Gelatin as a bioorganic reductant, ligand and support for palladium nanoparticles. Application as a catalyst for ligand- and amine-free Sonogashira-Hagihara reaction

Article abstract of DOI:10.1039/c0ob00253d

Palladium nanoparticles were deposited and reduced by gelatin as a safe edible, naturally occurring and cheap support. No extra reducing agents were used for the generation of Pd(0) nanoparticles from the Pd(ii) salt. The nanoparticles of Pd supported on

Full text of DOI:10.1039/c0ob00253d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Gelatin as a bioorganic reductant, ligand and support for palladium
nanoparticles. Application as a catalyst for ligand- and amine-free
Sonogashira–Hagihara reaction†
Habib Firouzabadi,* Nasser Iranpoor* and Arash Ghaderi
Received 14th June 2010, Accepted 15th October 2010
DOI: 10.1039/c0ob00253d
Palladium nanoparticles were deposited and reduced by gelatin as a safe edible, naturally occurring and
cheap support. No extra reducing agents were used for the generation of Pd(0) nanoparticles from the
Pd(II) salt. The nanoparticles of Pd supported on gelatin were characterized by SEM, TEM and AFM
images, UV-Vis and XRD spectra and the amount of palladium entrapped in the gelatin was measured
by ICP and atomic absorption analysis. The nanoparticles showed high catalytic activity for the
Sonogashira–Hagihara coupling reaction of various aryl iodides, bromides and chlorides as well as
heteroaryl halides and also b-bromo styrene with phenylacetylene under copper-, ligand- and
amine-free conditions. The reactions were carried out at 100 ◦C in molten tetrabutylammonium
bromide (TBAB) or polyethylene glycol (PEG400) in the presence of potassium acetate as a base in
argon atmosphere. Dimerization of phenylacetylene applying similar conditions in air is also described.
a wide variety of reducing agents such as NaBH4,8 citric acid,10
Introduction
hydrazine,11 HCOOH,12 ethyleneglycol,13 ethanol14 etc. have been
used for the reduction of transition metal salts to produce metal
nanoparticles.
Gelatin is a water soluble edible protein derived from partially
denatured collagen.1 Collagen occurs extensively in nature and is
insoluble in water, but the gelatin derived from it is freely soluble
in hot water. Eye-catching properties of gelatin, such as flexibility,
adhesiveness, low immunogenicity, promotion of cell adhesion and
growth, and low cost, make it suitable for practical use in many
areas of science.2 Gelatin contains free carboxyl groups on its
backbone and has the potential for chelating and reducing tran-
sition metals.3 Therefore, using gelatin as a support for important
transition metals such as palladium has two advantages, it reduces
Pd(II) to Pd(0) without using any extra reducing agent and also
acts as a highly functionalized support to catch and stabilize the
nanoparticles of palladium. In comparison with other reducing
agents employed for the generation of palladium nanoparticles,
such as NaBH4, gelatin is a weak reductant which generates and
deposits Pd(0) nanoparticles from Pd(II) very gently, which causes
the size of the particles to be smaller and the distribution of the
particles on the surface of gelatin to be more dispersed.
Palladium metal nanoparticles are employed in a diversity of
catalytic reactions including Mizoroki–Heck,4 Suzuki–Miyaura,5
Stille6 and Sonogashira–Hagihara reactions.7 To date, various
supports have been investigated to stabilize palladium nanoparti-
cles and prevent their aggregation.8,9 Chemical methods such as
the reduction of transition metal salts are the most convenient
ways to deposit the metallic nanoparticles onto supports. A
literature survey shows that, in the presence of a suitable support,
Despite significant advances in the synthesis of palladium
nanoparticles, the development of special supports which are
cheap, non-hazardous, environmentally friendly and naturally
degradable remains a subject of scientific interest and of vital
industrial significance. One of the choices which may be efficient in
this theme is using bioorganic materials for supporting palladium
nanoparticles which are readily available in nature and are not
expensive.3 To expand the use of naturally occurring materials in
the synthesis of nanoparticles, we decided to search for bioorganic
polymers with a potential reducing ability. For this aim, we
have chosen gelatin as a bed for the synthesis of palladium
nanoparticles.
One of the most successful methods for the formation of a
sp–sp2 carbon–carbon bond is Sonogashira–Hagihara reaction.15
The traditional procedure for the Sonogashira–Hagihara reaction
employs a Pd-complex of phosphines as a catalyst and copper
iodide salt as a co-catalyst. However, using copper salts as
co-catalysts sometimes leads to the homo-coupling reaction of
terminal alkynes (Glaser-type reaction) upon exposure of the
copper-acetylide intermediate to air or other oxidizing agents.16
Therefore, numerous improved methodologies were reported to
eliminate the copper co-catalyst from the Sonogashira–Hagihara
reaction.17 For instance, the complex PdClMe(bisimidazole) has
been demonstrated to be an efficient and recoverable catalyst
for the reaction.18 A copper-free Sonogashira–Hagihara reaction
was reported for coupling of vinyl tosylates and alkynes using
the Pd(OAc)2/PPh3 catalytic system.19 The reaction was also
performed in the presence of heterogeneous palladium supported
on a zeolite surface.20 Moreover, there are some other reports
available in the literature in which the reaction has been performed
in the absence of any copper salts.21
Department of Chemistry, College of Sciences, Shiraz University, Shi-
raz, 71454, Iran. E-mail: firouzabadi@chem.susc.ac.ir, iranpoor@chem.
susc.ac.ir; Fax: +98 711 2280926; Tel: +98 711 2284822
† Electronic supplementary information (ESI) available: General experi-
mental details for starting materials and instruments and also elemental
analysis, spectral data of all compounds and literature references for known
compounds. See DOI: 10.1039/c0ob00253d
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of Pd(II) to Pd(0) by the disappearance of the peak at 420 nm8
(Fig. 1). The SEM image of the gelatin revealed the regularly
dispersed Pd-particles on the surface of the gelatin (Fig. 2) and its
TEM pictures showed the average size of the particles entrapped
in gelatin framework to be around 4–7 nm (Fig. 3 and Figure S1†).
The AFM image also showed and confirmed the regularity of the
deposited particles on the gelatin (Fig. 4).
Table 1 ICP analysis results to show the amounts of traces of metal salts
in gelatin
Metals
Cobalt
Copper
Iron
Nickel
Palladium
mmol of metals 1.96 ¥ 10-4 2.50 ¥ 10-4 4.71 ¥ 10-4 4.96 ¥ 10-4 1.31 ¥ 10-4
per 1 g of gelatin
Using palladium nanoparticles as catalyst in a Sonogashira–
Hagihara reaction in the ionic liquid [bmim]BF4 was reported in
the presence of triethyl amine as a base at ambient temperature
under ultrasonic irradiation.22 In this report, aryl iodides worked
well and the desired coupling products were obtained in high
isolated yields. In the case of aryl bromides, only activated ones
reacted to give the product in moderate yields. Reusable palladium
nanoparticles supported on PVP as a catalyst for Sonogashira–
Hagihara reaction of aryl halides and terminal acetylenes at 80 ◦C
is also reported.23
In addition, the homo-coupling of terminal acetylenes is an
important approach towards the synthesis of conjugated enynes
to form building blocks of biologically active compounds, natural
products, electronic and optical materials. A number of transition
metal complexes have been employed for alkyne dimerization
reactions.24 In the most reported protocols, a mixture of regio- and
stereoisomeric products were obtained. Selective reaction proceeds
only under carefully controlled conditions. For example, head to
head dimerization of phenylacetylene has been obtained selectively
3
when (h -allyl-PdCl)2 and TDMPP were used in the presence of
Et2NH.25
In order to advance the successful results obtained by using
TBAB as a solvent or additive in the Mizoroki–Heck reaction26
and Suzuki–Miyaura27 cross coupling, now we want to release our
results using molten TBAB and PEG as media and employing
gelatin supported nanoparticles of palladium as the catalyst for
a ligand- and amine-free Sonogashira–Hagihara reaction and
dimerization of phenylacetylene.
Fig. 1 UV-Vis spectra of (a) Pd(II) before reduction and (b) Pd(0) after
reduction with gelatin.
Results and discussion
In this study, we have used edible gelatin as a support and reductant
for palladium nanoparticles. Since gelatin is a natural product its
composition is variable, depending on the source and its treatment,
so we have first determined the water content and amount of
contamination of gelatin with traces of inorganic salts. The water
content in the gelatin sample used for this study was determined,
using the Karl-Fischer method, to be 0.08 ml of water per 1 gram
of gelatin. According to ICP analysis, there exist traces of cobalt,
copper, iron, nickel and palladium salts in the gelatin. The results
are presented in Table 1.
Fig. 2 SEM picture of the immobilized palladium nanoparticles on
The gelatin supported palladium nanoparticles were prepared
on a gram-scale by dissolving the above mentioned gelatin
(1 g) in water at room temperature. To the resulting solution,
PdCl2 (100mL, 1 mM) in water was added and refluxed for
five hours. The obtained dark-grey solution was cooled to room
temperature and evaporation of the solvent under air flow resulted
a dark green-greyish solid. Our initial efforts were focused on the
characterization of the resulting solid material, which would be
used as the catalyst in the further studies for C–C bond formation
. First, we established the oxidation state of Pd on the surface
of gelatin by UV-Vis spectra which confirmed the conversion
gelatin.
X-ray diffraction (XRD) analysis did not show any peaks
related to a crystalline structure, indicating that the particles are
amorphous and the usual fcc structure of palladium metal does
not exist in these particles.28 The amount of palladium content
deposited on the surface of gelatin was determined by ICP and
atomic absorption analysis to be 0.09 mmol of palladium per gram
of gelatin. This amount and also SEM, TEM and AFM pictures
show that the gelatin has a high capacity to entrap palladium in a
good quantity without bulk aggregation of the metal.
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Table 2 Optimization conditions in Sonogashira–Hagihara reaction between 1-bromo-4-nitrobenzene and phenylacetylene (2) in the presence of Pd-
nanoparticles at 100 ◦C under argon atmosphere
Entry
Solvent
Base
T/◦C
Time/h
Conversion (%)
1
2
3
4
5
6
7
8
H2O
H2O/TBAB
TBAB
TBAB
TBAB
none
TBAB
TBAB
TBAB
KOAc
KOAc
KOAc
NaOAc
none
KOAc
Cs2CO3
NaOH
NaOH
morpholine
KOAc
KOAc
NaOH
Et3N
NaOH
Cs2CO3
KOAc
nPr3N
KOAc
NaOH
Cs2CO3
100
100
100
100
100
100
100
100
120
100
80
100
100
100
100
100
100
100
100
100
100
24
24
2
22
70
100
100
18
40
100
—
34
100
87
100
trace
trace
13
—
—
9
100
11
5
24
24
7
24
24
7
24
19
24
24
24
24
24
12
2
9
10
11
12
13
14
15
16
17
18
19
20
21
TBAB
TBAB
DMSO
DMSO
DMSO
DMSO/H2O
DMSO/H2O
NMP
none
PEG400
PEG400
PEG400
24
24
—
solvents and bases as well as changing the reaction temperature
upon the reaction of 1-bromo-4-nitrobenzene with phenylacety-
lene as a benchmark. First, we tried to conduct the reaction
in aqueous media. As shown in Table 2, the catalyst was not
efficient when the reaction was performed in water using KOAc
as a base at 100 ◦C. Addition of TBAB (1 mmol) as a phase
transfer agent made a good impact on the progress of the reaction.
This observation motivated us to check TBAB as a reaction
medium in its melt form (100 ◦C) instead of water. Switching
the solvent from water to TBAB in combination with KOAc as
the base achieved complete conversion of the starting material
within 2 h. We also investigated the effect of different kinds of
bases in molten TBAB. For instance, in the presence of NaOAc,
Cs2CO3 and morpholine, 100% conversion of the starting material
within 5, 7 and 7 h, respectively, has been observed. To show the
merit of the molten TBAB/KOAc system, we left out TBAB or
KOAc periodically from the reaction media. The reaction in the
absence of KOAc gave only 18% conversion after 24 h and when
TBAB was omitted from the reaction mixture, 40% conversion
of the starting material was observed by GC after the same
reaction time. A similar reaction was also studied in DMSO at
100 ◦C using different bases. The results of this study showed that
KOAc was also the most proper base for the reaction of 1-bromo-
4-nitrobenzene with phenylacetylene in DMSO which gave the
desired product in 100% conversion (GC) within 19 h. We have
also used NMP as a solvent in the presence of KOAc for the similar
reaction, which was not successful at all. In order to expand our
studies, we conducted a model reaction in polyethylene glycol
(PEG400). We observed that PEG400 was also a suitable medium
for the reaction in the presence of KOAc as a base to complete the
reaction within 2 h.
Fig. 3 TEM picture of the supported palladium nanoparticles on gelatin.
Fig. 4 3D AFM image of the gelatin-supported palladium nanoparticles.
In order to show the merit of gelatin supported palladium
nanoparticles as a catalyst in organic synthesis, we first applied the
gelatin loaded palladium for important Sonogashira–Hagihara
reaction.
Preliminary screening to compare different systems in the
Sonogashira–Hagihara reaction was performed by using different
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As shown in Table 3, a range of aryl iodides, bromides
and chlorides reacted with phenylacetylene to give the desired
products in high yields. As expected, the reaction of aryl iodides
bearing electron donating groups went to completion in longer
reaction times (Table 3, Entries 2, 3). Also, ortho-substituted aryl
iodides reacted in longer reaction times (Table 3, Entries 4, 5). 1-
Iodo naphthalene 1g, reacted smoothly to give the desired product
in 88% conversion within 5 h in molten TBAB while, when the
reaction was conducted in PEG400 at 100 ◦C, the desired product
was obtained in 90% isolated yield within 5.5 h (Table 3, Entry
7). The coupling reaction of sterically hindered iodomesitylene 1f,
did not give the product even after 24 h and the starting materials
remained intact in these reaction conditions showing the strong
effect of steric hindrance in this reaction (Table 3, Entry 6). The
coupling reaction of phenylacetylene with both electron-releasing
and electron-withdrawing aryl bromides afforded products in
high yields. Heterocyclic bromides such as 3-bromopyridine, 5-
bromopyrimidine and 3-bromothiophene led to the corresponding
bi-functionalized acetylene in desirable yields (Table 3, Entries
12–14). The catalytic system effect was also manifested for the
reaction of aryl chlorides with phenylacetylene. In these cases,
prolonged reaction times to 24 h were required to give the expected
products in good yields (Table 3, Entries 15–17). We also made an
effort to activate the strong C–F bond and study the coupling
reaction of aryl fluorides. Unfortunately, the reaction of 2,4-
dinitro-fluorobenzene with phenylacetylene failed. However, the
starting material of 2,4-dinitro-fluorobenzene was consumed and a
mixture of unidentified products was observed by TLC. In order to
show the wide applicability of our catalytic system, we applied our
protocol for the reaction of b-bromostyrene, a vinylic bromide, and
phenylacetylene under similar reaction conditions. The reaction
proceeded well within 15 h (70%) in molten TBAB and 17 h (61%)
in PEG400 (Scheme 1).
Scheme 2 Dimerization of phenylacetylene catalyzed by Pd-nanoparti-
cles supported on gelatin.
and reused three times which was accompanied by the loss of
its catalytic activity. According to ICP analysis, 31% leaching of
the catalyst into molten TBAB was observed after the third run.
SEM pictures of the recovered palladium nanoparticles after the
first and the second runs showed aggregation of the metal particles
(Fig. 5). However, when this catalyst is used for the similar reaction
in PEG400, the leaching of the catalyst into PEG400 was reduced
drastically to 12% after the third run, which was determined by
ICP analysis. We believe that the strong ionic character of molten
TBAB can easily remove the particles of Pd from the surface of
gelatin. The results are summarized in Table 4.
Scheme 1 Coupling reaction of b-bromostyrene with phenylacetylene
catalyzed by Pd-nanoparticles supported on gelatin.
We have also investigated the homocoupling reaction of pheny-
lacetylene as a model compound in the air under ligand- and
amine-free conditions in molten TBAB which resulted the homo-
coupled product in 75% isolated yield at 100 ◦C in 6 h. Similar
reaction in PEG 400 at 100 ◦C gave the desired product in
70% isolated yield in 8 h. As it is evident from 1H NMR of
the products, the reaction in both media proceeded with high
regio-and stereoselectivity producing the homo-coupled E-enyne
product (Scheme 2).
The recoverability of the catalyst was examined for the reaction
of 1-bromo-4-nitrobenzene with phenylacetylene. After comple-
tion of the reaction, the mixture was cooled to room temperature
and EtOAc was added to the reaction mixture. Addition of EtOAc
dissolves organic materials and TBAB as well, and the gelatin-
based catalyst remains intact at the bottom of the vessel. This was
employed for the subsequent reaction. This catalyst was recycled
Fig. 5 SEM pictures of the recovered Pd-nanoparticles supported on
gelatin after the reaction of 1-bromo-4-nitrobenzene with phenylacetylene
in TBAB (a) after the first run, (b) after the second run.
Conclusions
In conclusion, we have described a clean, eco-friendly and green
one-pot method to synthesize uniform nanoparticles supported
on gelatin as a cheap and available protein without using any
special reducing agents, in water. The synthesized palladium
nanoparticles were characterized using SEM, TEM, AFM, ICP,
UV-Vis and atomic absorption techniques. These particles showed
excellent catalytic activities in a Sonogashira–Hagihara reaction of
various aryl iodides, bromides and chlorides as well as heteroaryl
868 | Org. Biomol. Chem., 2011, 9, 865–871
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Table 3 Sonogashira-Hagihara reaction of aryl halides with phenylacetylene in the presence of Pd-nanoparticles in molten TBAB or PEG400 under Ar
atmosphere
Entry
1
Aryl halide
Product
Time/ha
Isolated Yield (%)a
90 (94)
45 min (1)
2
3
4
4.5 (5)
85 (80)
93 (93)
93 (91)
1.25 (1.5)
4 (4.25)
5
6
2 (2)
90 (91)
24
—
7
5 (5.5)
88 (90)
8
9
5.5 (6)
6 (6.5)
80 (74)
75 (72)
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Table 3 (Contd.)
Entry
10
Aryl halide
Product
Time/ha
2 (2)
Isolated Yield (%)a
81 (85)
11
12
13
14
24 (24)
2 (2.25)
8 (9)
80 (78)
77 (75)
75 (74)
81 (75)
21 (24)
15
16
24 (24)
24 (24)
74 (53)
70 (58)
17
18
24 (24)
60 (60)
Mixture of unidentified products
24
Starting material
was consumed
a The data indicated in parentheses refer to the reactions conducted in PEG400
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Table 4 Recycling of Pd-nanoparticles supported on gelatin for the
After completion of the reaction in the first run, ethyl acetate
(5 ¥ 10 ml) was added to the reaction mixture to extract the organic
compounds. The ethyl acetate solution was removed by filtration
and the catalyst, which is insoluble in ethyl acetate, was dried under
nitrogen flow. After complete drying, the catalyst was charged
again into the vessel containing starting materials and the reaction
was performed under the same conditions.
reaction of 1-bromo-4-nitrobenzene with phenylacetylene
Run
1a
2a
3a
Typical procedure for dimerization of phenylacetylene catalyzed
by palladium nanoparticles supported on gelatin:
Time for completion
of the reaction/h
2 (2)
6 (5)
15 (8)
Phenylacetylene (2 mmol) was added to a flask containing Pd-
nanoparticles (0.05 g of the catalyst) and KOAc (1.5 mmol) in
the presence of tetrabutyl ammonium bromide (TBAB) (1 g) as
solvent. The mixture was stirred at 100 ◦C under air atmosphere.
After completion of the reaction (monitored by TLC) the products
were isolated by column chromatography. Evaporation of the
solvent gave the desired pure product in high yield.
a The data shown in parentheses refer to the reaction times in PEG400
bromides with phenylacetylene in molten salt of TBAB or PEG400
in the presence of KOAc as base at 100 ◦C. We have also presented
the catalytic activity of the catalyst upon a dimerization reaction of
phenylacetylene as a model compound. The catalyst can be easily
recovered and recycled for at least three runs in the reaction. This
catalytic system is also suitable for large-scale operations.
Notes and references
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The authors are thankful to TWAS Chapter of Iran based at
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General procedure for Sonogashira-Hagihara reaction catalyzed by
palladium nanoparticles supported on gelatin in TBAB:
Aryl halide (1 mmol) and terminal acetylene (2 mmol) were
added to a flask containing Pd-nanoparticles (0.05 g of the
catalyst) and KOAc (1.5 mmol) in the presence of tetrabutyl
ammonium bromide (TBAB) (1 g) as solvent. The mixture was
stirred at 100 ◦C under argon atmosphere. After completion of the
reaction (monitored by TLC or GC) the products were isolated
by column chromatography. Evaporation of the solvent gave the
desired pure products in high yields.
General procedure for Sonogashira-Hagihara reaction catalyzed
by palladium nanoparticles supported on gelatin in PEG400:
Aryl halide (1 mmol) and terminal acetylene (2 mmol) were
added to a flask containing Pd-nanoparticles (0.05 g of the
catalyst) and KOAc (1.5 mmol) in the presence of polyethylene
glycol 400 (PEG400) (2 ml) as solvent. The mixture was stirred at
100 ◦C under argon atmosphere. After completion of the reaction
(monitored by TLC or GC) water (10 ml) and ethyl acetate (10 ml)
was added to the reaction mixture and decanted and the products
were purified by column chromatography. Evaporation of the
solvent gave the desired pure products in high yields.
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Large-scale Sonogashira-Hagihara reaction catalyzed by palla-
dium nanoparticles supported on gelatin in TBAB:
1-bromo-4-nitrobenzene (5 mmol) and phenylacetylene
(8 mmol) were added to a flask containing Pd-nanoparticles (0.3 g
of the catalyst) and KOAc (7 mmol) in the presence of tetrabutyl
ammonium bromide (TBAB) (4 g) as solvent. The mixture was
stirred at 100 ◦C under argon atmosphere for 3 h. After completion
of the reaction (monitored by TLC) the products were isolated
by column chromatography. Evaporation of the solvent gave the
desired pure products in 75% yield.
Reusability of the catalyst:
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