On the tandem Morita-Baylis-Hillman/transesterification processes. Mechanistic insights for the role of protic solvents

Article abstract of DOI:10.1016/j.molstruc.2017.10.039

Despite the remarkable rate acceleration under protic solvents such as alcohols and water, the use of acrylates as activated alkenes places a problem due to the possibility of ester hydrolysis or transesterification. Therefore, the tandem transesterification/Morita-Baylis-Hillman (MBH) reactions were investigated by ESI(+)-MS/(MS) and ¹H NMR techniques. For the first time, the MBH back-reaction was fully examined by ESI(+)-MS/(MS) using labelling reagents revealed the complex equilibrium involving the Michael-type addition step of DABCO to acrylate. C- and O-protonation were observed at this stage, showing the transesterification process occurs previous to the aldol step, which is the rate-determining step of the mechanism. At this stage, a short-lived tetrahedral intermediate might be involved and should be considered in these processes.

Full text of DOI:10.1016/j.molstruc.2017.10.039

Journal of Molecular Structure 1154 (2018) 83e91
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
On the tandem Morita-Baylis-Hillman/transesterification processes.
Mechanistic insights for the role of protic solvents
,
*
Arthur G. Carpanez a, Fernando Coelho b, Giovanni W. Amarante a
a
ꢀ
~
Chemistry Department, Federal University of Juiz de Fora, Cidade Universitaria, Sao Pedro, Juiz de Fora, MG, 36036-900, Brazil
b Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas - UNICAMP, P.O. Box 6154, 13083-970, Campinas, SP,
Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Despite the remarkable rate acceleration under protic solvents such as alcohols and water, the use of
acrylates as activated alkenes places a problem due to the possibility of ester hydrolysis or trans-
esterification. Therefore, the tandem transesterification/Morita-Baylis-Hillman (MBH) reactions were
investigated by ESI(þ)-MS/(MS) and 1H NMR techniques. For the first time, the MBH back-reaction was
fully examined by ESI(þ)-MS/(MS) using labelling reagents revealed the complex equilibrium involving
the Michael-type addition step of DABCO to acrylate. C- and O-protonation were observed at this stage,
showing the transesterification process occurs previous to the aldol step, which is the rate-determining
step of the mechanism. At this stage, a short-lived tetrahedral intermediate might be involved and
should be considered in these processes.
Received 16 August 2017
Received in revised form
10 October 2017
Accepted 11 October 2017
Available online 12 October 2017
Keywords:
Morita-Baylis-Hillman
Transesterification
MBH back reaction
NMR
© 2017 Elsevier B.V. All rights reserved.
ESI
1. Introduction
second zwitterionic intermediate is formed by an aldolic addition
of 3 to an aldehyde as demonstrated in the step II, being the CeC
The Morita-Baylis-Hillman (MBH) reaction is among the most
valuable CeC bond-forming transformation in organic synthesis
[1e4]. It involves the coupling of an activated alkenes and an
electrophile (an aldehyde or an imine) under Lewis base catalysis
(with 1,4-diazabicyclo[2.2.2]octane e DABCO e being the most
bond formation step.
The elimination step initiates with a proton transfer, then
returning the Lewis base to the catalytic cycle. It is important to
mention this step is still under discussion, regarding the McQuade,
Aggarwal and Singleton proposals. Per McQuade point of view, a
second aldehyde molecule facilitates the elimination of the aldol
product via a six-membered cyclic transition state in which the
Lewis base is eliminated and the MBH adduct is formed (when X is
labile group a dioxanone byproduct may be obtained), step IIIa.
Aggarwal suggestion the hydroxyl groups (forming adduct or sol-
vent) accelerated the MBH reaction, in this way, autocatalysis
promoted the elimination step via a six-membered ring interme-
diate, step IIIb. Per Singleton, the elimination step occurs via a
simple acid-base protonation/deprotonation mechanism. In this
case, an alcohol mediated MBH reaction without a cyclic interme-
diate involved due the difference of bond lengths, step IIIc.
Interestingly, despite the remarkable rate acceleration under
protic solvents such as alcohols and water [17e19], the use of ac-
rylates as activated alkenes leads to the possibility of ester hydro-
lysis [19] or transesterification, which is pronounced when the
acrylate is attached to a solid support due to substantial cleavage
from the polymer [20]. To our surprise, there is no systematic study
used) producing
Scheme 1.
b-hydroxy-a-methylene carbonyl patterns [5e7],
The elemental steps of the MBH reaction have been described by
Morita [8] and later by Hillman and Baylis [9]. Hill and Isaacs [10]
were the first to approach mechanistically the MBH reaction;
their study was then improved by a refined set of data proposed by
Aggarwal [11,12], McQuade [13,14], Pfaltz [15] and Singleton [16] in
which the mechanism was re-evaluated through kinetics and
theoretical studies. They, in fact, envisioned a better understand of
the reaction equilibrium as well as to determine the rate-
determining step of this reaction (Scheme 2).
The most general mechanism of the MBH reaction initiates (step
I) with the 1,4-Michael addition of the Lewis base catalyst to an
activated alkene forming the first zwitterionic intermediate. A
* Corresponding author.
E-mail address: giovanni.amarante@ufjf.edu.br (G.W. Amarante).
https://doi.org/10.1016/j.molstruc.2017.10.039
0022-2860/© 2017 Elsevier B.V. All rights reserved.

84
A.G. Carpanez et al. / Journal of Molecular Structure 1154 (2018) 83e91
Scheme 1. General scope for the MBH reaction.
Scheme 2. MBH mechanism based on the McQuade, Aggarwal and Singleton proposals to the “addition”, “aldol” and “elimination” steps.
in which the tandem transesterification of the Morita-Baylis-
Hilman adducts formed during the reaction. Therefore, we report
our findings based on reaction development and scope as well as
mechanism investigation by mass spectrometry and NMR studies
on the tandem transesterification/MBH reactions.
125 MHz. Chemical shifts are reported in ppm using the following
peak pattern abbreviations: br, broad; s, singlet; d, doublet; t,
triplet; q, quartet; pent, pentet; sext, sextet; m, multiplet. High-
resolution mass spectra, as well as mechanism investigation,
were acquired in the positive ion mode using a TOF mass spec-
trometer equipped with an electrospray ionization source.
2. Experimental section
2.2. General method: MBH adduct preparation
2.1. General methods
In
nitrobenzaldehyde, 3-nitrobenzaldehyde, 2-nitrobenzaldehyde, 2-
chlorobenzaldehyde, 4-chlorobenzaldehyde, 4-bromoben
zaldehyde, 2-fluorobenzaldehyde, 4-methylbenzaldehyde, cinna-
maldehyde, 4-methoxybenzaldehyde, 2-furaldehyde, (E)-N-(4-
chlorobenzylidene)-4-methylbenzenesulfonamide or pentanal)
(1.0 mmol), DABCO (1.0 mmol) and ethyl acrylate (10.0 mmol) were
dissolved in methanol (3.0 mL) and the reaction was maintained at
a
round-bottom flask, an electrophile (i.e., 4-
All purchased chemicals were used as received without further
purification. Solvents were dried according to standard procedures.
Analytical thin layer chromatography (TLC) was performed on TLC
plates (silica gel 60 F254) and visualized employing ninhydrin (2,2-
dihydroxyindane-1,3-dione) indicator. The chemical shifts are re-
ported in ppm relative to solvent residual peak. The 1H NMR spectra
were recorded at 500 MHz, 13C NMR spectra were recorded at

A.G. Carpanez et al. / Journal of Molecular Structure 1154 (2018) 83e91
85
4e8 ꢀC for 76 h. The crude reaction was extracted with ethyl acetate
128.73, 128.10, 126.55, 72.88, 52.19.
and the organic layers dried. The desired products were then pu-
rified by flash column chromatography.
2.4.6. Methyl 2-((4-bromophenyl)(hydroxy)methyl)acrylate, 12e
[23]
2.3. General method: ESI(þ)-MS experiments
1H NMR (CDCl3, 500 MHz):
d 7.49 (m, 2H), 7.27 (m, 2H), 6.37 (m,
1H), 5.85 (m, 1H), 5.53 (d, 1H, J ¼ 5.0 Hz), 3.76 (s, 3H), 3.10 (d, 1H,
In a round-bottom flask 4-bromobenzaldehyde (1.0 equiv.),
DABCO (1.0 equiv.) and ethyl acrylate (10.0 equiv.) were dissolved in
methanol or methanol-d4 (63.0 equiv.) and the reaction was
maintained at 4e8 ꢀC. Aliquots of the reaction medium were taken,
diluted in acetonitrile and injected directly at the ESI source after
24 h and 8 days of reaction. For the back-reaction analysis, in a
round-bottom flask, ethyl 2-((4-bromophenyl)(hydroxy)methyl)
acrylate (1.0 quiv.) was dissolved in methanol or deuterated
methanol (63.0 equiv.) in the presence of DABCO (1 equiv.) and the
reaction was maintained at 4e8 ꢀC. Aliquots of the reaction me-
dium were taken, diluted in acetonitrile and injected directly at the
ESI source after 24 h and 8 days of reaction.
J ¼ 5.0 Hz).
13C NMR (CDCl3, 125 MHz):
d 166.64, 141.53, 140.31, 131.56,
128.31, 126.31, 121.47, 72.84, 52.07.
2.4.7. Methyl 2-((2-fluorophenyl)(hydroxy)methyl)acrylate, 12f
[24]
1H NMR (CDCl3, 500 MHz):
d 7.48 (m, 1H), 7.28 (m, 1H), 7.16 (m,
1H), 7.02 (m, 1H), 6.34 (m, 1H), 5.88 (m, 1H), 5.75 (m, 1H), 3.76 (s,
3H).
13C NMR (CDCl3, 125 MHz):
d 166.83, 160.95, 158.99, 140.71,
129.49(d, J ¼ 33 Hz), 128.10 (d, J ¼ 15 Hz), 126.53 (d, J ¼ 2.6 Hz),
115,33 (d, J ¼ 86 Hz), 99.98, 67.17 (d, J ¼ 15 Hz), 52.08.
2.4. General method: NMR experiments
2.4.8. Methyl 2-(hydroxy(p-tolyl)methyl)acrylate, 12g [24]
1H NMR (CDCl3, 500 MHz):
d
7.28 (m, 2H), 7.18 (m, 2H), 6.35 (m,
1H), 6.58 (m, 1H), 5.56 (s, 1H), 3.74 (s, 3H), 2.26 (s, 3H).
13C NMR (CDCl3, 125 MHz):
166.80, 142.03, 138.33, 137.57,
129.15, 126.51, 125.90, 51.95, 21.14.
For the back-reaction analysis ethyl 2-(hydroxy(2-nitrophenyl)
methyl)acrylate (1 equiv.) was dissolved in deuterated methanol
(63 equiv.) in the presence of DABCO (1 equiv.) and transferred to a
NMR tube. The reaction was followed by 1H NMR over time. For the
cross transesterification experiment ethyl 2-(hydroxy(2-
nitrophenyl)methyl)acrylate (1.0 equiv.) and ethyl 2-(hydroxy(4-
nitrophenyl)methyl)acrylate (1.0 equiv.) were dissolved in DMSO-
d6 in the presence of DABCO (1.0 equiv.) and transferred to a NMR
tube. The reaction was followed by 1H NMR over time.
d
2.4.9. Methyl (E)-3-hydroxy-2-methylene-5-phenylpent-4-enoate,
12h [25]
1H NMR (CDCl3, 500 MHz):
d 7.42 (m, 2H), 7.34 (m, 2H), 7.29 (m,
1H), 6.71 (m, 1H), 6.33 (m, 2H), 5.95 (m, 1H), 5.15 (d, 1H, J ¼ 5 Hz),
3.82 (s, 3H), 2,95 (s, 1H).
13C NMR (CDCl3, 125 MHz):
d 166.80, 141.22, 136.46, 131.53,
2.4.1. Methyl 2-(hydroxy(4-nitrophenyl)methyl)acrylate, 11 [17]
129.19, 128.58, 127.87, 126.63, 125.93, 72.20, 52.06.
1H NMR (CDCl3, 500 MHz):
d 8.19 (m, 2H), 7.58 (m, 2H), 6.40 (m,
1H), 5.90 (m, 1H), 5.64 (d, 1H, J ¼ 5 Hz), 3.74 (s, 3H), 3.51 (d, 1H,
2.4.10. Methyl 2-(hydroxy(4-methoxyphenyl)methyl)acrylate, 12i
J ¼ 5 Hz).
[24]
13C NMR (CDCl3, 125 MHz):
d
166.39, 148.70, 147.43, 141.03,
1H NMR (CDCl3, 500 MHz):
d 7.32 (m, 2H), 6.90 (m, 2H), 5.87 (m,
127.39, 127.22, 123.61, 72.58, 52.21.
1H), 6.35 (m, 1H), 5.55 (d, 1H, J ¼ 5 Hz), 3.82 (s, 3H), 3.75 (s, 3H),
2.88 (d, 1H, J ¼ 5 Hz).
2.4.2. Methyl 2-(hydroxy(3-nitrophenyl)methyl)acrylate, 12a [21]
1H NMR (CDCl3, 500 MHz):
8.29 (m, 1H), 8.17 (m, 1H), 7.74 (m,
13C NMR (CDCl3, 125 MHz):
d 166.83, 159.27, 142.14, 133.43,
127.89, 125.70, 113.86, 72.87, 55.27, 51.94.
d
1H), 7.55 (m, 1H), 6.44 (s, 1H), 5.93 (m, 1H), 5.66 (d, 1H, J ¼ 5 Hz),
3.77 (s, 3H), 3.31 (d, 1H, J ¼ 5 Hz).
2.4.11. Methyl 2-(furan-2-yl(hydroxy)methyl)acrylate, 12j [24]
13C NMR (CDCl3, 125 MHz):
d
166.40, 148.43, 143.60, 140.93,
1H NMR (CDCl3, 500 MHz):
d
7.38 (m, 1H), 6.39 (m, 1H), 6.33 (m,
1H), 6.26 (m, 1H), 5.95 (m, 1H), 5.61 (s, 1H), 3.76 (s, 3H), 3.15 (s, 1H).
13C NMR (CDCl3, 125 MHz):
166.49, 154.12, 142.40, 139.41,
126.88, 110.44, 107.20, 67.43, 52.09.
132.64, 129.38, 127.32, 122.81, 121.56, 72.72, 52.23.
d
2.4.3. Methyl 2-(hydroxy(2-nitrophenyl)methyl)acrylate, 12b [21]
1H NMR (CDCl3, 500 MHz):
d 7.94 (m, 1H), 7.75 (m, 1H), 7.64 (m,
1H), 7.46 (m, 1H), 6.36 (m, 1H), 6.20 (s, 1H), 5.73 (m, 1H), 3.73 (s,
3H).
2.4.12. Methyl 2-((4-chlorophenyl)((4-methylphenyl)sulfonamido)
methyl)acrylate, 12k [26]
13C NMR (CDCl3, 125 MHz):
d
166.45, 148.14, 140.69, 136.12,
1H NMR (CDCl3, 500 MHz):
d 7.64 (m, 2H), 7.22 (m, 2H), 7.17
133.49, 128.91, 129.73, 126.52, 124.62, 67.71, 52.20.
(m,2H), 7.08 (m, 2H), 6.19 (s, 1H), 5.91 (d, 1H, J ¼ 9.15 Hz), 5.79 (m,
1H), 5.27 (d, 1H, J ¼ 9.15 Hz), 3.59 (s, 3H), 2.40 (s, 3H).
2.4.4. Methyl 2-((2-chlorophenyl)(hydroxy)methyl)acrylate, 12c
13C NMR (CDCl3, 125 MHz):
d 165.70, 143.66, 138.33, 137.58,
[22]
137.32, 133.71, 129.62, 128.74, 128.21, 128.04, 127.25, 58.59, 21.62.
1H NMR (CDCl3, 500 MHz):
d 7.60 (m, 1H), 7.38 (m, 1H), 7.32 (m,
1H), 7.27 (m, 1H), 6.36 (m, 1H), 6.00 (d, 1H, J ¼ 5.0 Hz), 5.60 (m, 1H),
2.4.13. Methyl 3-hydroxy-2-methyleneheptanoate, 12l [24]
3.81 (s, 3H), 3.27 (d, 1H, J ¼ 5.0 Hz).
1H NMR (CDCl3, 500 MHz):
d 6.21 (m, 1H), 5.79 (m, 1H), 4.38 (m,
13C NMR (CDCl3, 125 MHz):
d
167.05, 140.52, 138.21, 132.83,
1H), 3.77 (s, 3H), 2.60 (s, 1H), 1.64 (m, 2H), 1.32 (m, 4H), 0.99 (t, 2H,
129.49, 129.07, 128.07, 128.16, 127.07, 69.44, 52.15.
J ¼ 7.15 Hz).
13C NMR (CDCl3, 125 MHz):
35.95, 27.98, 22.48, 14.00.
d 167.09, 142.52, 124.97, 71.80, 51.88,
2.4.5. Methyl 2-((4-chlorophenyl)(hydroxy)methyl)acrylate, 12d
[21]
1H NMR (CDCl3, 500 MHz):
d
7.31 (m, 4H), 6.34 (m, 1H), 5.83 (m,
3. Results and discussion
1H), 5.53 (m, 1H), 3.73 (s, 3H).
13C NMR (CDCl3, 125 MHz):
d
166.78, 141.74, 139.91, 133.75,
The MBH reaction between the 4-nitrobenzaldehyde and ethyl

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A.G. Carpanez et al. / Journal of Molecular Structure 1154 (2018) 83e91
acrylate was chosen as the model reaction to start our in-
vestigations and establish the best condition to obtain the trans-
esterification product. Hence, a set of experimental conditions were
examined by variation of DABCO, ethyl acrylate and methanol to
evaluate their influence on the transesterification (Table 1).
The best reaction condition to access the methyl ester adduct is
the reaction of 1 equivalent of aldehyde with 10 equivalents of ethyl
acrylate in the presence of 1 equivalent of DABCO and excess (63
equiv.) of methanol at 4e8 ꢀC for 76 h. It is important to mention,
this consists a typical procedure for MBH reaction using acrylates;
excess of both acrylate and protic solvent. After, various aldehydes
were then reacted in the presence of methanol; for all cases, the
tandem MBH/transesterification processes were observed, afford-
ing the corresponding products in moderate to good isolated yields.
Despite of the low yield, the corresponding aza-MBH adduct was
also isolated. Thus, according to these observations, this competing
transesterification process should be considered in the entire
mechanism (Table 2).
We then turned our attention into the mechanism of the
transesterification reaction by monitoring ESI(þ)-MS experiments.
First, the conventional MBH reaction was monitored to establish a
pattern of ions, using 4-bromobenzaldehyde (1 equivalent), ethyl
acrylate (10 equivalents) and DABCO (1 equivalent) as the catalyst,
without solvent (Scheme 3).
Aliquots of the reaction medium were taken, diluted in aceto-
nitrile and directly injected at the ESI source after 24 h of reaction.
This reaction time was preferred since at this moment a greater
number of intermediates were intercepted. The ESI(þ)-MS spectra
(Fig. 1) of the reaction medium showed cationic intermediates
directly related to the MBH catalytic cycle. The ions of m/z 133
[DABCOþH], 213 [14þH] and 397 [15þH] are known intermediates
and were fully characterized in previous work [27e29].
We then focused our investigation towards the trans-
esterification reaction promoted by methanol as solvent. Aliquots
of the reaction solution were taken after 24 h and analyzed by
ESI(þ)-MS(/MS). The major change on the ESI(þ)-MS spectrum (see
Table 1
Influence of DABCO, ethyl acrylate and methanol on the transesterification reaction e optimization table.
Entry
DABCO
Ethyl acrylate
Aldehyde
MeOH
Ratio 11/11aa
1
2
3
4
6
7
8
1
2
3
1
1
1
1
10
10
10
5
15
10
10
1
1
1
1
1
1
1
63
63
63
63
63
10.5
21
6.8/1
4.1/1
2.6/1
3.8/1
4.2/1
0.1/1
0.8/1
a
The observed ratio correlates the MBH methyl ester adduct x MBH ethyl ester adduct. Measured from the 1H NMR analysis of the crude reaction mixture.
Table 2
Scope of the transesterification reaction under the optimized reaction conditionsa.
Entry
Electrophile
Number
Time
Yield (%)
1
2
3
4
5
6
7
8
4-nitrobenzaldehyde
3-nitrobenzaldehyde
2-nitrobenzaldehyde
2-chlorobenzaldehyde
4-chlorobenzaldehyde
4-bromobenzaldehyde
2-fluorobenzaldehyde
4-methylbenzaldehyde
Cinnamaldehyde
4-methoxybenzaldehyde
2-furaldehyde
(E)-N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide
Pentanal
11
76 h
76 h
76 h
76 h
76 h
76 h
76 h
76 h
76 h
76 h
76 h
76 h
30 days
70
69
70
45
43
49
47
30
30
7
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
9
10
11
12
13
25
13
10
a
The reaction was carried out using 1 equiv. of aldehyde with 10 equiv. of ethyl acrylate in the presence of 1 equiv. of DABCO and 63 equiv. of methanol.

A.G. Carpanez et al. / Journal of Molecular Structure 1154 (2018) 83e91
87
were carried out, first one with DABCO and second in the absence.
The outcome was rated by analyzing the crude 1H NMR of these
reactions. The presence of DABCO is essential for the back-reaction
transesterification process e evidenced by the singlet at
d 3.76 in
the crude reaction mixture 1H NMR analysis. A second experiment
was designed to evaluate the necessity of a label Lewis base.
Therefore, two new reactions; first one with triethylamine and a
second one with imidazole were launched. The control experi-
ments proved to be essential the presence of a labile basic or
nucleophilic Lewis base to allowed the back-reaction to occur;
otherwise, an addition reaction followed by water loss will take a
place, Fig. 1.
In an alternative approach, the possibility of a competitive
transesterification reaction due to the direct attack of the meth-
oxide anion, present in solution, to the carbonyl ester of the MBH
adduct was evaluated. Buffer systems of inorganic bases were
employed to reproduce the apparent pH of DABCO solution in
methanol. The outcome was rated by the crude 1H NMR analysis of
the reaction mixture, Table 3.
Scheme 3. General steps of the Morita-Baylis-Hillman reaction.
Supplementary Data) is the presence of the ion of m/z 199 assigned
to a new acrylic system derived from the transesterification reac-
tion. This intermediate illustrates the complex equilibrium involved
at the MBH reaction when a protic solvent is used and provides
strong evidences that the transesterification reaction occurs on the
acrylate system.
At this point, with the transesterification reaction established,
we focused our attention on the back-reaction promoted by the
Lewis base in the presence of methanol. The first experiment was
the evaluation of the DABCO demand; therefore, two reactions
The outcome, observed by the 1H NMR analysis of the crude
reaction mixture, corroborate the control experiment, showing the
MBH back-reaction demands a nucleophilic or even a basic labile
Lewis base. The direct attack of the methoxide anion, present in
solution, to the carbonyl ester of the MBH adduct does not occur.
In order to have a better understanding of the back-reaction
transesterification process, a labelling experiment was developed
using deuterated methanol as solvent. The aim of this study was to
Fig. 1. Control experiments of the back reaction promoted by Lewis bases.

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A.G. Carpanez et al. / Journal of Molecular Structure 1154 (2018) 83e91
Table 3
Evaluation of the transesterification reaction on buffers systems.
Entry
System (Buffer)
Apparent pH
Concentration (mmol)
MBH adduct (mmol)
Ratio 16a/16b
1
2
3
4
5
DABCO:H2O
10.98
9.92
9.90
12.43
6.90
0.1
1.0
1.0
1.0
1.0
0.1
0.1
0.1
0.1
0.1
1.0/0.4
NR
NR
NR
NR
Na2B4O7$10H2O
NaH2PO4/Na2HPO4
NaHCO3/Na2CO3
HOAc/NaOAc
NR ¼ No transesterification was observed by 1H NMR analysis of the crude reaction mixture.
Scheme 4. ESI(þ)-MS labelling experiment, highlighting the ions of m/z 202, 203, 204, 213, 214 and 215.
Scheme 5. Formation of DABCO salts form MBH adducts.

A.G. Carpanez et al. / Journal of Molecular Structure 1154 (2018) 83e91
89
Scheme 6. Decomposition of the MBH adduct monitored by in situ 1H NMR.
associated with a short-lived tetrahedral intermediate, which acts
as the link between both zwitterionic activated acrylic systems.
To illustrate the temporal profile of the MBH reaction, aliquots of
the reaction medium were taken, diluted in acetonitrile and
directly injected at the ESI source after 8 days of reaction. Inter-
estingly, for both the conventional and the MBH/transesterification
reactions new cationic intermediates were observed. It involves the
reaction of the MBH adduct formed and the Lewis base, used as
catalyst, leading to DABCO salts of the MBH adducts [30,31]
(Scheme 5). These intermediates, first time intercepted and fully
characterized by ESI(þ)-MS(/MS), might be related to the formation
of byproducts of the MBH reaction at long reaction time.
Additionally, the back-reaction transesterification process was
also used as a tool to obtain kinetic data, in order to see the reaction
order profile of the MBH adduct decomposition, assisted by DABCO
(Scheme 6). Therefore, in situ 1H NMR analysis based on the
methylenic diastereotopic hydrogens of the MBH adduct (11a,
4.12 ppm) and the methylenic hydrogens of the ethanol (25,
3.61 ppm) generated as byproduct, were continuously monitored
over 15 days, see Supplementary Data. Data obtained from the
crude 1H NMR analyses strongly suggest the back-reaction to be
first-order kinetics related to the corresponding MBH adduct
(Fig. 2).
A second experiment was then designed to evaluate the cross-
transesterification MBH back-reaction. Therefore, two MBH ad-
ducts were placed at the presence of DABCO and monitored by in
situ 1H NMR over 15 days (Scheme 7). The signals at 10.16 and
10.24 ppm proves the occurrence of the back-reaction since those
signals are assigned to the aldehydes. The loss of intensity of the
ABX3 pattern at 4.05 ppm and the triplet at 1.26 ppm and the
appearing of a new quartet at 4.13 ppm and a triplet at 1.21 ppm
indicates the occurrence of the cross-transesterification process,
Fig. 3.
Fig. 2. e First-order kinetics of the back-reaction of MBH adduct. Results based on
average of three runs.
compare the process with non-labelled reagents in order to see the
profile of back-reaction transesterification containing deuterium
incorporation. Interestingly, in this case, a new set of intermediates
of m/z 202, 203, 204, 213, 214 and 215 were intercepted and fully
characterized by ESI(þ)-MS/MS (Scheme 4). The formation of the
first zwitterionic intermediate, originated from the reverse MBH
reaction, is generally treated in a simplified form, however, the
reaction monitoring by ESI(þ)-MS clearly indicates an elaborated
equilibrium involving the C-protonation and the O-protonation of
both zwitterionic intermediates, 17, 18, 19, 20 and 21. Our working
hypothesis regarding the transesterification process is then
Scheme 7. Cross-transesterification MBH back-reaction.

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A.G. Carpanez et al. / Journal of Molecular Structure 1154 (2018) 83e91
Fig. 3. Temporal 1H NMR profile of the cross-transesterification back-reaction process.
4. Conclusions
the Rede Mineira de Química for financial support.
In summary, the MBH/transesterification processes have been
fully examined. A set of MBH methyl ester adduct derivatives were
synthesized in good yields. The use of back-reaction MBH/trans-
esterification processes gave new insights into the MBH reaction.
The observed equilibrium indicates the transesterification process
occurs during the Michael-type addition step, perhaps through a
short-lived tetrahedral intermediate, which is now considered in
the reaction mechanism. For the first time, ESI(þ)-MS(/MS) enables
the interception and fully characterization of cationic in-
termediates, which are consistent with the tandem MBH/trans-
esterification processes. Decomposition rates of the MBH adduct in
presence of DABCO revealed this reaction proceeds to first-order,
using in situ 1H NMR technique. All these findings concerning the
tandem MBH/transesterification reactions in the presence of acry-
late derivatives will be useful for the equilibrium controlling of the
MBH reaction as well as for further developments.
Appendix B. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.molstruc.2017.10.039.
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