Aqueous 1,3-dipolar cycloadditions promoted by copper nanoparticles in polydiacetylene micelles

Article abstract of DOI:10.1039/c7gc01017f

A novel colloidal catalyst was developed through the encapsulation of cuprous oxide nanoparticles in polydiacetylene micelles. The Cu-based catalyst was applied to the Huisgen cycloaddition reaction in fully aqueous medium. The process neither requires he

Full text of DOI:10.1039/c7gc01017f

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ARTICLE
Aqueous 1,3-dipolar cycloadditions promoted by copper
nanoparticles in polydiacetylene micelles
Damien Clarisse,a Praveen Prakash,a Valérie Geertsen,b Frédéric Miserque,c Edmond Gravel*a and
Eric Doris*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A novel colloidal catalyst was developed through the encapsulation of cuprous oxide nanoparticles in polydiacetylene
micelles. The Cu-based catalyst was applied to the Huisgen cycloaddition reaction in fully aqueous medium. The process
neither requires heating nor controlled atmosphere and the catalyst can be recycled in subsequent reactions without any
loss of activity.
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aqueous media as the lipophilic core of the micelles can
accommodate hydrophobic molecules, allowing their
dispersion and concentration.6 In addition, micelles are also
Introduction
The alkyne-azide 1,3-dipolar cycloaddition1 is a thoroughly
employed click reaction that has been applied in fields as
diverse as material chemistry or chemical biology.2-4 While the
thermally activated [3+2] cycloaddition reaction has initially
been disclosed by Huisgen in 1963,1a recent development by
Meldal[2] and Sharpless[3] led to the implementation of copper-
catalyzed azide−alkyne 1,3-dipolar cycloadditions (CuAAC)
which operate under milder conditions, with increased
regioselectivity and functional group tolerance. In the latter
transformations, a Cu(I) catalyst is classically required together
with a mixture of aqueous and organic solvents, but copper
salts are rather toxic and often difficult to eliminate from
reaction mixtures. Copper-free alternatives, involving
cyclooctynes, were more recently implemented by Bertozzi
and co-workers.5 Yet, the strained dipolarophiles are tricky to
synthesize and often lack of chemoselectivity.
able to encapsulate nanoparticles to make them water-
dispersible.7 However, micelles are dynamic structures which
disassemble in highly dilute conditions (below the CMC). To
reinforce the micellar architecture, our group has long been
involved in the development of polydiacetylene micelles for
biomedical applications.8 As opposed to “normal” micelles, the
architectures obtained from self-assembly of the diacetylene
amphiphiles can be reinforced by a photo-polymerization step,
leading to more robust micelles. Our objective here is thus to
encapsulate copper nanoparticles in polydiacetylene micelles
to provide access to a stable colloidal catalyst, and use the
micellar hybrid assembly as a nanoreactor for effecting dipolar
cycloaddition reactions in water. In addition, easy
recovery/removal of the catalyst is expected.
With these features in mind, we report here the
formulation of copper (I) nanoparticles into stable
polydiacetylene micelles for the promotion of the [3+2]
cycloaddition reaction in fully aqueous medium. Micelles
classically result from the aqueous self-assembly of
amphiphilic molecules at a concentration higher than the
critical micellar concentration (CMC). Above the CMC,
Results and discussion
Oleic acid-stabilized cuprous oxide nanoparticles (Cu2O NPs)
were synthesized according to the procedure described by
O’Brien et al.9 Briefly, copper(I) acetate, oleic acid (OA), and
trioctylamine were heated to 180 °C and 270 °C. The produced
nanoparticles were then precipitated in ethanol and
redispersed in hexane. Their color gradually changed from
reddish-brown to dark green. The Cu2O NPs were analyzed by
transmission electron microscopy (TEM) and were found to be
of spheroidal shape (Figure 1a) with an average diameter of
8.6 ± 1.8 nm (Figure S1). X-ray photoelectron spectroscopy
(XPS) analysis indicated that Cu2O was the major species, even
though CuO could also be detected, albeit in minor proportion
(Figure 1c). The as-prepared oleic acid-coated copper(I) oxide
amphiphiles aggregate into spherical structures with
a
hydrophobic core and outer hydrophilic layer interfacing with
the aqueous environment. Surfactant micelles were previously
shown to be beneficial to organic transformations run in
a.Service de Chimie Bioorganique et de Marquage (SCBM), CEA, Université Paris-
Saclay, 91191 Gif-sur-Yvette, France.
E-mail: edmond.gravel@cea.fr; eric.doris@cea.fr
b.NIMBE, CEA, CNRS, Université Paris-Saclay, 91191, Gif-sur-Yvette, France
c. Service d’Etude de Corrosion et du Comportement des Matériaux dans leur
Environnement (SCCME), CEA, Université Paris-Saclay, 91191 Gif-sur-Yvette,
France
nanoparticles
were
subsequently
encapsulated
in
polydiacetylene micelles. Micelles were first produced from
the assembly of amphiphilic units made of a lipophilic
diacetylene chain (DA) and a polyethyleneglycol (PEG, MW =
† Electronic Supplementary Informaꢀon (ESI) available: procedure for the synthesis
of DAPEG-amphiphile & copies of 1H and 13C spectra. See DOI: 10.1039/x0xx00000x
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550 Da) polar head (Figure 2). The DAPEG-amphiphiles were
synthesized in three steps according to a procedure that we
previously reported10 (see ESI for details). Amphiphilic units
were dispersed in water to allow spontaneous formation of
micelles which were further stabilized through photo-
polymerization. In fact, irradiation of the colloid under UV light
(254 nm), triggers a topochemical polymerization of the
diacetylene units, leading to the formation of an ene-yne
conjugated network in the core of each individual micelle and
providing better cohesion to the assembly. Dynamic light
scattering (DLS) analysis of the polymerized micelles (pDAPEG)
indicated that the assembly had a mean hydrodynamic
diameter of ca. 9 nm. The Cu2O NPs in hexane were then
added to pDAPEG micelles in water and the biphasic mixture
was probe-sonicated. This step led to the encapsulation of the
copper nanoparticles (that are coated with a lipophilic layer)
into the core of the polymerized micelles and subsequent
transfer of Cu2O NPs from the organic to the aqueous phase,
as evidenced by the green color transition. After further
sonication, evaporation of hexane took place and a clear dark
green Cu2O@pDAPEG colloid was obtained which can be
visualized by TEM (Figure 1b). Copper concentration of the
aqueous suspension was measured by inductively coupled
Figure 2. Overview of the synthetic pathway to the Cu2O@pDAPEG catalyst.
The micelle-encapsulated Cu2O nanoparticles were then
evaluated with regard to their catalytic properties, and more
specifically their ability to promote the Huisgen 1,3-dipolar
cycloaddition in aqueous medium, at room temperature.
Benzyl azide (1a) and phenylacetylene (2a) were chosen as
model substrates. When 1a and 2a were reacted together in
water in the absence of any Cu source, only trace amounts (<
5%) of 3aa were detected after 24 h (Table 1, entry 1). The use
of 0.35 mol% of copper(II) sulfate in combination with sodium
ascorbate in excess (classical “click” conditions) allowed the
reaction to reach mid-point conversion at 24 h (entry 2).
Adding pDAPEG micelles (1 mg mL−1) to the previous
experiment allowed for a slightly increased, yet not complete,
conversion (entry 3). Gratifyingly, the micelle-encapsulated
Cu2O particles more efficiently promoted the cycloaddition of
1a with 2a, and triazole 3aa was obtained in 99% yield after
the same reaction time (entry 4). Running the reaction in the
presence of “micelle-free” Cu2O NPs led to poor conversion
allowing the isolation of only 15% of 3aa (entry 5). On the
other hand, the use of “empty” pDAPEG micelles (1 mg mL−1)
failed to promote the reaction (entry 6).
plasma mass spectrometry (ICP-MS, [Cu] = 7 mM) and DLS
analysis indicated a mean hydrodynamic diameter of ca. 30
nm.
Table 1. Different conditions investigated for the Huisgen cycloaddition reaction.[a]
entry Cu (mol%)
additive
-
t (h)
yield (%)[b]
< 5[c]
1
2
-
24
CuSO4 (0.35)
Na ascorbate[d] 24
55
Na ascorbate[d]
24
3
CuSO4 (0.35)
75
pDAPEG[e]
4[f]
5
Cu2O (0.35)
Cu2O (0.35)
-
pDAPEG
-
24
24
24
99
15
6
pDAPEG[e]
< 5[e]
Figure 1. (a) TEM image of the OA-capped Cu2O particles. (b) TEM image of
the micelle-encapsulated Cu2O particles. (c) XPS spectrum highlighting Cu+ and
Cu2+ contributions (Cu-2p region).
[a] 1a (0.1 mmol), 2a (0.1 mmol), water (0.5 mL), Cu source (0.35 mol%) when
applicable, room temperature, 24 h. [b] Yield of isolated product. [c] 1H-NMR
yield. [d] 1.5 mmol. [e] 1 mg mL−1. [f] Cu2O@pDAPEG (0.35 mol% of Cu).
2 | J. Name., 2012, 00, 1-3
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These results emphasize the key role played by the micellar
system which not only acted as colloidal stabilizer of copper
nanoparticles but also as a nanoreactor which allowed the
aqueous dispersion of the reagents and their concentration
at the vicinity of the active sites of the catalyst.
No decrease in catalytic activity was observed in the course
of the different recycling experiments as the reactions
afforded in each case full conversion into cycloadduct 3ba
within 24 h (Table 3). In addition, no morphological
alterations of the catalyst were observed after five
consecutive cycles (Figure S2).
The Cu2O@pDAPEG-catalyzed reaction worked equally
well on a larger scale (e.g. 7.5 mmol) as a quantitative yield
of 3aa was obtained after 24h. We also investigated the
possibility of lowering the catalyst loading to 0.035 and
0.0035 mol% of Cu. However, although the cycloaddition
reaction was still operative, the overall process was much
slower. In fact, 0.035 mol% of the catalyst led to 75%
conversion after 24 h and full conversion after 72 h. Using
0.0035 mol% of Cu, the reaction was even slower and
provided only 70% conversion after 72 h.
Table 2. Scope of the Cu2O@pDAPEG-catalyzed aqueous Huisgen reaction.[a]
entry
1
azide 1
alkyne 2
yield (%)[b]
1a
2a
99
The scope of the Cu2O@pDAPEG-catalyzed aqueous
dipolar cycloaddition reaction was then studied on a variety
of alkynes and azides (Table 2). In addition to benzyl azide
2
3
4
5
1b
1c
1d
1e
2a
2a
2a
2a
99
(
1a, entry 1), different azido derivatives were reacted with
phenylacetylene (2a): a thioether derivative (1b, entry 2), a
sugar unit (1c, entry 3), an isothiocyanate-substituted aryl
40[c]
(
1d, entry 4), a fluorogenic coumarin (1e, entry 5), and an
ester (1f, entry 6). All these substrates underwent smooth
cycloaddition in very good to excellent yields (90–99%) with
the exception of 1c which only afforded the desired
cycloadduct in 40% yield. Compatibility of our system with
an array of alkynes was also investigated using azidomethyl
phenyl sulfide 1b as the 1,3-dipole. The scrutinized
99
90
dipolarophiles included 4-methoxy-phenylacetylene
(2b,
entry 7), phenethylacetylene (2c, entry 8), 6-chlorohex-1-
yne (2d, entry 9), coumarin 2e (entry 10), naphtylacetylene
2f (entry 11), and diphenylpropynol 2g (entry 12). To our
pleasure, the Cu2O@pDAPEG-based catalyst also efficiently
promoted the cycloaddition reaction of these substrates
with azidomethyl phenyl sulfide 1b in good to excellent
yields (85–99%). Although Cu2O has been previously
reported to promote click reactions in water, the latter
systems operated in lower yields and involved higher
catalyst loadings.11 In addition, inert atmosphere, organic
solvent or mixtures,12 and heating13 were, in some cases,
needed to provide a satisfactory yield of products. Taken
together, the above results show the versatility of our
catalytic system which is operative on an array of different
organic compounds in water, under air, at room
temperature, and with as little as 0.35 mol% catalyst
loading. The micellar strategy we have developed herein
thus allows the transition from a fully heterogeneous
6
7
1f
2a
2b
99
96
1b
8
9
1b
1b
2c
2d
99
86
10
1b
2e
95
11
12
1b
1b
2f
85
90
Cu2O14 catalyst into
a
semi-heterogeneous one15 that
efficiently operates under sustainable conditions.
To better establish the sustainable nature of our process
we assessed the recyclability of our catalyst. To this end,
five consecutive cycloaddition reactions involving
compounds 1b and 2a were carried out using the same
catalyst batch which was recovered after each run and
reused in subsequent reactions. After the reaction was
completed, the aqueous phase was simply extracted with
an organic solvent and the colloidal catalyst reused as such.
2g
[a] 1 (0.1 mmol), 2 (0.1 mmol), water (0.5 mL), Cu2O@pDAPEG (0.35 mol%),
room temperature, 24 h. [b] Yield of isolated product. [c] 1H-NMR yield.
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Table 3. Recycling experiment.[a]
Acknowledgements
P. P. thanks the Enhanced Eurotalents program for support. Dr.
Wai-Li Ling (IBS, CEA/Grenoble) and the TEM-team platform
(CEA) are acknowledged for help with TEM images. The
“Service de Chimie Bioorganique et de Marquage” belongs to
the Laboratory of Excellence in Research on Medication and
Innovative Therapeutics (ANR-10-LABX-0033-LERMIT).
entry
catalyst
t (h)
yield (%)[b]
1
2
3
4
5
Fresh
24
24
24
24
24
99
99
99
99
99
1st reuse
2nd reuse
3rd reuse
4th reuse
Notes and references
1
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[a] 1b (0.1 mmol), 2a (0.1 mmol), water (0.5 mL), Cu2O@pDAPEG (50 µL of a 7
mM aqueous suspension, 0.35 mol%), room temperature, 24 h. [b] Yield of
isolated product.
Fokin and K. B. Sharpless, Angew. Chem. Int. Ed., 2002, 41
2596; c) J. E. Hein and V. V. Fokin, Chem. Soc. Rev., 2010, 39
1302.
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Experimental
General procedure for the Huisgen cycloaddition: The reaction
of 1a and 2a is given as a representative example. Benzyl azide
(
1a, 0.1 mmol) and phenylacetylene (2a, 0.1 mmol) were
mixed in water (0.5 mL) containing Cu2O@pDAPEG (50 µL of a
7 mM aqueous suspension, 0.35 mol%). The mixture was
stirred in the dark for 24 h at room temperature. Extraction
with diethylether (3 × 3 mL), drying over MgSO4, filtration, and
solvent removal under vacuum afforded pure cycloadduct 3aa
in 99% yield.
6
7
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phenylacetylene (2a, 0.1 mmol) were mixed in water (0.5 mL)
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containing Cu2O@pDAPEG (50 µL of
a 7 mM aqueous
8
9
suspension, 0.35 mol%). The mixture was stirred in the dark
for 24 h at room temperature and then extracted with
diethylether (3 × 3 mL). The organic phase was worked-up as
described above, affording pure cycloadduct 3ba in 99% yield.
The remaining aqueous phase was reused to carry out further
reactions, by simple addition of 1b (0.1 mmol) and
phenylacetylene (2a, 0.1 mmol) for each additional run.
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A novel catalyst was developed through the encapsulation of
cuprous nanoparticles in pegylated polydiacetylene micelles.
The colloidal catalyst was applied to the promotion of the
Huisgen cycloaddition reaction for which the micelles acted
also as nanoreactors. The process neither requires heating nor
controlled atmosphere. Moreover, the catalyst can be
recovered and recycled in subsequent reactions without any
loss of activity over five consecutive runs.
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4 | J. Name., 2012, 00, 1-3
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TOC Entry
A colloidal catalyst was assembled from copper nanoparticles to efficiently promote alkyne-azide
cycloadditions in water.