Redox-responsive morphology transformation of self-assembled nanostructures based on thiol-disulfide interconversion

Article abstract of DOI:10.1016/j.tetlet.2012.06.063

One dimensional (1D) nanotubes and three dimensional (3D) flowerlike supernanostructures were transformed reversibly, which was controlled by the oxidation and reduction cycle of aromatic diamide-derived thiol 1 and disulfide 2, as evidenced by SEM study.

Full text of DOI:10.1016/j.tetlet.2012.06.063

Tetrahedron Letters 53 (2012) 4447–4451
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Redox-responsive morphology transformation of self-assembled
nanostructures based on thiol-disulfide interconversion
⇑
⇑
Zhi-Gang Tao, Ze-Yun Xiao, Xin Zhao , Xi-Kui Jiang, Zhan-Ting Li
State Key Lab of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
One dimensional (1D) nanotubes and three dimensional (3D) flowerlike supernanostructures were
transformed reversibly, which was controlled by the oxidation and reduction cycle of aromatic dia-
mide-derived thiol 1 and disulfide 2, as evidenced by SEM study. Their self-assembling patterns were
investigated by UV–vis, 1H NMR, X-ray crystallographic, and powder X-ray diffraction experiments.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 19 March 2012
Revised 31 May 2012
Accepted 12 June 2012
Available online 18 June 2012
Keywords:
Redox-responsive
Self-assembly
Nanostructures
Thiol-disulfide interconversion
Morphology transformation
Materials that can respond to external input have aroused con-
siderable interest in the past decades due to their crucial role in fun-
damental understanding of the stimuli-responsive phenomena of
biomolecules as well as practical application in fabricating the so-
called ‘smart materials’, which can adapt themselves to the change
of surroundings.1 In this context, molecular self-assembly, a process
that individual molecules are drawn together by noncovalent inter-
actions to form well-ordered aggregates, was regarded as an ideal
tool for the fabrication of such dynamically tunable materials
because the reversibility and weak binding strength of noncovalent
bonds usually enable self-assembled structures readily responsive
to the change of the environmental conditions. Up to date, a range
of stimuli, including changes in pH,2 temperature,3 concentration,4
polarity of medium,5 the formation of charge-transfer complex,6 or
even the application of external forces, such as shear, sonication or
agitation,7 have been employed to achieve efficient transformation
between assembled entities of distinctly different morphologies.
The examplesabove are mainly based on aggregates assembledfrom
identical building blocks and concerned on changes of noncovalent
interactions. We envisioned thatthe stimuli-responsive transforma-
tion should also be accessed for the entities assembled from
different building blocks, as long as the blocks themselves can
interconvert when exposed to external stimuli. For this require-
ment, the ‘dynamic covalent bond’ such as S–S should work well
due to its feature of reversible formation and cleavage upon
oxidation/reduction.8 By exploiting this advantage, Yang and co-
workers reported the fabrication of hydrogels in a homogeneous
and controllable way by reductive cleavage of the disulfide bond
which connects a hydrogelator and a hydrophilic molecule.9 Nilsson
and Bowerman demonstrated that the transformation of conforma-
tionally constrained cyclic peptides to unconstrained b-strand linear
peptides via reduction of disulfide led to the formation of hydro-
gels.10 However, the strategy employed in these examples just made
use of unidirectional process, this is, the reductive cleavage of disul-
fide bond. To further exploit the potential of the dynamic character
of disulfide bond for the constructionof responsive materials, we be-
came interested in developing the bidirectional process of both
reductive cleavage and oxidative formation of disulfide bond,
through which transformation between two well-defined structures
with distinctly different morphologies could be controlled revers-
ibly. We herein report that the reversible transformation between
1D nanotubes and 3D flowerlike supernanostructures can be regu-
lated via oxidation/reduction of thiol and disulfide, which repre-
sents a promising approach to controlling transformation between
two distinct nanostructures.
The structures used in this study are shown in Scheme 1. We
previously found 5-(benyloxy or isobutyloxy) substituted isoph-
thalamide could self-assemble into fine nanotubes in methanol.11
In the present study, the 5-position of the parent isophthalamide
was substituted with (4-mercapto-butyloxy) to give thiol 1 (see
ESI for the synthesis and characterizations), and thiol 1 could be
further oxidated to generate disulfide 2.12
⇑
Corresponding authors. Tel.: +86 21 54925023; fax: +86 21 64166128.
E-mail addresses: xinzhao72@yahoo.com, xzhao@mail.sioc.ac.cn (X. Zhao),
Initially, the self-assembly of thiol 1 and disulfide 2 in methanol
was investigated. Scanning electron microscopy (SEM) was
ztli@mail.sioc.ac.cn (Z.-T. Li).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.063

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Z.-G. Tao et al. / Tetrahedron Letters 53 (2012) 4447–4451
SH
S
S
O
O
O
O
O
O
O
O
O
NH
HN
NH
HN
NH
HN
1
2
Scheme 1. Chemical structures of compounds 1 and 2.
employed to characterize the morphology of the assembled struc-
tures. The samples were prepared by drop-casting of their metha-
nol solution onto freshly cleaved mica surface. The respective
images are illustrated in Figure 1. SEM images showed that com-
pound 1 self-assembled into 1D nanotubes with hundreds of nano-
meters in width and tens of microns in length. Their hollow nature
was readily evidenced by their open-ended features (Fig. 1a–b) and
was further confirmed by high-resolution TEM, which exhibited a
clear contrast between their inner and outside areas (Fig. 1d). How-
ever, under similar conditions, disulfide 2 gave rise to 3D flower-
shaped supernanostructures. As shown in Figure 1c, the ‘flower’
is constituted by multiple petals of hundreds of nanometers in
width, and the size of the whole ‘flowers’ is larger than 5 microns
(‘microflowers’). The different shape and dimension of the aggre-
gates fabricated from the thiol and disulfide thus create a favorable
platform on which the transformation of nanostructures with
distinctly different morphologies could be processed. The influence
of conditions for self-assembly on the formation of nanostructures
was also investigated. It was found that changing concentration or
PH did not have significant impact on the morphologies of the self-
assembled aggregates (ESI, Fig. S1–2).
thiol to disulfide (step 1). After stirring at room temperature for
0.5 h, the aggregates formed in solution was then subjected to
SEM observation, which revealed that the nanotubes totally
disappeared, while flowerlike supernanostructures were observed
( Fig. 2a), which should be generated from the self-assembly of
disulfide 2 in methanol. The as-prepared solution above was then
mixed with 60 equiv of dithiothreitol (DTT) (step 2), a strong
reducing reagent that can reduce disulfide to thiol. The morphol-
ogy of the assembled entities after reduction was characterized
by SEM again, which showed that tubular structures came back
while ‘microflowers’ totally disappeared (Fig. 2b). The above solu-
tion could be oxidized again with 50 equiv of iodine (step 3). For
the resulting solution, ‘microflowers’ were observed again and
tubular structures could not be found with SEM (Fig. 2c). These
results clearly demonstrated that well-controlled morphology
transformation of the two different nanostructures could be real-
ized on the basis of simple oxidation/reduction of thiol and disul-
fide. Because the accumulation of the oxidant and reductant had
an interference on the SEM observation, no further oxidation/
reduction cycle was performed after step 3.
In order to get insight to the assembling mechanism, 1H NMR
and UV–vis spectroscopies were used to probe the packing model
of the molecules in the aggregates. Compared to that in chloro-
form, in which aromatic stacking is reported to be weak,14 blue
shift and remarkable hypochromism effect were observed for both
1 and 2 in methanol (ESI, Fig. S3). This result provided evidence for
Compounds 1 and 2 can be interconverted reversibly via oxida-
tion and reduction.13 Thus, we further investigated if this intercon-
version could cause in situ reversible transformation between
different nanoscale architectures. In order to test this possibility,
0.5 equiv of iodine was added into a solution of thiol 1 to oxidize
Figure 1. SEM images of samples fabricated from (a) and (b) thiol 1 (2.0 mM), and (c) disulfide 2 (2.0 mM) in methanol, and (d) TEM image of sample obtained from thiol 1
(0.2 mM) in methanol.

Z.-G. Tao et al. / Tetrahedron Letters 53 (2012) 4447–4451
4449
a
c
b
d
Reduction
Oxidation
Oxidation
1
2
3
4
Cycles
Figure 2. SEM images of samples fabricated from (a) thiol 1 after oxidized by iodine, (b) further reduced by DTT, and (c) oxidized again by iodine, and (d) illustration of the
transformation process (j represents nanotubes, and ꢀ represents ‘microflowers’).
the
p
–
p
stacking of their aromatic cores and suggested H-type
of the nanotubes and ‘microflowers’, upon removal of the solvent
under the reduced pressure, exhibited the N–H stretching vibra-
tions around 3259 cmÀ1 (for nanotubes) and 3269 cmÀ1 (for
‘microflowers’), also indicating that the NH units were hydrogen-
bonded (ESI, Fig. S6 and S7). Attempts to grow single crystals from
1 and 2 suitable for the X-ray crystallography were not successful.
However, single crystals of compound 3 (Fig. 3), an analog of thiol
1, was grown by slow evaporation of its solution in methanol.16
aggregation (face-to-face stacking) arrangement of the mole-
cules.15 1H NMR dilution experiments for both compounds in chlo-
roform-d1 showed that the signals of the amides shifted downfield
while the protons of aromatic ring shifted upfield with the increase
of the concentration (ESI, Fig. S4 and S5), suggesting the amide pro-
tons were involved in the formation of intermolecular hydrogen
bonds and aromatic stacking existed. Furthermore, the IR spectra
O
b
O
O
3
NH
HN
a
Figure 3. The chemical structure of compound 3 and its packing structure in the single crystal: (a) viewing along a axis, and (b) viewing along b axis, highlighting the stacking
of molecules stabilized by hydrogen bonds and -stacking.
p

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Z.-G. Tao et al. / Tetrahedron Letters 53 (2012) 4447–4451
The crystallographic study on 3 revealed that the neighboring mol-
ecules were packed with each other in oppositely alternate man-
ner, which was stabilized by two pairs of hydrogen bonds: one
formed between oxygen of carbonyl and proton of amide with
the OÁ Á ÁH distance being 2.11 Å, while another formed between
oxygen of ethyloxyl and proton of amide with longer OÁ Á ÁH dis-
tance, being 2.42 Å (Fig. 3a–b). The crystal structure also revealed
that the aromatic units stacked in face-to-face manner with an
average distance of 3.44 Å, which is typical for the columnar stack-
ing of aromatic amides.17 The observation of hydrogen-bonding
and face-to-face stacking of benzene rings in the solid state of 3
is also consistent with the above 1H NMR and UV–vis results of 1
and 2 in solution, suggesting that the aggregates of 1 and 2 in solu-
tion should adopt similar molecular arrangement as that in the
crystal state of 3. On the basis of these results, we proposed that
the self-assembly of compounds 1 and 2 should be driven by their
self-assembling units, this is, the aromatic ring and the hydrogen-
bonding units, and the arrangement of their self-stacking of the
molecules might dictate a 1D growing process which firstly leads
to the formation of 1D ribbons and eventually evolves into nano-
tubes (Fig. 4).18 However, 2 bears two self-assembling units which
is connected by S–S bond. According to the reported crystal struc-
tures of several disulfides,19 the two substituents connected with
S–S bond adopt a roughly perpendicular conformation. We thus
proposed that the aromatic amide units of 2 adopted 1D stacking
at both ends of its disulfide, which resulted in a radial arrangement
of the molecules, leading to the formation of the flowerlike super-
nanostructures which can be regarded as radial arrangement of 1D
structures (Fig. 4). This assumption was supported by the powder
X-ray diffraction (XRD) analysis of 1 and 2 (Fig. 5). The as-prepared
nanotubes and ‘microflower’ displayed sharp diffraction peaks,
suggesting crystalline features of their aggregates. Diffraction
peaks near d-spacing of 3.4 Å were observed for both nanotubes
and ‘microflowers’, which are corresponding to the stacking.
p–p
The broad peak of the latter might reveal a less packed stacking
of aromatic units in the ‘microflowers’. Furthermore, both the
nanotubes and ‘microflowers’ also displayed diffraction peaks at
12.0 and 4.6 Å, further suggesting similar packing model for their
self-assembling units. Extra peaks at 6.0 and 4.9 Å were observed
for the ‘microflowers’ generated from 2, which might be corre-
sponding to some periodic arrangements deriving from its
branched packing (Fig. 4). Therefore, the transformation between
the two nanostructures is a result of the transformation between
the supramolecular building blocks, this is, thiol 1 and disulfide 2
under redox. Once thiol 1 is oxidized to disulfide 2, it adopts the
self-assembly behavior of disulfide to form ‘microflowers’. On the
other hand, the self-assembly property of thiol will be followed
to generate nanotubes after disulfide 2 is reduced to thiol 1.
In conclusion, by exploiting the advantage of the dynamic
feature of disulfide bond, the in situ reversible transformation be-
tween 1D and 3D nanostructures that respond to oxidation/reduc-
tion has been realized. This strategy, different from those reported
before, is built on the interconversion of supramolecular building
blocks in which the formation and cleavage of covalent bond are
involved. As demonstrated in this letter, the thiol-disulfide inter-
conversion can be exploited as a potential switch on which re-
dox-responsive system can be constructed. Although the example
shown here just concerns morphology transformation, reversible
interconversion between two functionalized systems constructed
on the basis of this strategy should also be expected. In this
context, supramolecular building blocks based on thiol and disul-
fide should be very promising to fabricate redox-responsive mate-
rials. Once well-defined self-assembling systems with certain
functions from derivatives of thiol and disulfide can be established
SH
O
O
O
1D
NH
HN
nanostructures
S
O
S
O
O
O
O
HN
NH
HN
O
3D
nanostructures
HN
Figure 4. Schematic representation of the formation of nanotubes and ‘microflowers’.

Z.-G. Tao et al. / Tetrahedron Letters 53 (2012) 4447–4451
4451
References and notes
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13. Procedure for the oxidative conversion of thiol 1 to disulfide 2: To a solution of
compound 1 (110 mg, 0.29 mmol) in methanol (10 mL), Et3N (1.0 mL) and
iodine (76 mg, 0.3 mmol) were added. The mixture was stirred at room
temperature until compound 1 was consumed. After removal of the solvent,
the resulting residue was dissolved in methylenechloride (30 mL), and then
washed with water (2 Â 10 mL), and saturated aqueous Na2SO3 (2 Â 10 mL)
and the organic phase was dried over anhydrous sodium sulfate. After removal
of the solvent with a rotavapor, the crude product was subjected to column
chromatography (methylenechloride/ethyl acetate, 20:1), to give compound 2
as a white solid (105 mg, 95%). 1H NMR (300 MHz, CDCl3): 1.45 (s, 36 H), 1.83–
1.93 (m, 8 H), 2.76 (s(br), 4 H), 4.01 (s(br), 4 H), 6.20 (s, 4 H), 7.27 (s, 4 H), 7.53
(s, 2 H). 13C NMR (75 MHz, CDCl3): 25.7, 27.9, 28.8, 38.6, 51.9, 67.8, 115.4,
116.8, 137.4, 159.0, 166.0. MS (ESI): 759.0 [M+H]+, 780.9 [M+Na]+. HRMS (ESI):
Calcd for C40H62N4NaO6S2: 781.40030. Found: 781.39973.
14. Procedure for the reductive conversion of disulfide 2 to thiol 1: A mixture of
compound 2 (30 mg, 0.04 mmol), dithiothreitol (731 mg, 4.7 mmol) and NEt3
(0.12 mL) in methanol (10 mL) was stirred under argon atmosphere until
compound 2 disappeared. The solvent was removed under reduced pressure
and the resulting residue was dissolved in chloroform (50 mL). The organic
phase was washed with water (2 Â 10 mL) and brine (10 mL) and then dried
over anhydrous sodium sulfate. After removal of the solvent with a rotavapor,
the crude product was subjected to column chromatography
(methylenechloride/ethylacetate, 30:1) to give compound 1 as a white solid
(27 mg, 90%).
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16. CCDC 807134 (Compound 3) contains the supplementary crystallographic data
for this paper. Copy of the data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.CCDC.cam.ac.uk/
data_request/cif.
Figure 5. Powder XRD patterns of the nanotubes formed from thiol 1 (top) and the
‘microflowers’ from disulfide 2 (bottom).
individually, the reversible transformation between the assembled
entities is readily accessed through oxidation and reduction cycle.
Acknowledgments
We thank NSFC (20972180, 20921091, 20974118), and the Sci-
ence and Technology Commission of Shanghai Municipality
(10PJ1412200) for the financial support.
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Meijer, E. W. Chem. Mater. 2001, 13, 2675.
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2011, 133, 2511.
Supplementary data
19. The crystallographic data for disulfides can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.CCDC.cam.ac.uk/
data_request/cif.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
063.