Effect of Amine Nature on Reaction Rate and Mechanism in Nucleophilic Substitution Reactions of 2,4-Dinitrophenyl X-Substituted Benzenesulfonates with Alicyclic Secondary Amines

Article abstract of DOI:10.1021/jo049812u

Second-order rate constants have been measured for reactions of 2,4-dinitrophenyl X-substituted benzenesulfonates with a series of alicyclic secondary amines. The reaction proceeds through S-O and C-O bond fission pathways competitively. The S-O bond fission occurs more dominantly as the amine basicity increases and the substituent X in the sulfonyl moiety becomes more strongly electron withdrawing, indicating that the regioselectivity is governed by the amine basicity as well as the electronic nature of the substituent X. The S-O bond fission proceeds through an addition intermediate with a change in the rate-determining step at pK_a° = 9.1. The secondary amines are more reactive than primary amines of similar basicity for the S-O bond fission. The k₁ value has been determined to be larger for reactions with secondary amines than with primary amines of similar basicity, which fully accounts for their higher reactivity. The second-order rate constants for the S-O bond fission result in linear Yukawa-Tsuno plots while those for the C-O bond fission exhibit poor correlation with the electronic nature of the substituent X. The distance effect and the nature of reaction mechanism have been suggested to be responsible for the poor correlation for the C-O bond fission pathway.

Full text of DOI:10.1021/jo049812u

Effect of Am in e Na tu r e on Rea ction Ra te a n d 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 Alicyclic Secon d a r y Am in es
Ik-Hwan Um,* Sun-Mee Chun, Ok-Mi Chae,† Mizue Fujio,‡ and Yuho Tsuno‡
Department of Chemistry, Ewha Womans University, Seoul 120-750, Korea, Department of Chemistry,
Kunsan National University, Kunsan 573-701, Korea, and Institute for Materials Chemistry and
Engineering, Kyushu University, Hakozaki, Higashi-ku, Fukuoka 812-8581, J apan
ihum@mm.ewha.ac.kr
Received February 2, 2004
Second-order rate constants have been measured for reactions of 2,4-dinitrophenyl X-substituted
benzenesulfonates with a series of alicyclic secondary amines. The reaction proceeds through S-O
and C-O bond fission pathways competitively. The S-O bond fission occurs more dominantly as
the amine basicity increases and the substituent X in the sulfonyl moiety becomes more strongly
electron withdrawing, indicating that the regioselectivity is governed by the amine basicity as well
as the electronic nature of the substituent X. The S-O bond fission proceeds through an addition
intermediate with a change in the rate-determining step at pKa° ) 9.1. The secondary amines are
more reactive than primary amines of similar basicity for the S-O bond fission. The k1 value has
been determined to be larger for reactions with secondary amines than with primary amines of
similar basicity, which fully accounts for their higher reactivity. The second-order rate constants
for the S-O bond fission result in linear Yukawa-Tsuno plots while those for the C-O bond fission
exhibit poor correlation with the electronic nature of the substituent X. The distance effect and the
nature of reaction mechanism have been suggested to be responsible for the poor correlation for
the C-O bond fission pathway.
In tr od u ction
for the reaction of carbonyl esters with amines has
generally been understood to proceed through a tetra-
Nucleophilic substitution reactions of carbonyl, phos-
phonyl, and sulfonyl derivatives have received consider-
able attention due to their importance in biological
processes and synthetic applications.1-11 The mechanism
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† Kunsan National University.
‡ Kyushu University.
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10.1021/jo049812u CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/06/2004
3166
J . Org. Chem. 2004, 69, 3166-3172

Reactions of Benzenesulfonates with Alicyclic Secondary Amines
SCHEME 1
hedral addition intermediate (T() in which the rate-
determining step (RDS) depends on the basicity of the
leaving group and nucleophiles.1-4 It has been suggested
that the RDS changes from expulsion of the leaving group
from T( to its formation as the amine becomes more basic
than the leaving group by 4-5 pKa units.1-4 However,
the mechanism of the corresponding reactions of phos-
phorus and sulfur centered esters has not completely
been understood.5-11 Some studies have suggested that
nucleophilic substitution reactions of phosphonyl and
sulfonyl esters proceed through a concerted mechanism5,6
while other studies have argued against a concerted
mechanism.7-11
We have recently reported that the reaction of 2,4-
dinitrophenyl X-substituted benzenesulfonates (1a -e)
with a series of primary amines proceeds through S-O
and C-O bond fission pathways competitively.11 The
S-O bond fission has been found to proceed through an
addition intermediate with a change in the RDS from
breakdown of the intermediate to its formation as the
amine becomes ca. 5 pKa units more basic than the
leaving 2,4-dinitrophenoxide anion, while the C-O bond
fission occurs through a Meisenheimer complex.11
We have now extended our study to reactions of 1a -e
with a series of alicyclic secondary amines to investigate
the effect of amine nature on the reaction rate and
mechanism by comparing the data obtained in this study
with those for the corresponding reactions with primary
leads to formation of substituted benzenesulfonates and
anilines increased as the amine basicity decreased or the
substituent X changed from a strong electron-withdraw-
ing group (EWG) to a strong electron-donating group
(EDG).
All the reactions in the present study obeyed pseudo-
first-order kinetics in the presence of excess amine.
Pseudo-first-order rate constants (kobsd) were calculated
from the equation ln(A∞ - At) ) -kobsdt + C. Correlation
coefficients of the linear regressions were usually higher
than 0.9995. The plots of kobsd vs amine concentration
were linear passing through the origin, indicating that
general base catalysis by the second amine molecule is
absent and the contribution of OH- and/or H2O to the
kobsd value is negligible. Five different amine concentra-
tions were generally used to determine the second-order
rate constants from the linear plot. The second-order rate
constant determined in this way corresponds to the
overall rate constant (kNtot).11 Thus, the second-order rate
constant for the S-O bond fission (kNS-O) and the C-O
bond fission (kNC-O) processes were calculated from the
following relationships:
S-O
tot
kN
) kN × the fraction S-O bond fission (1)
C-O
tot
S-O
kN
) kN - kN
(2)
Discu ssion
amines. The apparent second-order rate constants and
the microscopic rate constants associated with the reac-
tions of 1a -e have been determined. In this paper, we
report factors influencing the reaction mechanism and
regioselectivity as well as the origin of the higher
reactivity shown by alicyclic secondary amines compared
with isobasic primary amines.
Effect of Am in e Na tu r e on Rea ction Mech a n ism
for S-O Bon d F ission . As shown in Table 1, the second-
tot
order rate constants (kN and kNS-O) for the reaction of
2,4-dinitrophenyl benzenesulfonate (1c) with secondary
amines decreases as the amine basicity decreases. The
effect of amine basicity on rates for the S-O bond fission
process is illustrated in Figure 1. The Brønsted-type plot
exhibits a downward curvature, i.e., the ânuc value
decreases from 0.86 to 0.38 as the amine basicity
increases. A similar biphasic Brønsted-type plot has been
demonstrated in Figure 1 for the corresponding reactions
with primary amines.
A change in the RDS has been suggested to be
responsible for such a biphasic Brønsted-type plot, i.e.,
k-1/k2 > 1 for reactions with weakly basic amines,
k-1/k2 ) 1 at pKa°, the center of curvature on the
Brønsted-type plot and k-1/k2 < 1 for reactions with
strongly basic amines.1-4 Thus, the nonlinear Brønsted-
type plot in Figure 1 for the reaction of 1c with secondary
Resu lts
The reaction of 1a -e with secondary amines proceeded
competitively through the S-O and C-O bond fission
pathways as shown in Scheme 1. The S-O bond fission
that yields benzenesulfonamides and 2,4-dinitrophen-
oxide occurred exclusively for the reactions with strongly
basic secondary amines such as piperidine and 3-methyl-
piperidine. On the other hand, the C-O bond fission that
(11) 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. 69, No. 9, 2004 3167

Um et al.
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 (kNtot, kNS-O, a n d kNC-O) for Rea ction s of
2,4-Din itr op h en yl Ben zen esu lfon a te (1c) w ith Alicyclic Secon d a r y Am in es in 80 m ol % H2O/20 m ol % DMSO a t
25.0 ( 0.1 °C
a
b
amine
pKa
101kNtot/M-1 s-1
101kNS-O/M-1 s-1
103kN C-O/M-1 s-1
%
piperidine
3-methylpiperidine
piperazine
morpholine
1-formylpiperazine
piperazinium ion
11.02
10.80
9.85
8.65
7.98
5.95
111 ( 3
111 ( 3
105 ( 1
50.4
8.53
2.11
100
100
97
87
81
105 ( 1
52.0 ( 0.3
9.80 ( 0.08
2.60 ( 0.03
0.181 ( 0.003
160
127
49.0
6.20
0.119
66
a
b
pKa values in 80 mol % H2O/20 mol % DMSO were taken from ref 4f. Percent S-O bond fission.
Effect of Am in e Na tu r e on Rea ction Ra te for th e
S-O Bon d F ission . As shown in Figure 1, secondary
amines are more reactive than isobasic primary amines.
The reactivity of amines has often been reported to
increase as the amine nature changes from primary to
secondary and tertiary amines successively.2a,b,12-14 Since
solvation energy has been reported to decrease in the
order RNH3 > R2NH2 > R3NH+, solvent effect has
generally been suggested to be responsible for the
increasing reactivity order.2a,b,12-14 However, no system-
atic analysis has yet been performed in terms of micro-
scopic rate constants. Therefore, we have evaluated the
microscopic rate constants associated with the reaction
of 1c with secondary amines to investigate the origin of
their enhanced reactivity compared with isobasic primary
amines for the first time.
+
+
rate for S-O bond fission )
k1k2[S][R2NH]/(k-1 + k2) (4)
S-O
kN
) k1k2/(k-1 + k2)
) k1/(k-1/k2 + 1)
F IGURE 1. Brønsted-type plots for the reactions of 2,4-
dinitrophenyl benzenesulfonate (1c) with primary and alicylic
secondary amines for the S-O bond fission process in 80 mol
% H2O/20 mol % DMSO at 25.0 ( 0.1 °C. The solid lines were
calculated by eq 3. Data for the reactions with primary amines
were taken from ref 11.
(5)
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 [R2NH] represent the
concentration of the substrate and the amine studied,
amines has been analyzed using eq 32
log(kNS-O/kN°) ) â2(pKa - pKa°) - log[(1 + R)/2]
where
respectively. As shown in eq 5, a larger kN
value can
S-O
be obtained by increasing k1 or by decreasing k-1
.
S-O
However, k2 cannot affect the kN
value since it has
been reported to be independent of the nature and
basicity of amines.15-17 Thus, the microscopic rate con-
stants (e.g., k1 and k-1/k2) associated with the present
reactions are necessary to investigate the origin of the
log R ) (â2 - â1)(pKa - pKa°)
(3)
S-O
larger kN
value shown by the secondary amines
compared with isobasic primary amines as well as the
reaction mechanism.
The parameters â1 and â2 represent the slope of the
Brønsted-type plot for the reaction with strongly and
weakly basic secondary amines, respectively, while kN°
(12) (a) Terrier F.; Lelievre J .; Chatrousse A. P. J . Chem. Soc., Perkin
Trans. 2, 1985, 1479-1485. (b) Richard, J . P.; J encks, W. P. J . Am.
Chem. Soc. 1984, 106, 1373-1383. (c) Gregory, M. J .; Bruice, T. C. J .
Am. Chem. Soc. 1967, 89, 2327-2330.
S-O
refers to the kN
value at pKa°. The â1, â2, and pKa°
values for the reactions of 1c with secondary amines have
been determined to be 0.86, 0.38, and 9.1, respectively.
Therefore, one can suggest that the reaction of 1c with
secondary amines proceeds through an addition inter-
mediate in which the RDS changes at pKa ca. 9.1 from
breakdown of the intermediate to its formation as the
amine basicity increases. The pKa° value for the reaction
of 1c with primary amines has been reported to be 8.9,11
which is almost the same as that for the reaction of 1c
with secondary amines within an experimental error
range, indicating that the nature of amine (e.g., primary
vs secondary amines) does not affect pKa° significantly.
(13) (a) Bernasconi, C. F.; Hibdon, S. A. J . Am. Chem. Soc. 1983,
105, 4343-4348. (b) Spencer, T. A.; Kendall, M. C. R.; Reingold I. D.
J . Am. Chem. Soc. 1972, 94, 1250-1254.
(14) Castro, E. A.; Saavedra, C.; Santos, J . G.; Umana, M. I. J . Org.
Chem. 1999, 64, 5401-5407.
(15) (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.
(16) (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.
(17) (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.; Kwon, H. J .; Kwon,
D. S.; Park, J . Y. J . Chem. Res., Synop. 1995, 301.
3168 J . Org. Chem., Vol. 69, No. 9, 2004

Reactions of Benzenesulfonates with Alicyclic Secondary Amines
TABLE 2. Su m m a r y of Micr oscop ic Ra te Con sta n ts
Associa ted w ith Rea ction s of 2,4-Din itr op h en yl
Ben zen esu lfon a te (1c) w ith Alicyclic Secon d a r y Am in es
for th e S-O Bon d F ission P r ocess in 80 m ol % H2O/20
m ol % DMSO a t 25.0 ( 0.1 °Ca
amine
pKa
k-1/k2
k1/M-1 s-1
piperidine
3-methylpiperidine
piperazine
morpholine
1-formylpiperazine
piperazinium ion
11.02
10.80
9.85
8.65
7.98
5.95
0.0885
0.113
0.448
1.21
2.56
16.9
12.1
11.7
7.30
1.89
0.743
0.213
a
pKa values in 80 mol % H2O/20 mol % DMSO were taken from
ref 4f.
F IGURE 3. Brønsted-type plots for the reactions of 2,4-
dinitrophenyl benzenesulfonate (1c) with primary and alicylic
secondary amines for the S-O bond fission process in 80 mol
% H2O/20 mol % DMSO at 25.0 ( 0.1 °C. Data for the reactions
with primary amines were taken from ref 11.
primary amines, indicating that the k-1/k2 ratio cannot
be responsible for the higher reactivity of secondary
amines.
As shown in Figure 3, the k1 value increases linearly
as the amine basicity increases for both reactions with
primary and secondary amines. If steric effect plays an
important role, the k1 value is expected to be larger for
the reactions with primary amines compared with those
with secondary amines of similar basicity. However,
unexpectedly, secondary amines exhibit much larger k1
values than primary amines of similar basicity, indicating
that steric effect is insignificant in the present system.
Steric effect would be significant for reactions in which
the extent of bond formation between the electrophilic
center and nucleophile is greatly advanced. The extent
of bond formation in the present system is considered to
be insignificant on the basis of the small â1 value (e.g.,
0.38 and 0.41 for the reactions of 1c with secondary and
primary amines, respectively), which accounts for the
absence of the steric effect in the present system.
Therefore, one can suggest that the larger k1 value for
the reaction with secondary amines is fully responsible
for the higher reactivity shown by secondary amines
compared with the primary amines of similar basicity.
Effect of Non leavin g Gr ou p Su bstitu en ts on Rates
a n d Mech a n ism for th e S-O Bon d F ission . The effect
of nonleaving group substituents on reaction mechanism
is controversial.5f,11,17-20 Castro et al. have suggested that
the electronic nature of the substituent in the nonleaving
group affects the pKa° value for aminolyses of 2,4-
dinitrophenyl and S-4-nitrophenyl X-substituted ben-
zoates in aqueous ethanol.18 A similar conclusion has
F IGURE 2. Brønsted-type plots of log k-1/k2 vs pKa for
reactions of 2,4-dinitrophenyl benzenesulfonate (1c) with
primary and alicylic secondary amines for the S-O bond
fission in 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C.
Data for the reactions with primary amines were taken from
ref 11.
The k-1/k2 ratios associated with the reactions of 1c
with secondary amines have been determined using the
method reported by Castro et al.2 (see also eqs S1-S6 in
the Supporting Information). Equation 5 can be re-
arranged to eq 6, which has allowed us to calculate the
k1 value from k-1/k2 and kNS-O. In Table 2 are sum-
marized the microscopic rate constants (k-1/k2 and k1)
determined in this way.
k1 ) kNS-O(k-1/k2 + 1)
(6)
Table 2 shows that the k-1/k2 ratio increases as the
amine basicity decreases, i.e., k-1/k2 < 1 for pKa g 9.85
while k-1/k2 > 1 for pKa e 8.65, supporting the preceding
proposal that the RDS of the present reaction changes
at pKa ca. 9.1. The effect of amine basicity on the k-1/k2
ratio is illustrated in Figure 2. The Brønsted-type plots
are linear for both reactions with primary and secondary
amines. Interestingly, the k-1/k2 ratio for the secondary
amines is slightly larger than that for the isobasic
(18) (a) Castro, E. A.; Bessolo, J .; Aguayo, R.; Santos, J . G. J . Org.
Chem. 2003, 68, 8157-8161. (b) Castro, E. A.; Santander, C. L. J . Org.
Chem. 1985, 50, 3595-3600. (c) Castro, E. A.; Valdivia, J . L. J . Org.
Chem. 1986, 51, 1668-1672. (d) Castro, E. A.; Steinfort, G. B. J . Chem.
Soc., Perkin Trans. 2 1983, 453-457.
J . Org. Chem, Vol. 69, No. 9, 2004 3169

Um et al.
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 s of 2,4-Din itr op h en yl
X-Su bstitu ted Ben zen esu lfon a tes (1a -e) w ith P ip er id in e
a n d P ip er a zin iu m Ion for th e S-O Bon d F ission in 80
m ol % H2O/20 m ol % DMSO a t 25.0 ( 0.1 °C
It is shown that the second-order rate constant for the
reactions with piperidine decreases as the substituent in
the nonleaving sulfonyl moiety changes from an EWG
to an EDG, i.e., from 49.9 to 11.1 and 5.30 M-1 s-1 as the
substituent X changes from 4-NO2 to H and 4-MeO,
respectively. A similar result can be seen for the corre-
sponding reactions with piperazinium ion, although it is
ca. 103 times less reactive than piperidine.
The effect of sulfonyl substituent X on rates has been
demonstrated in Figure 4. The point for X ) 4-MeO
exhibits a negative deviation from the linear Hammett
plots for both reactions with piperazinium ion and
piperidine. One might consider that a change in the RDS
or mechanism is responsible for the negative deviation
from the linear Hammett plot. However, we have recently
shown that such a negative deviation is not due to a
change in RDS or reaction mechanism but due to
stabilization of the ground-state through resonance be-
tween the electron donating substituent and the sulfonyl
or carbonyl group as shown in resonance structures I T
II and III T IV.4c,11,17a
kNS-O/M-1 s-1
X
piperidine
piperazinium ion
4-NO2
4-Cl
H
4-Me
4-MeO
49.9 ( 0.5
15.1 ( 0.3
11.1 ( 0.3
8.20 ( 0.05
5.30 ( 0.07
(35.5 ( 0.2) × 10-3
(16.5 ( 0.6) × 10-3
(11.9 ( 0.3) × 10-3
(8.84 ( 0.3) × 10-3
(6.70 ( 0.2) × 10-3
If the ground-state resonance stabilization is respon-
sible for the negative deviation shown in Figure 4, one
can expect that the Yukawa-Tsuno equation (eq 7)21
would give much better correlation than the Hammett
equation.
F IGURE 4. Hammett plots for the reactions of 2,4-dinitro-
phenyl X-substituted benzenesulfonates with piperidine (b, the
inset) and piperazinium ion (O) for the S-O bond fission
process in 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C.
log(kX/kH) ) F[σ° + r(σ+ - σ°)]
(7)
been drawn for aminolyses of carbonate, thio, and dithio
esters by J encks19 and Lee et al.20 However, we have
recently reported that the effect of substituent in the
nonleaving group on reaction mechanism is insignificant
for various reactions of aryl benzoates and sulfonates
with amines as well as anionic nucleophiles (e.g., OH-,
CN-, and N3-) in 80 mol % H2O/20 mol % DMSO.5f,11,17
To investigate the effect of nonleaving group substitu-
ent on the reaction mechanism, we have performed
reactions of 2,4-dinitrophenyl X-substituted benzen-
sulfonates (1a -e) with piperidine and piperazinium ion.
One might expect a significant difference in the substitu-
ent effect between the two reaction series since their RDS
is considered to be not the same as discussed in the
preceding section (e.g., the k1 step for strongly basic
piperidine and the k2 step for weakly basic piperazinium
ion).
In fact, the Yukawa-Tsuno plots in Figure 5 exhibit
much better correlation than the Hammett plots in
Figure 4, indicating that the resonance structure II is
responsible for the negative deviation shown by 4-MeO
from the linear Hammett plots. Thus, the present study
further confirms our previous proposal that the electronic
nature of the substituent in the nonleaving group does
not affect the reaction mechanism and the negative
deviation on the Hammett plots is due to ground-state
stabilization through resonance.
The Yukawa-Tsuno equation has been applied to
numerous reaction systems in which a partial positive
charge develops in the transition state of the RDS.21-24
(21) (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.
(22) (a) Fujio, M.; Rappoport, Z.; Uddin, M. K.; Kim, H. J .; Tsuno,
Y. Bull. Chem. Soc. J pn. 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. J pn. 2002, 75, 1371-1379.
(23) (a) Nakashima, T.; Fujiyama, R.; Kim, H. J .; Fujio, M.; Tsuno,
Y. Bull. Chem. Soc. J pn. 2000, 73, 429-438. (b) Nakashima, T.;
Fujiyama, R.; Fujio, M.; Tsuno, Y. Bull. Chem. Soc. J pn. 1999, 72,
1043-1047. (c) Nakashima, T.; Fujiyama, R.; Fujio, M.; Tsuno, Y.
Tetrahedron Lett. 1999, 40, 539-542.
In Table 3 are summarized the second-order rate
constants for the reactions of 1a -e with piperidine and
piperazinium ion determined for the S-O bond fission.
(19) (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.
(20) (a) Oh, H. K.; Ku, M. H.; Lee, H. W.; Lee, I. J . Org. Chem. 2002,
67, 8995-8998. (b) Guha, A. K.; Lee, H. W.; Lee, I. J . Org. Chem. 2000,
65, 12-15.
3170 J . Org. Chem., Vol. 69, No. 9, 2004

Reactions of Benzenesulfonates with Alicyclic Secondary Amines
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-d In itr op h en yl
X-Su bstitu ted Ben zen esu lfon a tes (1a -e) w ith P ip er id in e
a n d P ip er a zin iu m Ion in 80 m ol % H2O/20 m ol % DMSO
a t 25.0 ( 0.1 °C
103kNC-O/M-1 s-1
X
piperidine
piperazinium ion
4-NO2
4-Cl
H
4-Me
4-MeO
a
a
a
a
a
10.0
5.20
6.20
4.16
3.60
a
C-O
The kN
value for reactions with piperidine could not be
determined due to the fact that no detectable C-O bond fission
products were found.
retarded by an EDG. Thus, one might expect a large F
value for a reaction in which nucleophilic attack is the
RDS. However, the rate of leaving group departure (k2)
would be decreased by an EWG in the nonleaving group
but increased by an EDG. Accordingly, one can expect
that the magnitude of the F value would be small for a
reaction in which leaving group departure is involved in
the RDS due to the opposing substituent effect. The F
values in Figure 5 have been determined to be 0.79 and
0.58 for the reactions with piperidine and piperazinium
ion, respectively. As discussed in the preceding section,
the RDS of the present reaction has been suggested to
change from the k2 to the k1 step as the nucleophile varies
from weakly basic piperazinium ion to strongly basic
piperidine. The result exhibiting a larger F for the
reactions with piperidine (0.79) than with piperazinium
ion (0.58), although the difference is not significant, is
consistent with the argument that the nature of the RDS
affects the magnitude of the F value.
F IGURE 5. Yukawa-Tsuno plots for the reactions of 2,4-
dinitrophenyl X-substituted benzenesulfonates with piperidine
(b) and piperazinium ion (O) for the S-O bond fission process
in 80 mol % H2O/20 mol % DMSO at 25.0 ( 0.1 °C.
Since an EDG can stabilize a positively charged transi-
tion state, the point for an EDG in the nonleaving group
has often exhibited
a positive deviation from the
Hammett plot with a negative F value.21-24 Interestingly,
the present reaction system results in an opposite result,
e.g., a negative deviation with a positive F value. How-
ever, the present result is not so surprising but consistent
with our proposal that an EDG in the nonleaving group
stabilizes the ground-state of the substrate as shown in
the resonance structures I T II.
Effect of Am in e Ba sicity a n d Su lfon yl Su bstitu -
The magnitude of the r value in a Yukawa-Tsuno plot
represents a relative extent of resonance contribution.
The r value has been reported to be as large as 1.53 for
solvolysis of 1-aryl-2,2,2-trifluoroethyl tosylates, in which
the resonance demand is significantly high due to the
R-CF3 group.24 The r value for the reactions of 1a -e with
secondary amines has been determined to be in a range
0.45-0.53. A similar r value (0.49-0.57) has recently
been reported for the corresponding reactions with
primary amines,11 indicating that the nature of amine
(primary vs secondary amines) does not affect the r value
greatly. However, the r value for the sulfonyl system
appears to be significantly smaller than that for the
carbonyl system; i.e., the r value has been reported to be
in a range 0.7-1.3 for the reaction of 4-nitrophenyl
X-substituted benzoates with secondary amines in the
same medium as in the present system.4c Thus, one can
suggest that the resonance contribution is much less
significant for I T II than for III T IV. This argument is
consistent with the report that a CdS bond is weaker
than a CdC bond due to inefficient overlap of 2p and 3p
orbitals.25
en t X on Ra te for C-O Bon d F ission . As shown in
C-O
Table 1, the kN
value for the reaction of 1c with
secondary amines increases as the amine basicity in-
C-O
creases up to pKa ) 9.85. However, no kN
value could
be determined for the more basic amines such as piperi-
dine and 3-methylpiperidine since no detectable C-O
bond fission products were found. Consequently, the plot
of log kNC-O vs amine basicity exhibited a poor correlation
(figure not shown). A similar result is shown in Table 4
C-O
(e.g., no kN
values for the reactions of 1a -e with
strongly basic piperidine), indicating that the regio-
selctivity is significantly influenced by the amine basicity.
One can also suggest that the regioselectivity is deter-
mined by the electronic nature of the substituent X from
the result in Table S2 in the Supporting Information
which shows that the percent of the C-O bond fission
increases as the substituent X changes from an EWD to
an EDG.
The magnitude of the kN
C-O
value, shown in Table 4,
for the reaction with piperazinium ion exhibits poor
correlation with the electronic nature of the substituent
X. This is a contrasting result to that obtained for the
S-O bond fission process (e.g., good linear Yukawa-
Tsuno plots as shown in Figure 5). However, a similar
result has recently been reported for the corresponding
The rate of nucleophilic attack (k1) would be acceler-
ated by an EWG in the nonleaving sulfonyl moiety but
(24) Murata, A.; Sakaguchi, S.; Mishima, M.; Fujio, M.; Tsuno, Y.
Bull. Chem. Soc. J pn. 1990, 63, 1129-1137.
(25) (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.
reaction with primary amines,11 indicating that the poor
C-O
correlation of the kN
value with the electronic nature
of the substituent X is common for reactions of 1a -e with
J . Org. Chem, Vol. 69, No. 9, 2004 3171

Um et al.
secondary amines as well as primary amines for the C-O
ary amines is fully responsible for their higher reactivity.
(4) The ground-state stabilization by resonance structures
I T II is responsible for the negative deviation on the
Hammett plots for reactions of 1a -e. However, the
resonance contribution to the ground-state stabilization
is less significant for the sulfonyl system than for the
corresponding carbonyl system. (5) The magnitude of the
kNC-O values exhibits poor correlation with the electronic
nature of the sulfonyl substituent X. The distance effect
and the nature of the reaction mechanism have been
suggested to be responsible for the poor correlation.
bond fission.
One can suggest two plausible explanations for the
C-O
poor correlation of the kN
value with the nature of
substituent X: (1) the distance effect and (2) the nature
of the reaction mechanism. The inductive effect exerted
by the substituent X would diminish with increasing the
distance between the substituent and the reaction site.
As shown in Scheme 1, the substituent X is one atom
farther from the reaction site of the C-O bond fission
than that of the S-O bond fission. Accordingly, one might
expect that the effect of sulfonyl substituent X on rate is
less significant for the C-O bond fission process than
for the S-O bond fission.
Exp er im en ta l Section
Ma t er ia ls. 2,4-Dinitrophenyl X-substituted benzenesul-
fonates (1a -e) were prepared as reported previously.11 Amines
and other chemicals were of the highest quality available and
were recrystallized or distilled before use whenever necessary.
The reaction medium was H2O containing 20 mol % DMSO to
eliminate solubility problems. DMSO was distilled over cal-
cium hydride at a reduced pressure and stored under nitrogen.
Doubly glass distilled water was further boiled and cooled
under nitrogen just before use.
Kin etics. The kinetic studies were performed using a UV-
vis spectrophotometer equipped with a constant-temperature
circulating bath for slow reactions (t1/2 > 10 s) or a stopped-
flow spectrophotometer for fast reactions (t1/2 e 10 s). The
reactions were followed by monitoring the appearance of 2,4-
dinitrophenoxide ion, as an S-O bond fission product. Typi-
cally, the reaction was initiated by adding 5 µL of a 0.02 M
substrate stock solution in CH3CN by a 10 µL syringe to a 10
mm UV cell containing 2.50 mL of the reaction medium and
the amine: [substrate] ) ca. 4 × 10-5 M, [amine] ) ca. (1.5-
95) × 10-3 M. 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 to 1 equiv of standardized HCl
solution to obtain a self-buffered solution. All the transfers of
solutions were carried out by means of gastight syringes.
Concentrations and pseudo-first-order rate constants (kobsd) for
the individual kinetic experiment are given in the Supporting
Information.
One can also suggest that the nature of the reaction
mechanism is responsible for the poor Hammett correla-
tion for the C-O bond fission process. SNAr reactions
have generally been suggested to proceed through a
Meisenheimer complex, in which the formation of the
complex is the RDS in most cases.26,27 When the RDS is
the expulsion of the leaving group from the Meisenheimer
complex, the kNC-O value should increase with increasing
the electron-withdrawing ability of the substituent in the
leaving sulfonyl moiety. However, if the leaving group
departure occurs after the RDS, the nature of the
substituent in the leaving group would not affect the
C-O
kNC-O value significantly. Thus, the result that the kN
value exhibits poor correlation with the nature of sub-
stituent X is consistent with the generally suggested
mechanism that the expulsion of the leaving group (e.g.,
the X-substituted benzenesulfonate in the present sys-
tem) from the Meisenheimer complex occurs rapidly after
the RDS.
Con clu sion s
The present study has allowed us to conclude the
following: (1) The reaction of 1a -e with alicyclic second-
ary amines proceeds through the S-O and C-O bond
fission pathways competitively. The regioselectivity is
governed by the amine basicity and the electronic nature
of the sulfonyl substituent X. (2) The S-O bond fission
proceeds through an addition intermediate with a change
in the RDS at pKa° ) 9.1. The nature of amine (e.g.,
primary vs secondary amines) does not affect the pKa°
value significantly. (3) Secondary amines are more reac-
tive than isobasic primary amines for the S-O bond
fission. The larger k1 value for the reaction with second-
P r od u ct An a lysis. The amount of 2,4-dinitrophenoxide ion
formed during the S-O bond fission process was determined
quantitatively by measuring the optical density with the same
UV-vis spectrophotometer used for the kinetic study. Other
products (e.g., benzenesulfonate, 1-(phenylsulfonyl)piperidine,
and 1-piperidino-2,4-dinitrobenzene) were analyzed by HPLC.
The eluent was 50/50 MeCN/MeOH (v/v) with with 1 mL/min
flow rate.
Ack n ow led gm en t. This work was supported by a
grant (KRF-2002-015-CP0223) from the Korea Research
Foundation. I.H.U. is also grateful for the J SPS fellow-
ship (L-03709) and helpful discussions with Professor
J . M. Dust.
(26) (a) Buncel, E.; Dust, J . M.; Terrier, F. Chem. Rev. 1995, 95,
2261-2280. (b) Smith, M. B.; March, J . March’s Advanced Organic
Chemistry; Wiley & Sons: New York, 2001; pp 850-853.
(27) (a) Buncel, E.; Dust, J . M.; Manderville, R. A.; Tarkka, R. M.
Can. J . Chem. 2003, 81, 443-456. (b) Buncel, E.; Park, K. T.; Dust, J .
M.; Manderville, R. A. J . Am. Chem. Soc. 2003, 125, 5388-5392. (c)
Boubaker, T.; Chatrousse, A. P.; Terrier, F.; Tangour, B.; Dust, J . M.;
Buncel, E. J . Chem. Soc., Perkin Trans. 2, 2002, 1627-1633. (d)
Annandale, M. T.; vanLoon, G. W.; Buncel, E. Can. J . Chem. 1998,
76, 873-883. (e) Dust, J . M.; Manderville, R. A. Can. J . Chem. 1998,
76, 662-671.
Su p p or tin g In for m a tion Ava ila ble: Equations to deter-
mine the k-1/k2 ratio (eqs S1-S6) and Tables S1-S16 for the
results of the kinetic studies for reactions of 1a -e with alicyclic
secondary amines in 80 mol % H2O/20 mol % DMSO at 25.0 (
0.1 °C. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O049812U
3172 J . Org. Chem., Vol. 69, No. 9, 2004