Evidence for a catalytic six-membered cyclic transition state in aminolysis of 4-nitrophenyl 3,5-dinitrobenzoate in acetonitrile: Comparative Br?nsted-type plot, entropy of activation, and deuterium kinetic isotope effects

Article abstract of DOI:10.1021/jo502303f

A kinetic study for reactions of 4-nitrophenyl 3,5-dinitrobenzoate (1a) with a series of cyclic secondary amines in acetonitrile is reported. Plots of the pseudo-firstorder rate constant (k_obsd) vs [amine] curve upward, while those of k_obs

Full text of DOI:10.1021/jo502303f

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Article
Evidence for a Catalytic Six-Member Cyclic Transition State in Aminolysis
of 4-Nitrophenyl 3,5-Dinitrobenzoate in Acetonitrile: Comparative Brønsted-
type Plot, Entropy of Activation and Deuterium Kinetic Isotope Effects
Ik-Hwan Um, Min-Young Kim, Ae-Ri Bae, Julian M. Dust, and Erwin Buncel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502303f • Publication Date (Web): 01 Dec 2014
Downloaded from http://pubs.acs.org on December 9, 2014
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Evidence for a Catalytic SixꢀMember Cyclic Transition State in Aminolysis of 4ꢀNitrophenyl
3,5ꢀDinitrobenzoate in Acetonitrile: Comparative Brønstedꢀtype Plot, Entropy of Activation
and Deuterium Kinetic Isotope Effects
*1
1
1
*2
*3
IkꢀHwan Um, MinꢀYoung Kim, AeꢀRi Bae, Julian M. Dust and Erwin Buncel
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1
Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120ꢀ750, Korea.
Eꢀmail: ihum@ewha.ac.kr
2
Departments of Chemistry and Environmental Science, Grenfell CampusꢀMemorial University of
Newfoundland, Corner Brook, Newfoundland and Labrador A2H 5G4, Canada
Eꢀmail: jmdust@grenfell.mun.ca
3
Department of Chemistry, Queen’s University, Kingston, Ontario K7L 3N6, Canada
Eꢀmail: buncele@chem.queensu.ca
O
k
2
H
Ar C
N
OAr'
uncat.
O
O
k
1
Ar C OAr'
Ar C OAr'
HN
δ
O
k
-1
Ar'
O
HN
cat.
HN
O
Ar C N
Ar
C
H
N
HN
T
k
3
δ
N
H
HOAr'
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Abstract
Kinetic study for reactions of 4ꢀnitrophenyl 3,5ꢀdinitrobenzoate (1a) with a series of cyclic
secondary amines in acetonitrile is reported. Plots of pseudoꢀfirstꢀorder rate constant (kobsd) vs
[
amine] curve upward, while those of kobsd /[amine] vs [amine] exhibit excellent linear correlations
0
1
2
3
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8
9
0
1
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0
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0
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0
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9
0
with positive intercepts, indicating that reaction proceeds through both uncatalyzed and catalyzed
routes. Brønstedꢀtype plots for uncatalyzed and catalyzed reactions are linear with βnuc = 1.03 and
‡
‡
0
.69, respectively. The ꢁH and ꢁS values measured for the catalytic reaction with morpholine are
‡
‡
–
0.80 kcal/mol and –61.7 cal/mol K, respectively. The negative ꢁH with a large negative ꢁS
suggests that the reaction proceeds through a highly ordered transitionꢀstate (i.e., a sixꢀmember
cyclic transitionꢀstate, which includes a second amine molecule that accepts a proton from the
aminium moiety of zwitterionicꢀtetrahedral intermediate and simultaneously donates a proton to the
aryloxyl oxygen of the nucleofuge with concomitant C–OAr bond scission). This proposal is
consistent with the smaller βnuc value for the catalyzed reaction as compared to the uncatalyzed
reaction. An inverse deuterium kinetic isotope effect (DKIE) value of 0.93 and a contrasting normal
primary DKIE value of 3.23 for the uncatalyzed and catalyzed routes, respectively, also support the
proposed cyclic TS.
Introduction
Nucleophilic substitution reactions of esters with amines have been the subject of extensive
experimental and theoretical studies, not least, due to their importance in biological processes (e.g.,
1
ꢀ10
enzyme action and peptide biosynthesis) but also in synthetic applications.
Experimental studies
based on linear free energy relationships (LFERs) have reported that aminolysis of carboxylic esters
proceeds through a concerted mechanism or via a stepwise pathway depending on reaction
conditions (e.g., the nature of the reaction medium and electrophilic center, basicity of the incoming
2ꢀ5
amine and leaving group, etc.). A curved or biphasic Brønstedꢀtype plot, often observed in
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aminolysis of esters possessing a weakly basic leavingꢀgroup (e.g., 2,4ꢀdinitrophenoxide), has been
2ꢀ5
taken as evidence for a stepwise mechanism with a change in the rateꢀdetermining step (RDS).
Recent theoretical studies have advanced three different mechanistic regimes: (1) a concerted
mechanism, (2) a stepwise mechanism with a neutral tetrahedral intermediate, and (3) a stepwise
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±
6ꢀ10
±
mechanism with a zwitterionic tetrahedral intermediate (T ).
However, the existence of T in the
±
gas phase or in aprotic solvents has been questioned, e.g., Ilieva et al. failed to identify T for the
8
a
reaction of methyl formate with ammonia, while Sung et al. reported that at least five explicit
±
10a
water molecules are required to stabilize T in the reaction of phenyl acetate with ammonia.
Our kinetic study has also shown that the nature of the reaction medium is a crucial factor that
4
governs the reaction mechanism. The reaction of 2,4ꢀdinitrophenyl benzoate with a series of cyclic
secondary amines has been proposed to proceed through a stepwise mechanism with a change in
4
a
RDS in H O on the basis of a curved Brønstedꢀtype plot (i.e., β = 0.74 and β = 0.34), but via a
2
2
1
4b
concerted pathway in MeCN on the basis of a linear Brønstedꢀtype plot with βnuc = 0.40. We have
±
previously proposed that instability of T in the aprotic solvent forces the reaction to proceed
4
b
11
through a concerted mechanism, because MeCN is a poor solvent for the ionic species.
Our present study comprises an extension to the reaction of 4ꢀnitrophenyl 3,5ꢀdinitrobenzoate
(1a) with a series of cyclic secondary amines in MeCN to further elucidate the reaction mechanism.
We wish to report that the aminolysis of 1a in the aprotic solvent proceeds through a stepwise
±
mechanism with T , which decomposes to the products in the rateꢀdetermining step (RDS) via
uncatalytic and catalytic routes. We present conclusive evidence that the catalytic reaction proceeds
through a sixꢀmember cyclic transitionꢀstate (TS), e.g., a comparative Brønstedꢀtype plot, a negative
enthalpy of activation with large negative entropy of activation, and deuterium kinetic isotope
effects (DKIEs) for the uncatalyzed as contrasted with the catalyzed routes.
Additionꢀelimination nucleophilic reactions at carbonyl electrophilic sites bear significant
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similarities to the additionꢀeliminition reaction of nucleophiles at electrophilic carbon in electronꢀ
12
deficient aromatic compounds, the S Ar mechanism. For both, the nucleophile attacks at the
N
2
electrophilic sp ꢀhybridized carbon that bears a good leaving group (or a leaving group that becomes
3
more nucleofugic subsequently) which rehybridizes to an sp center. A major difference is that in the
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SNAr mechanism nucleophilic attack results in loss of aromaticity and rearomatization occurs upon
expulsion of the leaving group from the reaction site. We have previously exploited this similarity to
13a,b
apply the Brønsted analysis to S Ar displacements
and, most recently, have applied the full
N
range of physical organic tools to probe the reaction of a series of 1ꢀ(Yꢀsubstitutedꢀphenoxy)ꢀ2,4ꢀ
13c
dinitrobenzenes with cyclic secondary amines in MeCN. This recent kinetic study revealed a
±
concerted pathway from the initially formed zwitterionic Meisenheimer complex, comparable to T
in the present work, involving a sixꢀmember TS. The present study, therefore, also explores the
similarities in the additionꢀelimination processes in aminolysis at C=O with S Ar displacement.
N
The current kinetic study is analyzed using comparative Brønstedꢀtype plot, activation parameters,
particularly various entropies of activation, and hydrogenꢀdeuterium kinetic isotope effects (DKIE).
Results and Discussion
The kinetic study was carried out spectrophotometrically by monitoring the appearance of the
leaving 4ꢀnitrophenoxide under pseudoꢀfirstꢀorder conditions with the amine nucleophile in excess.
All reactions in this study obeyed pseudoꢀfirstꢀorder kinetics and pseudoꢀfirstꢀorder rate constants
(kobsd) were calculated from the slope of plots of ln (A – A ) vs t, which were linear over 90 % of the
∞
t
2
total reaction (R > 0.9995). The uncertainty in the kobsd values is estimated to be less than 3 % as
determined from replicate runs. The plot of kobsd vs amine concentration curves upward for the
reaction of 1a with morpholine as shown in the representative Figure 1A. Similarly curved plots are
illustrated in Figures S1A – S8A in the Supporting Information (SI) for the reactions of 1a with the
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other amines used in this study.
A
B
0.010
0.10
0.05
0.00
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k
0.005
k
2
R = 0.9996
0
.000
0
.00
0.05
0.10
0.00
0.05
0.10
[
amine ] / M
[ amine ] / M
Figure 1. Plots of kobsd vs [amine] (A) and kobsd/[amine] vs [amine] (B) for the reaction of 4ꢀ
o
nitrophenyl 3,5ꢀdinitrobenzoate (1a) with morpholine in MeCN at 25.0± 0.1 C.
Traditionally, such upward curvature has been understood as evidence for reactions reported
±
previously to proceed through a stepwise mechanism with T , which decomposes to the products in
2
ꢀ5
the RDS via competitive uncatalyzed and catalyzed routes. Thus, one might suggest that the
±
current aminolysis of 1a proceeds through a stepwise mechanism with two intermediates (i.e., T
–
and its deprotonated form T ) as shown in Scheme 1. However, this is in contrast to the report that
the catalyzed process is absent for the corresponding reactions of 4ꢀnitrophenyl Xꢀsubstitutedꢀ
4b,5c
benzoates when X = H, 2ꢀMeO and 4ꢀMeO.
This demonstrates convincingly that the electronic
nature of the substituent X in the benzoyl moiety governs the reaction mechanism.
O
O
O
k
1
k2
H
N
Ar C OAr' HN
Ar C OAr'
HN
Ar C
OAr'
k
-1
1
a
T
Ar = 3,5-dinitrophenyl
OAr' = 4-nitrophenoxy
HN
H
k
3
HN
=
HN
Z
O
O
R
fast
Ar C OAr'
N
Ar C
N
OAr'
R = H, CH
3
.
Z = CH , NH, NCH CH OH, O.
2
2 2
T
Scheme 1
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Dissection of kobsd into Kk and Kk . The k for the aminolysis of 1a can be expressed as eq (1)
obsd
2
3
on the basis of the kinetic results and the reaction mechanism proposed in Scheme 1. Eq (1) can be
simplified to eq (2) under the assumption k–1 >> k + k [amine]. Accordingly, the plot of
2
3
kobsd/[amine] vs [amine] would be linear if the above assumption is valid. In fact, as shown in Figure
(B), the plot of kobsd/[amine] vs [amine] exhibits an excellent linear correlation with a positive
0
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1
intercept. The corresponding plots for the reactions with the other amines are also linear as shown in
Figures S1B – S8B in SI, indicating that the assumption k >> k + k [amine] is valid regardless of
–1
2
3
the amine basicity. Thus, the Kk and Kk values were calculated from the intercept and slope of the
2
3
linear plots, respectively, and are summarized in Table 1.
2
kobsd = (k k [amine] + k k [amine] ) / (k + k + k [amine])
(1)
(2)
1 2
1 3
–1
2
3
kobsd/[amine] = Kk + Kk [amine], where K = k /k
2
3
1
–1
Table 1. Summary of Rate Constants for the Aminolysis of 4ꢀNitrophenyl 3,5ꢀDinitrobenzoate (1a)
o
in MeCN at 25.0 ± 0.1 C
a
–1 –1
–2 –1
–1
amines
pKa
Kk /M s
Kk /M s
k /k /M
2
3
3
2
1
2
morpholine
1ꢀ(2ꢀhydroxyethyl)ꢀ 17.6
piperazine
16.6
0.0163
0.169
0.741
4.2
45.5
25.3
3
piperazine
18.5
1.32
2.02
2.88
38.3
21.3
22.4
29.0
10.5
7.78
4 3ꢀmethylpiperidine 18.6
piperidine 18.8
5
b
b
(
3.10)
(6.94)
a
b
The pK values in MeCN were taken from ref 14. The rate constant measured for the reaction with
a
deuterated piperidine.
As shown in Table 1, the Kk value increases as the amine basicity increases (e.g., it increases
2
–
1 –1
from 0.0163 to 0.169 and 2.88 M s as the pK of the conjugate acid of the amine increases from
a
16.6 to 17.6 and 18.8, in turn). A similar result is shown for Kk , except piperazine which possesses
3
two basic sites, although the rate constant for the catalyzed route (Kk ) is much larger than that for
3
the uncatalyzed process (Kk ) regardless of the basicity of the incoming amine. It is notable that the
2
catalytic effect exerted by a second amine molecule (i.e., the k /k ratio) decreases linearly as the
3
2
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amine basicity increases (see also Figure 2). Dependence of the catalytic effect on amine basicity
will be discussed in detail subsequently.
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2
1
q
2
k
3
k
4
1
0
5
slope = ꢀ0.34
2
R = 0.990
1
7
18
19
p
Ka + log( p / q )
Figure 2. Comparative Brønstedꢀtype plot for the reactions of 4ꢀnitrophenyl 3,5ꢀdinitrobenzoate
1a) with a series of cyclic secondary amines in MeCN at 25.0 ± 0.1 °C. The identity of points is
(
given in Table 1.
Brønstedꢀtype Analysis of Kk and Kk . The effect of amine basicity on Kk and Kk values is
2
3
2
3
2
illustrated in Figure 3. The Brønstedꢀtype plots exhibit excellent linear correlations (R ≥ 0.996)
with βnuc = 1.03 for Kk and β = 0.69 for Kk when the rate constants and pK values are
2
nuc
3
a
15
statistically corrected using p and q (i.e., p = 2 while q = 1 except q = 2 for piperazine). It is
important to note that the slope of the Brønstedꢀtype plots is much larger for Kk than for Kk ,
2
3
indicating that k is more sensitive to the amine basicity than k . This is consistent with our recent
2
3
report that βnuc is much larger for Kk than for Kk for aminolysis of 4ꢀpyridyl 3,5ꢀdinitrobenzoate
2
3
5
b
(
i.e., βnuc = 0.98 for Kk and β = 0.79 for Kk3) and for S Ar reactions of 1ꢀ(Yꢀsubstitutedꢀ
2 nuc N
phenoxy)ꢀ2,4ꢀdinitrobenzenes with the amines used in this study in MeCN (i.e., βnuc = 1.10 for Kk2
13c
and βnuc = 0.85 for Kk3).
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1
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2
2
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2
A
4
B
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q
q
1
0
1
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k
K
k
K
2
-
-
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βnuc = 1.03
βnuc = 0.69
2
2
R
= 0.9995
R
= 0.996
-
17
18
Ka + log(
19
17
18
Ka + log( p / q )
19
p
p
/
q
)
p
Figure 3. Brønstedꢀtype plots for the reactions of 4ꢀnitrophenyl 3,5ꢀdinitrobenzoate (1a) with cyclic
secondary amines in MeCN at 25.0 ± 0.1 °C. (A) for Kk and (B) for Kk . The identity of points is
2
3
given in Table 1.
Gresser and Jencks have concluded that amine basicity does not affect the k value in
2
quinuclidinolysis of aryl 2,4ꢀdinitrophenyl carbonates, because there is little or no electron donation
±
3b
from the aminium moiety of T to push out the leaving group. Castro et al. have drawn a similar
16a
conclusion for aminolyses of various thionocarbonates (e.g., ethyl phenyl thionocarbonate, methyl
1
6b
16c
4ꢀnitrophenyl thionocarbonate, 4ꢀmethyl 4ꢀnitrophenyl thionocarbonate and 3ꢀmethoxyphenyl
1
6d
4
ꢀnitrophenyl thionocarbonate ). It is also expected that amine basicity would not influence the k
3
value. Because a more basic amine would tend to deprotonate more rapidly from the aminium
±
moiety of T while the aminium ion would hold the proton more strongly as amine basicity increases.
Accordingly, one might expect that both k and k would be independent of amine basicity, if the
2
3
current reaction proceeds as shown in Scheme 1. However, in fact, the Brønstedꢀtype plot using Kk2
results in a much larger βnuc value than that involving Kk (Figure 3), a clear indication that k is
3
2
more sensitive to amine basicity than k . This is contrary to expectations if the reactions proceed as
3
proposed in Scheme 1. Thus, one might suggest that the catalyzed reaction may not proceed as
shown in Scheme 1.
Analysis of Activation Parameters. To obtain further information on the TS structure, activation
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‡
‡
parameters (ꢁH and ꢁS ) have been calculated from the rate constants measured at fiveꢀdifferent
temperatures for the reactions of 1a with morpholine in MeCN. The plots of kobsd vs [amine] curve
upward, while the plots of kobsd/[amine] vs [amine] exhibit excellent linear correlations with positive
intercepts in all cases (see Figures S5A and S5B in SI). Thus, Kk and Kk values were calculated
2
3
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23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
from the intercept and slope of the linear plots, respectively and summarized in Table 2.
Table 2. Summary of Kinetic Data for the Reactions of 4ꢀNitrophenyl 3,5ꢀDinitrobenzoate (1a) with
Morpholine and Piperidine Carried out at FiveꢀDifferent Temperatures in MeCN
Morpholine
Piperidine
–
1 –1
–2 –1
–1 –1
–2 –1
Kk /M s
Kk /M s
Kk /M s
Kk /M s
3
2
3
2
1
2
2
3
5.0 °C
0.0 °C
5.0 °C
0.0 °C
0.0109
0.0139
0.0163
0.0211
0.0253
0.751
0.748
0.741
0.739
0.734
2.16
23.7
2.53
2.88
3.40
3.84
22.8
22.4
21.5
21.3
35.0 °C
‡
–1
ꢁ
ꢁ
H /kcal mol
6.82 ± 0.28
–43.7 ± 1.0
–0.80 ± 0.02
–61.7 ± 0.1
4.51 ± 0.12
–41.2 ± 0.4
–1.55 ± 0.09
–57.5 ± 0.3
‡
–1 –1
S /cal mol K
As shown in Table 2, Kk increases as the reaction temperature increases. Interestingly, the Kk
2
2
term is not highly susceptible to modification of reaction temperature, e.g., the Kk value for the
2
–
1 –1
reaction of 1a with morpholine increases from 0.0109 to 0.0163 and 0.0253 M s as the reaction
o
temperature increases from 15.0 to 25.0 and 35.0 C, in turn. More interestingly, Kk decreases as
3
the reaction temperature increases, although the decrease in Kk is not large (i.e., the Kk value for
3
3
–2 –1
the reaction of 1a with morpholine decreases from 0.751 to 0.741 and 0.734 M s as the reaction
o
temperature increases from 15.0 to 25.0 and 35.0 C, in turn).
‡
‡
The activation parameters (ꢁH and ꢁS ) were calculated from the Arrhenius equation (3). As
shown in Figure 4, the Arrhenius plots for the reaction of 1a with morpholine performed at five
different temperatures resulted in good linear correlations for both the uncatalyzed and catalyzed
reactions. The slope of the linear plots of ln Kk (or Kk ) vs 1/T is equal to – E /R. The enthalpy of
2
3
a
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1
1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
‡
‡
activation (ꢁH ) was calculated using eq (4). The entropy of activation (ꢁS ) was calculated from eq
‡
‡
(
5). The ꢁH and ꢁS values calculated in this way are summarized in Table 2.
–
Ea/RT
k = Ae
or ln k = – E /RT + ln A
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ (3)
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ (4)
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ (5)
a
‡
ꢁ
ꢁ
H = E – RT
a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
‡
S = (ln A – ln T – ln K /h – 1)
B
-2
1
0
1
A
B
-
3
-4
-
-5
slope =
− 3730
slope = 103
intercept =
intercept = 8.44
−
0.643
2
R
= 0.997
2
R
= 0.984
-6
-2
0
.0032 0.0033 0.0034 0.0035
0.0032 0.0033 0.0034 0.0035
1/T
1/T
Figure 4. Arrhenius plots for the reactions of 4ꢀnitrophenyl 3,5ꢀdinitrobenzoate (1a) with
morpholine at fiveꢀdifferent temperatures in MeCN. (A) for Kk and (B) for Kk .
2
3
‡
As shown in Table 2, the ꢁH values for the uncatalyzed reactions are 6.82 and 4.51 kcal/mol for
‡
the reactions with morpholine and piperidine, respectively. However, surprisingly, the ꢁH values for
the catalyzed reactions are –0.80 and –1.55 kcal/mol for the reactions with morpholine and
1
7,18
piperidine, respectively. Such negative activation enthalpies are quite unusual
but is in accord
with the fact that the Kk values decrease as the reaction temperature increases (Table 2). More
3
‡
importantly, the entropy of activation for the catalyzed reaction (Kk ) is highly negative (i.e., ꢁS = –
3
6
1.7 and –57.5 cal/mol K for the reactions with morpholine and piperidine, respectively). Such large
±
negative entropy of activation would not arise through solvation of T in MeCN, because the
±
zwitterionic T , in which the negative charge is exposed on the O atom while the positive charge is
±
buried in the middle of T , would not be strongly solvated in the aprotic solvent. In fact, electronic
±
repulsion between the negative dipole end of MeCN and the negatively charged oxygen atom of T
1
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should predominate.
Deduction of Reaction Mechanism. We thus propose that the catalyzed reaction proceeds
through a concerted mechanism with a sixꢀmember cyclic TS structure as modeled by TScycl in
–
Scheme 2 rather than via the alternative stepwise pathway with an anionic intermediate T in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. This cyclic TS includes a second molecule of the amine that accepts a proton from the
±
aminium moiety of T and in concerted fashion donates a proton to the aryloxyl oxygen of the
leaving group with concomitant C–OAr bond scission. Such a sixꢀmember cyclic TS can account for
‡
the large negative ꢁS value since the rotational and vibrational degrees of freedom in the cyclic TS
are restricted. Furthermore, TScycl, in which the charges are dispersed, would be more favourable
–
than the anionic T in the aprotic solvent because the electronic repulsion would be less significant
–
for the chargeꢀdispersed cyclic TS than T .
O
O
O
k
1
k2
H
Ar C OAr' HN
Ar C OAr'
HN
Ar C
N
OAr'
k
-1
1
a
T
k
3
HN
δ
O
Ar'
O
O
Ar
C
H
Ar C
N
HOAr'
HN
δ
N
N
H
TScycl
Scheme 2
The cyclic TS proposed for the catalyzed process (i.e., TScycl in Scheme 2) can be further
supported by the fact the βnuc value is much smaller for the catalyzed reaction than for the
uncatalyzed reaction (Figure 3) and by the result that the k /k ratio decreases linearly as the amine
3
2
basicity increases (Figure 2). As mentioned in the preceding section, the k and k values would be
2
3
±
−
independent of amine basicity if the reaction proceeds through T and T as shown in Scheme 1.
However, if the catalyzed reaction proceeds via the cyclic TS (i.e., TScycl in Scheme 2), amine
1
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1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
basicity should affect k . Because the proton donation by the second amine molecule to the O atom
3
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 is consistent with the
fact that the catalytic effect (i.e., the k /k ratio) decreases linearly as the amine basicity increases
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Table 1 and Figure 2) and the catalyzed reaction results in a smaller βnuc value than the uncatalyzed
reactions (Figure 3).
Deuterium Kinetic Isotope Effect (DKIE). The proposed reaction mechanism in Scheme 2 is
further supported by deuterium kinetic isotope effects (DKIE). As shown in Table 1 (also in Figure
S8 in SI), the Kk value for the reaction with deuterated piperidine is larger than that for the reaction
2
H
D
with piperidine. Consequently, an inverse DKIE is obtained (i.e., Kk /Kk = 2.88/3.10 = 0.93).
2
2
One can attribute the inverse DKIE for the uncatalyzed reaction, where the deprotonation process
±
from the aminium moiety of T is absent, as a consequence of reduced steric hindrance, because the
amplitude of the stretching vibration of an N–D bond is smaller than that of an N–H bond. In
contrast, the Kk value for the reaction with deuterated piperidine is much smaller than that for the
3
H
D
reaction with piperidine (i.e., Kk /Kk = 22.4/6.94 = 3.23). The normal primary DKIE for the
3
3
catalyzed reaction is consistent with the proposed cyclic TS (i.e., TScycl), in which the deprotonation
and the donation of a proton by a second amine molecule occur in the RDS. That DKIE (3.23) is
smaller than theoretical (ca. 7) indicates that the TS is not symmetrical and proton transfer does not
2
0
occur in a linear fashion. Concerted but not synchronous protonꢀtransfer occurs.
The TScycl (Scheme 2) is reminiscent of the transition state that we have recently proposed for the
13c
catalyzed route in S Ar displacement of aryloxides by cyclic secondary amines in acetonitrile.
N
The fundamental similarity between the two types of additionꢀelimination reactions, namely
nucleophilic displacement at carbonyl and at electronꢀdeficient aromatic carbon, is, thus,
emphasized.
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Conclusions
Traditionally, the upward curvature in the plots of kobsd vs [amine] for the current aminolysis of 1a
±
–
has been taken as evidence for a stepwise mechanism with two intermediates (T and T ). However,
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42
43
44
45
46
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48
49
50
51
52
53
54
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56
57
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60
±
we have concluded that the catalyzed reaction (i.e., breakdown of T to the products) proceeds
through a concerted mechanism with a sixꢀmember cyclic TS (i.e., TScycl in Scheme 2) rather than
–
via the alternative stepwise pathway with an anionic intermediate T in Scheme 1. This proposal is
based on the following data: (1) The catalytic effect decreases with increasing basicity of the
incoming amine (a comparative Brønstedꢀtype plot). This is possible only when a second amine
±
molecule relays protons from the aminium moiety of T to the aryloxy leaving group. (2) A large
negative entropy of activation is caused by restriction of the rotational and vibrational degrees of
freedom in the cyclic TS. (3) An inverse DKIE is observed for the uncatalyzed reaction (i.e.,
H
D
Kk /Kk = 2.88/3.10 = 0.93) but a normal primary DKIE is obtained for the catalyzed process, in
2
2
which the deprotonation and the donation of a proton by a second amine molecule occur in the RDS
H
D
(
i.e., Kk /Kk = 22.4/6.94 = 3.23). The proposed TS for the catalyzed route, TS , also bears a
3
3
c
y
c
strong similarity to that previously advanced in the S Ar reaction of 1ꢀ(Yꢀsubstitutedꢀphehnoxy)ꢀ
N
2,4ꢀdinitrobenzenes with cyclic secondary amines in the same reaction medium (i.e., acetonitrile).
Experimental Section
Materials. 4ꢀNitrophenyl 3,5ꢀdinitrobenzoate (1a) was readily prepared from the reaction of 3,5ꢀ
dinitrobenzoyl chloride with 4ꢀnitrophenol in anhydrous ether under the presence of equimolar
2
1
triethylamine. The crude product was purified by column chromatography and the purity was
1
checked by the melting point and H NMR spectrum (500 MHz, CDCl ), e.g., δ 9.354ꢀ9.339 (m, 3H),
3
δ 8.415ꢀ8.397 (d, J = 9.0 Hz, 2H), δ 7.515ꢀ7.497 (d, J = 9.0 Hz, 2H). MeCN was distilled over P O5
2
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1
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1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and stored under nitrogen. Other chemicals, including the amines, were of the highest quality
available.
Kinetics. The kinetic study was carried out using a UVꢀVis spectrophotometer for slow reactions
(e.g., t1/2 ≥ 10 s) or a stoppedꢀflow spectrophotometer for fast reactions (e.g., t1/2 < 10 s) equipped
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
with a constant temperature circulating bath to maintain the reaction temperature. The reactions
were followed by monitoring the appearance of 4ꢀnitrophenoxide. All of the reactions in this study
were carried out under pseudoꢀfirstꢀorder conditions, in which the concentration of the amine was
kept in excess over that of the substrate. All solutions were transferred by gasꢀtight syringes.
Generally, the amine concentration in the reaction mixtures was varied over the range (5 – 150) ×
–3
–5
1
0 M, while the substrate concentration was ca. 4 × 10 M. Pseudoꢀfirstꢀorder rate constants (kobsd)
were calculated from the equation, ln (A – A ) = – k t + C. The plots of ln (A – A ) vs t were
∞
t
obsd
∞
t
linear over 90 % of the total reaction.
Products Analysis. 4ꢀNitrophenoxide ion (and/or its conjugate acid) was liberated quantitatively
and identified as one of the products by comparison of the UVꢀVis spectrum after completion of the
reaction with that of authentic sample under the same reaction condition.
Acknowledgement. This research was supported by Basic Science Research Program through the
National Research Foundation of Korea (NRF) funded by the Ministry of Education (2012ꢀR1A1Bꢀ
3001637). We further acknowledge support of this work by the Natural Sciences and Engineering
Research Council of Canada (NSERC) (E.B.) and Grenfell CampusꢀMemorial University (Viceꢀ
President’s Research Fund) (J. M. D.).
1
Supporting Information: Experimental conditions and results together with H NMR spectrum
of substrate 1a. This material is available free of charge via the Internet at http://pubs.acs.org.
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