Chemical stimuli-responsive supramolecular hydrogel from amphiphilic tris-urea

Article abstract of DOI:10.1002/asia.201000791

An-gel interceptor: An amphiphilic low-molecular-weight hydrogelator 1 was synthesized. Gel-to-sol phase-transitions were caused by adding a surplus of ConA to a hydrogel of 1 or by adding anions. This anion response allows for naked-eye detection of the hardness of mineral water.

Full text of DOI:10.1002/asia.201000791

COMMUNICATION
DOI: 10.1002/asia.201000791
Chemical Stimuli-Responsive Supramolecular Hydrogel from Amphiphilic
Tris-Urea
Masamichi Yamanaka,* Nana Haraya, and Sachiyo Yamamichi[a]
Hydrogels constructed from self-assemblies of low-molec-
ular-weight hydrogelators (LMWHGs) are an attractive ar-
chitecture in the field of supramolecular chemistry.[1] Supra-
molecular hydrogels have great potential as smart materi-
als.[2] Stimuli-responsive gelation can be achieved as an ad-
vantageous function of non-covalent assemblies. A variety
of supramolecular hydrogels that respond to stimuli, such as
light,[3] pH,[4] chemical,[5] ion,[6] enzyme,[7] and combinations
of these[8] have been reported. Despite these outstanding re-
sults, the rational design of LMWHGs is still challenging,
and many of them are found by serendipity or from wide
surveys. One practical strategy to make a LMWHG is the
hydrophilic modification of a low-molecular-weight organo-
gelator (LMWOG).[9] Supramolecular hydrogels that re-
spond to two different stimuli would be created by the intro-
molecular hydrogel of 1 would respond to both lectin and
anions.
The LMWHG 1 was synthesized by condensation of two
amines (2 and 3) and deprotection (Scheme 1). Penta-O-
acetyl-b-d-glucopyranose was converted into amine 2 by a
five-step synthesis. Amine 3 was prepared in two steps from
1,3,5-tris(bromomethyl)benzene.[10b] The structure of 1 was
duction of
a stimulus-responsive hydrophilic functional
group onto another stimulus-responsive LMWOG. Herein,
we report the synthesis of a LMWHG that is responsive to
two chemical stimuli.
Previously, we have reported that a C3-symmetric tris-
urea LMWOG showed an anion-responsive gel–sol phase
transition.[10] Amphiphilic LMWHG 1 was designed by the
introduction of hydrophilic glucoside groups onto the pe-
riphery of the hydrophobic LMWOG. The regulated aggre-
gation of 1 in one dimension would be caused by the hydro-
phobic interactions of the central part of 1 and the intermo-
lecular hydrogen bonding of the ureide groups. Saccharide is
an appropriate functional group, because it can act not only
as a hydrophilic group, but also as a probe for sugar-binding
proteins (lectin). The ureide groups of 1 would function as
anion-recognition sites. As a result, a self-assembled supra-
[a] Dr. M. Yamanaka, N. Haraya, S. Yamamichi
Department of Chemistry, Faculty of Science
Shizuoka University
836 Ohya, Suruga-ku, Shizuoka 422-8529 (Japan)
Fax : (+81)54-237-3384
E-mail: smyaman@ipc.shizuoka.ac.jp
Scheme 1. Synthesis of LMWHG 1. a) triphosgene (1.0 equiv), Et3N
(2.5 equiv), RT, 1 h, then 3 (0.33 equiv), D, 23 h, 55% yield; b) NaOEt
(12 equiv), RT, 24 h, (repeat twice), 88% yield.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000791.
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Chem. Asian J. 2011, 6, 1022 – 1025

1
determined using H and 13C NMR spectroscopy and elec-
(100 mL) afforded cloudy sols. The addition of appropriate
amounts of ConA enabled a reduction in the CGC of 1. A
mixture of 1 (1.0 mg, 0.43 mmol) and ConA (0.10~0.20 mg,
3.9~7.8 nmol) in H2O (100 mL) afforded a gel. The amounts
of ConA also influenced the Tgel values of the hydrogel (for
details, see the Supporting Information). The value of Tgel
was increased by adding an appropriate amount of ConA.
The value of Tgel of an opaque gel, prepared by mixing 1
(2.0 mg, 0.85 mmol) and ConA (0.20 mg, 7.8 nmol) in water
(100 mL), was estimated at 858C, which is about 508C higher
than the value of Tgel of 1 alone. Further addition of ConA
led to a decrease in the value of Tgel, and finally afforded
the sol discussed above. A suitable amount of ConA would
moderately cross-link the fibrous aggregates of 1 to rein-
force the thermal stability of the gel, whereas an excess of
ConA could lead to an excessive cohesion of the fibers to
obstruct any gelation (Figure 2). SEM images of the sol con-
taining 1 and ConA showed only unidentified larger objects,
and little production of nanofibers was observed (see the
Supporting information, Figure S2).
trospray ionization (ESI) mass spectrometry (see the Sup-
porting Information).
A pale-yellow transparent hydrogel was formed by mixing
1 with water, and leaving the mixture at ambient tempera-
ture for a few hours (gelation procedure I; Figure 1a). The
Figure 1. a) Photo of a hydrogel of 1 (2.0 wt%) prepared at ambient tem-
perature over 3 h (inset) and a SEM image of the xerogel. b) Photo of a
hydrogel of 1 (1.5 wt%), prepared by thermal treatment (inset), and a
SEM image of the xerogel.
critical gelation concentration (CGC) of 1 was estimated to
be 2.0 wt%. The thermal stability (Tgel)[11] of the hydrogel
was increased by increasing the concentration of 1 as a typi-
cal characteristic of the supramolecular gel (Tgel; 388C for
2.0 wt%, 648C for 4.0 wt%) (for details, see the Supporting
Information). Narrow fibers (average diameter=80 nm)
were observed in the scanning electron microscope (SEM)
images of the xerogel (Figure 1a). The transparent hydrogel
of 1 gradually lost its transparency under ambient condi-
tions, and changed into an opaque gel over a period of sev-
eral months. Xerogels prepared from the opaque gels
showed thicker fibers (up to 800 nm) than those from early
transparent gels (see the Supporting Information, Fig-
ure S1).
Figure 2. Schematic representation of the gel–sol phase transition trig-
gered by ConA and saccharide.
Thermal dissolution and cooling of an aqueous mixture of
1 also afforded a pale-yellow transparent hydrogel, and the
CGC of 1 was improved to 1.5 wt% (gelation procedure II;
Figure 1b). Slightly higher Tgel values were observed than
those for gelation procedure I (Tgel; 408C for 2.0 wt%, 668C
for 4.0 wt%; for details, see the Supporting information).
The gel obtained using this thermal procedure was stable,
and kept its form and transparency for more than a year
under ambient temperatures. SEM images of the xerogel
showed intertwining nanofibers with diameters between 100
and 250 nm (Figure 1b).
The dense glucosides on the surface of the fibrous aggre-
gates of 1 should work as recognition sites for lectin, with an
interaction appearing as a macroscopic alteration of the hy-
drogel. Well-established concanavalin A (ConA) was select-
ed as a lectin for the mixed gelation experiments with 1.[12]
Opaque gels were formed by mixing 1 (2.0 mg, 0.85 mmol)
and ConA (<0.35 mg, <13.6 nmol as a monomer) in water
(100 mL), and leaving the mixture at ambient temperature
for a few hours. However, mixtures of 1 (2.0 mg, 0.85 mmol)
and more than 0.35 mg of ConA (>13.6 nmol) in water
The addition of a saccharide to an aqueous mixture of 1
and ConA, which gave a cloudy sol in the absence of sac-
charide, would afford a gel, depending on the association
ratio of the saccharide with ConA (Figure 2). The results of
gelation experiments of
1 (2.0 mg, 0.85 mmol), ConA
(0.5 mg, 19.6 nmol), and various types and amounts of sac-
charides in water (100 mL) are summarized in Table 1. An
opaque gel was obtained in the presence of 1 equivalent of
a-methyl-d-mannoside (Me-a-Man) for ConA. The strong
binding of Me-a-Man to ConA (Ka =1.1ꢁ104 mÀ1)[12] would
partially prevent the interaction between 1 and ConA, and
thus enable the formation of a gel. The Tgel value of the
opaque gel was estimated to be 808C. The addition of an
excess of Me-a-Man (10 equivalents or more for ConA) to
an aqueous mixture of 1 and ConA afforded a semitranspar-
ent gel. The transparency of the gel would be restored from
the negation of the interaction between 1 and ConA. This
negation was reflected in the Tgel value of the semitranspar-
ent gel (Tgel =558C). Furthermore, reconstructed intertwin-
ing nanofibers were observed in the SEM images of the xe-
rogel (see the Supporting information, Figure S2). Addition
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M. Yamanaka et al.
COMMUNICATION
Table 1. Gelation of 1 in the presence of ConA and saccharide.[a]
ConA (equiv)
Saccharide
1.0
3.0
4.0
10
260
Me-a-Man
Me-a-Glc
Man
Isomal
Glc
OG
S
S
S
S
OG
OG
S
S
S
OG
OG
OG
OG
S
G
OG
OG
OG
OG
S
G
G
G
G
G
S
Gal
S
S
S
l-Glc
S
S
S
S
S
Mal
Me-b-Glc
S
S
S
S
OG
S
OG
S
G
OG
Figure 3. Photographs of rheological alteration of a mixture of 1 and
ConA by addition of saccharides (260 equiv for ConA).
[a] A mixture of 1 (2.0 mg), ConA (0.5 mg), and saccharide in H2O
(100 mL) was kept at ambient temperature for 3 hours. G=semitranspar-
ent gel, OG=opaque gel, S=cloudy sol, Me-a-Man=a-methyl-d-man-
noside, Me-a-Glc=a-methyl-d-glucoside, Man=d-mannose, Isomal=
isomaltose, Glc=d-glucose, Gal=d-galactose, l-Glc=l-glucose, Mal=d-
maltose, Me-b-Glc=b-methyl-d-glucoside.
Table 2. Anion responsive gel-to-sol phase transition.[a]
1 (equiv)
Salt
0.25
0.50
1.0
2.0
NaF
NaCl
–
–
–
–
–
–
–
–
–
G
G
G
G
G
OG
G
G
G
V
OG
OG
G
G
G
V
G
OG
OG
V
V
V
V
G
V
V
G
V
V
V
V
V
of
a large excess of a-methyl-d-glucoside (Me-a-Glc,
NaBr
NaI
NaOAc
Na2SO4
NaClO4
KCl
NH4Cl
MgCl2
MgSO4
CaCl2
3 equiv for ConA) was required to form a gel, since the
binding constant of Me-a-Glc to ConA (Ka =3.0ꢁ103 mÀ1)[12]
is smaller than that of Me-a-Man to ConA. The formation
of a gel was achieved by adding 4 equivalents of d-mannose
(Man) or isomaltose (Isomal) to ConA. The addition of
10 equivalents of d-glucose (Glc) was required to form an
opaque gel. These amounts were adequate, compared with
their binding constants to ConA (Man: Ka =2.2ꢁ103 mÀ1,
Isomal: Ka =1.7ꢁ103 mÀ1, Glc: Ka =8.0ꢁ102 mÀ1).[12] The
transparency of these gels containing Me-a-Glc, Man,
Isomal, or Glc improved by increasing the number of equiv-
alents, with semitransparent gels eventually being obtained.
In contrast with the above results, the addition of saccha-
rides with no- or lesser binding ability for ConA, such as d-
galactose (Gal) or l-glucose (l-Glc), did not form a gel,
even when a large excess was added (up to 260 equivalents
for ConA). The unknown binding constant of a saccharide
with ConA could be approximated using this gelation proce-
dure. Opaque gel formation was achieved by adding 4 equiv-
alents of d-maltose (Mal). This result resembles those from
gelation experiments in the presence of Man and Isomal.
The binding constant of Mal with ConA was inferred to be
around 1.7~2.2ꢁ103 mÀ1. An opaque gel was formed in the
presence of 260 equivalents of b-methyl-d-glucoside (Me-b-
Glc). This result indicates that the binding constant of Me-
b-Glc to ConA is much smaller than that of Glc to ConA.
However, the value should be a finite number. The succes-
sive addition of saccharide to a solvated mixture of 1 and
ConA in water gave the same results as shown in Table 1, al-
though the gelation required a longer period of time
(Figure 3).
OG
SG
SG
V
V
V
V
[a] Stock solution of salt was placed on the top of the hydrogel of 1
(2 wt%). G=gel, OG=opaque gel, SG=soft gel, V=viscous suspen-
sion.
low selectivity of the phase transition. The addition of two
equivalents of monovalent anions was sufficient to attain a
gel-to-sol phase transition. This is reasonable in that a small-
er amount of bivalent anions than monovalent anions led to
this phase transition. In exception, iodide and perchlorate
ions had a low capability for the phase transition because of
their low affinity for the ureide moiety of 1. These phase
transitions took place by adding smaller amounts of alka-
line-earth metal salts than those of alkali metal salts. For in-
stance, addition of 1.0 equivalent of NaCl maintained the
gel, whereas addition of 0.5 equivalents of MgCl2 caused a
viscous suspension. The interaction between the alkaline-
earth metal ions and the glucoside moiety of 1 may also
affect the phase transition.
An assessment of different types of mineral water, accord-
ing to their hardness, was realized by mixing samples with 1
(Figure 4). One particularly prevalent anion in mineral
water is sulfate ions, along with minor components such as
chloride, fluoride, and nitrate ions. The principal cationic el-
ements in mineral water are sodium, potassium, magnesium,
and calcium. The amounts of magnesium and calcium ions
were found to increase with increasing hardness, whereas
the quantities of sodium and potassium ions in each mineral
water remained approximately the same. Therefore, the al-
kaline-earth metal salt-sensitive and anion-nonspecific-re-
sponsive character of 1 is suited for the detection of the
The hydrogel of 1 exhibited a gel-to-sol phase transition
that was responsive to anions. Subsequent addition of
anions, such as chloride ions from NaCl, to a hydrogel of 1
gradually led to a phase transition at the point of contact be-
tween the gel and the salt. A variety of anions showed such
a phase transition, and the amounts required were similar
(Table 2). The hydration of anions may be the cause of the
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Chem. Asian J. 2011, 6, 1022 – 1025

Chemical Stimuli-Responsive Supramolecular Hydrogel from Amphiphilic Tris-Urea
Acknowledgements
We thank Mr. Takeshi Hirakawa and Dr. Mitsuru Kondo (Shizuoka Uni-
versity) for help with analysis of mineral waters and Dr. Kunihiko
Takabe and Dr.Nobuyuki Mase (Shizuoka University) for use of their po-
larimeter. This work was supported by the Tokuyama Science Foundation
and a Kurata Grant.
Keywords: gels
·
phase transitions
·
self-assembly
·
supramolecular chemistry · ureas
Figure 4. Photographs of mixtures of 1 and mineral waters. a) Crystal
Geyser (soft water), b) Paradiso (moderately hard water), c) Wattwiller
(hard water), and d) Contrex (hard water).
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hardness of mineral waters. Crystal Geyser, with a total
hardness of 38 mgLÀ1 (soft water), gave a transparent gel on
mixing with 2.0 wt% of 1. A mixture of 1 and Paradiso,
which is classified as a moderately hard water (total hard-
ness=290 mgLÀ1), formed an opaque gel. Cloudy sols were
obtained from mixtures of 1 with hard-water samples, such
as Wattwiller (total hardness=627 mgLÀ1) or Contrex (total
hardness=1551 mgLÀ1). The hardness of water was distin-
guished from the three different states observed, i.e., a
transparent gel, an opaque gel, and a cloudy sol.
In conclusion, we have synthesized a LMWHG 1 based
on the design of the amphiphile. The hydrogel showed that
the gel-to-sol phase transition responded to two different
types of stimuli: lectin and anion. These results demonstrate
the potential of supramolecular gels as innovative chemical
sensors.
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Experimental Section
Gelation Procedure I: Mixing at Ambient Temperature
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A mixture of 1 and H2O (200 mL) (f=6.2 mm) was left at ambient tem-
perature in a test tube. The viscosity of the mixture increased over time,
and gel formation was complete after 2~3 hours. Gel formation was eval-
uated by the “inverted tube” test. A mixture remaining at the top of an
inverted test tube was defined as a gel.
Gelation Procedure II: Thermal Treatment
A mixture of 1 and H2O (200 mL) (f=6.2 mm) was heated in a test tube
at 908C. The obtained solution was gradually cooled to ambient tempera-
ture. Gel formation was evaluated by the inverted-tube test. A mixture
remaining at the top of an inverted test tube was defined as a gel.
Received: November 5, 2010
Revised: November 30, 2010
Published online: February 17, 2011
Chem. Asian J. 2011, 6, 1022 – 1025
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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