Intermolecular hydrogen-bond interaction to promote thermoreversible 2'-deoxyuridine-based AIE-organogels

Article abstract of DOI:10.1016/j.cclet.2020.10.008

Fluorescent supramolecular nucleoside-based organogels or hydrogels have attracted increasing attention owing to their tunable stability, drug delivery, tissue engineering, and inherent biocompatibility for applications in designing sensors. As the temper

Full text of DOI:10.1016/j.cclet.2020.10.008

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CCLET-5899; No. of Pages 4
Chinese Chemical Letters xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Intermolecular hydrogen-bond interaction to promote
thermoreversible 2'-deoxyuridine-based AIE-organogels
*
Xuan Zhao, Long Zhao, Qiuyun Xiao, Hai Xiong
Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Fluorescent supramolecular nucleoside-based organogels or hydrogels have attracted increasing
attention owing to their tunable stability, drug delivery, tissue engineering, and inherent biocompatibili-
ty for applications in designing sensors. As the temperature of a constant TPE-Octa-dU gelator at MGC as
low as 0.2 wt% was increased with gel to sol transition, a progressive decrease in the fluorescence
intensity was observed. 1H NMR study in ethanol-d6/H2O revealed the existence of intermolecular
hydrogen-bond interaction between uridine nucleobase and triazole moieties. Based on these
experiments, thus organogels induced by hydrogen bonding can promote an aggregation-induced
emission (AIE) of TPE moiety. Thermoreversible gelation properties have been investigated systemati-
cally, including AIE-shapemorphing architecture owing to their unique solid-liquid interface and easy
processability. At the same line, the related TPE-EdU derivative which was synthesized from 5-ethynyl-
2'-deoxyuridine does not deliver organogels or hydrogels, and under similar circumstances TPE moiety of
TPE-EdU does not efficiently exhibit AIE phenomenon either.
Received 30 August 2020
Received in revised form 22 September 2020
Accepted 10 October 2020
Available online xxx
Keywords:
Supramolecular
Organogel
Aggregation-induced emission
Nucleoside
Click chemistry
© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Supramolecular nucleoside-based organogels or hydrogels
formed by the self-assembly of low molecular-weight nucleoside
moieties have attracted considerable interest due to their tunable
stability and inherent biocompatibility for applications in design-
ing sensors, drug delivery or tissue engineering [1–3]. To achieve
gelation, there must be a balance between the tendency of the
small molecules to dissolve or to aggregate. The development of 2'-
deoxyuridine derivatives with hydrophobic moieties has been a
long history as low molecular-weight organogels or hydrogels
since Kim group reported [4,5]. Physicochemical studies (differ-
ential scanning calorimeter, small-angle X-ray scattering, FT-IR, CD
spectroscopies, transmission or scanning electron microscopy)
have showed spontaneous assembling of supramolecular struc-
tures including vesicles, fibers, hydrogels, and organogels [4–9].
Moreover, guanosine-quarter-based supramolecular hydrogels are
usually stabilized by K+ or other alkali metal cations. Thus, the
effect of various parameters (concentration, nature of metal ion,
and temperature) on the properties of this gel is also reported [10–
13]. Furthermore, as a smart soft material, self-healing supramo-
lecular nucleoside hydrogels with photoluminescent property
have attracted much attention in the biomedical fields (biological
imaging, drug delivery and biosensors) and in engineering research
(optical switch, pH sensors and thermal sensors) [14–16].
In 2001, Tang et al. found aggregation-induced emission (AIE) of
1-methyl-1,2,3,4,5-pentaphenylsilole in the condensed state,
which is opposite to the classic aggregation-caused quenching
(ACQ) indicating a nonemissive fluorogen in a dilute solution is
induced to emit efficiently by aggregate formation [17]. Then
onwards, the second generation AIE bearing tetraphenylethene
(TPE) derivatives with specific analyte binding have been devel-
oped and showed advantage of the AIE effect on applications as
chemical sensors, biological probes and biomedical studies [18–
25]. Further, Tang et al. reported an entire gelation process of
chitosan in LiOH-urea aqueous system can be visualized by AIE
fluorescent imaging [26].
Copper catalyzed “click” reaction has also been applied to the
functionalization of nucleoside and oligonucleotide in our previous
work [27–31]. Herein, different from Tang group’s work of amino-
yne “click” polymerization [32–34], we established a novel self-
assembly system of TPE-Octa-dU by using 5-(octa-1,7-diynyl)-2'-
deoxyuridine (Octa-dU, 1) and azido TPE (TPE-N3, 3) via the “click”
reaction (Scheme 1, Tables S1, S2 and Figs. S4-S16 in Supporting
information). The supramolecular AIE-organogels based on TPE-
Octa-dU with water-resisting are formed in 5:5 mixed ethanol/
water due to the cross-linking of their monovalent polyvalent
networks. As comparison, higher hydrophilic TPE-EdU derivativing
from 5-ethynyl-2'-deoxyuridine (EdU, 2) did not form organogels
* Corresponding author.
E-mail address: hai.xiong@szu.edu.cn (H. Xiong).
https://doi.org/10.1016/j.cclet.2020.10.008
1001-8417/© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article as: X. Zhao, L. Zhao, Q. Xiao et al., Intermolecular hydrogen-bond interaction to promote thermoreversible 2’-
deoxyuridine-based AIE-organogels, Chin. Chem. Lett., https://doi.org/10.1016/j.cclet.2020.10.008

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Scheme 1. Synthesis of TPE-Octa-dU and TPE-EdU via the copper(I)-catalyzed “click” reaction.
or hydrogels in any of the tested solvents. To the best of our
knowledge, a very few studies have reported on AIE-nucleoside
organogels of TPE moiety. The nucleoside-based organogels as a
template for the preparation of shape-controlled nanofibers or
nanomaterials will be investigated in future study, and metal ion-
mediated supramolecular hydrogels based on TPE-Octa-dU ana-
logues will also be developed in molecular luminescence or
biosensors [35,36].
The gelation ability was determined by inverted vial method
[37]. The gelation capacity was found to depend on the alkyl chain
length and the hydrophilic five-ring triazole moiety. TPE-EdU
containing shorter hydrocarbon chains (ethynyl) did not yield gels
in any of the solvents tested. The organogels can be formed rapidly
when TPE-Octa-dU bearing longer chains (octadiynyl) were
dissolved in a mixture of organic solvents by heating, and then
cooled down to room temperature. As shown in Table S3
(Supporting information), the TPE-Octa-dU dissolved in a series
of individual or mixed solvents displays quite different gelation
properties, forming the best stable organogels at minimum
gelation concentration (MGC) as low as 0.2 wt% in a 5:5 ratio of
Fig. 1. (A) Fluorescence spectra of TPE-Octa-dU with increasing (A) concentrations
and (B) temperature; sol = solution; (C) Photoluminescence spectra in the form of
solution or organogels in mixed ethanol and water. Top: Photography of samples.
Bottom: same samples under ultraviolet illumination; (D) Fluorescence imaging of
gels on PMMA plate with microporous scales.
mixed VEtOH=H O (Fig. 1). Furthermore, stable opaque organogels
2
can also be formed in 5:5 ratio of mixed VMeOH=H O or VAcetone=H O at
2
2
concentrations as low as 0.3À0.4 wt% (Fig. S1 in Supporting
information). The best organogels was found to be stable for
several months at r.t. The gelation capacity depends on the chain
length and polarity of TPE-Octa-dU and TPE-EdU. Thermorever-
sible gel-sol phase transition temperature (Tgel) was investigated
using water-bath heating. The gel-sol interconversion was found to
be thermo reversible over several cycles of heating and cooling
steps, and the organogels were stable for months at r.t. Other
common mixture organic solvents and water did not support
gelation process even at high concentrations of TPE-Octa-dU. The
promising candidates for fabricating optical materials and sensors
[38,39]. In addition to the fluorescent study, as we expected,
solutions of TPE-Octa-dU are virtually non-fluorescent, and its gel
state with various concentrations shows strong fluorescence at the
excitation of 375 nm and emission of 478 nm in appropriate ratio of
mixed VEtOH=H O (Fig. 1A). Interestingly, as the temperature of gels
2
of TPE-Octa-dU was increased from 25 ꢀC to 70 ꢀC, a progressive
decrease in the fluorescence intensity was observed (Fig. 1B). This
effect was found to be significantly reversed as hot solutions were
gradually cooled to room temperature to form gels. For compari-
son, TPE-Octa-dU in the form of solution or gelation within various
ratios of ethanol and water was photographed under the white
light and UV lamp, respectively. The samples under ultraviolet
illumination (365 nm) indicated that TPE-Octa-dU retain their
fluorescence upon AIE (Fig. 1C). The results are agreed with the
Tgel value of TPE-Octa-dU dissolved in 5:5 ratio of mixed V
EtOH=H2O
is 61 ꢀC, which is significantly higher than that observed in 5:5 ratio
of mixed VMeOH=H O (55 ꢀC) or VAcetone=H O (52 ꢀC).
2
2
Natural purine and pyrimidine nucleosides are virtually
nonfluorescent and show short excited-state decay time, while
self-assembling organic fluorophores including rigid nucleolipids
that retain or exhibit enhanced fluorescence upon aggregation are
2

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previous studies have revealed that the restriction of intramolec-
ular rotations (RIR) in the aggregates is the main cause for the AIE
process [26].
Encouraged by these exciting results, we systematically studied
this kind of TPE-Octa-dU organogels by inverted fluorescent
microscope. In this study, the extremely dilute solution of TPE-
Octa-dU with 0.2 wt% was performed to form organogels and
further treated by drying procedure. The image of the solution
showed no specific patterns. Furthermore, the gelation provides
AIE-shape morphing architecture owing to their unique solid-
liquid interface and easy process ability. The PMMA plate with
microporous scales from approximately 0.5 mm to 2.5 mm
exhibited bright blue fluorescence under ultraviolet illumination
(365 nm), which indicated this kind of organogels maintains their
characterization of soft matter and fluorescence AIE (Fig. 1D).
Further, the bright stable pattern being with reticular structure
was also observed in xerogels state by using the inverted
fluorescent microscope (Fig. S3 in Supporting information).
Further, the viscoelastic properties of organogels were studied
by performing rheological measurements. The storage modulus
(G’) and loss modulus (G’’) of TPE-Octa-dU in mixture solvents
were monitored as a function of oscillating frequency at constant
strain. The higher value of G’ than G’’ at frequencies of 1À50 Hz
Fig. 3. 1H NMR spectra of TPE-Octa-dU in EtOH-d6 containing various ratios of H2O.
indicates that Gel-1 (in VEtOH=H O = 5:5) displays a solid-like
2
To gain insight into the microstructure of organogels, scanning
electron microscopy (SEM) analysis was performed on xerogels or
lyophilized samples. TPE-Octa-dU dissolved in mixing ethanol and
water, and the effect of TPE-Octa-dU in the form of solution and
organogels or precipitation was studied. In the case of TPE-Octa-dU
dissolving in ethanol and water (v/v = 7:3, the solution state), the
aggregation cluster can be found in Fig. 4A. Decreasing the ratio of
ethanol and water (v/v = 5:5, the gel state), regular pattern with the
sheet substructures is shown in Fig. 4B. Further, aggregation
cluster will be predominated in Fig. 4C (v/v = 4:6, the precipitation
behavior in this frequency range, but it is much more liquid-like
(G’’ > G’) at a higher frequency (Fig. 2) [40]. Compared to Gel-2
(VMeOH=H O = 5:5) and Gel-3 (VAcetone=H O = 5:5), the crosslink of
2
2
storage and loss modulus of Gel-1 is much higher (400 Pa for Gel-1
at a frequency of 50 Hz, 300 Pa and 50 Hz for Gel-2, 260 Pa for Gel-3
at 45 Hz), which shows that Gel-1 is much more stable than those
of other two. The result is in agreement with those of gel-sol phase
transition temperature (Tgel).
To obtain further information on the intermolecular hydrogen
bonding interaction between uridine or triazole moieties, we
measured the 1H NMR spectra of TPE-Octa-dU in EtOH-d6
containing various amounts of H2O. With increasing H2O content,
the chemical shifts of triazole-Ha shift to high field and that of
pyrimidine-Hb is reverse (Fig. 3). Addition of 20% H2O content, a
temperature varied 1H NMR experiment was further performed to
prove the intermolecular hydrogen bonding interaction or the p-p
stacking between the triazole and the aromatic ring of TPE. With
increasing temperature from 25 ꢀC to 60 ꢀC, the intermolecular
hydrogen bonding is decreasing, and both of the chemical shifts of
triazole-Ha and pyrimidine-Hb shift to high field (Fig. S15). On the
other hand, the chemical shift of the ribose-Hc is not obvious (Fig. 3
and Fig. S15). The addition of 25% H2O content, TPE-Octa-dU
molecules self-assemble and intermolecular hydrogen bonding
interaction probably further enhances. For up to about 30% H2O
content, TPE-Octa-dU will form organogels completely, without
NMR signals.
Fig. 4. SEM images of TPE-Octa-dU xerogels at the concentration as low as 0.2 wt%.
(A) Ethanol and water (v/v = 7:3); (B) Ethanol and water (v/v = 5:5); (C) Ethanol and
water (v/v = 4:6); (D) Methanol and water (v/v = 5:5); (E) Acetone and water (v/
v = 5:5); (F) The hierarchical sponge-like structures, ethanol and water (v/v = 5:5).
Fig. 2. Evolution of G’ and G’’ of TPE-Octa-dU at the concentration as low as 0.2 wt% was monitored as a constant of strain at different oscillating frequency. (A) Gel-1,
VEtOH=H O = 5:5; (B) Gel-2, VMeOH=H 5:5; (C) Gel-3, VAcetone=H 5:5.
=
=
2 O
2O
2
3

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state). Further, the effect of the protonized solvent was explored.
Using similar methanol as mixture organic solvent, regular sheet
substructures is shown in Fig. 4D. As comparisons, using acetone as
non-protonized solvent, the mesh pattern can be founded in
Fig. 4E. The hierarchical sponge-like structures can be seen in all
cases of TPE-Octa-dU xerogels dried from Gel-1 (Fig. 4F). These
results show that interactions of TPE-Octa-dU molecule are
depends upon its solubility and the ambient protonized solvent.
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Except for the p-p stacking between the triazole and the aromatic
ring of TPE, we supposed that hydrogen-bonding interactions of
nucleoside are also dominant for driving gelation process. All
above samples were treated by drying procedure. Finally, as
showed in Fig. 4, xerogels exhibit hierarchical three-dimensional
sponge-like structures with a thickness of approximately 5 mm,
and on their surfaces there shows a regular pattern of the sheet or
mesh substructures.
To our knowledge, this work is the first example of AIE
organogels based on 2'-deoxyuridine conjugating tetraphenyle-
thene. Except for the
p-p stacking between the triazole and the
aromatic ring of TPE, hydrogen-bonding interactions of modified
nucleosides are also demonstrated to be dominant for promoting
gelation process. It directly reveals that AIE process is caused in
their gelation aggregate. This kind of nucleoside-based organogels
or its xerogels maintains their characterization of soft matter and
fluorescence AIE, which can be applied in fluorescent 2D barcode
symbols and 3D printing. Furthermore, the biocompatibility and
safety of chiral TPE-Octa-dU analogues are being investigated by
cell culture assay with potential applications in cell imaging, drug
delivery system or tissue engineering.
Declaration of competing interest
The authors report no declarations of interest.
Acknowledgment
This work is supported by the Science and Technology
Innovation
Commission
of
Shenzhen,
China
(Nos.
KQJSCX20180328095517269 and JCYJ20170818143131729).
Appendix A. Supplementary data
Supplementarymaterialrelatedto thisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2020.10.008.
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