Kinetics and mechanism for the formation of o-carboxy(N-methyl)-benzohydroxamic acid in the cleavage of ethyl N-[o-(N-methyl-N-hydroxycarbamoyl)-benzoyl]carbamate in N-methylhydroxylamine, acetate, and phosphate buffers

Article abstract of DOI:10.1002/kin.10142

The rate of cleavage of ethyl N-[o-(N-methyl-N-hydroxycarbamoyl)benzoyl]-carbamate (ENMBC) in the buffer solutions containing N-methylhydroxylamine, acetate + N-methylhydroxylamine, and phosphate + N-methylhydroxylamine followed an irreversible consecutive reaction path: ENMBC →^{k 1 obs} A →^{k 2 obs} B where A and B represent N-hydroxyl group cyclized product of ENMBC and o-(N-methyl-N-hydroxycarbamoyl)benzoic acid, respectively.

Full text of DOI:10.1002/kin.10142

Kinetics and Mechanism
for the Formation of
o-Carboxy(N-methyl)-
benzohydroxamic Acid in
the Cleavage of Ethyl
N-[o-(N-Methyl-N-
hydroxycarbamoyl)-
benzoyl]carbamate in
N-Methylhydroxylamine,
Acetate, and Phosphate
Buffers
M. NIYAZ KHAN
Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
Received 16 December 2002; accepted 6 May 2003
DOI 10.1002/kin.10142
ABSTRACT: The rate of cleavage of ethyl N-[o-(N-methyl-N-hydroxycarbamoyl)benzoyl]-
carbamate (ENMBC) in the buffer solutions containing N-methylhydroxylamine, acetate + N-
methylhydroxylamine, and phosphate + N-methylhydroxylamine followed an irreversible con-
k1 obs
k2 obs
secutive reaction path: ENMBC → A → B where A and B represent N-hydroxyl group
cyclized product of ENMBC and o-(N-methyl-N-hydroxycarbamoyl)benzoic acid, respectively.
Correspondence to: M. Niyaz Khan; e-mail: niyaz@um.edu.my.
Contract grant sponsor: University of Malaya.
Contract grant number: F0718/2002B.
c
ꢀ
2003 Wiley Periodicals, Inc.

428
KHAN
Both rate constants k1 obs and k2 obs showed the presence of buffer catalysis, but buffer catalysis
turned out to be weak in the presence of N-methylhydroxylamine buffer, while it was strong
in the presence of acetate and phosphate ones. Buffer-independent rate constants k10 and
k20 increased linearly with the increase in aOH with definite intercepts. The values of molar
absorption coefficient of A, obtained under varying total buffer concentrations at a constant
pH, showed the presence of a fast equilibrium: A + CH3NHOH ꢀ C, where C represents N-[o-
(N-methyl-N-hydroxycarbamoyl)methyl]benzohydroxamic acid. ꢀ 2003 Wiley Periodicals, Inc.
C
Int J Chem Kinet 35: 427–437, 2003
pH’s were prepared by adding the required amounts of
NaOH just before the start of kinetic runs. Standard so-
lution (0.02 M) of NCPH was prepared in acetonitrile.
INTRODUCTION
The aqueous cleavage of phthalimide and substituted
phthalimides in the presence of primary and secondary
amines involves rather complex reaction mechanisms
[1–8]. Isolation of intermediates and end products in
these reactions provides a fruitful insight about the
mechanisms of these reactions. But the fine details of
these complex mechanisms are expected to be achieved
only from a systematic kinetic study that can indirectly
give support for the presence of highly reactive inter-
mediates of extremely short lifetimes (say ∼10−10 s).
The cleavage of N-ethoxycarbonylphthalimide
(NCPH) in aqueous buffers of N-methylhydroxyl-
amine has been found to follow an irreversible conse-
cutive reaction path: NCPH → ENMBC → A → 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-carboxy(N-methyl)benzohydroxamic acid, respec-
tively [9]. The mechanistic details of k1 step have been
studied earlier [10]. The consecutive nature of this re-
action has been kinetically analyzed by monitoring the
change in the concentrations of NCPH and A spec-
trophotometrically as a function of a reaction time [9].
In this study, the use of considerably high concentra-
tions of N-methylhydroxylamine buffer was restricted
because of the kinetic profiles, k1 ꢁ k2 and k3. This
experimental problem allowed to attain only a maxi-
mum of <0.025 M free amine. Under such conditions,
the buffer effects on k2 and k3 (if any) could not be
detected. The present study was initiated with an aim
to find out the occurrence or nonoccurrence of buffer
catalysis in k2 step and k3 step by covering consider-
ably high total buffer concentration range. The results
and probable explanation(s) are described in this paper.
Kinetic Measurements
The rate of the title reaction was studied spectropho-
tometrically by monitoring the change in absorbance
of the reaction mixture at 300 nm as a function of re-
action time. The reactant ENMBC was generated by
reacting NCPH with N-methylhydroxylamine under
the reaction conditions in which the rate of formation
of ENMBC was more than 75- and 10-fold larger than
that of cyclization of ENMBC to form intermediate in
the presence of N-methylhydroxylamine and acetate
buffer, respectively. The details of the kinetic proce-
dures were same as previously described [10].
k1
k2
k3
In view of the earlier reports on this reaction [9,10],
a brief reaction scheme for the title reaction may be
expressed by Eq. (1)
very fast
k1 obs
k2 obs
NCPH → ENMBC → A → B
(1)
where A and B represent benzo-3-methyl-2,3-oxazine-
1,4-dione (N-hydroxyl group cyclized product of
ENMBC) and o-(N-methyl-N-hydroxycarbamoyl)-
benzoic acid, respectively.
EXPERIMENTAL
Materials
All the chemicals used were of a reagent grade and
were obtained from Aldrich or Fluka. Buffer solutions
of N-methylhydroxylammonium chloride of desired
Both NCPH and A absorb strongly, while both EN-
MBC and B do not exhibit a detectable absorption

FORMATION OF o-CARBOXY(N-METHYL)BENZOHYDROXAMIC ACID
429
at 300 nm. Thus, the observed absorbance (Aobs) at
300 nm is essentially due to intermediate A because,
under the present reaction conditions, more than 99.9%
conversion of NCPH to ENMBC occurred within <100
and 200 s in the presence of N-methylhydroxylamine
andacetatebuffer, respectively. Theobserveddata, Aobs
versus t, were found to fit to Eq. (2)
experimental conditions has been previously described
[9].
RESULTS AND DISCUSSION
Effects of N-Methylhydroxylamine Buffer
on k1 obs, k2 obs, and E
app
Eapp[X]0k1 obs
Fourtofivekineticrunswerecarriedoutwithinthetotal
N-methylhydroxylamine buffer concentration ([Am]T
where [Am]T = [CH3NHOH] + [CH3NH2OH+])
range of ≥0.10 to ≤0.50 M at a constant pH. The
values of k1 obs, k2 obs, and Eapp were calculated from
Eq. (2) and these values of kinetic parameters at dif-
ferent [Am]T and pH are summarized in Table I. The
values of k1 obs and k2 obs were kinetically analyzed by
using Eqs. (3) and (4), respectively,
Aobs
=
[exp(−k1 obst) − exp(−k2 obst)]
)
(k2 obs − k1 obs
+ A0
(2)
where [X]0 = [NCPH]0 (initial concentration of NC-
PH), Eapp = EA − E, A0 = E[X]0 with E = EENMBC
and EENMBC ≈ EB. The notations EENMBC, EA, and
EB represent the molar absorption coefficients of EN-
MBC, A, and B, respectively. The assumption that
EENMBC ≈ EB at 300 nm is supported by the fact that
the values of A (=EB[X]0) obtained in the present
k1 obs = k10 + k1b[Am]T
k2 obs = k20 + k2b[Am]T
(3)
(4)
∞
study are similar to the corresponding values of A
∞
(=EENMBC[X]0 ≡ A0 in the present study) obtained in
a separate study where disappearance of NCPH was
monitored spectrophotometrically as a function of re-
where k10 and k20 are buffer-independent first-order
rate constants and k1b and k2b are buffer-dependent
second-order rate constants. The linear least-square
method was applied to estimate the values of k10, k20,
k1b, and k2b at different pH’s, as summarized in Table II.
The fitting of observed data to Eqs. (3) and (4) seems
reasonably good as demonstrated in the least-squares
calculated values of rate constants k1 cld and k2 cld as
shown in Table I and from the standard deviations as-
sociated with the calculated values of k10, k20, k1b, and
k2b, as shown in Table II.
action time at 300 nm [10]. The values of k1 obs, k2 obs
,
and Eapp were calculated from Eq. (2) by using the non-
linear least-squares technique. The observed data fit to
Eq. (2) reasonably well as evident from a typical plot of
Aobs versus reaction time (t) shown in Fig. 1. The prod-
uct B has been previously characterized as the sole end
product in the cleavage of NCPH under the aqueous
buffer solution of CH3NHOH [10]. A qualitative ex-
perimental evidence for formation of the intermediate
A through the cleavage of ENMBC under the present
The values of k1b and k2b are less reliable as com-
pared to the corresponding values of k10 and k20 be-
cause the maximum contributions of k1b[Am]T and
k2b[Am]T toward k1 obs and k2 obs in Eqs. (3) and (4), re-
spectively (obtained at the maximum values of [Am]T),
are <50%. However, the values of k1b are more reli-
able at lower pH as compared to those at higher pH.
The rate of cyclization of ENMBC to A appears to in-
volve specific base (HO−), general base (CH3NHOH),
and general acid (CH3NH2OH+) catalysis as shown by
Eq. (5).
k1w
k1OHaOH
ENMBC =
→ A
(5)
k1gb CH3NHOH
k1ga CH3NH2OH+
Figure 1 Plot showing the dependence of observed ab-
sorbance (Aobs at 300 nm) versus reaction time (t) for the
cleavage ENMBC at total N-methylhydroxylamine buffer
concentration ([Am]T) = 0.1 M, pH 6.86, and 30◦C. The
solid line is drawn through the data points calculated by the
least-square method using Eq. (2) and parameters listed in
Table I.
Thus, Eqs. (1) and (5) can lead to Eq. (6)
k1 obs = k1w + k1OHaOH
ꢀ
ꢁ
+ k1gb faAm + k1ga faAHm [Am]T
(6)

430
KHAN
Table I Values of Unknown Parameters, k1 obs, k2 obs, and EB, Calculated from Eq. (2)a
c
d
e
k1 obs
(10−4 s−1
k1 cld
k2 obs
(10−4 s−1
k2 cld
Eapp
(M−1 cm−1
Eapp cld
b
pH
[Am]T (M)
A0
)
(10−4 s−1
)
)
(10−4 s−1
)
)
(M−1 cm−1
)
5.86
5.88
5.87
5.87
6.28
6.29
6.28
6.26
6.24
6.66
6.66
6.66
6.66
6.86
6.87
6.89
6.89
6.90g
6.90g
6.90g
6.91g
7.04
7.05
7.05
7.06
7.53
7.53
7.54
7.55
0.10
0.15
0.20
0.25
0.10
0.20
0.30
0.40
0.50
0.10
0.15
0.20
0.25
0.10
0.15
0.20
0.25
0.10
0.15
0.20
0.25
0.10
0.15
0.20
0.25
0.10
0.15
0.20
0.25
0.037
0.063
0.065
0.061
0.017
0.029
0.059
0.054
0.109
0.027
0.044
0.049
0.071
0.028
0.032
0.075
0.088
0.056
0.064
0.100
0.100
0.020
0.045
0.059
0.081
0.060
0.094
0.114
0.148
8.40 0.17 f
9.54 0.25
10.7 0.2
12.7 0.4
17.1 1.6
23.6 1.2
26.1 3.0
27.9 1.9
32.2 2.7
30.5 1.7
33.6 2.0
35.0 1.4
31.2 1.7
44.7 1.6
41.6 0.9
42.9 2.9
42.1 2.3
45.4 1.4
49.0 1.8
54.2 2.2
53.6 2.1
64.3 2.3
69.4 3.2
68.5 3.4
71.3 1.9
8.23
9.63
11.0
12.4
18.5
21.9
25.4
28.8
32.3
32.1
32.4
32.8
33.1
43.8
43.1
42.5
41.8
46.1
49.1
52.0
55.1
65.4
67.4
69.4
71.4
186
3.70 0.27 f
4.11 0.39
4.22 0.61
4.22 0.61
5.62 0.38
5.70 0.22
6.45 0.68
5.81 0.35
6.81 0.52
7.23 0.36
7.58 0.44
9.65 0.34
11.2 0.6
10.2 0.4
12.6 0.2
11.7 0.7
12.6 0.7
9.62 0.22
10.5 0.3
10.8 0.3
11.6 0.3
9.08 0.27
9.99 0.41
13.7 0.5
13.7 0.3
17.4 0.3
18.7 0.3
19.6 0.3
19.5 0.5
3.81
3.98
4.14
4.31
5.58
5.83
6.08
6.33
6.58
6.82
8.22
9.62
11.0
10.8
11.5
12.1
12.7
9.69
10.3
10.9
11.6
8.98
10.7
12.5
14.3
17.7
18.4
19.2
19.9
1499 29 f
1299 31
1133 23
1008 33
1696 107
1231 41
1076 82
815 35
1477
1322
1152
988
1578
1357
1100
870
773 41
685
1743 65
1493 60
1364 37
1282 51
1681 39
1542 22
1420 64
1272 47
1600 31
1384 30
1212 29
1088 25
1735 33
1505 37
1388 40
1147 17
1481 19
1290 11
1073 12
905 15
1687
1554
1400
1241
1673
1555
1416
1270
1573
1412
1235
1064
1722
1544
1349
1161
1482
1284
1082
900
185
178
182
166
5
3
4
5
180
175
172
a Unless otherwise noted conditions: [NCPH]0 = [X]0 = 3.2 × 10−4 M; ionic strength 1.0 M (maintained by KCl); 30◦C; ꢀ = 300 nm; the
aqueous solvent for each kinetic run contained 1.6% v/v CH3CN.
b [Am]T (=[CH3NHOH] + [CH3NH2OH+]) is total N-methylhydroxylamine buffer concentration.
c Calculated from Eq. (3) as described in the text.
d Calculated from Eq. (4) as described in the text.
e Calculated from Eq. (9) with empirical parameters, Ea0pp and K, listed in Table III.
f
Error limits are standard deviations.
e Conditions: [NCPH]0 = [X]0 = 6.4 × 10−4 M; ionic strength 1.0 M (maintained by KCl); 30◦C; ꢀ = 300 nm; the aqueous solvent for each
kinetic run contained 3.2% v/v CH3CN.
where [Am]T = [CH3NHOH]
+
[CH3NH2OH+],
(=3.96 × 103 M−2 s−1) gave 103 k1ga = 2.28 M−1 s−1
with pKaAm = 6.24 [11].
Am
faAm = KaAm/(aH + KaAm),
f
= 1 − faAm
,
and
aH
KaAm = ([CH3NHOH]aH)/[CH3NH2OH+]. Compari-
The values of k2b, although not very reliable as con-
cluded earlier in the text, seem to follow a kinetic equa-
tion similar to Eq. (8) with the replacement of k1b,
k1gb, and k1ga by k2b, k2gb, and k2ga, respectively, where
k2ga = 0. The calculated values of k2b gave the value
son of Eqs. (3) and (6) gives
k10 = k1w + k1OHaOH
(7)
(8)
k1b = k1gb faAm + k1ga faAHm
of k2gb as (2.01 1.38) × 10−3 M−1 s−1
.
The values of Eapp show a decrease with the increase
in [Am]T at a constant pH (Table I). These data were
found to fit to the following empirical equation
Although most of the k1b values are unreliable as men-
tioned earlier, a linear plot of k1b/ faAm versus aH yielded
103 k1gb = 3.95
1.75 M−1 s−1 and k1ga/KaAm
=
ꢂꢀ
ꢁ
Eapp = Ea0pp 1 + K[Am]T2
(9)
(3.96 2.65) × 103 M−2
s
−1. The value of k1ga/KaAm

FORMATION OF o-CARBOXY(N-METHYL)BENZOHYDROXAMIC ACID
431
Table II Values of Buffer-Independent First-Order Rate Constants, k10 and k20, and Buffer-Dependent Second-Order
Rate Constants, k1b and k2b, Calculated from Eqs. (3) and (4)a
b
d
k10
(10−4 s−1
k10 cld
k1b
(10−4 M−1
k20
(10−4 s−1
k20 cld
k2b
c
e
pH
)
(10−4 s−1
)
s
−1) 100Y1
)
(10−4 s−1
)
(10−4 M−1 −1) 100Y2
s
N-Methylhydroxylamine buffer
5.87 0.01 5.41 0.54 f
6.27 0.02 15.0 1.5
6.66 0.00 31.4 4.1
6.88 0.02 45.1 2.2
42.8 1.4
6.67
12.0
25.0
28.1 3.0 f
34.5 4.5
7.0 22.4
−13 12
0
59.6 16.9
40.2 15.5
−106 52
0
56
53
5
3.48 0.24 f
5.33 0.40
4.02 0.91
9.57 1.6
3.44
3.87
4.93
6.10
3.33 1.32 f
2.49 1.26
28.0 4.9
12.6 8.6
19
19
64
25
39.4
41.1
56.8
0
27
14
6.90 0.01 40.1 3.1
7.05 0.01 61.3 2.9
8.45 0.28
5.47 1.8
16.3 0.8
6.24
7.52
16.6
12.5 1.5
35.1 9.6
14.4 4.5
27
62
18
7.54 0.01
196 10
178
8
169
0
Acetate buffer
5.45 0.01
6.97 0.66
(4.46)g
7.01 0.45
(4.38)
9.90 1.29
(7.11)
20.9 1.1
20.1 0.7
20.6 2.1
73
72
65
2.15 0.09
(1.87)g
2.53 0.06
(2.11)
3.63 0.43
(3.03)
0.43 0.15
1.64 0.10
3.02 0.69
15
37
43
4.47
5.31
6.76
3.26
3.33
3.49
5.66 0.06
5.88 0.08
Phosphate buffer
6.84 0.11 35.0 3.2
(33.6)
160 10
351 48
69
69
5.65 0.70
(5.01)
3.62 2.96
(2.88)
48.8 2.1
97.1 8.9
81
93
36.2
94.3
5.84
7.28 0.16
75.2 16.1
(73.7)
a Reaction conditions are described in Tables I and IV.
b Calculated from the relationship k1 cld = k1w + k1OHaOH with 104 k1w = 3.13 s−1 and 10−4 k1OH = 3.31 M−1 s−1 as described in the
text.
c Y1 = k1b [Buf]Tmax/(k10 + k1b [Buf]mT ax) where [Buf]mT ax represents the maximum total buffer concentration attained in the study.
d Calculated from the relationship k2 cld = k2w + k2OHaOH with 104 k2w = 3.15 s−1 and 10−4 k2OH = 0.270 M−1 s−1 as described in the text.
e Y2 = k2b [Buf]Tmax/(k20 + k2b [Buf]mT ax) where [Buf]mT ax represents the maximum total buffer concentration attained in the study.
f
Error limits are standard deviations.
g Parenthesized values stand for corrected k or k where k = k10 − (k1gb f Am + k )[Am]T with [Am]T = 0.1 M and 0.04 M for
cor
10
cor
20
cor
10
Am
1ga
acetate and phosphate buffer, respectively; kcor = k20 − k2gb faAm[Am]T with [Am]Ta= 0.1 M and 0.04 M for acetate and phosphate buffer,
20
respectively.
where Ea0pp and K are empirical constants. The non-
linear least-squares technique was used to calculate
Ea0pp and K and these calculated values at different
pH are summarized in Table III. Although the data
seem to fit to Eq. (9) reasonably well as evident from
the least-squares calculated values of Eapp shown in
Table I as Eapp cld and from the standard deviations as-
sociated with the values of Ea0pp and K (Table III), the
absolute magnitude of K at different pH are not very
reliable for the fact that the maximum contributions of
K[Am]2T toward 1 + K[Am]2T in Eq. (9) are <50% at
all pH values except at pH 6.27 where it is nearly 60%.
This notion may be seen in the values of K at pH 6.88
and 6.90, which differ from each other by nearly 50%
(Table III).
following reaction paths in the title reaction.
k1 obs
k2 obs
ENMBC
A
B
2
K [Am]T
CH3
N
O
C
OH
OH
(10)
N
C
O
CH3
C
where [Am]T = [CH3NHOH] + [CH3NH2OH+] and C
exists in a fast equilibrium with A during the course of
the reaction (i.e. ka[Am]2T ꢁ k2 obs and k−a ꢁ k1 obs with
The decrease in Eapp with increase in [Am]T at a
constant pH may be attributed to the occurrence of the

432
KHAN
Table III Values of Unknown Parameters, E0app and K, at Different pH, Calculated from Eq. (9)a
pH
Ea0pp (M−1 cm−1 K (M−2 K1 (M−1
N-Methylhydroxylamine bufferb
)
)
)
K2 (M−1
)
5.87 0.01c
6.27 0.02
6.66 0.00
6.88 0.02
6.90 0.01
7.05 0.01
7.54 0.01
1631 35c
10.4 0.6c
5.7 0.6
1669 104
1812 80
1780 13
1731 43
1896 49
1690 11
7.4 0.1.3
6.4 0.2
10.0 0.7
10.1 0.8
14.0 0.2
Acetate bufferd
5.45 0.01
1914 57
(1712 52)e
2062 35
(1891 48)
2035 18
2.71 0.30c
(1.59 0.12)e
1.93 0.15
(1.14 0.08)
0.55 0.05
0.56 0.08c
0.58 0.06
5.66 0.06
5.88 0.08
−0.13 0.08
(2062 15)
(0.64 0.02)
Phosphate buffer f
6.84 0.11
7.28 0.16
(3180 81)
(2932 58)
(0.49 0.10)
(0.22 0.07)
a Reaction conditions are described in Tables I and IV.
b The values of Ea0pp and K were calculated from Eq. (9) as described in the text.
c Error limits are standard deviations.
d The values of Ea0pp, K1 and K2 were calculated from Eq. (22) as described in the text.
e Parenthesized values were calculated from Eq. (23).
f
The values of Ea0pp and K1 were calculated from Eq. (23) as described in the text.
ka/k = K). The formation of A from ENMBC and
(EB − EENMBC)[B]. As concluded earlier, EB ≈
EENMBC and also EA ꢁ EENMBC at 300 nm and these
conclusions lead to the relationship
−a
C involves hydroxide-ion-catalyzed intramolecular
nucleophilic addition–elimination mechanism and the
rates of such reactions are highly sensitive and
almost insensitive to the pKa of conjugate acids
of leaving groups and nucleophiles, respectively
[2,5,12,13]. The value of second-order rate constant
for hydroxide-ion-catalyzed cyclization reaction of o-
(N-hydroxycarbamoyl)benzohydroxamicacidis∼1 ×
107 M−1 s−1 at30◦C[5]. ThevaluesofpKa ofconjugate
acids of leaving groups in the cyclization reactions of C
and o-(N-hydroxycarbamoyl)benzohydroxamic acid
Aobs = EA[A] + EENMBC[X]0.
(11)
But Eq. (10) shows that [A]T = [A] + [C] and hence
ꢂꢀ
ꢁ
[A] = [A]T 1 + K[Am]T2
(12)
Thus, Eqs. (10), (11), and (12) lead to Eq. (2), with
Eapp represented by Eq. (9) where Ea0pp = EA. It is
thus apparent that Ea0pp should be independent of pH
because it is the molar absorption coefficient of A. The
values of Ea0pp are almost independent of pH (Table III).
Although reasonably good fit of observed data to
Eq. (9) indicates the occurrence of general acid–base
(GA–GB) catalysis in N-methylhydroxylaminolysis of
A, i.e. ka step (formation of C from A) in Eq. (10), it is
further supported by the significant effect of the con-
centration of acetate buffer on Eapp at a constant value
of [Am]T (=0.1 M) and pH. The occurrence of GA–
GB catalysis in ka step [Eq. (10)] is conceivable for
the reason that these catalyses have been found to oc-
cur in the reaction of CH3NHOH with NCPH [9,10]
and both NCPH and A are highly and almost equally
reactive toward nucleophile HO−. Despite an earlier
should be nearly same and hence k ≈ 7.4 × 10−2 s−1
−a
at pH 5.87, which is nearly 100-fold larger than k1 obs at
pH 5.87 (Table I). An approximate value of k−a(7.4 ×
10−2
s
−1) and the value of K = 10.4 M−2 (Table III)
give ka[Am]2T ≥ 7.4 × 10−3 s−1 at [Am]T ≥ 0.1 M and
pH 5.87, which is approximately ≥20-fold larger than
k2 obs (Table I). The value of ka[Am]2T = 7.4 × 10−3 s−1
at [Am]T = 0.1 M and pH 5.87 may be compared
with kobs = 5.9 × 10−2 s−1 obtained for the reaction
of NCPH with CH3NHOH in N-methylhydroxylamine
buffer ([Am]T = 0.1 M) of pH 5.80 [9].
In view of Eq. (10), Aobs = EENMBC[ENMBC] +
EA[A] + EB[B] and [X]0 = [ENMBC] + [A] + [B].
Thus, Aobs = EENMBC[X]0 + (EA − EENMBC)[A] +

FORMATION OF o-CARBOXY(N-METHYL)BENZOHYDROXAMIC ACID
433
conclusion that K values are not very reliable, an at-
tempt has been made to analyze K values in terms of
conceivable mechanism(s). The most plausible mecha-
nism for the term K[Am]T2 in Eq. (9) is the occurrence
of GB catalysis in ka step (i.e. the formation of C from
A) and specific base (SB) catalysis in k−a step (i.e. the
formation of A from C). The occurrence of such GB
and SB catalysis in respect to ka and k−a steps predict a
linear plot of K(aH + Ka)2 versus aH with slope =(kgb
KaAm KaAm)/(ksb Kw), where kgb and ksb represent GB-
catalyzed third-order and SB-catalyzed second-order
rate constants, respectively. Such a plot did appear to
be linear within the pH range of 5.87–6.90, with some
significant scattering in the observed and calculated
data points. The value of K at pH 7.54 showed ex-
tremely large positive deviation from the theoretical
line. The slope [=(kgb KaAm KaAm)/(ksb Kw)] of the linear
shown in Table IV, were found to fit to Eqs. (3) and
(4), respectively, with [Am]T replaced by [Buf]T. The
least-squares calculated values of k10, k1b, k20, and k2b
at different pH are summarized in Table II. The extent
of reliability of the fit of observed data to Eqs. (3) and
(4) is evident from the least-squares calculated values
of rate constants k1 cld and k2 cld (Table IV) and from
the standard deviations associated with the calculated
parameters k10, k1b, k20, and k2b (Table II).
The rate of formation of A from ENMBC and B
from A in the presence of [Am]T and [Buf]T(=[BH] +
[B−], where BH and B− represent respective acid and
base components of buffer) may be given by Eqs. (14)
and (15), respectively.
Rate1 = (k1w + k1OHaOH + k1gb[Am] + k1ga[AmH+]
+ k1ꢂ gb[B−] + k1ꢂ ga[BH])[ENMBC]
Rate2 = (k2w + k2OHaOH + k2gb[Am] + k2ꢂ gb[B−]
+ k2ꢂ ga[BH])[A]
(14)
plot turned out to be (26.0 3.6) × 10−6
M
−1, which
gives kgb = 8 M−2 s−1 with ksb = 1 × 107 M−1 s−1 [5],
pKaAm = 6.24, and pKw = 14. Although the value of kgb
of 8 M−2 s−1 is expected to contain large uncertainty,
it is not inconceivable in view of the reported value of
kgb of 54 M−2 s−1 for the GB-catalyzed formation of
ENMBC from NCPH in the presence of CH3NHOH
buffer [9].
An alternative reaction scheme as shown by Eq. (13)
and suggested in the earlier report [9], to explain the
effects of [Am]T on Eapp, may be ruled out for the
following reasons. It can be easily shown
(15)
Thus, Eqs. (1), (14), and (15) can lead to Eqs. (16) and
(17)
ꢀ
ꢁ
k1 obs = k1w + k1OHaOH + k1gb faAm + k1ga faAHm [Am]T
ꢀ
Bufꢁ
+ k1ꢂ gb faBuf + k1ꢂ ga faH [Buf]T
(16)
k2 obs = k2w + k2OHaOH + k2gb faAm[Am]T
ꢀ
Bufꢁ
+ k2ꢂ gb faBuf + k2ꢂ ga faH [Buf]T
(17)
k1
k2 obs
ENMBC
A
B
B
where [Buf]T = [BH] + [B−], faBuf = KaBH/(aH
+
(13)
BH
aH
KaBH), f
= 1 − faBH, and KaBH = ([B−]aH)/[BH].
k3 [Am]T
Comparison of respective Eqs. (3) and (4) with (16)
and (17) gives
that Eq. (13) can lead to the relationships (i) k1 obs
=
k1 + k3[Am]T and (ii) Eapp = Ea0pp/(1 + (k3/k1)[Am]T).
But the relationship (ii) is not exactly similar to Eq. (9)
and the ratio k3/k1 [≡k1b/k10 in view of Eq. (3)] should
be negligible at pH ≥ 6.66. Thus, Eapp should be in-
dependent of [Am]T at pH ≥ 6.66 but such prediction
does not agree with Eapp values summarized in Table I.
k10 = k1w + k1OHaOH
ꢀ
ꢁ
+ k1gb faAm + k1ga faAHm [Am]T
(18)
(19)
k1b = k1ꢂ gb faBuf + k1ꢂ ga
f
aH
Buf
k20 = k2w + k2OHaOH + k2gb faAm[Am]T (20)
k2b = k2ꢂ gb faBuf + k2ꢂ ga
f
(21)
Buf
aH
Effects of Acetate and Phosphate Buffers
The values of k1b for acetate buffer show that
the values of k1b/ faBuf increase from 21.9 × 10−4 to
24.4 × 10−4 M−1 s−1 with the decrease in pH from
5.88 to 5.45. The linear plot of k1b/ faBuf versus aH gave
intercept (=k1ꢂ gb) and slope (=k1ꢂ ga/KaBH) as (20.1
(Buf) on k1 obs, k2 obs, and E
in the
app
Presence of a Constant Value of [Am]T
Five kinetic runs were carried out within the to-
tal buffer concentration ([Buf]T) range of ≥0.08 to
≤0.90 M at a constant pH, [Am]T(=[CH3NHOH] +
[CH3NH2OH+]), and temperature (30◦C). Such ob-
servations were obtained at different pH ranging from
≥5.45 to ≤7.28 for both acetate and phosphate buffers.
Pseudo-first-order rate constants k1 obs and k2 obs, as
0.9) × 10−4 M−1 s−1 and 116 34 M−2
s
−1, respec-
tively. The value of k1ꢂ ga/KaBH is less reliable for the
fact that it is associated with considerably large stan-
dard deviation (∼30%), and the maximum contribution
of (k1ꢂ ga/KaBH) aH toward k1b/ faBuf in Eq. (19), obtained

434
KHAN
Table IV Values of Unknown Parameters, k1 obs, k2 obs, and Eapp, Calculated from Eq. (2)a
c
d
e
b
k1 obs
(10−4 s−1
k1 cld
k2 obs
(10−4 s−1
k2 cld
Eapp
(M−1 cm−1
Eapp cld
[Buf]T
(M)
pH
A0
)
(10−4 s−1
)
)
(10−4 s−1
)
)
(M−1 cm−1
)
Acetate buffer f
5.44
5.45
5.44
5.45
5.45
5.58
5.64
5.67
5.72
5.71
5.75
5.88
5.91
5.94
5.94
0.15
0.45
0.60
0.75
0.90
0.15
0.45
0.60
0.75
0.90
0.15
0.45
0.60
0.75
0.90
0.060
0.077
0.081
0.100
0.068
0.050
0.050
0.047
0.072
0.054
0.046
0.062
0.063
0.076
0.046
10.2 1.2g
16.5 2.0
19.5 1.9
21.8 2.2
26.4 1.8
9.92 0.80
16.2 1.1
19.4 1.2
21.5 1.5
25.3 1.4
13.3 1.0
18.5 1.3
23.2 1.6
23.9 1.5
29.3 1.8
10.1
16.4
19.5
22.6
25.8
10.0
16.1
19.1
22.1
25.1
13.0
19.2
22.3
25.3
28.4
2.19 0.27g
2.34 0.26
2.43 0.23
2.58 0.24
2.44 0.23
2.74 0.21
3.30 0.18
3.53 0.19
3.82 0.22
3.94 0.19
3.82 0.27
5.42 0.30
5.32 0.32
6.20 0.32
6.02 0.34
2.22
2.34
2.41
2.47
2.54
2.78
3.27
3.52
3.76
4.01
4.08
4.99
5.45
5.90
6.35
1392 115g
965 68
1392
(1382)h
969
(997)
863
(875)
787
(780)
730
(703)
1629
(1616)
1222
(1251)
1110
(1125)
1027
(1021)
964
(935)
1876
(1881)
1609
(1601)
1495
(1499)
1393
(1393)
1299
(1308)
873 47
779 42
732 28
1629 97
1219 54
1117 42
1020 42
966 31
1875 132
1616 80
1488 69
1391 58
1302 49
Phosphate bufferi
6.66
6.81
6.87
6.91
6.95
7.01
7.26
7.32
7.37
7.42
0.08
0.24
0.32
0.40
0.48
0.08
0.24
0.32
0.40
0.48
0.092
0.134
0.151
0.186
0.210
0.096
0.144
0.173
0.191
0.226
50.3 1.0
70.0 0.6
84.6 1.4
47.9
73.5
86.3
99.2
112
103
160
188
216
244
9.73 0.20
17.5 0.1
21.0 0.3
24.4 0.4
29.8 0.5
13.2 0.1
25.8 0.2
32.8 0.3
40.4 0.4
53.4 2.2
9.55
17.4
21.3
25.2
29.1
11.4
26.9
34.7
42.4
50.2
3009 42
2926 17
2772 30
2644 34
2520 31
2877 13
2806 14
2743 21
2620 15
2692 81
(3059)
(2843)
(2745)
(2655)
(2570)
(2880)
(2783)
(2736)
(2691)
(2648)
101
113
105
152
184
237
2
2
1
1
3
3
232 13
a Conditions: [NCPH]0 = [X]0 = 5.6 × 10−4 M; ionic strength 1.0 M (maintained by KCl); 30◦C; ꢀ = 300 nm; the aqueous solvent for each
kinetic run contained 1.6% v/v CH3CN.
b [Buf]T(=[B−] + [BH] where B− = acetate anion or phosphate di-anion and BH = acetic acid or phosphate mono-anion) is total buffer
concentration.
c Calculated from Eq. (3) as described in the text.
d Calculated from Eq. (4) as described in the text.
e Calculated from Eq. (22) with empirical parameters Ea0pp, K1, and K2 listed in Table III.
f
Acetate buffer contains 0.1 M CH3NHOH for each kinetic run.
g Error limits are standard deviations.
h Parenthesized values were calculated from Eq. (23) with empirical parameters Ea0pp and K1, listed in Table III.
i Phosphate buffer contains 0.04 M CH3NHOH for each kinetic run.

FORMATION OF o-CARBOXY(N-METHYL)BENZOHYDROXAMIC ACID
435
at the lowest pH 5.45, is only ∼20%. However, the
shows that it is not statistically different from zero.
sb
value of k1ꢂ ga/KaBH (=116 M−2
s
−1) gave 104 k1ꢂ ga
=
The value of kꢂ2gb turned out to be (3.33 1.34) ×
24.2 M−1
s
−1, with pKaBH = 4.68 [10]. The values of
104 M−2 s−1 for acetate buffer with k2ꢂ gb = 0. A gen-
eral mechanism for catalyzed formation of B from A
k1b/ faBuf increase with the increaseꢂin pH, which show
sb
Buf
aH
the absence of GA catalysis (i.e. k1ga
f
≈ 0 in Eq.
may be shown in Scheme 2 where kꢂ2gb = 0 for N-
(19)) in the presence of phosphate buffer. These data
methylhydroxylamine buffer.
sb
suggest the presence of GB–SB catalyzed term k1ꢂ gb
The values of Eapp show a considerably large and
small decrease with the increase in [Buf]T for acetate
and phosphate buffer, respectively, at a constant pH and
[Am]T (Table IV). The reaction mechanism for k−a step
in Eq. (10) (i.e. the reaction step involving the forma-
tion of A from C) may be expected to be similar to that
for k1 obs step in Eq. (10) (i.e. the reaction step involv-
ing the formation of A from ENMBC) in the presence
of the same buffer. Similarly ka step in Eq. (10) (i.e.
the reaction step involving the formation of C from A)
should involve GB catalysis for the nucleophilic reac-
tion of CH3NHOH with A to form C. These probable
mechanisms, involved in forward reaction (i.e. ka step)
[B−] [HO−] [ENMBC] in the rate law for the forma-
tion of A from ENMBC. Although 2 data points linear
plot cannot give reliable values of intercept and slope,
significantly larger value of k1b/ faBuf (=0.0399 M−1 at
pH 7.28 than that at pH 6.84 (k1b/ faBuf = 0.0221 M−1
s
−1) asserts the definite existence of both k1ꢂ gb [B−]
sb
[ENMBC] and kꢂ1gb [B−] [HO−] [ENMBC] terms in
the rate law for the formation of A from ENMBC.
The most plausible general mechanism for the cat-
alyzed formation of A from ENMBC in the presence
of N-methylhydroxylamine, acetate, and phosphate
sb
buffers may be shown in Scheme 1 where kꢂ1gb = 0
and backward reaction (i.e. k step) of the equilib-
for both N-methylhydroxylamine and acetate buffers
and k1ꢂ ga = 0 for phosphate buffer.
−a
rium process between A and C in Eq. (10), and the
conclusions described earlier in the text may lead to
the relationship between Eapp and [Buf]T at a constant
[Am]T and pH as shown by Eq. (22)
The values of k2b/ faBuf for both acetate and phos-
phate buffers increased with the increase in pH
(Table II). These data show the presence of k2ꢂ gb[B−][A]
sb
and kꢂ2gb [B−][HO−][A] terms in the rate law for the
Ea0pp
K1[Buf]T
1+K2[Buf]T
formation of B from A under both acetate and phos-
Eapp
=
(22)
phate buffers. The linear plots of k2b/ faBuf versus aOH
,
1 +
containingonly3and2datapointsforacetateandphos-
phate buffer, respectively, yielded respective k2ꢂ gb and
where Ea0pp = Eapp at [Buf]T = [Am]T = 0 as well
as K1 and K2 are the functions of rate constants, pH,
and [Am]T. Thus, Ea0pp, K1, and K2 are constants at a
constant pH and [Am]T.
sb
kꢂ2gb as (−9.7 3.3) × 10−5 M−1 s−1 and (5.34
0.61) × 104 M−2 s−1 for acetate buffer as well as
42.5 × 10−4 M−1 s−1 and 3.59 × 104 M−2 ꢂ s−1 for
phosphate buffer. The negative value of k2gb with
∼34% standard deviation for acetate buffer merely
The values of Eapp at different [Buf]T (Buf = acetate
buffer) and at a constant pH and [Am]T(=0.1 M) were
Scheme 1

436
KHAN
Scheme 2
treated with Eq. (22) and the nonlinear least-squares
calculated values of Ea0pp, K1, and K2 are summarized
in Table III. Although the observed data fit reasonably
well to Eq. (22) as evident from the calculated values
of Eapp shown as Eapp cld in Table IV and from the stan-
dard deviations associated with the calculated values
Ea0pp, K1, and K2 (Table III), the values of K2 are less
reliable for the reason that the maximum contribution
of K2[Buf]T is only ∼35% compared to 1 in Eq. (22).
Thus, if K2[Buf]T is negligible compared to 1 under the
present experimental conditions, then Eq. (22) should
reduce to Eq. (23).
the expected mechanisms involved in the forward and
backward reactions of equilibrium process between A
and C in Eq. (10).
The values of k10 and k1co0r (in the presence of acetate
and phosphate buffers) at different pH fit to the rela-
tionshipk10 = k1w + k1OHaOH (whereaOH = 10pH−pK
w
with pKw = 13.84 [14]). The least-squares calculated
values of k1w and k1OH are (3.1
2.9) × 10−4 s−1
and (3.31 1.60) × 104 M−1
s
−1, respectively. The
cor
10
extent of reliability of the linear fit of k10 and k
with a definite intercept is evident from k10 cld values
summarized in Table II. The value of k1w is associ-
ated with considerably large (∼100%) standard devi-
ation and hence it is not reliable. The value of k1OH
is comparable with the corresponding values for re-
lated intramolecular nucleophilic addition–elimination
Ea0pp
Eapp
=
(23)
1 + K1[Buf]T
The values of Ea0pp and K1 were also calculated from
Eq. (23) by the use of nonlinear least-squares technique
and the results obtained are summarized in Table III.
The values of Eapp cld as shown in Table IV are not
significantly different from the corresponding values
of Eapp cld obtained by the use of Eq. (22) (Table IV).
The values of K1, obtained at three different pH, can be
explained in terms of suggested probable mechanisms
which led to derive Eq. (22). The calculated values
of Ea0pp are almost independent of pH which are in
agreement with Eq. (22) or (23).
reactions [5,12].
cor
20
The values of k20 and k
at different pH
(Table II) appeared to fit to the relationship k20
=
k2w + k2OHaOH. The least-squares calculated values of
k2w and k2OH are (3.15 0.67) × 10−4 s−1 and (0.270
0.039) × 104 M−1 s−1, respectively. Both k2w and k2OH
are not significantly different from the correspond-
ing values of kw(=2.6 × 10−4
s
−1) and kOH(=0.20 ×
104 M−1 s−1) for hydrolysis of NCPH [15]. It has been
shown elsewhere [9] that the pKa of conjugate acid of
leaving group in the hydrolysis of A is similar to the
pKa of conjugate acid of leaving group in the hydroly-
sis of NCPH.
An attempt to fit Eapp values for phosphate buffer to
Eq. (22) was unsuccessful probably for the reason that
the change in Eapp with change in [Buf]T from 0.08 to
0.48Misverysmall(TableIV). However, thesedataap-
pear to fit to Eq. (23) as evident from the Eapp cld values
summarized in Table IV. The least-squares calculated
values of Ea0pp and K1 are summarized in Table III. The
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pH 6.84 (K1 = 0.49 M−1) is conceivable in view of

FORMATION OF o-CARBOXY(N-METHYL)BENZOHYDROXAMIC ACID
437
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