Non-magnetic and magnetic supported copper(I) chelating adsorbents as efficient heterogeneous catalysts and copper scavengers for click chemistry

Article abstract of DOI:10.1002/adsc.201000530

Novel supported chelating adsorbents bearing diverse multidentate nitrogenated ligands with strong copper(I) affinities are easily prepared in non-magnetic and magnetic variants using silica and silica-coated magnetite nanoparticles as suitable supports a

Full text of DOI:10.1002/adsc.201000530

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DOI: 10.1002/adsc.201000530
Non-Magnetic and Magnetic Supported Copper(I) Chelating
Adsorbents as Efficient Heterogeneous Catalysts and Copper
Scavengers for Click Chemistry
Alicia Megia-Fernandez,a Mariano Ortega-MuÇoz,a Javier Lopez-Jaramillo,a
Fernando Hernandez-Mateo,a and Francisco Santoyo-Gonzaleza,*
a
Departamento de Quimica Organica, Facultad de Ciencias, Instituto de Biotecnologꢀa, 18071 Granada, Spain
Fax : (+34)-958243186; phone: (+34)-958248087; e-mail: fsantoyo@ugr.es
Received: July 5, 2010; Revised: September 9, 2010; Published online: December 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000530.
Abstract: Novel supported chelating adsorbents ble copper leaching, particularly in the case of the
bearing diverse multidentate nitrogenated ligands silica-based non-magnetic adsorbents, allowing a
with strong copper(I) affinities are easily prepared in simple operational protocol for their rapid and easy
non-magnetic and magnetic variants using silica and removal by filtration or magnetic decantation and
silica-coated magnetite nanoparticles as suitable sup- showing good recyclability properties. In their un-
ports and the aza-Michael-type addition of vinyl sul- complexed form, the non-magnetic chelating adsorb-
fones as the ligation tool. These adsorbents are ver- ents are very efficient copper scavengers that are
satile materials with applications in the copper-cata- able to remove any traces of metal contamination
lyzed alkyne-azide cycloaddition (CuAAC) click and that can be applied in tandem with any hetero-
chemistry where their complexation abilities enable geneous supported copper(I) catalysts or as stand-
them to act either as heterogeneous click catalysts alone copper removing system in any click protocol
when used in their complexed form or as copper(I) allowing the isolation of metal-free clicked com-
scavengers when used in their uncomplexed form. In pounds.
the first instance, they proved to be robust and effi-
cient heterogeneous catalysts to promote click reac- Keywords: chelates; click chemistry; heterogeneous
tions using extremely low doses and showing negligi- catalysis; magnetic nanoparticles; scavenger
Introduction
catalysts or mediators was revealed[4] shortly after the
discovery of the CuAAC coupling[5] and was shown to
The discovery of the catalytic effect of Cu(I) in the both enhance the reaction rate and to protect the in-
1,3-dipolar cycloaddition reaction of azides with al- herent thermodynamic instability of Cu(I) species
kynes (CuAAC)[1] was a milestone in the develop- from oxidation under aerobic and/or aqueous condi-
ment of the click chemistry concept[2] that has estab- tions. In addition, the application of microwave irradi-
lished this process as the most reliable “click” reac- ation has demonstrated its utility to increase the reac-
tion.[3] A prolific research activity in this area during tion rate and to improve yields with a dramatic reduc-
the last decade has led to the development of a ple- tion of reaction times being observed in most proto-
thora of protocols where the use of different Cu(I) cols.[6]
sources for homogeneous catalysis constitutes the
Despite the pivotal role played by Cu(I) in click cy-
bulk of the reported applications on many research cloaddition reaction of azides and alkynes, the use of
fields that have benefited from the high reliability of this metal is not without drawbacks, especially those
CuAAC reactions. The introduction of new variants related to contamination of clicked products with
to further improve the efficiency of the reaction has toxic metal which becomes an issue of utmost impor-
determined an outstanding level of development for tance particularly in bioconjugation and in biomedical
this ligation methodology. In particular, the use of and pharmaceutical applications of click chemistry.[7]
Cu(I) complexes with nitrogen-based ligands as click Nowadays, several approaches have been used to
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Non-Magnetic and Magnetic Supported Copper(I) Chelating Adsorbents
overcome this limitation. In this respect, the develop- copper-scavenging step has been reported as a feasi-
ment of elegant copper-free click strategies that ex- ble improvement in CuAAC reactions performed
ploit the ring strain of cyclooctyne reagents is particu- under continuous flow conditions.[24] Quadrapureꢂ
larly relevant.[8] However, the Cu(I)-catalyzed version thiourea resin and activated charcoal (Norite type A)
is expected to remain one of the most widely applied have been successfully applied in this methodology to
click reactions due to the straightforward access to remove Cu impurities by exploiting the metal scav-
clickable building blocks.[9]
enging properties of these supports that originate
The heterogenization of click catalysts constitutes from sulfur complexation and adsorption, respective-
an appealing alternative due to the advantages of ly. In addition, simple washing with EDTA has also
easy removal, recovery and reusability that they offer. demonstrated its effectiveness due to the strong che-
This heterogenization has been attained by the cova- lating properties of this complexation agent for Cu
lent and non-covalent immobilization of copper spe- species.[24b]
cies onto a variety of supports such as activated
Considering the present state-of-the-art, we hy-
carbon,[10] zeolites,[11] titanium oxide,[12] alumina,[13] pothesize that further progress in the development of
aluminium oxyhydroxide fibers,[14] silica,[15] cross- eco-friendly CuAAC protocols where copper contam-
linked poly(ethyleneimine),[16] basic Amberlyst,[17] ination is minimized or eliminated is possible by using
Tentagel Resin,[18] polystyrene,[15b] ionic polymers,[19] supported chelating materials with nitrogen-based li-
biopolymers[20] and carbon nantotubes.[21] In some of gands (Si-Lm) with enhanced Cu(I) complex capabili-
these heterogeneous catalysts, the immobilization of ties. These hybrid materials can conceptually be used
amine-based ligands with a contrasted ability as ho- as dual compounds with the capability to act both as
mogeneous click mediators for the synergetic exploi- click heterogeneous catalysts when complexed with
tation of their Cu(I) chelating capabilities and base Cu(I) and also as Cu(I) scavengers when used in their
character has demonstrated to be an efficient ap- uncomplexed form after
a
CuAAC reaction
proach for the design of such hybrid materials. In par- (Figure 1). Herein, we report on the preparation of
ticular dimethylaminomethyl,[17] tris[(1-benzyl-1H- some novel silica-based non-magnetic and magnetic
1,2,3-triazol-4-yl)methyl]amine (TBTA),[18] 3-amino- nanoparticles supported Cu(I) chelating adsorbents as
propyl,[15a] 3-[(2-aminoethyl)amino]propyl,[15a] and well as their application in click chemistry.
1,5,7-triazabicycloACTHNUTRGNEUNG
[4.4.0]dec-5-ene (TBD)[15b] have
been used as chelating frameworks by their grafting
onto a polysterene matrix or silica.
In a related context, magnetic heterogeneous cata-
lysts constitute also an attractive choice. Magnetic
nano- and microsized particles[22] have recently
emerged as viable and promising supports for immo-
bilization with applications in catalytic transforma-
tions as robust, readily available and high-surface-
area heterogeneous catalysts. They possess the added
advantage of being magnetically recoverable by an
external permanent magnet, thereby eliminating the
requirement of catalyst filtration after the reaction
which circumvents time-consuming and laborious sep-
aration steps, and allowing for practical continuous
catalysis. Despite the potential inherent stability, the
activity of such systems and the attractive operational
characteristics that these magnetic materials offer, at
the outset of this study only a recent contribution de-
scribing the use of copper nitride nanoparticles sup-
Figure 1. Applications of supported Cu(I) chelating adsorb-
ents in click chemistry.
ported on a mesoporous superparamagnetic silica mi- Results and Discussion
crospheres as efficient magnetic heterogeneous cata-
lyst in the presence of added tertiary amines had For the preparation of the new supported Cu(I) che-
been reported.[23]
lating materials with structural characteristics that fa-
Although all the reported heterogeneous click cata- cilitate the goal of obtaining copper uncontaminated
lysts have proved their high efficiency and practicabil- clicked compounds, we selected two bidentate and
ity, the problem of metal contamination is still a chal- two tridentate compounds, namely, 2-pycolylamine (1,
lenge to be overcome due to the leaching of active PMA), histamine (2, His), bispicolylamine (3,
copper species that is usually detected in these mate- BPMA) and bispyridylamine (4, BPA) (Figure 1)
rials. In this respect, the introduction of a subsequent from the wide range of available nitrogen-based li-
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Scheme 1. Strategies for the preparation of Si-Lm adsorbents and synthesis of Si-PMA, Si-His, Si-BPMA and Si-BPA.
gands on the basis of their well-known high affini-
ties[25] for Cu(I) and Cu(II)and ligand acceleration
effect on the kinetics of the CuAAC.[26] In addition,
their commercial availability allows a gain in opera-
tional simplicity. We further decided to use silica as
support for the covalent immobilization of these li-
gands because of the advantageous properties dis-
played by this material for the preparation of hybrid
Figure 2. Polymeric Dowex M-4195.
materials: excellent chemical and thermal stability,
good accessibility due to its high surface area and po-
rosity, and easy derivatization.[27] For anchoring the li-
Cu(I) was supported in the silica-based adsorbents
gands onto the surface of silica, the aza-Michael-type Si-Lm by simple treatment with a commercial CuCl
addition of vinyl sulfones to amines was thought to be solution as the metal source in deoxygenated water
an optimal and simple methodology if appropriately giving the corresponding Si-Lm·Cu+ complexes: Si-
functionalized silicas are used. Two plausible strat- PMA·Cu+, Si-His·Cu+, Si-BPMA·Cu+ and Si-
egies are depicted in Scheme 1 starting with vinyl sul- BPA·Cu+. In the case of Dowex M-4195 the as-re-
fone silica (5)[28] and amino functionalized silica (6),[29] ceived resin was first conditioned to remove any re-
easily prepared by silanization of activated commer- sidual organic and leached materials and then Cu(I)
cial silica. Reaction of 5 with amino derivatives 1 and loading was performed by the same treatment as in
2 afforded the Si-Lm adsorbents Si-PMA and Si-His, the case of the silica-based adsorbents giving the cor-
respectively, in high yields. Reaction of 6 with vinyl responding polystyrene-based Cu(I) complex Dw-
sulfone bipyridyl derivatives 7 and 8, obtained by re- BPMA·Cu+. The metal loadings of the novel Cu(I)
acting divinyl sulfone respectively with 3 and 4, gave supporting materials were evaluated by atomic ab-
Si-BPMA and Si-BPA in that order and in good sorption spectroscopy (AAS) and ranges from 2.4 to
yields.
10.4% were found as indicated in the Experimental
Considering that the bispicolylamine motif is also Section.
present in commercial Dowex M-4195 resin
To evaluate the catalytic click capabilities of the
(Figure 2), this polymer-supported chelating adsorb- novel supported Cu(I) materials, a variety of structur-
ent was also envisaged as a suitable material for our ally diverse alkynes 9–20 and azides 21–28 were se-
studies. In fact, Dowex M-4195 is a macroporous resin lected, comprising simple aliphatic and aromatic
with a polystyrene-divinylbenzene matrix with well- mono (9–14, 21, 22 and 26) and multi clickable deriv-
documented chelating capabilities[30] that forms stable atives (18–20, 27 and 28) as well as some alkyne and
complexes with a variety of transition metal cations, azide functionalized biomolecules such as sugars (15,
including Cu(I) and Cu(II), which has found commer- 16 and 23–25) and biotin (17) (Figure 3). The reac-
cial application for the adsorption of heavy metals.
tions were performed under a selection of reaction
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Non-Magnetic and Magnetic Supported Copper(I) Chelating Adsorbents
Figure 3. Representative clickable alkynes and azides.
conditions commonly employed in CuAAC, namely, reaction time. The results are summarized in Table 1,
aqueous t-BuOH, DMF or water as solvents or by Table 2 and Table 3.
direct mixing of the clickable reagents in the absence
From these experiments, it can be clearly concluded
of any solvent when this was allowed by the physical that all the Cu(I) chelated silicas Si-Lm·Cu+ are very
characteristics of the reagents. The reactions were efficient click catalysts since in all cases the 1,4-disub-
performed at room temperature or preferably under situted 1,2,3-triazoles were isolated as regiospecific
microwave (MW) irradiation in order to reduce the products in excellent yields by using strictly equimo-
Table 1. CuAAC reactions using Si-PMA·Cu+ and Si-His·Cu+ as heterogeneous catalysts.
Entry
R1
R2
Alkyne
Azide
Conditions[a]
Catalyst[b]
Time
Compound[c]
1
2
CH2OH
CH2NHBoc
CH2Ph
CH2Ph
9
10
21
21
A
A
Si-PMA·Cu+ (30)
45 min
90 min
29 (95)
32 (100)
Si-PMA·Cu+ (40)
3
CH2Ph
14
21
A
Si-PMA·Cu+ (25)
30 min
40 (85)
4
5
6
7
CH2OH
COOEt
NACHTUNGTRENNUNG
CH2Ph
CH2CH2OH
CH2Ph
9
21
22
21
23
A
A
B
C
Si-His·Cu+ (30)
Si-His·Cu+ (20)
Si-His·Cu+ (60)
Si-His·Cu+ (50)
45 min
60 min
10 min
45 min
29 (90)
36 (94)
50 (87)
42 (100)
11
20
15
a-Man
[a]
Conditions: equimolecular amounts of the alkyne (1 mmol) and azide (1 mmol) and A: t-BuOH:H2O (10:1, 10 mL), MW;
B: t-BuOH:H2O (10:1, 0,6 mL), MW; C: H2O (10 mL), MW.
Given as mg catalyst/mmol reagent.
[b]
[c]
Compound (yield [%]).
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Table 2. CuAAC reactions using Si-BPMA·Cu+ and Dw-BPMA·Cu+ as heterogeneous catalysts.
Entry
R1
R2
Alkyne
Azide
Conditions[a]
Catalyst[b]
Time
Compound[c]
1
2
3
4
5
6
7
8
9
10
CH2OH
CH2OH
CH2NHBoc
CH2OH
b-Glc
a-Man
Bt
CH2OH
CH2OH
CH2NHBoc
CH2Ph
CH2Ph
CH2Ph
b-Gal
a-Man
Tmb
9
9
21
21
21
24
23
28
27
21
21
21
A
B
B
B
C
D
D
A
B
B
Si-BPMA·Cu+ (10)
Si-BPMA·Cu+ (20)
Si-BPMA·Cu+ (20)
Si-BPMA·Cu+ (70)
Si-BPMA·Cu+ (150)
Si-BPMA·Cu+ (150)
Si-BPMA·Cu+ (150)
Dw-BPMA·Cu+ (20)
Dw-BPMA·Cu+ (50)
Dw-BPMA·Cu+ (50)
3 h
29 (96)
29 (96)
32 (92)
31 (99)
42 (100)
45 (90)
46 (89)
29 (80)
29 (56)
32 (70)
20 min
40 min
30 min
90 min
15 min
15 min
24 h
10
9
15
16
17
9
Etg
CH2Ph
CH2Ph
CH2Ph
9
10
40 min
40 min
[a]
Conditions: equimolecular amounts of the alkyne (1 mmol) and azide (1 mmol) and A: neat, room temperature; B: t-
BuOH:H2O (10:1, 10 mL), MW; C: H2O (10 mL), MW; D: DMF (10 mL), MW.
Given as mg catalyst/mmol reagent.
[b]
[c]
Compound (yield [%]).
Table 3. CuAAC reactions using Si-BPA·Cu+ as heterogeneous catalyst.
Entry
R1
R2
Alkyne
Azide
Conditions[a]
Catalyst[b]
Time
Compound[c]
1
2
3
4
5
6
7
8
9
CH2OH
CH2OH
CH2OH
CH2OH
CH2Ph
CH2Ph
CH2Ph
b-Gal
CH2CH2OH
CH2Ph
CH2CH2OH
b-Gal
9
9
9
9
11
10
10
10
10
21
21
21
24
22
21
22
24
26
A
B
C
B
B
B
B
D
E
30
30
20
70
20
55
55
20
20
24 h
1 h
15 min
1 h
1 h
1 h
1,5 h
10 min
30 min
29 (88)
29 (88)
29 (87)
31 (99)
36 (100)
32 (100)
33 (100)
34 (98)
35 (100)
COOEt
CH2NHBoc
CH2NHBoc
CH2NHBoc
CH2NHBoc
Ada
10
11
12
13
14
CH2Ph
12
13
13
13
14
21
22
21
21
21
B
B
B
C
C
50
50
40
5
1 h
37 (100)
39 (89)
38(83)
CH2CH2OH
CH2Ph
1,5 h
1 h
CH2Ph
15 min
15 min
38 (91)
40 (97)
CH2Ph
10
15
16
17
b-Glc
b-Glc
CH2CH2OH
b-Gal
a-Man
15
15
19
22
24
23
B
F
G
100
150
30
2 h
1 h
30 min
41 (100)
43 (85)
49 (85)
C
(CH2O)4
[a]
Conditions: equimolecular amounts of the alkyne (1 mmol) and azide (1 mmol) and A: t.BuOH:H2O (10:1, 10 mL), room
temperature; B: t-BuOH:H2O (10:1, 10 mL), MW; C: neat, MW; D: t-BuOH:H2O (10:1, 1.90 mL), MW; E: t-BuOH:H2O
(10:1, 0.6 mL), MW; F: H2O, MW; G: DMF, MW.
Given as mg catalyst/mmol reagent.
Compound (yield [%]).
[b]
[c]
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Non-Magnetic and Magnetic Supported Copper(I) Chelating Adsorbents
Table 4. Optimization of the Si-Lm·Cu+ catalyst loadings.
lecular amounts of the clickable reagents without the
use of any additives such as reducing agents or nitro-
genated bases. The catalytic ability was independent
of the chemical nature of the chelating ligand, as all
the Cu(I) supported silicas have a similar behaviour
and gave similar results when the reactions were per-
formed using the same reagents and reaction condi-
tions. This is clearly illustrated in the coupling of the
model propargyl alcohol (9) and benzyl azide (21),
where the corresponding 1,2,3-triazole 29 was ob-
tained in yields ranging from 88 to 96% when the re-
actions were carried out in aqueous t-BuOH under
MW irradiation (see Table 1, entries 1 and 4, Table 2,
entry 2 and Table 3, entry 2).
Entry Conditions[a] Catalyst[b]
mol% Cu I:II[c]
1
2
3
4
5
6
7
8
A
A
A
A
A
A
B
B
B
B
B
C
C
C
Si-BPA·Cu+(30) 1.53
1:0 (96)
1:0 (92)
1:0 (99)
1:0 (97)
n.r.
1:0 (93)
1:0 (87)
6.8:1 (86)
4:1 (89)
2.5:1 (94)
1.3:1 (83)
1:0 (97)
1:0 (85)
n.r.
Si-BPA·Cu+(10) 0.51
Si-BPA·Cu+(5) 0.25
Si-BPA·Cu
Si-BPA·Cu
+A
+A
G
Si-His·Cu
(1.0) 0.16
Si-BPA·Cu+(20) 1.02
The catalytic efficiency of the Si-Lm·Cu+ materials
was the same in all tested solvents. Particularly rele-
vant is the fact that the click reactions can be effi-
ciently performed under aerobic conditions using
water as solvent when the reagents are hydrosoluble.
Moreover, the use of these catalytic systems allows a
considerably solvent economy, as exemplified in the
case of catalyst Si-His·Cu+ (Table 1, entry 6) and Si-
BPA·Cu+ (Table 3, entries 8 and 9). The reactions can
even be executed in the absence of a solvent either at
room temperature or under MW irradiation when the
reagents can be mixed together homogenously
(Table 2, entry 1, Table 3 entries 3, 13 and 14). Al-
though these silica-based CuAAC reactions can be
carried out at room temperature, as expected MW as-
Si-BPA·Cu+(10) 0.51
9
Si-His·Cu+(10)
1.64
Si-BPA·Cu+(5) 0.25
none
10
11
12
13
14
–
Si-BPA·Cu+(10) 0.51
Si-His·Cu+(5)
0.82
none
–
[a]
Conditions: equimolecular amounts of the alkyne and
azide and A: t-BuOH:H2O (10:1), MW, 80 min, 608C; B:
neat, MW, 15 min, 608C; C: neat, room temperature, 3 h.
mg catalyst/mmol reagent.
[b]
[c]
(Yield [%]).
sistance reduces considerably the reaction times re- formed with compounds 19, 20, 27 and 28 (Table 1,
quired. entry 6; Table 2, entries 6 and 7; Table 3, entry 17).
An additional advantage offered by the use of On the other hand, a series of experiments were also
these hybrid materials as catalysts is the simplicity of carried out to study the minimum loadings required
the operational procedure since in all cases the tria- to maintain the catalytic activity of our supported sys-
zoles are obtained by direct filtration and evaporation tems (Table 4). In this regard, progressively reduced
of the solvent without the need of further chromato- amounts of catalyst were used in the model click reac-
graphic purification. This permits the easy recovery of tion between alkyne 9 and azide 21 either in solution
the catalysts facilitating their reuse. In fact, the recy- or under neat conditions. The results obtained showed
clability of the silica-based catalyst was tested for the that catalysis occurs with doses as low as 2.5 and
model reaction of alkyne 9 and azide 21 catalyzed by 1.0 mg of Si-BPA·Cu+ and Si-His·Cu+ per mmol of re-
Si-BPMA·Cu+ (see Experimental Section). This heter- agent, respectively, (entries 4 and 6) when the reac-
ogeneous catalyst could be reused at least four times tions were performed in solution. These minimal
in new cycloaddition experiments without any critical loadings should be slightly higher when the reactions
loss of activity or yield (97%, 96%, 97% and 94% for were performed under neat conditions either at room
the successive runs).
temperature or with MW irradiation (entries 7, 12 and
Further experiments also corroborated the robust- 13). Below this minimal dose, either no reaction
ness of the silica-supported Cu(I) adsorbents as click (entry 5) or formation of the thermal 1,5-regioisomer
catalysts. Thus, they exhibited an excellent efficiency is observed (entries 8–10). Finally, it should be noted
when sterically demanding clickable substrates were that the Si-Lm·Cu+ catalysts are air-stable compounds
used as denoted by the quantitative yield obtained in since their catalytic activity remains intact after long-
the reaction of the alkyne 10 with the azide adaman- term air exposure on storage.
tane derivative 26 (Table 3, entry 9). Moreover, the
Once the feasibility of the silica-based supported
preparation of multivalent structures by the concomi- Cu(I) adsorbents as click catalysts was clearly estab-
tant formation of multiple 1,2,3-triazole rings was lished, the capabilities of the polystyrene-supported
easily attained by the reaction of clickable derivatives Dw-BPMA·Cu+ were next investigated in order to
bearing multiple copies of either the alkyne or the determine possible benefits in the use of this hybrid
azide function as illustrated by the reactions per- material. This copper-containing matrix was assayed
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Table 5. Leaching values of CuAAC reactions catalyzed by supported Cu(I) chelating adsorbents.
Entry
Alkyne
Azide
Conditions[a]
Catalyst[b]
Leaching
% Cu released
Table.Entry
ppm Cu
in product
from initial Cu
1
2
3
4
5
6
7
9
9
15
9
10
9
15
21
21
24
21
21
22
22
A
B
C
A
B
C
C
Si-BPMA (10)
Si-BPMA (20)
Si-BPA (150)
Dw-BPMA (20)
Dw-BPMA (50)
Fe3O4@Si-BPA·Cu (10)
Fe3O4@Si-BPA·Cu (10)
36
17
62
1500
3200
690
260
1.9
0.4
0.5
15
18
7.4
8.9
2.1
2.2
3.16
2.8
2.10
7.1
7.4
[a]
Conditions: equimolecular amounts of the alkyne (1 mmol) and azide (1 mmol) and A: neat, room temperature; B: t-
BuOH:H2O (10:1, 10 mL), MW; C: H2O (10 mL), MW.
mg catalyst/mmol reagent.
[b]
to click the model alkynes 9 and 10 with benzyl azide to be negligible when quantified directly in the reac-
21 where it was demonstrated to have a click catalytic tion crudes. Thus, in the reactions of 9 with 21 and of
profile either in solution or under neat conditions 15 with 24 the levels of residual copper detected by
(Table 2, entries 8–10). A comparison of the reaction AAS were very low ranging between 0.4% and 1.9%
outcomes (yield and time) of these assays with those of the initial amount of copper present in the catalysts
of similar experiments using the homologous Si- employed (Table 5, entries 1–3). However, in the case
BPMA·Cu+ catalyst containing the same BPMA che- of the reactions catalyzed by the polystyrene-based
lating agent (Table 2, entries 1–3) reveals a lower per- Dw-BPMA·Cu+ catalyst the leaching values and con-
formance of the polymer-based catalyst since de- tamination of the clicked compounds are surprisingly
creased yields are obtained with increased reaction higher (Table 5, entries 4 and 5). The residual pres-
times and higher catalyst loadings.
ence of copper in the reaction media in the case of
Moreover, coloured green reaction crudes are ob- the silica-based catalyst is in accordance with our ex-
tained in spite of the conditioning protocol to which pectations based on the strong copper affinity of the
the commercial resin was subjected prior to the Cu(I) chelating ligands incorporated to the adsorbents when
immobilization, and chromatographic purification was they were conceptually designed allowing not only for
needed to obtain clear clicked compounds. This differ- the stabilization of Cu(I) but also for the readsorption
ent behaviour of both catalytic systems can be tenta- of the migrated metal onto the support after the cata-
tively ascribed to the higher particle size for Dw- lytic cycle is complete. The better performance of the
BPMA·Cu+ with respect to Si-BPMA·Cu+ that deter- Si-Lm·Cu+ catalysts over the Dw-BPMA·Cu+ coun-
mines a lower surface for the former heterogeneous terpart on that concerning the leaching of the sup-
catalyst. From these results, it can be stated that the ported metal is also indicative of an active role for
use of silica-based adsorbents is more advantageous the silica matrix in the adsorption of the copper spe-
for click catalysis purposes.
cies which is in agreement with previous observations
In the next phase, the leaching of active copper spe- reported in the literature.[31]
cies from the catalysts to the reaction media was eval-
At this point, a series of assays were designed to
uated as this is a key issue in our CuAAC study in prove that the catalytic activity of the supported
the search of protocols that allow the isolation of Cu(I) chelating adsorbents Si-Lm·Cu+ is associated to
copper-free clicked compounds (Table 5). The leach- the stabilization of Cu(I) attained by its heterogeniza-
ing from the silica-based Si-Lm·Cu+ catalysts showed tion through complexation with the nitrogenated li-
Scheme 2. Assays to probe the influence of the Cu(I) stabilization by Si-Lm adsorbents in their catalytic activity.
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Non-Magnetic and Magnetic Supported Copper(I) Chelating Adsorbents
Table 6. Use of Si-Lm adsorbents as stand-alone scavenger or in combination with alkyne and azide scavengers.
R1
R2
Alkyne
Azide
Alkyne/Azide
Compound (yield [%])
À
SiO2 X
Entry
1
2
3
4
5
CH2OH
b-Glc
Dpp
Dpp
b-Glc
CH2CH2OH
CH2CH2OH
CH2CH2OH
a-Man
9
22
22
22
23
25
1.0/1.0
1.0/1.0
1.0/2.0
1.0/2.4
2.0/1.0
–
–
–
30 (86)
41 (100)
47 (100)
48 (99)
44 (100)
15
18
18
15
À ꢀ
SiO2 C CH
SiO2 N3
À
CD
gands Lm (Scheme 2 and Supporting Information). Complete removal of the already insignificant metal
First, activated silica previously treated with a CuCl traces was evident after a new filtration. In this way,
solution was added to a mixture of the alkyne 9 with the isolation of uncontaminated materials was at-
the azides 21 or 24 as indicated in Scheme 2. In these tained in a facile manner (see Experimental Section).
cases, no cycloaddition products were observed in the
To explore the scope of the Si-Lm supported
assayed solvents (t-BuOH-H2O or H2O). These results copper chelating adsorbents as scavengers in CuAAC
suggest a complete oxidation of the Cu(I) to Cu(II) reactions and further expand their utility as stand-
during copper adsorption over the activated silica or alone copper removing systems, additional assays
under the reaction conditions used for the attempted were carried out (Table 6). First, the scavenging abili-
click reactions. To verify this point, ascorbate was si- ties were tested in click reactions performed using a
multaneously added to the activated silica treated homogeneous click catalyst. Thus, stoichiometric
with CuCl to act as a reducing agent in the reaction amounts of the alkynes 9, 15 and 18 with azide 22
of 9 and 24. The clicked 1,2,3-triazole 31 was obtained were reacted using CuCl[32] as a source of Cu(I)
in this way in the MW assisted reaction with an ac- (Table 6, entries 1–3). After the reaction was complet-
ceptable outcome in relation to that obtained in the ed, the scavenging treatment of the crudes with Si-
case of Si-BPMA·Cu+ although the leaching levels BPA or Si-His gave the clicked derivatives 30, 41 and
are higher in this case (28% of the initial amount of 47, respectively, free of any detectable copper con-
copper). Finally, the activated silica containing ad- tamination. It should be also mentioned that a similar
sorbed copper was first treated with ascorbate and, scavenger performance was observed for Dw-BPMA
after filtration, was directly used in the reaction of 9 in the reaction of 15 with 22 (see Supporting Informa-
with 24 to afford triazole 31 in a reduced yield after a tion, Table 2S). Secondly, bearing in mind that Cu-cat-
longer reaction time. Overall, these results clearly in- alyzed triazole formations are in many cases accom-
dicated the catalytic benefits obtained by immobiliz- plished using an excess of one of the clickable re-
ing Cu(I) on supported chelating adsorbents that pre- agents, particularly, a surplus of the azido building
À
vents its oxidation to Cu(II).
block to avoid C C coupling reactions of two alkyne
The excellent complexation attributes of the ligand moieties, and also the plausible implementation of the
incorporated to the supported chelating adsorbents Si-Lm adsorbents in click reactions under continuous
also point to the potential of their uncomplexed form flow conditions,[24] the dialkynyl derivative 18 and the
to act as copper scavengers. The inherent scavenging monoazide derivative of b-cyclodextrin 25 were react-
capabilities of both Si-Lm and Dw-BPMA were ini- ed with an excess of the complementary a-Man azide
tially verified by treating a commercial CuCl solution (23) and the b-Glc alkynyl (15) derivatives, respec-
with these materials where we observed a complete tively, using CuCl as catalyst (Table 6, entries 4 and
removal of the metal present by Si-BPA and Si-His 5). The extra amounts of the unreacted clickable re-
adsorbents and an almost quantitative elimination by agents were first removed by using alkyne or azido
Dw-BPMA (see Supporting Information, Table 1S). functionalized silicas[33] as “click chemistry scaveng-
To demonstrate the scavenging abilities in click reac- ers” followed by subsequent treatment with Si-BPA
tions, the Si-Lm adsorbents were first used in tandem to eliminate copper species. The use of comparable
with their complexed forms Si-Lm·Cu+. The crudes polystyrene-based functionalized alkyne and azide
obtained after filtration in the reactions of 9 with 21 resins as azide and alkyne scavengers has been previ-
and of 15 with 24 when catalyzed respectively by Si- ously reported in the literature.[34] Excellent results
BPMA·Cu+ and Si-BPA·Cu+ (Table 2, entry 2, and were obtained as pure uncontaminated triazoles 48
Table 3, entry 16) were simply mixed with the uncom- and 44 were respectively obtained in almost quantita-
plexed form of the catalyst, Si-BPMA and Si-BPA. tive yields in a expeditious manner due to the simulta-
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Scheme 3. Preparation of magnetic nanoparticles-supported Cu(I) Fe3O4@Si-BPA·Cu+.
neous use of MW irradiation that not only assists the their surface of chelating ligands Lm that in the pres-
click reaction but also speeds up the scavenging pro- ent study we restricted to the bispyridylamine ligand
cess of the clickable reagents. In addition, chromato- (4, BPA).
graphic purification is not necessary in this protocol.
To attain the covalent linkage of BPA onto the sur-
Having established the feasibility of the silica-sup- face of magnetite nanoparticles, the two main strat-
ported copper chelating adsorbents in their com- egies commonly used to incorporate functionalies
plexed and uncomplexed forms as both efficient and onto the surface of silica nanoparticles were envis-
robust heterogeneous click catalysts and Cu(I) scav- aged: a) post-synthesis functionalization (grafting)
engers, we decided to extrapolate these satisfactory and direct synthesis (co-condensation) (Scheme 3).
results to the preparation of a magnetic version of For both strategies monodisperse ferrite nanoparticles
those adsorbents for the synergetic exploitation of the (51) were first easily prepared using a variation of the
inherent properties offered by magnetic heterogene- solvothermal reduction methodology reported by Li
ous catalysts (magnetic recovery and recyclability) et al.[35] which constitutes a simple, general and inex-
with the enhanced Cu(I) complex capabilities of the pensive one-step procedure for the preparation of
chelating ligands.
such materials.
From the various magnetic materials available,
For the grafting strategy, the magnetic ferrite nano-
magnetite (Fe3O4) is one of the iron oxides most com- particles 51 were initially coated with a silica shell
monly used for the preparation of magnetic nanopar- using tetraethyloxysilane (TEOS) according to a stan-
ticles. For these particles, increasing attention has dard sol-gel literature method[36] and the resulting
been paid to develop protection strategies that ensure core/shell Fe3O4@Si particles (52) were next treated
their chemical stability against agglomeration or pre- with excess of aminopropyltriethoxysilane (APTS) as
cipitation as well as oxidation in air. In particular, the surface modification reagent in refluxing toluene
coating Fe3O4 with a thin layer of silica is an attrac- to yield the amino functionalized particles Fe3O4@Si-
tive alternative with additional advantages such as the NH2 (53). In fact, amino groups are one of the most
stability under aqueous conditions, the easy surface widely used functional groups on magnetic nanoparti-
modification and the facile control of interparticle in- cles to allow further modifications.[37] In our case, the
teractions of the resulting core-shell structures. Taken immobilization of the copper chelating ligand BPA
into account these facts, silica-based magnetite com- was attained by means of the aza-Michael-type addi-
posites were thought to be ideal candidates for the tion of the BPA vinyl sulfone derivative 8, in a similar
preparation of magnetic supported-Cu(I) catalysts maner to that used in the preparation of the silica
Fe3O4@Si-Lm·Cu+ through the immobilization on based adsorbents Si-Lm, giving an easy access to the
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Non-Magnetic and Magnetic Supported Copper(I) Chelating Adsorbents
Fe3O4@Si-BPA composite (55). Alternatively, this simplified procedure by taking advantage of the mag-
functionalized hybrid material was prepared with an netic decantation properties of those composites. A
identical outcome by the co-condensation strategy by TEM micrograph (Figure 4) confirmed the formation
reaction of the magnetic nanoparticles 51 with a mix- of the expected core/shell structure of the Fe3O4@Si-
ture of TEOS and the BPA-containing silane 54, pre- BPA nanoparticles showing a thin silica shell (25 nm)
viously prepared by the Michael addition of the vinyl and iron oxide cores possessing diameters of about
sulfone 8 and aminopropyltriethyloxysilane.
250 nm. The analysis of the magnetization curves (see
Cu(I) was then supported on the Fe3O4@Si-BPA Supporting Information) reveals that silica cover in-
nanoparticles (55) by simple treatment with commer- fluences the magnetic properties and that the
cial CuCl solution in deoxygenated water giving the Fe3O4@Si particles show only 80% of magnetic satu-
corresponding complex Fe3O4@Si-BPA·Cu+ (56) that ration value of the ferrite nanoparticles
showed metal loadings of 8.3% and 7% for the parti-
The catalytic capabilities of the copper containing
cles obtained by the grafting and the co-condensation magnetic nanoparticles Fe3O4@Si-BPA·Cu+ in click
strategies, respectively, according to the quantification reactions were then examined in a representative set
performed by atomic absorption spectroscopy (AAS). of click reactions using similar conditions as in the
It should be noted that either strategy involves a mul- case of the reactions catalyzed by their non-magnetic
tistep transformation of the magnetite silica-coated counterparts Si-Lm·Cu+. The results summarized in
particles 51 into the new magnetic nanoparticle-sup- Table 7 (entries 1–6) show that these magnetic sup-
ported Cu(I) 56 that can be performed in a one-pot ported-Cu(I) nanoparticles 56 have also an excellent
catalytic profile identical to that of the Si-Lm·Cu+ cat-
alysts. Thus, the 1,4-disubstituted 1,2,3-triazoles were
isolated in almost quantitative yields using precise
equivalent amounts of the clickable reagents and low
catalyst loading (10 mg per mmol of clickable re-
agent) in very short reaction times when the click li-
gation was assisted by MW irradiation or in accepta-
ble periods when the reaction is performed at room
temperature. The suitability of this magnetic-support-
ed Cu(I) catalyst in click reactions is further rein-
forced by its extremely easy manipulation and recov-
ery, which can be efficiently performed by magnetic
decantation in accordance with the pursued goal of
gaining in simplicity and recyclability. In fact, the re-
cycling efficiency was investigated in the case of the
reaction of alkyne 10 with azide 21 (Table 7, entry 3)
where no discernible loss of catalytic activity was de-
tected after three cycles, the resulting triazole 32
being isolated in almost quantitative yields after each
run (see Experimental Section). In addition, the use
Figure 4. TEM image of core/shell magnetite silica compo-
site-supported Cu(I) click catalyst 56.
Table 7. CuAAC reactions using magnetic composite Fe3O4@Si-BPA·Cu (56) as heterogeneous catalysts (entries 1–6) and
blank assays using Fe3O4@Si-BPA (55) (entries 7 and 8).
Entry
R1
R2
Alkyne
Azide
Composite
Conditions[a]
Time
Compound[b]
1
2
3
4
5
6
7
8
CH2OH
CH2OH
CH2NHBoc
b-Glc
CH2CH2OH
CH2Ph
CH2Ph
CH2CH2OH
a-Man
CH2Ph
9
9
10
15
15
20
9
22
21
21
22
23
21
21
21
56
56
56
56
56
56
55
55
A (10)
B (10)
C (20)
A (10)
A (10)
C (10)
B (10)
C (20)
10 min
15 h
30 (99)
29 (99)
32 (99)
41 (96)
42 (98)
50 (100)
n.r.[c]
15 min
10 min
15 min
10 min
24 h
b-Glc
N
N
CH2OH
CH2NHBoc
CH2Ph
CH2Ph
10
2 h
(10)[d]
[a]
Conditions: equivalent amounts of alkyne and azide and A: H2O (10 mL), MW, 608C; B: neat, room temperature; C t-
BuOH:H2O (10:1, 1 mL), MW, 608C; In parenthesis mg catalyst/mequiv reagent.
Compound (yield [%]).
[b]
[c]
[d]
No reaction.
A mixture of the 1,4-regiosiomer (32) and the corresponding 1,5-regioisomer was isolated in this case.
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of Fe3O4@Si-BPA·Cu+ as heterogeneous catalyst silica-based non-magnetic adsorbents, and exploit the
allows the use of minimal amounts of an aqueous al- attractive characteristics inherent to catalytic hetero-
cohol or even water when the reagents are hydrosolu- genization: rapid and easy removal by filtration or
ble. Moreover, the reactions can be executed in the magnetic decantation together with recyclability prop-
absence of any solvent when the reagents can be erties. This excellent catalytic profile is due to the sta-
mixed together reducing the use of organic solvent to bilization of Cu(I) mediated by its complexation. In
very small amounts for allowing the magnetic decant- the second case, the non-magnetic uncomplexed
ation and recovery of the catalyst. On that concerning copper chelating adsorbents are efficient scavengers
the leaching of active copper species from the catalyst that can operate in tandem with the Cu(I) complexed
to the reaction media, the copper content of the materials or as stand-alone copper removing system
crudes obtained in the reaction of alkynes 9 and 15 to eliminate the copper contamination from any
with azide 22 was evaluated by AAS showing disap- CuAAC reaction media. These materials open new
pointing values of 7.4 and 8.9% of the initial metal opportunities for the preparation of greener clicked
present in the catalyst (Table 5, entries 6 and 7). This compounds. Further work is in progress for the imple-
observation reinforces additionally the hypothesis mentation of these supported-Cu(I) chelating adsorb-
pointed out above about the synergistic role played ents in CuAAC reactions using flow conditions.
by the silica matrix in the non-magnetic Si-Lm ad-
sorbents on the decreasing of the leaching.
In a similar fashion as in the case of the non-mag- Experimental Section
netic Si-Lm·Cu+ catalysts, additional experiments
were carried out to demonstrate that the catalytic ac- General
tivity is exclusively related to complexed Cu(I) pres-
ent in the magnetic catalyst 56. Two blank experi-
[TEOS, (3-aminopropyl)trimethoxysilane, compounds 1–4,
Unless otherwise noted, commercially available reagents
ments were performed using uncomplexed Fe3O4@Si-
Lm particles (55) in the clicking of alkynes 9 and 10
with azide 21. As expected, no cycloaddition reaction
was detected when the reaction was performed under
neat conditions and long reaction times (Table 7,
entry 7) and a mixture of the 1,4- and 1,5-regioisom-
ers was isolated in very low yield when MW irradia-
tion was used (Table 7, entry 8) proving that thermal
cycloaddition is operative in the last case.
9, 11–14, 20, 26 and Cu(I)Cl solution (ca. 14%)], and sol-
vents were used as purchased without further purification.
The Dowex M-4195 resin was purchased from Supelco and
subjected to a conditioning treatment. The vinyl sulfone
propyl silica gel 5,[28] the aminopropyl silica gel 6,[29] the al-
kynes 10,[38] 15,[39] 16,[40] 17,[41] 18[42] and 19,[43] the azides
21,[44] 22,[45] 23,[46] 24,[47] 25,[48] 27,[49] and 28[50] and the alkyne
and azido functionalized silicas[33] used as click scavengers
were prepared according to reported procedures in litera-
ture. TLCs were performed on Merck Silica Gel 60 F254 alu-
minium sheets. Reagents used for developing plates include
ceric sulfate (1% w/v) and ammonium sulfate (2.5% w/v) in
10% (v/v) aqueous sulfuric acid, iodine, ethanolic sulfuric
acid (10% v/v) and by UV light when applicable. Microwave
assisted reactions were performed in a Milestone Star Mi-
crowave Labstation at 500 W until thin layer chromatogra-
phy and IR spectra showed complete disappearance of the
starting materials. Flash column chromatography was per-
formed on Merck silica gel (230–400 mesh, ASTM). Melting
points were measured on a Gallenkamp melting point appa-
ratus and are uncorrected. IR spectra were recorded on a
Conclusions
In summary, supported chelating adsorbents contain-
ing multidentate nitrogenated ligands with strong cop-
per(I) affinities are easily accessible in both non-mag-
netic and magnetic forms and are shown to be versa-
tile materials in click chemistry for the implementa-
tion of eco-friendly protocols that allow the isolation
of metal-free clicked compounds. These adsorbents
were prepared from silica or silica-coated magnetite
nanoparticles by the incorporation of the chelating li-
gands through a variety of efficient strategies based
on the aza-Michael-type addition of vinyl sulfone to
amines. The copper complexation abilities of these
materials enable them to play a dual role as heteroge-
neous click catalytic systems when used in their com-
plexed form and also as efficient copper scavengers in
their uncomplexed form. In the first instance, the
novel non-magnetic and magnetic Cu(I)-supported
hybrid materials proved to be robust and efficient
heterogeneous catalysts that are able to both promote
click reactions by using extremely low doses with neg-
ligible copper leaching, particularly in the case of the
1
Satellite Mattson FTIR. H and 13C NMR spectra were re-
corded at room temperature on
a Bruker (300–400–
500 MHz) spectrometer. J values are given in Hz. MALDI-
TOF and NALDI-TOF mass spectra were recorded on an
Autoflex Brucker spectrometer using HCCA and NaI, re-
spectively, as matrix. Electrospray ionization (ESI) mass
spectra were recorded on an LCT Premier Spectrometer.
Cu content was determined by atomic absorption spectros-
copy (AAS) using a spectrophotometer Perkin–Elmer AA-
nalyst100. XRD diffraction pattern was collected on a
PW101710/00 Philips diffractometer with CuKa radiation
(l=1.5418 ꢃ) and analyzed with XPOWDERꢄ.
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Non-Magnetic and Magnetic Supported Copper(I) Chelating Adsorbents
yields the Dw-BPMA·Cu+ catalyst. The Cu content was
evaluated by AAS: 7.08%.
Preparation of Silica-Supported Chelating Adsorbent
Si-PMA
Vinyl sulfone silica 5[28] (1.0 g) was suspended in THF-2-
propanol (1:1, 25 mL). 2-Picolylamine (1) (108 mg,
1.0 mmol) was then added. The reaction mixture was heated
at 608C for 16 h. Filtration and successive washing with di-
chloromethane (500 mL) and ether (500 mL) furnished the
corresponding functionalized silica Si-PMA that was dried
under vacuum (1 mm Hg) at 508C for 16 h; yield: 0.98 g.
General Procedure for the Synthesis of 1,2,3-Triazoles
Catalyzed by Cu-Supported Silica Catalysts Si-
Lm·Cu+ or Dw-BPMA·Cu+
A neat mixture or a solution in t-BuOH-H2O (10:1 or 2:1)
or H2O of equivalent amounts of the corresponding alkyne
9–20 (1 mmol) and azido derivatives 21–28 (1 mmol) was re-
acted at room temperature or by MW irradiation at 608C
after the addition of the Cu-supported catalyst Si-PMA·Cu+,
Si-His·Cu+, Si-BPMA·Cu+, Si-BPA·Cu+ or Dw-BPMA·Cu+
(the amounts of solvent and catalyst are indicated in
Table 1, Table 2, and Table 3). The reactions were followed
by TLC until complete disappearance of the starting materi-
als (reaction times are indicated in the tables). Filtration of
the catalyst was then directly performed in the case of the
reactions in solution or after the addition of CH2Cl2 (10 mL)
in the case of the neat reactions. Evaporation of the solvent
under vacuum afforded the pure 1,2,3-triazoles in the yields
indicated in the tables.
Preparation of the Silica-Supported Chelating
Adsorbent Si-His
Vinyl sulfone silica 5[28] (1.0 g) was suspended in a solution
of THF-2-propanol (1:1, 25 mL) containing histamine·2HCl
(184 mg, 1.0 mmol) and Et3N (420 mL, 3.0 mmol). The reac-
tion mixture was heated at 608C for 16 h. Filtration and suc-
cessive washing with dichloromethane (500 mL) and ether
(500 mL) furnished the corresponding functionalized silica
Si-His that was dried under vacuum (1 mm Hg) at 508C
for16 h; yield: 0.98 g.
Assay to Prove the Recyclability of the Si-Lm·Cu+
Catalysts
Preparation of the Silica-Supported Chelating
Adsorbents Si-BPMA and Si-BPA
Amino propyl silica gel 6[29] (1 g) was suspended in THF-2-
propanol (1:1, 50 mL). The corresponding vinyl sulfone
ligand derivative 7 or 8 (1.0 mmol) was added. The reaction
mixture was heated at 608C for 16 h. Filtration and succes-
sively washing with dichloromethane (500 mL) and ether
(500 mL) furnished the corresponding functionalized silicas
that were dried under vacuum (1 mm Hg) at 508C for16 h;
yields: 1.12 g for Si-BPA and 1.11 g for Si-BPMA.
Alkyne 9 (1.0 mmol) and azide 21 (1.0 mmol) in t-BuOH-
H2O (10:1, 10 mL) were reacted by MW irradiation at 608C
for 20 min after the addition of Si-BPMA·Cu+ (30 mg) as
catalyst. After centrifugation and separation of supernatant
solution, the Si-BPMA·Cu+ catalyst was washed with the re-
action solvent and reused in a second cycle of an identical
solution of the clickable reagents. The procedure was re-
peated until a fifth cycle. Evaporation of the corresponding
crude solutions obtaining in each cycle gave the triazole 29
in yields 97, 96, 97 and 94%.
Preparation of the Cu-Supported Silica Catalysts Si-
Lm·Cu+
Procedure for Copper Removal Using Si-BPMA or
Si-BPA as Scavenger in Reactions Catalyzed by Si-
BPMA·Cu+ or Si-BPA·Cu+
De-ionized water (30 mL) was first deoxygenated with
argon and functionalized silicas Si-PMA, Si-His, Si-BPMA
or Si-BPA (1.0 g) and commercial copper(I) chloride solu-
tion (1.7 mL) were added. The resulting suspension was
magnetically stirred at room temperature for 7 h. Filtration
and extensively washing with water and ether yields the cor-
responding Cu-supported silica catalysts Si-PMA·Cu+, Si-
His·Cu+, Si-BPMA·Cu+ and Si-BPA·Cu+ that were dried
under vacuum (1 mm Hg) at 508C for 16 h; yields: 1.10 g for
Si-PMA·Cu+, 1.11 g for Si-His·Cu+, 1.14 g for Si-BPMA·Cu+
and 1.09 g for Si-BPA·Cu+. The Cu contents were evaluated
by AAS: 5.28% for Si-PMA·Cu+, 10.42% for Si-His·Cu+,
2.44% for Si-BPMA·Cu+ and 3.24% for Si-BPA·Cu+.
The solution obtained after filtration in the reactions of
alkyne 9 or 15 with azide 21 or 24, using Si-BPMA·Cu+ or
Si-BPA·Cu+, respectively (Table 2, entry 2 and Table 3,
entry 16) that contains the triazole 29 or 43 and 0.4 ppm of
Cu as detected by AAS, corresponding to leaching from the
heterogeneous catalyst, was treated in batch for 6 h with Si-
BPMA or Si-BPA (25 mg), respectively. The solution was
then filtrated and the copper contamination was evaluated
by AAS giving a negative result in both cases. Evaporation
of the solution gave copper-free 29 and 43 in similar yields
that those obtained in the reactions where the scavenging
treatment was not performed.
Preparation of the Cu-Supported Dowex M4195
Catalysts Dw-BPMA·Cu+
Procedure for Copper Removal using Si-His or Si-
BPA as Scavenger in Reactions Catalyzed by CuCl
The as-received resin Dowex M-4195 (5.0 g) was first condi-
tioned by washing successively with DMF (2ꢅ50 mL) and
water (2ꢅ50 mL) under MW irradiation (15 min 808C).
After filtration, the resin (1.0 g) was suspended in de-ion-
ized water (30 mL) deoxygenated with Argon and then com-
mercial copper(I) chloride solution (1.7 mL) was added. The
suspension was magnetically stirred at room temperature for
7 h. Filtration and extensive washing with water and ether
A water solution (10 mL) of equivalent amounts of alkynes
9, 15 or 18 (0.7 mmol) with azide 22 (0.7 mmol for the reac-
tion with 9 and 15, and 0.14 mmol for the reaction with 18)
(Table 6, entries 1–3) was reacted using a commercial solu-
tion of CuCl (1% mol, 5 mL for the reaction with 9 and 15,
and 10 mL for the reaction with 18) under MW irradiation
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Alicia Megia-Fernandez et al.
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for 10 min. Copper content was evaluated by AAS (45 ppm
for the reaction with 9 and 15, and 90 ppm for the reaction
with 18). The reaction mixture was then filtered through a
short column containing Si-BPA or Si-His (0.25 g for the re-
action with 9 and 15, and 0.5 g for the reaction with 18).
New evaluation of the copper contamination by AAS gave
negative results. Evaporation of the solvent under vacuum
yield the copper-free 1,2,3-triazoles 30, 41 and 47 respective-
ly, in the yields indicated in Table 6.
1:1 (3ꢅ30 mL) and EtOH (30 mL) and used directly for the
next step by suspension in THF-2-propanol (2:1, 10 mL).
The vinyl sulfone ligand derivative 8 (30 mg, 0.1 mmol) was
added to this suspension and the reaction mixture heated at
608C for 16 h. Magnetic separation of the new particles
using a magnet and successively washing with THF-2-propa-
nol (2:1, 2ꢅ30 mL), dichloromethane (2ꢅ30 mL), EtOH
(2ꢅ30 mL) and water (30 mL), furnishing the magnetic che-
lating nanoparticles 55 (Fe3O4@Si-BPA); yield: 0.125 g.
Co-condensation method: Magnetite nanoparticles 51
(0.1 g) were suspendend in a mixture of EtOH (300 mL),
water (80 mL) and ammonia (10 mL). After addition of
TEOS (1.0 mL) and 54 (53 mg) the reaction mixture was
stirred under orbital stirring for 24 h at room temperature.
The resulting silica-coated particles were collected using a
magnet, washed successively with EtOH:H2O 1:1 (6ꢅ
50 mL) and EtOH (50 mL), and dried under vacuum (1 mm
Hg) at 508C for 16 h giving the magnetic chelating nanopar-
ticles 55 (Fe3O4@Si-BPA); yield: 0.115 g.
Procedure for the Use of Si-BPA as Copper
Scavenger in Combination with Azide and Alkyne
Functionalized Silica as Click Chemistry Scavengers
A water solution (10 mL) of alkyne 18 (0.7 mmol) or 15
(1.4 mmol) and azide 23 (1.68 mmol) or 25 (0.7 mmol) was
respectively reacted using a commercial solution of CuCl
(1% mol, 10 mL or 5 mL) under MW irradiation for 10–
20 min (Table 6, entries 4 and 5). Alkyne silica (0.93 g) or
azide silica (0.2 g)[33] was respectively added to the crude of
each reaction and reacted under MW irradiation for 30 min
to remove excess of the complementary clickable reagent.
Copper content was then evaluated by AAS (90 ppm and
45 ppm, respectively). The reaction mixture was then fil-
tered through a short column containing Si-BPA (0.5 g and
0.25 g, respectively). New evaluation of the copper contami-
nation by AAS gave negative results. Evaporation of the
solvent under vacuum yield the copper-free 1,2,3-triazole 44
and 48, respectively, in the yields indicated in Table 6.
Preparation of Magnetic Cu(I)-Supported Catalyst
Fe3O4@Si-BPA·Cu+ Nanoparticles (56)
Silica-coated magnetite nanoparticles Fe3O4@Si-BPA (55)
were suspended in de-ionized water (3 mL) previously de-
oxygenated with argon. Commercial copper (I) chloride so-
lution (0.3 mL) was added and the resulting mixture stirred
under orbital stirring at room temperature for 16 h. Magnet-
ic separation of the particles using a magnet and successive
washing with water (10ꢅ30 mL), EtOH (2ꢅ30 mL) gave the
corresponding magnetic nanoparticles supported-Cu(I) 56
(Fe3O4@Si-BPA·Cu+) that were dried under vacuum (1 mm
Hg) at 508C for 16 h.
Preparation of Magnetite (Fe3O4) Nanoparticles (51)
The magnetite nanoparticles were prepared by a modifica-
tion of the procedure described by Li et al.:[35] FeCl3
(815 mg, 5 mmol) was dissolved in ethylene glycol (40 mL)
to form a clear solution. After the addition of NaOAc
(3.6 g) the reaction mixture was vigorously stirred for
30 min and then heated at 2008C by means of an oil bath
for 8 h. After cooling, ethanol (30 mL) was added and the
resulting magnetite nanoparticles were collected using a
magnet. The particles were washed successively with EtOH
(4ꢅ30 mL), water (4ꢅ30 mL) and absolute EtOH (30 mL),
and dried under vacuum (1 mm Hg) at 508C for 16 h giving
51; yield: 0.446 g.
General Procedure for the Synthesis of 1,2,3-Triazoles
Catalyzed by Magnetic Cu(I)-Supported Catalyst
Fe3O4@Si-BPA·Cu+
A neat mixture or a solution in t-BuOH-H2O (10:1) or H2O
of equivalent amounts of the corresponding alkynes (10, 15
and 20) and azido derivatives (21–23) (Table 7) was reacted
at room temperature or by MW irradiation at 608C after the
addition of the Fe3O4@Si-BPA·Cu+ catalyst 56 (the amounts
of solvent and catalyst are indicated in Table 7, entries 1–6).
The reactions were followed by TLC until complete disap-
pearance of the starting materials (reaction times are indi-
cated in Table 7, entries 1–6). The catalyst was collected
using a magnet directly in the case of the reactions in solu-
tion or after the addition of CH2Cl2 (10 mL) in the case of
the neat reactions. After washing the catalyst with the reac-
tion solvent (10 mL), evaporation of the assembled solutions
under vacuum yielded the pure 1,2,3-triazoles 29, 30, 32, 41,
42 and 50 in the yields indicated in Table 7 (entries 1–6)
without any chromatographic purification.
Preparation of Silica-Coated Magnetite Nanoparticles
Fe3O4@Si-BPA (55)
Grafting method: Magnetite nanoparticles 51 (0.1 g) were
coated with silica by the Stçber method by suspending them
in a mixture of EtOH (300 mL), water (80 mL) and ammo-
nia (10 mL) and subsequent addition of TEOS (1.0 mL).
The mixture was stirred under orbital stirring for 24 h at
room temperature. The resulting silica-coated particles were
collected using
a
magnet, washed successively with
EtOH:H2O 1:1 (6ꢅ50 mL) and EtOH (50 mL), and dried
under vacuum (1 mm Hg) at 508C for 16 h giving 52; yield:
0.125 g. These nanoparticles were suspended in dried tolu-
ene (25 mL) and then (3-aminopropyl)triethoxysilane
(APTS) (0.120 mL) was added. The reaction mixture was
heated under reflux for 3 h. The resulting functionalized
silica-coated magnetite particles 53 (Fe3O4@Si-NH2) were
collected by using a magnet and washed with EtOH:H2O
Assay to Prove the Recyclability of the Fe3O4@Si-
BPA·Cu+ Catalyst
Alkyne 10 (1 mmol) and azide 21 (1 mmol) were reacted as
described above (Table 7, entry 3) using Fe3O4@Si-BPA·Cu+
(20 mg) as catalyst. After collecting the catalyst with a
magnet the reaction crude was decanted, the catalyst was
washed with the reaction solvent and reused in a second
3318
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Adv. Synth. Catal. 2010, 352, 3306 – 3320

Non-Magnetic and Magnetic Supported Copper(I) Chelating Adsorbents
cycle of an identical solution of the clickable reagents. The
procedure was repeated for a third cycle. Evaporation of the
corresponding collected solutions obtaining in each cycle
gave the triazole 32 in yields 99%, 100% and 97%, respec-
tively.
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Supporting Information
Syntheses of 7, 8 and 53, assays with supported Cu(I) silica
SiO2 +CuCl, assays to probe the inherent scavenging capa-
bilities of Si-His, Si-BPA and Dw-BPMA, assays to probe
the scavenging capabilities of Dw-BPMA in CuAAC reac-
tions, XRD pattern of ferrite nanoparticles , magnetization
curves of ferrite nanoparticles and silica coated ferrite nano-
particles, assay with uncomplexed magnetic nanoparticles
Fe3O4@Si-BPA (55), analytical and spectroscopic data of
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1
1,2,3-triazoles 29–50, and H- and 13C NMR spectra for new
compounds are available in the Supporting Information.
Acknowledgements
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2326.
Financial support was provided by Direcciꢀn General de In-
vestigaciꢀn Cientꢁfica y Tꢂcnica (DGICYT) (CTQ2008-
01754) and Junta de Andalucꢁa (P07-FQM-02899). A. M.-F.
thanks the Spanish Ministerio de Educacion for a research
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