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Mechanistic Questions about the Reaction of Molecular Oxygen with Palladium in Oxidase Catalysis.

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DOI: 10.1002/anie.200602138
Aerobic Oxidations
Mechanistic Questions about the Reaction of Molecular
Oxygen with Palladium in Oxidase Catalysis**
Keith M. Gligorich and Matthew S. Sigman*
homogeneous catalysis · molecular oxygen · oxidation ·
palladium · reaction mechanisms
xidation reactions are essential for
both manipulation of functional groups
and introduction of heteroatoms in
target synthesis. Therefore, the development of selective, practical oxidation
reactions is a continuing challenge facing chemists in both academia and
industry.[1] A key consideration in developing oxidation reactions is selection
of the stoichiometric oxidant where
versatility, expense, and environmental
impact need to be addressed. An attractive approach is the use of metal-catalyzed oxidations coupled to the reduction of a practical terminal oxidant.[2] As
an example, Pd-catalyzed oxidations
have emerged as a particularly promising reaction type owing to their ability to
directly couple O2 reduction.[3]
An important aspect of Pd-catalyzed
oxidation chemistry is that the catalysis
can be separated into two distinct half
reactions: 1) substrate oxidation using
PdII (generally a dehydrogenation reaction) and 2) O2-coupled regeneration of
the active PdII catalyst with ultimate
formation of H2O from disproportionation of H2O2 (Scheme 1).[3a] Thus, Pdcatalyzed oxidations have been termed
“oxidase”-type reactions wherein substrate oxidation does not occur by oxygen-atom transfer from O2. Oxidase
catalysis has broad implications in the
development of new reactions, in that
[*] K. M. Gligorich, Prof. M. S. Sigman
Department of Chemistry
University of Utah
315 S. 1400 E.
Salt Lake City, UT 84112 (USA)
Fax: (+ 1) 801-581-8433
[**] We thank the National Institutes of Health
(NIGMS RO1 GM3540) for financial support.
Scheme 1. Two pathways for the regeneration of the active PdII catalyst from the reaction of
Pd complexes with O2. SubH2 = substrate; SubOx = oxidized substrate.
nearly all catalyzed oxidative transformations of an organic substrate can be
coupled to O2 reduction. This is highlighted by the diversity of PdII-catalyzed
aerobic oxidative transformations such
as oxidative amination,[3, 4] alcohol oxidation,[3, 5] Wacker-type reactions,[3, 6]
and oxidative Heck reactions.[3, 7]
Because substrate oxidation is often
rate-limiting in Pd oxidative catalysis,[5c, 8] it has been difficult to mechanistically characterize how O2 interacts
with the Pd center in the catalysis.
Interestingly, the reaction of triplet-state
O2 with a Pd center is formally a spinforbidden process,[9] and this leads to the
question: how does O2 readily react with
Pd? Insight into this question will be
crucial for the development of new and
more efficient direct O2-coupled Pdcatalyzed oxidative transformations.
This highlight describes what has been
ascertained about the interactions of O2
with both PdII and Pd0 complexes and
the implications this has for catalysis.
Two different pathways have been
proposed for the reaction of Pd complexes with O2 (Scheme 1). The first
mechanistic possibility is the direct insertion of O2 into a PdII hydride B to
produce a PdII hydroperoxide species C,
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
which upon protonation releases H2O2
and reforms the PdII catalyst (Scheme 1,
top pathway).[10] It should be noted that
this pathway need not proceed through
Pd0. The other commonly proposed
Pd0 species D by reductive elimination
of HX from complex B and subsequent
oxygenation of D to yield an h2-peroxido PdII species E.[11] Protonation of E
leads to formation of a similar
PdII hydroperoxide intermediate C,
again with a second protonation liberating H2O2 and the active PdII catalyst
(Scheme 1, bottom pathway).
In these oxidation reactions, the
precipitation of Pd metal is common
and most likely stems from the aggregation of Pd0 centers that are produced
in the catalysis. This issue has affected
both the development of improved catalysts and characterization of the key
intermediates involved in Pd–O2 interactions. To overcome catalyst-decomposition issues, several groups have recently utilized oxidatively stable mono- and
ligands[3–7] and N-heterocyclic carbene
(NHC) ligands for these transformations (Figure 1).[3, 5c, 12] The use of these
ligands has allowed for the development
Angew. Chem. Int. Ed. 2006, 45, 6612 – 6615
Figure 1. Examples of oxidatively stable
ligands employed in aerobic Pd-catalyzed
oxidative transformations.
of more reactive and robust catalysts for
Pd-catalyzed oxidations capable of high
turnover numbers at lower pressures of
oxygen.[3, 5c, 13] Moreover, and of fundamental importance, the use of ligands
has also allowed researchers to kinetically and structurally characterize the
Pd complexes with O2.
Using both bathocuproine (bc)[11a]
and NHC ligands,[11b] Stahl and co-workers have studied the stoichiometric reactions of Pd0 complexes with O2 to
probe the possibility of direct oxygenation of Pd0 (Scheme 2). Indeed, upon
exposure of both the [Pd0(bc)(dba)]
(dba = dibenzylideneacetone) complex
and the [Pd0(IMes)2] complex 5 to O2,
the expected h2-peroxido species were
isolated. Both PdII h2-peroxido complexes were subsequently exposed to
acetic acid. Interestingly, only [Pd0(IMes)2] produced a PdII hydroperoxide
complex 7, which was the first example
of a dioxygen-derived PdII hydroperoxide complex. The authors reasoned that rapid cis–trans ligand isomerization of complex 7 slows the approach
of a second equivalent of acid, which is
required to liberate H2O2 and complex
Mechanistic studies on the oxygenation of [Pd0(bc)(dba)] showed a firstorder dependence on [O2] and no dependence of the reaction rate upon
addition of up to 10 equivalents of
dba.[11a] Furthermore, activation parameters obtained from a temperature-dependent study revealed a substantial
negative entropy of activation, DS° =
43(7) cal K 1 mol 1. Together, these
data support an associative oxygenation
Angew. Chem. Int. Ed. 2006, 45, 6612 – 6615
Scheme 2. The reaction of 5 with O2 and a
carboxylic acid.
reaction, which more closely resembles
an olefin substitution rather than an
oxidative addition. Interestingly, the
oxygenation of [Pd0(bc)(dba)] typically
takes 20–30 minutes at room temperature, while the [Pd0(IMes)2] complex
reacts extremely rapidly with O2 even at
78 8C. This observation suggests that
the oxygenation of [Pd0(bc)(dba)] could
be occurring by an associative olefin
substitution (loss of dba), whereas a
direct oxygenation pathway may be
occurring for the [Pd0(IMes)2] complex.
It is important to note that under typical
catalytic conditions PdII salts are used
and dba would not be present. Therefore, more efficient oxygenation of
[Pd0(bc)] would be expected under catalytic conditions.
Even though there is substantial
experimental evidence for the oxygenation of Pd0, the reaction of triplet-state
oxygen and Pd0 is formally spin-forbidden. Landis, Stahl, and co-workers investigated this question by using spinunrestricted density functional theory
(DFT).[9a] The results of their study
indicate an exothermic reaction, which
produces a triplet diradical PdI h1-superoxide intermediate, and a triplet-to-
singlet surface crossing ultimately yields
PdII peroxido
(Scheme 1). The formation of the di
radical, with one spin localized on oxygen and one on the Pd center allows for
a low kinetic barrier. Crossover to the
singlet state is most likely facilitated by
the relatively large spin–orbit coupling
of the Pd center.
Experimental and theoretical evidence supports the direct oxygenation
of Pd0, but can O2 insert directly into a
PdII hydride? Stahl and co-workers investigated this possibility by subjecting
[Pd0(IMes)2] to one equivalent of a
carboxylic acid, which produced the
PdII hydride 8 (Scheme 2).[14] Subsequent exposure of 8 to O2 yielded the
PdII hydroperoxide complex 7. The formation of the PdII hydroperoxide supports a direct insertion pathway. An
alternate pathway of reductive elimination of HX from 8 to yield [Pd0(IMes)2]
and subsequent oxygenation and protonation would produce the same species
and cannot be ruled out. Kinetic measurements of the reaction revealed a firstorder dependence on the concentration
of Pd hydride 8, and the rate of oxygenation with p-nitrobenzoate is almost
eightfold faster than when benzoate is
used as a ligand. The ligand dependence
suggests the possibility of rate-limiting
carboxylate dissociation followed by
oxygenation. However, the current data
could support either a direct insertion
pathway or a slow reductive elimination
followed by fast oxygenation and is
therefore insufficient to differentiate
the two pathways.
In this system, a linear increase of
the rate of oxygenation was observed
with respect to the addition of exogenous benzoic acid, which was unexpected owing to the possibility of preequilibrium reductive elimination of
HX from complex 8, which would inhibit the formation of [Pd0(IMes)2].
While the origin of these results is the
subject of future studies, these initial
data point toward either rate-limiting
carboxylate dissociation or the possibility of protonation of the PdII h2-peroxido species 6 in the rate-limiting step.
Our group has observed a similar dependence upon addition of exogenous
acid in the [PdII(IiPr)(OAc)2]-catalyzed
(Scheme 3).[5c] Kinetic measurements
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
dard and co-workers have recently disclosed a theoretical study of the direct
insertion of O2 into a [PdII{( )-sparteine}H(Cl)] complex L and a
[PdII(bipyridine)H(Cl)] complex, which
yields the respective PdII hydroperoxides (Scheme 5).[9b] The results of
Scheme 4. Insertion of O2 into a PdII hydride.
Scheme 3. Proposed mechanism of the [Pd (IiPr)(OAc)2]-catalyzed aerobic oxidation of alcohols.
of the oxidation reaction with greater
than 2 mol % of exogenous acetic acid
suggests that b-hydride elimination of
the PdII alkoxide intermediate H is ratelimiting. However, at lower concentrations of acetic acid (0–0.62 mol %) competitive turnover-limiting protonation of
a PdII peroxido species K is proposed
based upon kinetic isotope effect (KIE)
measurements and a partial positive
order on the concentration of acetic
acid. Catalyst decomposition occurs
with no added acetic acid and can be
attributed to reversible oxygenation of
the [Pd0(IiPr)] complex J. Therefore,
increasing the concentration of acetic
acid enhances the rate of protonation of
the PdII peroxido species K while simultaneously decreasing the rate of alcohol
oxidation by protonation of the
PdII alkoxide H which yields intermediate G. These results suggest that the
addition of exogenous acid can prevent
the formation of metallic palladium by
increasing the rate of catalyst turnover
in aerobic Pd-catalyzed oxidative transformations.
Because of the potential for a preequilibrium reductive elimination of
HX from complex 8, the question of
whether O2 can directly insert into a
PdII hydride remains. Goldberg, Kemp,
and co-workers have recently reported
the reaction of O2 with complex 10,
which cannot undergo reductive elimination (Scheme 4).[15] Exposure of 10 to
O2 yielded the expected PdII hydro-
peroxide 11 and the PdII hydroxide 12
in a 25:1 ratio. This is the first example
of what is assumed to be a direct
insertion of O2 into a PdII hydride.
Kinetic measurements of the reaction indicated a first-order dependence
on 10 and also a first-order dependence
upon oxygen pressure. A large KIE of
5.8(5) was measured for the insertion of
O2 into the PdII H(D) bond, which
indicates PdII hydride bond cleavage
in the rate-determining step. In order
to rule out the possibility of a radicalchain pathway, the authors performed
the reaction in the presence of radical
inhibitors 2,6-di-tert-butyl-4-hydroxytoluene (BHT) and 2,2,6,6,-tetramethyl-1-piperidinyloxy free radical (TEMPO), whereby no significant change in
the rate of the reaction was observed.[16]
Additionally, no substantial rate difference was measured for the disappearance of 10 when the reactions were
performed in the dark and under ambient light. However, PdII hydroperoxide 11 in a benzene solution at
room temperature slowly converts into
the PdII hydroxide 12. This reaction was
accelerated in the presence of light and
suggests a radical pathway similar to the
decomposition of organic peroxide analogues like tert-butyl hydroperoxide to
tert-butyl alcohol and O2.[17]
Together, these data support a
mechanism involving either coordination of O2 to the PdII hydride and
subsequent migratory insertion or direct
insertion of O2 into a PdII hydride bond.
In support of these hypotheses, God-
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 5. Mechanism proposed by Goddard
et al. for O2 insertion into [Pd{( )-sparteine}H(Cl)] (L) in toluene.
their DFT study indicate initial hydrogen bonding of triplet O2 directly to the
hydride intermediate M. Insertion of O2
yields a triplet PdI hydroperoxide complex N, in which the proton of the
hydroperoxido ligand is hydrogenbound to the anionic ligand. Subsequent
PdII hydroperoxide yields intermediate
O, which after protonation leads to the
formation of both the active catalyst and
In conclusion, oxygenation of Pd0
and direct insertion of O2 into a PdII
hydride bond have both been shown to
be possible pathways for the reaction
between O2 and Pd complexes. Experimental and theoretical evidence support the viability of both mechanisms,
but further experimental work will be
required to elucidate the details of these
pathways in which ligand and additives
will most likely have a profound influence. It should be noted that these
studies do not mimic catalytic conditions, and it is anticipated that characterizing the intermediates/pathways under
truly catalytic conditions will be quite
challenging. However, the insights garnered from these studies showcase why
Pd/ligand-catalyzed aerobic oxidation
chemistry is a rapidly growing field.
Published online: September 20, 2006
Angew. Chem. Int. Ed. 2006, 45, 6612 – 6615
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