An insight into the novel covalent functionalization of multi-wall carbon nanotubes with pseudopeptide backbones for palladium nanoparticles immobilization: A versatile catalyst towards diverse cross-coupling reactions in bio-based solvents

Article abstract of DOI:10.1016/j.poly.2019.114238

Materials functionalization with multicomponent reactions (MCRs) has grabbed a lot of attention nowadays due to the integration of outstanding features of MCRs with materials domains. Herein, we put the spotlight on the isocyanides and Meldrum's acid-based MCRs route for the one-pot covalent functionalization of multi-wall carbon nanotubes (MWCNTs) which led to pseudopeptide-decorated MWCNTs with the ability to immobilized palladium nanoparticles and serve as a neoteric catalytic system. Characterization of the synthesized nanocatalyst was carried out by FT-IR, ¹H NMR, XRD, SEM, TEM, EDX and TGA. The catalytic activities of the nanocatalyst for diverse carbon-carbon cross-coupling reactions were examined in bio-based solvents. The results showed the catalytic performance of the nanocatalyst for the formation of Csp²-Csp², Csp-Csp² and Csp-Csp bonds through homocoupling and intermolecular Ullmann, C[sbnd]H arylation, Mizoroki-Heck, Sonogashira and Glaser coupling reactions with considerable improvements in the yield, reaction times, bio-based media and chemoselectivity of the procedures. Additionally, this method demonstrated a high potential for recycling of heterogeneous catalysts by maintaining their initial performances without any evidence of the Pd leaching.

Full text of DOI:10.1016/j.poly.2019.114238

Journal Pre-proofs
An insight into the novel covalent functionalization of multi-wall carbon nano-
tubes with pseudopeptide backbones for palladium nanoparticles immobiliza-
tion: A versatile catalyst towards diverse cross-coupling reactions in bio-based
solvents
Ronak Afshari, Seyyed Emad Hooshmand, Mojtaba Atharnezhad, Ahmad
Shaabani
PII:
S0277-5387(19)30683-7
DOI:
https://doi.org/10.1016/j.poly.2019.114238
POLY 114238
Reference:
Polyhedron
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 July 2019
29 September 2019
3 November 2019
Please cite this article as: R. Afshari, S. Emad Hooshmand, M. Atharnezhad, A. Shaabani, An insight into the novel
covalent functionalization of multi-wall carbon nanotubes with pseudopeptide backbones for palladium
nanoparticles immobilization: A versatile catalyst towards diverse cross-coupling reactions in bio-based solvents,
Polyhedron (2019), doi: https://doi.org/10.1016/j.poly.2019.114238
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An insight into the novel covalent functionalization of multi-wall
carbon nanotubes with pseudopeptide backbones for palladium
nanoparticles immobilization: A versatile catalyst towards diverse
cross-coupling reactions in bio-based solvents
Ronak Afshari, Seyyed Emad Hooshmand, Mojtaba Atharnezhad and Ahmad Shaabani
Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran
 Corresponding author. Tel.: +982129902800; e-mail: a-shaabani@sbu.ac.ir
Abstract:
Materials functionalization with multicomponent reactions (MCRs) has grabbed a lot of attention
nowadays due to the integration of outstanding features of MCRs with materials domains.
Herein, we put the spotlight on the isocyanides and Meldrum’s acid-based MCRs route for the
one-pot covalent functionalization of multi-wall carbon nanotubes (MWCNTs) which led to
pseudopeptide-decorated MWCNTs with the ability to immobilized palladium nanoparticles and
serve as a neoteric catalytic system. Characterization of the synthesized nanocatalyst was carried
1
out by FT-IR, H NMR, XRD, SEM, TEM, EDX and TGA. The catalytic activities of the
nanocatalyst for diverse carbon-carbon cross-coupling reactions were examined in bio-based
solvents. The results showed the catalytic performance of the nanocatalyst for the formation of
Csp2-Csp2, Csp-Csp2 and Csp-Csp bonds through homocoupling and intermolecular Ullmann, C–

H arylation, Mizoroki-Heck, Sonogashira and Glaser coupling reactions with considerable
improvements in the yield, reaction times, bio-based media and chemoselectivity of the
procedures. Additionally, this method demonstrated a high potential for recycling of
heterogeneous catalysts by maintaining their initial performances without any evidence of the Pd
leaching.
Keywords: Heterogeneous catalyst, Multi-wall carbon nanotube, Palladium nanoparticles,
Cross-Coupling Reactions, Multicomponent reaction, Green media

1.
Introduction
Nanoscience and nanotechnology are not merely the forefront of modern research, promoting the
unification of most branches of science and technology, based on the unity of nature at the
nanoscale.1,2 From the philosophical perspective, the unity and convergence of different sciences
make it possible to combine the advantages of diverse fields without restrictions which caused to
create neoteric approaches. One of the emerging fields, based on this idea, is functionalization of
materials with multicomponent reactions (MCRs) that critically reviewed by our research group
in 2018 and reverberated the breakthroughs throughout this field.3 Functionalization of materials
with MCRs have grabbed the attention of many researchers in recent years than any other
category of emerging functionalization methods because of their rapid improvements and
outstanding features of MCRs. MCRs strategy caused to highly efficient organic motifs that
covalently attached on the surface of the materials in a one-pot manner that can be likened to
strength feathers of a bird, and, as we know, “Fine feathers make fine birds”.
As a consequence of the convergence of carbonaceous materials science and MCRs, highly
applicable functionalized-nanomaterials have been synthesized with the potential to serve in
modern technologies such as enzyme immobilization,4 genes and drug delivery,5,6
photosensitizer7 and a rare but superb combination for catalysis.8 An urgent task, then, is to find
new MCRs for the rational design of efficient ligands covalently attached on the surface of the
carbonaceous materials that can immobilize metal nanoparticles for catalyzing the organic
transformations.

Palladium-catalyzed coupling reactions comprise a family of cross-coupling reactions that
employ palladium complexes or nanoparticles as catalysts.9–12 The C–C cross-coupling reactions
have become truly fundamental routes in organic, medicinal, and supramolecular chemistry,
natural product synthesis, materials and polymer science, and also in catalysis.13,14 The award of
the Nobel Prize in Chemistry for 2010 to scientists in this context15–17 and also the existence of
various books and review articles in recent years are a testimony to the outstanding contribution
of cross-coupling reactions. A well-known coupling is a Mizoroki-Heck reaction, which
constitutes the interaction of unsaturated halides and alkenes to form substituted alkenes and also
even polymeric structure.18 The other important ones such as Glaser, Sonogashira, Ullmann,
Suzuki–Miyaura, Stille, and Buchwald–Hartwig are among the predominantly used reactions that
are catalyzed by metals.19–21 Notably, the role of the ligand in the Pd-catalyzed procedures,
especially those involving Pd0 catalysis, is significant. These ligands not only stabilize the Pd
center in the required oxidation states but caused to availability and therefore more reactivity of
the metal center.22
Our ongoing interest in the design of neoteric catalytic systems,23–25 also the tremendous utility
of Pd-catalyzed C-C cross-coupling reactions, prompted us for the design and preparation of the
neoteric catalyst through immobilization of Pd nanoparticles on the MCRs-functionalized multi-
wall carbon nanotube (MWCNT). This article examines the extraordinary empirical application
of single-pot isocyanide and Meldrum’s acid-based multicomponent reaction for the covalent
MWCNT functionalization that has caused a revival of the unity idea and presents the applicable
pseudopeptide scaffolds with the ability to immobilized palladium nanoparticles for the diverse
carbon-carbon cross-coupling reactions under sustainable conditions.
2.
Experimental

2.1
Materials and methods
MWCNTs (purity>95%, outer diameter: 10–20 nm, inner diameter: 5–10 nm, length: 30 mm,
special surface area: 220 m2 g-1) was purchased from Atoor Sanat Abtin, Tehran, Iran. The other
materials were purchased from Merck and Aldrich and used without further purification. Fourier
transform infrared (FT-IR) spectrum was recorded on a Shimadzu IR-470 spectrometer.
Thermogravimetric analysis (TGA) was carried out using NETZSCH TG 209 F1 Iris system at a
heating rate of 10 °C min−1 in a nitrogen flow. Field emission scanning electron microscopy (FE-
SEM) observations were carried out on an electron microscopy Philips XL-30 ESEM.
Transmission electron microscopy (TEM) was performed using a transmission microscope
(Philips CM30) with an accelerating voltage of 150 kV. Varian 3900 GC was used for hot
filtration test analyzing. Palladium determination was carried out on a FAAS (Shimadzu model
AA-680 flame atomic absorption spectrometer (AAS) with a Pd hollow cathode lamp at 244.8
nm, using an air-acetylene flame) and inductively coupled plasma optical emission spectrometer
(ICP-OES; Varian Vista PRO Radial). The elemental analyses were performed with an
Elementar Analysensysteme GmbH Vario EL. Melting points were measured on an
Electrothermal 9100 apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a
BRUKER DRX-500 AVANCE spectrometer at 500 and 125 MHz. NMR spectra were obtained
in CDCl3 and DMSO-d6.
2.2
Synthesis of carboxylated MWCNT (MWCNT-COOH)
This compound was synthesized according to the previously reported oxidation method.26 In a
typical procedure, MWCNTs (0.50 g) were added to a solution containing sulfuric acid (95–98%,
30 mL) and nitric acid (10 mL) mixture (v:v 3:1) and the solution was left in a round bottom
flask. The reactant was sonicated in a bath type sonicator at room temperature for 1 h, after that

the reaction flask was removed from the sonicator, and it was put into an oil bath and refluxed
under magnetic stirring (500 rpm) at 90 oC for 5 h. The mixture was cooled, neutralized with an
o
excess amount of deionized water followed by centrifugation (20000 rpm, 30 min, 8 C). The
obtained solid product was then washed out repeatedly with acetone and was dried in the oven at
60 oC for 24 h, yielding MWCNT–COOH.
2.3
Synthesis of acyl chloride MWCNT (MWCNT-COCl)
The conversion of a carboxylic acid group of MWCNT-COOH to acyl chloride was conducted
utilizing thionyl chloride (SOCl2). For this purpose, an excess amount of SOCl2 (30 mL) was
o
added to MWCNTCOOH (0.50 g). The suspension was refluxed for 48 h at 75 C. Then, the
sample was evaporated under reduced pressure, followed by the complete removal of unreacted
SOCl2 on a rotary evaporator with a vacuum pump. The remaining solid (MWCNT-COCl) was
washed three times with anhydrous tetrahydrofuran and dried in an oven at 60 oC for 5 h.
2.4
Synthesis of aminated MWCNT
In a pilot experiment, a mixture of solid MWCNT–COCl (0.50 g) and p-phenylenediamine (0.10
g, 1 mmol) in DMF was stirred at room temperature under N2 atmosphere for 24 h. Thereafter,
MWCNT–NH2 was collected on a 0.45 µm polycarbonate membrane and washed with THF 3
times. Finally, the black solid was dried at 60 oC overnight in the oven.
2.5
Synthesis of pentaamide-functionalized MWCNT
In a brief, to a magnetically stirred mixture of p-anisaldehyde (0.68 g, 5 mmol), Meldrum’s acid
(0.70 g, 5 mmol) and aminated MWCNT (0.50 g) in DCM/DMSO (3:1) a solution of cyclohexyl
isocyanide (0.54 g, 5 mmol) was added dropwise and stirred for 48 h at room temperature. After

completion of the reaction, the product was washed with ethanol and acetone and collected by
centrifuge (20000 rpm, 30 min, 8 oC, 5 times).
2.6
Synthesis of Pd NPs@pentaamide-f-MWCNT nanocomposite
Pd nanoparticles on the surface of the pentaamide-f-MWCNT nanocomposite were synthesized
according to the previous report.27 First, 0.10 g of the pentaamide-f-MWCNT were dispersed in
50 ml of water and sonicated at room temperature for 15 min for well-dispersing of the
nanocomposite. The 2.00 mM solution of the H2PdCl4 was prepared by mixing PdCl2 (0.09 g,
0.06 mmol), 6.00 mL of 0.20 M HCl in water and heated for 20 min at 80 oC and then allowed to
cool down to room temperature. Then, the Pd containing solution was added dropwise to the
solution of the pentaamide-f-MWCNT and stirred at room temperature for 15 h. The mixture was
then filtered by vacuum and washed with water and ethanol. In continuation, the mixture of
pentaamide-f-MWCNT-PdCl42- were dispersed in 20 mL water and sonicated for 5 min, then the
NaBH4 solution (8 eq. in 10 mL water) was added to the mixture and stirred at room temperature
for 8 h. The final product, Pd NPs@pentaamide-f-MWCNT nanocomposite, was obtained by
filtration and washing with water, ethanol and acetone.
2.7
Preparation of choline chloride-based deep eutectic solvent (DES)
Choline chloride-based deep eutectic solvent was prepared based on the previous literature.28
Two components of DES were mixed based on the mentioned proportions showed in Table 1 and
o
heated to 80 C until a homogeneous colorless liquid was collected. The obtained DESs were
used without any further purification.
2.8
General procedure for the Ullmann coupling reaction
In a brief, a mixture of Pd NPs@pentaamide-f-MWCNT nanocomposite (0.02 mol% of Pd),
K2CO3 (2 mmol) and an aryl halide or compound 7 (1 mmol) were placed in DES (2 mL) and

o
vigorously stirred at 100 C for a certain period of time (1-1.5 h, 4h for compound 7). After
completion of the reaction as indicated by TLC, the reaction mixture was cooled to room
temperature, followed by adding 10 mL water, separation of the catalyst by centrifuge and
dilution with ethyl acetate (10 mL). If necessary, the column or plate chromatography was used
for purification of the obtained product.
2.9
Synthesis of compound 7 through Ugi four-component reaction
In a typical procedure, 2-bromobenzaldehyde (116 µL, 1.00 mmol) and 2-iodoaniline (0.22 g,
1.00 mmol) were dissolved in TFE (10 mL) and magnetically stirred for 1 h at room temperature.
Then, cyclohexyl isocyanide (0.10 g, 1.00 mmol) and benzoic acid (0.12 g, 1 mmol) were added
o
and the resulting mixture was stirred at 50 C for 18 h. After completion of the reaction, the
solvent was removed by vacuum and the reaction mixture was diluted by n-hexane/ethyl acetate
and then the desired product was obtained by recrystallization in ethyl acetate.
2.10 General procedure for the synthesis of 2,3-diaryl imidazo[1,2-a]pyridine
2-Aminopyridine (0.09 g, 1.00 mmol), 2-bromoacetophenone (1.00 mmol), an aryl halide (1.20
mmol), Pd NPs@pentaamide-f-MWCNT nanocomposite (0.01 mol% of Pd) and KOAc (2 mmol)
o
were mixed in 4 mL water and magnetically stirred at 100 C for 10 h. After the completion of
the reaction, the reaction mixture was cooled to room temperature, the catalyst was removed by
centrifugation (20000 rpm) and the product was extracted from ethyl acetate (4×10 mL). The
plate chromatography was utilized if necessary.
2.11 General procedure for the Sonogashira coupling reaction
A mixture of acetylene (1.00 mmol), an aryl halide (1.00 mmol), KOAc (2.00 mmol), and Pd
NPs@pentaamide-f-MWCNT nanocomposite (0.02 mol% of Pd) in 4 mL of water was stirred at
o
100 C. After 1 h, the mixture was cooled to room temperature. After separation of and Pd

NPs@pentaamide-f-MWCNT nanocatalyst, the residue was centrifuged by ethyl acetate. Then,
the filtered mixture was concentrated and separated by column chromatography.
2.12 General procedure for the Glaser homocoupling reaction
The Pd NPs@pentaamide-f-MWCNT nanocatalyst (0.02 mol%), alkyne (1.00 mmol) and KOAc
(2.00 mmol) were added to the tube containing water (4 mL) and heated for 3 h at 100 oC. After
the completion of the reaction as indicated by TLC, the mixture was cooled down, following by
centrifugation for separation of the catalyst. Finally, the crude product was purified by
recrystallization from EtOAc: n-hexane (3:7).
2.13 Determination of palladium leaching
For the determination of the Pd leaching the hot filtration method was employed. In the next
step, the reaction mixture for the synthesis of compound 16a was allowed to run same as the
mentioned conditions in section 2-12. After the 50% conversion of the reaction (1 h), the catalyst
was separated by centrifugation and the reaction was extended for another 2h. No further
progress in the reaction was observed even after this period that monitored by GC.
3.
Results and discussion
In spite of utilization of different known MCRs for materials functionalization in the plethora of
applications, the little-known MCRs have been less investigated while may lead to significant
improvements in properties of anchored motifs and functionalized materials, specifically in the
ligand preparation field. Noteworthy, previous reports indicated that amino acids or
pseudopeptides attached on the sidewalls of CNTs have the high affinity for palladium
nanoparticles (Pd NPs) and more heteroatoms presented in the organic fragments caused to
higher interaction of ligand and nanoparticles which further led to better distribution and more

amount of Pd NPs immobilization.29 In this regard and for designing novel ligands with the
ability to immobilize the Pd NPs, we profited from one of the important MCRs based on the
isocyanide and Meldrum’s acid. This one-pot, flexible and a versatile MCR lead to the synthesis
of a wide variety of biologically active molecules and industrially remarkable compounds with
high atom economy, molecular complexity and diversity.30
Therefore, this pseudo-five-component reaction has been chosen for the synthesis of
pseudopeptide scaffolds on the sidewalls of MWCNTs in a one-pot procedure from readily
available compounds. For this purpose, the MWCNTs 1 were oxidized to prepare carboxylic acid
MWCNTs 2 and then aminated with p-phenylenediamine 3 for introducing desired nucleophiles
for this MCR. In the final step of functionalization, aminated-MWCNT 4, 4-
methoxybenzaldehyde 5, Meldrum’s acid 6 and cyclohexyl isocyanide 7 were reacted in a one-
pot vessel in DCM/DMSO at room temperature to produce pentaamide scaffolds covalently
attached on the surface of the MWCNT (pentaamide-f-MWCNT nanocomposite 8). In the final
step, the H2PdCl4 solution was added to the vessel and was given time (15 h) for better
complexation of bridging bis-dentate amide ligands with ions. Then, the reducing agent was
added and the Pd NPs were prepared and immobilized on the pentaamide ligands coated support
for the preparation of Pd NPs@pentaamide-f-MWCNT nanocomposite 9 (Scheme 1). The reason
for choosing p-phenylenediamine is the suitability of the aromatic amines in this class of
reaction.31

NH2
O
C
O
N
H
NH2
OH
O
O
C
SOCl2
N
H2SO4 + HNO3
OH
H
H2N
NH2
3
4
2
1
O
O
O
NH2
HN
O
O
HN
O
O
C
C
N
H
NH2
5
N
H
O
O
NH
O
O
DCM/DMSO
r.t.
C
N
C
N
H
O
O
6
H
O
NC
7
4
8
O
O
O
O
O
O
HN
HN
HN
HN
O
O
C
C
N
H
O
C
O
N
H
O
O
NH
NH
H2PdCl4, H2O, 15 h, r.t.
NaBH4, H2O, 8 h, r.t.
C
N
N
H
H
Pd NPs =
9
8
Scheme 1. Synthesis of pentaamide-functionalized MWCNT nanocomposite with isocyanide-
based pseudo-five component reaction for Pd NPs immobilization
Importantly, the pentaamide scaffolds synthesized from pseudo-five component reaction caused
to bridged amide ligands that have a great ability for interaction with palladium ions. Some
possible pathways for interactions between Pd ions and bis-dentate amide ligands are presented
in Scheme 2. In pathway a, the Pd ions were chelated with bis-dentate amide ligands that
produced from amidation of two vicinal carboxylic acids. The pathway b exhibited the chelation

of Pd ions with near amide groups beyond the benzene ring in one motif.32 The other pathway
might be possible when the amide groups tautomerized to imide groups. In this form, the lone
pair on the nitrogen can form a double bond with the carbon while the carbonyl bond breaks,
giving oxygen a negative charge. Notably, it is proved that some of the amide and peptide
scaffolds mostly existed in the O-protonated tautomer form,33 therefore, it could be imagined that
two O-heads from imide forms or O-site of imide form with the other N-site of the amide motifs
could have complex with the ions. Although further investigation will be needed for clearance of
the exact ligand role of these pentaamide structures. By the addition of the reducing agent, the Pd
ions were converted to Pd NPs in their fixed places. The quantitative content of the palladium
was obtained to be 9.2 ppm determined by ICP-OES.
(a)
(c)
(b)

Scheme 2. Possible pathways of the complexation of the Pd ions with bis-dentate amide ligands
The synthesized nanocatalyst was fully characterized. First, The CHN analysis, before and after
of I-MCR functionalization were carried out. The atomic percent of 2.43% for nitrogen
confirmed the formation of amide bonds between MWCNT-COCl and p-phenylenediamine
through the process of amination. The nitrogen content after I-MCR functionalization increased
to 10.43% that was proved the efficient covalent functionalization of MWCNTs through this
MCR with pseudopeptide scaffolds.
FT-IR spectroscopy was used to confirm the chemical structure of nanocomposites. The FT-IR
spectrum of pentaamide-f-MWCNT (Figure 1a) showed the C=O stretching vibration of different
amide bonds formed at 1735, 1674 and 1650 cm-1 that proved the formation of pentaamide
moieties on the side-walls of the MWCNT through pseudo-five component reaction. Also, a
broad peak at 3425 cm-1 corresponds to the stretching vibration of –NH bond. The peaks at 2923
and 2854 cm-1 attributed to the symmetric and asymmetric stretching vibration of methylene
groups of the cyclohexyl rings. Stretching band of –C-O and the in-plane bending of C-H in
benzene ring were appeared in 1026 and 1095 cm-1, respectively. The IR spectrum of
pentaamide-f-MWCNT showed a broad amide region with the peaks at 1735, 1674 and 1650 cm-
1
which attributed to the isocyanide attached amide and aromatic conjugated amides,
respectively. In the IR spectrum of the Pd NPs@pentaamide-f-MWCNT, a slight shift in amide
bonds were observed as well as the elimination of the aromatic amide bonds, which may describe
as a result of the weak interactions between ligand and Pd NPs and confirmed the more
interaction and chelation of the NPs to the aromatic amide bonds (Figure 2a).

Figure 1 FT-IR spectra of pentaamide-f-MWCNT (a) and Pd NPs@pentaamide-f-MWCNT
nanocomposite (b)
Interestingly, the pentaamide-f-MWCNT nanocomposite showed high dispersity in DMSO,
1
1
therefore we were able to get H NMR spectrum of the nanocomposite. The H NMR spectrum
confirmed the formation of the pentaamide scaffolds through the existence of the multiplet for
the methylene protons of the cyclohexyl ring (d = 1.04–1.66 ppm, 10H) and a singlet for the
methoxy group of 4-methoxybenzaldehyde (d = 3.73 ppm, 3H) (Figure 2).

Figure 2. Representative 1H NMR (DMSO-d6) spectrum of pentaamide-f-MWCNT
The XRD pattern of the final nanocomposite is displayed in Figure 3. It can be seen that Pd
NPs@pentaamide-f-MWCNT nanocomposite showed the diffractions peaks at 2θ = 25.53o and
44.02o which attributed to the (002) and (100) hexagonal graphite structure of MWCNT.
Additionally, the peaks at 2θ = 39.82o, 46.6o and 67.66o corresponding to the (111), (200) and
(220) crystalline planes of the face-centered cubic structures of the Pd (JCPDS No. 87-0643).
Also, the minor peak at 2θ = 37.36o may associate to the crystalline structure of the PdO NPs that
revealed a few oxidations of Pd NPs. Importantly, this oxidation could have a synergistic effect
on the efficiency of the catalyst for C-C coupling reactions.

Figure 3. XRD pattern of the Pd NPs@pentaamide-f-MWCNT nanocomposite
In a follow-up investigation, the SEM and TEM analysis were prepared for obtaining a better
view of the morphology of the nanocomposite. The SEM images of Pd NPs@pentaamide-f-
MWCNT nanocomposite revealed that the nanotube structure of MWCNT remained stable upon
functionalization with the pseudo-five-component reaction which confirmed the ability of this
synthetic route for functionalization of materials without any defeat or destruction of the physical
structures. Additionally, the high uniformly sized nanoparticles with a semispherical shape
demonstrated the presence of the Pd NPs (Figure 4a). The TEM images represented that the Pd
NPs were coated the side-walls of the f-MWCNT with the average size of the 5-10 nm (Figure
4b). Finally, the EDS data showed the elemental composition of (C, N, O and Pd) of synthesized
nanocomposite (Figure 4c). The above-mentioned results indicated that this pseudo-five
component reaction has a striking potential for the preparation of organic motifs on the sidewalls
of MWCNTs without any obvious destruction in the structure and morphology during a facile
one-pot procedure.

Figure 4. SEM (a), TEM (b) images and EDS (c) of Pd NPs@pentaamide-f-MWCNT
nanocomposite
To assess the thermal stability and the behavior of the Pd NPs@pentaamide-f-MWCNT
nanocomposite, TGA analysis was carried out by heating nanocomposite up to 800 °C under N2
at a heating rate of 10 °C min-1 (Figure 5). The TGA curve showed the initial weight loss of 3%

up to 200 °C related to the removal of physically adsorbed solvent and moisture. Obvious weight
loss can be observed in the temperature range of 200–450 °C, resulting from the decomposition
of organic scaffolds covalently attached on the side-walls of the MWCNT. Also, the
decrementation observed at 460 °C and further weight loss above 500 °C was attributed to the
pyrolysis and destruction of the graphite network, which is a normal phenomenon during the
functionalization of carbon-based materials.34
Figure 5. TGA curve of Pd NPs@pentaamide-f-MWCNT nanocomposite recorded at a heating
rate of 10 °C min-1
After preparation and characterization of the nanocatalyst, we started to examine its catalytic
efficiency in various cross-coupling transformations, starting by the Ullmann homocoupling
reaction for the synthesis of biaryl derivatives. Biaryl structures are widely applied as chiral
ligands in catalysis and also they are found in a broad spectrum of natural products and
biologically active compounds, therefore, several catalysts have been introduced for this
prominent reaction.35–37 Initially, the reaction was examined on homocoupling reaction of 4-

o
iodoanisole using Cs2CO3 as a base in DMSO at 120 C. Then, several bases such as K3PO4,
K2CO3 and KOAc as well as different solvents namely DMF, EtOH and water have been used in
this reaction (Table 1). Among these conditions, performing the reaction in DMF caused to better
yields in 6 hours. Because of the importance of green chemistry aspects and also our previous
acquaintance with deep eutectic solvents (DESs) as the green and neoteric media in organic38,39
and inorganic40 transformations, we decided to examine this reaction in DESs. Due to the several
advantages of DESs such as being biodegradable and sustainable, cheaper production process as
well as a wider liquid temperature range, nowadays, this booming solvent has been used in a
broad spectrum of chemical processes.41 Accordingly, choline chloride-based DES with urea and
glycerol were used. Gratifyingly, we observed that Ullmann homocoupling reaction carried out
in DES in shorter reaction time with higher yields in comparison to organic solvents. Pd
NPs@pentaamide-f-MWCNT in glycerol-based DES with K2CO3 as a base at 100 °C in just 1
hour provided the best result. Also, the effect of nanocatalyst amount was investigated and the
0.02 mol% was chosen as the best amount (Table 1-entry 9). The reactions that inherently
accompanied with the decrease of the entropy can be accelerated with the pressures that caused
from hole effect in DES medium and therefore the synergistic effect of the solvent and catalyst
along with the presence of an extensive hydrogen-bonding network caused to higher yield in this
reactions.42
O
I
O
O
1c
2c
Table 1. Optimization of the reaction parameters for the Ullmann homocoupling reactiona

Entry
Solvent
Time (h)
Temperature
(oC)
Base
Yield (%)b
1
2
3
4
5
6
7
6
6
6
6
6
6
1
120
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
85
48
DMSO
DMSO
DMSO
DMF
120
120
120
78
82
87
10
ETOH
H2O
100
120
Trace
74
Choline chloride:urea (1:2)
8
Choline chloride:glycerol
1
1
1
1
1
1
120
100
100
70
K2CO3
K2CO3
KOAc
K2CO3
K2CO3
K2CO3
97
97
72
58
49
97
(1:2)
Choline chloride:glycerol
(1:2)
9
10
11
12c
13d
Choline chloride:glycerol
(1:2)
Choline chloride:glycerol
(1:2)
Choline chloride:glycerol
(1:2)
100
100
Choline chloride:glycerol
(1:2)
a Reaction conditions: 4-iodoanisole (1.0 mmol), Base (2.0 mmol), solvent (2 mL), Pd NPs@pentaamide-
b
c
f-MWCNT (0.02 mol% Pd), Isolated yields, Pd NPs@pentaamide-f-MWCNT (0.01 mol% Pd), d Pd
NPs@pentaamide-f-MWCNT (0.04 mol% Pd)

With the optimized reaction conditions in hand, the scope of the catalytic activity of the
heterogeneous Pd catalyst in Ullmann homocoupling reaction for the synthesis of biaryls 2 was
extended to the various aryl halides 1 such as aryl iodides, bromides and chlorides. As illustrated
in Table 2, good to excellent yields were achieved in the reactions of aryl halides bearing both
electron-withdrawing and electron-donating groups. Also, a substrate which contains chloro
substituents carried out by appropriate yields but in a longer time (Table 2).
Table 2. Ullmann coupling reactions for the synthesis of biaryls
X
Pd NPs@pentaamide-f-MWCNT (0.02 mol%)
R
R
DES, 100 oC, K2CO3 (2 eq.)
2
1
R
Entry
X
R
H
Product
2a
Time (h)
Yields (%)a
1
2
3
4
5
I
1
1
90
88
97
80
92
I
Me
2b
I
OMe
NO2
NO2
2c
1
Cl
Br
2d
1.5
1
2e
a Isolated yields.
Subsequently, for further development of this catalytic system, a platform was designed for
intermolecular cross-coupling reaction. For this purpose, initially, a carboxamide structure was
prepared via an Ugi four-component reaction by condensation of commercially available 2-
iodoaniline 3, 2-bromobenzaldehyde 4, benzoic acid 5 and cyclohexyl isocyanide 6. In recent
years, post-Ugi approaches led to the direct synthesis of target scaffolds with remarkable
molecular complexity. As a result, the Ugi adduct 7 used as a substrate in our catalytic system

for further post-Ugi transformation.43 This new scaffold 7 contains two potential nucleophilic
sites, i.e. the -C of the secondary amide and the NH of the secondary amide, besides, iodide and
bromide functionality in the benzene motif as the leaving group in the subsequent cyclization.
Three pathways are expected for this post-Ugi reaction but the characterization results revealed
that 5-benzoyl-N-cyclohexyl-5,6-dihydrophenanthridine-6-carboxamide 8 was achieved through
an intramolecular Ullmann cross-coupling reaction (Scheme 3).
O
I
O
O
COOH
Chemoselective
post-ugi transformation
NH2
I
NC
N
TFE
50 o
N
+
+
+
DES, K2CO3
O
O
C
Br
Cat. 0.02 mol% Pd
100 oC,4 h
18 h
HN
4
6
HN
3
5
Br
65% yields
8
87% yields
7
Scheme 3 Post-Ugi process by Pd NPs@pentaamide-f-MWCNT via intramolecular Ullmann
reaction
Encouraged by these interesting results and due to the high importance of the imidazopyridine
frameworks, found in marketed drugs namely Zolpidem, Olprinone, Alpidem and various useful
molecules in biological testing and preclinical evaluation,44 we tested the catalytic utility of Pd
NPs@pentaamide-f-MWCNT for an efficient synthesis of the imidazopyridine scaffolds through
modified Mizoroki-Heck cross-coupling reaction by one-pot sequential condensation and C–H
arylation. For an initial assessment of the reaction, 2-aminopyridine 9, phenacyl bromide 10, and
phenyl iodide 1a were chosen as model substrates to optimize the reaction conditions. A variety
of solvents such as DMF, EtOH, water, glycerol, PEG and solvent free-conditions were
examined. Also, different bases were tested in this reaction such as Na2CO3, KOAc, K2CO3 and
K3PO4 (Table 3). Best results were obtained with DMF followed closely by water. Since water is

a green medium and the difference in the obtained yield was minimal, it was chosen as a solvent
for carrying this sequential three-component process.
Table 3. Optimization of the modified Mizoroki-Heck reaction conditionsa
Br
O
N
I
NH2
N
+
+
N
11
9
10
12a
Entry
Solvent
DMF
Base
T (°C)
130
130
78
Yields (%)b
1
2
K2CO3
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
KOAc
KOAc
KOAc
KOAc
80
66
DMF
3
EtOH
Glycerol
PEG
45
4
120
120
100
100
100
100
100
25
Trace
25
5
6
Water
Water
Water
Water
Water
Water
S.F.
68
7
34
8
46
9
78
10 c
11d
12
80
Trace
20
130
a Reaction conditions: 2-aminopyridine (1 mmol), phenacyl bromides (1 mmol), aryl bromide (1.2 mmol),
Base (2 mmol), Pd NPs@pentaamide-f-MWCNT (0.01 mol%), solvent (4 mL), time (10 h), b Isolated
yields, c After 12 h, d Under ultrasonic conditions for 1 h.
After optimization of the reaction conditions, the scope of the reaction catalyzed by Pd
NPs@pentaamide-f-MWCNT with a variety of aryl halides and phenacyl bromides with 2-

aminopyridine derivatives was explored. As shown in Scheme 4, a series of aryl halides and
phenacyl bromides containing electron-withdrawing and electron-donating substituents were
well examined under optimum reaction conditions.
Scheme 4 2,3-Diarylimidazo[1,2‑a]pyridines synthesis by Pd NPs@pentaamide-f-MWCNT
nanocomposite
Br
O
N
X
Y
NH2
N
Catalyst (0.01 mol%)
H2O, KOAc (2 eq), 100 oC
N
Y
N
Z
10
9
12
Z
1
N
N
Cl
N
N
N
O
Cl
X= I; 12a: 78%
N
X= I; 12c: 85%
X= I; 12b: 80%
N
N
Cl
Cl
O
N
N
N
NO2
NO2
X= I; 12d: 74%
X= Br; 12e: 84%
X= Br; 12f: 88%
There are few examples for this metal-catalyzed reaction and although they led to the desired
product by good yields these catalytic systems have shown some disadvantages such as using a
microwave as the heating resource, organic solvents and harsh reaction conditions.45–49 The
comparison between our catalytic system and previous reports for the synthesis of 2,3-
diarylimidazo[1,2-a]pyridines was established with respect to their yields, temperatures, solvent,

and the time of the reaction. Also, turnover frequency as an important factor in catalytic systems
calculated and evaluated (Table 4). The results confirmed that our catalytic system carried out in
the greenest medium of water as a solvent with appropriate yields with high turnover frequency
(up to 97%).
Table 4. Comparison of catalysts described in the literature and the one used in this research for
the synthesis of 2,3-diarylimidazo[1,2-a]pyridines
Entry Catalyst
Solvent
Time (h) T (oC) Yield (%) TOF (h-1)
Ref.
1
2a
3a
4a
5
Pd(OAc)2
DMAc
DMF
16
1
150
160
220
110
100
63-93
56-85
36-83
51-89
74-88
393-581
5.6-8.5
36-83
45
49
47
48
Pd(OAc)2
Pd(OAc)2
PEG
1
Pd NPs-nanosilica
DMAc
Water
0.75
10
340-593
740-880
Pd
NPs@pentaamide-f-
This
MWCNT
work
a Under microwave irradiation
To gain more insight into the chemoselectivity of the nanocatalyst in this synthetic method, an
intermediate which contains two active sites 13 (aryl halides and olefins) for coupling reaction
was also tested to evaluate the domination between Mizoroki-Heck and Ullmann carbon-carbon
1
cross-coupling reaction (Scheme 5). After several analyzes such as H and 13C NMR and
particularly mass analysis, it was found that just one product that accomplished through C-C
bond formation of olefin and aryl halide, Mizoroki-Heck reaction, was obtained.
I
an active site for Ullmann reaction
O
Br
NH2
N
N
N
O
Cl
Cl
+
N
N
13
an active site for Mizoroki-Heck reaction
Cl
O

Scheme 5 Chemoselectivity between Mizoroki-Heck and Ullmann cross-coupling reaction
In continuation, we decided to investigate the catalytic performance of our novel catalyst in the
other cross-coupling reactions under green medium. Hereupon, we tested Pd NPs@pentaamide-f-
MWCNT in Sonogashira reaction. The Sonogashira reaction is a striking cross-coupling
methodology used in several total synthesis, chemical process and industrial transformations.50,51
It is considered as a Pd-catalyzed carbon-carbon bond formation between aryl halides 1 and
terminal alkyne 14. Notably, this reaction associated with major problems in the reaction
conditions due to the simultaneous utilization of a palladium catalyst and a copper reagent (co-
catalyst) that caused to the coupling products contamination with metal residue. Additionally, the
Glaser dimerization of the alkyne substrate as a side reaction of the Sonogashira coupling
reaction is a proven fact. As shown in Scheme 6, we have successfully synthesis Sonogashira
adducts 15 with Pd NPs@pentaamide-f-MWCNT by high yields and selectivity in water under
copper-free conditions.
N
Ph
Ph
I
15a: 90%
1
14
15c: 84%
Water, KOAc
or
or
Catalyst 0.02 mol% Pd
100 oC, 1h
O
I
N
N
Ph
O
O
15d: 81%
15b: 87%
Scheme 6 Synthesis of Sonogashira adduct by Pd NPs@pentaamide-f-MWCNT in water
Since the novel catalyst showed admirable catalytic efficiency for the formation of Csp2-Csp2
and Csp-Csp2 bonds in cross-coupling reactions, we also examined the Pd NPs@pentaamide-f-
MWCNT catalyst for the Csp−Csp bond formation through Glaser reaction. The Glaser reaction

leads to 1,3-diynes that common in several natural products and biologically active molecules.52
Also, 1,3-diynes are efficient substrates for the preparation of advanced materials, such as
conjugated polymers and molecular wires.53 Based on these explanations, carrying out Glaser
reaction in water as a greenest medium is so considerable. Accordingly, catalytic utilization of
Pd NPs@pentaamide-f-MWCNT for Glaser reaction was demonstrated in water. The results
showed that the catalytic system led to the 1,3-diynes 16a-b with excellent yields (Scheme 7).
Ph
Ph
16a: 100%
2
Ph
Cat. (0.02 mol%), KOAc
Water, 100 oC
3 h
N
N
2
N
16b: 100%
Scheme 7 Glaser reaction catalyzed by Pd NPs@pentaamide-f-MWCNT in water
The easy reusability and recyclability of the nanocatalyst and the reaction medium or solvent are
also a priority for green chemistry metrics. In this regard, the recyclability of the Pd
NPs@pentaamide-f-MWCNT was examined during the Glaser reaction for the synthesis of
compound 16a as a model reaction. In each experiment, after the completion of the reaction, the
catalyst was separated by centrifugation washed with ethanol, distilled water and acetone, dried
under vacuum at 60 °C, and reused for the next run. The results confirmed that the nanocatalyst
is reusable at least seven times without a significant decrease in the isolated yield (Figure 6a).
Additionally, the TEM image of the recycled nanocatalyst after 7th run was obtained that clearly
showed the maintenance of the nanotube and semispherical morphology of MWCNT and Pd
nanoparticles, respectively, with a negligible agglomeration of Pd nanoparticles.

Figure 6 (a) Reusability and (b) TEM image of Pd NPs@pentaamide-f-MWCNT nanocatalyst in
the Glaser reaction for the synthesis of compound (16a) after 7th runs
Since the non-dissolution of the Pd NPs from the surface of the MWCNT is crucial for the
success of this designed catalytic system and for ensuring about the high efficiency of the
designed MCR-ligands for Pd immobilization, the impact of the Pd leaching after 7th cycles was
investigated for compound 16a. After the completion of the reaction, the Pd NPs@pentaamide-f-
MWCNT nanocatalyst was separated by centrifugation and washed with acetone, dried in the
oven. Then, the reaction mixture was analyzed using atomic absorption spectroscopy analysis
which indicates no existence of the Pd in the filtrate solution. In continuation and to prove the
heterogeneous nature of the Pd NPs@pentaamide-f-MWCNT nanocatalyst, the hot filtration test
was performed for the synthesis of compound 16a. For this purpose, the nanocatalyst was
separated from the reaction mixture at approximately 50% (1 h) conversion of the starting
substrates through centrifugation. The reaction was continued with the filtrate for another 2 h at
the same reaction conditions. Importantly, no increase in the conversion of the substrate to
compound 16a was observed in this period that indicated by GC analysis. To wrap up the

discussion, the results proved that the nature of the reaction process is heterogeneous and there is
no evidence of any type of the homogeneous pathway or Pd leaching.
Conclusion
This study demonstrated the vast and impressive work in the one-pot covalent functionalization
of multi-wall carbon nanotubes with isocyanide and Meldrum’s acid based-MCR caused to
pseudopeptide ligands that showed admirable efficiency for the immobilization of the palladium
nanoparticles. The catalytic performance of the designed nanocatalyst was examined in different
cross-coupling reactions like Ullmann, Mizoroki-Heck, Sonogashira and Glaser reactions in bio-
based solvents such as water and deep eutectic solvent system based on choline chloride along
with glycerol. Gratifyingly, this recyclable catalytic fashion showed admirable improvements in
every discussed reaction. The Ullmann homocoupling reaction was conducted in a green medium
of DES in a really short reaction times in comparison with almost all of the previous reports. The
catalytic system exhibited unprecedented chemoselectivity toward the intermolecular Ullmann
and modified Mizoroki-Heck coupling reactions. Notably, sequential condensation/ C-H
arylation reaction for the synthesis of 2,3-diarylimidazo[1,2‑a]pyridines was carried out for the
first time in water with high TOF (740-880). Moreover, Sonogashira and Glaser coupling
reactions were done with high yields in water. According to the fruitful results of the
performance of this catalytic system for diverse C-C bond formation and since Pd-based solid
catalysts, often in nanoparticle form, drive the overwhelming majority of industry’s chemical
processes we believe that this multi-task catalyst could serve as a great candidate for industrial
applications.
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