Formation of triple helical nanofibers using self-assembling chiral benzene-1,3,5-tricarboxamides and reversal of the nanostructure's handedness using mirror image building blocks

Article abstract of DOI:10.1039/b606371c

Intertwining triple helical nanofibers with an overall handedness have been formed from self-assembling chiral benzene-1,3,5-tricarboxamides 1, 2 and 3, whereas the achiral benzene-1,3,5-tricarboxamide 4 upon self-association gives rise to straight nanofi

Full text of DOI:10.1039/b606371c

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Formation of triple helical nanofibers using self-assembling chiral
benzene-1,3,5-tricarboxamides and reversal of the nanostructure’s
handedness using mirror image building blocks{
Partha Pratim Bose,a Michael G. B. Drew,b Apurba K. Dasa and Arindam Banerjee*a
Received (in Cambridge, UK) 5th May 2006, Accepted 5th June 2006
First published as an Advance Article on the web 21st June 2006
DOI: 10.1039/b606371c
scaffold14 or by using
a
mirror image self-assembling
Intertwining triple helical nanofibers with an overall
handedness have been formed from self-assembling chiral
benzene-1,3,5-tricarboxamides 1, 2 and 3, whereas the achiral
benzene-1,3,5-tricarboxamide 4 upon self-association gives rise
to straight nanofibers without any twist and transmission
electron microscopy images of chiral compounds clearly
demonstrate that the handedness of the triple helical nanofibers
can be reversed by using the enantiomeric benzene-1,3,5-
tricarboxamide building blocks.
oligopeptide.15 However, none of the above mentioned examples
show the further assembly of helical nanofibers, i.e. the formation
of double helical or triple helical nanofibers. Here, we present the
formation of triple helical nanofibers from self-assembling chiral
benzene-1,3,5-tricarboxamides 1, 2 and 3 and reversal of the
handedness of these chiral nanofibers using the enantiomeric
benzene-1,3,5-tricarboxamide (compounds 1 and 3 are enantio-
mers). To meet the challenge of controlling the chirality at different
hierarchical levels of molecular self-assembly, particularly in the
formation of chiral nanofibers, discotic molecules having opposite
chirality (Fig. 1) and an achiral molecular unit have also been
chosen to probe whether the chiral nanostructure is formed only
by chiral building blocks.
Nanofibers are ubiquitous and are found in both self-associated
biological and non-biological systems. They are observed in self-
assembling short peptides with 2–3 residues,1 medium sized
peptides,2 naturally occurring proteins,3 de novo designed proteins4
and lipids.5 In non-biological systems, the synthetic carbon
nanofiber is very common6 and the silicon carbide nanofiber7 is
also reported in the literature. Nanofiber structures based on
b-sheet forming self-assembling peptides have been widely
studied.8 Self-assembling peptide amphiphiles form nanofibers
and these nanofibers can be used for biomedical applications.9 It
has been reported that self-assembling peptide amphiphiles can be
reversibly self-assembled to form a nanofiber network, which
results in the formation of aqueous gel through pH changes.10
Ryadnov and Woolfson have successfully engineered the
morphology of self-assembling polypeptide-based nanofibers.11
An earlier example of the formation of helical nanofibers includes
the twisted fibers obtained from supramolecular liquid crystalline
species formed by polyassociation of complementary components
TP2 and TU2 (where T is D-, L- or meso tartaric acid, P is a
pyridine derivative and U is a uracil derivative). The chirality of
the nanofibers is controlled by using different types of tartaric
acids: D-, L- or the meso form.12 Recent studies of the formation of
helical nanofibers include the self-assembly of the molecular system
based on a dithienylethene unit functionalized with (R)-1-phenyl
ethylamine derived amides,13 self-association of dendron rod coil
molecules14 and b-sheet forming oligopeptides.15 The handedness
of the helical nanostructures can be reversed either by using the
enantiomeric form of the dendron rod coil as a molecular
A series of compounds 1–4 were synthesized,16 purified,
characterized and studied. A single crystal X-ray diffraction
study17 of compound 1 (crystallized from a methanol–water
system) reveals that the molecule has crystallographic 3-fold
symmetry within a hexagonal unit cell, space group P63. This
facilitates the formation of supramolecular columnar packing
along the axis parallel to the unique crystallographic c axis (Fig. 2).
The self-assembly of disc-shaped compound
1 exhibits a
supramolecular triple helical structure with an overall right-handed
twist and this architecture is formed through intermolecular
hydrogen bonds and other non-covalent interactions including p–p
stacking interactions between the central aromatic moieties (Fig. 2).
˚
The inter-ring centroid distance is 3.546 A in the crystal, which is
compatible with distances in the p-facial arrangement of various
C3-symmetrical columnar supramolecular architectures relying on
hydrogen bonding and p–p stacking.18 The present crystal
structure further revealed that the individual triple helical columns
are regularly aligned via non hydrogen bonding non-covalent
aDepartment of Biological Chemistry, Indian Association for the
Cultivation of Science, Jadavpur, Kolkata 700 032, India.
E-mail: bcab@mahendra.iacs.res.in; Fax: +91-33-2473-2805
bSchool of Chemistry, The University of Reading, Whiteknights,
Reading, UK RG6 6AD
{ Electronic supplementary information (ESI) available: Synthesis,
characterization, 1H NMR and mass spectra of all compounds, and
experimental procedures for TEM studies. See DOI: 10.1039/b606371c
Fig. 1 Schematic representation of benzene-1,3,5-tricarboxamides 1–4.
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Fig. 2 Crystal packing of compound 1 showing the self-assembly of
individual molecular building blocks, leads to the formation of an
intermolecularly hydrogen-bonded supramolecular triple helical structure
along the crystallographic c axis. Hydrogen bonds are shown as dotted
lines. Nitrogen atoms are blue, oxygen atoms are red and carbon atoms
are green. Non-hydrogen bonded hydrogen atoms and side chains of
L-valine residues are omitted for clarity.
Fig. 3 Transmission electron microscope (TEM) images of (a) com-
pound 1 and (b) compound 2 having the same chirality (S) giving a unique
intertwining triple helical nanofiber upon self-assembly. (c) TEM image of
compound 3 (having the reverse chirality (R) of compound 1) illustrating
the intertwining triple helical nanofiber of the reverse handedness upon
self-assembly. (d) TEM picture of the achiral compound 4 showing
straight nanofibers without any twist upon self-assembly. TEM micro-
graphs were taken without any staining.
interactions to form higher ordered supramolecular arrays along
the equivalent crystallographic a and b axes (ESI Fig. S10{).
Transmission electron microscope studies of benzene-1,3,5-
tricarboxamides were carried out using a methanol–water solution
(1 : 1) of the corresponding compound (3 mg in 1 mL) on a
carbon-coated copper grid (300 mesh) by slow evaporation and
vacuum drying at 30 uC for two days. The transmission electron
microscope (TEM) image of compound 1 shows a regular array of
intertwining triple helical nanofibers 130–150 nm in diameter
(width of individual nanofibers #40 nm). The TEM picture of the
compound 2 also reveals that the formation of an intertwining
triple helical nanofiber with 140–160 nm in diameter (width of
individual nanofibers #30 nm). The TEM image of compound 3
shows that the triple helical nanofibers with a reverse chirality from
that of compounds 1 and 2, with a width of 165–185 nm (width of
individual nanofibers #20 nm). However, the TEM picture of the
achiral compound 4 shows that it self-assembles to form
nanofibers (with a width of 45–65 nm) without any twist
(Fig. 3d). Both compounds 1 and 2 have the same chirality (S)
giving a unique intertwining triple helical nanofiber upon self-
assembly (Fig. 3a and b). Compound 3 is the enantiomer of
compound 1 and it self-assembles to form the intertwining triple
helical nanofiber of the reverse handedness that has been observed
in case of compound 1 or 2 (Fig. 3c). 3 mg of compounds 1 or 3
were dissolved in 1 mL of a methanol–water solution (1 : 1) with
continuous sonication (TELSONIC TEC15, model No. 900818),
33 kHz, power 70 W) for 3 min and TEM measurements were
performed by slow evaporation of benzene-1,3,5-tricarboxamide
solution on a carbon-coated copper grid (300 mesh). The TEM
images of the above mentioned samples upon sonication vividly
demonstrate that the appearance of single stranded helical
nanofibers for compounds 1 and 3 (ESI Fig. S11{) and these
nanofibers appear to be of the opposite hand when the
enantiomeric compounds were used. So, the construction and
self-assembly of the helical nanofibers can be programmed using
suitable self-assembling chiral molecular building blocks and the
handedness of the single stranded helical nanofibers and triple
helical nanofibers can be reversed using an enantiomeric
self-assembling benzene-1,3,5-tricarboxamide building block.
Helical tape structures of width 175–195 nm have been observed
when compound concentrations were increased (from 3 mg mL21
to 3.8 mg mL21 in 1 : 1 methanol–water) (ESI Fig. S12a{). When
compound concentrations were decreased (from 3 mg mL21 to
2 mg mL21 in 1 : 1 methanol–water), we observed narrower
nanofibers (of width 60–90 nm), which are lacking the feature of a
triple helical nanofiber (ESI Fig. S12b{). However, only wider
nanofibers (diameter ¢180 nm) without any twist have been
observed when 3 mg of compound 1 was dissolved in 1 mL of
dimethyl sulfoxide–water (1 : 1) solution and was subjected to
TEM experiments (ESI Fig. S12c{). So, compound concentrations
and the solvent system play a definite role in the formation of
single helical and triple helical nanofibers.
It is clear that compound 1 first self-assembles to form a triple
helical supramolecular structure and ultimately forms triple helical
nanofibers. Over and above this, the chirality is getting transmitted
from the primary to secondary and from the secondary to tertiary
structure of the molecular assemblage (Fig. 4). The secondary
structural aspect of the self-assembled molecules has been
established by single crystal X-ray diffraction studies of compound
1 and the crystal structure reveals the presence of columnar
secondary structural units along the crystallographic c axis (Fig. 2).
Each of these structural units has its own stereochemical integrity.
The crystal structure analysis of compound 1 further provides
insight about the tertiary assemblage of the chiral building blocks.
Viewing along the crystallographic a and b axes it is evident that
individual triple helical columns, i.e. the chiral secondary structural
units, are regularly aligned via non-hydrogen bonding non-
covalent interactions among the side-chain of the amino acid
residues to form the nanofibrillar tertiary structure (single stranded
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Triple helical nanofibers can be successfully constructed using
chiral molecular scaffolds (compounds 1, 2 and 3); the handedness
of the triple helical nanofibers can also be nicely tuned by reversing
the chiral nature of the molecular building blocks. The study
vividly exemplifies not only the construction of self-assembled
helical nanostructures but also shows the reversal of the
handedness of the nanostructured assemblage using mirror image
molecular building blocks. The achiral self-assembling benzene-
1,3,5-tricarboxamide molecule fails to form chiral nanostructures
indicating the transfer of molecular chirality into supramolecular
chirality.19,12 Functional chiral triple helical nanofiber formation
using suitable molecular building blocks are yet to be explored.
This work is supported by DST, New Delhi, India Project No
(SR/S5/OC-29/2003). We thank EPSRC and the University of
Reading, UK for funds for Marresearch Image Plate Systems. P. P.
Bose and A. K. Das wish to acknowledge the CSIR, New Delhi,
India for financial assistance. Thanks are also due to the partial
support from the Nanoscience and Technology Initiatives, DST,
Govt. of India, New Delhi.
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3
˚
˚
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contains a crystallographic 3-fold axis. The three equivalent asymmetric
carbon atoms were given S-chirality in accordance with the synthesis.
The final R values were R1 0.1011 and wR2 0.2557 for 1133 data with
I > 2s(I). The largest peak and hole in the final difference Fourier were
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