Michael addition kinetics of ethyl acetoacetate and 2-ethylhexyl acrylate in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2012.02.003

The Michael addition is one of the most common and versatile methods for making carbon-carbon bonds, however little is known about the potential of utilizing ionic liquids as solvents in these reactions. Initial work from our laboratory is presented, showing that model imidazolium- and phosphonium-based ionic liquid solvents can be used as effective reaction media in the Michael addition. Kinetic data are also reported and the results indicate that the use of ionic liquids as reaction media resulted in an observed rate enhancement when compared with more common organic solvents such as toluene, THF, and DMF. Observed rates were comparable to those observed in DMSO.

Full text of DOI:10.1016/j.tetlet.2012.02.003

Tetrahedron Letters 53 (2012) 1855–1858
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Michael addition kinetics of ethyl acetoacetate and 2-ethylhexyl acrylate
in ionic liquids
⇑
Brandy N. Bradford, Kevin M. Miller
Department of Chemistry, Murray State University, Murray, KY 42071-3300, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The Michael addition is one of the most common and versatile methods for making carbon–carbon bonds,
however little is known about the potential of utilizing ionic liquids as solvents in these reactions. Initial
work from our laboratory is presented, showing that model imidazolium- and phosphonium-based ionic
liquid solvents can be used as effective reaction media in the Michael addition. Kinetic data are also
reported and the results indicate that the use of ionic liquids as reaction media resulted in an observed
rate enhancement when compared with more common organic solvents such as toluene, THF, and DMF.
Observed rates were comparable to those observed in DMSO.
Received 14 December 2011
Revised 30 January 2012
Accepted 1 February 2012
Available online 9 February 2012
Keywords:
Ionic liquid
Michael addition
Imidazolium
Ó 2012 Elsevier Ltd. All rights reserved.
Phosphonium
Conjugate addition
An ionic liquid is typically defined as a salt consisting com-
pletely of transient cation–anion pairs that exists in a liquid state
below 100 °C. Over the past decade, it has been shown that many
ionic liquids possess low vapor pressures, flammabilities, and
toxicity levels.1 For this reason ionic liquids have been viewed as
possible ‘greener’ reaction media and continue to be placed at
the fore-front of ongoing research as potential replacements for
more common volatile organic solvents.
Current research efforts are primarily focused on ionic liquids as
solvents in more ‘classical’ organic reactions. A number of such reac-
tions have already been investigated and reported in the literature,
some of which include Diels–Alder cycloadditions,2 Grignard,3
Friedel–Crafts,4 aromatic nitration5 as well as more fundamental
SN1 and SN2 reactions.6,7 In these reactions, various combinations
of cations and anions were employed to determine their effects on
reaction products, yields, and occasionally kinetics.
2-addition of the enolate since the more stable carbon–oxygen
p
bond is maintained (versus the less stable carbon–carbon bond).
p
The work described here is a follow-up to results previously
published in part by our research group on the effects of catalyst
and solvent on the rate of the reaction between ethyl acetoacetate
and 2-ethylhexyl acrylate.8 As shown in Scheme 1, a base catalyst
is employed to deprotonate ethyl acetoacetate (pKa = 10.7), gener-
ating the enolate anion 1.9,10 The enolate will then react with the
electrophilic acrylate at the b-position, producing another enolate
anion 2. Rapid proton transfer is the last step of the reaction and
O
O
O
O
Base
fast
1
EtO
CH3
EtO
CH3
H
In this Letter, we report a series of studies which focus on the ini-
tial effects of imidazolium- and phosphonium-based ionic liquids
as reaction media for the Michael addition reaction. This reaction
is one of the most efficient and versatile methods of forming a
carbon–carbon bond in organic chemistry, and therefore finding
alternative solvents in which to perform the reaction is attractive.
The Michael addition involves the 1,4-conjugate addition of an
enolate anion (referred to as the Michael donor) to an activated
O
O
slow
RDS
O
O
O
O
Base-H
fast
2
EtO
CH3
EtO
CH3
O
a,b-unsaturated carbonyl containing compound (the Michael
acceptor). Conjugate addition is favored over the competing 1,
3
O
O
O
⇑
Corresponding author. Tel.: +1 270 809 3543; fax: +1 270 809 6474.
E-mail address: kmiller38@murraystate.edu (K.M. Miller).
Scheme 1. Michael addition mechanism.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.003

1856
B. N. Bradford, K. M. Miller / Tetrahedron Letters 53 (2012) 1855–1858
serves to regenerate the base catalyst and produce the final
Michael adduct 3.
literature.13 The preparation of [pnmim][NTf2] involved first
the synthesis of [pnmim][Br] through the reaction of
4
The reaction kinetics of the Michael addition have been studied
extensively and are dependent upon base type and concentration
as well as the concentrations of both the Michael donor (acetoace-
tate in this case) and the Michael acceptor (acrylate).10 We have
previously shown in our group that when moderate base catalysts
such as amines are employed, the concentration of the enolate an-
ion is approximately equal to the concentration of the base when
the acetoacetate is allowed to pre-equilibrate with the catalyst
prior to the addition of the acrylate.8,9 This results in a steady-state
concentration of the enolate anion and a rate law which follows
pseudo-first order kinetics with respect to the concentration of
the Michael acceptor (acrylate):
N-methylimidazole and 1-bromopentane. Anion exchange with
lithium bis(trifluoromethylsulfonimide) resulted in the desired
ionic liquid 5. The phosphonium ionic liquid 6 was prepared by
anion exchange of commercially available [THTDP][Br] with
lithium bis(trifluoromethylsulfonimide). Once the desired ionic liq-
uids were isolated, they were dried in a vacuum oven at 60 °C until
a constant mass was obtained to ensure that any trace solvent and/
or moisture had been removed (<0.01% water).
Once the ionic liquids were isolated and structural analysis
completed, a series of kinetic studies were conducted in which
the pseudo-first order loss of 2-ethylhexyl acrylate was monitored
by 1H NMR over time. Concentrations of DBU were held at either 1
or 3 mol %. Rate data, half-lives, solvent choice, and catalyst levels
are provided in Table 1. All kinetic runs were completed at 35 °C in
duplicate with an error of 2% and correlation coefficients of 0.998
or greater.
Rate ¼ kobs½Acrylateꢀ
Michael addition reactions have been conducted in a number of
different molecular solvents ranging from non-polar solvents such
as toluene and tetrahydrofuran to polar solvents such as N,N-
dimethylformamide (DMF) and dimethylsulfoxide (DMSO). Ionic
liquids provide a unique alternative to these more common molec-
ular solvents but have been reported sparingly in the literature.
Ranu and co-workers have shown that imidazolium ionic liquids
with a hydroxide counter-anion will self-catalyze the Michael
addition of activated methylene compounds to conjugated ketones
and esters.11 Toma and co-workers investigated the kinetics of the
addition of highly acidic/active methylene compounds to chalcone
and have found the reaction to proceed readily in imidazolium
ionic liquids; however, residual N-methylimidazole from the ionic
liquid synthesis is thought to have compromised the rate data.12 In
the present work, the system chosen avoids this complication
since ethyl acetoacetate that is not sufficiently acidic enough to
be deprotonated by residual ionic liquid precursors such as N-
methylimidazole.
The data in Table 1 show that both catalyst concentration and
solvent choice have a significant effect on the reaction rate of the
Michael addition. Increasing the catalyst level from 1 to 3 mol % in-
creases the steady-state concentration of enolate anion and thus
results in an expected rate enhancement.
When the catalyst level was held constant, molecular solvents
such as the relatively non-polar toluene and THF resulted in the
lowest observed reaction rates (entries 4–7), use of the more polar
DMF resulted in a moderate increase in observed reaction rates
(entries 8–9) while reactions in the highly polar DMSO gave rise
to the largest rate enhancements (entries 10–11). This relative rate
profile for molecular solvents observed here was expected and fol-
lows work we previously reported on for the Michael addition as
well as reports of other enolate addition reactions.8,14,15 Highly po-
lar solvents such as DMSO are known to disrupt enolate aggrega-
tion through cation solvation,14 thus providing
a stabilized
The present study will look to investigate the effects of various
solvents, including two model ionic liquids, on the Michael addition
reaction of ethyl acetoacetate and 2-ethylhexyl acrylate using the
base catalyst DBU (1,8-diazobicyclo[5.4.0]undec-7-ene). The
molecular solvents chosen have a wide range in dielectric constants
and include toluene, tetrahydrofuran (THF), N,N-dimethylformam-
ide (DMF), and dimethylsulfoxide (DMSO). The two model ionic
liquids that were prepared and used include N-pentyl-N0-methyl-
imidazolium bis(trifluoromethylsulfonamide) [pnmim][NTf2] and
trihexyltetradecyl-phosphonium bis(tri-fluoromethylsulfonamide)
[THTDP][NTf2].
transition state(s) for the reaction, leading to lower activation
energies and faster kinetics.
Use of the ionic liquids [pnmim][NTf2] and [THTDP][NTf2] as
reaction media (entries 12–13 and 15–16 respectively) resulted
in observed rates that were comparable to DMSO. This large rate
enhancement was unexpected since the reported studies concern-
ing the polarities of ionic liquids place them in the same range as
short chain alcohols (e
T = 11.45 for [pnmim][NTf2]).16 The source
of this unexpected rate enhancement cannot be fully explained
given the limited data presented here, however it has been specu-
lated that nucleophilicity may be enhanced in ionic liquids due to
some reduction in the degree of ion pairing.7,17 Additionally, one
could envision that the imidazolium and phosphonium cations
The syntheses of the model ionic liquids are shown in Scheme 2
and are based upon procedures previously reported in the
Scheme 2. Ionic liquid syntheses.

B. N. Bradford, K. M. Miller / Tetrahedron Letters 53 (2012) 1855–1858
1857
Table 1
Observed Michael addition rate data at 35 °C
Entry
Solvent
Catalyst
Catalyst load (%)
Rate constanta (kobs ꢁ 10ꢂ2
)
Relative rateb
Half-life t1/2 (min)
1
2
None
None
None
Toluene
Toluene
THF
THF
DMF
DMF
DMSO
DMSO
[pnmim][TNf2]
[pnmim][TNf2]
[pnmim][TNf2]
[THTDP][NTf2]
[THTDP][NTf2]
[THTDP][NTf2]
DBU
DBU
1 mol
3 mol
3 mol
1 mol
3 mol
1 mol
3 mol
1 mol
3 mol
1 mol
3 mol
1 mol
3 mol
—
1.11
4.66
—
1.00
1.00
—
62.5
14.9
—
3c
4
N-Methylimidazole
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
No catalyst
DBU
0.17
0.75
0.26
0.92
0.95
3.34
2.69
10.2
2.50
10.1
—
0.15
0.16
0.23
0.20
0.86
0.72
2.39
2.19
2.55
2.17
—
400
91.9
266
75.1
73.1
20.8
25.8
6.78
27.8
6.89
—
5
6
7
8
9
10
11
12
13
14c
15
16
17c
1 mol
3 mol
—
2.81
11.1
—
2.53
2.38
—
24.6
6.25
—
DBU
No catalyst
a
b
c
Average of duplicate runs (error 2 %).
Relative rates were determined for each catalyst load level (1 and 3 mol %).
No reaction was observed.
added to the solution are less likely to be strongly enthalpically
bound to the enolate, thereby providing little solvent stabilization
and increasing reactivity. Ionic liquids may also improve the dis-
persion of charge in the transition state, resulting in increased sta-
bilization. Additional studies are warranted in conjunction with
the present system to better identify the source of the unexpected
rate enhancements.
One potential issue with the use of imidazolium ionic liquids in
base-catalyzed reactions is the potential formation of N-heterocy-
clic carbenes (NHCs) as a result of deprotonation at the 2-position
on the imidazolium ring.18 The deprotonation, which has been re-
ported to occur despite an unfavorable difference in pKa values,19
generally leads to substitution products. In the present kinetic
studies however, no evidence of imidazolium substitution over
the course of the experiment was observed.
due to the properties of the ionic liquid as a solvent and that they
do not self-catalyze the reaction.
Figure 1 shows a comparative pseudo-first order plot of the log-
arithm of acrylate concentration verses time in the presence of
3 mol % DBU. The starting acrylate concentrations were normalized
to allow for an accurate comparison. Note that use of the imidazo-
lium and phosphonium-based ionic liquids resulted in a rate
enhancement when compared to non-polar solvents such as tolu-
ene and THF or even the more polar solvent DMF. Observed rates
were comparable to those found in DMSO. Any rate effects ob-
served in comparison to the solventless system are believed to
be due to a combination of factors, including solvent polarity and
dilution.
Figure 2 shows a comparative first-order plot of the logarithm
of acrylate concentration verses time in the presence of 1 mol %
DBU. As with the previously described data at 3 mol %, the model
ionic liquids show similar effects on the reaction rates in compar-
ison to other solvent systems.
Furthermore, no reaction was observed in [pnmim][NTf2] or
[THTDP][NTf2] without catalyst after several days at 35 °C. It was
also noted that N-methylimidazole (the precursor to the imidazo-
lium ionic liquids), at a concentration of 3 mol %, did not result in
any observable reaction over several days at 35 °C. This supports
the hypothesis that the observed rate enhancements are truly
In summary, initial attempts at employing ionic liquids as
reaction media in the Michael addition of ethyl acetoacetate and
2-ethylhexylacrylate were successful and reaction rates were
Figure 1. Pseudo-first order plot of ln[acrylate] versus time in various solvent systems at 3 mol % DBU.

1858
B. N. Bradford, K. M. Miller / Tetrahedron Letters 53 (2012) 1855–1858
Figure 2. Pseudo-first order plot of ln[Acrylate] versus time in various solvent systems at 1 mol % DBU.
determined for systems in which model imidazolium and phospho-
nium-based ionic liquids were used as solvents. When compared to
more common molecular solvents typically used in Michael addi-
tion reactions, the observed rates in ionic liquids were faster than
those found in toluene or THF by a factor of 10 or more, twice as fast
as rates in DMF and analogous to rates in DMSO. A better under-
standing of the source of this unexpected rate enhancement will
be the subject of future research.
versus time yielded linear trends with correlation coefficients
equal to or greater than 0.998. Product analysis during the kinetic
experiments indicated the formation of only Michael adduct 3, the
analysis of which matched the previously described data.8
Acknowledgments
The authors wish to thank the Department of Chemistry at
Murray State University and The Research Corporation for Science
Advancement (Cottrell College Science Award) for financial
support of this work.
Experimental
General
References and notes
Anhydrous solvents such as tetrahydrofuran (THF), N,N-dimeth-
ylformamide (DMF), toluene, and dimethylsulfoxide (DMSO) were
purchased from Acros Organics and used without any further puri-
fication. All other reagents were used as received from Acros
Organics or Sigma–Aldrich Chemicals. All water used in the ionic
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All kinetic studies were performed using a previously published
protocol developed by our group.8 In a sample experiment, ethyl
acetoacetate (0.92 g, 7.1 mmol) was dissolved in [pnmim][NTf2]
(2.23 g, a 50% dilution overall) and added to a round bottomed
flask containing DBU (65 mg, 0.43 mmol, 3 mol %) and a magnetic
stir bar. The resulting solution was stirred at 35 °C for 2 h. This
solution was then mixed with 2-ethylhexyl acrylate (1.31 g,
7.1 mmol, pre-warmed to 35 °C) and held for two minutes at
35 °C prior to the beginning of the kinetic run. Samples (ꢃ5 mg)
were taken periodically, quenched in a 0.4 M solution of acetic acid
in CDCl3, and analyzed by 1H NMR. For each datapoint, the multi-
plet which accounts for the two methyl groups of 2-ethylhexyl
acrylate at 0.85 ppm was used as the standard in which to measure
the disappearance of the vinylic signal at 5.80 ppm over time.
Experiments were followed for at least two half-lives and were
completed in duplicate with calculated rate constants ( 2% error).
Pseudo-first order plots of the logarithm of acrylate concentration
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