Expanding the limits of amide-triazole isosteric substitution in bisamide-based physical gels

Article abstract of DOI:10.1039/c9ra03316e

Gelation of organic solvents using N,N′-((1S,2S)-cyclohexane-1,2-diyl)didodecanamide (C₁₂-Cyc) is driven by its self-assembly via antiparallel hydrogen bonds and van der Waals intermolecular interactions. In this work we carried out a dual isos

Full text of DOI:10.1039/c9ra03316e

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Expanding the limits of amide–triazole isosteric
substitution in bisamide-based physical gels†
Cite this: RSC Adv., 2019, 9, 20841
Markus Tautz,a Juan Torras, bc Santiago Grijalvo,de Ramon Eritja, de Cesar Saldıas,f
´
´
´
bc
ag
*
Carlos Aleman
and David Dıaz Dıaz
´ ´
´
Gelation of organic solvents using N,N0-((1S,2S)-cyclohexane-1,2-diyl)didodecanamide (C12–Cyc) is driven
by its self-assembly via antiparallel hydrogen bonds and van der Waals intermolecular interactions. In this
work we carried out a dual isosteric substitution of the two amide groups with 1,2,3-triazole rings
affording the corresponding isosteric gelator (click-C12–Cyc). A detailed comparative study in terms of
the gelation ability and gel properties demonstrated that the 1,2,3-triazoles can take over all of the
functions derived from the amide groups offering a versatile strategy for tuning the properties of the
corresponding gels. This is not an obvious outcome because the directional amide groups in C12–Cyc
constitute the source of the hydrogen bonds to build the 3D self-assembled network. Furthermore,
theoretical calculations revealed that click-C12–Cyc can adopt a wide variety of interacting patterns,
whose relative stability depends on the polarity of the environment, this is in good agreement with the
experimental data obtained regarding its gelation ability. Other important features of click-C12–Cyc for
potential practical applications are its non-cytotoxic character and its phase-selective gelation of water–
oil mixtures.
Received 4th May 2019
Accepted 12th June 2019
DOI: 10.1039/c9ra03316e
rsc.li/rsc-advances
compounds in solution into 1D bers that are nanometers in
diameter and millimeters in length, followed by their physical
Introduction
entanglement generating a 3D scaffold. The solid-like appear-
ance of the gels results from the immobilization of solvent
molecules (the major component) into the interstices of the 3D
network via surface tension and capillary forces, increasing the
viscosity of the medium by factors up to 1010. Owing to the non-
covalent nature of the interactions, mainly hydrogen-bonding,
p-stacking and van der Waals interactions, most physical gels
show reversible gel-to-sol transitions that can be triggered by
different external stimuli (e.g. temperature, pH, ionic strength,
irradiation).20–22
Hierarchical gel-based materials have received increasing
attention over the past few decades1–3 owing to their fascinating
molecular architectures and potential for high-tech applica-
tions in various elds including, among others,4,5 the prepara-
tion of sensors,6 liquid crystals,7 conductive scaffolds,8,9
templates for cell growth10 and inorganic structures,11 catal-
ysis,12,13 cosmetics14 and food industries.15 In contrast to
chemical gels16 that are formed by covalent bonds, (e.g. cross-
linked polymers), physical (or supramolecular) gels17–19 are
formed by self-assembly of low-molecular-weight (LMW)
In 1996 Hanabusa and co-workers23 reported the remarkable
gelation ability of alkylamides derived from trans-1,2-dia-
minocyclohexane and the resulting chiral aggregates in organic
a
¨
¨
¨
Institut fur Organische Chemie, Universitat Regensburg, Universitatsstr. 31, 93053
Regensburg, Germany. E-mail: David.Diaz@chemie.uni-regensburg.de
solvents.
Specically,
N,N0-((1S,2S)-cyclohexane-1,2-diyl)
b
´
`
Departament d'Enginyeria Quımica, EEBE, Universitat Politecnica de Catalunya, C/
didodecanamide (C12–Cyc, Fig. 1) and its enantiomer were
found to gel different organic solvents. Molecular modeling and
mechanistic studies24 have shown that the two equatorial
amide–NH and amide–CO groups direct themselves antiparallel
to each other and perpendicular to the cyclohexyl ring, forming
an extended asymmetric molecular tape stabilized by two
intermolecular hydrogen bonds between each molecule.
Subsequently, the tape-like molecular aggregates are inter-
locked through van der Waals interactions and transformed
into helical ber-like aggregates, which nally immobilize the
organic uids. The length of the aliphatic chains has been
found to play a critical role in the gelation ability of this type of
Eduard Maristany, 10-14, Ed. 12, 08019, Barcelona, Spain
cBarcelona Research Center for Multiscale Science and Engineering, Universitat
`
Politecnica de Catalunya, C/Eduard Maristany, 10-14, 08019, Barcelona, Spain
dBiomedical Research Networking Centre in Bioengineering, Biomaterials and
Nanomedicine (CIBER-BBN), Jordi Girona 18-26, 08034 Barcelona, Spain
eInstitute of Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, 08034
Barcelona, Spain
fDepartamento de Quımica Fısica, Facultad de Quımica, Ponticia Universidad
´
´
´
´
Catolica de Chile, Casilla 302, Correo 22, Santiago, Chile
g
´
´
Instituto de Productos Naturales y Agrobiologıa del CSIC, Avda. Astrofısico Francisco
´
Sanchez 3, 38206 La Laguna, Tenerife, Spain. E-mail: d.diaz.diaz@ipna.csic.es
† Electronic supplementary information (ESI) available: Spectra (NMR, FT-IR,
XRD, CD), tabular data, additional plots and electron microscopy images. See
DOI: 10.1039/c9ra03316e
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(S,S)- and (R,R)-cyclohexanediamine were purchased from
Sigma-Aldrich, 1-dodecyne from TCI Europe, and 1-tridecyne
from Alfa Aesar. Additionally, double-distilled water was puri-
ed using a Millipore water-purifying system (Merck) prior to
usage.
Characterization methods
Characterization of compounds. Nuclear magnetic reso-
nance (NMR) spectra were recorded at 25 ꢀC on a Bruker Avance-
400. Chemical shis are denoted in d (ppm) relative to the
residual solvent peaks. Coupling constants, J, are given in Hertz.
Coupling patterns are indicated using the following
abbreviations: s ¼ singlet, d ¼ doublet, t ¼ triplet, m ¼ multi-
plet, dd ¼ doublet of doublets, and dt ¼ doublet of triplets. The
estimated error of the reported values is 0.01 ppm (d, 1H-NMR),
0.1 ppm (d, 13C-NMR) and 0.1 Hz (J, coupling constant).
Low-resolution mass spectroscopy (MS) was carried out on
a Varian MAT 311A. Elemental analyses were performed on
a Heraeus Mikro-Rapid analyzer. Ultraviolet-visible (UV-vis)
spectroscopy was performed using a Varian Cary 50 UV spec-
trophotometer and quartz–glass cuvettes of 0.5 cm thickness.
Fourier transform infrared (FT-IR) spectra were recorded at
room temperature using an Excalibur FTS 3000 FT-IR spec-
trometer (Biorad) equipped with a single reection ATR
(attenuated total reection) accessory (Golden Gate, Diamond).
Thin layer chromatography (TLC) analyses were performed
using uorescent-indicating plates (aluminum sheets precoated
with silica gel 60 F254, thickness 0.2 mm, Merck), and visuali-
zation was achieved using UV light (lmax ¼ 254 nm) and staining
with phosphomolybdic acid and/or iodine. Melting points were
measured on a Stuard SMP 10 apparatus. Optical activities were
measured using an Anton Paar MCP500 polarimeter.
Characterization of gel materials. The critical gelation
concentration (CGC) values (dened as the minimum concen-
tration of the compound at which gelation is observed) were
estimated by continuously adding aliquots of solvent (0.02–0.1
mL) into vials containing the potential gelator and performing
a typical heating–cooling protocol for gel-formation until no
gelation was observed. The starting point for CGC determina-
tions was 120 g Lꢁ1 in most cases. No further experiments were
made if gelation was not achieved at 200 g Lꢁ1. Non-gel con-
taining vials (i.e. clear solution aer 7 days) were le at RT and
visually monitored for possible gelation/crystallization over
time.
Fig. 1 Top: isosteric relationship between trans-amides and 1,4-
disubstituted 1,2,3-triazoles. Bottom: double isosteric replacement of
the LMW gelator C12–Cyc investigated in this work.
gelator, which should contain at least six carbons.25 Moreover,
the chiral gelator should also be enantiomerically pure in order
to maximize the gelation efficiency. The easy preparation and
reliability of this LMW gelator has made it one of the most
utilized and versatile systems in the eld of physical gels.26,27
Among the large number of LMW gelators with different struc-
tures, those containing triazole rings have attracted considerable
attention during the last few years.28–35 Recently, our group has
demonstrated that the isosteric substitution of amides by 1,2,3-tri-
azole groups in LMW gelators enables the modication of different
gel properties.36,37 In general, isosteres possess an almost equal
molecular shape and volume, approximately the same distribution
of electrons and exhibit similar physical properties.38,39 Although
this is still a recent concept in materials synthesis,36,37,40 it has a long
and successful history in medicinal chemistry for drug develop-
ment.41 In a previous and seminal work, we replaced an amide
group with a 1,2,3-triazole in a glutamic acid-derived LMW gelator.36
Therein, both the amide group and the carboxylic acid groups
played a key role in the aggregation pattern of the gelator via the
hydrogen bonds. Aer this study we wondered whether 1,2,3-tri-
azoles could replace all of the hydrogen bond centers in an LMW
gelator without sacricing its gelation capacity. To answer this
question, we decided to carry out a dual isosteric replacement of
both the amide groups in C12–Cyc with 1,2,3-triazole rings affording
the corresponding isostere click-C12–Cyc (Fig. 1). In principle, the
preservation of the gelation ability upon dual isosteric substitution
is not obvious because the directional amide groups in this example
constitute the source of hydrogen bonds to build the 3D network.
Herein, we describe the preparation of both isosteres and a detailed
comparative study in terms of the gelation ability and gel properties.
The results of this research have revealed the remarkable potential
of this approach for ne-tuning the functionality of physical gels.
The thermal gel-to-sol transition temperature (Tgel) values
were determined using a custom made set-up in which the
sealed vial containing 100 mL of the gel was placed into a mold
of an alumina block and heated at 1 ꢀC/5 min using an electric
heating plate equipped with a temperature control couple
(Fig. S1†). The obtained values were veried using differential
scanning calorimetry (DSC) measurements of one model gel
Experimental
Materials
(40 g Lꢁ1
which the gel started to break was dened as Tgel. Each
C12–Cyc in cyclohexane). Herein, the temperature at
Unless otherwise indicated, all chemicals, reagents and solvents measurement was repeated at least twice and the average value
were of analytical grade, purchased from commercial sources reported. Tgel values were found to be almost unaltered within
ꢀ
and used as received without further purication. Specically, a difference of 1–2 C aer several heating–cooling cycles.
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Oscillatory rheology was performed with an AR 2000 2H), 3.65 (m, 2H), 2.11 (m, 4H), 2.02 (m, 2H), 1.75 (m, 2H), 1.57
Advanced rheometer (TA Instruments) equipped with a Julabo C (m, 4H), 1.25 (s, 36H), 0.88 (t, J ¼ 6.44 Hz, 6H); 13C NMR (101
cooling system. A 1000 mm gap setting and a torque of 5 ꢂ MHz, CDCl3) d (ppm) 173.93, 53.63, 36.98, 32.43, 31.94, 29.67,
10ꢁ4 N mꢁ1 at 25 ꢀC were used for the measurements in a plain- 29.65, 29.55, 29.42, 29.37, 29.36, 25.86, 24.75, 22.71, 14.13; FT-
plate (40 mm, stainless steel). The following experiments were IR (ATR) nmax (cmꢁ1) 3276, 2918, 2851, 1636, 1543, 1468, 1379,
carried out for each sample, using ca. 2 mL total gel volume: (i) 1304, 1244, 1148, 1121; MS (ESI) m/z ¼ 479.5 [M + H]+, 501 [M +
dynamic strain sweep (DSS): variation of G0 (storage modulus) Na]+, 979.9 [2M + Na]+; [a]D20 ꢁ36.9 ꢃ 0.1ꢀ (c ¼ 1; H2O). Elemental
and G00 (loss modulus) with strain (from 0.01 to 100%); (ii) analysis calculated for C30H58N2O2: C, 75.26; H, 12.21; N, 5.85;
dynamic frequency sweep (DFS): variation of G0 and G00 with found: C, 75.04; H, 11.87; N, 5.58. The other enantiomer (i.e.
frequency (from 0.1 to 10 Hz at 0.1% strain); and (iii) dynamic N,N0-((1R,2R)-cyclohexane-1,2-diyl)didodecanamide)
was
time sweep (DTS): variation of G0 and G00 with time keeping the prepared following the same route using (R,R)-1,2-cyclo-
strain and frequency values constant and within the linear hexanediamine as the starting material.
viscoelastic regime as determined by the DSS and DFS
1H-Imidazole-4-sulfonyl azide (3). Azide transfer agent 3 was
measurements (strain ¼ 0.1% strain; frequency ¼ 1 Hz).
prepared following the procedure previously described43 with
Differential scanning calorimetry measurements were per- slight modications: a stirred solution of NaN3 (3.74 g, 57.5
ꢀ
formed on a PerkinElmer DSC 8000 differential scanning calo- mmol) in MeCN (50 mL) was cooled to 0 C. SO2Cl2 (6.75 g, 50
rimeter. The DSC thermogram was obtained under a dynamic mmol) was added dropwise and the mixture was allowed to
argon atmosphere (gas ow rate ¼ 25 mL minꢁ1) at a heating reach RT and stirred for 19 h. Thereaer, imidazole (6.47 g, 95
rate of 5 ꢀC minꢁ1 from 25 to 50 ꢀC and 1 ꢀC minꢁ1 from 50 to mmol) was added and the reaction was stirred for an additional
80 ꢀC. The measurement was carried out three times. An empty 3 h. Aer this time, the mixture was diluted with EtOAc (100
sample holder was used as the reference.
mL), washed with H2O and saturated NaHCO3 solution (3 ꢂ
The FT-IR spectra were recorded as indicated above for the 50 mL each) and dried over anhydrous Na2SO4. The obtained
characterization of compounds. The CD spectra were recorded solution was added dropwise to a solution of acetyl chloride
using a Jasco J-710 Spectropolarimeter. X-ray diffraction spec- (5.89 g, 5.33 mL, 75 mmol) in EtOH (20 mL) at 0 ꢀC. The desired
troscopy (XRD) was performed on a STOE STADI P powder product was allowed to precipitate for 12 h at ꢁ18 ꢀC. The
diffractometer (StartFragment Transmission mode, at product was ltrated, washed with EtOAc (3 ꢂ 15 mL) and dried
samples, Dectris MYTHEN 1Kk microstrip solid-state detector) under vacuum affording 1H-imidazole-4-sulfonyl azide (3) as
with CuKa radiation operating at 40 kV and 40 mA. Conditions a white solid in an 85% yield (7.38 g, 42.6 mmol). 1H NMR (400
were 0.015ꢀ, time 600 s per step, and a 2 theta range of 0–90ꢀ.
MHz, D2O) d (ppm) 9.36 (m, 1H), 7.92 (m, 1H), 7.52 (m, 1H).
(1S,2S)-1,2-Diazidocyclohexane (4). 4 was prepared following
Field emission scanning electron microscopy (FESEM, reso-
lution 0.8 nm) images of the xerogels were obtained using a Carl the general diazo transfer procedure previously described44 with
Zeiss Merlin, eld emission scanning electron microscope slight modications. To a stirred solution of K2CO3 (2.18 g, 15.8
equipped with a digital camera and operated at an accelerating mmol) and (1S,2S)-1,2-diaminocyclohexane (1) in a mixture of
voltage of 10 kV. For visualization, samples were prepared by the tBuOH and water (1 : 1 v/v, 100 mL) was added 1H-imidazole-4-
freeze-drying (FD) method: an Eppendorf tube containing the sulfonyl azide (3) (379 mg, 2.2 mmol), CuSO4$5H2O (11.4 mg,
corresponding gel-material (100–200 mL) was frozen in liquid 0.018 mmol) and K2CO3 (2.18 g, 15.8 mmol). The mixture was
nitrogen or dry ice/acetone and the solvent was immediately stirred for 3 days at RT and thereaer extracted with EtOAc (4 ꢂ
evaporated under reduced pressure (0.6 mmHg) for 2 days at 50 mL). The combined organic phases were dried over anhy-
room temperature (RT). The obtained brous solid was placed drous Na2SO4 and most of the solvent was removed under
on top of a tin plate and shielded by Pt (40 mA during 30 s; lm reduced pressure. The concentrated solution was puried using
thickness z 5 nm).
column chromatography (eluent: hexane/Et2O/CHCl3 100 : 3 : 3
(ref. 45)) and dissolved in toluene for safe storage. Several
batches afforded (1S,2S)-1,2-diazidocyclohexane (4) in yields
Synthesis of compounds
1
ranging from 31% to 97% (yields were determined by H NMR
N,N0-((1S,2S)-Cyclohexane-1,2-diyl)didodecanamide
(C12– by integral comparison using the toluene peaks as a reference).
Cyc). C12–Cyc was synthesized as described in the literature42 1H NMR (400 MHz, CDCl3) d (ppm) 3.20 (m, 2H), 2.07 (m, 2H),
with slight modications: to a stirred solution of (S,S)-1,2- 1.79 (m, 2H), 1.29 (m, 4H).
cyclohexanediamine (1) (114 mg, 1.0 mmol) in THF (18 mL)
(1S,2S)-1,2-Bis(4-decyl-1H-1,2,3-triazol-1-yl)cyclohexane
lauroyl chloride (2) (438 mg, 475 mL, 2.0 mmol) and Et3N (click-C12–Cyc). Click-C12–Cyc was prepared following the
(337 mg, 787 mL, 3.3 mmol) were added dropwise. The mixture general procedure previously described46 with slight modica-
was reuxed for 5 h and allowed to cool to RT. The precipitate tions: to a stirred solution of 1-dodecyne (5) (259 mg, 1.56
(triethylammonium chloride) was ltered off and the solvent of mmol) in a mixture of t-BuOH and water (1 : 1 v/v, 3.8 mL)
the remaining ltrate removed under reduced pressure. The a solution of 4 in toluene (123.5 mg, 0.743 mmol) was added.
obtained residue was washed with aqueous 1 M HCl (4 ꢂ 5 mL) Subsequently, separate solutions of CuSO4$5H2O (249.7 mg, 1
and water (4 ꢂ 5 mL), dried and recrystallized from acetone mmol) and sodium ascorbate (198.1 mg, 1 mmol) in water (1
affording C12–Cyc as a white solid in a 39% yield (187 mg, 0.391 mL) were added alternately until the product precipitated with
mmol). Mp 177 ꢀC;24 1H NMR (400 MHz, CDCl3) d (ppm) 5.88 (s, blurring of the clear solution. Aer stirring for 3 days, the
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reaction mixture was dissolved in a mixture of EtOAc and THF presence of cells for 24 h at 37 ꢀC. DMEM was removed and cells
(1 : 1 v/v, 100 mL) and washed with aqueous Na2EDTA were washed with phosphate buffer saline (PBS). Fresh DMEM
(0.1 mol Lꢁ1, 3 ꢂ 50 mL), brine (50 mL), water (50 mL) and dried was added (200 mL) and cells were incubated for an additional
over anhydrous Na2SO4. Finally, the solvent was removed under 2 h. A solution of MTT (25 mL) in PBS was added and the
reduced pressure and recrystallized from acetone affording resultant solution was incubated for 4 h. The solution was
click-C12–Cyc as a light yellow solid in a 32% yield (117 mg, removed and formazan crystals were dissolved in 100 mL of
1
ꢀ
0.236 mmol). Mp 129 C; H NMR (400 MHz, CDCl3) d (ppm) DMSO. The resultant solution was shaken at RT for 15 min and
6.79 (s, 2H), 4.73 (m, 2H), 2.52 (m, 4H), 2.31 (m, 4H), 2.04 (m, the absorbance was measured on a Glomax Multimode Micro-
2H), 1.59 (m, 2H), 1.49 (m, 4H), 1.24 (s, 28H), 0.88 (t, J ¼ 6.64 Hz, plate reader at 560 nm. Results were expressed as a relative
6H); 13C NMR (101 MHz, CDCl3) d (ppm) 32.46, 31.94, 29.65, percentage to the untreated control cells.
29.58, 29.38, 29.35, 29.25, 25.42, 24.65, 22.71, 14.13; FT-IR (ATR)
Statistical differences between the groups at signicance
nmax (cmꢁ1) 3146, 3068, 2952, 2915, 2848, 1543, 1446, 1223, levels greater than 95% were calculated using the Student's t
1054, 809, 719; MS (ESI): m/z ¼ 250.2 [M + 2H]2+, 499.4 [M + H]+, test. In all cases, p values of less than 0.05 were regarded as
997.9 [2M + H]+; [a]D20 ꢁ44.7 ꢃ 0.3ꢀ (c ¼ 1; H2O). Elemental signicant. Numerical data are presented as mean ꢃ SD.
analysis calculated for C30H54N6: C, 72.24; H, 10.19; N, 16.85;
found: C, 72.13; H, 10.61; N, 16.79. The other enantiomer (i.e.
Computational studies
(1R,2R)-1,2-bis(4-decyl-1H-1,2,3-triazol-1-yl)cyclohexane)
was
All calculations were performed using the M06-2X functional,47
which was combined with the 6-31G(d,p) basis set48 in the
Gaussian 09 computer package.49 The M06-2X functional
prepared following the same route using (1R,2R)-1,2-dia-
minocyclohexane as the starting material.
The synthetic procedure and characterization data for click-
˚
describes medium-range (i.e. #5 A) noncovalent interactions,
C
13–Cyc, as well as the NMR and FT-IR spectra of the synthe-
such as conventional (e.g. N–H/O and H–O/H) and non-
conventional (e.g. C–H/O) hydrogen bonds, and better than
usual DFT functionals.50 Thus, the M06 group of functionals is
able to describe the geometry and interaction energy of
complexes stabilized by non-covalent interactions, including p–
p stacking, with accuracy close to that of couple cluster calcu-
lations with both single and double substitutions.51 All geom-
etry optimizations were performed in vacuum, and in implicit
solvents of growing polarity such as cyclohexane (3 ¼ 2.0165),
methanol (3 ¼ 32.613) and nitromethane (3 ¼ 36.562), which
was described using a simple self consistent reaction eld
(SCRF) method. More specically, the polarizable continuum
model52,53 (PCM) was used to represent bulk solvent effects.
Frequency analyses were performed to verify the nature of the
minimum state of the stationary points located during geom-
etry optimizations, as well as to obtain zero-point energies and
thermal corrections to the energy, which were used for the
calculation of free energies. Binding energies (BE) were cor-
rected with the basis set superposition error (BSSE) by means of
the standard counterpoise (CP) method.54
sized compounds, can be found in the ESI (Fig. S2–S6†).
General procedure for the preparation of organogels
Typically, a weighed amount of the corresponding solid gelator
was placed into a 2 mL screw-capped vial (4 cm length ꢂ 1 cm
diameter). The desired solvent was added on top and the
mixture was gently heated with a heat-gun until the solid
material was completely dissolved. Unless otherwise noted, the
resulting isotropic solution was then spontaneously cooled to
RT. Ultrasound treatment of the mixture was also applied in
some cases as indicated in the main text. No control over
temperature rate during the heating–cooling process was
applied. The material was preliminarily classied as a “gel” if it
did not exhibit gravitational ow upon turning the vial upside-
down at RT. The state was further conrmed using rheological
measurements.
General procedure for phase selective gelation experiments
The desired organic solvent and water (1 mL) were placed into
a glass vial forming a biphasic mixture. Aer adding the gelator
as a solid or in solution, successful gelation was checked by
turning the vial upside-down at RT.
Results and discussion
Synthesis of isosteres
Cell viability studies
Low-molecular-weight C12–Cyc was rapidly synthesized with
The metabolic activity of the cells was evaluated aer 24 h of a modest yield (39%) in one step via the nucleophilic addition of
incubation at 37 ꢀC using the MTT assay (MTT ¼ 3-(4,5- (S,S)-1,2-cyclohexanediamine (1) to lauroyl chloride (2) in the
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). HeLa presence of Et3N as a neutralization base under reuxing THF
human tumor cells were exponentially passaged before they (Fig. 2). The isostere click-C12–Cyc was obtained with a modest
reached conuence. Cells (ꢄ8000 cells per well) were grown in yield (32% aer recrystallization) via the Huisgen cycloaddition
Dulbecco's Modied Eagle Medium (DMEM) supplemented “click” reaction55,56 between (1S,2S)-1,2-diazidocyclohexane (4)
with 10% fetal bovine serum (FBS) for 24 h before the experi- and 1-dodecyne (5) catalyzed by CuI in a mixture of tBuOH/H2O.
ment in a 96-well cell culture plate. Prepared working concen- The diazide 4 was synthesized by reacting 1 with 1H-imidazole-
trations of both gelators were placed in contact with HeLa cells 4-sulfonyl azide (3) as an azide transfer agent in the presence of
in order to get a nal concentration of 5, 10, 25, 50 and 100 mM K2CO3 and CuII in a mixture of tBuOH/H2O (Fig. 2). The
in a nal volume of 200 mL. Gelators were incubated in the synthesis of the imidazole sulfonyl azide 3 was accomplished in
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Fig. 3 Digital photographs of upside-down vials containing organo-
gels made of C12–Cyc and click-C12–Cyc in nine solvents at their
corresponding critical gelation concentrations.
Fig. 2 Synthetic scheme for the preparation of the LMW gelator C12
–
Cyc and its isostere click-C12–Cyc. The same procedures were used
for the synthesis of the corresponding enantiomers as well as the
analog click-C13–Cyc (see ESI†).
It is worth mentioning that the click-analogue with only one
extra methylene group (click-C13–Cyc) was able to form gels in
a broader array of solvents compared to click-C12–Cyc, and in
some cases (e.g. ethanol, propan-2-ol) even more efficiency than
C
12–Cyc (Table S2, see ESI†). This observation highlights the
a good yield (85%) by the addition of two equivalents of imid-
azole to chlorosulfonyl azide, which was prepared in situ by the
reaction of equimolar quantities of sodium azide with thionyl
chloride in acetonitrile (see ESI†).
importance of the aliphatic chain length in the design of new
LMW gelators. Moreover, triazole rings are chemically more
robust than amides,57 which may offer alternative uses for click-
gelators under harsh conditions.
Gel-to-sol transition temperature (Tgel), gelation time and
CGC
Solubility properties and gelation ability
The gelation abilities of C12–Cyc and click-C12–Cyc were inves-
tigated in a large library of solvents using the classical heating–
cooling cycle as described in the Experimental section (Tables
S1 and S2, see ESI†). Materials that did not show gravitational
ow upon turning the vial upside-down were initially classied
as stable gels. The viscoelastic nature of the selected gels was
later conrmed using oscillatory rheological experiments (vide
infra). In agreement with previous studies,23 the chiral structure
of the (C12–Cyc)-based aggregates in a model gel could be
conrmed using CD spectroscopy (Fig. S7, see ESI†). Both iso-
steres were able to gel different non-polar (e.g. cyclohexane,
hexane, oils) and polar-protic (e.g. ethylene glycol, methanol,
nitromethane) solvents. However, C12–Cyc showed a broader
solvent scope in terms of gelation (Table S2, see ESI†). For
instance, signicant nonpolar solvents, especially aromatic
solvents such as benzene and toluene, and alcohols with more
than two carbon atoms yielded clear solutions of click-C12–Cyc,
which turned into suspensions above 120 g Lꢁ1. Thus, the
intermolecular interactions responsible for the gel formation
(e.g. gelator–gelator, gelator–solvent, aggregate–solvent inter-
actions) were apparently more inuenced by the nature of the
solvent in the case of the click-isostere. Fig. 3 shows pictures of
selected gels prepared at their corresponding CGC. In general,
most gels were opaque except for those prepared in paraffin and
Tgel, gelation kinetics and CGC were also compared for gels
made from each isostere in nine solvents (Fig. 4). In general,
gels made of C12–Cyc showed similar or higher Tgel values than
those made of click-C12–Cyc, except in liquid paraffin in which
the opposite was observed. All gels showed full thermo-
reversibility with gelation kinetics ranging from seconds to
1 h. In general, gels made of click-C12–Cyc showed longer
gelation times, except when ethylene glycol was used. The
straight lines obtained in the ln–ln plots of Tgel and gelation
time vs. gelator concentration indicated a power law-decay with
similar values for both isosteres at high concentrations within
the same incremental concentration interval, whereas gels
made of C12–Cyc displayed a higher Tgel and lower gelation
times at low concentrations (Fig. S8, see ESI†). In other words,
one variable changes as a constant power of the other one for
both isosteric systems. In terms of the CGC, similar values were
found within the experimental error for both isosteres in
cyclohexane, gasoline, liquid paraffin and silicone oil. In other
solvents, click-C12-Cyc required higher concentrations for gela-
tion, especially for polar-protic solvents (e.g. ethylene glycol,
methanol, nitromethane).
Stability and stimuli-responsive map
silicon oil which were translucent. The opacity of the gels sug- Unless otherwise indicated, the gels prepared from both gela-
gested the formation of aggregates larger than the wavelength tors were stable for several months at room temperature
of visible light (ca. 350–750 nm), which was later conrmed without detriment of their consistency and visual appearance.
using electron microscopy imaging (vide infra).
As expected for physical (or supramolecular) gels, those made of
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Fig. 5 Representative stimuli responsive map of organogels made of
C
12–Cyc and click-C12–Cyc in cyclohexane (c ¼ 15 g Lꢁ1). Abbrevia-
tion: H ¼ heating; C ¼ cooling. [AcOH] ¼ 1 M.
or CuSO4$5H2O did not induce any phase transition. However,
rapid gel-to-sol transitions were observed in both gels upon
addition of solid PdCl2, which immediately began to diffuse
into the gel phase. A similar response was observed with the gel
made of C12–Cyc upon addition of FeCl3. However, the gel made
of click-C12–Cyc remained stable in the presence of FeCl3 for 3
days. Aerward, this gel was also dissolved. Subsequent addi-
tion of metal complexation agents such as aqueous Na2EDTA (1
M) in the case of PdCl2 or aqueous oxalic acid (1 M) in the case
of FeCl3 did not restore the gel phases. Manual mechanical
agitation led to dissolution of the gel made of click-C12–Cyc,
whereas the gel made of C12–Cyc remained stable. This quali-
tative observation was later correlated with the results obtained
from rheological measurements (vide infra).
Morphological properties
Fig. 4 Comparative plots of the Tgel, gelation kinetics and CGC values
for the organogels made of C12–Cyc and click-C12–Cyc in nine
organic solvents. Both the Tgel and gelation time values were estimated
at the corresponding CGC values. Inset (middle plot): gelation time in
hexane. Each experiment was repeated at least three separate times
and the error bars show the SDM.
In order to evaluate the possible effects of the isosteric
replacement on the morphology of the corresponding gel
networks, we recorded FESEM and TEM images of some xero-
gels (Fig. 6). Specically, for these measurements we selected
the gels made of C12–Cyc or click-C12–Cyc in cyclohexane (c ¼
20 g Lꢁ1) and in nitromethane (c ¼ 30 g Lꢁ1). Entangled brillar
networks were observed for the xerogels prepared in cyclo-
hexane regardless of the gelator. In general, the bers were 35–
75 nm in diameter and several micrometers in length. Never-
theless, spherical aggregates integrated into the brillar scaf-
fold reminiscent of a neural network were observed only in the
case of click-C12–Cyc. The most obvious differences were
observed with the xerogels prepared from the gels made in
nitromethane. Specically, coiled-coil helices were observed
within the brillar network of C12–Cyc, whereas the xerogel
made of Click-C12–Cyc displayed large planar structures
assembled from a highly organized parallel network of gelator
bers. These bers were much smaller in diameter than those
formed by the isostere C12–Cyc. In general, the observed struc-
tures were also in agreement with those obtained by TEM
(Fig. S9–S14, see ESI†). Although we have recorded representa-
tive images of the bulk materials using different techniques in
order to recognize any possible artifacts, it should be
C
12–Cyc or click-C12–Cyc (taking cyclohexane as a model organic
solvent) also showed clear responses to multiple external
stimuli. Remarkably, the gels remained stable under UV irra-
diation, sonication, and upon addition of deionized water,
seawater, phosphate buffer solution (0.1 mol Lꢁ1, pH 7.0), NaCl,
HCl or NaOH solutions (1 mol Lꢁ1 each). However, both gels
were easily dissolved aer adding either methanol or acetic acid
(1 M) (Fig. 5). The liquid phase obtained aer addition of
methanol could be transformed into a biphasic mixture with
a stable gel on top by adding water to dissolve a part of the
methanol and applying a heating–cooling cycle to the system. In
contrast, the gel dissolved using acetic acid could not be
restored by adding water or by neutralization with NaOH (1 M).
These additives compete for hydrogen bonding interactions
with the gelator molecules leading to the dissolution of the
supramolecular aggregates. The addition of solid NaCl, AgNO3
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the stability of both gels during aging at RT, 1 Hz frequency and
0.1% strain (Fig. S15, see ESI†).
In vitro cytotoxicity studies
Toxicity studies of both gelators (C12–Cyc and click-C12–Cyc)
were assessed via in vitro studies using the HeLa human tumor
cell line. The cellular viability percentage was studied for
concentrations that ranged from 5 to 100 mM and was compared
to the negative control (blank) in which HeLa cells were incu-
bated in the absence of the aforementioned gelators.
Both hydrophobic derivatives displayed cellular viabilities
greater than 80% in all concentrations tested. Specically, click-
C
12–Cyc did not affect the proliferation process of HeLa cells
aer 24 h of incubation when compared with the results ob-
tained in the presence of C12–Cyc (Fig. S16 and Table S3, see
ESI†). In this regard, a non-toxic behavior and signicant values
were found for concentrations 10, 25 and 50 mM (100% of
cellular viability in all cases) if we compare these results with
the toxicity values obtained for C12–Cyc using the same condi-
tions at 10 and 25 mM (88% of cellular viability with *p < 0.05
and 85% of cellular viability with **p < 0.01, respectively).
Interestingly, when the gelator concentration was increased to
50 and 100 mM, the same non-toxic tendency was also exhibited
(100 and 89%, respectively) for click-C12–Cyc, whereas the
cellular viabilities were slightly lower in the case of C12–Cyc (85
and 82%, respectively). These values did not show any signi-
cant difference. The aforementioned results suggest the gels
made of click-C12–Cyc could potentially be used as non-toxic
composites in release experiments of active substances or in
environmental applications.
Fig. 6 Representative FESEM images of xerogels obtained upon
freeze-drying the corresponding organogels made of (A) C12–Cyc in
cyclohexane (c ¼ 20 g Lꢁ1); (B) click-C12–Cyc in cyclohexane (c ¼ 20 g
L
ꢁ1); (C) C12–Cyc in nitromethane (c ¼ 30 g Lꢁ1); and (D) click-C12
–
Cyc in nitromethane (c ¼ 30 g Lꢁ1). See ESI† for additional pictures.
emphasized that signicant changes in the microstructures can
take place during the preparation of freeze-dried samples and,
hence, the interpretation of these images should always be
performed carefully.
Rheological measurements
Standard dynamic oscillatory rheology was conducted in order
to conrm the viscoelastic gel nature of selected gels and
compare the overall mechanical stabilities towards external
shear forces. DFS, DSS and DTS experiments for the organogels
made of C12–Cyc or click-C12–Cyc in cyclohexane (c ¼ 20 g Lꢁ1
)
Phase selective gelation
revealed that the storage modulus G0 was one order of magni-
tude higher in the case of C12–Cyc (Table 1 and Fig. S15, see
ESI†). This was in agreement with the visually stronger char-
acter observed for the gel made of C12–Cyc upon mechanical
agitation (vide supra). Interestingly, the lowest tan d was
observed for the gel made of click-C12–Cyc, indicating that this
gel acts in a more elastic way and has a greater potential to store
the load rather than dissipating it. These results suggest that
the amide-to-triazole isosteric replacement imposes, at least to
some extent, restrictions against the molecular motion of the
supramolecular polymer chains. Moreover, DSS experiments
conrmed that the gel derived from C12–Cyc was more brittle in
nature as suggested by the smaller maximum strain at break (g)
(i.e. 1.4% for the gel made of C12–Cyc vs. 2.3% for the gel made
of click-C12–Cyc). Finally, the DTS experiments also conrmed
The non-toxic behavior of the isosteric gelators prompted us to
investigate their phase selective gelation capacity, which
constitutes an important property of some gelators with
potential for use in oil spill treatment.58–60 In this study we
found that both gelators were able to selectively gel the organic
phases of biphasic mixtures made of seawater and different
organic solvents such as gasoline, hexane, cyclohexane and
PTFE oil. This observation indicated that the amide–triazole
isosteric replacement preserved this important feature of the
gelator while allowing ne-tuning of other functional properties
of the gels. In particular, the oil phase of a mixture of seawater
and PTFE oil was successfully gelled by adding click-C12–Cyc (c
¼ 30 g Lꢁ1) on top of the system and applying a classical
heating–cooling cycle (Fig. 7). Importantly, clean seawater could
easily be recovered aer gelation was complete by simple
ltration of the gelled oil phase.
In other cases in which a heating–cooling cycle is not rec-
ommended, the gelator can be sprayed on top of the biphasic
mixture as a highly concentrated solution. For instance, the
organic phase of a mixture of seawater and gasoline was
successfully gelled by spraying a pre-formed solution of click-
Table 1 Rheological data for selected organogels made of C12–Cyc
and click-C12–Cyc in cyclohexane (c ¼ 20 g Lꢁ1
)
G0
G00
Gelator
(kPa)
(kPa)
tan d
g (%)
C
12–Cyc in gasoline (c ¼ 200 g Lꢁ1) (Fig. 8). As in the previous
C
12–Cyc
15
3.5
1.4
0.7
0.25
0.12
1.4
2.3
click-C12–Cyc
example, the gelled phase could be rapidly separated by
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triazole hydrogen atom was shied 4 cmꢁ1 to a higher wave-
number, but only for the cyclohexane xerogel. This suggested
a higher electron density inside the p-system and, presumably,
a different aggregation pattern compared to the raw gelator and
the xerogel in nitromethane, in which it remained unaltered.
These results were in good agreement with the XRD data, which
revealed a slight decrease in the crystallinity of the xerogel
aggregates formed in cyclohexane compared to that of the solid
gelator (Fig. S19–S21, see ESI†). However, in the case of nitro-
methane, C12–Cyc was found to decrease the crystallinity,
whereas click-C12–Cyc showed a stronger crystalline character
compared to the solid gelator in concordance with the more
solid-like vibrational frequencies observed using FT-IR.
At this point, we decided to perform theoretical calculations
to visualize the key stabilizing interactions in each case. Thus,
the intermolecular interactions of click-C12–Cyc were modelled
in different environments by building complexes formed by two
interacting model molecules. More specically, the two C10H21
groups of each click-C12–Cyc molecule were replaced by C2H5
groups. In order to consider different non-covalent interactions
(i.e. stabilizing p–p stacking, dispersion, hydrogen bonding
and dipole–dipole interactions), a total of 30 complexes were
built varying the relative position between the two interacting
model molecules. All of these structures were used as starting
points for complete geometry optimizations in a vacuum,
cyclohexane, methanol and nitromethane, with 23–25 different
minima being obtained depending on the environment (i.e. the
rest of the starting structures converged aer geometry opti-
mization to a minimum already obtained from other starting
structures).
Fig. 7 Phase selective gelation cycle of PTFE oil on seawater: (A)
addition of 2 mL of PTFE oil to 2 mL of seawater; (B) addition of 60 mg
click-C12–Cyc (c ¼ 30 g Lꢁ1); (C) application of a heating–cooling
cycle leads to selective gelation of the PTFE oil phase; (D) filtration of
the gelled oil phase; and (E) recovery of clean seawater.
ltration. In addition, both gasoline and gelator could be
recycled multiple times upon distillation of the separated gel
phase.
Aggregation mode and computational studies
In order to get preliminary insights into the differences in the
aggregation mode of both isosteres, we conducted comparative
FT-IR studies in different solvents (i.e. cyclohexane, ethylene
glycol and nitromethane). The analysis of the solid gelators and
the corresponding xerogels revealed shied bands suggesting
the involvement of non-covalent molecular interactions of
different strengths during the formation of the gel networks. In
particular, the carbonyl C–O stretching vibration associated to
The minimum energy complexes were ranged and followed
an increasing order of free energies in a vacuum and labeled
using a letter (i.e. from A to Z). Fig. 9 displays the relative free
energies obtained for each structure in the four studied envi-
ronments. As it can be seen, the polarity of the medium dras-
tically affects not only the stability of the different minima, but
also the spread of free energies (i.e. the free energy difference
C
12–Cyc gave an identical value of 1636 cmꢁ1 for the solid
gelator and the xerogels prepared in cyclohexane and nitro-
methane. However, the N–H stretching vibration was shied
4 cmꢁ1 to a higher wavenumber suggesting weaker intermo-
lecular hydrogen bonding (Fig. S17 and S18, see ESI†). In the
case of click-C12–Cyc, the C–H stretching vibration of the
Fig. 8 Phase selective gelation cycle of gasoline on seawater: (A) Fig.
9 Relative free energy of model complexes calculation in
addition of 1.8 mL of gasoline to 10 mL of seawater; (B) addition of a vacuum, cyclohexane, methanol and nitromethane with respect to
0.2 mL of a warm solution containing 120 mg of click-C12–Cyc; (C) the lowest free energy minimum of the most stable complex in each
gelation of the system without external treatment; (D) filtration of the environment. Complexes have been labeled from A to Z, each letter
gelled gasoline phase; (E) transfer of the gel to distillation apparatus; referring to the complex optimized using the same starting point for
and (F) recycling of both the gelator and solvent is possible.
each environment.
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between the most and least favored complexes is 18.4, 13.6, complex is complex C, which is destabilized by 3.2, 0.4 and
11.2, and 10.1 kcal molꢁ1 in a vacuum, cyclohexane, nitro- 1.8 kcal molꢁ1 in a vacuum, cyclohexane and methanol,
methane and methanol, respectively). The lowest free energy respectively. Complex C is stabilized by two intramolecular p–p
complexes in a vacuum, cyclohexane, methanol and nitro- stacking interactions and two intermolecular N–H/N hydrogen
methane corresponds to structures A, B, T and C, respectively, bonds (Fig. 10D). Overall, the results presented in Fig. 10A and B
which are depicted in Fig. 10.
indicate that click-C12–Cyc molecules can adopt a wide variety of
Complex A (Fig. 10A) is mainly stabilized by a p–p stacking interacting patterns, whose relative stability depends on the
interaction between the two triazole rings, two N–H/p inter- polarity of the environment. This explains the noticeable
actions and the van der Waals interactions induced by the tendency of click-C12–Cyc to form gels in a remarkably wide
almost canonical stacking of the two cyclohexyl rings. Complex array of solvents.
A is unfavored by 4.0 kcal molꢁ1 in cyclohexane solution, while
Inspection of intermolecular BE calculated for the four
complex B is destabilized by 2.8 kcal molꢁ1 in a vacuum. considered environments (Fig. S22, see ESI†) provides similar
Complex B, which is the most favored in cyclohexane (Fig. 10B) conclusions. The BE expand from ꢁ8.9 to ꢁ19.3 kcal molꢁ1 in
exhibits two strong intermolecular N–H/N hydrogen bonds a vacuum, from ꢁ5.6 to ꢁ18.7 kcal molꢁ1 in cyclohexane, from
and p–p stacking between the two triazole rings, while the two ꢁ4.7 to ꢁ17.4 kcal molꢁ1 in methanol, and from ꢁ4.8 to
N–H/p interactions disappear. In methanol, the most favored ꢁ17.2 kcal molꢁ1 in nitromethane. These wide intervals are
structure corresponds to complex T (Fig. 10C), which preserves consistent with a large amount of stabilizing interactions that,
the p–p stacking and one N–H/N hydrogen bond. In addition, as discussed above, include hydrogen bonds, N–H/p, p–p
two non-conventional C–H/N hydrogen bonds, which has stacking and van der Waals interactions. As can be seen from
been proven to be important in assemblies involving small comparing Fig. 9 and S22 (see ESI†), complexes with more
organic molecules,61,62 are identied. It is worth noting that favorable BE do not necessarily correspond to the structures
complex T is destabilized by 11.4 and 8.0 kcal molꢁ1 in with lower free energies. This is attributed to the key role played
a vacuum and in cyclohexane solution, respectively, while by intramolecular interactions in the stability of model
complexes A and B are unfavored by 4.0 and 0.9 kcal molꢁ1
,
complexes, as these contributions are not included in the BE.
respectively, in methanol. In nitromethane the most favored
Conclusions
The aforementioned results prove that the application of isos-
teric substitution for ne-tuning of the functional properties of
physical gels is a promising approach for materials synthesis.
Herein, we have demonstrated that 1,2,3-trizole rings can
replace all amide groups existing in an LMW organogelator,
while preserving the most important features associated with
a precise hydrogen-bonding network. In particular, the gelation
of organic solvents using the bis-amide C12–Cyc is driven by self-
assembly via antiparallel hydrogen bonds and van der Waals
intermolecular interactions in isotropic solutions. Thus, the
substitution of the two amide groups, which in this example
constitutes the source of the hydrogen bonds, by isosteric 1,2,3-
triazoles (click-C12–Cyc) is not an obvious outcome to maintain
and/or tune the properties of the physical network. This study
demonstrates that 1,2,3-triazoles can take over all of the func-
tions derived from the amides groups offering a versatile
strategy to tune the properties of the corresponding bulk gels in
terms of gelation kinetics and stimuli-responsive behavior.
Modications in the critical gelation concentrations, as well as
in the gel-to-sol transition temperatures, were also derived from
the dual isosteric substitution. Theoretical calculations revealed
that click-C12–Cyc molecules can adopt a wide variety of inter-
acting patterns, whose relative stability depends on the polarity
of the environment, which is in good agreement with the
Fig. 10 Representation of the lowest free energy minima obtained in
(A) a vacuum (5G ¼ ꢁ1749.090117 au, BE ¼ ꢁ19.33 kcal molꢁ1); (B)
cyclohexane (5G ¼ ꢁ1749.09237 au, BE ¼ ꢁ16.35 kcal molꢁ1); (C)
methanol (5G ¼ ꢁ1749.106305 au, BE ¼ ꢁ15.57 kcal molꢁ1); and (D)
nitromethane (5G ¼ ꢁ1749.106021 au, BE ¼ ꢁ13.06 kcal molꢁ1). experimental data obtained regarding the gelation ability. Other
Hydrogen bonds are represented by dotted black lines, N–H/p
important features of click-C12–Cyc for potential practical
interactions as pink arrows and p–p stacking is shown as red double
arrows. Labels refer to the distances (in A˚) found for each stabilizing
interaction: H/O distance in the hydrogen bonds; H$$$center of
masses in N–H/p interactions; and the center of masses to the center
of masses in p–p stacking.
applications are its non-cytotoxic character and its phase-
selective gelation of water–oil mixtures. Moreover, the
increased chemical robustness of triazoles compared to amides
under different conditions also confers practical importance to
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this strategy for the synthesis of new functional materials 16 S.-k. Ahn, R. M. Kasi, S.-C. Kim, N. Sharma and Y. Zhou, So
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Conflicts of interest
There are no conicts to declare.
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Assembled Fibrillar Networks, Springer, New York, 2006.
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Acknowledgements
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