A unified mechanistic view on the Morita-Baylis-Hillman reaction: Computational and experimental investigations

Article abstract of DOI:10.1021/jo102094h

The thermodynamic properties and reaction mechanism of the Morita-Baylis-Hillman (MBH) reaction have been investigated through experimental and computational techniques. The impossibility to accelerate this synthetically valuable transformation by increasing the reaction temperature has been rationalized by variable-temperature experiments and MP2 theoretical calculations of the reaction thermodynamics. An increase in temperature results in a switching of the equilibrium to the reactants occurring at even moderate temperature levels. The complex reaction mechanism for the MBH reaction has been investigated through an in-depth analysis of the suggested alternative pathways, using the M06-2X computational method. The results provided by this theoretical approach are in agreement with all the experimental/kinetic evidence such as reaction order, acceleration by protic species (methanol, phenol), and autocatalysis. In particular, the existing controversy about the character of the key proton transfer in the MBH reaction (Aggarwal versus McQuade pathways) has been resolved. Depending on the specific reaction conditions both suggested pathways are competing mechanisms, and depending on the amount of protic species and the reaction progress (early or late stage) either of the two mechanisms will be favored.

Full text of DOI:10.1021/jo102094h

pubs.acs.org/joc
A Unified Mechanistic View on the Morita-Baylis-Hillman Reaction:
Computational and Experimental Investigations
David Cantillo*,† and C. Oliver Kappe*
Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry,
Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria. †On leave from the Departamento
´
ꢀ
de Quımica Organica e Inorganica, QUOREX Research Group, Facultad de Ciencias, Universidad de
ꢀ
Extremadura, E-06006 Badajoz, Spain
dcannie@unex.es; oliver.kappe@uni-graz.at
Received October 22, 2010
The thermodynamic properties and reaction mechanism of the Morita-Baylis-Hillman (MBH)
reaction have been investigated through experimental and computational techniques. The impossi-
bility to accelerate this synthetically valuable transformation by increasing the reaction temperature
has been rationalized by variable-temperature experiments and MP2 theoretical calculations of the
reaction thermodynamics. An increase in temperature results in a switching of the equilibrium to
the reactants occurring at even moderate temperature levels. The complex reaction mechanism for
the MBH reaction has been investigated through an in-depth analysis of the suggested alternative
pathways, using the M06-2X computational method. The results provided by this theoretical
approach are in agreement with all the experimental/kinetic evidence such as reaction order, accelera-
tion by protic species (methanol, phenol), and autocatalysis. In particular, the existing controversy
about the character of the key proton transfer in the MBH reaction (Aggarwal versus McQuade
pathways) has been resolved. Depending on the specific reaction conditions both suggested pathways
are competing mechanisms, and depending on the amount of protic species and the reaction progress
(early or late stage) either of the two mechanisms will be favored.
Introduction
reaction between a carbonyl-based electrophile and a Mi-
chael acceptor densely functionalized products containing a
new stereocenter can be obtained in a single-step operation
without generating any waste or byproducts (Scheme 1).
Because of its atom economic nature, the utilization of
relatively simple starting materials, and its comparatively
wide substrate scope, this carbon-carbon bond forming
protocol has found numerous applications in synthetic or-
ganic chemistry in the past two decades, including the
development of asymmetric and intramolecular versions.1,2
Despite the fact that the MBH reaction has been first
described more than 40 years ago,3 there is still an ongoing
debate in the scientific community on the exact reaction
mechanism and the kinetics of this important synthetic
The Morita-Baylis-Hillman (MBH) reaction is arguably
one of the most powerful and versatile carbon-carbon bond
forming methods in organic synthesis.1,2 In this catalytic
(1) For a recent review with more than 1000 references on the MBH
reaction, see: Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010,
110, 5447–5674.
(2) For other selected reviews, see: (a) Basavaiah, D.; Rao, K. V.; Reddy,
R. J. Chem. Soc. Rev. 2007, 36, 1581–1588. (b) Masson, G.; Housseman, C.;
Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614–4628. (c) Basavaiah, D.; Rao,
J. A.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–891. (d) Langer, P.
Angew. Chem., Int. Ed. 2000, 39, 3049–3052. (e) Ciganek, E. In Organic
Reactions; Paquette, L. A., Ed.; Wiley: New York, 1997; Vol. 51, pp 201-
350. (f ) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001–
8062. (g) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653–4670.
DOI: 10.1021/jo102094h
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Published on Web 11/17/2010
J. Org. Chem. 2010, 75, 8615–8626 8615
2010 American Chemical Society

Cantillo and Kappe
JOCArticle
SCHEME 1. The Morita-Baylis-Hillman (MBH) Reaction
and the General Reaction Mechanism Proposed by Hill and Isaacs
transformation.4-13 While the global mechanistic sequence
and catalytic cycle shown in Scheme 1 first suggested by Hill
and Isaacs in the late 1980s is widely accepted today,4 the
current discussion is focusing on the mechanism of the
proton 1,3-shift and the nature of the rate-determining step
(RDS). On the basis of the initial attempts to shed light on
the reaction mechanism through kinetic studies by Hill and
Isaac,4 the proposed RDS was assumed to be the carbon-
carbon bond formation in the aldolic addition reaction of the
zwitterionic amine-acrylate adduct 3 and an aldehyde mole-
cule 4. This proposal was supported by subsequent inde-
pendent investigations including the interception of all key
intermediates using electrospray ionization with mass and
tandem mass spectrometry5 and X-ray analysis of one the
intermediates in the catalytic cycle (3).6
FIGURE 1. Current mechanistic proposals for the Morita-Baylis-
Hillman (MBH) reaction.
autocatalysis after approximately 20% conversion,8 while
McQuade observed a second-order character for the alde-
hyde in the reaction.7 On the basis of these experimental
findings two new mechanistic hypotheses were proposed as
outlined in Figure 1. The viewpoints differ in the manner in
which the hydrogen migration takes place, and to date this
question has not been fully resolved. In fact, recent electro-
spray ionization mass spectrometry studies provide strong
experimental evidence that both mechanisms are possible.9
The ongoing debate about the character of the key path-
ways and transition states prompted Aggarwal and Harvey
to perform a detailed computational study on the MBH
reaction.10 In their work, the role of the alcohol species
(methanol) along with the mechanism proposed by McQuade
with a second-order kinetics for the aldehyde were discussed.
However, these theoretical investigations could not complete-
ly address all the known experimental findings in the MBH
reaction, such as the observed second-order kinetics for the
reaction even in the presence of protic solvents7 (which was
hypothesized by Aggarwal and Harvey to be the result of
different aldehyde reactivities), or the important influence
of temperature on the reaction thermodynamics.1,2 In our
opinion, these open points are likely to be the result of the
recently discovered extremely poor performance of the cho-
sen computational method (B3LYP) in predicting the barrier
heights for the MBH reaction,11 and the lack of vibrational
analysis that only allows an estimate of free energies.
However, more recently the groups of McQuade7 and
Aggarwal8 reinvestigated the kinetics of the MBH reaction
by means of the kinetic isotope effect (KIE) employing an
R-2H acrylate precursor and proposed the RDS to be the
proton transfer step 5 f 6. In the above-mentioned experi-
ments Aggarwal also observed that the reaction shows
(3) (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41,
2815–2815. (b) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113,
1972; Chem. Abstr. 1972, 77, 34174q.
(4) (a) Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem. 1990, 3, 285–288.
(b) Hill, J. S.; Isaacs, N. S. J. Chem. Res. 1988, 330. (c) Hill, J. S.; Isaacs, N. S.
Tetrahedron Lett. 1996, 27, 5007–5010.
(5) Santos, L. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.; Eberlin,
M. N. Angew. Chem., Int. Ed. 2004, 43, 4330–4333.
(6) Drewes, E.; Njamela, O. L.; Emslie, N. D.; Ramesar, N.; Field, J. S.
Synth. Commun. 1993, 23, 2807–2815.
(7) (a) Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org.
Lett. 2005, 7, 147–150. (b) Price, K. E.; Broadwater, S. J.; Walker, B. J.;
McQuade, D. T. J. Org. Chem. 2005, 70, 3980–3987.
(8) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew. Chem.,
Int. Ed. 2005, 44, 1706–1708.
(9) Amarante, G. W.; Milagre, H. M. S.; Vaz, B. G.; Ferreira, B. R. V.;
Eberlin, M. N.; Coelho, F. J. Org. Chem. 2009, 74, 3031–3037.
(10) Robiette, R.; Aggarwal, V. K.; Harvey, J. N. J. Am. Chem. Soc. 2007,
129, 15513–15525.
Apart from the Aggarwal/Harvey investigation mentioned
above,10 a few additional computational studies recently ap-
peared in the literature attempting to address mechanistic
questions in the MBH reaction, including the addition of
explicit water or methanol molecules.12 However, in all these
studies the inappropriate B3LYP method was used, or
potential electronic energies were employed to describe the
energetics instead of the more adequate free energies.12 In
this context, it should be mentioned that the theoretical
approach of Sunoj,13 who employed CBS-4 M and mPW1K
(11) Harvey, J. N. Faraday Discuss. 2010, 145, 487–505.
(12) (a) Xu, J. J. THEOCHEM 2006, 767, 61–66. (b) Li, J. J. Theor.
Comput. Chem. 2010, 9, 65–75. (c) Jian-Fen, F.; Chun-Hong, Y.; Liang-Jun,
H. Int. J. Quantum Chem. 2009, 109, 1311–1321. (d) Dong, L.; Qin, S.; Su, Z.;
Yang, H.; Hu, C. Org. Biomol. Chem. 2010, 8, 3985–3991.
(13) (a) Roy, D.; Sunoj, R. B. Org. Lett. 2007, 9, 4873–4876. (b) Roy, D.;
Sunoj, R. B. Chem.;Eur. J. 2008, 14, 10530–10534. (c) Roy, D.; Patel, C.;
Sunoj, R. B. J. Org. Chem. 2009, 74, 6936–6943.
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methods to compute the free energy barriers for the reaction,
is interesting but only compares the energetics of the direct
proton transfer pathways (via a four-membered transition
structure) and the proton 1,3-shift assisted by water, omit-
ting the possibility of the assistance by a second molecule of
aldehyde or other protic species.
SCHEME 2. The DABCO-Catalyzed Morita-Baylis-
Hillman (MBH) Reaction of Aryl Aldehydes (4) with Methyl
Acrylate (2)
In the present work we present a detailed computational
and experimental reinvestigation on the amine-catalyzed
MBH reaction of benzaldehyde with methyl acrylate. In
particular, issues relating to the hitherto neglected tempera-
ture dependence of the thermodynamic properties;which
prevents the use of elevated temperatures as an activation
method in the otherwise sluggish MBH reaction;are ad-
dressed. In addition, we computationally reinvestigate, em-
ploying the recently introduced M06-2X method14 that pro-
vides accurate thermodynamics for carbon-carbon bond
forming reactions,15 all the previously suggested mechanistic
proposals for this transformation, emphasizing the most
controversial step: the proton migration from the R-carbon
to the oxygen derived from the aldehyde counterpart (Figure 1).
To fully address the mechanistic conundrum surrounding the
MBH reaction, we also take into consideration the reagents/
additives reported in the literature to activate this proton
migration step: a second molecule of aldehyde,7 alcohols,16
water,16,17 phenol,18 and the observed autocatalysis.8 Grati-
fyingly, these new calculations can rationalize all existing
experimental evidence, and most importantly, can settle the
argument about the character of the hydrogen migration
step, in particular the Aggarwal versus McQuade proposals
(Figure 1). On the basis of the present theoretical study and a
reinterpretation of the available kinetic data it can be con-
cluded that both mechanisms are competing reactions, and
depending on the reaction progress and conditions either of
the two pathways is favored.
stationary points. Ground and transition states were character-
ized by none and one imaginary frequencies, respectively.
All the presented relative energies are free energies with
respect to the reactants. As in previous studies,7,8,10,13 the
reaction of benzaldehyde with methyl acrylate and DABCO
was chosen as the model for the MBH reaction. In addition,
4-nitrobenzaldehyde and 4-methoxybenzaldehyde were also
employed in order to observe substituent effects in the tempera-
ture dependence studies. Since along the mechanistic pathways
several diastereomeric transition structures can be formed, all
the possibilities have been investigated and are presented in the
Supporting Information.
Results and Discussion
Temperature Dependence of Thermodynamic Properties.
For the present study we have chosen the reaction between
benzaldehyde (4a) and methyl acrylate (2) catalyzed by
diazabicyclo[2.2.2]octane (DABCO) (1) in methanol as the
model system, since this reaction can be considered the
archetypal MBH reaction and is one of the most experimen-
tally studied examples (Scheme 2).1-10 The most relevant
experimental and theoretical mechanistic studies on the
MBH reaction by McQuade7 and Aggarwal8,10 were also
carried out with this system. Additional experimental data
with 4-nitrobenzaldehyde (4b) instead of benzaldehyde have
also been reported.7
Computational Details
The available computational data on this transformation,
with similar energies for the reactants and the product, point
to a reversible character for the MBH reaction.10 However,
in a previous study7 attempts to experimentally observe the
reversibility of this model reaction (the reaction of 4a was
chosen in this study) were unsuccessful. To clarify this issue
for our model system, a purified sample of MBH adduct 6a
was resubjected to the reaction conditions. After dissolving
adduct 6a in methanol in the presence of DABCO (2 equiv)
and heating the mixture at 120 °C for 1 h the formation of
aldehyde substrate 4a in considerable amounts (∼68% by
GC-FID) was observed. Importantly, by letting the reaction
mixture stand at room temperature and monitoring the
progress continuously by GC-FID the equilibrium again
shifted to the product side, with 72% MBH adduct 6a being
observable after 24 h. These simple experimental studies not
only verify the reversible character of the MBH reaction, but
also point to a strong temperature dependence of the equi-
librium constant, in the sense that the adduct (6a) is favored
at low temperatures, while the reactants 4a þ 2 are the major
species at elevated temperatures.
All geometries and energies, as well as frequency calculations,
were computed with use of the Gaussian09 package.19 The
MP220 method along with the 6-311þG(d,p) basis set was
employed for the temperature dependence studies. In the case
of the pathway simulations, the M06-2X14 density-functional
method with the 6-311G(d,p) basis was used.21 The geometries
were optimized including the solvation effect. For this purpose
the SMD22 solvation method was employed, using methanol or
tetrahydrofuran as solvent. The frequency calculations on all
the stationary points were carried out at the same level of theory
as the geometry optimizations to ascertain the nature of the
(14) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215–241.
(15) Pieniazek, S. N.; Clemente, F. R.; Houk, K. N. Angew. Chem., Int.
Ed. 2008, 47, 7746–7749.
(16) Aggarwal, V. K.; Emme, I. S.; Fulford, Y. J. Org. Chem. 2003, 68,
692–700.
(17) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org. Lett. 2002, 4, 4723–4725.
(b) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J. Org. Chem.
2002, 67, 510–514.
(18) Faltin, C.; Fleming, E. M.; Connon, S. J. J. Org. Chem. 2004, 69,
6496–6499.
(19) Gaussian 09, Revision A.1; Frisch, M. J. et al. ; Gaussian, Inc.,
Wallingford, CT, 2009.
(20) Head-Gordon, M.; Pople, J. A.; Frisch, M. J. Chem. Phys. Lett. 1988,
153, 503–506.
(21) Single points calculations for key transition structures with the
6-311þG(d,p) basis set were also performed to ensure that the addition of
diffuse functions does not affect the drawn conclusions.
(22) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378–6396.
This temperature dependence can in principle be observed
in computational studies on the MBH reaction. In the
previous theoretical study by Aggarwal and Harvey10 no
frequency analysis of the stationary points is presented, thus
avoiding the chance to determine any temperature influence.
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JOCArticle
In principle, the fact that the equilibrium constant of a
chemical reaction can be temperature dependent is well-
known.24 The switch of ΔG from exergonic to endergonic
(negative to positive), which turns K > 1, occurs at a tem-
perature given by eq 1. The MBH reaction is somewhat
unusual since its enthalpy and entropy values in eq 1 result
in a switch to endergonic reaction near room temperature
(ΔH/ΔS ≈ 330 K). This coincidence results in a rare inver-
sion of the equilibrium when increasing the temperature even
slightly.
ΔH
ΔH - T ΔS ¼ 0 w T ¼
ð1Þ
3
ΔS
FIGURE 2. Theoretical (line) and experimental (dots) temperature
dependence of the equilibrium constant Keq (left) and free energy
ΔG (right) in the MBH reaction of benzaldehyde (4a) with methyl
acrylate (2) (Scheme 2).
The MBH reaction with 4-nitrobenzaldehyde (4b) as starting
material presents an interesting case since this substrate has
also been widely used in the MBH reaction,1,2 including the
McQuade kinetic studies on the reaction mechanism.7 In addi-
tion, some authors have shown that using 4-nitrobenzaldehyde
as a substrate the reaction can be heated (for example, using
microwave dielectric heating),25 which points to a likely change
in the temperature effect.1,2 Therefore, similar experiments
and calculations were performed with 4-nitrobenzaldehyde (4b)
and methyl acrylate (2) under otherwise identical conditions.
Figure 3 shows a comparison between the experimental tem-
perature dependence of the equilibrium constants and free
energies for the MBH reactions with benzaldehyde (4a) and
4-nitrobenzaldehyde (4b) as substrates. The difference in
thermodynamic properties between the two substrates con-
firms the possibility of carrying out MBH reactions with
4-nitrobenzaldehyde (4b) at higher temperatures, as this pro-
cess becomes endergonic only at temperatures above approxi-
mately 380 K (107 °C). This suggests that using, for an example,
an excess of acrylate 2, comparatively high conversions can be
achieved even at elevated temperatures.1,2
To further confirm the suitability of the selected ab initio
method for these investigations, we also calculated the
theoretical plot for the temperature dependence for the
4-nitrobenzaldehyde reaction at the same level of theory
(Figure 4). In addition, the data for 4-methoxybenzaldehyde
(4c), which could not be experimentally accessed because
of the exceedingly long reaction times, are also included. As
expected, the theoretical plot for the 4-nitrobenzaldehyde
reaction is displaced to higher temperatures with respect
to benzaldehyde in agreement with the experimental data
(cf. Figure 3). For 4-methoxybenzaldehyde the calcula-
tions indicate the opposite effect and thus an unfavored
reaction. This explains the low conversions and yields
obtained with electron-donor substrates, and reveals the end-
ergonic character of these MBH reactions even at moderate
temperatures.1,2
The Sunoj13 theoretical work employs free energies, but
focuses on the reaction energy barriers omitting the ener-
getics of the global process. The DFT method used in most of
the above-mentioned papers is B3LYP.23 This DFT method
along with the 6-311þG(d,p) basis set and the SMD solva-
tion method (using methanol as solvent) predicts a reaction
free energy of þ14.4 kcal mol-1 at 298.15 K for the MBH
reaction 4a þ 2 f 6a (Scheme 2) . This is obviously incorrect
since the reaction is spontaneous at room temperature. This
erroneous energetics along with previous observations11
about the energy barriers computed with this DFT method
clearly reveal the inadequacy of the B3LYP approach to
model the MBH reaction.
To understand the temperature influence in the MBH
thermodynamics a more accurate computational approach
is therefore required. For the present work the ab initio
method MP2, with the 6-311þG(d,p) basis set was selected.
The geometries were optimized including the solvent effect
(SMD model, methanol as solvent). At this theoretical level
we obtained the theoretical enthalpy and entropy of reaction,
-15.0 kcal mol-1 and -45.01 cal mol-1 K-1, respectively.
With these data we were able to display the dependence of
free energy of reaction ΔG and of the equilibrium constant
Keq with the temperature, as depicted in the Figure 2.
Noticeably, above approximately 330 K (57 °C) the reac-
tion becomes endergonic, providing a rationalization for the
fact that MBH reactions generally cannot be performed at
elevated temperatures.1,2 To further confirm this hypothesis
experimentally, we carried out the reaction shown in
Scheme 2 at different temperatures ranging from 293 to
383 K (20-90 °C) (above this temperature range it is difficult
to avoid the decomposition of the DABCO catalyst and the
polymerization of methyl acrylate). The different equilibri-
um constants were obtained (a detailed description can
be found in the Experimental Section and the Support-
ing Information) taking data points from 3 h to 7 d using
GC-FID monitoring, and from these values the experimental
enthalpy and entropy of reaction were calculated. These
resulting values were ΔH = -13.94 kcal mol-1 and ΔS =
-41.3 cal mol-1 K-1. The experimental plots (Figure 2) show
endergonic reactions above approximately 330 K (57 °C), as
the ab initio calculations predicted, and experimental thermo-
dynamic properties very close to the MP2 theoretical values.
Since the MBH reaction is known to be rather sluggish
generally requiring long reaction times, interest in the past
decades has focused on methods to accelerate this syntheti-
cally very useful process.1,2 In the context of our temperature-
dependence studies, the use of microwave irradiation is par-
ticularly interesting. Since the proposed mechanism for the
MBH reaction involves a series of polar (zwitterionic) inter-
mediates (Figure 1) the possibility of the involvement of
(24) Atkins, P.; de Paula, J. In Physical Chemistry for the Life Sciences, 1st ed.;
W.H. Freeman: New York, 2005; Chapter 4, pp 151-199.
(25) For a review on microwave-assisted MBH reactions, see: De Souza,
R. O. M. A.; Miranda, L. S. M. Mini Rev. Org. Chem. 2010, 7, 212–220.
(23) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
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JOCArticle
FIGURE 3. Experimental temperature dependence of the equilibrium constant Keq (left) and the free energy ΔG (right) in the MBH reaction of
4-nitrobenzaldehyde (4b) with methyl acrylate (2) (Scheme 2). For comparison purposes, the experimental free energy data for benzaldehyde
(4a) (cf. Figure 2) are also shown (blue line). Experimental thermodynamic data for 4-nitrobenzaldehyde (4b): ΔH=-19.01 kcal mol-1 and
ΔS=-50.1 cal mol-1 K-1
.
energy (entropy term) in the Arrhenius equation for certain
types of reactions.27 Furthermore, a similar effect has been
proposed for polar reaction mechanisms, where the polarity is
increased going from the ground state to the transition state,
resulting in an enhancement of reactivity by lowering the
activation energy.27 Specific microwave effects have been sug-
gested for a wide variety of synthetic transformations,27 includ-
ing for the MBH reaction.25
To establish if nonthermal microwave effects are involved
in MBH reactions carried out in a microwave field,25 we have
repeated the experiments involving benzaldehyde as sub-
strate described above using a single-mode microwave reactor28
instead of a standard conductive heating method. When using
internal temperature monitoring employing a fiber-optic probe
to ensure that accurate reaction temperatures are obtained,29
no difference in the kinetic data compared to standard con-
ductive heating was obtained.30 In addition, to ensure that the
electric field component of the microwave irradiation has no ef-
fect on the reaction energetics, we also included a field of 105 V
m-1 into the theoretical calculations, a field strength that is
approximately 10 times higher than that typically attained in a
commercial single-mode microwave reactor.31 Since very small
changes are expected in the thermodynamic properties of the
reaction when including an electric field of this strength, we
improved the default accuracy of the Gaussian09 software in
order to detect these very small changes. Thus, the SCF conver-
gence criteria were set to 10-10 atomic units, and the 2-electron
integral accuracy parameter was set to 10-14. The “NoVarAcc”
keyword was also included in order to switch to full inte-
gral accuracy in the SCF calculation. Table 1 collects the
FIGURE 4. Comparison of theoretical temperature dependence on
the free energies ΔG for the MBH reaction with benzaldehyde (4a),
4-nitrobenzaldehyde (4b), and 4-methoxybenzaldehyde (4c) as sub-
strates (Scheme 2). Computed (MP2) thermodynamic data: 4-
nitrobenzaldehyde (4b): ΔH=-16.18 kcal mol-1 and ΔS=-46.0
cal mol-1 K-1; 4-methoxybenzaldehyde (4c) (MP2): ΔH = -13.7
kcal mol-1 and ΔS=45.4 cal mol-1 K-1
.
so-called nonthermal microwave effects, stabilizing these inter-
mediates (or transition states) cannot be ruled out.26,27 Essen-
tially, nonthermal microwave effects have been postulated to
result from a proposed direct interaction of the electric field
with specific molecules in the reaction medium that is not
related to a macroscopic temperature effect. It has been argued,
for example, that the presence of an electric field leads to
orientation effects of dipolar molecules or intermediates and
hence changes the pre-exponential factor A or the activation
(28) (a) Obermayer, D.; Gutmann, B.; Kappe, C. O. Angew. Chem., Int.
Ed. 2009, 48, 8321–8342. (b) Gutmann, B.; Obermayer, D.; Reichart, B.;
Prekodravac, B.; Irfan, M.; Kremsner, J. M.; Kappe, C. O. Chem.;Eur. J.
2010, 16, 12182–1294.
(29) (a) Herrero, M. A.; Kremsner, J. M.; Kappe, C. O. J. Org. Chem.
2008, 73, 36–47. (b) Obermayer, D.; Kappe, C. O. Org. Biomol. Chem. 2010,
8, 114–121.
(30) Data points were obtained at 80 (8 h) and 90 °C (6 h). These
experiments are described in more detail in the Experimental Section and
the Supporting Information.
(31) (a) Robinson, J.; Kingman, S.; Irvine, D.; Licence, P.; Smith, A.;
Dimitrakis, G.; Obermayer, D.; Kappe, C. O. Phys. Chem. Chem. Phys. 2010,
12, 4750–4758. (b) Robinson, J.; Kingman, S.; Irvine, D.; Licence, P.; Smith,
A.; Dimitrakis, G.; Obermayer, D.; Kappe, C. O. Phys. Chem. Chem. Phys.
2010, 12, 10793–10800.
(26) For a more detailed definition and examples for thermal, specific,
and nonthermal microwave effects, see: (a) Kappe, C. O. Angew. Chem., Int.
Ed. 2004, 43, 6250. (b) Kappe, C. O.; Dallinger, D.; Murphree, S. S. Practical
Microwave Synthesis for Organic Chemists-Strategies, Instruments, and
Protocols; Wiley-VCH: Weinheim, Germany, 2009; pp 20-44.
(27) For leading reviews on microwave effects, see: (a) Perreux, L.;
Loupy, A. Tetrahedron 2001, 57, 9199. (b) Perreux, L.; Loupy, A. In
Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; Chapter 3, pp 61-114. (c) Perreux, L.; Loupy, A. In
Microwaves in Organic Synthesis, 2nd ed.; Loupy, A., Ed.; Wiley-VCH:
Weinheim, Germany, 2006; Chapter 4, pp 134-218. (d) De La Hoz, A.; Diaz-
Ortiz, A.; Moreno, A. Chem. Soc. Rev. 2005, 34, 164. (e) De La Hoz, A.; Diaz-
Ortiz, A.; Moreno, A. In Microwaves in Organic Synthesis, 2nd ed.; Loupy,
A., Ed.; Wiley-VCH: Weinheim, Germany, 2006; Chapter 5, pp 219-277.
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TABLE 1. Calculated Thermodynamic Properties for the Morita-Baylis-Hillman Reaction of Benzaldehyde (1a) with Methyl Acrylate (2) in the
Presence and Absence of an Electric Field (Scheme 2)
electric field strength (V m-1
)
ΔH (kcal mol-1
)
ΔS (kcal mol-1
)
ΔG (kcal mol-1
)
Keq
-14.9240
-14.9240
-45.111
-45.113
-1.4742
-1.4736
12.012
12.000
105
FIGURE 5. Energy profile for the formation of the zwitterionic intermediate 5 calculated at the M06-2X/6-311G(d,p) level (kcal mol-1).
thermodynamic properties and theoretical equilibrium constants
for the MBH reaction of benzaldehyde with methyl acrylate
in methanol (Scheme 2) at 298.15 K in the presence and absence
of a static electric field with a strength of 105 V m-1. The
observed differences are very small and rule out the possibil-
ity of any direct electric field effects (orientation effects) derived
from microwave irradiation on the reaction. These theoreti-
cal calculations therefore confirm, as has already been dis-
cussed by Stuerga,32 that the electric field in microwave reactors
is orders of magnitude too small to influence the thermodyna-
mic properties of a chemical reaction, and therefore makes the
existence of nonthermal microwave effects extremely
unlikely.
Pathway Calculations: General Considerations. The excel-
lent agreement between the computed and experimental
thermodynamic properties for the MBH reaction described
above and the recently discovered poor performance pro-
vided by B3LYP suggest that a computational reinvestiga-
tion of the reaction pathway of the MBH reaction utilizing a
proper level of theory would be highly desirable. Unfortu-
nately, the time cost for computing at the MP2/6-311þG(d,p)
level some of the transition states in the proposed reaction mech-
anisms is prohibitively expensive. Accordingly, it was neces-
sary to find a suitable DFT method that is able to reproduce, at
least qualitatively, the thermodynamics of the MBH reaction
with a reasonable time cost. To accomplish this goal we have
evaluated the M06-2X14 method, which has been shown to
deliver improved thermodynamics for carbon-carbon bond
forming reactions,15 along with the 6-311G(d,p) basis set,21
optimizing the geometries including the solvent effects through
the SMD solvation approach (using methanol as solvent).
This approximation provided reasonably good values for the
thermodynamic properties for the benzaldehyde case of ΔH=
-12.7 kcal mol-1 and ΔS=-43.54 cal mol-1 K-1, very close
to the experimental and comparable to the MP2 values (see
above), in stark contrast with the poor performance obtained
through the B3LYP approach, which predicts a value for the
reaction enthalpy of ΔH=þ1.4 kcal mol-1, which results in
ΔG=þ14.4 kcal mol-1. To evaluate if this DFT method can
also model the effect of the nitro group, we calculated the
thermodynamics for the 4-nitrobenzaldehyde reaction, which
were found to be -15.1 kcal mol-1 and -46.5 cal mol-1 K-1
,
again being very close to the MP2 results (see above). Figure S1
in the Supporting Information compares the performance of
MP2 versus M06-2X for the temperature dependence of the
free energies in the MBH reaction for benzaldehyde and
4-nitrobenzaldehyde.
Carbon-Carbon Bond Formation. All mechanistic propos-
als for the MBH reaction start with the formation of the
intermediate 5 (Scheme 1 and Figure 1). The first step is the
reversible Michael addition of the tertiary amine, in this study
DABCO (1), to methyl acrylate (2), with an energy barrier of
15.3 kcal mol-1. The formation of the initial zwitterionic
intermediate 3 is endothermic by 11.0 kcal mol-1. The cou-
pling of 3 with the benzaldehyde is an aldol addition and one
of the proposed rate-determining steps (RDS) for the MBH
reaction to produce intermediate 5. The barrier for the
formation of 5 is 20.2 kcal mol-1 with respect to the separated
reactants. Figure 5 shows the calculated energy profile for the
formation of the intermediates, and Figure 6 the optimized
geometry for the key transition state 8. From this structure
there are different proposals for the formation of the MBH
adduct 6 (Figure 1), in which the proton transfer pathway is
the crucial problem to understanding the overall process.
Noncatalyzed Proton Transfer. There are several proposed
pathways to accomplish the proton transfer from the carbon
(32) Stuerga, D. In Microwaves in Organic Synthesis, 2nd ed.; Loupy, A.,
Ed.; Wiley-VCH: Weinheim, Germany, 2006; Chapter 1, pp 1-61.
8620 J. Org. Chem. Vol. 75, No. 24, 2010

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in intermediate 5 to the oxygen in intermediate 9, from a
direct proton transfer without any assistance via a four-
membered ring transition structure, to the aid of a second
molecule of aldehyde or a protic species (for example, alco-
hols, water, or even the MBH adduct).7,8,16-18
The direct proton transfer from 5 to form 9 through a four-
membered ring transition structure calculated at the M06-2X
level has an energy barrier of 41.8 kcal mol-1 with respect to
the separated reactants (Figure 7). This relatively high energy
barrier would explain the observed KIE when using isotopi-
cally labeled methyl acrylate and the low reaction rates.7,8 It
should be noted that the proton transfer step is exothermic
by 5.3 kcal mol-1. The intermediate 9 subsequently provides
the desired MBH adduct after the release of the catalyst. The
elimination of DABCO occurs with an energy barrier of
5.6 kcal mol-1, 15.0 kcal mol-1 with respect to the reactants.
Reaction in Nonprotic Media. The kinetic studies of
McQuade7 indicate a second-order reaction for the aldehyde
in the absence of other protic species. The previously described
proton transfer via a four-membered transition state cannot
explain these experimental observations. Thus, a new mecha-
nism was proposed involving the reaction of intermediate 5
with a second molecule of aldehyde, to form the hemiacetal
intermediate 13 (Figure 8). The formation of this intermediate
is slightly endothermic by 1.0 kcal mol-1, and the energy barrier
is only 3.5 kcal mol-1, being 18.3 kcal mol-1 taking as reference
the free energy of the reactants. From here, the proton transfer
takes place through a six-membered-ring transition structure 14
FIGURE 6. Optimized geometry for the transition state structure 8,
in one of the plausible rate-determining steps.
FIGURE 7. Energy profile for the direct proton transfer through
a 4-membered transition structure calculated at the M06-2X/
6-311G(d,p) level (kcal mol-1).
(Figure 9) with a free energy of activation of 22.4 kcal mol-1
,
FIGURE 8. Energy profile for the 1,3-hydrogen shift and MBH adduct formation via hemiacetal intermediates calculated at the M06-2X/
6-311G(d,p) level (kcal mol-1).
J. Org. Chem. Vol. 75, No. 24, 2010 8621

Cantillo and Kappe
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considerably lower than the direct proton transfer mentioned
above. In this case the proton transfer is also exothermic by
5.7 kcal mol-1. Since this energy barrier is still higher than the
carbon-carbon bond formation, this mechanistic proposal
explains both the KIE effect and the second-order kinetics for
the aldehyde component, agreeing with the previous computa-
tional studies by Aggarwal and Harvey.10 Once the intermedi-
ate 15 is formed, the elimination of the catalyst occurs through a
relatively low energy transition state, with a relative free energy
of 6.2 kcal mol-1. The resulting hemiacetal intermediate 17 can
then easily decompose to the MBH adduct 6a and benzalde-
hyde (4a), as previously pointed out,10 through a series of tran-
sition structures involving oxygen-oxygen proton transfers for
which no energy barrier was found.
Reaction Pathway in the Presence of Protic Species. The
well-known acceleration of the MBH reaction in the pres-
ence of protic species1,2 was initially explained by a stabili-
zation of the zwitterionic intermediates (Scheme 1) through
hydrogen bonding. However, subsequent studies shed more
light on the role of these hydrogen donor structures, pre-
sumably being a shuttle for proton transfer.10 Herein we report
the energetics of the alcohol-catalyzed reaction (methanol),
along with the assistance of other protic species known to be
efficient such as water, phenol, and the MBH adduct itself
(autocatalysis).
The methanol-catalyzed proton transfer (Figure 10) has an
energy barrier of 22.6 kcal mol-1, which is quite analogous to
the reaction assisted by a second molecule of aldehyde. These
similar energetics can result in competitive reactions, so
depending on the amount of protic species and the reaction
progress both pathways can take place. When the protic species
is water, the energy barrier is slightly higher (24.1 kcal mol-1).
Therefore, the water-assisted hydrogen 1,3-shift will also com-
pete with the second-order aprotic reaction.
The somewhat abnormal kinetic data obtained by
McQuade7 when adding water to the reaction mixture in
THF can now be explained when the possibility of competi-
tion mechanisms is taken into account. When adding a protic
species to the reaction mixture, the authors observed a
change in the kinetics, from second order for the aldehyde
to an intermediate reaction order (1.4-1.7 for the aldehyde).7
This was rationalized as being the result of the insolubility of the
reactants in the mixture.7 Assuming that both mechanisms
are in fact competing, we fitted the experimental data published
by McQuade to eq 2 representing two competitive pathways
(Figure 11). Gratifyingly, the correlation coefficients improved
appreciably compared to the originally reported values which
were calculated assuming a single reaction channel.7
FIGURE 9. Optimized structure for the six-membered transition
structure 14 proposed by McQuade.
D½Pꢀ
2
¼ kaprotic½ArCHOꢀ þ kprotic½ArCHOꢀ
ð2Þ
Dt
Figure 12 shows the variation of the experimental kinetic
constants with the addition of different amounts of water.
With low amounts of the protic solvent (approximately 0.08 M)
the protic pathway rate constant is close to zero, as expected,
and the corresponding rate constant for the aprotic pathway
is relatively low. When the amount of water is increased both
FIGURE 10. Energetics of the proton transfer assisted by methanol
and water through transition states 18 and 19, respectively, calcu-
lated at the M06-2X/6-311G(d,p) level (kcal mol-1).
FIGURE 11. Reinterpretation of the kinetic data obtained by McQuade assuming two competing mechanisms.7
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TABLE 2. Calculated Energy Barriers in THF for the MBH Reaction
of Benzaldehyde and 4-Nitrobenzaldehyde with Methyl Acrylate with
DABCO as Catalyst, Calculated at the M06-2X Level
substrate
C6H5CHO
4-NO2C6H4CHO
ΔGqaprotic (kcal mol-1)
ΔGqprotic (kcal mol-1)
28.9
24.5
29.8
24.7
FIGURE 12. Rate constants for the protic and aprotic pathways
when increasing the amount of water.
mechanisms increase their speed, while with high amounts of
water the aprotic path rate increases slowly and the protic
one becomes more significant. Since the kinetic constants
have different units they cannot be directly compared, but if
we assume, for example, a 1 M concentration of aldehyde at
the beginning of the reaction both constants can be put in
relation to each other, since in this case the rate constants and
reaction rates will be equivalent. Using this assumption it
appears that the aprotic pathway is always faster than the
reaction assisted by water, as predicted by our DFT calcula-
tions (the energy barriers for the proton transfer assisted
by the second molecule of aldehyde and water are 22.4 and
24.1 kcal mol-1, respectively), and this explains also why the
transformation is still second order for the aldehyde even after
the addition of water. However, taking into account that the
difference is not high (ΔΔGq=1.7 kcal mol-1), as the reaction
advances, the protic mechanism will become more important
and the reaction will not be second order for the aldehyde
anymore.
This dualistic nature of the MBH reaction has been pre-
viously suggested10 and experimentally addressed by Eberlin
and Coelho.9 In their experiments, the authors changed the
reaction conditions from nonprotic solvent-free to enriched
protic conditions by addition of β-naphthol or methanol,
and characterized the key intermediates of both pathways
by electrospray ionization mass spectrometry. However, no
evidence pointing to the fact that both mechanisms can take
place simultaneously in a competitive manner has been
presented.
It should be noted that, although benzaldehyde has been
used as model substrate in our pathway calculations, some of
the above-mentioned experiments were carried out with
4-nitrobenzaldehyde and THF-water mixtures as solvent.7
Therefore, to ascertain that our mechanistic conclusions are
also valid for the 4-nitrobenzaldehyde/THF/water system,
we have calculated the corresponding energy barriers for the
competing mechanisms including the nitro substituent and
THF as solvent (the geometries were optimized into the new
solvent). Table 2 shows the computed energy barriers.
Noticeably, both mechanism have analogous energetics in
THF compared to those observed in methanol, both for
benzaldehyde, as well as for 4-nitrobenzaldehyde. Thus, it
FIGURE 13. Energy barriers for the protic and aprotic pathways
vs dielectric constant of the media.
can be assumed that the mechanistic hypothesis about the
competitive pathways is also valid when employing different
substrates and/or when using a different solvent such as THF.
As expected, the energy barriers are lower in the case of the
nitro-substituted reactant, with a ΔΔGq of -4.4 and -5.1 kcal
mol-1 for the aprotic and protic pathways, respectively. It is
also of interest to note that the energy barriers found in THF
are higher in comparison to methanol, for both the aprotic as
well as the protic mechanisms. When adding water (ε=78.4)
to THF (ε=7.4) in sufficient amount, the dielectric constant
of the bulk medium will become intermediate between both
solvents and therefore similar to methanol (ε=32.6). In this
way the protic and aprotic pathways will become faster.
Therefore, our theoretical study can also explain the pre-
viously observed acceleration of the MBH reaction when
altering the solvent,1,2 as a result of the change in the dielec-
tric constant of the medium (Figure 13). The choice of reac-
tion pathway will depend on the amount of protic species and
the progress (early or late stage) of the reaction.
Even in the absence of any protic species in the reaction
medium, a second-order kinetics for the aldehyde is observed
only at the initial stages of the reaction. After approximately
20% conversion it is supposed that autocatalysis must take
place.8 However, the proton transfer assisted by a protic
species has a similar energy barrier as the second-order mech-
anism (i.e., assisted by a second molecule of aldehyde), being
even slightly higher in the case of water. To explain this point
the assistance of the OH group in the MBH adduct must be
more efficient than considering the OH group in methanol or
water. The calculation of the energetics of this proton
transfer step is therefore crucial for the mechanistic under-
standing of the MBH pathway. Figure 14 shows the different
energetics for the proton 1,3-shift in both pathways. The
autocatalyzed mechanism has a lower energy barrier by 2.6
kcal mol-1 with respect to the aprotic path, becoming even
slightly lower than that for carbon-carbon bond for-
mation. Taking into account these energetics, the autocata-
lyzed pathway will have the leading role after approximately
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JOCArticle
FIGURE 16. Calculated energy profile for the proton transfer in
the presence of phenol calculated at the M06-2X/6-311G(d,p) level
(kcal mol-1).
FIGURE 14. Energy profiles for the proton transfer catalyzed by a
second molecule of aldehyde and the hydroxyl group of the reaction
product 6a calculated at the M06-2X/6-311G(d,p) level (kcal mol-1).
Interestingly the autocatalyzed free energy of activation becomes
lower than for carbon-carbon bond formation. The geometry of
the transition state 20 is shown in Figure 15.
will evolve to the MBH adduct 6 and DABCO in the same
way as in the case of the noncatalyzed reaction.
The different steps for the formation of adduct 6 through
all the described reaction channels involve associative and
dissociative steps. Therefore, the changes in the system en-
tropy could play an important role when comparing these
transformations. However, it should be noted that for the
different catalytic cycles the same number of molecules are
gathered in the key transition structures, which should lead
to similar activation entropies. For example, if we compare
the reaction assisted by water, methanol, phenol, or the auto-
catalysis, in all the cases four particles are associated from
the reactants (DABCO, acrylate, aldehyde, and the protic
species). The calculated activation entropies for these exam-
ples are analogous, even more unfavorable for the phenol
assisted and autocatalyzed transformations in comparison
with the water and methanol accelerated proton migrations.
Thus, the enthalpy must play the leading role in the differ-
ences observed in free energies of activation calculated for all
the mechanisms.
FIGURE 15. Optimized geometry for the transition state 20 in-
volved in the autocatalyzed proton transfer.
20% conversion, and therefore the second-order kinetics is
only observed at the early stage of the reaction. Again, these
computational results nicely fit the experimental observations
for the MBH reaction mechanism.7,8
Conclusion
In summary, we have performed a detailed investigation
on the thermodynamics of the Morita-Baylis-Hillman
reaction in order to understand the nature of the reaction
equilibrium. Because of the observed enthalpy and the en-
tropy of the reaction, obtained by accurate ab initio MP2
computational methods and verified by variable-temperature
measurements of the equilibrium constant, the reaction
shifts from exergonic to endergonic when heated at tempera-
tures above ∼57 °C in the case of the benzaldehyde/methyl
acrylate system. The temperature for this equilibrium rever-
sal is higher for 4-nitrobenzaldehyde (∼107 °C), due to the
higher reaction exothermicity, accounting for the possibility
of reaction enhancement at higher reaction temperatures for
this substrate.
The reaction mechanism has been subjected to an in-depth
computational analysis, employing the M06-2X density-
functional method, which has demonstrated superior per-
formance compared to the standard B3LYP protocol. While
the M06-2X approach provides values for the reaction enthalpy
and entropy in quite good agreement with the experimental and
Another interesting recent observation in the MBH reac-
tion that has not been clarified from a mechanistic point of
view is the substantial rate improvement when using aro-
matic alcohols (e.g., phenol) as additives,18 which suggests
that the aromatic character of this protic species must be
important in the proton-transfer assistance. To substantiate
this hypothesis we have additionally calculated the energetics
of the proton transfer in the presence of phenol. Noticeably,
the energy barrier is significantly lower compared to that of
all alternative computed pathways (see above), 16.1 kcal mol-1
(Figure 16), and also considerably lower than the carbon-
carbon bond formation to provide intermediate 5. Thus, in
the presence of phenol the RDS of the MBH reaction changes,
and therefore using this additive will result in a significantly
faster process as compared to other protic additives such as
methanol or water.
It should be noted that in the pathways catalyzed by protic
species, after the proton transfer the resulting intermediate 9
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JOCArticle
FIGURE 17. Energetic summary for all the computed pathways for the proton migration step 5 f 6 (M06-2X/6-311G(d,p) level, kcal mol-1).
MP2 results (ΔH=-12.7 kcal mol-1 and ΔS=-43.54 cal
mol-1 K-1), the B3LYP method provided very poor results
for computing thermodynamic properties in the MBH reac-
tion. This lack of accuracy is in agreement with the pre-
viously reported general poor performance of the B3LYP
method in modeling energy barriers for the MBH reaction.11
The complete reaction pathway;including the different
proposals for the controversial proton migration step;has
been computed. The achieved energetics along with a re-
interpretation of the available kinetic data have allowed us to
arrive at the conclusion that the McQuade and Aggarwal
mechanistic proposals (Figure 1) are in fact competing
mechanisms, as demonstrated by the similar computed en-
ergy barriers of 22.4, 22.6, and 24.1 kcal mol-1 for reactions
in aprotic media, or catalyzed by methanol and water, re-
spectively (Figure 17). These conclusions have been corrob-
orated by a reinterpretation of the available kinetic data7
assuming the possibility of two reaction channels. The fitting
of the experimental kinetics when adding water with this new
hypothesis shows a very good correlation, improving on the
previously described data7 taking into account only one
reaction channel. Depending on the amount of protic species
and the reaction progress (early or late stage) both pathways
can be in operation. In addition, other experimental features
of the MBH reaction have been computed (Figure 17), such
as the importance of rate acceleration in the presence of
aromatic alcohols (phenol), which shows a significant de-
crease in the computed energy barrier, 16.1 kcal mol-1, more
than 6 kcal mol-1 below the above-mentioned energetics.
The observed autocatalysis can also be adequately computed
by using the M06-2X density-functional method. Thus, the
hydrogen migration assisted by the MBH adduct itself (6a)
shows an energy barrier of 19.8 kcal mol-1, significantly
lower in comparison with the assistance of a second molecule
of aldehyde, and explaining the experimental observation
of second-order kinetics in the early stage of the reaction.
The experiments and accurate calculations on the MBH reac-
tion presented herein therefore resolve the remaining open
questions regarding the reaction mechanism of this important
synthetic transformation.
Experimental Section
Microwave Irradiation Experiments and Reaction Monitoring.
Microwave irradiation experiments were performed with a
Monowave 300 single-mode microwave reactor from Anton
Paar GmbH (Graz, Austria).28 The reaction temperature was
monitored by an internal fiber-optic temperature probe (ruby
thermometer) protected by a borosilicate immersion well in-
serted directly into the reaction mixture. The precision of the
internal temperature measurement was provided by efficient
stirring at a fixed rate of 600 rpm. GC-FID analysis was per-
formed on a standard GC instrument with a flame ionization
detector, using a HP5 column (30 mꢁ0.250 mmꢁ0.025 mm).
After 1 min at 50 °C the temperature was increased in 25 deg
min-1 steps up to 300 °C and kept at 300 °C for 4 min. The
detector gas for the flame ionization is H2 and compressed air
(5.0 quality). Anhydrous solvents (stored over molecular sieves)
and chemicals were obtained from standard commercial ven-
dors and were used without any further purification.
Equilibrium Constant Measurements. To a solution of methyl
acrylate (0.450 mL, 5.0 mmol) in methanol (4 mL) was added
DABCO (560 mg, 5.0 mmol), and the corresponding aromatic
aldehyde (5.0 mmol). After stirring the volume of the reaction
mixture was measured to be 5.4 (for benzaldehyde) and 5.5 mL
(for 4-nitrobenzaldehyde), respectively. The reaction mixture
was either placed in a sealed Pyrex screw cap reaction vial and
heated on a hot plate equipped with a silicon carbide heating
block with a 6ꢁ4 deep well matrix,33 or irradiated in the micro-
wave instrument at the desired temperature. The reaction prog-
ress was monitored by GC-FID injecting samples of approxi-
mately 2 μL and diluted in acetonitrile.
(33) (a) Damm, M.; Kappe, C. O. Mol. Diversity 2009, 13, 529–543.
(b) Damm, M.; Kappe, C. O. J. Comb. Chem. 2009, 11, 460–468.
J. Org. Chem. Vol. 75, No. 24, 2010 8625

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Acknowledgment. This work was supported by a grant from
the Christian Doppler Research Society (CDG). D.C. thanks the
pathway descriptions, images of transition state structures,
Cartesian coordinates, energy, and imaginary frequency
(transition states) for all the calculated stationary points.
This material is available free of charge via the Internet at
http://pubs.acs.org.
ꢀ
Spanish Ministerio de Educacion y Ciencia for a fellowship and
the Fundacion Computacion y Tecnologıas Avanzadas de
´
ꢀ
ꢀ
Extremadura (COMPUTAEX) for computing resources.
Supporting Information Available: Equilibrium constant
and microwave heating details, complete ref 16, stereoisomeric
Note Added after ASAP Publication. Figure 1 was replaced
in the version reposted on November 22, 2010.
8626 J. Org. Chem. Vol. 75, No. 24, 2010