On the mechanism of palladium-catalyzed aromatic C-H oxidation

Article abstract of DOI:10.1021/ja1054274

The mechanism of Pd-catalyzed aromatic C-H oxidation chemistry continues to be vigorously discussed. Historically, Pd(II)/Pd(IV) catalysis cycles have been proposed. Herein, we present a detailed study of Pd(OAc)₂-catalyzed aromatic C-H chlorination and propose dinuclear Pd(III) complexes as intermediates. We have identified a succinate-bridged dinuclear Pd(II) complex, which self-assembles during catalysis, as the catalyst resting state. In situ monitoring of catalysis has revealed that chlorination proceeds with turnover-limiting oxidation of a dinuclear resting state, and that acetate ions, liberated during the formation of the catalyst resting state, catalyze the bimetallic oxidation. Informed by reaction kinetics analysis, relevant dinuclear Pd(III) complexes have been prepared and observed to undergo selective C-Cl reductive elimination. Based on the combination of kinetic data obtained during catalysis and explicit structural information of relevant intermediates, we propose a Pd(II)₂/Pd(III)₂ catalysis cycle for Pd(OAc)₂-catalyzed aromatic C-H chlorination.

Full text of DOI:10.1021/ja1054274

Published on Web 09/28/2010
On the Mechanism of Palladium-Catalyzed Aromatic C-H
Oxidation
David C. Powers, Daphne Y. Xiao, Matthias A. L. Geibel, and Tobias Ritter*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
Received June 21, 2010; E-mail: ritter@chemistry.harvard.edu
Abstract: The mechanism of Pd-catalyzed aromatic C-H oxidation chemistry continues to be vigorously
discussed. Historically, Pd(II)/Pd(IV) catalysis cycles have been proposed. Herein, we present a detailed
study of Pd(OAc)2-catalyzed aromatic C-H chlorination and propose dinuclear Pd(III) complexes as
intermediates. We have identified a succinate-bridged dinuclear Pd(II) complex, which self-assembles during
catalysis, as the catalyst resting state. In situ monitoring of catalysis has revealed that chlorination proceeds
with turnover-limiting oxidation of a dinuclear resting state, and that acetate ions, liberated during the
formation of the catalyst resting state, catalyze the bimetallic oxidation. Informed by reaction kinetics analysis,
relevant dinuclear Pd(III) complexes have been prepared and observed to undergo selective C-Cl reductive
elimination. Based on the combination of kinetic data obtained during catalysis and explicit structural
information of relevant intermediates, we propose a Pd(II)2/Pd(III)2 catalysis cycle for Pd(OAc)2-catalyzed
aromatic C-H chlorination.
Introduction
identified, isolated, and characterized the previously unantici-
pated catalyst resting state: a succinate-bridged dinuclear Pd(II)
Palladium typically undergoes two-electron redox chemistry.1
C-H functionalization reactions catalyzed by palladium are
commonly proposed to proceed via either Pd(0)/Pd(II) or Pd(II)/
Pd(IV) redox cycles.2 Pd(IV) intermediates have been suggested
in Pd-catalyzed aromatic C-H oxidation reactions since 1971,3
and Pd(II)/Pd(IV) catalysis cycles have subsequently become
generally accepted as the operative mechanisms for a large class
of Pd-catalyzed oxidation reactions. Over the past 5 years, many
synthetically useful Pd-catalyzed oxidation reactions have been
developed.4-6 Discussion of the mechanisms of these oxidation
reactions has often been based on stoichiometric organometallic
reactions of isolated Pd(IV) model complexes.4g Experimental
support for the viability of Pd(IV) intermediates during catalysis,
however, has not yet been reported,4e and the relevance of the
isolated Pd(IV) complexes to catalysis has not yet been
demonstrated.
(5) For directed C-H oxidations to form C-C bonds, see (a) Daugulis,
O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046–4048. (b)
Hull, K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006,
128, 14047–14049. (c) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem.
Soc. 2007, 129, 6066–6067. (d) Shi, Z.; Li, B.; Wan, X.; Cheng, J.;
Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem., Int. Ed. 2007,
46, 5554–5558. (e) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew.
Chem., Int. Ed. 2008, 47, 1115–1118. (f) Yang, S.-D.; Sun, C.-L.;
Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008,
47, 1473–1476. (g) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2009, 48, 6097–6100. (h) Wang, X.; Truesdale, L.; Yu, J.-Q.
J. Am. Chem. Soc. 2010, 132, 3648–3649. (i) Sun, C.-L.; Li, B.-J.;
Shi, Z.-J. Chem. Commun. 2010, 46, 677–685. C-O bonds, see: (j)
Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 9542–9543. (k) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am.
Chem. Soc. 2004, 126, 2300–2301. (l) Desai, L. V.; Malik, H. A.;
Sanford, M. S. Org. Lett. 2006, 8, 1141–1144. (m) Desai, L. V.;
Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285–
13293. (n) Wang, G.-W.; Yuan, T.-T.; Wu, X.-L. J. Org. Chem. 2008,
73, 4717–4720. (o) Zhang, J.; Khaskin, E.; Anderson, N. P.; Zavalij,
P. Y.; Vedernikov, A. N. Chem. Commun. 2008, 3625–3627. (p) Yu,
W.-Y.; Sit, W. N.; Zhou, Z.; Chan, A. S.-C. Org. Lett. 2009, 11, 3174–
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Chem. Soc. 2006, 128, 9048–9049. (r) Jordan-Hore, J. A.; Johansson,
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In this article we report kinetic data obtained during catalysis,
which implicate a dinuclear palladium complex in oxidation.
Informed by the kinetic data, we have identified and evaluated
a dinuclear Pd(III) complex implicated in catalysis. Interpretation
of relevant kinetic data has been possible because we have
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14530 J. AM. CHEM. SOC. 2010, 132, 14530–14536
10.1021/ja1054274  2010 American Chemical Society

Mechanism of Pd-Catalyzed Aromatic C-H Oxidation
A R T I C L E S
Scheme 1. Oxidative Functionalization of the C-H Bond Could
Proceed via Direct Electrophilic Substitution (A, redox neutral at
Pd), Oxidative Addition To Afford a Dinuclear Pd(III) Complex
Followed by Bimetallic Reductive Elimination (B), or Oxidative
Addition To Afford a Mononuclear Pd(IV) Complex (C) Followed by
Monometallic Reductive Elimination
redox mechanisms for Pd-catalyzed aromatic C-H oxidations.
Each of the three fundamental steps of the proposed Pd(II)/
Pd(IV) redox mechanismsspalladation of aromatic C-H bonds
by Pd(II) to afford Pd(II) aryl complexes,11 oxidation of Pd(II)
aryl complexes to afford Pd(IV) complexes,12 and reductive
elimination of C-C,13 C-O,14 C-Cl,15 and C-F16 bonds from
Pd(IV) complexesshave been independently documented in
stoichiometric organometallic reactions. However, the relevance
of the reported stoichiometric reactions of Pd(IV) complexes
to catalysis has not yet been established by in situ study of
catalysis.
complex. The combination of kinetic and structural information
has allowed, for the first time in the field of Pd-catalyzed
aromatic C-H oxidation, discussion of both structure and
oxidation state of the high-valent palladium complexes relevant
to redox catalysis. We propose a mechanism for Pd(OAc)2-
catalyzed C-H chlorination, which accounts for previously
reported results, including minor byproduct formation (<1%).
Our results suggest that dinuclear Pd(III) intermediates are
relevant in reactions previously believed to proceed via Pd(IV)
complexes.
Pd-catalyzed C-H oxidation reactions are commonly initiated
by C-H metalation to form a Pd-C bond.7 Conceptually,
subsequent oxidative functionalization of the nascent Pd-C
bond can proceed by several different mechanisms (Scheme 1).
Direct electrophilic Pd-C bond cleavage via intermediate A
would proceed without oxidation state change at palladium.8
Alternatively, metal-centered oxidation would afford a high-
valent Pd complex, such as dinuclear Pd(III) intermediate B or
mononuclear Pd(IV) intermediate C, which would afford the
observed products via reductive elimination.
In 2009, we reported C-Cl, C-Br, and C-O reductive
elimination reactions from well-defined dinuclear Pd(III) com-
plexes (1) and proposed that reductive elimination from related
dinuclear Pd(III) complexes may be the product-forming step
in a variety of palladium-catalyzed oxidative C-H functional-
izations (eq 1).17 Deprez and Sanford reported a study of
Pd(OAc)2-catalyzed oxidative C-C bond-forming reactions and
implicated dinuclear Pd intermediates.18 On the basis of these
studies, mechanisms involving dinuclear Pd(III) intermediates
in catalysis are emerging as a viable alternative to previously
accepted mononuclear Pd(IV)-based mechanisms.
Mononuclear Pd(IV) intermediates in Pd-catalyzed C-H
oxidation chemistry were first proposed by Henry in 1971.3
Stock,9 Crabtree,10 and Sanford5k proposed similar Pd(II)/Pd(IV)
Herein, we report an investigation of the mechanism of
Pd(OAc)2-catalyzed acetoxylation and chlorination of 2-phe-
nylpyridine derivatives. We discuss the difficulties inherent in
choosing appropriate model complexes for discussion of the
mechanism of catalysis and present data obtained under condi-
tions relevant to catalysis. Observation and isolation of the
catalyst resting state of chlorination, combined with measure-
ments of reaction kinetics during catalysis has implicated the
intermediacy of dinuclear complexes in the redox cycle of
catalysis. Informed by results obtained by in situ monitoring of
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J. AM. CHEM. SOC. VOL. 132, NO. 41, 2010 14531

A R T I C L E S
Powers et al.
Scheme 2. On the Basis of Stoichiometric Model Complexes,
catalysis, we have studied the organometallic chemistry of
dinuclear Pd(III) complexes relevant to catalysis.
Either Pd(II)/Pd(IV) or Pd(II)2/Pd(III)2 Redox Couples Can Be
Formulated for Pd-Catalyzed C-H Acetoxylation
Results and Discussion
Pd(OAc)2-Catalyzed Aromatic Acetoxylation. Palladium-
catalyzed acetoxylation of benzene was first reported in 1966.19
In 1971, Henry proposed Pd(IV) intermediates in aromatic
acetoxylation with K2Cr2O7.3 Reports by Stock9 and Crabtree10
also entertained the possibility of Pd(IV) intermediates in
aromatic acetoxylation reactions. Aromatic C-H palladation is
rate determining in the Pd(OAc)2-catalyzed acetoxylation of
benzene by PhI(OAc)2 reported by Crabtree.10 Kinetic data
obtained from the Crabtree reaction, therefore, provides infor-
mation regarding the mechanism of metalation, not the mech-
anism of oxidation; the identity of potential high-valent
intermediates during catalysis could not be probed. The observed
reactivity was most easily interpreted as an operating Pd(II)/
(IV) redox cycle. In 2004, Sanford disclosed the regioselective
ortho-oxidation of 2-phenylpyridine derivatives (eq 2).5k Sanford
proposed Pd(IV) intermediates during catalysis and put forth a
mechanism involving cyclometalation at Pd(II), oxidation of the
resulting Pd-aryl complex to Pd(IV), followed by product-
forming reductive elimination from Pd(IV).5j,k
intermediates relevant to redox chemistry in the catalytic cycle can
only be probed when the turnover-limiting step does not precede
the redox chemistry. The results presented in Scheme 2 therefore
have no demonstrated relevance to catalysis and there is no basis
for discrimination between potential mechanisms involving elec-
trophilic M-C cleavage (redox neutral at Pd; A, Scheme 1),
oxidation to a dinuclear Pd(III) intermediate (bimetallic redox path;
Scheme 2), or the intermediacy of a mononuclear Pd(IV) complex
(monometallic redox path).
Pd(OAc)2-Catalyzed Aromatic Chlorination. In 1970, Fahey
reported the directed chlorination of palladated azobenzene using
Cl2,23 and in 2004, Sanford reported the Pd-catalyzed chlorina-
tion of 2-phenylpyridine derivatives using N-chlorosuccinimide
(NCS) as the terminal oxidant (eq 3).5k
Pd(IV) complex 7 has been studied as a model complex of
the proposed Pd(IV) intermediates in acetoxylation (Scheme
2).14 Upon thermolysis, Pd(IV) complex 7 undergoes product-
forming C-O reductive elimination. The original authors
discussed 7 as a model complex and did not propose it to be an
intermediate in catalysis.4g Subsequently, we have shown that
7 is not a kinetically competent intermediate for catalysis.17b
We selected dinuclear Pd(II) complex 8 as a starting point
for our own investigation of C-H acetoxylation (Scheme 2),17b
because it is the product of cyclometalation of 2-phenylpyridine
(3) with Pd(OAc)2.20 Treatment of 8 with PhI(OAc)2 afforded
dinuclear Pd(III) complex 9. Subsequent thermolysis of 9 in
the presence of 20 equiv of 2-phenylpyridine (3)spseudocata-
lytic conditionssresulted in the formation of 4 in 91%.
Evaluation of dinuclear Pd(III) complex 9 during catalysis
revealed that 9 is a kinetically competent catalyst for acetoxylation.
Based on the stoichiometric organometallic reactions shown in
Scheme 2, synthesis cycles involving either mononuclear Pd(IV)
or dinuclear Pd(III) intermediates have been formulated.14b,17a
Which of these synthesis cycles most resembles the operative
catalysis cycle cannot be determined with currently available data.
Determination of the redox couple relevant during catalysis is not
possible for the reaction shown in eq 2 because, like in the
acetoxylation of benzene reported by Crabtree,10 C-H metalation
is the turnover-limiting step during acetoxylation of 3 (see
Supporting Information).17b,21 The nuclearity22 of the palladium
Analogous to Pd(IV) model complex 7, isolated by oxidation
of 6 with PhI(OAc)2, Pd(IV) chloride model complex 11 has
been isolated upon oxidation of 6 with NCS and observed to
undergo C-Cl reductive elimination upon thermolysis (eq 4).15
(19) (a) Davidson, J. M.; Triggs, C. Chem. Ind. (London) 1966, 457. (b)
Tisue, T.; Downs, W. J. J. Chem. Soc. D 1969, 410.
(20) Gutierrez, M. A.; Newkome, G. R.; Selbin, J. J. Organomet. Chem.
1980, 202, 341–350.
(21) Stowers, K. J.; Sanford, M. S. Org. Lett. 2009, 11, 4584–4587.
(22) Powers, D. C.; Benitez, D.; Tkatchouk, E.; Goddard, W. A., III; Ritter,
T. J. Am. Chem. Soc. 2010, 132, 14092-14103.
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14532 J. AM. CHEM. SOC. VOL. 132, NO. 41, 2010

Mechanism of Pd-Catalyzed Aromatic C-H Oxidation
A R T I C L E S
Scheme 3. Resting State of Pd-Catalyzed Chlorination of
Benzo[h]quinoline (10) Is Succinate-Bridged Dinuclear Pd
Complex 14, Not Acetate-Bridged Complex 13a
of the benzo[h]quinolinyl ligands are shifted upfield versus the
corresponding shifts for benzo[h]quinoline, characteristic of
dimeric complexes in which the aromatic ligands are held in
proximity to one another.20,26 In addition, an NOE between H-1
and H-11′ was observed, indicating that the two ligand planes
are held in proximity relative to one another in solution. Possible
aggregation of resting state 14 in solution to form higher order
aggregates was excluded by linear concentration-dependent
UV-vis spectra of 14 (up to 0.3 mM).27 On the basis of these
data, the structure of 14 in solution resembles the dinuclear solid-
state structure.
Dinuclear palladium complexes can exist as an equilibrium
mixture of mono- and dinuclear complexes in the presence of
nitrogenous ligands due to N-coordination to the metal center.28
It has been postulated that, in the presence of arylpyridine
derivatives, Pd should be sequestered in mononuclear com-
plexes.21 We have examined the potential monomer-dimer
equilibrium of succinate-bridged complex 14 and have experi-
mentally shown that dinuclear palladium complex 14 is favored
over mononuclear complex 15, derived from N-coordination of
pyridine at elevated temperatures (eq 5). Examination of the
equilibrium between 14 and the corresponding pyridine-ligated
mononuclear complex (15; for X-ray, see Supporting Informa-
tion) as a function of temperature revealed that dimer formation,
with concurrent expulsion of 2 equiv of nitrogenous ligand is
entropically favored (∆S ) -34.3 cal ·mol-1 ·K-1) relative to
related monomeric complexes (eq 5).
a ORTEP drawing of 14 with ellipsoids drawn at 50% probability
(hydrogen atoms omitted for clarity). Pd1-Pd2 distance in 14: 2.8628(4)
Å.
Unlike Pd(OAc)2-catalyzed acetoxylation, which proceeds
with turnover-limiting metalation, we have found that the
Pd(OAc)2-catalyzed chlorination of 10 with NCS (eq 3) proceeds
with turnover-limiting oxidation. Turnover-limiting oxidation
was implied by the observation of zero-order kinetic dependence
on substrate and first-order kinetic dependence on NCS. Rate-
determining oxidation allowed direct interrogation of the catalyst
structure during the redox cycle operative in catalysis, which
is not possible for transformations in which metalation is
turnover limiting.
Resting State of Pd(OAc)2-Catalyzed C-H Chlorination.
1
Inspection of the H NMR spectra of the chlorination reaction
shown in eq 3 during catalysis revealed that benzo[h]quinolyl
palladium acetate dimer 13, formed by reaction of 10 with
Pd(OAc)2, was not present in the reaction mixture (Scheme 3).
Instead, we found that succinate-bridged dinuclear palladium(II)
complex 14, was the only observable palladium-containing
compound present during chlorination. Resting state 14 self-
assembles from Pd(OAc)2, benzo[h]quinoline (10), and succin-
imide, which is generated by reduction of NCS, and was isolated
and characterized as a moisture and air stable crystalline solid.24
The dinuclear structure of 14 in the solid state was established
by single crystal X-ray diffraction. Complex 14 contains two
palladium nuclei held in proximity by bridging succinate
ligands,25 and is structurally similar to acetate-bridged deriva-
tives, such as 13. The Pd-Pd distance in 14 is 2.8628(4) Å,
which is 0.02 Å longer than the corresponding distance in
acetate-bridged complex 13.
Rate Law for Chlorination of Benzo[h]quinoline Catalyzed
by 14. Resting state 14 is a chemically competent catalyst for
the chlorination of benzo[h]quinoline with NCS; chlorination
proceeds in 84% isolated yield with 5 mol % 14. Resting state
14 is not a kinetically competent catalyst for the reaction shown
in eq 3; when isolated complex 14 is used as catalyst, the rate
of chlorination was approximately 1/4 the rate of chlorination
when Pd(OAc)2 was employed as catalyst.
When isolated and purified resting state 14 is employed as
catalyst, acetate ions, which are generated by acetate-for-
(25) (a) Serrano, J. L.; Garc´ıa, L.; Pe´rez, J.; Pe´rez, E.; Vives, J.; Sa´nchez,
G.; Lo´pez, G.; Molins, E.; Orpen, A. G. Polyhedron 2002, 21, 1589–
1596. (b) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F.; Sa´nchez, G.;
Lo´pez, G.; Serrano, J. L.; Garc´ıa, L.; Pe´rez, J.; Pe´rez, E. J. Chem.
Soc., Dalton Trans. 2004, 3970–3981. (c) Crawforth, C. M.; Fairlamb,
I. J. S.; Kapdi, A. R.; Serrano, J. L.; Taylor, R. J. K.; Sa´nchez, G.
AdV. Synth. Catal. 2006, 348, 405–412.
NMR and UV-vis spectroscopy have been used to establish
that resting state 14 is dinuclear in solution. The 1H NMR signals
(26) Navarro-Ranninger, C.; Zamora, F.; Mart´ınez-Cruz, L. A.; Isea, R.;
Masaguer, J. R. J. Organomet. Chem. 1996, 518, 29–36.
(27) (a) Jennette, K. W.; Gill, J. T.; Sadownick, J. A.; Lippard, S. J. J. Am.
Chem. Soc. 1976, 98, 6159–6168. (b) Bailey, J. A.; Hill, M. G.; Marsh,
R. E.; Miskowski, V. M.; Schaefer, W. P.; Gray, H. B. Inorg. Chem.
1995, 34, 4591–4599. (c) Yam, V. W.-W.; Yu, K.-L.; Cheung, K.-K.
J. Chem. Soc., Dalton Trans. 1999, 2913–2915. (d) Wong, K. M.-C.;
Zhu, N.; Yam, V. W.-W. Chem. Commun. 2006, 3441–3443. (e) Lo,
L. T.-L.; Ng, C.-O.; Feng, H.; Ko, C.-C. Organometallics 2009, 28,
3597–3600.
(23) (a) Fahey, D. R. Chem. Commun. 1970, 417. (b) Fahey, D. R. J.
Organomet. Chem. 1971, 27, 283–292.
(24) By 1H NMR, resting state 14 is the exclusive Pd-containing compound
present during the chlorination of benzo[h]quinoline. As the NCS
employed is not contaminated by succinimide (1H NMR) and the
resting state is formed prior to the observation of any C-Cl bond
formation, the succinimide content of the resting state comes neither
from an impurity nor from succinimide produced during the first
catalyst turnover of chlorination. Currently, the mechanism of forma-
tion of resting state 14 from benzo[h]quinoline, Pd(OAc)2, and NCS
is not known.
(28) (a) Powell, J. J. Chem. Soc. A 1971, 2233–2239. (b) Powell, J.; Jack,
T. Inorg. Chem. 1972, 11, 1039–1048. (c) Jack, T. R.; Powell, J. Can.
J. Chem. 1975, 53, 2558–2574. (d) Ryabov, A. D. Inorg. Chem. 1987,
26, 1252–1260.
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A R T I C L E S
Powers et al.
Scheme 4. Proposed Acetate-Assisted Bimetallic Oxidation of 14
Would Afford Dinuclear Pd(III) Complex 16 Immediately Following
Oxidationa
We interpreted this reaction order as consistent with a catalyst
resting state comprised of mono- and dinuclear palladium
complexes,28 and a dinuclear transition state. While the data
was correct, our results presented here show that interpretation
of a measured reaction order of Pd(OAc)2 could not lead to
elucidation of the mechanism: By changing the concentration
of Pd(OAc)2, we simultaneously varied both [Pd] and [AcO-]
and therefore unknowingly changed the concentrations of two
components appearing in the rate law.
Participation of 14, NCS, and acetate during oxidation implies
the electronic participation of both metal centers during oxida-
tion (Scheme 4). Whether concerted, simultaneous interaction
of acetate ions and NCS with 14, or pre-equilibrium association
of acetate with 14 followed by oxidation, two metal coordination
sites are required in order for 14 to interact with both NCS and
acetate. In dinuclear Pd(II) complex 14, one vacant apical
coordination site is accessible on each metal. Similar nucleo-
phile-assisted oxidation has been observed during the proton-
ation of Pt(II)-alkyl complexes and has been suggested as
evidence for metal-based oxidation as opposed to direct elec-
trophilic M-C bond cleavage.30
Previously, we have shown the kinetic advantage of bimetallic
reductive elimination over monometallic reductive elimination
in related dinuclear Pd(III) complexes.22 Redox cooperativity
between the two metals can reduce the activation barrier to
reductive elimination. Our results presented here suggest that
bimetallic oxidative addition, the rate-determining step in Pd-
catalyzed chlorination with NCS, is also favored over potential
monometallic oxidation of a Pd(II) complex to a Pd(IV)
complex.
Succinate-Bridged Pd(III) Complexes. Our data implicate
acetate-assisted oxidation of dinuclear Pd(II) resting state 14
in rate-determining oxidation. On the basis of the rate law, we
propose dinuclear Pd(III) complex 16 as the immediate product
of oxidation. Because oxidation is rate determining, we cannot
directly observe 16 during catalysis. Resting state 14 is the only
observable Pd-containing complex during catalysis.
Because we suggest complex 16 to be on the catalysis cycle,
we sought to interrogate whether 16 is a chemically competent
intermediate for the chlorination of 10. Complex 16, which
features one apical acetate ligand and one apical chloride ligand,
could potentially participate in either C-Cl or C-O bond
formation. Oxidation of Pd(II) complex 14 with acetyl hy-
pochlorite31 at -78 °C afforded thermally sensitive complex
16, which could be observed by 1H NMR spectroscopy at -90
°C (Scheme 5). Warming complex 16 to 23 °C in the presence
of 20 equiv of pyridine32 afforded 2a, the product of C-Cl bond
formation in 84% yield. Compound 2b, the product of compet-
ing C-O reductive elimination, was formed in 0.5% yield
(Scheme 5).
a Oxidation of the dinuclear core of 14 removes the two electrons in the
Pd-Pd σ* orbital (HOMO), and thus results in Pd-Pd bond formation.
succinate exchange during catalysis, are not present in the
reaction mixture. We postulated that resting state 14 by itself
is kinetically incompetent due to potential acetate ion cocatalysis
when Pd(OAc)2 is used as catalyst. This hypothesis was
confirmed by observation of rate enhancements upon addition
of either AcOH or acetate ions (nBu4NOAc) to the reaction
mixture. In the presence of 4.0 equiv of acetic acid with respect
to 14, as is liberated during self-assembly of 14 from Pd(OAc)2
during catalysis, resting state 14 is a kinetically competent
catalyst. Examination of the initial rates of chlorination as a
function of added acetic acid (or nBu4NOAc) concentration
revealed that chlorination is first order dependent on [AcO-].
The reaction orders of both oxidant and Pd complex 14 were
measured under pseudo-first-order conditions with respect to
AcOH. The rate of chlorination is first-order dependent on NCS,
consistent with rate-determining oxidation. The rate of chlorina-
tion is also first-order dependent on the concentration of
dinuclear resting state 14, consistent with rate-determining
oxidation of dinuclear 14 by NCS. The rate of chlorination is
zeroth-order in benzo[h]quinoline as well as in succinimide,
which is generated as a stoichiometric byproduct of oxidation.
Hence, identification of the previously unanticipated succinate-
bridged dinuclear Pd resting state enabled the determination of
a simple rate equation: rate ) k [14][NCS][AcO-]. On the basis
of the rigid dinuclear structure of the resting state and the
measured first-order rate dependence on resting state 14, acetate,
and NCS, we propose turnover-limiting bimetallic oxidation of
14 with nucleophilic assistance29 by acetate (Scheme 4). An
analogous resting state and rate equation was found for
chlorination of 2-phenylpyridine (3) (see Supporting Informa-
tion).
The observed predominant, but not exclusive, formation of
2a from Pd(III) complex 16 is consistent with the product
(30) (a) Belluco, U.; Giustiniani, M.; Graziani, M. J. Am. Chem. Soc. 1967,
89, 6494–6500. (b) Uguagliati, P.; Michelin, R. A.; Belluco, U. J.
Organomet. Chem. 1979, 169, 115–122. (c) Alibrandi, G.; Minniti,
D.; Romeo, R.; Uguagliati, P.; Calligaro, L.; Belluco, U.; Crociani,
B. Inorg. Chim. Acta 1985, 100, 107–113.
(31) Evans, J. C.; Lo, G. Y.-S.; Chang, Y.-L. Spectrochim. Acta 1965, 21,
973–979.
In our initial report regarding the mechanism of Pd(OAc)2-
catalyzed C-H chlorination of benzo[h]quinoline (10), we
reported a reaction order of 1.5 with respect to Pd(OAc)2.17a
(32) Pyridine is added to the reaction mixture because, during examinination
of stoichiometric reductive elimination from dinuclear Pd(III) com-
plexes (ref 17), we discovered that a nitrogenous ligand can participate
in reductive elimination from dinuclear Pd(III) complexes. Excess
nitrogenous ligand is present during catalysis, and thus, the addition
of pyridine mimics conditions under which catalysis proceeds.
(29) Umakoshi, K.; Ichimura, A.; Kinoshita, I.; Ooi, S. Inorg. Chem. 1990,
29, 4005–4010.
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14534 J. AM. CHEM. SOC. VOL. 132, NO. 41, 2010

Mechanism of Pd-Catalyzed Aromatic C-H Oxidation
A R T I C L E S
Scheme 5. Oxidation of 14 and Subsequent Reductive Elimination
from Dinuclear Pd(III) Complex 16
Scheme 6. Proposed Pd(II)2/Pd(III)2 Catalysis Cyclea
selectivity during catalysis. Examination of the product mixture
of Pd(OAc)2-catalyzed chlorination of benzo[h]quinoline (eq 3)
by mass spectrometry revealed formation of 2b, the product of
C-O bond formation in 0.5% yield, in addition to 2a (90%
yield).33 The similarity of product distributions during catalysis
and from 16 is consistent with the presence of complex 16
immediately following oxidation during catalysis. Chemose-
lective reductive elimination, as shown for the preferential
formation of 2a over 2b, is currently not understood but may
be a result of differing propensities of chloride and acetate to
dissociate from Pd.
The results reported here support our proposed catalysis cycle
for oxidative aromatic C-H functionalization shown in Scheme
6. Following C-H metalation, nucleophile-assisted bimetallic
oxidation affords a dinuclear Pd(III) complex. Previously, we
have found that acid (for example acetic acid) which is both
formed during catalysis by C-H palladation and also often used
as reaction solvent, can catalyze reductive elimination from
dinuclear Pd(III) complexes.22 Such acid-catalyzed, bimetallic
reductive elimination would generate the observed organic
products of catalysis as well as regenerate Pd(II).
Herein, we have been able to correlate relevant structural data
of dinuclear Pd intermediates with reaction kinetics, measured
during catalysis. Our previous work could provide structural
information of dinuclear Pd(III) complexes but could not identify
the structures in catalysis.17 Previous work by Sanford implied
dinuclear transition states in Pd-catalyzed oxidative C-C bond
formation but could not identify the structure of potential high-
valent intermediates; both Pd(III) and Pd(IV) were proposed.18
While our results were obtained during the study of the
chlorination of benzo[h]quinoline, they may be relevant to a
variety of other C-H oxidation reactions.4,5 Although experi-
mentation regarding the specific mechanism of individual Pd-
catalyzed oxidation reactions is needed, we suggest that
mechanisms based on bimetallic Pd(III) chemistry are more
common for Pd(OAc)2-catalyzed aromatic C-H oxidation
reactions than previously anticipated.
a All reactions studied to date, in which oxidation is likely turnover
limiting, proceed via dinuclear intermediates.
complexes, the relevance of the invoked model complexes to
catalysis has not yet been established.
We present results that implicate bimetallic oxidation of
a dinuclear catalyst resting state to a dinuclear Pd(III)
complex during Pd(OAc)2-catalyzed chlorination of benzo-
[h]quinoline. The catalyst resting state has been identified
as a succinate-bridged dinuclear Pd(II) complex (14), which
self-assembles during catalysis. Interpretation of the reaction
order of palladium, NCS, and acetate ions, liberated during
self-assembly of the catalyst resting state, has revealed
unanticipated cocatalysis by acetate ions during rate-limiting
bimetallic oxidative addition. Previously, we have shown by
experiment and computation that bimetallic redox participa-
tion during reductive elimination lowers the energy barrier
to reductive elimination.22 Here, we propose that bimetallic
oxidation with simultaneous redox participation of two metals
is operative during catalysis. Metal-metal cooperation lowers
the activation barrier for both oxidative addition and reductive
elimination and favors a Pd(II)2/Pd(III)2 catalysis cycle for
Pd-catalyzed aromatic C-H oxidations.
Historically, analysis of mechanisms of Pd-catalyzed transforma-
tions has been dominated by discussion of either Pd(0)/Pd(II) or
Pd(II)/Pd(IV) redox cycles. While, in some instances, the inter-
mediacy of discrete monometallic Pd(IV) complexes seems
likely,5bb,34 this should not be the default mechanistic assumption
in reactions in which substrate and oxidant are combined with Pd(II)
catalysts. Reaction mechanisms involving either redox chemistry
at more than one metal center or reactions which proceed without
the intermediacy of high-valent palladium are often underappre-
ciated. Based on the similarity of the conditions employed for C-H
chlorination with the conditions employed in several Pd-catalyzed
oxidative transformations,5,6 metal-metal cooperation may be
much more widespread in catalysis than generally appreciated.
Conclusions
Discussion of high-valent palladium intermediates in Pd-
catalyzed aromatic C-H oxidation has been based predomi-
nantly on observation of stoichiometric organometallic reactions
from isolated model complexes. General consensus regarding
the relevance of Pd(II)/Pd(IV) catalysis cycles for aromatic C-H
oxidation is evidenced by the frequency with which this proposal
is invoked. While evaluation of reductive elimination from
Pd(IV) model complexes has allowed the study of the mecha-
nism of reductive elimination from organometallic Pd(IV)
(34) (a) Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1988, 346,
C27–C30. For discussion of the proposed role of Pd(IV), see (b)
Ca´rdenas, D. J.; Mart´ın-Matute, B.; Echavarren, A. M. J. Am. Chem.
Soc. 2006, 128, 5033–5040. (c) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. ReV. 2007, 107, 174–238.
(33) The observation of C-O bond formation during C-H chlorination
was noted in ref 21.
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J. AM. CHEM. SOC. VOL. 132, NO. 41, 2010 14535

A R T I C L E S
Powers et al.
Acknowledgment. We thank the NSF (CHE-0952753) and the
NIH-NIGMS (GM088237) for financial support, Dr. Shao-Liang
Zheng and Michael Campbell for X-ray crystallographic analysis,
and Sanofi Aventis for a graduate fellowship for D.C.P.
Bimetallic catalysis with metal-metal cooperation is
conceptually distinct from Pd(II)/(IV) pathways because
cooperative metal-metal redox interaction can lower activa-
tion barriers in oxidative palladium catalysis for both
oxidative addition and reductive elimination. We anticipate
that the mechanism proposed herein will inspire further study
to probe the generality of bimetallic redox chemistry in
catalysis as well as to allow rational design and development
of synthetically viable methods of oxidation chemistry that
previously have not been accomplished.
Supporting Information Available: Detailed experimental
procedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA1054274
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14536 J. AM. CHEM. SOC. VOL. 132, NO. 41, 2010