Mechanistic studies of copper(I)-catalyzed 1,3-halogen migration

Article abstract of DOI:10.1021/ja511236d

An ongoing challenge in modern catalysis is to identify and understand new modes of reactivity promoted by earth-abundant and inexpensive first-row transition metals. Herein, we report a mechanistic study of an unusual copper(I)-catalyzed 1,3-migration of 2-bromostyrenes that reincorporates the bromine activating group into the final product with concomitant borylation of the aryl halide bond. A combination of experimental and computational studies indicated this reaction does not involve any oxidation state changes at copper; rather, migration occurs through a series of formal sigmatropic shifts. Insight provided from these studies will be used to expand the utility of aryl copper species in synthesis and develop new ligands for enantioselective copper-catalyzed halogenation.

Full text of DOI:10.1021/ja511236d

Article
pubs.acs.org/JACS
Mechanistic Studies of Copper(I)-Catalyzed 1,3-Halogen Migration
Ryan Van Hoveln,† Brandi M. Hudson,‡ Henry B. Wedler,‡ Desiree M. Bates,† Gabriel Le Gros,†
Dean J. Tantillo,*,‡ and Jennifer M. Schomaker*,†
†Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
‡Department of Chemistry, University of California, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: An ongoing challenge in modern catalysis is to identify and
understand new modes of reactivity promoted by earth-abundant and
inexpensive first-row transition metals. Herein, we report a mechanistic
study of an unusual copper(I)-catalyzed 1,3-migration of 2-bromostyrenes
that reincorporates the bromine activating group into the final product
with concomitant borylation of the aryl halide bond. A combination of
experimental and computational studies indicated this reaction does not
involve any oxidation state changes at copper; rather, migration occurs
through a series of formal sigmatropic shifts. Insight provided from these
studies will be used to expand the utility of aryl copper species in synthesis
and develop new ligands for enantioselective copper-catalyzed halogenation.
product.5 Typically, first-row transition metals prefer one-
INTRODUCTION
■
electron oxidation state changes, as in the oft-invoked Cu(I)/
The field of base metal catalysis is a vibrant area of research and
offers many potential advantages over more widely utilized
precious metal catalysts. Not only are earth-abundant, first-row
transition metals significantly less expensive and better from an
environmental perspective, but their differing electronic
structures compared to second- and third-row metals provide
Cu(II) and Fe(II)/Fe(III) mechanistic cycles.7 This renders
oxidative addition more challenging with earth-abundant
metals, often requiring the use of less convenient pseudoha-
lides, high temperatures, long reaction times, or a combination
of forcing conditions.8,9 Furthermore, one-electron chemistry
can complicate the reaction pathways, making both spectro-
promise for uncovering new reactivities that proceed through
scopic and mechanistic analyses difficult.7 While great strides
novel mechanistic pathways. While the mechanisms of precious
metal-catalyzed reactions have been studied extensively, the
have been made by several groups to promote Pd-like
mechanistic pathways with first-row metals,8,9 our group is
emphasis on better mechanistic understanding of reactions
catalyzed by base metals is more recent.1 In this vein, our group
taking an alternative approach by developing Cu-catalyzed
reactions that invoke unusual mechanistic pathways involving
has recently described a new mode of reactivity for Cu(I) that
no oxidation state changes at the metal center.2,3
exhibits some unusual features compared to traditional cross-
couplings.2−4 Key to the further development of this chemistry
Our work in this area was stimulated by a serendipitous
observation made during attempts to achieve a copper-
into synthetically useful, Cu-catalyzed carbon−carbon and
catalyzed carboxylation of styrenes.4 In the course of these
carbon−heteroatom bond-forming methodologies is an under-
studies, we attempted to synthesize a benzyl boronic ester via a
standing of the mechanistic details of this new reactivity.
Cu-catalyzed hydroboration of a 2-bromostyrene using a
The functionalization of arenes via cross-coupling is arguably
method recently reported by the Yun group (Scheme 1,
one of the most important and versatile reactions in organic
top).10 In Yun’s proposed mechanism, a phosphine-supported
copper-hydride, 1.1, which is generated in situ, adds to the
styrene in a Markovnikov fashion. A subsequent σ-bond
metathesis of the benzyl copper species 1.2 with pinacol
borane (HBpin) regenerates the catalyst and forms the product.
However, when 2-bromostyrene 1.3 was utilized with this
protocol, very little of the desired product was formed; instead
we observed small amounts (<10%) of what was eventually
identified as 1.4. Based on this initial observation, it appeared
that the benzyl copper intermediate preferred to undergo an
synthesis.5 The majority of these reactions use aryl or vinyl
halides with an organometallic coupling partner, such as a
boronic acid or ester (Suzuki), organozinc (Negishi), organo-
stannane (Stille), organosilane (Hiyama), or Grignard reagent
(Kumada).5,6 While the majority of cross-coupling reactions are
catalyzed by palladium, there has been much interest recently in
promoting these types of transformations using first-row
transition metals, including nickel, iron, and copper.5 However,
there are challenges associated with promoting the typical
mechanistic pathway invoked for cross-coupling, which involves
the oxidative addition of the metal into the aryl halide or
pseudohalide bond, transmetalation of the coupling partner to
the metal, and a final reductive elimination to yield the
Received: November 1, 2014
© XXXX American Chemical Society
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the halogen migration was most likely either an intramolecular
or a rapid dissociation and recombination pathway.2 To rule
out the possibility that the reaction proceeds via direct
borylation of the aryl halide, followed by bromination of the
styrene, 1,4-dibromobenzene was subjected to the reaction
conditions (eq 1). No reaction was observed, indicating that the
olefin is necessary for reactivity.2 When 3-bromostyrene was
subjected to the reaction conditions, only hydroboration
occurred, showing that the olefin’s location relative to the
bromine is also important (eq 2).2 This result supports the
conclusion from our crossover experiments suggesting that the
1,3-halogen migration is an intramolecular reaction. Finally,
subjecting the hydroboration product to the reaction conditions
resulted in no further reaction (eq 3); thus, the benzyl boronic
ester can be ruled out as a potential intermediate in this
transformation.
Scheme 1. Cu-Catalyzed Hydroboration vs Halogen
Migration
unexpected rearrangement, causing the bromine to migrate
from the aryl ring to the benzyl position with concomitant
borylation of the aryl carbon−bromine bond.2,3 The use of a
bis(1,2-dicyclohexylphosphino)ethane (dCype) ligand further
improved the yields of the 1,3-halogen migration/borylation
reaction. We were intrigued by this unusual transformation and
wanted to undertake a thorough mechanistic study to gain
insight into the features of both the catalyst and the substrate
that promote this pathway.11 With this mechanistic under-
standing in hand, we expected to be able to expand the scope
and utility of copper-catalyzed arene and benzyl functionaliza-
tion chemistries. The efforts described in this paper have
allowed us to (1) establish a reasonable energy profile for the
1,3-halogen migration via density functional theory (DFT)
studies, (2) identify the enantio-determining step in the
asymmetric version of this reaction, and (3) gain insight into
design principles for the development of new catalysts
exhibiting increased substrate scope.
Initial studies to better understand the nature of the copper
catalyst were undertaken. Although we suspected that the
phosphine-supported copper(I) hydride was the active catalyst,
these species are known to form dimers and other higher-order
oligomers and aggregates, which could complicate the
mechanistic picture.12 Fortunately, we have recently developed
an asymmetric version of the 1,3-halogen migration reaction,
which permitted a nonlinear effects study to gain insight into
the nuclearity of the catalyst (Figure 1).3 The absence of
nonlinear effects support the assumption that the active catalyst
in solution is monomeric in nature and argues against the
RESULTS AND DISCUSSION
In our previous report, crossover experiments using an
isotopically enriched styrene, 2.2 (Scheme 2), indicated that
■
Scheme 2. Crossover Experiments via 79/81Br Isotopic
Labeling
Figure 1. Dependence of product enantiomeric excess (ee) on ligand
ee.
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presence of off-cycle organocopper dimers or higher order
aggregates.13,14
Scheme 3. Pre-equilibrium Step Forming π-Olefin Complex
and Rate-Determining Step
An investigation of the kinetics of the 1,3-halogen migration
reaction using dCype as the ligand showed that there is no rate
dependence on either 2-bromostyrene or HBpin and that the
reaction is first order in catalyst at low catalyst concentrations
(Figure 2). At higher catalyst loadings, the reaction displayed
saturation behavior, presumably due to the decreased solubility
of the metal complex at higher concentrations.
in high concentration relative to the CuH, the concentration of
this intermediate is dictated by the concentration of the CuH.
The CuH then adds across the olefin in the rate-determining
step. This proposed pre-equilibrium accounts for the zero-order
rate dependence on the styrene, but still allows it to be involved
in the rate-determining step.17
In an effort to elucidate possible intermediates spectroscopi-
cally, stoichiometric studies were undertaken. The phosphine-
supported CuH was generated in situ by treating Cu(OAc)2 and
dCype with poly(methylhydrosiloxane) (PMHS), and then 1
equiv of 2-bromostyrene was added. Upon warming,
approximately 1% of what appeared to be an aryl copper was
rapidly formed (eq 5). At lower temperatures, the intermediate
was stable long enough to acquire a variety of spectra. In spite
of the fact that only a small amount of the ArCu was formed,
nearly all of the carbons and protons from the aryl skeleton
could be assigned. Notably, the aryl carbon bearing copper has
a chemical shift of 174 ppm. While this is an unusual chemical
shift for aryl carbons, it is typical for aryl carbons bearing
copper(I).14h,18 For more details and all spectra, see the
Supporting Information.
Based on these preliminary studies, a partial mechanism was
proposed (Scheme 4). The CuH 4.1 adds to the olefin in a
Scheme 4. Partial Proposed Mechanism for Cu(I)-Catalyzed
1,3-Halogen Migration Reaction
Figure 2. Time course of 1,3-halogen migration and rate dependence
on catalyst loading.
Deuteration of the terminal position of the olefin resulted in
a secondary kinetic isotope effect of 1.19 (eq 4).15 This
indicates that the terminal carbon of the styrene is undergoing a
hybridization change in the rate-determining step, despite the
fact that the overall reaction is zero-order in styrene. To explain
this result, we hypothesize that the active catalyst is the ligand-
supported CuH (Scheme 3); however, interaction of the Cu−H
with the styrene forms a π-olefin complex.16 Since the styrene is
C
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a
regioselective manner to give the benzyl copper intermediate
4.3. This species then undergoes a formal 1,3-rearrangement to
generate an aryl copper, 4.4, followed by σ-bond metathesis
with HBpin to form the benzyl bromide product and regenerate
the catalyst.19 The competing pathway involves direct meta-
thesis of the benzyl copper 4.3 with HBpin to afford the
unobserved benzyl boronic ester 4.6 originally reported by
Yun.10 This proposed mechanistic pathway raises two
important questions that need to be answered. First, it is
unclear what parameters in both the substrate and the catalyst
contribute to the tendency of the benzyl copper 4.3 to undergo
rearrangement, as opposed to immediate borylation. Second,
the nature of the migration of the benzyl copper 4.3 to the aryl
copper species 4.4 needs to be understood, especially as it
relates to transfer of chiral information in the enantioselective
version of the 1,3-halogen migration.
Scheme 5. Impact of Steric Bulk on Hydroboration
To answer the question as to why migration occurs only with
certain ligands, while other ligands give the benzyl boronic
ester, a blend of experimental and computational studies were
carried out. All structures throughout our studies were
optimized with Gaussian 0920 using the M06 functional21
with a 6-311G* basis set22 for H, B, C, O, P, and Br and a
LANL2TZ+ basis set23 for copper (results from calculations
using other basis sets and functionals are given in the
Supporting Information). A Solvent Model Density (SMD)
continuum model was used with tetrahydrofuran (THF) as the
solvent (except where noted).24 All minima were checked for
absence of imaginary vibrational modes, and all transition-state
structures were checked for one imaginary vibrational mode
and confirmed with intrinsic reaction coordinate calculations.25
The barriers of the σ-bond metathesis leading to the benzyl
boronic esters were calculated for the dCype, dMepe (1,2-
bis(dimethylphosphino)ethane), and dtBupe (1,2-bis(di-tert-
butylphosphino)ethane) ligands. The barrier for the dCype
ligand (TS-5.2) was higher than that of the dMepe ligand (TS-
5.2b) (Scheme 5). Since the dCype ligand prefers migration,
the barrier for hydroboration can provide an upper limit for the
energy required for migration, whereas the hydroboration using
the dMepe ligand may provide the lower limit. Thus, the barrier
for migration is most likely between 22.7 and 19.1 kcal/mol.
Presumably, this difference in barriers can be attributed to steric
bulk. Indeed, the barrier for hydroboration using dtBupe (TS-
5.2a) was the highest of the three, predicting that a more
sterically bulky ligand should favor migration to a greater extent
for substrates that currently give mixtures of products. This
design principle will be tested in future investigations of new
ligands for 1,3-halogen migration.
To examine the role the steric and electronic features of both
the substrate and the ligand play in controlling the distribution
of products between migration and hydroboration, a series of
ligands were investigated with a variety of substrates (Table 1).
In the case of 2-bromostyrene itself (entries 1−4), as predicted
by our calculations (Scheme 5), the smaller dMepe and dEtpe
(1,2-bis(diethylphosphino)ethane) ligands switched the reac-
tivity from exclusively migration to exclusively hydroboration
(entries 2 and 3). The larger (S,S)-Ph-BPE (1,2-bis[(2S,5S)-
2,5-diphenylphospholano]ethane) ligand (entry 4), used as a
surrogate for dtBupe, still gave exclusively the migration
product, albeit in much lower yield than dCype (entry 1). As
the substrate becomes more electron-poor, the hydroboration
product is increasingly favored with dCype, indicating that the
rate of halogen migration slows with electron-poor aromatics
(entries 5 and 7). However, the bulkier (S,S)-Ph-BPE ligand
a
Free energies shown are in kcal/mol relative to 5.1, 5.1a, and 5.1b
computed at SMD(THF)-M06/6-311G(d):LANL2TZ+ (Cu).
Table 1. Factors Impacting the Product Distribution in the
1,3-Halogen Migration
a
yield (%)
b
entry
R
ligand
hydroboration
migration
1
H
dCype
dMepe
dEtpe
0
91
98
0
94
0
2
H
3
H
0
4
H
Ph-BPE
dCype
Ph-BPE
dCype
Ph-BPE
dCype
dMepe
dEtpe
37
49
21
28
14
87
0
5
5-F
5-F
28
0
6
7
5-CF3
31
6
8
5-CF3
9
5-OMe
5-OMe
5-OMe
3,5-OMe
3,5-OMe
3,5-OMe
0
10
11
12
13
14
52
100
0
0
dCype
dMepe
dEtpe
98
16
17
40
32
a
Ligands:
b
NMR yields using 1,1,1,2-tetrachloroethane as an internal standard.
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still favored the migration product with these bromostyrenes,
showing that greater steric bulk does promote the migration
(entries 6 and 8). We were curious if increasing the electron
density of the 2-bromostyrene might enable less bulky ligands
to catalyze the 1,3-halogen migration (entries 9−14); however,
this did not appear to be the case when only one electron-
donating group was present on the arene (entries 9−11).
Nonetheless, the combination of a bulky, electron-rich catalyst
and an electron-rich aromatic gave near-quantitative yields of
the migration product. Increasing the electron density of the
substrate even further resulted in some migration product, even
with dMepe and dEtpe ligands (entries 13 and 14). From these
results, we can conclude that increasing the electron density of
the aromatic ring favors migration to a greater extent, while
decreasing electron density disfavors migration. Addtionally,
increasing the steric bulk of the ligand disfavors hydroboration,
while small ligands favor hydroboration.
adjacent carbons. If inversion is taking place, then product 6.6
should display a syn relationship between these same two
protons. Interestingly, the product obtained from this experi-
ment was a mixture of 1:1 of diastereomers, indicating the
presence of a stereoablative step in the migration process.
In our initial report, we proposed that the migration might
occur through an oxidative addition/reductive elimination
pathway via INT-3.4a (Figure 3, bottom).27 However, when
The second question concerning the mechanism involves the
nature of the migration event that transforms the benzyl copper
4.3 to an aryl copper species, 4.4. To better understand the
nature of the 1,3-halogen migration, an experiment was
designed to explore how stereochemical information in the
reaction is transferred from the benzyl copper to the aryl
copper species, and eventually to the final product. Such insight
would be valuable in determining which migration pathways are
feasible. A deuterated dihydronaphthalene substrate, 6.1, was
employed (Scheme 6) to determine if the stereochemistry set
Scheme 6. Transfer of Stereochemical Information during
a
the 1,3-Halogen Migration
Figure 3. Proposed oxidative addition pathway proceeding through a
Cu(I)/Cu(III) cycle. Free energies shown are in kcal/mol relative to
3.1 computed at SMD(THF)-M06/6-311G(d):LANL2TZ+ (Cu).
we investigated this pathway computationally, INT-3.4a could
not be optimized as a minimum on the potential energy surface.
To accommodate the formation of two new bonds in the
oxidative addition step, one of the phosphine ligands was
dissociated to yield INT-3.4. The energy required to form the
strained cupracycle INT-3.4, containing a high oxidation state
Cu(III), was very high at 50 kcal/mol; in addition, this pathway
did not account for the stereoablative step. Moreover, oxidative
addition generally proceeds more rapidly with electron deficient
Ar−X bonds; however, electron-poor substrates in our system
disfavor migration, further suggesting this chemistry does not
proceed through an oxidative addition/reductive elimination
pathway (for other pathways involving Cu(III), see Supporting
Information).28
Since a Cu(I)/Cu(III) pathway seemed unlikely, we
considered a pathway that would take advantage of a facile
Cu(I)/Cu(II) oxidation state change (Scheme 7).7 In this
pathway, bromine abstraction by copper would form an aryl
radical/Cu(II) species, 7.2. Homolytic cleavage of the benzyl
carbon−copper bond, followed by rapid recombination with
the aryl radical, would produce a relatively stable benzyl radical
intermediate, 7.4. From this intermediate, the bromine could
a
Diastereomeric ratio was determined by displacing the benzyl
bromide with LiSePh and then performing a selenoxide elimination.
during the initial hydrocupration step was retained, inverted or
ablated during the 1,3-halogen migration event. Since the
hydrocupration of a π-bond is precedented to occur in a syn
fashion to give 6.3,26 the stereochemistry of the bromine
relative to the deuterium in the product 6.2 should indicate
whether migration occurs with retention or inversion of
stereochemistry. In the case of retention, the product 6.7
should display an anti relationship between the two protons on
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We next investigated a dearomatization pathway that did not
involve changes in the oxidation state at copper (Figure
4).11b,29 The proposed mechanism consists of a three-step
process. While M06 results are shown here, calculations with
various theoretical methods (functionals and basis sets) on
systems with both bidentate and monodentate bisphosphine
coordination were performed (see Supporting Information);
the mechanistic pathways found for these systems were
qualitatively the same. Initially, INT-4.1 proceeds through a
dearomative η3 Cu(I) transition state, leading to non-aromatic
INT-4.3, where both bromine and Cu(I) are bound to the
same carbon. The carbon bearing the bromine, C2, can be
thought of as the “nucleophile” in the dearomatizing step,
whereas the copper can be thought of as the electrophile.
According to this model, increasing the electron density at this
carbon should favor migration; this has been borne out in
studies where the electronics of the substrate have been varied
(see Table 1). In INT-4.3, the Cu(I) occupies the pseudoaxial
position of the tetrahedral carbon while the bromine is in the
equatorial position, making bromine and the benzyl carbon, C7,
nearly coplanar. Since the bromine needs to add to the π-
system at C7, it must come from either above or below C7, not
in the C7−C2−Br plane. Thus, this geometry does not allow
for the correct trajectory for bromine migration to the benzyl
carbon without a conformational change. However, calculations
revealed a 1,2-Br shift onto the Cu(I) atom that proceeds
through a low-barrier transition-state structure to restore
aromaticity in INT-4.5. In this intermediate, the bromine and
the benzyl carbon are no longer coplanar, allowing the bromine
to be oriented in a manner that would permit transfer to the
benzylic position. A final 1,4-Br shift from Cu(I) to the benzylic
position results in the aryl copper INT-4.7. It should be noted
that INT-4.5 allows for free rotation to take place around the
C2−Cu(I) bond; thus, Br could be delivered to either face of
Scheme 7. Pathways Invoking Potential Cu(II)
Intermediates
a
a
Free energies shown are in kcal/mol relative to 7.1, computed at
SMD(THF)-M06/6-311G(d):LANL2TZ+ (Cu).
potentially undergo a 1,4-shift to form an aryl Cu(I) species,
7.5. Unfortunately, the aryl radical 7.2 was high in energy,
making the formation of this intermediate unlikely. Another
possible pathway that could lead to the benzyl radical/aryl
copper species 7.4 involves homolytic cleavage of the benzyl
carbon−copper bond of 7.1 to produce a benzyl radical and a
phosphine-supported Cu(0) intermediate, 7.3, followed by
oxidative addition of the metal into the aryl carbon−bromine
bond. This pathway proved to be even higher in energy than
the Cu(I)/Cu(II) pathway and was not considered further.
Figure 4. Proposed Cu-catalyzed 1,3-halogen migration pathway invoking a dearomatized intermediate. Free energies shown are in kcal/mol relative
to INT-4.1 computed at SMD(THF)-M06/6-311G(d):LANL2TZ+ (Cu). Select bond lengths shown are in angstroms.
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the benzylic carbon. The barrier for rotation (see Supporting
Information) was found to be comparable to the barrier from
INT-4.5 to TS-4.6 and the INT-4.5 → INT-4.7 reaction is
reversible, allowing stereochemistry to be scrambled at this
waypoint. The barrier for rotation was smaller than the barrier
from INT-4.5 to TS-4.6, confirming that stereochemistry can
be scrambled at this waypoint. This energetically viable
dearomative pathway accounts for the stereoablative step;
furthermore, this pathway is consistent with the electronic
effects of the substrate that impact selectivity between
migration and hydroboration (see Table 1). Additionally, the
same pathway computed with the dMepe ligand showed that
the migration pathway was higher in energy than hydroboration
(see Supporting Information).
The full proposed mechanism is illustrated in Scheme 8.
Phosphine-supported CuH 8.1 is the active catalyst that forms a
Scheme 8. Complete Catalytic Cycle for the Cu-Catalyzed
a
1,3-Halogen Migration/Borylation
With our current understanding of the mechanism in hand,
we wanted to return to the asymmetric 1,3-halogen migration
to investigate the nature of the enantio-determining step.10a,30
If we assume the dearomatization pathway described in Figure
4 is the operative mechanism, the step that sets the
stereochemistry of the final benzyl bromide product is the
1,4-bromide shift from the copper of INT-4.5 to the benzyl
carbon of INT-4.7. When the transition-state structures that
lead to both the (R) and the (S) products were optimized with
the (S,S)-Ph-BPE ligand, the transition-state structure that leads
to the (S) enantiomer (5.2) was slightly higher in energy,
which corresponds to our observed stereochemistry (Figure 5).
a
Free energies shown are in kcal/mol relative to 8.3 computed at
SMD(THF)-M06/6-311G(d):LANL2TZ+ (Cu).
π-olefin complex, 8.2, with 2-bromostyrene. This complex
undergoes hydrometalation to form a benzyl copper, 8.3.
Notably, the hydrometalation transition state is the highest in
energy, making this step the rate-determining step, which fits
well with our kinetics studies (see Figure 2). The benzyl copper
8.3 then either reacts with HBpin to form the undesired
hydroboration product or undergoes a 1,3-copper shift that
dearomatizes the ring. As the hydroboration pathway is higher
in energy than the dearomatization pathway, or any subsequent
transition state, the benzyl copper 8.3 prefers to undergo
migration in the presence of the appropriate ligand. While the
difference in energy between the hydroboration and 1,3-
migration pathway is small,32 this energy difference may not be
the only factor influencing selectivity. It is worth noting that the
hydroboration of 8.3 to 8.8 is a bimolecular process, while
conversion of 8.3 to 8.4 is unimolecular; thus, concentration
might be expected to impact selectivity. Indeed, monitoring
selectivity in the reaction of 2-bromo-5-fluorostyrene (which
produces a mixture of migration and hydroboration, see Table
1) shows an initial migration:hydroboration ratio of 1:1, which
increases to a final selectivity of 2:1 as the reaction progresses.
The dearomatized intermediate 8.4 rearomatizes in a 1,2-
bromide shift to form 8.5. This intermediate then transfers
bromine from copper to the benzyl carbon, which in the
presence of chiral ligand constitutes the enantio-determining
step. The aryl copper 8.6 then reacts with HBpin to form the
product and regenerate the CuH catalyst.
Figure 5. Transition-state structures for the enantio-determining step.
While the energy difference is relatively small, the expected
energy difference given the enantiomeric ratio for this substrate
(92:8) and the reaction conditions is ∼1.4 kcal/mol.31 In
transition-state structure 5.1 that leads to the observed
stereochemistry, the geometry is reinforced by a π-stacking
interaction between the substrate and one of the phenyl rings
on the ligand. In transition state 5.2, which leads to the minor
enantiomer, the phenyl ring of the ligand is directed away from
the substrate and, consequently, does not have any favorable π-
stacking interactions. Replacing the phenyl groups on the ligand
with π-extended aromatics, such as naphthyl groups, would
likely result in higher enantioselectivity; these design principles
will be incorporated into future studies.
The mechanistic proposal described herein is somewhat
unusual. It does not represent the most direct pathway to
products, and it involves uncommon steps. For example, the
conversion of INT-4.1 to INT-4.7 can be considered to be a
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formal dyotropic rearrangement. Dyotropic rearrangements
migrations of two groups, often past each other so that they
exchange positionshave a long history.33 The dyotropic
rearrangement described herein is only formal in nature; i.e., it
is stepwise rather than concerted. While other examples of
stepwise dyotropic processes are known,33,34 ours is unusual in
terms of the different pathways traveled by the two migrating
groups: while the copper migrates directly to its new position,
the bromine follows a more convoluted route. In addition, the
final step of our mechanism has a very small associated barrier,
comparable to that for stereochemical scrambling of INT-4.5.
This opens the door for nonstatistical dynamic control35 of
product stereochemistry.
Extreme Science and Engineering Discovery Environment
(XSEDE), which is supported by NSF (ACI-1053575 and
CHE030089). B.M.H. was supported by a U.S. Department of
Education GAANN Fellowship and H.B.W. was supported by a
NSF Graduate Research Fellowship.
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CONCLUSION
■
We have reported computational and experimental studies to
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an aryl bromide is reincorporated into the product via a
dearomative 1,3-shift. These in-depth studies have revealed that
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, computational details, and character-
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free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Authors
*djtantillo@ucdavis.edu
*schomakerj@chem.wisc.edu
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. David Grigg for many helpful
conversations. Sigma-Aldrich and Strem are thanked for a
kind donation of phosphine ligands used in this study. Dr.
Charlie Fry, Dr. Heike Hofstetter, and Dr. Monika Ivancic of
the University of Wisconsin are thanked for their assistance
with NMR spectroscopy and Dr. Martha Vestling for her
assistance with MS data. This research was supported by start-
up funds provided by the University of Wisconsin−Madison
and the ACS-PRF No. 53146-ND1. The NMR facilities at UW-
Madison are funded by the National Science Foundation (NSF;
CHE-9208463, CHE-9629688) and National Institutes of
Health (NIH; RR08389-01). The National Magnetic Reso-
nance Facility at Madison is supported by the NIH
(P41GM103399, S10RR08438, S10RR029220) and the NSF
(BIR-0214394). The computational cluster at UW-Madison is
funded by NSF Grant CHE-0840494. This work used the
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