Hybrid Molecular Container Based on Glycoluril and Triptycene: Synthesis, Binding Properties, and Triggered Release

Article abstract of DOI:10.1002/chem.201802981

We designed and synthesized a “hybrid” molecular container 1, which is structurally related to both cucurbit[n]uril (CB[n]) and pillar[n]arene type receptors. Receptor 1 was fully characterized by ¹H NMR, ¹³C NMR, IR, MS and X-ray single crystal diffraction. The self-association behavior, host–guest recognition properties of 1, and the [salt] dependence of K_a were investigated in detail by ¹H NMR and isothermal titration calorimetry (ITC). Optical transmittance and TEM measurements provide strong evidence that receptor 1 undergoes co-assemble with amphiphilic guest C10 in water to form supramolecular bilayer vesicles (diameter 25.6±2.7 nm, wall thickness ≈3.5 nm) that can encapsulate the hydrophilic anticancer drug doxorubicin (DOX) and the hydrophobic dye Nile red (NR). The release of encapsulated DOX or NR from the vesicles can be triggered by hexamethonium (8 c) or spermine (10) which leads to the disruption of the supramolecular vesicles.

Full text of DOI:10.1002/chem.201802981

A Journal of
Accepted Article
Title: Hybrid molecular container based on glycoluril and triptycene:
synthesis, binding properties, and triggered release
Authors: Wenjin Liu, Xiaoyong Lu, Weijian Xue, Soumen K Samanta,
Peter Y Zavalij, Zihui Meng, and Lyle Isaacs
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201802981
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Hybrid molecular container based on glycoluril and triptycene:
synthesis, binding properties, and triggered release
Wenjin Liu,[a,b] Xiaoyong Lu,[b] Weijian Xue,[b] Soumen K. Samanta,[b] Peter Y. Zavalij,[b] Zihui Meng,*[a]
and Lyle Isaacs*[b]
Dedication ((optional))
Abstract: We designed and synthesized a “hybrid” molecular
container 1 which is structurally related to both cucurbit[n]uril (CB[n])
and pillar[n]arene type receptors. Receptor 1 was fully characterized
by 1H NMR, 13C NMR, IR, MS and X-ray single crystal diffraction.
The self-association behavior, host-guest recognition properties of 1,
and the [salt] dependence of Ka were investigated in detail by 1H
NMR and isothermal titration calorimetry (ITC). Optical transmittance
and TEM measurements provide strong evidence that receptor 1
undergoes co-assemble with amphiphilic guest C10 in water to form
supramolecular bilayer vesicles (diameter 25.6 ± 2.7 nm, wall
thickness ≈ 3.5 nm) that can encapsulate the hydrophilic anticancer
drug doxorubicin (DOX) and the hydrophobic dye nile red (NR). The
release of encapsulated DOX or NR from the vesicles can be
triggered by hexamethonium (8c) or spermine (10) which leads to
the disruption of the supramolecular vesicles.
cationic guests in aqueous solution, as well as the stimuli
responsiveness of CB[n]·guest complexes.[5] Accordingly,
CB[n] have become popular components for the
construction of a variety of functional systems including
supramolecular polymers and materials, supramolecular
catalysts, chemical sensing ensembles, molecular
machines, and affinity capture materials.[6]
N
N
N
N
OH
N
N
O
O
N
N
HO
O
O
N
N
HO
HO
N
N
OH
O
N
O
N
O
O
N
N
OH
HO
HO
N
O
N
O
N
N
O
OH
O
OH
O
O
N
N
OH
n-5
Pillar[n]arene (n = 5, 6, 7)
N
N
N
N
n-6
N
N
HO
Introduction
CB[n] (n = 5, 6, 7, 8, 10, 14)
O
O
O
O
O
OR
OR
OR
With the aim of developing novel supramolecular assembly
systems with sophisticated architectures and functions, the
field of supramolecular chemistry has been extensively
studied since the pioneering work of Pedersen, Lehn, and
Cram.[1] One of the focal points for supramolecular chemists
is the design and synthesis of new macrocyclic compounds
that function as molecular containers for complementary
guests in aqueous.[2] Accordingly, several classes of
macrocyclic receptors (e.g. cyclodextrins, calixarenes and
cyclophanes) received intense investigation over the past
half century since the discovery of crown ethers.[3] More
recently, the supramolecular chemistry of cucurbit[n]urils
(CB[n], n=5, 6, 7, 8, 10, 14, Figure 1) – a class of pumpkin-
shaped molecular containers which are composed of n
glycoluril units connected by 2n methylene bridges – has
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
H
HH
H
N
OR
O
O
O
M2 R = (CH2)3SO3Na
N
N
N
N
O
O
OR
Receptor 1
RO
RO
OR
R = (CH2)3SO3Na
become
a focal point of research in supramolecular
Figure 1. Chemical structures of CB[n], prototypical acyclic CB[n]-type
molecular containers, Pillar[n]arenes and the pillar-shaped hybrid receptor 1.
chemistry.[4] The high interest in CB[n] stems in part from
the exceptionally high binding affinity (Ka up to 1017 M–1)
and selectivity displayed by CB[n] towards hydrophobic
Several years ago, the Isaacs group designed and
synthesized
a class of acyclic CB[n]-type molecular
[a] W. Liu, Prof. Dr. Z. Meng
School of Chemistry and Chemical Engineering
Beijing Institute of Technology
5 South Zhongguancun Street, Beijing 100081, P. R. China
E-mail: m_zihui@yahoo.com
[b] W. Liu, Dr. X. Lu, Dr. W. Xue, Dr. S. K. Samanta, Dr. P. Y. Zavalij,
Prof. Dr. L. Isaacs
containers (e.g. prototypical M2, Figure 1) which retained
the essential binding properties of macrocyclic CB[n].[7]
These acyclic CB[n]-type receptors feature a central C-
shaped glycoluril tetramer which promotes binding to
hydrophobic cations, two terminal substituted aromatic
sidewalls
(e.g.
substituted
benzenes,
substituted
Department of Chemistry and Biochemistry
University of Maryland
College Park, Maryland 20742, USA
E-mail: lisaacs@umd.edu.
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under http://doi.org/xxxxxxxx
napthalenes, and triptycene) to enable their recognition of
aromatic guests by π-π interactions, and four sodium
sulfonate groups that greatly enhance the aqueous
solubility of this class of compounds.[8] The structural
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10.1002/chem.201802981
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flexibility of these acyclic CB[n] receptors results in binding
toward not only the common CB[n] guests but also toward
unusual guests including carbon nanotubes, Stoddart’s blue
box and Fujita’s squares, nitrosamines, insoluble drugs and
O
O
OR
c)
a)
b)
neuromuscular
blocking
agents
which
are
less
complementary toward cyclic CB[n].[8-9] Moreover, acyclic
CB[n]-type receptors exhibit good biocompatibility in both
vitro and vivo tests, which makes them candidates for drug
formulation, delivery, and even the in vivo reversal of
neuromuscular blocking agents and drugs of abuse (e.g.
methamphetamine).[7] Water soluble C-shaped receptors
based on glycoluril, norbornene, and anthracene building
blocks with striking chemical and biological functions have
also been prepared by Nolte, Klärner, Schrader, Yoshizawa,
and Schneebeli.[10]
O
RO
5a R=H
O
2
3
4
5b R = (CH2)3SO3Na
a
b
O
O
OR
OR
i,j
k
e
N
N
N
N
N
N
N
N
d)
O
O
d
c
OR
OR
O
O
6
1 R=CH2CH2CH2SO3Na
A)
B)
f
g
h
Most recently, pillar[n]arenes (n = 5, 6, 7, Figure 1) have
emerged as an exciting class of molecular containers for
basic and applied supramolecular chemistry.[11] Unlike the
basket-shaped calixarenes which feature aromatic rings
bridged by methylene units in the meta-positions,
pillar[n]arenes are based on aromatic rings bridged by
methylene units at the para-positions, which gives rise to a
rigid pillar architecture.[11a] Because of their unique
physiochemical properties, facile preparation, and easy
functionalization, pillar[n]arenes are receiving more and
more attention in recent years. Pillar[n]arenes have been
used to create functional systems like mechanically
interlocked molecules, artificial transmembrane channels,
H3N
N
8a: n=1 (C4), 2I
8b: n=2 (C5), 2Br
8c: n=3 (C6), 2Cl
8d: n=4 (C7), 2Br
8e: n=5 (C8), 2Br
9a: n = 0 (C4)
9b: n = 1 (C5)
9c: n = 2 (C6)
N
n
2Cl
n
9
7
8
q
o
2Br
n
N
p
NH3
H3N
Cl
H2
N
N
NH3
m
11
H3N
N
H2
4Cl
10
l
H3N
N
N
N
chemosensors, and supramolecular amphiphiles and
N
12]
polymers.[11c,
Earlier this year, Feihe Huang’s group
Br
2Cl
2I
2Cl
I
reported the synthesis and recognition properties of an
acyclic “clip[4]arene” based on triptycene in acetone
solution.[13] We envisioned the possibility of creating a
water soluble hybrid acyclic receptor (1, Figure 2) whose
structure and properties would blend those of
pillar[n]arenes, (acyclic) CB[n]-type receptors, and
molecular clips. Receptor 1 contains a central glycoluril unit
that is capped with two triptycene walls (doubly para-linked)
that enforce a C-shaped curvature to the molecule similar to
the para-linked pillar[n]arene macrocycles. Receptor 1 also
contains four sulfonate groups which promote its aqueous
solubility and enhance ion-ion interactions in complexes
with cationic guests. In this paper, we report the synthesis
and molecular structure of receptor 1, its basic molecular
recognition properties, and the formation of supramolecular
vesicles for triggered release application.
12
13
14
15
16
NH3
N
N
Figure 2. A) Synthesis of triptycene derived wall 5b and receptor 1.
Conditions: a) xylene, reflux, 5.5 h, 75%; b) CH3COOH/HBr, reflux, 1 h, 88%;
c) propanesultone, 1,4-Dioxane/NaOH (1M), RT, overnight, 75%; d) TFA/Ac2O,
90 oC, 3.5 h, 34%. B) Structures of cationic guests (7 – 16) used in this study.
Design and synthesis of acyclic CB[n]-type receptor 1
We have previously described our building block approach
toward acyclic CB[n] receptors (e.g., M2) which is based on
the double electrophilic aromatic substitution between a
glycoluril oligomer bis(cyclic ether) and
a sulfonate
substituted aromatic building block to enable π-π
interactions and aqueous solubility.[7-8] For the design of
receptor 1 we employed a triptycene derivative as sidewall.
Triptycene can be viewed as a benzo fused derivative of
[2.2.2] bicyclooctane which imparts 120o bond angles
between the aromatic blades and high structural rigidity;
accordingly, triptycene and its derivatives have found wide
applications in crystal engineering, materials science and
molecular machines.[14] To connect these concave
triptycene binding units, we choose dimethylglycoluril
bis(cyclic ether) 6[15] such that the cavity of the resulting
receptor 1 is shaped by four aromatic rings and one
glycoluril ring similar to the cavity of pillar[5]arene. The
aromatic and glycoluril units result in an anisotropic
shielding region inside the cavity which allows for
straightforward monitoring of host•guest complexation by 1H
Results and Discussion
This results and discussion section is organized as follows.
First, we discuss the design and synthesis of receptor 1,
followed by the X-ray crystallographic determination of its
solid state structure. Next, we describe its self-association
behaviour and host-guest recognition properties. Finally, we
present the use of receptor 1 as a building block to
construct supramolecular vesicles and use these
supramolecular vesicles for the encapsulation and triggered
release of a hydrophilic drug and a hydrophobic dye.
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10.1002/chem.201802981
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NMR spectroscopy.
in this molecule is slightly twisted and the distance between
the ureidyl C=O O-atoms of the glycoluril unit of 1 within
1▪8e is 5.702 Å which is comparable to that observed for
M2 (5.645 - 6.184 Å)[8] but shorter than that observed for
CB[n] (≈ 6.1 Å).[4g] Accordingly, the cavity of this molecule
is also slightly twisted and asymmetric. For example, the
distances betweenthe O-atoms of the O(CH2)3R sidechains
are 7.134 Å (O⋯O distance B1) and 6.416 Å (O⋯O
distance B2), respectively (Fig 3b), which means the bottom
part of the cavity is narrower than the top part. Due to this
subtle asymmetry of the cavity, the guest molecule 8e is
asymmetrically accommodated within the cavity. For
example, the distances between the ureidyl C=O O-atoms
and the adjacent quaternary N-atom of the guest are 3.979
Å (N⋯O distance C1) and 5.909 Å (N⋯O distance C2),
respectively. The wider portal complexes the bulkier
quaternary ammonium region of the guest whereas the
more narrow lower portal complexes the (CH2)n region. The
lower quaternary ammonium ion appears to benefit from
The preparation of triptycene wall 5b followed a known
procedure, involving the Diels-Alder reaction of anthracene
(2) with 1,4-benzoquinone (3) to give 4 in 75% yield (Figure
2). Compound 4 was tautomerized to dihydroxy triptycene
(5a) in 88% yield under acidic conditions (CH3COOH, HBr,
reflux). Treatment of 5a with propanesultone under basic
conditions (NaOH, H2O, dioxane) gave the required wall 5b
bearing sodium sulfonate groups in 75% yield. Finally,
double electrophilic aromatic substitution reaction of 5b with
glycoluril bis(cyclic ether) (6) delivered receptor 1 in 34%
yield after purification by recrystallization from a mixture of
water and ethanol. As expected for the depicted C2v-
symmetric structure, the 13C NMR of 1 in water displayed
the expected 17 resonances and the 1H NMR displayed two
pairs of resonances for the two different o-xylylene rings of
receptor 1. The solubility of 1 in 20 mM NaH2PO4 buffered
D2O (pD 7.4, RT) is greater than 40 mM.
-
electrostatic interactions with the SO3 solubilizing groups.
The three dimensional packing of the molecules of 1 in the
crystal does not show any unusual features.
Self-association behaviour and binding properties of
receptor 1
A prerequisite for using receptor 1 as a molecular container
to encapsulate guest molecules is that it does not undergo
strong self-association which would compete with the host-
guest complexation.[8] Accordingly, we first studied the self-
association behaviour of receptor 1 by 1H NMR dilution
experiments in 20 mM NaH2PO4 buffered D2O at pD 7.4
(Supporting information). Solutions of receptor 1 were
diluted from 20 mM to 0.125 mM and the changes in
chemical shift of He were monitored and fitted to a standard
two-fold self-association model within ScientistTM as a
15b, 17]
function of concentration.[9d,
The self-association
constant (Ks) of 1 is determined to be 186 ± 11 M-1. This
dilution experiment establishes that 1 undergoes only weak
self-association which will not interfere with the
encapsulation of guest molecules at lower concentrations
(e.g. ≤ 1 mM) where 1 remains largely monomeric.
Figure 3. Cross-eyed stereoscopic representation of the geometry of one
molecule of 1▪8e from the X-ray crystal structure: a) from top view; b) from
side view. Color code: C, grey; H, white; N, blue; O, red; S, yellow.
X-ray crystal structure of receptor 1
Subsequently, we studied the binding ability of 1 toward
guests 7 – 16. Initially, the binding properties of 1 towards 7
– 16 were qualitatively screened by measuring 1H NMR
spectra for 1:1 and 1:2 mixtures of 1 (1 mM) with guests 7-
We were fortunate to obtain single crystals of receptor 1 as
its complex with hexamethyloctanediammonium ion (e.g.
1•8e) by slow evaporation from
a
mixture of
1
methanol/isopropanol and to solve its structure by X-ray
crystallography (CCDC-1846604). Figure 3 shows a cross-
eyed stereoview of one molecule of 1•8e in the crystal. As
expected, the unique three-dimensional rigid structure of
triptycene is retained, which helps define the acyclic pillar-
shaped cavity of receptor 1. The distances between the
centroids of the two opposite benzene rings are measured
to be 7.842 Å (Ar⋯Ar distance A1) and 7.880 Å (Ar⋯Ar
distance A2) (Figure 3a), smaller than the corresponding
distances of pillar[6]arene (9.974 Å) but similar to those of
pillar[5]arene (7.621 Å).[16] As observed in the crystal
structures of acyclic-CB[n] receptors, the sodium sulfonate
solubilizing groups of receptor 1 are oriented away from the
hydrophobic cavity, thus leaving the cavity free for host-
guest complexation. It is worth noting that the glycoluril unit
16 (Supporting Information). Figure 4 shows the H NMR
spectra recorded for 1 (1 mM) alone and in the presence of
bis(pyridinium)hexane guest 9c (1 mM and 2 mM). Protons
Hp and Hq of guest 9c undergo substantial upfield shifts
upon the formation of the 1•9c complex which indicates
they are located in the magnetic shielding region of the
18]
cavity of 1.[9d,
The presence of only a single set of
broadened resonances for the 1:2 mixture of 1 and 9c
indicates that guest exchange is in the intermeditate to fast
regime on the 1H NMR chemical shift timescale which is
commonly observed for complexes of modest affinity.[19]
Proton Ho adjacent to the N-atoms also undergoes upfield
shifts but not as large as Hp and Hq, which suggests that Ho
is located within the cavity of 1 but closer to the C=O
portals.[18] As expected, Hl – Hn on the aromatic rings of 9c
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undergo very small shifts because they are not included in
the cavity of receptor 1. Analogous experiments were
performed for the remainder of guests 7 – 16 and are
reported in the Supporting Information. We did not observe
any significant changes in chemical shift for solutions of 1
and two of the bulkier guests (Adamantaneammonium 11 or
p-xylenediammonium 13) which can be rationalized based
on the small and relatively rigid cavity of 1 which is
analogous to a pillar[5]arene which is known to prefer n-
alkane derived guests.[11d] When solutions of 1 are treated
with solutions of guests 10 (spermine) or 14 we observe the
formation of a precipitate containing both components. We
suspect that complexation between tetraanionic 1 and
tetracationic 10 gives a poorly soluble neutral zwitterionic
complex. The stoichiometry of the 1•8c complex is
confirmed to be 1:1 by Job plots (Supporting Information);
this 1:1 binding mode is common for the smaller (e.g. n = 5
– 7) pillar[n]arene and CB[n]-type receptors.[4g, 11d]
determined the binding constant for the 1•9c complex (Ka =
(3.03 ± 0.29) × 104 M-1). The binding constants for the
complexes with other guests were determined in an
analogous manner (Table 1, Supporting Information).
Table 1. Binding constants (Ka, M-1) measured for receptor 1 toward various
guests in 20 mM NaH2PO4 buffered D2O at pD 7.4 by 1H NMR titration.
Guest
7
Ka with 1 (M-1)
(1.93 ± 0.11) × 103
(4.78 ± 0.18) × 103
(1.55 ± 0.12) × 104
(4.05 ± 0.25) × 104
(1.35 ± 0.19) × 104
(1.19 ± 0.13) × 104
(4.54 ± 0.11) × 103
(3.38 ± 0.04) × 104
(3.03 ± 0.29) × 104
ppt
hexanediammonium
8a
8b
8c
8d
8e
9a
9b
9c
10
11
12
13
14
15
16
hexamethylbutanediammonium
hexamethylpentanediammonium
hexamethonium
hexamethylheptanediammonium
hexamethyloctanediammonium
butanebis(pyridinium)
pentanebis(pyridinium)
hexanebis(pyridinium)
spermine
adamantaneammonium
trimethylhexaneammonium
p-xylenediammonium
n.b.
(4.72 ± 0.05) × 102
n.b.
hexamethyl-p-xylenediammonium
methyl viologen
ppt
(3.50 ± 2.22) × 103
(3.17 ± 0.44) × 102
trimethyladamantaneammonium
n.b. = no binding detected. ppt = precipitation occurred.
The binding constants for 1 toward the guests 7 – 16 range
from no binding up to 4.05 x 104 M-1 for hexamethonium 8c.
Given the fact that receptor 1 has only one glycoluril unit in
its molecule, it is not surprising that the binding constants
measured for 1 are relatively low compared to those for
other CB[n]-type receptors.[15b] Below, we comment on
some of the trends (e.g. nature (1˚ versus 4˚) of ammonium
ion, chain length) seen in the Ka versus guest structure data.
Receptor 1 binds to primary hexanediammonium (7) weakly
with a Ka value of (1.93 ± 0.11) × 103 M-1 but 20-fold more
tightly to the quaternary diammonium 8c Ka = (4.05 ± 0.25)
× 104 M-1 with the same chain length. A similar result was
obtained for the interaction between 1 and 9c with a Ka
value of (3.03 ± 0.29) × 104 M-1, which suggests that
receptor 1 has a preference for quaternary ammonium
guests to primary ammonium guests. The influence of chain
length on the binding of CB[n]-type receptors toward
alkanediammonium ions is well known and seeks to
optimize ion-dipole interactions at both portals while
maintaining a maximal hydrophobic effect.[4f] For the rigid
CB[6], the maximum binding constants are observed for
pentanediammonium and hexanediammonium (7) and they
are greatly reduced for longer and shorter primary
diammonium ion guests.[4a, e] Less rigid acyclic CB[n] type
receptors (e.g. M2) are less selective toward the chain
lengths of guests but usually show a preference to longer
Figure 4. 1H NMR spectra recorded (400 MHz, D2O) for: a) 1 (1 mM), b) 1 and
9c (1:1), c) 1 and 9c (1:2), d) 9c (2 mM); e) Plot of the change in chemical shift
of Hk as a function of [9c] during the 1H NMR titration of 1 (0.25 mM) with 9c
(0-10 mM). The solid line is the best non-linear fit of the data to a 1:1 binding
model with Ka = (3.03 ± 0.29) × 104 M-1.
After having performed the qualitative binding study, we
1
performed quantitative H NMR binding titrations in 20 mM
NaH2PO4 buffered D2O (pD 7.4) to determine the binding
constants for these complexes. Figure 4e shows the
changes in the 1H NMR chemical shift of proton Hk of
receptor 1 as a function of [9c] monitored during the titration
of receptor 1 (0.25 mM) with 9c (0–10 mM). By fitting the
changes in chemical shift versus [9c] to a standard 1:1
binding model implemented within ScientistTM we
guests
such
as
heptanediammonium
(C7)
and
octanediammonium (C8) because the structural flexibility of
the acyclic CB[n] type receptors allows guests with longer
hydrophobic chains to fold inside their cavities.[20] In
contrast, pillar[5]arene shows a preference for cationic
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10.1002/chem.201802981
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guests with a shorter butane chain.[11d] Accordingly, the
chain length preferences of 1 toward guests 8a – 8e and 9a
10, 20, 40, 60, 80, 100 mM) were measured by isothermal
titration calorimetry (Supporting Information, Table S1,
– 9c were examined (Table 1). Similar to macrocyclic CB[n], Figure S41 and S42). In pure water, the Ka for 1•8c is 9.27
receptor 1 forms the tightest complex with hexane derived
guest 8c (Ka = (4.05 ± 0.25) × 104 M-1) although the
selectivities are modest with values of only 8.5 and 3.4,
respectively over 8a and 8e. The lower selectivity of 1
compared to CB[6] is probably due to the fact that 1 does
not contain a fully formed C=O portal and that electrostatic
interactions at the portals are less of a driving force than in
the case of CB[n]. A similar trend was observed for 9a – 9c
where 9a binds 8.4 and 6.7-fold weaker than the longer
guests 9b and 9c. We also measured the binding constants
of 1 towards alkanebis(pyridinium) guests 9a-9c which are
commonly used as guests in pillar[n]arene studies.
Unsurprisingly, Ka values of receptor 1 towards 9b (C5) and
9c (C6) are 8.4 and 6.7-fold larger than with shorter guest
9a (C4). It is noteworthy that for guests 8a and 9a, both with
four-carbon chains, the Ka values are decreased almost 10-
fold to (4.78 ± 0.18) × 103 M-1 and (4.54 ± 0.11) × 103 M-1
respectively compared to the Ka values of guests 8c and 9c
with six-carbon chains. The host-guest recognition
properties of 1 are distinct from CB[n] and pillar[n]arenes
from which it is conceptually derived.
Next, we explored the binding capacity of receptor 1 by
studies of guests 11, 13-16 which are larger and more
voluminous. For example, receptor 1 shows no binding
towards p-xylenediammonium (13) which has a similar
chain length to that of hexanediammonium (7). Apparently,
the wider p-phenylene ring of guest 13 greatly reduces the
binding affinity toward 1. Compound 14 with a similar p-
phenylene linker, but more complementary quaternary
ammonium ions does appear to form an insoluble complex
with 1 which precluded measurement of its Ka. Methyl
viologen 15 which has a similar p-arylene geometry and a
six carbon spacing between N-atoms forms the 1•15
complex with Ka = 3.50 × 103 M-1. As expected, receptor 1
does not bind to the even more voluminous
adamantaneammonium guest (11) according to 1H NMR.
x 104 M-1 whereas at 100 mM NaCl it is reduced 22-fold to
4.13 x 103 M-1. We attribute this reduction in binding affinity
– which is also commonly seen for CB[n]-type receptors[21]
– to the screening of ion-ion interactions between sulfonate
anion and ammonium cation and perhaps also to
competitive coordination of the Na+ ions to the glycoluril
C=O groups. Overall, the binding properties of 1 can be
seen as a blend of the preferences of the CB[n] and
pillararene receptors from which it is derived augmented by
the presence of the sulfonate solubilizing groups which
allows it to engage in direct ion-ion interactions.
The ability of receptor 1 to form supramolecular vesicles
with amphiphilic guest through self-assembly
Liposomes and vesicles are playing significant roles in the
field of drug delivery and have been widely studied during
the past decades. Moreover, the United States Food and
Drug Administration has approved the use of liposomes to
formulate some antitumor drugs used clinically.[22]
Compared to traditional liposomes and vesicles,
supramolecular vesicles are more stimuli responsive
because they are formed by discrete recognition processes
of their constituent supramolecular amphiphiles.[23] The
stimuli responsiveness of supramolecular vesicles makes it
easier to control the release of drugs encapsulated within
the vesicles, with the potential to improve the therapeutic
efficacy and mitigate the side effects of the drugs. The use
of pillar[n]arenes and their host•guest complexes with
amphiphilic guests to create supramolecular vesicles that
encapsulate drugs and undergo triggered release of guest
(drugs) has been extensively investigated in recent
years.[11c, 12a, h, i, 22c, 23b, 24] Based on the structural similarities
between receptor 1 and pillar[n]arenes, we next explored its
potential in the construction of supramolecular vesicles
when combined with an amphiphilic guest. Accordingly, we
modified hexamethonium 8c with a hydrophobic n-decyl
chain to obtain the amphiphilic guest C10 (Figure 5).
Hexamethonium (8c) was chosen in this study because it is
biocompatible and the Ka for 1•8c (Ka= 4.05 × 104 M-1) is of
comparable stability to host•guest assemblies used to
Since receptor
1
has
a
preference for quaternary
ammonium guests to primary ammonium guest, we also
checked the binding ability of 1 towards the corresponding
quaternary ammonium guest 16. The binding constant for
the 1•16 complex was determined to be (3.02 ± 0.46) × 102
M-1. However, analysis of 1H NMR chemical shifts gives no
evidence of cavity inclusion of the adamantane moiety, but
rather binding of the Me3N+ group near the portal in an
exclusion complexation type geometry.[4i] Accordingly, It
appears that 1 – similar to pillar[5]arene – prefers guests
construct pillar[n]arene-based supramolecular vesicles.[23b,
24d, e]
Guest C10 itself is an amphiphile with a long alkyl chain as
the hydrophobic tail and a hexamethonium moiety as the
hydrophilic head and therefore has the potential to
aggregate on its own to form micelles. Accordingly, we first
measured the critical aggregation concentration (CAC) of
guest C10 in the absence of receptor 1 by monitoring the
optical transmittance at 450 nm of an aqueous solution of
C10 (Supporting Information). No significant change of the
optical transmittance occurred as the concentration of guest
C10 was changed from 10 µM to 1.2 mM, which indicates
that guest C10 does not aggregate by itself over this wide
derived from n-alkanes. Receptor
1
is capable of
accommodating slightly larger guests in the form of p-
arylene derived guests 14 and 15.
Ion-ion electrostatic interactions also appear to play an
important role in the complexation behavior of 1. For
example, quaternary monoammonium ion 12 binds to 1 (Ka
=
4.72 ×
102 M-1) 86-fold weaker than quaternary
diammonium 8c does. To further confirm the importance of
electrostatic ion-ion and ion dipole interactions in the
complexation behavior of 1, the binding affinity of 1 toward
8c in water containing different concentrations of NaCl (0, 5,
concentration range.
We next performed the optical
transmittance measurements for 1:1 ratio of 1 and C10 but
did not observe a clear CAC which suggested aggregation
would occur at a different host:guest stoichiometry.
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Figure 5 Chemical structures of amphiphilic guest C10, doxorubicin (DOX) and nile red (NR) and schematic illustration of the formation of the bilayer vesicles and
the process of stimuli responsive release of doxorubicin (DOX) and nile red (NR).
transmittance at 450 nm versus the concentration of guest
C10, we are able to determine the complexation-induced
CAC of guest C10. At different concentrations of receptor 1
(20 µM, 50 µM, 100 µM) the corresponding CACs are
determined to be 28 µM, 72 µM, 150 µM, respectively
(Supporting Information). These results demonstrate that
the CAC of guest C10 as its 1•C10 complex in the presence
of excess C10 is significantly lower than uncomplexed C10.
This complexation induced decrease in CAC is a key
design criteria for the preparation of supramolecular
vesicles.[25] Next, we determined the best molar ratio
between receptor 1 and guest C10 that leads to the most
abundant and robust amphiphilic assembly using the
method described by Liu and co-workers for a related
system
employing
sulfonated
calix[4]arene
and
myristoylcholine.[23a] For this purpose, we measured the
change in the optical transmittance upon adding 1 into an
aqueous solution of C10 ([C10] = 200 µM). To eliminate
the influence of self-association of receptor 1, the changes
in the optical transmittance caused by the self-association
of receptor 1 alone was subtracted. Figure 6a shows the
plot of transmittance at 500 nm as a function of the molar
ratio of receptor 1 and guest C10. Upon the gradual
addition of 1, the transmittance decreases sharply until a
minimum appears at a [1]/[C10] ratio of 0.15 followed by an
increase with further addition of receptor 1 which eventually
reaches a plateau. The rapid decrease before the minimum
point indicates the formation of a higher-order complex of
receptor 1 and C10 to give a supra-amphiphilic assembly.
However, excess amount of receptor 1 in the solution leads
to the disassembly of the higher-order complex to afford a
simple 1:1 inclusion complex, which therefore results in the
recovery of the transmittance after the inflection point. So
for the receptor 1 and guest C10 system, the best molar
ratio for the amphiphilic assembly is 0.15 ([1]/[C10]). The
clear Tyndall effect (Figure 6a inset) exhibited by receptor 1
(30 µM) and guest C10 (200 µM) solution with a molar ratio
Figure 6 a) Dependence of the optical transmittance at 500 nm on receptor 1
concentration with a fixed guest C10 concentration (200 µM) at 25 °C. Insert:
Tyndall effect of free guest C10 ([C10] = 200 µM, left) and 1•C10 complex
([C10] = 200 µM, [1] = 30 µM right). b) TEM images of 1•C10 assembly with
different scale bar.
In contrast, when a solution of 1 is titrated with a solution of
guest C10 the transmittance decreases, suggesting that
aggregation occurs under these conditions. By plotting the
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0.15 provides strong evidence for the presence of vesicles
in solution. In contrast, the Tyndall effect is not observed
for a solution of free C10 (200 µM), further confirming that
free C10 does not form vesicular aggregates at this
concentration, which is in accord with the optical
transmittance studies. Further evidence of the amphiphilic
assembly of receptor 1 and guest C10 is provided by
transmission electron microscopy (TEM, Figure 6b) which
shows a relatively homogenous population of spherical
nanoparticles (See the Supporting Information for additional
and enlarged TEM images). We measured the diameter of
100 particles to determine the average diameter of the
vesicles as 25.6 ± 2.69 nm; the thickness of the walls of the
hollow vesicles is measured from the TEM images as ≈ 3.5
nm which is comparable to the length of two 1•C10
complexes with antiparallel packing, suggesting that the
vesicles have a bilayer wall. We also performed dynamic
light scattering (DLS) measurements of solutions of vesicles
formed from receptor 1 (30 µM) and guest C10 (200 µM)
which showed an average diameter of ≈ 200 nm which is
larger than that determined by TEM. We attribute this
discrepancy to the further agglomeration of the vesicles
which is apparent in the TEM image (Figure 6b, top left).
We find that a 10-fold dilution of the solution of vesicles ([1]
= 3 µM; [C10] = 20 µM) results in a decrease in the average
diameter measured by DLS to 140 nm (Supporting
Information) which lends further support to this
interpretation. Next, we performed optical transmittance
measurements as a function of time to monitor the stability
of the vesicles. The optical transmittance of 1•C10
aggregation does not change significantly within 48 hours at
25 ˚C, indicating that the vesicles are stable in water and
the vesicular structure can be maintained at least for 48
hours at room temperature (Supporting information).
be dissolved in water in the absence of vesicles formed by
receptor 1 and guest C10. The encapsulation of both
hydrophilic (DOX) and hydrophobic (NR) molecules within
the vesicles provides further evidence of their bilayer
structure.
Encapsulation and Chemical-responsive Release
Bilayer vesicles are able to encapsulate hydrophilic guest
molecules within their interior aqueous phase as well as
hydrophobic molecules inside the bilayer wall. Therefore,
the vesicles formed from receptor 1 and guest C10 were
utilized to encapsulate the hydrophilic drug doxorubicin
(DOX) hydrochloride and the hydrophobic dye nile red (NR).
Addition of an excess amount of DOX or solid NR to an
aqueous solution of vesicles ([1] = 30 µM; [C10] = 200 µM)
results in the encapsulation of DOX or NR, respectively
(Supporting information) as evidenced by UV/Vis or
Figure 7 a) Increase of fluorescence of DOX outside the dialysis bag during
the release process triggered by hexamethonium 8c from DOX@vesicles (λex
= 450 nm) inside the dialysis bag. b) Plot of release percentage of DOX based
on emission intensity at 590 nm versus time. c) UV/vis spectrum of (I) free NR
in water, (II) NR@vesicles in water, and (III) NR@vesicles in water after
treating with hexamethonium 8c (1 mM) for 24 h. d) Naked eye detection of
hydrophobic NR encapsulation and chemical-responsive release. e)
Fluorescence titration of NR@vesicles with 8c (λex = 580 nm) in water. f) Plot
of release percentage of NR based on emission intensity at 660 nm for
NR@vesicles in the absence of 8c versus time and separately with increasing
concentration of 8c.
fluorescence
spectroscopy.
For
hydrophilic
DOX
encapsulation, the excess free DOX was removed by
dialyzing the DOX@vesicles solution against water and
excess hydrophobic NR was simply removed by filtering the
NR@vesicles suspension through a 0.45 µM microfilter to
obtain a clear solution of NR@vesicles. The encapsulation
of NR can be visually observed by the intense color of the
solution (Figure 7d). As a control, we attempted to solubilize
NR under the same conditions in plain water, but the
solution remained nearly colorless.[26] These visual
observations were confirmed by UV/vis spectroscopy
(Figure 7c). The NR@vesicles solution displays an intense
UV/Vis absorbance while NR in water shows a weak
absorbance, indicating that only a small amount of NR can
We next sought to demonstrate the triggered release of the
encapsulated cargo DOX and NR. For this purpose, we
employed guest hexamethonium (8c) as
a chemical
stimulus because 8c should have the same binding affinity
towards receptor 1 as the amphiphilic guest C10 does,
which can compete with guest C10 to form the 1•8c
complex and thereby trigger the disruption of the vesicles.
Figure 7a shows the fluorescence emission spectra outside
the dialysis bag of the systems comprising DOX@vesicles
in the dialysis bag in the presence of 8c (1 mM) outside the
dialysis bag over a period of 12 h. The increase of the
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10.1002/chem.201802981
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fluorescence intensity signals that DOX is released from the
vesicles and accumulated outside the dialysis bag. The
normalized release of DOX (%) triggered by 8c at a series
of concentrations is plotted versus time in Figure 7b. Prior
to the use of the trigger, the supramolecular vesicles show
a premature leakage of ≈ 25% encapsulated DOX. In the
presence of guest 8c, the majority of the cargo is released
as a result of the competitive binding of guest 8c towards
comprises glycoluril and triptycene building blocks and that
can be viewed as a hybrid of CB[n] and pillar[n]arene type
receptors. X-ray crystallography confirms the expected
molecular conformation of the receptor with pillar[5]arene
sized cavity that is defined by four aromatic rings and one
glycoluril unit. Receptor 1 does not undergo significant self-
association in dilute aqueous solution (Ks = 186 M-1).
Receptor
1
binds to hydrophobic cations (e.g.
receptor
1
and the subsequent disruption of the
hexamethonium) in aqueous solution and displays guest
length, guest functional group (e.g. 1˚ versus 4˚ ammonium),
and [salt] dependent binding affinities that are reminiscent
of CB[n]-type hosts but is selective for narrow (CH2)n
derived guests as is commonly observed for pillar[5]arenes.
Receptor 1 and amphiphilic guest C10 co-assemble to form
supramolecular bilayer vesicles in water with an average
diameter of 25.6 ± 2.69 nm. The hydrophilic interior cavity
and the hydrophobic bilayer regions of the vesicles can be
utilized to encapsulate water soluble drug DOX and
hydrophobic dye NR, respectively, and their release can be
triggered by chemical stimulus in the form of 8c and 10 due
to competitive host•guest binding which induces disruption
of the vesicles. The work sets the stage for the use of 1
and related compounds in the variety of chemical and
biological applications now envisioned for pillararenes and
CB[n] including drug solubilization and delivery, optical
sensing, molecular machines, and polymer stabilization and
processing. In these latter areas, the acyclic nature of 1
may be particularly advantageous since it allows
complexation directly at the center of a chain rather than
translocation along the chain. Work along these directions
will be reported in due course.
supramolecular vesicles. The cumulative release efficiency
is 54% with 0.1 mM guest 8c which increases to 73% with
0.5 mM 8c and 83% with 1 mM 8c, respectively. For the
release of hydrophobic NR we simply added different
amounts of guest 8c into the NR@vesicles solutions and
kept them standing still for 24 h. Figure 7d shows the
pictures of the solution of NR@vesicles and precipitated NR
observed 24h later after the addition of guest 8c. The
UV/vis spectrum (Figure 7c) shows a dramatic drop of
absorption intensity after the addition of 20 mM guest 8c
into the NR@vesicles solution. These results further
establish that guest 8c displaces the amphiphilic guest C10
from the cavity of receptor 1 and triggers the disassembly
cascade that releases encapsulated NR. Similarly, the
fluorescence emission intensity at 660 nm of solutions of
NR@vesicles decreases substantially during the titration
with guest 8c (0 – 20 mM) (Figure 7e), reflecting the
chemical responsive release of NR from the hydrophobic
wall of bilayer vesicles constructed by receptor 1 and guest
C10. We calculate that 72% of NR is released due to the
addition of 20 mM guest 8c into the solution of
NR@vesicles (Figure 7f). We also measured the
fluorescence intensity of freshly prepared samples of
NR@vesicles without 8c over 12 h to test the premature
leakage and we did not observe significant changes in
fluorescence intensity over this period time (≤10% leakage
observed) for NR loaded vesicles (Supporting information),
which suggests the premature leakage of hydrophobic
drugs from vesicles constructed by receptor 1 and guest
C10 will not be problematic (Figure 7f).
Acknowledgements
We thank the National Science Foundation (CHE-1404911 and
CHE-1807486) and the International Graduate Exchange
Program of Beijing Institute of Technology for financial support.
Finally, we tried to improve the release efficiency of DOX
and NR by employing spermine (10) which causes the
precipitation of receptor 1 from 1•8c complex (Supporting
information). Unfortunately, the release efficiency of DOX
and NR is not improved when spermine (1 mM) is used as
trigger giving only 73% release of DOX over the period of
24 h. Similarly, the addition of spermine (20 mM) gave only
56% release of encapsulated NR (Supporting information).
In spite of its ability to precipitate receptor 1, spermine is a
relatively poor trigger for the disassembly of DOX@vesicles
or NR@vesicles. We attribute the relatively poor triggering
ability of spermine (10) to an inability to outcompete 8c as a
binder for 1 as might be expected based on the binding
properties of the other primary ammonium guests
measured above.
Conflicts of interest
The authors declare no conflict of interest.
Keywords: cucurbituril
• pillararene • hybrid• triptycene •
triggered release
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This article is protected by copyright. All rights reserved.

10.1002/chem.201802981
Chemistry - A European Journal
FULL PAPER
This article is protected by copyright. All rights reserved.

10.1002/chem.201802981
Chemistry - A European Journal
FULL PAPER
FULL PAPER
Wenjin Liu,[a,b] Xiaoyong Lu,[b]
Cucurbituril-pillararene hybrid
molecular container: we report
the synthesis, x-ray crystal
structure, molecular recognition
properties and triggered release
application of a hybrid receptor 1.
Weijian Xue,[b] Soumen K. Samanta,[b]
Peter Y. Zavalij,[b] Zihui Meng,*[a]
and Lyle Isaacs*[b]
Page No. – Page No.
Hybrid molecular container based on
glycoluril and triptycene: synthesis,
binding properties, and triggered release
This article is protected by copyright. All rights reserved.