Heterogeneous Pd-catalyzed biphenyl synthesis under moderate conditions in a solid-liquid two-phase system

Article abstract of DOI:10.1021/op010047k

The coupling of substituted halobenzenes to form biphenyls is effected at moderate temperature (65°C) using a reducing agent such as a formate salt and a base (NaOH) in the presence of a catalytic amount of phase-transfer catalyst and 5% Pd/C catalyst. The reaction conditions can be optimized to give reasonable selectivity, and the competing reduction process is minimized. The roles of temperature, catalyst loading, reducing agents, the base, and the phase-transfer catalyst are discussed. The catalyst can be efficiently recycled. However, an entirely different course of reaction occurs when a mixture of halobenzenes is utilized.

Full text of DOI:10.1021/op010047k

Organic Process Research & Development 2002, 6, 297−300
Technical Notes
Heterogeneous Pd-Catalyzed Biphenyl Synthesis under Moderate Conditions in
a Solid-Liquid Two-Phase System
†
Sudip Mukhopadhyay, Stanislav Ratner, Aviram Spernat, Nida Qafisheh, and Yoel Sasson*
Casali Institute of Applied Chemistry, Hebrew UniVersity of Jerusalem, Jerusalem 91904, Israel
Abstract:
Scheme 1
The coupling of substituted halobenzenes to form biphenyls is
effected at moderate temperature (65 °C) using a reducing agent
such as a formate salt and a base (NaOH) in the presence of a
catalytic amount of phase-transfer catalyst and 5% Pd/C
catalyst. The reaction conditions can be optimized to give
reasonable selectivity, and the competing reduction process is
minimized. The roles of temperature, catalyst loading, reducing
agents, the base, and the phase-transfer catalyst are discussed.
The catalyst can be efficiently recycled. However, an entirely
different course of reaction occurs when a mixture of haloben-
zenes is utilized.
of these processes are the formation of 25-35% reduction
product derived from the parallel hydrodehalogenation
1
a
reaction of haloaryls to arenes and the use of high
temperature.
6
A tandem one-pot biphenyl production process, com-
5
bining the reductive coupling of chlorobenzene to biphenyl
7
and the oxidative coupling of benzene to biphenyl was
explored, to minimize the reduction side reactions. The effort
was partly successful in avoiding the use of any oxidant or
reductant; however, this process requires further investiga-
Introduction
Halobenzene can be reduced to benzene by using Pd
catalyst and a reducing agent1 such as hydrogen gas or
formate salts. The selectivity is generally very high. Under
similar conditions, the addition of a surface active agent and
base can shift the selectivity to the coupling product,
biphenyl, the building blocks for numerous agrochemicals
6
a,b
tions regarding catalyst deactivation and separation of the
close boiling products before becoming an industrial process.
Unfortunately, in most of the cases a very high temper-
ature, 100-120 °C, is needed to achieve 60-70% selectivity
to biphenyl. Thus, in this report, we present the results of
process parameter studies of the highly selective and rapid
reductive coupling of haloaryls to biphenyls, catalyzed by
Pd/C at only 55 to 60 °C in methanol, with any one of
2
3
and pharmaceuticals. To meet market needs, several syn-
thetic approaches towards biphenyl coupling have been
4a-f
4a,b
4c-e
developed, from the classic general Ullmann, Suzuki,
4f
and Stille reactions to custom-tailored catalytic transforma-
tions aimed at specific molecules. Amongst the variety of
developed methods the most attractive one is the Pd-
catalyzed reductive coupling of haloaryls as it benefits from
simple reactor design, easy catalyst separation, and recycling.
8
formate, hydrogen gas, or Zn as the in situ catalyst
regenerator.
Results and Discussion
Chlorobenzene was chosen as a model substrate for the
process parameter studies (Scheme 1); however, good yields
for the coupling products were obtained using various
substrates, as shown in Table 1. No other products were
observed.
5
a-d
We recently demonstrated the reductive coupling
of
5a
5b
haloaryls in water using formate salts, hydrogen gas, or
zinc5 as reducing agents. However, the major drawbacks
c-e
*
Corresponding author. E-mail: ysasson@huji.ac.il.
Present address: Dept. of Chem. Eng., University of California, Berkeley,
†
(5) (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, 211. (d) Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Baidossi, M.;
Ponde, D. E.; Sasson, Y. J. Chem. Soc., Perkin Trans. 2 2000, 1809. (e)
For coupling reaction with Zn, see also: Venkatraman, S.; Li, C. J. Org.
Lett. 1999, 1, 1133.
CA 94720, USA. E-mail: sudip@uclink2.berkeley.edu.
(1) (a) Weiner, 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.
(2) (a) Bamfield, P.; Quan, P. M. Synthesis 1978, 537. (b) Hassan, J.; Penalva,
V.; Lavenot, L.; Gozzi, C.; Lemaire, M. Tetrahedron 1998, 54, 13793.
(3) For reviews on biaryl preparation methods and applications, see: (a)
Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990,
2
9, 977. (b) Sainsbury, M. Tetrahedron 1980, 36, 3327. (c) Stinson, S. C.
(6) Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Sasson, Y. J. Org. Chem.
2000, 65, 3107.
Chem. Eng. News 1999, 69.
(
4) (a) Ullmann, F. Ber. 1903, 36, 2389. (b) Fanta, P. E. Synthesis 1974, 9. (c)
Miyamura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513. (d)
Suzuki, A. Pure Appl. Chem. 1991, 63, 419. (e) Liu, S.-Y.; Choi, M. J.;
Fu, G. C. Chem. Commun. 2001, 2408. (f) Stille, J. K. Angew. Chem., Int.
Ed. Engl. 1986, 25, 508.
(7) (a) VanHelden, R.; Verberg, G, Recl. TraV. Chim. Pays-Bas., 1965, 84,
1263. (b) Mukhopadhyay, S.; Rothenberg, G.; Lando, G.; Agbaria, K.;
Kazanci, M.; Sasson, Y. AdV. Synth. Catal. 2001, 343, 455.
(8) Mukhopadhyay, S.; Rothenberg, G.; Wiener, H.; Sasson, Y. New. J. Chem.
2000, 24, 305.
1
0.1021/op010047k CCC: $22.00 © 2002 American Chemical Society
Vol. 6, No. 3, 2002 / Organic Process Research & Development
•
297
Published on Web 03/16/2002

Table 1. Pd-catalyzed reductive coupling reaction with
Table 3. Pd-catalyst reusabilitya
various starting materialsa
t,
%
conv.
% selec.,
biphenyl
% selec.,
benzene
t,
%
% selec., %selec.,
entry
catalyst
min
substrate
min conv. coupling reduction
1
2
3
4
5
fresh
35
35
35
35
35
100
100
100
100
96
71
70
72
71
71
29
30
28
29
29
chlorobenzene
bromobenzene
35 100
20 100
100 100
120 100
71
73
64
32
70
29
27
36
68
30
1st reuse
2nd reuse
3rd reuse
4th reuse
4
2
4
-chlorotoluene
-chlorotoluene
-chloro-1,1,1,-trifluorotoluene 55 100
a
Reaction conditions: chlorobenzene, 22 mmol; NaOH, 62 mmol; HCOONa,
a
26.4 mmol; 5% Pd/C catalyst, 0.53 mol % of substrate; TBAB, 4.9 mol % of
substrate; temperature, 65 °C; H O, 3.5 g; agitation speed, 900 rpm; solvent,
2
Reaction conditions: substrate, 22 mmol; NaOH, 62.5 mmol; HCOONa,
2
%
6.4 mmol; catalyst, Pd/C, 0.53 mol % of substrate on Pd basis; TBAB, 4.9 mol
MeOH (total volume) 25 mL.
2
of the substrate; H O, 3.5 g; temperature, 65 °C; agitation speed, 900 rpm;
solvent, MeOH (total volume) 25 mL.
Table 2. Effect of different process parameters on the rate
the coupling product (Table 2, entries 14-18). The use of
TBAB does not alter the chemical nature of the intermediates;
rather it modifies the physical microenvironment in the
and product selectivitya
t,
%
% selec., % selec.,
entry
parameter
temp., 45 °C
55 °C
65 °C
min conv. biphenyl benzene
1
1
proximity of the catalyst surface. The amount of water has
a strong impact on the rate of reaction. It has been described
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
35
35
35 100
25 100
43
89
48
62
71
72
49
71
75
77
39
53
59
71
69
27
53
71
69
59
-
52
38
29
28
51
29
25
23
59
47
41
29
31
73
47
29
31
41
-
42
29
29
30
54
29
51
43
77
1
a
elsewhere that water molecules should also be adsorbed
on the Pd surface to generate hydrogen from formate salt.
Thus, in all subsequent runs, 3.5 g of water was added to
obtain a faster rate and maximum selectivity to biphenyl
(Table 2, entries 19-21).
75 °C
Pd/C, 0.266 mol %
0.53 mol %
0.79 mol %
1.0 mol %
NaOH, 0 mmol
40 mmol
50 mmol
62 mmol
75 mmol
TBAB, 0 g
3.5 mol %
4.9 mol %
7.0 mol %
10 mol %
35
69
35 100
30 100
20 100
35
35
35
35 100
35 100
35
35
35 100
35 100
35 100
35
35
35 100
35 100
30 100
90 100
In terms of rate and selectivity almost identical results
were obtained when the reaction was performed in either
methanol or ethanol (Table 2, entries 22-24). Unlikely, the
reduction of chloroaryls to arenes was scarcely commenced
53
71
83
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
1
a
when methanol was used as the solvent. Also, while
carrying out the reactions in water; low biphenyl selectivity
was achieved.
61
91
To investigate the effects of utilizing different reducing
agents, Zn and H
salts (Table 2, entries 25-27). When formate salt was
replaced by H gas, the reduction reaction became dominant;
2
gas were also examined in place of formate
H
2
O, 0 g
7
79
2.0 g
3.5 g
solvent, MeOH
EtOH
2
H O
68
71
71
70
46
71
49
67
23
2
however, similar rate and selectivity were accomplished
when Zn replaced it.
Chlorobenzene was selectively reduced to benzene (77%)
in the absence of TBAB and NaOH. The rest was biphenyl
Reductant, HCOONa 35 100
(5 atm) 20 100
35 43
105 100
H
2
(
Table 2, entry 28). This is mainly due to formate salt, which
was dissociated on the Pd surface in the presence of water
to form H and bicarbonates. Thus, the basicity provided by
Zn
HCOONab
a
2
Reaction conditions: chlorobenzene, 22 mmol; HCOONa, 26.4 mmol;
catalyst, 5% Pd/C; speed of agitation, 900 rpm; solvent (total volume), 25 mL.
Reaction was performed in the absence of TBAB and NaOH.
the in situ generated bicarbonates in the system that was
sufficient to yield 23% coupling product. Particularly, when
b
2
chlorobenzene was reduced with molecular H under similar
The reaction temperature affects both rate and product
selectivity. With an increase in temperature the reaction
shifted favorably to the coupling product (Table 2, entries
conditions, 98% benzene selectivity was achieved.
An entirely different course of reaction occurred when a
mixture of chlorobenzene and bromobenzene was employed
for the coupling reaction. Initially, chlorobenzene did not
start to react until 86% of the bromobenzene had reacted.
This could be due to the differences in the relative rates of
adsorption of the two haloaryls on the Pd surface when they
were introduced in a mixture.
Also, the solid Pd/C catalyst was recycled without losing
its catalytic activity (Table 3) simply by filtration and
washing with methanol at room temperature (see also
Experimental Section).
5b,9
1-4). This was probably because of Ea,coupling > Ea,reduction.
Generally, at higher Pd-catalyst loading the rate of the
reaction increased linearly. It was observed initially that an
increase in catalyst loading increased the selectivity; however,
the selectivity remained unchanged with a further increase
in catalyst loading above 0.53 mol % (Table 2, entries 5-8).
5a,10
Also, addition of sodium hydroxide
9
(Table 2, entries
-13) or a phase-transfer catalyst, namely, tetrabytylam-
monium bromide (TBAB), shifted product selectivity towards
2,5a
(
9) Levenspiel, O. Chemical Reaction Engineering, 2nd ed.; Wiley: New York,
972; pp 238-239.
10) Zhang, H.; Chan, K. S. Tetrahedron Lett. 1996, 37, 1043.
1
(11) Mukhopadhyay, S.; Rothenberg, G.; Qafisheh, N.; Sasson, Y. Tetrahedron
Lett. 2001, 42, 6117.
(
298
•
Vol. 6, No. 3, 2002 / Organic Process Research & Development

Scheme 2
Conclusions
Biphenyls can be readily synthesized by the Pd-catalyzed
reductive homocoupling of aryl halides in the presence of
TBAB, NaOH, and H O at 65 °C in methanol. Altering the
2
process variables minimizes the occurrence of the competing
hydrodehalogenation reaction. The highest selectivity ob-
tained to biphenyl was 71%.
Experimental Section
The experimental results can be elucidated in terms of
Materials and Instrumentation. Melting points were
measured in glass capillaries using an Electrothermal 9100
instrument. H NMR spectra were measured on a Bruker
the mechanism represented by eqs 1-5 as displayed in
Scheme 2. Earlier, we suggested a mechanism5a for the
1
coupling of chloroaryls, consisting of two single-electron-
transfer (SET) processes from the Pd to two chlorobenzene
AMX 300 instrument at 300.13 MHz. GC and GC/MS
analyses were performed using an HP-5890 gas chromato-
graph with a 50% diphenyl-50% dimethylpolysiloxane
packed column (25 m × 0.53 mm). Chemicals were
purchased from commercial firms (>98% pure) and used
without further purification. Products were either isolated
1
2
•-
molecules, followed by dissociation of [Ar-Cl] radical
anions. Consequently, the coupling of haloaryls can be shown
as depicted in eq 1. The hydrogen thus generated from
1
a,13
formate salt (eq 2) in the presence of palladium
can
reduce PdCl to Pd and complete the catalytic cycle (eq 3).
2
1
and identified by comparison of their H NMR spectra to
Notwithstanding, hydrogen can also adsorb on the reduced
palladium species to form palladium hydride (eq 4), which
in turn may reduce chlorobenzene to benzene (eq 5). The
standard samples or identified by MS data and comparison
of their GC retention times with previously isolated
5a
II
-
-
reference samples. Reactions were performed in a 100-mL
glass reactor fitted with a six-bladed impeller and a con-
denser.
sequential Pd (H )(Cl ) species may then liberate HCl.
Clearly, the main difference between the reductive coupling
(eq 1) and the reduction (eq 5) is that the coupling requires
General Procedure for Coupling of Haloaryls. Ex-
electrons, while mainly H atoms initiate the reduction. To
2
ample: Biphenyl from C
charged with 2.5 g (22 mmol) of C
of HCOONa, 2.5 g (62.5 mmol) of NaOH, 0.35 g (4.9 mol
6 5
H Cl. A 100 mL glass reactor was
achieve better understanding of the mechanism, a reaction
was executed with a stoichiometric amount of Pd/C and
chlorobenzene in the presence of a base and TBAB (eq 1).
No reducing agent was introduced, yet a quantitative yield
of biphenyl was accomplished relative to the Pd amount. A
fresh batch of chlorobenzene addition could not produce
further reaction; however, addition of a stoichiometric
6 5
H Cl, 1.8 g (26.4 mmol)
%
%
) of TBAB, 0.5 g of 5% w/w Pd/C (50% water, 0.53 mol
Pd relative to C Cl), 3.5 g of water, and MeOH, 25
6 5
H
mL (total reaction volume). The reactor was then heated to
5 °C. Reaction progress was monitored by GC. The mixture
6
was stirred (900 rpm) at 65 °C for 35 min, cooled, and diluted
with water. The organic compounds were extracted with 40
2
amount of formate salt (recycling of PdCl to Pd, eqs 2 and
3) could carry the reaction further. These observations are
mL of CH
afforded 2.3 g (68 mol % based on C
2
Cl
2
. Solvent evaporation and recrystallization
Cl) of biphenyl,
69-71 °C). Found: C,
in good agreement with our mechanistic postulation.
Moreover, with an increase in Pd/C loading the number
of active Pd sites is increasing, which further results in an
increase in the rate of coupling reaction (according to eq 1).
The presence of water is crucial for the hydrogen generation
from formate salt (eq 2) which in turn reacts with Pd to form
6
H
5
1
4a,b
mp 69 °C (from cold EtOH) (lit.
3.26; H, 6.74. C12 10 requires C, 93.46; H, 6.54. H (CDCl
Me Si) 7.39 (2H, tt, aromatic 4,4′-H), 7.46 (4H, qt, aromatic
,3′, 5,5′-H), 7.59 (4H, dq, aromatic 2,2′, 6,6′-H) good
1
9
H
3
,
4
3
1
4c
agreement was found with literature values.
2
PdH (eq 4). Of course, when the reaction was performed in
The substituted biphenyls 4,4′-dimethylbiphenyl and 4,4′-
ditrifluoromethylbiphenyl were similarly prepared. 4,4′-
Dimethylbiphenyl: isolated yield 55% based on 4-chloro-
water as a solvent, the selectivity to coupling decreased due
to the higher rate of hydrodehalogenation reaction (eq 5).
The purpose of adding base in this reaction is to drag forward
the reaction in eq 3 (reversible reaction) by neutralizing the
HCl formed thereupon. It can also react with the HCl
generated by the dissociation of Pd (H )(Cl ) species. On
the contrary, the role of PTC is not fully understood.
However, it is realized that in the presence of a PTC, the
rate of reactions written in eqs 4 and 5 decreases by certain
1
4d
toluene, mp 119 °C (from CH
Found: C, 91.60; H, 7.63. C14
4,4′-Ditrifluoromethylbiphenyl: isolated yield 65% based on
-chloro-1,1,1-trifluorotoluene, mp 80 °C (from EtOH/H O)
lit. 93-94.5 °C). Found: C, 57.82; H, 2.90; F, 39.28.
2
Cl
2
) (lit. 120.7-121.5 °C).
H14 requires C, 92.30; H, 7.69.
II
-
-
4
(
2
1
4e
1
14 8 6 3
C H F requires C, 57.93; H, 2.75; F, 39.31. H (CDCl ,
Me Si) 7.69 (8H, m, ArH) (lit. 7.67).
4
1
4f
factors. This may be bacause of the PTC encapsulation
around the Pd(0) species as postulated before.11
Scale-Up Batch. A batch size of 15 times the usual
reaction has been carried out for the scale-up reaction, and
(
12) 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.; Gr a¨ tzel, M. J. Fluorine Chem.
(14) (a) Tamura, Y.; Chun, M. W..; Inoue, K.; Minamikawa, J. Synthesis 1978,
822. (b) Mukhopadhyay, S.; Rothenberg, G.; Sasson, Y. AdV. Synth. Catal.
2001, 343, 274. (c) Kamewaza, N. J. Magn. Reson. 1973, 11, 88. (d)
McKillop, A.; Elsom, L. F.; Taylor, E. C. Tetrahedron 1970, 26, 4041. (e)
Dictionary of Organic Compounds, 6th ed.; Chapman and Hall: London,
1996; Vol. 1, p 899. (f) Trost, B. M.; Arndt, H. C. J. Am. Chem. Soc.
1973, 95, 5288.
1
995, 73, 1.
(13) (a) Zaidman, B.; Weiner, H.; Sasson, Y. Int. J. Hydrogen Energy 1986,
1
1
1, 341. (b) Wiener, H.; Zaidman B.; Sasson, Y. Int. J. Hydrogen Energy
989, 14, 365; For the reverse reaction, see: (c) Wiener, H.; Blum, J.;
Feilchenfeld, Sasson, Y.; Zalmanov, N. J. Catal. 1988, 184.
Vol. 6, No. 3, 2002 / Organic Process Research & Development
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in 45 min, 100% conversion and 70% selectivity was
obtained. The isolated yield of biphenyl was 66 mol % on
chlorobenzene basis.
Pd Catalyst Recycling. The reaction was performed as
above, after which the liquids were filtered, and the solid
catalyst was washed with methanol (3 × 20 mL) and then
dried under vacuum. The same batch, when utilized in the
subsequent reactions, retained >99% of its initial activity.
Acknowledgment
We thank Mr. Mubeen Baidoosi for performing the GC/
MS experiments and Mr. Michael Rhodes and Mr. Konstan-
tin Pokrovski for their comments on the manuscript.
Received for review June 4, 2001.
OP010047K
300
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