Size control and compartmentalization in self-assembled nano-structures of a multisegment amphiphile

Article abstract of DOI:10.1039/c000337a

A "multisegment amphiphile" has been synthesized by covalently connecting two well known building blocks, a gelator and a micelle forming surfactant. Self-assembly results in the formation of compartmentalized nano-object displaying properties inherited f

Full text of DOI:10.1039/c000337a

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Size control and compartmentalization in self-assembled nano-structures
of a multisegment amphiphilew
Job Boekhoven,a Patrick van Rijn,a Aurelie M. Brizard,a Marc C. A. Stuartb and
Jan H. van Esch*a
Received 6th January 2010, Accepted 16th March 2010
First published as an Advance Article on the web 7th April 2010
DOI: 10.1039/c000337a
A ‘‘multisegment amphiphile’’ has been synthesized by covalently
connecting two well known building blocks, a gelator and a
micelle forming surfactant. Self-assembly results in the formation
of compartmentalized nano-object displaying properties inherited
from both parents.
Amphiphiles continue to attract widespread attention in
science and technology, not only because of their fascinating
self-assembly properties, but also because their numerous,
diverse applications in e.g. detergent formulations, catalysis,
and drug delivery. Despite their large chemical diversity,
amphiphiles share a common structure consisting of a hydro-
philic and a hydrophobic segment, giving rise to a limited
range of morphologies like micelles, vesicles, bilayers, and the
corresponding inverted phases.1 More recently, other building
blocks such as small molecule gelators and peptides have been
used to construct novel self-assembled architectures like
ribbons, helices and tubes2 with regular, well-defined structural
features at molecular length scales.3 Nevertheless, small
molecule based self-assembled structures cannot yet compete
with the sophisticated architectures found in natural systems,
especially with regard to the levels of compartmentalization,
size control, and hierarchical structure formation.4 Currently,
Scheme 1 (a) Schematic representation of hydrogelator 1 and micelle
such multicompartment structures of defined size and 3–50 nm
structural features can most easily be fabricated by controlled
phase separation of multiple covalently connected segments in
block copolymers, giving rise to a variety of multicompartment
assemblies5 and hierarchically structured materials.6 Only few
examples have been reported of self-assembled structures from
small molecules with a block structure.7 The challenge remains
to develop self-assembling systems based on small molecules
that allow size control, hierarchical structure formation
and compartmentalization at (sub)-molecular length scales.
Previously we and others showed that the orthogonal
self-assembly of certain hydrogelators and surfactants is a
valid strategy towards new nanoarchitectures, including self-
assembled interpenetrating networks and various organizations
of vesicles or micelles with fibrous networks (Scheme 1a).8,9
We anticipated that the covalent connection of two orthogonally
forming surfactant 2, which undergo orthogonal self-assembly into
their individual architectures. (b) Multisegment amphiphile 3 is
expected to give assemblies with structural features and compartments
inherited from the parent compounds 1 and 2. Light areas represent
hydrophilic domains whereas dark areas represent hydrophobic
domains.
self-assembling molecular building blocks would give rise
to microphase separation phenomena at the molecular length
scale.
Here we present a first example of such a ‘‘multisegment
amphiphile’’, as the small molecule counterpart of block
copolymers (Scheme 1b). We found that this multisegment
amphiphile self-assembles into well-defined aggregates with
compartments and structural features at molecular length
scales inherited from its parent compounds. Our results
suggest that this behavior results from strong spatial constraints
on a phase separating system at the molecular scale.
A first requirement for a multisegment amphiphile is that
the self-assembly of each segment is driven by incompatible
interactions. In this study we have combined a low-molecular-
weight hydrogelator and a surfactant, separated by a hydro-
philic linker. The parent hydrogelator 1 is a member of the
well-studied class of 1,3,5-cyclohexyltrisamide hydrogelators,
a Department of Chemical Engineering, Delft University of
Technology, Julianalaan 136, 2628 BL Delft, The Netherlands.
E-mail: j.h.vanesch@tudelft.nl
b Groningen Biomolecular Sciences and Biotechnology Institute,
University of Groningen, Nijenborgh 4, 9747 AG Groningen,
The Netherlands
w Electronic supplementary information (ESI) available: Experimental
procedures, synthesis and IR-data. See DOI: 10.1039/c000337a
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which self-assemble by hydrogen bonding and hydrophobic
interactions.10 In this study hydrogelator
has been
l
max of NR was observed. These results clearly show that self-
1
assembly of 3 is also driven by hydrophobic interactions
between the C8 tails, leading to the formation of hydrophobic
microdomains which are not present in assemblies of gelator 1.
In a control experiment with 2 the lmax of NR only shifted by
25 nm to 635 nm, which is significantly less than the 39 nm
blue shift observed with 3, indicating that the hydrophobic
domains in aggregates of 3 are more hydrophobic than in
surfactant 2. The onset of the blue shift of lmax of NR with 2
occurred at 8.0 mM, which is in nice agreement with the
reported value for the cmc of 2 (8.4 mM).11 Interestingly,
the hydrophobic microdomains in aqueous solutions of 3 are
already formed at a concentration around 0.01 mM, which is
more than two orders of magnitude lower than with surfactant
2, clearly showing that the gelator segment contributes
significantly to the stability of the hydrophobic domains.
The morphology of aggregates of 1 and 3 was investigated
in more detail with Cryo Transmission Electron Microscopy
(Cryo-TEM). Cryo-TEM of gelator 1 in water at 0.25 mM and
1.0 mM revealed the presence of fibers and extended sheets,
which is in good agreement with the observed viscosity and
turbidity of the samples (ESIw). Both the fibers and sheets
formed by 1 are highly disperse in width, with sizes ranging
from 50–500 nm, comparable to similar gelators.10b
functionalized with three hydrophobic phenyl alanine amino
acids and three tetra-ethylene glycol tails. In water 1 forms a
turbid viscous solution at concentrations below 7 mM,
whereas above this concentration turbid gels are formed.
The surfactant segment used in this study is based on tetra-
ethylene glycol mono-octyl ether 2 which self-assembles into
micelles above a critical micelle concentration (cmc) of 8.4 mM
due to hydrophobic interactions.11 Previous work showed that
self-assembly of non-ionic surfactants and cyclohexanetrisamide
based hydrogelators like 1 are orthogonal processes.8a
Multisegment amphiphile 3 was constructed by the covalent
connection of 1 and 2 (ESIw). Contrary to surfactant 2,
multisegment amphiphile 3 did not dissolve in water at room
temperature. Heating of the samples resulted in the formation
of a transparent solution, which is common for gelators like
1.10 Cooling to room temperature led to the formation of a
viscous transparent solution at [3] o0.25 mM and a turbid gel
for [3] 45 mM. In between these concentrations a turbid
viscous solution was formed (ESIw). The critical gelation
concentration (cgc) is comparable to 1 (7 mM), suggesting
that 3 aggregates in water in a similar way to 1. FT-IR showed
that N–H and CQO vibrations of a freeze-dried xerogel of 3
appeared at wavenumbers characteristic for hydrogen bonded
amides.12 Similar behavior was observed for 1, indicating both
1 and 3 are involved in hydrogen bonding (ESIw).
To see to which extent the C8-tails contribute to the stability
of the fibers, the thermostability of gels of 3 was investigated
by dropping ball measurements (Fig. 1a). Especially for
concentrations below 15 mM the gel-to-sol transition
temperature (Tm) was higher for 3 than for 1. These observations
suggest that gels of 3 display higher thermal stability as
compared to 1, which is most likely due to hydrophobic
interactions between the C8-tails.
In the case of multisegment gelator 3 Cryo-TEM revealed
that transparent and viscous samples of 3 at a concentration of
0.25 mM consisted primarily of monodisperse, elongated
fibers with a diameter of 9 nm. The diameter of these fibers
was very uniform pointing to a cylindrical shape. Furthermore,
these 9 nm fibers did not fuse or intertwine, but appeared to be
rigid with an estimated persistence length of approximately
0.5 mm (Fig. 2a). In some instances a splitting of the 9 nm
fibers into smaller and thinner fibrils with a diameter of
The presence of hydrophobic interactions between the C8
tails of 3 was further investigated by fluorescence spectroscopy
using the solvatochromic probe Nile Red (NR).13 In the
presence of 3 the emission intensity of NR showed a significant
increase together with a blue shift of the maximum emission
wavelength (lmax) from 660 nm in pure water to 622 nm in
aqueous solutions of 3 ([3] = 1.0 mM) (Fig. 1b and ESIw),
indicative of the formation of hydrophobic domains. For 1,
neither increase of the emission intensity nor blue shift of
Fig. 2 Cryo-TEM images of (a) fibrous network of 3 at 0.25 mM
displaying fibers with a diameter of 9 nm; (b) magnification of 3 at
0.25 mM displaying both 9 nm fibers and 3 nm fibrils; (c) fibrous network
of 3 at a concentration above 0.25 mM. Polydisperse twisted tapes of 50
to 200 nm in diameter are formed; (d) magnification of Fig. 3c showing
substructures consisting of fibrils of 3 nm in diameter. Scale bar: 100 nm.
Fig. 1 (a) Gel-to-sol phase transition temperature (Tm) of aqueous
gels of 1 and 3 as a function of concentration, as determined by
dropping ball measurements. (b) Emission maximum (lmax) of NR
(0.1 mM) as a function of concentrations 1, 2 and 3. Nile Red was
excited at 550 nm.
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In conclusion, starting from a molecular gelator and a
surfactant we have been able to develop a so-called multisegment
amphiphile, which self-assembles in a cooperative fashion into
compartmentalized fibers, showing well-defined structural
features at molecular length scales. These fascinating self-
assembly properties and the resulting structures originate from
orthogonal self-assembly of the parent compounds, spatially
constrained by their covalent connection within the multi-
segment amphiphile. The multisegment approach offers new
opportunities for the rational development of novel, molecular
based, multicompartment architectures thereby expanding
the scope of classic surfactant morphologies. Moreover, by
separately addressing the self-assembly processes of the individual
segments it will be possible to gain control over morphological
transitions and hierarchical structure formation.
Fig. 3 Schematic representation of the self-assembly of 3 into fibril,
hydrogen bonded in the z-direction. Additionally, due to hydrophobic
interactions between the surfactant segments, 5 to 7 fibrils assemble
into 9 nm fibers or up to 200 nm tapes depending on the concentration.
This work was supported by a NWO VICI grant. The
authors thank Dr K. J. C. van Bommel for helpful discussion.
approximately 3 nm was observed (Fig. 2b). Increasing the
concentration of 3 to above 0.25 mM resulted in the gradual
appearance of polydisperse, twisted tapes with diameter
ranging from 50–200 nm (Fig. 2c). At higher magnifications
the tapes showed a periodic fine structure of stripes parallel to
the long fiber axis, with a spacing of B3 nm (Fig. 2d), similar
to the diameter of the thinner fibrils observed at concentrations
below 0.25 mM. Most likely, both the 9 nm fibers and the
wider, twisted tapes are superstructures of the 3 nm fibrils.
Based on these observations a tentative model is proposed for
the self-assembly process and resulting aggregate structures
formed by multisegment amphiphile 3 (Fig. 3). The smallest
observed aggregates are the 3 nm fibrils, which nicely correspond
to the diameter of a single discotic molecule of 3. The high
aspect ratio of these fibrils is typical for the morphology of
other cyclohexane–trisamide gelators which are known to form
extended stacks of hydrogen-bonded moieties on top of each
other.10b Therefore, the 3 nm fibrils are most likely single stacks
of molecules of 3 hydrogen bonded in the z-direction.
Notes and references
1 (a) J. N. Israelachvili, D. J. Mitchell and B. W. Ninham, J. Chem.
Soc., Faraday Trans. 2, 1976, 72, 1525; (b) W. M. Gelbart and
A. Ben-Shaul, J. Phys. Chem., 1996, 100, 13169.
2 (a) J. van Esch and B. L. Feringa, Angew. Chem., Int. Ed., 2000, 39,
2263; (b) D. J. Abdallah and R. G. Weiss, Adv. Mater., 2000, 12,
1237; (c) R. G. Weis and P. Terech, Molecular Gels, Springer,
1st edn, Dordrecht, The Netherlands, 2006.
3 (a) A. Aggeli, I. A. Nyrkova, M. Bell, R. Harding, L. Carrick,
T. C. B. McLeish, A. N. Semenov and N. Boden, Proc. Natl. Acad.
Sci. U. S. A., 2001, 98(21), 11857; (b) M. George and R. G. Weiss,
J. Am. Chem. Soc., 2001, 123, 10393; (c) A. del Guerzo, A. G. L.
Olive, J. Reichwagen, H. Hopf and J.-P. Desvergne, J. Am. Chem.
Soc., 2005, 127, 17984; (d) S. Toledano, R. J. Williams,
V. Jayawarna and R. V. Ulijn, J. Am. Chem. Soc., 2006, 128,
´
1070; (e) F. Rodrıguez-Llansola, B. Escuder and J. F. Miravet,
J. Am. Chem. Soc., 2009, 131, 11478.
4 G. M. Whitesides and B. Grzybowski, Science, 2002, 295, 2418.
5 (a) J.-F. Gohy, N. Willet, S. Varshney, J.-X. Zhang and R. Jerome,
´
Angew. Chem., Int. Ed., 2001, 40, 3214; (b) Z. Zhou, Z. Li, Y. Ren,
M. A. Hillmyer and T. P. Lodge, J. Am. Chem. Soc., 2003, 125,
10182; (c) Z. Li, E. Kesselman, Y. Talmon, M. A. Hillmyer and
T. P. Lodge, Science, 2004, 306, 98; (d) D. J. Pochan, Z. Chen, H. Cui,
K. Hales, K. Qi and K. L. Wooley, Science, 2005, 306, 94;
In an additional step these thinner fibrils associate into
parallel bundles corresponding to the 9 nm fibers. A simple
geometric model revealed that a 9 nm bundle consists of 5–7
fibrils with a diameter of 3 nm, which most likely are held
together by hydrophobic interactions between the aliphatic
chains pointing to the center of these cylindrical fibers (ESIw).
The overall fibrous morphology is dominated by the highly
anisotropic interactions between the gelator segments, but the
regular diameter of the 9 nm fibers is reminiscent of the
well-defined size of micelles and results from competing inter-
actions including hydrophobic attraction between the alkyl
moieties and steric constraints from the gelator segments. At
higher concentrations twisted tapes are formed, which are,
most likely, not a superstructure of the 9 nm fibers, but also of
the 3 nm fibrils. It is not yet clear whether these twisted tapes
are formed by a morphological transition from the 9 nm
fibrils, or directly from the 3 nm fibrils. The periodic
striped pattern observed at higher magnifications is a strong
indication that the twisted tapes consisted of a layered
structure of 3 nm fibrils, which are also held together by
hydrophobic interactions in the plane of the layer. Alternative
models for the structure of the twisted tapes remain possible.
(e) F. Schacher, A. Walther and A. H. E. Muller, Langmuir, 2009,
¨
25, 10962; (f) F. Liu and A. Eisenberg, J. Am. Chem. Soc., 2003, 125,
15059; (g) R. Stoenescu and W. Meier, Chem. Commun., 2002, 3016.
6 O. Ikkala and G. ten Brinke, Science, 2002, 295, 2407.
7 (a) J. D. Hartgerink, E. Beniash and S. I. Stupp, Science, 2001, 294,
1684; (b) E. R. Zubarev, M. U. Pralle, E. D. Sone and S. I. Stupp,
J. Am. Chem. Soc., 2001, 123, 4105.
8 (a) A. Heeres, C. van der Pol, M. C. A. Stuart, A. Friggeri,
B. L. Feringa and J. H. van Esch, J. Am. Chem. Soc., 2003, 125,
14252; (b) A. M. Brizard, M. C. A. Stuart, K. van Bommel,
A. Friggeri, M. de Jong and J. H. van Esch, Angew. Chem., Int.
Ed., 2008, 47, 2063; (c) A. M. Brizard, M. C. A. Stuart and
J. H. van Esch, Faraday Discuss., 2009, 143, 345.
9 (a) J. van Herrikhuyzen, A. Syamakumari, A.P. H. J. Schenning and
E.W. Meijer, J. Am. Chem. Soc., 2004, 126, 10021; (b) K. Sugiyasu,
S.-I. Kawano, N. Fujita and S. Shinkai, Chem. Mater., 2008, 20,
2863; (c) J. R. Moffat and D. K. Smith, Chem. Commun., 2009, 316.
10 (a) K. Hanabusa, A. Kawakami, M. Kimura and H. Shirai, Chem.
Lett., 1997; (b) K. J. C. van Bommel, C. van der Pol, I. Muizebelt,
A. Friggerri, A. Heeres, A. Meetsma, B. L. Feringa and J. H. van
Esch, Angew. Chem., Int. Ed., 2004, 43, 1663.
11 Z. Kiraly, R. H. K. Borner and G. H. Findenegg, Langmuir, 1997,
´
¨
13, 3308.
12 W.-D. Jang and T. Aida, Macromolecules, 2004, 37, 7325.
13 M. C. A. Stuart, J. C. van de Pas and J. B. F. N. Engberts, J. Phys.
Org. Chem., 2005, 18, 929.
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3492 | Chem. Commun., 2010, 46, 3490–3492