A layered double hydroxide, a synthetically useful heterogeneous catalyst for azide?alkyne cycloadditions in a continuous-flow reactor

Article abstract of DOI:10.1016/j.apcata.2015.05.003

A Cu(II)Fe(III)-layered double hydroxide is shown to efficiently catalyze 1,3-dipolar cycloadditions of organic azides to alkynes leading to valuable 1,2,3-triazoles. The benefits of continuous processing were exploited for reaction optimization and synth

Full text of DOI:10.1016/j.apcata.2015.05.003

Accepted Manuscript
Title: A layered double hydroxide, a synthetically useful
heterogeneous catalyst for azide-alkyne cycloadditions in a
continuous-flow reactor
¨
´
Author: S a´ ndor B. Otv o¨ s Ad a´ m Georgi a´ des M o´ nika
´
Adok-Sipiczki Rebeka M e´ sz a´ ros Istv a´ n P a´ link o´ P a´ l Sipos
Ferenc F u¨ l o¨ p
PII:
S0926-860X(15)00293-8
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2015.05.003
APCATA 15373
To appear in:
Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
9-1-2015
16-4-2015
1-5-2015
¨
´
´
Please cite this article as: S.B. Otv o¨ s, A. Georgi a´ des, M. Adok-Sipiczki,
R. M e´ sz a´ ros, I. P a´ link o´ , P. Sipos, F. F u¨ l o¨ p, A layered double hydroxide, a
synthetically useful heterogeneous catalyst for azidendashalkyne cycloadditions
in
a
continuous-flow reactor, Applied Catalysis A, General (2015),
http://dx.doi.org/10.1016/j.apcata.2015.05.003
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Cu(II)Fe(III)-based-layered double hydroxide was prepared and fully characterized.
The as-prepared material was highly active as catalyst in alkyne‒azide cycloadditions.
The catalytic capabilities were investigated in continuo under high-p/T conditions.
No decrease of activity or destruction of the catalyst structure arose upon scaling-up.
Formation of reversible lattice defects were responsible for the observed activity.
Page 1 of 53

A layered double hydroxide, a synthetically useful heterogeneous
catalyst for azide‒alkyne cycloadditions in a continuous-flow reactor
a,b
a
c,d
Sándor B. Ötvös , Ádám Georgiádes , Mónika Ádok-Sipiczki , Rebeka
c,d
c,d
d,e
a,b
Mészáros , István Pálinkó , Pál Sipos and Ferenc Fülöp
a
Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, Eötvös u. 6, H-6720 Szeged, Hungary
Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720 Hungary
Material and Solution Structure Research Group, Institute of Chemistry, University of Szeged, H-6720 Szeged, Hungary
Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, Szeged, H-6720 Hungary
b
c
d
e
ABSTRACT
A Cu(II)Fe(III)-layered double hydroxide is shown to efficiently catalyze 1,3-dipolar
cycloadditions of organic azides to alkynes leading to valuable 1,2,3-triazoles. The benefits of
continuous processing were exploited for reaction optimization and synthesis, and the
production of triazoles was realized in an inherently safe and scalable manner. It was
established that the catalytic activity of the as-prepared material can be derived from in situ
reduction of Cu(II), generating lattice defects containing the catalytically active Cu(I) species.
It was verified that oxidative homocoupling of the alkyne component is responsible for the
conversion of Cu(II) to Cu(I), but a cooperation of certain structural items of the hydrotalcite-
like material may also contribute to the outstanding catalytic efficiency. After a successful
gram-scale triazole synthesis under high-pressure/high-temperature conditions, no destruction
of the catalyst structure was found, suggesting that the layered double hydroxide acts as a
highly robust catalytic system.
Keywords: layered double hydroxide; continuous-flow processing; 1,3-dipolar alkyne‒azide
cycloaddition; copper ions.

Corresponding author. Tel: +36 62545562, Fax: +36 62545705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp)
2
Page 2 of 53

1
. Introduction
Transition metal-containing hydrotalcites, particularly copper-containing layered
double hydroxides (LDHs) are receiving increased attention in diverse catalytic applications
1−5] because of their advantageous properties, such as large surface area, good thermal
[
stability and high anion-exchange capacity. For a long time, the main catalytic application of
LDHs focused on condensation reactions carried out with mixed oxides obtained by
calcination of the hydrotalcite-like materials [6, 7]. An important extension of catalytic
applications has been arisen recently, due to their unique ability to provide with acid-base
bifunctional catalysts with Lewis sites and base catalysts with Brønsted-type basic sites,
derived from the mixed oxide and the meixnerite-like structures, respectively [8]. Moreover,
due to their wide variety of compositions, LDHs are also attractive precursors of
multicomponent nanostructured catalysts. Using a variety of transition metals, composite
materials can be obtained with controllable metal−support interaction and cooperation,
widening the scope of catalytic applications even further [9−11].
The LDHs or hydrotalcite-like compounds (Fig. 1S), have the general formula of
II
1–x
III
x
q–
[M
M
(OH)
2
](A )x/q∙nH
2
O, where x can have values between 0.2 and 0.4 [12]. The basic
2+
structure of an LDH may be derived by substitution of a fraction of divalent cations (Mg ,
2+
2+
2+
2+
3+
3+
3+
Ca , Zn , Co , Ni , etc.) in a brucite lattice for trivalent cations (Al , Cr , Fe , etc.).
−
−
2−
Thus, the layers acquire positive charge, which is balanced by anions (Cl , NO
3
, CO
3
,
2
−
SO
4
together with, usually, water molecules) intercalated between the layers. A significant
extension of the catalytic properties can be achieved when the interlayer counterions are
exchanged to various catalytically interesting species (e.g., chiral anions) [13]. Although a
wide array of metal ions can be incorporated into the layers, Fe(III)-containing LDHs are at
scarce, because they are considered to be significantly less stable than the M(II)Al(III)-LDHs.
In spite of this, Fe(III)-based LDHs can be useful catalysts, thus, improving their synthetic
3
Page 3 of 53

route makes sense, especially of composites containing catalytically active noble metals in the
form divalent ions (e.g., Pd, Pt, Cu).
The 1,3-dipolar alkyne‒azide cycloaddition is a valued method for the regioselective
synthesis of 1,2,3-triazoles. The classical thermally induced reaction results in a mixture of
1,4- and 1,5-disubstituted 1,2,3-triazoles, and due to the high activation energy barrier, these
reactions are often very slow, even at elevated temperatures [14]. As a pioneering
improvement, Sharpless and Meldal discovered independently that the application of Cu(I)
catalysis leads exclusively to the formation of the 1,4-disubstituted regioisomer and within
short reaction times (Scheme 1) [15, 16]. In recent years, Cu(I)-catalyzed alkyne‒azide
cycloaddition (CuAAC) has become a versatile tool in many modern chemical fields
including polymer and materials sciences, peptidomimetic chemistry, supramolecular
chemistry and bioconjugation [17−20]. Moreover, the 1,2,3-triazole moiety is extensively
used as a pharmacophore in medicinal chemistry for the synthesis and modification of diverse
bioactive substances [21].
Scheme 1
The progress towards increased sustainability in organic synthesis has opened up new
routes in compact-scale chemical engineering, and continuous-flow (CF) chemistry has
recently emerged as a novel alternative for the conventional batch-based synthetic techniques
[22]. The well-regulated flow reactor concept involves an increased parameter space and
enables reactions to be performed with an unprecedented level of control due to the greatly
enhanced heat and mass transfer and improved mixing properties [23−26]. This implies
higher reaction rates, outstanding selectivity and inherently safer chemistry [27,
28],_ENREF_13 even when unstable reactants such as azides are handled [29]. These features
offer a plausible opportunity for automation and excellent transferability between laboratory-
4
Page 4 of 53

based investigations and industrial-scale production [30, 31],_ENREF_15 and have made
continuous approaches particularly appealing for CuAAC reactions [32−40].
According to the generally accepted mechanism, the catalytic effect in 1,3-dipolar
alkyne‒azide cycloadditions is originated from various Cu(I) species; however, certain
additives and stabilizing ligands are also known to boost the reactivity in CuAAC reactions
considerably [15, 41]._ENREF_28 Beyond the most common homogeneous Cu(I) catalysts,
4
such as Cu(I) salts and complexes or various redox systems (e.g., CuSO /sodium ascorbate)
leading in situ to active copper species [42, 43], heterogeneous Cu(I) sources have also been
described offering the additional benefits of easy catalyst recovery and recycling [44]. A
variety of solid materials has been reported as suitable supports for Cu(I) species, such as
zeolites, activated charcoal, polymers, silica and even magnetic nanoparticles [45−51]; and it
was recently shown that, due to the surface oxide layers, simple copper powder can also act as
a readily available Cu(I) catalyst, and accelerates alkyne‒azide cycloadditions [38, 39]. On
the other hand, there are recent reports on CuAAC reactions mediated by Cu(II)-based
catalysts without the need for exogenous reductants [52−61]._ENREF_42 In such cases, the
effective catalysis can obviously be attributed to the transformation of Cu(II) into Cu(I) in the
course of the reaction [52, 53, 56−59, 62]._ENREF_57 Owing to the general thermodynamic
instability of Cu(I), this approach can indeed be beneficial in the realization of ligand- or
additive-free triazole syntheses.
Herein, we present our results on the synthesis and physicochemical properties of a
Cu(II)-containing hydrotalcite-like material, as well as its flow chemistry-based application as
a highly active heterogeneous catalyst for the robust and selective synthesis of valuable 1,2,3-
triazoles via 1,3-dipolar cycloadditions of organic azides and alkynes. The catalyst was
5
Page 5 of 53

characterized as-prepared and after a 10-hour long reaction. The scope of the transformation
was also investigated.
2. Experimental
2.1. LDH synthesis
Cu(II)Fe(III)-LDH was prepared by a modified version of the simple co-precipitation
method as follows: a NaOH solution (VWR, a.r. grade; 0.15 M) was added dropwise into a
5 mL solution containing Cu(NO ·3H O (Molar Chemicals, puriss; 0.0012 mol) and
Fe(NO ·9H O (Molar Chemicals, puriss; 0.0003 mol) in a mixture of distilled water (15
3
3
)
2
2
3
)
3
2
mL), 1-propanol (Sigma-Aldrich, 15 mL) and ethylene glycol (Sigma-Aldrich, 5 mL) under
nitrogen atmosphere under vigorous stirring until the final pH of 8.5 is reached. The
application of 1-propanol and ethylene glycol represent the modification already described in
the literature [63] − the latter was used as a surfactant. The resulting slurry was thermally
2
treated at room temperature for 24 h. Mg Fe-LDH, used for a control experiment, was
prepared as describe in the literature [64].
2.2. Structural characterization of the Cu(II)Fe(III)-LDH
Powder XRD patterns of the as-prepared Cu(II)Fe(III)-LDH were registered in the 2Θ
4–60° range on a Rigaku Miniflex II instrument, using CuKα (λ = 1.5418 Å) radiation. The
=
FT-IR spectra were recorded on a BIORAD FTS-65A/896 spectrometer equipped with a
DTGS detector in diffuse reflectance. For the measurements, the samples were finely ground
−
1
and combined with KBr (without pressing into pellets). Spectral resolution was 4 cm and
6
Page 6 of 53

256 scans were performed for a spectrum. The spectra were baseline corrected and smoothed
using the WIN-IR software package. The morphologies of the samples were studied with a
Hitachi S-4700 scanning electron microscope (SEM) at various magnifications. The chemical
compositions of the materials were determined with a Röntec QX2 energy dispersive X-ray
spectrometer (EDX) coupled to the microscope. Thermal analytical measurements (TG/dTG)
–1
were performed using a Setaram Labsys derivatograph working at 4 °C min heating rate.
Determination of the iron and copper content of the LDH samples was done using a Thermo’s
IRIS Intrepid II inductively coupled plasma atomic emission spectrometer (ICP−AES). The
instrument was externally calibrated with a calibration solution series prepared from ICP
Multielement standard solution XXIII made by CertiPUR. X-ray photoelectron spectroscopy
(XPS) was performed with a KRATOS XSAM 800 XPS machine equipped with an
atmospheric reaction chamber. A conventional X-ray source (MgKα, 1253.64 eV and AlKα,
1486.65 eV) was used. The binding energies were determined relative to Cu 2p3/2 (932.5 eV).
2.3. Preparation of azides as starting materials
3
Organic azides were prepared from NaN and the corresponding bromides with
literature procedures in purities of ≥99%, and were, therefore, used without further
purification [38, 51, 65].
2.4. General procedures for the CF reactions
To investigate the catalytic applicability of the as-prepared Cu(II)Fe(III)-LDH, a CF
apparatus was assembled (Fig. 2S). The system consisted of an HPLC pump (JASCO PU-
880), which provided a continuous stream of the reaction medium, a backpressure valve and a
7
Page 7 of 53

stainless steel HPLC column (internal dimensions: 4.6×50 mm) as catalyst bed which
encompassed the LDH material. The catalyst bed was combined with a stainless steel coil
(with an internal diameter of 250 µm) for preheating of the reaction mixture before entering
the column. The catalyst bed and the preheating spiral were immersed into an oil bath for
heating purposes.
For the CF CuAAC reactions, 1 g of Cu(II)Fe(III)-LDH, Mg
powder (Sigma-Aldrich, average particle size: 200 µm) was employed in the catalyst bed. A
reaction mixture consisting of 1 equiv. of the azide and 1.5 equiv. of the alkyne in CH Cl was
2
Fe-LDH or copper
2
2
prepared and homogenized carefully. The azide was applied in 0.085 M, which was the
highest possible concentration without the precipitation of the resulting triazole in the reactor
channel. If necessary, 0.04 equiv. of glacial acetic acid (AcOH) and/or 0.04 equiv. of N,N-
diisopropylethylamine (DIEA) were added as additives. For small scale reactions, 5 mL of the
starting solution was pumped through the reactor under the appropriate conditions, and elution
of the starting materials was continued by washing with CH
2
Cl
2
for several additional minutes
(depending on the set flow rate). Between two CF experiments the system was equilibrated
–1
2 2
for 15 min by pumping CH Cl at a flow rate of 0.5 mL min . For the large-scale synthesis,
the concentration of the reactants was not varied, and 300 ml of the starting solution was
pumped through the instrument. The crude products were checked by thin-layer
chromatography with a mixture of n-hexane/EtOAc as eluent, and the solvent was evaporated
in vacuo. If necessary, column chromatographic purification was carried out on silica gel with
a mixture of n-hexane/EtOAc as eluent. To determine the residence time on the catalyst bed a
solution of a dye was pumped through the filled catalyst column, and the time that elapsed
between the first contact of the dye with the cartridge and the moment when the colored
solution appeared at the outlet was measured.
8
Page 8 of 53

2.5 Analysis of the triazole products
1
13
H and C NMR spectra were recorded on a Bruker Avance DRX 400 spectrometer,
in CDCl as solvent, with TMS as internal standard, at 400.1 and 100.6 MHz, respectively.
3
The detailed analytical data can be found in Supporting Information.
The copper concentration of the product samples was determined by inductively
coupled plasma mass spectrometry (ICP-MS), using an Agilent 7700x-type instrument
3
equipped with a collision cell after digestion with concentrated HNO . The determination was
63
carried out on the isotope Cu, with He as the collision gas.
3. Results and discussion
3.1. Synthesis of Cu(II)Fe(III)-LDH and the structural characterization of the as-prepared
sample
LDHs are simple and inexpensive to synthesize both in laboratory practice and on an
industrial production-scale using simple metal salts as precursors. The controlled co-
precipitiation of the corresponding di- and trivalent metal salts at an alkaline pH leads to the
condensation of hexaaqua complexes in solution, and to the build-up of brucite-like layers
with close to evenly distributed metallic cations and with solvated interlamellar anions,
usually being the counter anions in the starting salts. The co-precipitation of Cu(NO
with Fe(NO ·9H
readily resulted in the Cu(II)Fe(III)-LDH material after a short thermal treatment.
3
)
2
·3H
2
O
3
)
3
2
O in a mixture of water and 1-propanol, and ethylene glycol as a surfactant
9
Page 9 of 53

Many physico-chemical properties of LDHs are predetermined by their structural and
crystallographic features. Since synthetic LDHs are commonly not highly crystalline, various
and complementary techniques are needed to get the sufficient structural data.
The range of isomorphous cation substitutions in the brucite-like layers, the resulting
changes in the structure and incidental stacking faults and polytypes can be nicely
investigated by XRD. Powder XRD patterns of the as-prepared Cu(II)Fe(III)-LDH can be
indexed in a hexagonal lattice with an R-3m rhombohedral symmetry (Fig. 1a). Structural
data are given in Table 1 (as-prepared sample). Cell parameters a and c were calculated
assuming a 3R stacking sequence being a = 2d110 and c = 3d003, respectively [66]. The
interlayer distance, d003, is regulated by the water content together with the amount, size,
orientation, and charge of the anion located between the layers; and d110 is the average cation–
cation distance inside the lamellas [67]. The examination of the a parameter, is a simple way
2+
3+
of analyzing the isomorphous substitution of Cu by the Fe cation. In the same way, c gives
information on the nature, size and charge of the anion situated between the layers [68]. The
XRD patterns exhibit the characteristic reflections of LDH materials; however, the
interlamellar distances (d, calculated using the Bragg equation) are somewhat smaller than the
average, which may be due to the smaller layer thickness. In the layers, the octahedra are
distorted, being flattened along the c-axis, because of the Jahn-Teller effect on the oxygen
2+
coordination shell of Cu . The average crystal sizes (in the c axis direction, thus the
thickness" of the crystallites) were determined from the (003) reflections with the Scherrer
equation and denoted as D.
"
Figure 1
Table 1
FT-IR spectra of the as-synthesized LDH material indicate the presence of isolated
–1

(
3640 cm ) as well as hydrogen-bonded OH groups (Fig. 3Sa). Bands due to the presence of
10
Page 10 of 53

–
–1
NO
3
as interlayer ion can be found at 1070, 1352 and 1423 cm [69]. Bands under
−
1
1
000 cm may be assigned to the O–metal ion–O units of the layers. These vibrations are
dependent on the type of metals in the LDH, i.e., different metals will lead to different
vibrational mode assignments [70]. Evidences for the presence of 1-propanol and ethylene
–1
–1
–1
glycol could also be identified (vibrations at 2943 cm , 2860 cm and 1045 cm ). These
molecules were probably intercalated among the layers together with or partially replacing
water molecules.The shape of LDH particles depends on the mode of preparation. In the
standard co-precipitation method both nucleation and growth steps occur simultaneously
during synthesis. Morphology is also affected by chemical composition [71]. Elemental
analysis of the LDH material showed reasonable agreement with those of the starting
solutions, suggesting the completion of precipitation (Table 1S – as-prepared sample). The di-
and trivalent metal ions are largely evenly distributed in the samples, as it is seen in the
SEM−EDX elemental map (Fig. 4S). Elemental analysis showed that the ratio of Cu/Fe is
1.76 thus less copper is incorporated than expected (the theoretical ratio is 2). This may be
explaining the fact that the morphology of the crystals is more amorphous than usual for
MgAl-LDH, for instance (Fig. 2a).
Figure 2
Despite the diversity in composition most LDH materials exhibit similar thermal
decomposition behavior. Less stable than cationic clays, LDHs undergo structural collapse
upon heating even at rather moderate temperatures, finally leading to crystalline, three-
dimensional phases. The thermal behavior of the Cu(II)Fe(III)-LDH sample is depicted in Fig.
5S. Surprisingly, the majority of weight loss occurred in one sudden step at relatively mild
temperature (~175 °C). It is unusual but not unprecedented for LDHs [72]. Here, probably the
intercalated alcohols, which were absolutely necessary for the successful synthesis, were lost
in this low-temperature step, and this led to the collapse of the layered structure. This
11
Page 11 of 53

information is crucial, since the reaction temperature should not come close to 175 °C, if we
want to preserve the layered structure.
XPS measurements indicated the presence of Cu(II) ions only, as was expected (Fig.
6Sa).
3.2. Catalytic application of Cu(II)Fe(III)-LDH: continuous alkyne‒azide cycloadditions
The recent findings on CuAAC reactions promoted by Cu(II)-based catalytic systems
led us to assume that our Cu(II)Fe(III)-LDH is going to exhibit activity in 1,3-dipolar
alkyne‒azide cycloadditions, despite the fact that the presence of Cu(I) was not traceable in
the LDH lattice with any of our analytical methods [52−61].
In order to check the effects of different reaction parameters (p, T and flow rate), the
1,3-dipolar cycloaddition between benzyl azide and phenylacetylene was chosen as a model
reaction (Table 2) using CH
2
Cl
2
as solvent with the alkyne component in a slight excess (1.5
1
‒
equiv.) to improve the rates of the reaction. Initially, a flow rate of 0.5 mL min was applied,
which involved a residence time in the catalyst bed of 100 s, and thus, a reasonably short
process time.
Table 2
At ambient temperature and pressure, only trace quantities of triazole 1 could be
detected (entry 1), but upon heating to 50 °C, the reactivity increased, and a conversion of
16% was found (entry 2). Elevation of pressure removes the boiling point barrier of solvents
and, thus, allowed us to raise the reactor temperature without the boiling over of CH Cl [73].
2
2
Heating was continued under high-pressure conditions, and we were pleased to find that the
rate of the reaction increased steeply with the temperature from 50 to 100 °C (entries 3‒5 and
12
Page 12 of 53

7‒12). It is important to note that, according to the thermal analysis measurements the LDH
catalyst is thermally stable in this region, and, thus, no structural changes are expected. If
conversions obtained at various pressures (1 bar, 50 bar and 100 bar) are compared, it can be
noted that the rate of the triazole formation is slightly dependent on pressurizing. For
example, at 50 °C, conversions of 16, 18 and 23% were achieved at atmospheric pressure, 50
bar and 100 bar, respectively (entry 2 vs. 3 vs. 7). Besides Le Chatelier’s principle [38], this
observation may be explained by fact that pressure can aid the diffusion of the reactants in the
1
‒
LDH matrix and, thus, improve reactivity [74−76]. At a flow rate of 0.5 mL min , the best
results were obtained at 100 °C and 100 bar allowing for quantitative conversion and 98%
yield in the model reaction (entry12). Lower flow rates correspond to longer residence times,
1
and thus it is obvious that conversion remained quantitative at 0.25 mL min‒ (entry 13).
1
1
‒
‒
Whereas, the application of higher flow rates (1 mL min and 2 mL min ) at 100 °C and 100
bar resulted in a slight decrease in conversion and yield (entries 14 and 15).
Nitrogen bases are reported to accelerate triazole formation, in particular by
coordinating to the catalytically active Cu(I) species, and promoting their liberation from the
catalyst matrix, as well as improving their thermodynamic stability.[15, 42, 43, 77] Moreover,
due to their basic character, amines can contribute to the deprotonation of the alkyne
component [58]. As a result, amines as additives can assist in the formation of a distinct
Cu(I)‒acetylide intermediate, which has a generally accepted mechanistic significance in the
catalytic cycle (Scheme 2) [15, 41]. _ENREF_29Additionally, it was shown recently that
catalytic amounts of certain acids can further improve triazole formation through the
protonation of the copper triazolide intermediate and, at the same time, preventing the
accumulation of unwanted byproducts [78−80]. The joint use of basic and acidic additives can
13
Page 13 of 53

therefore be highly advantageous, as such a buffer system improves the activity of the Cu(I)
species and hampers byproduct formation simultaneously [38, 81]. Accordingly, when the
Cu(II)Fe(III)-LDH was replaced with copper powder in the catalyst column and 0.04 equiv. of
AcOH or 0.04 equiv. of DIEA were added as acid or base at ambient temperature, 100 bar and
1
‒
0
.5 mL min , higher conversion and yield were attained in the model reaction than without
any additive (entry 16 vs 17 and 18) [38]. When DIEA and AcOH were jointly applied with
copper powder as catalytic source, complete conversion and 98% yield were obtained at
ambient temperature under the same pressure, and flow rate (entry 19). In contrast, the
additives had literally no effect on the rate of the Cu(II)Fe(III)-LDH-mediated CuAAC
reaction. Either with the separate addition of the acid or the base, or with the joint use of both
additives, basically the same conversions were detected as in the previous CF reactions
without DIEA or AcOH (entry 6 vs. 20‒22 and entry 7 vs. 23). On the other hand, the
catalytic activity in the cycloaddition reaction can unambiguously be derived from the copper
2
content of the LDH, as demonstrated by the fact that with Mg Fe-LDH, which contains no
copper metal or ion of any kind, no conversion was detected in the reaction of benzyl azide
and phenylacetylene under the previously optimized conditions (100 °C, 100 bar and 0.5 mL
1
‒
min , entry 24). The inefficiency of the base additive is in correspondence with the
coordinational stability of the LDH material and supports the assumption that the formation of
the catalytically active Cu(I) species are continuous over the course of the CF reaction. The
findings related with the added acid are probably connected with the well-defined hydroxide
layers in the LDH lattice as a main structural feature.
Scheme 2
To probe the preparative capabilities of the Cu(II)Fe(III)-LDH-based CF catalytic
system, the model reaction between benzyl azide and phenylacetylene was scaled-up. Scale-
14
Page 14 of 53

up in continuous processing is straightforward and safe, as product output is a function of the
operation time and/or flow rate rather than the batch size; and, thus, the risks associated with
the accumulation of hazardous species are minimized [30, 31, 82]. The large-scale synthesis
was conducted under the previously optimized reaction conditions (100 °C, 100 bar and 0.5
1
‒
mL min ), with a fresh portion of LDH loaded into the catalyst bed. The concentration and
ratio of the starting materials were not changed upon scaling-up, and the eluting product
solution was collected continuously for 10 h into separate fraction in every 30 minutes. Each
fraction was analyzed separately, and no decrease in catalytic activity was detected in the
course of the experiment, resulting in complete conversion in all portions. As the result of the
large-scale synthesis, 5.7 g of triazole 1 was isolated after a simple evaporation, and an
overall yield of 95% was achieved. We were pleased to find that the LDH-mediated CuAAC
reaction was highly selective, since no traces of the 1,5-disubstituted triazole isomer was
detected. No work-up or purification steps was necessary, due to the volatility of the excess
alkyne and the quantitative conversion of the triazole product, in which only a small copper
1
‒
contamination of 45.3 ± 1.3 µg g was detected by ICP−MS.
To test whether the leached amount of copper can contribute to the triazole formation
in the homogeneous phase, additional experiments were carried out in a reaction coil using a
soluble copper source under similar conditions than in the LDH-mediated reaction. In the first
experiment, the benzyl azide‒phenylacetylene model reaction (the starting materials were
employed in the same concentration and ratio as in the previous experiments) was carried out
with 0.017 mol% of CuI as catalyst at 100 bar and 100 °C in acetonitrile (CuI was not soluble
1
‒
in CH
2
Cl
2
), maintaining a flow rate of 0.12 mL min , which afforded a residence time in a
1
‒
2
00-µl coil of 100 s (the same as in the LDH-loaded catalyst bed at 0.5 mL min ). The
15
Page 15 of 53

utilized catalyst loading corresponded to the copper amount previously detected as leaching
from the catalyst bed. Copper salts are often accompanied with nitrogen bases to achieve a
highly active catalytic system [42], thus, a second homogeneous flow reaction was carried out
in the presence of 0.017 mol% CuI and 0.017 mol% DIEA under the same conditions as
detailed above. None of the CuI mediated homogeneous reactions resulted in detectable
1
triazole formation according to H NMR measurements, strongly suggesting that the amount
of leached copper species are too low to contribute to the triazole formation appreciably, and
thus, the CuAAC reaction in the LDH-loaded catalyst bed can be regarded as a predominantly
heterogeneous process. We believe that the observed minimal leaching from the heated
3 2
catalyst bed may be attributed to Cu(NO ) traces adsorbed on the LDH surface after the co-
precipitation.
3.3. Structural characterization of the used Cu(II)Fe(III)-LDH sample
The structural and crystallographic features of the used Cu(II)Fe(III)-LDH were
determined after the large-scale synthesis. The morphology of the catalyst was found to be
basically unchanged, only some organic deposition could be observed on the surface, which is
also corroborated by the SEM−EDX elemental maps (Fig. 2b). The powder XRD pattern also
confirmed that the structure of the LDH remained intact during the catalysis (Fig. 1b). The
peak marked with asterisk is likely to be derived from the crystallization of organic
compounds during the cycloaddition. The cell parameters were practically identical to those
of the unused material, only the average particle size increased slightly (Table 1 – after the
1
0-hour long run). The repeated elemental analysis showed only negligibly small changes in
the catalyst composition and a Cu/Fe ratio of 1.76, just as in the as-prepared sample (Table 1S
after the 10-hour run). The IR spectrum of the used sample basically had the features of the
–
16
Page 16 of 53

as-prepared one (Fig. 3Sb). Some of the vibrations are not so sharp, probably due to the
deposition of some carbonaceous residues. XPS measurement revealed that valency of copper
remained unchanged in the used Cu(II)Fe(III)-LDH, presence of Cu(I) was still untraceable
after the large-scale reaction (Fig. 6Sb).
These findings clearly prove that, aside from some organic deposition, no structural
changes occurred, and the LDH network remained consistent even after 10 hours of
continuous use as heterogeneous catalyst. The successful gram-scale synthesis and the above
analytical results suggest that the Cu(II)Fe(III)-LDH acts as a highly robust catalytic system
for CuAAC reactions.
3.4. The scope of the reaction
To explore the scope and applicability of the Cu(II)Fe(III)-LDH as catalyst, a wide
array of CF CuAAC reactions (Table 3) were carried out using various azides and alkynes
1
‒
under the previously optimized conditions (100 °C, 100 bar and 0.5 mL min ).
Table 3
In the reactions of substituted benzylic azides with phenylacetylene as dipolarophile, it
was observed that either electron-withdrawing (Table 3, entries 2–6) or electron-releasing
functionalities (entries 7 and 8) are nicely tolerated, and excellent yields (84–98%) were
obtained irrespectively to the position of the substituents on the phenyl ring. For 2-
(
azidomethyl)naphthalene, a slightly lower conversion (84%) and yield (77%) were obtained
entry 9), which may be due to the size and highly apolar character of the naphtyl group.
(
Various non-aromatic azides were also effectively reacted in reactions with phenylacetylene
entries 10–16): excellent conversions and high yields (91–98%) were achieved with cyclic,
linear, branched and unsaturated azides, such as azidocyclohexane, ethyl 5-azidopentanoate,
(
17
Page 17 of 53

1-azidobutane and 4-azidobut-1-ene. The alkyne scope was also found considerably wide in
the reactions with benzyl azide. Besides aryl alkynes (phenylacetylene and 4-ethynylanisole),
non-aromatic ones, such as pent-1-yne, ethyl propiolate and propargyl acetate, were found to
be excellent substrates for the LDH-mediated CuAAC reaction with remarkable conversions
and yields of 80–98% (entries 17–22). Ferrocene–triazole conjugates are gaining increasing
importance in the labeling and detection of various biological systems, [83] thus, the CuAAC
of ethynyl ferrocene and benzyl azide was also attempted, and ferrocene-substituted triazole
23 was isolated in a yield of 85% (entry 23). Diethyl acetylenedicarboxylate, a non-terminal
alkyne, was also successfully reacted with benzyl azide, thereby resulting in a 1,4,5-
trisubstituted 1,2,3-triazole (24), which is itself a potent antitubercular agent (entry 24) [84].
In the above experiments, the formation of the 1,5-disubstituted 1,2,3-triazole isomers were
not detected, the corresponding 1,4-disubstituted products were formed regioselectively with
terminal alkynes. It is notable that when the triazole formation was quantitative and the excess
alkyne was sufficiently volatile, no work-up or purification steps were necessary; and
sufficiently pure products were isolated after evaporation (entries 1–5, 7, 8, 10 and 13–21).
Moreover, due to the short residence time in the catalyst bed, the flow process acts as an
obviously rapid synthetic tool as compared to the traditional batch methods [42, 43], and the
ease of product isolation further enhances applicability.
3.5. Mechanistic aspects
To understand the catalytic efficiency of the as-prepared Cu(II)Fe(III)-LDH in CF
CuAAC reactions, it should be underlined again that the presence of Cu(I) was not detected in
the catalyst matrix according to the detailed analytical study. Moreover, the individual
3 2 2 3 3 2
components (Cu(NO ) ·3H O and Fe(NO ) ·9H O) of the LDH proved to be inactive in the
18
Page 18 of 53

benzyl azide‒phenylacetylene model reaction (see Supporting Information). These facts made
us to assume that at least some of the Cu(II) cores undergoes reduction to Cu(I) in the LDH
lattice over the course of the CF reaction, thereby transiently generating the catalytically
active species required for the CuAAC. This involves that in the affected copper centers, the
octahedral coordination transforms into tetrahedral geometry, which is generally favored by
Cu(I) species, and the resulting lattice defects can be responsible for the observed catalytic
activity (Scheme 3).
Scheme 3
It is presumed that the reduction of copper may occur via oxidative homocoupling
(
OHC) of the alkyne component [58, 59, 85]._ENREF_70 To verify this possibility, a solution
of 4-ethynylanisole in CH Cl (the concentration of the alkyne was 0.128 M, similarly to the
CuAAC reactions) was pumped through the Cu(II)Fe(III)-LDH-filled column at 100 °C and
2
2
–1
1
00 bar applying a reasonably low flow rate of 25 µL min (which corresponds to a residence
time in the catalyst bed of 30 min, Scheme 4). Under these conditions, diyne 25 was formed
1
with a conversion of 16% according to the H NMR spectra of the crude material (see
Supporting Information). This proves that the OHC can be responsible for the Cu(II)–Cu(I)
reduction in the LDH lattice, although the overall low reactivity in the homocoupling suggests
that very small amounts of Cu(I) are generated in situ under the optimal conditions required
1
‒
for the CuAAC reaction (100 °C, 100 bar and 0.5 mL min ) [56]. The FT-IR spectra of the
as-synthesized Cu(II)Fe(III)-LDH showed 1-propanol traces in the catalyst matrix (Fig. 3Sa),
as a residual of the co-precipitation. The oxidation of 1-propanol may also contribute to the
conversion of Cu(II) to Cu(I) [53, 57, 58]; however, we did not find any traces for alcohol
oxidation products, such as aldehyde or carboxylic acid. The fact that no structural changes
were detected in the Cu(II)Fe(III)-LDH lattice after the large-scale triazole synthesis suggests
19
Page 19 of 53

that the above mentioned lattice defects are reversible, which is presumably closely related to
the stability of LDH materials [86].
Scheme 4
We believe that the role of the hydroxide layers in the LDH matrix is also crucial for
the observed catalytic activity, in particular by activating the alkyne component via
deprotonation [54, 56]. The ability of the catalyst to abstract an alkyne hydrogen is favorable
not only for the actual CuAAC catalytic cycle, but the basic hydroxide layers also improve the
alkyne OHC, and therefore, the generation of catalytic Cu(I) species [58]. Moreover, the well-
defined water content of the Cu(II)Fe(III)-LDH may contribute to protonation of Cu(I)-
triazolide intermediate, and may improve the conversion of the triazole product [56].
On the basis of kinetic, mechanistic, and theoretical investigations, dinuclear copper
species were proposed as key intermediates in the CuAAC catalytic cycle, and stable
dinuclear copper catalyst are known to exhibit extraordinary reactivity in azide‒alkyne
cycloadditions [58, 87, 88]. Moreover, it was recently shown that a Cu(I)/Cu(II) dinuclear
catalyst system can extraordinarily be active in CuAAC reactions due to various synergistic
effects of Cu(I) and Cu(II) species [58]. These facts implicate that the inherently polynuclear
nature of the LDH catalyst can also be responsible for the promisingly high overall activity in
CuAAC reactions.
4. Conclusions
In summary, a Cu(II)-containing hydrotalcite-like material (Cu(II)Fe(III)-LDH) was
prepared and fully characterized by means of various and complementary analytical
techniques. The as-prepared LDH exhibited high activity in the promotion of 1,3-dipolar
alkyne‒azide cycloadditions leading to valuable 1,2,3-triazoles in a CF system. It was found
20
Page 20 of 53

that the rate of the triazole formation was clearly dependent on the pressure, temperature and
residence time in the catalyst bed, but independent from the presence of base and/or acid as
additives. The Cu(II)Fe(III)-LDH proved to be a robust additive-free heterogeneous catalyst
for CuAAC reactions, as no decrease of catalytic activity and no destruction of the catalyst
structure was found after 10 h of continuous use under high-pressure/high-temperature
conditions. The scope of the methodology was found to be appreciable. Aromatic or aliphatic
azides and alkynes of widely different structural features regioselectively gave the
corresponding 1,4-disubstituted 1,2,3-triazoles in excellent conversions and yields. It was
verified that the observed catalytic properties of the Cu(II)Fe(III)-LDH can be originated from
in situ Cu(II)–Cu(I) reduction mediated by the alkyne component via OHC reaction, and,
thus, the reversible generation of catalytically active lattice defects in the catalyst matrix. We
also propose that some of the primordial structural features of the LDH material (such as the
hydroxide layers or the inherent polynuclear nature) can cooperatively add to the outstanding
catalytic properties observed in CuAAC reactions.
Although, hydrotalcite-like materials possess incredible potentials in catalytic uses, the
first example of the application of an LDH material as heterogeneous catalyst in a CF system
is described herein, to the best of our knowledge. Thus, we believe that this pioneering
example may contribute towards the widespread use of transition metal-containing LDHs as
novel, highly reactive, cheap and environmentally benign catalysts in continuous
manufacturing, and, as well as, in conventional batch-based organic syntheses.
Acknowledgments
This research was supported by the Hungarian Research Fund via the NK81371 and NK
106234 grants. The financial support is highly appreciated. S. B. Ötvös acknowledges the
21
Page 21 of 53

award of a fellowship from the Postdoctoral Research Program of the Hungarian Academy of
Sciences.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/. The supporting information file contains the schematic representation of the
LDH, the outline of the CF reaction system, the FT-IR and XPS spectra of the as-prepared
and the used LDH sample, results of thermal measurements, SEM−EDX elemental map, as
1
well as characterization data on the reaction products (melting points, H NMR data and
spectra). It also contains additional experimental data on the alkyne OHC experiment and on
the CuAAC reactions with the individual LDH components.
22
Page 22 of 53

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Legends to the schemes and figures
Scheme 1 1,3-Dipolar cycloadditions between alkynes and organic azides.
Scheme 2 The generally accepted catalytic cycle of the CuAAC reaction. L stands for a
n
ligand or a counterion. The brackets around “CuL ” symbolize that bi- or polynuclear Cu(I)
species involved in the reaction.
Scheme 3 Reduction of Cu(II) cores to Cu(I) in the LDH matrix (a part of one layer is shown)
results in tetrahedral lattice defects (circled), which can promote CuAAC reaction. (Blue
represents the +2 oxidation state of copper, red indicates +1.)
Scheme 4 Oxidative homocoupling of 4-ethynylanisole with the Cu(II)Fe(III)-LDH in
2 2
continuo (calkyne=0.128 M in CH Cl , 1 g of LDH packed into the reaction column, 100 bar,
–1
1
00 °C, 25 µL min flow rate).
Fig. 1. Powder XRD patterns of the Cu(II)Fe(III)-LDH: as-prepared material (a), after the 10-
hour long synthesis (b).
Fig. 2. SEM images of the as-prepared Cu(II)Fe(III)-LDH at various magnifications (a), SEM
image and elemental map of the LDH after 10 h of CF triazole synthesis (b, LDH surface
circled with red, organic deposition circled with green in the SEM micrograph).
26
Page 26 of 53

*Graphical Abstract (for review)
Page 27 of 53

Scheme 1 1,3-Dipolar cycloadditions between alkynes and organic azides.
Scheme 2 The generally accepted catalytic cycle of the CuAAC reaction. L stands for a ligand or a counterion.
The brackets around “CuL ” symbolize that bi- or polynuclear Cu(I) species involved in the reaction.
n
Scheme 3 Reduction of Cu(II) cores to Cu(I) in the LDH matrix (a part of one layer is shown) results in
tetrahedral lattice defects (circled), which can promote CuAAC reaction. (Blue represents the +2 oxidation state
of copper, red indicates +1.)
2
6
Page 28 of 53

Scheme 4 Oxidative homocoupling of 4-ethynylanisole with the Cu(II)Fe(III)-LDH in continuo (calkyne=0.128 M
–1
in CH Cl , 1 g of LDH packed into the reaction column, 100 bar, 100 °C, 25 µL min flow rate).
2
2
2
7
Page 29 of 53