A new family of "clicked" estradiol-based low-molecular-weight gelators having highly symmetry-dependent gelation ability

Article abstract of DOI:10.1039/c1cc13251b

Reported herein is the discovery of a novel family of "clicked" estradiol-based LMWGs whose gelation ability highly depends on the gelator symmetry. These LMWGs that gel different organic solvents in the presence of H₂O even at concentrations a

Full text of DOI:10.1039/c1cc13251b

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A new family of ‘‘clicked’’ estradiol-based low-molecular-weight gelators
having highly symmetry-dependent gelation abilitywz
Pedro Ramırez-Lopez,* Marıa C. de la Torre,* Marıa Asenjo, Julio Ramırez-Castellanos,
´ ´ ´ ´
´
a
a
a
b
b
c
c
´
´
Jose M. Gonzalez-Calbet, Alejandra Rodrıguez-Gimeno, Carmen Ramırez de Arellano and
´ ´
Miguel A. Sierra*d
Received 1st June 2011, Accepted 3rd August 2011
DOI: 10.1039/c1cc13251b
Reported herein is the discovery of a novel family of ‘‘clicked’’
estradiol-based LMWGs whose gelation ability highly depends on
the gelator symmetry. These LMWGs that gel different organic
solvents in the presence of H2O even at concentrations as low as
0.04 wt% are readily accessible using ‘‘click’’ chemistry.
The search for physical gels derived from low-molecular-weight
gelators (LMWGs) is currently an area of growing interest due
to their physical properties and practical applications in
different fields. Structurally diverse gelators that self-assemble
into entangled 3D networks through cooperative noncovalent
interactions have been reported.1 However, in spite of the
remarkable achievements of supramolecular chemistry in the
controlled self-assembly of small molecules, the structural
requirements for these LMWGs are still poorly understood.
Scheme 1 ‘‘Clicked’’ estradiol-based dimers.
Therefore, a rational correlation between the molecular structure
and the gelation ability is a challenging goal.
were tested for gelation properties.6 o- and p-Phenyl disubstituted
derivatives 2a–b were able to gel different non-protic polar
solvents such as DMSO, DMA, DMF and N-methylpyrrolidone
upon addition of water, gently heating and subsequently cooling
to room temperature. In this way robust and transparent gels at
concentrations below 1 wt% were obtained. It is worth noting
that the use of simple and easy to make estrone derivatives like 2
as ‘‘gelating’’ scaffolds is unknown.7
‘‘Click’’ chemistry has emerged as a versatile tool in different
areas of research.2 Although this methodology has been widely
applied for the synthesis of polymeric gelators,3 examples of the
use of ‘‘click’’ chemistry for the preparation of LMWGs gels are
scarce.4 During the course of our research program5 directed
to the preparation of natural product based macrocycles,6 we
observed that C2 symmetric ethynylestradiol-based precursor
2a formed swellable materials in aqueous DMSO (Scheme 1).
Subsequently, structurally diverse related dimeric hybrids such
as TMS-protected dimers 1a–d and terminal bis-alkynes 2a–d
Once demonstrated the gelation ability of dimers 2a–b the
structural requirements for these compounds as LMWGs and
their mode of aggregation were investigated by varying
systematically the different fragments within these amphiphilic
molecules. The critical gelation concentration (CGC) of the
gelators prepared through this work in DMSO/H2O (3/1 v/v)
was next determined. Firstly, C2 symmetric estradiol-based
compounds 3a–c lacking an ethynyl fragment at C-17 were
a
´
´
Instituto de Quımica Organica General, CSIC, Juan de la Cierva 3,
28006 Madrid, Spain. E-mail: pedror@iqog.csic.es (PR-L),
ctorre@iqog.csic.es (MCT)
b
c
d
´
Departamento de Quımica Inorganica, Facultad de Quımica,
Universidad Complutense, 28040-Madrid, Spain
´
Departamento de Quımica Organica, Universidad de Valencia,
46100-Valencia, Spain
´
Departamento de Quımica Organica. UCM, 28040 Madrid, Spain.
E-mail: sierraor@quim.ucm.es (MAS)
´
´
´
prepared and tested. Estradiol-based dimers o-3a (2.3 mg mLꢀ1
)
and p-3b (3.0 mg mLꢀ1) were efficient gelators albeit slightly worse
than compounds o-2a (1.5 mg mLꢀ1) and p-2b (2.3 mg mLꢀ1).
Thence, the terminal triple bond located at C-17 is not crucial for
the gelation process. By contrast, a change in the nature of the
triazole-linked spacers seems to alter the gelation event. In
fact, derivatives 2c and 2d bearing aliphatic taddol and
ferrocenyl linkers, respectively, were inefficient in gelling any
aqueous organic solvent tested. The absence of hydroxyl
´
w Electronic supplementary information (ESI) available: Complete
experimental procedures and compound characterization data for the
products described in the text, and the physicochemical characterization
of the gels, including SEM and TEM data, as well as X-ray data for
compound 3b. CCDC 786367. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc13251b
z The paper is dedicated to Professor Pavel Kocovsky on the occasion
of his 60th birthday.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10281–10283 10281

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groups in bis-acetylated o-phenyl 4a and the location of bulky
TMS-alkynyl groups in dimers 1a–d inhibited gelation providing
only precipitates.
To establish the role of potential stacking interactions
in assembling the gel, dimers 3e–f bearing extended
aromatic linkers were prepared (Scheme 1). Both biphenyl 3e
(1.5 mg mLꢀ1) and fluorene 3f (1.5 mg mLꢀ1) derivatives
produced improved CGC values with respect to those of the
p-phenyl 3b (2.3 mg mLꢀ1) and 3a (3 mg mLꢀ1) counterparts.
With the aim to identify the minimum structural requirements
needed for gelation we synthesized a series of monomers presenting
phenyl 5–6 and pyrenyl 7–8 aromatic groups (Scheme 2).
However, neither phenyl (5–6) nor pyrenyl (7–8) monomers gelled
any solvent tested producing either precipitates or crystals.
The symmetry of the gelating agent was next addressed. C3
symmetric trimers 9a–b6 and 10 and C2 symmetric tetramer 11
were studied (Scheme 2). Trimeric structures 9a–b and 10 did not
form gels providing basically precipitates in all solvents tested.
These results strongly contrast with the C2 symmetric tetramer
11, which gelled DMSO/H2O (3/1 v/v) at concentrations as low
as 0.37 mg mLꢀ1 (0.04 wt%). Furthermore, tetramer 11 was able
to gel a wider range of aqueous solvents (DMSO, DMF, DMA,
N-methylpyrrolidone, Py, AcOH and dioxane). These results
demonstrate that tetrameric compound 11 is much more efficient
than their dimeric analogues. In fact, tetramer 11 immobilizes
aqueous solvents such as DMSO, DMF, DMA, and N-methyl-
pyrrolidone at concentrations below 1.0 mg mLꢀ1 therefore
falling into the category of ‘‘super-gelators’’.8
Fig. 1 Sol–gel transition temperatures (Tg) for gels 2a–b, 3a–b, 3e–f
and 11/DMSO/H2O (3/1 v/v) as a function of gelator concentration
measured by the ‘‘dropping ball method’’.
behave as LMWGs, their monomeric and C3 symmetric
trimeric analogues do not.
To compare the thermal behaviour of the gels prepared
throughout this work, 2a–b, 3a–b, 3e–f and 11/DMSO/H2O
(3/1 v/v) gels with concentrations varying from 0.4 to
8.0 mg mLꢀ1 were studied by the ‘‘dropping ball method’’.9
Fig. 1 shows that thermal stability of the gels prepared from
gelators at different concentrations correlates well with their
gelation ability and CGC values. Thus, gels derived from
ethynyl estradiol-based dimers o-2a and p-2b present higher
Tg than their dimeric analogues o-3a and p-3b, respectively.
Furthermore, gels obtained from o-phenyl 2a and 3a are more
resistant toward temperature than those prepared from
p-phenyl 2b and 3b. A real improvement of thermal stability
is attained when extended aromatic linkers (compare 3e and 3f
with 3b) or a C2 symmetric tetrameric core (compare 11 with 3a)
is employed.
The scanning electron microscopy (SEM) image of the
xerogel of 3a reveals well-defined shape fibers that are about
2–30 mm wide and 110–540 mm long. In most cases, these thick
fibers have a tendency to form right-handed twisted ribbon
morphology with a regular pitch (Fig. 2a). Furthermore, these
fibers can undergo further aggregation giving rise to wire-like
fiber bundles in the gel network (Fig. 2b). To get some insight
into the interlayer interactions on the fiber structures, a high
resolution transmission electron microscopy (HRTEM)
characterization was carried out. The inset (Fig. 2c) shows a higher
magnification micrograph of the end of the fibers, confirming
that one fiber consists of many lamellae having crystalline
domains.10 Fig. 2e reveals a complex microstructure, where an
amorphous matrix contains highly ordered crystallized
Scheme 2 ‘‘Clicked’’ estradiol-based compounds 5–11.
Results above show that the gelation ability of this new
family of LMWGs is symmetry-dependent. In fact, while C2
symmetric dimeric and tetrameric estradiol-based structures
Fig. 2 SEM and TEM images of the xerogel of 3a (0.7 wt%)/DMSO/
H2O (v/v 2 : 1). For additional images of 3a and 11 see the ESI.w
c
10282 Chem. Commun., 2011, 47, 10281–10283
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domains randomly oriented. An average interplanar distance
of 3.6 A between planes can be measured and fits well with the
typical distance reported for p–p stacking aromatic
interactions.
and X-ray diffraction studies indicate that directional hydrogen
bonding, van der Waals and p-stacking interactions may be
responsible for the self-assembly process. SEM and TEM
studies reveal the formation of multilamellar right-handed
twisted ribbons.
A possible aggregation model for these C2 symmetric gelators
may be based on the molecular structure of 3bꢁ3CHCl3y,
which was established by X-ray analysis (Fig. 3). This
estradiol-based dimer forms infinite chains through O–Hꢁ ꢁ ꢁO
hydrogen bonds between terminal hydroxyl groups. These
chains are closely assembled forming molecular planes
through C(benzene)–Hꢁ ꢁ ꢁO, C(methylene)–Hꢁ ꢁ ꢁN and
C(triazole)–Hꢁ ꢁ ꢁp interactions (see ESIw). In the molecular
planes, C–H axial bonds of one estradiol moiety are oriented
towards the p cloud of the neighboring estradiol fragment.
Layers are assembled through C(methylene)–Hꢁ ꢁ ꢁN inter-
actions and a pꢁ ꢁ ꢁp stacking of the triazole moieties with an
average interplanar distance of 3.5–3.6 A. In the crystal, layers
assembly for 3b forms tubular voids of ca. 643 A3.11 It should
be noted that although the crystal structure of 3b12 may help to
understand the self-assembling process of ‘‘clicked’’ gelators,
great care must be taken because the single crystals were
obtained from a solvent mixture (CHCl3/MeOH/hexanes) of
different nature compared to that of the gel matrix. In this
context, it is most likely that assembly in the gel state is initially
driven by hydrophobic forces between estradiol fragments
favoring p-stacking of the aromatic linkers and then lateral
and directional hydroxyl groups at C-17 facilitate linear
hydrogen-bonded polymeric chains.13 In fact, C2 symmetric
dimeric and tetrameric structures would favor the formation
of linear hydrogen-bonded aggregates by enforcing alignment
along the axis oriented parallel to the hydrogen bonds between
hydroxyl groups forming arrays of supramolecular polymeric
chains that further assemble into fibres (see ESIw).
Financial support by the Spanish MCINN (CTQ2010-20714
and CSD2007-0006) and the CAM (P2009/PPQ1634) is
acknowledged. P.R.-L. and M.A. thank the CSIC-JAE
Program for postdoctoral and predoctoral grants,
respectively.
Notes and references
y X-Ray data for 3bꢁ3CHCl3: C53H63Cl9N6O4, Mr = 1167.14, triclinic,
P1, a = 6.6681(5), b = 11.0049(11), c = 21.379(2) A, a = 91.410(8)1,
b = 95.287(7)1, g = 106.366(8)1, V = 1496.8(2) A3, Z = 1, T =
120(2) K, 2ymax = 50.06, 22870/10521 reflns. collected/independent,
Rint = 0.1072, R1[I > 2s(I)] = 0.1092, wR2(all data) = 0.2675, Flack
parameter 0.12(14).
1 For a collection of review articles on LMWGs, see: J. H. van Esch
and B. L. Feringa, Angew. Chem., Int. Ed., 2000, 39, 2263;
O. Gronwald and S. Shinkai, Chem.–Eur. J., 2001, 7, 4328;
M. de Loos, B. L. Feringa and J. H. van Esch, Eur. J. Org. Chem.,
2005, 3615; M. George and R. G. Weiss, Acc. Chem. Res., 2006,
39, 489; A. R. Hirst, B. Escuder, J. F. Miravet and D. K. Smith,
Angew. Chem., Int. Ed., 2008, 47, 8002, and references therein.
2 M. Meldal and C. W. Tornøe, Chem. Rev., 2008, 108, 2952.
3 S. M. Park, Y. S. Lee and B. H. Kim, Chem. Commun., 2003, 2912;
G. Godeau and P. Barthelemy, Langmuir, 2009, 25, 8447; J. Lu,
J. Hu, Y. Song and Y. Ju, Org. Lett., 2011, 13, 3372.
4 N. Tzokova, C. M. Fernyhough, P. D. Topham, N. Sandon,
D. J. Adams, M. F. Butler, S. P. Armes and A. J. Ryan, Langmuir,
2009, 25, 2479; W. H. Binder and R. Sachsenhofer, Click Chemistry
on Supramolecular Materials, in Click Chemistry for Biotechnology
and Materials Science, ed. J. Lahann, John Wiley & Sons, Ltd,
Chichester, UK, 2009 and references therein.
5 M. C. de la Torre, A. M. Deometrio, E. Alvaro, I. Garcıa and
M. A. Sierra, Org. Lett., 2006, 8, 593; E. Alvaro, M. C. de la Torre
and M. A. Sierra, Chem.–Eur. J., 2006, 12, 6403; M. A. Sierra,
R. M. Torres, M. C. de la Torre and E. Alvaro, J. Org. Chem.,
2007, 72, 4213.
6 H. E. Montenegro, P. Ramırez-Lopez, M. C. de la Torre,
M. Asenjo and M. A. Sierra, Chem.–Eur. J., 2010, 16, 3798;
P. Ramırez-Lopez, M. C. de la Torre, H. E. Montenegro,
M. Asenjo and M. A. Sierra, Org. Lett., 2008, 10, 3555.
7 For cholesterol-based organogels, see: J. H. Jung, Y. Ono and
S. Shinkai, Angew. Chem., Int. Ed., 2000, 39, 1862; J. H. Jung,
H. Kobayashi, M. Masuda, T. Shimizu and S. Shinkai, J. Am.
Chem. Soc., 2001, 123, 8785 and references therein. For a review on
bile acid-based organogels, see: P. Babu, N. M. Sangeetha and
U. Maitra, Macromol. Symp., 2006, 241, 60.
8 J. Liu, P. He, J. Yan, X. Fang, J. Peng, K. Liu and Y. Fang, Adv.
Mater., 2008, 20, 2508 and references therein.
9 Dropping ball method: A. Takahashi, M. Sakai and T. Kato,
Polym. J., 1980, 12, 335.
10 Fig. 2d shows the Fast Fourier Transform (FFT) pattern corre-
sponding to the xerogel of 3a, which is obtained from the digitized
experimental HRTEM image. Few discrete and weak diffraction
spots (marked by a dashed circle) confirm the presence of crystal-
line domains.
11 Molecular voids: PLATON-SQUEEZE, A. L. Spek, J. Appl.
Crystallogr., 2003, 36, 7Crystal voids host CHCl3 molecules by
means of C–Hꢁ ꢁ ꢁN, C–Hꢁ ꢁ ꢁO and C–Hꢁ ꢁ ꢁCl interactions and
C–Clꢁ ꢁ ꢁCl–C type II contacts, see: N. Ramasubbu,
R. Parthasarathy and P. Murray-Rust, J. Am. Chem. Soc., 1986,
108, 4308.
Fig. 3 Crystal packing views showing layers assembly along the a
axis with solvent molecules omitted for clarity (top), and a tubular
void along the a axis including solvent molecules (bottom).
In summary, we reported the discovery of a novel family of
estradiol-based LMWGs that gel different organic solvents in
the presence of H2O even at concentrations as low as 0.04 wt%.
These compounds are readily accessible using ‘‘click’’ chemistry
from commercially available starting materials. A structure–
property relationship study for these gelators shows that their
gelation ability depends on the gelator symmetry. ATR-IR
12 CCDC 786367.
13 The presence of hydrogen bonded OH groups in the gel state is
corroborated by the ATR-IR spectrum of 3a/DMSO-d6/D2O (3/1
v/v) gel, after subtraction of the solvent-basedbackground, which
showed a broad band at 3426 cmꢀ1
.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10281–10283 10283