Key Non-Metal Ingredients for Cu-catalyzed “Click” Reactions in Glycerol: Nanoparticles as Efficient Forwarders

Article abstract of DOI:10.1002/chem.201604048

The effect of long-alkyl-chain amines in CuI-assisted azide–alkyne cycloadditions of terminal alkynes with organic azides in glycerol and other environmentally benign solvents (water, ethanol) has been examined. The presence of these additives favors the

Full text of DOI:10.1002/chem.201604048

DOI: 10.1002/chem.201604048
Full Paper
&
Copper Nanoparticles
Key Non-Metal Ingredients for Cu-catalyzed “Click” Reactions in
Glycerol: Nanoparticles as Efficient Forwarders
Marta Rodrꢀguez-Rodrꢀguez,[a, b] Patricia Llanes,[b] Christian Pradel,[a] Miquel A. Pericꢁs,*[b] and
Montserrat Gꢂmez*[a]
Abstract: The effect of long-alkyl-chain amines in CuI-assist-
ed azide–alkyne cycloadditions of terminal alkynes with or-
ganic azides in glycerol and other environmentally benign
solvents (water, ethanol) has been examined. The presence
of these additives favors the in situ formation of CuI-based
nanoparticles and results in an increase of the catalytic reac-
tivity. In glycerol, liquid-phase transmission electron micros-
copy (TEM) analyses, enabled by the negligible vapor pres-
sure of this solvent, proved that CuI nanoparticles are re-
sponsible for the observed catalytic activity. The wide variety
of alkynes and azides of which this effect has been investi-
gated (14 combinations) confirms the role played by these
additives in Cu-catalyzed Huisgen cycloadditions.
Introduction
trogen-based ligands have been proved as particularly efficient
copper partners, stabilizing CuI species[5] and enhancing the
rate of CuAAC processes.[6] In this area, CuI complexes contain-
ing tris-(triazolyl)methane tripodal ligands, which are highly
proficient in CuAAC reactions,[1f,7] represent an elegant ap-
proach to illustrate the role of Lewis bases (Figure 1). These li-
gands can efficiently stabilize catalytic precursors (I) and also
intermediates acting as hemi-labile scaffolds (II), which gener-
ates vacant sites for the coordination of reagents.
Copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions
represent a successful method for the synthesis of 1,2,3-tria-
zoles,[1] as indicated by the thousands of works published in
this field,[2a] including enantioselective CuAAC transforma-
tions.[2b,c] This remarkable success is mainly due to the process
versatility in terms of solvent compatibility, copper sources
(salts, well-defined complexes, preformed nanoparticles, (un)-
supported systems), functional group tolerance, and energy
supplies (conventional heating, microwave activation) among
others. However, this hands-on behavior leads to some con-
cerns with regard to understanding (“who does what”), associ-
ated with the lack of conclusive studies in relation to CuAAC
mechanism(s),[3] in particular for in situ generated systems
using CuI starting materials. The most frequently used precur-
sors, copper halides, are quite insoluble in the common organ-
ic solvents, especially CuI.[4] The presence of any additive (im-
purity) can improve the solubility of copper species in the
medium, inducing then an increase of catalytic activity. In this
context, organic bases play a decisive task, favoring both the
coordination to metal (as Lewis bases) and the formation of
active intermediates such as copper acetylides. Polydentate ni-
Figure 1. Tris(triazolyl)methane ligands for CuI-catalyzed AAC.[1f,7] Small
square denotes vacant site on copper.
In agreement with these important, ancillary tasks, base-free
catalytic CuAAC systems using CuI complexes as copper source
are rare. To the best of our knowledge, only one recent publi-
cation by Garcꢀa-Alvarez and Vidal reports on a CuI system able
to catalyze CuAAC reactions in glycerol in the absence of any
added base.[8]
[a] M. Rodrꢀguez-Rodrꢀguez, C. Pradel, Prof. M. Gꢁmez
Laboratoire Hꢂtꢂrochimie Fondamentale et Appliquꢂe (LHFA)
UPS and CNRS UMR 5069
Universitꢂ de Toulouse
118, route de Narbonne, 31062 Toulouse cedex 9 (France)
E-mail: gomez@chimie.ups-tlse.fr
Following our work on the use of glycerol as a solvent in
metal-catalyzed processes[9] and more recently in metal-free
AAC for the synthesis of fully substituted 1,2,3-triazoles,[10] in
which the activation of both alkynes and benzylazide by glyc-
erol was proved, we planned to evaluate the activity of CuI
salts towards click reactions in this solvent, with the aim of un-
[b] M. Rodrꢀguez-Rodrꢀguez, Dr. P. Llanes, Prof. M. A. Pericꢃs
Institute of Chemical Research of Catalonia (ICIQ)
The Barcelona Institute of Science and Technology
Avda. Pa¨ısos Catalans, 16, 43007 Tarragona (Spain)
E-mail: mapericas@iciq.es
Supporting information for this article can be found under http://
dx.doi.org/10.1002/chem.201604048.
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derstanding the role of added exogenous base in glycerol
medium.
Table 2. Azide-alkyne cycloaddition of phenylacetylene and the corre-
sponding azide in the presence of CuI and amine.[a,b]
Results and Discussion
We selected the cycloaddition between phenylacetylene and
benzyl azide as the benchmark reaction, using CuI as catalyst
source in neat glycerol at room temperature (Scheme of
Table 1). The reaction did not work at all at short reaction
times (1.5 h), 84% conversion being achieved after 24 h
(entry 1, Table 1). In the course of our research, the high effi-
ciency of this methodology under exactly the same “base-free”
reaction conditions was reported, triazole 1a being isolated by
these authors in 94% yield in short reaction times.[8] This seri-
ous discrepancy between independent runs of an easy-to-per-
form process, almost fulfilling the requirements in the Corn-
forth definition of an “ideal chemical process”[11] led us to think
that some uncontrolled factor was operating. Given the practi-
cal importance of azide–alkyne cycloadditions, we decided to
deeply characterize the different components involved in the
process in an attempt to rationalize this behavior.[12] This ana-
lytical study showed that the success of the reaction depended
on the quality (source) of BnN3 (entries 2–4, Table 1) and that,
rather surprisingly, high-purity samples of azide were unreac-
tive. In fact only one commercially available lot of BnN3 fa-
vored the cycloaddition (entry 2, Table 1).
Entry
1
Azide
Amine
Product, Conv. (yield) [%][b]
a
NH2(octyl)
1a, 96 (93)
52 (44)[c]
1a, 96 (93)
1a, 100 (>99)
98 (94)[c]
Run 4: 100 (85)[d]
1a, 100 (96)
95 (88)[c]
1a, 96 (88)
97 (73)[c]
1a, 28 (16)
1a, 36 (6)
1a, 37 (19)
1a, 20 (<5)
1a, 83 (70)
1a, 30 (12)
1a, 30 (10)
1a, 15 (6)
1a, 20(<5)
1a, 34(26)
1b, <5
2
3
a
a
NH2(undecyl)
Oleylamine
4
5
a
a
NH(octyl)2
N(octyl)3
6
7
8
a
a
a
a
a
a
a
a
a
a
b
b
NEt3
NEt(iPr)2
TOMACl
Aliquatꢄ336
TMEDA
EN
o-PDA
PHEN
Urotropine
2,6-lutidine
–
9[e]
10
11
12
13
14
15
16
17
Table 1. Azide–alkyne cycloaddition of phenylacetylene and benzyl azide
in the presence of CuI.[a]
NH2(octyl)
1b, 100 (94)
39 (9)[c]
Bn-N3 Source/Batch code[b]
Home-made
Conv. (yield) [%][c]
18
19
20
b
b
b
Oleylamine
NH(octyl)2
N(octyl)3
1b, 100 (98)
100 (87)[c]
1b, 83 (89)
88 (87)[c]
1b, 88 (88)
100 (12)[c]
1b, 10 (6)
1b, 70 (76)
1b, 21 (19)
1b, <5
Entry
1[d]
<5
84 (69)[e]
100 (80)
<5
2
3
4
Alfa-Aesar/C25Z013[f]
Alfa-Aesar/AE040501
Aldrich/BCBL4667V
<5
21
22
23
24
b
b
b
b
NEt3
TMEDA
EN
[a] Reaction conditions: CuI (1 mol%), benzyl azide (0.5 mmol), and phe-
nylacetylene (0.5 mmol) in glycerol (0.5 mL) at 258C for 1.5 h. Triazole 1a
was not obtained in the absence of copper (18% conversion, <5% yield
for 1a); [b] for certificates of analyses, see the Supporting Information;
[c] determined by 1H NMR analysis using 2-methoxynaphthalene as inter-
nal standard; conversions based on BnN3; [d] for BnN3 synthesis, see
ref. [24]; [e] in italics, data after 24 h reaction; [f] data coming from two
different commercial flasks.
Urotropine
[a] Reaction conditions: CuI (1 mol%), amine (5 mol%), benzyl or phenyl
azide (0.5 mmol), and phenylacetylene (0.5 mmol) in glycerol (0.5 mL) at
258C for 1.5 h; [b] determined by 1H NMR analysis using 2-methoxynaph-
thalene or 1,3,5-trimethoxybenzene as internal standard; conversions
based on BnN3; [c] in italics, conversion (yield) using 1 mol% of amine;
[d] see Figure S10 in the Supporting Information for the recycling of the
catalytic phase; [e] Aliquatꢄ 336: Ammonium salts containing a mixture of
C8 and C10 alkyl chains with C8 predominating.
We analyzed the “active” BnN3 by GC-MS and NMR (Figur-
es S1–S3 in the Supporting Information). In contrast to the
other BnN3 samples (Figures S4–S9 in the Supporting Informa-
tion), this one was contaminated by some compounds that, ac-
cording to MS, appeared to correspond to amines containing
long alkyl chains. To test the possible catalytic effect of these
impurities, we carried out the cycloaddition in the presence of
amines using high purity, home-made BnN3 (Table 2). We ob-
served that when 5 mol% of amine with respect to benzyl
azide was used, primary (entries 1–3), secondary (entry 4), and
tertiary (entry 5) long-alkyl-chain-based mono-amines led to
high yields of the corresponding 1,2,3-triazole, 1a. For short-
alkyl-chain derivatives, such as triethylamine or diisopropyle-
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thylamine, low yields were achieved (<16%, entries 6 and 7,
Table 2). When the amount of added amine decreased
(1 mol%), the reaction also worked (entries 1 and 3–5), espe-
cially for oleylamine, dioctyl, and trioctyl amine (entries 3–5).
Ammonium salts, such as trioctylmethylammonium chloride
(TOMACl) and Aliquatꢄ336 (ammonium salt containing a mix-
ture of C8 and C10 alkyl chains, often used as a metal extrac-
tion reagent[13]), did not favor the cycloaddition (entries 8 and
9).
Table 3. Azide-alkyne cycloaddition of phenylacetylene and benzyl azide
in the presence of CuI and amine.[a]
Entry
Solvent
Amine
Conv. (yield) [%][b]
1
2
3
4
5
6
7
8
H2O
EtOH
Dioxane
H2O
EtOH
Dioxane
H2O
EtOH
Dioxane
H2O
EtOH
–
–
–
NEt3
NEt3
NEt3
NH(octyl)2
NH(octyl)2
NH(octyl)2
Oleylamine
Oleylamine
Oleylamine
22 (13)
12 (<5)
11 (<5)
15 (<5)
17 (<5)
24 (11)
100 (93)
66 (48)
100 (99)
99 (94)
59 (48)
94 (81)
Dinitrogenated (EN=ethylenediamine; o-PDA=ortho-phe-
nylenediamine and PHEN=phenantroline, entries 11–13,
Table 2) and tetranitrogenated (urotropine, entry 14) ligands
did not trigger a positive outcome (yields <12%). TMEDA (tet-
ramethylethylenediamine) was an exception to this behavior
(70% yield, entry 10). The use of 2,6-lutidine, known by its per-
formance in CuAAC in aqueous medium,[14] gave a very low
yield (entry 15).
9
10
11
12
The same trend could be found when phenyl azide was
used instead of benzyl azide (entries 16–24, Table 2): The
system was inactive in the absence of an added amine
(entry 16). However, high yields could be isolated in the pres-
ence of amines containing a long alkyl chain (up to 94%, en-
tries 17–20). For “light” amines (entries 21–24, ), only the CuI/
TMEDA system was active, as previously observed with BnN3
(entries 10 and 22, Table 2).
Dioxane
[a] Reaction conditions: CuI (1 mol%), amine (5 mol%), benzyl azide
(0.5 mmol), and phenylacetylene (0.5 mmol) in the appropriate solvent
1
(0.5 mL) at 258C for 1.5 h; [b] determined by H NMR analysis using 2-me-
thoxynaphthalene or 1,3,5-trimethoxybenzene as internal standard; con-
versions based on BnN3.
Furthermore, this “super” amine effect was examined in
other polar solvents, such as water, ethanol, or 1,4-dioxane.
Under the same conditions as described above, the behavior
was comparable to that observed in glycerol. Without any ad-
ditive or in the presence of NEt3, low yields were obtained (<
13%, entries 1–6, Table 3). However, in the presence of dioctyl-
amine (entries 7–9) or oleylamine (entries 10–12), the increase
of catalytic activity was clearly apparent.
It is important to mention that the catalytic phase could be
recycled up to four times without significant loss of efficiency
(entry 3, Table 2; see Figure S10 in the Supporting Information),
showing the ability of glycerol to immobilize the catalyst. The
dramatic effect observed after the fourth run is undoubtedly
related to the leaching of copper (more than 1000 ppm deter-
mined by ICP-MS).
With these results in hand, a representative set of Cu-cata-
lyzed azide–alkyne cycloadditions involving the use of different
alkynes (1–10) and organo-azides (a, b) (Scheme 1) was carried
out in the presence of oleylamine. The corresponding triazoles
were obtained in high to quantitative yield. Even those tria-
zoles bearing alkyl substituents at C-4 (3a, 7a, 7b) were ob-
tained in moderate to high yields (53–91%). No transesterifica-
tion reactions with glycerol were detected for alkynes contain-
ing ester groups (2a, 4a). For selected triazoles, the reactions
were also carried out in the absence of added amine, as con-
trol experiments. In all cases, low yields (<25%, see Table S1 in
the Supporting Information) were recorded even at longer
times (up to 7 h). Unfortunately, this catalytic system, working
under favorable conditions, was not active using internal al-
kynes, such as diphenylacetylene, methyl phenylpropiolate, or
1-iodo-2-phenylacetylene (Figure S11 in the Supporting Infor-
mation).
Scheme 1. Scope of azide-alkyne cycloaddition catalyzed by CuI/amine
system in glycerol. Figures indicate isolated yields.
With the aim of understanding the observed reactivity, we
analyzed the structural behavior of copper salts. From a coordi-
nation point of view, the CuI motif leads to a large variety of
structures corresponding to both discrete molecular com-
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plexes[15] and polymeric networks,[16] depending on the nature
of the ligands involved and also the reaction conditions. This
structural variety is especially remarkable when N-based li-
gands are involved,[17] in particular for diamines (EN, TMEDA,
PHEN) and short-alkyl-chain tertiary amines (NEt3, NEtiPr2) like
those used in this work.[18] Some of them give complex struc-
tures based on closed-cubane “Cu4I4” tetramers;[18a,19] we could
prove this trend by the X-ray diffraction analysis of the Cu4I4-
TMEDA system (Figures S12 and S13 in the Supporting Infor-
mation).[20]
both Aliquatꢄ336 and sodium salt evidenced the formation of
micelle-like arrangements, giving high local density of copper
and therefore favoring the reactivity. This effect can especially
be observed in the case of the mixture Aliquatꢄ336/NaOAc,
where cylindrical micelles were identified, containing the
copper species at the surface (accessible to the reagents) and
the more hydrophobic constituents (ammonium alkyl species)
probably placed inside of these nano-objects. A similar trend
could be observed using TOMACl/NaN3 (Figure S15 in the Sup-
porting Information). It is important to note that CuI/NaN3 and
CuI/NaOAc systems (in the absence of any nitrogen-based
ligand) were not active. In addition, this reactivity behavior
points to the feasibility of CuAAC by a one-pot three-compo-
nent approach. Actually, with Bn-Br, NaN3 and phenylacetylene
as starting materials, 1a was isolated in 90% yield (see
Scheme S1 in the Supporting Information)
In contrast, long-alkyl-chain amines favor the stabilization of
metal (and metal oxide) nanoparticles.[21] Presuming the forma-
tion of copper-based nanoclusters under our reaction condi-
tions,[22] TEM analyses of CuI in glycerol and in the presence of
different amines were carried out (Table S2 in the Supporting
Information). Actually, the formation of well-dispersed nano-
particles was observed in the presence of long-alkyl-chain
amines, including ammonium derivatives (Figure 2). HR-TEM
and EDX analyses of a CuI/dioctylamine mixture in glycerol
confirmed the CuI nature of the nanoparticles and the pres-
ence of the amine on the nanoparticle surface (Figure S14 in
the Supporting Information). It is worth noting that ammoni-
um salts such as TOMACl and Aliquatꢄ336 did not lead to cata-
lytically active systems, although the formation of well-dis-
persed nanoparticles was also observed. The lack of catalytic
activity in these last cases is probably due to the very strong
electrostatic interaction between the ionic ligands and the
nanoparticles: As a result, CuI-based nanoparticles are tightly
surrounded by anion/cation shells, and this leads to small and
well-dispersed particles. However, this stabilizing interaction
shields the surface of the nanoparticles and prevents the requi-
site approach of the reactants to the catalytic copper centers.
In contrast, hemi-labile amine ligands, while still preventing
particle agglomeration by steric shielding, can be easily de-
tached, leading to free coordination sites on copper that are
necessary for the reaction to proceed.[23]
Correlating reactivity and structure, it seems that the forma-
tion of nanoparticles favors the catalytic process, which points
to a beneficial (cooperative) effect between neighboring CuI
centers for the activation of both azide and alkyne reactants
during the cycloaddition, as already noted in our previous
work involving the use of Cu2O nanoparticles as catalytic pre-
cursors in glycerol medium.[9a]
In fact, for short-chain alkyl amines such as DIPEA (DIPEA=
N,N-diisopropylethylamine), ethylenediamine, or urotropine,
agglomerates similar to those observed for CuI in the absence
of any additive were formed (Table S2 in the Supporting Infor-
mation), affording inactive catalytic systems (Table 2). Only CuI/
TMEDA led to the simultaneous formation of nanoparticles
and agglomerates. As we have already mentioned, this system
depicted high catalytic activity in azide–alkyne cycloadditions
(entries 10 and 22, Table 2).
We were also interested in establishing the oxidation state
of copper involved in the active species. For that, we reused
the catalytic phase corresponding to the active CuI/dioctyla-
mine system (after reaction between phenylacetylene and
benzyl azide). TEM analysis after catalysis showed smaller
nanoparticles than before (ca. 1.4 nm (after) vs. 2.1 nm
(before); Table S2 in the Supporting Information); the catalytic
phase was then much less active (33% in the second run
versus 100% in the first one). HR-TEM coupled to an electronic
diffraction analysis showed that particles after the first catalytic
Interestingly, the presence of additional ionic compounds in
the reaction medium was shown to influence the course of the
reaction as well. Thus, when an equimolar mixture of Ali-
quatꢄ336 and a sodium salt (NaOAc or NaN3) was added to the
non-productive reaction mixture, the system turned active
(Figure 3). TEM analyses of CuI in glycerol in the presence of
Figure 2. TEM images for CuI-based systems containing oleylamine (a), dioctylamine (b), and TOMACl (trioctylmethylammonium chloride) (c) in glycerol. Scale
bars=50 nm.
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Figure 3. Effect of the salts in azide–alkyne cycloaddition. TEM images corresponding to the mixtures of CuI, Aliquatꢄ 336, and NaX (1/5/5 ratio, respectively):
NaOAc (left; scale bar=1 mm, inset scale bar=100 nm), including an inserted image of one of the cylindrical micelle-like objects; NaN3 (right; scale
bar=50 nm).
run consisted of Cu0 (Figure S16 in the Supporting Informa-
tion). This indicated to us that the initially formed CuI-rich
nanoparticles suffer reductive deactivation as a concomitant
off-cycle of the CuAAC reaction. In contrast, the reutilization of
the CuI/oleylamine system gave the same activity as for the
first run (for both cases, nearly full conversion). HR-TEM/elec-
tronic diffraction analysis proved that in this case, nanoparti-
cles were mainly formed by CuI after catalysis (Figure S17 in
the Supporting Information). In addition, XPS analysis evi-
denced the absence of CuII species after reaction (absence of
the corresponding strong satellites, see Figure S18 in the Sup-
porting Information). These data point to CuI-based nanoparti-
cles as being responsible for the observed reactivity.
thesis of 1,4-disubstituted 1,2,3-triazoles under mild reaction
conditions (low metal loading of 1 mol%, short time of 1.5 h,
and room temperature), in environmentally benign glycerol. As
a consequence, a warning should be made on experimental
procedures for the CuAAC reaction in polar solvents not in-
volving the use of appropriate amines: Their success or failure
strongly depends on the presence/absence of amine-type im-
purities in the employed azide. The use of glycerol as a non-
volatile solvent enabled the (HR)TEM analysis of solutions con-
stituted by CuI and amine, before and after catalysis. It could
be learned from these studies that CuI, in the presence of
long-alkyl-chain amines in glycerol at room temperature, gives
rise to the formation of small and well-dispersed CuI nanoparti-
cles, in contrast with the agglomerates formed from either
bulk CuI or mixtures of CuI with low-weight amines. It is im-
portant to mention that the presence of ammonium salts
mainly containing C8 chains (TOMACl, Aliquatꢄ 336) did not
provide an efficient catalytic system in spite of the formation
of well-dispersed nanoparticles. This was almost certainly
caused by the stabilization of CuI nanoparticles by electrostatic
effect, thus blocking the access of reagents to the CuI centers.
However, tuning the ionic species present in the reaction
medium, the catalytic system turned active through the forma-
tion of organized systems.
Conclusions
In this work, we could prove the key role of “impurities” ran-
domly present in commercial samples of benzyl azide. Its accu-
rate analyses led us to identify them (long-alkyl chain amines)
and to examine their impact on CuI-based catalytic systems
applied in azide-alkyne cycloadditions in different solvents. As
a practical result of this study, we have been able to establish
that the addition of small amounts (5 mol%) of primary, secon-
dary, or tertiary amines containing C8, C11, or C18 carbon chains
(CuI/amine ratio=1/1 or 1/5) secures the success in the syn-
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[3] a) L. Jin, D. R. Tolentino, M. Melaimi, G. Bertrand, Sci. Adv. 2015, 1,
e1500304; b) S. Calvo-Losada, M. S. Pino-Gonzꢇlez, J. J. Quirante, J. Phys.
Chem. B 2015, 119, 1243–1258; c) R. Berg, B. F. Straub, Beilstein J. Org.
Chem. 2013, 9, 2715–2750; d) D. Astruc, L. Liang, A. Rapakousiou, J.
Ruiz, Acc. Chem. Res. 2012, 45, 630–640; e) M. Meldal, C. W. Tornoe,
Chem. Rev. 2008, 108, 2952–3015; f) C. Wang, D. Ikhlef, S. Kahlal, J.-V.
Saillard, D. Astruc, Coord. Chem. Rev. 2016, 316, 1–20.
Altogether, this study led us to establish a correlation be-
tween the in situ formation of CuI nanoparticles in glycerol
and other polar solvents and their catalytic activity. These
nano-objects, generated due to the presence of long-alkyl-
chain amines, favor the activation of both reagents, alkyne and
azide partners, by cooperative effect between neighboring CuI
centers.
[4] Solubility product constants for CuX: CuCl, 1.72ꢅ10À7; CuBr, 6.27ꢅ10À9
;
CuI, 1.27ꢅ10À12; data from: CRC Handbook of Chemistry and Physics,
90th ed. (Ed.: D. R. Lide), 2009–2010, CRC Press, Boca Raton.
[5] a) T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett. 2004, 6,
2853–2855; b) W. G. Lewis, F. G. Magallon, V. V. Fokin, M. G. Finn, J. Am.
Chem. Soc. 2004, 126, 9152–9153.
The inconsistencies found working under the “same” condi-
tions induce the desire to understand and discover new issues
for known reactions. The use of controlled-quality compounds
(reagents, catalysts, solvents) permits a dramatic reduction of
these effects, establishing reproducible and sustainable proto-
cols.
[6] a) V. O. Rodionov, S. I. Presolski, D. Dꢀaz Dꢀaz, V. V. Fokin, M. G. Finn, J.
Am. Chem. Soc. 2007, 129, 12705–12712; b) V. O. Rodionov, S. I. Presol-
ski, S. Gardinier, Y.-H. Lim, M. G. Finn, J. Am. Chem. Soc. 2007, 129,
12696–12704; c) S. I. Presolski, V. Hong, S.-H. Cho, M. G. Finn, J. Am.
Chem. Soc. 2010, 132, 14570–14576.
[7] For selected contributions, see: a) S. ꢈzÅubukÅu, E. Ozkal, C. Jimeno,
M. A. Pericꢁs, Org. Lett. 2009, 11, 4680–4683; b) E. Ozkal, P. Llanes, F.
Bravo, A. Ferrali, M. A. Pericꢁs, Adv. Synth. Catal. 2014, 356, 857–869.
[8] C. Vidal, J. Garcꢀa-Alvarez, Green Chem. 2014, 16, 3515–3521.
[9] a) F. Chahdoura, C. Pradel, M. Gꢂmez, ChemCatChem 2014, 6, 2929–
2936; b) F. Chahdoura, S. Mallet-Ladeira, M. Gꢂmez, Org. Chem. Front.
2015, 2, 312–318; c) F. Chahdoura, I. Favier, C. Pradel, S. Mallet-Ladeira,
M. Gꢂmez, Catal. Commun. 2015, 63, 47–51; d) F. Chahdoura, I. Favier,
M. Gꢂmez, Chem. Eur. J. 2014, 20, 10884–10893; e) F. Chahdoura, C.
Pradel, M. Gꢂmez, Adv. Synth. Catal. 2013, 355, 3648–3660.
Experimental Section
General procedure for the azide-alkyne cycloaddition
CuI (0.9 mg, 0.005 mmol) and the corresponding amine (0.005–
0.25 mmol) were added to glycerol (0.5 mL) in a Schlenk tube
equipped with a stirring bar under Ar atmosphere. The alkyne
[24]
(0.5 mmol) and the azide (0.5 mmol, 67 mg for BnN3 and 60 mg
for PhN3) were added consecutively to the reaction medium. The
mixture was stirred at 258C for 1.5 h (or the stated time). The or-
ganic products were extracted from the catalytic mixture with di-
chloromethane (6ꢅ2 mL). The combined chlorinated organic layers
were filtered through a Celiteꢄ pad and the resulting filtrate was
concentrated under reduced pressure. The products were purified
by chromatography (silica gel short column, eluent: cyclohexane/
ethyl acetate) in order to determine the isolated yields of the cor-
responding triazoles.
[10] M. Rodrꢀguez-Rodrꢀguez, E. Gras, M. A. Pericꢁs, M. Gꢂmez, Chem. Eur. J.
2015, 21, 18706–18710.
[11] “It does, for example, no good to offer an elegant, difficult and expen-
sive process to an industrial manufacturing chemist, whose ideal is
something to be carried out in a disused bathtub by a one-armed man
who cannot read, the product being collected continuously through
the drain hole in 100% purity and yield”: J. Cornforth, Chem. Br. 1975,
11, 432.
[12] Different glycerol sources and different commercially available CuI salts
were tested without observing any effect on the reactivity.
[13] For representative recent contributions, see: a) S. Sharma, C.-M. Wu, N.
Rajesh, RSC Adv. 2016, 6, 26668–26678; b) S. S. Swain, B. Nayak, N.
Devi, S. Das, N. Swain, Hydrometallurgy 2016, 162, 63–70.
Acknowledgements
[14] a) J. Garcꢀa-ꢉlvarez, J. Dꢀez, J. Gimeno, Green Chem. 2010, 12, 2127–
2130; b) J. Garcꢀa-ꢉlvarez, J. Dꢀez, J. Gimeno, F. J. Suꢇrez, C. Vincent, Eur.
J. Inorg. Chem. 2012, 5854–5863.
Financial support from the Centre National de la Recherche
Scientifique (CNRS), the Universitꢆ de Toulouse 3—Paul Sabati-
er, MINECO (grants CTQ2012-38594-C02-01 and CTQ2015-
69136-R), DEC (grant 2014SGR827) and ICIQ Foundation are
gratefully acknowledged. S. Ladeira and R. Brousses are ac-
knowledged for the resolution of the XRD structure. M.R.
thanks the CNRS and MINECO (CTQ2012-38594-C02-01) for
a PhD grant.
[15] For selected contributions, see: a) M. Vitale, P. C. Ford, Coord. Chem. Rev.
2001, 219–221, 3–16; b) F. De Angelis, S. Fantacci, A. Sgamellotti, E.
Cariati, R. Ugo, P. C. Ford, Inorg. Chem. 2006, 45, 10576–10584.
[16] For selected contributions, see: a) S. Kitagawa, R. Kitaura, S.-i. Noro,
Angew. Chem. Int. Ed. 2004, 43, 2334–2375; Angew. Chem. 2004, 116,
2388–2430; b) G. Fꢆrey, Chem. Soc. Rev. 2008, 37, 191–214; c) A. J.
Blake, N. R. Brooks, N. R. Champness, L. R. Hanton, P. Hubberstey, M.
Schrçder, Pure Appl. Chem. 1998, 70, 2351–2357.
[17] a) R. Peng, M. Li, D. Li, Coord. Chem. Rev. 2010, 254, 1–18; b) S. Yuan, H.
Wang, D.-X. Wang, H.-F. Lu, S.-Y. Feng, S. Sun, CrystEngComm 2013, 15,
7792–7802.
Keywords: azide–alkyne cycloaddition · copper · glycerol ·
long-chain amines · nanoparticles
[18] For selected contributions, see: a) X. Chai, S. Zhang, Y. Chen, Y. Sun, H.
Zhang, X. Xu, Inorg. Chem. Commun. 2010, 13, 240–243; b) Y. Yang, W.
Chai, L. Song, K. Shu, Acta Crystallogr. Sect. E 2010, 66, m1486; c) J.-H.
Yu, J.-Q. Xu, L. Han, T.-G. Wang, Z. Shi, W.-J. Jing, H. Dong, J.-N. Xu, H.-B.
Jia, J. Hua, Chin. J. Chem. 2002, 20, 851–857; d) M. F. Garbauskas, D. A.
Haitko, J. S. Kasper, J. Cryst. Spec. Res. 1986, 16, 729–738; e) P. C. Healy,
C. Pakawatchai, C. L. Raston, B. W. Skelton, A. H. White, J. Chem. Soc.
Dalton Trans. 1983, 1905–1916.
[19] S. Zhang, Y. Cao, H. Zhang, X. Chai, Y. Chen, R. Sun, J. Solid State Chem.
2008, 181, 3327.
[20] X-ray diffraction structure recently published: J.-J. Shen, J. Song, T.-L.
Yu, Y.-L. Fu, Chin. J. Struct. Chem. 2014, 33, 1025–1030.
[1] For selected reviews, see: a) J. E. Hein, V. V. Fokin, Chem. Soc. Rev. 2010,
39, 1302–1315; b) S. Dꢀez-Gonzꢇlez, Catal. Sci. Technol. 2011, 1, 166–
178; c) F. Alonso, Y. Moglie, G. Radivoy, Acc. Chem. Res. 2015, 48, 2516–
2528; d) E. Haldꢂn, M. C. Nicasio, P. J. Pꢆrez, Org. Biomol. Chem. 2015,
13, 9528–9550; e) S. Chassaing, V. Bꢆnꢆteau, P. Pale, Catal. Sci. Technol.
2016, 6, 923–957; f) P. Etayo, C. Ayats, M. A. Pericꢁs, Chem. Commun.
2016, 52, 1997–2010.
[2] a) More than 3400 references from SciFinder Scholar Database up to
March 2016 (search containing “copper and azide alkyne cycloaddition”
keywords); for selected recent asymmetric CuAAC contributions, see:
b) T. Song, L. Li, W. Zhou, Z.-J. Zheng, Y. Deng, Z. Xu, L.-W. Xu, Chem.
Eur. J. 2015, 21, 554–558; c) F. Zhou, C. Tan, J. Tang, Y.-Y. Zhang, W.-M.
Gao, H.-H. Wu, Y.-H. Yu, J. Zhou, J. Am. Chem. Soc. 2013, 135, 10994–
10997.
[21] For selected contributions, see: a) C. Pan, K. Pelzer, K. Philippot, B. Chau-
dret, F. Dassenoy, P. Lecante, M.-J. Casanove, J. Am. Chem. Soc. 2001,
123, 7584–7593; b) G. Salas, C. C. Santini, K. Philippot, V. Colliꢊre, B.
Chaudret, B. Fenet, P. F. Fazzini, Dalton Trans. 2011, 40, 4660–4668; c) J.
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Cure, Y. Coppel, T. Dammak, P. F. Fazzini, A. Mlayah, B. Chaudret, P. Fau,
Langmuir 2015, 31, 1362–1367.
[23] For a selected review concerning the stabilization of metal nanoparti-
cles, see: A. Roucoux, J. Schulz, H. Patin, Chem. Rev. 2002, 102, 3757–
3778.
[22] For recent contributions concerning Cu-based nanoparticles, see:
a) M. B. Gawande, A. Goswami, F.-X. Felpin, T. Asefa, X. Huang, R. Silva,
X. Zou, R. Zboril, R. S. Varma, Chem. Rev. 2016, 116, 3722–3811; b) H. R.
Ong, M. M. R. Khan, R. Ramli, Y. Du, S. Xi, R. M. Yunus, RSC Adv. 2015, 5,
24544–24549.
[24] S. G. Alvarez, M. T. Alvarez, Synthesis 1997, 413–414.
Received: August 25, 2016
Published online on && &&, 0000
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Full Paper
FULL PAPER
&
Copper Nanoparticles
M. Rodrꢀguez-Rodrꢀguez, P. Llanes,
C. Pradel, M. A. Pericꢃs,* M. Gꢁmez*
&& – &&
Key Non-Metal Ingredients for Cu-
catalyzed “Click” Reactions in
Glycerol: Nanoparticles as Efficient
Forwarders
Super amines: The noteworthy reactivi-
ty observed in copper-catalyzed azide–
alkyne cycloaddition reactions, with CuI
in the presence of long-chain amines as
starting catalytic materials, could be cor-
related to the in situ formation of CuI
nanoparticles. These amines, acting as
“super” ingredients, become crucial for
accelerating the process, in particular in
glycerol medium.
&
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Chem. Eur. J. 2016, 22, 1 – 8
www.chemeurj.org
8
ꢃ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!