Triazolyl-Based Molecular Gels as Ligands for Autocatalytic ‘Click’ Reactions

Article abstract of DOI:10.1002/chem.201600594

The catalytic performance of triazolyl-based molecular gels was investigated in the Huisgen 1,3-dipolar cycloaddition of alkynes and azides. Low-molecular-weight gelators derived from l-valine were synthesized and functionalized with a triazole fragment.

Full text of DOI:10.1002/chem.201600594

DOI: 10.1002/chem.201600594
Full Paper
&
Heterogeneous Catalysis
Triazolyl-Based Molecular Gels as Ligands for Autocatalytic ‘Click’
Reactions
Marco Araffljo, Santiago Díaz-Oltra, and Beatriu Escuder*[a]
Abstract: The catalytic performance of triazolyl-based mo-
lecular gels was investigated in the Huisgen 1,3-dipolar cy-
cloaddition of alkynes and azides. Low-molecular-weight ge-
lators derived from l-valine were synthesized and functional-
ized with a triazole fragment. The resultant compounds
formed gels either with or without copper, in a variety of
solvents of different polarity. The gelators coordinated CuI
and exhibited a high catalytic activity in the gel phase for
the model reaction between phenylacetylene and benzyla-
zide. Additionally, the gels were able to participate in auto-
catalytic synthesis and the influence of small structural
changes on their performance was observed.
Introduction
triazole ligands include the tris[(1-benzyl-1H-1,2,3-triazol-4-yl)-
methyl]amine (TBTA) or its analogue bearing bulky tert-butyl
groups, 2-[4-{(bis[(1-tert-butyl-1H-1,2,3-triazol-4-yl)methyl]ami-
no)methyl}-1H-1,2,3-triazol-1-yl]ethyl hydrogen sulfate (BTTES),
which is described as one of the most efficient ligands for the
copper-catalyzed azide-alkyne cycloaddition (CuAAC) reported
so far.[11] TBTA has also been investigated as a heterogeneous
catalyst for CuAAC after being anchored onto a NovaSynꢀ TG
amino resin.[9] Polymer solid supports containing Amberlist or
terpyridine, silica-supported CuI catalysts, metal organic frame-
works (MOF), or copper on charcoal (Cu/C) are other examples
tested in heterogeneous CuAAC.[12] Although a wide range of
organic and inorganic solid catalytic supports have been inves-
tigated, the application of supramolecular gels as heteroge-
neous catalytic media for the Huisgen 1,3-dipolar cycloaddition
of alkynes and azides is scarce.
The very useful and green concept that defines a click reaction
involves the binding of two molecular building blocks in
a facile, selective, high-yield reaction under mild, water-tolerant
conditions with little or no generation of by-products.[1,2] Of all
the reactions that achieve a “click status”, the Huisgen 1,3-di-
polar cycloaddition of alkynes and azides is regarded as the
premier example of a click reaction.[3] However, due to the
high activation energy, this cycloaddition is often very slow
even at high temperatures, producing mixtures of regioiso-
mers.[4] The discovery that CuI catalysts could dramatically in-
crease the reaction rate up to 107 times and improve regiose-
lectivity, affording exclusively 1,4-regioisomers, underlined the
importance of this reaction, enabling unique applications in
synthesis, medicinal chemistry and materials science.[5,6] The
most common catalysts used in azide-alkyne cycloadditions
are copper(II)/copper(I) salts, such as CuSO4, CuI, CuBr,
Cu(OAc), or copper(I) complexes such as [Cu(MeCN)4]PF6 or
[Cu(MeCN)4]OTf, in the presence of the reducing agent sodium
ascorbate.[7] Although these catalysts often provide reasonable
reaction conditions, the thermodynamic instability of CuI,
which usually results in easy oxidation to CuII and/or to dispro-
portion to Cu(0) and CuII, drove research into copper ligands
that are able to stabilize and modulate the catalytic activity of
the CuI center.[8] Recent investigations suggest that the com-
plexes of polytriazole ligands coordinated to CuI have the abili-
ty to catalyze the same reaction from which they are derived.[9]
The mild coordination ability of the triazole functionality allow
the stabilization of CuI oxidation state and prevents the occur-
rence of disproportion reactions.[10] Examples of efficient poly-
Supramolecular gels are nanostructured soft materials that
result from the self-assembly of low-molecular-weight mole-
cules, and are usually defined as gelators.[13–16] After a primary
self-organization of the gelator in one-dimensional aggregates
by noncovalent interactions, these 1D objects further assemble
into fibrilar architectures that, after physical crosslinking, form
a 3D network that percolates the solvent. If the gelator is func-
tionalized with a catalytic fragment, this assembly will result in
an expanded supramolecular material with built-in catalytic
sites. This organization of multiple catalytic sites at the surface
of the fibers could provide additional catalytic features, such as
multivalent interactions, neighboring effects and cooperativi-
ty.[17–19]
Several studies mentioning supramolecular gels as active
media for catalysis have been reported. Between them, the use
of PdII metallogels containing pyridine-based ligands as cata-
lysts for the aerobic oxidation of benzoyl alcohol to benzalde-
hyde, as well as the application of bolaamphiphilic l-proline
derived low-molecular-weight gelators as basic catalysts for
the Henry nitro-aldol reaction, are two clear examples of suc-
cess regarding the use of catalytic gels both in metallo- and or-
[a] M. Araffljo, Dr. S. Díaz-Oltra, Dr. B. Escuder
Departament de Química Inorgànica i Orgànica
Universitat Jaume I, 12071 Castelló (Spain)
E-mail: escuder@uji.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600594.
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ganocatalysis, respectively.[20,21] In the field of click reactions,
Liu and co-workers have reported an hydrogelator that self-as-
sembled into helical nanotubes in the presence of CuII, leading
to a chiral catalyst that was active for a Diels–Alder reaction,
whereas Gao and co-workers reported the application of chiral
binaphthylbispyridine-based copper(I) metallogels as catalysts
for the Huisgen 1,3-dipolar cycloaddition.[22,23] Herein, we
report the design, synthesis, and catalytic performance of low-
molecular-weight gelators derived from amino acid l-valine,
functionalized with triazole fragments as a supramolecular
mimic of the multivalent features of covalent polytriazole li-
gands such as TBTA. The catalytic activity of the synthesized
compounds on the Huisgen 1,3-dipolar cycloaddition of al-
kynes and azides, as well as their application in their autocata-
lytic synthesis have also been investigated.
On the other hand, CuI-PhTzValn metallogels were prepared by
heating the copper salt [Cu(MeCN)4]PF6 together with the
PhTzValn gelators in a 1:2 ratio, until complete dissolution, fol-
lowed by sonication (Figure 2).
Figure 2. Scheme of the CuI coordination to the gel network and macro-
scopic image of the metallogel. The presence of dinuclear CuI species
cannot be discarded.[25]
Results and Discussion
The l-valine phenyltriazolyl (PhTzValn) family of compounds
have been synthesized from simple peptide coupling of the ac-
tivated ester of bromobutyric acid to several alkylidendi-
amines,[24] followed by substitution of the terminal Br with
NaN3, to give the bisazide derivatives, respectively (N3ValnN3,
see Figure S1). The final step consisted of a Huisgen 1,3-dipolar
cycloaddition with commercially available phenylacetylene,
leading to PhTzValn products (Figure 1).
All the PhTzValn family of compounds were able to form
strong gels in methanol either with or without the presence of
copper, meaning that metal coordination was not the essential
driving force for the self-assembly of the compounds. Howev-
er, the presence of copper caused a slight decrease in the min-
imum gelation concentration (MGC) of the gelators PhTzVal6
and PhTzVal8, which means that it could positively contribute
to the gelation of these compounds (Table 2). This fact sug-
gests that there could be a difference within the family related
to the length of the central alkylidene fragment.
Table 2. Minimum gelation concentrations of the native gelators and of
the metallogels in methanol.[a]
Gelator
Concentration [mM]
Native
Metallogel
PhTzVal3
PhTzVal6
PhTzVal8
4.7
4.9
7.4
4.9
3.9
6.5
[a] Typical procedure: The gelator PhTzValn was heated in a 4 mL screw-
capped vial in the presence of solvent (500 mL), until complete dissolu-
tion. The resultant hot solution was then sonicated for 20 s, forming a gel
which was subsequently allowed to age for 20 min at RT. The minimum
gel concentration was defined as the minimum concentration of PhTzValn
required to form a gel that withstands gravity when turned upside down.
Figure 1. Structure of two families of gelators: N3ValnN3 and PhTzValn.
Self-assembly studies
The triazolyl functionalized compounds PhTzValn were able to
form self-sustainable gels in alcohols and water (Table 1). This
ability is related to the amphiphilic character of the molecules.
To assess whether the metal–ligand interaction influenced
the final structural arrangement of the hybrid metal-organic
gel networks, wide angle X-ray powder diffraction (WAXD) was
performed on the native and hybrid xerogels (Figure 3). The
diffractograms revealed that the gelator PhTzVal3 exhibits
Table 1. Gelation experiments with compounds PhTzValn.[a]
Solvent
PhTzVal3
PhTzVal6
PhTzVal8
a
completely amorphous pattern, whereas those having
a longer carbon chain self-assembled in a more ordered struc-
ture, with low-angle peaks at 21.8 Š (PhTzVal6) and 26.4 Š
(PhTzVal6) assignable to the length of partially extended mole-
cules, as described before for related analogues.[26] However, in
the presence of the metal, sharp diffraction peaks appeared to-
gether with the broad signals of gelators that can be assigned
ethanol
H2O
H2O/tBuOH (1:1)
2-propanol
methanol
G
G
G
G
G
G
I
G
SP
G
G
G
G
G
G
[a] I: Insoluble, G: Gel, SP: Swollen precipitate, c=11 mm.
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Figure 3. XRD analysis of gels A) PhTzVal3, B) PhTzVal6, C) PhTzVal8, and of D) CuI-PhTzVal3, E) CuI-PhTzVal6, and F) CuI-PhTzVal8 metallogels.
to a periodic disposition of copper atoms coordinated to the
network. It should be noted that these peaks do not corre-
spond to free copper salt Cu(MeCN)4PF6 (see Figure S16). As
mentioned before, the influence of the metal on the self-as-
sembly of the gelator molecules was revealed for shorter
carbon chain length gelator PhTzVal3 (Figure 3D).
the gelator with the shortest carbon chain self-assembles in
a different supramolecular packaging structure in comparison
to those having longer carbon chains, which is in accordance
with the WAXD studies on the native gelators (Figure 3). This
distinct supramolecular organization arises by the preferred
formation of hydrogen bonds between different hydrogen-
donor and hydrogen-acceptor atoms on two consecutive
column-packed molecules, leading to different energetically
stable molecular packaging models depending on the carbon
spacer length.[36] Furthermore, the appearance of a negative
band followed by a positive band in the CD spectrum of
PhTzVal3 may suggest that the molecule aggregates in an anti-
clockwise orientation.[37]
Although the presence of the metal is not the main driving
force for gelation, as observed for other reported metallo-
gels,[22–23,27–30] the metal–ligand interactions have some influ-
ence on the self-assembly of the gelator. It has already been
reported that metal–ligand interactions could influence the ge-
lation, resulting in multifunctional metallogels with new inter-
esting properties that could not be achieved in organogels,
such as optical, catalytic or magnetic properties.[31–33]
The presence of the metal did not have a pronounced influ-
ence on the final conformation of the gels, except for the gela-
tor PhTzVal3, for which a blueshift of the band at 224 to
217 nm followed by a decrease in intensity was observed (Fig-
ure 4B). A change in the signal of the positive band at 195 nm
was also detected. This suggests that the copper influences
the supramolecular packing of the gelator, probably by inter-
fering in the intermolecular interactions between the several
nanobjects during the self-assembly process, providing a differ-
ent orientation of the initial helical structure. In the metallogel
CuI-PhTzVal6, it seems that the addition of copper(I) induced
a helical-type arrangement, suggested by the appearance of
a positive band around 195 nm (Figure 4C), whereas for the
metallogel CuI-PhTzVal8 no significant differences were detect-
ed (Figure 4D).
The native gels and the corresponding metallogels were
also studied by circular dichroism spectroscopy to gain deeper
insight into the structural arrangement of the resultant self-as-
sembled materials (Figure 4). All the gels exhibited either a pos-
itive or negative dichroism signal, evidencing that the chiral in-
formation present at the molecular scale was transferred to
gel-phase assemblies (Figure 4A). The spectra of the native
gels having a longer carbon chain length PhTzVal6 and
PhTzVal8 are characterized by the presence of two strong nega-
tive bands at 207 and 197 nm, respectively, suggesting similar
supramolecular arrangement. The gel with the smallest carbon
chain length, PhTzVal3, seems to self-assemble in a different
conformation, presenting two negative bands at 224 and
207 nm together with a positive lobe at 190 nm, which is char-
acteristic of a helical type conformation.[34] Such kind of helical
arrangement has already been observed for l-valine derived
bolaamphiphilic gelators functionalized with proline fragments
and having a three-carbon spacer.[35] These results suggest that
The obtained metallogels were also analyzed by TEM, reveal-
ing some differences in the morphology of the fibers depend-
ing on the carbon chain length (Figure 5). Whereas it was pos-
sible to observe a highly crosslinked network of fibers having
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Figure 4. A) Superposition of the circular dichroism spectra of native gels with variable chain length [PhTzVal3 (bottom line), PhTzVal6 (middle line), PhTzVal8
(top line)], and B) superposition of CD spectra of the native gels PhTzVal3, C) PhTzVal6, and D) PhTzVal8 with the corresponding metallogels (thick lines).
Figure 5. TEM analysis of metallogels A) CuI-PhTzVal3, B) CuI-PhTzVal6, C) CuI-PhTzVal8. D and E) STEM analysis of metallogels formed by the compound
PhTzVal6, and F) the corresponding EDS elemental analysis.
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10–12 nm width in the gel having the shortest carbon chain
length (Figure 5A), the metallogels with longer carbon chain
length presented smaller fibers, suggesting some twists in the
case of the gel CuI-PhTzVal8 (Figure 5C). The presence of
copper in the gel network allowed us to characterize these
structures by STEM without staining. The white contrast of the
fibers (Figure 5D–E) constitutes further evidence for the
successful formation of a hybrid organic–inorganic network.
Energy-dispersive X-ray spectroscopy (EDS) analysis performed
on the fibers revealed the presence of Cu together with C and
O, confirming the successful coordination of the copper to the
gel (Figure 5F). The distribution of copper along the fibers con-
stitutes clear evidence of the proximity of the catalytic sites in
self-assembled systems.
tially higher than that reported for the copper salt [Cu-
(MeCN)4]PF6 during 72 h (4% conversion).[9,10] The successful
coordination of the CuI to the relatively labile triazole function-
ality of the gelators, allowing the formation of hemilabile
copper complexes during the catalytic cycle, may be origin of
this good catalytic activity. The presence of this kind of com-
plex facilitates the cooperativity between the copper centers
of the intermediate CuI-acetylide complex, leading to an accel-
eration of the reaction rate and preventing the formation of
CuI-acetylide aggregates.[18] The use of a metallogel as a hetero-
geneous catalyst facilitates the process of purification of the
final product, allowing the separation of the catalyst simply by
filtration, which could be attractive from an industrial point of
view.
Although it is known that the presence of the triazole frag-
ment positively influences the reaction rate, the 3D supra-
molecular arrangement of the hybrid metal-organic gel may
also have an important role in its catalytic activity. The self-as-
sembly of 1D aggregates in large fibers provides the formation
of a network with a large surface area in contact with solution.
Thus, the self-assembly of the gelators functionalized with the
triazole fragment results in the formation of an expanded cata-
lytic network in which the higher proximity of the catalytic
sites favors the occurrence of cooperative interactions, provid-
ing enhanced catalytic properties. As a result, CuI ions are dis-
tributed along the surface of the fibers (Figure 5D), providing
a high availability of the catalytic sites to the reactants. Addi-
tionally, the convergence of triazolyl ligands from different fi-
brils may also contribute to a better coordination of copper(I),
which tends to adopt a tetrahedral coordination geometry
(Figure 2).[27]
Catalysis
The fact that compounds PhTzValn were able to form hydrogels
allowed the possibility of gelating them in a system of solvents
in which the ‘click’ reaction generally occurs. This feature could
also allow these gelators to be applied in click reactions occur-
ring in biological environments. The catalytic activity of the hy-
drogel PhTzVal3 in the model reaction between phenylacety-
lene and benzylazide was first investigated (Figure 6).
Figure 6. Huisgen 1,3-dipolar cycloaddition between phenylacetylene and
Given that gelators PhTzValn are synthesized through a click
reaction (see the Supporting Information) we envisioned the
use of CuI-PhTzValn metallogels as catalysts for the ligand syn-
thesis starting from the azide precursors (autocatalysis)
(Figure 7). As observed for the PhTzValn family, the bis-azide
precursors N3ValnN3 (Figure 1) also form gels in methanol,
either in the presence or absence of copper. The obtained
N3ValnN3 gels were transparent and colorless but acquired
benzylazide.
The reaction was performed in a 1:1 tBuOH/H2O mixture in
the presence of CuI-PhTzValn catalyst (1 mol%), in air and at
room temperature, for periods of 3 to 8 h. The obtained results
are summarized in Table 3.
The metallogels successfully catalyzed Huisgen 1,3-dipolar
cycloaddition between phenylacetylene and benzylazide,
achieving 50–60% conversion in the first 8 h, which is substan-
Table 3. Study of the catalytic activity of compound PhTzVal3 in tBuOH/
H2O.
Entry
Catalyst
Conversion [%][a]
3 h
6 h
8 h
1
2
3
CuI-PhTzVal3
CuI-PhTzVal6
CuI-PhTzVal8
21
24
19
44
55
43
63
62
53
[a] Typical procedure: The reactants in stoichiometric proportion
(0.24 mmol) were mixed and added directly at the top of the metallogel
catalyst (1 mol%) composed of the gelator PhTzValn (4.8”10À2 mmol) and
the copper salt [Cu(MeCN)4]PF6 (2.4”10À2 mmol). At the end of the ex-
periment, the products were directly extracted with CDCl3 (700 mL). The
organic phase was dried over anhydrous MgSO4 and the conversion was
Figure 7. Huisgen 1,3-dipolar cycloaddition between N3ValnN3 and
phenylacetylene.
1
determined by H NMR spectroscopic analysis.
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^
Figure 8. Kinetics of the Huisgen 1,3-dipolar cycloaddition between N3ValnN3 and phenylacetylene in the presence of 5 mol% [Cu(MeCN)4]PF6 ( ), 10 mol%
I
I
I
~
&
[Cu(MeCN)4]PF6 ( ), and in the presence of 10 mol% metallogels ( ) A) Cu-PhTzVal3, B) Cu-PhTzVal6, and C) Cu-PhTzVal8, during the first 6 h of reaction.
a green color when gelated in the presence of the copper salt
[Cu(MeCN)4]PF6.
towards PhTzValn molecules close to the azide analogues. A
brief comparison between the results obtained in Figure 8 sug-
gest a positive influence of the carbon chain length on the cat-
alytic performance of the metallogelators, with the gels
PhTzVal6 and PhTzVal8 exhibiting a higher catalytic activity than
Thus, the autocatalytic ability of the metallogels CuI-PhTzValn
in the reaction represented in Figure 7 was investigated. For
this experiment, the reactant N3ValnN3, the gelator PhTzValn
and the copper salt [Cu(MeCN)4]PF6 in a ratio of 10:1:1 were
gelled together in a 4 mL screw-capped vial containing metha-
nol as solvent, and phenylacetylene was subsequently added
on the top of the two-component gel. In this case, a slight
excess of copper salt was used, attending to the possibility
that some of the N3ValnN3 gel could also participate in the
copper coordination. The aim of the autocatalysis experiment
was to establish whether there was an increase in the rate of
the reaction due to the continuous production of catalyst.
As shown in Figure 8, all the metallogels exhibited autocata-
lytic activity, being capable of catalyzing their own synthesis.
In the absence of an initial amount of CuI-PhTzValn metallogel,
an induction time with little or no conversion was observed,
corresponding to the lapse required to obtain a minimum
amount of active coordinated copper by slow catalysis of un-
coordinated [Cu(MeCN)4]PF6. This effect is particularly evident
in Figure 8A.
the corresponding analogue with
a three-carbon chain,
PhTzVal3. Any direct relationship between the observed catalyt-
ic activity and the amount of copper coordinated to the
PhTzValn gels or to the initial PhTzValn/N3ValnN3 two-component
gel mixtures was completely discarded, because the amount of
copper coordinated to them was found by ICP-MS analysis to
be more than 99% in all cases. Furthermore, the formation of
the CuI-PhTzVal8 complex was confirmed by mass spectrometry
analysis, whereby a peak corresponding to the mass of the ge-
lator coordinating one copper was observed (m/z [M+H]+
831.4097) (see Figure S17). To better understand whether the
difference observed in the catalytic performance of these ma-
terials is related to a different supramolecular arrangement of
the gel network, the mixtures were analysed by WAXD at dif-
ferent stages of the reaction. For comparison, bisazide metallo-
gels CuI-N3ValnN3 were also studied (Figure 9). The obtained dif-
fractograms suggest that the initial mixtures having a lower
periodicity (low short-range order) have a better catalytic per-
formance. These characteristics are readily observed in the ini-
tial hybrid mixtures CuI-PhTzVal6–N3Val6N3 (Figure 9F) and CuI-
PhTzVal8–N3VaL8N3 (Figure 9J), resulting in a higher catalytic ac-
tivity of these compounds. These results are quite reasonable
when we consider that a high interplanar distance between
the several gelator layers facilitates the formation of the phe-
nyltriazole fragment at the end of the reactant N3ValnN3 layers,
because of reduced steric hindrance. The expansion of the
structure resulting from the formation of the final product is
clearly observed in the multicomponent gel CuI-PhTzVal3–
N3Val3N3 after 20 h (Figure 9C) and 48 h reaction (Figure 9D)
and for CuI-PhTzVal8–N3Val8N3 after 20 h reaction (Figure 9L). In
the multicomponent gel CuI-PhTzVal6–N3Val6N3, this expansion
was observed to a lesser extent, because of the high similarity
between the supramolecular arrangement of the initial mixture
(Figure 9F) and that of the final product (Figure 8H), although
the peak around 21 Š becomes more defined along the reac-
It is remarkable that both reactant and catalyst are in the
gel phase. Therefore, it could be proposed that initially the re-
action could take place in those azide groups at the vicinity of
the Cu-Triazole (Tz) catalytic sites. However, as the reaction
continues, the number of azide groups near the catalytic cen-
ters would decrease and we could expect a decrease in the
catalytic activity with time. This is not the case, and the reac-
tion proceeds until completion; the time required to achieve
quantitative conversion was 48 h for the gelator PhTzVal3 and
14 h for gelators with longer carbon chain PhTzVal6 and
PhTzVal8 (see Figure S18). These results are not surprising
taking into consideration the well-known dynamic behavior of
molecular gels that involve a reversible disassembly–reassem-
bly process as well as the reported lability of Tz-Cu complexes,
which could allow the translocation of Cu ions throughout the
fibrillar network.5,10 These dynamic processes would be respon-
sible for the relocation of reactive N3ValnN3 components close
to the catalytic centers and/or the translocation of metal ions
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Figure 9. WAXD performed for the metallogels A) CuI-N3Val3N3, E) CuI-N3Val6N3, I) CuI-N3Val8N3 and for the multicomponent metallogels B–D) CuI-PhTzVal3–
N3Val3N3, F–H) CuI-PhTzVal6–N3Val6N3, and J–L) CuI-PhTzVal8–N3Val8N3 mixtures after 0 (B, F, J), 4 (G, K), 20 (C, H, L), and (D) 48 h of reaction.
tion time (Figure 9G and H). The lower catalytic activity of the
gelator CuI-PhTzVal3 may also be related to a possible coordi-
nation of CuI to N3Val3N3. The most intense peak present in the
diffractogram of CuI-N3Val3N3 appears at 3.9 Š (Figure 9A),
which is well in accordance with that belonging to the metal-
logelators CuI-PhTzValn (Figure 3D–F). On the other hand, this
peak is absent in the diffractograms corresponding to CuI-
N3Val6N3 and CuI-N3Val8N3 (Figure 9E and I, respectively). It is
well known that gelators having a central three-carbon spacer
self-assemble in a different way to bolaamphiphilic gelators
having a longer spacer.[38] This particular self-assembly behavior
may cause additional competition for the coordination of the
copper when the gelators PhTzVal3 and N3Val3N3 are heated to-
gether with the copper salt, causing a depletion in the catalyt-
ic performance of CuI-PhTzVal3. In all the diffractograms, it is
also important to highlight the appearance of a peak around
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4.5 Š, which, according to previously reported xerogels, can be
ascribed to the periodicity in the direction of the hydrogen-
bonding array, thus suggesting a self-assembly of the gelator
molecules in a vertical direction (z-axis) both in the azides and
in the final product.[39] XRD analysis performed on the hybrid
multicomponent metallogel mixtures at 50% conversion (Fig-
ure 9C, G, and K) revealed that the structural rearrangement of
the system may lead to a slowdown of the reaction, achieving
a kind of plateau at this stage (Figure 8). By looking at Fig-
ure 9C, G and K, it is observed that at this point of the reac-
tion, the structure of the hybrid multicomponent gel mixtures
resembles more that of the final product (Figure 9D, H, and L),
although 50% of reactant is still present. This structural rear-
rangement acts as an inflection point on the catalytic activity
of these compounds; after this plateau, the kinetics increases
again towards the completion of the reaction (Figure S18).
The morphology of the hybrid multicomponent organic–in-
organic gels was also analyzed at different stages of the reac-
tion by TEM (Figure 10). Figure 10A shows that the gel net-
Conclusion
l-Valine-derived low-molecular-weight gelators functionalized
with triazole units were successfully synthesized. The gelators
coordinated copper, building hybrid organic–inorganic gels ca-
pable of catalyzing the Huisgen 1,3-dipolar cycloaddition of al-
kynes and azides. The obtained metallogelators exhibited
a high copper loading capacity and can be regarded as effi-
cient heterogeneous catalysts. It was also found that the
supramolecular arrangement of these materials has a great in-
fluence on their catalytic performance. In contrast to other re-
ported metallogels applied as catalysts for the same reaction,
the metal was coordinated once the gel was formed, which
allows for the loading of other metals with affinity to triazole li-
gands without disturbing their capacity for gelation.[23] Further-
more, the formation of the metallogel in water or water/alco-
hol mixtures allow the study of the reaction under biological
conditions. The fact that these gelators are derived from
amino acids constitutes an additional advantage for the use of
these compounds as catalytic systems for bioconjugation click
reactions, regarding their biodegradability and biocompatibil-
ity.
Experimental Section
Structural and morphological characterization
1H and 13C NMR spectra measurements were recorded with
a Varian Mercury 300 MHz spectrometer at 308C. Powder X-ray dif-
fraction (XRD) was performed at RT with a Bruker D4 Endeavor X-
ray powder diffractometer by using Cu-Ka radiation. A sample of
the dried gel was placed on a sample holder and data were col-
lected for 2q values between 2 and 408 with a step size of 0.038
and a time step of 10 s. 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 record-
ed with a JEOL 2100 microscope.
Synthesis
Figure 10. TEM analysis of A) CuI-N3Val6N3, B) CuI-PhTzVal6–N3Val6N3, and
C) CuI-PhTzVal6–N3Val6N3 after 4 h of reaction, and D) CuI-PhTzVal6-N3Val6N3
after 20 h of reaction.
Detailed synthetic procedures and characterization are found in
the Supporting Information.
Gelation procedure
work of CuI-N3Val6N3 is composed of long, thin fibers exhibiting
a flower-like morphology. The presence of these fibers togeth-
er with some smaller fibers belonging to the catalyst was ob-
served in Figure 10B and C. In Figure 10C, some dark nuclei
can also be observed that probably belong to the final prod-
uct, considering their high similarity to the fibers present at
the end of the reaction (Figure 10D), which, in turn, have simi-
lar dimensions to the fibers represented in Figure 5B, belong-
ing to the pure metallogel. Although the synthesis of molecu-
lar gels using click chemistry is nowadays a common research
interest, the uniqueness of the present study lies in the judi-
cious utilization of click chemistry within a metallogel system
for the autocatalytic synthesis of the gelator.
The gelator PhTzValn (5.5”10À3 mmol) was heated in a 4 mL screw-
capped vial in the presence of solvent (500 mL), until complete dis-
solution. The resultant hot solution was then sonicated for 20 s,
forming a gel which was subsequently allowed to age for 20 min
at RT. The formation of a gel was confirmed by the inversion tube
test, whereby the resultant solid-like soft material did not flow
upon inversion of the flask. The formation of metallogels was ach-
ieved by heating together the gelator and the copper salt
Cu(MeCN)4PF6 in a 2:1 molar ratio.
For the formation of the two-component metallogels, N3ValnN3
(2.7”10À2 mmol) was heated together with 10 mol% catalyst, com-
posed of the gelator PhTzValn (2.7”10À3 mmol) and an equimolar
amount of the copper salt [Cu(MeCN)4]PF6, in MeOH (300 mL) until
complete dissolution. Gelation was achieved as described above.
Yellow translucent materials that retained the solvent upon inver-
sion of the vial were obtained.
Chem. Eur. J. 2016, 22, 8676 – 8684
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8683
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Full Paper
[5] V. Bock, H. Hiemstra, J. van Maarseveen, Eur. J. Org. Chem. 2006, 2006,
51–68.
Catalysis experiments
Catalysis experiments were performed at RT without stirring. All
the reactions were performed for periods of 3, 6, and 8 h by using
a 1:1 H2O/tBuOH mixture as solvent media. Briefly, the reactants in
stoichiometric proportion were mixed and added directly at the
top of the metallogel catalyst (1 mol%) composed of the gelator
PhTzValn (4.8”10À2 mmol) and the copper salt [Cu(MeCN)4]PF6
(2.4”10À2 mmol). At the end of the experiment, the products were
directly extracted with CDCl3 (700 mL). The organic phase was dried
over anhydrous MgSO4 and the conversion was determined by
1H NMR spectroscopic analysis.
[6] J. Hou, X. Liu, J. Shen, G. Zhao, P. Wang, Expert Opin. Drug Discovery
2012, 7, 489–501.
[7] R. Berg, B. Straub, Beilstein J. Org. Chem. 2013, 9, 2715–2750.
[8] J. Hein, V. Fokin, Chem. Soc. Rev. 2010, 39, 1302–1315.
[9] T. Chan, V. Fokin, QSAR Comb. Sci. 2007, 26, 1274–1279.
[10] T. Chan, R. Hilgraf, K. Sharpless, V. Fokin, Org. Lett. 2004, 6, 2853–2855.
[11] V. Bevilacqua, M. King, M. Chaumontet, M. Nothisen, S. Gabillet, D. Buis-
son, C. Puente, A. Wagner, F. Taran, Angew. Chem. Int. Ed. 2014, 53,
5872–5876; Angew. Chem. 2014, 126, 5982–5986.
[12] B. Dervaux, F. Du Prez, Chem. Sci. 2012, 3, 959–966.
[13] J. van Esch, B. Feringa, Angew. Chem. 2000, 39, 2263–2266.
[14] D. Smith, Nat. Chem. 2010, 2, 162–163.
[15] R. Weiss, P. Terech, Chem. Soc. Rev. 1997, 97, 3133–3160.
[16] A. Hirst, B. Escuder, J. Miravet, D. Smith, Angew. Chem. Int. Ed. 2008, 47,
8002–8018; Angew. Chem. 2008, 120, 8122–8139.
[17] B. Escuder, F. Rodríguez-Llansola, J. Miravet, New J. Chem. 2010, 34,
1044–1054.
Autocatalysis experiments
Catalysis experiments were performed at RT and without stirring.
Phenylacetylene (3 equiv) dissolved in MeOH (158 mL) was added
on the top of the two-component catalytic metallogel, composed
of N3ValnN3 and 10 mol% CuI-PhTzValn, and the resultant mixture
was allowed to react for 1 to 48 h. The reaction was stopped by
adding 35wt% H2O2 (20 mL) to promote the oxidation and conse-
quent precipitation of copper. The resultant mixture was dried
under nitrogen flow. For the control assays, the reactant was
added on the top of N3ValnN3 gelated in the presence of [Cu-
(MeCN)4]PF6 (10 mol%), and allowed to react under similar condi-
tions. The conversion was determined by 1H NMR spectroscopic
analysis in [D6]DMSO.
[18] D. Díaz-Díaz, D. Kühbeck, J. Koopmans, Chem. Soc. Rev. 2011, 40, 427–
448.
[19] B. Escuder, J. Miravet in Functional Molecular Gels, Vol. 1 (Eds.: J. Miravet,
B. Escuder), Royal Society of Chemistry, Cambridge, 2014, pp. 117–153.
[20] B. Xing, M. Choi, B. Xu, Chem. Eur. J. 2002, 8, 5028–5032.
[21] F. Rodríguez-Llansola, B. Escuder, J. Miravet, J. Am. Chem. Soc. 2009,
131, 11478–11484.
[22] Q. Jin, L. Zhang, H. Cao, T. Wang, X. Zhu, J. Jiang, M. Liu, Langmuir
2011, 27, 13847–13853.
[23] Y. He, Z. Bian, C. Kang„ Y. Cheng, L. Gao, Chem. Commun. 2010, 46,
3532–3534.
[24] J. Becerril, M. Bolte, M. Burguete, F. Galindo, E. Garcia-EspaÇa, S. Luis, J.
Miravet, J. Am. Chem. Soc. 2003, 125, 6677–6686.
Quantification of coordinated copper
[25] P. Donnelly, S. Zanatta, S. Zammit, J. White, S. Williams, Chem. Commun.
2008, 2459–2461.
[26] B. Escuder, S. Martí, J. Miravet, Langmuir 2005, 21, 6776–6787.
[27] J. Bunzen, T. Bruhn, G. Bringmann, A. Lützen, J. Am. Chem. Soc. 2009,
131, 3621–3630.
[28] S. Lam, V. Yam, Chem. Eur. J. 2010, 16, 11588–11593.
[29] J. Shen, G. Mao, Y. Zhou, Y. Jiang, H. Zhang, Dalton Trans. 2010, 39,
7054–7058.
[30] S. Joshi, N. Kulkarni, Chem. Commun. 2009, 17, 2341–2343.
[31] A. Tam, V. Yam, Chem. Soc. Rev. 2013, 42, 1540–1567.
[32] M. Piepenbrock, G. Lloyd, N. Clarke, J. Steed, Chem. Rev. 2010, 110,
1960–2004.
The catalytic metallogel was broken up with a spatula and the sur-
rounding solution was collected with a syringe and filtered
through a 0.22 mm filter. The metallogel was further washed with
acetonitrile (2”100 mL) to remove remaining uncoordinated
copper and the obtained solution was evaporated. The resultant
white solid was digested with 5% HNO3 aq. solution and the
amount of copper was quantified by ICP-MS analysis.
Acknowledgements
[33] J. Steed, Chem. Soc. Rev. 2010, 39, 3686–3699.
[34] S. Ham, Y. Lim, J. Polym. Sci. Part A 2014, 52, 596–599.
[35] F. Rodríguez-Llansola, J. Miravet, B. Escuder, Chem. Commun. 2009,
209–211.
This work was supported by the EU (Marie Curie ITN-Smartnet).
M.A. thanks the EU for an ESR Marie Curie contract.
[36] D. Tsekova, J. Sµez, B. Escuder, J. Miravet, Soft Matter 2009, 5, 3727–
3735.
[37] K. Murata, M. Aoki, T. Suzuki, T. Harada, H. Kawabata, T. Komori, F.
Ohseto, K. Ueda, S. Shinkai, J. Am. Chem. Soc. 1994, 116, 6664–6676.
[38] F. Rodríguez-Llansola, J. Miravet, B. Escuder, Chem. Commun. 2009,
7303–7305.
Keywords: click chemistry · gels · heterogeneous catalysis ·
self-assembly · supramolecular chemistry
[1] L. Liang, D. Astruc, Coord. Chem. Rev. 2011, 255, 2933–2945.
[2] V. Rostovtsev, L. Green, V. Fokin, K. Sharpless, Angew. Chem. 2002, 114,
2708–2711.
[39] B. Escuder, J. Miravet, J. Sµez, Org. Biomol. Chem. 2008, 6, 4378–4383.
[3] J. Moses, A. Moorhouse, Chem. Soc. Rev. 2007, 36, 1249–1262.
[4] L. Zhang, X. Chen, P. Xue, H. Sun, I. Williams, K. Sharpless, V. Fokin, G.
Jia, J. Am. Chem. Soc. 2005, 127, 15998–15999.
Received: February 8, 2016
Published online on May 11, 2016
Chem. Eur. J. 2016, 22, 8676 – 8684
www.chemeurj.org
8684
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim