Regioselectivity and the nature of the reaction mechanism in nucleophilic substitution reactions of 2,4-dinitrophenyl X-substituted benzenesulfonates with primary amines

Article abstract of DOI:10.1021/jo034190i

Second-order rate constants have been measured for the reaction of 2,4-dinitrophenyl X-substituted benzenesulfonates with a series of primary amines. The nucleophilic substitution reaction proceeds through competitive S-O and C-O bond fission pathways. The S-O bond fission occurs dominantly for reactions with highly basic amines or with substrates having a strong electron-withdrawing group in the sulfonyl moiety. On the other hand, the C-O bond fission occurs considerably for the reactions with low basic amines or with substrates having a strong electron-donating group in the sulfonyl moiety, emphasizing that the regioselectivity is governed by both the amine basicity and the electronic effect of the sulfonyl substituent X. The apparent second-order rate constants for the S-O bond fission have resulted in a nonlinear Bronsted-type plot for the reaction of 2,4-dinitrophenyl benzenesulfonate with 10 different primary amines, suggesting that a change in the rate-determining step occurs upon changing the amine basicity. The microscopic rate constants (k₁ and k₂/k_-1 ratio) associated with the S-O bond fission pathway support the proposed mechanism. The second-order rate constants for the S-O bond fission result in good linear Yukawa-Tsuno plots for the aminolyses of 2,4-dinitrophenyl X-substituted benzenesulfonates. However, the second-order rate constants for the C-O bond fission show no correlation with the electronic nature of the sulfonyl substituent X, indicating that the C-O bond fission proceeds through an S_NAR mechanism in which the leaving group departure occurs rapidly after the rate-determining step.

Full text of DOI:10.1021/jo034190i

Regioselectivity a n d th e Na tu r e of th e Rea ction Mech a n ism in
Nu cleop h ilic Su bstitu tion Rea ction s of 2,4-Din itr op h en yl
X-Su bstitu ted Ben zen esu lfon a tes w ith P r im a r y Am in es
Ik-Hwan Um,* J in-Young Hong, J ung-J oo Kim, Ok-Mi Chae, and Sun-Kun Bae†
Department of Chemistry, Ewha Womans University, Seoul 120-750, Korea
ihum@mm.ewha.ac.kr
Received February 11, 2003
Second-order rate constants have been measured for the reaction of 2,4-dinitrophenyl X-substituted
benzenesulfonates with a series of primary amines. The nucleophilic substitution reaction proceeds
through competitive S-O and C-O bond fission pathways. The S-O bond fission occurs dominantly
for reactions with highly basic amines or with substrates having a strong electron-withdrawing
group in the sulfonyl moiety. On the other hand, the C-O bond fission occurs considerably for the
reactions with low basic amines or with substrates having a strong electron-donating group in the
sulfonyl moiety, emphasizing that the regioselectivity is governed by both the amine basicity and
the electronic effect of the sulfonyl substituent X. The apparent second-order rate constants for
the S-O bond fission have resulted in a nonlinear Brønsted-type plot for the reaction of
2,4-dinitrophenyl benzenesulfonate with 10 different primary amines, suggesting that a change in
the rate-determining step occurs upon changing the amine basicity. The microscopic rate constants
(k1 and k2/k-1 ratio) associated with the S-O bond fission pathway support the proposed mechanism.
The second-order rate constants for the S-O bond fission result in good linear Yukawa-Tsuno
plots for the aminolyses of 2,4-dinitrophenyl X-substituted benzenesulfonates. However, the second-
order rate constants for the C-O bond fission show no correlation with the electronic nature of the
sulfonyl substituent X, indicating that the C-O bond fission proceeds through an SNAr mechanism
in which the leaving group departure occurs rapidly after the rate-determining step.
In tr od u ction
the leaving group; i.e., a change in the RDS occurs from
breakdown of an addition intermediate to its formation
as the attacking amine becomes more basic than the
leaving group by 4-5 pKa units.1a,2,3,5 Therefore, the
electronic nature of the substituent in the attacking
amine as well as in the leaving group has been under-
stood to influence the reaction mechanism significantly.
However, we have recently shown that the electronic
effect of the substituent in the benzoyl moiety (the
nonleaving group) does not significantly affect the reac-
tion mechanism for aminolyses of 4-nitrophenyl and 2,4-
dinitrophenyl X-substituted benzoates.5b,c A similar result
The mechanism of nucleophilic substitution reactions
of carbonyl, phosphoryl, and sulfonyl compounds has
been the subject of many recent investigations due to the
interest in biological processes as well as synthetic
applications.1-7 Aminolyses of carboxylic esters have
generally been suggested to proceed through an addition
intermediate in which the rate-determining step (RDS)
is dependent on the basicity of the attacking amine and
† Department of Chemistry, Kunsan National University, Kunsan
573-701, Korea.
has been found for the corresponding reactions with
(1) (a) Stefanidis, D.; Cho, S.; Dhe-Paganon, S.; J encks, W. P. J . Am.
Chem. Soc. 1993, 115, 1650-1656. (b) Andres, G. O.; Granados, A. M.;
Rossi, R. H. J . Org. Chem. 2001. 66, 7653-7657. (c) Baxter, N. J .;
Regoreau, L. J . M.; Laws, A. P.; Page, M. I. J . Am. Chem. Soc. 2000,
122, 3375-3385. (d) Adalsteinsson, H.; Bruice, T. C. J . Am. Chem. Soc.
1998, 120, 3440-3447. (e) Zhong, M.; Brauman, J . I. J . Am. Chem.
Soc. 1999, 121, 2508-2515.
(2) (a) Castro, E. A.; Aliaga, M.; Campodonico, P.; Santos, J . G. J .
Org. Chem. 2002, 67, 8911-8916. (b) Castro, E. A.; Andujar, M.;
Campodonico, P.; Santos, J . G. Int. J . Chem. Kinet. 2002, 34, 309-
315. (c) Castro, E. A.; Galvez, A.; Leandro, L.; Santos, J . G. J . Org.
Chem. 2002, 67, 4309-4315. (d) Castro, E. A.; Angel, M.; Arellano,
D.; Santos, J . G. J . Org. Chem. 2001, 66, 6571-6575. (e) Castro, E.
A.; Ruiz, M. G.; Santos, J . G. Int. J . Chem. Kinet. 2001, 33, 281-287.
(3) (a) Oh, H. K.; Ku, M. H.; Lee, H. W.; Lee, I. J . Org. Chem. 2002,
67, 8995-8998. (b) Lee, H. W.; Guha, A. K.; Lee, I. Int. J . Chem. Kinet.
2002, 34, 632-637. (c) Lee, I.; Hong, S. W.; Koh, H. J .; Lee, Y.; Lee, B.
C.; Lee, H. W. J . Org. Chem. 2001, 66, 8549-8555. (d) 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. (e) Oh, H. K.; Lee, J . Y.; Lee, H.
W.; Lee, I. New J . Chem. 2002, 26, 473-476.
- 5a
anionic nucleophiles such as OH-, CN-, and N3
.
(4) (a) Buncel, E.; Cannes, C.; Chatrousse, A. P.; Terrier, F. J . Am.
Chem. Soc. 2002, 124, 8766-8767. (b) Omakor, J . E.; Onyido, I.;
vanLoon, G. W.; Buncel, E. J . Chem. Soc., Perkin Trans. 2 2001, 324-
330. (c) Tarkka, R. M.; Buncel, E. J . Am. Chem. Soc. 1995, 117, 1503-
1507.
(5) (a) Um, I. H.; Han, H. J .; Ahn, J . A.; Kang, S.; Buncel, E. J . Org.
Chem. 2002, 67, 8475-8480. (b) Um, I. H.; Min, J . S.; Ahn, J . A.; Hahn,
H. J . J . Org. Chem. 2000, 65, 5659-5663. (c) Um, I. H.; Min, J . S.;
Lee, H. W. Can. J . Chem. 1999, 77, 659-666. (d) Um, I. H.; Lee, E. J .;
Lee, J . P. Bull. Korean Chem. Soc. 2002, 23, 381-384.
(6) (a) Um, I. H.; Buncel, E. J . Am. Chem. Soc. 2001, 123, 11111-
11112. (b) Um, I. H.; Lee, E. J .; Buncel, E. J . Org. Chem. 2001, 66,
4859-4864. (c) Um, I. H.; Hong, J . Y.; Buncel, E. Chem. Commun.
2001, 27-28.
(7) (a) Um, I. H.; Lee, S. E.; Kwon, H. J . J . Org. Chem. 2002, 67,
8999-9005. (b) Um, I. H.; Kim, M. J .; Lee, H. W. Chem. Commun.
2000, 2165-2166.
10.1021/jo034190i CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/21/2003
5180
J . Org. Chem. 2003, 68, 5180-5185

Reactions of Benzenesulfonates with Primary Amines
SCHEME 1
tot
TABLE 1. Su m m a r y of Secon d -or d er Ra te Con sta n ts (kN a n d kNS-O) for th e Rea ction of 2,4-Din itr op h en yl
Ben zen esu lfon a te w ith P r im a r y Am in es in Wa ter Con ta in in g 20 m ol % DMSO a t 25.0 ( 0.1 °C
tot
S-O
103[RNH2]b/
M
103kN
/
103kN
/
a
no.
RNH2
ethylamine
propylamine
ethylenediamine
glycine
pKa
M-1 s-1
M-1 s-1
1
2
3
4
5
10.67
10.89
10.32
10.06
9.67
29.1-56.2
33.3-57.0
46.8-81.0
39.3-66.8
78.6-146
46.8-81.0
119-198
82.2-206
79.8-200
123-206
1290 ( 20
1050 ( 20
832 ( 7
1290
1050
832
555
312
555 ( 4
ethanolamine
312 ( 6
260 ( 2
45.0 ( 0.3
21.5 ( 0.5
14.3 ( 0.19
0.593 ( 0.023
6
7
8
9
benzylamine
glycylglycine
glycine ethyl ester
1,2-diaminopropane-H+
trifluoroethylamine
9.46
8.31
7.68
7.13
257
43.7
19.1
12.7
0.468
10
5.70
a
b
pKa values were measured in H2O containing 20 mol % DMSO as in the kinetic study (see the text). The concentration of free base.
We have now extended our study to reactions of 2,4-
dinitrophenyl X-substituted benzenesulfonates with a
series of primary amines. Nucleophilic substitution reac-
tions of sulfonate esters have previously been reported
to proceed through competitive S-O and C-O bond
fission pathways.8,9 The regioselectivity has been reported
to be influenced greatly by the solvent, the polarizability
of the nucleophiles, and steric effects.8,9 However, the
effect of the substituent in the sulfonyl moiety on both
the regioselctivity and reaction mechanism has not
systematically been investigated. In this paper we report
the detailed reaction mechanism for both the S-O and
C-O bond fission pathways together with the effect of
the sulfonyl substituent on the regioselectivity (see
Scheme 1).
All the reactions studied in the this work obeyed
pseudo-first-order kinetics under excess amine. Pseudo-
first-order rate constants (kobsd) were obtained from the
equation ln(A∞ - At) ) -kobsdt + c. Correlation coefficients
of the linear regressions were usually higher than 0.9995.
Generally, five different concentrations of nucleophile
were used to obtain second-order rate constants from the
slope of the linear plot of kobsd vs the concentration of the
amine nucleophile. The second-order rate constant ob-
tained in this way corresponds to the overall rate
constant (kNtot). The plots of kobsd vs amine concentration
are linear and pass through the origin, indicating that
there is no general-base catalysis by a second amine
molecule, and the contribution by H2O or HO- ion from
the solvolysis to kobsd is negligible. Therefore, the second-
order rate constant for the S-O bond fission process
(kNS-O) and the one for the C-O bond fission (kNC-O) were
calculated from the following relationships:
Resu lts
The reactions of 2,4-dinitrophenyl X-substituted ben-
zenesulfonates with primary amines proceed through
both the S-O and C-O bond fission pathways as shown
in Scheme 1. The S-O bond fission that leads to forma-
tion of 2,4-dinitrophenoxide ion and benzenesulfonamides
was found to occur dominantly for the reactions with
highly basic amines or for those with a strong electron-
withdrawing group (EWG) in the sulfonyl moiety of the
substrates. On the other hand, the C-O bond fission that
yields substituted anilines and benzenesulfonates was
found to occur considerably for the reactions with low
basic amines or with a strong electron-donating group
(EDG) in the sulfonyl moiety of the substrates.
tot
kNS-O ) kN × the fraction of S-O bond fission (1)
C-O
tot
S-O
kN
) kN - kN
(2)
Discu ssion
Effect of Am in e Ba sicity on th e Ra tes a n d Mech -
a n ism for th e S-O Bon d F ission . As shown in Table
1, the second-order rate constant for the S-O bond fission
pathway (kNS-O) increases with increasing amine basicity
for the reaction of 2,4-dinitrophenyl benzenesulfonate
with 10 different amines whose basicity spans a range
of ca. 5 pKa units. The effect of amine basicity on
reactivity is graphically demonstrated in Figure 1 for the
S-O bond fission process. One can see a nonlinear
Brønsted-type plot which is statistically corrected by
(8) Choi, J . H.; Lee, B. C.; Lee, H. W.; Lee, I. J . Org. Chem. 2002,
67, 1277-1281.
(9) Um, I. H.; Kim, J . J .; Kim, M. J .; Kwon, D. S. Bull. Korean Chem.
Soc. 1996, 17, 353-357.
J . Org. Chem, Vol. 68, No. 13, 2003 5181

Um et al.
TABLE 2. Su m m a r y of Micr oscop ic Ra te Con sta n ts
Associa ted w ith th e Rea ction of 2,4-Din itr op h en yl
Ben zen esu lfon a te w ith P r im a r y Am in es for th e S-O
Bon d F ission P r ocess in Wa ter Con ta in in g 20 m ol %
DMSO a t 25.0 ( 0.1 °C
102k1/
no.
RNH2
ethylamine
propylamine
ethylenediamine
glycine
ethanolamine
benzylamine
glycylglycine
pKa
k2/k-1
M-1 s-1
1
2
3
4
5
6
7
8
9
10.67
10.89
10.32
10.06
9.67
9.46
8.31
7.68
7.13
12.8
16.4
6.12
6.41
4.13
3.26
0.890
0.437
0.330
0.0469
139
111
48.4
64.2
38.8
33.6
9.28
6.28
5.12
1.05
glycine ethyl ester
1,2-diaminopropane-H+
trifluoroethylamine
10
5.70
concentration of the substrate and the amine studied,
respectively.
rate for S-O bond fission )
k1k2[S][RNH2]/(k-1 + k2) (4)
S-O
kN
) k1k2/(k-1 + k2)
(5)
To obtain more information about the RDS, the k2/k-1
ratio associated with the aminolyses of 2,4-dinitrophenyl
benzenesulfonate has been determined using the method
reported previously (see also eqs S1-S6 in the Support-
ing Information).2,5 Table 2 shows that the k2/k-1 ratio
decreases as the amine basicity decreases. The plot of
log(k2/k-1) versus amine basicity results in excellent
linearity with a -â-1 value of 0.49 (see Figure S1 in the
Supporting Information). The magnitude of the â-1 value
represents the sensitivity parameter for the k-1 step,
since the k2 value has been suggested to be independent
of amine basicity.11,12 It is also noted that the k2/k-1 ratio
is smaller than unity for the weakly basic amines (pKa
< 8.89) but larger than unity for the strongly basic
amines (pKa > 8.89). Therefore, the k2/k-1 ratio obtained
in the present study clearly supports the preceding
proposal that the RDS changes from the k2 to the k1 step
as the amine basicity exceeds pKa ) 8.89.
F IGURE 1. Brønsted-type plot for S-O bond fission for the
reaction of 2,4-dinitrophenyl benzenesulfonate with primary
amines in water containing 20 mol % DMSO at 25.0 ( 0.1 °C.
The numbers refer to the amines in Table 1. The solid line
was calculated by eq 3.
using p and q, i.e., p ) 3 (except p ) 6 for 1,2-
diaminopropane-H+) and q ) 1 (except q ) 2 for
ethylenediamine).10 Nonlinear Brønsted-type plots have
often been observed for aminolyses of esters with a good
leaving group (e.g., 2,4-dinitrophenyl acetate and ben-
zoate); i.e., the magnitude of the ânuc values decreases
from 0.8 ( 0.3 to 0.3 ( 0.2 as the attacking amine
becomes more basic than the leaving group by 4-5 pKa
units.1a,2,3,5,7 Such a curved Brønsted-type plot has been
interpreted as a change in the RDS upon changing the
amine basicity. The nonlinear Brønsted-type plot in
Figure 1 has been analyzed using eq 3,2,7a
To calculate k1 values, eq 5 should be rearranged as
S-O
eq 6. Since kN
and k2/k-1 values are available in the
log(kNS-O/kN°) ) â2(pKa - pKa°) - log[(1 + R)/2]
present system, k1 values can be calculated from eq 6.
(3)
k1 ) kNS-O(k-1/k2 + 1)
(6)
log R ) (â2 - â1)(pKa - pKa°)
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 determined are as follows: log
kN° ) 1.16, pKa° ) 8.89, â1 ) 0.39, and â2 ) 0.88.
Therefore, one can suggest that the RDS for the reaction
of 2,4-dinitrophenyl benzenesulfonate with RNH2 changes
from the k2 to the k1 step as the amine basicity increases
on the basis of the magnitude of the â1 and â2 values.
Applying the steady-state conditions to the addition
intermediate for the S-O bond fission process, eqs 4 and
5 can be derived, where [S] and [RNH2] represent the
The k1 values determined in this way are summarized
in Table 2. One can see that the k1 value increases with
increasing amine basicity. A good linear Brønsted-type
plot has been obtained with a â1 value 0.41 (see Figure
S2 in the Supporting Information). The â1 value is
slightly smaller than the -â-1 value ()0.49) in the
present system, indicating that the amine basicity is less
sensitive to the k1 step than to the k-1 step.
Effect of th e Su lfon yl Su bstitu en t on th e Ra tes
a n d Mech a n ism for th e S-O Bon d F ission . As shown
(11) (a) Oh, H. K.; Kim, K. S.; Lee, H. W.; Lee, I. New J . Chem.
2001, 25, 313-317. (b) Oh, H. K.; Woo, S. Y.; Shin, C. H.; Park, Y. S.;
Lee, I. J . Org. Chem. 1997, 62, 5780-5784.
(12) (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.
(10) Bell, R. P. The Proton in Chemistry; Methuen: London, 1959;
p 159.
5182 J . Org. Chem., Vol. 68, No. 13, 2003

Reactions of Benzenesulfonates with Primary Amines
TABLE 3. Su m m a r y of Secon d -or d er Ra te Con sta n ts
(kNS-O) for th e Rea ction of 2,4-Din itr op h en yl
X-Su bstitu ted Ben zen esu lfon a tes w ith Ben zyla m in e,
Glycin e Eth yl Ester , a n d Tr iflu or oeth yla m in e in Wa ter
Con ta in in g 20 m ol % DMSO a t 25.0 ( 0.1 °C
trophenyl X-substituted benzenesulfonates proceeds by
mixed SN1 and SN2 mechanisms when the sulfonyl moiety
is substituted with strong EDGs such as 2,4,6-tri-
methyl.16 Since 4-MeO is also a strong EDG, one might
expect an SN1 mechanism to occur in the present ami-
nolysis.
103kNS-O/M-1 s-1
glycine
However, an SN1 mechanism can be clearly ruled out
in the present system on the basis of the experimental
result that the kobsd value increases linearly with increas-
ing concentration of the attacking amine as mentioned
in the Results. Besides, if the reaction of the substrate
with the 4-MeO or 4-Me group in the sulfonyl moiety
proceeded through an SN1 mechanism, the points for
these substrates should have deviated positively from the
Hammett plot. In fact, an upward curvature in the
Hammett plots has often been reported for nucleophilic
substitution reactions of the benzylic system or those of
various carboxylic esters (e.g., substituted phenyl esters
of 4-nitrophenylacetic acid) in which a change in reaction
mechanism occurs from SN1 to SN2 for the former case
and from a bimolecular reaction (either one step or a
stepwise addition-elimination mechanism) to an E1cB
mechanism for the latter case.17 Therefore, the negative
deviation shown by the two substrates would not be due
to a change in the reaction mechanism.
X
benzylamine
ethyl ester
trifluoroethylamine
4-NO2
3-NO2
4-Cl
1830 ( 10
1570 ( 5
401 ( 4
98 ( 2
1.86 ( 0.04
1.57 ( 0.04
0.558 ( 0.006
0.468 ( 0.023
0.300 ( 0.006
0.189 ( 0.008
84.5 ( 0.7
30.2 ( 0.4
19.1 ( 0.5
11.5 ( 0.2
7.33 ( 0.03
H
257 ( 2
4-CH3
4-OCH3
138 ( 3
83.9 ( 1.4
The RDS of a stepwise reaction as in the present
system is determined by the magnitude of the k2/k-1 ratio;
i.e., the RDS is the k1 step when k2/k-1 > 1, but the k2
step when k2/k-1 < 1. The electronic nature of the sulfonyl
substituent X would influence the magnitude of the k2
and k-1 values; i.e., an EWG in the sulfonyl moiety would
decrease the k2 and k-1 values, while an EDG would
increase the k2 and k-1 values. However, the magnitude
of the k2/k-1 ratios would be independent of the electronic
nature of the sulfonyl substituent, since the electronic
effect of the sulfonyl substituent X on the k2 and k-1
values would be in the same direction. In fact, we have
recently shown that the substituent X on the benzoyl
moiety does not significantly affect the k2/k-1 ratio for
reactions of 2,4-dinitrophenyl X-substituted benzoates
with amines5c and with various anionic nucleophiles.5a
F IGURE 2. Hammett plot for S-O bond fission for the
reaction of 2,4-dinitrophenyl X-substituted benzenesulfonates
with glycine ethyl ester in H2O containing 20 mol % DMSO
at 25.0 ( 0.1 °C.
S-O
in Table 3, the kN
value for the reaction of 2,4-
On the basis of above, we propose that the origin of
the negative deviations shown by the substrates with an
electron-donating substituent in the sulfonyl moiety
(shown in Figures 2, S3, and S4) is due to stabilization
of the ground state (GS) through resonance interaction
between the electron-donating substituent in the sulfonyl
moiety and the SdO bond as illustrated by resonance
structures I and II. In this situation, the Yukawa-Tsuno
dinitrophenyl X-substituted benzenesulfonates increases
with increasing electron-withdrawing ability of the sul-
fonyl substituent X for a given amine. The effect of the
S-O
sulfonyl substituent X on the kN
value has been
graphically illustrated in Figure 2. One can notice that
the point for the substrate, which is substituted with
4-MeO or 4-Me in the sulfonyl moiety, deviates negatively
from linearity for the reaction with glycine ethyl ester.
A similar result has also been obtained for the corre-
sponding reactions with benzylamine and trifluoroethy-
lamine (see Figures S3 and S4 in the Supporting Infor-
mation). Although the degree of deviation is not significant,
one might attribute such a deviation to a change in the
RDS or reaction mechanism upon changing the sulfonyl
substituent X. In fact, J encks, Lee, and Castro et al.
concluded that a change in the RDS occurs upon changing
the substituent X in the nonleaving group.13-15 Further-
more, Vizgert reported that the hydrolysis of 2,4-dini-
equation (eq 7)18 is more appropriate than the Hammett
equation. The term σ+ - σ° is the resonance substituent
constant measuring the capability for π-delocalization of
(13) (a) Gresser, M. J .; J encks, W. P. J . Am. Chem. Soc. 1977, 99,
6963-6970. (b) J encks, W. P. Catalysis in Chemistry and Enzymology;
McGraw-Hill: New York, 1969; pp 480-483.
J . Org. Chem, Vol. 68, No. 13, 2003 5183

Um et al.
TABLE 4. Su m m a r y of Secon d -or d er Ra te Con sta n ts
(kNC-O) for th e Rea ction of 2,4-Din itr op h en yl
X-Su bstitu ted Ben zen esu lfon a tes w ith Eth yla m in e,
Ben zyla m in e, Glycin e Eth yl Ester , a n d
Tr iflu or oeth yla m in e in Wa ter Con ta in in g 20 m ol %
DMSO a t 25.0 ( 0.1 °C
103kNC-O/M-1 s-1
glycine
trifluoro-
X
ethylamine benzylamine ethyl ester ethylamine
4-NO2
3-NO2
4-Cl
a
a
a
a
a
a
3.03
5.39
3.36
2.37
2.19
2.32
0.162
0.235
0.122
0.125
0.100
0.093
4.05
2.60
12.0
13.7
H
4-CH3
4-OCH3
19.8
19.9
a
The rate constant could not be determined due to the fact that
no detectable C-O bond fission products were found.
(r ) 0.7-1.4),5b indicating that the resonance contribution
is less significant for the sulfonate system than for the
benzoate system. Since the overlap of 2p and 3p orbitals
to form a CdS bond is not efficient,19 the contribution of
the resonance structure for the sulfonate system (I T II)
would not be as significant as that for the benzoate
system (III T IV). This argument explains the large
difference in the r value between the sulfonate and the
benzoate systems.
F IGURE 3. Yukawa-Tsuno plot for S-O bond fission for the
reaction of 2,4-dinitrophenyl X-substituted benzenesulfonates
with glycine ethyl ester in H2O containing 20 mol % DMSO
at 25.0 ( 0.1 °C.
Effect of Am in e Ba sicity a n d Su lfon yl Su bstitu -
en t on t h e R egioselect ivit y for t h e C-O Bon d
F ission . In Table 4 are summarized the second-order
C-O
the π-electron donor substituent, while the r value is a
parameter characteristic of the given reaction, represent-
ing the extent of resonance contribution.18 The Yukawa-
rate constants for the C-O bond fission process (kN
)
for reactions of 2,4-dinitrophenyl X-substituted benze-
nesulfonates with four different amines. The kNC-O value
for the weakly basic amines such as trifluoroethylamine
(pKa ) 5.70) and glycine ethyl ester (pKa ) 7.68) could
be determined for all the substrates regardless of the
log(kX/kH) ) F[σ° + r(σ+ - σ°)]
(7)
Tsuno equation becomes the Hammett equation when
r ) 0, or the Brown-Okamoto equation when r ) 1. As
shown in Figure 3, the Yukawa-Tsuno plot exhibits good
linearity for the reactions with glycine ethyl ester (r )
0.57). A similar result has been obtained for the corre-
sponding reactions with benzylamine and trifluoroethyl-
amine with r values of 0.49 and 0.55, respectively (see
Figures S5 and S6 in the Supporting Information).
Therefore, one can attribute the negative deviations
(shown in Figures 2, S3, and S4) to the GS stabilization
by resonance but not to a change in the RDS. Since the
r value is neither 0 nor 1, the Yukawa-Tsuno plot results
in much better correlation than the Hammett or Brown-
Okamoto plot, in which σ or σ+ constants are used alone.
The r value obtained in the present system is ca. 0.53
( 0.04. This value is much smaller than the one obtained
in aminolyses of 4-dinitrophenyl X-substituted benzoates
electronic nature of the substituent X on the sulfonyl
C-O
moiety. However, the kN
value for the reactions with
strongly basic benzylamine (pKa ) 9.46) and ethylamine
(pKa ) 10.67) could not be measured for the reaction of
the substrates in which a strong EWG such as 4-NO2 or
3-NO2 is substituted in the sulfonyl moiety, since the
reactions of these substrates produce no detectable C-O
bond fission products. Therefore, one can suggest that
the regioselectivity is governed by both the basicity of
the amines and the electronic nature of the sulfonyl
substituent X.
Table 4 shows that the kN
C-O
value increases as the
amine basicity increases when the sulfonyl substituent
X is an EDG such as 4-Me or 4-MeO. However, the
C-O
correlation of kN
with amine basicity is not good
(figure not shown). Furthermore, one can notice that
C-O
there is no correlation between the kN
value and the
electronic nature of the sulfonyl substituent X for a given
amine. This quite contrasts the result obtained for the
S-O bond fission process, e.g., a good linear Yukawa-
Tsuno plot with a large F value as shown in Figure 3.
One might suggest two plausible reasons for the con-
trasting results: (1) the proximity effect and (2) the
nature of the reaction mechanism. The reaction site of
the C-O bond fission is farther from the substituent X
(14) Guha, A. K.; Lee, H. W.; Lee, I. J . Org. Chem. 2000, 65, 12-
15.
(15) (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.
(16) Vizgert, R. V. Zh. Obshch. Khim. 1962, 32, 633-637.
(17) (a) Swansburg, S.; Buncel, E.; Lemieux, R. P. J . Am. Chem.
Soc. 2000, 122, 6594-6600. (b) Cevasco, G.; Guanti; G.; Hopkins, A.
R.; Thea, S.; Williams, A. J . Org. Chem. 1985, 50, 479-484. (c) Broxton,
T. J .; Dubby, N. W. J . Org. Chem. 1981, 46, 1186-1191.
(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. J pn. 1959, 32, 965-970.
(19) (a) Hill, S. V.; Thea, S.; Williams, A. J . Chem. Soc., Perkin
Trans. 2 1983, 437-446. (b) Oh. H. K.; Woo, S. Y.; Shin, C. H.; Park,
Y. S.; Lee, I. J . Org. Chem. 1997, 62, 5780-5784.
5184 J . Org. Chem., Vol. 68, No. 13, 2003

Reactions of Benzenesulfonates with Primary Amines
of triethylamine in anhydrous ether. Their purity was checked
by means of their melting point and spectral data such as IR
and H NMR characteristics. Amines and other chemicals were
of the highest quality available and were generally recrystal-
lized or distilled before use. The reaction medium was H2O
containing 20 mol % DMSO to eliminate solubility problems.
in the sulfonyl moiety than that of the S-O bond fission.
Since the inductive effect of the substituent diminishes
with the distance between the substituent and the
reaction site, one can expect that the effect of the sulfonyl
substituent would be less significant for the C-O bond
fission than for the S-O bond fission process. The nature
1
DMSO was distilled over calcium hydride at
a reduced
of the reaction mechanism would also be responsible for
pressure (bp 64-66 °C at 6-7 mmHg) and stored under
nitrogen. Doubly glass distilled water was further boiled and
cooled under nitrogen just before use.
C-O
the absence of the substituent effect on the kN
value.
It has well been known that SNAr reactions proceed
through a Meisenheimer complex, in which the RDS can
be either formation or breakdown of the complex.20 If the
Kin etics. The kinetic studies were performed with a UV-
vis spectrophotometer equipped with a constant-temperature
circulating bath. The reactions were followed by monitoring
the appearance of 2,4-dinitrophenoxide ion, an S-O bond
fission product, at 405 nm. All the reactions were carried out
under pseudo-first-order conditions in which the concentration
of the nucleophile was at least 20 times greater than the
substrate concentration. Typically, the reaction was initiated
by adding 5 µL of a 0.02 M substrate solution in MeCN by a
10 µL syringe into a 10 mm UV cell containing 2.50 mL of the
reaction medium and the amine nucleophile. The amine stock
solution of ca. 0.2 M was prepared in a 25.0 mL volumetric
flask under nitrogen by adding 2 equiv of amine hydrochloride
to 1 equiv of standardized NaOH solution to obtain a self-
buffered solution. All the transfers of reaction solutions were
carried out by means of gastight syringes.
leaving group departure from the Meisenheimer complex
C-O
occurs in the RDS, the magnitude of the kN
value
should increase linearly with increasing electron-with-
drawing ability of the substituent X in the leaving
C-O
sulfonyl moiety. However, as shown in Table 4, the kN
value remains nearly constant upon changing the sub-
stituent X from a strong EDG (e.g., 4-MeO) to a strong
EWG (e.g., 4-NO2) for a given amine. Therefore, the
present result clearly suggests that the C-O bond fission
proceeds through an SNAr mechanism in which the
leaving group departure from the Meisenheimer complex
occurs rapidly after the RDS.
P r od u ct An a lysis. The amount of 2,4-dinitrophenoxide
formed during the S-O bond fission process was determined
quantitatively by measuring the optical density using a UV-
vis spectrophotometer at 25.0 ( 0.1 °C. Other products such
as 2,4-dinitro-N-ethylaniline and N-ethylbenzenesulfonamide
were analyzed by HPLC. The flow rate was 1 mL/min, and
the eluent was 50/50 MeCN/MeOH (v/v). Quantitative analysis
was performed by comparison of the HPLC peak area of the
reaction mixture with that of the authentic sample. The results
obtained from UV-vis and HPLC were found to be consistent
with each other within an experimental error range (<3%) in
all cases.
Con clu sion s
The present study has allowed us to conclude the
following: (1) The nucleophilic substitution reaction
proceeds through the S-O and C-O bond fission path-
ways. The S-O bond fission occurs dominantly when the
amine is strongly basic or the substituent in the sulfonyl
moiety of the substrate is an EWG. However, the C-O
bond fission process occurs considerably when the amine
is weakly basic or the sulfonyl substituent X is a strong
EDG, indicating that the regioselectivity is governed by
both the amine basicity and the electronic nature of the
substituent X in the sulfonyl moiety of the substrate. (2)
The S-O bond fission proceeds through an addition
intermediate, in which the RDS for this process is
dependent on the basicity of the amine nucleophile, but
independent of the electronic nature of the substituent
Deter m in a tion of p Ka. pKa values of the conjugate acids
of the amines were determined by measuring the pH of
solutions containing equal amounts of the amine and the
corresponding amine hydrochloride with a glass electrode in
H2O containing 20 mol % DMSO.7a The pH values of the
solutions were practically independent of the amine concentra-
tion in the range of (20-200) × 10-3 M, which is the
concentration range used for the kinetic experiment.
S-O
in the sulfonyl moiety of the substrate. (3) The kN
values for the reactions of 2,4-dinitrophenyl X-substituted
benzenesulfonates result in a linear Yukawa-Tsuno plot
C-O
Ack n ow led gm en t. This work was supported by a
grant (KRF-2002-070-C00061) from the Korea Research
Foundation. We are also grateful for helpful discussions
with Professor J . M. Dust and comments from reviewers
with a large F value. However, the kN
values for the
corresponding reactions show no correlation with the
electronic nature of the sulfonyl substituent X, suggesting
that the C-O bond fission proceeds through an SNAr
mechanism in which the leaving group departure from
the Meisenheimer complex occurs rapidly after the RDS.
tot
concerning the kN values.
Su p p or tin g In for m a tion Ava ila ble: Equations to deter-
mine the k2/k-1 ratio (eqs S1-S6), Brønsted-type plots for k2/
k-1 and k1 for the S-O bond fission process (Figures S1 and
S2), and Hammett and Yukawa-Tsuno plots for reactions of
2,4-dintrophenyl X-substituted benzenesulfonates with
benzylamine and trifluoroethylamine (Figures S3-S6). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Exp er im en ta l Section
Ma t er ia ls. 2,4-Dinitrophenyl X-substituted benzenesul-
fonates were prepared from the reaction of 2,4-dinitrophenol
and X-substituted benzenesulfonyl chlorides in the presence
(20) (a) Annandale, M. T.; vanLoon, G. W.; Buncel, E. Can. J . Chem.
1998, 76, 873-883. (b) Dust, J . M.; Manderville, R. A. Can. J . Chem.
1998, 76, 662-671. (c) Smith, M. B.; March, J . March’s Advanced
Organic Chemistry; Wiley & Sons: New York, 2001; pp 850-853.
J O034190I
J . Org. Chem, Vol. 68, No. 13, 2003 5185