Mechanistic assessment of SNAr displacement of halides from 1-Halo-2,4-dinitrobenzenes by selected primary and secondary amines: Br?nsted and Mayr analyses

Article abstract of DOI:10.1021/jo301862b

Pseudo-first-order rate constants (k_obsd) have been measured spectrophotometrically for nucleophilic substitution reactions of 1-X-2,4-dinitrobenzenes (1a-d, X = F, Cl, Br, I) with various primary and secondary amines in MeCN and H₂O

Full text of DOI:10.1021/jo301862b

Article
pubs.acs.org/joc
Mechanistic Assessment of S Ar Displacement of Halides from
N
1
‑Halo-2,4-dinitrobenzenes by Selected Primary and Secondary
Amines: Brønsted and Mayr Analyses
†
,†
Ik-Hwan Um,* Li-Ra Im, Ji-Sun Kang, Samantha S. Bursey, and Julian M. Dust*
Department of Chemistry and Division of Nano Sciences, 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: Pseudo-first-order rate constants (kobsd) have been
measured spectrophotometrically for nucleophilic substitution reac-
tions of 1-X-2,4-dinitrobenzenes (1a−d, X = F, Cl, Br, I) with various
primary and secondary amines in MeCN and H O at 25.0 ± 0.1 °C.
2
The plots of kobsd vs [amine] curve upward for reactions of 1a (X = F)
with secondary amines in MeCN. In contrast, the corresponding plots
for the other reactions of 1b−d with primary and secondary amines in
MeCN and H O are linear. The Brønsted-type plots for reactions of 1a−d with a series of secondary amines are linear with β
=
2
nuc
1
.00 for the reaction of 1a and 0.52 ± 0.01 for those of 1b−d. Factors governing reaction mechanisms (e.g., solvent, halogen
atoms, H-bonding interactions, amine types) have been discussed. Kinetic data were also analyzed in terms of the Mayr
nucleophilicity parameter for the amines with each aromatic substrate. Provisional Mayr electrophilicity parameter (E) values for
1
-X-2,4-dinitrobenzenes have been determined: E = −14.1 for X = F, E = −17.6 for X = Cl and Br, and E = −18.3 for X = I.
These values are consistent with the range and order of E values for heteroaromatic superelectrophiles and normal 6-π aromatic
electrophiles.
INTRODUCTION
regioselectivity in MC formation is of interest with more highly
activated (i.e., electron-deficient) aromatics, MC-3,5 (not
■
25
1
−4
Nucleophilic displacement of halides from aromatic
and
5
,6
shown) have not been observed in our previous study in
heteroaromatic substrates, typically activated by one or more
26
7
,8
acetonitrile nor in similar investigations of amine reactions
powerful electron-withdrawing groups (e.g., NO , SO CF
2
2
3,
23,27
8
with related substrates.
F CSONSO CF , etc.), generally proceeds according to the
3
2
3
7
−11
Deprotonation of the zwitterionic adduct MC-1-Z leads to
the neutral Meisenheimer complex MC-1 and, then, to the
S Ar mechanism.
There has been considerable interest in
N
investigations of nucleophilic reactions of the highly reactive
0π neutral electrophiles, such as 4,6-dinitrobenzofuroxan
and structural analogues,
definitively classified as superelectrophiles on the Mayr
1
2,13
product dinitroaniline, DNA, in a k step involving expulsion of
3
1
−
1
4−16
the leaving group, X , a halide in the present study. If the k
3
many of which have been
15
step is rate limiting then catalysis by excess amine may be
observed. In principle, the inverse process involves loss of the
leaving group from MC-1-Z to give the conjugate acid of the
1
7
electrophilicity, E, scale. On the other hand, there has been
an equivalent surge of interest in nucleophilic aromatic
displacement reactions with more standard nitroaromatic
electrophiles but under more exotic conditions of me-
+
final product, DNAH , which rapidly equilibrates to favor the
final DNA in the basic reaction medium. Alternatively, proton
transfer may occur in MC-1-Z from the aminium cationic
moiety to the halide leaving group in a concerted fashion,
collapsing the two steps of proton transfer and loss of the (now
partly protonated) leaving group into a single step. For
simplicity, Scheme 1 does not show this possibility; it can be
imagined as following a diagonal line from MC-1-Z to DNA, a
1
8
dium such as the use of room temperature ionic liquids
1
9
for the reaction medium −or of stabilizing complexants such
2
0
21
as cavitands. Improved methods of stereoselective reaction,
of incorporation of these nucleophilic aromatic substitution
22
steps in cascade or tandem sequences, and in the preparation
of electrophilic derivatives of water-soluble polymers
2
3,24
have
11
single step.
been realized using S Ar displacements.
N
The similarity in the nucleophilic addition step in S Ar
The generally accepted pathways of S Ar reaction between
amines and 1-X-2,4-dinitrobenzenes are summarized in Scheme
N
N
displacement and the addition to carbonyl, CO, step in ester
decomposition, for example, is apparent. In both cases, addition
1
. In the first step (k ), nucleophilic attack at C-1 that bears the
1
leaving halide, X, results in formation of the zwitterionic σ-
bonded (Meisenheimer) complex, MC-1-Z. While reaction at
unsubstituted sites (C-3, C-5) may occur in principle, and
Received: August 29, 2012
Published: October 1, 2012
©
2012 American Chemical Society
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Scheme 1
RESULTS AND DISCUSSION
■
Reactions of 1-X-2,4-dinitrobenzenes 1a−d with amines were
monitored spectrophotometrically, and rate constants were
measured under pseudo-first-order conditions with the
concentration of amines maintained in greater than 20-fold
excess relative to substrate concentration. All reactions obeyed
first-order kinetics. Pseudo-first-order rate constants (kobsd
)
were calculated from the equation ln (A − A ) = −kobsdt + C.
∞
t
On the basis of duplicate runs, the uncertainty in the rate
constants is estimated to be less than ±3%. The kobsd values
together with detailed reaction conditions are summarized in
Tables S1−S46 in the Supporting Information.
As shown in Figure 1, the plot of k
vs [amine] for the
obsd
reaction of 1a with diethylamine in MeCN curves upward as a
Figure 1. Plots of kobsd vs [RR′NH] for the reaction of 1a with
diethylamine in MeCN and in H O (inset) at 25.0 ± 0.1 °C. The solid
2
line for the reaction in MeCN was calculated by eq 1.
2
3
to the sp carbon leads to rehybridization to sp to produce a
tetrahedral intermediate. Elimination of the leaving group in
function of increasing amine concentration but is linear for the
corresponding reaction carried out in H O (inset, Figure 1). A
2
2
subsequent step(s) restores the sp center. A fundamental
difference is that addition to a typical electron-deficient
aromatic substrate in an S Ar reaction entails loss of
aromaticity in the formation of the Meisenheimer intermediate;
aromaticity is regained upon expulsion of the leaving group. In
our previous paper concerning S Ar displacement we applied
Brønsted analysis to assess the rate-determining mechanistic
step. Although this tool has been used extensively for
similar upward curvature has been obtained for the reactions of
1
a with the other secondary amines employed in this study in
N
MeCN, e.g., Figure 2A for the reaction with diallylamine (and
Figures S1A and S2A for the reactions with N-methylbenzyl-
amine and diethanolamine, respectively, in the Supporting
Information). Since the upward curvature shown in Figure 1 is
typical of reactions reported previously to proceed through a
rate-limiting proton transfer (RLPT) mechanism, one can
suggest that the reaction of 1a with the secondary amines
examined in MeCN proceeds via two intermediates (i.e., a
zwitterionic adduct MC-1-Z and its deprotonated form MC-1)
as shown in Scheme 1.
N
2
6
2
8−31
nucleophilic reaction at CO,
its application to S Ar
N
3
2
reactions has been more modest.
The current work extends our study from aminolysis with
secondary amines and 1-fluoro-2,4-dinitrobenzene (DNFB) in
acetonitrile to aminolysis using various primary and secondary
amines with the full series of 1-X-2,4-dinitrobenzenes, where X
In contrast, the plots for the corresponding reactions of 1a
with primary amines and those for the reactions of the other 1-
X-2,4-dinitrobenzenes (X = Cl, Br, I, i.e., 1b−d) with secondary
and/or primary amines in MeCN are linear and pass through
=
F, Cl, Br, and I. The kinetic results will be dissected into the
appropriate microscopic constants, and these rate constants will
be considered using Brønsted analysis and also for selected
amines used in this study by application of the Mayr
nucleophilicity parameter, N. The Mayr analysis confirms
our assessment of the rate-determining steps involved with each
substrate and permits us to define the electrophilicity
parameter, E, for the 1-X-2,4-dinitrobenzene series. The utility
of the Mayr E and N equation for prediction of reaction rate
constants may be further expanded through the approximate E
values determined in the current work.
the origin. Moreover, the reactions of 1a−d in H O show linear
2
plots (e.g., the inset of Figure 1 for the reaction of 1a with
17
diethylamine), indicating that the rate-limiting deprotonation
process by a second amine molecule (i.e., the k step in Scheme
3
1) is absent for these reactions.
Accordingly, the second-order rate constants (k ) for these
1
reactions have been determined from the slopes of the linear
plots of kobsd vs [amine], and summarized in Table 1 together
with the k values for the reactions of 1a with cyclic and acyclic
1
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Figure 2. Plots of kobsd vs [diallylamine] (A) and kobsd/[diallylamine] vs [diallylamine] (B) for the reaction of 1a with diallylamine in MeCN at 25.0
0.1 °C.
±
−1 −1
Table 1. Summary of Second-Order Rate Constants (k /M s ) for Reactions of 1-Halo-2,4-dinitrobenzenes 1a−d with Amines
1
a
in MeCN and H O (in Parentheses) at 25.0 ± 0.1 °C
2
/M−
1 −1
k s
1
b
amine
pKa
N
1a
1b
1c
1d
c
1
2
3
piperidine
piperazine
18.8
18.5
17.6
17.35
380 (8.20)
0.558 (0.0432)
0.607
0.583 (0.0472)
0.692
0.167 (0.0179)
0.181
c
394
c
1-(2-hydroxyethyl)
piperazine
41.9
0.101
0.105
0.0317
c
4
5
6
7
8
9
0
1
2
1-formylpiperazine
morpholine
17.0
16.6
18.75
11.1
0.0653
0.0779
0.0210
c
15.65
15.10
17.8
0.0412
0.0418
5.58 × 10−3 (4.59 × 10−4
0.0122
1.57 × 10−3 (1.30 × 10−4
4.17 × 10− (3.36 × 10−4
3
)
)
)
)
diethylamine
3.54 (0.496)
0.897
18.2
10.2
8.61 (0.432)
)
diallylamine
N-methylbenzylamine
diethanolamine
n-butylamine
1.48 × 10 (9.27 × 10−4
−2
1.42 × 10 (1.09 × 10−3
−2
5.53 × 10 (4.50 × 10−4
−3
)
1
1
1
18.26
18.22
16.70
15.27
15.11
14.29
−
3
3
−2
−3
n-propylamine
benzylamine
8.05
1.83
9.46 × 10
1.67 × 10
1.06 × 10
2.01 × 10
2.47 × 10
6.60 × 10
−
−3
−4
a
b
c
pK data in MeCN were taken from refs 31b and 33a−e. N values were taken from ref 17. k values were taken from ref 26.
a
1
secondary amines (i.e., amines 1−9 in Table 1) in MeCN for
kobsd/[RR′NH] = Kk + Kk [RR′NH], where K = k /k
2
3
1
−1
(2)
comparison purposes. The k values for the reactions of 1a with
1
the acyclic secondary amines have been determined as follows.
Dissection of kobsd into Microscopic Rate Constants
In contrast, the plot of kobsd/[RR′NH] vs [RR′NH] for the
reaction with diethylamine is linear only up to ca. 0.04 M
(
k , k /k , and k /k Ratios for 1a. On the basis of the
1
2
−1
3
−1
Figure S3A in the Supporting Information) but curves
kinetic results and the mechanism proposed in Scheme 1, the
pseudo-first-order rate constant (kobsd) can be expressed as eq 1
for the reactions of 1a with the secondary amines in MeCN,
where [RR′NH] represents the concentration of amines.
Equation 1 may be simplified to eq 2 under the assumption,
k−1 ≫ k + k [RR′NH]. Accordingly, the relationship of kobsd/
downward as the concentration of amine increases further,
indicating that the above assumption is invalid for the reaction
with diethylamine in the high concentration region. However,
this is not surprising since the term k
increasing amine concentration. Understandably, then, when
the amine concentration is high enough, in fact: k
k [RR′NH]. Then, eq 1 simplifies to eq 3. As shown (Figure
3
[RR′NH] increases with
3
2
3
[
RR′NH] vs [RR′NH] would be expected to be linear if the
2
≪
reactions proceed as indicated by Scheme 1. In fact, as shown in
Figure 2B, the plot of kobsd/[RR′NH] vs [RR′NH] is linear up
to ca. 0.13 M for the reaction with diallylamine. Similar results
have been obtained for the reactions of 1a with the other
secondary amines (Figures S1B and S2B, Supporting
Information, for the reactions with N-methylbenzylamine and
diethanolamine, respectively).
S3B in the Supporting Information), the plot of [RR′NH]/kobsd
vs 1/[RR′NH] is linear in the region where the amine
concentration exceeds 0.04 M but exhibits downward curvature
as the amine concentration decreases. Considering the plot in
terms of two distinct regions permits extraction of 1/k
Kk values from the intercept and slope of the linear part of the
curvilinear plots, respectively. More reliable values of k and
and 1/
1
3
1
2
kobsd = (k k [RR′NH] + k k [RR′NH] )
then k /k−1, k /k−1 ratios have been determined through
2 3
1 2
1 3
nonlinear least-squares fitting of eq 1 to the experimental data
using the 1/k and 1/Kk values obtained above as input values
/
(k + k + k [RR′NH])
(1)
−
1
2
3
1
3
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Table 2. Summary of Microscopic Rate Constants for the Reactions of 1-Fluoro-2,4-dinitrobenzene 1a with Secondary Amines
a
in MeCN at 25.0 ± 0.1 °C
k (M− s−1
1
)
k2/k−1
Kk (M s−1
−1
)
k3/k−1 (M−1
)
Kk (M s−1
−2
)
amine
1
2
3
1
2
3
4
5
6
7
8
9
piperidine
piperazine
380
0.293
111
50.3
42.5
32.0
32.3
5.74
10.3
0.877
4.36
0.148
19000
16700
1340
359
394
0.137
54.0
1-(2-hydroxyethyl) piperazine
1-formylpiperazine
morpholine
41.9
11.1
17.8
3.54
0.897
18.2
10.2
0.182
7.63
0.180
2.00
0.0400
0.298
0.712
1.05
102
diethylamine
36.5
diallylamine
0.00530
0.0639
0.0110
0.00475
1.16
0.787
79.4
N-methylbenzylamine
diethanolamine
0.112
1.51
a
The data for the reactions with amines 1−5 were taken from ref 26. The k , k /k , and k /k ratios for the reactions with amines 6−9 were
1
2
−1
3
−1
determined from nonlinear least-squares fitting of eq 1.
for the reactions with all the secondary amines studied. The
microscopic rate constants determined in this way are
summarized in Table 2.
The energy barrier for the k process (i.e., departure of the
2
+
leaving group from MC-1-Z to give DNAH ) is expected to be
−
strongly dependent on the nucleofugality of the leaving X ion.
In contrast, the energy barrier for the k process (i.e., to form
MC-1 from MC-1-Z) should be little influenced by the nature
3
[
RR′NH]/kobsd = 1/k + 1/Kk [RR′NH]
(3)
1
3
of X. Besides, the energy barrier for the k process would be
3
As shown in Table 2, k /k ≪ 1 for the reactions of 1a with
2
−1
independent of amine basicity, since a more basic amine would
deprotonate more rapidly the aminium moiety of MC-1-Z but,
conversely, the aminium ion would tend to hold the proton
more strongly as the amine becomes more basic. Thus, the
amines 7−9, indicating that the assumption k ≫ k +
−1
2
k [RR′NH] is valid. This accounts for the linear plots of k
/
3
obsd
[
RR′NH] vs [RR′NH] (Figure 2B and Figures S1B, S2B in the
Supporting Information). In contrast, k /k = 0.298 for the
2
−1
reaction mechanism (i.e., presence or absence of the k process)
3
reaction with diethylamine, implying that the assumption k−1
k + k [RR′NH] is invalid in the high amine concentration
would be mainly governed by the nucleofugality of the leaving
≫
2
3
−
X ion.
region. This explains why the plot of k /[RR′NH] vs
obsd
Figure 3 illustrates a qualitative comparative energy profile
where reaction would proceed through MC-1-Z to MC-1 if the
energy barrier for the k process is higher than that for the k
[
RR′NH] (Figure S3A in the Supporting Information) curves
downward when the concentration of diethylamine exceeds
0
.04M.
2
3
path. Note that a concerted path where HX is lost in a single
step is not portrayed in Figure 3, for simple clarity. On the
contrary, the reactions would proceed through MC-1-Z to
Reactions of 1a with Secondary Amines in MeCN. As
discussed above on the basis of the upward curvature in the plot
of kobsd vs [amine] (e.g., Figure 1), reaction of 1a with the
secondary amines (cyclic or acyclic) studied in MeCN plausibly
proceeds through two intermediates (i.e., a zwitterionic adduct
MC-1-Z and its deprotonated form MC-1). In contrast, such a
deprotonation process is absent for the reactions of the other 1-
X-2,4-dinitrobenzenes (i.e., X = Cl, Br, I, 1b−d) with the same
secondary amines in MeCN, indicating that the nucleofugal
+
+
DNAH if the energy barrier to form DNAH from MC-1-Z is
−
lower than that to form MC-1. Since F ion is known to be an
extremely poor nucleofuge in dipolar aprotic solvents such as
MeCN or DMSO, where this hard anionic leaving group would
be expected to be highly destabilized in the aprotic solvent, the
energy barrier for the k process is reasonably higher for the
2
reaction of 1a compared to that for the reactions of 1b−d. This
idea accounts for the current results, namely, that the reaction
of 1a with secondary amines in MeCN proceeds through the
(
i.e., atom) effect on the reaction mechanism is significant.
To account for our finding that the nature of the nucleofuge
governs the presence/absence of the deprotonation process, a
RLPT mechanism while the k process is absent for the
qualitative energy profile is illustrated in Figure 3 for the
3
+
processes from MC-1-Z to DNAH and MC-1 (cf., Scheme 1).
corresponding reactions of 1b−d. On the other hand, the
energy barrier for the k process is expected to be lowered for
2
−
reaction of 1a in H O, since the nucleofugality of F ion in
2
water, where H-bonding provides stabilization, is not as poor as
that in the aprotic solvent. This idea is consistent with the fact
that the k process is absent for reaction of 1a with secondary
3
amines in H O.
2
Effect of Amine Nature on Reaction Mechanism. Our
previous study has shown that the reaction of 1a with the cyclic
secondary amines (i.e., amines 1−5 in Table 1) in MeCN
26
proceeds via the k path regardless of amine basicity. The
3
reaction of 1a with acyclic secondary amines (amines 6−9)
employed in this study in MeCN also exhibit upward curvature
in the plots of kobsd vs [amine]. Thus, one can suggest that the
reaction of 1a with secondary amines (either cyclic or acyclic)
in MeCN proceeds through the k path. In contrast, the linear
3
Figure 3. Qualitative comparative energy profile for the process from
MC-1-Z to DNAH and MC-1.
plots of kobsd vs [amine] for the reactions of 1a with primary
amines in MeCN indicate that the reactions proceed without
+
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intervention of the k process. Clearly, the current study
highlights the importance of the nature of amines (i.e., primary
and secondary amines) that governs the presence or absence of
corresponding reactions of 1b−d, i.e., β = 1.00 for 1a and
3
nuc
0.53 or 0.52 for 1b−d. The β value of 1.00 is consistent with
nuc
the proposed mechanism for the reactions of 1a in MeCN, in
which bond formation at the rate-determining step (RDS) is
fully advanced. In contrast, the βnuc value of 0.53 or 0.52 for
reaction of 1b−d indicates that bond formation in the
transition state of the RDS is not much advanced. The small
βnuc value is consistent with the preceding argument that the
reactions of 1b−d proceed through a rate-determining
the k process for the reactions of 1a in MeCN.
3
Since the F atom can form H-bonds, one can propose that
intramolecular H-bonding structures as modeled by I, II, and III
are possible for the reactions of 1a. It is apparent that such H-
bonding interactions would be expected to be more significant
for reactions in MeCN than in H O. The 4-membered H-
2
bonded structures can stabilize the transition state (or
formation of MC-1-Z (k , Scheme 1), in which bond formation
1
−
intermediate) and would assist the nucleofugality of F ion.
at the RDS is partially advanced, on the basis of the fact that the
k3 process in Scheme 1 is absent. Thus, the difference in the
βnuc value for the reaction of 1a−d also supports the proposed
mechanisms.
Accordingly, the energy barrier for the k process shown in
2
Figure 3 would decrease through the H-bonding interaction.
Note that the Brønsted-type plot that was previously
reported for aminolysis of 1a with amines 1−5 (Table 1) in
26
H O also had a slope, β , of 0.52, which was taken as
2
nuc
evidence for rate-limiting formation of MC-1-Z. The similarity
of βnuc for aminolysis of 1a in H O and β for 1b−d in MeCN
2
nuc
suggests that all of these systems involve rate-determining
amine attack on the various substrates, where the rate-
determining step is dependent on the solvent.
Effect of Electronegativity of Halogens on Reactivity.
As shown in Table 1, regardless of the nature of amine and
medium, the reactivity of 1-X-2,4-dinitrobenzenes 1a−d
increases as X becomes more electronegative (i.e., F > Cl ≈
Br > I), which is opposite to the reactivity order expected from
the nucleofugality of the leaving X− ions. The effect of
electronegativity of X on reactivity is illustrated in Figure 5 for
Understandably, intramolecular H-bonding would be more
facile for the reaction with primary amines (e.g., II) than for
that with secondary amines (e.g., I) on a simple statistical basis,
since the former has two hydrogens to engage in H-bonding.
Furthermore, the reactions with primary amines can also
involve H-bonding between the H atom of the aminium ion
moiety and the negatively charged O atom of the nitro group at
2
-position (e.g., III), which would cause further stabilization of
the transition state (or intermediate). This idea can explain why
the k process is absent for the reactions with the primary
3
amines.
Analysis of Brønsted-Type Plots. As shown in Figure 4,
the Brønsted-type plots are all linear for the reactions of 1a−d
with structurally similar amines 1−5, when the k and pK
1
a
values are corrected statistically using p and q (i.e., p = 2 and q
34
=
1 except q = 2 for piperazine). Interestingly, the βnuc value
for the reactions of 1a is significantly different from that for the
Figure 5. Plots of log k vs electronegativity of X for reactions of 1a−d
1
with piperidine in MeCN (●) and H O (○) at 25.0 ± 0.1 °C. Note
2
that the k values for the reaction of 1a in MeCN are used in the
1
correlation.
the reactions of 1a−d with piperidine. One can see linear
correlations between the reactivity and electronegativity of X
(
except X = Cl, which exhibits a negative deviation from
linearity) for both reactions in MeCN and H O, although 1a−d
2
are more reactive in the aprotic solvent than in water. Similar
results are obtained for the reactions with diethylamine and n-
butylamine.
Figure 4. Brønsted-type plots for reactions of 1a−d with cyclic
One would expect the opposite result for reactions in which
departure of the leaving group occurs in the RDS, since the
secondary amines 1−5 in MeCN at 25.0 ± 0.1 °C: 1a (●, β = 1.00),
nuc
1
b (■, β = 0.53), 1c (○, β = 0.53), 1d (◊, β = 0.52). Note that
nuc nuc nuc
−
−
−
−
leaving-group ability increases in the order F < Cl < Br < I .
Accordingly, the fact that the reactivity increases with
the k k /k values (taken from Table 2) for the reaction of 1a are
1
3
−1
used in the Brønsted-type correlation with q = 4 for piperazine. The
assignment of numbers is given in Tables 1 and 2.
−
decreasing nucleofugality of X ions indicates that expulsion
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The Journal of Organic Chemistry
Article
of the leaving group occurs after the RDS. This is consistent
with the preceding argument that the reactions of 1b−d
proceed through a rate-determining formation of MC-1-Z on
the basis of the βnuc value of 0.53 or 0.52 and absence of the k3
process.
Figure 5 shows that the reactions in MeCN result in a larger
slope in the plot of log k vs electronegativity than those in
1
H O, indicating that the effect of electronegativity of X on
2
reactivity is more sensitive for the reactions in the aprotic
solvent than for those in water. This is consistent with the
report that electronic effects become more significant as the
medium polarity decreases, e.g., the ρ value for dissociation of
benzoic acids in H O is 1.00 but was reported to be 1.96 and
2
35
2
.4 in ethanol and MeCN, respectively.
Mayr Analysis. Assignment of the Electrophilicity, E,
for the 1-X-2,4-Dinitrobenzenes. The Mayr group has
defined an equation whereby absolute nucleophilicities and
electrophilicities, assigned the symbols N and E, respectively,
may be defined from rate constant data:
Figure 6. Plot of log k1 vs N for the reactions of 1-fluoro-2,4-
dinitrobenzene 1a with amines in MeCN at 25.0 ± 0.1 °C. The
assignment of numbers is given in Table 1.
log k = s(E + N)
(4)
The defining eq 4 uses rate constant data measured at 20 °C
and is only valid for second-order rate constants with values
similar in value (ca. 0.8) as might be expected in reactions
where the only change in the electrophile stems from changing
F in 1a to Cl in 1b and so forth.
8
−1 −1
17,36
≤
10 M
s
(i.e., below the region of encounter-control).
The slope parameter, s, and the N value characterize
nucleophilicity. Normally, only the E value is required to
The values of the electrophilicity parameters, E, determined
as outlined above are, for each 1-X-2,4-dinitrobenzene: E =
−14.1 for X = F, E = −17.6 for X = Cl and Br, and E = −18.3
for X = I. These values, albeit provisional ones, are nonetheless
consistent with values recently assigned to other electrophiles
that engage either in Meisenheimer adduct formation or in
SNAr displacement reactions. Thus, the standard benchmark
normal (6π electron) aromatic electrophile in Meisenheimer
complexation is 1,3,5-trinitrobenzene (TNB) with an E value of
describe electrophilicity in a reaction. For S 2 displacements a
N
further term, s, specific to the electrophile (as is E) has been
37a
shown to be required. (Recently, the Mayr group has also
defined a nucleofugality parameter for fluoride ion in protic
37b
solvents or mixed solvents with a protic component.)
Normally, the N parameter is defined via eq 4 as the x
intercept when log k has the value 0 (i.e., N = −E at this
3
6b
point).
The essential form of this linear free energy
12
relationship (LFER) is made more obvious after expanding
the equation:
−13.19. The most reactive of the 1-X-2,4-dinitrobenzene
series is the 1-fluoro derivative with an approximate E value of
−
14.1. It is reasonable that 1-fluoro-2.4-dinitrobenzene be less
log k = sN + sE
(5)
electrophilic than TNB, but it is equally sound that it is the
most electrophilic of the 1-X-2,4-dinitrobenzene series.
Electrophiles that engage in Meisenheimer adduct forma-
If kinetic data for a single electrophile (invariant E value) are
plotted against N for a series of nucleophiles, namely the
primary and secondary amines of the present work where the N
values are known, then the slope of the line (if linearity is good)
provides the sensitivity of the reaction to nucleophilicity, s, as
the slope. The N values for the amines used were available from
the extensive tabulated data at the Web site maintained by the
tion/S Ar displacement may be profitably divided into
superelectrophiles, such as 4,6-dinitrobenzofuroxan
(DNBF),
also by the 1-X-2,4-dinitrobenzene series of this work.
The basis of the demarcation between the two classes of
electrophiles is the Mayr electrophilicity parameter, E.
Superelectrophiles have E values less negative that −8;
DNBF has a electrophilicity of −5.06 on the Mayr scale,
while the even more electrophilic 4,6-dinitrotetrazolo[1,5-
a]pyridine has become the new standard for superelectrophiles
with an E value of −4.67. Superelectrophiles are not only
highly reactive in Meisenheimer complex formation/S Ar
N
3
8,39
and normal electrophiles typified by TNB, but
3,4,14,15b
1
7c
36
Mayr group. Since E is a constant and the slope, s, is constant
for a good linear plot, the sE term is a constant, the y intercept
of the plot. From this intercept the electrophilicity, E, for the
single electrophile may be extracted. Note that in the present
work the rate constants were determined at 25 °C, and the E
values defined here should be taken as provisional values, as a
result. Nonetheless, the trends found here in the E values
provide important insights into the nucleophilic aromatic
displacements (vide infra).
15b
N
40
displacement but also show significant and versatile Diels−
1
2,14
Alder reactivity,
displaying a range of modes of cyclo-
with dienes. Electrophiles near E = −8 are termed
borderline such as N-(2,4-dinitrophenyl)-4,6-dinitrobenoztria-
41−45
Figure 6 (and Figures S4−S6 in the Supporting Information)
addition
depict Mayr plots as outlined above for 1a−d, in turn. For all
15b
plots the same rate constant for formation of MC-1-Z, i.e., k ,
zole 1-oxide (DNP-DNBT), a member of a series of 4,6-
dinitrobenzotriazole 1-oxides
1
14−16,46
was employed in the log k term. The plots all have reasonable
substituted by nitroaryl
2
linearity (R ≥ 0.979). This linearity indicates a dependence of
groups attached to 2-N of the 5-membered ring. As mentioned,
electrophiles with E values significant more negative than −8,
such as TNB and the present 1-X-2,4-dinitrobenzene series, are
normal electrophiles and do not show Diels−Alder-type
the rate constant on the nucleophilicity values of the amines. A
plot with extensive scatter or a break in the line would either
indicate no reliance on amine nucleophilicity or possibly a
change in mechanism. Moreover, the slopes of the plots all are
15b
reactivity.
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The Journal of Organic Chemistry
Article
The distinction between the two sets of electrophiles appears
to reside in the degree of aromaticity found in each set: the
heteroaromatic 10π superelectrophiles also have significantly
reduced aromaticity relative to the normal 6π normal
electrophiles.
The current 1-X-2,4-dinitrobenzene series are normal
electrophiles. The differences in E values along the series are
(partial bond formation in the TS). (5) The fact that the plots
of log k vs electronegativity result in good correlations with
1
large positive slopes implies that expulsion of the leaving group
occurs after the RDS. This conclusion is bolstered by the
finding of a good correlation between the appropriate rate
constants and the Mayr nucleophilicity parameters, N, for the
amines. These correlations permit definition of approximate E,
electrophilicity, parameters for the series of 1-X-2,4-dinitro-
benzenes: E = −14.1 for X = F, E = −17.6 for X = Cl and Br,
and E = −18.3 for X = I. The E values are cross-correlated with
the electronegativity values of the 1-halo substituents in the
series.
consistent with a wide range of kinetic studies of S Ar
N
4
7,48
displacement with the series.
The E values estimated in the
current study indicate that 1-fluoro-2,4-dinitrobenzene is much
more electrophilic (E = −14.1) than the chloro or bromo
derivatives whose E values are identical (E = −17.6), and these
substrates have electrophilicities greater than that of 1-iodo-2,4-
dinitrobenzene but to a smaller degree (ΔE (I − Cl/Br) = 0.7
versus ΔE (F − Cl/Br) = 3.5). The order of the electro-
philicities found here is in broad agreement with the leaving
Importantly, the E parameters will allow estimation of rate
constants for S Ar displacements with other nucleophiles
N
17c
whose N values have been characterized. In turn, the ability
to estimate these rate constants is expected to be of value in
organic syntheses involving these 1-X-2,4-dinitrobenzenes (or
in molecules containing the 2,4-dinitrobenzene moiety),
particularly those for which competitive nucleophilic attack
may arise. The approach used here to estimate Mayr
electrophilicities, E, may also be applicable to other systems
that we have studied and so open another pathway of analysis
group order found in a number of previous S Ar studies (based
N
on rate constants, k , for the initial addition step): F ≫ Cl ≈ Br
1
4
7,48
>
I.
As has previously been noted, however, this order is
also modified by the nature of the nucleophile. For methoxide
(
in methanol) the order is: F ≫ Cl > Br > I whereas for
49
methanethiolate the order is F ≫ Br > Cl > I. Here the
change in order is attributable to the significantly divergent
polarizabilities of the nucleophiles.
50,51
4
7,49b
for a wide range of nucleophilic−electrophilic reactions.
The Mayr E values for the 1-X-2,4-dinitrobenzene series are
cross-correlated with the electronegativities of the 1-X halo
groups. Thus, the rate constants correlate with these electro-
negativities and, similarly, the provisional E values determined
in the present work also correlate with the electronegativities of
the 1-halo substituents (E versus electronegativity; E = 2.87 ×
EXPERIMENTAL SECTION
■
Materials. 1-X-2,4-Dinitrobenzenes 1a−d and all amines studied
were of the highest quality available. MeCN was distilled over P O
and stored under nitrogen. Doubly glass-distilled water was further
boiled and cooled under nitrogen just before use.
Kinetics. The kinetic study was performed using a UV−vis
spectrophotometer for slow reactions (t1 > 10 s) or a stopped-flow
spectrophotometer for fast reactions (t1/2 ≤ 10 s) equipped with a
constant temperature circulating bath. The reactions were followed by
monitoring the appearance of N-(2,4-dinitrophenyl)amines at a fixed
wavelength corresponding to the maximum absorption (λmax, e.g., 379
nm for N-2,4-dinitrophenylpiperidine). Typically, the reaction was
initiated by injection of 3 μL of a 0.02 M 1-fluoro-2,4-dinitrobenzene
a stock solution (MeCN) via a 10 μL syringe into a 10 mm UV cell
containing 2.50 mL of the reaction medium and amine. The amine
stock solution (ca. 0.2 M) for the reactions in H O was prepared in a
5.0 mL volumetric flask under nitrogen by adding 2 equiv of amine to
equiv of standardized HCl solution to give a self-buffered solution.
2
5
2
electronegativity −25.7, R = 0.984; Figure S7 in the
Supporting Information). This is understandable since in
these reactions the only change is the minor modulation of
the 1-X leaving group whose influence on attack of the amine
nucleophile in the first step (rate determining for 1b-1d in
MeCN) rests primarily on the increase in electrophilicity that is
directly linked to the electronegativity of the 1-halo group.
Although approximate, the E values determined here should
allow the estimation of rate constants for other nucleophilic
aromatic displacements with nucleophiles whose N values are
/2
1
1
7c
2
known.
2
1
CONCLUSIONS
■
Transfer of solutions was carried out by means of gastight syringes. All
reactions were carried out under pseudofirst-order conditions in which
amine concentrations were at least 20 times greater than the substrate
concentration.
The current study has demonstrated that the reactions of 1a
with secondary amines in MeCN proceed through an RLPT
process. However, the deprotonation process by a general base
is absent for the corresponding reactions in H O and for the
Product Analysis. N-(2,4-Dinitrophenyl)amine was identified as
one of the products by comparison of the UV−vis spectra at the end of
the reactions with the authentic sample.
2
other reactions, e.g., reactions of 1b−d with secondary amines
and those of 1a−d with primary amines in either MeCN or
H O. Thus, we have concluded the following: (1) Poor
2
−
nucleofugality of F ion in the aprotic solvent is responsible for
ASSOCIATED CONTENT
■
preference for the k3 pathway, since the corresponding
reactions of 1b−d proceed without this deprotonation process.
*
S
Supporting Information
Plots of kobsd vs [amine] (A) and kobsd/[amine] vs [amine] (B)
for the reactions of 1a with N-methylbenzylamine and
diethanolamine, respectively. Plots of kobsd/[amine] vs
(
2) The deprotonation process is absent for the reactions of 1a
−
in H O, because the nucleofugality of F ion in water is not as
2
poor as that in the aprotic solvent. (3) The reactions of 1a with
[amine] (A) and [amine]/kobsd vs 1/[amine] (B) for the
primary amines in MeCN proceed without the k process.
3
reaction of 1a with diethylamine. Mayr plots of log k vs N for
Facile intramolecular H-bonding is responsible for the absence
1
the reactions of 1b−d with various amines in MeCN. Plot of
the Mayr E value estimated for 1-X-2,4-dinitrobenzenes vs
electronegativity of the halogen atoms. Tables containing the
kinetic conditions and results. This material is available free of
charge via the Internet at http://pubs.acs.org.
of the k process. (4) Analysis of the linear Brønsted-type plots
3
also supports the proposed mechanisms, i.e., βnuc = 1.00 for the
reactions of 1a with secondary amines in MeCN, which
proceed through MC-1-Z to MC-1, while βnuc = 0.52 or 0.53
for those of 1b−d, in which formation of MC-1-Z is the RDS
9
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The Journal of Organic Chemistry
Article
(
21) Snyder, S. E.; Carey, J. R.; Shvets, A. B.; Pirkle, W. H. J. Org.
AUTHOR INFORMATION
■
Chem. 2005, 70, 4073−4081.
Corresponding Author
(I.-H.U.) Tel: 82-2-3277-2349. Fax: 82-2-3277-2844. E-mail:
ihum@ewha.ac.kr. (J.M.D.) Tel: (709) 637-6200 ext 6330. Fax:
709) 639-8125. E-mail: jdust@grenfell.mun.ca.
(22) Dururgkar, K. A.; Gonnade, R. G.; Ramana, C. V. Tetrahedron
*
Lett 2009, 65, 3974−3979.
(23) Dust, J. M.; Harris, J. M. J. Polym. Sci. Chem. A 1990, 28, 1875−
(
1886.
(
24) Dust, J. M.; Secord, M. D. J. Phys. Org. Chem. 1995, 8, 810−824.
Notes
(
25) Buncel, E.; Dust, J. M.; Terrier, F. Chem. Rev. 1995, 95, 2261−
The authors declare no competing financial interest.
2
280 and references therein.
(
26) Um, I. H.; Min, S. W.; Dust, J. M. J. Org. Chem. 2007, 72, 8797−
ACKNOWLEDGMENTS
■
8803.
(
(
27) Sanger, F. Biochem. J. 1945, 39, 507−515.
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
28) (a) Jencks, W. P. Chem. Rev. 1985, 85, 511−527. (b) Stefanidis,
D.; Jencks, W. P. J. Am. Chem. Soc. 1993, 115, 6045−6050. (c) Berg,
U.; Jencks, W. P. J. Am. Chem. Soc. 1991, 113, 6997−7002.
(
NRF) funded by the Ministry of Education, Science and
Technology (2012-R1A1B-3001637). L.-R.I. and J.-S.K. are also
grateful for the BK 21 Scholarship. J.M.D. thanks Grenfell
Campus-Memorial University (Vice-President’s Research
Fund) for support. Laura Griffin is thanked for preliminary
experiments.
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