N,N′-bridged binuclear NHC palladium complexes: A combined experimental catalytic and computational study for the Suzuki reaction

Article abstract of DOI:10.1002/aoc.5870

This work examines how N-donor bridged spacer ligands affect N-heterocyclic carbene (NHC) palladium complexes catalytic activities for Suzuki coupling reaction. Different degrees of structural flexibility binuclear NHC palladium complexes were synthesized. The more flexible nitrogen-based alkyl chain ligand shows similar performance with cycloamine counterparts in the Suzuki coupling reaction. Suzuki coupling examples were used in air and ambient temperature to reach moderate to completion yields in short time. Density functional theory calculations showed that the chelate effect, associated with a single Pd complex mechanism, plays a fundamental role in the pre-catalysis stage, supporting a reasonable of the kinetic activity observed experimentally.

Full text of DOI:10.1002/aoc.5870

Received: 9 April 2020
DOI: 10.1002/aoc.5870
Revised: 21 May 2020
Accepted: 23 May 2020
F U L L P A P E R
0
N,N -bridged binuclear NHC palladium complexes: A
combined experimental catalytic and computational study
for the Suzuki reaction
1
1
1
2
Ming-Tsz Chen
| Bing-Yan Hsieh | Yi-Hung Liu | Kuo-Hui Wu
|
3
3
Natália Lussari
| Ataualpa A.C. Braga
1
Department of Applied Chemistry,
Providence University, Taichung, 43301,
Taiwan
This work examines how N-donor bridged spacer ligands affect N-heterocyclic
carbene (NHC) palladium complexes catalytic activities for Suzuki coupling
reaction. Different degrees of structural flexibility binuclear NHC palladium
complexes were synthesized. The more flexible nitrogen-based alkyl chain
ligand shows similar performance with cycloamine counterparts in the Suzuki
coupling reaction. Suzuki coupling examples were used in air and ambient
temperature to reach moderate to completion yields in short time. Density
functional theory calculations showed that the chelate effect, associated with a
single Pd complex mechanism, plays a fundamental role in the pre-catalysis
stage, supporting a reasonable of the kinetic activity observed experimentally.
2
Department of Chemistry, Graduate
School of Science, The University of
Tokyo, Tokyo, Japan
3
Departamento de Química Fundamental,
Instituto de Química, Universidade de S ~a o
Paulo, Avenida Professor Lineu Prestes,
7
48, S ~a o Paulo, 05508-000, Brazil
Correspondence
Ming-Tsz Chen, Department of Applied
Chemistry, Providence University,
Taichung 43301, Taiwan, ROC.
Email: mschen@pu.edu.tw
K E Y W O R D S
binuclear NHC–palladium complexes, density functional theory (DFT), N-donor, pre-catalysis,
Suzuki–Miyaura reaction
Ataualpa A. C. Braga, Departamento de
Química Fundamental, Instituto de
Química, Universidade de S ~a o Paulo,
Avenida Professor Lineu Prestes, 748, S ~a o
Paulo, 05508-000, Brazil.
Email: ataualpa@iq.usp.br
Funding information
Conselho Nacional de Desenvolvimento
Científico e Tecnológico, Grant/Award
Numbers: 146287/2017-7, 309715/2017-2;
Fundaç ~a o de Amparo à Pesquisa do
Estado de S ~a o Paulo, Grant/Award
Numbers: #2014/25770-6, #2015/01491-3;
Ministry of Science and Technology,
Taiwan, Grant/Award Number: MOST
107-2113-M-126-001-MY2
[
1]
1
| INTRODUCTION
activities. To date most applications have included the
construction of not only carbon–carbon but also carbon–
heteroatom bonds in a broad range of chemistry fields
such as bioactive, conductive and fluorescent com-
pounds, which are widely employed in pharmaceutical
In recent decades, N-heterocyclic carbene (NHC) ligands
have emerged as very highly powerful theme in transi-
tion metal organometallic chemistry with properties
including ease of preparation and modification, good sta-
bility, functionality tolerance, and good catalytic
[
2]
and materials sciences. Initial cross-coupling reactions
paid more attention to the rich variety of organometallic
Appl Organomet Chem. 2020;e5870.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
1 of 16
https://doi.org/10.1002/aoc.5870

2
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CHEN ET AL.
[
3]
nucleophiles that could be used for these reactions and
recent research interest has focused on the activation of
more varied and challenging electrophiles such as aryl
in literature review, fine-tuning steric hindrance has
led to major breakthroughs and improvements in
[
19]
catalysis.
Bulky ligands stabilize the active spe-
[4]
[5]
[6]
[7]
chlorides, aryl ethers, aryl esters, and aldehydes,
cies and disfavor bimolecular decomposition and
[4a,c–f,8]
[20]
or finding mild reaction conditions.
Resulted from
other deactivation events.
However, steric bulk
increasing numbers of studies gaining hands-on experi-
ences of developing catalysts as well as raising more
insight and clear information referred to mechanistic
hinders the approach of the substrate, which might
diminish catalytic activity. Although electron rich-
ness and steric bulk are important, a delicate bal-
ance with the degree of ligand flexibility seems to
be the key to successful enhancement of catalytic
efficacy. Fine-tuning flexibility/steric bulk allows the
ligand to adapt to the changing needs in the cata-
[2b,d,e,9]
studies have been investigated.
In NHC ligands the carbene is located in an N-
heterocyclic framework. Many different NHCs have been
presented in the literature, and much has been learned
about their properties and reactivity. Various studies have
been carried out on NHCs and have led to a growing
familiarity and understanding of them. Importantly, they
have been found to enhance reactivity on the combina-
tions different donors to cooperate metal centers. In cou-
pling reactions, high-performance catalysts bearing both
NHCs and different auxiliary ligands have been synthe-
[
21]
lytic cycle.
Therefore, a less sterically demanding
ligand is favorable for oxidative addition and tran-
smetalation, and reductive elimination should bene-
fit from more demanding conformations around the
[
22]
metal center.
To find out a good ligand to syn-
thesize a good activity of complex, we chose flexible
and labile tertiary alkyl diamines instead of
cycloamines bridged two NHC Pd complexes, as
depicted in Figure 1. Furthermore, depending on
experimental and density functional theory (DFT)
studies to discuss differences of catalytic systems in
Suzuki coupling reaction.
[
4e,8a,10]
[11]
sized, such as N-donors,
donors.
P-donors
and other
[
4c,12]
Attention has turned to designing an effec-
tive catalyst from a stable Pd(II) complex go into the
active Pd(0) species in the transition state during the cata-
lytic cycle is the vital research topic. From our previous
studies, the “throw-away” ligand(s) are the most crucial
key due to the “throw-away” property like a switch to
incorporate active metal center to produce active
2 | EXPERIMENTAL
[4e,f]
Pd(0) species during the catalytic process.
Hundreds of NHC palladium complexes exhibit
excellent activities toward the Suzuki coupling reaction
under mild conditions, such as oxygen-containing
2.1 | Reagents and methods
Unless otherwise noted, all experiments were performed in
air. All solvents and reagents were used as received. The
reagents were purchased from Sigma-Aldrich, Acros, Merck,
TEDIA, and Alfa-Aesar of USA. The imidazolium salt
IPrꢀHCl and NHC palladium complexes were prepared by
following literature procedures and their identities and
[4d]
donor groups,
as well as NHC palladacycle com-
plexes supported by an N-donor using IPA (Isopropyl
[13]
alcohol) as a solvent at room temperature.
In the
literature, examples of the impact of mononuclear
NHC Pd complexes bearing N-donor groups indicated
highly cooperating abilities because of labile or
1
[23]
purities were confirmed by H NMR spectroscopy.
[
1b]
hemi-labile properties of N-donor groups
have
All aryl halides and boronic acids were used as
received. Technical grade ethyl alcohol was used to carry
out Suzuki–Miyaura cross-coupling reactions. All reac-
tions were carried out in air at ambient temperature.
Flash chromatography was performed on silica gel
60 (230–400 mesh) using mixtures of hexanes/ethyl ace-
tate (10:1), unless otherwise noted.
[
14]
[4e,10b,15]
been presented by Organ,
Navarro,
Mononuclear NHC Pd
[
16]
[4f,17]
Lu,
and our group
complexes have been studied and show excellent
activity in coupling reactions. Less research has
focused on binuclear NHC Pd systems, and fewer
[
10n,18]
examples have been reported.
Also, attribution
FIGURE 1 The idea for
comparison catalytic studies

CHEN ET AL.
1
3 of 16
13
1
H and C{ H} NMR spectra were recorded on
Bruker-AV-400 (400 MHz) spectrometers in chloroform-d
at ambient temperature unless stated otherwise and
referenced internally to the residual solvent peak and
reported as parts per million relatives to tetramethylsilane.
Elemental analyses were performed by Elementarvario EL
III. The melting points were determined using a FARGO
MP-2D melting point apparatus.
49.7 (s, NCH ), 59.3 (s, NCH ), 123.8 (s, CH aromatic),
3
2
124.8 (s, CH aromatic), 130.1 (s, N–CH), 135.1 (s,
C aromatic), 146.8 (s, C aromatic), 154.2 (s, Ccarbene).
Anal. calcd for C H Cl N Pd : C 58.05, H 7.19, N
6
1
90
4
6
2
6.66; found: C 58.15, H 7.09, N 6.26. Melting point
ꢁ
278.5 C.
[
18b]
Synthesis of 1c
: The procedure for the prepa-
ration of 1c was similar to that used for 1a but used
The Suzuki–Miyaura cross-coupling reactions were
analyzed by two methods.
[Pd(μ-Cl)Cl(IPr)] (110 mg, 0.1 mmol), 1,4-diazabicyclo
2
[2.2.2]octane (11.2 mg, 0.1 mmol), and DCM (2 ml).
The pale yellow desired solid was obtained in 72%
yield (90 mg).
Method 1: Gas chromatography barrier ionization dis-
charge (GC-BID) on a Nexis GC-2030 gas chromatograph
coupled with a Shimadzu BID detector (Shimadzu Scien-
tific Instruments, Inc., Columbia, MD, USA) equipped
with a Bruker BR-5 ms column.
[
18b]
Synthesis of 1d
:
The procedure for the
preparation of 1d was similar to that used for 1a but used
[Pd(μ-Cl)Cl(IPr)] (110 mg, 0.1 mmol), pyrazine (8 mg,
2
Method 2: Gas chromatography–mass spectrometry
0.1 mmol), and DCM (2 ml). The pale yellow desired
(GC–MS) on a Bruker SCION 436 SQ instrument
solid was obtained in 90% yield (110 mg).
equipped with a Bruker BR-5 ms column. The MS detec-
tor was configured with an electronic impact ionization
source.
2.2 | X-ray data collection and structure
Synthesis of 1a: A vial was charged with [Pd(μ-Cl)Cl
refinement
0 0
IPr)] (110 mg, 0.1 mmol) and N,N,N ,N -tetramethyl-
2
(
ethylenediamine (11.6 μl, 0.1 mmol), with DCM (dic-
hloromethane, 2 ml) as solvent. The solution was stirred
at room temperature for 1 hr. The solution was filtered
through a pad of Celite, and the filtrate was removed
from the solvent to afford a pale yellow solid, obtaining
Crystals of complexes 1a–1c were grown from concen-
trated dichloromethane/hexane solution and isolated
by filtration. Suitable crystals were mounted on a glass
fiber using perfluoropolyether oil (FomblinY) and
cooled rapidly under a stream of cold nitrogen gas to
collect diffraction data at 150 K using a Bruker APEX2
diffractometer. The intensity data were collected in
1
the desired compound in 88% yield (110 mg). H NMR
(
400 MHz, CDCl ) δ: 1.02 (d, J = 6.8 Hz, CH(CH ) , 24H),
3 3 2
ꢁ
1
1
8
.35 (d, J = 6.8 Hz, CH(CH ) , 24H), 1.89 (s, N(CH ) ,
1350 frames with increasing ω (width of 0.5 per
3
2
3 2
2H), 2.56(s, NCH , 4H), 3.05 (sep, J = 6.8 Hz, CH(CH ) ,
frame). Absorption correction was applied using
2
3 2
[
24]
H), 7.00 (s, NCH, 4H), 7.25–7.28 (m, ArH, 8H), 7.41 (t,
SADABS.
The structure was solved by direct
13
1
[25]
J = 7.6 Hz, ArH, 4H). C{ H} NMR (100 MHz, CDCl ) δ:
methods using a SHELXTL package.
All non-H
3
2
3.0 (s, iPr), 26.3 (s, iPr), 28.6 (s, CHiPr), 50.2 (s, N
atoms were located from successive Fourier maps and
H atoms were refined using a riding model. Aniso-
tropic thermal parameters were used for all non-H
atoms and fixed isotropic parameters were used for H
atoms. Details of the data collection and refinement
are given in Supporting Information Table S1 (Data
2 in Supporting Information).
CCDC 1939941 and 1,939,943–1,939,944 are given in
the supplementary data for this paper. These detail crys-
tal data can be obtained free of charge from the Cam-
bridge Crystallographic Data Centre (www.ccdc.cam.ac.
uk/data_request/cif) and cif checked files can be obtained
in Supporting Information (Data 1).
(
CH ) ), 58.5 (s, NCH ), 123.9 (s, CH aromatic), 124.8 (s,
3
2
2
CH aromatic), 130.0 (s, CH aromatic), 135.3 (s,
C aromatic), 147.0 (s, C aromatic), 154.3 (s, Ccarbene).
Anal. calcd for C H Cl N Pd : C 57.74, H 7.11, N 6.73;
found: C 58.19, H 7.07, N, 6.52. Melting point 247.9 C.
Synthesis of 1b: The procedure for the preparation
of 1b was similar to that used for 1a but with [Pd
60
88
4
6
2
ꢁ
0
0
(
μ-Cl)Cl(IPr)] (110 mg, 0.1 mmol) and N,N,N ,N -tetra-
2
methyl-1,3-propanediamine (13.2 μl, 0.1 mmol) and
DCM (2 ml). The pale yellow desired solid was
obtained in 92% yield (110 mg). H NMR (400 MHz,
CDCl ) δ: 1.04 (d, J = 6.8 Hz, CH(CH ) , 24H), 1.26
1
3
3 2
(
m, CH (CH ) , 2H), 1.40(d, J = 6.8 Hz, CH(CH ) ,
2 2 2 3 2
2
4H), 1.93 (s, N(CH ) , 12H), 1.96–2.14 (m, overlap,
3
2
NCH CH CH N
J = 6.8 Hz, CH(CH ) , 8H), 7.03 (s, NCH, 4H), 7.27
+
N(CH ) , 18H), 3.10 (sep,
2.3 | Procedure for the Suzuki–Miyaura
2
2
2
3 2
cross-coupling reaction
3
2
(
d, J = 8 Hz, ArH, 8H) 7.41 (t, J = 7.6 Hz, ArH, 4H).
C{ H} NMR (100 MHz, CDCl ) δ: 23.2 (s, CHCH ),
1
3
1
Complex (1 mol% Pd), base (1.8 equiv.), and phe-
nylboronic acid (1.5 equiv.) were added in turn to a
3
3
2
5.3 (s, CH (CH ) ), 26.3 (s, CHCH ), 28.6 (s, CHCH ),
2 2 2 3 3

4
of 16
CHEN ET AL.
vial equipped with a magnetic bar and sealed with a
screw cap. Technical grade solvent (1 ml) was injected
into the vial and the mixture stirred on a stirring plate
at room temperature. Aryl chloride (0.5 mmol, if liq-
uid) was then injected (or charged if solid). The reac-
tion was monitored by GC-BID or GC–MS. When the
reaction was finished, the solvent was evaporated
under vacuum and the product isolated by flash chro-
matography. The amount of product shown is the
average of two runs.
3 | RESULTS AND DISCUSSION
3.1 | Synthesis of binuclear NHC
complexes
The practical and very efficient protocol for the prepara-
tion of binuclear NHC Pd complexes was carried out
[
4e,f,10b]
according to our previous studies.
Synthesis of
complexes 1a–1d was straightforward and they were
obtained from the corresponding parent [Pd(μ-Cl)Cl(IPr)]2
dimer combined with 1 equiv. of N-linker reagent in
CH Cl at room temperature for 1 hr. Synthetic details are
2
2
2
.4 | DFT studies
shown in Scheme 1. In order to discuss comparison of
the catalytic activities of complexes and complexes 1c-1d
[18b]
All calculations were performed at density functional
were prepared and checked with the literature.
The
[26]
theory (DFT) level
software (version D01).
the kinetic profile and its respective vibrational fre-
quencies were performed with M06L functional
gas phase; the 6-31G(d,p) basis set was applied for all
main group elements and the valence/relativistic-
available in Gaussian 09 suite
target complexes were isolated in satisfactory to good yields
of 88% for 1a, 92% for 1b, 72% for 1c, and 90% for 1d as
yellow solids by evaporating the solvent. Complexes 1a and
1b are new complexes that are moisture- and air-stable and
can be stored and handled in air.
[27]
Geometry optimizations for
[
28]
at
[29]
pseudopotential SDD
for palladium (Pd) atom.
Geometries for the thermodynamic analysis were opti-
mized in condensed-phase (ethanol) described by the
3.2 | Spectral and structural studies
[
29]
SMD (The Solvation Model based on Density)
continuum-dielectric solvation model. The intrinsic
Complexes 1a and 1b were fully characterized by elemen-
1
13
tal analysis as well as H and C NMR spectroscopy. An
[30]
13
1
reaction coordinate method
was used to confirm the
obvious and expected downfield shift in the C{ H} NMR
of the carbene carbon signal for the σ-donating of the N-
donor groups was observed for complexes 1a and 1b. The
connection between the transition states and the
corresponding intermediates. All the energy profiles
were discussed as a function of Gibson-free energies
relative to separated reactants and related energies and
cartesian coordinates can be obtained in Supporting
Information (Data 3 and 4).
1
3
C NMR spectra showed a diagnostic Pd–C
peak at
carbene
13
154.3 ppm for 1a and 154.2 ppm for 1b. These C signals
showed a similar trend as complexes 1c and 1d (1c
[
18b]
153.1 ppm; 1d 152.4 ppm).
SCHEME 1 Synthesis of bis(NHC)
PdCl -N-linker complexes 1a–1d
2

CHEN ET AL.
5 of 16
Solid-state structures were determined by single-
As shown in Figures 2–4, in complexes 1a–1c each Pd
center is a four-coordinated by an N-heterocyclic carbene
ligand, an N-donor from the bridged diamine ligand, and
two chloride ligands, with angles between adjacent
ligands ranging from 85.29(8) to 94.3(2) . The details of
structural structures analysis focused on the structural
parameters around the palladium centers, like the bond
angles and bond distances, are located in a similar range
to those found in mononuclear NHC palladium com-
plexes. Selected bond distances and angles are listed in
Table 1.
crystal X-ray diffraction for complexes 1a–1c. All crystal
structures were grown from dichloromethane or a mix-
ture of dichloromethane/hexane. Crystal structural
images of complexes 1a–1c are depicted in Figures 2–4.
The summary of the crystallographic data is given in
Supporting Information Table S1 (Data 2 in Supporting
Information). As expected, the structures of 1a–1c dem-
onstrated a dinuclear scaffold with two palladiums cen-
ters bound together by a tertiary diamine ligand. Each
palladium center adopted a lightly distorted square-
planar geometry with two chloride ligands perpendicular
to the plane of the NHC and a N-donor group trans to
it. Structures 1a–1c exhibited similar coordinative behav-
iors to those found in mononuclear NHC palladium
complexes.
ꢁ
ꢁ
3.3 | Catalytic studies for the Suzuki
coupling reaction
All molecular structures of 1a–1c bearing the same
NHC backbone are quite similar except for the substitu-
ent bridged N-donor ligands. The predominant molecular
geometry for 1a and 1c is a zigzag chain structure of N-
donor groups, N–C–C–N for 1a and N-C-C-N for 1c, in
which the NHC groups are oriented in opposite direc-
tions as reported in the literature for bridged diphosphine
Previous studies by our group have shown that mononu-
clear NHC palladium complexes bearing N,N -
0
dimethylbenzylamine are effective in the Suzuki coupling
reaction when aryl chlorides or benzyl chlorides are used
[
4f,17]
as the starting materials.
Here, we carried out cata-
lyst testing by screening the activities of complexes 1a–1d
in the Suzuki coupling reaction. In the initial studies, the
model reaction conditions used 2-chloro-m-xylene and
phenylboronic acid at room temperature. Four bases
[18c]
palladium complexes.
The two carbene ring planes
adopt a parallel geometry in complex 1a, but non-
t
coplanar carbene ring plane orientation was found with
(K PO , K CO , KOH, KO Bu) and five solvents (toluene,
3
4
2
3
ꢁ
vertical separation angles of 76.20 for complex 1b and
THF, DME, EtOH, IPA) were used to combine in a cross-
ing way to seek the best optimum condition. The results
are collected in Table 2.
ꢁ
4
9.70 for complex 1c. The dihedral angles between the
carbene ring plane and the Pd–C–N–Cl coordination
ꢁ
ꢁ
ꢁ
plane were 74.78 for complex 1a, 71.74 and 70.72 for
Based on this preliminary screening of conditions,
complex 1a achieved 60% and 64% yields for 12 hr at
ꢁ
ꢁ
complex 1b, and 71.96 and 70.91 for complex 1c, which
are located typically in NHC palladium complexes to
relieve steric congestion.
t
room temperature for KO Bu/EtOH and KOH/EtOH,
respectively (Table 2, entry 9 vs. 11). When arylchloride
FIGURE 2 Crystal structure of 1a with
thermal ellipsoids drawn at the 50%
probability level. Hydrogen atoms are
omitted for clarity

6
of 16
CHEN ET AL.
FIGURE 3 Crystal structure of 1b
with thermal ellipsoids drawn at the 50%
probability level. Hydrogen atoms are
omitted for clarity
FIGURE 4 Crystal structure of 1c with
thermal ellipsoids drawn at the 50% probability
level. Hydrogen atoms are omitted for clarity
ꢁ
Selected bond distances (Å) and angles ( ) around
was changed for 2-chloroanisole to compare their reactiv-
ity, the combination of KO Bu/EtOH showed better con-
TABLE 1
Pd in complexes 1a–1c
t
version (63%) than KOH/EtOH (42%) over 4 hr (Table 2,
entry 12 vs. 13). In addition, to modify the optimum con-
dition, we explored different equiv. values for phe-
1
a
1b
1c
Pd(1)–Cl
1)
Pd(1)–Cl
2)
Pd(1)–C
1)
Pd(1)–N
3)
C(1)–Pd
2.3139
(13)
2.2980 (7),
2.3024 (8)
2.284 (3),
2.303 (3)
a
a
a
t
(
nylbornoic acid and KO Bu (1.2, 1.8, and 2.4 equiv.).
t
2.2841
(15)
2.3138 (7),
2.3144 (9)
2.313 (3),
2.305 (3)
With 1.8 equiv. loading of phenylbornoic acid/KO Bu
a
(
gave completion yield for complexes 1c and 1d (Table 2,
entries 15–17). Complex 1a needed an extended reaction
time of 6 hr to reach 97% conversion (Table 2, entry 14).
We plotted conversion versus time to observe the cata-
lytic activity, and found that complexes 1b and 1d
afforded closed good activity than the others (Figure 5).
To determine the best catalytic performance, the catalyst
loading was reduced to half dosage as 0.5 mol% Pd. Only
complex 1b allowed the coupling to proceed in high yield
in a shorter reaction time at room temperature than the
other complexes including its parent complex, [Pd(μ-Cl)
1.958
(5)
1.962 (3), 1.964
1.972 (10),
1.958 (10)
a
a
(
(3)
2.180
(4)
2.187 (2), 2.159
(3)
2.166 (9),
2.162 (9)
(
88.06
(14)
85.29 (8), 86.40
87.4 (3), 89.5
a
a
(
(
1)–Cl
1)
(8)
(3)
C(1)–Pd
179.09
(18)
178.89 (10),
176.5 (4),
177.3 (4)
a
a
(
(
1)–N
3)
174.82 (13)
Cl(2)–Pd
92.84
(12)
91.10 (7), 91.95
89.0 (2), 94.3
Cl(IPr)] (Table 2, entries 18–21).
2
a
a
(
(
1)–N
3)
(10)
(2)
In the initial optimum conditions studies,
t
KO Bu/EtOH showed the best performance, giving
a
Reported structural data measured by the other Pd metal center.
higher yield when using 2-chloro-m-xylene or

CHEN ET AL.
7 of 16
a
TABLE 2
Optimum conditions for the Suzuki–Miyaura coupling reaction
b
Entry
Complex (mol%)
1a (0.5)
1a (0.5)
1a (0.5)
1a (0.5)
1a (0.5)
1a (0.5)
1a (0.5)
1a (0.5)
1a (0.5)
1a (0.5)
1a (0.5)
1a (0.5)
1a (0.5)
1a (0.5)
1b (0.5)
1c (0.5)
Solvent
Toluene
THF
Base
Time (hr)
12
Yield (%)
1
2
3
4
5
6
7
8
9
K
K
K
K
K
K
K
3
3
3
3
3
2
2
PO
PO
PO
PO
PO
4
4
4
4
4
0
12
0
DME
12
0
EtOH
IPA
12
38
0
12
Toluene
EtOH
Toluene
EtOH
DME
CO
3
3
12
1
CO
12
48
18
60
0
KOH
12
KOH
12
t
10
11
12
13
14
15
16
17
18
19
20
21
KO Bu
12
t
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
KO Bu
12
64
42
63
97
99
97
99
88
62
65
74
c
KOH
4
c
t
KO Bu
4
d
d
d
d
d
d
d
d
t
KO Bu
6
t
KO Bu
1.33
1.33
1.33
1.66
1.66
1.66
1.66
t
KO Bu
t
1d (0.5)
1b (0.25)
1c (0.25)
1d (0.25)
KO Bu
t
KO Bu
t
KO Bu
t
KO Bu
t
[Pd(μ-Cl)Cl(IPr)]
2
(0.25)
KO Bu
a
Reaction conditions: 2-chloro-m-xylene (0.5 mmol), phenylboronic acid (0.6 mmol), 1.2 equiv. base, 1 mol% Pd catalyst loading, and 1 ml
ꢁ
solvent, 27 C.
b
Determined by GC-BID, average of two runs.
c
Using 2-chloroanisole instead of 2-cholor-m-xylene.
d
t
Using 1.8 equiv. phenylboronic acid and 1.8 equiv. KO Bu.
2
-chloroanisole combined with phenylboronic acid as the
coupled products were obtained in a short time (from
minutes to 24h). Results are shown in Table 3.
starting materials in the presence of complex 1b
(
Table 2). The mono-, di-or tri-substituted coupling prod-
All reactions were carried out at room temperature
and in air. Under optimum conditions allowed the cou-
pling of mono-substituted activated, neutral and
unactivated aryl chlorides, all reaction time fall into 20 to
49 min to achieve 89–99% isolated yield (4a–4c, 4f–4i).
When using 2-chloroaniline as the starting material, a
longer reaction time was required to obtain moderate
yield (4d, 75%, 120 min). The catalyst poisoning starting
material such as 2-chlorothiophene took 120 min to
ucts between either of functionalized arylchlorides or
phenylboronic acid were examined (Table 3). To reduce
the cost, the amount of phenylboronic acid was reduced
to 1.5 equiv. and yield for the coupling results did not
decrease. Suzuki coupling reactions were carried out
using a 1:1.5 stoichiometric ratio of aryl chlorides and
t
phenylboronic acid, with 1.8 equiv. KO Bu and 1 mol%
Pd loading of complex 1b as precatalyst in nonpurified
ethanol medium at room temperature. The reactions
between aryl chlorides and phenylboronic acid were
found to proceed smoothly and the corresponding
ꢁ
afford 76% yield, but on heating to 60 C the completion
yield was reached in 10 min (4e). Because the competi-
tive coordination abilities of starting materials to

8
of 16
CHEN ET AL.
base ligands, like phosphines. This affords more stable
complexes then led to diminish the catalytic activity or
needed high activation energy to overcome in the reac-
tions. In the other words, if we choose more flexible
ligands such as tertiary amines (hard base) play an ancil-
lary ligand role, this will help to shorten the preactivation
step time in the catalytic cycle.
3.4 | Scale-up in the Suzuki reaction
The high cost and lack of availability of palladium are
important issues for any large-scale application. To exam-
ine the application of our synthesized Pd complexes, the
gram scale experiment was carried out with
a
4-cholorobenzadehyde and phenylboronic acid as the
FIGURE 5 Plotted conversion vs. time. Reaction
conditions:2-chloro-m-xylene (0.5 mmol), 1.8 equiv. phenylboronic
starting materials under the described optimum condi-
tions. After 2 min of reaction time, the completion yield
was observed by GC–MS. After column chromatography
purification, the cross-coupling biaryl product 4i was
obtained in 95% yield (1.73 g), as shown in Scheme 2.
t
acid, 1.8 equiv. KO Bu, 0.5 mol% complexes 1a–1d catalyst loading,
ꢁ
b
and 1 ml EtOH, 27 C. Determined by GC-BID, average of
two runs
palladium center led to more reaction time to reach good
yield. Di- substituted products were afforded in coupling
reaction: di-ortho- (4j and 4k), one ortho- and one meta-
3.5 | DFT studies
(
4l and 4m), one para- and one ortho- (4n–4p), one para-
From a review of reports in the literature, NHC Pd com-
plexes bearing alkyl amine(s) were found to exhibit
and one meta- (4q–4s), both para-(4t and 4u), and both
ortho-substituted (4v), and reaction times of 30–120 min
to afford 75–98% yield. Some tri-substituted products
were obtained after a longer time of 1–24 hr or by heating
at 60 C for 60 min to achieve 73–97% yield (5a–5g). After
these substrates were analysed, complex 1b showed
[
4e,f,15a,17]
higher activities than cycloamines.
Hence, some
computational studies were performed. And ry to under-
stand why the addition of one methylene group in the
central carbon chain resulted in 1a and 1b exhibiting dif-
ferent catalytic activities.
ꢁ
expected active abilities for Suzuki cross-coupling reac-
Entries 14–18 in Table 2 show that higher coupling
yields were observed, increasing the base and boronic
acid concentrations. Moreover, the yields also were
higher in presence of an electron-rich aryl halide such
as 2-chloroanisole (entries 12 and 13). These results
lead us to carry out computational studies on the tran-
smetalation and reductive elimination steps of the
Suzuki–Miyaura reaction mechanism. To obtain the
final biphenyl (Ar = Ph) product, the activation barrier
for the transmetalation step was 4.2 kcal/mol for 1a_1
to overcome the transition state and produce 1a_2
(Table 4, entry 1). Since the activation barrier for 1b_1
to 1b_2 was calculated to be 5.2 kcal/mol (Table 4,
entry 2), the barrier involving 1a complex is
1.0 kcal/mol lower than for the transmetalation step
catalyzed by 1b. In the case of the reductive elimina-
tion step, the activation barrier was calculated to be
10.9 kcal/mol for 1a_2 to produce 1a_3 (Table 4, entry
3) and 8.5 kcal/mol for intermediate 1b_2 to achieve
1b_3 (Table 4, entry 4). However, this reactivity inverts
if we calculate the same step for applying the o-xylenyl
[18b,c,e]
tion than cycloamine bridged ligands.
There have
been reports of multinuclear complexes displaying coop-
erative reactivity between multiple metal centers and are
far more catalytically active potential to outperform exis-
[31]
ting mononuclear counterparts.
Unfortunately, our
dinuclear palladium complex catalytic system did not
have a good synergy effect but demonstrated a similar
level of catalytic activity as Pd-PEPPSI catalyst (pyridine-
enhanced precatalyst preparation stabilization and initia-
tion) and exhibited higher activities in comparison with
NHC palladium complexes generated in situ. In overall
catalytic activities comparison jobs toward arylchlorides
as staring materials for Suzuki reaction, mononuclear
[
4e,f]
NHC palladium complexes bearing tertiary amines
showed the best performance than Pd-PEPPSI,
[14]
similar
referred to our dinuclear palladium complexes bearing
tertiary amines spacer, then mononuclear NHC palla-
dium complexes mixed with ligands, such as
[11d]
[11b]
phosphines,
or phosphites.
This is because the
soft acid of palladium(II) favors coordination with soft

CHEN ET AL.
9 of 16
a,b
TABLE 3
Suzuki–Miyaura coupling products
c
4
4
4
4
a: R
b: R
c: R
d: R
1
= H, 28 min, 99%
= CH , 49 min, 89%
= OCH , 35 min, 90%
= NH , 120 min, 75%
4e: 120 min, 76%
4f: R
4 g: R
4 h: R
4i: R
1
= CH
= OCH
= CF , 35 min, 97%
= C(O)H, 20 min, 98%
3
, 35 min, 96%
ꢁ
c
1
3
60 C, 10 min, 93%
1
3
, 40 min, 98%
1
3
1
3
c
1
2
1
4
4
j: R
1
= CH
3
, 50 min, 90%
, 30 min, 98%
4 l: R
1
= CH
3
, 45 min, 95%
, 35 min, 85%
4n: R
1
= CH
= CF
= C(O)H, 30 min, 97%
3
, 45 min, 90%
k: R
1
= OCH
3
4 m: R
1
= OCH
3
4o: R
1
3
, 35 min, 88%
4p: R
1
4
q: R
1
= CH
3
, 40 min, 85%
4 t: R
20 min, 75%
4u: R = OCH
1
= OCH
3
, R
2
2
= CO
2
CH
3
,
1 3
4v: R = CH , 80 min, 98%
1
4
r: R
1
= CF
3
, 40 min, 92%
1
3
, R
= CF
3
, 140 min, 87%
4
s: R
1
= C(O)H, 30 min, 96%
c
5
5
6
a: R
1
= CH
3
, 24 h, 73%
5c: R
1
= OCH
3
, R
2
= CH
3
, 24 h, 78%
5d: R
2
= CF
3
, 4 h, 85%
CH , 24 h, 75%
c
b: R
1
= OCH
3
, 24 h, 74%
5e: R
2
= CO
2
3
ꢁ
c
0 C, 60 min, 97%
(
Continues)

10 of 16
CHEN ET AL.
TABLE 3 (Continued)
5
f: R
1
= R
2
= CH
3
, 1.33 h, 85%
5 g: R
1
= R
2
= CH
3
, 1 h, 91%
a
t
ꢁ
Reaction conditions: 0.5 mmol arylchloride, 0.75 mmol arylboronic acid, 1.8 equiv. KO Bu, 0.5 mol% 1b, T = 27 C, and 1 ml EtOH.
b
Determined by GC-BID, average of two runs; values refer to isolated yield after column chromatography.
c
Determined by GC–MS.
SCHEME 2 Scale-up in the Suzuki reaction
TABLE 4
Relative activation barrier for transmetalation and reductive elimination for starting catalysts 1a and 1b considering mono-
and binuclear intermediates pathways
Entry
Reference intermediate
Starting catalyst
Method
ΔG
4.2
a
1
1a_1
1a
1b
1a
1b
1a
1b
1a
1b
M06L/6-31G(d,p)
M06L/6-31G(d,p)
M06L/6-31G(d,p)
M06L/6-31G(d,p)
M06L/6-31G(d,p)
M06L/6-31G(d,p)
oniom(m06l:pm6)/6-31G(d,p)
oniom(m06l:pm6)/
a
2
1b_1
5.2
b
3
1a_2
10.9
8.5
b
4
1b_2
c
5
1a_2a
1b_2a
duo1a_1
duo1b_1
16.8
17.3
25.2
29.1
c
6
a
7
a
8
6
-31G(d,p)
oniom(m06l:pm6)/
-31G(d,p)
oniom(m06l:pm6)/
-31G(d,p)
b
9
duo1a_2
duo1b_2
1a
1b
11.6
12.3
6
b
1
0
6
a
Transmetalation step, Ar = Ph.
Reductive elimination step, Ar = Ph.
b
c
Reductive elimination step, Ar = o-xylenyl. Relative free energies presented in kcal/mol.

CHEN ET AL.
11 of 16
as aryl group (Table 4, entries 5 and 6). In these cases,
the presence of o-xylenyl groups increases the steric
In the mechanistic studies of cross-coupling reactions,
precatalysis commonly involves Pd(II) reduction to Pd(0),
but this is rarely described in the literature due its high
complexity, especially if no phosphine species as reduc-
hindrance, so the activation barrier for 1a_2a
;
(
16.8 kcal/mol Table 4, entry 5) is lower than for
[
33]
1
b_2a at only 0.5 kcal/mol (17.3 kcal/mol; Table 4,
entry 6).
We also considered a mechanism in which both palla-
tive agents are present in the chemical system.
How-
ever, for the Suzuki reaction there already some
elucidations considering as part of the precatalysis a
reductive elimination step starting from transmetalation
dium centers could participate in the cross-coupling reac-
tion (Table 4, entries 7–10) because it was presumed that
catalyst 1b could be kinetically favorable compared to 1a
if both palladium centers are coordinated to two amine
heads during the transmetalation and/or reductive elimi-
nation steps. At 1b the two palladium centers are sepa-
rated by a longer distance (Figure 6), what would
contribute to reduce the steric hindrance, lowering the
activation barriers, when compared to the 1a complex.
The activation barrier for the transmetalation step was
lower for duo1a_1 (25.2 kcal/mol, Table 4, entry 7) than
for duo1b_1 (29.2 kcal/mol, Table 4, entry 8). It is impor-
tant to note that was calculated an increasing of about
[14,34]
aryl group from the arylboronic acid substrate.
Figure 7 shows two possible pathways based on the liter-
ature examples for arylboronic participation in
precatalysis after the cis site be obtained from a chelate
effect.
For the cheat effect and considering the higher
degree of freedom for the open chain linker of 1a and
1b compared with 1c and 1d, we presumed that it
could be possible that when the precatalyst splits into
two monopalladium center complexes, the free amine
head could substitute one of the chlorides ligands
affording the chelate effect, especially in the case of
the dimethylethyldiamine which presents the better
2
0.0 kcal/mol to the activation barriers in presence of
[
35]
monopalladium complexes. These results suggest that
mechanistic pathways through binuclear palladium inter-
mediates are less favorable than those through mononu-
clear palladium complexes. For the reductive elimination
bite angle
forming a five-membered ring (Figure 7,
1a_7).
Thermodynamic analysis (Figure 8) of the pre-
catalyst intermediates showed that both 1a and 1b
form stable chelate complexes with total energy stabili-
zation of −37.5 kcal/mol for 1a and −28.7 kcal/mol
for 1b. In addition, 1a_7 reduces the system total
energy in almost 10.0 kcal/mol compared to 1b_7 for-
mation. This step is exergonic for 1a_7 while for 1b_7
it is endergonic. We suppose that 1b linker although
also presents chelate effect, the propyl chain would
lead to lesser effect due to the six-membered ring pro-
viding worst bite angle.
The energetic profile also indicates the importance
of the chemical base used, since the precatalysis path-
way through chloride ligand dissociation to form 1a_4
(Figure 8, path a) is an endergonic process; if a base
substitution with the chloride occurs through concerted
(Ar = Ph), the increase in the total activation barrier was
less than 3.0 kcal/mol, but the selectivity inverts been
also lower for duo1a_2 than for duo_1b_2 (Table 4,
entries 9 and 10). This indicates that 1a should react
faster than 1b, i.e. the opposite of what is found by
kinetic experiments (Figure 5).
A mononuclear mechanism was expected since two
free active sites cis to each other at the palladium center
are needed for the oxidative addition and the reductive
step to occur. Hence, the starting binuclear precatalysts
1
a and 1b must suffer a discoordination liberating two
Pd(II) complexes at the bulk reaction at the precatalysis
step where the Pd(0) species is formed so the main
[
32]
Suzuki–Miyaura mechanism reaction cycle can start.
FIGURE 6 Optimized geometries for
model structures for 1a and 1b at condensed
phase (ethanol) with Pd–Pd distances shown in
Angstroms (Å)

12 of 16
CHEN ET AL.
FIGURE 7 Proposed route to active Pd(0) species via a common stable chelate intermediate 1_7 without (path a) and with (path b)
base assistance. Transm, transmetalation step; RE, reductive elimination step
mechanism (Figure 8, path b) to form 1a_6 and Pd
NHC)Cl , it becomes an exergonic process, reducing
reduction to Pd(0) via arylboronic acid is less favorable
than precatalysis pathways through (a) the oxidation of
the alcoholic solvent to a ketone or (b) a β-hydride
elimination involving a ligand olefin followed by base-
assisted deprotonation of the formed palladium
(
2
the total energy of the system by about −34 kcal/mol
for both starting catalysts reflected by the entropy con-
tribution and the oxophilic character of palladium cen-
ter, suggesting one of the reasons of the total yield
increasing when a stronger base is applied (Table 2,
entries 12 and 13). The total energy is slightly higher
[
36]
hydride.
In our case, solvent oxidation should occur,
but since there is no ligand or olefin-like substrate,
hydride elimination occurs via oxidation of the
alkylamine linker from both the 1_5 and 1_11 inter-
mediates. These intermediate structures also are stabi-
lized by an agostic bond between the alpha-amine
metilene hydrogen and the palladium center.
The activation barrier for 1a_11 conversion to 1a_12
was +10.9 kcal/mol (Figure S1, Data 1 in Supporting
Information) in an endergonic reversible step (reverse
barrier of only +0,4 kcal/mol from 1a_12). The same
trend was observed for 1b_11, forming 1b_12. Despite a
(
−34.0 kcal/mol for 1a_8 and −25.5 kcal/mol for 1b_8)
when the remaining chloride is replaced by base-
activated arylboronic acid, indicating the higher steric
hindrance of the group overcome the electronic advan-
tage of the new RO–Pd bond formation in this second
chloride substitution.
Mononuclear advantage over binuclear precatalysis
[32,36]
was also observed by recent literature.
However,
Hazari and co-workers suggested that catalyst

CHEN ET AL.
13 of 16
FIGURE 8 Thermodynamic profile in the condensed-phase (SMD-M06L/6-31G(d,p)) corresponding to palladium discoordination to
form Im1 starting from 1a and 1b, and the chelate effect associated with 1a_7and 1b_7. Relative free energies presented in kcal/mol
slightly higher activation barrier (12.6 kcal/mol, see
Supporting Information Figure S1), the step produces a
4 | CONCLUSIONS
less instable product, with
a
reverse barrier of
In summary, binuclear NHC palladium complexes bear-
ing nitrogen-based alkyl chain ligands were synthesized
and showed high activities in the Suzuki coupling reac-
tion under milder and easier conditions such as in air at
room temperature and user friendly operations-all
reagent are used directly without purification than
required for cycloamine ligands. Scope on hindered, acti-
vated, neutral or unactivated aryl chlorides coupled with
sterically hindered, electron-withdrawing,-donating or
neutral phenylboronic acids led to mono-, di- and tri-
+
3,4 kcal/mol from 1b_12 to 1b_11. 1b_13 is formed
from 1b_5 in an exergonic step, reducing the total energy
of the system to −10.0 kcal/mol (Figure 8). Although the
hydride elimination from 1_5 and 1_11 seems to be a
more straightforward pathway to achieve the starting
active Pd(0) catalyst, it is important to observe that this
reaction mechanism leads to a more energetically
demanding reaction pathway compared to the pathway
via arylboronic acid.

14 of 16
CHEN ET AL.
ortho-substituted biaryls in completion yields in very
shorter reaction time at room temperature in air. The
synthesized binuclear Pd complexes exhibited a similar
catalytic level to Pd-PEPPSI complexes. With the claim of
green chemistry, the environmental friendliness solvent-
ethanol and no heating condition were applied in general
case studies. Scale-up examination in gram experiment
was successfully carried out to prove the application of
our Pd catalytic system. DFT studies showed that the sin-
gle Pd complex mechanism is more consisted with our
experimental results and the precatalysis may be defini-
tive to improve our understanding of the kinetic activity
difference between 1a and the other starting catalysts.
The computational studies indicated that the Suzuki–
Miyaura reaction occurs through monopalladium com-
plexes and the base assistance for its generation through
a highly exergonic step followed by chelate species forma-
tion is more stable for the 1a starting catalyst than for 1b.
In terms of experimental and DFT studies, it is likely that
the role of mononuclear NHC Pd complexes designed is
more significant for Suzuki reaction.
Reactions 2nd Edition, WILEY-VCH Verlag GmbH &
ꢀ
Co. KGaA, Weinheim 2014. e) A. Molnár, Palladium-
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ACKNOWLEDGEMENTS
M.-T.C. is grateful to the Ministry of Science and Tech-
nology of Taiwan for financial support (grant number
MOST 107-2113-M-126-001-MY2). A.A.C.B thanks the
S ~a o Paulo Research Foundation (FAPESP) for Grants
[
5] a) M. Tobisu, N. Chatani, Acc. Chem. Res. 2015, 48, 1717.
b) G.-M. Ho, H. Sommer, I. Marek, Org. Lett. 2019, 21, 2913.
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2014/25770-6 and #2015/01491-3, and the support of
the High Performance Computing of Universidade de
S ~a o Paulo (HPC-USP). A.A.C.B and N.L.V. also thank the
Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq) of Brazil for academic support
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7] L. Guo, W. Srimontree, C. Zhu, B. Maity, X. Liu, L. Cavallo,
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[9] A. D. Meijere, S. Bräse, M. Oestreich, Metal-Catalyzed Cross-
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GmbH & Co. KGaA, Boschstr, Weinheim, Germany 2014
Ming-Tsz Chen https://orcid.org/0000-0002-7949-305X
Natália Lussari https://orcid.org/0000-0003-3133-8533
Ataualpa A.C. Braga https://orcid.org/0000-0001-7392-
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