Intramolecular interactions of a phenyl/perfluorophenyl pair in the formation of supramolecular nanofibers and hydrogels

Article abstract of DOI:10.1002/anie.201307500

A new system for the incorporation of a phenyl/perfluorophenyl pair in the structure of a peptide hydrogelator was developed. The strategy is based on the idea that the integration of an end-capped perfluorophenyl group and a phenylalanine with a phenyl moiety in the side chain forms an intramolecular phenyl/perfluorophenyl pair, which can be used to promote the formation of the supramolecular nanofibers and hydrogels. This work illustrates the importance of structure-hydrogelation relationship and provides new insights into the design of self-assembly nanobiomaterials. Intramolecular binding: The incorporation of a phenyl/perfluorophenyl pair into the structure of a peptide hydrogelator leads to the formation of the supramolecular nanofibers. The quadrupole-dipole- quadrupole (q-d-q) interactions between the aromatic rings facilitate self-assembly. This work illustrates the importance of the structure- hydrogelation relationship and provides new insights into the design of self-assembled nanobiomaterials. Copyright

Full text of DOI:10.1002/anie.201307500

Angewandte
Chemie
DOI: 10.1002/anie.201307500
Noncovalent Interactions
Intramolecular Interactions of a Phenyl/Perfluorophenyl Pair in the
Formation of Supramolecular Nanofibers and Hydrogels**
Shu-Min Hsu, Yu-Chun Lin, Jui-Wen Chang, Yu-Hao Liu, and Hsin-Chieh Lin*
Abstract: A new system for the incorporation of a phenyl/
perfluorophenyl pair in the structure of a peptide hydrogelator
was developed. The strategy is based on the idea that the
integration of an end-capped perfluorophenyl group and
a phenylalanine with a phenyl moiety in the side chain forms
an intramolecular phenyl/perfluorophenyl pair, which can be
used to promote the formation of the supramolecular nano-
fibers and hydrogels. This work illustrates the importance of
structure-hydrogelation relationship and provides new insights
into the design of self-assembly nanobiomaterials.
benzene or benzene in the crystal is that of a herringbone
structure,[13] whereas an equimolar mixture of hexafluoro-
benzene and benzene are stacked alternatively and paral-
lel.[14] Also, experimental studies in the gas and liquid phases
show that the molecular planes between arenes are close to
parallel.[15,16] The computational studies reveal that the
formation of alternating and parallel packing of a hexafluoro-
benzene/benzene pair is the result of an optimization of
À
À
quadrupole–quadrupole, dispersion, and C H···F C interac-
tions.[12,17] In addition to the dimeric structure of the two
aromatic rings in the presence of water, a trimeric complex of
hexafluorobenzene/water/benzene is also possible. An earlier
computational study on the potential energy surface of this
system suggests the presence of the water sandwiched
between two aromatics exhibits larger binding energy than
that of the dimer with water removed.[18] It is known that
a supramolecular nanofiber in a low-molecular-weight hydro-
gel may demand a well-ordered spatial arrangement in the p-
stacking direction.[6] Therefore, we believe that the lowest
ground-state energy from the alternating packing of the dimer
or the water-assisted trimeric structure would be useful in the
structural design of low-molecular-weight hydrogelators.
From a microscopic view, a supramolecular hydrogel is
constructed by physical crosslinks and entanglements of
supramolecular nanofibers which are composed of self-
assembled hydrogelators. An efficient way to construct
a low-molecular-weight hydrogelator is to attach an p-
conjugated system, such as fluorenylmethoxycarbonyl
(Fmoc) or naphthyl (Nap), to the N terminus of a short
peptide.[19] In this work, a new system incorporating the
phenyl/perfluorophenyl pair in the structure of a hydrogelator
has been developed. The strategy is based on the idea that the
incorporation of a perfluorophenyl group as the end-capped
p-conjugated part, and a linking amino acid of phenylalanine
with a phenyl moiety in the side chain forms a new intra-
molecular building block, a phenyl/perfluorophenyl pair, for
the efficient formation of supramolecular hydrogels
(Scheme 1). Note that the use of intermolecular interactions
for phenyl/perfluorophenyl pairs to promote the supramolec-
ular hydrogelation have been demonstrated recently.[20] We
stress that the presence of the intramolecular building block
would facilitate the intermolecular self-assembly in terms of
a low-energy alternate packing of phenyl/perfluorophenyl
systems in the crystals.[14] As shown in Scheme 1, there are two
possible routes to form self-assembled nanofibers. The
proposed route 1 represents the alternating packing of the
phenyl/perfluorophenyl pair as a result of a water-assisted
effect induced by the quadrupole–dipole–quadrupole inter-
actions.[18] The route 2 shows that the alternating arrangement
of two aromatics is the consequence of the balance of
H
erein, we demonstrate the first example of intramolecular
binding of a phenyl/perfluorophenyl pair for the formation of
supramolecular hydrogels as a candidate for potential bio-
materials. Supramolecular hydrogels, a gel state resulting
from self-assembly of small molecules in water, has become
a rapidly expanding field in soft biomaterials.[1] Nowadays,
a peptide-based supramolecular hydrogel is one of the most
attractive strategies for developing soft biomaterials because
of the tunable composition and architecture.[2] There are three
major categories of peptide hydrogels: peptide amphiphiles,[3]
ionic complimentary peptides,[4] and low-molecular-weight
hydrogels.[5–11] The smallest molecular unit of a supramolec-
ular hydrogel is denoted as a hydrogelator. A low-molecular-
weight hydrogelator minimizes the available functionality
which can participate in intermolecular interactions, thus
providing useful probes of the scope and limitations of the
molecules which form supramolecular hydrogels. Recently,
a number of applications based on low-molecular-weight
supramolecular hydrogels have been explored, including
tissue engineering,[5,6] drug delivery,[7] enzyme assay,[8] protein
separation,[9] biosensing,[10] and wound healing.[11]
The supramolecular synthon, the phenyl/perfluorophenyl
pair, has attracted considerable interest because this motif is
widely used in designing structures for crystal engineering and
for reaction control in solution.[12] The packing of hexafluoro-
[*] S.-M. Hsu, Y.-C. Lin, J.-W. Chang, Y.-H. Liu, Prof. Dr. H.-C. Lin
Department of Materials Science and Engineering
National Chiao Tung University
Hsinchu, 300, Taiwan (Republic of China)
E-mail: hclin45@nctu.edu.tw
[**] We thank Prof. Shiaw-Guang Hu for technical support. We also
thank the National Science Council of the Republic of China, Taiwan
(Grant No. NSC 100-2113M-009-015-MY2) and the “Aim for the Top
University” program of the National Chiao Tung University and
Ministry of Education, Taiwan, R.O.C. for funding. We are also
grateful to the National Center for High-performance Computing of
Taiwan for computer time and facilities.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307500.
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herein: 1) determination of the peptide sequences that are
valid for triggering molecular hydrogelation under neutral
conditions for the development of soft biomaterials, 2) char-
acterization of the intermolecular interactions and physical
properties of gel materials, and 3) elucidation of the impor-
tance of intramolecular building blocks on self-assembly and
hydrogelation.
All of the peptides (1–3) were synthesized by solid-phase
peptide synthesis (SPPS, see the Supporting Information for
details). The hydrogels of peptides were prepared by
a sequential change in pH, and the resulting optical images
were collected (insets of Figure 1). The microscopic nano-
structures of the negatively stained hydrogels were measured
by transmission electron microscopy (TEM; Figure 1). We
found that dissolving the amino-acid derivative 1 at a concen-
tration of 1 wt% with a pH of 5.0 in aqueous solution led to
the formation of a hydrogel (Figure 1). The TEM analysis
revealed that the hydrogel of 1 consisted of a fibrous network
and these nanofibers entangle to trap water and result in
a hydrogel. These observations indicate self-assembly and
hydrogelation occurred in 1. Alternatively, the analogue 2 in
the concentration range of 1–3 wt% remains a clear solution.
The dramatic change in the formation of the hydrogel for
1 compared with that of 2 illustrates the remarkable fluorous
effect on self-assembly and hydrogelation. The formation of
the hydrogel of 1 confirms that the direct attachment of
a pentafluorobenzyl group (PFB) to the N terminus of the l-
phenylalanine (l-Phe) is a valid approach for designing a new
supramolecular hydrogelator. To examine the applicability of
this newly discovered building block (PFB-l-Phe) for the
design of peptide-based hydrogelators, we prepared seven
PFB-capped molecules with various peptide sequences of l-
Phe-l-Gly (3a), l-Gly-l-Phe (3b), l-Phe-l-Ala (3c), l-Ala-
l-Phe (3d), l-Phe-l-Val (3e), l-Val-l-Phe (3 f) and l-Phe-l-
Phe (3g). The hydrogelation tests of 3a (1 wt%), and 3b (1–
3 wt%) show that only 3a formed a hydrogel, thus indicating
that the presence of the building block of PFB-l-Phe is
crucial. The different behavior between l-Phe-l-Gly and l-
Gly-l-Phe in the Fmoc-capped hydrogelators has been
described recently.[21] The molecular weights of 3a and 3b
are essentially the same. The only difference between the two
molecules is the position of the benzyl side chain of the amino
acid, thus implying the importance of the intramolecular
effect of the PFB-l-Phe building block of 3a for the formation
of the hydrogel, because the intermolecular interactions of
phenyl and pentafluorophenyl groups between different
molecules of 3b do not trigger the formation of self-assembly
Scheme 1. The proposed routes for intramolecular interactions and
intermolecular self-assembly of hydrogelators (q=quadrupole,
d=dipole, HB=hydrogen bonding).
quadrupole–quadrupole, dispersion, and CH–FC interac-
tions.[12,17] Both routes form the intramolecular alternative
pair which may facilitate the formation of self-assembled
nanofibers and hydrogels. A series of molecules (Scheme 2)
were prepared and the following features are addressed
Scheme 2. The chemical structures of the compounds 1–3.
Figure 1. Optical and negatively stained TEM images of hydrogels for a) 1, b) 3a, c) 3c, d) 3e, and e) 3g at a concentration of 1 wt% (scale
bar=50 nm).
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Table 1: Physical properties of peptide-based hydrogelators and related
compounds.
Entry pH Appearance[a] Conc.
Tgel-sol G’, G’’
Fiber
diameter
[nm]
(cgc)[b]
[wt%]
[8C]
[Pa]
1
5.0 SG
1 (1.0)
56
3.0ꢀ103, 31Æ5
1.5ꢀ102
2
3a
5.0 TS
7.0 TG
1–3
1 (0.2)
48
48
46
45
1.2ꢀ104, 8Æ1
1.5ꢀ103
3b
3c
7.0 TS
6.0 TG
1–3
1 (0.2)
4.4ꢀ103, 10Æ2
3.0ꢀ102
3d
3e
6.0 TS
6.0 SG
1–3
1 (0.2)
3.2ꢀ103, 14Æ2
8.7ꢀ101
3 f
3g
6.0 TSc
10.0 TG
1–3
1 (0.5)
3.4ꢀ104, 5Æ1
8.0ꢀ103
[a] TG: transparent gel; SG: semitranslucent gel; TS: transparent
solution. [b] cgc is the lower critical gelation concentration. [c] Trans-
parent viscous solution.
Figure 2. Normalized fluorescence emission spectra of a) 1 (pH 5),
and b) 3a (pH 7) in water. Solid line: 1 wt% (gel); dashed line:
0.01 wt% (solution). The inset of (b) is the emission spectra for 3a
(pH 7, dashed line) and 3b (pH 7, solid line). CD spectra of the
hydrogels of c) 1 (pH 5) and d) 3a (pH 7) in water. Solid line: 1 wt%
(gel); dashed line: 0.01 wt% (solution).
nanofibers. In addition to the dipeptide of 3a, the dipeptides
of 3c, 3e, and 3g formed supramolecular hydrogels at
a concentration of 1 wt% (Figure 1), thus showing the
generality of the use of the PFB-l-Phe in the structural
design of the peptide-based hydrogelators. The hydrogelation
of the dipeptides were dependent on pH values (Table 1),
which can be explained by the equilibrium between the
carboxylic acid and carboxylate.[22] It is noteworthy that the
hydrogelator 3a formed a hydrogel under neutral conditions.
The lower critical gel concentration (cgc) is 0.2 wt% for 3a,
3c, and 3e, and 0.5 wt% for 3g, thus indicating that the
presence of hydrophobic and bulky side chains near the
C terminus in 3g would lead to a higher cgc. The statistical
analysis of the TEM images of the dipeptides 3a, 3c, 3e, and
3g reveals that dipeptides form high-density and thinner
fibrils in the hydrogels compared to those of 1 (Table 1).
These results confirm that self-assembly nanofibers of 1, 3a,
3c, 3e, and 3g act as the matrices to sustain the hydrogels.
While it remains a challenge to determine the accurate
molecular arrangements of the hydrogelators in the gel state,
the spectroscopic characterization of the hydrogels provides
useful and relevant information regarding the interactions of
the hydrogelators.[6,21] The fluorescence emission was used to
monitor the environment of aromatic moieties of the hydro-
gelators to assess the aromatic–aromatic (p–p) interac-
tions.[19b] The emission spectra of 1 and 3a were obtained
with an excitation wavelength of l = 260 nm for aromatic
rings under the gelation conditions (Figure 2a and b). In
Figure 2a, a clear emission band at l = 308 nm for 1 in dilute
solution was observed. In the gel state, there appears to be
a red shift in the emission (ca. 350 nm), thus indicating p–p
interactions between aromatic rings occur in the gel state of 1.
The emission spectrum of the 3a gel exhibited a red-shifted
and broad peak in comparison with that of the dilute solution.
This change in the emission profile originates from the
intermolecular aromatic–aromatic interactions. In addition,
the emission spectra of 3a and 3b in dilute solutions are
shown in the inset of Figure 2b. The red shift for the emission
of 3a relative to 3b is essential. This difference is likely
a result of a stronger intramolecular aromatic–aromatic
interactions for the phenyl/pentafluorophenyl pair in 3a
(see the Supporting Information for 3c, 3e, and 3 f).[23]
Circular dichroism (CD) was used to explore the super-
structures of these self-assembled hydrogels. In Figures 2c
and d, both the CD spectra of the hydrogels of 1 and 3a
revealed bisignated Cotton effects, with a negative part at l =
261 nm and a positive part at l = 287 nm. According to the
exciton-coupling model,[24] a bisignated Cotton effect is
consistent with the interacting p-conjugated systems in an
ordered arrangement.[25] CD spectra of the hydrogels 3c and
3g showed similar bisignated Cotton effects, while by
increasing the bulkiness of the aliphatic side chain of the
amino acid, such with as 3e, there are fewer modes of
aromatic–aromatic interactions (l = 260–330 nm) between
phenyl and pentafluorophenyl rings (see the Supporting
Information for details). Furthermore, the CD spectrum is
also a useful tool to study the formation of the extended
hydrogen-bonding interactions such as in b-sheet or b-turn
structures.[19b] Except for the hydrogel of 1, the dipeptide
hydrogels of 3a, 3c, 3e, and 3g revealed few negative peaks in
the range of l = 215–240 nm, thus implying the possibility of
the formation of b-sheet and/or b-turn structures.[19b] To
confirm this, FT-IR was employed for the analysis of the
secondary structures of the self-assembly nanostructures in
hydrogels.[6,21] FT-IR spectrum of the hydrogel of 1 revealed
that there is no secondary structure formed in the hydrogel,
thus suggesting the flexibility of the hydrogelator 1 does not
allow the single amino acid to interlock in a b-sheet
conformation (see Figure S7 in the Supporting Information).
On the contrary, the spectra of 3a, 3c, 3e, and 3g gels showed
two intense peaks located around 1656 cmÀ1 and 1630 cmÀ1, as
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well as a less intense peak around 1545 cmÀ1, which is the
typical characteristic of extended b-sheet absorptions.[26] As
suggested by the spectroscopic data, the formation of
extended self-assembled nanostructures occurs under the
gelation conditions for 1, thus indicating that the aromatic–
aromatic interactions may be the major driving force behind
the self-assembly of the hydrogelators. Although we do not
observe extended hydrogen-bonding interactions for the
hydrogel of 1, a peak for the molecular dimer was found in
the mass spectrum.[27] This observation can be reasonably
explained by the hydrogen-bonding interactions of two
carboxy end groups.[28] According to the spectroscopic
characterizations of the dipeptide hydrogels of 3a, 3c, 3e
and 3g, the cooperative effect of aromatic–aromatic and
hydrogen-bonding interactions might constitute the main
driving force for the formation of the self-assembled nano-
fibers and hydrogels. Based on the spectroscopic data of 3a,
we have built a molecular packing model which can fulfill the
requirements of extended aromatic–aromatic interactions,
extended hydrogen-bonding interactions, and the intramo-
lecular alternative packing of phenyl and perfluorophenyl
rings (see Figure S8).
It is noteworthy that the hydrogelator 1 has the minimum
number of atoms (38 atoms) in an acyclic amino-acid-based
hydrogelator to date.[29] Based on the hydrogelation tests,
TEM images, and spectroscopic data, the experimental results
are quite consistent with our hypothesis of the formation of an
intramolecular building block. However, the exact nature of
the formation of nanofibers in aqueous solution is still
debatable, despite the well-documented preference of the
intramolecular alternating arrangement of the two aromatic
rings in 1. To prove this, we employed a 1H-19F HOESY
technique which has great utility in structural and conforma-
tional analysis of organic molecules in solution. This experi-
ment measures the distance-dependent nuclear Overhauser
effect between nonbonded nuclei separated by less than
0.5 nm.[30] Owing to these advantages, the 1H-19F HOESY
experiment was used to investigate the conformation of 1 in
D2O.[31] In the 19F NMR spectrum (Figure 3a), the appearance
of three peaks at d = À145.2, À166.4, and À159.8 ppm were
assigned to the ortho, meta, and para fluorine atoms,
respectively, of the pentafluorophenyl group.[32] The intra-
molecular correlations of two aromatic rings in 1 can be
discerned in a 1H-19F HOESY spectrum displaying cross-
correlations between the 19F signals of the pentafluorophenyl
group and 1H signals of phenyl ring in phenylalanine. As
shown in Figure 3b, these correlations between the ortho-
fluorine atoms (d = À145.2 ppm in the 19F NMR spectrum) of
the pentafluorophenyl group and hydrogen atoms (d =
Figure 3. Experimental a) 19F NMR and b) 1H-19F HOESY spectra of
1 dissolved in D2O.[31] Optimized geometries of c) 1-A and d) 1-B
calculated at the MP2 at 6-31G** level of theory.
water (Figure 3).[33] This method has been used extensively in
the studies of perfluoroarene/arene pairs, and has given
reliable results when compared to experimental data and
other highly extensive ab initio calculations.[33c] Recently,
a concerted effort on the experimental and theoretical studies
reveal that the dipole–quadrupole interactions between water
and the perfluorobenzene ring are essential.[34] An earlier
computational study on the potential energy surface of
perfluorobenzene/benzene systems suggests that the presence
of water sandwiched between two aromatics results in larger
binding energy compared with that of the aromatic dimer.[18]
A plausible reason for the formation of the trimeric structure
is that the benzene and perfluorobenzene rings can serve as
a proton acceptor and a lone pair acceptor, respectively. The
MP2 optimized geometries of 1-A and 1-B are shown in
Figures 3c and d, respectively. Both of them show the tilted
structures, and the higher stabilities of tilted structures
compared with parallel ones can be ascribed to the structural
flexibility and the attractive electrostatic interactions between
the oppositely charged peripheries of the phenyl and penta-
fluorophenyl rings.[18] The distances between the two arenes in
1-A and 1-B are listed in the Supporting Information. The
MP2 calculations of water–hydrogelator interactions were
a posteriori corrected by a standard counterpoise (CP)
procedure.[18,33c] The difference in total energies between 1-
A and 1-B + H2O is À4.3 kcalmolÀ1, thus indicating that the
presence of the water sandwiched between the arenes
stabilizes the ground-state energy of 1-A. Based on the
computational data, the sandwiched water in 1 may play
a pivotal role in accommodating an appropriate geometry
which facilitates the self-assembly and hydrogelation. The
1
7.2 ppm in the H NMR spectrum) on the phenyl side chain
1
of phenylalanine were detected as crosspeaks in the H-19F
HOESY experiment, thus implying that two aromatic rings
are situated in close proximity in 1.
To gather more insight into the geometry of 1, quantum-
chemical calculations were performed on 1 to explore
whether the water-assisted effect is possible in the ground
state of 1. The Moller-Plesset (MP2) perturbation theory with
a 6-31G** basis set was used to calculate the geometries and
energies for 1 with (1-A) and without (1-B) the sandwiched
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optimized geometry of 1-B reveals that all of fluorine atoms
should appear as crosspeaks in 1H-19F HOESY (see the
Supporting Information for details). However, there is no
crosspeak from the meta- or para-fluorine atoms in the 1H-19F
HOESY spectrum of 1. This result can be explained by the
structure of 1-A. In the presence of the sandwiched water,
only the fluorine atom at the ortho position correlates the
hydrogen atoms of the phenyl ring because the distances of
these atoms are less than 0.5 nm. Based on energy and
geometry considerations, the water-assisted effect originating
from dipole–quadrupole interactions between water and the
phenyl/perfluorophenyl pair might play a crucial role in the
formation of the supramolecular hydrogel of 1. The molecules
3a, 3c, 3e, and 3g behave similarly and the results are
collected in the Supporting Information. According to the
experimental and computational results, route 1 in Scheme 1
might be the plausible pathway to trigger the self-assembly in
the system.
Supramolecular hydrogels are potentially useful scaffolds
for the application in tissue engineering.[6] In terms of
a hydrogel as three-dimensional (3D) environment for cell
growth, the following criteria should be reached: 1) the gel-
to-sol transition temperature (Tgel-sol) of the hydrogel is higher
than body temperature, 2) the mechanical properties of the
hydrogel support the mass of a cell, and 3) the hydrogel is
biocompatible with no inhibitory effect on cell-matrix inter-
actions. In general, because live cells are usually cultured at
body temperature, the Tgel-sol of a 3D culture medium needs to
be higher than the physiologically relevant temperature (i.e.,
378C, body temperature). As shown in Table 1, all gel-to-sol
transition temperatures of hydrogels of 1, 3a, 3c, 3e, and 3g
are higher than 378C, thus pointing to potential uses of these
hydrogels as scaffolds for tissue engineering. The mechanical
property of a hydrogel can be assessed by oscillatory rheology.
This method provides two essential parameters for hydrogels.
They are the elastic and viscous responses which are denoted
as storage modulus (G’) and loss modulus (G’’), respectively.
While the ideal storage modulus varies depending on cell
type, a minimum storage modulus of around 100 Pa is
necessary to support the mass of a cell.[35–37] In comparison
with various hydrogels, the viscoelastic properties of all
hydrogels are determined at the concentration of 1 wt.% and
the data are collected in Table 1. In Figure 4a, the storage
moduli of hydrogels of 1 and 3a (see the Supporting
Information for 3c, 3e, and 3g) are found to be higher than
their loss moduli, thus indicating these hydrogels are stable
elastic materials rather than viscous ones. The storage
modulus of hydrogel 1 is 3 KPa which is sufficient to support
the mass of a cell. The storage moduli of dipeptides are
collected in Table 1, and the hydrogel of 3g exhibits the
highest storage modulus (34 KPa) among the dipeptides, thus
implying that the relatively thinner nanofibers (5 nm) cause
more significant physical crosslinks and entanglements in the
system.
Figure 4. a) The frequency sweep of the supramolecular hydrogels of
1 and 3a at a concentration of 1 wt%. G’ of 1 (closed square) and 3a
(closed circle); G’’ of 1 (open square) and 3a (open circle). Viability of
CTX TNA2 cells incubated with 10, 50, 100, 200, and 500 mm of b) 1
and c) 3a after 24 and 48 h.
trazolium bromide (MTT). The experiments (Figures 4b and
c) reveal that after being incubated with the hydrogelators
1 and 3a in a concentration range of (10–500 mm) for 48 hours,
cells that were grown in liquid medium showed the prolifer-
ation capacities with high viability. The survival ratio of 1 and
3a were above 80% at 500 mm, and their morphologies were
similar to the control cells that were grown in the medium
without hydrogelators. The concentrations of 1 and 3a
required for 50% inhibition (IC50) are higher than 500 mm,
thus indicating that the hydrogelators are biocompatible.[12b]
Furthermore, we also used a wound-healing assay[38] to
examine the capability of the hydrogels of 3a where the
cell/matrix interactions are held (see Figure S10). The pres-
ence of 3a in the cell culture shows little inhibitory effect on
the migration of the CTX TNA2 cells as compared with that
of the reference, which further supports the biocompatibility
of 3a.
Hydrogels of 1 and dipeptide 3a (hydrogelation in neutral
condition) were subsequently tested for their ability to
support the biocompatibilities of CTX TNA2 cells. The
biocompatibilities of 1 and 3a were examined using a colori-
metric assay with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte-
In summary, we have detailed a new series of low-
molecular-weight hydrogelators and proved that the intra-
molecular alternative packing of the phenyl/perfluorophenyl
pair can be used to promote the formation of the supra-
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tational results, the presence of the water sandwiched
between the aromatic rings may assist in the formation of
an intramolecular phenyl/perfluorophenyl complex. It is
noteworthy that the amino-acid derivative 1 has the minimum
number of atoms in an acyclic amino-acid-based hydrogelator
prepared to date, and this minimal self-assembled scaffold can
fundamentally achieve all the hydrogel features associated
with larger peptides. Additionally, the PFB dipeptides were
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gelation conditions of dipeptide hydrogelators, thus indicating
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Please note: Minor changes have been made to this manuscript since
its publication in Angewandte Chemie Early View. The Editor.
Received: August 26, 2013
Revised: October 17, 2013
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