Trimerization of β-cyclodextrin through the click reaction

Article abstract of DOI:10.1016/j.carbpol.2013.02.074

Triprop-2-ynyl benzene-1,3,5-tricarboxylate (A) is synthesized by the reaction of 1,3,5-benzenetricarbonyl trichloride with propargyl alcohol and (A) is clicked with mono-6-deoxy-6-azido-β-cyclodextrin (N₃-β- CD) in the presence of copper(I) bromide catalyst. N₃-β-CD has been prepared from β-cyclodextrin (β-CD) on treatment with toluenesulfonyl chloride (TsCl) and then with sodium azide (NaN₃) in two consecutive steps. Further trimer of β-CD is characterized by ¹H NMR and FTIR studies. Solubility of β-cyclodextrin (β-CD) in water can be increased by increasing the number of alcoholic OH functionalities and hydrophobic cavities in a molecule by the trimerization of β-CD.

Full text of DOI:10.1016/j.carbpol.2013.02.074

Carbohydrate Polymers 95 (2013) 295–298
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Carbohydrate Polymers
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Short communication
Trimerization of ␤-cyclodextrin through the click reaction
Kranthikumar Tungala, P. Adhikary, S. Krishnamoorthi∗
Department of Chemistry, Banaras Hindu University, Varanasi 221005, U.P., India
a r t i c l e i n f o
a b s t r a c t
Article history:
Triprop-2-ynyl benzene-1,3,5-tricarboxylate (A) is synthesized by the reaction of 1,3,5-
benzenetricarbonyl trichloride with propargyl alcohol and (A) is clicked with mono-6-deoxy-6-
azido-␤-cyclodextrin (N3–␤-CD) in the presence of copper(I) bromide catalyst. N3–␤-CD has been
prepared from ␤-cyclodextrin (␤-CD) on treatment with toluenesulfonyl chloride (TsCl) and then with
sodium azide (NaN3) in two consecutive steps. Further trimer of ␤-CD is characterized by 1H NMR and
FTIR studies. Solubility of ␤-cyclodextrin (␤-CD) in water can be increased by increasing the number of
alcoholic OH functionalities and hydrophobic cavities in a molecule by the trimerization of ␤-CD.
© 2013 Elsevier Ltd. All rights reserved.
Received 14 December 2012
Received in revised form 7 February 2013
Accepted 28 February 2013
Available online xxx
Keywords:
Click reaction
Triprop-2-ynyl
benzene-1,3,5-tricarboxylate
Trimer of ␤-cyclodextrin
1. Introduction
et al., 2010). We have clicked triprop-2-ynyl benzene-1,3,5-
tricarboxylate (A) with N3–␤-CD to synthesize ␤-CD trimer, having
Cyclodextrins are able to form host–guest complexes with
hydrophobic molecules because of the unique nature imparted
by their structure, therefore, these molecules have found num-
ber of applications in various fields (Nasir et al., 2012) like drug
delivery and pharmaceutical industry due to their complexation
ability and other versatile characteristics. One of the most com-
mon pharmaceutical applications of cyclodextrin is to enhance the
solubility, safety, stability and bioavailability of drug molecules
(Rasheed et al., 2008). ␤-CD, one of the cyclodextrins, is a cyclic
oligosaccharide consisting of 7-D (+)-glucopyranose units, with 7-
primary and 14-secondary alcoholic OH functional groups and
can accommodate various guest molecules into its truncated cone-
shaped hydrophobic cavity (Szejtli, 1998). Recently many works
have been done based on ␤-CD star copolymers by using different
techniques like ATRP (Gou et al., 2010; Storsberg et al., 2000) and
RAFT (Kollisch et al., 2006). In those techniques, the alcoholic OH
functionalities are the active parts. There are few papers, in which
dimerization of ␤-CD has been achieved through different linkages
like sulfur linkage (Tang et al., 2005), terephthalic acid bridge (Ohga
et al., 2005), ethylene diamine link (Tang et al., 2006), etc. and thus
they have improved the solubility of ␤-CD.
18-primary, 21-secondary alcoholic OH functional groups and 3-
truncated cone-shaped hydrophobic cavities in one molecule to
obtain better solubility in water.
2. Experimental
2.1. Materials
1,3,5-Benzenetricarbonyltrichloride (98%, Aldrich), propargyl
alcohol (Avra, Hyderabad), p-toluenesulfonyl chloride (TsCl)
(Spectrochem, Mumbai), sodium azide (NaN3) (99.5%, SDFCL,
Mubai), N,N,Nꢀ,Nꢀꢀ,Nꢀꢀ-pentamethyldiethylenetriamine (PMDETA)
(99%, Aldich), tetrahydrofuran (THF) (≥99%, MERCK, Mum-
bai), dichloromethane (DCM) (≥99%, MERCK), sodium hydrox-
ide (NaOH) (≥97%, MERCK, Mumbai) hydrogen chloride (HCl)
(35–38%, MERCK, Mumbai), acetone (SDFCL, Mumbai) and N,N-
dimethylformamide (DMF) (99.5%, SDFCL, Mumbai) were used as
received. ␤-Cyclodextrin hydrate (␤-CD) (Aldrich) and copper(I)
bromide (CuBr) (98% HIMEDIA, Mumbai) were purified and the
used.
In this paper, we have reported the synthesis of ␤-CD trimer
by the utilization of click reaction (Huan et al., 2012; Nielsen
2.2. Synthesis of triprop-2-ynyl benzene-1,3,5-tricarboxylate (A)
Propargyl alcohol (3.2 mL, 55 mmol) and triethylamine (697 ␮L,
5 mmol) were dispersed in 20 mL of THF in a 100 mL round bottom
flask. The mixture was cooled to 0 ◦C in an ice-water bath. 1,3,5-
Benzenetricarbonyl trichloride (982 ␮L, 5.5 mmol) was dissolved in
15 mL of THF and was introduced into the reaction mixture slowly
over a period of 30 min. Further the mixture was stirred at 0 ◦C for
∗
Corresponding author. Tel.: +91 5426702483.
E-mail addresses: kranthibhu@gmail.com (K. Tungala), dr.pubali@gmail.com
(P. Adhikary), dr.skmoorthi@gmail.com, dr.skmoorthi@rediffmail.com
(S. Krishnamoorthi).
0144-8617/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carbpol.2013.02.074

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K. Tungala et al. / Carbohydrate Polymers 95 (2013) 295–298
1 h and then at 40 ◦C for 18 h. White precipitate obtained was then
filtered out and filtrate was collected. The solvent was evaporated
from the filtrate, under vacuum. The product obtained was redis-
solved in dichloromethane and then washed with 10% HCl, aqueous
NaHCO3 and finally twice with distilled water. Dichloromethane
was subsequently removed by rotary evaporation and the crude
product was purified by column chromatography (Chen et al.,
2009). Yield 1.37 g, 75%.
then concentrated to half of its volume and cooled to room temper-
ature. Acetone (200 mL) was added to precipitate. Obtained white
solid was redissolved in water (10 mL) and reprecipitated in ace-
tone (200 mL). This process was repeated one more time. The white
solid was dried under vacuum at 60 ◦C for 2 days (Muderawan et al.,
2005). Yield 2.2 g, 96%.
2.5. Click reaction of (N3–ˇ-CD) with triprop-2-ynyl
benzene-1,3,5-tricarboxylate (D)
2.3. Synthesis of mono-6-deoxy-6-(p-tolylsulfonyl)-
Triprop-2-ynyl
benzene-1,3,5-tricarboxylate
(0.162 g,
ˇ-cyclodextrin (TsO–ˇ-CD) (B)
0.5 mmol), N3–␤-CD (1.762 g 1.5 mmol) and PMDETA (0.209 mL,
1 mmol) were dissolved in DMF(20 mL). CuBr (0.143 g, 1 mmol)
was introduced under the protection of nitrogen (N2) gas flow.
The reaction mixture was degassed by three freeze–pump–thraw
cycles, placed in an oil bath thermostated at 60 ◦C and stirred for
3 days (Huan et al., 2012). The reaction mixture was exposed to
air and evaporated to half of its volume. Then the mixture was
precipitated in excess of acetone and the precipitate was washed
several times with acetone. The crude product was dissolved in
water and passed through a basic alumina column to remove CuBr.
Further the mixture was precipitated by ethanol and the product
was washed with ether to get a white solid. Yield 1.25 g, 65%.
␤-Cyclodextrin hydrate (12.5 g, 11 mmol) was dissolved in
a solution which was prepared by dissolving 6.25 g of sodium
hydroxide in 375 mL of water in 1 L round bottom flask. The mix-
ture was cooled to 0–5 ◦C and stirred at same temperature in an
ice-water bath while p-toluenesulfonyl chloride (5 g, 26.25 mmol)
was being added in small portions. The reaction mixture was stirred
vigorously for 2 h at 0–5 ◦C and then p-toluenesulfonyl chloride
(7.5 g, 39.25 mmol) was added in small portions and the mixture
was stirred at 0–5 ◦C temperature for 3 h further. The reaction mix-
ture was filtered to separate unreacted tosyl chloride. Filtrate was
cooled at 0–5 ◦C while 10% aqueous hydrochloric acid (87.5 mL) was
being added. Resulting solution was stored for 8 h in a refrigerator
at 0 ◦C, and then filtered. The product was dried to constant weight
in a vacuum oven to yield a white solid of TsO–␤-CD. Further the
white solid was recrystallized three times by dissolving it in 40 mL
of boiling water and then cooling to room temperature (Brady et al.,
2000, 2004; Lovrinovic & Niemeyer, 2007). Yield 3.97 g, 28%.
3. Results and discussion
The above synthesized compounds A, B, C and D were confirmed
by 1H NMR and FTIR spectroscopies which are given in Figs. 1 and 2
respectively. Trimerization of ␤-CD was done by the click reaction
of triprop-2-ynyl benzene-1,3,5-tricarboxylate (A) with N3–␤-CD
(C). The detailed synthetic route for preparation of ␤-CD trimer is
shown in Scheme 1.
2.4. Synthesis of mono-6-deoxy-6-azido-ˇ-cyclodextrin
(N3–ˇ-CD) (C)
Compound (A): In 1H NMR, clear characteristic alkynyl sig-
A mixture of mono-6-deoxy-(p-tolylsulfonyl)-␤-cyclodextrin
(2.5 g, 2.0 mmol) and sodium azide (1.95 g, 30 mmol) in water
(10 mL) was stirred at 80 ◦C for 3 days. The resulting solution was
nal is present at 2.55 ppm. The integration ratio of
(ı = 2.56 ppm), phenyl protons (ı = 8.93 ppm) and CH2
(ı = 4.99–4.98 ppm) was calculated to be 1:1:2, indicating the
C
C
CH
C
Fig. 1. 1H NMR spectrum of purified compounds (A), (B), (C) and (D) (from top to bottom). Spectra were recorded at room temperature in CDCl3 and DMSO as shown above.

K. Tungala et al. / Carbohydrate Polymers 95 (2013) 295–298
297
formation of the desired product (A). FTIR has the characteristics
bands of
H stretching at 3288 cm−1, aromatic C H stretching
at 3008 cm−1 stretching at 2124 cm−1, C O stretching
at1732 cm−1, aromatic C C stretching at 1444 cm−1 and C
stretching at 1230 cm−1
C
,
C C
O
.
Compound (B): In 1H NMR, characteristic peaks of toluene-
sulfonyl group appeared at ı = 7.76 ppm (d), ı = 7.44 ppm (d) and
ı = 2.42 ppm (s). The integration ratio of aromatic protons, CH3
protons of toluenesulfonyl group and ␤-CD primary OH protons
was found to be 2:2:3:6 which confirmed that only one ␤-CD
primary OH group was involved in reaction with TsCl and the
remaining 6 OH groups remained as such. In FTIR, along with ␤-CD
signals, toluenesulfonyl group characteristic bands were present as
aromaticC Cstretchingat1599 cm−1, S Ostretchingat1366 cm−1
and S
O .
Ar stretching at 836 cm−1
Compound (C): In 1H NMR peaks of toluenesulfonyl group
had disappeared, two CH2 N3 protons signal was shifted to
ı = 1.64 ppm (s) and remaining CH2 protons of ␤-CD were present
at ı = 3.62–3.53 (m) along with all other proton signals of ␤-CD at
their respective positions, which confirmed the formation of com-
pound (C). Further it was confirmed by IR stretching frequency of
N3 at 2120 cm−1 and the absence of toluenesulfonyl group signals.
Compound (D): In 1H NMR, signals of aromatic protons at
ı = 8.53 ppm (s),
C H proton of triazole ring at ı = 7.92 ppm (s)
and CH2 ␤-CD proton signals at ı = 5.98 ppm along with other
C
␤-CD proton peaks were present and there was no signal of(C H at
ı = 2.56 ppm, which confirms all 3 alkyne groups were involved in
click reaction and formed triazole rings. Thus 1H NMR study con-
firms the formation of ␤-CD trimer. In FTIR, signals for aromatic
Fig. 2. FTIR spectrum of purified compounds (A), (B), (C) and (D). Spectra were
recorded at room temperature in KBr pellet.
C
C stretching were present at 1568 cm−1, N N stretching of tri-
azole ring at 2046 cm−1, C O stretching at 1709 cm−1, H2C
O C
stretching at 1156 cm−1 and N3 characteristic peak disappeared.
This confirms the formation of ␤-CD trimer.
It was observed that, ␤-CD gets soluble in water at higher tem-
perature (40–70 ◦C) where as ␤-CD trimer is readily soluble in
water, even at 1 ◦C. Solubility of ␤-CD in water is 18.5 mg/mL where
as solubility of ␤-CD trimer is 580 mg/mL at room temperature.
Thus trimerization of ␤-CD helped to increase the solubility.
4. Conclusions
Trimerization of ␤-CD was done successfully through click reac-
tion. Further ␤-CD trimer was characterized and showed better
solubility in water, even at room temperature. As ␤-CD trimer
is having 18-primary and 42-secondary alcoholic OH functional
groups and 3-cone-shaped hydrophobic cavities it can show much
better applications, than ␤-CD, in various fields.
Acknowledgement
The authors are grateful to UGC & DST, New Delhi, India, for the
financial support.
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