cycloadditions that involve substantial TS recrossing, and
the observed effect was in the opposite direction from New-
tonian KIEs. Little is known about either of these KIEs from
the single published examples. From our observations of
recrossing in the DielsꢀAlder reaction of acrolein with
of samples of cycloadduct generated from the dimerization
of 1 at 70 °C. The results from a total of 12 measurements
using two independent samples of 3 are shown in Figure 2.
6
methyl vinyl ketone, the dimerization of methacrolein (1)
appeared to be a candidate to exhibit both effects.
We describe here an experimental, standard computa-
tional, and dynamic trajectory study of the DielsꢀAlder
dimerization of 1. The results show how structure impacts
the multiple phenomena affecting selectivity in this ordi-
nary organic reaction. We introduce the idea of an atomic
motion reaction coordinate diagram to provide insight into
the race between carbon atoms underlying the selectivity in
this system.
Newtonian KIEs can arise on symmetrical bifurcating
energy surfaces (Figure 1a). In the area past the TS,
molecular forces are pushing atoms toward two possible
products. With isotopic substitution, the products are
inequivalent and Newton’s second law favors the product
arising from the steepest-descent path in mass-weighted
coordinates (the intrinsic reaction coordinate, or IRC).
This technical idea mathematically defines the direction of
the isotope effect, but it provides little intuition, indeed
none at all with regard to the magnitude of the selectivity.
Instead, we find it enlightening to consider reaction co-
ordinate diagrams that follow the motion of individual
atoms. In such diagrams, separate paths may be drawn for
each atom in a molecule, and the diagrams become inter-
esting when they compare the motions of two atoms
competing for two distinct positions in the product. In
forming an asymmetric product starting from a symme-
trical TS, the initially equivalent atoms of such “racing
pairs” take separate paths. With reflection, it may be
recognized that the preferred path, the IRC, will be that
in which the lighter isotope moves more as the atomic
motion paths separate. This idea will be examined later in
the context of the current example. Initially, since the
system here is subject to recrossing, we did not know
whether the race would be decided by light atoms accel-
erating faster or heavy atoms recrossing less.
Figure 1. (a) Symmetrical bifurcating energy surface. The IRC is
asymmetric due to isotopic substitution. (b) An atomic motion
reaction coordinate diagram. The two paths do not represent
separate reactions, but instead represent the differing motion of
two atoms of a racing pair as the product is formed.
Figure 2. TS and KIEs for the dimerization of 1.
In ordinary isotope effects resulting from ZPE changes,
C usually undergoes σ-bonding making/breaking faster
1
2
The dimerization of 1 is well set up for such a race.
Caramella had found that the lowest-energy TS (2) for the
dimerization is stabilized by “bis-pericyclic” character and
1
3
12
0
than C. The observed preference for C in position b
over b is in this direction, but the preference would only
make sense from a conventional perspective if the TS were
not symmetrical. With the symmetrical TS favored in a
wide variety of calculational methods (see the Supporting
7
has C symmetry. The product 3 is asymmetric, so the
2
geometry must formally break symmetry after the TS to
afford two structures that are indistinguishable in the ab-
1
3
0
0
sence of isotopic labeling. When a C is present in 1, the
Information (SI)), the positions in 2 leading to b and b
products are equivalent, so TS ZPE cannot explain the b/b
KIE. The KIEs at a/a and c/c are not obviously amenable
to any conventional explanation.
13
product may contain the C in either the diene (a, b, c, d) or
0
0
0
0
0
0
dienophile (a , b , c , ord ) portion of 3. The ratio of products
labeled in the paired positions is an intramolecular KIE.
Four intramolecular KIEs are observable in this reaction,
resulting from the pairs of products formed with a label in
position a, b, c, or d of 2. These ratios and KIEs were
All of the KIEs, however, fit with Newtonian expecta-
tions. IRCs were followed forward from 2 in B3PW91/6-
31þG** calculations (chosen because they fit best here
8
13
C
measured directly at natural abundance by NMR analysis
with high-level ab initio methods; see the SI), with a
placed in position a, b, c, or d (Figure 3). For positions a
and b of 2, the IRC is desymmetrized toward placing the
13
C in the diene portion of 3 (positions a and b as opposed
(
7) Toma, L.; Romano, S.; Quadrelli, P.; Caramella, P. Tetrahedron
Lett. 2001, 42, 5077–5080.
8) Singleton, D. A.; Szymanski, M. J. J. Am. Chem. Soc. 1999, 121,
455–9456.
(
0
0
13
9
to a and b ), while a C in position c of 2 ends up in the
Org. Lett., Vol. 14, No. 20, 2012
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