On the mechanism of palladium-catalyzed coupling of haloaryls to biaryls in water with zinc

Article abstract of DOI:10.1021/ol9912938

(matrix presented) Kinetics and process parameters of coupling and hydro-dehalogenation reactions of chloroaryls are studied in the presence of zinc, water, and catalytic Pd/C. Good yields are obtained for the coupling of chlorobenzene, 4-chlorotoluene, and 4-chloro-1,1,1-trifluorotoluene. It is shown that water is actually one of the reagents, reacting with zinc in the presence of palladium to give zinc oxide and hydrogen gas, which then regenerates the Pd⁰ catalyst for the coupling reaction.

Full text of DOI:10.1021/ol9912938

ORGANIC
LETTERS
2000
Vol. 2, No. 2
211-214
On the Mechanism of
Palladium-Catalyzed Coupling of
Haloaryls to Biaryls in Water with Zinc
Sudip Mukhopadhyay, Gadi Rothenberg,† Diana Gitis, and Yoel Sasson*
Casali Institute of Applied Chemistry, Hebrew UniVersity of Jerusalem, 91904, Israel
ysasson@Vms.huji.ac.il
Received November 30, 1999
ABSTRACT
Kinetics and process parameters of coupling and hydro-dehalogenation reactions of chloroaryls are studied in the presence of zinc, water,
and catalytic Pd/C. Good yields are obtained for the coupling of chlorobenzene, 4-chlorotoluene, and 4-chloro-1,1,1-trifluorotoluene. It is
shown that water is actually one of the reagents, reacting with zinc in the presence of palladium to give zinc oxide and hydrogen gas, which
then regenerates the Pd0 catalyst for the coupling reaction.
Synthesis of biaryl compounds is of importance for numerous
agrochemical and pharmaceutical applications.1 The classic
Ullmann2 and Suzuki3 methodologies are well-known in this
context. Owing to the versatile chemistry of palladium
compounds in carbon-carbon bond formation reactions,4
several palladium-catalyzed processes have been proposed
as eco-friendly replacements for the stoichiometric Ullmann
protocol.5 Essentially based on the Pd2+ T Pd0 redox cycle,
these processes require in situ regeneration of the active
palladium catalyst, which can be achieved using various
reagents; e.g., 2-propanol, hydrogen gas,6 or aqueous alkali
formate salts.7
Recently, we showed the feasibility of some of the above
transformations and discussed possible reaction mechanisms
for aryl-aryl coupling under heterogeneous and homoge-
neous catalysis conditions.6,7b A letter by Venkatraman et
al.,8 describing coupling of iodobenzenes using zinc and
palladium in an acetone-water system, prompted us to
publish our interesting findings in this field. In that paper,
coupling reactions were performed under an air atmosphere,
and, while in most cases good selectivity was achieved, the
proffered results left much to be explained.
† Current address: York Green Chemistry Group, Clean Technology
Centre, Department of Chemistry, University of York, Heslington, York
YO10 5DD, U.K. E-mail: gr8@york.ac.uk.
(1) For representative 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, 3327.
See also: (c) Stinson, S. C. Chem. Eng. News 1999, 69.
(2) (a) Ullmann, F. Ber. 1903, 36, 2389. (b) Fanta, P. E. 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) For an excellent recent monograph on palladium catalysis see: Tsuji,
J. Palladium Reagents and Catalysts; Wiley: New York, 1993.
(5) (a) Hennings, D. D.; Iwama T.; Rawal, V. H. Org. Lett. 1999, 1,
1205. (b) Hassan, J.; Penalva, V.; Lavenot, L.; Gozzi, C.; Lemaire, M.
Tetrahedron 1998, 54, 13793.
(8) Venkatraman, S.; Li, C.-J. Org. Lett. 1999, 1, 1133.
(9) Representative Experimental Procedure for Coupling of Halo-
aryls. Instrumentation, experimental apparatus, and product isolation and
identification methods have been described in detail previously (refs 6 and
7a). Example: 2a from 1a. In a 300 mL autoclave were charged 5.0 g (44
mmol) of 1a, 3.3 g (50 mmol) of Zn, 5.0 g (125 mmol) of NaOH, 1.5 g
(8.4 mol %) of PEG-400, 1.0 g of 5% w/w Pd/C (1.0 mol % Pd relative to
1a), and H2O (total reaction volume 50 mL). The autoclave was heated to
100 °C. Reaction progress was monitored by GC. The mixture was stirred
(950 rpm, see ref 11) at 100 °C for 2 h, cooled, and extracted with 40 mL
of CH2Cl2. Solvent evaporation and recrystallizing afforded 2.35 g of 2a
(68 mol % based on 1a), mp 69 °C (from cold EtOH) [lit. 69-71 °C
(Tamura, Y.; Chun, M.-W.; Inoue, K.; Minamikawa, J. Synthesis 1978, 822).
Found: C, 93.26; H, 6.74. C10H12 requires C, 93.46; H, 6.54. δH (CDCl3;
Me4Si) 7.39 (2H, tt, aromatic 4,4′-H), 7.46 (4H, qt, aromatic 3,3′,5,5′-H),
7.59 (4H, dq, aromatic 2,2′,6,6′-H). Good agreement was found with
literature values (Kamewaza, N. J. Magn. Reson. 1973, 11, 88). Please refer
to the Supporting Information for details of the synthesis of compounds 2b
and 2d.
(6) Mukhopadhyay, S.; Rothenberg, G.; Wiener H.; Sasson, Y. Tetra-
hedron 1999, 55, 14763.
(7) (a) Bamfield, P.; Quan, P. M. Synthesis 1978, 537. (b) Mukho-
padhyay, S.; Rothenberg, G.; Gitis, D.; Wiener H.; Sasson, Y. J. Chem.
Soc., Perkin Trans. 2 1999, 2481.
10.1021/ol9912938 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/28/1999

Here, we present the results of a kinetic investigation and
process optimization of the palladium-catalyzed coupling and
reduction reactions of haloaryls. The balanced stoichiometric
reaction equation presented here provides insight to the nature
of the reaction system. In particular, the role of water as the
hydrogen source and catalyst regenerator becomes apparent.
In a typical reaction (Scheme 1), chlorobenzene 1a, zinc,
A pseudo-first-order rate law, -d[1a]/dt ) kobs[1a], was
observed for fixed zinc and catalyst loading, with typical
kobs values ≈ 3.7-3.8 × 10-2 min-1.11
Performing the reaction at higher temperatures increased
selectivity to biphenyl, from 44% at 60 °C up to 74% at
100 °C, suggesting that Ea,coupling > Ea,reduction. The Arrhenius
energy of activation was found to be Ea,coupling ) 30.0 kJ
mol-1 (7.2 kcal mol-1, r2 ) 0.997 for four measurements at
60, 80, 100, and 120 °C) and Ea,reduction ) ∼8 kJ mol-1 (2
kcal mol-1). These findings characterize the reduction as a
mass-transfer controlled process,12 in contrast with the
chemically controlled coupling under these conditions.
The influence of various reaction parameters on substrate
conversion and product selectivity is shown in Table 2.
Increasing Zn loading (Table 2, entries 1-5), Pd/C catalyst
loading (entries 6-11), or the addition of sodium hydroxide
(entries 12-17) shifted product selectivity toward the
coupling product.
Scheme 1
The advantages resulting from the incorporation of surface-
active agents into this multiphase system has been discussed
elsewhere.13 Earlier studies in similar systems have shown
that choosing the appropriate surfactant is mostly a matter
of trial and error.7a Although ammonium salts such as CTAB
and PEG-400 displayed similar effects, PEG-400 was chosen
due to its low cost, higher solubility in the solvent system,
and ease of separation. The presence of PEG-400 increases
both conversion and selectivity (Table 2, entries 18-21).
We assume that PEG does not alter the chemical nature of
the intermediates, but rather, that it modifies the physical
microenvironment of the catalyst, facilitating the approach
of the organic substrate.
Performing the reaction using less water (Table 2, entries
25-28) increased the selectivity toward the coupling product,
although conversion was lower. This tallies with the proposed
reaction mechanism (vide infra). Working with less than 1.5
molar equiv of water to substrate proved ineffectual, due to
technical mixing and solubilization problems associated with
the solid zinc reagent.
water, sodium hydroxide, and catalytic amounts of poly-
(ethylene glycol) (PEG-400) and Pd/C were charged to an
autoclave. After 1-2 h of stirring at 60-120 °C, depending
on reaction conditions, biphenyl was found to be the major
product, together with some hydro-dehalogenation (reduc-
tion) product.9 Good to moderate yields for the coupling
products were obtained using various chloroaryls, as shown
in Table 1. No other products were observed.
Although water does not appear as a reagent in the
stoichiometry of the final reaction, it still plays a paramount
role. In fact, without water there would be no reaction.
Indeed, the results of Venkatraman et al. also show thiss
whenever they excluded water from their reaction using
MeCN or pure acetone as solventssthey observed only
7-8% conversion. This conversion was due to the 8 mol %
of palladium they put in, which was functioning as a
stoichiometric reagent rather than as a catalyst, because it
could not be regenerated in the absence of water.
Table 1. Coupling of Various Chloroarylsa
product (% yield)b
substrate
% convn
1a
1b
1c
1d
100
91
84
1b (68)c
2b (51)c
3b (27)c
4b (69)c
1c (30)
2c (38)
3c (45)
4c (27)
100
a Reaction conditions: substrate, 45 mmol; Zn, 50 mmol; 5% Pd/C, 1.0
mol % of substrate; PEG-400, 1.5 g (8.4 mol % of substrate); NaOH, 125
mmol; 100 °C; 2 h stirring; 50 mL total reaction volume (water). b Yield
based on GC area, corrected by the presence of an internal standard.
c Isolated yield.
(11) (a) To ensure that reaction rates were not mass transfer controlled,
agitation speed was varied from 200 to 950 rpm. Above 800 rpm, no increase
in conversion was detected. Thus, all measurements pertain to 950 rpm
stirring. (b) For reactions at different chlorobenzene concentrations, xylene
was added to make up for the volume of the organic phase.
(12) (a) Cf. Marques, C. A.; Selva, M.; Tundo, P. J. Org. Chem. 1994,
59, 3830, where hydro-dehalogenation was found to be of zero order in the
substrate. (b) Blackmond, D. G.; Rosner, T.; Pfaltz, A. Org. Proc. Res.
DeV. 1999, 3, 275.
(13) (a) Rothenberg, G.; Barak, G.; Sasson, Y. Tetrahedron 1999, 55,
6301. (b) A¨ıt-Mohand, S.; He´nin, F.; Muzart, J. Tetrahedron Lett. 1995,
36, 2473. (c) Bouquillon, S.; du Moulinet d’Hardemare, A.; Averbuch-
Pouchot, M.; He´nin, F.; J. Muzart, J. Polyhedron 1999, 18, 3511-3516.
Chlorobenzene 1a was chosen as a model substrate for
kinetic and process parameter studies.10 Reaction rates were
found to be a function of substrate concentration, Zn loading,
and Pd loading, i.e., -d[1a]/dt ) kobs[1a]1.05[Zn]0.66[Pd]0.86
.
(10) Please refer to the Supporting Information for details of the kinetic
studies.
212
Org. Lett., Vol. 2, No. 2, 2000

hydrogen gas as the catalyst regenerator (in the absence of
zinc, using either water or a dry organic solvent).6 Excess
dihydrogen can adsorb on the reduced catalyst surface to
form palladium hydride (eq 3), which in turn can reduce the
halobenzene substrate (eq 4). Another possible route for the
reduction reaction is direct hydrogen-transfer from water,
in the presence of zinc, to the organic substrate.14
Table 2. Coupling of 1a under Various Conditionsa
entry
parameter
% convn
% selection 2a b
Zn/mmol
1
2
3
4
5
10.0
20.0
45.3
50.0
60.0
21
46
68
74
73
69
57
90
97
100
Pd/C/mol %
6
7
none
1.0
0
18
32
44
90
91
0
69
70
72
73
75
8
2.0
9
3.0
10
11
4.0
6.0
[NaOH]/mmol
In contrast with the reduction reaction, coupling of aryl
halides occurs, in all probability, via two consecutive single
electron transfer (SET) processes, from two Pd0 to two aryl
halide molecules. This mechanism has been discussed in
detail elsewhere.7b
12
13
14
15
16
17
0.0
40.0
53
90
34
46
57
68
73
74
60.0
94
80.0
98
100.0
120.0
100
100
The addition of a base, e.g., NaOH, improves the selectiv-
ity toward the coupling product (Table 2, entries 12-17).
The significance of this lies in the coupling reaction’s
sensitivity to the effective concentration of available Pd0 sites.
While coordination of a single substrate molecule to one
catalytic site may suffice for reduction, coordination of two
substrate molecules to two available sites would probably
be required for the coupling reaction.15 The presence of
NaOH will result in a higher effective concentration of vacant
Pd0 sites, thus shifting the selectivity toward coupling. The
fact that higher catalyst loading increases the coupling:
reduction ratio also supports this argument.
The reason that Venkatraman et al. needed to use such a
large excess (300 mol %) of zinc in their reaction system is
also easily explained: the reaction between zinc and water
gives ZnO, a solid. However, because zinc itself is insoluble
in the reaction medium, a ZnO coating forms on the zinc
particles, causing deactiVation of the zinc particles. Evidence
supporting this was obtained from experiments using dif-
ferent sizes of zinc particles (Table 2, entries 22-24),
showing a strong correlation between conversion and zinc
particle size. Zinc oxide may also coat some of the palladium
catalyst surface, which may explain the slight drop in
catalytic activity upon recycling (78% conversion was
obtained with a recycled batch of palladium).16
Zinc-mediated coupling of aryl halides in the presence of
water and catalytic Pd/C is therefore the sum of two
reactions. One is the coupling of two aryl halide molecules
mediated by Pd0, which is oxidized in the course of the
reaction to Pd2+. The other is the reduction of water by zinc
to obtain hydrogen gas and zinc oxide, a reaction which is
itself catalyzed by Pd0/C. The hydrogen generated in situ
reacts with Pd2+ produced from the coupling reaction, to give
back the pristine Pd0 catalyst. Thus, water is not merely a
convenient solvent medium but is actually one of the reagents
in this remarkable Ullmann-type coupling reaction.
PEG-400/mol %
18
19
20
21
2.8
5.6
92
96
58
74
73
61
8.4
100
100
11.3
Zn particle/µm
22
23
24
40-60
60-100
∼1000
1a -water /mol-mol
solvent H2O
100
100
37
73
70
53
25
26
27
28
100
51
73
75
88
89
1:5.0
1:2.5
32
1:1.5
17
a
Standard reaction conditions: 1a, 45 mmol; Zn, 50 mmol; 5% Pd/C,
1.0 mol % of 1a; PEG-400, 1.5 g (8.4 mol % of 1a); NaOH, 100 mmol;
100 °C; 1 h stirring (2 h for entries 18-28); 50 mL total reaction volume
(water, except entries 25-27). b Selectivity based on GC area, corrected
by the presence of an internal standard.
The key reaction occurs between water and zinc in the
presence of a palladium catalyst (eq 1). In a closed vessel,
>60% conversion of water to hydrogen gas (based upon mol
% consumption of zinc) can be achieved through this
reaction. The dihydrogen reacts with the “used catalyst” and
regenerates it (eq 2). In fact, as we have shown elsewhere,
Pd-catalyzed coupling can be performed efficiently using
(14) For a detailed discussion of this reaction see: Mukhopadhyay, S.;
Rothenberg, G.; Wiener, H.; Sasson, Y. J. Chem. Soc., Perkin Trans. 2,
1999, in press. See also ref 6.
(15) No chlorobiphenyls were observed, so we may disregard the
possibility of phenyl radicals attacking substrate molecules in this system.
Thus, it is probable that the aryl radicals couple on the catalyst surface,
followed by desorption of biphenyl.
(16) Catalyst Recycling. The reaction mixture was cooled to 25 °C and
filtered. The solid residue was washed with H2O (3 × 40 mL) and MeOH
(3 × 10 mL). The catalyst retained >78% of its activity on a consecutive
run with fresh zinc.
Org. Lett., Vol. 2, No. 2, 2000
213

Acknowledgment. We thank Dr. Dave J. Adams (York
Green Chemistry Group, The University of York) for
valuable comments, and Dr. Jacques Muzart (University of
Reims) for discussions and preprints. G.R. thanks the Royal
Society and the Israeli Academy of Sciences and Humanities
for an exchange fellowship to visit the York Green Chemistry
Group.
Supporting Information Available: Synthetic procedures
and characterization data for compounds 2b and 2d; detailed
experimental procedures describing kinetic studies and
results; three additional references.
OL9912938
214
Org. Lett., Vol. 2, No. 2, 2000