Heterogeneous Rh/C-catalyzed direct reductive coupling of haloaryls to biaryls in water

Article abstract of DOI:10.1021/op020080m

Reductive coupling of haloaryls and substituted haloaryls to the respective biaryls is effected in water with good selectivity, using a reducing agent such as formate salts and a base, NaOH, in the presence of a catalytic amount of PEG-400 and 5% Rh/C catalyst at 115 °C temperature. The catalyst can be recycled. The competing reduction reaction is minimized with proper alteration of the operating conditions. The role of temperature, catalyst loading, reducing agents, base, and PEG-400 are discussed. The reaction follows a zero-order kinetics.

Full text of DOI:10.1021/op020080m

Organic Process Research & Development 2003, 7, 44−46
Heterogeneous Rh/C-Catalyzed Direct Reductive Coupling of Haloaryls to
Biaryls in Water
Sudip Mukhopadhyay,*,† Ashutosh V. Joshi, Liat Peleg, and Yoel Sasson*
Casali Institute of Applied Chemistry, Hebrew UniVersity of Jerusalem, Jerusalem 91904, Israel
Abstract:
arenes restricts the usage of this process for a commercial-
production scale. While side reactions can be minimized,
the implementation of this system becomes uneconomical
as a mixture of expensive catalysts8 and toxic solvents9 is
required. The use of expensive starting materials such as
haloaryls has been avoided by using benzene as the starting
material in the oxidative coupling reaction;10 however, this
necessitates the use of high pressure and a mixture of
homogeneous catalysts including PdCl2, which may not be
reusable.
Reductive coupling of haloaryls and substituted haloaryls to
the respective biaryls is effected in water with good selectivity,
using a reducing agent such as formate salts and a base, NaOH,
in the presence of a catalytic amount of PEG-400 and 5% Rh/C
catalyst at 115 °C temperature. The catalyst can be recycled.
The competing reduction reaction is minimized with proper
alteration of the operating conditions. The role of temperature,
catalyst loading, reducing agents, base, and PEG-400 are
discussed. The reaction follows a zero-order kinetics.
Therefore, there is an incentive to search for different
heterogeneous catalysts for reductive coupling reactions. In
fact, homogeneous Rh salts have previously been used for
biaryl synthesis from arylmercuric complexes,11 and recently,
these have also been used for the borylation of aromatic and
benzylic C-H bonds.12 As part of our continuing search for
a catalytic process for synthesizing biaryls, we present in
this communication results on the Rh/C-catalyzed reductive
coupling of haloaryls to biaryls in water. These reactions
are the first direct Rh-catalyzed reductive coupling of
haloaryls to form biaryls and were carried out at 115 °C in
water with formate salts as the in situ catalyst regenerator.
Introduction
The syntheses and utilization of biaryl compounds is a
subject of considerable contemporary interest as they rep-
resent important building blocks for numerous agrochemicals,
pharmaceuticals, and a large number of natural products of
varied structure, biological activity, and biosynthetic origins.
Also, biaryls are the structural units of the chiral skeleton
of many of the asymmetric catalysts.1 In addition to the
stoichiometric classic general Ullmann,2 Suzuki,3 and Stille4
coupling reactions, Pd-catalyzed reductive coupling of halo-
aryls have gained the attention of many researchers as this
process benefits from simple reactor design, easy catalyst
separation, and recycling.5 We have recently demonstrated
success in Pd-catalyzed reductive coupling6a-d of haloaryls
in water, using a variety of reductants in the presence of a
catalytic amount of phase-transfer agent. Use of hydrogen
gas as the reducing agent in water enhances the economic
viability of these Pd-catalyzed processes;6b however, the
formation of side products (25-35%), derived from the
concurrent hydrodehalogenation reactions7 of haloaryls to
Results and Discussion
In a typical reaction13 (see Experimental Section), a 300-
mL high-pressure autoclave was charged with halobenzene,
sodium hydroxide, sodium formate, water, and catalytic
amounts of PEG-400 and 5% Rh/C catalyst. After 18-23 h
at 115 °C, depending on reaction conditions, biphenyl and
benzene (ArH) were the major products. Good to moderate
yields of the coupling products (Ar-Ar) were obtained using
various substrates.
* Authors for correspondence. E-mail: sudip@uclink2.berkeley.edu;
ysasson@huji.ac.il.
(7) (a) Wiener, H.; Blum, J.; Sasson, Y. J. Org. Chem. 1991, 56, 6145. (b)
Marques, C. A.; Selva, M.; Tundo, P. J. Org. Chem. 1994, 59, 38303.
(8) Mukhopadhyay, S.; Rothenberg, G.; Sasson, Y. AdV. Synth. Catal. 2001,
343, 274.
† Present address: Chemical Engineering Department, University of California,
Berkeley, California 94720, U.S.A.
(1) For reviews on biaryl preparation methods and applications, see: (a)
Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990,
29, 977. (b) Sainsbury, M. Tetrahedron 1980, 36. (c) For the use of BINAP
ligands, see the Nobel lecture: Asymmetric catalysis: Science and op-
portunities. Noyori, R. Angew Chem. Int. Ed. 2002, 41, 2008.
(2) (a) Ullmann, F. Ber. 1903, 36, 2389. (b) P. E. Fanta, Synthesis 1974, 9.
(3) (a) Miyamura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
(b) Suzuki, A. Pure Appl. Chem. 1991, 63, 419. (c) Moreno-Man˜as, M.;
Pe´rez, M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346.
(4) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(5) (a) Bamfield, P.; Quan, P. M. Synthesis 1978, 537. (b) Hassan, J.; Penalva,
V.; Lavenot. L.; Gozzi, C.; Lemaire, M. Tetrahedron 1998, 54, 13793.
(6) (a) Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Wiener, H.; Sasson, Y.
J. Chem. Soc., Perkin Trans. 2 1999, 2481. (b) Mukhopadhyay, S.;
Rothenberg, G.; Wiener, H.; Sasson, Y. Tetrahedron 1999, 55, 14763. (c)
Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Sasson, Y. Org. Lett. 2000,
2, 21I.. (d) Mukhopadhyay, S.; Rothenberg, G.; Wiener, H.; Sasson, Y.
New J. Chem. 2000, 24, 305.
(9) (a) Kageyama, H.; Furusawa, O.; Kimura, Y. Chem. Express 1991, 6, 233.
(b) Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Baidossi, M.; Ponde, D.
E.; Sasson, Y. J. Chem. Soc., Perkin Trans. 2 2000, 1809. (c) Mukho-
padhyay, S.; Rothenberg, G.; Gitis, D.; Sasson, Y. J. Org. Chem. 2000, 65,
3107.
(10) (a) Mukhopadhyay, S.; Rothenberg, G.; Lando, G.; Agbaria, K.; Kazanci,
M.; Sasson, Y. AdV. Synth. Catal. 2001, 343, 455. (b) Yoshimoto, H.; Itatani,
H. J. Catal. 1973, 31, 8. (c) Kashima, M.; Yoshimoto, H.; Itatani, H. J.
Catal. 1973, 29, 92. (d) Itatani, H.; Yoshimoto, H. J. Org. Chem. 1973, 38,
76.
(11) (a) Wang, Y.; Wu, Y.-J. Chem. Res. Chin. UniV. 2000, 16, 131. (b) Larock,
R. C.; Bernhardt, J. C. J. Org. Chem. 1977, 42, 1680.
(12) (a) Simada, S.; Batsanov, A. S.; Howard, J. A. K.; Marder, T. B. Angew
Chem., Int. Ed. 2001, 40, 2168. (b) Demay, S.; Volant, F.; Knochel, P.
Angew. Chem., Int. Ed. 2001, 40, 1235.
(13) For bipenyl characterization, see: (a) Tamura, Y.; Chun, M.-W.; Inoue,
K.; Minamikawa, J. Synthesis 1978, 822. (b) Kamewaza, N. J. Magn. Reson.
1973, 11, 88.
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10.1021/op020080m CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/03/2003

Table 1. Rh/C-catalyzed reductive coupling of haloarylsa
Table 2. Effect of different process parameters on the
coupling reactiona
%
%
%
selectivity,
coupling
selectivity,
reduction
%
%
entry
haloaryl
conversion
%
selectivity, selectivity,
entry
parameter
temp, 95 °C
conversion Ar-Ar
Ar-H
1
2
3
4
5
6
7
8
9
10
ArIb
ArBr
ArClc
CTd
89
73
61
59
59
69
23
32
27
10
56
49
36
21
14
28
6
12
8
6
44
51
64
68
81
67
94
88
92
94
1
21
43
73
92
40
73
74
74
47
73
74
0
64
73
74
49
73
76
33
41
49
52
37
49
48
50
11
49
50
0
48
49
37
34
49
31
67
59
51
39
63
51
52
50
89
51
50
0
52
51
63
66
51
69
2
3
4
5
6
7
8
9
105 °C
115 °C
125 °C
5% Rh/C, 0.75 mol %
1.1 mol %
1.5 mol %
2.0 mol %
NaOH, 0 mol
0.125 mol
0.2 mol
CTe
CTTf
CAg
CPh
CBAi
BNj
10
11
a Reaction conditions: starting material, 0.044 mol; sodium formate, 4.76 g
(0.07 mol); sodium hydroxide, 5 g (0.125 mol); 5% Rh/C, 1.0 g (1.1 mol %);
PEG-400, 1.5 g (8.5 mol %); temperature, 115 °C, solvent, water (total volume)
50 mL; reaction time, 20 h. b 18 h. c 23 h. d 4-Chlorotoluene. e 2-Chlorotoluene.
f 4-Chloro-1,1,1-trifluorotoluene. g 4-Chloroanisole. h 4-Chlorophenol. i 4-Chloro-
benzoic acid. j 2-Bromonaphthalene.
12b formate, 0 mol
13
14
15
16
17
18
0.05 mol
0.07 mol
0.09 mol
PEG-400, 0 mol %
8.5 mol %
11 mol %
Table 1, entries 1-10, shows the reactivities of different
starting materials to form the coupling products. Iodobenzene
and bromobenzene are highly reactive to the coupling
reaction. Chlorobenzene is moderately reactive. Chlorotolu-
enes are less reactive than bromobenzene. 4-Chloroanisole,
4-chlorophenol, and 4-chlorobenzoic acid react minimally.
Bromonaphthalene is least reactive. The reaction did not go
to completion for any of the halobenzenes used. For example,
with bromobenzene, 73% conversion was achieved after 20
h. For the determination of kinetics and suitable process
parameters, bromobenzene was used as a model substrate.
The temperature plays a significant role on both the rate
of reaction and the selectivity to biphenyl. In particular, an
increase in temperature of the reaction shifted the selectivity
towards coupling (Table 2, entries 1-4). This may be due
to Ea,coupling > Ea,reduction;6b,14 however, at 125 °C, we observed
the formation of diphenyl ether (9%) in addition to the
biphenyl and benzene. This side product may be the result
of halo-substitution by OH- at the higher temperature. Also,
the general trend indicates that at higher Rh/C catalyst
loadings, the faster is the reaction. At low catalyst loadings,
there was a direct correlation between catalyst loading and
selectivity. However when the catalyst loading exceeded 1.1
mol %, no further increase in selectivity was observed (Table
2, entries 5-8). Conversely, addition of sodium hydroxide7
shifted the product distribution towards the coupling product
from 11 to 49%. Moreover, the addition of 0.125 mol NaOH
optimized the selectivity as well as the rate of reaction (Table
2, entries 9-11). In addition, further increases in these two
parameters were observed when formate was added, the
selectivity shifted towards the reduction product when
formate concentration exceeded 0.07 mol (Table 2, entries
12-15). Here, all subsequent reactions were performed with
0.07 mol formate concentration to attain a maximum
selectivity of 49% to biphenyl.
a Reaction conditions: bromobenzene, 6.9 g (0.044 mol); sodium hydroxide,
5 g (0.125 mol); PEG-400, 1.5 g (8.5 mol %); temperature, 115 °C, solvent,
water (total volume) 50 mL; reaction time, 20 h; breaction time was 10 h.
PEG-400 loadings, the yield was reduced due to competition
from a reductive side reaction of bromobenzene to benzene.
Presumably this is due to the hydrogen-donating nature of
PEG-400. While, PEG-400 does not alter the chemical nature
of the intermediates, it may modify the physical micro-
environment around the catalyst surface.15
Different reducing agents were also examined to optimize
the process. With H2 gas, reduction was much faster, and a
95% conversion was achieved in 10 h; however, the
selectivity to biphenyl was unexpectedly lower (33%) than
that of formate salts (49%).
The solid Rh/C catalyst could be recycled simply by
filtering and then suspending the solid in methanol-water
with stirring under 5 atm hydrogen pressure at 60 °C for 5
h. The same catalyst retained its activity when tested up to
five reuses. For an easy separation of the catalyst, a biphasic
reaction media (1:1 mixture of water and toluene) could be
used for this reaction; however, the conversion and selectivity
remained the same when bromobenze was used as the
substarte.
We previously proposed a mechanism6a for the Pd-
catalyzed coupling of chloroaryls which consists of two
single-electron-transfer (SET) processes from the Pd0 to two
chlorobenzene molecules,16 followed by dissociation of the
[Ar-Cl]•- radical anions. Similarly, the oxidized form of
Rh could be either Rh1+ or Rh3+ unlike the Pd which is
converted to Pd2+. The hydrogen generated from formate in
the presence of Rh0 could reduce Rh1+ or Rh3+ back to Rh0,
and ultimately completing the catalytic cycle. While there
With an increase in PEG-400 concentration from 0 to 8.5
mol % of the substrate, the rate of reaction increased
marginally (Table 2, entries 16-18). However, at higher
(15) Mukhopadhyay, S.; Rothenberg, G.; Qafisheh, N.; Sasson, Y. Tetrahedron
Lett. 2001, 42, 6117.
(16) A similar mechanistic approach was suggested for the Pd-catalyzed coupling
of halopyridines: Munavalli, S.; Rossman, D. I.; Szafraniec, L. L.; Beaudry,
W. T.; Rohrbaugh, D. K.; Ferguson, C. P.; Gra¨tzel, M. J. Fluorine Chem.
1995, 73, 1.
(14) Levenspiel, O. Chemical Reaction Engineering, 2nd ed.; Wiley: New York,
1998; pp 238-239.
Vol. 7, No. 1, 2003 / Organic Process Research & Development
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45

is experimental evidence to support the ability of Rh0 to form
hydrides17 and reduce chlorobenzene to benzene the mech-
anism is not yet known.
Experimental Section
Melting points were measured in glass capillaries using
an Electrothermal 9100 instrument. H NMR spectra were
1
The reaction using bromobenzene was also used to study
the reaction kinetics. Reaction rates were found to be
independent of bromobenzene concentration up to 52%
conversion of bromobenzene. The rate equation can be
expressed by eq 1
measured on a Bruker AMX 300 instrument at 300.13 MHz.
GC and GC/MS analyses were performed using an HP-5890
gas chromatograph with a 50% diphenyl-50% dimethyl-
polysiloxane packed column (25 m/0.53 mm). Chemicals
were purchased from commercial firms (>99% pure) and
used without further purification. Products were either
-dCA/dt ) k
1
isolated and identified by comparison of their H NMR
spectra to standard samples, or identified by MS data and
comparison of their GC retention times with previously
isolated reference samples in our laboratory. Reactions were
performed in a 300-mL high-pressure Parr autoclave fitted
with a six-bladed impeller, a pressure transducer, and a
condenser.
or
or
CA0 - CA ) kt
XA ) kobs
t
where kobs ) k/CA0
(1)
General Procedure for Coupling of Haloaryls. Ex-
ample: Biphenyl from C6H5Br. Into a 300-mL autoclave
fitted with a six-bladed impeller and a cooling coil, were
charged 6.9 g (44 mmol) of C6H5Br, 4.8 g (70 mmol) of
HCOONa, 5.0 g (125 mmol) of NaOH, 1.5 g (8.5 mol %)
of PEG-400, 1.0 g of 5% w/w Rh/C (1.1 mol % Rh relative
to C6H5Br), and water (total reaction volume 50 mL). The
reactor was heated to 115 °C, and the reaction progress was
monitored by a GC. The mixture was stirred (900 rpm) at
115 °C for 20 h and then cooled to 45 °C. After removing
the catalyst by hot filtration at 45 °C, water was added to
the filtrate, and the organic compounds were extracted with
(4 × 40 mL) CH2Cl2. Solvent evaporation and recrystalli-
zation afforded 46 mol % (based on C6H5Br) of biphenyl,
mp 69 °C (from cold EtOH).
The k values are found to be 0.0345, 0.072, 0.1256, and
0.1494 mol/min at 95, 105, 115, and 125 °C, respectively.
Thus, the experimental Arrhenius energy of activation is
found to be Eact, total ) 60 kJ mol-1 (14.5 kcal mol-1, r2 )
0.9483 for four measurements at 95, 105, 115, and 125 °C).
However, a shift of reaction order from zero- to first-order
was observed at higher conversion level (>52%). This may
be the reason for incomplete conversion of the starting
materials under the reaction conditions. To verify this we
added 0.022 mol of a fresh batch of bromobenzene to the
same reaction mixture after obtaining 52% conversion on
the initial bromobenzene loading. It was observed that the
reaction had proceeded again up to 52% conversion level
with zero-order kinetics. This rules out the possibility of
catalyst poisoning.
Catalyst Recycle. The solid Rh/C catalyst was recycled
without loosing any catalytic activity by simply washing with
water, filtering the solid off, and stirring it in 70-30
methanol-water mixture at 60 °C for 5 h under 5 atm H2
pressure. After filtration and drying, the same Rh/C retained
almost the same catalytic activity as that in the reusability
experiments.
Conclusions
Biphenyl was synthesized by the reductive homocoupling
of aryl halides in the presence of a phase-transfer catalyst,
PEG-400, and a base, at 115 °C in water. Conversion into
biphenyl as high as 50% was observed. Furthermore, reaction
conditions were optimized to minimize the occurrence of
the competing hydrodehalogenation reactions. Our results
demonstrate the promise of designing a highly chemoselec-
tive Rh catalyst. For example, a systematic ligand design
could be used to optimize the coupling of specific substrates,
for example, 4-chlorobenzaldehyde or dichlorobenzene.
Acknowledgment
We thank Mr. Larry Chan and Mr. Frank Ling of UC
Berkeley for their constructive comments on this manuscript.
(17) (a) Balfour, W. J.; Cao, J.; Qian, C. X. W. J. Mol. Spectrosc. 2000, 201,
244. (b) Pruchnik, F. P.; Smolenski, P.; Galdecka, E.; Galdecki, Z. S. Inorg.
Chim. Acta 1999, 293, 110. (c) Yeston, J. S.; Bergman, R. G. Organo-
metallics 2000, 19, 2947. (d) Heinrich, H.; Bargon, J.; Giernoth, R.; Brown,
J. M. Chem. Commun. 2001, 14, 1296.
Received for review September 17, 2002.
OP020080M
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Vol. 7, No. 1, 2003 / Organic Process Research & Development