Making Waxy Salts in Water: Synthetic Control of Hydrophobicity for Anion-Induced and Aggregation-Enhanced Light Emission

Article abstract of DOI:10.1002/anie.202100729

We show that multipodal polycationic receptors function as anion-responsive light-emitters in water. Prevailing paradigms utilize rigid holes and cavities for ion recognition. We instead built open amphiphilic scaffolds that trigger polar-to-nonpolar environment transitions around cationic fluorophores upon anion complexation. This ion-pairing and aggregation event produces a dramatic enhancement in the emission intensity, as demonstrated by perchlorate as a non-spherical hydrophobic anion model. A synergetic interplay of C?H???anion hydrogen bonding and tight anion–π⁺ contacts underpins this supramolecular phenomenon. By changing the aliphatic chain length, we demonstrate that the response profile and threshold of this signaling event can be controlled at the molecular level. With appropriate molecular design, inherently weak, ill-defined, and non-directional van der Waals interaction enables selective, sensitive, and tunable recognition in water.

Full text of DOI:10.1002/anie.202100729

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 10858–10864
International Edition:
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Supramolecular Chemistry
Making Waxy Salts in Water: Synthetic Control of Hydrophobicity for
Anion-Induced and Aggregation-Enhanced Light Emission
Soohyung Kim, Jongmin Kim, and Dongwhan Lee*
Abstract: We show that multipodal polycationic receptors
function as anion-responsive light-emitters in water. Prevailing
paradigms utilize rigid holes and cavities for ion recognition.
We instead built open amphiphilic scaffolds that trigger polar-
to-nonpolar environment transitions around cationic fluoro-
phores upon anion complexation. This ion-pairing and
aggregation event produces a dramatic enhancement in the
emission intensity, as demonstrated by perchlorate as a non-
spherical hydrophobic anion model. A synergetic interplay of
+
CÀH···anion hydrogen bonding and tight anion–p contacts
underpins this supramolecular phenomenon. By changing the
aliphatic chain length, we demonstrate that the response profile
and threshold of this signaling event can be controlled at the
molecular level. With appropriate molecular design, inherently
weak, ill-defined, and non-directional van der Waals interac-
tion enables selective, sensitive, and tunable recognition in
water.
Figure 1. Schematic representations of two different strategies to
control hydrophobicity for molecular recognition. a) Binding sites are
located inside a hydrophobic surface. b) Binding sites are exposed to
Introduction
the open space, yet conformationally preorganized and spatially
decoupled from aliphatic chains that facilitate ion recognition and
aggregation process in water.
Molecular recognition in water is an unperfected art in
[
1]
synthetic supramolecular chemistry. As a molecule, H O is
2
an unrelenting and robust competitor for hydrogen bonding
(
HB). As a medium, it is a strong dielectric that effectively
[2]
screens electrostatic attractions. While directional non-
covalent bonds such as HB or dipole–dipole interactions
have been widely exploited in supramolecular design, their
strength becomes significantly attenuated in water. In
contrast, the hydrophobic effect is maximized in water, but
À
molecular level to modulate their sensitivity toward ClO4 in
water.
[
3]
this non-directional, weak, and ill-defined interaction is Background and Design Principles
[
4]
difficult to control and quantify.
In this paper, we disclose the chemistry of multicationic
fluorophores and their applications for anion detection in
water. Taking non-conjugated 1,3,5-substituted benzene as
a core structural platform, three fluorogenic pendants and
three hydrophobic tails are installed in an alternating fashion
Supramolecular Chemistry of Ions
Recognition of ionic species in an aqueous environment is
a topic of significant importance in environmental and
[
5]
biological sciences. Cations engage in ion–dipole interac-
tions with macrocyclic or cage-like receptors. The concept of
“hole size fitting” has been successfully implemented here by
matching the host cavity size to the radius of the cations to be
(
Figure 1). A synergistic interplay of CÀH···anion HB and
+
intimate anion–p interactions results in a dramatic enhance-
ment in fluorescence intensity through hydrophobic collapse
and salt aggregation. By systematically varying the alkyl chain
length, we further demonstrate that the inherent hydro-
phobicity of these fluorogenic cations can be controlled at the
[6]
detected or sequestered. For anions, the situation becomes
more challenging. Compared with isoelectronic cations,
[7]
anions are larger in size. A lower ratio of charge-to-radius
makes electrostatic attraction less effective.
Selective detection of large, non-spherical, and charge-
diffuse anions is even more challenging if one relies solely on
[
*] S. Kim, J. Kim, Prof. Dr. D. Lee
Department of Chemistry, Seoul National University
[
8]
electrostatic interactions. There is no general rule to
construct host molecules by simply matching the size or the
geometry of irregularly-shaped and hydrophobic anions.
Moreover, a majority of known anion receptors work mostly
in organic-aqueous mixed-solvent systems. Due to the intrin-
1
Gwanak-ro, Gwanak-gu, Seoul 08826 (Korea)
E-mail: dongwhan@snu.ac.kr
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202100729.
1
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sic hydrophobicity of p-conjugated molecules, anion-respon-
sive fluorophores operating in water are rarer still.
assisting and regulating salt aggregation and fluorescence
[1,5]
enhancement. In the following sections are described impor-
tant lessons that we learned from these new amphiphilic
fluorophores.
Design Principles
Nature utilizes weak non-covalent interactions to recog- Results and Discussion
nize guests in water with remarkable selectivity and efficien-
[
9]
cy. For example, the strength of electrostatic and hydrogen-
bonding interactions is augmented by hydrophobic cavities or
channels that effectively protect binding sites from competing
Design and Synthesis of Model Fluorophore
As a first step to realize the idea outlined in Figure 1b, we
designed the simplest molecular prototype [1-Me]Cl (Sche-
me 1b). This compound was prepared by following the
general synthetic protocol outlined in Scheme 1a, starting
with methylation of the anilido-pyridine precursor A,
followed by acid-catalyzed condensation reaction with form-
[10]
water molecules. Artificial receptors have been designed
and synthesized to mimic binding in the “dehydrated” interior
space (Figure 1a). Such strategy is effective for the recog-
nition of small guests, yet it is challenging to customize the
shape and size of the cavity while maintaining specific binding
sites at designated positions on the inner wall. While the
space enclosed by the molecular skeleton is geometrically
well-defined, it also becomes the upper limit in the size scale
of the guest species to be entrapped.
Instead of using the rigid hydrophobic “cavity” (Fig-
ure 1a), we decided to use flexible aliphatic “tails” (Figure 1b
and Scheme 1) to build a low-dielectric environment that
promotes ion-pairing between cationic host and anionic guest
in water. Among many branched molecular scaffolds in
[
13]
[
4a]
[14]
aldehyde in HCl/1,4-dioxane (Scheme S1).
yellow precipitate was isolated by simple filtration.
The resulting
A single-crystal X-ray crystallographic (SC-XRD) study
on [1-Me]Cl confirmed the chemical connectivity, with the CÀ
H groups of the pyridinium ring and the methylene bridge
pointing to the same direction (Figure 2a). The molecular
electrostatic potential (MEP) map predicted that the two
carbon atoms (C1 and C2) associated with these CÀH bonds
are the most electron-deficient sites (Figure 2b). The highly
[11]
supramolecular chemistry, the privileged 1,3,5-trisubstitut-
polarized nature of these CÀH groups suggested their
[
12]
ed benzene is ideally suited for our purpose, since it allows
spatial decoupling of (i) cationic and fluorogenic recognition/
reporter module (Scheme 1a), and (ii) hydrophobicity con-
troller module (Scheme 1b). Through “steric gearing”, these
two functional components are placed alternately above and
below the benzene plane, and do not interfere with each other
when integrated into a single molecular platform (Figure 1b),
thus allowing for systematic investigation of structure–prop-
erty relationships.
potential role as hydrogen-bonding donor (HBD) toward
À
[15]
anionic species X as hydrogen-bonding acceptor (HBA).
This idea prompted our investigation of multicationic mole-
+
cules derived from [1-Me] that can engage in multiple CÀ
À
H···X contacts to make stronger adducts (vide infra).
In addition to functioning as a conformational lock, the
2
,4,6-trialkyl substituents in our system (Scheme 1b) actively
participate in the recognition of hydrophobic anion by
+
Figure 2. a) X-ray structure of [1-Me] cation as ORTEP diagrams with
thermal ellipsoids at the 50% probability level. Torsional angle for N1-
C5-C4-C3=15.38. b) Molecular electrostatic potential (MEP) map of [1-
+
Me] cation calculated by B3LYP-D3/6-31G(d,p) level of theory. The
[20]
circled regions (white) denote the C1 and C2 atoms.
Multicationic Molecular Scaffolds
By substitution reactions of the common intermediate A,
a series of cationic molecules were prepared in a straightfor-
ward manner. As summarized in Scheme 2, the chloride salt
3+
of tricationic [3a] was synthesized via substitution reactions
between A and 1,3,5-tribromomethyl benzene, followed by
acid-catalyzed condensation reactions with formaldehyde.
Both reactions proceeded in good yields (> 85%). For
2
+
comparative studies, dicationic [2] and monocationic [1-
+
Bz] were also prepared through the same procedure by using
1
,3-dibromomethyl benzene and bromomethyl benzene, re-
Scheme 1. Modular construction and structural elaboration.
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Figure 3. a) Changes in the fluorescence spectra (lexc =400 nm) of
3a]Cl (0.100 mM) with increasing volume fraction of THF (fTHF) in
[
3
H O–THF mixed solvent system at T=293 K. b) Plot of emission
2
intensity enhancement factor (DI/I ) at l=580 nm vs. fTHF. Inset:
0
photographs of [3a]Cl at f =0% (left) and 99% (right) under UV
3
THF
lamp irradiation (l=365 nm).
Specific Interactions Between the Fluorophore and Hydrophobic
Anion
[
20]
Scheme 2. Synthesis of mono-, di-, and tricationic fluorophores.
Intrigued by the fluorescence turn-on response of [3a]Cl3
in the hydrophobic environment (Figure 3), we proceeded to
test the feasibility of inducing self-assembly in water by using
hydrophobic anions instead. A preliminary screening showed
In the solid-state, [3a]Cl is fluorescent (l
= 585 nm;
max,em
3
F = 4.9%), but the emission is essentially quenched in H O
that an aqueous solution of [3a]Cl (3.3 mM) immediately
F
2
3
(
lmax,em = 590 nm; F < 1.0%) (Figure S1). A similar behavior
produces precipitates upon treatment with NaClO4
(50 equiv). This anion metathesis reaction product [3a]-
(ClO ) was subsequently characterized by SC-XRD (Fig-
F
was observed for the fluorophore core model [1-Me]Cl with
lmax,em = 555 nm (F = 27.8%) in the solid-state, and lmax,em
=
F
4
3
6
10 nm (F < 1.0%) in H O. In terms of the electronic
ure 4).
F
2
excitation, [3a]Cl3 in H O (lmax,abs = 400 nm; e =
As shown in Figures 4 and S5a, the solid-state structure of
2
À1
À1
1
0205 cm M ) behaves like a simple sum of electronically
[3a](ClO4)3 revealed the presence of both CÀH···anion
+
independent chromophores that retain the photophysical
hydrogen bonds and intimate anion–p contacts between
properties of the [1-Me]Cl (lmax,abs = 400 nm; e =
the fluorophore and perchlorate anion. We found that the
highly polarized pyridinium CÀH bond and the methylene
bridge CÀH groups engage in dipole–anion interactions with
À1
À1
3
648 cm
M
in H O) as local site model (Figure S2). In
2
support of this notion, [3a]Cl , [2]Cl , and [1-Bz]Cl also share
3
2
similar absorption and emission features arising from local-
ized light-absorbing and emitting units with no significant
electronic coupling (Figure S3).
d
= 3.303(4)–3.504(3) Š and
d
= 3.291(3)–3.449-
C–H···O
C–H···O
Aggregation-Induced Fluorescence Enhancement
The phase-dependent fluorescence properties of [3a]Cl3
(
Figure S1) prompted us to investigate the effects of fluid-to-
solid environment change on the excited-state photophysics.
Since [3a]Cl is highly soluble in water, we decided to add less
3
polar organic solvent THF to induce aggregation in H O–
2
THF mixed-solvent system (Figure 3). No significant change
was observed in fluorescence upon addition of THF with
a volume fraction (fTHF) of below 90%. However, when the
fTHF value exceeded 95%, the emission intensity was gradu-
ally increased, resulting in 5-fold enhancement at fTHF = 99%,
with a slight blue shift (lmax,em = 580 nm). Such optical
response has its origin in the aggregation-induced emission,
which was confirmed by dynamic light scattering (DLS)
studies conducted under the same conditions (Figure S4).
Figure 4. a) Capped-stick representation of the crystal packing struc-
ture of [3a](ClO ) based on crystallographically determined atomic
4
3
coordinates. Hydrogen atoms are omitted for clarity. Close-up views of
À
b) CÀH···ClO hydrogen bonding (green dashed lines), and c) anion–
4
+
p
[20]
contacts (red dashed lines).
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À
(
3) Š, respectively. In addition, the oxygen atom of ClO is
maintained in the solution phase as well. The larger electro-
static contribution of harder anion to the hydrogen bonding is
reflected on the large and systematic downfield shifts of the
4
3+
pointing to the centroid of pyridinium moiety of [3a] with
dpyridinium···O = 3.083(2) Š, which is within the range of typical
anion–p interactions. The X-ray structures of [1-Bz](ClO4)
and [2](ClO ) (Figures S5b, S5c, S6, and S7) consistently
show similar CÀH···anion and anion–p contacts as well, thus
confirming that these non-covalent interactions are position
specific, not biased by crystal packing.
[16]
participating protons when comparison is made between CÀ
À
À
H···Cl and CÀH···ClO . Comparative studies on [1-Bz]Cl vs.
4
2
4
+
[1-Bz](ClO ) (Figure 5), and [2]Cl vs. [2](ClO ) (Figure S10)
4
2
4 2
further validate this interpretation, and support the general
applicability of our anion recognition model.
In stark contrast to the perchlorate salts (Figures 4, S6,
and S7), the X-ray structures of the corresponding chloride
+
salts [1-Me]Cl and [1-Bz]Cl do not show any anion–p
Selective Recognition of Perchlorate Anion in Water
À
interactions (Figures S8 and S9). Only CÀH···Cl hydrogen
bonds were observed for the polarized (see the MEP map in
With spectroscopic and structural evidence obtained for
À
Figure 2b) pyridinium CÀH bonds (d
= 3.3948(18)–
= 3.4892-
the specific interactions with ClO4 ion, we investigated the
C–H···Cl
3
.6635(17) Š) and methylene CÀH groups (d
optical response of the fluorophore by titration methods.
C–H···Cl
(
19)–3.5035(18) Š). This contrasting behavior implicates that
Upon addition of NaClO (0–200 equiv), the fluorescence
4
the cationic fluorophore can engage in different types of non-
intensity (lmax,em = 570 nm) of [3a]Cl in water (0.100 mM)
3
covalent interactions depending on the nature of the anion.
was enhanced up to 10-fold (Figure 6a). Similar fluorescence
À
For large and charge-diffuse (= “soft”) ClO4 , both CÀ turn-on response occurred regardless of the choice of the
+
H···anion and anion–p interactions are involved, whereas
CÀH hydrogen bonding is mainly utilized for small and
counter cation (LiClO , NaClO , and KClO ) (Figure S11), or
4 4 4
solution pH (Figure S12b). In contrast, no spectral change was
À
À
À
À
À
compact (= “hard”) Cl .
observed with hydrophilic anions, such as F , Cl , Br , I ,
À
2À
À
À
2À
À
À
To confirm that the non-covalent interactions observed in
the solid-state are not crystal packing artifacts, we proceeded
HCO3 , CO3 , AcO , H PO , HPO4 , HSO4 , NO3 ,
2 4
ClO3 , and BF4 (all delivered as sodium salts) under
identical conditions (Figure 6b). When ClO4 was added
À
À
1
À
to carry out H NMR spectroscopic studies in solution. To
mimic the relatively non-polar environment of the solid-state,
CD Cl was chosen as a solvent. As shown in Figure 5, the
subsequently to the mixtures of [3a]Cl and these hydrophilic
anions, enhancement in fluorescence was consistently ob-
served with little interference (Figure S12a).
3
2
2
1
H NMR spectra of [3a]Cl and [3a](ClO ) show significant
3
4 3
differences in the pyridinium CÀH (Dd = 1.26 ppm, green
A combination of dynamic light scattering (DLS) and
SEM studies revealed that the fluorescence turn-on response
is accompanied by the formation of aggregates in solution
(Figure 7). An increasing amount of NaClO4 produced
aggregates of increasing hydrodynamic diameters (average
values: 124–183 nm; Figure 7). Spherical nanoparticles of
comparable sizes were also observed by SEM analysis
square) and methylene CH (Dd = 0.60 ppm, green circle)
2
proton resonances, while the rest of the signals in the aromatic
region are shifted only to a small extent.
This behavior supports the notion that the crystallo-
graphically observed CÀH···anion interactions (Figure 4) are
(
Figure 7, insets). For either pristine [3a]Cl or upon treat-
3
ment with lower (10 equiv) amount of NaClO , no aggrega-
4
tion was observed.
To investigate the effects of the overall charge of the
fluorophore on the anion-induced spectral changes, compa-
Figure 6. Changes in the fluorescence emission spectra of [3a]Cl3
(
(
0.100 mM) in H O (a) upon addition of NaClO (0–200 equiv), and
2 4
À
À
À
À
À
2À
b) other anions (200 equiv) including F , Cl , Br , I , HCO , CO3
,
3
1
À
À
2À
À
À
À
À
Figure 5. Partial H NMR spectra of [3a]Cl , [3a](ClO ) , [1-Bz]Cl, and
AcO , H PO , HPO4 , HSO4 , NO3 , ClO3 , and BF4 (gray lines).
2 4
3
4
3
[
1-Bz](ClO ) in CD Cl (concentration=1.0 mM; T=298 K) with the
In (b), the emission spectra of [3a]Cl (black dashed lines) and
response to ClO4 (blue line) are also overlaid for comparison.
lexc =400 nm; T=293 K.
4
2
2
3
À
pyridinium (square) and methylene CÀH (circle) resonances denoted
with symbols.
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Sensitivity Control by Intrinsic Hydrophobicity
Sensitivity is as important as selectivity in chemical
sensing. In the ion pairing-induced aggregation scheme, the
inherent hydrophobicity of the fluorophore should impact the
sensitivity towards the target anion in water. The tripodal
3
+
skeleton of the first-generation molecule [3a] is ideally
suited for this purpose since the remaining sites on the
benzene core can be modified by installing alkyl groups of
varying chain length (Figure 1b). The three-fold molecular
symmetry effectively multiplies the substituentsꢀ hydropho-
bicity effects, which are essentially decoupled from the charge
effects of the fluorophores appended as different branching
units. Such spatial separation and functional independence
are advantageous for systematic optimization of individual
components.
To realize this idea, compounds [3b]Cl , [3c]Cl , [3d]Cl ,
3
3
3
and [3e]Cl3 were prepared by taking the synthetic route
outlined in Scheme 3. The peripheral alkyl chains are varied
from ethyl to dodecyl groups to systematically increase the
hydrophobicity while keeping the same cationic pendants.
With increasing alkyl chain length, the fluorescence emission
of these chloride salts remains essentially unchanged in water,
except for only slight spectral blue shifts (Dl = 20 nm) and
Figure 7. DLS profiles of [3a]Cl (0.100 mM) in water obtained upon
3
addition of NaClO : a) 50 equiv, b) 100 equiv, c) 150 equiv, and
4
d) 200 equiv. Insets show the corresponding SEM images.
increase in the fluorescence quantum yields of emission (F =
F
0
.1–3.3%) (Table S2). No noticeable change was observed in
+
rative studies were carried out with monocationic [1-Bz]
the fluorescence intensity upon prolonged (up to 12 h)
exposure to the excitation light source (Figure S14).
2
+
(
[
0.300 mM), dicationic [2]
(0.150 mM), and tricationic
3
+
3a] (0.100 mM). Despite sharing the structurally identical
cationic pendants attached to the benzene core, [1-Bz]Cl and
2]Cl showed only negligible turn-on response under similar
Upon addition of NaClO , all compounds displayed
4
fluorescence turn-on response (Figures 8a and S15), albeit
with varying degrees of enhancement factors and the dose-
dependent growth of the saturation curves. This photophys-
ical change is also accompanied by the formation of solution
aggregates, as confirmed by DLS and SEM studies (Fig-
ure S16). With increasing alkyl chain length, the hydro-
dynamic diameter of the aggregates gradually decreased
[
2
conditions (Figure S13). A higher charge density of the
receptor molecule is thus important for anion binding and
aggregation.
3
+
3+
(160–20 nm) from [3a] to [3d] , but increased to 95 nm for
[20]
Scheme 3. Synthesis of structural variants with systematic increase in the aliphatic chain length.
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Conclusion
In water, nonpolar molecules minimize solvent-exposed
surfaces by structural collapse (i.e., folding) or self-associa-
tion. Oppositely-charged hydrophobic ions are also attracted
to each other to form neutral salts, the decreased overall
polarity of which lowers the solubility in water and induces
spontaneous aggregation. We demonstrate that this convo-
luted process is assisted by long alkyl pendants that are
strategically placed around a multipodal polycationic plat-
form. Upon anion complexation, a polar-to-nonpolar envi-
ronment change around the cationic fluorophore produces
a dramatic enhancement in the fluorescence intensity by AIE.
The response profile and threshold of this signaling event
can be controlled at the molecular level by changing the chain
length of the amphiphilic fluorophore in water. This strategy
has no previous example, and exploits inherently weak and
non-directional dispersive interactions for selective, sensitive,
and tunable recognition. We demonstrated its practical utility
Figure 8. a) Plots of fluorescence intensity at l=570 nm (normalized
to the maximum value, DI570 of each samples) vs. equiv of NaClO4
added to [3a]Cl , [3b]Cl , [3c]Cl , [3d]Cl , and [3e]Cl solution samples
À
by using ClO4 as a model of non-spherical hydrophobic
3
3
3
3
3
in water (concentrations=0.100 mM). Solid lines serve as visual
guides. b) Detection thresholds quantified as 95% of the final satu-
ration value of the fluorescence turn-on response. c) Normalized
fluorescence spectra (lexc =400 nm) of the aggregates at T=293 K.
anion that is difficult to detect with conventional macrocyclic
[19]
or cage-type receptors. Efforts are currently underway in
our laboratory to expand the scope of this chemistry by
structurally more elaborate amphiphilic receptor–fluoro-
phore conjugates.
3
+
[
3e] . Despite variations in size, the emission from the
aggregates all converge to lmax,em = 570 nm, and become Acknowledgements
indistinguishable when normalized (Figure 8c).
As a quantitative measure of sensitivity, we compared the
equiv of ClO4 that is needed to reach 95% of the final
This work was supported by the Samsung Science and
Technology Foundation (SSTF-BA1701-09).
À
saturation value of the fluorescence turn-on response. As
shown in Figure 8b, sensitivity is improved as the alkyl chain
3
+
length increases. Compared to the benchmark system [3a]
having simple hydrogen atoms at the benzene core, [3d]
Conflict of interest
3
+
having long nonyl chains shows ca. 50-fold enhancement in
sensitivity to perchlorate anion. A complete turn-on response
The authors declare no conflict of interest.
À
3+
was achieved by adding only 3 equiv of ClO4 to [3d] , which
Keywords: aggregation · anions · fluorescence ·
hydrophobic effect · molecular recognition
À
corresponds to 1 equiv of ClO relative to each fluorogenic
4
3
+ [17]
3+
pendant in [3d] . As in the case of [3a] (Figure 6b), little
3
+
spectral change was observed for [3d] with hydrophilic
[
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À
response to ClO4 (Figure S18).
This chain-length dependent sensitivity is consistent with
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chains would promote anion-induced aggregation in water.
3
+
2
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also increased the size mismatch of the cation-anion pair,
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