The site-selectivity and mechanism of Pd-catalyzed C(sp2)-H arylation of simple arenes

Article abstract of DOI:10.1039/d0sc05414c

Control over site-selectivity is a critical challenge for practical application of catalytic C-H functionalization reactions in organic synthesis. Despite the seminal breakthrough of the Pd-catalyzed C(sp2)-H arylation of simple arenes via a concerted metalation-deprotonation (CMD) pathway in 2006, understanding the site-selectivity of the reaction still remains elusive. Here, we have comprehensively investigated the scope, site-selectivity, and mechanism of the Pd-catalyzed direct C-H arylation reaction of simple arenes. Counterintuitively, electron-rich arenes preferably undergo meta-arylation without the need for a specifically designed directing group, whereas electron-deficient arenes bearing fluoro or cyano groups exhibit high ortho-selectivity and electron-deficient arenes bearing bulky electron-withdrawing groups favor the meta-product. Comprehensive mechanistic investigations through a combination of kinetic measurements and stoichiometric experiments using arylpalladium complexes have revealed that the Pd-based catalytic system works via a cooperative bimetallic mechanism, not the originally proposed monometallic CMD mechanism, regardless of the presence of a strongly coordinating L-type ligand. Notably, the transmetalation step, which is influenced by a potassium cation, is suggested as the selectivity-determining step.

Full text of DOI:10.1039/d0sc05414c

View Article Online
View Journal
Chemical
Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: D. Kim, G. Choi,
W. Kim, D. Kim, Y. Kang and S. H. Hong, Chem. Sci., 2020, DOI: 10.1039/D0SC05414C.
Volume
Number
9
1
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
7
January 2018
Pages 1-268
Chemical
Science
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
rsc.li/chemical-science
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 2041-6539
EDGE ARTICLE
Xinjing Tang et al.
Caged circular siRNAs for photomodulation of gene
expression in cells and mice
rsc.li/chemical-science

Please do not adjust margins
Page 1 of 11
Chemical Science
View Article Online
DOI: 10.1039/D0SC05414C
ARTICLE
Site-Selectivity and Mechanism of Pd-Catalyzed C(sp2)–H Arylation
of Simple Arenes
Daeun Kim,ab Geunho Choi, ab Wonjeong Kim,b Dongwook Kim,c Youn K. Kangd and Soon Hyeok
Received 00th January 20xx,
Accepted 00th January 20xx
Hong*a
DOI: 10.1039/x0xx00000x
Control over the site-selectivity is a critical challenge for practical application of catalytic C‒H functionalization reactions in
organic synthesis. Despite the seminal breakthrough of the Pd-catalyzed C(sp2)–H arylation of simple arenes via a concerted
metalation-deprotonation (CMD) pathway in 2006, understanding the site-selectivity of the reaction still remains elusive.
Here, we have comprehensively investigated the scope, site-selectivity, and mechanism of the Pd-catalyzed direct C‒H
arylation reaction of simple arenes. Counterintuitively, electron-rich arenes preferably undergo meta-arylation without the
need for a specifically designed directing group, whereas electron-deficient arenes bearing fluoro or cyano groups exhibit
high ortho-selectivity and electron-deficient arenes bearing bulky electron-withdrawing groups favor the meta-product.
Comprehensive mechanistic investigations through a combination of kinetic measurements and stoichiometric experiments
using arylpalladium complexes have revealed that the Pd-based catalytic system works via a cooperative bimetallic
mechanism, not the originally proposed monometallic CMD mechanism, regardless of the presence of a strongly
coordinating L-type ligand. Notably, the transmetalation step, which is influenced by a potassium cation, is suggested as the
selectivity-determining step.
Introduction
The functionalization of aromatic compounds is a central topic
in organic synthesis, which has great applicability.1 Among
them, electrophilic aromatic substitution (EAS) has been widely
used for the functionalization of arenes.2 Since the pioneering
work of Friedel and Crafts,3 its site-selectivity has been well
established, in which an electron-donating group (EDG) or
halogen substituent directs an incoming electrophile (E+) to the
ortho- and para-positions, whereas an electron-withdrawing
group (EWG) directs it to the meta-position (Scheme 1a).2b
Biaryls are one of the essential scaffolds found in many
types of natural products, pharmaceuticals, and functional
materials.4 Direct C(sp2)–H arylation is a powerful and attractive
tool used to construct the biaryls from arenes in an efficient
manner because traditional cross-coupling methods require the
preparation of prefunctionalized organometallic or main-group
reagents.1b, 1c, 4a, 4d, 5 To date, significant advances have been
6
achieved in the C–H arylation of heteroarenes5a,
and
electronically biased7 or chelation-assisted8 arenes to activate
a.Department of Chemistry, Korea Advanced Institute of Science and Technology
(KAIST), Daejeon 34141, Republic of Korea.
Scheme 1 Direct C–H arylation of simple arenes and selectivity.
b.Department of Chemistry, College of Natural Sciences, Seoul National University,
Seoul 08826, Republic of Korea.
certain C–H bonds. However, these approaches limit the
applicability of the reaction by requiring electronically activated
substrates or additional synthetic operations, such as the
installation and removal of a directing group to attain the target
compound. Therefore, site-selective C–H arylation of
unactivated, simple arenes is a fundamental challenge in
c. Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science
(IBS), Daejeon 34141, Republic of Korea
d.Department of Chemistry and Energy Engineering, Sangmyung University, Seoul
03016, Korea.
†Electronic Supplementary Information (ESI) available: Detailed experimental
procedures, computational details, and spectroscopic data for all new compounds.
See DOI: 10.1039/x0xx00000x
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 2 of 11
ARTICLE
Journal Name
catalysis to broaden the value of the reaction. Recently, site- operative even in the absence of a relatively strongly
View Article Online
selective C–H arylations of simple arenes have been achieved by coordinating L-type ligand, such as pDhOosI:p1h0i.1n0e39/oDr0SdCi0im54i1n4eC.
elaborately designed strategies. For example, para-selective Moreover, although it is crucial to achieve the site-selective
arylations of simple arenes have been reported using various catalytic C–H arylation of simple arenes, there has been no
arylating reagents such as diaryliodonium salts,9 arylsilanes,10 focused study on understanding the site-selectivity of the
electron-poor arenes,11 and aryl boronic acids.4e, 12 Inspired by reaction.
the Catellani reaction,13 Yu and co-workers developed a meta-
Herein, we investigate the scope and site-selectivity of the
selective arylation reaction of simple arenes such as anisole and Pd-catalyzed C–H arylation reaction of simple arenes with aryl
fluorobenzene with aryl iodide using a Pd/norbornene-based bromides (Scheme 1b). Comprehensive mechanistic studies
catalytic system to relay the palladium catalyst to the meta- have been conducted using a combination of extensive kinetic
position.14 The Larrosa group also reported a one-pot direct measurements and stoichiometric experiments with
meta-selective arylation of simple arenes using a traceless arylpalladium complexes to address the operating catalytic
directing group relay strategy utilizing CO2.4f, 15 To develop a cycle and factors determining the selectivity. Consequently, it is
highly selective and efficient catalytic system, it is crucial to demonstrated that the applied Pd-based catalytic system works
understand the underlying mechanism and factors that control via a cooperative bimetallic mechanism involving two Pd
the site-selectivity of the intrinsic palladium catalytic system.
catalytic species, which accounts for the observed
During the past decades, significant attention has been counterintuitive site-selectivity trend by disclosing the
focused on investigating the underlying mechanism of Pd(II)- transmetalation step as the selectivity-determining step.
catalyzed C(sp2)–H bond cleavage. In 1985, Ryabov and co-
workers proposed an electrophilic palladation pathway in the
Results and discussion
The reaction of ethoxybenzene 1a with 3-bromotoluene 2a in
directed C–H activation of N,N-dimethylbenzylamine by
Pd(OAc)2.16 Subsequently, Martinez17 and, Davies and
Macgregor18 suggested that the C–H bond cleavage proceeds
DMA was initially chosen to investigate both the reactivity and
via a concerted intramolecular proton abstraction by the
acetate ligand. This concerted metalation-deprotonation (CMD)
is regarded as an elegant system to cleave C–H bonds with the
base ligand as the proton shuttle and has been extensively
site-selectivity of the Pd-catalyzed direct C–H arylation (Table
1). The use of palladium acetate (Pd(OAc)2) and DavePhos,
employed under the Fagnou’s condition,20 afforded the desired
biaryl product 3aa in 54% yield with 69% meta-selectivity (entry
1). When using PtBu3 as a ligand, which is used for the arylation
of pyridine N-oxide,24, 27 Pd(OAc)2 exhibits similar reactivity to
DavePhos (entry 2). Increased reactivities in the C–H arylation
reaction were observed in the absence of a phosphine ligand,
as reported by the Hartwig group, along with slightly increased
meta-selectivity (entries 3 and 4).28 Changing the Pd precursor
to PdCl2 enhanced the reactivity (75%, entry 5). To our delight,
the use of Pd(CH3CN)2Cl2 further improved the reaction
efficiency to 79%, which could be attributed to the improved
solubility of the Pd precursor (entry 6). The previously reported
Pd–diimine catalyst also displayed good reactivity (81%) with
68% meta-selectivity (entry 7).26 Increasing the catalyst loading
(10 mol %) or the use of stoichiometric KOPiv instead of a
combination of PivOH and K2CO3 resulted in a much lower yield
(15% and 32%, respectively) accompanied by the homocoupling
and hydrodebromination of 2a (entries 8 and 9).20 It is
interesting to see that an appropriate choice of acid and base
rather than the Pd catalyst or ligand is essential to obtain high
efficiency and selectivity (entries 10–12 and Tables S1–S3).19b, 29
The meta-selectivity was noticeably decreased when Rb2CO3,
NaOPiv, or CsOPiv was used as the base instead of K2CO3 or
KOPiv, suggesting that there may be a cation effect on the site-
selectivity (entries 10–12). The use of other aryl halides
including aryl chloride and iodide gave poor reactivities (0% and
4.4%, respectively), suggesting the involvement of halide anion
in the catalytic cycle (entries 13 and 14). Control experiments
indicated that a source of pivalate is essential for the reaction,
which is consistent with previous reports (entry 15).20, 26, 29a
applied in various catalytic C–H functionalization reactions.4b, 7d,
19
In the pioneering work of Pd-catalyzed C–H arylation of
arenes by the Fagnou group, the CMD pathway efficiently
facilitates the aryl C–H bond activation step operating using the
combination of a sub-stoichiometric amount of pivalic acid
(PivOH) and K2CO3.20 Both the Brønsted acidity of the C–H bond
and distortion-interaction analysis of the CMD transition state
using density functional theory (DFT) studies have been
adopted to predict the site-selectivity of the Pd-catalyzed C–H
arylation of (hetero)arenes.21 However, the prediction was not
well-matched with various simple arenes such as anisole (1b
)
and benzotrifluoride (1m). For example, although the ortho C–
H bonds of 1b and 1m are the most acidic and reactive positions
based on the current understanding of the CMD mechanism,
the meta-isomers were observed as the major products in the
previously reported studies.20-21, 22
After the initial proposition of the Pd(II)-catalyzed
monometallic CMD mechanism in the C–H arylation with aryl
halide,17, 23 Hartwig and co-workers experimentally uncovered
that a cooperative bimetallic mechanism is operative in the C–
H arylation of pyridine N-oxide catalyzed by Pd(OAc)2 and
PtBu3.24 Gorelsky reported that the cooperative bimetallic
mechanism involving two palladium species is favored using
computational studies with phosphine-based Pd catalytic
systems.25 Our group has also reported that a Pd-diimine
catalyst facilitates the direct C–H arylation of benzene via a
cooperative bimetallic mechanism with noticeably improved
TONs.26 However, despite these advances, it is still questionable
whether the suggested bimetallic pathway is generally
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 11
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
Table 1 Optimization of the Reaction Conditionsa
Table 2. Substrate Scope with Respect to the Arenea
View Article Online
DOI: 10.1039/D0SC05414C
Entry
Catalytic condition
Base
Yield (%)
Selectivity
(o / m / p)
% Selectivity
(o / m / p)
1
2
Pd(OAc)2, DavePhos
Pd(OAc)2, PtBu3-HBF4
Pd(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOPiv
Rb2CO3
NaOPiv
CsOPiv
K2CO3
K2CO3
K2CO3
54
57
1 / 7.2 / 2.3
1 / 6.8 / 2.6
1 / 9.7 / 3.1
1 / 10.0 / 3.0
1 / 10.0 / 3.1
1 / 10.2 / 3.2
1 / 9.0 / 3.0
1 / 10.3 / 3.0
1 / 6.2 / 2.0
1 / 5.7 / 2.9
1 / 1.6 / 1.2
1 / 1.4 / 1.8
-
9 / 69 / 22
10 / 65 / 25
7 / 70 / 23
7 / 71 / 22
7 / 71 / 22
7 / 71 / 22
7 / 68 / 25
7 / 72 / 21
11 / 68 / 21
10 / 59 / 31
26 / 43 / 31
31 / 45 /24
-
3
68
4
Pd(OPiv)2
67
5
PdCl2
75
6
Pd(CH3CN)2Cl2
Pd(diimine)Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
79 (76b)
81
7
8c
9d
10
11d
12d
13e
14f
15d
15
32
75
1.3
4.3
0
4.4
0
1 / 2.0 / 4.0
-
14 / 29 / 57
-
aReaction conditions: 2a (0.2 mmol), 1a (60 equiv), [Pd] catalyst (3 mol %), ligand
(3 mol %), PivOH (0.3 equiv), base (2.5 equiv) and DMA (1.2 mL) at 120 °C for 18 h;
the total yield and regioselectivity (ortho / meta / para) were determined by GC
analysis of the reaction mixture using dodecane as an internal standard. bIsolated
yield. c[Pd] catalyst (10 mol %). dWithout PivOH. diimine=(1E,2E)-N1,N2-bis(2,6-
di(pentan-3-yl)phenyl)ethane-1,2-diimine. eWith 3-chlorotoluene. fWith 3-
iodotoluene.
With the optimized conditions in hand, the site-selectivity of
the direct C–H arylation of various simple arenes was examined
with 1-bromo-3,5-dimethylbenzene 2b as the coupling partner
(Table 2). The major isomers are illustrated in Table 2 and the
observed % site-selectivity reported in the parenthesis as (ortho
/ meta / para) or (α / β). To gain an idea of the correlation
between the C–H bond acidity and site-selectivity in the
transformation, the proton affinity at every C-position in the
various arenes was calculated (Table S17); however, no
consistent correlation was observed (Table 2). Various
monosubstituted electron-rich arenes exhibit good reactivities,
counter-intuitively providing the meta-isomer as the major
aReaction conditions: 2b (0.2 mmol), arene (60 equiv), Pd(CH3CN)2Cl2 (3 mol %),
PivOH (0.3 equiv), K2CO3 (2.5 equiv) and DMA (1.2 mL) at 120 °C for 18 h. All yields
are isolated yields. The regioselectivity (ortho / meta / para or α / β) was measured
by GC analysis of the reaction mixture using dodecane as an internal standard.
product (>60% selectivity). In
a
similar manner to
ethoxybenzene, anisole provided biaryl products 3bb in 58%
yield with 67% meta-selectivity. In the case of alkylbenzenes, an
almost statistical ratio of the meta- and para-isomers (~2:1) was
c
bArene (6 equiv). 3 h. dGC yield. eThe C-position with the lowest proton affinity
(calculated using G3MP2; see Table S17).
observed in excellent yields (3cb–3eb). N-methylacetanilide
provided biaryl products 3fb (>96%) with 62% meta-selectivity.
Electron-neutral arenes also exhibited good efficiency. Benzene
afforded biaryl 3gb in quantitative yield (>96%). Naphthalene
provided 3hb (70%) in a 1.7:1 ratio favoring the α-arylated
product. Various monosubstituted electron-deficient arenes
exhibit higher efficiency even when using a lower amount of the
arene (6 equiv) or shorter reaction time (3 h). Fluorobenzene
provided biaryl products 3ib in 96% yield with 88% ortho-
selectivity when using 6 equiv of arene over 3 h. Similarly, when
benzonitrile was subjected to the standard reaction conditions,
the arylated products 3jb were obtained in 72% yield in favor of
the ortho-isomer (69% selectivity). The ortho-selectivity
observed using the electron-deficient arenes has been well
acknowledged in the literature and attributed to both the most
acidic ortho C–H bond and its lower distortion energy in the
CMD transition state.21a, 21c However, we observed that the
steric effect of the substituent can significantly affect the site-
selectivity in the CMD catalytic system. Chlorobenzene, which is
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 4 of 11
ARTICLE
Journal Name
Table 3 Substrate scope with respect to the aryl bromidea
selectivity is observed in the case of electron-deficient arenes
View Article Online
containing fluoro or cyano groups, asDpOrI:e1v0i.o10u3s9ly/D0rSeCp0o5r4t1e4dC.
However, arenes bearing large electron-withdrawing groups
are arylated in favor of the meta-isomer rather than at the most
acidic ortho C–H position.
Next, we explored an array of aryl bromides as the coupling
partner in the C–H arylation of ethoxybenzene (Table 3). A
variety of electron-rich aryl bromides provided their
corresponding biaryl products efficiently (61–83%) with good
meta-selectivities (66–72%). Methyl- and dimethyl-substituted
aryl bromides displayed good reactivities (3aa
–3ad). Phenyl and
naphthyl groups also gave good product yields (3ae
–3ag). 4-
Bromoanisole (2h), an aryl ether, exhibited slightly decreased
reactivity (61%), but the meta-selectivity (70%) was maintained
(
3ah). Electron-deficient aryl bromides bearing trifluoromethyl,
chloro, or cyano substituents also provided their corresponding
biaryl products (3ai 3al) in moderate to good yields (44–69%).
–
However, to our surprise, the presence of an electron-
withdrawing substituent on the aryl bromide resulted in
dramatically decreased meta-selectivities (37–53%), contrary to
our expectation that the nature of aryl bromide would not
significantly affect site-selectivity. Similar results were observed
with stoichiometric amounts of ethoxybenzene (Scheme S2).
The results imply that the electronic property of aryl bromide
significantly affects the selectivity-determining step in the
catalytic cycle.
To understand the general reactivity and selectivity trends
mechanistically, the reaction rates were first compared with a
aReaction conditions: Aryl bromide (0.2 mmol), 1a (60 equiv), Pd(CH3CN)2Cl2 (3 mol
%), PivOH (0.3 equiv), K2CO3 (2.5 equiv) and DMA (1.2 mL) at 120 °C for 18 h; The
variety of arenes (Scheme 2). As rationally expected in the rate-
21b, 27
total yields and regioselectivity (ortho / meta / para) were determined by GC limiting proton-transfer CMD pathway,2a,
inductively
analysis of the reaction mixtures using dodecane as an internal standard. b48 h.
c140 °C.
arenes with inductively withdrawing groups reacted faster than
electron-rich arenes, which is a reversed tendency to the
reactivity profiles obtained for
substitution reactions.2b
electrophilic aromatic
predicted to exhibit a similar trend to fluorobenzene,21c
efficiently produced biaryls 3kb (95%) in favor of the meta-
isomer (64% selectivity). (Trifluoromethoxy)benzene and
benzotrifluoride gave products 3lb (64%) and 3mb (86%) with
good meta-selectivities (61% and 71%, respectively). When
using acetophenone as the arene substrate, α-arylation of the
ketone occurred exclusively because the α-C(sp3)–H bond
adjacent to the carbonyl group is much more acidic than the aryl
C(sp2)–H bond (Scheme S1).30 When pivalophenone was used to
block the undesired C(sp3)–H arylation, 3nb was produced in
91% yield with 66% meta-selectivity. Nitrobenzene provided
biaryl products 3ob (95%) with decreased meta-selectivity
(44%) and an almost statistical distribution of regioisomers. The
selectivity is significantly dependent on the solvents, as
demonstrated in the ortho-arylation of nitrobenzene by Fagnou
group29b and our solvent screening results (Table S4). The
current method is well suited for disubstituted arenes and
displays excellent regioselectivity. m-Xylene provided biaryl
product 3pb (53%) as the sole isomer functionalized at the least
sterically hindered meta-position with respect to the methyl
substituent. Fluorotoluene and fluoroanisole resulted in
R
F
NO2
CN
CF3
H
OEt
Me
krel
2.6
2.2
1.9
1.3
1
0.54
0.31
Scheme
2 Comparision of reaction rates. Combined yields of all isomers,
products 3qb–3sb, which were exclusively functionalized
adjacent to the fluoro group. In summary, the C–H arylation of
electron-rich arenes exhibits meta-selectivity. High ortho-
determined by GC using dodecane as an internal standard, were used for kinetic
plots. σp = Hammett constant. krel = Relative reaction rate vs k(R=H)
.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 11
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
(Figure S14–21). Notably, the Pd(OAc)2-based catVaielywtAicrticslyesOtnelimne
DOI: 10.1039/D0SC05414C
Standard kinetic isotope effect (KIE) experiments were without any external ligand (Table 1, entry 3) also exhibits
conducted using benzene 1g and benzene-d6 1g-d6 to gain
additional insight into the rate-limiting step (Scheme 3a). The
observed large primary KIE (kH/kD = 4.4) suggests that the C–H
bond cleavage step is involved in the rate-limiting step. This is
in agreement with that previously reported,26-27 implying the
involvement of C–H bond cleavage in the rate-limiting step. The
dependence of the reaction rate on [Pd], [ArBr], KOPiv and
K2CO3 was comprehensively investigated (Scheme 3b). A first-
order dependence with respect to [Pd] and a zero-order with
respect to [ArBr] and K2CO3 were observed. A positive
dependence of the reaction rate on KOPiv was observed,31 but
undesired homocoupling and hydrodebromination of 2b were
observed using higher amounts of pivalate (>0.2 equiv), which
retarded the reaction (Table 1, entry 9). These results indicate
that the C–H bond cleavage step follows the Pd–pivalate-
promoted CMD pathway.
Following the initial mechanistic studies, a mechanistic
outline involving Pd–pivalate-promoted C–H bond cleavage was
constructed. For the Pd-catalyzed C–H arylation reaction, two
pathways can be operative: (1) The originally proposed Pd(0/II)
monometallic mechanism (Scheme 4, top pathway) or (2) a
cooperative bimetallic mechanism (Scheme 4, bottom
pathway), based on the literature precedent.20, 24-26 As outlined
in Scheme 4, the most distinguishable difference between the
monometallic and cooperative bimetallic processes is the
presence of a transmetalation step that only exists in the
bimetallic mechanism. Stahl32 and Hong26 have previously
proposed that a Pd-catalyzed arylation reaction operated by a
cooperative bimetallic pathway can display a first-order
dependence at high [Pd], but second-order dependence at low
[Pd], where the transmetalation step becomes the rate-limiting
step. The second-order dependence can be more pronounced
in the deuterated substrate because the slower rate of C–D
bond cleavage significantly lowers [Pd–Ar] and thus, further
decelerates the rate of the transmetalation step. In previous
Pd–diimine catalyzed C–H arylations of simple arenes, we
proposed that the rigid bidentate diimine ligand drives the
cooperative bimetallic pathway because an open coordination
site for the C–H bond of the arene is required to undergo the
CMD process for the monometallic pathway to be operative. In
regard the current Pd catalytic system, we conjectured a
monometallic CMD pathway in operation because there is no
strongly coordinating ligand such as a diimine or electron-rich
phosphine present. To verify the operative catalytic cycle, we
investigated the dependence of the reaction rate at low
concentrations of Pd(CH3CN)2Cl2 in benzene-d6 (Scheme 4c). To
our astonishment, the kinetic study revealed the second-order
Scheme 3 Mechanistic studies.
dependence at very low [Pd], strongly supporting that the
reaction follows a cooperative bimetallic mechanism (Scheme
4b). Inspired by the results, we performed extensive kinetic to
determine whether the cooperative bimetallic mechanism is
generally operative. Second-order kinetics were consistently
observed at low concentrations of Pd(OAc)2 in the presence of
various phosphine ligands (DavePhos, PCy3, PPh3, and P(C6F5)3)
second order kinetics at very low concentrations of Pd(OAc)2
(Figure S13), indicating that the cooperative bimetallic pathway
is generally working in the Pd-catalyzed arylation of simple
arenes with aryl bromides under CMD conditions.
With evidence for the cooperative bimetallic mechanism in
hand, we attempted to elucidate the origin of the observed site-
selectivity. The meta-selectivity observed for many electron-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 6 of 11
ARTICLE
Journal Name
rich and electron-deficient arenes (Table 2) was unexpected, fluorobenzene, the site-selectivity slightly changed when using
View Article Online
DOI: 10.1039/D0SC05414C
2b and 2j. In the arylation of chlorobenzene, the site-selectivity
counter-intuitive, and contrary to previous reports suggesting
Scheme 5 C–H arylation of fluorobenzene and chlorobenzene with two different
aryl bromides.
was significantly varied from 46% meta-selectivity with 2b to
61% ortho-selectivity with 2j, supporting the validity of the
hypothesis that the C–H activation step is not the selectivity-
determining step.
To scrutinize which elementary step is the selectivity-
determining step, we first checked the reversibility of the
oxidative addition and the C–H cleavage steps. A competition
experiment was carried out using electronically different sets of
aryl bromides (Scheme 6a). The reaction was conducted using
2e and electron-rich aryl bromide 2a, while the other reaction
used 2e and electron-deficient aryl bromide 2i as the competing
substrate. In the former reaction, similar yields of 3ae and 3aa
were observed in a combined 54% yield. In contrast, only a trace
amount of 3ae was produced in the presence of 2i, and 3ai was
formed as the dominant product, albeit in a low yield (10%). If
the oxidative addition were reversible, the coupling reaction
with electron-richer aryl bromide 2e could occur in a reasonable
yield despite the predominant oxidative addition of the
electron-poor substrate 2i 34
. Instead, the observed poor yields
indicate that the oxidative addition step is irreversible. We
hypothesized that the electron-poor substrates exhibit poor
yields, despite the predominant oxidative addition, due to the
transmetalation step. The same trend of lower reactivity with
electron-poor aryl bromides was observed when examining the
substrate scope (Table 3, 2i–2l). Subsequently, deuterium
exchange reactions were carried out with stoichiometric
amounts of ethoxybenzene (1b) in the presence of D2O and
benzene-d6 (3a-d6), respectively, to confirm the reversibility of
the C–H bond cleavage step (Scheme 6b). Deuterium
incorporations in the aryl group of 3ab (10.2 and 6.4%,
Scheme 4 Mechanistic hypothesis and kinetic studies.
the CMD step is both the rate-limiting and selectivity-
determining step based on a monometallic mechanism.21a, 33
Because the C–H bond cleavage step is independent of the
oxidative addition of aryl bromides in the cooperative bimetallic
mechanism, the dependence of the selectivity on the electronic
effect of aryl bromides with ethoxybenzene (Table 3) indicates
that the C–H activation step is not the selectivity-determining
step. The site-selectivity distribution was further investigated
using electron-poor arenes, such as fluorobenzene (1i) and
chlorobenzene (1k), in the C–H arylation with two electronically
different aryl bromides (2b and 2j) under stoichiometric
conditions (Scheme 5). In the case of highly ortho-selective
2
respectively) via H/D scrambling were observed using H NMR
spectroscopy. If the C–H bond cleavage by the Pd–pivalate
species were irreversible, deuterium incorporation into 3ab
would not occur. These results strongly support the reversibility
of the C–H activation step. Therefore, the following steps,
transmetalation or reductive elimination, may govern the site-
selectivity of the reaction.
Stoichiometric reactions with arylpalladium complexes,
which are analogous intermediate, were designed to
affirmatively validate the cooperative bimetallic mechanism
and further explore the selectivity-determining step. Two
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 11
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
different arylpalladium pivalate complexes bearing either achieved by the cooperative bimetallic mechanism. When
View Article Online
electron-rich or electron-poor aryl groups (4a and 4b) were
complex 4b containing an o-chlorophenyDl gOrIo: 1u0p.10w3a9s/Ds0uSbCj0e5c4t1e4dC
Table 4 Stoichiometric reaction of Pd complexesa
Entry
[Pd]
Additive (equiv)
Yield of
3ac or
3am (%)
Selectivity
(o / m / p)
%
Selectivity
(o / m / p)
1
2
3
4a
4a
4a
None
0
-
-
PivOH (20), K2CO3 (160)
PivOH (20), K2CO3 (160),
nBu4NBr (10)
0.6
21
1 / 0.7 / 0.7
1 / 1.3 / 1.4
42 / 30 / 28
27 / 35 / 38
4
5
4a
4a
PivOH (20), K2CO3 (160),
Pd(CH3CN)2Cl2 (5)
PivOH (20), K2CO3 (160),
nBu4NBr (10),
26
65
1 / 0.8 / 1.6
1 / 6.2 / 2.6
29 / 24 / 47
10 / 64 / 26
Pd(CH3CN)2Cl2 (5)
PivOH (20), K2CO3 (160),
nBu4NBr (10)
6
7
4b
4b
7
1 / 0.1 / 0.1
1 / 0.7 / 0.4
84 / 8 / 8.0
48 / 33 / 19
PivOH (20), K2CO3 (160),
nBu4NBr (10),
65
Scheme 6 Competition experiments.
Pd(CH3CN)2Cl2 (5)
aThe total yield and regioselectivity (ortho / meta / para) were determined by GC
analysis of the reaction mixture using dodecane as an internal standard.
to the stoichiometric reactions, the selectivities observed in the
products 3am were completely different from those observed
with 4a. A high ortho-selectivity (84%), albeit in a low yield (7%),
was observed in the absence of an additional Pd complex (entry
6). Notably, when an additional Pd source was added, the ortho-
selectivity significantly decreased (from 84 to 48%) with
increased meta-selectivity (from 8 to 33%, entry 7). If the
reaction would follow a monometallic mechanism, the reaction
efficiency and selectivity would not vary significantly, regardless
of the addition of an external Pd complex. These results
consistently support that the reaction majorly operates via a
cooperative bimetallic mechanism and the C–H bond cleavage
step was not the selectivity-determining step because the C–H
activation is independent of the electronics of the aryl groups of
the arylpalladium species under the cooperative bimetallic
mechanism.
Scheme 7 Synthesis of arylpalladium pivalate complexes.
prepared upon the reaction of Pd(dba)2 with PtBu335 in neat aryl
iodide, followed by ligand exchange from iodide to pivalate
using AgOPiv (Scheme 7).28 The solid-state structure of Pd
complex 4b was confirmed by single-crystal X-ray diffraction
analysis (CCDC 2000400). Complex 4a containing the o-tolyl
group was subjected to stoichiometric reactions with
ethoxybenzene in DMA (Table 4). The reaction did not provide
the desired product 3ac in the absence of any additive (entry 1).
The addition of PivOH, K2CO3, and a bromide source increased
the reactivity up to 21%; however, the resulting meta-selectivity
was significantly low (30 and 35%, entries 2 and 3). In contrast,
when an additional Pd source, Pd(CH3CN)2Cl2, was added, the
meta-selectivity increased (24% and 64%, entries 4 and 5) to a
level similar to that observed under the standard conditions
using PtBu3 (65% meta-selectivity, Table 1, entry 2). These
results strongly suggest that meta-selectivity can be only
Notably, the effect of the cation in the carbonate base on
the site-selectivity of the C–H arylation of ethoxybenzene (1a
)
was observed (Table 1, entry 10). The cation effect was further
investigated upon the addition of 18-crown-6 under the
standard reaction conditions.36 As the amount of 18-crown-6
increased, the meta-selectivity in the C–H arylation of
ethoxybenzene gradually decreased (from 71 to 39%, Table 5).
Same phenomenon was also observed in the C–H arylation of
toluene
(1c), excluding the effect of potential cation-
ethoxybenzene interactions on the meta-selectivity (Table S17).
Amatore and Jutand demonstrated that counterion of the base
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 8 of 11
ARTICLE
Journal Name
can affect the rate of transmetalation by coordinating the previous studies on the reductive elimination processes
View Article Online
countercation to the Pd intermediate in Pd-catalyzed Suzuki– occurring in Pd-catalyzed biaryl crossD-cOoIu: 1p0l.i1n0g39/rDe0aScCt0io5n41s4.3C9
Miyaura cross-coupling reactions.37 Although we do not fully
Thus, we concluded that the transmetalation step is the
selectivity-
Table 5 Impact of crown ether additives on the C–H arylation reactiona
Table 6 Investigation of reductive elimination processes
Entry
18-crown-6
(x equiv)
Yielda (%)
Selectivity
(o / m / p)
% Selectivity
(o / m / p)
DFT calculateda
Experimental
%Selectivity
Arylation site
%Selectivity
(o / m / p)
∆G
∆G‡
∆∆G‡b
∆∆G‡b
(o / m / p)
1
2
3
4
5
6
-
79
91
90
85
80
59
1 / 10.2 / 3.2
1 / 8.0 / 2.6
1 / 4.4 / 1.9
1 / 2.8 / 1.5
1 / 2.0 / 1.4
1 / 1.4 / 1.2
7 / 71 / 22
9 / 69 / 22
14 / 60 / 26
19 / 53 / 28
23 / 47 / 30
29 / 39 / 32
Fluorobenzene
ortho
0.3
1
−5.0
−8.1
−7.0
13.3
12.2
13.6
0
0
meta
−1.1
0.3
(18 / 70 / 12)
1.3
3.0
(88 / 10 / 2)
2.5
5
para
Chlorobenzene
ortho
10
−3.3
−5.1
−6.8
14.2
13.9
12.5
0
0
aReaction conditions: 2a (0.2 mmol), 1a (60 equiv), Pd(CH3CN)2Cl2 (3 mol %), PivOH
(0.3 equiv), K2CO3 (2.5 equiv), 18-crown-6, and DMA (1.2 mL) at 120 °C for 18 h;
The total yield and regioselectivity (ortho / meta / para) were determined by GC
analysis of the reaction mixture using dodecane as an internal standard.
meta
−0.3
−1.7
(9 / 14 / 77)
–0.3
0.4
(34 / 46 / 20)
para
aFree energies in solution (kcal/mol) obtained at the B3LYP-D3(IEFPCM)/SDD/6-
311++G**//B3LYP-D3/LanL2DZ/6-31G** level of theory.40 bThe value obtained
using ΔG‡(ortho) – ΔG‡(position). A negative value indicates the lower energy
understand the Pd species involved in the transmetalation step,
the results indicate that a potassium cation can affect the site- barrier of the C-position than the ortho-position. Ar = 3,5-Dimethylphenyl.
selectivity in the transmetalation process rather than the
reductive elimination process.
determining step based on the overall observations and control
experiments. Due to the nature of the transition state and
intermediate in the transmetalation step still being
unknown,39a, 39b, 41 attempts to predict the site-selectivity using
computational studies were unsuccessful.
A summary of the investigated mechanism is illustrated in
Scheme 1. The Pd catalytic system without an external ligand
operates via a cooperative bimetallic mechanism. One Pd–Ar
Reductive elimination is a common process in transition-
metal catalysis and its mechanism is well understood.38 The
reductive elimination of [Pd(II)]ArAr’ complexes to form biaryls
has been thoroughly examined as a facile and irreversible
process, particularly at our reaction temperature of 120 °C.39 It
is less likely to be the selectivity-determining step of the
reaction. To confirm it further, we conducted DFT modelling of
the reductive elimination pathways to check whether the
reductive elimination process theoretically produces the
experimentally observed site-selectivity. C–H arylations of
fluorobenzene and chlorobenzene using 2b were selected as
model reactions for the computational studies. Scheme 5 shows
fluorobenzene and chlorobenzene undergo the arylation
reaction to produce biaryls 3ib (96%) with 88% ortho-selectivity
and 3kb (32%) with 46% meta-selectivity, respectively. To
compare with the experimental results, the reductive
elimination processes for each isomeric position were
calculated (Table 6 and Figure S23). The Gibbs free energy
changes (ΔG), energy barriers (ΔG‡), and energetic differences
(ΔΔG‡) are listed in Table 6. In the case of fluorobenzene, the
reductive elimination at the meta-position is preferred over at
the ortho-position, as indicated by the negative ΔΔG‡ value (–
1.1 kcal/mol). In the case of chlorobenzene, the para-position is
the most reactive in the reductive elimination process with a
negative ΔΔG‡ value of –1.7 kcal/mol. The obtained theoretical
selectivities, assuming the reductive elimination step is the
selectivity-determining step, are completely different from the
experimental results. Therefore, the possibility of the reductive
elimination being the site-selectivity determining step is
excluded using the computational investigations and the
species
of the aryl bromide (ArBr) to Pd(0)
species is generated from the rate-limiting C–H bond cleavage
of the arene (Ar’H) by Pd(II)–pivalate species . Both Pd species
and ) undergo transmetalation to afford Pd(II)ArAr’ and
regenerate Pd(II)–pivalate species Importantly, the
B
is generated from the irreversible oxidative addition
A
, while another Pd–Ar’
D
C
(B
D
E
C
.
transmetalation step is disclosed to be the selectivity-
determining step with the help of a potassium cation after the
reversible C–H activation step. Finally, the reductive elimination
of Pd(II)ArAr’
Pd(0) species
E
A
affords the desired biaryl product and the initial
, which then re-enters the catalytic cycle.
Conclusions
In conclusion, we have comprehensively investigated the scope and
site-selectivity of the Pd-catalyzed direct C–H arylation of simple
arenes using aryl bromides as a coupling partner. The site-selectivity
of the C–H arylation reaction is affected by the steric effect of the
substituents on the arene as well as the C–H bond acidity. Generally,
electron-rich arenes exhibit meta-selectivity. Although electron-
deficient arenes bearing fluoro or cyano groups result in high ortho-
selectivity, electron-deficient arenes bearing bulky electron-
withdrawing groups produce the meta-isomer as the major product.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 11
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
Hernández, J. N. Arokianathar and I. Larrosa, J. Am. Chem. Soc., 2016,
138, 3596-3606; (e) X. C. Cambeiro, N. AhlstDeOnIa: n10d.1I0.3L9a/rDro0SsaC,0J5.4A14mC.
Chem. Soc., 2015, 137, 15636-15639.
Thorough mechanistic investigations, including kinetic studies,
control experiments, and stoichiometric reactions with arylpalladium
complexes, suggest that the reaction follows a cooperative bimetallic
mechanism. Notably, the transmetalation step, which is influenced
by a cation, is identified as the selectivity determining step, which
refutes the previous understanding that the C–H bond cleavage step
determines the site-selectivity in the reaction.
View Article Online
(8) (a) P. Wang, M. E. Farmer, X. Huo, P. Jain, P.-X. Shen, M. Ishoey, J.
E. Bradner, S. R. Wisniewski, M. D. Eastgate and J.-Q. Yu, J. Am. Chem.
Soc., 2016, 138, 9269-9276; (b) T. W. Lyons and M. S. Sanford, Chem.
Rev., 2010, 110, 1147-1169; (c) Y. Aihara and N. Chatani, Chem. Sci.,
2013, 4, 664-670; (d) S. Rej, Y. Ano and N. Chatani, Chem. Rev., 2020,
120, 1788-1887; (e) D. Kalyani, K. B. McMurtrey, S. R. Neufeldt and
M. S. Sanford, J. Am. Chem. Soc., 2011, 133, 18566-18569; (f) R. J.
Phipps and M. J. Gaunt, Science, 2009, 323, 1593-1597.
(9) (a) A. M. Wagner, A. J. Hickman and M. S. Sanford, J. Am. Chem.
Soc., 2013, 135, 15710-15713; (b) C.-L. Ciana, R. J. Phipps, J. R. Brandt,
F.-M. Meyer and M. J. Gaunt, Angew. Chem. Int. Ed., 2011, 50, 458-
462.
(10) L. T. Ball, G. C. Lloyd-Jones and C. A. Russell, Science, 2012, 337,
1644-1648.
(11) R. G. Kalkhambkar and K. K. Laali, Tetrahedron Lett., 2011, 52,
5525-5529.
(12) Y.-X. Luan, T. Zhang, W.-W. Yao, K. Lu, L.-Y. Kong, Y.-T. Lin and M.
Ye, J. Am. Chem. Soc., 2017, 139, 1786-1789.
(13) (a) A. Martins, B. Mariampillai and M. Lautens, Top. Curr. Chem.,
2010, 292, 1-33; (b) J. Wang and G. Dong, Chem. Rev., 2019, 119,
7478-7528; (c) M. Catellani, F. Frignani and A. Rangoni, Angew.
Chem., Int. Ed., 1997, 36, 119-122.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank Jangwoo Koo for helping with the preliminary study,
and Jungwon Kim and Geon Seok Lee for their help with the
computational analyses. This work was supported by the
National
Research
Foundation
of
Korea
(NRF-
2019R1A2C2086875; NRF-2014R1A5A1011165, Center for New
Directions in Organic Synthesis; NRF-2018R1D1A1B07049976)
and the Korea Institute of Science and Technology Information
with supercomputing resources including technical support
(KSC-KSC-2018-CHA-0068 and KSC-2019-CRE-0182).
(14) (a) L.-Y. Liu, J. X. Qiao, K.-S. Yeung, W. R. Ewing and J.-Q. Yu,
Angew. Chem. Int. Ed., 2020, 59, 13831-13835; (b) L.-Y. Liu, J. X. Qiao,
K.-S. Yeung, W. R. Ewing and J.-Q. Yu, J. Am. Chem. Soc., 2019, 141,
14870-14877.
Notes and references
(15) J. Luo, S. Preciado and I. Larrosa, J. Am. Chem. Soc., 2014, 136,
4109-4112.
(16) A. D. Ryabov, I. K. Sakodinskaya and A. K. Yatsimirsky, J. Chem.
Soc., Dalton Trans., 1985, 2629-2638.
(17) M. Gómez, J. Granell and M. Martinez, Organometallics, 1997,
16, 2539-2546.
(18) D. L. Davies, S. M. A. Donald and S. A. Macgregor, J. Am. Chem.
Soc., 2005, 127, 13754-13755.
(19) (a) A. P. Walsh and W. D. Jones, Organometallics, 2015, 34, 3400-
3407; (b) Y. Tanji, N. Mitsutake, T. Fujihara and Y. Tsuji, Angew. Chem.
Int. Ed., 2018, 57, 10314-10317; (c) D. Lapointe and K. Fagnou, Chem.
Lett., 2010, 39, 1118-1126; (d) K. M. Engle, D.-H. Wang and J.-Q. Yu,
J. Am. Chem. Soc., 2010, 132, 14137-14151.
(20) M. Lafrance and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 16496-
16497.
(21) (a) S. I. Gorelsky, D. Lapointe and K. Fagnou, J. Org. Chem., 2012,
77, 658-668; (b) M. Lafrance, C. N. Rowley, T. K. Woo and K. Fagnou,
J. Am. Chem. Soc., 2006, 128, 8754-8756; (c) S. I. Gorelsky, Coord.
Chem. Rev., 2013, 257, 153-164.
(1) (a) J. Hassan, M. Sévignon, C. Gozzi, E. Schulz and M. Lemaire,
Chem. Rev., 2002, 102, 1359-1470; (b) D. J. C. Constable, P. J. Dunn,
J. D. Hayler, G. R. Humphrey, J. L. Leazer, Jr., R. J. Linderman, K.
Lorenz, J. Manley, B. A. Pearlman, A. Wells, A. Zaks and T. Y. Zhang,
Green Chem., 2007, 9, 411-420; (c) D. Alberico, M. E. Scott and M.
Lautens, Chem. Rev., 2007, 107, 174-238.
(2) (a) R. Taylor, Electrophilic aromatic substitution, J. Wiley,
Chichester, West Sussex, England; New York, 1990; (b) F. A. Carey
and R. J. Sundberg, Advanced Organic Chemistry: Part B: Reaction
and Synthesis, Springer, 5th edition edn., 2010.
(3) C. Friedel and J. Crafts, J. Chem. Soc., 1877, 32, 725-791.
(4) (a) C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot and
V. Snieckus, Angew. Chem. Int. Ed., 2012, 51, 5062-5085; (b) H. Bohra
and M. Wang, J. Mater. Chem. A, 2017, 5, 11550-11571; (c) D. A.
Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103, 893-
930; (d) G. P. McGlacken and L. M. Bateman, Chem. Soc. Rev., 2009,
38, 2447-2464; (e) X.-Y. Chen, X.-X. Nie, Y. Wu and P. Wang, Chem.
Commun., 2020, 56, 5058-5061; (f) M. Font, A. R. A. Spencer and I.
Larrosa, Chem. Sci., 2018, 9, 7133-7137.
(22) (a) Y.-N. Wang, X.-Q. Guo, X.-H. Zhu, R. Zhong, L.-H. Cai and X.-F.
Hou, Chem. Commun., 2012, 48, 10437-10439; (b) Q. Zhou, Y.-N.
Wang, X.-Q. Guo, X.-H. Zhu, Z.-M. Li and X.-F. Hou, Organometallics,
2015, 34, 1021-1028.
(23) (a) D. García-Cuadrado, A. A. C. Braga, F. Maseras and A. M.
Echavarren, J. Am. Chem. Soc., 2006, 128, 1066-1067; (b) D. García-
Cuadrado, P. de Mendoza, A. A. C. Braga, F. Maseras and A. M.
Echavarren, J. Am. Chem. Soc., 2007, 129, 6880-6886.
(24) Y. Tan, F. Barrios-Landeros and J. F. Hartwig, J. Am. Chem. Soc.,
2012, 134, 3683-3686.
(5) (a) C. Verrier, P. Lassalas, L. Théveau, G. Quéguiner, F. Trécourt, F.
Marsais and C. Hoarau, Beilstein J. Org. Chem., 2011, 7, 1584-1601;
(b) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem. Int.
Ed., 2009, 48, 5094-5115; (c) G. C. Fu, Acc. Chem. Res., 2008, 41,
1555-1564.
(6) (a) L. Joucla and L. Djakovitch, Adv. Synth. Catal., 2009, 351, 673-
714; (b) L. Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem. Int.
Ed., 2009, 48, 9792-9826; (c) R. J. Phipps, N. P. Grimster and M. J.
Gaunt, J. Am. Chem. Soc., 2008, 130, 8172-8174; (d) L. Wang and B.
P. Carrow, ACS Catal., 2019, 9, 6821-6836.
(25) S. I. Gorelsky, Organometallics, 2012, 31, 4631-4634.
(26) J. Kim and S. H. Hong, ACS Catal., 2017, 7, 3336-3343.
(27) L.-C. Campeau, S. Rousseaux and K. Fagnou, J. Am. Chem. Soc.,
2005, 127, 18020-18021.
(7) (a) D. Whitaker, J. Burés and I. Larrosa, J. Am. Chem. Soc., 2016,
138, 8384-8387; (b) O. René and K. Fagnou, Org. Lett., 2010, 12,
2116-2119; (c) L. Zhou and W. Lu, Organometallics, 2012, 31, 2124-
2127; (d) M. Simonetti, G. J. P. Perry, X. C. Cambeiro, F. Juliá-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 10 of 11
ARTICLE
Journal Name
(28) Y. Tan and J. F. Hartwig, J. Am. Chem. Soc., 2011, 133, 3308-3311.
(29) (a) Y. Tanji, R. Hamaguchi, Y. Tsuji and T. Fujihara, Chem.
Commun., 2020, 56, 3843-3846; (b) L. Caron, L.-C. Campeau and K.
Fagnou, Org. Lett., 2008, 10, 4533-4536.
View Article Online
DOI: 10.1039/D0SC05414C
(30) D. A. Culkin and J. F. Hartwig, Acc. Chem. Res., 2003, 36, 234-245.
(31) The kinetic order could not be precisely determined due to the
solubility issue of KOPiv.
(32) D. Wang, Y. Izawa and S. S. Stahl, J. Am. Chem. Soc., 2014, 136,
9914-9917.
(33) S. I. Gorelsky, D. Lapointe and K. Fagnou, J. Am. Chem. Soc., 2008,
130, 10848-10849.
(34) C. Colletto, S. Islam, F. Juliá-Hernández and I. Larrosa, J. Am.
Chem. Soc., 2016, 138, 1677-1683.
(35) Attempts to synthesize the aryl–Pd complex with acetonitrile or
DMA ligands were unsuccessful, presumably due to limited stability
of the resulting Pd complexes.
(36) S.-C. Sha, S. Tcyrulnikov, M. Li, B. Hu, Y. Fu, M. C. Kozlowski and
P. J. Walsh, J. Am. Chem. Soc., 2018, 140, 12415-12423.
(37) (a) C. Amatore, A. Jutand and G. Le Duc, Chem. Eur. J., 2012, 18,
6616-6625; (b) C. Amatore, G. Le Duc and A. Jutand, Chem. Eur. J.,
2013, 19, 10082-10093.
(38) (a) J. M. Brown and N. A. Cooley, Chem. Rev., 1988, 88, 1031-
1046; (b) V. P. Ananikov, D. G. Musaev and K. Morokuma, J. Am.
Chem. Soc., 2002, 124, 2839-2852.
(39) (a) J. Sherwood, J. H. Clark, I. J. S. Fairlamb and J. M. Slattery,
Green Chem., 2019, 21, 2164-2213; (b) P. Veerakumar, P.
Thanasekaran, K.-L. Lu, K.-C. Lin and S. Rajagopal, ACS Sustainable
Chem. Eng., 2017, 5, 8475-8490; (c) M. Pérez-Rodríguez, A. A. C.
Braga, M. Garcia-Melchor, M. H. Pérez-Temprano, J. A. Casares, G.
Ujaque, A. R. de Lera, R. Alvarez, F. Maseras and P. Espinet, J. Am.
Chem. Soc., 2009, 131, 3650-3657.
(40) (a) C. Lee, W. Yang and R. G. Parr, Phys. Rev. B Condens. Matter,
1988, 37, 785-789; (b) S. Grimme, J. Antony, S. Ehrlich and H. Krieg,
J. Chem. Phys., 2010, 132, 154104.
(41) (a) P. Nilsson, G. Puxty and O. F. Wendt, Organometallics, 2006,
25, 1285-1292; (b) A. L. Casado and P. Espinet, J. Am. Chem. Soc.,
1998, 120, 8978-8985; (c) A. L. Casado, P. Espinet and A. M. Gallego,
J. Am. Chem. Soc., 2000, 122, 11771-11782.
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 11 of 11
Chemical Science
View Article Online
DOI: 10.1039/D0SC05414C
R
R
[Pd]
+
ArBr
Ar
PivOH, K2CO3
Cooperative bimetallic mechanism
Ar
Br
PivOH
Ar'
LnPdII
PdII
Ln
Ar Br
LnPd0
K2CO3
KBr
Ar'
H
reversible
rate-limiting step
Ar
nPdII
L
LnPdII OPiv
Ar Ar'
Ar'
selectivity
determining step
The transmetalation step, not C‒H activation step, is suggested as the selectivity-determining step in Pd-
catalyzed C‒H arylation of simple arenes.