Efficient rate enhancement due to intramolecular general base (IGB) assistance in the hydrolysis of N-(o-hydroxyphenyl)phthalimide

Article abstract of DOI:10.1021/jo0624400

The rates of the hydrolyses of N-(o-hydroxyphenyl)phthalimide (1) and N-(o-methoxyphenyl)phthalimide (2), studied at different pH, show that the hydrolysis of 1 involves intramolecular general base (IGB) assistance where the o-O^- group of ionized 1 acts as IGB and H₂O as the reactant. The rate enhancement due to the IGB-assisted reaction of H ₂O with ionized 1 is >8 × 10⁴-fold. Pseudo-first-order rate constant for the reaction of water with 2 is ～2 × 10³-fold smaller than the first-order rate constant (0.10 s^-1) for pH-independent hydrolysis of 1 within the pH range of 9.60-10.10. Second-order rate constants (k_OH) for hydroxide ion-assisted hydrolysis of ionized 1 and 2 are 3.0 and 29.1 M^-1 s^-1, respectively. The solvent deuterium kinetic isotope effect (dKIE) on the rate of alkaline hydrolysis of 1 and 2 reveals that the respective values of k_OH/k_OD are 0.84 and 0.78, where k_OD represents the second-order rate constant for DO^--assisted cleavage of these imides (1 and 2). The value of k_w^H2O/k _d^D2O is 2.04, with k_w^H2O and k _d^D2O representing pseudo-first-order rate constants for the reactions of ionized 1 with H₂O and D₂O, respectively.

Full text of DOI:10.1021/jo0624400

Efficient Rate Enhancement Due to Intramolecular General Base
(IGB) Assistance in the Hydrolysis of
N-(o-Hydroxyphenyl)phthalimide
Yoke-Leng Sim, Azhar Ariffin, and M. Niyaz Khan*
Department of Chemistry, Faculty of Science, UniVersity of Malaya, 50603 Kuala Lumpur, Malaysia
niyaz@um.edu.my
ReceiVed NoVember 27, 2006
The rates of the hydrolyses of N-(o-hydroxyphenyl)phthalimide (1) and N-(o-methoxyphenyl)phthalimide
(2), studied at different pH, show that the hydrolysis of 1 involves intramolecular general base (IGB)
assistance where the o-O- group of ionized 1 acts as IGB and H2O as the reactant. The rate enhancement
due to the IGB-assisted reaction of H2O with ionized 1 is >8 × 104-fold. Pseudo-first-order rate constant
for the reaction of water with 2 is ∼2 × 103-fold smaller than the first-order rate constant (0.10 s-1) for
pH-independent hydrolysis of 1 within the pH range of 9.60-10.10. Second-order rate constants (kOH
)
for hydroxide ion-assisted hydrolysis of ionized 1 and 2 are 3.0 and 29.1 M-1 s-1, respectively. The
solvent deuterium kinetic isotope effect (dKIE) on the rate of alkaline hydrolysis of 1 and 2 reveals that
the respective values of kOH/kOD are 0.84 and 0.78, where kOD represents the second-order rate constant
D2O
H2O
for DO--assisted cleavage of these imides (1 and 2). The value of kwH O/kd
is 2.04, with kw
and
2
D2O
kd
representing pseudo-first-order rate constants for the reactions of ionized 1 with H2O and D2O,
respectively.
Introduction
many IGA-assisted reactions where EM values for more efficient
IGA-assisted reactions range from 103 to 105 M. The value of
EM for IGB-assisted hydrolysis of phenyl salicylate, where the
o-O- group acts as IGB, is ∼106 EM.8 We have been studying
the mechanistic aspects of GA-GB catalysis in addition-
elimination reactions where the leaving groups do not have free
rotation around the bond being cleaved in the rate-determining
step.9 In the continuation of such study, we have investigated
Intramolecular or induced intramolecular general acid (IGA)-,
general base (IGB)-, and coupled IGA-IGB-assisted rate
enhancements have been the subject of active study since the
awareness of the fact that such rate enhancements are the
essential part of the mechanism of action of many enzymes.
The efficiency of intramolecular reactions is generally measured
by the effective molarity (EM), which is the ratio of the
unimolecular rate constant (k1) for the intramolecular reaction
to that (k2) of the analogous (i.e., reference) bimolecular
reaction.1 Intramolecular general acid-base-assisted rate en-
hancement is intrinsically inefficient: EMs ranging from 1 to
10 M only.1 Pascal has argued the low effective molarity of
IGA-IGB assistance in terms of induced intramolecularity in
the reference reaction.2 Kirby and co-workers3-7 have studied
(3) Brown, C. J.; Kirby, A. J. J. Chem. Soc., Perkin Trans. 2 1997, 1081.
(4) Barber, S. E.; Dean, K. E. S.; Kirby, A. J. Can. J. Chem. 1999, 77,
792.
(5) Brown, C. J.; Kirby, A. J. J. Chem. Soc., Chem. Commun. 1996,
2355.
(6) Kirby, A. J.; Parkinson, A. J. Chem. Soc., Chem. Commun. 1994,
707.
(7) Abell, K. W. Y.; Kirby, A. J. J. Chem. Soc., Perkin Trans. 2 1983,
1171.
(8) Khan, M. N. J. Phys. Org. Chem. 1999, 12, 1.
(9) (a) Khan, M. N.; Ohayagha, J. E. J. Phys. Org. Chem. 1991, 4, 547.
(b) Khan, M. N. Int. J. Chem. Kinet. 2002, 34, 95.
(1) Kirby, A. J. AdV. Phys. Org. Chem. 1980, 17, 183.
(2) Pascal, R. J. Phys. Org. Chem. 2002, 15, 566.
10.1021/jo0624400 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/07/2007
2392
J. Org. Chem. 2007, 72, 2392-2401

Hydrolysis of N-(o-Hydroxyphenyl)phthalimide
where R, â, and Φ are empirical constants and [H+] ) 10-pH/γ
with activity coefficient γ ) 0.7 at 1.0 M ionic strength.11 The
nonlinear least-squares calculated values of R, â, and Φ are
(4.84 ( 0.30) × 10-10 M s-1, (-4.9 ( 10) × 10-4 s-1, and
(4.86 ( 0.35) × 10-9 M, respectively. The negative value of â
with standard deviation of more than 200% merely indicates
that the contribution of â[H+] compared to R is insignificant
under the pH range of the study. Thus, the values of R and Φ
were also calculated from eq 2 with â ) 0, and these respective
values are (4.78 ( 0.26) × 10-10 M s-1 and (4.79 ( 0.31) ×
10-9 M. The fitting of observed data to eq 2 is evident from
Figure 1, where a solid line is drawn through the calculated
data points, and also from the values of kcalcd listed in Table A
of Supporting Information.
TABLE 1. Values of k0 and kb, Calculated from Equation 1, for
the Cleavage of 1 Under Buffer of DABCO at pH g9.56a
b
pH
103 k0/s-1
103 kb /M-1 s-1
9.56 ( 0.01c
9.78 ( 0.01
9.90 ( 0.01
10.11 ( 0.01
92.8 ( 1.4c
95.5 ( 2.7
90.2 ( 1.3
95.5 ( 1.6
11.7 ( 2.7c
22.3 ( 5.5
43.7 ( 2.7
44.0 ( 3.1
a [1]0 ) 3 × 10-4 M, 35 °C, λ ) 300 nm, the aqueous reaction mixture
for each kinetic run contained 1% v/v CH3CN. b The values of kb at pH
<9.56 are statistically not different from zero, and total buffer concentration
range is 0.10-0.80 M. c Error limits are standard deviations.
the kinetics of aqueous cleavage of N-(o-hydroxyphenyl)-
phthalimide where the expected IGA (o-OH) or IGB (o-O-)
rate-enhancing group is attached to the leaving group. The
results and probable explanations are described in this paper.
A few kinetic runs for alkaline hydrolysis of 1 were also
carried out within [NaOH] range of 0.0020-0.0500 M, and the
values of kobs, obtained under these conditions, fit to eq 3 with
Results
0
least-squares calculated values of kw and kOH as (96.8 ( 3.0)
× 10-3 s-1 and 3.0 ( 0.1 M-1 s-1, respectively.
Hydrolysis of N-(o-Hydroxyphenyl)phthalimide (1) at
35 °C. A series of kinetic runs was carried out in buffer solutions
of sodium acetate (pH 3.97-5.12), NaH2PO4 (pH 6.08-7.43),
tris(hydroxymethylaminomethane) (TRIS) (pH 7.73-8.26), and
1,4-diazabicyclo[2.2.2]octane (DABCO) (pH 8.43-10.11).
Pseudo-first-order rate constants (kobs) were found to be
independent of total buffer concentration ([Buf]T) at a constant
pH for acetate buffer ([Buf]T range 0.20-0.80 M), phosphate
buffer ([Buf]T range 0.10-0.50 M), TRIS buffer ([Buf]T range
0.20-0.80 M), and DABCO buffer at pH e 9.38 ([Buf]T range
0.10-0.80 M). A mild buffer catalysis is observed in the
kobs ) kw0 + kOH[HO-]
(3)
The satisfactory fit of observed data to eq 3 is evident from the
plot of Figure 1, where a solid line with definite positive
intercept is drawn through the calculated data points. The value
of kw0 (96.8 × 10-3 s-1) is similar to R/Φ (0.10 s-1) calculated
from eq 2.
A few kinetic runs for the reaction of 1 were also carried out
within [HCl] range of 5.0 × 10-3 to 1.0 M. The values of kobs
,
within [HCl] range of 0.08-1.0 M, fit to eq 3 with replacement
of kOH and [HO-] with kH and [HCl], respectively. The linear
least-squares calculated values of kw0 and H+-catalyzed second-
order rate constant, kH, are (1.25 ( 0.07) × 10-6 s-1 and (4.20
( 0.11) × 10-6 M-1 s-1, respectively. The linear dependence
of kobs versus [HCl] may be attributed from hydronium ion-
catalyzed and uncatalyzed hydrolytic paths in the hydrolysis of
1 under such conditions.
presence of DABCO buffers of pH g 9.56. The values of kobs
under such conditions, fit to eq 1
,
kobs ) k0 + kb[Buf]T
(1)
where [Buf]T represents the total buffer concentration of
DABCO. The least-squares calculated values of buffer-indepen-
dent first-order rate constants, k0, and buffer-dependent second-
order rate constants, kb, at pH g 9.56 are summarized in Table
1. Perhaps it is noteworthy that the maximum contribution of
kb[Buf]T in eq 1, obtained at the maximum value of [Buf]T )
0.8 M, is e28% (Table 1), and consequently, the calculated
values of kb in Table 1 may not be considered as very reliable.
Although the values of kb are not reliable for the reason
mentioned earlier in the text, the value of the second-order rate
constant (kbSH) for the reaction of SH with free DABCO amine
base of nearly zero is plausible for the reason that a significant
value of kbSH should have caused perhaps higher values of kb at
pH e9.38 because the decrease in pH increases the value of
Solvent Deuterium Kinetic Isotope Effect (dKIE) on the
Rate of Alkaline Hydrolysis of 1 and 2. The reaction rates
for the cleavage of 1 were studied at 35 °C and within [NaOD]
range of 1.0 × 10-3 to 5.0 × 10-2 M in the solvents with D2O
and acetonitrile contents of 99 and 1% v/v, respectively. The
observed pseudo-first-order rate constants, kobsD, as shown in
Table B of Supporting Information, fit to eq 3 with replacement
of kobs, kw0, kOH, and [HO-] with kobsD, kdD, kOD, and [DO-],
D
respectively. The linear least-squares calculated values of kd
and kOD are (47.4 ( 0.6) × 10-3 s-1 and 3.58 ( 0.02 M-1 s-1
,
0
respectively. The respective values of kw and kOH, obtained
under similar experimental conditions with solvents containing
99% v/v H2O and 1% v/v acetonitrile, are (96.8 ( 3.0) × 10-3
s-1 and 3.0 ( 0.1 M-1 s-1. Similar D2O solvent isotope effect
on the rate of alkaline hydrolysis of 2 was also studied at 35 °C
and within [NaOD] range of 3.0 × 10-3 to 5.0 × 10-3 M in
the solvents with D2O and acetonitrile contents of 98 and 2%
[SH]/[S-] and pKa ) 8.42 and pKa
) 8.95 (Am )
SH
Am
DABCO),10a but under such conditions, the values of kb are
almost zero. These results show the absence of phosphate, TRIS,
and DABCO (at pH e9.38) buffer catalysis in the aqueous
cleavage of 1. We tried to fit the values of kobs, obtained at
different pH ranging from 3.97 to 10.11, as shown in Figure 1,
to the following empirical equation (eq 2)
D
v/v, respectively. The kobs values (Table C of Supporting
Information) were used to calculate kdD and kOD from eq 3 with
replacement of kobs, kw0, kOH, and [HO-] with kobsD, kdD, kOD
,
R + â[H+]
[H+] + Φ
and [DO-], respectively, and the respective calculated values
of kdD and kOD are (-12 ( 10) × 10-3 s-1 and 40.0 ( 2.7 M-1
s-1. The negative value with standard deviation of almost 100%
reveals the insignificant contribution of kdD compared with kOD
kobs
)
(2)
(10) (a) Khan, M. N. J. Chem. Soc., Perkin Trans. 2 1988, 1129. (b)
Khan, M. N. Micellar Catalysis. In Surfactant Science Series; CRC Press,
Taylor & Francis Group, LLC: Boca Raton, FL, 2006; Vol. 133, pp 378-
391. (c) Khan, M. N. J. Chem. Soc., Perkin Trans. 2 1990, 435.
(11) Hine, J.; Via, F. A.; Jensen, J. H. J. Org. Chem. 1971, 36, 2926.
J. Org. Chem, Vol. 72, No. 7, 2007 2393

Sim et al.
FIGURE 1. Plots showing the dependence of log kobs on pH for hydrolysis of 1 (with kobs ) k0 when kb * 0 in eq 1 at different pH) and 2, where
pH ranges 0.16-2.46 (0) maintained by HCl, 3.97-10.11 (9) maintained by buffers, and 10.74-12.31 (4) maintained by NaOH for 1 and pH
ranges 0.16-2.46 (O) maintained by HCl, 7.45-10.06 (b) maintained by buffers, and 10.88-11.41 (2) maintained by NaOH for 2. The solid lines
are drawn through the calculated data points using eq 2 for (9), eq 3 for (0), (4), (b), and (2), and eq 5 for (O) as described in the text. The broken
line is not drawn through the calculated data points but rather drawn arbitrarily.
[NaOD] in eq 3, and hence, a relatively more reliable value of
Since the o-OH group is only five atoms away from the
electrophilic carbonyl carbon, it is quite plausible to think that
pH-independent cleavage of 1 might involve an intramolecular
nucleophilic addition-elimination process, as shown in Scheme
D
kOD (37.5 ( 0.7 M-1 s-1) was obtained from eq 3 with kd
)
0. The value of kOH, obtained under similar experimental
conditions with solvent containing 98% v/v H2O and 2% v/v
acetonitrile, is 29.2 ( 1.9 M-1 s-1
.
D2O
2
1. Such a reaction mechanism predicts kwH O/kd
≈ 1.0, and
D2O
thus, the observed value of kwH O/kd
) 2.04 rules out the
2
The values of kOH/kOD for alkaline hydrolysis of 1 (kOH/kOD
) 0.84) and 2 (kOH/kOD ) 0.78) are consistent with the wide
held perception that DO- (in D2O) reacts faster than HO- (in
H2O) with esters and amides. These values of kOH/kOD are in
agreement with the reported values of kOH/kOD for alkaline
hydrolysis of formamide (kOH/kOD ) 0.77),12 endo-5-[4′(5′)-
imidazolyl]bicyclo[2.2.1]-hept-endo-2-yl trans-cinnamate (B1,
possibility of the occurrence of the reaction mechanism shown
D2O
in Scheme 1. However, a skeptic might argue that kwH O/kd
2
of >1 may be expected if the product in the k21 step is 5 formed
through transition state TS1. If this view is plausible, then it is
difficult to explain the observed unity or slightly inverse solvent
deuterium kinetic isotope effect (dKIE) obtained for alkaline
hydrolysis of esters and amides, including formamide,12,13 where
it is almost certain that expulsion of the leaving group is the
k
OH/kOD ) 1.0),13 endo-[4′(5′)-imidazolyl]bicyclo[2.2.2]-endo-
2-yl trans-cinnamate (B2, kOH/kOD ) 0.95),13 and other simple
amides and esters (kOH/kOD ) 0.71-0.77).12 The values of kOH
OD for the reactions of HO-/DO- with ionized phenyl salicylate
1
/
rate-determining step (similar to the k2 step) in an addition-
k
elimination mechanism for hydrolysis of amides and nonacti-
vated esters, while nucleophilic attack is the rate-determining
step for hydrolysis of activated esters. Although solvent dKIE
does not seem to favor the reaction mechanism shown by
Scheme 1, there is always a significant amount of uncertainty
in the mechanistic conclusion drawn from solvent dKIE.
However, other indirect evidence for the absence of formation
of 5- through reaction steps shown in Scheme 1 may be
described below.
and methyl salicylate are 0.98 and 1.04, respectively.14 Thus, it
seems that the values of kOH/kOD are independent of the nature
(whether nucleophilic attack or expulsion of leaving group) of
the rate-determining steps involved in these addition-elimina-
tion reactions.
D2O
The value of kwH O/kd
()kw0/kdD) ) 2.04 for 1 may be
2
compared with the reported values for hydrolysis of phenyl
salicylate (kwH O/kd
) 1.6,15 1.716), p-nitrophenyl 5-nitro-
D2O
2
salicylate (kwH O/kdD O ) 1.717), catechol monobenzoate (kw
/
H2O
2
2
A brief and plausible reaction scheme for the aqueous
kdD O ) 1.816), and B1 and B2 (kwH O/kdD O ) 3.013), where the
occurrence of intramolecular general base (IGB) assistance has
been strongly supported by some indirect chemical evidence.
2
2
2
cleavage of S- by both hydrolysis (kw step) and O-cyclization
2
(kf step) may be shown in Scheme 2 where kf2, kb , kw2, and
2
kOH represent pseudo-first-order rate constants.
The detailed mechanism for the reaction S- H 5 f 3- is
(12) Slebocka-Tilk, H.; Neverov, A. N.; Brown, R. S. J. Am. Chem. Soc.
2003, 125, 1851 and references cited therein.
(13) Komiyama, M.; Roesel, T. R.; Bender, M. L. Proc. Natl. Acad.
Sci. U.S.A. 1977, 74, 23.
(14) Khan, M. N. J. Chem. Soc., Perkin Trans. 2 1990, 675.
(15) Khan, M. N. J. Chem. Soc., Perkin Trans. 2 1989, 199.
(16) Capon, B.; Ghosh, B. C. J. Chem. Soc. B 1966, 472.
(17) Bender, M. L.; Kezdy, F. J.; Zerner, B. J. Am. Chem. Soc. 1963,
85, 3017.
(18) Shafer, J. A.; Morawetz, H. J. Org. Chem. 1963, 28, 1899.
(19) Fife, T. H.; DeMark, B. R. J. Am. Chem. Soc. 1976, 98, 6978.
(20) Fife, T. H.; Benjamin, B. M. J. Am. Chem. Soc. 1973, 95, 2059.
(21) Khan, M. N. J. Chem. Soc., Perkin Trans. 2 1988, 213.
(22) Khan, M. N.; Ismail, E. J. Phys. Org. Chem. 2004, 17, 376.
shown in Scheme 1, and thus comparing Scheme 2 and Scheme
1
1
1
2
1, kf2 ) k1 k2 /k-1 and kb ) (k-21Ka[HO-])/Kw provided aH
. Ka where Ka ) [5-]aH/[5] and Kw ) aHaOH. If kb2 ) kb′[HO-],
then kb′ ) k-21Ka/Kw. The reported values of kb′ for some related
reactions are shown in Table 2.
The reported data listed in Table 2 demonstrate that the kb′
values are highly sensitive and almost insensitive to the pKa of
conjugate acid of the leaving group anion (pKaLe) and nucleo-
philic anion (pKaNu), respectively. In all these reactions, the
expulsion of the leaving group does not accompany with any
2394 J. Org. Chem., Vol. 72, No. 7, 2007

Hydrolysis of N-(o-Hydroxyphenyl)phthalimide
SCHEME 1
× 10-1 M-1 s-1, respectively. The values of pKa of conjugate
acids of the leaving groups, amide anion, and methoxide ion in
these respective reactions are 14-1525 and ∼15,26 and therefore,
the ratio 27/0.125 ) 216 reflects the rate enhancement due to
release of the five-membered ring strain in the alkaline hy-
drolysis of N-methylphthalimide. The release of the eight-
membered ring strain in the conversion of 5 to 3- may increase
the kOH value but certainly <200-fold because the eight-
membered ring is probably less strained than a five-membered
ring. The value of pKa of 3- is 9.7, which is not significantly
different from pKa of phenol (pKa ) 9.9). Even if the increase
in kOH2 due to release of the eight-membered ring strain is 200-
fold, the value of the pseudo-first-order rate constant (k2) for
SCHEME 2
the concurrent conversion of S- to 3- through the kOH2 step is
2
∼7 × 10-5 to 7 × 10-6 s-1 (k2 ) kOH
,
kf2[HO-]/kb′[HO-],
eff
where kOH
,
) 200 × kOH), which is ∼1.4 × 10-3 to 1.4 ×
2
eff
10-4-fold smaller than kw (0.05 s-1).
2
release of ring strain for the reason that the leaving groups in
these cyclization reactions have free rotation about the bond
being cleaved during the rate-determining step. In view of the
reported values of kb′ and pKaLe in Table 2, it may be reasonable
to assume the value kb′ of 105-106 M-1 s-1 for conversion of
5 to S-.
Furthermore, in a recently published report27 on the intramo-
lecular carboxylic group-assisted cleavage of 3 at 0.05 M HCl,
the reactant 3 was generated in situ from alkaline hydrolysis of
S-, and the rate of reaction was initiated by adding 0.20 mL of
1.25 M HCl to the alkaline reaction mixture (4.80 mL) at ∼100
half-lifes of the reaction, which gave 3 in aqueous acidic solution
containing 0.049 M HCl. One kinetic run was also carried out
at 0.05 M HCl using synthesized 3 as the reactant. In both
reactions (one with synthetic 3 and the other with 3 obtained in
situ from alkaline hydrolysis of S-), the final products were
100% phthalic acid and o-hydroxyaniline. Since product 5
cannot hydrolyze to a significant extent within ∼900 s (equiva-
lent to ∼100 half-lifes for hydrolysis of 1 under a pH range of
9.60-10.11) at pH 9.60, a significant parallel formation of 5
could have caused less than 100% formation of phthalic acid
and o-hydroxyaniline in the acidic aqueous cleavage of 3, where
2
If one assumes arbitrarily an equal contribution of the kw
step and kf2 step in Scheme 2, then the value of kf2 is 0.05 s-1
because kobs ) kw + kf2 ) 0.1 s-1 at pH 9.60. The expected
2
value of kb′ ) 105-106 M-1 s-1 gives kb ) 9-90 s-1 at pH
2
9.60. Thus, [5]/[S-] ) kf2/kb ≈ 5.6 × 10-3 to 5.6 × 10-4 and
2
consequently [5]/([5] + [S-]) ≈ 5.6 × 10-3 to 5.6 × 10-4 at
pH 9.60. This shows the equilibrium presence of 5 and S- as
0.56-0.06% and 99.4-99.9%, respectively. Such a low pres-
ence of 5 (<0.6%) is hard to detect by any spectral method.
Furthermore, the half-life period for irreversible disappearance
2
2
of S- in the kw step (Scheme 2) is only ∼14 s if kw ) 0.05
s-1
.
The expected value of kb′ ()kb /[HO-]) is in the range of
105-106 M-1 s-1, which is nearly 1.5 × 105 to 1.5 × 106-fold
larger than kOH for alkaline hydrolysis of phenyl benzoate (kOH
) 0.68 M-1 s-1). The values of kOH for alkaline hydrolysis of
N-methylphthalimide23 and methyl benzoate24 are 27 and 1.25
2
(23) Ariffin, A.; Khan, M. N. Bull. Korean Chem. Soc. 2005, 26, 1037.
(24) Hegarty, A. F.; Bruice, T. C. J. Am. Chem. Soc. 1970, 92, 6575.
(25) Barlin, G. B.; Perrin, D. D. Quart. ReV. Chem. Soc. 1966, 20, 75.
(26) Hupe, D. J.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 451.
(27) Sim, Y.-L.; Azhar A.; Khan, M. N. Int. J. Chem. Kinet. 2006, 38,
746.
J. Org. Chem, Vol. 72, No. 7, 2007 2395

Sim et al.
2
TABLE 2. Values of kb′ for Cyclization Reactions Related to One in the kb Step of Scheme 2
3 was generated in situ from alkaline hydrolysis of S- because
the rate of H+-assisted hydrolysis is expected to be much slower
than HO--assisted hydrolysis of 5. So it is certain beyond any
reasonable doubt that the immediate detectable hydrolysis
product of S- is 3.
MeNH3+ is 10.85 and pKa of amide group of 5 is e14 at 30 °C
and under similar conditions). Furthermore, the 1H NMR
spectrum of 1 in 100% v/v D2O solvent containing 3.2 × 10-2
M 1 and 8.7 × 10-2 M NaOD obtained quickly turned out to
1
be similar to the H NMR spectrum of authentic 3 obtained
A perfect simple first-order rate law has been found for the
rate of reaction monitored both by disappearance of reactant
(S-) at 300 nm and appearance of product 3 at 320 nm as a
function of reaction time for the reaction period of ∼7.5 half-
lifes for each kinetic run. The value of kobs for the kinetic run
carried out at 300 nm was similar to kobs for the same kinetic
run carried out at 320 nm. The immediate products for these
kinetic runs were also the same in view of similar UV spectra
of authentic 3 and reaction mixtures obtained under similar
experimental conditions at 60-120 s (∼10-20 half-lifes). These
observations support the conclusion that the immediate hy-
drolysis product of S- is 3. In a closely related study on the
aqueous cleavage of N-(2-aminophenyl)phthalimide at pH range
of 0-6, Perry28 could not detect N-cyclization product similar
to O-cyclization product 5 of S-.
under similar conditions. This shows nearly 100% conversion
of 1 to 3 within the time period of obtaining the H NMR
1
spectrum. This is plausible for the fact that 10 half-lifes
(equivalent to ∼99.9% completion of the reaction) for hydrolysis
of 1, under the conditions of obtaining the 1H NMR spectrum,
is equivalent to only ∼70 s. Thus, these observations do not
show the presence of a 1H NMR detectable amount of I1 during
the course of the reaction.
Hydrolysis of N-(o-Methoxyphenyl)phthalimide (2) at
35 °C. The rate of hydrolysis of 2 was studied at different
[NaOH] ranging from 2.0 × 10-3 to 5.0 × 10-3 M, and
observed pseudo-first-order rate constants (kobs) were fit to eq
One of the reviewers suggested that I1 might be equal or even
more stable than S- at basic pH, which is apparently incom-
prehensible in view of the kinetic analysis described earlier in
the text. However, if the assumption that I1 might be equal or
even more stable than S-, then the value of equilibrium constant
3, which resulted in kw and kOH of (-1.4 ( 0.6) × 10-2 s-1
0
1
1
1
and 33.8 ( 1.6 M-1 s-1, respectively. The calculated negative
K1 ()k1 /k-1 in Scheme 1) must be g1 at basic pH. The
experimentally determined value of kobs within pH range of
9.60-10.11 is 0.10 s-1, and under such reaction conditions, kobs
0
value of kw is meaningless, and therefore, kOH was also
calculated from eq 3 with kw0 ) 0, and such a calculated value
of kOH is 29.2 ( 1.9 M-1 s-1. In an attempt to get a reliable
value of kw0, the rate of hydrolysis of 2 was also carried out at
different pH ranging from 7.45 to 10.06 maintained by N-methyl
morpholine and DABCO buffers. The values of kobs at different
total amine buffer concentrations, [Buf]T ([Buf]T range is 0.2-
0.8 M for both N-methyl morpholine and DABCO buffers) fit
to an empirical equation (eq 4)
1
) k2 K11 which gives k21 e 0.10 s-1. The value of k21 of e0.10
s-1 is >1010-fold smaller than rate constant ()3 × 109 s-1) for
the expulsion of methylamine from T,29 which is difficult to
explain in terms of structural features of I1 and T (pKa of
(28) Perry, C. J. J. Chem. Soc., Perkin Trans. 2 1997, 977.
(29) Gresser, M. J.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 6970.
2396 J. Org. Chem., Vol. 72, No. 7, 2007

Hydrolysis of N-(o-Hydroxyphenyl)phthalimide
k0 + kbappK[Buf]T
SCHEME 3
kobs
)
(4)
1 + K[Buf]T
app
where kb represents the apparent buffer-catalyzed pseudo-
first-order rate constant for the cleavage of 2 and K is an
empirical constant (most likely an equilibrium constant for
reactive complex formation between 2 and buffer). The non-
linear least-squares calculated values of k0, kbapp, and K at a
typical pH 8.94 ( 0.03 in DABCO buffer are (1.10 ( 0.09) ×
10-3 s-1, (4.01 ( 0.26) × 10-3 s-1, and 2.40 ( 0.59 M-1
,
respectively. The values of k0 fit to eq 3 where kobs ) k0, [HO-]
where kw ) k2w[H2O], kw′ ) k2w′[H2O], and KaSH ) [S-][H+]/
[SH]. Comparison of eqs 2 and 3 with eq 7 gives â ) kw, R )
) 10pH-pK /γ with pKw ) 13.6230 and activity coefficient, γ )
w
0.70.11 The least-squares calculated values of kw and kOH are
0
SH
kw′Ka + kOHKw′ with Kw′ ) [H+][HO-] and Φ ) KaSH. The
(5.3 ( 7.0) × 10-5 s-1 and 25.3 ( 0.5 M-1 s-1, respectively.
value of KaSH {) Φ ) (4.79 ( 0.31) × 10-9 M} is comparable
to KaSH ()5.33 × 10-9 M) at 35 °C determined independently
by UV spectrophotometric technique. At significantly high pH
where [H+] , KaSH, and kw [H+] , kw′ KaSH, eq 7 reduced to
0
The calculated value of kw with standard deviation of more
0
than 100% merely indicates that the contribution of kw is
insignificant compared with kOH[HO-] in eq 3. Thus, the kOH
0
()29.1 ( 6.7 M-1 s-1) was also calculated from eq 3 with kw
0
SH
eq 8 which is similar to eq 3 with kw ) kw′ + kOH Kw′/Ka
) 0. The satisfactory fit of k0 to eq 3 is evident from the plot
of log kobs versus pH (with kobs ) k0) shown in Figure 1, where
a solid line is drawn through the calculated data points, and
also from kcalcd values summarized in Table D of Supporting
Information.
The rate of aqueous cleavage of 2 has also been studied within
[HCl] range of 0.005-1.0 M. Although some light precipitates
visible to the naked eye appear in the reaction mixtures after
∼0.5 and 4 h at 0.02 and 0.5 M HCl, respectively, the reaction
mixtures remained transparent, and the observed data apparently
fit to eq 9 for the reaction period of g10 half-lifes for all kinetic
runs. The values of kobs followed the following empirical
equation (eq 5)
and kOH ) kOH′.
kobs ) kw′ + kOHKw′/KaSH + kOH′[HO-]
(8)
The kinetic terms k2w′[H2O][S-] and kOH[HO-][SH] in eq 6
are kinetically indistinguishable. However, if these kinetic steps
do not involve an efficient intramolecular assistance/catalysis,
then k2w′[H2O][S-] may be neglected compared to kOH[HO-][SH]
for the fact that, although [H2O] >> [HO-] under the
experimental conditions imposed, HO- is a much stronger
nucleophile than H2O (pKa of H2O is 15.74, while pKa of H3O+
is -1.74). Thus, under this conditions, R ) kOHKw′, and hence
kOH ) R/Kw′ ) 1.0 × 104 M-1 s-1 with 1014 Kw′ ) 4.9 M2.30
The value of kOH ) 1.0 × 104 M-1 s-1 is ∼330-fold larger
than kOH ()30 M-1 s-1) for 2, which cannot be explained in
terms of simple resonance and polar effects of o-OH and o-OMe
0
kw
kobs
)
(5)
1 + K[HCl]
substituents because σ*OH ) σ*OMe ) 1.8131 and σp-OH
)
where kw0 ()kobs at [HCl] ) 0) and K are empirical constants.
-0.3732 as well as σp-OMe ) -0.27.33 Nearly 330-fold larger
value of kOH for 1 than that for 2 demonstrates the occurrence
of intramolecular general acid (IGA)-assisted reaction of HO-
with nonionized 1 ()SH) involving transition state TS2.
However, under such circumstances, the occurrence of kineti-
cally indistinguishable intramolecular general base (IGB)-
assisted reaction of H2O with ionized 1 ()S-) involving
transition state TS3 cannot be ruled out based upon simply much
lower nucleophilicity of H2O compared to that of HO-.
0
The nonlinear least-squares calculated values of kw and K are
(6.20 ( 0.49) × 10-5 s-1 and 3.35 ( 0.96 M-1, respectively.
Discussion
A brief reaction scheme for buffer-independent cleavage of
1 at pH g4 is shown in Scheme 3.
The mechanisms for the k2w step and k2w′ step are similar to
the one shown in Scheme 7 with replacement of X with OH
and O-, respectively. Similarly, the mechanisms for the kOH
step and kOH′ step are similar to the one shown in Scheme 7
with respective replacement of X with o-OH and o-O-. Scheme
3 can lead to the rate law for the aqueous cleavage of 1 at pH
g4 as expressed by eq 6
rate ) k2w[H2O][SH] + k2w′[H2O][S-] + kOH[HO-][SH] +
kOH′[HO-][S-] (6)
where SH and S- represent nonionized and ionized form of 1,
respectively. The observed rate law (rate ) kobs[1]T, where [1]T
) [SH] + [S-]) and eq 6 can lead to eq 7
It is almost impossible to ascertain with absolute certainty
whether transition state TS2 or TS3 is involved in the pH-
(30) Ritchie, C. D.; Wright, D. J.; Huang, D.-S.; Kamego, A. A. J. Am.
Chem. Soc. 1975, 97, 1163.
kw[H+] + kw′KaSH (kOH[H+] + kOH′KaSH)[HO-]
(31) Fastrez, J. J. Am. Chem. Soc. 1977, 99, 7004.
(32) Hine, J. Structural Effects on Equilibria in Organic Chemistry;
Wiley: New York, 1975; pp 98-99.
kobs
)
+
[H+] + KaSH
[H+] + KaSH
(7)
(33) Khan, M. N. J. Mol. Catal. 1987, 40, 195.
J. Org. Chem, Vol. 72, No. 7, 2007 2397

Sim et al.
SCHEME 4
SCHEME 5
SCHEME 6
SCHEME 7
such solvent dKIE could not differentiate between intramolecular
general acid (IGA)-assisted nucleophilic reaction of HO- with
nonionized salicylate esters and IGB-assisted nucleophilic
reaction of H2O with ionized salicylate esters.17,33 However,
other indirect evidence reveals the occurrence of IGB-assisted
hydrolysis of ionized salicylate esters.17,33
(b) The classical way of differentiating between TS2 and TS3
is to use nucleophiles devoid of hydrogen at the nucleophilic
atom (such as R1R2R3N).17,33 Thus, to find out whether TS2 or
TS3 is involved in the hydrolysis of 1, the rates of cleavages of
1 and 2 have been studied in the presence of buffers of DABCO
(pH range 8.43 ( 0.03 to 10.11 ( 0.01 for 1 and 8.84 ( 0.01
to 10.11 ( 0.01 for 2). The values of kobs for the cleavage of 1
remain almost independent of total DABCO buffer concentration
within its range of 0.1-0.8 M at a constant pH e9.38. The
attempt to fit kobs to eq 1 resulted in kb values that were slightly
negative under such conditions. These results show that DABCO
is nonreactive toward the cleavage of 1. However, the values
of kobs for the cleavage of 2 at different total DABCO buffer
concentration ranging from 0.2 to 0.8 M at a constant pH fit to
eq 4. The value of kbapp at constant pH 8.94 ( 0.03 is (4.01 (
0.26) × 10-3 s-1. The absence and presence of DABCO buffer
catalysis in the aqueous cleavage of 1 and 2, respectively,
support the occurrence of IGB assistance (i.e., TS3) in the
reaction of H2O with 1 under alkaline pH.
independent hydrolysis of 1 because both transition states
constitute kinetically indistinguishable kinetic terms in the rate
law. The notion of absolute certainty in almost any scientific
domain, including the reaction mechanism, is difficult to show
with a high degree of confidence. Indirect evidence (both
experimental and theoretical) could be provided to give prefer-
ence to one among alternative transition states or reaction
mechanisms. Such an attempt is described below:
(a) An apparent look at TS2 and TS3 reveals that solvent dKIE
might be used to differentiate between the occurrence of TS2
and TS3. The observed value of kwH O/kdD O ) 2.04 is consistent
with the reaction mechanism involving transition state TS3.
However, if the reaction mechanism involving TS2 in the critical
rate-determining step is assumed to be operative, then kOH/kOD
2
2
However, a skeptic might argue that the reactions of non-
ionized 1 (i.e., SH) with HO- and DABCO involve, most likely,
4
nucleophilic attack (i.e., the k1 step) and expulsion of the
leaving group (i.e., the k24 step) as the rate-determining step in
an addition-elimination mechanism, as shown in Scheme 4.
Intramolecular general acid (IGA)-assisted rate enhancement is
D
()kwHKaHKwD/kd KaDKwH, where KaH and KaD represent ioniza-
tion constant of SH in H2O and D2O, respectively, KwH ) aHaOH
D
and Kw ) aDaOD) will give the measure of the solvent dKIE.
4
D
H
D
Using the values of KwH/Kw ) 6.5,17 Ka /Ka ) 4.2,16 and
expected only when the k1 step is the rate-determining step,
4
kwH/kd ) 2.04, one gets kOH/kOD ) 1.32. The values of kOH
/
D
while such rate enhancement disappears when the k2 step
becomes the rate-determining step. So the absence of IGA
assistance in the reaction of DABCO with SH does not
necessarily negate the presence of TS2. However, this specula-
tive perception is not entirely correct in view of the following
consideration. It has been convincingly shown that the rate of
k
OD for alkaline hydrolysis of esters and amides vary from 0.7
to 1.0.12,13 The calculated value of kOH/kOD ()1.32) for pH-
independent hydrolysis of 1 is slightly higher than the upper
range of kOH/kOD ()1.0), and consequently, it seems that solvent
dKIE is not in the favor of TS2. Perhaps it is noteworthy that
2398 J. Org. Chem., Vol. 72, No. 7, 2007

Hydrolysis of N-(o-Hydroxyphenyl)phthalimide
expulsion of a leaving group from an intermediate like I4
depends upon the pKa of the conjugate acid of the leaving group
and the electronic push provided by the other atoms attached
to the carbon to which the leaving group is also attached.29 It is
apparent from the structural feature of I4 that, although the
magnitudes of k-14 and k24 should be significantly larger in the
presence than in the absence of IGB assistance, the magnitudes
IGB-assisted reaction of H2O with S- involving TS3 is impos-
0
sible because [S-] ≈ 0. Nearly 40-50-fold larger value of kw
for 2 than that for 1 rules out the presence of IGA assistance
involving a transition state similar to TS2 with replacement of
nucleophile from HO- to H2O. As explained earlier, IGA
assistance should be detectable under the condition where either
nucleophilic attack or expulsion of the leaving group is the rate-
determining step. Thus, these observations support the absence
of IGA assistance under both acidic and alkaline pH.
4
of the ratio k2 /k-14 should be same in the presence and absence
of such IGB assistance because the electronic push provided
by OH group in the cleavage of C-Nu and C-N bonds in I4 is
the same. Thus, the IGA assistance is reflected by the value of
The occurrence of IGB assistance makes the kinetic term
k
OH[HO-][SH] insignificant compared to the kinetically indis-
tinguishable kinetic term k2w′[H2O][S-] in eq 6 and consequently
4
4
k1 and not by the value of k2 /k-14. Since experimentally
SH
4
4
R ) kw′Ka ) kw′ Φ. The calculated values of R ()4.78 ×
determined rate constant kb ) k1 if the k1 step is the rate-
10-10 M s-1) and Φ ()4.79 × 10-9 M) from eq 2 give kw′ )
0.10 s-1. The value of kw′ ) 0.10 s-1 is 8 × 104-fold larger
than kw0 ()1.25 × 10-6 s-1), where kw0 represents the pseudo-
first-order rate constant for pH-independent hydrolysis of
nonionized 1 (SH). Perhaps the more accurate rate enhancement
due to IGB-assisted hydrolysis of ionized 1 (S-) should be equal
to kw′(for 1)/kw′(for 6), where 6 represents ionized N-(p-
determining step and kb ) k1 k2 /k-14 if the k24 step is the rate-
determining step, the presence of IGA assistance should increase
the kb value compared to the absence of such assistance
regardless of whether the k14 or k24 step is the rate-determining
4
4
SH
SH
step. Almost zero value of kb (where kb represents the
second-order rate constant for the reaction of DABCO with SH)
app
and significant value of kb (eq 4) for DABCO-catalyzed
hydroxyphenyl)phthalimide. The values of σp-OH, σp-O-, and
cleavage of respective SH and 2 rules out the possibility of
σ+
are -0.37, -0.81 (not very reliable),34 and -2.6,35
-
occurrence of TS2 (i.e., Scheme 4 with Nu- ) HO-).
p-O
respectively. The value of pKa of the 2-hydroxyanilinium ion
is larger than the pKa of the anilinium ion by only 0.03 pK
units,36 which shows that σo-OH ≈ 0. These Hammett substituent
constant values predict that kw′(for 6) < kw0(for SH) provided
F > 0, and consequently, the rate enhancement due to IGB-
assisted hydrolysis of S- should be larger by >8 × 104-fold.
The value of the Taft reaction constant for alkaline hydrolysis
of N-substituted phthalimides is 1.0.37
A brief reaction mechanism for IGB-assisted nucleophilic
cleavage of S- is shown in Scheme 5. It is evident from Scheme
5 that IGB-assisted rate enhancements are expected when either
the k15 step or k25 step is the rate-determining step, and expected
5
5
IGA-assisted rate enhancements in the k-1 step and k2 step
5
5
do not change the value of k2 /k-15 compared to k2 /k-15 value
in the absence of IGA assistance. However, if the expected IGA-
assisted rate enhancements in the k-15 step and k25 step are such
5
5
A brief and plausible mechanism for alkaline hydrolysis of
2 is shown in Scheme 7 with X ) OMe, where the k17 step and
k37 step are presumably rate-determining steps. Hydroxide ion-
assisted hydrolysis of S- is also expected to involve reaction
steps shown by the k17 and k27 steps in Scheme 7 with X ) O-.
First- and second-order rate constants, kw and kOH, calculated
that the value of k2 /k-15 becomes larger than the k2 /k-15 value
5
5
in the absence of IGA assistance, then the value of kb ()k1 k2 /
0
0
5
5
5
k-15) would be larger than kb (where kb ) k1 k2 /k-1 when
5
5
5
the value of k2 /k-1 remains unchanged compared to the k2 /
k-15 value in the absence of IGA assistance). On the other hand,
if the IGA assistance decreases the value of k2 /k-15 compared
5
7
from eq 3, may be expressed as kOH ) k17 and kw0 ) k3 [H2O].
5
5
to k2 /k-1 in the absence of IGA assistance, then kb would be
smaller than kb . Thus, the value of IGB-assisted rate enhance-
ment depends not only on the IGB assistance in the k1 step
but also on expected IGA assistance in the k-1 step and k2
0
The value of kOH for 2 is nearly 2-fold smaller than kOH for
the cleavage of N-(p-methoxyphenyl)phthalimide (p-PT).38 If
polar (σI) and resonance (σR) components of σo-OMe and σp-OMe
are the only factors responsible for the kOH values, then the kOH
value for p-PT should have been lower than that for 2 because
substituent OMe acts as an electron donor by resonance
interaction, and this electron donor ability of OMe from the
para position is stronger than from the ortho position. The
change in coplanarity between the o-OMe substituent and the
benzene ring due to significant steric hindrance of o-OMe with
imide functionality reduces the electron-donating ability by
resonance of o-OMe compared to p-OMe. However, the values
of kOH seem to be almost insensitive to polar and resonance
effects of substituents attached to the leaving aryl group for
the reason that kOH values are almost the same for hydrolysis
of p-PT and N-(phenyl)phthalimides.39 This is plausible in view
5
5
5
5
step under the conditions when the k2 step is the rate-
determining step.
An alternative reaction mechanism for IGA-assisted nucleo-
philic cleavage of SH is shown in Scheme 6, which predicts
the absence of IGA-assisted rate enhancement if the k16 step is
the rate-determining step. However, under the reaction condi-
6
tions where the k2 step is the rate-determining step, IGA-
assisted rate enhancement is expected to occur. The rate-
determining steps in the reactions of SH with HO- and DABCO
6
6
are the k1 step and k2 step, respectively, and consequently,
IGA-assisted rate enhancement should be absent and present
in the reactions of SH with HO- and DABCO, respectively.
However, experimentally observed large rate enhancement in
the pH-independent rate of hydrolysis of 1 and absence of
DABCO buffer catalysis in the hydrolysis of 1 rule out the
possibility of occurrence of reaction mechanism shown in
Scheme 6.
(34) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165.
(35) Um, I.-K.; Lee, J.-Y.; Fujio, M.; Tsuno, Y. Org. Biomol. Chem.
2006, 4, 2979. We thank one of the reviewers for providing σ+ - value
p-O
and reference.
(36) Sim, Y.-L.; Ahmad, W. H. W.; Ariffin, A.; Khan, M. N. Submitted
for publication.
(37) Khan, M. N. Int. J. Chem. Kinet. 1987, 19, 143.
(38) Sim, Y.-L.; Ariffin, A.; Khan, M. N. Int. J. Chem. Kinet. 2004, 36,
316.
(39) Ariffin, A.; Leng, S. Y.; Lan, L. C.; Khan, M. N. Int. J. Chem.
Kinet. 2005, 37, 147.
(c) Pseudo-first-order rate constant (kw0) for pH-independent
(at pH >1 and <2.5, where concentration of ionized 1 is almost
zero) hydrolysis of 1 (106 kw ) 1.25 s-1) is ∼40-50-fold
0
smaller than the corresponding rate constant for 2 (106 kw
)
0
62.0 s-1) (Figure 1). Under such condition, the occurrence of
J. Org. Chem, Vol. 72, No. 7, 2007 2399

Sim et al.
TABLE 3. Values of Molar Extinction Coefficients of 1, 2, 3, 4, 7,
8, and 9 and Reaction Product Mixtures at t ) ∞ for Hydrolysis of
1 and 2a
of the reaction mechanism shown in Scheme 7, which predicts
a significant sensitivity of kOH values to substituents of leaving
aryl groups only when the k27 step is the rate-determining step.
7
λ ) 300 nm
λ ) 290 nm
However, the rate-determining step is the k1 step. However,
δ1
δ3
δ7
δ8 δ∞
δ2
δ4 δ8 δ9 δ∞
P1
P2
nearly 2-fold smaller value of kOH for 2 than for p-PT does
reveal a significant amount of steric hindrance affecting the
nucleophilic attack by nucleophile at the carbonyl carbon in
the k17 step (Scheme 7). Nearly 9-fold smaller value of kOH for
S- than kOH for 2 may be attributed to electrostatic repulsive
interaction between the anionic nucleophile (HO-) and the o-O-
pH
<2.5 2680 1930
40
30
2160 4550 470 175
[2400] [3730]
[30] [470]
>11.0 7530 5560 3410 ∼10
3100 5530 75 2190
[6870] [3740] [3330] [75]
0.16
0.25
70
90
560
640
7
group of S- in the k1 step.
0.46
150
670
7.16
7.79
5570
5580
5610
Conclusions
10.25
10.74
11.41
11.66
12.31
5370
Pseudo-first-order rate constants for hydrolysis of 1 and 2
under varying pH reveal the occurrence of IGB assistance in
the hydrolytic cleavage of 1 where the o-O- group of ionized
1 (S-) acts as IGB. The occurrence of kinetically indistinguish-
able IGA assistance due to the o-OH group of nonionized 1
(SH) in the reaction of HO- with SH has been ruled out based
upon indirect experimental evidence. The estimated rate ac-
celeration due to the IGB-assisted reaction of H2O with S- is
>8 × 104-fold.
5450
5650
5450
a [1]0 ) 3 × 10-4 M; [2]0 ) 2 × 10-4 M; values in square brackets are
δ∞P2 are apparent molar extinction coefficients of reaction product mixtures
at t ) ∞ for hydrolysis of 1 and 2, respectively.
P1
at 290 nm; the unit of molar extinction coefficient is M-1 cm-1; δ∞ and
of 1 and 2, in each kinetic run, were kept constant at 3.0 × 10-4
and 2.0 × 10-4 M, respectively. The details of the kinetic procedure
and data analysis are described elsewhere.10
Experimental Section
Product Identification. In order to identify the products of acidic
and alkaline hydrolysis of 1 and 2, the molar extinction coefficients
of expected hydrolysis products, N-(o-hydroxyphenyl)phthalamic
acid (3), N-(o-methoxyphenyl)phthalamic acid (4), o-hydroxyaniline
(7), phthalic acid (8), and o-methoxyaniline (9) have been deter-
mined under the reaction conditions of kinetic runs using authentic
samples of these compounds. These results are summarized in Table
3. The values of δ∞P ()A∞/[X]0) for a few typical kinetic runs are
also listed in Table 3, which reveal 3 and 4 as the hydrolysis
products of 1 at pH g6.1 and 2 at pH g7.2, respectively. However,
at pH e2.46, the hydrolysis products are 7 + 8 for 1 and 8 + 9 for
2. These observations are conceivable for the reason that the rate
of hydrolysis of 3 is >100-fold larger than that of its formation
from 1 within [HCl] range of 5.0 × 10-3 to 1.0 M.27 Similarly, the
pseudo-first-order rate constant (kobs) for the hydrolytic cleavage
Stock solutions of N-(o-hydroxyphenyl)phthalimide (1) (0.03 M)
and N-(o-methoxyphenyl)phthalimide (2) (0.01 M) were prepared
in acetonitrile. The buffer solutions of desired pH were freshly
prepared just before the start of the kinetic runs. The values of pH
for all kinetic runs at pH >3 were measured at the end of the kinetic
runs using a digital pH meter at 35 °C. The pH meter was calibrated
just before the pH measurements with standard pH buffers of pH
4.02 and 6.98 for pH <7.00 and of pH 6.98 and 9.16 for pH >7.00.
The pH meter was not used to determine the pH of the reaction
mixtures at [HCl] ranging from 5.0 × 10-3 to 1.0 M. The pH values
of these reaction mixtures were calculated from the relationship
pH ) -log(γ[H+]), where activity coefficient γ ) 0.70 at 1.0 M
ionic strength.
Kinetic Measurements. The rates of hydrolysis of 1 in the
presence of different [HCl], [NaOH], and buffers of different pH
were studied spectrophotometrically at 1.0 M ionic strength (NaCl)
and 35 °C by monitoring the disappearance of 1 at 300 nm as a
function of reaction time (t). Similarly, the rates of hydrolysis of 2
were studied at 290 nm by measuring the appearance of the
hydrolysis product of 2 and disappearance of 2 periodically at pH
g7.16 and pH e2.46, respectively. Pseudo-first-order rate constants
(kobs) for hydrolysis of 1 and 2 were calculated from eqs 9 and 10
for the reaction rate monitored by measuring respective disap-
pearance of reactant and appearance of products as a function of
t.10b
of 4 at 35 °C, 0.05 M HCl, is 130 × 10-5 s-1 27
which is ∼19-fold
,
larger than kobs obtained within [HCl] range of 5.0 × 10-3 to 1.0
M for the formation of 4 from 2.
P2
The values of δ∞ at pH >11 and <1 for the hydrolysis of 2
reveal the absence of possible hydrolysis of the methoxy group,
that is, hydrolytic conversion of 2 to 1 and 4 to 3, at these extreme
pH values. However, the possibility of hydrolysis of the methoxy
group of 2 to produce 1 under very low and very high pH may be
P2
ruled out for the following reasons. (i) The values of δ∞ are
significantly different from the values of δ1 or δ3 at these extreme
pH values (Table 3). (ii) If the rate of formation of 1 from 2 is
much faster than the rate of hydrolysis of 1 under such conditions,
then the log kobs - pH profiles for hydrolysis of 1 and 2 should
have been the same. Contrary to this, such log kobs - pH profiles
for 1 and 2, as shown in Figure 1, are very different from each
other. (iii) If the rate of hydrolysis of 1 is much faster than the rate
of its formation from hydrolytic cleavage of the o-methoxy group
Aobs ) δapp[X]0 exp(-kobst) + A∞
(9)
Aobs ) δapp[X]0[1 - exp(-kobst)] + A0
(10)
In eqs 9 and 10, Aobs represents absorbance of the reaction
mixture at a fixed wavelength (λ); δapp is an apparent molar
extinction coefficient of reaction mixture at λ; [X]0 is the initial
concentration of reactant, 1 or 2, A∞ ) Aobs at t ) ∞ and A0 ) Aobs
at t ) 0. The observed data (Aobs versus t), obtained for all kinetic
runs, were found to fit to eq 9 or eq 10 up to 3.5 (slowest reaction-
(s)) - 100 (fastest reaction(s)) half-lifes of the reactions. In the
observed data treatment with eqs 9 and 10, kobs, δapp, and A∞ or A0
were considered as three unknown parameters. A UV-visible
spectrophotometer equipped with thermostated multicell compart-
ment was used throughout the studies. The initial concentrations
P2
of 2, then the values of δ∞ should have been similar to the sum
of δ7 and δ8. However, such similarity does not exist at pH >11
P2
(Table 3). Although the values of δ∞ at pH <2.5 are not
significantly different from δ7 + δ8, the values of kobs for hydrolysis
of 2 are significantly larger than those for hydrolysis of 1 under
such conditions (Figure 1).
SH
Spectrophotometric Determination of pKa of 1 at 30 °C.
Significant initial absorbance, A0 (i.e., observed absorbance at
obs
reaction time t ) 0), change (∼1.39 absorbance units) has been
observed at 300 nm, 3.0 × 10-4 M 1 and within the pH range of
2400 J. Org. Chem., Vol. 72, No. 7, 2007

Hydrolysis of N-(o-Hydroxyphenyl)phthalimide
6.08-10.11 at 1.0 M ionic strength. These values of A0 were
from the percent residual errors [)100(A0 - A0calcd)/A0obs] of
obs
obs
used to calculate KaSH, δSH, and δS from eq 11
e4%. The calculated values of δSH and δS may be compared with
-
-
the corresponding values obtained experimentally at 300 nm and
0.05 M HCl (δSH ) 2.56 × 103 M-1 cm-1) as well as 0.005 M
SH
δSH[H+] + δ K
-
NaOH (δS ) 7.46 × 103 M-1 cm-1).
S
a
-
A0obs ) [X]0
(11)
SH
[H+] + Ka
Acknowledgment. The authors thank the Academy of
Sciences Malaysia for SAGA (Grant No. 66-02-03-0039), the
Malaysia Toray Science Foundation (Account No. 66-02-03-
0030), and the University of Malaya for financial support.
where KaSH is the ionization constant of 1, δSH and δS represent
molar extinction coefficients of nonionized and ionized 1, at 300
nm, respectively, and [X]0 is the initial concentration of 1 and [H+]
) 10-pH/γ with activity coefficient γ ) 0.7 at 1.0 M ionic strength.11
-
Supporting Information Available: Experimental section for
general procedures of synthesis of N-(o-hydroxyphenyl)phthalimide
(1) and N-(o-methoxyphenyl)phthalimide (2), Figures I and II as
well as Tables A, B, C, and D. This material is available free of
charge via the Internet at http://pubs.acs.org.
The nonlinear least-squares calculated respective values of KaSH
,
-
δ
SH, and δS are (3.91 ( 0.29) × 10-9 M, (2.80 ( 0.07) × 103
M-1 cm-1, and (7.53 ( 0.07) × 103 M-1 cm-1. A satisfactory fit
of observed data to eq 11 is evident from the standard deviations
associated with the calculated parameters, KaSH, δSH, and δS and
JO0624400
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J. Org. Chem, Vol. 72, No. 7, 2007 2401