Sequential copper catalyzed alkyne-azide and thiol-ene click reactions for the multiple functionalization of fullerene hexaadducts

Article abstract of DOI:10.1039/c0cc00252f

A fullerene hexakis-adduct incorporating complementary reactive centres with very different and selective reactivity has been prepared and functionalized with three different peripheral groups by successive alkyne-azide and thiol-ene click reactions.

Full text of DOI:10.1039/c0cc00252f

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Sequential copper catalyzed alkyne–azide and thiol–ene click reactions
for the multiple functionalization of fullerene hexaadductswz
Julien Iehl and Jean-Franc¸ ois Nierengarten*
Received 5th March 2010, Accepted 20th April 2010
First published as an Advance Article on the web 10th May 2010
DOI: 10.1039/c0cc00252f
A fullerene hexakis-adduct incorporating complementary reactive
centres with very different and selective reactivity has been
prepared and functionalized with three different peripheral
groups by successive alkyne–azide and thiol–ene click reactions.
reactive subunits allowing the successive attachment of three
different peripheral groups via successive click reactions.
Fullerene hexakis-adducts bearing either terminal alkyne or
azide functional groups allowing their further transformation
under the copper mediated Huisgen 1,3-dipolar cycloaddition
conditions have already been described.4 In contrast, examples
of thiol–ene click reactions on such building blocks have not
been reported so far. Whereas this click reaction has proven to
be powerful for the functionalization of a large variety of
building blocks,8 its compatibility with fullerene derivatives is
not obvious as the fullerene core might be reactive towards
thiyl radicals.10 Indeed, we have first prepared a simple
fullerene hexa-adduct bearing 12 allylic ester subunits and
decomposition was observed during all attempted reactions
with thiols. The allylic ester subunits are however not very
reactive under thiol–ene click conditions and the reaction is
quite slow. Therefore, side reactions with the fullerene core
took place. In order to overcome this problem, we have
decided to functionalize the fullerene core with more reactive
peripheral groups, namely methacrylate subunits (Scheme 1).
Hexakis-adduct 2 was synthesized by the reaction of C60
Fullerene hexakis-adducts with a Th-symmetrical octahedral
addition pattern are a unique class of three-dimensional
molecules.1 Their spherical framework is indeed an appealing
plateform for the preparation of new nanomaterials and
bioactive molecules.2 The direct synthesis of fullerene hexa-
adducts from C60 and malonates is however difficult and
generally restricted to relatively simple malonate derivatives,
thus limiting their accessibility.3 This major problem was
recently solved by producing easily accessible C60 hexakis-
adduct derivatives bearing 12 terminal groups allowing
their further functionalization to generate structurally more
complicated systems.4,5 Among them, the copper mediated
Huisgen 1,3-dipolar cycloaddition of azides and alkynes
resulting in 1,2,3-triazoles6 was found to be particularly
interesting as it allows for the incorporation of almost any
functional groups around the fullerene core.4 Furthermore,
this strategy prevents the use of protecting groups. For
example, fullerene hexakis-adducts bearing 12 peripheral
carbohydrate moieties have been prepared in excellent yields
by grafting unprotected sugar derivatives onto the fullerene
core.7 The development of an efficient toolbox for the synthesis
of fullerene hexakis-adducts bearing two or more different
peripheral functional subunits is now one of the major
challenges to produce a unique multifunctional nanomaterials
platform. Indeed, this goal can be in principle achieved
by combining the alkyne–azide click chemistry with the
radical thiol–ene click chemistry8,9 for the stepwise multi-
functionalization of the hexa-substituted fullerene scaffold. It
is obvious that such a strategy based on sequential click
reactions would serve as an extremely powerful process for
attaching virtually any functional groups to the fullerene
framework.9 As a proof of concept, we now report on the
preparation of a C60 hexakis-adduct bearing three different
(1 equiv.) with
1 (10 equiv.), CBr4 (100 equiv.) and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 20 equiv.) in
o-dichlorobenzene (ODCB) at room temperature. The mixture
was stirred for 72 h and evaporated. The resulting sample was
separated on a silica-gel column in a relatively straightforward
fashion to obtain 2 in 41% yield. The conditions for the
thiol–ene click reaction of compound 2 with thiols were first
adjusted with propanethiol (3a) (Scheme 1). The best results
were obtained under conditions using azobisisobutyronitrile
(AIBN) in carefully degassed benzene. Under optimized
conditions, a mixture of 2 (1 equiv.), 3a (20 equiv.) and AIBN
(3 equiv.) in benzene was stirred under Ar at 80 1C for 1 h.
After work-up and purification, compound 4a was thus
obtained in 51% yield. In this case, the reaction of the
fullerene core with the thiyl radicals does not significantly
compete with the extremely fast thiol–ene reaction leading to
the desired thioether derivatives. The reaction conditions used
for the preparation of 4a from 3a were then applied to thiols
3b–c. The thiol–ene products 4b–c were thus obtained in 35
and 52% yield, respectively. The structure of compounds 4a–c
1
was confirmed by their H and 13C NMR spectra. Inspection
´
´
´
Laboratoire de Chimie des Materiaux Moleculaires, Universite de
Strasbourg et CNRS (UMR 7509), Ecole Europeenne de Chimie,
of the 1H NMR spectra clearly indicates the disappearance of
the vinylic signals at d 5.50 and 6.03 ppm. As the thiol–ene
click reaction generates an asymmetric center, compounds
4a–c are indeed obtained as mixtures of diastereoisomers. As
a result, their 1H and 13C NMR spectra are quite broad.
However, all the expected resonances are clearly observed. It is
worth noting that we have also attempted the preparation of a
´
`
Polymeres et Materiaux (ECPM), 25 rue Becquerel,
67087 Strasbourg Cedex 2, France.
´
E-mail: nierengarten@chimie.u-strasbg.fr; Fax: +33-368-85-27-74
w This article is part of the ‘Carbon Nanostructures’ web-theme issue
for ChemComm.
z Electronic supplementary information (ESI) available: Experimental
details for the preparation of the new compounds and representative
NMR spectra. See DOI: 10.1039/c0cc00252f
ꢀc
This journal is The Royal Society of Chemistry 2010
4160 | Chem. Commun., 2010, 46, 4160–4162

ascorbate gave the clicked derivative 9. The expected signals of
the unique malonate addend are clearly distinguishable in the
1H and 13C NMR spectra. In other words, the TMS-protected
alkyne unit as well as the methacrylate group remained
unchanged and are not reactive under the conditions used
for the click reaction from 8. IR data also confirmed that
no azide (2094 cmꢂ1) residues remain in the final product.
Compound 9 was then desilylated in situ with tetrabutyl-
ammonium fluoride (TBAF) to form the corresponding
hexa-adduct bearing one terminal alkyne unit, to which benzyl
azide was subsequently clicked (Scheme 3). Fullerene hexa-
adduct 10 was thus obtained in 87% yield. The structure of
1
compound 10 was confirmed by its H and 13C NMR spectra
as well as by mass spectrometry. Inspection of the 1H and 13
C
NMR spectra clearly indicates the disappearance of the
TMS-protected alkyne unit. The 1H NMR spectrum of 10 shows
Scheme 1 Reagents and conditions: (i) C60, ODCB, DBU, CBr4, rt
(41%); (ii) AIBN, benzene, 80 1C (4a: 51%; 4b: 35%; 4c: 52%).
hexa-adduct surrounded with acrylate subunits in order to
prevent the generation of stereogenic centers upon functiona-
lization with the thiols. However, all attempts at preparation
of the fullerene hexa-adduct from the bis-acrylate analogue of
1 led to polymers.
Having shown that thiol–ene click reactions can be used
with fullerene hexa-adduct building blocks, the next step was
to produce a fullerene hexa-adduct bearing the appropriate
reactive groups allowing the grafting of different groups via
successive click reactions. The preparation of the key building
block (8) is depicted in Scheme 2. The reaction of compound 5
with C60, iodine and DBU under Bingel conditions11 gave
methanofullerene 6 in 50% yield. Treatment of 6 with an
excess of malonate 7,4a CBr4 and DBU in ODCB gave
building block 8 in 57% yield. Subsequent reaction with
phenylacetylene in the presence of CuSO4ꢁ5H2O and sodium
Scheme 2 Reagents and conditions: (i) C60, DBU, I2, PhMe, r.t.
(50%); (ii) DBU, CBr4, ODCB, r.t. (57%); (iii) phenylacetylene,
CuSO4ꢁ5H2O, sodium ascorbate, CH2Cl2–H2O, r.t. (66%).
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 4160–4162 | 4161

addend are clearly distinguishable. The other five malonate
addends appear as pseudo-equivalent and give rise to one set
of signals similar to the one observed for the corresponding
hexakis-adducts carrying just one type of addend.
In conclusion, we have developed a versatile fullerene
hexa-adduct building block incorporating complementary
reactive centres with very different and selective reactivity. In
this way, the successive grafting of three different groups on
the fullerene core has been efficiently achieved. As the click
reactions used for the functionalization of the fullerene
core are tolerant to a wide range of functional groups, this
methodology will allow for the easy preparation of a large
variety of unprecedented globular multifunctional nano-
materials with a controlled distribution of functional groups
on the spherical framework. Work in this direction is currently
under way in our group.
This work was supported by the CNRS (UMR 7509) and
the University of Strasbourg.
Notes and references
1 A. Hirsch and O. Vostrowski, Eur. J. Org. Chem., 2001, 829.
2 For selected examples, see: (a) T. Chuard, R. Deschenaux, A. Hirsch
and H. Schonberger, Chem. Commun., 1999, 2103; (b) T. Habicher,
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J.-F. Nierengarten, V. Gramlich and F. Diederich, Angew. Chem., Int.
Ed., 1998, 37, 1916; (c) D. Felder-Flesch, L. Rupnicki, C. Bourgogne,
B. Donnio and D. Guillon, J. Mater. Chem., 2006, 16, 304;
(d) S. Campidelli, T. Brandmuller, A. Hirsch, I. M. Saez,
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J. W. Goodby and R. Deschenaux, Chem. Commun., 2006, 4282;
(e) S. Gottis, C. Kopp, E. Allard and R. Deschenaux, Helv.
Chim. Acta, 2007, 90, 957; (f) M. Helmreich, E. A. Ermilov,
M. Meyer, N. Jux, A. Hirsch and B. Roder, J. Am. Chem. Soc.,
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2005, 127, 8376; (g) M. Diekers, C. Luo, D. M. Guldi and A. Hirsch,
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R. A. Carino and Y.-P. Sun, Org. Lett., 2005, 7, 859.
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J.-F. Nierengarten, Chem. Commun., 2008, 2450; (b) P. Pierrat,
S. Vanderheiden, T. Muller and S. Brase, Chem. Commun., 2009,
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1748; (c) J. Iehl and J.-F. Nierengarten, Chem.–Eur. J., 2009, 15, 7306.
Scheme 3 Reagents and conditions: (i) benzyl azide, TBAF, CuSO4ꢁ
5H2O, sodium ascorbate, CH2Cl2–H2O, r.t. (87%); (ii) 3a–c, AIBN,
THF, D, 1 h (11a: 70%, 11b: 91%, 11c: 62%).
5 P. Pierrat, C. Rethore, T. Muller and S. Brase, Chem.–Eur. J.,
´ ´
¨
2009, 15, 11458.
6 (a) R. Huisgen, Angew. Chem., Int. Ed. Engl., 1968, 7, 321;
(b) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem.,
Int. Ed., 2001, 40, 2004.
7 J.-F. Nierengarten, J. Iehl, V. Oerthel, M. Holler, B. M. Illescas,
´ ´
A. Munoz, N. Martın, J. Rojo, M. Sanchez-Navarro, S. Cecioni,
the typical signal corresponding to the benzylic CH2 protons at d
5.44 ppm. The two diagnostic resonances of the sp2 C atoms of
the newly formed triazole ring are also clearly observed at d 120.9
and 146.5 ppm in the 13C NMR spectrum of 10.
S. Vidal, K. Buffet, M. Durka and S. P. Vincent, Chem. Commun.,
2010, DOI: 10.1039/c0cc00034e.
Finally, compound 10 was subjected to the thiol–ene click
reaction with thiols 3a–c (Scheme 3). The fully clicked
derivatives 11a–c were thus obtained in 62 to 91% yield. The
8 For reviews on thiol–ene click reactions, see: (a) C. Remzi Becer,
R. Hoogenboom and U. S. Schubert, Angew. Chem., Int. Ed., 2009,
48, 4900; (b) C. E. Hoyle and C. N. Bowman, Angew. Chem., Int.
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Rev, 2010, 39, 1536; (d) C. E. Hoyle, A. B. Lowe and
C. N. Bowman, Chem. Soc. Rev., 2010, 39, 1355.
9 For examples of sequential click reactions, see: (a) L. M. Campos,
K. L. Killops, R. Sakai, J. M. J. Paulusse, D. Damiron,
D. E. Drockenmuller, B. M. Messmore and C. J. Hawker, Macro-
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11 C. Bingel, Chem. Ber., 1993, 126, 1957.
12 A. Herzog, A. Hirsch and O. Vostrowsky, Eur. J. Org. Chem.,
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1
structure of compounds 11a–c was confirmed by their H and
13C NMR spectra as well as by mass spectrometry. In all cases,
the 1H NMR spectra show complete disappearance of the
typical vinylic signals of the starting reagent (10) at d 5.51
and 6.04 ppm and the appearance of the expected signals arising
from the clicked thiol. As commonly observed for fullerene
hexa-adducts,4–12 the 13C NMR spectra of 11a–c reveal
the strong influence of the high local symmetry of the hexa-
substituted fullerene core. In each spectrum, three groups of
signals appear for the fullerene C atoms reminiscent of those of
the three non-equivalent fullerene C atoms of the hexakis-
adduct carrying just one type of addend (overall Th symmetry).
No influence of the overall symmetry of 11a–c which is Cs can
be deduced. The expected signals of the unique malonate
ꢀc
This journal is The Royal Society of Chemistry 2010
4162 | Chem. Commun., 2010, 46, 4160–4162