Kinetic study on michael-type reactions of β-nitrostyrenes with cyclic secondary amines in acetonitrile: Transition-state structures and reaction mechanism deduced from negative enthalpy of activation and analyses of LFERs

Article abstract of DOI:10.1021/jo4007442

A kinetic study is reported for the Michael-type reactions of X-substituted β-nitrostyrenes (1a-j) with a series of cyclic secondary amines in MeCN. The plots of pseudo-first-order rate constant k_obsd vs [amine] curve upward, indicating that th

Full text of DOI:10.1021/jo4007442

Article
pubs.acs.org/joc
Kinetic Study on Michael-Type Reactions of β‑Nitrostyrenes with
Cyclic Secondary Amines in Acetonitrile: Transition-State Structures
and Reaction Mechanism Deduced from Negative Enthalpy of
Activation and Analyses of LFERs
Ik-Hwan Um,*,† Ji-Sun Kang,† and Jong-Yoon Park‡
†Department of Chemistry and Division of Nano Sciences and ‡Department of Science Education, Ewha Womans University, Seoul
120-750, Korea
S
* Supporting Information
ABSTRACT: A kinetic study is reported for the Michael-type
reactions of X-substituted β-nitrostyrenes (1a−j) with a series
of cyclic secondary amines in MeCN. The plots of pseudo-first-
order rate constant kobsd vs [amine] curve upward, indicating
that the reactions proceed through catalyzed and uncatalyzed
routes. The dissection of kobsd into Kk2 and Kk3 (i.e., the rate
constants for the uncatalyzed and catalyzed routes, respec-
tively) revealed that Kk3 is much larger than Kk2, implying that
the reactions proceed mainly through the catalyzed route when
[amine] > 0.01 M. Strikingly, the reactivity of β-nitrostyrene (1g) toward piperidine decreases as the reaction temperature
increases. Consequently, a negative enthalpy of activation is obtained, indicating that the reaction proceeds through a relatively
stable intermediate. The Brønsted-type plots for the reactions of 1g are linear with βnuc = 0.51 and 0.61, and the Hammett plots
for the reactions of 1a−j are also linear with ρX = 0.84 and 2.10 for the uncatalyzed and catalyzed routes, respectively. The
reactions are concluded to proceed through six-membered cyclic transition states for both the catalyzed and uncatalyzed routes.
The effects of the substituent X on reactivity and factors influencing βnuc and ρX obtained in this study are discussed.
aprotic solvents. Accordingly, the reaction mechanism is not well
understood but remains controversial, i.e., a stepwise mechanism
versus a concerted pathway.6−8
INTRODUCTION
■
Michael-type reactions of olefins activated by strong electron-
withdrawing groups (e.g., 1−4) are an important type of reaction
not only for synthetic chemists but also for mechanistic
investigators. Accordingly, numerous synthetic and mechanistic
studies have been carried out.1−8 The Michael-type reactions of
activated olefins with anionic nucleophiles have generally been
reported to proceed through a stepwise mechanism in which
nucleophilic attack is the rate-determining step (RDS).1,4,5 The
reactions of activated olefins with amine nucleophiles have also
been reported to proceed through a zwitterionic intermediate
(T ) with imbalanced transition states (TSs) in aqueous
solution, in which the delocalization of the negative charge into
the activating group lags behind the C−N bond formation (i.e.,
the principle of nonperfect synchronization).4,5
The Michael-type reaction of β-nitrostyrene (1, Ar = Ph) with
anilines in MeCN has been reported to proceed through a
stepwise mechanism in which formation of T is the RDS.6a In
contrast, Jalani et al. reported that the reactions of β-nitrostyrene
with a series of benzylamines in MeCN proceed through a
stepwise mechanism, in which formation of T occurs in the
preequilibrium, and the decomposition of T to the reaction
product via proton transfer occurs through uncatalyzed and
catalyzed routes.6b A similar conclusion was drawn by Popov et
al. for the Michael-type reactions of E-(2-furyl)nitroethene with
primary and secondary amines in MeCN.7
Oh et al. also reported that the Michael-type reactions of β-
nitrostyrene with benzylamines in MeCN follow two mecha-
nistic routes (i.e., the uncatalyzed and catalyzed routes)8a as
reported previously by Jalani et al.6b However, Oh et al.
concluded that the reactions proceed through a concerted
mechanism with the TS structures TSI and TSII for the
uncatalyzed and catalyzed routes, respectively.8a Besides, the
reactions of 2−4 with benzylamines in MeCN have also been
concluded to proceed through a concerted mechanism with a
However, the mechanism for the Michael-type reactions of
activated olefins with amines in aprotic solvents has been much
less studied, although most organic syntheses are carried out in
Received: April 9, 2013
© XXXX American Chemical Society
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four-membered cyclic TS (e.g., similar to TSI).8b−d Clearly, the
concerted mechanism suggested by Oh et al.8a for the reaction of
β-nitrostyrene with benzylamines in MeCN contrasts with the
stepwise mechanism proposed by Jalani et el.6b for the same
reaction, indicating that more systematic studies are necessary to
clarify the reaction mechanism.
RESULTS AND DISCUSSION
■
The kinetic study was performed spectrophotometrically by
monitoring the disappearance of the substrate under pseudo-
first-order conditions (e.g., the concentration of the amines was
kept in excess over that of the substrates). All of the reactions
obeyed first-order kinetics, and the pseudo-first-order rate
constants (kobsd) were calculated from the equation, ln At =
−kobsdt + C. The plots of ln At vs t were linear over 90% of the
total reaction. The correlation coefficient for the linear regression
was always over 0.9998. The uncertainty in the kobsd values was
estimated to be less than 3% from duplicate runs. As shown in
Figure 1A, the plot of kobsd against the amine concentration [NH]
for the reaction of β-nitrostyrene (1g) with piperidine curves
upward as a function of the amine concentration. Similarly
curved plots are shown in Figures S1A −S13A in the Supporting
Information for the other reactions studied in this work. The kobsd
values together with detailed kinetic conditions are summarized
in Tables S1−S18 in the Supporting Information.
Dissection of kobsd into Kk2 and Kk3. The upward curvature
shown in Figure 1A (and in Figures S1A−S13A in the Supporting
Information) is typical of reactions in which a second amine
molecule behaves as a general acid/base catalyst. Thus, one can
suggest that the reactions in question proceed through a stepwise
mechanism as illustrated in Scheme 2, in which the resonance
structures I and II are the intermediate while TSIII (or TSIV) and
TSV represent the TS structures for the uncatalyzed and
catalyzed routes, respectively.
To shed more light on the reaction mechanism, we have
carried out a systematic study on the Michael-type reactions of X-
substituted β-nitrostyrenes (1a−j) with a series of cyclic
secondary amines in MeCN as shown in Scheme 1. The kinetic
Scheme 1
One can express kobsd as eq 1 on the basis of the kinetic results
and the mechanism proposed in Scheme 2, in which [NH]
represents the concentration of the amines studied. Equation 1
can be simplified as eq 2 under the assumption, k−1 ≫ k2 +
k3[NH]. Thus, one would expect the plot of kobsd/[NH] vs [NH]
to be linear if the above assumption is valid.
results have been analyzed through linear free energy relation-
ships (e.g., the Brønsted-type and Hammett correlations)
together with the activation parameters (e.g., ΔH⧧ and ΔS⧧).
A Brønsted-type analysis is possible now because the pKa values
of the cyclic secondary amines used in this study in MeCN have
only recently become available.9 We wish to report that the
reactions of 1a−j with the amines in MeCN proceed through a
stepwise mechanism, in which the formation of an intermediate
occurs in the preequilibrium state, and the decomposition of the
intermediate into the reaction product follows two mechanistic
routes, viz. uncatalyzed and catalyzed ones.
kobsd = (k1k2[NH] + k1k3[NH]2)/(k−1 + k2 + k3[NH])
(1)
kobsd/[NH] = Kk2 + Kk3[NH], where K = k1/k−1
(2)
In fact, as shown in Figure 1B, the plot of kobsd/[NH] vs [NH]
is linear for the reaction of 1g with piperidine. The corresponding
plots for the reactions of 1g with the other amines are also linear
Figure 1. Plots of kobsd vs [NH] (A) and kobsd/[NH] vs [NH] (B) for the reaction of β-nitrostyrene (1g) with piperidine in MeCN at 25.0 0.1 °C.
B
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Scheme 2
as shown in Figures S1B−S4B in the Supporting Information,
indicating that the above assumption is valid under the
experimental conditions. Thus, the Kk2 and Kk3 values were
calculated from the intercept and the slope of the linear plots of
kobsd/[NH] vs [NH], respectively. The Kk2 and Kk3 values
calculated in this way are summarized in Table 1 for the reactions
of 1g with all the amines studied.
through a concerted mechanism, but is much smaller than the
value of 0.9 0.1 reported for the reactions proceeding through a
stepwise mechanism.11−15 Thus, one might suggest that the
current reactions proceed through a concerted mechanism with
TS structures similar to TSIII and TSV for the uncatalyzed and
catalyzed routes, respectively, as proposed previously by Oh et al.
for the reactions of 1g with a series of benzylamines in MeCN.8a
However, we propose that the current reactions proceed
through a stepwise mechanism as illustrated in Scheme 2 for the
following reasons, although the βnuc value of 0.51 or 0.61
obtained in this study is much smaller than that reported for the
aminolysis of esters which proceeds through a stepwise
mechanism. It has been reported that the k2 and k3 values for
aminolysis of esters are independent of the amine basic-
ity.11−13,16,17 Gresser and Jencks concluded that amine basicity
does not affect k2 in the aminolysis of diaryl carbonates, since
there is little or no electron donation from the aminium moiety of
the zwitterionic tetrahedral intermediate T to push out the
nucleofuge.11a A similar conclusion was drawn by Castro et al. for
the aminolysis of ethyl phenyl thionocarbonate,16a methyl 4-
nitrophenyl thionocarbonate,16b 4-methylphenyl 4-nitrophenyl
thionocarbonate,16c and 3-methoxyphenyl 4-nitrophenyl thio-
nocarbonate.16d It is also well-known that k3 is independent of
the amine basicity, since a more basic amine would deprotonate
more rapidly from the aminium moiety of T , while the aminium
ion would tend to hold the proton more strongly as the amine
becomes more basic.17 In contrast, the k2 and k3 values in the
current reactions would be highly dependent on the amine
basicity. This is because the rate constants for the proton transfer
processes (i.e., k2 for the uncatalyzed route through TSIII or TSIV,
and k3 for the catalyzed route via TSV) should decrease as the
amine basicity increases or vice versa. This accounts for the fact
that the βnuc value obtained in this study is much smaller than that
reported for aminolysis of esters, which proceeds through a
stepwise mechanism.
Table 1. Summary of Kinetic Data for the Reactions of β-
Nitrostyrene (1g) with Cyclic Secondary Amines in MeCN at
25.0 0.1 °C
a
amine
pKa
Kk2/M−1s−1 Kk3/M−2s−1
1
2
3
4
5
piperidine
18.8
18.6
18.5
17.6
16.6
0.685
0.642
0.695
0.180
0.0546
428
307
720
3-methylpiperidine
piperazine
1-(2-hydroxyethyl)piperazine
morpholine
71.3
19.0
a
The pKa data for the conjugate acid of the amine in MeCN were
taken from ref 9.
As shown in Table 1, the Kk2 and Kk3 values for the reactions
of 1g decrease as the amine basicity decreases, except those for
the reaction with piperazine. However, this is not an unexpected
result, since piperazine has two basic sites. It is also noted that the
rate constant for the catalyzed route (Kk3) is much larger than
that for the uncatalyzed process (Kk2) in all cases, indicating that
the current reactions proceed mainly through the catalyzed
process when the amine concentration is high (e.g., [amine] >
0.01 M).
Brønsted-Type Analysis: Effect of Amine Basicity on k2
and k3. To obtain more information on the TS structures,
Brønsted-type plots have been constructed for the reactions of 1g
with the cyclic secondary amines. As shown in Figure 2, the
Brønsted-type plots exhibit excellent linear correlations with βnuc
= 0.51 for Kk2 and βnuc = 0.61 for Kk3, when the rate constants
and pKa values are corrected statistically by p and q (i.e., p = 2
while q = 1 except q = 2 for piperazine).10 The βnuc value found
for the current reactions is roughly βnuc = 0.5−0.6, which is
typical of aminolysis of esters reported previously to proceed
Negative Enthalpy of Activation: Evidence for Pres-
ence of a Stable Intermediate. To obtain further information
on the reaction mechanism, the activation parameters (ΔH⧧ and
ΔS⧧) for the reaction of 1g with piperidine have been calculated
from the rate constants measured at five different temperatures.
C
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Figure 2. Brønsted-type plots for the reactions of β-nitrostyrene (1g) with cyclic secondary amines in MeCN at 25.0 0.1 °C. log Kk2 vs pKa (A); log
Kk3 vs pKa (B). The identity of the points is given in Table 1.
Figure 3. Plots of kobsd vs [NH] (A) and kobsd/[NH] vs [NH] (B) for the Michael-type reaction of β-nitrostyrene (1g) with piperidine in MeCN at 15.0
■
□
●
○
▲
( ), 20.0 ( ), 25.0 ( ), 30.0 ( ), 35.0 ( )
0.1 °C.
Table 2. Summary of Kinetic Results for the Reactions of β-Nitrostyrene (1g) with Piperidine in MeCN at Five Different
Temperatures
15.0 °C
20.0 °C
25.0 °C
30.0 °C
35.0 °C
ΔH⧧ (kcal mol−1
)
ΔS⧧ (eu)
Kk2 (M−1 s−1
Kk3 (M−2 s−1
)
)
0.483
550
0.568
490
0.685
428
0.848
389
1.04
334
6.22 0.28
−38.3 1.0
−63.0 0.6
−4.92 0.18
As shown in Figure 3, the plots of kobsd vs [NH] curve upward
(A), while those of kobsd/[NH] vs [NH] are linear with positive
intercept (B). Strikingly, the kobsd value decreases as the reaction
temperature increases. It is also noted that the slope of the linear
plots in Figure 3B decreases as the reaction temperature
increases, while the intercept of the linear plots increases with
increasing reaction temperature.
The Kk2 and Kk3 values for the reactions of 1g with piperidine
calculated from the intercept and slope of the linear plots are
summarized in Table 2 and are illustrated graphically as a
function of 1/T in Figure 4. The Arrhenius plots exhibit excellent
linear correlations for both the uncatalyzed and catalyzed
reactions, indicating that the ΔH⧧ and ΔS⧧ values calculated in
this way are highly reliable.
As shown in Table 2, the ΔH⧧ values are 6.22 and −4.92 kcal
mol−1 for the uncatalyzed and catalyzed reactions, respectively.
The negative ΔH⧧ value found for the catalyzed route is quite
surprising. However, it results from the fact that the reactivity of
1g decreases as the reaction temperature increases. A negative
ΔH⧧ value is definitive evidence for reactions which proceed
through a relatively stable intermediate.18 Thus, one can suggest
that the zwitterionic intermediate I (or II) as illustrated in
Scheme 2 is stable even in the aprotic solvent.
It is well-known that MeCN is a good cation solvator, due to
the presence of nonbonding electrons.19 It is noted that the
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Figure 4. Arrhenius plots for the reactions of β-nitrostyrene (1g) with piperidine in MeCN. Kk2 (A) and Kk3 (B).
positive charge in the zwitterionic intermediate I (or II) is
localized on the NH+ moiety, while the negative charge is
delocalized through the β-carbon and the NO2 group.
Accordingly, I (or II), which might behave as a cation, could
be strongly solvated in MeCN through ion-dipole interactions.
This idea is consistent with the large negative ΔS⧧ values shown
in Table 2 (i.e., −38.3 and −63.0 eu for the uncatalyzed and
catalyzed processes, respectively).
Effect of Substituent X on Reactivity and Reaction
Mechanism. To obtain more conclusive information on the TS
structures, the reactions of X-substituted-β-nitrostyrenes (1a−j)
with piperidine have been carried out. As shown in Figures S5A-
S13A in the Supporting Information, the plots of kobsd vs [NH]
0.685 and 0.210 M−1 s−1 as the substituent X changes from 4-
NO2 to H and 4-NMe2, in turn. A similar result is observed for
the catalyzed reactions, although Kk3 is much larger than Kk2 for
a given substituent X.
The effects of the substituent X on Kk2 and Kk3 are illustrated
in Figure 5A and B, respectively. The Hammett plots are linear
with ρX = 0.84 for Kk2 and ρX = 2.10 for Kk3, indicating that the
rate constant for the catalyzed route (i.e., Kk3) is significantly
more sensitive to the electronic nature of the substituent X than
that for the uncatalyzed route (i.e., Kk2).
Many factors have been reported to influence the magnitude of
ρX (e.g., the charge type and basicity of nucleophile, the nature of
the reaction medium, the distance from the reaction site to the
substituent and the nature of the reaction mechanism).14b,21,22
Generally, a large ρX value has been reported for reactions with an
anionic nucleophile (or with a strongly basic nucleophile)21 and
for reactions in aprotic solvents,21 while a small ρX value has been
obtained for reactions of substrates possessing one −CH2− or
−CHCH− group14b,21 and for reactions reported to proceed
through an SN2 mechanism.22 The nucleophile, substrates and
reaction medium in this study are common for the catalyzed and
uncatalyzed routes. Thus, the above factors cannot be
responsible for the large difference in the ρX values found in
this study (i.e., ρX = 0.84 and 2.10 for Kk2 and Kk3, respectively).
The electronic nature of the substituent X would affect not
only the microscopic rate constants (i.e., K = k1/k−1, k2 and k3)
but also the contribution of the resonance structures I and II
illustrated in Scheme 2. The resonance structure I would be
expected to become the major contributor when the substituent
X is a strong EWG or vice versa. Besides, the equilibrium
constant K and the acidity of the NH+ moiety of the zwitterionic
intermediate should increase as the substituent X changes from
an EDG to an EWG. It is apparent that the enhanced acidity
would accelerate the proton transfer, if it occurs from the NH+
moiety to the negatively charged β-carbon. Thus, the Hammett
plots for both the Kk2 and Kk3 terms would result in a large ρX if
the reactions proceed through TSIII for the uncatalyzed routes
and via TSV for the catalyzed reactions.
curve upward in all cases. On the other hand, the plots of kobsd
/
[NH] vs [NH] shown in Figures S5B−S13B in the Supporting
Information are linear with a positive intercept, implying that k−1
≫ k2 + k3[NH]. Thus, the Kk2 and Kk3 values were calculated
from the intercept and slope of the linear plots of kobsd/[NH] vs
[NH], respectively. The Kk2 and Kk3 values calculated in this way
are summarized together with the σX values of the substituent X
in Table 3.
As shown in Table 3, the rate constant for the uncatalyzed
reactions (i.e., Kk2) decreases as the substituent X changes from a
strong electron-withdrawing group (EWG) to a strong electron-
donating group (EDG), e.g., it decreases from 5.08 M−1 s−1 to
Table 3. Summary of kinetic Data for the Reactions of X-
Substituted β-Nitrostyrenes (1a−j) with Piperidine in MeCN
at 25.0 0.1 °C
a
entry
X
σX
Kk2 (M−1 s−1
)
Kk3 (M−2 s−1
)
1a
1b
1c
1d
1e
1f
4-NO2
3-NO2
4-CN
4-Cl
0.78
0.71
0.66
0.23
0.12
0.12
0
5.08
11800
10700
7520
1190
499
3.21
2.93
1.11
3-MeO
3-OH
H
0.685
0.761
0.685
0.569
0.463
0.210
375
1g
1h
1i
428
4-Me
−0.17
−0.27
−0.83
165
On the contrary, if the proton transfer occurs from the NH+
moiety to the negatively charged oxygen atom of the NO2 group
(i.e., through TSIV for the uncatalyzed route), the rate of proton
transfer would not increase significantly although the substituent
4-MeO
4-NMe2
66.5
5.63
1j
a
The σX values were taken from ref 20.
E
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Figure 5. Hammett plots for the reactions of X-substituted β-nitrostyrenes (1a−j) with piperidine in MeCN at 25.0 0.1 °C. log Kk2 vs σX (A); log Kk3
vs σX (B). The identity of points is given in Table 3.
Kinetics. The kinetic study was carried out using a UV−vis
spectrophotometer for slow reactions (t1/2 > 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 disappearance of the substrate at a fixed wavelength
corresponding to the maximum absorption (λmax, e.g., 309 nm for β-
nitrostyrene). 1H NMR spectra for the reactions confirmed the reaction
products as previously reported.5,8a Typically, the reaction was initiated
by the injection of 5 μL of a 0.02 M β-nitrostyrene (1g) stock solution
(MeCN) via a 10 μL syringe into a 10 mm UV cell containing 2.50 mL of
the reaction medium and the amine. The amine stock solution (ca. 0.2
M) was prepared in a 25.0 mL volumetric flask under nitrogen. The
transfer of the solutions was carried out by means of gastight syringes. All
reactions were carried out under pseudo-first-order conditions in which
the amine concentrations were at least 20 times greater than the
substrate concentration.
X becomes a strong EWG. This is because the resonance
structure II, from which TSIV is formed, would be the minor
contributor when the substituent X becomes a strong EWG.
Accordingly, a small ρX value would be expected if the
uncatalyzed reactions proceed through TSIV. In fact, Figure 5
shows that the ρX value for the uncatalyzed reaction is much
smaller than that for the catalyzed reaction. Thus, one can
conclude that the uncatalyzed reactions proceed through TSIV,
but not via TSIII. This is consistent with the idea that the four-
membered cyclic TS (i.e., TSIII) would be much less stable than
the six-membered one (i.e., TSIV).
CONCLUSIONS
■
The current study has allowed us to conclude the following: (1)
The curved plots of kobsd vs [NH] suggest that the reactions
proceed through catalyzed and uncatalyzed routes. The
dissection of kobsd into Kk2 and Kk3 has revealed that the
reactions proceed mainly through the catalyzed route when
[amine] > 0.01M. (2) The Brønsted-type plots for the reactions
of 1g with the amines are linear with βnuc = 0.51 and 0.61 for the
uncatalyzed and catalyzed reactions, respectively. The decrease
in the rate of proton transfer from the NH+ moiety as the amine
basicity increases is responsible for the small βnuc values. (3) The
negative ΔH‡ value found in this study is definitive evidence for
the presence of a relatively stable intermediate. (4) The
electronic nature of the substituent X affects the contribution
of the resonance structures I and II, i.e., the former becomes the
major contributor when X is a strong EWG and vice versa. (5)
The Hammett plots for the reactions of 1a−j with piperidine are
linear with ρX = 0.84 and 2.10 for Kk2 and Kk3, respectively. The
small ρX value for the uncatalyzed reactions supports the
hypothesis that the reactions proceed through TSIV rather than
through TSIII.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures S1−S13 for plots of kobsd vs [NH] (A) and kobsd/[NH] vs
[NH] (B) for the reactions of β-nitrostyrenes with alicyclic
secondary amines in MeCN at 25.0 0.1 °C. Tables S1−S14 for
kinetic conditions and data for the reactions of β-nitrostyrenes
with alicyclic secondary amines in MeCN at 25.0
0.1 °C.
Tables S15−S18 for kinetic conditions and data for the reactions
of β-nitrostyrene 1g with piperidine in MeCN at 5 different
temperatures. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ihum@ewha.ac.kr.
Notes
The authors declare no competing financial interest.
EXPERIMENTAL SECTION
■
ACKNOWLEDGMENTS
■
Materials. X-Substituted β-nitrostyrenes (1a−j) were readily
synthesized by the literature methods.8a,23 The crude products were
purified by column chromatography (silica gel and 20% ethyl acetate/
80% n-hexane), and their purity was checked by their melting points and
1H NMR spectra. The amines studied were of the highest quality
available. MeCN was distilled over P2O5 and stored under nitrogen.
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(2012-R1A1B-3001637). J.S.K. is also grateful for the BK 21
Scholarship.
F
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(15) (a) Um, I. H.; Akhtar, K.; Shin, Y. H.; Han, J. Y. J. Org. Chem.
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J. Org. Chem. 2009, 74, 3073−3078.
(16) (a) Castro, E. A.; Cubillos, M.; Santos, J. G. J. Org. Chem. 1996, 61,
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