Weak Links to Differentiate Weak Bonds: Size-Selective Response of π-Conjugated Macrocycle Gels to Ammonium Ions

Article abstract of DOI:10.1021/jacs.9b01002

Molecular-level host-guest interactions can drive gel-to-sol phase transitions of the bulk material. Using supramolecular gels constructed from π-conjugated aza-crown macrocycles, we have investigated the effects of guest chemical structures on the kinetics of gel disassembly. While ammonium ions bind only weakly to the individual macrocycles in solution, gel-to-sol transitions of self-assembled macrocycles occur readily under ambient conditions. This net signal amplification process was monitored conveniently by time-dependent spectroscopic studies to reveal a straightforward correlation between the response rate and shape/size of the guest species. Well-designed weak links thus respond to subtle differences in weak bonds and translate them into visually discernible macroscopic signaling events.

Full text of DOI:10.1021/jacs.9b01002

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Article
Weak Links to Differentiate Weak Bonds: Size-Selective
Response of #-Conjugated Macrocycle Gels to Ammonium Ions
Suk-il Kang, Milim Lee, and Dongwhan Lee
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01002 • Publication Date (Web): 19 Mar 2019
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Weak Links to Differentiate Weak Bonds: Size-Selective Response of
π-Conjugated Macrocycle Gels to Ammonium Ions
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Suk-il Kang, Milim Lee, and Dongwhan Lee*
Department of Chemistry, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea
ABSTRACT: Molecular-level host–guest interactions can drive gel-to-sol phase transitions of the bulk material. Using
supramolecular gels constructed from π-conjugated aza-crown macrocycles, we have investigated the effects of guest chemical
structures on the kinetics of gel disassembly. While ammonium ions bind only weakly to the individual macrocycles in solution, gel-
to-sol transitions of self-assembled macrocycles occur readily under ambient conditions. This net signal amplification process was
monitored conveniently by time-dependent spectroscopic studies to reveal a straightforward correlation between the response rate
and shape/size of the guest species. Well-designed weak links thus respond to subtle differences in weak bonds, and translate them
into visually discernible macroscopic signaling events.
gels. Previous works on gelating macrocycles focused primarily
INTRODUCTION
13–
on the demonstration of guest-induced gel-to-sol transitions.
15,34–38
Supramolecular gels are two-component materials in which
gelating molecules form insoluble networks that trap solvent
molecules inside. If the non-covalent interactions that help
maintain the crisscrossing molecular networks can be weakened
by external stimuli, such as heat, light, or chemicals, a dramatic
While such visually discernible phase changes could
serve as straightforward signaling events, the experimental
setup provides only binary information of “to-gel” or “not-to-
gel”. No quantitative information could be obtained that reflects
molecular-level structural variations of the guest species.
1–9
gel-to-fluid transition (= degelation) occurs.
A detailed
understanding of the molecular mechanism that underpins such
macroscopic change should guide rational design of
supramolecular gels as stimuli-responsive materials for
BACKGROUND AND DESIGN PRINCIPLES
Preorganization of Crescent-Shaped π-Conjugation. Our
entry into the chemistry of π-conjugated aza-crown ether
ligands was prompted by the X-ray structure of 1 (Figure 2),
prepared initially as a model compound for aromatic foldamers
4–5,10–17
2,18–20
chemical sensing,
drug delivery,
and reaction
8
,21
control.
In this paper, we disclose the chemistry of
luminescent supramolecular gels of π-conjugated aza-crown
macrocycle M1 (Figure 1) which display size-selective
response to various ammonium ions in solution.
39
that we recently reported. A contiguous fused array of five-,
six-, and five-membered rings in the bis(triazolo)benzene core
of 1 nicely defines a crescent-shaped turn motif to support two
N-aryl substituents that face across the concave side of the
molecule.
Figure 1. Chemical structures of M1 (this work) and Cram’s
22,23
hemispherand
having rigid aromatic-rich hemisphere (in blue)
and polar aliphatic-rich flexible hemisphere (in gray).
The host–guest interaction of macrocyclic receptors and
ionic species is a textbook example of supramolecular
2
4–26
chemistry.
A large body of binding studies already exist in
literature that identify size and shape complementarity as a key
Figure 2. Conformational switching (top) and X-ray structure
(bottom; thermal ellipsoids at the 50% probability level) of 1
having a water molecule entrapped within the cavity. See text for
key interatomic distances involved in hydrogen bonding (dashed
lines).
24,27–32
factor for tight complexation in solution.
Within this
context, it is surprising that this intuitive size differentiation
2
4–26,33
model, often termed as the “hole-size fitting”,
has hardly
been established in a quantitative manner for supramolecular
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Even with a finite number of freely rotatable bonds, however, bis(triazolo)benzene π-skeleton of 5. Demethylation with BBr
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1 could still adopt at least three different conformations (Figure
2, top) when brought into co-planarity to maximize π-
conjugation. A serendipitous co-crystallization with a water
molecule, however, produced a single conformer in the solid
state (Figure 2, bottom), in which a converging array of
converted 5 to 6, which was divided into two separate reaction
batches and subjected to intramolecular cyclization reactions
using bistosylated tri- and biethyleneglycol to produce 7a and
7b, respectively. The single-crystal X-ray structure of 7b
unambiguously established the desired connectivity. The
exceptionally high yield (91%) of the 6-to-7a conversion seems
to benefit from the template effect of the cesium ion delivered
as carbonate salt. No cyclization product was obtained when
lithium carbonate was used as a base under otherwise identical
reaction conditions. To improve the solubility of aromatic-rich
macrocycles in polar solvents, oligoether tethering groups were
installed by Sonogashira–Hagihara coupling to prepare M1 and
M2 (Scheme 1). An open-chain analogue L was prepared
directly from 5 in a similar manner.
N
O
triazole···H–Owater (dN···O = 2.942(2)–3.010(2) Å) and Oether···H–
water (dO···O = 3.240(2)–3.247(2) Å) hydrogen bonds function
2
as conformational lock. With H O serving as a guest, the two
methoxy groups of 1 now point toward the concave side of the
molecule. A simple molecular modeling suggested that the
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crystallographically determined
Oether···Oether interatomic
distance of 6.445(2) Å here could be spanned by –(CH
2
2 n
CH O) –
linker groups with n = 2 or 3, without introducing severe steric
constraints.
A synthetic scheme was thus devised to strap two separate
ether groups into a single crown ether skeleton to build hemi-
rigid aza-crown ethers M1 and M2 shown in Scheme 1. Built
upon rigid π-conjugated platform and flexible oligoether
groups, these molecules are reminiscent of the classical
Supramolecular Gelation: Structure Dependence. Even
with the assistance of polar tethering groups, macrocycle M1
remains insoluble in EtOH at r.t. Upon increasing the
temperature to > 45 ˚C, however, the suspension becomes clear,
and turns into an opaque gel upon cooling to r.t. This heating–
cooling cycle can be repeated to drive reversible sol–gel phase
switching (Figure 3a), which is a characteristic thermal
2
2,23
hemispherand of Cram (Figure 1),
macrocycle has all-oxygen donor atoms.
although the latter
1
,40
behavior of supramolecular gels.
The morphology of the
dried gel, as studied by SEM imaging (Figure 3b), reveals
network structures with void spaces.
Scheme 1. Synthetic Routes to Macrocycles M1 and M2, and
Acyclic Derivative L
Figure 3. (a) Thermally induced gelation and degelation of M1 in
EtOH. (b) SEM images of dried gel (8 wt%) of M1. (c) Chemically
induced degelation of M1 by treatment of ammonium ion at T = 25
˚
C.
In stark contrast, structural analogues of M1 having smaller
macrocycle cavity (M2) or unlinked ether groups (L) do not
produce gel-like structures when subjected to similar thermal
treatment conditions; cooling the heated mixture produced only
precipitates (Figure 4). It makes intuitive sense that structural
rigidification through macrocyclization should help planarize
RESULTS AND DISCUSSION
Modular Synthesis of Aza-Crown Macrocycles. As
summarized in Scheme 1, our synthesis commenced with 2,
which was subjected to a azo coupling and copper(II)-mediated
oxidative cyclization reaction sequences to install the first
triazole unit. A second round of azo coupling and cyclization
reaction completed the construction of crescent-shaped
the π-extended molecular core for better self-association
11,41–43
through intermolecular contact.
This simplified
interpretation, however, fails to explain whyM1 and M2, which
differ only by the length of the oligoether strap, display such a
contrasting gelation behavior (Figure 4b vs Figure 4c).
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Chemically Induced Gel–Sol Transition: Size-Selective
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Response to Ammonium Ions. Selective encapsulation of
cationic species is the hallmark of crown ether host–guest
2
4,27–28
chemistry.
When the free-standing gel of M1 was treated
PF , degelation occurred
with a saturated EtOH solution of NH
4
6
at r.t. (Figure 3c). To gain a quantitative understanding of this
process, a simple experimental setup was devised. As shown in
Figure 6a, the bottom of a dual-path UV–vis quartz cell having
a narrow sample compartment was loaded with a fixed amount
(0.35 mL) of gel, which was layered with EtOH solvent (0.35
mL) as a buffer to minimize physical agitation during the
addition of guest solution as the topmost layer.
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Figure 4. Vial inversion tests on EtOH solution samples (2 wt%)
of (a) L, (b) M1, and (c) M2 to compare gelation properties.
A DFT computational study was thus carried out to
investigate the conformational preference of each molecule. As
shown in Figure 5, the geometry-optimized DFT model of M2
(with the peripheral tethers removed) overlaps nicely with the
crystallographically determined structure of 7b (Scheme 1)
which shares identical aza-crown core. However, an increase in
the length of the oligoether strap from M2 to M1 resulted in a
significant canting of the N-phenyl rings away from the
bis(triazolo)benzene plane (Figure 5, light blue) with computed
dihedral angles of 30˚ and 49˚ for M1, compared with 13˚ and
35˚ for M2. Such a large deviation from co-planarity could have
profound impacts on intermolecular π–π stacking, although it
remains to be answered how such molecular-level
conformational twisting would translate to macroscopic
gelation behavior (Figure 4).
Figure 6. (a) A schematic diagram of UV–vis measurement setup
to follow time-dependent gel-to-sol transition of M1. (b) Plots of
light intensity at l = 700 nm (normalized to the maximum value,
700
I ,max, of each sample) vs time. For samples that show no change
in detected light intensity (IIe, IIIa, IIIb, and IIIc), normalization
was carried out by dividing the raw data with the average I700,max
value of the rest of the samples. (c) Structure-dependent degelation
rates quantified as t1/2 (= time required to reach I700 = 0.5I700,max).
Figure 5. Capped-stick representations of the X-ray structure of 7b
(black) overlaid with DFT (B3LYP/6-31G(d) level) computational
models of M1 (light blue) and M2 (gray), in which oligoether
tethering groups have been removed.
For each sample, measurements were carried out three times under
identical conditions to determine the average t1/2 value and error
bar.
Due to the opaque nature of the gel, the intensity of the
incident light at l = 700 nm passing through the sample is
negligible, as monitored by a portable UV–vis spectrometer
with fiber optic cables. With the progress of degelation,
however, collapse of the opaque molecular network and release
of optically transparent M1 (i.e. having no absorption at l = 700
nm in solution) clears the beam path, resulting in a sharp rise in
the detected light intensity over time (Figure 6b). By plotting
time-dependent changes of I700, the degelation process can be
While the underlying molecular mechanism of self-assembly
is yet to be elucidated, the markedly different gelation behavior
of M1, M2, and L (Figure 4), all sharing identical π-conjugated
molecular backbone and peripheral oligoether tethers, points
toward the importance of the central macrocyclic cavity in this
process. We thus proceed to investigate the possibility of using
host–guest chemistry of aza-crown ether to modulate
supramolecular gelation of M1 and find practical applications.
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monitored under controlled experimental conditions for direct As shown in Figure 7, treatment of M1 with an increasing
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side-by-side comparison, as shown in Figure 6b.
4 6 6
amount of NH , delivered as a PF salt in acetone-d , resulted
–
in systematic downfield shifts of the resonances from the
ethylene glycol strap. Apparently, binding of the cationic guest
induces deshielding around the cavity region, whereas spectral
patterns from the rest of the molecule, including the aromatic
region, remain essentially invariant (Figure S1). The H NMR
titration data shown in Figure 7 was fitted with a 1:1 binding
A series of organic ammonium ions were prepared as PF
6
44
salts, and deployed for time-dependent measurements. As
shown in Figure 6c, primary ammonium and most of the
secondary ammonium elicited structural collapse of the gel. For
a quantitative measure, the experimentally determined t1/2
values are compared for the subsets of ammonium ions screened
1
isotherm (Figure S2) to determine the association constant of K
a
(
Figure 6c). Among the primary ammonium ions that we
–1
+
=
12.68±0.05 M for NH
4
at T = 25 ˚C. Spectral titration with
screened, longer alkyl chain slows down the response rate (Ia
vs Ib and Ic), but increase in the steric bulk at the chain-end
position has negligible effects (Ib vs Ic). A similar trend was
observed for the secondary ammonium ions, with longer chains
resulting in slower degelation (IIc vs IId). At the same time,
alleviation of the steric congestion around the nitrogen atom
through cyclization dramatically accelerates the kinetics of gel
collapse (IIa vs IIc). Intriguingly, comparable t1/2 values were
observed for secondary ammonium IIa and IIb having five- and
six-membered ring structures, respectively, which, in fact, are
as reactive as the primary ammonium Ib and Ic. Moving in the
opposite direction, an increase in steric bulk around the nitrogen
atom (IIe) completely shut down the degelating capability.
With tertiary ammonium ions IIIa, IIIb, and IIIc, as the
sterically most crowded subset, no degelation occurred.
+
–1
K afforded K
a
= 9.84±0.04 M (Figures S2 and S3).
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Our experimental results implicate that the steric bulk of
ammonium ions is a primary determinant of the degelating
reactivity. In so much as the chemical structure of macrocyclic
core dictates the gelating property of M1 (Figure 4), access to
this cavity by ionic guests seems to be critical to reversing this
process (Figure 6). We postulate that complexation of
ammonium group by aza-crown ether unit of M1 would disrupt
close intermolecular contacts sustaining the gel network. From
the experimentally determined overall trend of 1˚ > 2˚ > 3˚
ammonium ions to facilitate the degelation process, a
conceptual linkage could be drawn to the hole-size effect in
host–guest chemistry: larger ions do not fit well into the
receptor cavity and thus become less effective as degelating
agent.
1
Figure 7. Partial H NMR spectra of 8 in acetone-d
6
obtained in the
presence of (a) 0, (b) 2, (c) 6, (d) 12, (e) 20, and (f) 28 equiv of
NH PF at T = 25 ˚C.
4
6
For the acyclic analogue 9 (Scheme 2), however, no spectral
shifts were observed upon titration with either NH (Figure S4)
4
+
+
or K (Figure S5) under similar conditions. This findings
support the notion that despite structural preorganization to
present the [N,N]-bidentate donor motif, (i) crescent-shaped
bis(triazole)benzene π-backbone by itself is not sufficient, and
(ii) conformational lock by oligoether strap is needed to achieve
measurable binding affinities toward cationic guests.
Ammonium Binding by Individual Molecular Receptors
in Solution. If the molecular-level size match determines
macroscopically observed disassembly rates, how strongly does
M1 bind to an ammonium ion? To address this question, we
Even with the assistance of macrocyclization, the
experimentally determined binding constants of ~10 M for
or K still lie toward the lower end of typical aza-crown
receptors, which usually show K
conventional N-donors, the sp -nitrogen atoms of the triazole
ring (with three electronegative nitrogen atoms constituting the
five-membered aromatic ring) are poor donors, which rarely
bind to electron-deficient guests in the absence of negatively-
charged ancillary groups nearby.
interaction between the aza-crown cavity of 8 (and therefore
M1) and ammonium ion is not surprising. What is quite
remarkable, however, is the ability of the self-assembled gel of
M1 to amplify such low-affinity binding event, and translate it
to macroscopically observed phase-changes that can distinguish
even subtle steric differences around the charge center (Figure
–1
+
+
NH
4
1
proceeded to carry out H NMR titration studies. To avoid
-1 27,45
a
= 40–45000 M .
Unlike
complications from overlapping proton resonances of the
oligoether tethers and the crown ether core, compound 8
(Scheme 2) was employed as a simpler model of M1.
2
46–49
As such, the weak
Scheme 2. Synthetic Routes to Model Macrocycle and
Acyclic Analogue
6
). In retrospect, it makes perfect sense that one needs to use
weak interactions in order to measure weak forces, although this
simple and intuitive concept seems to have hardly been
exploited for ion-responsive supramolecular gels before.
Fluorescence Turn-On Detection by Ammonium-
Triggered Release of Entrapped Fluorophores. One notable
feature of triazoloarene-based π-conjugation is strong
fluorescence emission, which we previously exploited for
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reaction-based detection of transition metal ions,
and
a
underway in our laboratory to expand the scope of this
chemistry to different types of stimuli-responsive gels for
applications in chemical detection and controlled release.
52
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intramolecular resonance energy transfer.
bis(triazolo)benzene derivative, M1 shows intense (F
in CHCl ) emission at lmax = 390 nm (Figure S6) in solution,
As
= 36%;
F
3
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
which prompted us to devise a simple experimental setup as
proof-of-concept of target-specific fluorescence enhancement
response.
A fluorimeter cell was coated with a small amount (0.1 mL)
of M1-gel film at the bottom, and filled with EtOH (3 mL).
With the fluorophores entrapped as the gelating network, no
fluorescence was observed upon excitation of the solution at l
Synthesis and characterization; additional spectroscopic data
(PDF)
X-ray crystallographic data (CIF)
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=
365 nm. Upon addition of γ-amminobutyric acid (GABA; 0.3
mL of 1.0 M solution in H O:ethanol = 1:3, v/v) as a model
2
analyte, which functions as inhibitory neurotransmitter in
biological systems, a sharp rise in the solution fluorescence was
observed within 4 min (Figure 8).
AUTHOR INFORMATION
Corresponding Author
*dongwhan@snu.ac.kr
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the Basic Research Grant
(
(
2017R1A2B2006605) and Creative Materials Discovery Program
2017M3D1A1039558) through the National Research Foundation
of Korea (NRF). S.K. thanks the Fellowship for Fundamental
Academic Fields from SNU.
REFERENCES
(1) Sangeetha, N. M.; Maitra, U., Supramolecular Gels: Functions
Figure 8. Time-dependent changes in the fluorescence intensity at
l = 400 nm upon treatment of M1-gel with GABA (shown as its
zwitterionic form). See text for experimental conditions.
and Uses. Chem. Soc. Rev. 2005, 34, 821–836.
(
2) Truong, W. T.; Su, Y.; Meijer, J. T.; Thordarson, P.; Braet, F.,
Self-Assembled Gels for Biomedical Applications. Chem. Asian. J.
011, 6, 30–42.
3) Goh, C. Y.; Mocerino, M.; Ogden, M. I., Macrocyclic Gelators.
A gradual increase in the emission occurred subsequently
with further release of the entrapped fluorophore; the signal
intensity remained undiminished. Control studies using solvent-
only setup showed essentially no changes in the fluorescence
intensity, which unambiguously establishes the validity of our
design concept.
2
(
Supramol. Chem. 2013, 25, 555–566.
(4) Segarra-Maset, M. D.; Nebot, V. J.; Miravet, J. F.; Escuder, B.,
Control of Molecular Gelation by Chemical Stimuli. Chem. Soc. Rev.
2
013, 42, 7086–7098.
In typical displacement assays in solution phase, competitive
(5) Qi, Z.; Schalley, C. A., Exploring Macrocycles in Functional
Supramolecular Gels: From Stimuli Responsiveness to Systems
Chemistry. Acc. Chem. Res. 2014, 47, 2222–2233.
binding of the analyte to the pre-complexed host–indicator pair
53,54
sets off the signaling event.
For our system, a single-
(
6) Okesola, B. O.; Smith, D. K., Applying Low-Molecular Weight
component supramolecular gel serves the role of the latent host–
indicator complex, which, upon encountering the target analyte,
rapidly disintegrates and releases its emissive molecular
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