Aminolysis of O-aryl thionobenzoates: Amine basicity combines with modulation of the nature of substituents in the leaving group and thionobenzoate moiety to control the reaction mechanism

Article abstract of DOI:10.1021/jo801539w

(Chemical Equation Presented) A kinetic study is reported for aminolysis of O-Y-substituted phenyl thionobenzoates (la-f) and O-4-nitrophenyl X-substituted thionobenzoates (2a-f) in 80 mol % H₂O/20 mol % DMSO at 25.0 ± 0.1°C. The reaction proceeds through one or two intermediates (i.e., a zwitterionic tetrahedral intermediate T^± and its deprotonated form T^-) depending on the basicity difference between the nucleophile and nucleofuge, that is, the reaction proceeds through T ^± when the leaving aryloxide is less basic than the attacking amine, but through T^± and T^- when the leaving group is more basic than the amine. However, the reaction mechanism is not influenced by the electronic nature of the substituent X in the nonleaving group. The Hammett plot for the reactions of 2a-f with benzylamine is consisted of two intersecting straight lines, which might be interpreted as a change in the rate-determining step (RDS). However, the Yukawa-Tsuno plot for the same reactions exhibits an excellent linear correlation, indicating that the nonlinear Hammett plot is not due to a change in the RDS but caused by stabilization of the ground-state of the substrate through resonance interaction between the electron-donating substituent X and the thionocarbonyl moiety.

Full text of DOI:10.1021/jo801539w

Aminolysis of O-Aryl Thionobenzoates: Amine Basicity Combines
with Modulation of the Nature of Substituents in the Leaving Group
and Thionobenzoate Moiety to Control the Reaction Mechanism
Ik-Hwan Um,*,† So-Jeong Hwang, Sora Yoon, Sang-Eun Jeon,‡ and Sun-Kun Bae§
Department of Chemistry and Nano Science, Ewha Womans UniVersity, Seoul 120-750, Korea
ihum@ewha.ac.kr
ReceiVed July 12, 2008
A kinetic study is reported for aminolysis of O-Y-substituted phenyl thionobenzoates (1a-f) and O-4-
nitrophenyl X-substituted thionobenzoates (2a-f) in 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C.
The reaction proceeds through one or two intermediates (i.e., a zwitterionic tetrahedral intermediate T(
and its deprotonated form T-) depending on the basicity difference between the nucleophile and nucleofuge,
that is, the reaction proceeds through T( when the leaving aryloxide is less basic than the attacking
amine, but through T( and T- when the leaving group is more basic than the amine. However, the
reaction mechanism is not influenced by the electronic nature of the substituent X in the nonleaving
group. The Hammett plot for the reactions of 2a-f with benzylamine is consisted of two intersecting
straight lines, which might be interpreted as a change in the rate-determining step (RDS). However,
the Yukawa-Tsuno plot for the same reactions exhibits an excellent linear correlation, indicating
that the nonlinear Hammett plot is not due to a change in the RDS but caused by stabilization of the
ground-state of the substrate through resonance interaction between the electron-donating substituent
X and the thionocarbonyl moiety.
Introduction
a stepwise mechanism with a zwitterionic tetrahedral intermedi-
ate (T().1-9 Curved Brønsted-type plots have often been
reported for aminolysis of carboxylic esters that bear a good
leaving group; such curvature is taken to be diagnostic of a
change in the rate-determining step (RDS) of a stepwise
mechanism.1-6 Recent computational studies also favor a
stepwise mechanism although some studies failed to identify
the transition state and T( for aminolysis of carboxylic esters.7-9
In contrast, aminolysis of thiono (CdS) esters has been
suggested to proceed through one or two intermediates, that is,
T( and its deprotonated form T-.10-13 Factors proposed to
influence the mechanism include: basicity of the attacking
amines, the type of solvents (protic or aprotic) and the nature
Reactions of carboxylic acid derivatives with amines have
been intensively investigated due to their importance in bio-
chemical pathways (e.g., enzyme action, peptide biosynthesis,
etc.) as well as synthetic applications.1-9 Aminolysis of car-
boxylic esters has generally been reported to proceed through
† Tel.: 82-2-3277-2349. Fax: 82-2-3277-2844.
‡ Present Address: Environmental Research Complex, Incheon 404-708,
Korea.
§ Department of Chemistry, Kunsan National University, Kunsan 573-701,
Korea.
(1) (a) Jencks, W. P. Catalysis in Chemistry and Enzymology; McGraw-
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2637.
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485–493. (b) Williams, A. AdV. Phys. Org. Chem. 1992, 27, 2–55. (c) Menger,
F. M.; Smith, J. H. J. Am. Chem. Soc. 1972, 94, 3824–3829.
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Chem. Soc. 1985, 107, 7360. (b) Neuvonen, H. J. Chem. Soc., Perkin Trans.
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10.1021/jo801539w CCC: $40.75
Published on Web 09/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7671–7677 7671

Um et al.
SCHEME 1
of amines (primary or secondary). Castro et al. have reported
that reactions of thiono esters with weakly basic amines proceed
through T( and T- in aqueous solution, while the corresponding
reactions with strongly basic amines proceed without the
deprotonation process from T(.10 Thus, basicity of the attacking
amine has been proposed to be a crucial factor that selects the
mechanistic pathway.10On the other hand, Lee et al. have
reported that reactions of aryl dithiobenzoates with a series of
aniline and benzylamine derivatives proceed through T( in
MeCN.11d They have found that the deprotonation process from
T(, which has often been observed for the reactions performed
in H2O, is absent in this aprotic solvent even for reactions with
weakly basic anilines.11d Accordingly, the nature of the medium
has been suggested to be a determinant of the presence/absence
of the deprotonation process (i.e., T( f T-).11d
However, we have shown that the reaction of O-4-nitrophenyl
thionobenzoate (1b) with secondary amines (either cyclic or
acyclic) proceeds via both T( and T- in MeCN as well as in
H2O, while the corresponding reaction with primary amines
proceeds only through T( regardless of the basicity of amines.12
A similar confirmatory result has been found recently for
aminolysis of 4-nitrophenyl phenyl thionocarbonate, that is,
reactions with secondary amines proceed through T( and its
conjugate base T-, whereas the corresponding reactions with
primary amines again proceed solely via T(, indicating that the
nature of amines is an important factor to determine reaction
mechanism.13
(4) (a) Castro, E. A.; Echevarria, G. R.; Opazo, A.; Robert, P.; Santos, J. G.
J. Phys. Org. Chem. 2006, 19, 129–135. (b) Castro, E. A.; Campodonico, P. R.;
Contreras, R.; Fuentealba, P.; Santos, J. G.; Leis, J. R.; Garcia-Rio, L.; Saez,
J. A.; Domingo, L. R. Tetrahedron 2006, 62, 2555–2562. (c) Castro, E. A.;
Aliaga, M.; Gazitua, M.; Santos, J. G. Tetrahedron 2006, 62, 4863–4869. (d)
Castro, E. A.; Aguayo, R.; Bessolo, J.; Santos, J. G. J. Org. Chem. 2005, 70,
7788–7791. (e) Castro, E. A.; Aliaga, M.; Santos, J. G. J. Org. Chem. 2005, 70,
2679–2685. (f) Castro, E. A.; Gazitua, M.; Santos, J. G. J. Org. Chem. 2005,
70, 8088–8092. (g) Castro, E. A.; Aliaga, M.; Santos, J. G. J. Org. Chem. 2004,
69, 6711–6714. (h) Castro, E. A.; Andujar, M.; Toro, A.; Santos, J. G. J. Org.
Chem. 2003, 68, 3608–3613.
(5) (a) Lee, I.; Lee, H. W.; Yu, Y. K. Bull. Korean Chem. Soc. 2003, 24,
993–998. (b) Oh, H. K.; Park, C. Y.; Lee, J. M.; Lee, I. Bull. Korean Chem.
Soc. 2001, 22, 383–387. (c) Koh, H. J.; Han, K. L.; Lee, H. W.; Lee, I. J. Org.
Chem. 2000, 65, 4706–4711.
(6) (a) Um, I. H.; Park, Y. M.; Fujio, M.; Mishima, M.; Tsuno, Y. J. Org.
Chem. 2007, 72, 4816–4821. (b) Um, I. H.; Lee, J. Y.; Fujio, M.; Tsuno, Y.
Org. Biomol. Chem. 2006, 4, 2979–2985. (c) Um, I. H.; Jeon, S. E.; Seok, J. A.
Chem.sEur. J. 2006, 12, 1237–1243. (d) Um, I. H.; Lee, J. Y.; Lee, H. W.;
Nagano, Y.; Fujio, M.; Tsuno, Y. J. Org. Chem. 2005, 70, 4980–4987. (e) Um,
I. H.; Kim, K. H.; Park, H. R.; Fujio, M.; Tsuno, Y. J. Org. Chem. 2004, 69,
3937–3942.
(7) (a) Galabov, B.; Atanasov, Y.; Ilieva, S.; Schaefer, H. F., III. J. Phys.
Chem. A 2005, 109, 11470–11474. (b) Ilieva, S.; Galabov, B.; Musaev, D. G.;
Morokuma, K.; Schaefer, H. F., III. J. Org. Chem. 2003, 68, 1496–1502.
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Zipse, H.; Wang, L.; Houk, K. N. Liebigs Ann. 1996, 1511–1522.
(9) (a) Sung, D. D.; Koo, I. S.; Yang, K.; Lee, I. Chem. Phys. Lett. 2006,
432, 426–430. (b) Lee, I.; Lee, H. W.; Lee, B. C.; Choi, J. H. Bull. Korean
Chem. Soc. 2002, 23, 201–204. (c) Lee, I.; Kim, C. K.; Li, H. G.; Sohn, C. K.;
Kim, C. K.; Lee, H. W.; Lee, B. S. J. Am. Chem. Soc. 2000, 122, 11162–11172.
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Chem. 2006, 19, 555–561. (b) Campodonico, P. R.; Fuentealba, P.; Castro, E. A.;
Santos, J. G.; Contreras, R. J. Org. Chem. 2005, 70, 1754–1760. (c) Castro,
E. A.; Vivanco, M.; Aguayo, R.; Santos, J. G. J. Org. Chem. 2004, 69, 5399–
5404. (d) Castro, E. A.; Cubillos, M.; Aliaga, M.; Evangelisti, S.; Santos, J. G.
J. Org. Chem. 2004, 69, 2411–2416. (e) Castro, E. A.; Galvez, A.; Leandro, L.;
Santos, J. G. J. Org. Chem. 2002, 67, 4309–4315. (f) Castro, E. A. Chem. ReV.
1999, 99, 3505–3524.
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434–440. (b) Oh, H. K.; Ku, M. H.; Lee, H. W.; Lee, I. J. Org. Chem. 2002, 67,
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Org. Chem. 1997, 62, 5780–5784.
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We have extended our study to aminolysis of a series of O-Y-
substituted phenyl thionobenzoates (1a-f) and O-4-nitrophenyl
X-substituted thionobenzoates (2a-f) to dissect the interplay
of the factors determining the reaction mechanism. We have
employed various substituents both in the leaving and nonleav-
ing groups of the substrate. Moreover, three primary amines
have been chosen as nucleophiles to probe the mechanistic
behavior over an approximately 5 pKa units, that is, strongly
basic ethylamine (EtNH2, pKaEtNH + ) 10.67), moderately basic
3
BzNH3+
benzylamine (BzNH2, pKa
) 9.46) and weakly basic
trifluoroethylamine (CF3CH2NH2, pKaCF CH2NH3+ ) 5.70). We
have systematically investigated the effect of the basicity of
attacking amines, but combined it with the electronic nature of
the substituents X and Y, on reactivity and mechanism, as shown
in Scheme 1.
3
Results and Discussion
(13) (a) Um, I. H.; Yoon, S. R.; Park, H. R.; Han, H. J. Org. Biomol. Chem.
2008, 6, 1618–1624. (b) Um, I. H.; Kim, E. Y.; Park, H. R.; Jeon, S. E. J. Org.
Chem. 2006, 71, 2302–2306.
The kinetic study was performed spectrophotometrically. All
reactions proceeded with quantitative liberation of Y-substituted
7672 J. Org. Chem. Vol. 73, No. 19, 2008

Aminolysis of O-Aryl Thionobenzoates
FIGURE 2. Qualitative energy profile for the process from T( to T-
and PH+.
TABLE 1. Summary of Second-Order Rate Constants for
Reactions of O-Y-Substituted Phenyl Thionobenzoates (1a-f) with
Ethylamine (EtNH2, pKa ) 10.67) and Benzylamine (BzNH2, pKa )
9.46)a
kN/M-1s-1
entry
Y
pKa
EtNH2
BzNH2
1a
1b
1c
1d
1e
1f
3,4-(NO2)2
4-NO2
4-COMe
3-COMe
H
5.42
7.14
8.05
9.19
9.95
10.2
22.2
7.16
4.37
2.80
2.12
1.82
12.7
3.71
2.14
FIGURE 1. Plots of kobsd vs [amine] for the reaction of trifluoroethy-
lamine (CF3CH2NH2) with 1f and 1a (inset) in 80 mol % H2O/20 mol
% DMSO at 25.0 ( 0.1 °C.
1.87
(0.915)b
(0.871)b
4-Me
phenoxide ion or its conjugate acid under pseudofirst-order
conditions (i.e., the amine concentration in excess over the
substrate concentration). The reactions obeyed first-order kinetics
and pseudofirst-order rate constants (kobsd) were determined from
the equation, ln(A∞ - At) ) -kobsdt + C. Based on replicate
runs, it is estimated that the uncertainty in the kobsd values is
less than (3%. Plots of kobsd versus [amine] were linear or
curved upward depending on the basicity difference between
the entering amine and the leaving aryloxide, namely, the plot
was linear when the leaving aryloxide was less basic than the
attacking amine but curved upward when the leaving group was
more basic than the amine.
a In 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C. b The k1
values determined from eq 2.
Clearly, the current results show that the basicity of the leaving
group is also an important factor to determine the reaction
mechanism.
An important finding in the current study is that the basicity
difference between the attacking amine and the leaving aryloxide
(i.e., <130 > pKa ) pKaRNH + - pKaArOH) governs the presence/
3
absence of the deprotonation process (i.e., T( f T-). For
example, the reactions of 1a-f with strongly basic EtNH2 (i.e.,
pKaEtNH + ) 10.67) proceed without this deprotonation process,
3
Reactions of 1a-f with CF3CH2NH2 and EtNH2: Effect
of Amine Basicity. Reactions of O-Y-substituted phenyl thion-
obenzoates (1a-f) with weakly basic CF3CH2NH2 and strongly
basic EtNH2 were performed to investigate the effect of amine
basicity on mechanism. As shown in Figure 1, the plot of kobsd
versus [amine] for the reactions with weakly basic CF3CH2NH2
exhibited an upward curvature except for the reaction of 1a,
implying that the aminolysis of 1b-f proceeds through both
ArOH
where ∆pKa > 0 (i.e., pKa
e 10.2). On the contrary, the
reactions of 1b-f with weakly basic CF3CH2NH2 (i.e.,
pKa CH2NH3 ) 5.70) proceed through both T( and T-,
where ∆pKa < 0 (i.e., CF3CH2NH2 is less basic than all the
leaving groups of 1b-f), while the reaction of 1a proceeds
without this deprotonation process, where ∆pKa > 0 (i.e.,
CF3CH2NH2 is more basic than the leaving 3,4-dinitrophenoxide
in 1a). A similar result has been obtained for the reactions with
moderately basic BzNH2, that is, the deprotonation process from
T( is absent for the reactions of 1a-d, in which ∆pKa > 0,
while the reactions of 1e and1f proceed through T( and T-, in
which ∆pKa < 0.
CF3
+
T
( and T-. In contrast, the corresponding plots for the reactions
of 1a-f with strongly basic EtNH2 were linear (passing through
the origin), indicating that the deprotonation process from T(
by the second amine molecule (i.e., the k3 step in Scheme 1) is
absent and the contribution of H2O and OH- from protonation
of amine to the kobsd value is negligible. Accordingly, one can
suggest that the basicity of the attacking amine is an important
determinant of presence/absence of the deprotonation process
from T(.
A qualitative energy profile for the process from T( to T-
and PH+ is illustrated in Figure 2, which accounts for our finding
that ∆pKa governs the presence/absence of the deprotonation
process. The energy barrier for the k2 step (i.e., departure of
the leaving group from T( to give PH+; Scheme 1) is expected
to be strongly dependent on the basicity of the leaving aryloxide,
that is, it would increase with increasing the basicity of the
leaving group or vice versa. However, the energy barrier for
the k3 step (i.e., to form T- from T() would be independent of
amine basicity, because a stronger amine would deprotonate
more rapidly from the aminium moiety of T( but the aminium
ion would tend to hold the proton more strongly as the amine
becomes more basic. Accordingly, amine basicity would not
influence the energy barrier to form T- from T(.
Reaction of 1a-f with BzNH2: Effect of Leaving-Group
Basicity. Reactions of 1a-f with moderately basic BzNH2 were
performed to investigate the effect of leaving-group basicity on
mechanism. Plots of kobsd versus [amine] were linear for the
reactions of 1a-d but displayed upward curvature for those of
1e and1f; here the reaction proceeds through T( without the
deprotonation process when the substrate possesses a weakly
basic leaving group (e.g., 1a-d) but via the dual T( and T-
path when the leaving group is strongly basic (e.g., 1e and 1f).
J. Org. Chem. Vol. 73, No. 19, 2008 7673

Um et al.
TABLE 2. Summary of Microscopic Rate Constants for Reactions
of O-Y-Substituted Phenyl Thionobenzoates (1a-f) with
a
CF3CH2NH2
kN
103 k1 102 k2/ k3/k-1 k3/k2
entry
Y
pKa (M-1 s-1
)
(M-1s-1
)
k-1
(M-1
)
(M-1
)
1a 3,4-(NO2)2 5.42
0.109b
1b 4-NO2
1c 4-COMe
1d 3-COMe
7.14
8.05
9.19
9.95
28.7
13.5
7.16
2.74
1.97
25.3
13.3
5.32
3.14
2.46
28.8
15.8
6.80 128
4.28 136
3.47 141
114
119
1e
1f
H
4-Me
10.2
a In 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C. b The kN
value determined from the slope of the linear plot of kobsd vs [amine].
Figure 2 shows that reactions would proceed mainly through
T( and T- when the energy barrier for the k2 step is higher
than that for the k3 process. On the contrary, reactions would
proceed through T( (to PH+) when the energy barrier to form
PH+ is lower than that to form T- from T(. Thus, Figure 2
accounts for the current results, that is, the reaction proceeds
via both T( and T- when the leaving aryloxide is more basic
than the entering amine, but through T( without the deproto-
nation process when the leaving group becomes less basic than
amine.
Determination of Rate Constants. The rate law is given by
eq 1 for the reactions that resulted in linear plots of kobsd versus
[amine]. The second-order rate constants (kN) have been
determined from the slope of the linear plots of kobsd versus
[amine] for the reactions of 1a-f with EtNH2, 1a-d with
BzNH2, and 1a with CF3CH2NH2. The kN values determined
in this way are summarized in Tables 1 and 2.
FIGURE 3. Plots of kobsd/[amine] vs [amine] for the reactions of O-4-
methylphenyl thionobenzoate (1f) and O-4-nitrophenyl thionobenzoate
(1b; inset) with trifluoroethylamine (CF3CH2NH2) in 80 mol % H2O/
20 mol % DMSO at 25.0 ( 0.1 °C.
rate ) kobsd[sub], where kobsd ) kN[amine]
(1)
One can express kobsd as eq 2 for the reactions that resulted
in an upward curvature in the plot of kobsd versus [amine].
Because the k-1 value is expected to be large for reactions with
weakly basic CF3CH2NH2, eq 2 simplifies to eq 3 under the
assumption that k-1 . k2 + k3[amine]. In this case, the plot of
kobsd/[amine] vs [amine] is expected to be linear.
kobsd)(k1k2[amine] + k1k3[amine]2) ⁄ (k-1+k2+k3[amine])
(2)
kobsd⁄[amine] ) k1k2⁄k-1+k1k3[amine] ⁄ k-1
(3)
As shown in Figure 3 for the reaction of 1f with CF3CH2NH2,
the plot of kobsd/[amine] versus [amine] shows good linearity.
A similar result has been obtained for the corresponding reaction
of 1e (figure not shown).
FIGURE 4. Brønsted-type plots for reactions of O-Y-substituted phenyl
thionobenzoates (1a-f) with EtNH2 (b), BzNH2 (O), and CF3CH2NH2
(9) in 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C. The identity
of points is given in Tables 1 and 2.
In contrast, plots for the reactions of 1b-d exhibit downward
curvature as the amine concentration increases. Furthermore,
the downward curvature becomes more significant as the leaving
group becomes less basic (see the inset of Figure 3 for the
reaction of 1b). Thus, the assumption k-1. k2 + k3[amine] is
not valid for the reactions of 1b-d in the region where the
amine concentration is high. This is not an unexpected result
because the k2 value increases as the leaving group becomes
less basic and the term k3[amine] increases with an increase in
the concentration of amine. Accordingly, only k1k2/k-1 values
have been extracted from the intercept of the plot. More reliable
k1, k2/k-1, and k3/k-1 values have been determined through the
nonlinear least-squares fitting of eq 2 to the experimental data
by using the k1k2/k-1 values obtained above as input values.
The k1, k2/k-1 and k3/k-1 values determined in this way are
summarized in Table 2.
Table 2 shows that the microscopic rate constants for the
reactions of 1b-f with CF3CH2NH2 are dependent on the basicity
of the leaving group, that is, as the leaving aryloxide becomes more
basic, k1, k2/k-1, and k3/k-1ratios decrease while the k3/k2 ratio
increases. It is noteworthy that k2/k-1 < 1 for the reactions of
1b-f, indicating that formation of T( occurs before the RDS.
Further, the fact that k3/k2 > 102 implies that the k3 process
becomes dominant over the k2 process when [amine] . 0.01
M. Thus, the microscopic rate constants determined are con-
sistent with the proposed mechanism.
The effect of leaving-group basicity on kN and k1 is illustrated
in Figure 4 using the data in Tables 1 and 2. The Brønsted-
type plot for the reactions of 1a-f with EtNH2 is linear with
7674 J. Org. Chem. Vol. 73, No. 19, 2008

Aminolysis of O-Aryl Thionobenzoates
TABLE 3. Summary of Second-Order Rate Constants (kN) for the
Reactions of O-4-Nitrophenyl X-Substituted Thionobenzoates (2a-f)
a
with BzNH2
entry
X
kN (M-1 s-1
)
2a
2b
2c
2d
2e
2f
4-NMe2
4-OCH3
4-CH3
H
3-OCH3
3-Cl
0.0618
0.939
1.96
3.71
5.62
11.6
a In 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C.
ꢀlg ) -0.22. Such a small ꢀlg value indicates that departure of
the leaving group from T( is little advanced in the rate-
determining transition state. Interestingly, the Brønsted-type
plots for reactions of 1a-f with BzNH2 and CF3CH2NH2 are
also linear with ꢀlg ) -0.23 and -0.35, respectively, although
kN and k1 values are employed together to construct the plots.
It follows that kN is equivalent to k1 for reactions of 1a-f with
EtNH2, for those of 1a-d with BzNH2, and for nucleophilic
reaction of 1a with CF3CH2NH2.
The argument may be extended as follows. The ꢀlg value of
-0.3 ( 0.1 is typical of aminolyses that have been reported to
proceed via rate-determining formation of T(.1-6,14 Moreover,
one expects a small k-1 for the reactions with strongly basic
EtNH2 but a large k2 for the reactions of substrates that possess
a weakly basic leaving group. Consequently, it is reasonable to
assume that k-1 , k2 + k3[amine] for reactions in where ∆pKa
> 0 (i.e., when the entering amine is more basic than the leaving
group). It follows, then, that eq 2 simplifies to eq 4. Comparison
of eq 4 with eq 1 reveals that kN ) k1, as noted above. This is
consistent with the fact that the kN values for reactions where
∆pKa > 0 were determined from the slope of their linear plots
of kobsd versus [amine].
FIGURE 5. Hammett plot for reactions of O-4-nitrophenyl X-
substituted thionobenzoates (2a-f) with benzylamine (BzNH2) in 80 mol
% H2O/20 mol % DMSO at 25.0 ( 0.1 °C. The identity of points is
given in Table 3.
g 0. Such a biphasic Hammett plot has traditionally been taken
as evidence for change in RDS.15,16 In fact, Jencks reported a
nonlinear Hammett plot for the reactions of X-substituted
benzaldehydes with semicarbazide in weakly acidic solution (pH
) 3.9), that is, changeover from a large slope to a small one on
changing the substituent X from EDGs to EWGs. A change in
RDS was inferred by Jencks to be responsible for the nonlinear
Hammett plot.1a
In contrast to previous interpretations, we propose that the
nonlinear Hammett plot (Figure 5) does not arise from a change
in RDS. This follows from the idea that the k2/k-1 ratio, which
determines the RDS, would be independent of the electronic
nature of the substituent X. Because the leaving aryloxide and
amine depart from T( with the bonding-electron pair, an
electron-withdrawing substituent X in the thionobenzoyl moiety
would decrease both k2 and k-1 values while an electron-
donating substituent X would increase both. Accordingly, the
k2/k-1 ratio would not be influenced by the electronic nature of
the substituent X. In fact, we have recently shown that the k2/
k-1 ratio remains nearly constant on changing X in the
nonleaving group from strong EWG to strong EDG for
aminolyses of aryl X-substituted benzoates and their related
esters.6,17
kobsd)k1[amine]
(4)
Reaction of 2a-f with BzNH2: Effect of Nonleaving-
Group Substituent. To investigate the effect of the nonleaving-
group substituent on reactivity and potential change in mech-
anism, reactions of O-4-nitrophenyl X-substituted thionobenzoates
(2a-f) with the moderately basic benzylamine (BzNH2) were
performed. Plots of kobsd versus [amine] for reactions of 2a-f
with BzNH2 were linear passing through the origin, indicating
that the reaction proceeds through T( (to PH+) and the
deprotonation process from T( is absent regardless of the
electronic nature of the substituent X in the nonleaVing group.
Note that BzNH2 (pKa ) 9.46) is more basic than the leaving
group, 4-nitrophenoxide (pKa ) 7.14). This result is in accord
with the preceding argument that the deprotonation process from
T( is absent for reactions in which ∆pKa > 0. Thus, the kN
values have been determined from the slope of the linear plots
of kobsd versus [amine] and summarized in Table 3. One can
see that the kN value is highly dependent on the nature of the
substituent X, that is, it increases from 0.0618 M-1 s-1 to 11.6
M-1 s-1, an approximately 190-fold increase, as the substituent
X changes from 4-NMe2 to 3-Cl.
Origin of Nonlinear Hammett Plot. We propose that
stabilization of the ground state (GS) through resonance
interaction, as illustrated by resonance structures I and II for
the substrates, is responsible for the nonlinear Hammett plot
shown (Figure 5). This idea can be supported by the fact that
(15) Carrol, F. A. PerspectiVes on Structure and Mechanism in Organic
Chemistry; Brooks/Cole: New York, 1998; pp 371-386.
(16) (a) Bernasconi, C. F., Ed. Techniques of Organic Chemistry, 4th ed.;
Wiley: New York, 1986; Vol. 6. (b) Lewis, E. S., Ed. Techniques of Organic
Chemistry, 3rd ed.; Wiley: New York, 1974; Vol. 6, part 1. (c) Chapman, N. B.,
Shorter, J. Eds. AdVances in Linear Free Energy Relationships; Plenum: London,
1972.
The effect of the substituent X on reactivity is illustrated in
Figure 5. The Hammett plot consists of two intersecting straight
lines, that is, FX ) 2.22 when σX < 0 and FX ) 1.33 when σX
(14) (a) Um, I. H.; Akhtar, K.; Shin, Y. H.; Han, J. Y. J. Org. Chem. 2007,
72 (14), 3826–3829. (b) Um, I. H.; Shin, Y. H.; Han, J. Y.; Mishima, M. J.
Org. Chem. 2006, 71, 7715–7720.
(17) (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.
J. Org. Chem. Vol. 73, No. 19, 2008 7675

Um et al.
Conclusions
Our study has allowed us to conclude the following: (1) The
current aminolysis of O-Y-substituted phenyl thionobenzoates
(1a-f) proceeds either through T( or through T( and T-,
depending on the basicity difference between the entering amine
and the leaving aryloxide. (2) The basicity of the amine
nucleophile and the aryloxide leaving group has been shown to
be an important determinant of presence/absence of the depro-
tonation process from T(, that is, reactions proceed through
T
( (to PH+ and, thence, to P) when amines are more basic than
aryloxides but through both T( and T- when amine becomes
less basic than the leaving group. (3) The electronic nature of
the substituent X in the nonleaving group does not influence
the reaction mechanism. (4) The reactions of 2a-f with BzNH2
resulted in a biphasic Hammett plot but a linear Yukawa-Tsuno
plot, indicating that the nonlinear Hammett plot is not due to a
change in the RDS but is caused by stabilization of the GS of
the substrate through resonance interaction between the electron-
donating substituent and the thionocarbonyl moiety. (5) Deduc-
tion of reaction mechanism based solely on observation of a
nonlinear Hammett plot can be misleading. In summary, amine
basicity combines with modulation of the electronic nature (i.e.,
EDG vs EWG) of X and Y substituents to control the reaction
mechanism.
FIGURE 6. Yukawa-Tsuno plot for reactions of O-4-nitrophenyl
X-substituted thionobenzoates (2a-f) with BzNH2 in 80 mol % H2O/
20 mol % DMSO at 25.0 ( 0.1 °C. The identity of points is given in
Table 3.
the negative deviation from the Hammett plot is more significant
as the substituent X in the nonleaving group becomes a stronger
EDG.
Experimental Section
Materials. Compounds1a-f and 2b-f were prepared as
reported previously.12,21,22 Compound 2a was synthesized readily
by reaction of 4-dimethylaminothionobenzoic acid with 4-ni-
trophenol under presence of N, N′-dicyclohexyl carbodiimide
in anhydrous ether. The purity of 2a was checked by means of
1
the melting point (171-173 °C), H NMR characteristics (250
MHz, CDCl3) δ 8.34-8.31 (d, J ) 7.5 Hz, 2H), 8.29-8.26 (d,
J ) 7.5 Hz, 2H), 7.31-7.28 (d, J ) 7.5 Hz, 2H), 6.73-6.70 (d,
J ) 7.5 Hz, 2H), 3.05 (s, 6H) and elemental analysis (Calcd for
C15H14N2O3S: C, 59.59; H, 4.67. Found: C, 59.48; H, 4.72). Other
chemicals, including the amines used, were of the highest quality
available. The reaction medium was H2O containing 20 mol %
DMSO due to low solubility of the substrates in pure H2O.
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 for slow reactions (t1/2 g 10 s) or with a
stopped-flow spectrophotometer for fast reactions (t1/2 < 10 s)
equipped with a constant temperature circulating bath to maintain
the temperature in the reaction cell at 25.0 ( 0.1 °C. The reaction
was followed by monitoring the appearance of the leaving
Y-substituted phenoxide ion or its conjugate acid. All the
reactions were carried out under pseudofirst-order conditions in
which amine concentrations were at least 30 times greater than
the substrate concentration. The amine stock solution of about
0.2 M was prepared by dissolving 2 equiv of amine hydrochloride
and 1 equiv of standardized NaOH solution to keep the pH
constant in this self-buffered solution. All solutions were
prepared freshly just before use under nitrogen and transferred
by gastight syringes. Typically, the reaction was initiated by
adding 5 µL of a 0.02 M solution of the substrate in CH3CN by
a 10 µL syringe to a 10 mm quartz UV cell containing 2.50 mL
of the thermostatted reaction mixture made up of solvent and
aliquot of the amine stock solution.
To further delineate this argument, the Yukawa-Tsuno
equation (eq 5) has been employed. We have previously found
application of eq 5 to be particularly useful in analyzing reaction
mechanism.6,17 The r value in the Yukawa-Tsuno equation
represents the resonance demand of the reaction center or the
extent of the resonance contribution, whereas the term (σ+
-
σ°) represents the resonance substituent constant that measures
the capacity for π-delocalization of a given π-electron donor
substituent.18-20
log(kX⁄kH) ) FX[σ° + r(σ+ - σ°)]
(5)
The Yukawa-Tsuno plot (Figure 6) for the reactions of 2a-f
with BzNH2 exhibits an excellent linear correlation (R2 ) 0.996)
with FX ) 1.39 and r ) 0.64, indicating that the nonlinear
Hammett plot (Figure 5) results from GS stabilization through
resonance interaction (e.g., I T II) but, clearly, is not caused
by a switch in RDS. Thus, deduction of reaction mechanism
based just on linear or nonlinear Hammett plots can be
misleading.
(18) (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.
(19) (a) Fujio, M.; Alam, M. A.; Umezaki, Y.; Kikukawa, K.; Fujiyama, R.;
Tsuno, Y. Bull. Chem. Soc. Jpn. 2007, 80, 2378–2383. (b) Fujio, M.; Umezaki,
Y.; Alam, M. A.; Kikukawa, K.; Fujiyama, R.; Tsuno, Y. Bull. Chem. Soc. Jpn.
2006, 79, 1091–1099.
(20) (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.
(21) Campbell, P.; Lapinskas, B. A. J. Am. Chem. Soc. 1977, 99, 5378–
5382.
(22) Um, I. H.; Lee, J. Y.; Kim, H. T.; Bae, S. K. J. Org. Chem. 2004, 69,
2436–2441.
7676 J. Org. Chem. Vol. 73, No. 19, 2008

Aminolysis of O-Aryl Thionobenzoates
Product Analysis. Y-Substituted phenoxide (and/or its conjugate
acid) was liberated quantitatively and identified as one of the
products by comparison of the UV-vis spectrum at the end of
reaction with the authentic sample under the experimental condition.
acknowledged. Sora Yoon and So-Jeong Hwang are also grateful
for the BK 21 scholarship.
Supporting Information Available: Tables S1-S18 for the
kinetic conditions and data for reactions of 1a-f with EtNH2,
BzNH2, and CF3CH2NH2. Tables S19 - S23 for the kinetic
data for reactions of 2a-f with BzNH2. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by a grant from
Korea Research Foundation (KRF-2005-015-C00256). Helpful
discussions with Professor J. M. Dust (Sir Wilfred Grenfell
College, Memorial University of Newfoundland) are warmly
JO801539W
J. Org. Chem. Vol. 73, No. 19, 2008 7677