A bimetallic system for the catalytic hydroxylation of remote primary C- H bonds in functionalized organics using dioxygen

Article abstract of DOI:10.1021/ja993457l

In a mixture of trifluoroacetic acid and water, the combination of metallic palladium and copper chloride catalyzes the hydroxylation of remote primary C-H bonds of a variety of acids, alcohols, and aliphatic halides, in the presence of carbon monoxide and dioxygen. Experiments suggest that the principal role of metallic palladium is to generate hydrogen peroxide in situ and that the species responsible for the remote hydroxylation of the substrate by hydrogen peroxide is copper chloride. The unusual preference for the catalytic hydroxylation of primary C-H bonds was also found in an experiment involving competition between ethane and either cumene or p- isopropylbenzoic acid: even though the solution concentration of ethane was significantly lower than the competing substrate, the vast majority of the oxidation product (ethanol) was derived from ethane. In the reactions studied, acetic acid and formic acid were formed through C-C cleavage steps. An examination of the site of C-C cleavage in propionic acid indicated that both C-C bonds were being broken.

Full text of DOI:10.1021/ja993457l

J. Am. Chem. Soc. 2000, 122, 4029-4031
4029
A Bimetallic System for the Catalytic Hydroxylation of Remote
Primary C-H Bonds in Functionalized Organics Using Dioxygen
Chengyu Shen, Eduardo A. Garcia-Zayas, and Ayusman Sen*
Contribution from the Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
ReceiVed September 24, 1999
Abstract: In a mixture of trifluoroacetic acid and water, the combination of metallic palladium and copper
chloride catalyzes the hydroxylation of remote primary C-H bonds of a variety of acids, alcohols, and aliphatic
halides, in the presence of carbon monoxide and dioxygen. Experiments suggest that the principal role of
metallic palladium is to generate hydrogen peroxide in situ and that the species responsible for the remote
hydroxylation of the substrate by hydrogen peroxide is copper chloride. The unusual preference for the catalytic
hydroxylation of primary C-H bonds was also found in an experiment involving competition between ethane
and either cumene or p-isopropylbenzoic acid: even though the solution concentration of ethane was significantly
lower than the competing substrate, the vast majority of the oxidation product (ethanol) was derived from
ethane. In the reactions studied, acetic acid and formic acid were formed through C-C cleavage steps. An
examination of the site of C-C cleavage in propionic acid indicated that both C-C bonds were being broken.
Introduction
Experimental Section
Caution. Appropriate precautions should be taken while working
with gases under high pressures. Particular attention should be paid
to flammability limits of gas mixtures.
General. The following chemicals were used as received: 5% Pd/
carbon (60 µmol surface Pd atoms/g catalyst, as determined by
The catalytic functionalization of aliphatic C-H bonds is one
of the most important problems in chemistry. In particular, the
selective oxidation of remote primary C-H bonds of organic
substrates continues to be an intellectual and practical challenge
despite past efforts by organic and organometallic chemists. To
date, the only examples of metal-catalyzed functionalization
1
dihydrogen chemisorption studies) (Johnson Matthey); CuCl
2
, CuCl,
CuBr , Cu(CF CO , 50% H , propionic acid, butyric acid, n-
2
3
2
)
2
2 2
O
propanol, ethanesulfonic acid sodium salt monohydrate, propanesulfonic
acid sodium salt monohydrate, ethylphosphonic acid, n-propyl chloride,
cumene, p-isopropyl benzoic acid, ethylbenzene, p-ethylbenzene sul-
fonic acid, trifluoroacetic acid, NaCl, and chlorine (Aldrich); ethane,
(
hydroxylation) of remote primary C-H bonds involve the
2-
2-
1a,b,2
combination of PtCl4 /PtCl6 (the Shilov system).
Despite
its many attractive features, however, the Shilov system suffers
from one crippling drawback: dioxygen cannot be used ef-
ficiently as the reoxidant.3
13
dioxygen, dinitrogen, and carbon monoxide (Matheson); C
2 5
H COOH;
and CD CH COOH (Cambridge Isotopes). Reactions under pressure
3
2
were carried out in 300 mL Parr general purpose stainless steel bombs
We had earlier reported that, in a mixture of trifluoroacetic
acid and water, the combination of metallic palladium and
copper chloride catalyzes the oxidation of alkanes in the
presence of carbon monoxide.1a,e,4 We now report that this
system is also effective for the hydroxylation of remote primary
C-H bonds of functional organics. Further experiments also
confirm that the oxidations do not involve free alkyl radicals.
1
with glass liners. Reaction products were identified by their H and
13
C NMR spectra recorded on a Bruker AM 300 FT-NMR spectrometer
using an external standard consisting of a capillary tube containing 1
µL of DMSO in 60 µL of D O for lock, reference, and as an integration
2
standard. The identity of specific NMR resonances was confirmed by
comparison to standard reference spectra and/or co-injection of
standards.
Procedure. The substrate, anhydrous CuCl
were added to a glass liner containing 1.5 mL of CF
mL of H O. The liner was then placed in a high-pressure reactor (bomb)
which was then sealed. The reactor was purged and then pressurized
to 200 psi with CO, to 1000 psi with N , and to 1100 psi with O . The
2
, and 5% Pd on carbon
3
COOH and 0.5
(
1) Recent reviews: (a) Sen, A. Acc. Chem. Res. 1998, 31, 550. (b) Stahl,
S. S.; Labinger, J. A.; Bercaw, J. E. Angew. Chem., Int. Ed. 1998, 37, 2181.
c) Jones, W. D. Top. Organomet. Chem. 1999, 3, 9. (d) Kakiuchi, F.; Murai,
S. Top. Organomet. Chem. 1999, 3, 47. (e) Sen, A. Top. Organomet. Chem.
999, 3, 81. (f) Sen, A. In Applied Homogeneous Catalysis with Organo-
metallic Compounds; Herrmann, W. A., Cornils, B., Eds.; VCH: Weinheim,
2
(
2
2
contents were stirred at 70-90 °C for 18 h. The reactor was
subsequently cooled and the gases slowly released. The reaction mixture
was then directly analyzed by NMR spectroscopy.
1
1
996; Vol. 2, p 1081. (g) Crabtree, R. H. Chem. ReV. 1995, 95, 987. (h)
Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.; Peterson, T. H. Acc. Chem.
Res. 1995, 28, 154. (i) Labinger, J. A. Fuel Process. Technol. 1995, 42,
Results and Discussion
3
25. (j) Hall, T. J.; Hargreaves, J. S. J.; Huchings, G. J.; Joyner, R. W.;
Taylor, S. H. Fuel Process. Technol. 1995, 42, 151. (k) Olah, G. A.; Moln a´ r,
A. Hydrocarbon Chemistry; Wiley: New York, 1995. (l) Also see: Liu,
F.; Pak, E. B.; Singh, B.; Jensen, C. M.; Goldman, A. S. J. Am. Chem. Soc.
Table 1 summarizes our results on remote oxidation of C-H
bonds in aliphatic acids and alcohol. Since the reactions were
carried out in the presence of CF3COOH, a significant amount
of the alcohol formed was converted to the ester. Thus, the yield
of hydroxylated product was calculated as the sum of the alcohol
plus the corresponding ester. Table 1 shows that the Pd/CuCl2
system is effective as a remote functionalization agent for a
1
999, 121, 4086.
2) Review: Shilov, A. E. ActiVation of Saturated Hydrocarbons by
Transition Metal Complexes; Reidel: Dordrecht, 1984; Chapter V.
3) (a) Geletii, Yu. V.; Shilov, A. E. Kinet. Katal. 1983, 24, 486. (b)
Freund, M. S.; Labinger, J. A.; Lewis, N. S.; Bercaw, J. E. J. Mol. Catal.
994, 87, L11.
(
(
1
1
0.1021/ja993457l CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/18/2000

4030 J. Am. Chem. Soc., Vol. 122, No. 17, 2000
Shen et al.
Table 1. Remote Oxidation of Substrates by the Pd-C/CuCl
2
Systema
5
% Pd-C/CuCl
2
time
(h)
convnb
(%)
yieldb
(%)
substrate (mmol)
COOH (1.34)
COOH (1.09)
(mg/mg)
products
C
2
H
5
3/10
3/15
18
18
40
59
3-hydroxypropionic acid
4-hydroxybutyric acid
-hydroxybutyric acid
2-hydroxyethanesulfonic acid
3-hydroxypropanesulfonic acid
-hydroxypropanesulfonic acid
2-hydroxyethanephosphonic acid
1,3-propanediol
,2-propanediol
22
22
24
10
13
10
7
3 7
n-C H
3
C
2
H
5
SO
3
Na (0.67)
Na (0.61)
3/15
3/15
18
18
36
38
n-C
3
7
H SO
3
2
C
2
H
5
PO
3
H (0.90)
3/15
3/15
18
18
17
46
n-C
3
7
H OH (1.34)
15
10
1
a
O, 1.5 mL/0.5 mL, 75 °C. b Relative to substrate.
Reaction conditions: CO/N /O , 200 psi/800 psi/100 psi; CF COOH/H
2 2 3 2
Table 2. The Effect of Varying the Amount of CuCl
Oxidation of Propionic Acid
2
on the
Table 3. Oxidation of n-Propanol by Hydrogen Peroxidea
a
propane- propane-
CuCl
2
C
2
H
5
3
COOH HCOOH
5% Pd-C CuCl
2
1,3-diol
(mmol)
3
1,2-diol CH COOH HCOOH
(mg) (final mmol)
(mmol)
(mg)
(mg)
(mmol)
(mmol)
(mmol)
0
3
5
5
1.30
0.55
0.81
1.10
0
0.07
0.20
0.19
0.07
tr.
0
25
0
0
0
25
0
0
0.40
0
0
0.35
0.1
2.3
1.1
0.1
1.4
3.1
.5
0.23
0.22
0.16
0.71
0.44
0.17
1
2
a
Reaction conditions: 6.5 mmol of n-propanol, 7.5 mL of CF
2.5 mL of 50% H (added by syringe pump), 90 °C, 18 h.
3
COOH,
a
Reaction conditions: 1.34 mmol of C
COOH, 0.5 mL of H O, 800 psi N
, 75 °C, 18 h.
2
H
5
COOH, 3 mg of 5% Pd-
2 2
O
C, 1.5 mL of CF
psi O
3
2
2
, 200 psi CO, 100
Table 4. Comparison of CO/O
2
versus Cl
CH(X)CH
2
as Oxidants for
CH COOH HCOOH
2
a
2
ClCH CH
2 3
CH
broad spectrum of substrates, including a variety of acids,
alcohol, and aliphatic halide (cf., Table 4). In all reactions,
carbon monoxide and water are necessary since little or no
oxidation occurred in their absence. We believe the same
ClCH
2
CH
(mmol)
2
CH
2
X ClCH
2
3
3
oxidant
(mmol)
(mmol)
(mmol)
CO/O2 0.12 (X ) OH)
0.14 (X ) OH)
0.35 (X ) Cl)
0.06
0
0.37
0
Cl
2
0
mechanism operates here as was proposed for the oxidation of
a
Reaction conditions: 1.14 mmol of ClC
, 1.5 mL of CF COOH, 0.5 mL of H
, 200 psi CO or 90 psi Cl , 75 °C, 18 h.
3
H
7
, 3 mg of 5% Pd-C,
alkanes.1
a,e,4,5
This mechanism involves a metal-catalyzed water
1
0 mg of CuCl
100 psi O
2
3
2
O, 800 psi N
2
,
gas shift reaction and the subsequent formation of hydrogen
2
2
peroxide.6
The system is clearly catalytic with turnovers of 1666 and 4
relative to surface Pd atoms and CuCl2, respectively, for the
formation of 3-hydroxypropionic acid. Both Pd on carbon and
CuCl2 are required for the reaction. We had earlier demonstrated
that a critical function of Pd is to generate hydrogen peroxide.
In the absence of CuCl2, however, very little oxidation and no
remote hydroxylation was observed with propionic acid (Table
Given the observation that little substrate oxidation occurs
in the absence of added CuCl2, the possibility arises that the
principal role of metallic Pd is to generate hydrogen peroxide
in situ and that the species responsible for the oxidation of
substrate by hydrogen peroxide is CuCl2. To test this hypothesis,
the oxidation of n-propanol by hydrogen peroxide was attempted
in the presence of Pd on carbon or CuCl2. To minimize the
parallel metal-catalyzed decomposition of hydrogen peroxide,
the oxidant was added slowly through a syringe pump. Although
the reaction conditions were inevitably different from those in
Table 1, it is clear from Table 3 that remote hydroxylation of
n-propanol is observed only in the presence of CuCl2! Ad-
ditionally, the ratio of 1,3- and 1,2-diols formed is similar to
that observed with the bimetallic system (Table 1). Thus, at
least to a first approximation, in the bimetallic system metallic
Pd is responsible for the generation of hydrogen peroxide and
CuCl2 is responsible for the remote hydroxylation step.
2). Increasing the amount of Pd on carbon results in an increase
in the conversion of the substrate. For example, in CF3COOH/
D2O in 18 h, the conversion of 1.34 mmol of propionic acid
increased from 8% to 28% and the yield of 3-hydroxypropionic
acid increased from 0.10 to 0.26 mmol as the amount of Pd on
carbon was increased from 1 to 11 mg in the presence of 25
mg of CuCl2. An interesting issue is whether the active form
of Pd is the metal itself or the Pd2 ion present in the solution
phase. When the oxidation of propionic acid was repeated in
the presence of 2 drops of metallic Hg, no significant formation
of any of the oxidation products was observed. This suggests
+
In the bimetallic system, the CuCl2 also appears to suppress
the formation of products due to overoxidation and C-C
cleavage, and this is illustrated in Table 2. However, as shown
in Table 2, the use of excess CuCl2 also results in decreased
conversion of the substrate. Clearly, the best yield (conversion
(
but does not prove, since Hg could be acting as a reductant
2+
for Pd ) that metallic Pd is the active ingredient since Hg would
deactivate the surface atoms through amalgamation.
7
(
4) Lin, M.; Hogan, T. E.; Sen, A. J. Am. Chem. Soc. 1997, 119, 6048.
×
selectivity) of the remote hydroxylation product is obtained
(5) Pifer, A.; Hogan, T.; Snedeker, B.; Simpson, R.; Lin, M.; Shen, C.;
with a moderate amount of CuCl2. Both copper(II) and halide
ions are essential for the formation of the desired product. In
the presence of either Cu(O2CCF3)2 or NaCl (but not both),
and palladium on carbon, little oxidation and no remote
hydroxylation was observed with propionic acid. However, a
1:2 molar ratio of Cu(O2CCF3)2 and NaCl was found to be
similar to CuCl2. Finally, the effectiveness of halide ion in
combination with copper(II) was found to decrease in the order
Sen, A. J. Am. Chem. Soc., 1999, 121, 7485.
6) The formation of hydrogen peroxide through palladium-catalyzed
(
reaction between carbon monoxide, water, and dioxygen has been the subject
of several recent reports: (a) Bianchi, D.; Bortolo, R.; D’Aloisio, R.; Ricci,
M. Angew. Chem., Int. Ed. 1999, 38, 706. (b) Rossella, B.; D’Aloisio, R.;
Bianchi, D. European Patent Application, EP 788,998, 1997. (c) Bianchi,
D.; Rossella, B.; D’Aloisio, R.; Ricci, M.; Soattini, S. European Patent
Application, EP 808,796 A1, 1997.
(7) Whitesides, G. M.; Hackett, M.; Brainard, R. L.; Lavalleye, J.-P. P.
M.; Sowinski, A. F.; Izumi, A. N.; Moore, S. S.; Brown, D. W.; Staudt, E.
M. Organometallics 1985, 4, 1819.
-
-
-
Cl > Br > I .

Catalytic Hydroxylation of Remote Primary C-H Bonds
J. Am. Chem. Soc., Vol. 122, No. 17, 2000 4031
Table 5. Competition between Ethane and Either Cumene or p-Isopropylbenzoic Acida
substrate (initial mmol)
substrate (final mmol)
C
2
H
5
OH (mmol)
CH
3
COCH
3
(mmol)
CH
3
COPhX (mmol)
CH
3
COOH (mmol)
i-C
i-C
3
H
H
7
Ph (0.72)
PhCOOH (0.31)
i-C
i-C
3
3
H
H
7
Ph (0.47)
0.44
0.24
0.26
0.04
0.01 (X ) H)
0.06 (X ) COOH)
0.20
0.03
3
7
7
PhCOOH (0.26)
a
Reaction conditions: 3 mg of 5% Pd-C, 10 mg of CuCl
PhCOOH) C , 300 psi (i-C Ph) or 500 psi (i-C
mmol/2 mL) at 550 psi.
2
, 1.5 mL of CF
3
COOH, 0.5 mL of H
2
2 3 7
O, 200 psi CO, 100 psi O , 550 psi (i-C H Ph)
or 500 psi (i-C
H
3 7
2
H
6
3
H
7
3
H
7
PhCOOH) N , 75 °C, 18 h. Solubility of C H in water: 0.03 M (0.06
2
2
6
Interestingly, copper(I) chloride was not effective in sup-
pressing the formation of unwanted products. However, a 1:1
molar mixture of CuCl and NaCl gave similar product distribu-
tion as CuCl2. For example, in CF3COOH/D2O in 18 h, the
sum of acetic acid and formic acid formed from 1.34 mmol of
propionic acid increased from 0.73 to 0.91 mmol when CuCl
was increased from 2 to 20 mg in the presence of 3.5 mg of Pd
on carbon. On the other hand, 15 mg of CuCl and 6 mg of
NaCl in combination reduced that yield to 0.22 mmol.
observed in the unreacted starting material when the oxidation
of propionic acid-H6 was carried out in CF3COOH/D2O. When
1
CD3CH2COOH was employed, H NMR silent CD3COOH was
1
expected for cleavage of the C1-C2 bond and H NMR active
CH3COOH for cleavage of the C2-C3 bond. In fact, CH3COOH
was observed indicating the occurrence of C2-C3 bond
cleavage (this does not rule out C1-C2 bond cleavage occurring
1
3
in parallel). In another experiment CH3CH2 COOH was
1
employed and a H NMR spectrum was obtained at the end of
1
3
In the case of butyric acid, propanesulfonic acid, and
n-propanol (Table 1) and n-propyl chloride (Table 4) hydroxy-
lation occurred at both ω-methyl and ω-1-methylene carbons
the reaction. The presence of C uncoupled CH3COOH would
13
be indicative of C1-C2 bond cleavage while C coupled CH3-
COOH would be evidence for C2-C3 bond cleavage. However,
1
3
(
1
the relative preference on a per C-H bond basis was 0.6, 0.9,
a mixture of C coupled and uncoupled CH3COOH was
obtained due to cleavage occurring at both sites. Finally, the
formation of formic acid from sulfonic acids and phosphonic
acid also shows the C2-C3 bond can be cleaved under the
reaction conditions.
, and 0.6, respectively). The significant degree of attack at a
stronger, primary, C-H bond in the presence of secondary C-H
bonds is clearly inconsistent with a mechanism involving the
formation of radicals through H-atom abstraction. This is further
highlighted by a direct comparison of functionalization regi-
oselectivity between the present system and chlorination in the
presence of Pd/CuCl2. As shown in Table 4, (radical) chlorina-
tion under similar conditions occurred exclusiWely at the
secondary C-H bond. To further confirm the very unusual
preference of the present system for the catalytic hydroxylation
of primary C-H bonds, experiments involving competition
between ethane and either cumene or p-isopropylbenzoic acid
were run. As shown in Table 5, even though the solution
concentration of ethane was significantly lower than the
competing substrate, the vast majority of the oxidation product
Conclusion
We have discovered the first catalytic system that uses
dioxygen for the hydroxylation of remote primary C-H bonds
of functional organics. There appears to be an interesting
synergism between the two metals with metallic Pd activating
and converting dioxygen to hydrogen peroxide and CuCl2 using
the hydrogen peroxide to carry out the hydroxylation of the
substrate. The system exhibits several interesting features. First,
the reactions are very specific with respect to the degree of
oxidation: only hydroxylation is observed and further oxidation
to the corresponding aldehyde and carboxylic acid functionality
does not occur. Second, the C-C cleavage and overoxidation
can be minimized under suitable conditions. While the system
represents a significant advance over the currently known
(ethanol) was derived from ethane. This is despite the very weak
tertiary (and benzylic) C-H bond that is present in the
competing substrate. An identical trend was also found in
competitions involving ethane and either ethylbenzene or
p-ethylbenzene sulfonic acid.
1
procedures, further improvement in regioselectivity (e.g., ω
In each of the reactions examined, significant amounts of
acetic acid and formic acid were formed through C-C cleavage
steps. One possible mechanism for C-C cleavage would involve
the loss of CO2 from a carboxyl radical. An examination of the
site of C-C cleavage in propionic acid indicated that the
situation was more complex. Significant H/D exchange was not
versus ω-1) is clearly needed before the procedure can become
practical.
Acknowledgment. This research was supported by a grant
from the National Science Foundation.
JA993457L