Amphiphilic dendritic peptides: Synthesis and behavior as an organogelator and liquid crystal

Article abstract of DOI:10.3762/bjoc.7.26

New amphiphilic dendritic peptides on dendritic polyaspartic acid were designed and synthesized. The organogel and liquid crystal properties of these amphiphilic dendritic peptides were fully studied by field-emission SEM, temperature dependent FT-IR, dif

Full text of DOI:10.3762/bjoc.7.26

Amphiphilic dendritic peptides: Synthesis and
behavior as an organogelator and liquid crystal
Baoxiang Gao*, Hongxia Li, Defang Xia, Sufang Sun and Xinwu Ba
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 198–203.
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis,
Ministry of Education, College of Chemistry and Environment
Science, Hebei University, Baoding 071002, P.R. China
doi:10.3762/bjoc.7.26
Received: 02 November 2010
Accepted: 09 January 2011
Published: 11 February 2011
Email:
Baoxiang Gao* - bxgao@hbu.edu.cn
Editor-in-Chief: J. Clayden
* Corresponding author
© 2011 Gao et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
amphiphilic; dendritic peptides; liquid crystal; organogels
Abstract
New amphiphilic dendritic peptides on dendritic polyaspartic acid were designed and synthesized. The organogel and liquid crystal
properties of these amphiphilic dendritic peptides were fully studied by field-emission SEM, temperature dependent FT-IR, differ-
ential scanning calorimetry, polarization optical microscopy and X-ray diffraction experiments. Amphiphilic dendritic peptides G3
show good organogel properties with a minimum gelation concentration as low as 1 wt %. Furthermore, amphiphilic dendritic
peptides G3 can form a hexagonal columnar liquid crystal assembly over a wide temperature range.
Introduction
Peptide self-assembly has drawn a significant attention due to as a particularly powerful strategy to direct the self-assembly of
potential applications, especially in the fields of biomedicine relatively simple peptide building blocks toward sophisticated
and bionanotechnology [1-3]. Programmed self-assembly of nanostructures [8]. Furthermore, the natural amino acid based
peptides into highly ordered nanostructures creates bio- dendrons or dendrimers are of great significance because of
materials that display a wide range of physical properties often their similarity to proteins in composition and topology [9-11],
exceeding those of synthetic polymers [4,5]. Peptide- as well as their architectural difference from currently prevalent
amphiphiles (PAs) represent an attractive class of bioactive linear model peptides. However, little attention has been paid to
molecules as they self-assemble into a variety of nanostructures, the self-assembly of natural amino acid based dendrimers, and
many of which have promising biological activity due to the especially to their gelation and liquid crystal properties [12,13].
exposed peptide regions on their outer surface [6,7]. The self- Recently, a type of amphiphilic dendritic dipeptide was
assembly of amphiphilic oligopeptide systems is thus emerging described by Percec et al. as self-assembling in helical pores
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Beilstein J. Org. Chem. 2011, 7, 198–203.
[14]. In addition, Takashi Kato and co-workers have recently
reported that dendritic oligopeptides can act as useful building
blocks for chiral supramolecular liquid crystals [15,16].
Herein, we present the synthesis of amphiphilic dendritic
peptides (ADPs) composed of an aspartic acid core and an ali-
phatic periphery, and their self-assembly which leads not only
to organogels but also to liquid crystals.
Results and Discussion
Synthesis and characterization
The amphiphilic dendritic peptides were synthesized conver-
gently as depicted in Scheme 1 via standard EDCI coupling of
N-carbobenzyloxy-L-aspartic acid and L-aspartic acid dodecyl
ester (readily prepared by the esterification of aspartic acid with
1-dodecanol). The second (G2) and third generations (G3) were
synthesized convergently in 75 and 60% yields, respectively, by
repeating a two-reaction cycle, i.e., by removal of the carboben-
zyloxy group of the lower-generation dendron by hydro-
genation, and then coupling the resulting N-deprotected inter-
mediate to the C-deprotected G1, prepared by hydrogenolysis
of the benzylated peptide. 1H NMR, MALDI-TOF mass spec-
trometry, and elemental analyses were used to verify the struc-
ture and purity of the amphiphilic dendritic peptides.
Investigation of gelation
All amphiphilic dendritic peptides were subjected to gelation
tests in a variety of organic solvents. Each compound was
combined with solvent in a screw-capped sample tube and
heated until the solid completely dissolved. The solution was
then cooled to room temperature, and gelation monitored by
inverting the sample tube to see whether the solution flows or
not. The observed gelation behavior of each solution is sum-
marized in Table 1. Compound G1 showed good solubility in a
range from non-polar (n-hexane) to polar solvents (ethanol),
and showed no gelation in any solvent tested. Compound G2
can gel only in the nonpolar n-hexane. Compound G3 gelled in
Scheme 1: Synthetic sequence of amphiphilic dendritic peptides: (i)
1-dodecanol, EDCI, DMAP, dichoromethane, 25 °C. (ii) H2, Pd/C,
ethanol, 25 °C. (iii) N-carbobenzyloxy-L-aspartic acid, EDCI, HOBt,
dichoromethane, 25 °C.
n-hexane, toluene, 1,4-dioxane, and ethanol but was soluble in FE-SEM images of the xerogel of G3 formed in n-hexane.
dichloromethane.
These images clearly show that organogels assembled from G3
formed thin fibres that underwent further aggregation to form
The microscopic structure of the gel was investigated by field- fibre bundles. These fibre bundles constitute a highly de-
emission SEM (FE-SEM). Figure 1 shows representative veloped entangled network.
Table 1: Gelation of organic solvents by the amphiphilic dendritic oligopeptidesa.
n-hexane
toluene
dichloromethane
1,4-dioxane
ethanol
G1
G2
G3
S
S
S
S
S
S
S
S
S
S
G (cgc = 3%)
G (cgc = 1%)
G (cgc = 5%)
G (cgc = 6%)
G (cgc = 2%)
acgc: gelation concentration (w/w %). G: gel. S: solution.
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Beilstein J. Org. Chem. 2011, 7, 198–203.
Figure 1: (A) SEM images of the xerogels of G3 from n-hexane (B) magnification of the xerogels structure.
Figure 2 shows the XRD scan of organogelator G3 and liquid
crystal G3. Being different from the liquid crystal, the XRD of
organogelator shows no reflection peaks in the small-angle
region which indicates that molecular arrangement in the
organogelator is disordered. Figure 3 shows the FT-IR of G3 as
an organogelator and as a liquid crystal. The absorption at 3081
cm−1 is ascribed to the N–H stretching frequency of the
hydrogen bonds. The absorption intensity at 3081 cm−1
decreases in the organogelator which indicates the loss of
hydrogen bonds.
Figure 3: FT-IR of G3 as an organogelator and liquid crystal.
which hydrogen bonds form more easily. It is therefore
reasonable that the minimum gelation concentration of
G3 (1 wt %) was lower than G2 (3 wt %) in the same
(n-hexane) solvent.
Investigation of the liquid crystalline behavior
Thermotropic behavior of ADPs was investigated by a com-
bination of differential scanning calorimetry (DSC), polar-
ization optical microscopy (POM) and X-ray diffraction (XRD)
experiments. Figure 4 shows DSC curves of amphiphilic
Figure 2: X-ray diffraction patterns of G3 as an organogelator and
liquid crystal.
Hydrogen bonds as physical cross-linking points in these dendritic peptides. In the DSC scan from −60 °C to 200 °C, G1
compounds are an essential factor for gelling. With more showed three phase transitions at 15 °C, 25 °C and 40 °C,
physical cross-linking points, compound G3 gels more which are attributed to phase transitions of recrystallization and
easily. Compound G2 can gel only in n-hexane. Compared crystal to isotropic melt. G2 only showed a phase transitions at
with the other solvents, n-hexane is a poor solvent, in 71 °C, which is attributed to the phase transition of crystal to
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Beilstein J. Org. Chem. 2011, 7, 198–203.
isotropic melt. DSC analysis of G3 showed phase behavior,
where a LC mesophase, on a second cooling, appeared at 40 °C
and then disappeared at 145°C to form an isotropic melt
(Figure 4). The high temperature for the isotropic melt of G3 is
the result of hydrogen bond interactions of the amide groups
which reinforce the columnar organization.
Figure 5: Temperature dependent FT-IR of G3.
Figure 4: Differential scanning thermograms of ADPs registered
during the second heating–cooling cycle with scanning rate 10 K
min−1.
The presence of hydrogen bonds in the liquid-crystalline phases
of G3 is demonstrated by temperature dependent FT-IR studies
(Figure 5). Cooling from 160 °C (isotropic state) to 20 °C
(liquid crystalline state), the absorption intensities of the free
amide groups at 1685 cm−1 decrease. The absorption intensities
of the hydrogen bonding amide groups 1648 cm−1 increase.
Furthermore, the N–H stretching frequency of G3 shifts from
3354 cm−1 (160 °C) to 3288 cm−1 (20 °C), and the absorption
intensities at 3084 cm−1 (the N–H streching frequency of the
hydrogen bonds) also increase which indicates that hydrogen
bonds form in liquid crystalline. With the high selectivity and
directionality of hydrogen bonds, the formation of the hydrogen
bonds should contribute to the columnar liquid crystalline
properties.
Cooling from 160 °C to 145 °C, G3 begins to form the conic
fan-shaped textures (Figure 6A), which are characteristic of
hexagonal columnar liquid crystals. The conic fan-shaped
textures of G3 grow (Figure 6B), and no longer change at 50 °C
(Figure 6C). Figure 7 shows the XRD scan for the birefringent
phase of G3 at 50 °C. The birefringent phases of G3 were
further confirmed as a hexagonal columnar liquid crystal phase
through assignment of the reflections. In the wide angle region,
the diffused halo at around 4.5 Å is due to the disorder of the
Figure 6: . Polarized optical micrographs of G3 at 145 °C (A), 140 °C
(B), and 50 °C (C).
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Beilstein J. Org. Chem. 2011, 7, 198–203.
calorimeter (DSC7) with heating and cooling rates of 10 K/min.
Phase transitions were also examined by a polarization optical
microscope (POM) Olympus BX51 with a T95-PE temperature-
controlled THMS-600 hot stage. X-ray diffraction measure-
ments were performed on a D8 Advance (Bruker AXS Inc.)
with Cu Kα1: 1.54051 Å. FT-IR spectra were recorded with a
Varian 640-IR in the range of 400–4000 cm−1. SEM measure-
ment was performed with XL30 field emission scanning elec-
tron microscope.
G1: 2.67 g N-carbobenzyloxy-L-aspartic acid (10.0 mmol) was
dissolved in 60 mL of DCM. 4.79 g EDCI (25.0 mmol) was
added and the mixture stirred at 0 °C for 30 min. 3.72 g
1-Dodecanol (20.0 mmol) and 0.25 g DMAP (2.0 mmol) were
added and the mixture stirred at room temperature for 24 h.
Solvent was removed by rotary evaporation. The residue was
purified by column chromatography on silica gel with meth-
Figure 7: X-ray diffraction patterns of G3 at 50 °C.
terminal alkyl chains. In the small-angle region, the XRD ylene chloride as the eluent to afford G1 as a white solid
profile of G3 shows two reflection peaks corresponding to (5.32 g, 88%). 1H NMR (300 MHz, CDCl3, δ) 7.36–7.30 (m, 5
d spacing of 24.8 and 12.5 corresponding to (100) and (200) H), 5.76 (d, J = 8.5 Hz, 1H), 5.14 (s, 2H), 4.63 (dd, J = 8.7 Hz,
reflections. The XRD results show the compound G3 self- 1H), 4.13 (d, J = 3.6 Hz, 2H), 4.06 (t, J = 6.8 Hz, 2H),
assembles into columnar structures.
3.04–2.82 (m, 2H), 1.63–1.57 (m, 4H), 1.30–1.26 (m, 36H),
0.88 (t, J = 7.1 Hz, 6H). Anal. Calcd for C36H61NO6: C, 71.60;
H, 10.18; N, 2.32. found: C, 71.83; H, 10.02; N, 2.01. m/z
Conclusion
In summary, we designed and synthesized amphiphilic peptides [MALDI–TOF]: 604.7 (M + H+).
on dendritic polyaspartic acid. These new amphiphilic dendritic
peptides are capable of gelling a variety of organic solvents to G2: 1.335 g N-carbobenzyloxy-L-aspartic acid (5 mmol) was
form stable organogels via cooperative non-covalent forces, dissolved in 60 mL of DCM, 2.880 g EDCI (15 mmol) was
with a minimum gelation concentration as low as 1 wt %. It is added, and the mixture stirred at 0 °C for 30 min. 7.035 g
interesting that amphiphilic dendritic peptides G3 can form a L-Aspartic acid dodecyl ester (15 mmol) and 2.280 g HOBt
hexagonal columnar liquid crystals over a wide temperature (15 mmol) were added and the mixture stirred at room tempera-
range.
ture for 24 h. Solvent was removed by rotary evaporation. The
crude product was purified by column chromatography on silica
gel with methylene chloride:ethanol (100:1) as an eluent to
Experimental
L-Aspartic acid and N-carbobenzyloxy-L-aspartic acid were afford G2 as a white solid (4.38 g, 75%). 1H NMR (300 MHz,
purchased from Yangzhou Baosheng Bio-Chemical Co. Ltd. CDCl3, δ) 0.89 (t, 12H, CH3), 1.26 (s, 72H, CH2), 1.62 (s, 8H,
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochlo- CH2), 2.64 (t, 2H, CH2), 2.81 (m, 2H, CH2), 2.95–3.01 (m, 2H,
ride (EDCI), 4-dimethylaminopyridine and 1-hydroxy benzotri- CH2), 2.93–3.01 (m, 8H, CH2), 4.59 (s, 1H, CH), 4.80 (s, 2H,
azole were purchased from Shanghai Medpep Co. Ltd. 1-Dode- CH), 5.13 (d, 2H, CH2), 6.71 (s, 1H, NH), 6.73 (s, 1H, NH),
canol and solvents were purchased from Sinopharm Chemical 7.29–7.36 (m, 5H, C6H5), 7.59 (s, 1H, NH). Anal. Calcd for
Reagent Co. Ltd, and used without any further purification. C68H119N3O12: C, 69.76; H, 10.25; N, 3.59. found: C, 70.04; H,
Solvents used for precipitation and column chromatography 10.06; N, 3.70. m/z [MALDI–TOF]: 1192.8 (M + Na+)
were distilled under normal atmospheric pressure. 1H NMR
spectra were recorded at 20 °C on a 300 MHz NMR spectro- G3: 0.133g N-carbobenzyloxy-L-aspartic acid (0.5 mmol) was
meter (Bruker). Chemical shifts are reported in ppm at room dissolved in 30 mL of DCM, 0.288 g EDCI (1.5 mmol) was
temperature in CDCl3 with tetramethylsilane as internal stan- added, and the mixture stirred at 0 °C for 30 min. 1.553 g of the
dard unless indicated otherwise. Mass spectra were carried out second generation L-aspartic acid dodecyl ester (1.5 mmol) and
using MALDI-TOF/TOF matrix assisted laser desorption 0.228 g HOBt (1.5 mmol) were added and the mixture stirred at
ionization mass spectrometry with Autoflex III Smartbeam room temperature for 24 h. Solvent was removed by rotary
(Bruker Daltonics Inc). Differential scanning calorimetry (DSC) evaporation. The crude product was purified by column chro-
was carried out with a Perkin Elmer differential scanning matography on silica gel with methylene chloride:ethanol
202

Beilstein J. Org. Chem. 2011, 7, 198–203.
15.Nishii, M.; Matsuoka, T.; Kamikawa, Y.; Kato, T. Org. Biomol. Chem.
2005, 3, 875–880. doi:10.1039/b416474a
(100:3) as an eluent to afford G3 as a white solid (0.69 g, 60%).
1H NMR (300 MHz, CDCl3, δ) 0.88 (t, 24H, CH3), 1.29 (s,
144H, CH2), 1.59 (s, 16H, CH2), 2.70 (s, 8H, CH2), 2.83 (m,
4H, CH2), 2.93 (m, 2H, CH2), 4.02–4.12 (m, 16H, CH2), 4.54
(s, 1H, CH) , 4.82 (m, 6H, CH), 5.11 (s, 2H, CH2), 6.32 (d, 1H,
NH), 7.11 (m, 2H, NH), 7.26–7.36 (m, 5H, C6H5), 7.69–7.97
(m, 4H, NH). Anal. Calcd for C132H235N7O24: C, 68.80; H,
10.25; N, 4.25. found: C, 68.55; H, 10.16; N, 4.51. m/z
[MALDI–TOF]: 2326.8 (M + Na+)
16.Kamikawa, Y.; Kato, T. Org. Lett. 2006, 8, 2463–2466.
doi:10.1021/ol060580q
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Acknowledgements
This work was supported by the Science Research Project of
Department of Education of Hebei Province (Nos.2007413), the
National Natural Science Foundation of Hebei Province (Nos.
B2007000146), the National Natural Science Foundation of
China (Nos.20804012).
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
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