A multi-state, allosterically-regulated molecular receptor with switchable selectivity

Article abstract of DOI:10.1021/ja503506a

A biomimetic, ion-regulated molecular receptor was synthesized via the Weak-Link Approach (WLA). This structure features both a calix[4]arene moiety which serves as a molecular recognition unit and an activity regulator composed of hemilabile phosphine alkyl thioether ligands (P,S) chelated to a Pt(II) center. The host-guest properties of the ion-regulated receptor were found to be highly dependent upon the coordination of the Pt(II) center, which is controlled through the reversible coordination of small molecule effectors. The environment at the regulatory site dictates the charge and the structural conformation of the entire assembly resulting in three accessible binding configurations: one closed, inactive state and two open, active states. One of the active states, the semiopen state, recognizes a neutral guest molecule, while the other, the fully open state, recognizes a cationic guest molecule. Job plots and ¹H NMR spectroscopy titrations were used to study the formation of these inclusion complexes, the receptor binding modes, and the receptor binding affinities (K_a) in solution. Single crystal X-ray diffraction studies provided insight into the solid-state structures of the receptor when complexed with each guest molecule. The dipole moments and electrostatic potential maps of the structures were generated via DFT calculations at the B97D/LANL2DZ level of theory. finally, we describe the reversible capture and release of guests by switching the receptor between the closed and semiopen configurations via elemental anion and small molecule effectors.

Full text of DOI:10.1021/ja503506a

Article
pubs.acs.org/JACS
A Multi-State, Allosterically-Regulated Molecular Receptor With
Switchable Selectivity
Jose Mendez-Arroyo,† Joaquín Barroso-Flores,§ Alejo M. Lifschitz,† Amy A. Sarjeant,† Charlotte L. Stern,†
and Chad A. Mirkin*,†
†Department of Chemistry and International Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston,
Illinois 60208, United States
§Centro Conjunto de Investigacion
Cayetano, Toluca, Estado de Mexico C. P. 50200, Mex
́
en Química Sustentable, UAEM-UNAM, Carretera Toluca-Atlacomulco Km 14.5, Unidad San
ico
́
́
S
* Supporting Information
ABSTRACT: A biomimetic, ion-regulated molecular receptor was synthe-
sized via the Weak-Link Approach (WLA). This structure features both a
calix[4]arene moiety which serves as a molecular recognition unit and an
activity regulator composed of hemilabile phosphine alkyl thioether ligands
(P,S) chelated to a Pt(II) center. The host−guest properties of the ion-
regulated receptor were found to be highly dependent upon the
coordination of the Pt(II) center, which is controlled through the reversible coordination of small molecule effectors. The
environment at the regulatory site dictates the charge and the structural conformation of the entire assembly resulting in three
accessible binding configurations: one closed, inactive state and two open, active states. One of the active states, the semiopen
state, recognizes a neutral guest molecule, while the other, the fully open state, recognizes a cationic guest molecule. Job plots and
1H NMR spectroscopy titrations were used to study the formation of these inclusion complexes, the receptor binding modes, and
the receptor binding affinities (Ka) in solution. Single crystal X-ray diffraction studies provided insight into the solid-state
structures of the receptor when complexed with each guest molecule. The dipole moments and electrostatic potential maps of the
structures were generated via DFT calculations at the B97D/LANL2DZ level of theory. Finally, we describe the reversible
capture and release of guests by switching the receptor between the closed and semiopen configurations via elemental anion and
small molecule effectors.
exhibited the ability to encapsulate and release small organics,31
INTRODUCTION
■
therapeutic agents,32 and biomolecules33 as a response to
changing chemical environment. While the applications of such
structures in phase transfer catalysis,34−36 drug delivery,37 and
sensing38 have been reported, the usefulness of this approach
could be greatly expanded through the development of an
abiotic platform to allosterically toggle a single cavitand
between an inactive and multiple active states with different
recognition properties. However, controlling molecular capsu-
les through this approach remains a significant challenge, since
regulation must then involve several chemical and structural
transformations around the cavitand that must be orthogonal to
one another.
Allosteric control of binding sites in proteins and enzymes plays
a major role in the regulation of a diverse array of critical
biological processes, such as protein folding1 and oxygen
transport.2 Enzymatic activity in these processes is often
regulated either by controlling the steric profile or the chemical
affinity of the binding site for different substrates.3 The former
type of allosteric control is commonly employed to regulate
physical access to a binding site, as in the case of protein folding
in molecular chaperonins, thus enabling toggling between an
active and an inactive state.4−6 In contrast, the switching
between multiple and distinct active states requires the ability
to control the chemical affinity of the reactive cavity for a
variety of guests without hindering the substrates’ access to it.
As such, changes in pH and their associated effects on the
structure of hemoglobin are used to regulate the binding of
oxygen and carbon dioxide by the same protein, providing an
efficient mechanism for the control of gas concentrations in
biological tissues.7,8
Herein, we report the synthesis of a novel calix[4]arene ion-
regulated receptor assembly whose encapsulation properties
can be modulated via small molecule displacement reactions of
hemilabile ligands coordinated to d8 metal centers strategically
positioned above the cavitand (Scheme 1). Our design is based
on the Weak-Link Approach (WLA)25,39−41 to the synthesis of
supramolecular structures, which has been previously used to
construct abiotic allosteric enzyme mimics with applications in
sensing,42,43 signal amplication,24 and control of catalytic
In order to mimic the properties and regulatory capabilities
of reactive cavities in biological machinery, a number of abiotic
counterparts have been developed in which the steric profile
and the size of molecular cages are regulated via pH
changes,9−12 photochemistry,13−16 redox processes,17−19 and
coordination chemistry.20−30 Such abiotic systems have
Received: April 14, 2014
© XXXX American Chemical Society
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Scheme 1. Allosteric Modulation of Calix[4]arene Ion-
regulated Receptor Assemblies via the WLA
RESULTS AND DISCUSSION
■
Synthesis. Calix[4]arenes are commonly studied molecules
whose host−guest properties can be synthetically adjusted via
transformations on the cavitand’s upper and lower rims.45−47
Generally, modifications of the upper rim result in extension of
the cavitand’s depth and lead to higher binding affinities for
certain aromatic guests.45−48 For this reason, it was
hypothesized that bifunctionalization of calix[4]arene in the 5
and 17 positions with hemilabile phosphine-alkyl thioether
(P,S) moieties through phenyl spacers would create a high-
affinity binding pocket suitable for small aromatic guests. The
synthesis of compound 4 was thus achieved via a convergent
process in 8 steps from commercially available calix[4]arene
tetrol (7) (Scheme 2). In order to preserve the integrity and
flexibility of the binding site throughout coordination chemistry
transformations, the calix[4]arene was first locked in a cup
conformation through tetraalkylation of the lower rim. This
transformation was followed by halogenation with N-
bromosuccinimide to incorporate four bromide units along
the calix[4]arene’s upper rim. Symmetric debromination of two
of these four brominated positions was achieved via selective
lithiation with 2 equiv of n-butyl lithium and quenching with
methanol. The remaining brominated moieties were coupled to
sulfide protected P,S ligands via Pd catalyzed cross-coupling.
Finally, removal of the protecting sulfide in compound 11 was
achieved via reaction with Schwartz’s reagent to yield the air-
sensitive hemilabile ligand 4 in 14% overall yield.
Assembly of the Pt(II)-containing ion-regulated receptor
system 1 was achieved following well-established WLA
protocols.39−41 Addition of a dichloro Pt(II) precursor to
compound 4 in dichloromethane yields a mixture of Pt(II)-
containing species in which the Cl− anions are dynamically
exchanging in and out of the inner coordination sphere,
partially displacing the P,S moieties. Both chlorides can be
abstracted from the inner coordination sphere through either
an increase in solvent polarity (addition of methanol),
precipitation of Cl− from solution, or via displacement with
strongly coordinating anions. In particular, abstraction of 1 or 2
activity.44 In the present work we demonstrate that the size and
charge of a WLA ion-regulated receptor assembly can be
modulated using small molecule effectors, thus enabling access
to three exclusive supramolecular configurations, each with
unique host−guest properties. In particular, this system features
a physically blocked inactive state and two unique active states
that display similar cavity sizes while showing distinct chemical
affinity for different types of guest molecules. The character-
istics of each receptor binding state (1, 2, or 3) are determined
by the coordination modes of the hemilabile moieties extending
from the cavitand and the associated electrostatic characteristics
of the cavity, all of which are regulated with molecular effectors
(Cl− and CN−). The combined control of both cavity size and
chemical affinity in this coordination-controlled assembly
makes use of the most prevalent mechanisms of allosteric
regulation found in biological machinery and offers a promising
strategy to the development of biometic supramolecular
assemblies.
Scheme 2. Synthesis of Calix[4]arene Functionalized Hemilabile Ligand 4
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equiv of Cl− using stoichiometric amounts of NaBArF yields
interaction with the molecular receptor in the closed complex 1
or semiopen complex 2 (Figure 1). While the lack of binding
affinity of 5 for closed complex 1 is understandable, based on
the reduced cavity size that the coordination mode imparts on
the calix[4]arene, the same behavior in the semiopen complex 2
suggests that the WLA can be exploited to alter the intrinsic
affinity of calix[4]arene receptors for electron-deficient guests.
Indeed, the lack of encapsulation found in 2 can be attributed
to the electrostatic repulsion between the Pt(II) regulatory site
and the cationic guest 5. Accordingly, the formation of a 1:1
host−guest complex can only be observed between cationic
guest 5 and the molecular receptor in its neutral, fully open
configuration 3, indicating that the electrostatic repulsion
between 5 and 2 plays a major role dictating the host−guest
selectivity. Neutral guest 6, on the other hand, does not form
any detectable inclusion complexes with fully open receptor 3,
only very small changes in the chemical shift of guest molecule
6 are observed. Only the positively charged semiopen complex
2 is able to encapsulate guest molecule 6 in the form of a 1:1
inclusion complex (Figure 1). Closed complex 2 does not
incorporate 6, presumably due to the collapse of the binding
cavity and steric inaccessibility. Taken together, the ability to
regulate the recognition of guest molecules 5 and 6, simply by
adjusting the size and charge of the host pocket using discrete
ion-driven reactions, underscores how the WLA can be used to
create multi-state molecular receptors that can be addressed via
well-defined chemical events.
4
semiopen complex 2 or closed complex 1, respectively, in
quantitative yield. Closed complex 1 can be in turn converted
to semiopen complex 2 and fully open complex 3 via addition
of 1 equiv of Cl− or 2 equiv of CN−, respectively (Scheme 1).
Although complexes 1 and 3 are stable in solution and exist as
well-defined entities, the ion-regulated receptor 2 displays a fast
dynamic exchange in solution in which the two thioether
linkages compete for coordination with Pt(II), alternating
between bound and displaced states. This fluxional process
commonly occurs in WLA systems when the coordination
strength of two thioether linkages is similar, and it has been
extensively documented in the literature.41,49,50 A complete
account of synthetic procedures and associated characterization
data (1H NMR, 31P{1H}NMR, and ESI-MS) of compounds 4
and 8−15 can be found in the Supporting Information.
Formation of Inclusion Complexes. N-substituted
pyridine derivatives are a diverse class of electron-deficient,
aromatic compounds that are well-known to form inclusion
complexes with functionalized calix[4]arenes.51−54 Two guests,
cationic N-methylpyridinium BArF − (5) and neutral N-oxide
4
pyridine (6), were thus selected in order to probe the binding
properties of molecular receptors 1−3. Formation of inclusion
1
complexes was determined by H NMR titration of guests 5
and 6 into solutions of complexes 1−3 (Figure 1). The binding
stoichiometry of host−guest complexes was determined by
using Job plots (see Supporting Information). In the case of
1H NMR Titrations and Solution Behavior. Structural
rearrangement of 2 and 3 upon formation of complexes 6∩2
1
cationic guest 5, H NMR titration displays no significant
1
and 5∩3 was investigated by tracking changes in H NMR
spectroscopy resonances through the titration of 6 and 5 into
CD3CN and CD2Cl2 solutions of 2 and 3, respectively. From
these data, the binding affinities (Ka) and binding modes of
guests 5 and 6 for their respective hosts 3 and 2 were
elucidated. Figure 2 shows the 1H NMR spectra resulting from
the addition of up to 18 equiv of 5 to receptor 3. The signals
assigned to N-methyl protons (ω) in 5 exhibit a characteristic
large upfield shift upon cavitand encapsulation of guest.45,46
Upfield chemical shifts of the α, β, and γ protons in 5 are also
observed, suggesting that the entire guest molecule is in the
cavity.45−48,51−53 Furthermore, the binding of 5 by ion-
regulated receptor 3 also reveals general structural reorganiza-
tion of the assembly upon encapsulation, resulting in chemical
changes in the chemical shift of the proton resonances
corresponding to the P,S ligands and the calix[4]arene. In
particular, the ethyl protons (b1,b2) in the P,S ligands, which
appear as broad features prior to guest incorporation, are split
into two distinct triplets. This splitting suggests reduced
mobility of the flexible ethyl bridge and stabilization into an
overall more rigid conformation. Accordingly, the two sets of
signals from methyl protons at the end tail of the propyl chains
(d1,d2) in the calix[4]arene bottom rim coalesce into a broad
triplet. This phenomenon is attributed to the reduction in
anisotropy of the calix[4]arene cup to achieve a more uniform
conformation that allows for a larger volume, which can
accommodate the guest.
1
Figure 1. H NMR traces for ion-regulated receptor assemblies 1−3
and their corresponding inclusion complexes. All titrations were
performed at room temperature with a total concentration of host and
guest of 30 mM in CD3CN, except for fully open complex 3, which
was studied in CD2Cl2 due to poor solubility in CD3CN. Note that
receptor 2, when dissolved in CD2Cl2 does not form an inclusion
complex with 5, ruling out the difference between 2 and 3 being purely
a solvent effect. The 1H NMR resonances of the N-methyl group (ω)
were used as a probe for 5, and in titrations involving 6 the resonance
of the β proton was used.
1
Similar effects on H NMR resonances are observed upon
titration of 32 equiv of 6 into a solution of 2 (Figure 2). In
particular, the aromatic protons in 6 are also shifted upfield, as
in the case of host−guest complex 5∩3, suggesting the
inclusion inside the cavity of 2. The broad signals of the
ethyl spacers (b1,b2) of the P,S ligands in 2 also undergo a
process of rearrangement with increasing concentrations of 6.
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1
Figure 2. (Left) H NMR titration of guest 5 (18 equiv) into ion-regulated receptor 3. Titration was performed at room temperature with a host
concentration of 26 mM in CD2Cl2. (Right) 1H NMR titration of guest 6 (32 equiv) into ion-regulated receptor 2. Titration was performed at room
temperature with a host concentration of 30 mM in CD3CN.
This is seen in the downfield shift and coalescence of these
ethyl H NMR signals into a single broad resonance at high
Solid-State Characterization of Host−Guest Com-
plexes. Single crystals suitable for X-ray diffraction of 1,
6∩2, and 5∩3 were grown to gain further insight into the
structural features of the three ion-receptor configurations and
their respective host−guest complexes. The solid-state structure
of 1 confirms that both P,S ligands chelate to the Pt(II) metal
center in a square planar coordination geometry causing the
collapse of the calix[4]arene cavity (Figure 3). In particular, the
distance between the centroids of the two phenyl groups
extending from the P,S ligands is 3.668 Å, which physically
prevents complex 1 from engaging in host−guest interactions,
since the distance lies within the range of π−π stacking.
Furthermore, this closed configuration forces the distortion of
the flexible calix[4]arene upper rim into an ellipsoid that is
approximately 7.718 by 4.784 Å. The disorder of the lower-rim
propyl tails observed in the solid-state structure arises from the
multiple orientations the alkyl tails can adopt in the face-on
arrangement found in solid-state structure of 1.
1
guest concentrations. Furthermore, as in the case of the 5∩3
complex, the resonances for the methyl tail in the propyl chains
(d1,d2) of 2 also show the same coalescing trend, suggesting
that inclusion of 6 imparts a change in the shape of the flexible
1
calix[4]arene cup. The binding affinities determined via H
NMR titrations above are shown in Table 1. In both cases, 5∩3
Table 1. Binding Affinities of Inclusion Complexes
guest
host
Ka
solvent
Δppm
a
5
6
3
2
691 99
3.3 0.4
CD2Cl2
CD3CN
0.30
0.21
b
a
b
3 is not soluble in any appreciable amount in CD3CN. 6 in CD2Cl2
is non-innocent and reacts with 2 to decompose the complex.
Comparisons between the Ka values obtained in different solvents
must be treated with caution due to the different stabilization provided
by each solvent.
The solid-state structure of 6∩2 displays a coordination
environment around Pt(II) corresponding to a semiopen
configuration, in which only one P,S moiety is fully chelated,
and the remaining two coordination sites are occupied solely by
monodentate P-bound hemilabile ligand and Cl− (Figure 4).
Upon complexation of 6 by 2, the mondentate P-bound
hemilabile moiety of 2 extends outward in order to incorporate
the guest. Indeed, the total distance between phenyl spacers
attached to the P,S ligands is 7.392 Å, allowing enough space
for an aromatic guest such as 6 to fit snuggly within the cavity
and remain bound through π−π stacking interactions.
Interestingly, guest molecule 6 does not reside at the center
of the cavity but is instead 0.349 Å closer to the phenyl ring
attached to the nonchelating P,S ligand, as compared to the
chelated one. This interaction between 6 and the monodentate
P-bound hemilabile ligand reduces the dihedral angle between
and 6∩2 complexes, the resonance in the host (Table 1)
displays the greatest shift and the least overlap with other
resonances and therefore was used to calculate the guest
binding affinity. In complex 6∩2, the most notable changes in
the 1H NMR spectra upon encapsulation occur in the aromatic
region, to the signal corresponding to the (β) hydrogen signal
in 6. In both cases the aromatic signals of the hosts show
smaller but significant shifts. The binding affinities of 5 for 3 are
within the expected magnitude range for similar calix[4]arenes
host−guest systems that rely solely on cation−π based
interactions (<1000 M−1 for calix[4]arenes with N-methylpyr-
idinium salts).45−48,51−53,55 Similarly, the determined binding
affinity of 6 for 2 is comparable to other previously reported
calix[4]arene host guest systems involving neutral guests (<200
M−1).45−48,51−53,56,57
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Figure 3. (Left) Solid-state structure of 1 drawn with 30% probability
thermal ellipsoids. Counterions and solvent molecules are omitted for
clarity. (Right) Space-filling representation of 1 showing the physically
blocked cavity by the π−π interaction between the two phenyl rings
extending from the P,S ligands. Color scheme for the atoms: platinum,
black; sulfur, yellow; phosphorus, magenta; oxygen, red; carbon, gray;
hydrogen, white.
the P-bound ligand’s phenyl spacer and the calix[4]arene to
12.03°, compared to dihedral angles of 26.42° observed for the
phenyl spacer in the P,S chelated ligand. In addition to π−π
stacking, the alignment of 6 inside 2 suggests an electrostatic
interaction between the negatively charged oxygen in 6 and the
cationic Pt(II) in 2. Although the Pt···O distance (6.421 Å) is
too long for a bonding interaction, the dipole interaction
between the O atom in 6 and the positively charged Pt(II)
center is strong enough to direct the orientation of 6 when
incorporated inside 2. Furthermore, the incorporation of 6 into
2 also seems to reduce the anisotropy of the calix[4]arene
upper rim into a more circular ellipsoid measuring 7.230 by
5.945 Å, which is consistent with the observations made via 1H
NMR spectroscopy.
In the solid-state structure of 5∩3 (Figure 4), the phosphine
groups bound to the Pt(II) metal center display a trans
conformation, as opposed to complexes 1 and 2 in which the
phosphine moieties are cis to one other. This coordination
geometry is a result of the large trans effect of the two cyanides,
forcing the P,S ligands far away from each other, largely
expanding the cavity in the supramolecular framework.
Although ion-regulated receptor 3 is theoretically flexible
enough for the phenyl spacers to reach distances of over ∼10
Å from phenyl to phenyl, the solid-state structure shows that
the distances between ligands is only 7.635 Å. This occurs
because the receptor 3 adapts its cavity size to create the most
appropriate binding environment for guest 5. As in the case of
6∩2, guest 5 is located closer to one of the P,S ligands, rather
than being located symmetrically at the center of the cavity.
The dihedral angle between the phenyl spacer closest to the
guest and the calix[4]arene is decreased to 1°, presumably
allowing the guest to engage in stronger face-on π−π
interactions. As opposed to the 6∩2 host−guest complex, in
Figure 4. (Top) Solid-state structure of 6∩2 drawn with 50%
probability thermal ellipsoids. (Bottom) Solid-state structure of 5∩3
drawn with 50% probability thermal ellipsoids. BArF − counterions and
4
solvent molecules are omitted for clarity. Color scheme for the atoms:
platinum, black; sulfur, yellow; nitrogen; blue; chloride, green;
phosphorus, magenta; oxygen, red; carbon, gray; hydrogen, white.
which the dipole−cation interaction plays a major role in the
alignment of the guest inside the cavity, sterics seem to play a
more significant role in the orientation of 5 upon inclusion in 3.
The Pt(II) center is positioned away from the cavity, and the
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N-methyl group in 5 is located in such a fashion that allows for
a short contact (2.380 Å) between the CN− ligand and the N-
methyl protons. Furthermore, 5 lays lower in the calix[4]arene
cavity, as compared to 6∩2, suggesting a higher contribution of
cation-π interactions to the formation of the inclusion complex.
In Situ Allosteric Regulation of Host−Guest Proper-
ties. The quantitative and reversible coordination chemistry-
induced transformation between complexes 1−2 and the
parallel formation of host−guest complex 6∩2 was studied in
tandem to probe the potential for in situ control of host−guest
properties of the present ion-regulated receptor system. This
was accomplished via the regulation of the Pt(II) coordination
environment by sequential addition and abstraction of Cl− in a
CD3CN solution containing 6. The solid-state structure of 1
shows no guest binding can occur in the closed configuration,
and Job plots data are consistent with this conclusion for 1
Indeed, the formation of both 1 and 2 corresponds to very
rapid processes that are complete within seconds, even after
multiple cycles, highlighting the potential of the ion-regulated
receptor assembly to be applied in dynamic systems with
kinetically fast responses.
Computational Studies. In order to further investigate the
orbital origins of the intermolecular interactions that give rise to
the selectivity observed in this ion-regulated receptor system,
DFT calculations were carried out on the solid-state structures
of 6∩2 and 5∩3 with the use of the Gaussian 09, rev D.158,59
suite of programs at the B97-D/LANL2DZ level of theory. The
selected functional, B97-D, is a density functional of the
generalized gradient approximation (GGA) type whose
performance in describing noncovalently bound systems,
through the inclusion of dispersion effects, has been
reported.60−63 Figure 6 shows the electrostatic potential
1
dissolved in CD3CN. Indeed, the H NMR chemical shift
values for the resonances for 6 in the presence of 1 are identical
to those for free guest in solution (Figure 5). On the other
Figure 6. Electrostatic potential map of 5∩3 and 6∩2 showing the
charge distribution throughout the inclusion complexes. Regions of
high electron density are color coded red, and electron poor regions
are blue. Stabilization of host−guest complexes seems to be driven by
the interaction of electron-donor and electron-acceptor regions of the
complex.
mapped onto the electron isodensity surface of 6∩2 and 5∩3
in their solid-state structures. The orientation of guests within
the cavity correlates with the alignment between high electron
density regions and poor electron density. This pattern seems
to be particularly important in the case of 6∩2, where the
cationic Pt(II) metal center and the electron-rich calix[4]arene
framework generates a total permanent dipole of 19.2 D across
the cavity. Guest 6 has a dipole moment of 4.8 D, and its vector
is antiparallel with the dipole of the host 2 upon formation of
6∩2. Host 3 has a much smaller permanent dipole (3.34 D)
compared to 2, and the dipole vector of 5 in host−guest
complex 5∩3 is not particularly aligned with the host’s dipole.
A second-order perturbation analysis on the natural
population analysis performed on the X-ray structure of the
inclusion complexes assess the most important delocalization
interactions between host and guest. In 6∩2, two interactions
between the oxygen atom in 6 and the Pt(II) atom in 2 were
observed. First, the lone pairs on the oxygen atom of 6 interact
with the lowest virtual natural hybrid orbital on Pt(II) with
energies of 2.2 and 1.7 kcal/mol, respectively. A second, slightly
weaker interaction (1.43 kcal/mol) was observed between one
of the lone pairs on the oxygen atom in 6 and the antibonding
orbital of the C−H bond in the ethyl spacer of the P,S ligand.
This interaction arises from the excess of electron density on
the oxygen atom that is transferred to the neighboring
antibonding orbitals. Finally, the bonding orbital between the
Figure 5. (Top) Allosteric regulation of ion-regulated receptors 1 and
2 demonstrating the ejection and incorporation of guest 6 in CD3CN.
Formation of 1 from 2 was achieved by abstraction of Cl− with
stoichiometric amounts of NaBArF . Formation of 2 from 1 was
4
achieved by addition of stoichiometric amounts of tetrabutyl
1
ammonium chloride. (Bottom) H NMR traces in CD3CN showing
the reversible conversion of 2 to 1 in the presence of 6.
1
hand, the H NMR data clearly show the formation of an
inclusion complex with 6 when 1 is transformed into semiopen
complex 2. Abstraction of Cl− from 2 with NaBArF4 regenerates
complex 1, resulting in the expulsion of 6 from the cavity and
reappearance of the 1H NMR signals for free guest molecule 6.
The cycles of coordination transformations can be repeated
with no apparent loss in encapsulation performance (Figure 5).
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closed complex 1 with BArF − counterions was prepared by dissolving
β and γ carbons in guest 6 exhibits a π−π interaction (1.27
kcal/mol) with the antibonding orbital of the calix[4]arene
phenyl ring. Interestingly, in complex 5∩3, the most significant
interactions found were π−π stacking interactions (1.05 kcal/
mol) between the bonding orbital of the calix[4]arene phenyl
ring and the antibonding orbital of β and γ carbons in guest of
5.
4
the corresponding chloride complex in 3 mL of CH3OH in the
presence of 2.0 equiv NaBArF4 (141.3 mg, 0.158 mmol). The mixture
was left to stir for 2 h, followed by solvent evaporation and dissolution
in CH2Cl2. The NaCl precipitate was removed using a 0.2 μm syringe
membrane filter, and the remaining solution was evaporated to afford
the corresponding closed complex 1 as a light-yellow solid (107.1 mg,
95%). 1H NMR (400 MHz, 25 °C, CD2Cl2) δ 7.79 (s, 16H), 7.64 (d, J
= 7.6 Hz, 4H), 7.60 (s, 8H), 7.48 (s, 8H), 7.34−7.21 (m, 12H), 7.04
(t, J = 7.4 Hz, 2H), 6.88 (d, J = 8.1 Hz, 4H), 6.73 (d, J = 8.1 Hz, 4H),
6.37 (s, 4H), 4.60 (d, J = 13.5 Hz, 4H), 4.20−4.14 (m, 4H), 3.77 (t, J
= 6.7 Hz, 4H), 3.29 (d, J = 13.6 Hz, 4H), 2.97 (s, broad, 8H), 2.12−
1.91 (m, 8H), 1.19 (t, J = 7.4 Hz, 6H), 0.98 (t, J = 7.4 Hz, 6H).
31P{1H} NMR (161.98 MHz, 25 °C, CD2Cl2): δ 47.1 (JP−Pt = 3052.9
Hz, 2P). HRMS (ESI+) m/z calcd for C80H82O4P2PtS2 [M]+:
1427.4777; found: 1427.4728.
CONCLUSION
■
In summary, we have reported the synthesis and operation of a
novel calix[4]arene ion-regulated receptor system assembled via
the WLA. By controlling the coordination environment around
a Pt(II) regulatory center via the use of small coordinating
anions, we have shown that three independent supramolecular
configurations can be accessed, each with unique properties
based on overall cavity size and charge. Specifically, we have
shown that the coordination geometry at the regulatory site
dictates the size of the cavity and the nature of the possible
electrostatic and dipole interactions, giving rise to selective
substrate binding. Crystallographic analysis, NMR spectrosco-
py, and DFT computational studies shed light on the particular
orientations of the guests inside the cavities and the
intermolecular forces that dictate the spatial arrangement of
the ion-regulated receptor pairs. Finally, we have shown that in
situ reversible control of host−guest properties can be achieved
by controlling the coordination modes through multiple cycles
of chemical inputs. Overall, this work establishes the WLA as a
powerful platform for the development of cavitand-based
receptors that allow for the design of allosterically regulated
enzyme mimics, overcoming some of the assembly limitations
that have previously hindered the development of this field.
Semiopen Ion-Regulated Receptor Complex (2) prepared from 4.
Semiopen complex 2 with chloride counterions was prepared in a
similar manner as 1. Under inert atmosphere, a solution of hemilabile
calix[4]arene ligand 4 (94.5 mg, 0.076 mmol) in 3 mL of CH2Cl2 was
added to a suspension of dichloro(1,5-cyclooctadiene) platinum(II)
(28.7 mg, 0.076 mmol) in 3 mL of CH2Cl2. The solution volume was
reduced to approximately 1 mL, and the product was precipitated with
pentane. The product was placed in a centrifuge tube, sonicated for 10
min, centrifuged, collected as a precipitate, and washed with pentane.
This procedure was repeated three times to yield the dichloride
complex species. The semiopen complex 2 with BArF − counterions
4
was prepared by dissolving the corresponding chloride complex in 3
mL of CH3OH in the presence of 1.0 equiv NaBArF4 (67.8 mg, 0.076
mmol). The mixture was allowed to stir for 2 hours, followed by
solvent evaporation and dissolution in CH2Cl2. The NaCl precipitate
was removed using a 0.2 μm syringe membrane filter, and the
remaining solution was evaporated to afford the corresponding
1
semiopen complex 2 as a yellow solid (174.3 mg, 97%). H NMR
(400.16 MHz, 25 °C, CD2Cl2): δ 7.77 (s, 8H), 7.65−7.56 (m, 8H),
7.53−7.36 (m, 16H), 7.29 (d, J = 7.4 Hz, 4H), 7.08 (t, J = 7.4 Hz, 2H),
6.95 (d, J = 8.0 Hz, 4H), 6.70 (d, J = 7.9 Hz, 4H), 6.38 (s, 4H), 4.58
(d, J = 13.5 Hz, 4H), 4.16 (m, 4H), 3.75 (t, J = 6.6 Hz, 4H), 3.27 (d, J
= 13.6 Hz, 4H), 3.12−3.00 (s, 8H), 2.06 (m, 4H), 1.96 (q, J = 7.1 Hz,
4H), 1.18 (t, J = 7.4 Hz, 6H), 0.98 (t, J = 7.4 Hz, 6H).31P{1H} NMR
(161.98 MHz, 25 °C, CD2Cl2−CD3OD): δ 50.37 (JP−Pt = 2714.6 Hz,
JP−P = 19.2 Hz, 1P), 7.10 (JP−Pt = 3349.1 Hz, JP−P = 19.2 Hz, 1P).
HRMS (ESI+) m/z calcd for C80H82ClO4P2PtS2 [M + H]+:
1463.4466; found: 1463.4494.
Fully Open Ion-Regulated Receptor Complex (3) prepared from
4. Fully open complex 3 was prepared in a similar manner as 1. Under
inert atmosphere via a solution of hemilabile calix[4]arene ligand 4
(161.6 mg, 0.131 mmol) in 3 mL of CH2Cl2 was added to a
suspension of dichloro(1,5-cyclooctadiene) platinum(II) (49.0 mg,
0.131 mmol) in 3 mL of CH2Cl2. The solution volume was reduced to
approximately 1 mL, and the product was precipitated with pentane.
The product was placed in a centrifuge tube, sonicated for 10 min,
centrifuged down, and washed with pentane. This procedure was
repeated three times to afford the dichloride complex species. Fully
open complex was prepared by, dropwise addition of NaCN in
CH3OH (0.146 M, 0.625 mL, 0.095 mmol) into a 4 mL 1:1 CH2Cl2−
CH3OH solution of the dichloride complex (71.2 mg, 0.047 mmol).
The mixture was left to stir for 2 h, followed by solvent evaporation
and dissolution in CH2Cl2 upon gentle heating. The NaCl precipitate
was removed using a 0.2 μm syringe membrane filter, and the
remaining solution was evaporated to afford the corresponding closed
complex as a white solid (182.4 mg, 94%). 1H NMR (400.16 MHz, 25
°C, CD2Cl2): δ 7.84−7.64 (m, 8H), 7.62−7.48 (m, 12H), 7.23 (d, J =
7.4 Hz, 4H), 7.02 (d, J = 8.2 Hz, 4H), 6.71 (d, J = 8.3 Hz, 4H), 6.45 (s,
4H), 4.56 (d, J = 13.0 Hz, 4H), 4.17 (m, 4H), 3.73 (t, J = 6.8 Hz, 4H),
3.28−3.21 (m, 12H), 2.13 (m, 4H), 1.97 (m, 4H), 1.16 (t, J = 7.4 Hz,
6H), 0.98 (t, J = 7.5 Hz, 6H). 31P{1H} NMR (161.98 MHz, 25 °C,
CD2Cl2): δ 8.35 (JP−Pt = 2176.9 Hz, 2P). HRMS (ESI+) m/z calcd for
C82H82N2O4P2PtS2 [M + Na]+: 1503.6848; found: 1503.4781.
EXPERIMENTAL SECTION
■
General Methods. P,S ligand 4 was synthesized and stored using
standard Schlenk line conditions, under an inert nitrogen atmosphere.
The syntheses of semiopen 2 and closed complex 1 from 4 were
performed under inert atmosphere. Transformations between 1, 2, and
3 were performed under ambient conditions. N-methylpyridinium
BArF − was synthesized and stored in the dark under ambient
4
conditions. All solvents were purchased as HPLC grade and degassed
under a stream of argon prior to use. Deuterated solvents were
purchased from Cambridge Isotope Laboratories and used as received.
Dichloro(1,5-cyclooctadiene) platinum(II), NaBArF , NaCN were
4
purchased from Strem Chemicals, Inc.,and tetrabutyl ammonium
chloride was purchased from Aldrich Chemical Co. and used without
further purification. Pyridine N-oxide was purchased from Aldrich
Chemical Co. and subsequently purified by vacuum sublimation. NMR
spectra were recorded on a Bruker Avance 400 MHz. 1H NMR spectra
were referenced to residual proton resonances in the deuterated
solvents. 31P{1H} NMR spectra were referenced to an 85% H3PO4
aqueous solution in a sealed locker tube. All chemical shifts are
reported in ppm. High-resolution mass spectra (HRMS) measure-
ments were recorded on an Agilent 6120 LC-TOF instrument in
positive ion mode. Electrospray ionization mass spectra (ESI-MS)
were recorded on a Micromas Quatro II triple quadrapole mass
spectrometer.
Synthesis. Closed Ion-Regulated Receptor Complex (1). Closed
complex 1 was prepared under inert atmosphere via the dropwise
addition of a solution of hemilabile calix[4]arene ligand 4 (98.3 mg,
0.079 mmol) in 3 mL of CH2Cl2 to a suspension of dichloro(1,5-
cyclooctadiene) platinum(II) (29.8 mg, 0.079 mmol) in 3 mL of
CH2Cl2. The solution volume was reduced to approximately 1 mL,
and the product was precipitated with pentane. The product was
placed in a centrifuge tube, sonicated for 10 min, centrifuged, collected
as a precipitate, and washed with pentane. This procedure was
repeated three times to afford the dichloride complex species. The
G
dx.doi.org/10.1021/ja503506a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Fully Open Ion-Regulated Receptor Complex (3) from 1 or 2.
Fully open complex 3 was prepared under ambient conditions by
dropwise addition of 2.0 equiv of NaCN in CH3OH (0.146 M, 0.625
mL, 0.095 mmol) into a 4 mL 1:1 CH2Cl2-CH3OH solution of
complex 1 or 2 (1.0 equiv, 0.047 mmol). The mixture was left to stir
for 2 h, followed by solvent evaporation and dissolution in CH2Cl2
upon gentle heating. The NaCl precipitate was removed using a 0.2
μm syringe membrane filter, and the remaining solution was
evaporated to afford the corresponding closed complex as a white
and DGCTIC−UNAM for granting access to their computing
facilities.
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X-ray Crystallography. Crystallographic data are displayed in the
Supporting Information. Crystals suitable for X-ray diffraction of 1
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AUTHOR INFORMATION
Corresponding Author
chadnano@northwestern.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This material is based upon work supported by the following
awards, National Science Foundation CHE-1149314, U.S.
Army W911NF-11-1-0229. J.M.A. acknowledges a fellowship
from Consejo Nacional de Ciencia y Tecnologia (CONACYT)
and J.B.F. is grateful to DGAPA−UNAM contract IB200313
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