Thixotropic hydrogel formation in various aqueous solutions through self-assembly of an amphiphilic tris-urea

Article abstract of DOI:10.1002/asia.201300779

Transition stress management: The amphiphilic tris-urea 1 was designed and synthesized as a low-molecular-weight gelator. The minimum gelation concentration of 1 is 1.9 mM. The hydrogel is thixotropic, and shows a reversible gel-sol phase transition in re

Full text of DOI:10.1002/asia.201300779

Supporting Information
ꢀ Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2013
Thixotropic Hydrogel Formation in Various Aqueous Solutions through Self-
Assembly of an Amphiphilic Tris-Urea
Daisuke Higashi,[a] Masaru Yoshida,[b] and Masamichi Yamanaka*[a]
asia_201300779_sm_miscellaneous_information.pdf

General
1
Chemicals and solvents required were obtained from commercial suppliers. H and 13C NMR spectra were
recorded on a JEOL JNM-ECA600 spectrometer. Mass spectra were measured on a JEOL JMS-T100LC
AccTOF spectrometer. SEM studies were carried out on a JEOL JSM-6300 spectrometer.
Synthesis and physical properties
R
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N
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1 t i h
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C C 2C 2C
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enzene
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2 O
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c
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C C 2C
C
,
2
NH
O
=
2
NH
c
A
O
O
R
c
A
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R
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c
O
A
2 O
c
A
O
5
S1

Synthesis of Tris-urea (5). To a soltion of amine 21 (375 mg, 0.71 mmol) in 1,2-dichloroethane (1.5 mL)
were added triphosgene (218 mg, 0.74 mmol) in 1,2-dichloroethane (1.5 mL) and Et3N (220 µL, 1.56 mmol)
successively under argon atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 40
min. The low boiling point compounds were removed under reduced pressure and corresponding isocyanate
was obtained as white solid. To the crude isocyanate were added 1,2-dichloroethane (2.9 mL) and
1,3,5-tris(aminomethyl)benzene (3)2 (40 mg, 0.24 mmol) successively under argon atmosphere. The reaction
mixture was stirred at 90 °C for 48 h and then cooled to room temperature and added saturated aqueous
NH4Cl solution. The aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with
brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was
purified by column chromatography (SiO2, acetone/ CH2Cl2 1/3 to 1/0). The desired product (5) was obtained
as a white solid (347 mg, 78%). M.p. 165−166 °C; [α]D26 = −16.7 °(c = 1.0 in DMSO); 1H NMR (600 MHz,
DMSO-d6) δ 1.93 (s, 9H), 1.97 (s, 9H), 1.98 (s, 9H), 2.01 (s, 9H), 3.54−3.62 (m, 6H), 3.63−3.70 (m, 9H),
3.80-3.83 (m, 3H), 4.00−4.03 (m, 12H), 4.17 (dd, J = 5.2, 12.0 Hz, 3H), 4.25 (d, J = 6.2 Hz, 6H), 4.76 (t, J =
8.9 Hz, 3H), 4.84 (d, J = 8.2 Hz, 3H), 4.89 (t, J = 9.6 Hz, 3H), 5.25 (t, J = 9.6 Hz, 3H), 6.49 (t, J = 5.8 Hz,
3H), 6.79 (d, J = 8.9 Hz, 6H), 7.10 (s, 3H), 7.27 (d, J = 8.9 Hz, 6H), 8.32 (s, 3H); 13C NMR (150 MHz,
acetone-d6) 20.66, 20.73, 20.78, 20.80, 44.23, 62.88, 68.65, 69.57, 69.91, 70.59, 71.09, 72.28, 72.48, 73.64,
101.51, 115.65, 121.53, 125.81, 134.54, 141.65, 155.25, 156.96, 169.90, 170.13, 170.43, 170.87; HRMS
(ESI, M+Na+) calcd for C84H108N6NaO39: 1847.6550; found 1847.6598.
R
R
H
N
H
N
H
N
H
N
HN
HN
O
O
O
O
R
R
HN
HN
a
N
Et
O
Et
H
O
NH
H
NH
O
O
c
A
O
H
O
NH
=
NH
=
O
O
c
A
O
O
R
R
R
R
O
O
c
H
O
A
O
2 O
2 O
c
H
O
A
O
1
5
S2

Synthesis of Tris-urea (1). A mixture of tris-urea 5 (593 mg, 0.32 mmol) and NaOEt (78 mg, 1.15 mmol) in
ethanol (7.7 mL) was stirred at room temperature for 3 d. The reaction mixture was purified by membrane
dialysis, and the solvent was removed under reduced pressure. The desired product 1 was obtained as pale
1
brown solid (424 mg, 99%). M.p. 185−186 °C; [α]D26 = -18.4 ° (c = 1.0 in DMSO); H NMR (600 MHz,
DMSO-d6) δ 2.92−2.99 (m, 3H), 3.01−3.05 (m, 3H), 3.07−3.10 (m, 3H), 3.11-3.14 (m, 3H), 3.41−3.45 (m,
3H), 3.60−3.66 (m, 12H), 3.72 (dd, J = 4.1, 5.5 Hz, 6H), 3.87−3.91 (m, 3H), 4.00 (t, J = 4.5 Hz, 6H), 4.16 (d,
J = 8.2 Hz, 3H), 4.26 (d, J = 6.2 Hz, 6H), 4.49 (t, J = 5.8 Hz, 3H), 4.88 (d, J = 4.8 Hz, 3H), 4.92 (d, J = 4.8
Hz, 3H), 4.98 (d, J = 4.8 Hz, 3H), 6.49 (t, J = 5.8 Hz, 3H) , 6.81 (d, J = 8.9 Hz, 6H), 7.11 (s, 3H), 7.28 (d, J =
8.9 Hz, 6H), 8.32 (s, 3H); 13C NMR (150 MHz, DMSO-d6) 52.35, 70.63, 76.82, 77.42, 78.60, 79.38, 79.60,
82.94, 86.27, 86.41, 112.53, 124.10, 129.09, 134.05, 143.18, 150.18, 162.69, 164.96; HRMS (ESI, M+Na+)
calcd for C60H84N6NaO27: 1343.5282; found 1343.5291.
R
R
H
N
H
N
H
N
H
N
HN
HN
O
O
O
O
R
R
HN
HN
6 M HCl
∆
NH
H
NH
O
O
H
O
NH
NH
R
O
O
O
=
=
R
R
R
H
O
H
O
2 O
2 O
H
O
1
4
Synthesis of Tris-urea (4). A mixture of 1 (20 mg, 15 µmol) and 6 M HCl (0.44 mL) was heated on a hot
plate for 10 min. The obtained hydrogel was purified by membrane dialysis, and the solvent was removed
under reduced pressure. The tris-urea 4 was obtained as pale brown solid (12 mg, 95%). M.p. 224−226 °C;
1H NMR (600 MHz, DMSO-d6) δ 3.46−3.48 (m, 6H), 3.50-3.52 (m, 6H), 3.70 (t, J = 4.8 Hz, 6H), 4.00 (t, J =
4.8 Hz, 6H), 4.26 (d, J = 6.2 Hz, 6H), 4.61 (t, J = 5.5 Hz, 3H), 6.50 (t, J = 5.8 Hz, 3H), 6.80 (d, J = 8.9 Hz,
6H), 7.11 (s, 3H), 7.27 (d, J = 8.9 Hz, 6H), 8.32 (s, 3H); 13C NMR (150 MHz, DMSO-d6) 42.80, 60.25, 67.32,
69.03, 72.46, 114.55, 119.53, 124.51, 133.66, 140.65, 153.16, 155.40; HRMS (ESI, M+Na+) calcd for
C42H54N6NaO12: 857.3697; found 857.3690.
S3

1H NMR spectrum (600 MHz, DMSO-d6) of tris-urea 5
13C NMR spectrum (150 MHz, acetone-d6) of tris-urea 5
S4

1H NMR spectrum (600 MHz, DMSO-d6) of tris-urea 1
13C NMR spectrum (150 MHz, DMSO-d6) of tris-urea 1
S5

1H NMR spectrum (600 MHz, DMSO-d6) of tris-urea 4
13C NMR spectrum (150 MHz, DMSO-d6) of tris-urea 4
S6

Figure S1. Storage modulus (G’) and loss modulus (G’’) of hydrogel (1.0 wt% of 1): a) frequency sweep at
the strain of 0.1%, b) strain sweep at the frequency of 1.0 Hz.
Figure S2. Photograph and SEM image of disassembled hydrogel of 1 (1.0 wt%) by mechano-stress.
S7

solution
pH
3.0
MGC (wt%)
0.25
photograph
Glycine−HCl buffer
Phosphate−NaOH buffer
HEPES buffer
6.9
7.0
7.4
8.3
9.0
9.1
9.4
7.2
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
Tris−HCl buffer
Tris−Borate−EDTA buffer
Glycine−NaOH buffer
Borate−NaOH buffer
PBS
D-MEM
HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, Tris: tris(hydroxymethyl)aminomethane,
EDTA: ethylenediaminetetraacetic acid, PBS: phosphate buffered saline, D-MEM: Dulbecco's modified Eagle medium
Table S1. Gelation experiments of buffers by amphiphilic tris-urea 1.
S8

Figure S3. Photographs and SEM images of 0.25 wt% of 1 and 700 equivalents of a) NaF (gel), b) NaCl
(gel), c) NaBr (gel), and d) NaI (sol).
S9

Figure S4. Thixotropic properties of a) sat. NaCl gel of 1 (1.0 wt%), b) 8 M HCl gel of 1 (4.0 wt%), and c) 7
M KOH gel of 1 (2.0 wt%).
References
(1) S. Yamamichi, Y. Jinno, N. Haraya, T. Oyoshi, H. Tomitori, K. Kashiwagi, M. Yamanaka, Chem.
Commun. 2011, 47, 10344−10346.
(2) a) W. Kiggen, F. Voegtle, S. Franken, H. Puff, Tetrahedron 1986, 42, 1859-1872; b) A. Granzhan, C.
Schouwey, T. Riis-Johannessen, R. Scopelliti, K. Severin, J. Am. Chem. Soc. 2011, 133, 7106−7115.
S10