Gallic acid-derived palladium(0) nanoparticles as in situ-formed catalyst for Sonogashira cross-coupling reaction in ethanol under open air

Article abstract of DOI:10.1016/j.catcom.2016.10.034

A simple and eco-friendly protocol using gallic acid-derived palladium(0) nanoparticles as in situ-formed catalyst for Sonogashira reactions in ethanol under optimum thermal conditions have been developed. Excellent yields were obtained with the addition of a small amount of gallic acid (1 mol%) to the reaction mixture. The formation of the PdNPs was confirmed by using UV/Vis spectroscopy, and their size and morphology were determined by TEM and XRD analysis. Both aliphatic and aromatic terminal alkynes displayed efficient reactivity with the catalytic system. Moreover, the reaction condition is highly compatible with less reactive aryl bromides at moderate temperature, and further can be reused repeatedly up to four cycles. Since gallic acid is a non-toxic naturally abundant phytochemical, the present method provides an efficient alternative route for Sonogashira reaction with natural feedstock as additive.

Full text of DOI:10.1016/j.catcom.2016.10.034

Gallic acid-derived palladium(0) nanoparticles as in situ-formed catalyst for
Sonogashira cross-coupling reaction in ethanol under open air
Manashi Sarmah, Manoj Mondal, Shivanee Borpatra Gohain, Utpal Bora
PII:
DOI:
Reference:
S1566-7367(16)30408-3
doi:10.1016/j.catcom.2016.10.034
CATCOM 4839
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
14 August 2016
27 October 2016
28 October 2016
Please cite this article as: Manashi Sarmah, Manoj Mondal, Shivanee Borpatra Gohain,
Utpal Bora, Gallic acid-derived palladium(0) nanoparticles as in situ-formed catalyst for
Sonogashira cross-coupling reaction in ethanol under open air, Catalysis Communications
(2016), doi:10.1016/j.catcom.2016.10.034
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ACCEPTED MANUSCRIPT
Gallic acid-derived palladium(0) nanoparticles as in situ-formed catalyst for
Sonogashira cross-coupling reaction in ethanol under open air
Manashi Sarmah,a Manoj Mondal,b Shivanee Borpatra Gohaina and Utpal Bora*a
a Department of Chemical Sciences, Tezpur University, Tezpur 784 028, Assam, India
b Department of Chemistry, Dibrugarh University, Dibrugarh 786 004, Assam, India
E-mail: utbora@yahoo.co.in; ubora@tezu.ernet.in
Abstract
A simple and eco-friendly protocol using gallic acid-derived palladium(0) nanoparticles as in situ-
formed catalyst for Sonogashira reactions in ethanol under optimum thermal conditions have been
developed. Excellent yields were obtained with the addition of a small amount of gallic acid (1 mol
%) to the reaction mixture. The formation of the PdNPs was confirmed by using UV/Vis
spectroscopy, and their size and morphology were determined by TEM and XRD analysis. Both
aliphatic and aromatic terminal alkynes displayed efficient reactivity with the catalytic system.
Moreover, the reaction condition is highly compatible with less reactive aryl bromides at moderate
temperature, further can be reused repeatedly up to four recycles. Since gallic acid is a non-toxic
naturally abundant phytochemical, the present method provides an efficient alternative route for
Sonogashira reaction with natural feedstock as additive.
Keywords: Sonogashira coupling, palladium nanoparticle, gallic acid, ligandfree, ethanol, air,
1. Introduction
The C-C triple bond of alkynes occurs in various molecules of biochemistry and material sciences and
is one of the most ideal functional group for the synthesis of significant and versatile organic
molecules [1,2]. The Pd/Cu-catalyzed Csp2-Csp Sonogashira coupling of aryl halides with terminal
acetylene is one of the most powerful tool to prepare these functionalized alkyne derivatives [3,4].
Since its discovery, most of the catalyst systems for these transformation are composed of Pd(0) or
Pd(II) derivatives associated with various ligands such as phosphanes [5], amines [6], NHC [7], salen
[8], hydrazone [9], pyrimidine [10], ligand-free [11] and also with salt additives [12] in organic
medium or solvent-less [5], using excess amount of base [13]. These developments have
significantly reduced the use of toxic and volatile solvents and stoichiometric amount of reagent.
However, the prime drawback still associated with Sonogashira reaction is the formation of side-
products due to homo-coupling of terminal alkynes in the presence of copper salts or at high
temperature [14] or in air (Glaser coupling [15] or Hay coupling [16]). This hampers isolation and
purification processes of the desired products due to similar chromatographic mobility [17]. Thus,
the designs of ideal synthetic protocol to remove these drawbacks are prime necessity of present
development.
Literature reports reveals that copper acetylide undergoes homo-coupling in air or O2 [16, 18], or
in some cases inhibits the cross-coupling reaction [19]. By careful selection, Ho et al. have found that

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the Sonogashira reaction proceeds more efficiently in an atmosphere of hydrogen gas diluted with
nitrogen or argon [20]. Under this condition the side product due to terminal acetylene (homo-
coupling) can be reduced to nearly 2%. Although, the exact role of hydrogen was not known, it was
assumed that it may reduces O2 in the presence of nascent Pd(0) [21] to form water and decreases its
concentration during the reaction. Thus, a reducing atmosphere which controls the excessive
paramagnetic oxygen may lower the acetylene homodimers to enhance cross-coupling [22].
Therefore, a high level of efficiency could be achieved by using preformed Pd(0) catalyst, or more
precisely a Pd(0) nanoparticle (PdNPs) as catalyst [23]. However in majority of cases, synthesis of
PdNPs requires high temperature, sonication and additional stabilizer, thereby making the process
tedious and lengthy [24]. The development of process to prepare PdNPs in minimum step with
reducing agent from renewable source has emerged to be the growing interest as it serves to be green
and eco-friendly alternative with least chemical waste.
Gallic acid is an inexpensive antioxidant commonly found in considerable amounts in bio-wastes
such as grape pomace or oak bark and gallnuts etc [25]. Recently, Yun et al.[26] have reported the
preparation of Pd(0) nanoparticle from Pd(II) using gallic acid as both reducing and stabilizing agent.
Recently, we have reported the gallic acid derived PdNPs-catalyzed Suzuki-Miyaura cross-coupling
of aryl halides and arylboronic acid [27]. This led us to develop a mild and efficient Sonogashira
protocol for the coupling of aryl halides with terminal alkynes to fulfill our objective of safe reaction
strategy.
2. Experimental
2.1. Catalytic Sonogashira Reaction
In a 50 ml round bottom flask, a mixture of aryl halide (0.5 mmol), terminal alkyne (0.65 mmol),
Pd(OAc)2 (1 mol%), gallic acid (1 mol%) and K2CO3 (1.5 mmol) in 4 ml EtOH was stirred at 40 °C.
After completion (vide TLC); the reaction mixture was diluted with H2O and extracted with ethyl
acetate (3×10 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (eluent: Hexane) to give corresponding functionalized alkyne. Purity of
isolated product was confirmed by comparing 1H, 13C NMR data with authentic compounds.
3. Results and Discussion
At the onset, to examine the effectiveness of gallic acid in Sonogashira reaction, we performed
the reaction using 4-iodonitrobenzene, phenylacetylene, K2CO3 and Pd(OAc)2 (1 mol%) with gallic
acid (1 mol%) in ethanol (Table 1). Initial investigation at room temperature (ca. 27 °C) proceeds
with the formation of 85% isolated product. However, on increasing the temperature to 40 °C, the
reaction proceeds to completion and 95% coupling product was isolated (Table 1, entry 1-2). By
lowering the Pd loading to 0.5 mol% poor conversion, even on increasing the reaction time up to 7 h,
was observed (Table 1, entry 3). Optimization results showed nearly a quantitative formation of the

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cross-coupling product with equimolar loading of Pd(OAc)2 and gallic acid (i.e. 1 mol%) under an
environmentally preferred alcoholic reaction medium (Table 1, entry 2). On using higher gallic acid
loading the reaction progress decreases significantly (Table 1, entries 5-6). High gallic acid loading
prevents the increase in the size of PdNPs, because excess reducing agent diminishes the Ostwald
ripening process [28, 29] by capping most of the free Pd surface sites and lowers the accessibility of
the Pd particle at the surface for catalysis. When the reaction was performed without Pd(OAc)2-gallic
acid or base or with gallic acid without Pd(OAc)2 no conversion was noticed, signifying the role of the
catalyst and added base (Table 1, entries 7-9). The reaction gives low yield in the absence of gallic
acid or with PdCl2 (Table 1, entries 10 and 11). The lower activity with PdCl2 could be due to
different coordinating ability of anions to the nanoparticle surface [30]. The weak coordination of
chloride ion to Pd compared to acetate ion decreases the stability of PdNPs. This enhances the rate of
palladium leaching and thus lowers the reaction activity. It is noteworthy to mention here that the
preformed PdNPs also deliver identical reactivity (Table 1, entry 12).
Table 1
Screening of catalytic effect on Sonogashira couplinga
Entry
1
Catalyst (mol%)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (0.5)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
-
Gallic acid (mol%)
Time (h)
Yield (%)b
1
1
5
5
85c
95
60
50
65
50
-
2
3
1
7
4
0.5
2
12
7
5
6
5
7
7
-
24
24
24
12
6
d
8
Pd(OAc)2 (1)
-
1
-
9
1
-
10
11
12
Pd(OAc)2 (1)
PdCl2 (1)
PdNPs (preformed)
-
50
70
93
1
5
a Reaction conditions: 4-nitroiodobenzene (0.5 mmol), phenylacetylene (0.75 mmol), K2CO3 (1.5 mmol), EtOH
(4 ml) at 40 °C. b Isolated yield, c at r.t. (ca 27 °C), d without base.
Next, we investigated the effect of different solvents on catalytic efficiency (Table 2) and the reaction
proceeds efficiently in EtOH providing excellent isolated yield. This is in consistent with our earlier
report on Sonogashira coupling [31]. The catalytic activity of the in situ catalyst was studied in water
to follow green chemistry approach. However, catalytic efficiency decrease drastically in water and in
aqueous alcohol (1:1) and lower yields were obtained upon prolonged reaction time (Table 2, entries
1-3). This discrepancy is may be due to the poor interactions between the low-polar reactants and
active catalyst, which may form clusters during the reaction. Since, a well chosen base is often
significant for the success of the cross-coupling reaction; we next studied the role of a number of
bases under optimized reaction condition for a more improve coupling condition (Table 2). Upon

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optimizing the reaction, best result was obtained in ethanol at 40 °C with Pd(OAc)2 (1 mol%) and
gallic acid (1 mol%) using Cs2CO3 (2 equiv.) within 3 h (Table 1, entry 9).
Table 2
Screening the solvent and base.a
Entry
Solvent
H2O
EtOH/H2O
iPrOH/H2O
EtOH
Base (mmol)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1)
Time(h)
Yield (%)b
1
2
3
4
5
6
7
8
9
23
12
12
5
6
6
9
6
3
7
50
60
50
95
60
85
40
40
97
30
40
EtOH
EtOH
iPrOH
EtOH
EtOH
K2CO3 (2)
K2CO3 (1.5)
NaOAc (1.5)
Cs2CO3 (1)
NaOH (1.5)
Na2CO3
10
11
EtOH
EtOH
8
a Reaction conditions: 4-nitroiodobenzene (0.5 mmol), phenylacetylene (0.65 mmol), Pd(OAc)2 (1 mol%), gallic
acid (1 mol%), solvent (4 mL) at 40 °C. b Isolated yield.
Finally, to probe the scope of the catalytic system, using our standard conditions, we have evaluated
various aryl halides and terminal alkynes (Table 3). The reaction system is compatible with a wide
array of electronically diverse substituents. When investigating the influence of the nature of the
halide (entries 1-5) as predicted a slight decrease in conversion was observed when going from iodide
to bromide. In case of bromide, an increase in the reaction temperature improves the conversion with
low reaction time. However, substitution at para-position drastically lowers the reaction yield even
when the reaction time was increased to 6 h (Table 3, entries 3-5). Using substituted aryl iodide as
substrate we evaluated coupling with various acetylene (Table 3, entries 6-17). Aryl iodides
possessing an electron withdrawing group (e.g. NO2) at para- or meta-position affords improved yield
on coupling with phenyl acetylene (Table 3, entry 1 and 6). Conversions were always complete for
para- and meta-substituted derivatives (Table 3, entries 1 and 6-10), but decreased efficiency was
observed for 2-iodonitrobenzene, probably due to steric hindrance (Table 3, entry 13). The
effectiveness of the present protocol was also studied for aliphatic alkynes, and to our delight
moderate to high yield of cross-coupling products was observed in all cases (Table 3, entry 14-17).
Moreover, the catalytic system also worked well with the coupling of 3-iodopyridine under present
reaction conditions (Table 3, entry 18).
Table 3
Substrate scope of Sonogashira coupling a
Entry
1
X
I
R1
R2
Time(h)
3
Yield(%)b
97
4-NO2
C6H5

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2
Br
Br
Br
Br
I
I
I
I
I
I
I
I
I
I
I
I
I
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
7
4
6
6
4
3
4
4
4
3
5
8
5
5
5
5
12
70
95
80
65
92
98
95
95
80
98
97
40
80
85
90
80
90
3c
4c
5c
6
4-CH3
4-NO2
3-NO2
4-Me
4-Me
3-Me
4-OMe
H
H
2-NO2
H
H
H
7
8
9
C6H5
4-MeC6H4
C6H5
C6H5
C6H5
4-MeC6H4
C6H5
n-octyl
n-butyl
cyclohexyl
n-butyl
C6H5
10
11
12
13
14
15
16
17
18
4-Me
3-iodopyridine
a Reaction conditions: aryl halide (0.5 mmol), acetylene (0.65 mmol), Pd(OAc)2 (1 mol%), gallic acid (1 mol%),
Cs2CO3 (1 mmol), EtOH (4 mL) at rt. b Isolated yield, c at 60 °C
It is well established from the literature that well dispersed PdNPs are formed from Pd(II) with gallic
acid wherein gallic acid acts as both reductant and stabilizer [26]. In order to further clarify the active
species in the present Sonogashira reaction, transmission electron microscope (TEM) was used for the
analysis of the size and distribution of PdNPs. TEM images showed that the PdNPs were well
fabricated and are average dimension of the spherical particles (mean diameter 13.7 nm) after
completion of the reaction (Figure S1, see ESI†). This stabilization of PdNPs by gallic acid is
thought to be due to the high anionic charge of the gallate ions [32, 33]. Thus, it is obvious that the
active catalytic species of the reaction is the in situ formed PdNPs. To identify the true active catalytic
species, we performed the mercury-poisoning test [34, 35] For this, gallic acid and Pd(OAc)2 were
.
stirred in ethanol containing Cs2CO3 and excess of Hg(0) (molar ratio to [Pd] ~400) for 30 min prior
to addition of the reacting substrates. After 3 hours of adding the reactants, negligible amount of
coupling product formation was observed. This suggested that the PdNPs is acting as a true
heterogeneous catalyst, and the reaction is occurring on the molecular surface. To further verify the
reducing role of gallic acid in the formation of PdNPs, we have prepared PdNPs using gallic acid and
Pd(OAc)2 without adding the substrates. For this, Pd(OAc)2 (5 mg) and gallic acid (5 mg) were mixed
in EtOH (4 mL) at room temperature under aerobic conditions. Instant change in colour of the
resulting solution from orange to black indicates the reduction of Pd(II) ions to Pd(0). In UV/Vis
analysis, the disappearance of a peak at 281 nm, due to Pd(OAc)2, confirms the reduction of Pd(II)
ions to Pd(0). Moreover, appearance of a characteristic absorption peak at 361 nm attributes the
formation of Pd(0) particles (Figure S3-S4, see ESI†). Powder X-ray diffraction (PXRD)
measurements of the black palladium particles were consistent with the formation of Pd(0) clusters,
and matches well with the standard XRD database (JCPDS card no. 89-4897). The diffraction peak
observed at 40.11°, 46.66° and 68.12° corresponds to the crystal plane (111), (200), (220) reflections,

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respectively (Figure S5, see ESI†). The reduction of Pd(II) ions was further confirmed by the
appearance of significant vibration bands in the FT-IR spectrum (Figure S6, see ESI†). The
observation of a peak at 1664 cm-1 and the disappearance of vibrational peaks at 1602 cm-1 (due to Pd-
O), 1570 cm-1 (due to the C=O) and 1424 cm-1 (due to acetate) signifies the perfect interaction
between gallic acid and Pd(II) ions. These data are consistent with the literature reports [26] and
confirms the reducing-capping role of gallic acid in the formation mono-sized PdNPs.
From the green chemistry viewpoint, the major challenge of a metal catalysis is its ability for
recycling. The reusability of the PdNPs was investigated by consecutive Sonogashira coupling
reactions of iodobenzene and phenylacetylene. After the first catalytic cycle, the reaction mixture was
extracted with ethyl acetate and centrifuged and the organic fraction was removed for purification and
the recovered residue was directly used for further catalytic cycle by the addition of fresh reactants.
Identical results were obtained upto 2nd run, thereafter the yields gets slightly decrease in 3rd and 4th
cycles (Table S1, see ESI†). TEM image showed that the size of nanoparticles get reduced (mean
diameter 4.7 nm) after 2nd cycle (Figure S2, see ESI†). This could be due to the aggregation and
precipitation of the large sized nanoparticles, which leaves smaller nanoparticles in solution [29]. This
decrease of active particles from the surface may lowered the catalytic activity of the coupling
reaction. Moreover, the accumulation of salt byproducts during the successive catalyst recycling may
also lower the catalytic efficiency.[27] To ensure reproducibility for practical industrial applications,
we performed a large scale Sonogashira coupling with 10 mmol 4-iodonitrobenzene loading. The
cross-coupling preceded smoothly giving 99% isolated yield of the desired product. In contrast to the
earlier reported methods on PdNPs, these results are superior in terms of palladium loading, reactions
conditions and yields (see Table S2, ESI†).
4. Conclusion
In conclusion, a simple, efficient and sustainable method for the use of gallic acid-derived PdNPs
in the Sonogashira reaction between aryl halides and terminal acetylene derivatives was developed.
The in situ formed spherical PdNPs showed excellent catalytic activities in ethanol, under aerobic
conditions, with low catalyst loading (1 mol% Pd) with four times recyclability. Overall, good to
excellent yields were achieved with various electronically diverse substrates under optimum thermal
conditions. The catalytic system is easily accessible, environmentally benign and avoids the use of
unfavorable ligands and toxic solvent.
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Highlights
1. Gallic acid derived in situ PdNPs is developed as reusable catalyst for Sonogashira
reactions.
2. Natural feedstock is used as additive
3. The catalyst is easily accessible, mild and avoids use of unfavorable ligands and toxic solvent
4. The new catalyst is effective for diverse range aryl halides and terminal acetylenes