Operando Spectroscopic and Kinetic Characterization of Aerobic Allylic C-H Acetoxylation Catalyzed by Pd(OAc)2/4,5-Diazafluoren-9-one

Article abstract of DOI:10.1021/jacs.9b04699

Allylic C-H acetoxylations are among the most widely studied palladium(II)-catalyzed C-H oxidation reactions. While the principal reaction steps are well established, key features of the catalytic mechanisms are poorly characterized, including the identity of the turnover-limiting step and the catalyst resting state. Here, we report a mechanistic study of aerobic allylic acetoxylation of allylbenzene with a catalyst system composed of Pd(OAc)₂ and 4,5-diazafluoren-9-one (DAF). The DAF ligand is unique in its ability to support aerobic catalytic turnover, even in the absence of benzoquinone or other co-catalysts. Herein, we describe operando spectroscopic analysis of the catalytic reaction using X-ray absorption and NMR spectroscopic methods that allow direct observation of the formation and decay of a palladium(I) species during the reaction. Kinetic studies reveal the presence of two distinct kinetic phases: (1) a burst phase, involving rapid formation of the allylic acetoxylation product and formation of the dimeric Pd^I complex [Pd^I(DAF)(OAc)]₂, followed by (2) a post-burst phase that coincides with evolution of the catalyst resting state from the Pd^I dimer into a π-allyl-Pd^II species. The data provide unprecedented insights into the role of ancillary ligands in supporting catalytic turnover with O₂ as the stoichiometric oxidant and establish an important foundation for the development of improved catalysts for allylic oxidation reactions.

Full text of DOI:10.1021/jacs.9b04699

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Article
Operando Spectroscopic and Kinetic Characterization of Aerobic Allylic
C–H Acetoxylation Catalyzed by Pd(OAc)2/4,5-Diazafluoren-9-one
Jonathan N. Jaworski, Caitlin V. Kozack, Stephen J. Tereniak, Spring
Melody M Knapp, Clark R. Landis, Jeffrey T Miller, and Shannon S. Stahl
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 11 Jun 2019
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Operando Spectroscopic and Kinetic Characterization of Aerobic Allylic
C–H Acetoxylation Catalyzed by Pd(OAc)2/4,5-Diazafluoren-9-one
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Jonathan N. Jaworski, Caitlin V. Kozack, Stephen J. Tereniak, Spring Melody M. Knapp, Clark
R. Landis,† Jeffrey T. Miller,‡ Shannon S. Stahl*†
† Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue
Madison, WI, 53706, United States
‡ David School of Chemical Engineering, Purdue University, 480 Stadium Mall Dr., West
Lafayette, IN 47907, United States
RECEIVED DATE
Abstract: Allylic C–H acetoxylations are among the most widely studied palladium(II)-catalyzed C–H
oxidation reactions. While the principal reaction steps are well established, key features of the catalytic
mechanisms are poorly characterized, including the identity of the turnover-limiting step and the catalyst
resting state. Here, we report a mechanistic study of aerobic allylic acetoxylation of allylbenzene with a
catalyst system composed of Pd(OAc)2 and 4,5-diazafluoren-9-one (DAF). The DAF ligand is unique in its
ability to support aerobic catalytic turnover, even in the absence of benzoquinone or other co-catalysts.
Herein, we describe operando spectroscopic analysis of the catalytic reaction using X-ray absorption and
NMR spectroscopic methods that allow direct observation of the formation and decay of a palladium(I)
species during the reaction. Kinetic studies reveal the presence of two distinct kinetic phases: (1) a burst
phase, involving rapid formation of the allylic acetoxylation product and formation of the dimeric PdI
complex [PdI(DAF)(OAc)]2, followed by (2) a post-burst phase that coincides with evolution of the catalyst
resting state from the PdI dimer into a p-allyl-PdII species. The data provide unprecedented insights into the
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role of ancillary ligands in supporting catalytic turnover with O2 as the stoichiometric oxidant and establish
an important foundation for the development of improved catalysts for allylic oxidation reactions.
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Introduction
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The Wacker process for industrial production of acetaldehyde from ethylene was discovered
in 1959,1 and three years later Vargaftik et al. reported the first example of PdII-mediated allylic
acetoxylation of olefins.2 The latter reaction employed stoichiometric PdCl2 in acetic acid and
generated linear allyl acetates from terminal olefins, such as 1-hexene. Shortly thereafter,
Anderson and Winstein reported allylic acetoxylation of cyclohexene with stoichiometric
Pd(OAc)2.3 In the subsequent half century, extensive efforts were directed toward the development
of catalytic methods for this reaction through the combination of PdII sources with a stoichiometric
oxidant capable of promoting reoxidation of Pd0 to PdII.4 The most widely used oxidant is
benzoquinone,2-13 but other oxidants include CuCl2,14,15 inorganic and organic peroxides,16-19 and
hypervalent iodine reagents.20,21 Molecular oxygen is also a viable oxidant, typically when used in
combination with one or more redox active cocatalysts to facilitate regeneration of the PdII
catalyst.22-30
The development of ligand-supported catalyst systems has stimulated renewed interest in Pd-
catalyzed allylic oxidation reactions in recent years.7,8,12,31 These catalyst systems, which contrast
the simple PdII salts [e.g., PdCl2 or Pd(OAc)2] primarily employed as catalysts during the first four
decades of the field, facilitate catalyst optimization efforts and introduce new opportunities to
achieve catalyst controlled selectivity in the reactions. For example, chelating ligands bearing one
or two sulfoxides have been used in reactions that generate branched allyl acetates from terminal
olefins,7,12 rather than the more commonly observed linear allyl acetates. This ligand-controlled
regioselectivity has been implemented in a number of synthetic applications,32-34 and other ligand-
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supported catalysts have begun showing promise in enantioselective and diastereoselective
reactions.9,35-38 Ligands can also support more efficient catalysis,39-41 as revealed by the ability of
4,5-diazafluoren-9-one (DAF) to support aerobic catalytic turnover, even in the absence of redox-
active co-catalysts.31
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In spite of the long history and recent progress, Pd-catalyzed allylic oxidation reactions remain
at a relatively early stage of development in comparison to other Pd-catalyzed reactions, with none
of the existing catalyst systems exhibiting a full complement of desirable characteristics. For
example, catalyst systems that support aerobic catalytic turnover generate only linear allyl acetate
products with terminal olefins,30,31 while catalyst systems that enable branched product formation
exhibit relatively poor catalytic performance (e.g., 3-10 turnovers, 48–72 h reaction times) and are
not effective with O2 as the oxidant.8,12 The mechanistic origin of these limitations is poorly
understood. While the basic reaction steps associated with Pd-catalyzed allylic C–H oxidation are
well established, few insights are available into the catalytic mechanisms, such as the identity of
the turnover limiting step, the composition of the catalyst resting state, and the influence of
ancillary ligands on these features. Insights of this type have played a major role in advancing
other classes of homogeneous catalytic reactions. For example, Pd-catalyzed cross-coupling
methods are some of the most versatile methods in synthetic chemistry. The basic reaction steps
involved in these reactions were well established by the early 1970s, but the development of more
efficient catalysts, expansion of the synthetic scope and utility, and the emergence of new reaction
classes (e.g., Buchwald-Hartwig reactions) in subsequent decades benefitted greatly from
mechanistic studies of catalytic reactions.42-45 For example, insights into the kinetic bottlenecks of
the catalytic cycle and characterization of the catalyst species, including on- and off-cycle
species,46-48 provided a foundation for the discovery of new ligands,49-51 catalyst systems,52 and
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reaction conditions that overcame existing limitations.53,54 The iterative synergy between empirical
and mechanistic studies is much less evident in the field of Pd-catalyzed allylic oxidation reactions;
however, the emergence of ligand-supported catalyst systems amenable to this approach is still
relatively recent.
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Here, we report the first kinetic and mechanistic investigation of a Pd-catalyzed method for
aerobic allylic C–H oxidation, focusing on DAF/Pd(OAc)2-catalyzed acetoxylation of
allylbenzene, for which the basic steps are illustrated in Scheme 1. The initial report of this catalyst
revealed that DAF is unique in its ability to support aerobic catalytic turnover among a series of
(bi)pyridyl-based ligands (Scheme 2),31,55,56 and investigation of stoichiometric reactions with p-
allyl-PdII species showed that DAF promotes reductive elimination57 of the allyl acetate
product.31,58 The implications of these observations were not extended to catalytic conditions,
however, and the present study provides a comprehensive analysis of the catalytic mechanism,
including kinetic studies and operando X-ray absorption spectroscopy (XAS) and NMR
spectroscopic analysis of the catalytic reaction, which reveal changes in the identity of the turnover
limiting step and evolution of the catalyst species during the reaction. The results provide valuable
insights into Pd-catalyzed allylic oxidation reactions and the ability of DAF to support aerobic
catalytic turnover,59-69 and this study establishes an important foundation for future empirical and
mechanistic efforts directed toward the identification of more efficient and synthetically useful
allylic C–H oxidation catalyst systems.
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Scheme 1. Proposed Mechanism for DAF-Promoted Pd-Catalyzed Aerobic Acetoxylation.
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5% Pd(OAc)2/DAF (1), 0.2 equiv NaOAc
Ph
Ph
OAc
3:1 dioxane/AcOH, O2 (1 atm), 60 °C
8
9
Catalyst
Regeneration
H2O2
R
C-H Activation
HOAc
DAF/Pd(OAc)2
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1
2 HOAc
O
-OAc
R
(DAF)Pd+
N
N
O
O
Pd
N
N
4,5-diazafluorenone (DAF)
(Reversible)
Reductive
Elimination
R
OAc
(DAF)Pd0
Catalyst
Oxygenation
O2
R
OAc
Scheme 2. DAF-Promoted Pd-Catalyzed Aerobic Allylic Acetoxylation of Alkenes.31
5 mol% Ln/Pd(OAc)2
Ph
Ph
OAc
80 °C, AcOH, O2 (1 atm), 18 h
Ln = None
4%
N
N
N
N
4%
4%
9%
O
N
N
N
N
2
N
N
N
81%
4%
Results and Discussion
Initial mechanistic observations. In a recent study, we showed that DAF/Pd(OAc)2-catalyzed
allylic acetoxylation of allylbenzene exhibits a kinetic burst at the beginning of the reaction and
generates a dimeric PdI species under the catalytic conditions.70 These preliminary results,
reproduced in Figure 1, provided a starting point for the present investigation, with the goal of
understanding the origin and implications of these observations. The burst is accompanied by a
change in the color of the reaction solution from yellow to red, but, as the reaction progresses past
the burst, the reaction solution changes color again from red to yellow. The latter color persists for
the remainder of the reaction.71 A red PdI dimer, [PdI(DAF)(OAc)]2 2, was independently
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synthesized and characterized by X-ray crystallography (Figure 1B), and it exhibits a UV-visible
absorption spectrum that closely matches the UV-vis spectra observed from the catalytic reaction
mixture (Figure 1C).70
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5% Pd(OAc)2/DAF (1), 0.2 equiv NaOAc
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Ph
OAc
3:1 dioxane/AcOH, O2 (1 atm), 80 °C
A.
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AcO
Pd
N
N
O
O
N
Pd
N
OAc
2
Pd
Pd
Figure 1. Previous observations from allylic acetoxylation of allylbenzene catalyzed by
DAF/Pd(OAc)2. (A) Time course of the acetoxylation reaction at 80 °C. (B) Drawing and X-ray
crystal structure of the PdI dimer, [PdI(DAF)(OAc)]2 2. (C) UV-vis absorption spectra obtained
during the burst phase of the catalytic reaction. Figures adapted with permission from ref. 70.
Copyright 2017 John Wiley & Sons, Inc.
Interrogation of the catalyst speciation by X-ray absorption spectroscopy. The data noted
above imply that the oxidation state of the Pd catalyst changes during the course of the reaction.
Palladium K-edge X-ray absorption spectroscopy probes the excitation of Pd 1s electrons, and the
“near edge” absorption energy, corresponding to the 1s ® 5p orbital transition, provides insight
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into the oxidation state of Pd complexes.72,73 This technique has been used to probe a number of
homogeneous Pd-catalyzed reactions,74-79 including recent analysis of a Pd-catalyzed aerobic
oxidation of an aromatic C–H bond.80 In order to conduct analogous experiments for the allylic
acetoxylation reaction, a reactor was designed and constructed to enable operando studies on the
high photon-flux beamline at Argonne National Laboratories (see Supporting Information for
details; Figures S3–S6).
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Pd K-edge XANES spectra were obtained for a series of Pd0, PdI, and PdII reference
compounds: Pd0 (Pd2(dba)3), PdI ([PdI(DAF)(OAc)]2 (2)), and PdII (1:1 DAF/Pd(OAc)2 (1);
[PdII(p-cinnamyl)(OAc)]2 (3); and [PdII(DAF)(p-cinnamyl)]BF4 (4)). Similar spectra were then
acquired during the course of the catalytic reaction,81 with a time course of the edge energy shown
together with selected reference compounds in Figure 2A. Upon initiation of the reaction by
injecting allylbenzene, the edge energy shifts rapidly from its initial position associated with 1 to
a lower energy position, consistent with reduction of the catalyst during the burst (spectrum B).
The new edge energy is very similar to that of the PdI dimer reference (cf. 2, Figure 2B). Analysis
of the extended X-ray absorption fine-structure (EXAFS) region of the spectra revealed three
prominent scattering peaks during the first 13 min of the reaction, and these peaks are very similar
to those observed with an authentic sample of the PdI dimer 2 (Figure 3A). Collectively, the
XANES and EXAFS spectra support the formation of PdI species 2 as a catalytic intermediate
during the burst phase of the reaction.
As the reaction proceeds, the edge increases gradually to higher energy, ultimately reaching an
energy intermediate between that of DAF/PdII(OAc)2 1 and the PdI dimer 2 (Figure 2A). An
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1.0
A.
B.
Pd0 – Pd2(dba)3
PdI – [PdI(DAF)(OAc)]2 (2)
PdII – DAF/Pd(OAc)2 (1)
End of Burst (13 min) (B)
Post-Burst (PB)
1
0.8
0.6
0.4
0.2
0
0.75
1 → B
1
0.50
0.25
0.0
PdI – [PdI(DAF)(OAc)]2 (2)
PdII – DAF/Pd(OAc)2 (1)
End of Burst (13 min) (B)
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1 → B
24.35
24.36
24.37
2
3
Isosbestic Point
Energy (keV)
1.0
0.75
0.50
0.25
0.0
C.
B → PB
[Pd(OAc)(p-cinnamyl)]2 (3)
[Pd(DAF)(p-cinnamyl)]+ BF4- (4)
PdII – DAF/Pd(OAc)2 (1)
Post-Burst (PB)
4
24.345
24.350
24.355
24.360
24.365
24.370
24.35
24.36
24.37
Energy (keV)
Energy (keV)
Figure 2. XAS K-edge analysis of Pd reference compounds and the catalyst during the allylic
oxidation reaction (note: "B" refers to the "burst" phase and "PB" refers to the "post-burst" phase
of the reaction). (A) Operando Pd K-edge time course overlay from 13-110 minutes with overlaid
references for comparison. (B) Operando Pd K-edge time course overlay of 0 and 13 minutes with
comparison of [PdI(DAF)(OAc)]2 (2) reference. (C) Comparison of the post-burst with neutral p-
allyl PdII acetate dimer, [PdII(p-cinnamyl)(OAc)]2 (3) and cationic p-allyl PdII monomer,
[PdII(DAF)(p-cinnamyl)]BF4 (4). The catalytic reaction was carried out on a 3 mL scale in 3:1
dioxane:AcOH where [allylbenzene] = 0.27 M, [NaOAc] = 0.54 mM, and [DAF/Pd(OAc)2] = 13.5
mM in a PEEK cell with an O2 balloon.
PdI – [PdI(DAF)(OAc)]2 (2)
End of Burst (13 min) (B)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
1.4
1.2
1
[Pd(OAc)(p-cinnamyl)]2 (3)
[Pd(DAF)(p-cinnamyl)]+ BF4- (4)
PdII – DAF/Pd(OAc)2 (1)
Post-Burst (PB)
B.
A.
0.8
0.6
0.4
0.2
0
1
2
3
4
5
6
1
2
3
4
5
6
Radial Distance (Å)
Radial Distance (Å)
Figure 3. Operando EXAFS k2-weighted four transforms at t = 13 min and post-burst turnover.
(A) Comparison of the EXAFS at t = 13 min and PdI dimer [PdI(DAF)(OAc)]2 (2) reference. (B)
Comparison of the EXAFS from the post-burst period of the catalytic reaction with DAF/Pd(OAc)2
(1) and the p-allyl-PdII reference compounds (3) and (4). The catalytic reaction was carried out on
a 3 mL scale in 3:1 dioxane:AcOH where [allylbenzene] = 0.27 M, [NaOAc] = 0.54 mM, and
[DAF/Pd(OAc)2] = 13.5 mM in a PEEK cell with an O2 balloon.
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isosbestic point is evident in the XANES spectra during this phase of the reaction (cf. Figure 2A),
suggesting that the PdI dimer converts directly into a new Pd species, which has a higher formal
oxidation state. The XANES spectrum for the catalyst resting state in the post-burst phase (PB) is
clearly different from the DAF/PdII(OAc)2 pre-catalyst 1, and it closely resembles the spectra of
the independently prepared p-allyl-PdII species, the dimeric species [PdII(p-cinnamyl)(OAc)]2 (3)
and the monomeric DAF-ligated p-allyl-PdII species, [PdII(DAF)(p-cinnamyl)]BF4 (4) (Figure
2C). The changes evident in the XANES spectra were also evident in a comparison of the inflection
point in the spectra for the Pd species present during the reaction relative to the approximate edge
energies of the PdI and PdII reference compounds (Figure 4). Analysis of the EXAFS spectral
region during the post-burst portion of the reaction also reveal similarities between the post-burst
PdII intermediate (PB) and the p-allyl-PdII reference compounds (Figure 3B).
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5% Pd(OAc)2/DAF (1), 0.2 equiv NaOAc
Ph
0.27 M
Ph
OAc
3:1 dioxane/AcOH, 80 °C
PEEK Cell, 1 atm O2 balloon
24.3550
24.3545
24.3540
DAF/Pd(OAc)2, T=0 (1)
24.3535 [Pd(DAF)(p-cinnamyl)]+ (4)
[Pd(OAc)(p-cinnamyl)]2 (3)
24.3530
24.3525
24.3520
PdI Dimer (2)
24.3515
0
50
100
150
200
Time (min)
Figure 4. Time course plot of the XANES edge energy of the Pd catalyst during the catalytic
allylic acetoxylation reaction, relative to the edge energies corresponding to well-defined Pd
reference compounds.
Interrogation of catalyst speciation by NMR spectroscopy. The catalyst speciation during
the reaction time course was also interrogated by NMR spectroscopic methods. The reaction
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employs a mixture of AcOH/NaOAc as the solvent and source of acetate nucleophile, and the
predominant palladium species observed by 1H NMR spectroscopy at the start of the reaction was
identified as an "ate" complex, Na[(k1-DAF)PdII(OAc)3] (5). This assignment was supported by
NMR integrations and independent titration studies involving addition of NaOAc to a solution of
DAF and PdII(OAc)2 (Figures S20-S24). A time course of the reaction was monitored by 1H NMR
spectroscopy by using a sealed NMR tube pressurized with 3.2 atm of static O2. The data reveal
rapid product formation with concurrent conversion of the PdII ate complex 5 into the PdI dimer 2
(Figure 5). The concentration of PdI maximizes at the end of the kinetic burst of product formation
(t ~ 20 min), after which the rate of cinnamyl acetate product formation decreases to a steady-state
rate. Unligated DAF becomes evident in the reaction mixture and its concentration increases
during the steady state reaction period (Figure 5 - expansion).
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Figure 5. Initial investigations into the resting state of the catalyst as followed by an NMR time
course of product formation and DAF speciation with 3.2 atm static O2 at 60 °C and expansion of
DAF speciation in the NMR time course. Lines reflect smooth fits to the data to guide the eye.
To investigate the catalyst speciation at early reaction times (i.e., during the burst period),
thick-walled NMR tubes were prepared with different pressures of O2.82-84 Plots showing the
formation of cinnamyl acetate and the PdI dimer (2) at 0.2-6.2 atm O2 are provided in Figure 6.
Nearly identical rates of product formation (i.e., independent of the pO2) are evident during the
burst phase; however, the rate of product formation after the burst phase increases with increasing
pO2 (Figure 6A). Complementary analysis of the Pd species shows that the amount of PdI dimer 2
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generated during the burst phase decreases with increasing pO2 (Figure 6B; see Supporting
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Cinnamyl Acetate
[PdI(μ-DAF)(OAc)]2 2
B.
A.
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0.2 atm
1.2 atm
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0.2 atm
3.2 atm
6.2 atm
0
0
20 40 60 80 100 120
Time (min)
0
20 40 60 80 100 120
Time (min)
Figure 6. Time courses with different initial pressures of O2 (static) monitored by NMR
spectroscopy. Conditions: [DAF] = 13.5 mM, [Pd(OAc)2] = 13.5 mM, [allylbenzene] = 0.27 M,
[NaOAc] = 54 mM, 60 °C. (A) [cinnamyl acetate] over time at pO2 = 0.2 to 6.2 atm. (B) [[PdI(μ-
DAF)(OAc)]2] over time at pO2 = 0.2 to 6.2 atm. Lines reflect a smooth fit to the data to guide the
eye.
To complement these data, the recently developed Wisconsin High Pressure NMR Reactor
(WiHP-NMRR)85-87 was used to monitor the dependence of the rate on O2 pressure (pO2). This
apparatus provides continuous gas circulation in the liquid during the NMR relaxation delay (d1).
This dynamic gas supply allows for better control of dissolved O2 concentration during the reaction
and avoiding complications that can arise from the lack of gas-liquid mixing in an NMR tube when
a static pressure of O2 is used.88 Consistent with the data in Figure 6, the rate of product formation
during the burst phase was not affected by changes in pO2, while a saturation dependence of the
rate on pO2 was evident from kinetic data after the burst (Figure 7).
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5% Pd(OAc)2/DAF (1)
3:1 dioxane-d8/AcOD-d4, 60 °C
OAc
F
F
O2 pressures varied
0.269 M
WiHP-NMRR
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0
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pO 2(atm)
pO 4(atm)
2
2
Figure 7. Dependence of the rate of allylic acetoxylation on pO2 (dynamic) during (A) burst and
(B) post-burst phase of the reaction. Conditions: [DAF/PdII(OAc)2] = 13.5 mM, [4-
fluoroallylbenzene] = 0.27 M, 0–4.6 atm pO2 using 9% O2 in N2, 60 °C; NaOAc was not used in
order to prevent clogging of the gas inlet capillary. ds = 0, ns = 2, d1 = 4s, circulation delay between
scans = 0.5 s, aq = 0.3 s. The line in (B) reflects a smooth fit to the data to guide the eye.
Another set of studies was conducted to probe the influence of substrate concentration on the
reaction rate and Pd speciation during the early periods of the reaction (0.135–1.08 M
allylbenzene). The overall rate of product formation increased with higher [allylbenzene] (Figure
8A). An increase in the rates of formation and decay of the PdI dimer 2 with increasing
[allylbenzene] results in a similar maximum concentration of 2 under all conditions, but a shorter
lifetime for this species at higher substrate concentration (Figure 8B).
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Cinnamyl Acetate
[PdI(μ-DAF)(OAc)]
2 2
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0.54 M
0.54 M
0.27 M
0.135 M
1.08 M
0
0
20 40 60 80 100 120
Time (min)
0
20 40 60 80 100 120
Time (min)
Figure 8. Time courses with different concentrations of allylbenzene monitored by NMR
spectroscopy under static O2 pressure. Conditions: [DAF] = 13.5 mM, [Pd(OAc)2] = 13.5 mM,
[allylbenzene] = 0.135-1.08 M, [NaOAc] = 54 mM, 60 °C, 1.2 atm O2 (static). (A) [cinnamyl
acetate] over time. (B) [[PdI(μ-DAF)(OAc)]2] over time. Lines reflect a smooth fit to the data to
guide the eye.
Kinetic studies and isotope effects. More thorough kinetic studies were performed to probe
the contributions of each of the reaction components to the reaction rate during the burst and post-
burst phases of the reaction (Figures 9 and 10). These studies were conducted at 40 °C and 80 °C,
respectively, by removing aliquots of the reaction mixture and analyzing product formation by gas
chromatography (GC). Analysis of the burst phase was carried out at lower temperature to enable
acquisition of more precise data, but the results are consistent with general trends observed at
higher temperatures. A linear dependence of the rate on the 1:1 DAF/PdII(OAc)2 catalyst
concentration [1] was observed during the burst phase, while a slight saturation dependence was
evident in the post-burst regime (Figures 9A and 10A, respectively). In both the burst and post-
burst phases, the rate exhibits a nearly linear dependence on [DAF] up to a 1:1 DAF/PdII(OAc)2
ratio; however, increasing [DAF] beyond a 1:1 ratio decreases the rate of the burst, while it does
not affect the rate during post-burst turnover (Figures 9B and 10B). A nearly linear dependence on
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Pd(OAc)2, DAF, NaOAc
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Ph
Ph
OAc
1.2
3:1 dioxane/AcOH, 1 atm O2, 40 °C
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0
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1.5
2
[DAF/Pd(OAc)2]1(mM)
[DAF]3(mM)
[allylbenzene]3(M)
Figure 9. Kinetic dependencies of reaction components for the burst phase. All experiments were
performed at 40 °C in an orbital mixer with 1 atm of O2 and 54 mM NaOAc. (A) [DAF] =
[Pd(OAc)2] = 0-18 mM, [allylbenzene] = 0.27 M. (B) [DAF] = 0-54 mM, [Pd(OAc)2] = 13.5 mM,
[allylbenzene] = 0.27 M. (C) [DAF/PdII(OAc)2] = 13.5 mM, [allylbenzene] = 0.14-1.8 M. Average
of multiple runs. Error within 10%. The line in (B) reflects a smooth fit to the data to guide the
eye.
Pd(OAc)2, DAF, NaOAc
Ph
Ph
OAc
2.5
3:1 dioxane/AcOH, 1 atm O2, 80 °C
0.6
0.5
0.4
0.3
0.2
0.1
0
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B.
C.
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60
0
0.5
1
1.5
2
[DAF/Pd(OAc)2]3(mM)
[DAF]3(mM)
[allylbenzene]0(M)
Figure 10. Kinetic dependencies of reaction components after the burst phases of the reaction. All
experiments were performed at 80 °C in an orbital mixer with 1 atm of O2 and 54 mM NaOAc.
(A) [DAF/PdII(OAc)2] = 0-18 mM, [allylbenzene] = 0.27 M. (B) [DAF] = 0-54 mM, [Pd(OAc)2]
= 13.5 mM, [allylbenzene] = 0.27 M. (C) [DAF/PdII(OAc)2] = 13.5 mM, [allylbenzene] = 0.14-1.8
M. Average of multiple runs. Error within 10%. The lines for (A) and (B) represents a hyperbolic
fit to the data, i.e., rate = c1·x /(c2 + c3·x), with a non-zero intercept for (B).
[allylbenzene] was observed in the burst and post-burst phases (Figures 9C and 10C), but the data
intersect at the origin for the burst kinetics, while the post-burst kinetic data exhibit a substantial
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non-zero intercept. The positive order in [allylbenzene] in both cases correlates with the kinetic
influence of allylbenzene on the rate of formation and decay of the PdI dimer 2 observed in the
NMR spectroscopic studies shown in Figure 8B.
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Two deuterium-labeled substrates were synthesized to probe intramolecular and
intermolecular kinetic isotope effects (KIEs). 4-Allylbiphenyl (6) was selected as the substrate for
these studies because it is not volatile and is easier to purify than the parent allylbenzene.89
Independent rates were measured with 6 and 6-d2 substrates, and intramolecular competition KIEs
with 6-d1 were determined via 1H NMR spectroscopy by quantifying the product formation derived
from C–H or C–D activation. The primary KIEs evident in the burst phase from both sets of
experiments (Table 1, entries 1 and 2) are rather small, but very similar to that observed in a recent
allylic amination reaction.90 In the period of the reaction after the burst, the intramolecular
competition experiment revealed a KIE similar to that observed in the burst phase (cf. entry 3 vs
entries 1 and 2), but essentially no KIE was observed from the independent rate measurements
(entry 4).
Table 1. Kinetic Isotope Effects Obtained via Independent Rate Measurements with 6/6-d2-
Labeled Substrates and via Intramolecular Competition Using the 6-d1-Labeled Substrate.
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II
p
Evolution of a -cinnamyl-Pd resting state following the burst. The XAS data described
5
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above implicate the possibility of a p-allyl-PdII species as the catalyst resting state during the post-
1
burst phase of the reaction. Initial attempts to observe such a species directly by H NMR
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spectroscopy were unsuccessful, however, possibly reflecting a high degree of fluxionality
associated with such a species.91 -93 The NMR time course in Figure 5 suggests that the DAF ligand
dissociates from the Pd center during the reaction, a feature that could further contribute to the
fluxionality of a p-allyl-PdII species and complicate its detection by 1H NMR spectroscopy.
To overcome this complication, we analyzed the catalytic acetoxylation of 4-
fluoroallylbenzene to probe the reaction by 19F NMR spectroscopy. Operando analysis of the
catalytic reaction was conducted throughout the time course using the WiHP-NMRR in an effort
to identify possible intermediates. During the burst phase, 19F NMR resonances are evident only
for the alkene starting material (-113.4 ppm) and cinnamyl acetate product (-110 ppm) (e.g., Figure
11a). As the reaction proceeds, however, a new resonance becomes evident at -109.2 ppm. (Figure
11b; see Figure S12 for additional spectra). The chemical shift of this peak, denoted I, is very
similar that observed from an independently prepared sample of the 4-fluorophenyl derivative of
the p-cinnamyl-PdII dimer 3 (i.e., 3F) and the same compound in the presence of DAF (DAF:Pd =
1:1) (Figures 11c and 11d). Integration of this resonance during the course of the catalytic reaction
show that this species accounts for nearly all of the Pd catalyst present in solution (Figure 12),
thereby providing direct support for evolution of the catalyst into a p-allyl-PdII resting state
following the burst.
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Figure 11. In situ detection of a p-cinnamyl-PdII resting state during the acetoxylation of 4-
fluoroallylbenzene using the WiHP-NMRR. Pd(OAc)2 as precatalyst, (A) 20 min and (B) 10 h
after reaction initiation, 3F/DAF without substrate (C), and 3F under ambient conditions without
other reaction components (D). Conditions: [Pd] = 13.5 mM, [DAF] = 13.5 mM (except for the
bottom spectrum, where [DAF] = 0), 3-fluoroanisole internal standard. [I.S.] = 55.7 mM, 3:1
dioxane:AcOD-d4.
Figure 12. Time course of DAF/PdII(OAc)2-catalyzed allylic acetoxylation of 4-
fluoroallylbenzene analyzed by 19F NMR spectroscopy using the WiHP-NMRR. See Figure 11 for
reaction conditions. The superimposed points in the red data correspond to the representative NMR
spectra depicted in the Supporting Information, Figure S12.
In light of these observations, the initial time course of the catalytic acetoxylation of
allylbenzene was analyzed by comparing reactions conducted with Pd(OAc)2 and [PdII(p-
cinnamyl)(OAc)]2 (3) as the source of Pd catalyst, under otherwise identical conditions. The data
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in Figure 13 show that no burst is observed when 3 is used as the Pd precatalyst, and the initial
rate in this reaction resembles that of the post-burst rate observed from the reaction initiated with
Pd(OAc)2 as the precatalyst.
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Figure 13. Kinetic interrogation of the resting state. Pd precatalyst = DAF/PdII(OAc)2 1 or [PdII(p-
cinnamyl)(OAc)]2 3.
II
p
Investigation of allyl acetate reductive elimination from [Pd ( -cinnamyl)(OAc)]2.
Identification of a p-allyl-PdII resting state during the catalytic reaction prompted us to prepare the
well-defined [PdII(p-cinnamyl)(OAc)]2 species 3 to explore its reactivity under catalytically
relevant conditions (Figure 14). As a control experiment, negligible reductive elimination of
cinnamyl acetate57 was observed under N2 in the absence of the DAF ligand (Figure 14, condition
a). Some reactivity was observed upon addition of DAF to the solution of 3 under N2 (condition
b), consistent with previously reported observations,31 and further enhancement of the reaction
was observed upon adding an equivalent of DAF/PdII(OAc)2 (condition c). The latter conditions
led to significant formation of the PdI dimer 2. These reactions were also enhanced by conducting
the reaction under an atmosphere of O2 (conditions d and e). The last of these conditions (e)
resemble the reaction conditions present during the burst phase of the catalytic reaction, when
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allylic C–H activation and formation of an allyl-PdII intermediate will take place in the presence
of additional DAF/PdII(OAc)2 pre-catalyst, which can react with the Pd0 species formed upon
reductive elimination of cinnamyl acetate and generate the PdI dimer 2 (see further discussion
below). The presence of allylbenzene has negligible effect on the rate of reductive elimination (see
Figure S17 in the Supporting Information), suggesting that the beneficial kinetic effect of
allylbenzene after the burst (cf. Figure 10C) does not arise from the reductive elimination step, but
rather from its contribution to catalyst speciation (i.e., by promoting conversion of PdI dimer 2 into
the steady-state PdII catalyst; cf. Figure 8B).
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Additives
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e. DAF, DAF/Pd(OAc)2, O2
8
d. DAF, O2
c. DAF, DAF/Pd(OAc)2, N2
6
4
2
0
b. DAF, N2
a. None, N2
0
40
80
120
160
Time (min)
Figure 14. Stoichiometric reductive elimination reactions of [PdII(p-cinnamyl)(OAc)]2.
Conditions: [PdII(cinnamyl)(OAc)]2 = 6.75 mM, [DAF] = 13.5 mM, [DAF/Pd(OAc)2] = 13.5 mM,
[NaOAc] = 54 mM, 60 °C, 3:1 dioxane:AcOD-d4, N2 or O2. The lines reflect smooth fits to the
data to guide the eye.
Catalytic mechanism: Overview of observations. The data presented above provide key
insights into the DAF/PdII(OAc)2-catalyzed acetoxylation of allylic C–H bonds, including factors
that affect the rate of the reaction and the identity of the catalyst resting state (Table 2). Briefly,
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the kinetic burst phase evident at the beginning of the reaction is characterized by a primary
deuterium KIE (independent rate measurement) and a lack of rate-dependence on pO2, and the Pd
catalyst evolves from a DAF-ligated PdII-acetate species into a DAF-bridged PdI dimer. The
ensuing post-burst phase lacks a primary KIE, exhibits a rate-dependence on pO2, and the Pd
catalyst resting state evolves from the DAF-bridged PdI dimer into p-allyl-PdII species with bound
and unbound DAF ligand.
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Table 2. Summary of the Mechanistic Observations for the Burst and Post-Burst Regimes.
Burst
Post-Burst
Primary Allylic
C–H KIE
Yes
No
pO2 Dependence
No
Yes
DAF ligated to
Appearance of
free DAF
DAF Speciation
PdII or PdI
PdI dimer →
Catalyst
Evolution
DAF/PdII →
PdI dimer
p-allyl-PdII species
Turnover-
Limiting Step
Pd0 oxidation
by O2
C–H activation
Analysis of the burst phase of the reaction. The deuterium kinetic isotope effect observed
during the burst supports allylic C–H activation as the rate-limiting step during this phase.90,94,95
The resulting allyl-PdII intermediate undergoes reductive elimination of cinnamyl acetate to afford
a Pd0 species that reacts with a DAF/PdII(OAc)2 species to afford the PdI dimer 2 (Scheme 3; cf.
Figure 14). The mechanistic details of reduction elimination and PdII/Pd0 comproportionation steps
are not well understood and warrant attention in future studies, but formation of analogous dimeric
PdI species has been studied extensively in Pd-catalyzed cross-coupling reactions.52,96 PdI species
have also been identified in oxidative carbonylation reactions,97-100 but the DAF-ligated dimer 2
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represents the first example of a PdI intermediate identified in ligand-supported Pd-catalyzed
aerobic oxidation reactions.70 A second example was recently reported by Albéniz and Maseras,
who detected a PdI dimer in the aerobic oxidative homocoupling of alkynes with Ph3P as an
ancillary ligand.101 The use of PdI dimers as air-stable catalyst precursors in many non-oxidative
coupling reactions reactions52 raises prospects for similar opportunities in aerobic oxidation
reactions.
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Scheme 3. Mechanism of the Burst Phase of DAF/PdII(OAc)2-Catalyzed Allylic Acetoxylation.
O
Na
R.D.S.
N
N
R
- HOAc
1° KIE
- NaOAc
O
O
N
N
OAc
OAc
AcO Pd
N
Pd+
AcO Pd
AcO
N
R
-OAc
R
5
8
4
Na
N
O
OAc
AcO Pd
AcO
N
OAc
N
5
Pd
N
O
Comproportionation and
C-O Bond Formation
O
N
Pd
N
OAc
R
OAc
2
NaOAc
Analysis of the post-burst phase of the reaction. The burst phase concludes as DAF-ligated
PdII-acetate species are depleted and the PdI dimer concentration reaches a maximum. The
collection of kinetic and spectroscopic insights obtained from the reaction following the burst are
incorporated into the overall catalytic mechanism proposed in Scheme 4. Previous studies have
shown that the PdI dimer can undergo oxidation to a DAF/PdII-acetate species in the presence of
O2,70,102 and the NMR data in Figure 10 show that allylbenzene promotes the conversion of PdI
dimer into a new PdII form of the catalyst, identified as the allyl-PdII species 3 (cf. Figure 12),
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Scheme 4. Full Mechanism of DAF/PdII(OAc)2-Catalyzed Allylic Acetoxylation, Including the
Burst and Post-Burst Phases of the Reaction.
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7
8
9
R
Burst
DAF/Pd(OAc)2
DAF/Pd(OAc)2
See Scheme 3
1
R
H2O2
R
OAc
+ HOAc
+ NaOAc
8
2 HOAc
Na
R
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OAc
Pd
N
N
HOAc
O
Post-
Burst
N
N
N
O
O
O
OAc
N
2
Pd
O
N
Pd
AcO Pd
AcO
N
9
OAc
-OAc
(DAF)Pd+
OAc
5
-DAF
Pd
2
+DAF
O2
R
R
2
[(DAF)Pd0]
4
3
7
R
OAc
which serves as the catalyst resting state following the burst. This structure is consistent with the
appearance of free DAF ligand under these conditions. The stoichiometric reactivity studies with
3, depicted in Figure 14, show that reductive elimination of cinnamyl acetate57 is promoted by
DAF, O2, and DAF/Pd(OAc)2; however, following the burst, excess DAF/Pd(OAc)2 species are
no longer available in the reaction mixture to promote reductive elimination. This difference
between the burst and post-burst conditions rationalizes the change in catalyst speciation and
turnover-limiting steps (cf. Table 2). These changes, in turn, account for the lack of a deuterium
KIE for C–H activation during the post-burst phase of the reaction and the similarity between the
of post-burst turnover rate and the rate of the reaction when p-allyl-PdII dimer 3 is used as the pre-
catalyst (cf. Figure 13).
DAF plays an important role in supporting catalytic turnover under steady-state (post-burst)
conditions by facilitating reductive elimination of cinnamyl acetate from the allyl-PdII species.
DAF coordination to the allyl-PdII dimer 3 is proposed to generate the monomeric DAF-ligated
allyl-PdII species 4, which can undergo reversible formation of cinnamyl acetate (Figure 15).31,58
This reaction is driven by trapping of Pd0 (7) by O2, which is proposed to be the turnover limiting
step during this phase of the reaction (Table 2).103,104 No build-up of PdI dimer 2 is observed after
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the burst phase due to the low steady-state concentration of the DAF/PdII-acetate species available
to trap Pd0 species generated in the reductive elimination step. The reaction of O2 with the Pd0
species 7 is proposed to proceed in a manner similar to previously reported reactions between O2
and related well-defined nitrogen-chelated Pd0 model complexes.41,105-107
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OAc
DAF/Pd(OAc)2
Alkene Binding
C-H Activation
1
N Pd N
Burst
kC > kA
C
N Pd N
OAc
2
Ph
N
N
A
B
Pd+
[(DAF)Pd0]
DAF/Pd(OAc)2
–OAc
1
7
R
OAc
R
HOAc
4
N
N
O
Post-Burst
C′
Pd
O
kA > kC′
O2
9
Figure 15. Reaction scheme depicting trapping of Pd0 by PdII (1) or by O2 during the burst and
post-burst phases of the reaction, with concurrent changes in the rate determining step of the
reaction.
As noted in the Introduction, very few mechanistic studies of Pd-catalyzed allylic oxidation
reactions have been reported. The two most thorough precedents were reported recently by the
groups of Labinger/Bercaw10 and Fristrup,94 and focused on bipyrimidine (bpym)/PdII(OAc)2 and
bis(sulfoxide)/PdII(OAc)2 catalyst systems, respectively. The turnover-limiting step in the former
reaction was identified as alkene binding to (bpym)PdII(OAc)2, while the latter reaction was
attributed to C–H activation. The presence of a p-allyl-PdII catalyst resting state and turnover-
limiting reductive elimination are unprecedented, and these two observations likely reflect the use
of O2, rather than benzoquinone, as the stoichiometric oxidant. Benzoquinone was used as the
stoichiometric oxidant in both of the previously studied catalytic reactions, and it is known to
promote reductive elimination from p-allyl-PdII species.7,58,108,109 These considerations highlight
opportunities for the development of improved catalyst systems and/or ligand designs that support
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more effective reductive elimination while also enabling efficient reaction of Pd0 with O2. Efforts
toward this end have been initiated.
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Conclusion.
This study has implemented a number of different experimental approaches to gain insights
into a Pd-catalyzed allylic oxidation reaction that is capable of using O2 as the stoichiometric
oxidant due to the use of 4,5-diazafluoren-9-one (DAF) as an ancillary ligand. Operando XAS and
NMR spectroscopic studies provide clear evidence for two kinetic phases, characterized by
different catalyst resting states and turnover-limiting steps. The initial burst phase features the
formation of an unusual DAF-bridged dimeric PdI species, which then evolves into a p-allyl-PdII
catalyst resting state following the burst phase of the reaction. Allylic C–H activation is the rate
determining step during the burst phase, while catalyst reoxidation by O2 is turnover-limiting
following the burst. The results described herein provide valuable new insights into this widely
studied catalytic reaction, perhaps most importantly shedding light on the contribution of ancillary
ligands to key steps in the catalytic mechanism. These insights provide a foundation for the
exploration of new ancillary ligands and catalyst designs capable of efficient Pd-catalyzed allylic
C–H oxidation.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge on the ACS
Publications website: Experimental details and compound characterization data (PDF);
Crystallographic data for 3 and 4 (CIF).
AUTHOR INFORMATION
Corresponding Author
*stahl@chem.wisc.edu
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Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
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We would like to thank Dr. Nicholas J. Beach, Mr. Steve Myers and Mr. Kendall Schneider for
their assistance in designing and constructing the reactor used at Argonne. Drs. James R. Gallagher
and James B. Gerken were instrumental in performing XAS experiments on the beamline. We are
grateful to Dr. Kelsey Miles, Dr. Brian Dolinar and Dr. Ilia Guzei for assistance in performing
XRD analysis. Drs. Jamie Y. C. Chen and Paul White for insightful discussions. This work was
funded by the NSF (CHE-1665120), and builds upon initial work supported by the NIH (R01
GM67173). NMR instrumentation was supported by NSF CHE-1048642, NSF CHE-9709065,
NIH S10 OD012245 and a generous gift from Paul J. and Margaret M. Bender. The WiHP-NMRR
was supported by the Dow Chemical Company. Use of the Advanced Photon Source is supported
by the U.S. Department of Energy, Office of Science, and Office of Basic Energy Sciences, under
Contract DE-AC02-06CH11357. MRCAT operations are supported by the Department of Energy
and the MRCAT member institutions. C. V. K. was supported in part by the National Science
Foundation Graduate Research Fellowship Program under Grant No. DGE-1256259. Any
opinions, findings, and conclusions or recommendations expressed in this material are those of the
authors and do not necessarily reflect the views of the National Science Foundation. Support was
also provided by the Graduate School and the Office of the Vice Chancellor for Research and
Graduate Education at the University of Wisconsin-Madison with funding from the Wisconsin
Alumni Research Foundation.
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