Synthesis and study of N-acetyl d-glucosamine triazole derivatives as effective low molecular weight gelators

Article abstract of DOI:10.1016/j.tetlet.2015.02.123

Sugar based low molecular weight gelators have many potential uses for the formation of advanced soft materials. Here we have synthesized a series of peracetylated d-glucosamine triazole derivatives via the Cu catalyzed azide/alkyne cycloaddition reaction (CuAAc) and studied their self-assembling properties in several organic solvents, aqueous solutions, and water. Among the sixteen compounds synthesized and studied, many were able to function as organogelators for multiple solvents. Also seven compounds were able to form hydrogels at low concentrations such as 0.2-1.0 wt %. These indicate that peracetylated d-glucosamine triazole analogs are effective small molecular gelators.

Full text of DOI:10.1016/j.tetlet.2015.02.123

Accepted Manuscript
Synthesis and study of N-acetyl D-glucosamine triazole derivatives as effective
low molecular weight gelators
Hari P.R. Mangunuru, Jayasudhan Reddy Yerabolou, Guijun Wang
PII:
S0040-4039(15)00416-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.123
TETL 45993
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 December 2014
20 February 2015
24 February 2015
Please cite this article as: Mangunuru, H.P.R., Yerabolou, J.R., Wang, G., Synthesis and study of N-acetyl D-
glucosamine triazole derivatives as effective low molecular weight gelators, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.02.123
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Synthesis and study of N-acetyl D-glucosamine triazole derivatives as effective
low molecular weight gelators
Hari P. R. Mangunuru, Jayasudhan Reddy Yerabolou, Guijun Wang*
*Corresponding Author:
Guijun Wang
PhD, Professor
Department of Chemistry and Biochemistry
Old Dominion University
4541 Hampton Boulevard
Norfolk, VA 23529-0126
Email: g1wang@odu.edu
Telephone: (757) 683-3781
Fax: (757) 683-4628
1

Graphical Abstract:
2

Abstract:
Sugar based low molecular weight gelators have many potential uses for the formation of
advanced soft materials. Here we have synthesized a series of peracetylated D-glucosamine
triazole derivatives via the Cu catalyzed azide/alkyne cycloaddition reaction (CuAAc) and
studied their self-assembling properties in several organic solvents, aqueous solutions, and water.
Among the sixteen compounds synthesized and studied, many were able to function as
organogelators for multiple solvents. Also seven compounds were able to form hydrogels at low
concentrations such as 0.2-1.0 wt%. These indicate that peracetylated D-glucosamine triazole
analogs are effective small molecular gelators.
Keywords: Hydrogelator, glucosamine, triazoles, self-assembly, organogels
3

Introduction
Low molecular weight gelators (LMWGs) or molecular gelators are an interesting class of
compounds that are able to form reversible gels in organic solvents or aqueous solutions.1-4
Because gelation by LMWGs occurs mainly through non-covalent interactions, it may be
possible to design certain chemical structures in which the non-covalent forces can lead to
effective gelation of certain solvents. Intermolecular interactions, such as π-π stacking, hydrogen
bonding, and hydrophobic interactions can be modulated to obtain effective supramolecular
structures that are able to entrap solvent molecules. The supramolecular gels formed by LMWGs
especially hydrogels are interesting soft materials which may be utilized in many biomedical
applications such as tissue engineering scaffolds and drug delivery vehicles.5-10 Therefore a great
deal of effort has been devoted to finding new types of LMWGs and understanding the structure
influences leading to gel formation.11-30
Among the many classes of compounds have been found to be able to gelate water or organic
solvents, carbohydrate based systems are especially interesting since they can lead to
biocompatible materials.24-30 In recent years, the Cu (I) catalyzed azide/alkyne cycloaddition
reaction (CuAAc), the click reaction, has found important applications in many research areas
such as in drug discovery, chemical biology, and materials chemistry.31-36 The formation of
triazole by click chemistry has been used extensively in synthesizing glycoconjuates and
glycomemitics.32-33 The triazole ring can participate in π-π interactions and hydrogen bonding
which may enhance or induce gelation. Many triazole containing compounds have been
synthesized and studied over the past few decades, and several triazole based low molecular
weight gelators have been reported.30, 34-36 But, there is no systematic study on the gelation
4

properties of N-acetyl glucosamine derived triazole compounds yet. Previously, we have studied
the functionalization of 4,6-benzylidene acetal protected monosaccharides and obtained effective
sugar based LMWGs.25-28 We found that for D-glucose and D-glucosamine analogs with similar
functionalizations, the glucosamine analogs are more effective in the gelation of a variety of
polar solvents and water. Recently we have shown that peracetyled D-glucosyl triazoles are
effective LMWGs for alcohols and aqueous mixtures of organic solvents, however they are not
very effective for water alone.29 In this research, we synthesized a series of peracetylated
glucosamine triazole analogues using the CuAAc click reaction, and analyzed their gelation
properties in several organic solvents and aqueous mixtures.
Results and Discussions
As shown in Scheme 1, coupling of the peracetylated glucosamine azide 1 with various alkynes,
a library of triazole derivatives can be obtained readily. The selection of the alkyne functional
groups is based on their polarity and many of them are analogs to the glucose derivatives. We
synthesized glucosamine triazol derivatives 4-19, which include the typical functional groups
such as amino (4), hydroxyl (5-10), aryl (12-13), and alkyl groups (14-16) by coupling with the
corresponding monoalkyne. Compounds 5 and 12 have been reported as O-GlcNAcase
inhibitors.33b,c The dimeric compounds 17-19 with four to six methylene linkers were synthesized
using dialkyne starting materials. These compounds were then tested for their gelation properties
in several solvents. The results are shown in Table 1.
5

Scheme 1. Synthesis of D-glucosamine triazole derivatives by the CuAAC ‘click’ reaction.
From Table 1, we can see that a majority of the compounds were able to form gels in at least one
of the tested solvents. The compounds with less polar substituents tend to be more effective
gelators. At 20 mg/mL, all of the compounds were insoluble in hexane. Four compounds were
able to gelate toluene, the short chain alcohol derivatives 8 and 9, the acid 11, and aryl analog 12.
A majority of the compounds were soluble in ethanol and isopropanol, only two compounds
6

were able to form gels in the tested alcohols. The dimer 17 formed a gel in isopropanol and the
long alkyl chain derivative 16 formed a gel in ethanol. Though they are not effective gelators for
pure alcohols, we were pleased to find that many of the compounds were efficient gelators for
aqueous mixtures of ethanol or DMSO, and seven compounds were also effective hydrogelators.
The compounds with short chain amino group 4 and alcohols 5-7 are soluble in all tested
solvents at 20 mg/mL. But with increasing methylene groups in the molecule, they become
effective gelators. Compounds 8 and 9 were able to form transparent gels in toluene at 0.2 wt%
and 0.17 wt%, respectively. The long alkyl alcohol 10 is an effective gelator for water and
DMSO water mixture, while the long fatty acid derivative 11 is a versatile gelator for organic
solvents, aqueous ethanol and DMSO, and water. The compounds containing nonpolar long alkyl
chain (14-16) or aryl groups (12-13) are effective gelators for polar solvents and water as well.
When R group contains non-polar functional groups such as in 12-16, typically the products are
able to form gels in the aqueous mixtures. The dimeric analogs with longer spacers are more
effective towards the gelation of these solvents. For instance, compound 19 was much more
efficient in comparison to compound 17 with shorter spacer. In comparison to the analogues
from the D-glucose series, the D-glucosamine derivatives are much more efficient as
hydrogelators.
7

Table 1. Gelation test results for the library compounds in several solvents.
Compoun Hexane Toluene i-PrOH EtOH EtOH:H2O
EtOH:
DMSO:
DMSO: H2O
d
4
(1:1)
H2O (1:2)
H2O (1:1) H2O (1:2)
I
I
I
I
I
I
I
I
I
I
I
I
I
S
S
S
S
S
S
S
P
S
S
S
S
S
P
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
5
S
S
S
S
6
S
S
S
S
S
7
G 2.0
S
S
S
S
8
G 1.7
S
S
S
S
9
I
S
P
P
P
G 4.0 G 2.8
G 20.0 G 4.0
10
11
12
13
14
15
16
G 2.8
S
G 10.0
P
G 10.0
G 6.7
G 2.8
G 6.6
G 6.6
G 5.0
S
G 5.0
P
G 10.0
G 10.0
G 2.2
G 2.0
G 2.5
G 2.2
P
S
S
S
I
S
G 2.5
G 3.3
G 2.2
G 5.0
G 2.2 G 2.2
G 1.9 G 2.0
G 1.7 G 10.0
S
S
G 10.0
G 3.3
P
P
I
I
I
S
I
G 20.0
P
P
S
P
P
P
17
18
PG 20.0
PG 20.0
PG 20.0
G 10.0 G 10.0
G 10.0 G 5.0
I
I
PG 20.0 PG 20.0 PG 20.0
PG 20.0
G 10.0
19
G, gel at room temperature, the numbers are the corresponding minimum gelation concentrations
(MGCs) in mg/mL; PG, partial gel or unstable gel; I, insoluble; C, crystallize or precipitate; S,
soluble at ~20 mg/mL.
8

The morphologies of several gels were then studied using optical microscope. Fig. 1 shows the
optical micrographs of the gels formed by compounds 10, 13, 14, and 15. These images are taken
while the gels still contain solvents. As a general feature, these various gelators formed self-
assembled fibrous networks. Compound 10 formed a translucent gel in water at 2.8 mg/mL, the
morphology (Fig. 1a) shows continuous fibrous assemblies. The phenyl derivative 13 formed a
translucent gel in ethanol water mixture, the assemblies are composed of many long, curvy, thin
and uniform fibrous networks (Fig. 1b). The hydrogel formed by compound 14 also exhibits self-
assembled fibrous features and the fibers or tubules have larger diameters (Fig. 1c, d); the
compound 14 formed gel in ethanol water mixture and showed uniform fibers or tubules, these
fibers appeared to have similar widths and are less branched (Fig. 1e), and lastly the hydrogel
formed by compound 15 showed thin fibrous assemblies, and some fibers seem to merge to form
thicker cylindrical tubules (Fig. 1f).
9

Fig. 1 Optical micrographs of the gels formed by several compounds: a) compound 10 in H2O
2.8 mg/mL; b) compound 13 in EtOH/H2O (1:2) at 2.8 mg/mL; c-d) compound 14 in H2O at 2.0
mg/mL; e) compound 14 in in EtOH/H2O (1:2) at 6.6 mg/mL; f) compound 15 in EtOH/H2O
(1:2) at 2.0 mg/mL.
We also studied the dynamic rheology properties for three compoungs. In Fig. 2 the dynamic
moduli G′ and G′′ are shown as a function of angular frequency ω at their minimum gelation
concentrations for compounds 10, 13 and 15. As shown in Fig. 2, the storage modulus G′ is
greater than the Loss modulus G′′ for all these compounds. The fact that G' is greater than G'' is
10

an indication that the gels are elastic semisolid.
Fig. 2. Rheological properties of the gels formed by compounds 10 (H2O, 2.8 mg/mL), 13 (H2O,
2.2 mg/mL) and 15 (DMSO: H2O, 1:1, 2.0 mg/mL) at their minimum gelation concentration.
Conclusions
In summary, we have synthesized a series of N-acetyl glucosamine based triazole derivatives and
studied their self-assembling properties. Among the analogues studied, we found that the
compounds containing long aliphatic spacers are generally effective low molecular weight
gelators. More importantly, seven efficient hydrogleators have also been obtained; many of them
were able to form hydrogels at concentrations lower than 1.0 wt%. These results indicate that
peracetylated D-glucosamine triazole analogs are very effective small molecular gelators. The
glucosamine based hydrogels may find potential applications in biomedicine and as advanced
materials.
11

Acknowledgement
We are grateful for financial support by a grant from NSF CHE 1153129 and Old Dominion
University.
Supplementary data
Electronic Supplementary Information (ESI) available: The 1H and 13C characterization data of
compounds 4-19 are provided.
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