Self-assembled fibrillar networks of a multifaceted chiral squaramide: Supramolecular multistimuli-responsive alcogels

Article abstract of DOI:10.1039/c5sm02997j

Chiral N,N′-disubstituted squaramide 1 has been found to undergo self-assembly in a variety of alcoholic solvents at low concentrations leading to the formation of novel nanostructured supramolecular alcogels. The gels responded to thermal, mechanical, op

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TOC
The self-assembly of a chiral squaramide allows for the formation of
supramolecular fibrillar gel networks selectively in alcoholic solvents

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PAPER
Self-assembled fibrillar networks of a multifaceted chiral squaramide:
Supramolecular multistimuli-responsive alcogels†
Jana Schiller,a Juan V. Alegre-Requena,a,b Eugenia Marqués-López,b Raquel P. Herrera,b Jordi
Casanovas,c Carlos Alemánd and David Díaz Díaz*a,e
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Chiral N,N'ꢀdisubstituted squaramide 1 has been found to undergo selfꢀassembly in a variety of alcoholic
solvents at low concentrations leading to the formation of novel nanostructured supramolecular alcogels.
The gels responded to thermal, mechanical, optical and chemical stimuli. Solubility studies, gelation
10 ability tests and computer modeling of a series of structurally related squaramides proved the existence of
a unique combination of nonꢀcovalent molecular interactions and favorable hydrophobic/hydrophilic
balance in 1 that drive the anisotropic growth of alcogel networks. The results have also revealed a
remarkable effect of ultrasound on both the gelation kinetics and the properties of the alcogels.
study of their selfꢀassembly properties in solution for the
synthesis of soft functional materials has remained virtually
35 unexplored.15
Introduction
15 Squaramides are fourꢀmembered vinylogously conjugated
diamides derived from squaric acid and possess a very high
synthetic versatility.1 Overall, the field of squaramides has
experienced an extraordinary growth since the pioneering study
of Rawal and coꢀworkers2 using these compounds as
20 organocatalysts. Moreover, squaramides have been recognized as
bioisosteres of ureas3 exhibiting appealing properties for diverse
research areas beyond organocatalysis,4ꢀ6 such as biomedicine,1
synthesis7 and crystal engineering.8ꢀ12 One of the most important
features of these scaffolds is their capacity for selectively binding
25 to different hydrogen bond acceptors through their acidic NH
groups. Remarkably, squaramides play a dual role as they are also
able to act as good hydrogen bond acceptors, making them
suitable as receptors for cation recognition. This property has
been explored to find promising candidates for the development
30 of novel drugs1,13,14 and in the field of organocatalysis as chiral
hydrogen bond donor catalysts.4 However, despite the increasing
number of squaramideꢀbased compounds in the literature, the
Within this context, hierarchical gelꢀbased materials have
received increasing attention over the last decades16ꢀ27 due to their
unique architectures and potential for highꢀtech applications in
numerous fields including, among others,28ꢀ32 the fabrication of
40 sensors,33 liquid crystals,34 electrically conductive scaffolds,35,36
templates for the growth of cells and inorganic structures,37,38
chemical catalysis,39 as well as in cosmetic and food industries.16
In contrast to chemical gels40ꢀ42 that are based on covalent bonds,
(e.g., crossꢀlinked polymers), physical gels1,43ꢀ50 are typically
45 made of low molecular weight compounds selfꢀassembled
through nonꢀcovalent interactions (e.g., hydrogenꢀbonding, van
der Waals, chargeꢀtransfer, dipoleꢀdipole, πꢀπ stacking and
coordination interactions), which usually provides reversible gelꢀ
toꢀsol phase transitions as response to environmental stimuli.51,52
50 Systems based on both types of connections are also known.53,54
The solidꢀlike appearance and rheological properties of the gels
result from the immobilization of the liquid (major component)
into the interstices of a solid matrix (minor component) through
capillary forces.51,55 The formation of the 3Dꢀnetwork with
a
Institut
für Organische
Chemie,
Universität
Regensburg,
Universitätsstr. 31, 93053 Regensburg, Germany. E-mail:
David.Diaz@chemie.uni-regensburg.de; Fax: + 49 941 9434121; Tel.:
+ 49 941 9434373
55 numerous junction zones56,57 is
a
consequence of the
entanglement of 1Dꢀpolymeric strands of gelator molecules16
typically of nm diameters and ꢀm lengths.58,59
b
Laboratorio de Organocatálisis Asimétrica, Departamento de Química
Orgánica, Instituto de Síntesis Química
y Catálisis Homogénea
Herein, we report the unprecedented selfꢀassembly properties
of a chiral squaramide in numerous alcoholic solvents leading to
60 the formation of multistimuliꢀresponsive supramolecular alcogels.
The remarkable effect of ultrasound during the preparation of the
gels as well as the plausible gelation mechanism supported by
quantum mechanical calculations are also discussed. This work
expands the applications of squaramides towards materials
65 synthesis.
(ISQCH), CSIC-Universidad de Zaragoza, Pedro Cerbuna 12, 50009
Zaragoza, Spain
Departament de Química, EPS, Universitat de Lleida, Jaume II 69,
25001 Lleida, Spain
Departament d’Enginyeria Química – ETSEIB and Center for Research
in Nano-Engineering, Universitat Politècnica de Catalunya, Av.
Diagonal 647, 08028 Barcelona, Spain
IQAC-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain
Electronic Supplementary Information (ESI) available: Spectroscopy,
c
d
e
†
rheology, additional experimental and calculation details, pictures and
tables. See DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry 2011
Soft Matter, 2015, [vol], 00–00 | 1

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DOI: 10.1039/C5SM02997J
140.5 (1C), 132.3 (1C), 127.9 (1C), 126.5 (1C), 125.0 (1C), 124.2
(1C), 119.3 (2C), 114.5 (2C), 72.3 (1C), 61.1 (1C), 55.2 (1C),
39.3 (1C). IR (KBr film) (cm–1) ν 3413, 3278, 2923, 2853, 1795,
60 1656, 1605, 1565, 1541, 1517, 1496, 1459, 1426, 1419, 1377,
1351, 1321, 1257, 1209, 1183, 1157, 1140, 1116, 1099, 1032,
1001, 872, 861, 801, 773, 747, 637, 599, 439. MS (ESI+) 373.2
[M+Na]. HRMS (ESI+) calcd for C20H18N2NaO4 373.1159;
found 373.1151 [M + Na].
Experimental
A) Synthesis and characterization of compounds
Materials
Unless otherwise noted, all solvents and reagents were purchased
from commercial suppliers and used as received.
5
Characterization methods: Purification of reaction products
was carried out by filtration. Analytical thin layer
chromatography was performed on 0.25 mm silica gel 60ꢀF
65 N-((1R,2R)-2-((2-(Hexylamino)-3,4-dioxocyclobut-1-en-1-
yl)amino)cyclohexyl)-4-methylbenzenesulfonamide
Following the above general procedure using 1.2 mmol of 11,
compound 10 was obtained after 5 h of reaction at room
temperature as a white solid in 74% yield. Mp 210ꢀ212 ºC. [α]D
(10):
plates. ESI ionization method and mass analyzer type MicroTofꢀ
1
10 Q were used for the MS measurements. HꢀNMR spectra were
recorded at 400 MHz and 13CꢀNMRꢀAPT spectra were recorded
at 100 MHz, using DMSOꢀd6 as deuterated solvent. Chemical
shifts were reported in the δ scale relative to residual DMSO
30
70 = +18.2º (c 0.64, DMSO). 1HꢀNMR (300 MHz, DMSOꢀd6) δ 7.61
(d, J = 8.2 Hz, 2H), 7.54 (d, J = 7.7 Hz, 1H), 7.32 (br s, 1H), 7.29
(d, J = 8.1, 2H), 7.18 (d, J = 7.9 Hz, 1H), 3.60ꢀ3.36 (m, 3H),
3.12ꢀ2.96 (m, 1H), 2.36 (s, 3H), 1.92ꢀ1.78 (m, 1H), 1.66ꢀ1.00 (m,
14H), 0.96ꢀ0.77 (m, 4H). 13CꢀNMRꢀAPT (75 MHz, DMSOꢀd6) δ
75 182.0 (1C), 181.8 (1C), 167.7 (1C), 167.2 (1C), 142.0 (1C), 139.3
(1C), 129.2 (2C), 125.9 (2C), 56.8 (1C), 56.4 (1C), 43.1 (1C),
33.0 (1C), 32.5 (1C), 30.7 (1C), 30.5 (1C), 25.4 (1C), 24.0 (2C),
21.9 (1C), 20.8 (1C), 13.8 (1C). IR (KBr film) (cm–1) ν 3197,
2956, 2923, 28569, 1798, 1656, 1650, 1572, 1521, 1465, 1342,
80 1162, 1094, 814, 665, 575, 549, 419. MS (ESI+) 470.3 [M+Na].
HRMS (ESI+) calcd for C23H33N3NaO4S 470.2084; found
470.2066 [M + Na.
1
(2.50 ppm for HꢀNMR and 39.43 ppm for 13CꢀNMRꢀAPT). The
15 1HꢀNMR and 13CꢀNMR spectra of compounds 1,60 2,61 3,62 4,60
7,60 8,60 and 960 were consistent with those previously reported in
the literature.
General procedure for the synthesis of compounds 5, 6 and
10: To a solution of 3,4ꢀdimethoxyꢀ3ꢀcyclobuteneꢀ1,2ꢀdione (11)
20 (1.2 or 3 mmol) in MeOH (3ꢀ3.75 mL), amine 12 (1.2 or 3 mmol)
was added at room temperature. After the corresponding reaction
time (t1), amine 13 (1.2 or 3 mmol) was then added dissolved in
MeOH (9 or 11.25 mL). After the corresponding reaction time
(t2), the reaction flask was placed in the freezer (ꢀ20 ºC) for 30
25 minutes and the obtained product was purified by filtration. See
ESI (Scheme S1) for exact solvent volumes and reaction times in
each case.
B) Preparation and characterization of gel materials
Characterization
methods:
Oscillatory
rheological
85 measurements were performed at 25 ºC with an AR 2000
Advanced rheometer (TA Instruments) equipped with a Julabo C
cooling system (Universität Regensburg). A 40 mm plain plate
geometry (stainless steel) was used. Typically, the following
experiments were carried out using 2 mL total gel volume: a)
90 Dynamic strain sweep (DSS) was performed between 0.01% and
100% strain and a frequency of 1 Hz in order to estimate the
strain value at which reasonable torque values were given; b)
dynamic frequency sweep (DFS) experiments were performed
between 0.1 to 10 Hz and a strain of 0.1%; and c) dynamic time
95 sweep (DTS) measurements were performed with constant values
of frequency and strain within the linear viscoelastic regime as
determined with DSS and DFS (0.1% strain, 1 Hz frequency).
Additionally, the thixotropic nature of the gels was confirmed
with a threeꢀstep loop test: (1) application of a low shear strain
100 (0.1%) at 0.1 Hz frequency for 10 min (i.e., material is in gel
state: G' > G''), (2) increase of the strain until the gel fractures
(1000%) at 0.1 Hz frequency for 5 min (material turns into a
viscous fluid: G' < G''), and (3) application of the initial strain
value (0.1%) at 1 Hz frequency for 30 min (gel is recovered: G' >
105 G'').
FTIR spectra were recorded using an Agilent Carry 630
spectrophotometer (Universität Regensburg) spectrophotometer.
Morphological characterization of the bulk samples was
carried out by field emission scanning electron microscopy
110 (FESEM), transmission electron microscopy (TEM) and atomic
force microscopy (AFM). a) FESEM: Images were obtained with
a Carl Zeiss Merlin field emission scanning electron microscope
(0.8 nm resolution) equipped with a digital camera (SAI,
Universidad de Zaragoza) and operating at 3 kV and 158 pA.
3-(((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-4-
(phenylamino)cyclobut-3-ene-1,2-dione (5): Following the
30 above general procedure using 3 mmol of 11, compound 5 was
obtained after 9 h of reaction at room temperature as a white solid
30
in 86% yield. Mp 248ꢀ250 ºC Decomp. [α]D = +39.6º (c 0.61,
1
DMSO). HꢀNMR (300 MHz, DMSOꢀd6) δ 9.90 (br s, 1H), 8.07
(d, J = 9.1 Hz, 1H), 7.49 (d, J = 7.8 Hz, 2H), 7.42ꢀ7.21 (m, 6H),
35 7.07ꢀ6.96 (m, 1H), 5.54 (br s, 1H), 5.54 (dd, J = 8.8, 5.0 Hz, 1H),
4.58 (dt, J = 4.9, 1.6 Hz, 1H), 3.14 (dd, J = 15.7, 4.4 Hz, 1H),
2.88 (dd, J = 16.3, 1.4 Hz, 1H). 13CꢀNMRꢀAPT (75 MHz,
DMSOꢀd6) δ 183.9 (1C), 180.3 (1C), 169.0 (1C), 163.7 (1C),
141.3 (1C), 140.5 (1C), 139.1 (1C), 129.2 (2C), 127.9 (1C), 126.6
40 (1C), 125.0 (1C), 124.2 (1C), 122.4 (1C), 117.8 (2C), 72.3 (1C),
61.1 (1C), 39.3 (1C). IR (KBr film) (cm–1) ν 3426, 3283, 2923,
2853, 1797, 1661, 1606, 1567, 1543, 1455, 1423, 1377, 1092,
760, 751, 744, 430. MS (ESI+) 343.1 [M+Na]. HRMS (ESI+)
calcd for C19H16N2NaO3 343.1053; found 343.1046 [M + Na]
45 3-(((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-4-
((4-methoxyphenyl)ami-no)cyclobut-3-ene-1,2-dione
(6):
Following the above general procedure using 3 mmol of 11,
compound 6 was obtained after 10 h of reaction at room
temperature as a white solid in 88% yield. Mp 254ꢀ256 ºC
29
1
50 Decomp. [α]D = +41.8º (c 0.60, DMSO). HꢀNMR (300 MHz,
DMSOꢀd6) δ 9.80 (s, 1H), 8.07 (br d, J = 8.9 Hz, 1H), 7.41 (d, J =
8.9 Hz, 2H), 7.46ꢀ7.19 (m, 4H), 6.93 (d, J = 9.0 Hz, 2H), 5.55 (br
s, 1H), 5.53 (dd, J = 9.0, 4.8 Hz, 1H), 4.57 (dt, J = 4.8, 1.6 Hz,
1H), 3.73 (s, 3H), 3.14 (dd, J = 16.3, 4.9 Hz, 1H), 2.87 (dd, J =
55 16.5, 1.3 Hz, 1H). 13CꢀNMRꢀAPT (75 MHz, DMSOꢀd6) δ 183.3
(1C), 180.4 (1C), 168.6 (1C), 163.7 (1C), 155.1 (1C), 141.4 (1C),
2
|
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Sample preparation: Xerogel specimens were prepared by freezeꢀ
drying. Prior to imaging, a 5 nm sized Pt film was sputtered (40
mA, 30 seconds) on the samples placed on carbon tape. b) TEM:
Images were recorded using a JEOLꢀ2000 FXII transmission
electron microscope (0.28 nm resolution) equipped with a CCD
Gatan 694 digital camera (SAI, Universidad de Zaragoza) and
operating at 200 kV (accelerating voltage). Sample preparation:
10 ꢁL of the gel suspension was allowed to adsorb onto carbonꢀ
coated grids (300 mesh, from Aname). The grid was placed over
10 a piece of filter paper in order to absorb the excess of solvent. c)
AFM: Imaging was performed on a Multimode 8 (Bruker)
instrument (LMAꢀINA, Zaragoza) in tapping mode at 0.5 Hz
scanning rate using freshly cleaved mica surface as substrate and
again after each measurement to check for possible leakage.
60 General procedure for the preparation of organogels:
Solvents (p.a. grade) used for gelation tests were purchased from
commercial suppliers. In general, a certain amount of triturated
squaramide was weighted and placed into a screwꢀcap vial (4.5
cm length × 1.2 cm diameter) and 1 mL of the corresponding
65 solvent was added. Standard protocols for gel formation: (1) The
heatingꢀcooling protocol for the gel formation involved gently
heating of the closed vial with a heat gun until the solid
compound was completely dissolved, followed by spontaneous
cooling of the isotropic solution to room temperature. (2)
70 Alternatively, the heatingꢀultrasound protocol involved the
application of ultrasound (ultrasound bath USC200TH, VWR™)
directly after the heating. In each case, the material was classified
as gel if no flow was observed upon turning the vial upsideꢀdown
at room temperature. This phase was further confirmed by
75 rheological measurements of model systems. Note: In some cases
(see Table 1) the samples had to be pretreated in order to
facilitate the dissolution of the compound during the standard
protocols (i.e., heatingꢀcooling or heatingꢀultrasound). The
pretreatment consisted of gently heating followed by ca. 30 s
80 sonication.
5
a
single crystal silicon tip (TAP150A, 0.01ꢀ0.025 ꢂꢀcm,
15 Antimony doped Si) at 128ꢀ152 kHz drive frequency. Drive
amplitude ranged from 300 to 400 mV. Sample preparation: 10
ꢁL of the alcogel suspension (ca. 5ꢀfold dilution in MeOH) was
placed on the substrate and homogeneously dispersed to form a
thin layer that was allowed to dry in air overnight before
20 measurement.
The growth of crystals in the gel phase was monitored using a
Wild Makroskop M420 optical microscope equipped with a
Canon Power shot A640 digital camera (Universität Regensburg).
A polarization filter was used to observe the birefringence of the
25 gels under polarized light.
Phase-selective gelation experiments: Distilled water (1 mL)
and 1ꢀhexanol (1 mL) were added to compound 1 (7 mg, 0.014
mmol) placed into a screwꢀcapped vial (4.5 cm length × 1.2 cm
diameter). The vial was sealed and gently heated with a heat gun
85 until the compound was completely dissolved. The mixture was
sonicated for 1 min and kept undisturbed for 30 min, resulting in
the gelation of the organic phase. The state of the material was
established by turning the vial upsideꢀdown.
Temperatureꢀdependent 1HꢀNMR studies were carried out on a
400 MHz Bruker Avance instrument (Universität Regensburg)
equipped with a BVT 2000 heating system (Bruker BioSpin
GmbH).
Powder Xꢀray diffraction (PXRD) patterns were collected on a
STOE STADI P powder diffractometer (Universität Regensburg)
(StartFragment Transmission mode, flat samples, Dectris
MYTHEN 1k microstrip solidꢀstate detector) with CuKα1
radiation operated at 40 kV and 40 mA. Conditions: a) 0.015°,
35 time 1200 s/step, 2 theta range 10–55° (short measurement); b)
StartFragment 0.015°, time 320 s/step, 2 theta range 2–90° (long
measurement).
UVꢀvis spectra were recorded in a Varian Cary 50 Bio UVꢀ
Visible spectrophotometer.
30
Responsiveness to external ions: Comparative experiments were
90 made using the following metal salts: FeCl3, Ni(OAc)2·3H2O,
NiCl2·6H2O and CuCl2. A) Gels in methanol (1 mL) were
prepared by heatingꢀcooling using squaramide 1 at c = 10 g L–1.
After equilibration of the gels for 4 h, the desired metal salt
solution (1 M in methanol) was added to each gel in 1 µL
95 portions and left to rest for at least 18 h until the cation reached a
concentration of 60 mM in the gel. The integrity of the gel phase
was evaluated by visual inspection. B) In order to crosscheck the
values obtained in A), 10 mg of compound 1 was added to 1 mL
of the corresponding metal salt solution in methanol prepared at
100 the critical concentration defined by experiment A) (i.e.,
concentration where a response of the gel was evident to the
naked eye). The mixture was heated for complete dissolution of
the materials and subsequently cooled down to room temperature.
The state of the bulk gel was monitored over time.
40
Critical gelation concentrations (CGC) were determined by
adding solvent in several portions (0.1 mL each) into the vial
until everything remained dissolved, precipitation and/or gelation
took place upon heatingꢀcooling (and/or ultrasound) treatment as
described above. The initial concentration for gelation tests was
45 100 g L–1.
Gelꢀtoꢀsol transition temperatures (Tgel) were determined by
the inverseꢀflow method by placing the sealed vials containing
the organogels into a thermoblock (Figure S1), which was heated
up at the rate of 2 ºC minꢀ1. In this work, the temperature at which
50 the gel started to break was defined as Tgel. The average values of
at least two random experiments were given. These values were
correlated with the first differential scanning calorimetry (DSC)
endothermic transition of model using a DSC7 (Perkin Elmer)
instrument (Universität Regensburg) at a scan rate of 2 ºC minꢀ1
55 under nitrogen atmosphere (gas flow rate = 20 mL min–1). For the
measurements, an appropriate amount of gel was placed into a
preꢀweighted Al pan (PerkinꢀElmer), which was sealed and
weight on a sixꢀdecimal plate balance. The pans were weighted
105 C) Quantum mechanical calculations
All calculations were performed using the M06L functional,63,64
which was combined with the 6ꢀ31+G(d,p) basis set65 (i.e.,
M06L/6ꢀ31+G(d,p) level) The M06L is
a
metaꢀhybrid
generalized gradient approximation (GGA) functional with very
110 good response under dispersion forces, improving one of the
biggest deficiencies in Density Functional Theory (DFT)
methods. Thus, the M06L functional is able to describe the
geometry and interaction energy of complexes stabilized by nonꢀ
covalent interactions, including πꢀπ staking, with accuracy close
This journal is © The Royal Society of Chemistry [year]
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to that of couple cluster calculations with both single and double
Scheme 1 Oneꢀpot synthesis of squaramide 1 in MeOH.
substitutions.66 All geometry optimizations were performed in
methanol (ε = 32.6), which was described through a simple Self
Consistent Reaction Field (SCRF) method. More specifically, the
Polarizable Continuum Model67,68 (PCM) was used in the
framework of the M06L/6ꢀ31+G(d,p) level to represent bulk
solvent effects.
To correlate the structural functionalities of 1 with its gelation
50 properties, we designed and synthesized the library of
squaramides outlined in Figure 1. Specifically, different
analogous squaramides 7-10 were designed by incorporating
substituents with different steric and electronic properties,
following the same synthetic procedure.60,71 For this purpose,
55 squaramides 7 and 9, with electronꢀwithdrawing groups, or
squaramide 8 with an electronꢀdonating substituent in the
aromatic ring, or 10 in the absence of the aromatic ring, were
synthesized with the aim of modifying the basicity and/or
conferring distinctive solvation properties to these organic
60 compounds, which is believed to play a key role on the gelation
phenomena.16ꢀ27 In all these cases (1, 7-10), the stereochemical
configuration and the structural core were maintained. On the
other hand, squaramides 2 and 3 were included for comparison
with 1, since we also observed that the viscosity of MeOH
65 increased during their preparation. Additionally, and encouraged
by our last work with ureaꢀbased compounds as efficient
gelators,74 we also carried out the preparation of squaramide 4,
which is the equivalent squaramide to the best urea compound
used in our previous work.74 Related with compound 4,
70 squaramide 5, lacking the substituent in the aromatic ring, or 6,
bearing a methoxy group, were also explored.
5
Complexes formed by two interacting molecules (dimers) were
considered for model squaramides 1, 3, 7, 8 and 10. For this
10 purpose, around 50 starting geometries were constructed for each
dimer by varying the relative position between the two interacting
molecules. Accordingly, the formation of different specific and
nonꢀspecific intermolecular interactions, as well as different
geometries for each of such interactions, were considered. All
15 these starting arrangements were submitted to geometry
optimization at the PCMꢀM06L/6ꢀ31+G(d,p) level. Interaction
energies (ꢁEi) were corrected with the basis set superposition
error (BSSE) by means of the standard counterpoise (CP)
method.69 Calculations were performed using the Gaussian 0970
20 computer package.
Results and discussion
Design and synthesis of squaramides
In the frame of our interdisciplinary research program focused on
the development of new hydrogen bond based functional
25 molecules, some of us have recently focused on the synthesis of
new squaramide structures,60,71 due to their important ability for
selectively binding through cooperative hydrogen bonds to
different acceptors.1,4ꢀ7 During the synthesis of squaramide 1
(Scheme 1) we observed a clear tendency to increase the viscosity
30 of the solvent (i.e., MeOH). Hence, we decided to investigate in
detail the formation of supramolecular aggregates in solution,
after taking also into consideration a) the facile and scalable
synthesis of this family of compounds, b) the intrinsic potential as
highly substituted scaffolds and c) the isosteric relationship with
35 ureas, which represent ubiquitous synthons in supramolecular
chemistry72 including the formation of softgels.73
In this context, unsymmetrical substituted squaramide 1 was
easily accessible following our own developed procedure in a
oneꢀpot synthesis using equimolar amounts of commercially
40 available 3,4ꢀdimethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀdione (11), 4ꢀtertꢀ
butylaniline (12a) and Nꢀ((1R,2R)ꢀ2ꢀaminocyclohexyl)ꢀ4ꢀ
methylbenzenesulfonamide (13a) in methanol at room
temperature (Scheme 1). After 4 hours of reaction, squaramide 1
was obtained in very good yield (80%) after simple filtration as a
45 powdered material with mesoscale ordering as indicated by
PXRD analysis (Figure S16).
Fig. 1 Library of additional squaramides 2ꢀ10 synthesized for this work.
All synthesized squaramides 1-10 were appropriately
75 characterized after purification by a simple and straight filtration
(see Experimental Section).
Solubility and gelation properties
The gelation ability of compound 1 was initially screened for 34
different solvents using the heatingꢀcooling protocol within a
80 broad concentration range (Tables 1 and S1). For instance,
squaramide 1 was found to be insoluble in dichloromethane,
chloroform, ethyl acetate, diethyl ether, dibutyl ether, toluene,
glycerol, 1,3ꢀdichlorobenzene and water upon heating and/or
sonication. Unexpectedly, 1 showed an unusual selectivity to
85 form stable gels in a number of alcoholic solvents (alcogels),
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including primary, secondary, tertiary, lineal and branched
alcohols. The only exception to this rule was the gel obtained in
acetone. However, it should be considered that although acetone
is present at >99% keto form at equilibrium, the formation of
values estimated for the gels obtained with 1 ranged between 3
and 21 g L–1 (see the Experimental Section for the procedure).
These values indicate that hundreds or thousands of solvent
molecules are immobilized per gelator molecule (e.g., the highest
5
hydrogen bonding gel networks could stabilize to some extend 20 solvent/gelator ratio ~ 1750:1 was obtained in methanol). As far
the enol form of the acetone (2ꢀpropenol). In sharp contrast, no
gelation tendency was detected for squaramides 2ꢀ10. These
results suggested the existence of unique molecular interactions
and a hydrophilic/hydrophobic balance that favor the selfꢀ
as we are aware, the only precedent in the literature describing
the formation of an organogel with squaramides corresponds to a
recent report from Ohsedo and coꢀworkers15 describing a series of
squarylium monoalkylamides and dialkylamides. Therein,
10 assembly of 1 in alcohols. This was later confirmed by 25 gelation was only observed in DMF (forming opaque gels) and in
computational studies (vide infra).
some cases only after cooling down the mixture to ꢀ15 ºC.
The gel nature of the samples was initially confirmed by the
absence of flow upon turning the vial upsideꢀdown and further
confirmed by oscillatory rheological measurements in model
15 solvents (vide infra). The critical gelation concentration (CGC)
30
Table 1 Gelation capacity of 1, optical appearance of the gel phase, critical gelation concentration (CGC), gelation time, gelꢀtoꢀsol transition temperature
(Tgel), procedure for gel formation and temporal stability of the gels.
temporal stabilityk
–
1
CGC (g L )e
entry
solventa
phaseb optical appearance
gelation timef Tgel (ºC)g
procedureh
24 ± 2 h
nd
45
nd
nd
46
57
47
67
42
54
70
64
56
47
36
39
36
35
75
nd
54
81
65
65
53
heatingꢀcooling
heatingꢀcooling
> 6 months
nd
1
2
methanol
G
transparent
nd
7
nd
20
2ꢀmethylpentanꢀ1ꢀol G + U
24 ± 6 h
10 min
5 min
heatingꢀcoolingi
> 4 months
cryst. after 18 h
> 1 month
> 1 week
3
butanꢀ2ꢀol
ethanol
G
G
transparent
translucent
translucent
translucent
translucent
opaque
5.8
3
heating-ultrasound
heating-ultrasound
heating-ultrasoundj
heating-ultrasoundj
heating-ultrasound
heating-ultrasoundj
heating-ultrasoundj
heatingꢀcooling
4
5
2ꢀmethylpropanꢀ2ꢀol
butaneꢀ1,4ꢀdiol
2ꢀmethylpropanꢀ1ꢀol
phenylmethanol
acetone
G
5.5
4
10 min
1 min
6
G
> 1 week
7
G
21
7.1
3.3
5.2
5.2
10
6.1
8.4
8.4
9.1
7
8 min
> 2 months
> 1 week
8
G
1 min
9
G
translucent
translucent
opaqued
5 min
> 2 weeks
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2ꢀmethylbutanꢀ2ꢀol
propanꢀ1ꢀol
G
2 h
> 6 months
> 4 months
> 2 months
> 1 week
G + C
G
5 min
heating-ultrasound
heatingꢀcooling
propanꢀ1ꢀol
translucent
opaque
15 min
12 min
3.5 ± 0.25 h
6 min
pentaneꢀ1,5ꢀdiol
pentaneꢀ1,5ꢀdiol
butanꢀ1ꢀol
G
heating-ultrasound
heatingꢀcooling
G
translucent
transparent
transparent
transparent
transparent
transparent
translucent
transparent
transparent
transparent
translucent
> 1 month
> 1 month
> 1 week
G
heating-ultrasound
heatingꢀcoolingj
heating-ultrasoundj
heatingꢀcoolingj
heating-ultrasoundj
butanꢀ1ꢀol
G
9 min
hexanꢀ1ꢀol
G + C
G
Gc
1 min
> 2 months
> 1 month
> 2 months
> 1 month
> 2 months
cryst. during gelation
> 1.5 months
hexanꢀ1ꢀol
5
20 ± 4 h
2 min
3ꢀmethylbutanꢀ2ꢀol
3ꢀmethylbutanꢀ2ꢀol
pentanꢀ2ꢀol
3.7
5.5
5.0
4.7
3.9
G
11 ± 1 d
1 min
heatingꢀcooling
G
heating-ultrasound
heatingꢀcooling
pentanꢀ2ꢀol
G
2.3 ± 0.15 h
2 min
2ꢀmethylbutanꢀ1ꢀol
2ꢀmethylbutanꢀ1ꢀol
G + C
G
heating-ultrasound
a
b
c
Solvent volume = 1 mL. Systematic IUPAC name is provided for each case. Abbreviations: G = gel; U = undissolved gelator; C = crystals.
d
Approximately 10% of the total volume remained ungelled. Cluster of white needles are visible within the fresh gel sample, which turned into a
–
35 transparent gel after 12 days (vide infra). e Values calculated by the inverseꢀflow method. Estimated error ± 0.5ꢀ1 g L . Abbreviations: h = hour; min =
minute; d = day. Unless otherwise noted, estimated error ± 1 min (for gelation times > 1 min). g Estimated error ± 2 ºC. h The heatingꢀultrasound treatment
for the preparation of gels are highlighted in bold font. i To form this gel it was necessary to predissolve 1 in 20 ꢀL of DMSO. j The sample was pretreated
1
f
k
by heatingꢀultrasound as explain in the experimental section. The gels were stable at least for the indicated period. Symbol “ > ” indicates that the
stability could possibly be much longer although it was not monitored. Abbreviation: nd = not determined due to unreliable variables; cryst =
40 cyrstallization.
be formed by heatingꢀcooling, whereas ca. 82% could be
Stable gels were classified in 3 different groups depending on 50 prepared by a heatingꢀultrasound protocol (blue shaded rows).
the experimental protocol that was used for their preparation. The
first group could only be formed by the classical heatingꢀcooling
45 protocol (entries 1ꢀ3), the second group could only be formed by
applying heating and subsequent ultrasound treatment (entries 4ꢀ
Although there is not an apparent correlation between the type of
alcohol and the gel preparation method, heating followed by
ultrasound was found to be a very convenient technique for the
gelation of branched alcohols within minutes regardless the
10) and the third group could be formed by any of these two 55 degree of substitution at the αꢀcarbon. Based on these groups, we
methods (entries 11ꢀ24). Thus, ca. 47% of the obtained gels could
selected one model solvent of each group (i.e., methanol, phenyl
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methanol and hexanꢀ1ꢀol) for further characterization and
comparisons. So obtained alcogels displayed different degree of
translucency (Figure 2). Such optical differences indicate the
formation of aggregates of different sizes.
5
Ultrasoundꢀinduced gelation (sonogelation), mainly by solvent
cavitation, has attracted much attention over the last few years.75ꢀ
During our work we found that the application of ultrasound
78
after heating not only allowed the fabrication of stable gels that
could otherwise (i.e., via heatingꢀcooling) not be formed, but also
10 decreased the gelation time drastically (e.g., entries 11, 15, 19,
21, 23 vs entries 12, 16, 20, 22, 24, respectively). The most
impressive case was pentanꢀ2ꢀol that needed more than 10 days to
be gelled by heatingꢀcooling and only 1 min by heatingꢀ
ultrasound even at lower concentration (entry 21 vs entry 22).
15 This is very appealing since the application of ultrasound to an
already isotropic solution seems counterintuitive. However,
sonication of the hot clear solution prior gelation may hinder the
selfꢀassembled system (nonꢀentangled nanofibers) to fall into its
lowest energy level making possible the formation of new gel
20 networks. In addition, both the CGC was reduced in practically
all cases in which the heatingꢀultrasound protocol was used
instead of heatingꢀcooling. This was also accompanied by certain
reduction of the Tgel values. The case of hexanꢀ1ꢀol should not be
considered prematurely as an exception because the heatingꢀ
25 cooling protocol gave a combination of gel and crystals (entry 17
vs entry 18). Remarkably, the dynamic nature of the gels was
evidenced by a gradual increase over time of the Tgel for the gel
prepared by heatingꢀultrasound reaching eventually the same
value obtained by heatingꢀcooling (i.e., Tgel (fresh gel made in
30 propanꢀ1ꢀol) = 56 ºC; Tgel (3ꢀmonth old gel made in propanꢀ1ꢀol)
= 63 ºC). As observed with the solid squaramide gelator 1, the
xerogels obtained by freezeꢀdrying the corresponding alcogels
were found to have mesoscale ordering as demonstrated by
PXRD analysis (Figure S16 and Table S2). However, clear
35 differences were observed between both spectra. The peaks
observed for the solid sample (i.e., as synthesized 1) are centered
at (2θ = 4.41º, 6.71º, 11.51º, 16.35º and 17.90º, corresponding to
lattice spacings d of 20 Å, 13.16 Å, 7.68 Å, 5.42 Å and 4.95 Å,
respectively (calculated from Bragg’s law). In contrast, the peaks
40 centered at 11.51º and 17.90º disappeared completely in the
xerogel sample, whereas all other peaks slightly shifted to low
angles (i.e., 3.96º, 6.18º and 15.70º, respectively; these peaks
correspond to d values of 22.28 Å, 14.3 Å and 5.64 Å,
respectively). This suggests that the interactions of the solvent
45 molecules with the gelator (or gelatorꢀbased aggregates) during
gelation cause disorder and expansion of the potential crystal
packing of the gelator, at least to some extent.
Fig. 2 Representative photographs of upsideꢀdown vials containing
55 organogels made of gelator 1 in different alcohols prepared at the
corresponding CGC (Table 1) via heatingꢀcooling (HꢀC) or heatingꢀ
ultrasound (HꢀU).
Phase-selective gelation capacity: Very interestingly, squaramide
1 was also able to gel selectively the organic phase of
60 alcohol/water mixtures. In principle, such phaseꢀselective
gelation is always challenging due to the expected alteration of
the hydrogen bonding network.79 As a proofꢀofꢀconcept, 1 (c = 7
g L–1) was dissolved in 1:1 v/v water/hexanꢀ1ꢀol by heating and
subsequently submitted to sonication for 1 min. After 30 min of
65 resting, only the organic phase was completely gelled, which was
stiff enough to hold the liquid water phase upon inversion of the
vial. Due to the partial solubility of hexanꢀ1ꢀol in water (i.e., 5.9
g L–1 at 20 ºC), the aqueous phase was not completely clear after
gelation of the alcohol. However, after 24 h the water phase got
70 clearer and the organic phase more turbid (Figure 3). This was
presumably due to the disruption of the microemulsion and
diffusion of the tiny fraction of gelator molecules that could be
trapped into the aqueous phase. Phaseꢀselective gelation using
waterꢀsoluble alcohols such as methanol was not successful. The
75 addition of 10ꢀ20% water either before or after gel formation
resulted in the collapse of the gel after several days caused by a
thick precipitation (Figure S14).
In addition, UVꢀvis analysis during the solꢀtoꢀgel transition did
not show a shift of the absorption maximum (Figure S17),
50 suggesting that the aggregation mode of 1 in solution (and
probably in the solid state, vide infra) resembles that in the gel
phase.
Fig. 3 Phaseꢀselective gelation and change in opacity of hexanꢀ1ꢀol /water
–
1
80 mixture after 24 h (gelator 1, c = 7 g L ). Total volume = 2 mL. Yellow
arrow indicates the boundary between phases.
Thermal and temporal stability of alcogels
In general, the supramolecular gels were thermoreversible and
stable to multiple heatingꢀcooling cycles. The gelꢀtoꢀsol transition
85 temperatures (Tgel) were estimated by the inverse flow method
(IFM). Due to the dependence of this method with the cooling
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rate and thermal history of the sample, we confirmed the good
remained stable for several months without visible crystallization
agreement of the Tgel with the first endothermic transition 45 when stored in dark at room temperature.
observed by differential scanning calorimetry (DSC) of a model
gel (Figure S5).
5
As usually observed in physical gels, Tgel values increased as
the gelator concentration increased until reaching a plateau before
visible crystal nucleation. For example, Tgel of the gel made in
methanol increased ca. 23 ºC upon increasing ca. 3ꢀfold the
concentration of 1 with respect to the CGC (7 g L–1). Crystal
10 formation was observed over 22 g L–1 within 10 min (Figure 4).
Although these results might be in agreement with the formation
of more entangled networks at higher gelator concentrations, the
change in Tgel is likely due to solution thermodynamics where the
phase boundary, or liquidus line, increases at low concentration
15 and levels off at higher concentration.
Fig. 5 A) Digital photograph showing crystal growth in the gel made of 1
–
1
in 2ꢀmethylbutanꢀ1ꢀol (c = 4.7 g L ) by heatingꢀcooling. B) Optical
microscope picture of the crystals observed in A). C) Gradual crystal
–
1
50 growth observed during the gelation of hexanꢀ1ꢀol using 1 (c = 9.1 g L )
and the heatingꢀcooling protocol. The gelator concentration corresponds
to the CGC (Table 1).
Although gelꢀtoꢀgel transitions have already been reported,86ꢀ89
it is still a rare phenomenon. The gels made in phenylmethanol
55 showed an optical transition from transparent to opaque within 30
min at the CGC (Figure 6A). This behavior is typically observed
during the growth of fibrilar aggregates over time. Intriguingly,
the uncommon opposite phenomenon was observed with the
alcogel prepared in propanꢀ1ꢀol by heatingꢀcooling. In this case,
60 initial macroscopic crystallization was observed during the
gelation process leading to a transient opaque gel, which turned
into a thermodynamically stable transparent gel within 12 days
(Figure 6B). However, additional detailed experimentation to
determine the exact packing arrangement of the gelator
65 molecules, and prove its gradual change, is still necessary in
order to confirm the apparent gelꢀtoꢀgel transition in this case.
Fig. 4 Phase diagram and variation of Tgel as a function of the
concentration of gelator 1 in methanol.
Very interestingly, in several cases we have observed an
20 enhancement of both the gelation kinetics and the gel stability
when the gels were reformed after being thermally destroyed for
the first time. We believe that the gelꢀtoꢀsol thermal transition
could be controlled to avoid the complete dissociation of the
supramolecular network (even when behaving as a fluid from the
25 rheological
standpoint).
This
could
preserve
the
thermodynamically more stable aggregates through a selfꢀsorting
mechanism, thus providing a more robust starting platform for
rebuilding the gel structure. We believe that such “preformation
hypothesis” could be more general and become an important
30 contribution to the gelation theory. We are currently studying this
in detail and we will publish our results at due course.
On the other hand, gelꢀtoꢀcrystal transitions have been
previously related to Ostwald rule of stages.80,81 The subtle
equilibrium between the metastable gel phase and the
35 thermodynamically stable crystalline phase82ꢀ85 could also be
monitored in several of our alcogels. For instance, macroscopic
crystallization in the form of long needles was observed first at
the interface between air and the developing gel phase made of 1
in 2ꢀmethylbutanꢀ1ꢀol, hexanꢀ1ꢀol or propanꢀ1ꢀol via heatingꢀ
40 cooling (Figure 5). Nevertheless, the robustness of the gel phase
allowed in most of the cases the coexistence of crystalline and gel
phases for at least one month supporting the inversion of the test
tube. In general, the alcogels prepared via heatingꢀultrasound
Fig. 6 A) Transparentꢀtoꢀopaque transition recorded for the gel made of 1
–
1
in phenylmethanol (c = 21 g L ) within 30 min after gel formation via
70 heatingꢀultrasound. B) Opaqueꢀtoꢀtransparent transition observed in the
–
1
gel made of 1 in propanꢀ1ꢀol (c = 5.2 g L ) within 12 days after gel
formation via heatingꢀcooling. The concentrations of gelator correspond
to the CGC (Table 1).
Influence of gelator enantiopurity on gel formation
75 Chirality plays
a fundamental role in the formation of
supramolecular gel networks.90 Therefore, we also examined the
influence of the enantiomeric purity of 1 on its gelation ability.
Samples with different enantiomeric excesses (ee) were prepared
by combining (R,R)ꢀ1 with the appropriate amount of the racemic
80 compound, which was prepared following the general synthetic
procedure using the corresponding racemic diamine (see
Experimental Section). Stableꢀtoꢀinversion gels could only be
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formed with the enantiomerically pure (R,R)ꢀ1. The squaramide
found in the xerogel of 1 do not appear in the other solid
compounds, except compound 7 that also showed two peaks in
the same region as well as the new additional peaks at higher
angle. In other compounds (e.g., compounds 6, 8) only one of the
45 two mentioned peaks was present together with the additional
peaks at higher angle. Thus, although we can not provide a
unique reason why squaramide 1 is the only one that forms gels,
it seems that the complex gelation phenomenon, frequently
defined as a “frustrated crystallization”, finds here a unique
50 example, where both the structure of the gelator and the solvent
must play a crucial and synergistic role in turning the phase
balance towards gelation in the case of compound 1 vs. 2ꢀ10.
In order to gain a clearer insight into the potential aggregation
mode of 1 and its unique gelation ability, comparative PCMꢀ
55 M06L/6ꢀ31+G(d,p) calculations in methanol were carried out on
model dimers of 1, 3, 7, 8 and 10. It should be remarked that this
methodology, which is not appropriated to evaluate why only
alcohols and acetone give gels, is suitable to describe precisely
specific interactions and evaluate differences among the
60 interaction patterns in the different dimers. Moreover, 1, 3, 7, 8
and 10 are similar enough to represent the solvent using a
polarized continuum dielectric medium, like the PCM one.
Accordingly, these calculations do not intend to ascertain the role
of the solvent in the gelation mechanism but differences among
65 molecules in a given solvent. For simplicity, analyses of the
results were restricted to the minima of lower relative energy,
which correspond to those with more attractive interaction
energies (ꢁEi). Thus, 13 of the 22 minima obtained for 1 exhibit
ꢁEi values lower than –6 kcal/mol. More specifically, ꢁEi ranges
70 from –26.1 to –6.1 kcal mol–1 (Figure 8).
with 80% ee yielded a weak partial gel after 88 h. Macroscopic
crystallization of the gelator was observed after 9 days. The use
of 1 with ee < 80% led to snow flakeꢀlike precipitation of 1
without any gel formation (Figure 7).
5
Fig. 7 Influence of enantiomeric purity of gelator 1 on its gelation ability
–
1
in methanol (c = 7 g L ) monitored over time. Enantiomeric excesses are
given in percentages.
10 Driving forces for molecular aggregation
The comparison of FTIR spectrum of solid squaramide 1 with
those of the xerogel (prepared by freezeꢀdrying the corresponding
alcogel) and 1 in solution revealed only slight alteration with
small frequency shifts to lower wavelengths (ꢁλ < 4 cm–1) for
15 characteristic peaks (e.g, stretching absorptions bands for C=O
~1658ꢀ1794 cm–1; secondary amines ~3210ꢀ3345 cm–1; aromatic
CꢀH ~2910ꢀ3005 cm–1; aromatic CꢀN ~1265ꢀ1370 cm–1) (Figure
S4). This suggests that 1 may also be aggregated in the solid state
involving intuitive hydrogen bonding and πꢀstacking interactions
20 similarly to its analogue ureaꢀbased organogelator.74 This is also
in agreement with the results obtained by UVꢀvis measurements
during the solꢀtoꢀgel transition (vide supra).
On the other hand, temperatureꢀdependent 1HꢀNMR
experiments could provide additional information regarding
25 phase interconversions. However, it should be noted that NMR
signals of gelator molecules are unlikely to be observed in the gel
phase due to long correlation times. Therefore, the observed
signals are typically ascribed to small amounts of gelator
molecules dissolved in the immobilized solvent.91,92 Preliminary
30 NMR measurements of the alcogel made of 1 in d4ꢀmethanol with
increasing temperature from 25 ºC to 60 ºC showed gradual
chemical shifts (δ) of almost all protons of 1 suggesting at least
conformational changes and/or expected modification in the
aggregation pattern (e.g., through hydrogen bonding, πꢀstacking
35 and/or electrostatic interactions) (Figure S6).
Fig. 8 For the most stable complexes of each family, representation of the
interaction energy (ꢁEi) of complexes calculated for 1, 3, 7, 8 and 10 with
ꢁEi ≤ 5.0 kcal mol–1.
75 Inspection of the lowest energy dimer (Figure 9A) revealed that
the squaramide moiety of each molecule is involved in different
intermolecular interactions. In addition to the conventional N–
H···O hydrogen bond, which involves the squaramides of the two
molecules, this dimer also exhibits stabilizing N–H···π and C–
80 H···π intermolecular interactions. In addition to such interactions,
the two molecules involved in this complex show intramolecular
π···π stacking interactions, as is illustrated for one of the two
monomers (Figure 9A, right). These attractive interactions
involve three aromatic rings forming a multiple phenyl···phenyl
85 and squaramide···phenyl stacking, which provide extra stability
to the complex. Moreover, careful inspection of the complexes
ꢁEi < –15 kcal mol–1 (9 of the 13 minima represented in Figure 8)
In contrast to the PXRD pattern of compound 1, nonꢀgelators
2ꢀ10 showed additional peaks after 17º (Figure S16 and Table
S2). Some of these compounds showed even higher crystallinity
than the squaramide gelator 1 (e.g., compounds 5, 7). On the
40 other hand, the two major peaks at low angle (around 4º and 6º)
8
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revealed that similar interꢀ and intramolecular interactions coexist
in all cases. However, although in all cases intramolecular
interactions involve the stacking of the three aromatic rings,
lack of the third aromatic ring absence precludes the formation of
intramolecular π···π stacking interactions. Comparison of
complexes obtained for 1 and 3 suggests that both the lower
intermolecular interactions typically consists of two C=O···H–N 25 number of intermolecular hydrogen bonds and the lack of
5
hydrogen bonds involving the squaramides or a single S=O···H–
N hydrogen bond. This is illustrated in Figures 10B and 10C,
which display the second (ꢁEi= –22.5 kcal mol–1) and third
minima (ꢁEi= –21.5 kcal mol–1) in the energy ranking,
intramolecular π···π stacking interactions are responsible for the
relatively high ꢁEi values and poor stability of the latter with
respect to the former.
In comparison with 3, the interaction patterns of complexes
30 derived from 7, 8 and 10 are more similar to those observed for 1,
even though there are also some differences among the formers
and the latter. Thus, the lower energy complexes calculated for 7
and 10 exhibited two N–H···O intermolecular hydrogen bonds
(Figures S19 and S20, respectively), while those derived from 8
35 show only one of such interactions (Figure S21). Furthermore, no
N–H···π and C–H···π intermolecular interactions were detected
in 7, 8 and 10. Accordingly, intermolecular interactions seem to
be weaker for 8 than for 7, 10 and, specially, 1.
respectively.
This image cannot currently be displayed.
Regarding to intramolecular interactions 7, 8 and 10 display
40 π···π stacking, even though they also present some relevant
differences. Specifically, such π···π interactions are apparently
weaker for 7 and 10 than those obtained for 1 and 8. Thus, three
aromatic rings participate in each π···π interaction identified in
complexes of the two latter compounds (Figures 9 and S21),
45 while only two aromatic rings are involved in those found in the
complexes of the formers (Figures S19 and S20). The reduction
in the intensity of π···π interactions for 7 and 10 has been
attributed to the repulsive effects provoked by the fluoride
substituents and to replacement of an aromatic ring by an
50 aliphatic chain, respectively. These results clearly indicate that
dimers calculated for 1 show a large and complex network of
interꢀ and intramolecular interactions that provides an additional
stability to the complex. This network of interactions becomes
weaker and smaller for the complexes that involve the rest of
55 compounds and, therefore, such extra stability disappears.
This image cannot currently be displayed.
10
Fig. 9 Representation of the three most stable complexes obtained for 1:
A) ꢁEi= −26.1 kcal mol–1; B) ꢁEi= −22.5 kcal mol–1 and C) ꢁEi= −21.5
kcal mol–1. Intermolecular (left) and intramolecular (right) interactions are
displayed for the complex and a single molecule of the complex,
15 respectively. Hydrogen bonds are represented by black dashed lines, N–
H···π and C–H···π interactions by read and blue arrows, respectively, and
intramolecular π···π stacking interactions by green double arrows.
Fig. 10 Representation of the two most stable complexes obtained for 3:
A) ꢁEi= −18.8 kcal mol–1 and B) ꢁEi= −17.3 kcal mol–1. Intermolecular
and intramolecular interactions are displayed for each complex. Interꢀ and
60 intramolecular hydrogen bonds are represented by black dashed lines, and
N–H···π interactions by read arrows.
Complexes of 3 tend to be stabilized by intermolecular N–
H···O hydrogen bonds and N–H···π interactions, while
20 intramolecular interactions consists of N–H···N hydrogen bonds
(Figure 10). It should be noted that, in comparison with 1, the
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Additional PCMꢀM06L/6ꢀ31+G(d,p) calculations were
performed for dimers of 1 in water and chloroform (ε = 4.7 and
78.4, respectively). Results were similar to those obtained in
methanol suggesting that the influence of the solvent on the
gelation ability of this compound is not due to simple electrostatic
effects induced by the polarization of the solvent but to the role of
the first solvation shell in the network of interꢀ and intramolecular
interactions discussed above. Unfortunately, continuum models,
like PCM, are unable to describe the effects associated to
5
10 solute···solvent interactions in the first solvation shell. Therefore,
considering the remarkable selectivity of the gelator for alcoholic
solvents, the differences in PXRD patterns (e.g., as synthesized
gelator vs. xerogel) and the standard gelation mechanism
associated to supramolecular gels,1,43ꢀ50 we should not dismiss the
15 potential role of at least some solvent molecules acting, for
instance, as bridges between gelator molecules. This has been
proved by additional PCMꢀM06L/6ꢀ31+G(d,p) calculations on
complexes formed by two interacting molecules of 1 and two
methanol molecules positioned between them (Figure S22). It is
20 worth noting that each molecule of 1 interacts simultaneously
with methanol and with the second molecule of 1. Unfortunately,
the theoretical methodology used in this work is suitable to
examine the ability of the different compounds to form
intermolecular interactions but it is not appropriated for a
25 systematic exploration of this bridgeꢀlike gelation mechanism.
Thus, due to the huge number of possibilities, other theoretical
approaches based on statistical sampling procedures would be
more appropriated for such purpose.
45
Fig. 11 Representative FESEM images of the xerogels prepared by
freezeꢀdrying of the corresponding organogels made of 1 in different
solvents at their CGC (Table 1). A) methanol (heatingꢀcooling, c = 7 g L–
–
1
1), B) phenylmethanol (heatingꢀultrasound, c = 21 g L ), C) hexanꢀ1ꢀol
–
1
50 (heatingꢀultrasound, c = 7 g L ) and D) hexanꢀ1ꢀol (heatingꢀcooling, c =
–
1
9.1 g L ). Note: The selected images are representative of the bulk
material. For additional images see ESI.
Morphological properties of alcogels
30 Field emission scanning electron microscopy (FESEM) of the
corresponding xerogels showed a remarkable influence of the
solvent on the morphologies. For instance, straight laths of ca.
0.2ꢀ1.4 ꢀm in width were observed for gel made in
phenylmethanol (Figure 11B), whereas dense fibrilar networks
35 with entangled fibers of ca. 10ꢀ20 nm in diameter were
characteristic of the gels made in hexanꢀ1ꢀol (Figure 11CꢀD) and
methanol (Figure 11A). The exact molecular mechanism
associated with each morphology remains unclear. No major
differences were apparently observed for the gel phase obtained
40 either by heatingꢀcooling or heatingꢀultrasound for the gel made
in hexanꢀ1ꢀol (Figures 11CꢀD and S8). However, transmission
electron microscopy (TEM) seems to reveal a less dense fibrilar
network for the gel prepared by heatingꢀultrasound (Figures 12
and S9).
Fig. 12 Representative TEM images of xerogels of the corresponding
55 organogels made of 1 in different solvents at the CGC (Table 1): A)
–
1
Methanol (heatingꢀcooling, c = 7 g L ), B) hexanꢀ1ꢀol (heatingꢀ
–
1
ultrasound, c = 7 g L ). Note: The selected images are representative of
the bulk material. For additional images see ESI.
As expected, complementary fibril structures with average
60 heights between ca. 4 nm and 10 nm were also observed by
atomic force microscopy (AFM) (Figure 13). Certain fiber
helicity was detected by FESEM and AFM imaging (Figure S10).
Although we have recorded images of the nanostructures by
different techniques in order to identify any possible artifact, it
65 should be emphasized that important changes in the structures
could occur during preparation of the samples and, therefore, the
interpretation of the images should always be done carefully
without overselling.
10
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Fig. 13 Representative AFM images of the gel made of 1 in methanol
Furthermore, these gels were also found to be thixotropic,94
a
–
1
(heatingꢀcooling) at the CGC (c = 7 g L ). Note: The selected images are 30 key property for realꢀlife applications of many gelꢀbased
representative of the bulk material. For additional images see ESI.
materials.95 This behavior was confirmed by a threeꢀsteep
rheological loop test consisting of (1) application of shear strain
as defined by DTS experiments (G' > G''), (2) subsequent
increase of the strain until the gel collapses (G' < G'') and (3)
35 return to the starting strain value (G' > G''). Full recovery of the
gel strength was observed within seconds after each cycle (Figure
15). This selfꢀhealing behavior was also macroscopically
observed upon vigorous shaking of the vial containing the bulk
In addition, the anisotropic and thermoreversible features of
the alcogels allowed turning on/off their birefringence under
polarized light (Figure S11). The ability to control the refractive
index of soft materials constitutes an important property for
applications in optical devices.93
5
Rheological properties of alcogels
gel followed by a resting period (Figure S18F).
10 The viscoelastic properties of the model gels were confirmed by
oscillatory rheological measurements (Figure S7). The storage
(G') and loss modulus (G'') were measured at room temperature
as a function of the shear strain (dynamic strain sweep, DSS) and
the frequency (dynamic frequency sweep, DFS) to define the
15 linear viscoelastic regime of the material (Figures 14 and S7).
Although all gels should be defined as weak gels according to the
moduli values, reasonably constant values of the tan δ (G''/G')
during the measurements indicated a relative good tolerance of
the materials towards low external forces. Moreover, the value of
20 the storage modulus was always ca. one order of magnitude
higher than the loss modulus. The aging stability of the gels at
room temperature was confirmed by dynamic time sweep (DTS)
measurements within the predetermined linear limits (i.e., 0.1%
This image cannot currently be displayed.
40
strain, 1 Hz frequency).
This image cannot currently be displayed.
Fig. 15 Rheological loop test of the gel made of 1 in butanꢀ1ꢀol at CGC (c
–
1
= 8.4 g L ). Steps: 1) 1 Hz, 0.1 % strain, 10 min; 2) 0.1 Hz, 1000 %
strain, 5 min; 3) 1 Hz, 0.1 % strain, 30 min. Steps 2 and 3 were repeated
for a second cycle.
45 Responsiveness to external ions
Since squaramide derivatives are known to coordinate to anions
at the NꢀH groups and to cations at the carbonyl moiety, we
expected a response of the alcogels to the presence of external
ions. In order to confirm this, a small amount of different metal
50 salt solutions in methanol (i.e., FeCl3, Ni(OAc)2·3H2O,
NiCl2·6H2O, Cu(NO3)2 and CuCl2) were layered over 1 mL of the
–
1
model gel made of 1 in methanol (c = 10 g L ). Potential
complexation of the ions with the gelator molecule may disrupt
the nanofibers causing the gradual collapse of the gel network. As
55 a matter of fact, this was observed in preliminary experiments
upon addition of either 30 mM FeCl3 or 60 mM NiCl2·6H2O
stock solutions within 3.5 h and 6 h, respectively (Figures 18Cꢀ
D). Interestingly, the addition of 60 mM CuCl2 or
Ni(OAc)2·3H2O did not cause visible decomposition of the gel
60 network within 72 h (Figures 16AꢀB), suggesting different effects
of metal ions and counterions on the gel stability. The response of
the gel was independent on the procedure used for the preparation
of the hybrid material (Figure 16E). Future research is still
necessary to elucidate the exact nature of the metal complexes
65 and the dominant mechanism for the gel destruction.
25
Fig. 14 Representative oscillatory rheological plots of the model gel made
–
1
of 1 in methanol at CGC (c = 7 g L ). Top: DFS experiment. Bottom:
DSS experiment.
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This image cannot currently be displayed.
50 are acknowledged for financial support. We thank the Servicio
General de Apoyo a la InvestigaciónꢀSAI (Universidad de
Zaragoza) for electron microscopy, the Laboratorio de
Microscopías Avanzadas at Instituto de Nanociencia de Aragón
(LMAꢀINA) for AFM imaging and Centre de Supercomputació
55 de Catalunya (CESCA) for the computational resources provided.
J.V.A.ꢀR. thanks DGA for a predoctoral fellowship. D.D.D.
thanks DFG for the Heisenberg Professorship Award.
Fig. 16 Effect of external ions on the stability of the gel made of 1 in
–
1
methanol (c = 10 g L ). A) 60 mM CuCl2: stable gel. B) 60 mM
Ni(OAc)2·3H2O: stable gel. C) 30 mM FeCl3: gel decomposition in 3.5 h.
D) 60 mM NiCl2·6H2O: gel decomposition within 6 h. E) Left: addition of
1 to metal solution (30 mM FeCl3) followed by heatingꢀcooling. Right:
addition of metal solution (30 mM FeCl3) to preformed gel via heatingꢀ
cooling. Gel colours correspond to the colours of the metal salt solutions.
Notes and references
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