Effects of mixed H2O-CH3CN solvents on the Bronsted coefficient for the intramolecular general base-catalyzed cleavage of ionized phenyl salicylate in the presence of primary and secondary amines

Article abstract of DOI:10.1002/(SICI)1097-4601(2000)32:3<153::AID-KIN5>3.0.CO;2-W

Nucleophilic second-order rate constants, k_n^ms, for the reactions of several primary and secondary amines with ionized phenyl salicylate (PS^-) show a nonlinear decrease with the increase in the content of CH₃CN from 2 to ≤50% v/v in mixed aqueous solvent. The values of k_n^ms remain almost unchanged with the change in the content of CH₃CN at >50% v/v. The nucleophilic reactivity of primary and secondary amines toward PS^- reveal Bronsted plots of different Bronsted coefficients, β_nuc, at a constant content of CH₃CN in mixed aqueous solvents. The values of β_nuc decrease from 0.4 to nearly 0 for primary amines and from 0.22 to 0.12 for secondary amines with the increase in CH₃CN content from 2 to 70% v/v. The values of k_n^ms/k_MeOH^ms (where k_MeOH^ms represents the nucleophilic second-order rate constant for the reaction of MeOH with PS^- in H₂O-CH₃CN solvents), obtained within 2-50% v/v CH₃CN, fit to an empirical equation: log (k_n^ms/k_MeOH^ms) = θ+λX where X is the % v/v content of CH₃CN, and θ and λ are empirical constants. It has been shown empirically that both θ and λ are the function of Bronsted coefficient β_lg. The values of λ are used to calculate β_lg and these β^lg values for all amines except Tris lie within -0.32 to -0.46. The effects of mixed water-acetonitrile solvents on pK_a of leaving the group, phenol, and conjugate acid of amine nucleophile have been concluded to be the major source for the observed solvent effects on k_n^ms. The β_lg for Tris is unusually very close to zero.

Full text of DOI:10.1002/(SICI)1097-4601(2000)32:3<153::AID-KIN5>3.0.CO;2-W

Effects of Mixed H2O–
CH3CN Solvents on the
Brønsted Coefficient for the
Intramolecular General
Base-Catalyzed Cleavage of
Ionized Phenyl Salicylate in
the Presence of Primary
and Secondary Amines
M. NIYAZ KHAN, Z. ARIFIN, A. GEORGE, I. A. WAHAB
Department of Chemistry, Faculty of Science, University Malaya, 50603 Kuala Lumpur, Malaysia
Received 24 June 1999; accepted 8 November 1999
ABSTRACT: Nucleophilic second-order rate constants, knms, for the reactions of several primary
Ϫ
and secondary amines with ionized phenyl salicylate (PS ) show a nonlinear decrease with
the increase in the content of CH3CN from 2 to Յ50% v/v in mixed aqueous solvent. The values
of knms remain almost unchanged with the change in the content of CH3CN at Ͼ50% v/v. The
Ϫ
nucleophilic reactivity of primary and secondary amines toward PS reveal Brønsted plots of
different Brønsted coefficients, ␤nuc, at a constant content of CH3CN in mixed aqueous sol-
vents. The values of ␤nuc decrease from 0.4 to nearly 0 for primary amines and from 0.22 to
0.12 for secondary amines with the increase in CH3CN content from 2 to 70% v/v. The values
ms
ms
of knms/kMeOH (where kMeOH represents the nucleophilic second-order rate constant for the
Ϫ
reaction of MeOH with PS in H2O–CH3CN solvents), obtained within 2–50%v/v CH3CN, fit to
an empirical equation: log (knms/kMeOHms) ϭ ␪ ϩ ␭X where X is the % v/v content of CH3CN,
and ␪ and ␭ are empirical constants. It has been shown empirically that both ␪ and ␭ are the
function of Brønsted coefficient ␤lg. The values of ␭ are used to calculate ␤lg and these ␤lg
values for all amines except Tris lie within Ϫ0.32 to Ϫ0.46. The effects of mixed water–ace-
tonitrile solvents on pK of leaving the group, phenol, and conjugate acid of amine nucleophile
a
Correspondence to: M. NiyazKhan (e-mail: niyaz@kimia.um.
edu.my)
Contract grant sponsor: National Science Council for R & D,
IRPA, Malaysia
Contract grant number: 09-02-03-0003
᭧ 2000 John Wiley & Sons, Inc.

154
NIYAZ KHAN ET AL.
have been concluded to be the major source for the observed solvent effects on knms. The ␤lg
for Tris is unusually very close to zero. ᭧ 2000 John Wiley & Sons, Inc. Int J Chem Kinet 32: 153–164,
2000
INTRODUCTION
distilled water. However, stock solutions of 0.25 M
CH3NH3Cl and (CH3)2NH2Cl were freshly prepared in
0.30 M NaOH. Stock solutions of 0.25 M hydrazine
sulfate (NH2NH2 · H2SO4) were freshly prepared in
0.56 M NaOH.
Almost all the biological reactions and a large fraction
of reactions involved in chemical research, including
pharmaceutical developments, occur in aqueous or
mixed aqueous–organic solvents. Although vigorous
efforts have been made for the last several decades to
understand theoretically the effects of such solvents
on rates of reactions, there seems to be no adequate
theory that could explain the complexities of the sol-
vent effects on reaction rates. A huge amount of work
on the effects of mixed aqueous–organic solvents on
the rates of neutral, and acid- and base-catalyzed sol-
volysis of organic molecules has been carried out for
many decades [1]. However, studies of the effects of
mixed aqueous–organic solvents on rates of amino-
lysis of esters, amides, and imides are rare. A few re-
ports have appeared on mixed aqueous–organic sol-
vent effects on rates of aminolysis of esters [2–9]. The
probable cause for the lack of such studies is described
elsewhere [3].
Many enzyme-catalyzed and a large fraction of mi-
cellar as well as vesicle-mediated reactions are be-
lieved to occur in a microreaction medium of consid-
erably low dielectric constant (␧) compared with ␧ of
pure water solvent. Thus, the study on the effects of
mixed aqueous–organic solvents of varying ␧ on the
rates of organic reactions may be of considerable im-
portance [10–12]. The effects of H2O–CH3CN sol-
vents on rates of hydrolysis [13], alkanolysis [14], and
aminolysis [15] of ionized phenyl salicylate (PSϪ)
have been studied. However, the data on aminolysis
of PSϪ were not sufficient to draw any mechanistic
conclusion. We therefore extended the study on the
effects of H2O–CH3CN solvents on rates of amino-
lysis of PSϪ by selecting additional primary and sec-
ondary amines. The results and their probable mech-
anistic implications are discussed in this article.
Kinetic Measurements
The rates of aminolysis of PSϪ were studied by mon-
itoring the disappearance of PSϪ spectrophotometri-
cally at 350 nm. In a typical kinetic run, all the reaction
ingredients (i.e., desired amount of amine, and 0.01 M
NaOH with 4.9 ml of mixed water–acetonitrile sol-
vent containing the required proportion of water and
acetonitrile) except phenyl salicylate, were placed in
a 25-mL reaction vessel, which was, in turn, placed in
a thermostated water bath. The reaction solution (4.9
ml) was allowed to equilibrate for 5–10 min at 35ЊC.
The reaction was then initiated by adding 0.1 ml of
0.01 M phenyl salicylate. An aliquot of ca. 2.5 ml
was quickly withdrawn from the reaction mixture
and transferred to a 3-ml quartzcuvette kept in the
thermostated cell compartment of the spectrophotom-
eter. The decrease in absorbance, Aobs, with time, t, at
350 nm was monitored by the use of a Shimadzu UV-
visible–near infrared or diode–array spectrophotom-
eter.
Almost all the kinetic runs that involved the stock
solutions of nonprotonated amines were studied in the
presence of 0.01 M NaOH. However, all kinetic runs
involving stock solutions of protonated amines [such
as CH3NH3Cl, (CH3)2NH2Cl, and H2NNH2H2SO4]
were carried out in the presence of NaOH ranging
from 0.014 to 0.034 M. Details of the data analysis
and product characterization study are described else-
where [16,17].
RESULTS AND DISCUSSION
؊
Effects of [Am]T on Aminolysis of PS
EXPERIMENTAL
Materials
in Mixed Aqueous –Acetonitrile Solvents
Containing a Constant Concentration
of NaOH
Reagent grade chemicals (obtained from Fluka, BDH,
and Aldrich) were used in the entire study. Stock so-
lutions of phenyl salicylate were prepared in acetoni-
trile. Stock solutions of free amines (i.e., amine bases)
were freshly prepared in both acetonitrile and glass-
A few kinetic runs were carried out at different [Am]T
(ϭ total concentration of amine), at 35ЊC, and at a
constant content of acetonitrile in mixed aqueous sol-
vent. Pseudo-first-order rate constants (kobs) obeyed
Eq. (1)

EFFECTS OF MIXED H2O–CH3CN SOLVENTS
155
kobs Ϫ k0 ϭ knms[Am]T
(1)
to be unchanged with the change in the contents of
CH3CN in mixed aqueous solvents. This shows the
presence of a 100% ionized form (PSϪ) of phenyl sal-
icylate.
where k0 is the pseudo-first-order rate constant for hy-
ms
drolysis and kn is the apparent nucleophilic second-
order rate constant for the reaction of amine with PSϪ.
The value of k0 at a specific experimental condition
was obtained from literature [18,19]. The least-
The increase in the content of CH3CN from 2 to
50% v/v in mixed aqueous solvents decreased knms by
ca. 3.6- to 7.0-fold for various primary and secondary
amines (see Table I). It is noteworthy that minimum
decreases (ϳ3.6-fold) were found for those amines [2-
hydroxyethylamine, hydrazine, morpholine, and N-(2-
hydroxyethyl)piperazine] whose pKa values were
found to be almost independent of % v/v content of
CH3CN within its range of 2–50% v/v (preceding ar-
ticle). The rate constants, knms, were almost indepen-
dent of acetonitrile content at Ն50% v/v CH3CN for
ms
squares-calculated values of kn at different contents
of CH3CN are summarized in Table I. The fitting of
observed data to Eq. (3) is evident from some repre-
sentative plots of Figure 1 where solid lines are drawn
through the least-squares-calculated points and from
the standard deviations associated with the calculated
values of knms (see Table I).
The change in [Am]T at a constant [NaOH] and
[H2O] in mixed acetonitrile solvents is bound to
change [OHϪ]T (ϭ total concentration of hydroxide
ions) due to reaction: H2O ϩ Am L AmHϩ ϩ OHre
where Am and AmHϩ represent unprotonated and pro-
tonated amine, respectively. However, such a change
in [OHϪ]T is not sufficient to cause a nonlinear in-
crease in kobs with the increase in [Am]T at a constant
added [NaOH].
most of the amines.
ms
The rate constants, kn
, for tris-(hydroxy-
Ϫ
methyl)aminomethane (Tris) revealed an increase, al-
though modest, with the increase in the content of
CH3CN from 2 to 70% v/v (see Table I). These results
may be considered to be unusual compared with those
for other amines of the present study. Transesterifi-
cation has been shown to be unimportant compared
with aminolysis in the reaction of Tris with PSϪ in
aqueous solvent containing 0.8% v/v CH3CN [16].
The concentration of protonated amines was con-
sidered to be negligible under the experimental con-
ditions of the present study. This assertion is based on
the fact that the increase in [NaOH] from 0.01 to 0.04
Effects of Mixed Aqueous –Acetonitrile
Solvents on the Rate of Cleavage of PS at
ms
M did not show an increase in kn (see Table I) for
؊
the reaction of PSϪ with 1,3-diaminopropane at 70%
v/v CH3CN. Similarly, an increase in [NaOH] from
0.01 to 0.03 M did not reveal a significant effect on
a Constant [NaOH] in the Presence of
Tertiary Amines
kn for dimethylaminolysis of PSϪ at 2 and 10% v/v
The effects of H2O–CH3CN solvents on the rate of
cleavage of PSϪ were studied by carrying out a few
kinetic runs at different concentrations of N-ethylpi-
peridine and N-(2-hydroxyethyl)morpholine. Pseudo-
first-order rate constants (kobs), obtained at different
total amine concentrations ([Am]T) and at 2 and 60%
v/v CH3CN, are summarized in Table II. It is evident
from the results in Table II that the rate of cleavage of
PSϪ is independent of [N-ethylpiperidine] at both 2
and 60% v/v CH3CN. Similar results were obtained
with several other tertiary amines in aqueous solvents
containing Ͻ2% v/v CH3CN [21–23]. The values of
kobs at different [Am]T are comparable with the cor-
responding values of kobs obtained under similar ex-
perimental conditions in the absence of tertiary amines
[18,19].
ms
CH3CN (see Table I). The increase in the content of
CH3CN either decreased slightly or had no effect on
pKams of amines of the present study until the CH3CN
content became 50–60% v/v. The pKams values of
these amines at 70% v/v CH3CN became equal to or
slightly larger than the corresponding pKa at 2% v/v
CH3CN (preceding article). The pKams value of H2O is
expected to increase with the increase in the content
of CH3CN in mixed aqueous solvents. Thus, the prob-
ability of the presence of AmHϩ decreases with the
increase in the content of CH3CN. A slightly lower
ms
value of kn at 0.04 M NaOH than that at 0.01 M
NaOH for the reaction of PSϪ with 1,3-diaminopro-
pane at 70% v/v CH3CN may be attributed to negative
salt effect [20].
Nonionized phenyl salicylate (PSH) does not ab-
Pseudo-first-order rate constants, kobs, increased
slightly with the increase in the total concentration of
N-(2-hydroxyethyl)morpholine at a constant content
of CH3CN (see Table II). Tertiary amines did not show
nucleophilic reactivity toward PSϪ, and therefore the
amino group of N-(2-hydroxyethyl)morpholine cannot
be expected to react with PSϪ. However, ionized
sorb to a detectable level while PSϪ absorbs strongly
1
(molar extinction coefficient, ␦ Ϸ 6000 MϪ1 cmϪ ) at
350 nm [17]. The values of the initial absorbance (i.e.,
absorbance at the reaction time, t ϭ 0) at 350 nm of
the reaction mixtures for the kinetic runs carried out
under the present experimental conditions were found

Table I Nucleophilic Second-Order Rate Constants (knms) Calculated from Eq. (1)a
ms
b
CH3CN
(% v/v)
103kn
M
[Am]T
(M)
No.
of Runs
Ϫ
1
Ϫ1
Amine
s
1,4-Diaminobutane
2
10
20
30
40
50
60
70
149 Ϯ 4c
(2.59)d
104 Ϯ 3
(2.43)
65.4 Ϯ 1.6
(2.23)
42.2 Ϯ 1.1
(2.26)
31.2 Ϯ 1.0
(2.29)
23.2 Ϯ 0.3
(2.55)
22.0 Ϯ 0.5
(2.91)
0.02–0.10
0.02–0.10
0.02–0.10
0.02–0.10
0.02–0.10
0.02–0.10
0.02–0.06
0.02–0.06
5
5
5
5
5
5
5
5
20.1 Ϯ 0.7
(3.48)
1,3-Diaminopropane
2
10
20
30
40
50
60
70
70e
2
10
20
30
40
50
60
70
2
10
20
30
40
50
60
70
2
10
20
30
40
50
60
70
2
126 Ϯ 3
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.12
0.04–0.12
0.04–0.12
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.12
0.04–0.12
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.12
0.04–0.12
0.20–0.10
0.02–0.10
0.02–0.10
0.02–0.10
0.02–0.10
0.02–0.10
0.02–0.06
0.02–0.06
0.02–0.10
0.02–0.10
0.02–0.10
0.02–0.10
0.02–0.10
0.02–0.10
0.02–0.05
0.02–0.05
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
88.2 Ϯ 3.3
58.0 Ϯ 1.7
37.7 Ϯ 1.0
28.9 Ϯ 0.7
24.6 Ϯ 0.3
20.8 Ϯ 0.6
22.1 Ϯ 0.7
18.1 Ϯ 0.5
34.8 Ϯ 1.0
26.6 Ϯ 1.0
18.7 Ϯ 1.0
12.6 Ϯ 0.6
10.9 Ϯ 0.6
9.63 Ϯ 0.33
10.0 Ϯ 0.4
9.84 Ϯ 0.20
69.6 Ϯ 1.0
50.0 Ϯ 1.7
30.4 Ϯ 1.7
18.4 Ϯ 1.8
13.6 Ϯ 1.0
10.6 Ϯ 0.3
8.94 Ϯ 0.35
7.70 Ϯ 0.14
207 Ϯ 3
2-Hydroxyethylamine
n-Propylamine
Methylaminef
161 Ϯ 3
103 Ϯ 4
67.7 Ϯ 2.9
50.7 Ϯ 2.0
39.4 Ϯ 2.3
34.0 Ϯ 0.8
29.5 Ϯ 1.9
150 Ϯ 4
Hydrazineg
10
20
30
40
50
60
70
114 Ϯ 4
74.6 Ϯ 1.6
54.8 Ϯ 2.5
42.9 Ϯ 8.2
40.3 Ϯ 3.9
42.1 Ϯ 3.4
41.1 Ϯ 7.8
(Continued)

Table I (Continued)
ms
b
CH3CN
(% v/v)
103kn
M
[Am]T
(M)
No.
of Runs
Ϫ
1
Ϫ1
Amine
s
Benzylamine
2
10
20
30
40
50
60
70
2
10
20
30
40
50
60
70
2
35.2 Ϯ 1.2
24.3 Ϯ 2.0
15.1 Ϯ 0.6
9.93 Ϯ 0.40
7.34 Ϯ 0.53
5.00 Ϯ 0.24
5.03 Ϯ 0.37
3.76 Ϯ 0.08
6.06 Ϯ 0.17
6.28 Ϯ 0.17
6.59 Ϯ 0.41
6.37 Ϯ 0.24
7.16 Ϯ 0.29
8.15 Ϯ 0.35
10.2 Ϯ 1.2
14.8 Ϯ 1,6
143 Ϯ 3
0.03–0.12
0.03–0.12
0.03–0.12
0.03–0.12
0.03–0.15
0.03–0.15
0.03–0.15
0.03–0.15
0.2–0.6
0.2–0.6
0.2–0.6
0.2–0.6
0.2–0.6
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
4
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
4
5
5
5
5
5
5
5
5
5
5
5
5
5
Tris
0.2–0.6
0.2–0.6
0.1–0.4
Morpholine
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.12
0.04–0.12
0.02–0.06
0.02–0.06
0.02–0.06
0.02–0.06
0.02–0.06
0.02–0.06
0.02–0.06
0.02–0.06
0.02–0.06
0.02–0.06
0.02–0.07
0.02–0.07
0.02–0.06
0.02–0.07
0.02–0.07
0.02–0.07
0.02–0.07
0.02–0.06
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.20
0.04–0.12
0.04–0.12
10
20
30
40
50
60
70
2
107 Ϯ 2
75.7 Ϯ 1.9
53.8 Ϯ 1.7
43.6 Ϯ 1.1
38.2 Ϯ 1.3
36.0 Ϯ 0.9
36.0 Ϯ 0.8
613 Ϯ 15
648 Ϯ 9
474 Ϯ 5
478 Ϯ 10
308 Ϯ 5
202 Ϯ 4
145 Ϯ 5
Dimethylaminef
2g
10
10g
20
30g
40
50
60
70
2
10
20
30
40
50
60
70
2
10
20
30
40
50
60
70
116 Ϯ 4
96.6 Ϯ 4.3
78.6 Ϯ 4.9
419 Ϯ 5
312 Ϯ 3
217 Ϯ 2
155 Ϯ 3
120 Ϯ 2
103 Ϯ 2
100 Ϯ 3
99.9 Ϯ 3.6
148 Ϯ 3
110 Ϯ 6
75.3 Ϯ 1.6
55.8 Ϯ 2.3
44.8 Ϯ 1.4
40.4 Ϯ 1.3
39.8 Ϯ 1.1
42.8 Ϯ 0.7
Piperazine
N-(2-Hydroxyethy)piperazine
a [Phenyl salicylate]0 ϭ 2 ϫ 10Ϫ4 M, 35ЊC, ␭ ϭ 350 nm, and unless otherwise noted [NaOH] ϭ 0.01 M.
b
Total amine concentration.
c Error limits are standard deviations.
d
Parenthesized values are for kMeOHms obtained from reference [14].
e [NaOH] ϭ 0.04 M.
f Stock solution of methylammonium chloride (0.25 M) was prepared in 0.30 M NaOH.
g
Stock solution of hydrazineammonium sulfate (0.25 M) was prepared in 0.56 M NaOH.

158
NIYAZ KHAN ET AL.
coholic group of triethanolamine showed significant
nucleophilic reactivity toward PSϪ [16]. The absence
of transesterification of PSϪ in the presence of primary
and secondary amines containing alcoholic groups is
due to the fact that amino groups of these amines are
much more reactive than their alcoholic groups.
Pseudo-first-order rate constants, kobs, were at-
tempted to fit to equation: kobs ϭ k0 ϩ kROH [Am]T and
the least-squares-calculated values of k0 and kROH are
4
1
4
(7.78 Ϯ 0.59) ϫ 10Ϫ sϪ and (7.04 Ϯ 2.26) ϫ 10Ϫ
MϪ1 sϪ1 at 2% v/v CH3CN and (3.42 Ϯ 0.16) ϫ 10Ϫ
4
sϪ and (6.47 Ϯ 1.32) ϫ 10Ϫ MϪ sϪ at 60% v/v
CH3CN, respectively. The values of k0 at 2 and 60%
v/v CH3CN may be compared with kobs obtained in the
presence of N-ethylpiperidine at 2 and 60% v/v
CH3CN (see Table II). The increase in the content
of CH3CN from 2 to 60% v/v decreased kROH from
1
4
1
1
7.04 ϫ 10Ϫ to 6.47 ϫ 10Ϫ MϪ sϪ . A similar mild
effect of CH3CN was obtained in methanolysis of
PSϪ [14]. It is interesting to note that the value of kROH
4
4
1
1
Figure 1 Effect of total concentration of morpholine—
[Am]T—on corrected pseudo-first-order rate constants
4
1
1
(ϭ 7.04 ϫ 10Ϫ MϪ sϪ ) at 2% v/v CH3CN is not
Ϫ
(kobscorr ϭ kobs Ϫ k0) for the cleavage of PS at 2 ( ), 10 (᭛),
significantly different from kROH obtained for the re-
1
actions of PSϪ with ethanol (kROH ϭ 6.26 ϫ 10Ϫ4 MϪ
20 (᭞), 30 (ٗ), 50 (᭝), and 70% CH3CN (᭺). The solid lines
are drawn through the least-squares-calculated points using
Eq. (1) and parameters listed in Table I.
1
4
sϪ ) [18] and triethanolamine (kROH ϭ 5.53 ϫ 10Ϫ
1
MϪ1 sϪ , statistically corrected value) [16] at 30ЊC.
ms
ms
The Dependence of kn on pKa of
phenyl salicylate, PSϪ, undergoes transesterificationin
the presence of alcohols [17]. Thus, in the absence of
nucleophilic reactivity of the amino group, alcoholic
group of N-(2-hydroxyethyl)morpholine revealed de-
tectable nucleophilic reactivity toward PSϪ. The al-
Conjugate Acids of Primary and Secondary
Amines at a Constant Content of CH3CN
The reactions of PSϪ with primary and secondary
amine, water, and alcohols involve intramolecular
Ϫ
Table II Pseudo-First-Order Rate Constants (kobs) for the Cleavage of PS in the Presence of Tertiary Amines at
Different Contents of CH3CNa
b
c
CH3CN
(% v/v)
[Am]T
(M)
104kobs
104kcalcd
(s )
Ϫ
1
Ϫ1
Amine
(s
)
N-(2-Hydroxyethyl)morpholine
2
2
2
60
60
60
2
2
2
60
60
60
0.04
0.20
0.40
0.04
0.10
0.18
0.02
0.10
0.20
0.02
0.05
0.08
8.32 Ϯ 0.05d
8.71 Ϯ 0.11
10.8 Ϯ 0.2
8.06
9.18
10.6
3.68
4.07
4.58
3.74 Ϯ 0.02
3.96 Ϯ 0.02
4.63 Ϯ 0.05
8.07 Ϯ 0.08
7.82 Ϯ 0.07
8.32 Ϯ 0.07
3.04 Ϯ 0.03
3.32 Ϯ 0.04
3.36 Ϯ 0.02
N-Ethylpiperidine
a,b
Notations have same meaning as mentioned in Table I.
c Calculated from the equation: kobs ϭ k0 ϩ kROH[Am]T using the calculated values of k0 and kROH as described in the text.
d
Error limits are standard deviations.

EFFECTS OF MIXED H2O–CH3CN SOLVENTS
159
general base (IGB) catalysis where the ionized phe-
nolic group (o–OϪ) of PSϪ acts as an IGB catalyst.
The simplest mechanism of these reactions is shown
in Scheme I, which involves the formation of
Figure 2 Brønsted plots for the nucleophilic reactivity of
primary amines toward ionized phenyl salicylate at 2 (᭺),
40 (᭝), and 70% CH3CN (᭞). Statistical corrections were
intramolecular intimate ion pair (IIP) and internally
hydrogen-bonded complex (IHP). The nature of the
rate-determining steps in hydrolysis [28], alkanolysis
[23], and aminolysis [16,29] of PSϪ has been dis-
cussed in the previous reports. In view of these reports,
the k4step (see Scheme I) is the rate-determining step
for aminolysis of PSϪ [16,29].
The dependence of the nucleophilic second-order
rate constants (knms) on the pKa of the conjugate acids
of amine nucleophiles at a few CH3CN contents is
shown in Figures 2 and 3. The plots of Figures 2 and
3 at low contents of CH3CN indicate that the rate con-
stants (knms) for the reactions of PSϪ with primary and
secondary amines constitute the Brønsted plots of dif-
ferent slopes. The Brønsted slopes (␤nuc1 and ␤nuc2) for
the nucleophilic reactions of primary and secondary
amines with PSϪ were calculated from Brønsted Eqs.
(2) and (3), respectively.
ms
made to both kn and pKa of diamines. In the plots, 1 rep-
resents 1,4-diaminobutane; 2, 1,3-diaminopropane; 3, 2-hy-
droxyethylamine; 4, n-propylamine; 5, methylamine; 6,
benzylamine; 7, Tris; 8, n-butylamine [9]; 9, 3-hydroxypro-
pylamine [15]; 10, 1,2-diaminoethane [15]; and 11, glycine
[15]. The solid lines are drawn through the least-squares-
calculated points using Eq. (2) and parameters listed in
Table III.
able because of a rather narrow range of pKa (ϳ3 pK
units) of nucleophiles covered in the calculation of
these Brønsted slopes, these values do indicate that
␤
nuc1
Ͼ ␤nuc2 at different contents of CH3CN ranging
from 2 to 30% v/v. However, the values of ␤nuc1 and
nuc2 become almost zero at 70% v/v CH3CN. In terms
␤
of the traditional interpretation of Brønsted slopes
(␤nuc), the different values of ␤nuc1 and ␤nuc2 indicate
the involvement of different locations or structures of
transition state on the reaction coordinate [30]. The
mechanistic interpretation of the different values of
ms
log kn
ϭ C1 ϩ ␤nuc1pKa
(2)
(3)
,RNH2
ms
log kn ,R2NH ϭ C2 ϩ ␤nuc2pKa
␤
nuc1
and ␤nuc2, obtained in an aqueous solvent con-
The least-squares-calculated values of C1, ␤nuc1, C2,
and ␤nuc2 at different contents of CH3CN are summa-
rized in Table III. Statistical corrections to kn and
taining 0.8% v/v CH3CN, is given in some detail else-
where [16].
The increase in CH3CN content from 2 to 70%
v/v into the reaction medium decreased both ␤nuc1 and
ms
pKa2 were made for diamines in the calculation of
Brønsted slopes. Although the calculated values of
␤nuc2. Similar observations have been reported on other
␤nuc1 and ␤nuc2 may not be considered to be very reli-
acyl-transfer reactions in dimethyl sulfoxide

160
NIYAZ KHAN ET AL.
[33–36] the reacting system should be more reactive
in CH3CN–H2O solvent containing 70% v/v CH3CN
than in water solvent. The observed results, however,
do not appear to agree with this prediction. For the
2%
typical amines of pKa range 8–11, the values of kn
/
70%
2%
70%
kn
(kn and kn
represent nucleophilic second-
order rate constants for the reactions of amine with
PSϪ in CH3CN–H2O solvent containing 2 and 70%
v/v CH3CN, respectively) were 3.5–9.4 for primary
amines and 3.0–7.8 for secondary amines. However,
kn2%/kn70% ϭ 0.4 for only Tris (see Table I).
The increase in the acetonitrile content from 2 to
70% v/v in mixed aqueous solvent increased pKa of
phenol from 10.17 to 13.38 (see preceding article).
Thus, the pKams of PSH (conjugate acid of PSϪ) is
expected to increase by ϳ3 pK units with an increase
in acetonitrile content from 2 to 70% v/v. However,
pKams values of all amines decreased slightly (ϳ0.1–
0.4 pK units) with the increase in the content of
CH3CN from 2 to 60% v/v while the pKams values at
70% v/v CH3CN became equal or slightly larger (by
Յ0.7 pK units) than the corresponding pKams at 2%
v/v CH3CN (see preceding article). If the assumption
that the pKa of ammonium ion moiety in IIP is similar
to that of the conjugate acid of free amine [37–40],
then the increase in the acetonitrile content from 2 to
60% v/v should slightly decrease the pKa of ammo-
nium ion moiety in IIP. The pKa of ammonium ion
moiety in IIP at 70% v/v should be similar or slightly
larger than pKa at 2% v/v CH3CN. It should be noted
that the amount of the charge density on negatively
charged oxygen of phenolate ion and positively
charged nitrogen of ammonium ion moieties in IIP
(see Scheme I) and hence in the transition state de-
pends on the pKa of PSH and conjugate acid of amine
nucleophile. It is now apparent that the increase in the
content of CH3CN from 2 to 70% v/v should decrease
Figure 3 Brønsted plots for the nucleophilic reactivity of
secondary amines toward ionized phenyl salicylate at 2 (᭺),
40 (᭝), and 70% CH3CN (᭞). Statistical corrections were
ms
made to both kn and pKa of diamines. In the plots, 1 rep-
resents morpholine; 2, dimethylamine; 3, piperazine; 4,
N-(2-hydroxyethyl)piperazine; 5, piperidine [9]; and 6, pyr-
rolidine [9]. The solid lines are drawn through the least-
squares-calculated points using Eq. (3) and parameters listed
in Table III.
(DMSO)–H2O [31] and ethanol–water [2] solvents.
If the usual interpretation that the decrease in ␤nuc val-
ues shows the shift of the transition state toward the
reactant side is correct, then in terms of the Hammond
postulate [32] and the reactivity–selectivity principle
Table III Values of Parameters, C and ␤nuc, Calculated from Eqs. (2) and (3) at Different Contents of CH3CN in
Mixed Aqueous Solvents
Primary
Secondary
Class of amine
CH3CN/%v/v
ϪC1
␤
ϪC2
␤
nuc2
nuc1
2
10
20
30
40
50
60
70
5.32 Ϯ 0.60a
5.04 Ϯ 0.58
4.50 Ϯ 0.62
4.24 Ϯ 0.66
3.89 Ϯ 0.74
3.48 Ϯ 0.72
3.02 Ϯ 0.82
1.91 Ϯ 0.79
0.40 Ϯ 0.06a
0.36 Ϯ 0.06
0.29 Ϯ 0.06
0.25 Ϯ 0.07
0.20 Ϯ 0.07
0.15 Ϯ 0.07
0.10 Ϯ 0.08
Ϫ0.02 Ϯ 0.08
2.73 Ϯ 0.57a
2.80 Ϯ 0.68
2.92 Ϯ 0.76
2.89 Ϯ 0.76
2.94 Ϯ 0.78
2.84 Ϯ 0.79
2.68 Ϯ 0.81
2.56 Ϯ 0.74
0.22 Ϯ 0.06a
0.21 Ϯ 0.07
0.21 Ϯ 0.08
0.19 Ϯ 0.08
0.18 Ϯ 0.08
0.17 Ϯ 0.08
0.15 Ϯ 0.08
0.12 Ϯ 0.07
a Error limits are standard deviations.

EFFECTS OF MIXED H2O–CH3CN SOLVENTS
161
the positive charge density on nitrogen of ammonium
ion moiety and negative charge density on the oxygen
of phenolate ion moiety in IIP.
It has been elegantly argued by Jencks et al. [41–
43] and Williams [44] that the magnitude of ␤nuc ob-
tained for nucleophilic substitutions may be a measure
of the positive charge development on the attacking
atom in the critical transition state. Although this pro-
posal is not free from objections [42], if we assume its
validity, then the decrease in the values of ␤nuc1 and
molecular reaction involving a neutral and an ionic
reactants should increase with the decrease in ␧ of the
reaction medium [47]. The decrease in knms with partial
loss of the efficiency of intramolecular general base
(IGB) catalysis due to IP formation at relatively low
relative permittivity of the reaction solvent containing
a predominantly aprotic cosolvent, CH3CN, cannot be
completely ruled out.
␤
nuc2
with the increase in the content of CH3CN is in
agreement with the conclusion that the increase in the
content of CH3CN should decrease the positive charge
density on cationic nitrogen in IIP and consequently
in the transition state of the rate-determining step (i.e.,
k4 step of Scheme I).
It is interesting to note that the change in the di-
electric constant (␧) from ␧ for pure water—75.04 at
35ЊC [45]— to ␧ for mixed aqueous solvent contain-
ing 70% v/v CH3CN—␧ for pure acetonitrile is 37.5
70%
at 20ЊC [45]—resulted in the values of kn2%/kn
in
the range of 3.5–9.4 for primary amines and 3.0–7.8
for secondary amines of the present study. This shows
that the rates of intramolecular-catalyzed reactions of
this kind are not greatly affected by the change in the
polarity of the bulk of the reaction medium. An at-
tempt to interpret the enzymatic reactions involving
intramolecular general base catalysis as greatly influ-
enced by the change in the polarity of the active site
of enzyme compared with that of the bulk solvent re-
quires careful reconsideration.
The rate of the reactions of H2O with PSϪ, ionized
methyl salicylate (MSϪ), and ethyl salicylate (ESϪ) re-
sulted in an extremely weak sensitivity to the pKa of
leaving groups (␤lg ϭ Ϫ0.03 Ϯ 0.01) [28]. Similarly,
the values of the second-order rate constants for meth-
4
1
1
anolysis of PSϪ and ESϪ are 25.9 ϫ 10Ϫ MϪ sϪ at
35ЊC [14] and 3.8 ϫ 10Ϫ MϪ sϪ at 37ЊC [24], re-
spectively. However, the secondary amines did not
show a detectable nucleophilic reactivity toward MSϪ
4
1
1
Effects of Mixed Aqueous –Acetonitrile
ms
Solvents on kn
[16,29,48,49]. The values of (kn Ϫ/kn
)
RNH2 [where
PS
MSϪ
PS
Ϫ
MSϪ
The rate of a chemical reaction is generally influenced
by the specific solute–solvent interaction as well as
the polarity, permittivity, polarizability, acidity, basic-
ity, and structural features of the solvent. It is almost
impossible to dissect these effects from the overall sol-
vent effect on a reaction rate. Generally, all these ef-
fects are not equally influential toward the rate of a
chemical reaction. Very often some of these effects
oppose each other and thus overall solvent effect ap-
pears to be small. It is known that aqueous acetonitrile
is microheterogeneous on the molecular level [46]*.
Such microheterogeneity might produce a microreac-
tion environment of rather low dielectric constant (␧)
compared with ␧ of bulk solvent for a reaction system.
However, the presence of such an apparent low ␧ in
the vicinity of the reaction between PSϪ and R1R2NH
kn
and kn
represent the nucleophilic second-
order rate constants for the reactions of primary
amines (RNH2) with PSϪ and MSϪ, respectively], as
summarized in Table IV, show that the respective rates
of aminolysis and methanolysis of ionized salicylate
esters are highly and weakly sensitive to the basicity
of the leaving groups.
The effects of polarity, permittivity, polarizability,
specific solute–solvent interaction, structure of the
solvent and IP, and formation on reactant state (PSϪ,
XH, and IIP in Scheme I) are expected to be essentially
the same for aminolysis and methanolysis of PSϪ. The
k2 step—rate-determining step for hydrolysis [28] and
methanolysis [23]—involves internal proton transfer
that may be insensitive to the pKa of the leaving group
while the k4 step—rate-determining step for amino-
ms
is expected to increase kn because the rate of a bi-
lysis [29]—involves the cleavage of C9O bond cou-
ms
pled with internal proton transfer. Thus, the ratio kn
/
ms
ms
ms
* We thank one of the reviewers for providing this information.
kMeOH
(where kn
and kMeOH
represent the

162
NIYAZ KHAN ET AL.
Table IV Values of the Parameters, ␪ and ␭, Calculated from Eq. (6) for Various Amines
Ϫ102␭
Ϫ
1
a
PS
Ϫ
MS
Ϫ
b
c
Amine
␪
(% v/v)
Ϫ␤lg
(kn /kn
)
Ϫ␤lg
1,4-Diaminobutane
1,3-Diaminopropane
2-Aminoethan-1-ol
n-Propylamine
Methylamine
Hydrazine
Benzylamine
Tris
Morpholine
Dimethylamine
Piperazine
N-(2-Hydroxyethyl)piperazine
2-Methoxyethylamine
1,2-Diaminoethane
Hydroxylamine
3-Aminopropan-1-ol
1.77 Ϯ 0.03d
1.69 Ϯ 0.04
1.13 Ϯ 0.04
1.45 Ϯ 0.03
1.93 Ϯ 0.02
1.76 Ϯ 0.04
1.15 Ϯ 0.02
0.36 Ϯ 0.02
1.74 Ϯ 0.03
2.42 Ϯ 0.02
2.21 Ϯ 0.03
1.75 Ϯ 0.03
1.70 Ϯ 0.08d
1.52 Ϯ 0.12
1.21 Ϯ 0.12
1.76 Ϯ 0.11
1.55 Ϯ 0.08
1.25 Ϯ 0.13
1.76 Ϯ 0.07
Ϫ0.24 Ϯ 0.06
1.23 Ϯ 0.10
1.61 Ϯ 0.08
1.30 Ϯ 0.09
1.21 Ϯ 0.11
0.45
0.40
0.32
0.46
0.41
0.33
0.46
Ϫ0.06
0.32
0.42
0.34
0.32
376
271
170
0.47
0.44
0.41
223
22
0.43
0.24
250
300
41
0.44
0.45
0.29
0.38
1.51 Ϯ 0.02
1.32 Ϯ 0.02
1.38 Ϯ 0.05
1.39 Ϯ 0.05
0.36
0.36
130
a
1
␤
ϭ ␭/⌿ where ⌿ ϭ 3.81 ϫ 10Ϫ2 (%v/v)sϪ
.
lg
b
c
d
These values were obtained from references [16,29] and [48,49].
P
MS
␤
ϭ log (kn Ϫ/kn Ϫ)/(pKaMeOH Ϫ pKaPhOH), where pKaMeOH ϭ 15.2 and pKaPhOH ϭ 9.67.
lg
Error limits are standard deviations.
nucleophilic second-order rate constants for the reac-
tions of PSϪ with amine and methanol, respectively,
in mixed aqueous–acetonitrile solvents) should be the
measure of the effect of mixed water–acetonitrile sol-
vents on the pKa of the leaving group in the k4 step
(i.e., the pKa of phenol) and the differential effects of
the mixed water–acetonitrile solvents on pKa of con-
jugate acids of amine bases and methanol (i.e., the pKa
where ␾ and ␤lg (Brønsted coefficient) are empirical
constants, and pKams represents the pKa of phenol.
As discussed in the preceding article, the values of
pKams for phenol, obtained within the acetonitrile con-
tent range 2–50% v/v, fit an empirical equation
pKams ϭ ␩ ϩ ⌿X
(5)
ϩ
of CH3OH2 ).
where X represents % v/v content of CH3CN in mixed
aqueous solvent and ␩ as well as ⌿ are empirical
parameters. The calculated values of ␩ and ⌿ are
The increase in the content of CH3CN from 2 to
ms
50% v/v showed a mild effect on pKams or pK2 of
ammonium ions (preceding article). Although we
could not find any report on the effects of mixed wa-
2
1
10.05 Ϯ 0.04 and (3.81 Ϯ 0.14) ϫ 10Ϫ (% v/v)Ϫ ,
respectively.
ϩ
ter–acetonitrile solvents on pKa of CH3OH2 , the val-
Equations (4) and (5) lead to Eq. (6)
ϩ
ues of pKa for CH3OH2 should not be significantly
affected by the change in the content of acetonitrile in
mixed aqueous solvents because the CH3OH molecule
is a highly hydrophilic and ionization of CH3OH2
log (knms/kMeOHms) ϭ ␪ ϩ ␭X
(6)
ϩ
where ␪ ϭ ␾ ϩ ␩␤lg and ␭ ϭ ⌿␤lg.
represents an isoelectric reaction. Thus, it appears that
the increase in acetonitrile content from 2 to 50% v/v
does not change the nucleophilicity of amine and
CH3OH nucleophiles to a significant extent. Thus, the
ratio knms/kMeOHms may be considered to be essentially
dependent on pKams of the leaving group, phenol,
within the acetonitrile content range of ϳ2–50% v/v
and hence in terms of Brønsted hypothesis
ms
Equation (6) predicts that the plots of log (kn
/
kMeOHms) against X should be linear and such plots
turned out to be linear as evident from some repre-
sentative plots of Figure 4 for a few typical amines.
The linear least-squares technique was used to calcu-
late ␪ and ␭ from Eq. (6) and these results are sum-
marized in Table IV. The calculated values of ␭ for
all amines except Tris were negative (see Table IV).
The observed data for Tris yielded considerably small
positive values of ␭ (see Table IV). The observed data
log (knms/kMeOHms) ϭ ␾ ϩ ␤lg pKams
(4)

EFFECTS OF MIXED H2O–CH3CN SOLVENTS
163
The calculated value of ␤lg (ϭ 0.06) for Tris, al-
though not very different from zero, seems to be un-
usual in that all the other primary amines yielded large
negative ␤lg. Similarly, the rate constants knms for Tris
did not show any appreciable deviation from Brønsted
plots (Fig. 2, Table III, and reference 16). This is sur-
prising in view of the large steric requirements for a
nucleophilic attack at carbonyl carbon [51,52]. The
nearly zero value of ␤lg for Tris may be explained if
the hydroxyl moiety rather than the amino moiety of
Tris is acting as the nucleophilic site. However, the
product characterization study had ruled out the oc-
currence of transesterification [16]. Furthermore, a
nearly 10-fold larger value of kn for Tris (see Table I)
4
1
1
than for ethanol (kn ϭ 6.3 ϫ 10Ϫ MϪ sϪ at 30ЊC)
[18,19] is difficult to explain if transesterification is
involved in the cleavage of PSϪ under the presence of
Tris.
CONCLUSION
ms
1. The linear Brønsted plots of log kn vs. pKams
,
Figure 4 Plots of log Y (where Y ϭ knms/kMeOHms ) vs. X—
where X ϭ % v/v content of CH3CN in mixed aqueous sol-
vent—for morpholine (᭝), benzylamine (᭺), methylamine
(᭞), and dimethylamine (ٗ). The solid lines are drawn
through the least-squares-calculated points using Eq. (6) and
parameters listed in Table IV.
obtained within the CH3CN content range 2–
70%, reveal the absence of a change in the rate-
determining step with a change in the content of
CH3CN in mixed aqueous solvents. The increase
in the content of CH3CN is concluded to in-
crease and decrease the pKa of PSH and proton-
ated amine, respectively. The decrease in the
values of ␤nuc1 and ␤nuc2 with the increase in the
content of CH3CN is attributed to the decrease
in the positive charge density on the attacking
nitrogen atom in the critical transition state (k4
step of Scheme I).
point at Ͼ50% v/v CH3CN deviated positively from
linearity of the plot (see Fig. 4). One of the various
possible reasons for such deviations is the increase in
pKa of the conjugate acids of amine nucleophiles with
the increase in the content of CH3CN at Ͼ50% v/v
CH3CN (preceding article).
2. The effects of mixed H2O9CH3CN solvents on
pKa of conjugate acids of the leaving group
(phenolate ion) and nucleophile (amine) were
ascribed to be the major factors for the observed
change in knms with the change in the content of
CH3CN in mixed aqueous solvents. The ob-
The values of ␤lg for various nucleophiles were cal-
culated from the relationship: ␭ ϭ ⌿␤lg using known
2
values of ␭ (Table IV) and ⌿ [ϭ 3.81 ϫ 10Ϫ
(% v/v)Ϫ ] calculated from Eq. (5). These calculated
1
values of ␤lg are shown in Table IV. The values of ␤lg
ms
served data, kn vs. X (where X represents %
for some amines were also calculated from the pub-
PS
Ϫ
MS
Ϫ
content of CH3CN in mixed aqueous solvents),
coupled with a few empirical equations, were
used to calculate ␤lg (Brønsted coefficient) for
various amine nucleophiles.
lished values of kn
and kn
(see Table IV) using
the relationship: ␤lg ϭ log (kn Ϫ/kn Ϫ)/(pKaMeOH
Ϫ
PS
MS
pKaPhOH) where pKaMeOH (ϭ 15.2) [41] and pKaPhOH
(ϭ 9.67) [50] represent pKa of methanol and phenol,
respectively. These ␤lg values are also listed in Table
IV. Although the ␤lg values obtained from the rela-
tionship: ␤lg ϭ log (kn Ϫ/kn Ϫ)/(pKaMeOH Ϫ pKaPhOH
)
PS
MS
BIBLIOGRAPHY
are not very reliable because they are derived from
only two data points, these ␤lg values are comparable
with the corresponding ␤lg values obtained from the
relationship: ␤lg ϭ ␭/⌿.
1. Kirby, A. J. In: Comprehensive Chemical Kinetics, Vol.
10. Bamford, C. H.; Tipper, C. F. H., Eds.; Elsevier:
Amsterdam, 1972; p 57.

164
NIYAZ KHAN ET AL.
2. Castro, E. A.; Ureta, C. J Chem Res (S) 1987, 358; (M)
1987, 3008.
27. Khan, M. N.; Arifin, Z. Langmuir 1997, 13, 6626 and
references cited therein.
3. Um, I.-H.; Shin, E.-H.; Kwon, D.–S. Bull Korean Chem
Soc 1996, 17, 234.
28. Khan, M. N.; Gambo, S. K. Int J Chem Kinet 1985, 17,
419.
4. Castro, E. A.; Valdivia, J. L. J Org Chem 1986, 51,
1668.
5. Castro, E. A.; Santander, C. L. J Org Chem 1985, 50,
3595.
6. Castro, E. A.; Cubillos, M.; Munooz, G.; Santos, J. G.
Int J Chem Kinet, 1994, 26, 571.
7. Um, I.-H.; Kwon, H.-J.; Kwon, O.-S.; Park, J.-Y. J
Chem Res (S) 1995a, 301; (M) 1995b, 1801.
8. Castro, E. A.; Hormazabal, A.; Santos, J. G. Int J Chem
Kinet 1998, 30, 267.
29. Khan, M. N. J Chem Soc Perkin Trans 2 1990, 675.
30. Jencks, W. P. Acc Chem Res 1976, 9, 425; 1980, 13,
161; Chem Soc Rev 1981, 10, 345.
31. Buncel, E.; Um, I.-H.; Hoz, S. J Am Chem Soc 1989,
111, 971.
32. Hammond, G. S. J Am Chem Soc 1955, 77, 334.
33. Pross, A. Adv Phys Org Chem 1977, 14, 69.
34. Buncel, E.; Chuaqui, C. J Org Chem 1980, 45, 2825.
35. Hoz, S. J Org Chem 1980, 47, 3545.
36. Buncel, E.; Wilson, H. J Chem Educ 1987, 64, 475.
37. Fox, J. P.; Jencks, W. P. J Am Chem Soc 1974, 96,
1436.
9. Khan, M. N.; Arifin, Z.; Hanifiah, M. A. M.; Lasidek,
M. N.; George, A. Indian J Chem B, in press.
10. Jencks, W. P. Catalysis in Chemistry and Enzymology;
McGraw–Hill: New York, 1969.
38. Page, M. I.; Jencks, W. P. J Am Chem Soc 1972, 94,
8828.
11. Bunton, C. A. Catal Rev Sci Eng 1979, 20, 1.
12. Shaskus, J.; Haake, P. J Org Chem 1983, 48, 2036 and
references cited therein.
13. Khan, M. N.; Fatope, I. L.; Isaak, K. I.; Zubair, M. O.
J Chem Soc Perkin Trans 2 1986, 655, 10.
14. Khan, M. N.; Arifin, Z.; Yahya, A. H.; Ahmad, F. React
Kinet Catal Lett 1995, 55, 283.
39. Satterthwait, A. G.; Jencks, W. P. J Am Chem Soc 1974,
96, 7031.
40. Cox, M. M.; Jencks, W. P. J Am Chem Soc 1981, 103,
572.
41. Jencks, W. P. Chem Rev 1985, 85, 5111.
42. Hupe, D. J.; Jencks, W. P. J Am Chem Soc 1977, 99,
451 and references cited therein.
15. Khan, M. N. Int J Chem Kinet 1998, 30, 301.
16. Khan, M. N. J Chem Soc Perkin Trans 2 1989, 199.
17. Khan, M. N. J Chem Soc Perkin Trans 2 1990, 445.
18. Khan, M. N. Int J Chem Kinet 1987, 19, 757.
19. Khan, M. N.; Arifin, Z. J Chem Res (S) 1995, 132.
20. Khan, M. N.; Audu, A. A. J Phys Org Chem 1992, 5,
129.
21. Khan, M. N. J Mol Catal 1987, 40, 195.
22. Capon, B.; Ghosh, B. C. J Chem Soc B 1966, 472.
23. Khan, M. N. J Phys Chem 1988, 92, 6273.
24. Irwin, W. J.; Masuda, Q. N.; Li Wan Po, A. Int J Pharm
1984, 21, 35.
43. Gresser, M. J.; Jencks, W. P. J Am Chem Soc 1977, 99,
6963.
44. Williams, A. Acc Chem Res 1984, 17, 425.
45. Anantakrishnan, S. V. J Sci Ind Res 1971, 30, 319.
46. Marcus, Y.; Migron, Y. J Phys Chem 1991, 95, 400.
47. Frost, A. A.; Pearson, R. G. Kinetics and Mechanism,
2nd ed.; John Wiley & Sons: New York, 1961.
48. Khan, M. N. J Org Chem 1983, 48, 2046.
49. Khan, M. N. Int J Chem Kinet 1987, 19, 415.
50. Parsons, G. H.; Rochester, C. H. J Chem Soc Faraday
1 1975, 71, 1058.
51. Jencks, W. P.; Carriuolo, J. J Am Chem Soc 1960, 82,
1778.
52. Khan, M. N. J Chem Soc Perkin Trans 2 1985, 1977.
25. Irwin, W. J.; Masuda, Q. N.; Li Wan Po, A. Tetrahedron
1984, 40, 5217.
26. Irwin, W. J.; Masuda, Q. N.; Li Wan Po, A. J Pharm
Biomed Anal 1985, 3, 241.