The [RPPhPd as a catalyst precursor for the heck cross-coupling reaction by in situ formation of stabilized Pd(0) nanoparticles

Article abstract of DOI:10.1055/s-0032-1317963

Pd(II) anionic, square planar complexes of the type [RPPhPdl, where X = Cl, Br, have been applied for the first time as a catalyst precursor for the Heck reaction carried out in DMF at 140 °C. The highest yield was obtained for the most reducible ones, [MePPhPdrl, in DMF in the presence of NaHCOas a base. It was found that during the reaction, phosphonium halide stabilized Pd(0) nanoparticles of about 10 nm, which have been formed in situ from the palladium(II) precursor and Pd(0) colloidal nanoparticles acts as the reservoir for Pd(II) species via activation of the metal surface through the oxidative addition of aryl halides. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317963

254▌
LETTER
letter
The [RPPh3]2[Pd2X6] as a Catalyst Precursor for the Heck Cross-Coupling
Reaction by in situ Formation of Stabilized Pd(0) Nanoparticles
Catalyst Precursor for the Heck Cross-Coupling Reaction
Abdol Reza Hajipour,*a,b Ghobad Azizib
a
Department of Pharmacology, University of Wisconsin Medical School, 1300 University Avenue, Madison, WI 53706-1532, USA
b
Pharmaceutical Research Laboratory, College of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran
Fax +98(311)3912350; E-mail: haji@cc.iut.ac.ir
Received: 10.11.2012; Accepted after revision: 10.12.2012
Dimeric palladium(II) ammonium, imidazolium and pyr-
Abstract: Pd(II) anionic, square planar complexes of the type
idinium complexes have been previously used as catalysts
[RPPh3]2[Pd2X2Cl4], where X = Cl, Br, have been applied for the
for chemical reactions in literature.4–7 However, to the
best of our knowledge, dimeric palladium(II) phosphoni-
first time as a catalyst precursor for the Heck reaction carried out in
DMF at 140 °C. The highest yield was obtained for the most reduc-
ible ones, [MePPh3]2[Pd2Br2Cl4], in DMF in the presence of um complexes have never been used before as catalyst
NaHCO3 as a base. It was found that during the reaction, phospho-
nium halide stabilized Pd(0) nanoparticles of about 10 nm, which
have been formed in situ from the palladium(II) precursor and Pd(0)
precursors for the chemical reactions.
Phosphonium salts display higher stability towards ther-
mal and chemical degradation in comparison to their am-
monium counterparts. A few reports are available for the
preparation of dipalladium(II) complexes containing
phosphonium counterion8,9 and these dipalladium com-
plexes have never been used before as catalyst precursors.
Kaufmann reported the application of hexadecyltribu-
tylphosphonium bromide as reaction medium for Heck re-
action of aryl halides at 100 °C in 16–43 hours.10 Capretta
explored the effect of counter anion matched to the phos-
phonium cation on the yields of the Heck reaction. He
found that the best counter anion were Cl and decanoate.11
In this work, we prepared and examined the catalysts 1–5
with different halogen bridge and R group attached to the
phosphonium salt in the Heck reaction (Figure 1).
colloidal nanoparticles acts as the reservoir for Pd(II) species via ac-
tivation of the metal surface through the oxidative addition of aryl
halides.
Key words: olefination, arylation, catalysis, palladium, nano-
structures
Since its discovery in the early 1970s, the Heck reaction
has been applied to a diverse array of fields, ranging from
natural products synthesis to materials science as well to
bioorganic chemistry. This powerful carbon–carbon
bond-forming process has been practiced on an industrial
production of fine chemicals, such as octyl methoxycinna-
mate.1 This kind of reaction possesses several advantages
in comparison to the most classical organic methods, in-
cluding their excellent functional group tolerance, mild
reaction conditions, less waste, and sometimes fewer
steps than the original stoichiometric routes.2 In the past
decade, new generations of homogeneous catalysts such
as palladacycles, Pincer ligands, and more recently bulky
electron-rich ligands have extended the scope of the reac-
tion to all aromatic halides, even the poorly reactive aryl
chlorides. In general, homogeneous catalysis suffers from
several shortcomings, such as: the ligands are required to
form the active catalyst, the ligands may be expensive or
not commercially be available in bulk; furthermore, re-
moval of residual ligand or palladium provides a challeng-
ing task for chemists in the pharmaceutical industry to
reduce the palladium to a level that satisfies specifications
required by regulators.3 Herein, we report the use of a pal-
ladium complex of the type [RPPh3]2[Pd2X2Cl4] with the
quaternary phosphonium salts for the first time as an effi-
cient catalyst for Heck reaction of aryl halides with al-
kenes with quantitative yields.
R
Cl
Cl
P
Cl
Cl
X
X
R
P
Pd
Pd
1 R = Bn, X = Cl
2 R = Bu, X = Br
3 R = Bn, X = Br
4 R = Me, X = Br
5 R = 9-anthryl, X = Cl
Figure 1 Dimeric palladium(II) complexes prepared from PdCl2 and
various phosphonium halides
Our first goal was to synthesize the palladium(II) catalysts
with the general formula [RPPh3]2[Pd2X2Cl4] with differ-
ent substituent R on phosphonium cations and Cl or Br
ions coordinated to Pd(II) as shown in Figure 1. Phospho-
nium salts were prepared from the reaction of triphe-
nylphosphine and alkyl or benzyl bromides/chlorides and
the resulting phosphonium salts then were reacted with
palladium chloride in toluene at reflux temperature to pre-
pare the catalysts 1–5 and then the applications of the re-
sulting catalysts were investigated in the Heck coupling of
4-bromoacetophenone to determine the effect of phospho-
SYNLETT 2013, 24, 0254–0258
Advanced online publication: 08.01.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317963; Art ID: ST-2012-B0968-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Catalyst Precursor for the Heck Cross-Coupling Reaction
255
nium salt counter cations and halogen bridges in the cata-
lysts on the yield of the reaction. Figure 2 shows the
results for the reaction of 4-bromoacetophenone and
methyl acrylate using [RPPh3]2[Pd2X2Cl4] as the catalysts
and NaHCO3 as the base. Results showed that in contrast
to the Capretta, the counter anion on the phosphonium cat-
ion and bulkiness of the phosphonium cation plays no sig-
nificant role in the outcome of the reaction, which may be
due to the decreasing selectivity at a higher temperatures.
Although the results for these catalysts were comparable,
we chose [MePPh3]2[Pd2Cl6] (4) as the catalyst.
Figure 3 UV–VIS spectrum before (---) and after (––) two minutes of
reaction of 4-bromoacetophenone and methyl acrylate in the presence
of [MePPh3]2[Pd2Br2Cl4]
formation of Pd nanoparticles during the Heck reaction
having an average diameter of 10 nm. The cyclic voltam-
metry (CV) diagram of the catalysts 1–5 (Figure 5)
showed that the order of reducibility is R = Me > R = Bu
> R = Bn > R = anthrylmethyl and X = Br > X = Cl. From
the cyclic voltammetry diagram, it was determined that
[MePPh3]2[Pd2Br2Cl4] has the highest susceptibility for
reduction to palladium nanoparticles. As can be seen from
Figure 2, this catalyst has the highest yield in the Heck re-
action.
Figure 2 Observed cis/trans ratio of the product in the presence of
catalysts 1–5
As demonstrated in Figure 2 the cis/trans selectivities for
catalysts 1–5 are similar. Therefore, it can be concluded
that: (1) if the homogenous Pd(II) acts as active catalyst,
phosphonium cation may be far from the palladium(II)
center, or (2) the active Pd(0) species with Pd(0) colloidal
nanoparticles or highly active forms of low coordinated
Pd(0) species are the active sites of reaction, so, the type
of bridge or aryl/alkyl groups of phosphonium catalyst
does not significantly affect the yield and selectivity of the
reaction. To determine that the Pd(II) or Pd(0) is involved
in this reaction, we performed the mercury poisoning test
with Hg(0). This test is based on the deactivation of col-
loidal metal via amalgam formation. The addition of ex-
cess of Hg(0) to the Heck reaction showed an extremely
strong inhibition of the catalytic activity, which implies
the presence of active Pd(0) species.
In all of the Heck reactions under study, with different
substrates, a thick colloid of Pd(0) was formed after about
two minutes. Its formation was first signalized by the
change of the red color of Pd(II) solution to the almost
black Pd(0) after about two minutes due to the change in
the UV–VIS spectra of the catalyst. As shown in Figure 3,
palladium(II) complex exclusively reduced to Pd(0) and
the band at λ = 267 nm, which has been assigned to
[MePPh3]2[Pd2Br2Cl4], disappeared. Decomposition of
this complex leads to the formation of phosphonium chlo-
ride that may act as a stabilizer for the palladium nanopar-
ticles.12
Figure 4 TEM image of the reaction mixture of Heck reaction
These results indicate that the Pd(0) nanoparticles may act
as a reservoir for Pd(II) species via activation of the metal
surface with haloarenes.13 Therefore, we suggest the pos-
sible catalytic cycle for this reaction as described in
Scheme 1.
Initially, for finding the best conditions for coupling of 4-
bromoacetophenone and methyl acrylate in the presence
of catalyst 4, several conditions including the effects of
solvent, base, temperature, reaction time and the amount
Figure 4 shows the TEM image of the reaction solution af-
ter about two minutes of reaction of 4-bromoacetophe-
none and methyl acrylate. This image clearly indicated the
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 254–258

256
A. R. Hajipour, G. Azizi
LETTER
Figure 6 Observed cis/trans ratio against time for the reaction of 4-
bromoacetophenone and methyl acrylate in the presence of catalyst 4
Table 1 Base Optimization in Heck Reaction of 4-Bromoacetophe-
none and Methyl Acrylate
Base
Conv. (%)
cisa
transa
Figure 5 Cyclic voltammetry diagram of complexes 1–5
K2CO3
Na2CO3
NaOAc
KOH
99.52
99.65
98.95
87.19
74.77
99.61
100
1.66
1.82
1.81
0.8
97.86
97.83
97.14
86.39
74.21
99.19
99.8
of catalysts on the yield of the coupling reaction were in-
vestigated.
As is demonstrated in Figure 6, this reaction leads to the
formation of trans isomer exclusively in 99% conversion
based on GC. Several bases were tested for the reaction
and the results showed that the effect of bases on the reac-
tion was significant (Table 1). When no base was used in
this reaction, only trace amount of the desired product was
detected. A comparative study of various bases, such as
KOH, Et3N, Na2CO3, NaHCO3 and K2CO3, revealed that
NaHCO3 gave the best result. Using, two equivalents of
NaHCO3 gave the coupling reaction in highest yields.
Et3N
0.56
0.42
0.20
NaHCO3
NaHCO3
b
a GC yields. Reaction conditions: 4-bromoacetophenone (0.25
mmol), methyl acrylate (1.5 mmol), catalyst (0.01 mmol), base (0.25
mmol), DMF (1.5 mL), 140 °C (oil bath) and 45 min.
b The amount of base used was 2 equiv.
2–
Cl
Cl
Cl
Cl
Br
Br
Pd
Pd
P
P
R
R
X
Ar
oxidative addition
surface activation
Pd0
Pd2+
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
bulk
Pd0
Pd0
bulk
Pd0
Pd0
MePPh3Br
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
surface Pd0
Pd0
Pd0
R
R
Ar
Ar
R
Ar
R
Pd2+
Pd2+
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
bulk
Pd0
bulk
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
Pd0
Scheme 1 Proposed catalytic cycle for the Heck reaction of aryl halides and olefins in the presence of palladium(II) complex
Synlett 2013, 24, 254–258
© Georg Thieme Verlag Stuttgart · New York

LETTER
Catalyst Precursor for the Heck Cross-Coupling Reaction
257
The amount of catalysts was also evaluated by using var- As shown in Table 3, all aryl iodides were rapidly con-
ious concentration of [MePPh3]2[Pd2Br2Cl4]. The highest verted into the corresponding Heck products with excel-
yield was obtained for 0.04 mmol, whereas at lower and lent yields (Table 3, entries 8, 11, 17 and 18). Although
higher concentrations of the catalyst precursor, the ob- the coupling of bromoarenes with an electron-donating
tained yields were lower. It is probably due to the forma- substituent (entry 4) was considerably decreased, the cou-
tion of larger palladium nanoparticles at higher pling reaction of both electron-deficient and electron-rich
concentrations.
aryl bromides with the olefins proceeded smoothly with
Furthermore, the effect of the solvent was investigated
(Table 2) and polar aprotic solvents were found to be bet-
ter solvents than water and alcohols and the best result
(99.5%) was obtained for the reaction in DMF. For DMAc
and NMP, the conversion was 79.2% and 97.7% respec-
tively, whereas for water, MeCN and ethanol, no products
were obtained. In addition, temperature as an important
factor for this reaction was examined by choosing the
range of 100–140 °C and the results are shown in Figure 7.
Table 3 Heck Reactions of Aryl Halides with Alkenes Catalyzed by
Palladium Nanoparticlesa
Pd0
Pd0
Pd0
Pd0
bulk
Pd0
Pd0
Pd0
Pd0
R3
Pd0
R3
X
Pd0
Pd0
R1
+
R2
R2
DMF, NaHCO3, 140 °C
R1
Entry R1
X
R2
R3
Time
(min)
Yield
(%)
1
2
4-CN
3-Ac
4-Ac
Br
Br
Br
Br
Br
Br
Br
I
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
25
40
92
93
91
62
91
92
90
93
88
91
94
85
80
82
94
91
90
93
89
91
93
95
60
90
50
3
35
4
4-OMe
4-CHO
4-NO2
H
600
80
5
6
55
7
40
8
H
12
9
2-Cl
Br
Br
I
35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3-Cl
25
Figure 7 Temperature optimization in Heck reaction of 4-bromoace-
tophenone and methyl acrylate
4-OMe
H
15
I
720
480
840
45
Table 2 Solvent Optimization in Heck Reaction of 4-Bromoaceto-
phenone and Methyl Acrylate
4-OMe
3-Cl
I
Ph
Solvent
Conv. (%)
cisa
transa
Br
Br
Br
I
Ph
3-Cl
COOMe
COOMe
COOMe
COOMe
COOH
COOH
COOH
COOH
Me
Me
Me
Me
H
NMP
DMF
DMAc
MeCN
EtOH
H2O
98.91
99.57
80.03
0
1.21
0.07
0.83
0
97.7
99.5
79.2
0
4-CN
H
45
40
4-OMe
4-CN
4-Ac
4-CHO
3-Cl
I
70
Br
Br
Br
Br
40
0
0
0
H
45
0
0
0
a GC yields. Reaction conditions: 4-bromoacetophenone (0.25
mmol), methyl acrylate (1.5 mmol), catalyst (0.01 mmol), NaHCO3
(0.5 mmol), solvent (1.5 mL), 140 °C (oil bath) and 45 min.
H
40
H
30
1-bromonaphthalene
9-bromophenanthrene COOMe
Cl COOMe
COOMe
H
30
By employing the mentioned optimized conditions, other
substrates including, aryl iodides, bromides, chlorides and
olefins were coupled with methyl acrylate, methyl meth-
acrylate, acrylic acid and styrene in the presence of cata-
lyst 4.
H
50
H
H
1440
a Reaction conditions: aryl halide (1 mmol), alkene (1.2 mmol),
[MePPh3]2[Pd2Br2Cl4] (0.04 mmol), NaHCO3 (2 mmol), DMF (1.5
mL) at 140 °C without protection of inert atmosphere.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 254–258

258
A. R. Hajipour, G. Azizi
LETTER
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methyl acrylate, methyl methacrylate and acrylic acid
were faster than that with styrene.
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The catalyst was also confirmed to be very active for 1,1-
disubstituted alkene substrates. For example, methyl
methacrylate was transformed into α-methyl cinnamate
derivatives in good yields and only small amounts of dia-
rylated products were detected (Table 3, entries 15–18).
Aryl chlorides needed longer times and provided lower
yields. This lower reactivity may be attributed to the re-
luctance of the aryl–chloride bond at oxidative addition
step.1
In this contribution we have demonstrated the applicabil-
ity of dimeric palladium(II) phosphonium complexes in
Heck coupling reactions and investigated the effect of
several reaction parameters such as temperature, amount
of catalyst, base and starting compounds on catalytic ac-
tivity.14 By using the Hg(0) test, UV–VIS spectroscopy,
transmission electron microscopy and cyclic voltamme-
try, we concluded that Pd(0) colloidal nanoparticles act as
reservoir for Pd(II) species via activation of the metal sur-
face with haloarenes.
(10) Kaufmann, D. E.; Nouroozian, M.; Henze, H. Synlett 1996,
1091.
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Tetrahedron Lett. 2004, 45, 7629.
(12) Bhattacharya, S.; Srivastava, A.; Sengupta, S. Tetrahedron
Lett. 2005, 46, 3557.
(13) Precht, M. H. G.; Scholten, J. D.; Dupont, J. Molecules 2010,
15, 3441.
Acknowledgment
We gratefully acknowledge the funding support received for this
project from the Isfahan University of Technology (IUT), IR Iran
(A.R.H.) and Grant GM 33138 (A.E.R.) from the National Institutes
of Health, USA. Further financial support from the Center of Ex-
cellency in Chemistry Research (IUT) is gratefully acknowledged.
(14) Typical Procedure for the Heck Arylation of Aryl
Halides with Methyl Acrylate: Palladium complex
([MePPh3]2[Pd2Br2Cl4]) (0.01 mmol), methyl acrylate (0.5
mmol), aryl halides (0.25 mmol), NaHCO3 (0.5 mmol) and
DMF (1.5 mL) were added to a 5-mL round-bottomed flask
equipped with an efficient condenser and stirred at 140 °C in
an oil bath for the time specified in Table 3. The course of
the reaction was monitored by periodically taking samples
and analyzing them by means of GC analysis. After cooling
of the reaction mixture to r.t., the aqueous solution was
extracted with hexane, the organic phase was dried over
MgSO4, and the solvent was then removed under vacuum.
Column chromatography on silica gel afforded the desired
product. The product was characterized by 1H NMR and IR.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
(1) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
Synlett 2013, 24, 254–258
© Georg Thieme Verlag Stuttgart · New York