Cation Molecular Exchanger Based on a Conformational Hinge

Article abstract of DOI:10.1021/acs.orglett.8b02687

A cation molecular exchanger has been developed that consists of the bipyridine and crown ether receptor subunits. It has been shown that binding of the zinc(II) cation to the bipyridine subunit induces the conformational switching of the crown ether subunits, which results in a release of the potassium cation. Two conformational states of the cation exchanger have been supported by the results from solution- and solid-state studies. It has been demonstrated that the cation exchanger is able to communicate with a cation sensor induced by a chemical stimulus.

Full text of DOI:10.1021/acs.orglett.8b02687

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cation Molecular Exchanger Based on a Conformational Hinge
Anil Ravi,† P. Sivarama Krishnarao,† Tatiana A. Shumilova,† Victor N. Khrustalev,‡,§ Tobias Ruffer,†
̈
Heinrich Lang,† and Evgeny A. Kataev*,†
†
̈
Institute of Chemistry, Technische Universitat Chemnitz, 09107 Chemnitz, Germany
‡National Research Center Kurchatov Institute, Acad Kurchatov Square 1, 123182 Moscow, Russian Federation
§Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklay Street 6, 117198 Moscow, Russian Federation
S
* Supporting Information
ABSTRACT: A cation molecular exchanger has been
developed that consists of the bipyridine and crown ether
receptor subunits. It has been shown that binding of the
zinc(II) cation to the bipyridine subunit induces the
conformational switching of the crown ether subunits, which
results in a release of the potassium cation. Two conforma-
tional states of the cation exchanger have been supported by
the results from solution- and solid-state studies. It has been demonstrated that the cation exchanger is able to communicate
with a cation sensor induced by a chemical stimulus.
reported molecular exchanger belongs to the group of
he activity of enzymes is regulated by conformational
Tchanges induced by reversible binding of one or more receptors with homotropic negative cooperativity.15−22 In
contrast to our system, the known systems utilize metal cations
together with organic cations23 or neutral molecules.17,19 Such
types of molecular exchangers have a great potential in various
applications such as sensing, ion-transport, and molecular
electronics.24,25
guest molecules. This allosteric behavior is used by nature to
transduce information on the molecular level.1 The majority of
signal outputs are small molecules and ions, which are
generated in response to a recognition event. Examples are
receptor enzymes or plasma membrane receptors, such as
insulin receptor, β-adrenergic receptor, gated ion channels, and
many others. The complexity of natural systems has raised
interest among scientists to design synthetic systems that are
able to process the information on the molecular level.2,3 To
date, a number of synthetic molecules and supramolecular
ensembles have been developed that communicate with each
other4−7 or perform logic operations with one and more input
and output functions.8 Success has also been achieved in
designing functional receptors capable of selective transport
and ion exchange across the membrane.9 However, systems
that link two cation receptors sites in order to transmit the
effect of binding at one site to another through a conforma-
tional hinge are unknown. To realize the idea of allosterically
interacting binding sites, a certain degree of rigidity between
these sites should be introduced.10,11
Cyclohexanes are attractive molecules for the construction
of molecular devices because the orientation of the axial and
equatorial positions in the ring are alternated by a ring flip.26
This property has been successfully utilized to construct a
series of molecular switches. For instance, cyclohexanes have
been functionalized with binding sites to recognize cations.27,28
Synthetic receptors containing thiourea fragments have been
demonstrated to bind and detect malonate, succinate29 and
maleate anions.30 A number of switches have been developed
bearing pyrene subunits for sensing applications.29,31−33
Coordination of, e.g., Zn2+ induced a ring flip and, thus,
effected excimer/monomer emission of the pyrene moi-
eties.31,32 A series of cyclohexane-based conformational
switches with pH-dependent conformational equilibrium
have been also reported.34−36
To design a cation molecular exchanger in which two
receptor subunits remotely communicate with each other, we
have functionalized the cyclohexane ring in positions 1, 2 and
4, 5 (Scheme 1). The substituents on the right and on the left
sides have different configurations, axial and equatorial,
respectively. Binding of a cation (Zn2+) to two bipyridine
subunits should lead to a rearrangement of a pair of
substituents connected to the crown ether from equatorial
(state A) to axial positions (state B) in a concerted way. As a
As detailed below, we have now developed a “cation
molecular exchanger”, which combines two recognition sites
linked through a conformational hinge. The molecular
exchanger releases one cation (K+) upon coordination of
another cation (Zn2+). This design represents the converse of
what has typically been the goal of supramolecular chemists,
namely to create an allosteric system, wherein the binding of
one cation increases the affinity for binding of additional
cations12,13 or anions.14 To the best of our knowledge, this is
the first metal-cation molecular exchanger with two interacting
receptor sites through a cyclohexane ring, wherein binding to
one site switches off the cation affinity of the other site. The
Received: August 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02687
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the chloroform solution of 6 (Figure 1a). The sodium ion is
bound to the crown ether and coordinates the alcohol groups
Scheme 1. General Idea for the Design of a Cation
Molecular Exchanger
a
a
Figure 1. (a) Structure of complex 6·NaClO4 according to the single-
crystal X-ray analysis showing part of the coordination network
formed by the interaction between the hydroxyl group and sodium.
(b) Structure of complex 7·Zn(ClO4)2. Hydrogen atoms, perchlorate,
and solvent molecules were removed for clarity.
Binding of cation M2 to receptor subunit R2 induces a release of the
cation M1 from subunit R1. Structure of the cation exchanger and the
mechanism of Zn2+/K+ exchange.
result, the crown ether will lose the affinity for, e.g., K+ because
of the conformational change.
of two other neighboring receptors. As a result, crown ether
molecules form a coordination network in the crystal.
Coordination of zinc(II) ion to 7 inverts the cyclohexane
ring and thus elongates the crown ether subunit (Figure 1b).
The crown ether loses the appropriate orientation of oxygen
atoms to bind, e.g., sodium or potassium cations. Interestingly,
zinc(II) coordinates two ether oxygen atoms, making the
structure even more rigid.
The design of our cation exchanger combines 18-crown-6
and bipyridine receptor subunits capable of selective
recognition of alkali (Na+, K+) and transition-metal cations
(Zn2+, Cu2+), respectively. Receptor 7 was prepared as a
racemic mixture by the stepwise opening of the epoxides 221
and 5 obtained from 1,4-cyclohexadiene (Scheme 2). Finally,
receptor 6 was alkylated with 2,2′-bipyridine subunits37 to
yield 7 in a moderate yield.
To understand the conformation of the free receptor in
solution, we conducted a series of COSY, ROESY, and
temperature-dependent NMR measurements. In the COSY
spectrum of free 7 we observed cross peaks Ha−Hax and Hb−
Heq, which are indicative of equatorial positions of the ether
groups belonging to the crown ether (state A, Scheme 1).36 On
the contrary, the COSY spectrum of the zinc(II) complex
revealed cross signals Hb−Hax and Ha−Heq (Figures S1−S4).
This fact provides evidence of the axial orientation of ether
groups (state B). With the help of temperature-dependent
NMR measurements, we determined the energy barrier (ΔG⧧,
free activation energy) for switching from state A to state B,
which is 7 1 kcal/mol. By cooling the solution to −60 °C the
distance between signals of Hax and Heq protons increases. The
coalescence temperature was observed at −45 °C (Figure S9
and Figure 2).
Two states of the molecular exchanger shown in Scheme 2
were successfully characterized by single-crystal X-ray analysis.
The sodium complex was obtained by addition of NaClO4 to
Scheme 2. Synthesis of 7
Next, we investigated cation-binding properties of receptor 7
in pure methanol and in a 1:1 methanol−water mixture by
1
using H NMR and UV−vis spectroscopy. According to the
NMR measurements in CD3OD, 7 binds K+ and Na+ with
stability constants of 3380
20 and 1120
10 M−1,
respectively. Binding of Zn2+ is extremely strong, so that
spectra of both the complex and the receptor are observed
during the NMR titration (Figure S8). Addition of K+ or Na+
cations to the zinc(II) complex of 7 does not induce any
proton shifts. This fact indicates that crown ether in an
B
DOI: 10.1021/acs.orglett.8b02687
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Figure 2. 1H NMR spectra showing positions of the cyclohexane
proton shifts (1) of free receptor 7 in CD3OD, (2) after addition of
10 equiv of potassium salt to 7, (3) after addition of 1 equiv of
zinc(II) salt to 7, and (4) of free receptor 7 at −60 °C.
elongated form does not bind the cations with the detectable
affinity (K < 10 M−1). Moreover, 1H NMR spectra obtained by
addition of Zn2+ to the receptor in the presence and in the
absence of a large excess of K+ appeared to be identical. To
determine the association constant of 7 with Zn2+ ,we
conducted UV−vis titrations in a methanol−water mixture
with constant ionic strength (5 mM tetrabutylammonium
perchlorate). The calculated stability constant of the
corresponding complex was 2.7 × 107 M−1, which is close to
the accuracy limit of the method. Similar titration of the
receptor with Zn2+ in the presence of 200 equiv of K+ (as
perchlorate salts) resulted in a slightly lower affinity, 1.8 × 107
M−1. Thus, these experiments suggest that binding of the
zinc(II) cation should switch the conformation of the receptor
leading to a release of the bound potassium from the crown
ether subunit. We also determined the stability constants of 7
Figure 3. (a) Changes in the absorption of picrate induced by
addition of zinc(II) perchlorate to a solution of 7 (0.01 mM) and
potassium picrate (0.04 mM) in methanol. (b) Changes in the
fluorescence spectrum of cation sensor 8 during the addition of
zinc(II) perchlorate to a methanol solution 7 (0.01 mM), 8 (0.01
mM), and potassium perchlorate (0.5 mM). Conditions: ex 440 nm,
em 530 nm.
with K+ (501
5 M−1) and Na+ (186
3 M−1) in a 1:1
which has lower affinity for potassium than receptor 7. The
absorption and emission spectra of the naphthalimide dye (ex
440 nm, em 530) does not interface with the spectra of 7 (ex
290 nm, em 340 nm). According to fluorescence titrations in
methanol, receptor 8 binds K+ and Zn2+ cations with a “turn-
on” response and binding constants 240 5 and 2950 50
M−1, respectively (Figures S13 and 14). Thus, in the solution
containing both receptor 7 and 8, the larger part of the
potassium cations should be bound to 7. As can be seen in
Figure 3b, addition of Zn2+ to this solution until 1 equiv results
in a small fluorescence enhancement, which is indicative of the
redistribution of potassium cations between receptors 7 and 8
favoring the formation of the potassium complex with 8. The
observed fluorescence enhancement (F/F0) is comparable with
that observed for titration of free 8 with K+. An excess of Zn2+
in solution leads to a much stronger fluorescence increase
because Zn2+ replaces K+ in crown ether 8 due to the higher
stability of the zinc(II) complex.
In summary, we have demonstrated that simple conforma-
tional switching of the cyclohexane ring can be translated to a
more sophisticated mechanism of controlling the binding
properties of the receptors with an external chemical stimulus.
The present functional molecule represents the first example of
a molecular cation exchanger. We have shown that binding of
the zinc(II) cation to the bipyridine receptor subunit induces
the conformational switching of the crown ether subunit,
methanol−water mixture, which were ca. 1 order of magnitude
lower than those found in pure methanol. The complete loss of
affinity of complex 7·Zn2+ for potassium cation can be also
explained by the repulsion between two cations with distance
of ca. 9 Å. However, in systems with a similar cation distance
positive cooperativity was observed, indicating that solvent
strongly reduces repulsion interactions.38,39
To demonstrate that our cation exchanger can participate in
chemical communication processes, we conducted two experi-
ments. In the first experiment, potassium picrate was added in
excess to a solution of 7 in methanol. The absorption of the
picrate (340−440 nm) is well separated from the absorption of
the zinc(II) complex of the receptor. Interaction between the
potassium cation bound to the crown ether and the picrate
anion is expected to be very strong in organic solvents.40
Therefore, slow addition of Zn2+ to the potassium complex of
7 should result in a release of the potassium cation together
with the picrate anion. This dissociation process should be
detected by UV−vis spectroscopy. Indeed, in such an
experiment, we observed an increase in the absorption of
picrate up to 1 equiv of Zn2+ followed by a decrease of the
absorption because of its interaction with the zinc(II) cation
(Figure 3a).
In the second experiment, we prepared cation sensor 8,
naphthalimide-functionalized aza-15-crown-5 (Figure 3b),
C
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which results in a release of the potassium cation. Two
conformational states of the cation exchanger have been
supported by the results from solution- and solid-state studies.
Chemical signal transduction has been studied between the
cation exchanger and a crown ether-based sensor. This system
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ASSOCIATED CONTENT
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Accession Codes
CCDC 1854672 and 1856527 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: evgeny.kataev@chemie.tu-chemnitz.de.
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Victor N. Khrustalev: 0000-0001-8806-2975
Tobias Ruffer: 0000-0001-8948-1477
̈
Heinrich Lang: 0000-0001-9744-7906
Evgeny A. Kataev: 0000-0003-4007-8489
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Deutsche Forschungsgemeinschaft DFG Grant No.
3444/12-1 (E.A.K.) and RUDN University Program “5-100”
(V.N.K.) for financial support.
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DOI: 10.1021/acs.orglett.8b02687
Org. Lett. XXXX, XXX, XXX−XXX