Effect of amine nature on reaction mechanism: Aminolyses of O-4-nitrophenyl thionobenzoate with primary and secondary amines

Article abstract of DOI:10.1021/jo0259360

Pseudo-first-order rate constants (k_obs) have been measured spectrophotometrically for reactions of O-4-nitrophenyl thionobenzoate (2) with a series of primary and acyclic secondary amines. The plots of k_obs vs amine concentration are linear for the reaction of 2 with primary amines. The slope of the Bronsted-type plot for the reaction of 2 with primary amines decreases from 0.77 to 0.17 as the amine basicity increases, indicating that the reaction proceeds through a zwitterionic addition intermediate in which the rate-determining step changes from the breakdown of the intermediate to the reaction products to the formation of the intermediate as the amine basicity increases. On the other hand, for reactions with all the acyclic secondary amines studied, the plot of k_obs vs amine concentration exhibits an upward curvature, suggesting that the reaction proceeds through two intermediates, e.g., a zwitterionic addition intermediate and an anionic intermediate. The microscopic rate constants (k₁, k_-1, k₂, and k₃ where available) have been determined for the reactions of 2 with all the primary and secondary amines studied. The k₁ value is larger for the reaction with the primary amine than for the reaction with the isobasic acyclic secondary amines, while the k_-1 value is much larger for the latter reaction than for the former reaction. The k₃ value for the reaction with secondary amine is independent of the amine basicity. The small k₂/k_-1 ratio is proposed to be responsible for the deprotonation process observed in aminolyses of carbonyl or thiocarbonyl derivatives.

Full text of DOI:10.1021/jo0259360

Effect of Am in e Na tu r e on Rea ction Mech a n ism : Am in olyses of
O-4-Nitr op h en yl Th ion oben zoa te w ith P r im a r y a n d Secon d a r y
Am in es
Ik-Hwan Um,* Seung-Eun Lee, and Hey-J in Kwon
Department of Chemistry, Ewha Womans University, Seoul 120-750, Korea
ihum@mm.ewha.ac.kr
Received May 14, 2002
Pseudo-first-order rate constants (kobs) have been measured spectrophotometrically for reactions
of O-4-nitrophenyl thionobenzoate (2) with a series of primary and acyclic secondary amines. The
plots of kobs vs amine concentration are linear for the reaction of 2 with primary amines. The slope
of the Brønsted-type plot for the reaction of 2 with primary amines decreases from 0.77 to 0.17 as
the amine basicity increases, indicating that the reaction proceeds through a zwitterionic addition
intermediate in which the rate-determining step changes from the breakdown of the intermediate
to the reaction products to the formation of the intermediate as the amine basicity increases. On
the other hand, for reactions with all the acyclic secondary amines studied, the plot of kobs vs amine
concentration exhibits an upward curvature, suggesting that the reaction proceeds through two
intermediates, e.g., a zwitterionic addition intermediate and an anionic intermediate. The
microscopic rate constants (k1, k-1, k2, and k3 where available) have been determined for the reactions
of 2 with all the primary and secondary amines studied. The k1 value is larger for the reaction
with the primary amine than for the reaction with the isobasic acyclic secondary amines, while
the k-1 value is much larger for the latter reaction than for the former reaction. The k3 value for
the reaction with secondary amine is independent of the amine basicity. The small k2/k-1 ratio is
proposed to be responsible for the deprotonation process observed in aminolyses of carbonyl or
thiocarbonyl derivatives.
In tr od u ction
that aminolyses of carboxylic and carbonate esters (e.g.,
1 and 3, respectively) proceed through a zwitterionic
addition intermediate in which the rate-determining step
(RDS) depends on the basicity of the attacking amine and
the leaving group, i.e., the RDS changes from the
breakdown of the intermediate to the reaction products
to the formation of the intermediate as the attacking
amine becomes more basic than the leaving group by 4-5
pKa units.1,6-10
Aminolyses of carbonyl compounds have intensively
been investigated, and their reaction mechanisms have
been well clarified.1-10 It has generally been suggested
* Phone: (822) 3277-2349. Fax: (822) 3277-2844.
(1) (a) Satterthwait, A. C.; J encks, W. P. J . Am. Chem. Soc. 1974,
96, 7018-7031. (b) Hupe, D. J .; J encks, W. P. J . Am. Chem. Soc. 1977,
99, 451-464. (c) Gresser, M. J .; J encks, W. P. J . Am. Chem. Soc. 1977,
99, 6963-6970. (d) J encks, W. P.; Brant, S. R.; Gandler, J . R.; Fendrich,
G.; Nakamura, C. J . Am. Chem. Soc. 1982, 104, 7045-7051. (e)
Stefanidis, D.; Cho, S.; Dhe-Paganon, S.; J encks, W. P. J . Am. Chem.
Soc. 1993, 115, 1650-1656.
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3824-3829. (b) Menger, F. M.; Eliseev, A. V.; Khanjin, N. A.; Sherrod,
M. J . J . Org. Chem. 1995, 60, 2870-2878.
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3440-3447.
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(b) Fife, T. H.; Chauffe, L. J . Org. Chem. 2000, 65, 8830-8830.
(5) DeTar, D. F. J . Am. Chem. Soc. 1982, 104, 7205-7212.
(6) (a) Ba-Saif, S.; Luthra, D. F.; Williams, A. J . Am. Chem. Soc.
1989, 111, 2647-2652. (b) Williams, A. Chem. Soc. Rev. 1994, 23, 93-
100.
(7) (a) Castro, E. A.; Gil, F. J . J . Am. Chem. Soc. 1977, 99, 7611-
7612. (b) Castro, E. A.; Freudenberg, M. J . Org. Chem. 1980, 45, 906-
910. (c) Castro, E. A.; Santander, C. L. J . Org. Chem. 1985, 50, 3595-
3600. (d) Castro, E. A.; Valdivia, J . L. J . Org. Chem. 1986, 51, 1668-
1672. (e) Castro, E. A.; Ureta, C. J . Org. Chem. 1990, 55, 1676-1679.
(f) Castro, E. A.; Ibanez, F.; Lagos, S.; Schick, M.; Santos, J . G. J . Org.
Chem. 1992, 57, 2691-2694.
However, aminolyses of thione esters (e.g., 2 and 4)
have been much less investigated. The first kinetic study
has been performed by Campbell et al. for the reaction
of 2 with diethylamine and a series of primary amines
in H2O containing 20% CH3CN.11 The reaction with
(9) (a) Asubiojo, O. I.; Brauman, J . I. J . Am. Chem. Soc. 1979, 101,
3715-3724. (b) Wilbur, J . J .; Brauman, J . I. J . Am. Chem. Soc. 1994,
116, 9216-9221. (c) Han, C. C.; Brauman, J . I. J . Am. Chem. Soc. 1990,
112, 7835-7835.
(8) (a) Koh, H. J .; Lee, J . W.; Lee, H. W.; Lee, I. Can. J . Chem. 1998,
76, 710-716. (b) Koh, H. J .; Han, K. L.; Lee, I. J . Org. Chem. 1999,
64, 4783-4789. (c) Lee, H. W.; Yun, Y. S.; Lee, B. S.; Koh, H. J .; Lee,
I. J . Chem. Soc., Perkin Trans. 2 2000, 2302-2305.
(10) (a) Um, I. H.; Min, J . S.; Ahn, J . A.; Han, H. J . J . Org. Chem.
2000, 65, 5659-5663. (b) Um, I. H.; Chung, E. K.; Lee, S. M. Can. J .
Chem. 1998, 76, 729-737. (c) Um, I. H.; Min, J . S.; Lee, H. W. Can. J .
Chem. 1999, 77, 659-666.
10.1021/jo0259360 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/12/2002
J . Org. Chem. 2002, 67, 8999-9005
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Um et al.
as IR and 1H NMR characteristics. Other chemicals used,
including the amines, were of the highest quality available.
The reaction medium was H2O containing 20 mol % DMSO to
eliminate solubility problems. DMSO was distilled over CaH2
at a reduced pressure (bp 64-66 °C/6-7 mmHg) and stored
under nitrogen. Doubly glass-distilled water was further boiled
and cooled under nitrogen just before use.
primary amines has been suggested to proceed through
a zwitterionic addition intermediate on the basis of the
nonlinear Brønsted-type plot obtained.11 However, the
microscopic rate constants involved in the aminolysis
reaction have not been determined. Furthermore, the
mechanism for the reaction with the secondary amine
has not been elucidated either. More systematic studies
for thiocarbonyl derivatives have been performed by
Castro and Lee et al.12,13 Castro et al. have recently
carried out the reaction of various thiocarbonyl deriva-
tives (e.g., 4) with a series of pyridines and alicyclic
secondary amines.12a The reaction with pyridines has
been suggested to proceed through an addition interme-
diate, while the one with alicyclic secondary amines has
been proposed to proceed through one or two intermedi-
ates depending on the amine basicity, i.e., the reaction
with strongly basic amines proceeds through a zwitter-
ionic addition intermediate (T(), while the one with
weakly basic amines proceeds through two intermediates,
T( and its deprotonated species T-.12a Therefore, the
amine basicity has been suggested to be an important
factor in determining the presence or absence of the
deprotonation process.12 Lee et al. have performed kinetic
studies for reactions of substituted phenyl dithioacetates
with a series of anilines and benzylamines in CH3CN.13a
The reactions have been suggested to proceed through a
zwitterionic addition intermediate without the deproto-
nation process, which has often been observed in the
aminolysis of thiono and dithio esters conducted in
aqueous solution, indicating that a solvent effect is also
an important factor in governing the deprotonation
process.13a
Kin etics. 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 keep
the temperature in the reaction cell at 25.0 ( 0.1 °C. The
reaction was followed by monitoring the appearance of the
leaving 4-nitrophenoxide at 410 nm (or 4-nitrophenol at 340
nm for the reaction with trifluoroethylamine). All reactions
were carried out under pseudo-first-order conditions in which
the amine concentrations were at least 30 times greater than
the substrate concentration. 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 (or 2 equiv of amine
hydrochloride and 1 equiv of standardized NaOH solution) to
keep the pH constant by making a self-buffered solution. All
solutions were freshly prepared 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 2 in
CH3CN by a 10 µL 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.
Deter m in a tion of p Ka . pKas of the conjugate acids of
amines were determined by measuring the pH of the solution
containing equal amounts of free amine and amine hydrochlo-
ride with a glass electrode. The pKa value was independent of
the amine concentration in the range of (10-100) × 10-3 M,
in which most of the rate constants were measured. The pKa
values so determined are listed in Tables 1 and 2.
P r od u ct An a lysis. 4-Nitrophenoxide (and/or its conjugate
acid) was identified as one of the products of the aminolysis
of 2 by comparison of the UV-vis spectrum at the end of
reaction with the authentic sample under the kinetic experi-
mental conditions. The other product N-ethyl thiobenzoamide
was analyzed by HPLC. The flow rate was 1 mL/min, and the
eluent was 50% MeCN in MeOH (v/v). Quantitative analysis
was performed by comparison of the HPLC peak area of the
reaction mixture with that of the authentic sample.
Recently, we have performed a systematic kinetic study
for the aminolysis of 2 with a series of alicyclic secondary
amines in water containing 20 mol % dimethyl sulfoxide
(DMSO) and found that the reaction proceeds through
two intermediates (T( and T-) regardless of the amine
basicity.14 We have extended our study to the reaction of
2 with a series of primary and acyclic secondary amines
and found that the effect of the amine nature on the
reaction mechanism is remarkable. Here we report a
detailed reaction mechanism together with all the mi-
croscopic rate constants involved in the reactions of 2
with the primary and secondary amines.
Resu lts
Reactions of 2 with the primary and secondary amines
proceeded with quantitative liberation of 4-nitrophenox-
ide and/or its conjugate acid. The kinetic study was
performed spectrophotometrically under pseudo-first-
order reaction conditions, e.g., the amine concentration
in excess over the substrate concentration. All reactions
obeyed first-order kinetics over 90% of the reaction.
Pseudo-first-order rate constants (kobs) were calculated
from the equation ln(A∞ - At) ) -kobst + C. The kobs
values obtained in this way are summarized in Table S1
(Supporting Information) along with the kinetic condi-
tions. It is estimated from the replicate runs that the
uncertainty in the rate constants is less than (3%. The
plot of kobs vs amine concentration is linear and passes
through the origin for the reaction of 2 with all the
primary amines studied. However, the corresponding plot
for the reaction with all the secondary amines exhibits
an upward curvature as the amine concentration in-
creases (Figure S1, Supporting Information).
Exp er im en ta l Section
Ma ter ia ls. O-4-Nitrophenyl thionobenzoate (2) was syn-
thesized from the reaction of thiobenzoyl chloride with 4-ni-
trophenol as reported previously.11,14 The purity of 2 was
checked by means of the melting point and spectral data such
(11) Campbell, P.; Lapinskas, B. A. J . Am. Chem. Soc. 1977, 99,
5378-5382.
(12) (a) Castro, E. A.; Leandro, L.; Quesieh, N.; Santos, J . G. J . Org.
Chem. 2001, 66, 6130-6135. (b) Castro, E. A.; Pavex, P.; Santos, J . G.
J . Org. Chem. 2001, 66, 3129-3132. (c) Castro, E. A.; Garcia, P.;
Leandro, L.; Quesieh, M.; Rebolledo, A.; Santos, J . G. J . Org. Chem.
2000, 65, 9047-9053. (d) Castro, E. A. Chem. Rev. 1999, 99, 3505-
3524. (e) Castro, E. A.; Cubillos, M.; Santos, J . G. J . Org. Chem. 1999,
64, 6342-6346.
(13) (a) Oh, H. K.; Woo, S. Y.; Shin, C. H.; Park, Y. S.; Lee, I. J .
Org. Chem. 1997, 62, 5780-5784. (b) Oh, H. K.; Kim, K. S.; Lee, H.
W.; Lee, I. New J . Chem. 2001, 25, 313-317. (c) Oh, H. K.; Kim, S. K.;
Cho, I. H.; Lee, H. W.; Lee, I. J . Chem. Soc., Perkin Trans 2 2000,
2306-2310. (d) Oh, H. K.; Kim, S. K.; Lee, H. W.; Lee, I. J . Chem.
Soc., Perkin Trans. 2 2001, 1753-1757.
Discu ssion
Rea ction s w ith P r im a r y Am in es. Since the plots of
kobs vs [RNH2] are linear and pass through the origin,
(14) Um, I. H.; Kwon, H. J .; Kwon, D. S.; Park, J . Y. J . Chem. Res.,
Synop. 1995, 301; J . Chem. Res., Miniprint 1995, 1801-1817.
9000 J . Org. Chem., Vol. 67, No. 25, 2002

Aminolyses of O-4-Nitrophenyl Thionobenzoate
8.8, which is much smaller than the one reported for the
corresponding aminolysis of 4-nitrophenyl benzoate, 1
(e.g., pKa° >11.0).14 A similar result has been found by
Campbell et al. in the aminolysis of 1 and 2 run in
aqueous CH3CN (e.g., pKa° > 11 for the reaction of 1 and
pKa° ) 9.2 for the reaction of 2).11 J encks1c and Castro16
have suggested that a smaller k2/k-1 ratio is responsible
for the smaller pKa° value for the reaction of thiocarbonyl
derivatives compared to their oxygen analogues.
One can get important information about the reaction
mechanism from the magnitude of ânuc values. Generally,
ânuc has been reported to be 0.8 ( 0.2 when the break-
down of the addition intermediate to the reaction prod-
ucts is the RDS and 0.2 ( 0.1 when the formation of the
addition intermediate is the RDS.1,6-10 The nonlinear
Brønsted-type plot in Figure 1 has been analyzed using
eq 3,1b,12 where â1 and â2 represent the slope of the
Brønsted-type plot in Figure 1 for the reaction with
strongly and weakly basic RNH2, respectively. The
parameters kN° and pKa° refer to a hypothetical amine,
for which k-1 ) k2 in Scheme 1. The parameters deter-
mined are as follows: log kN° ) 0.25, pKa° ) 8.8, â1 )
0.17, and â2 ) 0.77. Therefore, one can suggest that the
RDS for the reaction of 2 with RNH2 changes from the
k2 to the k1 step as the amine basicity increases on the
basis of the magnitude of â1 and â2 values.
F IGURE 1. Brønsted-type plot for the kN (statistically cor-
rected using p and q, see ref 15) for the reaction of 2 with
primary amines in water containing 20 mol % DMSO at 25.0
( 0.1 °C. The identity of the points is given in Table 1. The
solid line was calculated by eq 3.
SCHEME 1
log(kN/kN°) ) â2(pKa - pKa°) - log[(1 + R)/2]
log R ) (â2 - â1) (pKa - pKa°)
(3)
To shed more light on the reaction mechanism, the
microscopic rate constants (k1, k-1, and k2) involved in
the reaction of 2 with RNH2 are required. As discussed
above, the RDS of the reaction of 2 with RNH2 is
considered to change from the k2 to the k1 step as the
basicity of RNH2 increases. Therefore, eq 2 can be
simplified to eqs 4 and 5. Then, â1 and â2 can be
expressed as eqs 6 and 7, respectively.
the contribution of hydroxide and/or H2O to the kobs value
is negligible under the present reaction conditions. The
kinetic results and the product analysis suggest that the
reaction of 2 with RNH2 proceeds as depicted in Scheme
1. The kinetic law obtained is shown in eqs 1 and 2,
where [S] and [P] represent the concentrations of sub-
strate 2 and one of the reaction products, 4-nitrophenox-
ide (or 4-nitrophenol), respectively. The kN values were
determined from the slope of the linear plots of kobs vs
[RNH2] and are summarized in Table 1.
kN ) k1k2/k-1, when k2 , k-1
kN ) k1, when k2 .k-1
(4)
(5)
(6)
â1 ) d(log k1)/d(pKa)
-d[S]/dt ) d[P]/dt ) kobs[S]
(1)
â2 ) d(log k1k2/k-1)/d(pKa)
) â1 + d(log k2/k-1)/d(pKa)
kobs ) kN[RNH2], where kN ) k1k2/(k-1 + k2) (2)
(7)
As shown in Table 1, the kN value increases as the
amine basicity increases. The effect of the amine basicity
on the kN value is graphically demonstrated in Figure 1.
The Brønsted-type plot, which is statistically corrected
using p and q,12,14,15 is nonlinear. Such a nonlinear
Brønsted-type plot has often been observed for aminoly-
ses of carboxylic esters with a good leaving group and
used as evidence for a change in the RDS. The pKa value
at the center of the curvature of a nonlinear Brønsted-
type plot has been defined pKa°, where a change in the
RDS occurs (e.g., k-1 ) k2 at pKa°).1,12-14,16,17 The pKa°
value in the present system has been determined to be
Eq 7 can be rearranged as eq 8. The integral of eq 8 from
pKa° to pKa results in eq 9. Since k2 ) k-1 at pKa°, the
term (log k2/k-1)pKa° is zero. Therefore, one can calculate
the k2/k-1 values for the reactions of 2 with all the
primary amines studied from eq 9 using â1 ) 0.17, â2 )
0.77, and pKa° ) 8.8.
â2 - â1 ) d(log k2/k-1)/d(pKa)
(log k2/k-1 pK - (log k2/k-1 pK °
(8)
)
)
)
a
a
(â2 - â1)(pKa - pKa°) (9)
(15) Bell, R. P. The Proton in Chemistry; Methuen: London, 1959;
p 159.
(16) (a) Castro, E. A.; Ibanez, F.; Santos, J . G.; Ureta, C. J . Org.
Chem. 1992, 57, 7024-7028. (b) Castro, E. A.; Cubillos, M.; Santos, J .
G.; Tellez, J . J . Org. Chem. 1997, 62, 2512-2517.
(17) (a) Castro, E. A.; Ibanez, F.; Santos, J . G.; Ureta, C. J . Org.
Chem. 1993, 58, 4908-4912. (b) Castro, E. A.; Ibanez, F.; Santos, J .
G.; Ureta, C. J . Chem. Soc., Perkin Trans. 2 1991, 1919-1924.
J . Org. Chem, Vol. 67, No. 25, 2002 9001

Um et al.
where [T(] represents the concentration of the zwitteri-
onic addition intermediate (T().
SCHEME 2
d[P]/dt ) k2[T(] + k3[T(][R2NH]
) k1(k2 + k3[R2NH])[R2NH][S]/
(k-1 + k2 + k3[R2NH]) (11)
kobs ) k1(k2 + k3[R2NH])[R2NH]/(k-1
+
k2 + k3[R2NH]) (12)
Eq 2 can be rewritten as eq 10, which allows one to
calculate the k1 value using the kN and k2/k-1 values
determined above. The k1 values calculated in this way
are summarized in Table 1. It is shown that the k1 value
increases as the amine basicity increases. It is also noted
that the k1 value is always larger than the corresponding
kN value. However, the difference between the k1 and kN
values becomes smaller with increasing amine basicity,
as expected from eq 10 and the proposed reaction
mechanism.
Since the first step in Scheme 2 is a preequilibrium, one
can assume that k-1 . k2 + k3[R2NH]. Then, eq 12 can
be simplified to eq 13.
kobs/[R2NH] ) Kk2 + Kk3[R2NH], where K ) k1/k-1
(13)
The plots of kobs/[R2NH] vs [R2NH] are linear for weakly
basic secondary amines such as diallylamine (Figure S2,
Supporting Information) and diethanolamine (Figure not
shown), indicating that the assumption k-1 . k2 + k3-
[R2NH] is valid for the reaction of 2 with the weakly basic
R2NH. Therefore, the Kk2 and Kk3 values can be deter-
mined from the intercept and the slope of the linear plots
of kobs/[R2NH] vs [R2NH]. However, as shown in Figure
S2, the plot for the strongly basic R2NH (diethylamine)
is linear only at a low concentration region but exhibits
a downward curvature as the amine concentration in-
k1 ) kN (k-1/k2 +1)
(10)
To calculate the k-1 values from the k2/k-1 values, the
k2 value should be determined. The k2 value has been
suggested to be dependent on the basicity of the leaving
group and the structure of the acyl moiety but indepen-
dent of the basicity and the nature of amines.1,13,14,17 Since
the k2 value cannot be measured directly, Castro et al.
have estimated that k2 ) 1.0 × 108 s-1 for aminolysis of
S-4-nitrophenyl thioacetate17a and 106 s-1 < k2 < 107s-1
for aminolysis of phenyl dithioacetate.17b The smaller k2
value for the latter system was attributed to the de-
creased ability of C-S- to form a CdS bond compared
to the ability of C-O- to form a CdO bond due to a
weaker π-bonding energy of the thiocarbonyl (a dπ-pπ
bond) compared to the carbonyl group (a pπ-pπ
bond).13a,17,18 We have recently estimated that k2 ) 1.0 ×
106 s-1 for the reaction of 2 with a series of alicyclic
secondary amines.14 Since the k2 value has been sug-
gested to be independent of the nature of the amine,12,17
the k2 value of 1.0 × 106 s-1 has been used again for the
reactions of 2 with the primary amines in order to
calculate the k-1 value. The k-1 values calculated in this
way are summarized in Table 1. It is shown that the k-1
value is larger than the k2 value for the reactions with
weakly basic amines but becomes smaller than the k2
value for the reactions with strongly basic amines. This
result clearly supports the preceding proposal that a
change in the RDS occurs as the amine basicity increases.
The effect of amine basicity on the k1, k-1, and K values
will be discussed later.
creases highly. Therefore, the assumption k-1 . k2
+
k3[R2NH] appears to be valid only at a low concentra-
tion region for the reaction of 2 with the strongly basic
R2NH. This argument can be explained by the reasons
given below. (1) The k2 value has been suggested to be
independent of the amine basicity.1,12,14,16,17 (2) The k-1
value would decrease as the amine basicity increases. (3)
The k3 value would be insensitive to the amine basicity
since the proton transfer is from the aminium ion moiety
of T( to the corresponding free amine.14,16,17 However, the
term k3[R2NH] increases with increasing [R2NH].
Since the assumption k-1 . k2 + k3[R2NH] appears to
be invalid for the reaction with strongly basic R2NH at a
high amine concentration region, one can assume that
k2 , k3[R2NH]. Then, eq 12 can be reduced to eq 14. The
plots of [R2NH]/kobs vs 1/[R2NH] are linear for the
reactions of 2 with the strongly basic R2NH as shown in
Figure S3 (Supporting Information). Therefore, 1/k1 and
k-1/k1k3 values can be determined from the intercept and
the slope of the linear plots of [R2NH]/kobs vs 1/[R2NH],
respectively.
[R2NH]/kobs ) k-1/k1k3[R2NH] + 1/k1
(14)
R ea ct ion s w it h Secon d a r y Am in es. As shown in
Figure S1 (Supporting Information), the plot of kobs versus
[R2NH] exhibits an upward curvature for the reaction of
2 with diethylamine. Such an upward curvature has also
been obtained for the reaction of 2 with all the other
acyclic secondary amines studied, indicating that the
reaction proceeds through two intermediates, e.g., a
zwitterionic addition intermediate (T() and an anionic
intermediate (T-) as shown in Scheme 2.
The microscopic rate constants (k1, k-1, and k3) have
also been determined from a nonlinear least-squares
fitting of eq 12 to the experimental data using the same
k2 value used for the reactions with the primary amines
(k2 ) 1.0 × 106 s-1). The microscopic rate constants
determined in this way have been found to be identical
to those obtained from the graphical method using eqs
13 and 14 within an experimental error range. The k1,
Under the assumption of steady-state conditions for
the addition intermediate, one can derive eqs 11 and 12,
(18) Hill, S. V.; Thea, S.; Williams, A. J . Chem. Soc., Perkin Tans.
2 1983, 437-446.
9002 J . Org. Chem., Vol. 67, No. 25, 2002

Aminolyses of O-4-Nitrophenyl Thionobenzoate
TABLE 1. Su m m a r y of Ap p a r en t Secon d -Or d er Ra te Con sta n ts (kN) a n d Micr oscop ic Ra te Con sta n ts for th e Rea ction
of 2 w ith P r im a r y Am in es in Wa ter Con ta in in g 20 Mol % DMSO a t 25.0 ( 0.1 °Ca
b
Amine
pKa
kN/M-1s-1
k1/M-1s-1
k-1/106 s-1
K/10-6 M-1
1. trifluoroethylamine
2. glycineethylester
3. glycylglycine
4. benzylamine
5. ethanolamine
6. glycine
5.70
7.68
8.31
9.46
9.67
0.0261
0.876
1.68
3.70
4.10
1.00
3.00
3.38
4.47
4.74
14.2
7.44
37.3
2.42
1.01
0.207
0.155
0.137
0.0389
0.0268
1.24
3.34
21.6
30.6
10.06
10.67
12.5
7.16
104
191
7. ethylamine
a
b
k2 ) 1.0 × 106 s-1
.
The pKa of the conjugate acid of amines determined in 20 mol % DMSO at 25.0 ( 0.1 °C. The uncertainty in the
pKa values is estimated to be less than ( 0.1 in pKa unit.
TABLE 2. Su m m a r y of Micr oscop ic Ra te Con sta n ts In volved in th e Rea ction of 2 w ith Acyclic a n d Alicyclic Secon d a r y
Am in es in Wa ter Con ta in in g 20 Mol % DMSO a t 25.0 ( 0.1 °Ca
k1/M-1s-1
k-1/106 s-1
K/10-6 M-1
k3/109 M-1s-1
b
Amine
pKa
Acyclic secondary amine
8. diethanolamine
9. diallylamine
9.24
9.37
9.77
0.0643
0.852
16.6
242
197
72.8
52.5
2.66 × 10-4
4.32 × 10-3
0.228
0.997
0.886
1.02
10. N-benzylmethylamine
11. diethylamine
11.14
2.29
0.0436
0.878
Alicyclic secondary aminec
12. piperazinium ion
13. morpholine
5.95
8.65
9.85
10.80
11.02
1.42
18.3
104
153
173
740
1.92 × 10-3
0.201
2.81
12.4
16.8
0.737
1.61
1.53
0.790
1.07
91.0
37.0
12.3
10.3
14. piperazine
15. 3-methyl piperidine
16. piperidine
a
b
k2 ) 1.0×106 s-1
.
The pKa of conjugate acid of amines determined in 20 mol % DMSO at 25.0 ( 0.1 °C. c The data for the reaction
of 2 with alicyclic amines are taken from ref 14. The uncertainty in the pKa values is estimated to be less than ( 0.1 in pKa unit.
k-1, and k3 values determined from the nonlinear regres-
sion method are summarized in Table 2 along with the
corresponding data in the literature14 for the reactions
of 2 with a series of alicyclic secondary amines for
comparison. The effect of the amine nature on these
microscopic rate constants will be discussed in the
following section.
Effect of Am in e Na tu r e on Ra te, Equ ilibr iu m , a n d
Rea ction Mech a n ism . As shown in Tables 1 and 2, the
k1 value for the reaction with the acyclic secondary amine
is much smaller than the one for the reaction with the
isobasic primary amine. On the contrary, the k-1 value
for the reaction with the acyclic secondary amine is much
larger than the one for the reaction with the primary
amines, implying that the zwitterionic addition interme-
diate for the reaction with the secondary amines is more
unstable than the one for the reaction with the primary
amines. It is also noted that the K value for the reaction
with the secondary amines is much smaller than the one
for the reaction with the primary amines.
F IGURE 2. Brønsted-type plots for k1 (statistically corrected
using p and q, see ref 15) for the reaction of 2 with primary
(O) and alicyclic secondary (b) amines in water containing 20
mol % DMSO at 25.0 ( 0.1 °C. The identity of the points is
The effect of amine basicity on the k1, k-1, and K values
is illustrated in Figures 2, 3, and 4, respectively, for the
reactions of 2 with the primary amines along with the
corresponding data for the reactions with the alicyclic
given in Tables 1 and 2.
secondary amines for comparison. However, the data for
the reactions of 2 with the acyclic secondary amines are
not demonstrated due to a poor correlation.
less sensitive to amine basicity than for the reaction with
the alicyclic secondary amines. However, the â1 value of
0.17 is compatible with the ones obtained for aminolyses
of various carbonyl and thiocarbonyl esters in which the
RDS is the formation of an addition intermediate (the k1
step).1,12,16,17
Figure 3 shows the effect of amine basicity on the k-1
value for the reactions of 2 with the primary and alicyclic
secondary amines. One can see that the k-1 value
increases linearly with decreasing amine basicity. The
As shown in Figure 2, the magnitude of the k1 value
increases linearly with increasing amine basicity, result-
ing in good linear Brønsted-type plots for both the
primary and alicyclic secondary amine systems. The slope
of the linear Brønsted-type plot (â1) has been calculated
to be 0.17 and 0.44 for the reactions with the primary
and secondary amines, respectively, indicating that the
k1 value for the reaction with the primary amines is much
J . Org. Chem, Vol. 67, No. 25, 2002 9003

Um et al.
slopes of the linear Brønsted-type plots (âeq) have been
calculated to be 0.77 and 0.84 for the reactions of 2 with
the primary amines and with the alicyclic secondary
amines, respectively, indicating that the positive charge
developed on the N atom would be slightly larger for the
reaction with the secondary amines than for the reaction
with the primary amines.
As shown in Table 2, the magnitude of k3 values has
been determined to be ca. 1 × 109 M-1 s-1 for the
reactions of 2 with the acyclic and alicyclic secondary
amines and remains nearly constant upon changing the
amine basicity. This result is consistent with the sug-
gestion that the k3 value is insensitive to amine basic-
ity.14,16,17 Castro et al. have estimated the k3 value of 1 ×
1010 M-1 s-1 for aminolyses of various thiocarbonyl esters
in H2O.12,16,17 Therefore, the k3 value determined in the
present aminolysis carried out in 20 mol % DMSO
appears to be smaller than the one estimated by Castro
et al. for the aminolyses performed in H2O.12,16,17 How-
ever, this is not an unexpected result. Since proton
mobility in H2O has been suggested to be abnormally
high,19 the addition of DMSO to H2O would decrease
proton mobility significantly. Accordingly, one can expect
a decrease in the k3 value upon changing the solvent from
pure H2O to H2O containing 20 mol % DMSO. This
argument is consistent with recent reports that the k3
value for aminolysis of thiocarbonyl esters is smaller in
F IGURE 3. Brønsted-type plots for k-1 (statistically corrected
using p and q, see ref 15) for the reaction of 2 with primary
(O) and alicyclic secondary (b) amines in water containing 20
mol % DMSO at 25.0 ( 0.1 °C. The identity of the points is
given in Tables 1 and 2.
aqueous ethanol (k3 ) 4 × 109 M-1 s-1) than in pure H2O
(k3 ) 1 × 1010 M-1 s-1
)
and that the k3 process becomes
12a
absent in an aprotic solvent, CH3CN.13a
J encks et al. have found that aminolyses of carboxylic
esters proceed through one or two intermediates depend-
ing on the nature of the leaving group, i.e., the reaction
of carboxylic esters possessing a poor leaving group
proceeds through the deprotonation of a zwitterionic
addition intermediate (T(), which can be deprotonated
to yield an anionic intermediate (T-).1a Castro et al. have
suggested that aminolyses of various thiocarbonyl esters
proceed through deprotonation of T( to give T- for
reactions with weakly basic amines but without the
deprotonation process for those with strongly basic
amines.12,16,17 Accordingly, the basicity of amines has been
suggested to be an important factor that governs the
presence or absence of the deprotonation process (the k3
path) for aminolyses of thiocarbonyl esters.12,16,17 Inter-
estingly, the present result has clearly showed that the
reaction of 2 with the primary amines proceeds without
the k3 path, while the reaction with the secondary amines
(for both acyclic and alicyclic amines) proceeds through
the k3 path regardless of the amine basicity, suggesting
that the amine nature (primary vs secondary) is another
important factor that determines the k3 path.
A common feature for the aminolysis reaction, which
proceeds through the k3 path, is that the k2/k-1 ratio is
small. The introduction of a poor leaving group as in
J encks’ system1a would decrease the k2 value but would
not affect the k-1 value. On the other hand, a decrease
in the amine basicity as in Castro’s system12,16,17 would
increase the k-1 value but would not influence the k2
value. For both systems, the k2/k-1 ratio becomes small.
As shown in Tables 1 and 2, the k-1 value is much larger
for the reaction with the secondary amine than for the
F IGURE 4. Brønsted-type plot for K (statistically corrected
using p and q, see ref 15) for the reaction of 2 with primary
(O) and alicyclic secondary (b) amines in water containing 20
mol % DMSO at 25.0 ( 0.1 °C. The identity of the points is
given in Tables 1 and 2.
slope of the linear Brønsted-type plots (â-1) has been
determined to be -0.60 and -0.39 for the reactions with
the primary amines and with the alicyclic secondary
amines, respectively, indicating that the k-1 process is
influenced more sensitively by the amine basicity for the
reaction with the primary amines than for the reaction
with the secondary amines.
The effect of amine basicity on the equilibrium constant
K () k1/k-1) is demonstrated in Figure 4 for the reaction
of 2 with the primary and the alicyclic secondary amines.
One can see good linear Brønsted-type plots for both the
primary and the alicyclic secondary amine systems. The
(19) Eigen, M. Angew. Chem., Int. Ed. Engl. 1964, 3, 1.
9004 J . Org. Chem., Vol. 67, No. 25, 2002

Aminolyses of O-4-Nitrophenyl Thionobenzoate
reaction with the isobasic primary amine, while the k2
value remains constant. Consequently, the k2/k-1 ratio
becomes smaller for the reaction with the secondary
amine (both acyclic and alicyclic amines) than for the
reaction with the isobasic primary amine. Therefore, it
is proposed that a small k2/k-1 ratio is a plausible cause
of the deprotonation process observed in aminolyses of
carbonyl and thiocarbonyl derivatives.
for the reactions with acyclic secondary amines. The k1
value is larger for the reaction of 2 with primary amines
than for the one with acyclic secondary amines, while the
k-1 value is much smaller for the former reaction than
for the latter reactions. The small k2/k-1 ratio is consid-
ered to be responsible for the deprotonation process
observed in the aminolyses of carbonyl and thiocarbonyl
derivatives.
Ack n ow led gm en t. This work was supported by a
grant (R01-1999-000-00047-0) from Korea Science &
Engineering Foundation.
Con clu sion s
The present study has allowed us to conclude the
following. The reaction of 2 with primary amines proceeds
through an addition intermediate, in which the RDS
changes from the breakdown of the addition intermediate
to the products to the formation of the intermediate as
the amine basicity increases (pKa° ) 8.8). However, the
reaction of 2 with secondary amines proceeds through
two intermediates, e.g., a zwitterionic addition interme-
diate (T() and an anionic intermediate (T-). The effect
of the amine basicity on the microscopic rate constants
(k1, k-1, and K) shows a good linear correlation for the
reaction of 2 with primary amines but a poor correlation
Su p p or tin g In for m a tion Ava ila ble: Experimental condi-
tions and kobs values for the reaction of 2 with primary and
acyclic secondary amines (Table S1), plots of kobs vs amine
concentration for the reaction of 2 with benzylamine and
diethylamine (Figure S1), and plots of kobs/[amine] vs [amine]
for the reaction of 2 with diethylamine and diallylamine
(Figure S2), plots of [amine]/kobs vs 1/[amine] for the reaction
of 2 with diethylamine and benzylmethylamine (Figure S3).
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0259360
J . Org. Chem, Vol. 67, No. 25, 2002 9005