Highly chemoselective heterogeneous Pd-catalyzed biaryl synthesis from haloarenes: Reaction in an oil-in-water microemulsion

Article abstract of DOI:10.1021/op020094s

Heterogeneous Pd/C-catalyzed reductive coupling of substituted haloarenes to the respective biaryls is effected with very high chemoselectivity in an oil-in-water microemulsion, using a reducing agent such as formate and a base, NaOH, in the presence of a catalytic amount of tetrabutylammonium bromide (TBAB) at 75°C. Almost 100% biphenyl selectivity is obtained with iodobenzene. High coupling yields are achieved with 4-chlorotoluene and 4-chlorobenzaldehyde as the substrate. The competitive reduction reaction becomes predominant when the water-in-oil microemulsion is used as the solvent medium.

Full text of DOI:10.1021/op020094s

Organic Process Research & Development 2003, 7, 641−643
Articles
Highly Chemoselective Heterogeneous Pd-Catalyzed Biaryl Synthesis from
Haloarenes: Reaction in an Oil-in-Water Microemulsion
,
†
‡
‡
§
,‡
Sudip Mukhopadhyay,* Anan Yaghmur, Mubeen Baidossi, Buddhadeb Kundu, and Yoel Sasson*
Department of Chemical Engineering, UniVersity of California, Berkeley, California 94720, U.S.A., Casali Institute of
Applied Chemistry, Hebrew UniVersity of Jerusalem, Jerusalem 91904, Israel, and Bharat Petroleum Corporation Ltd.,
Mumbai, India
3
Abstract:
numerous agrochemicals and pharmaceuticals. The selectiv-
4
Heterogeneous Pd/C-catalyzed reductive coupling of substituted
haloarenes to the respective biaryls is effected with very high
chemoselectivity in an oil-in-water microemulsion, using a
reducing agent such as formate and a base, NaOH, in the
presence of a catalytic amount of tetrabutylammonium bromide
ity is usually low due to the parallel reduction reaction.
However, the reductive coupling of haloarenes benefits from
simple reactor design, easy catalyst separation, and recycling.
5
The reaction has been carried out in different solvent media
5
a-d
5e
5f
5g
such as water,
DMF, methanol, and acetic acid in
the presence of formate salts, hydrogen gas, or zinc5c,h,i
as the reducing agent, a base, and catalytic amount of phase
transfer catalyst (PTC). Regardless, water is the best solvent
for this process scheme. The PTC has a remarkable effect
on the selectivity of these processes.
5
a
5b
(
TBAB) at 75 °C. Almost 100% biphenyl selectivity is obtained
with iodobenzene. High coupling yields are achieved with
-chlorotoluene and 4-chlorobenzaldehyde as the substrate. The
4
competitive reduction reaction becomes predominant when the
water-in-oil microemulsion is used as the solvent medium.
It has recently been shown that the coupling selectivity
can be improved by administering the PTC on a carbon
support, which is presumed to be modifying the micro-
6
Introduction
environment around the catalyst surface and, thus, increasing
the rate of reaction and biaryl selectivity. However, we
considered it useful to modulate the system using micro-
emulsions as the reaction media. This turned out to be an
exciting finding in terms of chemoselectivity.
Besides stoichiometric classic Ullman, Suzuki,1c-e and
1a,b
1f
Stille coupling reactions, the selective Pd-catalyzed reduc-
7
2
tive coupling reaction of haloarenes to biaryls has attracted
the attention of process chemists, as it is a precursor of
Here, we present the results and discuss how the micro-
structure in a microemulsion could turn the reaction chemo-
selectively towards the coupling side. One-phase isotropic
microstructured systems have been used before as micro-
reactors in chemical as well as enzymatic reactions.7
Noteworthy, Davydov and Beletskaya have reported the use
†
University of California. E-mail: sudip@uclink2.berkeley.edu.
Hebrew University of Jerusalem. E-mail: ysasson@huji.ac.il; mubeen@
‡
pob.huji.ac.il; anan.yaghmur@uni-graz.at.
§
Bharat Petroleum Corporation Ltd. E-mail: kundub@bharatpetroleum.com.
a-e
(
1) (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) Moreno-Ma n˜ as, M.; P e´ rez,
M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346. (f) Stille, J. K. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 508.
2) (a) Bamfield, P.; Quan, P. M. Synthesis 1978, 537. (c) Lei, A.; Zhang, X.
Tetrahedron Lett. 2002, 43, 2525. (b) Wong, M. S.; Zhang, X. L.
Tetrahedron Lett. 2001, 42, 4087. (c) Hassan, J.; Gozzi, C.; Lemaire, M.
C. R. Acad. Sci., Ser. IIc: Chim. 2000, 3, 517. (d) Hossain, K. M.; Shibata,
T.; Takagi, K. Synlett 2000, 8, 1137. (e) Hennings, D. D.; Iwama, T.; Rawal,
V. H. Org. Lett. 1999, 1, 1205. (f) Domenico, A.; Landini, D.; Penso, M.;
Petricci, S. Synlett 1999, 2, 199. (g) Luo, F.-T.; Jeevanandam, A.; Basu,
M. K. Tetrahedron Lett. 1998, 39, 7939. (h) Penalva, V.; Hassan, J.; Lavenot,
L.; Gozzi, C.; Lemaire, M. Tetrahedron Lett. 1998, 39, 2559. (i) Kang,
S.-K.; Namkoong, E.-Y.; Yamaguchi, T. Synth. Commun. 1997, 27, 641.
(3) For reviews on biaryl preparation methods and applications, see: (a) Littke,
A. F.; Fu, G. C. Angew Chem. Int. Ed. 2002, 41, 4176. (b) Hassan, J.;
Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102,
1359. (c) Stanforth, S. P. Tetrahedron 1998, 54, 263. (d) Bringmann, G.;
Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977. (e)
Sainsbury, M. Tetrahedron 1980, 36, 3327.
(
(4) (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.
(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.; Sasson, Y. AdV. Synth. Catal.
2001, 343, 274. (e) Hassan, J.; Penalva, V.; Lavenot, L.; Gozzi, C.; Lemaire,
M. Tetrahedron 1998, 54, 13793. (f) Mukhopadhyay, S.; Ratner, S.; Spernat,
A.; Qafisheh, N.; Sasson, Y. Org. Process. Res. DeV. 2002, 6, 297. (g)
Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Sasson, Y. J. Org. Chem.
2000, 65, 3107. (h) Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Baidossi,
M.; Ponde, D. E.; Sasson, Y. J. Chem. Soc., Perkin Trans. 2 2000, 1809.
(i) Mukhopadhyay, S.; Rothenberg, G.; Wiener, H.; Sasson, Y. New. J.
Chem. 2000, 24, 305.
(
j) Jutand, A.; Mosleh, A. J. Org. Chem. 1997, 62, 261. (k) Raynal, F.;
Barhdadi, R.; Perichon, J.; Savall, A.; Troupel, M. AdV. Synth. Catal. 2002,
44, 45. (l) Chen, C. Synlett. 2000, 1491. (m) Iyoda, M.; Otsuka, H.; Sato,
3
K.; Nisato, N.; Oda, M. Bull. Chem. Soc. Jpn. 1990, 63, 80. (n) Vanderesse,
R.; Brunet; J. J.; Caubere, P. J. Organomet. Chem. 1984, 264, 263. (o) For
a representative review on the homogeneous Pd-catalyzed coupling mech-
anism, see: (p) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314. (q)
Amatore, C.; Carre, E.; Jutand, A.; Tanaka, H.; Quinghua, R.; Torii, S.
Chem. Eur. J. 1996, 2, 957. (r) Amatore, C.; Jutand, A.; Khalil, F.; Nielsen,
M. F. J. Am. Chem. Soc. 1992, 114, 7076. (s) Reetz, M. T.; Westermann,
E. Angew. Chem., Int. Ed. 2000, 39, 165. (t) Kim, S.-W.; Kim, M.; Lee,
W. Y.; Hyeon, T. J. Am. Chem. Soc. 2002, 124, 7643.
(6) Mukhopadhyay, S.; Rothenberg, G.; Qafisheh, N.; Sasson, Y. Tetrahedron
Lett. 2001, 42, 6117.
1
0.1021/op020094s CCC: $25.00 © 2003 American Chemical Society
Vol. 7, No. 5, 2003 / Organic Process Research & Development
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641
Published on Web 08/07/2003

Table 1. Coupling reaction of haloaryls in microemulsiona
Scheme 1. Proposed mechanism for the coupling
conv. sel.% sel.%
entry microemulsion haloaryl t, h
%
Ar-Ar ArH
1
2
3
4
5
6
7
8
O/W
O/W
O/W
O/W
O/W
O/W
W/O
none
ArCl
ArBr
ArI
5.5 100
3.5 100
3.5 100
92
94
98
89
92
53
31
54
8
6
2
11
8
47
69
46
b
c
CT
CB
6
5
22
83
92
92
d
e
ArCl
ArCl
ArCl
selectivity to biphenyl was increased from 73 to 92%, with
an increase in 5% Pd/C amount from 0.75 to 1.0 g. A further
increase to 2.6 g was not advantageous for this reaction.
The temperature also has a governing role on both rate
of reaction and on the biphenyl selectivity. Generally, the
rate increased with an increase in temperature from 65 to
5.5 100
100
f
4
a
Reaction conditions: haloaryls, 0.013 mol; 5% Pd/C, 1 g; TBAB, 1 g.;
b
sodium formate, 1.5 g; NaOH, 1.5 g; temperature, 75 °C. CT is 4-chlorotoluene.
c
Toluene. d CB is 4-chlorobenzaldehyde. e No TBAB is used. Water is used
f
as the solvent.
7
5 °C as well as the selectivity from 83 to 92%. A further
of a basic water-butanol emulsion7f,g in the presence of
sodium dodecyl sulfate as an emulsifier and a homogeneous
Pd complex as the catalyst, for the low-yield (30-50%)
increase in temperature to 85 °C did not help in terms of
selectivity. Therefore, all subsequent reactions were per-
formed at 75 °C.
7f
homocoupling of aryl iodides and bromides. However, to
the best of our knowledge, this is the first example of a
chemoselective reductive coupling reaction of haloaryls in
a solid (Pd/C catalyst) and microemulsion7h two-phase
system, where the two competetive reactions, reduction and
coupling, become entirely one way, depending on the
microstructure (W/O or O/W).
Performing the reaction in an O/W microemulsion without
adding PTC (tetrabutylammonium bromide, TBAB), only
5
3% selectivity to the coupling product at 92% chloroben-
zene conversion was achieved in 22 h (Table 1, entry 6).
When the amount of PTC was increased from 0 to 1 g, the
selectivity to biphenyl increased from 53 to 92%.
Conversely, changing the microstructure from O/W to
W/O or using no microemulsion changes the path of the
reaction selectively to the reduction side (Table 1, entries 1,
Results and Discussion
In a typical reaction, 1 g of 5% Pd/C was mixed with the
oil-in water (O/W) microemulsion in a 100 mL glass reactor
7
-8). It is surprising that the W/O microemulsion is not
helpful for biphenyl selectivity and in fact leads to a higher
benzene selectivity.
(see Experimental Section). The mixture was heated to 75
°
C. The reaction mixture was stirred for 5-7 h, depending
However, it is realized that when NaOH, PTC, and Pd
catalyst are all together present in the O/W microemulsion
media, the rate and selectivity accomplished are the highest
under the reaction conditions. The solid Pd/C catalyst can
be recycled without losing any catalytic activity. Also, the
microemulsion once formed is stable for at least two months
on the reaction conditions at that temperature. Following the
reaction, the reactor was cooled to room temperature, and
the solution was analyzed by GC.
Exceptional yields for the coupling products were obtained
using various substrates, as shown in Table 1, entries 1-5.
For iodobenzene, the selectivity was almost 98%. With
bromobenzene as the substrate, 94% selectivity to biphenyl
was achieved. Excellent coupling selectivity (89%) was
achieved with 4-chlorotoluene, whilst 92% selectivity to the
coupling products was obtained with both 4-chlorobenz-
aldehyde and chlorobenzene as the substrate. This is the best
selectivity ever reported on these substrates in a liquid-phase
heterogeneous Pd-catalyzed reductive coupling reaction. In
all cases, except for a few percent reduction product, no other
byproducts were observed. Chlorobenzene (ArCl) was chosen
as the model compound for further process studies.
When the reaction was executed in an O/W micoemulsion
at room temperature.
Unlike homogeneous Pd-catalyzed coupling reactions,2q-s
the mechanism of the heterogeneous Pd-catalyzed reactions
is not yet understood. In fact, we previously proposed a
5a,8
mechanism for the reductive coupling of halobenzenes to
biphenyls. The basic reactions are depicted by eqs 1-5 in
Scheme 1. The basic difference between the reductive
coupling and the reduction is that the homocoupling requires
only electrons, whilst reduction requires hydrogen atoms. As
5a
has been proposed before, the selectivity to the coupling
0
products depends on the number of vacant active Pd sites,
which in turn reflects the balance between the reduction of
(see Experimental Section) with varied Pd amounts, the
2+
2+
-
2
Pd (eq 3), and the formation of Pd (H ) via eq 4. The
latter reaction is a function of the available dihydrogen
concentration on the active site. Obviously, with an increase
in the amount of Pd the number of Pd active sites is
increasing, and thus, an enhanced selectivity is attained.
The other experimental results obtained could be ex-
plained if we realize how the reactions shown in eqs 4 and
(
7) For representative review of the use of microemulsions in organic,
bioorganic, and pharmaceutical reactions, see: (a) Holmberg, K. AdV.
Colloid Interface Sci. 1994, 51, 137. (b) Paul, B. K.; Moulik, S. P. J. Dispers.
Sci. Technol. 1997, 18, 301. (c) Tenjarla, S. Crit. ReV. Ther. Drug. 1996,
0
1
6, 461. (d) Stamatis, H.; Xenakis, A.; Kolisis, F. N. Biotechnol. AdV. 1999,
7, 293. (e) Handbook of Microemulsion Science and Technology; Kumar,
1
P., Mittal, K. L., Eds.; Mercel Dekker: New York, 1999. (f) Davydov, D.
V.; Beletskaya, I. P. IzV. Akad. Nauk, Ser. Khim. 1995, 6, 1180. (g) For
Pd- and Cu-catalyzed diarylacetylenes synthesis in a water-organic
emulsion, see: Davydov, D. V.; Beletskaya, I. P. IzV. Akad. Nauk, Ser.
Khim. 1995, 5, 995. (h) For preparative method of temperature insensitive
microemulsion, see also: Garti, N.; Yaghmur, A.; Leser, M. E.; Clement,
V.; Watzke, H. J. J. Agric. Food Chem. 2001, 49, 2552.
(8) 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. Fluor. Chem.
1995, 73, 1.
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5
were suppressed to give a higher selectivity to biphenyl.
Preparation of Oil-in-Water Microemulsion(O/W). In
a round-bottom flask 1.5 g (0.013 mol) of chlorobenzene,
3.125 g of dodecane, and 3.125 g of ethyl alcohol were mixed
and stirred for 15 min to make the oil phase. In another
round-bottom flask 18.75 g of water, 1.5 g of sodium
formate, 1.5 g of NaOH, 1 g of TBAB, 18.75 g of propylene
glycol, and 6.25 g of surfactant (Brij 96V) were mixed, and
the contents were stirred for 30 min at room temperature.
The contents of the first round-bottom flask were then poured
into the second flask and stirred for another 30 min. Thus,
a clear and transparent O/W microemulsion was obtained,
which was then transferred to the reactor for the coupling
reaction.
This could apparently be due to lower hydride formation rate
on the Pd surface. The phenomenon of enhanced selectivity
obtained in an oil-in-water microemulsion could be due to
the following: (a) PTC microencapsulation6,9 of the Pd
surface prior to the contact of the oil phase with the solid
Pd surface in case of an oil-in-water microemulsion and (b)
or the lower rate of formate adsorption on the Pd surface
2
which is essentially the source of H .
The low selectivity obtained in water-in-oil microemulsion
is not understood; however, it is realized that under these
conditions the rate of reactions written in eqs 4 and 5 are
increased. Solubility or distribution of PTC in this system,
though not clear, might have influenced the observed
selectivity.
Preparation of Water-in-Oil Microemulsion(W/O). The
procedure for W/O microemulsion preparation was the same
as described above; however, the composition of the phases
was different. Thus, the water phase contained 8.75 g of
deionized water, 1.5 g of NaOH, 1.5 g of sodium formate,
Conclusions
In summary, biaryls are chemoselectively synthesized for
the first time in very high yield by the heterogeneous Pd-
catalyzed reductive homocoupling of aryl halides in the
presence of TBAB, formate salt, and NaOH at 75 °C in an
O/W microemulsion. In the case of a reverse microstructure,
the reduction reaction of haloaryls to arenes becomes
predominant. The chemoselectivity has thus shifted to the
reduction side. This work shows that many industrially
important substituted biaryls may be amenable to synthesis
in very high yields by simply modifying the solvent
assemblage.
1
g of TBAB (phase-transfer catalyst), 8.75 g of propylene
glycol, and 18.75 g of Brij 96V (the surfactant). The oil phase
contained 9.375 g of dodecane, 9.375 g of ethyl alcohol,
and 1.5 g of chlorobenzene.
General Procedure for Coupling of Haloarenes. In a
1
00 mL glass reactor equipped with a reflux condenser, the
oil-in-water microemulsion and 1.0 g of 5% Pd/C (3.6 mol
) were added, and the mixture was then heated to 75 °C.
%
The reaction mixture was stirred for 5-7 h, depending on
the reaction conditions at that temperature. Following the
reaction, the reactor was cooled to room temperature, and
the solution was analyzed by GC, and the products were
Experimental Section
1
identified by MS and H NMR.
Melting points were measured in glass capillaries using
1
Scale-Up Reaction. A 10 times larger batch size was tried
using the best conditions described above. A 100% conver-
sion of chlorbenzene with 87% selectivity to biphenyl was
obtained after 7 h of reaction. The isolated yield of biphenyl
was 81%.
an Electrothermal 9100 instrument. H NMR spectra were
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
Acknowledgment
We thank Mr. Larry Chan and Dr. Frank Ling of UC
Berkeley for their critical comments on this manuscript.
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 those of
previously isolated reference samples in our laboratory.
Received for review November 15, 2002.
OP020094S
(
9) Selva, M.; Tundo, P.; Perosa, A. J. Org. Chem. 1998, 63, 3266.
Vol. 7, No. 5, 2003 / Organic Process Research & Development
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