Pd/C as a highly active catalyst for Heck, Suzuki and Sonogashira reactions

Article abstract of DOI:10.1055/s-2002-32589

A specially optimized air-stable Pd on activated carbon catalyst is demonstrated to be a highly active (TON up to 36,000), selective and convenient heterogeneous catalyst for CC couplings of aryl halides in Heck, Suzuki, and Sonogashira reactions. The Pd/C catalyst developed allows extremely low Pd concentrations (down to 0.0025 mol% for Heck coupling, 0.005 mol% for Suzuki coupling) and high conversions of aryl bromides within a few hours. Easy and complete Pd separation and recovery is possible.

Full text of DOI:10.1055/s-2002-32589

1118
LETTER
Pd/C as a Highly Active Catalyst for Heck, Suzuki and Sonogashira Reactions
Pd/C
as
H
ighly A
o
ctive Cataly
l
st and G. Heidenreich,a Klaus Köhler,*a Jürgen G. E. Krauter,b Jörg Pietschb
a
Anorganisch-chemisches Institut, Technische Universität München, Lichtenbergstraße 4, 85747 Garching bei München, Germany
Fax +49(89)28913473; E-mail: klaus.koehler@ch.tum.de
b
Degussa AG, Catalysts & Initiators, Rodenbacher Chaussee 4, 63403 Hanau, Germany
Fax +49(6181)594691; E-mail: juergen.krauter@degussa.com
Received 8 April 2002
Another CC coupling reaction of considerable interest is
the Sonogashira coupling of alkynes.4 However, a major
drawback of all these reactions is that the homogeneous
catalysts require the use of ligands, which are often not
Abstract: A specially optimized air-stable Pd on activated carbon
catalyst is demonstrated to be a highly active (TON up to 36,000),
selective and convenient heterogeneous catalyst for CC couplings
of aryl halides in Heck, Suzuki, and Sonogashira reactions. The Pd/
C catalyst developed allows extremely low Pd concentrations easy to handle (e.g. air sensitive basic phosphines). In ad-
(down to 0.0025 mol% for Heck coupling, 0.005 mol% for Suzuki
dition the removal of the catalyst from reaction mixture
coupling) and high conversions of aryl bromides within a few hours.
and product is difficult in most cases. This includes the
Easy and complete Pd separation and recovery is possible.
ligand as well as the expensive precious metal.
Key words: aryl halides, catalysis, coupling, heterogeneous, palla-
For Heck reactions, the problem of catalyst separation and
dium
Pd recovery has been tried to overcome by immobilization
of Pd complexes and by use of Pd particles on solid sup-
ports.5 However, these systems do not reach the excellent
Heck and Suzuki reactions of aryl halides, belonging to
activities that are observed with homogeneous catalysts
the most important CC coupling reactions in organic syn-
and convert the interesting and broadly available aryl bro-
thesis,1 are generally catalyzed by homogeneous palladi-
mides in some special cases of the Heck reactions,
um catalysts. In the last years, the development of new
only.5d,6
highly active Pd complexes even allowed the activation
and conversion of aryl chlorides,2,3 which are far less re-
active than the corresponding bromides and iodides.
Many publications focus on the reaction mechanism of the
heterogeneously catalyzed Heck reaction and the results
Br
Pd/C, NaOAc
+
+
NMP, 140 °C
R
R
- HBr
R
1
2
E- und Z-isomers
respectively 3 and 4
5
R = H, OCH3, COCH3, Cl
Scheme 1 Heck coupling of bromoarenes with styrene
Pd/C, base
R
X
R
+
B(OH)2
NMP/water, 120 °C
- XB(OH)2
1
6
7
R = H, OCH3, CN, COCH3, OH
X = Br, Cl
Scheme 2 Suzuki coupling of arylhalides with phenylboronic acid
Synlett 2002, No. 7, 01 07 2002. Article Identifier:
1437-2096,E;2002,0,07,1118,1122,ftx,en;G08902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Pd/C as a Highly Active Catalyst for Heck, Suzuki and Sonogashira Reactions
1119
support that Pd leached from the solid catalyst into solu- and a high water content (~55%). It was originally opti-
tion represents the catalytically active species. The result- mized for the model Heck reaction of bromobenzene and
ing problem of the quantitative separation of palladium styrene and the results were reported very recently.6h This
from the reaction mixture of heterogeneous systems could catalyst as well as the reaction conditions have been fur-
be solved, however, by rather simple procedures (control ther optimized and revealed the highest activities for Heck
of Pd leaching).7
coupling of aryl bromides with styrene reported so far for
heterogeneous catalysts (Table 1).10,11
Promising results about heterogeneously catalyzed Suzu-
ki cross coupling reactions have been reported recently. Turnover numbers (TON) of up to 36,000 and turnover
Here, the attractive aryl chlorides could be coupled with frequencies (TOF) of up to 18,000 h–1 (for bromobenzene)
various phenylboronic acids.8a However, long reaction are achieved using extremely low Pd concentrations down
times up to 48 hours8a and large amounts of the palladium to 0.0025 mol% (Table 1, entry 3). Complete conversion
catalyst were used (3–15 mol%8a,d and 47 mol%8c respec- within a few hours for activated, non-activated as well as
tively). For industrial applications of CC coupling deactivated bromoarenes makes the catalyst an appealing
reactions9 the amount of the expensive palladium used system to the organic chemist. The surprisingly lower ac-
plays a dominant role for the process economy.3e
tivity for the activated arenes compared to non-activated
ones is probably due to the temperature window and reac-
tion parameters, where the catalyst develops its optimal
action: its extraordinarily high activity seems to be con-
nected with dissolution-re-precipitation processes and
dissolved Pd species present at this temperature and con-
ditions (NMP or DMAc as solvent, NaOAc as base), re-
spectively.6h However, activated bromoarenes like p-
bromoacetophenone can also be converted completely
(96% conversion, >90% yield) with the same catalyst
within 6 hours at 80 °C and NMP as solvent. Low catalyt-
ic activity in Heck coupling was found with pre-reduced
Pd/C catalysts (Table 1, line 4 and 5). This corresponds
well with Pd/C catalysts reported for Heck reactions in
the literature before.6b The dramatic decrease in activity of
Also for applications in the organic-chemical laboratory,
reaction time, ease of catalyst handling, price and avail-
ability of starting materials and even the catalyst price has
to be regarded. Based upon this, the main focus of the
present investigation was the development and optimiza-
tion of a simple, easy to handle catalyst system for Heck,
Suzuki and Sonogashira coupling reactions (Scheme 1,
Scheme 2 and Scheme 3), where very small amounts of
palladium and short reaction times (a few hours) are a nec-
essary prerequisite.
The best Pd/C catalyst (E 105 CA/W 5% Pd, product of
Degussa AG) used for all present experiments described
in this publication is characterized by a high palladium
dispersion (36%), a low reduction degree [mainly Pd(II)]
Pd/C, base
I
+
H
solvent, 100 °C
- HI
8
9
10
Scheme 3 Sonogashira coupling of iodobenzene with phenylacetylene
Table 1 Heterogeneous Heck Coupling of Different Bromoarenes with Styrene (Scheme 1)10
Entry
R
Catalyst[mol%] t [h]
Conversion [%] Yield 3 [%]
Yield 4 [%]
Yield 5 [%]
TONa
19200
18000
36000
58
TOFb [h–1]
4800
18000
18000
3
1
COCH3
H
0.005
0.005
0.0025
1.0
4
1
96
90
90
83
83
52
10
92
80
63
0
1
1
0
0
1
1
0
5
6
6
5
1
7
9
7
2
3
H
2
90
4c
5d
6
H
20
20
6
58
H
1.0
12
12
<1
Cl
0.05
0.05
0.01
100
92
2000
1840
7200
333
7
OCH3
OCH3
2
920
8
2
72
3600
a TON = moles of aryl halide converted/moles of Pd.
b TOF = moles of aryl halide converted/moles of Pd per hour.
c Reduced under H2 atmosphere at 300 °C for 1 h.
d Treated under N2 atmosphere at 500 °C for 1 h.
Synlett 2002, No. 7, 1118–1122 ISSN 0936-5214 © Thieme Stuttgart · New York

1120
R. G. Heidenreich et al.
LETTER
Table 2 Heterogeneous Suzuki Coupling of Arylhalides with Phenylboronic Acid (Scheme 2)10
Entry
X
R
Catalyst
[mol%]
Ratio of
Base
t [h]
Conversion Yield 7 [%] TONb
[%]
TOFc [h–1]
solventsa
1
2
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
CN
0.01
0.005
0.01
0.005
0.005
0.2
10:4
10:4
10:4
10:4
10:4
10:4
10:4
10:3
10:3
10:3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaOH
1.5
2
100
100
100
100
83
100
100
100
100
83
10000
20000
10000
20000
16600
375
6666
10000
5000
10000
16600
93
H
3
OH
2
4
OCH3
OCH3
OCH3
OCH3
COCH3
COCH3
COCH3
2
5
1
6d
7e
8
4
75
75
0.2
4
43
43
215
53
0.25
0.10
0.05
4
100
90
98
400
100
9
NaOH
2
88
900
450
10
NaOH
2
80
78
1600
800
a 10 mL NMP and 3 or 4 mL water (distilled twice).
b TON = moles of aryl halide converted/moles of Pd.
c TOF = moles of aryl halide converted/moles of Pd per hour.
d Reduced under H2 atmosphere at 300 °C for 1 h.
e Treated under N2 atmosphere at 500 °C for 1 h.
reduced catalysts can be seen in TON/TOF values, which The activity and – in contrast to the Heck reaction – also
are several orders of magnitude lower than TON/TOF of selectivity strongly depends on a variety of reaction pa-
non-reduced ones.
rameters. As reported in the literature,8a the addition of
water to the organic solvent increases the activity. The op-
timum solvent/water ratio found for the present system
differs from literature values. The optimized reaction con-
ditions are: Na2CO3 in 10:4 NMP:water mixtures for bro-
moarenes and NaOH in 10:3 NMP:water mixtures for
chloroarenes. A crucial influence is found for the base:
Na2CO3 gives the best results for couplings of aryl bro-
mides, whereas NaOH promotes the deborylation and de-
halogenation resulting in a decreased selectivity. In
contrast, NaOH is found to be the best choice for activated
aryl chlorides under the conditions applied (120 °C,
NMP/water). Again it is surprising that the optimum reac-
tion temperature (120 °C) found is rather high compared
to typical homogeneously catalyzed Suzuki reactions. We
interpret this in the same context as mentioned above with
the Heck reaction. Further investigations concerning the
Suzuki coupling are in progress and will be published in
detail soon.
The non-reduced catalyst (E 105 CA/W 5% Pd) shows
similarly high activity and selectivity in the Suzuki reac-
tion of phenylboronic acid with a variety of aryl halides,
particularly bromides (Table 2).10,12 All bromoarenes
(Scheme 2) investigated can be coupled quantitatively
with phenylboronic acid within 2 hours using extremely
low Pd concentrations of only 0.005–0.01 mol% (Table 2,
entries 1–4).
To the best of our knowledge, these are the highest activ-
ities (TON up to 20,000) reported so far for a heteroge-
neously catalyzed Suzuki coupling of bromoarenes. Also
deactivated bromoarenes like p-bromoanisole can be
converted up to 83% without dehalogenation within 60
minutes (Table 2, entry 5). TOF up to 16,600 h–1 can be
achieved. 100% selectivity to the Suzuki coupling prod-
uct (cross coupling) is found nearly without exception.
p-Chloroacetophenone can be converted quantitatively
within 4 hours and Pd concentrations of 0.25 mol%. Con-
versions up to 90% can be achieved after 2 hours using
0.05–0.10 mol% Pd. As shown for Heck reactions
(Table 1, line 4 and 5) small catalytic activity was found
for Suzuki coupling as well (Table 2, line 6 and 7). TON
and TOF values decreased by at least two orders of mag-
nitude compared to the values of the non-reduced cata-
lysts (Table 2, line 4 and 5). Only catalysts fulfilling these
properties discussed above are found to be highly active
for CC coupling reactions (high Pd dispersion: e.g. >50%,
low reduction degree = mainly Pd(II), i.e. no pre-reduc-
tion before use, in particular not at higher temperatures;
and high water content: 50%).
There are only few applications of a heterogeneous cata-
lyst for Sonogashira reactions (Scheme 3).13 Although
only iodides could be coupled effectively, high yields up
to 80% could be achieved e.g. in the coupling of iodoben-
zene with phenylacetylene10,14 without addition of cop-
per(I) (Table 3, entries 2–4). Conversions up to 74% were
found after 30 minutes using Pd concentrations of only
0.125 mol% (Table 3, entry 6; TON = 592, TOF = 1184).
The addition of copper(I), which is proposed as co-cata-
lyst in the literature4,13 was tested as well. However, no in-
crease neither in activity nor in selectivity was observed.
Synlett 2002, No. 7, 1118–1122 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Pd/C as a Highly Active Catalyst for Heck, Suzuki and Sonogashira Reactions
1121
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Table 3 Heterogeneous Sonogashira Coupling of Iodobenzene with
Phenylacetylene (Scheme 3)
Entry Catalyst Solvent
[mol%]
Base
t [h] Conver- Yield
sion [%] 10 [%]
1
2
3
4
5
6
0.50
Piperidine Piperidine
Pyrrolidine Pyrrolidine
6
6
6
6
1
77
88
61
80
77
80
54
53
0.50
0.125
0.125
0.125
0.125
DMAc
NMP
Pyrrolidine
Pyrrolidine
Pyrrolidine
100
96
DMAc
DMAc
79
Pyrrolidine 0.5
74
Larger amounts of copper even decreased activity and se-
lectivity (data not shown).
The Pd/C catalyst investigated combines extremely high
activity, short reaction times and high selectivity for a va-
riety of reactions and substrates with the advantages of
easy and complete Pd separation and recovery. In particu-
lar, the reaction system is easy to handle (stability against
air and moisture, no inert atmosphere and no ligands are
necessary) and commercially available. For practical ap-
plications it must be taken into account that the choice of
solvent, base and reaction temperature can be of crucial
importance and that the activity is remarkably reduced (by
more than 50%), when the catalyst is re-used. This is due
to dissolution-re-precipitation of palladium during the re-
action (changes in Pd distribution as well as dispersion).
The Pd leaching during and at the end of the reaction was
investigated thoroughly for Heck reactions and could be
minimized down to 0.05 ppm by careful choice of the re-
action conditions and by addition of NaHCO2 at the end of
the reaction.7 Investigations of the palladium leaching in
Suzuki couplings are in progress.
(7) Heidenreich, R. G.; Krauter, J. G. E.; Pietsch, J.; Köhler, K.
J. Mol. Catal. A: Chem. 2002, 182-183, 499.
Acknowledgement
(8) (a) LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R. Jr.
Org. Lett. 2001, 3, 1555. (b) Mubofu, E. B.; Clark, J. H.;
Macquarrie, D. J. Green Chem. 2001, 3, 23. (c) Kabalka, G.
W.; Namboodiri, V.; Wang, L. Chem. Commun. 2001, 775.
(d) Cammidge, A. N.; Baines, N. J.; Bellingham, R. K.
Chem. Commun. 2001, 2588. (e) Macquarrie, D. J.; Gotov,
B.; Toma, S. Platinum Metal Rev. 2001, 45, 102.
(9) (a) Ennis, D. S.; McManus, J.; Wood-Kaczmar, W.;
Richardson, J.; Smith, G. E.; Carstairs, A. Org. Process Res.
Dev. 1999, 3, 248. (b) Raggon, J. W.; Snyder, W. M. Org.
Process Res. Dev. 2002, 6, 67.
(10) Due to dissolution/re-precipitation processes (Pd leaching)
during the reaction no exact number of catalytically active
species or sites can be given. For this reason ‘turnover
numbers’ (TON) and ‘turnover frequencies’ (TOF) per Pd
atom are given as a measure of the catalytic activity that refer
to the total amount of Pd applied (and not to active species
or sites): TON = conversions of bromo-/chloroarene per
total amount of palladium in the catalyst (TOF: per hour).
(11) General Procedure for Heck Reaction: Reactions were
performed in sealed pressure tubes after 5 min purging with
argon using non-dried solvents (Only a small decrease in
Financial and technical support from Degussa AG is gratefully
acknowledged. RGH thanks S. Bauer and S. Mitschke for excellent
laboratory support.
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R. G. Heidenreich et al.
LETTER
arylhalides and yield of the product 7 using diethylene
activity but a large increase in Pd leaching was detected
without argon atmosphere). Yields and product
glycol-n-butyl ether as internal standard.
identification were determined by GLC and GC-MS,
separation of catalyst by filtration. Typical reaction
conditions: 10 mmol bromobenzene, 15 mmol styrene, 12
mmol NaOAc, 0.0025–0.05 mol% Pd (E 105 CA/W 5% Pd,
product of Degussa AG), 10 mL NMP (N-methyl-2-
pyrrolidone) or DMAc (N,N-dimethylacetamide) for
thermally treated(reduced) catalysts; T = 140 °C.
(13) (a) Kabalka, G. W.; Wang, L.; Namboodiri, V.; Pagni, R. M.
Tetrahedron Lett. 2000, 41, 5151. (b) Bates, R. W.;
Boonsombat, J. J. Chem. Soc., Perkin Trans. 1 2001, 654.
(c) Buchmeister, M. R.; Schareina, T.; Kempe, R.; Wurst, K.
J. Organomet. Chem. 2001, 634, 39. (d) Quignard, F.;
Larbot, S.; Goutodier, S.; Choplin, A. J. Chem. Soc., Dalton
Trans. 2002, 1147.
Conversion of the bromoarenes and yields of the products 3–
5 using diethylene glycol-n-butyl ether as internal standard.
(12) General Procedure for Suzuki Coupling: Reactions were
performed in sealed pressure tubes after 5 min purging with
argon using non-dried solvents. Yields and product
(14) General Procedure for Sonogashira Coupling: Reactions
were performed in sealed pressure tubes after 5 min purging
with argon using non-dried solvents. Yields and product
identification were determined by GLC and GC-MS,
separation of catalyst by filtration. Typical reaction
conditions: 5 mmol iodobenzene, 6 mmol phenylacetylene,
6 mmol base, 0.125–0.50 mol% Pd (E 105 CA/W 5% Pd,
product of Degussa AG), 10 mL solvent; T = 100 °C.
Conversion of iodobenzene and yield of the product 10 using
diethylene glycol-n-butyl ether as internal standard.
identification were determined by GLC and GC-MS,
separation of catalyst by filtration. Typical reaction
conditions: 5 mmol bromobenzene, 6 mmol phenylboronic
acid, 6 mmol base, 0.005–0.25 mol% Pd (E 105 CA/W 5%
Pd, product of Degussa AG), T = 120 °C. Conversion of
Synlett 2002, No. 7, 1118–1122 ISSN 0936-5214 © Thieme Stuttgart · New York