Aerobic dehydrogenation of cyclohexanone to cyclohexenone catalyzed by Pd(DMSO)2(TFA)2: Evidence for ligand-controlled chemoselectivity

Article abstract of DOI:10.1021/ja4031648

The dehydrogenation of cyclohexanones affords cyclohexenones or phenols via removal of 1 or 2 equiv of H₂, respectively. We recently reported several Pd^II catalyst systems that effect aerobic dehydrogenation of cyclohexanones with different product selectivities. Pd(DMSO) ₂(TFA)₂ is unique in its high chemoselectivity for the conversion of cyclohexanones to cyclohexenones, without promoting subsequent dehydrogenation of cyclohexenones to phenols. Kinetic and mechanistic studies of these reactions reveal the key role of the dimethylsulfoxide (DMSO) ligand in controlling this chemoselectivity. DMSO has minimal kinetic influence on the rate of Pd(TFA)₂-catalyzed dehydrogenation of cyclohexanone to cyclohexenone, while it strongly inhibits the second dehydrogenation step, conversion of cyclohexenone to phenol. These contrasting kinetic effects of DMSO provide the basis for chemoselective formation of cyclohexenones.

Full text of DOI:10.1021/ja4031648

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Article
Aerobic Dehydrogenation of Cyclohexanone to Cyclohexenone Catalyzed
by Pd(DMSO)2(TFA)2: Evidence for Ligand-Controlled Chemoselectivity
Tianning Diao, Doris Pun, and Shannon S. Stahl
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 13 May 2013
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Aerobic Dehydrogenation of Cyclohexanone to
Cyclohexenone Catalyzed by Pd(DMSO)2(TFA)2:
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Evidence for Ligand-Controlled Chemoselectivity
Tianning Diao, Doris Pun and Shannon S. Stahl*
Department of Chemistry, University of Wisconsin - Madison, 1101 University Avenue,
Madison, Wisconsin 53706
Supporting Information Placeholder
Abstract
The dehydrogenation of cyclohexanones affords cyclohexenones or phenols via removal of one
or two equivalents of H2, respectively. We recently reported several PdII catalyst systems that
effect aerobic dehydrogenation of cyclohexanones with different product selectivities.
Pd(DMSO)2(TFA)2 is unique in its high chemoselectivity for the conversion of cyclohexanones
to cyclohexenones, without promoting subsequent dehydrogenation of cyclohexenones to
phenols. Kinetic and mechanistic studies of these reactions reveal the key role of the
dimethylsulfoxide (DMSO) ligand in controlling this chemoselectivity. DMSO has minimal
kinetic influence on the rate of Pd(TFA)2-catalyzed dehydrogenation of cyclohexanone to
cyclohexenone, while it strongly inhibits the second dehydrogenation step, conversion of
cyclohexenone to phenol. These contrasting kinetic effects of DMSO provide the basis for
chemoselective formation cyclohexenones.
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Introduction
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Dehydrogenation of saturated C–C bonds represents an important class of C–H
functionalization reactions. Homogeneous catalysts, such as iridium/PCP-pincer complexes,
have been investigated extensively for such transformations, and they have proven to be quite
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,
effective in the conversion of alkanes to alkenes or arenes.1 2 These reactions are performed with
a sacrificial H2 acceptor, such as tert-butylethylene, or under "acceptorless" conditions, in which
H2 is physically removed from the reaction mixture. Oxidative dehydrogenation, using O2 as the
hydrogen acceptor, represents an appealing alternative method to introduce sites of unsaturation
into organic molecules. The majority of precedents in this area, however, feature high-
temperature, gas-phase conditions for commodity chemical applications. Prominent targets
include the conversion of ethane to ethylene, propane to propylene or ethylbenzene to styrene.3
The reaction methods and conditions for these transformations are unsuitable for use with fine-
chemicals, pharmaceuticals, or related molecules bearing diverse functional groups.
Homogeneous PdII catalysts could find utililty in such applications; however, precedents are
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quite limited.4 6 Until recently, little effort has been made to expand the scope and synthetic
utility of such reactions.7
We recently reported three different catalyst systems that promote aerobic dehydrogenation
of cyclohexanones and other carbonyl compounds (Chart 1). A Pd(TFA)2/2-Me2Npy (TFA =
trifluoroacetate, 2-Me2Npy = 2-dimethylaminopyridine) catalyst system exhibits good activity
for the dehydrogenation of cyclohexanones and cyclohexenones to phenols.8 A Pd(TFA)2/4,5-
diazafluorenone catalyst exhibits similar reactivity, but is especially useful for α,β-
dehydrogenation of heterocyclic carbonyl compounds and exhibits some success in the
dehydrogenation of acyclic carbonyl compounds.9 , 10 Finally, a Pd(DMSO)2(TFA)2 catalyst
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enables selective dehydrogenation of cyclohexanones to cyclohexenones. 11 The reactions
mediated by these catalysts provide compelling routes to substituted phenols and/or enones, and
they serve as an important foundation for the development of other aerobic dehydrogenation
methods. A number of related transformations, including reactions for the synthesis of aryl ethers
and anilines from cyclohexanones and cyclohexenones, have been reported by other groups over
the past year.12
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Chart 1. Pd Catalyst Systems for Aerobic Dehydrogenation of Carbonyl Compounds.
Catalyst 1:
Pd(TFA)2
OH
/
N
NMe2 /TsOH in DMSO
2-Me2Npy
OH
OH
OH
Me
Me
Ph
Me
OH
OH
OH
F
Me
p-tol
Ph
Me
Me
CO2Et
precursor to LH antagonist
O
Catalyst 2:
Pd(TFA)2
/
in DMSO
N
N
4,5-diazafluorenone
O
O
O
H
H
MeO
Ph
H
Ph
CO2Et
OH
O
O
O
precursor to mGluR drug
F
O
HO
O
O
apigenin
Ph
Me
OH
Catalyst 3:
Pd(DMSO)2(TFA)2 in AcOH, EtOAc or toluene
O
O
O
O
O
Me
precursor to (–)-terpestacin
N
O
Boc
OTBS
O
O
CO2Me
H
Et
H
H
precursor to (–)-mersicarpine
O
Ph
H
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Further development of oxidative dehydrogenation reactions of this type would benefit from
mechanistic insights. The catalytic dehydrogenation of a cyclohexanone could lead to
cyclohexenone and/or phenol products, and, in the reaction of unsubstituted cyclohexanone, the
three catalyst systems in Chart 1 exhibit different selectivity patterns (Scheme 1). The first two
catalysts systems, Pd(TFA)2/2-Me2Npy and Pd(TFA)2/diazafluorenone, favor formation of
phenol, whereas Pd(DMSO)2(TFA)2 promotes highly selective formation of cyclohexenone.
Kinetic modeling of the reaction time courses has been used to obtain relative rate constants for
the first and second dehydrogenation steps with each of these catalyst systems (Scheme 1B).13
The results show that the first two catalyst systems promote dehydrogenation of cyclohexenone
to phenol more rapidly than cyclohexanone to cyclohexenone (i.e., k1/k2 < 1; Scheme 1B). The
opposite trend is observed with Pd(DMSO)2(TFA)2 as the catalyst (k1/k2 = 10–33, depending on
the solvent14). These kinetic differences have important synthetic implications, as the k1/k2 ratio
with Pd(DMSO)2(TFA)2 is sufficiently high that excellent yields of cyclohexenone products can
be obtained for a wide range of substrates, with minimal phenol byproducts.11
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Scheme 1. Relative Rate Constants for Different Catalyst Systems in the Dehydrogenation of
Cyclohexanone.
(A)
Cat. 3: 5% Pd(DMSO)2(TFA)2
O2 (1 atm )
AcOH, EtOAc, toluene
O
O
OH
1/2 O2, – H2O
1/2 O2, – H2O
k1
k2
Cat. 1: 3-5% Pd(TFA)2/2-Me2Npy/TsOH
O2 (1 atm ), DMSO
Cat. 2:
5% Pd(TFA)2/4,5-diazafluorenone
O2 (1 atm ), DMSO
(B)
k1/k2
Catalyst
Pd(TFA)2/2-Me2Npy/TsOH
Solvent
0.61
0.36
>10
Cat. 1:
DMSO
Cat. 2: Pd(TFA)2/4,5-diazafluorenone DMSO
Pd(DMSO)2(TFA)2
Cat. 3:
AcOH, EtOAc, toluene
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A plausible catalytic cycle for dehydrogenation of cyclohexanone derivatives involves
formation of a PdII-enolate followed by β-hydride elimination (steps 1 and 2, Scheme 2). This
sequence is analogous to that proposed for Saegusa-type dehydrosilylation of silyl enol ethers.15
Oxidation of the PdII–hydride intermediate is expected to proceed via Pd0, as has been
demonstrated for well-defined model systems (steps 3-5).16 A similar catalytic cycle can be
proposed for the dehydrogenation of cyclohexenone to phenol.
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Scheme 2. Proposed Mechanism for Pd-Catalyzed Dehydrogenation of Cyclohexanones
O
H
H2O2
(1/2 O2
+ H2O)
LnPdIIX2
R
HX
O
5
2 HX
1
R
O
LnPd
O2
LnPd
O
X
2
4
O
OH
+ 1/2 O2
– H2O
H
X
LnPd0
LnPd
3
R
R
HX
The simplified analysis above does not account for the different selectivity patterns observed
with the different catalyst systems in Scheme 1. Here, we present a kinetic and mechanistic
investigation of Pd(DMSO)2(TFA)2-catalyzed dehydrogenation of cyclohexanone to
cyclohexenone, and this work sheds light on three key mechanistic issues: (1) the identity of the
turnover-limiting step; (2) the role of ligand in the catalyst system; (3) the origin of the
chemoselectivity for enone relative to phenol. The results show that DMSO serves as a ligand
that stabilizes a homogeneous PdII catalyst and that inhibits conversion of cyclohexenone to
phenol. These results complement a companion study of Pd(TFA)2/2-Me2Npy-catalyzed
dehydrogenation of cyclohexanone, in which the PdII catalyst is found to undergo in situ
conversion into Pd nanoparticles that facilitate full dehydrogenation of cyclohexanone to
phenol.17
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Results and Discussion
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Kinetic Studies of Pd(DMSO)2(TFA)2-Catalyzed Oxidation of Cyclohexanone.
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The catalytic dehydrogenation of cyclohexanone with Pd(DMSO)2(TFA)2 in EtOAc (eq 1)
proceeds smoothly and reaches complete conversion after approx 24 h at 60 °C under 1 atm O2
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(Figure 1). The time course data fit well to an A → B → C kinetic model (Figure 1). Good mass
balance reveals that negligible side reactions occur. The rate constants for the first (k1) and
second (k2)oxidation steps are estimated to be 0.13 h-1 and 0.013 h-1, respectively, resulting in a
ratio of k1/k2 = 10. Higher selectivity can be achieved in other solvents (e.g., k1/k2 = 33 in AcOH),
but use of the lower-selectivity solvent EtOAc was chosen for the present studies to facilitate
study of both dehydrogenation steps.
O
O
OH
Pd(TFA)2 5 mol%
DMSO 10 mol%
+
(1)
O2 (1 atm), EtOAc, 60 °C
Figure 1. Reaction time course of Pd(DMSO)2(TFA)2-catalyzed aerobic dehydrogenation of
cyclohexanone. Estimated std. dev. for individual points: ≤ 5%. Reaction conditions:
[cyclohexanone] = 0.8 M (0.8 mmol), [Pd(TFA)2] = 0.04 M (0.04 mmol), [DMSO] = 0.08 M
(0.08 mmol), O2 (1 atm), EtOAc (1 mL), 60 °C.
The lack of an induction period in the reaction time course for Pd(DMSO)2(TFA)2-catalyzed
dehydrogenation of cyclohexanone allowed us to employ initial-rates methods to determine the
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kinetic orders of each reaction component. The conversion of cyclohexenone to phenol is
negligible within the first two turnovers, and the concentration of cyclohexenone was monitored
by gas chromatography to determine the initial rates. The reaction exhibits a first order
dependence on [cyclohexanone] and [Pd(DMSO)2(TFA)2] (Figure 2A and 2B, respectively).
Systematic analysis of the O2-pressure dependence was complicated by Pd black formation at
lower pO2; however, increasing the O2 pressure from 1.7 to 3.2 atm had minimal impact on the
rate, consistent with a zero-order dependence on O2 (Figure S1).
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(A)
(B)
Figure 2. Kinetic orders for Pd(DMSO)2(TFA)2-catalyzed dehydrogenation of cyclohexanone to
cyclohexenone: dependence of the initial rate on (A) substrate concentration (B)
Pd(DMSO)2(TFA)2 concentration. Estimated std. dev. for individual points: ≤ 5%. Reaction
conditions: EtOAc (1 mL), O2 (1 atm), 60 °C; (A) [Pd(TFA)2] = 0.01 M (0.01 mmol), [DMSO] =
0.02 M (0.02 mmol); (B) [cyclohexanone] = 0.2 M (0.2 mmol).
Variation of [DMSO] at fixed [cyclohexanone] and [Pd(TFA)2] reveals that increasing the
quantity of DMSO has only a minor inhibitory effect on the reaction rate (Figure 3A).
Comparison of the time courses in the absence and presence of 2 equiv DMSO, however, reveals
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that the catalyst undergoes rapid deactivation in the absence of DMSO (Figure 3B). Concomitant
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formation of Pd black is observed under these ligandless conditions. Minimal Pd black formation
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is observed with ≥2 equiv DMSO.
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(B)
Figure 3. (A) Effect of the DMSO ligand on Pd-catalyzed dehydrogenation of cyclohexanone to
cyclohexenone evident from the dependence of the initial rate on the DMSO/Pd ratio. (B)
Comparison of time courses for the dehydrogenation of cyclohexanone in the absence and
presence of DMSO. Estimated std. dev. for individual points: ≤ 5%. Reaction conditions: EtOAc
(1 mL), O2 (1 atm), 60 °C; (A) [cyclohexanone] = 0.2 M (0.2 mmol), [Pd(TFA)2] = 0.01 M (0.01
mmol); (B) [cyclohexanone] = 0.8 M (0.8 mmol), [Pd(TFA)2] = 0.04 M (0.04 mmol), (DMSO =
0.08 M (0.08 mmol) (blue)).
Deuterium kinetic isotope effects (KIE) were determined by independent measurements of
the initial rates with the protio, α-deuterated (cyclohexanone-d4) and fully deuterated
(cyclohexanone-d10) substrates (Figure 4). Cyclohexanone reacts 2.9 (± 0.27) times faster than
cyclohexanone-d4, reflecting a primary KIE for cleavage of the α-C–H. The reaction time
courses for cyclohexanone-d4 and cyclohexanone-d10 are nearly identical, and the ratio of the
rates, 1.1 (± 0.20), reflects a negligible KIE for cleavage of the β-hydrogen atom (Figure 4). GC-
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MS and 1H NMR spectroscopic analyses reveal that no proton incorporation takes place into the
α position under the reaction conditions. The intrinsic KIE for α-C–H cleavage was obtained
from an intramolecular competition experiment with spiro[4,5]decan-6-one-7-d1 (eq 2). The
corresponding enone is formed slowly as the sole product. After 24 h, a 13 % yield of enone is
obtained, with the H/D products obtained in a ratio of 1:2.7, corresponding to a nearly identical
KIE relative to that obtained from the independent rate measurements.
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O
O
O
D
D
D
D
D
D
D
D
D
D
D
D
D
D
Initial rate
(10-6 M s-1
1.0 ± 0.03
0.34 ± 0.03
0.32 ± 0.05
)
KIE
2.9 ± 0.3
1.1 ± 0.2
Figure 4. Deuterium kinetic isotope effects (KIE) derived from independent initial rates
measurements for dehydrogenation of cyclohexanone (performed in triplicate). The plots are
labeled with the corresponding cyclohexanone-dn substrate. Estimated std. dev. for individual
points: ≤ 5%. Reaction conditions: [Substrate] = 0.2 M (0.2 mmol), [Pd(TFA)2] = 0.01 M (0.01
mmol), [DMSO] = 0.02 M (0.02 mmol), EtOAc (1 mL), O2 (1 atm), 60 °C.
O
O
O
Pd(DMSO)2(TFA)2
10 mol%
D
D
H
H
+
(2)
EtOAc, 60 °C
13%
0.4 M
2.7 (± 0.1) : 1
Replacement of Pd(TFA)2 with Pd(OAc)2 leads to reduced initial rate (Figure 5). When a
mixture of Pd(TFA)2 and Pd(OAc)2 is used as the Pd source, maintaining the total [Pd] at 5 mol
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%, increased initial rates are observed. The maximum rate was observed at an
acetate:trifluoroacetate ratio of 1:1.
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Figure 5. Dependence of the initial rate of Pd-catalyzed oxidation of cyclohexanone on different
anionic ligands of Pd. Estimated std. dev. for individual points: ≤ 5%. Reaction conditions:
[cyclohexanone] = 0.2 M (0.2 mmol), [Pd]total = 0.01 M (0.01 mmol), [DMSO] = 0.02 M (0.02
mmol), EtOAc (1 mL), O2 (1 atm), 60 °C.
Pd(DMSO)2(TFA)2-Catalyzed Dehydrogenation of Cyclohexenone to Phenol.
Cyclohexenone-to-phenol dehydrogenation proceeds very slowly under the conditions of
Pd(DMSO)2(TFA)2-catalyzed dehydrogenation of cyclohexanones (cf. Scheme 1), but
independent insights into cyclohexenone reactivity could be obtained by increasing the catalyst
loading from 5 to 10 mol % (eq 3), and increasing the substrate concentration from 0.2 to 0.8 M.
In contrast to the well-behaved kinetics observed for cyclohexanone-to-cyclohexenone
dehydrogenation, the cyclohexenone-to-phenol reaction exhibits an induction period and a
sigmoidal time course for formation of phenol (Figures 6 and S6). Control reactions with 10 mol
% phenol or H2O added to the initial reaction mixture exhibit identical rates (Figure S8),
indicating that the sigmoidal time course does not arise from product-induced autocatalysis.
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O
OH
Pd(TFA)2 10 mol%
(DMSO 20 mol%)
(3)
4
O2 (1 atm), EtOAc, 60 °C
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Figure 6. Time courses of Pd(TFA)2-catalyzed dehydrogenation of cyclohexenone to phenol in
the presence (blue squares) and absence (black circles) of DMSO. Estimated std. dev. for
individual points: ≤ 5%. Reaction conditions: [cyclohexenone] = 0.8 M (0.8 mmol), [Pd(TFA)2]
= 0.08 M (0.08 mmol), ([DMSO] = 0.16 M (0.16 mmol)), EtOAc (1 mL), O2 (1 atm), 60 °C.
Pd black is observed after the reaction, but the reaction mixture remains deep yellow,
suggesting that the PdII catalyst is partially retained in solution. If Pd(TFA)2 is used as the
catalyst (i.e., in the absence of DMSO), cyclohexenone dehydrogenation proceeds without an
induction period to high conversion. More Pd black formation is observed relative to the reaction
in the presence DMSO, and the solution is colorless after 24 h, suggesting near-complete
conversion of PdII into Pd black during the reaction. The Pd black obtained from the reaction
mixture is not an effective catalyst for the reaction.18 More thorough analysis of the effect of
DMSO on the reaction reveals that increasing the [DMSO] has a significant inhibitory effect on
the rate of phenol formation (Figure 7). Similarly, higher [DMSO] increases the length of the
induction period (Figure 8 and S6 and Table S1). Collectively, these results are consistent with
formation of Pd nanoparticles or intermediate-sized aggregates under the reaction conditions that
exhibit higher activity than PdII for the dehydrogenation of cyclohexenone (see further discussion
below). The inhibitory effect of DMSO can be attributed to its ability to stabilize the
homogeneous PdII catalyst and slow formation of these particles.
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Figure 7. Dependence of the initial rate (i.e. during the induction period) of Pd-catalyzed
dehydrogenation of cyclohexenone to phenol on the DMSO/Pd ratio. Estimated std. dev. for
individual points: ≤ 5%. Reaction conditions: [cyclohexenone] = 0.8 M (0.8 mmol), [Pd(TFA)2]
= 0.08 M (0.08 mmol), EtOAc (1 mL), O2 (1 atm), 60 °C.
Figure 8. Dependence of the length of induction period on the Pd-catalyzed dehydrogenation of
cyclohexenone to phenol on [DMSO]. Estimated std. dev. for individual points: ≤ 10 %.
Reaction conditions: [cyclohexenone] = 0.8 M (0.8 mmol), [Pd(TFA)2] = 0.08 M (0.08 mmol),
EtOAc (1 mL), O2 (1 atm), 60 °C.
Cyclohexenone dehydrogenation by PdII could be initiated by activation of the C–H bond at
the 4- or 6-position of the ring, as relevant precedents exist for both. For example, deprotonation
of cyclohexenone by lithium diisopropylamide (LDA) affords 2-oxylcyclohexa-1,3-dienyl
lithium (eq 4),19,20 and deuterated Brønsted acids lead to isotopic scrambing of the α-C–H
position, leaving the allylic C–H position unaffected.21 In contrast, cyclohexenone reacts with
sodium tetrachloropalladate to afford a dimeric π-allyl-PdII species, corresponding to cleavage of
the allylic C–H bond (eq 5).22,23 And, Imahori et al. recently reported a Pd-catalyzed C–H
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arylation-aromatization of cyclohexenone that furnishes 4-arylphenol derivatives, again
consistent with Pd-mediated cleavage of the allylic C–H bond.12b
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O
OLi
OLi
LDA
(4)
9
not observed
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O
O
reflux
15 min
+ Na2PdCl4
(5)
Pd
Cl
Isotopically labeled cyclohexenones were prepared to probe the site of C–H cleavage in
Pd(DMSO)2(TFA)2-catalyzed dehydrogenation of cyclohexenone.24 Initial rates were monitored
for reactions of cyclohexenone-d0, 2,6,6-cyclohexenone-d3, and 2,4,4,6,6-cyclohexenone-d5
under the standard reaction conditions (Figure 9). The unlabeled cyclohexanone exhibits a rate
2.9-fold faster than the two deuterium-labeled substrates, both of which react with identical rates.
These data indicate the presence of a primary kinetic isotope effect (2.9 ± 0.2) associated with
cleavage of the α-C–H bond in the conversion of cyclohexenone to phenol, which not only
establishes the site of C–H cleavage, but also reveals that this step is rate-determining in Pd-
mediated dehydrogenation of cyclohexenone.
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O
O
O
D
D
D
D
D
D
D
1.9 ± 0.07
D
Initial rate
(10-6 M s-1)
5.5 ± 0.3
1.9 ± 0.03
KIE
2.9 ± 0.2
1.0 ± 0.04
Figure 9. Deuterium kinetic isotope effects for dehydrogenation of cyclohexenone to phenol
derived from independent measurement of initial rates (performed in triplicate). The plots are
labeled with the corresponding cyclohexenone-dn substrate. Reaction conditions: [substrate] =
0.8 M (0.4 mmol), [Pd(TFA)2] = 0.04 M (0.02 mmol), [DMSO] = 0.08 M (0.04 mmol), EtOAc
(1 mL), O2 (1 atm), 60 °C.
Mechanistic Analysis
(A) DMSO ligand-controlled chemoselectivity in the dehydrogenation of cyclohexanone.
The mechanistic data presented above provide a number of insights into the Pd(DMSO)2(TFA)2-
catalyzed dehydrogenation of cyclohexanone. Perhaps most striking is the dramatically different
effects of DMSO on the cyclohexanone-to-cyclohexenone and cyclohexenone-to-phenol
dehydrogenation steps. DMSO has negligible impact on the rate of the first reaction (Figure 3A),
but it strongly inhibits the second (Figure 7). These contrasting effects provide the basis for
selective formation of cyclohexenone, rather than phenol, in the catalytic reaction.
The inhibitory effect of DMSO on cyclohexenone-to-phenol dehydrogenation is attributed to
two factors: (1) a dramatic decrease in the initial rate (Figure 7) and (2) an increase in the length
of the induction period (Figure 8) with increasing [DMSO]. The effect of [DMSO] on the initial
rate can be explained by DMSO dissociation from PdII prior to activation of cyclohexenone,
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while the effect of [DMSO] on the induction period appears to be associated with Pd aggregation
into Pd nanoparticles and Pd black. DMSO serves as a stabilizing ligand for the homogeneous
catalyst, inhibiting Pd aggregation. This effect is needed to achieve high conversion in the
dehydrogenation of cyclohexanone to cyclohexenone (cf. Figures 3B). In contrast,
dehydrogenation of cyclohexenone to phenol appears to benefit from catalyst aggregation, as
reflected by the enhanced rate following the induction period. The latter reaction proceeds most
rapidly under ligand-free conditions, in the absence of DMSO.
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The sigmoidal time course observed for cyclohexenone-to-phenol dehydrogenation in the
presence of DMSO (Figure 6) resembles reactions that undergo in situ transformation of a
molecular catalyst-precursor into catalytically active nanoparticles.25 Pd nanoparticle formation
has been characterized recently in the Pd(TFA)2/2-Me2Npy-catalyzed dehydrogenation of
cyclohexanone to phenol,17 and the Pd nanoparticles were found to be more active than the PdII
catalyst precursor for dehydrogenation of cyclohexenone. Extrapolation of these results to the
present catalyst system supports the proposal that the inhibitory effect of DMSO on the
cyclohexenone-to-phenol step (cf. Figure 7) arises from DMSO stabilization of homogeneous Pd
and inhibition of Pd-nanoparticle formation. Thus, the high selectivity for enone formation with
Pd(DMSO)2(TFA)2 appears to correlate with the presence of a (relatively) stable homogeneous
PdII catalyst.
(B) Mechanism of Pd(DMSO)2(TFA)2-catalyzed dehydrogenation of cyclohexanone.
We recently characterized the solution-phase structure of Pd(DMSO)2(TFA)2 in a number of
different solvents.26 In EtOAc, this complex exists as an equilibrium mixture of S,S- and S,O-
ligated bis-DMSO complexes (eq 6). Pd(DMSO)2(TFA)2-catalyzed dehydrogenation of
cyclohexanone is envisioned to proceed by a series of three steps (Scheme 3): (i) formation of a
PdII-cyclohexanone adduct, (ii) cleavage of the α-C–H bond, with concomitant loss of TFAH, to
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afford a PdII-enolate species, and (iii) β-hydride elimination to afford the cyclohexenone product
2
3
4
5
and a PdII–hydride.
6
7
8
9
Me
S
Me
Me
Keq = 0.17
60 °C
Me
PdII
TFA
S
O
TFA
O
PdII
(6)
O
O
TFA
S
TFA
S
EtOAc
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Me
Me
Me
Me
Scheme 3. Proposed Mechanism for Pd(DMSO)2(TFA)2-Catalyzed Dehydrogenation of
Cyclohexanone.
(i) PdII–cyclohexanone adduct formation
O
O
k1
TFA
DMSO
+ Pd(DMSO)2(TFA)2
PdII
k-1
TFA
DMSO
(ii) α-C–H cleavage (turnover-limiting step)
O
O
k2
TFA
DMSO
DMSO
PdII
+ CF3COOH
PdII
TFA
TFA
DMSO
DMSO
(iii) β–H elimination
O
O
k3
(fast)
H
(DMSO)2PdII
DMSO
+
PdII
TFA
TFA
DMSO
An alternative pathway for the formation of the PdII-enolate species could involve reversible
ketone-enol tautomerization, followed by activation of the enol by PdII (eq 7). This mechanism
would resemble that of Saegusa-type oxidations of silyl enol ethers;15 however, it is not
consistent with the significant primary kinetic isotope effect observed here (cf. Figure 4).
O
OH
O
Pd(DMSO)2(TFA)2
– CF3COOH
DMSO
PdII
(7)
TFA
DMSO
The experimental data reveal a first-order kinetic dependence on [cyclohexanone] and
[Pd(DMSO)2(TFA)2]. Whereas a primary KIE is observed for cleavage of the α-C–H bond, no
KIE is observed for cleavage of the β-hydrogen atom. These data are consistent with pre-
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equilibrium or steady-state formation of the PdII-cyclohexanone adduct followed by turnover-
limiting cleavage of the α-C–H bond, as proposed in Scheme 3, steps i and ii.
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7
8
9
The minimal effect of DMSO on the reaction rate suggests that DMSO does not dissociate
prior to the turnover-limiting step. Application of the steady-state approximation to the PdII-
cyclohexanone adduct results in the rate law shown in eq 8, which is consistent with the first-
order dependence on [cyclohexanone] and [Pd(DMSO)2(TFA)2]. Subsequent β-hydride
elimination27 and aerobic oxidation of the PdII–hydride16 are rapid and kinetically invisible under
the catalytic conditions.
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d[cyclohexenone]
k1k2[cyclohexanone][Pd(DMSO)2(TFA)2]
k2 + k-1
=
(8)
dt
The comparison of acetate and trifluoroacetate as anionic ligands shows that the Pd(TFA)2-
derived catalyst is approximately three-fold more active. This effect is attributed to the enhanced
electrophilicity of the TFA-ligated catalyst, which should favor formation of the cyclohexanone
adduct and possibly enhance the rate of C–H cleavage. The maximum rate of cyclohexanone is
observed, however, with a 1:1 TFA:OAc ratio. Studies of PdII-mediated C–H activation have
highlighted "concerted metalation-deprotonation" mechanisms in which Pd–C bond formation
takes place in concert with C–H deprotonation by a coordinated carboxylate,28 and we have
recently observed a similar beneficial effect of mixed TFA/OAc anionic ligands in Pd-catalyzed
C–H activation of arenes.29 These observations potentially reflect a need to balance the
electrophilicity of the PdII center and the basicity of the carboxylate ligand. On the basis of these
considerations and the lack of an inhibitory effect by DMSO, we propose the five-coordinate
transition structure 1 for α-C–H cleavage. This structure closely resembles the five-coordinate
transition state 2 proposed for Pd(py)2(OAc)2-catalyzed aerobic oxidation/dehydrogenation of
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alcohols, which is supported by experimental and DFT computational studies.30 The initially
formed O-bound enolate should be able to isomerize readily under the reaction conditions into a
C-bound enolate that can undergo β-hydride elimination.
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ArCH2
H
O
H
O
O
O
CH3
py
AcO
O
py
DMSO
TFA
O
DMSO
Pd
R
Pd
1
R = CH3, CF3
2 py = pyridine
A mechanism analogous to Scheme 3, involving a soluble PdII species, appears to be
operative in the dehydrogenation of cyclohexenone during the induction period (cf. Figure 6).
The alkene in cyclohexenone is probably a better ligand for Pd than the carbonyl oxygen atom.
The resulting alkene adduct may not be on the pathway for α-C–H cleavage, however, and could
slow the net dehydrogenation process for this substrate. Furthermore, the loss of DMSO in this
step (evident from the inhibitory effect of DMSO) could make the catalyst more susceptible to
aggregation into Pd nanoparticles upon reduction to Pd0. For reasons that have not yet been
elucidated, the resulting Pd nanoparticles exhibit higher activity than the molecular PdII catalyst
precursor.
Conclusion
Pd(DMSO)2(TFA)2 catalyzes the chemoselective formation of cyclohexenone, rather than
phenol, in the aerobic dehydrogenation of cyclohexanone. The selectivity of this reaction
originates from the different kinetic effect of DMSO on the two sequential dehydrogenation
steps: DMSO has little impact on the rate of the first dehydrogenation step, whereas it strongly
inhibits the second step. DMSO is found to stabilize the homogeneous PdII catalyst, which
mediates efficient ketone-to-enone dehydrogenation. The same catalyst is not effective for
cylohexenone-to-phenol dehydrogenation. Efficient catalysis of the latter reaction is only
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observed under conditions that enable conversion of the homogeneous Pd into Pd nanoparticles.
These findings may be compared to our companion study of the Pd(TFA)2/2-Me2Npy catalyst
system, which promotes full dehydrogenation of cyclohexanone to phenol.17 In this reaction, the
PdII catalyst precursor transforms rapidly into Pd nanoparticles that mediate both
dehydrogenation steps. Together, these studies represent a rare demonstration of different
selectivity patterns that can arise from homogeneous versus nanoparticle catalysis.31
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ASSOCIATED CONTENT
Supporting Information. Experimental details for data acquisition and additional kinetic data
are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* stahl@chem.wisc.edu
ACKNOWLEDGMENT
Financial support of this work was provided by the NIH (R01-GM100143) and the NSF (CHE-
1041934 - fellowship to DP). The O2 dependence experiment was performed on a HEL high
pressure (HP) ChemSCAN unit, which was funded by the NSF (CHE-0946901).
References
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Yi, C. S.; Lee, D. W. Organometallics 2009, 28, 947. (b) Zhang, X.; Wang, D. Y.; Emge, T. J.;
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(4) Muzart, J. Eur. J. Org. Chem. 2010, 3779.
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(9) Diao, T.; Wadzinski, T. J.; Stahl, S. S. Chem. Sci. 2012, 3, 887.
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(10) For a concurrent report on Pd/diazafluorenone-catalyzed dehydrogenation, see: Gao, W.;
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homogeneous Pd catalysts will provide better selectivity for enone versus phenol formation. The
mechanistic basis for such stabilization effects is not fully known, but multiple factors could
contribute. Possible effects include the relative O2 solubility, the coordinating ability of the
solvent, and/or other effects that contribute to the partitioning between catalyst reoxidation by O2
versus aggregation of Pd0 into nanoparticles.
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(16) (a) Popp, B. V.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 4410. (b) Konnick, M. M.;
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(18) The heterogeneous Pd was isolated by filtration through Celite. Efforts to use this material
in the dehydrogenation of cyclohexenone under the standard reactions conditions led to
disproportionation of cyclohexenone into cyclohexanone and phenol. For a precedent for this
disproportionation reactivity with Pd/C, see: Horning, E. C.; Horning, M. G.; Walker, G. N. J.
Am. Chem. Soc. 1949, 71, 169. For similar observations with cyclohexene, see refs 6b and 6i.
(19) Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1977, 42, 1051.
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base: Kawanisi, M.; Itoh, Y.; Hieda, T.; Kozima, S.; Hitomi, T.; Kobayashi, K. Chem. Lett. 1985,
647.
(21) Forsyth, D. A.; Botkin, J. H.; Osterman, V. M. J. Am. Chem. Soc. 1984, 106, 7663.
(22) Kasahara, A.; Tanaka, K.; Asamiya, K. Bull. Chem. Soc. Jpn. 1967, 40, 351.
(23) For related Pd-mediated cleavage of allylic C–H bonds to form π-allyl-Pd complexes, see
ref. 6b and Parshall, G. W.; Wilkinson, G. Inorg. Chem. 1962, 1, 896.
(24) The syntheses of 2,6,6-cyclohexenone-d3 and 2,4,4,6,6-cyclohexenone-d5 are based on
procedures described in following paper: Lambert, J. B.; Clikeman, R. R. J. Am. Chem. Soc.
1976, 98, 4203. In this paper, 2,6,6-cyclohexenone-d3 is inaccurately assigned to 2,4,4-
1
cyclohexenone-d3. Our H NMR and 1D NOESY data confirm that the resulting deuterated
substrate is 2,6,6-cyclohexenone-d3.
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(25) See, for example: (a) Widegren, J. A.; Finke, R. G. J. Mol. Catal A: Chem. 2003, 198,
317. (b) Crabtree, R. H. Chem. Rev. 2011, 112, 1536.
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(26) Diao, T.; White, P.; Guzei, I.; Stahl, S. S. Inorg. Chem. 2012, 51, 11898.
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(27) For a fundamental study of β-hydride elimination from a PtII-enolate, see: Alexanian, E.
J.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 15627.
(28) (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005, 127,
13754. (b) García-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem.
Soc. 2006, 128, 1066. (c) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
10848. (d) Balcells, D.; Clot, E.; Eisenstein, O. Chem. Rev. 2010, 110, 749. (e) Ackermann, L.
Chem. Rev. 2011, 111, 1315.
(29) Izawa, Y.; Stahl, S. S. Adv. Synth. Catal. 2010, 352, 3223.
(30) Steinhoff, B. A.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126, 11268.
(31) Homogeneous vs. nanoparticle catalysis was recently invoked to explain a switch in
selectivity between alcohol oxidation and Wacker-type oxidation of alkenes: Mifsud, M.;
Parkhomenko, K. V.; Arends, I. W. C. E.; Sheldon, R. A. Tetrahedron 2010, 66, 1040.
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OH
Pd(DMSO)2(TFA)2
O2 (1 atm)
O
O
Pd(DMSO)2(TFA)2
O2 (1 atm)
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inhibited
by DMSO
negligible DMSO
effect
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