molecules

Review
Recent Advances in Recoverable Systems for the
Review
Recent Advances inAzide-Alkyne
Copper-Catalyzed Recoverable Systems for the
Cycloaddition
Copper-Catalyzed
Reaction (CuAAC)Azide-Alkyne Cycloaddition
Reaction (CuAAC)
Alessandro Mandoli 1,2

Mandoli 1,2 e Chimica Industriale Università di Pisa, Via G. Moruzzi 13, Pisa 56124, Italy;
1 Dipartimento di Chimica
Alessandro
1
alessandro.mandoli@unipi.it; Tel.: +39-050-221-9280
Dipartimento di Chimica e Chimica Industriale Università di Pisa, Via G. Moruzzi 13, Pisa 56124, Italy;
2 ISTM-CNR, Via C. Golgi 19, Milano 20133, Italy
alessandro.mandoli@unipi.it; Tel.: +39-050-221-9280
2Academic Editor:
ISTM-CNR, ViaMaurizio
C. GolgiBenaglia
19, Milano 20133, Italy
Received: 1 August 2016; Accepted: 30 August 2016; Published: 3 September 2016
Academic Editor: Maurizio Benaglia
Received: 1 August 2016; Accepted: 30 August 2016; Published: 5 September 2016
Abstract: The explosively-growing applications of the Cu-catalyzed Huisgen 1,3-dipolar
cycloaddition
Abstract: reaction
The between organic azides
explosively-growing and alkynes
applications (CuAAC)
of the have stimulated
Cu-catalyzed Huisgenan 1,3-dipolar
impressive
number of reports,
cycloaddition in the
reaction last years,
between focusing
organic azideson recoverable
and variants have
alkynes (CuAAC) of thestimulated
homogeneous or quasi-
an impressive
homogeneous
number catalysts.
of reports, Recent
in the advances
last years, in the on
focusing field are reviewed,
recoverable withofparticular
variants emphasis on
the homogeneous or
systems immobilized onto polymeric organic or inorganic supports.
quasi-homogeneous catalysts. Recent advances in the field are reviewed, with particular emphasis on
systems immobilized onto polymeric organic or inorganic supports.
Keywords: supported catalysts; click-chemistry; continuous-flow chemistry; 1,2,3-triazoles
Keywords: supported catalysts; click-chemistry; continuous-flow chemistry; 1,2,3-triazoles

1. Introduction
1. Introduction
Efforts towards selectivity, atom economy, generation of molecular diversity, and experimental
Efforts towards
convenience have been selectivity,
a constantatom economy,
drive generation
in modern organic of molecular
synthesis. diversity,
Still, and in
their union experimental
the context
convenience have been
of bond-forming a constant
(”ligation”) drive in with
processes, modern
theorganic synthesis. Still,
conceptualization their union in the context
of ”click-chemistry“ by Kolb,of
bond-forming (”ligation”)
Finn, and Sharpless processes,
[1], appears with
to have the conceptualization
become a potent trigger ofofchemists’
”click-chemistry“ by Kolb,
inventiveness Finn,
in recent
and Sharpless [1], appears to have become a potent trigger of chemists’ inventiveness in recent years.
years.
Essential to this outcome was the parallel and independent
independent introduction, by the groups of Meldal
and Sharpless, of the copper-catalyzed azide-alkyne cycloaddition
cycloaddition reaction
reaction (Scheme
(Scheme 1)1) [2,3]. In
In fact,
fact,
the orthogonal character vs. the the reactivity
reactivity of most functional groups, complete regioselectivity in
favor of the 1,4-disustituted-1,2,3-triazole product 11 (“triazole”
1,4-disustituted-1,2,3-triazole product (“triazole” hereafter,
hereafter, if not noted otherwise),
otherwise),
mild reaction conditions, and easy installation of the required azide and terminal alkyne moieties in
the reactive partners, render the metal-promoted version of the long-standing
long-standing Huisgen 1,3-dipolar
cycloaddition reaction the most prominent
prominent technique
technique in
in the
the click-chemistry
click-chemistry toolbox
toolbox [4,5].
[4,5].

R1 R1
cat. Cu(I) N 1 R2 5 N 1
R1 N3 + R2 N + N
(base, solvent) N N
R2 4 1 2

Scheme
Scheme 1.
1. The
The copper-catalyzed
copper-catalyzed azide-alkyne
azide-alkyne cycloaddition reaction (CuAAC).
cycloaddition reaction (CuAAC).

With
Withapplications
applicationsranging
rangingfrom
frommaterial
materialscience
scienceto to
medicinal
medicinalchemistry
chemistryit isitnot
is surprising
not surprisingthat
investigations
that connected
investigations with the
connected CuAAC
with topic, or just
the CuAAC making
topic, usemaking
or just of this technique,
use of this are technique,
appearing
with impressive and increasingly high frequency in the literature. As shown in Figure
are appearing with impressive and increasingly high frequency in the literature. As shown in Figure 1, these 1,
advancements
these comprise
advancements long-standing
comprise topicstopics
long-standing and some incompletely
and some settled
incompletely aspects
settled like, like,
aspects e.g., e.g.,
the
reaction
the mechanism,
reaction as well
mechanism, as as
as well new
newtrends
trendsand
andexamples
examplesofofuseuseofof CuAAC
CuAAC in unprecedented
directions [6–61].

Molecules 2016, 21, 1174; doi:10.3390/molecules21091174 www.mdpi.com/journal/molecules

Molecules 2016, 21, 1174; doi:10.3390/molecules21091174 www.mdpi.com/journal/molecules

Molecules 2016, 21, 1174 2 of 43
Molecules 2016, 21, 1174 2 of 41
Molecules 2016, 21, 1174 2 of 41

Enzyme modification and

Polymer modification and linking [6-10]. Enzyme modification and
immobilization [60,61].
Polymer modification
New polymer and linking
architectures [6-10].
[11-14]. immobilization [60,61].
New polymer
Synthesis architectures[15,16].
of macrocycles [11-14].
Synthesis of macrocycles [15,16].
Immobilization of small molecules for catalysis [54,55],
Immobilization of small
sensing [56,57], molecules for[58],
chromatography catalysis [54,55],
and metal
Smart materials, including stimuli- sensing [56,57], chromatography
sorption [59]. [58], and metal
Smart materials,
responsive including
polymers stimuli-
[17,18] and sorption [59].
responsive
carbon polymers [17,18]
nanocomposites and
[19-21].
carbon nanocomposites [19-21]. Solid-phase and combinatorial
Solid-phase and [52,53].
chemistry combinatorial
Surface modification [22-24] chemistry [52,53].
Surface modification
and [22-24]
coating [25].
and coating
Polymer [25].
adhesives [26]. Conjugation and labeling of bio-molecules [43],
Polymer adhesives [26]. Conjugation
including and labeling
peptides [44-46],ofpolysaccharides
bio-molecules [43],
[47-
including49],
peptides [44-46], polysaccharides
and nucleic acids [50,51]. [47-

New catalytic systems and 49], and nucleic acids [50,51].

New catalytic
reaction systems
mechanism and
[27-30].
reaction mechanism [27-30]. Synthesis of bio-compatible materials [36-38],
Synthesis
drugs, and of bio-compatible
other materials [36-38],
bio-active compounds [39-42].
drugs, and other bio-active compounds [39-42].
Non-classical CuAAC reaction
Non-classical
conditions CuAAC
(e.g. flow andreaction
microwave
conditions (e.g. flow and microwave Enantioselective CuAAC [34,35].
activation [31-33]).
Enantioselective CuAAC [34,35].
activation [31-33]).

Figure
Figure 1. 1.Main
Mainpublication
publicationareas
areasof
of CuAAC-related
CuAAC-related papers
papersand
andselected
selectedexamples
examplesofof
recent trends.
recent trends.
Figure 1. Main publication areas of CuAAC-related papers and selected examples of recent trends.

In In addition
addition of of being
being anan effective
effective way
way forfor linking
linking together
together different
different molecules,
molecules, thethe appreciation
appreciation that
that In
theaddition
triazole ofstructural
being an effective
motif way have
may for linking together different
pharmacologic molecules,
relevance, e.g., as the
a appreciation
more stablefor
the triazole structural motif may have pharmacologic relevance, e.g., as a more stable replacement
that the triazole
replacement structural
for peptide bondsmotif
andmay have ofpharmacologic
in virtue relevance,
its dipole moment, e.g., as a more
hydrogen-bonding, andstable
π-π
peptide bonds and in virtue of its dipole moment, hydrogen-bonding, and π-π stacking capabilities [42],
replacement for peptide bonds and in virtue of its dipole moment, hydrogen-bonding,
stacking capabilities [42], improved further the interest towards CuAAC in the medicinal chemistry and π-π
improved
stacking further the interest
capabilities [42], towards further
improved CuAACthe in interest
the medicinal
towardschemistry
CuAAC field.
in the Even if less chemistry
medicinal represented
field. Even if less represented than the isomeric 1,2,4-triazole motif, contained in various approved
than theEven
field. isomeric
if less 1,2,4-triazole
represented motif,
than the contained
isomeric in various motif,
1,2,4-triazole approved drugsin[62,63],
contained various examples
approved of
drugs [62,63], examples of bio-active compounds that embed the 1,2,3-triazole nucleus keep
bio-active compounds
drugs [62,63], that
examplesin of embed the 1,2,3-triazole nucleus keep appearing continuously in the
appearing continuously thebio-active compounds
literature or have already that embed the clinical
an established 1,2,3-triazole nucleus
use (Figure keep
2) [40,42].
literature
appearing or have already in
continuously antheestablished
literature clinical
or have use (Figure
already 2) [40,42]. clinical use (Figure 2) [40,42].
an established

Figure 2. Selected examples of drugs and other bioactive compounds containing the 1,2,3-triazole nucleus.
Figure2.2. Selected
Figure examples
Selected of drugs of
examples anddrugs
other bioactive compounds
and other containing
bioactive the 1,2,3-triazole
compounds nucleus.the
containing
1,2,3-triazole nucleus.
Molecules 2016, 21, 1174 3 of 43

Despite
Molecules 2016,the many successes of CuAAC, the underlying chemistry suffers from three
21, 1174 3 ofmain
41
drawbacks that pose limits to its usefulness, not only in a medicinal chemistry perspective but
often alsoDespite
in the thecase
many successes for
of materials of special
CuAAC,applications:
the underlying chemistry
(i) use suffers
of organic from which
azides, three main
are not
drawbacks that pose limits to its usefulness, not only in a medicinal
easy to purify and handle at scale because of their potential instability; (ii) contamination chemistry perspective but often
of the
alsoproduct
click in the case
withofcatalyst
materials for special applications:
components, copper above (i) all;
use and
of organic azides, which
(iii) instability of theare not oxidation
Cu(I) easy to
purify and handle at scale because of their potential instability; (ii) contamination of the click product
state, which imposes inert-atmosphere handling techniques or the addition of an excess of a reducing
with catalyst components, copper above all; and (iii) instability of the Cu(I) oxidation state, which
agent like sodium ascorbate [64]. In the specific context of the modification of bio-molecules like, e.g.,
imposes inert-atmosphere handling techniques or the addition of an excess of a reducing agent like
polysaccharides and polypeptides, further problems may arise then from the generation of highly
sodium ascorbate [64]. In the specific context of the modification of bio-molecules like, e.g.,
reactive species (H2 O2 , hydroxyl radicals, and dehydroascorbic acid), which cause chain cleavage or
polysaccharides and polypeptides, further problems may arise then from the generation of highly
denaturation [65–67].
reactive species (H2O2, hydroxyl radicals, and dehydroascorbic acid), which cause chain cleavage or
In addition[65–67].
denaturation to the use of flow-chemistry [32], a potentially general solution for the former problem
is represented by
In addition in to
situthe
generation of the organic azide
use of flow-chemistry [32], aunder multi-component
potentially reaction
general solution forconditions
the former [68].
In problem
principle, is represented by in situ generation of the organic azide under multi-component reactionthe
with this approach it is possible to realize the consumption of the organic azide in
CuAAC step,[68].
conditions as soon as it forms,
In principle, withandthisthen avoiditany
approach build-up
is possible in the reaction
to realize mixture.ofDepending
the consumption the organicon
theazide
nature of the azide intermediate (e.g., aliphatic or aromatic) and of the starting
in the CuAAC step, as soon as it forms, and then avoid any build-up in the reaction mixture. material selected
forDepending
the purpose, on different
the naturepossibilities
of the azideexists in this respect.
intermediate As summarized
(e.g., aliphatic or aromatic)in and
Scheme 2, those
of the startingmet
more frequently,
material selectedandfordiscussed
the purpose,in detail in thepossibilities
different following sections,
exists ininvolve the use
this respect. Asof:
summarized in
Scheme 2, those met more frequently, and discussed in detail in the following sections, involve the
• useAlkyl
of: halides (Scheme 2a), often of the “activated” type (benzyl, allyl, α-halocarbonyls) with
respect to the nucleophilic substitution reaction;
• Alkyl halides (Scheme 2a), often of the “activated” type (benzyl, allyl, α-halocarbonyls) with
• Epoxides (Scheme 2b), which can lead to the formation of differently substituted triazoles (3 and 4)
respect to the nucleophilic substitution reaction;
• in Epoxides
dependence of the2b),
(Scheme regioselectivity
which can leadoftoattack of azide of
the formation ions on the oxirane
differently ring;triazoles (3 and
substituted
• Aromatic diazonium
4) in dependence ofsalts (Scheme 2c), either
the regioselectivity commercially
of attack of azide ions available (e.g., tetrafluoroborate
on the oxirane ring; salts)
• or produced in situ by diazotisation of the corresponding aromatic amine;
Aromatic diazonium salts (Scheme 2c), either commercially available (e.g., tetrafluoroborate
• Aromatic
salts) orboronic
produced acids (Scheme
in situ 2d), whichof
by diazotisation maythe undergo azido-deboronation
corresponding aromatic amine; under the action of
• theAromatic
same copper catalyst
boronic acids involved
(Scheme 2d), in the CuAAC
which process [69].
may undergo azido-deboronation under the action
of the same copper catalyst involved in the CuAAC process [69].

Scheme 2. Three-components CuAAC reactions (a–d) discussed in this paper.

Scheme 2. Three-components CuAAC reactions (a–d) discussed in this paper.

On the contrary, the problems associated with the use of the copper catalyst have been tackled
On the contrary, the problems associated with the use of the copper catalyst have been tackled by
by adopting widely different strategies, including the use of strained alkynes or highly reactive
adopting widely different strategies, including the use of strained alkynes or highly reactive azides,
azides, that do not require metal catalysis at all [65,70–72], and reactants with chelating capability,
which allow to reduce the catalyst loading [73]. Besides, many efforts were committed to the
Molecules 2016, 21, 1174 4 of 43

that do not require metal catalysis at all [65,70–72], and reactants with chelating capability, which allow
to reduce the catalyst loading [73]. Besides, many efforts were committed to the development of
more effective catalytic systems based on copper or other metals [30]. Especially in the case of
rhodium-catalyzed process, the latter choice may display a useful complementary profile with respect
to CuAAC in that –with the proper choice of the catalytic complex-1,5-disubstituted-1,2,3-triazole
products or even trisubstituted ones can be obtained from the reaction of terminal and internal alkynes,
respectively. However, these alternatives still suffer from contamination of the product with transition
metals and, usually, require more expensive catalyst precursor than CuAAC itself.
As far as copper is concerned, some of the shortcomings associated with traditional systems
(e.g., CuX salts in the presence of an amine co-catalyst or CuSO4 with an excess of sodium ascorbate)
were eliminated with the introduction of stabilizing ligands for the +I oxidation state of the metal and
proper scavenging of reactive by-products [66,74]. Under these conditions CuAAC proceeds often
under air, with catalyst concentration in the µM range and copper loading that, in some cases, can be
reduced down to 0.01 mol % with respect to the substrates. Even so, the use of low-molecular weight
soluble catalytic systems leaves unanswered the problem of contamination of the crude product with
metal and, possibly, ligand residues. For instance, in the case above a copper content up to 25 ppm
might be found in the crude from a CuAAC reaction forming a compound of average molecular
weight. This concentration exceeds the metal amount often quoted as acceptable for pharmaceutical
applications (15 ppm) [75].
Considering also that the use of 0.01 mol % of copper catalyst represents more the exception
than the rule, especially when structurally complex triazoles have to be prepared, one may expect
that such a threshold is surpassed by several order of magnitude when this chemistry is employed in
scenarios of practical synthetic relevance. In this regard it is worth noting that while the possibility
of running CuAAC reactions with catalysts loadings in the low ppm range has been reported with
systems comprising self-assembled gel [76], dendrimeric ligands [77], and homogeneous catalysts
comprising a molecularly-enlarged water-soluble tris-triazole ligand [78], demonstration of the scope
of these approaches to molecules more complex of those usually employed for benchmarking new
CuAAC protocols are just beginning to appear [78].
Together with the fact that copper removal can be difficult, in particular for highly functionalized
or sensitive products [79], these problems tend to collide with the goal of prompt product purification
underlying in the concept of click-chemistry. Therefore it is not surprising that many attempts have
been described in the course of the years, aimed to separate the CuAAC catalytic system from the
reaction mixture in more effective ways.
Some of these approaches rely on known homogeneous catalysts employed under alternative
conditions like, e.g., recent reports making use of supercritical CO2 [80], glycerol, poly(ethylene
glycol) (PEG), room-temperature ionic liquids, and their combinations thereof, as neoteric reaction
media [81–85]. Similarly, water-soluble catalytic systems can provide an excellent opportunity for
separation and recycling [78,86].
Albeit straightforward, this choice shows occasional limitations in terms of catalytic activity,
seamless general implementation and, above all, effectiveness in reducing the residual copper content
to an extent that might cope with the said regulatory requirements. In an alternative strategy,
catalytic systems specifically designed for easier separation were therefore developed, typically
by immobilization of copper species onto insoluble supports or quasi-homogeneous materials,
like nanoparticles. Even if the degree of success may greatly vary from case to case, as discussed in
the next sections, on the average this route appears better fit for the effective removal of the catalytic
system from the reaction mixture and for the abatement of copper content in the crude by techniques
amenable of use even at scale, like filtration, centrifugation, and magnetic decantation.
Of course, with this choice an opportunity arises also for catalyst recovery and reuse. In this
respect it might be argued that, given the cheapness of most Cu(I/II) catalyst precursors, this goal is
not necessarily the primary objective in the development of improved catalytic systems for CuAAC.
Molecules 2016, 21, 1174 5 of 43

Nevertheless, the possibility of recycling the metal species and any associated ligand, recovered
“for free” at the product purification stage, is an appealing feature that stimulated much work in
this direction.
The topic of recoverable systems for CuAAC has been briefly summarized before [87], up to
the comprehensive reviews by Haldon et al. in 2015 [88], and Chassaing et al. [89], early this year.
In addition, some specific aspects were covered in context like the use of supported ionic liquid phase
catalyst [90], nanostructured and nanoporous Cu catalysts [91], CuO nanoparticles [92], and in the
recent accounts by the groups of Alonso and of Astruc on the use of copper nanoparticles (CuNPs) [93],
magnetic or dendritic catalysts [55], and present trends in azide-alkyne cycloaddition reactions [30].
Even so, the pace of research in the field of recoverable catalytic systems for CuAAC is so fast at
present, that many more examples have appeared since the publication of the reference works above.
The discussion of these recent advances, mostly published in the period 2015–mid 2016, is the aim of
the present review.
In this regard, it must be pointed out that while recoverable systems for CuAAC will be
covered in the broadest sense, the focus will be essentially on catalysts on insoluble supports and
quasi-homogeneous systems where the presence of an organic polymer plays a decisive role. In general,
an effort will be made for summarizing preparation method, characterization, conditions of use, activity,
and scope of the various systems. Whenever possible, and for the reasons discussed above, the specific
issues of catalyst leaching and product contamination will be examined in detail.

2. Cu, Cu2 O, CuO, and CuX Nanoparticles and Nanocomposites

Like in many other catalytic processes [94], nanoparticles have received a great deal of attention
in the context of CuAAC. Although just a fraction of the metal centers are actually exposed to
the surrounding reaction medium (e.g., 28% for a spherical CuO nanoparticle with a diameter
dp = 4.7 nm) [95], nano-sized systems may nonetheless display high specific activity that, in some
cases, appears related with facet index [96]. Because Cu2 O is chemically unstable in air and Cu(0)
nanoparticles tend to sinter or dissolve under CuAAC reaction conditions [93,97], some kind of
stabilization is normally required. Similarly to the oxide layer covering bulk copper [75], the same
problem is apparently met with porous forms of the metal and CuNPs prepared in solution, for which
recent reports do not describe any recycle at all or show relatively fast loss of catalytic activity [98–101].
In many instances a solution to these problems is provided by the use of an insoluble support with
suitable complexing sites, like amino groups [102], which may be very effective in preventing particle
aggregation and extensive metal leaching.

2.1. Carbon Supports

Copper-in-charcoal (Cu/C) has been repeatedly employed as a cheap and relatively effective
catalyst in CuAAC reactions [88,89]. While the occurrence of CuO and Cu2 O particles is generally
acknowledged in Cu/C obtained by calcination [103–105], recently Buckley et al. [106] identified
unsupported gerhardite (Cu2 (OH)3 NO3 ) as the likely catalyst precursor in materials prepared by
the Lipshutz0 low-temperature carbon impregnation method [107,108]. Upon exposure to CuAAC
conditions, the Cu(II) salt was found to transform into the actual active form, deemed to be a polymeric
Cu(I) acetylide. The latter could be recovered by filtration, along with unreacted gerhardite, but no
recycling of the material was reported. In this context it is worth noting also that Decan and Scaiano
provided a detailed picture of commercial Cu/C catalyst under in operando conditions [109]. The study,
based on single molecule fluorescence microscopy for mapping CuAAC events, suggested that 90%
of the charcoal particles in the sample were devoid of any active site. Moreover, for the remaining
10% ones the active sites were estimated to represent just a minute fraction (approximate 0.003%) of
the total surface. These results might help to explain the scarce catalytic activity, reported in some
investigations for Cu/C samples from commercial sources [106,110].
Molecules 2016, 21, 1174 6 of 43

An on-purpose prepared Pd-Cu bimetallic catalytic system on charcoal was studied by Rossy et al.
for one-pot sequential Sonogashira-click and click-Heck reactions [111]. Unfortunately, an attempt to
recycle the material in the former reaction evidenced essentially complete loss of its catalytic activity.
D’Haullin et al. prepared ultra-small copper oxide nanoparticles on graphite by stirring a
suspension of the powdered support in a solution of Cu(OAc)2 in MeOH, kept under H2 [112].
The catalysts, which consisted of CuO, Cu(OH)2 and minor amounts of Cu2 O, displayed fair activity in
three-component CuAAC reactions of halides and styrene oxide (Scheme 2a,b). Although no recycling
Molecules 2016, 21, 1174 6 of 41
of the material was apparently attempted, filtration of the reaction mixture through a Nylon membrane
permitted
membranethe prompt removal
permitted the prompt of the insoluble
removal system
of the and left
insoluble only and
system traceleft
amounts of copper
only trace amountsin theof
filtrate (6 ppb).
copper in the filtrate (6 ppb).
Cu nanoparticles on
Cu22O nanoparticles ongraphene
grapheneoxideoxide(GO, (GO, 6), 6),
werewere obtained
obtained by Niaby etNiaal.etthrough
al. through
high-
high-temperature treatment in an Ar stream of GO impregnated with Cu(OAc)
temperature treatment in an Ar stream of GO impregnated with Cu(OAc)2 [110].2The material proved [110]. The material
proved more than
more active activecommercial
than commercial
Cu/C Cu/C
and Cu and
2O Cu 2 O in two-components
in two-components CuAAC CuAAC reactions
reactions (Scheme(Scheme 1),
1), but
but a relatively large catalyst loading ◦
a relatively large catalyst loading (2 (2 mol
mol %)%) andextended
and extendedreaction
reactiontime
time(48(48hhatat 40
40 °C)C) were still
still
necessary for attaining good
necessary for attaining good results. results. Moreover, recycling experiments in the benchmark reaction
the benchmark reaction
between benzyl azide
between benzyl azideand andphenylacetylene
phenylacetylenein in THF THF showed
showed a marked
a marked decrease
decrease of theofproduct
the product
yield
yield
already already in the run
in the fourth fourth
(99%run→ 55%). → 55%). Interestingly,
(99% Interestingly, 6 was effective 6 was
also effective
in the bulk also in the bulk
cross-linking of
cross-linking of a mixture of alkyne and azide trifunctional macromolecular
a mixture of alkyne and azide trifunctional macromolecular reactants 7 and 8, based on star reactants 7 and 8, based on
star poly(isobutylene)
poly(isobutylene) (PIB)(PIB) chains
chains (Scheme
(Scheme 3). 3). Although
Although in in thesecases
these casestrapping
trapping of of the copper
copper
nanocomposite
nanocomposite inside the resulting resin 9 prevents its reuse, it is worth mentioning
prevents its reuse, it is worth mentioning that a kineticthat a kinetic
study
study ofof click-polymerizations
click-polymerizations promoted
promoted by by66 was
waspublished
publishedalso also[113].
[113].

Scheme 3.
Scheme 3. Click
Click polymerization
polymerization of
of alkyne
alkyne and
and azide
azide PIB
PIB trifunctional
trifunctional reactants.
reactants.

More recently,
More recently,the
thesame
samegroup
groupreported
reportedhighly
highly dispersed
dispersed copper
copper clusters
clusters on
on carbon
carbon nano-tubes
nano-tubes
(CNT) and chemically-reduced graphene oxide (CRGO) [114]. These systems
(CNT) and chemically-reduced graphene oxide (CRGO) [114]. These systems 10, supposed to 10, supposed to embed
embed
Cu(carbene)X or
Cu(carbene)X or Cu-Cu
Cu-Cufragments
fragmentsononthethe basis of literature
basis of literature precedents for Ag(I)
precedents analogs
for Ag(I) [115],[115],
analogs were
obtained by a stepwise procedure culminating (Scheme 4) in the decoration of
were obtained by a stepwise procedure culminating (Scheme 4) in the decoration of the supports withthe supports with
triazole-imidazolium units and formation of Cu(I)-carbene clusters. Despite the not so
triazole-imidazolium units and formation of Cu(I)-carbene clusters. Despite the not so much dissimilarmuch dissimilar
copper content
copper content ofof CNT
CNTand andCRGO-based
CRGO-basedmaterials
materials10,10,
thethe
latter displayed
latter a higher
displayed catalytic
a higher activity
catalytic and
activity
better recycling profile than the former (respectively, 99% → 91% and 60% → 45% yield
and better recycling profile than the former (respectively, 99% → 91% and 60% → 45% yield in 10 runs) in 10 runs) in
two-components
in two-components CuAAC
CuAAC reactions
reactions(Scheme
(Scheme1)1)and
andin in the
the click-reticulation
click-reticulation process mentioned above
process mentioned above
(Scheme 3).
(Scheme 3).
Even in this case, the runs had to be carried for long time (24–72 h at 40 ◦ C) and with substantial
amounts of catalyst (2 mol %–8 mol %). In spite of this, copper concentration in the filtrate from the
reaction mixture was reportedly too low for accurate quantification.
Another instance of copper oxide nanoparticles on GO was described by Reddy et al. [116].
The preparation of the supported system was achieved through a published procedure [117], whose key
steps are the intercalation of Cu(II) between GO sheets and the subsequent exfoliation of the
material, caused by nucleation and growth of CuO crystallites. TEM and XRD characterization
of the nanocomposite confirmed the presence of CuO nanoparticles (15–50 nm) onto a graphene-like
support. At variance with the examples discussed above and Cu2 O on bare CRGO [118], the GO-CuO
system proved highly active in water at 25 ◦ C, even at 0.227 mol % loading. Under these conditions
the addition of various benzyl or aryl azides to terminal alkynes (Scheme 1) proceeded in 10–20 min

Scheme 4. Preparation of Cu(I)-carbene clusters 10 on carbon nano-materials.

 Scheme 3. Click polymerization of alkyne and azide PIB trifunctional reactants.
Molecules 2016, 21, 1174 7 of 43
More recently, the same group reported highly dispersed copper clusters on carbon nano-tubes
(CNT) and chemically-reduced graphene oxide (CRGO) [114]. These systems 10, supposed to embed
to Cu(carbene)X
give the corresponding triazoles on
or Cu-Cu fragments in high yield
the basis of (85%–96%). In addition
literature precedents to good
for Ag(I) dispersion
analogs of the
[115], were
nanocomposite, the result was attributed to hydrophobic phenomena at the carbon
obtained by a stepwise procedure culminating (Scheme 4) in the decoration of the supports with surface [119,120],
related to the so called “Breslow
triazole-imidazolium effect” [121].
units and formation Filtration through
of Cu(I)-carbene a 0.2
clusters. µm PTFE
Despite membrane
the not allowed the
so much dissimilar
separation of GO-CuO and its reuse in five cycles, where some decrease of product yield
copper content of CNT and CRGO-based materials 10, the latter displayed a higher catalytic activity was and
noted
even the adoption of progressively longer reaction time (approximate 96% →
better recycling profile than the former (respectively, 99% → 91% and 60% → 45% yield in 10 runs)effect
with 90%). The in
was ascribed to leaching
two-components CuAAC ofreactions
CuO in the water1)phase,
(Scheme and inestimated to occur atprocess
the click-reticulation a pace of around 0.6
mentioned wt %
above
per(Scheme
cycle. 3).

Molecules 2016, 21, 1174 7 of 41

steps are the intercalation of Cu(II) between GO sheets and the subsequent exfoliation of the material,
caused by nucleation and growth of CuO crystallites. TEM and XRD characterization of the
nanocomposite confirmed the presence of CuO nanoparticles (15–50 nm) onto a graphene-like
support. At variance with the examples discussed above and Cu2O on bare CRGO [118], the GO-CuO
system proved highly active in water at 25 °C, even at 0.227 mol % loading. Under these conditions the
addition of various benzyl or aryl azides to terminal alkynes (Scheme 1) proceeded in 10–20 min to give
the corresponding triazoles in high yield (85%–96%). In addition to good dispersion of the
nanocomposite, the result was attributed to hydrophobic phenomena at the carbon surface [119,120],
related to the so called “Breslow effect” [121]. Filtration through a 0.2 μm PTFE membrane allowed the
separation of GO-CuO and its reuse in five cycles, where some decrease of product yield was noted
even with the adoptionScheme4.
Scheme of4.Preparation
progressively
Preparationof longer reaction
ofCu(I)-carbene
Cu(I)-carbene time10
clusters
clusters (approximate
10 on
oncarbon 96% → 90%). The effect was
carbonnano-materials.
nano-materials.
ascribed to leaching of CuO in the water phase, estimated to occur at a pace of around 0.6 wt % per cycle.
Even
A last in this
lastrecent
recent case,inthe
entry
entry intheruns
the
list had
list
of of to be carried
GO-based
GO-based for long
materials
materials fortime
for (24–72
CuAAC
CuAAC hcomes
at 40
comes °C)
fromfromandwork
the with
the substantial
work
of of Dabiri
Dabiri et al.
amounts
et al.
(Scheme 5) of
(Scheme catalyst
5) [122].
[122]. (2Inmol
In this this%–8
study,
study, molGO
GO %).was
was In spite of
reacted
reacted this,
withwith copper concentration
ethylenediamine
ethylenediamine in
with
with thethe
thefiltrate
aimaimof offrom the a
preparing
preparing
3D reaction
a 3Dgraphene mixture
graphene was reportedly
hydrogel
hydrogel that,inina atoo
that, low for accurate
subsequent
subsequent step,was
step, quantification.
was decorated with
decorated with oxidized
oxidized CuNPs,
CuNPs, from the
Another instance
reduction of Cu(NO33)22,, to of copper
to give oxide nanoparticles
give 11. In a series of two- and on GOthree-components
was described by Reddy
three-components et al.
reactions
reactions in[116].
in EtOH-H
EtOH-HThe2O
2
preparation of the supported system was achieved through
resulting system a published procedure
system resembled that of other [117], whose key
other carbon-based
carbon-based
(1:1), the catalytic activity in CuAAC of the resulting
materials noted above. In particular, relatively high loading and reaction temperature (5 mol % and
◦ C) respectively,
70 °C) had to be adopted for attaining good yields within
respectively, had within 1–7 h (81%–99%). On the other
hand, the 3D-graphene material displayed a better recyclability than most of the analogous systems,
as witnessed by minimal reduction of product yield at fixed reaction time even after 10 consecutive consecutive
cycles (99% → → 97%).
97%).

Scheme 5.
Scheme 5. Preparation
Preparation of
of 3D-graphene/CuNPs
3D-graphene/CuNPs nanocomposite
nanocomposite 11.

2.2. Insoluble Synthetic Organic Polymers

CuAAC catalytic systems on organic polymers, 12 and 13 (Scheme 6), were obtained recently by
depositing nanoparticles of cuprous halides on a poly(styrene-co-maleic anhydride) imide (SMI) or
polyaniline (PANI). The former support material, studied by Hashemi et al., was obtained by treating
Molecules 2016, 21, 1174 8 of 43

2.2. Insoluble Synthetic Organic Polymers

CuAAC catalytic systems on organic polymers, 12 and 13 (Scheme 6), were obtained recently by
depositing nanoparticles of cuprous halides on a poly(styrene-co-maleic anhydride) imide (SMI) or
polyaniline (PANI). The former support material, studied by Hashemi et al., was obtained by treating
styrene-maleic anhydride copolymer with 4-aminopyridine under dehydrating conditions [123].
Subsequent refluxing with CuI nanoparticles, prepared by DMF precipitation of the cuprous salt
from a MeCN solution, led 12, that was shown by SEM to contain an uniform dispersion of copper
halide crystals within the fiber-like polymeric matrix. In a similar approach, 13 was obtained by
Saadat et al. by refluxing PANI and CuI in EtOH, under an inert atmosphere [124]. The catalytic
activity of the materials was evaluated in three-component CuAAC reactions of activated halides or
methyl
Molecules iodide
2016, 21, (Scheme
1174 2a). The reactions were typically carried out in boiling water, with 1 mol 8 of %
41
of 12 or, respectively, 5 mol % of 13. Despite the potential solvolytic instability of the halide reactants
under these conditions,
these conditions, fair to fair
goodto yields
good yields were reported
were reported in bothin both
studiesstudies (71%–92%
(71%–92% in 15–145
in 15–145 min).min).
The
The scarce
scarce solubility
solubility of the
of the respective
respective support
support material
material in in water,asaswell
water, wellasasin
inmost
most organic
organic solvents,
allowed
allowed the therecovery
recoveryand andreuse
reuseofofthe
thecatalytic systems.
catalytic Also
systems. from
Also this
from point
this of view,
point the the
of view, findings of the
findings of
two investigations
the two investigationswerewere
quitequite
similar, withwith
similar, somesome
decrease of product
decrease yieldyield
of product (approximate 92% →
(approximate 92%83%→
and
83%92%and → 92% → 88%,
88%, respectively) and a and
respectively) moderate reduction
a moderate of metal
reduction ofloading on the support
metal loading (5% and (5%
on the support 3%,
respectively) after fiveafter
and 3%, respectively) consecutive runs.
five consecutive runs.

CuI, MeCN-DMF
(0.35 mmol Cu g-1,
SMI SMI/CuI (12)
reflux, 5 h d P = 53-101 nm) n
Ph O O
N N
H n

CuI, EtOH -1
(0.94 mmol Cu g , SMI PANI
PANI PANI/CuI (13)
d P = 20-60 nm) N
reflux, 12 h

Scheme 6. Preparation
Scheme 6. Preparation of
of CuI nanocrystals on
CuI nanocrystals on SMI
SMI and
and PANI
PANI polymeric
polymeric supports,
supports, 12
12 and
and 13.
13.

Savva et
Savva etal.al.
investigated
investigated the use
the ofuse
electrospinning as a mean
of electrospinning asfor a obtaining
mean forCuobtaining
2O nanoparticles
Cu2 O
embedded into membranes made of cross-linked poly(N-vinyl pyrrolidone)
nanoparticles embedded into membranes made of cross-linked poly(N-vinyl pyrrolidone) (PVP) [125]. (PVP) [125]. The
preparation route (Scheme 7a) involved hydrazine reduction of a
The preparation route (Scheme 7a) involved hydrazine reduction of a mixture of linear PVP andmixture of linear PVP and
Cu(OAc)22,, followed
Cu(OAc) followedby byelectrospinning
electrospinningofofthe the resulting
resulting colloidal
colloidal solution
solution on aon a target
target collector
collector and
and final
curing at 180 C. With this procedure, initially formed Cu(0) clusters were probably oxidized to Cu2to
final curing at◦ 180 °C. With this procedure, initially formed Cu(0) clusters were probably oxidized O
Cu2O
and and a material
a material 14 was obtained
14 was obtained that, contrarily
that, contrarily to linear
to linear PVP, PVP,
resulted resulted
insoluble in insoluble in water.
water. Interestingly,
Interestingly,
the curing stage thedid
curing stage did
not cause not cause
dramatic dramatic
variations variations
of the of the of
morphology morphology
the membrane, of theinmembrane,
particular
in particular for what it concerns the occurrence of cylindrical polymer fibrils
for what it concerns the occurrence of cylindrical polymer fibrils supporting a uniform dispersion supporting a uniformof
dispersion of metal oxide particles. The electrospun composite membrane
metal oxide particles. The electrospun composite membrane 14 was effective in promoting the CuAAC 14 was effective in
promoting
addition the CuAAC
of benzyl azide toaddition of benzyl
phenylacetylene azide to phenylacetylene
in 1,4-dioxane and in the presence in 1,4-dioxane
of an equivalent andamount
in the
presence of an equivalent amount of Et 3N. However, a rather high metal loading (5 mol % Cu) was
of Et3 N. However, a rather high metal loading (5 mol % Cu) was used in these experiments in order
used
to in these
obtain experiments
the triazole product ininorder
87% to obtain
yield afterthe
2 htriazole
at 60 ◦ C.product
Moreover, in 87%
reuseyield after
of the 2 h atin60three
material °C.
Moreover, reuse of the material in three consecutive runs indicated a gradual
consecutive runs indicated a gradual loss of catalytic activity (87% → 77% yield), accompanied by loss of catalytic activity
(87% → 77%phenomena
aggregation yield), accompanied by aggregation
of the polymer fibers. phenomena of the polymer fibers.
The use of poly(vinyl alcohol) (PVA) for stabilizing Cu2 O nanoparticles was explored by
Hajipour et al. [97]. In this case, the preparation of the catalytic system (Scheme 7b) involved the
initial formation of a gel from PVA and CuSO4 in alkaline NaOH solution, followed by reduction
with sodium ascorbate, aging, filtration, and washing. Drying in air afforded a reddish product 15,
characterized by a broad UV band centered around 491 nm and an XRD pattern matching that of
Cu2 O. Interestingly, the choice of basic conditions (pH = 12) proved essential for the reduction to Cu(I)
because the same step, carried out without the addition of NaOH, led to a material featuring the XRD
diffractions of metallic copper. Screening of PVA-Cu2 O in CuAAC involved reactions of preformed
 Scheme 6. Preparation of CuI nanocrystals on SMI and PANI polymeric supports, 12 and 13.

Savva et al. investigated the use of electrospinning as a mean for obtaining Cu2O nanoparticles
embedded into membranes made of cross-linked poly(N-vinyl pyrrolidone) (PVP) [125]. The
preparation route (Scheme 7a) involved hydrazine reduction of a mixture of linear PVP and
Molecules
Cu(OAc)2016,2,21, 1174
followed by electrospinning of the resulting colloidal solution on a target collector and 9 of 43
final curing at 180 °C. With this procedure, initially formed Cu(0) clusters were probably oxidized to
Cu2O and a material 14 was obtained that, contrarily to linear PVP, resulted insoluble in water.
aromatic azides (Scheme 1), or benzyl azides formed in situ from the corresponding halides and NaN3
Interestingly, the curing stage did not cause dramatic variations of the morphology of the membrane,
(Scheme 2a). In both cases the reactions were run in water with a low, yet unspecified, copper loading
in particular for what it concerns the occurrence of cylindrical polymer fibrils supporting a uniform
and in the presence
dispersion of metalof tetrabutylammonium bromide. Rather
oxide particles. The electrospun surprisingly,
composite the latter
membrane proved
14 was beneficial
effective in
even
promoting the CuAAC addition of benzyl azide to phenylacetylene in 1,4-dioxane and in the to
in the former scenario, i.e., where the action of a typical phase-transfer catalyst was expected
be presence
marginalofdue an to the lack amount
equivalent of ionic reactants. Under the
of Et3N. However, said conditions
a rather high metal the CuAAC
loading runs
(5 mol proceeded
% Cu) was
smoothly to give the expected triazoles in reasonable yield (68%–95% in 1–9 h). Moreover,
used in these experiments in order to obtain the triazole product in 87% yield after 2 h at 60 °C. the activity
of the pristinereuse
Moreover, catalyst was
of the retained
material with the
in three insolubleruns
consecutive material recovered
indicated by decantation
a gradual andactivity
loss of catalytic washing,
as (87% → 77%byyield),
confirmed essentially constant
accompanied byresults in the phenomena
aggregation course of 4 reaction (95% → 94% yield).
cycles fibers.
of the polymer

Molecules 2016, 21, 1174 9 of 41

preformed aromatic azides (Scheme 1), or benzyl azides formed in situ from the corresponding
halides and NaN3 (Scheme 2a). In both cases the reactions were run in water with a low, yet
unspecified, copper loading and in the presence of tetrabutylammonium bromide. Rather
surprisingly, the latter proved beneficial even in the former scenario, i.e., where the action of a typical
phase-transfer catalyst was expected to be marginal due to the lack of ionic reactants. Under the said
conditions the CuAAC runs proceeded smoothly to give the expected triazoles in reasonable yield
(68%–95% Scheme
in 7. Preparation
1–97.h). Moreover,
Preparation ofof PVP/Cu
the
PVP/Cu 2O membrane 14 (a) and of PVA/Cu2O composite 15 (b).
activity of the pristine catalyst was retained with15the (b).insoluble
Scheme 2 O membrane 14 (a) and of PVA/Cu 2 O composite
material recovered by decantation and washing, as confirmed by essentially constant results in the
The use of poly(vinyl alcohol) (PVA) for stabilizing Cu2O nanoparticles was explored by
courseIn ofan4unusual
reactionapproach,
cycles (95% → 94%
Patil et al.yield).
immobilized the ascorbate reducing agent on a polystyrene
Hajipour et al. [97]. In this case, the preparation of the catalytic system (Scheme 7b) involved the
resinIn decorated with N-methylimidazolium
an unusual approach, Patil et al. immobilized ionic fragments [126].reducing
the ascorbate The material
agent 16 on was obtained
a polystyrene
initial formation of a gel from PVA and CuSO4 in alkaline NaOH solution, followed by reduction
(Scheme
resin 8) by reacting
decorated a Merrifield resin with
with N-methylimidazolium N-methylimidazole, exchanging hydroxide ions for
with sodium ascorbate, aging, filtration, and ionic fragments
washing. Drying in[126]. The material
air afforded a reddish16 was
productobtained
15,
the chloride
(Scheme 8) byones and
reacting then
a treating
Merrifield the
resin basic
with form of the material
N-methylimidazole, with ascorbic
exchanging
characterized by a broad UV band centered around 491 nm and an XRD pattern matching that acid.
hydroxide The supported
ions forofthe
reducing
chloride agentand
ones (16 mol
Cu2O. Interestingly, then %)
the was employed
treating
choice thebasic
of inform
three-components
basicconditions of the
(pHmaterial CuAAC reactionsfor
with essential
= 12) proved ascorbic inthe
acid.water
The of aromatic
supported
reduction to
diazonium
Cu(I) because the same step, carried out without the addition of NaOH, led to a material featuringthe
reducing tetrafluoroborates
agent (16 mol %) was (Scheme
employed 2c),
in implemented
three-components by making
CuAAC use of CuSO
reactions in 4 (4
water molof %) as
aromatic
soluble
diazonium
the XRD catalyst precursor.
tetrafluoroborates
diffractions While
of metallic this
(Scheme choice
copper. is expected
2c),Screening
implemented to lead
by
of PVA-Cu 2Oto
making inprogressive
use of CuSO
CuAAC consumption
4 (4 mol
involved %) as
reactions ofofthe
ascorbate co-catalyst,
soluble catalyst TEM-EDS
precursor. WhileandthisXPSchoiceanalyses of the resin
is expected to leadrecovered at the end
to progressive of CuAACofruns
consumption the
suggested the presenceTEM-EDS
ascorbate co-catalyst, of CuNPsand on the
XPSmaterial
analyses (probably CuO,
of the resin approximate
recovered 0.52
at the end mmol ·g−1 ). Atruns
of CuAAC the
same time, no metal was
suggested the presence of CuNPs on found in the filtrate by AAS, thus offering the possibility
material (probably CuO, approximate 0.52 mmol·g ). At the of recycling
−1

the
same (intime,
situ)noimmobilized catalyst.
metal was found in theThis wasby
filtrate effected withoffering
AAS, thus reasonable albeit incomplete
the possibility of recycling efficiency,
the (in
as confirmed
situ) immobilized by the observation
catalyst. This wasofeffected
significant
with yield valuesalbeit
reasonable through 6 consecutive
incomplete efficiency, reaction cycles
as confirmed
by the observation of significant yield values through 6 consecutive reaction cycles (94% → 85%).
(94% → 85%).

(1) N N Me
N
toluene, reflux, 24 h N Me
Cl
(2) KOH, water, 18 h OH
O
(3) Ascorbic acid H O
water, 12 h O
HO
Merrifield resin
OH 16
(2% DVB, 2-4 mmol Cl g-1)

Scheme 8. Preparation
Scheme 8. Preparation of
of resin-supported ascorbate 16.
resin-supported ascorbate 16.

2.3. Metal-Organic
2.3. Metal-Organic Frameworks
Frameworks
Metal-organic frameworks
Metal-organic frameworks (MOFs)
(MOFs) represent
represent an interesting class
an interesting class of
of hybrid
hybrid organic-inorganic
organic-inorganic
porous materials with tunable properties [127]. The preparation of Cu O nanoparticles immobilized
porous materials with tunable properties [127]. The preparation of Cu2 O nanoparticles immobilized
2

within the pores of (Zn(Himdc)(bipy)0.5) (Himdc = 4,5-imidazoledicarboxylate; bipy = 4,4′-bipyridine,

Scheme 9) was achieved by Jayaramulu et al. through reduction with hydrazine hydrate of the CuSO4-
impregnated MOF [128]. XRD, XPS, and TEM characterization of the resulting solid 17 showed the
presence of Cu2O nanoparticles (mainly 2–3 nm in size and containing minor amounts of CuO),
dispersed within the pores of the essentially intact Zn(II)-ligands framework. Two-components CuAAC
 OH 16
(2% DVB, 2-4 mmol Cl g-1)

Scheme 8. Preparation of resin-supported ascorbate 16.

2.3. Metal-Organic Frameworks

Molecules 2016, 21, 1174 10 of 43
Metal-organic frameworks (MOFs) represent an interesting class of hybrid organic-inorganic
porous materials with tunable properties [127]. The preparation of Cu2O nanoparticles immobilized
within 0 -bipyridine,
within the
the pores
pores of
of(Zn(Himdc)(bipy)
(Zn(Himdc)(bipy)0.5 0.5) (Himdc = = 4,5-imidazoledicarboxylate; bipy == 4,4 4,4′-bipyridine,
Scheme 9) 9)was
wasachieved
achievedbyby Jayaramulu
Jayaramulu et through
et al. al. through reduction
reduction with hydrazine
with hydrazine hydratehydrate of the
of the CuSO 4-
CuSO 4 -impregnated
impregnated MOFXRD,
MOF [128]. [128]. XPS,
XRD,andXPS,TEMand characterization
TEM characterization
of theofresulting
the resulting
solidsolid 17 showed
17 showed the
the presence
presence of 2Cu
of Cu O nanoparticles
O 2nanoparticles (mainly
(mainly 2–32–3 nmnm ininsize
sizeand
andcontaining
containingminor
minoramounts
amounts of of CuO),
dispersed within the pores of the essentially intact Zn(II)-ligands framework. Two-components CuAAC
catalytic runs (Scheme
(Scheme 1), in the presence of an equivalent amount of Et33N
equivalent amount N and
and 0.5
0.5 mol
mol % of 17 in
t-BuOH-H2O O (2:1), afforded nearly quantitative yields after 7 h at 50 ◦°C. C. The MOF-supported catalyst
could be recovered
recovered byby filtration,
filtration, dissolution
dissolution of of the
the triazole
triazole product
product in
in CHCl
CHCl33 and centrifugation,
centrifugation, thus
allowing the completion
completion of of three
three reaction
reactioncycles
cycleswith
withreportedly
reportedlyunchanged
unchangedactivity.
activity.

Scheme
Scheme
Molecules 2016, 21, 9. Preparation
1174 9. Preparation of
of Cu
Cu22O
O nanoparticles
nanoparticles in
in 2D
2D metal-organic framework, 17.
metal-organic framework, 17. 10 of 41

Considering also that TEM, XRD, and CO CO22 adsorption measurements showed no significant
changes with respect to the pristine material, these result led to the conclusion that pendant Himdc
carboxylate groups in the MOF structure may have a positive
positive role
role in
in stabilizing
stabilizing Cu
Cu22O nanoparticles
and preventing their aggregation. Unfortunately, the lack
Unfortunately, the lack of any information about the content of
copper and MOF components in the crude triazoles (either Zn(II) or the organic ligands) makes it
difficult to draw any conclusion about this interesting CuAAC system from the point of view of
product contamination.

2.4. Polymers from Natural Sources

With the
thespecific
specificgoal
goalofofovercoming
overcoming thethe
modest
modest yields in the
yields CuAAC
in the CuAAC of some glycosyl
of some azides
glycosyl with
azides
the standard
with CuSO4CuSO
the standard /sodium ascorbate
4/sodium system,
ascorbate Yu et al.
system, Yuendeavored to prepare
et al. endeavored to CuNPs
prepareon cellulose
CuNPs on
(Scheme
cellulose 10), by reduction
(Scheme 10), by of Cu(NO3 )of
reduction 2 with
Cu(NO hydrazine
3) 2 with in the presence
hydrazine in of
the the polymeric
presence of support
the [129].
polymeric
Despite the
support fact
[129]. that distinction
Despite between
the fact that Cu(0)between
distinction and Cu(I) is not
Cu(0) always
and Cu(I) easy
is not[130], theeasy
always observation
[130], thea
XPS Cu 2p3/2a XPS
observation peakCu at 932.68 eV in
2p3/2 peak at the spectrum
932.68 eV in theof the insoluble
spectrum material
of the 18 was
insoluble taken18
material as was
a proof of
taken
the occurrence of clusters containing metallic copper. Evaluation of the activity of
as a proof of the occurrence of clusters containing metallic copper. Evaluation of the activity of 18 in18 in the CuAAC
reaction
the CuAACof phenylacetylene with acetylatedwith
reaction of phenylacetylene α-L-arabinopyranosyl azide displayedazide
acetylated α-L-arabinopyranosyl a good activity at
displayed a
r.t. in several
good activityorganic solvents.
at r.t. in severalHowever, for the sake
organic solvents. of betterfor
However, eco-compatibility
the sake of better water was eventually
eco-compatibility
selected
water as the
was mediumselected
eventually of choice,asresulting
the mediumin an optimized
of choice, protocol
resultingthat
in required
an optimizedthe use of 10 mol
protocol %
that
of supported catalyst ◦
required the use of 10 at
mol60 %Coffor 12 h. Under
supported theseatconditions,
catalyst 60 °C for 12a range
h. Underof protected glycosylaazides
these conditions, range
were coupledglycosyl
of protected with different
azidesalkynes, to provide
were coupled withthe corresponding
different alkynes,triazoles
to provide in good
the isolated yields
corresponding
(84%–94%).
triazoles in good isolated yields (84%–94%).

Scheme
Scheme 10.
10. Preparation
Preparation of
of Cu
Cu nanoparticles on cellulose,
nanoparticles on cellulose, 18.
18.

Because the cellulosic material and the triazole products were all poorly soluble in water,
recovery of the catalyst required solvent extraction with AcOEt of the residue obtained by filtering
the reaction mixture. Even if no apparent loss of supported system was noted at this stage, reuse of
the material across five CuAAC cycles caused an evident decrease of product yield (93% → 84%). In
consideration of the minute amounts of found copper into the filtrate (0.3–1.9 ppm), leaching
Molecules 2016, 21, 1174 11 of 43

Because the cellulosic material and the triazole products were all poorly soluble in water, recovery
of the catalyst required solvent extraction with AcOEt of the residue obtained by filtering the reaction
mixture. Even if no apparent loss of supported system was noted at this stage, reuse of the material
across five CuAAC cycles caused an evident decrease of product yield (93% → 84%). In consideration
of the minute amounts of found copper into the filtrate (0.3–1.9 ppm), leaching phenomena were
concluded to be irrelevant in this regard. On the contrary, the origin of the problem was tentatively
related to oxidation phenomena, as suggested also by the observation of new peaks at 933.28 and
934.88 eV in the XPS spectrum of the spent catalyst, attributed to Cu(I) and Cu(II) species.

2.5. Oxides and Other Inorganic Supports

Although details of the preparation and structure are not entirely clear, Agalave et al. reported
the use of CuI on bare neutral alumina as a cost-effective supported CuAAC catalyst [131].
The material was used in the reactions of activated halides (Scheme 2a) or a few preformed azides
(Scheme 1), in water or DMF-water (4:1) with microwave (MW) or ultrasound (US) irradiation.
The former conditions (MW) led to the fastest conversion rate and furnished good yields in 6–13 min,
even in the case of triazole products with relatively complex structure (70%–98%). Reuse of the
recovered catalyst in the course of eight reaction cycles displayed a progressive decrease of efficiency
(approximate 98% → 89% yield), accompanied by some reduction of the copper content of the material
(4.2 wt % → 3.8 wt %).
KIT-5 mesoporous silica modified with aminopropyl groups was employed by Mirsafaei et al. for
supporting CuI nanoclusters [83]. In spite of the fact that the aminated support was simply stirred at
r.t. in a solution of CuI in MeCN or DMF, XRD measurements identified the presence of crystalline
CuI (Marshite structure, estimated size 12–40 nm) in the resulting materials. The usefulness of the
supported catalyst in CuAAC was assessed in the three-component process with activated alkyl
halides (Scheme 2a). Good yields were generally obtained in refluxing water, in some cases after very
short reaction time (69%–95% in 15–150 min). In addition, the recovered material could be used in
6 consecutive cycles with just a minor decrease of product yield (approximate 96% → 91%) and an
unspecified small variation of the copper content.
Reduction of Fehling solution with glucose in boiling water, in the presence of various insoluble
materials (silica gel, hydroxyapatite, cellulose, basic alumina), was used by Gupta et al. for preparing
supported Cu2 O nanoparticles [132]. Amongst the systems examined, that based on silica gel
showed maximum activity in the three-component reaction (Scheme 2a) between phenylacetylene,
benzyl chloride, and sodium azide. The reaction was carried out with a relatively high catalyst
loading (5 mol %), preferentially in water at r.t. Under these conditions very good yields (91%–97%)
were obtained in reasonable time (2–8 h), also on switching to the use of less reactive alkyl halides
(e.g., n-butyl chloride). Reuse of the catalyst resulted in only slight reduction of product yield in the
course of 5 cycles (96% → 92%).
Albadi et al. employed a CuO/CeO2 nanocomposite (approximate 5 wt % Cu) for performing
three-components reactions with activated bromides (Scheme 2a) and Amberlite-supported azide [133].
The latter was selected with the intent of reducing the environmental impact of the process and to
avoid handling toxic NaN3 , at least in the CuAAC step. Optimization of the conditions revealed
that the rate of CuAAC was maximum in refluxing ethanol, where different triazole products were
obtained in good yield within 45–120 min (88%–92%). Interestingly, the CuO-CeO2 nanocomposite
and the resin were recovered together by filtration and the latter was restored in the azide form by
stirring with aqueous NaN3 . With this procedure, the attainment of nearly unchanged yields in the
course of five reaction cycles (91% → 88%) required a slight increase of the reaction time, from 65 min
to 75 min.
The same group prepared CuO/ZnO nanocomposites by co-precipitation of the metal nitrates
with aqueous NaHCO3 [134]. The use of the material in three-component CuAAC reactions of benzyl
halides (Scheme 2a) provided best results in boiling water and with a high loading of the catalyst
Molecules 2016, 21, 1174 12 of 43

(89%–92% yield in 15–65 min with approximate 17 mol % Cu). Also in this case, reuse of the recovered
solid led to an evident decrease of catalytic activity after just five consecutive reaction cycles (92% yield
in 20 min → 88% yield in 32 min).
Very recently, Rad et al. described the CuAAC preparation of β-hydroxyalkyltriazoles, containing
carbazolemethyl side chains, by the use of copper-doped silica cuprous sulfate [135]. Contrarily to
previous work by the same group [136], no recycling of the catalyst was reported in this example of
application to the synthesis of bioactive compounds.

2.6. Magnetically Recoverable Systems

The use of nano-sized super-paramagnetic supports offers the opportunity of catalyst recovery by
the use of an external magnet. In principle, this technique can be more advantageous than filtration or
centrifugation, even at scale, thus justifying the interest towards the approach in last decade [137,138].
Hence, irrespective of the fact that many of these materials embed additional organic or inorganic
components, recent advances with nano-structured copper catalysts that can benefit from such a
specificity recovery mechanism are discusses separately in the present section.
Magnetic Cu-Ni nano-alloy particles were obtained by Biswas et al. through reduction of nickel
acetate and copper acetate with hydrazine [139]. The preparation (Scheme 11a) was carried out in
the presence of PEG or poly(4-vinylphenol) (PVPh) as a polymer stabilizer, to give well dispersible
organic-inorganic hybrid materials 19. TEM and XPS analyses showed the presence of spherical
alloy nanoparticles containing a Cu(I) surface layer and assembled in chain-like structures through
the interaction of their magnetic dipoles. Benchmark runs (Scheme 1) between benzyl azide and
phenylacetylene were carried out at r.t. in water or DMF, with an amount of nano-alloy corresponding
to about 2 mol % of copper. Under these conditions, the PEG-containing catalyst 19 was found to be
equally effective in both reaction media.
By contrast, the PVPh-stabilized one proved significantly more active in DMF than in water,
a difference attributed to the collapsed state of the less polar PVPh coating in the latter solvent.
In any case, with the proper choice of reaction conditions either catalytic system provided acceptable
results in CuAAC reactions involving other low-molecular weight reactants (56%–82% yield),
a propargylated imidazolium ionic liquid, or azide-terminated substrates containing a tripeptide
or a poly(methyl methacrylate) chain. Recovery of the catalyst by magnetic separation allowed the
use of 19 (PEG) in three consecutive benchmark runs, albeit with reduction of the triazole yield
(96% → 87%). Because the XPS analysis of the recovered material showed some increase of Cu(I) peaks
but not of those of Cu(II), this trend does not appear to be related to severe oxidation of the nano-alloy
surface. On the contrary, it might be connected with particle aggregation phenomena, evidenced by
TEM analysis of the spent catalyst.
A tris-metallic system, entailing Cu(0) nanoparticles on glutamate-coated NiFe2 O4 (Scheme 11b),
was prepared by Lu et al. by sequentially loading the super-paramagnetic core nano-sheets with the
amino acid ligand and Cu(OAc)2 , followed by reduction with N2 H4 and NaBH4 [140]. The resulting
material 20 was examined as a catalyst in multi-component CuAAC reactions in water, involving
activated halides, epoxides, or aromatic boronic acids (Scheme 2a,b,d, respectively). In the presence of
the composite catalyst (1 mol %–5 mol % Cu) the reaction proceeded in relatively short times at r.t.
(1.5–8.5 h), allowing the preparation of a rather large library of triazole products in fair to excellent
yields (50%–95%). Recovery with an external magnet and washing made it possible to reuse the
supported catalyst in ten successive cycles, with moderate decrease of the product yield (95% → 88%).
material 20 was examined as a catalyst in multi-component CuAAC reactions in water, involving
activated halides, epoxides, or aromatic boronic acids (Scheme 2a,b,d, respectively). In the presence
of the composite catalyst (1 mol %–5 mol % Cu) the reaction proceeded in relatively short times at r.t.
(1.5–8.5 h), allowing the preparation of a rather large library of triazole products in fair to excellent
yields (50%–95%).
Molecules 2016, 21, 1174 Recovery with an external magnet and washing made it possible to reuse 13 ofthe
43
supported catalyst in ten successive cycles, with moderate decrease of the product yield (95% → 88%).

Scheme 11.
Scheme 11. Preparation
Preparation of
of CuNPs
CuNPs on
on super-paramagnetic supports with
super-paramagnetic supports with PEG
PEG or
or PVPh
PVPh (a);
(a), LL-glutamic
-glutamic
acid (b);
acid (b), chitosan
chitosan (c);
(c), and
and EDACell
EDACell (d)
(d) stabilizing
stabilizing agents.
agents.

CuAAC reactions promoted by Cu(0) nanoparticles on chitosan (CS)-magnetite have been

described by Chetia et al. [141]. The nanocomposite was prepared by a three-step process (Scheme 11c),
that began with the NaOH induced co-precipitation of CS, Fe(II), and Fe(III) from an AcOH solution.
Characterization of the resulting material 21 by an array of techniques led to the conclusion that
copper was present in the crystalline elemental form, as 10 nm spherical nanoparticles. Despite the fact
that these dimensions do not appear much different from those estimated for the Fe2 O3 -CS support
(10–15 nm), a uniform dispersion of copper on the surface of the nanocomposite was inferred at the
SEM resolution level. Two-components CuAAC runs (Scheme 1) were preferentially carried out in
CH2 Cl2 , with 1.5 mol % of the catalyst, to afford good to excellent yields in 12 h at r.t. (77%–96%).
A high yield was recorded also in the reaction of dimethyl acetylenedicarboxylate with phenyl azide
(96% in 12 h), from which it was concluded that 21 was effective even for internal alkynes. In this
respect it should be noted, however, that acetylenedicarboxylate esters are known to undergo the
thermal Huisgen 1,3-dipolar cycloaddition reaction at rate not dissimilar to that demonstrated in
the study under exam, or even faster [142]. On this ground, the catalytic role of the nanocomposite
material in the specific reaction of such an internal acetylene appears therefore far less than obvious.
Magnetic separation of the catalyst beads allowed their recycling with just a moderate reduction of
efficiency along four consecutive runs (96% → 91% yield). The occurrence of aggregation phenomena,
as a possible cause of performance loss, and of catalytic activity in solution, due to leached specie,
Molecules 2016, 21, 1174 14 of 43

were examined and ruled out by TEM microscopy and through a standard “filtration experiment”
(Maitlis0 test) [143], respectively.
An organic-inorganic hybrid material (Scheme 11d), consisting in a layer of ethylenediamine-
functionalized cellulose (EDACell) adsorbed onto silica gel-coated Fe3 O4 particles, was recently
employed by Bhardwaj et al. as a novel support for CuAAC catalytic systems [144]. Reduction with
NaBH4 of the material loaded with CuCl2 gave a dark solid 22 that, according to XRD and electron
microscopy, contained metallic copper clusters uniformly dispersed on the surface of around one
order of magnitude larger core-shell magnetic nanoparticles. The activity of the supported system was
probed in the CuAAC reaction between acetylenes and aromatic azides, with the latter formed in situ
by substitution with NaN3 on the product of diazotisation of the corresponding aniline in HCl-H2 O
(1:1) (Scheme 2c). An initial optimization stage demonstrated good performance at r.t. with as little
as 0.25 mol % of the copper catalyst. Therefore, the same conditions were applied to the CuAAC of
different substrates, to afford uniformly good results in relatively short reaction time (92%–95% yield
in 3.5–5 h). Despite the use of a strongly acidic reaction medium, filtration tests did not reveal any
significant catalytic activity in the solution. In addition, the copper content of the solid recovered by
magnetic separation proved almost identical to that of the pristine material and its recycling led to
almost unchanged results in the course of six consecutive runs (96% → 93% yield).
In addition to hybrid (organic-inorganic) magnetic catalytic systems above, some progress
with purely inorganic materials were reported also. These examples, mentioned here for the
sake of completeness, include the use of commercially available copper ferrite (CuFe2 O4 ) and
Fe3 O4 @TiO2 /Cu2 O nanocomposites [145,146].

2.7. Polymer-Stabilized Soluble Systems and Quasi-Homogeneous CuNPs

Leaf extracts from Otostegia persica and Ginkgo biloba were recently examined by
Nasrollahzadeh et al. as green reducing agents in the preparation of unsupported CuNPs [147,148].
These systems showed reasonable catalytic activity and possibility of reuse in three-component CuAAC
reactions. Similarly to other quasi-homogeneous nanostructured materials reported in the last two
years, i.e., lanthanum-loaded CuO nanoparticles [149], porous copper [99], copper salts reduced in
ethylene glycol [101], and Cu2 O nanocubes [96], these systems do not appear however to involve any
additional polymeric component. Therefore, according to the scope of this review they will not be
discussed in further detail herein.
On the contrary, Chahdoura et al. prepared polymer-stabilized Cu2 O nanoparticles, by dihydrogen
reduction of21,
Molecules 2016, copper
1174 acetate in glycerol in the presence of PVP (Scheme 12a) [95]. As confirmed 14 ofby
41
TEM, XRD and IR analyses, the use of glycerol as the solvent, H2 as the reducing agent, and PVP as
the
andstabilizer
PVP as the turned out to
stabilizer be allout
turned important
to be allfor obtaining
important foroxidation-stable Cu2 O clusters
obtaining oxidation-stable Cu2Odevoid of
clusters
Cu(0)
devoidorofCu(II)
Cu(0)phases.
or Cu(II) phases.

Scheme
Scheme 12.
12. Preparation
Preparation of
of soluble
soluble and
and quasi-homogeneous CuAAC catalysts
quasi-homogeneous CuAAC catalysts 23
23 (a)
(a) and
and 24
24 (b).
(b).

The synthesized nanoparticles 23 proved moderately active in two- and three-components

CuAAC reactions (Scheme 1 and Scheme 2a). The catalytic runs were carried out with 2.5 mol % Cu2O at
100 °C for 2 h to give an array of different triazoles in high yield (91%–98%) and with complete
1,4-regioselectivity. In this regard it is worth noting that, even if the thermal reaction proceeded
appreciably in neat glycerol at 100 °C (40% yield in 2 h), as expected both regioisomeric products 1
Molecules 2016, 21, 1174 15 of 43
Scheme 12. Preparation of soluble and quasi-homogeneous CuAAC catalysts 23 (a) and 24 (b).

The synthesized nanoparticles 23 proved moderately active in two- two- and

and three-components
three-components
CuAAC reactions
reactions(Scheme
(Schemes 1 and 2a). The catalytic runs were carried
1 and Scheme 2a). The catalytic runs were carried out out with 2.5mol
2.5 mol%%Cu Cu
2O2 O
at
at ◦
100100 C for
°C for 2h2 htotogive
giveananarray
arrayofofdifferent
differenttriazoles
triazoles in
in high
high yield
yield (91%–98%)
(91%–98%) and with complete
complete
1,4-regioselectivity.
1,4-regioselectivity. In In this regard it is worth noting that, even if the thermalthermal reaction
reaction proceeded
proceeded
appreciably in neat glycerol at 100 ◦°C C (40% yield in 2 h), as expected
expected both regioisomeric products 1
and 2 (see Scheme 1) formed in substantial amounts (4:1 ratio) in the absence of the copper catalyst. catalyst.
Combination
Combination withwith Ullmann
Ullmann chemistry
chemistry was
was also
also feasible and provided
provided a tandem process for preparing
arylaminoethyl-functionalized triazoles (Scheme
arylaminoethyl-functionalized triazoles (Scheme 13). The The separation
separation of of the products in standard
standard
CuAAC runs was was effected
effected by
by extraction
extraction with
with CHCH22Cl22 or pentane of the
the catalyst-containing
catalyst-containing glycerol
layer. Afterwards,
Afterwards, the the glycerol
glycerol phase
phase was
was heated under vacuum for removing the volatiles and
employed in a new experiment. With this procedure ten cycles of the reaction between benzyl azide
and
and phenylacetylene
phenylacetylenewere werecarried out,out,
carried obtaining the corresponding
obtaining triazoletriazole
the corresponding productproduct
in nearlyinconstant
nearly
yield (94%–97%).
constant yield (94%–97%).

Scheme
Scheme 13.
13. Tandem CuAAC-Ullmann three-component
Tandem CuAAC-Ullmann three-component coupling
coupling promoted
promoted by
by 23.
23.

Polyoxometalates (POMs)
Polyoxometalates (POMs) and and heteropolyacids
heteropolyacids (HPAs)
(HPAs) are are ionic
ionic compounds
compounds containing
containing cations
cations
and large
and large polyanion
polyanionclusters
clusters made,
made,e.g.,e.g.,
by theby condensation
the condensation of MOx of polyhedra
MOx polyhedra[150,151].[150,151].
Besides
having catalytic activity on their own, these materials find use as supports for other
Besides having catalytic activity on their own, these materials find use as supports for other catalytic catalytic systems
and for the
systems andstabilization of metal of
for the stabilization nanoparticles. An example
metal nanoparticles. in this latter
An example sense
in this was
latter reported
sense recently
was reported
by AminibyetAmini
recently al. (Scheme 12b), who
et al. (Scheme prepared
12b), Cu2O/CuO
who prepared Cu2nanoparticles on a molybdenum
O/CuO nanoparticles POM by
on a molybdenum
treating a suspension of (NH 4)12(Mo36(NO)4O108(H2O)16) in AcOEt with Cu(NO3)2 [152]. With this
POM by treating a suspension of (NH4 )12 (Mo36 (NO)4 O108 (H2 O)16 ) in AcOEt with Cu(NO3 )2 [152].
procedure,
With the occurrence
this procedure, of the Cu(I)
the occurrence compound
of the in the resulting
Cu(I) compound material 24
in the resulting was supposed
material to derive
24 was supposed
from
to direct
derive fromreduction of the Cu(II)
direct reduction salt atsalt
of the Cu(II) theatPOM surface.
the POM Three-components
surface. Three-components CuAAC
CuAAC runs of
runs
activate halides (Scheme 2a) were typically performed in water, where the resulting
of activate halides (Scheme 2a) were typically performed in water, where the resulting nanocomposite nanocomposite
was soluble.
was soluble. InIn the
theevent,
event,this
thispermitted
permittedthe therecovery
recovery ofof the
thecatalytic system
catalytic system in the aqueous
in the aqueousphase, by
phase,
filtering off the insoluble triazole product at the end of the experiment. Despite
by filtering off the insoluble triazole product at the end of the experiment. Despite the rather high the rather high
catalyst loading
catalyst loading andand reaction
reaction temperature
temperature adopted
adopted in in these
these runs
runs (5 mol %
(5 mol % and
and 70
70 ◦°C, respectively),
C, respectively),
recycling of the POM solution led, however, to rapid degradation of catalytic performance already
after a few reaction cycles (approximate 88% → 44% yield in three runs).

3. Discrete Cu(I/II) Complexes

Well-defined Cu(I) salts and complexes with nitrogen, phosphorous, oxygen and carbon-based
ligands have played a prominent role in the development of new effective systems for CuAAC [64,153].
Because properly designed ligands, firmly anchored onto an insoluble support, might prevent metal
ions to leach from the material, it is not surprising that immobilized catalytic systems of this kind,
as well as analogous Cu(II) pre-catalysts, were actively investigated [88,89].

3.1. Cross-Linked Synthetic Organic Polymer Supports

After the introduction in 2006 of CuI on Amberlyst A-21 by Girard et al. [154], this supported
Cu(I) system has been successfully employed as a recoverable catalyst in CuAAC reactions carried
out under batch or continuous-flow conditions (for a discussion of previous work, see refs. [88,89]).
Occasional observations of C-5 iodinated triazole by-products in the cycloaddition process catalyzed
prevent metal ions to leach from the material, it is not surprising that immobilized catalytic systems
of this kind, as well as analogous Cu(II) pre-catalysts, were actively investigated [88,89].

3.1. Cross-Linked Synthetic Organic Polymer Supports

After
Molecules the
2016, 21, introduction
1174 in 2006 of CuI on Amberlyst A-21 by Girard et al. [154], this supported 16 of 43
Cu(I) system has been successfully employed as a recoverable catalyst in CuAAC reactions carried
out under batch or continuous-flow conditions (for a discussion of previous work, see refs. [88,89]).
by A-21/CuI
Occasional led the same
observations group
of C-5 to investigate
iodinated the possibleincauses
triazole by-products of such a side-reaction
the cycloaddition process catalyzed[155].
After examining various factors, potential mistakes were identified in the preparation
by A-21/CuI led the same group to investigate the possible causes of such a side-reaction [155]. After of the supported
catalyst
examining andvarious
in the conduct
factors,of CuAACmistakes
potential runs, which wereresult in the obtainment
identified of substantial
in the preparation of theamounts
supported of
iodinated
catalyst and triazoles (up to 12
in the conduct ofmol
CuAAC%). In turn,which
runs, this allowed
result into establish
the obtainment optimized conditions,
of substantial whose
amounts of
adoption is expected to reduce the formation of by-products below the 0.5
iodinated triazoles (up to 12 mol %). In turn, this allowed to establish optimized conditions, whose mol %–1 mol % level.
A ionically
adoption is expected to reduce N-heterocyclic
immobilized the formation ofcarbene (NHC)-Cu(I)
by-products below the catalyst
0.5 mol25 (Scheme
%–1 14a) was
mol % level.
prepared by Velazquez et al. by suspending the gel-type, quaternary
A ionically immobilized N-heterocyclic carbene (NHC)-Cu(I) catalyst 25 (Scheme 14a) was ammonium resin Amberlyst
IRA-402
preparedinbyanVelazquez
aqueous solution
et al. by of the metal the
suspending complex [67].quaternary
gel-type, After washing with water,
ammonium resin the loaded
Amberlyst
resin
IRA-402(2 mol
in an%aqueous
of Cu) solution
was tested in metal
of the three-component
complex [67].CuAAC reactionwith
After washing between
water,benzyl bromide,
the loaded resin
sodium azide, and phenylacetylene in water (Scheme 2a). Possibly
(2 mol % of Cu) was tested in three-component CuAAC reaction between benzyl bromide, sodium due to poor solubility of the
reactants
azide, andinphenylacetylene
water, and thence hindered
in water (Scheme access toPossibly
2a). the catalytic
due tosites,
poormechanical
solubility ofstirring resulting
the reactants in
ineffective under hindered
water, and thence these conditions.
access to the The problem
catalytic was
sites, circumvented
mechanical stirring byresulting
resorting to ultrasound
ineffective under
irradiation, whichThe
these conditions. permitted
problem to was
attaincircumvented
full conversion by in five hours
resorting at r.t. Remarkably,
to ultrasound irradiation, thewhich
same
conditions
permitted to worked
attain fine also for the in
full conversion rarely
five investigated three-component
hours at r.t. Remarkably, reaction
the same involving
conditions acetylene
worked fine
as the dipolarophile partner. Recycling of the resin was studied in the former
also for the rarely investigated three-component reaction involving acetylene as the dipolarophile process and involved
extraction of the product
partner. Recycling with CH
of the resin was2 Cl 2 , removal
studied in theofformer
the water phase
process andbyinvolved
syringe, extraction
and subsequent
of the
addition
product withof fresh
CHreactants
2Cl2, removaland solvent.
of the water By carrying
phase by outsyringe,
all the steps under an argon
and subsequent addition atmosphere,
of fresh
four consecutive
reactants runsBy
and solvent. could be performed,
carrying albeitunder
out all the steps with anan argon
appreciable
atmosphere,reduction
four of product yield
consecutive runs
could→
(99% performed, albeit with an appreciable reduction of product yield (99% → 75%).
be75%).

Scheme 14.
Scheme 14. Preparation
Preparation of
of NHC-Cu(I/II)
NHC-Cu(I/II) complexes
complexes on
on insoluble
insoluble organic
organic supports,
supports, 25
25 (a)
(a) and
and 26
26 (b).
(b).

A further attempt to reuse the supported complex was reported to lead to a dramatic,
yet unspecified, further decrease. Although some details of the measurements are not entirely
clear, XRF analysis suggested that leaching of Cu(I) species into the solution might be the cause
of the problem.
Another instance of carbene-stabilized CuAAC catalyst on a resin support was reported very
recently by Jia et al. [156]. The first step of the preparation route (Scheme 14b) consisted in the
covalent immobilization of 1,3-dibenzylbenzimidazolium chloride into a hyper-crosslinked matrix,
obtained by “knitting” the ligand precursor with benzene, 1,2-dichloroethane, and methylal under
Friedel-Crafts conditions. Loading the resulting, highly porous insoluble material with different
amounts of CuCl and t-BuONa led to the corresponding supported metal-carbene complexes 26.
Despite the fact that XPS analysis revealed the presence of Cu(II), instead of Cu(I), all the resins could
 analysis suggested that leaching of Cu(I) species into the solution might be the cause of the problem.
Another instance of carbene-stabilized CuAAC catalyst on a resin support was reported very
recently by Jia et al. [156]. The first step of the preparation route (Scheme 14b) consisted in the
covalent immobilization of 1,3-dibenzylbenzimidazolium chloride into a hyper-crosslinked matrix,
obtained by “knitting” the ligand precursor with benzene, 1,2-dichloroethane, and methylal under
Molecules 2016, 21, 1174 17 of 43
Friedel-Crafts conditions. Loading the resulting, highly porous insoluble material with different
amounts of CuCl and t-BuONa led to the corresponding supported metal-carbene complexes 26.
Despitethe
catalyze thethree-components
fact that XPS analysis revealed
CuAAC the presence
reaction of Cu(II),
of benzyl halides instead
in EtOHof Cu(I),
(Schemeall the resins
2a). Bestcould
results
catalyze
were the three-components
provided CuAAC
by the material with thereaction of benzyl
largest metal halides
content in EtOH
that, at the (Scheme
relatively 2a).
lowBest results of
loading
were
0.45 molprovided by the material
% Cu, afforded with the
the expected largestproducts
triazole metal content
in goodthat,toatexcellent
the relatively
yieldslow loading
within 8 hof 80 ◦ C
at0.45
mol % Cu, afforded the expected triazole products in good to excellent yields
(61%–99%). Separation of the resin by centrifugation made it possible to use the supported catalyst within 8 h at 80 °C in
six(61%–99%).
consecutive Separation of the
cycles with resin by centrifugation
essentially made(98%
unchanged results it possible
→ 96% to yield).
use the supported catalyst in
sixCommercial
consecutive cycles with essentially unchanged results (98% → 96% yield).
poly(4-vinylpyridine-co-divinylbenzene) was employed by Zarchi and Nazem for
Commercial poly(4-vinylpyridine-co-divinylbenzene) was employed by Zarchi and Nazem for
preparing the CuAAC pre-catalyst 27 (Figure 3), through absorption of aqueous CuSO4 on the gel-type
preparing the CuAAC pre-catalyst 27 (Figure 3), through absorption of aqueous CuSO4 on the
resin [157]. After in situ reduction of the blue polymer with sodium ascorbate, the material was
gel-type resin [157]. After in situ reduction of the blue polymer with sodium ascorbate, the material
tested as a catalyst in three-component CuAAC of halides (Scheme 2a). Following an initial solvent
was tested as a catalyst in three-component CuAAC of halides (Scheme 2a). Following an initial
screening, the reactions were performed in biphasic t-BuOH-H2 O (1:1) medium to give various triazole
solvent screening, the reactions were performed in biphasic t-BuOH-H2O (1:1) medium to give
products in fair to excellent isolated yields and short reaction time (69%–96% in 30–135 min). In this
various triazole products in fair to excellent isolated yields and short reaction time (69%–96% in
respect
30–135 it min).
must Inbethis
noted, however,
respect it mustthat heating
be noted, to 70 ◦ Cthat
however, washeating
required and,
to 70 °C more important,
was required and,amore
higher
than
important, a higher than stoichiometric catalyst amounts was applied (225 mol % Cu, on the basisdata).
stoichiometric catalyst amounts was applied (225 mol % Cu, on the basis of published of
Even
published data). Even though the polymeric material could be used in six reaction cycles with slightthe
though the polymeric material could be used in six reaction cycles with slight reduction of
triazole yieldof(91%
reduction → 87%),yield
the triazole its catalytic
(91% →performance appears
87%), its catalytic therefore somewhat
performance less impressive
appears therefore somewhat than
forless
many other recoverable
impressive CuAAC
than for many othersystems reported
recoverable CuAAC to date.
systems reported to date.

Figure3.3. CuAAC
Figure catalysts
CuAAC and pre-catalysts
catalysts 27–30, on insoluble
and pre-catalysts 27–30, organic supportsorganic
on insoluble from commercial
supportsresins.
from
commercial resins.
Following their seminal paper on CuAAC with copper catalysts on DIAION resins [158,159],
more recently Kitamura et al. investigated the use of the highly porous styrene-divinylbenzene (DVB)
Following their seminal paper on CuAAC with copper catalysts on DIAION resins [158,159],
material 28, under solventless conditions [160]. Two-component catalytic runs (Scheme 1) were
more recently Kitamura et al. investigated the use of the highly porous styrene-divinylbenzene (DVB)
carried out at r.t. under Ar, with 1 mol % of the catalyst and the addition of substoichiometric
material 28, under solventless conditions [160]. Two-component catalytic runs (Scheme 1) were carried
amounts of Et3N to the neat reactants. Under these conditions, CuAAC between different azides and
out at r.t. under Ar, with 1 mol % of the catalyst and the addition of substoichiometric amounts of Et3 N
alkynes led to largely variable product yields after 4 h (47%–100%). The observation that worst results
to were
the neat reactants.
obtained Under these conditions,
with dipolarophiles CuAAC between
devoid of Lewis-basic different
heteroatoms azides
(N, O) in theand alkynes
proximity of led
the to
largely variable
C-C triple product
bond, yields
led the after 4toh conclude
Authors (47%–100%).
thatThe observation thatparticipation
neighboring-group worst resultsmay
wereplay
obtained
an
with dipolarophiles devoid of Lewis-basic heteroatoms (N, O) in the proximity of the C-C triple bond,
led the Authors to conclude that neighboring-group participation may play an important role in the
system under exam. Due to the fact that many triazoles are solid, isolation of the product required
dilution with water and AcOEt before removal of the polymeric material by filtration. At variance
with previous results with 28 in toluene [159], reuse of the resin under neat conditions showed a
marked decrease of activity over four cycles (100% → 27% triazole yield). As expected, given the lack
of strongly coordinating groups in HP-20, the origin of the problem was traced back to metal leaching
which was indeed found to occur to a significant extent (19%) even in a single run. Moreover, assay of
the separated liquid layers from product isolation (vide supra) revealed more than twelve-fold higher
metal concentration in the AcOEt phase than in the aqueous one. Although copper contamination in
Molecules 2016, 21, 1174 18 of 43

the crude triazoles was not explicitly reported, an estimation of around 400 ppm (dry weight basis)
can be made on the basis of published data.
A Cu(I) chelate catalyst 29, immobilized on polystyrene resin, was described by Movassagh and
Rezaei [161]. The supported complex was obtained by alkylating the diazacrown macrocyclic ether
Kryptofix® 22 with a Merrifield resin and then charging the resulting polymeric material with CuI in
refluxing EtOH. Perhaps because of limited solubility of the copper salt in EtOH or scarce compatibility
of the polystyrene backbone with the protic medium, the metal loading attained in the last step was
considerably lower than the cryptand content of the resin. Nevertheless, 29 displayed appreciable
activity in two- and three-components CuAAC reactions, especially when water was used as the
reaction medium. Under air and at 0.3 mol % catalyst loading, several azides were added to acetylenic
substrates (Scheme 1) to provide the corresponding triazole products in good to excellent yield after
10 h at r.t. (78%–99%). Analogous three-component CuAAC runs (Scheme 2a) with alkyl chlorides,
bromides, or iodides and 0.6 mol % of supported complex were slower (56%–99% yield in 15–21 h
at r.t.). Given also the structure of some of the halides used in the screening (e.g., cyclohexyl bromide
and 1-adamantyl bromide), these variations are likely to reflect more the difficulty of the latter to be
converted into the corresponding azide intermediate than actual differences in catalyst performance
under alternative reaction conditions. Recovery of the supported system by filtration, washing, and
drying with an air stream made it possible four consecutive reaction cycles, with a drop of product
yield more evident under three-component conditions (99% → 71%) than under two-components ones
(approximate 99% → 87%).
In a multi-step solid-phase synthesis approach, Tavassoli et al. pursued the preparation on
Merrifield resin of a dicationic ligand provided with 1,2-dithioether chelating site [162]. Stirring of the
material with Cu(OTf)2 in MeOH led to the corresponding Cu(II) complex 30, characterized inter alia
by cyclic voltammetry on glassy carbon electrode. Notwithstanding the presence of iodide in the
material, addition of sodium ascorbate turned out to be essential for obtaining a catalytically active
system for CuAAC.
In the presence of the reducing agent and with 0.2 mol % of 30 in PEG400 at 65 ◦ C, quite fast
reaction kinetics (87%–99% yield in 10–25 min) were observed in three-components CuAAC runs
with mono-functional activated bromides (Scheme 2a). By contrast, somewhat reduced yields were
recorded in the reaction of bis(bromomethyl)benzene starting materials, even after longer reaction
time (68%–88% in 45–60 min). Despite the observation of some copper leaching in the first run (<2%),
the supported system displayed a reasonable recyclability, with just a modest drop of product yield
after seven consecutive cycles (approximate 99% → 94%).
A 1,10-phenanthroline-CuI catalytic system on Merrifield resin, 31, was reported by Wu et al. for
the click-polymerization of di-functional azide and alkyne reagents (Scheme 15) [163]. Similarly to
previous work from the same group [79], the solubility in THF of the resulting linear polymers allowed
the separation of the supported catalyst and the obtainment of polytriazole materials containing
relatively low amounts of copper (190–410 ppm). At variance with the precedent study, however,
in this case the process was found to proceed only in the presence of air and no recycling of the
supported catalyst was attempted.
Molecules 2016, 21, 1174 19 of 43
Molecules
Molecules 2016,
2016, 21,
21, 1174
1174 18
18 of
of 41
41

Scheme 15. Click-polymerization

Scheme 15. Click-polymerization of
of di-functional monomers in
di-functional monomers in the
the presence
presence of
of 31.
31.

In addition
In addition toto the
the systems
systems above,
systems above, obtained
above, obtained from commercially
obtained from commercially available resins,
commercially available resins, examples
examples werewere
described also of materials prepared
materials prepared
described also of materials prepared by by radical
by radical copolymerization
radical copolymerization
copolymerization of of functional
of functional monomers.
functional monomers. For
monomers. For the the
purpose of
purpose of increasing
increasing the the loading
loading capacity
capacity of of GO
GO and
and its
its effectiveness
effectiveness in in retaining
retaining copper
copper ions,
ions,
Pourjavadi et
Pourjavadi et al. al. resorted
al. resorted
resorted to to the
to the entrapment
the entrapment
entrapment of of the carbonaceous
of the carbonaceous support into a
carbonaceous support into a cross-linkedcross-linked
cross-linked
poly(vinyl imidazole)
poly(vinyl imidazole) matrix
matrix (Pim)
(Pim) [164].
[164]. With this aim,
With this aim, N-vinylimidazole
aim, N-vinylimidazole
N-vinylimidazole and and the
the corresponding
corresponding
corresponding
1,4-bis-(imidazolium)butane di-functional
1,4-bis-(imidazolium)butane di-functional
1,4-bis-(imidazolium)butane monomer
di-functional monomer were radically polymerized
polymerized in solution, in
monomer were radically polymerized in solution, the
in the
presence of
presence of GOGO as
GO as a filler
as aafiller (Scheme
filler(Scheme 16a).
(Scheme16a). Interestingly,
16a).Interestingly,
Interestingly,while
while
whileSEM
SEM SEMexamination
examination
examination of Pim
of Pim devoid
devoid
of Pim devoidof GO
of GO
of
showed
showed
GO aa smooth
showed smooth
a smooth surface,
surface, the
thethe
surface, nanocomposite
nanocomposite
nanocomposite was
was
wasfound
foundto
found totopossess
possessaaa corrugated
possess corrugated morphology,
corrugated morphology,
attributed to
attributed to the
the embedded
embedded GO GO sheets.
sheets. Soaking
Soaking thethe material
material in in aqueous
aqueous
aqueous CuSOCuSO
CuSO444 led
led to load aa
to load
considerable amount of metal salt, corresponding to about one
considerable amount of metal salt, corresponding to about one half of the imidazolehalf of the imidazole units content
imidazole units content
estimated
estimated for
estimated for the
forthe material.
thematerial.
material. A preliminary
A preliminary
A preliminary optimization
optimization
optimization stage
stage stage for
for thefor the three-component
CuAAC CuAAC
the three-component
three-component CuAAC
reaction
reaction
reaction
of of phenylacetylene,
of phenylacetylene,
phenylacetylene, benzyl
benzyl bromide, bromide,
benzyl bromide,
and NaN and
and NaN 3 suggested the use of 1 mol % of the supported
NaN3 suggested
3 suggested the use the
of 1use
molof%1 of
mol %supported
the of the supported
Cu(II)
Cu(II)
Cu(II) complex
complex 32 and32
complex 10and
32 mol10
and % mol
10 mol %
% of
of sodiumof sodium
sodium ascorbate,
ascorbate,
ascorbate, in waterin
inatwater at
at 50
50 ◦ C.
water 50 °C.
°C.

Scheme 16.
16. Preparation
Scheme 16. Preparation of supported
of supported Cu(I/II)
Cu(I/II) complex
supported Cu(I/II) complex 32 (a) and 33 (b) onto resins obtained by radical
Scheme Preparation of complex 32
32 (a)
(a) and
and 33
33 (b)
(b) onto
onto resins
resins obtained
obtained by
by radical
radical
copolymerization
copolymerization and
and plausible
plausible structures
structures of
of Pim
Pim and
and P(im/IL)(X).
P(im/IL)(X).
copolymerization and plausible structures of Pim and P(im/IL)(X).
Molecules 2016, 21, 1174 20 of 43

When the same experimental set-up was applied to the CuAAC of other terminal alkynes with
benzyl or alkyl chlorides or bromides (Scheme 2a), good yields were uniformly recorded in 0.5–3.5 h
(80%–96%). Remarkably, the reaction was found to proceed even with as little as 0.002 mol % of
catalysts, but in this case a significantly longer reaction time was required for completion (20 h).
Examination of leaching-related issues in the study under exam entailed a standard filtration test and
the quantification of copper in the filtrate by ICP-OES. As desirable for a highly stable supported system,
no evidence for catalytic activity in solution was gained by the former experiment, while in the latter
the metal concentration was found to be below the detection limit. Therefore, the moderate reduction
in product yield and TOF, observed in the course of eight recycle runs (approximate 99% → 92%
and 195 → 140 h−1 , respectively), was tentatively ascribed to catalyst loss during washing and
recovery procedures.
The radical copolymerization of N-vinylimidazole with 3-methacrylamidopropyl trimethyl
ammonium chloride and N,N0 -methylenebisacrylamide (Scheme 16b) was employed by
Pourjavadi et al. for preparing the cross-linked P[im/IL][X] material, provided with imidazole units
for copper complexation and ionic trimethylammonium groups for tuning the catalytic properties
by variation of the counter-ion X [165]. In fact, before charging with CuSO4 , the resin was subjected
to ion-exchange for the purpose of replacing chloride with other anions. Even though the result
might look counterintuitive, because of the presence of a large excess of azide ions, when the different
Cu(II)-loaded resins 33 were employed in three-component CuAAC runs (Scheme 2a) the activity of
the supported systems was found to depend on the nature of the counter-ion in the order: Cl− > AcO−
> Br− > BF4 − > NO3 − . Therefore, the chloride form 33 (X = Cl) was selected for being examined in
more detail. This resulted in an optimized procedure that, with the use of 0.1 mol % of the supported
system and 10 mol % of sodium ascorbate in t-BuOH-H2 O (1:3) at 55 ◦ C, provided high yields of
triazole products in 1.5–6 h (85%–99%). Remarkably, when the catalyst amount was lowered to 0.0013
mol % (130 mol ppm) a respectable 91% yield was still obtained after 18 h (TOF = 3889 h−1 ). Moreover,
under standard conditions the reuse of the material recovered by centrifugation allowed to perform
12 reaction cycles, without any appreciable reduction of product yield and turnover frequency.
A few resins and other insoluble polymers for the immobilization of CuAAC catalytic systems
were obtained also by condensation or oxidative routes. For instance, an original approach to the
preparation of a polymer-supported Cu(I) systems led Ul Islam et al. to realize polymer formation
and copper immobilization at once, by addition of CuSO4 in DMF to 2-aminobenzoic acid in water,
under open air (Scheme 17a) [166]. At SEM magnification, the resulting green precipitate 34 appeared
to consist of robust fibers, devoid of metal particles down to the TEM resolution level. Therefore,
the inference was made that the material was a complex between poly(2-aminobenzoic acid) (pABA),
from the oxidative polymerization of the amino acid precursor, and Cu(I), from the partial reduction
of the copper salt. The conclusion was strengthened by Raman, XPS and XRD analyses, with the
latter additionally showing the crystalline nature of the organic polymer. Despite the low surface area
(7.8 m2 ·g−1 ), the solid proved active in the benchmark addition of benzyl azide to phenylacetylene,
reportedly carried out with 0.01 mol % Cu in solvents of different polarity. As revealed by kinetic
measurements, the addition of Et3 N (1 equiv. with respect to the reactants) was essential in order to
improve the reaction rate and to avoid the occurrence of an initial induction period. Because H2 O-Et3 N
led to best results, this medium was selected in the subsequent investigation of substrate scope, that led
to the attainment of good to excellent yields at r.t. (84%–98% in 3–7 h) under both two-components
(Scheme 1) and three-component reaction conditions (Scheme 2a). Although limited details of the
procedure are provided, filtration of the reaction mixture and extraction of the triazole product with
EtOAc allowed the recovery of the supported catalyst and its reuse.
Molecules 2016, 21, 1174 21 of 43
Molecules 2016, 21, 1174 20 of 41

Scheme
Scheme 17. 17. Preparation
Preparation ofof supportedCu(I/II)
supported Cu(I/II) complexes
complexes34
34(a),
(a),3535(b),
(b),and
and3636
(c)(c)
onto resins
onto obtained
resins obtained
by oxidation or condensation routes and plausible structures of SNW and p[C4R-NH2].
by oxidation or condensation routes and plausible structures of SNW and p[C4R-NH2 ].

This cause to some reduction of product yield across five cycles of a benchmark reaction
This cause to some reduction of product yield across five cycles of a benchmark reaction
(98% → 83%), explained in terms of catalyst losses during the washing stage. In this context, it is
(98% → 83%),
worth explained
of note in terms
that, while ICP-MS of catalyst
analysislosses
ruled during the washing
out significant metalstage.
leachingIn this context,
in the it TEM
filtrate, is worth
of note that, while ICP-MS analysis ruled out significant metal leaching in the
examination of the catalyst after the first cycle showed the formation of rather large CuNPs (10–40 filtrate, TEM examination
of the catalyst
nm). Because after
thethe first activity
specific cycle showed the formation
of the latter of rather
is essentially unknown,largeit CuNPs
cannot be (10–40 nm).that
excluded Because
some the
specific
kind activity of thee.g.,
of sintering, latter
byisclustering
essentiallyofunknown,
Cu(I) speciesit cannot be excluded that
or over-reduction, might some kind of to
contribute sintering,
the
e.g.,observed
by clustering of Cu(I)ofspecies
deterioration catalystorperformance.
over-reduction, might contribute to the observed deterioration of
catalyst The condensation of melamine with terephthalaldehyde allowed Taskin et al. to prepare a
performance.
microporous
The condensation Schiff-base network polymer
of melamine (SNW) as a rigid allowed
with terephthalaldehyde and insoluble
Taskinyellowet al. topowder
prepare
(Scheme 17b) Schiff-base
a microporous [167]. Solid-state
network CP-MASS,
polymer 13C-NMR and FT-IR characterization of the material
(SNW) as a rigid and insoluble yellow powder
identified
(Scheme 17b)the[167].presence of aminal
Solid-state units, as13 C-NMR
CP-MASS, well as residual
and FT-IR functional groups of of
characterization thethestarting
material
compounds. This evidence prompted the Authors to depict the structure of the
identified the presence of aminal units, as well as residual functional groups of the starting compounds. network as containing
the diaminomethyl structural motif (-CH(NH-)2) instead of the expected Schiff base (-CH=N-) one.
This evidence prompted the Authors to depict the structure of the network as containing the
Prolonged stirring with CuBr in MeCN afforded the corresponding Cu(I) loaded material 35 that,
diaminomethyl structural motif (-CH(NH-)2 ) instead of the expected Schiff base (-CH=N-) one.
similarly to the bare support, was found to possess a rather large micropore surface area (306 m2·g−1
Prolonged stirring with CuBr in MeCN afforded the corresponding Cu(I) loaded material 35 that,
and 548 m2·g−1, respectively). Testing of the immobilized catalytic system in two-components CuAAC
similarly to the
reactions bare support,
(Scheme was found
1), at unspecified to possess
loading, a rather
evidenced large micropore
a relatively fast process surface
in MeCN areaat(306 m2 · g − 1
r.t., with
2 − 1
548 m ·g of ,the
andformation respectively). Testinginoffair
thetoimmobilized catalytic system in two-components
expected triazoles good yields (61%–98% in 90–300 min). This provedCuAAC true
reactions
even for a substrate, like propargyl acrylate, that can face selectivity problems in in
(Scheme 1), at unspecified loading, evidenced a relatively fast process theMeCN
Huisgen at r.t.,
withcycloaddition
formation ofreaction
the expected triazoles in
[168]. Recycling offair
the to good yields
material (61%–98%
recovered in 90–300
by filtration min). sustained
displayed This proved
truecatalytic
even for a substrate,
activity like propargyl
in the course (98% → 94%
of 7 runs acrylate, thatyield),
can face
whileselectivity problems
AAS analysis of the in the Huisgen
filtrate from
the reaction mixture could not detect any copper down to the ppb level.
cycloaddition reaction [168]. Recycling of the material recovered by filtration displayed sustained
catalyticAactivity
more complex systemof
in the course was reported
7 runs (98%by →Mouradzadegun
94% yield), while andAASMostafavi,
analysis who of immobilized
the filtrate fromCuI the
on a 3D-network
reaction mixture could polymer madeany
not detect by polycondensation
copper down to the of calix [4] resorcinarene and formaldehyde
ppb level.
(Scheme
A more17c) [169]. With
complex system thiswas
aim,reported
the resinby was initially modifiedand
Mouradzadegun by the introduction
Mostafavi, whoofimmobilized
aminopropylCuI
chains and then loaded with a solution of the cuprous salt in DMF
on a 3D-network polymer made by polycondensation of calix [4] resorcinarene and formaldehyde to give 36. The system was tested
in the three-component CuAAC reaction of halides in water (Scheme 2a). Even though the catalyst (5
(Scheme 17c) [169]. With this aim, the resin was initially modified by the introduction of aminopropyl
mol %) displayed reasonable activity at room temperature, reflux conditions were ultimately selected
chains and then loaded with a solution of the cuprous salt in DMF to give 36. The system was tested
in the three-component CuAAC reaction of halides in water (Scheme 2a). Even though the catalyst
Molecules 2016, 21, 1174 22 of 43

Molecules 2016, 21, 1174 21 of 41

(5 mol %) displayed reasonable activity at room temperature, reflux conditions were ultimately selected
as as they
they could
could providegood
provide goodyields
yields(80%–97%)
(80%–97%) within
within 5–30
5–30 min.
min. Recovery
Recoveryofofthetheresin
resinbybyfiltration and
filtration and
solvent washing permitted to confirm its potential reuse, with just a slight reduction
solvent washing permitted to confirm its potential reuse, with just a slight reduction of product yieldof product yield
in the
in the course
course ofof 5 cycles(97%
5 cycles (97%→ →94%).
94%). At
At the
the same
same time,
time, AAS
AASanalysis
analysisofofthe
thefiltrate
filtrateevidenced
evidenced a not
a not
specified “trace amount” of copper ions.
specified “trace amount” of copper ions.
After introducing PEG-modified melanin as a platform for multimodality imaging [170], Sun et
After introducing PEG-modified melanin as a platform for multimodality imaging [170], Sun et al.
al. explored its use as a nanosized support for CuAAC catalytic systems [171]. The preparation of the
explored its use as a nanosized support for CuAAC catalytic systems [171]. The preparation of the
material (Scheme 18) began with the dissolution of synthetic melanine granules into NaOH, followed
material (Scheme 18) began with the dissolution of synthetic melanine granules into NaOH, followed
by US-assisted re-precipitation of the polymer on lowering the pH. After this step, aimed to
by US-assisted re-precipitation of the polymer on lowering the pH. After this step, aimed to disentangle
disentangle the macromolecular chains, the resulting water-insoluble melanine nanoparticles were
thesubjected
macromolecular chains,
to chemical the resulting
modification water-insoluble
with NH2-PEG5000-NH melanine nanoparticles were subjected to
2 [170]. This second stage afforded
chemical modification
nanoparticles with that,
37 (M-dots) NH2 -PEG 5000 -NH
probably 2 [170].
thanks Thissurface
to their second stage (−2.2
charge afforded nanoparticles
mV zeta potential), 37
(M-dots) probably thanks to their surface charge ( −
resulted well dispersible in water but could be recovered by centrifugal separation through dispersible
that, 2.2 mV zeta potential), resulted well a 30 kDa
in water but could be recovered by centrifugal separation through a 30 kDa cutoff filter.
cutoff filter.

Scheme18.
Scheme 18. Preparation
Preparation of the M-dots/Cu(I)
of the nanoparticles
M-dots/Cu(I) and likely
nanoparticles structure
and likelyofstructure
M-dots (Note: The
of M-dots
formula shown for the latter is the dihydroxyindole tautomer of the dihydroindolequinone one
(Note: The formula shown for the latter is the dihydroxyindole tautomer of the dihydroindolequinone
depicted in the original publication [171]).
one depicted in the original publication [171]).

After loading with an aqueous solution of CuSO4 and reducing with sodium ascorbate, the same
After loading with an aqueous solution of CuSO and reducing with sodium ascorbate, the same
technique was applied for the purification of the4 corresponding supported Cu(I) complex 38.
technique was applied for the purification of the corresponding supported Cu(I) complex 38.
Characterization of the material by ICP-MS revealed that, on the average, each M-dot particle was
Characterization
loaded with 50 ±of2the material
copper by whose
centers, ICP-MS +I revealed
oxidationthat,
state on
wasthe average,by
confirmed each
XPS. M-dot particle
Specific was
tests on
loaded 50 ±
the M-dots/Cu(I) system evidenced just a modest metal leaching in phosphate PBS buffer at pH = 7.4on
with 2 copper centers, whose +I oxidation state was confirmed by XPS. Specific tests
theand
M-dots/Cu(I)
no toxicity system
against evidenced
two cellular just a modest
lines. metal leaching
In addition, in phosphate
M-dots displayed PBS buffer
the ability at pHthe
to quench = 7.4
and no toxicity
production of against
hydroxyltwo cellular
radicals lines.
in the In addition, M-dots
Cu(II)-ascorbate reactive displayed
system, thus thecircumventing
ability to quench
one ofthe
production
the main of hydroxyl
issues when radicals in the is
this chemistry Cu(II)-ascorbate reactive system,
applied for bio-conjugation thus circumventing
purposes. one of the
The appealing features
main issues
of 38 when this
prompted chemistry
its study is applied
in CuAAC for bio-conjugation
reactions purposes.weight
between low molecular The appealing
reactants features
(Scheme of 1) 38
prompted
and for its
thestudy in CuAAC reactions
click-derivatisation between low
of biomolecules. molecular
In the weight reactants
former scenario, very good (Scheme
product1)yields
and for
the(90%–95%) were obtained
click-derivatisation in 30 min at r.t.,
of biomolecules. In by
thestirring
formerthe azide and
scenario, very alkyne
goodreactants in PBS (90%–95%)
product yields buffer in
theobtained
were presence in of 30
0.1min
mol at
% r.t.,
of thebycopper
stirringcatalyst. Similar,
the azide albeit slightly
and alkyne reactants worse results
in PBS (67%–90%
buffer yield)
in the presence
were obtained in the corresponding three-component process with halides in
of 0.1 mol % of the copper catalyst. Similar, albeit slightly worse results (67%–90% yield) were obtained PBS-DMSO (Scheme
2a). corresponding
in the Reusability of three-component
the catalytic system waswith
process studied in in
halides thePBS-DMSO
reaction of(Scheme
phenylacetylene and a of
2a). Reusability
tetra(ethylene glycol)-derived azide. With this choice, 38 could be separated by
the catalytic system was studied in the reaction of phenylacetylene and a tetra(ethylene glycol)-derived centrifugal filtration
fromWith
azide. the solution containing
this choice, 38 couldthe be triazole
separated product, without filtration
by centrifugal leaving behind
from the measurable amounts ofthe
solution containing
copper. The subsequent direct reuse of the recovered catalyst, i.e., without adding any reducing agent,
triazole product, without leaving behind measurable amounts of copper. The subsequent direct reuse
afford then reasonably constant results in the course of seven reaction cycles (88% → 82% yield).
of the recovered catalyst, i.e., without adding any reducing agent, afford then reasonably constant
In a second set of applications, 38 was used for click-modifying biotin and AE105 or RGDyK
results in the course of seven reaction cycles (88% → 82% yield).
polypeptide derivatives, provided with either alkyne or azide side chains. Moreover, the same
In a second set of applications, 38 was used for click-modifying biotin and AE105 or RGDyK
protocol could be applied to the fluorescent tagging of a 3’-alkyne DNA strand with the cyanine
polypeptide derivatives, provided with either alkyne or azide side chains. Moreover, the same protocol
5.5-azide dye, in this case using a 10 kDa cut-off centrifugal filter for separating the polynucleotide
could be applied
product from 38.toInthe fluorescent
a final noteworthytagging of a the
example, 3’-alkyne
in situ DNA
imaging strand
of thewith the cyanine
integrin 5.5-azide
αVβ3 receptor in
dye, in this case using a 10 kDa cut-off centrifugal filter for separating
human glioblastoma U87MG cells was realized. In this case, the procedure involved preliminary the polynucleotide product
Molecules 2016, 21, 1174 23 of 43

from 38. In a final noteworthy example, the in situ imaging of the integrin αV β3 receptor in human
Molecules 2016, 21, 1174 22 of 41
glioblastoma U87MG cells was realized. In this case, the procedure involved preliminary labelling
the receptor
labelling the sites withsites
receptor RGD-alkyne, followed followed
with RGD-alkyne, by exposure of the whole
by exposure cells
of the to Cyanine
whole cells to5.5-azide
Cyanine dye 5.5-
and 38. As for the other biomolecules mentioned above, the possibility
azide dye and 38. As for the other biomolecules mentioned above, the possibility of using the of using the melanine-based
Cu(I) catalytic system,
melanine-based without the
Cu(I) catalytic needwithout
system, of any added
the needascorbate, was undoubtedly
of any added ascorbate, was a major advantage
undoubtedly a
in order
major to prevent
advantage inunwanted side reactions
order to prevent unwanted in the
sideCuAAC
reactions process.
in the CuAAC process.
As anticipated
As anticipatedininthe the Introduction,
Introduction, thethe necessity
necessity of handling
of handling potentially
potentially explosiveexplosive
azides azides
under
under
safe safe conditions
conditions prompted prompted
severalseveral
studies studies on continuous-flow
on continuous-flow CuAAC CuAAC [31]. [31].
In this In this context,
context, the
the combination of flow-chemistry with another enabling technology
combination of flow-chemistry with another enabling technology [172], viz. the use of supported [172], viz. the use of supported
catalytic systems,
catalytic systems, standsstands as as one
one of of the
the most
most promising
promising trends trends of of current
current efforts
efforts towards
towards the the
improvement of
improvement of the
thereaction.
reaction.Accordingly,
Accordingly, several
several examples
examples of inofcontinuo
in continuo CuAAC CuAAC reactions
reactions have
have appeared
appeared in the in the literature,
literature, most ofmostwhich of make
whichuse make use of tubular
of copper copper tubular
reactors reactors
or supported or supported
systems
systems in meso-sized fluidic devices [32]. Given the interest
in meso-sized fluidic devices [32]. Given the interest of fast CuAAC reactions on the pico-moleof fast CuAAC reactions onscale
the
pico-mole
as a tool for, scale as aidentifying
e.g., tool for, e.g., identifying
enzyme enzyme
inhibitors inhibitors
[173,174], Li et [173,174],
al. explored Li ettheal.preparation
explored the of
preparation of glass-poly(dimethylsiloxane)
glass-poly(dimethylsiloxane) (PDMS) (PDMS)
chip chip micro-reactors
micro-reactors containing
containing immobilized
immobilized
tris(triazolylmethyl)-amine-Cu(I)units
tris(triazolylmethyl)-amine-Cu(I) units 39 (Scheme
39 (Scheme 19) [175].
19) [175]. The step The bystep by step of
step progress progress of the
the fabrication
fabrication sequence was verified by XPS analyses on test wafers,
sequence was verified by XPS analyses on test wafers, while radiochemical assay with CuSO4/sodium while radiochemical
64 assay
with 64 CuSO /sodium ascorbate allowed to quantify the capacity of the device in retaining Cu(I)
ascorbate allowed 4 to quantify the capacity of the device in retaining Cu(I) (1136 ± 272 nmol or
(1136
81 ± 20 ± nmol·cm 81 ± 20ofnmol
272 nmol−2).orTesting ·cm−2 ). Testing
the microfluidic reactorof the microfluidic reactor
in two-components CuAAC in two-components
(Scheme 1) was
CuAAC (Scheme 1) was performed in a semi-batch fashion, by filling
performed in a semi-batch fashion, by filling the channels with the reactants in ammonium the channels with the reactants
acetatein
ammonium acetate buffer the
andreaction
then allowing the reaction to proceed for some ◦
buffer and then allowing to proceed for some time (15–30 min) time
at 37(15–30
°C under min)stopped-
at 37 C
underconditions.
flow stopped-flow conditions.
Application of theApplication
procedureoftothe theprocedure
CuAAC couplingto the CuAAC between coupling between the
the azide-modified
azide-modified
fluorescent dye fluorescent
Flu568-N3 and dye Flu568-N
propargylamine3 and propargylamine
led to productled to product
yields that, asyields
expected,that, increased
as expected, at
increased
larger at larger
incubation incubation
times (e.g., 83% times
after(e.g.,
50 min83%vs.after
55%50 min15vs.
after min).55% after 15 min).
Interestingly, Interestingly,
the protocol was
the protocol
effective for was effectivealso
performing for performing
the click reaction also thebetween
click reaction between the azide-containing
the azide-containing cyclic penta-peptide cyclic
penta-peptide cyclo(RGDfK)-N
cyclo(RGDfK)-N3 and the functionalized 3 and the functionalized dye Flu568-acetylene, with better
dye Flu568-acetylene, with better results in the flow device results in the
flow device
than than underbatch
under analogous analogous batch conditions
conditions (75% yield(75% vs. 54%yield vs. 54%
yield withyield
60 mol with% 60of mol % of catalyst).
catalyst). Control
Control experiments showed good reproducibility between different
experiments showed good reproducibility between different reactors and confirmed that the catalyticreactors and confirmed that the
catalyticofactivity
activity of non-specifically
non-specifically bound Cu(I), bound Cu(I), in
as found as bare
found in bare
chips, waschips,
just awas just aoffraction
fraction of that
that observed
observed
in in the ligand-functionalized
the ligand-functionalized devices.devices. The latter
The latter couldcould be used
be used 4–64–6 times
times beforean
before an appreciable
appreciable
reduction of
reduction product yield
of product yield ensued. After that,
ensued. After that, full
full “regeneration”
“regeneration” could could be be achieved
achieved by by reloading
reloading the the
channels with
with CuSO /sodiumascorbate.
CuSO4/sodium ascorbate.Arguably,
Arguably,whilewhilethisthis observation
observation points points to to aa good stability
of the supported ligand units, it evidences also possible leaching phenomena, whose extent was not
quantified, in the product-containing
product-containing liquid liquid phase.
phase.

H O N O H
(1) H2O2-aq.HCl 3
N N 3
O
(2) N N N N
(MeO)3Si O
Glass or PDMS

OH O H
70°C, 2 h Si O N N N Cu(I)
O N
OH O 3
O
(3) L, aq. borax, 47°C
OH OH 39
(4) CuSO4, sodium ascorbate

H O N O H
3
N N 3
N N N N

N N NH2
L N O
3

Scheme 19. Immobilization

Scheme 19. Immobilization of tris(triazolylmethyl)amine ligand/Cu(I)
of tris(triazolylmethyl)amine ligand/Cu(I) inside
inside aa glass-PDMS
glass-PDMS chip
chip
reactor 39.
reactor 39.

3.2. Polymeric Organic Supports From Natural Sources

As noted already in Section 2.6, chitosan, the biodegradable polymer obtained by deacetylation
of chitin, is still attracting much interest as catalyst support in view of its low cost, inoffensive nature,
Molecules 2016, 21, 1174 24 of 43

3.2. Polymeric Organic Supports from Natural Sources

As noted already in Section 2.6, chitosan, the biodegradable polymer obtained by deacetylation of
chitin, is still attracting much interest as catalyst support in view of its low cost, inoffensive nature,
and prompt adsorption of metal ions by surface hydroxy and amino groups. After early contributions
by Chtchigrovsky et al. [176], the use in CuAAC of CS-Cu(I/II) complexes was examined recently by
Nasir Baig et al. and by Anil Kumar et al. [177,178]. In both studies the supported polymeric catalysts
were obtained by suspending CS in the solution of a proper Cu(I/II) salt, followed by filtration or
centrifugation, washing, and drying of the insoluble material. Characterization of the solid indicated
an appreciable copper content (5.1 wt % by ICP-AES), but no signals pertinent to crystalline forms were
observed by XRD. The former group tested CS-CuSO4 , at low catalyst loading (0.4 mol % of Cu) in
water, in CuAAC between alkyl azides and aliphatic or aromatic alkynes (Scheme 1). On the contrary,
the latter focused on the three-component CuAAC reaction between aromatic boronic acids, sodium
azide, and aromatic alkynes (Scheme 2d). Also in this case water proved to be the solvent of choice,
but the experiments involved the use of considerably larger amounts of catalyst (typically 10 mol %
of CS-CuSO4 ). Under the said conditions good to excellent yields (71%–99%) were attained in both
studies in 4–12 h at r.t. The CS-supported catalyst could be recovered by decantation and reused,
albeit with variable degrees of success depending upon the specific reaction: With preformed azides,
essentially quantitative yields were obtained in five initial runs and constant, yet reduced values (28%),
were recorded in five additional reaction cycles carried out at five-fold larger S/C ratio. On the contrary,
with boronic acids an appreciable reduction of yield was observed in the initial 5 cycles (90% → 79%),
which appears to mirror quite closely the progressively larger losses of insoluble material along the
reaction series (approximate 18% of the initial amount after the 5th reaction cycle).
Cuttlebone, the rigid structural component of the cuttlefish body, is an hybrid material composed
of calcium carbonate (aragonite form), proteins, and β-chitin [179]. In view of the complexing/reducing
properties of the latter component, Ghodsinia et al. explored the use of cuttlebone as a support for
CuAAC catalytic systems [180]. Because XPS analysis of the solid obtained by treating powdered
cuttlebone with CuCl2 in water confirmed the presence of copper in the Cu(I)/Cu(II) mixed oxidation
state, the material was tested directly in the three-components CuAAC reaction of benzyl bromide
and phenylacetylene. Strangely enough, bare cuttlebone displayed some catalytic activity itself but,
as expected, the reaction rate in the presence of metal-loaded material proved significantly higher.
Best results were attained by using 8.5 mol % of the supported copper catalyst in water at 40 ◦ C,
conditions under which the CuAAC multi-component reaction of other reactive bromides led to good
triazole yields (72%–95%) within 5–80 min. Recovery by filtration and washing with different solvents
allowed the reuse of the catalytic material in seven reaction cycles. This led to observe some decrease of
substrate conversion and product yield (100% → 90% and 95% → 85%, respectively) and the reduction
of the metal loading on the cuttlebone support (1.77 mmol·g−1 → 1.54 mmol·g−1 ). In spite of this,
the measured amount of leached copper was found to be relatively modest, with reported levels in
selected isolated triazole products ranging between 37 ppm and 46 ppm.

3.3. Linear Organic Polymer Supports

In the course of their investigation of new Cu(II) complexes with ferrocene-containing Schiff-base
ligands, Liu et al. developed a molecularly-enlarged CuAAC pre-catalyst 40 anchored to linear
poly(methyl methacrylate) (PMMA) [181].
The material was obtained by coupling PMMA to the pre-formed complex by trans-esterification
(Scheme 20a) and, thanks to its poor solubility in EtOH, was employed as a heterogeneous catalyst in
CuAAC runs in this solvent.
Molecules 2016, 21, 1174 25 of 43
Molecules 2016, 21, 1174 24 of 41

(a)
OH
Me Me
5 1
Fc = Fe
(1) t-BuOK, THF CO2Me
O O
Me reflux, overnight
N O
Cu +
n
(2) Concentration
N O CO2Me

Me Fc PMMA N O
(M w 35 000) Cu
N O

Me Fc 40 (1 mmol Cu g-1)

(b)
Bn Bn
N N
N (1) CuSO4, N
N degassed H2O N
O O
Me O Me O
n
N Bn (2) Sodium ascorbate n
N N NN Bn
N N N
N N N N Cu(I) 41
Bn
Bn

20. Preparation of the

Scheme 20. the molecularly
molecularly enlarged Cu(II) pre-catalyst 40 (a) and
and the
the water-soluble
water-soluble
Cu(I) complex 41 (b).
41 (b).

Two-component reactionsreactions (Scheme

(Scheme1),1),forfor 24 24
h ath r.t.
at with
r.t. with
2 mol2%mol of 40%reduced
of 40 reduced with
with sodium
sodium
ascorbate,ascorbate,
led to lednearlyto nearly
constantconstant
results results
in thein the course
course of ofthree
threeconsecutive
consecutive reaction
reaction cycles
cycles
(approximate
(approximate88% 88%oror95%95%yields, depending
yields, depending on the
onspecific alkynealkyne
the specific substrate). Moreover,
substrate). efforts directed
Moreover, efforts
to address
directed to the issuethe
address of issue
metalofleaching by TEMby(detection
metal leaching of metal
TEM (detection of nanoparticles) and 1 H-NMR
metal nanoparticles) and 1H-
(complexation-induced
NMR (complexation-induced shift byshift
Cu(I/II) salts) did
by Cu(I/II) notdid
salts) provide any clue
not provide anyabout
clue the occurrence
about of suchof
the occurrence a
phenomenon.
such a phenomenon.No attempt was reported,
No attempt however,however,
was reported, for quantifying the copperthe
for quantifying content
copperbycontent
a technique,
by a
e.g., ICP-AES,
technique, e.g.,better fit forbetter
ICP-AES, accurate determinations
fit for at the ppm at
accurate determinations level.
the ppm level.
In a very recent example, Wang et et al. examined the
al. examined the use
use of the water solublesoluble complex
complex 41 [78].
41 [78].
Striking features of this system were the possibility to effectively catalyze CuAAC reactions in water
down to 10 10 mol
mol ppm
ppm loading
loading level
level (with
(with TONTONand andTOF TOFvalues
valuesof of86,000
86,000and 3600hh−−11, respectively)
and3600
and its suitability for the click modification of dendrimers and substrates of potential pharmaceutical
interest (typically at 50–500 mol ppm ppm loading).
loading). Because the PEG-containing complex 41 was expected
to be
bepoorly
poorlysoluble
solublein cold diethyl ether, suchsuch
in cold diethyl ether, solvent
solvent was employed
was employed for recovering
for recovering the product
the triazole triazole
product
from thefrom the reaction
reaction mixture
mixture while whilethe
leaving leaving
catalysttheincatalyst in the phase.
the aqueous aqueous phase. the
Although Although
procedurethe
procedure
allowed the allowed thecatalyst
use of the use of the catalyst
solution insolution in 6 consecutive
6 consecutive reaction
reaction cycles, cycles, a significant
a significant decrease ofdecrease
product
of product
yield yield was(95%
was observed → 53%).
observed (95%The→problem
53%). The was problem
attributedwastoattributed to the unavoidable
the unavoidable loss of copper loss of
ions,
copper ions,
due to the due to
strong the strongability
complexing complexing ability of thenucleus
of the heterocyclic heterocyclic
of thenucleus
triazole of the triazole product.
product.

3.4.
3.4. Inorganic
Inorganic Supports
Supports
In additiontotothe
In addition themany
many examples
examples published
published in past
in the the past
yearsyears [88,89],
[88,89], a fewsupported
a few new new supported
Cu(I/II)
Cu(I/II) complexes have been disclosed recently, which contain low molecular weight organic
complexes have been disclosed recently, which contain low molecular weight organic ligands covalently ligands
covalently
anchored ontoanchored onto a(or
(or within) within)support
siliceous a siliceous support
(Figure (Figure
4). Because 4). materials
these Because these
do notmaterials do
contain any
not contain
polymeric any polymeric
component, component,
but the butitself,
oxidic support the oxidic support
they will itself, they
be mentioned onlywill be mentioned
briefly here. only
briefly here.
Molecules 2016, 21, 1174 26 of 43
Molecules 2016, 21, 1174 25 of 41

Figure 4. Cu(I/II) complexes with organic ligands covalently immobilized on insoluble

Figure 4. Cu(I/II) complexes with organic ligands covalently immobilized on insoluble inorganic supports.
inorganic supports.

Silica gel decorated with a sulfur-containing ligand was developed by Tavassoli et al. as a new
Silica gel decorated with a sulfur-containing ligand was developed by Tavassoli et al. as a new
support material for Cu(I/II) [182]. In situ reduction with sodium ascorbate of the complex obtained
support material for Cu(I/II) [182]. In situ reduction with sodium ascorbate of the complex obtained
by stirring the modified silica with CuCl2 or Cu(OTf)2 afforded the corresponding CuAAC catalyst
by stirring the modified silica with CuCl2 or Cu(OTf)2 afforded the corresponding CuAAC catalyst 42.
42. Under optimized conditions, which included inter alia the use of 0.05–0.1 mol % of the triflate
Under optimized conditions, which included inter alia the use of 0.05–0.1 mol % of the triflate catalyst at
catalyst at r.t. in PEG400–H2O (1:1), fair to nearly quantitative yields (72%–99%) were obtained in
r.t. in PEG400 –H2 O (1:1), fair to nearly quantitative yields (72%–99%) were obtained in three-component
three-component CuAAC reactions (Scheme 2a), after a reaction time comprised between 15 min and
CuAAC reactions (Scheme 2a), after a reaction time comprised between 15 min and−11 h. In the most
1 h. In the most favorable case, this translated into a remarkable TOF value of 7920 h . Unfortunately,
favorable case, this translated into a remarkable TOF value of 7920 h−1 . Unfortunately, reuse of the
reuse of the supported system in a series of six benchmark CuAAC runs caused some reduction of
supported system in a series of six benchmark CuAAC runs caused some reduction of product yield
product yield (approximate 5%).
(approximate
Compared 5%).
to the previous example, the MCM-41 supported Cu(I)-NHC complex 43, described
by Garcés et al. to
Compared the previous
[183], example,
and especially the the MCM-41 supportedon
Cu(I)-acetylacetonate Cu(I)-NHC
HMS silica complex 43, described
44, studied by Lai et by al.
Garcés et al. [183], and especially the Cu(I)-acetylacetonate on HMS silica
[184], displayed lower catalytic activity in two- or three-components CuAAC reactions (Scheme 1 and 44, studied by Lai et al. [184],
displayed
Scheme 2a). lower
In thecatalytic
case of activity
the latterinsystem,
two- orhowever,
three-components
the material CuAAC
could be reactions
used four(Schemes
times in1 aand 2a).
model
In the case of the latter system, however, the
reaction, with essentially identical results (99% → 98% yield). material could be used four times in a model reaction,
with essentially
While mostidentical results (99%
of the reported → 98% yield).
approaches rely on surface functionalization of pre-formed oxide
supports, Naeimi et al. resorted to the sol-gel rely
While most of the reported approaches on surface
process functionalization
for immobilizing a copperofcomplex
pre-formed oxide
containing
supports, Naeimi et al. resorted to the sol-gel process for immobilizing a
trimethoxysilane groups in a templated organosilica matrix [185]. Contrarily to most other studies incopper complex containing
trimethoxysilane
the field, testinggroups of theincatalytic
a templated organosilica
properties of the matrix [185].45Contrarily
material to most other
was performed studies ina
by adopting
the field, testing of the catalytic properties of the material 45 was performed
Box-Behnken factorial design of experiments in order to optimize an ultrasound-promoted by adopting a Box-Behnken
factorial design of experiments
three-component CuAAC reaction in order
in to optimize
water with an ultrasound-promoted
styrene oxide (Scheme 2b). three-component
The approach CuAAC
led to
reaction
identify in thewater with styrene
best conditions in oxide
the use(Scheme 2b). %
of 0.33 mol Theof approach
the supportedled tocatalyst,
identifyunder
the best conditions
irradiation in
at 40
the use of 0.33 mol % of the supported catalyst, under irradiation at 40
kHz for 7 min. By adopting the same experimental set-up, different epoxides could be converted into kHz for 7 min. By adopting
the
the same experimental
corresponding set-up,
triazole different
products epoxides
in fair could yield
to excellent be converted
(74%–99%, intoTOF
the corresponding
up to 2926 h−1). triazole
In spite
products in fair to excellent yield (74%–99%, TOF up to 2926 h −1 ). In spite of the mechanical stress
of the mechanical stress put on the siliceous material by sonication, the supported system maintained
put
intactonits
theactivity
siliceousin material by sonication,
six consecutive runs (98% the →
supported
98% yield) system
and no maintained
copper was intact its activity
reportedly in six
detected
consecutive
in the filtrateruns (98% → 98% yield) and no copper was reportedly detected in the filtrate by AAS.
by AAS.
3.5. Magnetically Recoverable Systems
3.5. Magnetically Recoverable Systems
Similarly to materials containing copper and copper oxide clusters on super-paramagnetic
Similarly to materials containing copper and copper oxide clusters on super-paramagnetic
supports (Section 2.6), the last few years saw progresses also for what it concerns magnetically
supports (Section 2.6), the last few years saw progresses also for what it concerns magnetically
recoverable systems containing Cu(I/II) species on a polymeric organic layer (Scheme 21). Advances in
recoverable systems containing Cu(I/II) species on a polymeric organic layer (Scheme 21). Advances
this direction were reported, for instance, by Pourjavadi et al. [186]. With an approach in some respects
in this direction were reported, for instance, by Pourjavadi et al. [186]. With an approach in some
respects analogous to that already discussed for the GO-based material 32 (Section 3.1), N-
Molecules 2016, 21, 1174 27 of 43
Molecules 2016, 21, 1174 26 of 41

analogous to that
vinylimidazole, already discussed for the GO-based
N-ethyl-N′-vinylimidazolium material and
tetrafluoroborate, 32 (Section N-vinylimidazole,
3.1),cross-linking
a dicationic agent
N-ethyl-N
were 0 -vinylimidazolium
subjected tetrafluoroborate,
to radical copolymerization. andcase
In this a dicationic
the processcross-linking
was carried agent
out inwerethesubjected
presence
to core-shell
of radical copolymerization. In this case the
Fe3O4-silica gel nanoparticles process
bearing was methacrylate
surface carried out ingroups,
the presence
in order of core-shell
to endow
Fe3 O
the -silica
polymeric
4 gel nanoparticles
material (55 wt bearing
% by surface
TGA) with methacrylate
a covalently groups,
embedded in order to
magnetic endowcore.the polymeric
Charging of
the resin with CuSO4 in the final step led to the supported catalyst precursor 46. The activity of the
material (55 wt % by TGA) with a covalently embedded magnetic core. Charging of the resin with
CuSO4 inwas
material the final
testedstepin led
the to the supported catalyst
three-components CuAAC precursor
reaction46.ofThe activity
benzyl of the with
bromide, material was
sodium
tested in the
ascorbate three-components
as the reducing agent.CuAAC reaction
Compromise of benzyl
conditions forbromide,
minimizing withboth
sodium ascorbate
catalyst loading asand
the
reducingtime
reaction agent. Compromise
were determined conditions
to be the for
useminimizing
of 0.75 mol both
% of catalyst
supported loading
copper andcomplex
reactionintime were
water at
50 °C. With to
determined this
bechoice,
the usedifferent
of 0.75 molchlorides or bromides
% of supported and complex
copper terminal in alkynes,
water at 50 ◦ C.
either aliphatic
With this or
aromatic (Scheme
choice, different 2a), could
chlorides or be effectively
bromides andcoupled
terminalinalkynes,
2–4 h (80%–97% yield). or
either aliphatic Filtration
aromatic of(Scheme
the mixture 2a),
was
couldconfirmed
be effectivelyto halt completely
coupled in 2–4the reaction progress
h (80%–97% and ICP-AES
yield). Filtration of theassay
mixtureof thewasfiltrate
confirmeddid notto
detect any significant
halt completely concentration
the reaction progressofand
copper. Still, assay
ICP-AES a moderate
of the reduction
filtrate didofnotturnover frequency
detect any was
significant
recorded
concentrationin theofcourse
copper.ofStill,
6 recycle runs ofreduction
a moderate the benchmark reaction,
of turnover which was
frequency forced to increase
recorded in the the time
course
from 150 min
of 6 recycle to of
runs 170themin in order reaction,
benchmark to maintain
whichtheforced
product yield in the
to increase the time
rangefrom90%–95%.
150 minAs to in
170other
min
cases,
in orderthetotrend was the
maintain related to mechanical
product yield in thelosses
rangeof90%–95%.
the supportedAs insystem during
other cases, thethe separation
trend was relatedand
washing steps.losses of the supported system during the separation and washing steps.
to mechanical
A similar
similarapproach
approach waswas followed
followed by Zohreh
by Zohreh et the
et al. for al. preparation
for the preparation of magnetically
of magnetically recoverable
recoverable
nanoparticlesnanoparticles
consisting of aconsisting
Fe3 O4 coreofembed
a Fe3into
O4 core embed
silica gel into silica gel
and cross-linked and cross-linked
poly(methyl acrylate)
poly(methyl
(PMA) acrylate)
shell layers (PMA) shell layers [187].
[187].

Scheme 21. Preparation

Preparation ofof supported
supported Cu(II)
Cu(II) salts
salts 46–48 onto organic cross-linked polymers with
super-paramagnetic core.

Aminolysis
Aminolysis of the ester groups of the latter latter with
with N,N-dimethylethylenediamine
N,N-dimethylethylenediamine allowed the
installation of
ofchelating
chelatingunits,
units, exploited
exploited in last
in the the step
last for
step for adsorbing
adsorbing CuSO4 CuSO 4 from
from an an aqueous
aqueous solution.
solution.
When When
tested tested in three-components
in three-components CuAAC reactions
CuAAC reactions (Scheme
(Scheme 2a), 2a), the resulting
the resulting supported supported
complex
complex
47 afforded47 afforded bestinresults
best results water in 50 ◦ C,atat500.3
at water °C,mol
at 0.3 mol % loading
% loading andpresence
and in the in the presence of an
of an excess
excess of sodium
of sodium ascorbate.
ascorbate. Under Under these conditions,
these conditions, different different
triazole triazole
productsproducts were smoothly
were smoothly formed
formed
from thefrom the corresponding
corresponding alkyne andalkyne
alkyland alkyl chloride,
chloride, bromidebromide or (75%–97%
or tosylate tosylate (75%–97% yield h).
yield in 1.5–4 in
1.5–4 h).
While noWhile
ICP-OESno ICP-OES
detectable detectable
metal was metal
foundwas in found in the
the liquid liquidfrom
phases phases from
seven seven consecutive
consecutive reaction
reaction runs, analysis
runs, analysis of the magnetic
of the magnetic materialmaterial
recoveredrecovered in the
in the last lastindicated
cycle cycle indicated
a slighta reduction
slight reduction
of the
of the copper content with respect to the original system (0.54 vs. 0.57 mmol·g−1). In addition, some
mass loss of the nanoparticles as a whole was recorded. As suggested, this fact may represent the
Molecules 2016, 21, 1174 28 of 43

copper content with respect to the original system (0.54 vs. 0.57 mmol·g−1 ). In addition, some mass
loss of the nanoparticles as a whole was recorded. As suggested, this fact may represent the likely
explanation of the progressively longer reaction time required for attaining constant conversion in
consecutive CuAAC runs. Still, it cannot be excluded that metal leaching might play a role in the
problem, as seemingly supported by the fact that TOF values corrected for mass loss underwent also
some decrease on passing from the first to the last reaction cycle (160 h−1 → 142 h−1 ).
Coating of Fe3 O4 -silica gel core-shell magnetic nanoparticles with a cross-linked organic polymeric
layer was tackled also by Pourjavadi et al. [188]. In this case, the macromolecular material was obtained
by copolymerization of acrylamide and N,N0 -methylenebisacrylamide, in the presence of starch and
support nanoparticles bearing methacrylate groups on the surface. Loading with CuCl2 afforded the
insoluble catalyst precursor 48, which was examined in three-components CuAAC reactions of halides
(Scheme 2a). With sodium ascorbate as the reducing agent, the use of 0.5 mol % of the system in water
required to warm the reaction mixture to 50 ◦ C for obtaining the triazole products in good yield after a
short reaction time (82%–99% in 1–5 h). A standard ‘filtration experiment0 and ICP-OES determination
of copper in the separated reaction mixture excluded significant amounts of metal in the solution.
At the same time, the reuse of recovered magnetic nanoparticles revealed a reasonable durability of the
catalyst. Indeed, while a step drop of average turnover frequency was observed on passing from the
5th to the 6th reaction cycle (TOF approximate 400 h−1 → 300 h−1 ), no further reduction of turnover
rate was recorded in the next five runs. Because FT-IR and ICP-OES data for the recovered catalyst
were not very dissimilar from those of the original material, the trend was attributed to mechanical
losses during the isolation step.
At the borderline between low molecular weight ligands and high-polymeric ones, functional
dendrimers have proved to be very effective in the development of recoverable catalytic systems [189],
including those for CuAAC [77]. Very recently, Bahrami and Arabi described the preparation of a
triazine-based, 2nd generation dendrimer-Cu(II) complex on ferromagnetic nanoparticles 49 (Figure 5)
and its use in three-component CuAAC reactions [190]. The material was obtained by initially coating
the Fe3 O4 nanoparticles with an aminopropylsilica layer and then reacting the surface functional
groups with trichlorotriazine and ethylenediamine, in a two-round iterative fashion. Although these
solid-phase steps were found not to be complete, the final material showed an appreciable adsorbing
capacity towards Cu(OAc)2 and eventually provided the supported Cu(II) complex as a dark-green
solid. Examination of the powder by various techniques (SEM, XRD, and TEM) revealed the presence
of well dispersed particles, uniform in shape and size (35 nm average diameter) and consisting of a
Fe3 O4 core coated by a thinner silica shell.
The catalytic activity of 49 was optimized in the reaction between benzyl chloride, sodium azide,
and phenylacetylene, rather unusually carried out in the presence of an equivalent amount of Na2 CO3 .
In spite of the relatively low catalyst loading (mostly 0.3 mol % of Cu), nearly quantitative yields
were recorded in 10–15 min at r.t. in EtOH-H2 O (1:1). The same conditions were therefore adopted
for the CuAAC of other alkynes and halides (Scheme 2a), to give the corresponding triazoles with
excellent yield in no more than 40 min (90%–99%). Surprisingly, this held true not only in the case
of very reactive halides (benzyl, allyl, and α-halocarbonyl chlorides and bromides) but even for a
reactant, like hexyl bromide, which is expected to undergo the halogen/azide exchange at much
slower rate. Recycling of the nanoparticles by magnetic decantation showed some slight reduction
of activity along six consecutive runs in the aforementioned benchmark relation (99% → 93% yield).
Such a trend was tentatively assigned to “the normal loss the catalyst during the work-up stage”,
but no clue was provided about the possible relevance of missing nanoparticles for the problem of
product contamination.
Molecules 2016, 21, 1174 29 of 43
Molecules 2016, 21, 1174 28 of 41

Figure
Figure 5. Cu(I/II) complexes
5. Cu(I/II) complexes 49–53, containing organic
49–53, containing organic ligands
ligands immobilized
immobilized on
on magnetically
magnetically
recoverable supports.
recoverable supports.

Also for this

this class
class of
ofrecoverable
recoverableCuAAC CuAACcatalytic
catalyticsystems,
systems,examples
examples were
were reported
reported recently
recently of
of materials
materials embedding
embedding discrete
discrete organic
organic ligands
ligands (Figure
(Figure 5). Considering
5). Considering that cyclodextrins
that cyclodextrins (CDs)(CDs)
have
have
foundfounduse inuse in CuAAC
CuAAC reactions,
reactions, withwith probable
probable rolesroles ranging
ranging from from phase-transfer
phase-transfer agents
agents [191],
[191], to
to ligands
ligands forfor Cu(II)
Cu(II) oror Cu(I)[192,193],
Cu(I) [192,193],Mahdavi
Mahdavietetal.al.used
usedaasurface
surfacesilanization
silanization approach
approach for binding
β-CD units to super-paramagnetic iron nanoparticles [194]. Treatment of the resulting white material
β-CD
with
with CuCl
CuClunder
underalkaline
alkalineconditions
conditions afforded
afforded a dark powder
a dark powder 50 that, although
50 that, hardhard
although to assess for what
to assess for
it concerns
what oxidation
it concerns state, aggregation
oxidation degree, and
state, aggregation location
degree, andoflocation
Cu centers,of Cudisplayed
centers,satisfactory
displayed
catalytic
satisfactoryactivity in a four-components
catalytic reaction involving
activity in a four-components reaction a CuAAC
involving click step (Scheme
a CuAAC 22). Reuse
click step (Scheme of
the
22).magnetically-recovered nanoparticles nanoparticles
Reuse of the magnetically-recovered led to nearly constant yieldsconstant
led to nearly in the course
yieldsofin5thecycles andof
course a
cumulative
5 cycles andTON of 8300 after
a cumulative TON10ofruns 8300(average
after 10 TOF
runs = 347 h−1TOF
(average ). A ‘filtration
= 347 h−1).experiment’, in which the
A ‘filtration experiment’,
supported
in which the catalyst was stirred
supported catalyst with EtOH–H
was O for EtOH–H
stirred2with 24 h revealed
2O fora 24very low metalaconcentration
h revealed very low metal in
the liquid phase
concentration in(<1
theppm by ICP-AES)
liquid phase (<1 that,
ppmexpectedly,
by ICP-AES) did not
that,lead to any appreciable
expectedly, did not lead conversion
to any
when standard
appreciable reactants when
conversion of the standard
process above were of
reactants added to the solution.
the process above were Nonetheless,
added tothe thefact that in
solution.
some documented cases copper leaching was significantly larger in the presence
Nonetheless, the fact that in some documented cases copper leaching was significantly larger in the of CuAAC substrates
and products,
presence than insubstrates
of CuAAC the reaction andsolvent alone
products, [75],
than inmakes it difficult
the reaction solventto evaluate
alone [75],themakes
relevance of the
it difficult
experiment
to evaluatefor thetherelevance
problem of ofmetal release underfor
the experiment actual
the four-component
problem of metal reaction conditions.
release under actual
four-component reaction conditions.
Molecules 2016, 21, 1174 30 of 43
Molecules 2016, 21, 1174 29 of 41

Scheme 22. Four-component condensation-click process promoted by 50.

Given the thestrong

strongtendency
tendency of triazoles
of triazoles to bind copper,
to bind the same
copper, thestructural motif hasmotif
same structural been has
exploited
been
in the pastin
exploited forthe
retaining
past forCu(I/II)
retainingonto an insoluble
Cu(I/II) onto ansupport
insoluble bearing
support tris-triazole units, e.g., ofunits,
bearing tris-triazole the TBTAe.g.,
type [195]. More recently, Moghaddam et al. examined the use for the
of the TBTA type [195]. More recently, Moghaddam et al. examined the use for the same purpose of same purpose of mono-triazoles
provided with an
mono-triazoles ancillarywith
provided coordination
an ancillary sitecoordination
[196,197]. Grafting of ligandGrafting
site [196,197]. units wasof realized
ligand unitseitherwasby
reaction
realized ofeither
surface-anchored
by reaction functional groups with afunctional
of surface-anchored preformedgroups triazolewithderivative, or by generating
a preformed triazole
the heterocycle
derivative, or by nucleus in a three-components
generating the heterocycle nucleus CuAAC in step. In the latter caseCuAAC
a three-components the resulting
step. Inmaterial 51
the latter
was
case obtained already
the resulting charged
material 51 with Cu(I). Instead,
was obtained already in the former
charged caseCu(I).
with the supported
Instead, inCu(II) complex
the former 52
case
was prepared by stirring the magnetic nanoparticles
the supported Cu(II) complex 52 was prepared by stirring the magnetic with CuCl 2 in water. At 0.5 mol % loading
nanoparticles with CuCl2 in and
in the presence
water. At 0.5 mol of sodium
% loading ascorbate, bothpresence
and in the systems of were activeascorbate,
sodium in three-component
both systemsCuAACwere reactions
active in
in water with alkyl
three-component halidesreactions
CuAAC or tosylates (Scheme
in water with2a) andhalides
alkyl afforded or the corresponding
tosylates (Scheme 2a) triazoles in high
and afforded
yield, after 2–8 h at 55 ◦ C (85%–98%). Recycling of the materials proved feasible, with slight reduction
the corresponding triazoles in high yield, after 2–8 h at 55 °C (85%–98%). Recycling of the materials
of product
proved yield (approximate
feasible, 5%) in the course
with slight reduction of productof 10 yield
consecutive runs.
(approximate 5%) in the course of 10
Similarly,
consecutive 2,20 -bis(imidazole) on core-shell Fe3 O4 -SiO2 nanomagnetite particles was obtained
runs.
by Tajbakhsh
Similarly,et2,2′-bis(imidazole)
al. through reaction of the ligand
on core-shell Fe3O4with
-SiO2the chloropropyl-modified
nanomagnetite particles was support
obtained [198].
by
Loading
Tajbakhsh with
et different
al. through metal salts led
reaction of tothetheligand
corresponding
with thecomplexes, among whichsupport
chloropropyl-modified that prepared
[198].
from
LoadingCuI with
(53) showed
differentthe highest
metal saltsactivity
led to in thethree-component CuAAC reactions
corresponding complexes, among(Scheme
which that 2a).prepared
With the
use
fromofCuI0.85(53)
molshowed
% of this thecatalyst
highestatactivity
r.t., in water or EtOH–H2 O CuAAC
in three-component (1:1), various chlorides,
reactions (Scheme bromides
2a). With or
tosylates
the use ofwere
0.85 transformed
mol % of thiseffectively
catalyst atinr.t.,
theincorresponding
water or EtOH–H triazole within
2O (1:1), 0.5–3.5chlorides,
various h (88%–99% yield).
bromides
Reuse of the were
or tosylates magnetically
transformedrecovered material
effectively in demonstrated
the corresponding goodtriazole
preservation
withinof0.5–3.5
its catalytic activity,
h (88%–99%
with
yield).a Reuse
measurable
of the drop of product
magnetically yield only
recovered in the
material 5th cycle (99%
demonstrated good→preservation
93%) (and the attainment
of its catalytic
of a still with
activity, respectable 96% yield
a measurable in the
drop 6th run, yield
of product carried outin
only with
thesomewhat → 93%)
extended
5th cycle (99% reaction
(andtime:
the
30 min → 40
attainment ofmin).
a still No textural 96%
respectable changes
yieldininthe therecovered solid were
6th run, carried out with noticed by electron
somewhat extendedmicroscopy,
reaction
but
time: 30 min
copper was →detected
40 min).in No minute amounts
textural changes (0.08%in of
thetherecovered
initial quantity) in thenoticed
solid were productby phase after
electron
the 5th run. On this ground, reloading of the magnetic material with
microscopy, but copper was detected in minute amounts (0.08% of the initial quantity) in the product CuI was effected, to give a
“regenerated”
phase after thesystem5th run. with
On the
thissame
ground,activity of the of
reloading original one. material with CuI was effected, to
the magnetic
give a “regenerated” system with the same activity of the original one.
4. Cu-Exchanged Clays and Other Inorganic Materials
4. Cu-Exchanged Clays
Although purely and Other
inorganic Inorganic
materials Materials
fall outside the main focus of the present review, for the sake
of completeness recentinorganic
Although purely advances materials
on the topicfallare only briefly
outside summarized
the main focus of the in this section.
present review, for the
sake of completeness recent advances on the topic are only briefly summarized in this section. in the
ZMS-5 zeolite exchanged with Cu(II) and Co(II) was used by Safa and Mousazadeh
three-component
ZMS-5 zeoliteCuAAC reaction
exchanged withofCu(II)
benzylandbromides
Co(II) and
was propargyl
used by Safa alcohol,
and carried
Mousazadehout in in
water
the
under thermal or US-promoted conditions [199]. The most interesting findings
three-component CuAAC reaction of benzyl bromides and propargyl alcohol, carried out in water of the study were
the observation
under thermal orthat the mixed Cu/Co
US-promoted system
conditions [199].was
Themore
mosteffective than
interesting an analogous
findings ZMS-5
of the study zeolite
were the
exchanged
observationwiththatCu(II) alone and
the mixed the system
Cu/Co fact that,was
under sonication,
more effectivethe reaction
than time couldZMS-5
an analogous be shortened
zeolite
from several
exchanged hours
with to 5alone
Cu(II) min. and
The the
possibility
fact that,was alsosonication,
under mentionedthe of reaction
reusing thetimecatalyst
could be eighth times
shortened
without significant loss of activity. However, no specific data was provided, neither
from several hours to 5 min. The possibility was also mentioned of reusing the catalyst eighth timesin this respect nor
for what significant
without it concernslosspotential leaching
of activity. issues. no specific data was provided, neither in this respect
However,
nor for what it concerns potential leachingcatalysts
A comparative evaluation of different issues. for the CuAAC reaction between dipropargylated
alloxan and various benzyl azides was undertaken
A comparative evaluation of different catalysts by Dubeyforet the
al. [200].
CuAAC Apartreaction
for the nature
between of
the reactants, thealloxan
dipropargylated study strictly mirrored
and various in methods
benzyl azides wasandundertaken
conclusionsbythoseDubeyof Mohammed et al. for
et al. [200]. Apart for
the nature of the reactants, the study strictly mirrored in methods and conclusions those of
Molecules 2016, 21, 1174 31 of 43

three-components CuAAC reactions involving aromatic boronic acids (Scheme 2d) [201]. Among the
systems included in the screening, a Cu(II)-exchanged clay proved superior to other Cu(I/II) catalysts
examined in the work. Recovery and recycling of the catalyst was possible, but some decrease of
the product yield was observed in the course of five reaction cycles with a fixed reaction time of 3 h
(96% → 81%).
In their continuing interest in flow-chemistry, Ötvös et al. examined a Cu(II)-Fe(III) layered double
hydroxide (LDH) as an heterogeneous catalyst for in continuo two-components CuAAC reactions [202].
When the material was used in a stainless-steel reactor provided with a back-pressure regulator set
to 100 bar, optimal results (77%–98% yield) were obtained in CH2 Cl2 at 100 ◦ C with contact time as
short as 100 s. With this experimental set-up, the system could be kept working for 10 h without any
evident decrease in activity and provided the expected triazole product with a final TON around 5 and
a residual copper content of 45.3 ppm. Although the resting state of the catalyst was found to be Cu(II),
its activity in CuAAC was explained by reasoning that under the vigorous reaction conditions cupric
ions might undergo in situ reduction (e.g., by dehydrogenative homocoupling of the alkyne substrate),
to generate Cu(I) active sites as defects in the LDH lattice.
González-Olvera et al. carried out a comparison of the catalytic properties in CuAAC of a
Cu-Al LDH, with those of the Cu(Al)O mixed oxide obtained by high temperature calcination of the
former [203]. The mixed oxide was found to be more active and better fit for recycling than the LDH,
especially when calcination was used before each new run in order to get rid of any organic material
deposited on its surface. Both materials displayed some tendency to leach copper in the solution,
albeit to an extent significantly larger for LDH than for the mixed oxide (0.4% and 4%, respectively).
The phenomenon, attributed to the capability of sodium ascorbate to chelate metal ions, translated into
an appreciable catalytic activity in the filtrate. This let the Authors to conclude that, at variance with
most of the supported CuAAC catalysts reported in related studies, homogeneous and heterogeneous
type of catalysis coexisted in their system.
Another instance of a copper-exchanged clay material, in this case natural montmorillonite, was
described recently by Mekhzoum et al. [204]. Rather surprisingly in view of the very low solubility
of CuI in water (approximate 4.2 × 10−4 M at 18–20 ◦ C) [205], the material was reportedly prepared
by vigorous stirring of the clay in a saturated aqueous solution of the copper salt. The activity of the
system was probed in the two-components CuAAC reactions (Scheme 1), performed in water at r.t.
and with about 2 mol % of supported catalyst (88%–98% yield in 2 h). Reuse of the material recovered
by filtration proved also feasible, albeit with a slight decrease of product yield in five consecutive
cycles (97% → 92%).
Finally, the entrapment of Cu(II) in a silica matrix by sol-gel process allowed Diz et al.
to prepare spherical nanoparticles (<100 nm in size) containing variable amounts of the metal
(0.05 wt %–9.4 wt %) [206]. Stirring with an aqueous solution of sodium ascorbate led to
complete fading of the pale-blue color of the solid and afforded an EPR silent material with
reasonable activity in two- and three-components CuAAC reactions in DMF or t-BuOH-H2 O (3:1)
(Schemes 1 and 2a: 80%–98% yield in 3–6 h at r.t., at 5 mol % loading and with three equiv. of added
N,N-diisopropylethylamine). Recyclability of the catalytic system was verified in two series of 10
consecutive runs (93% → 87% or 89% → 87% yield), while the nature of catalysis was confirmed to
be heterogeneous by running not only a standard “filtration experiment”, but also a “three-phase
test” with a benzylic azide derivative anchored to Wang resin. Remarkably, when the filtrates from
two CuAAC runs were subjected to copper quantification by ICP-MS, a very low metal content was
found (approximate 0.1–0.2 ppb). Even if the figures for dry triazole products are at least one order of
magnitude larger, it seems therefore that copper contamination by the system under exam is one of the
lowest reported to date for any recoverable CuAAC catalyst.
Molecules 2016, 21, 1174 32 of 43

5. Conclusions
With a cost ranking among the lowest for transition metals employed in organic synthesis, it might
be argued that recovery and recycling of the copper catalyst used in CuAAC is not of prime importance
for the economics of the process. Still, the difficulty of removing the metal from highly functionalized
products or polymeric materials and the specific problems raised by biomolecules, prompted the
introduction of new and more effective protocols in the past years. Almost invariably, this resulted in
the use of relatively expensive soluble ligands that in addition could not solve completely the issue of
product contamination. Especially in the perspective of synthesizing triazole compounds supposed to
undergo biological screening, or whose functional properties (e.g., fluorescence) are adversely affected
by copper contamination, this state of facts justifies the efforts currently devoted to the quest for
improved CuAAC catalytic systems.
As shown also by the cases discussed in the present review, the proposed solutions range from
very simple materials to very complex ones. In the case of the former, once the separation issue is
granted and a large enough turnover is achieved, the possibility of reusing the catalyst is probably a
useful, but not strictly essential feature of the system. On the contrary, in the case of catalyst comprising
expensive components the attainment of extensive recycling (presumably much beyond what disclosed
in the examples reported to date) appears to be an additional mandatory requirement, at least in view
of their possible use at scale [207].
In this context it is worth of note that, although the need or reducing copper contamination is
generally acknowledged in the introductory section of most of the published works, little care is paid
in a surprisingly large number of papers to provide reliable data on this aspect. In perspective, with the
introduction of additional components in the catalytic system that might be even more toxic (e.g., Ni)
or more difficult to spot than copper (e.g., organic contaminants from partially soluble polymeric
components in the material), this situation is at risk of taking the research in the field, very far from its
stated target.
As noted in the review of Haldon et al., “almost any copper source that delivers catalytically active
Cu(I) species in the reaction mixture can be employed as a pre-catalyst in the CuAAC reaction” [88].
Although the same conclusions can be drawn also for the recoverable systems discussed in the present
paper, different materials display nonetheless a broad spectrum of activity: Some work at low loading
and temperatures close to 25 ◦ C, in the very spirit of click-chemistry, other require high-boiling solvents
at reflux temperature. While this allows certainly some kind of ranking between the systems that keep
being published, also from this point of view a punctual comparison is severely hampered in some
cases by the lack of relevant data like, e.g., catalyst loading.
Considering the degree of ingenuity demonstrated in many of the examples reported to date,
the unquestionable success with some of the disclosed systems, and the relevance for the development
of greener synthetic processes, further developments in the field of recoverable catalyst for CuAAC
are expected. Hopefully, these advancements will strive to take the issues above into greater account
and make an effort to adhere more strictly to recommended best practices for benchmarking new
catalysts [208].

Acknowledgments: Financial support by the Università di Pisa (PRA_2016_46 “Studio di sistemi confinati:
verso un approccio multiscale”) and by MIUR (FIRB Project RBFR10BF5V “Multifunctional hybrid materials for
the development of sustainable catalytic processes”).
Conflicts of Interest: The author declares no conflict of interest.

Abbreviations
The following abbreviations are used in this manuscript:
AAS Atomic absorption spectroscopy
AES Atomic emission spectroscopy
Bipy 4,40 -Bipyridine
CD Cyclodextrin
Molecules 2016, 21, 1174 33 of 43

CNT carbon nano-tubes

CP-MASS Cross-polarization magic angle spinning spectroscopy
CRGO Chemically-reduced graphene oxide
CS Chitosan
CuAAC Copper-catalyzed azide-alkyne cycloaddition
CuNPs Copper nanoparticles
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
DVB divinylbenzene
EDACell Ethylenediamine-modified cellulose
EDS Energy-dispersive (X-ray) spectroscopy
FT-IR Fourier-transform infra-red spectroscopy
GO Graphene oxide
Himdc 4,5-Imidazoledicarboxylate
HPA Heteropolyacid
ICP Inductively-coupled plasma
LDH Layered double hydroxide
M-dots Melanine nanoparticles
MOF Metal-organic framework
MS Mass spectrometry
MW Microwave, molecular weight
NHC N-Heterocyclic carbene
OES Optical emission spectroscopy
pABA Poly(2-aminobenzoic acid)
PANI Polyaniline
PIB Poly(isobutylene)
PEG Poly(ethylene glycol), poly(ethylene oxide)
Pim Poly(vinyl imidazole)
p[C4R-NH2 ] amine-modified calix[4]resorcinarene-formaldehyde resin
P[im/IL] Imidazole-ionic liquid copolymer
PMMA Poly(methyl methacrylate)
POM Polyoxometalate
ppm, ppb parts per milion, parts per bilion
PTFE Poly(tetrafluoroethylene)
PVA Poly(vinyl alcohol)
PVP Poly(N-vinyl pyrrolidone)
PVPh Poly(4-vinylphenol)
r.t. Room temperature
SEM Scanning electron microscopy
SMI Poly(styrene-co-maleic anhydride) imide
SNW Schiff-base network polymer
TBTA Tris[(1-benzyl-1,2,3-triazole-4-yl)methyl]amine
TEM Transmission electron microscopy
TGA Thermogravimetric analysis
THF Tetrahydrofurane
TOF Turnover frequency
TON Turnover number
UV Ultraviolet spectroscopy
XPS X-ray photoelectron spectroscopy
XRD X-ray (powder) diffraction analysis
XRF X-ray fluorescence analysis

References
1. Kolb, H.C.; Finn, M.G.; Sharpless, K.B. Click chemistry: Diverse chemical function from a few good reactions.
Angew. Chem. Int. Ed. Engl. 2001, 40, 2004–2021. [CrossRef]
2. Tornoe, C.W.; Christensen, C.; Meldal, M. Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific
copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem. 2002, 67, 3057–3064.
[CrossRef] [PubMed]
3. Rostovtsev, V.V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. A stepwise Huisgen cycloaddition process:
Copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed. Engl.
2002, 41, 2596–2599. [CrossRef]
Molecules 2016, 21, 1174 34 of 43

4. Gil, M.V.; Arevalo, M.J.; Lopez, O. Click chemistry—What’s in a name? Triazole synthesis and beyond.
Synthesis 2007, 1589–1620. [CrossRef]
5. Tong, R.; Tang, L.; Ma, L.; Tu, C.; Baumgartner, R.; Cheng, J. Smart chemistry in polymeric nanomedicine.
Chem. Soc. Rev. 2014, 43, 6982–7012. [CrossRef] [PubMed]
6. Golas, P.L.; Matyjaszewski, K. Marrying click chemistry with polymerization: Expanding the scope of
polymeric materials. Chem. Soc. Rev. 2010, 39, 1338–1354. [CrossRef] [PubMed]
7. Mansfeld, U.; Pietsch, C.; Hoogenboom, R.; Becer, C.R.; Schubert, U.S. Clickable initiators, monomers and
polymers in controlled radical polymerizations—A prospective combination in polymer science. Polym. Chem.
2010, 1, 1560–1598. [CrossRef]
8. Sumerlin, B.S.; Vogt, A.P. Macromolecular engineering through click chemistry and other efficient
transformations. Macromolecules 2010, 43. [CrossRef]
9. Delaittre, G.; Guimard, N.K.; Barner-Kowollik, C. Cycloadditions in modern polymer chemistry.
Acc. Chem. Res. 2015, 48, 1296–1307. [CrossRef] [PubMed]
10. Espeel, P.; Du Prez, F.E. “Click”-inspired chemistry in macromolecular science: Matching recent progress
and user expectations. Macromolecules 2015, 48. [CrossRef]
11. Altintas, O.; Vogt, A.P.; Barner-Kowollik, C.; Tunca, U. Constructing star polymers via modular ligation
strategies. Polym. Chem. 2012, 3, 34–45. [CrossRef]
12. Chow, H.-F.; Lo, C.-M.; Chen, Y. Triazole-based polymer gels. Top. Heterocycl. Chem. 2012, 28, 137–162.
13. Wan, L.; Cai, C. Multicomponent synthesis of 1,2,3-triazoles in water catalyzed by silica-immobilized
NHC-Cu(I). Catal. Lett. 2012, 142, 1134–1140. [CrossRef]
14. Zheng, Y.; Li, S.; Weng, Z.; Gao, C. Hyperbranched polymers: Advances from synthesis to applications.
Chem. Soc. Rev. 2015, 44, 4091–4130. [CrossRef] [PubMed]
15. Pasini, D. The click reaction as an efficient tool for the construction of macrocyclic structures. Molecules 2013,
18, 9512–9530. [CrossRef] [PubMed]
16. Pangilinan, K.; Advincula, R. Cyclic polymers and catenanes by atom transfer radical polymerization (ATRP).
Polym. Int. 2014, 63, 803–813. [CrossRef]
17. Schumers, J.-M.; Gohy, J.-F.; Fustin, C.-A. A versatile strategy for the synthesis of block copolymers bearing a
photocleavable junction. Polym. Chem. 2010, 1, 161–163. [CrossRef]
18. Michael, P.; Binder, W.H. A mechanochemically triggered “click” catalyst. Angew. Chem. Int. Ed. 2015, 54,
13918–13922. [CrossRef] [PubMed]
19. Rana, S.; Cho, J.W. Functionalization of carbon nanotubes via Cu(I)-catalyzed Huisgen [3+2] cycloaddition
“click chemistry”. Nanoscale 2010, 2, 2550–2556. [CrossRef] [PubMed]
20. Segura, J.L.; Castelain, M.; Salavagione, H. Synthesis and properties of [60]fullerene derivatives
functionalized through copper catalyzed Huisgen cycloaddition reactions. Curr. Org. Synth. 2013, 10,
724–736. [CrossRef]
21. Segura, J.L.; Salavagione, H.J. Graphene in copper catalyzed azide-alkyne cycloaddition reactions: Evolution
from [60]fullerene and carbon nanotubes strategies. Curr. Org. Chem. 2013, 17, 1680–1693. [CrossRef]
22. Chen, Y.-X.; Triola, G.; Waldmann, H. Bioorthogonal chemistry for site-specific labeling and surface
immobilization of proteins. Acc. Chem. Res. 2011, 44, 762–773. [CrossRef] [PubMed]
23. Li, Y.; Cai, C. Click chemistry-based functionalization on non-oxidized silicon substrates. Chem. Asian J. 2011,
6, 2592–2605. [CrossRef] [PubMed]
24. Deng, X.; Lahann, J. Orthogonal surface functionalization through bioactive vapor-based polymer coatings.
J. Appl. Polym. Sci. 2014, 131, 40315–40323. [CrossRef]
25. Kantheti, S.; Narayan, R.; Raju, K.V.S.N. The impact of 1,2,3-triazoles in the design of functional coatings.
RSC Adv. 2015, 5, 3687–3708. [CrossRef]
26. Accurso, A.A.; Delaney, M.; O’Brien, J.; Kim, H.; Iovine, P.M.; Díaz, D.D.; Finn, M.G. Improved
metal-adhesive polymers from copper(I)-catalyzed azide–alkyne cycloaddition. Chem. Eur. J. 2014, 20,
10710–10719. [CrossRef] [PubMed]
27. Hein, J.E.; Fokin, V.V. Copper-catalyzed azide–alkyne cycloaddition (CuAAC) and beyond: New reactivity
of copper(I) acetylides. Chem. Soc. Rev. 2010, 39, 1302–1315. [CrossRef] [PubMed]
28. Jin, L.; Tolentino, D.R.; Melaimi, M.; Bertrand, G. Isolation of bis(copper) key intermediates in Cu-catalyzed
azide-alkyne “click reaction”. Sci. Adv. 2015, 1, e1500304. [CrossRef] [PubMed]
Molecules 2016, 21, 1174 35 of 43

29. Makarem, A.; Berg, R.; Rominger, F.; Straub, B.F. A fluxional copper acetylide cluster in CuAAC catalysis.
Angew. Chem. Int. Ed. Engl. 2015, 54, 7431–7435. [CrossRef] [PubMed]
30. Wang, C.; Ikhlef, D.; Kahlal, S.; Saillard, J.-Y.; Astruc, D. Metal-catalyzed azide-alkyne “click” reactions:
Mechanistic overview and recent trends. Coord. Chem. Rev. 2016, 316. [CrossRef]
31. Otvos, S.B.; Fulop, F. Flow chemistry as a versatile tool for the synthesis of triazoles. Catal. Sci. Technol. 2015,
5, 4926–4941. [CrossRef]
32. Kappe, C.O.; van der Eycken, E. Click chemistry under non-classical reaction conditions. Chem. Soc. Rev.
2010, 39, 1280–1290. [CrossRef] [PubMed]
33. Pistara, V.; Rescifina, A.; Chiacchio, M.A.; Corsaro, A. Use of microwave heating in the synthesis of
heterocycles from carbohydrates. Curr. Org. Chem. 2014, 18, 417–445. [CrossRef]
34. Brittain, W.D.G.; Buckley, B.R.; Fossey, J.S. Asymmetric copper-catalyzed azide-alkyne cycloadditions.
ACS Catal. 2016, 6, 3629–3636. [CrossRef]
35. Chen, M.-Y.; Song, T.; Zheng, Z.-J.; Xu, Z.; Cui, Y.-M.; Xu, L.-W. Tao-phos-controlled desymmetrization of
succinimide-based bisalkynes via asymmetric copper-catalyzed Huisgen alkyne-azide click cycloaddition:
Substrate scope and mechanism. RSC Adv. 2016, 6, 58698–58708. [CrossRef]
36. Van Dijk, M.; Rijkers, D.T.S.; Liskamp, R.M.J.; van Nostrum, C.F.; Hennink, W.E. Synthesis and applications
of biomedical and pharmaceutical polymers via click chemistry methodologies. Bioconjugate Chem. 2009, 20,
2001–2016. [CrossRef] [PubMed]
37. Nimmo, C.M.; Shoichet, M.S. Regenerative biomaterials that “click”: Simple, aqueous-based protocols for
hydrogel synthesis, surface immobilization, and 3D patterning. Bioconjugate Chem. 2011, 22, 2199–2209.
[CrossRef] [PubMed]
38. Hvilsted, S. Facile design of biomaterials by click chemistry. Polym. Int. 2012, 61, 485–494. [CrossRef]
39. Tron, G.C.; Pirali, T.; Billington, R.A.; Canonico, P.L.; Sorba, G.; Genazzani, A.A. Click chemistry reactions
in medicinal chemistry: Applications of the 1,3-dipolar cycloaddition between azides and alkynes.
Med. Res. Rev. 2008, 28, 278–308. [CrossRef] [PubMed]
40. Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Click chemistry for drug development and diverse
chemical-biology applications. Chem. Rev. 2013, 113, 4905–4979. [CrossRef] [PubMed]
41. Lutz, J.-F.; Zarafshani, Z. Efficient construction of therapeutics, bioconjugates, biomaterials and bioactive
surfaces using azide-alkyne “click” chemistry. Adv. Drug Deliv. Rev. 2008, 60, 958–970. [CrossRef] [PubMed]
42. Zhou, C.H.; Wang, Y. Recent researches in triazole compounds as medicinal drugs. Curr. Med. Chem. 2012,
19, 239–280. [CrossRef] [PubMed]
43. Sokolova, N.V.; Nenajdenko, V.G. Recent advances in the Cu(I)-catalyzed azide-alkyne cycloaddition:
Focus on functionally substituted azides and alkynes. RSC Adv. 2013, 3, 16212–16242. [CrossRef]
44. Holub, J.M.; Kirshenbaum, K. Tricks with clicks: Modification of peptidomimetic oligomers via
copper-catalyzed azide-alkyne [3+2] cycloaddition. Chem. Soc. Rev. 2010, 39, 1325–1337. [CrossRef]
[PubMed]
45. Meldal, M.; Tornoee, C.W.; Nielsen, T.E.; Diness, F.; Le Quement, S.T.; Christensen, C.A.; Jensen, J.F.;
Worm-Leonhard, K.; Groth, T.; Bouakaz, L.; et al. Hirschmann award address 2009: Merger of organic
chemistry with peptide diversity. Biopolymers 2010, 94, 161–182. [CrossRef] [PubMed]
46. Chan-Seng, D.; Lutz, J.-F. Solid-phase synthesis as a tool for the preparation of sequence-defined oligomers
based on natural amino acids and synthetic building blocks. ACS Symp. Ser. 2014, 1170, 103–116.
47. Aragão-Leoneti, V.; Campo, V.L.; Gomes, A.S.; Field, R.A.; Carvalho, I. Application of copper(I)-catalysed
azide/alkyne cycloaddition (CuAAC) “click chemistry” in carbohydrate drug and neoglycopolymer
synthesis. Tetrahedron 2010, 66, 9475–9492. [CrossRef]
48. Elchinger, P.-H.; Faugeras, P.-A.; Boens, B.; Brouillette, F.; Montplaisir, D.; Zerrouki, R.; Lucas, R.
Polysaccharides: The “click” chemistry impact. Polymers 2011, 3, 1607–1651. [CrossRef]
49. Tiwari, V.K.; Mishra, B.B.; Mishra, K.B.; Mishra, N.; Singh, A.S.; Chen, X. Cu-catalyzed click reaction in
carbohydrate chemistry. Chem. Rev. 2016, 116, 3086–3240. [CrossRef] [PubMed]
50. Amblard, F.; Cho, J.H.; Schinazi, R.F. Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction
in nucleoside, nucleotide, and oligonucleotide chemistry. Chem. Rev. 2009, 109, 4207–4220. [CrossRef]
[PubMed]
51. Kore, A.R.; Charles, I. Click chemistry based functionalizations of nucleoside, nucleotide and nucleic acids.
Curr. Org. Chem. 2013, 17, 2164–2191. [CrossRef]
Molecules 2016, 21, 1174 36 of 43

52. Harju, K.; Yli-Kauhaluoma, J. Recent advances in 1,3-dipolar cycloaddition reactions on solid supports.
Mol. Divers. 2005, 9, 187–207. [CrossRef] [PubMed]
53. Castro, V.; Rodríguez, H.; Albericio, F. CuAAC: An efficient click chemistry reaction on solid phase.
ACS Comb. Sci. 2016, 18. [CrossRef] [PubMed]
54. Fernandes, A.E.; Jonas, A.M.; Riant, O. Application of CuAAC for the covalent immobilization of
homogeneous catalysts. Tetrahedron 2014, 70, 1709–1731. [CrossRef]
55. Wang, D.; Deraedt, C.; Ruiz, J.; Astruc, D. Magnetic and dendritic catalysts. Acc. Chem. Res. 2015, 48,
1871–1880. [CrossRef] [PubMed]
56. Bunz, U.H.F. Adventures of an occasional click chemist. Synlett 2013, 24, 1899–1909. [CrossRef]
57. Cernat, A.; Tertis, M.; Cristea, C.; Sandulescu, R. Applications of click chemistry in the development of
electrochemical sensors. Int. J. Electrochem. Sci. 2015, 10, 6324–6337.
58. Chu, C.; Liu, R. Application of click chemistry on preparation of separation materials for liquid
chromatography. Chem. Soc. Rev. 2011, 40, 2177–2188. [CrossRef] [PubMed]
59. Ouerghui, A.; Elamari, H.; Dardouri, M.; Ncib, S.; Meganem, F.; Girard, C. Chemical modifications of
poly(vinyl chloride) to poly(vinyl azide) and “clicked” triazole bearing groups for application in metal cation
extraction. React. Funct. Polym. 2016, 100, 191–197. [CrossRef]
60. Palomo, J.M. Click-chemistry in biocatalysis. Curr. Org. Chem. 2013, 17, 691–700. [CrossRef]
61. Schoffelen, S.; van Hest, J.C.M. Chemical approaches for the construction of multi-enzyme reaction systems.
Curr. Opin. Struct. Biol. 2013, 23, 613–621. [CrossRef] [PubMed]
62. Roughley, S.D.; Jordan, A.M. The medicinal chemist’s toolbox: An analysis of reactions used in the pursuit
of drug candidates. J. Med. Chem. 2011, 54, 3451–3479. [CrossRef] [PubMed]
63. Hou, J.; Liu, X.; Shen, J.; Zhao, G.; Wang, P.G. The impact of click chemistry in medicinal chemistry.
Expert Opin. Drug Discov. 2012, 7, 489–501. [CrossRef] [PubMed]
64. Meldal, M.; Tornoe, C.W. Cu-catalyzed azide-alkyne cycloaddition. Chem. Rev. 2008, 108, 2952–3015.
[CrossRef] [PubMed]
65. Lallana, E.; Fernandez-Megia, E.; Riguera, R. Surpassing the use of copper in the click functionalization of
polymeric nanostructures: A strain-promoted approach. J. Am. Chem. Soc. 2009, 131, 5748–5750. [CrossRef]
[PubMed]
66. Hong, V.; Presolski, S.I.; Ma, C.; Finn, M.G. Analysis and optimization of copper-catalyzed azide-alkyne
cycloaddition for bioconjugation. Angew. Chem. Int. Ed. 2009, 48, 9879–9883. [CrossRef] [PubMed]
67. Diaz Velazquez, H.; Ruiz Garcia, Y.; Vandichel, M.; Madder, A.; Verpoort, F. Water-soluble NHC-Cu catalysts:
Applications in click chemistry, bioconjugation and mechanistic analysis. Org. Biomol. Chem. 2014, 12,
9350–9356. [CrossRef] [PubMed]
68. Hassan, S.; Mueller, T.J.J. Multicomponent syntheses based upon copper-catalyzed alkyne-azide
cycloaddition. Adv. Synth. Catal. 2015, 357, 617–666. [CrossRef]
69. Tao, C.-Z.; Cui, X.; Li, J.; Liu, A.-X.; Liu, L.; Guo, Q.-X. Copper-catalyzed synthesis of aryl azides and
1-aryl-1,2,3-triazoles from boronic acids. Tetrahedron Lett. 2007, 48, 3525–3529. [CrossRef]
70. Ostrovskis, P.; Volla, C.M.R.; Turks, M.; Markovic, D. Application of metal free click chemistry in biological
studies. Curr. Org. Chem. 2013, 17, 610–640. [CrossRef]
71. Jiang, Y.; Chen, J.; Deng, C.; Zhong, Z.; Suuronen, E.J. Click hydrogels, microgels and nanogels: Emerging
platforms for drug delivery and tissue engineering. Biomaterials 2014, 35, 4969–4985. [CrossRef] [PubMed]
72. Qin, A.; Liu, Y.; Tang, B.Z. Regioselective metal-free click polymerization of azides and alkynes.
Macromol. Chem. Phys. 2015, 216, 818–828. [CrossRef]
73. Uttamapinant, C.; Tangpeerachaikul, A.; Grecian, S.; Clarke, S.; Singh, U.; Slade, P.; Gee, K.R.; Ting, A.Y.
Fast, cell-compatible click chemistry with copper-chelating azides for biomolecular labeling. Angew. Chem.
Int. Ed. 2012, 51, 5852–5856. [CrossRef] [PubMed]
74. Rodionov, V.O.; Presolski, S.I.; Gardinier, S.; Lim, Y.-H.; Finn, M.G. Benzimidazole and related ligands for
Cu-catalyzed azide-alkyne cycloaddition. J. Am. Chem. Soc. 2007, 129, 12696–12704. [CrossRef] [PubMed]
75. Fuchs, M.; Goessler, W.; Pilger, C.; Kappe, C.O. Mechanistic insights into copper(I)-catalyzed azide-alkyne
cycloadditions using continuous flow conditions. Adv. Synth. Catal. 2010, 352, 323–328. [CrossRef]
76. Yamada, Y.M.A.; Sarkar, S.M.; Uozumi, Y. Amphiphilic self-assembled polymeric copper catalyst to parts per
million levels: Click chemistry. J. Am. Chem. Soc. 2012, 134, 9285–9290. [CrossRef] [PubMed]
Molecules 2016, 21, 1174 37 of 43

77. Deraedt, C.; Pinaud, N.; Astruc, D. Recyclable catalytic dendrimer nanoreactor for part-per-million CuI
catalysis of “click” chemistry in water. J. Am. Chem. Soc. 2014, 136, 12092–12098. [CrossRef] [PubMed]
78. Wang, C.; Wang, D.; Yu, S.; Cornilleau, T.; Ruiz, J.; Salmon, L.; Astruc, D. Design and applications of an
efficient amphiphilic “click” Cu(I) catalyst in water. ACS Catal. 2016, 6, 5424–5431. [CrossRef]
79. Wu, H.; Li, H.; Kwok, R.T.K.; Zhao, E.; Sun, J.Z.; Qin, A.; Tang, B.Z. A recyclable and reusable supported
Cu(I) catalyzed azide-alkyne click polymerization. Sci. Rep. 2014, 4, 5107. [CrossRef] [PubMed]
80. Zhang, W.; He, X.; Ren, B.; Jiang, Y.; Hu, Z. Cu(OAc)2 ·H2 O—An efficient catalyst for Huisgen-click reaction
in supercritical carbon dioxide. Tetrahedron Lett. 2015, 56, 2472–2475. [CrossRef]
81. Vidal, C.; Garcia-Alvarez, J. Glycerol: A biorenewable solvent for base-free Cu(I)-catalyzed 1,3-dipolar
cycloaddition of azides with terminal and 1-iodoalkynes. Highly efficient transformations and catalyst
recycling. Green Chem. 2014, 16, 3515–3521. [CrossRef]
82. Billault, I.; Pessel, F.; Petit, A.; Turgis, R.; Scherrmann, M.-C. Investigation of the copper(I) catalyzed
azide-alkyne cycloaddition reactions (CuAAC) in molten PEG2000. New J. Chem. 2015, 39, 1986–1995.
[CrossRef]
83. Mirsafaei, R.; Heravi, M.M.; Ahmadi, S.; Moslemin, M.H.; Hosseinnejad, T. In situ prepared copper
nanoparticles on modified KIT-5 as an efficient recyclable catalyst and its applications in click reactions in
water. J. Mol. Catal. A Chem. 2015, 402, 100–108. [CrossRef]
84. Singh, N. A concise and simple click reaction catalyzed by immobilized Cu(I) in an ionic liquid leading to
the synthesis of β-hydroxy triazoles. C. R. Chim. 2015, 18, 1257–1263. [CrossRef]
85. Yao, W.; Wang, H.; Cui, G.; Li, Z.; Zhu, A.; Zhang, S.; Wang, J. Tuning the hydrophilicity and hydrophobicity
of the respective cation and anion: Reversible phase transfer of ionic liquids. Angew. Chem. Int. Ed. 2016, 55,
7934–7938. [CrossRef] [PubMed]
86. Purohit, V.B.; Karad, S.C.; Patel, K.H.; Raval, D.K. Cu(N-heterocyclic carbene)chloride: An efficient catalyst
for multicomponent click reaction for the synthesis of 1,2,3-triazoles in water at room temperature. RSC Adv.
2014, 4, 46002–46007. [CrossRef]
87. Dervaux, B.; Du Prez, F.E. Heterogeneous azide-alkyne click chemistry: Towards metal-free end products.
Chem. Sci. 2012, 3, 959–966. [CrossRef]
88. Haldon, E.; Nicasio, M.C.; Perez, P.J. Copper-catalysed azide-alkyne cycloadditions (CuAAC): An update.
Org. Biomol. Chem. 2015, 13, 9528–9550. [CrossRef] [PubMed]
89. Chassaing, S.; Beneteau, V.; Pale, P. When CuAAC “click chemistry” goes heterogeneous. Catal. Sci. Technol.
2016, 6, 923–957. [CrossRef]
90. Hagiwara, H. Development of noncovalent supported ionic liquid phase catalyst (SILPC) for liquid-phase
reaction as a benign and sustainable protocol to immobilize homogeneous catalyst. Synlett 2012, 23, 837–850.
[CrossRef]
91. Jin, T.; Yan, M.; Yamamoto, Y. Click chemistry of alkyne-azide cycloaddition using nanostructured copper
catalysts. ChemCatChem 2012, 4, 1217–1229. [CrossRef]
92. Woo, H.; Kang, H.; Kim, A.; Jang, S.; Park, J.C.; Park, S.; Kim, B.-S.; Song, H.; Park, K.H. Azide-alkyne
Huisgen [3+2] cycloaddition using CuO nanoparticles. Molecules 2012, 17, 13235–13252. [CrossRef] [PubMed]
93. Alonso, F.; Moglie, Y.; Radivoy, G. Copper nanoparticles in click chemistry. Acc. Chem. Res. 2015, 48,
2516–2528. [CrossRef] [PubMed]
94. Astruc, D.; Lu, F.; Aranzaes, J.R. Nanoparticles as recyclable catalysts: The frontier between homogeneous
and heterogeneous catalysis. Angew. Chem. Int. Ed. 2005, 44, 7852–7872. [CrossRef] [PubMed]
95. Chahdoura, F.; Pradel, C.; Gomez, M. Copper(I) oxide nanoparticles in glycerol: A convenient catalyst for
cross-coupling and azide-alkyne cycloaddition processes. ChemCatChem 2014, 6, 2929–2936. [CrossRef]
96. Tsai, Y.-H.; Chanda, K.; Chu, Y.-T.; Chiu, C.-Y.; Huang, M.H. Direct formation of small Cu2 O nanocubes,
octahedra, and octapods for efficient synthesis of triazoles. Nanoscale 2014, 6, 8704–8709. [CrossRef]
[PubMed]
97. Hajipour, A.R.; Mohammadsaleh, F. Polyvinyl alcohol-stabilized cuprous oxide particles: Efficient and
recyclable heterogeneous catalyst for azide-alkyne cycloaddition in water at room temperature. J. Iran.
Chem. Soc. 2015, 12, 1339–1345. [CrossRef]
98. Jiang, Y.; Kong, D.; Zhao, J.; Qi, Q.; Li, W.; Xu, G. Cu(OAc)2 ·H2 O/NH2 NH2 ·H2 O: An efficient catalyst
system that in situ generates Cu2 O nanoparticles and HOAc for Huisgen click reactions. RSC Adv. 2014, 4,
1010–1014. [CrossRef]
Molecules 2016, 21, 1174 38 of 43

99. Chen, Y.; Zhuo, Z.-J.; Cui, D.-M.; Zhang, C. Copper catalyzed synthesis of 1-aryl-1,2,3-triazoles from aryl
iodides, alkynes, and sodium azide. J. Organomet. Chem. 2014, 749, 215–218. [CrossRef]
100. Huang, L.; Liu, W.; Wu, J.; Fu, Y.; Wang, K.; Huo, C.; Du, Z. Nano-copper catalyzed three-component reaction
to construct 1,4-substituted 1,2,3-triazoles. Tetrahedron Lett. 2014, 55, 2312–2316. [CrossRef]
101. Gang, F.; Dong, T.; Xu, G.; Fu, Y.; Du, Z. Nano-copper catalyzed three-component tandem cycloaddition and
N-alkylation reaction from aminophenylacetylenes, sodium azide and alkyl halides. Heterocycles 2015, 91,
1964–1971.
102. Jumde, R.P.; Evangelisti, C.; Mandoli, A.; Scotti, N.; Psaro, R. Aminopropyl-silica-supported Cu nanoparticles:
An efficient catalyst for continuous-flow Huisgen azide-alkyne cycloaddition (CuAAC). J. Catal. 2015, 324,
25–31. [CrossRef]
103. Tsoncheva, T.; Vankova, S.; Mehandjiev, D. Effect of the precursor and the preparation method on copper
based activated carbon catalysts for methanol decomposition to hydrogen and carbon monoxide. Fuel 2003,
82, 755–763. [CrossRef]
104. Zhao, J.; Liu, Z.; Sun, D. TPO-TPD study of an activated carbon-supported copper catalyst-sorbent used for
catalytic dry oxidation of phenol. J. Catal. 2004, 227, 297–303. [CrossRef]
105. Tseng, H.-H.; Wey, M.-Y. Study of SO2 adsorption and thermal regeneration over activated carbon-supported
copper oxide catalysts. Carbon 2004, 42, 2269–2278. [CrossRef]
106. Buckley, B.R.; Butterworth, R.; Dann, S.E.; Heaney, H.; Stubbs, E.C. “Copper-in-charcoal” revisited:
Delineating the nature of the copper species and its role in catalysis. ACS Catal. 2015, 5, 793–796. [CrossRef]
107. Lipshutz, B.H.; Frieman, B.A.; Tomaso, A.E., Jr. Copper-in-charcoal (Cu/C): Heterogeneous, copper-catalyzed
asymmetric hydrosilylations. Angew. Chem. Int. Ed. 2006, 45, 1259–1264. [CrossRef] [PubMed]
108. Lee, C.-T.; Huang, S.; Lipshutz, B.H. Copper-in-charcoal-catalyzed, tandem one-pot diazo transfer-click
reactions. Adv. Synth. Catal. 2009, 351, 3139–3142. [CrossRef]
109. Decan, M.R.; Scaiano, J.C. Study of single catalytic events at copper-in-charcoal: Localization of click activity
through subdiffraction observation of single catalytic events. J. Phys. Chem. Lett. 2015, 6, 4049–4053.
[CrossRef] [PubMed]
110. Shaygan Nia, A.; Rana, S.; Doehler, D.; Noirfalise, X.; Belfiore, A.; Binder, W.H. Click chemistry promoted by
graphene supported copper nanomaterials. Chem. Commun. 2014, 50, 15374–15377. [CrossRef] [PubMed]
111. Rossy, C.; Majimel, J.; Delapierre, M.T.; Fouquet, E.; Felpin, F.-X. Palladium and copper-supported on
charcoal: A heterogeneous multi-task catalyst for sequential Sonogashira-click and click-Heck reactions.
J. Organomet. Chem. 2014, 755, 78–85. [CrossRef]
112. D’Halluin, M.; Mabit, T.; Fairley, N.; Fernandez, V.; Gawande, M.B.; Le Grognec, E.; Felpin, F.-X.
Graphite-supported ultra-small copper nanoparticles—Preparation, characterization and catalysis
applications. Carbon 2015, 93, 974–983. [CrossRef]
113. Shaygan Nia, A.; Rana, S.; Doehler, D.; Osim, W.; Binder, W.H. Nanocomposites via a direct
graphene-promoted “click”-reaction. Polymer 2015, 79, 21–28. [CrossRef]
114. Shaygan Nia, A.; Rana, S.; Doehler, D.; Jirsa, F.; Meister, A.; Guadagno, L.; Koslowski, E.; Bron, M.;
Binder, W.H. Carbon-supported copper nanomaterials: Recyclable catalysts for Huisgen [3+2] cycloaddition
reactions. Chem. A Eur. J. 2015, 21, 10763–10770. [CrossRef] [PubMed]
115. Saif, M.J.; Flower, K.R. A general method for the preparation of N-heterocyclic carbene-silver(I) complexes
in water. Transit. Met. Chem. 2013, 38, 113–118. [CrossRef]
116. Reddy, V.H.; Reddy, Y.V.R.; Sridhar, B.; Reddy, B.V.S. Green catalytic process for click synthesis promoted
by copper oxide nanocomposite supported on graphene oxide. Adv. Synth. Catal. 2016, 358, 1088–1092.
[CrossRef]
117. Zhu, J.; Zeng, G.; Nie, F.; Xu, X.; Chen, S.; Han, Q.; Wang, X. Decorating graphene oxide with CuO
nanoparticles in a water-isopropanol system. Nanoscale 2010, 2, 988–994. [CrossRef] [PubMed]
118. Roy, I.; Bhattacharyya, A.; Sarkar, G.; Saha, N.R.; Rana, D.; Ghosh, P.P.; Palit, M.; Das, A.R.; Chattopadhyay, D.
In situ synthesis of a reduced graphene oxide/cuprous oxide nanocomposite: A reusable catalyst. RSC Adv.
2014, 4, 52044–52052. [CrossRef]
119. Lamblin, M.; Nassar-Hardy, L.; Hierso, J.-C.; Fouquet, E.; Felpin, F.-X. Recyclable heterogeneous palladium
catalysts in pure water: Sustainable developments in Suzuki, Heck, Sonogashira and Tsuji-Trost reactions.
Adv. Synth. Catal. 2010, 352, 33–79. [CrossRef]
Molecules 2016, 21, 1174 39 of 43

120. Putta, C.; Sharavath, V.; Sarkar, S.; Ghosh, S. Palladium nanoparticles on β-cyclodextrin functionalised
graphene nanosheets: A supramolecular based heterogeneous catalyst for C-C coupling reactions under
green reaction conditions. RSC Adv. 2015, 5, 6652–6660. [CrossRef]
121. Breslow, R. Hydrophobic effects on simple organic reactions in water. Acc. Chem. Res. 1991, 24, 159–164.
[CrossRef]
122. Dabiri, M.; Kasmaei, M.; Salari, P.; Movahed, S.K. Copper nanoparticle decorated three dimensional graphene
with high catalytic activity for Huisgen 1,3-dipolar cycloaddition. RSC Adv. 2016, 6, 57019–57023. [CrossRef]
123. Hashemi, E.; Beheshtiha, Y.S.; Ahmadi, S.; Heravi, M.M. In situ prepared CuI nanoparticles on modified
poly(styrene-co-maleic anhydride): An efficient and recyclable catalyst for the azide-alkyne click reaction in
water. Transit. Met. Chem. 2014, 39, 593–601. [CrossRef]
124. Saadat, S.; Nazari, S.; Afshari, M.; Shahabi, M.; Keshavarz, M. Copper(I) iodide nanoparticles
on polyaniline as a green, recoverable and reusable catalyst for multicomponent click synthesis of
1,4-disubstituted-1H-1,2,3-triazoles. Orient. J. Chem. 2015, 31, 1005–1012. [CrossRef]
125. Savva, I.; Kalogirou, A.S.; Chatzinicolaou, A.; Papaphilippou, P.; Pantelidou, A.; Vasile, E.; Vasile, E.;
Koutentis, P.A.; Krasia-Christoforou, T. PVP-crosslinked electrospun membranes with embedded Pd and
Cu2 O nanoparticles as effective heterogeneous catalytic supports. RSC Adv. 2014, 4, 44911–44921. [CrossRef]
126. Patil, J.D.; Patil, S.A.; Pore, D.M. A polymer supported ascorbate functionalized task specific ionic liquid:
An efficient reusable catalyst for 1,3-dipolar cycloaddition. RSC Adv. 2015, 5, 21396–21404. [CrossRef]
127. Liu, J.; Chen, L.; Cui, H.; Zhang, J.; Zhang, L.; Su, C.-Y. Applications of metal-organic frameworks in
heterogeneous supramolecular catalysis. Chem. Soc. Rev. 2014, 43, 6011–6061. [CrossRef] [PubMed]
128. Jayaramulu, K.; Suresh, V.M.; Maji, T.K. Stabilization of Cu2 O nanoparticles on a 2D metal-organic framework
for catalytic Huisgen 1,3-dipolar cycloaddition reaction. Dalton Trans. 2015, 44, 83–86. [CrossRef] [PubMed]
129. Yu, W.; Jiang, L.; Shen, C.; Xu, W.; Zhang, P. A highly efficient synthesis of N-glycosyl-1,2,3-triazoles using a
recyclable cellulose-copper(0) catalyst in water. Catal. Commun. 2016, 79, 11–16. [CrossRef]
130. Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Unsupported copper nanoparticles in the 1,3-dipolar cycloaddition
of terminal alkynes and azides. Eur. J. Org. Chem. 2010, 2010, 1875–1884. [CrossRef]
131. Agalave, S.G.; Pharande, S.G.; Gade, S.M.; Pore, V.S. Alumina-supported copper iodide: An efficient and
recyclable catalyst for microwave-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles via three-component
reaction in water. Asian J. Org. Chem. 2015, 4, 943–951. [CrossRef]
132. Gupta, M.; Gupta, M.; Paul, S.; Kant, R.; Gupta, V.K. One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles
via Huisgen 1,3-dipolar cycloaddition catalysed by SiO2 -Cu(I) oxide and single crystal X-ray analysis of
1-benzyl-4-phenyl-1H-1,2,3-triazole. Monatsh. Chem. 2015, 146, 143–148. [CrossRef]
133. Albadi, J.; Shiran, J.A.; Mansournezhad, A. Click synthesis of 1,4-disubstituted-1,2,3-triazoles catalysed by
CuO-CeO2 nanocomposite in the presence of amberlite-supported azide. J. Chem. Sci. 2014, 126, 147–150.
[CrossRef]
134. Albadi, J.; Alihosseinzadeh, A.; Mansournezhad, A. Regioselective synthesis of 1,2,3-triazoles catalyzed over
ZnO supported copper oxide nanocatalyst as a new and efficient recyclable catalyst in water. Acta Chim. Slov.
2015, 62, 617–624. [CrossRef] [PubMed]
135. Rad, M.N.S.; Behrouz, S.; Behrouz, M.; Sami, A.; Mardkhoshnood, M.; Zarenezhad, A.; Zarenezhad, E. Design,
synthesis and biological evaluation of novel 1,2,3-triazolyl β-hydroxy alkyl/carbazole hybrid molecules.
Mol. Divers. 2016, 20, 705–718. [CrossRef] [PubMed]
136. Soltani Rad, M.N.; Behrouz, S.; Doroodmand, M.M.; Movahediyan, A. Copper-doped silica cuprous sulfate
as a highly efficient and new heterogeneous nano catalyst for [3+2] Huisgen cycloaddition. Tetrahedron 2012,
68, 7812–7821. [CrossRef]
137. Varma, R.S. Nano-catalysts with magnetic core: Sustainable options for greener synthesis. Sustain. Chem. Process.
2014, 2. [CrossRef]
138. Karimi, B.; Mansouri, F.; Mirzaei, H.M. Recent applications of magnetically recoverable nanocatalysts in C-C
and C-X coupling reactions. ChemCatChem 2015, 7, 1736–1789. [CrossRef]
139. Biswas, M.; Saha, A.; Dule, M.; Mandal, T.K. Polymer-assisted chain-like organization of CuNi alloy
nanoparticles: Solvent-adoptable pseudohomogeneous catalysts for alkyne-azide click reactions with
magnetic recyclability. J. Phys. Chem. C 2014, 118, 22156–22165. [CrossRef]
Molecules 2016, 21, 1174 40 of 43

140. Lu, J.; Ma, E.-Q.; Liu, Y.-H.; Li, Y.-M.; Mo, L.-P.; Zhang, Z.-H. One-pot three-component synthesis of
1,2,3-triazoles using magnetic NiFe2 O4 -glutamate-Cu as an efficient heterogeneous catalyst in water.
RSC Adv. 2015, 5, 59167–59185. [CrossRef]
141. Chetia, M.; Ali, A.A.; Bhuyan, D.; Saikia, L.; Sarma, D. Magnetically recoverable chitosan-stabilised
copper-iron oxide nanocomposite material as an efficient heterogeneous catalyst for azide-alkyne
cycloaddition reactions. New J. Chem. 2015, 39, 5902–5907. [CrossRef]
142. Gonzaga, F.; Sadowski, L.P.; Rambarran, T.; Grande, J.; Adronov, A.; Brook, M.A. Highly efficient divergent
synthesis of dendrimers via metal-free “click” chemistry. J. Polym. Sci. Part A Polym. Chem. 2013, 51,
1272–1277. [CrossRef]
143. Widegren, J.A.; Finke, R.G. A review of the problem of distinguishing true homogeneous catalysis from
soluble or other metal-particle heterogeneous catalysis under reducing conditions. J. Mol. Catal. A Chem.
2003, 198, 317–341. [CrossRef]
144. Bhardwaj, M.; Jamwal, B.; Paul, S. Novel Cu(0)-Fe3 O4 @SiO2 /NH2 cel as an efficient and sustainable magnetic
catalyst for the synthesis of 1,4-disubstituted-1,2,3-triazoles and 2-substituted-benzothiazoles via one-pot
strategy in aqueous media. Catal. Lett. 2016, 146, 629–644. [CrossRef]
145. Anil Kumar, B.S.P.; Harsha Vardhan Reddy, K.; Satish, G.; Uday Kumar, R.; Nageswar, Y.V.D. Synthesis of
β-hydroxy-1,4-disubstituted-1,2,3-triazoles catalyzed by copper ferrite nanoparticles in tap water using click
chemistry. RSC Adv. 2014, 4, 60652–60657. [CrossRef]
146. Nemati, F.; Heravi, M.M.; Elhampour, A. Magnetic nano-Fe3 O4 @TiO2 /Cu2 O core-shell composite:
An efficient novel catalyst for the regioselective synthesis of 1,2,3-triazoles using a click reaction. RSC Adv.
2015, 5, 45775–45784. [CrossRef]
147. Nasrollahzadeh, M.; Mohammad Sajadi, S. Green synthesis of copper nanoparticles using Ginkgo biloba
leaf extract and their catalytic activity for the Huisgen [3+2] cycloaddition of azides and alkynes at room
temperature. J. Colloid Interface Sci. 2015, 457, 141–147. [CrossRef] [PubMed]
148. Nasrollahzadeh, M.; Sajadi, S.M.; Mirzaei, Y. An efficient one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles
at room temperature by green synthesized Cu NPs using Otostegia persica leaf extract. J. Colloid Interface Sci.
2016, 468, 156–162. [CrossRef] [PubMed]
149. Sasikala, R.; Rani, S.K.; Easwaramoorthy, D.; Karthikeyan, K. Lanthanum loaded CuO nanoparticles:
Synthesis and characterization of a recyclable catalyst for the synthesis of 1,4-disubstituted 1,2,3-triazoles
and propargylamines. RSC Adv. 2015, 5, 56507–56517. [CrossRef]
150. Wang, S.-S.; Yang, G.-Y. Recent advances in polyoxometalate-catalyzed reactions. Chem. Rev. 2015, 115,
4893–4962. [CrossRef] [PubMed]
151. Mizuno, N.; Misono, M. Heterogeneous catalysis. Chem. Rev. 1998, 98, 199–218. [CrossRef] [PubMed]
152. Amini, M.; Naslhajian, H.; Farnia, S.M.F.; Kang, H.K.; Gautam, S.; Chae, K.H. Polyoxomolybdate-stabilized
Cu2 O nanoparticles as an efficient catalyst for the azide-alkyne cycloaddition. New J. Chem. 2016, 40,
5313–5317. [CrossRef]
153. Diez-Gonzalez, S. Well-defined copper(I) complexes for click azide-alkyne cycloaddition reactions: One click
beyond. Catal. Sci. Technol. 2011, 1, 166–178. [CrossRef]
154. Girard, C.; Oenen, E.; Aufort, M.; Beauviere, S.; Samson, E.; Herscovici, J. Reusable polymer-supported
catalyst for the [3+2] Huisgen cycloaddition in automation protocols. Org. Lett. 2006, 8, 1689–1692. [CrossRef]
[PubMed]
155. Slimi, R.; Kalhor-Monfared, S.; Plancq, B.; Girard, C. A-21·CuI as a catalyst for Huisgen’s reaction: About
iodination as a side-reaction. Tetrahedron Lett. 2015, 56, 4339–4344. [CrossRef]
156. Jia, Z.; Wang, K.; Li, T.; Tan, B.; Gu, Y. Functionalized hypercrosslinked polymers with knitted N-heterocyclic
carbene-copper complexes as efficient and recyclable catalysts for organic transformations. Catal. Sci. Technol.
2016, 6, 4345–4355. [CrossRef]
157. Karimi Zarchi, M.A.; Nazem, F. One-pot three-component synthesis of 1,4-disubstituted 1H-1,2,3-triazoles
using green and recyclable cross-linked poly(4-vinylpyridine)-supported copper sulfate/sodium ascorbate
in water/t-BuOH system. J. Iran. Chem. Soc. 2014, 11, 1731–1742. [CrossRef]
158. Monguchi, Y.; Nozaki, K.; Maejima, T.; Shimoda, Y.; Sawama, Y.; Kitamura, Y.; Kitade, Y.; Sajiki, H.
Solvent-free Huisgen cyclization using heterogeneous copper catalysts supported on chelate resins.
Green Chem. 2013, 15, 490–495. [CrossRef]
Molecules 2016, 21, 1174 41 of 43

159. Kitamura, Y.; Taniguchi, K.; Maegawa, T.; Monguchi, Y.; Kitade, Y.; Sajiki, H. Copper/HP20: Novel and
polymer-supported copper catalyst for Huisgen cycloaddition. Heterocycles 2009, 77, 521–532.
160. Kitamura, Y.; Taniguchi, K.; Maegawa, T.; Monguchi, Y.; Kitade, Y.; Sajiki, H. Cu/HP20-catalyzed solvent-free
Huisgen cycloaddition at ordinary temperatures. Heterocycles 2014, 88, 233–243.
161. Movassagh, B.; Rezaei, N. Polystyrene resin-supported CuI-cryptand 22 complex: A highly efficient and
reusable catalyst for three-component synthesis of 1,4-disubstituted 1,2,3-triazoles under aerobic conditions
in water. Tetrahedron 2014, 70, 8885–8892. [CrossRef]
162. Tavassoli, M.; Landarani-Isfahani, A.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Mohammadpoor-
Baltork, I. Polystyrene-supported ionic liquid copper complex: A reusable catalyst for one-pot three-
component click reaction. Appl. Catal. A 2015, 503, 186–195. [CrossRef]
163. Wu, H.; Dong, W.; Wang, Z.; Yao, B.; Chen, M.; Sun, J.; Qin, A.; Tang, B.Z. An air-stable supported Cu(I)
catalyst for azide-alkyne click polymerization. Sci. China Chem. 2015, 58, 1748–1752. [CrossRef]
164. Pourjavadi, A.; Safaie, N.; Hosseini, S.H.; Bennett, C. Graphene oxide/poly(vinyl imidazole) nanocomposite:
An effective support for preparation of highly loaded heterogeneous copper catalyst. Appl. Organomet. Chem.
2015, 29, 601–607. [CrossRef]
165. Pourjavadi, A.; Hosseini, S.H.; Matloubi Moghaddam, F.; Ayati, S.E. Copper loaded cross-linked
poly(ionic liquid): Robust heterogeneous catalyst in ppm amount. RSC Adv. 2015, 5, 29609–29617. [CrossRef]
166. Islam, R.U.; Taher, A.; Choudhary, M.; Witcomb, M.J.; Mallick, K. A polymer supported Cu(I) catalyst for the
“click reaction” in aqueous media. Dalton Trans. 2015, 44, 1341–1349. [CrossRef] [PubMed]
167. Taskin, O.S.; Dadashi-Silab, S.; Kiskan, B.; Weber, J.; Yagci, Y. Highly efficient and reusable microporous
Schiff base network polymer as a heterogeneous catalyst for CuAAC click reaction. Macromol. Chem. Phys.
2015, 216, 1746–1753. [CrossRef]
168. Ladmiral, V.; Legge, T.M.; Zhao, Y.; Perrier, S. “Click” chemistry and radical polymerization: Potential loss of
orthogonality. Macromolecules 2008, 41, 6728–6732. [CrossRef]
169. Mouradzadegun, A.; Alsadat Mostafavi, M. Copper-loaded hypercrosslinked polymer decorated with
pendant amine groups: A green and retrievable catalytic system for quick [3+2] Huisgen cycloaddition in
water. RSC Adv. 2016, 6, 42522–42531. [CrossRef]
170. Fan, Q.; Cheng, K.; Hu, X.; Ma, X.; Zhang, R.; Yang, M.; Lu, X.; Xing, L.; Huang, W.; Gambhir, S.S.; et al.
Transferring biomarker into molecular probe: Melanin nanoparticle as a naturally active platform for
multimodality imaging. J. Am. Chem. Soc. 2014, 136, 15185–15194. [CrossRef] [PubMed]
171. Sun, Y.; Hong, S.; Ma, X.; Cheng, K.; Wang, J.; Zhang, Z.; Yang, M.; Jiang, Y.; Hong, X.; Cheng, Z. Recyclable
Cu(I)/melanin dots for cycloaddition, bioconjugation and cell labelling. Chem. Sci. 2016, 7, 5888–5892.
[CrossRef]
172. Wegner, J.; Ceylan, S.; Kirschning, A. Flow chemistry—A key enabling technology for (multistep) organic
synthesis. Adv. Synth. Catal. 2012, 354, 17–57. [CrossRef]
173. Lin, W.-Y.; Wang, Y.; Wang, S.; Tseng, H.-R. Integrated microfluidic reactors. Nano Today 2009, 4, 470–481.
[CrossRef] [PubMed]
174. Wang, Y.; Lin, W.-Y.; Liu, K.; Lin, R.J.; Selke, M.; Kolb, H.C.; Zhang, N.; Zhao, X.-Z.; Phelps, M.E.;
Shen, C.K.F.; et al. An integrated microfluidic device for large-scale in situ click chemistry screening.
Lab Chip 2009, 9, 2281–2285. [CrossRef] [PubMed]
175. Li, H.; Whittenberg, J.J.; Zhou, H.; Ranganathan, D.; Desai, A.V.; Koziol, J.; Zeng, D.; Kenis, P.J.A.;
Reichert, D.E. Development of a microfluidic “click chip” incorporating an immobilized Cu(I) catalyst.
RSC Adv. 2015, 5, 6142–6150. [CrossRef] [PubMed]
176. Chtchigrovsky, M.; Primo, A.; Gonzalez, P.; Molvinger, K.; Robitzer, M.; Quignard, F.; Taran, F. Functionalized
chitosan as a green, recyclable, biopolymer-supported catalyst for the [3+2] Huisgen cycloaddition.
Angew. Chem. Int. Ed. Engl. 2009, 48, 5916–5920. [CrossRef] [PubMed]
177. Baig, R.B.N.; Varma, R.S. Copper on chitosan: A recyclable heterogeneous catalyst for azide-alkyne
cycloaddition reactions in water. Green Chem. 2013, 15, 1839–1843. [CrossRef]
178. Anil Kumar, B.S.P.; Harsha Vardhan Reddy, K.; Karnakar, K.; Satish, G.; Nageswar, Y.V.D. Copper on chitosan:
An efficient and easily recoverable heterogeneous catalyst for one pot synthesis of 1,2,3-triazoles from aryl
boronic acids in water at room temperature. Tetrahedron Lett. 2015, 56, 1968–1972. [CrossRef]
179. Cadman, J.; Zhou, S.; Chen, Y.; Li, Q. Cuttlebone: Characterisation, application and development of
biomimetic materials. J. Bionic Eng. 2012, 9, 367–376. [CrossRef]
Molecules 2016, 21, 1174 42 of 43

180. Ghodsinia, S.S.E.; Akhlaghinia, B.; Jahanshahi, R. Direct access to stabilized CuI using cuttlebone as a
natural-reducing support for efficient CuAAC click reactions in water. RSC Adv. 2016, 6, 63613–63623.
[CrossRef]
181. Liu, X.; Novoa, N.; Manzur, C.; Carrillo, D.; Hamon, J.-R. New organometallic Schiff-base copper complexes
as efficient “click” reaction precatalysts. New J. Chem. 2016, 40, 3308–3313. [CrossRef]
182. Tavassoli, M.; Landarani-Isfahani, A.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Mohammadpoor-
Baltork, I. Copper dithiol complex supported on silica nanoparticles: A sustainable, efficient, and eco-friendly
catalyst for multicomponent click reaction. ACS Sustain. Chem. Eng. 2016, 4, 1454–1462. [CrossRef]
183. Garces, K.; Fernandez-Alvarez, F.J.; Garcia-Orduna, P.; Lahoz, F.J.; Perez-Torrente, J.J.; Oro, L.A. Grafting of
copper(I)-NHC species on MCM-41: Homogeneous versus heterogeneous catalysis. ChemCatChem 2015, 7,
2501–2507. [CrossRef]
184. Lai, B.; Huang, Z.; Jia, Z.; Bai, R.; Gu, Y. Silica-supported metal acetylacetonate catalysts with a robust and
flexible linker constructed by using 2-butoxy-3,4-dihydropyrans as dual anchoring reagents and ligand
donors. Catal. Sci. Technol. 2016, 6, 1810–1820. [CrossRef]
185. Naeimi, H.; Nejadshafiee, V.; Masoum, S. Highly efficient copper-imprinted functionalized mesoporous
organosilica nanocomposites as a recyclable catalyst for click synthesis of 1,2,3-triazole derivatives under
ultrasound irradiation: Multivariate study by factorial design of experiments. RSC Adv. 2015, 5, 15006–15016.
[CrossRef]
186. Pourjavadi, A.; Hosseini, S.H.; Zohreh, N.; Bennett, C. Magnetic nanoparticles entrapped in the cross-linked
poly(imidazole/imidazolium) immobilized Cu(II): An effective heterogeneous copper catalyst. RSC Adv.
2014, 4, 46418–46426. [CrossRef]
187. Zohreh, N.; Hosseini, S.H.; Pourjavadi, A.; Bennett, C. Immobilized copper(II) on nitrogen-rich
polymer-entrapped Fe3 O4 nanoparticles: A highly loaded and magnetically recoverable catalyst for aqueous
click chemistry. Appl. Organomet. Chem. 2016, 30, 73–80. [CrossRef]
188. Pourjavadi, A.; Motamedi, A.; Hosseini, S.H.; Nazari, M. Magnetic starch nanocomposite as a green
heterogeneous support for immobilization of large amounts of copper ions: Heterogeneous catalyst for click
synthesis of 1,2,3-triazoles. RSC Adv. 2016, 6, 19128–19135. [CrossRef]
189. Mery, D.; Astruc, D. Dendritic catalysis: Major concepts and recent progress. Coord. Chem. Rev. 2006, 250,
1965–1979. [CrossRef]
190. Bahrami, K.; Sheikh Arabi, M. Copper immobilized ferromagnetic nanoparticle triazine dendrimer
(FMNP@TD-Cu(II))-catalyzed regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles. New J. Chem.
2016, 40, 3447–3455. [CrossRef]
191. Shin, J.-A.; Lim, Y.-G.; Lee, K.-H. Copper-catalyzed azide-alkyne cycloaddition reaction in water using
cyclodextrin as a phase transfer catalyst. J. Org. Chem. 2012, 77, 4117–4122. [CrossRef] [PubMed]
192. Kaboudin, B.; Mostafalu, R.; Yokomatsu, T. Fe3 O4 nanoparticle-supported Cu(II)-β-cyclodextrin complex as
a magnetically recoverable and reusable catalyst for the synthesis of symmetrical biaryls and 1,2,3-triazoles
from aryl boronic acids. Green Chem. 2013, 15, 2266–2274. [CrossRef]
193. Kaboudin, B.; Abedi, Y.; Yokomatsu, T. One-pot synthesis of 1,2,3-triazoles from boronic acids in water
using Cu(II)-β-cyclodextrin complex as a nanocatalyst. Org. Biomol. Chem. 2012, 10, 4543–4548. [CrossRef]
[PubMed]
194. Mahdavi, M.; Lijan, H.; Bahadorikhalili, S.; Ma.bxsolid.mani, L.; Rashidi Ranjbar, P.; Shafiee, A. Copper
supported β-cyclodextrin grafted magnetic nanoparticles as an efficient recyclable catalyst for one-pot
synthesis of 1-benzyl-1H-1,2,3-triazoldibenzodiazepinone derivatives via click reaction. RSC Adv. 2016, 6,
28838–28843. [CrossRef]
195. Chan, T.R.; Fokin, V.V. Polymer-supported copper(I) catalysts for the experimentally simplified azide-alkyne
cycloaddition. QSAR Comb. Sci. 2007, 26, 1274–1279. [CrossRef]
196. Moghaddam, F.M.; Ayati, S.E.; Firouzi, H.R.; Ghorbani, F. Immobilization of copper ions onto
α-amidotriazole-functionalized magnetic nanoparticles and their application in the synthesis of triazole
derivatives in water. Appl. Organomet. Chem. 2016, 30, 488–493. [CrossRef]
197. Moghaddam, F.M.; Ayati, S.E. Copper immobilized onto a triazole functionalized magnetic nanoparticle:
A robust magnetically recoverable catalyst for “click” reactions. RSC Adv. 2015, 5, 3894–3902. [CrossRef]
Molecules 2016, 21, 1174 43 of 43

198. Tajbakhsh, M.; Farhang, M.; Baghbanian, S.M.; Hosseinzadeh, R.; Tajbakhsh, M. Nano magnetite supported
metal ions as robust, efficient and recyclable catalysts for green synthesis of propargylamines and
1,4-disubstituted 1,2,3-triazoles in water. New J. Chem. 2015, 39, 1827–1839. [CrossRef]
199. Safa, K.D.; Mousazadeh, H. A simple and efficient synthesis of organosilicon compounds containing
1,2,3-triazole moieties catalyzed by ZSM-5 zeolite-supported Cu-Co bimetallic oxides. Monatsh. Chem. 2016.
[CrossRef]
200. Dubey, N.; Sharma, P.; Kumar, A. Clay-supported Cu(II) catalyst: An efficient, heterogeneous, and recyclable
catalyst for synthesis of 1,4-disubstituted 1,2,3-triazoles from alloxan-derived terminal alkyne and substituted
azides using click chemistry. Synth. Commun. 2015, 45, 2608–2626. [CrossRef]
201. Mohammed, S.; Padala, A.K.; Dar, B.A.; Singh, B.; Sreedhar, B.; Vishwakarma, R.A.; Bharate, S.B. Recyclable
clay supported Cu(II) catalyzed tandem one-pot synthesis of 1-aryl-1,2,3-triazoles. Tetrahedron 2012, 68,
8156–8162. [CrossRef]
202. Ötvös, S.B.; Georgiádes, Á.; Ádok-Sipiczki, M.; Mészáros, R.; Pálinkó, I.; Sipos, P.; Fülöp, F. A layered double
hydroxide, a synthetically useful heterogeneous catalyst for azide-alkyne cycloadditions in a continuous-flow
reactor. Appl. Catal. A 2015, 501, 63–73. [CrossRef]
203. Gonzalez-Olvera, R.; Urquiza-Castro, C.I.; Negron-Silva, G.E.; Angeles-Beltran, D.; Lomas-Romero, L.;
Gutierrez-Carrillo, A.; Lara, V.H.; Santillan, R.; Morales-Serna, J.A. Cu-Al mixed oxide catalysts for
azide-alkyne 1,3-cycloaddition in ethanol-water. RSC Adv. 2016, 6, 63660–63666. [CrossRef]
204. Mekhzoum, M.E.M.; Benzeid, H.; Qaiss, A.E.K.; Essassi, E.M.; Bouhfid, R. Copper(I) confined in interlayer
space of montmorillonite: A highly efficient and recyclable catalyst for click reaction. Catal. Lett. 2016, 146,
136–143. [CrossRef]
205. Weast, R.C. CRC Handbook of Chemistry and Physics, 55th ed.; CRC Press: Cleveland, OH, USA, 1974.
206. Diz, P.; Pernas, P.; El Maatougui, A.; Tubio, C.R.; Azuaje, J.; Sotelo, E.; Guitian, F.; Gil, A.; Coelho, A.
Sol-gel entrapped Cu in a silica matrix: An efficient heterogeneous nanocatalyst for Huisgen and Ullmann
intramolecular coupling reactions. Appl. Catal. A 2015, 502, 86–95. [CrossRef]
207. Hübner, S.; de Vries, J.G.; Farina, V. Why does industry not use immobilized transition metal complexes as
catalysts? Adv. Synth. Catal. 2016, 358, 3–25. [CrossRef]
208. Bligaard, T.; Bullock, R.M.; Campbell, C.T.; Chen, J.G.; Gates, B.C.; Gorte, R.J.; Jones, C.W.;
Jones, W.D.; Kitchin, J.R.; Scott, S.L. Toward benchmarking in catalysis science: Best practices, challenges,
and opportunities. ACS Catal. 2016, 6, 2590–2602. [CrossRef]

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