Binding Selectivity of Macrocycle Ionophores in Ionic Liquids versus Aqueous Solution and Solvent-free Conditions

Article abstract of DOI:10.1002/cphc.201500477

The understanding of supramolecular recognition in room-temperature ionic liquids (RTILs) is key to develop the full potential of these materials. In this work, we provide insights into the selectivity of the binding of alkali metal cations by standard cy

Full text of DOI:10.1002/cphc.201500477

DOI: 10.1002/cphc.201500477
Articles
Binding Selectivity of Macrocycle Ionophores in Ionic
Liquids versus Aqueous Solution and Solvent-free
Conditions
Francisco Gµmez, Ana R. Hortal, Paola Hurtado, Juan R. AvilØs-Moreno, Said Hamad, and
Bruno Martínez-Haya*[a]
The understanding of supramolecular recognition in room-
temperature ionic liquids (RTILs) is key to develop the full po-
tential of these materials. In this work, we provide insights into
the selectivity of the binding of alkali metal cations by stan-
dard cyclodextrin and calixarene macrocycles in RTILs. A direct
laser desorption/ionization mass spectrometry approach is em-
ployed to determine the relative abundances of the inclusion
complexes formed through competitive binding in RTIL solu-
tions. The results are compared with the binding selectivities
measured under solvent-free conditions and in water/methanol
solutions. Cyclodextrins and calixarenes in which the peripheral
OH groups are substituted by bulkier side groups preferentially
bind to Cs+. Such specific ionophoric behavior is substantially
enhanced by solvation effects in the RTIL. This finding is ration-
alized with the aid of quantum mechanical calculations, in
terms of the conformational features and steric interactions
that drive the solvation of the inclusion complexes by the
bulky RTIL counterions.
1. Introduction
Room-temperature ionic liquids (RTILs) are currently used as
solvents in numerous applications such as “green” chemical
synthesis, catalysis, electrochemistry, and analytical tech-
niques.[1–8] A key aspect of RTILs is their broad range of solva-
tion interactions, owing to the complexity and variety of the
possible constituent counterions.[9–11] The combination of
charged and polar centers with hydrophobic groups within the
cations and anions of the salt, can make a single RTIL suitable
for a large spectrum of solvation and chemical processes.
Moreover, with the appropriate choice of molecular functional
groups, RTILs can act as task-specific reaction environments.[7]
The understanding of supramolecular recognition in RTILs
constitutes a major challenge in modern chemistry. For the de-
velopment of novel applications of RTILs, it is essential to de-
termine to what extent the scientific community can borrow
concepts from supramolecular behavior from the vast body of
knowledge established over the years in aqueous and organic
solutions.
In this work, we investigate the cation-binding selectivity of
standard macrocycles in the bulk of a RTIL solution. In particu-
lar, our study focuses on the alkali metal cation complexes
formed by two families of macrocycles with a central role in
supramolecular chemistry, namely, cyclodextrins and calixar-
enes (see Figure 1).[12–18] Perhaps surprisingly, the host–guest
ionophoric behavior of these macrocycles in RTILs has been
Figure 1. Top: Cyclodextrin (a, b) and calixarene (c) macrocycles investigated
in this work. Bottom: The counterions of the RTIL employed in most of the
experiments; 2,5-dihydroxybenzoate and protonated n-butylamine.
scarcely investigated, in spite of its recognized potential for
the extraction of metals from complex solutions, including nu-
clear waste.[19–24] As model RTILs for the present investigation,
we have chosen different combinations of the anionic aromatic
chromophore 2,5-dihydroxybenzoate (DHBÀ) with different
protonated amines as countercations. This type of RTIL allows
the use of laser desorption mass spectrometry to probe the
chemical composition of the solvated species.[25–29]
[a] Dr. F. Gµmez, Dr. A. R. Hortal, Dr. P. Hurtado, Dr. J. R. AvilØs-Moreno,
Dr. S. Hamad, Prof. B. Martínez-Haya
Department of Physical, Chemical and Natural Systems
Universidad Pablo de Olavide, 41013 Seville (Spain)
E-mail: bmarhay@upo.es
Here, we show that native cyclodextrins in RTILs bind alkali
metal cations with relative affinities that are dependent on the
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cphc.201500477.
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Articles
sizes of the macrocycle and the cation. In contrast, cyclodex-
trins and calixarenes derivatized with bulky side chains are
shown to display a pronounced preference for binding specific
cations of the series (Cs+ in the present case). Such binding
specificity can be appreciably enhanced by the RTIL solvent in
comparison with conventional aqueous or organic solutions.
We will discuss these findings in terms of molecular interac-
tions and steric effects with the aid of quantum mechanical
computations.
The most relevant details of the experimental and computa-
tional methodologies involved in this study are outlined in the
Methodology Section. In particular, the desorption/ionization
mass spectrometry approach employed in this investigation
provides a rapid means to determine the relative abundances
of the inclusion complexes formed in the RTIL, and should be
of general application in the field.
2. Results and Discussion
2.1. Laser Desorption Experiments in RTIL Solutions
The experimental study began with the evaluation of the sen-
sitivity of the supramolecular behavior of the macrocycles to
the composition of the RTIL solvents. In particular, the influ-
ence of the countercation of the RTIL was probed with the ex-
pectation that it could have an influence on the solvation in-
teractions with the complexes, and/or it could bind efficiently
to the macrocycle host.[30] For this purpose, the cation affinities
of the individual macrocycles were determined for four 2,5-di-
hydroxybenzoate-based RTILs with either propylamine, butyla-
mine, isobutylamine, or aniline, in protonated form, as the cat-
ionic counterpart. The DHBÀ anionic component of the RTIL
was kept the same in all cases.
Figure 2. Laser desorption mass spectra (positive-ion mode) of RTIL solutions
(2,5-DHBÀ/nBuNH3+) of the three cyclodextrins studied in this work, with
equimolar amounts of the alkali metal cations, M+ =Li+–Cs+. The relative in-
tensities of the peaks in each spectrum reflect the corresponding alkali
metal cation affinities of the cyclodextrin in the RTIL. Note the significant en-
hancement in the selectivity for Cs+ in the tri-O-methylated cyclodextrin
(hCD), relative to the native cyclodextrins (aCD and bCD).
of the macrocycle–cation complexes, and hence, the binding
affinities, in the bulk RTIL were derived from the integrated in-
tensities of the corresponding peaks in the mass spectrum.
Table 1 summarizes the relative binding affinities obtained in
this way from the experiments.
According to our laser desorption experiments, the relative
abundances of the macrocycle–alkali metal complexes in the
recorded mass spectra are weakly dependent on the choice of
RTIL cation. Figure S1 in the Supporting Information illustrates
this finding for the bCD complexes, for which the only appreci-
able trend in the mass spectra is a moderate enhancement of
the stability of the complexes of the macrocycles with the
heavier alkali metal cations (K+, Rb+ and Cs+) in the butyla-
mine and aniline RTILs relative to the propylamine and isobu-
tylamine RTILs. Remarkably, no appreciable signal correspond-
ing to complexes formed between the macrocycle and the
RTIL cation was observed in any of the spectra. Hence, none of
the RTIL cations presently explored appear to compete favora-
bly with the alkali metal cations for binding to the macrocy-
cles. In conclusion, the RTIL cation is found to play a relatively
minor role in the complexation of the investigated macrocycles
with alkali metals. Therefore, throughout this paper we will
refer to measurements performed in only one of the RTILs,
that is, the one with the butylamine-based cationic component
(i.e., n-butylammonium, henceforth nBuNH3+).
For the native cyclodextrins (CDs; Figure 2), the abundances
of the alkali metal complexes follow a smooth trend relative to
the size of the alkali metal cation. aCD binds all five alkali
metal cations with similar affinities, within 20% for Li+–K+ and
within approximately 50% for the whole alkali metal series.
Due to its larger cavity, bCD has more favorable binding affini-
ties to the heavier cations., but it still displays affinities that do
not differ by more than 50% for Na+–Cs+. The mass spectra of
the heptakis-(2,3,6-tri-O-methyl)-b-cyclodextrin (hCD)–M+ com-
plexes reveal affinity ratios that are qualitatively different from
those of the native cyclodextrins. In particular, hCD shows
a marked preference for the Cs+ cation. As the size of bCD
and hCD are essentially the same, this Cs+ selectivity must be
attributed to the substitution of the peripheral OH groups
with bulkier and less-polar methylated groups. This aspect is
discussed below in detail in Section 2.3.
Interestingly, 4-tert-butylcalix[6]arene hexaacetic acid hex-
aethyl ester (Cesium Ionophore II; CI) displays an even clearer
preference than hCD for Cs+ relative to the other the alkali
metal cations (Figure 3). For the CI calixarene, the Li+ and Na+
complexes are barely detected in the spectrum. The K+ and
Rb+ complexes do have significant abundances, which are
Figures 2 and 3 show the laser desorption mass spectra re-
corded in positive ion mode for RTIL (DHBÀ/nBuNH3+) solu-
tions of the five alkali metal cations (Li+–Cs+) and either the
cyclodextrin or calixarene macrocycle. The relative abundances
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and containing only CsCl as the cation precursor. Figure 3
shows the mass spectrum recorded for this sample, reflecting
the competitive binding of the cation by the calixarene and
the cyclodextrin. It can be appreciated that the abundance of
the hCD–Cs+ complex in the mass spectrum is roughly four
times greater than that of the CI–Cs+ complex. Hence, the ex-
periments show that, although CI displays a more pronounced
selectivity for Cs+ relative to the smaller alkali metal cations
than hCD, the complex formed by the cyclodextrin with Cs+ is
energetically more stable.
It seems timely to stress that the laser desorption mass spec-
tra recorded for the RTIL samples reflects the solution behavior,
and are free from gas-phase complexation occurring during
the desorption process. Complexes formed in the gas phase
would reflect solvent-less binding affinities and interfere with
the present determination of the affinities in the bulk of the
RTIL. Previous studies have demonstrated that the stability of
these inclusion complexes in the gas phase is maximal for Li+
and decreases rapidly with the size of the cation.[31,32] This was
specifically shown for cyclodextrins in solvent-free laser de-
sorption experiments in which, for instance, a 10-fold greater
abundance was found for the aCD–Li+ complex relative to the
aCD–K+ complex.[31] Similar solvent-free measurements per-
formed here for the CI calixarene corroborate those findings
(see Section 2.2).
Figure 3. Top: Laser desorption mass spectrum (positive-ion mode) of the
RTIL solution (2,5-DHBÀ/nBuNH3+) of 4-tert-butylcalix[6]arene hexaacetic acid
hexaethyl ester (CI) with equimolar amounts of the alkali metal cations M+=
Li+ÀCs+. Bottom: MALDI spectrum measured for an equimolar solution of
the CI calixarene and the hCD cyclodextrin, with CsCl as the only cation pre-
cursor. The calixarene displays a strong Cs+ binding selectivity relative to
the rest of alkali metal cations, whereas the cyclodextrin forms Cs+ com-
plexes with greater absolute binding energies.
The isolated macrocycle–cation complexes observed in the
mass spectra recorded in the positive-ion mode, discussed
thus far, are formed after the weakly bound RTIL solvent mole-
cules are detached during the laser desorption process. In an
effort to characterize the first solvation shell of the complexes
in the RTIL, we performed laser desorption mass spectrometry
experiments in the negative-ion mode, with the aim of detect-
ing clusters of the macrocycle–metal complexes with DHBÀ
anions. Clusters of this type are difficult to observe in our ex-
periments, as they tend to decompose upon desorption and
yield appreciably weaker intensities than those of the bare,
positively charged complexes. Nevertheless, we could actually
observe solvated clusters in measurements recorded in the
negative-ion mode, although only at low laser pulse energies,
just above the threshold for the appearance of the ion yield in
our experiments (<1 mJpulseÀ1). This is illustrated in the mass
spectrum shown in Figure 4, in which peaks associated with
the negatively charged clusters (hCD)·(DHBÀ) and (hCD–Cs+)
·(DHBÀ)2 can be identified. Importantly, no clusters with more
than two DHBÀ anions were detected; this is in concordance
with the prediction of the theoretical study discussed in
Section 2.3.
Table 1. Relative alkali metal cation affinities measured for the cyclodex-
trin and calixarene macrocycles investigated in this work. The experi-
ments were performed either in the RTIL solvent (2,5-DHBÀ/nBuNH3+), in
aqueous solution (1:1 water/methanol, with added 10% DMSO for the
calixarene sample), or under solvent-less conditions, as indicated.[a]
Macrocycle/solvent
Li+
Na+
K+
Rb+
Cs+
aCD/RTIL
bCD/RTIL
hCD/RTIL
hCD/aqueous
CI/RTIL
0.79
0.32
0.72
0.60
0.17
0.29
7.15
1.00
1.00
1.00
1.00
1.00
1.00
1.00
0.83
1.45
0.79
0.68
5.90
0.63
0.36
0.58
0.94
0.86
1.00
8.60
1.30
0.28
0.51
0.75
2.15
0.95
46.7
2.86
0.14
CI/aqueous
CI/solvent-free
[a] For convenience, the values for each system are expressed relative to
the affinity obtained for the Na+. Such relative values are affected by an
error of Æ10%, as determined from repetitions of the measurements.
Note the significant enhancement of the Cs+ selectivities of the hCD cy-
clodextrin and the CI calixarene in the RTIL versus aqueous solution and
solvent-less conditions.
2.2. Experiments in Aqueous and Solvent-free Environments
nevertheless more than five times lower than that of the domi-
nant Cs+ complex.
To further assess the role of the RTIL solvent in the Cs+-bind-
ing selectivity displayed by the hCD and CI macrocycles, we
performed two additional types of experiments. On the one
hand, complexes formed in aqueous solution (1:1 water/meth-
anol for hCD and 0.2:1:1 DMSO/water/methanol for CI) were
probed by using electrospray ionization (ESI) measurements
and, on the other hand, complexes formed in the gas phase,
The strong preference of the CI calixarene for Cs+, served as
motivation to directly compare the relative Cs+-binding pro-
pensity of this macrocycle with that of hCD in a specific experi-
ment. For this purpose, laser desorption was performed on
a RTIL solution containing equimolar amounts of CI and hCD,
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Figure 4. Laser desorption mass spectrum in negative-ion mode of the RTIL
solution (2,5-DHBÀ/nBuNH3+) of the cyclodextrin hCD with CsCl as the
cation precursor. The two main peaks in the spectrum correspond to clusters
of the cyclodextrin with one DHBÀ anion (m/z=1581.7) and of the hCD–Cs+
complex solvated by two DHBÀ anions (m/z=1867.6), as labeled in the
graph. The less intense peaks in the spectrum could not be identified.
Figure 5. Electrospray mass spectra of the complexes formed in aqueous so-
lution (1:1 water/methanol) by the hCD (top) and CI (bottom) macrocycles
and the five alkali metal cations, Li+–Cs+. Note that the preference for the
binding of Cs+ of the two macrocycles is reduced with respect to the RTIL
solution (see Table 1).
that is, in a solvent-free environment, were measured by
means of laser desorption mass spectrometry. The correspond-
ing relative abundance ratios are included in Table 1.
The ESI measurements (Figure 5) show that hCD binds Cs+
efficiently, but not selectively within the alkali metal series. In
fact, the relative abundances of all the hCD–M+ complexes lie
within 50% of each other, and the Rb+ and Na+ complexes
have a similar or even slightly higher intensity than the Cs+
complex in the mass spectrum. For the CI calixarene, the ESI
spectrum does show a preferential binding for Cs+ in the
aqueous solution, although it is significantly less marked than
that found in the RTIL solution.
The laser desorption mass spectra recorded under solvent-
free conditions for solid mixtures of the CI macrocycle and
pairs of alkali metal cations are shown in Figure 6. Each mea-
surement probes the relative stability of the corresponding
pair of CI–M+ complexes when formed under isolated condi-
tions (in the gas phase). In these experiments, the difference in
lattice energy of the alkali metal salts employed as cation pre-
cursors prevents the use of more than two cations in a single
sample.[31,32] The solvent-free measurements corroborate the
behavior found for cyclodextrins and polyethers in previous in-
vestigations;[31,32] in the absence of solvent, the stability of the
complexes is highest for Li+, and decreases rapidly with in-
creasing cation size. This is a consequence of the greater
charge density of the smaller cations, which leads to a tighter
coordination with the oxygen atoms of the host, involving
shorter interaction distances.
Figure 6. Illustrative set of matrix-assisted laser desorption mass spectra
(positive-ion mode) of alkali metal cation complexes of the CI calixarene
formed under solvent-free conditions in the gas phase. In each spectrum,
the relative affinity is probed against a pair of alkali metal cations. Note the
overwhelmingly greater binding preference for Li+, which is in strong con-
trast to the behavior found in the RTIL and in aqueous solution (see
Table 1).
COH groups (primary side) present in the bCD, are substituted
by OCH3 and COCH3 groups, respectively. The introduction of
the methylated groups disrupts coordination with the cation
found for the native cyclodextrins, which relies largely on the
formation of stable intramolecular H-bonding networks.[31,33]
The stability of the hCD–M+ complexes is then driven by the
coordination of the metal cation with the ether oxygen atoms
of the COCH3 primary groups. In the CI calixarene, the OH end
groups of butylcalix[6]arene are substituted by significantly
bulkier acetic acid ethyl ester groups, which provide the polar
centers for coordination with the cation.[17,34,35]
The dramatic change in the alkali metal cation binding affini-
ties of the macrocycles when going from the gas-phase isolat-
ed state to an aqueous solution and to a RTIL solution is intri-
guing. The rationalization of the substantial enhancement of
the selectivity for the binding of Cs+ to both hCD and CI de-
mands a deeper insight into the molecular framework underly-
ing the macrocycle systems, including solvation effects. In the
hCD macrocycle, all the end OH groups (secondary side) and
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RTILs have bulky constituents, thus steric effects that hinder
efficient coordination to charge centers embedded in inclusion
complexes can be expected to be more crucial than for exam-
ple, for water or light alcohol solvents. For the present RTILs,
the solvation energy of the complexes relies primarily on the
coordination of the DHBÀ anions with the alkali metal cation
bound to the macrocycle, and on the way that this coordina-
tion disturbs the optimum intrinsic structure of the macrocy-
cle–cation complex. It can be anticipated that the complexes
of the larger cations may be stabilized, owing to their more
stretched structures, which provide more facile access of the
solvent molecules, to form coordination arrangements with
the alkali metal cation. These aspects are further discussed in
Section 2.3 in the light of both, classical molecular dynamics
(MD) simulations and quantum mechanical calculations.
Figure 7. Lowest energy conformations obtained in the present DFT calcula-
tions for the hCD–Cs+, CI–Cs+ and CI–Na+ complexes microsolvated by two
DHBÀ RTIL anions. The bottom drawings depict the full molecular structures
(the H atoms have been removed for clarity, and the oxygen atoms are in
dark grey). The partial structures represented on top highlight the coordina-
tion arrangements of the cation with the oxygen atoms of the macrocycles
and the carboxylate groups of DHBÀ (interatomic distances are given in Ang-
strom). Note the differences in the coordination of the two DHBÀ anions
with the alkali metal cation in each complex.
2.3. Computational Results
To elucidate the main conformational features and interactions
responsible for the stability of the macrocycle–metal com-
plexes in RTILs, we performed two types of calculations. Firstly,
MD simulations were run to model large, bulk-like solvated sys-
tems. Secondly, density functional theory (DFT) calculations
were employed to characterize the coordination structures at-
tained by the DHBÀ anions of the RTIL with the metal cation
embedded in the macrocycle.
achieved by the coordination of the cation with the oxygen
atoms of the CH2OCH3 side groups and with the carboxylate
groups of the DHBÀ anions. In the calixarene, the alkali metal
cation interacts with the oxygen atoms from the ether and the
carbonyl ester groups of the side chains. The conformation of
the CI complexes involves an appreciable folding of the calixar-
ene backbone and the side chains, leading to significant steric
interactions associated with the bulky acetyl ester groups. In
fact, the access of DHBÀ to the alkali metal cation is somewhat
hindered in the calixarene, leading to greater overall coordina-
tion distances with the alkali metal cation. For instance,
Figure 7 shows that the closest (ÀCOOÀ)–Cs+ distances in-
crease from 2.8 Š in the hCD complex to 3.0 Š, in the CI com-
plex. These features are probably be responsible for the
weaker binding of the Cs+ cation by the CI, in comparison to
the hCD–Cs+ complex. Furthermore, they serve to explain the
marked Cs+ selectivity of the CI calixarene, as the smaller alkali
metal cations demand a more pronounced folding of the calix-
arene for coordination, leading to more significant backbone
distortions, steric effects, and exclusion of solvent anions from
the interior of the calixarene cavity, especially of the anion
penetrating from the hydrophilic face, due to the bulky side
chains. This is well-illustrated by the CI–Na+ complex in
Figure 7 in which the DHBÀ anion is pushed out of the calixar-
ene cavity by the side chains to distances as large as 5.0 Š, as
the macrocycle folds to achieve coordination with the alkali
metal cation.
Figure S2 in the Supporting Information depicts a typical
snapshot of the MD simulation of the CI–Cs+ complex. The
MD study leads to the general conclusion that at most two
DHBÀ anions are able to coordinate simultaneously with the
alkali metal cation inside the cavity, although no more than
one DHBÀ anion coordinates from each side of the macrocycle.
Hence, a primary arrangement of tight interactions may be de-
scribed in terms of clusters of the type (macrocycle–
M+)·(DHBÀ)n (n=1,2). These clusters are then further solvated
in the bulk of the RTIL by a shell of more weakly interacting
ions that do not have any close contact with the metal cation
bound inside the macrocycle. Notably, this prediction is in con-
cordance with the negatively charged clusters detected in our
experiments (Figure 4).
Figure 7 depicts the most stable DFT conformation obtained
in this study, for representative cation complexes of the hCD
cyclodextrin (Cs+) and the CI calixarene (Cs+ and Na+), solvat-
ed by two DHBÀ anions. The relevant coordination sites of the
cation with each of the macrocycles and with the DHBÀ anions
are highlighted. It can be observed that the negatively charged
COOÀ carboxylate group of DHBÀ coordinates with the cation,
whereas the aromatic rings of the anions tend to interact with
the interior of the macrocycle and the side chains, in a similar
way as found in previous studies of related systems.[36] Of par-
ticular importance are the steric restrictions to the access of
DHBÀ to the alkali metal cation that are imposed by the mac-
rocycle backbone and side chains.
Natural bond orbital (NBO) analysis of the lowest energy
conformers of the complexes helps to reveal the dominant sta-
bilizing interactions between the alkali metal cation, the mac-
rocycle, and the DHBÀ solvent anions. The first general conclu-
sion of the NBO analysis is that the complex displays host–
guest interactions featuring 97% Lewis structure and 3% non-
Lewis structure. These values reflect an appreciable degree of
The docking site of the alkali metal cation in the complexes
is located on the rim of one the macrocycle faces, namely, the
primary face of the hCD cyclodextrin, and the hydrophilic face
of the CI calixarene. In the cyclodextrin, a stable complex is
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charge delocalization in the intermolecular coordination bonds
that stabilize the complex. Furthermore, the analysis indicates
that the stability of the solvated complex is mainly due to two
types of delocalization towards the n* orbital of the alkali
metal cation, which arise from the macrocycle and the DHBÀ
moieties. For the particular case of the calixarene complexes,
the delocalization from the CI molecule involves the aromatic
CÀC and the ether CÀOÀC bonding orbitals, as well as the
lone pairs of the oxygen atom in the ester C=O group. In the
case of the two DHBÀ solvent anions, the delocalization to-
wards the cation arises primarily from the carboxylate group
through its CÀO bonding orbitals and lone pairs of the oxygen
atoms. The NBO analysis of these latter DHBÀ interactions is ex-
plicitly depicted in Figure 8, as it is directly related to the solva-
tion interactions provided by the RTIL anions, and is therefore
of particular relevance to the present work. An extended set of
NBO results, which also include a broad range of interactions
between the calixarene and the cation, is presented as Sup-
porting Information (Figure S3).
calculation for the equilibrium geometry of the CI–Cs+ com-
plex indicates that the DHBÀ anion approaching from the hy-
drophilic face of the calixarene (hexaacetic acid hexaethyl ester
side groups), provides a greater contribution to the stabiliza-
tion energy than the anion entering from the hydrophobic
face (tert-butyl groups), namely 25 kJmolÀ1 versus 19 kJmolÀ1,
respectively. The hydrophobic face is, however, more open and
allows more facile access into the interior of the cavity for the
DHBÀ. In fact, the MD simulations showed that in all the com-
plexes solvated by a single DHBÀ, the anion enters from the
hydrophobic side to coordinate with the alkali metal cation
inside the calixarene cavity. Access through the hydrophilic
face is significantly hindered by the bulky acetic acid ethyl
ester side chains, and this aspect appears to be key for binding
selectivity. Consistently, when the NBO calculations were per-
formed for the equilibrium geometry of the CI–Na+ complex,
the stabilization energy, due to the DHBÀ anion approaching
from the hydrophilic face decreases to 10 kJmolÀ1 (hence,
a factor 2.5 smaller than for the CI–Cs+ conformation). The
large size of the Cs+ cation stretches the calixarene cavity, in
particular the hydrophilic face, thereby increasing the separa-
tion between the side chains and opening a channel for the in-
sertion of the second DHBÀ solvent anion. In this way, the sta-
bilization of the complex is greatly increased. Although this
effect may also be important in small-molecule solvents (such
as water or methanol), it can be expected to be significantly
more relevant in solvents with a greater molecular volume, as
is the case for most RTILs.
The NBO study showed that the two solvating DHBÀ, which
coordinate with the alkali metal cation, each has a different
impact on the stabilization of the complex; this result is of par-
ticular importance for the understanding of the cation-binding
selectivity of the calixarene. As indicated in Figure 8, the NBO
3. Conclusions
The ionophoric behavior of cyclodextrin and calixarene macro-
cycles in RTIL solution was characterized through the determi-
nation of their relative alkali metal cation binding affinities by
using direct laser desorption mass spectrometry experiments.
Complementary experiments in aqueous and solvent-free envi-
ronments served to assess the role of the solvent in determin-
ing the binding selectivity of the macrocycles. In fact, evidence
was provided for the potential of RTILs to enhance molecular
recognition processes mediated by inclusion complexes.
In the bulk of the RTILs, the native cyclodextrins displayed
a binding preference for Na+ and K+, with a positive correla-
tion between the size of the macrocycle cavity and the ionic
diameter of the cation that was most strongly bound. In
marked contrast, the fully permethylated hCD cyclodextrin and
the CI calixarene macrocycles presented a strong selectivity for
Cs+. Hence, both of these latter macrocycles act as efficient
cesium ionophores in the ionic medium provided by the RTIL.
In this context, two complementary features are of particular
relevance. On the one hand, the greater abundance of hCD–
Cs+ complexes relative to CI–Cs+ complexes in the competi-
tive experiments indicates that the hCD cyclodextrin binds Cs+
more strongly than the CI calixarene. On the other hand, the
CI calixarene displays a stronger selectivity for Cs+ relative to
the smaller alkali metal cations.
Figure 8. Most relevant NBOs involved in the intermolecular charge transfer
responsible for the solvation of the calixarene–cation complexes by the
DHBÀ anion, as illustrated for the lowest energy conformation of the CI–Cs+
complex. Delocalization of the carboxylate orbitals of the anion towards the
n* orbital of the alkali metal cation occurs, leading to the indicated stabiliza-
tion energies. The position of the alkali metal cation is represented by
a sphere. Note that the DHBÀ anion approaching from the hydrophilic face
of the calixarene (top panel) contributes more significantly to the stabiliza-
tion of the complex than the one entering from the hydrophilic face
(bottom panel). See text for details and the Supporting Information for a rep-
resentation in full color.
The theoretical modeling of these systems allowed the ra-
tionalization of the stronger binding of Cs+ by hCD compared
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mixture was sonicated until a homogeneous viscous fluid was ob-
tained after the evaporation of methanol at room temperature (at
least 24 h).
with CI, in terms of a more facile coordination of the cation
with the oxygen atoms of the CH2OCH3 side groups and of the
carboxylate moiety of the solvating DHBÀ anions. In the case
of the CI calixarene, the significant size of the side chains im-
posed steric effects that hindered the access of the solvating
DHBÀ anions to the alkali metal cation. The selectivity of the CI
calixarene for Cs+ then arises from the fact that the CI–Cs+
complex displays a comparably stretched conformation that
provides sufficient exposure of the cation for coordination
with two RTIL anions. In contrast, the smaller alkali metal cat-
ions leads to more folded conformations of the calixarene sub-
strate upon binding, thereby enhancing steric effects and ren-
dering a progressively less efficient solvation. A similar trend
affects the hCD complexes, although to a lesser extent, due to
the more open structure and the shorter side chains of the cy-
clodextrin, hence leading to a less marked selectivity for Cs+.
Overall, the Cs+ binding selectivity achieved by the hCD and
CI macrocycles in the RTIL was significantly enhanced with re-
spect to that observed in the aqueous solution. The measure-
ments under solvent-less conditions demonstrated that the
binding energy of the isolated inclusion complexes decreases
rapidly with growing cation size and is therefore greatest for
Li+. Hence, the Cs+ selectivity of hCD and CI must be attribut-
ed to solvent effects mediated by the conformational con-
straints imposed by the architecture of the macrocycles and
their side groups.
The measurements for the macrocycle–cation complexes involved
the preparation of two types of RTIL solutions: 1) solutions of one
macrocycle and the chlorides of the five alkali metal cations (molar
ratio macrocycle/salt 1:100) and 2) solutions with equimolar
amounts of the two macrocycles and with 1:100 molar excess of
a single alkali metal chloride. The first type of sample was em-
ployed to determine the relative alkali metal cation affinities of
each macrocycle on the basis of competitive binding. The second
type of sample was similarly employed to evaluate the relative
binding affinities of a pair of macrocycles for a given individual
cation.
The macrocycles were added to the RTIL in small aliquots as solu-
tions in organic solvents (methanol for the cyclodextrins and
chloroform for the calixarene). A separate stock solution of the
alkali metal salts in the RTIL was prepared in a similar way. In each
case, the organic solvent was subsequently allowed to evaporate.
The RTIL solutions of the macrocycle and the alkali metal cations
were finally mixed in the appropriate proportions. This procedure
was meant to ensure that the interactions of the macrocycles and
the cations occur solely in the RTIL. Hence, no solvent effects other
than those induced by the RTIL are expected to have any influence
on the present experiments.
The laser desorption experiments were performed in an UltrafleXt-
reme MALDI-TOF (Bruker-Daltonics). RTIL solutions were irradiated
with about 2000 pulses of a Nd:YAG laser (355 nm, 3 mJpulseÀ1
,
We hope that the present results guide future developments
and applications in the field. The qualitative features described
here for model cyclodextrins and calixarene are likely to consti-
tute a benchmark for the general behavior of inclusion com-
plexes in RTILs, or in polar solvents made of bulky molecular
components. Furthermore, the laser desorption mass spec-
trometry methodology outlined in this paper merges earlier
developments to provide a means of a direct interrogation of
supramolecular processes in the bulk of ionic liquids.
500 Hz pulse repetition rate). The ionic species desorbed from the
sample were analyzed with a time-of-flight mass spectrometer in
reflectron mode. The intensity ratios of the peaks detected in each
mass spectrum were taken as a measure for the relative stability of
the corresponding complexes in the bulk of the RTIL. Mass spectra
in negative mode were also performed to investigate the negative-
ly charged clusters formed by partial solvation of the macrocycle
and its alkali metal complexes by one or several DHBÀ anions.
Additional solvent-free laser desorption experiments were carried
out in the same MALDI-TOF equipment to probe the cation bind-
ing affinities of the macrocycles under isolated conditions. In this
method, finely ground powders of the macrocycle, pairs of alkali
metal salts, and dithranol (as the matrix to assist laser desorption)
were mixed and applied directly to the sample plate. Under these
conditions, competitive complexation takes then place in a gas-
phase solvent-less environment, after the initiation of the laser de-
sorption process, and the relative abundances of the different
complexes are monitored in the mass spectrum.[31,32,37] For these
type of measurements, it is crucial that the cation precursors in the
sample are equally efficient and yield molar fractions of the cations
in the gas phase that resemble those of the sample. This was ach-
ieved by combining pairs of alkali metal salts of similar lattice
energy in each sample, such as LiI/NaBr, NaI/KCl, KBr/RbCl, KI/CsBr,
and RbBr/CsCl (see Ref. [31,32] for details).
Methodology
Experimental Methods
The macrocycles included in this study are depicted in Figure 1: a-
cyclodextrin (aCD, 98% purity), b-cyclodextrin (bCD, 97% purity),
heptakis-(2,3,6-tri-O-methyl)-b-cyclodextrin (hCD, 90% purity), and
the calixarene 4-tert-butylcalix[6]arene hexaacetic acid hexaethyl
ester (or Cesium Ionophore II; CI; 97% purity). As alkali metal pre-
cursors, chloride salts (99% purity) were employed. All of these
chemicals were purchased from Sigma–Aldrich and used as re-
ceived. The experiments were performed with freshly prepared sol-
utions. Ultrapure water of mili-Q quality and methanol, chloroform,
and dimethylsulfoxide of HPLC quality were employed as solvents.
Finally, to explore the binding behavior in an aqueous environ-
ment, ESI was performed in an ion-trap spectrometer (HCT, Bruker-
Daltonics), on 1:1 water/methanol solutions with concentrations of
1 mm for one individual macrocycle and 10 mm for each of the
alkali metal cations. In the case of the calixarene, 10% volume of
dimethyl sulfoxide was added to the water/methanol solvent to
enhance its solubility. The relative abundances of the complexes
formed in solution are neatly monitored in the recorded mass
spectrum, without any relevant contribution from complexation
The present investigation focused on ionic liquids with 2,5-dihy-
droxybenzoate (DHBÀ) as the chromophoric anion, i.e., the conju-
gate base of the common 2,5-DHB acid commonly employed in
matrix-assisted laser desorption ionization (MALDI).[25] Four differ-
ent RTILs were synthesized in our laboratory, with countercations
provided by protonated amine bases of different sizes and func-
tionalities, namely propylamine, butylamine, isobutylamine, and
aniline. The synthesis of the RTILs involved mixing equimolar
amounts of 2,5-DHB and the amine in methanol. In each case, the
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Articles
occurring in the gas phase during the electrospray process, as
shown below.
was analyzed. On the other hand, to probe the qualitative charac-
teristics of the selective Cs+ complexes observed in this study, ap-
proximate NBO calculations was performed with the most stable
geometry of the (CI–Cs+)(DHBÀ)2 complex, but replacing the Cs+
cation with Na+ (while keeping the molecular geometry of the
cluster frozen).
Calculations
MD as well as quantum mechanical calculations based on DFT,
were performed to determine the most stable structures of the
macrocycle cation complexes in the RTIL. Particular efforts were de-
voted to gain insights into the cesium ionophoric behavior of the
hCD cyclodextrin and the CI calixarene, and into the role played by
the RTIL solvent.
Acknowledgements
The research activity of our group is currently supported by the
Government of Spain, through projects CTQ2012-32345 and Con-
solider-Ingenio CSD2009-00038, and by Junta de Andaluca-FEDER
through project P12-FQM-4938.
The MD simulations employed the ab initio optimized COMPASS
force field, which is known to accurately describe the conforma-
tions and most relevant interactions of a wide range of organic
molecules.[38] The systems under study encompassed a single mac-
rocycle–cation complex, solvated in an ensemble of 64 DHBÀ/
Keywords: calixarenes
·
cyclodextrins
·
ionic liquids
·
+
nBuNH3 counterion pairs (plus an extra DHBÀ anion to balance
macrocycles · supramolecular chemistry
the total charge to neutrality). The simulations were run in the iso-
thermal–isobaric NPT ensemble with a timestep of 0.5 fs over an
initial equilibration period of 100 ps, followed by a production run
of 200 ps. The temperature and pressure were kept at 300 K and
1 atm., respectively, by means of the Nose thermostat and Berend-
sen barostat. The size of the cubic MD simulation cell oscillates
around 28.1 Š. This cell size is large enough to ensure that the in-
teractions between adjacent images are not significant for the con-
formational problem of interest to this work (the minimum dis-
tance between atoms of the macrocycles in adjacent images in the
simulations was around 10 Š).
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Manuscript received: June 16, 2015
Accepted Article published: September 8, 2015
Final Article published: September 30, 2015
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