Sustainable Ligand-Free, Palladium-Catalyzed Suzuki–Miyaura Reactions in Water: Insights into the Role of Base

Article abstract of DOI:10.1002/cssc.201902853

A simple and efficient system was developed for the ligand-free Pd-catalyzed Suzuki–Miyaura reaction in water under mild conditions. Quaternary ammonium hydroxides with long chains were found to be very suitable bases. This ligand-free Pd-catalyzed Suzuki–Miyaura reaction showed improved durability in water with Pd loadings decreased to ppm level. Bases were shown to stabilize active palladium species in addition to acting as a base during the catalytic process. In the catalytic system with a strong base, the soluble active Pd^II ion exhibited anti-reduction properties, which prevented aggregation and deactivation of Pd species. The entire catalytic system could be recycled after separating the product by simple filtration. The water-compatible and air-stable effective catalytic protocol described herein represents an attractive and green synthetic advance in Suzuki–Miyaura couplings.

Full text of DOI:10.1002/cssc.201902853

Accepted Article
Title: Sustainable Ligand-Free, ppm Palladium Catalyzed Suzuki-
Miyaura Reactions in Water: Insights on the Role of Base
Authors: Yanyan Wang, Yuanyuan Liu, Wei-Qiang Zhang, Huaming
Sun, Kan Zhang, Yajun Jian, Quan Gu, Guofang Zhang,
Jiyang Li, and Ziwei Gao
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.201902853
Link to VoR: http://dx.doi.org/10.1002/cssc.201902853
A Journal of
www.chemsuschem.org

ChemSusChem
10.1002/cssc.201902853
FULL PAPER
Sustainable Ligand-Free, ppm Palladium Catalyzed Suzuki-
Miyaura Reactions in Water: Insights on the Role of Base
[a]
[a]
[a]
[a]
[a]
[a]
Yanyan Wang, Yuanyuan Liu, Wei-qiang Zhang, Huaming Sun, Kan Zhang, Yajun Jian,
[a]
[a]
[b]
[a]
Quan Gu, Guofang Zhang, Jiyang Li,* and Ziwei Gao*
Abstract: A simple and efficient system is proposed for the ligand-
free Pd-catalyzed Suzuki–Miyaura reaction in water under mild
conditions. Quaternary ammonium hydroxides with long-chain have
been found to be high calibre candidate base. The ligand-free Pd-
catalyzed Suzuki–Miyaura reaction has improved durability in water
with Pd loading down to ppm level. Bases have been shown to
stabilize active palladium species, not just as a base during the
catalytic process. In the catalytic system with a strong base, the
soluble active Pd(II) ion exhibits anti-reduction properties, which
prevent aggregation and deactivation of Pd species. The entire
catalytic system can be recycled after seperating the product by
simple filtration. The water-compatible and air-stable effective
catalytic protocol described herein represents an attractive green
synthetic advance in Suzuki-Miyaura couplings.
HandaPhos.[12] Other effort has been paid on immobilizing Pd
nanoparticles on supports,[13] including crystallized porous
materials[ and photocatalyst supports.
14]
[15]
In the absence of
additional ligands and supports, the use of so-called Deep
Eutectic Solvent as environmentally responsible reaction media
has allowed Suzuki-Miyaura cross-coupling reaction to proceed
under mild conditions in air owing to the role of eutectic
components.7d However, it is not clear for what can stabilize the
palladium in water in addition to the ligand. And sustainable
ligand-free palladium catalyzed Suzuki-Miyaura reaction in
aqueous media is still far from being well developed.[
16]
For the Suzuki-type C-C coupling, base is demonstrated to be
essential and the identity of the base is critical to the success of
the catalysis, although the role is still indistinct.[17] It is commonly
admitted that the base favors the rate-determining
transmetalation and the reductive elimination.[17b] Some previous
findings support that the main role of base in the Suzuki-Miyaura
reaction is converting the oxidative addition product ArylPdX to
Introduction
the competent ArylPdOH species when aqueous mixtures are
employed.[18] Therefore, comprehensive screening of suitable
base and well-matched catalytic system is required for the
rational design of cross-coupling reaction.[19] Recently, the base-
controlled orthogonal reactivity with ligand-free catalysts has
been systematically studied, and the possibility of designing
cross-coupling reactions based on the base has been
proposed.[20] Besides, J. Schatz et al. have reduced the
The
palladium-catalyzed
Suzuki-Miyaura
cross-coupling
reactions have served as one of the most versatile and powerful
strategy for achieving C-C bond formation in the syntheses of
fine chemicals and pharmaceuticals.[1] Given the extremely low
contents of Pd in the Earth’s crust, significant efforts have been
devoted to maximizing utilization of catalyst as well as
developing sustainable “green chemistry”. In recent years, the
progressive replacement of toxic and volatile organic solvents
with neoteric, recyclable reaction media, has contributed to the
development of sustainable metal-catalyzed chemistry.[3] Among
the various media, water is an attractive solvent for its
inexpensive, non-flammable and nontoxic features, which has
long been accepted as an exemplary green solvent.[4] By the
ever-evolving techniques associated with water-compatible
catalysts and emulsification, scepticism regarding the practical
use of water as
mitigated. However, palladium is easily aggregated during
catalysis, resulting in deactivation.[6] The catalyst is still
ineffective with Pd loading of >1.0 mol %. To activate and
stabilize palladium, an effective strategy is to utilize the delicate
designed ligands,[8] such as disulfonated 9-(3-phenyl-propyl)-9’-
[2]
Pd(OAc)
2
loading from 3.0 mol % to 0.4 mol % by adjusting pH
[21]
value of the system using different bases.
Herein, we describe a conceptually novel protocol that active
species are stabilised by the bases to realize ligand-free, ppm
level Pd catalyzed Suzuki-Miyaura cross-coupling reactions in
an aqueous solution. A commercially available surfactant Triton
X-100 has been used as emulsifier to solubilize the organic
substrates in water. The role of base on the palladium have
been explored with electrochemistry and X-ray photoelectron
spectroscopy (XPS) studies to gain deeper insights on the
catalysis. A combination of experimental methods including
transmission electron microscopy (TEM) and UV-Vis spectrum
have provided a better understanding of the active catalytic
species in the reaction. Pd species exhibited an extraordinary
activity with Pd loading down to ppm level, which was
compatible to that in traditional homogeneous catalytic system
with ligand. In such system, the catalyst might be isolated by
filtration, and the whole catalytic system was easily to be reused
after filtration.
a reaction medium has been gradually
[5]
[
7]
PCy
2
-fluorene,[9]
oxime
palladacycles,[10]
EvanPhos,[11]
[
a]
b]
Y.Y. Wang, Y.Y. Liu, W.-Q. Zhang, H.M. Sun, K. Zhang, Y.J. Jian,
Q. Gu, Prof. Dr. G.F. Zhang, Prof. Dr. Z.W. Gao
Key Laboratory of Applied Surface and Colloid Chemistry MOE,
School of Chemistry and Chemical Engineering, Shaanxi Normal
University, Xi’an 710119, P. R. China.
E-mail: zwgao@snnu.edu.cn
Prof. Dr. J.Y Li
State Key Laboratory of Inorganic Synthesis and Preparative
Chemistry, College of Chemistry, Jilin University, Changchun,
30012, P.R. China.
[
Results and Discussion
Optimizing the base for maximum efficiency of the catalysis is
challenging because of solubility and compatibility issues.
Initially, screening of several bases for the Suzuki-Miyaura
cross-coupling reaction of 1-bromonaphthalene and 4-
1
E-mail: lijiyang@jlu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201902853
FULL PAPER
methoxyphenylboronic acid in the presence of Pd(NH
3
)
4
Cl
2
(0.06
100 (0.1 mL),
nanomicelles for catalytic system without substrates given by DLS analyses;
c] the size of nanomicelles for filtrate after catalytic reaction given by DLS
analyses; [d] yields determined by GC with the dodecane as an internal
standard.
2
H O (9 mL), bases, at 45 °C, air, 2 h; [b] the size of
mol %) was carried out in water containing 1 wt% Triton X-100.
A mild heating of 45 °C was performed for the reaction in air.
The results are summarized in Table 1 (entries 1-11). In the
catalytic system, 1 wt % Triton X-100 generated nanomicelles in
water to proceed catalysis by increasing the contact area
between organic substrates, Pd species and base. Dynamic light
scattering (DLC) measurements are in line with the formation of
extra-fine nanomicelles, 5-18 nm. Base was essential for the
coupling reaction for that no coupling occurred without base
[
As shown in Figure 1, similar nanomicelles, ~13 nm, have
been detected in the catalytic system, by just adding strong
bases, such as NaOH and TBAOH, to the catalytic nanomicelles
environment without substrates and heating at 45 °C for 2h. This
result demonstrated that strong bases did little bad influence on
the system. After undergoing the model catalytic reaction, the
size of nanomicelles for the filtrates varied in different bases. In
NaOH, there was a growth for the nanomicelles, which might be
due to the generation of the by-product, NaBr, who possessed a
demulsification effect. In TBAOH with long-chain, the size of
nanomicelles became smaller and closer to the original system.
This might be attributed to the by-product, tetrabutylammonium
bromide (TBAB), which not only did not break the emulsion, but
was also an emulsifier itself. Thus, quaternary ammonium
hydroxides with long chain are a kind of high calibre candidate
base in the aqueous catalytic system.
(
Table 1, entry 1). Unsatisfactory results were given by Na
2 3
CO ,
Cs CO , K PO , and Tri-n-butylamine (Bu N), who caused
2
3
3
4
3
serious damage to the nanomicelles environment (Table 1,
entries 2-5). Strong inorganic bases, such as NaOH and CsOH,
were compatible to the nanomicelles, which showed moderate
activity giving yield from 48 % to 66 % (Table 1, entries 6-7).
Interestingly, quaternary ammonium hydroxides afforded good to
excellent results. Tetramethylammonium hydroxide (TMAOH)
gave a yield of 89 % (Table 1, entry 8). Tetraethylammonium
hydroxide (TEAOH), tetrapropylammonium hydroxide (TPAOH)
and tetrabutylammonium hydroxide (TBAOH) were the most
efficient bases in this system (Table 1, entries 10-11).
Correspondingly, the quaternary ammonium hydroxides have
little adverse effect on the nanomicelles of the catalytic system,
indicating the compatibility of these bases.
Table 1. Effect of bases and pre-catalyst on Suzuki-Miyaura Cross-Coupling
of 1-Bromonaphthxsalene with 4-Methoxyphenylboronic acid.[a]
Br
B(OH)
2
Base (2equiv.)
0.06 mol%)
OMe
(
3
)
4Cl
2
Pd(NH
+
Triton X-100 (1 wt%)
o
OMe
H
2
O, 45 C, 2h
Entry
Base
Size (d nm) [b]
Size (d nm)[c]
Yield (%)[d]
1
2
3
4
5
6
7
8
9
-
5-18
5-18
0
Na
2
CO
CO
PO
Bu
3
18-77
7.4-44
13-56
1430-3485
7-24
1681-4443
240-747
424-1681
261-636
13-78
10
9
Figure 1. DLS analyses of the nanomicelles for aqueous catalytic system of 1
wt % Triton X-100, the controlled catalytic system (1 wt % Triton X-100 with
NaOH or TBAOH) that without substrates but heated at 45 °C for 2 h, and the
Cs
2
3
filtrate
after
a
coupling
reaction
of
bromobenzene
and
4-
K
3
4
37
20
66
48
89
>99
>99
>99
methoxyphenylboronic acid by using NaOH or TBAOH as base.
3
N
NaOH
CsOH
The efficiency of various palladium precursors was examined
in the model reaction of the coupling by using TBAOH as base
5.8-24
6-32
16-65
(
Table 2). Cross-coupling reaction did not occur when no pre-
catalyst was added (Table 2, entry 1). The catalysts with ligands,
such as Pd[P(C and Pd(acac) exhibited moderate
TMAOH
TEAOH
TPAOH
TBAOH
8-58
6
H
5
)
3
]
4
2
,
6-32
10-32
catalytic activity, with reaction time of 4 h being enough to
recover the product (Table 2, entries 2-3). The Pd salts with poor
water-solubility also gave moderate catalytic activity, and it was
possible for all of them to recover the target product in
quantitative yield by prolonging reaction time or increasing Pd
loading (Table 2, entries 4-7). The water-soluble Pd salt,
1
0
1
6-24
7-32
1
5-32
6-18
[a]
Reaction
conditions:
1-bromonaphthalene
(1.00
mmol),
( (0.06 mol %), Triton X-
4-
methoxyphenylboronic acid (1.20 mmol), Pd(NH
3
4
) Cl
2
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201902853
FULL PAPER
Pd(NH
3
)
4
Cl
2
, gave the desired product in a short period, 50 min,
3 4 2
around 290 nm suggests the transitions of Pd(NH ) Cl from
at 45 °C (Table 2, entry 8). These results reveal that this
catalytic system is active for the all pre-catalysts. And
Pd(NH ) Cl has been chosen as an optimal pre-catalyst.
3 4 2
solute state to another.[22] Indeed, a transparent solution with
Tyndall phenomenon was achieved in the solution after being
heated at 45 °C for 1 hour, but not for the initial solution. After
heating for 6 h, the peak around 290 nm began to decline, which
may be due to the abundant deposition of nanoparticles. This
result is corresponding to the growing of palladium black on the
face of Teflon coated magnetic stir bar after several hours.
When 1 wt % Triton X-100 was added into the solution, Pd black
was formed as well after mild heating (Figure S1b). The
difference was that they dispersed well in the solution. TEM
images showed that nanoparticles of palladium were dispersed
in the Triton X-100 with sizes of 5 ± 3 nm (Figure 2b). This may
be attributed to the fact that PEG part of Triton X-100 can
donate electrons to stabilize transition metals, which help the
metal achieving the needed 18 electrons for its outer shell. The
lattice fringe of 0.21 nm in the HRTEM images may be attributed
Table 2. Palladium optimization for Pd catalysis of Suzuki-Miyaura Cross-
Coupling of 1-Bromonaphthxsalene with 4-Methoxyphenylboronic acid. [a]
Br
B(OH)
2
Pre-catalyst
OMe
TBAOH (2equiv.)
+
Triton X-100 (1 wt%)
o
H O, 45 C, 2h
2
OMe
Entry
Pre-catalyst
Catalyst
loading
Yield
(%)[
Yield
(%)
TON
TOF
(h )
b]
[c]
−1
[mol %]
2
to the (110) plane of PdO∙xH O (PDF #09-0254). The TEM
1
2
3
4
5
6
7
8
--
Pd[P(C
Pd(acac)
Pd(OAc)
0
0
0
result reveals that Triton X-100 can not block the generation of
PdO nanoparticles, nevertheless, it is clear from Figure 2b that
Triton X-100 can hinder the aggregation of the ultra-small PdO.
6
H
5
)
3
]
4
0.12
0.06
0.12
0.06
0.7
27
27
67
23
>99
37
>99
>99
>99
>99
89
825
206
412
206
370
35
2
1650
825
2
PdCl
PdCl
2
2
1483
141
2
Na PdCl
4
0.12
0.06
>99
825
206
1980
Pd(NH
)
3 4
Cl
2
1650
[a] Reaction conditions, unless otherwise stated: 1-Bromonaphthalene (1.00
mmol), 4-Methoxyphenylboronic acid (1.20 mmol), pre-catalyst, TBAOH (2.0
mmol), Triton X-100 (0.1 mL), in water (7 mL) at 45 °C, refluxed for 50 min ~ 4
h under aerobic conditions, yields were determined by GC with the dodecane
as an internal standard; [b] yield with reaction time to be 50 min; [c] yield with
reaction time to be 4 h.
One interesting question is that what stabilizes the catalyst
species in this ligand-free catalytic system. Hence, the stability
of the Pd species in water was studied. Firstly, we prepared [Pd]
solution as pre-catalyst by solving Pd(NH ) Cl into water, which
3 4 2
can be stable even for half a year at room temperature. However,
Pd black has been generated in the [Pd] solution after heating at
4
5 °C for 3 hours indicating the agglomeration of Pd(II), as
shown in Figure S1a. The Pd black was studied by typical
transmission electron microscopy (TEM) image (Figure 2a). The
image at lower magnification shows that the Pd species have
aggregated and fused together. The d-spacing of 0.26 nm in
high-resolution TEM (HRTEM) image matches well with the (101)
planes of PdO (PDF #41-1107). The d-spacings of 0.36 nm and
Figure 2. TEM and HRTEM image of the aggregating Pd black generated in
(a) [Pd] solution and (b) [Pd] solution with 1 wt % Triton X-100; the inset in (a)
is the representative photograph of the solution; the inset in (b) is the
representative photograph of the solution and the size distribution of the
nanoparticles from TEM image.
0
.24 nm are consistent with the (110) and (301) planes of PdCl
respectively (PDF #45-0482). These results suggest that
Pd(NH Cl are instable in water which tend to generate PdO or
PdCl under mild heating. Accordingly, the UV-Vis spectra of [Pd]
2
,
3
)
4
2
2
Fortunately, we obtained a stable Pd solution successfully on
the participation of strong bases, such as NaOH or TBAOH
solution exhibited obvious time-dependent changes, indicating
its instability at 45 °C (Figure S2). The emergence of the peak
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201902853
FULL PAPER
(
Figure S1c and S1d). No Pd black nor Tyndall phenomenon
from -0.8 to +0.4 V are shown in Figure 3b. The anodic peak at
E0 = -0.12 V for pure [Pd] solution is associated with the
reduction of Pd(II). Quaternary ammonium hydroxides exhibit
similar reductive-resistance feature on Pd(II). Take TBAOH as
an example, such anodic peak moves to -0.32 V when TBAOH
is added, indicating that the reduction of Pd(II) becomes more
difficult. Similar result has been observed in 1 wt% Triton X-100
aqueous solution confirming that Triton X-100 did not affect the
redox potential (Figure S3). Besides, other bases such as NaOH,
were found in the solution with these bases at 45 °C even for 30
h. The good solubility of Pd species in strong alkaline solution is
in good agreement with the result given by C. F. Base and Jr. R.
E. Mesmer.[23] As shown in reaction (1), the Pd(OH)
to be formed when OH is introduced into the solution from the
hydrolyzation of Pd(II). Meanwhile, the basic species with solid
2
(aq) tends
−
phase, Pd(OH)
Reaction (2)). As a contrast, if using Na
2
, are soluble at high concentrations of OH−
CO or K PO instead
(
2
3
3
4
of NaOH, Pd solution can be stable at 45 °C for 3 h. But Pd
black formed as well after heating for a long time (Figure S1e
and S1f). Therefore, the strong base in the catalytic system
plays an important role on stabilizing and thereafter dispersing
Pd2+ species in the aqueous solution.
2 3 3 4
K CO and K PO , also exhibit reductive-resistance feature on
Pd(II) (Figure S4). Thus, the base helped to stabilise the Pd(II)
oxidation state. The stabilization of soluble Pd(II) in water by
base follows: quaternary ammonium hydroxides ~ NaOH >
3 4 2 3
K PO > K CO . This is consistent with their reactivity order in
Suzuki-Miyaura coupling. Therefore, we can assume that there
is some positive correlation between the reactivity of Pd species
and base on the reduction of Pd(II) in this system.
It should be noted that the Pd species in solution is too tiny to
be separated, which cannot be isolated from the filtrate after a
coupling reaction even by centrifugation under 11000 rpm for 30
min. In order to study the electronic states of Pd centre, USY
(
aq)
Pd2+
Pd(OH)
2H
+
2 H O
2
Pd(OH)
2
(1)
(2)
(c)
Pd(OH) (aq)
2
2
(
Ultra-stable Y) zeolite with FAU topology was used to adsorb
Pd species from the solvent and form Pd@USY (Figure 4a).
Firstly, the controlled experiments were performed by heating at
4
5 °C for 2h for the following solutions: [Pd] solution, a; [Pd]
solution + 1 wt% Triton X-100, b; [Pd] solution + 1 wt% Triton
solution + Aryl-B(OH) , c; [Pd] solution + 1 wt% Triton X-100 +
substrates (Aryl-B(OH) + Aryl-Br), d; [Pd] solution + 1 wt%
Triton solution + substrates (Aryl-B(OH) + Aryl-Br) + TBAOH, e.
2
2
2
Then, a series of Pd@USY was obtained by dispersing USY into
the above solutions after stirring for 2h at 45 °C.
White Pd@USY(a) was isolated from a. The successful
element Pd dopings in Pd@USY were confirmed by the high-
angle annular dark-field scanning transmission electron
microscopy (HAADF-STEM) image with elemental mapping, as
shown in Figure 4b. XPS analyses were performed on the
Pd@USY to study the valence of Pd species. Well-defined
peaks corresponding to Pd species can be detected. The XPS
spectra of Pd@USY(a) in Figure 4c shows two Pd 3d5/2 peaks at
3
36.7 and 338.3 eV, corresponding to two possible coordination
forms of Pd(II) at zeolite. In the solution of b, namely, adding
Triton X-100 to a, white Pd@USY(b) was obtained. The Pd 3d5/2
peaks on XPS curve are similar to that of Pd@USY(a) indicating
the Triton X-100 did not affect the valence of Pd species. In c,
2
namely, adding substrate Aryl-B(OH) to b, black Pd@USY(c)
was obtained. The Pd 3d5/2 peaks moved toward smaller value
than that of Pd@USY(b), which might be associated with partial
reduction of Pd(II) to Pd(0). In d, namely, adding substrate Aryl-
Figure 3. (a) CV curves for [Pd] solution with TBAOH (red) or without TBAOH
black); (b) DPV curves for [Pd] solution with quaternary ammonium
hydroxides (colored) or without quaternary ammonium hydroxide (black).
(
2
Br to c or adding substrates (Aryl-B(OH) and Aryl-Br) to b, black
Pd@USY(d) was obtained. The Pd 3d5/2 peaks on XPS curve, at
335.2 and 336.0 eV, moved toward smaller value than that of
Pd@USY(b) and Pd@USY(c), which may be ascribed to the
metallic Pd(0). This result indicate that the substrates play a
reductive role on the Pd catalyst. However, when we added
TBAOH into the solutions up, forming a complete catalytic
system, white Pd@USY(e) was obtained. Accordingly, the
doublet in Fig. 4c with binding energies of 336.8 (Pd 3d5/2) and
To further reveal the role of base on catalyst, electrochemistry
studies were recorded in 0.06 mM solution of Pd salts in 0.3 M
neutral potassium chloride buffer using glassy carbon as the
working electrode in a single compartment electrochemical cell.
The CV curves show that the Pd(NH
without TBAOH possess quite different redox potential profiles
Figure 3a). The differential pulse voltammetry (DPV) traces
3 4 2
) Cl solution with and
(
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201902853
FULL PAPER
3
38.9 eV (Pd 3d3/2) can be assigned to the +2 oxidation state of
played a resistant role in the reduction of Pd(II), which was
potential to provide a balance for the oxidation state of Pd to
stabilize the active species.
Pd, indicating the oxidation occurred in the catalytic system.
These results confirmed that Pd(II) can be reducted by the
substrates and tend to aggregate as deactive species. TBAOH
Figure 4. (a) The diagram of Pd@USY that Pd species are adsorbed in USY zeolite; (b) HAADF-STEM image with Al, Si and Pd element mappings for
Pd@USY(a); (c) XPS Pd 3d core level XPS spectra of the catalyst that is extracted by USY zeolite in solution of (a) [Pd] solution, a; [Pd] solution + 1 wt% Triton
X-100, b; Pd(NH
Triton solution + substrates (Aryl-B(OH)
and blue lines correspond to the deconvoluted components. The grey lines indicate the position of the assigned Pd(II) and Pd(0) species.
3 4
) Cl
2
2 2 3 4 2
+ 1 wt% Triton solution + Aryl-B(OH) , c; [Pd] solution + 1 wt% Triton X-100 + substrates (Aryl-B(OH) + Aryl-Br), d; Pd(NH ) Cl + 1 wt%
2
+ Aryl-Br) + TBAOH, e. The black dotted lines show the fitted result of the raw data (open circles), whereas the orange
As stated in most reports, small palladium clusters of three
and four atoms (Pd3-4) are recognized as the active catalytic
species which are formed in situ during C-C bond-forming
reactions, regardless of the starting palladium source.[24] To
pursue a high TON value of the catalyst, the Pd3-4 clusters was
stabilized by ligands or supports in the traditional homogeneous
system and heterogeneous system, respecitvely. For the ligand-
free and support-free catalytic system in water, most reports
have studied the effect of bases on catalysis.[25] In this work, we
found that OH− played a crucial role on stabilizing active Pd
species, even though the specific morphology of Pd species was
resistant role on the reduction of Pd(II). During the catalytic
process, the OH− inhibits the rapid and massive reduction of
Pd(II). Therefore, the aggregation of Pd(0) species is of great
possibility to be prevented during the reaction, and thereafter to
avoid the deactivation of the catalyst. This may be the reason
why this catalytic system has a higher utilization rate of Pd and
higher reactivity to the Suzuki-Miyaura reaction. As a fact, the
catalyst species in this system can be stable and even the
filtrate can remain the highly activity for at least one month.
OH
OH
3 4 2
unclear. As shown in Scheme 1, Pd(NH ) Cl , a water-soluble
Heating
Substrates
Aggeragation
Pd(0)
Deactivated Pd
Pd(II) salt, has been demonstrated as the optimal pre-catalyst.
In the aqueous solution without substrates, the Pd(II) tend to
form the aggregated PdO under mild heating (45 °C), which lead
to the deactivation of catalyst. The OH− from the base could
solublize Pd(II) in water to stabilize the pre-catalyst. In the
catalytic system without base, Pd(II) is easily to be reducted by
substrates, which causes an aggregation of Pd(0). According to
our experimental results above, OH− of bases exhibits a
PdO
Pd(II)
Scheme 1. The proposed role of OH− on stabilizing pre-catalyst and active
species.
The relationship between the content of external base and
reactivity of the reaction has been studied by reducing the
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201902853
FULL PAPER
loading of Pd. For the model reaction between 4-
methoxyphenylboronic acid and bromobenzene, the reaction
have been completed in 2 h, when Pd(NH
reduced to 0.003 mol % (30 ppm), which gives a TON value of
3000 (Table 3, entry 1). As a comparison, the decreasing or
3 4 2
) Cl loading was
3
increasing of TBAOH exhibited a negative effect on the reactivity
of the catalytic system, indicating that an appropriate amount
was necessary for TBAOH (Table 3, entries 2-3). Besides,
3 4 2
kinetics has been studied for Pd(NH ) Cl loading of 0.0006
mol % (6 ppm) and 0.0003 mol % (3 ppm), respectively. As
shown in Figure 5, it is observed that vigorous stirring at 45 °C
was sufficient to drive the coupling to be completed in a 98-hour
period with Pd loading of 6 ppm, which gives a TON value of
1
9
55000. Pd(NH
3 4 2
) Cl loading of 3 ppm offered a yield of 48 % at
8 h. The content of water exerted little effect on the coupling in
this system. However, if the base (4 equiv.) have been doubled,
the reaction rate declined significantly. The excessive base
showed obvious negative effect. These results reveal that the
amount of external base has a great influence on the reactivity
of the catalyst.
Figure 5. Kinetics of the coupling of 4-methoxyphenylboronic acid with
bromobenzene catalyzed by Pd(NH
ppm) and 0.0003 mol % (3 ppm) in 1 wt% Triton X-100 aqueous solution at
5 °C.
3 4 2
) Cl at Pd loadings of 0.0006ꢀmol % (6
4
Table 3. Reduction of the Pd(NH
Miyaura reaction between 4-methoxyphenylboronic acid and bromobenzene.
3 4 2
) Cl loading using the ligand-free Suzuki-
With the satisfactory system, we sought to capitalize by
[
a]
exploring the scope of reaction with a variety of aryl halides and
arylboronic acids. For 33 examples, the isolated yields are
shown in Scheme 2. The targeted products were separated by
filtration and purified by washing thoroughly with water. For most
examples, the extent of boronic homocoupling was negligible
even when we used 1.2 equivalent of phenylboronic acid.
Therefore, all products were not further purified by other
Br
B(OH)
2
OMe
3
)
4Cl
2
TBAOH
Pd(NH
+
Triton X-100 (1 wt %)
o
H O, 45 C
OMe
2
methods. The resulting compounds were characterized by 1
H
Entry
Pd
loading
TBAOH
Reaction
time (h)
Yield
(%)[
TON
TOF
and 13C NMR spectra. In general, the use of aryl halides and
b]
−1
(h )
arylboronic acids with either electron-donating or electron-
withdrawing substituents resulted in high conversions. When we
adjusted the amount of phenylboronic acid to 1.0 and not 1.2
equivalent, there was some losing yield for 3ab. But we have
obtained a high yield as well for some products, such as 3ah
(
ppm)
1
2
2
30
30
30
2 equiv.
1 equiv.
4 equiv.
2
2
6
>99
90
33000
30000
25000
16500
15000
4100
(
99%). When aryl chloride was used as substrate, no cross-
75
coupling product was detected even if the reaction time was
extended to 24 h. The suppression of catalytic reactivity for PhCl
may be attributed to the larger activation barrier in the oxidative
[
a] Reaction conditions: bromobenzene (1.00 mmol), 4-
methoxyphenylboronic acid (1.20 mmol), TBAOH (1-4 mmol), Triton
X-100 (0.1 mL), H O (7 mL), at 45 °C, air. [b] Yields determined by
GC with the dodecane as an internal standard.
2
addition step, which makes it difficult to start the cross-coupling
catalytic
cycle.[
26]
Interestingly,
by
combining
4-
bromophenylacetic acid and phenylboronic acid, Felbinac, an
anti-inflammatory drug, can be prepared in high yield of 99 %.
This indicates that the potential applicability of this catalytic
system in the synthesis of molecules that display a variety of
pharmaceutical and biological properties.[27] A large-scale of the
coupling reaction for Felbinac has been tested. As shown in
Figure S5, the catalytic conditions with Pd loading of 0.06 mol %
were employed in a round-bottom flask on gram scale reaction.
3
h under 45 °C was enough for the reaction. Then Felbinac was
obtained after adding 3 equiv. HCl into the reagent, and white
product, in >99% yield (4.24 g), was isolated by simple filtration.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201902853
FULL PAPER
R2
4Cl
2
Pd(NH
3
)
R2
B(OH)
2
+
TBAOH (2 equiv.)
Ar
Ar Hal
HaI = I, Br
R1
Triton X-100 (1 wt %)
R1
o
1
2
H
2
O, 45 C
3
Me
OMe
NO2
OMe
MeO
MeO
3ac: (>99 %, I, 1h)
MeO
3aa: (>99 %, I, 1h)
3
ab: (>99 %, I, 1h) 3ab: (95 %, I, 1h)
3ba: (>99 %, I, 1h)
3bb: (>99 %, Br, 2h)
(
(
77 %, Br, 2h)
0, Cl, 24h)
(98 %, Br, 2h)
(>99 %, Br, 2h)
(>99 %, Br, 2h)
(
>95 %, Br, 2h)
90 %, Br, 2h)a
(0, Cl, 24h)
(
F
F
F
F
Cl
Cl
F
OMe
OMe
F
OMe
MeO
MeO
H N
2
3ag: (14 %, 66 %,b I, 2h)a
3
bc: (94 %, Br, 2h)
3ad: (93 %, Br, 2h)
OMe
3af: (83 %, I, 2h)a
3bd
: (76 %, Br, 2h)
3ae
: (95 %, Br, 2h)
OMe
OMe
OMe
OMe
OMe
Me
CHO
OHC
O
S
O
Me
Me
HO
I, 2h)a
I, 2h)
ah: (99 %, Br, 2h)a 3ai: (66 %, Br, 2h)a
(80 %, Br, 2h)a 3ak: (37 %, 55 %,b
: (90 %, I, 2h)a 3am: (14 %, 88 %,b
3al
a
3
3aj
:
OMe
OMe
OMe
COOH
O
MeO
ap
:
(98 %, I, 2h)a
3be: (>99 %, Br, 2h)
3
3an: (99 %, Br, 2h) 3ao: (>99 %, I, 1h)
>99 %, Br, 2h)
3ao: (>99 %, I, 1h)
(>99 %, Br, 2h)
(
Scheme 2. Synthesis of biaryls 3 through Suzuki-Miyaura coupling between arylboronic acids 1 and aryl halides 2 in an aqueous mixture. Unless otherwise noted,
reaction conditions: (hetero)aryl halide (1.0 mmol), phenylboronic acid (1.2 equiv.), TBAOH (2.0 equiv.), Pd(NH
3
)
4
Cl
2
(1 mL, 600 ppm), Triton X-100 (0.1 mL),
water (7 mL) in air; the yields reported are for products isolated by filtration and washed by water. a With phenylboronic acid to be 1.0 equiv.; Yields determined
b
by GC with the dodecane as an internal standard.
On the way towards greener transition-metal-catalyzed
process, water usage is one part of the overall picture.[28]
Especially, limited solubility of biaryls in water makes it possible
to develop an efficient method of filtration for product purification
from the aqueous catalytic system, as reported in some
literatures.[5a,5f,5g,5h] In the catalytic system of this work, most of
the product of biaryls crystallized in situ during coupling, as
shown in Figure 6a. The product can be isolated directly by
filtration and washed by water. For the model reaction between
gave a yield of 100% in the first run. After separating the
products by a filtration, a transparent solution with a nano effect
of Tyndall phenomenon was achieved on the filtrate. Then the
filtrate containing nanomicelles, residual base and palladium
species was reused in the next cycle. Considering the loss of
emulsion, a moderate augmentation of Triton X-100 (~0.03 mL)
was required in each cycle. As we expected, the catalytic
system resulted in high coupling yields for eight cycles after
adding substrates and 1 equiv. TBAOH, as shown in Figure 6b.
During the recycling test, we did not add any palladium again to
the subsequent runs, even though it was partially lost in each
filtration. This may be attributed to the high activity of Pd species
4
-methoxyphenylboronic acid and bromobenzene, we studied
the recyclability of the system (details see Supporting
Information). With Pd loading of 600 ppm, the catalytic system
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201902853
FULL PAPER
that even 30 ppm of Pd is enough to complete the cross-
coupling reaction. The well recyclability of the catalytic system
indicates that the size of Pd species is small enough that can
remain in the filtrate, and the activity of Pd species is stable
during the recycles. Rather than using an “in flask” extraction
process that requires an organic solvent, an even lower E factor
can be achieved by filtering the product from catalytic system.
The facile recycling of the aqueous filtrate containing Triton X-
the optimal base for the coupling reaction. The precious Pd
species as well as the whole catalytic system could be reused
without appreciable loss in activity. Although the base’s effect on
stabilizing catalyst is still indistinct, the water-compatible and air-
stable effective catalytic protocol described here opens a new
perspective towards the green synthesis in pharmaceutical and
agrochemical industries.
1
00, water, base and Pd suggest a E factor down to near zero,
for that there is almost no waste being produced in this process.
Experimental Section
Catalyst preparation. The reagents and solvents employed in the
synthesis were commercially available and used as received without
further purification. 0.0163 g Pd(NH
water to make a [Pd] solution with Pd content of 6.00×10 mol/L. The
Pd] solution can be stable at room temperature for at least half a year.
3 4 2 2
) Cl ∙H O was solved into 100 mL
−
4
[
General Procedure for Performing Suzuki C-C Coupling. The reaction
was set according to the catalysis protocols for the respective catalyst
(
e.g. 1 mL [Pd] solution that containing 6.00×10−4 mmol Pd) under air
conditions. Firstly, aryl halide (1.00 mmol) and organobororon coupling
partner (1.2 mmol) were added in a vial of 40 mL. Then, 7mL H O, 0.1
2
mL Triton X-100 and 1mL [Pd] solution (Pd content: 6.00×10−4 mmol)
were added in to disperse the substrates. The mass percentage of Triton
X-100 in this aqueous media is about 1 wt %. After the base, such as
tetrabutylammonium hydroxide (TBAOH, 25% in water, 2.00 mmol),
being introduced, the reaction vial was put into a reaction block for
parallel synthetic chemistry, which had already been heated at 45 °C.
Then the reaction mixture was simultaneously stirred vigorously by a
magnetic stirrer under ambient atmosphere. At the end of the reaction,
most of the product would be crystallized in situ in the reacted solution.
Then the target product was obtained by filtration and washed by water
for several times. And the filtrate containing Pd catalyst, Triton X-100 and
remaining base could be reused. For Felbinac, white product was
obtained by adding 3 equiv. HCl to acidify the alkaline system at the end
of the reaction.
Figure 6. (a) Representative photographs of the reaction agent after Suzuki-
Miyaura cross-coupling reaction of 1-bromonaphthalene and 4-
methoxyphenylboronic acid and the corresponding filtrate; (b) Recycling of
catalytic system including Pd, Triton X-100, and TBAOH, used for Suzuki-
Miyaura reaction between 4-methoxyphenylboronic acid and bromobenzene.
Gram scale synthesis of Felbinac. A 500-mL round-bottom flask
containing an oblong shaped magnetic stir bar was consecutively
charged with Pd(NH
) Cl solvent (20 mL, 0.012 mmol), 25% TBAOH in
3 4 2
water (32 mL, 40 mmol), 4-bromophenylacetic acid (4.34 g, 20 mmol),
phenylboronic acid (3.0 g, 24.0 mmol), Triton X-100 (2.0 g) and water
(160 mL). The flask was submerged in a heated water bath (bath
temperature 45 oC) and stirred vigorously for 2 h. Then the mixture was
acidized with HCl (5 mL, 60 mmol) and solid product crystallized in the
reagent. After cooling to room temperature, the target product as a white
powder (4.24 g, >99%) was obtained by filtration, washing with water for
several times and then drying to constant weight in air.
Conclusions
In conclusion, we developed an efficient and environmentally
sound ppm level Pd catalyzed Suzuki-Miyaura reaction in water
under atmospheric conditions without ligand. A Pd/base/Triton
2
X-100/H O system was provided to be an effective catalytic
system, with quaternary ammonium hydroxides as base. The
system showed high catalytic activity and offered promising
green development in terms of reaction time, wide scope of
applicability, good to excellent yields of the desired products,
operational simplicity and excellent recyclability of Pd metal. We
have initially explored the stabilizing effect of alkali on the
catalyst by using XPS, TEM, UV and electrochemistry studies.
Base was demonstrated to be essential to stabilize the liquid
Pd2+ in this system. Moreover, strong base featured a resistance
on the reduction of Pd(II) which might prevent the aggregation of
Pd(0) in aqueous solution. The compatible quaternary
ammonium hydroxides with long chains was considered to be
Characterization Methods. The high-resolution TEM (HRTEM) were
carried out on a FEI Tecnai G2 F20 instrument at an accelerating voltage
of 200 KV. X-ray Photoelectron Spectroscopy (XPS) measurements of
the Pd species adsorbed by zeolite USY were performed on an Kratos
AXIS ULTRA instrument using a monochromated Al Kα X-ray source. For
high resolution data, the lowest binding energy C 1s peak was set at
284.6 eV and used as the reference for the other elements. The curve
fitting used a combination of Gaussian/Lorenzian function with the
Gaussian percentages being at 80% or higher. The mean size and size
distribution of the nanomicelles for the aqueous catalytic system before
and after coupling were measured by dynamic light scattering (DLS)
(Malvern, Autoszer 4700). UV-vis spectra were conducted on a Thermo
Scientific™ Evolution 260 Bio UV-Visible Spectrophotometer. Liquid
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201902853
FULL PAPER
NMR was obtained on a DMX-400 MHz JEOL instrument using CDCl
3
as
Pore, A. A. Kamble, Res. Chem. Intermed. 2018, 44, 265–275; d) F. A.
Harraz, S. E. El-Hout, H. M. Killa, I. A. Ibrahim, J. Catal. 2012, 286,
184–192; e) S. N. Jadhav, C. V. Rode, Green Chem. 2017, 19, 5958–
5970; f) G. La Sorella, G. Strukul, A. Scarso, Green Chem. 2015, 17,
644–683; g) A. Steven, Synthesis 2019, 51, 2632–2647; h) B. H.
Lipshutz, S. Ghorai, M. Cortes-Clerget, Chem. Eur. J. 2018, 24, 6672–
6695.
a solvent and TMS as an internal standard. GC data were recorded on a
890A Gas Chromatograph (Agilent Technologies). The electrocatalytic
7
behaviors of Pd salts in aqueous solution were assessed by differential
pulse voltammetry (DPV) on an electrochemical analyzer, CHI660E
electrochemical workstation. All the electrochemical experiments were
done in a conventional 3-electrode system. The neutral potassium
chloride buffer solution (0.3 M) was utilized as a supporting electrolyte,
the glassy carbon electrode was the working electrode, the Ag/AgCl
[6]
a) K. Okamoto, R. Akiyama, H. Yoshida, T. Yoshida, S. Kobayashi, J.
Am. Chem. Soc. 2005, 127, 2125–2135; b) V. P. Ananikov, I. P.
Beletskaya, Organometallics 2012, 31, 1595–1604; c) P. G. Gildner, T.
J. Colacot, Organometallics 2015, 34, 5497–5508; d) V. P. Ananikov, D.
G. Musaev, K. Morokuma, J. Am. Chem. Soc. 2002, 124, 2839–2852;
e) J. Jover, N. Fey, M. Purdie, G. C. Lloyd-Jones, J. N. Harvey, J. Mol.
Catal. A-Chem. 2010, 324, 39–47.
(saturated KCl solution) electrode was the reference and platinum wire
was the counter electrode, respectively. DPV (an amplitude of 0.05 V, a
pulse period of 0.5 s with a pulse width of 0.05 s and increment potential
of 0.004 V) was conducted to determine METZ in a potential range of 0.4
to −0.8 V.
[7]
a) B. P. Bandgar, S. V. Bettigeri, J. Phopase, Tetrahedron Lett. 2004,
45, 6959–6962; b) D. Saha, K. Chattopadhyay, B. C. Ranu,
Tetrahedron Lett. 2009, 50, 1003–1006; c) A. F. Shmidt, A. A.
Kurokhtina, Russ. J. Appl. Chem. 2010, 83, 1248–1253; d) G. Dilauro,
S. M. García, D. Tagarelli, P. Vitale, F. M. Perna, V. Capriati,
ChemSusChem 2018, 11, 3495–3501.
Acknowledgements
We acknowledge financial support from the National Natural
Science Foundation of China (Project Nos. 21771122, 21571121,
[8]
V. Polshettiwar, A. Decottignies, C. Len, A. Fihri, ChemSusChem 2010,
3, 502–522.
2
1701108 and 21602129), the National Key Research and
[9]
C. A. Fleckenstein, H. Plenio, Green Chem. 2007, 9, 1287–1291.
Development Program of China (Grant No. 2016YFB0701100),
the Natural Science Foundation of Shaanxi Provincial
Department of Education (Program No. 2018JQ2012), China
Postdoctoral Science Foundation (No. 2017M623110). We thank
the team from Shaanxi Normal University (Prof. Baoxin Li) for
DLS analyses.
[
10] L. Botella, C. Nájera, Angew. Chem. Int. Ed. 2002, 41, 179–181; Angew.
Chem. 2002, 114, 187–189.
[
11] E. B. Landstrom, S. Handa, D. H. Aue, F. Gallou, B. H. Lipshutz, Green
Chem. 2018, 20, 3436–3443.
[12] B. S. Takale, R. R. Thakore, S. Handa, F. Gallou, J. Reilly, B. H.
Lipshutz, Chem. Sci. 2019, 10, 8825-8831.
[
13] a) L. Liu, A. Corma, Chem. Rev. 2018, 118, 4981–5079; b) W. Xu, H.
Sun, B. Yu, G. Zhang, W. Zhang, Z. Gao, ACS appl. Mater. Interfaces
Keywords: cross-coupling • sustainable chemistry • palladium •
2
014, 6, 20261–20268; c) P. Veerakumar, P. Thanasekaran, K.-L. Lu,
S.-B. Liu, S. Rajagopal, ACS Sustainable Chem. Eng. 2017, 5, 6357–
376; d) S. Doherty, J. G. Knight, T. Backhouse, E. Abood, H. Al-shaikh,
water • base
6
[
1]
a) A. Biffis, P. Centomo, A. Del Zotto, M. Zecca, Chem. Rev. 2018, 118,
249-2295; b) M. Lamblin, L. Nassar-Hardy, J.-C. Hierso, E. Fouquet,
A. R. Clemmet, J. R. Ellison, R. A. Bourne, T. W. Chamberlain, R.
Stones, N. J. Warren, I. J. S. Fairlamb, K. R. J. Lovelock, Adv. Synth.
Catal. 2018, 360, 3716–3731.
2
F.-X. Felpin, Adv. Synth. Catal. 2010, 352, 33–79; c) Á. Molnár, Chem.
Rev. 2011, 111, 2251–2320; d) A. Suzuki, Angew. Chem. Int. Ed. 2011,
[14] a) V. Pascanu, P. R. Hansen, A. Bermejo Gómez, C. Ayats, A. E.
Platero-Prats, M. J. Johansson, M. À. Pericàs, B. Martín-Matute,
ChemSusChem 2015, 8, 123–130; b) A. Kumbhar, Topics Curr. Chem.
2016, 375, 2; c) T.-L. Cui, W.-Y. Ke, W.-B. Zhang, H.-H. Wang, X.-H. Li,
J.-S. Chen, Angew. Chem. Int. Ed. 2016, 55, 9178–9182; Angew.
Chem. 2016, 128, 9324–9328; d) W. Ke, T. Cui, Q. Yu, M. Wang, L. Lv,
H. Wang, Z. Jiang, X. Li, J. Chen, Nano Research 2018, 11, 874–881.
[15] a) F. Raza, D. Yim, J. H. Park, H.-I. Kim, S.-J. Jeon, J.-H. Kim, J. Am.
Chem. Soc. 2017, 139, 14767–14774; b) B. Guo, H.-X. Li, C.-H. Zha, D.
J. Young, H.-Y. Li, J.-P. Lang, ChemSusChem 2019, 12, 1421–1427.
[16] a) I. Hussain, J. Capricho, M. A. Yawer, Adv. Synth. Catal. 2016, 358,
3320–3349; b) S. Hübner, J. G. de Vries, V. Farina, Advanced
Synthesis & Catalysis 2016, 358, 3-25; c) Z. Chen, E. Vorobyeva, S.
Mitchell, E. Fako, M. A. Ortuño, N. López, S. M. Collins, P. A. Midgley,
S. Richard, G. Vilé, J. Pérez-Ramírez, Nat. Nanotech. 2018, 13, 702–
707.
50, 6722–6737; Angew. Chem. 2011, 123, 6854–6869; e) C. C. C.
Johansson Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus,
Angew. Chem. Int. Ed. 2012, 51, 5062–5085; Angew. Chem. 2012, 124,
5
150–5174; f) I. J. S. Fairlamb, Angew. Chem. Int. Ed. 2014, 53,
3001–13002; Angew. Chem. 2014, 126, 13215–13216.
1
[2]
a) F. Požgan, J. Roger, H. Doucet, ChemSusChem 2008, 1, 404–407;
b) B. Yuan, Y. Pan, Y. Li, B. Yin, H. Jiang, Angew. Chem. Int. Ed. 2010,
49, 4054–4058; Angew. Chem. 2010, 122, 4148–4152; c) G. Clavé, F.
Pelissier, S. Campidelli, C. Grison, Green Chem. 2017, 19, 4093–4103;
d) K. V. Kutonova, N. Jumg, M. E. Trusova, V. D. Filimonov, P. S.
Postnikov, S. Bräse, Synlett 2017, 49, 1680–1688; e) S. Zhao, T.
Gensch, B. Murray, Z. L. Niemeyer, M. S. Sigman, M. R. Biscoe,
Science 2018, 362, 670–674.
[
3]
4]
a) J. García-Álvarez, E. Hevia, V. Capriati, Chem. Eur. J. 2018, 24,
14854–14863; b) J. Sherwood, J. H. Clark, I. J. S. Fairlamb, J. M.
Slattery, Green Chem. 2019, 21, 2164–2213.
[17] a) A. A. C. Braga, N. H. Morgon, G. Ujaque, F. Maseras, J. Am. Chem.
Soc. 2005, 127, 9298–9307; b) C. Amatore, A. Jutand, G. Le Duc,
Chem. Eur. J. 2011, 17, 2492–2503; c) A. J. J. Lennox, G. C. Lloyd-
Jones, Angew. Chem. Int. Ed. 2013, 52, 7362–7370; Angew. Chem.
2013, 125, 7506–7515; d) A. A. Thomas, S. E. Denmark, Science 2016,
352, 329–332.
[
a) T. Kitanosono, K. Masuda, P. Xu, S. Kobayashi, Chem. Rev. 2018,
118, 679–746; b) E. Levin, E. Ivry, C. E. Diesendruck, N. G. Lemcoff,
Chem. Rev. 2015, 115, 4607–4692; c) A. Chatterjee, T. R. Ward, Catal.
Lett. 2016, 146, 820–840; d) S. Handa, B. Jin, P. P. Bora, Y. Wang, X.
Zhang, F. Gallou, J. Reilly, B. H. Lipshutz, ACS Catal. 2019, 9, 2423–
2
431; e) V. R. Bhonde, B. T. O'Neill, S. L. Buchwald, Angew. Chem. Int.
[18] a) C. Amatore, A. Jutand, G. Le Duc, Chem. Eur. J. 2012, 18, 6616–
6625; b) A. A. Thomas, A. F. Zahrt, C. P. Delaney, S. E. Denmark, J.
Am. Chem. Soc. 2018, 140, 4401–4416.
Ed. 2016, 55, 1849–1853; Angew. Chem. 2016, 128, 1881–1885.
a) S. Handa, Y. Wang, F. Gallou, B. H. Lipshutz, Science 2015, 349,
[5]
1
087–1091; b) B. Jin, F. Gallou, J. Reilly, B. H. Lipshutz, Chem. Sci.
[19] a) D. N. Korolev, N. A. Bumagin, Tetrahedron Lett. 2006, 47, 4225–
4229; b) C. Amatore, G. Le Duc, A. Jutand, Chem–Eur. J. 2013, 19,
2019, 10, 3481–3485; c) D. S. Gaikwad, K. A. Undale, D. B. Patil, D. M.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201902853
FULL PAPER
1
0082–10093; c) S.-T. Kim, B. Pudasaini, M.-H. Baik, ACS Catal. 2019,
[25] a) T. Hirakawa, Y. Uramoto, D. Mimura, A. Takeda, S. Yanagisawa, T.
Ikeda, K. Inagaki, Y. Morikawa, J. Phys. Chem. B 2017, 121, 164–173;
b) T. Hirakawa, Y. Uramoto, S. Yanagisawa, T. Ikeda, K. Inagaki, Y.
Morikawa, J. Phys. Chem. C 2017, 121, 19904–19914.
9, 6851-6856.
[
20] E. Fernández, M. A. Rivero-Crespo, I. Domínguez, P. Rubio-Marqués,
J. Oliver-Meseguer, L. Liu, M. Cabrero-Antonino, R. Gavara, J. C.
Hernández-Garrido, M. Boronat, A. Leyva-Pérez, A. Corma, J. Am.
Chem. Soc. 2019, 141, 1928–1940.
[26] a) T. Hirakawa, Y. Uramoto, D. Mimura, A. Takeda, S. Yanagisawa, T.
Ikeda, K. Inagaki, Y. Morikawa, J. Phys. Chem. B 2017, 121, 164–173;
b) T. Hirakawa, Y. Uramoto, S. Yanagisawa, T. Ikeda, K. Inagaki, Y.
Morikawa, J. Phys. Chem. C 2017, 121, 19904–19914.
[
21] I. Hoffmann, B. Blumenröder, S. Onodi neé Thumann, S. Dommer, J.
Schatz, Green Chem. 2015, 17, 3844–3857.
[
22] S.-M. Kang, C. H. Kwak, M. Rethinasabapathy, S.-C. Jang, S.-R. Choe,
C. Roh, Y.-K. Han, Y. S. Huh, Separation and Purification Technology
[27] For selected examples, see: a) D. G. Brown, J. Boström, J. Med. Chem.
2016, 59, 4443–4458; b) P. Devendar, R.-Y. Qu, W.-M. Kang, B. He,
G.-F. Yang, J. Agric. Food Chem. 2018, 66, 8914–8934; c) D. A.
Patrick, M. A. Ismail, R. K. Arafa, T. Wensler, X. Zhu, T. Pandharkar, S.
K. Jones, K. A. Werbovetz, R. Brun, D. W. Boykin, R. R. Tidwell, J. Med.
Chem. 2013, 56, 5473–5494; d) L. Andernach, L. P. Sandjo, J. C.
Liermann, R. Schlämann, C. Richter, J.-P. Ferner, H. Schwalbe, A.
Scheffler, E. Trines, T. Opatz, J. Nat. Prod. 2016, 79, 2718–2725.
[28] B. H. Lipshutz, N. A. Isley, J. C. Fennewald, E. D. Slack, Angew. Chem.
Int. Ed. 2013, 52, 10952–10958; Angew. Chem. 2013, 125, 11156–
11162.
2018, 197, 220-227
[23] C. F. Baes, R. E. Mesmer, The Hydrolysis of Cations, Wiley-
interscience, 1976, p. 264.
[
24] a) M. Pérez-Lorenzo, J. Phys. Chem. Lett. 2012, 3, 167-174; b) A.
Leyva-Pérez, J. Oliver-Meseguer, P. Rubio-Marqués, A. Corma, Angew.
Chem. Int. Ed. 2013, 52, 11554–11559; Angew. Chem. 2013, 125,
11768–11773; c) F. Fu, J. Xiang, H. Cheng, L. Cheng, H. Chong, S.
Wang, P. Li, S. Wei, M. Zhu, Y. Li, ACS Catal. 2017, 7, 1860–1867; d)
D. B. Eremin, V. P. Ananikov, Coordin. Chem. Rev. 2017, 346, 2–19.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201902853
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
A green sustainable catalytic system
stabilized by a base is proposed,
which can be used for the ligand-free
Pd catalyzed Suzuki-Miyaura cross-
coupling reaction in water. The entire
system is recyclable and the coupling
reaction can be driven with Pd loading
of ppm-level.
Yanyan Wang, Yuanyuan Liu, Wei-qiang
Zhang, Huaming Sun, Kan Zhang, Yajun
Jian, Quan Gu, Guofang Zhang, Jiyang
Li,* and Ziwei Gao*
Page No. – Page No.
Sustainable Ligand-free, ppm
Palladium Catalyzed Suzuki-Miyaura
Reactions in Water: Insights on the
Role of Base
This article is protected by copyright. All rights reserved.