Supramolecular Hydrogels Based on Minimalist Amphiphilic Squaramide–Squaramates for Controlled Release of Zwitterionic Biomolecules

Article abstract of DOI:10.1002/chem.201701029

Supramolecular hydrogels with tunable properties have innovative applications in biomedicine, catalysis, and materials chemistry. Minimalist low-molecular-weight hydrogelators based on squaramide and squaramic acid motifs have been designed. This approach benefits from the high acidity of squaramic acids and the aromaticity of squaramides. Moreover, substituents on the aryl ring tune the π density of the arylsquaramide motif. Thus, materials featuring distinct thermal and mechanical properties have been successfully prepared. The hydrogel (G′≈400 Pa, G′′≈57 Pa; at 1.0 % w/v; 1 Hz) obtained from 4-nitrophenylsquaramide motif 1 is thermoreversible (T=57 °C at 0.2 % w/v), thixotropic, self-healable, and undergoes irreversible shrinking in response to saline stress. Furthermore, the hydrogel is injectable and can be loaded with substantial amounts (5:1 excess molar ratio) of zwitterionic biomolecules, such as l-carnitine, γ-aminobutyric acid (GABA), or d,l-Ala-d,l-Ala, without any loss of structural integrity. Then, the release of these molecules can be modulated by saline solutions.

Full text of DOI:10.1002/chem.201701029

A Journal of
Accepted Article
Title: Supramolecular Hydrogels Based on Minimalist Amphiphilic
Squaramide-Squaramates for Controlled Release of Zwitterionic
Biomolecules
Authors: Antonio Costa, Carlos López, Marta Ximenis, Francisca
Orvay, and Carmen Rotger
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201701029
Link to VoR: http://dx.doi.org/10.1002/chem.201701029
Supported by

10.1002/chem.201701029
Chemistry - A European Journal
COMMUNICATION
Supramolecular Hydrogels Based on Minimalist Amphiphilic
Squaramide-Squaramates for Controlled Release of Zwitterionic
Biomolecules
Carlos López, Marta Ximenis, Francisca Orvay, Carmen Rotger and Antonio Costa*
Abstract: Supramolecular hydrogels with tunable properties have
innovative applications in biomedicine, catalysis and materials
chemistry. Herein, we have designed minimalist low molecular
weight hydrogelators based on squaramide and squaramic acid
motifs. Our approach benefits from the high acidity of squaramic
acids and the aromaticity of squaramides. Moreover, the
which contain hydrophilic (charged) and hydrophobic side chains,
have been successfully used as LMWHs.[1,6] In this vein,
disecondary
squaramides
and
squaramic
acids
are
advantageous as they can establish synergic hydrogen bonding-
aromaticity relationships that control the outcome of the
aggregation process[7] in the solid state[8] and in solution.[9]
However, N-aryl-substituted squaramic acids[10] are highly acidic
compounds (pKa 0.8-2) that have never used for hydrogel
construction. High acidity is crucial when using squaramic acids
as the hydrophilic portion of an LMWH because the acidity
ensures complete ionization over a broad pH range.[10a] As with
the squaramides, squaramic acid salts (named as squaramates)
are moderately aromatic.[8b] Both, aryl squaramides and aryl
squaramates are planar and can form antiparallel stacked
dimers in the solid state (Figure 1a, 1b).[8b,11,12] Overall, the
hydrolytic stability[13] and the aggregation capabilities of
squaramides and squaramates, renders their use as synthons
for LMWH attractive.
substituents on the aryl ring tune the
π density of the aryl-
squaramide motif. Thus, we successfully prepared materials
featuring distinct thermal and mechanical properties. The hydrogel
(G' ≈ 400 Pa, G'' ≈ 57 Pa; at 1.0 % w/v; 1 Hz) obtained from the 4-
nitrophenylsquaramide motif 1 is thermoreversible (T = 57 °C at
0.2 % w/v), thixotropic, self-healable and undergoes irreversible
shrinking in response to saline stress. Furthermore, the hydrogel is
injectable and can be loaded with substantial amounts (5:1 excess
molar ratio) of zwitterionic biomolecules such as L-carnitine, GABA
or DL-Ala-DL-Ala, without any loss of structural integrity. Then, the
release of these molecules can be modulated by saline solutions.
Inspired by the solid-state structures of reported squaramide
derivatives, we hypothesized that the combination of aryl-
squaramide and aryl-squaramate motifs would enhance the
stacking interactions of the resulting squaramide-squaramate
ensemble (Figure 1c). Herein, we report that LMWHs based on
the squaramide-squaramate couple (Figure 1) self-assemble to
form supramolecular hydrogels. The role of the substituents -
NO2 and -CF3 on the aryl squaramide moiety is intended to
modulate the molecular aggregation of the LMWHs to tune the
macroscopic properties of the resulting hydrogels.
Supramolecular hydrogels,[1] formed through the non-covalent
assembly of low molecular weight hydrogelators (LMWHs), are
materials of scientific interest for innovative applications in
biomedicine,[2] catalysis,[3] and material chemistry.[4] Because of
their essential reversible character, water gelation by small
molecules provides gel-to-sol transitions and a rapid response to
external stimuli. Of equal importance, appropriate design and
the limited synthetic effort required in their preparation allow
effective control over the assembled structures and their
responses on the macroscopic level. This control is highly
desirable for practical applications as it enables the creation of
hydrogels with tunable mechanical properties.[1a]
Because of the complexity of the self-assembly phenomenon,
the ex novo design of supramolecular hydrogels using LMWHs
is challenging. There is a consensus that LMWHs possess
amphiphilicity and require non-covalent interactions such as π-π,
hydrogen bonding, and charge interactions among the
constituent molecules to build three-dimensional networks in
water.[5] Specifically, peptides and other amide-like compounds,
[a]
Carlos López, Marta Ximenis, Francisca, Orvay, Prof. C.
Rotger, Prof. A. Costa
Figure 1. (a) Partial X-ray structure illustrating the planar stacked-offset
arrangement of the p-nitrophenyl squaramide motif.[12] (b) X-ray structure of a
phenyl squaramic acid.[8d] (c) Chemical structures of amphiphilic squaramide-
squaramic LMWHs 1-3.
Departament de Química, Facultad de Ciències
Universitat de les Illes Balears
Ctra. Valldemossa, Km. 7.5, Palma 07122, Spain
E-mail: antoni.costa@uib.es
Full synthetic and experimental procedures are provided in the
Supporting information which can, as well as the ORCID
identification of the author(s) of this article, be found under
http://
This article is protected by copyright. All rights reserved.

10.1002/chem.201701029
Chemistry - A European Journal
COMMUNICATION
In this work, we synthesized the amphiphilic LMWHs 1-3.
Precursors 1-3 share
a common squaramide-squaramate
framework but surprisingly show strikingly distinct aggregation
properties in water. The addition of NaOH triggers the self-
assembly and hydrogelation of 1 (R1 = NO2; R2 = H) in minutes
at a pH range from 3-9, with or without heating. The resulting
hydrogel 1A passes the vial inversion test at a relatively low
concentration (0.1-0.2 % w/v) (Figure 2a).
Similarly, squaramide 2 (R1 = H; R2 = CF3) also gelifies but
requires heating to obtain the hydrogel, and the critical gelation
concentration is higher (1.6 % w/v) (Figure 2b and Table S1).
However, after similar treatment, squaramide 3 remains as a
suspension even with extensive sonication and heating. A
comparison of the atomic force microscopy (AFM) images of
freshly prepared samples of the hydrogels 1A and 2A (Figure 2e,
f) reveals marked morphologic differences. Aside from the
micrometer-size disordered fibers observed in the two hydrogels,
1A shows bundled fibrous assemblies composed of one or more
strands with an apparent width of 42 nm (2 nm height) (Figure
S1). Meanwhile, the morphology of 2A comprises both right and
left-handed helical ribbons with an average diameter of 52 nm
twisting around the central axis of the fiber (Figures 2g-j and S2).
SEM and TEM images of dried samples of hydrogels 1A and 2A
confirm the formation of networks of bundled fibers characteristic
of hydrogels (Figures 2c,d, S3 and S4). Undoubtedly, the
different morphologies of hydrogels 1A and 2A and the failure of
hydrogel formation of precursor 3 reflect the influence of the
peripheral substituents on the self-assembly of the precursor
hydrogelators.
To shed light on the initial self-assembly events, we studied
1
the evolution of the H NMR spectra of solutions of 1 (1.0 × 10-3
M) in different [D6]-DMSO/H2O solvent mixtures. Upon
increasing the amount of water in the solvent mixture, all
aromatic protons exhibit significant upfield shifts (-0.1 to -0.5
ppm), indicating the growing influence of the aromatic stacking
interactions that occur in water (Fig. 3). Previously, we have
reported that a dynamic equilibrium driven by hydrogen bonding
between the monomeric and dimeric forms of 1 exists in [D6]-
DMSO.[14] In agreement, the NH proton of the squaramate first
moves downfield and then reverses direction, indicating
hydrogen bond breaking, in DMSO/H2O mixtures containing >
50 % of H2O.
The electrospray high-resolution mass spectrometry ESI(-)-
HRMS analysis of very diluted solutions of 1-3 (c ≈ 10-6 M) also
provides clues about the aggregation of these precursors.
Squaramide 1 shows an intense base peak at m/z 433.0789
assigned to the monomer [M-H]- anion with 44 % contribution of
the doubly charged dimer, [2M-2H]2-. The base peak of 2
appears at 524.0681 and the contribution of the dimer increases
to 68 %. In both cases, several minor peaks at higher m/z
assigned to low oligomers were also observed, albeit at a
proportion < 5 % compared to the dimer. In contrast, the
molecular peak of 3 at m/z 389.3670 contains less than 3 % of
dimer thus indicating the low aggregation ability of 3 (Figures
S5-S7).
Figure 2. (a, b) Vial inversion tests performed on slow-cooled samples of 1A
and 2A, after gentle heating at 70°C for 1 h. The values on the vials indicate
the % w/v of the hydrogelators 1 and 2, respectively. (b, c) TEM images of
fibrils from self-assembly of 1A (0.03 % w/v; c = 0.58 mM) and 2A (0.018 %
w/v; c = 0.41 mM) in water. The hydrogels were negatively stained with 1%
w/v phosphotungstic acid before observation. (e, f) AFM images obtained on
mica by depositing 60 µL aliquots of diluted hydrogels 1A (0.015 % w/v; c =
0.34 mM) and 2A (0.015 % w/v; c = 0.29 mM), respectively. (g) Enlarged
image of two helices, one right-handed (R) and another left-handed (L), and its
corresponding amplitude image (h). (I, j) Cross-section profiles plotted
following the dash lines of the image (g) indicates the direction of rotation of
the two helices. The colors of the dash arrows on each peak are referenced to
the correspondent fragment of the cross section.
This article is protected by copyright. All rights reserved.

10.1002/chem.201701029
Chemistry - A European Journal
COMMUNICATION
influence their responsiveness to external stimuli such as heat
and shear. We analyzed the thermal behavior of hydrogels 1A
and 2A by differential scanning calorimetry (DSC) and the vial
inversion method (Table S2). A DSC thermogram of 1A (0.25 %
w/v) from 25-90°C (Figure S10), exhibits an endothermic peak at
T = 57 °C. The peak is concentration-dependent and its broad
shape reveals the continuous character of the transitions that
occur in the hydrogel. Moreover, the hydrogel is
thermoreversible, that is, it evolves into solution upon heating
and then returns to the hydrogel form upon cooling at room
temperature. In contrast, the DSC thermogram of 2A registered
over the same temperature range displays a flat line, indicating
that hydrogel 2A is thermally stable.
We confirmed the hydrogel nature of 1A and 2A by
conducting dynamic rheological experiments. The frequency-
sweep experiments show a value of the storage modulus (G’)
10-fold greater than that of the loss modulus (G'') over the entire
frequency range (1 % strain; frequency range 0.1-100 Hz),
characteristic of viscoelastic fibrous networks (Figure S13). At
the same concentration (2 % w/v), the magnitude of the G'
modulus for 2A is ten times greater than that for 1A, thus
demonstrating its greater resistance against mechanical
disturbance.
Figure 3. Partial 1H NMR spectra (300 MHz) of a solution of the sodium salt of
1 (1.0 × 10-3 M) at room temperature in [D6]-DMSO-H2O solvent mixtures
containing increasing percentages of H2O. All the spectra were registered
using WATERGATE pulse sequences for water-suppression.
The formation of aggregates from 1 and 2 was assessed by
static light scattering (SLS) and UV-vis measurements. A plot of
scattered intensity as a function of concentration displays almost
superimposable curves for the two hydrogels (Figure 4a). From
these data, the critical aggregation concentration (CAC) for the
two hydrogels calculated at the junction is 8.0 ± 1.0 × 10-5
M
similar to that found by UV-vis for 1 (Figure 4b). However, the
change between the two lines is not as abrupt as one would
expect for a cooperative aggregation model.
To gather further information, we explored the aggregation of
hydrogel 1A by UV-vis. Hydrogelator 1, being more soluble than
2, allows aggregation equilibria to be studied over a broader
range of concentrations.
The UV-vis spectra of solutions of 1 in water, registered
below the CAC, do not show isosbestic points indicating the
absence of other equilibria, i.e., acid-base.[12a,15] The high-
intensity band at 318 nm is common to all squaramide and
squaramic derivatives, and hence,[10] its diagnostic value is
minimal. The lowest-energy band appears at approximately 388
nm (Figure 4c), and we assigned it to the S0 - S1 electronic
transition of the 4-nitrophenyl squaramide chromophore. Upon
increasing the concentration of 1, the band at 388 nm vanishes
completely, and a new band appears blue-shifted as a shoulder
at 355 nm, suggesting H-aggregation. Remarkably, the band at
388 nm reappears upon heating (Figure S9), thus indicating the
reversible character of the aggregation and providing clear
Figure 4. (a) Scattered intensity (s-1) as a function of concentration, log [M], of
1 (red) and 2 (blue). (b) Molar extinction coefficient of 1 at 390 nm as a
function of concentration of 1. In both cases, the calculated CAC at the line
junctions are indicated on the plots. (c) Concentration-dependent UV-vis
spectra of hydrogel 1A obtained in a concentration range between 4.6 × 10-5
(red line) and 7.0 × 10-3 M (black line). The arrows indicate the direction of the
movement upon increasing the concentration of 1A. (d) Molar fraction (α) of
aggregated molecules as a function of concentration of the hydrogel 1A. The
line was obtained by fitting the experimental UV-vis data with the isodesmic
model.
evidence that the aggregation of
1
involves electronic
squaramide
interactions between the 4-nitrophenyl
chromophores. In agreement, the apparent molar absorption
coefficient at 388 nm could be fitted to the isodesmic (equal-K)
model of aggregation (Figure 4d), producing an association
constant of 800 ± 75 M-1 which compares well with published
values.[16]
In order to evaluate the biocompatibility of 1, U87 cells were
subconfluently grown in the presence of hydrogelator 1 at
increasing concentrations. The toxicity was evaluated by a
luminiscent test. No toxicity was found for concentrations of 1 up
to 500 µM (Figure S11). Thus, the lack of toxicity and the weak
The phenyl substituents of 1 (-NO2) and 2 (-CF3), not only
modify the initial hydrogel core formation capabilities but strongly
This article is protected by copyright. All rights reserved.

10.1002/chem.201701029
Chemistry - A European Journal
COMMUNICATION
stacking interactions that govern the structure of 1A translate
into a set of properties of high interest for biotechnological
applications. In addition to being thermoreversible at a relatively
low temperature, hydrogel 1A is thixotropic (its viscosity
diminishes under compression); therefore 1A flows into small
channels, and it is readily injectable (Figure 5b and TOC). We
assessed the thixotropic behavior of 1A by applying stepwise
cycles of high and low stress to a sample of 1A (2 % w/v)
(Figure 5a). Under low strain, the hydrogel displays a storage
modulus an order of magnitude higher than the loss modulus,
which is consistent with its gel state. At high strain, both storage
and loss moduli drop reaching similar values, indicating a phase
transition from gel to a solution.[17] The application of low strain
allowed the moduli to recover rapidly the same magnitudes as
before the stress.
When dipped in water, the hydrogel remains unaltered for
weeks. However, the addition of saline solutions (such as NaCl,
Et4NCl, KCl, MgCl2, Me4NOAc, or acetylcholine chloride) to 1A
causes homogeneous and irreversible shrinking, in such a way
that the shrunken gel keeps the shape of its container. The
magnitude of the macroscopic phase transition depends on the
total concentration of the salt added and its molar ratio to the
hydrogelator (Figures 5c and S12). The kinetics of the process is
fast since, after four hours from the addition of the salt solution,
the hydrogel has shrunk practically to its final volume. When
completely shrunken, the stiffness of the resulting hydrogel 1B
increases considerably compared to 1A (1Hz, G'1B/G'1A ≈ 25,
G''1B/G''1A ≈ 20) (Figure S14).
Finally, in contrast with the shrinking effect of added salts,
hydrogel 1A can be loaded, with a variety of zwitterionic
molecules, such as L-carnitine, GABA and DL-Ala-DL-Ala,
without disturbing the hydrogel structure. These molecules can
be added in a 5:1 excess molar ratio to 1, before heating,
without disturbing the mechanical stability of the resulting loaded
hydrogel. However, the addition of related organic salts, such as
tetramethylammonium acetate or acetylcholine chloride to the
solution of 1, causes shrinking of the hydrogel.
Figure 5. (a) Rheology time sweep of 1A (2 % w/v) at 1 Hz applying four
cycles of low strain (0.1 %, 6 min) and high strain (15 %, 90 seconds) at 25 ºC.
(b) Photograph of a hydrogel 1A (1.0 % w/v) (1 Hz; G' ≈ 400 Pa, G'' ≈ 57 Pa)
indicating fluid-like properties. (c) Photograph of hydrogels 1A (500 µL) before
and after the addition of a NaCl solution (50 µL, 50 mM) showing shrinking at
equilibrium (24 h). The concentration of 1A (% w/v) is labeled on the vials. (d)
Comparative release profile of L-carnitine (69 mM) loaded in 1A (0.6 % w/v,
100 µL) at 25°C and covered by 500 µL of water (red), 100 mM NaCl (blue)
and 300 mM NaCl (green), respectively.
Conclusions
In conclusion, we have demonstrated the formation of hydrogels
based on squaramide-squaramate ensembles. We have utilized
squaramic acids for the first time as the hydrophilic component
of minimalist LMWHs, joined to an aryl squaramide unit as the
hydrophobic moiety. The aryl substituents (NO2 and CF3) induce
dramatic thermal and mechanical differences in the aggregation
of the hydrogels. The hydrogel containing the 4-nitrophenyl
squaramide motif is thermoreversible, thixotropic, injectable and
The loaded hydrogel can release the zwitterions in a
controlled manner upon covering the hydrogel with water (Figure
5d). Depending on the compound used as payload, 30-70 % of
the zwitterion release into water in less than 24 h.
Alternatively, stimulated release is observed in the presence
of saline solutions with a concomitant reduction in the total
amount discharged. Thus, while 47 % of L-carnitine is released
in water within 10 hours, in a NaCl 0.3 M media, the same
amount is reached in 2 hours although in this case part of the
payload remain entrapped in the shrunken hydrogel. In all cases
tested, the release follows a pseudo second-order kinetic model,
characteristic of solid-liquid sorption processes (Figure S15).
The above experiments highlight the structural, thermal and
mechanical differences existing between hydrogels 1A, 1B and
2A. These differences arise from the different contributions of
the aryl squaramide substituents. The results obtained provide
clear evidence that parallel stacking of the 4-nitrophenyl
squaramide governs the aggregation of 1 to 1A. However, the
two CF3 substituents of the 3,5-bistrifluoromethylphenyl
squaramide can establish additional CAr–H•••F–C(sp3) and
C(sp3)–F•••F–C(sp3) interactions. In addition to aromatic
stacking, fluorine interactions likely contribute to the aggregation
of 2, as has been observed in the solid-state structure of a
related squaramide derivative.[13b]
can be loaded with
a substantial amount of zwitterionic
biomolecules, rarely used as payloads. Overall, we have
demonstrated the technological potential of the squaramide-
squaramate couple as
supramolecular hydrogels.
a
new tool for the design of
Acknowledgements
We thank the Ministry of Economy and Competiveness for
financial support (grant ref. CTQ2014-57393-C2-1-P) and C. L.
thanks Government of the Balearic Islands (CAIB) and
European Social Funds (FSE) for a predoctoral fellowship. We
thank Dr. G. Martorell and Dr. R. Gomila (SCT-UIB) for
assistance with HRMS measurements, and Prof. Priam
Villalonga and Dr. Guillem Ramis for evaluation of cytotoxicity.
This article is protected by copyright. All rights reserved.

10.1002/chem.201701029
Chemistry - A European Journal
COMMUNICATION
[8]
a) A. Portell, M. Font-Bardia, R. Prohens, Cryst. Growth Des. 2013, 13,
4200-4203; b) R. Prohens, A. Portell, M. Font-Bardia, A. Bauzá, A.
Frontera, Cryst. Growth. Des. 2014, 14, 2578-2587, c) C. Estarellas, M.
C. Rotger, M. Capó, D. Quiñonero, A. Frontera, A. Costa, P. M. Deyà,
Org. Lett. 2009, 11, 1987-1990; d) C. Rotger, B. Soberats, D.
Quiñonero, A. Frontera, P. Ballester, J. Benet-Buchholz, P. M. Deyà, A.
Costa, Eur. J. Org. Chem. 2008, 1864-1868.
Keywords: hydrogel • squaramide • squaramic • stacking•
supramolecular aggregation
[1] a) M. J. Webber, E. A. Appel, E. W. Meijer, R. Langer, Nat. Mater. 2016,
15, 13-26; b) R. Dong, Y. Pang, Y. Su, X. Zhu, Biomater. Sci. 2015, 3,
937-954; c) D. Yuan, B. Xu, J. Mater. Chem. B. 2016, 4, 5638-5649; d)
M. D. Segarra-Maset, V. J. Nebot, J. F. Miravet, B. Escuder, Chem.
Soc. Rev. 2013, 42, 7086-7098; e) X. Du, J. Zhou, J. Shi, B. Xu, Chem.
Rev. 2015, 115, 13165-13307.
[9]
a) B. Soberats, L. Martínez, E. Sanna, A. Sampedro, C. Rotger, A.
Costa, Chem. Eur. J. 2012, 18, 7533-7542; b) J. Schiller, J. V. Alegre-
Requena, E. Marqués-López, R. P. Herrera, J. Casanovas, C. Alemán,
D. Díaz Díaz, Soft. Matter. 2016, 12, 4361-4374.
[2]
For recent examples, see: a) E. V. Alakpa, V. Jayawarna, A. Lampel, K.
V. Burgess, C. C. West, S. C. Bakker, S. Roy, N. Javid, S. Fleming, D.
A. Lamprou, Chem. 2016, 1, 298-319; b) M. J. Webber, E. A. Appel, E.
W. Meijer, R. Langer, Nat. Mater. 2016, 15, 13-26, and references
therein; c) H. Shigemitsu, T. Fujisaku, S. Onogi, T. Yoshii, M. Ikeda, I.
Hamachi, Nat. Protoc. 2016, 11, 1744-1756.
[10] Squaramic acid stands for 3-hydroxy-4-amino-cyclobut-3-ene-1,2-
dione. a) C. López, M. Vega, E. Sanna, C. Rotger, A. Costa, RSC.
Advances. 2013, 3, 7249-7253; b) J. Xie, A. B. Comeau, C. T. Seto,
Org. Lett. 2004, 6, 83-86.
[11] E. Sanna, L. Martínez, C. Rotger, S. Blasco, J. González, E. García-
España, A. Costa, Org. Lett. 2010, 12, 3840-3843.
[3]
N. Singh, K. Zhang, C. A. Angulo-Pachón, E. Mendes, J. H. van Esch,
B. Escuder, Chem. Sci. 2016, 7, 5568-5572.
[12] M. Ximenis, E. Bustelo, A. G. Algarra, M. Vega, C. Rotger, M. G.
Basallote, A. Costa, J. Org. Chem. 2017, 82, 2160-2170.
[13] a) V. Amendola, G. Bergamaschi, M. Boiocchi, L. Fabbrizzi, M. Milani,
Chem. –Eur. J. 2010, 16, 4368-4380; b) R. B. Elmes, P. Turner, K. A.
Jolliffe, Org. Lett. 2013, 15, 5638-5641.
[4]
[5]
[6]
M. D. Konieczynska, J. C. Villa-Camacho, C. Ghobril, M. Perez-Viloria,
K. M. Tevis, W. A. Blessing, A. Nazarian, E. K. Rodriguez, M. W.
Grinstaff, Angew. Chem. Int. Ed. 2016, 55, 9984-9987.
a) L. A. Estroff, A. D. Hamilton, Chem. Rev. 2004, 104, 1201-1218; b) S.
S. Babu, V. K. Praveen, A. Ajayaghosh, Chem. Rev. 2014, 114, 1973-
2129.
[14] C. López, E. Sanna, L. Carreras, M. Vega, C. Rotger, A. Costa, Chem.
–Asian. J. 2013, 8, 84-87.
a) Y. Li, F. Wang, H. Cui, Bioeng. Transl. Med. 2016, 1, 306-312; b) J.
W. Steed, Chem. Soc. Rev. 2010, 39, 3686-3699; c) Y. Wan, Z. Wang,
J. Sun, Z. Li, Langmuir. 2016, 32, 7512-7518; d) R. Liang, Z. Luo, G.
Pu, W. Wu, S. Shi, J. Yu, Z. Zhang, H. Chen, X. Li, RSC Adv. 2016, 6,
76093-76098.
[15] X. Ni, X. Li, Z. Wang, J. P. Cheng, Org. Lett. 2014, 16, 1786-1789.
[16] Z. Chen, A. Lohr, C. R. Saha-Möller, F. Würthner, Chem. Soc. Rev.
2009, 38, 564-584.
[17] H. Ye, C. Owh, X. J. Loh, RSC Adv. 2015, 5, 48720–48728.
[7]
V. Saez Talens, P. Englebienne, T. T. Trinh, W. E. Noteborn, I. K.
Voets, R. E. Kieltyka, Angew. Chem. Int. Ed. 2015, 54, 10502-10506.]
This article is protected by copyright. All rights reserved.

10.1002/chem.201701029
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Smart supramolecular hydrogels,
Carlos López, Marta Ximenis,
based
squaramate
on
squaramides
synthons
and
were
Francisca Orvay, Carmen Rotger and
Antonio Costa*
developed. A hydrogel (R1 = NO2, R2
= H) is thermoreversible, thixotropic
and injectable. It can be loaded with
Page No. – Page No.
Supramolecular Hydrogels Based on
Minimalist Amphiphilic Squaramide-
Squaramates for Controlled Release
of Zwitterionic Biomolecules
zwitterions
and
displays
ion-
stimulated shrinking and release of
the payload. This combination of
properties
is
unusual
in
supramolecular hydrogels derived
from LMWH.
This article is protected by copyright. All rights reserved.