Effect of o-methyl group on rate, mechanism, and resonance contribution: Aminolysis of Y-substituted phenyl X-substituted 2-methylbenzoates

Article abstract of DOI:10.1021/jo050172k

Second-order rate constants have been determined spectrophotometrically for the reactions of 4-nitrophenyl X-substituted 2-methylbenzoates (2a-e) and Y-substituted phenyl 2-methylbenzoates (3a-e) with alicyclic secondary amines in 80 mol % H₂O/20 mol % DMSO at 25.0 ± 0.1 °C. The o-methyl group in the benzoyl moiety of 2a-e retards the reaction rate but does not influence the reaction mechanism. The Hammett plots for the reactions of 2a-e are nonlinear, while the corresponding Yukawa-Tsuno plots are linear with large r values (1.06-1.70). The linear Yukawa-Tsuno plots suggest that stabilization of the ground-state through resonance interaction between the electron donating substituent X and the carbonyl group is responsible for the nonlinear Hammett plots, while the large r values imply that the ground-state resonance interaction is significant. The reactions of 2a-e resulted in smaller ρ_X values but larger r values than the corresponding reactions of 4-nitrophenyl X-substituted benzoates (1a-e). The small ρ_X value for the reactions of 2a-e (e.g., ρ_X = 0.22) is suggested to be responsible for the large r value (e.g., r = 1.70). The reactions of 3a-e with piperidine are proposed to proceed in a stepwise manner with a change in the rate-determining step on the basis of the curved Bronsted-type plot obtained. Microscopic rate constants associated with the reactions of 3a-e are also consistent with the proposed mechanism.

Full text of DOI:10.1021/jo050172k

Effect of o-Methyl Group on Rate, Mechanism, and Resonance
Contribution: Aminolysis of Y-Substituted Phenyl X-Substituted
2-Methylbenzoates
Ik-Hwan Um,* Ji-Youn Lee, Hai Whang Lee,† Yoshiya Nagano,‡ Mizue Fujio,‡ and
Yuho Tsuno‡
Department of Chemistry, Ewha Womans University, Seoul 120-750, Korea, Department of Chemistry,
Inha University, Inchon 402-751, Korea, and Institute for Materials Chemistry and Engineering,
Kyushu University, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
ihum@mm.ewha.ac.kr
Received January 27, 2005
Second-order rate constants have been determined spectrophotometrically for the reactions of
4-nitrophenyl X-substituted 2-methylbenzoates (2a-e) and Y-substituted phenyl 2-methylbenzoates
(3a-e) with alicyclic secondary amines in 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C. The
o-methyl group in the benzoyl moiety of 2a-e retards the reaction rate but does not influence the
reaction mechanism. The Hammett plots for the reactions of 2a-e are nonlinear, while the
corresponding Yukawa-Tsuno plots are linear with large r values (1.06-1.70). The linear Yukawa-
Tsuno plots suggest that stabilization of the ground-state through resonance interaction between
the electron donating substituent X and the carbonyl group is responsible for the nonlinear Hammett
plots, while the large r values imply that the ground-state resonance interaction is significant.
The reactions of 2a-e resulted in smaller FX values but larger r values than the corresponding
reactions of 4-nitrophenyl X-substituted benzoates (1a-e). The small FX value for the reactions of
2a-e (e.g., FX ) 0.22) is suggested to be responsible for the large r value (e.g., r ) 1.70). The reactions
of 3a-e with piperidine are proposed to proceed in a stepwise manner with a change in the rate-
determining step on the basis of the curved Brønsted-type plot obtained. Microscopic rate constants
associated with the reactions of 3a-e are also consistent with the proposed mechanism.
Introduction
solvents,2,3 the nature of the amines,4-6 and the structure
of the substrates.5-13 Particularly, the effect of substrate
Aminolyses of esters have been suggested to proceed
either concertedly or in a stepwise manner with a
zwitterionic tetrahedral intermediate T(, depending on
the reaction conditions.1-13 Factors influencing the reac-
tion mechanism have intensively been investigated, e.g.,
(1) (a) Jencks, W. P. Chem. Rev. 1985, 85, 511-527. (b) Page, M. I.;
Williams, A. Organic and Bio-organic Mechanisms; Longman: Harlow,
U.K., 1997; Chapter 7. (c) Castro, E. A. Chem. Rev. 1999, 99, 3505-
3524.
(2) (a) Lee, I.; Sung, D. D. Curr. Org. Chem. 2004, 8, 557-567. (b)
Oh, H. K.; Park, J. E.; Sung, D. D.; Lee, I. J. Org. Chem. 2004, 69,
9285-9288. (c) Oh, H. K.; Ha, J. S.; Sung, D. D.; Lee, I. J. Org. Chem.
2004, 69, 8219-8223. (d) Oh, H. K.; Park, J. E.; Sung, D. D.; Lee, I. J.
Org. Chem. 2004, 69, 3150-3153. (e) Oh, H. K.; Lee, J. M.; Sung, D.
D.; Lee, I. Bull. Korean Chem. Soc. 2004, 25, 557-559. (f) Lee, I.; Lee,
H. W.; Yu, Y. K. Bull. Korean Chem. Soc. 2003, 24, 993-998.
* Corresponding author. Phone: 82-2-3277-2349. Fax: 82-2-3277-
2844.
† Inha University.
‡ Kyushu University.
10.1021/jo050172k CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/18/2005
4980
J. Org. Chem. 2005, 70, 4980-4987

Aminolysis of Substituted 2-Methylbenzoates
analogues.11b In all cases, the Hammett plots have been
found to be curved downwardly (i.e., electron-donating
substituents exhibit negative deviations from the Ham-
mett plots, and the degree of deviations is more signifi-
cant for a stronger electron-donating substituent). Tra-
ditionally, such a curved Hammett plot has been
interpreted as a change in the rate-determining step.13,14
However, we have suggested that the stabilization of the
ground-state as illustrated by resonance structures I T
II is responsible for the nonlinear Hammett plots, since
SCHEME 1
the corresponding Yukawa-Tsuno plots are all linear
with large r values.5,6,10,11
The r value in the Yukawa-Tsuno equation (eq 1)
structures on the reactivity and reaction mechanism has
intrigued chemists for a long time.5-13
Jencks et al. have concluded that the nonleaving
phenoxy moiety influences the reaction mechanism for
the reactions of X-substituted phenyl 3,4-dinitrophenyl
carbonates with quinuclidines.7 A similar conclusion has
been drawn by Castro et al. for aminolyses of 2,4-
dinitrophenyl X-substituted benzoates8 and S-4-nitro-
phenyl X-substituted thiobenzoates.9 They have sug-
gested that an electron-withdrawing substituent in the
nonleaving group retards the rate of the leaving group
departure from T( (the k2 in Scheme 1) but accelerates
the expulsion of the amine from T( (the k-1 in Scheme
1).7-9 Thus, it has been concluded that the substituent
in the nonleaving group of the carbonates and benzoates
affects the reaction mechanism.7-9
However, we have shown that the k2/k-1 ratio is
independent of the electronic nature of the substituent
X for the reactions of 4-nitrophenyl X-substituted ben-
zoates (1a-e) with a series of alicyclic secondary amines.10
A similar result has been shown for the aminolyses of
2,4-dinitrophenyl X-substituted benzoates5 and benzene-
sulfonates6 and the alkaline hydrolyses of 2,4-dinitro-
phenyl X-substituted benzoates11a and their thiono
log (kX/kH) ) FX[σo + r(σ+ - σo)]
(1)
represents the resonance demand of the reaction center
or the extent of resonance contribution.15-17 The largest
r value reported for benzylic systems is 1.53 for solvolysis
of 1-aryl-2,2,2-trifluoroethyl tosylates, in which the reso-
nance demand is remarkably high due to the strong
electron-withdrawing ability of the R-CF3 group.15-17 On
the other hand, the r value has been suggested to
decrease significantly as the planarity of the aryl moiety
and the reaction center is hindered by twisting the aryl
moiety.15,18
Thus, we have extended our study to the reactions of
4-nitrophenyl X-substitued 2-methylbenzoates (2a-e)
(3) Menger, F. M.; Smith, J. H. J. Am. Chem. Soc. 1972, 94, 3824-
3829.
(4) (a) Castro, E. A.; Aliaga, M.; Santos, J. G. J. Org. Chem. 2004,
69, 6711-6714. (b) Castro, E. A.; Cubillos, M.; Santos, J. G. J. Org.
Chem. 2004, 69, 4802-4807. (c) 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.
(6) (a) Um, I. H.; Chun, S. M.; Chae, O. M.; Fujio, M.; Tsuno, Y. J.
Org. Chem. 2004, 69, 3166-3172. (b) Um, I. H.; Hong, J. Y.; Kim, J.
J.; Chae, O. M.; Bae, S. K. J. Org. Chem. 2003, 68, 5180-5185.
(7) Gresser, M. J.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 6963-
6970.
and Y-substituted phenyl 2-methylbenzoates (3a-e) with
a series of alicyclic secondary amines, as shown in
(14) (a) Carrol, F. A. Pespectives 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.
(15) (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. (c)
Yukawa, Y.; Tsuno, Y. Bull. Chem. Soc. Jpn. 1959, 32, 965-970.
(16) (a) Fujio, M.; Rappoport, Z.; Uddin, M. K.; Kim, H. J.; Tsuno,
Y. Bull. Chem. Soc. Jpn. 2003, 76, 163-169. (b) Nakata, K.; Fujio, M.;
Nishimoto, K.; Tsuno, Y. J. Phys. Org. Chem. 2003, 16, 323-335. (c)
Uddin, M. K.; Fujio, M.; Kim, H. J.; Rappoport, Z.; Tsuno, Y. Bull.
Chem. Soc. Jpn. 2002, 75, 1371-1379.
(17) Murata, A.; Sakaguchi, S.; Mishima, M.; Fujio, M.; Tusno, Y.
Bull. Chem. Soc. Jpn. 1990, 63, 1129-1137.
(18) (a) Nakata, K.; Fujio, M.; Saeki, Y.; Mishima, M.; Nishimoto,
K.; Tsuno, Y. J. Phys. Org. Chem. 1996, 9, 561-572. (b) Nakata, K.;
Fujio, M.; Saeki, Y.; Mishima, M.; Tsuno, Y.; Nishimoto, K. J. Phys.
Org. Chem. 1996, 9, 573-582.
(8) (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.
(9) (a) Castro, E. A.; Bessolo, J.; Aguayo, R.; Santos, J. G. J. Org.
Chem. 2003, 68, 8157-8161. (b) Castro, E. A.; Vivanco, M.; Aguayo,
R.; Aguayo, R.; Santos, J. G. J. Org. Chem. 2004, 69, 5399-5404.
(10) Um, I. H.; Min, J. S.; Ahn, J. A.; Hahn, H. J. J. Org. Chem.
2000, 65, 5659-5663.
(11) (a) Um, I. H.; Hahn, H. J.; Ahn, J. A.; kang, S.; Buncel, E. J.
Org. Chem. 2002, 67, 8475-8480. (b) Um, I. H.; Lee, J. Y.; Kim, H. T.;
Bae, S. K. J. Org. Chem. 2004, 69, 2436-2441.
(12) (a) Um, I. H.; Seok, J. A.; Kim, H. T.; Bae, S. K. J. Org. Chem.
2003, 68, 7742-7746. (b) Um, I. H.; Lee, S. E.; Kwon, H. J. J. Org.
Chem. 2002, 67, 8999-9005.
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2000, 122, 6594-6600.
J. Org. Chem, Vol. 70, No. 13, 2005 4981

Um et al.
TABLE 1. Apparent Second-Order Rate Constants (kN, M-1 s-1) for the Reactions of 4-Nitrophenyl X-Substituted
Benzoates (1b, 1c, and 2c) with Alicyclic Secondary Amines in 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °Ca
102kN/M-1 s-1
1c
(X ) H)
1b
2c
aminesa
pKa
(X ) 4-Me)
(X ) 2-Me)
b
1, 1-formylpiperazine
2, morpholine
3, 1-(2-hydroxyethyl)piperazine
4, piperazine
5, piperidine
7.98
8.65
1.00 ( 0.04
8.76 ( 0.07
19.5 ( 0.3
85.1 ( 0.2
594 ( 2
0.707 ( 0.001
6.59 ( 0.01
14.7 ( 0.3
62.9 ( 0.1
368 ( 1
0.217 ( 0.001
1.22 ( 0.01
2.63 ( 0.01
10.9 ( 0.04
50.4 ( 0.3
9.38
9.85
11.02
a The numbers 1-5 refer to the labels in Figure 1. b The pKa data in 20 mol % DMSO and the rate constant data for the reactions of
1b and 1c were taken from ref 10.
Scheme 1. One might expect that the o-methyl group
would influence the reactivity of 2a-e and 3a-e. More
importantly, the CdO bond would experience steric
hindrance exerted by the o-methyl group in the benzoyl
moiety of 2a-e and 3a-e. The steric hindrance would
disturb the planarity of the benzoyl moiety. If the CdO
bond and the phenyl ring in the benzoyl moiety of 2a-e
are not on the same plane, the resonance contribution of
the π-electron donor substituent should decrease signifi-
cantly. Thus, one might expect that the r value, repre-
senting the resonance contribution, should be smaller for
the reactions of 2a-e than for the corresponding reac-
tions of 1a-e. We report the effect of the o-methyl group
in the benzoyl moiety of 2a-e and 3a-e on reaction
rates, mechanism, and r values together with factors
influencing the magnitude of the Brønsted â value.
Results and Discussion
All the reactions in this study obeyed pseudo-first-order
kinetics in the presence of a large excess of amine.
Pseudo-first-order rate constants (kobsd) were determined
from the equation ln(A∞ - At) ) -kobsdt + C. The
correlation coefficient for the linear regressions was
always higher than 0.9995. All the plots of kobsd vs amine
concentration were linear, passing through the origin,
indicating that general base catalysis by a second amine
FIGURE 1. Brønsted-type plots for the reactions of 4-nitro-
molecule is absent and the contribution of H2O and/or
phenyl X-substituted benzoates (1b, 1c, and 2c) with alicyclic
OH- from hydrolysis to the kobsd is negligible. Second-
secondary amines in 80 mol % H2O/20 mol % DMSO at 25.0 (
0.1 °C. The identity of the points is given in Table 1.
order rate constants (kN) were determined from the slope
of the linear plots of kobsd vs amine concentration and are
summarized in Tables 1-3. The uncertainty in the kN
values is estimated to be less than 3% from replicate
runs. The detailed reaction conditions and kinetic results
are shown in the Supporting Information.
is not solely responsible for the low reactivity of 2c. One
can attribute the lower reactivity of 2c compared with
1b to the steric hindrance exerted by the o-methyl group
in 2c.
Effect of o-Methyl Group on Rate and Mecha-
nism. As shown in Table 1, 1b is only slightly less
reactive than 1c, while 2c is up to ca. 12 times less
reactive than 1c (e.g., the second-order rate constant ratio
Table 1 shows that the second-order rate constant kN
for the aminolysis of 1b, 1c, and 2c increases as the
basicity of amines increases. The effect of amine basicity
on the reactivity is illustrated in Figure 1. The Brønsted-
type plots are all linear with a similar ânuc value.
The magnitude of ânuc values has been used as a
measure of reaction mechanism.1 The ânuc value has
generally been reported to be 0.5 ( 0.1 for reactions that
proceed through a concerted mechanism.1,20,21 On the
other hand, for reactions proceeding in a stepwise man-
ner, the ânuc value has often been shown to decrease from
kN1c/kN ) 1.4-1.6 while kN1c/kN ) 4.6-12). One can
suggest that the electron-donating ability of the methyl
group in the benzoyl moiety of 1b and 2c is responsible
for their low reactivity. However, if the electronic effect
were the only factor to determine the reactivity, 1b and
2c should have exhibited a similar reactivity, since the
electronic effect of the methyl group in 1b and 2c was
suggested to be similar.19 Thus, the fact that 2c is much
less reactive than 1b indicates that the electronic effect
1b
2c
(20) (a) Lee, H. W.; Guha, A. K.; Lee, I. Int. J. Chem. Kinet. 2002,
34, 632-637. (b) Lee, H. W.; Guha, A. K.; Kim, C. K.; Lee, I. J. Org.
Chem. 2002, 67, 2215-2222. (c) Oh, H. K.; Lee, Y. H.; Lee, I. Int. J.
Chem. Kinet. 2002, 32, 131-135.
(19) Charton, M. Progress in Physical Organic Chemistry, Vol. 8.;
John Wiley and Sons: New York,1971; pp 235-317.
4982 J. Org. Chem., Vol. 70, No. 13, 2005

Aminolysis of Substituted 2-Methylbenzoates
TABLE 2. Summary of Apparent Second-Order Rate
Constants (kN, M-1 s-1) for the Reactions of
4-Nitrophenyl X-Substituted 2-Methylbenzoates (2a-e)
with Alicyclic Secondary Amines in 80 mol % H2O/20 mol
% DMSO at 25.0 ( 0.1 °C
102 kN/M-1 s-1
1-formyl-
piperazine
1-(2-hydroxyethyl)-
piperazine
no., X
piperidine
2a, 4-MeO 0.105 ( 0.001
1.12 ( 0.01
1.96 ( 0.04
2.63 ( 0.01
3.20 ( 0.02
4.25 ( 0.02
19.8 ( 0.1
37.2 ( 0.1
50.4 ( 0.3
75.0 ( 0.4
120 ( 0.3
2b, 4-Me
2c, H
0.168 ( 0.001
0.217 ( 0.001
0.245 ( 0.002
0.292 ( 0.001
2d, 3-Cl
2e, 3-NO2
0.9 ( 0.2 to 0.3 ( 0.1 as the nucleophile becomes more
basic than the leaving group.1-10 A change in the rate-
determining step has been suggested to be responsible
for the decrease in the ânuc value.1-10 The ânuc values
determined in this study for the reactions of 1b, 1c, and
2c are 0.80, 0.82, and 0.70, respectively. These ânuc values
are typical for aminolysis reactions that proceed through
T(, with its breakdown to the products being the rate-
determining step. Thus, one can suggest that the ami-
nolysis of 2c also proceeds through a stepwise mecha-
nism, as suggested previously for the reactions of 1b and
1c,10 indicating that the o-methyl group in 2c does not
influence the reaction mechanism.
Effect of o-Methyl Group on r and GX Values. As
shown in Table 2, the reactivity of 2a-e increases as the
substituent X changes from an electron-donating group
to an electron-withdrawing group. The effect of substitu-
ent X on the reactivity is illustrated in Figure 2.
All the Hammett plots are nonlinear, while the Yuka-
wa-Tsuno plots shown in the inset of Figure 2 are all
linear with large r values, indicating that the nonlinear
Hammett plots are definitely not due to a change in the
rate-determining step. One can attribute the negative
deviation shown by 2a from the Hammett correlation to
the ground-state stabilization through a resonance in-
teraction between the p-methoxy and the carbonyl group,
as illustrated by resonance structures III T IV. Thus,
FIGURE 2. Hammett and Yukawa-Tsuno plots (the inset)
for the reactions of 4-nitrophenyl X-substituted 2-methylben-
zoates (2a-e) with piperidine (b), 1-(2-hydroxyethyl)piperazine
(O), and 1-formylpiperazine (Y) in 80 mol % H2O/20 mol %
DMSO at 25.0 ( 0.1 °C.
for aminolyses of 1a-e,10 2,4-dinitrophenyl X-substituted
benzoates.5a For example, the r values reported are 0.75,
1.05, 1.20, 1.29, and 1.38 while the FX values are 0.75,
0.54, 0.51, 0.44, and 0.42 for the reactions of 1a-e with
piperidine, piperazine, 1-(2-hydroxyethyl)piperazine, mor-
pholine, and 1-formylpiperazine, respectively.10 The re-
lationship between the r and FX values is illustrated in
Figure 3. As shown, the r value increases linearly as the
FX value decreases.
One might expect that the o-methyl group in the
benzoyl moiety of 2a-e would twist the phenyl ring and
the CdO bond by exerting steric hindrance. If the benzoyl
moiety is not planar, the resonance interaction between
the electron-donating substituent X and the carbonyl
group should decrease. Then, the r value, representing
the resonance contribution, should be smaller for the
reactions of 2a-e than for the corresponding reactions
of 1a-e. However, unexpectedly, the r values have been
determined to be larger for the former reactions than for
the latter reactions (see also Figure 3). Furthermore, the
r value of 1.70 for the reactions of 2a-e with 1-formylpip-
erazine is even larger than the largest r value ever
reported for the solvolysis of 1-aryl-2,2,2-trifluoroethyl
tosylates.17 Thus, one can suggest that the o-methyl
group does not inhibit the ground-state resonance inter-
action (e.g., III T IV).
the present result confirms our previous proposal that
determination of the reaction mechanism based just on
a linear or nonlinear Hammett plot can be mislead-
ing.5,6,10,11
Although the r and FX values might include some
extent of uncertainty due to the limited number of
substituents, the r value determined in this study
increases from 1.06 to 1.45 and 1.70 as the FX value
decreases from 0.49 to 0.31 and 0.22 for the reactions of
2a-e with piperidine, 1-(2-hydroxyethyl)piperazine, and
1-formylpiperazine, respectively. A similar inverse rela-
tionship between the r and FX values has been reported
We have calculated the ground-state structure of 2c
by a density functional theory (DFT) method (at the
B3LYP/6-31+G* level). The result of the molecular
orbital calculations has revealed that the phenyl ring and
the carbonyl group of 2a-e are not on the same plane
as expected (see the calculated structures of 1c and 2c
shown in the Supporting Information). The dihedral
(21) (a) Castro, E. A.; Angel, M.; Arellano, D.; Santos, J. G. J. Org.
Chem. 2001, 66, 6571-6575. (b) Castro, E. A.; Cubillos, M.; Santos, J.
G. J. Org. Chem. 2001, 66, 6000-6003. (c) Castro, E. A.; Pavez, P.;
Santos, J. G. J. Org. Chem. 2001, 66, 3129-3132. (d) Castro, E. A.;
Pavez, P.; Santos, J. G. J. Org. Chem. 1999, 64, 2310-2313.
J. Org. Chem, Vol. 70, No. 13, 2005 4983

Um et al.
TABLE 3. Summary of Apparent Second-Order Rate
Constants (kN, M-1 s-1) for the Reactions of Y-Substituted
Phenyl 2-Methylbenzoates (3a-e) with Piperidine in 80
mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C
pKa
no., Y
(Y-C6H4OH)a
102kN/M-1 s-1
3a, 3-COMe
3b, 4-COMe
3c, 4-CHO
9.19
8.05
7.66
7.14
5.42
(5.00 ( 0.01) × 10-3
1.03 ( 0.01
8.05 ( 0.08
50.4 ( 0.3
3d, 4-NO2
3e, 3,4-(NO2)2
1350 ( 2
a pKa values were taken from Jencks, W. P.; Regenstein, J. In
Handbook of Biochemistry, 2nd ed.; Sober, H. A., Ed.; Chemical
Rubber Publishing Co.: Cleveland, OH, 1970; p J-195.
FIGURE 3. Plot showing dependence of the r value on the FX
value for the aminolysis of 2a-e (O) and 1a-e (b) in 80 mol
% H2O/20 mol % DMSO at 25.0 ( 0.1 °C.
angle between the phenyl ring and the CdO bond in the
benzoyl moiety of 2c is ca. 6°.
It has been suggested that the efficiency of resonance
interaction is proportional to cos2 θ, where θ is the
dihedral angle between the two overlapping p-orbit-
als.15,18 The θ determined in this study is ca. 6°. Since
cos2 6 ° ≈ 1, the o-methyl group would not reduce the
efficiency of the resonance interaction between the
electron-donating substituent X and the carbonyl bond
in the benzoyl moiety of 2a-e. This accounts for the
result that the r values are not smaller for the reactions
of 2a-e than for the corresponding reactions of 1a-e.
Since the FX values and the observed r values exhibit an
inverse relationship in this and other aminolysis reac-
tions, as mentioned above, one can attribute the large r
value found for the reactions of 2a-e to the decreased
FX values by the o-methyl group in the benzoyl moiety of
2a-e.
Effect of Leaving Group Substituent on Rate and
Mechanism. To obtain more information about the
reaction mechanism, the reactions of 3a-e with piperi-
dine have been performed. As shown in Table 3, the
reactivity of 3a-e increases as the leaving group becomes
less basic, i.e., the second-order rate constant kN increases
from 5.00 × 10-5M-1 s-1 to 8.05 × 10-2 and 13.5 M-1 s-1
as the substituent Y in the leaving group changes from
3-COMe to 4-CHO and 3,4-(NO2)2, respectively.
FIGURE 4. Brønsted-type plot for the reactions of Y-substi-
tuted phenyl 2-methylbenzoates (3a-e) with piperidine in 80
mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C.
in Scheme 1, the nonlinear Brønsted-type plot shown in
Figure 4 has been analyzed using a semiempirical
equation (eq 2).
log (kN/kN°) ) â1(pKa - pKa°) - log [(1 + R)/2]
where
log R ) (â1 - â2)(pKa - pKa°)
(2)
In eq 2, â1 and â2 represent the slope of the Brønsted-
type plot shown in Figure 4 for the weakly basic and
strongly basic leaving groups, respectively, while kN°
refers to the kN value at pKa° (defined as the center of
the curvature of the curved Brønsted-type plot, where
k2 ) k-1). The â1, â2, and pKa° values determined are
-0.38, -1.98, and 6.7, respectively. The â1 value might
involve some extent of uncertainty due to limited points.
Interestingly, the â2 value is much larger than unity. The
origin of the large â2 value will be discussed later.
The effect of leaving group basicity on reactivity is
illustrated in Figure 4. The Brønsted-type plot for the
reactions of 3a-e with piperidine is curved downwardly
as the basicity of the leaving aryloxide decreases. Such
a curved Brønsted-type plot is typical for reactions that
proceed through T( with a change in the rate-determin-
ing step. Thus, on the basis of the proposed mechanism
4984 J. Org. Chem., Vol. 70, No. 13, 2005

Aminolysis of Substituted 2-Methylbenzoates
TABLE 4. Summary of the Microscopic Rate Constants
Associated with the Reactions of Y-Substituted Phenyl
2-Methylbenzoates (3a-e) with Piperidine in 80 mol %
H2O/20 mol % DMSO at 25.0 ( 0.1 °C
The pKa° determined in this study is 6.7, which is ca.
4.3 pKa units smaller than the pKa of the conjugate acid
of the attacking piperidine (pKa ) 11.02). This is consis-
tent with the reports that the rate-determining step
changes 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 Thus, one can suggest that the reactions
of 3a-e proceed through T( with a change in the rate-
determining step at pKa ca. 6.7, i.e., the reactions of 3a-d
with piperidine proceed through the rate-determining
breakdown of T( to the products while the reaction of 3e
with piperidine proceeds through the rate-determining
formation of T(.
no., Y
pKa
k1/M-1 s-1
k2/k-1
3a, 3-COMe
3b, 4-COMe
3c, 4-CHO
9.19
8.05
7.66
7.14
5.42
0.482
1.50
2.85
3.05
13.6
1.04 × 10-4
0.00692
0.0291
0.198
3d, 4-NO2
3e, 3,4-(NO2)2
112
Origin of Large Brønsted â Values. We have
determined the microscopic rate constants associated
with the reactions of 3a-e with piperidine to investigate
further information about the reaction mechanism and
the origin of the large Brønsted â value determined in
this study. On the basis of the proposed mechanism in
Scheme 1, the apparent second-order rate constant kN
can be expressed as eqs 3 and 4 by applying the steady-
state conditions to the intermediate.
rate ) k1k2 [substrate][piperidine]/(k-1 + k2) (3)
kN ) k1k2/( k-1 + k2)
) k1/( k-1/k2 + 1)
(4)
The k2/k-1 ratios for the reactions of 3a-e with
piperidine have been calculated as follows. Equation 4
can be simplified to eqs 5 and 6. Then, â1 and â2 can be
expressed as eqs 7 and 8, respectively.
kN ) k1 k2/k-1 when k2 , k-1
kN ) k1 when k2 >> k-1
â1 ) d(log k1)/d(pKa)
(5)
(6)
(7)
FIGURE 5. Brønsted-type plot for k1 for the reactions of
Y-substituted phenyl 2-methylbenzoates (3a-e) with piperi-
dine in 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C.
â2 ) d(log k1k2/k-1)/d(pKa)
) â1 + d(log k2/k-1)/d(pKa)
indicating that the electrophilicity of the carbonyl carbon
of 3a-e increases as the substituent Y in the leaving
group becomes a stronger electron-withdrawing group.
However, one can suggest that the electronic nature of
substituent Y does not significantly influence the rate of
nucleophilic attack on the basis of the small â value.
We have recently reported that the â values are -0.49
and -0.34 for the alkaline hydrolysis of Y-substituted
phenyl benzoates11a and their thiono analogues,11b re-
spectively. These reactions have been suggested to pro-
ceed through an addition intermediate with its formation
being the rate-determining step.11 Besides, a â value of
ca. 0.3 ( 0.1 has often been reported for aminolyses of
various esters in which the formation of T( is the rate-
determining step.1 Thus, a â value of ca. 0.3 ( 0.1 appears
to be typical for the nucleophilic attack process or for
reactions which proceed through a rate-determining
formation of T(, regardless of the type of nucleophiles
(neutral amines or anions) and the electrophilic centers
(carbonyl or thionocarbonyl).
(8)
Equation 8 can be rearranged as eq 9. Integration of
eq 9 from pKa° results in eq 10. Since k2 ) k-1 at pKa°,
the term (log k2/k-1 pK is zero. Therefore, one can
)
a
calculate the k2/k-1 ratio for the reactions of Y-substituted
phenyl 2-methylbenzoates with piperidine from eq 10
using â1 ) -0.38, â2 ) -1.98, pKa° ) 6.7.
â2 - â1 ) d(log k2/k-1)/d(pKa)
(log k2/k-1 pK ) (â2 - â1)(pKa - pKa°)
(9)
)
(10)
a
The k1 values have been determined from eq 4 using
the kN values in Table 3 and the k2/k-1 ratios calculated
above. The results are summarized in Table 4.
Table 4 exhibits that the k1 value increases as the
leaving group basicity decreases, i.e., k1 increases from
0.482 to 2.85 and 13.6 M-1 s-1 as the pKa of the conjugate
acid of the leaving aryloxide decreases from 9.19 to 7.66
and 5.42, respectively. The effect of the leaving group
basicity on the k1 value is illustrated in Figure 5. The
Brønsted-type plot is linear with a â value of -0.38,
Table 4 shows that the k2/k-1ratio increases as the
leaving group becomes less basic, i.e., k2/k-1 < 1 for
pKa g 7.14, while k2/k-1 > 1 for pKa e 5.42. This result
J. Org. Chem, Vol. 70, No. 13, 2005 4985

Um et al.
second step being the rate-determining step as in the
present study.
Conclusions
The present study has allowed us to conclude the
following: (1) The o-methyl group of 2c retards the
reactivity by exerting steric hindrance but does not
influence the reaction mechanism. (2) The Yukawa-
Tsuno plots are linear with large r values for the
reactions of 2a-e. The r value increases as the FX value
decreases, and the reactions of 2a-e exhibit larger r
values than the corresponding reactions of 1a-e. (3) The
density functional theory (DFT) calculations have re-
vealed that the phenyl ring and the carbonyl group of
2c are twisted with a dihedral angle θ of ca. 6°. The small
θ does not reduce the ground-state resonance interaction;
instead, it increases the r value by decreasing the FX
value. (4) The reactions of 3a-e proceed through a
stepwise mechanism with a change in the rate-determin-
ing step (pKa° ) 6.7). (5) The Brønsted â value can be
much larger than unity for reactions that proceed through
T( with its breakdown being the rate-determining step.
Experimental Section
Materials. Compounds 2a-e and 3a-e were readily pre-
pared from the reactions of Y-substituted phenol and X-
substituted 2-methylbenzoic acid under the presence of dicy-
clohexyldiimide (DCC) in methylene chloride and purified by
column chromatography. Their purity was checked by their
melting points, 1H NMR spectra, and elemental analysis data
(see Supporting Information). Amines and other chemicals
used are of the highest quality available and were generally
recrystallized or distilled before use. Due to the low solubility
of these compounds in pure water, aqueous DMSO (20 mol %
DMSO/80 mol % H2O) was used as the reaction medium.
Doubly glass-distilled water was further boiled and cooled
under nitrogen just before use.
Kinetics. The kinetic study was performed with a UV-vis
spectrophotometer equipped with a constant temperature
circulating bath at 25.0 ( 0.1 °C. The reactions were followed
by monitoring the appearance of Y-substituted phenoxide at
a fixed wavelength corresponding to the λmax. All the reactions
were carried out under pseudo-first-order conditions in the
presence of excess amine. Typically, the reaction was initiated
by adding 5 µL of a 0.02 M of substrate solution in MeCN by
a 10 µL gastight syringe to a 10 mm quartz UV cell containing
2.50 mL of the thermostated reaction mixture made up of
solvent and an aliquot of the amine stock solution. The amine
stock solution of ca. 0.2 M was prepared by dissolving 2 equiv
of free amine and 1 equiv of standardized HCl solution to make
a self-buffered solution. All the solutions were transferred by
gastight syringes under nitrogen. Generally, the amine con-
centration was varied over the range (1-100) × 10-3 M, while
the substrate concentration was 4 × 10-5 M. The plots of
ln(A∞ - At) vs time were linear over ca. 90% of the total
reaction. Usually five different amine concentrations were used
to determine the kN value from the slope of the linear plot of
kobsd vs amine concentration.
FIGURE 6. Plot of log k2/k-1 vs pKa for the reactions of
Y-substituted phenyl 2-methylbenzoates (3a-e) with piperi-
dine in 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C.
is consistent with the preceding proposal, on the basis of
the curved Brønsted-type plot shown in Figure 4, that
the reactions of 3a-e with piperidine proceed through a
stepwise mechanism with a change in the rate-determin-
ing step.
The effect of leaving group basicity on the k2/k-1 ratio
is demonstrated in Figure 6. The plot is linear with a â
value of -1.60. Since the nucleofugality of the leaving
group from T( would be influenced significantly by the
electronic nature of the substituent Y in the leaving
group, the k2 value would increase strongly as the
substituent Y becomes a stronger electron-withdrawing
group or as the leaving group becomes less basic. On the
contrary, the expulsion of the amine from T( would be
more difficult as the electron-withdrawing ability of the
substituent Y increases. Accordingly, the k2/k-1 ratio
should exhibit great dependence on the electronic nature
of the substituent Y, which is responsible for the large â
value (-1.60) shown in Figure 6.
One can also account for the large â2 value (-1.98)
shown in Figure 4 using the microscopic rate constants
determined above. Equation 4 becomes eq 5 when the
breakdown of T( to the products is the rate-determining
step. In this case, the kN value is determined by both k1
and k2/k-1 ratio. Thus, the â value for kN should be the
sum of the â values for k1 and k2/k-1 ratio. The slopes of
the Brønsted-type plots shown in Figures 5 and 6 are
-0.38 and -1.60, respectively. The sum of these values
is -1.98, which is the same as the â2 value shown in
Figure 4. Thus, the present study shows that the Brøn-
sted â value can be much larger than unity, depending
on the nature of the reaction mechanism and the rate-
determining step, e.g., a stepwise mechanism with the
Calculations. Density functional theory (DFT) calculations
were performed with the Gaussian 98 system of programs.22a
The DFT method is particularly useful for calculations involv-
ing a large number of nonhydrogen atoms at the correlated
level. The B3LYP hybride exchange-correlation functionals are
known to give good equilibrium geometries and vibrational
frequencies and accurate molecular atomization energies.22b
Geometries were optimized and confirmed by calculating the
harmonic frequencies at the B3LYP/6-31+G* level.
4986 J. Org. Chem., Vol. 70, No. 13, 2005

Aminolysis of Substituted 2-Methylbenzoates
Products Analysis. 4-Nitrophenoxide (or Y-substituted
phenoxide) was liberated quantitatively and identified as one
of the reaction products in the reactions of 2a-e (or 3a-e) by
comparison of the UV-vis spectra after the completion of the
reactions with those of the authentic samples under the same
reaction conditions.
Acknowledgment. This work was supported by
Korea Science and Engineering Foundation (R01-2004-
10279).
Supporting Information Available: General synthetic
procedures for the preparation of compounds 2a-e and 3a-e
and their analytical data, such as their 1H NMR spectra,
elemental analysis data, and lists of their melting points; the
kinetic conditions and results for the reactions of 2c with a
series of alicyclic secondary amines (Tables S1-S5), for the
reactions of 2a-e with 1-formylpiperazine, 1-(2-hydroxyethyl)-
piperazine, and piperidine (Tables S6 -S17), and for the
reactions of 3a-e with piperidine (Tables S18-S22); the
structures of 1c and 2c calculated by a DFT method (at the
B3LYP/6-31+G* level) and their calculated electronic energies
and Z-matrixes. This material is available free of charge via
the Internet at http://pubs.acs.org.
(22) (a) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J.
A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle,
E. S.; Pople, J. A. Gaussian 98, Revision A.6. Gaussian, Inc., Pittsburgh,
PA, 1998. (b) Levine, I. N. Quantum Chemistry, 5th ed.; Prentice
Hall: Upper Saddle River, NJ, 2000; p 573.
JO050172K
J. Org. Chem, Vol. 70, No. 13, 2005 4987