Baylis-Hillman mechanism: A new interpretation in aprotic solvents

Article abstract of DOI:10.1021/ol047739o

(Chemical Equation Presented) Using reaction rate data collected in aprotic solvents, we have determined that the Baylis-Hillman rate-determining step is second order in aldehyde and first order in DABCO and acrylate. On the basis of these data, we have p

Full text of DOI:10.1021/ol047739o

ORGANIC
LETTERS
2005
Vol. 7, No. 1
147-150
Baylis−Hillman Mechanism: A New
Interpretation in Aprotic Solvents
Kristin E. Price, Steven J. Broadwater, Hyun M. Jung, and D. Tyler McQuade*
Department of Chemistry and Chemical Biology, Cornell UniVersity,
Ithaca, New York 14853
dtm25@cornell.edu
Received November 3, 2004
ABSTRACT
Using reaction rate data collected in aprotic solvents, we have determined that the Baylis−Hillman rate-determining step is second order in
aldehyde and first order in DABCO and acrylate. On the basis of these data, we have proposed a new mechanism involving a hemiacetal
intermediate. The proposed mechanism was then supported using two different kinetic isotope experiments.
The Baylis-Hillman (BH) reaction, also known as the
Morita-Baylis-Hillman reaction, efficiently converts simple
starting materials into highly functionalized products.1-3 This
reaction became popular in the early 1980s with the first
application to synthesis,4 the first “arrow pushing” mecha-
nism,5 and the first physical organic studies. On the basis of
pressure-dependence data, Hill and Isaacs proposed the well-
accepted mechanism depicted in Scheme 1.6,7 Bode and Kaye
poor aldehydes and is reversible in some cases.9 Many groups
have reported the influence of solvents,10-13 Lewis acids,14,15
Lewis bases,2 temperatures,16 and substrates on the BH
reaction.17
We recently reported the synthesis of a novel polymeriz-
able amphiphile using the BH reaction.18 To optimize the
(1) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001-
8062.
(2) Ciganek, E., Ed. The Catalyzed R-Hydroxyalkylation and R-Ami-
noalkylation of ActiVated Olefins (the Morita-Baylis-Hillman Reaction);
John Wiley & Sons: New York, 1997; Vol. 51.
(3) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103,
811-891.
Scheme 1. Accepted Baylis-Hillman Mechanism
(4) Drewes, S. E.; Emslie, N. D. J. Chem. Soc., Perkin Trans. 1 1982,
2079-2083.
(5) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1983,
22, 795-796.
(6) Hill, J. S.; Isaacs, N. S. Tetrahedron Lett. 1986, 27, 5007-5010.
(7) Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem. 1990, 3, 285-288.
(8) Bode, M. L.; Kaye, P. T. Tetrahedron Lett. 1991, 32, 5611-5614.
(9) Fort, Y.; Berthe, M. C.; Caubere, P. Tetrahedron 1992, 48, 6371-
6384.
(10) Auge, J.; Lubin, N.; Lubineau, A. Tetrahedron Lett. 1994, 35, 7947-
7948.
(11) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J. Org.
Chem. 2002, 67, 510-514.
(12) Yu, C. Z.; Liu, B.; Hu, L. Q. J. Org. Chem. 2001, 66, 5413-5418.
(13) Krishna, P. R.; Manjuvani, A.; Kannan, V.; Sharma, G. V. M.
Tetrahedron Lett. 2004, 45, 1183-1185.
(14) Aggarwal, V. K.; Tarver, G. J.; McCague, R. Chem. Commun. 1996,
2713-2714.
supported this mechanism with rate data and a rate law.8
Fort et al. showed that the BH reaction is faster with electron-
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© 2005 American Chemical Society
Published on Web 12/14/2004

Scheme 2. Proposed Mechanism
Figure 1. Changes in rate as a function of reagent or solvent concentration. (A) Methyl acrylate. (B) DABCO. (C) 4-Nitrobenzaldehyde.
(D) DMSO using DMF or CHCl3 as the cosolvent. A, B, and C were run in THF/DMSO mixtures where the DMSO concentration was held
constant. An F-test comparing a nonlinear and a linear fit for the data in C indicates with >99% confidence that the nonlinear fit is valid.
reaction, we performed rate studies using a variety of solvents
and p-nitrobenzaldehyde, an ideal aldehyde that reacts
quickly and cleanly.19 We also examined the mechanism by
measuring isotope effects with isotopically labeled aldehyde
and methyl acrylate. We now report that the rate-determining
step (RDS) is not the 1,2-addition as previously reported but
the proton abstraction (elimination) from intermediate 7
(Scheme 2). In addition, we report that the rate law is second
order in aldehyde.
aldehyde (Figure 1C). On the basis of the order plots depicted
in Figure 1, we propose the rate law shown in eq 1. This
rate law indicates that 2 equiv of aldehyde must be present
in the RDS of the BH reaction. Therefore, the 1,2-addition
cannot be the RDS and the product-forming elimination must
be more complicated than previously proposed (Scheme 1).
We therefore propose the mechanism outlined in Scheme 2.
The reaction begins with combination of acrylate and Lewis
base (5) and 1,2-addition of 5 onto the aldehyde (6) as
initially proposed; however, the mechanism continues by
reacting with a second equivalent of aldehyde to yield a
hemiacetal (7). The hemiacetal then undergoes a rate-limiting
deprotonation to yield 9, which breaks down to the BH
product in a series of post-rate-limiting steps.
As shown in Figure 1A and B, the BH reaction is first
order in DABCO and methyl acrylate;8 however, in contrast
to previous reports, the BH reaction is second order in
(15) Aggarwal, V. K.; Mereu, A.; Tarver, G. J.; McCague, R. J. Org.
Chem. 1998, 63, 7183-7189.
(16) Rafel, S.; Leahy, J. W. J. Org. Chem. 1997, 62, 1521-1522.
(17) Lee, W. D.; Yang, K. S.; Chen, K. M. Chem. Commun. 2001, 1612-
1613.
rate ) kobs[aldehyde]2[DABCO][acrylate]
(1)
148
Org. Lett., Vol. 7, No. 1, 2005

The dual role of the aldehyde is necessary because the
alkoxide resulting from the 1,2-addition (6) is unable to act
as an intramolecular base due to geometric constraints.
Hemiacetal 7 can deprotonate the R-position in the RDS via
a six-membered transition state (8), cleaving the C-H bond
and eliminating DABCO. The deuterium label removed from
the R-position resides on the alcohol of the BH product,
providing modest evidence that multiple post-rate-limiting
steps must occur. The hemiacetal intermediate was inspired
by the aldol-Tishchenko reaction, another reaction involving
2 equiv of aldehyde.20 The aldol-Tishchenko reaction shows
large inverse equilibrium isotope effects (a product of two
inverse equilibrium isotope effects) when the aldehyde proton
is labeled, a result similar to that in our system (vide infra).
To support the proposed mechanism, we used two different
kinetic isotope experiments. The first isotope experiment we
performed used methyl R-2H acrylate. The labeled acrylate
was prepared using known methods, and the results of the
isotope experiments are shown in Table 1.21 If the proposed
In these cases, maximum KIEs were observed when the
proton was equally shared among heavy atoms in the
transition state (i.e., ∆pKa is zero).23 For the BH reaction,
∆pKa equals zero when the pKa of the R-2H acrylate and
resulting hemiacetal (7) are equivalent. We propose that as
the solvent polarity decreases, the ∆pKa between the
abstracting base and the R-proton increases, producing a
muted KIE.
The second isotope experiment we performed used R-deu-
terio-p-nitrobenzaldehyde (Scheme 2).24 The 2 equiv of
aldehyde used in the reaction both undergo sp2 to sp3 geom-
etry changes. These changes are expected to yield large in-
verse equilibrium isotope effects manifested as KIEs (because
the kobs will be a product of K1, K2, K3, and k4).21,25 The
observed values of aldehyde-isotope effects were 0.72-0.80,
which are large inverse isotope effects, providing further
support for the proposed mechanism.
In addition to the results of KIE experiments, support for
the mechanism is found in a number of reports of dioxanone
(12) byproducts.26-29 These byproducts result when hemi-
acetal intermediates 7 or 9 undergo intramolecular transes-
terification with the ester, forming a six-membered ring
(Scheme 3). As expected, the dioxanone byproducts form
only when the acrylate is an activated ester.
Table 1. Rate Data for the Baylis-Hillman Reaction
Scheme 3. Proposed Dioxanone Formation
b
c
aldehydea solvent
kH/kD
kH/kD
krel ꢀ/ET(30)
10
10
10
10
10
DMSO 5.2 ( 0.6 0.75 ( 0.05
36
10
7
2
1
47/45
38/43
37/46
8/37
DMF
MeCN
THF
2.9 ( 0.2 N/A
4.2 ( 0.1 N/A
2.4 ( 0.1 0.80 ( 0.07
2.2 ( 0.2 0.72 ( 0.03
CHCl3
5/39
a Reactions were performed using 0.84 M methyl acrylate, 0.83 M
aldehyde, and 0.27 M DABCO. b Observed kinetic isotope effect (KIE)
using R-deuterio methyl acrylate. c Observed KIE using deuterio-labeled
aldehyde.
The BH reaction rate shows a nonlinear but systematic
dependence on solvent polarity (Table 1). In particular,
reactions using DMSO exhibit rates much faster than those
of reactions using other comparable polar solvents such as
DMF and acetonitrile. As shown in Figure 1D, the BH
reaction rate increases linearly with DMSO concentration
for both low- and high-polarity cosolvents (chloroform and
DMF, respectively). These results suggest that the BH
reaction has a first-order dependence on DMSO; however,
after careful consideration, we cannot assign a molecular role
for DMSO. As such, we suggest that DMSO may uniquely
solvate the transition state and thus provide accelerated rates.
Using multiple isotope-labeling experiments and order
data, we propose that the RDS is the elimination of the
mechanism is correct, a primary kinetic isotope effect (KIE)
will be observed because the R-2H acrylate bond is cleaved
in the proposed RDS. The magnitude of the KIE is expected
to be muted because the observed KIE will be a product of
the KIE for C-H bond cleavage and an inverse equilibrium
isotope effect resulting from geometry changes during the
1,2-addition preequilibrium. We observed a primary KIE in
all solvents tested. The magnitude of the KIE was observed
to be highest in polar solvents. These data are clear evidence
for a rate-limiting C-H cleavage, which is consistent with
our proposed mechanism. Others have reported similar
solvent-dependent changes in KIEs for proton abstractions.22
(23) McLennan, D. J.; Wong, R. J. J. Chem. Soc., Perkin Trans. 2 1974,
526-532.
(24) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
(25) Amaral, L. D.; Bull, H. G.; Cordes, E. H. J. Am. Chem. Soc. 1972,
94, 7579-7580.
(26) Drewes, S. E.; Emslie, N. D.; Field, J. S.; Khan, A. A.; Ramesar,
N. S. Tetrahedron Lett. 1993, 34, 1205-1208.
(27) Perlmutter, P.; Puniani, E.; Westman, G. Tetrahedron Lett. 1996,
37, 1715-1718.
(28) Brzezinski, L. J.; Rafel, S.; Leahy, J. W. Tetrahedron 1997, 53,
16423-16434.
(29) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am.
Chem. Soc. 1999, 121, 10219-10220.
(18) Jung, H. M.; Price, K. E.; McQuade, D. T. J. Am. Chem. Soc. 2003,
125, 5351-5355.
(19) Preliminary evidence with other aldehydes indicates that the
proposed mechanism is general.
(20) Abu-Hasanayn, F.; Streitwieser, A. J. Org. Chem. 1998, 63, 2954-
2960.
(21) Baldwin, J. E.; Cianciosi, S. J. J. Am. Chem. Soc. 1992, 114, 9401-
9408.
(22) Melander, L.; Saunders, W. H. Reaction Rates of Isotopic Molecules;
Wiley-Interscience: Hoboken, NJ, 1980.
Org. Lett., Vol. 7, No. 1, 2005
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R-proton by a hemiacetal intermediate. Preliminary evidence
suggests that this mechanism is general for aryl aldehydes.
We will present results from experiments using a greater
variety of aldehydes and reactions run with alcohol additives
shortly.
Training Grant) for support and David Collum, Barry
Carpenter, and Charlie Wilcox for general discussion.
Supporting Information Available: General experimen-
tal procedure, rate plots, and selected NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Cornell University, Dreyfus
Foundation, 3M, NSF (CCMR-MRSEC), and NIH (CBI
OL047739O
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