Aromatically functionalized pseudo-crown ethers with unusual solvent response and enhanced binding properties

Article abstract of DOI:10.1039/c8ob00100f

Conformational flexibility in the host's structure is often considered detrimental to its binding. Flexible pseudo-crown ethers with aromatic donor/acceptor groups at the chain ends, however, displayed enhanced binding affinity and selectivity, particularly when the direct binding interactions were compromised by unfavorable solvents.

Full text of DOI:10.1039/c8ob00100f

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Aromatically Functionalized Pseudo Crown Ethers with Unusual
Solvent Response and Enhanced Binding Properties
Xiaoyu Xing and Yan Zhao*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Conformational flexibility in the host’s structure is often considered contribute to the binding equilibrium, binding becomes
detrimental to its binding. Flexible pseudo crown ethers with stronger than what can be obtained from the direct binding
aromatic donor/acceptor groups at the chain ends, however, interactions alone. As a result, binding in these receptors is
displayed enhanced binding affinity and selectivity, particularly delocalized over the entire host structure instead of being
when the direct binding interactions were compromised by confined at the host–guest interface.21
unfavorable solvents.
Herein, we report two oligoether hosts with aromatic
donor/acceptor (D/A) groups at the chain ends. The aromatic
groups not only could preorganize the chain into a pseudo
crown ether but also interacted more strongly in the presence
of the guest. The result was usually strong binding for the guest,
particularly in unfavorable solvents. Despite its conformational
flexibility, such receptors could possess good binding selectivity.
Our study involved four receptors (1–4). Receptors 1 and 2
are podands31-35 with an electron-rich naphthyl and pyrenyl
group, respectively, that can interact with the electron-deficient
Biopolymers such as proteins have rich conformational
dynamics essential to their functions. Foldamers are synthetic
mimics of these biopolymers with controlled conformational
changes.1-5 Foldamer-based supramolecular hosts differ from
conventionally preorganized hosts because guest-induced
conformational change is often an inherent property of the
host,6-9 sometimes leading to unusual molecular motions during
binding.10 Extreme sensitivity to the environment can be easily
obtained from the conformational mobility.11-14 Meanwhile,
due to their highly programmable structures, foldamers can be
designed to bind complex organic molecules with high
structural precision.15-18
Guest-induced conformational change traditionally is
considered detrimental to the binding affinity because the
energetic cost associated with the change is assumed to be paid
out of the binding energy.19 Intuition also suggests that flexible
hosts, being so accommodating, would be less selective in its
binding. Although this has been the dominant view in
supramolecular chemistry, it is puzzling that conformationally
mobile biofoldamers can obtain extremely high binding affinity
and selectivity far better than rigid synthetic hosts.20
naphthalene diimide (NDI) on the other end of the chain. We
chose aromatic rings as the intrahost-interacting groups
because they can be tuned easily in strength and can be
monitored spectroscopically.36-39 The direct binding groups are
oligo(ethylene oxide), akin to an open-chain crown ether that
can bind a sodium ion through electrostatic interactions (vide
In recent years, an alternative strategy to achieve strong and
selective binding has been proposed21-23 and experimentally
verified.24-30 Representative examples include the anion-
binding peptidic bismacrocycle by Kubik and Otto,24 the crown
ether-like receptor by Carrillo and co-workers,25-27 and our
infra for the binding of other alkali metal ions).40, 41 Receptor
replaces the electron donor of and with a methyl group and
3
1
2
glutamic acid-functionalized oligocholate foldamer.28 Rational
thus is devoid of the aromatic interactions needed for the
proposed intramolecular enhancement. Crown ether derivative
30
designs are also possible.29,
In these hosts, disengaged
noncovalent interactions within the host are “turned on” by the
guest. Because these guest-triggered intrahost interactions
(together with the solvation/desolvation changes) also
4
is a covalent control, preorganized in the conventional
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methanol in the solvent—i.e., larger ET(30)—should strengthen
the aromatic interactions between NDI and naphthyl48-50 and
thus help the compound fold. Intermolecular aggregation was
ruled out by a dilution study (Figure S1 in ESI)
Pyrene emits much more strongly than NDI and the emission
spectrum of 2 is dominated by the pyrene emission (Figure 1b).
Upon addition of methanol, significant quenching occurred and
the quenching profile was a partial sigmoidal curve (Figure 2a,

). The curve also fit well to the two-state model, which shows
Fig 1. Normalized fluorescence emission spectra of compounds 1
(a), 2 (b), and 3 (c) in mixtures of methanol and DCM. [1] = 2.0 µM.
[2] = 20 µM. [3] = 30 μM. λex = 358 nm for compounds 1 and 3. λex
= 278 nm for compound 2.
a higher population of folded conformer in than in at any
2
1
given solvent composition (Figure 2b). Aromatic donors and
acceptors tend to stack face-to-face and solvophobic
interactions are known to be the major contributor to the
binding interactions, especially in polar solvents such as
methanol.48-50 Since the larger-sized pyrenyl group in
2
is
expected to provide a stronger solvophobic driving force to the
folding, better folding in is expected.
The binding properties of compounds
manner to bind sodium. Its dansyl group on the side chain
makes it easy for us to study the binding by spectroscopy.
2
Syntheses of
1–3 are reported for the first time and the
1–3 were determined
details are given in the Electron Supplementary Information
by UV titrations using sodium thiocyanate as the guest. The UV
absorptions of these compounds displayed very little change
during the solvent titration (in DCM/methanol mixtures) and
thus better reflects the effect of binding than the changes in
emission.51 As shown by the titration curves (Figures S2 and S3),
(ESI). Compound
procedure.42
4 was synthesized according to a literature
Figure 1a,c shows the emission spectra of
methanol and dichloromethane (DCM).43 Compounds
were excited at λex = 358 nm, where naphthyl had no
absorption. Although quenching was observed in both to a 1:1 binding isotherm, from which the binding constant
1–
3
in mixtures of
1
and
3
the UV absorbance (at 358 nm for
1 and 382 nm for 2) fit well
could be determined.
compounds, the emission peaks changed in shape in
1 but
Figure 3a shows the relationship between log Ka of
mostly decreased in intensity in , presumably due to the NDI–
naphthyl interactions in the former. When the emission
intensity of NDI at ~390 nm was plotted against solvent polarity
3
compounds
binding for sodium by
methanol/DCM mixtures and thus was not included.
The preorganized receptor ( ) displayed a monotonous
1
,
2, and
4
and the solvent composition. The
3
was hardly measurable in
(Figure 2a), compound
compound a straight line (
decrease in emission intensity in
effect on the NDI, as no other fluorophore was present in this
1
afforded a sigmoidal curve (
). It is likely that the linear
was from a generic solvent
) but
4, 
3

decrease in log Ka with increasing solvent polarity (larger
ET(30))—this is the conventional solvent effect for the binding.
Because methanol solvates both the binding functionalities
(oxygen atoms on the ether chain) and the sodium guest, higher
methanol in the solvent increases the desolvation cost of the
binding. In addition, the higher dielectric constant of methanol
over DCM screens the electrostatic interactions between the
host and the guest and also weakens the binding.
3
compound. The sigmoidal transition in 1, on the other hand, is
a hallmark of cooperative conformational changes.44
As shown in Figure 2, the fluorescence data for compound
1
() fit well to the two-state transition model (unfolded 
folded), which assumes the compound only exists in the folded
or unfolded form and the free energy for the conformational
change is linearly related to solvent polarity.44 Two-state
conformational changes are frequently observed in foldamers
stabilized by solvophobic interactions.12, 45-47 In our case, higher
(a)
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
(a)
1
0.8
0.6
0.4
0.2
50
51
52
53
54
55
56
ET(30) (kcal/mol)
Fig 3. (a) Binding constant of compounds 1 (), 2 (), and 4 ()
for sodium determined by UV-vis titrations against solvent polarity
in methanol/DCM mixtures. The binding constants were averages
from triplicate titrations at 90% confidence level. Titrations curves
are reported in the ESI (Figures S2–S5) and binding constants in
Table S1. (b) Unfolded fraction of 1 as a function of solvent polarity
(black line) and log Ka of 1 for NaSCN (red line). The solid smooth
curve was from nonlinear least-squares fitting of the intensity to
the two-state transition model.
0
49 50 51 52 53 54 55 56
ET(30) (kcal/mol)
Fig 2. (a) Normalized fluorescence emission intensity at 390 nm as
a function of solvent polarity for compounds 1 (), 2 (), and 3
(). The emission intensity of compound 3 fit well to a linear
relationship with R = 0.995. (b) Unfolded fraction as a function of
solvent polarity for compound 1 () and 2 (). Details of fitting are
found in ESI.
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Both the naphthyl–NDI (1, ) and pyrenyl–NDI receptor (2,
that the naphthyl and NDI are separated by a significant
distance in the NMR sense (Figure S8). Addition of sodium
significantly enhanced the naphthyl–NDI contact and numerous
naphthyl–NDI cross peaks appeared (Figure S10). The NDI
protons also became closer to the ethylene oxide protons,

) behaved differently, showing a decrease in binding followed
by increasing ET(30) (Figure 3a). In low-polarity solvents, log Ka
followed the order of . This trend supports the
importance of preorganization in this solvent region. Receptor
has the best preorganization among the three, being
covalently formed. The D–A aromatic interactions in and
serve to preorganize the compound into a pseudo crown ether
4
> 2 > 1
4
supporting the sodium-triggered “ring closure” in
1. Our
1
2
fluorescence data indicate that the population of folded 1 was
over 90% in methanol (Figure 2b). The CT band in the UV-vis
spectrum (Figure S6) indicates that some of the naphthyl and
NDI groups were in reasonable proximity. Taken together, the
spectroscopic data support a loosely bound donor–acceptor
pair, hypothesized to be essential to the cooperatively
enhanced binding.
and the stronger D–A interactions in
2 makes it better
preorganized for binding sodium.
The inflection points in the log Ka curves suggest that a
different binding mechanism began to dominate in more polar
solvents for
1 and 2 (Figure 3a). Several pieces of evidence
support that the guest-triggered D–A interactions dominated
after the inflection points.
First, since the direct binding force between oligo(ethylene
oxide) and Na+ was weakened continuously by polar solvents
Fifth, although by itself not conclusive, the extremely weak
binding of
3
was consistent with the intramolecular
enhancement. Without an appropriate donor, intramolecular
D–A interactions do not exist in this compound. Without the D–
A interactions, neither preorganization nor intramolecular
enhancement could operate and the weak binding was an
expected result.
Figure 3a also shows that the onset of intramolecular
enhancement was earlier for 1 than for 2. The most likely reason
for this is the interplay between the preorganization and
intramolecular enhancement. In general, very strong D–A
interactions favor preorganization but a weakly bound D–A pair
with “room for improvement” is best for intramolecular
(evident from the weaker binding of the control receptor
4), the
increase in log Ka for and beyond the inflection points must
1
2
have other sources. Better preorganization by methanol to
strengthen the D–A interactions cannot explain the trend, as the
order of binding reversed for
As mentioned above, the stronger D–A interactions in the
pyrenyl receptor ( ) should better preorganize the compound
1 and 2 after the inflection points.
2
for binding. Interactions between the imide carbonyls and
sodium could not explain the reversal either. (Besides, even
with the imide carbonyls, 3 always displayed weak binding.)
Second, the key feature of intramolecular enhancement is
that guest-triggered intramolecular interactions become part of
the overall binding energy. Such enhancement is expected to
occur only if the donor and acceptor are not fully engaged prior
enhancement. In the case of
2, the stronger pyrenyl–NDI
interactions serve to better preorganize the oligo(ethylene
oxide) chain for binding, and thus can promote the principle of
preorganization and make it last longer.
to the guest binding. Given that
2 folded almost fully in
To be selective in binding, preorganized receptors typically
are fairly rigid so that only the best-fitted guest can enter the
binding site to engage the largest number of binding
interactions possible. Intramolecularly enhanced receptors
obtain their binding selectivity in a different way—by having the
best guest turn on the largest number of intrareceptor
interactions while maintaining as much direct binding
interaction as possible.29, 30
methanol (Figure 2b), it is quite likely that the pyrenyl and NDI
were simply bound too well prior to guest-binding so that
further improvement from the guest binding was minimal.
Weaker naphthyl–NDI interactions in 1, on the other hand,
made it possible for the guest to strengthen the D–A
interactions. Thus, the model of intramolecular enhancement
correctly predicts the weaker binding of
inflection points.
2 than 1 after the
Receptor
1 indeed displayed significant binding selectivity,
Third, when 10% water was added to methanol,
precipitous drop in binding was observed for
(Ka < 10 M-1,
Figure 3b, red dashed line) while was barely affected (Ka went
a
despite its flexibility.52, 53 In methanol, among common alkali
metal ions, it showed insignificant binding for Li+, bound Na+
with Ka = 1.6 × 103 M-1, and bound K+ with Ka = 4.2 × 102 M-1
(Figure S12). The Na/K ratio in the binding affinity was nearly
4:1. In contrast, the binding constants of 15-crown-5 for Na+ and
K+ are reported to be 1.7 × 103 and 2.7 × 103 M-1, respectively,
with a Na/K ratio of 1:1.5—18-Crown-6 has a Na/K ratio of 1:54.
1
4
from 200 to 180 M-1). Thus, the small amount of water did not
change the direct binding force significantly but completely shut
down the intramolecular enhancement. Addition of water
served to increase the solvophobic interactions between the
donor and acceptor, evident from the enhanced charge-transfer
54
Therefore, at least in this example, the flexible
band near 450 nm for
1 (Figure S6). Once the D–A pair became
intramolecularly enhanced receptor
1 actually displayed a
tightly bound before the guest binding, the very basis of
intramolecular enhancement—guest-triggered strengthening
of intrahost interactions—was removed. Similar observation
was made in other intramolecularly enhanced receptors.28-30
Fourth, the sodium-enhanced D–A interaction was
confirmed spectroscopically. As shown by UV-vis spectroscopy,
higher binding selectivity for sodium than the traditionally
preorganized crown ether.
In summary, flexible structures with intramolecular
enhancement offer an interesting strategy to strong and
selective receptors. As shown by Figure 3a, they become
particularly competitive when the direct binding forces are
weakened by unfavorable solvents. Binding selectivity,
meanwhile, does not have to suffer. These are very useful
properties and could help chemists design a new generation of
biomimetic receptors.
when sodium was added to
1 in methanol, the charge-transfer
band near 450 nm increased steadily, supporting a closer
contact between the donor and acceptor induced by the guest
(Figure S7). Receptor
1 displayed no NOE signals between the
NDI and the naphthyl protons in methanol at 213 K, suggesting
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We thank NSF (CHE-1303764 and CHE-1708526) for 29. R. W. Gunasekara and Y. Zhao, J. Am. Chem. Soc., 2015, 137,
supporting this research.
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Notes and references
Department of Chemistry, Iowa State University, Ames, Iowa
50011-3111, USA. Fax: + 1-515-294-0105; Tel: +1-515-294-5845;
E-mail: zhaoy@iastate.edu
† Electronic Supplementary Informa on (ESI) available: syntheses
and characterization of materials, experimental procedures for
the binding studies, additional data and Figures. See
DOI: 10.1039/c000000x/.
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