A well-defined complex for palladium-catalyzed aerobic oxidation of alcohols: Design, synthesis, and mechanistic considerations

Article abstract of DOI:10.1002/anie.200351997

A breath of fresh air: A variety of alcohols are oxidized using 0.5-0.1 mol% of the catalyst, and in some cases the oxidation can simply be carried out open to the air (see scheme). Mechanistic insight into the mechanism is provided by a crystal structure that shows remarkable hydrogen bonds between the coordinated water and acetate ligands and an unprecedented large kinetic isotope effect.

Full text of DOI:10.1002/anie.200351997

Communications
Aerobic Oxidation of Alcohols
A Well-Defined Complex for Palladium-
Catalyzed Aerobic Oxidation of Alcohols:
Design, Synthesis, and Mechanistic
Considerations**
David R. Jensen, Mitchell J. Schultz, Jaime A. Mueller,
and Matthew S. Sigman*
The PdII-catalyzed oxidation of an alcohol using molecular
oxygen as the terminal oxidant is potentially a powerful
transformation for organic synthesis.[1–3] Of the reported
oxidations, monodentate nitrogenous ligands in combination
with Pd(OAc)2 have generally provided active catalyst
mixtures, yet many of these oxidations suffer from relatively
high catalyst loadings, an excess of ligand or base, and/or high
oxygen pressures. Mechanistic explanations for these trends
have recently been sought in several studies.[4] Key findings
include: 1) base is necessary for catalysis,[4a,b] 2) an excess of
ligand is needed to prevent catalyst decomposition,[2a,4c] and
3) a ligand must dissociate to allow alcohol binding and/or b-
hydride elimination.[2a,4,5] Unfortunately, the need for excess
ligand to prevent decomposition of the catalyst leads to less-
efficient oxidation as a result of inhibition of either alcohol
binding or b-hydride elimination. Herein, we report the
design, use, and preliminary mechanistic studies of a well-
defined Pd complex for alcohol oxidation that circumvents
[*] Prof. Dr. M. S. Sigman, D. R. Jensen, M. J. Schultz, J. A. Mueller
Department of Chemistry
University of Utah
315 S. 1400 East, Salt Lake City, UT 84112 (USA)
Fax: (+1)801-581-8433
E-mail: sigman@chem.utah.edu
[**] This work was supported by the National Institutes of Health
(NIGMS no. RO1 GM63540). D.R.J. is supported by an ACS
Division of Organic Chemistry Graduate Fellowship sponsored by
the Schering–Plough Research Institute. Pd salts were provided by
Johnson Matthey. The crystal-structure analysis was performed by
Atta Arif.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200351997
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Angewandte
Chemie
this conflict and is consequently suitable for oxidation using
lower catalyst loadings and an ambient air atmosphere.
Based on the above discussion, a highly effective PdII-
catalyzed alcohol oxidation might be achieved using a well-
defined complex that does not require excess ligand to
prevent decomposition of the catalyst. Directed by our
previous studies, we considered using a palladium(ii) acetate
complex with a single N-heterocyclic carbene (NHC) ligand,
since the NHC should act as a strong ligand to stabilize PdII
and Pd0 intermediates without the need for excess ligand.[6]
Furthermore, PdII–NHC complexes have been shown to
facilitate alcohol oxidation with the tertiary diamine (À)-
sparteine as base.[3c] The acetate ligands were envisioned to
serve two purposes: as a ligand for the PdII center and as a
base to deprotonate the Pd-bound alcohol.[7] Since the acetate
base would be masked as an anionic ligand, an intriguing
possibility is that the acetate group could facilitate an
intramolecular deprotonation (Scheme 1). Not only should
this enhance the rate of deprotonation, but the resulting Pd–
alkoxide should also have a readily accessible coordination
site for b-hydride elimination.
procedure under the following conditions: 0.5m alcohol in
toluene, 0.5 mol% 1, 2.0 mol% HOAc, activated 3-Š molec-
ular sieves, and a balloon of oxygen.
A variety of benzylic and allylic alcohols were cleanly
oxidized to the corresponding aldehyde or ketone under these
conditions, and high yields of the isolated products could be
obtained by simple filtration through a plug of silica (Table 1,
entries 1, 3, 5, and 7). The catalyst is capable of up to
Table 1: Oxidation of alcohols using pure O2.
Entry[a] Substrate
R
R’
t [h] Yield [%][b,c]
1[d]
2a
2a
2b
2b
2c
Ph
CH3
5
13
>99 (98)
>99
2[e]
3[d]
4-MeOC6H4
H
3.5 >99 (99)
20
4[d],[f]
5[d]
>99
>99 (99)
91
91 (84)
99 (93)
92
>99
97
85 (76)
(85)
3-CF3C6H4
Ph
CH3 12
tBu 14
CH3 12
CH3 13
12
6[d],[g] 2d
7[d]
8[h]
2e
2 f
2g
2h
2i
1-cyclohexenyl
CH3(CH2)7
3-Me-cyclohexenol
cis-4-Me-cyclohexanol
myrtenol
9[d]
10[h]
11[i]
13
20
10
10
12[i],[j]
13[i],[j]
2j
2k
CH3(CH2)10
CH3(CH2)16
H
H
[a] See Supporting Information for details. [b] GC conversion. [c] Yield of
isolated compound in parenthesis. [d] 2 mol% HOAc. [e] Catalyst
prepared in situ using 0.5 mol% Pd(OAc)2, 0.65 mol% IiPr–HBF4,
0.7 mol% KOtBu. [f] 0.1 mol% 1. [g] 1 mol% 1. [h] 1 mol% HOAc.
[i] 5.0 mol% Bu4NOAc. [j] 0.75 mol% 1. MS=molecular sieves.
Scheme 1. Proposed intramolecular deprotonation.
1000 turnovers with the activated substrate 2b (Table 1,
entry 4). For synthetic simplicity, the catalyst can be pre-
generated in the same reaction pot using Pd(OAc)2, the IiPr–
HBF4 salt, and KOtBu, and applied successfully to the
transformation (Table 1, entry 2). The sterically encumbered
alcohol 2d reacted slower but underwent good conversion by
increasing the catalyst loading to 1.0 mol% (Table 1, entry 6).
Only 1.0 mol% of acetic acid was needed for the clean
oxidation of less reactive aliphatic alcohols to their corre-
sponding ketones (Table 1, entries 8 and 10). Oxidation of
non-benzylic, primary alcohols was accompanied by degra-
dation of the aldehyde product which hindered catalysis.
Several changes to the reaction conditions were required
since auto-oxidation of aldehydes is possible under slightly
acidic conditions. Removing the HOAc, adding Bu4NOAc,
and diluting the substrate to 0.125m resulted in good yields of
the aldehydic product (Table 1, entries 11–13).
To test these ideas complex 1 (Figure 1) was generated
in situ from AgOAc and the requisite PdCl2–NHC dimer and
used for the oxidation of alcohol 2a. The oxidation proved
effective with 5 mol% of catalyst and gave > 99% conversion
in less than 2 h. [Pd(IiPr)(OAc)2(H2O)] (1) was characterized
by X-ray crystallography.[8] Our initial experiments were
aimed at producing a reliable procedure at low catalyst
loading, and, surprisingly, lowering the catalyst loading from
5 mol% to 0.5 mol% was found to give inconsistent results.
However, the addition of a small amount of acetic acid to the
reaction eliminated these inconsistencies and gave a reliable
A substantial practical improvement for aerobic oxida-
tions is to replace the pure O2 with air. Increasing the amount
of acetic acid used enabled the oxygen balloon to be removed
and the reaction carried out under the ambient atmosphere
(no balloon necessary), with only slightly extended reaction
times (Table 2). Increasing the amount of acetic acid to
5 mol% allowed the reaction to be scaled up to one gram in
air, and gave > 99% conversion in 14 h with the product
isolated in a yield of 97% (Table 2, entry 1). Replacement of
O2 with air at ambient pressure usually leads to decomposi-
Figure 1. ORTEP and ChemDraw views of [Pd(IiPr)(OAc)2(H2O)] (1).
Hydrogen bond lengths [Š]: O(1)-H(1a)=0.89(4), O(1)-
H(1b)=0.85(4), O(4)-H(1a)=1.73(4), O(5)-H(1b)=1.82(4), O(1)-
O(4)=2.571(3), O(1)-O(4)=2.627 (3), and hydrogen bond angles [8]:
O(1)-H(1A)···O(4)=156(3), O(1)-H(1B)···O(5)=159(3).
Angew. Chem. Int. Ed. 2003, 42, 3810 –3813
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Communications
Table 2: Oxidation of alcohols using air.
alcohol A gives a Pd–alkoxide B. Rate-limiting transfer of a b-
hydride to a readily accessible coordination site gives the
carbonyl product and the Pd–hydride C. Reductive elimina-
tion of acetic acid from C gives a Pd0–NHC complex D, which
can be oxidized by molecular oxygen to give a PdII–NHC
peroxo complex E.[4f] Protonation with two equivalents of
acetic acid regenerates the Pd(OAc)2–NHC complex F and
completes the catalytic cycle. While the precise role(s) of
added acetic acid is not defined, added acetic acid could affect
the turnover of the Pd0–NHC peroxo intermediate E,
reprotonation of Pd–alkoxide B, or an equilibrium between
Pd–hydride C and Pd0 species D.[13]
In conclusion, a robust and effective Pd catalyst for
aerobic alcohol oxidation that is effective for a variety of
alcohols with turnover numbers of up to 1000 has been
discovered and studied. Using a slightly higher concentration
of acetic acid and extending the reaction times, the oxidations
can be carried out under an ambient atmosphere of air, as
showcased by the oxidation of alcohol 2a on a one-gram scale.
Mechanistic and structural data support proposals of intra-
molecular deprotonation and transfer of a b-hydride to a
readily accessible coordination site. Future directions for this
project include identifying chiral NHC ligands and/or carbox-
ylates for an asymmetric variant and applying this catalyst
system to other Pd-catalyzed reactions. A full study of the
mechanism will be reported in due course and should
elucidate the role(s) of acetic acid in the current oxidation
as well as an evolved understanding of b-hydride elimination
from Pd complexes.
Entry[a] Substrate
1[d,e]
2a
R
R’
t [h] Yield [%][b,c]
Ph
CH3 14
CH3 14
CH3 20
>99 (97)
>99 (93)
>99
2[f]
2l
4-MeOC6H4
3-CF3C6H4
4-CH3C6H4
CH3(CH2)7
1-indanol
3[f]
4[f]
5 g]
6[f]
7[f]
2c
2m
2 f
2n
2h
H
14
>99
CH3 14
99 (91)
>99
96
14
14
cis-4-Me-cyclohexanol
[a] See Supporting Information for details. [b] GC conversion. [c] Yield of
isolated product in parenthesis. [d] 5 mol% HOAc. [e] 1.0 g scale.
[f] 4 mol% HOAc. [g] 2 mol% HOAc.
tion of the catalyst in Pd-catalyzed aerobic oxidation of
alcohols, thus the use of air in the current reactions is notable
and can be considered a tribute to the robustness of this
catalyst system.[9]
The crystal structure lends credence to our initial hypoth-
esis of the acetate group acting as an intramolecular base
(Figure 1): when the complex forms, a molecule of water is
captured by the complex, with formation of a dative bond to
the Pd and a hydrogen bond to each acetate ligand.[10,11] The
presence of the hydrogen bonds between the water and the
acetate oxygen atoms is quite remarkable as they suggest that
an acetate ligand could indeed facilitate an intramolecular
deprotonation. With evidence to suggest that the acetate
ligand could function as an intramolecular base, several
mechanistic experiments were undertaken to determine what
effect(s) this might have on catalysis. After determining a
first-order dependence on both [alcohol] and [1], the kinetic
isotope effect (KIE) for the b-hydride (deuteride) of 2a was
measured. In contrast to the typically small KIE (1.3–2.5) for
rate-limiting elimination of a b-hydride from a Pd–alkoxide
complex,[12] an unusually large primary KIE of 6.8 Æ 0.7 was
determined. The magnitude of this KIE is similar to the
Received: May 28, 2003 [Z51997]
Published online: August 1, 2003
Keywords: alcohols · oxidation · oxygen · palladium ·
.
reaction mechanisms
[1] For recent reviews, see a) R. A. Sheldon, I. W. C. E. Arends, G.
ten Brink, A. Dijksman, Acc. Chem. Res. 2002, 35, 774; b) R. A.
Sheldon, I. W. C. E. Arends, A. Dijksman, Catal. Today 2000, 57,
157.
[2] For examples, see a) M. J. Schultz, C. C. Park, M. S. Sigman,
Chem. Commun. 2002, 3034; b) N. Kakiuchi, Y. Maeda, T.
Nishimura, S. Uemura, J. Org. Chem. 2001, 66, 6620; c) K.
Hallman, C. Moberg, Adv. Synth. Catal. 2001, 343, 260; d) G.
ten Brink, I. W. C. E. Arends, R. A. Sheldon, Science 2000, 287,
1636; e) T. Nishimura, T. Onoue, K. Ohe, S. Uemura, J. Org.
Chem. 1999, 64, 6750; f) K. P. Peterson, R. C. Larock, J. Org.
Chem. 1998, 63, 3185.
À
calculated value for a transition state with no C H(D) bond
vibration and is consistent with a readily accessible coordi-
nation site for b-hydride elimination. The lower KIEs
measured in other systems may be attributed to agostic
interactions needed to displace a relatively strong ligand (for
example, pyridine or chloride).
A reasonable catalytic cycle can be proposed (Scheme 2)
from the structural and mechanistic data. The catalytic cycle
begins with the binding of the alcohol to 1 and concomitant
loss of water. Intramolecular deprotonation of the Pd-bound
[3] For the use of Pd-catalyzed alcohol oxidation for kinetic
resolution, see a) S. K. Mandal, D. R. Jensen, J. S. Pugsley,
M. S. Sigman, J. Org. Chem. 2003, 68, 4600; b) J. T. Bagdanoff,
E. M. Ferreira, B. M. Stoltz, Org. Lett. 2003, 5, 835; c) D. R.
Jensen, M. S. Sigman, Org. Lett. 2003, 5, 63; d) E. M. Ferreira,
B. M. Stoltz, J. Am. Chem. Soc. 2001, 123, 7725; e) D. R. Jensen,
J. S. Pugsley, M. S. Sigman, J. Am. Chem. Soc. 2001, 123, 7475.
[4] For mechanistic studies, see a) J. A. Mueller, M. S. Sigman, J.
Am. Chem. Soc. 2003, 125, 7005; b) J. A. Mueller, D. R. Jensen,
M. S. Sigman, J. Am. Chem. Soc. 2002, 124, 8202; c) B. A.
Steinhoff, S. S. Stahl, Org. Lett. 2002, 4, 4179; d) B. A. Steinhoff,
S. R. Fix, S. S. Stahl, J. Am. Chem. Soc. 2002, 124, 766; e) G.
ten Brink, I. W. C. E. Arends, R. A. Sheldon, Adv. Synth. Catal.
Scheme 2. Proposed mechanism.
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Chemie
2002, 344, 355; f) S. S. Stahl, J. L. Thorman, R. C. Nelson, M. A.
Kozee, J. Am. Chem. Soc. 2001, 123, 7188.
group P21/a. The structure was solved by a combination of
direct methods and heavy atom using SIR 97. All of the non-
hydrogen atoms were refined with anisotropic displacement
coefficients. Hydrogen atoms were located and refined isotropi-
cally except those on the C31 atom which were assigned
isotropic displacement coefficients U(H) = 1.5U(C methyl),
and their coordinates were allowed to ride on their respective
carbon atoms using SHELXL97. The weighting scheme
employed was w = 1/[s2(Fo2) + (0.0257P)2 + 2.171P] where P =
(F2o + 2F2c)/3. The refinement converged to R1 = 0.0303, wR2 =
0.0726, and S = 1.027 for 6402 reflections with I > 2s(I), and
R1 = 0.0353, wR2 = 0.0758, and S = 1.027 for 7162 unique
reflections and 517 parameters. The maximum D/s value in the
final cycle of the least-squares was 0.001, and the residual peaks
[5] A notable exception is the phenathrolene-based catalyst.[2d] In
this catalyst, a bidentate ligand is used. Since the solvent is H2O
at 1008C and 30 atm, the oxidation precedes by dissociation of
anionic ligands.
[6] For a review of NHC ligands, see W. A. Hermann, Angew. Chem.
2002, 114, 1342; Angew. Chem. Int. Ed. 2002, 41, 1290.
[7] For evidence of acetate acting as a base, see ref. [4b].
[8] CCDC-213715 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk). A yellow prism-shaped crystal 0.30 ꢀ 0.23 ꢀ
0.18 mm in size was mounted on a glass fiber with traces of
viscous oil and then transferred to a Nonius KappaCCD
diffractometer equipped with MoKa radiation (l = 0.71073 Š).
Ten frames of data were collected at 150(1) K with an oscillation
range of 1 deg/frame and an exposure time of 20 s/frame.
Indexing and unit-cell refinement based on all observed
reflection from those ten frames indicated a monoclinic P lattice.
on the final difference-Fourier map ranged from À0.594 to
À3
0.869 eŠ
.
[9] For a homogeneous Pd catalyst using air, see ref. [2c]. For a
heterogeneous Pd catalyst using air, see ref. [2b].
[10] The H2Omolecule binds when the complex is formed and not
during recrystallization, as evidenced by identical 1H NMR
spectra for the complex formed in situ and after recrystallization.
[11] The hydrogen atoms of the water molecule were located and
found to be within the van der Waal radii of the acetate and the
water. See Supporting Information for details.
A
total of 12906 reflections (lmax = 27.58) were indexed,
integrated, and corrected for Lorentz, polarization, and absorp-
tion effects using DENZO-SMN and SCALEPAC. Post refine-
ment of the unit cell gave a = 9.59400(10), b = 19.1341(3), c =
17.1480(3) Š, b = 92.3451(5)8, and V= 3145.27(8) Š3. Axial
photographs and systematic absences were consistent with the
compound having crystallized in the monoclinic space
[12] See ref. [4b,c,e] and G. Noronha, P. M. Henry, J. Mol. Catal. A
1997, 120, 75.
[13] For the reversible formation of PdII–hydride species under acidic
conditions, see C. Amatore, A. Jutand, G. Meyer, I. Carelli, I.
Chiarotto, Eur. J. Inorg. Chem. 2000, 1855.
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