Mechanism of Catalytic Oxidation of Styrenes with Hydrogen Peroxide in the Presence of Cationic Palladium(II) Complexes

Article abstract of DOI:10.1021/jacs.7b05413

Kinetic studies, isotope labeling, and in situ high-resolution mass spectrometry are used to elucidate the mechanism for the catalytic oxidation of styrenes using aqueous hydrogen peroxide (H₂O₂) and the cationic palladium(II) compound, [(PBO)Pd(NCMe)₂][OTf]₂ (PBO = 2-(pyridin-2-yl)benzoxazole). Previous studies have shown that this reaction yields acetophenones with high selectivity. We find that H₂O₂ binds to Pd(II) followed by styrene binding to generate a Pd-alkylperoxide that liberates acetophenone by at least two competitive processes, one of which involves a palladium enolate intermediate that has not been previously observed in olefin oxidation reactions. We suggest that acetophenone is formed from the palladium enolate intermediate by protonation from H₂O₂. We replaced hydrogen peroxide with t-butyl hydroperoxide and found that, although the palladium enolate intermediate was observed, it was not on the major product-generating pathway, indicating that the form of the oxidant plays a key role in the reaction mechanism.

Full text of DOI:10.1021/jacs.7b05413

Article
pubs.acs.org/JACS
Mechanism of Catalytic Oxidation of Styrenes with Hydrogen
Peroxide in the Presence of Cationic Palladium(II) Complexes
Katherine L. Walker,†,§ Laura M. Dornan,
and Mark J. Muldoon*
†,‡,§
Richard N. Zare, Robert M. Waymouth,*
†
,†
,
‡
†
Department of Chemistry, Stanford University, Stanford, California 94305, United States
‡
School of Chemistry and Chemical Engineering, Queen’s University Belfast, Belfast, Northern Ireland, BT9 5AG, United Kingdom
S Supporting Information
*
ABSTRACT: Kinetic studies, isotope labeling, and in situ high-
resolution mass spectrometry are used to elucidate the mechanism
for the catalytic oxidation of styrenes using aqueous hydrogen
peroxide (H O ) and the cationic palladium(II) compound,
2
2
[
(PBO)Pd(NCMe) ][OTf] (PBO = 2-(pyridin-2-yl)benzoxazole).
2 2
Previous studies have shown that this reaction yields acetophenones
with high selectivity. We find that H O binds to Pd(II) followed by
2
2
styrene binding to generate a Pd-alkylperoxide that liberates
acetophenone by at least two competitive processes, one of which
involves a palladium enolate intermediate that has not been
previously observed in olefin oxidation reactions. We suggest that
acetophenone is formed from the palladium enolate intermediate by
protonation from H O . We replaced hydrogen peroxide with t-butyl hydroperoxide and found that, although the palladium
2
2
enolate intermediate was observed, it was not on the major product-generating pathway, indicating that the form of the oxidant
plays a key role in the reaction mechanism.
39
INTRODUCTION
Scheme 1. Oxidation of Styrene with H O
2 2
■
The catalytic oxidation of alkenes provides an expedient
synthesis of carbonyl compounds. Despite recent advances,
1
−3
many challenges remain. The Wacker process for aerobic
oxidation of ethylene to acetaldehyde with palladium chloride/
copper chloride is a textbook example of industrial oxidation of
4
an alkene; however, this catalyst system is typically less
5
,6
effective for alkenes other than ethylene. Efforts to replace
the copper salts with other electron-transfer mediators to
facilitate the reoxidation of Pd(0) have been met with some
7
−24
25−28
success,
as have efforts to employ alternative oxidants.
Direct aerobic oxidations of alkenes in the absence of
2
9−38
mediators are also known,
styrenes,
but for the oxidation of
43
3
3,34
oxidations dates to the 1960s, considerably less is known
regarding the mechanism of alkene oxidations mediated by
these systems typically require high loadings of Pd
catalyst (5−10 mol %) and lengthy reaction times. The
Muldoon group recently reported efficient catalytic oxidation of
styrenes with hydrogen peroxide (H O ) in the presence of
4
4,45
46−49
relative to those employing O ,
hydroperoxides.
or alkyl
Herein we describe kinetic investigations,
isotope labeling studies, and in situ high-resolution mass
2
H O2
2
50−54
2
2
cationic Pd complexes ligated with 2-(pyridin-2-yl)benzoxazole
55−57
39
spectrometry
of Pd(II)/H O2 catalyzed oxidation of
(
PBO), [(PBO)Pd(NCMe) ][OTf] (A, Scheme 1). While
2
2
2
styrenes. These studies provide clear evidence for a mechanism
involving the initial formation of a Pd-hydroperoxide
this catalyst is selective for styrenyl substrates, aliphatic terminal
alkenes are isomerized rapidly and give low yields of their
50,54
39
intermediate
which reacts with styrene to generate a Pd-
corresponding 2-ketones. Internal alkenes do not undergo
oxidation under these conditions.
alkylperoxide intermediate that liberates acetophenone by at
least two competitive processes, one of which involves an
unusual palladium enolate intermediate (Scheme 1).
4
0
Hydrogen peroxide is an attractive oxidant;
it is
inexpensive, degrades only to O and H O, and has been
2
2
41
utilized industrially for the production of pharmaceuticals as
well as large scale commodity chemicals such as propylene
oxide. While the use of aqueous H O for Wacker-type
Received: May 25, 2017
4
2
2
2
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b05413
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Journal of the American Chemical Society
Article
RESULTS
■
Kinetic Studies. The catalytic oxidation of styrene with
H O (5 equiv relative to styrene) in ambient air in the
2
2
presence of [(PBO)Pd(NCMe) ][OTf] , A, affords acetophe-
2
2
39
none in 80% yield after 24 h (Scheme 1). The kinetics were
analyzed by monitoring the concentrations as a function of time
by gas chromatography. The initial rates were determined by
monitoring the concentration of styrene up to 10−15%
conversion. These experiments reveal that the initial rates
exhibited a linear dependence on both [styrene] and [Pd]
(Figure 1).
Figure 2. Initial rates for the oxidation of styrene by A as a function of
[
H O ] and [H O]. (A) Conditions: 0.255 M styrene, 2.55 mM A,
2 2 2
2
.534 M H O, MeCN, total volume 4.33 mL. (B) Conditions: 0.255
2
M styrene, 2.55 mM A, 1.275 M H O , MeCN, total volume 4.33 mL.
2
2
Error bars represent one standard deviation for three replicate runs.
Scheme 2. Product Formation via Aerobic Wacker Oxidation
Figure 1. Initial rates for the oxidation of styrene by A with H O . (A)
2
2
The initial rates for a range of substituted styrenes were
investigated to probe the influence of electronic effects on the
rate of styrene oxidation (Figure 3). These data revealed a
Initial rates vs [styrene] (conditions: 2.55 mM A, 1.275 M H O ,
2
2
2
.534 M H O, MeCN, total volume 4.33 mL). (B) Initial rates vs [Pd].
2
(
conditions: 0.255 M styrene, 1.275 M H O , 2.534 M H O, MeCN,
2 2 2
total volume 4.33 mL). Error bars represent one standard deviation for
three replicate runs.
The initial rates exhibited saturation behavior with the
concentration of hydrogen peroxide; for [H O ] ≤ 0.3 M
2
2
(
approximately 1.2 equiv of H O relative to styrene), the rate
2 2
increases linearly with [H O ], after which the rate is
2
2
independent of peroxide concentration (Figure 2). The initial
rates exhibited a similar saturation behavior with the
concentration of water, exhibiting a linear increase in rate for
[
H O] ≤ 2.5 M, but the initial rates do not change significantly
2
at higher [H O]. Control experiments reveal that oxidation of
2
styrene under similar conditions in the absence of H O affords
2
2
39
a 24% yield of acetophenone (Scheme 2), indicating that
aerobic Wacker oxidation of styrene can also occur under these
conditions and may be responsible for some fraction of the
acetophenone generated, even in the presence of H O .
Figure 3. Hammett plot for substituted styrenes (conditions: 0.255 M
styrene, 2.55 mM A, 2.534 M H O, 1.275 M H O MeCN, total
volume 4.33 mL).
2
2
2
2
2
B
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1
linear free energy relationship between the logarithm of the rate
vs the Hammett σ parameter. This plot yields a negative slope
with ρ = −1.61, indicating slower rates for more electron-
deficient styrenes.
thesized and characterized. The H and 13C NMR spectra of
this compound are consistent with its formulation as a C-bound
enolate. The ESI-MS of phen-C afforded an envelope of ions
centered at 405.0219 m/z corresponding to [(phen)Pd-
(CH COPh)] ; furthermore, the CID spectrum had the same
pattern of daughter peaks as those observed from [C] ,
providing indirect evidence that the enolate [C] is C-bound
and not O-bound. Treatment of a CD CN solution of this
enolate with 1 M D O afforded acetophenone in 5% yield,
63
+
Mass Spectrometry and Isotope Labeling. To provide
insight on the nature of catalytic intermediates and the
speciation of Pd species during the catalytic reaction, we
utilized high-resolution electrospray mass spectrometry (ESI-
MS), combined with isotope-labeling studies to monitor the
catalytic oxidation of styrene with [(PBO)Pd(NCMe) ][OTf] ,
2
+
+
63
3
2
2
91% of which was d -acetophenone. When an analogous
2
2
1
A. Analysis of catalytic reactions by ESI-MS techniques coupled
reaction was carried out with H O and analyzed by ESI-MS,
2
2
+
with other mechanistic tools and kinetic studies can provide
the ion corresponding to [(phen)Pd−OOH] was observed;
these results indicate that the C-bound enolates can be
protonated by H O to afford acetophenone, although this
48,55,58−61
valuable insights into complex catalytic mechanisms.
We have recently used ESI-MS to investigate the mechanisms
2
2
56,62
of aerobic Pd(II) catalysis for alcohol oxidation
disproportionation.
and H O2
process is not very efficient with the phen ligand (phen had
2
57
been previously shown to be a poor ligand for the catalytic
39
Oxidations of 0.2 M styrene in ambient air with 1 M H O in
oxidation of styrene ).
2
2
the presence of 2 mM A in MeCN/H O were investigated by
To provide further information on the processes that lead to
the Pd-enolate ion and its role in the oxidation reaction, a series
of isotope labeling studies was carried out. The catalytic
oxidation of 0.2 M styrene with 1 M D O (approximately 98%
2
taking aliquots and diluting them directly before analyzing the
reaction mixture by ESI-MS (Scheme 3). Immediately, an
2
2
Scheme 3. Ions Observed from ESI-MS
D-labeled) in MeCN/D O catalyzed by 2 mM A afforded a
2
mixture of d -acetophenone (67%) and acetophenone (33%)
1
(
Scheme 4a). Kinetic experiments revealed a primary kinetic
isotope effect of k /kD (H O /D O ) = 1.92. A control
H
2
2
2
2
experiment under the same D O conditions with acetophe-
2
2
none instead of styrene yielded no d -acetophenone, indicating
1
that d -acetophenone is not derived from the product
1
acetophenone. When the reaction of styrene with D O was
2
2
monitored by ESI-MS, two overlapping ion envelopes centered
at 334.9656 m/z and 335.9700 m/z were observed,
+
+
corresponding to a mixture of [B] and [PBOPd−OOD] ,
1
+
[
d -B] . However, the ion corresponding to the Pd-enolate was
envelope of peaks centered at 334.9638 m/z is observed at
reaction times as short as 1 mincorresponding to the Pd-
observed at 421.0164 m/z, indicating that the enolate generated
under these conditions contains no deuterium. These
+
+
hydroperoxide species [(PBO)Pd−OOH] , [B] . This ion
appears early in the reaction and is observed throughout the
reaction. At early reaction times, another envelope of peaks is
evident at 469.4429 m/z but is not present after tens of minutes
and later reaction times. This ion is formulated as the trimeric
observations suggest that d -acetophenone likely arises from
1
deuterolysis of the C-bound Pd-enolate.
Catalytic oxidation of 0.2 M α-D-styrene with 1 M H O and
2
2
2
mM [A] in MeCN/H O leads to a mixture of d -
2
1
2+
acetophenone (30%) and unlabeled acetophenone (70%)
Scheme 4b). Kinetic studies revealed a negligible kinetic
[
PBO Pd O ] , an ion analogous to that observed and
3 3 2
(
characterized in O or H O mediated oxidations with cationic
2
2
2
5
6,57
isotope effect, k /kD = 0.97 (styrene vs α-D-styrene). In
Pd neocuproine complexes.
H
contrast, when the oxidation of α-D-styrene was carried out in
After 1 h of reaction, the major observed species is an ion at
D O /D O, over 92% of the acetophenone was deuterated
4
21.0151 m/z, corresponding to the formula [PBOPd−
2
2
2
+
+
63
(
Scheme 4b). When this reaction was monitored by ESI-MS,
CH COPh] , [C] , which we assign as a Pd-enolate. This
2
+
the undeuterated enolate [C] was observed, indicating that the
Pd-enolate derived from α-D-styrene lost its deuterium atom.
When the catalytic oxidation of 20 mM styrene with 2 mM A
was carried out with O-labeled hydrogen peroxide (0.1 M
H O ) in MeCN/H O, GCMS analysis revealed that 74% of
ion remains the dominant species throughout the reaction. This
was an unexpected observation, as such a species has rarely
been observed or postulated in Wacker-type reactions of
styrene. To more fully characterize this ion, collision induced
dissociation (CID) mass spectrometry was carried out and
18
18
2 2 2
18
revealed daughter ions that have lost either CO or CH CO,
the acetophenone product is O labeled (Scheme 4c). The
ESI-MS of this reaction revealed ions at 338.9739 m/z
corresponding to the palladium hydroperoxide containing two
2
63
which agrees with a Pd-enolate ion. ESI-MS of analogous
reactions using 4-fluorostyrene and 3-nitrostyrene gave ions at
18
18
+
4
39.0051 m/z and 465.9989 m/z, respectively, consistent with
O atoms, [ O -B] . The ion corresponding to the palladium
2
1
8
+
corresponding palladium enolates. When the product aceto-
phenone was subjected to the typical catalytic conditions in the
absence of styrene, no ions corresponding to the Pd-enolate
could be observed, implying that these ions are not derived
from acetophenone.
enolate shifts to 423.0211 m/z, [ O-C] , which indicates that
the oxygen in the enolate is derived from the labeled hydrogen
peroxide. When an analogous experiment was carried out with
unlabeled H O in labeled H O water, the ion corresponding
to the Pd-enolate did not incorporate the O from water (see
the Supporting Information).
18
2
2
2
18
Attempts to independently prepare the proposed [PBOPd-
(
CH COPh)][OTf] were unsuccessful. However, the analo-
Efforts to investigate the influence of radical traps or
hydrogen atom donors on the oxidation of styrene with
H O were ambiguous. Addition of TEMPO or TEMPOH
2
gous 1,10-phenanthroline (phen) complex, [(phen)Pd-
CH COPh)(NCMe)][OTf] (phen-C), was successfully syn-
(
2
2
2
C
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Scheme 4. Isotope-Labeling Studies
(TEMPO = (2,2,6,6-tetramethylpiperidin-1-yl)oxyl) completely
styrene and 2 M H O in MeCN catalyzed by 2 mM A in the
2
2
shut down the reaction, and was thus not informative. The
addition of 1 equiv (relative to styrene) of 1,4-cyclohexadiene
presence of 0.2 M CHD revealed an envelope of ions at
439.0274 m/z in low relative abundance at early time points
(Scheme 5). This ion corresponds to the formula
(
CHD) to a styrene oxidation reaction with H O resulted in a
2 2
+
+
decrease in rate but exhibited a similar selectivity to those
[PBOPdCH CH(OOH)Ph)] , [D] , corresponding to a Pd-
2
carried out with D O or α-D-styrene in the absence of CHD.
alkylperoxide, an intermediate which had been previously
2
2
4
4,50
51,54
We were encouraged to look at this reaction by ESI-MS to
assess if the lower rates observed in the presence of CHD might
enable observation of short-lived intermediates that might not
otherwise be detectable. Analysis of the reaction of 0.2 M
proposed by Mimoun
and Sigman
in peroxide-
mediated oxidations of olefins. Other intermediates with
CHD coordinated to the Pd center were also observed (see
the Supporting Information).
D
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Scheme 5. Ions Observed from ESI-MS with CHD Additive
the peak at 421.0179 m/z (corresponding to Pd-enolate) began
to grow in, albeit in a much lower relative abundance than that
observed in the presence of H O . This peak was also present
2
2
when D O was used instead of H O.
2
2
Other Peroxide Oxidants. The observation of the Pd-
enolate intermediate was unexpected, as this intermediate had
1
not been commonly invoked in Wacker-type oxidations. To
assess the generality of this observation and the potential role of
Pd-enolates in other olefin oxidation reactions, we investigated
the oxidation of styrene with t-butyl hydroperoxide (TBHP)
52,54
under conditions analogous to those reported by Sigman.
In an effort to identify short-lived intermediates, alternative
electrospray techniques were employed. Desorption electro-
spray ionization (DESI) MS is a useful technique for observing
When the catalytic oxidation of α-D-styrene with (Quinox)-
PdCl /AgSbF6 (Quinox = 2-(4,5-dihydro-2-oxazolyl)-
2
64,65
quinolone) was carried out in CH Cl with TBHP (70%
2
2
species that form on the microsecond time scale.
For these
solution in water), analysis of the reaction mixture revealed that
8% of acetophenone generated was monodeuterated.
When the oxidation of styrene with TBHP was monitored by
experiments, an acetonitrile solution of the Pd precursor A was
deposited on a porous Teflon sheet and allowed to dry. A
solution of styrene and H O in MeCN was then sprayed onto
9
2
2
ESI-MS, two major species were observed after 15 min: an ion
at 497.1047 m/z and one at 423.0322 m/z (see the Supporting
Information). The former corresponds to the formula
it using an ESI source, and the secondary microdroplets
generated were analyzed by MS. One of the first ions observed
+
was the Pd−OOH ion [B] ; subsequently, ions corresponding
+
+
+
[(Quinox)Pd−CH CH(OOtBu)Ph)] , [E] , and the latter to
2
to the Pd-enolate [C] grew in slowly over about a minute.
+
+
+
[(Quinox)Pd−CH COPh)] , [F] (Scheme 7). The CID
2
These experiments suggest that the hydroperoxide [B] is
spectrum of [E]+ (Figure S42) shows, instead of loss of
styrene, fragmentation peaks consistent with O−O bond
formed rapidly upon contact of hydrogen peroxide with the
cationic Pd precursor A. These experiments were corroborated
utilizing a theta capillary nanoESI experiment. In this
technique, two solutions are simultaneously sprayed from two
barrels of a single capillary with an ∼2 μm tip, resulting in
mixing just prior to formation of the primary droplets.
Depending on the distance of the spray from the mass
spectrometer, this technique results in mixing times on the
+
cleavage to produce [F] as well as loss of the t-butyl group.
This fragmentation pattern is most consistent with a palladium
alkylperoxide, rather than a palladium peroxide with a
coordinated styrene. When the same reaction was carried out
with α-D-styrene, analysis of the mass spectra revealed ions
corresponding to the Pd-alkylperoxide [(Quinox)Pd−CH CD-
2
+
+
6
6−68
(OOtBu)Ph)] , [d -E] , containing one deuterium; in contrast,
1
order of 10−1000 μs.
When separate MeCN solutions of
the ion corresponding to the Pd-enolate did not contain a
A and styrene mixed with H O were sprayed through the theta
2
2
54
44
deuterium label. Both Sigman and Mimoun had proposed
that alkylperoxides are key intermediates in the peroxide-
mediated oxidations of olefins. The results of the in situ mass
spectroscopy measurements are fully consistent with this
hypothesis.
capillary, the predominant ion observed (other than the
2
+
precursor [(PBO)Pd(NCMe) ] ) was that corresponding to
2
+
[
B] . Ions corresponding to the palladium enolate were not
observed under these conditions, from which we conclude that
the Pd-hydroperoxide is formed prior to the Pd-enolate.
3
9
Analogous experiments were carried out with [(PBO)Pd-
Aerobic Wacker Oxidation. As prior studies had
suggested that some fraction of the acetophenone produced
when styrene is oxidized with H O in air may derive from a
(
NCMe) ][OTf] , A, in an effort to assess the role of both the
2 2
ligand and the oxidant on the distribution of deuterium in the
products. Oxidation of α-D-styrene with TBHP in the presence
of A afforded 60% yield of acetophenone after 1 h where 98%
of the acetophenone was deuterated (Scheme 8). Analysis of a
reaction with perprotio styrene by ESI-MS revealed ions
2
2
competitive aerobic Wacker reaction (Scheme 2, 24% after 24 h
in air vs 80% with H O ), we carried out several experiments to
2
2
monitor the oxidation of styrene in air in the absence of
hydrogen peroxide (Scheme 6). When 0.2 M styrene was
+
corresponding to the Pd-tertbutylperoxide, [G] (391.0289 m/
+
z), the Pd-alkylperoxide, [H] (495.0918. m/z), and the Pd-
Scheme 6. Aerobic Wacker Isotope Labeling Studies
+
enolate, [C] (421.0189 m/z).
These latter experiments are informative as they clearly
indicate that, with the same ligand system (PBO), the nature of
the oxidant has a significant influence on the fate of the
deuterium derived from α-D-styrene and on the observed
intermediates by ESI-MS. When H O is used as the oxidant,
2
2
only 30% of the resulting acetophenone is labeled with
deuterium, whereas, when TBHP is the oxidant, 98% of the
acetophenone is labeled.
DISCUSSION
oxidized in air in 4 M D O (in MeCN) with 2 mM A, analysis
■
2
of the resulting acetophenone revealed undetectable amounts
of deuterium incorporation. In contrast, for α-D-styrene under
similar conditions, 82% of the acetophenone was labeled.
When these reactions were analyzed by ESI-MS, at early
reaction time points, the mass spectrum was similar to that of
The results of this study indicate that the catalytic oxidation of
styrene with [(PBO)Pd(NCMe) ][OTf] , A, and H O as the
terminal oxidant proceeds by several competitive pathways
(Scheme 9, represented with α-D-styrene), including a
competitive oxidation pathway mediated by O2 (aerobic
Wacker reaction). In the following, we will describe the
2
2
2
2
[
(PBO)Pd(NCMe) ][OTf] in wet MeCN. However, after 1 h,
2 2
E
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Scheme 7. Ions Observed from ESI-MS for the Quinox/TBHP System
Scheme 8. PBOPd with TBHP Deuterium Labeling
cumulative evidence obtained from kinetic measurements,
isotope labeling, and in situ mass spectrometry that is
consistent with this proposal.
is strong evidence that this Pd-hydroperoxide is the result of
direct reaction of the Pd catalyst with H O .
2
2
The reaction of intermediate B with styrene is proposed to
generate the alkylperoxide intermediate H (Scheme 9); related
Experimental data from DESI and theta capillary nanoESI
provide compelling evidence that the initial intermediate
formed within microseconds upon reaction of A with H O is
44
intermediates have been proposed by both Mimoun and
44,51,54
2
2
Sigman.
This is consistent with linear kinetics plots
44,50
69,70
the Pd−OOH intermediate B. Mimoun
and others
had
obtained with varying styrene concentration. Although this
intermediate was not observed directly by ESI under the typical
reaction conditions, an ion at 439.0274 m/z corresponding to
previously proposed the formation of a Pd−OOR intermediate
as a first step in olefin oxidation reactions by hydrogen peroxide
51,54
or alkyl hydroperoxides.
This hypothesis that intermediate
+
+
the alkylhydroperoxide [(PBO)PdCH CH(OOH)Ph)] , [D] ,
2
B is the first step of the mechanism is also supported by the first
order kinetics observed with [Pd], the saturation-type kinetics
observed with H O , and the kinetic isotope effect (H O /
was observed in the oxidation of styrene with H O in the
2
2
presence of 1,4-cyclohexadiene. Moreover, when the oxidation
of styrene was carried out with THBP as the terminal oxidant,
2
2
2
2
D O ) of 1.92. Pd-hydroperoxide species can be generated
2
2
ions corresponding to the alkylperoxide [(L)Pd−CH CH-
from aerobic pathways, either from the direct reaction of
2
+
(
OOtBu)Ph)] were observed with Pd complexes ligated by
molecular oxygen with Pd−H species or via protonation of Pd-
1
,71−75
18
peroxo species.
The use of labeled H O and the
both the Quinox and PBO. Collision-induced dissociation
(CID) performed on this intermediate H shows that the
2
2
1
8
observation of subsequent O-incorporation in Pd−OOH (B)
F
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Article
Scheme 9. Proposed Pathways for the Oxidation of α-D-Styrene with H O to Generate Acetophenone
2
2
structure of this intermediate is indeed the Pd-alkylperoxide
rather than simply the styrene-bound Pd−OOH species I.
The deuterium labeling studies strongly imply that the
oxidation of styrene with H O generates acetophenone by at
abundant ions observed, and the independent synthesis of an
analogous compound with a 1,10-phenanthroline ligand is
consistent with its formulation as a carbon-bound enolate.
63,80
When the oxidation of α-D-styrene was monitored by ESI-
MS, the ion corresponding to the enolate C contained no
deuterium, which is consistent with the observation that
approximately 70% of the acetophenone generated from α-D-
styrene contains no deuterium. When unlabeled styrene is
oxidized with D O , the ion corresponding to the enolate C
2
2
least three competitive pathways (Scheme 9). Control
experiments (Scheme 2) indicate that, in the absence of
H O , acetophenone is formed in 24% yield after 24 h by an
2
2
4
7,76−78
aerobic Wacker reaction mediated by O and H O.
The
2
2
degree to which the aerobic Wacker competes with the H O -
2
2
2
2
mediated oxidation is not clear, but the fact that 74% of the
likewise contains no deuterium, although approximately 67% of
the resulting acetophenone contains one deuterium. This latter
observation could be explained by the protonolysis of the
enolate by D O (Scheme 9). The lack of an observable KIE for
1
8
acetophenone is O-labeled when styrene is oxidized with
18
H2 O (Scheme 4c) suggests that some of the acetophenone
2
may be generated by the aerobic Wacker pathway as the water
2
2
present is 16O. However, the O-labeled acetophenone could
16
the oxidation of α-D-styrene/styrene is consistent with the loss
of the deuterium label prior to Pd-enolate decomposition.
The proposed rearrangement of the Pd-alkylhydroperoxide
to the Pd-enolate is precedented in the chemistry of
18
also come from an oxygen exchange between the O-labeled
1
6
79
acetophenone and the H2 O.
For the H O -mediated oxidation, the labeling and mass
2
2
8
1−83
spectrometry data imply two additional pathways: one that
generates acetophenone by a 1,2-hydride shift from the Pd-
alkylperoxides.
are known to cleave to ketones by the Kornblum−DeLaMare
84
Alkylperoxides bearing α-hydrogen atoms
44,51,54
81−83
82,83
alkylhydroperoxide
and another pathway that generates
rearrangement;
both heterolytic
and homolytic
acetophenone by the protonolysis of the novel Pd-enolate
intermediate. Mimoun and Sigman had previously proposed a
related 1,2-hydride shift to account for the formation of d1-
acetophenone from the oxidation of α-D-styrene with TBHP.
mechanisms for this rearrangement are precedented. Shown
in Scheme 10 are two possible mechanisms for the formation of
the Pd-enolate from the Pd-alkylhydroperoxide intermediate:
one involving deprotonation facilitated by the coordination of
81−83
That approximately 30% of d -acetophenone is observed in the
the hydroperoxide to the cationic Pd center
and another
1
oxidation of α-D-styrene with H O with A is consistent with a
involving hydrogen-atom abstraction of the α-H(D) and
2
2
84
1,2-hydride shift mechanism. However, some fraction of the d1-
homolysis of the O−O bond. Although either of these
processes could account for the loss of the deuterium label
when using α-D-styrene as a substrate (Scheme 4b), our data to
date do not allow us to distinguish between these two
possibilities.
acetophenone could come from the competitive background
aerobic Wacker mechanism.
The observation that a significant percentage (approximately
70%) of the acetophenone generated from α-D-styrene is
unlabeled and that a similar percentage (approximately 67%) of
styrene is deuterated upon oxidation by D O suggests that
another competitive pathway must exist for the formation of
acetophenone. We propose that this pathway involves the Pd
C-bound enolate. The ESI-MS data reveals that ions
corresponding to the Pd-enolate C are among the most
The observation of a Pd-enolate in these H O -mediated
2
2
oxidations was unexpected, as such species are rarely invoked in
the oxidation of olefins by Pd. While we were unable to prepare
this species independently with the PBO ligand, the isotope-
labeling and ESI data provide compelling, if indirect, support
for the intermediacy of carbon-bound Pd-enolates in the H O -
2
2
2
2
G
DOI: 10.1021/jacs.7b05413
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 10. Two Potential Mechanisms for Pd-Enolate
Formation from a Pd-Alkylperoxide
AUTHOR INFORMATION
Corresponding Authors
waymouth@stanford.edu
m.j.muldoon@qub.ac.uk
■
*
*
ORCID
Katherine L. Walker: 0000-0002-7924-8185
Laura M. Dornan: 0000-0003-4177-8364
Richard N. Zare: 0000-0001-5266-4253
Robert M. Waymouth: 0000-0001-9862-9509
Author Contributions
§
K.L.W., L.M.D.: These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
We acknowledge support from the Department of Energy
Office of Basic Energy Science, Catalysis Science Program,
Award DE-SC0005430, R.M.W.), the Air Force Office of
Scientific Research (Grant FA-9550-16-1-0113, R.N.Z.), and
the Department of Employment and Learning (DEL),
Northern Ireland and Queen’s University Ionic Liquids
Laboratories (M.J.M. and L.M.D.). K.L.W. acknowledges the
Center for Molecular Analysis and Design (CMAD, Stanford)
for a fellowship and the National Science Foundation Graduate
Research Fellowship Program for support (GRFP). K.L.W.
would like to thank Erik Jansson for help with the theta
capillary experiments. L.M.D. would like to thank the US-UK
Fulbright Commission for a fellowship.
mediated oxidation of styrene with [(PBO)Pd(NCMe) ]-
2
[
OTf] , A, and therefore provide new insights on oxidation
2
mechanisms of olefins with peroxides.
While Pd-enolate intermediates were also observed in the
oxidation of styrenes with the alkylperoxide TBHP using either
[
(PBO)Pd(NCMe) ][OTf] (Scheme 8) or the (Quinox)-
2
2
5
4
PdCl system (Scheme 7), the observation that 98% of the
2
acetophenone was deuterated with α-D-styrene implies that the
enolate pathway is only a minor contributor when TBHP is
used as the oxidant, irrespective of the diimine ligand. These
results suggest that the different reactivities between the two
peroxide oxidants can be rationalized by the different
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DOI: 10.1021/jacs.7b05413
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