Electrostatic and allosteric cooperativity in ion-pair binding: A quantitative and coupled experiment-theory study with aryl-triazole-ether macrocycles

Article abstract of DOI:10.1021/jacs.5b05839

Cooperative binding of ion pairs to receptors is crucial for the manipulation of salts, but a comprehensive understanding of cooperativity has been elusive. To this end, we combine experiment and theory to quantify ion-pair binding and to separate alloste

Full text of DOI:10.1021/jacs.5b05839

Article
pubs.acs.org/JACS
Electrostatic and Allosteric Cooperativity in Ion-Pair Binding: A
Quantitative and Coupled Experiment−Theory Study with Aryl−
Triazole−Ether Macrocycles
Bo Qiao, Arkajyoti Sengupta, Yun Liu, Kevin P. McDonald, Maren Pink, Joseph R. Anderson,
Krishnan Raghavachari, and Amar H. Flood*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
S
* Supporting Information
ABSTRACT: Cooperative binding of ion pairs to receptors is crucial for
the manipulation of salts, but a comprehensive understanding of
cooperativity has been elusive. To this end, we combine experiment and
theory to quantify ion-pair binding and to separate allostery from
electrostatics to understand their relative contributions. We designed
aryl−triazole−ether macrocycles (MC) to be semiflexible, which allows ion
pairs (NaX; X = anion) to make contact, and to be monocyclic to simplify
analyses. A multiequilibrium model allows us to quantify, for the first time,
the experimental cooperativity, α, for the equilibrium MC·Na+ + MC·X− ⇌
MC·NaX + MC, which is associated with contact ion-pair binding of NaI (α
= 1300, ΔGα = −18 kJ mol−1) and NaClO4 (α = 400, ΔGα = −15 kJ mol−1)
in 4:1 dichloromethane−acetonitrile. We used accurate energies from
density functional theory to deconvolute how the electrostatic effects and
the allosteric changes in receptor geometry individually contribute to cooperativity. Computations, using a continuum solvation
model (dichloromethane), show that allostery contributes ∼30% to overall positive cooperativity. The calculated trend of
electrostatic cooperativity using pairs of spherical ions (NaCl > NaBr > NaI) correlates to experimental observations (NaI >
NaClO4). We show that intrinsic ionic size, which dictates charge separation distance in contact ion pairs, controls electrostatic
cooperativity. This finding supports the design principle that semiflexible receptors can facilitate optimal electrostatic
cooperativity. While Coulomb’s law predicts the size-dependent trend, it overestimates electrostatic cooperativity; we suggest
that binding of the individual anion and cation to their respective binding sites dilutes their effective charge. This comprehensive
understanding is critical for rational designs of ion-pair receptors for the manipulation of salts.
achieve due to the need to identify and then evaluate multiple
equilibria4b that represent all the important supramolecular
processes. We do this here using a coupled experiment−theory
approach11c,15−18 and distinguish, for the first time, allostery
from electrostatics to help reveal the fundamental features
controlling and benefitting electrostatic cooperativity when
using semiflexible ion-pair receptors (Figure 1).
INTRODUCTION
■
Cooperativity is a powerful strategy for forming high-fidelity
species1 during molecule-mediated recognition of ion pairs2
and for effecting allosteric control over binding events.3 Such
ion-pair recognition has many applications, including ion
extraction,4 membrane transport,5 and catalysis.6 Despite
these many roles, ion complexation has primarily focused on
the binding of cations7 and anions8 individually. The associated
counterions have often gone unobserved9 or overlooked, yet it
has become increasingly apparent that these counterions play
critical roles9−11 in complexation events. When ion-pair binding
is examined specifically, such as in cascade complexes12 and
ion-pair receptors,13 synergistic effects exist and offer a means
There are two accepted mechanisms13 by which coopera-
tivity can emerge in ion-pair binding: conformational allostery
and electrostatic. With positive conformational allostery, binding
the cation helps organize the receptor for the anion, thus the
geometrical deformation penalty is lower for binding the ion
pair than for either cation and anion separately.10,19 Electro-
static cooperativity is expected to come from the attraction,
to modulate strength, selectivity, and population fidelity.14
A
E
Coul, between the anion and cation inside the receptor20 and to
quantitative account of the factors that dictate these synergies
will allow for an understanding of the behaviors of ion pairs in
various applications4−6 and for the design of receptors with
targeted selectivities. However, quantitative studies in previous
literature that outline the geometric and electrostatic
contributions to the cooperativity are rare. Obtaining a
comprehensive picture of ion-pair binding is challenging to
be governed by Coulomb’s law,21
ECoul = q1q2/4πε0εd
(1)
Received: June 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 1. Chemical structures of the macrocycles and principal equilibrium studied in this work. Macrocycle MC1 for ion-pair binding bears
extrinsically polarized triazoles (red) for CH hydrogen-bonding to anions and the ethylene glycol ether (blue) for cations. MC2 serves as an anion-
only control receptor, MC3 and MC4 for crystal structure determinations, and MC5 for computational studies.
where q1 and q2 are the charges on the cation and anion, d is
the cation−anion distance, ε0 is the permittivity of vacuum, and
ε is the dielectric constant of the medium.
ion-pair complex to a calix[4]pyrrole−crown-ether receptor to
analyze various binding modes, and Dutasta27 calculated the
cation−anion distances of ion pairs in a hemicryptophane
receptor to explain the observed selectivity. These recent works
provided more quantitative detail than the turn-on factors and
deepened our understanding of ion-pair binding but did not
directly focus on the origin of the cooperativity within the 1:1:1
complexes formed between cation, anion, and receptor.
There are several challenges facing a full quantitative
investigation of cooperativity in ion-pair binding. First, ion-
pair binding involves multiple equilibria that demand
sophisticated binding models and rely upon several affinity
measurements of contributing equilibria. Some of those
experiments can be limited by the solubility of the salts or
the binding strength of the receptors.4b Second, both
conformational and electrostatic factors contribute to the net
cooperativity displayed during ion-pair binding. It is almost
impossible to deconvolute these two factors from each other
using experiment alone. Yet, all these challenges need to be
overcome in order to provide a comprehensive picture of
cooperativity in ion-pair binding.
Many but not all15b,19,22 of the literature examples of ion-pair
binding used phenomenological turn-on factors to demonstrate
positive cooperativity. Therein, an anion’s apparent affinity for
the receptor increases when an appropriate cation is premixed
with the receptor. Using turn-on factors, Reinhoudt demon-
strated conformational allostery in a calix[4]arene receptor,19a
Smith showed the benefits of reducing cavity size for binding
NaCl with bicyclic amide−crown-ether receptors,20a,23 and
Beer explored allosteric selectivity as dictated by the
stoichiometry of cation binding of a calix[4]arene crown-
ether receptor.24 Other studies have built on these lessons.13,25
However, and as Roelens26 noted, this turn-on method of
evaluation is phenomenological and, therefore, does not
provide the thermodynamic data needed for accurately
determining the origin and strength of cooperativity in ion-
pair binding.
Quantification of cooperativity is all-important for the
understanding and rational design of ion-pair receptors with
desired affinity and selectivity. Recent works have started to
reveal more detail. Using experiment, Ballester treated ion pairs
as entire guests in a model set of equilibria to analyze the
cooperativity of multiple ion-pair binding to a bis(calix[4]-
pyrrole) receptor.22b Sessler and Moyer established multi-
equilibria models to characterize biphasic, liquid−liquid
extractions of radioactive ions by calix[4]pyrrole receptors.4a
Using theory, Sessler and Hay20b optimized geometries of an
We address these challenges by pairing experiment with
theory to quantify cooperativity of binding ion pairs (NaClO4,
NaI, NaBr, and NaCl) inside a ditopic aryl−triazole−ether
macrocycle (MC1, Figure 1). Instead of using turn-on factors,
we employed an accurate binding model4b,26 that faithfully
represents all the important equilibria present in solution.
These include anion binding, Kanion, cation binding, Kcation, and
B
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 1. Modular Synthesis of Macrocycles MC1, MC2, MC3, and MC4 (TBTA = tris[(1-benzyl-1H-1,2,3-triazol-4-
yl)methyl]amine)
second-row elements, and the LANL2DZdp basis set (which bears an
extra set of diffuse and polarization functions) on bromine and
iodine.32 All geometries were confirmed to be minima with no
imaginary frequencies. Single-point energy calculations were carried
out subsequently using the significantly larger 6-311++G(3df,2p) basis
sets to obtain the binding energies with greater accuracy. Single-point
implicit solvent computations were performed on the optimized
geometries at the M06-2X/6-311++G(3df,2p) level of theory. Since
the larger basis set was not previously available for iodine, an
appropriate basis set was constructed by addition of a set of diffuse s
and p functions, two d functions, and one f function to the 6-311G(d)
basis set for iodine.
the ternary ion-pair binding, βoverall (Figure 1), from which we
determine the cooperativity factor, α:
α = βoverall/KanionKcation
(2)
Cooperativity factors that are greater than 1 indicate additional
stabilization is present within the ternary ion-pair complex, i.e.,
positive cooperativity. We determined the cooperativity factors
in solution-phase experimental studies involving NaClO4 and
NaI binding. In a complementary manner, we established a set
of quantum chemical calculations to investigate cooperativity
across an overlapping range of ion-pairs (NaCl, NaBr, and
NaI). These are examined both in the gas phase and with the
inclusion of a continuum solvation model. A distinct benefit of
the theoretical approach is that the deformation penalty, Dion,
associated with all the binding events can be explicitly
calculated allowing us to determine conformational coopera-
tivity, also known as allostery, in ion-pair binding for the first
time. Thus, we have also determined the pure electrostatic
contribution to the overall cooperativity for the first time. It was
found that when our semiflexible ion-pair receptor allows the
ion pairs to have close contact, they display their “intrinsic”
electrostatic cooperativity in a manner that depends on the size
of the ions: smaller ions will naturally have higher cooperativity.
While Coulombic interactions are expected to be proportional
to 1/d, to the best of our knowledge, this is the first quantitative
and comprehensive examination of this idea in ion-pair binding.
Overall, these insights help establish a quantitative basis for
both the design of ion-pair receptors and the understanding of
how ion pairs engage with functional molecules.4−6,28
RESULTS AND DISCUSSION
■
Design and Synthesis of Aryl−Triazole−Ether Recep-
tors for Ion Pairs. A heteroditopic macrocycle was designed
for binding contact ion pairs. The macrocycle combines a rigid
aryl−triazole crescent9a,18d,33 for binding anions together with a
glycolic linker for stabilizing cations. In contrast to the more
common use of polycyclic receptors13 designed to achieve
unique affinities and/or selectivities, the simplicity of this
monocyclic structure will greatly aid in the analysis of
cooperativity. We also expect the modest cavity size and the
flexibility of the glycol chain to ensure that, once the ions are
bound inside the receptor, they will make direct contact with
each other.
The various macrocycles (Figure 1) all share a central core
and are customized for specific purposes. Macrocycle MC1
bears long solubilizing side chains for solution-phase binding
studies. While MC1 is designed to be a receptor for ion pairs,
MC2 is a control molecule in which the cation-binding glycols
have been replaced with an isosteric non-interacting alkyl chain.
Therefore, it represents an anion-only receptor. Macrocycles
MC3 and MC4 with bulky tert-butyl side groups were designed
for growing single crystals for X-ray diffraction. With MC5, all
the side chains were removed for the purpose of simplifying the
computational studies.
METHODS
■
1H NMR Titrations. Titrations were conducted with MC1 to
determine equilibrium constants. All titrations were conducted by
adding increasing amounts of the corresponding salt into solutions of
MC1 or MC2 (2 mM, 4:1 v/v CD2Cl2:CD3CN). Titration data were
monitored by 1H NMR spectroscopy (500 MHz) at room temperature
(298 K). In a typical experiment, 500 μL of a 2 mM macrocycle
solution was prepared in screw-cap NMR tubes equipped with PTFE/
silicone septa. Aliquots from a 40 mM salt solution in a screw-cap vial
equipped with PTFE/silicone septa were added using 10 and 100 μL
gastight microsyringes.
All the macrocycles investigated experimentally were
prepared (Scheme 1) from the copper-catalyzed azide−alkyne
cycloadditions34 between bis-alkynyl phenylenes and bis-azido
chains in high dilution conditions. Phenylenes 1, 2, and 3 were
prepared according to reported procedures,11c,33 and building
c
DFT Calculations. All computations have been carried out using
the Gaussian suite of programs.29 The starting geometries were
obtained from the crystal structures and optimized with the widely
used M06-2X functional30 both in the gas phase and with CH2Cl2
solvation based on the IEFPCM model (integral equation formalism
polarizable continuum model).31 Optimized geometries, vibrational
frequencies, zero-point energy corrections, and thermal corrections
have been evaluated using the 6-31+G(d,p) basis set on the first- and
blocks 4 and 5 were prepared in three steps from 3-
iodophenol.35
Qualitative Analysis of Ion-Pair Binding. The hetero-
ditopic character of the receptor’s design was made evident
from the electrostatic potential (ESP) map18b of macrocycle
MC3 (Figure 2a) and its solid-state structure complexed with a
C
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 2. (a) Electrostatic potential map of MC3 (HF/3-21G*). (b) Chemical and solid-state structure of MC3·CH3CN with short-distance (<3.0
Å) hydrogen bonds marked.
Figure 3. (a) 1H NMR spectra of MC1 (2 mM, 4:1 CD2Cl2:CD3CN, 500 MHz, 298 K) with five equivalents of NaBPh4 (black), TBAClO4 (blue),
1
and NaClO4 (red) compared to the free receptor (magenta). (b) H NMR chemical shifts of the triazole proton Ha in MC1 with increasing
equivalents of the various salts.
solvent molecule MC3·CH3CN (Figure 2b). An ordered
acetonitrile molecule forms short CH···N (2.6 Å) hydrogen
bonds from the anion-binding triazoles (colored red) and CH···
O (2.6 Å) hydrogen bonds to the cation-binding ether oxygens
at the glycol end of the cavity. The parent macrocycle MC1 has
essentially the same ESP map as MC3. Based on spatial 1H−1H
couplings between protons Ha, Hb, and Hc observed in the
NOESY NMR spectra18d,33 of MC1 (Supporting Information),
the geometry of macrocycle MC1 is believed to be the same as
the macrocycle in the MC3·CH3CN crystal. Thus, MC1 is
preorganized with the triazole CH bond donors pointing into
the central cavity.
To begin, cooperative ion-pair binding was found to be
present when studying qualitatively the binding of NaClO4 with
1
macrocycle MC1 (Figure 3). The peak shifts in the H NMR
spectra accompanying the addition of NaClO4 were compared
to shifts for addition of the constituent ions (Na+ or ClO4 )
−
when they were added “alone”. The Na+ was added as the
−
−
tetraphenylborate (BPh4 ) salt and ClO4 as the tetrabuty-
lammonium (TBA+) salt. These counterions are too large to
associate with the receptor. A 4:1 mixture of CD2Cl2 and
D
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 4. Stacked 1H NMR spectra of MC1 with increasing amounts of (a) NaClO4 and (b) NaI. Conditions: [MC1] = 2 mM, 4:1 CD2Cl2:CD3CN,
298 K, 500 MHz.
Figure 5. (a) Chemical structure of MC4·NaClO4 highlighting short contacts (dashed pink lines). (b) Top and (c) side views of solid-state structure
of MC4·NaClO4. (d) Upper part of the structure highlighting the exterior Na+ binding site of MC4. (e) A supramolecular polymer formed by MC4·
NaClO4 monomers in the solid state. Solvent molecules removed for clarity.
CD3CN was used to provide good solubility to both the
receptor and all titrated salts. Addition of 5 equiv of either the
The strong binding of NaClO4 to MC1 and weak binding of
ClO4 and Na+ was further verified by adding increasing
−
Na+ cation (NaBPh4) or the ClO4 anion (TBAClO4) to
amounts of their respective salts to solutions of MC1. Addition
of NaClO4 (Figure 4a) induces Ha to shift until saturation is
achieved just prior to 5 equiv, indicative of complete conversion
from free MC1 to the MC1·NaClO4 complex. A comparison of
−
1
macrocycle MC1 did not show significant changes to the H
NMR spectra (2 mM, Figure 3a), indicative of weak individual
binding. However, upon addition of the NaClO4 ion pair
(Figure 3a), many of the protons shift to new positions
indicative of complex formation. The protons in the electro-
positive anion-binding cavity of MC1 (Ha, Hb, and Hc) shift
downfield consistent with CH···anion hydrogen-bonding. The
ethylene glycol’s signals also shift downfield with the presence
of NaClO4 (Figure 3a, Hf, Hj, Hk), which is consistent with
prior NMR analyses of alkali cation binding to crowns.36
−
NaClO4 binding to those of the constituent ions, ClO4 and
Na+ (Figure 3b), shows that when the ions are alone they do
not saturate the receptor. The same experiments were carried
out to test binding of the iodide version, NaI, and the result was
similar: strong NaI binding to MC1 (Figure 4b) but weak
binding of the I− anion and Na+ cation alone (Supporting
Information). The saturation seen for the ion pairs relative to
E
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
the constituent ions (Figure 3b) is a qualitative indicator of
cooperativity.
The X-ray structure of the ion-pair complex with macrocycle
MC4 (Figure 5) confirms the formation of a contact ion pair
inside the cavity. The solid-state structure shows NaClO4
perches in the receptor pocket and that neither anion nor
cation has a perfect fit for the cavity. Only one oxygen atom in
the perchlorate is in close contact with the five CH hydrogen
bond donors within the electropositive end of the cavity (CH···
O distances range from 2.4 to 3.2 Å). Furthermore, sodium
does not appear to be an ideal guest for the cation pocket; only
three of the possible five Na+···O close contacts are formed
with distances ranging from 2.3 to 3.0 Å. The nonideal fit of
either ion into their half of the binding cavity is consistent with
the poor binding seen for the ions alone (Figure 3).
Figure 6. Solid-state structure of MC4·NaI in (a) front and (b) side
views.
The cation and anion sit close to each other inside this
macrocycle. The Na···O distance of the bound NaClO4 ion pair
is 2.3 Å, and the Na···Cl distance is 3.6 Å. These distances can
be compared to the few organic crystals identified in the
Cambridge Structure Database in which NaClO4 is also being
stabilized by other non-covalent interactions. Most of these
idea, to quantify cooperativity, and to reveal its origins, we
require models for interpreting the experimental and computa-
tional data.
Model for Cooperative Ion-Pair Binding. An appropriate
binding model (eqs 3−5) to analyze how ion pairs bind to
receptors needs to include three independent equilibria: anion
binding, Kanion, cation binding, Kcation, and the overall 1:1:1
involve the Na+ cation bound by a receptor with the ClO4
−
paired to the cation but residing outside the receptor. In these
−
cases, the sodium−oxygen distance (Na···O−ClO3 ) ranges
from 2.3 to 3.0 Å.37 The crystal structure of MC4·NaClO4
showing NaClO4 nestled in the receptor may be the first of its
kind. Overall, these short cation−anion distances are indicative
of strong electrostatic interactions.
ternary binding, βoverall
:
MC + X− ⇌ MC·X−
MC + M+ ⇌ MC·M+
Kanion (3)
Kcation (4)
The NaClO4 complex also shows the formation of CH···
anion hydrogen bonds that involve the methylene CH groups
from the glycol chain (He, Figure 5). Compared to the crystal
structure of MC3·CH3CN, the methylene CH groups appear to
have redirected inside the cavity. Presumably, this interac-
tion11c,38 also offers additional stabilization to the ion-pair
complex. 1H NMR titration data of MC1 with NaClO4 showed
(Figure 4a) a downfield shift in proton He that is consistent
with such an interaction being present in solution.39
MC + M+ + X− ⇌ MC·MX β
(5)
overall
The cooperativity factor, α, is the overall binding constant
divided by the product of ion binding (eq 2). The associated
free energy, ΔGα, is defined as the overall binding, ΔGoverall
minus the anion and cation binding free energies, ΔGanion and
ΔGcation
,
:
ΔGα = ΔGoverall − ΔGanion − ΔGcation
(6)
An unexpected feature present in the crystal structure
involves chelation of the sodium cation by the two amide
carbonyl groups of a neighboring MC4 (Figure 5d) enabling the
formation of a 1D supramolecular polymer (Figure 5e). The
existence of this second external Na+ binding site was verified in
The cooperativity parameters, α and ΔGα, are the equilibrium
constant and the free energy associated with the following
reaction:
MC·X− + MC·M+ ⇌ MC·MX + MC
α, ΔGα
(7)
1
solution by H NMR titration of NaBPh4 and NaClO4 with
MC4, showing Na+ cations occupying both sites (Supporting
Information). We believe this binding site enhances the
perched binding mode. For all these reasons, the quantitative
solution-phase studies were conducted using MC1, which does
not have this external site.
When ΔGα is less than zero (Figure 7), products are favored by
an additional stabilization that is only present when the ions are
bound as a pair. On the basis of eq 6, if the three binding
energies (anion, cation, and overall) can be determined
individually, either by experiment or by theoretical calculations,
then the cooperativity, ΔGα, can be quantitatively obtained.
Model for Electrostatic and Allosteric Cooperativity.
Cooperativity can be further deconvoluted into its components
to start building a comprehensive understanding of its origin. It
is generally assumed that there are cooperativity contributions
arising from electrostatic stabilization, ΔGelec, and from
Macrocycle MC4 was also found to bind NaI in the solid
state (Figure 6) with almost exactly the same geometry as
NaClO4 (Figure 5). The close contact distance between Na+
and I− is 3.2 Å, which falls within the range of Na+···I− contact
ion-pair distances (2.9−3.6 Å) seen in other NaI complexes
with organic molecules.40 Furthermore, the structural similarity
allows any energetic differences between NaClO4 and NaI to be
rationalized from electrostatics.
With the two ions in direct contact, both complexes are
expected to benefit from electrostatic attraction, however, the
extent of such stabilization has never been rigorously tested.
For NaClO4 and NaI in our solution conditions41 (ε ≈ 16.1 for
4:1 CH2Cl2:CH3CN) and using the distances obtained from
the crystals, it is hypothesized from Coulomb’s law that they
should be cooperatively stabilized by ∼25 kJ mol−1. To test this
conformational allostery, ΔGallos
:
ΔGα = ΔGelec + ΔGallos
(8)
We believe that the electrostatic cooperativity is straightforward
to describe as the additional attraction energy between cation
and anion when they are bound at the same time (Figure 8a).
All ion-pair receptors that bring their cation and anion
reasonably close to each other are expected to benefit from
this type of stabilization.
F
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
after ΔGanion, ΔGcation, and ΔGoverall for equilibria 3−5 are all
measured. Sodium perchlorate and sodium iodide were selected
as representative ion pairs for measuring the binding
cooperativity of MC1. Both ion pairs consist of singly charged
−
ions that are spherical (Na+, I−) or pseudo-spherical (ClO4 )
and have reasonably good solubility in organic solvents. Unlike
the previous studies employing turn-on factors, the quantifica-
tion of cooperativity (Figure 7) demands4,26 an accurate means
of evaluating all the binding equilibria.
Titrations conducted for qualitative assessments of cooper-
ativity (see Figures 3 and 4 and Supporting Information) were
then analyzed quantitatively to obtain ΔGanion, ΔGcation, and
ΔGoverall, respectively. All of the titration data were fitted using
HypNMR by following the changing chemical shift positions of
multiple protons (Supporting Information). For the titrations
with TBAClO4, TBAI, NaBPh4, NaClO4, and NaI, multiple
equilibria (ion binding, ion pairing, and ion-pair complexation)
Figure 7. Representation of the additional free energy, ΔGα, under
conditions of positive cooperativity, that emerges when comparing the
overall free energy of binding the ion pair to the sum of binding the
cation and anion individually.
−
were included. For example, fitting the ClO4 anion titration
includes the anion binding, Kanion (eq 10), the native ion pairing
of TBAClO4, Kip (eq 11), and the ion-pair complexation of the
receptor−anion complex with the countercation, Kipc (eq 12).
The ion-pairing constants, Kip, of titrated salts (TBAClO4,
TBAI, NaBPh4, NaClO4, and NaI) were measured in separate
experiments and used as fixed values in the fitting to simplify
refinements and enhance accuracy (see Supporting Information
for determination of Kip).
The conformational contribution to cooperativity is less
obvious and has not, to the best of our knowledge, been
rigorously investigated. We define conformational coopera-
tivity, ΔGallos (eq 9, Figure 8b), from the difference in
deformation energy, Di, within reaction 7. Any individual
deformation energies, Di, are always going to be penalties
because perfect preorganization is an unattainable ideal. These
energies are associated with reorganizing the receptor upon
binding the guest (Figure 8b). Thus, the difference between the
overall deformation penalty, Doverall (for binding the ion pair),
MC + X− ⇌ MC·X−
M+ + X− ⇌ MX
Kanion (10)
Kip (11)
and the sum of cation and anion deformation penalties, Dcation
Danion (for binding cation and anion individually), defines
ΔGallos
+
MC·X− + M+ ⇌ MC·MX Kipc (12)
:
The results of the titrations (Table 1) show that receptor MC1
ΔGallos = D
− D
− D
(9)
overall
cation
anion
−
has moderate affinities for ClO4 (50 M−1) and Na+ (50 M−1)
If the deformation penalty of binding the whole ion pair is less
than the penalty of binding the anion and the cation
individually, then it is more beneficial to bind the ions as a
pair. This benefit corresponds to positive conformational
allostery. Irrespective of whether the conformational coopera-
tivity is positive or negative, it is almost universally present
but shows strong ion-pair binding (106 M−2) indicating positive
cooperativity. The cooperativity factor for MC1 with NaClO4,
α(NaClO4), was determined to be 400 (= βoverall/KanionKcation
=
1 000 000 M−2/50 M−1 × 50 M−1)) with a corresponding free
energy ΔGα(NaClO4) = −15 1 kJ mol−1. For NaI, the I−
affinity was 50% higher at 80 M−1, but the cooperativity factor
was enhanced 3-fold to 1300 with ΔGα(NaI) = −18 1 kJ
mol−1.
since it is extremely unlikely for Doverall to equate to Danion
Dcation
+
.
With the models developed here for determining the
cooperativity and deconvoluting it into its two components,
we now present the data and its analysis.
Experimental Analysis of the Cooperativity. Exper-
imentally, the extent of cooperativity, ΔGα, can be determined
Since multiple equilibria were involved in determining the
cooperativity, we conducted titrations with the anion-binding
control macrocycle MC2 (Figure 1) to test the validity of our
model. This macrocycle is isosteric with MC1 but it only bears
a binding pocket for anions. Consistently, the anion affinities
Figure 8. (a) Representation of electrostatic cooperativity, ΔGelec, in ion-pair binding. (b) Representation of conformational allostery, ΔGallos, as the
difference between Doverall and the sum of Danion + Dcation, where Di is the deformation energy penalty for each state i.
G
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
cooperativity was determined in the same solvent mixture, the
principal difference between ion pairs is the charge separation
distance. Assuming the positive and negative charges are
located at the center of the ions and that solution structures
resemble those in the solid state (Figure 9a), the shorter charge
separation distance in the MC1·NaI complex matches its higher
cooperativity (Figure 9b). It is remarkable that the ratio of ion−
ion distances is close to the inverse ratio of cooperativity:
Table 1. Equilibrium Constants for Ion-Pair Binding of
NaClO4 and NaI to MC1 and MC2 (CD2Cl2:CD3CN = 4:1,
298 K)
a
b
ion-pair receptor MC1
anion receptor MC2
ClO4−, Kanion (M−1
Na+, Kcation (M−1
)
50 10
60 40
)
50 30
NaClO4, βoverall (M−2
)
1 000 000 600 000
400 250
<10 000
cooperativity α
d
NaClO /dNaI ≈ ΔGα,NaI/ΔGα,NaClO (Figure 9b). That is,
4
4
I−, Kanion (M−1
Na+, Kcation (M−1
)
80
5
100 10
<8000
Coulomb’s law correlates with the observed cooperativity
difference even though it overestimates the absolute values by 9
kJ mol−1: ECoul(NaI) = −27 kJ mol−1 and ECoul(NaClO4) = −24
kJ mol−1.
)
50 30
NaI, βoverall (M−2
cooperativity α
)
5 000 000 1 000 000
1300 600
a
To summarize the experimental findings, MC1 binds
NaClO4 and NaI with the same geometry but the cooperativity
of NaI is stronger than NaClO4. The distance dependence of
the cooperativity hints at electrostatic attraction as the origin of
the differences in cooperativity. However, Coulomb’s law
overestimates the cooperativity. There could be two possible
explanations for this overestimation. Ion-pair binding to MC1
may have 9 kJ mol−1 of negative allostery, making the net
cooperativity smaller than Coulomb’s law predictions. Alter-
natively, when the ions are bound inside MC1, their charges are
diluted by multiple secondary interactions within the receptor
(e.g., hydrogen-bonding and ion−dipole). As a result, the
effective ionic charges are less than 1, which makes the
attraction weaker than Coulomb’s law. Experiments cannot
differentiate between these two hypotheses. Testing requires
deeper analysis with the aid of computational studies to
calculate allostery and include all the secondary interactions.
These computations allow us to test if the distance dependence
originates from electrostatics and if Coulomb’s law is a good
predictor of electrostatic cooperativity.
Ion pairing was also included in the fits to the model: Kip (TBAClO4
= 250 60 M−1, NaBPh4 = 2 1 M−1, NaClO4 = 200 50 M−1,
b
TBAI = 80 10 M−1, and NaI = 60 10 M−1). Fitting gives an
upper limit for βoverall (MC2).
are similar between MC1 and MC2. Furthermore, MC2 is not
an ion-pair receptor, and measurements confirm MC2 is
significantly weaker than MC1 at binding ion pairs (Table 1).
The low βoverall values for MC2 are believed to be the product
of weak anion binding (Kanion ≈ 50) and weak pairing between
the negatively charged complex MC2·X− and Na+ ion. This
pairing likely produces an outer-sphere complex with the
countercation:
MC2·X− + Na+ ⇌ [MC2·X−···Na+], K < 200 M−1
(13)
The similarities and differences between MC1 and MC2 verify
that our method of analysis is able to resolve anion binding
from ion-pair binding in order to assess them separately.
The smaller ionic size of I− (r = 2.1 Å) relative to ClO4− (r =
2.4 Å), as determined from thermochemical radii,42 is
consistent with the greater cooperativity in binding NaI.
Given the fact that all these ions are singly charged and the
Computational Analysis of Cooperativity in Ion-Pair
Binding. A parallel approach to analyzing the cooperativity was
undertaken by using calculations to help deconvolute
Figure 9. (a) Comparison of ion−ion separation distances in the crystal structures and (b) their impact on the expected Coulombic interactions,
ECoul, relative to observed cooperativities, ΔGα.
H
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
conformational allostery from electrostatic cooperativity. The
computational study was based on the same binding model as
experiments (Figure 7 and eqs 3−7). Three simplifications
were undertaken. First, we used model receptor MC5 without
side chains (Figure 1) as an isosteric version of MC1. Second,
the ion pairs studied in the calculations involved spherical ions:
NaCl, NaBr, and NaI. One unresolved issue emerged when
Table 2. DFT Calculated Binding Energies, ΔE, and
Deformation Penalties, D, in kJ mol−1 for MC5
gas phase
ΔEgas
CH2Cl2 solvation
ΔEsol
M+
X−
Dgas
Dsol
Cl−
Br−
I−
−212
−189
−172
−246
16
13
11
48
−58
−51
−52
−39
9
6
−
studying nonspherical ions like ClO4 . They are believed to be
5
rapidly tumbling18c,e,f,43 within the receptor, and this averaging
factor could not be readily accounted for in the present
computational approach.44 Third, a solvation model using
CH2Cl2 was selected for being closest to the 4:1
CH2Cl2:CH3CN mixture used experimentally. With these
simplifications, the calculations will not provide absolute values
for matching the experiment. Rather, the computational study
is a self-consistent analysis that can provide insight on the
origin of the ion−ion size dependence and on the accuracy of
Coulomb’s law predictions.
Na+
29
Na+
Na+
Na+
Cl−
Br−
I−
−767
−737
−711
24
22
23
−156
−145
−140
21
20
19
reduces more significantly upon solvation to be weaker than the
anions. The deformation penalties are generally less sensitive to
solvation (Table 2). The following discussion will highlight the
structures and values obtained with solvation model. The gas-
phase structures can be found in the Supporting Information,
and the gas-phase values are included in the main text. All the
trends seen with solvation also hold true for the gas phase.
The geometries and the related energies (Table 2) of the ion
complexes provide the basis from which to evaluate
cooperativity. Optimized geometries of anion-bound complexes
MC5·X− (X− = Cl−, Br−, and I−) have similar structures
(Figure 11). Anions sit inside the macrocycle held by triazole
CH hydrogen-bonding, with CH···X− distances ranging from
2.4 to 2.9 Å. The binding energies scale with anion size (Table
2). The MC5·Na+ structure (Figure 11d) shows how the cation
forms close contacts with four oxygen atoms in the glycol chain
leaving one oxygen atom outside the cation-binding cavity.
The anion-binding site is more rigid while the cation-binding
glycol is more flexible. Consistently, the deformation penalties,
Dion (Table 2), for binding anions are small and close to each
other: DXsol ranges from 5 to 9 kJ mol−1. The cation binding has
The binding energies, ΔEion (Figure 10a), associated with
each guest were obtained from geometry-optimized structures
a higher deformation penalty, DNa = 29 kJ mol−1, which is
sol
attributed to glycol flexibility.
Geometries of complexes formed with the ion pairs (Figure
12) show anions and cations in direct contact. The binding
energies of ion pairs follow similar trends as seen for anion
binding. Their charge separation distances, dcomplex (Table 3),
are very close to the values obtained with the ion pairs
optimized in the absence of the receptor, dfree pair. The flexible
glycol in MC5 reorganizes to accommodate the bound pairs
which have direct contact. The deformation penalties for ion-
pair binding are in between those for the anions and cation.
The overall and allosteric cooperativity of ion-pair binding
(Table 3) was determined (analogous to eq 6) using the data in
Table 2. The electrostatic cooperativity, ΔEelec, was then
calculated using ΔEelec = ΔEα − ΔEallos. Contrary to our first
hypothesis, we find both allostery and electrostatic coopera-
tivity are positive. While both these factors get smaller when the
system is solvated, the electrostatic contribution is more
sensitive to solvation. Nevertheless, the conformational
allostery, ΔEallos, of MC5 binding NaCl, NaBr, and NaI
remains smaller than electrostatics (ΔEallos is 20−30% of
ΔEelec) in the CH2Cl2 solvent. It also shows a smaller (2 kJ
mol−1) variation across the ion pairs. Therefore, net
cooperativity, ΔEα, variation of 10 kJ mol−1 across the series
NaCl, NaBr, and NaI mainly stems from variations in the
electrostatic contribution (8 kJ mol−1). Consequently, the
electrostatic contribution to cooperativity dominates the
decreasing trend in cooperativity.
Figure 10. Energy diagrams illustrating how (a) binding energy, ΔEion
,
is obtained from the optimized geometries of reactants and products,
and (b) deformation penalty, Dion, is defined by the difference in
energies for the receptors in the geometry of the empty macrocycle
and when the macrocycle is complexed.
of the reactants (free MC5 and free guest) and the product
(MC5·guest complex). The deformation penalties, Dion
,
associated with the binding events were determined in a similar
way (Figure 10b). Deformation penalties were calculated as the
difference in energy between the optimized geometry of free
MC5 and the geometry of the MC5·guest complex with the
guest deleted from the structure.
In the computational study, every species (MC5, MC5·X−,
MC5·Na+, and MC5·NaX) was optimized both in the gas phase
and with CH2Cl2 solvation model to give structures, binding
energies, and deformation penalties for the two phases. The
geometries in the gas phase did not show significant changes
upon solvation. The anion binding energies (Table 2) reduce to
∼30% upon CH2Cl2 solvation. Interestingly, the gas-phase
binding of Na+ (Table 2) is stronger than the anions but
I
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 11. Geometry-optimized structures of (a) MC5·Cl−, (b) MC5·Br−, (c) MC5·I−, and (d) MC5·Na+.
Figure 12. Geometry-optimized structures of MC5 with (a) NaCl, (b) NaBr, and (c) NaI.
Table 3. Calculated Binding Cooperativity, ΔEα,
Conformational Allostery, ΔEallos, and Electrostatic
Cooperativity, ΔEelec, All in kJ mol−1, and Charge Separation
Distances within MC5·Ion-Pair Complexes, dcomplex, and
Free Pairs, dfree pair, in Å, in Gas and Solvent Phases
a
ΔEα
ΔEallos
ΔEelec
dcomplex
dfree pair
∑rion
Gas Phase
−269
−263
NaCl
NaBr
NaI
−309
−302
−292
−40
−39
−36
2.5
2.7
2.9
2.4
2.5
2.7
2.7
2.8
3.1
−256
CH2Cl2 Solvent
NaCl
NaBr
NaI
−59
−55
−49
−17
−15
−15
−42
−40
−34
2.7
2.8
3.1
2.6
2.8
3.0
2.7
2.8
3.1
Figure 13. Plots of electrostatic cooperativity determined computa-
tionally, ΔEelec (red), and from Coulomb’s law, ECoul (black), as a
function of the charge separation distances, 1/dcomplex, derived from the
optimized MC5·ion-pair complexes using CH2Cl2 as solvent medium.
a
∑rion = rNa + rX (X = Cl, Br, I), where rCl = 1.7 Å, rBr = 1.8 Å, rI = 2.1
Å, and rNa = 1.0 Å.
Interpretation of Observed and Computed Coopera-
tivity. The calculations (Table 3) show that electrostatic
cooperativity is dominated by the charge separation distances,
(e.g., hydrogen-bonding and ion−dipole) would not be
included. The computational model incorporates all these
interactions and thus offers a more accurate estimate of
electrostatic cooperativity, ΔEelec, for the ion-pair binding
within MC5. Ion−ion distance is seen to dictate the trend in
ΔEelec across the halide series (Figure 13, red line). However,
the absolute value is less than from a Coulomb’s law prediction
by ∼20 kJ mol−1. We attribute this difference to the secondary
interactions present within the receptor−anion−cation ternary
d
complex, as suggested by Coulomb’s law (eq 1). This is a simple
model that is based on a contacting ion pair with the
macrocycle omitted. Coulomb’s law would also have given the
variation of electrostatic cooperativity with ion−ion distance
(Figure 13, black line). However, the presence of other
interactions present inside the binding cavity of the macrocycle
J
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
complex that dilute the effective charges of the ions to be less
than 1.
electrostatic cooperativity but overestimated the absolute value
by not accounting for the putative charge dilution that occurs
when the ions bind to their respective anion/cation sites. The
analyses and findings presented here provide a new approach
for the investigation of cooperativity that is expected to aid in
the future rational designs and understanding of receptor-
mediated ion-pair binding.
The electrostatic cooperativity, ΔEelec, is dictated by anion−
cation distance, dcomplex, which can be correlated with the size of
the constituent ions, ∑rion (Table 3). This correlation arises as
a consequence of the semiflexible character of macrocycle
MC5. The macrocycle allows the ions to optimize their
electrostatic interaction by contacting each other. Consistent
with this idea, the internuclear distance in the complex, dcomplex
,
ASSOCIATED CONTENT
■
is similar to the ion−ion distances of free ion pairs, dfree pair
(Table 3). Consequently, in semiflexible receptors where ion
pairs have direct contact, electrostatic cooperativity is tuned by
ionic sizes. This finding also explains the experimental
observation that the smaller NaI ion pair has higher
cooperativity than NaClO4 within MC1.
S
* Supporting Information
Computational methods, syntheses, NMR data, titration
analyses, X-ray data, and optimized structures. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/jacs.5b05839.
Summarizing the computational study, it was found that
complexes with NaCl, NaBr, and NaI have very similar
geometries but their cooperativities decrease. This trend
matches the experiments conducted with NaI and NaClO4,
and questions raised by experiment have been answered with
calculations. First, the difference in cooperativity originates
from electrostatics; allostery contributes to the cooperativity
but it has minimal variation across the series (NaCl−NaI). The
electrostatic cooperativity depends on ion−ion distance within
the semiflexible receptor. Second, Coulomb’s law can only
predict the trend of electrostatic cooperativity; it overestimates
the absolute value of cooperativity by missing secondary
interactions. Finally it was revealed that allostery is less sensitive
to solvation. As a consequence, increasing solvent polarity may
reduce the electrostatic contribution significantly while having a
smaller effect on allostery.
AUTHOR INFORMATION
■
Corresponding Author
*aflood@indiana.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge support by the Chemical
Science, Geosciences and Biosciences Division, Office of Basic
Energy Sciences, U.S. Department of Energy (DE-FG02-
09ER16068). Y.L. thanks the Raymond Siedle Materials
Fellowship for support. J.R.A. thanks Indiana University for
summer research scholarship for support.
We further postulate that with a rigid receptor, which cannot
reorganize itself, there may exist only a few ion pairs that will
allow ion binding into the separate ion pockets at the same time
as directing ion pairs to make contact. This situation is expected
to give rise to peak selectivity for those few ion pairs. Many
previously reported rigid ion pair receptors showing various
selectivities appeared to take advantage of this design
principle.20a,23,25b,27,45 Our computational analysis also reveals
that the electrostatic term, ΔEelec, included in eq 8, contains
contributions from pure ion−ion electrostatic attraction in
addition to the secondary interactions. These secondary effects
will always lessen electrostatic attraction and its ensuing impact
on the cooperativity of binding contact ion pairs in receptors.
REFERENCES
■
(1) Lehn, J.-M. Supramolecular Chemistry: Concepts and Perspectives;
VCH: Weinheim, 1995.
(2) Smith, B. D. Ion Pair Recognition by Ditopic Receptors. In
Macrocyclic Chemistry: Current Trends and Future Prospectives; Gloe, K.,
Antonioli, B., Eds.;; Kluwer: London, 2005.
(3) Kovbasyuk, L.; Kramer, R. Chem. Rev. 2004, 104, 3161−3188.
̈
(4) (a) Wintergerst, M. P.; Levitskaia, T. G.; Moyer, B. A.; Sessler, J.
L.; Delmau, L. H. J. Am. Chem. Soc. 2008, 130, 4129−4139.
(b) Aydogan, A.; Coady, D. J.; Kim, S. K.; Akar, A.; Bielawski, C.
W.; Marquez, M.; Sessler, J. L. Angew. Chem., Int. Ed. 2008, 47, 9648−
9652. (c) McConnell, A. J.; Beer, P. D. Angew. Chem., Int. Ed. 2012, 51,
5052−5061. (d) Romanski, J.; Piatek, P. Chem. Commun. 2012, 48,
11346−11348. (e) McDonald, K. P.; Qiao, B.; Twum, E. B.; Lee, S.;
Gamache, P. J.; Chen, C.-H.; Yi, Y.; Flood, A. H. Chem. Commun.
2014, 50, 13285−13288.
CONCLUSIONS
■
(5) (a) Tong, C. C.; Quesada, R.; Sessler, J. L.; Gale, P. A. Chem.
Commun. 2008, 6321−6323. (b) Davis, J. T.; Okunola, O.; Quesada,
R. Chem. Soc. Rev. 2010, 39, 3843−3862. (c) Kim, D. S.; Sessler, J. L.
Chem. Soc. Rev. 2015, 44, 532−546.
(6) (a) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D.
Science 2011, 334, 1681−1684. (b) Mahlau, M.; List, B. Angew. Chem.,
Int. Ed. 2013, 52, 518−533. (c) Brak, K.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2013, 52, 534−561.
(7) Gokel, G. W. Molecular Recognition Receptors for Cationic
Guests. In Comprehensive Supramolecular Chemistry; Lehn, J.-M.,
Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Vogtle, F., Eds.;
Pergamon: Oxford, 1996; Vol. 1.
(8) (a) Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor
Chemistry; Royal Society of Chemistry: Cambridge, 2006. (b) Gale, P.
A.; Busschaert, N.; Haynes, C. J. E.; Karagiannidis, L. E.; Kirby, I. L.
Chem. Soc. Rev. 2014, 43, 205−241.
(9) (a) Li, Y.; Flood, A. H. Angew. Chem., Int. Ed. 2008, 47, 2649−
2652. (b) Li, Y.; Flood, A. H. J. Am. Chem. Soc. 2008, 130, 12111−
12122.
Cooperativity is the central concept in ion-pair binding, yet
only a few studies have focused on quantitatively evaluating the
degree and origin of cooperativity. In this work, we established
a binding model that allowed experimental and computational
analyses to be used together for a comprehensive examination
of cooperativity in ion-pair binding. Our method is capable of
generating more quantitative information on ion-pair binding
than conventional turn-on factors. For the first time, the
cooperativity factor was determined experimentally from
thermodynamic quantifications of anion, cation, and overall
ion-pair binding. It was found that NaI has higher cooperativity
than NaClO4 in our model system. Using density functional
theory calculations, we provided the first separate examination
of conformational allostery and electrostatic cooperativity. This
study revealed that the size of the ions dictated the electrostatic
cooperativity but only if the ions could make direct contact
with each other. Coulomb’s law could predict the trend of
K
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(10) Sessler, J. L.; Gross, D. E.; Cho, W.-S.; Lynch, V. M.;
Schmidtchen, F. P.; Bates, G. W.; Light, M. E.; Gale, P. A. J. Am. Chem.
Soc. 2006, 128, 12281−12288.
(25) (a) Lankshear, M. D.; Cowley, A. R.; Beer, P. D. Chem.
Commun. 2006, 612−614. (b) Romanski, J.; Piatek, P. J. Org. Chem.
2013, 78, 4341−4347.
(26) Roelens, S.; Vacca, A.; Francesconi, O.; Venturi, C. Chem. - Eur.
J. 2009, 15, 8296−8302.
(11) (a) Bianchi, A.; Bowman-James, L.; García-Espana, E.
̃
Supramolecular Chemistry of Anions; Wiley-VCH: New York, 1997.
(b) Beer, P. D.; Gale, P. A.; Smith, D. K. Supramolecular Chemistry;
Oxford: New York, 1999. (c) Hua, Y.; Ramabhadran, R. O.; Uduehi, E.
O.; Karty, J. A.; Raghavachari, K.; Flood, A. H. Chem. - Eur. J. 2011, 17,
312−321. (d) Hua, Y.; Liu, Y.; Chen, C.-H.; Flood, A. H. J. Am. Chem.
Soc. 2013, 135, 14401−14412.
(12) Comarmond, J.; Plumere, P.; Lehn, J.-M.; Agnus, Y.; Louis, R.;
Weiss, R.; Kahn, O.; Morgenstern-Badarau, I. J. Am. Chem. Soc. 1982,
104, 6330−6340.
(13) Kim, S. K.; Sessler, J. L. Chem. Soc. Rev. 2010, 39, 3784−3809.
(14) Douglass, E. F.; Miller, C. J.; Sparer, G.; Shapiro, H.; Spiegel, D.
A. J. Am. Chem. Soc. 2013, 135, 6092−6099.
(15) (a) Yoon, D.-W.; Gross, D. E.; Lynch, V. M.; Sessler, J. L.; Hay,
B. P.; Lee, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5038−5042. (b) Kim,
S. K.; Sessler, J. L.; Gross, D. E.; Lee, C.-H.; Kim, J. S.; Lynch, V. M.;
Delmau, L. H.; Hay, B. P. J. Am. Chem. Soc. 2010, 132, 5827−5836.
(c) Cai, J.; Hay, B. P.; Young, N. J.; Yang, X.; Sessler, J. L. Chem. Sci.
2013, 4, 1560−1567. (d) Kim, S. K.; Lynch, V. M.; Hay, B. P.; Kim, J.
S.; Sessler, J. L. Chem. Sci. 2015, 6, 1404−1413.
(16) (a) Sachleben, R. A.; Bryan, J. C.; Engle, N. L.; Haverlock, T. J.;
Hay, B. P.; Urvoas, A.; Moyer, B. A. Eur. J. Org. Chem. 2003, 2003,
4862−4869. (b) Hay, B. P.; Gutowski, M.; Dixon, D. A.; Garza, J.;
Vargas, R.; Moyer, B. A. J. Am. Chem. Soc. 2004, 126, 7925−7934.
(c) Hay, B. P.; Firman, T. K.; Moyer, B. A. J. Am. Chem. Soc. 2005,
127, 1810−1819.
(17) (a) Custelcean, R.; Bosano, J.; Bonnesen, P. V.; Kertesz, V.;
Hay, B. P. Angew. Chem., Int. Ed. 2009, 48, 4025−4029. (b) Custelcean,
R.; Bonnesen, P. V.; Duncan, N. C.; Zhang, X.; Watson, L. A.; Van
Berkel, G.; Parson, W. B.; Hay, B. P. J. Am. Chem. Soc. 2012, 134,
8525−8534. (c) Jia, C.; Hay, B. P.; Custelcean, R. Inorg. Chem. 2014,
53, 3893−3898.
(18) (a) Bandyopadhyay, I.; Raghavachari, K.; Flood, A. H.
ChemPhysChem 2009, 10, 2535−2540. (b) Hua, Y.; Ramabhadran,
R. O.; Karty, J. A.; Raghavachari, K.; Flood, A. H. Chem. Commun.
2011, 47, 5979−5981. (c) Ramabhadran, R. O.; Hua, Y.; Flood, A. H.;
Raghavachari, K. Chem. - Eur. J. 2011, 17, 9123−9129. (d) McDonald,
K. P.; Ramabhadran, R. O.; Lee, S.; Raghavachari, K.; Flood, A. H. Org.
Lett. 2011, 13, 6260−6263. (e) Ramabhadran, R. O.; Hua, Y.; Flood,
A. H.; Raghavachari, K. J. Phys. Chem. A 2014, 118, 7418−7423.
(f) Ramabhadran, R. O.; Liu, Y.; Hua, Y.; Ciardi, M.; Flood, A. H.;
Raghavachari, K. J. Am. Chem. Soc. 2014, 136, 5078−5089.
(19) (a) Scheerder, J.; van Duynhoven, J. P. M.; Engbersen, J. F. J.;
Reinhoudt, D. N. Angew. Chem., Int. Ed. Engl. 1996, 35, 1090−1093.
(b) Gavette, J. V.; Lara, J.; Reling, L. L.; Haley, M. M.; Johnson, D. W.
Chem. Sci. 2013, 4, 585−590. (c) Howe, E. N. W.; Bhadbhade, M.;
Thordarson, P. J. Am. Chem. Soc. 2014, 136, 7505−7516. (d) Kim, S.
K.; Sessler, J. L. Acc. Chem. Res. 2014, 47, 2525−2536. (e) Saha, I.;
Park, K. H.; Han, M.; Kim, S. K.; Lynch, V. M.; Sessler, J. L.; Lee, C.-
H. Org. Lett. 2014, 16, 5414−5417.
(27) Perraud, O.; Robert, V.; Martinez, A.; Dutasta, J.-P. Chem. - Eur.
J. 2011, 17, 4177−4182.
(28) (a) Shi, D.; Schwall, C.; Sfintes, G.; Thyrhaug, E.; Hammershøj,
P.; Cardenas, M.; Simonsen, J. B.; Laursen, B. W. Chem. - Eur. J. 2014,
́
20, 6853−6856. (b) Haketa, Y.; Sasaki, S.; Ohta, N.; Masunaga, H.;
Ogawa, H.; Mizuno, N.; Araoka, F.; Takezoe, H.; Maeda, H. Angew.
́
Chem., Int. Ed. 2010, 49, 10079−10083. (c) Gonzalez-Rodríguez, D.;
van Dongen, J. L. J.; Lutz, M.; Spek, A. L.; Schenning, A. P. H. J.;
Meijer, E. W. Nat. Chem. 2009, 1, 151−155.
(29) Frisch, M. J.; et al. Gaussian Development Version, Revision H.32;
Gaussian Inc.: Wallingford, CT, 2010.
(30) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−241.
(31) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151−5158.
(32) Check, C. E.; Faust, T. O.; Bailey, J. M.; Wright, B. J.; Gilbert, T.
M.; Sunderlin, L. S. J. Phys. Chem. A 2001, 105, 8111−8116.
(33) Lee, S.; Hua, Y.; Park, H.; Flood, A. H. Org. Lett. 2010, 12,
2100−2102.
(34) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596−2599. (b) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057−3064.
(35) Andersen, J.; Madsen, U.; Bjorkling, F.; Liang, X. Synlett 2005,
̈
2209−2213.
(36) (a) Amini, M. K.; Shamsipur, M. J. Phys. Chem. 1991, 95, 9601−
9604. (b) Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R. L.
Chem. Rev. 1995, 95, 2529−2586. (c) Shamsipur, M.; Irandoust, M. J.
Solution Chem. 2008, 37, 657−664.
(37) (a) Plenio, H.; Diodone, R. J. Am. Chem. Soc. 1996, 118, 356−
367. (b) Khan, F. A.; Parasuraman, K.; Sadhu, K. K. Chem. Commun.
2009, 45, 2399−2401.
(38) Pedzisa, L.; Hay, B. P. J. Org. Chem. 2009, 74, 2554−2560.
(39) The chemical shift change of He at 4.4 ppm upon binding is
greater than those of the other glycol protons in MC1 (Hf, Hj, Hk),
which display shifts attributed to the binding of Na+.
(40) (a) Pascu, S. I.; Naumann, C.; Kaiser, G.; Bond, A. D.; Sanders,
J. K. M.; Jarrosson, T. Dalton Trans. 2007, 3874−3884. (b) Thatcher,
R. J.; Johnson, D. G.; Slattery, J. M.; Douthwaite, R. E. Chem. - Eur. J.
2012, 18, 4329−4336. (c) Kang, H.; Facchetti, A.; Stern, C. L.;
Rheingold, A. L.; Kassel, W. S.; Marks, T. J. Org. Lett. 2005, 7, 3721−
3724.
(41) Maryott, A. A.; Smith, E. R. Table of Dielectric Constants of Pure
Liquids; NBS Circular 514; National Bureau of Standards:
Washington, DC, 1951.
(42) Roobottom, H. K.; Jenkins, H. D. B.; Passmore, J.; Glasser, L. J.
Chem. Educ. 1999, 76, 1570.
(43) Hirsch, B. E.; Lee, S.; Qiao, B.; Chen, C.-H.; McDonald, K. P.;
Tait, S. L.; Flood, A. H. Chem. Commun. 2014, 50, 9827−9830.
−
(44) As a consequence, we believe that the size of ClO4 present in
the calculations is an underestimate of the averaged size of the
tumbling anion characterized experimentally (Supporting Informa-
tion).
(45) (a) Beer, P. D; Dent, S. W. Chem. Commun. 1998, 34, 825−826.
(b) Park, I.-W.; Yoo, J.; Adhikari, S.; Park, J. S.; Sessler, J. L.; Lee, C.-
(20) (a) Mahoney, J. M.; Beatty, A. M.; Smith, B. D. J. Am. Chem. Soc.
2001, 123, 5847−5848. (b) Kim, S. K.; Lynch, V. M.; Young, N. J.;
Hay, B. P.; Lee, C.-H.; Kim, J. S.; Moyer, B. A.; Sessler, J. L. J. Am.
Chem. Soc. 2012, 134, 20837−20843.
́ ́
H. Chem. - Eur. J. 2012, 18, 15073−15078. (c) Oton, F.; Gonzalez, M.
d. C.; Espinosa, A.; Ramírez de Arellano, C.; Tar
Org. Chem. 2012, 77, 10083−10092.
́
raga, A.; Molina, P. J.
́
(21) Coulomb, C. A. Histoire de l’Academie Royale des Sciences;
Imprimerie Royale: Paris, 1788; pp 569−577.
(22) (a) Ni, X.-L.; Rahman, S.; Zeng, X.; Hughes, D. L.; Redshaw, C.;
Yamato, T. Org. Biomol. Chem. 2011, 9, 6535−6541. (b) Valderrey, V.;
Escudero-Adan
6898−6902.
́
, E. C.; Ballester, P. Angew. Chem., Int. Ed. 2013, 52,
(23) Deetz, M. J.; Shang, M.; Smith, B. D. J. Am. Chem. Soc. 2000,
122, 6201−6207.
(24) Beer, P. D.; Drew, M. G. B.; Knubley, R. J.; Ogden, M. I. J.
Chem. Soc., Dalton Trans. 1995, 3117−3123.
L
DOI: 10.1021/jacs.5b05839
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX