Angewandte
Communications
Chemie
Cell-SH is omitted from the reaction mixture (compounds 3,
Cell-SH was inefficient in promoting the cycloaddition and
5, yield without Cell-SH shown in brackets). Having validated
our method with a set of simple triazoles, we extended our
study to the use of densely decorated coupling partners in
order to evaluate the robustness and make a balanced analysis
of the usefulness of the method. Since we reasoned that our
practical Cell-SH device could be useful for biologists and
analytical chemists, we used azides and alkynes bearing sugar,
rhodamine, coumarin, and cholesterol moieties, which are
often used in cell recognition, sensing, or labelling.[21] The
scope of the reaction proved to be quite broad, with no
obvious limitations, since the cycloaddition proceeded with
both highly complex alkynes and azides. Impressively, free
carbohydrates also reacted smoothly either as azide or alkyne
derivatives (18–19), thus illustrating the high tolerance of this
process. Actually, the main limitation of this process is related
to the limited solubility of highly lipophilic substrates, which
significantly alters the reaction rate. In order to increase the
dispersion of structurally complex and poorly soluble part-
ners, such as alkynes bearing cholesterol and rhodamine
moieties, and attain reasonable rates, the cycloaddition was
performed with 4 mol% Cu and in ternary mixtures of
solvents with either THF, MeOH, or CH2Cl2 as additional
solvents (compounds 15–16, 21–23). As expected, the cyclo-
addition occurs regioselectively in favor of the 1,4-disubti-
tuted triazoles, though the 1,5-disubstituted regioisomer was
detected in small amounts for compounds 10 and 16. In
summary, our catalytic system is compatible with highly
complex partners possessing either lipophilic or chelating
properties, even those bearing a pyridine group (compound
20), provided that the experimental conditions (e.g., solvent
and/or time) are adapted.
removing copper species in solution since only a marginal
amount of copper was adsorbed on the material and the
reaction yield was disappointingly low (entry 2). Using a four-
fold molar excess of Cell-SH with respect to the copper
greatly increased the copper remediation to ca. 60%, but
unfortunately the reaction yield remained unchanged
(entry 3). By contrast, 94% of the copper species in solution
were removed when a piece of paper corresponding to
16 mol% SH was used, and the reaction yield for triazole 3
reached 87% (entry 4). Upon increasing the loading of thiol
functions to 24 and 32 mol%, copper removal marginally
increased to around 97% and the reaction yield reached
a plateau at around 90% (entries 5–6). These results reveal
that the use of an eight-fold molar excess of SH functions with
respect to copper constitutes the best compromise regarding
copper removal efficiency and the atom economy.
While we have demonstrated that Cell-SH enables the
adsorption of approximately 95% of the Cu initially intro-
duced, we wondered whether the paper strip removed after
completion of the reaction could be reused in a second run
without requiring additional Cu. The reuse of Cell-SH was
explored for the cycloaddition of benzyl azide 1 with prop-
argyl alcohol 2. An identical yield was observed for the
second run (88%), while a sharp decrease occurred on the
third use (ca. 50% yield) due to the fragility of the paper upon
successive reuses, which leads to a loss of physical integrity.
We also analyzed the nature of the copper species adsorbed
onto Cell-SH after one cycle. Scanning electron microscopy
showed the formation of spherical copper nanoparticles (Cu
NPs) with an average diameter of around 36 nm (Figure S1 in
the Supporting Information). X-ray photoelectron spectros-
copy of the Cu NPs in the Cu2p region showed an absence of
satellite peaks near 938–945 eV, while the peaks at 932.5 and
952.3 eV, which are attributed to Cu2p3/2 and Cu2p1/2 spin-
orbit components, suggest the formation of Cu2O NPs (Fig-
ure S2).
Having demonstrated the powerful reducing properties of
Cell-SH toward copper sulfate, to promote the [3+2]-cyclo-
addition of organic azides with alkynes, we explored the
adsorption properties of this unusual material (Table 3). To
accurately determine the level of copper removal, we
analyzed the crude solution by inductively coupled plasma
mass spectrometry (ICP-MS) after the paper strip was
removed by filtration. We calculated the percentage of
copper removal with respect to the initial amount introduced
for the reaction (2 mol% Cu). The use of a slight excess of
Since similar behavior was observed for Cu in the absence
of coupling partners,[18] we deduce from these results that
Cell-SH rapidly adsorbs and reduces CuSO4·5H2O to Cu2O
NPs that act as a catalyst for the transformation.
In summary, we present a new approach for the [3+2]-
cycloaddition of organic azides with alkynes using a hetero-
geneous reducing agent that also acts has a powerful adsorb-
ent for copper species in solution, thereby leaving the crude
product almost free of both copper residues and reducing
agent. This method involves the use of cellulose paper as
a heterogeneous biopolymer for supporting covalent thiol
functions and was inspired by living systems that reduce CuII
to CuI with cysteine residues from proteins. The robustness of
our catalytic system was demonstrated by the preparation of
highly complex substrates. Inspiration from nature to uncover
more sustainable methods is a field of research deserving of
attention and we believe that this contribution will be of great
interest to synthetic chemists and biologists.
Table 3: Adsorption properties of Cell-SH.
Entry[a]
SH loading (mol%)
Cu adsorbed [%]
Yield [%][b]
1
2
3
4
5
6
0
3.2
8
16
24
32
0
4
58
94
97
97.5
<5
41
43
87
88
91
[a] Reaction conditions: azide (1 mmol), alkyne (1.5 mmol),
CuSO4·5H2O (2 mol%), and Cell-SH (see table) were stirred in 5 mL of
tBuOH/H2O (1:1) at 708C for 14 h. [b] Yield of isolated product.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
These are not the final page numbers!
Rull-Barrull, Jordi
