Controlling Selectivity by Controlling the Path of Trajectories

Article abstract of DOI:10.1021/jacs.5b08635

Consideration of the role of dynamic trajectories in [1,2]- and [2,3]-sigmatropic rearrangements suggests a counterintuitive approach to controlling the selectivity. In our hypothesis, [2,3] selectivity can be promoted by reaction conditions that thermodynamically disfavor the [2,3] rearrangement step and thereby make the transition state later. The application of this idea has led to a successful prescription for dictating the selectivity in Stevens/Sommelet-Hauser rearrangements of ammonium ylides. A combination of kinetic isotope effects, crossover experiments, and computational dynamic trajectories support the idea that the selectivity is controlled through control of the path of trajectories.

Full text of DOI:10.1021/jacs.5b08635

Subscriber access provided by Washington University | Libraries
Communication
Controlling Selectivity by Controlling the Path of Trajectories
Bibaswan Biswas, and Daniel A. Singleton
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b08635 • Publication Date (Web): 09 Nov 2015
Downloaded from http://pubs.acs.org on November 10, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Controlling Selectivity by Controlling the Path of Trajectories
Bibaswan Biswas and Daniel A. Singleton*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas 77842, United States
Supporting Information Placeholder
met with little success, peppered with occasional results that
ABSTRACT: Consideration of the role of dynamic trajectories
are spectacular but enigmatic.4,6,7,8
in [1,2]- and [2,3]-sigmatropic rearrangements suggests a
counterintuitive approach to controlling the selectivity. In
our hypothesis, [2,3] selectivity can be promoted by reaction
conditions that thermodynamically disfavor the [2,3] rear-
rangement step and thereby make the transition state later.
The application of this idea has lead to a successful prescrip-
tion for dictating the selectivity in Stevens / Sommelet-
Hauser rearrangements of ammonium ylides. A combination
of kinetic isotope effects, crossover experiments, and compu-
tational dynamic trajectories support the idea that the selec-
tivity is controlled through control of the path of trajectories.
In previous work, we examined the factors impacting selec-
tivity as trajectories passing through a single transition state
are partitioned into separate products. A critical factor de-
9
10
termining the selectivity is a form of “dynamic matching,” in
which the favored product is the result of a linear continua-
tion of the motions passing through the initial transition
state. We reasoned that in desired [2,3]-sigmatropic rear-
rangements, dynamic matching engenders a particular prob-
lem. That is, transition states for [2,3]-sigmatropic rear-
rangements tend to be both “early” (reactant-like) and
“loose,” so that motion through the transition state (the tran-
sition vector) is largely dissociative in character (Figure 1).1
The continuation of this motion leads to fragment radical or
pairs that ultimately lead to [1,2]-rearrangement products.
The advent of new physical ideas in reaction mechanisms
is interesting in itself, but it can also provide new approaches
to the rational control of reactions. We describe here how
recognition of the role of dynamics in sigmatropic rear-
rangements leads to a counterintuitive but successful strategy
for dictating the product of these reactions.
- - - - early motion - - - - - - - - late motion - - - -
Y
Y
Y
Y
Y
N
+
N
N
Y
N
N
–
N
In conventional chemistry, it is implicitly assumed that the
selectivity of reactions is decided by the relative energy of the
transition states leading to the products. Selectivity can then
be enhanced by lowering the energy of the transition state
leading to the desired product, or raising the energy of alter-
native transition states. Synthetic chemists routinely apply
this idea in a qualitative fashion, for example when adjusting
a steric environment to favor one stereoisomer over another.
[2,3]
product
linear motion
fragment radical
or ion pair
[1,2]
product
Figure 1. Qualitative depiction of atomic motions along the
reaction coordinate for a [2,3]-sigmatropic rearrangement of an
ammonium ylide. With a loose transition state, the early motion
is dominated by bond breaking.
From this analysis, the fragmentation leading to [1,2]
products can be minimized if the transition state is made
either “tighter” or “later.” There is no obvious way to engi-
neer tighter transition states without changing the reactant
structure. By Hammond’s postulate, however, the transition
state should shift later when the reaction is made more en-
dergonic. In reactions of ylides, this may be achieved using
reaction conditions that stabilize the polar starting material
relative to the neutral product. Overall, our hypothesis is that
selectivity may be shifted from [1,2] to [2,3] by conditions that
thermodynamically disfavor the [2,3] rearrangement.
We recently suggested that the pervasive co-occurrence of
formally allowed [2,3]-sigmatropic rearrangements and for-
mally forbidden [1,2]-sigmatropic rearrangements is the
result of a partitioning of dynamic trajectories passing
1
through a single [2,3]-rearrangement transition state. This
idea poses a thorny problem from a synthetic standpoint:
how can one direct the selectivity for a reaction with only
one transition state? There has been a long history of at-
tempts to control the [2,3] versus [1,2] selectivity of these
2,3,4,5
reactions.
Reactant structural effects can certainly direct
which product is formed. Control of the product for a given
reactant of interest is much more difficult. Attempts at con-
trol through changes in reaction conditions have most often
To explore this idea, we chose the base-mediated rear-
rangement of 1a. With the ylide 2a derived from 1a, the
[1,2] (Stevens) rearrangement product 4a predominates
11
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
under ordinary reaction conditions. For example, treatment
of 1 with KH, KOMe, or NaOMe in DMSO affords exclu-
sively 4a (Table 1). These conditions were hypothesized to
involve an uncoordinated “naked” ylide. Neither solvent po-
larity nor the presence of small amounts of methanol (from
the NaOMe) affected the selectivity (Table 1, entries 2 -4).
Switching to methanol as the solvent, however, led to a rever-
sal of the selectivity, giving the [2,3] (Sommelet-Hauser)
rearrangement product 5a in a 75:25 ratio versus 4a. In
methanol, the enolate oxygen of ylide 2a should be tightly
hydrogen bonded, increasing the barrier for the reaction. In
line with this, the reaction in methanol is impractically slow,
several orders of magnitude slower than the reaction in
DMSO (see the Supporting Information (SI)).
12
13
14
15
16
17
18
19
20
1a
1b
1c
1d
1e
1b
1c
1d
1e
CCl4
DBU
KH
99 : 1 (91%)b,c
0 : 100 (70%)
8 : 92 (56%)b,d
0 : 100 (65%)b
5 : 95 (57%)
87 : 13 (76%)b,d
98 : 2 (86%)b
55 : 45
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
KH
KH
KH
DBU
DBU
DBU
DBU
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
98 : 2 (90%)b
aUnless otherwise noted, the reactions were carried out at 25
°C. The reaction times were 5 min or 1 h for product ratios and
ranged from 15 min to 3 h for isolated yields. Isolated yield of
b
MeO
O
MeO
O– or
c
purified major product. Isolated yield obtained using a mixture
O–----H–X
Me2N
CO2Me
H
Me
Me
of CCl4 and CH2Cl2 as solvent. dIsolated yield obtained at 43 °C.
+
N
+
N
Br–
Me
base
Me
[2,3]
This provides a prescription for controlling the outcome of
these reactions in the related examples in Table 1. The naked
ylides obtained using alkali metal bases lead to predominant
or exclusive [1,2] rearrangement (entries 1-4, 13-16). Maxi-
mally hydrogen-bonded ylides obtained using DBU in a non-
polar solvent afford major or predominant [2,3] rearrange-
ment (entries 12, 17-20). The contrasting conditions allow a
choice of products in high yields.
X
X
X
1
2
3
a X=NO2
b X=Cl
[1,2]
rearomatization
c X=CF3
d X=H
e X=CN
Me2N
CO2Me
Me2N
Me
CO2Me
In principle, the DBU could simply be catalyzing the re-
aromatization of 3 to 5, preventing its reversal to 2 or cleav-
age leading to 4. This has been previously proposed in other
systems.7 However, varying the amount of DBU from 0.5 to 2
equivalents had no effect on the product ratio in CH2Cl2 or
DMSO. The use of excess NaOMe also had no effect on the
selectivity in DMSO or methanol. The selectivity was not
affected by ultraviolet irradiation. These results weigh against
the importance of rearomatization in the selectivity.
X
X
4
5
To maximize the expected influence of ylide hydrogen
bonding, we explored the use of amine bases. No reaction
occurred with simple amines, but rapid reactions occurred
with the stronger base DBU. Most strikingly, the DBU-
mediated reactions result in substantial formation of the
[2,3]-product 5. The impact of the DBU increased as the
solvent polarity was decreased (Table 1, entries 7 to 12),
culminating in a 99:1 ratio of [2,3] to [1,2] products when
DBU was used with CCl4 as solvent.
To more directly probe the nature of the transition state
leading to the [2,3] product, the intramolecular kinetic iso-
tope effect (KIE) for the formation of 5a was determined.
Table 1. Effect of reaction conditions on [1,2]- versus [2,3]-
13
When 1a contains a C ortho to the ammonium group, the
sigmatropic rearrangements.a
13C may end up in either the substituted position (5a’) or in
the spectator position (5a”) (Figure 2). The ratio of these
entry reactant
solvent
DMSO
DMSO
CH2Cl2
CCl4
base
KH
5 : 4 ([2,3] : [1,2])
0 : 100 (70%)b
0 : 100
products is the intramolecular KIE, and this was readily de-
termined at natural abundance by NMR methodology.
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
12
A
NaOMe
NaOMe
NaOMe
NaOMe
DBU
total of 12 KIE measurements were made on samples of 5a
obtained from two independent reactions of 1a mediated by
DBU in DMSO. The observed KIE of 1.005 0.002 is signif-
icant but quite small. Qualitatively, the KIE does not fit well
with any transition state involving substantial bonding
changes at the ortho carbon, such as product-determining
deprotonation of 3. The KIE would fit with a sufficiently
loose and early [2,3]-sigmatropic transition state. Quantita-
tively, the KIE matches that predicted below based on the
relevant calculated transition structure.
3
0 : 100
4
0 : 100
5
MeOH
MeOH
DMSO
MeCN
acetone
2-butanone
CH2Cl2
75 : 25
6
75 : 25
7
DBU
33 : 67
8
DBU
45 : 55
9
DBU
80 : 20
10
11
DBU
89 : 11
Crossover observations were used to gauge the intramo-
lecular versus intermolecular nature of the rearrangements.
DBU
94 : 6
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
Crossover was negligible (≈1%) in the [2,3]-product 5d that 4a ensues from the dissociation process. For the reaction
1
2
3
4
5
6
7
8
obtained from a DBU-mediated reaction of a mixture of 1d
and 1d-D13 (labeled in both the benzylic and dimethylamino
groups) in acetonitrile. This shows that the [2,3] product is
predominantly formed by an intramolecular process. Crosso-
ver in the [1,2]-product 4d was significant (≈14%), showing
that the [1,2] product results from a mixture of intermolecu-
lar and intramolecular processes. This is consistent with par-
tial recombination / partial diffusional separation of a gemi-
nate pair, as seen previously with allylic rearrangements.1 It is
uncertain whether the geminate pair is diradical or ionic in
nature, but it seems notable that electron-rich aromatics are
unreactive under these conditions.11b
in methanol, fully classical trajectories were performed in a
sphere of 101 methanol molecules on an ONIOM surface,
using M06-2X/6-31G* for the solute and PM3 for the sol-
vent molecules. Equilibrated trajectories constrained to the
area of 6‡ in methanol were deconstrained then integrated
forward and backward in time.
Me2N
CO2Me
H
9
‡
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[2,3]
Me
O
Me H
N
O– or
NO2
Me
O–----H–OMe or
O–----H–DBU+
3a
b
2a
a
trajectories
H
NO2
H
Me2N
CO2Me Me2N
CO2Me
7----8
complex
6‡
DBU
Me
Me
+
*
1a*
+ 4a
dissociation
(> 3.2 Å)
DMSO
*
NO2
NO2
* = 13
C
Me2N+=CHCO2Me
5a'
5a"
–
+
NO2
predicted KIE for 6‡----H-DBU+
(MO6-2X/6-31+G**/PCM)
1.005
KIE = 5a" : 5a'
=1.005 ± 0.002
7
8
Figure 2. Experimental and predicted intramolecular KIE for
the formation of 5a (25 °C).
Table 2. Polarity and hydrogen-bonding effects on ΔG°, transition
state distances, and trajectory results for the rearrangement of 2a.
trajectory results
[2,3] : dissociation
The lowest-energy transition structure for the reaction of
2a in diverse calculations (see the SI) is 6‡.11 In the gas phase
ΔG° a
conditions
a
b
13
using M06-2X/6-31+G** calculations, 6‡ is formally a
DMSO, no coord.
4.0 2.19
2.8 2.19
9.1 2.36
9.6 2.36
2.74
0 : 108
(exptl: 0 : 100)
[2,3]-rearrangement transition structure. That is, the mini-
mum-energy path (MEP) through 6‡ leads to the [2,3] initial
product 3a. The geometry of 6‡ changes negligibly (only 0.01
Å in key distances a and b) in calculations employing a PCM
solvent model for CH2Cl2 or DMSO, but the MEP through
6‡ no longer affords 3a. Instead, the MEP leads to a complex
of iminium ion 7 and nitrobenzyl anion 8. The 7----8 com-
plex is a potential energy minimum, but it will be seen below
that trajectories rarely linger in this area.
CH2Cl2, no coord.
2.74
2.68
2.67
0 : 54
(exptl: 0 : 100)
hydrogen bonded to
H-OMe in MeOH
17 : 29
(exptl: 75:25)
hydrogen bonded to
58 : 2
(exptl: 99:1)
H-DBU+ in CCl4
aCalculated from M06-2X/6-31+G**/PCM free energies of 3a
versus 2a (kcal/mol), hydrogen-bonded when appropriate.
Although solvent polarity has no effect on 6‡, hydrogen
bonding to the enolate oxygen of the ylide by methanol or
the conjugate acid of DBU (H-DBU+) has substantial effects
(Table 2). The stabilization of the ylide in either case lowers
the ylide free energy versus 3a by over 5 kcal/mol, and this
predictably leads to a later transition state. The C-N distance
a in 6‡ is increased by about 0.2 Å while the C-C distance b is
decreased. The predicted intramolecular KIE for 6‡----H-
DBU+ is 1.005, matching the experimental KIE.
The trajectory results (Table 2) reflect the trends seen in
the experimental observations. The trajectories of naked
ylides in both DMSO and CH2Cl2 rapidly pass through the
area of the 7----8 complex and dissociate with median times
after 6‡ of 118 and 134 fs, respectively. This dissociation is in
line with the exclusive formation of 4 in each solvent using
alkali-metal bases. Methanol as solvent leads to a 75:25 ratio
of [2,3] and [1,2] products experimentally, while the trajec-
tories in explicit methanol modestly favor dissociation lead-
ing to the [1,2] product. Considering the limitations of the
calculations, the agreement of the ratios is satisfactory. Most
importantly, the trajectories involving hydrogen bonding to
6‡ by H-DBU+ lead predominantly to the [2,3]-adduct 3 in
CCl4, matching the experimental observation.
The outcome of trajectories passing through 6‡ in its vari-
14
ous forms was studied by direct-dynamics calculations. For
reactions in DMSO, CH2Cl2, and CCl4, quasiclassical trajec-
tories were initiated at 25 °C from the transition structures
(see the SI for details) and integrated forward and backward
in time on an M06-2X/6-31+G**/PCM surface until the
[2,3]-adduct 3a was formed, 2a was reformed, or the frag-
ments fully separated (defined by a and b > 3.2 Å. This pro-
cess will be referred to here as “dissociation” though the
fragments are initially still associated within a solvent cage).
No trajectories were observed to form 4a, and it was assumed
There is no intrinsic reason to expect high accuracy in the
M06-2X surface for this reaction, and our previous explora-
tion of a [2,3]-sigmatropic rearrangement found that DFT
methods provided an exceptional diversity of predictions.1
Rather, the calculations here should be viewed as providing a
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
Supporting Information
mechanistic model that accounts for both the selectivity ob-
servations and the experimental KIE. We can then query this
model for further insight into the selectivity.
1
2
3
4
5
6
7
8
Complete descriptions of experimental and computational pro-
cedures, calculated structures and energies, and trajectory plots.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Examination of the trajectories suggests that our initial hy-
pothesis for selectivity control was only partially accurate.
Approximately 50% of the 6‡----H-DBU+ trajectories afford
3a within 80-160 fs. Such trajectories are indistinguishable
from ordinary concerted trajectories in asynchronous pericy-
clic reactions. It is notable that the MEP through 6‡----H-
DBU+ leads to the 7----8 complex but the “quick” half of the
trajectories bypass the complex to give 3a directly. (See the
SI for plots of the course of the trajectories.) The remaining
“slow” trajectories complete C-N bond breakage without
progressing in the C–C bond formation that would con-
summate the [2,3] rearrangement. Instead, these trajectories
pass into the area of the 7----8 complex. Yet these trajectories
rarely dissociate, unlike the inevitable fragment separation
seen in reactions of naked ylides. Instead, they return to the
[2,3] product, mostly within a 160-350 fs. A plausible expla-
nation is that the nascent 7 is held to 8 by the combination of
hydrogen bonding between 7 and H-DBU+ and the electro-
static attraction of 8 and H-DBU+. Overall then, the H-DBU+
controls the paths of the trajectories on two levels, the first
arising from its effect on the transition state geometry, pro-
moting simple concerted trajectories, and the second being
its inhibition of dissociative trajectories. Our initial hypothe-
sis anticipated the first control element but not the second.
AUTHOR INFORMATION
Corresponding Author
singleton@mail.chem.tamu.edu
Notes
The authors declare no competing financial interest.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACKNOWLEDGMENT
We thank the NIH (Grant GM-45617) for financial support.
REFERENCES
(1) Biswas, B.; Collins, S. C.; Singleton, D. A. J. Am. Chem. Soc. 2014
136, 3740-3743.
(2) (a) Hauser, C. R.; Kantor, S. W.; Brasen, W. R. J. Am. Chem. Soc.
1953, 75, 2660-2663. (b) Schöllkopf, U.; Fellenberger, K. Annalen 1966,
698, 80-85. (c) Millard, B. J.; Stevens, T. S. J. Chem. Soc. 1963, 3397-3403.
(d) Baldwin, J. E.; Hackler, R. E. J. Am. Chem. Soc. 1969, 91, 3646-3647.
(e) Rautenstrauch, V. Chem. Commun. 1970, 4-6. (f) Baldwin, J. E.; Brown,
J. E.; Cordell, R. W. Chem. Commun. 1970, 31-32.
(3) (a) Chantrapromma, K.; Ollis, W. D.; Sutherland, I. O. Chem. Com-
mun. 1977, 97-99. (b) Chantrapromma, K.; Ollis, W. D.; Sutherland, I. O.
J. Chem. Soc. Perkin Trans. I 1983, 1029-1039. (c) Jemison, T. L.; Ollis, W.
D.; Sutherland, I. O. J. Chem. Soc. Perkin Trans. I 1980, 1458-1461.
(4) (a) Tayama, E.; Takedachi, K.; Iwamoto, H.; Hasegawa, E. Tetrahe-
dron 2010, 66, 9389-9395. (b) Yayama, E.; Kimura, H. Angew. Chem. Int.
Ed. 2007, 46, 8869-8871.
The trajectory results in methanol allow an interesting
comparison of rearrangement trajectories with those under-
going dissociation. The [2,3]-rearrangement trajectories
giving 3a in discrete methanol are fast, occurring with a me-
dian time of 210 fs and with 80% finishing within 300 fs. The
dissociative trajectories are slow, taking a median time of 560
fs. As was seen with 6‡----H-DBU+, the trajectories rapidly
forming 3a have bypassed the formation of the MEP-favored
7----8 complex. Unlike with 6‡----H-DBU+, the trajectories
that proceed into the area of the 7----8 complex mainly dis-
sociate. In this way, the methanol reaction lacks the second
level of trajectory control present in the DBU reaction, and
the selectivity for the [2,3] product is lower.
(5) Yamamoto, Y.; Oda, J.; Inouye, Y. Tetrahedron Lett. 1979, 2411-
2414.
(6) Hayashi, Y.; Oda, R. Tetrahedron Lett. 1968, 9, 5381-5384. Pine, S.
H.; Munemo, E. M.; Phillips, T. R.; Bartolini, G.; Cotton, W. D.; Andrews,
G. C. J. Org. Chem. 1971, 36, 984-991.
(7) (a) Tanaka, T.; Shirai, N.; Sugimori, J.; Sato, Y. J. Org. Chem. 1992,
57, 5034-5036. (b) Narita, K.; Shirai, N.; Sato, Y. J. Org. Chem. 1997, 62,
2544-2549.
(8)Kocharyan, S. T.; Karapatyan, V. E.; Razina, T. L.; Babyan, A. T.
Russ. J. Gen. Chem 1990, 18, 2277-2282.
(9) (a) Thomas, J. R.; Waas, J. R.; Harmata, M.; Singleton, D. A. J. Am.
Chem. Soc. 2008, 130, 14544-14555. (b) Wang, Z.; Hirschi, J. S.; Singleton,
D. A. Angew. Chem. Int. Ed. Engl. 2009, 48, 9156-9159. (c) Kelly, K. K.;
Hirschi, J. S.; Singleton, D. A. J. Am. Chem. Soc. 2009, 131, 8382-8383. (d)
Gonzalez-James, O. M.; Kwan, E. E.; Singleton, D. A. J. Am. Chem. Soc.
2012, 134, 1914-1917.
(10) Carpenter, B. K. J. Am. Chem. Soc. 1995, 117, 6336-6344.
(11) (a) A computational advantage of the p-nitro-substituted system
for this study it that the key stationary points, particularly 6‡ and 7----8, are
RHF→UHF stable. (b) No CIDNP could be detected for this reaction, and
no products corresponding to radical homocoupling could be detected.
(12) (a) Singleton, D. A.; Szymanski, M. J. J. Am. Chem. Soc. 1999, 121,
9455-9456. (b) Singleton, D. A.; Schulmeier, B. E. J. Am. Chem. Soc. 1999,
121, 9313-9317. (c) Gonzalez,-James, O. M.; Zhang, X.; Datta, A.; Hrovat,
D. A.; Borden, W. T.; Singleton, D. A. J. Am. Chem. Soc. 2010, 132, 12548-
12549.
Mechanistic understanding is the key to the rational design
and control of reactions, but it is fair to ask how much detail
is really needed in mechanisms. Simple “electron-pushing”
mechanisms certainly provide substantial insight by them-
selves. Rate laws, rate-limiting steps, and the understanding
of transition state geometries and energies provide much
more insight, and this knowledge is integral to modern reac-
tion development. The results here show that the considera-
tion of dynamics in reactions can also be important and can
provide unexpected strategies for the direction of reactions.
We are continuing to pursue the application of dynamics-
based ideas to the control of reactions.
(13) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157-167.
(14) Hase, W. L.; Song, K. H.; Gordon, M. S. Comp. Sci. Eng. 2003, 5,
36-44.
ASSOCIATED CONTENT
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment