Kinetic Evidence for the Occurrence of Kinetically Detectable Intermediates in the Cleavage of N-Ethoxy-carbonylphthalimide under N-Methylhydroxylamine Buffers

Article abstract of DOI:10.1002/kin.10023

The kinetics of the aqueous cleavage of N-ethoxycarbonylphthalimide (NCPH) in CH3NHOH buffers of different pH reveals that the cleavage follows the general irreversible consecutive reaction path NCPH(k_1obs) -> ENMBC(k_2obs) -> A(k_3obs) -> B, where ENMBC, A, and B represent ethyl N-[o-(N-methyl-N-hydroxycarbamoyl)benzoyl]carbamate, N-hydroxyl group cyclized product of ENMBC, and o-(N-methyl-N-hydroxycarbamoyl)benzoic acid, respectively. The rate constant k_1obs at a constant pH, obeys the relationship k_1obs = k_w + k_n^app [Am]T + k_b[Am]T², where [Am]T is the total concentration of CH3NHOH buffer and k_w is first-order rate constant for pH-independent hydrolysis of NCPH. Buffer-dependent rate constant k_b shows the presence of both general base and general acid catalysis. Both the rate constants k_2obs and k_3obs are independent of [Am]T (within the [Am]T range of present study) at a constant pH and increase linearly with the increase in α_OH with definite intercepts.

Full text of DOI:10.1002/kin.10023

Kinetic Evidence for the
Occurrence of Kinetically
Detectable Intermediates in
the Cleavage of N-Ethoxy-
carbonylphthalimide under
N-Methylhydroxylamine
Buffers
M. NIYAZ KHAN
Department of Chemistry, Faculty of Science, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
Received 24 April 2001; accepted 7 August 2001
ABSTRACT: The kinetics of the aqueous cleavage of N-ethoxycarbonylphthalimide (NCPH) in
CH3NHOH buffers of different pH reveals that the cleavage follows the general irreversible con-
k2 obs k 3 obs
secutive reaction path NCPH k → ENMBC → A → B , where ENMBC, A, and B represent ethyl
1 obs
N-[o-(N-methyl-N-hydroxycarbamoyl)benzoyl]carbamate, N-hydroxyl group cyclized product
of ENMBC, and o-(N-methyl-N-hydroxycarbamoyl)benzoic acid, respectively. The rate constant
app
k1 obs at a constant pH, obeys the relationship k1 obs = kw + kn
[Am]T + kb[Am]T2, where
[Am]T is the total concentration of CH3NHOH buffer and kw is first-order rate constant for
pH-independent hydrolysis of NCPH. Buffer-dependent rate constant kb shows the presence
of both general base and general acid catalysis. Both the rate constants k2 obs and k3 obs are
independent of [Am]T (within the [Am]T range of present study) at a constant pH and increase
C
linearly with the increase in aOH with definite intercepts. 2001 John Wiley & Sons, Inc. Int J
Chem Kinet 34: 95–103, 2002
tant and useful aspect of such research studies. Iron-
ically, majority of the solution phase reactions either
obey or are made to obey first-order kinetics under so-
called pseudo-first-order reaction kinetic conditions.
Kinetic studies on the rate of two or more than two
step reactions (i.e. consecutive reactions) are relatively
limited partly because of the complex kinetic equa-
tions produced by solving the rate laws of such reac-
tions. Generally these complex kinetic equations are
mathematically known as transcendental equations
INTRODUCTION
The use of kinetics in the diagnosis of the fine de-
tailed reaction mechanisms has been the most impor-
Correspondence to: M. Niyaz Khan; e-mail: niyaz@kimia.um.
edu.my.
Contract grant sponsor: IRPA.
Contract grant number: 09-02-03-0785.
2001 John Wiley & Sons, Inc.
DOI 10.1002/kin.10023
c

96
KHAN
whose exact solutions are almost impossible, and hence
they are difficult to solve for intended rate constants by
theuseofanyconventionalmathematicaltechnique[1].
In the past when computers were unavailable or hardly
available for data analysis, various approximation tech-
niques were used to determine the rate constants for the
consecutive reactions [1–7]. In the modern age when
computers are easily accessible, the kinetics of con-
secutive reactions can be studied relatively more easily
[8–10].
N-methylhydroxylaminolysis product to another
stable intermediate product was not kinetically inves-
tigated. The present work was initiated with the aim of
exploring in some detail the occurrence of minima and
maxima in the plots of Aobs (at 300 nm) versus t for
the reaction of N-methylhydroxylamine with NCPH.
The results and probable explanation(s) are described
in this paper.
EXPERIMENTAL
Materials
Phthalamide and N,N0-disubstituted phthalamides
undergo cyclization reactions to produce cyclized
products such as imide and N-substituted imides
[11–16]. Under typical reaction conditions, the reac-
tions of N-hydroxyphthalimide with hydroxylamine
[17] and N-methylhydroxylamine [18] produced
cyclic stable intermediates formed presumably by
the intramolecular nucleophilic attack of hydroxyl
moiety at the most electrophilic carbonyl carbon
of the respective aminolysis immediate products,
o-(N-hydroxycarbamoyl)benzohydroxamic acid and
o-(N -methyl-N-hydroxycarbamoyl)benzohydroxamic
acid. In a study aimed at diagnosing the occur-
rence of intermolecular general acid and general
base catalysis in N-methylhydroxylaminolysis of
N-ethoxycarbonylphthalimide (NCPH), it has been
All the chemicals used were of reagent grade and were
obtained from Aldrich or Fluka. Buffer solutions of
N-methylhydroxylammonium chloride of desired pH
were prepared by adding required amounts of NaOH
just before the start of kinetic runs. Standard solution
(0.02 M) of N-ethoxycarbonylphthalimide (NCPH)
was prepared in acetonitrile.
Kinetic Measurements, Product
Characterization, and Data Analysis
The details of the kinetic procedure were same as
described elsewhere [19]. The observed data for a
few typical kinetic runs are shown as the plots of
observed absorbance at 300 nm (Aobs) versus reac-
tion time (t) in Fig. 1. These observed data indi-
cate that the immediate product, ethyl N-[o-(N-methyl-
observed that the plots of observed absorbance (Aobs
)
versus reaction time (t) contained both minima and
maxima [19]. The occurrence of maxima in these
plots that revealed the conversion of immediate
FIGURE 1 Plots showing the dependence of observed absorbance (Aobs at 300 nm) versus reaction time (t) for the cleavage
of NCPH at total N-methylhydroxylamine buffer concentrations [Am]T = 0.06 M and pH 5.55 (1), [Am]T = 0.05 M and pH
5.80 ( ), and [Am]T = 0.04 M and pH 6.14 (∇). The solid lines are drawn through the least squares calculated data points using
Eq. (2) and parameters listed in Table I.

CLEAVAGE OF N-ETHOXYCARBONYLPHTHALIMIDE IN CH3NHOH BUFFERS
97
N-hydroxycarbamoyl)benzoyl] carbamate (ENMBC),
of N-methylhydroxylaminolysis of NCPH converts
to another product, A, which absorbs significantly at
300 nm and it further converts to hydrolysis product,
B, which does not absorb at 300 nm.
The characterization of end reaction product(s) was
carried by using the ferric hydroxamic acid assay [20]
which, however, cannot differentiate between B and
C (a probable hydrolysis product of ENMBC). But,
based upon purely polar and resonance effects (the re-
the following experiment was carried out. The reac-
tion mixture (18 ml) containing 0.8 M KCl and 0.2 M
CH3NHOH buffer of pH 6.43 was temperature equili-
brated at 30 C for about 5–10 min. The reaction was
then initiated by adding 7.0 ml of 0.02 M NCPH solu-
tion prepared in acetonitrile. The reaction mixture thus
contained 28% v/v CH3CN. Under such conditions,
the complete conversion of NCPH to ENMBC was ex-
pected to occur within <20 s. The formation of A or
D was monitored by measuring the increase in Aobs at
300 nm. The value of Aobs was found to increase until
nearly 30 min and then a slow decrease in Aobs was
observed. After exactly 43 min when it was assumed
that the reaction mixture did not contain any significant
amount of either NCPH or ENMBC (Scheme 1), the re-
action mixture was made acidic by adding nearly 0.25
ml of 10.5 M HCl, so that all the free amine base
(CH3NHOH) could become in protonated form. The
reaction mixture was then extracted 4 times with ether
and each time with 25 ml ether. The total volume of
ether extract became 100 ml. Just after the total ex-
traction, the value of Aobs of aqueous layer ( 25 ml)
spective values of and R(BA) are 0.27 and 0.61
I
for OCH3 and 0.10 and 0.11 for C6H5 [21]), the
most probable hydrolysis product of ENMBC should
be B and not C. The overall main reaction steps in the
cleavage of NCPH in the presence of aqueous buffers
of CH3NHOH may be represented by Scheme 1. The
possibility of the formation of the possible product D
through the cyclization of ENMBC in the k2-step of
Scheme 1 may be ruled out based upon the following
observations.
In order to test whether A or D is the product of
the cyclization of ENMBC in the k2-step of Scheme 1,
Scheme 1

98
KHAN
was 0.15 whereas Aobs value of ether layer, after nearly
4 times dilution (i.e. total volume 400 ml) was 1.05.
These observations support the formation of A rather
than D. In the event of the formation of D, the aqueous
layer ( 25 ml) might have resulted in Aobs value much
more higher than 0.15.
from Eq. (2) using the nonlinear least-squares (NLS)
technique, a technique now normally used to solve tran-
scendental equations such as Eq. (2). But it is well
known that in the use of NLS technique, the reliability
of the values of calculated unknown parameters de-
creases with the increase in the number of unknown
parameters. Hence, it is common practice in such data
analysis to reduce the number of unknown parame-
ters to a minimum possible value. Since, in the present
A skeptic might argue that the absence of D in aque-
ous layer is due to extremely high reactivity of cationic
imide D towards nucleophile H2O in aqueous medium.
But it can be shown that the value of Aobs (1.05) of ether
layer accounts almost 100% expected product. The ini-
tial concentration of NCPH into reaction mixture was
56 10 4 M. Although the total volume of ether layer
of 400 ml is very approximate, if one assumes that
the molar absorptivity of A (EA) remained unchanged
with the change in the solvent from water to ether, then
the concentration of A in 400 ml ether layer is 4
reacting system, k1 obs
k2 obs and k3 obs, the values
of k1 obs and ENC were calculated from Eq. (3) us-
ing the observed data points in the initial phase of
the reaction through a technique described elsewhere
[19].
Aobs = ENC[X]0 exp( k1 obs t) + A0
(3)
∞
4
1
1
10 M because the value of EA is 2500 M cm
,
The values of k2 obs, k3 obs, EA, and A were calcu-
∞
as can be seen later in the kinetic data analysis for
lated from Eq. (2) by the use of NLS technique consid-
data obtained at pH 6.14. The value of A concentration
(4 10 M) is nearly 15% higher than the expected
ering ENC and k1 obs as known parameters.
4
value of 3.5 10 4 M (25 56 10 4/400), which is
conceivable within the domain of uncertainty in the as-
sumed total volume of ether layer ( 400 ml) and also
in the assumption that EA is same in both water and
ether solvents.
RESULTS AND DISCUSSION
The cleavage of NCPH was kinetically studied
by carrying out kinetic runs within the total N-
methylhydroxylamine buffer concentration ([Am]T
where [Am]T = [CH3NHOH] + [CH3NH2OH+]) ra-
nge 0.03–0.10 M at a constant pH 5.20 0.01. Simi-
lar observations were obtained at different pH (5.55
0.00, 5.80 0.01, and 6.14 0.01). Pseudo-first-order
rate constant k1 obs calculated from Eq. (3) are shown
graphically in Fig. 2. The values of k2 obs, k3 obs, EA, and
The absorption due to ENMBC and B should be ex-
pected to be negligible at 300 nm in view of the reported
values of molar absorptivity of phthalamic acid ( 40
1
1
M
cm 1) and phthalic acid ( 40 M cm 1) [22].
Thus, the observed absorbance (Aobs) of the reaction
mixture at 300 nm may be expressed as
A
were calculated from Eq. (2) as described earlier
∞
Aobs = ENC[NCPH] + EA[A] + A
(1)
∞
in the text and these results at different pH are summa-
rized in Table I.
where ENC and EA represent molar absorptivity of
NCPH and A, respectively, at 300 nm and A is
∞
the residual final absorbance. Reaction steps shown in
Scheme 1 and Eq. (1) can lead to Eq. (2)
Kinetic and Mechanistic Analysis of k1 obs
The values of k1 obs, at a constant pH, were found to fit
to Eq. (4)
Aobs
2
k1 obs kw = knapp[Am]T + kb[Am]T
(4)
= ENC[X]0 exp( k1 obs t)
EA[X]0 k1 obs k2 obs
where kw, knapp, and kb represent buffer-independent
first-order, apparent nucleophilic second-order, and
buffer-catalyzed third-order rate constants, respec-
tively, for the cleavage of NCPH. The value of kw (2.6
10 4 s 1) was obtained from an earlier report [23]. The
values of knapp and kb were calculated from Eq. (4) us-
ing least-squares technique. The values of knapp and kb
at different pH are shown in Table II. Reasonably good
fitting of observed data to Eq. (4) is evident from the
plots of Fig. 2, where solid lines are drawn through the
+
(k2 obs k1 obs)(k3 obs k1 obs)(k3 obs k2 obs
[(k3 obs k2 obs) exp( k1 obs t)
)
(k3 obs k1 obs) exp( k2 obs t)
+ (k2 obs k1 obs) exp( k3 obs t)] + A
(2)
∞
where [X]0 represents initial concentration of NCPH.
In principle, observed data (Aobs versus t) can be
used to calculate k1 obs, k2 obs, k3 obs, ENC, EA, and A
∞

CLEAVAGE OF N-ETHOXYCARBONYLPHTHALIMIDE IN CH3NHOH BUFFERS
99
where kn, kgb, and kga represent nucleophilic second-
order, general base-catalyzed, and general acid—
catalyzed third-order rate constant, respectively.
Observed rate law (rate = k1 obs [NCPH]) and Eq. (5)
can lead to Eq. (6)
2
k1 obs kw = kn fAm[Am]T + kgb fAm
2
+ kga fAm fAmH [Am]T
(6)
where fAm = KaAm/(aH + KaAm) and fAmH = aH/(aH
app
+ KaAm). Equation (6) is similar to Eq. (4) with kn
2
= kn fAm and kb = kgb fAm + kga fAm fAmH. Alth-
app
ough the values of kn
are not very reliable, rela-
app
tively more reliable kn values at pH 5.20 and 6.14
1
(Table II) yielded kn as 0.19 and 0.21 M
s
1, re-
Am
spectively, with pKa = 6.24. The average value of
1
1
kn (=0.20 M
s
) is 30–fold smaller than kn for
1
HNHOH (kn = 6.4 M
s
1) obtained under essen-
tially similar experimental conditions [23]. The value
of kn (=0.012 M 1 s 1) for the reaction of CH3NHOH
with N-hydroxyphthalimide (NHPH) [18] appears to
1
1
be more than 30-fold smaller than kn ( 1.5 M
s
although this value is not very reliable because it is
derived from less reliable data and obtained at a sin-
gle pH) for the nucleophilic reaction of HNHOH with
NHPH [13]. It is interesting to note that the value of
kn for CH3NHOH is only 1.2-fold smaller than that for
HNHOH in the intramolecular general base-catalyzed
aminolysis of ionized phenyl salicylate (PS ) [24].
The relative nucleophilic reactivity of CH3NHOH
and HNHOH toward NCPH and PS indicates that
the mechanism of the reaction of these nucleophiles
with NCPH is different than that with PS . The ␣-
effect nitrogen nucleophiles (such as CH3NHOH and
HNHOH) have been observed to exhibit abnormally
high reactivity in nucleophilic addition–elimination re-
actions (at the carbonyl carbon) where expulsion of
the leaving group is the rate-determining step [25–
29]. But in those reactions where nucleophilic attack
is rate-determining, these nucleophiles have exhibited
considerably small rate enhancement [30,31]. Kinetic
data on hydroxylaminolysis of NCPH have revealed
the occurrence of a stepwise mechanism [23]. The oc-
currence of intermolecular general acid–base catalysis
in the reaction of CH3NHOH with NCPH has been
explained in terms of a stepwise mechanism [19]. Sig-
nificantly lower nucleophilic reactivity of CH3NHOH
(pKa 6.24) compared with HNHOH (pKa 5.97) to-
ward NCPH and NHPH is difficult to explain in terms
of steric hindrance. If steric hindrance is the main
cause for such characteristic difference in the nucle-
ophilic reactivity of these nucleophiles, then it re-
mains to explain almost similar nucleophilic reactivity
FIGURE 2 Effects of total N-methylhydroxylamine buffer
concentration ([Am]T) on hydrolysis corrected pseudo-first-
order rate constants (kobs kw, where kw is pH-independent
pseudo-first-order rate constant for hydrolysis of NCPH) for
N-methylhydroxylaminolysis of NCPH at pH 5.20 (1), pH
5.55 ( ), pH 5.80 (∇), and pH 6.14 ( ). The solid lines are
drawn through the least squares calculated data points using
Eq. (4) and parameters listed in Table II.
app
calculated data points. The calculated values of kn
are not very reliable because they are associated with
large standard deviations especially at pH 5.55 and 5.80
(Table II).The values of kb at pH 5.55 and 5.80 were
app
also calculated from Eq. (4) by setting kn = 0 and
these results are also shown in Table II. The large stan-
app
dard deviations associated with kn values are due
app
to significantly low contribution of kn [Am]T term
2
compared with kb [Am]T term in Eq. (4) under the
experimental conditions imposed. The maximum con-
tributions of knapp [Am]T, obtained at the lowest values
of [Am]T are 43, 30, 6, and 40% at pH 5.20, 5.55, 5.80,
and 6.14, respectively.
The general rate law for the reaction of CH3NHOH
with NCPH may be given as
rate = {kw + (kn + kgb[CH3NHOH]
+ kga[CH3NH2OH+]) [CH3NHOH]}[NCPH]
(5)

100
KHAN
Table I Values of Unknown Parameters, k2 obs, k3 obs, EA and A , Calculated from Eq. (2)a
∞
b
c
c
[Am]T
(M)
k1 obs
(10
ENC
k2 obs
k3 obs
EA
(M cm
3
1
1
1
4
1
4
1
1
1
pH
s
)
(M cm
)
(10
s
)
(10
s
)
A
∞
5.54
5.55
5.55
5.55
5.55
5.79
5.80
5.80
5.80
5.81
6.12
6.13
6.14
6.14
6.14
6.15
0.025
0.040
0.060
0.100
0.120
0.015
0.020
0.030
0.040
0.050
0.015
0.020
0.030
0.035
0.040
0.050
2.20
4.42
9.43
21.7
32.7
1.56
2.71
5.70
7.51
2200
2150
2100
2000
2000
2150
2100
2000
1950
1900
2200
2150
2100
2000
1900
1850
5.78 0.45d
6.28 0.45
6.40 0.68
7.75 0.98
5.93 1.28
6.49 0.89
7.12 0.56
7.56 0.31
7.51 0.33
6.94 0.45
13.6 0.8
15.2 0.8
15.9 0.4
14.7 0.5
13.9 0.5
13.5 1.0
2.15 0.14d
2.02 0.12
2.22 0.21
2.24 0.26
2.99 0.64
2.80 0.33
2.72 0.20
2.78 0.11
2.94 0.11
3.32 0.20
3.65 0.15
3.84 0.29
3.79 0.10
4.11 0.12
4.57 0.17
5.20 0.39
1572 78d
1638 73
1601 114
1410 117
1484 254
1971 174
1929 104
1905 55
1914 56
1926 98
2648 73
2520 94
2560 43
2549 51
2563 66
2492 131
0.012 0.002d
0.001 0.002
0.008 0.002
0.004 0.003
0.015 0.003
0.024 0.003
0.036 0.002
0.017 0.001
0.023 0.001
0.025 0.001
0.011 0.002
0.011 0.001
0.010 0.002
0.004 0.002
0.011 0.002
0.013 0.003
14.9
3.31
6.04
11.5
15.0
19.2
28.2
aConditions: [NCPH]0 = [X]0 = 2.8 10 4 M; ionic strength 1.0 M (maintained by KCl); 30 C; ␭ = 300 nm; the aqueous solvent for each
kinetic run contained 1.4% v/v CH3CN.
b[Am]T (= [CH3NHOH] + [CH3NH2OH+]) is total N-methylhydroxylamine buffer concentration.
cCalculated from Eq. (3) as described in the text.
dError limits are standard deviations.
of dimethylamine [32] and methylamine [12] toward
phthalimide.
for the reason that the acetic acid (pKa 4.68) is a
stronger acid than CH3NH2OH+ (pKa 6.24) by 1.56 pK
units.
2
The relationship kb = kgb fAm + kga fAm fAmH was
used to calculate kgb and kga from calculated values of
kb at different pH (Table II). The least-squares calcu-
2
1
lated values of kgb and kga are 54 13 M
s
and
Kinetic and Mechanistic Analysis of k2 obs
2
4.2 2.0 M
s
1, respectively. The value of kga is
The values of k2 obs appear to be independent of [Am]T
and dependent upon pH. The average values of k2 obs at
associated with high standard deviation and hence it
is not very reliable. The respective values of kgb (=54
three different pH fit to the relationship k2 obs = k2 O
+
2
2
M
s
1) and kga (=4.2 M
s
1) are nearly 9-fold
k2 OH aOH (where aOH = 10pH 14). The least squares
calculated values of k2 O and k2 OH are (2.8 1.4)
larger and 25-fold smaller than the corresponding val-
ues of kgb (=6.2 M 2 s 1) and kga (=111 M 2 s 1) for
acetate buffer [19]. These results are conceivable
4
1
1
10
s
and (8.3
1.6)
104
M
s
1, re-
spectively. The values of the second-order rate con-
stants (kOH) for hydroxide ion-catalyzed cyclization of
ethyl N-[o-(N-hydroxycarbamoyl)benzoyl]carbamate
(EBC) to N-hydroxyphthalimide (NHPH) and ethyl
o-hydroxymethylbenzoate to phthalide are 4.1
Table II Values of Apparent Nucleophilic Second-
Order Rate Constant, knapp, and Buffer-Catalyzed
Third-Order Rate Constant kb, Calculated from Eq. (4)
app
a
1
1
1
1
104 M
s
[13] and 104 M
s
[33], respectively
kn
kb
M
[Am]T
(M)
3
1
1
1
1
pH
(10
M
s
1) (10
s
)
and these values may be compared with k2 OH (=8.3
1
104 M
s
1). The pKa of H2NCOOCH2CH3 is pre-
5.20 0.01b 15.9 2.6b
6.93 0.32b 0.030–0.100
sumably similar to that of acetamide (pKa 15.4 [34])
because (0.28) and (BA)(0.16) for Ac (COCH3)
5.55 0.00
5.80 0.01
6.14 0.01
23.1 17.3
20.2 1.7
25.3 3.7
57.3 1.3
59.0 1.5
94.1 3.4
0.025–0.120
0.015–0.050
0.015–0.050
I
R
0
are not significantly different from
(0.30) and
5.16 5.40
0
91.3 13.7
I
R
(BA) (0.14) for COOCH2CH3 [21]. Thus, the pKa of
H2NCOOCH2CH3 is also similar to pKa of ethanol
(pKa 16.0 [35]). It has been concluded mechanistically
elsewhere [13] that the basicity of the neutral nucle-
ophile has essentially no effect on kOH values, while
a Total N-methylhydroxylamine buffer concentration ([CH3NH
OH] + [CH3NH2OH+]) range.
bError limits are standard deviations.

CLEAVAGE OF N-ETHOXYCARBONYLPHTHALIMIDE IN CH3NHOH BUFFERS
101
the basicity of the leaving group has significant effect
on kOH values for such cyclization reactions.
may involve intramolecular general base catalysis as
shown in Scheme 2. However, an alternative possibil-
ity of the occurrence of intramolecular nucleophilic
catalysis as shown in Scheme 3 is also conceivable in
view of the report of such catalysis in an almost similar
reaction system [36].
Another possibility for the increase in EA with the
increase in pH is the fast equilibrium formation of E as
shown in Eq. (8).
Although the value of k2O (2.8 10 4) is associated
with considerably high standard deviation ( 50%), it
does show the presence of a definite intercept (i.e.
uncatalyzed term) in the rate law for the cycliza-
tion of ENMBC to A (Scheme 1). The cyclization
of EBC to NHPH under essentially similar experi-
mental conditions did not reveal the occurrence of
uncatalyzed reaction path. These results are conceiv-
able for the reason that, based upon the resonance ef-
fect which is presumably stronger than the effect of
relative electronegativity of atoms to which the lone
pair of electrons are attached, the neutral nitrogen
is a weaker base than hydroxyl group oxygen of o-
K
I
A + CH3NHOH
E
(8)
J
HO
But fast attainment of such an equilibrium should
cause the decrease in both EA and k3 obs with the
increase in [Am]T at a constant pH. But both EA and
k3 obs are almost independent of [Am]T at a constant
pH (Table I). It should be noted that the mechanisms
of forward and backward reactions in Eq. (8) are most
likely different from each other in view of specific
base catalysis.
CON(CH3)HOH group of ENMBC. The value of k2O
4
(2.8 10
s
1) is comparable with the rate constant
(kw = 27.4 10 4 s 1 at 50 C) for pH-independent hy-
drolysisof N-phenylphthalamicacid, wherehydrolysis
was assisted by intramolecular nucleophilic participa-
tion of nonionized o-carboxylic group [22].
The increase in pH from 5.55 to 6.14 increased the
1
1
value of EA from 1540 80 to 2560 50 M cm
(Table I). Since the intermediate A does not contain
any easily ionizable proton, the values of EA should
have been independent of pH. These observations may
be explained if it is assumed that the disappearance of
ENMBC occurs through two parallel reaction steps as
shown in Eq. (7)
k20 w
I
ENMBC
A + H2NCOOCH2CH3
k2 OH(aOH
)
Kinetic and Mechanistic Analysis of k3 obs
I B + H2NCOOCH2CH3
00
k
2 w
The pseudo-first-order rate constant k3 obs is indepen-
dent of [Am]T at a constant pH (Table I) and show a
linear relationship k3 obs = k3 O + k3 OH aOH, although
a 3 data points linear plot is not so reliable. The least-
squares calculated values of k3 O and k3 OH are (1.7
(7)
where the k020 w-step represents pH-independent or spe-
cific acid-catalyzed hydrolysis of ENMBC. It is evi-
dent from Scheme 1 and Eq. (7) that k2 obs = k0
+
2
w
k020 + k2 OH (aOH). The formation of B from ENMBC
0.1) 10
s
and (1.8 0.1) 104 M
s ,
4
1
1
1
w
Scheme 2

102
KHAN
Scheme 3
4
1
8. Wilson, J. M.; Bayer, R. J.; Hupe, D. J. J Am Chem Soc
1977, 99, 7922.
9. Hine, J.; Kaufmann, J. C.; Cholod, M. S. J Am Chem
Soc 1972, 94, 4590.
respectively. The value of k3 O (=1.7
10
s
)
may be compared with the rate constant kw (=2.6
4
10
s
1) for pH-independent hydrolysis of NCPH.
The value of pKa of conjugate acid of leaving group in
the hydrolysis of NCPH is 11.3 [37]. In the absence of
the reported value of pKa of conjugate acid of leaving
group in the hydrolysis of A, an approximate value of
its pKa may be estimated as follows. The values of pKa
of CH3CONH2, CH3CON(CH3)H, C6H5CONH2, and
(CH3CO)2NH are 15.4 [34], 17.1 [38], 14–15 [34], and
12.9 [39]. Thus, the replacement of NH2 by HNCOCH3
in CH3CONH2 decreases pKa by 2.5 pK units. The re-
placement of H in HOH by (CO)2N decreases pKa of
HOH by 9.7 pK units (pKa of N-hydroxyphthalimide
is 6.0). Thus, the pKa of C6H5CON(CH3)OH should
be equal to 10.2. The replacement of o-H by o-CO2
group in C6H4CON(CH3)OH is bound to increase its
pKa slightly. It seems that the pKa of conjugate acid of
leaving group in the hydrolysis of A is similar to that
of leaving group in the hydrolysis of NCPH. It is there-
fore conceivable that the values of k3 O and k3 OH are
nearly of the same order of the corresponding values
10. Khan, M. N.; Khan, A. A. J Org Chem 1975, 40, 1793.
11. Shafer, J. A.; Morawetz, H. J Org Chem 1963, 28, 1899.
12. Khan, M. N.; Ohayagha, J. E. React Kinet Catal Lett
1996, 58, 97.
13. Khan, M. N. J Chem Soc, Perkin Trans 2 1988, 213.
14. Khan, M. N. Indian J Chem 1994, 33B, 646.
15. Khan, M. N. J Org Chem 1996, 61, 8063.
16. Khan, M. N. Int J Chem Kinet 1996, 28, 421.
17. Khan, M. N. Indian J Chem 1991, 30A, 777.
18. Khan, M. N. Indian J Chem 1996, 35B, 1275.
19. Khan, M. N. Int J Chem Kinet 1997, 29, 647.
20. Kirsch, J. F.; Jencks, W. P. J Am Chem Soc 1964, 86,
837.
21. Ehrenson, S.; Brownlee, R. T. C.; Taft, R. W. Progr Phys
Org Chem 1973, 10, 1.
22. Blackburn, R. A. M.;Capon, B.;McRitchie, A. C. Bioorg
Chem 1977, 6, 71.
23. Khan, M. N. J Chem Soc, Perkin Trans 2 1988, 1129.
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25. Jencks, W. P.; Gilchrist, M. J Am Chem Soc 1968, 90,
2622.
26. Dixon, J. E.; Bruice, T. C. J Am Chem Soc 1971, 93,
3248.
4
1
of kw (= 2.6 10
s
1) and kOH (= 0.2 104 M
s
1) for hydrolysis of NCPH [23].
27. Dixon, J. E.; Bruice, T. C. J Am Chem Soc 1971, 93,
6592.
28. Dixon, J. E.; Bruice, T. C. J Am Chem Soc 1972, 94,
2052.
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CLEAVAGE OF N-ETHOXYCARBONYLPHTHALIMIDE IN CH3NHOH BUFFERS
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