Benzoate Cyclometalation Enables Oxidative Addition of Haloarenes at a Ru(II) Center

Article abstract of DOI:10.1021/jacs.8b08150

The first Ru(II)-catalyzed arylation of substrates without a directing group was recently developed. Remarkably, this process only worked in the presence of a benzoate additive, found to be crucial for the oxidative addition step at Ru(II). However, the exact mode of action of the benzoate was unknown. Herein, we disclose a mechanistic study that elucidates the key role of the benzoate salt in the C-H arylation of fluoroarenes with aryl halides. Through a combination of rationally designed stoichiometric experiments and DFT studies, we demonstrate that the aryl-Ru(II) species arising from initial C-H activation of the fluoroarene undergoes cyclometalation with the benzoate to generate an anionic Ru(II) intermediate. The enhanced lability of this intermediate, coupled with the electron-rich anionic Ru(II) metal center renders the oxidative addition of the aryl halide accessible. The role of an additional (NMe₄)OC(CF₃)₃ additive in facilitating the overall arylation process is also shown to be linked to a shift in the C-H pre-equilibrium associated with benzoate cyclometalation.

Full text of DOI:10.1021/jacs.8b08150

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Article
Benzoate cyclometallation enables oxidative
addition of haloarenes at a Ru(II) center
Marco Simonetti, Rositha Kuniyil, Stuart A. Macgregor, and Igor Larrosa
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08150 • Publication Date (Web): 22 Aug 2018
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Journal of the American Chemical Society
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Benzoate cyclometallation enables oxidative addition of haloarenes
at a Ru(II) center
Marco Simonetti,† Rositha Kuniyil,‡ Stuart A. Macgregor,‡,* Igor Larrosa†,*
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† School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, U.K.
‡ Institute of Chemical Sciences, HeriotꢀWatt University, Edinburgh, EH14 4AS, U.K.
Supporting Information Placeholder
ABSTRACT: The first Ru(II)ꢀcatalyzed arylation of substrates without a directing group was recently developed. Remarkably, this
process only worked in the presence of a benzoate additive, found to be crucial for the oxidative addition step at Ru(II). However,
the exact mode of action of the benzoate was unknown. Herein, we disclose a
mechanistic study that elucidates the key role of the benzoate salt in the C–H
arylation of fluoroarenes with aryl halides. Through a combination of rationally
designed stoichiometric experiments and DFT studies, we demonstrate that the
aryl–Ru(II) species arising from initial C–H activation of the fluoroarene underꢀ
goes cyclometallation with the benzoate to generate an anionic Ru(II) intermeꢀ
diate. The enhanced lability of this intermediate, coupled with the electronꢀrich
anionic Ru(II) metal center renders the oxidative addition of the aryl halide acꢀ
cessible. The role of an additional (NMe4)OC(CF3)3 additive in facilitating the
overall arylation process is also shown to be linked to a shift in the C–H preꢀ
equilibrium associated with benzoate cyclometallation.
1. INTRODUCTION
Biaryls 3bb and 3bb’ were formed only when the benzoate
was added. Remarkably, the structurally related pivalate salt
did not promote the transformation. These empirical results,
along with mechanistic studies and DFT calculations, led us to
suggest a catalytic cycle where, although the initial C–H actiꢀ
vation of the fluoroarene is assisted by pivalate, the formal
The polyfluorobiphenyl unit is a recurrent building block
found as a structural component in drugs,1aꢀc agrochemicals1e,f
and numerous functional materials1gꢀm such as organic lightꢀ
emitting diodes (OLEDs)1j and liquid crystals.1k,i Although
crossꢀcoupling methods can be applied to access these biaryl
moieties,2 C–H arylation strategies have been acknowledged
as a more sustainable alternative strategy to selectively form
aryl–aryl bonds.3 In this context, fluorinated biaryls can be
generated under Pd catalysis employing fluoroarenes with
coupling partners such as aryl (pseudo)halides,4aꢀd aryl boronic
donors,4e or simple arenes.4f,g Alternatively, Cuꢀ5 or Auꢀ
catalysts6 can be used to promote analogous transformations.
Recently, our group expanded upon the range of transition
metal catalysts able to promote this particular type of couꢀ
pling.7 The arylation of fluoroarenes with aryl halides occurred
Scheme 1. The Importance of the Benzoate Additive in the
Ru-Catalyzed Arylation of Fluorobenzenes
1a
2a
with
a) Catalytic arylation of
[Ru(t-BuCN)6][BF4]2 (4 mol %)
(NMe4)OPiv (0.4 equiv)
(NMe4)(4-F-C 6H4CO2) (0.35 equiv)
(NMe4)OC(CF3)3 (2.5 equiv)
F
OBu
Br
F
OBu
F
F
F
F
F
+
F
°
t-BuCN, 115 C, 16 h
1a
2a
3aa 82%
with
a Ru(II) catalyst, [Ru(t-BuCN)6][BF4]2, aided by
without (NMe4)(4-F-C 6H4CO2)
0%
(NMe4)OPiv and (NMe4)(4ꢀFꢀC6H4CO2) coꢀcatalysts, and
(NMe4)OC(CF3)3 base in t-BuCN (Scheme 1a). Notably, this
methodology is the first Ruꢀcatalyzed C–H arylation process
operating without the need for a directing group in the arene.
Crucially, this Ruꢀcatalyzed C–H arylation only proceeded
when a benzoate salt was present, with all other bases and
carboxylates tested unable to switch on the reaction. Indeed,
when the arylation of polyfluoroarene 1a was carried out with
bromobenzene 2a under optimized reaction conditions in the
absence of the benzoate additive, no crossꢀcoupled product
3aa was formed. To further clarify the surprising role of the
benzoate source, a stoichiometric arylation between the cataꢀ
lytically active intermediate tetrafluorophenyl–Ru(II) complex
Ru1b and 5ꢀbromoꢀmꢀxylene 2b was performed (Scheme 1b).
O
O
F
NMe4
Xyl
Ru1b
2b
b) Stoichiometric arylation of
with
= 3,5-(CH3)2C6H3
Xyl
BF4
F
F
Br
additive
(2.5 equiv)
Xyl
F
F
F
F
F
F
F
F
F
+
+
NCt-Bu
t-BuCN, 2 h
F
Me
Me
t-BuCN Ru NCt-Bu
115 °C
Xyl
t-BuCN
(3 equiv)
NCt-Bu
Ru1b
3bb'
3bb
2b
3bb (%)
3bb' (%)
additive
none
0
0
0
0
(NMe4)OC(CF3)3
(NMe4)OPiv
0
0
(NMe4)(4-F-C 6H4CO2)
35
14
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2.2. Kinetic and isotopic studies. With this mechanistic
oxidative addition of the aryl halide could only proceed when
benzoate was present.7 However, the mechanism by which
benzoate may facilitate oxidative addition remained unknown.
Herein, we report mechanistic studies elucidating the
role of the benzoate salt. Surprisingly, our experiments
demonstrate that aryl–Ru(II) species such as Ru1b, which
are inert towards oxidative addition with aryl bromides 2,
can undergo cyclometallation with the benzoate salt to
form an anionic Ru(II) intermediate that is highly reactive
towards oxidative addition, and is essential to the reactivity
of the system. In a similar vein, we have also recently proꢀ
posed that the mechanism of the Ru(II)ꢀcatalyzed C–H aryꢀ
lation of N–chelating substrates with aryl (pseudo)halides
involves a bisꢀcyclometallated Ru(II) species as the key
intermediate required for oxidative addition to occur.8
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4
5
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framework in mind, and given the possibility of isolating catiꢀ
onic intermediate II, we decided to examine stoichiometric
arylation reactions to directly probe the cyclometallation and
the oxidative addition steps without interference from the iniꢀ
tial C–H activation of the fluoroarene (from I to II, Scheme
2). Thus, we started investigating the kinetic profile of the
coupling of pentafluorophenyl–Ru(II) species Ru1c with broꢀ
moarene 2b in the presence of a variety of benzoate derivaꢀ
tives (Figure 1). In order to standardize the measurements,
Ru1c was preꢀincubated for 20 min at 90 °C with the benzoate
salt prior to the addition of 2b. In agreement with our hypotheꢀ
sis, 2,6ꢀdisubstituted benzoate sources, which cannot undergo
orthoꢀC–H activation, did not give any biaryl 3cb irrespective
of the electronic effect of these groups. Instead, paralleling our
previous observations, (NMe4)(C6H5CO2) triggered the desired
coupling. In view of the often reversible nature of the C–H
activation in Ru(II) catalysis,11 we predicted that the addition
of an external base would shift the equilibrium III-IV towards
IV (Scheme 2), thus enhancing the reactivity. Indeed, when
(NMe4)(C6H5CO2) was used in combination with the base
(NMe4)OC(CF3)3, a conspicuous acceleration of the rate of
arylation was obtained.12 These data strongly suggest that the
proposed orthoꢀmetallation to generate intermediate IV is a
key step en route towards the formation of the aryl–aryl bond.
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2. RESULTS AND DISCUSSION
2.1. Mechanistic hypothesis for the role of the benzoate.
The specific requirement for a benzoate salt for the reaction to
proceed led us to hypothesize that the benzoate may be underꢀ
going orthoꢀC–H activation as its mode of action. Scheme 2
outlines our proposed catalytic cycle for the process. After the
initial C–H activation of the fluoroarene 1 to form the cationic
fluoroaryl–Ru(II) complex II, a second C–H activation event
on the benzoate would generate anionic Ru(II)ꢀspecies IV
featuring a cyclometallated benzoate unit. This more electronꢀ
rich Ru(II) intermediate IV would be more reactive towards
oxidative addition with the aryl halide (to V) than the cationic
complex II or the neutral species III. Reductive elimination
from V would then produce the biaryl product. In contrast, an
aliphatic carboxylate such as pivalate would be unable to unꢀ
dergo cyclometallation and thus would be unable to promote
the desired arylation reaction. Indeed, whereas the cyclometalꢀ
lation of aromatic benzoates by Ru(II) complexes is wellꢀ
known and recognized,9,10 the more challenging
βꢀcyclometallation of aliphatic carboxylic acids has yet to be
observed.
Br
Me
Me
BF4
F
Ar
(
−CO2)(NMe4)
(2.5 equiv)
(NMe4)OC(CF3)3
(0 or 3 equiv)
F
F
F
F
Me
2b
Me
(2 equiv)
F
F
F
F
NCt-Bu
NCt-Bu
t-BuCN [0.1 M],
20 min, 90 °C
time, 90 °C
Ru
t-BuCN
t-BuCN
F
NCt-Bu
Ru1c
3cb
Scheme 2. Proposed Catalytic Cycle
Figure 1. Stoichiometric arylation of Ru1c with 2b employing
(NMe4)ꢀ2,6ꢀdisubstituted benzoates or simple benzoate in the
presence or in the absence of (NMe4)OC(CF3)3 base. Yield deterꢀ
mined by GCꢀFID using hexadecane as internal standard.
In order to test this hypothesis further, catalytic arylation
of nonꢀvolatile polyfluoroarene 1a with bromoarene 2b was
carried out utilizing the deuterated (NMe4)(C6D5CO2) under
standard optimised reaction conditions7 (Scheme 3). Analysis
of the reaction mixture after 15 min revealed the formation of
biaryl 3ab in 16% yield. More importantly, recovered
fluoroarene 1a, showed 14% deuteration, and recovered benꢀ
zoic acid revealed a 41% of H enrichment at the ortho posiꢀ
tions. Since the only source of D was the benzoate salt, this
experiment highlights the reversible nature of the steps from
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Scheme 3. Catalytic Arylation of 1a with Bromoarene 2b
Employing (NMe4)C6D5CO2 (Xyl = 3,5-dimethylphenyl).
2.3. Hammett and Jaffé Plots. In order to gain further
1
mechanistic insights into the cyclometallation step of the benꢀ
zoate additive, we compared the initial rates of formation of
biaryl 3cb in the stoichiometric arylation reactions of Ru1c
with 2b in the presence of a variety of electronically diverse 4ꢀ
substituted benzoate salts (Table 1).14 Firstly, and surprisingly,
the rate of arylation (kobs) increased with both electronꢀrich and
electronꢀpoor benzoates, with the parent unsubstituted benzoꢀ
ate displaying the slowest rate. A second observation from
these data can be extracted from the corresponding Hammett
plots (Figure 3).15 Since both meta and para positions to the
substituent are potentially involved in the process, we plotted
log(kx/kH) versus both σm and σp. In both plots most substituꢀ
ents fit well to a Vꢀshaped Hammett plot (blue diamonds),
suggesting that there are both a meta and a para effect. Interꢀ
estingly, there are four clear outliers (red circles and green
triangles). From the σ constants of the groups studied, it can be
seen that those highlighted in blue have similar σm and σp valꢀ
ues. In contrast, the groups in red and green have significantly
different values for their σm and σp constants. For example, the
OMe and OEt groups have negative σp values (ꢀ0.27, ꢀ0.24)
but positive σm (0.12, 0.10). These two groups show higher
reactivity than would be expected from Figure 3, where only
their σm or σp are considered in isolation. This implies that
opposite electronic effects are synergistically combining to
lower the overall ΔG‡, thus enhancing the arylation rate. These
observations indicate that both σm and σp must be considered at
the same time. This is reasonable in the system under study as
both the kinetically relevant cyclometallation (III to IV) and
the rateꢀlimiting aryl bromide oxidative addition (IV to V)
2
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6
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d1-1a : 1a (5.1 : 94.9)
[Ru(t-BuCN)6][BF4]2
OBu
OBu
(4 mol %)
F
F
F
F
(NMe4)OPiv
(0.4 equiv)
(NMe4)(C6D5CO2)
(0.35 equiv)
(NMe4)OC(CF3)3
(2.5 equiv)
F
F
F
F
+
D
H
OBu
d1-1a, 14%
1a (2.58 equiv)
F
F
F
F
+ Xyl−Br
OBu
41% H
CO2H
D/H
t-BuCN (3 equiv)
F
F
F
H/D
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H
°
115 C, 15 min
F
1a
2b
D
D
Xyl
(3 equiv)
(1 equiv)
D
(0.32 equiv)
3ab, 16%
intermediate I to IV of the catalytic cycle (Scheme 2) and proꢀ
vides further evidence for the cyclometallation of the benzoic
acid. Unfortunately, all attempts at isolation or in situ detecꢀ
tion of IV starting from Ru1c in the presence of benzoate salts
were unsuccessful, and this likely reflects the high energy of
intermediate IV (see SI Section 5 for details and DFT studies
below).
Subsequently, we set out to investigate whether a KIE was
associated with the benzoate cyclometallation step. The initial
arylation rates of two independent stoichiometric couplings of
pentafluorophenyl–containing Ru1c (intermediate II in
Scheme 2) with 5ꢀbromoꢀmꢀxylene 2b using either
(NMe4)(C6H5CO2) or (NMe4)(C6D5CO2) were therefore recꢀ
orded (Figure 2). The rate of formation of biaryl 3cb with the
benzoate source was 1.36 faster than the one with the perdeuꢀ
terated benzoic salt, suggesting that the cyclometallation of the
benzoate (III to IV in Scheme 2) is kinetically relevant and
likely an equilibrium under the reaction conditions.13
Table 1. Hammett Plots: Initial Rates Data of the Aryla-
tion of Ru1c with Bromoarene 2b employing different 4-
Substituted Benzoates.
(NMe4)(C6H5CO2)
Br
NMe4
O
Me
Me
or
Br
BF4
Me
Me
BF4
F
F
(NMe4)(C6D5CO2)
(2.5 equiv)
(NMe4)OC(CF3)3
(3 equiv)
O
F
F
F
F
F
F
F
F
R
(2.5 equiv)
Me
2b (2 equiv)
time, 90 °C
Me
F
F
F
F
Me
2b
Me
(2 equiv)
time, 90 °C
(NMe4)OC(CF3)3
(3 equiv)
F
F
F
F
NCt-Bu
NCt-Bu
NCt-Bu
t-BuCN [0.1 M],
t-BuCN [0.1 M],
Ru
t-BuCN Ru NCt-Bu
t-BuCN
t-BuCN
t-BuCN
20 min, 90 °C
20 min, 90 °C
F
NCt-Bu
Ru1c
F
NCt-Bu
3cb
Ru1c
initial rate of arylation
3cb
kobs
(%/min)
log
(k/k0)
Entry
σm
σp
1
NMe2
-0.16
-0.10
-0.07
0
-0.83
-0.20
-0.17
0
1.7334
0.7858
0.7283
0.5602
1.0770
1.8236
2.5290
2.7943
1.7610
1.5220
2.4571
1.7222
0.4906
0.1470
0.1140
0
2
t-Bu
Me
3
4
H
5
CH2CN
C6F5
OCF3
CF3
OMe
OEt
OPh
F
0.16
0.26
0.38
0.43
0.12
0.10
0.25
0.34
0.18
0.27
0.35
0.54
-0.27
-0.24
-0.03
0.06
0.2839
0.5126
0.6546
0.6979
0.4974
0.4341
0.6411
0.4877
6
7
8
9
10
11
12
Figure 2. Stoichiometric arylation of Ru1c with 2b employing
(NMe4)(C6H5CO2) or (NMe4)(C6D5CO2) and (NMe4)OC(CF3)3.
Yield determined by GCꢀFID using hexadecane as internal standꢀ
ard.
Stoichiometric arylation of Ru1c with 2b employing paraꢀ
substituted (NMe4)ꢀbenzoates and (NMe4)OC(CF3)3 base. Initial
arylation rates in formation of 3cb were determined by GCꢀFID
using hexadecane as internal standard.
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log ꢀꢁꢁꢂꢄ ꢅ ρꢆσꢆ ꢇ ρꢈσꢈ
(1)
(see also the DFT studies below). To validate further this hyꢀ
pothesis, we applied Jaffé’s analysis of the Hammett equation
Hammett equation:
ꢃ
1
2
3
4
5
6
7
8
9
to our system. This modification allows the correlation of subꢀ
stituent perturbations that influence more than one reactive
center at the same time to be plotted (Figure 5).17 In the Jaffé
equation, the Hammett equation is divided by one of the two σ
values. Depending on which σ constant is in the denominator,
the slope of the plot gives one ρ value, while the yꢀintercept
provides the other ρ value (equations 2 and 3). In order to veriꢀ
fy the LFER, both plots should result in the same values of ρm
and ρp. As shown in Figure 5, this treatment of the data led to
two plots showing a LFER valid for all the substituents. Simiꢀ
lar ρ values were obtained in both cases (ρm ≅ 2.2; ρp ≅ ꢀ1.2),
thus validating our mechanistic framework. The magnitude of
the ρ values, indicate that the electronic perturbation on the
CAr–H/[Ru]–CAr bonds (ie meta) has a greater effect on the
overall rate. Furthermore, the signs of ρm and ρp indicate that
the overall rate is enhanced by paraꢀEDGs and by metaꢀ
EWGs, which is consistent with the observation that OMe and
OEt substituents are visibly outliers in both Vꢀshaped Hamꢀ
mett plots. Importantly, as the meta effect is more significant
than the para one, it should also be noted that in the para Vꢀ
shaped Hammett plot both OPh and F significantly deviate
from linearity, as both rates are largely underestimated due to
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ꢍ
ꢂ
ꢃ
ꢉꢊꢋꢌ
ꢎ ꢅ
ꢒ ꢇ ρꢆ
ꢏ
ꢐ
(2)
ꢑ
ꢒ
ꢏ
ꢍ
Jaffé equation:
ꢏ
ꢐ
Figure 3. Evaluation of benzoate electronic effect on rate. Hamꢀ
mett plots: log(kX/kH) vs σm (top) and σp (bottom).
steps may be affected by electronic perturbation at the meta
and para sites of the benzoate substrates (CAr–H (σm), C(O)O–
/H (σp), CAr–[Ru] (σm), C(O)O–[Ru] (σp),) at several points in
the arylation process (Figure 4). We return to deconvolute
these meta and the para effects in the computational section
below. Importantly, considering the Hammett equation 1, a
Hammett plot should only result in a linear free energy relaꢀ
tionship (LFER) if the electronic influence of the R group
affects only one position of the aromatic (meta or para) of a
kinetically relevant step (i.e., if ρpσp >> ρmσm or ρmσm >> ρpσp).
Although Vꢀshaped Hammett plots are usually associated
with a change in the mechanism of the process,16 the lowering
of the overall ΔG‡ due to a weighed variation of the electronic
properties of the meta and para positions of the benzoates
associated with the kinetically relevant cyclometallation, proꢀ
vides a more logical explanation for our experimental data
ꢍ
ꢂ
ꢉꢊꢋꢌ
Jaffé equation:
ꢎ ꢅ
ꢐ ꢇ ρꢈ
(3)
ꢑ
ꢏ
ꢍ
ꢐ
ꢃ
ꢏ
ꢏ
ꢒ
ꢒ
ArF
[Ru]
O
O
Br
O
O
O
ArF
[
]
Ar
O
Ru
Ru
[
]
p
p
p
p
R
R
CO2
p
m
m
ArBr
ArF
m
H
CO2H
R
R
R
(III)
(IV)
(V)
Figure 4. The influence of the R group on the electronic properꢀ
ties at multiple meta and para positions affecting the kinetically
relevant cyclometallation, as well as the oxidative addition step.
Figure 5. Jaffé plots displaying a linear free energy relationship
between the benzoate source and the reaction rate (ρm ≅ 2.2; ρp ≅
-1.2).
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the greater contribution of the meta effect. Instead in the meta
Vꢀshaped Hammett plot OPh and F are marginally underꢀ and
1
overestimated, respectively. Although both substituents have
positive σm (F= 0.34, OPh= 0.25), OPh has a slightly negative
σp (ꢀ0.03), while F has a slightly positive one (0.06), which
explains why OPh lies above, and F below, the linear fitting.
2.4. DFT Studies. We have also probed the mechanism of
these benzoateꢀassisted arylation reactions with density funcꢀ
tional theory (DFT) calculations. The reaction of a model sysꢀ
tem, [Ru(C6F5)(MeCN)5]+ (denoted II'), with PhBr in the
2
3
4
5
6
7
8
9
–
Figure 7. Geometries of alternative C–H activation transition
states with selected key distances in Å and relative free energies
in kcal/mol (L = MeCN, ArF = C6F5). Geometric data for the exꢀ
ternal CMD transition state are for R = C(O)Ph; see ESI for more
details and alternative isomers (Figures S8 and S9).
presence of PhCO2 was considered, with all geometries optiꢀ
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60
mized with the BP86 functional using a modest basis set (BS1,
see Computational Details, SI Section 9). Energies were then
recomputed using the ωB97XꢀD functional with a def2ꢀTZVP
basis set and incorporating MeCN solvation via a PCM correcꢀ
tion. Test calculations indicated the use of MeCN in place of
the tꢀBuCN ligands had little effect on the overall profile, with
most stationary points being destabilized by 2ꢀ4 kcal/mol (see
Figure S21). Figure 6 summarizes the most accessible comꢀ
puted free energy profile based on the proposed catalytic cycle
in Scheme 2. For each step alternative geometric isomers were
assessed and details are supplied in the SI (Figures S3ꢀS7).
Intermediates involved in ligand exchange steps are omitted
here for clarity but are considered in the kinetic modeling (see
below, Figure 9(a)). Starting with [Ru(C6F5)(MeCN)5]+, II',
Alternative C–H bond activation mechanisms were also
assessed and shown to be energetically less accessible (Figure
7 and Figures S8ꢀS9). Thus transition states for external CMD
–
at [Ru(C6F5)(MeCN)3(κ1ꢀPhCO2)] by PhCO2 lie above 30
kcal/mol. A direct role for –OC(CF3)3 as a base in C–H activaꢀ
tion was also ruled out, either as an external CMD process, or
as an intramolecular base (AMLAꢀ4/CMD). We return to the
role of –OC(CF3)3 in promoting the arylation reaction below.
PhBr activation at fac-IV' requires initial MeCN substituꢀ
tion and, in principle, could occur at 6ꢀcoordinate
[Ru(C6F5)(MeCN)2(κꢀC,OꢀC6H4CO2)(PhBr)]–, either as a conꢀ
certed oxidative addition to yield 18e– Ru(IV)
[Ru(C6F5)(MeCN)2(κꢀC,OꢀC6H4CO2)(Ph)(Br)]–, or via nucleoꢀ
philic displacement of Br– to form 16e– Ru(C6F5)(MeCN)2(κꢀ
C,OꢀC6H4CO2)(Ph)] (see Figure 8 and Figures S10ꢀS11). Such
processes, however, proved to have very large barriers. Instead
a second MeCN ligand is lost to form squareꢀpyramidal
[Ru(C6F5)(MeCN)(κꢀC,OꢀC6H4CO2)(κꢀBrꢀPhBr)]–, Int(IV'-
V'). This species has 12 possible geometric isomers of which
11 proved to be local minima (see Figure S7); the lowest enerꢀ
gy form is shown in Figure 6 and benefits from having the
strong donor aryl ligand in the axial position as well as the
weak PhBr ligand opposite the high trans influence C6F5.
PhBr is computed to prefer binding through the Br substituent
over alternative η2ꢀC6H5Br forms and IRC calculations
–
exchange of two MeCN ligands with PhCO2 yields merꢀ
[Ru(C6F5)(MeCN)3(κ2ꢀPhCO2)], mer-III', which, at ꢀ5.57
kcal/mol, proves to be the most stable intermediate prior to the
–
C–H and C–Br bond activation events. Further MeCN/PhCO2
substitution forms [Ru(C6F5)(MeCN)2(κ1ꢀPhCO2)(κ2ꢀPhCO2)]–
Int(III'-IV')1 at ꢀ4.57 kcal/mol. This species then undergoes a
2ꢀstep C–H activation via agostic intermediate Int(III'-IV')2
at +4.53 kcal/mol from which C–H bond cleavage proceeds
via an AMLAꢀ6/CMD transition state (ambiphilic metalꢀ
ligand assistance/concerted metallation deprotonation),18
TS(III'-IV')2, at +15.63 kcal/mol (see also Figure 7 for geoꢀ
metric details). This gives a cyclometallated species Int(III'-
IV')3 at +9.90 kcal/mol as
a benzoic acid adduct.
PhCO2H/MeCN substitution then forms fac-IV' at +9.62
kcal/mol.19 The overall barrier to C–H activation is 21.20
kcal/mol and the formation of fac-IV' is endergonic by 15.19
kcal/mol.
ArF
O
O
Ru
Br
L
TS(IV'-V')
TS(V'-VI')
+14.38
+19.30
Ph
TS(III'-IV')2
Int(IV'-V')
+15.22
+15.63
- 2L
+PhBr
ArF
- PhCO2H
+9.90
TS(III'-IV')1
+6.95
L
L
L
+11.27
ArF
Ru
L
+ L
+9.62
ArF
Ru
L
ArF
O
O
O
L
L
O
Ph
O
II'
0.0
O
L
L
Ru
+4.53
ArF
Ru
L
- 2L
L
Br
L
L
O
OH
-
O
Ru
+ PhCO2
V'
-
fac-IV'
+ PhCO2
Int(III'-IV')3
Ar
H
-4.57
O
F
F
O
- L
-5.57
ArF
O
ArF
Ru
F
Int(III'-IV')2
Ph
Ph
F
L
L
O
O
Ph
L
L
L
F
Ru
O
O
O
O
Ru
Br
Int(V'-VI')
L
O
mer-III'
Ph
Ph
Int(III'-IV')1
-19.44
Figure 6. Computed free energy reaction profile (ωB97XꢀD(BS2, acetonitrile)//BP86, L = MeCN, ArF = C6F5, kcal/mol) for the arylation
of C6F5H with PhBr starting from model intermediate [Ru(C6F5)(MeCN)5]+, II'.
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Concerted Oxidative
Addition at 5-coordinate
Concerted Oxidative
Addition at 6-coordinate
Nucleophilic Displacement
at 6-coordinate
subsequently confirmed that this Brꢀbound intermediate lies
1
2
3
4
5
6
7
8
directly on the pathway for concerted oxidative addition. This
proceeds via TS(IV'-V') at 19.30 kcal/mol to give V' at
+11.27 kcal/mol. Ph–C6F5 reductive coupling then readily
occurs via TS(V'-VI') at +14.38 kcal/mol and gives Int(V'-
VI') (ꢀ19.44 kcal/mol) in which the biaryl product is bound in
an η2ꢀfashion to Ru.20 The free energy profile for arylation in
Figure 6 indicates that the overall rateꢀlimiting process is asꢀ
sociated with C–Br activation via TS(IV'-V') at +19.30
kcal/mol and that this corresponds to an overall barrier of
24.87 kcal/mol. C–H activation is therefore a preꢀequilibrium,
the endergonic nature of which is consistent with reversible
C–H activation leading to H/D exchange at the ortho position
and a modest (equilibrium) kinetic isotope effect.
ArF
ArF
ArF
2.57
2.18
L
L
L
2.85
2.08
2.73Br
Ru
Ru
2.98
Ru
O
O
Br
2.88
L
L
O
O
1.94
Br
O
O
TS(III'-IV')2
+19.30 (+22.29)
+41.25 (+45.01)
+36.63 (41.37)
Figure 8. Geometries of alternative C–Br activation transition
states with selected key distances in Å and relative free energies
in kcal/mol (L = MeCN, ArF = C6F5). Examples shown are the
lowest energy transition states located for each process; full deꢀ
tails of isomers are in the SI (Figures S10ꢀS11). Data in parentheꢀ
sis are those where the PCM correction for acetonitrile solvent is
included in the optimisation procedure.
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As discussed above and shown in Figure 7, the role of the
–OC(CF3)3 additive in promoting arylation cannot be ascribed
–
Figure 9. (a) Kinetic model for the reaction of II' (denoted A in the kinetic model) with PhBr in the presence of benzoates 4ꢀRꢀC6H4CO2
to give Int(V'-VI') (denoted N; L = MeCN, ArF = C6F5). Ligand addition steps are assumed to proceed at the diffusionꢀcontrolled limit and
are indicated by TS energies shown in parentheses. (b) Computed reaction profile (kcal/mol) with PhCO2 highlighting the effect of the –
–
–
–
OC(CF3)3 additive; see Figures S12ꢀS13 for equivalent diagrams computed with 4ꢀNMe2ꢀC6H4CO2 and 4ꢀCF3ꢀC6H4CO2 . (c) Computed
kinetic profiles at 363 K comparing arylation (i) in the presence of PhCO2 , with and without the –OC(CF3)3 additive, (ii) in the presence of
–
benzoates 4ꢀRꢀC6H4CO2– (R = H, NMe2 and CF3) without –OC(CF3)3, and (iii) in the presence of benzoates 4ꢀRꢀC6H4CO2– (R = H, NMe2
and CF3) with added –OC(CF3)3.
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to any direct participation in the C–H activation event. Instead
we postulate that OC(CF3)3 affects the position of the C–H
Table 2. Selected computed data (kcal/mol unless other-
wise stated) for the arylation reaction with different ben-
zoates 4-R-C6H4CO2 .
–
1
2
3
4
5
6
7
8
– a,b
activation preꢀequilibrium via deprotonation of the benzoic
acid produced in this process. Based on the pKa values of
PhCO2H and HOC(CF3)3 in water (4.2 and 5.2 respectively)
this implies a free energy change of ꢀ1.4 kcal/mol upon deproꢀ
tonation. To quantify this effect a kinetic model accommodatꢀ
ing all the steps linking II' to Int(V'-VI') was constructed (see
Figure 9(a)) where any ligand substitution processes were
treated as dissociative in nature with the ligand addition steps
assumed to occur at the diffusionꢀcontrolled limit
(k = 1010 Mꢀ1sꢀ1, corresponding to a barrier of 4.78 kcal/mol at
363 K). This allows for the rate of the related ligand dissociaꢀ
tion to be defined, based on the equilibrium constant computed
ꢀOC(CF3)3
ꢀG‡
ꢀGCHA
ꢀG‡
ꢀG‡
span
t1/2 (s)
CHA
PhBr
H
N
Y
21.20
19.77
19.84
+17.74
+16.34
7.13
24.87
23.40
18102
2954
NMe
2
N
Y
+13.93
+13.65
7.32
7.61
21.25
20.97
106
81
CF3
N
Y
+16.15
+14.19
23.76
21.80
6084
446
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aDefinitions: ꢀG‡
= ꢀG(TSH-I – E); ꢀGCHA = ꢀG(J –
CHA
E); ꢀG‡
= ꢀG(TSL-M – J); ꢀG‡
= ꢀG(TSL-M – E);21 t1/2
=
PhBr
span
–
time to 50% conversion. See Figure 9 for labels of stationary
for the overall ligand exchange. Within this model OC(CF3)3
b
–
points. Corrections for the effect of OC(CF3)3 are based on the
pKas of HOC(CF3)3 (5.2) and PhCO2H (4.2) in water; pKas for the
4ꢀRꢀC6H4CO2H acids (R = NMe2: 5.03; R = CF3: 3.66) are based
on the difference in the σp Hammett parameters and the relationꢀ
ship σ = −(pKa(4ꢀRꢀC6H4CO2H) – pKa(PhCO2H)).
intervenes upon loss of PhCO2H from species I and its effect
is modelled by a 1.4 kcal/mol stabilization of all species from
J onwards (rightꢀhand shaded area, Figure 9(b)). This leaves
the rates of the onward reactions unchanged, but reduces the
rate of the backwards reaction (i.e. J + PhCO2H → I). The
effect is seen in Figure 9(c), plot (i) which shows that product
formation (modelled by species N) is approximately doubled
and H+ transfer to a second benzoate to form a C(O)O–H bond
which will be more dependent on σp. As discussed above the
C–Br activation step shows little dependency on R and so we
–
over a 1 h period in the presence of the OC(CF3)3 additive
(compare the dotted and solid red lines). This is in good
agreement with experimental observations which indicate a ca.
3ꢀfold rate enhancement (Figure 1).
have focused on deconvoluting how σm and σp affect ꢀGCHA
.
To this end we have computed the free energy changes for
the model cyclometallation processes (4) and (5) for all the
The profile in Figure 9(b) was recomputed with two subꢀ
–
–
stituted benzoates, 4ꢀRꢀC6H4CO2 , with R = NMe2 and CF3.
4ꢀRꢀC6H4CO2 substrates studied experimentally (see Figure
10 and Table S5). In (4) cyclometallation of the parent benzoꢀ
These substituents have distinctly different σp and σm Hamꢀ
mett parameters, yet experimentally both provide significantly
enhanced reactivity compared to the parent benzoate (Table
1). In each case a similar overall profile was computed, with
the transition state for C–Br activation lying above that for
C–H activation (see Table 2 and Figures S12ꢀS13). The results
again emphasize the sensitivity of the overall outcome to the
inclusion of the –OC(CF3)3 additive in the model. This is more
–
ate in E proceeds with different 4ꢀRꢀC6H4CO2 acting as the
base: ꢀG(4) should therefore reflect how σp promotes C–H
activation. In (5) the cyclometallation of different 4ꢀRꢀ
C6H4CO2– in E proceeds with the parent benzoate acting as the
base. ꢀG(5) should be dominated by the breaking of the CAr–H
bond and the formation of the new [Ru]–CAr bond, and as
such, should correlate with σm. However, σp may also play a
role here by influencing how the C(O)O–[Ru] interaction varꢀ
ies due to the κ2ꢀκ1 change in substrate binding mode. This
point was considered in process (6) and was found to be faꢀ
vored by electronꢀdonating paraꢀsubstituents. This effect is
relatively weak, however, with a plot of ꢀG(6) vs. σp giving a
straight line of gradient 2.1 (R2 = 0.92, see Graph S9).
Plots of ꢀG(4) vs. σp and ꢀG(5) vs. σm are displayed in
Figure 10. In both cases a good correlation is found; moreover
the plots provide further evidence for the counterꢀbalancing
effects of the paraꢀ and metaꢀsubstituents. Thus the cyclomeꢀ
tallation is facilitated by electronꢀdonating paraꢀsubstituents
which enhance substrate basicity (ꢀG(4) vs. σp) while for a
given base substrate cyclometallation is favored by electronꢀ
withdrawing metaꢀsubstituents (ꢀG(5) vs. σm).23 Importantly,
the gradients indicate the latter meta effect is approximately
twice as large as the former para effect, in excellent agreeꢀ
ment with the conclusions from the Jaffé plots in Figure 5.
The trend in the meta effect as defined in process (5) must
relate to differences in the CAr–H and [Ru]–CAr bond energies.
Direct computation of the CAr–H homolytic bond dissociation
energies shows little variation as a function of R, with most
benzoates giving a value of 102 ± 0.5 kcal/mol (see SI, Table
S6). The [Ru]–CAr bond strength must therefore dominate,
with these being stronger with electronꢀwithdrawing substituꢀ
ents. There is precedent for this in the selective C–H activation
of fluoroarenes,24 and in M–C bond strengths being more senꢀ
sitive to substituent effects than their equivalent C–H bonds.25
–
apparent for 4ꢀCF3ꢀC6H4CO2 for which a reduction of 2.16
kcal/mol in ꢀGCHA leads to an order of magnitude reduction in
the computed t1/2, the time required to reach 50% conversion.
The higher pKa of 4ꢀNMe2ꢀC6H4CO2H means the effect here is
less dramatic, but in this case the computed barrier in the abꢀ
sence of –OC(CF3)3 is already significantly lower than the
– –
PhCO2 / OC(CF3)3 system.
The data in Table 2 indicate that the overall barrier to aryꢀ
lation (ꢀG‡span) depends more on the free energy change of the
C–H activation (ꢀGCHA) rather than the subsequent barrier to
PhBr activation (ꢀG‡PhBr). The variation in ꢀGCHA is mirrored
in the trend in the 2ꢀstep C–H activation (G→I: R = NMe2
(+12.23 kcal/mol) < R = CF3 (+13.74 kcal/mol) < R = H
(14.47 kcal/mol)). The fact that both an electronꢀdonating and
an electron withdrawing substituent reduce the barrier to C–H
activation over the unsubstituted parent has parallels in the
trends computed by Gorelsky and Fagnou for C–H activation
of (hetero)aromatics at Pd(Ph)(OAc)(PMe3),4d,22 although the
–
variations are much smaller here. The effect of the OC(CF3)3
base is also a significant factor in accelerating the reaction,
especially with the 4ꢀCF3ꢀC6H4CO2– additive.
As highlighted in Figure 4 electronic perturbation arising
from the benzoate substituent, R, could manifest itself at sevꢀ
eral points along the reaction pathway. The initial cyclometalꢀ
lation involves CAr–H bond cleavage and formation of a
CAr–[Ru] bond, both of which should be sensitive to σm; simiꢀ
larly this process involves varying the C(O)O–[Ru] interaction
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neutral
[Ru(C6F5)(MeCN)3(PhBr)]+
and
ArF
Ru
ArF
Ru
R
R
riers
at
[Ru(C6F5)(MeCN)2(κ2ꢀPhCO2)(PhBr)] prohibitively high. This
1
2
O
O
ꢀG(4)
(∝ σp)
L
L
L
L
L
+
(4)
is still the case for [Ru(C6F5)(MeCN)(κ1ꢀPhCO2)2(PhBr)]–,26
+
O
p
p
[Ru(C6F5)(κ2ꢀPhCO2)(κ1ꢀ
3
4
5
6
7
8
L
although
interestingly
for
O
O
O
HO
O
PhCO2)2(PhBr)]– the barrier to C–Br activation falls to only
3.97 kcal/mol. This is in fact slightly lower than the barrier
from cyclometallated L (4.08 kcal/mol), although in this case
the low energy of L (+15.22 kcal/mol) allows C–Br activation
to proceed via TSL-M/TS(IV'-V') at only +19.30 kcal/mol. The
role of the cyclometallated benzoate is therefore not just to
enhance the electronꢀrich character of the Ru(II) center, but
also to facilitate ligand dissociation and thus render the 5ꢀ
coordinate precursor to C–Br activation accessible. The high
trans influence of the cyclometallated arm is therefore a key
factor in promoting reactivity.
E
O
H
(mer-III')
ArF
Ru
(fac-IV')
ArF
Ru
L
O
O
ꢀG(5)
L
L
L
L
+
(5)
+
p
L
(∝ σm)
m
O
9
O
O
O
p
HO
O
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E
O
m
H
R
(mer-III')
(fac-IV')
R
ArF
ArF
ꢀG(6)
(∝ σp)
L
L
L
L
L
(6)
Ru
+ L
Ru
O
L
L
O
(i) via cationic precursors
O
O
p
ArF
ArF
Ru
p
C
E
L
L
L
L
L
L
+49.52
Ru
(mer-III')
Ph
R
R
BrPh
Br
+25.77
+43.19
(ii) via neutral precursors
ArF
ArF
Ru
O
O
L
O
O
L
+29.58
Ru
Ph
Ph
Ph
BrPh
Br
+21.78
+23.96
(iii) via (non-cyclometallated) anionic precursors
ArF
ArF
Ru
L
+30.69a
- Br-
L
PhCO2
PhCO2
PhCO2
PhCO2
Ru
Ph
BrPh
Br
+19.45
+11.29
ArF
ArF
O
Ph
O2CPh
O
Ph
+23.84
O2CPh
Ph
Ru
Ru
O
O
BrPh
Br
+19.87
+8.15
Int(IV'-V')/L
(iv) via the cyclometallated anionic precursor
ArF
ArF
TS(IV'-V')/TS L-M
+19.30
L
L
Ru
Ru
O
O
O
O
Ph
BrPh
Br
Int(IV'-V')/L
+15.22
V'/M
+11.27
Figure 11. Lowest energy pathways (kcal/mol, L = MeCN, ArF =
C6F5) computed for C–Br activation at 5ꢀcoordinate cationic, neuꢀ
tral and anionic precursors, placing the Ph group cis to C6F5.
aProceeds via nucleophilic displacement of Br–; all other pathꢀ
ways involve a concerted oxidative addition. See Figures S15ꢀS19
for details and alternative pathways.
Figure 10. Model reactions considered to isolate σp and σm efꢀ
fects and the resultant plots of ꢀG(4) vs. σp and ꢀG(5) vs. σm.
2.5 The role of benzoate cyclometallation in promoting
arylation. Although the C–Br activation step proving insensiꢀ
tive to substituent effects on the benzoate, cyclometallation
remains the key to making the overall arylation process accesꢀ
sible. To understand this more fully, C–Br activation was
modelled at cationic, neutral and nonꢀcyclometallated anionic
analogues of L/Int(IV'-V') and the most accessible processes
for each case are shown in Figure 11. The data show two
trends when moving from cationic through neutral and then to
anionic systems: (i) the 5ꢀcoordinate precursor to C–Br activaꢀ
tion becomes more accessible and (ii) the subsequent barrier to
C–Br activation is reduced. Both factors make the overall barꢀ
The cyclometallated benzoate ligand also plays an imꢀ
portant role in dictating the selectivity of the C–C coupling
process. The computed structures of the 6ꢀcoordinate Ru(IV)
species such as intermediate M formed upon C–Br activation
show a marked distortion away from an octahedral geometry,
with a narrowing of the transꢀC1ꢀRuꢀC2 bond that pushes one
of the dπ orbitals up in energy (see Figure 12).27 This distorꢀ
tion will tend to favor a low spin d4 configuration, whereas
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and C6F5 can be mutually cis, thus facilitating the observed
1
2
3
4
5
6
7
8
9
10
selectivity of the subsequent C–C coupling.
The computed data highlight how a C–H functionalization
process can be promoted through use of a base additive such
as (NMe4)OC(CF3)3, and how a subtle perturbation of a C–H
activation preꢀequilibrium step can have a significant effect on
the overall reaction efficiency. Group 1 carbonate salts,
M2CO3, have often been proposed as proton sinks in direct
arylation reactions29 and the choice of the Group 1 M+ cation
can significantly impact the end result when expressed as a
reaction yield. The results here highlight how such variations
can result from small changes in the efficiency of these proꢀ
cesses that could reflect, for example, changes in additive conꢀ
centration due to varying solubilities in organic reaction meꢀ
dia.
Figure 12. (a) Changes in the relative energies of the metalꢀbased
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dπ orbitals and preferred spin state upon narrowing one transꢀLꢀ
MꢀL angle in d4 ML6 complexes. (b) Computed geometry of inꢀ
termediate M highlighting the reduced transꢀC1ꢀRuꢀC2 angle.
3. CONCLUSIONS
geometries computed in the triplet state (which are often enerꢀ
getically competitive for these Ru(IV) species28) exhibit more
regular pseudoꢀoctahedral structures.
A detailed experimental and in silico mechanistic investigation
allowed the elucidation of the role of the benzoate salt in proꢀ
moting aryl halide oxidative addition in the Ru(II)ꢀcatalyzed
C–H arylation of fluoroarenes. The inability of 2,6ꢀ
disubstituted benzoate sources to trigger the desired arylation
event, along with D/H scrambling and kinetic isotope effect
experiments, supported the hypothesis for the requirement of a
cyclometallation step of the benzoate salt. Thus, the resulting
highly electronꢀrich anionic Ru(II) intermediate rapidly underꢀ
goes oxidative addition with the aryl halide to furnish the biarꢀ
yl product via a selective reductive elimination step. The preꢀ
equilibrium associated with the kinetically relevant benzoate
cyclometallation leads to a Jaffé relationship reflecting the
influence of the benzoate substituents at multiple distinctive
sites in this process. Indeed, simple Hammett plots correlating
the electronic perturbation at only one reactive site at the time
could not provide a linear free energy relationship that acꢀ
commodated all the substituents studied.
DFT calculations provide support for a mechanism involvꢀ
ing reversible C–H activation and formation of an anionic
cyclometallated intermediate. The enhanced lability of this
species allows access to a reactive 5ꢀcoordinate intermediate
capable of C–Br bond cleavage. A kinetic model based on the
computed mechanism captures the rate enhancement observed
with pꢀsubstituted benzoates bearing both electron withdrawꢀ
ing and electron donating substituents. The role of a
(NMe4)OC(CF3)3 additive in promoting reactivity is pinpointꢀ
ed to the deprotonation of the carboxylic acid formed upon
cyclometallation that shifts the preꢀequilibrium associated with
benzoate cyclometallation. This effect is particularly marked
for less basic benzoates such as (NMe4)(4ꢀCF3ꢀC6H4CO2), the
conjugate acids of which will be more readily deprotonated by
the (NMe4)OC(CF3)3 additive. Both the experimental and
computational results highlight the counterꢀbalancing effects
of electronꢀwithdrawing groups meta to the site of benzoate
cyclometallation and electron donating groups para to the
protonꢀaccepting carboxylate group in promoting reactivity,
with the former having the larger influence by a factor of apꢀ
proximately 2.
Distortion of the singlet is most favorable when strong σꢀ
donors adopt a mutually trans arrangement and so the most
stable isomers of Ru(IV) species M feature the three strongly
donating aryl ligands in a mer configuration. One of these,
M(ii), has Ph trans to C6F5 and is actually more stable than M
itself (see Figure 13); moreover C–C coupling with the benzoꢀ
ate ligand in M(ii) proceeds through a lower transition state,
TSM(ii)-N(ii) (+11.76 kcal/mol), than that for Ph–C6F5 coupling
via TSM-N (+14.38 kcal/mol). The fact that benzoate–Ph couꢀ
pling is not observed is due to M(ii) being kinetically inaccesꢀ
sible, either through C–Br activation at L(ii)(via TSL(ii)-M(ii)
,
+27.63 kcal/mol) or through isomerization of M. The lowest
energy isomerization pathway involves Br– loss to form the
neutral trigonal bipyramidal intermediate IM-M(ii) followed by
Br– reꢀassociation to give M(ii); this second step involves tranꢀ
sition state TSM-M(ii)2 which, at 17.63 kcal/mol, is > 3 kcal/mol
higher than TSM-N at 14.38 kcal/mol. Benzoate–C6F5 coupling
from either M or M(ii) is also significantly less accessible (see
Figure S20). More generally, for the systems in Figure 11 that
lack a cyclometallated ligand, C–Br activation is computed to
be more accessible when the Ph ligand moves trans to C6F5.
The presence of the cyclometallated benzoate therefore proꢀ
motes the formation of a Ru(IV) intermediate where the Ph
C6F5
−
Ph Coupling
TSL-M
TSM-N
ArF
Ru
ArF
Ru
ArF
Ph
+19.30
+14.38
L
L
Ph
L
Ru
O
O
O
O
O
O
BrPh
Br
Br
L
M
N
(+15.22)
(+11.27)
(-19.44)
ArF
TSM-M(ii)1
+ Br-
+14.36
L
Isomerisation
Ru
Ph
O
O
- Br-
TSM-M(ii)2
+17.63
IM-M(ii)
(+3.76)
Benzoate
−Ph Coupling
ArF
Ru
Ph
TSL(ii)-M(ii)
+27.63
TSM(ii)-N(ii)
ArF
ArF
Ph
L
L
Br
+11.76
Finally, this mechanistic breakthrough has important imꢀ
plications on the design of new catalytic systems involving an
oxidative addition at Ru(II) centers, which have been signifiꢀ
cantly underdeveloped due to the lack of knowledge surroundꢀ
ing this fundamental step.
L
Ru
Ru
Br
O
O
O
BrPh
O
O
O
L(ii) (+18.33)
M(ii) (+6.08)
N(ii) (-19.87)
Figure 13. Key stationary points (kcal/mol) for the competition
between C6F5–Ph coupling via intermediate M and benzoate–Ph
coupling via intermediate M(ii) (L = MeCN, ArF = C6F5).
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Tani, S.; Uehara, T. N.; Yamaguchi, J.; Itami, K. Chem. Sci. 2014, 5,
ASSOCIATED CONTENT
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(12) When (2,6ꢀMeꢀC6H3CO2)(NMe4), (2,6ꢀFꢀC6H3CO2)(NMe4)
and (2,6ꢀOMeꢀC6H3CO2)(NMe4) were tested in the presence of added
(NMe4)OC(CF3)3, no crossꢀcoupled product was detected.
(13) In light of the reversibility of steps IꢀIV (Scheme 3), the obꢀ
served KIE of 1.36 could also be associated with the C–H activation
step of C6F5H/D, which may be generated in situ via proꢀ
to/deuterodemetallation of Ru1c with concomitant release of
Ru(C6H5CO2)x(tꢀBuCN)y species. In order to rule this hypothesis out,
we preꢀincubated C6F5H (1 equiv), [Ru(tꢀBuCN)6](BF4)2 (1 equiv),
(C6H5CO2)(NMe4) (2.5 equiv) and (NMe4)OC(CF3)3 (3.0 equiv) in tꢀ
BuCN (0.1 M) at 90 °C for 20 min. After this time, 5ꢀbromoꢀmꢀxylene
(2 equiv) was added and then the reaction was stopped after 18 min,
which correspond to the last kinetic data point taken into consideraꢀ
tion for calculating the KIE (3cb(18 min)= 11.65%). The reaction was
analysed by calibrated GCꢀFID revealing only traces of biaryl product
(3cb(18 min)= 0.02%). As this experiment was carried out mimicking
the extreme case scenario in which the equilibrium IꢀIV is totally
shifted towards I under the reaction conditions used for the determinꢀ
ing the KIE, it further validates that the value of 1.36 is exclusively
1
2
3
4
5
6
7
8
Supporting Information. Experimental procedures and characꢀ
terization data are available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*igor.larrosa@manchester.ac.uk
*s.a.macgregor@hw.ac.uk
Notes
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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35
36
37
38
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40
41
42
43
44
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60
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We gratefully acknowledge the Engineering and Physical Sciencꢀ
es Research Council (EPSRC, EP/L014017/2) for funding and the
European Research Council for a Starting Grant (to I.L.). We
thank Prof Eric Clot (Université de Montpellier) for valuable disꢀ
cussion regarding the kinetic simulations, EU COST Action
CM1205 – CARISMA for a ShortꢀTerm Scientific Mission award
to RK and HeriotꢀWatt University for support.
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Journal of the American Chemical Society
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PhCO2)(κ1ꢀPhCO2)(PhBr)]–
and
[Ru(C6F5)(MeCN)2(κꢀC,Oꢀ
C6H4CO2)(PhBr)]– may reflect the geometry imposed on the metal
center by the κ2ꢀPhCO2– (OꢀRuꢀO= 62°) and cyclometallated (CꢀRuꢀO
=
82°) ligands; in comparison the OꢀRuꢀO angle in
[Ru(C6F5)(MeCN)(κ1ꢀPhCO2)2(PhBr)]– is 90°. A similar bite angle
effect is known to promote oxidative addition in d10 ML2 species by
destabilizing an occupied metalꢀbased dπ orbital.26b,c The low symꢀ
metry of the current systems causes significant orbital mixing and
thus complicates a detailed analysis; however the average energies of
the three occupied dπ orbitals in [Ru(C6F5(κ2ꢀPhCO2)(κ1ꢀ
PhCO2)(PhBr)]– and [Ru(C6F5)(MeCN)2(κꢀC,OꢀC6H4CO2)(PhBr)]–
are 6ꢀ7 kcal/mol above those for [Ru(C6F5)(MeCN)(κ1ꢀ
PhCO2)2(PhBr)]–, suggesting that a bite angle effect could also conꢀ
tribute to reducing the barrier to Ph–Br activation here. (b) Albright T.
A.; Burdett J. K.; Whangbo M. H. Orbital Interactions in Chemistry,
2nd edn. Wiley, New York, 2013. (c) Wolters, L. P.; Bickelhaupt, F.
M., in Computational Studies in Organometallic Chemistry, Macꢀ
gregor, S. A.; Eisenstein, O., Eds. 2016, 167, 139–161.
9
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
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52
53
54
55
56
57
58
59
60
(27) Hoffmann, R.; Howell, J. M.; Rossi, A. R. J. Am. Chem. Soc.
1976, 98, 2484–2492.
(28) The triplet state of the Ru(II) precursors is always strongly disꢀ
favored and so C–Br activation pathways computed on the triplet
surface were found to be prohibitively high in energy.
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K. J. Am. Chem. Soc. 2010, 132, 10692–10705. (b) Sun, H.ꢀY.;
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(19) A more stable merꢀisomer is computed at +7.29 kcal/mol, but
the isomerization pathway to form this species involves a transition
state at +24.05 kcal/mol and, as such, is less accessible than the onꢀ
ward PhBr activation via TS(IV'-V'). See Figure S14.
(20) A triplet transition state for PhBr activation was located at
+61.41 kcal/mol and the triplet state was also assessed for all isomers
of the Ru(II) precursor Int(IV'-V') and found to be very high in enerꢀ
gy. Reaction via a triplet spin state can therefore be ruled out (see
Figures S5 and S7).
(21) TSK-L is in fact slightly higher than the C–Br activation transiꢀ
tion state TSL-M for all three benzoates. Based on this ꢁGspan is 25.57
kcal/mol, 21.84 kcal/mol and 24.02 kcalmol for R = H, NMe2 and CF3
respectively, and thus follows the same trend as the data in the table.
(22) (a) Gorelsky, S. I.; Lapointe, D.; Fagnou, K., J. Am. Chem.
Soc. 2008, 130, 10848–10849. (b) Gorelsky, S. I.; Lapointe, D.;
Fagnou, K., J. Org. Chem. 2012, 77, 658–668.
(23) For a recent example where the net effect of arene para subꢀ
stituents is the result of two counterꢀbalancing effects see: Frasco, D.
A.; Mukherjee, S.; Sommer, R. G.; Perry, C. M.; Lambic, N. K.; Abꢀ
boud, K. A.; Jakubikova, E.; Ison, E. A. Organometallics 2016, 35,
2435–2445.
(24) (a) Eisenstein, O.; Milani, J.; Perutz, R. N. Chem. Rev. 2017,
117, 8710–8753. (b) Clot, E.; Eisenstein, O.; Jasim, N.; Macgregor, S.
A.; McGrady, J. E.; Perutz, R. N. Acc. Chem. Res. 2011, 44, 333–348.
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