Pd-catalyzed aerobic oxidative coupling of arenes: Evidence for transmetalation between two Pd(II)-aryl intermediates

Article abstract of DOI:10.1021/ja505405u

Pd-catalyzed aerobic oxidative coupling of arenes provides efficient access to biaryl compounds. The biaryl product forms via C-H activation of two arenes to afford a Pd^IIArAr' intermediate, which then undergoes C-C reductive elimination. The key Pd^IIArAr' intermediate could form via a monometallic pathway involving sequential C-H activation at a single Pd^II center, or via a bimetallic pathway involving parallel C-H activation at separate Pd^II centers, followed by a transmetalation step between two Pd^II-aryl intermediates. Here, we investigate the oxidative coupling of o-xylene catalyzed by a PdX ₂/2-fluoropyridine catalyst (X = trifluoroacetate, acetate). Kinetic studies, H/D exchange experiments, and kinetic isotope effects provide clear support for a bimetallic/transmetalation mechanism.

Full text of DOI:10.1021/ja505405u

Communication
pubs.acs.org/JACS
Pd-Catalyzed Aerobic Oxidative Coupling of Arenes: Evidence for
Transmetalation between Two Pd(II)-Aryl Intermediates
Dian Wang, Yusuke Izawa, and Shannon S. Stahl*
Department of Chemistry, University of WisconsinMadison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
boxylate, a monomeric precursor to Upilex.8 In subsequent
ABSTRACT: Pd-catalyzed aerobic oxidative coupling of
arenes provides efficient access to biaryl compounds. The
biaryl product forms via C−H activation of two arenes to
afford a PdIIArAr′ intermediate, which then undergoes C−
C reductive elimination. The key PdIIArAr′ intermediate
could form via a “monometallic” pathway involving
sequential C−H activation at a single PdII center, or via
a “bimetallic” pathway involving parallel C−H activation at
separate PdII centers, followed by a transmetalation step
between two PdII−aryl intermediates. Here, we investigate
the oxidative coupling of o-xylene catalyzed by a PdX2/2-
fluoropyridine catalyst (X = trifluoroacetate, acetate).
Kinetic studies, H/D exchange experiments, and kinetic
isotope effects provide clear support for a bimetallic/
transmetalation mechanism.
decades, numerous additional examples of Pd-catalyzed methods
for oxidative homocoupling of arenes have been reported.3,9 The
vast majority of work in this area has focused on empirical
development of new catalyst systems, but important mechanistic
questions remain unanswered.
A reasonable mechanism for Pd-catalyzed oxidative coupling
of arenes consists of a PdII/Pd0 catalytic cycle with three general
steps (Scheme 1): (i) PdII-mediated activation of two aryl C−H
Scheme 1. Pd-Catalyzed Aerobic Oxidative Biaryl Coupling
and Two Mechanistic Possibilities for PdArAr′ Formation
he oxidative coupling of hydrocarbons (eq 1) is an
T
important contemporary topic with significant commercial
implications. Prominent targets include the conversion of
methane to higher hydrocarbons and the coupling of arenes to
biaryls. The latter application is relevant to the industrial
production of heat transfer fluids (e.g., biphenyl1) and
monomers for high-performance polymers (e.g., Upilex2).
Moreover, oxidative cross-coupling of arenes represents an
efficient route to unsymmetrical biaryls relevant to the
pharmaceutical, agrochemical, and fine chemical industries.3
PdII catalysts show significant promise in oxidative coupling
reactions as they are eminently compatible with O2 as the
stoichiometric oxidant and therefore could be accomplished with
near-ideal atom economy. Mechanistic understanding of key
steps could facilitate the development of new and/or improved
reactions of this type.4 Here, we address unresolved mechanistic
questions related to C−H activation and C−C bond formation in
the Pd-catalyzed aerobic oxidative homocoupling of o-xylene, a
reaction relevant to Upilex production.5
bonds to produce a PdIIArAr′ intermediate, (ii) reductive
elimination of Ar−Ar′ from PdIIArAr′,10 (iii) and aerobic
oxidation of Pd0 to PdII.11 While the mechanism of arene C−H
activation by PdII has been the focus of considerable
investigation,12 the pathway for formation of PdIIArAr′ is not
clear. At least two different mechanisms are possible. A
“monometallic” mechanism (Scheme 1A) involves sequential
C−H activation at a single PdII center, while a “bimetallic”
mechanism (Scheme 1B) involves parallel C−H activation at two
separate PdII centers followed by transmetalation between the
two PdII−aryl species.
cat.
R−H + R′−H + [O] ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ R−R′ + [O]H2
(R,R′ = alkyl, aryl)
(1)
The first example of PdII-mediated oxidative biaryl coupling,
reported by van Helden and Verberg in 1965,6 featured the
oxidative coupling of benzene with stoichiometric PdCl2 and
NaOAc. Within a few years, several groups reported PdII-
catalyzed biaryl coupling methods that used O2 as the oxidant.7
Related catalytic methods were later developed for the
commercial synthesis of 3,4,3′,4′-tetramethyl biphenyltetracar-
The “monometallic” mechanism has been commonly invoked
in recent reports, especially in the context of Pd-catalyzed
oxidative cross-coupling reactions,13 and C−H activation of
arenes by PdIIArX species has been studied experimentally14 and
Received: May 29, 2014
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
computationally.15 The bimetallic pathway was suggested in
1968 by Davidson and Triggs;16 however, no experimental data
were provided to support the proposal and few subsequent
reports consider this pathway.17 Transmetalation of an aryl
group between well-defined PdII−aryl species has been
investigated,18 but its direct relevance to oxidative biaryl coupling
has not been established.
Our mechanistic studies focus on the recently reported aerobic
homocoupling of o-xylene with a PdX2/2Fpy catalyst system [X =
TFA (trifluoroacetate) or OAc (acetate), 2Fpy = 2-fluoropyr-
idine].5b This reaction proceeds with high selectivity to the
symmetrical biaryl product shown in Figure 1. Kinetic studies
Figure 2. Kinetic isotope effects derived from initial rate measurements
(ν) for oxidative coupling of o-xylene. Reaction conditions: [arene] = 4.5
M (4 mmol), [Pd] = 22.5 mM (0.02 mmol), solvent (0.4 mL), O2 (1
atm), 80 °C, 0−4 h.
Figure 1. Kinetic dependence of the rate of Pd-catalyzed oxidative
coupling of o-xylene on [Pd]. Reaction conditions: [o-xylene] = 4.5 M (4
mmol), [Pd] = 2−50 mM (0.0016−0.04 mmol), HOAc (0.4 mL), O2 (1
atm), 80 °C, 0−4 h.
were carried out to establish the dependence of the reaction rate
on [Pd] (2−50 mM, 0.04−1.0 mol % with respect to o-xylene)
(Figure 1). Initial rates of the reactions, monitored by gas
chromatography, reveal a second-order dependence at low [Pd]
(≤5 mM; inset, Figure 1) and a first-order dependence at high
[Pd] (≥15 mM; Figure 1). To our knowledge, this is the first
observation of a second-order [Pd] dependence in oxidative
biaryl coupling, and it provides preliminary support for the
bimetallic mechanism in Scheme 1.
Deuterium kinetic isotope effects (KIEs) were evaluated to
gain insight into the contribution of C−H activation to the
overall turnover rate. The oxidative coupling of o-xylene and o-
xylene-d10, monitored independently with 0.5 mol % [Pd] in
HOAc (Figure 2), reveal a very large KIE: kH/kD = 24 2. This
value is significantly larger than KIEs observed previously for Pd-
based oxidative biaryl coupling reactions (kH/kD ≈ 2−5).19 The
reaction was also performed in DOAc to probe solvent isotope
Figure 3. (A) H/D exchange experiments at 0.5 mol % [Pd] (B) H/D
exchange and product yields at different [Pd]. Reaction conditions: [o-
xylene-d10] = 4.5 M (4 mmol), [Pd] = 5−25 mM (0.0045−0.0225
mmol), HOAc (0.4 mL), O2 (1 atm), 80 °C, 17 h.
occurs exclusively at aromatic positions and favors exchange at
meta positions.20 The 2:1 meta/ortho regioselectivity for H/D
exchange is substantially lower than the regioselectivity of biaryl
product formation, which exhibits ∼10:1 selectivity for meta−
meta over ortho−meta coupling (ortho−ortho coupling is not
observed).
The above data led us to undertake a more systematic
assessment of kinetic isotope effects as a function of [Pd].
Substrate and solvent KIEs were determined at four different
[Pd] (2.5−67.5 mM, 0.06−1.5 mol % of substrate) (Figure 4; see
Supporting Information for individual kinetic plots), and the data
reveal that the substrate KIE can vary from 7.9 to 25, depending
on the [Pd] and solvent (HOAc vs DOAc) (Figure 4A). The
reciprocal of the solvent KIE (i.e., kDOAc/kHOAc) varies similarly
from 3.1 to 23 (Figure 4B). At least three general trends are
worth noting. The substrate KIEs are significantly larger in
HOAc (KIE = 18−25) than in DOAc (KIE = 7.9−12). The
reciprocal solvent KIEs increase significantly as the [Pd] is
lowered and also are substantially larger with o-xylene-d10 than
with o-xylene.
effects, and a significant inverse KIE was observed: kHOAc/kDOAc
=
0.31 0.02 (Figure 2).
Further insights into PdII-mediated C−H activation and the
origin of the substrate and solvent isotope effects were obtained
from H/D exchange experiments. The reaction of o-xylene-d10 in
HOAc (0.5 mol % [Pd]) shows that H/D exchange occurs ∼30-
fold faster than biaryl product formation (Figure 3A); however,
this ratio changes at different [Pd]. For example, H/D exchange
is favored over biaryl formation by a ratio of ∼120:1 at 0.1 mol %
[Pd]. Plots of H/D exchange and biaryl product yields show that
H/D exchange exhibits a first-order dependence on [Pd] while
biaryl product formation is second-order in [Pd] (Figure 3B).
The latter observation complements the second-order [Pd]-
dependence data at low [Pd], shown in Figure 1. H/D exchange
Collectively, the kinetic data, KIEs, and H/D-exchange results
clearly distinguish between the two possible mechanisms in
Scheme 1. Rate laws derived for both mechanisms (eqs 2−4; see
B
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Journal of the American Chemical Society
Communication
intermediate) requires only a single Pd species, while the
competing transmetalation process requires two LnPdArX
intermediates. The higher regioselectivity observed for biaryl
product formation relative to H/D exchange suggests that the
transmetalation step exhibits a strong preference for meta- rather
than ortho-substituted PdII-xylyl intermediates. Further, this
transmetalation selectivity is higher than the selectivity of PdII-
mediated C−H activation. These observations have important
implications for controlling the regioselectivity of oxidative C−
H/C−H coupling reactions.21
Finally, the bimetallic mechanism explains the unusually large
KIE values observed for this reaction. The largest substrate KIEs
will be obtained when transmetalation is rate-limiting because
the isotope effect associated with C−H activation (k1′) is squared
(eq 4). The reversibility of the C−H cleavage does not reduce the
KIE because the acidic solvent means that k−1′ is the same for
both substrate isotopologs (Scheme 1B and eq 4). Previously
reported KIEs for PdII-mediated arene C−H activation vary from
3 to 5,22 which corresponds to a net KIE of 9−25 when this value
is squared. Therefore, the KIEs of 18−25 in Figure 4A are not
unusual and fit in the range expected for a bimetallic mechanism
when transmetalation is rate-limiting.23 Under conditions that
lead to rate-limiting C−H activation, the KIE will approach the
intrinsic isotope effect associated with C−H activation (i.e., 3−
5). We never fully reach this limit under the conditions of our
experiments, and the lowest KIE that we observe is 7.9 (Figure
4A).
Inverse solvent isotope effects are evident in all of the reactions
described here, and they arise from faster protonolysis of the
LnPdArX intermediate by HOAc relative to DOAc. The slower
protonolysis with DOAc will lead to a higher steady-state
concentration of the LnPdArX intermediate and result in a higher
rate of product formation via transmetalation from this species.
The inverse solvent KIE will be most substantial when
transmetalation is rate-limiting. Under these conditions, C−H
activation is reversible, and the isotope effect associated with
protonolysis of LnPdArX (k‑1′) is squared in the denominator of
eq 4 (because two LnPdArX species are needed for the
transmetalation step). This scenario is favored when [Pd] is
low and o-xylene-d10 is the substrate, as evident in Figure 4B.
Both conditions reduce the steady-state concentration of
LnPdArX.24
This mechanistic study of aerobic oxidative coupling of o-
xylene with the PdX2 (X = OAc, TFA)/2Fpy catalyst system
provides clear evidence for a bimetallic/transmetalation
mechanism. Evidence for this pathway includes a bimolecular
kinetic dependence on [Pd] (Figure 1) and unusually large
substrate and solvent KIEs (Figures 2 and 4). The bimetallic
mechanism, but not the monometallic mechanism, readily
accommodates these observations. The insights obtained from
the relatively simple catalytic reaction described here provide an
important foundation for future studies of more complex Pd-
catalyzed oxidative biaryl coupling reactions, such as those that
employ redox-active cocatalysts (e.g., CuII and polyoxometa-
lates), as well as cross-coupling reactions between two different
arenes.
Figure 4. Substrate and solvent KIE values at different [Pd]. Reaction
conditions: [arene] = 4.5 M (4 mmol), [Pd] = 2.7−67.5 mM (0.0024−
0.06 mmol), solvent (0.4 mL), O2 (1 atm), 80 °C.
SI for derivations) show that the monometallic mechanism
always exhibits a first-order dependence on [Pd], while the
bimetallic mechanism could have a first-order or second-order
dependence on [Pd], depending on the identity of the rate-
limiting step. The switch from second-order to first-order kinetic
behavior as [Pd] is increased (cf. Figure 1) provides support for
the bimetallic mechanism. At low [Pd], a lower steady-state
concentration of the [LnPdIIArX] intermediate leads to rate-
limiting transmetalation (cf. eq 4). At higher [Pd], the bimetallic
transmetalation rate will increase faster than the unimolecular
C−H activation step, and C−H activation can become rate-
limiting.
Rate law for Monometallic mechanism:
k1k2[Pd][ArH]2
d[ArAr]/dt =
≈ kobs[Pd]
k−1[HX] + k2[ArH]
(2)
Rate law for Bimetallic mechanism (rate-limiting C−H
activation):
d[ArAr]/dt = k1′/2[Pd][ArH] ≈ kobs[Pd]
(3)
Rate law for Bimetallic mechanism (rate-limiting trans-
metalation):
(k1′)2k2′[Pd]2[ArH]2
d[ArAr]/dt =
≈ kobs[Pd]2
(k−1′)2[HX]2
ASSOCIATED CONTENT
(4)
■
S
* Supporting Information
The bimetallic mechanism in Scheme 1 also rationalizes the
H/D exchange results. Under the conditions of the experiments
depicted in Figure 3, H/D exchange is more prominent at lower
[Pd] because this process (i.e., protonolysis of a LnPdArX
Experimental procedures, reaction time courses, additional
mechanistic experiments and discussion. This material is
available free of charge via the Internet at http://pubs.acs.org.
C
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Journal of the American Chemical Society
Communication
5837. (f) Liu, B.; Huang, Y.; Lan, J.; Song, F.; You, J. Chem. Sci. 2013, 4,
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AUTHOR INFORMATION
■
Corresponding Author
stahl@chem.wisc.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Paul White for helpful discussion of the reaction
mechanism. Financial support of this work was provided by the
NIH (R01 GM67173) and Mitsubishi Chemical Corporation
(YI). NMR spectroscopy facilities were provided using a
generous gift from Paul J. Bender.
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