Modification of dextran using click-chemistry approach in aqueous media

Article abstract of DOI:10.1016/j.carbpol.2010.04.025

In this paper, dextran was modified using click-chemistry. Each reaction step was done under aqueous conditions, including the introduction of azide functionalities to the backbone of the polysaccharide. The reaction consisted of the synthesis of 1-azido-2,3-epoxypropane, which was etherified onto the backbone of the polysaccharide using base-catalysis in water/isopropanol mixture at ambient temperature. The achieved degree of substitution (DS) of azide groups in dextran was up to 0.20. Alkyne-end-functionalized poly(ethylene glycol) monomethyl ether (PEG-MME) was then grafted onto the synthesized azide-functionalized dextran having a DS of 0.08 or 0.16 by copper-catalyzed azide-alkyne cycloaddition (CuAAC). In the case of the lower DS valued dextran, a quantitative reaction of the azides was achieved within an hour, whereas the CuAAC-reaction of dextran having DS = 0.16 yielded a DS = 0.10 of grafted poly(ethylene glycol). Prolonging the reaction time to 24 h did not further improve the conversion of azides, which may be due to steric factors.

Full text of DOI:10.1016/j.carbpol.2010.04.025

Carbohydrate Polymers 82 (2010) 78–82
Contents lists available at ScienceDirect
Carbohydrate Polymers
journal homepage: www.elsevier.com/locate/carbpol
Modification of dextran using click-chemistry approach
in aqueous media
Nikolaos Pahimanolis, Arja-Helena Vesterinen, Jaana Rich, Jukka Seppala∗
Polymer Technology, Department of Biotechnology and Chemical Technology, Aalto University School of Science and Technology,
P.O. Box 16100, 00076 Aalto, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
In this paper, dextran was modified using click-chemistry. Each reaction step was done under aqueous
conditions, including the introduction of azide functionalities to the backbone of the polysaccharide. The
reaction consisted of the synthesis of 1-azido-2,3-epoxypropane, which was etherified onto the backbone
of the polysaccharide using base-catalysis in water/isopropanol mixture at ambient temperature. The
achieved degree of substitution (DS) of azide groups in dextran was up to 0.20. Alkyne-end-functionalized
poly(ethylene glycol) monomethyl ether (PEG-MME) was then grafted onto the synthesized azide-
functionalized dextran having a DS of 0.08 or 0.16 by copper-catalyzed azide–alkyne cycloaddition
(CuAAC). In the case of the lower DS valued dextran, a quantitative reaction of the azides was achieved
within an hour, whereas the CuAAC-reaction of dextran having DS = 0.16 yielded a DS = 0.10 of grafted
poly(ethylene glycol). Prolonging the reaction time to 24 h did not further improve the conversion of
azides, which may be due to steric factors.
Received 19 February 2010
Received in revised form 26 March 2010
Accepted 13 April 2010
Available online 20 April 2010
Keywords:
Biopolymers
Click-chemistry
Functionalization of polysaccharides
Modification
Polyethers
Polysaccharides
© 2010 Elsevier Ltd. All rights reserved.
1. Introduction
been reported in several publications (Bernard, Save, Arathoon,
& Charleux, 2008; De Geest et al., 2008a, 2008b; Hafrén, Zou, &
There is a growing interest towards renewable raw materials,
such as polysaccharides, which with a slight chemical modification
could be used in many applications. Due to their non-toxicity, bio-
compatibility and biodegradability, the applications may vary from
paper quality enhancement chemicals (Maurer & Kearney, 1998)
to more sophisticated applications such as gene-therapy vectors
(Rinaudo, 2008).
In order to elegantly tailor the properties of natural-based
polymers, “click”-chemistry offers a straightforward and efficient
way to avoid multiple reaction and purification steps (Kolb, Finn,
& Sharpless, 2001). Moreover, click-chemistry concepts, such as
ambient reaction temperatures and high tolerance towards oxy-
gen and water, conveniently match with the chemical needs for
the modification of these natural polymers.
Córdova, 2006; Hasegawa et al., 2006; Liebert, Hänsch, & Heinze,
2006; Schatz, Louguet, Le Meins, & Lecommandoux, 2009; Tankam,
Müller, Mischnick, & Hopf, 2007) However, a major challenge in the
exploitation of CuAAC in the modification of polysaccharides is the
difficulty of introducing the azide or alkyne functionalities neces-
sary for the subsequent CuAAC-reaction. In most cases, dry reaction
conditions and solvents, such as dimethyl sulfoxide (DMSO) or
dimethyl formamide (DMF), have to be used in order to introduce
the required azide or alkyne groups. This is not necessarily suit-
able for all polysaccharides and in some occasions it would be more
convenient to use water as a solvent in every modification reaction.
In this paper, synthesis of dextran-g-poly(ethylene glycol)
was done using CuAAC. The azide functionalities needed for
the reaction were introduced by the etherification of 1-azido-
2,3-epoxypropane onto the backbone of the polysaccharide in
water/isopropanol mixture using different NaOH concentrations
and temperatures. The introduced azides where further used in
the grafting of alkyne-end-functionalized poly(ethylene glycol)
monomethyl ether (PEG-MME). In this way, aqueous reaction
media and ambient temperatures could be used, avoiding tedious
drying or solvent-exchange steps and solubility problems often
encountered when working with polysaccharides. The obtained
dextran derivatives were characterized by 1H, 13C NMR, DEPT-135
and Fourier transform infrared (FT-IR) spectroscopies as well as
with dynamic light scattering (DLS) studies.
The most referred “click”-reaction employed in polymer syn-
thesis is the copper-catalyzed azide–alkyne cycloaddition (CuAAC)
which offers various possibilities to tailor polymer properties
(Binder
& Sachsenhofer, 2007, 2008; Fournier, Hoogenboom,
& Schubert, 2007; Meldal, 2008; Rostovtsev, Green, Fokin, &
Sharpless, 2002; Tornoe, Christensen, & Meldal, 2002). The uti-
lization of CuAAC on the modification of polysaccharides has
∗
Corresponding author. Tel.: +358 9 47022614; fax: +358 9 47022622.
E-mail address: jukka.seppala@tkk.fi (J. Seppala).
0144-8617/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carbpol.2010.04.025

N. Pahimanolis et al. / Carbohydrate Polymers 82 (2010) 78–82
79
Table 1
The effect of added NaOH on the obtained degree of substitution (DS) in the etherification reaction of dextran with 1-azido-2,3-epoxypropane.
Entrya
Added NaOH (mmol)
pH
DS theoretical
DS observedb
Conversion of epoxidec (%)
Reaction efficiency (%)
A
B
C
D
E
F
5
4
3
2
1
0
13
13
13
13
12
11
1.34
1.34
1.34
1.34
1.34
1.34
0.13
0.13
0.17
0.15
0.12
0.00
100
100
100
100
88
10
10
13
11
9
60
0
a
Reaction time 21 h at 30 ◦C. 7.9 ml (3.2 mmol) of 1-azido-2,3-epoxypropane solution, 0.388 g of dextran (2.39 mmol of sugar-units) in 20 ml of H2O.
b
c
Calculated based on 13C NMR analysis.
Calculated based on 1H NMR analysis.
reaction mixture was stirred for 21 h at 30 ◦C, until 1H NMR anal-
ysis showed complete consumption of the epoxide. The solution
was then neutralized with acetic acid and the polysaccharide was
purified twice by precipitation to 150 ml of ethanol. The white pre-
cipitate was collected and dried overnight at 40 ◦C under vacuum.
13C NMR (D2O): ı = 97.96, 73.72, 71.60, 70.47, 69.82, 65.66 (dex-
tran C–O), 72.21, 69.62 (C–O), 53.42 (C–N3).
2. Materials and methods
2.1. Materials
Dextran (average molecular weight 60,000 g/mol) and HNO3
(65%) were obtained from Fluka Chemicals and used as received.
Poly(ethylene glycol) monomethyl ether (molecular weight
500 g/mol) was from Fluka Chemicals and it was dried overnight
at 30 ◦C under vacuum prior to use. Propargyl bromide (80 wt% in
toluene), l-ascorbic acid (99%), CuSO4·5H2O (99%), epichlorohydrin
(99%) and NaNO2 (97%) were purchased from Sigma–Aldrich and
used as received. NaN3 (99%), acetic acid (100%) and NaOH (99%)
were purchased from Merck and used as received.
FT-IR: (KBr): ꢀ = 3378 (OH), 2927 (CH), 2108 (N3).
2.4. Preparation of alkyne-end-functionalized poly(ethylene
glycol)
Dried poly(ethylene glycol) monomethyl ether (PEG-MME)
(5.00 g, 10.0 mmol) was dissolved in 10 ml of THF, previously dried
with molecular sieves. NaH (0.300 g, 12.5 mmol) was added to the
solution and the mixture was stirred at 30 ◦C under argon for 10 min
until the formation of hydrogen gas ceased. Propargyl bromide
(1.4 ml, 12.6 mmol) was then added dropwise and the reaction was
continued for 2 h at 30 ◦C, after which isopropanol (0.5 ml) was
added. The reaction mixture was centrifuged to remove any formed
salts and then poured to cold (0 ◦C) hexane. The precipitated pale
brown polymer was collected, dissolved in THF, precipitated again
in cold hexane and dried overnight in vacuum at 40 ◦C. The achieved
alkyne-functionalization was approximately 90% based on 1H and
13C NMR analyses, the yield being 85%.
2.2. Preparation of 1-azido-2,3-epoxypropane
The synthesis of 1-azido-2,3-epoxypropane was done starting
from epichlorohydrin. The ring-opening reaction of the epoxide
with azide-ion was done according to a slightly modified method
(Fringuelli, Piermatti, Pizzo, & Vaccaro, 1999). Isopropanol (16.6 ml)
and acetic acid (1.1 ml, 19.2 mmol) were mixed with a solution
of NaN3 (11.2 ml, 19.1 mmol) in water. Epichlorohydrin (1.0 ml,
12.8 mmol) was then added under stirring and the reaction was
continued at 30 ◦C for 21 h, until 1H and 13C NMR analyses showed
complete consumption of the epoxide. A water solution of NaNO2
(1.8 ml, 6.5 mmol) was then added, followed by the dropwise addi-
tion of HNO3 (0.9 ml, 13.0 mmol) to eliminate any excess azide-ions.
The obtained solution of 1-azido-3-chloropropanol (yield 100% by
1H and 13C NMR analyses) was stored in dark at room temperature
and used without further purification.
1H NMR (d6-DMSO): ı = 4.20–4.10 (propargyl CH2), 3.80–3.10
(PEG-MME).
13C NMR (d6-DMSO): ı = 80.31, 77.03 and 57.49 (propargyl
ether), 71.3, 69.60 and 68.52 (PEG), 58.05 (methyl ether).
1H NMR (D2O, ppm): ı = 3.36–3.54 (CH2–Cl), 3.56–3.73
(CH2–N3).
2.5. Grafting of PEG onto dextran using CuAAC
13C NMR (D2O, ppm): ı = 70.50 (C–OH), 53.92 (C–N3), 46.69
(C–Cl).
The azidated dextran (Table 2, entry O, 0.916 g, DS = 0.08,
0.19 mmol of azide functionalities) and excess of the alkyne-end-
functionalized PEG (0.172 g, 0.31 mmol) were dissolved in 8 ml
of water. A freshly prepared solution of CuSO4·5H2O (0.008 g,
0.031 mmol) and ascorbic acid (AAc) (0.011 g, 0.062 mmol) in 2 ml
of water was added and the reaction was carried out for 1 h at 30 ◦C.
The product was precipitated to 150 ml of ethanol, redissolved in
water, precipitated in ethanol two more times and dried overnight
at 40 ◦C.
The conversion of 1-azido-3-chloropropanol to 1-azido-2,3-
epoxypropane was done just prior to use, by adding 1 ml of 5 M
NaOH to every 7.9 ml of the prepared 1-azido-3-chloropropanol-
solution and stirring the mixture for 5 min, until the pH dropped
from approximately 14–12. The obtained epoxide-solution (yield
100% by 1H and 13C NMR analyses) was immediately used for the
azidation of dextran.
1H NMR (D2O): ı = 2.77–2.87 and 2.89–2.99 (CH2O), 3.21–3.42
(CH2–N3), 3.67–3.81 (CHO).
1H NMR (D2O): ı = 8.73–8.36 (triazole), 5.33–5.15 and 4.35–3.70
(dextran), 4.02–3.92 (PEG-MME).
13C NMR (D2O): ı = 52.41 (C–N3), 52.11 (CHO), 46.15 (CH2O).
13C NMR (D2O): ı = 144.21, 126.37 (triazole), 98.09, 73.78, 71.76,
70.58, 70.03, 66.07 (dextran ether), 71.35, 69.91, 58.44 (PEG-MME).
2.3. Azidation of dextran using 1-azido-2,3-epoxypropane
2.6. Characterization
The introduction of azide groups onto the backbone of dex-
tran was done as follows (Table 1, entry C): to a water solution
of dextran (0.388 g, 2.4 mmol of sugar-units), 0.60 ml of 5 M NaOH
solution was added under stirring, the total amount of water being
20 ml. 7.9 ml (3.2 mmol) of freshly prepared solution of 1-azido-
2,3-epoxypropane was then added. The obtained colorless clear
1H, 13C NMR and DEPT-135 spectra were recorded on a Varian
Gemini 2000 300 MHz spectrometer in deuterium oxide (D2O) or
deuterated dimethyl sulfoxide (d6-DMSO). A pulse width of 13.1 ␮s
(90◦), relaxation delay of 10 s and acquisition time of 3 s was used
for 1H NMR. For quantitative 13C NMR, a 90◦ pulse width of 18.0 ␮s

80
N. Pahimanolis et al. / Carbohydrate Polymers 82 (2010) 78–82
Table 2
The effect of reaction conditions on the obtained degree of substitution (DS) in the etherification of dextran with 1-azido-2,3-epoxypropane.
Entrya
Temp. (◦C)
AEP (mmol)
Dextran (g)
Sugar-units (mmol)
DS theoretical
DS observedb
Reaction efficiencyc (%)
C
G
H
I
J
K
L
M
N
O
P
30d
30d
30d
55e
70e
70e
55e
70e
55e
55e
55e
55e
3.2
6.4
6.4
3.2
3.2
3.2
6.4
6.4
3.2
3.2
6.4
9.6
0.388
0.388
1.038
0.388
0.388
1.038
1.038
1.038
1.038
2.076
2.076
2.076
2.4
2.4
6.4
2.4
2.4
6.4
6.4
6.4
6.4
1.34
2.67
1.00
1.34
1.34
0.50
1.00
1.00
0.50
0.25
0.50
0.75
0.17
0.16
0.20
0.10
0.12
0.07
0.17
0.16
0.07
0.08
0.13
0.19
14
6
20
8
9
14
17
16
14
32
26
25
12.8
12.8
12.8
Q
a
3 mmol of added NaOH in 20 ml of H2O, pH = 13.
Calculated based on 13C NMR analysis.
b
c
100% conversion of the epoxide based on 1H NMR analysis.
Reaction time 21 h.
d
e
Reaction time 4.5 h.
was used, the relaxation delay and acquisition time being 6 s and
1.8 s. 5000 scans were accumulated for each sample, and the decou-
pler was gated on only during acquisition, in order to suppress
the nuclear Overhauser effect. DEPT-135 analysis was performed
using 140 Hz average JCH bond coupling. The infrared-spectra were
obtained with Nicolet Magna IR750 from KBr-pellets. Dynamic
light scattering measurements were done using Zetasizer Nano ZS
(Malvern Instruments). The samples were prepared to concentra-
tions of 1 mg/ml and filtered through 0.45 ␮m filter.
at different time points from the reaction mixture. A growing peak
at 2110 cm−1, belonging to the azide group indicates that the reac-
tion is taking place. In addition, 13C NMR and DEPT-135 analyses of
the reaction product (Fig. 2) show C–O peaks from the substituents
at 72 and 69 ppm and a C–N3 peak at around 53 ppm. In these con-
ditions however, long reaction times of at least 21 h have to be used
in order to achieve complete consumption of the epoxide and the
reaction efficiency is rather low, ranging from only 9–13%.
Raising the reaction temperature from 30 ◦C to 55 ◦C or 70 ◦C
slightly lowers the reaction efficiency (Table 2), but speeds up the
reaction, consuming all of the epoxide within 4.5 h. Using higher
concentrations of dextran give reaction efficiencies up to 30%, as
more dextran hydroxyl groups become available for the etherifi-
cation, but since the initial ratio of epoxide to dextran is lower,
the obtained DS values are also lower. Adding more epoxide-
solution gives respectively slightly higher DS values, but again,
lowers the reaction efficiency. Noteworthy though that these reac-
tions are not fully comparable, since the total volume of the reaction
mixture is not equal. The epoxide-solution, which could not be
concentrated or purified for safety reasons, contains isopropanol
3. Results and discussion
3.1. Introduction of azide functionalities to the backbone of
dextran
The introduction of azide groups was done by the reaction of 1-
azido-2,3-epoxypropane with dextran under alkaline conditions, a
method similar to which is commonly employed for the hydrox-
ypropylation of polysaccharides, e.g. starch, using epoxypropane
(Tomasik & Schilling, 2004). In this way, azide groups necessary
for the subsequent CuAAC-reaction were introduced in a relatively
simply way, without solvent-exchange or drying steps involved in
the synthesis. Dextran was used in all reactions due to its relatively
simple structure and good water solubility.
The preparation of 1-azido-2,3-epoxypropane was done in two
steps starting with the ring-opening of epichlorohydrin with azide-
ion in the presence of acetic acid, giving 1-azido-3-chloropropanol,
which in turn was converted to the epoxide-form with alka-
line treatment in high yield (Fringuelli et al., 1999). Due to the
known fact that low-molecular weight organic azides are poten-
tially explosive substances, there were no attempts to purify or
concentrate the obtained 1-azido-2,3-epoxypropane solution, but
it was used directly for further reactions.
Table 1 shows the effect of the amount of added NaOH to the
obtained degree of substitution (DS) for the azide groups in dextran.
As expected, the azidation does not occur when no additional NaOH
is used, since the amount of NaOH from the preparation of 1-azido-
2,3-epoxypropane alone is insufficient to elevate the pH value. In
this case, there is not enough reactive alkoxides formed on the
backbone of the polysaccharide that can undergo the ring-opening
of the epoxide. Adding sodium hydroxide raises the pH, allowing
the azidation to take place, and a maximum value of DS = 0.17 is
observed when 3 mmol of NaOH is added. Adding more base low-
ers the obtained DS, probably due to the increasing proportion of
the competitive reaction, that is, the direct addition of hydroxide
Fig. 1. FT-IR spectra of samples taken at different time points from the etheri-
fication reaction of dextran with 1-azido-2,3-epoxypropane (Table 1, entry C). A
growing peak 2110 cm−1 indicates that azide groups are introduced to the backbone
of dextran.
ion to the epoxide giving a diol, a compound observed by 1H and 13
NMR analyses. Fig. 1 shows typical FT-IR spectra of samples taken
C

N. Pahimanolis et al. / Carbohydrate Polymers 82 (2010) 78–82
81
Fig. 3. FT-IR spectra of dextran containing azide groups used as starting mate-
rial (A) DS = 0.08 and (C) DS = 0.16. (B) and (D) the obtained grafted products
after the copper-catalyzed azide–alkyne cycloaddition reaction with alkyne-end-
functionalized poly(ethylene glycol).
Fig. 2. DEPT-135 and 13C NMR analyses (in D2O) of the product obtained from the
etherification reaction of dextran with 1-azido-2,3-epoxypropane (Table 1, entry C).
to ensure solubility of the epoxide. The solution also contains
sodium acetate, NaCl and NaNO3 salts from the preparation of
1-azido-2,3-epoxypropane, which may have some effect on the
reaction outcome. The obtained DS values are similar to those
observed with hydroxypropylation of starch in aqueous alkaline
conditions (Tuschhoff, 1986). Higher azide functionalization has
been reported with dextran using the tosylation approach in dry
reaction conditions (Heinze, Michealis, & Hornig, 2007), however
the etherification method is a simple one step synthesis and very
useful when aqueous media is preferred.
3.2. Grafting of alkyne-end-functionalized PEG-MME to dextran
Two synthesized azido-dextrans of DS = 0.16 and DS = 0.08
(Table 2, entries G and O) were used to prepare dextran-g-
poly(ethylene glycol). This was done by grafting alkyne-end-
functionalized PEG-MME to the backbone of the polysaccharide
utilizing copper-catalyzed azide–alkyne cycloaddition. The dextran
with lower DS value (DS = 0.08) reacted quantitatively within 1 h,
which can be seen from FT-IR-analysis, where the azide peak at
2110 cm−1 has disappeared (Fig. 3A and B). In addition, both 1H
and 13C NMR spectra (Fig. 4) show peaks characteristic to both dex-
tran and PEG, as well as signals at 8.4–8.7 ppm (1H NMR), 144.21
and 126.37 ppm (13C NMR) indicating the presence of triazole-rings
formed in the CuAAC-reaction.
In the case of the dextran of higher azide content (DS = 0.16), the
FT-IR spectrum of a sample taken from the reaction mixture after
1 h (Fig. 3C and D) shows that the azide functionalities are con-
sumed in the reaction, since the peak at 2110 cm−1 belonging to
Fig. 4. 1H and 13C NMR spectra (D2O) of the obtained dextran-g-poly(ethylene gly-
col), DS = 0.08.

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N. Pahimanolis et al. / Carbohydrate Polymers 82 (2010) 78–82
polysaccharide concentration, efficiencies up to 32% were achieved.
The introduced azide functionalities could successfully be used
for the grafting of alkyne-end-functionalized poly(ethylene glycol)
monomethyl ether by CuAAC, yielding dextran-g-poly(ethylene
glycol) of DS = 0.10 within 1 h of reaction. The presented combi-
nation of both traditional epoxide reactions and the more recently
discovered copper-catalyzed azide–alkyne cycloaddition (CuAAC)
allows aqueous reaction media to be used throughout the synthe-
sis, making it convenient for the modification of polysaccharides
for various applications.
Acknowledgement
This work has been funded by the Finnish Funding Agency for
Technology and Innovation (TEKES).
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Fig. 5. Particle size distribution analyzed by dynamic light scattering of (A) dex-
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1 h of reaction and (C) dextran-g-poly(ethylene glycol) after 24 h of reaction. The
prolonged reaction time of 24 h may have resulted in degradation of the polymer.
azide has reduced. However, the proportional amounts of PEG and
dextran units calculated from 1H and 13C NMR analyses correspond
to a DS of 0.10, suggesting that a considerable amount (38%) of unre-
acted azide groups remains in the material, which can also be seen
from FT-IR-analysis. Prolonging the reaction time to 24 h has no
effect on the conversion, regardless of the excess of the alkyne func-
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the polysaccharide backbone (Lallana, Fernandez-Megia, & Riguera,
2009) and/or poly(ethylene glycol) grafts, since dynamic light scat-
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4. Conclusions
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