., S-). The rate constant k000 is for the reaction
between either H2O and S- or HO- and SH (i.e.,
nonionized 1). The calculated negative value of k000 is
physicochemically meaningless. Therefore, a more reliable
The values of kobs were found to be independent of
[Buf]T at constant pH for the Cl2AcA buffer. Similar
value of k of 2.84 0.50 M-1 s-1 was obtained from
00
OH
Table 1 Values of kobs for the hydrolysis of 1 at different [HCl], [NaOH], and at 50 °C
HCl/M
106kobs=sꢂ1
106kcaalcd=sꢂ1
NaOH/M
104kobs=sꢂ1
104kcaalcd=sꢂ1
0.03
0.05
0.10
0.20
0.30
0.50
0.80
1.00
39.0 1.0
40.0 0.7
47.2 1.0
58.4 1.0
68.2 3.0
86.8 3.0
40.0
42.0
46.9
56.8
66.7
86.4
116
1.5 9 10-3
2.0 9 10-3
2.5 9 10-3
3.0 9 10-3
4.0 9 10-3
5.0 9 10-3
6.0 9 10-3
7.0 9 10-3
29.0 1.0b
45.5 1.0
63.6 1.0
85.5 2.0
109 3.0
30.3
46.8
63.3
80
113
146
179
212
147
178
212
3
3
3
117
134
3
5
136
Conditions: [1]0 = 2.5 9 10-4 M, ionic strength 1.0 M, k = 300 nm, 50 °C. For each kinetic run, the solvent contained 1 % CH3CN and 99 %
H2O. Alkaline hydrolysis of 1 was monitored at 410 nm
a
Rate constants were calculated using Eq.(1) and the calculated parameters k0 and kH or k0 and kOH
b
Error limits are the standard deviations
123

Base-catalyzed hydrolysis of N-hydroxyphthalimide
Table 2 Values of pH, k0, kbap,
and kb for the cleavage of 1
1301
Buffer
pHa
106k0b=sꢂ1
106kbapc=Mꢂ1sꢂ1
106kbd=Mꢂ1sꢂ1
[Buf]T range/
M
at different pH values
Cl2AcA
1.14 0.01e
1.47 0.3
1.94 0.2
2.35 0.01
2.46 0.01
2.61 0.01
2.99 0.03
3.26 0.03
1.98 0.05
2.09 0.04
2.33 0.02
2.51 0.01
2.70 0.01
2.95 0.01
3.03 0.01
3.25 0.01
3.42 0.01
3.88 0.03
4.11 0.03
4.25 0.04
4.37 0.03
4.42 0.03
4.92 0.07
5.17 0.10
5.35 0.03
5.51 0.03
5.60 0.03
5.76 0.03
5.98 0.02
6.12 0.04
6.32 0.03
6.54 0.02
7.48 0.1
7.77 0.0
7.98 0.0
8.12 0.0
8.33 0.0
(35.8 1.0e)f
(31.7 1.2)
(28.0 2.8)
32.6 1.0
30.3 0.5
33.5 0.5
36.3 1.0
37.4 2.0
32.2 1.0
32.2 1.0
29.5 0.4
28.2 0.8
30.7 0.8
30.4 1.0
36.8 1.0
32.8 1.0
36.7 4.0
32.6 2.0
34.3 1.0
49.7 3.0
45.2 2.0
37.3 4.0
50.7 3.0
50.9 4.0
37.6 1.0
38.1 1.0
39.2 2.0
38.4 3.0
40.9 3.0
39.6 3.0
42.3 2.0
14.9 1.0
84.8 6.0
0.1–0.75
0.1–0.8
0.1–0.8
0.1–0.75
0.1–0.75
0.1–0.75
0.1–0.8
0.1–0.8
0.1–0.8
0.1–0.8
0.1–0.75
0.1–0.8
0.1–0.8
0.1–0.8
0.1–0.75
0.1–0.8
0.1–0.8
0.1–0.8
0.1–0.6
0.1–0.8
0.1–0.8
0.1–0.8
0.1–0.75
0.1–0.8
0.1–0.8
0.1–0.8
0.1–0.75
0.1–0.75
0.1–0.8
0.1–0.8
0.1–0.75
0.1–0.8
0.1–0.8
0.1–0.8
0.1–0.8
0.1–0.8
0.1–0.8
ClAcA
4.8 2.0e
13.2 1.0
16.0 1.0
22.3 3.0
26.0 3.0
15.3 2.0
16.5 2.0
22.9 1.0
25.8 2.0
42.2 2.0
59.4 3.0
38.8 3.0
60.5 2.0
87.3 8.0
94.2 3.0
16.0
33.0
32.0
31.4
32.5
51.0
41.3
45.8
43.5
60.3
74.3
129
151
175
135
136
260
218
204
243
200
191
174
165
142
131
129
102
129
527
520
497
459
457
Gly
ForNa
AcNa
MES
109
2
78.0 6.0
87.2 4.0
102
170
158
38.1
43.6
8
7
9
3
2
[1]0 = 2.5 9 10-4 M, 50 °C,
k = 300 nm. For each kinetic
run, the aqueous solvent
contained 1 % of CH3CN
a
The pH values were
calculated by averaging the pH
measurements performed at a
constant pH
49.6 3.0
56.7 7.0
65.6 3.0
77.1 6.0
71.1 5.0
k0 and kbap values were
obtained from Eq. (2)
b,c
d
The values of kb were
obtained from the relationship
103
2
kb ¼ kap=fb
Error limits are the standard
TRIS
160 12
260 25
299 49
322 13
365 18
b
e
134
1
202 26
deviations
f
Values in parentheses were
obtained using the average
values of kobs
138
109
7
9
observations were made at different pH values within the
pH range 1.14–1.94. These observations indicate that buf-
fer catalysis did not occur. Thus, the average of the
different kobs values obtained at a constant pH was con-
sidered to be k0 (Table 2). Similarly, an insignificant
contribution (*10 %) from kbap [Buf]T in Eq. (2) was found
at the lowest pH (2.35) with ClAcA buffer. As a conse-
quence, the calculated value of kbap = 4.8 2.0 M-1 s-1
(Table 2) at pH 2.35 cannot be considered to be very
represents the fraction of free base), as shown in Table 2,
are almost independent of pH for all buffer bases except for
MES.
The mean values of kb ¼ kavgfor all buffers except for
b
MES are shown in Table 3. The values of kb for MES
buffer exhibit a nonlinear decrease with increasing pH
within the pH range 5.35–6.54 (Table 2). These results
may be explained as follows. The value of pKa of 1 at
30 °C is 5.99 [15], which is used to estimate the value of
pKaSH as 5.36 at 50 °C. It is evident from this pKaSH value of
reliable. The calculated values of kb ¼ kap=fb (where fb
b
123

1302
W. H. W. Ahmad et al.
100
90
80
70
60
50
40
30
20
10
0
Scheme 1
O
O
K aSH
H+
N O
N OH
O
O
SH
S-
"
'
k 0
k 0
kb' B
kb – B
2
2-
210
0.0
0.2
0.4
0.6
0.8
1.0
[Buf]T/M
190
170
150
130
110
90
Fig. 1 Plot of kobs vs. [Buf]T at different pH values for the hydrolysis
of 1 with [Buf]T = [MES]T at pH 5.35 (filled circles), 5.60 (open
circles), 5.98 (filled squares), 6.32 (open squares), and 6.54 (filled
rectangles), respectively. Solid lines representing the fits to Eq. (2) are
drawn through the calculated data points, as described in the text
Table 3 Values of kbavg, kb0 and kb for the buffer-catalyzed cleavage
of 1
ꢂ
b
c
Buffer
pKaa
106kbavg
/
106kb0
/
106kbd
ꢂ /
M-1 s-1
M-1 s-1
M-1 s-1
Cl2AcA
ClAcA
Gly
1.47 0.3e
2.61 0.01
2.35 0.02
3.42 0.01
4.42 0.03
5.98 0.02
7.77 0.0
-1.74
31.8 4.0e
32.2 0.7
52.7 12.6
145 18
70
0
0.2
0.4
0.6
0.8
fSH
ForNa
AcNa
MES
TRIS
H2O
Fig. 2 Plot of kbap vs. fSH for the hydrolysis of 1 with B = MES. A
solid fit line (based on Eq. 5) has been drawn through the calculated
data points, as described in the text
225 26
248.1
78.7 6.0
492 33
0.65f
a
pKa values were obtained from the pH values at fb = 0.50
The values of kbavgare the mean values of kb
kobs ¼ k00 fSH þ k000fS þ ðkb0 fSH þ kb fS ÞfB½BufꢁT;
ð3Þ
ꢂ
ꢂ
ꢂ
b
c
d
e
f
where fSH ¼ [SH]/[1]T, fS ¼ 1 ꢂ fSH ¼ [S-]/[1]T, and
fB = [B]/[Buf]T. A comparison of Eqs. 2 and 3 gives Eqs. 4
and 5:
Rate constant for MES-buffer-catalyzed hydrolysis of nonionized 1
Rate constant for MES-buffer-catalyzed hydrolysis of ionized 1
Error limits are the standard deviations
ꢂ
The value of kbavgwas obtained from the relationship kbavg
¼
k0 ¼ k00 fSH þ k000fS
ð4Þ
ð5Þ
ꢂ
kw=½H2Oꢁ with kw = 34.2 9 10-6 s-1, as obtained using Eq. (6) and
kbap ¼ ðk0 fSH þ kb fS ÞfB:
[H2O] = 55.5 M
ꢂ
ꢂ
b
Equation 5 predicts that the plot of kbð¼ kap=fBÞ vs. fSH
b
5.36 that the rate of MES buffer-catalyzed hydrolysis of 1
involves both nonionized (SH) and ionized (S-) forms of 1,
as shown in Scheme 1. It can be easily shown that
the observed rate law (rate = kobs[1]T where
[1]T = [SH] ? [S-]) and Scheme 1 lead to Eq. (3):
should be linear with an intercept and slope equal to
0
ꢂ
ꢂ
kb and ðkb ꢂ kb Þ, respectively. Such a plot, as shown in
Fig. 2, is linear, with respective least-squares-calculated
values of kb and ðkb ꢂ kb Þof 78.7 6.0 9 10-6 M-1 s-1
0
ꢂ
ꢂ
and 169.4 14.0 9 10-6 M-1 s-1. The calculated values
123

Base-catalyzed hydrolysis of N-hydroxyphthalimide
1303
0
of kb and ðkb ꢂ kb Þ give the value of kb0 as
ꢂ
ꢂ
Mechanistic interpretation of k0 and kb
248.1 9 10-6 M-1 s-1. The values of kb0 and kb are also
ꢂ
shown in Table 3, where kb0 is equivalent to kb for other
buffers. The values of kb for MES are almost independent
of pH within the pH range 5.3–6.3, which indicates that
k00 ꢃ k000 in Eq. (4).
The [Buf]T-independent rate constant, k0, represents the
uncatalyzed, H?–HO- and catalyzed reactions of water
with 1. Thus, k0 may be expressed under such conditions as
k0 ¼ kw þ kH½Hþꢁ þ kOH½HOꢂꢁ;
ð6Þ
The rate constant k00 is equivalent to k0, and was obtained
using buffers at pH B 4.3, where the concentration of
ionized 1 (i.e., [S-]) is negligible compared with [SH]
because pKaSH= 5.36. The rate of buffer-uncatalyzed
hydrolysis of 1 may be expressed as v ¼ kw[H2O][SH] and
consequently k0 ¼ k00 ¼ kw[H2O]. The rate constant k000
represents the pseudo-first-order rate constant for the pH-
independent hydrolysis of 1, where the rate of reaction
v ¼ kw00 [H2O][S-], which is kinetically indistinguishable
where kw represents the pseudo-first-order rate constant for
the uncatalyzed reaction of H2O with 1. The values of k0
obtained within the pH range 1.1–8.3 (Table 2) were used
to calculate kw = 34.2 7.0 9 10-6 s-1 from Eq. (6),
using the known parameters kH = 98.6 1.0 9
10-6 M-1 s-1 and kOH = 2.84 0.50 M-1 s-1 and the
observed data summarized in Table 1. The values of k0 at
different pH are shown logarithmically in Fig. 3. It is worth
noting that the contribution of the kH[H?] ? kOH[HO-]
term ðk0minÞ in Eq. (6) at the pH (= pHmin) where the plot of
logkobs vs. pH exhibits a minimum can be calculated using
Eq. (7) [19, 20]:
from v ¼ kOH
aOH[SH]. Thus, under such conditions, either
k000 ¼ kw00 [H2O] or k000 ¼ kOHKw=KaSH. This kinetic indistin-
guishability was resolved by applying plausible kinetics
reasoning, which favors k000 ¼ kOHKw=KaSH [16]. The
reported value of pKw (= 13.26) was obtained at zero ionic
strength [17]. The reported values of the activity coeffi-
cients of H? and HO- at 50 °C and an ionic strength of
1.0 M are 0.77 and 0.67, respectively [18]. The activity-
coefficient-corrected value of pKw at an ionic strength of
1.0 M and 50 °C is 13.55. The mean value of k0ð¼ k000Þ
obtained within the pH range [4.3 to B6.5 (Table 2)
is 40.4 9.20 9 10-6 s-1. Thus, the relationship k000 ¼
1=2
k0min ¼ 2ðkHkOHKwÞ
;
ð7Þ
where Kw = [H?][HO-]. Thus, the experimentally
determined rate constants (k0) for the pH-independent
hydrolysis of 1 may be expressed as
k0 ¼ kw þ k0min
;
ð8Þ
which predicts the presence of kw only if k0=k0min [ 1. The
value of k0min can be calculated from Eq. 7 using known
values of kH, kOH, and Kw The value of k0min calculated for 1
at 50 °C in this manner is = 5.62 9 10-9 s-1 ðlog k0minis
k
OHKw=KaSH gives kOH= 5.1 9 102 M-1 s-1
.
-8.25) with kH = 98.6 1.0 9 10-6 M-1 s-1, kOH
=
2.84 0.50 M-1 s-1, and Kw = 2.82 9 10-14 M2. The
calculated value of k0min is therefore negligible compared
with that of kw.
The average values of the general base-catalyzed sec-
ond-order rate constants ðkbavgÞ for different buffers
(Table 3) were used to construct the Brønsted plot shown
in Fig. 4. The least-squares-calculated values of the inter-
cept (C) and the Brønsted slope (b) were found to be
-5.19 0.20 and 0.29 0.05, respectively, when the
values of kbavg for all buffers (Table 3) were included. The
values of C and b become -5.36 0.10 and 0.42 0.04
when the data fitted to the Brønsted equation ðlog kbavg
¼
C þ bpKaÞ include buffers containing carboxylate groups
as general base site catalysis.
General acid (GA) and general base (GB) catalysis may
be expected to occur in reactions where proton transfer is
the rate-determining step [21]. However, GA-GB catalysis
has been observed in reactions where the proton transfer
step cannot be considered the rate-determining step [6].
Nucleophilic addition as well as addition–elimination
reactions involve fast proton transfer, yet many such
reactions have been found to involve GA-GB catalysis.
Fig. 3 Logarithmic plot of k0 vs. pH for the uncatalyzed hydrolysis
of 1 at 50 °C. The solid line drawn through the values of k0
corresponds to Eq. (6) with kw = 34.2 7.0 9 10-6 s-1
,
kH = 98.6 1.0 9 10-6 M-1 s-1, and kOH = 2.84 0.50 M-1 s-1
123

1304
W. H. W. Ahmad et al.
-2
-2.5
-3
Fig. 4 The second-order
buffer-catalyzed rate constant,
kbavg, obtained for the hydrolysis
of 1. The lines (solid and
dashed) are least-squares fits
drawn through the values of
log kbavg calculated from the
Brønsted equation for either
(i) all of the buffers [H2O (a),
Cl2AcA (b), ClAcA (c), Gly (d),
ForNa (e), AcNa (f), MES (g),
and TRIS (h); solid line with
C = -5.19 0.20 and
h
g
-3.5
-4
f
e
c
d
b
-4.5
-5
b = 0.29 0.05] or (ii) all
buffers except for MES and
TRIS (dashed line with
C = -5.36 0.10 and
b = 0.42 0.04)
-5.5
-6
a
-6.5
-2
-1
0
1
2
3
4
5
6
7
8
pKA
Scheme 2
O
O
2
k 1
N OH
H2O
+
N OH
k –2
1
O
OH2
O
T1
1
k42[B]
k–2 [B]
k–22[B]
k22[B]
4
O
O
C OH
O
O
NHOH
OH
k –2
3
fast
N OH
OH
NH2OH
+
OH
O
2
H2O
k 3
HO
0
2
T1
GA-GB catalysis occurs in such reactions, including the
neutral hydrolysis of 1, due to the large change in the pKa
of the acidic sites of the reactants during product formation
[22, 23].
state. General base-catalyzed hydrolysis of ethyl dichlo-
roacetate (3) by a series of different types of GB catalyst
resulted in a b value of 0.47 [26], which is slightly larger
than the b value (= 0.3 or 0.4) obtained in the current GB-
catalyzed hydrolysis of 1. The Ka value of the conjugate
acid of the leaving group in the GB-catalyzed hydrolysis of
1 is 1.06 9 10-9 M [16], and that for 3 is 3.0 9 10-16 M.
The almost 3 9 106-fold larger Ka value of the conjugate
acid of the leaving group for the hydrolysis of 1 than the
corresponding value for 2, as well as the release of the five-
membered ring strain energy in the hydrolytic cleavage of
1, may be attributed to the difference in the observed b
Plausible reaction mechanisms for the specific acid
(H?)-[9] and specific base (HO-)-catalyzed [4, 24]
hydrolysis of N-substituted phthalimides have been dis-
cussed in previous reports. In bimolecular GB-catalyzed
reactions, the Brønsted b values usually range from 0.2 to
0.5 (see [25] and references cited therein). A small b value
implies only moderate proton transfer from the water
molecule (nucleophile) to the GB catalyst in the transition
123

Base-catalyzed hydrolysis of N-hydroxyphthalimide
1305
values for the GB-catalyzed hydrolysis of 1 and 3. A
plausible reaction mechanism for the GB-catalyzed
hydrolysis of 1 is shown in Scheme 2, where the k12 and k42
steps represent alternative reaction paths for the formation
of the highly reactive intermediate T10; and the GB catalysts
include H2O. If the k12 path is energetically favorable
compared with the k42 path for the formation of T10, then it
has been concluded elsewhere [16] that the k22 step is the
rate-determining step for B = H2O. However, if the k42 step
is energetically favorable for the formation of T10, then the
k42 step should be the rate-determining step. This conclu-
sion is based upon two facts: (1) the pKa value of the
conjugate acid of the leaving group in the k32 step is more
than 6 pK units lower than that in the kꢂ2 4 step, and (2)
there is a release of five-membered ring strain energy in the
k32 step, while there is no such effect in the kꢂ2 4 step. These
facts suggest that k32 [ kꢂ2 4; and consequently that the k42
step is the rate-determining step.
performed under pseudo-first-order reaction kinetic condi-
tions with a limiting concentration of 1 (2.5 9 10-4 M).
Kinetic runs were carried out for [4 half-lives. The
immediate hydrolysis product of 1 is N-hydroxyphthalamic
acid (2) which, at pH \ 3, converts into phthalic acid and
hydroxylamine in a relatively fast step. The details for
product characterization and data analysis (Aob vs. t) are the
same as those described elsewhere [16].
Acknowledgments We thank the Ministry of Higher Education
(MOHE) and the University of Malaya (UM) for financial assistance
through research grant UM.C/HIR/MOHE/SC/07.
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The plot of [Buf]T-independent rate constants k0 for the
hydrolysis of 1 versus pH revealed that the values of k0 are
independent of pH within the pH range 1.5–6.3. Under
such conditions, k0 ꢃ kw; where kw represents the pseudo-
first-order rate constant for the reaction of H2O with 1. The
value of kw is 35.8 9 10-6 s-1 at 50 °C. The hydrolysis of
1 within the pH range 1.5–6.3 is catalyzed by buffers. The
general base-catalyzed rate constants conform to the
Brønsted plot, with a Brønsted slope (b) of 0.30–0.40.
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Experimental
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The rate of hydrolytic cleavage of 1, under a variety of
reaction conditions, was studied spectrophotometrically by
monitoring the decrease in the absorbance (Aob) as a
function of reaction time (t) at 300 and 410 nm [16] during
the alkaline hydrolysis of 1. The kinetic study was
123