Enhanced Mechanical and Thermal Strength in Mixed-Enantiomers-Based Supramolecular Gel

Article abstract of DOI:10.1021/acs.langmuir.8b02729

Mixing supramolecular gels based on enantiomers leads to re-arrangement of gel fibers at the molecular level, which results in more favorable packing and tunable properties. Bis(urea) compounds tagged with a phenylalanine methyl ester in racemic and enantiopure forms were synthesized. Both enantiopure and racemate compounds formed gels in a wide range of solvents and the racemate (1-rac) formed a stronger gel network compared with the enantiomers. The gel (1R+1S) obtained by mixing equimolar amount of enantiomers (1R and 1S) showed enhanced mechanical and thermal stability compared to enantiomers and racemate gels. The preservation of chirality in these compounds was analyzed by circular dichroism and optical rotation measurements. Analysis of the scanning electron microscopy (SEM) and atomic force microscopy (AFM) images revealed that the network in the mixed gel is a combination of enantiomers and racemate fibers, which was further supported by solid-state NMR. The analysis of the packing in xerogels by solid-state NMR spectra and the existence of twisted-tape morphology in SEM and AFM images confirmed the presence of both self-sorted and co-assembled fibers in mixed gel. The enhanced thermal and mechanical strength may be attributed to the enhanced intermolecular forces between the racemate and the enantiomer and the combination of both self-sorted and co-assembled enantiomers in the mixed gel.

Full text of DOI:10.1021/acs.langmuir.8b02729

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Interface Components: Nanoparticles, Colloids, Emulsions, Surfactants, Proteins, Polymers
Enhanced mechanical and thermal strength in
mixed enantiomers based supramolecular gel
Daníel Arnar Tómasson, Dipankar Ghosh, Zala Kržišnik, Luiz Henrique Fasolin, António
Augusto Vicente, Adam D. Martin, Pall Thordarson, and Krishna Kumar Damodaran
Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b02729 • Publication Date (Web): 01 Oct 2018
Downloaded from http://pubs.acs.org on October 14, 2018
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Enhanced mechanical and thermal strength in mixed
enantiomers based supramolecular gel
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Daníel Arnar Tómasson,†,⊥ Dipankar Ghosh,†,⊥ Zala Kržišnik,† Luiz Henrique Fasolin,‡ António A. Vi-
cente,‡ Adam D. Martin,§ Pall Thordarson,§ and Krishna K. Damodaran*,†
† Department of Chemistry, Science Institute, University of Iceland, Dunhagi 3, 107 Reykjavík, Iceland. Tel: +354 525 4846,
Fax: +354 552 8911.
‡ Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal
§ School of Chemistry, The Australian Centre for Nanomedicine and the ARC Centre of Excellence in Convergent Bio-Nano
Science and Technology, University of New South Wales, Sydney-2052, Australia
Supporting Information Placeholder
ABSTRACT: Mixing supramolecular gels based on enantiomers leads to re-arrangement of gel fibers at the molecular level, which re-
sults in more favorable packing and tuneable properties. Bis(urea) compounds tagged with a phenylalanine methyl ester in racemic and
enantiopure forms were synthesized. Both enantiopure and racemate compounds formed gels in a wide range of solvents and the racemate
(1-rac) formed a stronger gel network compared to the enantiomers. The gel (1R+1S) obtained by mixing equimolar amount of enantio-
mers (1R and 1S) showed enhanced mechanical and thermal stability compared to enantiomers and racemate gels. The preservation of
chirality in these compounds was analyzed by circular dichroism and optical rotation measurements. Analysis of the SEM and AFM imag-
es revealed that the network in the mixed gel is a combination of enantiomers and racemate fibers, which was further supported by solid
state NMR. The analysis of the packing in xerogels by solid state NMR spectra and the existence of twisted-tape morphology in SEM and
AFM images confirmed the presence of both self-sorted and co-assembled fibers in mixed gel. The enhanced thermal and mechanical
strength may be attributed to the enhanced intermolecular forces between the racemate and enantiomer and the combination of both self-
sorted and co-assembled enantiomers in the mixed gel.
vidual gels.18 An excellent strategy is to use enantiomers, for ex-
ample chiral gels to design multi-component systems with struc-
INTRODUCTION
Supramolecular gels based on low molecular weight gelators
(LMWGs)1-9 have witnessed a tremendous growth over the last
decade due to their emerging potential applications10-16 such as
dynamic gels, biological applications using gels as cell growth
scaffolds and also as a medium to control crystal growth, drug
delivery etc. Although the majority of these gelators are based on
individual molecules, gels based upon multi-component systems
have emerged as smart materials due to their application in tuning
gel state properties.17-30 Multi-component gels are formed when
two or more components are mixed together in a well-defined
turally similar components.
stoichiometry and also by introducing an external entity such as
33
nanoparticles,31 graphene,32,
carbon nanotubes,34 clay
nanosheets,35 liquid crystal,36 surfactants37, 38 and polymers39-41 to
an individual system to trigger gelation process. Multi-component
gels based on mixing individual gels are less explored, which will
lead to the co-assembly or self-sorting of individual gels either
constructively or destructively resulting in mixtures of gel and
crystals42 or “multi-gelator” gels.20, 43-45 The self-sorting processes
of multi-component gels can be analyzed by various analytical
methods (NMR, XRD etc.)8, 45, 46 and also by direct and real-time
imaging of self-sorted supramolecular fibers.47 However, predict-
ing the formation of co-assembled or self-sorted multicomponent
gels is challenging due to the differences in their mutual interac-
tions and the gelation conditions. The co-assembly and self-
sorting is often dictated by the structural similarity between indi-
Scheme 1. Self-assembly modes in mixed gels.
Chiral LMWGs have proved to be an excellent class of soft mate-
14, 43, 48-50
rials
due to their potential applications in the field of
asymmetric catalysis, chiral nano-materials and chiral recognition.
Gel fibers often show chirality at a mesoscopic scale, which is
evident from their morphology (helical cylinders or multiple heli-
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1
ces)48 and Gunnlaugsson and Pfeffer’s group showed that chirality
of the gelator dictates the self-assembly processes of gels resulting
in the formation of helical materials.51 Chirality plays an im-
portant role in controlling and mediating the self-assembly of
LMWGs, which clearly explains the occurrence of stereogenic
centers14, 43, 48, 49, 52 in most LMWGs. LMWGs based on enantio-
merically pure chiral molecules display strong gelling ability
compared to their racemates.43, 46, 53, 54 Interestingly, when pure
enantiomers are less efficient gelators or non-gelators, a reverse
phenomenon is observed.55-62 A racemate LMWG can be consid-
ered as a multi-component gel, where two structurally similar
compounds are present in stoichiometric ratio. Mixing enantio-
mers lead to self-recognition at the molecular level and pure enan-
tiomers would interact with enantiomers, which may lead to more
favorable packing and better gels.18, 63-65
ester as white powder. Yield: 4.99 g, 92%. H NMR (400 MHz,
CDCl3): δ [ppm] = 7.32-7.18 (m, 5H), 3.74 (dd, J=8.0, 5.2, 1H),
3.72 (s, 3H), 3.09 (dd, J=13.5, 5.1, 1H), 2.86 (dd, J=13.5, 7.9,
1H), 1.47 (s, 2H).
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General Synthesis of R-R bis(urea) (1R) and S-S bis(urea) (1S)
compounds: The phenylalanine methyl ester hydrochloride (1.3 g,
6.0 mmol, either R or S) was dissolved in 60 mL chloroform and
3
mL of trimethylamine was added. A solution of 1,6-
disocyanatohexane (482 µL, 3.0 mmol) in chloroform (40 mL)
was added dropwise under N2 atmosphere over a period of one
hour. The solution was then refluxed at 60 °C overnight, cooled to
room temperature and the solvent was evaporated to yield a white
oil. The oil was dried in air and suspended in 50 mL distilled wa-
ter and stirred. The suspension was filtered, washed with ethyl
acetate and dried to yield the desired product as white powder.
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1
Multi-component self-assembled gels obtained by mixing en-
antiomers have shown different properties compared to the indi-
vidual gels.63, 65-69 For example, Schneider’s group reported mix-
ing an equimolar ratio of enantiomers enhanced the mechanical
strength of amino acid based gels.67, 70 This is due to the structural
similarity of enantiomers, which will either self-sort or co-
assemble depending upon the environment. Self-sorting occurs
when enantiomers independently assemble and retain their chirali-
ty, whereas in the case of co-assembly it may result in random or
specific co-assembly similar to its racemate (Scheme 1). In a
mixed enantiomer system, the interaction of enantiomers with the
same conformation results in separate aggregates via self-sorting,
which may lead to conglomerate formation.18 Based on their stud-
ies on amphipathic peptides, Nilsson and co-workers proposed
that enantiomers form co-assembled rippled β-sheet fibrils rather
than self-sorting.63 In this work, we have designed multicompo-
nent gels based on amino acid compounds to analyze the differ-
ence between the self-assembly of pure and mixed enantiomers.
Enantiomeric multicomponent gels based on amino acid deriva-
tives are ideal candidates due to their availability in enantiomeric
and racemic forms, easily accessible, relatively cheap and easi-
ness in modifying the substituent groups.64
1R: Yield: 1.50 g, 95.0%. H NMR (400 MHz, DMSO-d6) δ 7.31
– 7.13 (m, 10H), 6.11 (d, J = 8.2 Hz, 2H), 6.05 (t, J = 5.7 Hz, 2H),
4.39 (td, J = 8.0, 5.6 Hz, 2H), 3.59 (s, 6H), 2.99 – 2.82 (m, 8H),
1.35 – 1.16 (m, 8H). 13C NMR (100 MHz, DMSO-d6) δ 173.19,
157.49, 137.19, 129.21, 128.34, 126.62, 54.09, 51.74, 39.15,
37.71, 29.94, 26.13. HRMS (APCI) Calcd for C28H38N4O6 526.28;
found 549.26 [M+Na]+.
1
1S: Yield: 1.46 g, 92.3%. H NMR (400 MHz, DMSO-d6) δ 7.38
– 7.07 (m, 10H), 6.12 (d, J = 8.2 Hz, 2H), 6.06 (t, J = 5.9 Hz, 2H),
4.40 (td, J = 8.0, 5.6 Hz, 2H), 3.59 (s, 6H), 2.93 (m, J = 17.1, 8.9,
7.9 Hz, 8H), 1.42 – 1.09 (m, 8H). 13C NMR (100 MHz, DMSO-
d6) δ 173.20, 157.52, 137.20, 129.22, 128.35, 126.64, 54.11,
51.76, 39.17, 37.73, 29.96, 26.14. HRMS (APCI) Calcd for
C28H38N4O6 526.28; found 549.26 [M+Na]+.
Synthesis of racemic bis(urea) (1-rac) The rac-phenylalanine
methyl ester (1.11 g, 6.2 mmol) was dissolved in 60 mL chloro-
form and 2 mL of trimethylamine was added. A solution of 1,6-
disocyanatohexane (500 µL, 3.1 mmol) in chloroform (40 mL)
was added dropwise under N2 atmosphere over a period of one
hour. The resulting mixture was refluxed at 60 °C overnight,
cooled to room temperature and a similar reaction workup for 1R
was followed to yield desired product as white powder. Yield:
1
1.57 g, 96.3%. H NMR (400 MHz, DMSO-d6) δ 7.33 – 7.12 (m,
EXPERIMENTAL SECTION
Materials and Methods
10H), 6.11 (d, J = 8.2 Hz, 2H), 6.05 (t, J = 5.7 Hz, 2H), 4.39 (td, J
= 8.1, 5.6 Hz, 2H), 3.59 (s, 6H), 3.00 – 2.82 (m, 8H), 1.34 – 1.24
(m, 4H), 1.24 – 1.15 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ
173.22, 157.55, 137.21, 129.24, 128.37, 126.66, 54.13, 51.78,
39.18, 37.74, 29.97, 26.15. HRMS (APCI) Calcd for C28H38N4O6
526.28; found 549.26 [M+Na]+.
All starting materials and reagents were commercially available
(Sigma Aldrich) and used as supplied. Deionised water was used
for gelation test and solvent chloroform was distilled over P2O5,
and methanol over Mg turnings in presence of small amount of
iodine.
Synthesis
Gelation details
Methyl-rac-phenylalaninate:
5
g
(30.0 mmol) of rac-
Gelation test: 10 mg of gelator was taken in a test tube and 1 mL
of the appropriate solvent was added, the solution was heated until
the compound completely dissolved. The test tube was then soni-
cated and left undisturbed for gelation and the gel formation was
confirmed by inversion test.
phenylalanine was dissolved in 70 mL of methanol and 2 mL of
conc. H2SO4 was added. The solution was refluxed overnight and
then cooled to room temperature. Methanol was evaporated and
the white oil obtained was stirred with 2% NaHCO3 solution. The
solution was extracted with DCM (3 x 75 mL), the combined
organic layers were dried over Na2SO4 and evaporated to yield the
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Minimum gel concertation (MGC): 10 mg of the gelators 1R, 1S
a through lens detector at an operating voltage of 5 kV, with a
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or 1-rac was placed in a vial and 1 mL of solvent was added. The
vial was heated until a clear solution was obtained. The solution
was then sonicated and left to cool to room temperature for gela-
tion. Additional solvent was added in portions and the gelation
process was repeated until a small amount of solvent was left on
top of the gel, the excess solvent was then decanted and MGC was
calculated by weight. Similar experiments were performed for the
1R+1S mixed gel, which was prepared by mixing equal amount
of 1R and 1S.
working distance of between 4.9-5.7 mm.
Atomic Force Microscopy: Gels of 1R, 1S (0.7 wt%), 1-rac
(0.15 wt%) and 1R+1S (0.3 wt%) were dispersed in appropriate
solvent (toluene or EtOH/water), heated to dissolve and the gels
were formed in 5 minutes after cooling. The solutions were dilut-
ed 5 x (100 µL + 400 µL solvent) and 10 x (100 µL + 900 µL
solvent), One drop of the organogel in its solution phase was cast
onto a mica substrate, followed by spreading of the drop over the
mica using a glass slide, with the excess liquid wicked away using
capillary action. Samples were left to dry overnight before imag-
ing. Imaging was undertaken on a Bruker Mulitmode 8 Atomic
Force Microscope in Scanasyst Air (PeakForce Tapping) mode,
which is based upon tapping mode AFM, but the imaging parame-
ters are constantly optimized through the force curves that are
collected, preventing damage of soft samples. Bruker Scanasyst-
Air probes were used, with a spring constant of 0.4–0.8 nm and a
tip radius of 2 nm.
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gel experiment: 10 mg of the gelator (1R, 1S or 1-rac) was taken
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in a standard 7 mL vial and 1 mL of appropriate solvent was add-
ed. The solution was heated and sonicated to dissolve the com-
pound and allowed to stand undisturbed. After 24 hours, a small
spherical glass ball (92 mg) was placed on the top of the gel. The
vial was placed over an oil bath equipped with a magnetic stirrer
and a thermometer. The oil bath was gradually heated and the
observation was noted. The temperature at which the glass ball
touched the bottom of the vial was recorded as Tgel. Similar exper-
iments were performed for the 1R+1S mixed gels by mixing 5 mg
of each 1R and 1S.
Circular Dichroism: The data was collected using a Chiras-
canPlus CD spectrometer (Applied Photophysics, UK) scanning
between wavelengths of 180–500 nm with a bandwidth of 1 nm,
0.6 s per point, and step of 1 nm. The gels of 1R, 1S, 1-rac and
1R+1S were prepared at their minimum gel concertation in
EtOH/water (1:1 v/v). After 24 hours the gel was dispersed in
EtOH/water (1:1 v/v) to obtain various concentrations (0.005,
0.025 and 0.05 wt%) for CD experiments. CD experiments in
solution state were performed by dissolving 2.5 mg of the gelator
(either 1R, 1S, 1-rac or 1R+1S) in 10 mL of absolute ethanol.
Rheology: The rheological study was performed by using a TA
Instruments Advanced Rheometer 2000 and toluene was selected
as the gelling solvent. The gels of 1R, 1S and 1-rac were prepared
by heating 50 mg of corresponding gelator in 1 mL toluene and
the resulting solutions were kept at room temperature without
disturbing for one hour. The 1R+1S gel was prepared by mixing
equal amount of 1R and 1S (25 mg in 0.5 mL toluene), heated and
left at room temperature without disturbing for one hour. A stain-
less steel cone-plate geometry (20 mm, 2° angle, truncation 64
ꢀm) was used. Viscoelastic properties were evaluated by oscilla-
tory measurements, using a frequency sweep between 0.1 and 10
Hz within the linear viscoelasticity domain (0.05% deformation).
Complex moduli (G*) and tanδ were evaluated. Mechanical prop-
erties were determined by uniaxial compression measurements
using a TA HD Plus Texture Analyzer (Stable Micro Systems,
UK) with a stainless steel 0.5 mm probe. The probe penetrated
80% of the initial height using a crosshead speed of 1 mm/s.
Optical rotation measurements (OD): The OD experiments for
both enantiomers, the racemic mixture and the mixed gel (at 50/50
wt/wt) were carried out at 589 nm, on an Autopol V from Ru-
dolph research analytical, in both a gelling solvent (toluene) and a
non-gelling solvent (2-butanol). Due to the opaque nature of the
gel, the concentration was kept under the minimum gel-
concentration.
1
NMR Experiments: The solution state H and 13C-NMR spectra
were recorded on Bruker Advance 400 spectrometer (1H-NMR:
400 MHz, 13C-NMR: 100 MHz). The solid state NMR spectra
were recorded on Bruker Avance III 700 MHz spectrometer on
xerogels of 1R, 1S, 1-rac and 1R+1S in toluene at 1 wt%.
Scanning Electron Microscopy (SEM): 20 mg of the gelator
(1R, 1S or 1-rac) was dissolved in 1 mL of toluene/ethyl acetate
by heating and sonicating. The solution was allowed to stand un-
disturbed to form the gel. After 24 hours, it was filtered through
filter paper and the residue was dried in air. The 1R+1S xerogel
was prepared by same procedure from the gel obtained by mixing
equal amount of 1R and 1S. The xerogels were gold coated and
placed on a Leo Supra 25 microscope for scanning electron mi-
croscopy and the morphologies of the dried gels were examined
by SEM. The EtOH/water xerogels were lightly dusted onto dou-
ble sided carbon tape and was then coated with a 30 nm layer of
platinum using a Leica EM ACE600, where the thickness was
monitored using a film thickness monitor. The SEM imaging for
EtOH/water gels were undertaken on a NanoSEM 230 fitted with
RESULT AND DISCUSSION
We have selected the bis(urea) moiety as a hydrogen bonding
backbone, which has been extensively used as a supramolecular
synthon for the self-assembly of gelators in LMWGs with tunea-
ble properties.71-76 Compounds based on bis(urea) ligands form a
α-urea tape structure, which will result in a 1-dimensional tape
like network (fibrils) and these fibrils aggregate to form an inter-
connected, entangled 3-D framework capable of immobilizing
solvent molecules thereby inducing gelation in small molecules.7,
77-81
Enantiopure R-R (1R) and S-S (1S) bis(urea) compounds
based on amino acid derivatives were synthesized by reacting
1,6-diisocyanatohexane and corresponding methyl ester protected
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amino acid hydrochloride in chloroform.81-83 The racemate
The 1-rac gels formed in toluene, chlorobenzene and xylenes
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bis(urea) compound (1-rac), which is a statistical mixture of R-S,
R-R and S-S (see supporting information) was synthesized by
reacting racemate phenylalanine methyl ester with 1,6-
diisocyanatohexane in chloroform (Scheme 2). The gelation prop-
erties of these compounds were tested in a series of solvents.
(ortho-, meta- and para-) can be classed as super gelators. Specif-
ically, less than half the concentration was required to form the
gels for 1-rac gels compared to enantiomerically pure gels, indi-
cating that the presence of both isomers increases gelling ability.
This may be attributed to the π−π interaction between the solvents
and gelator molecules in the 3-D network, within which the sol-
vent molecules are entrapped. Furthermore, the α-sheet like struc-
ture of the urea network could be preserved due to the absence of
the strong hydrogen bonding moieties. These results clearly indi-
cate that both 1R and 1S self-assemble to form a strong network
in the racemate form 1-rac. This lead to an interesting question,
what happens when two enantiomers are mixed? Will 1R and 1S
undergo self-sorting or co-assembly to form conglomerate or
racemate? This prompted us to evaluate the gelation property of
mixed enantiomers, which was performed by mixing equal
amount of 1R and 1S in a series of solvents at 1 wt% resulting in
mixed gels. The mixed gel turned out to be an excellent multi-
component gel and gels were formed in 23 solvents. Analyzing
the gelation results revealed that 1R+1S formed gel at 1 wt% in
solvents such as acetonitrile, tetrahydrofuran, acetone, 2-butanol,
n-butanol and 1,4-dioxane and 2 wt% in n-propanol respectively,
whereas 1R, 1S and 1-rac did not form gel in these solvents (Ta-
ble S1, see supporting information). The experiments performed
on mixed gels prepared by mixing equimolar solutions of 1R and
1S resulted in similar gelation properties.
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Scheme 2. Synthesis of 1R, 1S, 1-rac bis(urea) compounds
Gelation experiments: The initial screening was performed in a
series of solvents with 1 wt% of the compound. In a typical exper-
iment, the compounds were heated and sonicated in a particular
solvent to get a clear solution, cooled to room temperature and the
gel formation was confirmed by inversion test (Figure 1). All the
three bis(urea) compounds (1R, 1S and 1-rac) formed gels in 1,2-
dichloroethane, benzene, toluene, o-xylene, m-xylene, p-xylene,
chlorobenzene, ethyl acetate, 2-butanone and nitrobenzene. This
is quite interesting that all the three forms (both enantiomeric and
racemate) show gelation for a wide range of solvents. Generally,
selective gelation is observed with either the enantiomers or
racemate,46, 53, 54, 56, 84 but gel formation of both enantiomers and
racemate are rare.56, 57, 85, 86 The selective gelation of 1-rac at 1
wt% was observed in cyclohexanone and mesitylene. (Table S1,
see supporting information) The occurrence of partial gels
prompted us to check the gelation of the compounds at higher
concentrations, and gels were obtained at higher wt% for 1R and
1S in mesitylene (2 wt%). Gels were formed at 2 w% for the
racemate 1-rac in isopropanol, 2-pentanol and n-pentanol and in
ethanol at 3 wt%. We have also checked the gelation properties in
aqueous solution by using 50% (v/v) of water and a co-solvent
(either methanol, ethanol, DMA, DMF and DMSO) to dissolve
the compounds. Hydrogels were obtained at 1 wt% for most of the
cases except for 1-rac in DMF/water and DMSO/water, where
gelation occurred at 2 wt%.
Table 1. Gel-Sol transition temperature (°C) of the enanti-
omers, racemate and mixed gels at 1 wt%.
Solvent
1R
1S
1-rac
85.0
61.0
98.0
97.0
90.0
40.0
75.5
52.5
1R+1S
106.5
73.5
Toluene
91.0
55.0
94.0
99.0
92.0
38.0
73.0
51.5
86.5
54.5
91.0
95.0
91.0
37.5
70.5
44.5
Ethyl acetate
p-xylene
102.0
102.0
99.0
m-xylene
o-xylene
2-butanone
Chlorobenzene
EtOH/Water
55.5
90.5
55.5
Gel strength: The thermal stability of the gel network was evalu-
ated using gel to solution transition temperature test (Tgel). In or-
der to compare gel strength, we have selected solvents such as
toluene, ethyl acetate, xylenes (ortho-, meta- and para-), 2-
butanone, chlorobenzene and EtOH/water (50% v/v) and the gel
concentration was fixed at 1 wt%. Analysis of the results revealed
that Tgel of 1R in toluene, m-xylene and p-xylene is higher com-
pared to 1S and 1-rac gels (Table 1). In other cases, the 1-rac gel
displayed the highest Tgel value indicating a thermally stronger
network whereas 1S showed similar or lower values than 1R.
Figure 1. Gel images (left) in toluene and (right) EtOH/water
(50%, v/v).
The minimum gel concentration of the gelators were evaluated in
solvents such as ethyl acetate, 2-butanone, toluene, chloroben-
zene, xylenes (ortho-, meta- and para-) and nitrobenzene (Table
S2, see supporting information). Interestingly, 1-rac compounds
formed gels at lower concentration compared to the 1R and 1S.
Interestingly, there is a distinct difference in 1R+1S mixture Tgel
,
which is higher than pure enantiomers and racemate in all cases
(Table 1). A difference of 10 to 20 °C was observed for toluene,
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4x106
3x106
ethyl acetate and 2-butanone. This clearly indicate that the 3-D
network in the enantiomers and the mixed gels are different. This
1
2
3
4
5
6
7
8
9
was confirmed by variable temperature rheology experiments in
toluene (Figure S1, see supporting information). We have also
compared the Tgel of the hydrogels obtained from EtOH/water
(1:1, v/v) and 1R+1S gels showed greater thermal stability com-
pared to the enantiomers and the racemate gels. The enhanced
thermal stability of the mixed gel (1R+1S) gel may be attributed
to the self-assembly of these components into a new or mixed
network as compared to the enantiomer and racemate fibrils. The
Tgel experiments performed on 1 wt% of mixed gels by varying
the concentration of both 1R and 1S revealed that the gel for-
mation of 1R+1S depends on 1R and 1S concentrations respec-
tively (Figure 2).
2x106
106
9x105
8x105
7x105
6x105
1R+1S
1-rac
1S
1R
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60
5x105
0.1
1
Frequency (Hz)
10
Figure 3. Complex modulus G* for gels produced with 1R, 1S, 1-
rac and 1R+1S in toluene at 5 wt%.
Toluene
110
105
100
95
90
85
80
75
70
65
60
55
50
45
40
35
Chlorobenzene
Ethyl Acetate
2-butanone
It is worth mentioning that a strain sweep was also carried out to
determine the linear viscoelastic region. This ensured that the
systems did not undergo an irreversible deformation during the
experiments and the original structure of the organogels can be
evaluated. All organogels showed gel-like behavior with no fre-
quency dependence (Figure 3). The 1R, 1S and 1-rac gels exhib-
ited very similar G* behavior. However, the 1R+1S gel had a
slightly lower complex modulus (G*) value, indicating the pres-
ence of a weak fibrous network in comparison to the other gels. It
should be noted that the 1R+1S G´ values were not so different
from the other gels, but the viscous contribution (G´´) was higher
for 1R, 1S and 1-rac systems, leading to higher values of G*.
Indeed, tanδ results presented lower values for the 1R+1S system,
while the other gels remained very close to each other (Figure S2,
see supporting information). The lower tanδ value indicates a
prevailing elastic modulus (G´), i.e. more solid characteristic,
which will enable the network to withstand higher applied forces
without irreversible deformation. The mechanical strength of all
gels was compared by evaluating the force required to penetrate a
certain distance through a gel, force vs distance was plotted (Fig-
ure 4). Unlike rheological analysis, mechanical properties meas-
ure high and irreversible deformation, complementing the rheo-
logical results, which are performed at small deformations. These
results clearly indicate that 1R, 1S and 1-rac showed similar be-
havior with maximum forces with same magnitude. On the other
hand, a higher maximum force was observed for the mixed gels
(1R+1S). Moreover, a larger area under the curve also means a
stronger structure, which was observed for 1R+1S, indicating that
this gel was stronger in comparison to the other systems. Mechan-
ical results corroborated rheological tests, showing that 1R+1S
presented more solid character with higher resistance to applied
forces.
0
20
40
60
80
100
% of R
Figure 2. Tgel of 1R+1S gels by varying the concentration of both
1S and 1R in toluene, ethyl acetate chlorobenzene and 2-
butanone.
Rheology: Rheology was used to evaluate the structural charac-
teristics of supramolecular gels, which enables us to elucidate
information regarding factors controlling the gelation, gel strength
and the solid-like properties of pure gels. For example, Adams
and co-workers reported the combination of self-sorted LMWGs
and photo responsive gelators offer the possibility of spatially
controlling the rheological properties of LMWG.45 We performed
frequency sweep experiments to compare the relative gel behavior
of 1R, 1S, 1-rac and 1R+1S in toluene at 5 wt%. Elastic (G´) and
viscous (G´´) moduli were evaluated, as well as the complex
modulus (ꢀ∗ = √ꢀ´ꢁ + ꢀ´´ꢁ) and tanδ (G´´/G´).
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1400
1200
1000
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600
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0
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1R+1S
1-rac
1S
1R
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0
2
4
Distance (mm)
6
8
10
Figure 4. Comparison of mechanical strength for gels 1R, 1S, 1-
rac and 1R+1S in toluene at 5 wt%.
Gel morphology: The morphologies of all gels were analysed by
scanning electron microscopy (SEM). All gels were prepared at 2
wt% in toluene and ethyl acetate, then filtered and dried under a
fume hood for 2-3 days. A small portion of the dried gel was
placed on a pin mount with graphite planchets on top and was
coated with gold for three minutes. The SEM images revealed that
all xerogels display a typical fibrous and helical network (Figure 5
and 6). The SEM images of xerogels from ethyl acetate showed
that 1R and 1S form helical fibrous network (Figure S3). The
individual fibrils form helical fibrous aggregates with varying
dimensions and the thickness of each helical fibers varied from 25
to 40 nm. The larger bundles of 100 nm to 150 nm are formed by
wrapping of individual fibers around each other in a helical man-
ner resulting in a physically entangled networks, this type of
twisting is often observed in chiral compounds.84, 87, 88 The helici-
ty of single fibers for 1R and 1S clearly indicate that molecular
chirality had been successfully transferred to the hierarchical ag-
gregates (Figure 5a). The morphology of racemate xerogel 1-rac
is different from its enantiomers and tape like fibers were ob-
served (Figure 5b). The thickness of each fiber varied from 50 to
200 nm with few fibrils wrapped around each other. Interestingly,
a twisted tape like architecture was observed in 1R+1S with bun-
dles of varying dimension from 50 to 200 nm indicating the pres-
ence of both enantiomers and racemate (Figure 6a). The SEM of
xerogels obtained from toluene showed similar morphologies,
both 1R and 1S form helical fibrous network with a thickness of
30 to 70 nm (Figure S4, see supporting information). These small
fibers merge with each other to form a thicker helix of diameter
150 – 200 nm.
Figure 5. SEM images of (a) 1S and (b) 1-rac xerogels in ethyl
acetate, inset shows the magnified images.
Xerogels of 1-rac from toluene shows similar tape like morpholo-
gy (Figure S5, see supporting information) The 1R+1S xerogel
displayed twisted tape morphology similar to ethyl acetate gels
and the diameter of the fibers were found to be 100 – 250 nm. The
SEM analysis of xerogels obtained from EtOH/water (50% v/v)
also support the presence of mixed network in 1R+1S gels (Figure
S6, see supporting information). The presence of two types of
networks in the SEM images corroborate well with the rheology
results. In mixed networks, elastic character of the gel network
was increased due to higher entanglement, which is evident from
the rheology results of 1R+1S compared to other gels.
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Figure 7. AFM images of 1R and 1S showing the left and right
handed helical fibers; inset shows the magnified images.
Interestingly, the mixed gel 1R+1S showed both twisted and tape
like morphology. This may be attributed to self-sorting and co-
assembly of 1R and 1S fibrils when they are mixed and heated
together. Similar morphologies were observed for EtOH/water
(50%, v/v) gels and the AFM images of 1R and 1S showed helical
fibers, a tape like morphology for 1-rac and both twisted and tape
like morphology for 1R+1S (Figure S9-S10, see supporting in-
formation).
Figure 6. SEM images of 1R+1S xerogels in (a) ethyl acetate and
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(b) toluene, inset shows the twisted tape morphology.
Atomic Force Microscopy (AFM): The morphology of the gel
fibers was further analyzed by AFM studies. The gels were made
by dissolving the 1R (0.7 wt%), 1S (0.7 wt%) and 1-rac (0.15
wt%), in toluene. The 1R+1S gel was prepared by dissolving
individual 1R and 1S in toluene (0.3 wt%) and then heated. All
these gels were further dispersed in toluene (10x), dropped on a
plate, dried at room temperature and analyzed by AFM. Analysis
of the AFM images of 1R and 1S revealed that both the enantio-
mer have twisted single helix with uniform right and left-handed
morphology respectively (Figure 7). However, a tape like mor-
phology was observed for 1-rac, which clearly indicate that the
helicity was cancelled due to the co-assembly of both R and S
fibrils (Figure 8).
Figure 8. AFM images showing tape like architecture in 1-rac
and a mixture of tape and helical morphology in 1R+1S; inset
shows the magnified images.
Circular dichroism (CD): The sensitivity of CD to chiral pertur-
bations will provide information about molecular chirality and the
difference between CD signals of self-assembled and isolated
state will enable us to elucidate the structural information of the
assembled hierarchical structure.89 Although, we screened a series
of solvents, which are capable of forming gels with 1R, 1S and 1-
rac, these solvents were discarded due to background absorption.
We have selected EtOH/water mixture for our studies, which
showed an absorption cut-off at around 190-200 nm. The CD
experiments were performed at various concentrations in dis-
persed gel state and weak signals were observed below 0.005 wt%
for all gelators. On the other hand, increasing the concentration
above 0.05 wt% resulted in saturation of CD signals. Thus, we
selected 0.025 wt% as the optimum concentration for the enanti-
omers, racemate and the mixed gels (Figure 9a). The CD signal
maxima was observed at 200 nm and 220 nm for 1S may be at-
tributed to the existence of π–π stacking interactions from the
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aromatic units.90, 91 The CD spectrum of 1R showed negative
We have also performed optical rotation measurements for 1R,
1
2
3
4
5
6
7
8
signals, which is similar to the mirror image of the CD signal of
1S. The gels of 1-rac and 1R+1S (50% v/v) displayed linear CD
signal indicating the presence of both enantiomers in the gel state.
In order to get an insight to the self-assembly process the CD of
these compounds in the solution state was also analyzed (Figure
9b) and compared to the gel state CD, which indicate the for-
mation of self-assembled networks in gel state. The small peak at
240 nm observed in the gel state CD is likely due to stacking of
the aromatic phenylalanine groups within the gel. We have also
performed the CD experiments of 1R+1S by varying the concen-
tration of 1R and 1S. The CD spectrum of 1R+1S (75% 1R v/v)
mixture displayed negative maxima indicating the presence of
excess 1R (Figure S11, see supporting information). Similarly, the
experiments with 1R+1S (25% 1R v/v) displayed positive maxi-
ma.
1S, 1-rac and 1R+1S at 589 nm in solution (2-butanol) and gel-
ling solvent (toluene) at concentrations below minimum gel con-
centrations (Table S4, see supporting information). The observa-
tions were similar to that of the CD experiments.
Xerogel 1R+1S
Xerogel 1-rac
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Xerogel 1S
1R+1S solution
8
a)
200
180
160
140
120
100
80
60
40
20
0
6
1R
1S
ppm
Figure 10. Comparison of the solid state and solution state 13C
NMR of 1R, 1S, 1-rac and 1R+1S.
4
2
1-rac
1R+1S
Nuclear Magnetic Resonance Spectroscopy (NMR): The self-
assembly of 1R, 1S, 1-rac and 1R+1S were studied by NMR
0
1
spectroscopy. The H and 13C NMR of 1R, 1S, 1-rac and 1R+1S
-2
-4
-6
-8
in solution state was recorded in DMSO-d6 and similar NMR
spectra suggest that enantiomers, racemate and mixed enantio-
mers have an identical environment in the solution state (Figure
S12 and S13, see supporting information). In order to analyze
their self-assembly in the gel state, solid state NMR was per-
formed on the xerogels of 1R, 1S, 1-rac and 1R+1S by filtering 1
wt% gels, followed by drying and compared with the solution
state NMR (Figure 10).
200
220
240
260
280
300
Wavelength (λ)
b)
8
6
1R
1S
1-rac
1R+1S
1R+1S
1-rac
4
2
0
-2
-4
-6
-8
1S
1R
200
220
240
260
280
300
Wavelength (λ)
75
50
25
0
Figure 9. CD spectra of 1R, 1S, 1-rac and 1R+1S in dispersed
gel state (a) and in solution state (b).
Figure 11. Comparison of the solid state 13C NMR of 1R, 1S, 1-
rac and 1R+1S for the aliphatic region showing the mixed net-
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work in solid state for 1R+1S (*indicates the corresponding peaks
in enantiomers and racemate).
ASSOCIATED CONTENT
Supporting Information
1
2
3
4
5
6
7
8
9
Analysis of the 13C NMR of the four samples revealed that the
solid state packing of the xerogels are not identical (Figure S14,
see supporting information), which may be attributed to the dif-
ference in molecular self-assembly. Generally, the morphology
and molecular arrangement of original gels are translated to the
xerogels but in some cases the removal of solvent may result in
artefacts due to dissolution and recrystallization, changes in mor-
phology or polymorphic phase transition.9 The NMR spectrum of
enantiopure 1R and 1S were identical due to the similar 3-
dimensional packing in these structures because of their mirror
image. This observation corroborates nicely with the SEM and
AFM images, where a helical fibrous network was observed for
1R and 1S. However, the peak at δ = 42.5 ppm was missing in
racemic 1-rac but more peaks were observed at δ = 26.0, 31.8,
36.3 and 40.9 ppm (Figure 11). Thus, the self-assembly in the
racemate is different from its enantiomers and is evident from the
tape like fibers in SEM and AFM images. The packing mode of
1R+1S was analyzed by comparing the NMR spectra of 1R, 1S
and 1-rac with 1R+1S (Figure 11). It is clear from the spectrum
that 1R+1S network is a mixture of fibers from both enantiomers
and the racemate, which indicates the presence of both self-sorted
and co-assembled fibers in 1R+1S.
Further gelation test, MGC experiments, Tgel experiments, SEM
and AFM images, CD and OD experiments, rheology and NMR
spectra. “This material is available free of charge via the Internet
at http://pubs.acs.org.”
AUTHOR INFORMATION
⊥ Authors contributed equally to the work.
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Corresponding Author
E-mail: krishna@hi.is.
Notes
The authors declare no competing financial interests.
KEYWORDS
Supramolecular gel, Multi-component gel, Enantiomers, Race-
mate, Self-assembly, Self-sorting and Co-assembly
ACKNOWLEDGMENT
We thank University of Iceland Research Fund for financial sup-
port. DG thanks University of Iceland for the Doctoral Research
grant and ZK thanks University of Ljubljana for the Erasmus
exchange program. We thankfully acknowledge Dr. A. Rawal,
The Mark Wainwright Analytical Centre, UNSW for solid state
NMR studies and Dr. Sigríður Jónsdóttir, University of Iceland
for solution NMR and Mass spectroscopy. PT thanks the Australi-
an Research Council for an ARC Centre of Excellence grant
(CE140100036) and ADM thanks the National Health and Medi-
cal Research Council for a Dementia Development Research Fel-
lowship (APP1106751). LF and AV thank the FCT
(UID/BIO/04469/2013), COMPETE 2020 (POCI-01-0145-
FEDER-006684) and Norte2020 - Programa Operacional Region-
al do Norte (BioTecNorte operation, NORTE-01-0145-FEDER-
000004) for rheological studies. The rheological study was sup-
ported by a STSM Grant from COST Action CM1402 Crystallize.
Conclusions
We have successfully synthesized the enantiopure (1R) and race-
mic (1-rac) forms of bis(urea) based phenylalanine methyl ester.
The known enantiomeric form (1S) was also synthesized and all
the isomers were found to be excellent gelators capable of gelling
a wide range of solvents. Multi-component gels based on enanti-
omers were prepared by mixing the equal amount of pure enanti-
omers as well as varying individual enantiomer concentrations.
The gels were characterized using standard gelation techniques
and the morphology was analyzed by SEM, AFM and solid state
NMR. The mixed gel displayed higher thermal and mechanical
strength compared to the enantiomer and racemate gels. CD ex-
periments performed in the solution sate and gel state revealed the
preservation of chirality in the gel fibers. The enantiopure gels
displayed helical fibers and the racemate showed tape like archi-
tecture indicating co-assembly of individual enantiomers. The
mixed gel of the enantiopure gels displayed twisted tapes indicat-
ing the presence of both enantiomers and the racemate gels. This
was also confirmed by solid state NMR studies where the NMR
spectrum of the xerogel of mixed gel displayed both the forms.
This clearly indicates that in mixed gels system the fibrils re-
arrange to form self-sorted and co-assembled fibers. The en-
hanced mechanical and thermal stability of the mixed gel com-
pared to the enantiomer and racemate gel may be attributed to the
presence of both self-sorted and co-assembled fibers. The tuning
of mechanical and thermal strength as a function of self-assembly
will enable supramolecular chemists to design multi-component
systems with enhanced mechanical and thermal stability.
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Transcription
of
Organogel
Fibers
Comprised
of
Chiral
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