The Heck reaction in ionic liquids: A multiphasic catalyst system

Article abstract of DOI:10.1021/ol9907771

(matrix presented) Heck coupling of aryl halides or benzoic anhydride with alkenes can be performed with excellent yields in room-temperature ionic liquids, which provide a medium that dissolves the palladium catalyst and allows the product and byproducts to be easily separated. Consequently, the catalyst and ionic liquid can be recycled and reused.

Full text of DOI:10.1021/ol9907771

ORGANIC
LETTERS
1999
Vol. 1, No. 7
997-1000
The Heck Reaction in Ionic Liquids:
A Multiphasic Catalyst System
Adrian J. Carmichael,† Martyn J. Earle,* John D. Holbrey,†
Paul B. McCormac, and Kenneth R. Seddon‡
School of Chemistry, The Queen’s UniVersity of Belfast, Stranmillis Road,
Belfast, Northern Ireland, U.K., BT9 5AG
m.earle@qub.ac.uk
Received July 1, 1999
ABSTRACT
Heck coupling of aryl halides or benzoic anhydride with alkenes can be performed with excellent yields in room-temperature ionic liquids,
which provide a medium that dissolves the palladium catalyst and allows the product and byproducts to be easily separated. Consequently,
the catalyst and ionic liquid can be recycled and reused.
The Heck reaction is of major importance in synthetic organic
chemistry, as a carbon-carbon bond-forming reaction.1 It
is often used to functionalize aromatic rings and as an
alternate to the Friedel-Crafts reaction.2 The Heck reaction
usually involves the interaction of an aromatic halide3 or
anhydride4 with an alkene, in the presence of a palladium
catalyst at typically a 1-2 mol % concentration, to give an
aryl alkene. The reaction normally requires a base to be
present,5,6 particularly in the reactions of aryl halides (but
not anhydrides).4 A major problem with the Heck reaction
is that the palladium catalyst is often lost at the end of the
reaction.6 Hence, a process for recycling the catalyst system
is of importance.
Room-temperature ionic liquids have been used to great
effect as solvents for a number of reactions, for example,
Friedel-Crafts reactions,7 isomerizations of fatty acid de-
rivatives,8 dimerization reactions of alkenes,9 Diels-Alder
reactions,10 and hydrogenation reactions.11 Ionic liquids such
as 1-butyl-3-methylimidazolium hexafluorophosphate12
([bmim][PF6]) have a particularly useful set of properties,
being virtually insoluble in water and alkanes but readily
dissolving many transition metal catalysts.13 Such biphasic
† The QUESTOR Centre, The Queen’s University of Belfast, Stranmillis
Road, Belfast, Northern Ireland, U.K., BT9 5AG.
(7) Adams, C. J.; Earle, M. J.; Roberts, G.; Seddon, K. R. Chem.
Commun. 1998, 2097.
(8) Adams, C. J.; Earle, M. J.; Hamill, J.; Lok, C. M.; Roberts, G.;
Seddon, K. R. World Patent WO 98 07679, 1998.
‡ The QUILL Centre, The Queen’s University of Belfast, Stranmillis
Road, Belfast, Northern Ireland, U.K., BT9 5AG.
(1) (a) Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40, 1083. (b)
Kim, J.-I. I.; Patel, B. A.; Heck R. F. J. Org. Chem. 1981, 46, 1067. (c)
Bender, D. D.; Stakem, F. G.; Heck, R. F. J. Org. Chem. 1982, 47, 1278.
(2) Olah, G. A. Friedel-Crafts Chemistry; Wiley-Interscience: New
York, 1973.
(3) Namyslo, J. C.; Kaufmann, D. E. Synlett 1999, 114.
(4) Stephan, M. S.; Teunissen, A. J. J. M.; Verzijl, G. K. M.; Vries, J.
G. de Angew. Chem. Int. Ed. Engl. 1998, 37, 662.
(9) (a) Ellis, B.; Keim, W.; Wasserscheid, P. Chem. Commun. 1999, 337.
(b) Einloft, S.; Olivier, H.; Chauvin, Y. U.S. Patent US 5550306, 1996.
(10) Earle, M. J.; McCormac, P. B.; Seddon, K. R. Green Chem. 1999,
1, 23.
(11) (a) Fisher, T.; Sethi, A.; Welton, T.; Woolf, J. Tetrahedron Lett.
1999, 40, 793. (b) Adams, C. J.; Earle, M. J.; Seddon, K. R. Chem. Commun.
1999, 1043.
(12) Huddleston, J. G.; Willauer, H. D.; Swatloski, R. P.; Visser, A. E.;
Rogers, R. D. Chem. Commun. 1998, 1765.
(13) Dullius, J. E. L.; Suarez, P. A. Z.; Einloft, S.; De Souza, R. F.;
Dupont, J.; Fischer, J.; De Cian, A. Organometallics 1998, 17, 815.
(5) Jeffery, T.; J. Chem. Soc., Chem. Commun. 1984, 1287.
(6) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem.
1998, 63, 6546.
10.1021/ol9907771 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/16/1999

Figure 1. A triphasic mixture of [bmim]2[PdCl4] and P(o-tol)318 in [bmim][PF6] (lower layer), water (middle layer), and cyclohexane (top
layer).
ionic liquid systems have been used to enable simple
extraction of products.14 Furthermore, if benzoic anhydride
is used as a source of aryl moiety, then a base is not required
for the reaction (the byproduct in this case is an aryl
carboxylic acid which can be recovered at the end of the
reaction and converted back to an anhydride).4
We have found that the Heck reaction can be performed
in a number of low melting point N,N′-dialkylimidazolium
or N-alkylpyridinium ionic liquids with halide, hexafluoro-
phosphate, or tetrafluoroborate anions. For our work, we
concentrated on using salts with a limited number of anions
and cations, so that a correlation between reactivity in the
Heck reaction and structural differences in the salts could
be determined. For the cation, 1-butyl-3-methylimidazolium
([bmim]), 1-pentyl-3-methylimidazolium ([pmim]), or N-
hexylpyridinium ([C6py]) species were chosen.15
As mentioned above, the high solubility of both [bmim]2
[PdCl4]13 and [Pd(OAc)2(PPh3)2] in ionic liquids and their
low solubility in organic solvents (such as toluene or hexane)
enables the products of the reaction to be separated from
the ionic liquid and catalyst by solvent extraction with an
organic solvent or by distillation from the reaction vessel.
Furthermore, if a hydrophobic ionic liquid is chosen (e.g.
[bmim][PF6] or [C6py][BF4]), then water can also be used
(14) (a) Bader, A.; Arlt, D.; Seng, F. E.U. Patent EP 0 459 258, 1991.
(b) Blanchard, L. A.; Hancu, D.; Beckman, E. J.; Brennecke, J. F. Nature
1999, 399, 28.
(15) (a) Gordon, C. M.; Holbrey, J. D.; Kennedy, A. R.; Seddon, K. R.
J. Mater. Chem. 1998, 8, 2627. (b) Holbrey, J. D.; Seddon, K. R. J. Chem.
Soc., Dalton Trans. 1999, 2133.
998
Org. Lett., Vol. 1, No. 7, 1999

as an extraction solvent to remove the salt byproducts formed
in the reaction. A clear demonstration of this phase behavior
is given in Figure 1, where the preferential solubility of the
yellow palladium catalyst in the lower ionic phase is clearly
apparent.
3 and 4), higher reaction temperatures are needed. Of these
two anions, the tetrafluoroborate ionic liquid gives higher
yields. In contrast to the chloride-based systems, the addition
of a phosphine ligand (such as Ph3P) was found to promote
the reaction in the imidazolium salt [bmim][PF6] (entry 5).
This ionic liquid/catalyst combination can operated under
triphasic conditions and give ethyl cinnamate in greater than
95% yield over many reaction cycles,19 without loss of
catalytic activity.
In the Heck reaction of iodobenzene with ethyl acrylate
(Table 1), the reaction proceeds smoothly to produce the
Table 1. Heck Reaction of Iodobenzene and Ethyl Acrylate To
Give trans-Ethyl Cinnamate in Ionic Liquids with 2 mol % of
Pd(OAc)2
To test whether less reactive aromatic compounds could
reliably undergo the Heck reaction, the reaction of 4-bro-
moanisole (the relative reactivity in the Heck reaction is as
follows: 4-(MeO)C6H4Br < C6H5Br < 4-(CHO)C6H4Br)20
with ethyl acrylate was investigated, in the ionic liquid
[bmim][PF6], using triethylamine as the base and a range of
Group 15 ligands (Table 2). The reactions were carried out
ionic
temp, time, yield,
entry
liquid
additive
none
none
base
Et3N
NaHCO3
NaHCO3
NaHCO3
Et3N
°C
h
%
1
2
3
4
5
[C6py]Cl
[C6py]Cl
[C6py][PF6] none
[C6py][BF4] none
[bmim][PF6] Ph3P
40
40
80
80
100
24 99
24 98
72 42
72 99
1
95-9919
Table 2. Heck Reaction of 4-Bromoanisole and Ethyl Acrylate
To Give Ethyl 4-Methoxycinnamate with Various Group 15
Ligands in [bmim][PF6] with Triethylamine as the Base
(4 mol %)
Ph3P
(4 mol %)
Ph3P
(4 mol %)
none
6
7
[C6py]Cl
[C6py]Cl
NaHCO3
40
24 82
24 99
NaHCO3 100
temp, time, yield,
entry
11 none
12
13 triphenylphosphine
14
15 tri-o-tolylphosphine
16
17
Group 15 ligand added (4 mol %)
°C
h
%
8
9
[pmim]Cl
[pmim]Cl
Et3N
NaHCO3 100
NaHCO3 40
80
72 10
24 19
24 77
100
140
100
140
100
100
140
100
140
100
140
20
18 94
7
none
DMF
10 [C6py]Cl
72
24
4
24
18
24
24
18 <1
24 13
18 <1
65
98
55
65
99
1.5
31
expected trans-ethyl cinnamate in excellent yields.16 For
reactions carried out in the chloride salts (entries 1, 2, and
6-10), the N-hexylpyridinium salts give rise to higher yields
than the corresponding reactions in imidazolium salts. The
addition of a phosphine ligand to the palladium species in
the reaction in the pyridinium salt decreased the yield, and
a higher reaction temperature was then required to force the
reaction to completion (entries 6 and 7). Several authors have
reported that a cosolvent such as DMF or N-methylpyrro-
lidinone (NMP) is required for this reaction;4,17 however we
have found that they are not required and can often decrease
the yield of the reaction (entry 10).
18 triphenyl phosphite
19
20 1,2-bis(diphenylphosphino)ethane27
21
22 1,1'-bis(diphenylphosphino)ferrocene27 100
23
140
100
140
100
140
18
12
20
72 <1
24 24
95
2
99
24 triphenylarsine
25
26 triphenylstibine
27
For the reactions carried out in hexafluorophosphate or
tetrafluoroborate room-temperature ionic liquids (entries
at two temperatures: 100 °C and 140 °C. As expected, the
Group 15 ligand on the palladium catalyst had a significant
effect on the yield and conditions required to complete the
reaction.
As shown in Table 2, three of the ligands chosen were
unsuitable for this reaction, giving poor yields. These were
triphenyl phosphite, triphenylstibine, and 1,2-bis(diphen-
ylphosphino)ethane (entries 19, 21, and 27). In the case of
triphenylstibine and 1,2-bis(diphenylphosphino)ethane, the
(16) General Procedure for the Heck Reaction in Ionic Liquids. To
a round-bottom flask (25 cm3), equipped with a magnetic stirrer flea and
reflux condenser, were added 1-butyl-3-methylimidazolium hexafluoro-
phosphate (5.0 g), palladium(II) acetate (0.045 g, 0.20 mmol), and
triphenylphosphine (0.105 g, 0.40 mmol), and the mixture was heated to
80 °C for 5 min with stirring to form the ionic liquid solution of the catalyst.
A mixture of triethylamine (1.51 g, 15.0 mmol), iodobenzene (2.04 g, 10.0
mmol), and ethyl acrylate (1.25 g, 12.5 mmol) was added, and the mixture
was heated to 100 °C for 1 h. Gas chromatographic analysis of the product
showed that no iodobenzene was present. The product was extracted from
the reaction vessel by the addition of hexane (10 cm3), followed by decanting
off a hexane solution of the product. This was repeated three further times.
The combined hexane extracts were concentrated on a rotary evaporator,
and the product was purified by Kugelrohr distillation. This gave 1.67 g of
a colorless oil (yield ) 95%). The spectroscopic properties of this oil were
in accordance with those of authentic trans-ethyl cinnamate.
(19) The reaction was carried out six times without loss of activity of
the catalyst. The product (trans-ethyl cinnamate) was extracted from the
reaction vessel with cyclohexane, and the triethylammonium iodide salt
was removed by solvent extraction with water. It is important to note that
this reaction will work in the presence of a very large excess of water (a
50-fold excess does not hinder this reaction).
(17) (a) Amatore, C.; Broeker, G.; Jutand, A.; Khalil, F. J. Am. Chem.
Soc. 1997, 119, 5176. (b) Amatore, C.; Jutand, A. Coord. Chem. ReV. 1998,
180, 511.
(18) The catalyst was made by dissolving [bmim]2[PdCl4] (1 equiv) and
P(o-tol)3 (2 equiv) in [bmim][PF6] at 70 °C. For background information
of this reaction, see: Herrmann, W. A.; Bohn, V. P. W. J. Organomet.
Chem. 1999, 572, 141.
(20) (a) Reetz, M. T.; Lohmer, G.; Schwickardi, R. Angew. Chem. Int.
Ed. 1998, 37, 481. (b) Herrmann, W. A.; Brossmer, C.; O˜ fele, K.; Reisinger,
C.-P.; Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl.
1995, 34, 1844.
Org. Lett., Vol. 1, No. 7, 1999
999

palladium catalyst formed inactive insoluble complexes. As
for the other reactions, over 94% yields were readily obtained
at 140 °C. Two of ligands gave rise to reactions with rates
lower than those in the absence of added ligand (entries 13-
17).21 The ligands triphenylphosphine and tri-o-tolylphos-
phine gave rate enhancements over the absence of Group
15 ligand at 100 °C. It should be noted that in the case of
tri-o-tolylphosphine, a palladacycle17b,22 has been observed
from the reaction of tri-o-tolylphosphine and palladium(II)
acetate, and this species may be the active catalyst. These
observations appear to show that the electron rich or bidentate
ligands reduce the reactivity of the catalyst. In the case where
no ligand was present, the reaction was not effective at 100
°C. This is thought to be due to the formation of palladium
black. At the higher reaction temperature of 140 °C, the
palladium redissolves and the reaction proceeds smoothly.
This order of reactivity is summarized in Figure 2.
The reaction of benzoic anhydride with alkenes has also
been investigated in ionic liquids in the absence of a base
(Table 3). The reaction of butyl acrylate with benzoic
Table 3. Heck Reaction of Benzoic Anhydride and Butyl
Acrylate in Ionic Liquids
temp, time, yield,
entry ionic liquid
catalyst
°C
h
%
28
29
[C6py]Cl
PdCl2 (2 mol %)
160
20
3
90
95
[bmim][BF4] Pd(OAc)2‚2 P(o-tol)3 200
(2 mol %)
anhydride gave trans-butyl cinnamate in 90-95% yields.23
Typically the product and byproduct (benzoic acid) are
extracted with ether, and fresh reagents can be added. As
can be seen, the reaction works well in chloride salts (entry
28). With the room-temperature ionic liquid [bmim][BF4],
higher reaction temperatures are required (entry 29), but the
reaction still works efficiently.
In general, there is a considerable difference in reactivity
in the Heck reaction between imidazolium and pyridinium
ionic liquids. In the case of imidazoium ionic liquids, the
2-H proton is acidic and in the presence of a base can be
deprotonated to form a carbene.24 These imidazolylidine
carbenes are known to act as ligands to metals such as
palladium(II) and an imidazolylidine-palladium carbeneoid
species may be implicated.25 This may also explain why
insoluble palladium black redissolves at above 100 °C in
reactions carried out without Group 15 ligands. In the case
of reactions carried out in the pyridinium salts (particularly
the chloride), phosphine ligands on the palladium catalyst
hinder the reaction (see entry 6). It has been suggested that
in a chloride (or halide) rich environment, this reaction
involves a Pd(II)/Pd(IV) redox cycle,26 whereas in the cases
where the phosphine ligands accelerate the reaction, a
mechanism involving Pd(0) and Pd(II) species is involved.4,17
In conclusion, ionic liquids such as [bmim][PF6] are
excellent media for the Heck reaction. They can selectively
dissolve the palladium catalyst in preference to water or
alkane solvents, allowing for ionic liquid and catalyst
recycling.
Figure 2. The relative order of reactivity for different ligands in
the Heck reaction at 100 °C (Table 2).
The reaction of 4-bromoanisole with alkyl acrylates can
give rise to modest yields of the corresponding 4-methoxycin-
namates.20b Therefore the yield in this reaction is a good test
of the performance of the catalyst, solvent, and methodology
used. For the reactions of 4-bromoanisole performed in the
ionic liquid (Table 2), the yields in this reaction exceed the
literature yields.20b Furthermore, the product is easily isolated
by solvent extraction, and the catalyst and ionic liquid can
be recycled.
(21) (a) Boyes, A. L.; Butler, I. R.; Quayle, S. C. Tetrahedron Lett. 1998,
39, 7763.
(22) Beller, M.; Fischer, H.; Herrmann, W. A.; Ofele, K.; Brossmer, C.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1848.
(23) Owing to the high reaction temperatures (above the boiling point
of butyl acrylate), the reaction was carried out in a sealed thick walled
glass reaction vessel.
(24) Herrmann, W. A.; Kocher, C. Angew. Chem., Int. Ed. Engl. 1997,
36, 2163.
(25) McGuinness, D. S.; Cavell, K. J.; Skelton, B. W.; White, A. H.
Organometalics 1999, 18, 1596.
Acknowledgment. We thank the following for financial
support: the EPSRC (M.J.E. and P.B.M.); the EPSRC and
the Royal Academy of Engineering for the award of a Clean
Technology Fellowship (K.R.S.); the ERDF Technology
Development Program and the QUESTOR Centre (J.D.H.
and A.J.C.).
(26) Shaw, B. L. New J. Chem. 1998, 22, 77.
(27) 2 mol % of ligand was added (4 mol % in P atoms).
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Org. Lett., Vol. 1, No. 7, 1999