Effects of CH3OH-H2O and CH3OH Solvents on Rate of Reaction of Phthalimide with Piperidine

Article abstract of DOI:10.1002/1097-4601(20010101)33:1<29::AID-KIN4>3.0.CO;2-0

Pseudo-first-order rate constants (κ_obs) for the cleavage of phthalimide in the presence of piperidine (Pip) vary linearly with the total concentration of Pip ([Pip]-) at a constant content of methanol in mixed aqueous solvents containing 2 percent v/v acetonitrile. Such linear variation of κ_obs against [Pip]_t exists within the methanol content range 10 percent - 80 percent v/v. The change in κ_obs with the change in [Pip]_t at 98 percent v/v CH3OH in mixed methanol-acetonitrile solvent shows the relationship: κ_obs = Sk_n^app[Pip]_t + k_gb^app[Pip]_t², where respective Sk_n^app and k_gb^app represent apparent second-order and third-order rate constants for nucleophilic and general base-catalyzed piperidinolysis of phthalimide. The values of κ_obs obtained within [Pip]_t range 0.02-0.40 M at 0.03 M NaOH and 20 as well as 50 percent v/v CH3OH reveal the relationship: κ_obs = κ₀/(1+[κ_n(Pip)]/κ_ox[^-OX]_t), where κ₀ is the pseudo-first-order rate constant for hydrolysis of phthalimide, κ_n and κ_ox represent nucleophilic second-order rate constants for the reaction of Pip with phthalimide and for the XO^--catalyzed cyclization of N-piperidinylphthalamide to phthalimide, respectively, and [^-OX]_t) = [NaOH] + [^-OX_re], where [_-OX_re] = [^-OH_re] + [CH3O_re^-]. The reversible reactions of Pip with H2O and CH3OH produce ^-OH_re and CH3O_re^- ions. The effects of mixed methanol-water solvents on the rates of piperidinolysis of PTH reveal a nonlinear decrease in κ_n^app with the increase in the content of methanol.

Full text of DOI:10.1002/1097-4601(20010101)33:1<29::AID-KIN4>3.0.CO;2-0

Effects of CH3OH-H2O and
CH3OH Solvents on Rate of
Reaction of Phthalimide
with Piperidine
M. NIYAZ KHAN
Department of Chemistry, Faculty of Science, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
Received 12 January 2000; accepted 7 July 2000
ABSTRACT: Pseudo-first-order rate constants (kobs) for the cleavage of phthalimide in the pres-
ence of piperidine (Pip) vary linearly with the total concentration of Pip ([Pip]T) at a constant
content of methanol in mixed aqueous solvents containing 2% v/v acetonitrile. Such linear
variation of kobs against [Pip]T exists within the methanol content range 10%–ϳ80% v/v. The
change in kobs with the change in [Pip]T at 98% v/v CH3OH in mixed methanol-acetonitrile
app
2
app
solvent shows the relationship: kobs ϭ kanpp[Pip]T ϩ k [Pip]T , where respective kanpp and k
gb
gb
represent apparent second-order and third-order rate constants for nucleophilic and general
base-catalyzed piperidinolysis of phthalimide. The values of kobs, obtained within [Pip]T range
0.02–0.40 M at 0.03 M NaOH and 20 as well as 50% v/v CH3OH reveal the relationship: kobs ϭ
Ϫ
k0/(1 ϩ {kn[Pip]/kOX[ OX]T}), where k0 is the pseudo-first-order rate constant for hydrolysis of
phthalimide, kn and kOX represent nucleophilic second-order rate constants for the reaction
of Pip with phthalimide and for the XOϪ-catalyzed cyclization of N-piperidinylphthalamide
Ϫ
Ϫ
Ϫ
Ϫ
to phthalimide, respectively, and [ OX]T ϭ [NaOH] ϩ [ OXre], where [ OXre] ϭ [ OHre] ϩ
[CH3O re ]. The reversible reactions of Pip with H2O and CH3OH produce ϪOHre and CH3Ore
Ϫ
Ϫ
ions. The effects of mixed methanol-water solvents on the rates of piperidinolysis of PTH
reveal a nonlinear decrease in kanpp with the increase in the content of methanol. ᭧ 2000 John
Wiley & Sons, Inc. Int J Chem Kinet 33: 29–40, 2001
INTRODUCTION
larity, permittivity, hydrogen bonding, and hydropho-
bicity. The kinetics of aminolysis of organic reactions
in aqueous solution have been studied to a great extent
with the aims explained elegantly in several reviews
[1–6] and books [7–9]. The mechanistic aspects of
aminolysis of esters in pure aprotic organic solvents
have been studied by a few investigators [10–12]. The
systematic kinetic studies on the effects of mixed
aqueous-organic solvents on rates of aminolysis of es-
ters and related compounds are relatively rare [13–
22]. The most obvious reasons for the limited attempts
at such studies are described elsewhere [13,22]. Apart
from some importance of such studies to enzyme-cat-
alyzed and micellar mediated reactions (where the re-
actions are believed to occur in a micro reaction en-
Solvent and mixed aqueous-organic solvent play an
important yet extremely complex role in the reaction
rates and chemical behavior of solution phase reac-
tions. The complexity of the solvent effects on reaction
rates is evident from the fact that there is no perfect
single theory to deal with such complexity and there
are several empirical equations that are claimed to ex-
plain only certain specific solvent effect such as po-
Correspondence to: M. Niyaz Khan (niyaz@kimia.um.edu.my)
Contract grant sponsor: National Science Council for R & D, IRPA
Contract grant number: 09-02-03-0003.
᭧ 2000 John Wiley & Sons, Inc.

30
KHAN
vironment of water concentration much lower than
water concentration in pure water solvent [7,23]),
these studies are also important for organic synthesis
[24].
a pseudo-first-order rate law. The reactions were gen-
erally followed up to 2–6 half-lives of the reactions.
Pseudo-first-order rate constants (kobs) were calculated
from Eq. (1),
The effects of mixed aqueous-organic solvents on
the rate of intramolecular general base-catalyzed hy-
drolysis [25], methanolysis [26], and aminolysis [22]
of ionized phenyl salicylate have been reported. Re-
cently, the effects of mixed aqueous-acetonitrile and
pure acetonitrile solvents on the rate of nucleophilic
reaction of piperidine (Pip) with phthalimide [27] have
been studied, where the rate of piperidinolysis of
phthalimide was uncatalyzed within the acetonitrile
content range 2%–80% v/v in mixed aqueous sol-
vents. But the rate of nucleophilic reaction of Pip with
phthalimide in pure acetonitrile solvent revealed the
absence of uncatalyzed and the presence of intermo-
lecular general base-catalyzed reaction paths, respec-
tively. The permittivity of acetonitrile is not signifi-
cantly different from that of methanol [28–30]. But
acetonitrile and methanol represent aprotic and protic
solvent systems, respectively, and mixed aqueous-
protic organic solvents and aqueous-aprotic organic
solvents show quite different effects on the rate
of hydrolysis of esters [31] and imides [24,32]. In the
continuation of our search for the effects of mixed
aqueous-aprotic and aqueous-protic organic solvents
on the rates of aminolysis of esters and imides,
the effects of CH3OH-H2O and CH3OH solvents con-
taining 2% v/v CH3CN on the rate of reaction of Pip
with phthalimide have been studied. The results and
their probable explanation(s) are described in this
article.
A
obs ϭ ␦app[X]0exp(Ϫkobst) ϩ Aϱ
(1)
using the nonlinear least-squares technique, where kobs
,
␦
(apparent molar extinction coefficient), and Aϱ
app
(absorbance at reaction time t ϭ ϱ) were considered
as unknown parameters. In Eq. (1), Aobs represents ob-
served absorbance at any reaction time, t, [X]0 is
the initial concentration of phthalimide, and ␦app
ϭ
␦SH-␦P, where ␦SH and ␦P are molar extinction coeffi-
cients of phthalimide and products (phthalamic acid
and N-piperidinylphthalamide), respectively. The fit-
ting of the observed data to Eq. (1) was good, as ev-
ident from standard deviations associated with some
representative calculated parameters listed in Tables I
and III.
Product analysis was carried out spectrophotomet-
rically, as described elsewhere [33,34].
RESULTS AND DISCUSSION
Effect of CH3OH-H2O on kobs for Hydrolysis
of Phthalimide at 0.01 M NaOH in the
Absence of Pip
A few kinetic runs were carried out within the CH3OH
content range 0–80% v/v in mixed aqueous solvents
containing 2% v/v CH3CN and 0.01 M NaOH at 35ЊC.
Pseudo-first-order rate constants (kobs) are shown in
Table I. The increase in CH3OH content from 0 to 80%
v/v decreased kobs by 13-fold; a similar increase in
CH3OH and CH3CN content decreased kobs by 50-fold
for N-hydroxyphthalimide [35,36] and by 22-fold for
phthalimide [37,38], respectively.
The presence of 0.01 M NaOH in mixed H2O-
CH3OH solvent would cause the production of
CH3OϪ, and it may be shown that [CH3OϪ]/[HOϪ] ϭ
K[CH3OH]/[H2O], where K ϭ KCa H OH/KaH O. It appears
that CH3OϪ reacts with acetyl salicylate ion [39] and
phenyl acetate [40] nearly 60 times faster than HOϪ
in mixed aqueous-methanol solvents. The pKa of
methanol (pKCa H OH ϭ 15.7) [41] is not significantly
different from pKa of water (pKHa O ϭ 15.75) [41];
hence, the nearly 60 times larger nucleophilic reactiv-
ity of CH3OϪ than of HOϪ toward carbonyl carbon of
esters should make the rate of hydrolysis negligible
compared with the rate of methanolysis of phthalimide
under the present experimental conditions. It should
EXPERIMENTAL
Materials
All the reagents used were supplied by Fluka, Aldrich,
or SIGMA and were of the highest purity commer-
cially available. Stock solutions of phthalimide were
prepared in acetonitrile.
3
2
Kinetic Measurements
The rates of reactions of piperidine (Pip) with phthal-
imide were studied by monitoring the disappearance
of phthalimide spectrophotometrically at 300 nm.
Details of the experimental procedure and data
analysis are the same as described elsewhere
[33].
3
2
All the kinetic runs were carried out under the ex-
perimental conditions where the reaction rates obeyed

EFFECTS OF SOLVENTS ON RATE OF REACTION OF PHTHALIMIDE WITH PIPERIDINE
31
Table I Values of kobs, ␦app and Aϱ Calculated from Eq. (1) for Hydrolysis of Phthalimide at Different Contents of
CH3OHa
Ϫ1
Ϫ
1
Ϫ1
CH3OH (% v/v)
104 kobs (s
)
␦
app (M cm
)
Aϱ
0
10
20
30
40
50
60
80
22.9 Ϯ 0.5b
18.6 Ϯ 0.2
14.8 Ϯ 0.1
10.8 Ϯ 0.1
7.64 Ϯ 0.15
5.69 Ϯ 0.09
4.20 Ϯ 0.06
1.73 Ϯ 0.01
2100 Ϯ 20b
2077 Ϯ 11
2022 Ϯ 6
2050 Ϯ 12
2091 Ϯ 20
2053 Ϯ 18
1974 Ϯ 19
1887 Ϯ 5
Ϫ0.009 Ϯ 0.005b
0.000 Ϯ 0.003
0.001 Ϯ 0.001
Ϫ0.007 Ϯ 0.003
Ϫ0.013 Ϯ 0.004
Ϫ0.009 Ϯ 0.004
Ϫ0.004 Ϯ 0.004
0.009 Ϯ 0.001
a [SH0]0 ϭ 2 ϫ 10Ϫ4 M; [NaOH] ϭ 0.01 M; 35ЊC; ␭ ϭ 300 nm; mixed aqueous-methanol solvent for each kinetic run contained 2% v/v
CH3CN.
b Error limits are standard deviations.
be noted that the rate of hydrolysis of phthalimide at
0.01 M NaOH involves hydroxide ion and nonionized
phthalimide (SH) as the reactants [42]. But the rate
constants (kobs) listed in Table I represent hydrolysis
and not methanolysis of phthalimide. This may be ex-
plained as follows.
The rate constants for hydrolysis of phthalimide
were found to be almost independent of [HOϪ] within
its range 0.0025–0.05 M in an aqueous solvent con-
taining 1.6% v/v CH3CN [43,44]. Under such condi-
tions, the hydrolysis of phthalimide involves HOϪ and
SH as the reactants [42]. But upon increasing the
CH3OH content in the solution, [HOϪ] decreases be-
cause CH3OϪ is formed, but [HOϪ] ϩ [CH3OϪ] is con-
stant, thus [SH] should be constant. Since [HOϪ] de-
creases, the pseudo-first-order rate constant must
decrease.1 The increase in CH3OH content from 0 to
80% v/v decreases [HOϪ] by nearly 2.5-fold, provided
Scheme I
KCa H OH/KaH O remains unchanged with the change in
[CH3OH]. The ionization of both H2O and CH3OH
constitutes nonisoelectric reactions, and ionization
constants of such ionization reactions are significantly
affected by the presence of organic cosolvents in
mixed aqueous solutions [45]. The pKW increased
from 14.00 to 15.43 [46] and the pKa of phenol in-
creased from 10.00 to 11.34 [47] with the increase in
CH3OH content from 0 to 70% w/w. In view of these
results, the methanolysis of phthalimide may be also
assumed to involve SH and CH3OϪ as the reactants at
[CH3OϪ] Յ 0.01 M. Thus, the cleavage of phthalimide
in CH3OH-H2O solvents containing 0.01 M NaOH
may be shown by a simple reaction scheme
(Scheme I).
3
2
The value of k2 is 26 MϪ1 sϪ1 at 30ЊC in an aqueous
1
1
1
solvent containing Յ2% v/v CH3CN [43]. If k1 /k2
Ϸ
60, then k1 Ϸ 1560 MϪ sϪ at 30Њ C. The values of
the second-order rate constants (kOH) for HOϪ-cata-
lyzed cyclization of methyl o-carbamoylbenzoate,
methyl o-(aminomethyl)benzoate, and ethyl o-(hy-
droxymethyl)benzoate are 3.1 ϫ 103 (25.9ЊC) [48], 7
ϫ 103 (30ЊC) [49], and 10 ϫ 103 MϪ1 sϪ1 (30ЊC) [50],
respectively. These values of kOH predict a value of
1
1
1
1
kϪ 1 as Ϸ103 sϪ , provided Ka/Kw Ϸ 1 MϪ1 (where Ka
is the ionization constant of 1H), because kOH
kϪ 1Ka/Kw. The reported value of pKa of benzamide is
14–15 [51]. Although o-substituent effect on pKa is
not easily predictable [46], the pKa of 1H may not be
significantly different from that of benzamide. It may
be noted that pseudo-first-order rate constants for the
cyclization of nonionized phthalamic [24] and N-sub-
1
ϭ
1
1 I thank one of the reviewers for pointing this out.

32
KHAN
stituted phthalamic [52] acids to phthalic anhydride
remained almost unchanged with the change in the
content of CH3CN from 0 to 80% v/v in mixed aque-
2 might occur through rapid HOϪ-catalyzed hydrol-
؊
؊
ysis of 1H (i.e., the formation of 2 occurs through
the k31 step rather than k21 step in Scheme I). If this is
correct, then the overall rate law (rate ϭ kest[PT]T,
where [PT]T ϭ [SH]T ϩ [1H] Ϸ [SH]T because [SH]T/
[1H] Ϸ 8 ϫ 103) and Scheme I can lead to the rela-
ous solvent. Thus, the value of kOH or kϪ 1 may not be
1
expected to be significantly affected by the increase in
the content of methanol in mixed aqueous solvents
because, as concluded earlier in the text, such a change
in the mixed solvent should not affect significantly the
ratio Ka/KW. The reported values of second-order rate
constants (kЈOH) for hydroxide ion-catalyzed hydrolysis
of methyl benzoate, methyl o-methoxybenzoate, and
dimethylphthalate are 0.125 (30ЊC) [53], 0.075 (35ЊC)
tionship: kest ϭ k3 k1 [CH3OϪ]fSH/kOH Ϸ 1 ϫ 10Ϫ7 sϪ
1
1
1
at 10% v/v CH3OH with k3 Ϸ 0.1 MϪ sϪ , k1
ϭ
1
1
1
1
1560 MϪ sϪ , [CH3OϪ] ϭ 5 ϫ 10Ϫ4 M, fSH ϭ 4.7 ϫ
1
1
3
1
10Ϫ , and kOH ϭ 3 ϫ 103 MϪ1 sϪ . The estimated value
1
of rate constant kest (Ϸ1 ϫ 10Ϫ7 sϪ ) is more than 104-
fold smaller than the experimentally observed value of
1
1
1
[54], 0.031 (35ЊC) [55], and 0.065 MϪ sϪ (25ЊC)
kobs (ϭ 18.6 ϫ 10Ϫ4 sϪ ) at 10% v/v methanol (Table
[31], respectively. In view of these results, the value
I). This analysis thus rules out the possibility of the
formation of 2 via intermediate 1H. This shows that
؊
of kЈ (ϭ k31 in Scheme I) for the HOϪ-catalyzed con-
OH
؊
1
؊
1
version of 1H to 2 should be ca. 0.1 MϪ1 sϪ . But the
the formation of 2 must occur via the k2 -step
value of kOH for HOϪ-catalyzed cyclization of 1H to
SH is 3.1 ϫ 103 MϪ sϪ1 (25.9) [48]. Furthermore, at
(Scheme I). Under such a condition, kest ϭ k2 [HOϪ]fSH
1
1
4
1
Ϸ 12 ϫ 10Ϫ sϪ at 30ЊC, which is not very different
4 1
10% v/v CH3OH (the lowest methanol content in the
from kobs (ϭ 18.6 ϫ 10Ϫ sϪ ) at 10% v/v methanol
and 35ЊC (Table I).
4
present study), the value of [CH3OϪ] Ϸ 5 ϫ 10Ϫ
M
{[CH3OϪ] ϭ KX[ϪOH]T/(1 ϩ KX), where K ϭ
The decrease in kobs (Table I) with increasing
CH3OH content in mixed aqueous solvent may be at-
tributed to several factors, such as permittivity, polar-
ity, polarizability, basicity, preferential solvation, hy-
drogen bonding, and hydrophobicity of the reaction
medium. These factors are not equally influential, and
some of them oppose each other toward a particular
reaction rate. The increase in the content of CH3OH
decreased permittivity (␧) of the reaction medium,
which in turn increased the pKa of conjugate acids
of both nucleophile (HOϪ) and leaving group
(—CONHϪ). The increase in pKa of conjugate acids
of leaving group and nucleophile should decrease and
increase the rate of reaction, respectively. But the nu-
cleophilicity of HOϪ is bound to decrease partially due
to more stable ion-pair formation between HOϪ and
its counter ion (Naϩ) with decrease in ␧. The ion-pair
formation between leaving group and Naϩ should be
less stable for the reason that full unit negative charge
cannot develop on the nitrogen of leaving group in the
transition state and such a partial negative charge is
also not as localized as full unit negative charge on
hydroxide ion in the ground state.
KCa H OH/KHa O, X ϭ [CH3OH]/[H2O], and [ϪOH]T
ϭ
1
3
2
0.01 M}, and hence the value of k1 Ϸ 1560 MϪ sϪ
1
1
gives k1 [CH3OϪ] Ϸ 0.78 sϪ . The value of k2 [HOϪ]
1
1
1
ϭ 0.26 sϪ at 0.01 M NaOH and 98% v/v H2O. The
1
values of k1 [CH3OϪ] and k2 [HOϪ] become Ͼ0.78 sϪ
1
1
1
and Ͻ0.26 sϪ , respectively, at methanol content of
1
Ͼ10% v/v. Thus, k1 [CH3OϪ] is more than 3-fold
1
larger than k2 [HOϪ] at 10% v/v CH3OH. Thus, the
1
nearly 104-fold larger value of kOH for the conversion
؊
of 1H to SH than that of 1H to 2 and Ͼ3-fold larger
value of k1 [CH3OϪ] compared with k2 [HOϪ] at 10%
v/v methanol caused rapid equilibrium formation be-
tween SH and 1H. It may be noted that the conclusion
1
1
remains unchanged even if kϪ Ϸ 104 sϪ because
1
1
1
under such conditions, the rate of conversion of 1H
to SH becomes ϳ105-fold larger than that of 1H
؊
to 2 .
Based upon Scheme I, [SH]/[1H] ϭ kϪ 1Ka/
1
k1 [CH3OϪ][Hϩ] ϭ kOHKw/k1 [CH3OϪ][Hϩ] because
1
1
kϪ 1 ϭ kOHKw/Ka. Since [SH] ϭ fSH[SH]T where fSH ϭ
1
[Hϩ]/([Hϩ] ϩ KЈa) with KЈ ϭ [SϪ][Hϩ])/[SH] and
a
[SH]T ϭ [SH] ϩ [SϪ]. Therefore, the value of [SH]T/
[1H] ϭ kOHKw/(fSH k1 [CH3OϪ][H Ϸ 8 ϫ 103 at 10%
1
v/v methanol with kOH ϭ 3 ϫ 103 MϪ sϪ (25.9ЊC)
1
1
[48], Kw ϭ 1.4 ϫ 10Ϫ M2, k1 ϭ 1560 MϪ sϪ
14
1
1
1
Effects of CH3OH-H2O and CH3OH
Solvents on kobs for the Reaction of
Phthalimide with Pip in the Absence of
Added NaOH
(30ЊC), [CH3OϪ] ϭ 5 ϫ 10Ϫ4 M, [Hϩ] ϭ 1.4 ϫ 10Ϫ
12
M, fSH ϭ 4.7 ϫ 10Ϫ3 (KЈ ϭ 3 ϫ 10Ϫ10 M at 30ЊC [47]).
a
This analysis shows the presence of an insignificant
amount of 1H compared to that of phthalimide during
the course of the cleavage of phthalimide in CH3OH-
H2O solvent containing 0.01 M NaOH and 10% v/v
methanol.
In order to discover the effects of CH3OH-H2O on the
rate of reaction of phthalimide with Pip, a few kinetic
runs were carried out within the attainable total piper-
idine concentration ([Pip]T) range at a constant content
A skeptic may argue that the formation of product

EFFECTS OF SOLVENTS ON RATE OF REACTION OF PHTHALIMIDE WITH PIPERIDINE
obs Ϫ k0 ϭ knapp[Pip]T
33
k
(2)
where k0 is the pseudo-first-order rate constant for the
cleavage of phthalimide obtained within the [HOϪ]
range where the rate of cleavage of phthalimide is in-
dependent of [HOϪ] in the absence of Pip (Table I)
and kanpp is apparent nucleophilic second-order rate
constant for the reaction of Pip with phthalimide. The
least-squares calculated values of kanpp at different con-
tents of CH3OH are summarized in Table II. The fit-
ting of the observed data to Eq. (2) is evident from the
plots of Figure 1, where solid lines are drawn through
the calculated points.
The calculated values of ␦app appeared to be inde-
pendent of [Pip]T at a constant content of CH3OH. The
average values of ␦app with their standard deviations
at different contents of CH3OH are summarized in
Table II. The values of ␦app are nearly 25–30% smaller
than the corresponding values of ␦app obtained in the
absence of Pip. Since ␦app ϭ ␦SH Ϫ ␦P, where ␦P Ϸ 0
؊
؊
because 1H, 1 , and 2 do not absorb to a detectable
level at 300 nm. Nearly 25–30% lower values of ␦app
in the presence of Pip indicate that the value of ␦P is no
longer zero. Since phthalamic acid (hydrolysis product
of phthalimide) and N-piperidinylphthalamide (piperi-
dinolysis product of phthalimide) do not absorb at 300
nm, ␦P must be for equilibrium-cyclized product
(phthalimide) of N-piperidinylphthalamide. In the re-
cent studies, the kinetic evidence for the formation of
small but definite amounts of N-substituted phthal-
imides (Յ20%) has been shown to occur in the cleav-
age of phthalimide under the buffers of 2-hydroxy-
ethylamine [56], 2-methoxtethylamine [56], and
methylamine [57]. Thus, a brief reaction mechanism for
Figure 1 Plots showing the dependence of corrected
pseudo-first-order rate constants, kobs (ϭ kobs Ϫ k0), upon
the total concentration of piperidine, [Pip]T, for the reaction
of Pip with phthalimide at 10 (᭟), 20 (᭛), 30 (᭞), 40 (ٗ),
50 (᭝), and 60% v/v CH3OH (᭺) in mixed aqueous solvent
containing 2% v/v CH3CN.
cor
of CH3OH in mixed aqueous solvent at 35ЊC. Pseudo-
first-order rate constants (kobs) at a constant content of
CH3OH but Յ60% v/v, as shown graphically in Fig-
ure 1, obeyed Eq. (2)
Table II Effects of Methanol Content on knapp Calculated from Eq. (2) at 35ЊCa
103 knapp (M
s
)
103 kn
(M
s
)
103 kne (M
s
)
103 kgbf (M
s )
b
Ϫ
1
Ϫ1
c
Ϫ1
Ϫ1
app d
Ϫ1
Ϫ1
Ϫ1
Ϫ1
Ϫ2
Ϫ1
CH3OH (% v/v)
␦
(M cm
)
␪
app
10
20
30
40
50
60
80
1432 Ϯ 90g
1441 Ϯ 38
1468 Ϯ 28
1502 Ϯ 15
1538 Ϯ 11
1532 Ϯ 44
1657 Ϯ 27
2.2
2.5
2.5
2.6
3.0
3.5
7.2
180 Ϯ 17g
112 Ϯ 5
239 Ϯ 6g
131 Ϯ 7
73.0 Ϯ 6.9
41.9 Ϯ 4.5
28.8 Ϯ 1.3
19.3 Ϯ 0.6
164
93.6
52.1
30.3
21.6
15.0
66.1 Ϯ 4.3
39.3 Ϯ 3.3
27.6 Ϯ 0.9
18.7 Ϯ 0.7
10.8 Ϯ 1.0
10.2 Ϯ 0.6
9.0
1.86 Ϯ 0.88g
8.08 Ϯ 0.81
98
1458 Ϯ 72
4.92 Ϯ 0.54
a [SH0]0 ϭ 2 ϫ 10Ϫ4 M; ␭ ϭ 300 nm; mixed aqueous-methanol solvent for each kinetic run contained 2% v/v CH3CN.
b Average value of ␦app obtained at five different [Pip]T at a constant content of methanol.
c
␪ ϭ ␦app/(␦0 Ϫ ␦app), where ␦0( ϭ ␦app in Table I) is the apparent molar extinction coefficient obtained under similar experimental con-
ditions with [Pip]T ϭ 0.
d The values of knapp were calculated from Eq. (2) with [Pip]T changed to [Pip]T Ϫ [PipHϩ].
e kn ϭ ␪ knapp/(1 ϩ ␪) (i.e., Eq. (6)).
f Calculated from Eq. (7).
g Error limits are standard deviations.

34
KHAN
the cleavage of phthalimide under the presence of Pip
may be shown in Scheme II. It can be shown that
kn[Pip]T ϾϾ k0 under the experimental conditions of the
present study and kOH or kOX ϾϾ kOЈH (where kЈOH rep-
resents the HOϪ-catalyzed second-order rate constant
for hydrolysis of 3. Thus, the equilibrium between SH
and 3 is considered to be independent of the k0 step and
hydrolysis of 3 in Scheme II.
[HOreϪ] at different [Pip]T may be calculated from Eq.
(3):
[HOreϪ] ϭ [ϪY ϩ (Y2 ϩ 4Y[Pip]T)1/2]/2
(3)
where Y ϭ Kw/KPaip and KaPip ϭ [Pip][Hϩ]/[PipHϩ].
The calculation of kanpp from Eq. (2) is based upon
the assumption that [Pip] Ϸ [Pip]T. But the values of
[HOreϪ] (ϭ[PipHϩ]), calculated from Eq. (3) at dif-
ferent [Pip]T, indicate that the assumption [Pip] Ϸ
[Pip]T is not entirely true. Thus, relatively more ac-
curate values of kanpp were obtained from Eq. (2) with
[Pip]T changed to [Pip]T Ϫ [PipHϩ], where [PipHϩ] ϭ
[HOreϪ]. These calculated values of kanpp are also sum-
marized in Table II. The values of [HOreϪ] at different
[Pip]T were calculated from Eq. (3). The reported val-
ues of pKw at different contents of ethanol [46] were
used in the present study assuming the effects of meth-
anol-water and ethanol-water on pKw are nearly the
same. The values of pKPaip at different contents of
methanol were assumed to be the pKPaip at the corre-
sponding contents of acetonitrile [62] in mixed aque-
ous solvents.
Scheme II
The rate of hydrolysis of 3 may be considered to
be negligible compared with the rate of hydrolysis of
phthalimide under the present experimental conditions
([HOreϪ] range 0.008–0.018 M) because pseudo-first-
order rate constants for hydrolysis of benzamide and
phthalimide at [HOreϪ], range 0.008–0.018 M, are 13
ϫ 10Ϫ6 to 29 ϫ 10Ϫ6 sϪ1 at 100.4ЊC [58]; 9 ϫ 10Ϫ8 to
The immediate stable product of piperidinolysis of
PTH is 3. Pthalamide [48] and N,NЈ-disubstituted
phthalamide [48] are known to cyclize to produce SH
and N-substituted SH, respectively, through intramo-
lecular nucleophilic participation of o-carboxyamido
group in alkaline aqueous solvents. The presence of
HOϪ in mixed H2O-CH3OH solvent would produce
CH3OϪ. But the assumption that HOϪ and CH3OϪ are
equally effective catalysts for the cyclization of 3 to
phthalimide can be made to reduce the kinetic com-
plexity involved in the present reacting system. This
assumption is conceivable because these catalysts cat-
alyze cyclization reaction merely by abstracting the
acidic hydrogen of the amide group of 3, and the val-
ues of pKa of conjugate acids of HOϪ and CH3OϪ are
8
1
6
6
20 ϫ 10Ϫ sϪ at 25ЊC [59], 9 ϫ 10Ϫ to 20 ϫ 10Ϫ
sϪ at 100ЊC [60], and 1.3 ϫ 10Ϫ sϪ at 30ЊC [61],
1
3
1
respectively. The value of kЈOH for 3 may not be ex-
pected to be significantly different from kЈ for ben-
OH
zamide because the favorable substituent effect is most
likely counterbalanced by the unfavorable steric effect
of
in 3. This conclusion is based upon the
o-CON
reported values of kOЈH for methyl benzoate (kЈ
ϭ
OH
0.125 MϪ sϪ at 30ЊC [52], 0.075 MϪ sϪ at 35ЊC
1
1
1
1
[53]), methyl o-methoxybenzoate (kЈ ϭ 0.031 MϪ
1
OH
sϪ1 at 35ЊC [54]), dimethylphthalate (kЈ ϭ 0.065 MϪ
1
OH
1
1
1
sϪ at 30ЊC [31]), benzamide (kЈOH ϭ 0.0011 MϪ sϪ
at 100ЊC [59]), and o-methoxybenzamide (kЈ
ϭ
OH
؊
nearly the same. Anionic phthalimide (S ) absorbs
0.0011 MϪ1 sϪ1 at 100ЊC [59]). The values of second-
order rate constants (kOH) for HOϪ-catalyzed cycliza-
tion of phthalamide and N,NЈ-dimethylphthalamide
1
؊
strongly (␦SϪ ϭ 2000Ϫ2100 MϪ1 cmϪ ), while 2 and
3 do not absorb (␦2 Ϸ ␦3 Ϸ 0) at 300 nm. Thus, the
Ϫ
extent of reversibility of the reversible reaction in
Scheme II can be easily established by comparing the
values of ␦app and ␦0, where ␦0 and ␦app were obtained
under similar conditions with the absence and pres-
ence of Pip, respectively. Since the equilibrium be-
tween SH and 3 is independent of the k0 step and rate
of hydrolysis of 3, Scheme II leads to Eq. (4):
1
1
1
1
are 4.9 MϪ sϪ and 7.6 MϪ sϪ at 25.9ЊC [48], re-
spectively. The value of kOH or kOX (Scheme II) may
not be very different from the corresponding kOH for
phthalamide or N,NЈ-dimethylphthalamide. Hence the
value of kOH or kOX Ϸ 5 MϪ1 sϪ , which is many-fold
1
larger than kЈ (Ϸ 0.0011 MϪ sϪ at 100ЊC [59] for
1
1
OH
HOϪ-catalyzed hydrolysis of benzamide) for 3.
Piperidine is a base strong enough to produce a
significant amount of HOϪ when dissolved in aqueous
solvents through the reaction H2O ϩ Pip L HOreϪ ϩ
PipHϩ, where Pip and PipHϩ represent nonprotonated
and protonated piperidine, respectively. The values of
kn[Pip]
[3]e
A0 Ϫ Ae
ϭ
ϭ
-
kOX[XOre ] [SH]e
Ae
␦
app
ϭ
ϭ ␪ (4)
␦0 Ϫ ␦app

EFFECTS OF SOLVENTS ON RATE OF REACTION OF PHTHALIMIDE WITH PIPERIDINE
35
app
where [XOreϪ] ϭ [HOreϪ] ϩ [CH3OreϪ], subscripts 0
and e represent initial state (i.e., at reaction time t ϭ
0) and equilibrium state, respectively, and A represents
absorbance at 300 nm. The values of ␦app were found
to be independent of [Pip]T at a constant content of
In Eq. (7), k represents apparent third-order rate con-
gb
stant for general base-catalyzed piperidinolysis of SH.
The least-squares calculated values of kanpp and k are
app
gb
shown in Table II. The value of kanpp obtained from Eq.
(7) is only 6% lower compared to kanpp obtained from
app
2
CH3OH (Table II). This shows that ␪ is independent
Eq. (2) and the maximum contribution of k [Pip]T
gb
Ϫ
of [Pip]T and hence the values of kn[Pip]/kOX[XOre
]
term to kobs Ϫ k0 is 13% (obtained at [Pip]T ϭ 0.8 M).
The values of kobs at 98% v/v CH3OH obeyed Eq.
(7), with k0 ϭ 0. The least-squares calculated values
remain constant within the [Pip]T range of present
study. Reaction Scheme II shows that the corrected
pseudo-first-order rate constants (kobs Ϫ k0) are related
to kn and kOX by Eq. (5):
app
of kanpp and k are summarized in Table II. The min-
gb
app
2
imum and maximum contributions of k [Pip]T term
gb
in Eq. (7) are 30% (at the lowest [Pip]T ϭ 0.2 M) and
64% (at the maximum [Pip]T ϭ 0.8 M), respectively.
The fitting of the observed data to Eq. (7) is evident
from the plots of Figure 2, where solid lines are drawn
through the calculated data points.
Ϫ
k
obs Ϫ k0 ϭ kn[Pip] ϩ kOX[XOre
]
(5)
Eqs. (2), (4), and (5) yield Eq. (6):
kanpp ϭ kn(1 ϩ ␪)/␪
(6)
Effects of [Pip]T on the Cleavage of
Phthalimide in Aqueous Solvent Containing
20 and 50% v/v CH3OH and 0.03 M NaOH
at 35ЊC
The values of kn at different contents of CH3OH were
calculated from Eq. (6) with known values of ␪ and
kanpp. These results are shown in Table II.
The rate constants (kobs) obtained at 80% v/v
CH3OH and within the [Pip]T range 0.16–0.80 M, as
shown graphically by Figure 2, were found to fit to
Eq. (7) slightly better than to Eq. (2):
The equilibrium between phthalimide and 3 (Scheme
II) may be expected to be reached much faster if the
rate of backward reaction (i.e., kOX step) is increased
by external addition of NaOH into the reaction mix-
ture. In order to test this speculation, a few kinetic runs
were carried out for the cleavage of phthalimide within
the [Pip]T range 0.02–0.40 M at 0.03 M NaOH at 20
and 50% v/v CH3OH. The absorbance of the reaction
mixture showed a sharp drop in the initial phase fol-
lowed by a slow monotonic drop in the final phase of
the reaction, as evident from some representative plots
in Figure 3. The final phase of the reaction followed
a pseudo-first-order rate law. Pseudo-first-order rate
constants (kobs) and apparent pseudo-molar extinction
coefficients, ␦Јapp {ϭ ␦SHe Ϫ ␦P, where ␦SHe and ␦P rep-
resent molar extinction coefficients for reactants (SHe
app
2
k
obs Ϫ k0 ϭ kanpp[Pip]T ϩ k [Pip]T
(7)
gb
؊
and 3e) at equilibrium and product (2 ), respectively,
at 300 nm}, were calculated from Eq. (1) with [X]0 ϭ
[SH]0 (i.e., initial concentration of phthalimide). These
results are summarized in Table III. Since ␦P Ϸ 0 be-
؊
cause 2 does not absorb to a detectable level at 300
nm, ␦Јapp Ϸ ␦SHe. The increase in [Pip]T should increase
the concentration of 3e and consequently decrease
[SHe] (Scheme II), provided the rate of backward re-
action (i.e., the conversion of 3 to SH) is not increased
proportionately due to a simultaneous increase in
([HOϪ] ϩ [CH3OϪ]). Such an effect of the increase in
[Pip]T on [SHe] should decrease ␦Јapp {obtained from
Eq. (1) using data of the final phase of the reaction
where the initial concentration of phthalimide
Figure 2 Effect of total concentration of piperidine, [Pip]T,
on pseudo-first-order rate constants, kobs, for the reaction of
Pip with phthalimide at 80 (᭝) and 98% v/v CH3OH (᭺) in
mixed aqueous solvent containing 2% v/v CH3CN.
4
([SH]0 ϭ 2 ϫ 10Ϫ M) was considered as [SHe]0}.
Thus, ␦aЈpp would be concentration-independent only if

36
KHAN
Figure 3 Variation of observed absorbance, Aobs, vs. reaction time, t, for the typical kinetic runs where reaction mixture
Ϫ
4
contained [SH0]0 ϭ 2 ϫ 10 M, [NaOH] ϭ 0.03 M, [Pip]T ϭ 0.1 M, 35ЊC and mixed aqueous solvent containing 2% v/v
CH3CN and 20 (᭺) as well as 50% v/v CH3OH (᭝).
[SHe]0 ϭ [SH]0. The observed decrease in ␦Јapp with
increase in [Pip]T (Table III) indicates that [SHe]0 ꢀ
[SH]0.
Scheme II shows that the initial fast drop in Aobs
(Figure 3) represents the attainment of equilibrium be-
tween piperidinolysis of SH and cyclization of 3,
while the slow drop in Aobs in the final phase of the
reaction represents the hydrolysis of phthalimide after
the attainment of equilibrium between SH and 3.
These conclusions are supported by the decrease in
␦aЈpp with increase in [Pip]T at a constant [NaOH] (Ta-
ble III).
The observed rate law (rate ϭ kobs[SH]T, where
SH]T is the total concentration of phthalimide) and
Scheme II can lead to Eq. (8):
k
obs ϭ k0 /{1 ϩ (kn[Pip]/kOX[XOϪ]T)}
(8)
where [Pip] ϭ [Pip]T-[PipHϩ], k0 ϭ kXOH ϭ kOXKw/
KЈ with KЈ ϭ [SϪ][Hϩ]/[SH] as well as kXOH and kOX
a
a
Table III Effects of [Pip]T on Pseudo-First-Order Rate Constants (kobs) and Apparent Pseudo-Molar Extinction
Coefficients (␦aЈpp) for the Cleavage of Phthalimide at 0.03 M NaOH and 35ЊCa
CH3OH/v/v ϭ 20
CH3OH/v/v ϭ 50
[Pip]T
(M)
␦aЈpp
(M cm
␦aЈpp
(M cm
Ϫ1
Ϫ
1
Ϫ1
Ϫ1
Ϫ
1
Ϫ1
104 kobs (s
)
)
tb (s)
nc
104 kobs (s
)
)
tb (s)
nc
0.02
0.06
0.10
0.20
0.30
0.40
13.1 Ϯ 0.1d
11.5 Ϯ 0.1
9.92 Ϯ 0.11
7.26 Ϯ 0.12
6.42 Ϯ 0.14
5.76 Ϯ 0.11
1907 Ϯ 3d
1554 Ϯ 5
1352 Ϯ 5
1123 Ϯ 8
938 Ϯ 1
120–1736
120–1980
120–2540
120–2030
120–1896
120–3026
14
14
14
14
14
14
5.71 Ϯ 0.07d
5.11 Ϯ 0.07
4.75 Ϯ 0.04
4.01 Ϯ 0.11
3.66 Ϯ 0.04
2.85 Ϯ 0.02
1948 Ϯ 9d
1761 Ϯ 9
1603 Ϯ 4
1328 Ϯ 18
1221 Ϯ 7
1193 Ϯ 3
240–2721
360–2955
360–5400
360–2655
360–3084
360–10,800
12
11
13
11
11
10
789 Ϯ 7
a [SH0]0 ϭ 2 ϫ 10Ϫ4 M; ␭ ϭ 300 nm; mixed aqueous-methanol solvent for each kinetic run contained 2% v/v CH3CN; kobs and ␦aЈpp were
calculated from the relationship: Aobs ϭ [SH0]0␦aЈppexp(Ϫkobst) ϩ Aϱ, where Aobs and Aϱ represent absorbance at 300 nm and at any reaction
time t and at t ϭ ϱ, respectively. It may be noted that the actual kinetic equation for the calculation of kobs and the apparent molar extinction
coefficient (␦app) for the second phase of the reaction should be expressed as Aobs ϭ [SHe]0␦appexp(Ϫkobst) ϩ Aϱ, where [SHe]0 is the concen-
tration of phthalimide when equilibrium between SH and 3 is reached. Thus, it is apparent that ␦aЈpp ϭ ([SHe]0/[SH0]0)␦app
b Reaction time range of observed absorbance (Aobs) used to calculate kobs and ␦aЈpp.
c Total number of data points used in the calculation of kobs and ␦aЈpp.
.
d Error limits are standard deviations.

EFFECTS OF SOLVENTS ON RATE OF REACTION OF PHTHALIMIDE WITH PIPERIDINE
37
and hence, under such experimental conditions,
[Pip] Ϸ [Pip]T.
Eq. (8) predicts that the plot of 1/kobs vs. [Pip]T/
[XOϪ]T should be linear. Such plots, as shown in Fig-
ure 4, are essentially linear. The fitting of the observed
data to Eq. (8) is evident from the plots of Figure 4,
where solid lines are drawn through the calculated data
points. The reaction step involving the reaction be-
tween SϪ and HOϪ is not included in Scheme II for
the reason that the rate of hydrolysis of phthalimide is
independent of [HOϪ] within its range 0.0025–0.050
M and the value of the second-order rate constant (kOH
)
3
1
for the reaction of HOϪ with SϪ is 3.48 ϫ 10Ϫ MϪ
1
sϪ at 30ЊC in aqueous solvent containing Ͻ2% v/v
CH3CN [43,44]. Furthermore, reasonably good fitting
of observed data to Eq. (8) rules out the significance
of kOH[HOϪ][SϪ] compared with kOH[HOϪ][SH] or ki-
netically indistinguishable kH O[H2O][SϪ]. The least-
2
squares calculated values of 1/k0 and kn/kOXk0 at dif-
ferent methanol content are summarized in Table IV.
The values of kobs obtained at 20 and 50% v/v
CH3OH in the absence of Pip at 0.01 M NaOH
(Table I) are comparable with the corresponding
values of k0 (Table IV). The value of kOX at 20
and 50% v/v CH3OH (Table IV) are within the
expected range based upon the reported values of kOH
Figure 4 Plots showing the dependence of 1/kobs upon
[Pip]T/[XO ]T (where X ϭ H, CH3) for the cleavage of
phthalimide within the [Pip]T range 0.02–0.40 M at 0.03 M
NaOH and 20 (᭝) and 50% v/v CH3OH (᭺).
Ϫ
1
1
for cyclization of phthalamide (kOH ϭ 2.5 MϪ sϪ ,
represent rate constants for the reactions of XOH with
SϪ and XOϪ with SH, respectively, and [XOϪ]T ϭ
[NaOH] ϩ [XOreϪ] with [NaOH] ϭ 0.03 M. In order
to treat the observed data (kobs vs. [Pip]T) to Eq. (8),
the values of [XOre Ϫ] at different values of [Pip]T were
calculated from Eq. (9):
statistically corrected value at 25.9ЊC) [48], o-amino-
1
1
methylbenzamide (kOH ϭ 0.16 MϪ sϪ at 30ЊC)
[59], and o-hydroxymethylbenzamide (kOH ϭ 0.04
1
1
1
1
MϪ sϪ at 25ЊC [63] and 0.154 MϪ sϪ at 30ЊC
[64]).
[XOreϪ] ϭ [ϪZ ϩ (Z 2 ϩ 4Y [Pip]T)1/2]/2 (9)
Mechanistic Speculations
where Z ϭ [NaOH] ϩ Y and Y ϭ Kw/KPaip. The cal-
culated values of [XOreϪ] at different [Pip]T in the
presence of 0.03 M NaOH revealed that the values of
The increase in the content of methanol in mixed aque-
ous solvent from 10 to 98% v/v changed kn from a
sharp decrease in the water-rich region followed by a
slow decrease in the methanol-rich region of kn vs. the
% v/v CH3OH profile (Table II). Such a solvent effect
on the rate of piperidinolysis of phthalimide may be
attributed to several factors, as described elsewhere
[22]. But it seems more appropriate to discuss the sol-
3
[PipHϩ] (ϭ[XOreϪ]) range from 1.36 ϫ 10Ϫ to 18.2
3
3
ϫ 10Ϫ M at 20% v/v CH3OH and 0.3 ϫ 10Ϫ to 5.0
ϫ 10Ϫ3 M at 50% v/v CH3OH within the [Pip]T range
0.02–0.40 M. These results show that [PipHϩ] Ͻ 7%
at 20% v/v CH3OH and Ͻ2% at 50% v/v CH3OH
Table IV Values of 1/k0 and kn/k0k⌷⌾ Calculated from Eq. (8)a
Ϫ1
Ϫ1
k⌷⌾b (M
Ϫ1
CH3OH (% v/v)
1/k0 (s)
kn/k0k⌷⌾ (s)
104 k0 (s
)
s )
20
50
665 Ϯ 30c
1623 Ϯ 101
132 Ϯ 6c
150 Ϯ 15
15.0
6.16
0.47
0.23
a Conditions are described in Table III.
3
3
1
1
b The values of k⌷⌾ were calculated from the calculated values of 1/k0 and kn/k0k⌷⌾, with kn ϭ 93.6 ϫ 10Ϫ and 21.6 ϫ 10Ϫ MϪ sϪ at
20 and 50% v/v methanol, respectively (Table II).
c Error limits are standard deviations.

38
KHAN
vent effect on the rate of an addition-elimination re-
action in terms of the solvent effect on nucleophilicity
of nucleophile (i.e., the pKa of conjugate acid of nu-
cleophile) and on the leaving ability of the leaving
group (i.e., the pKa of conjugate acid of leaving
group).
tonitrile solvents involves addition-elimination reac-
tion mechanisms, as discussed elsewhere [27]. The
same mechanisms are assumed to occur in mixed
aqueous-methanol and methanol solvents. The piper-
idinolysis of phthalimide was found to be uncatalyzed
in both mixed aqueous-acetonitrile and aqueous-meth-
anol solvents until the content of organic cosolvent
became 80% v/v. But in pure acetonitrile solvent, the
uncatalyzed kinetic term (kn[Pip]T[SH]) became insig-
nificant compared with the catalyzed kinetic term
The mixed aqueous-organic solvents (both protic
and aprotic organic cosolvents) should have little ef-
fect on the ionization constants (Ka) of isoelectric ion-
ization reactions (i.e., reactions of the type: BHϩ L
B ϩ Hϩ). This may be true only if the reactant and
product molecules are not highly hydrophobic and
product molecules are neutral. The effects of mixed
aqueous-organic solvents on pKa of conjugate acids of
several amines have been reported where the increase
in the contents of organic cosolvents increases the Ka
to the certain range (ϳ50–80% v/v) of the contents
of organic cosolvents [14,22,65,66]. The pKa values
of conjugate acids are larger by several pK units in
pure CH3CN solvent compared to those in pure water
solvent [67]. Similarly, pKa values of several amidines
in mixed aqueous-ethanol showed that pKa at 95.6%
w/w Ͼ pKa at 80% w/w Ͻ pKa at 50% w/w Ͻ pKa at
30% w/w ethanol [68]. The pKa of PipHϩ decreased
from 11.37 to 10.98 with the increase in the con-
tent of acetonitrile from 2 to 50% v/v, while it
increased from 10.98 to 11.36 with the increase in ace-
tonitrile content from 50 to 70% v/v [62]. The pKa of
PipHϩ became 18.92 at 100% CH3CN [13–22]. Meth-
anol, being a protic polar solvent, is a better ion-sol-
vating solvent than aprotic acetonitrile solvent. Thus,
the effect of mixed methanol-water solvent
on the pKa of PipHϩ may be expected to be milder
than that of mixed acetonitrile-water solvent. This
conclusion is supported by the reported values of
pKa of phenol as 14.36 [47] and 27.2 [13] in
pure methanol and pure acetonitrile solvent, re-
spectively.
2
{⌿[Pip]T [SH]/(1 ϩ ⌽[Pip]T)} in the rate law, where
the presence of ⌽[Pip]T in the denominator was attrib-
uted as the kinetic evidence for the occurrence of a
stepwise mechanism in pure acetonitrile solvent. Fig-
ure 2 indicates that both uncatalyzed and catalyzed
kinetic terms are significant in methanol solvent con-
taining 2% v/v acetonitrile. The absence of a
kn[Pip]T[SH] term in pure acetonitrile solvent and
the difference in the kinetic behavior of catalyzed
2
reaction steps {⌿[Pip]T [SH]/(1 ϩ ⌽[Pip]T) in
2
acetonitrile and ⌿[Pip]T [SH] in methanol solvents}
in pure acetonitrile and methanol solvents may
be explained qualitatively through reaction
Scheme III.
Unlike the ionization constant (Ka) of an isoelectric
ionization reaction, the ionization constant (Ka) of a
nonisoelectric ionization reaction (AH L AϪ ϩ Hϩ)
decreased continuously with the increase in the
content of organic cosolvent (both protic and
aprotic) in mixed aqueous solvent [45,47,69]. The
pKa of phenol increased from 10.17 to 13.38 with
the increase in the content of acetonitrile from 2
to 70% v/v [45], and from 10.0 to 11.34 with the
increase in methanol content from 0 to 70% w/w
[47]. Similarly, the pKa of benzoic acid showed
continuous nonlinear increase from 4.2 to 6.4 with
the increase in the content of ethanol from 0 to
70% w/w [46].
Scheme III
The mechanism for piperidinolysis of phthalimide
in pure acetonitrile solvent revealed the change in the
rate-determining step from the k2 step to the k3 step
with the increase in [Pip]T, while the k43 step was the
rate-determining step in mixed aqueous-acetonitrile
3
3
The cleavage of phthalimide in the presence of pi-
peridine in mixed aqueous-acetonitrile and pure ace-

EFFECTS OF SOLVENTS ON RATE OF REACTION OF PHTHALIMIDE WITH PIPERIDINE
39
solvents [27]. The absence of change in the slope of
the plot of kanpp vs. [Pip]T at 98% v/v CH3OH indicates
that the k33 step cannot be the rate-determining step in
the [Pip]T range 0.2–0.8 M. Thus, it appears that the
k43 step is the rate-determining step in the mixed aque-
ous-methanol solvents, while both the k2 and k4 steps
are rate-determining steps in the methanol solvent con-
taining 2% v/v CH3CN.
this solvent effect is attributed to several factors,
including the effect of solvent on the pKa of con-
jugate acids of nucleophile (HOϪ) and leaving
group (—CONHϪ). Although CH3OϪ is a
many-fold stronger nucleophile than HOϪ
toward the nucleophilic attack at carbonyl car-
bon of esters, it is concluded that the observed
rate constants, kobs, represent for hydrolysis and
not for methanolysis of phthalimide.
3
3
Although the dielectric constants of acetonitrile and
methanol are not significantly different from each
other, the protic methanol solvent should stabilize
highly unstable zwitterionic intermediate (TϮ) more
strongly than aprotic acetonitrile solvent. The value of
2. The absence and presence of general base ca-
talysis in the reaction of Pip with phthalimide
within the methanol content range 0–ϳ80%
v/v and at 98% v/v CH3OH, respectively, are
concluded to be from the solvent effect on
the stability of highly reactive zwitterionic in-
termediate (TϮ) involved in a stepwise addition-
elimination reaction mechanism. The monotonic
decrease in the values of nucleophilic second-
order rate constants (kn) for the reaction of Pip
with phthalimide with the increase in methanol
content is attributed to the most probable factor,
which involves the solvent effect on the pKa of
conjugate acids of nucleophile (Pip) and the
leaving group (—CONHϪ).
3. The rate of reaction of Pip with phthalimide,
studied in the absence of added NaOH, indicates
a weak presence of equilibrium between reac-
tants (SH ϩ Pip) and product (N-piperidiny-
phthalamide, 3). The presence of such an equi-
librium became more apparent when the rate of
reaction of phthalimide with Pip was studied in
the presence of 0.03 M NaOH.
3
k4 should be larger in methanol than in acetonitrile
solvent for the reason that the pKa of conjugate acid
of leaving group (—CONH2) should be larger in ace-
3
tonitrile than in methanol solvent. The values of k2
and kϪ 3 are not expected to be influenced significantly
2
with the change in the solvent from methanol to ace-
tonitrile because the reactions involved in these steps
3
are isoelectric reactions. Thus, it is apparent that k4
3
3 [HN
]
ϽϽ k2
in acetonitrile solvent, while k is no
4
3
longer insignificant compared with k2
in
[HN
]
3
methanol solvent. Just like the value of k4 , the value
of k3 should be significantly larger in methanol than
3
in acetonitrile solvent. It is therefore obvious that
3
3
3 [H2Nϩ
]
k3 ϾϾ kϪ
in methanol solvent, while k
2
-2
3
[H2Nϩ
(Ͼ0.6 M).
]
ϾϾ k in acetonitrile solvent at high [Pip]T
3
It is evident from the results in ref. [27] and in Table
II that, at constant content of organic cosolvent in
mixed aqueous solvent, the value of kanpp is larger in
aqueous methanol than in aqueous-acetonitrile. This is
3
3
3
due to larger values of k1 /kϪ and k4 in aqueous-
1
methanol than in aqueous-acetonitrile because the
The work was supported financially by the National Science
Council for R & D, IRPA, Grant No. 09-02-03-0003.
equilibrium formation of (TϮ) from SH or SϪ and Pip
3
(i.e., equilibrium constant k1 /kϪ 3) constitutes a non-
1
isoelectric process.
In summary, the absence and presence of general
base catalysis in mixed H2O-Z (where Z ϭ CH3OH
and CH3CN) with Z Յ 80% v/v and pure Z solvent,
respectively. These observations appear to be the
consequence of the decrease in the stability of TϮ
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