Dualistic nature of the mechanism of the morita-baylis-hillman reaction probed by electrospray ionization mass spectrometry

Article abstract of DOI:10.1021/jo802578t

The Morita-Baylis-Hillman (MBH) reaction allows chemists to form new σ C-C bonds in a single-step straightforward manner and thus to construct densely functionalized molecules for further chemical manipulation. Using electrospray ionization for transferri

Full text of DOI:10.1021/jo802578t

Dualistic Nature of the Mechanism of the Morita-Baylis-Hillman
Reaction Probed by Electrospray Ionization Mass Spectrometry
Giovanni W. Amarante,† Humberto M. S. Milagre,‡ Boniek G. Vaz,‡ Bruno R. Vilacha˜
Ferreira,† Marcos N. Eberlin,*,‡ and Fernando Coelho*,†
Laboratory of Synthesis of Natural Products and Drugs and ThoMSon Mass Spectrometry Laboratory,
Institute of Chemistry, State UniVersity of Campinas, UNICAMP, 13084-971 Campinas, Sa˜o Paulo, Brazil
coelho@iqm.unicamp.br; eberlin@iqm.unicamp.br
ReceiVed NoVember 20, 2008
The Morita-Baylis-Hillman (MBH) reaction allows chemists to form new σ C-C bonds in a single-step
straightforward manner and thus to construct densely functionalized molecules for further chemical manipulation.
Using electrospray ionization for transferring ions directly from solution to the gas phase, and mass (and
tandem mass) spectrometry for mass and structural assignments, new key intermediates for the rate-determining
step of the MBH reaction have been successfully intercepted and structurally characterized. These ESI-MS
data provide experimental evidence supporting recent suggestions, based on kinetic experiments and theoretical
calculations, for the dualist nature of the proton-transfer step of the MBH mechanism.
Introduction
formation allowing chemists to construct, via efficient formation
of new C-C σ bonds, a myriad of densely functionalized
R-methylene-ꢀ-hydroxy derivatives.1-3These derivatives are
known as MBH adducts and are formed by coupling an
electrophile (an aldehyde or an imine) with an activated
The Morita-Baylis-Hillman (MBH) reaction (Scheme 1)
constitutes a broad range, synthetically useful chemical trans-
* To whom correspondence should be addressed. Tel: (+55) 19 3521-3085
or (+55) 19 3521-3073. Fax: (+55) 19-3521-3023.
† Laboratory of Synthesis of Natural Products and Drugs.
‡ ThoMSon Mass Spectrometry Laboratory.
(1) (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41,
2815–2815.
10.1021/jo802578t CCC: $40.75
Published on Web 03/13/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3031–3037 3031

Amarante et al.
SCHEME 1. General Scope and First Catalytic Cycle Proposed by Hoffmann/Hill and Isaacs for the Morita-Baylis-Hillman
Reaction
(normally with an electron-withdrawing group) alkene in the
presence of a Lewis base catalyst (most often DABCO). The
MBH reaction has been used to form building blocks for the
total synthesis of many heterocycles, natural products, and
drugs.4 Based on its atom economy and feasibility, the MBH
reaction is currently regarded as one of the most efficient
transformations in organic chemistry.5
focusing on the proton-transfer step. According to McQuade,
the MBH reaction is second order relative to the aldehyde and
shows significant kinetic isotopic effect (KIE: kH/kD ) 5.2 (
0.6 in DMSO). Interestingly, regardless of the solvents (DMF,
MeCN, THF, CHCl3), the KIE were found to be greater than 2,
indicating the relevance of proton abstraction on the rate-
determining step. Based on these new data, McQuade et al.
proposed a new mechanism view for the proton-transfer step
(Scheme 2), suggesting IV as the RDS. Soon after, Aggarwal,
also on the basis of kinetic studies, proposed that the reaction
kinetic is second order in relation to the aldehyde but only at
its beginning (e20% of conversion), then becoming autocata-
lytic. Apparently, the MBH adducts 7 may act as a proton donor
Hoffmann, in 1983, was the first to propose a mechanism
for the MBH reaction,6 which was refined from kinetic data by
Hill and Isaacs7a and others (Scheme 1).7b,c The first reaction
step I involves 1,4-addition of the catalytic tertiary amine 1 to
the activated alkene 2 (R,ꢀ-unsaturated carbonyl compounds,
nitriles, ect.) to generate the zwitterionic aza-enolate 3. In step
II, 3 forms intermediate 5 by adding to aldehyde 4 via an aldolic
addition reaction. Step III involves intramolecular proton shift
within 5 to form 6, which in step IV forms the final MBH adduct
7 via E2 or E1cb proton-transfer in the presence of a Lewis
base. The last step IV returns 1 to the catalytical cycle. Due to
the low kinetic isotopic effect (KIE ) 1.03 ( 0.1, using
acrylonitrile as nucleophile for the MBH reaction) measured
by Hill and Isaacs and the dipole increase by charge separation,
II was initially considered as the MBH rate-determining step
(RDS, Scheme 1).
(4) For some examples, see: (a) Amarante, G. W.; Rezende, P.; Cavallaro,
M.; Coelho, F. Tetrahedron Lett. 2008, 49, 3744–3748. (b) Coelho, F.; Veronese,
D.; Pavam, C. H.; de Paula, V. I.; Buffon, R. Tetrahedron 2006, 62, 4563–
4572. (c) Perez, R.; Veronese, D.; Coelho, F.; Antunes, O. A. C. Tetrahedron
Lett. 2006, 47, 1325–1328. (d) Silveira, G. P. D.; Coelho, F. Tetrahedron Lett.
2005, 46, 6477–6481. (e) Almeida, W. P.; Coelho, F. Tetrahedron Lett. 2003,
44, 937–940. (f) Feltrin, M. A.; Almeida, W. P. Synth. Commun. 2003, 33, 1141–
1146. (g) Rossi, R. C.; Coelho, F. Tetrahedron Lett. 2002, 42, 2797–2800. (h)
Mateus, C. R.; Feltrin, M. P.; Costa, A. M.; Coelho, F.; Almeida, W. P.
Tetrahedron 2001, 57, 6901–6908. (i) Iwabuchi, Y.; Furukawa, M.; Esumi, T.;
Hatakeyama, S. Chem. Commun. 2001, 2030–2031. (j) Iwabuchi, Y.; Sugihara,
T.; Esumi, T.; Hatakeyama, S. Tetrahedron Lett. 2001, 42, 7867–7871. (k)
Masunari, A.; Ishida, E.; Trazzi, G.; Almeida, W. P.; Coelho, F. Synth. Commun.
2001, 31, 2127–2136. (l) Ameer, F.; Drewes, S. E.; Houston-McMillan, M. S.;
Kaye, P. T. S. Afr. J. Chem. 1986, 39, 57–63. (m) Hoffmann, H. M. R.; Rabe,
J. HelV. Chim. Acta 1984, 67, 413–415. (n) Hoffmann, H. M. R.; Rabe, J. J.
Org. Chem. 1985, 50, 3849–3859. (o) Drewes, S. E.; Emslie, N. D. J. Chem.
Soc., Perkin Trans. 1 1982, 2079–2083.
Recently, McQuade et al.8 and Aggarwal et al.9 re-evaluated
the MBH mechanism using kinetics and theoretical studies,
(2) Baylis, A. B.; Hillman, M. E. D. Chem. Abstr. 1972, 77, 34174q; German
Patent 2155113, 1972.
(5) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259–281, and references
cited therein.
(6) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. 1983, 22, 796–
797.
(7) (a) Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem. 1990, 3, 285–290. (b)
Kaye, P. T.; Bode, M. L. Tetrahedron Lett. 1991, 32, 5611–5614. (c) Fort, Y.;
Berthe, M.-C.; Caube`re, P. Tetrahedron 1992, 48, 6371–6384.
(3) For comprehensive reviews on the Morita-Baylis-Hillman reaction, see:
(a) Almeida, W. P.; Coelho, F. Quim. NoVa 2000, 23, 98–101; Chem. Abstr.
2000, 132, 236562e. (b) Basavaiah, D.; Rao, A. J.; Satyanarayama, T. Chem.
ReV. 2003, 103, 811–891. (c) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem.
Soc. ReV. 2007, 36, 1581–1588. (d) Singh, V.; Batra, S. Tetrahedron 2008, 64,
4511–4574.
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Mechanism of the Morita-Baylis-Hillman Reaction
SCHEME 2. New Mechanistic Proposals from for the Proton-Transfer Step IV of the MBH Reaction
SCHEME 3. Morita-Baylis-Hillman Reaction Monitored
technique that may allow even short-lived or loosely bounded
intermediates16 to be transferred efficiently from the reaction
solution to the gas phase. ESI-MS has provided therefore consistent
snapshots of the ionic composition of reaction solutions,16-18 thus
functioning as an interesting “ion-fishing” plus ion characterization
technique and a major technique for solution mechanistic studies
in chemistry19 and biochemistry.20 The mechanistically important
new propositions about the proton-transfer step of the MBH
reaction just discussed have therefore stimulated us to perform
complementary investigations on the MBH reaction mechanism
via ESI-MS(/MS) aiming to intercept and characterize the new
intermediates postulated for the dualist nature of the key RDS
proton-transfer step.
by ESI-MS(/MS)
and therefore can assist the proton-transfer step via a six-
membered intermediate (Scheme 2).
This new kinetic evidence has stimulated further theoretical
studies on the MBH mechanism conducted initially by Xu10
and Sunoj.11 Aggarwal performed recently an extensive theo-
retical study which has supported both their own kinetic
observations as well as those of McQuade about the proton-
transfer step.12 They suggested that step IV can proceed via
two pathways: (a) in the absence of a proton source, proton
shift is assisted by a second molecule of aldehyde (8), as
proposed by McQuade, or (b) in the presence of a proton source
such as an alcohol; however, the proton shift proceeds via
intermediate 10 or similar species (Scheme 2).
To investigate the MBH mechanism, we have used electrospray
ionization mass spectrometry, ESI-MS(/MS), and have been able
to characterize key MBH reaction intermediates.13 Using ESI-MS-
(/MS), we also shed light on the cocatalyst role of ionic liquids in
MBH reactions.14 ESI-MS15 is a gentle, fast, and high-sensitivity
Results and Discussion
Our investigation began with the ESI-MS monitoring of
the reaction of methyl acrylate with an excess of benzalde-
hyde (4a, Scheme 3) catalyzed by DABCO without solvent.21
DABCO (1 equiv), methyl acrylate (1 equiv) and benzalde-
hyde (3 equiv) were mixed without additional solvent. Aliquots
of the reaction medium (0.05 µL) were taken, diluted in
acetonitrile with a trace of formic acid, and injected directly to
the ESI source. Although neutral zwitterionic species participate
in MBH reactions, in solution they are in equilibrium with their
protonated or cationized forms and in such cationic forms may
be detected by ESI-MS.13 Just after mixing the reagents for the
reaction outlined in Scheme 3, an aliquot was taken and the
reaction stopped by addition of 100 µL of acetonitrile acidified
with traces of formic acid. As before,13 the ESI-MS (Figure
1a) of such a reaction solution intercepts three covalently bonded
cationic species directly related to the MBH catalytic cycle
(Scheme 4): [1a + H]+ of m/z 113, [3a + H]+ of m/z 199, and
[6a + H]+ of m/z 305. But for the first time, due to high
concentration, two new species are also intercepted and
putatively assigned to [11 + K]+ of m/z 323 and [12 + K]+ of
m/z 409.22 The formation of covalent species is indicated by
the relatively high kinetic energy set for the extraction of gas-
phase ions from the ESI source into the mass spectrometer
(acceleration cone voltage of 20-30 V) and the optimized
declustering properties of the ESI source. Under such conditions,
loosely bonded species should not survive.
(8) (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 .
(9) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew. Chem., Int.
Ed. 2005, 44, 1706–1708.
(10) Xu, J. J. THEOCHEM 2006, 767, 61–66.
(11) Roy, D.; Sunoj, R. B. Org. Lett. 2007, 9, 4873–4876.
(12) Robiette, R.; Aggarwal, V. K.; Harvey, J. N. J. Am. Chem. Soc. 2007,
129, 15513–15525.
(13) Santos, L. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.; Eberlin, M. N.
Angew. Chem., Int. Ed. 2004, 43, 4330–4333.
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F.; Eberlin, M. N. Tetrahedron Lett. 2006, 47, 8427–8431. (b) Santos, L. S.;
Silveira Neto, B. A.; Consorti, C. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.;
Dupont, J.; Eberlin, M. N. J. Phys. Org. Chem. 2006, 19, 731–736.
(15) (a) Whitehouse, C. M.; Dreyer, R. N.; Yamashita, M.; Fenn, J. B. Anal.
Chem. 1985, 57, 675–679. (b) Fenn, J. B.; Mann, M.; Meng, C. K.; Wong, S. F.;
Whitehouse, C. M. Science 1989, 246, 64–71. (c) Cole, R. B. In Electrospray
Ionization Mass Spectroscopy; John Wiley & Sons, Inc.: New York, 1997.
The ions of m/z 113 [1a + H]+ and m/z 199 [3a + H]+ have
been fully characterized in our previous investigation (see also
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Amarante et al.
FIGURE 1. ESI(+)-MS of the MBH reaction of methyl acrylate with benzaldehyde: (a) t ) 0 min; (b) t ) 10 min.
FIGURE 2. ESI-MS(/MS) of the ion of m/z 433 (8a).
the Supporting Information for their ESI-MS(/MS)).13 For
structural characterization of the new species, the ions of m/z
323, m/z 305, and m/z 409 were individually selected for
collision-induced dissociation (CID) with argon via tandem mass
spectrometric (ESI-MS(/MS)) experiments (Figure S1, Sup-
porting Information). The [11 + K]+ ion of m/z 323 forms the
3034 J. Org. Chem. Vol. 74, No. 8, 2009

Mechanism of the Morita-Baylis-Hillman Reaction
SCHEME 4. MBH Reaction for Methyl Acrylate and Benzaldehyde Catalyzed by DABCO, Showing the Protonated or
Cationized Species Intercepted and Structurally Characterized by ESI-MS and ESI-MS(/MS)
SCHEME 5. MBH Reaction Monitored after 10 min
fragment ion of m/z 211 by losing a molecule of DABCO
(Figure S1a, Supporting Information) and protonated DABCO
of m/z 113 by losing a neutral species of 210 Da, characterized
as the K+ adduct of the anionic product resulting of a Michael
addition of the aza-enolate 3a on the acrylate. Note the close
analogy of this CID process to that of the final MBH reaction
step (Scheme 2). The ion [12 + K]+ of m/z 409 dissociates
predominantly by the loss of the neutral species of 210 Da to
yield protonated aza-enolate [3a + H]+ of m/z 199 (Figure S1b).
The key MBH intermediate [5a +H]+ of m/z 305 dissociates,
as observed before, mainly by the loss of the MBH adduct 7a
of 192 Da to form protonated DABCO of m/z 113 (Figure S1c,
Supporting Information).
After 10 min, another aliquot of the MBH reaction solution
was diluted in acetonitrile and its ESI-MS collected (Figure 1b).
To our delight, it seems that ESI-MS intercepted now intermedi-
ate 8a proposed by McQuade9 from the nucleophilic attack of
the MBH alkoxyde to the aldehyde (Scheme 5) as the [8a +
Na]+ ion of m/z 433. Using freshly distilled benzaldehyde, the
analogous protonated species of m/z 411 was also detected and
characterized by ESI-MS(/MS) (see the Supporting Information).
Ion [8a + Na]+ of m/z 433 shows a characteristic and unique
dissociation pattern via ESI-MS(/MS). It loses (most probably)
PhCdO-Na+ (128 Da) and PhCHO (106 Da) to afford the
protonated form of the aza-enolate of m/z 199 as well as forms
protonated DABCO of m/z 113 (Figure 2).23
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Amarante et al.
FIGURE 3. ESI-MS(/MS) of the ion of m/z 449.
FIGURE 4. ESI-(+)-MS(/MS) spectrum of the ion of m/z 337.
Considering Aggarwal’s proposal for proton sources,9 we
monitored the MBH reaction performed with the same experi-
mental protocol but added an additional 3 equiv of ꢀ-naftol (an
external proton source). Immediately after the reagents were
mixed, an aliquot of the reaction solution was subjected to ESI-
MS (Figure S2, Supporting Information), and again a new
species [10a + H]+ of m/z 449 was detected whereas the ions
of m/z 305 and 433 were nearly absent. The ESI-MS(/MS) of
this new ionic species of m/z 449 was collected (Figure 3),
showing the ion to dissociate by the sequential losses of ꢀ-naftol
and benzaldehyde to afford [3a + H]+of m/z 199. The
interception and characterization of [10a + H]+ agrees therefore
with Aggarwal’s proposition that a proton source participates
in the proton-transfer step by assisting the removal of the base.
(16) (a) Cooks, R. G.; Zhang, D. X.; Koch, K. J.; Gozzo, F. C.; Eberlin,
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Mechanism of the Morita-Baylis-Hillman Reaction
were acquired using a Micromass (Manchester, UK) QTof instru-
ment of ESI-QTof configuration with 5.000 mass resolution and
50 ppm mass accuracy in the TOF mass analyzer. The following
typical operating conditions were used: 3 kV capillary voltage, 8
V cone voltage, and desolvation gas temperature of 100 °C. Tandem
ESI-MS/MS were collected after 4-32 eV collision-induced
dissociation (CID) of mass-selected ions with argon. Mass-selection
was performed by Q1 using a unitary m/z window, and collisions
were performed in the rf-only hexapole collision cell, followed by
mass analysis of product ions by the high-resolution orthogonal
reflectron TOF analyzer.
To collect additional evidence for the action of an external
proton source, we repeated the MBH reaction using methanol
as solvent. Just after the reagents were mixed, an aliquot of the
reaction solution was subject to ESI-MS (Figure S3, Supporting
Information). A new ion of m/z of 337 [10b + H]+ was
intercepted and characterized via ESI-MS(/MS) (Figure 4). As
expected from its more loosely bonded nature, the ion lost
methanol to yield the fragment of m/z 305, which subsequently
dissociated by the loss of benzaldehyde and methyl acrylate to
form protonated DABCO of m/z 113.
The monitored Morita-Baylis-Hillman was carried out as
follows: To a mixture of benzaldehyde (70 mg, 0.66 mmol) and
DABCO (25 mg, 0.22 mmol) was added methyl acrylate (19 mg,
0.22 mmol). The resulting mixture was stirred at room temperature
for 6 h. Aliquots from this reaction medium were taken at different
times and diluted in a mixture of acetonitrile with a tiny amount of
formic acid.
Conclusions
New intermediates of the MBH reaction (8a, 10a-b, 11, and
12) have been, for the first time, successfully intercepted and
structurally characterized via ESI-MS(/MS) monitoring. Inter-
mediates 8a and 10a-b provide the first structural evidence
supporting the mechanistic propositions recently made by
McQuade et al.9 and Aggarwal et al.10 for the key RDS proton-
transfer step IV of MBH reactions. The “fishing” and structural
characterization of these key intermediates exemplifies the
complex equilibrations occurring during MBH reactions, and
the interception of intermediates 8a and 10a-b confirms the
dualistic nature of the RDS proton-transfer step. These findings
may also help develop general asymmetric versions of MBH
reactions, which should consider all major equilibria and use a
fast and efficient proton-transfer promoter.
Acknowledgment. We acknowledge the Sa˜o Paulo State
Science Foundation (FAPESP) and the Brazilian National
Science Council (CNPq) for financial support. F.C. and M.N.E.
thank CNPq and G.W.A., H.M.S.M. and B.G.V. thank FAPESP
for research fellowships. B.R.V.F. thanks Unicamp for a
fellowship.
Supporting Information Available: ESI-MS/MS for prod-
ucts intercepted in the MBH reaction of methyl acrylate with
benzaldehyde (Figure S1); ESI-MS of the Morita-
Baylis-Hillman reaction in the presence of ꢀ-naftol (Figure S2);
ESI-MS of the Morita-Baylis-Hillman reaction in the presence
of methanol (Figure S3); ESI-MS(/MS) of the ion of m/z 423
obtained in the Morita-Baylis-Hillman reaction carried out
with benzaldehyde-d6 (Figure S4); ESI-MS/MS of the ion of
m/z 311 obtained in the Morita-Baylis-Hillman reaction
carried out with benzaldehyde-d6 (Figure S5); ESI-MS(/MS) of
the ion of m/z 411 obtained in the Morita-Baylis-Hillman
reaction carried out with distilled benzaldehyde and recrystal-
lized DABCO (Figure S6). This material is available free of
charge via the Internet at http://pubs.acs.org.
Experimental Section
General Procedures. All reagents were used without purifica-
tion. ESI mass and tandem mass spectra in the positive-ion mode
(21) (a) Almeida, W. P.; Coelho, F. Tetrahedron Lett. 1998, 39, 8609–8612.
(b) Coelho, F.; Almeida, W. P.; Mateus, C. R.; Veronese, D.; Lopes, E. C. S.;
Silveira, G. P. C.; Rossi, R. C.; Pavam, C. H. Tetrahedron 2002, 58, 7437–
7447. (c) Coelho, F.; Lopes, E. C. S.; Veronese, D.; Rossi, R. C. Tetrahedron
Lett. 2003, 44, 5731–5735.
(22) Benzaldehyde is stabilized by 2 ppm of a potassium salt; hence, it may
function as the K+ source.
(23) Additional information regarding the structure of this intermediate
(detected as the sodiated form of m/z 433) came from reactions using Na+ and
K+ free benzaldehyde and benzaldehyde-d6. The analogous protonated species
of m/z 411 and 423 were intercepted, and their ESI-MS/MS are shown in Figures
S4 and S6 (see the Supporting Information).
JO802578T
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