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Hydrogen-Bonded Hexamers Self-Assemble as Spherical and Tubular Superstructures on the Sub-Micron Scale.

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Angewandte
Chemie
Supramolecular Chemistry
DOI: 10.1002/anie.200600671
Hydrogen-Bonded Hexamers Self-Assemble as
Spherical and Tubular Superstructures on the
Sub-Micron Scale**
Michael W. Heaven, Gareth W. V. Cave,
Robert M. McKinlay, Jochen Antesberger,
Scott J. Dalgarno, Praveen K. Thallapally, and
Jerry L. Atwood*
In the advancing fields of supramolecular chemistry and
nanotechnology, the ability to manipulate and control supraand supermolecular self-assembly is a prerequisite. Within the
realms of supramolecular chemistry at least, these recently
developed abilities have been exploited in the design of
complementary molecules that form interesting spherical or
capsular architectures that are, as is often the case in nature,
of high symmetry.[1–3] These supramolecular assemblies have
potential in drug delivery, selective catalysis, or cell mimicry.
In terms of nanotechnology and supermolecular self-assembly, related examples include complex interlocking capsules
that can envelop unstable materials,[4] enhance reaction
rates,[5] or provide transportation through otherwise
unfriendly environments.[6] Covalent and noncovalent tubular
architectures show ever increasing promise for application[7, 8]
and complex combinations of phospholipid containers and
nanotubes have been used to form microscopic networks that
allow the passage of molecular material through interlinking
tubules.[9] Biological examples of the interaction between
“spheres” and “tubules” include the cell-to-cell communication through nanotubular cytonemes (as probed with fluorescently labeled wheat germ agglutinin)[10] and the synergic
action between amphiphysin and dynamin in clathrin-mediated endocytosis.[11]
Herein we describe the supermolecular self-assembly of a
nanometer-scale supramolecular architecture into sub-micron
spheres and tubules, or combinations thereof. By using
[*] M. W. Heaven, Dr. G. W. V. Cave, R. M. McKinlay, J. Antesberger,
Dr. S. J. Dalgarno, Dr. P. K. Thallapally, Prof. J. L. Atwood
Department of Chemistry
University of Missouri-Columbia
601 South College Avenue, Columbia, MO 65211 (USA)
Fax: (+ 1) 573-882-2754
E-mail: atwoodj@missouri.edu
Dr. G. W. V. Cave
School of Biomedical and Natural Sciences
Nottingham Trent University
Clifton Lane, Nottingham, NG11 8NS (UK)
[**] We acknowledge the NSF for financial support of this work. We
thank the University of Missouri Structural Biology Core for
technical assistance and use of the light scattering instrument, and
the Electron Microscopy Core for the use of the TEM and SEM
facilities.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 6221 –6224
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6221
Communications
various electron or force microscopy techniques these superstructures are shown to link and/or bud from one another. The
tecton in question (16 or 36·Ga12, Figure 1), a near spheroidal
hexameric nanocapsule based on pyrogallol[4]arene (Pg or 1,
2, and 3, general structure shown in Figure 1), is held together
Figure 1. The formation of hydrogen-bonded and metal-coordinated
pyrogallol[4]arene hexameric capsules. A) Crystallization from an
appropriate solvent (ethyl acetate, for example) results in the formation of hydrogen-bonded hexamers with radiating alkyl chains. The
average diameter of a single hexamer in the solid state is approximately 4 nm.[13] B) Reaction of gallium nitrate hydrate in a water/
acetone mixture of 3 results in the formation of metal-coordinated
capsules within which metal centers replace hydrogen atoms of the
pyrogallol[4]arene hydroxo groups; gray C, white H, red O, green Ga;
ethyl acetate and water molecules removed for clarity.[23]
by 72 hydrogen bonds, and has lipophilic alkyl chains of
varying length that radiate from the spheroid shell to different
extents depending on the precursor selected.[12–14] For particular carbon-chain lengths, the hydrogen-bonded “seams” or
“faces” of the spheroid can become exposed (in the solid state
at least) and it is proposed that these combined factors may
play a crucial role in superstructure stabilization on the submicron level.
Pyrogallol[4]arenes crystallize in either bilayer or hexameric nanocapsule motifs depending on the crystallization
solvent employed.[12–14] The stability of these hexamers in
either polar or nonpolar media has been demonstrated in a
number of solution-phase studies.[15–17] Indeed, this stability
has been recently utilized in the spectroscopic study of
capsule-bound fluorescent probe molecules with a view to
reporting on the interior order of the assembly.[14] To date
however, little is known of the aggregation and supermolecular assembly of these solution-stable entities. Using dynamic
light scattering (DLS) techniques, large supermolecular
aggregates were observed for different Pg hexamers under
dilute conditions (typical concentration ca. 10 3 m).[18] The
diameters of the aggregates were found to be in the range of
80–120 nm. Sonication of these solutions resulted in the
formation of species of roughly 4 nm size, indicative of
individual Pg hexamers (Figure 1 A). Over a number of hours,
the larger aggregates re-formed and could be detected by
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subsequent DLS studies. This aggregation phenomenon was
not however observed in the aqueous phase, and only discrete
hexamers were detected using DLS. Given the stability and
recurring nature of the aggregates in solvents other than
water, we employed transmission electron microscopy
(TEM), scanning electron microscopy (SEM), and atomic
force microscopy (AFM) techniques to examine the particles,
the results of which were to some extent unexpected.
Upon evaporation of an approximately 10 4 m acetone
solution of the Pg hexamer (16, where R = isobutyl, Figure 1 A) under ambient conditions, large aggregates were
observed by TEM (Figure 2 A). The aggregates were found to
be spherical, of uniform shape, and to be of wide-ranging
diameters (92 42 nm) when formed from acetone solutions.
In addition, spherical aggregates were, on occasion, found to
be linked by interesting tubular architectures (Figure 2 B).
The rate of evaporation was found to play a role in aggregate
formation, as when solvents of a higher boiling point were
employed, the number of observed aggregates was reduced,
and also led to alternative crystal growth as observed by TEM
studies.[19]
At similar concentrations in acetonitrile (ca. 10 4 m), or
upon moving to higher concentrations in chloroform
(ca. 10 2 m), the spherical aggregates could be stacked upon
one another rather than coalescing (Figure 2 C,D). Notably,
TEM studies of an aqueous solution of 16 repeatedly showed
amorphous material rather than spherical aggregates. Ethyl
acetate was also found to be a poor solvent for aggregate
formation, presumably owing to the high boiling point[20] and
that a number of Pg hexamers are readily crystallized from
this solvent.[13]
For a direct hexamer and bilayer comparison using TEM,
16 was recrystallized in the bilayer motif from acetone, a
solvent known to retain the supramolecular assembly motif
whether hexamer or bilayer (note: ethyl acetate exclusively
forms hexamers). The bilayer arrangement, when observed
using TEM, showed only a limited number of the sub-micron
spherical aggregates and a large mass of amorphous material
(see Supporting Information). The fact that some spherical
aggregates were observed implied that bilayer to hexamer
conversion was occurring over time, a phenomenon that was
elucidated by X-ray powder diffraction (see Supporting
Information) and further TEM studies.[20]
With respect to the sphere-connecting tubular architectures, these were most readily observed when samples were
prepared from chloroform or methylene chloride solutions
(although formation was also observed in acetonitrile or
acetone on occasion, Figure 2 B). In general, these tubular
connectors were of smaller diameter than the spherical
aggregates (which were often found at the tubule ends) and
were found to exist in both smooth and rugged morphologies
(Figure 2 E–J). The smoother tubes were more prevalent and
were most commonly formed with lengths approaching one
micrometer (Figure 2 E–I). The rugged tubes were most
commonly formed from chloroform solutions, and were
found to be of greater diameter and shorter in length than
the smooth analogues (lengths approaching 400 nm, Figure 2 J). Examination of the smooth and rugged tubes using
TEM and SEM, respectively, showed hemispheric swellings
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 6221 –6224
Angewandte
Chemie
Figure 3. AFM image of hexamer 26 (R = pentyl, Figure 1 A) in acetone
showing height measurements of spheroidal aggregates.
Figure 2. TEM and SEM images of aggregates formed from pyrogallol[4]arene hexamers. A) TEM of spherical aggregates formed from
an acetone solution of 16 (R = isobutyl, Figure 1 A). B) Expansion of
marked area in (A) showing a tubular connection between two
spheres. C) TEM of a chloroform solution of 16 showing aggregate
layering. D) TEM of spherical aggregates formed from an acetonitrile
solution of 16. E,F) TEM of spheres and tubes formed from a chloroform solution of 16. G) TEM of a network of spheres and tubes formed
from a methylene chloride solution of 16. H–J) SEM of spheres and
tubes formed from a chloroform solution of 16. K,L) TEM of metalcoordinated capsules 36·Ga12 (R = propyl, Figure 1 B) formed from an
acetone solution (Scale bars. A,G: 200 nm; B,D: 20 nm; C,E,H–J:
100 nm; F,K,L: 50 nm).
that appeared to be spherical aggregates budding from the
tubular architectures (Figure 2 E,F,H–J). These budding
aggregates are spread randomly across the length of the
tubes and are of comparable diameter.
AFM corroborated the electron microscopy findings with
regard to both structure and spatial height of the spherical
superstructures. Examination of the aggregates using contact
mode AFM showed spherical regions with heights in the 60–
80 nm range (aggregates formed from 26, Figure 1 A, Figure 3
Angew. Chem. Int. Ed. 2006, 45, 6221 –6224
and Supporting Information). This result correlates well with
the aggregate diameters found in both DLS and TEM studies.
To determine whether the sub-micron aggregates were
composed of pyrogallol[4]arene based layers or hexamers,
metal-coordinated capsules (hexamers that are incapable of
disassembly in the solvent systems employed) were studied
using TEM (gallium-coordinated hexamer 36·Ga12, Figure 1 B).[21] Spherical aggregates that are of comparable
dimensions to those of the hydrogen-bonded hexamers were
observed by TEM, although the images were significantly
darker, presumably owing to the high content of gallium in
the resultant superstructures (Figure 2 K,L). This evidence
indicates that the spherical aggregates are indeed composed
of many discrete hexamer building blocks, and are not a
bilayer related motif. This conclusion is further supported by
the studies of Coleman et al. in which p-acylcalix[4]arene was
manipulated into solid lipid nanoparticles (SLNs).[22] In those
studies, the formation of large objects of 250 nm in diameter
was observed although these flattened slightly during the
drying process. From their studies, Coleman et al. deduced
that the objects were matricial. Liposomal systems cannot
survive under such conditions (they collapse), and therefore
we conclude that the objects observed in the current studies
are also matricial, made up of many neighboring hexamers
rather than a bilayer based motif (Figure 4).
Figure 4. Theoretical representation of hexamers assembling as A) spherical and B) tubular superstructures. Inset: Negative of
Figure 2 B, which is modeled in (B) (Scale bar: 20 nm).
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6223
Communications
Unlike almost all examples of artificial molecular-based
vesicle systems, the supramolecular system herein is unique in
that the self-assembly of the hexamer takes place prior to the
formation of larger aggregates. Solvent properties are very
important in the formation of these large structures, and an
abundance of water appears to hinder aggregate formation,
thereby suggesting that hexamer-to-hexamer interactions
may be disturbed under such conditions. Although the
specific interhexamer interactions are unknown to date, the
aggregation phenomenon is general for a number of pyrogallol[4]arenes.[23] The large aggregates may either be stabilized by a large number of van der Waals interactions between
neighboring alkyl chains, or by face-to-face hexamer interactions between hydrophilic regions of the discrete supramolecular assemblies, as is observed in the solid state.[13] The
ability to attach a range of functionalities to the alkyl chains of
the nanospheroids, coupled with the ability to modify the
interior of the hexamers with a range of guest molecules will
undoubtedly prove useful in the future study and application
of these spherical and tubular sub-micron assemblies.
Received: February 20, 2006
Revised: May 16, 2006
Published online: July 25, 2006
.
Keywords: calixarenes · electron microscopy · materials science ·
self-assembly · supramolecular chemistry
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[18] The Pg hexamers were crystallized from ethyl acetate over a
period of 12–48 h, except for 36·Ga12 (crystallized from acetone/
water). The crystals were weighed and the appropriate solvent
added to make stock solutions of desired molarity. All samples
were stored in glass vials and were analyzed within 12 h of the
crystals being dissolved, except when long-term viability was
being assessed. See Supporting Information for analytical
techniques involved.
[19] This was typically observed when high-boiling-point solvents
were employed in sample preparation. Single-crystal growth was
observed by TEM when ethyl acetate or a water/acetone mixture
was used, although small amounts of microcrystalline material
was also found on occasion for other solvents.
[20] An acetone solution of re-dissolved bilayer crystals of the Pg
hexamer 16 was found to revert to the corresponding hexamer
when allowed to stand overnight, as indicated by subsequent Xray powder diffraction and TEM studies. TEM studies on the
solution showed the formation of approximately 80-nm spherical
aggregates. The remaining solution was evaporated at room
temperature and the solid residue examined using X-ray powder
diffraction, which showed reflections indicative of hexamer
formation.
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[23] Information regarding the assembly and examination of aggregates based on other pyrogallol[4]arene hexamers can be found
in the Supporting Information.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 6221 –6224
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