Functionalized chitosan as a green, recyclable, biopolymer-supported catalyst for the [3+2] huisgen cycloaddition

Article abstract of DOI:10.1002/anie.200901309

Clean and green: Copper(I) complexes of phenanthroline-based ligands anchored on the chitosan polymer are good catalysts for the "click" cycloaddition of azides with terminal alkynes (see scheme; the scanning electron microscopy image shows the porous str

Full text of DOI:10.1002/anie.200901309

Communications
DOI: 10.1002/anie.200901309
Heterogeneous Catalysis
Functionalized Chitosan as a Green, Recyclable, Biopolymer-
Supported Catalyst for the [3+2] Huisgen Cycloaddition**
Mꢀlanie Chtchigrovsky, Ana Primo, Philippe Gonzalez, Karine Molvinger, Mike Robitzer,
Franꢁoise Quignard,* and Frꢀdꢀric Taran*
In memory of Charles Mioskowski
Owing to increasing concern about environmental impact,
tremendous effort has been made towards the development of
new processes that minimize pollution in chemical synthesis.
For this reason and others (catalyst removal, recovery, and
recycling), heterogeneous catalysis is clearly on the rise,
including in industry.[1] Of the many systems that have been
developed over the past decades, metallic species supported
on inorganic materials (e.g. SiO2, Al2O3) or on charcoal are
the most common.[2] The immobilization of transition metals
on polymer supports derived from petrochemicals (e.g.
polystyrenes) has also been the focus of many efforts.[3]
Recent developments for cleaner, sustainable chemistry
are being driven by a shift from petrochemical-based feed-
stocks to biological materials. There is considerable interest in
exploiting natural polymer macrostructures, and in particular
those of polysaccharides, to create high-performance and
environmentally friendly catalysts. Indeed, polysaccharides
present many advantages that may stimulate their use as
polymeric supports for catalysis: 1) They are present in
enormous quantity on earth, 2) they contain many function-
alities that can be used readily for the anchoring of
organometallic species, 3) they contain many stereogenic
centers, and 4) they are chemically stable but biodegradable.[4]
Surprisingly, although there has been a worldwide realization
that nature-derived polysaccharides can provide the raw
materials needed for the production of numerous industrial
consumer goods, their use as supports for catalysis is still in its
infancy.
chitosan results from incomplete deacetylation of chitin. At
least 10 gigatons of chitin are constantly present in the
biosphere; thus, chitosan is a renewable green material.[6] Of
Figure 1. A) Chemical structure of chitosan. B) Photograph of chitosan
aerogel beads. C) Scanning electron microscopy image of the chitosan
aerogel.
the numerous methods that have been used to chemically
modify chitosan,[7] Schiff base formation through the reaction
of amine groups on the chitosan backbone with aldehydes is
one of the most straightforward. For example, chitosan
derivatives obtained by treatment with acetylacetone, salicyl-
aldehyde, and pyridine-2-carboxaldehyde have been pre-
pared to enhance copper adsorption[8] or to promote copper-
catalyzed cyclopronation[9] or oxidation[10] reactions.
Chitosan (Figure 1A) is a particularly attractive polysac-
charide for application in catalysis[5] owing to the presence of
readily functionalizable amino groups and its insolubility in
organic solvents. A copolymer of b(1!4)-2-amino-2-deoxy-
d-glucopyranose and 2-acetamido-2-deoxy-d-glucopyranose,
The capacity of imine derivatives of chitosan to strongly
chelate copper salts prompted us to study the ability of this
type of complex to catalyze the azide–alkyne Huisgen [3+2]
cycloaddition reaction. This reaction, the most robust and
useful of the so-called “click” reactions, affords triazoles with
high chemoselectivity.[11] The typical reaction conditions
involve the use of copper salts, introduced directly as CuI
salts[12] or generated in situ by the reduction of CuII (usually by
sodium ascorbate)[13] or the oxidation of Cu0,[14] in conjunction
with an added base. Heterogeneous CuI sources have recently
emerged as more practical systems that enable catalyst
removal and recycling. A series of heterogeneous CuI systems
have recently been reported, including CuI salts supported on
basic Amberlyst,[15] cationic polystyrene,[16] cross-linked
poly(ethyleneimine),[17] alumina,[18] and zeolites,[19] and
copper nanoparticles in charcoal.[20] Although these hetero-
geneous catalysts proved their high efficiency and practic-
ability, the cycloaddition reaction often required 1–10 mol%
of the catalyst to proceed.
[*] Dr. A. Primo, Dr. P. Gonzalez, K. Molvinger, M. Robitzer,
Dr. F. Quignard
Institut Charles Gerhardt, UMR 5253 CNRS-UMII-ENSCM-UMI
8 rue de l’Ecole Normale, 34296 Montpellier Cedex 5 (France)
E-mail: quignard@enscm.fr
M. Chtchigrovsky, Dr. F. Taran
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage
91191 Gif sur Yvette (France)
Fax: (+33)1-6908-7991
E-mail: frederic.taran@cea.fr
[**] This research was supported by the French National Research
Agency (ANR) as part of the GreenCat project.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901309.
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On the basis of the well-known ligand-acceleration effect
on the kinetics of this reaction,[21] we hypothesized that more-
active heterogeneous systems might be obtained by anchoring
appropriate CuI ligands onto chitosan microspheres. An
added bonus of these hybrid systems results from the textural
properties of chitosan aerogels, which should be well-suited to
the development of highly efficient hybrid catalysts. Indeed,
we showed in previous studies[22] that chitosan microspheres
dried in supercritical CO2 (Figure 1B) provided a porous
support with large surface areas (over 100 m2 gꢀ1) that were
entirely accessible as a result of the open-pore structure of the
network (pore size > 10 nm; Figure 1C). Moreover, this
drying technique makes the amine groups of the polymer
(loading: 5 mmolgꢀ1) more accessible to reactants.
chitosan, and that cross-linking might occur in the case of
functionalization with dialdehydes. The corresponding imine
solids (Im1–Im11) were characterized by IR spectroscopy,
and their surface areas, SBET, were determined from the
adsorption–desorption isotherms of N2 on the corresponding
aerogels.[24] The results (Table 1) indicate that the solids have
Table 1: Textural and copper(I)-complexation properties of the function-
alized chitosan solids Im0–Im11.
Entry
Aldehyde
Im (SBET [m2 gꢀ1])
C (complexed Cu [%];
loading [mmolgꢀ1])[a]
1
2
3
4
5
6
7
8
9
none
1
2
3
4
5
6
7
8
Im0 (329)
Im1 (234)
Im2 (258)
Im3 (285)
Im4 (208)
Im5 (407)
Im6 (387)
Im7 (283)
Im8 (387)
Im9 (426)
Im10 (220)
Im11 (166)
C0 (11; 0.5)
C1 (48; 1.5)
C2 (26; 0.7)
C3 (49; 0.5)
C4 (55; 1.7)
C5 (60; 2.0)
C6 (64; 1.7)
C7 (66; 0.5)
C8 (77; 1.8)
C9 (83; 0.6)
C10 (41; 1.0)
C11 (23; 0.5)
A series of 11 aldehydes were chosen to be anchored to
chitosan (Scheme 1). After Schiff base formation between
chitosan and aldehydes 1, 2, 4, 5, and 6, the corresponding
10
11
12
9
10
11
[a] Complexation was carried out with CuOTf (1.2 equiv) at 258C for 16 h.
The amount of complexed copper (%) was calculated after quantification
of the remaining copper salt by UV spectroscopic analysis.
high surface areas, which should enable efficient metal
complexation. The CuI complexes C0–C11 were obtained
after the incubation of Im0–Im11 with a solution of CuOTf
and sodium ascorbate at room temperature, followed by
repeated washing (see the Supporting Information). All
functionalized chitosan derivatives, Im1–Im11, displayed
higher complexation capabilities than that of chitosan itself
(Table 1). The percentage of anchored ligands that chelated
copper varied from 23 to 83%; thus, chelation resulted in
various metal loadings ranging from 0.5 to 2.1 mmol of CuI
per gram of the hybrid catalyst.
To evaluate the putative catalytic activity of C0–C11 for
the Huisgen [3+2] cycloaddition reaction under different
reaction conditions, we decided to use the coumarin-based
fluorogenic probe 12, the design of which was inspired by a
previously described study (Figure 2).[25] This probe enabled
us to monitor the reaction by a simple fluorescence measure-
ment of the corresponding triazole product 13a (lex = 320 nm;
lem = 420 nm). Results summarizing the influence of solvents
and the presence of a reducing agent on the efficiency of
heterogeneous C0–C11 and a homogeneous copper–phenan-
throline catalyst are presented in a color-code format in
Figure 2.
The screening results first indicated a significant solvent
effect on all tested catalysts, including the homogeneous
catalyst, whereby the highest yields were observed when the
reaction was carried out in DMSO. Generally speaking, the
hybrid catalysts C were most effective in highly polar solvents.
The use of EtOH, which is compatible with green chemistry,
interested us in particular. Three heterogeneous catalysts, C6,
C8, and C9, were found to function efficiently (yields > 95%)
Scheme 1. Preparation of the hybrid catalysts. Tf=trifluoromethanesul-
fonyl.
imines should coordinate CuI salts as bidentate N,N ligands
close to the sugar backbone. Aldehydes 8, 10, and 11, which
contain phenanthroline or guanidine moieties (known for
their ability to chelate copper), and dialdehydes 3, 7, and 9,
designed to induce cross-linking throughout the chitosan
network,[23] were also selected.
Upon the treatment of chitosan with aldehyde reactants
(1.5 equiv with respect to the NH2 groups in chitosan) in
EtOH, quantitative conversion of the amine groups on the
polysaccharide support into imines was observed, as indicated
by gas chromatographic quantification of the remaining
aldehydes. Only half an equivalent of dialdehydes 3, 7, and
9 was consumed, even in the presence of an excess of the
reactants. These results suggest that ligand anchoring occur-
red throughout the entire internal surface area of porous
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in EtOH under reducing conditions. Interestingly, only C9
even after four cycles. Quantitative analysis of the product
from each cycle by inductively coupled plasma (ICP)
spectrometry revealed no detectable leaching of copper. To
further verify whether the observed catalysis is truly hetero-
geneous or caused by a leached copper species, C9
was removed from the reaction mixture after 1 h at
708C, and the filtrate was heated further for several
hours. The formation of 14a was stopped completely
by the removal of C9 (see the Supporting Informa-
tion).
retained its catalytic efficiency in the absence of sodium
ascorbate, which suggests that a particular CuI stabilization
within the C9 network avoided the need for a reducing agent.
To examine the scope of catalysis by C9 in the
absence of an additive, we conducted a series of
reactions with the hybrid catalyst (0.1 mol%). 1,4-
Triazoles were obtained in high yields even with
hindered and basic nitrogen-containing reactants
(Scheme 3). Furthermore, reactions were catalyzed
efficiently in pure H2O.[27] Although the hybrid
catalyst C9 has a sugar backbone, it was found to be
thermally quite stable: compound 14c (pure 1,4-
isomer) was formed quantitatively within minutes
under microwave irradiation (1m in EtOH/TEA
(95:05), 1508C, 15 min) in the presence of C9
(0.1 mol%). No significant macroscopic change in
the C9 beads was observed after this treatment, and
14c was again obtained quantitatively when the same
beads were used to catalyze the reaction a second
time. Such thermostability might be explained by the
Figure 2. Screening results for a “click” reaction of the fluorophore 12 with a
variety of catalysts derived from chitosan (and a homogeneous catalyst), with or
without sodium ascorbate (25 mm). Substrate concentration: 10 mm.
DMF=N,N-dimethylformamide, DMSO=dimethyl sulfoxide.
cross-linking of chitosan chains, which should stabi-
lize the fibrous network of C9. The physical charac-
terization of C9 showed a high surface area of
368 m2 gꢀ1 and a high dispersion of copper within
the network.
Under these conditions, C9 appeared to be more active than
the homogeneous system itself, a result that was confirmed by
Table 2: Optimization of the reaction conditions.[a]
kinetic experiments (see the Supporting Information).
The high value of C9 with regard to its efficiency and
practical use under sustainable conditions was further con-
firmed by a series of experiments conducted on a 1 mmol
scale on a model reaction (Scheme 2). Indeed, only 0.1 mol%
Entry
Catalyst
Base
Conditions
t
Yield of
(loading [mol%])
[h]
14a [%]
1
2
3
4
5
6
7
8
9
C9 (1)
C9 (1)
none
none
none
none
none
none
none
none
air, 258C
air, 708C
air, 708C
air, 708C
air, 708C
N2, 708C
air, 708C
N2, 708C
air, 708C
air, 708C
air, 708C
air, 708C
18
2
95
98
99
trace
25
98
23
92
96
97
93
90
C9 (0.1)
C0 (0.1)
C8 (0.1)
C8 (0.1)
C6 (0.1)
C6 (0.1)
C9 (0.1)
C9 (0.1)
C9 (0.1)
C9 (0.1)
12
12
12
12
12
12
12
2
pyridine[b]
TEA[b]
DBU[b]
NaOH[c]
Scheme 2. Model reaction. Bn=benzyl.
10
11
12
12
2
of C9 (< 1% w/w) was required in EtOH at 708C for
complete conversion of the starting materials into the 1,4-
triazole product (Table 2, entry 3). The benefit of chitosan
functionalization on catalytic efficiency (compare entries 3
and 4 in Table 2) and the superior air stability of C9 (compare
entry 3 with entries 5–8 in Table 2) were confirmed. Shorter
reaction times were observed in the presence of triethylamine
(TEA)[26] or under aqueous basic conditions; other bases had
no significant effect (Table 2, entries 9–12). Further experi-
ments showed that C9 is quite a robust catalyst: reuse of the
catalyst for the reaction of phenylacetylene with benzyl azide
produced the expected 1,4-triazole in near quantitative yield
[a] Experiments were carried out at a substrate concentration of 1m.
[b] The reaction was carried out with 1 equivalent of the base. [c] The
reaction was carried out in ethanol/aqueous NaOH (9:1; pH 9). DBU=
1,8-diazabicyclo[5.4.0]undec-7-ene.
In conclusion, we have described new readily recoverable
hybrid catalysts which combine the catalytic power of
transition-metal complexes with the architecture of polysac-
charides and display particularly high efficiency for the
Huisgen [3+2] cycloaddition. The reaction conditions
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Experimental Section
General procedure (no precautions were taken to exclude oxygen):
Two beads of C9 (1.4 mg, 0.87 mmol, 0.1 mol%), the alkyne (1 mmol,
1.1 equiv), and the azide (0.9 mmol, 1 equiv) were heated in EtOH or
H2O (0.9 mL) at 708C for 14 h in a closed vial. The mixture was
separated from the catalyst with a pipette, and the solvent was
removed in vacuo to afford the pure product 14, except in the case of
triazoles 14e, f, and m, which needed recrystallization.
Received: March 9, 2009
Published online: July 2, 2009
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Keywords: click chemistry · copper · cycloadditions ·
heterogeneous catalysis · polysaccharides
.
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