Aminolysis of Y-substituted phenyl X-substituted benzoates with piperidine: Effect of nonleaving group substituent

Article abstract of DOI:10.1021/jo0606958

The title reaction has been suggested to proceed through a zwitterionic tetrahedral intermediate with a change in the rate determining step on the basis of the curved Bronsted-type plots obtained. The curvature center of the curved Bronsted-type plots is at pK_a = 6.4 regardless of the electronic nature of the substituent X in the benzoyl moiety.

Full text of DOI:10.1021/jo0606958

change at the curvature center of the curved Brønsted-type plot,
defined as pKa˚. 1-10
Aminolysis of Y-Substituted Phenyl X-Substituted
Benzoates with Piperidine: Effect of Nonleaving
Group Substituent
The pKa˚ value increases as the substituent in the nonleaving
group becomes a stronger electron withdrawing group (EWG)
for quinuclidinolysis of diaryl carbonates in water as reported
by Gresser and Jencks.8 This has been explained through the
argument that the departure of the amine from T( is favored,
over that of the leaving group, as the electron withdrawing
ability of the substituent in the nonleaving group increases.8
Castro et al. have found a similar result for pyridinolysis of
2,4-dinitrophenyl X-substituted benzoates (i.e., pKa˚ ) 9.5 when
X ) H but pKa˚ > 9.5 when X ) Cl, CN, or NO2)9 and S-2,4-
dinitrophenyl X-substituted thiobenzoates (i.e., pKa° increases
from 8.5 to 8.9 and 9.9 as X changes from 4-Me to H and
4-NO2, respectively) in aqueous ethanol.10
Ik-Hwan Um,*,† Ji-Youn Lee,† Seung-Hak Ko,‡ and
Sun-Kun Bae‡
Department of Chemistry, Ewha Womans UniVersity, Seoul
120-750, Korea, and Department of Chemistry, Kunsan National
UniVersity, Kunsan 573-701, Korea
ihum@ewha.ac.kr
ReceiVed March 31, 2006
In contrast, we have shown that the pKa˚ value is not
influenced by the electronic nature of the substituent in the
nonleaving group for reactions of 2,4-dinitrophenyl X-substi-
tuted benzoates and benzenesulfonates with alicyclic secondary
amines in H2O containing 20 mol % dimethyl sulfoxide
(DMSO).5,7 It has been found that the Hammett plots for these
reactions are curved downwardly as the substituent in the
nonleaving group changes from electron donating groups (EDG)
to EWG.5,7 Such a curved Hammett plot has traditionally been
interpreted as a change in the RDS.11 However, we have shown
that stabilization of the ground state through resonance interac-
tion between the π-electron donor substituent and the carbonyl
or sulfonyl functionality is responsible for the nonlinear
Hammett plots since the Yukawa-Tsuno plots for the same
reactions are linear.5,7
The title reaction has been suggested to proceed through a
zwitterionic tetrahedral intermediate with a change in the
rate determining step on the basis of the curved Brønsted-
type plots obtained. The curvature center of the curved
Brønsted-type plots is at pKa ) 6.4 regardless of the
electronic nature of the substituent X in the benzoyl moiety.
(4) (a) Castro, E. A.; Aliaga, M.; Santos, J. G. J. Org. Chem. 2005, 70,
2679-2685. (b) Castro, E. A.; Gazitua, M.; Santos, J. G. J. Org. Chem.
2005, 70, 8088-8092. (c) Castro, E. A.; Aliaga, M.; Santos, J. G. J. Org.
Chem. 2004, 69, 6711-6714. (d) Castro, E. A.; Cubillos, M.; Santos, J. G.
J. Org. Chem. 2004, 69, 4802-4807. (e) Castro, E. A.; Cubillos, M.; Aliaga,
M.; Evangelisti, S.; Santos, J. G. J. Org. Chem. 2004, 69, 2411-2416.
(5) (a) Um, I. H.; Kim, K. H.; Park, H. R.; Fujio, M.; Tsuno, Y. J. Org.
Chem. 2004, 69, 3937-3942. (b) Um, I. H.; Min, J. S.; Lee, H. W. Can. J.
Chem. 1999, 77, 659-666. (c) Um, I. H.; Chun, S. M.; Chae, O. M.; Fujio,
M.; Tsuno, Y. J. Org. Chem. 2004, 69, 3166-3172. (d) Um, I. H.; Hong,
J. Y.; Kim, J. J.; Chae, O. M.; Bae, S. K. J. Org. Chem. 2003, 68, 5180-
5185. (e) Um, I. H.; Hong, J. Y.; Seok, J. A. J. Org. Chem. 2005, 70,
1438-1444.
Aminolyses of esters have been suggested to proceed concert-
edly or through a stepwise mechanism with a zwitterionic
tetrahedral intermediate T(,1-10 depending on the reaction
conditions (e.g., solvents,1-3 the nature of amines,1,4,5 and the
structure of substrates1,6-10). Aminolysis of esters with a good
leaving group has often resulted in a curved Brønsted-type plot
(i.e., the slope (ânuc) decreases from ca. 0.8 to ca. 0.3 as the
amine becomes more basic than the leaving group by 4-5 pKa
units).1-10 Such a curved Brønsted-type plot has been interpreted
as evidence of a stepwise mechanism with a change in the rate
determining step (RDS).1-10 The RDS has been suggested to
(6) (a) Um, I. H.; Kim, E. J.; Park, H. R.; Jeon, S. E. J. Org. Chem.
2006, 71, 2302-2306. (b) Um, I. H.; Han, H. J.; Baek, M. H.; Bae, S. K.
J. Org. Chem. 2004, 69, 6365-6370. (c) Um, I. H.; Lee, S. E.; Kwon, H.
J. J. Org. Chem. 2002, 67, 8999-9005.
(7) (a) Um, I. H.; Lee, J. Y.; Lee, H. W.; Nagano, Y.; Fujio, M.; Tsuno,
Y. J. Org. Chem. 2005, 70, 4980-4987. (b) Um, I. H.; Min, J. S.; Ahn, J.
A.; Hahn, H. J. J. Org. Chem. 2000, 65, 5659-5663.
(8) Gresser, M. J.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 6970-
6980.
* Corresponding author. Tel.: 82-2-3277-2349; fax: 82-2-3277-2844.
† Ewha Womans University.
(9) (a) Castro, E. A.; Santander, C. L. J. Org. Chem. 1985, 50, 3595-
3600. (b) Castro, E. A.; Valdivia, J. L. J. Org. Chem. 1986, 51, 1668-
1672. (c) Castro, E. A.; Steinfort, G. B. J. Chem. Soc., Perkin Trans. 2
1983, 453-457.
(10) (a) Castro, E. A.; Aguayo, R.; Bessolo, J.; Santos, J. G. J. Org.
Chem. 2005, 70, 7788-7791. (b) Castro, E. A.; Aguayo, R.; Bessolo, J.;
Santos, J. G. J. Org. Chem. 2005, 70, 3530-3536. (c) Castro, E. A.;
Vivanco, M.; Aguayo, R.; Aguayo, R.; Santos, J. G. J. Org. Chem. 2004,
69, 5399-5404. (d) Castro, E. A.; Aguayo, R.; Santos, J. G. J. Org. Chem.
2003, 68, 8157-8161.
(11) (a) Carrol, F. A. PerspectiVes on Structure and Mechanism in
Organic Chemistry; Brooks/Cole: New York, 1998: pp 371-386. (b)
Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry, 3rd ed.; Harper Collins Publishers: New York, 1987; pp 143-
151.
‡ Kunsan National University.
(1) (a) Jencks, W. P. Chem. ReV. 1985, 85, 511-527. (b) Castro, E. A.
Chem. ReV. 1999, 99, 3505-3524. (c) Page, M. I.; Williams, A. Organic
and Bio-organic Mechanisms; Longman: Harlow, UK, 1997; Ch. 7.
(2) (a) Oh, H. K.; Oh, J. Y.; Sung, D. D.; Lee, I. J. Org. Chem. 2005,
70, 5624-5629. (b) Lee, I.; Sung, D. D. Curr. Org. Chem. 2004, 8, 557-
567. (c) Oh, H. K.; Park, J. E.; Sung, D. D.; Lee, I. J. Org. Chem. 2004,
69, 9285-9288. (d) Oh, H. K.; Ha, J. S.; Sung, D. D.; Lee, I. J. Org. Chem.
2004, 69, 8219-8223. (e) Oh, H. K.; Lee, J. M.; Sung, D. D.; Lee, I. Bull.
Korean Chem. Soc. 2004, 25, 557-559.
(3) (a) Um, I. H.; Jeon, S. E.; Seok, J. A. Chem.sEur. J. 2006, 12, 1237-
1243. (b) Um, I. H.; Seok, J. A.; Kim, H. T.; Bae, S. K. J. Org. Chem.
2003, 68, 7742-7746. (c) Menger, F. M.; Smith, J. H. J. Am. Chem. Soc.
1972, 94, 3824-3829.
10.1021/jo0606958 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/24/2006
5800
J. Org. Chem. 2006, 71, 5800-5803

TABLE 1. Summary of Apparent Second-Order Rate Constants
(kN, M-1 s-1) for the Reactions of Y-Substituted Phenyl
X-Substituted Benzoates with Piperidine in H2O Containing 20 mol
% DMSO at 25.0 ( 0.1 °C
pKa
(Y-PhOH ) X ) NO2 (1) Cl (2) H (3) Me (4) MeO (5)
k )
N (M-1 s-1
Y
a, 3-COMe
b, 3-Cl
c, 4-COMe
d, 4-CHO
e, 4-NO2
9.19
9.02
8.05
7.66
7.14
5.42
0.0208
0.0519
0.673
2.61
0.00650
0.00226
0.0203 0.0159 0.0105 0.00619
0.236
0.852
0.0982
0.328
1.95a
21.0a
1140
8.14a 5.94a
3.68a
75.8
f, 3,4-(NO2)2
251
191
32.3
a Data from ref 7b.
We have extended our study to the reactions of Y-substituted
phenyl X-substituted benzoates with piperidine to obtain more
conclusive information about the pKa˚ and reaction mechanism.
Various substituents X and Y have been employed both in the
nonleaving and in the leaving group, respectively. In the
previous studies,2-10 the leaving group was fixed with a weakly
basic aryloxide or thioaryloxide (e.g., 2,4-dinitrophenoxide or
2,4-dinitrothiophenoxide), while the basicity of the attacking
amine and the substituent in the nonleaving group were changed.
In the current study, the nucleophile is fixed with piperidine, a
strongly basic alicyclic secondary amine, while the substituents
both in the leaving and in the nonleaving groups are changed.
All reactions in this study obeyed pseudo-first-order kinetics
over 90% of the total reaction. Pseudo-first-order rate constants
(kobsd) have been determined from the equation ln(A∞ - At) )
-kobsdt + C. All the plots of kobsd versus the piperidine con-
centration were linear passing through the origin, indicating that
general base catalysis by a second amine molecule is absent
and that the contribution of H2O and/or OH- from hydrolysis
to the kobsd is negligible. Thus, the rate law is given by eq 1, in
which [S] and [NH] represent the concentration of the substrate
and piperidine, respectively. The apparent second-order rate con-
stants (kN) have been determined from the slopes of the linear
plots of kobsd versus the piperidine concentration and summarized
in Table 1. The uncertainty in the kN values is estimated to be
less than 3% from replicate runs. The detailed reaction condi-
tions and kinetic results are shown in the Supporting Informa-
tion.
FIGURE 1. Brønsted-type plots for the reactions of 1a-f(O), 3a-
f(b), and 5a-f(0) with piperidine in H2O containing 20 mol % DMSO
at 25.0 ( 0.1 °C. The identity of points is given in Table 1.
SCHEME 1
âlg2 represent the slope of the Brønsted-type plots for the
weakly basic and strongly basic leaving groups, respectively,
while kN° refers to the kN value at pKa°.
rate ) kobsd[S], where kobsd ) kN[NH]
(1)
Effect of Leaving Group Substituent on Reactivity and
Mechanism. As shown in Table 1, the kN for the reactions with
piperidine increases as the substituent X or Y becomes a stronger
EWG. The effect of the substituent Y in the leaving group on
reactivity is illustrated in Figure 1. The Brønsted-type plots for
the reactions of 1a-f, 3a-f, and 5a-f with piperidine are
curved downwardly as the basicity of the leaving group
decreases. Such a nonlinear Brønsted-type plot is typical for
the aminolysis of esters, which proceeds through a zwitterionic
tetrahedral intermediate (T() with a change in the RDS (Scheme
1) (i.e., from breakdown of T( to its formation as the basicity
of the leaving group decreases).
log(kN/kN°) ) âlg1(pKa - pKa°) - log[(1 + R)/2],
where log R ) (âlg1 - âlg2)(pKa - pKa°) (2)
The pKa° determined for the reactions of 1a-f, 3a-f, and
5a-f with piperidine is 6.4, which is ca. 4.6 pKa units smaller
than the pKa of the conjugate acid of the attacking piperidine
(pKa ) 11.02). This is consistent with the report that a change
in the RDS occurs when the attacking amine becomes more
basic than the leaving group by 4-5 pKa units or the leaving
group becomes less basic than the amine nucleophile by 4-5
pKa units.1,3,5,8-10 It is noted that the pKa° determined in this
study remains constant regardless of the electronic nature of
the substituent in the nonleaving group. This result supports
our previous conclusion that the pKa° is not influenced by the
electronic nature of the substituent in the nonleaving group for
aminolyses of 2,4-dinitrophenyl X-substituted benzoates and
benzenesulfonates.5,7
The nonlinear Brønsted-type plots shown in Figure 1 have
been analyzed using a semiempirical equation (eq 2) on the
basis of the proposed mechanism.7a,8,10,12 In eq 2, âlg1 and
(12) Gresser, M. J.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 6963-
6970.
J. Org. Chem, Vol. 71, No. 15, 2006 5801

However, Castro et al. have recently argued against our
conclusion.10a,b They have suggested that the aminolysis of 2,4-
dinitrophenyl X-substituted benzoates performed by us proceeds
very likely through a concerted mechanism, although the kinetic
study resulted in curved Brønsted-type plots.10a,b It is because
the slopes of the curved Brønsted-type plots are not in
accordance with those obtained for reactions that have been
suggested to proceed through a stepwise mechanism (i.e., â2 )
0.74 at the low pKa region is not large enough, e.g., â2 ) 0.8-
1.0), while â1 ) 0.34 at the high pKa region is not small enough
for a stepwise mechanism (e.g., â1 ) 0.1-0.3).10a,b
To examine the previous argument, the microscopic rate
constants (i.e., the k2/k-1 ratio and k1) associated with the
reactions of 1a-f, 3a-f, and 5a-f with piperidine have been
calculated as shown in the Supporting Information using the
eqs S1-S8. The k2/k-1 ratio has been calculated to be strongly
dependent on the basicity of the leaving group (i.e., the k2/k-1
for the reactions of 1a-f increases from 6.19 × 10-4 to 0.0356
and 13.4 as the substituent Y in the leaving group changes from
3-COMe to 4-CHO and 3,4-(NO2)2, respectively (Table S20 in
the Supporting Information)). A similar result has been obtained
for the reactions of 3a-f and 5a-f. On the contrary, the k2/k-1
ratio is not dependent on the substituent X in the nonleaving
group. As shown in Table S20, the k2/k-1 ratio remains nearly
constant on changing the substituent X in the benzoyl moiety
(e.g., (6.20 ( 0.4) × 10-4 for the least reactive 1a, 3a, and 5a
or 13.4 ( 0.3 for the most reactive 1f, 3f, and 5f). Thus, the
current result is consistent with our preceding argument that
the k2/k-1 ratio is independent of the electronic nature of the
substituent in the nonleaving group for the aminolysis of 2,4-
dinitrophenyl benzoates and benzenesulfonates.5,7
FIGURE 2. Hammett plots and Yukawa-Tsuno plots (inset) for the
reactions of 1b-5b(0), 1e-5e(b), and 1f-5f(O) with piperidine in
H2O containing 20 mol % DMSO at 25.0 ( 0.1 °C. The identity of
points is given in Table 1.
zenesulfonates, and other related esters.5,13 In all cases, ânuc has
been reported to increase as the substituent X in the nonleaving
group changes from an EDG to an EWG.5,13
The effect of the leaving group basicity on the k2/k-1 ratio is
illustrated in Figure S1 in the Supporting Information. It is
shown that k2 ) k-1 at pKa ) 6.4, regardless of the substituent
in the nonleaving group. Besides, the k2/k-1 ratio exhibits a
strong dependence on the basicity of the leaving group (i.e.,
the slope of the linear plots is ca. 1.15 ( 0.01). Such a large
slope can be explained as follows. The nucleofugality of the
leaving group from T( (k2) would be influenced by the electronic
nature of the substituent Y in the leaving group (i.e., k2 would
increase as the substituent Y becomes a stronger EWG (or as
the leaving group becomes less basic)). On the contrary,
expulsion of the amine from T( (k-1) would be more difficult
as the substituent Y becomes a stronger EWG since the amine
departs from T( with the bonding electron pair. Accordingly,
the k2/k-1 ratio is strongly dependent on the electronic nature
of the leaving group substituent.
Effect of Nonleaving Group Substituent on Reactivity and
Mechanism. As shown in Table 1, kN increases as the
substituent X in the nonleaving group changes from an EDG
to an EWG. The effect of substituent X on the rate is illustrated
in Figure 2. All the Hammett plots consist of two intersecting
straight lines. A curvature in Hammett plots has generally been
interpreted as a change in the RDS or the reaction mechanism
depending on the shape of the curvature: convex and concave
(i.e., downward and upward curvature, respectively).11,14-16 The
downward curvature in the Hammett plots observed in this study
might be interpreted as a change in the RDS (i.e., from the
breakdown of T( to its formation as the substituent X changes
from EWG to EDG). This argument appears to be reasonable,
at first sight, since an EWG in the benzoyl moiety would
accelerate the attack of the nucleophile (k1) but retard the
departure of the negatively charged leaving group from T( (k2),
while an EDG would decrease k1 but increase k2.
Using the kN values in Table 1 and the k2/k-1 ratios in Table
S20 in the Supporting Information, the k1 values have been
calculated and summarized in Table S21 in the Supporting
Information. One can see that k1 increases as the leaving group
basicity decreases. The effect of the leaving group basicity on
k1 is illustrated in Figure S2 in the Supporting Information. The
slope of the linear Brønsted-type plots (-âlg1) increases as the
reactivity increases (i.e., -âlg1 increases from 0.23 to 0.33 and
0.39 as the substituent X changes from 4-MeO to H and 4-NO2,
respectively), indicating that the reactivity-selectivity principle
(RSP) is not applicable to the current reaction system. Similar
results have been reported for the aminolyses of 4-nitrophenyl
X-substituted benzoates, 2,4-dinitrophenyl X-substituted ben-
However, we propose that the curved Hammett plots shown
in Figure 2 are not due to a change in the RDS, on the basis of
the following argument. The RDS is not determined by the
magnitude of k1 and k2. This is because k1 and k2 cannot be
(13) (a) Lee, I. Chem. Soc. ReV. 1995, 223-229. (b) Oh, H. K.; Yang,
J. H.; Sung, D. D.; Lee, I. J. Chem. Soc., Perkin Trans. 2 2000, 101-105.
(14) Swansburg, S.; Buncel, E.; Lemieux, R. P. J. Am. Chem. Soc. 2000,
122, 6594-6600.
(15) (a) Um, I. H.; Lee, J. Y.; Kim, H. T.; Bae, S. K. J. Org. Chem.
2004, 69, 2436-2441. (b) Um, I. H.; Hahn, H. J.; Ahn, J. A.; Kang, S.;
Buncel, E. J. Org. Chem. 2002, 67, 8475-8480.
(16) Cevasco, G.; Guanti, G.; Hopkins, A. R.; Thea, S.; Williams, A. J.
Org. Chem. 1985, 50, 479-484.
5802 J. Org. Chem., Vol. 71, No. 15, 2006

compared directly due to the difference in their units (e.g., M-1
s-1 vs s-1). Accordingly, the RDS should be determined by the
k2/k-1 ratio. It is obvious that k2 and k-1 are strongly dependent
on the basicity of the leaving group and the nucleophile,
respectively. The nucleophile used in this study is piperidine,
and the leaving group is also fixed for a given Hammett plot in
Figure 2. Accordingly, the k2/k-1 ratio should be constant for
each Hammett plot since the k2/k-1 ratio has been shown to
remain nearly constant on changing the electronic nature of the
substituent in the benzoyl moiety (Table S20 in the Supporting
Information). Thus, one cannot attribute the nonlinear Hammett
plots in Figure 2 to a change in the RDS.
Experimental Section
Y-substitued phenyl X-substituted benzoates were readily
prepared and purified as reported.3c,19,20 A kinetic study was
performed with a UV-vis spectrophotometer for slow reactions
(t1/2 > 10 s) or a stopped-flow spectrophotometer for fast
reactions (t1/2 e 10 s). Detailed kinetic methods and a product
analysis are described in the Supporting Information.
Acknowledgment. This work was supported by the Korea
Science and Engineering Foundation (R01-2004-000-10279-0).
Supporting Information Available: Tables S1-S19 for the
kinetic conditions and results for the reactions of Y-substituted
phenyl X-substituted benzoates with piperidine. Eqs S1-S8 to
determine the microscopic rate constants k1 and the k2/k-1 ratios.
Table S20 for the summary of the k2/k-1 ratios in the reactions of
1a-f, 3a-f, and 5a-f with piperidine. Figure S1 for the plots of
log k2/k-1 versus pKa for the reactions of 1a-f(?), 3a-f(?), and
5a-f(?) with piperidine. Table S21 for the summary of k1 in the
reactions of 1a-f, 3a-f, and 5a-f with piperidine. Figure S2 for
the plots of log k1 versus pKa for the reactions of 1a-f(?), 3a-
f(?), and 5a-f(?) with piperidine. This material is available free
of charge via the Internet at http://pubs.acs.org.
A careful examination of Figure 2 reveals that the substrate
with a π-electron donating substituent in the benzoyl moiety
deviates negatively from the Hammett plots. Besides, the
deviation is more significant for the substrate with a stronger
EDG. Accordingly, one can ascribe the nonlinear Hammett plots
to stabilization of the ground state through the resonance
interaction between the π-electron donor substituent and the
carbonyl functionality. This argument can be further supported
by employing the Yukawa-Tsuno equation (eq 3).17,18 As
shown in the inset of Figure 2, the Yukawa-Tsuno plots exhibit
excellent linearity with an r value of 0.75 in all cases.
JO0606958
(17) (a) Tsuno, Y.; Fujio, M. AdV. Phys. Org. Chem. 1999, 32, 267-
385. (b) Tsuno, Y.; Fujio, M. Chem. Soc. ReV. 1996, 25, 129-139.
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Bull. Chem. Soc. Jpn. 2003, 76, 163-169. (b) Nakata, K.; Fujio, M.;
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log kX/kH ) F[σ˚ + r(σ+ - σ˚)]
(3)
In summary, (1) the reactions of Y-substituted phenyl
X-substituted benzoates with piperidine proceed through T( with
a change in the RDS. (2) A change in the RDS occurs at
pKa ) 6.4, which is independent of the substituent X in the
nonleaving group.
J. Org. Chem, Vol. 71, No. 15, 2006 5803