Aminopropyl-silica-supported Cu nanoparticles: An efficient catalyst for continuous-flow Huisgen azide-alkyne cycloaddition (CuAAC)

Article abstract of DOI:10.1016/j.jcat.2015.01.014

Cu nanoparticles prepared by metal vapor synthesis (MVS) were immobilized on 3-aminopropyl-functionalized silica at room temperature. HRTEM analysis of the catalyst showed that the copper nanoparticles are present with mean diameters limited in the range

Full text of DOI:10.1016/j.jcat.2015.01.014

Journal of Catalysis 324 (2015) 25–31
Contents lists available at ScienceDirect
Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
Aminopropyl-silica-supported Cu nanoparticles: An efficient catalyst for
continuous-flow Huisgen azide-alkyne cycloaddition (CuAAC)
Ravindra P. Jumde a, Claudio Evangelisti a, , Alessandro Mandoli a,b, Nicola Scotti a, Rinaldo Psaro a,
⇑
⇑
a CNR, Institute of Molecular Science and Technologies (ISTM), Via G. Fantoli 16/15, 20138 Milan, Italy
b Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 3, 56124 Pisa, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Cu nanoparticles prepared by metal vapor synthesis (MVS) were immobilized on 3-aminopropyl-func-
tionalized silica at room temperature. HRTEM analysis of the catalyst showed that the copper nanopar-
ticles are present with mean diameters limited in the range 1.0–4.5 nm. TPR analysis was performed in
order to study the oxidation state of the supported copper nanoparticles. The supported catalyst was used
both in batch and in a packed-bed reactor for continuous-flow CuAAC reaction. The activation of the cop-
per catalyst by reduction using phenyl hydrazine in continuous-flow conditions was demonstrated. Along
with the high catalytic activity (productivity up to 1689 mol/mol), the catalyst can be used several times
with negligible Cu leaching in the product (<9 ppm), less than allowed Cu contaminant in pharmaceuti-
cals. The applicability of packed-bed flow reactor was showed by sequentially converting different sub-
strates in their corresponding products using same column.
Received 15 October 2014
Revised 22 December 2014
Accepted 14 January 2015
Keywords:
Catalyzed azide-alkyne cycloaddition
Supported copper nanoparticles
Flow chemistry
Metal vapor synthesis
Ó 2015 Elsevier Inc. All rights reserved.
1. Introduction
Here we report the preparation of Cu nanoparticles supported
on 3-aminopropyl-functionalized silica (APSiO2) by metal vapor
The regioselective Cu(I) catalyzed 1,3-dipolar azide-alkyne
cycloaddition leading to 1,4-disubstituted-1,2,3-triazoles (CuAAC)
was independently introduced by the groups of Meldal and Sharp-
less [1–3]. Since then, the broad applicability, ease reliability, and
high efficiency of this reaction stimulated an increasing interest
for a wide range of synthetic applications, from drug discovery to
material science and chemical biology [4–12]. Different copper
sources have been described for the CuAAC, including simple halide
salts and coordination complexes in homogeneous or heteroge-
neous form [13–22]. From the last decade, nanostructured Cu sys-
tems are being explored in both homogeneous and heterogeneous
form in CuAAC reactions [13,14,23–30]. The combination of sup-
ported Cu-based catalysts and flow reactor technologies represents
a step forward in terms of reliability, time, safety, and costs over tra-
ditional batch reaction conditions. Recently, considerable efforts in
this direction have been devoted to the preparation of innovative
Cu-based catalysts by using different strategies to perform CuAAC
in flow [31–38]. However, the development of highly recyclable het-
erogeneous systems with a copper contamination content into the
final product at the acceptable levels still remains a challenge [35].
synthesis (MVS) technique and their use as catalyst both in batch
and in continuous-flow Huisgen azide-alkyne cycloaddition
(CuAAC). Supported Cu catalyst showed remarkable activity and
stability in continuous-flow CuAAC with a very low Cu leaching
in the product. In addition, the activation and regeneration of
the catalyst by flowing phenyl hydrazine as a reducing agent
for copper were demonstrated. In order to better understand
the morphology and the active phase of the supported copper
nanoparticles, high-resolution electron microscopy and tempera-
ture-programmed reduction (TPR) analysis, both in the pristine
state and after use in catalysis, were performed.
2. Experimental
2.1. General
All the reactions involving sensitive compounds were carried
out under dry argon by using conventional Schlenk technique.
All anhydrous solvents were either purchased in Sure/Seal™ bot-
tles or dried by standard procedure. Cu shots, 2–8 mm, 99.999%
trace metals basis, were purchased from Strem Chemicals. Ace-
tone (Aldrich product) was dried over molecular sieves and stored
under dry argon. 3-Aminopropyl-functionalized silica gel (40–
⇑
Corresponding authors.
E-mail addresses: claudio.evangelisti@istm.cnr.it (C. Evangelisti), rinaldo.
psaro@istm.cnr.it (R. Psaro).
63
lm, extent of labeling: ꢀ1 mmol/g NH2) was purchased from
http://dx.doi.org/10.1016/j.jcat.2015.01.014
0021-9517/Ó 2015 Elsevier Inc. All rights reserved.

26
R.P. Jumde et al. / Journal of Catalysis 324 (2015) 25–31
Silicycle. If not noted otherwise, the other compounds were used
as received. TLC analyses were carried out with Macherey-Nagel
ALOX-25 UV254 plates (0.25 mm) and chromatography purifica-
tions with Merck 9385 flash grade silica gel (230–400 mesh).
Unless noted otherwise, 1H and 13C NMR spectra were recorded
as CDCl3 solutions on a Varian INOVA-600 spectrometer operating
at 600 MHz and 150 MHz for 1H and 13C, respectively. Chemical
shifts are reported in ppm relative to TMS (1H) or to the solvent
2.2. Preparation of Cu nanoparticles supported on 3-aminopropyl-
silica (Cu/APSiO2)
The synthesis of Cu/acetone-solvated metal atoms (SMA) was
carried out in a static MVS reactor, similar to those previously
described [39,40]. In a typical experiment, copper vapors, gener-
ated by resistive heating of an tungsten–alumina crucible filled
with ca. 500 mg of copper shots, were co-condensed at liquid nitro-
gen temperature with acetone (100 mL) in the glass reactor cham-
ber of the MVS apparatus in ca. 2 h (P = 5 ꢂ 10ꢁ4 mBar). The reactor
chamber was warmed to the melting point of the solid matrix (ca.
ꢁ80 °C), and the resulting brown solution was siphoned at low
temperature in a Schlenk tube and kept in a refrigerator at
ꢁ40 °C. The content of the copper in SMA was 0.4 mg/mL, as deter-
mined by ICP-OES analysis. A portion of 50 mL (20 mg of Cu) was
added to a suspension of 3-aminopropyl-functionalized silica sup-
port (2 g, previously degassed for three times at 25 °C and kept
under dry argon atmosphere) in acetone (20 mL). The mixture
was stirred for 12 h at room temperature. The colorless solution
was removed, and the light-brown solid, containing 1 wt.% of
Cu, was washed 3 times with n-pentane (20 mL) and dried under
reduced pressure. The same procedure was used to prepare
Cu/APSiO2 system containing 0.55 wt.% of Cu. The catalysts were
stored under dry argon atmosphere by using standard Schlenk
techniques.
(
13C, CDCl3 at 77.16 ppm). Data are summarized as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, dd = doublet of doublets, ddd = doublet
of doublet of doublets, dt = doublet of triplets, td = triplet of dou-
blets and br = broad), coupling constants, and integration. Electro-
spray mass analyses were carried out in the positive [MS(ESI+)] or
negative [MS(ESIꢁ)] ion mode on methanolic solutions, with a
Perkin-Elmer-Sciex Api 3000 spectrometer. Inductively Coupled
Plasma-Optical Emission Spectrometer (ICP-OES; iCAP 6200 Duo
upgrade, Thermo Fischer Scientific). For ICP-OES,
a sample
(1 mL) of solution was heated over a heating plate in a porcelain
crucible in the presence of aqua regia (2 mL) for four times,
dissolving the solid residue in 0.5 M aqueous HCl. The limit of
detection (lod) calculated for copper was 0.01 ppm. Electron
micrographs were obtained with a Zeiss LIBRA 200FE, equipped
with: 200 kV FEG, in column second-generation omega filter for
energy selective spectroscopy (EELS) and imaging (ESI), HAADF
STEM facility, EDS probe for chemical analysis, integrated tomo-
graphic HW and SW. Before introduction in the instrument, the
samples were ultrasonically dispersed in isopropyl alcohol, and
a drop of the suspension was deposited on a holey carbon gold
grid (300 mesh). The histograms of the metal particle size distri-
bution for the Cu samples were obtained by counting at least 500
particles onto the micrographs. The mean particle diameter (dm)
2.3. CuAAC reaction in batch conditions: general procedure
A 25-mL Schlenk tube fitted with a glass frit and stopcock side
arm, was charged under argon with Cu/APSiO2 (65 mg, 1 wt.% of
Cu, 0.01 mmol, 0.02 equiv.) and with dry THF (2 mL), followed by
benzyl azide (62.5
lL, 0.5 mmol, 1 equiv.) and phenyl acetylene
P
P
was calculated by using the formula dm
=
dini/ ni, where ni is
(65.9 L, 0.6 mmol, 1.2 equiv.). The flask was closed under argon
l
the number of particles with diameter di. Temperature-pro-
grammed reductions (TPR) profiles were recorded with a modi-
fied version of the Micromeritics Pulse Chemisorb 2700
apparatus. The catalysts (50 mg) were diluted with quartz, pre-
treated under Ar at 150 °C, and reduced at 8 °C/min with a 8%
H2/Ar mixture at 15 mL/min.
and kept stirring at 25 °C, for the time t (Table 1). Then, the mixture
was filtered through the enclosed frit, collecting the filtrate and cat-
alyst rinses with THF (2 ꢂ 2 mL). For the regeneration, the catalyst
was treated with the solution of PhNHNH2 (34 lL, 0.35 mmol) in
THF (5 mL) for 15 h at room temperature. Then, catalyst was washed
with THF (2 ꢂ 5 mL), dried under argon flow, and used in next run.
Table 1
CuAAC reaction in batch reaction conditions using Cu/APSiO2 catalyst.
b
Entry
1
Catalyst
Time (h)
Conversion (%)a
Specific activity (SA) (hꢁ1
)
Leaching (%)c
0.005
Cu/APSiO2
1.0 wt.%
Recycled from run 1
2
6
2
6
2
38
100
21
100
9
9.5
2
3
5.25
2.25
<limit
0.05
Recycled from run 2
24
24
2
99
79
70
4
Recycled from run 3
Cu/APSiO2
1
17.5
0.06
1.9
5d
1.0 wt.%
Recycled from run 5
4
2
100
50
6
7
12.5
3.75
1.5
1.3
6
2
100
15
Recycled from run 6
4
30
12
2
6
2
6
100
71
93
22
76
8
9
CuI/APSiO2
1.0 wt.%
Recycled from run 8
17.7
5.5
16
14
5
10d
Recycled from run 9
2
29
7.3
6
66
Reaction conditions: Cu/APSiO2 1.0 wt.% (65 mg, 0.01 mmol of Cu) benzyl azide (0.5 mmol, 1 equiv.), phenyl acetylene (0.6 mmol, 1.2 equiv.), THF (2 mL), T = 25 °C.
a
Determined by 1H NMR.
Calculated as moles of benzyl azide converted/moles of Cu per hour (calculated after 2 h).
Determined by ICP-OES, on the basis of the total available copper.
Catalyst pre-activated using PhNHNH2 (34 lL, 0.35 mmol) in THF (5 mL).
b
c
d

R.P. Jumde et al. / Journal of Catalysis 324 (2015) 25–31
27
2.4. Control experiments for catalytic activity in solution
Each of two 25-mL Schlenk tubes (A and B) fitted with a med-
ium porosity glass frit and stopcock side arm was charged under
argon with Cu/APSiO2 (65 mg, 1 wt.% of Cu, 0.01 mmol, 0.02
equiv.). The catalyst in Schlenk-A was pre-activated with PhNHNH2
(9.8 lL, 0.1 mmol), washed with THF, and dried as above, while the
catalyst in Schlenk-B was used in its pristine form. Each tube was
charged with THF (2 mL), benzyl azide (0.5 mmol, 1 equiv.), and
phenyl acetylene (0.6 mmol, 1.2 equiv.), sealed under argon, and
kept stirring at 25 °C, for 2 h. Then, the mixtures were filtered
through the enclosed frit under argon into another Schlenk tube.
NMR analysis of small amount of mixture from Schlenk-A and
Schlenk-B at this stage showed 50% and 35% conversion, respec-
tively. Keeping reaction mixture at 25 °C under argon for additional
4 h showed only slight increase in conversion of benzyl azide to
1,2,3-triazol product (see Fig. 2S).
2.5. Preparation of Cu/APSiO2 packed-bed reactor
Packed-bed reactor was prepared in a commercially available
PTFE tubing with Luer-lock fitting (Fig. 1S, 161 ꢂ 1 mm i.d.). As
shown in Fig. 1, glass wool and a piece of smaller PTFE tube (o.d.
1/1600) were used as a frit at the tubing end devoid of the Luer-lock
fitting. Catalyst was packed by sucking Cu/APSiO2 from Schlenk
tube with the help of vacuum. In order to keep the catalyst bed
in place, glass wool and a short piece of 1/1600 o.d. PTFE tubing were
also placed at the other end of the reactor.
35
30
25
20
15
10
d
= 2.5 nm; Sd = 0.6
m
2.6. CuAAC reaction under continuous-flow conditions: general
procedure
The Luer-lock PTFE tubing packed with Cu/APSiO2 (190 mg
Cu/APSiO2, 1 wt.% or 230 mg 0.55 wt.% Cu loading, respectively)
was connected to a 5-mL SGE gas-tight syringe and flushed with
5
0
dry THF for 30 min at 50 l
L minꢁ1 flow rate. The CuAAC reaction
0
1
2
3
4
5
6
7
8
9
10
Particle Size (nm)
was then carried out at 25 °C, by flushing the solution of reagents
(benzyl azide (1), 3.75 mmol, 1 equiv.; phenyl acetylene (2),
4.5 mmol, 1.2 equiv.; solvent = THF, 15 mL) through the reactor
Fig. 1. Transmission electron microscopy (TEM) image of a freshly prepared Cu/
APSiO2 sample.
at 50
with PhNHNH2 (103
flow rate. For the runs carried out in presence of reducing agent,
PhNHNH2 (30 L, 0.30 mmol) was used in the feed mixture. The
l
L minꢁ1 flow rate. For regeneration, the reactor was flushed
l
L, 1.05 mmol) in THF (5 mL) at 50 l
L minꢁ1
alkyl amines to stabilize Cu nanoparticles [43], and the strong ten-
dency of amino-functionalized silica to bind copper species [44–
48].
l
catalyst was washed with anhydrous THF (2 ꢂ 5 mL) after each
run as well as after regeneration. The copper content in the crude
product was determined at this stage, by ICP-OES analysis of the
combined eluates from each run. For purification purposes, the
reaction mixture was treated with water (20 mL) and extracted
with CH2Cl2 (2 ꢂ 15 mL). The combined organic layers were dried
over Na2SO4, the volatiles were removed with a rotary evaporator,
and the residue was purified by flash chromatography (SiO2, n-
hexane:AcOEt = 3:1).
Transmission electron microscopy (TEM) analysis was per-
formed in order to study the metal particle size distribution of
the Cu/APSiO2 samples. Copper nanoparticles turned out to be
highly dispersed on the functionalized silica support and mainly
present in a narrow size distribution (ranging 1.0–4.5 nm), with
an average diameter close to 2.5 nm (Fig. 1). A very low amount
of larger particles ranging from 10 to 15 nm in diameter was also
detected.
In order to investigate the crystalline phase of starting Cu (0)
nanoparticles obtained by MVS approach, high-resolution TEM
analysis was performed on the Cu/APSiO2 catalyst (Fig. 2) [49]. Lat-
tice planes extend to the whole particle without any stacking faults
or twins, indicating their single-crystalline nature. Lattice fringe
analysis recorded on larger Cu particles (>10 nm, Fig. 2A) exhibited
spots in the FFT pattern at 2.1 Å which are ascribed to the spacing
of (111) planes of the face-centered cubic (fcc) structure of metal-
lic Cu [50]. Besides, the FFT pattern of smaller Cu nanoparticles
(<5 nm) showed spots at 2.5 Å which can be attributed to the
(002) lattice spacing of Cu(II) oxide (Fig. 2B) [51]. Moreover,
high-resolution micrographs revealed an amorphous phase bonded
to the surface of the Cu particles that can be due to the presence of
3. Results and discussion
3.1. Preparation and characterization of Cu nanoparticles supported
on 3-aminopropyl-functionalized silica (Cu/APSiO2)
Cu nanoparticles were prepared by MVS technique [41,42] and
supported on APSiO2 (see Section 2.2). The MVS approach allowed
to deposit very small copper nanoparticles (<5 nm) at room tem-
perature directly in its reduced form, so that, calcination and acti-
vation processes, which can eventually modify the structure of
hybrid organic/inorganic support, were avoided. The choice of
amino-functionalized silica was dictated by the ability of primary

28
R.P. Jumde et al. / Journal of Catalysis 324 (2015) 25–31
A
B
A
2.1 Å
2.5 Å
B
Fig. 2. HRTEM micrograph of Cu nanoparticles and inverted FFT pattern taken from A and B squared areas, respectively.
the residual APSiO2 support. The data showed that the starting
small Cu nanoparticles prepared in their reduced form are readily
oxidized after exposition in air.
Temperature-programmed reduction (TPR) was carried out in
order to get detailed information about the nature, oxidation state,
and reducibility of supported Cu catalyst [52]. The analysis consists
in
a reductive treatment of the catalyst under controlled
temperature program and hydrogen concentration conditions.
The reducibility of the supported phase strongly depends on the
particles dimension, the metal oxidation state, and the interaction
with the matrix used as the support. The TPR of the Cu/APSiO2
(Fig. 3a) shows a narrow peak with a maximum at 260 °C, which
further confirms the presence of very uniform and small particles
that are easy reduce under H2 flow. The reduction temperature is
in agreement with the presence of a Cu(II) oxide, as detected by
HRTEM [52].
3.2. Catalytic behavior of Cu/APSiO2 catalyst
In order to evaluate the catalytic efficiency of the supported Cu
nanoparticles, the Cu/APSiO2 system was first employed under
batch reaction conditions (Table 1).
We were pleased to find that full conversion of 1 to the
1,2,3-triazole product 3 was achieved in 6 h by using 2 mol.% of
Cu catalyst at room temperature. Remarkably, the reaction pro-
ceeded in the absence of any basic additive, suggesting that the
primary amine groups on the support could play a dual role, as
a stabilizer of Cu particles and as a heterogeneous base. The
recovered catalyst could be reused in next 3 runs (entries 1–4,
Table 1), albeit at the expense of a steady decrease of the specific
activity (SA). The ICP-OES analysis showed a very low amount of
Cu species leached in the reaction mixture after each catalytic run
(<0.05 wt.% of the total available Cu content, corresponding to
0.39 ppm in solution, entries 1–4, Table 1). Given the negligible
metal leaching, oxidation of the Cu particles to less active Cu(II)
oxide, as also evidenced by HRTEM and TPR analysis, was
therefore considered as the most likely explanation of the loss
of catalytic activity on recycling [53].
Fig. 3. TPR profiles of Cu/AP-SiO2: freshly prepared (blue line), reduced with
phenylhydrazine (red line) and air-exposed after the reduction (green line). (For
interpretation of the references to color in this figure legend, the reader is referred
to the web version of this article.)

R.P. Jumde et al. / Journal of Catalysis 324 (2015) 25–31
29
Table 2
In order to test this hypothesis, the effect of the treatment of the
CuAAC reaction in continuous-flow reaction conditions using Cu/APSiO2 catalyst.
Cu/APSiO2 catalyst with phenyl hydrazine (PhNHNH2) was evalu-
ated. The use of this reducing agent for selectively obtaining
Cu(I) species has been reported in different reactions [54,55]. Inter-
estingly, the SA of the PhNHNH2-treated system was almost dou-
bled with respect to the non-activated catalyst (entry 5 vs. entry
1). TPR analysis of the PhNHNH2-treated system (Fig. 3b) exhibited
a shift of the reduction peak at higher temperature (500 °C) and a
shoulder at around 400 °C. This change in the TPR profile confirms
that a new copper phase appears after the treatment with phenyl
hydrazine, which can be attributed to formation of Cu2O phase
[56]. Recycling this catalyst showed similar decreasing trend of
activity as that of first set of reaction; nonetheless, pre-activation
allowed a more effective use of supported catalyst, as higher SA
values were noticed (entries 5–7 vs. entries 1–4). These results
agree with the previously reported evidences on the role of Cu(I)
as catalytically active species in CuAAC reaction. Indeed, as demon-
strated by theoretical and experimental studies, the reaction
mechanism involves the initial formation of Cu(I) acetylide species
followed by the azide attack [41,57,3,58–67]. On the other hand,
the ICP-OES data showed comparatively larger amounts of copper
species released in the reaction mixture under these conditions.
From the above results, it was clear that PhNHNH2 is able to reduce
the oxidized surface layer of copper particles and keep it in the
active state, but at the same time it favors to some extent the
release of the metal in the reaction mixture [68]. In order to estab-
lish the nature of the catalytic systems, we monitored two test
reactions performed in batch conditions with the Cu/APSiO2 sys-
tem untreated and pre-treated with phenyl hydrazine, respectively
(Fig. 2S). After conducting the reaction of phenylacetylene and ben-
zyl azide for 2 h, 1,2,3-triazole was produced in a yield of 35%
(untreated Cu/APSiO2) and 50% (pre-activated Cu/APSiO2), respec-
tively. After that, the catalysts were removed from the reaction
vessels, the reaction was stirred for further 4 h at 25 °C, and in
absence of the catalysts, a further conversion of less than 5% was
observed. The results point out the significant heterogeneous con-
tribution of the copper-based catalyst confirming that the click
reaction can occur at the surface of the supported copper particle,
as recently reported [69].
b
Entry
Conversion (%)a
Specific activity (SA) (hꢁ1
)
Leaching (%)c
1d
2
99
73
50
85
100
94
24.7
18.3
12.5
21.2
25.0
23.5
19.7
<0.01
0.2
0.3
2.7
1.2
3
4d
5e
6e
7e
5.2
4.8
79
Reaction conditions: Cu/APSiO2 1.0 wt.% (190 mg, 0.03 mmol of Cu), benzyl azide
(3.75 mmol, 1 equiv.), phenyl acetylene (4.5 mmol, 1.2 equiv.), THF (15 mL), flow
rate = 50 l
L minꢁ1, T = 25 °C, t = 5 h.
a
Determined by 1H NMR.
Calculated as moles of benzyl azide converted/moles of Cu per hour (calculated
b
after 2 h).
c
Determined by ICP-OES, on the basis of the total available copper.
d
e
Catalyst pre-activated using PhNHNH2 (103
lL, 1.05 mmol) in THF (5 mL).
PhNHNH2 (30 L, 0.30 mmol) was added to the reaction feed.
l
pre-reduced with PhNHNH2 and then exposed to air (Fig. 3c). Inter-
estingly, the reduction profile of the air-exposed sample showed a
relatively small peak with a maximum at around 250 °C, which can
be traced back to the formation of the CuO phase. At the same time,
the broad peak with shoulder at higher temperature, related to
Cu2O nanoparticles, was still present, thus showing that only par-
tial reoxidation of the metal occurs when the phenylhydrazine-
treated catalyst is handled in air in the dry state. Moreover, com-
paratively lower copper leaching was observed in continuous-flow
runs than in batch. This could be explained by the reduced
mechanical stress on the catalyst with respect to the stirred-flask
conditions where, indeed, some grinding of silica particles by mag-
netic stirring was noticed. Furthermore, the catalytic activity was
increased significantly if the flow reactor was regenerated before
next use by flushing with PhNHNH2 (1.05 mmol, 0.21 M in THF)
(entry 4) and restored completely when the reducing agent
(0.3 mmol, 0.02 M) was included in the reaction feed (entry 5).
With this latter modification, the catalyst provided rather constant
SA values in subsequent runs (entries 6 and 7) albeit, as already
noticed in batch, at the expense of some increase in the copper
leaching (entries 4–7 vs. 1–3).
The catalytic behavior of MVS-derived Cu catalyst was com-
pared with that of previously reported CuI immobilized on APSiO2
(CuI/APSiO2) [65]. For this purpose, CuI/APSiO2 catalyst was pre-
pared following the reported procedure [69]. Despite its easy prep-
aration and high SA (entry 8), freshly prepared CuI/APSiO2 turned
out to suffer from a nearly one order of magnitude larger metal
leaching (16% of total Cu content) than the MVS catalyst. Not sur-
prisingly, this led to a significant drop of catalytic activity upon
recycling CuI/APSiO2 (entry 9) and the inability to recover the ini-
tial performance by treatment with PhNHNH2 (entry 10).
Overall the packed-bed reactor could be used effectively for
seven times (entries 1–7), thus obtaining higher total productivity
of catalyst (Pn = 727) [70] than in batch (Pn = 200 and 150 for the
two sets of reactions, Table 1 entries 1–4 and 5–7, respectively).
The amount of copper present in the combined products from all
the flow reactions (53 ppm) was much less than reported for other
With these promising results in hand, we set out to evaluate the
performance of this system under continuous-flow conditions. The
flow experiments were carried out using a home-made reactor
packed with Cu/APSiO2 (see Supporting Information). Given the
findings in the batch runs, the catalyst was subjected to pre-activa-
tion in flow, by flushing the reactor with PhNHNH2 in THF. After
brief initial optimization of flow rate, 3.75 mmol of 1 was quanti-
tatively converted in 5 h into the corresponding 1,2,3-triazole
product 3 at 50 l
L minꢁ1 (Table 2, entry 1).
The same flow reactor was employed next in two additional
runs, without any intermediate regeneration of the catalyst
(entries 2–3). Even though the recorded SA values were higher
than obtained in batch (Table 2, entries 1–3 vs. Table 1, entries
5–7), a steady reduction of the conversion was noted in the course
of the successive cycles. Reasoning that the activity decrease could
be due to the partial oxidation of the catalyst by adventitious
oxygen, TPR analysis was performed on a sample of Cu/APSiO2
Fig. 4. Continuous-flow click reaction between phenyl acetylene and benzyl azide
using Cu/APSiO2 (0.55 wt.%). Reaction conditions for each run: Cu/APSiO2 0.55 wt.%
(230 mg, 0.02 mmol of Cu), benzylazide (3.75 mmol), phenylacetylene (4.5 mmol),
THF (15 mL), PhNHNH2 (9.8
Pre-activated with PhNHNH2 (69
rate, pre-activated and reaction run in presence of PhNHNH2 (69
l
L, 0.1 mmol), flow rate = 50
l
L minꢁ1, T = 25 °C. (a)
lL, 0.7 mmol in 5 mL THF); (b) 25
l
l
L minꢁ1 flow
L, 0.7 mmol)
added to the feed.

30
R.P. Jumde et al. / Journal of Catalysis 324 (2015) 25–31
Table 3
Substrate scope in continuous-flow CuAAC reaction using Cu/APSiO2 catalyst.
Substrate 1 Substrate 2
Product
Conversion (%)a
99
99
99
99
Reaction conditions: Cu/APSiO2, 0.55 wt.% (223 mg, 0.019 mmol of Cu), benzyl azide (2.5 mmol, 1 equiv.), phenyl acetylene (3.0 mmol, 1.2 equiv.), THF (10 mL), PhNHNH2
(9 L, 0.095 mmol), flow rate = 50 L, 0.67 mmol in 5 mL THF).
L minꢁ1, T = 25 °C. Before each run, the catalyst was activated with PhNHNH2 (66
l
l
l
a
Calculated by 1H NMR.
supported Cu systems [31–38]. Nonetheless, the leaching level in
these initial experiments was still above the generally accepted
Cu contamination in pharmaceuticals (15 mg kgꢁ1) [35]. In order
to solve this problem, we speculated that lowering the amount of
Cu on APSiO2 could increase the stability of supported nanoparti-
cles, due to the availability of comparatively more amino groups
on the silica surface. Moreover, decreasing the reducing agent to
the minimum amount required for keeping the catalyst in the
active form could help to limit the metal dissolution.
and para position reacted to give the corresponding 1,2,3-triazole
products 3a–d in essentially quantitative yields. Remarkably, the
same packed-bed reactor was used for running CuAAC reaction of
the four different substrates, by intermediate washing of catalyst
bed with THF and treatment with PhNHNH2.
4. Conclusions
To investigate the assumptions made above, a new batch of cat-
alyst with lower Cu loading (0.55 wt.%) was prepared and second
set of flow experiments was carried out (Fig. 4). Despite the com-
paratively lower amount of Cu immobilized in the device, the reac-
tor was still able to quantitatively convert 1 to the 1,2,3-triazole
New 3-aminopropylsilica supported copper catalysts have been
developed, which showed remarkable activity and recyclability in
continuous-flow CuAAC. With respect to other immobilized Cu
catalysts reported to date, including nanostructured ones
[35,36,73–78], these novel systems displayed improved perfor-
mances especially for what it concerns the low metal leaching
and extended reuse under optimized conditions. Arguably, these
unique properties can be traced back to the use of MVS-derived
Cu nanoparticles and the possibility to prepare, by this technique,
supported metal catalyst containing particles in the low nanome-
ter range and without contamination by foreign substances. More-
over, the results confirmed that the 3-aminopropylsilica support is
able to stabilize Cu particles without compromising the catalytic
activity. As a matter of facts, the flow reactions positively compete
with the batch ones, thus affording larger quantity of product (i.e.,
greater Pn of catalyst) and simplified separation procedures. Care-
ful tailoring of reaction conditions and Cu loading on APSiO2
allowed exploiting the supported catalyst more effectively and
for longer time and also to diminish the metal leaching in the
reaction medium. In this context, the feasibility of extending
the catalyst’s lifetime by reduction in continuo of phenylhydrazine
was also demonstrated for the first time. The versatility of the flow
system was also proved by sequentially converting different sub-
strates to 1,2,3-triazole products with the same column.
product 3 at 50 l
L minꢁ1 flow rate (run 1, Fig. 2). After the initial
activation, a minute amount of PhNHNH2 in the feed (0.10 mmol,
0.007 M) was able to keep the catalyst active for the next five runs.
Afterward, a clear decrease in activity was noticed from run 6 to 8.
Regeneration at this stage with PhNHNH2 in THF permitted restor-
ing the activity of catalyst to a large extent (runs 9 and 10), while
almost the initial conversion could be attained by decreasing the
flow rate to 25 l
L minꢁ1 and adding a larger amount of reducing
agent (0.05 M) to the feed (runs 11 and 12). Comparison of the
results of Fig. 4 with those obtained in the initial set of flow exper-
iments (Table 1, entries 11–17) confirmed the anticipated advanta-
ges of using Cu/APSiO2 (0.55 wt.%) instead of Cu/APSiO2 (1.0 wt.%).
Indeed, with proper modification of the reaction conditions, the
former could be used very effectively for 12 times and provided
notably higher and stable SA values than the latter. As a conse-
quence, the total productivity obtained with Cu/APSiO2
(0.55 wt.%) in flow (Pn = 1689) was more than two times larger of
that achieved with Cu/APSiO2 (1.0 wt.%) under comparable condi-
tions (vide supra) [71]. Most importantly, ICP-OES data for all the
flow reactions showed now very low copper leaching in the reac-
tion mixture (8.1 ppm) [72], which is below the maximum allowed
limit for pharmaceuticals and demonstrates the unique features of
the nanostructured MVS system described in this work with
respect to bulk copper catalysts and devices reported to date
[31,34–37].
In order to further demonstrate the applicability of our packed-
bed flow reactor, the substrate scope was briefly examined (Table 3).
A new device containing Cu/APSiO2 (0.55 wt.%) was prepared and
employed to sequentially promote in continuo the CuAAC reaction
of different substituted azides (1a–d) with phenylacetylene. Func-
tional groups on the azide partner seem not to have a decisive effect
on the catalytic activity, as benzyl azides with substituents at meta
Acknowledgment
This work was supported by the Italian Ministry of University
and Scientific Research (MIUR) under the FIRB 2010 Program
(RBFR10BF5V).
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jcat.2015.01.014.

R.P. Jumde et al. / Journal of Catalysis 324 (2015) 25–31
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