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.
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