One-pot triple functionalization of carbon nanotubes

Article abstract of DOI:10.1002/chem.201003050

Carbon nanotubes (CNTs) are very promising as carriers for the delivery of bioactive molecules. The multifunctionalization of CNTs is necessary to impart multimodalities for the development of future CNT-based multipotent therapeutic constructs. In this context, we report the first example of covalent trifunctionalization of different types of CNTs. Our strategy is a simple and efficient methodology based on the simultaneous functionalization of the nanotube surface with three different active groups. The reaction is performed in one step by arylation with diazonium salts generated in situ. The CNTs are functionalized with benzylamine moieties blocked with three different protecting groups that can be selectively removed under specific conditions. The trifunctionalized CNTs were characterized by TEM, thermogravimetric analysis, and Raman and UV/Vis/NIR spectroscopy, while the amine loading was determined by using the Kaiser test. The sequential removal of the protecting groups of the amine functions allows the grafting of the molecules of interest on the nanotube surface to be con-trolled

Full text of DOI:10.1002/chem.201003050

DOI: 10.1002/chem.201003050
One-Pot Triple Functionalization of Carbon Nanotubes
[
a]
[b]
[b]
[a]
Cꢀcilia Mꢀnard-Moyon,* Chiara Fabbro, Maurizio Prato, and Alberto Bianco*
Abstract: Carbon nanotubes (CNTs)
are very promising as carriers for the
delivery of bioactive molecules. The
multifunctionalization of CNTs is nec-
essary to impart multimodalities for
the development of future CNT-based
multipotent therapeutic constructs. In
this context, we report the first exam-
ple of covalent trifunctionalization of
different types of CNTs. Our strategy
is a simple and efficient methodology
based on the simultaneous functionali-
zation of the nanotube surface with
three different active groups. The reac-
tion is performed in one step by aryla-
tion with diazonium salts generated in
situ. The CNTs are functionalized with
benzylamine moieties blocked with
three different protecting groups that
can be selectively removed under spe-
cific conditions. The trifunctionalized
CNTs were characterized by TEM,
thermogravimetric
analysis,
and
Raman and UV/Vis/NIR spectroscopy,
while the amine loading was deter-
mined by using the Kaiser test. The se-
quential removal of the protecting
groups of the amine functions allows
the grafting of the molecules of interest
on the nanotube surface to be con-
trolled.
Keywords: carbon nanotubes · drug
delivery · nanotechnology · one-pot
reactions · protecting groups
Introduction
tems to specific cell populations is of great importance to in-
crease the therapeutic efficiency and reduce side effects by
avoiding collateral consequences for healthy tissues.
[1]
[2]
[14]
Due to their unique electrical, mechanical, and optical
[
3]
properties, carbon nanotubes (CNTs) have played an im-
portant role in the rapidly developing field of nanotechnolo-
Moreover, the attachment of a tracking probe, such as a flu-
[15]
[14a,16]
orophore or a radionuclide,
may provide optical sig-
[
4]
gy. Applications in many fields, including biology and
nals for imaging and localization of the CNT–drug conju-
gates. Several strategies have been developed for the double
[5]
[6]
[7]
nanomedicine, for drug delivery and imaging have been
thoroughly investigated. Due to their lack of solubility and
strong tendency to aggregate, it is imperative to functional-
ize the surface of CNTs to fully exploit their properties.
Both covalent and noncovalent approaches have been devel-
oped to increase dispersibility and to introduce chemical
[9a,17]
functionalization of CNTs.
For example, we have re-
cently covalently tethered methotrexate (MTX) to the side-
walls of oxidized multiwalled carbon nanotubes
(MWCNTs), while a fluorophore was attached to the car-
[18]
boxylic functions that are mainly located at the tips. We
observed internalization of the MTX–CNT conjugates into
human breast cancer cells with an enhanced antitumor acti-
[8]
functionalities on their sidewalls and tips. In particular, the
multiple functionalization of CNTs is necessary to achieve
multimodalities. For instance, it is of interest to use CNTs as
multimodal drug delivery systems because CNTs have
[17e]
vity.
Recently, Heister et al. reported the functionaliza-
tion of single-walled carbon nanotubes (SWCNTs) with
three molecules of interest: 1) the anticancer drug doxorubi-
cin, 2) a monoclonal antibody able to target the tumor
marker carcinoembryonic antigen, and 3) fluorescein for
[9]
[10]
shown high potential as carriers of small drugs, peptides,
[
11]
[12]
proteins, and nucleic acids. The development of nano-
vectors able to carry one or more therapeutic agents with
targeting and imaging capability is essential, for example, in
[19]
imaging.
The antibody and fluorescein were covalently
[
13]
the treatment of cancer or different types of infections. In
addition, the molecular targeting of CNT-based delivery sys-
linked to protein bovine serum albumin, which was then
bound to carboxylic groups of oxidized SWCNTs, whereas
doxorubicin was subsequently adsorbed on the nanotube
surface. To avoid a premature release of the therapeutic
agent, to better control the amount of different functionali-
ties on the nanotubes, and to increase the stability of the
CNT-based conjugates, a reliable approach is to modify
CNTs by covalent functionalization. For this purpose, we de-
scribe herein a simple methodology for the covalent intro-
duction of three different functional groups on the sidewall
of different types of CNTs, both SWCNTs and MWCNTs,
that were pristine, purified, or oxidized. The functional
groups contain amino functions blocked by three quasi-or-
thogonal protecting groups. We also report the selective de-
[
a] Dr. C. Mꢀnard-Moyon, Dr. A. Bianco
CNRS, Institut de Biologie Molꢀculaire et Cellulaire
Laboratoire dꢁImmunologie et Chimie Thꢀrapeutiques
UPR 9021, 67000 Strasbourg (France)
Fax : (+33)388-61-06-80
E-mail: c.menard@ibmc-cnrs.unistra.fr
a.bianco@ibmc-cnrs.unistra.fr
[
b] C. Fabbro, Prof. M. Prato
Dipartimento di Scienze Farmaceutiche
Universitꢂ di Trieste, Trieste 34127 (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003050.
3222
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3222 – 3227

FULL PAPER
protection of each amine function under specific conditions.
This allows the control of the attachment of three molecules
of interest to CNTs in a sequential manner. Thus, the tri-
functionalization approach would afford the possibility to
covalently attach a drug, a targeting ligand, and a fluoro-
phore. Tethering the drug to the nanotube backbone
through a cleavable linker is also envisaged because it will
(PTFE) membrane with 0.45 mm pore size. The solid recov-
ered on the filter was dispersed in methanol, sonicated for
30 min in a water bath, and filtered again over a PTFE
membrane. This sequence was repeated twice with DMF,
methanol, dichloromethane, and diethyl ether. The resulting
solid was dried under vacuum.
[17e,20]
facilitate the controlled release at the site of action.
To
Characterization of trifunctionalized SWCNTs: The trifunc-
tionalized SWCNTs (f-SWCNTs) 4 were characterized by
different techniques, including TEM, thermogravimetric
analysis (TGA), and Raman and UV/Vis/NIR spectroscopy.
First of all, it is important to note that trifunctionalization
imparts better dispersibility of the SWCNTs (Figure S1 in
the Supporting Information). Indeed, the solubility of 4 is
significantly improved in organic solvents, such as DMF, rel-
ative to p-SWCNTs. The suspension of p-SWCNTs is not
stable because reaggregation takes place rapidly and
SWCNTs settle down. On the contrary, the dispersion of 4 is
highly stable for several hours. A TEM image of 4 shows
that the nanotubes are present in small bundles (Figure 1a).
The morphology of the nanotubes after the functionalization
process does not seem to have been altered by the chemical
treatment. TGA results for 4 and p-SWCNTs performed
under a nitrogen atmosphere are shown in Figure 1b. As ex-
pected, the weight loss of p-SWCNTs is minor as CNTs are
robust under nitrogen atmosphere, whereas 4 loses 25% of
the total weight at 7008C. The weight loss can be attributed
to the functional groups attached to the nanotube surface.
The Raman spectra of p-SWCNTs and 4 are given in Fig-
ure 1c. The multiple peaks seen in the radial breathing
mode (RBM) are due to the distribution of tube diameters
in the sample; the frequency of the RBM is inversely pro-
portional to the diameter (Figure S2 in the Supporting Infor-
the best of our knowledge, the triple covalent functionaliza-
tion of CNTs has not yet been reported. We believe that
this approach will expand the potential of carbon nanotubes
in the biomedical and nanomedicine fields.
Results and Discussion
Trifunctionalization of SWCNTs: Our strategy for the triple
functionalization of CNTs relies on the simultaneous reac-
tion of an equimolar mixture of three aryldiazonium salts
with the nanotube surface. The aryldiazonium salts are gen-
erated in situ and contain amine functions blocked with
three different protecting groups. The arylation of CNTs
with diazonium salts is an efficient method for the function-
alization of CNTs, originally developed by the group of
[21]
Tour. The reaction can be performed under various condi-
[22]
tions with the possibility of scaling up. We have prepared
-aminomethyl-anilines 1–3 protected with phthalimide
4
(
(
Pht), tert-butyloxycarbonyl (Boc), and benzyloxycarbonyl
Z) moieties, respectively (Scheme 1). These protecting
groups were selected because conditions exist to remove
them sequentially without affecting those remaining on the
[17a,23]
nanotube surface (see below).
In a typical experiment,
pristine SWCNTs (p-SWCNTs) were sonicated in o-dichloro-
benzene (ODCB) for a short time by using a sonication tip
[24]
À1
mation). The weak band centered at 1292 cm is attribut-
3
(
see the Experimental Section). A solution of an equimolar
ed to disorder-induced mode (D band), mainly due to sp -
2
mixture of 4-aminomethyl-anilines 1–3 in acetonitrile was
A
H
U
G
R
N
N
hybridized carbon atoms in the hexagonal sp -hybridized
added to this suspension. The dispersion was sonicated
again for 5 min with a tip and for 30 min in a water bath.
After bubbling with argon, isoamyl nitrite was added and
the reaction mixture was heated at 608C for 19 h. After
cooling to room temperature, the suspension was diluted
with methanol and filtered over a polytetrafluoroethylene
carbon atom framework of the nanotube sidewall. The spec-
trum of 4 exhibits an increased intensity of the D band (I )
D
À1
relative to that of the G band (I ) at 1593 cm . It is an ex-
G
pected result of the introduction of functional groups cova-
lently bound to the nanotube surface, wherein a significant
2
number of sp -hybridized carbon atoms have been converted
Scheme 1. One-pot trifunctionalization of SWCNTs.
Chem. Eur. J. 2011, 17, 3222 – 3227
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3223

C. Mꢀnard-Moyon, A. Bianco et al.
Figure 1. a) A TEM image of 4. b) TGA of p-SWCNTs (c) and 4 (a) under a nitrogen atmosphere (heating rate 108CminÀ1). c) Raman spectra
(
785 nm, normalized on the G-band) of p-SWCNTs (c) and 4 (a). d) UV/Vis/NIR absorption spectra of p-SWCNTs (c) and 4 (a) in DMF.
3
[25]
to sp hybridization. The I /I ratio increased from 0.1 to
0
tions, both Boc and Z moieties are stable. Then, the Boc
group was removed by using a 4m solution of HCl in diox-
ane to give 6. This treatment is enough acidic to cleave the
Boc group, but not strong enough to remove the Z moiety.
Finally, a mixture of trifluoroacetic acid (TFA), trimethyl-
silyl trifluoromethanesulfonate (TMSOTf), and p-cresol was
used to cleave the Z group, leading to 7. At each step, the
amine loading was determined by using the Kaiser test. This
is a colorimetric test commonly used in peptide synthesis to
assess the amount of primary amine functions (see Support-
D
G
.6 after functionalization of the SWCNTs. Moreover, the
overall intensity of the RBM peaks decreased to give fur-
ther confirmation of the covalent character of the function-
alization of the nanotube surface (Figure S2 in the Support-
ing Information). UV/Vis/NIR analyses of p-SWCNTs and 4
are given in Figure 1d. The absorption spectrum of p-
SWCNTs shows the characteristic van Hove singularities in
the density of states (DOS), which are attributed to band-
gap transitions. These features are significantly reduced in
the spectrum of 4. This is indicative of significant electronic
perturbation of the SWCNTs due to disruption of the ex-
tended p network and change in hybridization of a high
number of carbon atoms. This effect is consistent with cova-
lent functionalization of the nanotube sidewall, which is in
agreement with observations from Raman spectroscopy
[26]
[27]
ing Information). The values obtained by the Kaiser test
are reported in Scheme 2 and in Table 1, entry 1.
Even if an equimolar amount of the three anilines 1–3
was employed in the functionalization reaction with the p-
SWCNTs, the degree of functionalization of the nanotube
surface with each of the three benzylamines was not identi-
cal (Figure S3a in the Supporting Information). This could
be explained by the fact that the reagents were used in
excess and that side reactions between the corresponding di-
azonium salts, which are highly reactive, could occur during
the functionalization reaction. However, the equimolarity of
the mixture of the three anilines 1–3 can, in principle, be
modified to tune the relative degree of functionalization and
[21]
analysis.
Sequential removal of the three protecting groups: The
three protecting groups were sequentially removed under
specific conditions (Scheme 2). The Pht group was cleaved
by treatment of 4 with a solution of hydrazine in ethanol to
afford 5 (see the Experimental Section). Under these condi-
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ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3222 – 3227

One-Pot Triple Functionalization of Carbon Nanotubes
FULL PAPER
amines is remarkably different
between 4 and 9 (cf. entries 1
and 2 in Table 1). This result
can be explained by a differ-
ence in terms of reactivity of p-
and ox-SWCNTs. However, the
order of reactivity of 1–3 is sim-
ilar in both cases: 2 (Boc)ꢀ1
(
Pht)>3 (Z). We assume that
the Pht- and Z-protected 4-ami-
nomethylanilines 1 and 3 are
likely to adsorb on the nano-
tube surface through p–p inter-
actions, thereby lowering their
reactivity, contrary to the bulky
Boc-protected 4-aminomethyla-
niline 2.
The triple functionalization
of shortened SWCNTs has an
additional advantage because
the carboxylic functions intro-
duced by oxidation, mainly at
[18]
the tips, can be further deriv-
atized to prepare even more so-
phisticated multifunctionalized
CNTs. The COOH groups may
indeed be used as anchor point
of a fourth molecule of interest
or for the grafting of molecules
to further enhance the dispersi-
Scheme 2. Sequential removal of the three protecting groups of 4 and the corresponding amine loadings deter-
mined by the Kaiser test.
Table 1. Loading capacity of 4, 9, 10, and 12 prepared in organic or aque-
ous media.
bility of the nanotubes.
[
a]
[a]
[a]
Entry
Compound
Pht
NH
Boc
Z
Total NH
2
ACHTUNGTNRENUNG[ mmolg ]
À1
À1
2
loading [mmolg ] ([%])
Trifunctionalization of MWCNTs: Following this straightfor-
ward approach to modify carbon nanotubes with multiple
functions, we have explored the possibility to extend our
1
2
3
4
5
4
9
10
12
12
0.12 (21)
0.11 (39)
0.05 (14)
0.13 (51)
0.17 (24)
0.36 (61)
0.11 (39)
0.17 (43)
0.03 (13)
0.49 (73)
0.11 (18)
0.06 (22)
0.17 (43)
0.09 (36)
0.02 (3)
0.59
0.28
0.39
0.25
0.68
[
[
b]
c]
strategy to MWCNTs. The MWCNTs are indeed reactive to-
[28]
wards diazonium salts.
Initially, we used purified
MWCNTs and repeated the reactions described for
SWCNTs. The f-MWCNTs 10 were characterized by TGA
and TEM (Figures S5 and S6 in the Supporting Information,
respectively). The amine loading values determined by the
Kaiser test after sequential removal of the protecting groups
are reported in Table 1, entry 3. Boc-protected 2 is still the
most reactive aniline (Figure S3c in the Supporting Informa-
tion). In a comparative study, one-pot trifunctionalization
was also applied to ox-MWCNTs 11. For this purpose,
MWCNTs were first oxidized to shorten them to 315 nm on
average. TEM images show that the oxidative treatment
dramatically reduces the nanotube length. The one-pot tri-
functionalization reaction was performed in two different
solvent systems, namely, in water and in a mixture of o-di-
chlorobenzene and acetonitrile (Figure S7 in the Supporting
Information). Water is a green alternative to organic sol-
vents and it is advantageous for potential scaleup. The f-ox-
MWCNTs 12 prepared under both conditions were analyzed
again by TEM and TGA (Figures S8 and S9 in the Support-
ing Information, respectively). The three protecting groups
[
[
a] Protecting group removed. [b] Reaction performed in organic media.
c] Reaction performed in aqueous media.
to vary the ratio between the three benzylamines linked to
the surface of the nanotubes.
For comparison, we then performed one-pot trifunctional-
ization on oxidized SWCNTs (ox-SWCNTs) 8 (Figure S4 in
the Supporting Information). Pristine SWCNTs were first
treated with 3m nitric acid at reflux for 70 h. This treatment
reduces the length of the CNTs, which is particularly impor-
tant for biomedical applications. The one-pot trifunctional-
ization was applied to 8 and the three different protecting
groups of the trifunctionalized oxidized SWCNTs (f-ox-
SWCNTs) 9 were sequentially removed by using the same
conditions described above. The amine loading values and
the corresponding percentage of each of the three protected
amines, determined by the Kaiser test, are reported in
Table 1, entry 2, and displayed in Figure S3b in the Support-
ing Information. The proportion between the protected
[29]
[5]
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ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3225

C. Mꢀnard-Moyon, A. Bianco et al.
were sequentially removed and the corresponding amine
loading values determined by the Kaiser test are summar-
ized in Table 1, entries 4 and 5, and represented in Figur-
es S3d and S3e in the Supporting Information. The total
amine loading is higher for 12 when the reaction is per-
sonicated by using a tip (5 min cycle, 5 s ON, 5 s OFF, 30% amplitude)
and then by using a water bath for 30 min. Argon was bubbled in the sus-
pension for 10 min. Isoamyl nitrite (0.37 mL, 2.8 mmol) was added and
the reaction mixture was immediately heated at 608C for 19 h. After
cooling to room temperature, the suspension was diluted with methanol
(100 mL) and filtered over a PTFE (0.45 mm, Omnipore JHWP, Milli-
pore) membrane. The solid recovered on the filter was dispersed in meth-
anol (300 mL), sonicated for 30 min in a water bath, and filtered over a
PTFE (0.45 mm) membrane. This sequence was repeated twice with
DMF, methanol, dichloromethane, and diethyl ether. The resulting solid
was dried under vacuum.
À1
À1
formed in water (0.68 mmolg versus 0.25 mmolg ), which
is in agreement with observations from TGA weight loss
(
Figure S9 in the Supporting Information). As a conse-
quence, by changing the conditions, it is possible to modu-
late the level of functional groups on oxidized and short-
ened MWCNTs.
Preparation of 5: Deprotection of the Pht group: Hydrazine hydrate
(28 mL) was added to a suspension of 4 (7 mg) in ethanol (8 mL). The dis-
persion was sonicated in a water bath for 5 min and stirred for 17 h.
Then, the suspension was diluted with methanol (75 mL), sonicated for
5
min in a water bath, and filtered over a PTFE (0.45 mm) membrane.
Conclusion
The solid recovered on the filter was dispersed in methanol (75 mL), so-
nicated for 10 min in a water bath, and filtered over a PTFE (0.45 mm)
membrane. This sequence was repeated twice with methanol, dichloro-
methane, and diethyl ether. The resulting solid was dried under vacuum.
We have developed a methodology to covalently functional-
ize CNTs with three different active groups in one step by
arylation with diazonium salts. The CNTs are functionalized
with benzylamine moieties blocked with three different pro-
tecting groups that can be selectively removed under specif-
ic conditions. The trifunctionalized CNTs were characterized
by TEM, TGA, and Raman and UV/Vis/NIR spectroscopy,
and the level of functionalization was assessed by using the
Kaiser test. The trifunctionalization approach is simple,
rapid, and versatile because it can be applied to different
types of CNTs, in terms of diameter, number of walls
Preparation of 6: Deprotection of Boc group: A suspension of 5 (5.9 mg)
in HCl (3.9 mL, 4m in dioxane (purchased from Sigma–Aldrich)) was so-
nicated in a water bath for 5 min and stirred for 5 h. Then, the mixture
was diluted with diethyl ether (50 mL), sonicated for 5 min in a water
bath, and filtered over a PTFE (0.45 mm) membrane. The solid recovered
on the filter was dispersed in methanol (50 mL), sonicated for 5 min in a
water bath, and filtered over a PTFE (0.45 mm) membrane. This se-
quence was repeated twice with methanol, dichloromethane, and diethyl
ether. The resulting solid was dried under vacuum.
Preparation of 7: Deprotection of Z group: A mixture of 6 (3 mg) in
TFA (195 mL), TMSOTf (52 mL), and p-cresol (26 mg) was stirred for
1
5
7 h. Then, the mixture was diluted with methanol (50 mL), sonicated for
(
SWCNTs, MWCNTs), and length (pristine and shortened
min in a water bath, and filtered over a PTFE (0.45 mm) membrane.
CNTs). Further derivatization of the amine groups with a
small drug, a fluorophore, and a targeting agent is currently
being performed in our laboratory to use these multimodal
CNTs for targeted drug delivery. We assume that the se-
quential removal of the protecting groups of the amine func-
tions will allow the grafting of the molecules of interest onto
the nanotube surface to be precisely controlled.
The solid recovered on the filter was dispersed in methanol (50 mL), so-
nicated for 5 min in a water bath, and filtered over a PTFE (0.45 mm)
membrane. This sequence was repeated twice with DMF, methanol, di-
chloromethane, and diethyl ether. The resulting solid was dried under
vacuum.
Acknowledgements
Experimental Section
This work was supported by the Centre National de la Recherche Scienti-
fique (CNRS), the University of Trieste, the Italian Ministry of Educa-
tion MIUR (Cofin Prot. 20085M27SS and Firb RBIN04HC3S) and the
Regione Friuli Venezia-Giulia. Partial support by European Union FP7
ANTICARB program (HEALTH-2007-201587) and the CARBONANO-
BRIDGE (ERC-2008-AdG-227135) program is also acknowledged. TEM
images were recorded at the RIO Microscopy Facility Platform of Espla-
nade Campus (Strasbourg, France). Jacky Rose and Marc Mermillon-
Fournier are gratefully acknowledged for FTIR measurements. Nicolas
Izard is also acknowledged for fruitful discussions on Raman spectrosco-
py.
Materials and methods: SWCNTs were purchased from Unidym (HiPco
Single-Walled Carbon Nanotubes, Lot# R1912) and MWCNTs were pur-
chased from Nanocyl (Thin MWCNT 95+ % C purity, Nanocyl 3100,
batch no. 071119, average diameter and length: 9.5 nm and 1.5 mm, re-
spectively). All reagents and solvents were purchased from different
commercial suppliers and used as received. TEM was performed on a Hi-
tachi 600 microscope with an accelerating voltage of 75 kV. The CNTs
were dispersed in ethanol by sonication, deposited on a carbon TEM
grid, and dried. Thermogravimetric analyses were performed by using a
À1
TGA Q500 TA instrument with a ramp of 108Cmin under N
2
using a
À1
flow rate of 60 mLmin . Raman spectroscopy analysis was performed on
an inVia Raman microscope (Renishaw) by using 785 nm laser light. The
UV/Vis/NIR spectra were recorded on a Varian Cary 5000 spectropho-
tometer. When stated, suspensions of CNTs were sonicated either in a
water bath (Transsonics Digitals Elma, 20 W, 40 kHz) or by using tip
sonication (Vibra-Cel Ultrasonic Processor).
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(
(
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One-Pot Triple Functionalization of Carbon Nanotubes
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Published online: February 9, 2011
Chem. Eur. J. 2011, 17, 3222 – 3227
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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