Confirmation of Suzuki-Miyaura Cross-Coupling Reaction Mechanism through Synthetic Architecture of Nanocatalysts

Article abstract of DOI:10.1021/jacs.0c04804

Despite widespread use of heterogeneous Pd catalysts in Suzuki-Miyaura coupling reactions, detailed roles of Pd, especially the nature of its active species, are still a topic of controversial debate. While some studies showed an active surface of Pd nanoparticles or nanoclusters acting heterogeneously, others claimed soluble Pd species leached from the metallic Pd to be active species which are homogeneous in nature. Besides, within the homogeneous mechanism, how the Pd leaches and promotes the cross-coupling reaction is then another question that needs to be addressed. It could be envisioned that if the soluble Pd species and solid-phase Pd are physically separated, the mechanism of Suzuki-Miyaura coupling could then be confirmed through examining the catalytic activity in different reaction regions. Herein we use microporous St?ber silica as a membrane to separate the soluble Pd species from solid Pd and conduct size-selective reactions which allow the passage of leaching Pd species, but not of reactants or products larger than the membrane aperture. With this strategy, we have been able to differentiate the surface reaction from the solution cross-coupling. We find that the leached Pd species are the only genuine catalytic intermediate in the cross-coupling reactions. We also confirm that oxidative addition of aryl halides to the solid Pd leads to leaching of the soluble Pd species which is necessary to promote Suzuki-Miyaura reactions.

Full text of DOI:10.1021/jacs.0c04804

Subscriber access provided by the University of Exeter
Article
Confirmation of Suzuki-Miyaura Cross-Coupling Reaction
Mechanism through Synthetic Architecture of Nanocatalysts
Bo Sun, Lulu Ning, and Hua Chun Zeng
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04804 • Publication Date (Web): 15 Jul 2020
Downloaded from pubs.acs.org on July 15, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Confirmation of Suzuki-Miyaura Cross-Coupling Reaction Mechanism
through Synthetic Architecture of Nanocatalysts
Bo Sun1, Lulu Ning2, Hua Chun Zeng1,*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1 Department of Chemical and Biomolecular Engineering, Faculty of Engineering, National University of Singapore, 10
Kent Ridge Crescent, Singapore 119260. 2 College of Bioresource Chemical and Materials Engineering, Shaanxi Univer-
sity of Science and Technology, Shaanxi, China 710021.
KEYWORDS: catalyst design, core-shell, Suzuki-Miyaura coupling reaction, homogeneous, leaching
ABSTRACT: Despite widespread use of heterogeneous Pd catalysts in Suzuki-Miyaura coupling reactions, detailed roles of
Pd, especially the nature of its active species are still a topic of controversy debate. While some studies showed active surface
of Pd nanoparticles or nanoclusters acting heterogeneously, others claimed soluble Pd species leached from the metallic Pd
to be active species which are homogeneous in nature. Besides, within the homogeneous mechanism, how the Pd leaches and
promotes the cross-coupling reaction is then another question needed to be addressed. It could be envisioned that if the
soluble Pd species and solid-phase Pd are physically separated, the mechanism of Suzuki-Miyaura coupling could then be
confirmed through examining the catalytic activity in different reaction regions. Herein we use microporous Stӧber silica as
a membrane to separate the soluble Pd species from solid Pd and conduct size-selective reactions which allow the passage of
leaching Pd species, but not of reactants or products larger than the membrane aperture. With this strategy, we have been
able to differentiate the surface reaction from the solution cross-coupling. We find that the leached Pd species are the only
genuine catalytic intermediate in the cross-coupling reactions. We also confirm that oxidative addition of aryl halides to the
solid Pd leads to leaching of the soluble Pd species which is necessary to promote Suzuki-Miyaura reactions.
prospect, nevertheless, we recognize that the diverse re-
sults and conclusions in this field of study were likely asso-
ciated with varied reaction conditions adopted and differ-
ent forms of catalysts developed by individual research
groups, because it is extremely difficult to conduct a com-
plete investigation to address so many questions under ex-
actly same experimental settings. Obviously, there is a need
to revisit the reported reaction routes, and assemble con-
firmed piece of “Jigsaw Puzzle” into a fuller up-to-date pic-
ture under identical reaction conditions if possible.
1. INTRODUCTION
Pd-catalyzed Suzuki-Miyaura cross-coupling reactions be-
tween aryl halides with organoboron nucleophiles, which is
an efficient and clean strategy for selective construction of
carbon-carbon (CC) bonds in organic synthesis, presents a
wide range of applications in productions of polymers, ag-
rochemicals, pharmaceutical intermediates, and high-tech
materials.1-6 Motivated by easy separation and reusability of
solid catalysts, in addition to conventional homogeneous
Pd-based organometallic catalysts, a number of novel het-
erogeneous catalysts including Pd nanoparticles (NPs) and
nanoclusters (NCs) or supported Pd composites have been
developed for these reactions in recent decades.7-12 How-
ever, despite the widespread usage of condensed phase Pd
catalysts in Suzuki-Miyaura coupling reactions, detailed
roles of Pd, especially the nature of the real active Pd cata-
lytic species, are still a matter of current debate.13-15 While
some studies show solid surfaces of Pd NPs or NCs as active
catalytic centers functioning heterogeneously,16-20 others
claim soluble Pd species leaching from solid palladium to be
active, and then the reactions virtually belonging to homo-
geneous catalysis.21-25 Regarding the homogeneous mecha-
nism, in which metallic Pd particles could serve as a reser-
voir of palladium, there still remains a debate on whether
the Pd leaching is triggered by the oxidative addition of aryl
halide electrophile alone,22, 26 or both aryl halide and aryl
boronic acid together,27 or synergistic action between aryl
boronic acid and added alkali in reaction.28 From a broader
Clearly, it is highly challenging to distinguish between the
two reaction mechanisms and to answer how they are re-
lated to pathways of palladium dissolution and metal recov-
ery in the catalytic cycle based on reaction kinetic data
alone, due to dynamic exchanges linking different types of
Pd species in solution and supported Pd acting as supplying
reservoirs, in addition to intricate reactions taking place
simultaneously both on the surface of condensed phase (i.e.,
Pd NPs/NCs) and in the bulk solution. Besides, there is a
multistep process with many intermediates involved, and
competing phase equilibria are often present. Moreover, it
is even more difficult to directly monitor the structural
change of nanocatalysts during these liquid-phase reac-
tions. Therefore, to date, it still remains unclear regarding
the nature of the true catalytic species in Suzuki-Miyaura
cross-coupling reactions.29-32 Apart from the determination
of genuine active species, furthermore, how the Pd solubil-
izes and promotes homogeneous reactivity then becomes
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 11
another important question needed to be answered if the good chemical and thermal stability, high optical transpar-
1
2
3
4
5
6
7
8
process is indeed through the homogeneous mechanism.
ency in visible and near-IR region, and good biocompatibil-
ity. The most widely used synthetic method to prepare core-
shell silica particles on a large scale is the classical Stöber
method where silica shell is formed by the complete hydrol-
ysis of tetraethyl orthosilicate (TEOS) and subsequent con-
densation of the as-formed silicic acid.47 It should be men-
tioned that the Stӧber silica is not condensed and contains
micropores,48, 49 which could be used as a membrane and in
principle it will impose the size selectivity onto different
molecules involved in reactions.
Within a reaction system, the above two catalytic mecha-
nisms would seem to be always intertwined, because the Pd
leaching may be catalyzed by one or several steps of the cat-
alytic cycle. Nevertheless, it could be envisioned that if ho-
mogeneous leaching (Pd) species and heterogeneous Pd
NPs/NCs can be physically separated, the leaching process
and the cross-coupling reaction can be conducted simulta-
neously in different locations within the same reacting sys-
tem. Under such a reaction setting, in principle, the mecha-
nism of Suzuki-Miyaura reactions could be investigated and
confirmed through examining the catalytic activity in each
reaction location or region. Apparently, how to separate the
Pd leaching from the reaction process becomes a key to de-
termine Suzuki-Miyaura coupling mechanism under a nom-
inal heterogeneous catalysis environment.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In the current work, nanostructures with active Pd core
and semipermeable Stӧber silica shell were used in Suzuki-
Miyaura coupling reactions. The semipermeable silica shell
not only serves as a barrier layer to stabilize active Pd NPs
against detachment/enlargement during reaction, but also
endows a size-selective permeability of reactant molecules
accessing to the confined Pd NPs. With this core-shell archi-
tecture, we can now devise and carry out a range of reaction
experiments which provide direct evidence that the Pd spe-
cies produced from the metal leaching are the genuine ac-
tive components in Suzuki-Miyaura CC coupling reactions.
We then investigate the pathways for Pd leaching and con-
firm that oxidative addition of aryl halides to the surface
metal atoms leads to leaching of the soluble active interme-
diates which are necessary to promote Suzuki-Miyaura
cross-coupling reactions.
In view of rapid development of synthetic strategies of na-
nomaterials and nanocomposites over the past two dec-
ades, we have reasons to believe that the new development
might endow us new capability to investigate unsolved is-
sues in some well-established fields such as catalysis. In-
deed, it had brought to our attention that there might be
new possibility to investigate overall seemingly controver-
sial mechanistic issues through design-made catalytic nano-
materials and/or nanocomposites. Apparently, feasibility of
such investigations heavily relies on our synthetic ability to
fabricate traditional catalysts with reactor-like characteris-
tics.33-36 Through nanoscale engineering, very often, these
newly attained properties of reactor-like nanocatalysts al-
low surface processes to be separated from bulk processes.
For example, we had recently synthesized multi-shelled
nanocomposites of noble metals and ZIFs with a Matry-
oshka-type architecture for studying hydrogen spillover
phenomenon of Pt NPs inside a ZIF-8 matrix.37 Encouraged
by that work, herein we sought to use the strategy of cata-
lyst design to ascertain which mechanism is in fact generally
operative in Suzuki-Miyaura reaction. It has been well
known that microporous materials with pore diameter be-
low 2 nm can exhibit size selectivity by serving as a mem-
brane.38, 39 When the microporous membrane is used, which
allows the passage of leaching Pd species but not of reac-
tants or products larger than the membrane aperture, sup-
ported Pd NPs or NCs will not participate in the reaction due
to imposed size restriction of the membrane. As a result, the
heterogeneous mechanism could be separated from the ho-
mogeneous one. In other words, if Suzuki-Miyaura coupling
reactions are triggered on the condensed catalysts, Pd NPs
or NCs (i.e., the heterogeneous mechanism), no product will
be found due to mass-transfer limitation implemented by
the small pore channels (i.e., molecular size selectivity).
Otherwise, the homogeneous mechanism must become op-
erative, once the size restriction can be lifted and the cross-
coupling reaction will be observed outside the membrane.
2. EXPERIMENTAL SECTION
2.1 Chemicals. Polyvinylpyrrolidone (k30, PVP, Sigma-
Aldrich), iron(III) chloride anhydrous (98%, Sigma-Al-
drich), PdCl2 (≥99.9%, Sigma-Aldrich), iodobenzene (98%,
Sigma-Aldrich), phenylboronic acid (98%, Sigma-Aldrich),
4-tert-butylphenylboronic acid (Sigma-Aldrich), 4-ben-
zyloxyphenylboronic acid (≥95%, TCI), 1-benzyloxy-4-io-
dobenzene (≥95%, TCI), styrene (99.9%, Sigma-Aldrich),
cyclohexene (≥99.0%, Sigma-Aldrich), 4-methylstyrene
(96%, Sigma-Aldrich), 4-vinylbiphenyl (98%, Sigma-Al-
drich), ethanol (99.99%, Fisher), commercial Pd/C catalyst
(10 wt.% Pd, Sigma-Aldrich), potassium carbonate (99%,
Sigma-Aldrich), tetraethyl orthosilicate (TEOS, 98%, Sigma-
Aldrich), ammonia solution (25%, VWR), and cetyltrime-
thylammonium bromide (CTAB, 99%, Sigma-Aldrich).
2.2 Materials Characterization and Chemical Analysis.
The microscopic features of the samples were characterized
by scanning electron microscopy (SEM, JEOL-6700F), trans-
mission electron microscopy (TEM, JEM-2010, 200 kV) and
high-resolution transmission electron microscopy (HRTEM,
JEM-2100F, 200 kV) equipped with energy dispersive X-ray
spectroscopy (EDX, Oxford Instruments). The crystallo-
graphic information was established by X-ray diffraction
(XRD, Bruker D8 Advance) equipped with a Cu Kα radiation
source. Specific surface areas and average pore size of stud-
ied samples were determined using N2 physisorption iso-
therms at 77 K (Micromeritics 3Flex). Pd content was deter-
mined by inductively coupled plasma optical emission spec-
trometry (ICP-OES, Optima 7300 DV, Perkin Elmer) and in-
ductively coupled plasma-mass spectrometry (ICP-MS; Ag-
ilent-5977A). Reaction products in the supernatants of hy-
drogenation of alkenes (Section 2.8) and Suzuki-Miyaura
Searching for a membrane material to meet the above
purpose, chemically inert and thermally stable inorganic
materials seem to be suitable candidates. In particular, silica
particles with a core-shell structure have been studied ex-
tensively in diverse fields such as catalysis,40, 41 chemical
sensing,42-44 and controlled drug delivery,45, 46 due to their
ACS Paragon Plus Environment

Page 3 of 11
Journal of the American Chemical Society
cross-coupling reactions (Section 2.9) were analyzed by gas
ensure the complete reduction of Pd2+ ions. The final prod-
1
2
3
4
5
6
7
8
chromatography (GC; Agilent-7890A; equipped with a ca-
pillary column (HP-5, 30.0 m  320 µm  0.25 µm) and a
flame ion detector (FID)), gas chromatograph-mass spec-
trometry (GC-MS, Agilent, 7890A), and nuclear magnetic
resonance (NMR, Bruker, 400 MHz).
uct was collected, washed with deionized water and ethanol
in sequence, and dried at 60oC overnight. The resultant sam-
ples were used in two types of reactions described in Sec-
tion 2.8 and Section 2.9.
2.8 Catalytic hydrogenation of alkenes. The hydrogena-
tion reaction was carried out in a magnetically stirred glass
reactor (capacity: 25 mL) by dispersing Pd/FeOx@ SiO2-600
(5 mg) in 10 mL of ethanol, 1 mmol of alkene, together with
0.1 mL of n-dodecane used as internal standard. The reac-
tion was conducted at room temperature and atmospheric
pressure under constant stirring at 500 rpm. Hydrogen gas
was continuously bubbled into the reaction mixture at 30
mL∙min−1. After the reaction, the mixture system was centri-
fuged to separate the catalyst from the reaction solution,
while the liquid solution was filtered through a membrane
filter and its composition was examined by GC analysis, as
well as by other analytical tools list in Section 2.2.
2.3 Preparation of β-FeOOH spindles. Monodisperse β-
FeOOH particles with a spindle morphology was synthe-
sized by a previously reported method with minor modifi-
cations.40 Briefly, FeCl3 (4 mmol) and PVP (1 g) were dis-
solved in 40 mL of deionized water, the resulting solution
was transferred to oil bath and kept at 85 oC for 12 h. After
that, the sample was collected by centrifugation, washed
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
with deionized water three times, and dried at 60 C over-
night.
2.4 Preparation of Pd/β-FeOOH. A deposition-precipita-
tion method was employed for introduction of metallic Pd
NPs onto the β-FeOOH support. Briefly, 100 mg of β-FeOOH
was added into 10 mL of deionized water. The pH of the so-
lution was adjusted to 10.0 using 1.0 M NaOH. After that 250
µL of PdCl2 (56.4 mM) solution was added under stirring.
The product was centrifuged, rinsed with deionized water
and ethanol several times, and dried in an electric oven at
60 oC for 5 h. Then the obtained Pd/β-FeOOH was calcined
at 250 oC for 3 h.
2.9 Suzuki-Miyaura cross-coupling reactions. In a typ-
ical reactional study, 5 mg of Pd/FeOx@SiO2-x nanocatalyst
(Section 2.7) was placed in a round-bottom flask containing
10 mL of ethanol, 0.5 mmol of aryl halide, 1 mmol of aryl
boronic acid, 0.1 mL of n-dodecane (as an internal standard
for GC), 2 mmol of K2CO3. The reaction mixture was stirred
and heated to 85 oC in an ambient atmosphere for a given
period of time. The mixture was then centrifuged at 10000
rpm for 10 min to separate the catalyst from the liquid
phase. The supernatant was analyzed by various analytical
techniques listed in Section 2.2. Finally, the recyclability of
the most used catalyst Pd/FeOx@SiO2-600 was evaluated in
the Suzuki-Miyaura coupling reaction between iodoben-
zene and phenylboronic acid. After each cycle of the reac-
tion, the catalyst was retrieved by centrifugation, washed
with ethanol several times and then reused in the next con-
secutive run under the same reaction conditions.
2.5 Preparation of Pd/FeOx@mSiO2. In a typical synthe-
sis, 30 mg of the above Pd/β-FeOOH was dispersed in a mix-
ture containing 10 mL of ethanol, 10 mL of deionized water,
60 mg of cetyltrimethylammonium bromide (CTAB), and 1
mL of aqueous ammonia solution under vigorous stirring.
Then 60 μL of TEOS was added and the mixture was vigor-
ously stirred for 5 h, giving rise to a solid precursor Pd/β-
FeOOH@mSiO2 which was then at 600 oC in laboratory air
for 3 h; this heat-treatment was to convert the Pd/β-FeOOH
to Pd/FeOx core and to remove the CTAB template to form
the mesoporous silica (mSiO2) shell. The resultant product
was redispersed in 10 mL of deionized water. Then a freshly
prepared aqueous solution of NaBH4 (20 mM) was added
and stirred for 0.5 h to ensure the complete reduction of
Pd2+ ions after the heat treatment. The final product
Pd/FeOx@mSiO2 was collected, washed with deionized wa-
ter and ethanol in sequence, and dried at 60oC overnight for
control hydrogenation reactions described in Section 2.8.
2.10 Calculation of molecule size. Before estimating the
dimensions of molecules, the orientations of all the mole-
cules have been adjusted. Packages La1.0 and Orient
(https://www.ks.uiuc.edu/Research/vmd/script_library/
scripts/orient/) of VMD50 were employed to align the three
principal axes of molecules with x, y, z directions. Then the
x, y, z dimensions of molecules had been estimated by the
following two steps (as shown in Figure S1): first, calculate
the difference values between maximum and minimum co-
ordinates of x, y, z respectively, then add the van der Waals
radii of boundary atoms to the respective difference values.
To validate the method, dimensions of several molecules
have been estimated and the values have been compared to
experimental results.51 As shown in Table S1, the values es-
timated by our method are close to experimental data,
which indicates the reliability of the method.
2.6 Preparation of Pd/β-FeOOH@SiO2. In a typical syn-
thesis, 30 mg of Pd/β-FeOOH was dispersed in a mixture
containing 10 mL of ethanol, 10 mL of deionized water, and
1 mL of aqueous ammonia solution, and the suspension was
sonicated for 30 min in an ultrasound cleaner. Subse-
quently, a solution containing TEOS (150 μL) and ethanol (1
mL) was slowly added into the suspension under soni-
cation. After 90 min, the product was then collected, washed
with deionized water, and dried at 60oC overnight.
2.7 Preparation of Pd/FeOx@SiO2-x. The above pre-
pared sample Pd/β-FeOOH@SiO2 was heat-treated at differ-
ent temperatures in laboratory air for 5 h, resulting in nano-
catalysts Pd/FeOx@SiO2-x (x = 500, 600, 700, and 800),
where x represents the heating temperature applied in each
catalyst. 30 mg of Pd/FeOx@SiO2-x was redispersed in 10
mL of deionized water. Then a freshly prepared aqueous so-
lution of NaBH4 (20 mM) was added and stirred for 0.5 h to
3. RESULTS AND DISCUSSION
In order to minimize Pd NPs agglomeration during the ther-
mal treatment (Section 2.7), iron oxide FeOx was used to
serve as a stable support. The synthetic process for prepar-
ing these designed core-shell catalysts was illustrated in
Figure 1a. Firstly, the monodisperse β-FeOOH spindles with
diameters of ca. 2030 nm and lengths of 100120 nm were
prepared through the hydrolysis of iron chloride in the
ACS Paragon Plus Environment

Journal of the American Chemical Society
presence of PVP (Figure 1b); the powder XRD pattern in Fig-
Page 4 of 11
1
2
3
4
5
6
7
8
ure S2 confirmed the β-FeOOH crystal structure (JCPDS card
No. 34-1266). Secondly, with a controlled deposition-pre-
cipitation method, Pd NPs with an average size of about 3
nm were formed and distributed evenly on the β-FeOOH
spindles, resulting in Pd/β-FeOOH nanocomposite (Figure
1c-1d). Using TEOS as silica source, nanostructured Pd/β-
FeOOH@SiO2 core-shell was prepared with a modified
Stӧber method (Figure 1e-1g; Section 2.6). As can be seen in
Figure 1f-1g, the original Pd/β-FeOOH spindle cores were
encapsulated completely by silica phase with a shell thick-
ness of 10 nm. The corresponding elemental mapping image
of Pd/β-FeOOH@SiO2 was displayed in Figure 1h, revealing
the uniform distribution of Pd NPs. The sample was then
heated to 500, 600, 700, and 800oC in air for 5 h, producing
Pd/FeOx@SiO2-x (x = 500, 600, 700, and 800) where the
number represents the temperature in the heat treatments.
TEM images for the formation process of these nanocata-
lysts are displayed in Figure S3. Upon the calcination, the
pristine β-FeOOH spindles retained their shapes, but small
pores were created inside the iron oxide phase due to the
volume reduction resulting from the phase transformation
of structurally looser β-FeOOH to denser FeOx.52 After heat-
ing at an increased temperature of 800 ℃, the inner iron ox-
ide became almost entirely hollow. As observed in Figure
S3d, Pd NPs were distributed on the walls and cavities of the
iron oxide FeOx hollow structure and essentially retained
their particle size due to protecting confinement of the mi-
croporous silica shell in these heat-treated nanocatalysts.
It has been well known that Stӧber silica is not entirely
condensed and it contains micropores.48, 53 Therefore, phy-
sisorption experiments were first performed to character-
ize the porosity and other textural properties of Pd/β-
FeOOH@SiO2 and Pd/FeOx@SiO2-x (x = 500, 600, 700 and
800) samples using nitrogen adsorption-desorption tech-
nique (Figure 2a-2b). The surface area and pore size distri-
bution were estimated by the Brunauer-Emmett-Teller
(BET) theory and the Horvath-Kawazoe (HK) method re-
spectively. As displayed in Figure 2a, these heat-treated
nanocomposites all show a typical Type-II sorption iso-
therm, which suggests either surface adsorption or nonpo-
rous structures. The specific surface area of Pd/β-
FeOOH@SiO2 determined by BET model is 442 m2∙g−1 (Ta-
ble S2), while most pore size simulated by HK method is
smaller than 1 nm (Figure 2b). As reported in Table S2, BET
surface area and pore volume decrease continuously with
increasing heat-treatment temperature. As for the samples
heated to 800 oC, they became nearly nonporous due to a
significantly enhanced degree of condensation of the
SiOSi bonds (Figure 2a). This observation is in good
agreement with J. D. Wells’ report that Stӧber silica became
nonporous after heated to 800 oC in air for 3 h or longer.48
Because of reducing the porosity of silica shell upon the
thermal treatment, it is likely that Pd/FeOx@SiO2-x will ex-
hibit different catalytic activity in reaction application ow-
ing to their different pore structures. To verify this hypoth-
esis, our Pd/FeOx@SiO2-x nanocatalysts were first used in
the Suzuki coupling reaction between two small reactants,
iodobenzene and phenylboronic acid (Table S3). In general,
as displayed in Figure 2c, the catalytic activity decreases
with the heat treatment temperature increasing from 500
to 800 oC. For the sample of Pd/FeOx @SiO2-800, quite ex-
pectedly, no product was observed since the silica shell of
this catalyst became entirely nonporous after the heat treat-
ment. However, it is still difficult to determine the accurate
pore size by gaseous N2 physisorption method alone due to
the small surface area and pore size. Nonetheless, we recog-
nized that it is of importance to probe the accurate pore size
of catalyst under actual reaction conditions. Furthermore, it
is commonly understood that reactant molecules larger
than the pore diameter of the silica shell would be unable to
pass through the silica and the contribution of catalytic sur-
face of Pd NPs to the reaction could then be excluded. In ad-
dition to the BET/HK measurements, we also used the liq-
uid phase hydrogenation of olefin as an alternative molecu-
lar probe to determine the actual microporous pore diame-
ter of the silica shell under solidliquid reaction environ-
ments. In particular, Pd/FeOx@SiO2-600 sample was se-
lected in the next experiments in view of its appropriate mi-
croporosity that strikes the balance between the size and
the pore volume (Figure 2b). Pd/FeOx@SiO2-600 was also
characterized by XRD. The XRD pattern shown in Figure S4
demonstrates that no obvious Pd diffraction pattern, con-
firming the small size of Pd nanoparticles. The FeOx phase
in this core-shell sample is essentially amorphous after
transforming from β-FeOOH at 600 oC (Figure S4).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. (a) Illustrations of controlled synthesis of Pd/FeOOH
@SiO2 catalyst precursor. TEM images of (b) β-FeOOH spindles,
(c) Pd/β-FeOOH, (d) HRTEM image of Pd NP, (e) SEM image, (f,
g) TEM images, and (h) EDX elemental mapping images of the
as-prepared Pd/β-FeOOH@SiO2.
For reactor-like core-shell composites to be catalytically
active, accessibility of reactants to active core is essential.54
Taking Pd/FeOx@SiO2-600 as an example, only reactants
ACS Paragon Plus Environment

Page 5 of 11
Journal of the American Chemical Society
smaller than the pore size of silica shell could penetrate into are devised to differentiate heterogeneous surface reac-
1
the active core of Pd NPs and proceed with the reaction,
whereas molecules larger than the pore diameter would be
rejected. Thus, semipermeable Pd/FeOx@SiO2 sample
would serve as a viable platform to probe the pore diameter
of Stӧber silica shells in solution. In order to demonstrate its
effectiveness, four kinds of olefins with different molecular
size were evaluated. The size of molecules was estimated
based on the method provided in Section 2.10 (Figure S1,
Tables S1 and S3). As reported in Figure 2d, the use of
Pd/FeOx@SiO2-600 led to significantly different activity for
the studied olefins (Figures S5-S8). For the small cyclohex-
ene (6.35.74.5 Å, Table S3), 100% conversion could be
achieved in 120 min (Figure S5). For the slightly larger mol-
ecules, styrene (8.56.04.0 Å, Table S3) and 4-methylsty-
rene (9.86.03.4 Å, Table S3), the conversion rate de-
creased to 28.0% and 10.0% (Figures S6 and S7) respec-
tively after the same reaction time 120 min. When the sub-
strate size became even larger, such as 4-vinylbiphenyl
(12.05.73.4 Å, Table S3), it could hardly pass through the
silica shell. Therefore, negligible activity was observed (Fig-
ure S8). In addition to these control experiments, olefin hy-
drogenation reactions were carried out under the same con-
ditions using the Pd/FeOx@mSiO2 (see Section 2.5; TEM im-
ages in Figure S9) as a catalyst. As shown in Figure S10, the
Pd/FeOx@mSiO2 displays a Type IV isotherm with a clearly
defined hysteresis loop indicating well-developed mesopo-
rous characteristics, which is also clearly visible in TEM im-
ages of Figure S9. The pore diameter of the Pd/FeOx@mSiO2
nanocomposite was about 2.1 nm (Figure S10). It is noted
that both reactants and products could diffuse through the
mesoporous silica shell, reaching active sites of Pd NPs. As
presented in Figure 2e, the catalyst shows decent activities
for cyclohexene, styrene, 4-methylstyrene, and 4-vinylbi-
phenyl with a conversion rate of 100%, 93%, 83%, and 74%
respectively after 60 min of hydrogenation reaction (Fig-
ures S11-S14); the observed gradual decrease in conversion
can be attributed to an increase in molecular size in this se-
ries of reactions which led to diffusion difficulty in the mes-
oporous silica shell. GC-MS was also used to confirm the hy-
drogenation products (Figures S15-S18). On contrast in Fig-
ure 2d, the significant reduction in activity observed in the
same hydrogenation reaction of 4-vinylbiphenyl but using
Pd/FeOx@SiO2-600 is an indication that the pore size of sil-
ica shell in this catalyst is so small that the relatively large
4-vinylbiphenyl (12.05.73.4 Å, Table S3) could not pass
through the shell and reach the Pd active sites (Figure S8).
Together, the experiments of Figure 2d and 2e suggest that
the pore diameter of silica shell of Pd/FeOx@SiO2-600 lies
between 9.8 and 12.0 Å, which allows the penetration of
small molecules or ionic species in this size range, while re-
pelling any molecules larger than 12.0 Å.
tions from homogeneous solution reactions.
2
3
4
5
6
7
8
9
The Pd/FeOx@SiO2-600 core-shell was selected in testing
reactions of iodobenzene (8.55.94.0 Å, Table S3) with
three different arylboronic acids with increasing molecular
sizes as benchmark reactions to assess the homogeneous or
heterogeneous nature of Suzuki-Miyaura cross-coupling
(Figure 2f). While the small iodobenzene is the same, this
testing series can be classified into two types of reaction
(Figure S19a and 19b), depending on the size of arylboronic
acid in each reaction. The size of the three arylboronic acids
(i.e., phenylboronic acid, 4-tert-butylphenylboronic acid,
and 4-benzyloxyphenylboronic acid) is 8.46.23.4 Å,
10.86.05.8 Å, and 14.86.33.0 Å, respectively (Table S3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. (a) Isothermal nitrogen adsorption-desorption loops
and (b) corresponding pore size distributions of Pd/β-
FeOOH@SiO2 and Pd/FeOx@SiO2-x. (c) Catalytic performance
of Suzuki-Miyaura coupling reaction between iodobenzene and
phenylboronic acid over Pd/FeOx@SiO2-x. Reaction conditions:
iodobenzene (0.5 mmol), phenylboronic acid (1.0 mmol),
K2CO3 (2 mmol), ethanol (10 mL); reaction temperature: 85 °C
under atmospheric pressure. Reaction time: 120 min. Kinetic
behaviors of (d) Pd/FeOx@SiO2-600 and (e) Pd/FeOx@mSiO2
toward hydrogenation of alkenes: cyclohexene, styrene, 4-me-
thylstyrene, and 4-vinylbiphenyl. Reaction conditions: olefin (1
mmol), ethanol (10 mL), catalyst (5 mg), H2 flow (30 mL∙min1),
60 min at room temperature and atmospheric pressure. (f) Cat-
alytic performance of the cross-coupling reaction between io-
dobenzene and three different phenyl boronic acids: (i) phenyl-
boronic acid, (ii) 4-tert-butylphenylboronic acid, and (iii) 4-
benzyloxyphenylboronic acid over Pd/FeOx@SiO2-600, reac-
tion conditions: iodobenzene (0.5 mmol), arylboronic acid (1.0
mmol), K2CO3 (2 mmol), ethanol (10 mL); reaction tempera-
As a result, owing to the semipermeable properties of
Stӧber silica shell, the Pd/FeOx@SiO2-600 core-shell nano-
composite was chosen to determine whether the Suzuki-
Miyaura coupling reaction occurred through a heterogene-
ous or homogeneous mechanism. On the basis of our im-
posed shell porosity and architected catalyst configuration,
Suzuki-Miyaura coupling reaction must be a heterogeneous
reaction once size selectivity for all participating reactants
is observed. Otherwise, the reaction is then a homogeneous
one. In Figure S19, therefore, four basic types of reactions
o
ture: 85 C under atmospheric pressure. Reaction time: 120
min.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 11
Understandably, the reaction did not proceed without cata- In view of the reported controversies in literature, it is rec-
1
2
3
4
5
6
7
8
lyst or only trace amount of product was detected over a
palladium-free blank catalyst which had a similar core-shell
configuration (i.e., FeOx@SiO2-600; this control catalyst was
prepared following the same procedures described in Sec-
tion 2.6 and Section 2.7, except for no PdCl2 addition in Sec-
tion 2.4). The maximum dimensional size of iodobenzene,
phenylboronic acid, 4-tert-butylphenylboronic acid, and 4-
benzyloxyphenylboronic acid is 8.5, 8.4, 10.8, and 14.8 Å, re-
spectively (Table S3). Considering of size restriction of the
silica shell, as illustrated in Figure S19b, it would be ex-
tremely difficult for 4-benzyloxyphenylboronic acid to pass
through the silica shell and reach the active solid Pd sites,
because its molecular size is much larger than the pore size
of silica shell (9.812.0 Å). According to the reaction setting
of our study, if the reaction is an exclusively heterogeneous
catalytic process, both reactants would have to come into
contact by colliding onto the confined surface of Pd NPs but
not react within the bulk solution outside the catalyst. In
this regard, no catalytic activity would be observed for the
reaction between iodobenzene and 4-benzyloxyphenyl-
boronic acid due to the presence of diffusion limitation in-
troduced by the silica shell. As shown in Figure 2f, however,
the CC formation reaction could still be catalyzed by
Pd/FeOx@SiO2-600 under the set conditions. More specifi-
cally, nearly 100% yield was achieved for the reaction be-
tween iodobenzene and phenylboronic acid (Figure S19a,
Figure S20) or 4-tert-butylphenylboronic acid (Figure S19a,
Figure S21), and the reaction yield between iodobenzene
and 4-benzyloxyphenylboronic acid was also as high as
79.4% (Figure S19b, Figure S22). In addition to the GC re-
sults, the products from the above reactions were also con-
ognized that without an elaborate design of catalysts as well
as a thorough characterization of catalysts, results from re-
actional investigations alone may not be able to provide an
entire picture on the observed leaching process. Therefore,
in the current study, we aim to obtain direct experimental
evidence in order to identify which hypothesis of Pd disso-
lution pathway is actually operational by paying more at-
tention to synthetic architecture of catalysts and by con-
ducting size selective Suzuki-Miyaura cross-coupling reac-
tions with our core-shell model nanocatalysts.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Herein, firstly, the effect of base addition on the Pd leach-
ing was examined. More specifically, the Pd/FeOx@SiO2-600
was used as a catalyst in the cross-coupling reaction be-
tween two large reactants, 1-benzyloxy-4-iodobenzene and
4-benzyloxyphenylboronic acid (Table S3), in which potas-
sium carbonate was adopted as an alkali source (Figure 3a).
The sizes of the two large molecules are 14.85.83.0 Å and
14.86.33.0 Å (Table S3), respectively. As depicted in Fig-
ure S19c, because both reactants are larger than the pore
size of our silica shell in the Pd/FeOx@SiO2-600, the possi-
bility of arylboronic acid or aryl halide causing Pd leaching
is excluded. In this case, the base is then the only candidate
to introduce Pd leaching. However, after 60 min of reaction,
no reaction was observed (Figure 3a, Figure S26). In com-
parison, when used a commercial catalyst Pd/C, a full con-
version of aryl halide was observed after the same reaction
time 60 min (Figure 3a, Figure S27). These results unambig-
uously elucidate that Pd leaching is not triggered by the
base (potassium carbonate) alone. Therefore, that either
aryl halide or arylboronic acid, or both of them are the real
carrier etchants for Pd leaching should be further investi-
gated. According to the description of homogeneous mech-
anism, one or more reactants must come into contact by col-
liding onto the surface of Pd NPs, then gradually erode the
metallic Pd into soluble Pd-species which can catalyze the
cross-coupling reaction directly. In our present study, thus,
we imposed size selection by introducing the semipermea-
ble silica shell for reactants that can contribute to the Pd
leaching in their Suzuki-Miyaura coupling reactions. In
other words, when a substrate which leads to Pd leaching is
larger than the pore diameter of the silica shell, negligible
catalytic activity will be observed in bulk solution. As a re-
sult, the semipermeable barrier of the silica shell in our cat-
alysts could perform the molecular screening and thus iden-
tify the real cause of the Pd leaching.
1
firmed by H NMR and 13C NMR techniques (Figures S23-
S25). Therefore, the absence of size selectivity in the above
reaction experiments using our nanocatalysts provides di-
rect evidence for the homogeneous mechanism in Suzuki-
Miyaura cross-coupling reactions.
Clearly, on the basis of the above observations (e.g., Fig-
ure 2f), Pd-leaching from the interior core of Pd/FeOx into
bulk solution must be taking place during the reactions, es-
pecially in the case of between iodobenzene and 4-ben-
zyloxyphenylboronic acid (Figure S19b). The next im-
portant issue of our study is to address what is the cause of
this process. It has been reported that the Pd leaching does
not depend on solvents.26, 27 Thus one or more of the reac-
tants that are participating in Suzuki-Miyaura cross-cou-
pling, i.e., aryl halide, aryl boronic acid or the base, are re-
sponsible for causing the Pd leaching. Extensive mechanis-
tic studies on homogeneous reactivity proposed that oxida-
tive addition of aryl halide to the surface of Pd NPs/NCs
leads to the formation of soluble active Pd species (i.e.,
yielding catalytic intermediate of R1-Pd-X) in solution
phase.14, 26 According to Chen et al, oxidative addition of ar-
ylboronic acid is another pathway for the Pd-leaching.27
However, Fang et al suggested that the same palladium
metal leaching is triggered by the synergistic action of both
phenylboronic acid and K2CO3.28 Apparently, achieving a
structurally defined catalyst may serve as a key to resolve
any observed discrepancy, because such proposed path-
ways might be operative under different experimental set-
tings or adopting different preparative methods of catalysts.
Secondly, the effect of arylboronic acids on the Pd leaching
was studied. The reaction between 1-benzyloxy-4-iodoben-
zene and phenylboronic acid with the Pd/FeOx@SiO2-600 as
catalyst was selected as a benchmark reaction (Figure 3b).
In this case, as illustrated in Figure S19d, phenylboronic
acid (8.46.23.4 Å, Table S3) could easily pass through the
silica shell resulting in the Pd leaching, whereas 1-ben-
zyloxy-4-iodobenzene (14.85.83.0 Å, Table S3) which is
much larger than the pore diameter of the silica shell could
not. Under this reaction setting, the small arylboronic acid
(phenylboronic acid) is the only possible etchant for erod-
ing Pd NPs. However, after the reaction for 60 min, no con-
version activity was observed (Figure S28). In another con-
trol experiment where the commercial Pd/C was used in-
stead, the same aryl halide 1-benzyloxy-4-iodobenzene
ACS Paragon Plus Environment

Page 7 of 11
Journal of the American Chemical Society
Figure 3. (a) Catalytic performances of Suzuki-Miyaura cross-
could reach a full conversion within the same reaction
1
2
3
4
5
6
7
8
coupling reactions between 4-benzyloxyphenylboronic acid
and 1-benzyloxy-4-iodobenzene over Pd/FeOx@SiO2-600 and
over a commercial catalyst Pd/C. (b) Catalytic performance of
Suzuki-Miyaura cross-coupling reactions between phenyl-
boronic acid and 1-benzyloxy-4-iodobenzene over Pd/FeOx@
SiO2-600 and the commercial catalyst Pd/C. (c, d) Recycle tests
of Pd/FeOx@SiO2-600 in the reaction between iodobenzene
and phenylboronic acid. Reaction conditions: iodobenzene (0.5
mmol), phenylboronic acid (1.0 mmol), K2CO3 (2 mmol), etha-
nol (10 mL); reaction temperature: 85 oC under atmospheric
conditions. Reaction time: (c) 50 min and (d) 120 min.
timeframe (60 min; Figure 3b, Figure S29). Based on the
above findings, we can exclude the possibility that the Pd
leaching was provoked by the arylboronic acids or by the
synergistic action of the arylboronic acids and K2CO3.
From the two sets of experiments reported in Figure 3a
and Figure 3b, we can clearly see that the Pd-etching can be
undoubtedly attributed to the important role of aryl halides
in the reaction. To have a fuller picture, the effect of aryl hal-
ides in Suzuki-Miyaura coupling reactions was further in-
vestigated in detail. In the reaction between iodobenzene
(8.55.94.0 Å, Table S3) and 4-benzyloxyphenylboronic
acid (14.86.33.0 Å, Table S3), as shown in Figure 2f, the
conversion rate of iodobenzene was achieved at 79.4% after
120 min. In this case, 4-benzyloxyphenylboronic acid,
which is much larger than the pore diameter of the silica
shell, could not pass through the silica shell and reach the
Pd NPs. Iodobenzene is then the only working etchant for
the Pd leaching. In light of the above observations so far,
once again, we elucidated that the metal leaching is not
caused by oxidative addition of arylboronic acid or the syn-
ergistic action between the arylboronic acid and K2CO3,
while the oxidative addition of the aryl halide (iodoben-
zene) to the metallic Pd is confirmed to be the main reaction
for the Pd leaching. To further affirm this finding and to
prove whether the large aryl halide molecules would take
part in the following reaction after Pd leaching happens, we
had conducted an additional control reaction. Briefly, 5 mg
of Pd/FeOx@SiO2-600 nanocatalyst was placed in a round-
bottom flask containing 10 mL of ethanol, 0.5 mmol of iodo-
benzene, 0.5 mmol of 1-benzyloxy-4-iodobenzene, 1.5
mmol of phenylboronic acid, and 2 mmol of K2CO3. The mix-
ture was stirred and heated to 85 oC. As displayed in Figure
S30, after 120 min of reaction, the conversion rate of iodo-
benzene and 1-benzyloxy-4-iodobenzene was 86.4 % and
73.4 %, respectively. From this control experiment, large
aryl halide could also take part in the following reaction af-
ter Pd(0) species was released by the small aryl halide mol-
ecules of iodobenzene. In other words, oxidative addition of
1-benzyloxy-4-iodobenzene with in-situ regenerated Pd(0)
species also took place within the same solution phase, after
the oxidative addition of smaller iodobenzene with the me-
tallic Pd NPs on the Pd/FeOx core in the first place, although
it was too large to directly contact the catalyst core.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
It has been reported that the active dissolved Pd species
could redeposit onto the support after full conversion of the
substrates and the Pd content in solution starts to decrease
when a high percentage of substrates has been consumed.26,
55 In order to estimate the theory, two series of recyclability
experiments were evaluated in Suzuki-Miyaura cross-cou-
pling reaction between iodobenzene (8.55.94.0 Å, Table
S3) and phenylboronic acid (8.46.23.4 Å, Table S3) with
a freshly prepared catalyst Pd/FeOx@SiO2-600 in 10 mL of
ethanol. In the first series of recycle tests, each reaction run
was stopped after 50 min with a conversion rate of iodoben-
zene at 43.2% (Figure 3c). For the second series of the tests,
the catalyst was recycled when iodobenzene was fully con-
sumed after 120 min (Figure 3d). After every run of the re-
action, the catalyst was retrieved by centrifugation, washed
with ethanol three times and then reused in the next con-
secutive run under the same reaction conditions. As shown
in Figure 3c, for the first test series, the Pd/FeOx@SiO2-600
showed a decent conversion rate in the first run, but this
rate decreased significantly to 7.6% in the second run, and
no product was observed in the third and fourth runs (Fig-
ure S31). While for the second series of the tests with reac-
tion lifetime up to 120 min, the catalyst could be easily re-
cycled 4 times without significant activity loss (Figure 3d,
Figure S32). To explain these results, TEM investigation was
also carried out to characterize spent catalysts. As reported
in Figure S33, in the first recycle series (Figure 3c), no ap-
preciable morphological change of the catalyst
Pd/FeOx@SiO2-600 is observed after each recycle experi-
ment. In contrast, for the second series of the tests (Figure
3d), Pd NPs of about 35 nm can be observed outside the
silica shell (Figure S34). Since our studies have revealed
that the leached Pd species are the main active species for
the CC coupling reaction, we believe that the significant
difference between the two series recycle experiments can
be ascribed to the following process. In the presence of aryl
halides (i.e., R1-X) in reaction, the Pd NPs can be leached into
solution phase via forming soluble active R1-Pd-X species,
which then enters into the reacting solution, catalyzing the
reaction directly. In the second series of the tests, the
leached Pd species can be largely captured and redeposited
on the external surface of the catalyst after reaction. Be-
cause R1-X has been totally consumed in the first run (con-
version 100%, Figure 3d), as a result, the spent catalyst can
provide an almost equal amount of soluble Pd species again
from the redeposited Pd NPs through leaching in the next
consecutive run, maintaining sufficient active Pd species for
the reaction. On the contrary, in the first series of experi-
ACS Paragon Plus Environment

Journal of the American Chemical Society
ments (Figure 3c), the catalyst was retrieved by centrifuga-
Page 8 of 11
1
tion after 50 min with a conversion of 43.2%. A significant
amount of soluble active Pd species was still present in liq-
uid phase (which was discarded upon the cessation of the
test), and would not be involved in the next recycle run.
Since Pd-leaching was demonstrated in our studied Suzuki
reactions, the concentration of soluble-Pd species in the re-
action solution was then measured by ICP-MS. In the reac-
tion between iodobenzene and phenylboronic acid with a
conversion rate of 43.2 %, the content of Pd in solution was
measured at 141 ppb. On the contrary, after iodobenzene
was fully consumed, the dissolved-Pd species decreased
sharply to 27 ppb (Table S4). The amount of Pd in the solid
catalysts was also determined by ICP-OES. The Pd weight
contents were 0.85 %, 0.76 % and 0.82 % for the fresh cat-
alyst, spent catalyst after reaction for 50 min, and spent cat-
alyst after reaction for 120 min, respectively (Table S5).
This finding is in agreement with the ICP-MS results for the
Pd content in the reaction solution. Additionally, it has been
reported that low-coordinated Pd atoms at corners and
edges of palladium nanoparticles could serve as a starting
point of dissolution process of Pd species.14, 56 The direct
loss of the active palladium content by discarding dissolved
Pd species in every run of experiment in the first series of
recycle reactions (Figure 3c) was the main cause of the de-
activation of the catalyst, because such a discarded leaching
solution was still catalytically very active (Figure S35). Fur-
thermore, the population of soluble low-coordinated Pd
also lost consecutively and eventually no reaction product
was found in the third and fourth runs due to lacking in sol-
uble Pd species in the used catalyst.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Mechanism for Pd-catalyzed Suzuki-Miyaura cross-
coupling reactions: (a) oxidative addition of R1-X, (b) the Pd
leaching via formation of soluble R1-Pd-X, (c) addition of R2-M
and transmetalation of R1-Pd-R2, and (d) reductive elimination
of Pd and formation of final product R1-R2, where R1 and R2
stand for aryl functional groups, X stands for a halide functional
group, and R2-B(OH)2 for an arylboronic acid. Original or rede-
posited Pd(0) solid or soluble Pd(II) in solution is represented
by small light olive spheres; FeOx support for Pd(0) is shown as
spindle-like core with cider color; and microporous silica shell
in gray is depicted on the outmost layer of the catalyst; and the
soluble base used for transforming R1-Pd-X to R1-Pd-OH (prior
to step (c)) in the reaction is not depicted above.
4. CONCLUSION
In summary, we have designed a core-shell catalytic
nanostructure in which iron oxide supported palladium na-
noparticles were precisely wrapped by a layer of Stӧber sil-
ica and the system was used in Suzuki-Miyaura cross-cou-
pling reactions. The microporous silica shell not only serves
as a barrier layer to stabilize active palladium nanoparticles
against aggregation during reaction, but also allows a size-
selective permeability of reactant molecules to the sup-
ported palladium nanoparticles. With the core-shell nano-
composites as catalysts, we devised a range of reaction ex-
periments and confirmed the oxidative-addition-promoted
homogeneous origin in nanoscale metallic Pd-catalyzed Su-
zuki-Miyaura CC coupling reactions. Accessibility of aryl
halides to solid palladium is the main factor for the Pd leach-
ing. Dissolved palladium species will redeposit back at the
end of the reaction, completing the homogeneous catalytic
cycle. Taking advantage of maturing synthetic chemistry of
nanomaterials and nanocomposites, we also demonstrated
that resolution and confirmation of apparently controver-
sial mechanistic observations and/or hypotheses can also
be done by deliberate design of nanocatalysts and careful
selection of reactant substrates, in addition to the state-of-
the-art analytical approaches. Apart from making more ef-
fective catalysts to enhance their activity and selectivity,
clearly, nanoscience and nanotechnology will continue giv-
ing us new capacity to contribute even more to the field of
mechanistic research in catalysis if we pay more attention
to the integrative design and synthetic architecture of nano-
composite-based catalysts.
According to the above experimental evidence and find-
ings, a homogeneous mechanism which involves oxidative
addition-transmetalation-reductive elimination sequences
can now be described in Scheme 1. In step (a), aryl halides
(R1-X) diffuse through the microporous silica shell and then
arrive at active sites of Pd NPs. In step (b), the Pd leaching
originates from the oxidative reaction between the infiltrat-
ing R1-X and the interior Pd/FeOx core, which turns Pd(0) to
Pd(II) and gives rise to the formation of surface species R1-
Pd-X. The surface intermediate (R1-Pd-X) would then de-
sorb and transfer across the microporous silica shell, enter-
ing into the reaction solution. In step (c), transmetalation of
the R1-Pd-X and arylboronic acid takes place, resulting in
the formation of biaryl palladium species biaryl-Pd(II) (i.e.,
R1-Pd-R2). And finally, in step (d), biaryl (i.e., R1-R2) is pro-
duced through the reductive elimination of Pd in the biaryl-
Pd(II) intermediate. At the same time, Pd(II) can be reduced
to Pd(0). As expected, in the final step, the reduction of
Pd(II) to Pd(0) could be carried out on the surface of the Pd
NPs (i.e., on the original Pd/FeOx core) located behind the
silica shell and/or simply on the external surface of the sil-
ica shell owing to difficult back diffusion of much larger size
of intermediate reaction product biaryl-Pd(II) (i.e., R1-Pd-
R2) across the silica shell. Indeed, due to the microporous
barrier exerted by the shell, the observed back deposition
of palladium took place largely on the external surface of the
silica shell in the recycle experiments (Figure 3d and Figure
S34) using our nanocatalysts.
ASSOCIATED CONTENT
ACS Paragon Plus Environment

Page 9 of 11
Journal of the American Chemical Society
Prepared through the Transformation of MIL-96(Al) Nanocrystals.
ChemCatChem 2016, 8, 1283-1287.
The Supporting Information is available free of charge on the
ACS Publications website.
1
2
3
4
5
6
7
8
(13) Li, Y.; Zhang, Z.; Fan, T.; Li, X.; Ji, J.; Dong, P.; Baines, R.; Shen,
J.; Ye, M., Magnetic Core-Shell to Yolk-Shell Structures in Palladium-
Catalyzed Suzuki-Miyaura Reactions: Heterogeneous versus Ho-
mogeneous Nature. ChemPlusChem 2016, 81, 564-573.
(14) Pérez-Lorenzo, M., Palladium Nanoparticles as Efficient
Catalysts for Suzuki Cross-Coupling Reactions. J. Phy. Chem. Lett.
2012, 3, 167-174.
(15) Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W., On the Nature
of the Active Species in Palladium Catalyzed Mizoroki–Heck and
Suzuki–Miyaura Couplings–Homogeneous or Heterogeneous Ca-
talysis, A Critical Review. Adv. Synth. Catal. 2006, 348, 609-679.
(16) Zhao, Y.; Du, L.; Li, H.; Xie, W.; Chen, J., Is the Suzuki-Miyaura
Cross-Coupling Reaction in the Presence of Pd Nanoparticles Het-
erogeneously or Homogeneously Catalyzed? An Interfacial Sur-
face-Enhanced Raman Spectroscopy Study. J. Phys. Chem. Lett.
2019, 10, 1286-1291.
(17) Ellis, P. J.; Fairlamb, I. J.; Hackett, S. F.; Wilson, K.; Lee, A. F.,
Evidence for the Surface-Catalyzed Suzuki-Miyaura Reaction over
Palladium Nanoparticles: an Operando XAS Study. Angew. Chem.
Int. Ed. 2010, 49, 1820 –1824.
(18) Fu, F.; Xiang, J.; Cheng, H.; Cheng, L.; Chong, H.; Wang, S.; Li,
P.; Wei, S.; Zhu, M.; Li, Y., A Robust and Efficient Pd3 Cluster Catalyst
for the Suzuki Reaction and Its Odd Mechanism. ACS Catal. 2017, 7,
1860-1867.
(19) Maegawa, T.; Kitamura, Y.; Sako, S.; Udzu, T.; Sakurai, A.;
Tanaka, A.; Kobayashi, Y.; Endo, K.; Bora, U.; Kurita, T.; Kozaki,
A.; Monguchi, Y.; Sajiki, H., Heterogeneous Pd/C-Catalyzed Ligand-
Free, Room-Temperature Suzuki-Miyaura Coupling Reactions in
Aqueous Media. Chem. Eur. J. 2007, 13, 5937-5943.
(20) Kurokhtina, A. A.; Larina, E. V.; Schmidt, A. F.; Malaika, A.;
Krzyżyńska, B.; Rechnia, P.; Kozłowski, M., Mechanistic Studies of
the Suzuki-Miyaura Reaction with Aryl Bromides using Pd Sup-
ported on Micro- and Mesoporous Activated Carbons. J. Mol. Catal.
Chem. 2013, 379, 327-332.
(21) Richardson, J.; Jones, C., Strong Evidence of Solution-phase
Catalysis Associated with Palladium Leaching from Immobilized
Thiols during Heck and Suzuki Coupling of Aryl Iodides, Bromides,
and Chlorides. J. Catal. 2007, 251, 80-93.
(22) Niu, Z.; Peng, Q.; Zhuang, Z.; He, W.; Li, Y., Evidence of an
Oxidative-Addition-Promoted Pd-Leaching Mechanism in the Su-
zuki Reaction by Using a Pd-Nanostructure Design. Chem. Eur. J
2012, 18, 9813-9817.
(23) Albiñana, P. A.; Haskouri, J. E.; Marcos, M. D.; Estevan, F.;
Amorós, P.; Úbeda, M. Á.; Pérez-Pla, F., A New Efficient, Highly Dis-
persed, Pd Nanoparticulate Silica Supported Catalyst Synthesized
from an Organometallic Precursor. Study of the Homogeneous vs.
Heterogeneous Activity in the Suzuki-Miyaura Reaction. J. Catal.
2018, 367, 283-295.
(24) Collins, G.; Schmidt, M.; O’Dwyer, C.; McGlacken, G.; Holmes,
J. D., Enhanced Catalytic Activity of High-Index Faceted Palladium
Nanoparticles in Suzuki–Miyaura Coupling Due to Efficient Leach-
ing Mechanism. ACS Catal. 2014, 4, 3105-3111.
(25) Newton, M. A.; Ferri, D.; Mulligan, C. J.; Alxneit, I.; Emerich,
H.; Thompson, P. B. J.; Hii, K. K., In Situ Study of Metal Leaching from
Pd/Al2O3 Induced by K2CO3. Catal. Sci. Technol. 2020, 10, 466-474.
(26) Soomro, S. S.; Ansari, F. L.; Chatziapostolou, K.; Köhler, K.,
Palladium Leaching Dependent on Reaction Parameters in Suzuki–
Miyaura Coupling Reactions Catalyzed by Palladium Supported on
Alumina under Mild Reaction Conditions. J. Catal. 2010, 273, 138-
146.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chezhc@nus.edu.sg
ORCID: Hua Chun Zeng: 0000-0002-0215-7760
9
Notes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors acknowledge the financial supports provided by
Green Energy Program, National University of Singapore, and
National Research Foundation (NRF) of Singapore under its
Campus for Research Excellence and Technological Enterprise
(CREATE) program.
REFERENCES
(1) Miyaura, N.; Suzuki, A., Palladium-Catalyzed Cross-Coupling
Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457-
2483.
(2) Yin, L. X.; Liebscher, J., Carbon-carbon Coupling Reactions
Catalyzed by Heterogeneous Palladium Catalysts. Chem. Rev. 2007,
107, 133-173.
(3) Miyaura, N.; Yanagi, T.; Suzuki, A., The Palladium-Catalyzed
Cross-Coupling Reaction of Phenylboronic Acid with Haloarenes in
the Presence of Bases. Synth. Commun. 2006, 11, 513-519.
(4) Shen, D.; Xu, Y.; Shi, S. L., A Bulky Chiral N-Heterocyclic Car-
bene Palladium Catalyst Enables Highly Enantioselective Suzuki-
Miyaura Cross-Coupling Reactions for the Synthesis of Biaryl Atro-
pisomers. J. Am. Chem. Soc. 2019, 141, 14938-14945.
(5) Malapit, C. A.; Bour, J. R.; Brigham, C. E.; Sanford, M. S., Base-
free nickel-catalysed decarbonylative Suzuki-Miyaura coupling of
acid fluorides. Nature 2018, 563, 100-104.
(6) Hooshmand, S. E.; Heidari, B.; Sedghi, R.; Varma, R. S., Recent
Advances in the Suzuki–Miyaura Cross-Coupling Reaction using Ef-
ficient Catalysts in Eco-friendly Media. Green Chem. 2019, 21, 381-
405.
(7) Chen, Z.; Vorobyeva, E.; Mitchell, S.; Fako, E.; Ortuno, M. A.;
Lopez, N.; Collins, S. M.; Midgley, P. A.; Richard, S.; Vile, G.; Perez-
Ramirez, J., A Heterogeneous Single-atom Palladium Catalyst Sur-
passing Homogeneous Systems for Suzuki coupling. Nat. Nanotech.
2018, 13, 702-707.
(8) Scheuermann, G. M.; Rumi, L.; Steurer, P.; Bannwarth, W.;
Mulhaupt, R., Palladium Nanoparticles on Graphite Oxide and Its
Functionalized Graphene Derivatives as Highly Active Catalysts for
the Suzuki-Miyaura Coupling Reaction. J. Am. Chem. Soc. 2009, 131,
8262-8270.
(9) Ye, T. N.; Lu, Y.; Xiao, Z.; Li, J.; Nakao, T.; Abe, H.; Niwa, Y.;
Kitano, M.; Tada, T.; Hosono, H., Palladium-bearing Intermetallic
Electride as an Efficient and Stable Catalyst for Suzuki Cross-Cou-
pling Reactions. Nat. Commun. 2019, 10, 5653.
(10) Destito, P.; Sousa-Castillo, A.; Couceiro, J. R.; López, F.; Cor-
rea-Duarte, M. A.; Mascarenas, J. L., Hollow Nanoreactors for Pd-
Catalyzed Suzuki-Miyaura coupling and O-propargyl Cleavage Re-
actions in Bio-relevant Aqueous Media. Chem. Sci. 2019, 10, 2598-
2603.
(27) Chen, J.-S.; Vasiliev, A. N.; Panarello, A. P.; Khinast, J. G., Pd-
Leaching and Pd-Removal in Pd/C-Catalyzed Suzuki Couplings.
Appl. Catal. A: Gen. 2007, 325, 76-86.
(28) Fang, P. P.; Jutand, A.; Tian, Z. Q.; Amatore, C., Au-Pd Core-
Shell Nanoparticles Catalyze Suzuki-Miyaura Reactions in Water
through Pd Leaching. Angew. Chem. Int. Ed. 2011, 50, 12184-
12188.
(11) Zhan, G. W.; Zeng, H. C., Smart Nanocatalysts with Stream-
line Shapes. ACS Cent. Sci. 2017, 3, 794-799.
(12) Zhou, Y.; Zeng, H. C., Alumina-Supported Metal Catalysts in-
side a Mesoporous Aluminum-Silicate Shell: Nanoscale Reactors
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
(29) Schmidt, A. F.; Kurokhtina, A. A., Distinguishing Between
(44) Hamon, C.; Sanz-Ortiz, M. N.; Modin, E.; Hill, E. H.; Scarabelli,
the Homogeneous and Heterogeneous Mechanisms of Catalysis in
the Mizoroki-Heck and Suzuki-Miyaura Reactions: Problems and
Prospects. Kinet. Catal. 2012, 53, 714-730.
L.; Chuvilin, A.; Liz-Marzán, L. M., Hierarchical Organization and
Molecular Diffusion in Gold Nanorod/Silica Supercrystal Nano-
composites. Nanoscale 2016, 8, 7914-7922.
1
2
3
4
5
6
7
8
9
(30) Eremin, D. B.; Ananikov, V. P., Understanding Active Species
in Catalytic Transformations: From Molecular Catalysis to Nano-
particles, Leaching, “Cocktails” of Catalysts and Dynamic Systems.
Coord. Chem. Rev. 2017, 346, 2-19.
(31) Biffis, A.; Centomo, P.; Zotto, A. D.; Zecca, M., Pd Metal Cata-
lysts for Cross-Couplings and Related Reactions in the 21st Cen-
tury: A Critical Review. Chem. Rev. 2018, 118, 2249-2295.
(32) Webb, J. D.; MacQuarrie, S.; McEleney, K.; Crudden, C. M.,
Mesoporous Silica-Supported Pd catalysts: An Investigation into
Structure, Activity, Leaching and Heterogeneity. J. Catal. 2007, 252,
97-109.
(33) Zeng, H. C., Integrated Nanocatalysts. Acc. Chem. Res. 2013,
46, 226-235.
(34) Zhan, G. W.; Zeng, H. C., Integrated Nanocatalysts with Mes-
oporous Silica/Silicate and Microporous MOF Materials. Coord.
Chem. Rev. 2016, 320-321, 181-192.
(35) Zhan, G. W.; Li, P.; Zeng, H. C., Architectural Designs and Syn-
thetic Strategies of Advanced Nanocatalysts. Adv. Mater. 2018, 30,
e1802094.
(36) Li, B. W.; Zeng, H. C., Architecture and Preparation of Hollow
Catalytic Devices. Adv. Mater. 2019, 31, e1801104.
(37) Zhan, G. W.; Zeng, H. C., Hydrogen Spillover through Matry-
oshka-type (ZIFs@)n-1ZIFs Nanocubes. Nat. Commun. 2018, 9,
3778.
(38) Wang, G.-H.; Chen, K.; Engelhardt, J.; Tüysüz, H.; Bongard,
H.-J.; Schmidt, W.; Schüth, F., Scalable One-Pot Synthesis of Yolk–
Shell Carbon Nanospheres with Yolk-Supported Pd Nanoparticles
for Size-Selective Catalysis. Chem. Mater. 2018, 30, 2483-2487.
(39) Wang, Q.; Cui, Z.-M.; Cao, C.-Y.; Song, W.-G., 0.3 Å Makes the
Difference: Dramatic Changes in Methanol-to-Olefin Activities be-
tween H-ZSM-12 and H-ZSM-22 Zeolites. J. Phy. Chem. C 2011, 115,
24987-24992.
(40) Sun, B.; Feng, X.; Yao, Y.; Su, Q.; Ji, W.; Au, C.-T., Substantial
Pretreatment Effect on CO Oxidation over Controllably Synthesized
Au/FeOx Hollow Nanostructures via Hybrid Au/β-FeOOH@SiO2.
ACS Catal. 2013, 3, 3099-3105.
(41) Qin, R.; Zeng, H. C., Confined Transformation of UiO-66
Nanocrystals to Yttria-Stabilized Zirconia with Hierarchical Pore
Structures for Catalytic Applications. Adv. Funct. Mater. 2019, 29,
1903264.
(42) Chatterjee, S.; Li, X. S.; Liang, F.; Yang, Y. W., Design of Mul-
tifunctional Fluorescent Hybrid Materials Based on SiO2 Materials
and Core-Shell Fe3O4@SiO2 Nanoparticles for Metal Ion Sensing.
Small 2019, 15, e1904569.
(43) Bodelón, G.; Montes-García, V.; López-Puente, V.; Hill, E. H.;
Hamon, C.; Sanz-Ortiz, M. N.; Rodal-Cedeira, S.; Costas, C.; Celiksoy,
S.; Pérez-Juste, I.; Scarabelli, L.; Porta, A. L.; Pérez-Juste, J.; Pastor-
iza-Santos, I.; Liz-Marzán, L. M., Detection and Imaging of Quorum
Sensing in Pseudomonas aeruginosa Biofilm Communities by Sur-
face-enhanced Resonance Raman Scattering. Nat. Mater. 2016, 15,
1203-1211.
(45) Lin, F. C.; Zink, J. I., Probing the Local Nanoscale Heating
Mechanism of a Magnetic Core in Mesoporous Silica Drug-Delivery
Nanoparticles Using Fluorescence Depolarization. J. Am. Chem. Soc.
2020, 142, 5212-5220.
(46) Yang, G.; Liu, Y.; Wang, H.; Wilson, R.; Hui, Y.; Yu, L.; Wibowo,
D.; Zhang, C.; Whittaker, A. K.; Middelberg, A. P. J.; Zhao, C. X., Bioin-
spired Core-Shell Nanoparticles for Hydrophobic Drug Delivery.
Angew. Chem. Int. Ed. 2019, 58, 14357-14364.
(47) Stöber, W.; Fink, A., Controlled Growth of Monodisperse Sil-
ica Spheres in the Micron Size Range. J. Colloid Interface Sci. 1968,
26, 62-69.
(48) Wells, J. D.; Koopal, L. K.; Keizer, A. d., Monodisperse, Non-
porous, Spherical Silica Particles. Colloids Surf. A Physicochem. Eng.
Asp. 2000, 166, 171-176.
(49) Kosari, M.; Borgna, A.; Zeng, H. C., Transformation of Stöber
Silica Spheres to Hollow Nanocatalysts. ChemNanoMat 2020, 6,
889-906.
(50) Humphrey, W.; Dalke, A.; Schulten, K., VMD: Visual Molecu-
lar Dynamics. J. Mol. Graph. 1996, 14, 33-38.
(51) Gutiérrez, A. M.; González E.; Echevarría, M.; Hernández, C.
S.; Whittembury, G., The Proximal Straight Tubule (PST) Basolat-
eral Cell Membrane Water Channel: Selectivity Characteristics. J.
Mebrane Biol. 1995, 143, 189-197.
(52) Piao, Y.; Kim, J.; Na, H. B.; Kim, D.; Baek, J. S.; Ko, M. K.; Lee,
J. H.; Shokouhimehr, M.; Hyeon, T., Wrap-Bake-Peel Process for
Nanostructural Transformation from beta-FeOOH Nanorods to Bi-
ocompatible Iron Oxide Nanocapsules. Nat. Mater. 2008, 7, 242-
247.
(53) Farrando-Pérez, J.; López, C.; Silvestre-Albero, J.; Gallego-
Gómez, F., Direct Measurement of Microporosity and Molecular Ac-
cessibility in Stöber Spheres by Adsorption Isotherms. J. Phys.
Chem. C 2018, 122, 22008-22017.
(54) Sudarsanam, P.; Peeters, E.; Makshina, E. V.; Parvulescu, V.
I.; Sels, B. F., Advances in Porous and Nanoscale Catalysts for Viable
Biomass Conversion. Chem. Soc. Rev. 2019, 48, 2366-2421.
(55) Vaerenbergh, B. V.; Lauwaert, J.; Thybaut, J. W.; Vermeir, P.;
Clercq, J. D., Pd Nanoparticle and Molecular Pd2+ Leaching Path-
ways for a Strongly Acid versus Strongly Basic Resin Supported Pd
Nanoparticle Catalyst in Suzuki Coupling. Chem. Eng. J. 2019, 374,
576-588.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(56) Collins, G.; Schmidt, M.; O'Dwyer, C.; Holmes, J. D.;
McGlacken, G. P., The Origin of Shape Sensitivity in Palladium-Cat-
alyzed Suzuki-Miyaura Cross Coupling Reactions. Angew. Chem. Int.
Ed. 2014, 53, 4142-4145.
ACS Paragon Plus Environment

Page 11 of 11
Journal of the American Chemical Society
Insert Table of Contents artwork here
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
11
ACS Paragon Plus Environment