Kinetics and mechanism of intramolecular carboxylic acid participation in the hydrolysis of N-methoxyphthalamic acid

Article abstract of DOI:10.1039/b300662j

The rate of formation and disappearance of phthalic anhydride (PAn) intermediate in the aqueous cleavage of N-methoxyphthalamic acid (NMPA) under acidic pH was studied spectrophotometrically in mixed CH₃CN-H₂O solvents. The rate of formation of PAn from NMPA is almost independent of the change in acetonitrile content from 20 to 70% v/v in mixed aqueous solvents. The rate constants for the formation of PAn from NMPA are ～ 10-fold smaller than the corresponding rate constants for the formation of PAn from o-carboxybenzohydroxamic acid (OCBA). These observations are ascribed to the consequence of the occurrence of slightly different mechanisms in these reactions.

Full text of DOI:10.1039/b300662j

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Kinetics and mechanism of intramolecular carboxylic acid
participation in the hydrolysis of N-methoxyphthalamic acid
M. Niyaz Khan* and Azhar Ariffin
Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur,
Malaysia
Received 16th January 2003, Accepted 26th February 2003
First published as an Advance Article on the web 18th March 2003
The rate of formation and disappearance of phthalic anhydride (PAn) intermediate in the aqueous cleavage of
N-methoxyphthalamic acid (NMPA) under acidic pH was studied spectrophotometrically in mixed CH3CN–H2O
solvents. The rate of formation of PAn from NMPA is almost independent of the change in acetonitrile content from
20 to 70% v/v in mixed aqueous solvents. The rate constants for the formation of PAn from NMPA are ∼10-fold
smaller than the corresponding rate constants for the formation of PAn from o-carboxybenzohydroxamic acid
(OCBA). These observations are ascribed to the consequence of the occurrence of slightly different mechanisms in
these reactions.
contrast to this prediction, the value of kobs for the hydrolytic
Introduction
cleavage of OCBA turned out to be more than 10-fold larger
Intramolecular carboxylic acid participation in the hydrolytic
than that of phthalamic acid.12
cleavage of amide bonds has been the subject of much interest
Unexpected and significantly high reactivity of OCBA com-
pared to that of phthalamic acid may be attributed to the pres-
ence of internally hydrogen-bonded complex 2 (where the OH
group of the –NHOH moiety provides intramolecular general
acid catalysis for nucleophilic attack to form 1) or 3 (where the
OH group of the –NHOH moiety provides intramolecular gen-
since the appearance of classic papers on the hydrolysis of
phthalamic acid.1 Major aspects of the mechanism of these
reactions are already well understood.1–11 The brief general
mechanism, involved in these reactions, is shown in Scheme 1.
Pseudo-first-order rate constants (kobs) for hydrolysis of
N-substituted phthalamic and related acids gave negative
eral base assistance to stabilize 1) in the formation of 1 (Scheme
ρ (Hammett reaction constant) and ρ* (Taft reaction con-
1). It is apparent from the structural features of 2 and 3 that the
stant).6–9 † The value of ρ or ρ* for equilibrium constant Kf in
presence of 2 is unlikely while that of 3 is likely in the hydrolytic
Scheme 1 is expected to be positive. Since experimentally
observed value of ρ or ρ* is the sum of ρ or ρ* for Kf and for k,
kgb or kga (Scheme 1) and therefore the observed negative value
of ρ or ρ* reveals that ρ or ρ* value for k, kgb or kga must be
cleavage of N-methoxyphthalamic acid (NMPA) under acidic
pH. Thus, the question whether 2 or 3 is involved in the hydro-
lytic cleavage of OCBA may be resolved by studying the rate of
hydrolysis of NMPA under conditions similar to those used for
negative with sufficiently high absolute magnitude to result in
OCBA. Intramolecular reactions are considered to be the
an overall negative value for observed reaction constant. Based
model reactions for many enzyme-mediated reactions and it is
upon the reported values of ρ or ρ* in all such studies, (at
least to the knowledge of these authors), the value of kobs for
the hydrolytic cleavage of o-carboxybenzohydroxamic acid
(OCBA) should be significantly smaller than that of phthal-
widely believed that enzyme-mediated reactions occur in a
micro reaction environment of considerably low water activity
compared to that of pure water solvent. Thus, the effects of
mixed aqueous–organic solvents on the rates of intramolecular
amic acid under similar experimental conditions. But, in
reactions could provide valuable information regarding the
effects of less hydrated reaction medium of enzyme-mediated
reactions. The present study was initiated with an aim to resolve
whether 2 or 3 is responsible for the unexpected rate enhance-
ment observed in the hydrolytic cleavage of OCBA12 in mixed
aqueous–acetonitrile solvents containing different contents of
acetonitrile.
Experimental
Scheme 1
Materials
N-Methoxyphthalimide (NMEPT) was synthesized from
† A referee has pointed out that the substituent parameters relate to
substituents on aryl and alkyl groups because ρ* has been applied
to ortho substituents
N-hydroxyphthalimide by using standard procedures and its
1
purity was established by the use of H NMR and 13C NMR
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 4 0 4 – 1 4 0 8
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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spectroscopic techniques. All other chemicals used were reagent
grade commercial products. Stock solutions of NMEPT were
frequently prepared in acetonitrile.
in the final phase of the reaction (shown for a typical kinetic
run in Fig. 1), observed in almost all kinetic runs, is in agree-
ment with the reaction scheme shown by eqn. (2). The change in
Aobs due to change in [PAn] during the course of the reaction is
Kinetics
given by eqn. (3) (provided k2obs ≠ k3obs
)
(a) Alkaline hydrolysis of NMEPT in mixed H2O–CH3CN
solvent. The rate of alkaline hydrolysis of N-methoxyphthal-
imide (NMEPT) was studied spectrophotometrically by moni-
toring the disappearance of reactant (NMEPT) as a function of
time at 300 nm. The half-life periods, t1/2, for the formation of
phthalamic and N-substituted phthalamic acids from respective
phthalimide and N-substituted phthalimides, and phthalic acid
from phthalamic and N-substituted phthalamic acids, at 0.1 M
NaOH and 30 ЊC are ∼0.3 s and 17500 h, respectively.13 Simi-
larly, the rate of alkaline hydrolysis of o-carboxybenzohydrox-
amic acid was found to be negligible compared to the rate of
alkaline hydrolysis of N-hydroxyphthalimide.14 Thus, the rate
of alkaline hydrolysis of the immediate hydrolysis product
(N-methoxyphthalamic acid) of NMEPT should be insignifi-
cant compared to the rate of alkaline hydrolysis of NMEPT.
The details of the kinetic procedure may be seen elsewhere.15
Pseudo-first-order rate constants (k1obs) were calculated from
eqn. (1)
Fig. 1 Plot showing the dependence of observed absorbance (Aobs at
310 nm) versus reaction time (t) for the cleavage NMPA at 30 ЊC in
mixed aqueous solution containing 2 × 10Ϫ3 M NMPA, 60% v/v
CH3CN and 0.03 M HCl. The solid line is drawn through the least
squares calculated data points using eqn. (3) and parameters listed in
Table 2.
Aobs = δapp[X]0exp(Ϫ k1obst) ϩ A∞
(1)
using a nonlinear least squares technique considering δapp
(apparent molar absorption coefficient) and A∞ (the absorbance
at t = ∞) as unknown parameters. In eqn. (1), Aobs is the absorb-
ance at any reaction time, t, and [X]0 is the concentration of
NMEPT at t = 0. The observed data fitted well to eqn. (1) for up
to 6–23 half-lives.
(3)
where all the symbols have their usual meanings as described
elsewhere.12,13 The details of the calculation of k2obs, k3obs and
δappЈ from eqn. (3) are also described elsewhere.12,13
The values of k2obs/k3obs change from >1 to <1 with the
change in the % v/v content of CH3CN within its range 20–80%
v/v in mixed aqueous solvent. Thus, at a certain content of
(b) Aqueous cleavage of N-methoxyphthalamic acid
(NMPA) under acidic medium in mixed H2O–CH3CN solvent.
The formation of phthalic anhydride (PAn) as a stable
intermediate in the hydrolysis of phthalamic acid and its
N-substituted derivatives under acidic medium has been
unequivocally ascertained.1,8,11 Thus, the aqueous cleavage of
NMPA under acidic medium is expected to follow an irrevers-
ible consecutive reaction path (eqn. (2))
CH3CN, k2obs/k3obs may be very close to 1 and when k2obs/k3obs
=
1, the change in Aobs due to change in [PAn] as a function of
reaction time, t, is given by
(2)
Aobs = k t [X]0δappЈ exp (Ϫ k t) ϩ A0
(4)
where PA represents phthalic acid, k2obs and k3obs represent
pseudo-first-order rate constants for hydrolysis of NMPA and
PAn, respectively. The values of δ (molar absorption coefficient)
for phthalamic acid, PAn and PA, at 310 nm in pure water
solvent, are ∼20, ∼1000 and ∼20 MϪ1 cmϪ1, respectively.8 Thus,
the rate of formation (k2obs-step) and decay (k3obs-step) of PAn
were easily studied spectrophotometrically at 310 nm in mixed
water–organic solvents.8,11–13
In a typical kinetic run with a total volume of 4.8 ml of the
reaction mixture containing 1.0 ml of 0.01 M N-methoxy-
phthalimide (NMEPT), 0.2 ml of 0.5 M NaOH and required
volume of acetonitrile, the reaction (i.e. hydrolysis of NMEPT)
was allowed to complete a period of more than 50 half-lives at
30 ЊC. The hydrolysis of hydrolytic product (NMPA) of
NMEPT, was then initiated by adding 0.2 ml of 1.25 M HCl to
the reaction mixture. The resulting reaction mixture, having a
total volume of 5.0 ml, contained 2 × 10Ϫ3 M NMPA (assuming
100% conversion of NMEPT to NMPA within a period of >50
half-lives for k1obs-step) and 0.03 M HCl. The change in Aobs at
310 nm was monitored as a function of reaction time, t, using
either a diode-array or Shimadzu UV–visible spectrophoto-
meter.
where k = k2obs = k3obs. The nonlinear least squares technique
may be used to calculate k, δappЈ and A0 from eqn. (4).
Results and discussion
(a) Effects of mixed H2O–CH3CN solvents on the rate of
alkaline hydrolysis of N-methoxyphthalimide (NMEPT). In
order to know an approximate number of half-life periods for
the complete (∼100%) conversion of N-methoxyphthalimide to
NMPA at different contents of CH3CN in mixed aqueous sol-
vents, a few kinetic runs for the hydrolysis of NMEPT were
carried out at 0.001 M NaOH and 30 ЊC in mixed H2O–CH3CN
solvents with CH3CN content range 10–80% v/v. Pseudo-
first-order rate constants (kobs) for hydrolysis of NMEPT
are summarized in Table 1. The nonlinear decrease in kobs with
the increase in CH3CN content is not an unusual observation
for such bimolecular reactions involving a neutral reactant and
a negatively charged reactant (HOϪ). Although theoretical
explanations for solvent effects on rates of organic reactions
are difficult to provide, some qualitative explanations could
be given for such observations.13,16 However, an empirical
approach to provide empirical explanations for such data may
be considered of some importance because of its predictive
power of giving the value of dependent variable (such as rate
constant) at any known value of independent variable (such as
% v/v content of acetonitrile in the present case). The values of
Kinetic data analysis
A monotonic increase in Aobs in the initial phase of the reaction
(hydrolysis of NMPA) followed by a monotonic decrease in Aobs
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Table 1 Effect of [CH3CN] on k1obs, δapp and A∞ calculated from eqn. (1), for the cleavage of NMEPT in an alkaline mediuma
[CH3CN] %, v/v
103 k1obs /sϪ1
δapp /MϪ1 cmϪ1
A∞
tb/ s
103 k1cald c/sϪ1
10
20
30
40
50
60
70
80
78.0 2.8d
62.5 2.0
39.6 1.0
32.0 1.0
24.0 0.8
18.7 1.0
13.3 1.0
12.9 2.0
1783 74d
1694 62
1594 53
1581 44
1590 33
1506 39
1428 47
1132 78
0.059 0.001d
0.064 0.001
0.059 0.002
0.064 0.001
0.065 0.002
0.062 0.003
0.064 0.005
0.085 0.002
363
993
703
1028
728
1248
1248
1248
78.7
58.7
43.7
32.6
24.3
18.1
13.5
10.1
a [NMEPT]0 = 2 × 10Ϫ4 M, [NaOH] = 0.001 M, mixed H2O–CH3CN solvent, 30 ЊC, λ = 300 nm. b Maximum reaction time attained in the kinetic run.
c Calculated from eqn. (5) with k10 = 0.106 sϪ1 and Ψ = 2.93 × 10Ϫ2 (% v/v)Ϫ1 d Error limits are standard deviations.
.
Table 2 Effect of [CH3CN] on k2obs, k3obs and δappЈ, calculated from eqn. (3), for the cleavage of NMPA in an acidic mediuma
b
c
d
[CH3CN] (% v/v)
20
104k2obs /sϪ1
105 k3obs /sϪ1
δappЈ /MϪ1 cmϪ1
A0
Afin
Amax
te /s
105 kobs f /sϪ1
1.21 0.12g
2.61h
576 53g
637
287 30
1960 270g
0.060
0.098
139
9935
637
1080 (610)i
0.060 (0.051)
0.020 (0.014)
0.022 (0.017)
0.013 (0.004)
0.032 (0.017)
0.030 (0.037)
0.030 (0.026)
30
40
50
60
70
80
2.53 0.31
2.47 0.12
2.01 0.10
1.73 0.05
2.15 0.51
1.37 0.12
876 146 (514)
706 51 (379)
653 46 (308)
575 24 (254)
296 66 (217)
295 23 (171)
0.042
0.033
0.032
0.055
0.095
0.261
0.145
0.181
0.204
0.255
0.278
0.327
15880
17040
17164
19670
19735
19670
328
162
90.5
38.8
16.3
6.1
160
9
90.8 5.1
52.0 1.9
16.7 3.9
6.69 0.72
a [NMPA]0 = 2 × 10Ϫ3 M, [HCl] = 0.03 M, mixed H2O–CH3CN solvent, 30 ЊC, λ = 310 nm. b Parenthesized values were obtained by extrapolation of
Aobs values to reaction time t = 0. c These values represent Aobs at maximum reaction time attained in the kinetic run. d Observed maximum
absorbance at 310 nm. e Maximum reaction time attained in the kinetic run. f Pseudo-first-order rate constants, kobs, for hydrolysis of phthalic
anhydride at 0.005 M HCl, and 30 ЊC11 (it should be noted that pseudo-first-order rate constants, kobs, were found to be almost unchanged with
change in [HCl] from 0.005 to 1.0 M in aqueous solvents containing 2 % CH3CN11). g Error limits are standard deviations. h This value of k2 obs was
calculated from the relationship: k2obs = k3obs/χ with 104 k3obs = 63.7 sϪ1 and χ = 24. The value of χ (= 24) was calculated from eqn. (6) (as described in
the text) with Aobs,cor = 0.059, [X]0 = 0.002 M and δappЈ = 1080 MϪ1 cmϪ1
.
i Values in parentheses were obtained from the hydrolysis of phthalic
max
anhydride at 0.005 M HCl and 30 ЊC.11
k1obs fit reasonably well (as is evident from the least squares
calculated values of k1 cald, Table 1) to the following empirical
equation
Aobs,cormax = [X]0 δappЈ χχ/(1 Ϫ χ)
(5)
where χ = k3obs/k2obs and Aobs,cormax = Aobsmax Ϫ A0. Equation (5)
is valid for all values of χ except χ = 1. The rearrangement of
eqn. (5) gives eqns. (6) and (7)
k1obs = k10 exp (Ϫ Ψ [OCS])
where k10 and Ψ are empirical constants and [OCS] = % v/v
content of organic co-solvent (acetonitrile) in mixed aqueous
solvent. The nonlinear least squares calculated values of k10 and
(6)
(7)
Ψ are (106 4 sϪ1) × 10Ϫ3 sϪ1 and (2.93 0.15) × 10Ϫ2 (% v/v)Ϫ1
.
(b) Acidic aqueous cleavage of NMPA in mixed aqueous–
acetonitrile solvents. Several kinetic runs were carried out
within the CH3CN content range 20–80% v/v at 0.03 M HCl
and 30 ЊC. The observed kinetic data (Aobs versus t) were used to
calculate k2obs, k3obs, and δappЈ from eqn. (3) at a most appropri-
ate value of A0. These calculated kinetic parameters at different
contents of CH3CN are summarized in Table 2. Although the
observed data (Aobs versus t) at 20% v/v CH3CN showed a satis-
factory fit to eqn. (3) in terms of per cent residual error, RE
(= 100(Aobs i Ϫ Acalcd i)/Aobs i) with maximum RE value of ∼4%
in the vicinity of the maximum in Aobs versus t profile, the value
The value of χ can be calculated from eqn. (6) if χ > 1 and
eqn. (7) if χ < 1 by the use of the method of iteration18 provided
Aobs,cormax, [X]0 and δappЈ are known. For a typical kinetic run at
20% v/v CH3CN, Aobs,cormax = 0.059 (obtained from the observed
absorbance at tmax and A0 value), [X]0 = 0.002 M and δappЈ =
1080 MϪ1 cmϪ1 (obtained from the extrapolation of the plot
of δappЈ versus % v/v content of CH3CN). These values of
Aobs,cormax, [X]0 and δappЈ were used to calculate χ from eqn. (6)
by using the method of iteration.18 The values of χ (= 24) and
of δappЈ (= 1960 MϪ1 cmϪ1) is rather high compared to δapp
Ј
(= 610 MϪ1 cmϪ1) obtained for hydrolysis of PAn under similar
k3obs (= 637 × 10Ϫ5
s =
Ϫ1, obtained from ref. 18), gave k2obs
experimental conditions. The most obvious cause for this is the
26.1 × 10Ϫ5 sϪ1 which is also showed in Table 2.
max
significantly low value of Aobs
obtained at tmax where tmax is
The values of k2obs are almost independent of CH3CN con-
tent within the range 20–70% v/v. But the value of k2obs at 80%
v/v CH3CN is nearly 40% lower than those obtained at ≤70%
v/v CH3CN. However, k2obs values for the acidic aqueous cleav-
age of OCBA remained almost independent of CH3CN content
within the range 20–80% v/v.12 The values of k3obs are compar-
able with pseudo-first-order rate constants for hydrolysis of
PAn obtained under similar experimental conditions19 (Table
2). The rate constant k3obs decreased by nearly 100-fold while
k2obs remained almost unchanged with the increase in CH3CN
content from 20 to 80% v/v. These observations show that the
defined as the reaction time at which [PAn] becomes maximum
during the course of such consecutive reactions. A low value of
Aobsmax (= 0.139) is due to a significantly large value of k3obs/k2obs
at 20% v/v CH3CN. Perhaps, an alternative kinetic analysis of
these observed data carried out by a procedure described else-
where for similar observations11 may provide a more reliable
value of k2obs
.
For an irreversible first-order consecutive reaction as shown
by eqn. (2), Aobsmax is related to rate constants k2obs and k3obs by
eqn. (5)11,17
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 4 0 4 – 1 4 0 8
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rates of intramolecular and intermolecular nucleophilic reac-
tions involving neutral reactants or reaction sites are almost
insensitive and highly sensitive, respectively, to the change in the
relative permittivity of the reaction medium.
Although the values of δappЈ at different CH3CN contents are
dissimilar to the corresponding δappЈ values obtained from
acidic hydrolysis of PAn, they are, however, not very different
from each other and the trend of variation of δappЈ with the
change in CH3CN content is the same (Table 2). One possible
explanation of this marked dissimilarity is the high sensitivity
of δappЈ values to A0 values. For example, at 40% v/v CH3CN for
NMPA, a change in A0 from 0.020 to 0.025 changed k2obs, k3obs
,
,
,
δappЈ and Σdi2 (where di = Aobs Ϫ Acalcd i) from 23.7 × 10Ϫ5 sϪ1
i
164 × 10Ϫ5 sϪ1, 756 MϪ1 cmϪ1 and 3.57 × 10Ϫ4 to 26.3 × 10Ϫ5 sϪ1
152 × 10Ϫ5
s
Ϫ1, 636 MϪ1 cmϪ1 and 3.65 × 10Ϫ4, respectively.
However, these and similar calculated values show that the
values of k2obs and k3obs are less sensitive to A0 values.
The general mechanism for the acidic cleavage of phthal-
amic, N-substituted phthalamic acids1b,7,8 and related com-
pounds6,9 is shown in Scheme 2. The other probable routes for
the formation of 4 have been ruled out based upon qualitative
Scheme 3
2
conclusions and the k4 -step has been concluded to be the
cannot be completely ruled out. The present data are also not
sufficient to rule out the formation of 4 from T1 (where R = OH)
through a solvent assisted proton switch mechanism. The value
of k2obs for hydrolysis of NMPA should be smaller than that
for hydrolysis of phthalamic acid because of expected negative
value of ρ* and σ*H (= 0.49)20 is significantly smaller than
σ*OMe (= 1.80).20 But the observed value of k2obs for hydrolysis
of NMPA (Table 2) is similar to that for phthalamic acid.13
These results show the possible stabilization of intermediate 4
due to probable internal hydrogen bonding as shown in 3.
rate-determining step.11
Acknowledgements
We wish to thank the Universiti Malaya for financial support
(Vote F0375/2001B and Vote F0718/2002B).
Scheme 2
References
An approximately 10-fold larger value of k2obs for hydrolysis
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as co-operative (also called ‘synergistic’) catalysis where the
oxygen of the –NHOH moiety was proposed to act as a conduit
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molecular nucleophilic attack by anionic oxygen of o-COOϪ
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In view of this proposed mechanism, the value of k2obs for
hydrolysis of OCBA is expected to be larger by only ∼2-fold
(due to a statistical factor of 2) compared to that for hydrolysis
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20 The similarity of
σ*OH and σ*OMe is also evident from the pKa values of a number
of HORNR1R2Hϩ and MeORNR1R2Hϩ acids.21
Thus, nearly 10-fold larger value of k2obs for hydrolysis of
OCBA than that for NMPA indicate the occurrence of a differ-
ent mechanism in the acidic aqueous cleavage of OCBA and
NMPA. The most appropriate mechanisms for the cleavage of
NMPA and OCBA in acidic aqueous medium are shown in
Schemes 2 (where R = OCH3) and 3, respectively. However, the
conversion of T1 to products through the transition state TS1
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 4 0 4 – 1 4 0 8
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 4 0 4 – 1 4 0 8
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