Size-regulable vesicles based on anion-π interactions

Article abstract of DOI:10.1002/chem.201400074

Taking tetraoxacalix[2]arene[2]triazine as a functionalization platform, a series of new amphiphilic molecules were synthesized in 18 to 53% yields by using a fragment coupling protocol. These amphiphilic molecules self-assembled into stable vesicles in a

Full text of DOI:10.1002/chem.201400074

DOI: 10.1002/chem.201400074
Full Paper
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Vesicles
Size-Regulable Vesicles Based on Anion–p Interactions
Qing He,[a] Yuchun Han,[b] Yilin Wang,[b] Zhi-Tang Huang,[a] and De-Xian Wang*[a]
Abstract: Taking tetraoxacalix[2]arene[2]triazine as a func-
tionalization platform, a series of new amphiphilic molecules
were synthesized in 18 to 53% yields by using a fragment
coupling protocol. These amphiphilic molecules self-assem-
bled into stable vesicles in a mixture of THF and water, with
the surface of the vesicles engineered by electron-deficient
cavities. Various anions are able to selectively influence the
size of self-assembled vesicles, following the order of FÀ <
ClO4À <SCNÀ <BF4À <BrÀ <ClÀ <NO3À, as revealed by DLS
measurements. Such a sequence was independent with the
hydration cost and in agreement with the binding strength
of anions with tetraoxacalix[2]arene[2]triazine host molecule,
indicating that the anion–p interaction most probably com-
peted over other possible weak interactions and accounted
for this interesting selectivity. In addition, the chloride per-
meation process across the membrane of the vesicles was
also preliminarily studied by means of fluorescent experi-
ments. This study, in addition to providing the potentiality
of heteracalixaromatics as new models to construct function-
al vesicles, opens a new avenue to study the anion–p inter-
actions in aqueous and also potentially in living systems.
face recognition[5d,6a,b,8b] and the sequential aggregation,[6e] and
responsiveness to external stimuli.[6d,7d,i,8d] Heteracalixaromatics
are an emerging generation of macrocyclic host molecules in
supramolecular chemistry.[10–12] In contrast to conventional cal-
ixarenes, the introduced heteroatoms, instead of the methyl-
ene moieties on the bridges of the macrocycles, result in the
formation of unique cavities of varied conformations.[11a] The
electronic nature of the bridging heteroatoms also enables the
macrocylic molecules to self-adjust their conformations to best
fit the guests, leading to versatile molecular recognition prop-
Introduction
Anion–p interactions are new motifs in supramolecular chemis-
try. Since the first theoretical studies by Mascal, Deyꢀ, and Al-
korta, the past decade has witnessed an increasing interest in
anion–p interactions.[1] Whereas experimental evidences ob-
tained from several groups including ourselves have substanti-
ated the existence, generality, binding strength, and structure
of anion–p interactions,[2] exploration of the applications of
anion–p interactions in the functional molecular and supra-
molecular systems is one of the biggest challenges in the
field.[1k,3] In this respect, the groups of Matile[1k,4a–c] and Balles-
ter[4b] have reported examples of ion channels and catalysis
based on anion–p interactions. However, application of anion–
p interactions to the regulation of supramolecular assemblies
is lacking.
erties towards various guests.[11,2c–e] As
a representative
member of heteracalixaromatics, tetraoxacalix[2]arene[2]tri-
azine adopts a 1,3-alternate conformation with the two triazine
rings forming an electron-deficient V-shaped cleft.[12] In addi-
tion, the cleft has been shown to serve as a pair of tweezers to
interact with the included anions through cooperative anion–p
and lone-pair electron–p interactions, depending on the
nature and geometry of anions.[2c,e] Our interests in anion–p in-
teractions and cell membrane mimicry led us to carry out the
current study. We envisioned that the unique structure, func-
tionalization, and anion-recognition properties of tetraoxaca-
lix[2]arene[2]triazine would make it an ideal molecular architec-
ture for the construction of vesicles. The vesicles, bearing only
anion-p interaction motifs on the surface, provide a pure
model to study the anion effects on the properties of vesicles
based on anion–p interactions. Reported herein is an unprece-
dented example of the regulation of vesicles using the emerg-
ing, new-type of anion–p interaction.
Owing to the host–guest recognition properties of macrocy-
clic hosts (including crown ethers,[5] cyclodextrins,[6] calixarenes
and resorcinarenes,[7] cucurbiturils[8] and pillararenes),[9] amphi-
philic molecules, consisting of such a macrocyclic core struc-
ture, have been used to fabricate vesicles. As a consequence,
the resulting vesicles show unique characteristics, such as sur-
[a] Q. He, Prof. Z.-T. Huang, Prof. D.-X. Wang
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing, 100190 (P.R. China)
E-mail: dxwang@iccas.ac.cn
[b] Dr. Y. Han, Prof. Y. Wang
Key Laboratory of Colloid and Interface Science, Institute of Chemistry
Chinese Academy of Sciences, Beijing, 100190 (P.R. China)
Results and Discussion
The target amphiphilic macrocyclic molecules were readily ob-
tainable by the introduction of long alkyl chains on the larger
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400074.
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rims of tetraoxacalix[2]arene[2]triazine. We chose a secondary
amido group as the linker between the polar macrocyclic head
and the hydrophobic tail with the purpose of regulating the
self-assembly through intermolecular hydrogen bonds. An effi-
cient fragment coupling protocol was applied for the prepara-
tion of the molecules. We initiated the synthesis of the trimers
3a–f from the treatment of 1a–f (for synthesis of 1a–f, see
Scheme S2 in the Supporting Information) with cyanuric chlo-
ride 2, as illustrated in Scheme 1. In the presence of diisopro-
of the aggregates formed with each compound. The exceed-
ingly large diameters of the aggregates in comparison with
the extended molecular length (1.61–2.85 nm, Figure S28, the
Supporting Information) suggested that the amphiphilic mole-
cules form vesicles rather than micelles. Spherical morpholo-
gies of the vesicles were confirmed with SEM (Figure 1A and
Figures S1–S5, the Supporting Information) and TEM (Figure 1B
and Figures S9–S14, the Supporting Information), and the ob-
served diameters of the spheres are in agreement with the
DLS results. In addition, as re-
flected by the images in Fig-
ure S14 (the Supporting Informa-
tion), the sharp contrast be-
tween the periphery and center
of the spheres verifies the
hollow vesicular feature. In the
case of 4 f, moreover, collapsed
spheres were observed, which
also support the hollow feature
of the vesicles (Figures S5 and
S13, the Supporting Informa-
tion). Furthermore, laser scan-
ning confocal microscopic ex-
periments (LSCM) were per-
formed by preparing the vesicles
in a solution containing lucige-
nin followed by repeated dialysis
to remove the fluorescent agent
outside the vesicles. Blue spots
were observed in Figure 1C and
Scheme 1. Synthesis of molecules 4a–h.
Figures S18–S22 (in the Support-
ing Information), corresponding
pylethylamine (DIPEA) as an acid scavenger, 1a–f underwent
nucleophilic aromatic substitution smoothly with two equiva-
lents of cyanuric chloride 2 at 08C to afford the corresponding
intermediates 3a–f in yields ranging from 30 to 52%. A 3+
1 fragment coupling reaction was then performed by treating
the trimers 3a–f with the corresponding monomers 1a–f at
room temperature to give the desired compounds 4a–f in 18
to 53% yields. As a comparison, compounds 4g and 4h with
tetradecyloxyl and N-methyl-N-tetradecyl formacyl groups at-
tached on the larger rim of benzene rings of tetraoxacalix[2]ar-
ene[2]triazine were also synthesized under similar reaction con-
ditions (Scheme 1 and Schemes S3 and S4, the Supporting In-
formation).
to the entrapped dye inside the vesicles. The above outcomes
confirmed the formation of the vesicles. In addition, such vesi-
cles are stable for over four months at ambient temperature
with the vesicular morphology remained almost unchanged as
With the amphiphilic molecules 4b–f in hand, we investigat-
ed their self-assembly systematically. The compounds 4b–f
were firstly dissolved in tetrahydrofuran (THF; 0.3 mL), followed
by the addition of water (0.7 mL). The final concentration of
4b–f is 5.0ꢂ10À5 m. The mixtures were then placed in an ultra-
sonic bath for 30 min, yielding a slightly cloudy suspension
that remained stable for at least four months at ambient tem-
perature. DLS experiments revealed that the average hydrody-
namic diameters of the aggregates are 569, 332, 239, 225, and
217 nm for 4b–f, respectively (Figure 1D and Figures S23–S27,
the Supporting Information). The measured polydispersities
(PDIs) are lower than 0.17, indicating a narrow size distribution
Figure 1. A) SEM, B) TEM, and C) LSCM images and D) DLS result of aggre-
gates prepared from 4c in a mixture of THF and H2O (3:7, v/v).
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revealed by SEM experiments (Figure S8, the Supporting Infor-
mation).
To shed light on the mechanism of the self-assembly of am-
phiphilic molecules 4b–f into vesicles, a series of studies were
performed. As illustrated by the Corey–Pauling–Koltun space-
filling (CPK) models in Figure S28 (the Supporting Information),
the molecular mechanics calculation shows that the extended
lengths of the molecules are 1.61, 2.11, 2.36, 2.61, and 2.85 nm
for 4b–f, respectively. On the basis of the small-angle X-ray
scattering (SAXS) results illustrated in Figure S29 (the Support-
ing Information), the thicknesses of the vesicle membrane are
3.11, 3.35, 3.76, 3.85, and 4.26 nm for 4b–f, respectively. The
measured thicknesses of the membranes are nearly double
that of the extended molecular length, indicating most likely
the formation of a double layer. We then examined the effect
of intermolecular hydrogen bonding on the regulation of the
vesicles. Amphiphilic compounds 4g and 4h derived of ester
or tertiary amido moieties, respectively, formed some irregular
aggregates instead of well-assembled vesicles as observed by
SEM (Figures S6 and S7, the Supporting Information) and TEM
(Figures S16 and S17, the Supporting Information), suggesting
that the secondary amido groups of 4b–f played important
roles on the formation of vesicles. To assist in understanding
the hydrogen-bonding details of the secondary amido groups
from molecular level, a single crystal of the model compound
4a bearing 3-C alkyl chains on the larger rims of tetraoxaca-
lix[2]arene[2]triazine was cultivated through slow evaporation
of a methanol solution. As illustrated in Figure S30 (the Sup-
porting Information), compound 4a adopts a 1,3-alternate
conformation with the two triazine rings forming a V-shaped
electron-deficient cavity, similar to its parent molecule tetraox-
acalix[2]arene[2]triazine.[12] The long distances between NÀH
atoms and carbonyl oxygen atoms of 4.619 ꢃ (dO5ÀO8) and
4.785 ꢃ (dO6ÀN7), respectively, exclude the formation of intramo-
lecular hydrogen bonds between the secondary amido groups.
Surprisingly, the secondary amido groups of one molecule of
4a do not form intermolecular hydrogen bonds directly with
another molecule, but through a solvent (water or methanol)
molecule as a hydrogen bond bridge (Figure S30, the Support-
ing Information). The steric hindrance of the rigidity cavity of
4a and the rotation hindrance of the secondary amido groups
most probably leads to the formation of solvent-bridged hy-
drogen bonding. The observed intermolecular hydrogen
bonds of 4a suggest that the secondary amido groups of 4b–f
contributed to the formation of vesicles probably also through
an intermolecular hydrogen-bond network among secondary
amido moieties and water bridges. Together with the hydro-
phobic effect of long alkyl chains, intermolecular hydrogen
bonds provide possible driving forces for the formation of vesi-
cles. A postulated structure of the vesicle is illustrated in
Figure 2.
Figure 2. Schematic illustration of the vesicle.
Figure 3. DLS measurements for: A) effect of NaCl on the vesicular size distri-
bution of 4b–f, and B) effect of various anions on the diameter of vesicles of
4d.
of hydrodynamic diameter with and without the salt) of the
aggregates corresponding to 4b–f, respectively, increased with
the increasing sodium chloride concentration, indicating the
formation of larger aggregates, as depicted in Figure 3A. To in-
vestigate the selective interaction between vesicles and ions,
compound 4d was applied as a representative example and
treated with various anions (as sodium salts). Figure 3B shows
that different anions affect the aggregate sizes (expressed as
As illustrated in Figure 2, one unique feature of the resulting
vesicles is the location of V-shaped clefts or cavities of macro-
cyclic tetraoxacalix[2]arene[2]triazine on the surface.[7j] Encour-
aged by the anion-binding properties of the macrocyclic archi-
tecture,[2c–e] interactions of the vesicles and anions were then
investigated. The relative size distribution (expressed as ratio
hydrodynamic diameter) in a selective manner, with incre-
À
ments of the aggregates following the order of FÀ <ClO4
<
SCNÀ <BF4À <BrÀ <ClÀ <NO3À. Such a sequence is in contrast
to anion effects on membranes containing positively charged
or neutral (zwitterionic) phospholipids, in which Hofmeister
series are mostly obeyed.[13] For example, the most hydrated
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FÀ only marginally affects the size of aggregates. The free hy-
À
dration energy of NO3 (ÀDGhydr =306 kJmolÀ1) is lower than
that of ClÀ (ÀDGhydr =347 kJmolÀ1
)
and BrÀ (ÀDGhydr
=
À
321 kJmolÀ1),[14a] but NO3 most strongly affects the aggregate
sizes. In another case, BF4À, an anion has smallest free hydra-
tion energy (ÀDGhydr =200 kJmolÀ1) in the investigated anion
list,[14b] causes larger increments of the aggregate sizes over
SCNÀ and ClO4À. The outcomes indicated consequently that
among the interactions between surface (macrocyclic cavities),
anions and solvents, the interaction between anions and mac-
rocyclic cavities most probably play more important roles. In
our previous report, we have demonstrated that the V-shaped
electron-deficient cavity of the parent tetraoxacalix[2]arene[2]-
triazine (host) served as a pair of tweezers to selectively inter-
act with the included anions, giving the binding constants in
the order of host·SCNÀ (239mÀ1) <host·PF6 (291mÀ1) <
À
À
host·BF4 (673mÀ1)< host·FÀ (4036mÀ1) <host·ClÀ (4246mÀ1)
À
<host·NO3 (16950mÀ1).[2c,e] The effect of anions on the size of
aggregates, hence, is almost in agreement with the order of
binding constants, with the exception of fluoride, in which the
host–FÀ interaction was extremely prohibited owing to its
strong hydration in the aqueous system. The host–anion rec-
ognition study also provided an explanation of selective anion
influence on the vesicles from molecular level.[2e] According to
À
Figure 4. A) Normalized fluorescence intensity of lucigenin inside the vesi-
cles of 4d in response of transmembrane ClÀ permeation. Line a: initial nor-
malized intensity of lucigenin included in the vesicles. Line d: normalized in-
tensity of lucigenin after injection of NaCl (5 mL). Line c: normalized intensity
of lucigenin after injection of NaCl (10 mL). Line b: normalized intensity of lu-
cigenin after dialysis to remove NaCl outside the vesicle. Line e: re-injection
of NaCl (5 mL) after dialysis. The inset shows the variations of the normalized
fluorescence intensity at 506 nm with each step of the experimental proce-
dures. B) Schematic illustration of anion permeation across the membrane.
the crystal structure of the host·NO3 complex reported else-
where,[2e] nitrate interacts with the triazine rings through stron-
gest cooperative noncovalent and dual weak s-type anion–p
interactions, leading to its largest binding strength (up to
16950mÀ1) with the macrocyclic cavity. Host–anion crystal
structures also revealed that though both BF4 and SCNÀ
À
formed dual noncovalent anion–p interactions with the host
molecule, the former was in a more cooperative manner judg-
ing from the self-tuning of the cavity, and hence a larger bind-
ing constant. The above discussions indicated that anion–p in-
teraction most probably competed over other possible weak
interactions and account for this interesting selectivity. The af-
finity of anions on the surface of the vesicle was further con-
firmed by the Zeta (z) potential measurements. The measured
negative z potentials listed in Table S1 (the Supporting Infor-
mation) indicate indeed that the initially neutral surface of the
vesicles become negatively charged in salt solutions. The pro-
cedure, however, is not fully clear currently for the formation
of larger aggregates (Figure S15, the Supporting Information)
upon the affinity of anions, the change of the surface z poten-
tial of the vesicles should be one of the contributions.
tion of chloride across the vesicle membrane from outside to
inside, driven by the concentration gradient. Dialysis was then
carried out to remove the salt outside the vesicles. Such proce-
dure led to the reversed concentration gradient across the
membrane. Consequently, the partially recovered intensity of
lucigenin (line b) was observed from Figure 4A, which was
probably due to the release of chloride from inside the vesi-
cles. After dialysis, another treatment of the vesicles with NaCl
(5 mL, 2.5m) quenched the emission of lucigenin again (Fig-
ure 4A, line e). The repeated procedure is illustrated in the
inset graph of Figure 4A. Figure 4B gives a schematic illustra-
tion of the transmembrane permeation of chloride.
Encouraged by the observations of anion effect on vesicle
sizes caused by affinity of anions on the surface, we then ex-
plored the sequential anion permeation through the mem-
brane using a fluorescence protocol (Figure 4). Lucigenin, a se-
lective fluorescent sensor for chloride, was incubated with 4d
during the preparation of vesicles. The fluorescent reagent out-
side the vesicles was removed through repeated dialysis. As il-
lustrated in Figure 4A, after addition of NaCl (5 mL, 2.5m) to
the vesicle-containing solution (2 mL), the emission of inside
lucigenin at 506 nm was quenched dramatically (line d). Fur-
ther quenching (Figure 4A, line c) was observed with addition
of another aliquot of NaCl (5 mL, 2.5m), proving the permea-
Conclusion
Unique vesicles, with surfaces that are engineered by synthetic
anion receptors, that is, tetraoxacalix[2]arene[2]triazines, have
been successfully fabricated. Various anions were able to selec-
tively influence the size of self-assembled vesicles through the
noncovalent anion–p interactions. To the best of our knowl-
edge, this is an unprecedented example of the regulation of
vesicles by using anion–p interactions. In addition, anion per-
meation across the membrane of the vesicles was also prelimi-
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Experimental Section
General procedures for the synthesis of 4a–f
Both solutions of 3a (0.84 g, 1.7 mmol) and 1a (0.33 g, 1.7 mmol),
3b (0.40 g, 1.5 mmol) and 1b (0.85 g, 1.5 mmol), 3c (0.69 g,
1.1 mmol) and 1c (0.36 g, 1.1 mmol), 3d (0.95 g, 1.5 mmol) and 1d
(0.37 g, 1.5 mmol), 3e (0.68 g, 1.0 mmol) and 1e (0.38 g, 1.0 mmol),
3 f (0.71 g, 1.0 mmol) and 1 f (0.41 g, 1.0 mmol), respectively, in
acetone (100 mL) were added dropwise to
a solution of
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2.6 mmol for 4e and 4 f) in acetone (250 mL) within 8 h. The result-
ing mixtures were stirred at room temperature for another 48 h.
After removal of the solvent under vacuum, the residue was chro-
matographed on a silica gel column (100–200 mesh) with a mixture
of petroleum ether and ethyl acetate (10/1, v/v) as eluent to give
pure 4a (0.22 g, 21%), 4b (0.26 g, 22%), 4c (0.18 g, 18%), 4d
(0.38 g, 28%), 4e (0.52 g, 53%), and 4 f (0.69 g, 30%) as white
solids.
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Preparation of vesicles
The compounds 4b–f, respectively, were dissolved in tetrahydro-
furan (THF, 0.3 mL), followed by the addition of water (0.7 mL). The
final concentration of 4b–f is 5.0ꢂ10À5 m. The mixtures were put
under supersonic for about 30 min, yielding a slightly cloudy sus-
pension. The resulting vesicle suspension was dried for SEM and
TEM experiments.
Acknowledgements
We thank the NNSFC (91127008, 21272239), MOST
(2011CB932501, 2013CB834504) for financial support. We also
thank Dr. Xiaojun Huang and Dr. Gang Ji from CBI, IBCAS for
cryo-TEM measurements.
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Received: January 8, 2014
Published online on && &&, 2014
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FULL PAPER
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Vesicles
Q. He, Y. Han, Y. Wang, Z.-T. Huang,
D.-X. Wang*
&& – &&
Size-Regulable Vesicles Based on
Anion–p Interactions
Accommodating hosts: Vesicles with
surfaces engineered by tetraoxacalix[2]-
arene[2]triaizines were fabricated (see
figure). The sizes of the vesicles are re-
sponsive to various anions, following
BrÀ < ClÀ < NO3À. This study gives an
unprecedented example of the regula-
tion of vesicles by using the emerging,
new-type anion–p noncovalent interac-
tions.
À
À
the order FÀ < ClO4 < SCNÀ < BF4
<
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
7
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ