Three-Dimensional Printing in Catalysis: Combining 3D Heterogeneous Copper and Palladium Catalysts for Multicatalytic Multicomponent Reactions

Article abstract of DOI:10.1021/acscatal.7b02592

Two 3D-hybrid monolithic catalysts containing immobilized copper and palladium species on a silica support were synthesized by 3D printing and a subsequent surface functionalization protocol. The resulting 3D monoliths provided a structure with pore sizes around 300 μm, high mechanical strength, and easy catalyst recyclability. The devices were designed to perform heterogeneous multicatalytic multicomponent reactions (MMCRs) based on a copper alkyne-azide cycloaddition (CuAAC) + palladium catalyzed cross-coupling (PCCC) strategy, which allowed the rapid assembly of variously substituted 1,2,3-triazoles using a mixture of tBuOH/H₂O as solvent. The reusable multicatalytic system developed in this work is an example of a practical miniaturized and compartmental heterogeneous 3D-printed metal catalyst to perform MMCRs for solution chemistry.

Full text of DOI:10.1021/acscatal.7b02592

Subscriber access provided by READING UNIV
Article
3D Printing in Catalysis: Combining 3D Heterogeneous Copper and
Palladium Catalysts for Multicatalytic Multicomponent Reactions
Antonio S Díaz-Marta, Carmen Rial Tubio, Carlos Carbajales, Carmen Fernández, Luz
Escalante, Eddy Sotelo, Francisco Guitian, Victoria Laura Barrio, Alvaro Gil, and Alberto Coelho
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02592 • Publication Date (Web): 26 Nov 2017
Downloaded from http://pubs.acs.org on November 26, 2017
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 free 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 accessible to all
readers and 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.
ACS Catalysis 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 19
ACS Catalysis
1
2
3
4
5
6
7
8
9
3D Printing in Catalysis: Combining 3D Heterogeneous Copper and
Palladium Catalysts for Multicatalytic Multicomponent Reactions
Antonio S. Díaz-Marta,1,‡ Carmen R. Tubío,2,‡ Carlos Carbajales,1 Carmen Fernández,1 Luz Escalante,1
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
Eddy Sotelo,1,4 Francisco Guitián,2 V. Laura Barrio,3 Alvaro Gil*,2 and Alberto Coelho*,1,4
1Centro Singular de Investigación en Química Biolóxica e Materiáis Moleculares (CIQUS), Universidade de Santiago de
Compostela, 15782, Spain
2Instituto de Cerámica, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, Spain
3Escuela de Ingeniería. Universidad del País Vasco, Alameda Urquijo s/n, 48013, Bilbao, Spain
4Departamento de Química Orgánica, Facultad de Farmacia. Universidade de Santiago de Compostela, 15782, Santiago de
Compostela, Spain
ABSTRACT: Two 3D-hybrid monolithic catalysts containing immobilized copper and palladium species on a silica support were
synthesized by 3D printing and a subsequent surface functionalization protocol. The resulting 3D monoliths provided a structure
with pore sizes around 300 µm, high mechanical strength, and easy catalyst recyclability. The devices were designed to perform
heterogeneous Multicatalytic Multicomponent Reactions (MMCRs) based on a Copper Alkyne-Azide Cycloaddition (CuAAC) +
Palladium Catalyzed Cross-Coupling (PCCC) strategy, which allowed the rapid assembly of variously substituted 1,2,3-triazoles
using a mixture of tBuOH/H2O as solvents. The reusable multicatalytic system developed in this work is an example of a practical
miniaturized and compartmental heterogeneous 3D-printed metal catalyst to perform MMCRs for solution chemistry.
KEYWORDS: 3D-Printing, Heterogeneous catalysts, CuAAC, Palladium, Multicatalytic Multicomponent reactions.
pendently reported by Sharpless12 and Meldal,13 who described
the dramatic improvement of the original Huisgen process
through the use of a copper(I) catalyst. Another paradigm of
INTRODUCTION
chemical efficiency is represented by the palladium-catalyzed
The application of efficient catalytic processes instead of
cross-coupling reactions (PCCCR).14 In terms of industrial
stoichiometric ones is one of the main requirements for sus-
applications, Suzuki coupling is by far the most widely used
tainable and environmentally friendly chemistry.1 Among the
reaction of this type, followed by Heck, Sonogashira and Stille
known catalytic transformations, Transition Metal-Catalyzed
couplings. Despite the impact of CuAAC and PCCCRs, and
Reactions (TMCRs)2 form one of the main pillars of Modern
given the drawbacks related to their application under homo-
Organic Chemistry and they are of great importance for appli-
geneous conditions on an industrial scale as discussed above,
cations in the chemical, pharmaceutical, and biochemical
efforts to carry out these transformations under heterogeneous
industries. However, the use of homogeneous TMCRs on an
conditions have attracted the attention of chemists in the last
industrial scale suffers from serious drawbacks that concern
two decades.15
the final product.3 For instance, the synthesis of active phar-
On considering the use of efficient transformations, the mul-
maceutical ingredients in the pharmaceutical industry is sub-
ticomponent reactions (MCRs)16,17 are particularly powerful
ject to strict safety regulations and trials to determine the pres-
chemical methodologies. These reactions are characterized by
ence of traces of metals in the final products.4 Therefore, im-
their convergence, atom economy, and the avoidance of inter-
mobilizing catalytic metal species on solid reusable supports
mediate purification processes. As a consequence, these reac-
for an easier catalyst separation and reuse while avoiding
tions have considerable advantages over classical linear syn-
leaching processes is currently a key priority to develop clean-
theses. Although most of the established MCRs do not require
er and more sustainable chemistry. Attempts to increase the
a catalyst, the search for new MCR products has resulted in
flexibility of heterogeneous solid catalysts have been made by
great effort to find catalysts and new catalyzed MCRs.18 Con-
synthesizing hybrid organic–inorganic structured solids that
sequently,
Multicatalytic
Multicomponent
Reactions
(MMCRs)19 have emerged as a highly valuable synthetic tool.
In an MMCR, two or more catalysts are present from the onset
of the reaction and these operate independently and in a con-
secutive manner. Cooperative catalysis provided by copper
and palladium sources has been explored20,21 in an exhilarating
and fruitful manner as well as rhodium/palladium,22 rhodi-
um/palladium/copper,23 indium/palladium,24 copper/rhodium25
and rhodium/iridium26 combinations, although in these proce-
dures the pairs were always used as homogeneous catalysts.
Despite the impressive possibilities provided by the combina-
tion of heterogeneous metal catalysts in different multicompo-
nent cocktails, to our knowledge, examples of compartmental-
contain active sites in either one or both components. Such
solids include hybrid zeolites,5 periodic mesoporous organo-
silicas (PMOs),6 metal–organic frameworks (MOFs),7,8 and, in
general, hybrid organic–inorganic catalysts.9
The overall objective for truly sustainable chemistry is not
only achievable through the discovery of new recoverable
solid heterogeneous catalysts based on novel materials, but
also through the synergistic application of these devices in
modular, robust and efficient chemical transformations. In
2001, Sharpless, Finn, and Kolb laid out the philosophy of
click chemistry,10 an innovative approach to chemical synthe-
sis. The prototypical click chemistry reaction, the copper cata-
lyzed azide-alkyne cycloaddition (CuAAC),11 was inde-
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 19
ized bulky 3D monolithic heterogeneous catalytic systems in attachment of appropriate linkers containing coordination sites
for catalytic metal species.36 In this work, we carried out the
synthesis of two new silica-based Pd and Cu heterogeneous
monolithic catalysts [3D-SiO2-APTS-Cu and 3D-SiO2-
AAPTS-Pd] by 3D printing of a silica support followed by
surface functionalization and we evaluated the catalytic activi-
ty of these materials in newly designed CuAAC + So-
nogashira, CuAAC + Stille or CuAAC + Suzuki MMCRs. The
experimental protocol was performed in six stages: (1) Prepa-
ration of concentrated colloidal gel ink in which SiO2 ceramic
powder and polymer binders were mixed to obtain a good
homogeneity. (2) Extrusion to build a 3D woodpile structure.
(3) Sintering of the structure at high temperature. (4) Surface
activation in acid media and subsequent functionalization by
silanization and metallation to give the final 3D-monolithic
copper (3D-SiO2-APTS-Cu) and palladium (3D-SiO2-AAPTS-
Pd) structures. (5) Validation of the catalytic efficacy in Cu-
AAC, Sonogashira, Stille and Suzuki reactions and finally (6)
Evaluation of the combined use of both catalytic systems in
MMCRs.
1
2
3
4
5
6
7
8
MMCRs have not been reported (at least two catalysts in the
reaction mixture). The use of monolithic catalysts in catalytic
processes offers significant advantages compared to traditional
catalytic materials such as powders, pellets and extrudates,
thus offering an easier handling and a better reusability. A
powerful argument for the use of 3D monoliths in catalysis is
related to the individual recovery and recycling after an
MMCR or tandem process. For example, on using the tradi-
tional catalytic systems cited above, the complexity of per-
forming a powder solid-solid separation during work up (only
achievable by the incorporation of magnetic properties27,28 on
supports or the use of the Houghten ‘Tea bag’ method29) can
be solved by the simple compartmentalization of immobilized
active catalytic metal species within 3D monolithic structures.
Although the use of monoliths in liquid batch reactions (espe-
cially on a large scale) may suffer certain problems related to
transport phenomena and limited reaction rates, 3D monolithic
catalysts also have numerous advantages over packed-bed
reactors and these include high transport rates of heat and
mass per unit pressure drop, small transverse temperature
gradients, and ease of scale up.30
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
EXPERIMENTAL SECTION
Shape and size are key aspects in the design of heterogene-
ous catalysts31 and 3D printing offers the possibility of modu-
lating of these macroscopic aspects for catalysts. This revolu-
tionary technology stands out due to the key advantage of the
fabrication of three-dimensional physical objects from a digi-
tal model by taking a virtual design from computer-aided
design (CAD) software and reproducing it layer by layer until
the physical definition of the layers gives the designed prod-
uct.32 The 3D printing technique enables the fabrication of
monoliths with different cross sections, pore sizes, and wall
thicknesses, thus maximizing the catalytic surface. More im-
portantly, the fabrication parameters can be tuned to obtain
parts with excellent mechanical properties. A wide range of
3D printing materials can produce tough functional prototypes
for highly accurate performance testing, or realistic models
that look and feel like the finished products. Therefore, 3D
printing provides knowledge on exactly how a 3D-catalyst will
look and perform before investing in tooling.
In recent years, 3D-printed monoliths based on doped pol-
ymers, carbon materials, metal and metal oxides, or zeolites
have received considerable attention for use in adsorption
systems as well as 3D-printed inorganic monoliths for single
catalytic transformations.33 A combination of 3D printing and
surface modification was recently explored by directly inte-
grating a Br-containing vinyl-terminated initiator into the 3D
resin followed by surface-initiated atomic-transfer radical
polymerization (ATRP) and subsequent electroless plating in a
process that enables the formation of complex metallic archi-
tectures.34 The development of catalysts based on ceramic
materials is a great challenge for 3D printing technology.
Recently, our group reported the first 3D printed heterogene-
ous copper catalyst on an alumina support (obtained by a
copper/Al2O3-based ink extrusion and subsequent sintering to
obtain a CuO surface) and its application in Ullmann reac-
tions.35 We later proposed the fabrication of hybrid (inorganic
support/organic functionality on the surface) heterogeneous
3D printed monolithic catalysts obtained by chemical surface
modification and their application in new MMCRs.
3D printed SiO2 monolith fabrication. The SiO2 colloidal
ink was prepared as described previously37 by mixing 50 g of
SiO2 powder (average particle size 6.3 µm), 12.08 g of
poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate) (PVB-
PVA-PVAc, 80 wt% vinyl butyral) and 3.99 g of polyethylene
glycol (PEG, Mw = 600) in 32.55 mL of 2-propanol (≥
99.5%). All reagents were obtained from Sigma-Aldrich. The
ink was mixed in a planetary centrifugal mixer (ARE-250,
Thinky Corp., Tokyo Japan) at 2000 rpm for 5 cycles of 2
min. The ink was transferred into a 3 mL syringe barrel (Nord-
son EFD, USA) fitted to a cylindrical nozzle (diameter of 410
µm, EFD). An air pressure system (Performus VII with HP7x,
EFD) was attached to the syringe barrel to provide the re-
quired pressure to extrude the ink through the nozzle. The
structures were printed using a robotic deposition apparatus
(Model A3200, Aerotech Inc., USA). The resulting catalysts
consisted of cylinder structures of 40 layers and 10 mm diame-
ter with a body-centered tetragonal (bct) symmetry, a rod
diameter of 410 µm and rod spacing of 1 mm. After fabrica-
tion and drying, the samples were debinded at 400 °C for 1 h
at a heating rate of 2 ºC/min and subsequently sintered at 1500
°C for 3 h at a heating rate of 5 ºC/min.
Surface activation. A SiO2-monolith (1.3 cm in height ×
0.8 cm diameter) was submerged in a solution of H2O2 (30%)
and heated under reflux at 150 ºC for 30 min. The monolith
was removed from the flask and treated with distilled water at
100 ºC for 30 min. After this treatment, the monolith was dried
under vacuum for 1 h. Kimble® vials in a PLS (6 × 4) Organic
Synthesizer were used to perform the surface functionalization
of the SiO2-monoliths and the CuAAC, PCCCRs, and
MMCRs.
Silanization. Silanization for the synthesis of the 3D-SiO2-
APTS-Cu catalyst: in a Kimble vial, an activated 3D-monolith
was submerged in
a
solution of (3-aminopropyl)tri-
methoxysilane (APTS) (0.5 mL) in dry toluene (8 mL). The
mixture was heated at 120 ºC for 24 h under argon. The mono-
lith was filtered off, washed with toluene and ethanol and
dried under vacuum for 24 h. The same conditions as before,
but using [3-(2-aminoethylamino)-propyl]trimethoxysilane
(AAPTS) as the reagent, were used for silanization prior to the
synthesis of the 3D-SiO2-AAPTS-Pd catalyst.
Silica-based surfaces show both excellent mechanical stabil-
ity and reactivity against silanization compared to other oxides
(Al2O3, clays, silicon, TiO2, SnO, Fe2O3, etc.). Silanization
allows the functionalization of the monolithic surface and the
2
ACS Paragon Plus Environment

Page 3 of 19
ACS Catalysis
Metallation. The 3D-SiO2-APTS monolith obtained in the
High resolution mass spectra (HR-MS) were obtained on an
Autospec Micromass spectrometer.
1
2
3
4
5
6
7
8
previous step was treated with a solution of CuI (10 mg) in 8
mL of acetonitrile (MeCN) at 40 °C with orbital stirring dur-
ing 12 h to obtain 3D-SiO2-APTS-Cu. Similarly, the 3D-SiO2-
AAPTS monolith was reacted with a solution of Pd(AcO)2 (15
mg) in 8 mL of anhydrous N,N-dimethylformamide (DMF) at
60 ºC with orbital stirring overnight to give the 3D-SiO2-
AAPTS-Pd catalyst. The resulting colored monolithic catalysts
were washed and sonicated with distilled water, methanol
(MeOH), dichloromethane (CH2Cl2), and diethyl ether, and
finally dried under reduced pressure for 24 h.
Catalyst characterization. The microstructural surface
morphology of the 3D printed SiO2 catalysts were examined
by scanning electron microscopy (SEM) (JEOL 6400, JEOL
Corp., Japan). Optical microscopy images were obtained on an
Olympus SZX12 stereomicroscope (Olympus, Japan). Specific
surface area measurements of the 3D printed monoliths were
performed according to the Brunauer–Emmett–Teller (BET)
nitrogen adsorption method at 77 K in a Gemini 2360 po-
rosimeter (Micrometitics, USA). All samples were degassed at
300 ºC for 2 h before the BET analysis. The chemical compo-
sition of the catalysts was evaluated by energy dispersive X-
ray spectrometry (AZTEC/Xact, Oxford, UK). The copper and
palladium loadings of the structures were determined by in-
ductively coupled plasma-optical emission spectroscopy (ICP-
OES, Varian Liberty 200). The oxidation states of Cu and Pd
were determined by X-ray photoelectron spectroscopy (XPS)
Synthesis of compound 1 by CuAAC. In a coated Kimble
vial were dissolved sodium azide (0.5 mmol), 2-iodobenzyl
bromide (0.5 mmol), DIPEA (1.5 mmol) and phenylacetylene
(0.5 mmol), in a mixture of tBuOH (3 mL)/H2O (1 mL). To
this solution was added the 3D-SiO2-APTS-Cu catalyst (total
Cu content on the monolith: 0.6 mg, 2 % mol Cu). The mix-
ture was orbitally stirred for 12 h at room temperature. The
white solid formed in the vessel was dissolved in AcOEt. The
monolithic catalyst 3D-SiO2-APTS-Cu was then removed
from the solution, washed and sonicated with
EtOH/CH2Cl2/H2O and dried under vacuum for reuse. The
resulting solution was washed with H2O. The organic phase
was extracted with AcOEt and dried with anhydrous Na2SO4.
The solvent was removed under reduced pressure and the
resulting solid was recrystallized (iPrOH) to give compound 1
as a light white solid.
Synthesis of compound 2 by Sonogashira reaction. In a
coated Kimble vial the iodotriazole 1 (0.5 mmol), DIPEA (1.5
mmol) and phenylacetylene (0.6 mmol) were dissolved in a
mixture of tBuOH (3 mL)/H2O (1 mL). To this solution was
added the 3D-SiO2-AAPTS-Pd monolithic catalyst (total Pd
content on monolith: 1.6 mg, 3 % mol Pd). The mixture was
heated with orbital stirring at 100 °C for 6 h until the starting
material had been consumed. The mixture was allowed to cool
and the catalyst was removed, washed and sonicated with
EtOH/CH2Cl2/H2O for reuse. The mixture was washed with
H2O. The organic phase was extracted with AcOEt and dried
with anhydrous Na2SO4. The solvent was removed under
reduced pressure and the resulting solid was purified by flash
cromatography (AcOEt/Hexane,1:4) and recrystallized
(iPrOH) to give compound 2 as a light white solid.
Synthesis of compound 14 by Stille reaction. In a coated
Kimble vial, the iodotriazole 1 (0.5 mmol) and the correspond-
ing organostannane (0.6 mmol) were dissolved in a mixture of
tBuOH (3 mL)/H2O (1 mL). To this solution was added the
3D-SiO2-AAPTS-Pd catalyst (total Pd content on monolith:
1.6 mg, 3 % mol Pd). The mixture was heated at 80 °C with
orbital stirring for 2 h until the starting material had been
consumed. The mixture was allowed to cool and the catalyst
was extracted from the vial, washed and recovered for reuse.
The mixture was washed with a solution of KF (1M, 3 × 10
mL) for removing tin byproducts. The organic phase was
extracted with AcOEt and dried with anhydrous Na2SO4. The
solvent was removed under reduced pressure and the solid was
purified by flash cromatography (DCM/MeOH) and recrystal-
lization (iPrOH) to give compound 14 as a light yellow solid.
Synthesis of compound 20 by Suzuki reaction. In a coated
Kimble vial the iodotriazole 1 (0.5 mmol), DIPEA (2.5 mmol)
and the corresponding boronic acid (0.6 mmol) were dissolved
in a mixture of tBuOH (3 mL)/H2O (1 mL). To this solution
was added the 3D-SiO2-AAPTS-Pd catalyst (total Pd content
on monolith: 1.6 mg, 3 % mol Pd). The mixture was heated at
90 °C for 2 h until the starting material had been consumed.
The mixture was allowed to cool and the catalyst was re-
moved, washed and sonicated with EtOH/CH2Cl2/H2O for
reuse. The mixture was washed with H2O. The organic phase
was extracted with AcOEt and dried with anhydrous Na2SO4.
The solvent was removed under reduced pressure and the
resulting solid was purified by recrystallization (iPrOH) to
give compound 20 as a light white solid.
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
using
a Thermo Scientific K-Alpha ESCA instrument
equipped with aluminum Kα monochromatized radiation at
1486.6 eV as the X-ray source. Due to the non-conducting
nature of the samples it was necessary to use an electron flood
gun to minimize surface charging. Neutralization of the sur-
face charge was performed by using both a low energy flood
gun (electrons in the range 0 to 14 eV) and a low energy Ar-
gon ion gun. The XPS measurements were carried out using
monochromatic Al-Kα (1486.6 eV) X-ray radiation. Photoe-
lectrons were collected from a take-off angle of 90º relative to
the sample surface. The measurement was carried out in Con-
stant Analyzer Energy mode (CAE) with a 100 eV pass energy
for survey spectra and 20 eV pass energy for high resolution
spectra. Time of Flight Secondary Ions Mass Spectrometry
(TOF-SIMS) was used to record the 2D chemical MAPS of
the 3D-SiO2-APTS-Cu and 3D-SiO2-AAPTS-Pd catalyst sur-
faces. TOF-SIMS measurements were performed with an
ION-TOF GmbH instrument (TOF-SIMS 4) using a 25 keV
pulsed 208Bi3+ primary analysis Ion Gun and a raster size of
500 × 500 µm2 producing a sample current of 0.37 pA.
Evaluation of the catalytic activity. All reactions were
monitored by TLC with 2.5 mm Merck silica gel GF 254 strips
and the purified compounds showed a single spot. Detection of
compounds was performed by UV light and/or iodine vapor.
Purification of isolated products was carried out by flash
chromatography with an ISCO Combiflash system that em-
ploys prepacked silica gel columns. The synthesized com-
pounds were characterized by spectroscopic and analytical
data. The NMR spectra were recorded on Bruker AM 300
MHz (1H) and 75 MHz (13C) and XM500 spectrometers.
Chemical shifts are given as δ values against tetramethylsilane
as internal standard and J values are given in Hz. Proton and
carbon nuclear magnetic resonance spectra (1H, 13C NMR)
were recorded in CDCl3. Melting points were determined on a
Gallenkamp melting point apparatus and are uncorrected.
Mass spectra were obtained on a Varian MAT-711 instrument.
General procedure for CuAAC + Sonogashira MMCRs
(synthesis of compounds 2–7). In a coated Kimble vial were
3
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 19
dissolved sodium azide (0.5 mmol), the corresponding iodo- the corresponding alkyne (0.5 mmol) and the boronic acid
1
2
3
4
5
6
7
8
benzyl bromide (0.5 mmol), DIPEA (1.5 mmol) and the al-
kyne (1.2 mmol) in a mixture of tBuOH (3 mL)/H2O (1 mL).
To this solution were added the 3D-SiO2-APTS-Cu (total Cu
content on monolith: 0.6 mg, 2 % mol Cu) and 3D-SiO2-
AAPTS-Pd (total Pd content on monolith: 1.6 mg, 3 % mol
Pd) monolithic catalysts. The mixture was heated at 100 ºC for
12 h with orbital stirring. The solid formed on the vessel wall
was dissolved in AcOEt. The monolithic catalysts were then
removed from the solution, sonicated and washed with
EtOH/CH2Cl2/H2O and dried under vacuum for reuse. Final
products were isolated by extraction with AcOEt/H2O. The
organic phase was dried with anhydrous Na2SO4, the solvent
was removed under reduced pressure and the resulting product
was purified by flash cromatography and recrystallization to
give compounds 2-7.
General procedure for the sequential one-pot CuAAC +
Sonogashira MMCRs (3CR +1, synthesis of compounds 8–
13). In a coated Kimble vial sodium azide (0.5 mmol), the
corresponding iodobenzyl bromide (0.5 mmol), DIPEA (1.5
mmol) and the first alkyne (0.5 mmol) were dissolved in a
mixture of tBuOH (3 mL)/H2O (1 mL). To this solution were
added the 3D-SiO2-APTS-Cu (total Cu content on monolith:
0.6 mg, 2 % mol Cu) and 3D-SiO2-AAPTS-Pd (total Pd con-
tent on monolith: 1.6 mg, 3 % mol Pd). The mixture was kept
under orbital stirring for 12–16 hours at room temperature
until the CuAAC reaction was complete (TLC). The corre-
sponding second alkyne (0.6 mmol) was added and the mix-
ture was heated at 100 ºC for 6 h until the corresponding iodo-
intermediate had been consumed. The solid formed on the
vessel wall was dissolved in AcOEt. The monolithic catalysts
were then removed from the solution, sonicated and washed
with EtOH/CH2Cl2/H2O and dried under vacuum for reuse.
Final products were isolated by extraction with AcOEt/H2O.
The organic phase was dried with anhydrous Na2SO4, the
solvent was removed under reduced pressure and the resulting
product was purified by flash cromatography and recrystalliza-
tion to give compounds 8-13.
General procedure for CuAAC + Stille MMCRs (synthe-
sis of compounds 14–19). In a coated Kimble vial containing
the 3D-SiO2-APTS-Cu (overall Cu content on monolith: 0.6
mg, 2 % mol Cu) and 3D-SiO2-AAPTS-Pd (overall Pd content
on monolith: 1.6 mg, 3 % mol Pd) monolithic catalysts, sodi-
um azide (0.5 mmol), the corresponding iodobenzyl bromide
(0.5 mmol), DIPEA (1.5 mmol), the corresponding alkyne (0.5
mmol) and the organostannane (0.55 mmol) were dissolved in
a mixture of tBuOH (3 mL)/H2O (1 mL). The mixture was
heated at 80 ºC for 12 h. The mixture was allowed to cool. The
solid formed on the vessel wall was dissolved in AcOEt. The
monolithic catalysts were then removed from the solution,
sonicated and washed with EtOH/CH2Cl2/H2O and dried under
vacuum for reuse. The mixture was washed with a solution of
KF (1M, 2 × 10 mL). The organic phase was extracted with
AcOEt and dried with anhydrous Na2SO4. The solvent was
removed under reduced pressure and the resulting product was
purified by flash cromatography and recrystallization to give
compounds 14-19.
(0.55 mmol) were dissolved in a mixture of tBuOH (4 mL)
H2O (1 mL). The mixture was heated at 90 ºC for 12 h. The
mixture was allowed to cool. The solid formed on the vessel
wall was dissolved in AcOEt. The monolithic catalysts were
then removed from the solution, sonicated and washed with
EtOH/CH2Cl2/H2O and dried under vacuum for reuse. Final
products were isolated by extraction with AcOEt/H2O. The
organic phase was dried with anhydrous Na2SO4, the solvent
was removed under reduced pressure and the resulting product
was purified by flash cromatography to give compounds 20–
25.
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
RESULTS AND DISCUSSION
Design, preparation and characterization of the cata-
lysts. The design of the catalysts described here followed an
overall strategy based on the achievement of a thin catalytic
layer deposited on a monolithic silica support. The presence of
catalytic species only on the surface of the monolith is an
advantage from the point of view of minimizing the cost of
production. If we compare this strategy with the manufacture
of composite materials, where metal species are also inside the
mass of the support -and not necessarily accessible to the
reagents-, the amount of metal -the most expensive compo-
nent- is necessarily much larger in the case of composite mate-
rials. Consequently, in this work we have used simple and
economical procedures for the preparation of these monoliths.
The SiO2-based ink was extruded to assemble 3D-periodic
structures with cylindrical symmetry. SiO2 was selected be-
cause it is a material that can be easily extruded by 3D print-
ing. This property, along with the possibility of sintering the
printed structures at high temperature, provided monoliths
with suitable mechanical strength and specific surface for
applications in successive reaction cycles. Furthermore, SiO2
has excellent reactivity for silanization, which enables easy
functionalization of the surface, as discussed previously. An
optimized ink based on 2-propanol and organic polymer bind-
ers was used to synthesize the printable SiO2 support. The
printability of the ink was controlled by adjusting the rheolog-
ical properties and the processing conditions. The printed
structures had a cylindrical woodpile design with an optimal
geometry adapted to the dimensions of the Kimble vials in
which the reactions were carried out (Figures 1e,i). The SiO2
ink was extruded through nozzles with diameters of 410 µm
and patterned layer by layer. The layers were formed by paral-
lel rods of the extruded material separated by 1 mm and each
layer was rotated by 90º. The final result was a structure with
orthogonally interconnected rods. An as-prepared 3D SiO2
structure with 40 layers is shown in Figure 1a.
A robust and reusable heterogeneous catalyst needs to have
chemical stability and sufficient mechanical strength to resist
the continuous contact with the reactor. In order to produce a
structure with these properties, the printed structures were
dried and calcined at high temperature (1500 ºC). During this
process, the polymers and solvents were removed and the
structure was sintered. The result is an interconnected struc-
ture of SiO2 with suitable mechanical strength for numerous
catalytic reactions. The XRD pattern (JCPDS 89–3434) of the
calcined structure at 1500 ºC (Figure 1d) contained the peaks
of the crystalline cristobalite phase of SiO2. The SEM images
(Figure 1b,c) show the microstructure of the sintered SiO2
support. These images reveal the interconnected pores with a
homogeneous periodicity and without defects or cracks. These
images also show that the sintered support exhibited volumet-
General procedure for CuAAC + Suzuki MMCRs (syn-
thesis of compounds 20–25). In a coated Kimble vial contain-
ing the 3D-SiO2-APTS-Cu (overall Cu content on monolith:
0.6 mg, 2 % mol Cu) and 3D-SiO2-AAPTS-Pd (overall Pd
content on monolith: 1.6 mg, 3 % mol Pd) monolithic cata-
lysts, sodium azide (0.5 mmol), CsF (0.6 mmol), the corre-
sponding iodobenzyl bromide (0.5 mmol), DIPEA (2.5 mmol),
4
ACS Paragon Plus Environment

Page 5 of 19
ACS Catalysis
silanes and the silane effectiveness is optimal on silica sub-
ric shrinkage, resulting in a rod diameter of 307 µm and inter-
1
2
3
4
5
6
7
8
rod spacing of 607 µm, which correspond to an open porosity
of ~ 50%. The term porosity in this material should be under-
stood here as the distance provided by the gaps in the grid.
In order to maximize the silanization process the monolith
surface was activated by following the protocol described
above. The use of silanes with three alkoxy groups is the most
common starting point for substrate modification. These mate-
rials tend to be deposited as polymeric films and this gives
total coverage and maximizes the introduction of organic
functionality. Silica forms stable condensation products with
strates. In order to immobilize copper and palladium species
on the surface of the monolith we used two known and well-
established silanes that contain coordinating amino groups,
namely (3-aminopropyl)trimethoxysilane (APTS)38–41 and [3-
(2-aminoethylamino)propyl] trimethoxysilane (AAPTS)36,42
for the immobilization of copper and palladium species,41,43–45
respectively (Scheme 1). The silanization reaction between the
–OH groups on the silica surface of the Si(OMe)3 groups
occurs readily in refluxing anhydrous toluene in 24 hours.
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) As-prepared woodpile structure of SiO2. SEM images of the sintered SiO2 structure: (b) Top-view and (c) side-view,
and (d) the corresponding X-ray diffraction (XRD) pattern. Optical images of the 3D-SiO2-APTS-Cu structure: (e) in the Kimble
reactor, (f) top-view, (g) high-magnification top-view, and (h) the corresponding EDS spectrum. Optical images of 3D-SiO2-
AAPTS-Pd structure: (i) in the Kimble reactor, (j) top-view, (k) high-magnification top-view, and (l) the corresponding EDS spec-
trum.
Once the silanizations had been carried out, the 3D printed
monoliths were metallized with copper (CuI) or palladium
[Pd(AcO)2] species to give the target monoliths 3D-SiO2-
APTS-Cu and 3D-SiO2-AAPTS-Pd. Optical images of the
functionalized 3D-SiO2-APTS-Cu and 3D-SiO2-AAPTS-Pd
catalysts before reaction cycles are shown in Figures 1e–g and
i–k. The figures show how the color of the structures changes
after the functionalization. The cream color of the 3D-SiO2-
APTS-Cu and the dark gray color of the 3D-SiO2-AAPTS-Pd
are due to the presence of Cu and Pd, respectively. The ele-
mental composition of the structure surface was determined by
Energy Dispersive Spectroscopy (EDS) analysis. These results
unequivocally confirmed the presence of Cu (Figure 1h) and
Pd (Figure 1l) in the respective samples. The Si and O peaks
correspond to the SiO2 substrate and the C peak corresponds to
the carbon chain of the silane compound. In addition, the EDS
spectrum shows the presence of an escape peak at 0.020 keV
obtained with the Si(Li) EDS detector. The presence of a gold
peak in both samples is due to the conductive surface sputtered
onto the sample to avoid charging effects during measurement.
The copper and palladium loadings on the monolith surfaces
were determined by inductively coupled plasma-optical emis-
sion spectroscopy (ICP-OES) and the values were 1.6 mg of
Pd on the 3D-SiO2-AAPTS-Pd monolith and 0.6 mg of Cu on
the 3D-SiO2-APTS-Cu monolith (average for 10 monolithic
samples). All of the Pd and Cu contents are exclusively on the
surface of the monolith (BET area for both monoliths: 0.3
m2/g) thus representing the amount of catalytically available
metal for the catalytic processes. This represents a percentage
of 2 mol% of Cu and 3 mol% of Pd present in each catalytic
reaction.
XPS experiments (Figure 2) were carried out to determine
the oxidation state of palladium and copper. According to the
literature, curve fitting of the Cu 2p3/2 region shows two differ-
ent copper species with binding energies (BE) of 932.6 eV and
934.9 eV, which on the basis of their BEs are assigned to
Cu2O and/or Cu metal and CuO, respectively.46 Pure Cu2O, Cu
metal, CuO and Cu(OH)2 standards were analyzed and their
BEs were found to be 932.6, 933.0, 933.5 and 934.0 eV, re-
spectively. For the 3D-SiO2-APTS-Cu sample, a deconvolu-
tion procedure used for the Cu 2p3/2 core level was performed
(Figure 2a). A unique peak with a maximum at 932.2 eV was
assigned to Cu(0/I). There was no evidence for the presence of
Cu(II) species in the material. Due to the similar binding ener-
gies between Cu(I) and Cu(0), Auger electron spectroscopy
was used to distinguish the copper species. Unfortunately, the
5
ACS Paragon Plus Environment

ACS Catalysis
Auger signal was too weak to distinguish between Cu(I) and
Page 6 of 19
1
2
3
4
5
6
7
8
Cu(0) oxidation states, but the presence of iodine in EDS
analysis confirms the prevalence of Cu(I). For the 3D-SiO2-
AAPTS-Pd sample, the peak deconvolution and curve fitting
of the Pd 3d core level region were also performed (Figure
2b). According to the literature, the set of double peaks at
335.5 and 340.8 eV are assigned to Pd(0), while the other
double peaks at 336.9 and 342.2 eV belongs to the Pd(II)
oxidation state.47 Other elements (Si, N, O, C) were also de-
tected in the survey XPS spectra in both monoliths (see sup-
porting information).
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 3. ToF-SIMS images showing the signal intensity of Cu
and Si at SiO2-APTS-Cu surface: (a) Cu, (b) Si, (c) Overlay of
the sum of Cu and Si, and at the SiO2-AAPTS-Pd surface: (d)
Pd, (e) Si, (f) Overlay of the sum of Pd and Si. The intensities
are represented on a scale with light colors indicating high
intensities. MC – maximum signal (counts) per pixel. TC –
total counts in the entire image. Field of view 500×500 µm2.
Evaluation of the catalytic performance in MMCRs. The
triazole nucleus is one of the most important and well-known
heterocycles, which is a common and integral feature of a
variety of natural products and medicinal agents. A large
amount of research has been carried out on triazole and its
derivatives and this has proved the pharmacological im-
portance of this heterocycle.48 The procedures developed in
this work are intended to provide an efficient assembly of
1,2,3-triazoles while also allowing the expansion of chemical
diversity around this ring in a rapid and efficient way by intro-
ducing different functionalities (alkenes, alkynes, aryls, he-
terocycles), through the use of a suitable coupling partner, at
positions close to this framework. The general strategy of the
catalytic process is represented in Scheme 2. In this type of
transformation, four new bonds are formed during a multi-
component reaction using sodium azide, 2-, 3- or 4-iodo ben-
zyl bromides, alkynes and a coupling partner (an organostan-
nane reagent, boronic acid or a second molecule of alkyne). In
order to connect both catalytic processes (CuAAC and
PCCCR) we selected commercial 2-, 3- or 4-iodobenzyl bro-
mides as key bifunctional reagents that are able to undergo a
nucleophilic displacement of the benzylic bromo-substituent
by sodium azide to form in situ the organic azide and an oxi-
dative addition at the iodo-substituent position on the aromatic
ring. The initial CuAAC between the alkyne and the in situ
generated organic azide would be promoted by 3D-SiO2-
APTS-Cu while the coupling of organostannanes (Stille),
boronic acids (Suzuki) or a second molecule of alkyne (So-
nogashira) would be catalyzed by 3D-SiO2-AAPTS-Pd. Ac-
cording to the initial design of the synthetic procedure, all of
these multicatalytic processes would be developed into a one-
pot version either through true MMCRs (CuAAC + Stille,
CuAAC + Suzuki or CuAAC + Sonogashira 3CR) or through
sequential one-pot reactions (CuAAC + Sonogashira 3+1CR,
Scheme 1. Synthetic route for 3D-SiO2-APTS-Cu and 3D-
SiO2-AAPTS-Pd. The predominant oxidation states Cu(I)
and Pd(II) are showed in brackets.
Figure 2. XPS spectra for Cu and Pd on 3D-SiO2-APTS-Cu
and 3D-SiO2-AAPTS-Pd surfaces.
The ToF-SIMS images of the 3D-SiO2-APTS-Cu and 3D-
SiO2-AAPTS-Pd monolith cylinder surfaces are shown in
Figure 3. These images show the surface distribution of Cu,
Pd, and Si on the SiO2 monolith surface. In both 3-D catalysts,
Cu and Pd were found to be present throughout the sample
with a homogeneous distribution along the cylinder surface.
6
ACS Paragon Plus Environment

Page 7 of 19
ACS Catalysis
consideration, we initially decided to optimize separately the
using two different alkynes). A fundamental aspect in the
1
2
3
4
5
6
7
MMCRs is the compatibility and stability of different unsup-
ported reagents and solvents to carry out one-pot processes.
Another challenge is the coexistence of catalytic metal species
in the appropriate oxidation state to perform each catalytic
process in the appropriate manner. Taking these aspects into
two catalytic transformations (CuAAC and PCCCRs) using a
monolith for each single reaction type in an effort to find
‘consensus’ conditions (optimal common base, solvent, and
temperature) and finally merging the optimal conditions to
give the designed MMCR.
R1
N
N
R1
N
3CR
8
CuAAC + Sonogashira MMCR
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
3D-SiO2-AAPTS-Pd
3D-SiO2-APTS-Cu
R1
(excess)
Base, solvent
R1
3D-SiO2-AAPTS-Pd
3D-SiO2-APTS-Cu
3D-SiO2-AAPTS-Pd
3D-SiO2-APTS-Cu
R1
N
R1
N
N
N
Br
N
N
I
S
Base, solvent
S
Base, solvent
S
B(OH)2
S
Sn Bu3
NaN3
CuAAC + Stille MMCR
CuAAC + Suzuki MMCR
3D-SiO2-AAPTS-Pd
3D-SiO2-APTS-Cu
4CR
4CR
Base, solvent
R1
N
N
N
I
R2
R2
R1
N
N
3+1CR
N
CuAAC + Sonogashira MMCR
Scheme 2. General outline for the strategy of Cu-Pd MMCRs.
Catalytic optimization for single CuAAC and PCCCRs.
We first tested the effectiveness of 3D-SiO2-APTS-Cu in the
three-component version of the CuAAC. We focused our
efforts on obtaining optimum yields, no leaching and simple
conditions using environmentally friendly solvents, such as the
H2O/tBuOH mixture. As a model test, we studied the reaction
of phenylacetylene, sodium azide and 2-iodobenzyl bromide to
give 1-(2-iodobenzyl)-4-phenyl-1,2,3-triazole (1) in the pres-
ence of a soluble base. Although the surface of the 3D-SiO2-
APTS-Cu catalyst contains basic centers due to the relatively
large excess of base required for CuAAC (as well as for So-
nogashira and Suzuki reactions), in order to favor the initial
organic azide formation by reaction of sodium azide and 2-
iodobenzyl bromide before the alkyne assembly, we envi-
sioned that the presence of a large excess of an effective solu-
ble base would ensure the effectiveness of the click process.49
The results of the optimization process for CuAAC are shown
in Table 1. Although the copper catalyst showed good effi-
ciency on using different bases and solvents, to our satisfac-
tion the use of equimolar amounts of alkyne, sodium azide and
2-iodobenzyl bromide in the presence of excess (3 equiva-
lents) of DIPEA in tBuOH/H2O (3:1) led the transformation to
occur optimally at room temperature overnight and without the
need to carry out the process in the presence of an inert atmos-
phere or any other reducing additive. Glaser–Eglinton homo-
coupling byproducts were not detected and neither was the
presence of copper-promoted alkyne insertion products at the
5-position of the triazole ring or dimerization products.49 Im-
mediately after checking the efficiency of 3D-SiO2-APTS-Cu
in the click reaction using the latter conditions, we checked the
reusability of the catalyst after washing and drying by repeat-
ing the same experiment (entry 5). The catalytic activity was
virtually unchanged and an almost identical yield was ob-
tained. The minimum amount of catalyst required for CuAAC
was optimized. Smaller monoliths, containing fewer copper
species on the surface resulted in poorer yields.
Having optimized the conditions for the CuAAC, we pro-
ceeded to test the effectiveness of 3D-SiO2-AAPTS-Pd in
Sonogashira, Stille and Suzuki PCCRs. An excess of base (3
equivalents) was used in order to guarantee basic conditions
for efficient Sonogashira and Suzuki transformations. Firstly,
we evaluated the catalytic activity of 3D-SiO2-AAPTS-Pd in
the Sonogashira reaction without the presence of a copper co-
catalyst. As proof of concept we chose triazole 1 and phenyla-
cetylene as the starting materials while changing the base,
solvent and temperature. As can be seen from the results in
Table 2, 3D-SiO2-AAPTS-Pd was effective for the coupling of
phenylacetylene under different reaction conditions, although
high temperatures were necessary to perform the coupling.
TEA and particulary DIPEA worked well in solvents such as
DMF or the tBuOH/H2O (3:1) mixture. Once again, as in the
optimization process for the catalytic performance of 3D-SiO2-
APTS-Cu in CuAAC, we evaluated the reusability of 3D-
SiO2-AAPTS-Pd (entry 6) in a second run. Changes in the
catalytic behavior were not observed after two or three cycles
and significant leaching (<0.1% Pd) was not detected in these
studies.
7
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 19
Table 1: Optimization for CuAAC (3CR)
of the 3D-SiO2-AAPTS-Pd in the presence of an organostan-
1
2
3
4
5
6
7
8
nane and the iodotriazole 1, using the solvent mixture
(tBuOH/H2O) that was compatible with CuAAC. It can be
seen from the results in Table 2 that the reactivity of 3D-SiO2-
AAPTS-Pd is excellent in organic solvents such as toluene or
on using the tBuOH/H2O (3:1) solvent mixture (entry 8). The
reusability was immediately checked in a second test and
changes in the reaction performance were not observed (entry
9). Finally, we checked the catalytic efficiency of 3D-SiO2-
AAPTS-Pd in the Suzuki PdCCCR using phenylboronic acid
as a standard reagent in conjunction with different bases and
solvents. Excellent results were obtained both in the presence
of inorganic (K2CO3) and organic bases, particulary with
DIPEA in combination with tBuOH/H2O (1:1) for the Suzuki
coupling, which gave outstanding results (Table 2). As in the
case of 3D-SiO2-APTS-Cu, smaller monoliths, containing less
Pd on the surface, gave worse results, so that the concentration
of catalytic species on surface is optimized using the condi-
tions of Table 2.
Entry
Base
NaHCO3
K2CO3
TEA
Solvent
Yield (%)a
1
2
3
4
5
tBuOH/H2O
tBuOH/H2O
tBuOH/H2O
tBuOH/H2O
tBuOH/H2O
90
87
92
97
95b
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
DIPEA
DIPEA
aIsolated yields. All reactions were performed using sodium az-
ide (0.5 mmol), 2-iodobenzyl bromide (0.5 mmol), base (1.5
mmol) and phenylacetylene (0.5 mmol) a monolith 3D-SiO2-
APTS-Cu (containing 0.6 mg on surface, 2 % mol Cu), in a mix-
b
ture of tBuOH (3 mL)/H2O (1 mL). Isolated yield with reused
Catalytic activty of 3D-SiO2-APTS-Cu and 3D-SiO2-
AAPTS-Pd in (CuAAC + PCCRs) MMCRs. Once the effi-
ciency of 3D-SiO2-APTS-Cu and 3D-SiO2-AAPTS-Pd mono-
lithic catalysts in single catalytic transformations (CuAAC or
PCCRs) had been verified, we merged those optimized condi-
tions in new MMCRs, using both catalytic monoliths simulta-
neously in a cooperative manner.
3D-SiO2-APTS-Cu.
Table 2: Optimization for PCCCR (Sonogashira, Stille and
Suzuki reactions)
Ph
N
Sonogashira (A)
Stille (B)
Ph
N
Ph
N
N
N
Ph
N
H2C=CH-SnBu3
N
N
N
3D-SiO2-AAPTS-Pd
3D-SiO2-AAPTS-Pd
CuAAC + Sonogashira MMCRs. The possibility of carry-
ing out a click reaction in conjunction with a Sonogashira
coupling of a second alkyne molecule at the iodinated position
of the benzyl group of the triazole in the presence of both
monoliths was explored. On using equimolar amounts of sodi-
um azide and iodobenzyl bromides, 3 equivalents of DIPEA
and an excess (2.5 equivalents) of alkyne in tBuOH/H2O (3:1),
in the presence of the 3D-SiO2-APTS-Cu and 3D-SiO2-
AAPTS-Pd monolithic catalysts, most of the transformations
occurred satisfactorily within 6-12 hours (Table 3). Interest-
ingly, when 2-iodobenzyl bromide was used in this tandem
transformation under our reaction conditions there was no
evidence for the formation of triazolo[5,1-a]isoindoles –as
reported by Corma and co-workers– using Pd-Cu MOFs.50
This finding means that the cycloaddition to generate the
corresponding iodotrizole-intermediates is a favored process.
In contrast, a possible intramolecular cycloaddition promoted
by an initial insertion of an alkyne on the benzenic ring (pro-
moted by Pd catalysis when using 2-iodobenzylbromide), and
benzylic azide is not favored.
I
1
2
14
Ph-B(OH)2
Suzuki (C)
3D-SiO2-AAPTS-Pd
Ph
N
N
N
20
Entry
Compound
Solvent
Yield (%)a
/Method/Base
2/A/TEA
2/A/DIPEA
2/A/K2CO3
2/A/TEA
2/A/DIPEA
2/A/DIPEA
14/B
1
2
DMF
DMF
85b
87 b
70 b
88 b
90 b
88 b,c
95 d
92 d
90 c,d
94 e
3
tBuOH/H2O
tBuOH/H2O
tBuOH/H2O
tBuOH/H2O
Toluene
4
5
6
7
8
14/B
tBuOH/H2O
tBuOH/H2O
9
14/B
10
20/C/K2CO3
Tolu-
ene/H2O
11
12
13
20/C/K2CO3
20/C/DIPEA
20/C/DIPEA
tBuOH/H2O
tBuOH/H2O
tBuOH/H2O
98 e
99 e
99 c,e
aIsolated yields. b100 ºC, 6 h. Yield with reused 3D-SiO2-
c
APTS-Pd. d80 ºC, 2 h. e90 ºC, 2 h.
The Stille reaction is less highly valued in terms of the de-
velopment of sustainable chemistry because of the inherent
toxicity of tin. Despite this, due to the relative mechanistic
simplicity, the stability and functional group tolerance of
stannanes and its chemoselectivity, we explored the behavior
8
ACS Paragon Plus Environment

Page 9 of 19
Table 3: CuAAC + Sonogashira MMCR (3CR)
ACS Catalysis
Table 4: CuAAC + Sonogashira (sequential-3+1CR)
1
2
3
4
5
6
7
8
Compound
Alkyne1
Halide Alkyne2 Yield (%)a
85
Compound
2
Alkyne
Halide
Yield (%)a
87 b
8
9
3
85b
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
9
87
82
10
4
5
6
79 c
87 b
81 b
11
12
13
83
80
82
7
80 b
aIsolated yields after purification. All reactions were performed
using sodium azide (0.5 mmol), corresponding iodobenzyl bromi-
de (0.5 mmol), DIPEA (1.5 mmol) and first alkyne (0.5 mmol), a
3D-SiO2-APTS-Cu monolith (containing 0.6 mg on surface, 2 %
mol Cu), a 3D-SiO2-AAPTS-Pd monolith (containing 1.6 mg on
surface, 3 % mol Pd), in a mixture of tBuOH (3 mL)/H2O (1 mL).
Iodo-intermediates not isolated. TLC monitoring after 12 h con-
firmed completion of the first step (CuAAC) for all samples,
before addition of the second alkyne (0.6 mmol).
aIsolated yields. All reactions were performed using sodium
azide (0.5 mmol), corresponding iodobenzyl bromide (0.5 mmol),
DIPEA (1.5 mmol) and alkyne (1.2 mmol), a monolith 3D-SiO2-
APTS-Cu (containing 0.6 mg on surface, 2 % mol Cu), a 3D-
SiO2-AAPTS-Pd monolith (containing 1.6 mg on surface, 3 %
b
mol Pd), in a mixture of tBuOH (3 mL)/H2O (1 mL). Isolated
yield with reused 3D-SiO2-APTS-Cu. bReaction completed after 6
h. cReaction completed after 12 h.
CuAAC + Stille MMCRs. The combined use of 3D-SiO2-
APTS-Cu and 3D-SiO2-AAPTS-Pd catalysts in Cu-AAC +
Stille MMCRs was studied using different organostannanes as
the coupling partner and the previously optimized
base/solvent/temperature system (DIPEA/tBuOH-H2O/80 ºC).
Interestingly, under these reaction conditions only traces of a
second alkyne insertion on the iodinated position of the ben-
zenic ring were detected. Therefore, the Pd cross-coupling
reaction on the iodinated position of the benzyl ring is almost
exclusively generated by the organostannane-mediated
transmetallation. The reaction products were formed in excel-
lent yields (Table 5) and in many cases, after cooling the reac-
tion mixture, the final product crystallized on the walls of the
vial (Figure 4b). These reaction conditions were used to cou-
ple vinyl, ethoxyvinyl or 4-pyridyl fragments to the benzyl
ring with satisfactory yields and significant differences were
not found in reactivity on using different benzyl iodides in the
presence of alkynes such as phenylacetylene or propynols.
These results demonstrate not only the effectiveness of the
combined use of the two monoliths for this type of transfor-
mation but also the compatibility of organostannanes in this
type of catalytic cocktail.
CuAAC + Suzuki MMCRs. Boronic acids are in many as-
pects ideal partners in the CuAAC reaction methodology. The
organoboron derivatives employed frequently exhibit air and
water stability at ambient temperature, show little toxicity
when compared to other ubiquitous organometallics and allow
a range of other synthetic manipulations to be performed in
their presence. Copper is known to be insert to the carbon–
boron bond, which leads to useful coupling reactions when
desired.46,51 In practice, boronic acids have very different
stabilities in the presence of Cu(I) and Cu(II).
CuAAC + Sonogashira (one-pot sequential-3+1CR).
Great structural richness can be brought about by the incorpo-
ration of diversity by two different alkynes on the triazole and
on the aromatic ring of the benzyl moiety. As a consequence,
the coupling of a different second alkyne molecule at the io-
dinated position was studied by suitable control of the reaction
conditions. In order to avoid competition between alkynes in
the first process (CuAAC), the strategy involved monitoring
the initial click reaction in the presence of 1 equivalent of the
first alkyne, and once the iodinated intermediate 1,2,3-triazole
had been assembled, the addition of an excess of a second
alkyne would provide the final products (Table 4). The for-
mation of the 1,2,3-iodo-triazole intermediates occurs in a few
hours in the presence of both catalysts 3D-SiO2-APTS-Cu and
3D-SiO2-AAPTS-Pd at room temperature. Thus, the simple
addition of an excess of a second alkyne generates the final
products in satisfactory yields and only traces of the CuAAC +
Sonogashira MMCR compounds generated exclusively by the
first alkyne were detected.
9
ACS Paragon Plus Environment

ACS Catalysis
Table 6: CuAAC + Suzuki MMCR (4CR)
Page 10 of 19
Table 5: CuAAC + Stille MMCR (4CR)
1
2
3
4
5
6
7
8
9
Compound
14
Alkyne
Halide
S
Yield (%)a
88
85
87
Compound
20
Alkyne
Halide
S
Yield (%)a
85
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
15
16
21
22
78
80
17
18
19
88
87
88
23
24
25
82
85
79
aIsolated yields. Reaction completed after 12 h. All reactions
were performed using sodium azide (0.5 mmol), the corres-
ponding iodobenzyl bromide (0.5 mmol), DIPEA (1.5 mmol),
the alkyne (0.5 mmol), the organostannane (0.55 mmol), a 3D-
SiO2-APTS-Cu monolith (containing 0.6 mg on surface, 2 %
mol Cu) and a 3D-SiO2-AAPTS-Pd monolith (containing 1.6
mg on surface, 3 % mol Pd), in a mixture of tBuOH (3
mL)/H2O (1 mL), 12 h.
aIsolated yield. Reaction completed after 12 h. All reactions
were performed using sodium azide (0.5 mmol), CsF (0.6
mmol), the corresponding iodobenzyl bromide (0.5 mmol),
DIPEA (2.5 mmol), the corresponding alkyne (0.5 mmol), the
boronic acid (0.55 mmol), a 3D-SiO2-APTS-Cu monolith
(containing 0.6 mg on surface, 2 % mol Cu) and a 3D-SiO2-
AAPTS-Pd monolith (containing 1.6 mg on surface, 3 % mol
Pd), in a mixture of tBuOH (3 mL)/H2O (1 mL), 12 h.
Reusability, leaching studies, and characterization after
catalytic performance. Recycling studies were carried out
using the general procedures for single CuAAC (3D-SiO2-
APTS-Cu), Sonogashira, Stille and Suzuki (3D-SiO2-AAPTS-
Pd) transformations. After completing the reactions, each
monolithic catalyst was easily removed from the reaction
mixture. Both catalysts were exhaustively washed and sonicat-
ed with EtOH, CH2Cl2, and H2O to remove residual salts and
organics from the surface. Prior to reuse, the catalysts were
dried under vacuum at room temperature. The results of the
recycling process are provided in Figure 4c. As can be seen,
although some changes in the oxidation state were detected for
both catalysts after several runs (Figure 4d–f), both of them
could be recycled and reused at least 10 times in all types of
single transformations mentioned above without a noticeable
drop in the product yields or catalytic activity. In the same
way, when MMCRs were performed, the Pd or Cu catalysts
could be reused separately in new reaction cycles.
Heterogeneous catalysts often suffer extensive leaching of
the active metal species during reactions and eventually lose
their catalytic activity. Another problematic issue is the case of
fast back-redeposition of soluble species on the support. To
determine these aspects, and if our copper and palladium
monolithic catalysts operate through true heterogeneous catal-
ysis, we performed complementary experiments at two levels.
Firstly, elemental analysis (ICP) of the filtrate after the reac-
tion demonstrated that leaching of Cu (in CuAAC) or Pd (in
Sonogashira, Stille or Suzuki reactions) is negligible. In all
cases, less than 1 ppm of Pd and Cu was present in the solu-
tions at the end of the reactions, corresponding to a loss of
only 0.07% (for 3D-SiO2-APTS-Cu) and 0.03% (for 3D-SiO2-
AAPTS-Pd) of the initially added catalyst. Final content on
Encouraged by the success of the previous MMCRs using
both catalysts simultaneously in a cooperative manner, we
initially studied the catalytic behavior of our system following
a CuAAC + Suzuki strategy using 3D-SiO2-APTS-Cu and 3D-
SiO2-AAPTS-Pd in a new MMCR by mixing a boronic acid,
sodium azide, the corresponding alkyne, the iodobenzyl bro-
mide, and the DIPEA/tBuOH-H2O system at 90 °C. Unfortu-
nately, these conditions led to different degrees of degradation
of the boronic acid (probably due to the insertion of Cu at the
boron center). Consequently, the yields of this reaction were
low on using these initial conditions, with the iodinated inter-
mediate obtained to a large extent. In order to overcome these
drawbacks to perform the classical CuAAC without interfer-
ence from the reactivity between boronic acids and azide, we
used CsF (which protects boronic acid in the copper(I)-
mediated click reaction)52 as a key component in the multi-
component mixture in order to protect boron from copper
coordination. Under these conditions, the reaction products
were obtained in satisfactory yields and with the presence of
only traces of side products (Table 6). Furthermore, the ab-
sence of Chan–Lam coupling by-products (aryl azides)51
demonstrates that Cu(II) catalysis is not operating under our
reaction conditions. The application of the multicomponent
strategy involving boronic acids (CuAAC + Suzuki) or or-
ganostannanes (CuAAC + Stille) in the cocktail represents a
saving of several synthetic steps with respect to previous pro-
cedures for the preparation of this kind of bis-aryl triazole.53
10
ACS Paragon Plus Environment

Page 11 of 19
ACS Catalysis
55,56
organic products were also measured by ICP, showing 0.01
et al.
mation).
(for detailed procedures, see supporting infor-
Silica supported 4-Bromo-benzamide 3-
1
2
3
4
5
6
7
8
ppm of Cu for compound 1 and 0.09 ppm of Pd for compound
20. Secondly, two key experiments (a hot filtration test and
three phase tests) were carried out to evaluate whether the
leached metal species are responsible for the catalytic activity.
These methods are simple and powerful ways to identify when
the starting solid catalytic material is a reservoir of active
soluble palladium species (i.e., the filtrate conserving the same
activity).
propyltriethoxy-silane was prepared. A model Suzuki reaction
was performed. To ensure that an active catalyst is present, a
soluble aryl halide, i.e., 4-bromoacetophenone, is added. After
reaction, the soluble portion was analyzed after filtration while
the amide is hydrolyzed from the support and isolated as car-
boxylic acid. 1-([1,1'-biphenyl]-4-yl)ethanone was isolated.
But [1,1'-biphenyl]-4-carboxylic acid formation was not de-
tected. It demostates apparent no leaching of Pd from our
monolith.
Catalyst characterization after catalysis. The SEM imag-
es did not show significant changes in the monolithic surface
morphology of 3D-SiO2-APTS-Cu and 3D-SiO2-AAPTS-Pd
after carrying out the different catalytic reactions. This reflects
their good stability after reuse (see Figure S1, supporting
information).
A slight change in color (from slightly brown to slightly
greenish) was often observed in 3D-SiO2-APTS-Cu and 3D-
SiO2-AAPTS-Pd turned even darker after 10 cycles. In order
to determine whether during the reaction cycles a progressive
change occurs in the oxidation state of surface metal species,
XPS analysis of different samples after catalysis were per-
formed. The studies performed on 3D-SiO2-APTS-Cu indicat-
ed a slight oxidation of copper present on surface. A small
deconvoluted peak of Cu(II) (35% content) is observed at
933.5 eV (Figure 4d). However, a total reactivation of the
oxidation state (0/I) in 3D-SiO2-APTS-Cu catalyst can be
carried out by treatment of the reused catalyst with an aqueous
solution of sodium ascorbate (2M) for 3 h (Figure 4e). In the
case of the palladium catalyst, XPS spectra performed in dif-
ferent samples indicated that during the different reaction
cycles, the 3D-SiO2-AAPTS-Pd catalyst presented a high
conversion of the initially existing Pd(II) fraction to Pd(0).
However, this reduction process of the palladium does not
affect the catalytic activity (see Figure 4f).
Hot filtration tests. Two couples of twin experiments were
carried out for both model CuAAC and PCCCRs. In the first
case, the synthesis of compound 1 was studied using sodium
azide, 2-iodobenzyl bromide, and phenylacetylene, using
DIPEA and tBuOH/H2O, at room temperature in the presence
of 3D-SiO2-APTS-Cu (same conditions of Table 1, entry 4).
After 6 hours (50% conversion), 3D-SiO2-APTS-Cu was re-
moved from the vial. The CuAAC course in the filtrate was
followed by TLC and compared with the twin experiment in
which the catalyst was maintained. In the same manner, for the
study of a possible leaching of 3D-SiO2-AAPTS-Pd in a model
PCCCR, we first analyzed the synthesis of compound 20 by
Suzuki reaction using the iodotriazole 1, phenylboronic acid,
DIPEA in tBuOH/H2O (same conditions of Table 2, entry 12)
performing two twin experiments as before, and removing the
catalyst in one of the experiments after 50% of the transfor-
mation (TLC control). As a common result for both transfor-
mations, in the filtrates, the formation of both final products (1
for CuAAC, 20 for Suzuki reaction) did not proceed further.
These filtering experiments indicated that with these monolith-
ic catalysts we are dealing with heterogeneous catalytic sys-
tems.
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
Three Phase Tests. In the case of 3D-SiO2-APTS-Cu mon-
olith, the three-phase test was carried out in analogy to the
procedure published by our group.54 A couple of experiments
using a supported azide demonstrated no leaching of copper
from the monolith (see supporting information). For 3D-SiO2-
AAPTS-Pd: we followed the synthesis presented by Crudden
Figure 4. Photographs showing a Kimble vial in a typical CuAAC + Stille MMCR experiment (compound 14) using 3D-SiO2-
APTS-Cu and 3D-SiO2-AAPTS-Pd in tBuOH/H2O (a) before addition of the starting materials and carrying out the reaction (b)
after the CuAAC + Stille MMCR. (c) Reusability of 3D-SiO2-APTS-Cu and 3D-SiO2-AAPTS-Pd. (d) XPS spectra of the Cu on 3D-
SiO2-APTS-Cu after catalytic reactions and (e) after treatment with sodium ascorbate. (f) XPS spectra of Pd on 3D-SiO2-AAPTS-
Pd after catalytic reactions (10 cycles).
11
ACS Paragon Plus Environment

ACS Catalysis
Page 12 of 19
(4)
Ciriminna R., Cará P. D., Sciortino M., Pagliaro M. Adv.
Synth. Catal. 2011, 353, 677–687.
1
2
3
4
5
6
7
8
(5)
2527.
(6)
Millini, R.; Bellussi, G. Catal. Sci. Technol. 2016, 6, 2502–
Zhou, H.-C. “Joe”; Kitagawa, S. Chem. Soc. Rev. 2014, 43,
CONCLUSIONS
Recently, the relationships between catalyst structures and
catalytic performance have received a great deal of attention.
Modulation of these aspects can be performed by 3D printing,
an emerging technology that enables the fabrication of com-
plex 3D catalysts in a more efficient way compared with tradi-
tional manufacturing processes. In this work, we have demon-
strated that a combination of 3D printing of silica monoliths
and an appropriate surface modification on the silica support
(i.e., silanization and metallation) is an excellent approach for
the fabrication of new, efficient, robust and easy reusable
monolithic Pd- and Cu-based catalysts to perform MMCRs.
Since these heterogeneous catalysts are stable – they show
negligible metal leaching – they can be reused more than 10
times. In addition, compartmentalization of Pd and Cu species
in these monoliths allows individual recycling after perform-
ing each kind of MMCR. The catalytic effectiveness and ease
of handing of these monolithic prototypes in work up process-
es make these devices very suitable for solution phase chemis-
try in industrial applications.
5415–5418.
(7)
Gascon, J.; Corma, A.; Kapteijn, F.; Llabrés i Xamena, F.
X. ACS Catal. 2014, 4, 361–378.
(8)
Parvulescu, V. I.; Kemnitz, E. In New Materials for Cata-
lytic Applications; Elsevier, 2016; p 13.
(9)
Díaz, U.; Brunel, D.; Corma, A. Chem. Soc. Rev. 2013, 42,
9
4083–4097.
(10) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.
Int. Ed Engl. 2001, 40, 2004–2021.
(11) Liang, L.; Astruc, D. Coord. Chem. Rev. 2011, 255, 2933–
2945.
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
(12) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed Engl. 2002, 41, 2596–2599.
(13) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057–3064.
(14) Johansson Seechurn, C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem. Int. Ed Engl. 2012, 51, 5062–5085.
(15) Pagliaro, M.; Pandarus, V.; Ciriminna, R.; Béland, F.;
Demma Carà, P. ChemCatChem 2012, 4, 432–445.
(16) Herrera, R. P.; Marqués-López, E. In Multicomponent Re-
actions: Concepts and Applications for Design and Synthesis; John
Wiley & Sons, 2015; p 1.
(17) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem. 2014,
16, 2958.
(18) Climent, M. J.; Corma, A.; Iborra, S. RSC Adv. 2012, 2,
16–58.
(19) Galván, A.; Fañanás, F. J.; Rodríguez, F. Eur. J. Inorg.
Chem. 2016, 9, 1306–1313.
(20) Lebel, H.; Ladjel, C.; Bréthous, L. J. Am. Chem. Soc. 2007,
129, 13321–13326.
(21) Gu, S.; Xu, D.; Chen, W. Dalton Trans. 2011, 40, 1576–
1583.
(22) Tsoung, J.; Panteleev, J.; Tesch, M.; Lautens, M. Org. Lett.
2014, 16, 110–113.
(23) Zhang, L.; Sonaglia, L.; Stacey, J.; Lautens, M. Org. Lett.
2013, 15, 2128–2131.
(24) Qiu, G.; Ding, Q.; Ren, H.; Peng, Y.; Wu, J. Org. Lett.
2010, 12, 3975–3977.
(25) Lee, D. J.; Han, H. S.; Shin, J.; Yoo, E. J. J. Am. Chem.
Soc. 2014, 136, 11606–11609.
(26) Ramos-Fernandez, E. V.; Garcia-Domingos, M.; Juan-
Alcañiz, J.; Gascon, J.; Kapteijn, F. Appl. Catal. Gen. 2011, 391,
261–267.
(27) Liu, J.; Sun, W. In Magnetic Nanomaterials: Applications
in Catalysis and Life Sciences; The Royal Society of Chemistry: UK,
2017; p 59–98.
(28) Phan, N. T. S.; Gill, C. S.; Nguyen, J. V.; Zhang, Z. J.;
Jones, C. W. Angew. Chem. Int. Ed. 2006, 45, 2209–2212.
(29) Houghten, R. A. Proc. Natl. Acad. Sci. U. S. A. 1985, 82,
5131–5135.
ASSOCIATED CONTENT
Supporting Information
(The Supporting Information is available free of charge on the
ACS Publications website at DOI: -------------------).
Detailed experimental procedures, supporting figures and tables
(PDF)
AUTHOR INFORMATION
Corresponding Author
*A.C. albertojose.coelho@usc.es
*A.G. alvaro.gil@usc.es
Author Contributions
‡Antonio S. Díaz-Marta and Carmen R. Tubío contributed equal-
ly. The manuscript was written through contributions of all au-
thors. All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work received financial support from the Xunta de Galicia
(EM2014/022 to A. Coelho and ED431B2016/028 to F. Guitián
and ED431B2017/70 to E. Sotelo). The work was also funded by
the Consellería de Cultura, Educación e Ordenación Universitaria
(Centro singular de investigación de Galicia accreditation 2016-
2019, ED431G/09) and the European Regional Development
Fund (ERDF).
(30) Yashnik, S. A.; Denisov, S. P.; Danchenko, N. M.;
Ismagilov, Z. R. Appl. Catal. B Environ. 2016, 185, 322–336.
(31) Corma, A. Angew. Chem. Int. Ed. 2016, 55, 6112–6113.
(32) Lewis, J. A.; Smay, J. E.; Stuecker, J.; Cesarano III, J. J.
Am. Ceram. Soc. 2006, 89, 3599–3609.
(33) Zhou, X.; Liu, C. Adv. Funct. Mater. 2017, 27, 1701134.
(34) Wang, X.; Guo, Q.; Cai, X.; Zhou, S.; Kobe, B.; Yang, J.
ACS Appl. Mater. Interfaces 2014, 6, 2583–2587.
(35) Tubío, C. R.; Azuaje, J.; Escalante, L.; Coelho, A.; Guitián,
F.; Sotelo, E.; Gil, A. J. Catal. 2016, 334, 110–115.
(36) Zhu, M.; Lerum, M. Z.; Chen, W. Langmuir ACS J. Surf.
Colloids 2012, 28, 416–423.
REFERENCES
(1)
and practice; Oxford University Press: New York, 1998; p 30.
(2) Petrone, D. A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116,
8003–8104.
Anastas, P. T.; Warner, J. C. In Green chemistry: theory
(37) Lu, X.; Lee, Y.; Yang, S.; Hao, Y.; Evans, J. R. G.; Parini,
C. G. J. Eur. Ceram. Soc. 2010, 30, 1–10.
(38) Howarter, J. A.; Youngblood, J. P. Langmuir ACS J. Surf.
Colloids 2006, 22, 11142–11147.
(3)
Crawley, M. L.; Trost, B. M. In Applications of Transition
Metal Catalysis in Drug Discovery and Development: An Industrial
Perspective; John Wiley & Sons, 2012; p 13.
12
ACS Paragon Plus Environment

Page 13 of 19
ACS Catalysis
(39) Wang, S.; Wen, S.; Shen, M.; Guo, R.; Cao, X.; Wang, J.;
Shi, X. Int. J. Nanomedicine 2011, 6, 3449–3459.
(40) Shen, M.; Cai, H.; Wang, X.; Cao, X.; Li, K.; Wang, S. H.;
Guo, R.; Zheng, L.; Zhang, G.; Shi, X. Nanotechnology 2012, 23,
105601.
(41) Xiong, X.; Cai, L. Catal. Sci. Technol. 2013, 3, 1301–1307.
(42) Zhang, L.-Y.; Wang, L. Chin. J. Chem. 2008, 26, 1601–
1606.
(43) Li, H.; Wang, L.; Li, P. Synthesis 2007, 11, 1635–1642.
(44) Miao, T.; Wang, L. Synthesis 2008, 3, 363–368.
(45) Jumde, R. P.; Evangelisti, C.; Mandoli, A.; Scotti, N.;
Psaro, R. J. Catal. 2015, 324, 25–31.
(46) He, Z.; Lin, H.; He, P.; Yuan, Y. J. Catal. 2011, 277, 54–
63.
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
(47) Priolkar, K. R.; Bera, P.; Sarode, P. R.; Hegde, M. S.; Emu-
ra, S.; Kumashiro, R.; Lalla, N. P. Chem. Mater. 2002, 14, 2120–
2128.
(48) Kharb, R.; Sharma, P. C.; Yar, M. S. J. Enzyme Inhib. Med.
Chem. 2011, 26, 1–21.
(49) Angell, Y.; Burgess, K. Angew. Chem. Int. Ed. 2007, 46,
3649–3651.
(50) Arnanz, A.; Pintado-Sierra, M.; Corma, A.; Iglesias, M.;
Sánchez, F. Adv. Synth. Catal. 2012, 354, 1347–1355.
(51) Grimes, K. D.; Gupte, A.; Aldrich, C. C. Synthesis 2010, 9,
1441–1448.
(52) Jin, S.; Choudhary, G.; Cheng, Y.; Dai, C.; Li, M.; Wang,
B. Chem. Commun. Camb. Engl. 2009, 21, 5251–5253.
(53) White, J. R.; Price, G. J.; Schiffers, S.; Raithby, P. R.; Plu-
cinski, P. K.; Frost, C. G. Tetrahedron Lett. 2010, 51, 3913–3917.
(54) Coelho, A.; Diz, P.; Caamaño, O.; Sotelo, E. Adv. Synth.
Catal. 2010, 352, 1179–1192.
(55) Webb, J. D.; MacQuarrie, S.; McEleney, K.; Crudden, C.
M. J. Catal. 2007, 252, 97–109.
(56) Bedford, R. B.; Singh, U. G.; Walton, R. I.; Williams, R.
T.; Davis, S. A. Chem. Mater. 2005, 17, 701–707.
13
ACS Paragon Plus Environment

ACS Catalysis
Page 14 of 19
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
14
ACS Paragon Plus Environment

Page 15 of 19
ACS Catalysis
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
Figure 1. (a) As-prepared woodpile structure of SiO2. SEM images of the sintered SiO2 structure: (b) Top-
view and (c) side-view, and (d) the corresponding X-ray diffraction (XRD) pattern. Optical images of the 3D-
SiO2-APTS-Cu structure: (e) in the Kimble reactor, (f) top-view, (g) high-magnification top-view, and (h)
the corresponding EDS spectrum. Optical images of 3D-SiO2-AAPTS-Pd structure: (i) in the Kimble reactor,
(j) top-view, (k) high-magnification top-view, and (l) the corresponding EDS spectrum.
177x114mm (300 x 300 DPI)
ACS Paragon Plus Environment

ACS Catalysis
Page 16 of 19
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
ACS Paragon Plus Environment

Page 17 of 19
ACS Catalysis
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
Figure 3. ToF-SIMS images showing the signal intensity of Cu and Si at SiO2-APTS-Cu surface: (a) Cu, (b)
Si, (c) Overlay of the sum of Cu and Si, and at the SiO2-AAPTS-Pd surface: (d) Pd, (e) Si, (f) Overlay of the
sum of Pd and Si. The intensities are repre-sented on a scale with light colors indicating high intensities. MC
– maximum signal (counts) per pixel. TC – total counts in the entire image. Field of view 500×500 µm2.
84x99mm (300 x 300 DPI)
ACS Paragon Plus Environment

ACS Catalysis
Page 18 of 19
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
Figure 4. Photographs showing a Kimble vial in a typical CuAAC + Stille MMCR experiment (compound 14)
using 3D-SiO2-APTS-Cu and 3D-SiO2-AAPTS-Pd in tBuOH/H2O (a) before addition of the starting materials
and carrying out the reaction (b) after the CuAAC + Stille MMCR. (c) Reusability of 3D-SiO2-APTS-Cu and
3D-SiO2-AAPTS-Pd. (d) XPS spectra of the Cu on 3D-SiO2-APTS-Cu after catalytic reactions and (e) after
treatment with sodium ascorbate. (f) XPS spectra of Pd on 3D-SiO2-AAPTS-Pd after catalytic reactions (10
cycles).
177x102mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 19 of 19
ACS Catalysis
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
Scheme 1. Synthetic route for 3D-SiO2-APTS-Cu and 3D-SiO2-AAPTS-Pd. The predominant oxidation states
Cu(I) and Pd(II) are showed in brackets.
84x50mm (300 x 300 DPI)
ACS Paragon Plus Environment