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Direct arylation of C60Cl6 and C70Cl8 with
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carboxylic acids: a synthetic avenue to
Cite this: DOI: 10.1039/c9cc08400b
water-soluble fullerene derivatives with
Received 27th October 2019, promising antiviral activity†
Accepted 9th December 2019
DOI: 10.1039/c9cc08400b
Olga A. Kraevaya, ab Alexander S. Peregudov,c Ivan A. Godovikov,c
Elena V. Shchurik,b Vyacheslav M. Martynenko,b Alexander F. Shestakov,bd
rsc.li/chemcomm Jan Balzarini,de Dominique Schols e and Pavel A. Troshin *ab
We report unprecedented Friedel–Crafts arylation of chlorofullerenes
C60Cl6 and C70Cl8 with unprotected carboxylic acids as an efficient
single-step synthesis of the inherently stable water-soluble fullerene
derivatives. Using this method, a series of previously unaccessible
compounds was obtained without chromatographic purification in
almost quantitative yields. Promising anti-HIV activity comparable
to characteristics of commercial drugs was demonstrated for some
of these compounds.
Fullerenes and their functional derivatives are considered as
very promising materials for biomedical applications since they
demonstrate pronounced gene delivery,1 neuroprotective,2
antitumor,3 antioxidant,4 and antibacterial properties5 as well as
pronounced antiviral activity against Human immunodeficiency
virus (HIV),6 Herpes simplex virus (HSV), Cytomegalovirus (CMV),7
Influenza virus8 and Ebola pseudo typed viruses.9 Non-
functionalized fullerenes are highly hydrophobic substances and
can hardly be used in biomedicine without prior functionalization.10
Chemical modification of the fullerene cage can provide solu-
bility of these compounds in aqueous media and add a broad
range of chemical functionalities tuning their properties.11
Though introducing multiple addends on the fullerene cage
is highly desirable, the number of methods for regioselective
functionalization is very limited.12 Among them, methods based
on substitution of the halogen atoms on the fullerene cage appear
to be the most promising. Single isomers of chlorofullerenes,
such as C60Cl6 and C70Cl8, can be easily obtained from C60 and
a
Skolkovo Institute of Science and Technology, Nobel St. 3, Moscow, 143026,
Russia. E-mail: troshin2003@inbox.ru
b
IPCP RAS, Semenov Prospect 1, Chernogolovka, 141432, Russia
c
INEOS RAS, Vavylova St. 28, B-334, Moscow, 119991, Russia
d
Faculty of Fundamental Physics & Chemical Engineering, Moscow Lomonosov
State University, GSP 1, 1-51 Leninskie Gory, Moscow 119991, Russia
e
Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven,
Belgium
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9cc08400b
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C70 with quantitative yields and high purity.13 Additionally,
chlorine substitution reactions proceed with high selectivity
and usually save the original arrangements of addends on the
fullerene cage, e.g. cyclopentadienyl-type and equatorial-type
patterns for C60 and C70, respectively.14
Halogen atoms on the fullerene cage can be easily substituted
with a broad range of functional groups attached to the fullerene
cage via C–N, C–P, C–S and C–O bonds. These reactions mostly
proceed in one step with almost quantitative yields, but the
resulting fullerene derivatives appeared to be unstable in aqueous
solutions due to a hydrolytic cleavage of the C–N, C–O, C–P and
C–S bonds between the fullerene cage and solubilizing addends.15
In contrast, water-soluble fullerene derivatives with organic addends
attached to the carbon cage via C–C bonds are inherently stable
to hydrolysis in aqueous and physiological media and, there-
fore, appear to be the most promising.
Unfortunately, such water-soluble fullerene derivatives with the
C–C addend bonding mode are hardly accessible due to their
complicated synthesis. The FeCl3-catalysed Friedel–Crafts arylation
of chlorofullerenes was among the first reactions discovered for
the synthesis of these compounds.16 However, preparation of water-
soluble fullerene derivatives using this reaction requires the
following steps: (1) conversion of precursor carboxylic acids to
e.g. methyl esters, (2) performing arylation of chlorofullerene,
which is usually poorly selective and, therefore, time- and solvent-
consuming chromatographic separation has to be applied to isolate
target compounds in modest yields and (3) acid-promoted hydro-
lysis of ester groups to obtain polycarboxylic fullerene acids, which
is a slow reaction (typically requires 3–5 days) and sometimes gives
multiple byproducts due to partial decarboxylation (Fig. 1).17
Obviously, such a method can be applied to the synthesis of a
very limited variety of fullerene derivatives due to the harsh
conditions applied in the last two steps.
We have addressed this problem and developed the first
straightforward and highly efficient approach to the synthesis of a
wide variety of C–C functionalized water-soluble fullerene derivatives
using a single step SnCl4-catalysed arylation of C60Cl6 and
Chem. Commun.

Communication
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Fig. 1 Single-step Friedel–Crafts arylation method developed in this work.
C70Cl8 (Scheme 1) with aromatic acids. To the best of our
knowledge, this work reports the first examples of Friedel–
Crafts functionalization of unprotected carboxylic acids. Excel-
lent selectivity of these reactions is enabled by high reactivity of
chlorofullerenes C60Cl6 and C70Cl8 as well as optimization of
the reaction conditions. Importantly, the developed single-step
arylation procedure allowed us to prepare previously inaccessible
compounds, e.g. those with amide bonds, with high yields (up to
95%) and without using chromatographic purification.
The synthetic procedure to obtain arylated water-soluble
fullerene derivatives is very simple and scalable. Typically,
Scheme 1 Single step synthesis of the arylated water-soluble fullerene
derivatives.
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chlorofullerene C60Cl6 or C70Cl8 and aromatic carboxylic acid
is dissolved or dispersed in nitrobenzene or 1,2-dichlorobenzene
under an inert atmosphere. Afterward, Lewis acid (SnCl4)
is added and the reaction mixture is stirred at 70–80 1C for
1 hour until TLC shows complete consumption of the pristine
chlorofullerene. Then, hexane is added to cause precipitation of
the product. The obtained powder is washed with hexane and
acetonitrile and dissolved in aqueous potassium carbonate. The
resulting solution is filtered and the fullerene derivative is
reprecipitated by adding an excess of hydrochloric or acetic acid.
The precipitate is collected by centrifugation, washed with
distilled water and dried in vacuo.
Highly selective substitution of Cl atoms in chlorofullerenes
with residues of aromatic carboxylic acids was achieved via a
thorough optimization of the Lewis acid used as a promoter in
the Friedel–Crafts reaction. The conventional approach involving
FeCl3 as the catalyst leads to the formation of complex mixtures
of products as confirmed by NMR spectroscopy. In contrast,
changing the catalyst to SnCl4 improved dramatically the selec-
tivity of the reactions. This effect is illustrated by the HPLC
profiles of the crude products obtained in a model reaction of
C60Cl6 with the methyl ester of hydrocinnamic acid using either
FeCl3 or SnCl4 as catalysts (Fig. S1, ESI†). The reaction catalyzed
by FeCl3 afforded B50% of the C60Ar5Cl (retention time
B8.5 min) in the reaction mixture, while a similar reaction
catalyzed by SnCl4 produced 480% of the target product.
The method developed in this work is simple, scalable and
does not require protection of carboxylic groups in precursor
reagents and their deprotection by acidic hydrolysis at the final
step. This advantage was used for the synthesis of the pre-
viously inaccessible water-soluble derivatives 4, 5, 7, and 8 that
incorporated amino acid residues in their structures (see the
ESI† for the details of the synthesis and characterization of
aromatic amides of aminoacids 12a–b).
Additionally, using SnCl4 as the catalyst allowed us to obtain a
new family of compounds with attached residues of thiophene-
substituted carboxylic acids. Using FeCl3 is not appropriate for
thiophene derivatives since it leads to the oxidative polymeriza-
tion of the thiophene units,18 while SnCl4 showed no side
reactions. Unfortunately, this method does not allow fullerene
derivatives with furanyl addends to be synthesized due to the
degradation of furane derivatives under the action of SnCl4.
Molecular structures of compounds 1–11 were confirmed by
NMR spectroscopy and mass spectrometry. All synthesized C60 and
C70 fullerene derivatives were shown to have the same Cs symmetry
as C60Cl6 and C70Cl8 precursors as deduced from their 1H, 19F, 13C
and 2D (COSY, HSQC, HMBC) NMR spectra (Fig. S2–S59, ESI†).
Exemplary 1H and 13C NMR spectra of compound 10 shown in
Fig. 2 fully confirm the proposed molecular structure with the
equatorial-type arrangement of eight functional addends. The NMR
spectra shown in Fig. 2 and Fig. S2–S59 (ESI†) confirm also the
high purity of the synthesized fullerene derivatives isolated
without using chromatographic separation.
All synthesized compounds 1–11 belong to the family of
polycarboxylic fullerene derivatives and therefore demonstrate
high solubility in DMSO, THF, and aqueous K2CO3.
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Compounds 2K, 6K, 9K, 10K and 11K showed pronounced

activities against HIV-1/NL4.3 (X4) with EC50 values close to 1 mM.
As it is shown in Table 1, compound 6 is even more active against
this virus than the well-known commercial drug tenofovir.
Compounds 2–11K also inhibit R5 HIV-1/BaL replication in
the low mM range, comparable to tenofovir. Activities against
HIV-2 were also determined and the EC50 values of the investi-
gated compounds were comparable to tenofovir. The presented
initial results of the anti-HIV screening of water-soluble fullerene
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derivatives can be considered as promising.

To summarize, we developed a single-step Friedel–Crafts
arylation method for the preparation of a variety of water-
soluble fullerene derivatives starting from readily available
C60Cl6 or C70Cl8 and aromatic acids or their amides as pre-
cursors. In contrast to other reactions previously reported
for chlorofullerenes, the presented approach allowed us to
combine synthetic efficiency with excellent stability of the
prepared compounds in aqueous and physiological media.
High product yields and no need for time- and solvent-
1 13
consuming chromatographic purification makes the designed
Fig. 2 H (a) and C (b) NMR spectra of compound 10.
fullerene derivatives available on a large scale with potential for
industrial upscaling. Highly promising results of the preliminary
Water-soluble forms of compounds 1–11 were prepared antiviral screening of the synthesized unique compounds points
using a standard procedure. Fullerene derivatives 1–11 were towards their potential applications in the development of
dissolved in a stoichiometric amount of aqueous K2CO3, and principally new antiviral pharmaceuticals.
the obtained transparent solutions were filtered through PES This work was supported by the Russian Science Foundation
syringe filters and freeze-dried to obtain the corresponding (project 19-13-00411).
potassium salts 1K–11K.
Antiviral properties of the synthesized fullerene derivatives
1K–11K were investigated in vitro against Human immuno- Conflicts of interest
deficiency viruses (HIV-1 NL4.3(X4), HIV-1 BaL (R5) and HIV-2
ROD) (Table 1). There are no conflicts to declare.
HIV enters cells by binding of the gp120 envelope glycopro-
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