Cooperative self-assembly of linear organogelators. Amplification of chirality and crystal growth of pharmaceutical ingredients

Article abstract of DOI:10.1039/c2cc31818k

Linear organogelators 1 and 2, which self-assemble cooperatively into fibrillar structures, act as efficient crystal growth media for common pharmaceutical ingredients like ASP, CAF, IND and CBZ. This journal is

Full text of DOI:10.1039/c2cc31818k

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COMMUNICATION
Cooperative self-assembly of linear organogelators. Amplification of
chirality and crystal growth of pharmaceutical ingredientsw
Fatima Aparicio, Emilio Matesanz and Luis Sa
´ ´
nchez*a
a
b
Received 12th March 2012, Accepted 30th March 2012
DOI: 10.1039/c2cc31818k
Linear organogelators 1 and 2, which self-assemble cooperatively into
fibrillar structures, act as efficient crystal growth media for common
pharmaceutical ingredients like ASP, CAF, IND and CBZ.
upon adding small amounts of chiral 2, and the use of
these organogelators as crystal growth media for common
pharmaceutical ingredients like aspirin (ASP), caffeine (CAF),
indomethacin (IND) and carbamazepine (CBZ) (Fig. 1) are
investigated.
The self-assembly of low-molecular-weight organogelators
Organogelators 1 and 2 are readily prepared in only four
(
LMWGs) renders supramolecular gels by the operation of
synthetic steps following previously reported procedures
9
hierarchical non-covalent forces. These organized structures
are being applied in a number of research areas like drug
delivery systems, biomaterials, electronic devices, and templates
(
Scheme S1, ESIw). All the intermediates and the final compounds
have been fully characterized by NMR and FTIR spectroscopy
and HRMS (ESI) spectrometry (see ESIw). We have initially
utilized FTIR spectroscopy to evaluate the strength of the
H-bonding interactions and also the interdigitation of the
peripheral paraffinic side chains, responsible for the gelation
of these compounds. The stretching N–H and amide I bands
as well as the bending amide II band of 1 (n B 3277, 1633, and
1
for nanostructures. Particularly interesting is the exploitation of
supramolecular gels as media for the crystal growth of molecular
species since it is possible to attain different polymorphs and
2
crystal habits, a key issue in pharmaceutical industry. To the
best of our knowledge, the mineralization of hydroxyapatite
directed by the fibres resulting in the self-assembly of an
ꢀ
1
ꢀ1
3
amphiphilic peptide, the growth of calcium carbonate into a
1
544 cm ) and 2 (n B 3290, 1635, and 1543 cm ) suggest
10a,b
4
bis-urea hydrogel, and the crystal growth of a variety of
that the amide groups are strongly H-bonded (Fig. S1, ESIw).
However, a more efficient interdigitation of the alkyl chains in
5
pharmaceuticals into bis-urea based gels are the scarce examples of
ꢀ
1
compound 1 (n B 2921 and 2853 cm ) in comparison to
compound 2 (n B 2954, 2927 and 2868 cm ) can be inferred
the use of LMWGs as the crystallization media. An outstanding
advantage of supramolecular gels over conventional hydrogels—
amply utilized for the growth of crystals of different nature—is that
the sol-to-gel transition can be modulated by a number of stimuli
ꢀ
1
from the sharp waves corresponding to the –CH – groups
1
2
0c
Fig. S1, ESIw).
The self-assembly mechanism of the chiral organogelator 2
(
6
like pH, sonication, light irradiation, or addition of anions.
has been investigated by circular dichroism (CD) in methyl-
cyclohexane (MCH) (Fig. 2). The bisignated Cotton effect—with
a positive maximum at 222 nm and a negative maximum at
Most of the reported organogelators self-assemble into
monodimensional fibrillar structures that originate the gel
upon capturing the solvent. Therefore, from a conceptual point of
view, the formation of a supramolecular gel can be considered
as an example of supramolecular polymerization in which
2
66 nm—implies the organization of compound 2 into left-handed
1
1
helical structures. Variable temperature (VT) CD experiments
7
single supramolecular polymers bundle to form the gel. The
supramolecular polymerization processes involving chiral
building blocks are of special significance since they have been
shown as powerful tools to investigate the amplification of
chirality, that is, the process in which minute enantiomeric
excesses are able to convert racemates into enantiomerically
8
enriched mixtures. Herein, the supramolecular polymerization
mechanism, the amplification of chirality experienced by achiral 1
a
Departamento de Quı´mica Orga´nica, Facultad de Ciencias Quı´micas,
Universidad Complutense de Madrid, 28040 Madrid, Spain.
E-mail: lusamar@quim.ucm.es; Fax: +34 913944103
C.A.I. Difraccion de Rayos X, Facultad de Ciencias Quı´micas,
b
Universidad Complutense de Madrid, 28040 Madrid, Spain
w Electronic supplementary information (ESI) available: Supplementary
Figures S1–S15, Tables S1–S17 and experimental section. See DOI:
Fig. 1 Chemical structure of the organogelators 1 and 2, and aspirin
(
ASP), caffeine (CAF), indomethacin (IND), and carbamazepine
10.1039/c2cc31818k
(CBZ).
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Chem. Commun., 2012, 48, 5757–5759 5757

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ꢀ5
Fig. 2 CD spectra of 2 (MCH, 1 ꢁ 10 M). The inset depicts the
ꢀ1
melting curve from 363 to 283 K at intervals of 1 K min . Red and
yellow lines in the inset are the fits corresponding to the elongation and
nucleation processes, respectively.
Fig. 3 (a) Pictures of the gel–sol phase transitions of 1 and 2 (toluene,
wt%, respectively). AFM height (b) and phase (c) images of the
1
show that the sample becomes CD-silent upon heating at
ꢀ5
diluted (1 ꢁ 10 M in toluene) gel of 2 onto HOPG (z scale = 15 nm).
3
63 K the resulting melting curve being non-sigmoidal which
7
for 1 and 2 indicate that these compounds self-assemble into
helical, columnar supramolecular structures that, subsequently,
interact through the peripheral paraffinic chains. The resulting
bundles of fibers could form organogels. In fact, both 1 and 2
readily form colorless and highly transparent gels in toluene at a
concentration of 1 wt%. These organogels were verified to be
stable by inversion of the glass vial and experience a gel-to-sol
transition upon heating (Fig. 3). The morphology of the
supramolecular gels formed from 1 and 2 has been firstly
studied by scanning electron microscopy (SEM). The SEM
images demonstrate a very different morphology of the gels
formed from achiral 1 or chiral 2: while the organogel formed
from 1 exhibits a dense network of intertwined fibrillar
structures, this fibrillar network is not visualized in the organogel
formed from 2 in which a smooth surface of globular aggregates
with no pores between them is observed (Fig. S3, ESIw). To
characterize the fine structure of the fibres constitutive of the gel,
we have carried out an atomic force microscopy (AFM) analysis
at different concentrations and surfaces. AFM images of the
supports a nucleation–elongation mechanism. Fitting these
data to eqn (1) and (2) allows the extraction of relevant
thermodynamic information like the enthalpy released during
e
elongation (h ), the temperature at which the nucleation regime
changes into elongation (T ), and the degree of cooperativity
e
1
2
expressed by Ka.
ꢂ
ꢀ
ꢁꢃ
ꢀ
he
f ¼ f
1 ꢀ exp
ðT ꢀ TeÞ
ð1Þ
ð2Þ
n
SAT
2
e
RT
ꢀ
ꢁ
he
1
=3
ꢀ1=3
f ¼ Ka exp ð2=3K
ꢀ 1Þ
ðT ꢀ TeÞ
n
a
RTe2
The supramolecular polymerization of chiral 2 is highly
ꢀ
1
exothermic (h = ꢀ135.7 kJ mol ), with K and T values
e
a
e
ꢀ3
of 5.5 ꢁ 10 and 339 K, respectively. These data imply that
the combination of four H-bonded amide groups, the p–p
stacking of the three benzene rings and the van der Waals
interactions between the peripheral chains strongly reinforce
the self-assembly of these organogelators in comparison with
other linear bis-amides previously reported by our group that
ꢀ
4
xerogels of 1 and 2 at 1 ꢁ 10 M in toluene, and using HOPG
or mica as surfaces, confirm that the bundles are formed by
intertwined long chiral fibres (Fig. S4 and S5, ESIw). The fibrillar
nature of the aggregates formed by the self-assembly of gelator 2
is maintained even at very low concentration (1 ꢁ 10ꢀ M in
toluene). Under these conditions, the AFM images also clearly
show the presence of left-handed intertwined helical nanofibers in
good agreement with the CD measurements performed in
solution (Fig. 3b and c and Fig. S6, ESIw).
1
3
did not show a significant chirooptical response.
The dynamic character of supramolecular polymers allows
the intercalation of minute amounts of chiral species in a
columnar supramolecular structure formed from achiral
monomeric units. This amplification of chirality results in the
conversion of an equimolar mixture of P- and M-type helices
into an enantiomerically enriched mixture, in which only one of
5
8
the two helices predominates. The addition of increasing
The gels formed from 1 and 2 have been utilized as the
crystallization media for APIs like ASP, CAF, IND or CBZ
that have been reported to crystallize in toluene as solvent
(Table 1). All the crystallization experiments were done per
duplicate. The crystals obtained inside the organogels can be
easily recovered by successive rinsing of the mixture with
toluene, shaking and filtering. This procedure does not alter
the polymorphic outcome of the studied APIs and avoids the
amounts of chiral 2 into a solution of achiral 1, keeping constant
the total concentration of the mixture, leads to the appearance
of a chirooptical response that varies non-linearly with the
8,14
amount of the chiral tetra-amide added (Fig. S2, ESIw).
It is well-established that LMWGs usually self-assemble
into monodimensional fibrillar structures with a strong trend
to bundle. The resulting bundles of fibers originate the gel upon
capturing the solvent. The FTIR and VT-CD data extracted
5
addition of any other chemical species. The first entry in Table 1
5
758 Chem. Commun., 2012, 48, 5757–5759
This journal is c The Royal Society of Chemistry 2012

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Table 1 Crystallization of APIs in gels 1 and 2, and in toluene as
solvent
ASP, CAF, IND and CBZ. The crystals obtained inside the
a
organogels can be easily recovered by successive rinsing of the
mixture with toluene, shaking and filtering. This procedure
does not alter the polymorphic outcome of the studied APIs
and avoids the addition of any other chemical species and does
not alter the crystallization outcome of the crystals.
API
Compound 1
Compound 2
Toluene
CBZ
ASP
CAF
IND
III
I
II (b)
III (b)
II + III
I
II (b)
III (b)
III
I
II (b)
III (b)
Financial support from UCM (GR42/10-962027) and the
MINECO of Spain (CTQ2011-22581) is acknowledged. F. A.
is indebted to MEC of Spain for a FPU studentship.
a
Crystallization performed at a concentration of 1 wt% for both
organogelator and API. In brackets, the Greek notation of poly-
morphs II and III of CAF and IND, respectively, is included.
Notes and references
shows the difference found in the polymorphism of CBZ
1
For recent reviews on LMWGs, see: (a) J. van Esch and B. L. Feringa,
Angew. Chem., Int. Ed., 2000, 39, 2263; (b) M. George and R. G. Weiss,
Acc. Chem. Res., 2006, 39, 489; (c) M. Sada, N. Takeuchi, M. Fujita,
M. Numata and S. Shinkai, Chem. Soc. Rev., 2007, 36, 415;
(d) A. Ajayaghosh, V. K. Praveen and C. Vijayakumar, Chem. Soc.
Rev., 2008, 37, 109; (e) J. W. Steed, Chem. Soc. Rev., 2010, 46, 3686;
crystallized inside the organogel prepared from 1 and 2 at
1
wt%. The XRD pattern of the CBZ crystals before and after
washing with toluene remains unaltered (Fig. S7 and Tables
S2–S7, ESIw). The XRD analysis of the CBZ crystals obtained
from the gel of achiral 1 corresponds to polymorph III (Fig. S7
and Tables S2 and S5, ESIw, and Table 1), similarly to the
crystals formed upon crystallization of CBZ in toluene (Fig. S8 and
(f) J. W. Steed, Chem. Commun., 2011, 47, 1379.
2
(a) G. R. Desiraju, Cryst. Growth Des., 2008, 8, 3; (b) G. P. Stahly,
Cryst. Growth Des., 2007, 7, 1007.
3 J. D. Hartgerink, E. Beniash and S. I. Stupp, Science, 2001, 294, 1684.
1
5
Table S8, ESIw). However, the X-ray diffractogram of the crystals
obtained inside organogel 2 and also in the organogel formed upon
mixing 1 and 2 in a 9/1 ratio, respectively, shows peaks corres-
ponding to a mixture of polymorphs II and III (Fig. S7 and S9, and
4
5
6
L. A. Estroff, L. Addadi, S. Weiner and A. D. Hamilton, Org.
Biomol. Chem., 2004, 2, 137.
J. A. Foster, M.-O. M. Piepenbrock, G. O. Lloyd, N. Clarke,
J. A. K. Howard and J. W. Steed, Nat. Chem., 2010, 2, 1037.
(a) M.-O. M. Piepenbrock, G. O. Lloyd, N. Clarke and
J. W. Steed, Chem. Rev., 2010, 110, 1960; (b) A. R. Hirst,
B. Escuder, J. F. Miravet and D. K. Smith, Angew. Chem., Int.
Ed., 2008, 47, 80028; (c) H. Maeda, Chem.–Eur. J., 2008, 36, 11274.
1
5
Tables S3 and S6, ESIw). It is well-known that the crystallization
of CBZ in toluene is unreliable and is often controlled by rates of
cooling and agitation. Therefore, the changes observed in the
polymorphism of CBZ could be ascribed to the retardation of
diffusion, nucleation and convection currents present in the crystal
7 T. F. A. De Greef, M. M. J. Smulders, M. Wolffs, A. P. H. J. Schenning,
R. P. Sijbesma and E. W. Meijer, Chem. Rev., 2009, 109, 5687.
8
9
A. R. A. Palmans, Angew. Chem., Int. Ed., 2007, 46, 8948.
(a) P. Mukhopadhyay, Y. Iwashita, M. Shirakawa, S. Kawano,
N. Fujita and S. Shinkai, Angew. Chem., Int. Ed., 2006, 45, 1592;
1
6
growth media and/or to a heteronucleation phenomenon. The
different polymorphic outcome of CBZ (1 wt%) upon modifying
the concentration of organogelators 1 or 2 in toluene could be
ascribed to heteronucleation (Table S1, and Fig. S10 and S11,
ESIw). In addition, the different morphology of the organogels
formed from achiral 1 and chiral 2, demonstrated by the
corresponding SEM images, could induce changes in the
diffusion, nucleation and convection currents thus conditioning
the polymorphic outcome of CBZ.
(
b) S. Ghosh, X.-Q. Li, V. Stepanenko and F. Wu
Chem.–Eur. J., 2008, 14, 11343.
0 (a) S. Prasanthkumar, A. Saeki, S. Seki and A. Ajayaghosh, J. Am.
Chem. Soc., 2010, 132, 8866; (b) J. Puigmartı-Luis, V. Laukhin,
¨
rthner,
1
´
A. P. del Pino, J. Vidal-Gancedo, C. Rovira, V. N. Laukhin and
D. B. Amabilino, Angew. Chem., Int. Ed., 2007, 46, 238;
(c) T. Nakanishi, T. Michinobu, K. Yoshida, N. Shirahata,
K. Ariga, H. Mohwald and D. G. Kurth, Adv. Mater., 2008, 20, 443.
¨
11 Stereochemistry of Organic Compounds, ed. E. L. Eliel, S. H. Wilen
and L. N. Mander, Wiley-Interscience, Chichester, UK, 1994.
12 (a) P. Jonkheijm, P. van der Schoot, A. P. H. J. Schenning and
E. W. Meijer, Science, 2006, 313, 80; (b) M. M. J. Smulders,
A. P. H. J. Schenning and E. W. Meijer, J. Am. Chem. Soc.,
2008, 130, 606.
We have also tested the crystallization of ASP and
1
7,18
CAF—able to crystallize into two polymorphs
—and
1
9
IND, that can crystallize into four polymorphs, inside the
organogels obtained from 1 and 2 in comparison with toluene.
These APIs did not exhibit any polymorphic difference as
demonstrated by the corresponding X-ray diffraction (XRD)
data (Fig. S12–S14, ESIw). Optical images of the CAF, and
IND crystals obtained inside organogelators 1 and 2, and also
from pure solvent show a dense network of needle-like objects
of bigger size than those observed in the solvent (Fig. S15,
ESIw). In good correlation with the data previously reported
1
3 F. Aparicio, F. Vicente and L. Sa
4
´
nchez, Chem. Commun., 2010,
6, 8356.
1
4 Unfortunately, the chemical structure of the organogelators impedes
to record CD spectra in toluene since the solvent absorbance will
overlap with the dichroic response of the chiral compound.
1
5 (a) A. L. Grzesiak, M. D. Lang, K. Kim and A. J. Matzger,
J. Pharm. Sci., 2003, 92, 2260; (b) M. M. J. Lowes, M. R. Cairo,
a. P. Lotter and J. G. van der Watt, J. Pharm. Sci., 1987, 76, 744;
(c) J. P. Reboul, B. Cristau, J. C. Soyfer and J. P. Astier, Acta
Crystallogr., Sect. B, 1981, 37, 1844; (d) M. D. Lang, J. W. Kampf
and A. J. Matzger, J. Pharm. Sci., 2002, 91, 1186; (e) J.-B. Arlin,
L. S. Price, S. L. Price and A. J. Florence, Chem. Commun., 2011,
5
for bis-urea based organogelators, amides 1 and 2 act as
efficient crystallization media for these APIs, although no
differences in their polymorphism are observed.
47, 7074.
16 Crystal Growth in Gels, ed. H. K. Henisch, Pennsylvania State
University Press, University Park, 1970.
In summary, we report on the cooperative supramolecular
polymerization and amplification of chirality of simple, linear
tetra-amides that self-assemble into helical structures by the
operation of amide CQOꢂ ꢂ ꢂH–N H-bonds. These helical
fibers have been visualized by AFM imaging. The interaction
of single helical, columnar aggregates into bundles allows the
gelation of toluene. The toluene organogels formed from 1 and 2
have been utilized as crystal growth media for common APIs like
1
1
1
7 (a) A. D. Bond, R. Boese and G. R. Desiraju, Angew. Chem., Int.
Ed., 2007, 46, 615; (b) A. D. Bond, R. Boese and G. R. Desiraju,
Angew. Chem., Int. Ed., 2007, 46, 618.
8 (a) D. J. Sutor, Acta Crystallogr., 1958, 11, 453; (b) G. D. Enright,
V. V. Terskikh, D. H. Brouwer and J. A. Ripmeester, Cryst.
Growth Des., 2007, 7, 1406.
9 N. Kaneniwa, M. Otsuka and T. Hayashi, Chem. Pharm. Bull.,
1985, 33, 3447.
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5757–5759 5759