Tandem catalysis of an aldol-'click' reaction system within a molecular hydrogel

Article abstract of DOI:10.3390/molecules21060744

A heterogeneous supramolecular catalytic system for multicomponent aldol-'click' reactions is reported. The copper(I) metallohydrogel functionalized with a phenyltriazole fragment was able to catalyze the multicomponent reaction between phenylacetylene, p

Full text of DOI:10.3390/molecules21060744

molecules
Article
Tandem Catalysis of an Aldol-‘Click’ Reaction System
within a Molecular Hydrogel
Marco Araújo, Iván Muñoz Capdevila, Santiago Díaz-Oltra and Beatriu Escuder *
Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12071 Castelló, Spain;
cerqueir@uji.es (M.A.); munozi@uji.es (I.M.C.); sdiaz@uji.es (Q.D.-O.)
* Correspondence: escuder@uji.es; Tel.: +34-964-729-155
Academic Editor: J.A.A.W. Elemans
Received: 26 April 2016; Accepted: 3 June 2016; Published: 8 June 2016
Abstract: A heterogeneous supramolecular catalytic system for multicomponent aldol-‘click’ reactions
is reported. The copper(I) metallohydrogel functionalized with a phenyltriazole fragment was able to
catalyze the multicomponent reaction between phenylacetylene, p-nitrobenzaldehyde, and an azide
containing a ketone moiety, obtaining the corresponding aldol products in good yields. A possible
mechanistic pathway responsible for this unexpected catalytic behavior has been proposed.
Keywords: aldol addition; click reaction; tandem catalysis; supramolecular gels; multicomponent
system
1. Introduction
Enzymes, the catalysts used by living organisms, are a clear example of nature efficiency.
These organisms are responsible to perform diverse chemical transformations with high selectivity
and specifity, being able to produce structurally complex compounds through multienzimatic cascade
reactions [1]. By contrast, in classical synthetic chemistry, individual transformations are conducted as
stepwise processes, punctuated by the purification and isolation of intermediates at each stage of the
sequence. In an attempt to mimic different aspects of synthetic strategies that operate in biological
systems, chemists have been challenged to design artificial systems that simulate the enzymatic
ability of performing multistep reactions [2]. Supramolecular systems such as multicomponent
transition metal materials formed by self-assembly of programmed ligand building blocks, molecular
gels, metal-organic frameworks, cyclodextrin derived compounds, or dendrimers have been widely
investigated as biomimetic systems [3–10]. As a result of a growing interest in mimicking nature
processes, much attention has been directed to “one-pot” processes involving multiple catalytic
transformations followed by a single work up [11]. “One-pot” tandem reactions, where multiple
catalysts and reagents combined in a single reaction vessel embark in a sequence of precisely staged
catalytic steps have become highly attractive [12]. Depending on the number of catalytic species or
whether there is intervention in the reaction system, tandem catalysis can be subcategorized in three
different categories: orthogonal, auto-tandem, or assisted tandem catalysis [13]. In orthogonal tandem
catalysis sequential catalytic processes occur through two or more functionally distinct, and preferably
non-interfering catalytic cycles whereas, in auto-tandem or assisted tandem processes, the catalysis
occurs in the presence of a unique catalyst [14]. The main feature that distinguishes between these last
two processes is the spontaneity of the catalytic processes. While auto-tandem catalysis involves two or
more mechanistically distinct catalysis promoted by a single catalyst precursor, where both cycles occur
spontaneously by cooperative interaction of several species (catalyst, substrate, additional reagents
if required) present from the outset of the reaction, assisted tandem catalysis requires deliberate
intervention in the reaction system to switch between two catalytic mechanisms [13].
Molecules 2016, 21, 744; doi:10.3390/molecules21060744
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From the synthetic chemistry point of view, ideal reaction strategies for the preparation of
structurally complex substances should involve sequences in which stereocontrolled formation of
multiple carbon-carbon bonds occur in a single step starting from simple and readily available
materials [15]. In this field, aldol addition reactions are among the transformations that have greatly
simplified the construction of asymmetric C-C bonds, being particularly important both in complex
molecule synthesis and in the preparation of optically active small molecule building blocks [16]. These
reactions are usually catalyzed by L-proline, following a mechanistic pathway which involves the
formation of an intermediary enamine [17,18]. Indeed, supramolecular catalytic gels functionalized
with L-proline fragments have been reported as efficient catalysts for aldol addition reactions [19,20].
Several tandem or multicomponent systems comprising combinations of aldol reactions with others,
such as aldol-allylation [21], 1,4-addition-aldol [22,23], Michael-aldol [24], or amination-aldol [25] have
been investigated for the synthesis of natural products or respective building blocks. On the other hand,
in the field of ‘click’ chemistry such systems are scarce. ‘Click’ reactions are a set of powerful, highly
reliable, versatile, and selective reactions that quickly generate new molecules by “clicking” small units
together through heteroatom links (C-X-C) and has become the preferred strategy for the development
of new compounds with desired property profiles [26]. Between all the reactions that can afford a ‘click’
status, the copper(I) catalyzed Huisgen 1,3-dipolar cycloaddition of alkynes and azides (CuAAC) is
regarded as the premier example of a ‘click’ reaction, particularly due to the mild reaction conditions
and regioselectivity, affording exclusively 1,4-regioisomers [27–29]. Molecular triazole functionalized
gels have been recently reported as efficient heterogeneous supramolecular catalysts for the Huisgen
1,3-azide alkyne cycloaddition [30]. Particularly for CuAAC reaction, between the very few examples of
multicomponent systems found in literature, the “one-pot” synthesis of 1,4-disubstituted 1,2,3-triazoles
starting from
α
-bromoketone is considered one of the most practical and useful, since terminal
32]. A clear
acetylene reacts with the in situ generated azide, providing a safer synthetic procedure [31
,
example of a tandem ‘click’ reaction is the tandem enantioselective biocatalytic epoxide ring opening
and [3+2] azide-alkyne cycloaddition, which occurs in the presence of halohydrin dehalogenase and
the traditional catalytic mixture copper(II) sulphate/sodium ascorbate [33]. However, very little work
has been done on matching together in a “one-pot” system aldol and ‘click’ reactions, which are
nowadays highly important in the field of pharmaceutical and materials industries [34,35]. Joining
together two reactions in a “one-pot” system often results in time and economy-efficient greener
synthetic processes, which are highly attractive in the industrial point of view.
Having this in mind, our investigation was focused on joining these two reactions in
an auto-tandem catalytic ‘click’/aldol system. In a green and sustainable chemistry perspective, water
was used as the preferred solvent to carry out the multicomponent reaction. The catalytic performance
of the self-assembled triazole functionalized metallogel Cu(I)-PhTzVal3, particularly suitable for the
catalysis of ‘click’ reactions, was evaluated in the three-component system and a possible catalytic
mechanistic pathway has been proposed.
2. Results and Discussion
2.1. Design and Synthesis
The bolaamphiphilic L-valine derived gelator is composed by a central diaminopropane core
linked to a L-valine fragment in each side and functionalized with a phenyltriazole moiety separated
by a four carbon alkyl chain. The gelator has in its structure four amide bonds that, together with
the aromatic rings, could behave as gelation motifs, promoting the self-assembly of the compound
(Figure 1).
The synthesis of the PhTzVal3 gelator involved the attachement of the activated ester of the
bromobutyric acid to the three carbon alkylidendiamine [36] by simple peptide coupling, followed by
a nucleophilic substitution of the halide with an azide and consequent coupling with the commercially
available phenylacetylene through a copper(I) catalyzed Huisgen 1,3-diplolar cycloaddition (see
Supplementary Materials).

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Figure 1. Structure of the PhTzVal3 gelator.
2.2. Self-Assembly Studies
The PhTzVal3 gelator was able to aggregate in water at concentrations of 5.7 mM, returning
a swollen precipitate that can flow along the solution. The gelation procedure consisted of heating
the gelator until complete dissolution, followed by 20 s of sonication. Typical thermotropic and
viscoelastic properties such as gel-to-sol transitions or minimum gelation concentration have not been
investigated since it was impossible to obtain a gel that did not flow upon inversion of the test tube.
Unlike most metallogels described in literature [37–42], the PhTzVal3 gelator was able to aggregate
with and without the presence of the copper salt CuBr, discarding a metal-induced self-assembly
process. Moreover, the gelator PhTzVal3 exhibited an appreciable copper loading capacity, being able
to coordinate 71% CuBr initially present in solution, as determined by ICP-MS.
It is thought that the PhTzVal3 molecules aggregate in such a way that the triazole
fragments coordinate copper(I) in a tetrahedral morphology, resembling the well-described TBTA
complexes [43,44]. Thus, a possible interference of the metal on the self-assembly of the gelator was
investigated by wide-angle X-ray diffraction (WAXD) (Figure 2).
Figure 2. Diffractograms obtained for the hydrogels PhTzVal3 (A) and Cu(I)-PhTzVal3 (B).
The obtained diffractograms suggest that the gelator PhTzVal3 aggregates in a semi-amorphous
structure both in the presence and absence of the copper salt CuBr. It is curious to observe that, in the
presence of copper, it seems that the gelator acquires an even more unorganized structure (Figure 2B).
The native gel and the corresponding metallogel were also analyzed by circular dichroism
spectroscopy to get a deeper insight on the influence of the metal on the final structural arrangement
of the gel (Figure 3). This technique provides information on the conformational arrangement of
self-assembled structures [45].
The native gel PhTzVal3 exhibits a strong positive signal around 207 nm, which is inverted in the
presence of the copper salt. This might suggest that during the self-assembly process, the coordination
of the copper(I) with the triazole fragments of the gelator molecules provide an inversion in the
final conformational orientation of the gel, probably due to crosslinking between the metal and the
gelator molecules.
The influence of the metal on the morphology of the hydrogel aggregates was investigated by
Transmission Electron Microscopy (Figure 4).

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Figure 3.
Circular dichroism spectra obtained for the hydrogels PhTzVal3 (grey) and
Cu(I)-PhTzVal3 (black).
Figure 4. TEM analysis of the metallogel Cu(I)-PhTzVal3
and corresponding EDS spectrum (C).
(A); STEM analysis of Cu(I)-PhTzVal3 (B)
The Cu(I)-PhTzVal3 metallogel exhibits an entangled crosslinked network of long and thin fibers.
The presence of the metal allowed the acquisition of STEM pictures without staining the samples.
The coordination of copper(I) to the gel resulted in the formation of an extended fibrous network
exhibiting a wide copper(I) distribution along the fibers, as evidenced by the white contrast of the
metallogel network (Figure 4B). The presence of copper was further confirmed by EDS analysis, where
only carbon, oxygen, copper, and nickel were detected, this last one arising from the sample grid.
The absence of a 1:1 Cu:Br ratio in the EDS spectrum supports the successful coordination of the metal
to the pheyltriazole gel, resulting in the formation of an extended organometallic network.
2.3. Catalysis
2.3.1. Design of the Tandem Catalytic System
The design of the multicomponent catalytic system requires the presence of, at least, one
bifunctional compound that could undergo both ‘click’ and aldol addition reaction. The synthesis
of this reactant (N3Cet) was achieved by simple reaction of the chloroacetone with sodium azide, as
reported elsewhere [46]. The compounds chosen to complete the tandem system were the commercially
available phenylacetylene and p-nitrobenzaldehyde (Figure 5).
Figure 5. Structures of reactants and possible products involved in the tandem ‘click’-aldol
reaction system.

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As usual in aldol addition reactions, two possible diastereoisomers can be obtained as main
reaction products such as 2.syn and 2.anti in both antipodal forms: (R, R), (S, S) and (R, S), (S, R)
for syn and anti diastereoisomers, respectively. Considering the stronger acidity of the
positioned between the azide and carbonyl group, the formation of the compound , arising from
a possible addition on the methyl group of reactant , would not be expected. Preliminary experiments
α-hydrogen
3
1
performed on these reactions confirmed the absence of NMR signals corresponding to this product.
This complex reaction system can be divided in four stepwise ‘click’ and aldol addition reactions,
as represented in Figure 6.
Figure 6. Click and aldol reactions guiding to the formation of the possible intermediates
final products 2.syn and 2.anti.
4 and 6 and
The formation of the intermediate products 4.syn and 4.anti or
6 will highly depend on the
competitiveness of the three-component reaction system. These intermediate products will further
undergo ‘click’ or aldol addition, yielding the final reaction products (Figure 6).
2.3.2. Catalysis of the Tandem ‘Click’-Aldol Reaction System
The catalytic ability of the gelator Cu(I)-PhTzVal3 was evaluated in the three-component system
(Figure 7). The reactions were carried out in distilled water at room temperature and with stirring, for
periods of four days, using 10 mol % of Cu(I)-PhTzVal3 catalyst. Blank experiments in the presence of
CuBr or without any catalyst were also performed.
Figure 7. Structures of reactants and products involved in the tandem system.
An excess of
1 (10 eq) was used in order to avoid the occurrence of possible retro-aldol reactions.
Consequently, a similar molar ratio of the commercially available phenylacetylene was also used

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to assure the formation of the intermediate product
6
in excess. The conversions achieved were
determined by 1H-NMR (Table 1), where it could be observed the presence of a single diastereoisomer
(see Supplementary Materials). The coupling constant between the CHN and CHOH protons
determined to this product (J = 3.2 Hz) was similar to the one found for the same protons on the
intermediate 4.syn, allowing its identification as 2.syn [46].
Table 1. Conversions achieved for the three-component reaction system after four days 1.
Entry
Catalyst (10 mol %)
4.syn (%)
2.syn (%)
6 (%) 2
1
2
3
4
Cu(I)-PhTzVal3
<5
0
0
33
0
0
97
0
96
0
PhTzVal3
CuBr
-
0
0
1
The reactant p-nitrobenzaldehyde (0.86 mg; 5.7
ˆ
10´3 mmol) was dissolved in
1
(5.6 mg; 5.7
ˆ
10´2 mmol)
and the resultant mixture transferred to a 8 mL screw-capped vial containing 2 mL of water and, if desired,
10 mol % of catalyst. Phenylacetylene (5.82 mg; 5.7
10´2 mmol) was subsequently added and the mixture
allowed to react at room temperature and under stirring for four days. At the end of the experiment, the
products were directly extracted with CDCl3 (3 330 L). The organic phase was dried over anhydrous MgSO4
and the conversion determined by 1H-NMR. 2 The conversion of
was calculated based on the phenylacetylene,
ˆ
ˆ
µ
6
while the conversion of 4 and 2 was determined considering the p-nitrobenzaldehyde as the limiting reagent.
The obtained results highlight the good catalytic performance of the metallogel Cu(I)-PhTzVal3
for both ‘click’ and aldol addition reactions, although in the former only 30% conversion has been
achieved (Table 1, entry 1). However, this conversion was still considerably higher than the one
obtained in the presence of pure PhTzVal3 aggregates, CuBr or only in water, where no final aldol
product has been detected (Table 1, entries 2–4). Although it is widely known from literature the good
catalytic performance of triazole ligands in the copper(I) catalyzed Huisgen 1,3-cycloaddition [47], the
conversions achieved for this reaction were relatively similar in the presence of Cu(I)-PhTzVal3 or
CuBr, probably due to the long reaction times (Table 1, entries 1 and 3). However, no ‘click’ product
6
has been obtained when the reaction was carried in the absence of copper (I) (Table 1, entries 2 and 4).
The catalytic behavior of the metallogel Cu(I)-PhTzVal3 towards the aldol addition reaction is
quite surprising, since to the best of author’s knowledge, there is no evidence in literature about the
catalysis of aldol reactions in the presence of copper(I) coordinated triazole fragments. In an attempt
to better understand the interesting catalytic behavior of the hydrogel Cu(I)-PhTzVal3 towards the
three-component system, the catalytic performance was followed for periods ranging between 8 h to
4 days (Table 2). The reactions were carried in similar conditions as the ones mentioned above and the
conversions determined by 1H-NMR.
Table 2.
of Cu(I)-PhTzVal3
Conversions achieved for the three-component reaction system in the presence
1
.
Reaction
Time
Reactants Proportion
(p-Nitrobenzaldehyde:1:Phenylacetylene)
Entry
4.syn (%)
2.syn (%)
6 (%) 2
1
2
3
4
5
6
8 h
1:10:10
1:10:10
1:10:10
1:10:10
1:10:10
1:20:10
<5
<5
<5
<5
<5
55
20
26
61
31
33
35
13
19
95
97
97
97
1 day
2 days
3 days
4 days
4 days
1
Typical procedure: The reactant p-nitrobenzaldehyde (0.86 mg; 5.7
amount of and the resultant mixture transferred to a 8 mL screw-capped vial containing 3 mL of water and
10 mol % of Cu(I)-PhTzVal3 catalyst, composed by the gelator PhTzVal3 (8 mg; 11.4
10´3 mmol) and the
copper salt CuBr (0.82 mg; 5.7
10´3 mmol). Phenylacetylene (5.82 mg; 5.7 10´2 mmol) was subsequently
added and the mixture allowed to react at room temperature and under stirring for four days. At the end of the
experiment, the products were directly extracted with CDCl3 (3 330 L). The organic phase was dried over
anhydrous MgSO4 and the conversion determined by 1H-NMR. 2 The conversion of
was calculated based on
was determined considering the p-nitrobenzaldehyde as
ˆ
10´3 mmol) was dissolved in the desired
1
ˆ
ˆ
ˆ
ˆ
µ
6
the phenylacetylene, while the conversion of
the limiting reagent.
4 and 2

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The results indicated in Table 2 clearly highlight the good catalytic activity of the metallogel
Cu(I)-PhTzVal3 towards the three-component reaction system, achieving 61% of conversion to the
final product
(Table 2, entry 3). It is also curious to observe that the conversions achieved for
similar between each other during the first two days (Table 2, entry 1–2), suggesting that the
2
just after two days of reaction in the presence 10 mol % of the metallogel catalyst
and were relatively
formed
2
6
6
was immediately reacting with the p-nitrobenzaldehyde available in the reaction medium. However, it
appears that there is an accentuated increase in the kinetics of the ‘click’ reaction towards its completion
after two days of reaction, which coincides with the highest conversion achieved for
2. The lower
conversions achieved after three and four days of reaction, 31% and 33%, respectively, might be caused
by a possible reversion of the aldol addition due to the scarce solubility of the intermediate
instability of the final product (Table 2, entries 4–5).
6 or possible
The compound
2 can also be obtained if 20 eq excess of 1 is used in the three-component reaction
system, in the presence of 10 mol % Cu(I)-PhTzVal3 (Table 2, entry 6). Although the final product was
formed in a relatively low amount (Table 2, entry 6), the conversion achieved for the intermediate
product
in the presence of 10 equivalents of
Thus, it can be suggested that the presence of a high excess of
addition between and the p-nitrobenzaldehyde to the products, resulting in the formation of a higher
amount of . Further ‘click’ coupling of the intermediate product 4.syn with the commercially available
4
(55%) was considerably higher in comparison with the one obtained for the reactions carried
, where the conversion did not reach the 5% (Table 2, entries 1–5).
displaces the equilibrium of the aldol
1
1
1
4
phenylacetylene guides to the formation of the final product 2.syn.
This behavior suggests that the three-component reaction system is able to follow two different
pathways depending on the competitiveness and on the initial reaction conditions, as represented in
Figure 8.
Figure 8. Possible reaction pathways involved in the three-component system.
When initial equimolar amounts of
system follows pathway B, where the ‘click’ reaction between the
kinetically favored guiding to the formation of the intermediary . This intermediate product can
further undergo an aldol addition to achieve the formation of the final product . However, in the
presence of 20 eq. of , the equilibrium of the aldol addition between and the p-nitrobenzaldehyde
is displaced and the reaction can proceed through pathway A, favoring the formation of
This intermediate product can subsequently undergo a ‘click’ reaction with the phenylacetylene
to achieve the final product . However, the relatively similar conversion achieved for the final product
(35%) through both pathways after four days’ reaction suggest that the pathway B does not favor the
formation of a higher amount of final product in comparison with pathway A (Table 2, entries 5–6).
1
and phenylacetylene are present, the three-component
1
and the phenylacetylene is
6
2
1
1
4.
2
2

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Nevertheless, independently on the reaction pathway followed during the multicomponent reaction
system, it is clear that the gelator Cu(I)-PhTzVal3 acts as a good tandem catalyst for both the aldol
and ‘click’ reactions occurring in this three-component system The 55% conversion achieved in this
aldol addition reaction between
for the ‘click’ reaction between
1
1
and p-nitrobenzaldehyde together with the 98% conversion obtained
and the phenylacetylene, using 20 eq , supports the good catalytic
1
activity of the metallogel Cu(I)-PhTzVal3 for both reactions (Table 2, entry 6).
To isolate and completely characterize the final product , the three-component reaction was
2
performed in higher scale in the presence of 10 mol % Cu(I)-PhTzVal3 for two days, following similar
conditions as the ones used represented in Figure 7, and the resultant crude mixture purified through
column chromatography using silica flash. However, the 1H-NMR of the resultant fractions exhibited
a mixture of peaks characteristic of product degradation, which was probably caused by the acidity of
the silica. This high instability of the product 2 may support the low yields obtained after four days’
reaction. Thus, the same reaction was mounted again for two days and the mixture purified by column
chromatography using alumina type II as stationary phase. Also in this case, the resultant 1H-NMR was
not completely pure, but some peaks of 2 could be detected together with characteristic degradation
peaks. The presence of this product was further confirmed by high-resolution mass-spectrometry,
giving a protonated adduct at m/z = 353.1249 (see Supplementary Materials). The enantiomeric excess
was also determined by high pressure liquid chromatography (HPLC), suggesting that
a racemic mixture (see Supplementary Materials).
2 is formed as
The mechanistic pathway by which the metallogel Cu(I)-PhTzVal3 is able to catalyze this tandem
three-component reaction may be similar to the one followed by type II (fuculose-1-phosphate)
aldolase, where the substrate is activated by the presence of the Zn2+ coordinated to a histidine
fragment [48]. The type II aldolases use dihydroxyacetone phosphate (DHAP) as substrate to produce
2-keto-3,4-dihydroxy adducts. It has been reported that in this reaction, the Zn2+ polarizes the carbonyl
group of the substrate by coordination, facilitating the removal of the α-hydrogen by the glutamate
residue present in the enzyme structure. In this mechanism, a tyrosine residue from the adjoining
subunit also assists in the activation of the incoming aldehyde by donating a proton to stabilize the
developing charge. This hydrogen bond is responsible for the asymmetric induction at C-4, while the
shielding of the Si face of the DHAP enediolate by protein assures the correct stereochemistry of the
C-3 product [49].
In our specific case, the mild coordination of the triazole ligand to copper(I) may favor the
coordination of the carbonyl group of the substrate of the aldol addition reaction, leading to the
formation of a tetrahedral complex. Depending on the predominant reaction pathway, an azido or
a triazole group of the substrate may also coordinate to the metal center (Figure 9).
Figure 9. Proposed complexes formed between Cu(I) coordinated to the triazole fragments of the
metallogel and the aldol addition substrate. Complex A is formed if reaction undergoes through
pathway A and coordination complex B is present if reaction proceeds through pathway B.
Similarly to type II aldolases, this coordination of the substrate to the metal center polarizes the
carbonyl group, increasing the acidity of the
α-methylene hydrogen. In addition, a possible increase
in the basicity of the medium arising from the gelation of Cu(I)-PhTzVal3 may result in the easiest

Molecules 2016, 21, 744
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removal of the
the p-nitrobenzaldehyde (Figure 10). Once
α
-hydrogen proton from the substrate and consequent attack on the carbonyl group of
is formed, the mild coordination ability of the triazole
2
moiety would allow the detachment of the final product from the molecular gel, making it available to
embark in a new catalytic cycle.
Figure 10. Proposed catalytic mechanism for the aldol reaction in the presence of the gel catalyst
Cu(I)-PhTzVal3. The represented catalytic mechanism is illustrative of reactions following pathway A.
It is important to remind that by using only CuBr as catalyst (10 mol %), no aldol product has
been observed in the three-component reaction (Table 1, entry 3). This result reinforces the important
role of the metallogel on the catalysis of this aldol addition reaction, suggesting that an aggregation
effect may also be determinant in this catalytic activity. The change in the basicity of the medium
arising from a self-assembly process has already been reported for bolaamphiphilic gels functionalized
with L-proline fragments [50]. Rodríguez-Llansola et al. reported that such supramolecular-induced
enhancement of basicity aroused from the close proximity of the pyrrolidinic residues on the surface of
the gel fibers, which was suggested to favor the cooperative assistance of several basic groups on the
deprotonation of the substrate and consequent formation of an intermediate enolate [19].
In the case of this three-component system, a small increase in the basicity of the medium provided
by the formation of the Cu(I)-PhTzVal3 coordination complex together with the proximity of triazole
sites in the hydrogel fibres could easily catalyze the multicomponent reaction, considering the acidic
nature of the α-hydrogen of 1. The acidic environment of this proton arises not only from its position
between a carbonyl and an azide group, but also from the polarization of the carbonyl group upon
coordination of the substrate to the copper(I) center. Some additional contribution on the increase on
the basicity of the medium due to coordination of water to the metallohydrogel complex, as reported in
literature for some copper complexes, cannot be discarded [51]. This multicomponent reaction follows
an auto-tandem catalytic process, since it occurs in the presence of a single catalyst and all the species
are present from the beginning of the reaction.
This tandem catalytic system join together the features of aldol addition and ‘click’ reactions,
leading to the “one-pot” synthesis of a molecule containing a triazole moiety together with two adjacent
stereocenters. The reported biological activities of 1,2,3-triazoles, such as anticancer, antifungal,
antibacterial, antivirus, coupled with the presence of asymmetric C-C bonds potentiate the use of the
resultant products as important building blocks in the synthesis of biologically active molecules [26].

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3. Materials and Methods
3.1. Structural and Morphological Characterization
1H- and 13C-NMR spectra measuremen˝ts were recorded in a Varian Mercury 300 MHz
spectrometer (Varian, Palo Alto, CA, USA) at 30 C. Powder X-ray diffraction (XRD) was performed at
room temperature with a Bruker D4 Endeavor X-ray powder diffractometer (Bruker AXS, Madison,
WI, USA) by using Cu-K radiation. A sample of the dried gel was placed on a sample holder and data
˝ ˝
were collected for 2θ values between 2 and 40 with a step size of 0.03 and a time step of 10 s. Circular
dichroism (CD) spectra were recorded in a Jasco J-810 spectropolarimeter (Jasco, Peabody, MA, USA).
The measurements were performed on pellets composed by 1 mg of lyophilized gel and 50 mg of KBr.
For transmission electron microscopy (TEM), a small portion of the gel was placed on a nickel grid
coated with carbon and allowed to dry on air. Images were recorded in a JEOL 2100 microscope (JEOL,
Peabody, MA, USA). Catalytic enantiomeric excess was determined by HPLC (Agilent Technologies,
Santa Clara, CA, USA) using a Chiralpack IA column,
rate = 1.5 mL/min.
λ = 254 nm, Ethanol/Hexane (v/v: 15/85), flow
3.2. Synthesis
Detailed synthetic procedures and characterisation are found in the Supplementary Materials.
3.3. Gelation Procedure
The gelator PhTzVal3 (8 mg; 11.4
ˆ
10´3 mmol) was heated in a 8 mL screw-capped vial for
5 min, in the presence of 2 mL of water. The resultant hot solution was then sonicated for 20 s,
forming a swollen precipitate, which was subsequently allowed to age for 20 min at room temperature.
The formation of the metallogels was achieved by heating together the gelator and the copper salt
CuBr in a 2:1 molar ratio.
3.4. Quantification of Coordinated Copper
After the formation of the catalytic metallogel, 100
a 1 mL syringe and filtered through a 0.22 m filter. The filter was washed with a solution of 5% HNO3
(2 1 mL) in Milli-Q water to remove remaining uncoordinated copper. A 25 mL solution of the sample
µL of surrounding solution were collected with
µ
ˆ
in 5% HNO3 was prepared and the concentration of copper(I) determined by inductively coupled
plasma-mass spectrometry (ICP-MS) using an Agilent 7500 cx (Agilent Technologies, Santa Clara,
CA, USA).
3.5. General Procedure for Catalytic Experiments
The reactant p-nitrobenzaldehyde (0.86 mg; 5.7
and the resultant mixture added directly on a 8 mL screw-capped vial containing 2 mL of water
and, when needed, 10 mol % of the desired catalyst. Phenylacetylene (5.82 mg; 5.7
10´2 mmol)
ˆ
10´3 mmol) was dissolved in th desired amount
of
1
ˆ
was subsequently added and the mixture allowed to react at room temperature and under stirring
for an adequate period of time. At the end of the experiment, the products were directly extracted
with CDCl3 (3
ˆ
330 µL). The organic phase was dried over anhydrous MgSO4 and the conversion
determined by 1H-NMR. The catalytic experiments were performed in triplicate to assure the accuracy
of the results.
4. Conclusions
The design and synthesis of a gelator that could be used in the catalysis of a multicomponent
‘click’-aldol reaction system was successfully achieved. The three-component reaction was performed
in the presence of metallogel Cu(I)-PhTzVal3 (10 mol %), achieving around 65% conversion in only
two days. Furthermore, the competitiveness between the reactions in the multicomponent system
could be tuned by simply adjusting the amount of reactants that are present from the outset of the

Molecules 2016, 21, 744
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reaction. The fact that both intermediates
4 and 6 could be obtained in high yields when 20 eq of 1
is present at the outset of the multicomponent reaction highlights the good catalytic activity of the
metallogel Cu(I)-PhTzVal3 for both reactions.
It is proposed that the catalysis of the aldol addition in the presence of the metallogel
Cu(I)-PhTzVal3 follows a type II aldolase mechanistic pathway, where the coordination of the substrate
to the metal center results in the polarization of the carbonyl group and consequent acidification of the
α
-hydrogen, whose removal might be assisted by an increase in the basicity of the medium provided
by the supramolecular gelation of the catalyst.
This unexpected biomimetic catalytic activity shown by the metallogel Cu(I)-PhTzVal3 may
open a new insight on the application of triazole functionalized compounds on the catalysis of
aldol-type reactions, as well as on the tandem catalysis of similar ‘click’-aldol multicomponent systems.
Furthermore, the amino acid derived nature of this tandem metallohydrogel catalyst may confer it
with additional biocompatibility and biodegradability, allowing its use in similar tandem reactions
occurring in a biological environment.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
6/744/s1.
Acknowledgments: This work was supported by the EU (Marie Curie ITN-Smartnet, Grant PITN-GA-
2012-316656). M. A. thanks EU for an ESR Marie Curie contract.
Author Contributions: B.E. and S.D.-O. conceived and designed the experiments; M.A. and I.M.C. performed the
experiments; M.A. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
The following abbreviations are used in this manuscript:
ICP-MS
WAXD
CD
Inductively Coupled Plasma-Mass Spectrometry
Wide-Angle X-Ray Diffraction
Circular Dichroism
TEM
Eq
Transmission Electron Microscopy
Equivalents
NMR
HPLC
Nuclear Magnetic Resonance
High-Performance Liquid Chromatography
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Sample Availability: Samples of the compounds PhTzVal3, 1, 4 and 6 are available from the authors.
©
2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).