Thixotropic stiff hydrogels from a new class of oleoyl-d-glucamine-based low-molecular-weight gelators

Article abstract of DOI:10.1039/c7ra07244a

A series of new compounds comprising oleoyl, amino acid and d-glucamine moieties were synthesised using mild reaction conditions, and their hydrogelation ability was evaluated. The gels exhibited improved stiffness and thixotropic properties dependent on the chemical structure of the amino acid linker and the number of potential hydrogen bonding sites.

Full text of DOI:10.1039/c7ra07244a

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Thixotropic stiff hydrogels from a new class of
oleoyl-D-glucamine-based low-molecular-weight
gelators†
Cite this: RSC Adv., 2017, 7, 41686
Yutaka Ohsedo, *abc Masashi Oono, Kowichiro Saruhashi, Hisayuki Watanabe
and Nobuyoshi Miyamoto
d
d
cd
a
Received 30th June 2017
Accepted 22nd August 2017
A series of new compounds comprising oleoyl, amino acid and D-glucamine moieties were synthesised
using mild reaction conditions, and their hydrogelation ability was evaluated. The gels exhibited
improved stiffness and thixotropic properties dependent on the chemical structure of the amino acid
linker and the number of potential hydrogen bonding sites.
DOI: 10.1039/c7ra07244a
rsc.li/rsc-advances
N-alkylaldonamides tend to crystallise in aqueous solution,
unless a surfactant is added to the hydrogel system.
Introduction
9
Low-molecular-weight gelators (LMWGs) have received much
Recently, we reported that the onset of thixotropic behaviour
attention owing to their ability to be tuned by chemical in molecular organogels can be induced simply by mixing two
synthesis to form so matter (i.e. molecular gels) with desired alkyl-chain substituted homologues of commercially available
1,2
12a,b
12c,e,h
12d
12f,g
properties. In the last two decades, there have been numerous hydrazides,
amides,
ureas and hydrogelators
such
attempts to synthesise molecular gels comprising LMWGs and as N-alkyl-D-glucamides. Although mixing induced thixotropy is
13,14
organic (organogel) or aqueous (hydrogel) media for so matter observed in other systems,
newer gelators that form func-
applications in elds such as medical science and optoelec- tional gels are needed to promote the study of molecular gels.
3
,4
tronics.
Therefore, LMWGs that form stimuli-responsive
In this study, we evaluate the potential of a new class of
5
molecular gels have been extensively studied. To improve the D-glucamine derivatives for their hydrogelation abilities. Our
mechanical properties of gels, the relationship between thixo- design of the hydrogelator constitutes three structural motifs:
tropic behaviour, i.e. mechanically reversible sol-to-gel transi- a D-glucamine moiety (head), an amino acid (linker), and an
6
tions, and their network structure has been extensively studied.
oleoyl moiety (tail). The three moieties are linked by two amide
In particular, thixotropic behaviour is required for injectable bonds (OG-G, OG2-G, OG3-G, and OA-G, Scheme 1). We
and ointment-type gels for biomaterials in medical consider that the oleoyl group, which is more hydrophobic than
3
applications.
a stearoyl group and the long alkyl chain present in surfactants,
For the creation of molecular hydrogels, bre micelle and
hydrogel formation of N-alkylaldonamides such as n-octyl- and
7
n-dodecyl-D-glucamides was extensively studied. These mole-
cules, which can be obtained by simple amidation, are efficient
hydrogelators. Several widely studied derivatives of N-alky-
laldonamides exhibit unique nano- and micro-metre scale
7–11
architectures such as tubular micelles.
The original
a
Department of Life, Environment and Materials Science, Fukuoka Institute of
Technology, 3-30-1, Wajiro-Higashi, Higashi-ku, Fukuoka 811-0295, Japan. E-mail:
josedo@bene.t.ac.jp; Fax: +81 92-606-3977; Tel: +81 92-606-3977
b
Comprehensive Research Organization, Fukuoka Institute of Technology, 3-30-1,
Wajiro-Higashi, Higashi-ku, Fukuoka 811-0295, Japan
c
Global Innovation Center, Kyushu University, 6-1 Kasuga-koen Kasuga-city, Fukuoka
8
16-8580, Japan
d
Nissan Chemical Industries, Ltd., 2-10-1 Tsuboinishi, Funabashi, Chiba 274-8507,
Japan
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c7ra07244a
1
Scheme 1 Chemical structures of oleoyl-D-gluconamide derivatives.
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can facilitate gelation of water owing to its increased hydro-
Thermal analysis was performed with an EXSTAR6000
15
phobicity relative to linear alkyl chains. Furthermore, the differential scanning calorimeter DSC (Seiko Instruments Inc.)
covalent amide bond linking the components can provide better using an Ag-made closable sample pan. Tgel / sol and Tsol /
chemical stability than the corresponding esters moieties gel of gels were determined as extrapolated onset temperatures
present in other gelators. Finally, the hydrogen bonding ability from the DSC curves.
of the molecules can be chemically tuned by introducing
SEM images were recorded with a SU-8000 scanning electron
glycine(s) or its homologue as the linker between the oleoyl and microscope (Hitachi High-Technologies Corporation) at 1.0 kV;
D-glucamine groups.
the SEM sample was vacuum dried and placed on a conductive
tape on the SEM sample stage. Pt, as a conductive material, was
used as a coating on the sample (Pt coating is 10 nm thick). The
xerogel for SEM sample was obtained from freeze-drying of the
hydrogel at the concentration of critical gelation concentration
by using dry ice/acetone as a refrigerant.
Experimental
Materials and methods
b-Alanine (99%), D-glucamine (95%), glycine (99%), glycylgly-
cine (99%), glycylglycylglycine (98%) and 1-hydroxybenzo-
triazole monohydrate (HOBt, 97%) were purchased from Tokyo
Chemical Industry Co., Ltd. and used without further purica-
tion. All organic solvents, buffer aqueous solutions, 1-ethyl-3-(3-
Rheological measurements of frequency sweep were per-
formed with an MCR-301 rheometer (Anton Paar Japan K.K.)
with a parallel plate (8 mm diameter) at a gap of 0.50 mm and g
of 0.01% (measurement temperature: 25 C). Rheological
measurements of strain sweep were performed with an MCR-
ꢂ
dimethylaminopropyl)carbodiimide
soluble carbodiimide (WSC)), hydrochloric acid, oleoyl chloride
97%) and sodium hydroxide were purchased from Wako Pure
hydrochloride
(water
3
01 rheometer with a parallel plate (8 mm diameter) at a gap
ꢁ1
of 0.50 mm and constant angular frequency 1 rad s
(
ꢂ
(measurement temperature: 25 C). For rheological measure-
Chemical Industries, Ltd. and used without further purica-
tion. Water was deionised with an Elix UV 3 Milli-Q integral
water purication system (Nihon Millipore K.K.). Phosphate
buffered saline (1ꢀ PBS (ꢁ)) was obtained by diluting 10ꢀ PBS
ments, the hydrogel sample was applied onto the parallel plate
and sample stage (the overow gel was swept). The hydrogel
sample for rheological measurements was placed on a parallel
plate and a sample stage (the overow gel was swept). Step-
shear measurement was carried out by applying normal strain
(
ꢁ) buffer (Wako Pure Chemical Industries, Ltd.) with water.
1 13
H-NMR and C-NMR spectra were acquired using an
(
(
strain amplitude 0.01% and frequency 1 Hz) and large strain
shear rate 3000 s for 0.1 s), repeatedly.
AVANCE 500 (500 MHz, Bruker BioSpin K.K.) spectrometer.
Mass spectra were recorded on an LTQ Orbitrap spectrometer
ꢁ1
X-ray diffraction data were recorded on a D8 Discover X-ray
(ESI FTMS, Thermo Fisher Scientic K.K.) or a 3100 Mass
ꢂ
diffractometer (Bruker AXS K.K.) with CuKa at 26 C (the
sample was lled in a quartz glass capillary tube of 1 mm
diameter).
detector equipped with e2695 Separations module and an s2489
UV/Visible detector (Nihon Waters K.K.). Elemental analysis was
performed with a JM10 elemental analyzer (J-SCIENCE LAB CO.,
Ltd.).
Infrared spectroscopy was performed with an FT/IR-620
(JASCO Corporation) using the ATR method (ZnSe prism).
The gelation tests were performed using the vial inversion
method. A crystal of gelator was placed in a vial with a solvent at
a set concentration (wt%) and capped. The vial was heated in
Synthesis of OG-G, OG2-G, OG3-G and OA-G
ꢂ
a dry bath of 100 C until the crystal of gelator was dissolved.
Synthesis of oleoyl amino acid derivatives (general synthesis
Gelator solution was le for 1 h at room temperature, and 1, Scheme 2). Oleoyl amino acids were synthesized following the
1
5,16
gelation was checked with naked eyes by inverting the vial.
reported method.
Oleoyl chloride (13.29 mmol) in absolute
atmosphere over
The thixotropic behaviour was evaluated using the vial THF (20 mL) was added slowly under N
2
inversion method. The hydrogel in vial was shaken and a 30 min period, with a dropping funnel, in an aqueous NaOH
collapsed by a vortex genie (Scientic Industries, Inc). Then the (2 M) solution (40 mL) of amino acid (19.94 mmol), which was
obtained sol was le for the set time at room temperature, the immersed in ice bath. The solution, along with the generated
recovery of the gel state from the sol state was checked with white precipitate, was stirred in an ice bath for an additional
naked eyes by inverting the vial.
hour, and then at rt for 12 h. Subsequently, water (10 mL) was
Scheme 2 Synthesis of oleoyl amino acid derivatives.
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Scheme 3 Coupling of oleoyl amino acids with D-glucamine.
added to dissolve the precipitate, and then aq. HCl (3 M, 20 mL) 0.86 (t, 3H J ¼ 6.9 Hz). LC-MS (ESI): calcd for C21
3
H39NO , 353.29;
ꢁ
was added to reduce the pH of the solution to <2. The generated found m/z ¼ 352.2 [M ꢁ H] .
white precipitate was ltered, rinsed with water, and subse-
OG-G. OG-G (white crystals) was synthesized in 71.4% yield
quently dried in vacuo. The dried precipitate was recrystallised by coupling OG with D-glucamine following the protocol
1
from MeOH to yield the oleoyl amino acids.
described in general synthesis 2. H-NMR (500 MHz, DMSO-d ,
6
Coupling of oleoyl amino acids with D-glucamine (general TMS, d, ppm): 8.00 (t, 1H, J ¼ 5.7 Hz), 7.70 (t, 1H, J ¼ 5.5 Hz),
synthesis 2, Scheme 3). The synthesis of OG-G is described here 5.31 (t, 2H, J ¼ 5.5 Hz), 4.78 (d, 1H, J ¼ 4.7 Hz), 4.50 (d, 1H, J ¼
as an example. The synthesis of other gelators followed a similar 5.7 Hz), 4.40 (d, 1H, J ¼ 6.3 Hz), 4.37 (t, 1H, J ¼ 5.4 Hz), 4.31 (d,
protocol. Both D-glucamine and water-soluble carbodiimide 1H, J ¼ 6.6 Hz), 3.71 (m, 2H, J ¼ 5.7 Hz), 3.59 (m, 3H), 3.49 (m,
(
5.26 mmol each) were added under an atmosphere of N
2
to the 1H), 3.38 (m, 2H), 3.27 (m, 1H), 3.04 (m, 1H), 2.11 (d, 2H, J ¼
solution of oleoyl amino acid, OG (4.78 mmol) and 1-hydroxy- 7.6 Hz), 1.97 (m, 4H), 1.53 (m, 2H), 1.24 (m, 20H), 0.85 (t, 3H, J ¼
1
3
benzotriazole monohydrate (5.26 mmol) in absolute DMF 6.6 Hz). C-NMR (125 MHz, DMSO-d , TMS, d, ppm): 173.38,
6
ꢂ
(
(
20 mL) at 0 C. The solution was stirred in an ice bath for 1 h 170.10, 130.43, 130.38, 72.82, 72.44, 70.68, 64.21, 42.94, 42.85,
the solution became opaque), and then at rt for 12 h (the 36.08, 32.16, 30.06, 30.00, 29.73, 29.63 (4C), 29.56, 29.49, 27.52,
50 2 7
opaque solution became gel-like). DMF was removed in vacuo 27.46, 26.01, 22.96, 14.72. LC-MS (ESI): calcd for C26H N O ,
+
and the white residue was recrystallised twice in MeOH to yield 502.36; found m/z ¼ 503.37 [M + H] . Elemental anal. calcd (%)
OG-G (yield 71.4%, white crystal). for C26 : C, 62.12; H, 10.03; N, 5.57. Found: C, 62.07; H,
OG. OG (white crystals) was prepared from oleoyl chloride 10.01; N, 5.52.
and glycine (G) according to general synthesis 1 in 76.5% yield. OG2-G. OG2-G (white crystals) was synthesized in 81.9%
50 2 7
H N O
1
H-NMR (500 MHz, DMSO-d , TMS, d, ppm): 8.11 (t, 1H, J ¼ yield by coupling OG2 with D-glucamine following the protocol
6
1
5
2
3
.8 Hz), 5.33 (t, 2H, J ¼ 4.7 Hz), 3.72 (d, 2H, J ¼ 6.0 Hz), 2.10 (m, described in general synthesis 2. H-NMR (500 MHz, DMSO-d ,
6
H, J ¼ 7.4 Hz), 1.99 (m, 4H), 1.50 (m, 2H), 1.27 (m, 20H), 0.86 (t, TMS, d, ppm): 8.08 (m, 2H), 7.71 (s (br), 1H), 5.32 (t, 2H, J ¼
H J ¼ 6.8 Hz). LC-MS (ESI): calcd for C22
H38NO
3
, 339.28; found 5.4 Hz), 4.78 (s (br), 1H), 4.50 (d, 1H, J ¼ 5.4 Hz), 4.40 (d, 1H, J ¼
6.0 Hz), 4.34 (t, 1H, J ¼ 5.0 Hz), 4.29 (d, 1H, J ¼ 6.0 Hz), 3.70
ꢁ
m/z ¼ 338.2 [M ꢁ H] .
OG2. OG2 (white crystals) was prepared from oleoyl chloride (m, 4H, J ¼ 3.5 Hz), 3.59 (m, 3H), 3.49 (m, 1H), 3.42 (m, 2H), 3.29
and glycylglycine (G2) according to general synthesis 1 in 63.0% (m, 1H), 3.06 (m, 1H), 2.15 (d, 2H, J ¼ 7.6 Hz), 1.92 (m, 4H), 1.54
1
13
yield. H-NMR (500 MHz, DMSO-d
6
, TMS, d, ppm): 8.14 (t, 1H, (m, 2H), 1.25 (m, 20H), 0.86 (t, 3H, J ¼ 6.6 Hz). C-NMR (125
J ¼ 5.7 Hz), 8.05 (t, 1H, J ¼ 5.8 Hz), 5.33 (t, 2H, J ¼ 5.2 Hz), 3.75 MHz, DMSO-d , TMS, d, ppm): 173.3, 169.82, 169.36, 130.07,
6
(
5
d, 2H, J ¼ 6.0 Hz), 3.73 (d, 2H, J ¼ 6.0 Hz), 3.70 (d, 2H, J ¼ 130.04, 72.43, 72.05, 70.20, 63.79, 42.62, 42.54, 35.65 (2C), 31.75,
.7 Hz), 2.12 (t, 2H, J ¼ 7.4 Hz), 1.99 (m, 4H), 1.51 (m, 2H), 1.25 29.63, 29.57, 29.53, 29.31, 29.20 (3C), 29.14, 29.06, 27.10, 27.05,
(
C
m, 20H), 0.86 (t, 3H, J ¼ 6.8 Hz). LC-MS (ESI): calcd for 25.57, 22.54, 14.36. LC-MS (ESI): calcd for C28
H
53
N
3
O
8
, 559.38;
found m/z ¼ 560.39 [M + H] . Elemental anal. calcd (%) for
: C, 60.08; H, 9.54; N, 7.51. Found: C, 59.78; H, 9.48;
ꢁ
+
22
H
40
N
2
O
4
, 396.30; found m/z ¼ found 395.2 [M ꢁ H] .
OG3. OG3 (white crystals) was prepared from oleoyl chloride
28 53 3 8
C H N O
and glycylglycylglycine (G3) according to general synthesis 1 in N, 7.41.
1
3
7.8% yield. H-NMR (500 MHz, DMSO-d
6
, TMS, d, ppm): 8.20
OG3-G. OG3-G (white crystals) was synthesized in 69.5%
(
5
5
t, 1H, J ¼ 6.0 Hz), 8.13 (t, 1H, J ¼ 5.7 Hz), 8.07 (t, 1H, J ¼ 5.7 Hz), yield by coupling OG3 with D-glucamine following the protocol
1
.33 (t, 2H, J ¼ 5.2 Hz), 3.75 (d, 2H, J ¼ 5.7 Hz), 3.71 (d, 2H, J ¼ described in general synthesis 2. H-NMR (500 MHz, DMSO-d ,
6
.7 Hz), 2.12 (t, 2H, J ¼ 7.4 Hz), 1.48 (m, 2H) 1.25 (m, 20H), 0.86 TMS, d, ppm): 8.13 (t, 1H, J ¼ 5.7 Hz), 8.10 (t, 1H, J ¼ 5.7 Hz),
(
t, 3H, J ¼ 6.9 Hz). LC-MS (ESI): calcd for C23
H
41
N
3
O
5
, 439.30; 8.02 (t, 1H, J ¼ 5.7 Hz), 7.70 (t, 1H, J ¼ 5.4 Hz), 5.33 (t, 2H, J ¼
5.7 Hz), 4.77 (d, 1H, J ¼ 4.4 Hz), 4.50 (d, 1H, J ¼ 5.4 Hz), 4.41 (d,
ꢁ
found m/z ¼ 438.3 [M ꢁ H] .
OA. OA (white crystals) was prepared from oleoyl chloride 1H, J ¼ 6.0 Hz), 4.36 (t, 1H, J ¼ 5.4 Hz), 4.29 (d, 1H, J ¼ 6.6 Hz),
and b-alanine (A) according to general synthesis 1 in 67.5% 3.72 (td, 6H, J ¼ 9.9 Hz, J ¼ 5.6 Hz), 3.59 (m, 3H), 3.48 (m, 1H),
1
yield. H-NMR (500 MHz, DMSO-d
6
, TMS, d, ppm): 7.86 (t, 1H, 3.42 (m, 2H), 3.29 (m, 1H), 3.06 (m, 1H), 2.16 (d, 2H, J ¼ 7.3 Hz),
J ¼ 5.4 Hz), 5.33 (t, 2H, J ¼ 4.7 Hz), 3.21 (q, 2H, J ¼ 6.6 Hz), 2.35 1.95 (m, 4H), 1.52 (m, 2H), 1.24 (m, 20H), 0.86 (t, 3H, J ¼ 6.9 Hz).
1
3
(
m, 2H, J ¼ 6.9 Hz), 2.00 (m, 4H), 1.51 (m, 2H), 1.24 (m, 20H),
C-NMR (125 MHz, DMSO-d , TMS, d, ppm): 173.19, 170.13,
6
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1
(
2
69.55, 169.31, 130.08, 130.05, 72.43, 72.02, 70.21, 63.79, 42.54 biological studies. In Table 1, OG-G showed hydrogelation,
2C), 35.64 (3C), 31.74, 29.62, 29.57, 29.52, 29.30, 29.20 (3C), except with aq. NaCl and PBS, and OA-G formed a hydrogel in
9.13, 29.06, 27.10, 27.05, 25.57, 22.54, 14.37. LC-MS (ESI): calcd deionised water and carbonate buffer. The CGCs in buffer
+
for C H N O , 616.40; found m/z ¼ 617.4 [M + H] . Elemental solutions become higher than those in deionised water.
3
0
56 4 9
anal. calcd (%) for C30
H
56
N
4
O
9
: C, 58.42; H, 9.15; N, 9.08. Furthermore, in higher salt concentrations (1 M NaCl), the
Found: C, 58.56; H, 9.18; N, 8.99.
CGCs become higher than those in buffer solutions; the pres-
OA-G. OA-G (white crystals) was synthesized in 72.5% yield ence of salt and acid or base may change the polarity of aqueous
by coupling OA with D-glucamine following the protocol solutions, making hydrogelation difficult by disturbing inter-
1
described in general synthesis 2. H-NMR (500 MHz, DMSO-d
6
,
molecular hydrogen bonding between gelators. Although
TMS, d, ppm): 7.81 (m, 1H), 7.70 (m, 1H), 5.33 (t, 2H, J ¼ 5.0 Hz), hydrogelation in deionised water and buffered solutions occurs
4
4
1
7
6
1
3
2
.74 (s (br), 1H), 4.47 (d, 1H, J ¼ 5.0 Hz), 4.37 (d, 1H, J ¼ 5.7 Hz), at moderate CGCs for all gelators, the gel is maintained for over
.33 (s (br), 1H), 4.22 (d, 1H, J ¼ 6.3 Hz), 3.57 (m, 3H), 3.49 (m, 6 months without onset of crystallisation. N-alkyl-D-glucamines,
H), 3.40 (m, 2H), 3.22 (m, 3H), 3.05 (m, 1H), 2.24 (d, 2H, J ¼ compounds where the polar head is directly connected to the
.1 Hz), 2.00 (m, 6H), 1.48 (m, 2H), 1.27 (m, 20H), 0.86 (t, 3H, J ¼ alkyl tail (i.e. in the absence of an amino acid linker), demon-
1
3
6
.6 Hz). C-NMR (125 MHz, DMSO-d , TMS, d, ppm): 172.95, strate poor gel stability in the absence of a surfactant. Therefore,
71.59, 130.48, 130.47, 73.01, 72.61, 72.41, 70.45, 64.23, 42.87, the better gel stability observed in this study is attributed to the
6.40, 36.24, 36.19, 32.14, 30.02, 29.97, 29.92, 29.70, 29.57, presence of the peptide moiety in these molecules. In addition,
9.54, 29.46, 29.44, 27.49, 27.45, 26.13, 22.94, 14.77. LC-MS it is thought that the balance of hydrogen bonding (involving
(
ESI): calcd for C H N O , 516.38; found m/z ¼ 517.37 [M + the peptide moieties) and hydrophobicity of gelators play an
2
7
52 2 7
+
H] . Elemental anal. calcd (%) for C H N O : C, 62.76; H, important role in hydrogelation. The better CGC observed in the
2
7
52 2 7
1
0.14; N, 5.42. Found: C, 62.72; H, 10.11; N, 5.47.
case of OG2-G and OG3-G may be the result of a higher number
of hydrogen bonding sites when compared OG-G and OA-G
Moreover, the changes in the CGC with the introduction of
a single methylene group (OA-G has one more methylene unit
than OG-G) show that an appropriate chemical structure can
enhance the gelation properties in this family of LMWGs (OA-G
hydrogels showed inferior CGCs due to increased hydropho-
bicity in this system). Additionally, the CGC of OG-G hydrogels
Results and discussion
Molecules containing glycine (OG-G, OG2-G, and OG3-G) and
b-alanine (OA-G) as the linkers are synthesised by condensation
of N-glucamine with alkyloylamino acid in DMF under mild
conditions. Aer DMF is removed in vacuo, recrystallisation
affords the pure compound. Note that column chromatography
is unnecessary for the purication. Elemental analysis and
comparison with the predicted values further conrmed the
purity. The alkyloylamino acids used in the above condensation
are synthesised from the appropriate amino acid and the alky-
15
are superior to those of SG-G (strearoylamido-D-glucamine),
likely due to the increased hydrophobic interactions of the
oleoyl group.
The rheometric results (Fig. 2) show the existence of a gel
17
state, similar to that observed in polymer gels. Because of an
increase in the applied stress, the relationship between storage
16
loyl chloride in aqueous NaOH.
0
17
00
0
0
modulus, G , and the loss modulus, G , changed relative to G >
The hydrogelation ability of these new compounds are
examined at various pH values and in the presence of salts to
obtain the critical gelation concentration (CGC) (Fig. 1, S1, S2,
ESI† and Table 1). These newly synthesised compounds, OG2-G
and OG3-G, can gelate water in a pH range from 2 to 10, as well
as in the presence of a high concentration of NaCl (1 M) and
phosphate buffered saline (PBS), which is generally used in
0
0
G systems. In the frequency sweep, a pseudo plateau with G >
0
0
G
(gel state) is observed. On comparing the response of the
hydrogels to applied shear stress, stable values with a modulus
4
5
of a higher magnitude (10 to 10 Pa) was observed compared to
the SG-G analogue with the same number of alkyl carbons
(stearoyl group). The only exception was for the weak hydrogels
formed with OA-G, likely caused by unbalanced hydrophobicity
resulting in a weaker gel bre or network. In the stiffness of
hydrogels, OG-G and OG3-G showed similar stiffness; OG2-G
Table 1 Critical gelation concentrations (CGCs) of hydrogelators
Solvent
OG-G
OG2-G
OG3-G
OA-G
SG-G
d
d
d
e
e
Deionised water
Oxalate buffer
3.0
2.0
2.0
3.0
3.0
a
d
d
d
d
g
4.0
3.0
3.0
5.0f
5.0
b
d
d
d
g
Phosphate bufferc
4.0
3.0
3.0
5.0
5.0
d
d
d
d
g
Carbonate buffer
4.0f
3.0
3.0
5.0f
5.0
d
d
f
1
M NaCl aq.
5.0f
5.0
4.0
4.0
5.0f
5.0
5.0
i
d
h
f
PBS(ꢁ)
a
3.0
3.0
5.0
b
c
d
e
f
pH ¼ 1.68. pH ¼ 6.86. pH ¼ 10.11. Turbid gel. Clear gel. Crystal
g
h
i
Fig. 1 Evaluation of hydrogelation in deionised water: (a) OG-G, (b) gel. Partial gel. Opaque gel. PBS: phosphate buffered saline. The
OG2-G, (c) OG3-G, and (d) OA-G.
CGC values are expressed as wt%.
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Fig.
3
Thixotropic behaviour of hydrogel formed with OG3-G
(2.0 wt%).
example, re-gelation of a shaken OG3-G (2.0 wt%) hydrogel is
clearly observed (Fig. 3). Evaluation of the qualitative thixo-
tropic behaviour of hydrogels is performed with rheometry
(
Fig. 4, full version shown in Fig. S4, ESI†). The hydrogels show
0
00
better recovery for G than G even aer being repeatedly sub-
jected to a large deformation shear. Higher recoveries are
observed for the stiffer and more stable hydrogels obtained
15
from OG-G, OG2-G, and OG3-G compared to OA-G and SG-G
hydrogels; an observation that may result from the introduction
of the hydrogen bonding amino acid moieties and more
hydrophobic oleoyl group that can facilitate the rebuilding of
Fig. 2 Dynamic rheological properties of hydrogels formed with a damaged network. In addition, thixotropic behaviour was
OG-G (3.0 wt%), OG2-G (2.0 wt%), OG3-G (2.0 wt%), and OA-G observed for OG3-G 3.0 wt% PBS hydrogel (Fig. S5, ESI†),
(
3.0 wt%): (a) frequency sweep and (b) strain sweep.
whereas OG2-G 3.0 wt% PBS hydrogel did not show such
behaviour. Further investigations on thixotropic properties of
hydrogels, including other types of aqueous solutions, are
underway. The results indicate that these hydrogels will be
applicable in the healthcare and medical elds.
Scanning electron microscope (SEM) images of xerogels
prepared by freeze-drying the corresponding hydrogels at the
CGC show a network structure composed primarily of sub-
micrometre thick bres (Fig. 5). Considering that freeze-
drying promotes the bundling of bres, it is possible that the
hydrogels consist of a ner network than what is observed in
xerogels. Subsequently, these networks in the hydrogel can
formed the stiffest hydrogel, likely due to balanced hydropho-
bicity and hydrogen bonding yielding a stronger gel bre or
network. In recent studies of molecular gel systems, higher G
values near 10 Pa were obtained by Yu (over 10 Pa for 1.5%
(
and Shinkai (over 10 Pa for 1 mM organogels). Importantly,
our molecular hydrogel systems demonstrated a similar degree
of high stiffness to those shown in the studies of Yu, Steed and
Shinkai. This indicates that a stiff and stable hydrogel can be
obtained by introducing an oleoyl group, instead of stearoyl
chain, and glycine linker between the polar head and alkyl tail
of N-alkyl-D-glucamines (note that the structure of glycine is
more rigid than that of b-alanine).
0
5
6
18
5
19
w/v) organogels), Steed (over 10 Pa for 1% (w/v) organogels)
4
20
Temperature-dependent data of sol-to-gel and gel-to-sol
changes of the hydrogels measured by differential scanning
calorimetry (DSC, Fig. S3 and Table S1, ESI†) show that similar
DH values are involved in these reversible transitions. Sol-to-gel
and gel-to-sol transition temperatures of hydrogels increase
with the increase in the number of glycine repeat units, i.e. from
OG-G to OG3-G, probably due to an increase in the interaction
between glycine moieties, in addition to the increased molec-
ular weight. Furthermore, the effect on thermal transitions by
introduction of a methylene group in OA-G is similar to the
addition of a second glycine unit, as in OG2-G. Considering the
results of the gelation test, the transition temperatures may
reect the bre properties, rather than the network properties
of gel in this system (Table S1†).
Fig. 4 Periodical step-shear test results for OG-G (3.0 wt%), OG2-G
Investigations into the mechanical properties of hydrogels
21
(2.0 wt%), OG3-G (2.0 wt%), and OA-G (3.0 wt%) hydrogels. For full
show reveal thixotropic behaviour, even at the CGC. For version see Fig. S4, ESI.†
41690 | RSC Adv., 2017, 7, 41686–41692
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extension, in the gel state, it is possible that the molecules of the
gelators can form bilayered or lamellar structures in the bre
(Fig. 6d). Also, in the xerogels, gelator molecules can form
bilayered or lamellar structures. As shown in the xerogels of
OG-G, OG2-G, and OG3-G, gelator molecules can also form tight
bilayered or lamellar structures likely due to the absence of
water molecules, and the XRD peaks might occur from a larger
periodic structure corresponding to the length of two gelators.
To investigate the interaction of gelators, IR measurements
were carried out. As seen in the IR spectra of different states of
gelator systems, hydrogen bonding of gelators may play an
important role in the driving force of bre formation (Fig. S6,
ESI†).
Fig. 5 SEM images of xerogels prepared from the corresponding
hydrogels: (a and b) OG-G (3.0 wt%), (c and d) OG2-G (2.0 wt%), (e and Conclusions
f) OG3-G (2.0 wt%), and (g and h) OA-G (3.0 wt%). The values in
parenthesis denote the concentration of hydrogels before drying.
In conclusion, we have created a new family of oleoyl- and
D-glucamine-based hydrogelators by introducing glycine-based
linkers connecting the two moieties. The molecules, prepared
under mild reaction conditions, form hydrogels that demon-
strate thixotropic properties and improved stiffness compared
to the stearoyl analogue. These results suggest that N-alky-
laldonamides can be chemically tuned to generate functional
hydrogels by introducing an amino acid linker and an oleoyl
group, rather than the stearoyl group. Their thixotropic nature
suggests that these hydrogels will have extensive applications in
the healthcare and medical elds for use as biomaterials.
exhibit polymer-like functions, as demonstrated by the
observed thixotropic behaviour.
To study the molecular packing structure in the bre, X-ray
diffraction (XRD) measurements were performed. The XRD
results (Fig. 6a and b), when analysed in the context of the
contour length of the gelators (Fig. 6c), suggests that the peak
positions of hydrogels are different from those of correspond-
ing xerogel samples and larger than the corresponding contour
15
˚
length of gelators (for example, 31.1 A for OG-G). As previously
shown, N-alkyl-D-aldonamide molecules with similar structures
to the gelators in this study form bre micelles and lamellar
Conflicts of interest
structures, based on the belayed structures of the molecules. By There are no conicts to declare.
Acknowledgements
We thank Nissan Chemical Industries, Ltd. for nancial and
technical supports. A part of this work was supported by
Research Center for Materials and Energy Devices of Fukuoka
Institute of Technology (FIT-ME) (Strategic Research Founda-
tion Grant-Aided Project for Private University from MEXT,
Japan) as well as by Canon Foundation, KEKENHI (#24104005,
#15K05610 and #15K05657) and Network Joint Research Center
for Materials and Devices (#201507 and #20166009). A part of
this work was also supported by the Nanotechnology Network
Project (Kyushu-area Nanotechnology Network) of the MEXT,
Japan. The SEM measurement was performed at the Center of
Advanced Instrumental Analysis, Kyushu University. We are
indebted to the Service Center of the Elementary Analysis of
Organic Compounds, Kyushu University for elemental analysis.
We would like to thank Enago (http://www.enago.jp) for the
English language review.
Notes and references
Fig. 6 XRD data of (a) hydrogels at CGC and (b) xerogels formed with
OG-G, OG2-G, OG3-G, and OA-G, (c) contour length and the length
of OG-G, OG2-G, OG3-G and OA-G obtained from MM2 calculation in
ChemDraw and (d) schematic illustration of possible lamella packing
structure of OG-G.
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41692 | RSC Adv., 2017, 7, 41686–41692
This journal is © The Royal Society of Chemistry 2017