Kinetics and mechanism of large rate enhancement in an acidic aqueous cleavage of the tertiary amide bond of N-(2-methoxyphenyl)-N′-morpholinophthalamide (1)

Article abstract of DOI:10.1016/j.bioorg.2008.03.003

The rate of conversion of 1 to N-(2-methoxyphenyl)phthalimide (2) within [HCl] range 5.0 × 10^-3-1.0 M at 1.0 M ionic strength (by NaCl) reveals the presence of both uncatalyzed and specific acid-catalyzed kinetic terms in the rate law. Intramolecular carboxamide group-assisted cleavage of amide bond of 1 reveals rate enhancement of much larger than 10⁶-fold compared to the expected rate of analogous intermolecular reaction.

Full text of DOI:10.1016/j.bioorg.2008.03.003

Bioorganic Chemistry 36 (2008) 178–182
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Kinetics and mechanism of large rate enhancement in an acidic aqueous cleavage
of the tertiary amide bond of N-(2-methoxyphenyl)-N0-morpholinophthalamide (1)
*
Yoke-Leng Sim, Azhar Ariffin, M. Niyaz Khan
Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
The rate of conversion of 1 to N-(2-methoxyphenyl)phthalimide (2) within [HCl] range 5.0 ꢀ 10ꢁ3–1.0 M
at 1.0 M ionic strength (by NaCl) reveals the presence of both uncatalyzed and specific acid-catalyzed
kinetic terms in the rate law. Intramolecular carboxamide group-assisted cleavage of amide bond of 1
reveals rate enhancement of much larger than 106-fold compared to the expected rate of analogous inter-
molecular reaction.
Article history:
Received 31 January 2008
Available online 25 April 2008
Keywords:
N-(2-Methoxyphenyl)-N0-
morpholinophthalamide
N-(2-Methoxyphenyl)phthalimide
Acidic hydrolysis
Ó 2008 Elsevier Inc. All rights reserved.
Kinetics
Intramolecular rate enhancement
Reaction mechanism
1. Introduction
tively the probable rate enhancement in the intramolecular amide
group-assisted cleavage of another neighboring amide bond of 1 at
The classical paper of Shafer and Morawetz revealed more than
106-fold rate enhancement in the specific base-catalyzed carbox-
amide group-assisted cleavage of amide bond of phthalamide
and N,N0-dimethylphthalamide in aqueous solvent [1]. Since the
huge rate enhancements due to intramolecularity of reactions bear
a striking resemblance to enzyme-catalyzed reactions [2] a surge of
interest in this area of research can be seen in the literature
[2d,2e,3]. Almost all such and closely related studies involve cycli-
zation coupled with only hydroxide ion and general base catalysis
[4]. A search of literature reveals only one report on intramolecular
aminolysis of amides where the cyclization of 2-aminomethylben-
zamide to phthalimidine has been also studied within the pH 5 to
5 M HCl [5]. But the kinetic data analysis for data obtained within
the pH 5 to 5 M HCl was complicated due to the presence of rather
more basic 2-aminomethyl group in the substrate containing the
amide group. Cohen and Lipowitz [6] reported acid-catalyzed
hydrolysis of o-benzamido-N,N-dicyclohexylbenzamide where
neighboring amide group assistance turned out to be >104-fold.
These authors followed a synthetic approach and consequently a
quantitative estimation of neighboring amide group assistance as
well as fine details of mechanism remained unclear. Nearly 104-
to 1014-fold rate enhancement has been reported in the intramo-
lecular carboxyl group–assisted cleavage of amide bond at
pH 6 3 [7]. The aim of the present study was to explore quantita-
pH < 3. The observed results and their probable explanation(s) are
described in this manuscript.
2. Experimental
2.1. Materials
Synthesis of N-(2-methoxyphenyl)phthalimide (2) is described
elsewhere [8]. Synthesis of N-(2-methoxyphenyl)-N0-morpholin-
ophthalamide (1), N-benzoylmorpholine (3), kinetic measure-
ments and product identification are described in Supplementary
Data (SD). Stock solutions of 1 (0.025 M) and 3 (0.01 M) were pre-
pared in acetonitrile.
3. Results and discussion
3.1. Aqueous cleavage of 1 at different [HCl] and 35 °C
The rate of aqueous cleavage of 1 was studied within [HCl]
range 5.0 ꢀ 10ꢁ3–1.0 M at constant ionic strength of 1.0 M (by
NaCl). It is noteworthy that light precipitates appeared into the
reaction mixtures after reaction time t P 4.7 h (i.e. Pꢂ1 halflife)
at 60.05 M HCl. But this kinetic problem is solved as described in
the ‘Kinetic Measurements’ in Supplementary Data (SD).
Similar observations were obtained into the reaction mixture for
* Corresponding author. Fax: +60 3 79674193.
E-mail address: niyaz@um.edu.my (M.N. Khan).
acid-catalyzed hydrolysis of
2 under similar conditions [8].
0045-2068/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.bioorg.2008.03.003

Y.-L. Sim et al. / Bioorganic Chemistry 36 (2008) 178–182
179
Pseudo-first-order rate constants (kobs) at different [HCl] fit to the
following empirical equation
25.0
20.0
15.0
10.0
5.0
3.0
2.0
1.0
0.0
k0 þ kcK½HClꢃ
kobs
¼
ð1Þ
1 þ K½HClꢃ
where k0, kc and K represent empirical constants. The nonlinear
least-squares calculated values of k0, kc and K are summarized in
Table 1. The extent of the reliability of observed data fit to Eq. (1)
is evident from the plot of Fig. 1 where solid line is drawn through
the least-squares calculated data points. The absolute percent resid-
ual errors {ARE = 100 ꢀ |(kobsi ꢁ kcalcdi)/kobsi|} where kobsi and kcalcdi
represent respective observed and calculated values of pseudo-
first-order rate constants at the ith value of [HCl]} are 62% at
P0.01 M HCl while ARE = 5–6% at 5.0 ꢀ 10ꢁ3 M HCl.
0.00 0.02 0.04 0.06 0.08 0.10
The standard deviation (=36%) associated with k0 is signifi-
cantly large and consequently a skeptic might think that k0 is
not significantly different from zero. Although the standard devi-
ation is large (36%), perhaps it is not too large to believe that k0 is
different from zero for the following calculated results. (i) The
contributions of k0 compared to kcK[H+] in the numerator of Eq.
(1) are 62, 45, 14, 8 and 4% at 0.005, 0.01, 0.05, 0.1 and 0.2 M
HCl, respectively. (ii) The attempt to calculate kc and K from Eq.
(1) with k0 = 0 resulted in systematic positive ARE as 59, 42, 13,
3 and < 1% at the respective 0.005, 0.01, 0.05, 0.1 and >0.1 M
HCl. But the values of ARE at the corresponding values of [HCl],
turned out to be ꢁ6, ꢁ2, 2, ꢁ1 and < 1% when the data treatment
with Eq. (1) involved k0, kc and K as three unknown parameters.
The results described above as (i) and (ii) demonstrate that k0
cannot be neglected compared to kcK[H+] within the [HCl] range
of present study.
The downward curvature of the plot of Fig. 1 does not seem to
be visible to the naked eye. So a few kinetic runs were carried out
within 2.0–5.0 M HCl in the absence of NaCl (i.e. ionic strength was
not kept constant) and the kobs values, under such conditions,
showed upward curvature (Fig. 2) which could be ascribed to the
ionic strength effect. Thus, a few kinetic runs were also carried
out at constant ionic strength (5.0 M by NaCl) and within [HCl]
range 2.0–5.0 M. An attempt to carry out the kinetic run at 1.0 M
HCl and 5.0 M ionic strength (by NaCl) was unsuccessful because
the reaction mixture became turbid at t > ꢂ300 s. The values of kobs
within [HCl] range 2.0–5.0 M HCl at 5.0 M ionic strength were trea-
ted with Eq. (1) considering k0 as known parameter and the nonlin-
ear least-squares calculated values of kc and K are shown in Table
1, where k0 = 2.19 ꢀ 10ꢁ5 sꢁ1. The data fit appears satisfactory as
evident from Fig. 2.
0.0
0.00
0.20
0.40
0.60
0.80
1.00
[HCl] / M
Fig. 1. The plot showing the dependence of pseudo-first-order rate constants, kobs
,
upon [HCl] for acidic hydrolysis of 1 at 2.0 ꢀ 10ꢁ4 M 1, 1.0 M ionic strength (by
NaCl) and 35 °C. The solid line is drawn through the least-squares calculated data
points using Eq. (1).
Unlike NaCl, the use of NaBr to maintain the constant ionic
strength at 5.0 M did not produce turbidity problem into the reac-
tion mixture at 61.0 M HCl. Thus, a few kinetic runs were also car-
ried out within [HCl] range 0.2–5.0 M. The values of kobs obtained
under such conditions, as shown graphically in Fig. 2, were found
to fit to Eq. (1) and the nonlinear least-squares calculated values
of k0, kc and K are shown in Table 1. Negative value of k0 with stan-
dard deviations of more than 600% merely indicates that the con-
tribution of k0 compared to kc K[HCl] in the numerator of Eq. (1)
is insignificant and hence a relatively more reliable values of kc
and
K were obtained from Eq. (1) by considering k0 = 21.9
ꢀ 10ꢁ6 sꢁ1 obtained at 1.0 M ionic strength. Such calculated values
of kc and K are also summarized in Table 1.
Table 1
Values of k0, kc and K calculated from Eq. (2) for the aqueous cleavage of 1 and 3a
lb (M)
Temp (°C)
107 k0 (sꢁ1
)
104 kc (sꢁ1
)
102 K (Mꢁ1
)
pKa
[HCl] range (M)
# of runs
c
Amide
1
1.0
5.0
5.0f
35
35
35
219 78d
219
104 9d
262 17
227 11
25.3 2.8d
33.3 4.7
46.9 6.8
45.7 3.3
ꢁ0.60 (ꢁ0.75)e
ꢁ0.48
0.005–1.0
2.0–5.0
0.2–5.0
0.2–5.0
10
4
8
ꢁ740 4640
ꢁ0.33
219
229
7
ꢁ0.34
8
3
1.0b
6.0i
65
0.36 3.54
0
0
0.165 0.060
0.161 0.036
2.81 ꢀ 10ꢁ3
(8.34 0.28) ꢀ 10ꢁ3
66.7 39.7
69.8 23.5
ꢁ0.18
ꢁ0.16
0.05–1.0
0.05–1.0
6
6
65
35g
Benzamideh
25
0
81.0 9.7
ꢁ0.09
1.0–6.0
6
a
[10] = 2.0 ꢀ 10ꢁ4 M, k = 290 nm, aqueous reaction mixture for each kinetic run contained 0.8% v/v CH3CN. [30] = 1.3 ꢀ 10ꢁ4 M, k = 230 nm, aqueous reaction mixture for
each kinetic run contained 1.3% v/v CH3CN.
b
Ionic strength was maintained by NaCl.
pKa = logK.
Error limits are standard deviations.
Thermodynamic pKa (=concentration pKa + log c where activity coefficient c = 0.70 at 1.0 M ionic strength).
Ionic strength was kept constant by NaBr.
The value of kc at 35 °C was estimated from kc value at 65 °C using Eyring equation.
The observed data (kobs versus [HCl]) were obtained from Ref. [9].
Ionic strength was kept constant by LiCl.
c
d
e
f
g
h
i

180
Y.-L. Sim et al. / Bioorganic Chemistry 36 (2008) 178–182
The values of kobs, obtained for hydrolysis of benzamide within
[HCl] range 1.0–6.0 M at 25 °C and constant ionic strength 6.0 M
(by LiCl) [9], were found to fit reasonably well to Eq. (1) with
k0 = 0 and the nonlinear least-squares calculated values of kc and
K are shown in Table 1. The effects of [HCl] on kobs for hydrolysis
of benzamide and N,N-dimethylbenzamide reveal ꢂ3-fold larger
value of kobs for benzamide than that for N,N-dimethylbenzamide
under similar experimental conditions [9].
16.0
12.0
8.0
Unlike the mechanisms of thoroughly studied highly efficient
hydroxide ion-catalyzed intramolecular carboxamide group-as-
sisted cleavage of amide bonds, the mechanisms of rarely studied
specific acid (hydronium ion)-catalyzed such reactions are not well
explored. However, a plausible mechanism of such a reaction as de-
scribed in the present manuscript may be shown by Scheme 1
where the protonation of 1 in an acidic medium is shown by an equi-
librium process with equilibrium constant Ke1q
.
In Scheme 1, if the expected immediate intramolecular addition
product, Tꢄ1 and TIþN in respective k11-step and k12-step are too unsta-
MeO
4.0
MeO
O
O
O
Keq1 [H+]
H
H
N
N
N
N
OH
O
O
1H+
0.0
0.00
1
1.00
2.00
3.00
4.00
5.00
1
1
1
1
k-1 k1
[HCl] / M
k-2 k2
Fig. 2. The plots showing the dependence of pseudo-first-order rate constants, kobs
,
upon [HCl] for aqueous cleavage of 1 at 2.0 ꢀ 10ꢁ4 M 1, 5.0 M ionic strength (by
NaBr (j) and by NaCl (N)) and 35 °C. The solid lines are drawn through the least-
squares calculated data points using Eq. (1). The symbol (D) represents kobs obtai-
ned in the absence of NaCl, i.e. ionic strength was not kept constant in these kinetic
runs.
O
H
MeO
O
MeO
N
N
N
N
HO
HO
O
O
It may be noted that the values of kobs, obtained within [HCl]
range 2.0–5.0 M 5.0 M ionic strength, vary by < 7% in the presence
of NaCl and NaBr. However, the observed data fit to Eq. (1) at 5.0 M
ionic strength by NaCl is considered to be less reliable compared to
that at 5.0 M ionic strength by NaBr because of the lack of kobs
value at 61.0 M HCl in the presence of NaCl.
+
0
TMN
T1
1
1
k4
- H+
k3
H
N
O
+
3.2. Aqueous cleavage of N-benzoylmorpholine (3) at different [HCl]
and 65 °C
N
O
O
O
Me
Rate of specific acid-catalyzed hydrolysis of 3 was studied with-
in [HCl] range 0.05–1.0 M at 1.0 M ionic strength (by NaCl). Pseu-
do-first-order rate constants (kobs), as shown graphically in Fig. I
(Supplementary Data, SD), showed reasonably good fit to Eq. (1).
The nonlinear least-squares calculated values of k0, kc and K are
summarized in Table 1. The calculated value of k0 is associated
with extremely high (ꢂ10-fold) standard deviation (Table 1) which
shows insignificant contribution of k0 compared to kc K[HCl] in Eq.
(1) and consequently the calculated value of k0 is unreliable. Thus,
the values of kc and K were also calculated from Eq. (1) with k0 = 0
and such calculated values of kc and K are shown in Table 1. It is
evident from Table 1 that the values of kc and K remained almost
2
O
O
MeO
MeO
H
H
N
N
N
N
HO
O
O
O
+
T1
TIN
MeO
MeO
O
C
O
unchanged with change in k0 value from 0.0 to 3.6 ꢀ 10ꢁ8 sꢁ1
.
N
N
The k0-step could not be detected in the specific acid-catalyzed
hydrolysis of various amides [9,10]. The value of kobs
(=1.39 ꢀ 10ꢁ8 sꢁ1) at 0.1 M HCl and 1.0 M ionic strength may be
compared with kobs = 1.7 ꢀ 10ꢁ9 sꢁ1 obtained for hydrolysis of
N,N-dimethylbenzamide at 0.12 M HCl and 0.12 M ionic strength
and 35 °C [9]. The value of pseudo-first-order rate constant (k0)
for neutral uncatalyzed hydrolysis of formamide is 6 ꢀ 10ꢁ10 sꢁ1
(at 35 °C) [11].
C
H
H
H
H
O
H
O
N
O
HO
N
H
O
O
TS1
TS2
Scheme 1. Structures Tꢄ1 ; TIþN; TS1; TS2.

Y.-L. Sim et al. / Bioorganic Chemistry 36 (2008) 178–182
181
ble to exist for aþperiod of longer than 10ꢁ13 s [12], then the forma-
OH
O
Keq2 [H+]
tion of T01 and TMN are expected to occur through transition states
TS1 and TS2, respectively. The fact that the pKa of conjugate acid of
leaving group is larger in k41-step than that in kꢁ1 1-step and also the
release of five-membered ring strain in k1ꢁ1-step make kꢁ1 1 ꢅ k14
and this inequality leads to k14-step as the rate-determining step.
N
O
N
O
3H+
3
The pKa of conjugate acid of leaving group in k1-step is significantly
2
k12 H2O
2
3
k-2
k22 H2O
k-1
smaller than that in kꢁ1 2-step which in turn imply that k31 ꢅ k1ꢁ2
.
But the release of five-membered ring strain in k1ꢁ2-step makes
k1ꢁ2 ꢅ k1. Thus, the combined effects of relative pKa of conjugate
OH
C
OH
3
acids of leaving groups in k31-step and kꢁ1 2-step as well as release
of five-membered ring strain in only k1ꢁ2-step would dictate
whether k13-step or k12-step is the rate-determining step. The
observed rate law: rate = kobs [1]T and Scheme 1 can lead to Eq. (2)
N
H
O
C
N
O
OH
OH
+
0
TN
T2
- H+
fast
k14K11 þ k13K12Ke1q½Hþꢃ
2
2
k4
k3
kobs
¼
ð2Þ
1 þ K1eq½Hþꢃ
where K11 ¼ k11=k1ꢁ1, and K21 ¼ k21=kꢁ1 2. Eq. (2) is similar to Eq. (1) with
H
N
k0 ¼ k1K1; kc ¼ k1K1 and K ¼ Ke1q. Thus, the ratio kc/k0 (ꢆ 500) shows
COOH
4
1
3
2
that specific acid-catalytic factor is ꢂ500-fold in the cyclization of 1
+
to 2.
O
One of the reviewers has raised an interesting point that whether
the amide group acts as a nitrogen nucleophile through the enol
form—which is the only species with a lone pair of electrons on N
available to act as a nucleophile, or not.1 It is well known that CAN
bond in an amide is neither a pure single bond nor a pure double bond.
The nucleophilicity of the amide nitrogen is essentially governed by
its basicity. The reported pKa values of MeC„NH+, Me2C@NHMe+
and MeNHþ3 are ꢁ10.1, 5.5 and 10.7, respectively [13]. The values of
rCpOMe ¼ 0:50, rmCOMe ¼ 0:38, rCpOPh ¼ 0:44, rCmOPh ¼ 0:36, rꢁCOMe ¼ 0:82
and rꢁR (COMe) = 0.32 [14]. In view of these findings, it seems difficult
to believe that the amide nitrogen is a stronger base in pure enol form
(where lone pair of electrons of N exist in sp2 orbital) than in pure keto
form (where sp3 orbital contains lone pair of electrons of the amide
N). Although the kinetic data of the present study are not sufficient
to rule out completely the possibility of the sp2 nitrogen of the enol
form of the amide acting as the nucleophile in the conversion of 1
to 2, the mechanism shown in Scheme 1 is considered to be more
appropriate for the following reasons: (i) experimental and theoreti-
cal evidence for enol formation in the aqueous solutions of primary
and secondary amides are lacking (at least to the best of our literature
search) and (ii) the enol form of the amide group has not been consid-
ered in any closely related studies [7g,15,16].
O
C
OH
C
N
O
N
O
OH2
OH2
+
TO
T2
H
O
O
OH
H
N
H
O
N
O
O
O
H
H
H
H
O
H
TS3
TS4
Scheme 2. Structures Tꢄ2 ; TOþ; TS3; TS4.
where k21 and k22 represent second-order rate constants for uncata-
lyzed and specific acid-catalyzed hydrolysis of 3. Empirical Eq. (1)
The specific acid-catalyzed hydrolysis of amides has been
extensively studied [17]. In view of these extensive experimental
studies and a recent theoretical study [18], a plausible reaction
mechanism for hydrolysis of 3 in an acidic aqueous solution is
shown in Scheme 2 where the catalytic reaction involves k22-step
as the rate-determining step [17–19]. In Scheme 2, if the immedi-
ate intermolecular addition intermediates Tꢄ2 and TOþ in respective
k21-step and k22-step become too unstable to exist as intermediates,
then the formation of T02 and TNþ involves transition states TS3 and
TS4, respectively. The pKa of conjugate acid of leaving group is sig-
nificantly larger in k24-step than that in kꢁ2 1-step and consequently
k2ꢁ1 ꢅ k24 which leads to k24-step as the rate-determining step. Sim-
is similar to Eq. (3) with k0 ¼ k21 [H2O], kc ¼ k2 [H2O] and K ¼ K2
.
2
eq
It is evident from Schemes 1 and 2 that K1eq ¼ 1=Ka1Hþ and
K2eq ¼ 1=K3aHþ where Ka represents concentration ionization con-
stant. The calculated values of Kð¼ K1eq or Ke2q) were used to calcu-
late Ka for 1H+ and 3H+ which are summarized in Table 1. The value
of thermodynamic pKa (= ꢁ1.17) for protonated N,N-dimethylben-
zamide, determined spectrophotometrically in the absence of an
inert salt [9], may be compared with concentration pKa (= ꢁ0.60)
for 1H+. The value of concentration Ka for 1H+ is ꢂ3-fold larger than
that for 3H+ at 1.0 M ionic strength (Table 1) which could be partly
attributed to steric hindrance due to 2-CONHC6H4OMe-20 group in
1H+ [14]. The value of Ka for 1H+ at 1.0 M ionic strength is ꢂ1.3- to
1.8-fold larger than that at 5.0 M ionic strength (Table 1). Similarly,
the calculated concentration Ka (=1.23 M) value for benzamide at
6.0 M ionic strength (by LiCl), calculated from kinetic data of Ref.
[20], is ꢂ28- to 117-fold smaller than thermodynamic Ka (=34,
55, 62 and 144 M) obtained spectrophotometrically in the absence
of an inert salt [9]. Various reports show that the values of pKa of O-
protonated amide groups vary in the range of 0 to ꢁ3 [21].
ilarly, the pKa of conjugate acid of leaving group is larger in kꢁ2 2
-
step than that in k32-step and this leads to k23 ꢅ kꢁ2 2 which in turn
reveals k22-step as the rate-determining step. The observed rate
law: rate = kobs [3]T and Scheme 2 give Eq. (3)
k2½H2Oꢃ þ k2½H2OꢃK2 ½Hþꢃ
1
2
eq
kobs
¼
ð3Þ
1 þ K2eq½Hþꢃ
In order to assess the rate enhancement due to intramolecular-
ity of the reaction as displayed by Scheme 1, one requires the value
1
We thank the reviewer for suggesting this point.

182
Y.-L. Sim et al. / Bioorganic Chemistry 36 (2008) 178–182
of second-order rate constant (k2) for the bimolecular reaction (Eq.
Appendix A. Supplementary data
(4)) carried out under the experimental condition of present study.
Fig. I, Experimental details for synthesis of 1, 3, kinetic measure-
ments, product identification and NMR spectra for 1. Supplemen-
tary data associated with this article can be found, in the online
version, at doi:10.1016/j.bioorg.2008.03.003.
O
C
O
C
O
C
O
N
H
N
O
C
H
N
N
O
k
N
+
O
C
2
H
N
C
O
O
OMe
MeO
OMe
5
4
References
ð4Þ
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than that of imide (5) formation from 4 under the present experi-
mental conditions. This speculation is based upon, at least, follow-
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may not be significantly different from that of H2O in terms of
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than that of H2O. (ii) The concentration of H2O is ꢂ2.7 ꢀ 105-fold
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and the effective molarity (=2 ꢀ 106 M) due to intramolecularity
in the acidic aqueous cleavage of
1 may give k0/[H2O] as
1.1 ꢀ 10ꢁ11 Mꢁ1 sꢁ1 (=2.19 ꢀ 10ꢁ5 sꢁ1/2 ꢀ 106 M) for 3 provided
kc/k0 value remained same for the aqueous cleavage of both 1 and
3. Thus, the estimated value of k0 = 6 ꢀ 10ꢁ10 sꢁ1 for uncatalyzed
hydrolysis of 3 is similar to the corresponding reported k0 value
for uncatalyzed hydrolysis of formamide [11].
4. Conclusions
Perhaps this is the first report which reveals the rate enhance-
ment of much more than 106-fold due to intramolecular carboxam-
ide group assistance in the cleavage of the amide bond in mild
acidic aqueous solution. Intermolecular specific acid catalytic com-
ponent is ꢂ500-fold. The present finding predicts an efficient con-
version of phthalamide, N-substituted, N,N0-disubstituted and
N,N,N0-trisubstituted phthalamides to the corresponding phthali-
mide and N-substituted phthalimides under mild acidic pH. The
finding of large rate enhancement in the intramolecular amide
nitrogen-assisted cleavage of an amide bond under neutral/mild
acidic pH reveals the possibility that the acidic hydrolysis of a pep-
tide can be assisted by a neighboring amide group, which could be
relevant to the action of numerous enzymes.
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Acknowledgments
The authors thank the Ministry of Science, Technology and
Innovation for ScienceFund (Project No.: 14-02-03-4014) and the
University of Malaya for financial support.