Carbohydrate conjugation through microwave-assisted functionalization of single-walled carbon nanotubes using perfluorophenyl azides

Article abstract of DOI:10.1016/j.carres.2014.09.006

Carbohydrate-functionalized single-walled carbon nanotubes (SWNTs) were synthesized using microwave-assisted reaction of perfluorophenyl azide with the nanotubes. The results showed that microwave radiation provides a rapid and effective means to covalently attach carbohydrates to SWNTs, producing carbohydrate-SWNT conjugates for biorecognition. The carbohydrate-functionalized SWNTs were furthermore shown to interact specifically with cognate carbohydrate-specific proteins (lectins), resulting in predicted recognition patterns. The carbohydrate-presenting SWNTs constitute a new platform for sensitive protein- or cell recognition, which pave the way for glycoconjugated carbon nanomaterials in biorecognition applications.

Full text of DOI:10.1016/j.carres.2014.09.006

Accepted Manuscript
Carbohydrate conjugation through microwave-assisted functionalization of sin-
gle-walled carbon nanotubes using perfluorophenyl azides
Na Kong, Manishkumar R. Shimpi, Olof Ramström, Mingdi Yan
PII:
S0008-6215(14)00352-8
DOI:
http://dx.doi.org/10.1016/j.carres.2014.09.006
CAR 6845
Reference:
Carbohydrate Research
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 June 2014
18 September 2014
19 September 2014
Please cite this article as: Kong, N., Shimpi, M.R., Ramström, O., Yan, M., Carbohydrate conjugation through
microwave-assisted functionalization of single-walled carbon nanotubes using perfluorophenyl azides,
Carbohydrate Research (2014), doi: http://dx.doi.org/10.1016/j.carres.2014.09.006
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Carbohydrate Conjugation through Microwave-Assisted
Functionalization of Single-Walled Carbon Nanotubes Using
Perfluorophenyl Azides
Na Kong,a Manishkumar R. Shimpi,a Olof Ramström,a,* and Mingdi Yan,a, b,
*
a KTH - Royal Institute of Technology, Department of Chemistry, Teknikringen 30,
S-10044 Stockholm, Sweden;
b Department of Chemistry, University of Massachusetts Lowell, 1 University Ave.,
Lowell, MA 01854, United States.
E-mail: Mingdi_Yan@uml.edu; ramstrom@kth.se.

Abstract
Carbohydrate-functionalized single-walled carbon nanotubes (SWNTs) were synthesized
using microwave-assisted reaction of perfluorophenyl azide with the nanotubes. The results
showed that microwave radiation provides a rapid and effective means to covalently attach
carbohydrates to SWNTs, producing carbohydrate-SWNT conjugates for biorecognition. The
carbohydrate-functionalized SWNTs were furthermore shown to interact specifically with
cognate carbohydrate-specific proteins (lectins), resulting in predicted recognition patterns.
The carbohydrate-presenting SWNTs constitute a new platform for sensitive protein- or cell
recognition, which pave the way for glycoconjugated carbon nanomaterials in biorecognition
applications.
Keywords
Single-walled carbon nanotubes, microwave, perfluorophenyl azide, covalent
functionalization, carbohydrate, lectin

Introduction
Single-walled carbon nanotubes have attracted much attention from a fundamental
physics/chemistry perspective, as well as for applied fields such as nanoelectronics and
nanomedicine. This is in part due to their unusual properties resulting from the
pseudo-one-dimensional nanosize and the unique structure. However, several disadvantages
limit their biological applications, such as poor water solubility, lack of reactive
functionalities, and potentially high cytotoxicity.1, 2 An effective way to overcome these
limitations is to introduce an organic coating on the carbon materials, for example, by using
polar structures such as carbohydrates.3-7 Functionalization of carbon nanotubes (CNTs) with
carbohydrates not only increases the biocompatibility and solubility, but also introduces
molecular recognition features, which can impact cellular interactions and uptake of CNTs.
These features of carbohydrate-functionalized carbon nanomaterials have been demonstrated
in biomedical applications such as biosensing and drug delivery.3-5 For example, Zhang et al.
wrapped SWNTs with boronic acid-derivatized phenoxy dextran. The resulting complex
demonstrated a concentration-dependent riboflavin recognition resulting from the redshift of
emission upon addition of riboflavin, which could be reversed by the addition of a
riboflavin-binding protein.8 Torres and coworkers covalently functionalized fewer-layer
graphene and SWNTs with α-D-mannosyl dendrons, and used the resulting glyco-SWNTs for
the selective interaction with lectin.9 In the work of Sun and coworkers,
monosaccharide-modified SWNTs were used to effectively bind B. anthracis spores in the
presence of Ca 2+.10, 11
For CNTs and graphene, the most common way to achieve covalent functionalization is to
use the oxidized forms. Oxidation generates oxygen-containing functional groups at the
material surfaces, such as epoxides and carboxylic acids, which can subsequently be used to

conjugate various entities such as amine-functionalized carbohydrates.10-13 Oxidation,
however, may lead to extensive structural damage of the carbon materials, impacting the
lattices and intrinsic properties. Milder conjugation methods are therefore desired. A number
of alternative reactions have been developed for the chemical functionalization of CNTs,
including radical additions via diazonium salts, alkyl or aryl peroxides, carbene or nitrene
cycloadditions, as well as electrophilic and nucleophilic addition reactions.14, 15 However,
owing to the relatively low reactivities of the pristine carbon materials, these reaction often
require lengthy reaction times at elevated temperatures.
In this context, microwave radiation has become a standard technique in organic synthesis,
inducing molecular collisions with direct impact on the reagents of the reaction. The efficient
heating and milder reaction conditions generally result in faster kinetics, higher reaction
yields and lower side products as compared to the traditional heating protocol.16, 17
Microwave radiation has also been successfully used in the process for the chemical
modification of CNTs and fullerenes.9, 18-20
Organic azides provide a particularly attractive functionalization method related to carbon
nanomaterials.21-26 Azides may thus undergo cycloaddition reactions with reactive alkenes,
eventually resulting in aziridines.27 Of particular interest is the fact that thermal or light
activation of organic azides leads to nitrogen extrusion, generating nitrene intermediates that
add to the sp2 carbons of the carbon material, forming aziridine adducts. Perfluorophenyl
azides (PFPAs) are especially useful, being among the most reactive aryl azides,28 and
resulting in singlet perfluorophenyl nitrenes that have longer lifetime than other aryl nitrenes,
thus promoting efficient covalent adduct formation.29, 30 We have for example shown that
pristine graphene can be effectively functionalized with PFPA either photochemically or

thermally.21-23In addition, Fréchet and coworkers used a PFPA structure bearing an ATRP
initiator entity to functionalize SWNT forests, and then generated polymer brushes by in situ
polymerization.31 Besides light and heat, PFPAs can also be activated by other energy
sources such as electrons and X-rays.28, 32
In this work, we investigated the potential for microwave-assisted functionalization of
SWNTs by PFPA derivatives, in order to generate functional nanoplatforms for carbohydrate
presentation. Following conjugation, the biorecognition properties of the resulting
glyconanomaterials were evaluated from analysis of the cognate lectin binding.
Results and Discussion
As-prepared SWNTs are usually contaminated with a variety of impurities including residual
metal catalysts and carbonaceous impurities such as amorphous carbon and carbon
nanoparticles.33 The degree of contamination and the percent impurity vary depending on the
preparation method and the manufacturers. Of the three common synthesis methods used to
produce SWNTs, i.e., chemical vapor deposition (CVD), laser ablation and arc discharge, the
lower temperature CVD technique has become a preferred production method owing to the
better control over nanotube alignment, size, purity and density.34 The HiPco SWNTs sample
used in this study was produced by CVD with 85wt﹪purity, and the purity was further
inspected by TEM before use. The TEM image shows large ropes which were bundled
nanotubes, as well as dark particles that were mostly residual catalysts coated with
amorphous carbon (Figure 1A).33, 35 To remove these impurities, chemical oxidation and
physical purification methods are employed to purify as-prepared CNTs. The chemical
oxidation selectively oxidizes carbonaceous impurities, however, the method often leads to

structure damage by the oxidizing agent. In order to avoid damage of the pristine SWNTs, a
mild, non-oxidative purification method was preferred. Thus, a differential centrifugation
protocol was adopted to remove the metal catalysts, carbonaceous impurities or heavy
bundles based on their weight difference. This process resulted in improved sample purity
and smaller nanotube bundles (Figure 1B).
Figure 1. TEM images of (A) purchased SWNTs without purification, and (B) SWNTs after
purification.
To functionalize SWNTs, the reaction was first carried out by heating a suspension of
o
SWNTs and PFPA-NHS in 1,2-dichlorobenzene (DCB) at 130 C in an oil bath. The azide
functionality, showing a characteristic IR absorption band at ~2130 cm-1, was used as a
convenient way to monitor the reaction by FTIR (indicated by arrows in Figure 2A). The
reaction was in this case relatively sluggish, where the PFPA was converted in 3 days (Figure
2A). The reaction was subsequently carried out in a microwave reactor under the same
conditions, resulting in almost complete conversion in 6 h. Upon increasing the temperature
o
to 150 C, the reaction proceeded considerable faster, resulting in only trace amount of PFPA
after 1 h radiation (Figure 2B). No other changes could be detected, indicating that the

components were not further affected under the reaction conditions. These microwave
o
reaction conditions (150 C, 1 h) were thus chosen for the subsequent studies.
Figure 2. IR spectra of the reaction of PFPA-NHS with SWNTs under (A) conventional oil
bath heating at 130 oC for 3 days, and (B) microwave radiation at 150 oC for 1 h before (black)
and after (red) reactions. The arrows indicate the azide absorption, which are enlarged in the
insets.

Figure 3. Raman spectra of pristine SWNTs (black) and NHS-PFPA-functionalized SWNTs
prepared using microwave-assisted reaction conditions (red).
Further evidence for the covalent functionalization was provided by Raman spectroscopy.
Conversion of sp2 carbons to sp3 carbon atoms is expected to lead to an increase in the
intensity of the disorder (D) band (1250~1450 cm-1) along with a decrease in the graphite (G)
band (1500-1605 cm-1). The intensity ratio of the D and G bands, ID/IG, is thus commonly
used to evaluate the degree of functionalization; the larger the value, the higher the degree of
functionalization.36 In addition, covalent functionalization of SWNTs would reduce the
intensity of the radial breathing mode (RBM, between 100-300 cm-1), and this band would
completely disappear for SWNTs having high degrees of functionalization.11 In the present
study, the Raman spectra were recorded for SWNTs before and after functionalization with
PFPA-NHS (Figure 3). The ID/IG values were calculated to be 0.15 and 0.43 for purified
SWNTs and PFPA-NHS-functionalized SWNTs, respectively. The increase in ID/IG value
observed for the modified SWNTs compared to that of pristine SWNTs is consistent with the

covalent functionalization of the nanotube lattice.37 SWNTs functionalized by the
conventional thermal reaction and the microwave-assisted reaction gave similar ID/IG values
(Table 1S, Supporting Information), and in both case the RBM signals almost completely
disappeared, demonstrating high degrees of functionalization.
Figure 4. (A) NHS-PFPA-functionalized SWNTs (left) and as-purified SWNTs (right) in
acetone. (B) TEM image of NHS-PFPA-functionalized SWNTs. (C) Man-SWNTs (left) and
as-purified SWNTs (right) in water. (D) TEM image of Man-SWNTs.
The functionalized SWNTs prepared using the microwave-assisted reaction were also
evaluated for solvation by sonicating the samples in acetone and allowing them to settle
overnight. The results were in this case clear, and NHS-PFPA-functionalized SWNTs

dispersed well in acetone, whereas the unfunctionalized SWNTs precipitated out of the
solution to a large degree (Figure 4A). Furthermore, large bundles were observed in the TEM
micrographs of the purified SWNTs (Figure 1B), whereas smaller bundles were present after
functionalization with PFPA-NHS, likely due to the improved solubility (Figure 4B).
Scheme 1. Functionalization of SWNTs using PFPA-NHS and subsequent conjugation with
carbohydrates.
With NHS-PFPA-functionalized SWNTs at hand, we next addressed the carbohydrate
functionalization of the SWNTs. To demonstrate this feasibility, two carbohydrate
derivatives, Man-EG2-NH2 and Gal-EG2-NH2 were allowed to react with the PFPA-NHS-
functionalized SWNTs in DMF to give Man- and Gal-presenting SWNTs, respectively
(Scheme 1). Conjugation of the carbohydrates to SWNTs drastically increased their dispersity
in water. While the pristine SWNTs were completely insoluble, Man-SWNTs and
Gal-SWNTs were readily dispersed in water yielding homogeneous dispersions (Figure 4C).

The dispersions were stable for over one week without obvious precipitation. In addition, the
carbohydrate-conjugated SWNTs displayed improved debundling, and no large aggregates
were observed by TEM (Figure 4D) compared with unfunctionalized SWNTs (Figure 1B).
The biorecognition properties of the carbohydrate-presenting SWNTs were furthermore
evaluated by treating the carbohydrate-conjugated SWNTs with fluorescein-labeled
Concanavalin A (FITC-Con A), a lectin specific for α-D-mannopyranosides and to a lower
extent to α-D-glucopyranosides.38, 39 Con A exists as a homotetramer at neutral pH, and may
induce significant agglomeration of multivalent scaffolds owing to the mutual crosslinking
effect. This property was also observed in the present case, and when Man-SWNTs were
treated with FITC-Con A, the fluorescence intensity of the solution decreased (Figure 5).
This can be attributed to the interactions between multiple copies of Man on the Man-SWNTs
and FITC-Con A causing aggregation between the two interaction partners. Upon
examination of the agglomerates by fluorescence microscopy, bright fluorescence was also
observed (Figure 1S, Supporting Information). These effects were selective for the
mannosylated glyco-SWNTs, whereas, for comparison, the Gal-SWNTs produced no
agglomeration effect with FITC-Con A under the same conditions (Figure 5).

Figure 5. Fluorescence spectra of FITC-Con A (black), and after it was treated with
Man-SWNTs (blue) and Gal-SWNTs (purple). Inset: percent of decrease in fluorescence
intensity after FITC-Con A was treated with Man-SWNTs (blue column) and Gal-SWNTs
(purple column).
Conclusions
In summary, we have demonstrated an effective method to conjugate carbohydrate structures
to pristine SWNTs using microwave-assisted reaction of perfluorophenyl azides. This is a
first example of applying microwave radiation to PFPA activation, representing a new way to
synthesize carbon nanotube-based glyconanomaterials. Our method used pristine SWNTs
instead of oxidized SWNTs, avoiding extensive alteration to the lattice and the intrinsic
properties of SWNTs. The resulting materials were less bundled and well dispersed in water
compared to pristine SWNTs. In addition, the conjugated carbohydrates retained their
binding selectivity toward cognate lectins, and furthermore induced extensive agglomeration
resulting from the crosslinking of multiple carbohydrate ligands with multimeric lectins. The
method developed here can be readily adapted to conjugate a variety of biomolecules and

biomaterials facilitating the use of CNTs materials in bioanalytical and biomedical
applications.
Experimental
Materials
The SWNTs were obtained from Unidym (HiPco, Lot# P2150). Methyl pentafluorobenzoate,
D-(+)-mannose, β-D-(+)-galactose pentaacetate,
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), sodium metabisulfide
(Na2S2O5) and palladium (10％ on carbon) were purchased from Alfa Aesar. Boron
trifluoride ethyl etherate (BF3·Et2O), N-hydroxysuccinimide (NHS), N-(3-
dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC·HCl), 1,
2-dichlorobenzene (DCB), and bovine serum albumin (BSA) were obtained from
Sigma-Aldrich. Sodium azide (NaN3) and sodium methoxide (CH3ONa) were acquired from
Fluka. 2-[2-(2-Chloroethoxy)-ethoxy]ethanol was obtained from TCI Japan. Concanavalin A
(fluorescein conjugate, lectin from Jack bean) was purchased from Molecular Probes
(Eugene, Oregon). All chemicals were used as received without purification. Water used was
from a Milli-Q ultrapure water purification system. PFPA-NHS was synthesized following
previously reported procedures.40, 41 Man-EG2-NH2 and Gal-EG2-NH2 were synthesized
following previously established procedures (see Supporting Information for detailed
synthesis and characterization).42-44
Instrumentation
1H and 13C NMR spectra were recorded on a Bruker DMX 500 instrument at 500 MHz (1H)
or 125 MHz (13C) in CDCl3 or D2O. Thin layer chromatography (TLC) was performed on

pre-coated Cromatofolios AL silica gel 60 F254 plates (Merck). Column chromatography
was performed using silica gel 60, 0.040-0.063 mm (SDS). Microwave reactions were carried
out using a Personal Chemistry Smith Creator Microwave Assisted Organic Synthesizer
(Biotage Sweden AB). Infrared spectra were collected on a Mettler Toledo ReactIRTM iC 10
in situ FTIR spectrometer (Columbia, MD). Raman spectra were obtained using a Bio-Rad
FTS6000 Raman spectrometer with an NdYAg-laser (1064 nm) as the excitation source.
Fluorescence measurements were conducted on a Varian Cary Eclipse fluorescence
spectrophotometer (Agilent Technologies). TEM images were obtained on a JEOL 100CX
transmission electron microscope operating at an accelerating bias voltage of 100 kV.
Fluorescence microscopy images were obtained on a Nikon Ellipse E600 Epi-fluorescence
microscope.
Purification of SWNTs
In a sealed conical flask, SWNT fine powder (100 mg) was suspended in DMF (300 mL).
The mixture was sonicated for 3 h in an ultrasound bath (Model 2510, BransonTM) to break
up the bundles and separate SWNTs from the impurities. The suspension was allowed to
settle for 3 days. The supernatant was collected and then centrifuged at 5,000 rpm for 30 min.
The precipitate was removed and the supernatant was centrifuged at 8,000 rpm for 30 min.
After removal of the precipitate, the supernatant was centrifuged at 12,000 rpm for 1 h. The
precipitate was collected as purified SWNTs (~25 mg), which was used in the subsequent
studies.
Functionalization of SWNTs and Conjugation of Carbohydrates
The SWNTs were functionalized and subsequently conjugated with carbohydrates as shown
in Scheme 1. For the conventional thermal method, purified SWNTs (5.0 mg) and

PFPA-NHS (138 mg) were dispersed in DCB (5.0 mL) in a 25 mL round-bottom flask. The
mixture was sonicated for 15 min to give a visually homogenous solution, which was heated
to 130 oC for 3 days under nitrogen.
The microwave-assisted reaction was carried out as follows. In a 10 mL glass tube (Biotage
Pressurized Reaction Vials), purified SWNTs (5.0 mg) and PFPA-NHS (138 mg) were
dispersed in DCB (3.0 mL). The mixture was sonicated for 15 min, and then sealed with a
Teflon cap prior to microwave irradiation. A time series of reactions were carried out at 130
oC under microwave irradiation for 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h. In addition,
o
reactions were carried out under microwave irradiation at different temperature (130 C, 150
oC, 180 oC) for 1 h. The reaction progress was monitored by taking the IR spectra of the
reaction mixtures. After the reaction, the brown reaction mixture was centrifuged at 14,000
rpm for 30 min. The precipitate was washed sequentially with DMF and acetone (3 x 14,000
rpm, 30 min) to remove unreacted SWNTs and excess PFPA-NHS until no brown color was
observed in the solution. The precipitate was finally dried under reduced pressure to give
NHS-PFPA-functionalized SWNTs (~3.5 mg).
The modified SWNTs (3.5 mg) were mixed with Man-EG2-NH2 (2.7 mg, Scheme 1) in DMF
(3.0 mL) and stirred at RT overnight, after which the reaction mixture was centrifuged at
14,000 rpm for 30 min. The precipitate was washed with H2O (3 x) followed by acetone
(14,000 rpm, 30 min), and the precipitate was dried under reduced pressure to give
Man-SWNTs (~2.6 mg). Gal-conjugated SWNTs was prepared using the same procedure to
give Gal-SWNTs (~2.6 mg). Samples for TEM imaging were prepared by dropping an
ethanol solution containing the SWNTs sample (10 µL) onto a 200 mesh copper grid, and
dried the sample in air.

Binding of Glyco-SWNTs with Lectin
FITC-Con A was used to evaluate the binding affinity and selectivity of the
carbohydrate-functionalized SWNTs. Man-SWNTs or Gal-SWNTs (1.0 mg) were incubated
in a solution of BSA (3%) in pH 7.2 HEPES buffer (1.0 mL, 10 mM) for 30 min, and
subsequently centrifuged. The precipitate was then incubated in a fresh pH 7.2 HEPES buffer
for another 20 min and centrifuged. The resulting Man-SWNTs or Gal-SWNTs were
subsequently treated with a solution of FITC-Con A in HEPES buffer (2.0 mL, 10 µg/mL)
containing MnCl2 (1.0 mM) and CaCl2 (1.0 mM) under ambient condition for 1 h while
shaking. The mixture was centrifuged to separate the supernatant that contained unbound
FITC-Con A, and the precipitate was washed with fresh HEPES buffer to remove physically
adsorbed FITC-Con A from the treated nanotubes.45
Acknowledgements
The study was in part supported by the Royal Institute of Technology, the National Institutes
of Health (R01GM080295), and the National Science Foundation (CHE-1112436). N.K.
thanks the China Scholarship Council for a special scholarship award. M.S. acknowledges
support from the European Commission through the Erasmus Mundus India4EU program.
Supporting Information
Synthesis of Man-EG2-NH2 and Gal-EG2-NH2, additional Raman and characterization data.

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Carbohydrates Conjugation through Microwave-Assisted
Functionalization of Single-Walled Carbon Nanotubes Using
Perfluorophenyl Azides
Na Kong,a Manishkumar R. Shimpi,a Olof Ramström,a,* and Mingdi Yan,a, b,
*
a KTH - Royal Institute of Technology, Department of Chemistry, Teknikringen 30, S-10044
Stockholm, Sweden;
b Department of Chemistry, University of Massachusetts Lowell, 1 University Ave., Lowell,
MA 01854, United States.

Highlights
• A general and effective method to functionalize pristine SWNTs
• Microwave radiation greatly facilitated reaction kinetics
• Carbohydrate-SWNT conjugates showed good bioaffinity and binding selectivity