Kinetic study on SNAr reaction of 1-(Y-Substituted-phenoxy)-2,4- dinitrobenzenes with cyclic secondary amines in acetonitrile: Evidence for cyclic transition-state structure

Article abstract of DOI:10.1021/jo5011872

A kinetic study is reported for S_NAr reactions of 1-(Y-substituted-phenoxy)-2,4-dinitrobenzenes (1a-1h) with amines in MeCN. The plots of pseudo-first-order rate constant versus amine concentration curve upward, indicating that the reactions are catalyzed by a second amine molecule. The Br?nsted-type plots for the reaction of 1-(4-nitrophenyl)-2,4- dinitrobenzene (1a) with secondary amines are linear with β_nuc = 1.10 and 0.85 for the uncatalyzed and catalyzed reactions, respectively, while the Yukawa-Tsuno plots for the reactions of 1a-1h with piperidine result in excellent linear correlations with ρ_Y = 1.85 and r = 0.27 for the uncatalyzed reaction and ρ_Y = 0.73 and r = 0.23 for the catalyzed reaction. The catalytic effect decreases with increasing amine basicity or electron-withdrawing ability of the substituent Y in the leaving group. Activation parameters calculated from the rate constants measured at five different temperatures for the catalyzed reaction of 1a with piperidine are ΔH^? = 0.38 kcal/mol and ΔS^? = -55.4 cal/(mol K). The catalyzed reaction from a Meisenheimer complex (MC ^±) is proposed to proceed through a concerted mechanism with a cyclic transition-state rather than via a stepwise pathway with an anionic intermediate, MC^-. Deuterium kinetic isotope effects provide further insight into the nature of the concerted transition state.

Full text of DOI:10.1021/jo5011872

Article
pubs.acs.org/joc
Kinetic Study on SNAr Reaction of 1‑(Y-Substituted-phenoxy)-2,4-
dinitrobenzenes with Cyclic Secondary Amines in Acetonitrile:
Evidence for Cyclic Transition-State Structure
Ik-Hwan Um,* Min-Young Kim, Tae-Ah Kang,† and Julian M. Dust*,‡
†Department of Chemistry and Nano Science and Department of Life Science, Ewha Womans University, Seoul 120-750, Korea
‡Departments of Chemistry and Environmental Science, Grenfell Campus-Memorial University of Newfoundland, Corner Brook,
Newfoundland and Labrador A2H 6P9, Canada
S
* Supporting Information
ABSTRACT: A kinetic study is reported for SNAr reactions of 1-(Y-substituted-
phenoxy)-2,4-dinitrobenzenes (1a−1h) with amines in MeCN. The plots of
pseudo-first-order rate constant versus amine concentration curve upward,
indicating that the reactions are catalyzed by a second amine molecule. The
Brønsted-type plots for the reaction of 1-(4-nitrophenyl)-2,4-dinitrobenzene (1a)
with secondary amines are linear with βnuc = 1.10 and 0.85 for the uncatalyzed and
catalyzed reactions, respectively, while the Yukawa−Tsuno plots for the reactions
of 1a−1h with piperidine result in excellent linear correlations with ρY = 1.85 and r
= 0.27 for the uncatalyzed reaction and ρY = 0.73 and r = 0.23 for the catalyzed
reaction. The catalytic effect decreases with increasing amine basicity or electron-
withdrawing ability of the substituent Y in the leaving group. Activation parameters
calculated from the rate constants measured at five different temperatures for the
catalyzed reaction of 1a with piperidine are ΔH‡ = 0.38 kcal/mol and ΔS‡ = −55.4
cal/(mol K). The catalyzed reaction from a Meisenheimer complex (MC ) is proposed to proceed through a concerted
mechanism with a cyclic transition-state rather than via a stepwise pathway with an anionic intermediate, MC−. Deuterium
kinetic isotope effects provide further insight into the nature of the concerted transition state.
dinitrobenzofuroxan (DNBF) and structural analogues8,9
INTRODUCTION
■
including even more electrophilic substrates,10 according to
Reactions of nucleophiles, charged or neutral, with sufficiently
the Mayr scale of electrophilicity,11 undergo not only aromatic
electron deficient aromatic substrates (activated by one or more
displacement reactions8−10,12 but also Diels−Alder cyclo-
powerful electron withdrawing groups, NO2, SO2CF3,1,2
additions.13,14 Not only has the synthetic versatility of these
F3CSONSO2CF3,2 etc.) that incorporate a leaving group,
electron-poor heteroaromatics been highlighted,15 but the
often proceed via the SNAr mechanism3,4 of nucleophilic
demarcation boundary16 between normal electrophiles such
aromatic displacement. In this mechanism, essentially, attack of
as 1-chloro-2,4,6-trinitrobenzene and superelectrophiles like
the nucleophile at the position bearing the leaving group results
DNBF has been defined by the Mayr scale. For super-
in formation of a σ-bonded adduct, usually termed a
Meisenheimer complex (MC),5 in an addition step. Expulsion,
electrophiles, interest has been stimulated in their dual
reactivity as substrates for SNAr displacements and as dienes/
often rapid, of the leaving group from the MC gives the product
dienophiles in pericyclic reactions.17,18
in the subsequent elimination step. This mechanism advanced
by Bunnett and Zahler3,4 is, therefore, of the addition−
Interest in normal electrophiles in nucleophilic aromatic
displacement19,20 arises partly from studies involving exotic
solvent media,21 including room temperature ionic liquids22
and aqueous surfactant systems, notably with surfactants that
include nucleophilic counterions in the surfactant head-
groups.23
elimination kind.6 We, among others, have noted the similarity
of the SNAr addition to sp2-hybridized aromatic carbon to the
addition of nucleophiles to the carbonyl (and related) sp2-
hybridized carbon centers in esters and derivatives and have
exploited it, through Brønsted analysis, to assess the nature of
the rate-determining step in the reaction of secondary amines
with 2,4-dinitrofluorobenzene in acetonitrile (MeCN).7
With amines, SNAr pathways (Scheme 2) generally involve
nucleophilic attack at C-1, which bears the leaving group, ArO−
1-(Y-substituted phenoxide) in the present study, in a first step
(k1) that generates a zwitterionic Meisenheimer complex, MC .
Interest in the mechanism of nucleophilic aromatic displace-
ment has been aroused in two different ways. First, impetus to
explore further the reactions of electron-deficient aromatics has
come from the finding that highly reactive 10π neutral
heteroaromatic electrophiles (superelectrophiles) such as 4,6-
Received: May 27, 2014
© XXXX American Chemical Society
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Reaction at unsubstituted sites (C-3,5) may occur in
principle,24 but the corresponding Meisenheimer complexes
have not been detected in the current nor previous studies of
the reaction of amines with 1-X-2,4-dinitrobenzenes in
acetonitrile.7,25−27 The zwitterionic complex, MC , may be
deprotonated to give MC− in a second step (k3[NH]) that is
catalyzed by the amine (NH, here), after which the aryloxide is
rapidly expelled to give the product P. Alternatively, the
aryloxide may be ejected from MC in a noncatalytic step to
give the protonated form of the product, PH+, (k2 step) that
yields the same N,N-dialkyl-2,4-dinitroaniline upon deprotona-
tion.
20-fold excess over the substrate concentration. All the
reactions in this study obeyed first-order kinetics; the pseudo-
first-order rate constants (kobsd) were calculated from the
equation ln(A∞ − At) = −kobsdt + C. As shown in Figure 1A,
In the present study, the kinetics of the reaction of a series of
1-(Y-substituted phenoxy)-2,4-dinitrobenzenes (1a−1h) with a
set of secondary amines (shown in Scheme 1) have been
Scheme 1
Figure 1. Plots of kobsd vs [amine] (A) and kobsd/[amine] vs [amine]
(B) for the reaction of 1-(4-nitrophenoxy)-2,4-dinitrobenzene (1a)
with piperidine in MeCN at 25.0 0.1 °C.
the plot of kobsd versus amine concentration curves upward for
the reaction of 1-(4-nitrophenoxy)-2,4-dinitrobenzene (1a)
with piperidine. Similarly curved plots are demonstrated for the
reactions of 1a with all the other amines used in this study and
for those of the 1b−1h series with piperidine in Figures S1A−
S11A in the Supporting Information section. Such curved plots
have often been reported for reactions in which a second amine
molecule behaves as a general base catalyst.7,25,27 Thus, one
might suggest that the SNAr reactions of 1a−1h proceed
through a stepwise mechanism with two intermediates (i.e.,
MC and MC−) as shown in Scheme 2, that is, a catalytic route
to form MC− from MC and thence to product, P, and a
noncatalytic route to yield the product PH+ that equilibrates to
give P.
followed in acetonitrile solvent. The results were analyzed using
Brønsted-type plots, made possible by the publication of the
relevant pKa values for the conjugate acids of the amines in
MeCN.28 We have previously found such an approach useful in
determining the nature of the rate-determining step in reaction
of amines with 1-halo-2,4-dinitrobenzenes.7,25 Although
Brønsted analysis has been widely used for nucleophilic
reactions at CO and related electrophilic centers,29,30 it has
been applied to a more limited extent to SNAr displace-
ments.19,31 The presence of substituents in the 1-aryloxy moiety
of the substrates also permits consideration of the reaction
through the use of Hammett- and Yukawa−Tsuno-type
correlations.
Scheme 2
What emerges from these assessment tools, as well as
activation parameters for the catalytic path, is support for
formation of a cyclic transition state (TS) involving both MC
and another molecule of the amine (k3[NH], Scheme 3).
Within this TS, both deprotonation of MC and protonation of
the aryloxide leaving group occur. A similar pathway in SNAr
displacements, where proton transfer from the aminium moiety
in MC to the leaving group occurs, has been previously
advanced by Rees and Capon.6c In water or mixed aqueous
media Bernasconi6a,b has shown that a base-catalyzed rate
limiting proton transfer from an initially formed zwitterionic
intermediate (MC ) to give the deprotonated intermediate
(MC−, Scheme 2) is rate determining, which rapidly collapses
to product or where intramolecular proton transfer from
nitrogen of MC to the oxygen of aryloxyl leaving group
effectively avoids free ions in solution.4b This could apply to the
uncatalyzed pathway described below.
In low polarity aprotic solvents such as benzene or
cyclohexane, 2,4-dinitroanisole reacts with cyclohexylamine to
give an upward curved plot similar to Figure 1A; however, the
plot comparable to Figure 1B is linear at higher temperatures
but shows downward curvature at lower temperatures. These
results have been attributed by Nudelman and Palleros6d and
Hirst6e to amine dimers in solution that lead to cyclic transition
states including the amine and MC that collapse either to
RESULTS AND DISCUSSION
■
The kinetic study was performed under pseudo-first-order
conditions wherein the amine concentration was kept in at least
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products, P, or to MC . One can derive eq 1 on the basis of the
kinetic results and the reaction mechanism suggested in
Scheme 2. Equation 1 transforms into eq 2 under the
assumption that k−1 ≫ k2 + k3[amine]. Thus, the plot of
kobsd/[amine] versus [amine] is expected to be linear if the
assumption is valid.
(k1k2[amine] + k1k3[amine]2)
(k−1 + k2 + k3[amine])
kobsd
=
(1)
(2)
k
obsd/[amine] = Kk2 + Kk3[amine], where
K = k1/k−1
Figure 2. Brønsted-type plots of Kk2 (A) and Kk3 (B) for the reactions
of 1-(4-nitrophenoxy)-2,4-dinitrobenzene (1a) with a series of cyclic
In fact, as shown in Figure 1B, the plot of kobsd/[amine]
versus [amine] is linear with a large positive intercept for the
reaction of 1a with piperidine. The corresponding plots for the
reactions of 1a with all the other amines studied and for those
of 1b−1h with piperidine are also linear as shown in Figures
S1B−S11B (Supporting Information). This indicates that the
assumption k−1 ≫ k2 + k3[amine] is valid under the reaction
conditions in all cases. Thus, the rate constants for the
noncatalytic and catalytic reactions (i.e., Kk2 and Kk3,
respectively) have been calculated from the intercept and
slope of the linear plots, in turn. The Kk2 and Kk3 values
calculated in this way are summarized in Table 1 for the
reactions of 1a with a series of cyclic secondary amines and in
Table 2 for those of 1a−1h with piperidine.
secondary amines in MeCN at 25.0
numbers is given in Table 1.
0.1 °C. The assignment of
carbonates with quinuclidine, since there is little or no electron
donation from the aminium moiety of T to expel the leaving
group.33 A similar conclusion has been reported by Castro et al.
for aminolyses of ethyl phenyl thionocarbonate,34a methyl 4-
nitrophenyl thionocarbonate,34b 4-methylphenyl 4-nitrophenyl
thionocarbonate,34c and 3-methoxyphenyl 4-nitrophenyl thio-
nocarbonate.34d In these examples, the nucleophilic amine
attacks a CO or CS moiety. However, we,7,25 among
others, have previously drawn the connection between stepwise
reaction of amines at the sp2-hybrized carbon of carbonyls and
at the sp2-hybrized carbon of an electron deficient aromatic
ring, as in the current study.
On the other hand, it is reasonable to expect that the k3 value
in Scheme 2 would not be affected by amine basicity either.
Because a more basic amine would tend to deprotonate the
aminium moiety of MC more rapidly, while the aminium
moiety would equally tend to hold the proton more strongly as
the amine becomes more basic. Accordingly, one might expect
that both k2 and k3 would be independent of amine basicity, if
the current reaction proceeds as shown in Scheme 2. However,
Figure 2 shows that, in fact, the Brønsted-type plot using Kk2
results in a larger βnuc value than that involving Kk3, a clear
indication that k2 is more sensitive to amine basicity than k3.
This is contrary to expectations if the reactions proceed as
proposed in Scheme 2. Thus, one might suggest that the
current catalyzed reaction may not proceed as shown in
Scheme 2.
Table 1. Summary of Kinetic Data for the Reactions of 1-(4-
Nitrophenoxy)-2,4-dinitrobenzene (1a) with a Series of
a
Cyclic Secondary Amines in MeCN at 25.0 0.1 °C
Kk2
Kk3
k3/k2
amines
piperidine
pKa
(M−1 s−1
)
(M−2 s−1
)
(M−1
)
1
2
3
4
18.8
18.6
18.5
17.6
0.300
0.221
0.136
0.0125
2.64
2.25
3.22
0.175
8.80
10.2
23.7
14.0
3-methylpiperidine
piperazine
1-(2-hydroxyethyl)
piperazine
5
morpholine
16.6
0.00132
0.0448
33.9
a
The pKa values in MeCN were taken from refs 25 and 28.
Effect of Amine Basicity on Reactivity and Reaction
Mechanism. As shown in Table 1, the rate constant for the
noncatalytic reactions decreases as the amine basicity decreases,
e.g., Kk2 decreases from 0.300 to 0.00132 M−1 s−1, a greater
than 200-fold decrease in this kinetic term, as the pKa value of
the conjugate acid of the entering amine decreases from 18.8 to
16.6, respectively. The rate constant for the catalytic reactions
also decreases with decreasing the amine basicity, although Kk3
is generally larger than Kk2 for a given amine. It is also notable
that the catalytic effect exerted by a second amine molecule
(i.e., the k3/k2 ratio) decreases with increasing amine basicity.
The effect of amine basicity on the rate constants Kk2 and
Kk3 are illustrated in Figure 2. The Brønsted-type plots exhibit
excellent linear correlations with βnuc = 1.10 for the uncatalyzed
route and βnuc = 0.85 for the catalyzed process, when the rate
constants and pKa values are statistically corrected using p and q
(i.e., p = 2 while q = 1 except q = 2 for piperazine).32 It is
notable that the βnuc value for the catalyzed reaction is clearly
smaller than that for the uncatalyzed reaction.
Effect of Leaving-Group Basicity on Reactivity and
Reaction Mechanism. To obtain further information on the
reaction mechanism, reactions of 1-(Y-substituted-phenoxy)-
2,4-dinitrobenzenes (1a−1h) with piperidine were performed.
The rate constants for the uncatalyzed and catalyzed reactions
are summarized in Table 2. As shown in Table 2, the Kk2 value
decreases as the substituent Y in the leaving group changes
from a strong electron-withdrawing group (EWG) to an
electron-donating group (EDG); for example, it decreases from
0.300 to 0.0191 and 0.00257 M−1 s−1 as the substituent Y
changes from 4-NO2 to 3-Cl and to 4-Me, in turn. The Kk3
value also decreases from 2.64 to 1.18 and 0.499 M−2s−1 as the
substituent Y changes from 4-NO2 to 3-Cl and to 4-Me, in turn.
However, it is notable that the catalytic effect exerted by a
second amine molecule (i.e., the k3/k2 ratio) decreases as the
substituent Y becomes a stronger EWG.
−
Gresser and Jencks have concluded that amine basicity does
not affect k2 for the reactions of aryl 2,4-dinitrophenyl
Hammett plots have been constructed using σY and σY°
constants to examine the reaction mechanism proposed in
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Table 2. Summary of Kinetic Data for the Reactions of 1-(Y-
Substituted-phenoxy)-2,4-dinitrobenzenes (1a−1h) with
Piperidine in MeCN at 25.0 0.1 °C
Y
Kk2/M−1 s−1
Kk3/M−2s−1
k3/k2/M−1
a
a
a
1a
1b
1c
1d
1e
1f
4-NO2
4-CN
4-CHO
4-COMe
3-Cl
0.300 (0.321)
0.105
2.64 (2.03)
2.47
8.80 (6.32)
23.5
0.0627
1.76
28.1
0.0356
1.50
42.1
0.0191
1.18
61.8
4-Cl
0.0143
1.05
73.4
1g
1h
H
0.00459
0.00257
0.577
0.499
126
194
4-Me
a
The rate constants for the reactions with deuterated piperidine.
Figure 4. Yukawa−Tsuno plots for the reactions of 1-(Y-substituted-
phenoxy)-2,4-dinitrobenzenes (1a−1h) with piperidine in MeCN at
25.0
0.1 °C (A) for Kk2 and (B) for Kk3. The assignment of
Scheme 2. One might expect that the Hammett plot of Kk2
with σY constants would result in a better linear correlation
−
numbers is given in Table 2.
than that built with σY° constants, because expulsion of the
charged aryloxide leaving group occurs in the rate-determining
step (RDS) for the uncatalyzed reaction. In contrast, σY−°
constants would exhibit a better Hammett correlation than σY
constants for the catalyzed process, if the reaction proceeds as
shown in Scheme 2. This is because the reaction mechanism
proposed in Scheme 2 describes expulsion of the leaving group
from MC− as occurring in a rapid separate step after the RDS.
As shown in Figure 3, σY° constants result in a marginally
better Hammett correlation (R2 = 0.98) than σY− constants for
0.99 for both) with ρY = 1.85 and r = 0.27 for the uncatalyzed
reaction and ρY = 0.73 and r = 0.23 for the catalyzed reaction.
log kNY/kNH = ρ [σY + r(σY− − σY°)]
°
(3)
Y
The r value in eq 3 represents the resonance demand of the
reaction center or the extent of resonance contribution between
−
the reaction site and the substituent Y, while the term (σY
−
σY°) is the resonance substituent constant that measures the
capacity for π-delocalization of the π-electron acceptor
substituent.37,38 The r value of 0.23 or 0.27 obtained for the
catalyzed or uncatalyzed reactions indicates that a partial
negative charge develops on the O atom of the leaving group,
which can be delocalized to the substituent Y through
resonance interactions. Thus, one can suggest that expulsion
of the leaving group occurs in the RDS although the degree of
the C−OAr bond rupture is advanced only a little in the TS on
the basis of the small r values.
The r value of 0.27 for the uncatalyzed reactions is consistent
with the reaction mechanism proposed in Scheme 2, in which
expulsion of the leaving group occurs in the RDS. However, the
r value of 0.23 for the catalyzed reactions is clearly inconsistent
with the reaction mechanism proposed in Scheme 2 where the
RDS envisaged for the catalyzed reaction is the deprotonation
process to form MC− from MC and where expulsion of the
leaving group from MC− occurs after this RDS. This constitutes
the second piece of evidence that the catalyzed reactions do not
proceed as shown in Scheme 2. Rather, this is consistent with
the Brønsted analysis of the sensitivity of k2 compared with k3
to amine basicity in the preceding section where it was shown
that the catalyzed reactions result in a smaller βnuc value than
the uncatalyzed reactions.
Deduction of Reaction Mechanism. To account for the
kinetic results that expulsion of the leaving group occurs in the
RDS for the catalyzed reactions, we propose that the current
SNAr reaction proceeds as shown in Scheme 3. The new
mechanism proposed in Scheme 3 is that the catalytic process
from MC proceeds through a concerted mechanism with a
cyclic TS as modeled by TSMC rather than through a stepwise
pathway with an anionic intermediate MC−, that is, the second
amine molecule deprotonates from the aminium moiety of
MC as a general base catalyst and simultaneously donates its
proton to the O atom of the leaving group as a general acid
catalyst.
−
Figure 3. Hammett correlations of log Kk2 with σY (A) and σY° (B)
constants for the reactions of 1-(Y-substituted-phenoxy)-2,4-dinitro-
benzenes (1a−1h) with piperidine in MeCN at 25.0 0.1 °C. The
assignment of numbers is given in Table 2.
the uncatalyzed reactions (R2 = 0.97). A similar result has been
demonstrated in Figure S12 in the Supporting Information
section for the catalyzed reactions (i.e., the Hammett plot
constructed with σY° constants results in a slightly better
−
correlation than that using σY constants). However, both
Hammett plots exhibit many scattered points. Thus, one cannot
obtain any conclusive information on the TS structure from
these poorly correlated Hammett plots.
We have previously found that the Yukawa−Tsuno equation,
eq 3, is highly effective to clarify ambiguities in the reaction
mechanism for nucleophilic substitution reactions of various
types of esters with neutral amines,30,35 as well as with anionic
36
nucleophiles (e.g., N3 , CN−, OH−, and CH3CH2O−). Thus,
Yukawa−Tsuno plots have been constructed to probe the
nature of the reaction mechanism. As shown in Figure 4, the
Yukawa−Tsuno plots exhibit excellent linear correlations (R2 >
−
While a similar mechanism involving a TS akin to TSMC
(Scheme 3) has been advanced in nonpolar aprotic solvents,
D
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substituent Y in the leaving group becomes a stronger EWG
(Table 2).
Scheme 3
Deduction of TS Structure from Activation Parame-
ters. To obtain further information on the TS structure,
activation parameters (ΔH⧧ and ΔS⧧) for the reaction of 1a
with piperidine have been calculated from the rate constants
measured at five different temperatures. As shown in Figure S13
in the Supporting Information, the plots of kobsd versus [amine]
curve upward (A), while those of kobsd/[amine] versus [amine]
are linear with positive intercept (B) in all temperatures
studied. Thus, the Kk2 and Kk3 values for the reaction of 1a
with piperidine calculated from the intercept and slope of the
linear plots are summarized in Table 3. As shown in Table 3,
Table 3. Summary of Kinetic Data for the Reactions of 1-(4-
Nitrophenoxy)-2,4-dinitrobenzene (1a) with Piperidine at
Five Different Temperatures
Kk2, M−1 s−1
Kk3, M−2s−1
15.0 °C
20.0 °C
25.0 °C
30.0 °C
0.217
0.258
0.300
0.349
0.409
4.95
2.44
2.54
2.64
rate-limiting proton transfer has been most commonly found in
aqueous or aquatic cosolvent media,6 and the specific base−
general acid route most commonly found in polar aprotic
solvents,3a,4 to the best of our knowledge this is the first
suggestion of such a cyclic six-member transition state in the
catalyzed conversion of MC direct to products in acetonitrile,
a polar aprotic solvent.
2.67
35.0 °C
2.73
ΔH⧧, kcal mol−1
ΔS⧧, cal mol−1 K−1
0.38
−44.3
−55.4
the rate constants increase with increasing reaction temper-
ature. However, the effect of reaction temperature on the rate
constants is almost negligible for the catalyzed reaction; for
example, Kk3 increases from 2.44 to 2.64 and 2.73 M−2 s−1 as
the reaction temperature increases from 15.0 to 25.0 and 35.0
°C, in turn.
The concerted mechanism proposed in Scheme 3 for the
catalyzed process can be further supported by the experimental
results that the βnuc value is smaller for the catalyzed reaction
than for the uncatalyzed reaction and that the k3/k2 ratio
decreases as the amine basicity increases. As mentioned in the
preceding section, the k2 and k3 values would be independent of
amine basicity if the reactions proceed with MC and MC− as
shown in Scheme 2. However, if the catalyzed reactions
proceed via a TS modeled by TSMC (rather than with a discrete
anionic intermediate MC−) as shown in Scheme 3, amine
basicity should affect k3, because the proton transfer from the
second amine molecule to the O atom of the leaving group
would be retarded as a function of increasing amine basicity.
Accordingly, the catalytic effect would decrease as the amine
basicity increases. This argument accounts for the kinetic result
that the k3/k2 ratio decreases as the amine basicity increases
(Table 1) and that the catalyzed reactions result in a smaller
βnuc value than the uncatalyzed reactions (Figure 2).
It is also notable that the k3/k2 ratio decreases as the
substituent Y in the leaving group becomes a stronger EWG
(Table 2) and that the ρY value is much smaller for the
catalyzed reactions than for the uncatalyzed reactions (Figure
4). One might expect a large ρY value for the uncatalyzed
reactions, since the k2 value would increase as the substituent Y
becomes a stronger EWG. In contrast, the k3 value in Scheme 3
would decrease as the substituent Y becomes a stronger EWG.
Because a stronger EWG in the leaving group would retard the
proton transfer from the second amine molecule to the O atom
of the leaving group by decreasing the electron density of the O
atom. Accordingly, the catalytic effect exerted by the second
amine molecule would decrease on changing the substituent Y
in the leaving group from 4-Me to 4-NO2. This idea is
consistent with the kinetic result that the ρY value is much
smaller for the catalyzed reactions than for the uncatalyzed
reactions (Figure 4) and that the k3/k2 ratio decreases as the
The Arrhenius plots illustrated in Figure S14 (Supporting
Information) exhibit excellent linear correlations. Thus, the
activation parameters (ΔH⧧ and ΔS⧧) calculated from the
Arrhenius plots are considered reliable. The ΔH⧧ and ΔS⧧
values shown in Table 3 for the uncatalyzed reaction are 4.95
kcal mol−1 and −44.3 cal mol−1 K−1, respectively. Interestingly,
the ΔH⧧ and ΔS⧧ values for the catalyzed reaction are 0.38 kcal
mol−1 and −55.4 cal mol−1K−1, respectively. This indicates that
the catalyzed reaction is governed almost entirely by the TΔS⧧
term rather than by the ΔH⧧ term. More importantly, the large
negative ΔS⧧ value indicates that the TS for the catalyzed
reaction is highly ordered even in MeCN, which is known to be
a poor solvent for ionic species.39 This is consistent with the
preceding proposal that the catalyzed reaction proceeds
through a cyclic TS structure as modeled by TSMC, in which
the rotational and vibrational degrees of freedom are restricted
to a certain degree. The large negative ΔS⧧ value found for the
catalyzed reaction also supports the preceding argument that
expulsion of the leaving group is advanced only a little in the
TS on the basis of the small r value found in Figure 4.
Further evidence for the cyclic TS has been obtained from
studies of the deuterium kinetic isotope effect (DKIE) for the
reaction of 1a with piperidine and deuterated piperidine. Table
2 shows that Kk2 = 0.321 and Kk3 = 2.03 for the reactions of 1a
with deuterated piperidine (i.e., DKIE < 1 for the uncatalyzed
reaction, while DKIE > 1 for the catalyzed process). The
inverse DKIE for the uncatalyzed reaction is mainly a reflection
of the reduced steric hindrance, since the amplitude of the
stretching vibration of a N−D bond is smaller than that of a
N−H bond. An inverse DKIE is expected for the uncatalyzed
E
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Article
substituted-phenol under the presence of triethylamine in anhydrous
diethyl ether as reported previously.27 The crude products were
purified by short pathway silica gel column chromatography. Their
reaction, since the deprotonation process occurs after the RDS.
The normal DKIE for the catalyzed reaction is consistent with
the proposed mechanism, in which the deprotonation and the
donation of a proton by a second amine molecule occur in the
RDS. However, the DKIE for the catalyzed reaction is 1.30,
which appears to be quite small for a primary DKIE. One might
suggest that the small DKIE for the catalyzed reaction is in
accord with the preceding proposal that the degree of proton
transfer (or C−OAr bond rupture) is advanced only a little in
the TS of RDS on the basis of the small r values found for the
reactions of 1a−1h. Another possible reason that might
account for the small primary DKIE can be found from the
model transition state, TSMC, which is shown in Scheme 3 as
being not only cyclic but symmetrical. In fact, the DKIE results
for the catalyzed pathway suggest that proton transfer either
from the aminium site or to the aryloxyl oxygen site occurs
neither in a linear fashion (which should yield close to a
maximum primary DKIE, that is, ca. 7) nor in the symmetrical
structure shown.40 Proton transfer from the ammonium moiety
to the amine or from the amine to the aryloxyl oxygen occurs in
a nonsynchronous manner. This factor also accounts for the
relatively low DKIE for a rate-limiting process involving proton
transfer.
1
purity was checked by their melting point, H and 13C NMR spectra;
these were in good agreement with literature. Amines and other
chemicals were of the highest quality available and used without
further purification.
Kinetics. Kinetic study was carried out by using a UV−vis
spectrophotometer equipped with a constant-temperature circulating
bath to maintain the reaction temperature at 25.0
0.1 °C. The
reactions were followed by monitoring the appearance of N-(2,4-
dinitrophenyl)amines at a fixed wavelength corresponding to their
maximum absorption (λmax, e.g., 379 nm for N-2,4-dinitrophenyl-
piperidine). All reactions were carried out under pseudo-first-order
conditions in which the concentration of amines was kept at least 20
times greater than that of the substrate. Typically, the reaction was
initiated by adding 5 μL of a 0.01 M of substrate stock solution in
MeCN by a 10 μL syringe to a 10 mm UV cell containing 2.50 mL of
solvent and the amine nucleophile. Reactions were followed generally
up to 9−10 half-lives, and kobsd were calculated using the equation
ln(A∞ − At) = −kobsdt + C. Based on the replicate runs, it is estimated
that the uncertainty in the kobsd values is less than 3%.
Products Analysis. N-(2,4-Dinitrophenyl)piperidine was identi-
fied as one of the products by comparison of the UV−vis spectra at the
end of the reactions with the authentic sample.
Taken in total, the kinetic results analyzed by the Brønsted
treatment, the substituent effect analysis via the Yukawa−
Tsuno correlations, the activation parameters with their large
negative entropy of activation (cf. also Figure S15 in
Supporting Information), and, finally, the DKIE data strongly
support a concerted pathway for breakdown of the MC to
products. This pathway involves a cyclic transition state in
which proton transfer from the aminium moiety to the aryloxyl
oxygen of the leaving group that is expelled simultaneously
occurs through a relay involving another molecule of the
secondary amine. This deprotonation/protonation while
concerted is not synchronous.
ASSOCIATED CONTENT
* Supporting Information
Detailed kinetic conditions and results. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
*E-mail: ihum@ewha.ac.kr.
*E-mail: jmdust@grenfell.mun.ca.
Notes
■
The authors declare no competing financial interest.
CONCLUSIONS
■
ACKNOWLEDGMENTS
■
The current study has allowed us to conclude the following: (1)
The curved plots of kobsd versus [amine] indicate that the
current SNAr reactions are catalyzed by a second amine
molecule. (2) The Brønsted-type plots for the reactions of 1a
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (Grant 2012-R1A1B-3001637). J.M.D. thanks
Grenfell Campus-Memorial University (Vice-President’s Re-
search Fund) for support and Dr. D-R. Parkinson for valuable
discussions.
with a series of cyclic secondary amines are linear with βnuc
=
1.10 and 0.85 for the uncatalyzed and catalyzed reactions,
respectively. (3) The Yukawa−Tsuno plots for the reactions of
1a−1h with piperidine result in excellent linear correlations
with ρY = 1.85 and r = 0.27 for the uncatalyzed reaction and ρY
= 0.73 and r = 0.23 for the catalyzed reaction, indicating that
expulsion of the leaving group occurs in the RDS although the
C−OAr bond rupture is advanced only a little. (4) The catalytic
effect decreases as the amine becomes more basic or the
substituent Y becomes a stronger EWG. (5) The catalyzed
reaction from MC proceeds through a concerted mechanism
with a cyclic TS as modeled by TSMC rather than via a stepwise
pathway with the anionic MC−. The cyclic transition state is
unlikely to be symmetrical, however, and DKIE data suggest
that the proton transfers are not synchronous in TSMC. (6) The
large negative ΔS⧧ value with a small ΔH⧧ value is consistent
with the cyclic TS structure, in which expulsion of the leaving
group is advanced only a little.
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