Palladium(II)-pivaloyl thiourea complexes: Synthesis, characterisation and their catalytic activity in mild Sonogashira cross-coupling reaction

Article abstract of DOI:10.1016/j.cplett.2020.137842

We report herein the synthesis of Pd(II) complexes featuring pivaloylthiourea derivatives to investigate their catalytic behaviour in Sonogashira cross-coupling reactions as the homogenous catalyst. The SN₂ reactions have resulted in pivaloyl thiourea derivatives ligands with general formula (CH₃)₃C(O)NHC(S)NHR introducing different substituent groups of NO₂ (L1), OCH₃ (L2), and H (L3) prior to form complexation with Pd(II) (MC1, MC2, and MC3 respectively). All synthesised compounds were characterised via typical selected spectroscopic and analytical methods. Hence, catalytic screening activity revealed that Pd(II)-pivaloyl thiourea catalysed, featuring MC3, is the best catalyst as it gave a high conversion rate up to 99%.

Full text of DOI:10.1016/j.cplett.2020.137842

Journal Pre-proofs
Research paper
Palladium(II)-Pivaloyl Thiourea Complexes: Synthesis, Characterisation and
Their Catalytic Activity in Mild Sonogashira Cross-Coupling Reaction
Wan M. Khairul, Falynee Faha Abdul Wahab, Siti Kamilah Che Soh,
Mustaffa Shamsuddin, Adibah Izzati Daud
PII:
S0009-2614(20)30757-0
DOI:
https://doi.org/10.1016/j.cplett.2020.137842
CPLETT 137842
Reference:
To appear in:
Chemical Physics Letters
Received Date:
Revised Date:
Accepted Date:
30 June 2020
31 July 2020
31 July 2020
Please cite this article as: W.M. Khairul, F. Faha Abdul Wahab, S. Kamilah Che Soh, M. Shamsuddin, A. Izzati
Daud, Palladium(II)-Pivaloyl Thiourea Complexes: Synthesis, Characterisation and Their Catalytic Activity in
Mild Sonogashira Cross-Coupling Reaction, Chemical Physics Letters (2020), doi: https://doi.org/10.1016/
j.cplett.2020.137842
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Palladium(II)-Pivaloyl Thiourea Complexes: Synthesis,
Characterisation and Their Catalytic Activity in Mild Sonogashira
Cross-Coupling Reaction
a
a
a
Wan M. Khairul *, Falynee Faha Abdul Wahab , Siti Kamilah Che Soh ,
b
c
Mustaffa Shamsuddin and Adibah Izzati Daud
aFaculty of Marine Science and Environment, Universiti Malaysia Terengganu, 21030
b
Kuala Nerus, Terengganu, Malaysia; Department of Chemistry, Faculty of Science,
c
Universiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia; Department of
Chemical Engineering Technology, Faculty of Engineering Technology, Universiti
Malaysia Perlis, 02100 Padang Besar, Perlis, Malaysia.
*
Corresponding author. Email: wmkhairul@umt.edu.my
ABSTRACT
We report herein the synthesis of Pd(II) complexes featuring pivaloylthiourea
derivatives to investigate their catalytic behaviour in Sonogashira cross-coupling
reactions as the homogenous catalyst. The SN reactions have resulted in pivaloyl
2
thiourea derivatives ligands with general formula (CH ) C(O)NHC(S)NHR
3
3
introducing different substituent groups of NO (L1), OCH (L2), and H (L3)
2
3
prior to form complexation with Pd(II) (MC1, MC2, and MC3 respectively). All
synthesised compounds were characterised via typical selected spectroscopic and
analytical methods. Hence, catalytic screening activity revealed that Pd(II)-
pivaloyl thiourea catalysed, featuring MC3, is the best catalyst as it gave a high
conversion rate up to 99%.
Keywords: pivaloyl-thiourea; spectroscopic; Sonogashira; Pd-catalyst; phosphine-
free

1
. Introduction
The uprising research in transition metal-catalysed carbon-carbon cross-coupling
reactions has attracted the highest intention among researchers in the practice of
organic synthesis in the last two decades [1,2] due to its recognition as convenient
one-step methods for the construction of carbon-carbon bonds. The chemistry and
significance of alkynes derivatives are directly related with their existence in various
natural product interest especially as biologically active substances [3,4] as well as
for the production and development of materials for advanced materials application
namely, organic light-emitting diode (OLED) [5,6] organic photovoltaic solar cells
[7-9] non-linear optical devices [10,11] and liquid crystals properties [12]. Thus, the
prominence development of methods for incorporating carbon-carbon triple bonds
into the desired molecular framework remains an important research area to date.
Besides, one of the prominent monoligated precatalyst backbones is to carry out the
reaction under air-stable palladacycles that can be activated by deprotonation under
mild reaction conditions to obtain the monoligated Pd(0)complex via reductive
elimination of the intramolecular amine–aryl group from the pivaloyl-thiourea
ligand [13,14].
Conventionally, the catalytic reaction of Sonogashira cross-coupling reaction is
performed by palladium complexes in combination with phosphine based, copper
iodide (CuI) as co-catalyst and a significant excess of tertiary amines such as
triethylamine. However, problems associated with phosphine ligands are air and
moisture sensitive in which involved high cost, demand for the inert environment.
They arise with toxicity issues, which, to some extent, would limit any large scale of
industrial applications. The presence of excess phosphine also can lead to the high
toxicity of the reaction as well as can slow down the reaction rate due to the
presence of steric hindrance [15]. The importance of ligands in modern
homogeneous transition metal catalysis cannot be exaggerated. The coordination of
ligand can change the structure and reactivity of a metal catalyst, in which it
inherently changes the activation energy of elementary steps in a given catalytic
process.
Therefore, there has been a great interest in the line to develop a non-phosphine
catalyst for the higher achievement of activity, stability, and substrate tolerance,

which may allow the coupling reaction to be conducted under mild reaction
conditions or at ambient environment. Thus, among a variety of synthesised ligands,
thiourea derivatives seem to be very interesting due to the easily synthesised and
able to form complexes with various transition metals, especially palladium [16].
The low cost of starting materials and insensitivity towards air and humidity have
made thiourea a perfect ligand of choices. Previously, we also have reported our
work related to thiourea derivative featuring propionic acid moiety coordinated to
Pd(II) for Heck cross-coupling reaction and gave promising 100% conversion rate
[17].
In a continuation of our research directions on the use of a palladium catalyst in
cross-coupling reactions, herein, we report an efficient and mild catalytic system
featuring pivaloylthiourea reacted with various amines of choice, namely, 4-
nitroaniline, 4-methoxyaniline, and aniline. The selection of these ligands is due to
their distinctive advantages such as a simple approach to synthesis ligands and their
corresponding complexes, as well as they have never been utilised as ligands and
catalysts in any reported cross-coupling reactions. Besides, the presence of various
substituents strength either as an electron-donating or electron-withdrawing group
gives a significant contribution to catalytic activity. The choice of palladium as a
metal center in compounds attributed to its high stability, selectivity, and reactivity.
Therefore, the suitability and performance of synthesised Pd(II) pivaloylthiourea
complexes as a homogenous catalyst have been evaluated in Sonogashira cross-
coupling reactions of phenylacetylene and various bromo-halides.
2
. Materials and Characterisation
All chemicals used in this study were purchased from standard commercial
suppliers and used as received without further purification. The Infrared (IR) spectra
were recorded on Perkin Elmer Spectrum 100 Fourier Transform-Infrared (FTIR)
-1
-1
Spectrometer by using KBr disc in the range between 4000 cm to 400 cm . UV-
Vis spectra were recorded using Shimadzu UV-Vis Spectrophotometer in the range
3
between 200 to 600 nm by using methanol as a solvent in a quartz cell (1 cm ). The
1
13
proton ( H) 400.11 MHz and carbon-13 ( C) 100.61 MHz Nuclear Magnetic
Resonance (NMR) spectra were obtained on Bruker Avance III 400 spectrometer in

deuterated chloroform (CDCl ) as solvent at room temperature in the range between
3
H 0-13 ppm and  0-190 ppm, respectively. Furthermore, Gas Chromatography
C
(GC-Hewlett Packard-5890 series II) was used to determine the product conversions
from catalytic testing using Flame Ionization Detection (FID) method. The
microliter samples were injected at 50 °C. The temperature increment was set at 30
°
C per minute, and the final temperature was at 280 °C. The conversion percentage
(%) of the reactant was calculated as in Equation (1), where Ainitial represents peak
area of reactant before reaction, while Afinal represents the peak area of reactant after
the reaction.
[
퐴푖푛푖푡푖푎푙 ― 퐴푓푖푛푎푙] 푥 100
%
푐표푛푣푒푟푠푖표푛 =
(1)
퐴푖푛푖푡푖푎푙
3
. Methodology
.1 Preparation of N-(4-nitrophenyl)-N’-pivaloylthiourea (L1)
A solution of pivaloyl chloride (5.87 g, 48.7 mmol) in 30 mL acetone was added
3
dropwise into a solution of ammonium thiocyanate (3.70 g, 48.7 mmol) in 50 mL
acetone in 250 mL three-necked round bottom flask. The reaction mixture was
stirred continuously and put at reflux for ca. 2 hours until the colourless solution
turned into light yellow with the formation of white precipitate. The progress of the
reaction was monitored by thin-layer chromatography (TLC) in 7:3
(dichloromethane: hexane). Then, equivalent molar of 4-nitroaniline (6.21 g, 48.7
mmol) in 50 mL acetone was added into the solution and put at reflux for ca. 4
hours. After adjudged completion, the reaction mixture was cooled into room
temperature and filtered before the addition of ice cubes to the filtrate. The
precipitate formed was then filtered and recrystallised from methanol to afford
yellow crystalline solid of the title product, L1 (5.5 g, 19.55 mmol, 44%). The
schematic pathway to the synthesis of pivaloylthiourea derivatives (L1-L3) is, as
shown in Scheme 1.

Scheme 1. The synthetic pathway to the synthesis of pivaloylthiourea derivatives
L1-L3).
(
3
.2 Preparation of N-(4-methoxyphenyl)-N’-pivaloylthiourea (L2)
In a similar manner to the synthesis of L1, a brownish-purple precipitate of title
compound L2 (6.60 g, 24.80 mmol, 51%) afforded from the reaction of pivaloyl
chloride (5.87 g, 48.70 mmol), ammonium thiocyanate (3.70 g, 48.70 mmol) and 4-
methoxyaniline (6.00 g, 48.70 mmol).
3
.3 Preparation of N-(4-phenyl)-N’-pivaloylthiourea (L3)
In a similar manner to the synthesis of L1, the white precipitate of L3 (4.80 g,
0.26 mmol, 42%) afforded from the reaction between pivaloyl chloride (5.87 g,
8.70 mmol), ammonium thiocyanate (3.70 g, 48.70 mmol) and aniline (4.54 g,
8.70 mmol).
2
4
4
3
.4 Preparation of palladium(II) complexes
3
.4.1 Preparation of bis(benzonitrile)palladium(II) dichloride (M1)
The experimental details concerning the synthesis of Pd(II)-thiourea derivatives
had already been reported in the previous literature [18]. A solution of benzonitrile
15 mL) was added dropwise to PdCl (0.50 g, 2.82 mmol) in 100 mL three-necked
(
2
round bottom flask. The reaction mixture was heated (50 °C) in an oil bath for ca. 8

hours. The change of solution colour was observed from reddish to dark reddish-
brown after 5 hours of heating. The reaction mixture was then left undisturbed at
room temperature overnight to allow the formation of a red-orange crystalline
precipitate. The solid was collected by vacuum filtration to give a product of M1
(0.10 g, 20%). Scheme 2 illustrates the schematic pathway to the synthesis of Pd(II)
complex.
Scheme 2. the schematic pathway to the synthesis of Pd(II) complex.
2
3
.4.2 Preparation of dichloro [N-(4-nitrophenyl)-N’-pivaloylthiourea-κ S,O]
palladium(II) (MC1)
A solution of L1 (0.10 g, 0.36 mmol) in 3 mL acetonitrile was added dropwise
into a solution of M1 (0.14 g, 0.36 mmol) in 8 mL acetonitrile in a three-necked
round bottom flask. Then, the reaction mixture was put at reflux and stirred
continuously for ca. 3 hours under dry-nitrogen flow. The colour of the solution
changed from light red-brick to brownish solution after 3 hours of reaction. The
precipitate formed was filtered, and the solvent removed in-vacuo. The synthetic
approach applied to the synthesis of Pd(II) complexes is as shown in Scheme 3. The
green-brownish solid formed labelled as MC1 (0.10 g, 64%).

Scheme 3. The synthetic approach to the synthesis of Pd(II)-pivaloyl thiourea
complexes.
2
3
.4.3 Preparation of dichloro [N-(4-methoxyphenyl)-N’-pivaloylthiourea-κ S,O]
palladium(II) (MC2)
In a similar manner to the synthesis of MC1, an orange-brown precipitate of
MC2 (0.10 g, 82%) was obtained from the reaction of M1 (0.17 g, 0.44 mmol) and
L2 (0.12 g, 0.44 mmol) in acetonitrile as solvent.
2
3
.4.4 Preparation of Dichloro [N-(4-phenyl)-N’-pivaloylthiourea-κ S,O]
palladium(II) (MC3)
In a similar manner to the synthesis of MC1, a brown precipitate of MC3 (0.14
g, 74%) was obtained from the reaction of M1 (0.30 g, 0.79 mmol) and L3 (0.18 g,
0
.79 mmol) in acetonitrile as solvent. (0.14 g, 74%).
3
.5 General procedure for the Sonogashira cross-coupling reaction
Aryl bromides (1.00 mmol) and terminal alkynes (1.10 mmol) were charged to a
mixture of 1.00 mol% Pd(II) pivaloylthiourea derivatives (MC1-MC3), CuI (1.00
mol%), and triethylamine as a base (2 mmol) in 5 mL N, N’-dimethylformamide
(DMF) in a tube of Radley’s 12-placed carousel. The mixture was heated (60 °C)
with constant nitrogen flow for 24 hours. The aliquot was taken out after 24 hours

and analysed by GC-FID to investigate the percentage of product conversion. The
reaction mixture was then cooled to room temperature and extracted with ethyl
acetate and water. The collected organic layer was acidified with 2% hydrochloric
acid (HCl) to yield white-brownish precipitate. The precipitate was filtered and
dried in-vacuo to give a brown solid cross-coupling product.
4
. Results and discussion
4
.1 Spectroscopic studies
4
.1.1 Infrared spectroscopy analysis of L1-L3
The presence of different vibrational modes of functional groups in all
synthesised ligands (L1-L3) was determined by using Fourier-Transform Infrared
-1
(
FT-IR) spectroscopy in the range 400-4000 cm . From the experimental data, it
showed five major absorption bands of interest, namely, ν(N-H), ν(C=O), ν(C=N),
ν(C-N) and ν(C=S). Two absorption bands of ν(N-H) in the secondary thioamide
-1
-1,
group can be observed at 3290 to 3123 cm and 3149 to 3036 cm which represent
asymmetric and symmetric stretching vibration respectively. These assignments
were supported by previous studies, which stated that ν(N-H) could be seen above
-1
3
000 cm due to the occurrence of intramolecular hydrogen bonding [19, 20].
Influential absorption band, which is accredited to carbonyl stretching vibration
-1
ν(C=O), appears at about 1678 to 1666 cm in synthesised ligands, apparently
decreasing in frequencies compared to the ordinary carbonyl absorption, 1710 cm-1
[21,22]. This resulted from its conjugated resonance with the phenyl ring and the
formation of intramolecular hydrogen bonding with N-H in the -C(O)NHC(S)NH-
moiety.
The existence of intramolecular hydrogen bonds led to an increase in their
polarity, which decreases the strength of the double bond and thus, moves the
absorption to a lower wavenumber as reported. The most crucial changes were
-1
observed for the presence of the C=S stretching frequency at 741-760 cm . The
frequencies for ν(C=S) were found at low frequency due to the decrease of double-
bond character and the lower nucleophilic character of the sulfur atom in the C=S

moiety of the synthesised materials. The infrared spectra for all synthesised ligands
L1-L3 are illustrated in supporting information (Fig. S.I 1 – Fig. S.I 3).
4
.1.2 Infrared spectroscopy analysis of MC1 – MC3
Three palladium complexes have been successfully synthesised by the reaction
between ligand L1, L2, and L3, respectively, with bis(benzonitrile)palladium(II)
dichloride (M1) to afford corresponding palladium complexes labelled as MC1,
MC2, and MC3. Due to the unsuccessful single crystals growth for single-crystal
X-ray Diffraction analysis, the molecular structures of the complexes were
suggested from the spectroscopic results of FTIR, NMR, and electronic transition
analyses. From FTIR spectra, the frequencies of essential bands of interest namely
ν(N -H ), ν(N -H ), ν(C=O), ν(C-N) and ν(C=S) are evaluated and compared
1
1
2
2
between the free ligands and its corresponding metal complexes. Both ν(N -H ) and
1
1
-1
ν(N -H ) bands shifted to lower frequencies at ca. 132 to 137 cm and 108 to 173
2
2
cm-1, respectively, in complexes of MC1 and MC3 rather than their designated
ligands. However, MC2 complex reported higher frequency shifting at around 7.83
cm-1 in ν(N -H ) and slightly shifted to lower wavenumber in ν(N -H ) at
1
1
2
2
-1
approximately 8.77 cm in comparison to their free ligand.
According to previously reported literature [23], the stretching of N-H vibrations
is usually observed in lower frequencies and form a weak and broad band at
-1
approximately 2900-3200 cm in complexes relative to their ligands which suggest
the alteration of the double bond and single bond character of L1, L2 and L3 due to
the complexation with palladium(II) [24,25]. Besides, an upward shift of ν(C=O) is
-1
identified from 1666 to 1678 cm in the spectra of the free ligands to 1686 to 1695
-1
cm in the complexes of MC1, MC2, and MC3, which might be attributed to π
back donation that occur between the thiocarbonyls and the metal centre. Besides,
the ν(C-N) stretching vibration of L1 has shifted to lower frequencies at
-1
approximately 10 cm upon coordination to palladium, but surprisingly, in MC2
-1
and MC3, the ν(C-N) bands are shifted by ca. 23 to 25 cm to higher frequencies,
as a moderately strong band. The changes towards a higher shift of C-N bands
indicate the weakening of the C-N or C=S bonds on coordination. The C=S bond
tends to lose its double bond character while the C-N gains electron density, raising
its bond character. Table 1 indicates the comparison of vibrational analyses between

free ligands L1-L3 and their complexation with Pd(II) (MC1-MC3). The infrared
spectra for all synthesised ligands MC1-MC3 are illustrated in supporting
information (Fig. S.I 4 – Fig. S.I 6).
Table 1. Comparison of vibrational analyses of all synthesized ligands and
complexes.
-1
FTIR absorption bands (cm )
Compounds
ν(N -H )
ν(N -H )
ν(C=O)
1678
ν(C-N)
1325
ν(C=S)
737
1
1
2
2
L1
3284
3149
MC1
L2
3147
3123
2977
3036
1695
1314
732
1666
1324
743
MC2
L3
3131
3290
3159
3027
3149
3041
1688
1676
1686
1349
1326
1349
724
736
764
MC3
4
.1.3 NMR analysis of L1-L3
1
13
For structural elucidation, both H and C NMR of L1-L3 are consistent with
the expected molecular structures. Two singlet resonances were observed at
deshielded region at two different environments δ 8.58-8.63 ppm and δ 12.33-
H
H
1
3.00 ppm accordingly in which were allocated for the appearance of NH-C=O and
NH-C=S moieties due to the anisotropic effect from aromatic moieties and
…
intramolecular hydrogen bonding (N-H O) from the trans-cis conformation of
thiourea derivatives [26,27], N-H resonances for L1 shifted further downfield to δH
8
.64 and 13.00 ppm due to the presence of a strong electron-attracting group, -NO2
which leads to stronger interaction of hydrogen bonding compared to the existence
of the electron-donating group, -OMe (L2) and H (L3). The distinctive multiplet
resonance presence in the range of δ 6.50-8.00 ppm attributed to the presence of
H
1
3
aromatic protons. For C NMR, two signals within shielded region δ 26.9-27.0
C
ppm and δ 39.9-40.1 ppm represent methyl carbons and quaternary carbons,
C
respectively. Meanwhile, the aromatic carbons resonances can be found in between
δC 114.0-158.0 ppm for all compounds. The carbonyl and thione carbons can be
observed within range δ 178.5-179.8 ppm at the most deshielded region due to the
C

formation of intramolecular hydrogen bonding and the presence of electronegative
atoms of oxygen and sulfur. The signal of thione carbon (C=S) appears at the
highest values δ 179.8 ppm due to the lower excitation energy of n→π*, which
C
suggests the existence of very strong electron-withdrawing substituent that reduce
1
13
the nucleophilic character of the C=S group. The spectra for H and C NMR for all
synthesised ligands L1-L3 illustrated in supporting information (Fig. S.I 7 – Fig.
S.I 12).
4
.1.4 NMR analysis of MC1-MC3
1
In H NMR analyses of all complexes, the N-H signals became less intense as
well as shifted towards the downfield region upon coordination with palladium. The
resonance for N -H proton exhibited the most significant shift towards the
1
1
downfield area from δ 8.58-8.64 ppm (L1-L3) to δ 11.10-11.30 ppm upon
H
H
complexation. Besides, the proton for N -H experience slightly changes from δ
H
2
2
1
2.33-13.00 ppm (L1-L3) to δ 12.46-13.05 ppm in their corresponding complexes,
H
MC1-MC3. The substantial downfield shifting is affected by the reduced electron
density around N -H due to the effect from the metal ion, which resulted in a
1
1
reduction of the π-electron character of thione and thiocarbonyl and decreasing the
number of unshared pairs of electrons from two to one prior coordination with
Pd(II). From this fact, this indicates that the synthesised ligands L1-L3 are
coordinated to palladium (II) via thione and thiocarbonyl moieties. In addition, the
proton resonances of the phenyl ring in free ligands are attributed around δ 6.90-
H
8
.27 ppm, while, for the formation of complexes, the resonances are assigned
around δ 6.94-8.36 ppm. The most crucial shift in all compounds MC1-MC3 is on
H
carbonyl and thione moieties, which may arise due to coordination towards the
metal centre. The signal for carbonyl slightly shifted upfield while thione has shifted
towards the downfield region. Moreover, the carbons on the phenyl rings also
shifted towards the upfield and downfield region compared to their corresponding
values in the free ligands. This may be attributed to the fact that coordination of
oxygen and sulfur atoms through their lone pairs may lead to two opposing effects
which are, the presence of the electron-withdrawing effect of Pd(II) through σ-
bonding and NO substituent on the phenyl ring, would decrease the electron density
2
around C=S and carbon atoms of the ring. Additionally, a π-back bonding occurs

through d -p interaction between Pd(II) and a π* orbital of C=O which able to
π
π
accept electrons from the metal, thereby increasing the electron density at the carbon
atoms of carbonyl, hence, shifted the δ value to the higher field. Based on the
C
1
13
results obtained from FTIR, H, and C NMR can be concluded that the ligands are
coordinated to the metal centre, Pd(II) through C=O and C=S. The suggested
molecular structures of all complexes obtained are as illustrated in Fig. 1. The
spectra for H and 13C NMR for all synthesised metal complexes (MC1-MC3)
shown in supporting information (Fig. S.I 13 – Fig. S.I 18).
1
Fig. 1. General molecular structure for Palladium(II)-Pivaloyl thiourea complexes.
4
.1.5 Electronic analysis
The electronic transition of L1-L3 shows two influential bands represent
chromophores for carbonyl (C=O) and thione (C=S), which exhibit mixed
transitions of n→π* and π→π*. The broad and weak intensity of absorption bands
observed at 231-261 nm represent the carbonyl group, which is believed to exhibit
n→π* and π→π* transitions. These n→π* transitions involve the excitation of an
electron in a nonbonding atomic orbital such as unshared electrons on O, N, S, or a
halogen atom, to an antibonding π* orbital. However, from the absorption of C=O, a
hypsochromic shift occurred due to the presence of auxochrome methoxy and
hydrogen in the compound. Besides, the broad and weak intensity of the absorption
band can be observed at 269-294 nm is assigned to the transition involving the
mixed transition of n→π* and π→π* in thione moiety (C=S). The π→π* transition
involves molecules that contain double or triple bonds or aromatic rings having π
electron is excited to an antibonding π* orbital. A presence of NO band is observed
2
in the UV spectrum of L1 with maximum absorption observed at 334 nm. The
appearance of a shoulder or weak band is attributed to a highly conjugated system in
every synthesised compound. After complexation occurred, a valuable shift of these

bands to the low frequency is observed, which indicates the participation of
functional groups in coordination to the metal centre. UV-Vis experimental results
revealed that new absorption bands or a “hump” appeared in region 400 – 682 nm
that could be assigned as charge transfer (CT) of ligand to metal, O→Pd(II) and
S→Pd(II) as well as Pd(II) d-d bands. These observations are associated with the
participation of the ligand C=O and C=S groups in coordination to the central metal
ion. However, in this study, the d-d bands are not well resolved as observed in the
spectra of complexes, in which the bands attributed as weak shoulder and low molar
absorptivity, which may occur because of the charge transfer (CT) transition of the
ligand is overlapped with d-d transitions. The significant electronic absorption bands
for the ligands and their complexes are given in Table 2. The electronic transition
spectra for all synthesised ligands L1-L3 and their metal complexes, MC1-MC3 are
illustrated in supporting information (Fig. S.I 19 – Fig. S.I 24).
Table 2. UV-Vis data for the ligands (L1-L3) and their corresponding complexes
(MC-MC3).
Absorption λ/nm (Extinction
Compound
Possible Assignment
-1
-1
Coefficient ε/ M cm )/
L1
231.2 (14011)
n→π* and π→π*
n→π* and π→π*
n→π* and π→π*
n→π* and π→π*
n→π* and π→π*
n→π* and π→π*
n→π* and π→π*
n→π* and π→π*
n→π* and π→π*
n→π* and π→π*
CT and d-d
2
3
69.4 (17700)
34.6 (13206)
L2
L3
261.0 (12043)
85.6 (8568)
247.6 (14825)
94.2 (11430)
237.5 (5040)
2
2
MC1
2
3
70.5 (4022)
45.5 (4659)
4
70.0 (674)
258.0 (11107)
27.5 (7833)
35.0 (563)
277.0 (18371)
59.0 (747)
MC2
MC3
n→π* and π→π*
n→π* and π→π*
CT and d-d
3
4
n→π* and π→π*
CT and d-d
4

4
.2 Catalytic activity of Pd(II)-pivaloyl thiourea derivatives (MC1-MC3) in
Sonogashira cross-coupling reactions
The use of metal transition complexes as a catalyst has given a considerable
revolution in this field of cross-coupling reactions between a terminal alkyne and
aryl halides, in which they are widely used for the rapid and efficient synthesis of
alkyne derivatives. The catalytic activity of the homogenous MC1-MC3 catalysts
was investigated in the Sonogashira cross-coupling on the model reaction of 4-
bromoacetophenone with phenylacetylene catalysed by 1.00 mol% catalysts MC1-
MC3, copper (I) iodide as co-catalyst, triethylamine as a base in 5 mL N-N’-
dimethylformamide (DMF) as solvent under constant nitrogen flow at 60 °C for 24
hours (Scheme 4). A control reaction was conducted by following the same
procedure in the absence of Pd-catalysts. After 24 hours of reaction, each of the
reaction mixtures was analysed by GC-FID to determine the percentage conversion
of catalytic activity obtained by the MC1-MC3 catalyst. The remaining mixture was
then cooled to room temperature prior to extraction. As shown in Table 3, MC3
gave an excellent performance with almost 99% of product conversion, followed by
MC2 and MC1, which exhibit 35% and 27% of product conversion, respectively.
Apparently, without any metal-catalysed, the control reaction gave only a 22%
conversion of limiting reactant into the product. MC3 and MC2 act as the most
significant catalyst due to the presence of electron-donating substituent, MC2
(
OCH ), and MC3 (H), which can donate more electrons and can facilitate better in
3
transmetallation process [28].
Scheme 4. The general protocol for Sonogashira cross-coupling reaction.

a
Table 3. The effect of different catalyst MC1-MC3 on the Sonogashira cross-
coupling reaction.
Entry
Cat.
-
MC1
MC2
MC3
Base
Solvent
DMF
DMF
DMF
DMF
Yield (%)b
1
2
3
4
Triethylamine
Triethylamine
Triethylamine
Triethylamine
22
27
35
99
aReaction conditions: 4-bromoacetophenone (1.00ꢀmmol), phenylacetylene (1.10ꢀmmol),
catalyst (1.00 mol %), CuI (1.00 mol %), base (2.00ꢀmmol), solvent (5ꢀmL), 60 °C, 24 h.
b
GC yield against calibrated internal standard.
4
.3 Optimisation of catalytic activity
The presence of the base is one of the essential roles in defining the rate of
reaction and product formation in the Sonogashira cross-coupling reaction. Without
a base, only 15% of the targeted product was produced [29, 30]. Various types of
bases such as organic base, namely triethylamine (Et N) and inorganic bases, for
3
example, sodium carbonate (Na CO ), sodium hydrogen carbonate (NaHCO ) and
2
3
3
sodium acetate (NaOAc)were screened in the reaction model of 4-
bromoacetophenone with phenylacetylene to assess their catalytic activity. Amongst
them, Et N was found to be the most efficient base in terms of product yield, which
3
gave almost 99% of product conversion, while inorganic bases such as NaOAC and
NaHCO exhibit an acceptable percentage of product conversion 76% and 72%
3
respectively. The least capable base for the reaction model is Na CO which only
2
3,
gave 26% of product conversion (Table 4). The usage of Et N as a base has resulted
3
in a remarkably higher yield in the Sonogashira reaction, which might occur due to
its high solubility in the reaction mixture. Based on previously reported literature, it
was reasonable to suggest that the improvement of base solubility in the solvent
would lead to the acceleration of the reaction rate [31, 32]. Results indicated that
organic amines are more efficient than inorganic base because they efficiently trap
hydrogen halide formed in the reaction. Thus, it proves that the use of Et N helps in
3
the enhancement of catalysis as well as in the absorption of hydrogen halide.

The amount of catalyst loading in the catalytic system is another critically
important in the Sonogashira cross-coupling reaction as it may affect the efficiency
of overall catalytic activity. In this study, four different palladium catalysts loading,
which is 0.25, 0.50, 1.00, and 1.50 mol%, were used to study the effect of catalyst
loading on the conversion of 4-bromoacetophenone at 60 °C. As expected, the
model reaction gave the lowest product conversion in the absence of catalyst, and
most of the starting material remained intact (Table 3, entry 1). From the results
obtained in Table 5, the conversion of 4-bromoacetophenone increases with
increasing catalyst loading. However, as can be seen from Table 5, using a higher
amount of the catalyst has not resulted in further enhancement in the effectiveness
of reaction (Table 5, entry 4). When 1.50 mol% of catalyst loading was used, the
percentage of conversion decreased to give poor yield. Thus, at higher catalyst
loadings, the intrinsic catalytic activity is lower. This implicates the formation of
large unreactive Pd(0) clusters, formed via aggregation, at higher catalyst loadings,
which may serve as a reservoir for the reactive Pd(0), possibly a mononuclear,
catalytic species [33]. Meanwhile, the highest turnover number (TON) value of 100
was achieved when using 1.00 mol% of catalyst loading for 24 hours reaction. Thus,
the choice of 1.00 mmol% catalyst loading is suitable as it gave the highest TON
after the same period of reaction time compared to other catalyst loadings. From the
observations tabulated in Table 3-Table 5, we conclude that 1.00 mol% of the
catalyst (MC3), Et N (1.00 mmol) as the base in DMF at 60 °C, is the appropriate
3
reaction parameters for this product synthesis in Sonogashira cross-coupling
reaction.
Under the optimised reaction conditions, all the complexes (MC1-MC3) were
tested for a variety of activated and un-activated aryl bromides (Table 6). As shown
in Table 6, MC1-MC3 catalysts gave a high yield under optimum reaction
conditions, proving their wide substrate tolerance. From the results obtained, high
catalytic activity with good to excellent yields was observed in the coupling of
electron-deficient aryl bromides possessing an electron-withdrawing group such as
4
-bromoacetophenone (Table 6, entry 1). On the other hand, the reaction efficiency
of non-substituted bromobenzene and electron-rich aryl bromides with electron-
donating (4-bromoanisole) in (Table 6, entry 2 and 3) were low probably due to the

possible homo-coupling of alkynes in association with the decrease reaction rate in
the oxidative addition step of carbon-bromo bonds to the palladium metal while
using deactivated aryl bromides [34, 35]. As expected, the reactants of aryl
bromides consist of electron-withdrawing or electron-donating groups exhibited a
noticeable alteration in reactivity, indicating that the reaction was sensitive to the
electronic characteristics of the substituent under the present reaction conditions. In
this Sonogashira cross-coupling reaction, we believe that the pivaloyl thiourea
derivatives associated with Pd(II) complexes (MC1-MC3) provide the synergetic
steric and electronic effects to confer the appropriate properties to the metal centre
to optimise it for the critical steps of the catalytic cycles. Therefore, the proposed
mechanism for the Sonogashira cross-coupling reaction [29] is demonstrated in
Scheme 5. The first step of oxidative-addition involved the activation of the catalyst
to yield the chloride-free catalytic species before the addition of aryl bromide to this
active site of the complex. The next step is the addition of phenylacetylene and
formation of a Pd-acetylide complex via the transmetallation route. The final step is
the formation of the product via a reductive‒elimination process and liberating the
catalyst for the next catalytic cycle.
a
Table 4. Effect of bases on Sonogashira reaction of phenylacetylene and 4-
bromoacetophenone.
Entry
Base
Catalyst
MC3
MC3
MC3
MC3
Solvent
DMF
DMF
DMF
DMF
Yield (%)b
1
2
3
4
Et N
99
26
72
76
3
Na CO
2
3
NaHCO3
NaOAc
aReaction condition: [substrate]= 1.00 mmol; [base]=2.00 mmol; [catalyst loading]=
1
.00 mol%; [CuI] = 1.00 mol%, DMF=5 mL; temperature 60 °C; time = 24 hours.
b
GC yield against calibrated internal standard.
a
Table 5. Effect of catalyst loading on the Sonogashira reaction of phenylacetylene and
4
-bromoacetophenone.
Entry
Base
Catalyst
Catalyst
loading (%)
0.25
Solvent
DMF
Yield (%)b
1
2
3
4
Et N
3
MC3
MC3
MC3
MC3
17 (68)
28 (56)
99 (100)
18 (12)
Et N
3
0.50
DMF
DMF
DMF
Et N
3
1.00
Et N
3
1.50

a
Reaction condition: [substrate] = 1.00 mmol; [CuI] = 1.00 mol%, [Et N] = 2.00 mmol;
3
DMF = 5 mL; temperature 60 °C; time = 24 hours; Turn over number (TON) = mmol
product/ mmol catalyst used.
b
GC yield against calibrated internal standard.
a
Table 6. Sonogashira reaction of several aryl bromides with phenylacetylene.
Conversion of Aryl Bromides (%)b
Entry
Aryl Bromides
Control
MC1
27
19
MC2
35
17
MC3
99
1
2
3
4-bromoacetophenone
4-bromoanisole
22
9
20
39
bromobenzene
13
26
19
a
Reaction condition: [substrate] = 1.00 mmol; [catalyst] = 1.00 mol%, [CuI] = 1.00
mol%, [Et N] = 2.00 mmol; DMF = 5 mL; temperature 60 °C; time = 24 hours.
3
b
GC yield against calibrated internal standard.
Scheme 5. The proposed mechanism for the Sonogashira cross-coupling reaction.
5
. Conclusions
We have synthesised three derivatives of palladium-pivaloylthiourea complexes.
This Pd (II) complexes have been employed as catalysts in Sonogashira cross-

coupling reactions. For the Sonogashira coupling reaction, MC3 exhibited efficient
catalytic activity under copper(I) iodide co-catalyst in the Et N base and DMF
3
solvent in an inert atmosphere. In this work, palladium complexes have been
employed to act as a homogeneous catalyst in the Sonogashira cross-coupling
reaction in which the compounds were tested as a homogeneous catalyst in the
reaction model of phenylacetylene and 4-bromoacetophenone. The performances of
all catalysts were investigated by using less reactive substrates of aryl bromides
such as 4-bromoanisole and bromobenzene. Based on the experimental results
obtained, these catalysts are effective for activated aryl bromides that possess an
electron-withdrawing group. The activity follows in the order COCH >H>OMe.
3
Acknowledgements
The authors would like to acknowledge the financial support from Ministry of
Education, Malaysia for Fundamental Research Grant Scheme FRGS 59158,
MyBrain 15 for the postgraduate scholarship, Institute of Marine Biotechnology for
NMR analysis, Institute of Ibnu Sina, Universiti Teknologi Malaysia and Universiti
Malaysia Terengganu for research facilities and supports. We also would like to
wish everyone to stay safe and be strong during this hard time dealing with Covid-
1
9 pandemic and we will get through this very soon.
Disclosure statements
No potential conflict of interest was reported by the author(s).

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Credit author statement:
Wan M. Khairul: Supervision, writing-reviewing and editing; Falynee Faha Abdul
Wahab: Synthesis and characterisation work, methodology and data analysis; Siti
Kamilah Che Soh: reviewing for catalysis part; Mustaffa Shamsuddin: Supervision for
catalysis studies and reviewing for data and analysis for catalysis part; Adibah Izzati
Daud: Draft preparation and data analysis.
Declaration of interests
☒
The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in this
paper.
☐
The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:

Highlights
include 3 to 5 bullet points (maximum 85 characters, including spaces, per bullet point).



Palladium(II)-Pivaloyl thiourea complexes successfully synthesized and
characterized.
The Pd(II) complexes gave significant results in the Sonogashira catalytic
activity.
MC3 with no substitution exhibit the best catalyst as it gave a high conversion
rate.