Comparison of aminolysis of 2-pyridyl and 4-pyridyl x-substituted benzoates in acetonitrile: Evidence for a concerted mechanism involving a cyclic transition state

Article abstract of DOI:10.1021/jo402629e

A kinetic study on reactions of 2-pyridyl X-substituted benzoates (6a-i) with a series of cyclic secondary amines in MeCN is reported. The Hammett plot for the reaction of 6a-i with piperidine consists of two intersecting straight lines while the Yukawa-Tsuno plot exhibits an excellent linear correlation with ρ_X = 1.28 and r = 0.63, indicating that the nonlinear Hammett plot is not caused by a change in the rate-determining step but rather by resonance stabilization of substrates possessing an electron-donating group (EDG) in the benzoyl moiety. The Bronsted-type plots are linear with β_nuc = 0.59 ± 0.02, which is typical of reactions reported to proceed through a concerted mechanism. A cyclic transition state (TS), which forces the reaction to proceed through a concerted mechanism, is proposed. The deuterium kinetic isotope effect of 1.3 ± 0.1 is consistent with the proposed mechanism. Analysis of activation parameters reveals that ΔH^? increases linearly as the substituent X changes from an electron-withdrawing group (EWG) to an EDG, while TΔS ^? remains nearly constant with a large negative value. The constant TΔS^? value further supports the proposal that the reaction proceeds through a concerted mechanism with a cyclic TS.

Full text of DOI:10.1021/jo402629e

Article
pubs.acs.org/joc
Comparison of Aminolysis of 2‑Pyridyl and 4‑Pyridyl X‑Substituted
Benzoates in Acetonitrile: Evidence for a Concerted Mechanism
Involving a Cyclic Transition State
Ik-Hwan Um,*,† Ae-Ri Bae,† and Tae-Il Um‡
†Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, Korea
‡Dongbuk High School, Seoul 134-060, Korea
S
* Supporting Information
ABSTRACT: A kinetic study on reactions of 2-pyridyl X-substituted
benzoates (6a−i) with a series of cyclic secondary amines in MeCN
is reported. The Hammett plot for the reaction of 6a−i with
piperidine consists of two intersecting straight lines while the
Yukawa−Tsuno plot exhibits an excellent linear correlation with ρX =
1.28 and r = 0.63, indicating that the nonlinear Hammett plot is not
caused by a change in the rate-determining step but rather by
resonance stabilization of substrates possessing an electron-donating
group (EDG) in the benzoyl moiety. The Brønsted-type plots are linear with βnuc = 0.59 0.02, which is typical of reactions
reported to proceed through a concerted mechanism. A cyclic transition state (TS), which forces the reaction to proceed through
a concerted mechanism, is proposed. The deuterium kinetic isotope effect of 1.3
0.1 is consistent with the proposed
mechanism. Analysis of activation parameters reveals that ΔH‡ increases linearly as the substituent X changes from an electron-
withdrawing group (EWG) to an EDG, while TΔS‡ remains nearly constant with a large negative value. The constant TΔS‡ value
further supports the proposal that the reaction proceeds through a concerted mechanism with a cyclic TS.
reaction of O-4-nirophenyl thionobenzoate (4) was concluded
to proceed through a stepwise mechanism with two
intermediates (i.e., T and its deprotonated form T−) since
the plots of kobsd vs [amine] curved upward.7b,c Thus, the
nature of the electrophilic center (e.g., PO, PS, CO, and
CS) has been proposed an important factor to govern the
reaction mechanism.6,7
INTRODUCTION
■
Aminolysis of esters is an important class of reactions not only
in synthetic applications but also in biological processes (e.g.,
peptide biosynthesis and enzyme actions).1 Nucleophilic
substitution reactions of esters with amines have been reported
to proceed either through a concerted mechanism or via a
stepwise pathway with a zwitterionic tetrahedral intermediate
(T ) as shown in Scheme 1, depending on reaction conditions
(e.g., the nature of the electrophilic center, reaction medium,
etc.).2−7
Scheme 1
Linear free energy relationships such as Brønsted-type and
Hammett equations are the most common and popular tools
for deducing reaction mechanisms. A curved Brønsted-type
plot, which is often observed for the aminolysis of esters
possessing a weakly basic leaving group (e.g., 2,4-dinitrophen-
oxide), has been taken as evidence for a change in the rate-
determining step (RDS) of a stepwise mechanism.2 It is now
firmly understood that RDS changes at pKao, defined as the pKa
at the center of the Brønsted curvature, from breakdown of T
to its formation as the incoming amine becomes more basic
than the leaving group (or the leaving group becomes less basic
than the leaving group) by 4−5 pKa units.2 However, the effect
Aminolysis of 4-nitrophenyl diphenylphosphinates (1) and
diphenylphosphinothioates (2) was reported to proceed
through a concerted mechanism on the basis of a linear
Brønsted-type plot with βlg = 0.5 0.1.6 In contrast, aminolysis
of 4-nitrophenyl benzoate (3) was suggested to proceed
through a stepwise mechanism with T on the basis of a linear
Brønsted-type plot with βnuc = 0.81,7a while the corresponding
Received: November 28, 2013
Published: January 7, 2014
© 2014 American Chemical Society
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of nonleaving-group substituents on the pKao is controversial.
Gresser and Jencks found that the pKao for the quinuclidinolysis
of 2,4-dinitrophenyl X-substituted phenyl carbonates increases
as the substituent X becomes a stronger electron-withdrawing
group (EWG).8 Similar results were reported by Castro et al.
for the pyridinolysis of 2,4-dinitrophenyl X-substituted
benzoates and the aminolysis of S-2,4-dinitrophenyl X-
substituted thiobenzoates9 and by Oh et al. for the pyridinolysis
of aryl dithiobenzoates.10 Thus, it has been concluded that an
EWG in the nonleaving group of esters increases pKa° by
decreasing the k2/k−1 ratio.8−10 In contrast, we have suggested
that the k2/k−1 ratio is not governed by the electronic nature of
the nonleaving-group substituents, since an EWG in the
nonleaving group would retard both the k2 and k−1 processes
while an electron-donating group (EDG) would accelerate
them.11 This is because the nucleofuges (e.g.., amine and
aryloxide) depart from T with the bonding electrons. In fact,
we have previously shown that the k2/k−1 ratio is little
influenced by the electronic nature of the substituent X for the
aminolysis of 2,4-dinitrophenyl X-substituted benzoates and X-
substituted benzenesulfonates.11
In contrast, we have recently reported that the electronic
nature of the substituent X governs the reaction mechanism but
not the RDS for the aminolysis of 4-pyridyl X-substituted
benzoates (5a−i) in MeCN; i.e., the plot of kobsd vs [amine]
curves upward when the substituent X is a strong EWG but is
linear when the substituent X is a weak EWG or an EDG.12
Thus, it has been concluded that the reaction of substrates
possessing a strong EWG in the benzoyl moiety proceeds
through a stepwise mechanism with two intermediates (T and
T−) but the deprotonation process to yield T− from T is
absent for the reaction of substrates bearing a weak EWG or an
EDG.12
RESULTS AND DISCUSSION
■
The kinetic study was carried out spectrophotometrically by
monitoring the appearance of the leaving 2-pyridyloxide under
pseudo-first-order conditions (e.g., the concentration of amines
was kept in large excess of that of substrates 6a−i). All of the
reactions in this study obeyed first-order kinetics, and the
pseudo-first-order rate constants (kobsd) were calculated from
the equation, ln (A∞ − At) = −kobsdt + C. The uncertainty in
the rate constants was estimated to be less than 3% from
replicate runs. The plots of kobsd vs [amine] were linear and
passed through the origin in all cases, indicating that general
base catalysis by a second amine molecule is absent. Thus, the
second-order rate constants (kN) were calculated from the
slope of the linear plots of kobsd vs [amine]. The kN values
calculated in this way are summarized in Tables 1−4.
Table 1. Summary of Second-Order Rate Constants for
Nucleophilic Substitution Reactions of 2-Pyridyl X-
Substituted Benzoates (6a−i) with Piperidine in MeCN at
25.0 0.1 °C
entry
X
kN/M−1s−1
6a
6b
6c
6d
6e
6f
3,5-(NO2)2
4-NO2
3-NO2
4-CN
4.48 0.03
0.556 0.006
0.545 0.006
0.409 0.007
4-Cl
0.118 0.001
H
0.0558 0.0009
0.0313 0.0005
0.0161 0.0003
0.00144 0.00004
6g
6h
6i
4-Me
4-MeO
4-Me2N
Effect of Substituent X on Reactivity. The kN values for
the reactions of 6a−i with piperidine is summarized in Table 1.
The kN value is strongly dependent on the electronic nature of
the substituent X; e.g., it decreases from 4.48 M−1 s−1 to 5.58 ×
10−2 M−1 s−1 and then to 1.44 × 10−3 M−1 s−1 as the
substituent X changes from 3,5-(NO2)2 to H and then to 4-
Me2N.
The effect of the substituent X on the reactivity of 6a−i is
illustrated in Figure 1. The Hammett plot consists of two
intersecting straight lines, i.e., the ρX changes from 1.33 to 1.94
Our study has now been extended to the reactions of 2-
pyridyl X-substituted benzoates (6a−i) with a series of cyclic
secondary amines in MeCN to obtain further information on
the reaction mechanism (Scheme 2). We wish to report that
Scheme 2
the electronic nature of the substituent X in the nonleaving
group does not affect the reaction mechanism including the k2/
k−1 ratio, which is contrary to the result reported recently for
the corresponding reactions of 5a−i. However, modification of
the leaving group from 4-pyridyloxide (5a−i) to 2-pyridyloxide
(6a−i) changes the reaction mechanism from a stepwise
mechanism to a concerted pathway.
Figure 1. Hammett plot for the reactions of 2-pyridyl X-substituted
benzoates (6a−i) with piperidine in MeCN at 25.0
0.1 °C. The
identity of points is given in Table 1.
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as the substituent X changes from EWGs to EDGs. Tradition-
ally, such a nonlinear Hammett plot has been interpreted as a
change in the RDS of a stepwise reaction.1,13 In fact, Jencks has
previously concluded that the reactions of X-substituted
benzaldehydes with semicarbazide in a weakly acidic medium
(pH = 3.9) proceed through a stepwise mechanism with a
change in RDS on the basis of a nonlinear Hammett plot, i.e.,
from a large positive ρX to a small one as the substituent X
changes from EDGs to EWGs.1c Thus, one might suggest that
the reactions of 6a−i with piperidine proceed through a
stepwise mechanism with a change in RDS on the basis of the
nonlinear Hammett plot shown in Figure 1, i.e., from formation
of T (the k1 step) to its breakdown (the k2 step) as the
substituent X changes from EDGs to EWGs. This idea appears
to be reasonable because an EWG in the benzoyl moiety would
accelerate the nucleophilic attack (i.e., an increase in k1) but
retard departure of the negatively charged leaving group (i.e., a
decrease in k2), while an EDG would decrease the k1 step but
increase the k2 process.
resonance contribution between the reaction site and the
+
o
substituent X, while the term (σX − σX ) is the resonance
substituent constant that measures the capacity for π-
delocalization of the π-electron donor substituent.15,16
log kNX/kN = ρ [σX + r(σX+ − σX )]
H
o
o
(1)
X
As shown in Figure 2, the Yukawa−Tsuno plot for the
reactions of 6a−i with piperidine exhibits an excellent linear
However, we do not attribute the nonlinear Hammett plot to
a change in RDS, since RDS should be determined by the k2/
k−1 ratio but not by the magnitude of k1 and k2 (i.e., RDS = the
k1 step when k2/k−1 > 1 but RDS = the k2 step when k2/k−1
<
1). Furthermore, k1 and k2 cannot be compared directly since
the former is a second-order rate constant with a unit of
M
−1 s−1, while the latter is a first-order rate constant whose unit
is s−1.
Scrutiny of the nonlinear Hammett plot in Figure 1 reveals
Figure 2. Yukawa−Tsuno plot for the reactions of 2-pyridyl X-
substituted benzoates (6a−i) with piperidine in MeCN at 25.0 0.1
°C. The points are identified in Table 1.
that the substrates possessing an EDG in the benzoyl moiety
(e.g., 6g−i) deviate negatively from the linear line composed of
the substrates bearing an EWG (e.g., 6a−f). Furthermore, the
negative deviation is more significant for the substrate
possessing a stronger EDG. It is apparent that an EDG in
the benzoyl moiety could stabilize the GS of the substrate
through resonance interactions between the EDG in the
benzoyl moiety and the CO bond as modeled by the
resonance structures I and II. Since such resonance stabilization
could cause a decrease in reactivity, we propose that
stabilization of the substrate possessing an EDG is responsible
for the nonlinear Hammett plot. This idea is consistent with the
conclusion drawn for the solvolysis of methyl chloroformate
and acetyl chloride in aqueous acetone.14a The former has been
reported to be 9 × 103 times less reactive than the latter.14a
Kevill has concluded that the GS stabilization through
resonance interactions (e.g., III ↔ IV), analogous to that
suggested in the current systems, is responsible for the
decreased reactivity of methyl chloroformate since such
resonance interaction is not possible for acetyl chloride.14b
correlation with ρX = 1.28 and r = 0.63. Such a linear Yukawa−
Tsuno plot clearly indicates that the nonlinear Hammett plot is
not caused by a change in RDS but rather by the resonance
stabilization of substrates possessing an EDG in the benzoyl
moiety and, further, that the electronic nature of the substituent
X in the nonleaving group does not cause a change in the RDS
of the current reaction.
Deduction of Reaction Mechanism. The linear Yukawa−
Tsuno plot with ρX = 1.28 and r = 0.63 alone does not give any
conclusive information on the reaction mechanism, e.g., a
concerted or stepwise mechanism. To further elucidate the
reaction mechanism, the kN values for the reactions of 2-pyridyl
3,5-dinitrobenzoate (6a), 2-pyridyl 4-nitrobenzoate (6b), and
2-pyridyl benzoate (6f) with a series of cyclic secondary amines
in MeCN were measured. As shown in Table 2, the kN for the
Table 2. Summary of Second-Order Rate Constants (kN) for
the Reactions of 2-Pyridyl 3,5-Dinitrobenzoate (6a), 2-
Pyridyl 4-Nitrobenzoate (6b) and 2-Pyridyl Benzoate (6f)
a
with Amines in MeCN at 25.0 0.1 °C
kN/M−1 s−1
amines
piperidine
pKa
6a
6b
0.556
6f
1
2
3
4
18.8 4.48
18.6 4.00
18.5 4.14
17.6 1.03
0.0558
0.0438
0.0433
0.00859
3-methylpiperidine
piperazine
0.500
0.486
0.110
1-(2-hydroxyethyl)
piperazine
To examine the validity of the above argument, the Yukawa−
Tsuno equation (eq 1) has been used. Equation 1 was originally
derived to rationalize the kinetic data obtained from solvolysis
of benzylic systems in which a partial positive charge develops
in the transition state (TS).15,16 The r value in eq 1 represents
the resonance demand of the reaction center or the extent of
5
morpholine
16.6 0.251
0.0265
0.00266
βnuc
=
βnuc
=
βnuc
=
0.58
0.61
0.61
a
The pKa data in MeCN were taken from refs 17 and 18.
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reaction of 6a decreases with decreasing amine basicity; e.g., it
decreases from 4.48 M−1 s−1 to 0.251 M−1 s−1 as the pKa of the
conjugate acid of amines decreases from 18.8 to 16.6,
respectively. A similar result is shown for the reactions of 6b
and 6f, although they are less reactive than 6a.
The effect of amine basicity on reactivity is graphically
illustrated in Figure 3 for the reactions of 6a. The Brønsted-
A similar cyclic intermediate would be possible for the
reactions of 6a−i as modeled by VI, which might gain high
stability through the intramolecular H-bonding interaction.
However, a careful examination of VI reveals that the H-
bonding interaction would cause a significant decrease in the
leaving-group basicity by changing the highly basic 2-pyridyl-
oxide (e.g., the pKa = 11.62 in H2O) to the weakly basic 2-
pyridiniumoxide (e.g., the pKa = 0.75 in H2O) or to its
tautomer 2-pyridone. It is apparent that the decreased basicity
of the leaving group would cause a remarkable increase in its
nucleofugality. Thus, we suggest that the intramolecular H-
bonding interaction in the intermediate VI shortens its lifetime
and forces the aminolysis of 6a−i to proceed through a
concerted mechanism with a TS structure similar to VI. It is
noted that the intramolecular H-bonding interaction shown in
VI is structurally not possible for the reactions of 5a−i. This
accounts for the contrasting reaction mechanisms, i.e., a
stepwise mechanism for the reactions of 5a−i and a concerted
pathway for those of 6a−i.
Figure 3. Brønsted-type plot for the reactions of 2-pyridyl 3,5-
dinitrobenzoate (6a) with a series of cyclic secondary amines in
MeCN at 25.0 0.1 °C. The points are identified in Table 2.
Deuterium Kinetic Isotope Effect (DKIE). To examine
the validity of the above argument that the intramolecular H-
bonding interaction governs the reaction mechanism, second-
order rate constants for the reactions of 6a, 6b, and 6f with
deuterated piperidine (i.e., kND) were measured. The rate
constants for the uncatalyzed and catalyzed reactions of 4-
pyridyl 3,5-dinitrobenzoate (5a) with deuterated piperidine
type plot exhibits an excellent linear correlation with βnuc = 0.58
when the kN and pKa values are corrected statistically using p
and q (i.e., p = 2 while q = 1 except q = 2 for piperazine).19
A
D
D
(i.e., Kk2 and Kk3 , respectively) were also measured for
comparison. The plot of kobsd vs [amine] curves upward for the
reaction of 5a with deuterated piperidine, while the plot of
similar result is shown for the corresponding reactions of 6b
and 6f with βnuc = 0.61 in the Supporting Information (Figures
S1 and S2). The βnuc value of 0.58 (or 0.61) is much smaller
than that reported for reactions which proceed through a
stepwise mechanism, e.g., βnuc = 0.98 for the corresponding
reactions of 4-pyriyl 3,5-dinitrobenzoate (5a).12 Since a linear
Brønsted-type plot with βnuc = 0.5 0.1 is typical of reactions
reported previously to proceed through a concerted mecha-
nism,2 we suggest that the current reactions also proceed
through a concerted mechanism regardless of the electronic
nature of the substituent X. This is in contrast to the report that
the corresponding reactions of 5a−i (the isomers of 6a−i)
proceed through a stepwise mechanism with one or two
intermediates depending on the electronic nature of the
substituent X, e.g., through T and T− for the reaction of
substrates possessing a strong EWG (5a−d) but via T only for
the reaction of those bearing a weak EWG or an EDG (5e−
i).12 Clearly, the modification of the leaving group from 4-
pyridyloxide to 2-pyridyloxide affects the reaction mechanism.
It has been reported that the aminolysis of 4-nitrophenyl 2-
methoxybenzoate in MeCN proceeds through a stepwise
mechanism with an intermediate as modeled by V, which is
stabilized through the intramolecular H-bonding interaction
between the 2-MeO group and the aminium moiety of T .18
This idea has been further supported by the experimental result
that the substrate possessing a 2-MeO group at the 2-position
of the benzoyl moiety is much more reactive than those bearing
a 2-MeO group at the 3- or 4-position; e.g., 4-nitrophenyl 2-
methoxybenzoate is 20 and 74 times more reactive than its
isomers 4-nitrophenyl 3-methoxybenzoate and 4-nitrophenyl 4-
methoxybenzoate, respectively.18
k
obsd/[amine] vs [amine] is linear (Figure S3 A and B in the
SI). Thus, the rate constants Kk2D and Kk3D for the uncatalyzed
and catalyzed reactions were calculated from the intercept and
slope of the linear plot of kobsd/[amine] vs [amine],
respectively. The kinetic results are summarized in Table 3.
Table 3. Summary of Second-Order Rate Constants for the
Reactions of 2-Pyridyl 3,5-Dinitrobenzoate (6a), 2-Pyridyl 4-
Nitrobenzoate (6b), 2-Pyridyl Benzoate (6f), and 4-Pyridyl
3,5-Dinitrobenzoate (5a) with Piperidine (kNH) and
a
Deuterated Piperidine (kND) in MeCN at 25.0 0.1 °C
kNH/M−1 s−1
kND/M−1 s−1
kNH/kN
D
6a
6b
6f
4.48
3.02
1.48
1.26
1.26
0.556
0.0558
0.442
0.0442
a
D
DKIE for the reaction of 5a: Kk2H/Kk2 = 0.154/0.182 = 0.85 and
Kk3H/Kk3 = 25.8/11.6 = 2.22.
D
D
As shown in Table 3, the DKIE (i.e., the kNH/kN ratio) is
1.48 for the reaction of 6a and 1.26 for those of 6b and 6f. In
contrast, the DKIE for the reaction of 5a is 0.85 and 2.22 for
the uncatalyzed route and the catalyzed route, respectively. The
DKIE of 0.85 is mainly a reflection of the reduced steric
hindrance, since the amplitude of the stretching vibration of a
N−D bond is smaller than that of a N−H bond. Thus, the
inversed DKIE is as expected for the uncatalyzed reaction, in
which the deprotonation process to yield T− from T is absent.
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The primary normal DKIE of 2.22 for the catalyzed route is
also consistent with the proposed mechanism, in which the
deprotonation process by a second piperidine molecule occurs
in the RDS.
of the electronic nature of the substituent X, indicating that the
substituent dependence of the reactivity of 6a−i is governed
almost entirely by the ΔH‡ term rather than by the TΔS‡ term.
More importantly, the large negative ΔS‡ indicates that the TS
is highly ordered. This is consistent with the proposal that the
reactions of 6a−i with amines proceed through a TS structure
similar to VI, in which the rotational and vibrational degrees of
freedom are restricted to a certain degree. Furthermore, the fact
that ΔS‡ remains nearly constant indicates that the intra-
molecular H-bonding interaction shown in VI is not influenced
by the electronic nature of the substituent X. This is also
consistent with the kinetic result that the electronic nature of
the substituent X does not affect the reaction mechanism in this
study.
The DKIE value of 1.48 or 1.26 observed for the reactions of
6a, 6b, and 6f is similar to those reported for reactions
proceeding through a concerted mechanism with a TS structure
similar to VII or VIII; e.g., DKIE = 1.21−1.48 for reactions of
aryl cyclopropanecarboxylates with deuterated benzylamines in
MeCN,20 and DKIE = 1.05−1.36 for reactions of aryl
dithioacetates with deuterated benzylamines in MeCN.21
Thus, the DKIE value of 1.48 or 1.26 observed for the current
reactions of 6a, 6b, and 6f supports the preceding argument
that the reactions proceed through a forced concerted
mechanism with a TS structure similar to VI, in which the
H-transfer from the aminium moiety to the N atom of the
leaving group occurs in the RDS.
CONCLUSIONS
■
Based on the experimental results, we present the following
conclusions. (1) The nonlinear Hammett plot is not caused by
a change in RDS but rather by stabilization of the substrate
possessing an EDG through resonance interactions. (2) The
linear Brønsted-type plot with βnuc = 0.60 0.01 obtained in
this study supports the proposal that the aminolysis of 6a−i
proceeds through a forced concerted mechanism with a TS
structure similar to VI. (3) The DKIE value of 1.48 (or 1.26) is
consistent with the cyclic TS structure, in which the proton
transfer from the aminium moiety of VI to the N atom of the
leaving group occurs in RDS. (4) The large negative ΔS‡ value
further supports the proposal that the reactions of 6a−i
proceed through a cyclic TS structure. (5) Modification of the
leaving group from 4-pyridyloxide to 2-pyridyloxide affects the
reaction mechanism by changing it from a stepwise mechanism
to a concerted pathway.
Analysis of Activation Parameters. To obtain further
information on the TS structure, activation parameters (i.e.,
ΔH‡ and ΔS‡) were calculated using the kinetic data obtained
for the reactions of 6a, 6b, 6f, and 6h with piperidine at five
different temperatures (i.e., 15.0, 20.0, 25.0, 30.0, and 35.0 °C).
The Arrhenius equation, k = Ae−E /RT, was used to calculate
a
enthalpies of activation. Equation 2 is derived from the
Arrhenius equation. The slope of the linear plot of ln kN vs
1/T is equal to −Ea/R (Figure S4 in the Supporting
Information). The enthalpy of activation (ΔH‡) was then
calculated using eq 3. The entropies of activation (ΔS‡) were
calculated from eq 4. The ΔH‡ and ΔS‡ values calculated in this
way are summarized in Table 4.
EXPERIMENTAL SECTION
■
Materials. Compounds 6a−i were readily prepared from the
reaction of the respective X-substituted benzoyl chloride with 2-
hydroxypyridine in methylene chloride as reported previously.22 The
crude products were purified by column chromatography, and their
ln kN = −Ea/RT + ln A
(2)
1
purity was confirmed from mps and H NMR characteristics for the
known compounds. The final yields of products are 35−43%. The
identity of the unknown compounds (i.e., 6a, 6b, and 6i) was
confirmed by elementary analysis, mps, and 1H NMR spectra
(Supporting Information). MeCN was distilled over P2O5 and stored
under nitrogen. The amines and other chemicals used were of the
highest quality available.
ΔH‡ = Ea − RT
ΔS‡ = R(ln A − ln T − ln KB/h − 1)
Table 4 shows that ΔH‡ is strongly dependent on the
electronic nature of the substituent X; e.g., it increases from
3.85/kcal mol−1 to 4.80 and then to 7.04/kcal mol−1 as the
substituent X changes from 3,5-(NO2)2 in 6a to 4-NO2 in 6b
and then to 4-MeO in 6h (see also a linear plot of ΔH‡ vs σX
shown in Figure S5 in the Supporting Information). In contrast,
ΔS‡ remains nearly constant at ca. 43 cal mol−1 K−1 regardless
(3)
(4)
1
2-Pyridyl 3,5-Dinitrobenzoate (6a). Data: mp 120−122 °C; H
NMR characteristics (500 MHz, CDCl3) δ 9.359−9.355 (d, J = 2 Hz,
2H), δ 9.321−9.313 (t, J = 2 Hz, 1H), δ 8.512−8.504 (dd, J = 2 Hz,
1H), δ 7.953−7.918 (dt, J = 7.5 Hz, 1H), δ 7.397−7.372 (dd, J = 7.5
Hz, 1H), δ 7.280−7.263 (d, J = 8 Hz, 1H); and elemental analysis
(Calcd for C12H7N3O6: C, 49.84; H, 2.44. Found: C, 49.89; H, 2.42).
a
Table 4. Summary of Kinetic Results for the Reactions of 2-Pyridyl X-Substituted Benzoates (6a, 6b, 6f, and 6h) with
Piperidine at Five Different Temperatures
102 kN/M−1s−1
15.0 °C
20.0 °C
25.0 °C
30.0 °C
35.0 °C
ΔH‡/kcal mol−1
ΔS‡/eu
6a
6b
6f
358
405
448
512
598
3.85
4.80
6.58
7.04
−42.6
−43.6
−42.3
−43.2
41.3
3.46
0.946
44.9
4.32
1.25
55.6
5.58
1.61
62.9
6.39
1.88
75.0
7.85
2.27
6h
a
X = 3,5-(NO2)2 (6a), 4-NO2 (6b), H (6f), 4-MeO (6h).
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1
2-Pyridyl 3-Nitrobenzoate (6b). Data: mp 88−90 °C; H NMR
characteristics (500 MHz, CDCl3) δ 9.074−9.067 (t, J = 2 Hz, 1H), δ
8.564−8.524 (dd, J = 7 Hz, 1H), δ 8.522−8.506 (d, J = 8 Hz, 1H), δ
8.500−8.484 (dd, J = 8 Hz, 1H), δ 7.915−7.880 (dt, J = 8 Hz, 1H), δ
7.763−7.732 (t, 8 Hz, 1H), δ 7.349−7.323 (dd, J = 8 Hz, 1H), δ
7.257−7.241 (d, J = 8 Hz, 1H); and elemental analysis (Calcd for
C12H8N2O4: C, 59.02; H, 3.30. Found: C, 59.07; H, 3.28).
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2-Pyridyl 4-N,N-Dimethylaminobenzoate (6i). Data: mp 160−
162 °C; H NMR characteristics (500 MHz, CDCl3) δ 8.446−8.433
1
(dd, J = 2 Hz, 1H), δ 8.089−8.072 (d, J = 8 Hz, 2H), δ 7.817−7.783
(dt, J = 8 Hz, 1H), δ 7.231−7.196 (m, 2H), δ 6.696−6.678 (d, J = 8
Hz, 2H), δ 3.072 (s, 6H); and elemental analysis (Calcd for
C14H14N2O2: C, 69. 41; H, 5.82. Found: C, 69.37; H, 5.84).
Kinetics. The kinetic study was performed using a UV−vis
spectrophotometer equipped with a constant temperature circulating
bath. All of the reactions in this study were carried out under pseudo-
first-order conditions in which the amine concentration was at least 20
times greater than the substrate concentration. Typically, the reaction
was initiated by adding 5 μL of a 0.02 M substrate stock solution in
MeCN by a 10 μL syringe to a 10 mm UV cell containing 2.50 mL of
the reaction medium and amine. The reactions were followed by
monitoring the appearance of the leaving group up to nine half-lives.
Product Analysis. 2-Pyridyloxide was liberated quantitatively and
identified as one of the products by comparison of the UV−vis
spectrum at the end of reaction with that of the authentic sample
under the experimental conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
1
Kinetic conditions and results including H NMR spectra for
compounds 6a, 6b, and 6i. This material is available free of
charge via the Internet at http://pubs.acs.org.
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67, 8995−8998. (b) Oh, H. K.; Ku, M. H.; Lee, H. W.; Lee, I. J. Org.
Chem. 2002, 67, 3874−3877. (c) Oh, H. K.; Kim, S. K.; Lee, H. W.;
Lee, I. New J. Chem. 2001, 25, 313−317.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ihum@ewha.ac.kr.
■
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71, 5800−5803. (b) Um, I. H.; Hong, J. Y.; Seok, J. A. J. Org. Chem.
2005, 70, 1438−1444.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education (2012-R1A1B-
3001637). T.I.U. is also grateful for the Intensive Science
Program of Dongbuk High School.
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