Elucidating the significance of β-hydride elimination and the dynamic role of acid/base chemistry in a palladium-catalyzed aerobic oxidation of alcohols

Article abstract of DOI:10.1021/ja047794s

The mechanistic details of aerobic alcohol oxidation with catalytic Pd(I/Pr)(OAc)₂(H₂O) (I/Pr = 1,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene) are disclosed. Under optimal conditions, β-hydride elimination is rate-limiting supported by kinetic studies including a high primary kinetic isotope effect (KIE) value of 5.5 ± 0.1 and a Hammett p value of -0.48 ± 0.04. On the basis of these studies, a late transition state is proposed for β-hydride elimination, which is further corroborated by theoretical calculations using density functional theory. Additive acetic acid modulates the rates of both the alcohol oxidation sequence and regeneration of the Pd catalyst. With no additive [HOAc], turnover-limiting reprotonation of intermediate palladium peroxo is kinetically competitive with β-hydride elimination, allowing for reversible oxygenation and decomposition of Pd(O). With additive [HOAc] (>2 mol %), reprotonation of the palladium peroxo is fast and β-hydride elimination is the single rate-controlling step. This proposal is supported by an apparent decomposition pathway modulated by [HOAc], a change in alcohol concentration dependence, a lack of [O₂] dependence at high [HOAc], and significant changes in the KIE values at different HOAc concentrations.

Full text of DOI:10.1021/ja047794s

Published on Web 07/20/2004
Elucidating the Significance of â-Hydride Elimination and the
Dynamic Role of Acid/Base Chemistry in a
Palladium-Catalyzed Aerobic Oxidation of Alcohols
Jaime A. Mueller, Christopher P. Goller, and Matthew S. Sigman*
Contribution from the Department of Chemistry, UniVersity of Utah, 315 South 1400 East,
Salt Lake City, Utah 84112
Received April 16, 2004; E-mail: sigman@chem.utah.edu
Abstract: The mechanistic details of aerobic alcohol oxidation with catalytic Pd(IiPr)(OAc)
2 2
(H O) (IiPr )
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) are disclosed. Under optimal conditions, â-hydride elimina-
tion is rate-limiting supported by kinetic studies including a high primary kinetic isotope effect (KIE) value
of 5.5 ( 0.1 and a Hammett F value of -0.48 ( 0.04. On the basis of these studies, a late transition state
is proposed for â-hydride elimination, which is further corroborated by theoretical calculations using density
functional theory. Additive acetic acid modulates the rates of both the alcohol oxidation sequence and
regeneration of the Pd catalyst. With no additive [HOAc], turnover-limiting reprotonation of intermediate
palladium peroxo is kinetically competitive with â-hydride elimination, allowing for reversible oxygenation
and decomposition of Pd(0). With additive [HOAc] (>2 mol %), reprotonation of the palladium peroxo is
fast and â-hydride elimination is the single rate-controlling step. This proposal is supported by an apparent
decomposition pathway modulated by [HOAc], a change in alcohol concentration dependence, a lack of
2
[O ] dependence at high [HOAc], and significant changes in the KIE values at different HOAc concentrations.
Introduction
In their procedure, 1 mol % PdCl and 5 mol % NaOAc are
2
used under the relatively mild conditions of 1 atm of O2 at 38
The observation that alcohols are oxidized by Pd(II), or at
least that Pd(II) is reduced to Pd(0) in the presence of an alcohol,
was first made over 175 years ago when Berzelius observed Pd
°C in ethylene carbonate as solvent for the oxidation of a variety
of alcohols. The major drawback to this procedure is the long
reaction times required for high conversions (typically ∼100 h).
It was not until 1998 that two groups reported significant
improvements in palladium-catalyzed aerobic oxidation of
1
metal precipitate out of a heated alcoholic solution of Pd(II).
While the use of stoichiometric Pd(II) as an oxidant is not a
2
practical approach to oxidizing alcohols, the ability to use a
7
alcohols. The first was reported by Peterson and Larock, who
catalytic amount of Pd(II), along with a stoichiometric amount
of a simple oxidant, such as molecular oxygen, to reoxidize
found the use of 5 mol % Pd(OAc)2, in combination with an
appropriate carbonate base, provides an effective catalyst system
for the oxidation of benzylic and allylic alcohols when DMSO
3
the Pd(0) is highly attractive. Moiseev was the first to report
a Pd-catalyzed oxidation of an alcohol under aerobic conditions
8
-10
is used as solvent at 1 atm of O2 and 80 °C.
The second is
4
in the presence of CuCl2 in 1963. In 1967, Lloyd disclosed a
a Pd(OAc)2/pyridine catalyst system developed by Uemura and
study of Pd-catalyzed aerobic oxidations of alcohols focusing
largely on the role of additives to facilitate the reoxidation of
(7) Peterson, K. P.; Larock, R. C. J. Org. Chem. 1998, 63, 3185-3189.
(8) This oxidative system has been extended to several transformations. For
intramolecular cyclizations, heterocyclizations, and carbocylizations, see:
(a) Toyota, M.; Sasaki, M.; Ihara, M. Org. Lett. 2003, 5, 1193-1195. (b)
Toyota, M.; Rudyanto, M.; Ihara, M. J. Org. Chem. 2002, 67, 3374-3386.
5
Pd. The most important observation made in this study was
catalytic amounts of PdCl2, without any additive, could facilitate
the oxidation of alcohols under aerobic conditions although with
very low efficiency. In 1977, Blackburn and Schwartz were the
first to develop a synthetically useful procedure for the oxidation
(
c) Toyota, M.; Ihara, M. Synlett 2002, 1211-1222. (d) Toyota, M.;
Ilangovan, A.; Okamoto, R.; Masaki, T.; Arakawa, M.; Ihara, M. Org. Lett.
002, 4, 4293-4296. (e) Toyota, M.; Odashima, T.; Wada, T.; Ihara, M.
2
J. Am. Chem. Soc. 2000, 122, 9036-9037. (f) Toyota, M.; Rudyanto, M.;
Ihara, M. Tetrahedron Lett. 2000, 41, 8929-8932. (g) Toyota, M.; Wada,
T.; Ihara, M. J. Org. Chem. 2000, 65, 4565-4570. (h) Toyota, M.; Wada,
T.; Fukumoto, K.; Ihara, M. J. Am. Chem. Soc. 1998, 120, 4916-4925. (i)
Larock, R. C.; Hightower, T. R. Synlett 1998, 522-524. (j) R o¨ nn, M.;
Andersson, P. G.; B a¨ ckvall, J.-E. Tetrahedron Lett. 1997, 38, 3603-3606.
(k) R o¨ nn, M.; Andersson, P. G..; B a¨ ckvall, J.-E. Acta Chem. Scand. 1997,
51, 773-777. (l) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson,
K. P. J. Org. Chem. 1996, 61, 3584-3585. (m) R o¨ nn, M.; B a¨ ckvall, J.-E.;
Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749-7752. (n) van Bentham,
R. A. T. M.; Hiemstra, H.; van Leeuwen, P. W. N. M.; Geus, J. W.;
Speckamp, W. N. Angew. Chem., Int. Ed. Engl. 1995, 34, 457-460. (o)
van Bentham, R. A. T. M.; Hiemstra, H.; Longarela, G. R.; Speckamp, W.
N. Tetrahedron Lett. 1994, 35, 9281-9284. (p) van Bentham, R. A. T.
M.; Hiemstra, H.; Michels, J. J.; Speckamp, W. N. J. Chem. Soc., Chem.
Commun. 1994, 357-359. (q) Larock, R. C.; Hightower, T. R. J. Org.
Chem. 1993, 58, 5298-5300.
6
of alcohols under aerobic conditions without a copper additive.
(
1) Berzelius, J. J. Ann. Phys. Chem. 1828, 13, 435-488.
(
2) (a) Moreno-Manas, M.; Pleixats, R.; Villarroya, S. Organometallics 2001,
2
0, 4524-4528. (b) Bellosta, V.; Benhaddou, R.; Czernecki, S. Synlett 1993,
8
61-863. (c) Benhaddou, R.; Czernecki, S.; Ville, G.; Zegar, A. Organo-
metallics 1988, 7, 2435-2439. (d) Zaw, K.; Lautens, M.; Henry, P. M.
Organometallics 1983, 2, 197-199. (e) Tomioka, H.; Takai, K.; Oshina,
K.; Nozaki, H. Tetrahedron Lett. 1981, 22, 1605-1608.
(
3) For a recent review on Pd-catalyzed oxidations of alcohols, see: Muzart,
J. Tetrahedron 2003, 59, 5789-5816.
(
4) Nikiforova, A. V.; Moiseev, I. I.; Syrkin, Y. K. Zh. Obshch. Khim. 1964,
3
3, 3239-3242.
(
(
5) Lloyd, W. G. J. Org. Chem. 1967, 32, 2816-2819.
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9724
9
J. AM. CHEM. SOC. 2004, 126, 9724-9734
10.1021/ja047794s CCC: $27.50 © 2004 American Chemical Society

Pd-Catalyzed Aerobic Oxidation of Alcohols
A R T I C L E S
co-workers.11 In this system, 5 mol % Pd(OAc)2, 20 mol %
pyridine, and activated 3 Å molecular sieves prove an effective
combination for the oxidation of benzylic and aliphatic alcohols
at 1 atm of O2 and 80 °C. For allylic alcohols, greater amounts
of pyridine are required for efficient oxidation. In addition to
displaying good substrate scope, high conversions are achieved
in relatively short times (∼2 h) for most substrates. Uemura
and others have extended this oxidation system to a variety of
other interesting transformations.1
Scheme 1. Design of a New Pd(II) Catalyst for Aerobic Oxidation
of Alcohols
2-16
Since the reemergence of Pd-catalyzed aerobic oxidations of
alcohols, several other groups have reported new catalysts.
Sheldon and co-workers have developed a system for the
oxidation of alcohols in aqueous solutions using a water-soluble
phenanthroline ligand.17 The reaction is carried out under forcing
Pd catalyst without adequate support by ligand and/or solvent,
(2) excess amine ligand inhibits alcohol oxidation, and (3) base
is mandatory for alcohol oxidation. Stahl’s investigations of
2
2
23
Larock’s and Uemura’s systems highlighted the need for
substantial support of Pd(0) species during regeneration of the
catalyst. In Larock’s system, the soft, donating character of the
solvent dimethyl sulfoxide was found to have a stabilizing effect
to prevent aggregation of Pd(0) species. In Uemura’s Pd(OAc)2/
pyridine and our Pd(OAc)2/triethylamine aerobic alcohol oxida-
tions, excess amine ligand is necessary for a competent oxidation
presumably through stabilization of Pd(0) intermediates. A
caveat to this is excess amine ligand also inhibits alcohol
oxidation, leading to the need for higher catalyst loadings (3-5
mol %) for effective oxidations. Investigations of these systems
indicate that the inhibition is most likely due to either competi-
tive binding of the amine with the alcohol substrate or the need
to dissociate an amine ligand to allow for rate-limiting â-hydride
conditions, 100 °C and 30 atm of air pressure, but these
conditions do allow the use of rather low palladium catalyst
loadings (typically 0.1-0.5 mol %). Moberg and co-workers
have developed a catalyst system using an oxazoline-pallada-
1
8
cycle complex. While this reaction is not as efficient as some
of the previous examples, it is important as the first example
of a homogeneous Pd catalyst for alcohol oxidation using
19
ambient air atmosphere instead of pure O2. We have developed
the first method for Pd-catalyzed aerobic alcohol oxidation at
room temperature using 3 mol % Pd(OAc)2 and 6 mol %
triethylamine with a scope similar to that of Uemura’s sys-
2
0,21
tem.
While excellent progress has been made in catalyst
development for palladium-catalyzed aerobic oxidation of
alcohols, all suffer from high catalyst loadings, the use of high
pressures of O2, and/or high temperatures.
2
0,23
elimination.
An additional role of amine ligand is as an
exogenous Brønsted base to deprotonate a palladium-bound
alcohol to form a palladium alkoxide for subsequent â-hydride
With clear limitations in reported palladium-catalyzed aerobic
oxidations of alcohols, we sought to develop a more active and
robust catalyst. The basis of this effort was to take recently
reported mechanistic information on the fundamental steps
involved to design an improved catalyst. Key observations
include (1) Pd(0) species decompose during regeneration of the
2
4
elimination.
On the basis of this analysis, the two design elements for
improved aerobic alcohol oxidation catalysts are (1) a mono-
dentate ligand to support Pd species involved and to provide a
readily accessible coordination site to lower the energy barrier
for rate-limiting â-hydride elimination and (2) a base that does
not inhibit the oxidation. For ligand selection, N-heterocyclic
carbene (NHC) ligands meet the above criteria and have proven
(
2
9) For dehydrosilylation of silyl enol ethers using Pd(II)/O in DMSO, see:
Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D.
Tetrahedron Lett. 1995, 36, 2423-2426.
25
effective in various Pd(0)-catalyzed processes as well as an
(
2
10) For oxidative C-C bond cleavage of tertiary alcohols using Pd(II)/O in
DMSO, see: (s) Park, S.-B.; Cha, J. K. Org. Lett. 2000, 2, 147-149.
11) (a) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999,
oxidative kinetic resolution using (-)-sparteine as the exogenous
(
26
base. Acetate was also selected as a ligand for Pd(II) to serve
6
4, 6750-6755. (b) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S.
Tetrahedron Lett. 1998, 39, 6011-6014.
both as a counterion and as a Brønsted base to deprotonate the
(
(
(
(
(
(
12) For a review, see: Nishimura, T.; Ohe, K.; Uemura, S. Synlett 2004, 2,
2
4b,c
Pd-bound alcohol.
Since the acetate base would be masked
2
01-216.
13) For ring opening of hydroxycyclopropanes, see: Park, S.-B.; Cha, J. K.
Org. Lett. 2000, 2, 147-149.
as an anionic ligand, an intriguing possibility is acetate could
facilitate an intramolecular deprotonation (Scheme 1).
To test the catalyst design, [Pd(IiPr)Cl2] dimer (IiPr ) 1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene) was submitted to
AgOAc metathesis to form the monomeric complex Pd(IiPr)-
14) For intramolecular oxidative amination, see: Fix, S. R.; Brice, J. L.; Stahl,
S. S. Angew. Chem., Int. Ed. 2002, 41, 164-166.
15) For a Wacker cyclization, see: Trend, R. N.; Ramtohul, E. M.; Ferreira,
E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2003, 42, 2892-2895.
16) For annulation of indoles, see: Ferreira, E. M.; Stoltz, B. M. J. Am. Chem.
Soc. 2003, 125, 9578-9579.
17) (a) ten Brink, G.-J.; Arends, I. W. C. E.; Hoogenraad, M.; Verspui, G.;
Sheldon, R. A. AdV. Synth. Catal. 2003, 345, 497-505. (b) ten Brink,
G.-J.; Arends, I. W. C. E.; Sheldon, R. A. AdV. Synth. Catal. 2002, 344,
(22) Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. J. Am. Chem. Soc. 2002, 124,
766-767.
3
55-369. (c) Sheldon, R. A.; Arends, I. W. C. E.; ten-Brink, G.-J.;
(23) Steinhoff, B. A.; Stahl, S. S. Org. Lett. 2002, 4, 4179-4181.
(24) For mechanistic studies and elucidation of the role of base in Pd[(-)-
Dijksman, A. Acc. Chem. Res. 2002, 35, 774-781. (d) ten Brink, G.-J.;
Arends, I. W. C. E.; Sheldon, R. A. Science 2000, 287, 1636-1639.
18) (a) Hallman, K.; Moberg, C. AdV. Synth. Catal. 2001, 343, 260-263. For
a related catalyst, see: (b) Paavola, S.; Zetterberg, K.; Privalov, T.; Cs o¨ regh,
I.; Moberg, C. AdV. Synth. Catal. 2004, 346, 237-244.
2
sparteine]Cl -catalyzed oxidative kinetic resolution of secondary alcohols,
(
(
see: (a) Mandal, S. K.; Sigman, M. S. J. Org. Chem. 2003, 68, 7535-
7537. (b) Mueller, J. A.; Sigman, M. S. J. Am. Chem. Soc. 2003, 125,
7005-7013. (c) Mueller, J. A., Jensen, D. R.; Sigman, M. S. J. Am. Chem.
Soc. 2002, 124, 8202-8203. (d) Jensen, D. R.; Pugsley, J. S.; Sigman, M.
S. J. Am. Chem. Soc. 2001, 123, 7475-7476. Simultaneously and
independently a related kinetic resolution was reported; see: (e) Ferreira,
E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725-7726. (f)
Bagdanoff, J. T.; Ferreira, E. M.; Stoltz, B. M. Org. Lett. 2003, 5, 835-
837. (g) Bagdanoff, J. T.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43,
353-357.
19) Heterogeneous and biphasic Pd catalyst systems have been reported
to oxidize alcohols under air atmosphere; see: (a) G o´ mez-Bengoa, E.;
Noheda, P.; Echavarren, A. M. Tetrahedron Lett. 1994, 35, 7097-7098.
(
b) A ¨ı t-Mohand, S.; H e´ nin, F.; Muzart, J. Tetrahedron Lett. 1995, 36, 2473-
2
476.
20) Schultz, M. J.; Park, C. C.; Sigman, M. S. Chem. Commun. 2002, 3034-
035.
21) For the use of catalytic Pd(II) and NEt
Timokhin, V. I.; Anastasi, N. R.; Stahl, Shannon S. J. Am. Chem. Soc.
003, 125, 12996-12997.
(
(
3
3
in oxidative amination, see:
(25) For a review, see: Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41,
1290-1309.
(26) Jensen, D. R.; Sigman, M. S. Org. Lett. 2003, 5, 63-65.
2
J. AM. CHEM. SOC.
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VOL. 126, NO. 31, 2004 9725

A R T I C L E S
Mueller et al.
Figure 1. Optimized alcohol oxidation conditions using catalyst 1.
Scheme 2. A Proposed Mechanism for the Pd(II)-Catalyzed
Oxidation of Alcohols Using 1
Figure 2. Ortep representation of 1.
(OAc)2(H2O), 1. At 5 mol %, this complex was effective in
oxidizing sec-phenethyl alcohol to acetophenone with >99%
conversion in less than 2 h at 50 °C. Upon discovery of such
an active catalyst, the system was optimized to lower catalyst
loadings. The optimized catalytic system includes 0.5 mol %
1
, 2 mol % HOAc, and 3 Å molecular sieves in toluene at 60
1
27
Figure 3. Overlaid H NMR spectra from -60 to 0 °C of 1 in CDCl .
°
C under a balloon pressure of O2 (Figure 1). For activated
3
substrates, up to 1000 turnovers can be accomplished, represent-
ing one of the most effective Pd catalysts for aerobic alcohol
oxidation reported to date. This system converts primary and
secondary benzylic, allylic, and aliphatic substrates to aldehydes
and ketones in high yields. The robustness of the catalyst is
demonstrated by the effective oxidation of alcohols using an
ambient air atmosphere.
Considering the unique activity of this catalyst and the
mechanistic approach used for the discovery, we set out to
confirm the rationale of the catalyst design through mechanistic
studies. In addition, one anomalous additive, acetic acid, was
necessary for consistent oxidation. Herein, we describe a detailed
investigation of the nature of â-hydride elimination through
experiment and theory as well as identification of the dynamic
role of acid/base chemistry.
to re-form A and 1 equiv of H2O2. This sequence will be referred
to as the Pd(II) catalyst regeneration realm of the catalytic cycle.
A key preliminary step in elucidating the mechanistic details
was structural characterization of 1. A single crystal was grown
from dichloromethane/hexanes. X-ray crystallographic analysis
revealed a square planar structure with the carbene ligand bound
monodentate and an acetate counterion on each side (Figure
27
2
). Interestingly, the oxygen of a water molecule is datively
bound to fill the last coordination site on Pd trans to the carbene.
Additionally, the hydrogen atoms on the water molecule are
bound to the carbonyl oxygen of each acetate ligand. This
hydrogen-bonding phenomenon supports the proposal of an
intramolecular deprotonation of the Pd-bound alcohol through
the assistance of hydrogen bonding to the acetate carbonyl
oxygen.
To determine whether the water molecule was an artifact of
crystallization or if it was incorporated as the complex formed,
Results and Discussion
A general proposed mechanism for the aerobic oxidation of
alcohols with 1 is depicted in Scheme 2. Dissociation of water
to form A initiates the catalytic cycle with the water presumably
trapped by molecular sieves. Alcohol substrate 2 binds to A,
forming Pd-bound alcohol B. Intramolecular deprotonation of
B forms palladium alkoxide C followed by subsequent â-hydride
elimination to expunge carbonyl product and form palladium
hydride D. This sequence will be referred to as the alcohol
oxidation realm of the catalytic cycle. Palladium hydride D
undergoes reductive elimination of acetic acid to yield Pd(0)
species E. E is oxygenated to Pd(II) by molecular oxygen to
produce palladium peroxo F, which is protonated by acetic acid
1
the isolated crystalline complex was examined by H NMR.
1
The H NMR spectrum of the crystallized material in CDCl3
was identical to that of the initial complex used. This suggests
that they are the same complex; however, the expected peak of
a bound water molecule was not observed in either spectrum.
To address this discrepancy, the crystallized complex was
1
studied from -60 to 0 °C by variable-temperature H NMR at
2
0 °C intervals (Figure 3). This set of spectra clearly displays
a broad peak emerging as the temperature is decreased below
°C. The peak sharpens with a further decrease in temperature
0
until it appears as a singlet at ∼8.6 ppm at -60 °C, demonstrat-
ing the inclusion of a water molecule in solution.
Kinetic Characterization of Optimized Conditions. Using
in situ Fourier transform infrared spectroscopy to measure
(
27) Jensen, D. R.; Schultz, M. J.; Mueller, J. A.; Sigman, M. S. Angew. Chem.,
Int. Ed. 2003, 42, 3810-3813.
9726 J. AM. CHEM. SOC.
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Pd-Catalyzed Aerobic Oxidation of Alcohols
A R T I C L E S
Figure 4. log kobs vs σ for the oxidation of benzylic alcohols at 50 °C.
Conditions: 0.5 mol % 1, 0.45 M alcohol, 2 mol % AcOH in benzene,
with 3 Å molecular sieves and a balloon charged with O2.
oxidation rates, initial kinetic studies revealed the alcohol
oxidation sequence is rate limiting under slightly modified
2
8
29
optimal conditions with first-order dependencies on [1] and
sec-phenethyl alcohol concentration. Large primary kinetic
isotope effects (KIEs) of 5.5 ( 0.1 for sec-phenethyl alcohol
and 5.5 ( 0.5 for 2-decanol oxidation were observed, which
are consistent with rate-limiting â-hydride elimination. Due to
the unusual magnitude of these KIE values (vide infra), a
Hammett plot was constructed to evaluate the electronic effects
at the benzylic center (eq 1).30 A linear free energy relationship
was observed with a calculated F value of -0.48 ( 0.04 (Figure
Figure 5. Transition-state model for â-hydride elimination using catalyst
1.
predicting the monodentate ligand leaves an accessible coor-
dination site for â-hydride elimination, thereby altering the
reactivity of the catalyst and the nature of the transition state.
The high KIE value for this system indicates a transition state
with minimal vibrational energy differences, maximizing ∆∆Gq
between R-H and R-D sec-phenethyl alcohol. Traditionally,
linear, symmetric transition states are the models for systems
with high KIE values because bond vibrations are minimal in
4
). The negative F value signifies a positive charge buildup in
the transition state, further supporting rate-limiting â-hydride
elimination.
31
the transition state. However, it is difficult to imagine a linear
transition state for â-hydride elimination which leads to another
model to describe the observed large KIE values.32
A high KIE value can be measured when the vibration in the
transition state is minimal and/or the difference in vibrational
3
3
energy levels in the transition state is small. Both criteria for
a high KIE are met when the transition state is late in this
transformation with almost complete C-H (C-D) bond cleav-
age and Pd-H (Pd-D) bond formation. The magnitude of
vibration and the difference in vibrational energy levels in the
transition state are minimized when the weaker bond of
hydrogen with a significantly heavier atom, Pd-H (bond
Nature of â-Hydride Elimination. The initial kinetic
evidence establishes â-hydride elimination as rate determining.
However, the substantial magnitude of the measured KIE value
(5.5 ( 0.1 for sec-phenethyl alcohol oxidation) implicates the
nature of â-hydride elimination is unique compared to that of
rate-limiting â-hydride elimination in other Pd-catalyzed alcohol
oxidations. Significantly smaller KIE values have been measured
for these other systems, which include a KIE of 1.31 ( 0.04
we reported for the oxidation of (S)-sec-phenethyl alcohol with
Pd(II)/(-)-sparteine,2 a KIE of 1.3 ( 0.1 reported by Stahl
et al. in evaluating Uemura’s Pd(II)/pyridine-catalyzed oxidation
of benzyl alcohol (0.1 M),23 and a KIE of 1.4 reported by
Sheldon et al. for the Pd(II)/bathophenanthroline disulfonate-
catalyzed oxidation of sec-phenethyl alcohol.1
-
1 34
stretching frequency 1953 cm ), is more fully formed and
the stronger bond of hydrogen to a lighter atom, C-H (bond
-
1
stretching frequency 2900 cm ), is nearly cleaved (Figure 5).
A readily accessible coordination site on Pd(II) should facilitate
a late transition state. This contrasts with other Pd-catalyzed
alcohol oxidations where a ligand saturates the coordination
sphere. As a comparison, (-)-sparteine binds datively to Pd(II)
in two coordination sites; the other two sites are occupied by
anionic ligands (either chloride or alkoxide), rendering the
square planar coordination sphere saturated (Figure 6). Two
4b,c
7c
This considerable disparity in KIE values measured for the
monodentate carbene system and other Pd-catalyzed aerobic
alcohol oxidation systems can provide insight into the modula-
tion of â-hydride elimination. The catalyst was designed
(31) For a discussion on the magnitude of kinetic isotope effects, see:
Westheimer, F. H. Chem. ReV. 1961, 61, 265-273.
(
32) Other scenarios have been reported where reactions with nonlinear transition
states give high KIE values. The high KIE values were attributed to
significant intermolecular force constants. For discussion of this concept,
see: Motell, E. L.; Boone, A. W.; Fink, W. H. Tetrahedron 1978, 34, 1619-
1626. Additionally, for discussion of proton-transfer reactions and KIE,
see: O’Ferrall, R. A. M. In Proton-Transfer Reactions; Caldin, E. F., Gould,
V., Eds.; Chapman & Hall: NewYork, 1975; Chapter 8.
(
28) The sec-phenethyl alcohol concentration was decreased to 0.45 M, with
the relative mole percentages of all other reagents remaining the same.
These reactions were performed at 50 ( 0.1 °C in benzene. See the
Supporting Information for details.
(
29) Determined by measurement of the initial oxidation rate of sec-phenethyl
alcohol with 0-1 mol % Pd(IiPr)(OAc)
2
(H
2
O).
(33) Collins, C. J.; Bowman, N. S. Isotope Effects in Chemical Reactions; Van
Nostrand Reinhold Co.: New York, 1970.
(
30) σ values were obtained from Lowry, T. H.; Richardson, K. S. Mechanism
and Theory in Organic Chemistry 3rd ed.; Harper and Row: New York,
(34) Andrews, L.; Wang, X.; Alikhani, M. E.; Manceron, L. J. Phys. Chem. A
2001, 105, 3052-3063.
1
987; p 144.
J. AM. CHEM. SOC.
9
VOL. 126, NO. 31, 2004 9727

A R T I C L E S
Mueller et al.
q
Table 1. Selected Lengths and Angles of 2C, 2C , and 2D
q
2C
2C
2D
Lengths (Å)
2.00
2.18
2.23
2.70
1.10
1.48
Pd-O1
Pd-O2
Pd-O3
Pd-H1
C2-H1
C2-O1
2.17
2.07
3.11
1.60
1.97
1.31
2.14
2.06
3.14
1.57
3.01
1.28
Angles (deg)
110.2
87.5
164.1
106.8
60.9
Pd-O1-C2
Pd-H1-C2
C1-Pd-O3
O1-Pd-O3
O2-Pd-O3
O1-Pd-C1
C2-Pd-C1
89.0
89.3
131.2
116.3
47.9
100.4
95.0
123.3
75.8
120.2
123.5
47.4
98.6
92.4
Figure 6. Limiting pathways for â-hydride elimination with 4-coordinate
Pd.
89.0
103.2
limiting scenarios can be envisioned for â-hydride elimination:
(
1) a dissociative pathway where a ligand/counterion dissociates
program using B3LYP38,39 and the LANL2DZ40,41 basis set,
completely prior to rate-limiting â-hydride elimination or (2)
an associative pathway where the â-hydride and the ligand/
counterion are partially coordinated to Pd(II) in the transition
state. In the former case, a KIE similar to that of the Pd(IiPr)-
42,43
which includes relativistic effective core potentials.
geometry of 2C was elucidated using the QST2 search
The
q
44
q
method. Frequency calculations were used to determine ∆GH
q
and ∆GD . All energies reported include zero-point and entropy
(OAc)2(H2O) system where a late transition state is proposed
corrections for the experimental temperature and pressure
would be expected if â-hydride elimination remained rate
limiting. For the latter case, there is not a readily accessible
coordination site for â-hydride elimination; thus, the carbonyl
product and palladium hydride are formed through a 5-coordi-
nate transition state. In this scenario, the transition state is earlier,
where H(D) is bound more to the carbon atom than to Pd(II),
leading to a greater separation of the vibrational energy levels
in the transition state and lowering the observed KIE values.
Therefore, this associative substitution (5-coordinate transition
state) scenario is most consistent with the smaller observed KIE
values for both the Pd-catalyzed oxidative kinetic resolution of
4
5
(
323.15 K and 1 atm). Examination of key bond lengths and
angles revealed the ground-state palladium alkoxide 2C has an
optimized geometry very similar to that of the solved crystal
structure of 1 (Figure 2).
q
The calculated transition state, 2C , correlates well with our
proposed product-like transition-state model. Comparison of the
bond lengths Pd-H1 and C2-H1 in the three structures reveals
that the transition state is more comparable to product 2D than
to palladium alkoxide ground state 2C (Table 1). The Pd-H1
distance is 2.70 Å in the ground state 2C, while the Pd-H1
bond length in 2D is 1.57 Å. The Pd-H1 distance is only 1.60
alcohols using (-)-sparteine and Uemura’s Pd(II)/pyridine
q
alcohol oxidation system.35
Å in 2C , indicating the hydride is nearly completely bonded
Other experimental evidence also highlights the differences
between the oxidation of alcohols with 1 and Pd[(-)-sparteine]-
Cl2. Although a F value of -0.48 ( 0.04 measured for the
oxidation of substituted benzyl alcohols with 1 supports rate-
limiting â-hydride elimination, it differs significantly from the
(
36) Initial calculations performed on both cis- and trans-Pd(IiPr)(OAc) alkoxides
the NHC ligand was truncated) revealed the Pd complex with the alkoxide
(
cis to the carbene ligand was found to be significantly lower in energy
than the trans geometric isomer. See the Supporting Information for details.
37) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Stratmann, R. E.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Iyengar, S.; Petersson,
G. A.; Ehara, M.; Toyota, K.; Nakatsuji, H.; Adamo, C.; Jaramillo, J.;
Cammi, R.; Pomelli, C.; Ochterski, J.; Ayala, P. Y.; Morokuma, K.;
Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Strain, M.
C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, T. Keith, D. J.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.;
Replogle, E. S.; Pople, J. A. Gaussian 01, Development Version (Revision
B.01); Gaussian, Inc.: Pittsburgh, PA, 2001.
(
value measured using Pd[(-)-sparteine]Cl2 (F ) -1.41 (
4b
0
.15).2 The smaller F value of -0.48 ( 0.04 observed for
oxidation of alcohols with 1 indicates that electronics have a
relatively subtle influence on â-hydride elimination. This is
consistent with the proposed late-transition-state model (Figures
5
and 6) where positive charge buildup stabilization is less
important for facile oxidation. For the Pd(II)/(-)-sparteine
system, electron-donating groups clearly play a more important
role by stabilizing the positive charge generated in the transition
state, increasing the nucleophilicity of the hydride.
(
(
(
38) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Becke, A. D.
J. Chem. Phys. 1993, 98, 1372-1377. (c) Becke, A. D. Phys. ReV. A 1988,
38, 3098-3100.
39) (a) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989,
157, 200-206. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37,
To further understand the unusually high KIE values and to
gain a more detailed understanding of â-hydride elimination,
computational studies using density functional theory were
785-789.
40) (a) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270-283. (b) Wadt,
W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284-298. (c) Hay, P. J.; Wadt,
W. R. J. Chem. Phys. 1985, 82, 299-310.
q
undertaken. The geometries of Pd(IiPr)(OAc) species 2C, 2C ,
(
41) Dunning, T. H., Jr.; Hay, P. J. In Modern Theoretical Chemistry; Schaefer,
H. F., III, Ed.; Plenum: New York, 1976; pp 1-28.
and 2D36 (Figure 7) were fully optimized in the Gaussian
37
(
42) (a) Frenking, G.; Antes, I.; Boehme, M.; Dapprich, S.; Ehlers, A. W.; Jonas,
V.; Neuhaus, A.; Otto, M.; Stegmann, R.; Veldkamp, A.; Vyboishchikov,
S. F. ReV. Comput. Chem. 1996, 8, 63-143. (b) Cundari, T. R.; Benson,
M. T.; Lutz, M. L.; Sommerer, S. O. ReV. Comput. Chem. 1996, 8, 145-
202.
(
35) A similar proposal was recently reported; see: (a) Trend, R. M.; Stoltz, B.
M. J. Am. Chem. Soc. 2004, 126, 4482-4483. (b) While the current paper
was in review, a computational model of the Pd(II)-catalyzed oxidative
kinetic resolution of secondary alcohols using (-)-sparteine was reported.
In this study, the authors report that the chloride ion is closely associated
with the Pd(II) center (3.0 Å) at the transition state for â-hydride
elimination; see: Nielsen, R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W.
A., III. J. Am. Chem. Soc. 2004, 126, 7967-7974.
(43) (a) Kohn, W.; Sham, L. J. Phys. ReV. A 1965, 140, 1133-1138. (b)
Hohenberg, P.; Kohn, W. Phys. ReV. B 1964, 136, 864-871.
(44) Peng, C.; Schlegel, H. B. Isr. J. Chem. 1993, 33, 449-454.
(45) No scaling factors were applied to frequency calculations. No solvent
corrections were applied.
9728 J. AM. CHEM. SOC.
9
VOL. 126, NO. 31, 2004

Pd-Catalyzed Aerobic Oxidation of Alcohols
A R T I C L E S
Figure 7. Optimized ground-state and transition-state structures for the oxidation of sec-phenylethyl alcohol with catalyst 1 using the B3LYP and the
LANL2DZ basis sets.
Figure 8. Translation of the acetate counterion from the ground state to
q
the transition state. Dihedral angles (C1-Pd-O2-C3) of 2C and 2C are
1
81.1° and 145.1°, respectively.
Figure 9. Eyring plots of benzyl alcohol, sec-phenethyl alcohol, and
-decanol oxidation using catalyst 1. Conditions: 0.5 mol % 1, 0.45 M
alcohol, 2 mol % AcOH in benzene, with 3 Å molecular sieves and a balloon
to Pd. The trend is similar for the C2-H1 distances in the Pd-
bound alkoxide. The bond length of C2-H1 is 1.10 Å in the
ground state 2C, while the corresponding distance in 2D is 3.01
Å. The bond distance of 1.97 Å in the transition state indicates
the hydrogen-carbon bond is nearly cleaved. The KIE was
determined from the difference in the calculated free energies
of the transition state. The theoretically determined KIE value
is 3.8. This large value is reasonably consistent with our
experimentally determined KIE value of 5.5 ( 0.1, indicating
our model is relevant with the caveat that error values in these
calculations are difficult to estimate.
2
charged with O2, temperature range from 40 to 55 °C.
Table 2. Activation Parameters for Alcohol Oxidation at 50 °C
Using Catalyst 1
4
6
Further examination of the computational models reveals finer
detail of this â-hydride elimination. The computational studies
depict the acetate counterion in the Pd square plane weakly
chelating the carbonyl oxygen in 2C (Figure 8). Transition-
q
state model 2C shows the acetate counterion rotated out of
plane during â-hydride elimination. This change from the ground
state to the transition state is supported experimentally by com-
parison of the activation parameters at 50 °C for the oxidations
of sec-phenethyl alcohol, benzyl alcohol, and 2-decanol (Figure
Scheme 3. An Unlikely Alternative Scenario That May Lead to a
Large KIE
9
, Table 2). Interestingly, benzyl alcohol and 2-decanol have
q
q
positive ∆S values, while the ∆S for sec-phenethyl alcohol is
close to unity. The positive values indicate there is less
organization in the transition state than in the ground state. This
is consistent with the computational model with a gain in
rotational degrees of freedom when acetate is rotated out of
plane in the transition state compared to the ground state, where
the acetate is chelated in the square plane of Pd. It is important
should be considered that may account for the large KIE. One
possibility involves direct â-hydride elimination to the acetate
counterion to form Pd(0), acetic acid, and ketone product
through a possible linear transition state (Scheme 3). APT charge
calculations on each atom of 2C indicate O(3) and O(2) to be
q
to note that the experimental ∆G of 21.2 ( 0.7 at 50 °C
q
correlates well with the calculated ∆G of 22.6 kcal/mol.
47
electron rich. These calculations indicate hydride nucleophilic
Alternative Scenarios for a Large KIE Value. The experi-
mental data and literature precedent thus far point toward rate-
limiting â-hydride elimination. However, alternative scenarios
attack on either acetate oxygen is highly unlikely. In fact, all
attempts to optimize a direct transition state failed, with the
acetate oxygen strongly repulsing the hydride. Experimental
evidence considering the electronics of different carboxylates
(vide infra) further contradicts this proposal.
(
46) Shaowen Zhang, Thanh N. Truong, VKLab version 1.0, University of Utah,
2
001.
J. AM. CHEM. SOC.
9
VOL. 126, NO. 31, 2004 9729

A R T I C L E S
Mueller et al.
Another possibility could be that reductive elimination is rate
limiting, where a large KIE could be observed through a linear-
type transition state. A linear transition state could only occur
through an intermolecular deprotonation of the hydride. While
this type of process cannot be completely ruled out, the
concentration of exogenous base (acetate) is very low under
the acidic reaction conditions, which renders this an unlikely
alternative. In this case, a highly organized transition state would
q
be predicted, leading to a large negative ∆S , which is
not observed. Additionally, under acidic conditions, reductive
elimination has been shown to be reversible, which leads
to insignificance in the measurement of a KIE.48 Although
this circumstantial evidence does point toward rate-limiting
â-hydride elimination, it is impossible to rule out a scenario
where the large KIE value is derived from the combination of
reversible â-hydride elimination (an equilibrium isotope effect)
and rate-limiting reductive elimination (a primary KIE).
Roles of Acetic Acid. While the initial goal of the catalyst
design was to avoid additives, it was found empirically that
additive acetic acid was mandatory for consistent oxidation
reactions. However, the selection of acetic acid as an additive
in the optimization process was based on the proposed mech-
anism where acetic acid is a byproduct or functional reagent in
several steps. Additionally, by increasing the amount of acetic
acid in the reaction, air can be substituted for pure O2,
showcasing the ability of acetic acid to modulate the catalysis.
Therefore, identifying the role(s) of acetic acid should provide
insight into the robust features of this catalyst system.
Figure 10. Rate dependence of sec-phenethyl alcohol oxidation using
various HOAc concentrations at 50 °C. Conditions: 0.5 mol % 1, 0.45 M
alcohol in benzene, with 3 Å molecular sieves and a balloon charged with
O2. The range of [AcOH] is 0-67.5 mM (0-15 mol %).
Considering the initial kinetic evidence strongly suggests rate-
limiting â-hydride elimination, a predicted role of additive acetic
acid is reprotonation of the palladium alkoxide, thus inhibiting
the alcohol oxidation and decreasing the oxidation rates. A
simplified rate equation describing this kinetic scenario shows
the rate should have an inverse first-order dependence on acetic
acid concentration (eq 2). To determine whether acetic acid
Figure 11. Inverse first-order rate dependence on [HOAc] for the oxidation
of sec-phenethyl alcohol using 1. The plotted range of [AcOH] is from
6.75 to 67.5 mM (from 1.5 to 15 mol %).
kobs[1][2]
rate )
(2)
[HOAc]
simply inhibits alcohol oxidation or has a more profound role
within the catalytic system, the dependence of oxidation rate
on acetic acid concentration was evaluated from 0 to 67.5 mM
(
from 0 to 15 mol %). Interestingly, an initial rate increase was
observed at low concentrations of additive acetic acid (Figure
0). A maximal rate was achieved at 2.79 mM (0.62 mol %)
1
acetic acid followed by inhibition as more acetic acid was added.
When the data ranging from 6.75 to 67.5 mM (from 1.5 to 15
mol %) were fit to a simple inverse first-order equation using
nonlinear least-squares analysis, the agreement was excellent
Figure 12. Natural logarithm of sec-phenethyl alcohol concentration vs
time at various HOAc concentrations at 50 °C (every 10 time points
displayed). Conditions: 0.5 mol % 1, 0.45 M alcohol in benzene, with 3 Å
molecular sieves and a balloon charged with O2.
(Figure 11). The results under these conditions are consistent
with a simple rate equation similar to eq 2. However, the
observations from 0 to 1.5 mol % allude to a more complicated
scenario with acetic acid playing multiple roles within the
catalytic system.
To understand how acetic acid enhances the rates of alcohol
oxidation under low concentrations, the rates of alcohol dis-
appearance were examined at different HOAc concentrations
(Figure 12). Analysis of these data using a pseudo-first-order
plot showed distinct linearity for the reactions carried out
with 2 and 3 mol % HOAc. This confirms the first-order rate
dependence on sec-phenethyl alcohol concentration and the
relative simplicity of the oxidation when >2 mol % HOAc is
added. The plots also show the relative retardation of oxidation
rate by adding 3 mol % HOAc compared to 2 mol % HOAc
predicted by eq 2. However, analysis of the data for the reactions
(
47) Mulliken charges and APT charges were both calculated. The APT charges
best correlated with a â-hydride elimination mechanism. Mulliken charges
indicated the â-H to be more proton-like; therefore, this analysis was not
used.
(
48) For the reversible formation of palladium(II) hydride species under acidic
conditions, see: Amatore, C.; A. Jutand, A.; Meyer, G.; Carelli, I.;
Chiarotto, I. Eur. J. Inorg. Chem. 2000, 1855-1859.
9730 J. AM. CHEM. SOC.
9
VOL. 126, NO. 31, 2004

Pd-Catalyzed Aerobic Oxidation of Alcohols
A R T I C L E S
Table 3. KIE Values at Various HOAc Concentrations
[
HOAc]
KIE
value
[HOAc]
(mM)
KIE
value
[HOAc]
(mM)
KIE
value
(mM)
0
2
1.7
2.7
2.79
4.50
3.1
3.4
6.75
9.00
5.2
5.5
.12
Scheme 4. Revised Proposed Mechanism: Possible
Rate-Influencing Steps of Pd-Catalyzed Aerobic Oxidation
Figure 13. log-log plot of the rate of sec-phenethyl alcohol oxidation vs
sec-phenethyl alcohol concentration. Conditions: 2.25 mM 1, 0% AcOH
in benzene, with 3 Å molecular sieves and a balloon charged with O2. The
range of sec-phenethyl alcohol concentration is from 0.03 to 0.45 M.
run at 0 and 0.75 mol % HOAc shows a significant deviation
from linearity. The oxidation at 0 mol % HOAc did not proceed
to completion, while the reaction at 0.75 mol % had a much
greater intial oxidation rate and overall conversion of alcohol,
demonstrating that low concentrations of additive HOAc
increase oxidation rates. These data support a time-dependent
process, presumably a catalyst decomposition pathway, is
occurring at low acid concentration.
observed, which is consistent with two transition states of
comparable free energy. That is, â-hydride elimination within
51
the manifold of alcohol oxidation is competitive with the
turnover-limiting step of Pd(II) catalyst regeneration. To further
explore this, a KIE value of 1.7 ( 0.2 was measured with no
additive acetic acid. This value is much smaller than the KIE
value measured (5.5 ( 0.1) when 9 mM (2 mol %) acetic acid
is included. Although not large, the KIE value of 1.7 ( 0.2 is
a significant primary KIE, which implies that â-hydride
elimination influences the rate when no additive acetic acid is
present, but the considerable diminishment of the KIE and a
partial order dependence on alcohol concentration suggest a step
in Pd(II) catalyst regeneration is competitive. To explore this
hypothesis, the KIE values for sec-phenethyl alcohol oxidation
were measured at acetic acid concentrations ranging from 0 to
Previous studies indicate Pd-catalyzed oxidation of alcohols
involves generation of Pd(0) species which are oxidized by
4
9
molecular oxygen. A proposed pathway of catalyst decom-
position is the aggregation of Pd(0) species to form inactive
5
0
Pd. Additive acetic acid can decrease catalyst decomposition
by retarding the rate of alcohol oxidation through reprotonation
of C, thus preventing the buildup of Pd(0) species. This alcohol
oxidation rate retardation was clearly demonstrated in Figure
1
1 from 6.75 to 67.5 mM (from 1.5 to 15 mol %) acetic acid.
The assumption of catalyst decomposition with no additive
acetic acid suggests that a step involved in Pd(II) catalyst
regeneration also influences the rate. By adding acetic acid,
Pd(0) concentration can be decreased with concomitant slowing
of the decomposition rate through two possible turnover steps.
With rate-limiting oxygenation, oxidative addition of acetic acid
to Pd(0) species can re-form palladium hydride D.48 Additive
acetic acid can also accelerate the protonation of palladium
peroxo F, preventing formation of Pd(0) through reversible
oxygenation.
To probe these possible scenarios, the rate dependence on
sec-phenethyl alcohol concentration was evaluated by measuring
initial rates with no additive acetic acid. A log-log plot was
constructed (Figure 13), and a partial order of 0.50 ( 0.02 was
9
mM (from 0 to 2 mol %) (Table 3). The KIE values gradually
increase as the concentration of additive acetic acid is increased.
This is consistent with a change in rate-influencing steps from
a combination of â-hydride elimination and a turnover-limiting
step to only â-hydride elimination at 9 mM (2 mol %) acetic
acid.
The two scenarios in which a turnover-limiting step can
influence Pd catalyst decomposition are (1) turnover-limiting
oxygenation with reversible reductive elimination and/or (2)
reversible oxygenation with protonation of palladium peroxo F
to form A and evolution of H2O2 (Scheme 4). If oxygenation
(
k5[E][O2]) is turnover limiting at 0 mM HOAc, a rate depend-
(
49) Two pathways have been suggested to describe how molecular oxygen
re-forms the active Pd catalyst: (1) O
2
insertion into the Pd-H bond or
ence on molecular oxygen concentration should be observed.
The alcohol oxidation rate dependence on percent molecular
oxygen was measured from 0 to 100% (molecular oxygen and
(
2) reductive elimination of Pd(X)-H to form a Pd(0) species which is
reoxidized by O
2
to form a palladium peroxo species. The latter of these
pathways is supported by the isolation of a palladium peroxo-bathocuproin
(
bc) complex by Stahl and co-workers formed by exposure of Pd(0)(bc) to
52
nitrogen mixtures) at balloon pressure. At 0 mol % acetic acid,
molecular oxygen; see: Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee,
M. A. J. Am. Chem. Soc. 2001, 123, 7188-7189. They demonstrated the
palladium peroxo-bc species yields Pd(OAc)
2
(bc) and hydrogen peroxide
(51) For recent examples, see: (a) Dewanti, A. R.; Xu, Y.; Mitra, B. Biochemistry
2004, 43, 1883-1890. (b) Dewanti, A. R.; Mitra, B. Biochemistry 2003,
42, 12893-12901. (c) Waas, W. F.; Rainey, M. A.; Szafranska, A. E.;
Dalby, K. N. Biochemistry 2003, 42, 12273-12286. (d) Kimura, Y.;
Toyoshima, N.; Hirakawa, N.; Okamoto, K.; Ishijima, A. J. Mol. Biol. 2003,
328, 939-950. (e) Fatin-Rouge, N.; Blanc, S.; Leize, E.; Van Dorsselaer,
A.; Baret, P.; Pierre, J.-L.; Albrecht-Gary, A.-M. Inorg. Chem. 2000, 39,
5771-5778. (f) Bebelis, S.; Zeritis, A. S.; Tiropani, C.; Neophytides, S.
G. Ind. Eng. Chem. Res. 2000, 39, 4920-4927.
when exposed to acetic acid. A related Pd-bathocuproine complex was
shown to be an excellent catalyst by Sheldon and co-workers for
Pd-catalyzed aerobic oxidation of alcohols in aqueous conditions (see ref
1
7).
(
50) For a discussion on the nontriviality of Pd(0) turnover, see: Tsuji, J.
Palladium Reagents and Catalysts: InnoVations in Organic Synthesis; John
Wiley and Sons: New York, 1995; p 20. For an example of Pd(0)
aggregation to precipitate Pd black in the Wacker oxidation, see: Tang,
H. G.; Sherrington, D. C. J. Catal. 1993, 142, 540-551.
(52) See the Supporting Information for details.
J. AM. CHEM. SOC.
9
VOL. 126, NO. 31, 2004 9731

A R T I C L E S
Mueller et al.
ination and the protonation of F are assumed as irreversible
5
2,53
(eq 3).
k [2]k k k k [O ]k [HOAc][Pd ]
1
2
3
4
5
2
6
T
rate )
(3)
k6[HOAc]k
+ k [2]k
prot 1 alc
kprot ) k k k k [O ] + k k k k [O ] +
2
3
4
5
2
-1
3
4
5
2
k k [HOAc]k k [O ] + k [2]k k k [O ] +
-
1
-2
4
5
2
1
3
4
5
2
k [HOAc]k [2]k k [O ] + k [2]k k k [O ] +
-
2
1
4
5
2
1
2
4
5
2
k [2]k k k [O ] + k [2]k k k [HOAc] + k [2]k k k
2 3 4
1
2
3
5
2
1
2
3
-4
1
kalc ) (k k k [HOAc]k + k k k k + k k k k [O ])
2
3
-4
-5
2
3
4
-5
2
3
4
5
2
Figure 14. Initial rates of the sec-phenethyl alcohol oxidation at 50 °C
using various AcOH concentrations and oxygen/nitrogen mixtures. Condi-
tions: 0.5 mol % 1, 0.45 M sec-phenethyl alcohol, with 3 Å molecular
sieves and a balloon charged with O2.
In eq 3, kprot is all terms in the denominator that k6[AcOH] can
be factored from, kalc is the remaining terms in the denominator
with k1[2] factored out, and [PdT] is the total concentration of
all Pd species. When no acetic acid is added, the full derived
rate law describes the kinetic events. The terms in the
denominator, k6[AcOH]kprot and k1[2]kalc, must be comparable
because of the observation of a partial order dependence on
alcohol concentration and a partial order dependence on acetic
acid concentration. As more acetic acid is added to the reaction,
the magnitude of k6[AcOH]kprot increases dramatically compared
to that of k1[2]kalc. Therefore, k6[AcOH]kprot completely governs
over the other terms in the denominator at higher [HOAc],
leading to a simplification of the rate law (eq 4). Two
observations allow for further simplification to eq 5: There is
no dependence on oxygen concentration, and the rate is limited
by â-hydride elimination at high [HOAc]. This equation
describes rate-limiting â-hydride elimination in the steady-state
form. If equilibrium conditions are assumed, the rate simplifies
to eq 2.
a zeroth-order rate dependence is observed from 29% to 100%
O2/N2 (Figure 14). However, significant decomposition was
noted immediately upon alcohol addition at 23% O2/N2. These
results indicate oxygenation is not turnover limiting under these
conditions, but a minimal concentration of oxygen must be
present for Pd(II) catalyst regeneration. This also is congruent
with being unable to effectively oxidize alcohols using air under
these conditions. Additionally, oxygen dependence was evalu-
ated at 3 and 7 mol % (13.5 and 31.5 mM) HOAc from 5% to
1
00% O2/N2. At 3 mol % acetic acid, there is no dependence
on oxygen concentration from 23% to 100% O2/N2. From 5%
to 23% O2/N2, significant decomposition is observed. At a higher
acetic acid concentration, 7 mol %, the rate dependence is zeroth
order in oxygen concentration from 5% to 100% oxygen with
no observed decomposition. These observations demonstrate
how air can be used as an effective O2 source by using increased
concentrations of acetic acid. From 0 to 7 mol % acetic acid,
decomposition occurs at progressively lower percentages of
oxygen until it is not detected at 7 mol % HOAc. It is important
to note that this phenomenon corresponds to a significant
decrease in alcohol oxidation rate due to inhibition through
reprotonation (C to B), which regulates the concentration of
O2 needed for efficient catalyst regeneration.
k [2]k k k k [O ][Pd ]
1
2
3
4
5
2
T
rate )
(4)
(5)
kprot
k [2]k k [Pd ]
1
2
3
T
rate )
k k + k k + k k [HOAc]
2
3
-1
3
-1 -2
pKa Dependence. Considering the significance of acetic acid
in Pd(IiPr)(OAc)2(H2O)-catalyzed oxidation of alcohols, it is
logical that a pKa effect could be observed when the carboxylate
ligand and additive carboxylic acid are changed. Several
catalysts were synthesized by submitting Pd(IiPr)Cl2 dimer
complex to salt metathesis with different silver carboxylates.
These new Pd(IiPr)(carboxylate)2 complexes were tested for
catalytic activity with a 2 mol % concentration of the corre-
sponding carboxylic acid (eq 6). A Brønsted-type plot was
Competitive turnover-limiting protonation of peroxo F is most
consistent with the above kinetic data and the observation of a
partial positive order acetic acid concentration dependence from
0
to 2.79 mM (from 0 to 0.62 mol %). With this proposal, the
observation of decomposition at 0 mM acetic acid suggests
reversible oxygenation. Therefore, as more acetic acid is added,
the rate of protonation of F increases while the rate of alcohol
oxidation decreases from inhibition through reprotonation of
C. When >2 mol % acetic acid is added, protonation of F is
fast relative to alcohol oxidation, leading to observed rate-
limiting â-hydride elimination under these conditions. This
scenario rationalizes the change in alcohol dependence from
partial order at low concentrations of acetic acid to first order
at higher concentrations of acetic acid. It is also consistent with
the change in KIE values from 1.7 at 0 mM acetic acid when
there is a combination of rate-influencing steps to 5.5 at 9 mM
constructed by comparing the measured initial oxidation rates
to the pKa of the corresponding carboxylic acid in H2O (Figure
5
4,55
1
5).
A linear free energy relationship was observed with a
calculated R value of 1.44 ( 0.13. An R value of 1.44 ( 0.13
(
2 mol %) acetic acid when only â-hydride elimination is rate
limiting.
Using the King-Altman method, a rate law can be derived
to mathematically describe Scheme 4, where â-hydride elim-
(53) For the King-Altman method, see: Cornish-Bowden, A. Principles of
Enzyme Kinetics; Butterworth: London, 1976; pp 38-40.
(
54) Isaacs, N. Physical Organic Chemistry, 2nd ed.; Prentice Hall: Harlow,
U.K., 1995; pp 381-384.
9732 J. AM. CHEM. SOC.
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Pd-Catalyzed Aerobic Oxidation of Alcohols
A R T I C L E S
Figure 15. Brønsted-type plot of alcohol oxidation with a 2 mol %
concentration of the corresponding acid at 50 °C. Conditions: 0.5 mol %
Pd catalyst, 0.25 M sec-phenethyl alcohol in benzene, with 3 Å molecular
sieves and a balloon charged with O2.
Figure 16. Brønsted-type plot of alcohol oxidation with 0 mol % additive
acid at 50 °C. Conditions: 0.5 mol % Pd catalyst, 0.25 M sec-phenethyl
alcohol in benzene, with 3 Å molecular sieves and a balloon charged
with O2.
is very large, indicating a significant pKa effect. By definition,
R values should not exceed 1.00 if describing only one step.
Since the anionic ligand was changed as well as the added acid,
two influences are manifested in this R value: the basicity of
the anionic ligand/base for deprotonation of Pd-bound alcohol
B and the acidity of the acid for reprotonation of palladium
alkoxide C. With such a large R value, reprotonation is probably
the dominant step, with a weaker carboxylic acid leading to
higher alcohol oxidation rates.56
Of note is the log(kobs) value for Pd(IiPr)(pivalate)2 has a
standard residual value of 1.6. Pivalate was the largest coun-
terion tested in this experiment. Relief of steric strain through
formation of the alkoxide as well as the higher basicity of
pivalate provides an explanation for the increased catalytic
activity relative to those of other carboxylate catalysts. These
studies have led to the development of a highly active Pd(IiPr)-
(pivalate)2 catalyst for oxidation of alcohols at room temperature
To differentiate the influence of carboxylate/carboxylic acid
pKa on deprotonation of B and on reprotonation of C, the Pd-
57
using air, which will be reported in due course.
Overall Mechanistic Implications. The details for the
aerobic oxidation of alcohols with Pd(IiPr)(OAc)2(H2O) have
been elucidated, confirming much of the mechanistic rationale
used to design it. Using a monodentate dative ligand and an
anionic ligand as an internal base yields a highly effective
catalyst system for alcohol oxidation. Initially, kinetic experi-
ments revealed a relatively simple system, but as the alcohol
oxidation was evaluated at other conditions, it became clear the
entire scenario is much more complicated. Two results highlight
the unique nature of the catalytic system: a large KIE value
and the dynamic dependence on [HOAc].
The observed large KIE value leads to a proposed late
transition state with significant Pd-H character. Theoretical
studies support this late-transition-state model for â-hydride
elimination from the Pd(IiPr)(OAc) alkoxide, and the calculated
KIE value of 3.8 correlates with the experimentally determined
KIE value of 5.5 ( 0.1. As demonstrated by large differences
in KIE and F values, the nature of the ligand has a significant
influence on â-hydride elimination. A single monodentate ligand
provides an open coordination site leading to the proposed late
transition state, while a bidentate ligand (or two monodentate
ligands) most likely involves a 5-coordinate early transition state.
These results reveal the ability to modulate â-hydride elimination
by careful selection of ligand and lead to significant implications
in the design of asymmetric catalysts.
(
IiPr)(carboxylate)2 complexes were assessed with no additive
52
carboxylic acid, where reprotonation of C should be negligible.
However, performing these experiments at 0 mol % acetic acid
conditions changes the scenario of rate-limiting steps. Under
these conditions, previous experimental observations show
turnover-limiting protonation of F is competitive with â-hydride
elimination. Therefore, the acid/base effects most likely being
evaluated under these conditions are deprotonation of Pd-bound
alcohol B by carboxylate and protonation of peroxo F by
carboxylic acid. A carboxylate from a higher pKa carboxylic
acid provides for a better base for deprotonation of B. In
contrast, a carboxylic acid with a lower pKa facilitates proto-
nation of peroxo F. A positive linear free energy relationship
was observed with a calculated R value of 0.31 ( 0.04 (Figure
1
6). This value is significantly smaller than the value of
1
.44 ( 0.13 at 2 mol % carboxylic acid conditions and within
the typical range from 0 to 1.00. The positive slope indicates a
stronger conjugate base facilitates the overall reaction. This
corresponds with deprotonation of the Pd-bound alcohol being
more sensitive to pKa effects than protonation of peroxo F with
no added acid. These results showcase the importance of the
basicity of the carboxylate ligands for an efficient Pd catalyst
for oxidation of alcohols.
(
55) For pK
a
values in water, see: Lide, D. R., Ed. CRC Handbook of Chemistry
Acetic acid plays multiple roles in aerobic oxidation of
alcohols with Pd(IiPr)(OAc)2(H2O). Acetic acid is vital to the
system to prevent decomposition of the catalyst and maintain
consistent reactions. A key observation is increasing acetic acid
concentration modulates the steps that influence the alcohol
oxidation and Pd catalyst regeneration rates. When no acetic
acid is present, â-hydride elimination works synergistically with
turnover-limiting protonation to influence the overall reaction
and Physics, 75th ed.; CRC Press Inc.: Boca Raton, FL, 1995. For the
a
pK value of trifluoroacetic acid, see: Budavari, S., Ed. Merck Index, 12th
ed.; Merck & Co., Inc.: Whitehouse Station, NJ, 1996.
(
56) Another consideration is the change in carboxylate ligand may also affect
â-hydride elimination since this ancillary ligand is bound to palladium
alkoxide C during rate-limiting â-hydride elimination. If the bound
carboxylate has a significant effect on â-hydride elimination, electron-
withdrawing groups on the carboxylate should increase the electrophilicity
a
of the Pd(II) center. Thus, carboxylic acids with lower pK values should
lead to increases in rate. The Brønsted-type plot at 2 mol % additive
carboxylic acid shows the opposite trend where carboxylate ligands with
electron-donating groups show increased reaction rates. Thus, the influence
of different carboxylate ligands on â-hydride elimination is probably
minimal compared to the acid/base effects present.
(57) Hamilton, S.; Schultz, M. J.; Sigman, M. S. Unpublished results.
J. AM. CHEM. SOC.
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VOL. 126, NO. 31, 2004 9733

A R T I C L E S
Mueller et al.
rate. Addition of acetic acid increases the rate of protonation
of F until it is no longer rate influencing, rendering â-hydride
elimination the single rate-controlling step. The discovery of Pd
catalyst decomposition when protonation of the peroxo species
F influences the overall rate suggests oxygenation is reversible,
allowing for a decomposition pathway through Pd(0). Key
studies of rate dependence on oxygen percent reveal additive
acetic acid decreases alcohol oxidation rates and prevents
deoxygenation through reversible peroxo formation. This ability
to balance alcohol oxidation with Pd catalyst regeneration events
allows for the use of air as a viable oxygen source.
Conclusions
The development of a well-defined catalyst, Pd(IiPr)(OAc)2-
(H2O), represents a clear example where catalyst design was
significantly enhanced by detailed structural and kinetic infor-
mation. The study of this catalyst has led to a fascinating picture
of â-hydride elimination and how it can be modulated by careful
selection of ligand and counterion. For other Pd-catalyzed aero-
bic oxidations of alcohols, only one realm of the catalytic cycle
has been studied kinetically. Elucidation of the roles of acetic
acid allowed for the concomitant study of Pd-catalyzed alcohol
oxidation and catalyst regeneration by molecular oxygen. Further
studies are aimed at understanding the precise mechanism of
decomposition and using these studies as a foundation to design
new catalysts for other Pd-catalyzed aerobic oxidations.
The balance of alcohol oxidation and Pd catalyst regeneration
events with additive acetic acid has allowed for insight into both
realms of the catalytic cycle. This insight allows for the analysis
of other mechanistic pathways for regeneration. It has been
proposed for Pd-catalyzed aerobic alcohol oxidations that a
palladium hydroperoxide species can be converted directly to
the palladium alkoxide by alcohol especially under basic
Acknowledgment. This work was supported by the National
Institutes of Health (NIGMS Grant No. RO1 GM63540) and
supported by a Research Innovation Award sponsored by
Research Corp. We thank the University of Utah Research
Foundation, Merck Research, Rohm and Haas Research, and
Invenux Inc. for partial support of this research. We thank the
donors of the Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this research
(PRF Grant No. 37536-G1). We thank Johnson Matthey for
supplies of various palladium salts. The X-ray crystal structure
analysis was performed by Atta Arif. We also thank David R.
Jensen and Professor Thanh N. Truong for insightful discussions.
3
,11a
conditions.
The need of acetic acid for efficient catalyst
turnover implies a Pd(II) species such as A is formed. This
can bind the alcohol as a Lewis acid to increase the acidity of
the hydroxyl proton, allowing for effective deprotonation and
formation of palladium alkoxide B. If the palladium peroxo F
can be converted directly to B when exposed to alcohol in the
presence of base, addition of NBu4OAc should promote turn-
over of the Pd catalyst and prevent decomposition. Instead,
significant decomposition is observed with addition of NBu4OAc
to the extent that initial rates can only be measured to 3 mol %
Supporting Information Available: Statistical analyses, rate
tables, rate law derivation, preparation of catalyst derivatives,
DFT calculation data, and NMR spectra (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
5
2
NBu4OAc in the oxidation of sec-phenethyl alcohol. These
observations contradict base-promoted turnover of the palladium
peroxo species directly to the palladium alkoxide C, but strongly
support the regeneration of A, followed by substrate binding
and subsequent deprotonation to C.
JA047794S
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VOL. 126, NO. 31, 2004