Chirality controlled responsive self-assembled nanotubes in water

Article abstract of DOI:10.1039/c6sc02935c

The concept of using chirality to dictate dimensions and to store chiral information in self-assembled nanotubes in a fully controlled manner is presented. We report a photoresponsive amphiphile that co-assembles with its chiral counterpart to form nanotu

Full text of DOI:10.1039/c6sc02935c

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Chirality Controlled Responsive Self-Assembled Nanotubes in
Water
Received 00th January 20xx,
Accepted 00th January 20xx
†,a
†,a
a,b
a
,a
D. J. van Dijken, P. Štacko, M. C. A. Stuart, W. R. Browne and B. L. Feringa*
DOI: 10.1039/x0xx00000x
The concept of using chirality to dictate dimensions and store chiral information in self-assembled nanotubes in a fully
controlled manner is presented. We report a photoresponsive amphiphile that co-assembles with its chiral counterpart to
form nanotubes and demonstrate how chirality can be used to effect the formation of either micrometer long, achiral
nanotubes or shorter (~ 300 nm) chiral nanotubes that are bundled. The nature of these assemblies is studied using a
variety of spectroscopic and microscopic techniques and it is shown that the tubes can be disassembled with light, thereby
allowing the chiral information to be erased.
www.rsc.org/
[6]
[7]
been applied in supramolecular polymers, gels, organic
[
8]
[9]
nanotubes, liquid crystals and other assemblies.
[10]
Introduction
The
groups of Aida and Meijer in parallel pioneered the possibility
to amplify chirality in supramolecular systems, exploring the
A
fascinating aspect and crucial feature of complex,
multifunctional self-assembled objects found in Nature is that
they are dynamic, allowing a multitude of biological processes
[8c,11]
majority rules” principle,
“
where the major enantiomer
[1]
determines the chirality of the entire assembly. In addition,
the “sergeant-soldier” principle has been reported for transfer
to rely on feedback-controlled communication. In other
words, the self-assembled structure can adopt in response to
an input signal. This ability to adjust in response to stimuli is
of
chirality
from
monomers
to
supramolecular
[
12–14]
[
2] aggregates.
In the sergeant-soldier principle, as
crucial for correct functioning of many bioprocesses.
[15]
introduced by Green and coworkers, a minor amount of the
chiral compound (sergeant), used as dopant, dictates the
overall chirality of a system that is made up of mainly achiral
material (soldiers).
Therefore, the design and synthesis of artificial systems that
can respond to external stimuli is highly warranted in order to
better understand and mimic highly sophisticated natural
systems. Furthermore, such systems potentially provide a basis
for novel smart materials and nanoscale devices, for example
In natural phospholipids, the most abundant constituent of cell
membranes, the chiral information is often present in the
aliphatic tails and the specific chiral information in these
phospholipid backbones, present on the internal hydrophobic
side of the self-assembled phospholipid bilayer, is of major
[3]
for sensing and drug delivery.
The use of chirality to control or initiate self-assembly offers a
particularly interesting approach, as the living world around us
is made up of chiral molecules of a unique handedness. Many
natural systems, such as for example enzymes, are extremely
effective in discriminating enantiomers and in the assembly of
biomaterials like proteins and DNA, stereochemistry is key
with a delicate interplay of molecular and supramolecular
[16]
importance. It is therefore remarkable that in most artificial
[8c,11–14,17]
systems, to the best of our knowledge,
the chiral
information is introduced in the part of the molecules that are
not involved in the main binding interactions that lead to
assembly into a larger aggregate. Often, changes in this
hydrophobic part of the self-assembling molecules distorts
their packing to such an extent that well-defined
supramolecular structures are no longer obtained.
[4]
chirality. Amplification of chirality is necessary for the
emergence of homochirality from a pool of nearly racemic
compound and is thought to be essential in the origin of life
[5]
and the emergence of biomaterials and bionanosystems. In
recent years, amplification of chirality has been exploited in
the field of supramolecular chemistry and this principle has
Results and Discussion
Design
Inspired by Nature, the present study focuses on the use of
chirality as a tool to govern defining parameters in complex
supramolecular assemblies and we show that through
molecular design, properties of the well-defined aggregates as
a whole, such as dimensions, aggregation, overall chirality and
photoresponsiveness, can be controlled. Previously, a light-
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responsive, self-assembled nanotube system based on
photochemically active amphiphile has been developed Synthesis
Figure 1). We envisioned that amplification of chirality may
be possible in such rigid supramolecular nanotubes by doping
achiral amphiphile with small amounts of a closely related
a
1
[18]
(
A major challenge is the synthesis of both
1 and 2 in sufficient
amounts to conduct the sergeant-soldier experiments. The
synthesis of both amphiphiles is lengthy and contains some
1
chiral analogue and that we can use this stereochemical
feature as a distinct control element for self-assembled
difficult steps. In this work, an efficient synthesis route for
and the chiral analogue was developed (Schemes 1–2, see
also Supporting Information).
1
2
nanotubes. Toward this goal, chiral
bears two stereocenters in the hydrophobic part of the
amphiphile. The structure of amphiphiles and contains a
2 was designed, which
1
2
photosensitive overcrowded alkene unit that links two
hydrophilic oligo-ethylene glycol headgroups with two
hydrophobic alkyl tails. The bis-thioxanthylidene core provides
[19]
a photoreactive and fluorescent functionality, and the oligo-
ethylene glycol units facilitate solubility in water. The
hydrophobic alkyl chains are positioned at the core structure
to maximise interaction and facilitate supramolecular
assembly by interdigitating upon aggregation to form a very
robust bilayer, resulting in the formation of nanotubular
[18]
assemblies.
Scheme 1. Synthesis of hydrophilic precursor thioketone 10. Reagents and
conditions: (a) (1) SOCl (2.4 equiv), CH Cl , reflux, 1 h; (2) Et NH (4.0 equiv),
°C to RT, 2 h, 98%; (b) BBr (5.0 equiv), CH Cl , 0 °C to RT, 16 h, quant;
c) TsO(CH CH O) H (2.0 equiv), Cs CO (5.0 equiv), DMF, 110 °C, 16 h, 85%;
d) TBDPSCl (2.5 equiv), imidazole (3.3 equiv), CH Cl , 0 °C to RT, 1 h, 75%.
2
2
2
2
0
3
2
2
(
(
2
2
3
2
3
2
2
Selective functionalisation of (thio)xanthones in the desired
- and 5-positions is not a trivial task and the key building
block was therefore prepared using a bottom-up approach.
-Methoxybenzoic acid was transformed into its acid chloride
and quenched with diethylamine to give amide in excellent
yield. Oxidation of 2-methoxybenzenethiol yields disulfide
which was added to
s-BuLi and TMEDA at -78 °C to give thioxanthone precursor
4
7
Figure 1. Design and structure of amphiphiles 1 (achiral) and 2 (chiral).
3
3
Here we show how chirality and morphology of self-assembled
supramolecular nanotubes is controlled by changing the molar
fraction of chiral constituent in the co-assembled nanotubes.
The well-defined nanotubes have different diameters and
show different behaviour depending on the ratio of chiral to
achiral amphiphile building blocks. The chiral information,
displayed by the nanotubes, can be erased with light via
disassembly of the nanotubes. The nanotube systems
presented here have several distinct differences compared to
2
,
3
after selective ortho-lithiation with
5.
Regioselective lithiation using freshly prepared lithium
diisopropylamine resulted in ring-closure to form , which was
subsequently deprotected with BBr to give dihydroxy building
block in an overal yield of 78% over four linear steps.
Hydrophilic ethylene glycol chains were introduced by
6
3
7
[
6–10] deprotonation of the hydroxy moieties with Cs CO3 and
2
a number of supramolecular materials reported to date.
addition of an equimolar amount of mono-tosyl ethylene
The nanotubes are remarkably rigid, self-assemble in water
and are photoresponsive, which means that they can be
glycol. The terminal glycol groups of
8 were protected with
[18]
TBDPS-groups and
9
was subsequently converted to its
.
disassembled with light.
Furthermore, the fact that our
thioketone derivative 10
nanotubes form in water gives future opportunities for
biocompatibility.
Hydrophobic chains were introduced by deprotonation of the
hydroxy functionalities of (Scheme 3) and addition of either
7
As the hydrophobic half of the molecule makes up the internal
part of the bilayer after self-assembly, and is most probably
dodecyl bromide or the chiral analogue 19 that was prepared
[18]
using Evans methodology in analogy to the literature
densely packed, we envisioned that the largest effect on the
overall chirality could be obtained by introducing chirality in
the hydrophobic alkyl chains. We furthermore reasoned that
the packing of the molecules upon self-assembly would be
least disturbed if the chirality is installed close to the aromatic
core of the amphiphile. Two methyl groups were therefore
[20–23]
procedures.
Only one diastereomer of the latest reported
intermediate was observed (see Supporting Information for
details) and it was therefore concluded that the bromide 19 is
enantiomerically pure. Compounds 11 and 20 were converted
to their thioketone analogues in order to increase their
reactivity and subsequently converted to hydrazones 13 and
introduced in amphiphile
2 at the C2 position of the alkyl
21, respectively, using hydrazine monohydrate at room
chains (Figure 1) to generate single enantiomers with the
stereogenic information.
temperature. The Barton-Kellogg reaction is routinely used for
2
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the construction of highly demanding tetra-substituted double linear structures that were uniform in nature. A distinct
bonds, but commonly suffers from low yields. The original difference between nanotubes of pure achiral and chiral is
synthesis of the amphiphile was considerably improved by that nanotubes of (Figure 2a) are typically longer than a
employing a mild oxidation of the hydrazones using MnO at micrometre, while tubes of (Figure 2b) are shorter; typically
°C and subsequent addition of thioketone 10 yielded only ~300 nm long.
episulfides 14 and 22 in 90% yield. The desulfurisation of the
episulfides was achieved with PPh and deprotection of the
hydroxyl moieties with TBAF yielded achiral amphiphile and
its chiral analogue in 45% and 35% overall yield for the
longest linear sequences (10 steps).
1
2
1
2
2
0
3
1
2
Figure 2. Cryo-TEM microscopy images of self-assembled nanotubes in
water at a total concentration of 1 mg/mL. a) Nanotubes of achiral 1 with
DOPC (1:1). b) Nanotubes of chiral 2 with DOPC (1:1). c) Nanotubes of 1 and
2
with DOPC (0.6:0.4:1). Arrows indicate nanotubes bending away from the
Scheme 2. Synthesis of achiral amphiphile 1 and chiral analogue 2. Reagents
and conditions: (a) CH (CH 11Br (2.6 equiv), Cs CO (5.0 equiv), DMF, 110 °C,
6 h, 90%; (b) 19 (2.6 equiv), K CO (5.0 equiv), DMF, 100 °C, 24 h, 91%;
c) NH NH ·H
O (39 equiv), THF, RT, 10 min, quant; (d) (1) Lawesson’s In addition, we found that tubes of
reagent (1.5 equiv), toluene, reflux, 2 h; (2) NH NH ·H O (19 equiv), THF, RT, more extensively (tube aggregation) than those of
0 min, 83%; (e) TBAF (2.8 equiv), THF, 0 °C to RT, 24 h, 86–90%.
“
bundle”. d) Nanotubes of 1 and 2 with DOPC (0.4:0.6:1).
3
2
)
2
3
1
(
2
3
2
tend to pack together
at the
2
2
2
2
2
2
1
1
same concentration, as observed by cryo-TEM. Figure 2b–c for
example, shows a type of network in which several nanotubes
align and pack together to form “bundles” for high content of
Self-Assembly
With achiral
confirmed by cryo-TEM measurements. Amphiphile
assembles into micrometre long nanotubes (Figure 2a) when
co-assembled with 1,2-dioleoyl-sn-glycero-3-phosphocholine nanotubes of
1
and enantiopure
2
in hand, aggregation was first (or exclusively)
self- and we found no evidence that they align with one another to
significant extent. While the reduced length of the
may be explained by a difference in packing
DOPC) 1:1. Much to our delight, starting from a 1:1 mixture due to the presence of the two methyl moieties in the
of and DOPC, the formation of nanotubes from the chiral interacting hydrophobic tails (increase in hydrophobic
amphiphile was also observed (Figure 2b). Henceforth, volume), we do not currently know why the shorter tubes tend
assembly experiments were always conducted with to bundle together. Nanotubes of both
and capped with
amphiphile and DOPC in a ratio of 1:1 to the total amphiphile DOPC vesicles were also found as reported for
concentration. The nanotubes of resemble the structures and the tubes are not different in this regard. After confirming
formed by amphiphile
that both enantiopure amphiphile and achiral amphiphile
The bilayers, making up the nanotube walls, were found to be form nanotubes, we set out to perform sergeant-soldier
nm thick for both the tubes of pure achiral and the experiments by mixing varying ratios of
and . In the mixed
homochiral amphiphile and differences in bilayers were not nanotubes (Figure 2c–d), nanotube formation was not
observed by cryo-TEM. No other types of aggregates were inhibited at any ratio of amphiphiles
. Increasing the
found for either or . Furthermore, nanotubes of are fraction of chiral
to over 50% (Figure 2d compared to 2c)
generally very straight and virtually no bends or turns were results in tubes that are shorter than nanotubes of pure achiral
observed in the nanotubes. Although we observed that for
, typically ~ 300 nm in length, and more bundled, reminiscent
nanotubes of a higher amount of bent tubes was formed, of the tubes of pure
(Figure 2b). It should be noted that
compared to tubes of
2. Nanotubes of achiral 1 are typically isolated
1
a
2
[
18]
(
2
1
2
[
18]
1
previously,
2
1.
2
1
3
1
1
2
2
1:2
1
2
1
2
1
2
2
1, nanotubes of
2
showed in general while in all samples both long and short tubes could be
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observed, below 50% of
2, the long tubes are far more nanotubes for the same samples, as measured by cryo-TEM
abundant while mainly short tubes are present in the mixtures (Figure 2).
containing over 50% chiral . Another observation is that the We next set out to probe the induction of chirality based on
tubes of mixed amphiphiles bend more, as can be seen in the sergeant-soldier principle.
2
[
12–14, 17]
We found that a solution
3
2 in CHCl is CD silent (Figure 3c, dotted line), likely because
Figure 2c (nanotubes are bending away from the “bundle” as of
indicated with black arrows).
the chromophore is remote from, or not influenced by, the
presence of the stereogenic centres. This offers good
prospects for the concept of reading and erasing chiral
Spectroscopic Studies
[
10a,25]
information in the supramolecular assembly.
of achiral are also CD silent, as expected (Figure 3c, solid
line). On the other hand, CD spectroscopy shows that
nanotubes of chiral amphiphile in water, exhibit Cotton
Nanotubes
After having confirmed that nanotubes could be formed at
1
different ratios of
studied (Figure 3).
1 and 2, the spectroscopic properties were
2
effects with negative maxima at λ = 303, 256 and 225 nm and a
positive maximum at λ = 208 nm (Figure 3c, dashed line).
Subsequently, sergeant-soldier experiments were performed
to investigate if a small fraction of chiral
chirality in the otherwise achiral nanotubes of
5% of in the co-assembled aggregates, the mixed
nanotubes are indeed chiral as shown by plotting the CD
maximum (303 nm) as function of the fraction of (Figure 3d).
Nanotubes with less than 25% of , however, do not show any
CD signal and plotting the CD maximum (λ = 303 nm) as a
function of the fraction of chiral component (Figure 3d),
reveals a similar relation as between the absorption and the
fraction of (Figure 3b). In contrast to the Uv-vis absorption,
which shows a sigmoidal relation with a sharp increase at 40%
of , however, the CD signal increases when the fraction of
exceeds 25% and reaches a maximum at
λ = 303 nm as a function of the fraction of 2 in co-assembled nanotubes of 1 35%, after which it decreases and reaches a constant value.
and (data was fitted to sigmoidal curve using Origin software).
c) CD spectra of nanotubes of 1 (solid line, 1.6·10 M in water) and 2
2
is able to induce
1. Starting at
2
2
2
2
2
2
Figure 3. UV-vis absorption and CD spectra of nanotubes of 1 and 2.
-
4
2
a) UV-vis absorption spectra of assemblies of pure 1 (solid line, 1.6·10 M in
-4
water) and pure 2 (dashed line, 1.6·10 M in water). b) Absorption at chiral compound
2
2
Above a fraction of 50% of
homogeneous and no differences could be observed for tubes
that consist of 50–100% of the chiral amphiphile (Figure 3d).
function of the fraction 2 in co-assembled nanotubes of 1 and 2. Figure 4 shows a schematic model for the observed behaviour
2, the nanotubes appear to be
-4
-4
-5
(
dashed line, 1.6·10 M in water) and a solution of 2 (dotted line, 2.5·10
M
2
in CHCl ; cut-off for CHCl is λ = 260 nm). b) CD maximum at λ = 303 nm as a
3
3
Measurements were performed in triplo and error bars are shown.
and properties of nanotubes consisting of achiral
with DOPC in a ratio of 1:1 amphiphile:DOPC) as a function of
the fraction of
1 and chiral 2
(
Larger aggregates scatter more light and consequently, the
2
.
[
24]
baseline in absorption spectra increases.
samples of pure chiral show more scattering than those of
pure achiral (Figure 3a), indicating the formation of the
Self-assembled
2
1
relatively large bundles of nanotubes, consistent with the
observations by cryo-TEM (Figure 2). Mixed nanotubes that
are composed of < 50% the chiral amphiphile
absorption spectra as pure (see Supporting Information for
all UV-vis absorption spectra). Plotting the absorption
λ = 303 nm) as a function of the fraction of chiral amphiphile
in the mixed nanotubes, reveals a significant increase in
scattering when the fraction of exceeds 40%, with an
2 show similar
1
(
2
2
undulation point at 47% (calculated by fitting a sigmoidal curve
in Origin software; Figure 3b). Interestingly, the absorption
remains nearly unchanged when increasing the fraction of
chiral
2 from 50% to 100% (Figure 3b), which leads us to
propose that a homogeneous population of bundled, shorter Figure 4. Schematic model for the observed behaviour of nanotubes
consisting of achiral 1 and chiral 2 (with DOPC in a ratio of 1:1
nanotubes is formed when chiral
2 is the major component,
amphiphile:DOPC) as a function of the amount of 2. a) Pure 1; long, isolated
achiral nanotubes. b) 25% 2; long, isolated achiral nanotubes.
c) 25–50% 2; long, isolated chiral nanotubes. d) > 50% 2; short, bundled
chiral nanotubes. e) Pure 2; short, bundled chiral nanotubes.
while the formation of longer, isolated nanotubes is favoured
when the tubes mainly consist of achiral . This is in
agreement with the observation of more bundled, shorter
<
1
4
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Cryo-TEM showed that the mixed nanotubes are micrometres under the given conditions. We hypothesise that upon initial
long (Figure 2) until becomes the major component (> 50%) irradiation, few molecules are cyclised and disassembly of the
and it was hypothesised that mixtures of the amphiphiles nanotubes initiates after certain threshold of
containing less than 50% of lead to the formation of long, photochemically cyclised amphiphile is reached. After the lag
chiral nanotubes (Figure 4c), which causes a sharp increase in period, initial disassembly is relatively fast and slows down in
CD signal after exceeding a threshold of 20% of (Figure 3d). time. After approximately 2–3 h, the samples are CD silent, the
In the long nanotubes, the CD signal is more pronounced than chiral information in the system erased due to disassembly of
2
a
2
2
[
26]
in the short nanotubes.
Apparently, the long nanotubes the tubes.
(larger aggregated structures) have a higher preference for the
absorption of light of a particular handedness, compared to
the shorter nanotubes, which leads to a maximum value for
the CD signal at 35% of 2. At higher fractions of chiral 2, an
increase in absorption is observed, signifying the appearance
of shorter, bundled tubes and a consequent decrease in CD as
in the short nanotubes, the chirality is less pronounced. When
2
is the major component (> 50%) in the mixed tubes, both the
UV-vis absorption (Figure 3b) and CD spectra (Figure 3d)
become nearly constant, indicating that further increasing the
fraction of chiral component
2 in the mixed nanotubes does
not result in different self-assembled structures (Figure 4d-e).
These results show that chirality is a distinctive factor in
controlling the length of individual self-assembled nanotubes,
the aggregation of nanotubes and the chirality of the
assembly.
The core of amphiphiles
1 and 2 is photoresponsive and can
undergo a cyclisation reaction induced by light (see Supporting
Information Figure S19 for details) which affects the packing in
the nanotubes. We were interested to see if nanotubes of
and mixtures of these compounds can be disassembled by
light. In addition, as nanotubes of and mixed nanotubes of
and , where the fraction of is higher than 25%, show a
1, 2
2
1
2
2
significant CD signal, light-triggered disassembly of the chiral
nanotubes would provide a way to erase the chiral information
with light, offering intriguing possibilities for the development
[27]
of soft memory devices. We followed the disassembly of the
different nanotubes in real time, using widefield fluorescence
microscopy and CD spectroscopy, showing the transition from
nanotubes to less defined, larger aggregates (Figure 5). As
expected, long nanotubes were observed for samples of pure
1
(with DOPC 1:1, Figure 5a), while the shorter nanotubes of
pure
2 (with DOPC 1:1, Figure 5c) showed large clusters of
nanotubes in accordance with observations by cryo-TEM Figure 5. Photochemical disassembly of self-assembled nanotubes in water
(
Figure 2b). Irradiation in situ leads to the deformation, and followed in time by widefield fluorescence microscopy (a–d) and CD
spectroscopy (e). a) Image of pure 1 with DOPC (1:1) before irradiation.
ultimately disassembly, of the isolated nanotubes of pure
1
Isolated nanotube indicated with a red arrow. b) As in (a) after irradiation
t = 53 s, λirr = 390 nm). c) Image of pure 2 with DOPC (1:1) before
irradiation. d) As in (c) after irradiation (t = 53 s, λirr = 390 nm). e) Low
although visualisation of this process is complicated by their intensity irradiation (λirr = 265 nm, 8 W) of long chiral nanotubes
(
Figure 5b). Nanotube aggregates of pure
2 change
(
morphology under the same conditions as well (Figure 5d),
-4
size and the resolution of the microscope. For the concomitant (1:2:DOPC 0.65:0.35:1, blue diamonds, 1.6·10 M) and short chiral
-
4
nanotubes (1:2:DOPC 0.45:0.55:1, red squares, 1.6·10 M); inset is an
expansion of t = 0–4 min.
CD measurements (Figure 5e), nanotube samples containing
5% and 55% of were diluted and irradiated with low
3
2
intensity UV light (λirr = 265 nm, 8 W, see Supporting
Information). Note that the light intensity of the widefield
microscopy setup is much higher, and the wavelength
different, than that of the low intensity UV lamp, causing
faster disassembly (Figure 5a–d compared to Figure 5e, further
details in the Supporting Information). Both long and short
chiral nanotubes show a lag period for disassembly of 2 min
Conclusions
In summary, the design, synthesis and study of nanotube-
forming light-responsive amphiphiles in which chirality can be
used as a means to control the morphology of self-assembled
structures is presented. To the best of our knowledge, this
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comprises the first example of such nano-objects where the
point chirality (stereogenic centre) is present in the
hydrophobic part of the amphiphiles, much like in natural
membranes. We hypothesise that the hydrophobic volume of
T. Shibata, in Catalytic Asymmetric Synthesis, John Wiley &
Sons, Inc., Hoboken, N.J, USA, 2010, pp. 891–930.
(a) F. Helmich, M. M. Smulders, C. C. Lee, A. P. H. J.
6
Schenning and E. W. Meijer, J. Am. Chem. Soc. 2011, 133
2238; (b) F. García, P. M. Viruela, E. Matesanz, E. Ortí and
L. Sánchez, Chem. Eur. J. 2011, 17 7755;
,
1
the chiral amphiphile
achiral amphiphile , due to the two methyl moieties in C2 of
the hydrophobic tails. The increase in hydrophobic volume
distorts the long range packing of amphiphile , unlike in other
2
is increased, compared to that of the
–
,
1
(c) A. L. Nussbaumer, D. Studer, V. L. Malinovskii and
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We thank W. A. Velema and Dr. W. Szymański for insightful
comments and useful discussions. This work was supported by
the European Research Council (Advanced Investigator grant
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