Hydrolysis of N-Substituted Phthalimides
0.0015, 0.0020, and 0.0025 M at pH 8.11 as well as ∼15% at
[Am]T ) 0.001 M and pH 7.65.
Although weak effects of [Am]T on kobs do not appear to be
irregular, one might consider kobs values to be independent of
[Am]T at a constant pH. But this is not correct for the reason
that average values of kobs () kav) as shown in Table 2 are nearly
2-fold larger than the corresponding values of k0 calculated from
the relationship k0 ) θ/(aH + Φ) with θ ) 3.34 × 10-10 M s-1
and Φ ) 3.36 × 10-9 M.7 Thus, it is apparent that the observed
data at pH 7.03, 7.23, 7.57, and 7.88 (Figure 2) should obey eq
1.
An attempt to fit the observed data at pH 7.03, 7.23, 7.57,
and 7.88 to eq 1 was unsuccessful. However, these observed
data were used to calculate R and â from eq 2 where, at least,
the values of R may be considered as very close to kbapp values
because the average values of kobs () kav) at different pH,
obtained within [Am]T range at a constant pH attained in the
study, are not significantly different from the corresponding
values of R (Table 2). Furthermore, the values of R at pH 7.66
and 8.12 (Table 2) are similar to kbapp values at the corresponding
pH (Table 1). The least-squares calculated values of R and â at
different pH are summarized in Table 2.
Discussion
The second-order rate constant (kOH) for hydroxide ion
FIGURE 2. Plots showing the dependence of pseudo-first-order rate
constants kobs on total N-methylmorpholine buffer concentrations,
[Am]T, for the aqueous cleavage of 2 at pH 7.03 ([), 7.23 (b), 7.57
(2), 7.65 (∆), 7.88 (9), and 8.11 (0), respectively. The solid lines are
drawn through the calculated data points using eq 2 and the parameters
listed in Table 2 as well as eq 1 and the parameters listed in Table 1
for the plots (pH 7.65 ∆ and pH 8.11 0) shown as inset.
catalyzed cleavage of the amide bond in phthalamide (kOH
)
4.9 M-1 s-1)8 is ∼107-fold larger than that in benzamide (kOH
) 6 × 10-7 M-1 s-1).9 More than a million-fold rate enhance-
ment in the alkaline hydrolysis of phthalamide is attributed to
intramolecular carboxamide group assistance in the mild alkaline
medium. The kinetics of the rate of aqueous cleavage of
phthalimide under the buffers of primary10 and secondary
amines11 have been found to be complicated due to fast
equilibrium formation of N-substituted phthalamide followed
by a slow rate of hydrolysis of phthalamide as shown in Scheme
3.
nucleophilic substitution cationic-anionic product (14-, Scheme
5) formed in the reaction of N-methylmorpholine with anionic
2 contains an additional positive charge compared to anionic
2. The rate of hydrolysis of 14- may be more sensitive to the
specific salt effect compared to that of anionic 2. Although we
could not find any report on the effects of salt(s) on the rate of
hydrolysis of closely related cationic amide(s), the mild decrease
(5-35%) in kobs with an increase in [Am]T (Figure 2) may be
ascribed to a N-methylmorpholinium chloride salt effect.
Pseudo-first-order rate constants for hydrolysis of acetylimida-
zole at 0.1 M HCl and 25 °C decreased by ∼67% with the
increase in [NaCl] from 0.0 to 3.0 M.4a
In view of Scheme 3, a plausible reaction mechanism for the
cleavage of 1 in the presence of buffers of tertiary amines
(R1R2R3N) may be shown in Scheme 4.
The observed rate law (rate ) kobs[1]T where [1]T ) [1] +
[11]) and Scheme 4 can lead to eq 3
kOH4[HO-] + (kw [H2O] + k2 [HO-])K′[Am]T
1 + K′[Am]T
4
4
kobs
)
Following the suggestion of one of the reviewers, a few more
kinetic runs were carried out at two higher pH values (pH 7.65
( 0.02 and 8.11 ( 0.03) where the values of [Am]T were
attained as low as 0.001 and 0.0015 M. The values of kobs as
shown in Figure 2 reveal the presence of maxima in the plots
of kobs versus [Am]T. Although the decrease in pH (∆pH) during
a kinetic run was significant at [Am]T e 0.005 M (e.g., ∆pH )
0.10, 0.21, 0.30, and 0.49 at [Am]T ) 0.005, 0.003, 0.002 and
0.0015 M, respectively, at pH 8.11 as well as ∆ pH ) 0.10,
0.18, 0.25, and 0.54 at respective [Am]T ) 0.005, 0.003, 0.002,
and 0.001 M at pH 7.65), the observed data (Aobs versus t) for
all these kinetic runs fit perfectly to eq 6 for the reaction periods
of >10 half-lives. The values of kobs, within [Am]T range 0.003-
0.10 M at pH 8.11 and 0.002-0.15 M at pH 7.65, were found
to fit to eq 1 with kbapp and K as unknown parameters, and the
(3)
where K′ ) fbK4[H2O]/[HO-], fb ) KaAm/(aH + KaAm), Ka
)
Am
[Am]aH/[AmH+], K4 ) [11][HO-]/[1][H2O][Am] ) k1 /k-1
,
4
4
and Am ) R1R2R3N. Equation 3 is similar to eq 1 with k0 )
kOH4[HO-], kb ) kw4[H2O] + k2 [HO-], and K ) K′. The
app
4
relationships kbapp ) kw [H2O] + k2 [HO-] and K ) fbK4[H2O]/
[HO-] predict that the plots of kbapp versus [HO-] and K[HO-]
versus fb should be linear. Such plots as shown in Figures 3
and 4 appear to be linear but with significant deviations of
observed data points from linearity at higher values of fb in
Figure 4. As discussed earlier in the text, the values of K at
higher values of fb are not reliable, and consequently, the large
4
4
app
(8) Shafer, J. A.; Morawetz, H. J. Org. Chem. 1963, 28, 1899.
(9) Bunton, C. A.; Nayak, B.; O’Connor, C. J. Org. Chem. 1968, 33,
572.
(10) Khan, M. N. J. Org. Chem. 1995, 60, 4536.
(11) Khan, M. N. Colloids Surf. A 2001, 181, 99.
least-squares calculated values of kb and K are summarized
app
in Table 1. These calculated values of kb and K predict the
decrease in kobs compared to the corresponding calculated rate
constants (kcalcd) by ∼15, 10, and 9% at respective [Am]T )
J. Org. Chem, Vol. 72, No. 22, 2007 8455