Carboxylate-assisted C(sp3)-H activation in olefin metathesis-relevant ruthenium complexes

Article abstract of DOI:10.1021/ja5021958

The mechanism of C-H activation at metathesis-relevant ruthenium(II) benzylidene complexes was studied both experimentally and computationally. Synthesis of a ruthenium dicarboxylate at a low temperature allowed for direct observation of the C-H activation step, independent of the initial anionic ligand-exchange reactions. A first-order reaction supports an intramolecular concerted metalation-deprotonation mechanism with ^? _298K = 22.2 ± 0.1 kcal·mol^-1 for the parent N-adamantyl-N-mesityl complex. An experimentally determined ^? =-5.2 ± 2.6 eu supports a highly ordered transition state for carboxylate-assisted C(sp³)-H activation. Experimental results, including measurement of a large primary kinetic isotope effect (k _H/k_D = 8.1 ± 1.7), agree closely with a computed six-membered carboxylate-assisted C-H activation mechanism where the deprotonating carboxylate adopts a pseudo-apical geometry, displacing the aryl ether chelate. The rate of cyclometalation was found to be influenced by both the electronics of the assisting carboxylate and the ruthenium ligand environment.

Full text of DOI:10.1021/ja5021958

Article
pubs.acs.org/JACS
Carboxylate-Assisted C(sp3)−H Activation in Olefin Metathesis-
Relevant Ruthenium Complexes
Jeffrey S. Cannon,† Lufeng Zou,‡ Peng Liu,‡ Yu Lan,‡ Daniel J. O’Leary,*,§ K. N. Houk,*,‡
and Robert H. Grubbs*,†
†Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute
of Technology, Pasadena, California 91125, United States
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
§Department of Chemistry, Pomona College, Claremont, California 91711, United States
S
* Supporting Information
ABSTRACT: The mechanism of C−H activation at meta-
thesis-relevant ruthenium(II) benzylidene complexes was
studied both experimentally and computationally. Synthesis
of a ruthenium dicarboxylate at a low temperature allowed for
direct observation of the C−H activation step, independent of
the initial anionic ligand-exchange reactions. A first-order
reaction supports an intramolecular concerted metalation−
deprotonation mechanism with ΔG⧧
= 22.2
0.1 kcal·mol−1 for the parent N-adamantyl-N′-mesityl complex. An
298K
experimentally determined ΔS⧧ = −5.2 2.6 eu supports a highly ordered transition state for carboxylate-assisted C(sp3)−H
activation. Experimental results, including measurement of a large primary kinetic isotope effect (kH/kD = 8.1 1.7), agree
closely with a computed six-membered carboxylate-assisted C−H activation mechanism where the deprotonating carboxylate
adopts a pseudo-apical geometry, displacing the aryl ether chelate. The rate of cyclometalation was found to be influenced by
both the electronics of the assisting carboxylate and the ruthenium ligand environment.
C(sp2)−H activation at ruthenium has been studied in only a
INTRODUCTION
■
single family of complexes.5d,12 The CMD C−H activation
mechanism, which is particularly common with palladium
carboxylate catalysts, is largely unexplored with ruthenium.
Furthermore, inner-sphere activation of methylene C(sp3)−H
bonds is quite rare and is essentially unprecedented for
ruthenium.
The activation of C−H bonds by transition metal complexes
has become an important, growing field in organic synthesis.1
At the core of this field is the need to understand the general
mechanisms of the C−H activation step in order to harness the
reactivity for synthetic processes. As a result, mechanistic and
computational studies have been of great interest to organic
and inorganic chemists in order to elucidate the mechanisms of
C−H activation reactions by transition metals, including Pd,1b,2
Ir,3 Rh,4 Ru,5 and others.6
Carboxylate-assisted C−H activation has recently garnered
attention as a generally mild method for C−H activation at
transition metal centers.1a,c The use of carboxylates in catalytic
C−H activation reactions has grown tremendously in recent
years, and several reports investigating the mechanism have
appeared.7 The majority of these reactions involve activation of
aromatic or vinylic C(sp2)−H bonds, and only sparing
examples of carboxylate-assisted C(sp3)−H activation have
been reported.1c Computational and mechanistic studies have
been primarily focused on palladium carboxylate-catalyzed
C−H activations, which often involve a concerted
metalation−deprotonation (CMD) mechanism with a six-
membered transition state.2e,i,7d,8 Activation of C(sp3)−H
bonds with ruthenium complexes is particularly rare9 and
typically occurs through C−H oxidative addition to ruth-
enium9n,10 or C−H radical abstraction with a ruthenium-oxo/
nitrenoid.11 The mechanism of carboxylate-mediated
We recently reported the synthesis of a new family of
cyclometalated ruthenium benzylidene complexes (1−3, Figure
1).13 These ruthenium complexes were found to be highly
selective for Z-olefins (typically >90% Z) in a number of olefin
metathesis reactions, including macrocyclic ring-closing meta-
thesis,14 cross metathesis,15 asymmetric ring-opening cross
metathesis,16 ring-opening metathesis polymerization,13d and
ethenolysis reactions.17 These findings were complementary to
the reactivity of molybdenum and tungsten catalysts reported
by Schrock and Hoveyda.18
Cyclometalated complexes 1−3 are highly interesting
organometallic species. These complexes contain a stable
Ru−C bond in the presence of a reactive ruthenium alkylidene.
Previous observations of C−H bond activation in ruthenium
alkylidene complexes led to decomposition of the Ru−C bond,
typically through insertion into the alkylidene followed by
hydride elimination reactions.19 The stable cyclometalated
Received: March 3, 2014
© XXXX American Chemical Society
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THF-d8:CD3OD at 40 °C. Both THF and methanol are
required for this reaction because of the limited solubility of
complexes 4 and 3 in pure methanol and of sodium pivalate in
pure THF. The reaction progress could be easily monitored by
1
observation of benzylidene peaks (δ 15−20 ppm) in H NMR
spectra.
These reactions were characterized by a first-order decay of
the starting complex, with a buildup of two intermediates
identified as the mono- and dicarboxylates resulting from salt
exchange with the chloride ligands (Figure 2). This initial
Figure 1. Cyclometalated ruthenium metathesis catalysts.
Scheme 1. Synthesis of Cyclometalated Complexes
Figure 2. Reaction progress of cyclometalation of complex 4a: blue =
[4a], green = [5a], purple = [6a], red = [3a].
complexes are synthesized by the reaction of a ruthenium
dichloride complex with an excess of a pivalate salt (Scheme 1).
While silver pivalate was found to efficiently provide cyclo-
metalated complexes,13a,b product stability to the reaction
conditions was improved by the use of sodium carboxylate
salts.13c In light of this initial advance in cyclometalation
methodology, kinetic studies on the cyclometalation of these
complexes would enable the synthesis of a broader family of
potentially useful ruthenium alkylidene complexes. Further-
more, because of the high stability of complexes 1−3 and the
lack of in-depth kinetic studies on the activation of C(sp3)−H
bonds, it was envisioned that an investigation into the reactivity
of complexes 4 toward cyclometalation would be a valuable
addition to the C−H activation literature.
ligand exchange resulted in a short induction period prior to the
generation of cyclometalated complex 3. In the specific case of
N-adamantyl complex 4a, the salt metathesis was slow,
generating low concentrations of mono- and dicarboxylate
species.
The C−H activation of mesityl complex 4b was also followed
1
by H NMR spectroscopy (Figure 3). The production of 3b
This report contains a detailed study of the mechanism of
C(sp3)−H activation at ruthenium(II) alkylidenes. By com-
plementing direct observation of the elementary C−H
activation step with density functional theory (DFT) studies,
unique and important features of a carboxylate-assisted CMD at
metathesis-relevant ruthenium(II) complexes could be eluci-
dated.
RESULTS
■
Figure 3. Reaction progress of cyclometalation of complex 4b: blue =
[4b], green = [5b], purple = [6b], red = [3b].
Dichloride Reactivity. Initial experiments were conducted
to investigate the kinetics of C−H activation as it proceeds
from the dichloride complex (4, Scheme 2). Complexes 4 were
exposed to 10 equiv of sodium pivalate as a solution in 1:1
Scheme 2. Proposed Mechanism of C−H Activation of Ruthenium Complex 4a
B
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was characterized by the same induction period as observed
with complex 3a; however, the equilibrium more heavily
favored the carboxylate complexes. In this case, equilibrium was
also reached more rapidly, with only 3% of the dichloride
complex observable at the first time point.
Cyclometalation of N-t-Bu-N′-mesityl-substituted NHC
ruthenium complex 4c was also monitored by 1H NMR
spectroscopy (Figure 4). Much like complex 4a, ligand
observed upon exposure of complex 5b to the reaction
conditions in the absence of excess sodium pivalate. Addition
of sodium pivalate (9 equiv) to a THF/MeOH solution of 5b
provides cyclometalated product 3b after heating to 40 °C,
indicating the intermediacy of monocarboxylate 5b in the
formation of 3b. It should also be noted that C(sp2)−H
activation occurs competitively at complexes 4 with aryl groups
bearing ortho hydrogen atoms; however, these complexes
rapidly decompose upon insertion into the benzylidene.19a
Activation of Dicarboxylate Complexes. In order to
study the central C−H activation step, a method for the
independent synthesis of dipivalates 6 was developed. It was
envisioned that replacing the chloride ligands with more rapidly
exchanged X-type ligands would allow dicarboxylates to be
synthesized at temperatures where C−H activation was
sufficiently retarded (Scheme 4). To achieve this, dichlorides
Scheme 4. Synthesis and C−H Activation of Dicarboxylate
Precursor for Kinetic Studies
Figure 4. Reaction progress of cyclometalation of complex 4c: blue =
[4c], green = [5c], red = [3c]; 6c was not observed.
exchange to provide the dipivalate was slow, and only the
monocarboxylate complex could be observed in the reaction
mixture. The overall rate was only slightly faster than for the
previous complexes.
The C−H activation of a complex with N-adamantyl-N′-2,6-
diisopropylphenyl (DIPP, 4d) substitution of the NHC ligand
was also monitored. It was found to possess a notably decreased
rate when compared to complexes 4a−c. For instance, whereas
cyclometalation of complex 4a reaches completion after
approximately 4 h, DIPP-substituted complex 4d is not fully
consumed until after 96 h. During the course of this
experiment, negligible amounts of carboxylate-ligated com-
plexes 5d or 6d were observed.
In order to study the nature of the salt-exchange steps that
precede C−H activation, monochloride monopivalate complex
5b was synthesized (Scheme 3).13e Complex 5b is a stable
green solid that does not undergo ligand disproportionation in
THF/MeOH solution. Furthermore, no cyclometalation was
4 were treated with 4 equiv of silver triflate in benzene. Stable
bis-triflate complexes 7 were isolated after removal of silver salts
by filtration of the reaction mixture. Both N-mesityl complex 7a
and N-DIPP complex 7d could be synthesized in this manner.
Though the bis-triflate analogue of mesityl complex 4b is
known, it was found to be unstable to cyclometalation
conditions.13e,20 The bis-triflate analogue of tert-butyl complex
4c could not be synthesized. Immediate general decomposition
of 4c was observed upon exposure to silver triflate. Importantly,
triflates 7 did not undergo C−H activation upon heating.
It was found that bis-triflate 7a could be treated with as little
as 3 equiv of sodium carboxylate salts to cleanly generate
dicarboxylate 6a in situ. Complete conversion to the
dicarboxylate was typically achieved in under 30 min at 0 °C,
and no cyclometalated products (e.g., 3a) were generated
within this time frame. While a THF/MeOH solvent mixture
was not necessary to observe C(sp3)−H activation (reaction
could be achieved in benzene or pure THF), 1:1 THF/MeOH
was chosen for these studies to enable both increased reaction
homogeneity and ready comparison to reactions that proceed
from dichlorides 4.
Scheme 3. Synthesis and Reactivity of Monopivalate
Complex 5b
The C−H activation of dicarboxylate 6a was then directly
observed after the solution was warmed to the reaction
temperature. The reaction was found to be first order in
dicarboxylate, with rate constant k313K = (1.6 0.1) × 10−3 s−1.
A similar procedure was used to study the C−H activation of
N-DIPP complex 6d, and the rate constant was determined to
be k313K = (1.4 0.2) × 10−3 s−1.
C
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Eyring Analysis. The method described in Scheme 4 was
used to conduct an Eyring analysis of the C−H activation step
(Figure 5). The reaction was monitored over a temperature
Figure 6. Linear free energy relationships with ruthenium dibenzoates
8a−e.
Figure 5. Rate plots (top) and Eyring analysis (bottom) of
cyclometalation of ruthenium complex 6a.
range from 15 to 55 °C. A linear Eyring plot was generated with
an excellent fit. Analysis of the slope of the plot and the
y-intercept provided the energies of activation. It was found that
the conversion of dipivalate 6a to cyclometalated ruthenium
benzylidene 3a requires ΔH⧧ = 20.6 0.8 kcal·mol−1, with a
negative entropy of activation, ΔS⧧ = −5.2
2.6 eu. This
provides a Gibbs free energy of activation, ΔG⧧ = 22.2 0.1
kcal·mol−1 at 25 °C.
Linear Free Energy Relationships. The effect of the
electronic properties of the carboxylate was probed by
establishing a linear free energy relationship between the
Hammett substituent constants and the rate of cyclometalation.
Previous computational Hammett studies revealed that C−H
σ-bond metathesis with Tp(CO)Ru(II)−X (X = R, NH2, OR,
or BOR2) is insensitive to the electronic property of the C−H
bond.21 Dicarboxylates 8a−e were synthesized by using the
sodium salts of various 4-substituted benzoic acids (Figure 6).
While the rate of activation by substituted benzoic acids
correlated only moderately with Hammett σ values, the
correlation was increased when σ+ values were utilized. A
moderately negative ρ value of −0.24 was observed (Figure 6).
The electronic influence of substitution of the benzylidene
chelate on the rate of C−H activation was also investigated
(Figure 7). Substitution of the benzylidene chelate has
demonstrated effects on the initiation rates of metathesis
catalysts.22 Using the Hammett σpara values, substitution of the
4-position of the benzylidene chelate provided insignificant
correlation. The strongest correlation was observed when using
the corresponding σmeta values. This observation indicates a
much stronger influence of benzylidene substituents on the
2-position of the chelate, inductively to the ruthenium center.
The ρ value for this plot was found to be +0.53.
Figure 7. Linear free energy relationships with substituted ruthenium
chelates 10a−d.
Initiation rates of related dichloride complexes (10a−d; OPiv
= Cl) were measured by observing the rate of decay of the
benzylidene peak after the complex was treated with butyl vinyl
ether.23 While the initiation rates were also affected by the
D
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ments, the rates of C−H and C−D activation were measured.
At 25 °C, KIE = 8.1
1.7 was found. At an elevated
temperature of 50 °C, the value was reduced to KIE = 6.4
1.1.
Computational Studies on the Mechanism of C−H
Activation. We performed DFT calculations to investigate the
mechanism of the C−H activation pathways and to explain the
effects of N-substituents on the reactivity and selectivity of C−
H activation. The calculations were performed using the
theoretical method that was found satisfactory in our recent
computations with ruthenium metathesis catalysts.17,19a,25 The
geometries were optimized with B3LYP and the SDD basis set
for Ru and 6-31G(d) for other atoms. Single-point energies
were calculated with M06 and the SDD basis set for Ru and the
6-311+G(d,p) basis set for other atoms. The SMD solvation
model was employed in the single-point energy calculations.
THF was used as the solvent in the calculations. All calculations
were performed with Gaussian 09.26
Figure 8. Relationship between initiation rate of dichlorides and rate
of cyclometalation of dicarboxylates 3.
Table 1. Kinetic Isotope Effects
The calculations indicated that the C−H activation of
ruthenium dichloride complex 4a occurs through the pathway
shown in blue in Figure 9. The monopivalate pathway shown in
red is unfavorable (vide infra). The anion-exchange steps to
replace both chlorides in 4a with pivalates are exergonic by 1.4
and 4.0 kcal·mol−1, respectively. The reaction with silver
pivalate is expected to be even more favorable, driven by the
formation of solid silver chloride precipitate. The pivalate in
complex 5a and both pivalates in complex 6a are monoligated
(Figure 10). The binding site trans to the benzylidene in these
16-electron complexes is blocked by the bulky N-adamantyl
group.27 The most favorable C−H activation pathway from the
dipivalate complex 6a involves rotation of the o-isopropox-
yphenyl group (12a-TS) and dissociation of the Ru−O chelate
to form 13a, followed by deprotonation of the adamantyl C−H
bond by a bottom-bound pivalate (14a-TS-A) via a CMD
mechanism. The C−H activation step leads to a pivalic acid-
bound complex 15a, which then liberates pivalic acid and
generates Ru−C cyclometalated catalyst 3a. The rate-
determining step was found to be the C−H activation via
a
a
entry
k
T (°C)
value (s−1
)
KIE
1
2
3
4
kH
kD
kH
kD
25
25
50
50
(2.8 0.4) × 10−4
(3.5 0.6) × 10−5
(4.3 0.3) × 10−3
(6.7 1) × 10−4
8.1 1.7
6.4 1.1
a
Uncertainty reported with 90% confidence intervals.
electronic nature of the benzylidene chelate, the rate of C−H
activation also has little correlation with the initiation rates of
the related dichloride complexes (Figure 8). Initiation rates also
did not correspond well with Hammett σ values.
Kinetic Isotope Effects. Kinetic isotope effects (KIEs) are
a common measurement when studying the mechanism of
C−H activation with transition metals.24 In order to measure
the KIE (= kH/kD) of C(sp3)−H activation at these ruthenium
complexes, deuterated dicarboxylate 6a-d6 was synthesized
utilizing d6-1-adamantylamine (Table 1). In separate experi-
Figure 9. Free energy profile of the C−H activation of 4a to form cyclometalated complex 3a; all energies in kcal·mol−1 at 25 °C.
E
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membered CMD transition states in palladium acetate-
catalyzed C−H activations.2e,i,7d,8
C−H(D) insertion KIEs were calculated31 using the
Bigeleisen−Mayer equation32 with scaled (0.97)33 harmonic
frequencies obtained from B3LYP/LANL2DZ-6-31G* ground-
state structure 6a and transition structures 14a-TS-A−D
(Figure 12). B3LYP/SDD-6-31G(d) and M06/SDD-6-
Figure 10. Optimized geometries of the monopivalate complex 5a,
dipivalate complex 6a, the monopivalate C−H activation transition
state 16a-TS, and the o-isopropoxyphenyl rotation transition state
12a-TS.
intramolecular CMD (14a-TS-A) and requires an overall free
energy barrier of 23.5 kcal·mol−1 (6a → 14a-TS-A).28
Figure 12. Kinetic isotope effects computed at 25 and 50 °C (in
parentheses) for potential C−H(D) activation transition states.31
Several isomeric C−H activation transition states from the
dipivalate complex 6a have been calculated and are all found to
be less stable than 14a-TS-A (Figure 11). In 14a-TS-B, the C−
H bond is deprotonated by the pivalate bound to the side
position (i.e., cis to the NHC). Although this orientation
maintains the Ru−O(isopropoxy) chelation, such side-bound
C−H activation is 6.9 kcal·mol−1 less favorable than the
bottom-bound C−H activation. The four-membered-ring
CMD transition state 14a-TS-C, which is also referred to as
σ-bond metathesis in the literature,8c is 14 kcal·mol−1 less
favorable, as the oxygen coordinated to the Ru is less basic.8a,29
An outer-sphere deprotonation transition state involving an
unbound pivalate was also located (14a-TS-D) and is also
unfavorable.30 This is consistent with the preference for the six-
31G(d) models provided comparable KIE estimates for the
14a-TS-A C−H insertion process at 25 °C (6.47 and 6.42,
respectively). The computed KIEs decreased with increasing
temperature (Figure 12) and were found to originate primarily
from zero-point energy contributions.
DISCUSSION
■
Salt Metathesis Affects the Overall Rate of Cyclo-
metalation. The results outlined above support a general
mechanism that requires two salt metathesis steps to preform a
ruthenium dicarboxylate species. These salt metathesis events
Figure 11. Four possible transition states for cyclometalation of dipivalate complex 6a.
F
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have a profound effect on the observed rate of the
cyclometalation reaction when starting from dichloride
complexes (Table 2). For instance, the N-mesityl (4a) and
Rate of Cyclometalation Can Be Tuned Electronically.
Experimental data reveal some of the electronic characteristics
of the C−H activation reaction. The carboxylate ligand acts as a
base, as indicated by the negative ρ value for the linear free
energy relationship of ruthenium dibenzoates in the C−H
activation reaction (Figure 6). Additionally, the stronger
correlation to the σ+ value suggests an accumulation of positive
charge at the carboxylate carbon that is stabilized by resonance
with the aromatic system. These results are supported by
computational evidence that more basic carboxylates have
lower activation barriers to C−H activation (Table 3).34
Table 2. Summary of Rate Information for Ruthenium
a
Complexes 4 and 6
d
k from 4
k from 6
b
calcd k from 6
b
c
entry
4
(×10−4 s−1
)
4:5:6
(×10−3 s−1
)
(×10−4 s−1
)
1
2
3
4
4a
4b
4c
4d
2.7 0.1
1.2 0.1
2.0 0.1
<0.1
69:25:6
1.6 0.1
2.7
3:38:59
−
−
0.084
1.7 × 106
2.6
56:43:<1
>98:<1:<1
1.4 0.2
Table 3. Activation Free Energies (at 25 °C) for
Cyclometalation with Different Carboxylate Ligands
a
b
All data from experiments conducted at 40 °C. Uncertainty reported
c
with 90% confidence intervals. Relative concentrations of complexes
at equilibrium. See Supporting Information for details.
d
N-DIPP (4d) dichloride complexes differ greatly in observed
rates of cyclometalation, but the rates for cyclometalation from
the dipivalate complexes 6a and 6d are roughly equal (entries 1
and 4). This reduction in the cyclometalation rate of 4d can be
attributed to the poor equilibrium concentrations of reactive 6d
under the standard conditions. This same effect was also
observed for complex 4c, which is computationally expected to
undergo cyclometalation at a much faster rate than 4a.
Interestingly, complex 4b underwent cycloaddition at a rate
similar to that of 4a, although computations predicted the
reaction from 6b to be slower than that from 6a.
In general, acceleration of the salt metathesis steps enhanced
the overall rate of cyclometalation. For instance, cyclo-
metalation occurred rapidly in the presence of silver pivalate
salts as a result of the rapid nature of silver-mediated salt
metathesis.13b This hypothesis is further supported by the
observation that cyclometalation by exposure of triflate
complexes 7 occurs rapidly at low temperature because of the
more facile exchange of triflate ligands.
Dicarboxylate Stabilizes the Cyclometalation Tran-
sition State. Based on control experiments, only the
ruthenium dicarboxylate species 6 is able to undergo C−H
activation. This was further supported by computational
evidence that the C−H activation transition state of
monochloride-monocarboxylate 5a is 8.9 kcal·mol−1 less stable
than the corresponding transition state (16a-TS, red, vs 14a-
TS, blue, Figure 9). The monopivalate C−H activation also
involves a bottom-bound six-membered transition state (16a-
TS, Figure 10), similar to 14a-TS-A. The lower energy of the
dipivalate TS is in part due to the stronger binding energy of
pivalate compared to chloride, as shown in the ground-state
structures (6a vs 5a). Additionally, the pivalate is bound to
ruthenium in a κ2 fashion in 14a-TS-A and the final product 3a.
This binding mode offers additional stabilization compared to
the κ1 pivalate species prior to the C−H activation (5a and 6a).
In the reaction with monopivalate, there is no such stabilization
in the cyclometalation transition state 16a-TS, since the
bidentate-bound pivalate is now replaced with chloride.
In addition, the chelating carboxylate ligand allows for further
stabilization of the de-chelation of the benzylidene chelate (i.e.,
13a). Since the most energetically favorable cyclometalation
transition state involves a pseudo-apically oriented carboxylate,
the additional carboxylate ligand avoids any unstable 14-
electron complexes involved in achieving the required
transition-state geometry.
entry
R
dicarboxylate
ΔG⧧ (kcal·mol−1
)
pKa
1
2
3
t-Bu
Me
Ph
6a
23.5
24.0
26.2
5.03
4.76
4.20
18a
8a
Natural population analysis (NPA) calculations of 14a-TS-A
indicated polarization of the C−H bond being cleaved: the
negative charge at C increases by −0.09, while the positive
charge at H increases by +0.23 relative to that of dicarboxylate
6a.35 These electronic characteristics further support the CMD
mechanism with the carboxylate acting as a base.
The electronic effects of the benzylidene chelate also reveal
some characteristics of the ruthenium center during the C−H
activation step. The lack of a strong correlation to either the
σpara or σmeta values for substituents at the 4-position of the
benzylidene chelate indicates a subtle competing effect of the
electronics at both the chelating oxygen (σpara values) and the
ruthenium benzylidene (σmeta values). Though a stronger
correlation to the σmeta values with a positive ρ value supports
an increased importance of electron deficiency at ruthenium
over the lability of the chelate, definitive conclusions cannot be
drawn from the current experimental data. In addition,
computations indicate no correlation between the benzylidene
de-chelation energy and the C−H activation rate with different
benzylidene chelates, 10a−d.36 These conclusions are further
muddied by the absence of a correlation between the initiation
rates of dichlorides and the rates of cyclometalation of the
corresponding dipivalate complexes 10a−d, even though both
reactions include de-chelation of the isopropyl ether as a key
organizational step.
The importance of increased positive charge at the
ruthenium center on the observed rate of the reaction (Figure
7) agrees with the requirement of a dicarboxylate species. The
additional electronic stabilization provided by the κ2 pivalate
ligand would stabilize the electrophilic character of the
ruthenium center. This is further supported by the reduction
in positive charge at ruthenium by −0.16 in the transition state,
as calculated by natural population analysis. This reduction in
positive charge indicates an accumulation of electrons
G
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throughout the reaction, a feature that would be more favorable
for a more electron-deficient ruthenium center.
experiment. Activation of the mesityl C−H bond requires 27.7
kcal·mol−1 (14-TS-F), 4.2 kcal·mol−1 higher than the
adamantyl C−H bond activation (14a-TS-A). The transition
state in which the benzylidene is syn to the C−H bond on the
adamantyl (14a-TS-E) is 2.1 kcal·mol−1 less stable. The major
product 3a is also thermodynamically the most stable among
the three isomers.
Pseudo-Apically Oriented Six-Membered Concerted
Metalation−Deprotonation Transition-State Geometry.
The results reported above support the reorganization of
ligands to a transition-state geometry as depicted in 14a-TS-A
(Figure 11). The close agreement between the experimental
ΔG⧧298K = 22.2 0.1 kcal·mol−1 and the computed ΔG⧧ = 23.5
kcal·mol−1 lends credence to the computed geometries.
Computations indicated that other isomeric C−H activation
transition states (14a-TS-B/C/D) are at least 6.9 kcal·mol−1
less favorable than 14a-TS-A. Furthermore, the large, negative
Steric interactions in the transition state disfavor activation of
the weaker benzylic C−H bonds of 6a (Figure 13). There is
ΔS⧧ = −5.2
2.6 eu obtained from the Eyring analysis
supports a highly ordered cyclic transition state.
The pseudo-apical orientation of the deprotonating carbox-
ylate in 14a-TS-A is also supported by the KIE (Figure 12).
The measured KIE = 8.1
1.7 more closely reflects the
computed isotope effects for the two transition states that
involve ligand reorganization to place the participating
carboxylate in a pseudo-apical position (14a-TS-A and 14a-
TS-C). Furthermore, the small and computationally predicted
reduction to KIE = 6.4 1.1 at elevated temperatures excludes
significant tunneling and lends additional support for this
mechanism of C−H insertion.
Site Selectivity of C−H Activation Is Controlled by
Steric Effects. In the C−H activation reaction with unsym-
metrically substituted NHC complexes such as N-adamantyl-
N′-mesityl complex 6a, it is somewhat unexpected that the
weaker mesityl C−H bond remains intact while reaction occurs
exclusively at the adamantyl C−H bond.2e,f,37 In addition, the
C−H activation in the stereogenic-at-Ru complex is completely
stereoselective. Only a single diastereomer of 3a is observed, in
which the benzylidene is anti to the C−H bond on the
adamantyl (Scheme 5). Computations predicted the same
major C−H activation product (3a) as that observed in
Figure 13. Transition-state geometry 14a-TS-F.
substantial distortion in 14a-TS-F because of the steric
repulsion between one of the ortho Me groups on the mesityl
and a methylene group on the NHC backbone. This repulsion
prevents the other methyl substituent from rotating into
proximity of the ruthenium center. In addition, orientation of
the bulky N-adamantyl group toward the benzylidene leads to
steric interactions with the carbene carbon atom (H···C
distance of 2.46 Å).
In 14a-TS-A and the resulting cyclometalated intermediate
3a, the α-C−H bond on adamantyl is anti to the Ru-
benzylidene double bond in a staggered conformation, while
complexes 14a-TS-E and epi-3a assume an eclipsed con-
formation with the α-C−H bond syn to the Ru-benzylidene
bond (Figure 14). The staggered anti transition state 14a-TS-A
Scheme 5. Activation Free Energies (in kcal·mol−1) of C−H
Activation at Different Sites of 6a
Figure 14. Comparison of the diastereomeric C−H activation
transition states 14a-TS-A (anti) and 14a-TS-E (syn). Insets are
Newman projections along the forming Ru−C bond. Energies are
relative to 6a.
is favored by 2.1 kcal·mol−1. The anti intermediate 3a is also
more stable than the syn intermediate epi-3a to a greater extent
(3.9 kcal·mol−1).
Effects of N-Substituents on the Barriers for C−H
Activation. Barriers for C−H activation with N-t-Bu-N′-Mes
complex 6c and N-Adm-N′-DIPP complex 6d were computed
(Figure 15). Replacing the adamantyl group with the smaller
tert-butyl group significantly decreased the barrier to 15.2 kcal·
mol−1. There are fewer steric repulsions in the activation of the
primary C−H bond in t-Bu than the secondary C−H bond on
H
dx.doi.org/10.1021/ja5021958 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
ruthenium metathesis catalysts and for functionalization of C−
H bonds in general.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, NMR spectra of new compounds,
additional kinetics data, optimized Cartesian coordinates and
energies, details of computational methods, and complete ref
26. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
doleary@pomona.edu
houk@chem.ucla.edu
rhg@caltech.edu
Figure 15. Computed activation barriers at 25 °C for cyclometalation
of complexes 6b−d.
Notes
The authors declare no competing financial interest.
adamantyl. This reactivity trend agrees with palladium-catalyzed
C(sp3)−H activations,1b,2k,38 in which less-hindered primary
C−H bonds are preferred. In contrast, iron oxo-catalyzed
reactions are governed by a combination of steric and electronic
effects.39
On the other hand, replacing the N-mesityl group with
N-DIPP has negligible effects on the activation barrier. The
N-mesityl and N-DIPP groups both remain perpendicular to
the NHC ring in the dipivalate resting state and in the
transition state. There are no significant steric repulsions with
either the N-mesityl or N-DIPP group in the dipivalate complex
or in the transition state.40
ACKNOWLEDGMENTS
■
This work was financially supported by the NIH (NIH R01-
GM031332 and NRSA to J.S.C.: F32-GM103002), the NSF
(CHE-1212767, CHE-1059084), and the NSF CCI Center for
Stereoselective C−H Functionalization (CHE-1205646). NMR
spectra were obtained by instruments supported by the NIH
(RR027690). Materia, Inc. is acknowledged for the generous
donation of complex 4b. D.J.O. thanks Pomona College for
supporting a portion of this research. Calculations were
performed on the Hoffman2 cluster at UCLA and the Extreme
Science and Engineering Discovery Environment (XSEDE),
which is supported by the NSF. K. M. Engle, J. Hartung, and
Z. K. Wickens are gratefully acknowledged for helpful
discussions.
CONCLUSION
■
Studies in the development of a new family of Z-selective olefin
metathesis catalysts revealed an interesting and relevant C−H
activation reaction at ruthenium(II). This reaction involves a
carboxylate-assisted concerted metalation−deprotonation via
an organized six-membered metallacyclic transition state. The
resulting ruthenium alkyl complexes are unusually stable, and
these benzylidene complexes exhibit high levels of Z-selectivity
in olefin metathesis reactions.
REFERENCES
■
(1) (a) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118.
(b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(c) Ackermann, L. Chem. Rev. 2011, 111, 1315. (d) Yamaguchi, J.;
Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960.
(e) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.
(f) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012,
45, 788. (g) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(2) (a) Canty, A. J.; Ariafard, A.; Sanford, M. S.; Yates, B. F.
Organometallics 2013, 32, 544. (b) Lyons, T. W.; Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2011, 133, 4455. (c) Baxter, R. D.; Sale, D.;
Engle, K. M.; Yu, J.-Q.; Blackmond, D. G. J. Am. Chem. Soc. 2012, 134,
4600. (d) Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K. J.
Am. Chem. Soc. 2010, 132, 10692. (e) Gorelsky, S. I.; Lapointe, D.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848. (f) Gorelsky, S. I.;
Lapointe, D.; Fagnou, K. J. Org. Chem. 2012, 77, 658. (g) Sun, H.-Y.;
Gorelsky, S. I.; Stuart, D. R.; Campeau, L.-C.; Fagnou, K. J. Org. Chem.
2010, 75, 8180. (h) Wakioka, M.; Nakamura, Y.; Hihara, Y.; Ozawa, F.;
Sakaki, S. Organometallics 2013, 32, 4423. (i) García-Cuadrado, D.;
Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006,
128, 1066. (j) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094. (k) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
Isolation of the dicarboxylate complexes 6 allowed for the
direct study of the C−H activation reaction. Kinetic studies
revealed first-order reaction kinetics, and thermodynamic
results agreed with computed transition states. Furthermore,
ΔS⧧ values agree with a highly ordered intramolecular
transition state. Computational studies revealed an interesting
pseudo-apically oriented carboxylate geometry in the key
cyclometalation step and confirmed that a second carboxylate
ligand is necessary for transition-state stabilization. Electronic
effects of the complex control the rate by modulating either the
electron density at the ruthenium center or the overall basicity
of the assisting carboxylate.
Experimental and computational results showed that steric
effects control the site-selectivity of C−H activation, directing
metalation toward typically less-reactive C−H bonds. The
computational model was then able to corroborate indirect
mechanistic evidence about the relative rates of cyclometalation
at complexes that could not be studied directly.
(3) (a) Davies, D. L.; Donald, S. M. A.; Al-Duaij, O.; Macgregor, S.
A.; Polleth, M. J. Am. Chem. Soc. 2006, 128, 4210. (b) Li, L.;
̈
Brennessel, W. W.; Jones, W. D. Organometallics 2009, 28, 3492.
(c) Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864. (d) Mkhalid, I. A. I.;
Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev.
2010, 110, 890.
New mechanistic information was developed regarding the
inner-sphere activation of methylene C(sp3)−H bonds. It is
envisioned that the results of this study will enable the further
development of CMD C(sp3)−H activation at ruthenium
centers both for the more efficient synthesis of selective
(4) (a) Rhinehart, J. L.; Manbeck, K. A.; Buzak, S. K.; Lippa, G. M.;
Brennessel, W. W.; Goldberg, K. I.; Jones, W. D. Organometallics 2012,
I
dx.doi.org/10.1021/ja5021958 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
31, 1943. (b) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(c) Davies, H. M. L.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857.
(d) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem.
Res. 2012, 45, 814.
Am. Chem. Soc. 2011, 133, 8525. (c) Rosebrugh, L. E.; Herbert, M. B.;
Marx, V. M.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135,
1276. (d) Rosebrugh, L. E.; Marx, V. M.; Keitz, B. K.; Grubbs, R. H. J.
Am. Chem. Soc. 2013, 135, 10032. (e) Endo, K.; Herbert, M. B.;
Grubbs, R. H. Organometallics 2013, 32, 5128.
(5) (a) Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Giardiello, M.; Hilton,
S. T.; Russell, D. R. Dalton Trans. 2003, 4132. (b) Arockiam, P. B.;
Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879.
(c) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886.
(d) Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org.
Lett. 2010, 12, 5032. (e) Hashiguchi, B. G.; Young, K. J. H.;
Yousufuddin, M.; Goddard, W. A., III; Periana, R. A. J. Am. Chem. Soc.
2010, 132, 12542. (f) Gruver, B. C.; Adams, J. J.; Warner, S. J.;
Arulsamy, N.; Roddick, D. M. Organometallics 2011, 30, 5133.
(6) (a) Gephart, R. T., III; Warren, T. H. Organometallics 2012, 31,
7728. (b) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. Chem. 2013,
19.
(7) (a) Ryabov, A. D.; Sakodinskaya, I. K.; Yatsimirsky, A. K. J. Chem.
Soc., Dalton Trans. 1985, 2629. (b) Kurzeev, S. A.; Kazankov, G. M.;
Ryabov, A. D. Inorg. Chim. Acta 2002, 340, 192. (c) Maleckis, A.;
Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2013, 135, 6618.
(d) Sanhueza, I. A.; Wagner, A. M.; Sanford, M. S.; Schoenebeck, F.
Chem. Sci. 2013, 4, 2767.
(8) (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem.
Soc. 2005, 127, 13754. (b) García-Cuadrado, D.; de Mendoza, P.;
Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007,
129, 6880. (c) Balcells, D.; Clot, E.; Eisenstein, O. Chem. Rev. 2010,
110, 749. (d) Ke, Z.; Cundari, T. R. Organometallics 2010, 29, 821.
(e) Musaev, D. G.; Kaledin, A.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc.
2012, 134, 1690. (f) Giri, R.; Lan, Y.; Liu, P.; Houk, K. N.; Yu, J.-Q. J.
Am. Chem. Soc. 2012, 134, 14118. (g) Yang, Y.-F.; Cheng, G.-J.; Liu,
P.; Leow, D.; Sun, T.-Y.; Chen, P.; Zhang, X.; Yu, J.-Q.; Wu, Y.-D.;
Houk, K. N. J. Am. Chem. Soc. 2014, 136, 344. (h) Cheng, G.-J.; Yang,
Y.-F.; Liu, P.; Chen, P.; Sun, T.-Y.; Li, G.; Zhang, X.; Houk, K. N.; Yu,
J.-Q.; Wu, Y.-D. J. Am. Chem. Soc. 2014, 136, 894. (i) Sokolov, V. I.;
Troitskaya, L. L.; Reutov, O. A. J. Organomet. Chem. 1979, 182, 537.
(14) Marx, V. M.; Herbert, M. B.; Keitz, B. K.; Grubbs, R. H. J. Am.
Chem. Soc. 2013, 135, 94.
(15) (a) Herbert, M. B.; Marx, V. M.; Pederson, R. L.; Grubbs, R. H.
Angew. Chem., Int. Ed. 2013, 52, 310. (b) Cannon, J. S.; Grubbs, R. H.
Angew. Chem., Int. Ed. 2013, 52, 9001. (c) Quigley, B. L.; Grubbs, R.
H. Chem. Sci. 2014, 5, 501.
(16) (a) Hartung, J.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135,
10183. (b) Hartung, J.; Grubbs, R. H. Angew. Chem., Int. Ed. 2014, 53,
3885.
(17) Miyazaki, H.; Herbert, M. B.; Liu, P.; Dong, X.; Xu, X.; Keitz, B.
K.; Ung, T.; Mkrtumyan, G.; Houk, K. N.; Grubbs, R. H. J. Am. Chem.
Soc. 2013, 135, 5848.
(18) (a) Meek, S. J.; O’Brien, R. V.; Llaveria, J.; Schrock, R. R.;
Hoveyda, A. H. Nature 2011, 471, 461. (b) Flook, M. M.; Jiang, A. J.;
Schrock, R. R.; Muller, P.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131,
̈
7962. (c) Marinescu, S. C.; Levine, D. S.; Zhao, Y.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 11512. (d) Jiang, A. J.;
Zhao, Y.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131,
16630. (e) Yu, M.; Ibrahem, I.; Hasegawa, M.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 2788.
(19) (a) Herbert, M. B.; Lan, Y.; Keitz, B. K.; Liu, P.; Endo, K.; Day,
M. W.; Houk, K. N.; Grubbs, R. H. J. Am. Chem. Soc. 2012, 134, 7861.
(b) Hong, S. H.; Chlenov, A.; Day, M. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2007, 46, 5148. (c) Mathew, J.; Koga, N.; Suresh, C. H.
Organometallics 2008, 27, 4666. (d) Poater, A.; Cavallo, L. J. Mol.
Catal. AChem. 2010, 324, 75. (e) Poater, A.; Bahri-Laleh, N.;
Cavallo, L. Chem. Commun. 2011, 47, 6674. (f) Leitao, E. M.;
Dubberley, S. R.; Piers, W. E.; Wu, Q.; McDonald, R. Chem.Eur. J.
2008, 14, 11565.
(20) Krause, J. O.; Nuyken, O.; Wurst, K.; Buchmeiser, M. R.
́
(9) (a) Prokopcova, H.; Bergman, S. D.; Aelvoet, K.; Smout, V.;
Herrebout, W.; Van der Veken, B.; Meerpoel, L.; Maes, B. U. W.
Chem.Eur. J. 2004, 10, 777.
(21) (a) Ess, D. H.; Nielsen, R. J.; Goddard, W. A., III; Periana, R. A.
J. Am. Chem. Soc. 2009, 131, 11686. (b) Ess, D. H.; Goddard, W. A.,
III; Periana, R. A. Organometallics 2010, 29, 6459.
Chem.Eur. J. 2010, 16, 13063. (b) Bergman, S. D.; Storr, T. E.;
́
Prokopcova, H.; Aelvoet, K.; Diels, G.; Meerpoel, L.; Maes, B. U. W.
Chem.Eur. J. 2012, 18, 10393. (c) Kumar, N. Y. P.; Jeyachandran, R.;
Ackermann, L. J. Org. Chem. 2013, 78, 4145. (d) Jun, C.-H.; Hwang,
D.-C.; Na, S.-J. Chem. Commun. 1998, 1405. (e) Dastbaravardeh, N.;
(22) (a) Thiel, V.; Hendann, M.; Wannowius, K.-J.; Plenio, H. J. Am.
Chem. Soc. 2012, 134, 1104. (b) Bujok, R.; Bieniek, M.; Masnyk, M.;
Michrowska, A.; Sarosiek, A.; Step̧ owska, H.; Arlt, D.; Grela, K. J. Org.
Chem. 2004, 69, 6894. (c) Van Veldhuizen, J. J.; Gillingham, D. G.;
Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003,
125, 12502. (d) Zaja, M.; Connon, S. J.; Dunne, A. M.; Rivard, M.;
Buschmann, N.; Jiricek, J.; Blechert, S. Tetrahedron 2003, 59, 6545.
(23) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 6543.
Kirchner, K.; Schnurch, M.; Mihovilovic, M. D. J. Org. Chem. 2013, 78,
̈
658. (f) Dastbaravardeh, N.; Schnurch, M.; Mihovilovic, M. D. Org.
̈
Lett. 2012, 14, 3792. (g) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda,
T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935.
(h) Weissman, H.; Song, X.; Milstein, D. J. Am. Chem. Soc. 2001, 123,
337. (i) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue,
Y. Org. Lett. 2001, 3, 2579. (j) Ozdemir, I.; Demir, S.; Çetinkaya, B.;
́
(24) (a) Jones, W. D. Acc. Chem. Res. 2003, 36, 140. (b) Gomez-
Gourlaouen, C.; Maseras, F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem.
Soc. 2008, 130, 1156. (k) Ackermann, L. Org. Lett. 2005, 7, 3123.
(l) Padala, K.; Jeganmohan, M. Org. Lett. 2011, 13, 6144. (m) Burling,
S.; Paine, B. M.; Nama, D.; Brown, V. S.; Mahon, M. F.; Prior, T. J.;
Pregosin, P. S.; Whittlesey, M. K.; Williams, J. M. J. J. Am. Chem. Soc.
Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857. (c) Simmons,
E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 3066.
(25) Liu, P.; Xu, X.; Dong, X.; Keitz, B. K.; Herbert, M. B.; Grubbs,
R. H.; Houk, K. N. J. Am. Chem. Soc. 2012, 134, 1464.
(26) Frisch, M. J.; et al. Gaussian 09, Revision B.01; Gaussian, Inc.:
Wallingford, CT, 2009.
2007, 129, 1987. (n) Haller, L. J. L.; Page, M. J.; Macgregor, S. A.;
̈
Mahon, M. F.; Whittlesey, M. K. J. Am. Chem. Soc. 2009, 131, 4604.
(10) Diggle, R. A.; Kennedy, A. A.; Macgregor, S. A.; Whittlesey, M.
K. Organometallics 2008, 27, 938.
(27) Ragone, F.; Poater, A.; Cavallo, L. J. Am. Chem. Soc. 2010, 132,
4249.
(28) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10,
2299.
(29) (a) Bischof, S. M.; Ess, D. H.; Meier, S. K.; Oxgaard, J.; Nielsen,
R. J.; Bhalla, G.; Goddard, W. A., III; Periana, R. A. Organometallics
2010, 29, 742. (b) Ess, D. H.; Gunnoe, T. B.; Cundari, T. R.; Goddard,
W. A., III; Periana, R. A. Organometallics 2010, 29, 6801. (c) Ess, D.
H.; Bischof, S. M.; Oxgaard, J.; Periana, R. A.; Goddard, W. A., III
Organometallics 2008, 27, 6440.
(30) The outer-sphere deprotonation transition state may be
stabilized by coordination of solvent molecules with the unbound
pivalate. Because of the implicit solvation model used in this study, the
(11) (a) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-Y.; Che, C.-M.
Angew. Chem., Int. Ed. 2002, 41, 3465. (b) McNeill, E.; Du Bois, J. J.
Am. Chem. Soc. 2010, 132, 10202. (c) Harvey, M. E.; Musaev, D. G.;
Du Bois, J. J. Am. Chem. Soc. 2011, 133, 17207. (d) McNeill, E.; Du
Bois, J. Chem. Sci. 2012, 3, 1810.
(12) (a) Ferrer Flegeau, E.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. J.
Am. Chem. Soc. 2011, 133, 10161. (b) Fabre, I.; von Wolff, N.; Le Duc,
G.; Ferrer Flegeau, E.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. Chem.
Eur. J. 2013, 19, 7595.
(13) (a) Keitz, B. K.; Endo, K.; Patel, P. R.; Herbert, M. B.; Grubbs,
R. H. J. Am. Chem. Soc. 2012, 134, 693. (b) Endo, K.; Grubbs, R. H. J.
J
dx.doi.org/10.1021/ja5021958 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
energy difference between 14a-TS-D and 14a-TS-A might be
overestimated.
(31) Saunders, M.; Laidig, K. E.; Wolfsberg, M. J. Am. Chem. Soc.
1989, 111, 8989.
(32) (a) Bigeleisen, J.; Mayer, M. G. J. Chem. Phys. 1947, 15, 261.
(b) Bigeleisen, J.; Wolfsberg, M. Adv. Chem. Phys. 1958, 1, 15.
(33) Halls, M. D.; Tripp, C. P.; Schlegel, H. B. Phys. Chem. Chem.
Phys. 2001, 3, 2131.
(34) Carboxylates have minimal effects on the de-chelation of the
benzylidene chelate. The energy difference between 6a and 13a is 6.7,
6.7, and 6.4 kcal·mol−1 respectively for pivalate, acetate, and benzoate.
(35) For details, see the Supporting Information.
(36) The energy differences between the Hoveyda chelate (10a−d)
and the C−H coordinated complex (analogue of 13a) are similar (5.3,
5.5, 6.7, and 4.7 kcal·mol−1 respectively for X = OMe, Me, H, and Cl).
(37) For computational investigations on regioselectivity in
́
palladium carboxylate-catalyzed C−H activations: (a) Guihaume, J.;
Clot, E.; Eisenstein, O.; Perutz, R. N. Dalton Trans. 2010, 39, 10510.
(b) Petit, A.; Flygare, J.; Miller, A. T.; Winkel, G.; Ess, D. H. Org. Lett.
2012, 14, 3680.
́
(38) (a) Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem., Int.
Ed. 2003, 42, 5736. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.;
Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129,
3510.
(39) (a) Chen, M. S.; White, M. C. Science 2010, 327, 566.
(b) Hitomi, Y.; Arakawa, K.; Funabiki, T.; Kodera, M. Angew. Chem.,
Int. Ed. 2012, 51, 3448. (c) Bigi, M. A.; Liu, P.; Zou, L.; Houk, K. N.;
́
White, M. C. Synlett 2012, 23, 2768. (d) Prat, I.; Gomez, L.; Canta,
M.; Ribas, X.; Costas, M. Chem.Eur. J. 2013, 19, 1908.
(40) See the Supporting Information for 3D structures of complexes
14b-TS, 14c-TS, and 14d-TS.
K
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