Dynamic origin of the stereoselectivity of a nucleophilic substitution reaction

Article abstract of DOI:10.1021/ol300817a

A nucleophilic substitution on a dichlorovinyl ketone was studied experimentally and computationally. A mixture of products is observed experimentally, but a conventional computational analysis does not account for the formation of the minor stereoisomer. Instead, the product mixture is predicted accurately from a dynamic trajectory study on a bifurcating energy surface. The dynamic origin of the stereoselectivity of the reaction is discussed.

Full text of DOI:10.1021/ol300817a

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Dynamic Origin of the Stereoselectivity of
a Nucleophilic Substitution Reaction
Xavier S. Bogle and Daniel A. Singleton*
Department of Chemistry, Texas A&M University, PO Box 30012, College Station,
Texas 77842, United States
singleton@mail.chem.tamu.edu
Received March 30, 2012
ABSTRACT
A nucleophilic substitution on a dichlorovinyl ketone was studied experimentally and computationally. A mixture of products is observed
experimentally, but a conventional computational analysis does not account for the formation of the minor stereoisomer. Instead, the product
mixture is predicted accurately from a dynamic trajectory study on a bifurcating energy surface. The dynamic origin of the stereoselectivity of the
reaction is discussed.
Many forms of nucleophilic substitution reactions are
intrinsically stereospecific, in that their products are de-
fined in their mechanisms by the stereochemistry of the
starting materials. Others are stereoselective, in that their
product stereochemistry is defined by the choice among
pathways leading to stereoisomeric products. The normal
implicit assumption in the latter case is that any kinetic
stereoselectivity is understandable from transition state
theory (TST) and is determined by the free energies of
competitive transition states (TSs) leading to the products.
Theoretical studies have long recognized that this
assumption need not be correct on complex energy sur-
faces,1,2 and our work has focused on the experimental
evidence for such energy surfaces in ordinary organic reac-
tions and their experimental consequences.3ꢀ8 We describe
(2) (a) Itoh, S.; Yoshimura, N.; Sato, M.; Yamataka, H. J. Org.
Chem. 2011, 76, 8294–8299. (b) Yamamoto, Y.; Hasegawa, H.; Yamataka,
H. J. Org. Chem. 2011, 76, 4652. (c) Katori, T.; Itoh, S.; Sato, M.;
Yamataka, H. J. Am. Chem. Soc. 2010, 132, 3413–3422.
(3) (a) Singleton, D. A.; Hang, C.; Szymanski, M. J.; Meyer, M. P.;
Leach, A. G.; Kuwata, K. T.; Chen, J. S.; Greer, A.; Foote, C. S.; Houk,
K. N. J. Am. Chem. Soc. 2003, 125, 1319–1328. (b) Singleton, D. A.;
Hang, C.; Szymanski, M. J.; Greenwald, E. E. J. Am. Chem. Soc. 2003,
125, 1176–1177. (c) Bekele, T.; Lipton, M. A.; Singleton, D. A.; Christian,
C. F. J. Am. Chem. Soc. 2005, 127, 9216–9223.
(4) Wang, Z.; Hirschi, J. S.; Singleton, D. A. Angew. Chem., Int. Ed.
2009, 48, 9156–9159.
(5) Ussing, B. R.; Hang, C.; Singleton, D. A. J. Am. Chem. Soc. 2006,
128, 7594–7607.
(6) Thomas, J. B.; Waas, J. R.; Harmata, M.; Singleton, D. A. J. Am.
Chem. Soc. 2008, 120, 14544–14555.
(7) Gonzalez-James, O. M.; Kwan, E. E.; Singleton, D. A. J. Am.
(1) (a) Metiu, H.; Ross, J.; Silbey, R.; George, T. F. J. Chem. Phys.
1974, 61, 3200–3209. (b) Valtazanos, P.; Ruedenberg, K. Theor. Chim.
Acta 1986, 69, 281–307. (c) Windus, T. L.; Gordon, M. S.; Burggraf,
L. W.; Davis, L. P. J. Am. Chem. Soc. 1991, 113, 4356–4357. (d)
Tachibana, A.; Okazaki, I.; Koizumi, M.; Hori, K.; Yamabe, T.
J. Am. Chem. Soc. 1985, 107, 1190–1196. (e) Zhou, C.; Birney, D. M.
Org. Lett. 2002, 4, 3279–3282. (f) Wei, H.; Hrovat, D. A.; Borden, W. T.
J. Am. Chem. Soc. 2006, 128, 16676–16683. (g) Shaik, S.; Danovich, D.;
Sastry, G. N.; Ayala, P. Y.; Schlegel, H. B. J. Am. Chem. Soc. 1997, 119,
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r
10.1021/ol300817a
XXXX American Chemical Society

here an experimental, standard computational, and dy-
namic trajectory study of a nucleophilic substitution at
an sp2 carbon in which the stereoselectivity is not decided
by TS energies but rather is decided dynamically on the
downhill slope of a “bifurcating energy surface.”4
readily observable. The particular reaction of 1 with
sodium p-tolylthiolate is convenient, occurring rapidly
and cleanly in dry ethanol at 25 °C.18
The conventional mechanism for nucleophilic substitu-
tion at sp2 carbons involves a stepwise additionꢀelimination
process proceeding through a tetrahedral intermediate.9
In some reactions, however, experimental and computa-
tional studies have supported concerted substitutions,
particularly when the reaction involves good leaving
groups. Williams showed that nucleophilic substitution
reactions at acyl carbons can occur via a concerted
mechanism,10 and a series of experimental studies by
Castro and Santos have shown that a variety of acyl
The determination of the stereoselectivity in this reac-
tion was complicated by the susceptibility of the initial
products 2 and 3 to further reactions affording the disub-
stituted product 4. Due to the rapidity of the reaction, the
complete kinetic modeling of the reaction including the
absolute rate constants was not feasible. However, we were
able to determine the kinetic selectivity between 2 and 3 as
well as the relative rates of their conversion to 4 by
analyzing the product mixture versus conversion on add-
ing successive aliquots of sodium p-tolylthiolate. The
relative amounts of 1ꢀ4 were obtained at a series of
substitutions can occur in a concerted fashion.11ꢀ13
A
theoretical basis for concerted mechanisms was estab-
lished by Guthrie using multidimensional Marcus theo-
ry, and he particularly defined structural conditions
under which substitutions are likely to be concerted.14
Schlegel and Bach studied nucleophilic substitutions on
vinylic chlorides in the gas phase and established the
viability of a concerted mechanism, though they sug-
gested that the presence of electron-withdrawing groups
could favor a stepwise process.15 Indeed, with activa-
tion by multiple electron-withdrawing groups, there has
long been strong evidence for intermediates in vinylic
substitutions.16,9
We considered that the concerted mechanism could lead
to an intriguing phenomenon in the nucleophilic substitu-
tion reactions of electrophiles containing two leaving
groups, such as carbonates or vinylic dihalides. When
there are two leaving groups in a stepwise mechanism,
the selectivity between leaving groups is decided by the
relative energies of the competing TSs for loss of the
leaving groups. For a concerted process, however, it
seemed possible that the reaction could involve only a
single TS that is passed through before the structural
“decision” has been made as to which of the two leaving
groups will be lost. In such a circumstance, the selectivity
between leaving groups, and the product selectivity, could
be decided by dynamic effects on the slope of the potential
energy surface beyond the TS.
1
conversions by the H NMR analysis of worked-up ali-
quots, based on the integrationsofthevinylic peak for each
compound, located in d6-benzene at δ 6.24, 6.37, 5.87, and
5.63 for 1, 2, 3, and 4, respectively. The ratio of 2 to 3
changed little, less thanthe scatter of repeat measurements,
in mixtures obtained from reactions using 0.2ꢀ1.4 equiv of
thiolate, interestingly suggesting that 2 and 3 are equally
reactive (k3 ≈ k4, within 20%). Allowing for the scatter in
the measurements and extrapolating to zero conversion,
the ratio of k1 to k2 was 4.2 ( 0.3. This preference for
formation of 2 over 3 in an 81((1.5):19 ratio is consistent
with previous observations of nucleophilic substitution
reactions of 1 and related compounds.18ꢀ21
The unusual observation here is that 3 is formed at all, as
a conventional computational study does not account for
its formation. The reaction of 1 with p-tolylthiolate anion
was studied systematically in B3LYP/6-31þG**/PCM-
(ethanol) and M06-2X/6-31þG**/PCM(ethanol) calcu-
lations. For each DFT method, a series of six TSs were
located for the nucleophilic addition process, arising from
a combination of s-cis and s-trans conformations of
the enone and three different modes of approach of the
p-tolylthiolate. Structure 5 was the lowest-energy TS with
each method; the higher-energy structures are given in the
Supporting Information. The preference for 5 was 0.9 kcal/
mol in the B3LYP calculations including zero-point energy.
Three features of the calculational results were striking.
The first is that no intermediates could be located. There is
To explore this possibility, nucleophilic substitution on
the 4,4-dichloro-3-buten-2-one17 (1) was chosen for study.
In 1, the good chloride leaving groups should promote
a concerted mechanism, based on the ideas of Guthrie.
In addition, reactions of 1 exhibit a stereoselectivity that is
(9) Rappoport, Z. Acc. Chem. Res. 1981, 14, 7–15.
(10) Williams, A. Acc. Chem. Res. 1989, 22, 387–392.
(11) Castro, E. A.; Ramos, M.; Santos, J. G. J. Org. Chem. 2009, 74,
6374–6377.
(12) Castro, E. A.; Soto, C.; Vasquez, B.; Santos, J. G. ARKIVOC
2008, 10, 151–160.
(13) Castro, E. A.; Gazitua, M.; Santos, J. G. J. Org. Chem. 2005, 70,
8088–8092.
(14) Guthrie, J. P. J. Am. Chem. Soc. 1996, 118, 12878–12885.
(15) Bach, R.; Baboul, A. G.; Schlegel, H. B. J. Am. Chem. Soc. 2001,
123, 5787–5793.
(18) Gudkova, A. S. Izv. Akad. Nauk SSSR, Ser. Khim. 1962, 1248–
1254.
(19) Barrett, A. G. M.; Morris, T. M.; Barton, D. H. R. J. Chem. Soc.,
Perkin Trans. 1 1980, 2272–2277.
(20) Dieter, R. K., III; Silks, L. A.; Fishpaugh, J. R.; Kastner, M. E.
J. Am. Chem. Soc. 1985, 107, 4679–4692.
(16) Rappoport, Z. J. Org. Chem. 1982, 47, 1397–1408.
(17) Wilson, B. D. Synthesis 1992, 283–284.
(21) Tsaikova, S.; Aleksiev, D.; Kostov, G. God. Vissh. Khim.
Tekhnol. Inst. Burgas 1985, 19, 95–100.
B
Org. Lett., Vol. XX, No. XX, XXXX

some question whether a PCM solvent model would be
satisfactory for locating intermediates in reactions of this
type, but the concerted process would also fit with the
general expectations of these reactions as outlined by
Guthrie due to the high nucleofugality of the chlorides.
Exploration of a simplified model reaction in CCSD(T)/
6-31þG**/PCM calculations also supports the absence of
an intermediate (see the Supporting Information). The
second feature is that at TS 5, no clear structural decision
has been made regarding which chloride will be displaced.
The bond lengths of the two CꢀCl bonds in 5 are nearly
˚
equal, differing by less than 0.02 A. The third and most
striking feature is that only TSs leading to 2 were locatable.
Despite extensive effort, no substitution TS leading by
intrinsic reaction coordinate (IRC) analysis to 3 could be
found in any of the calculations with either DFT method.
For each of the six possible 1/p-tolylthiolate orienta-
tions, the energy surfaces include a second saddle point
in which the carbonꢀsulfur bond has fully formed. IRC
analyses indicated that these structures were formally TSs
for the interconversion of 2 and 3 by a process of chloride
addition/conformational rotation/loss of chloride passing
over a single potential energy barrier. The “rotational TS”
6 corresponding to 5 is shown in Figure 1; the others are
given in the Supporting Information.
These results are characteristic of an energy surface for
the nucleophilic substitution reaction that resembles that
shown in Figure 1. On this “bifurcating energy surface”,5,6
the steepest-descent path passing through 5 leads only to 2,
but trajectories passing through 5 could afford either 2 or 3.
The adjacent TS 6 serves to define the “monkey-saddle”
shape of the surface, but it is not involved in the reaction
in a normal way in that trajectories approach it from
higher energies.
Is this picture correct? The reliability of any simple
calculational model, by itself, for a polar reaction in
solution is intrinsically questionable. We sought to gauge
the accuracy of the calculated surface by seeing if it could
account for the experimental selectivity. For ordinary
kinetic selectivity arising from two separate TSs leading
to separate products, TST could be used to predict the
selectivity for comparison with experiment. On bifurcating
energy surfaces, it is usually, though not always,7,22 neces-
sary to employ trajectory calculations to predict the selec-
tivity. Trajectory studies have been impressively successful
at predicting product ratios,3b,4ꢀ8,23 but of course such
success would be unlikely if the energy surface were
qualitatively incorrect.
Figure 1. Qualitative energy surface for the reaction of 1 with
sodium p-tolylthiolate.
a Boltzmann sampling of additional energy appropriate
for 298.15 K, with a random phase and sign for its
initial velocity. The mode associated with the imaginary
frequency was given a Boltzmann sampling of energy
“forward” over the col. A Verlet algorithm was employed
to propagate the trajectories and 1-fs steps were taken until
one of the products were formed or the starting materials
were reformed. The median time for formation of products
2 and 3 was found to be 135 and 152 fs, respectively. This is
a short time that fits with the absence of an intermediate.
TS recrossing was not a significant factor in this system,
as only 12 out of 197 trajectories reformed the starting
materials.
Of the 185 trajectories that formed products, 156 af-
forded 2 and 29 afforded 3. Within a 95% confidence
range, the percentage of 2 in the mixture based on these
trajectories would be 84 ( 5, which is in striking agreement
with the experimental 81:19 ratio of products. This agree-
ment supports the approximate accuracy of the bifurcating
energy surface and role of dynamics in deciding the
stereoselectivity.
What is the origin of the selectivity for 2 over 3? Our
results with DielsꢀAlder reactions of cyclopentadienones
supported the importance of the shape of the potential
energy surface as a control element for selectivity on
bifurcating energy surfaces.6 However, later work with
other DielsꢀAlder reactions and with [2 þ 2] cycloaddi-
tions of ketenes hasfound that the choiceof product is often
controlled by the continuation of motion along a particular
TS normal mode.4,7,8 Such control by momentum through
Toward that end, quasiclassical direct-dynamics
trajectories24 on a B3LYP/6-31þG**/PCM(ethanol) en-
ergy surface were initiated from the area of 5. Each normal
mode of the TS was given its zero point energy plus
(22) Gonzalez-Lafont, A.; Moreno, M.; Lluch, J. M. J. Am. Chem.
Soc. 2004, 126, 13089–13094.
(23) (a) Doubleday, C.; Nendel, M.; Houk, K. N.; Thweatt, D.; Page,
M. J. Am. Chem. Soc. 1999, 121, 4720–4721. (b) Doubleday, C.;
Suhrada, C. P.; Houk, K. N. J. Am. Chem. Soc. 2006, 128, 90–94.
(24) Hase, W. L.; Song, K. H.; Gordon, M. S. Comp. Sci. Eng. 2003,
5, 36–44.
Org. Lett., Vol. XX, No. XX, XXXX
C

the TS is a form of “dynamic matching.” The two types of
control elements are not mutually exclusive; the shape of
the potential energy surface can control the overall odds of
getting one product versus the other, while the motion in a
mode at the TS controls what happens in a particular
trajectory. In the current case, we expected that the selec-
tivity for 2 versus 3 could be understood by simply con-
sidering the shape of the energy surface. In TS 5, the
approach of the thiolate occurs at a dihedral angle versus
the carbonyl carbon of the acyl group (dihedral angle “R”,
Figure 2) that is acute (80°) versus the acylgroup, while R in
6 is obtuse (95°). The acute angle in 5 may be viewed as
resulting from a twisting that minimizes a Cl/acyl group
repulsion in favor of a lesser Cl/H repulsion. TS 6 is the
minimum-energy point on an energetic dividing line be-
tween 2 and 3, and continuation of CꢀS bond formation
from 5 leads to a geometry that is on the “2-side” of 6. This
general idea explains the preferred formation of 2. Our
initial hypothesis was that product 3 would be formed only
when the motion of the p-tolylthiolate in 5 quickly increases
the R to greater than 95°.
in deciding whether a trajectory may afford 3. Mode 8 is
essentially a torsional mode that is twisting about the
breaking carbonꢀcarbon double bond. When the trajec-
tories have an initial positive sign for the mode-8 velocity
(defining positive as in Figure 2), then 29 out of 93
trajectories afford 3. When the mode-8 velocity is negative,
however, 0 out of92trajectories afford3. Mode8 is equally
likely to have a positive versus negative sign, and the
overall selectivity results from a 50:50 mixture of the two.
Despite the chaotic appearance of the trajectories in the
first 100 fs after 5, the dynamic matching effect of the
mode-8 motion imposes a hidden order on the system that
completely predetermines whether a trajectory has the
possibility of forming 3.
Recent work by Truhlar and co-workers has proposed
an alternative model for understanding selectivity that
occurs after dynamical bottlenecks as in the current
reaction.25 In the “canonical competitive nonstatistical
model00 (CCNM), the branching between products is
00
00
divided into indirect00 and direct00 components, the for-
mer being predicted from TST and the later predicted from
phase space theory. The absence of an intermediate leads
the CCNM model to allocate 100% of the reaction to the
direct component, which is dominated by the stability of
the initially formed conformers of the products. However,
the initial conformer of 3 is 4.1 kcal/mol more stable than
that for 2. The CCNM model thus predicts that 3 would be
strongly favored and fails qualitatively in this case.
The consideration above of the shape of the energy
surface and the motions along it in deciding the product
mixture is intriguing because it is so foreign to the normal
analyses of selectivity. TST is the underlying paradigm
within which chemists understand selectivity, and it would
normally be assumed, albeit implicitly, that TS energies
were governing the stereoselectivity of a nucleophilic
substitution. TST greatly simplifies the understanding of
reactions, as it lets one ignore the actual motions of atoms
and considers only the energies of single structures, but we
are finding that TST is often inapplicable in ordinary
organic reactions in solution. The example here adds to
the growing list of classes of reactions that are most easily
understood by consideration of dynamic effects.
Figure 2. Relevant dihedral angles in 5 and 6 and motion
associated with “mode 8” of 5.
Examination of the trajectories does not support such a
simple picture. Starting from 5, it takes 50ꢀ100 fs (71 fs on
average) for the CꢀS bond to form fully, defined by a CꢀS
˚
distance of less than 1.9 A. At the point where the CꢀS
˚
distance passes 1.9 A, 19 of the 29 trajectories leading to 3
haveR’slessthan95° and seven haveR’s lessthan80°. Over
60% (98 out of 156) of the trajectories leading to 2 have R’s
greater than 80° at this point. Neither R nor any other
discernible geometrical parameter in the structures along
the first 100 fs of the trajectories reliably predicts which
product will be formed.
Acknowledgment. We are grateful for NIH grant No.
GM-45617 for support of this research.
However, the direction of the motion through the TS
is highly predictive. In particular, a low-energy (96 cmꢀ1
vibrational mode, (called here “mode 8” because it is the
eighth lowest in energy) is a dominant controlling factor
Supporting Information Available. Experimental and
computational procedures, and energies and full geome-
tries of all calculated structures. This material is available
free of charge via the Internet at http://pubs.acs.org.
)
(25) Zheng, J.; Papajak, E.; Truhlar, D. G. J. Am. Chem. Soc. 2009,
131, 15754–15760.
The authors declare no competing financial interest.
D
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