Intramolecularly Hydrogen-Bonded Aromatic Pentamers as Modularly Tunable Macrocyclic Receptors for Selective Recognition of Metal Ions

Article abstract of DOI:10.1021/jacs.5b07123

Despite the tremendous progress that has been made in macrocyclic chemistry since the discovery of corands, cryptands, and spherands more than four decades ago, macrocyclic systems possessing a high level of controllability in structural configuration con

Full text of DOI:10.1021/jacs.5b07123

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Article
Intramolecularly H-Bonded Aromatic Pentamers as Modularly Tunable
Macrocyclic Receptors for Selective Recognition of Metal Ions
Ying Liu, Jie Shen, Chang Sun, Changliang Ren, and Huaqiang Zeng
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07123 • Publication Date (Web): 03 Sep 2015
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Intramolecularly H-Bonded Aromatic Pentamers as Modularly
Tunable Macrocyclic Receptors for Selective Recognition of
Metal Ions
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Ying Liu,†,丄 Jie Shen,‡,丄 Chang Sun,§,丄 Changliang Ren,‡ and Huaqiang Zeng*,‡
† Prinbury Biopharm. Co., Ltd, 538 Cailun Road, Zhangjiang Hi-Tech Park, Pudong District, Shanghai, 201203, China
‡ Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669
§ College of Textiles and Clothing, Jiangnan University, 1800 Lihu Avenue, Wuxi, Jiangsu, 214122, China
ABSTRACT: Despite the tremendous progress that has been made in macrocyclic chemistry since the discovery of corands, cryptands
and spherands more than four decades ago, macrocyclic systems possessing a high level of controllability in structural configuration
concurrent with a systematic tunablity in function are still very rare. Employing an inner design strategy to orient H-bonding forces
toward a macrocyclic cavity interior while convergently aligning exchangeable ion-binding building blocks that dictate a near-identical
backbone curvature, we demonstrate here a novel pentagonal framework that not only enables its variable interior cavity to be maintained
at near-planarity but also allows its ion-binding potential to be highly tunable. The H-bonded macrocyclic pentamers thus produced have
allowed a systematic and combinatorial evolution of ion-selective pentamers for preferential recognition of Cs+, K+ or Ag+ ions.
macrocyclic folding backbone is characterized by its unique H-
bond-enforced conformational bias that determines and
parameterizes the backbone curvature and macrocyclic cavity.
Thus, the cavity-enclosing propensity of these folding
macrocycles is mostly independent of the macrocyclic ring
constraint. This foldamer-based approach has consistently
allowed the efficient creation of sizable interior cavities ranging
from 1.4 Å to 15 Å in radius in the H-bonded macrocycles2e,2f
with a number of them expressing tailor-made functions such as
stabilization of G-quadruplex structures,4a ion transport,4b
recognition of ionic4c-g or neutral4h-j guests, solvent gelation,4j
reaction catalysis4k and selective demethylation.4l
INTRODUCTION
With the increasingly engendered attention from researchers
worldwide over the past five decades since the seminal reports on
macrocyclic cation-binding corands by Pedersen,1a,1b cryptands
by Lehn1c,1d and spherands by Cram,1e,1f the notion that
macrocyclic chemistry has thus far prospered to become one of
the most dynamic and promising frontiers of chemical research,
cutting across many traditional scientific boundaries among
chemistry, physics, biology, medicine and engineering, seems
inescapable. Simultaneous with the innovatively stirring
progresses on the cavity-containing functional macrocycles of
varying designs and sizes are their highly interdisciplinary
applications that involve all sorts of host-guest interactions as a
focal entry point into a wide variety of fields including catalysis,
environmental remediation, molecular machines, enzyme
mimetics, medical diagnostics, tumor and antiviral therapeutics
One salient characteristic of macrocyclic hosts is a degree of
substantial rigidity that physically confers a particular shape onto
the host-guest structure, directly contributing to the enhanced
stability over that of the similar acyclic host. Traditionally, this
so-called “macrocyclic effect” is mostly derived from the
macrocyclic covalent constraints. An elegant strategy that is
recently advanced by Hamilton,2a Gong,2b,2c and others2d-f
explores the conformational pre-organization of the folding
molecules, i.e., foldamers,3 using non-covalent intramolecular H-
bonding forces, followed by ring-closing reactions to furnish H-
bonded macrocyclic aromatic foldamers. In this tactic, every
monomer of varying designs to be incorporated into the
Over the past few years,2e,2f we have been applying an inner
design strategy to systematically develop H-bonded macrocyclic
aromatic pentamers, which possess unique aesthetically pleasing
fivefold symmetry, in terms of structure,4e,5 rapid synthesis6 and
function.4d-f,4j-l As illustrated by our recently reported
intramolecular H-bonded macrocycles 1-3 respectively built from
monomeric methoxybenzene (A),5a pyridone (B)4e and
fluorobenzene (C)5b motifs (Figure 1a), our molecular approach
features the utilization of a continuous intramolecular H-bonding
network that points toward the interior of the macrocycle instead
of its exterior. This inner design strategy not only provides the
much-needed, entropically favorable preorganization force to
guide the folding of an otherwise randomly orienting backbone
into a defined, rigid conformation, but also affords (1) an
arrangement of five properly spaced convergently aligned
electron-rich donor atoms around an enclosed cavity of 1.4 Å in
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pentamers. To the best of our knowledge, a modularly tunable
a)
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system with such a high degree of controllability in interior
property confined within the same type of well-maintained near-
planar molecular framework (e.g., the pentameric backbone in
this work) has no literature precedents among the hitherto
reported ion-binding macrocycles including corands,1a,1b
cryptands,1c,1d spherands,1e,1f torands,7a or other shape-persistent
aromatic macrocycles including porphyrin derivatives or
analogues,7b,7c arylene ethynylene macrocycles,7d macrocyclic
Schiff bases,7e cyanostar macrocycles,7f and intramolecular H-
bonded macrocycles.2d-f
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RESULTS AND DISCUSSION
b)
c)
d)
Computational and crystallographic determination of
intrinsic backbone curvature associated with building blocks
A-E. An enlightened observation from our recent crystallographic
studies on pentamers 15a and 3,5b and current work on the crystal
structure of 2a8 reveals a fascinating and intrinsic propensity
exhibited by building blocks A-C; all require five repeating units
to form a nearly planar five-residue macrocyclic backbone
(Figure 1). This unique feature can be substantiated
computationally by the first-principle computations at the
B3LYP/6-31G(d,p) level (Figure 1c-d). Nevertheless, in order to
eliminate any possible effect the macrocyclic ring constraint
might have on the backbone curvature truly intrinsic to the
oligomers derived from monomeric building blocks A-C and
other closely related building blocks D and E (Figure 2a), we
focus on the amidated trimers (A)3-(E)3 with a general structure
exemplified by (B)3 that comprises three Bs (Figure 2b) to more
accurately determine the intrinsic curvatures solely inducible by
these units. On the basis of angle  defined by the electron-rich
atoms highlighted in red as the external angle of a polygon to be
formed (Figure 2b), the number of units (n) required to form an
idealized polygon free of ring strains can be calculated by using
the equation n = 360º/.
2a
1
2 (R = Me)
3
Figure 1. Structural features of pentamers 1-3. (a) Structures of pentamers
1-3 derived from monomeric building blocks A-C, respectively, each
containing an interior cavity of ~ 2.8 Ǻ in diameter defined by oxygen or
fluorine atoms. (b)-(d) illustrate the top and side views of crystal
structures 1, 2a and its computationally determined structure as well as 3
and its computationally determined structure. In the bottom of (b), the five
interior methyl groups were removed for a unblocked view of a sizable
cavity in 1. The yellow balls in (c) refer to the five exteriorly arrayed tert-
butyl groups that have been removed for clarity of view. The
computationally determined structures for both 2a and 3 illustrate five-fold
symmetry and a planar pentagonic backbone contained in this family of
pentamers.
From the values of  and n summarized in Table 1 that were
determined from the computationally optimized trimers (A)3-(E)3
at the B3LYP/6-31G(d,p) level (Figure S1), the methoxybenzene
building block A is the only one that is perfectly compatible with
a regular pentagon, and so should produce pentamer 1 that is free
of ring strain. Computationally, however, the steric crowding
involving the five interior methyl groups destabilizes 1 by 2-3
radius after excluding the volumes of the donor atoms such as O-
atoms, which is suitable for binding such as K+ ions (radius =
1.38 Å), and (2) a covalent nanoscaffolding for the expedient
exchange of a multitude of modular functional groups that
decorate the macrocyclic interior surface. In this regard, our
principal motivation has been to design and assemble readily
adjustable convergent binding elements around a cavity for the
selective recognition of diverse cations. In line with this vision
and by using five exchangeable build blocks A-E (Figures 1 and
2), we now report a novel class of discrete shape-persistent
macrocyclic hybrid pentamers, which contain a high degree of
precisely tunable interior properties, including effective cavity
size, steric crowding, cavity hydrophobicity and cation-binding
capacity for the speedy evolution of ion-selective hybrid

Figure 2. (a) Schematic illustration of additional building blocks D and E
for constructing macrocyclic hybrid pentamers such as 4 (b). Amidated
trimer as represented by (B)3 in (c) was used for calculating  values and
the number of residues (n) required for A-E to form a regular pentagon. In
(c), angle  is defined by the atoms in red as the external angle of a
pentagon to be formed, which will be computationally determined by the
first principle calculation at the B3LYP/6-31G(d,p) level and compared to
the crystallographically derived values.
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Table 1. Computationally determined values for  and the corresponding number of residues (n) required for various building blocks A-E to form a regular
pentagon by using computationally optimized amidated trimmers (A)3-(E)3 as represented by (B)3 in Figure 2b and the experimental values obtained from
the crystal structures 5a-5e in Figure 3.
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By Computationa
By X-ray Crystallography
b
b
b
b
c
d
(A)3
(B)3
(C)3
(D)3
(E)3
(A)3
(B)3
(C)3
A(C)2
(A)2Cb,
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 (º)
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5.33
71.0
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72.1
4.99
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5.03
68.0
5.30
73.1
4.93
70.0
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68.9
5.22
n (=360/)
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a
Structural optimizations were carried out at the B3LYP/6-31G(d,p) level in the gas phase, and except for (D)3, all the other trimeric structures were found to take a planar or
nearly planar backbone (Figure S1) .b The  values were obtained by planarizing the slighted twisted backbones in (D)3, 5a,10a 5b, 5c, and 5e, respectively. c The averaged value
over the two  values found in tetramer 5d. d One of the unit A in 5e contains a benzyl rather than methyl group.
a)
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( = 71.6 °, n = 5.03)
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( = 68.0 °, n = 5.30) ( = 73.1 °, n = 4.93)
( = 70.0 °, n = 5.14) ( = 68.9 °, n = 5.22) ( = 70.9 °, n = 5.07)
5d 5e 5f
5b
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Figure 3. Crystallographic verification of computationally determined values of  and n listed in Table 1 for H-bonded oligomers 5a-5f that were derived
from monomeric building blocks A-C. For clarity of view, exterior side chains, some aromatic building blocks and H-atoms were removed. In (a) and (b),
the large yellow balls refer to the exterior side chains. In (c), the large yellow ball refers to the bipyridine fragment. In (e), the large yellow balls refer to the
fragment at the ester end and the benzyl group. And the smaller yellow balls in (f) refer to the interior benzyl and tert-butyl side chains whose H-atoms
were removed for clarity of view.
kcal/mol at the B3LYP/6-311+G(d,p) level,4k thus making 1
slightly distorted (Figure 1b). On the other hand, the larger ethyl
groups in D seem to significantly distort the pentameric backbone
(D)5 comprising five Ds (Figure S2a), while the plasticity of the
amide bond2f enables slightly imperfect units B, C and E to nicely
fit into a pentameric framework, producing perfectly planar
backbones in 2 and 3 (Figure 1c-d), and nearly planar one in (E)5
(Figure S2b).9
The obtained computational results were then subject to
scrutiny by X-ray crystallography using crystal structures
determined for acyclic oligomers 5a-5f built from units A-E
(Figure 3). As compiled in Table 1, both  and n values for
acyclic oligomers 5a-5d are remarkably comparable with the
computed values, highlighting high reliability and accuracy of the
first principle calculation at the B3LYP/6-31G(d,p) level that has
consistently allowed us to predict the structures of a series of
analogous H-bond-rigidified foldamer molecules that were
verified experimentally later by their crystal structures,10a
Significantly, the intramolecular H-bonding forces seem to be
strong enough to withstand a co-existance of two benzyl groups
as in 5e (Figure 3e), or two benzyl and one iso-butyl groups as in
trimer 5f with a  value of 70.9º and n value of 5.07 (Figure 3f).
Combinatorial aspect of macrocyclic hybrid pentamers. On
the above computational and experimental grounds and further
considering a modular nature of the pentameric backbones, we
proposed here an efficient means of generating a rich family of
cation-binding hybrid pentamers with a 2D-shaped pentagonic
backbone as represented by 4 (Figure 2c). The underlying
molecular strategy involves a combinatorial use of compatible
and exchangeable units A-E that occupy five circular positions in
a pentameric framework. The corresponding library size N can be
calculated based on the following equation, whereas m is the
number of different units used in the library construction.
The library size N apparently increases rapidly with an increase
in the number of exchangeable units. For instance, 8 and 629
hybrid pentamers can be produced from two and five different
units, respectively, and the use of nine different units would
quickly lead to 11,817 structures that possibly can be achieved by
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further incorporating functional groups including pyridine N-
oxides, sulfanes,11a thiol groups or halogen atoms11b into the same
pentameric framework (Figure S3).11c Thus,
substantial
a)
b)
1
2
3
a
perspective on cation-binding potential becomes readily
envisionable on the basis of the following premises: (1) the ion-
binding cavity in the hybrid pentamers is tunable between 0 Å as
in 1 whose cavity was completed blocked by the five interior
methyl groups and ~ 1.4 Å as in 2 or 3, while the ionic radius of
the majority metal cations falls within 0.6 - 1.4 Å, (2) the ion-
binding interior is decorated by five properly spaced convergently
aligned donor atoms in a preorganized manner for possibly
enhanced binding affinity and selectivity, (3) the ion-binding
ability of the donor atoms toward metal ions differs significantly
among units A-E with B being the strongest, C the weakest, and
A, D and E as the moderate binders, (4) the methyl and ethyl
groups in A and D are sterically bulky and hydrophobic in nature
and may have subtly different orientations, additionally
facilitating the fine-tuning of cation-binding affinity and
selectivity, (5) under favourable circumstances, the hydroxyl
group in E might become stronger binders upon a possibly
selective deprotonation mediated by certain metal ions, further
augmenting the ion binding potential of the system,10b and (6)
futuristic introduction of additional building blocks (N-oxide,
sulphur and halogen atoms, Figure S3) would create similarly
sized cavities with higher electron densities, likely endowing the
hybrid pentamers with the ability to such as differentiate heavy
metal ions from alkali metal ions.
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6a
6b
Figure 4. Top and side views of crystal structures of 6a (a) and 6b (b),
demonstrating a near-planar pentagonic backbone that encloses a cavity
with a radius of ~1.4 Å decorated by electron-rich atoms for cation
recognition. For clarity of view, exterior benzyl side chains in 6a were
replaced with two dummy yellow atoms, and H-atoms in benzyl groups in
both 6a and 6b were removed. Balls in red and light blue refer to O- and
F-atoms, respectively. The most extractable K+ ions and the second most
extractable Ca2+ ions whose extractability lies within 80% of K+ ions are
highlighted in the cavity.
Crystallographic aspect of macrocyclic hybrid pentamers.
Toward further characterizing our design, a total of 16 pentamers,
i.e., pentamers 6-20 (Figures 4 and 5), were synthesized (Scheme
S1) and crystallizations were attempted to elucidate the structural
features of hybrid pentamers and to evaluate their ability to
selectively recognize metal ions. However, obtaining X-ray
quality crystals for pentagon-shaped molecules has always been
exceptionally challenging. For instance, both X-ray quality
crystals for 2a8 and 35b shown in Figure 1c-d took us 2-3 years
after trying many different crystallization conditions containing
2a or 3 at various concentrations. In particular, crystals for 3 were
eventually obtained by slow cooling of a solution containing 1.1
mg/ml of 3 in hot DMSO from 110 C to 25 C at one degree per
day over three months. Likewise, after countless unsuccessful
attempts involving all the 16 pentamers 6-20 under various
crystallization conditions at various concentrations of pentamers,
single crystals of 6a and 6b were obtained via extremely slow
diffusion of the top methanol layer into the middle layer
containing dichloromethane and methanol (1:1, v/v), which
subsequently diffuses into the bottom pentamer-containing
dichloromethane or chloroform layer at room temperature for a
few months. And all the other pentamers failed to yield X-ray
quality crystals under the conditions tested. Both pleasantly and
excitingly, the determined crystal structures demonstrate a highly
sought-after folding of both 6a and 6b into an almost planar disk
arrangement in solid state with the five electron-rich atoms and
Selective recognition of metal ions by macrocyclic hybrid
pentamers. Our unpublished works reveal no detectable
extractions of any metal ion within the instrument’s sensitivity by
the hybrid pentamers that contain four or five As such as 1. This
implies that the existence of four or more methoxy groups simply
imposes too much steric hindrance or hydrophobicity onto the
cavity, either blocking the cavity or making pentamers unable to
compensate for the loss of hydration energy during the
dehydration process when the hydrated cations enter the cavity.
Similarly, 3 containing five Cs poorly extracts any metal ion from
aqueous solution to organic phase, confirming the electron-rich
fluorine atom with the highest electronegativity as an
extraordinarily poor electron-donor that can hardly compete with
the water molecules in binding aqueous metal ions. In sharp
contrast, pentamer 2b composed of five Bs (Figure 1a) displays a
high-capacity extraction of larger metal ions such as Cs+, Ba2+, K+
and Rb+ over the other fourteen smaller metal ions.4f This high-
capacity extraction mostly arises from a greatly enhanced electron
density around the O-atom from the carbonyl group in B as a
result of an electron-donating effect from the N-atom at the para-
position in pyridone unit B via an aromatic resonance structure in
which the N-atom is positively charged and the carbonyl O-atom
carries a negative charge. This resonance effect makes the
carbonyl O-atom in B possess a higher yet donarable electron
density than the O-atoms found in unit A, 18-crown-6 (21) and
amide protons pointing inward to form
a
continuous
intramolecularly H-bonded network. This H-bonding network not
only rigidifies the amide linkages, but also produces a well-
defined, rigid, circularly folded conformation with a pentagon
shape, convergently bringing electron-rich donor atoms to enclose
a cavity of ~1.4 Å in radius for potentially selective ion
recognition (Figure 4).
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Figure 5. Structures of hybrid pentamers 7-20 employed to probe the potential for selective recognition of metal ions by a family of macrocyclic hybrid
pentamers with modularly tunable interior properties. The ion-extraction profiles determined under the identical conditions for the three well-known
ligands, i.e., 18-crown-6 (21), dibenzo-21-crown-7 (22) and kryptonfix-222 (23), were included for comparison purpose. The ions whose extractability lies
within 80% of the most extractable ones are additionally highlighted below the most extractable ones in the cavity.
kryptonfix-222 (23), which in turn are higher in donarable
electron density than the F-atom found in unit C. Therefore, it is
expected that hybrid pentamers 6-20 built from units A-E would
bind larger metal ions including Cs+, Ba2+, K+ and Rb+ more
weakly than 2, but might have distinctively different selectivity
profiles. To examine how the cation-binding function is related to
variable interior properties, all the 16 hybrid pentamers 6-20 have
been tested against 20 metal ions to obtain their ion recognition
patterns especially in comparison with 2b and other
oxygen/nitrogen-containing macrocycles 21-23 (Figure 5).
In a typical experimental set-up using biphasic water–CHCl3
extraction system of equal volumes, the concentration of each
metal ion in H2O is set constant at 0.03 mM and the total
concentration for 20 metal ions is therefore 0.60 mM. The
concentration of macrocycles in CHCl3 is varied from 0.10 to
1.20 mM. After shaking the biphasic water–CHCl3 solution for 24
hours at 25 oC, ion extractions from aqueous phase to chloroform
layer were monitored by measuring the residual concentrations of
various metal ions in H2O layer. To ensure that the data obtained
are reproducible, the measurements for the same extracted
solution were repeated three times, and the whole experiment
including preparation of a new batch of sample solutions,
extractions and measurements were repeated one more time.
Averaging the data over 6 runs gave the final extraction data with
relative errors of  3%. From the measured ion-extraction profiles
associated with macrocycles 2b and 6-23 (Tables S1 and S2),
important binding information including total ion-extraction
capacity, the most extractable ions and the relative extractability
among the individual ions can be derived, and are presented in
Figure 6.
Consistent with our expectation, an excellent tunability in
interior properties indeed imparts experimentally measurable ion-
binding selectivity onto these macrocyclic hybrid pentamers 6-20.
Among the 17 pentamers, four (2b and 7-9, Figure 6a) are Cs+-
selective, four (10, 15, 17 and 20, Figure 6b) are Ag+-selective,
and three (13, 18 and 19, Figure 6b) are K+-selective. Given that
the extractability of the second most extractable ion lies within
80% of the most extractable one by the same host (Figure 6b and
Table S1), the remaining six pentamers could be considered as
having a dual selectivity, including three K+/Na+-selective hosts
(13, 18 and 19), two K+/Ca2+-selective hosts (6a and 6b) and one
Ag+/K+-selective host (16). For comparison, hosts 21 and 23 both
are K+/Na+-selective, and 22 is Cs+-selective.
In more details, replacing one pyridone unit B in 2b either with
one methoxybenzene unit A as in 7 or one bulkier ethoxybenzene
unit D as in 8 or one fluorobenzene unit C to weaken the binding
affinity as in 9 makes the resultant pentamers more Cs+-selective
than 2b, with increased Cs+ extraction percentage from 37% for
2b to 44% for 7, 50% for 8, and 51% for 9 (Figure 6a). Further
calculation on the basis of the extraction data in Table S2 shows
that this improved selectivity is remarkably accompanied by
steadily decreasing extraction percentages for both K+ and Na+
ions. These lead to the extraction percentage ratios of Cs+:K+ and
Cs+:Na+ increasing in the order of 2b < 7 < 8 < 9 from 4.1 to 5.7,
7.0 and 9.9, and from 7.9 to 8.0, 11.7 and 12.1, respectively. The
fact that extraction of Cs+ is as much as 63% with undetectable
extractions of both K+ and Na+ ions at 0.1 mM of 9 suggests
actual ion selectivities against K+ and Na+ ions to be much higher
than 9.9 and 12.1, respectively, and so a possible use of 9 for
selectively removing radioactive 134Cs and 137Cs from
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Pb2+ (3.3%)
Ca2+ (1.9%)
Cu2+ (0.7%)
Ca2+ (3.1%)
Pb2+ (1.8%)
Ba2+ (1.3%)
Cu2+ (0.4%)
a)
Cs+
Ba2+
Tl+
Rb+
K+
Ag+ Na+
1
2
3
4
5
6
7
8
Cs+
Cs+
Cs+
Tl+
Rb+
K+
Ag+ Na+
Tl+
Rb+
Rb+
Ag+
K+
Tl+
Ag+ Na+
Ca2+ (2.5%)
Cu2+ (0.5%)
Ca2+ (2.0%)
Pb2+ (2.0%)
Ba2+ (1.0%)
Cu2+ (1.0%)
K+ Na+
9
10
11
12
13
14
15
16
17
18
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b)
Tl+ (1%)
Ca2+
Ag+
Na+
K+
Na+
Na+
Ca2+
K+
Na+
K
Na+
K
Ag+
K+
K+
Ag+
Ag+
K+
K+
K+
K+
Cs+
K
Ag
Figure 6. Schematic illustrations of ion-binding selectivities by macrocycles 2b and 6-23. A host is considered to have a dual selectivity if the extractability
of the second most extractable ion lies within 80% of the most extractable one by the same host (Table S1). The most extractable ions and those ions whose
extractability lies within 80% of the most extractable ones are additionally highlighted in the cavity to illustrate the ion-binding selectivity among the
varying hosts.
contaminated seawater from Fukushima Daiichi nuclear
disaster.12 Curiously, the ability of 2b to efficiently extract the
second most extractable Ba2+ ions is sharply aborted via a single
“mutation” of unit B to either A, C or D while ions including Tl,+
Rb+ and Ag+ still remain extractable to good extents by all the
four pentamers 2b and 7-9. On the basis of the computationally
determined structure for the partially hydrated 2bBa2+ complex
(Figure S4a) and the poor electron-donating ability of the F-atom
in 9, the inability of 9 to bind a Ba2+ ion might imply that the
bond strength of Ba2+O found in the pentamerBa2+ complexes
such as 2bBa2+ roughly lies within 80-100% of that of Ba2+O
bond formed between the Ba2+ ion and water molecules.
For the other 13 pentamers 6 and 10-20 having two or more
sterically hindered unit As (Figure 6b), the most extractable ions
are either K+ ions that occur in 8 cases or Ag+ ions in 5 cases,
with the second most extractable ions being K+ ions in 5 cases,
Na+ ions in 5 cases, and Ca2+ ions in 3 cases. Coincidently,
whereas the K+ ions are the second most extractable ions, the Ag+
ions, not Na+, Ca2+ or other ions, are always the most extractable
ones, highlighting a possibly intrinsic ability of such sterically
hindered pentameric framework to preferentially recognize K+
over all the other non-Ag+ ions. More generally but more
narrowly, K+ ions appear to be intrinsically favored over many
extractable ions such as Na+, Ca2+, Pb2+ and Cu2+ ions by all the
17 pentameric hosts 2b and 6-20, while sterically much hindered
6 and 10-20 prefer K+, Ag+, Na+ and Ca2+ over all the other ions.
Except for K+-selective 14, the other three hydroxyl-containing
pentamers 15-17 are all Ag+ selective. An interesting point to note
is that all the Ag+-selective pentamers (10, 15-17 and 20) display
a higher extraction capacity toward Ag+ ions than all the K+-
selective pentamers toward K+ ions (85-98% for Ag+ vs 59-82%
for K+ at the host concentration of 0.6 mM, Table S1). Of high
interest is pentamer 17, which recognizes Ag+ ions in a high-
affinity yet highly selective manner (e.g., a selectivity factor of 7
over K+ ions and excellent extraction efficiencies of 53% and
95% at the host concentrations of 0.1 mM and 0.3 mM,
respectively, Figure 6b and Table S2). This unusually high
affinity recognition and high capacity extraction of Ag+ ions
likely can be accounted for by the complexation-induced
deprotonation of one of the three phenolic hydroxyl groups in 17
by the Ag+ ion.10c
Lastly, it might be worth further comparing with well-known
ligands such as 18-crown-6 (21) and kryptonfix-222 (23). By
using picrate extraction experiments developed by Cram,13
pentamer 2b was found to extract Li+, Na+, K+, Rb+ and Cs+ ions
from aqueous solution into chloroform layer with extraction
efficiencies of 94%, 95%, 88%, 95% and 96%, respectively,
while the corresponding extraction efficiencies are 0%, 11%, 81%,
74% and 51% for 18-crown-6, and 23%, 94%, 93%, 97% and
46% for kryptonfix-222. On the basis of these extraction data, the
binding constants of 2b toward these five alkali metal picrate salts
(Li+, Na+, K+, Rb+ and Cs+) were determined to be on the order of
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109 M-1, which are much higher than those exhibited by 18-
a)
1
crown-6 and comparable to kryptonfix-222 (Table 2). Compared
to 18-crown-6 that is more selective toward K+ and Rb+ ions and
kryptonfix-222 that is highly selective toward Na+, K+ and Rb+
ions, pentamer 2b turns out to be not very selective in ion binding
toward alkali metal picrate salts. Nevertheless, by switching
picrate to chloride salts and using the host concentration at 0.10
mM and each of the twenty metal ions at 0.03 mM (Table S2), 2b
is not only much more selective but also better in binding
capacity than both 18-crown-6 and kryptonfix-222. More
specifically, while 2b becomes Cs+-selective and is able to extract
62% of Cs+, 26% of Ba2+, 21% of Tl+, 17% of Rb+ and 13% of K+,
both 18-crown-6 and kryptonfix-222 are only able to extract three
metal ions (Na+, K+ and Ca2+) and incapable of discriminating K+
from Na+ ions with their corresponding extraction efficiencies
toward Na+, K+ and Ca2+ being 23%, 28% and 12% for 18-crown-
6, and 19%, 23% and 10% for kryptonfix-222. Anomalously,
kryptonfix-222 appears to possess a weaker, rather than stronger
(Table 2), binding strength toward both K+ and Na+ ions in their
chloride salts than 18-crown-6 across all the concentrations
studied (Table S2).
2
3
4
5
6
7
8
9
3
3
2
2
1
1
(14)2 K+
10
11
12
13
14
15
16
17
18
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1: 3.15 Å 2: 2.67 Å 3: 3.02 Å
b)
3
1
2
2
1
3
c)
Table 2. Binding constants Ka for 2b, 18-crown-6 (21) and kryptonfix-222
(23) complexing alkali picrate salts from Li+ to Cs+ in H2O/CHCl3 at 10
mM at 25 oC obtained by Cram’s method.13
Ka [M-1]a
Picrate
Salt
kryptonfix-222
3.3 x 106
2b
18-crown-6
Li+
Na+
K+
0
8.9 x 109
9.1 x 109
7.2 x 108
1.2 x 109
4.4 x 109
8.2 x 105
2.4 x 108
5.0 x 107
7.1 x 106
4.7 x 109
2.0 x 109
2.2 x 109
4.8 x 106
Rb+
Cs+
Figure 7. Crystal structure and 2D molecular packing of a K+-containing
complex (14)2K+. (a) A pair of enantiomeric complexes exist in the solid
state. (b) Top and side views of the complex made up of two identical
enantiomeric pentamers. (c) Molecular packing involving the two
enantiomeric complexes highlighted in yellow and blue, respectively. In
(b), the yellow atoms refer to the benzyl groups.
a Averaged values over three runs with the assumption of 1:1 guest:host
binding stoichiometry. All the binding constants have a relative error of ≤
10%.
Structural insights into the pentamermetal ion complexes.
After many unsuccessful attempts, the X-ray quality crystals of
(14)2K+ were the only ones obtained by us, which were grown
out using a four-layer technique involving extremely slow
diffusion of top KNO3-containing methanol layer successively
into the second layer containing methanol, the third layer
containing 1:1 mixed methanol and dichloromethane, and finally
the bottom 14-containing dichloromethane layer over months at
room temperature. In the crystal structure, two enantiomeric
pentameric hosts can be found (Figure 7a), and the same two
enantiomers sandwich a potassium ion to form a 2:1 complex
(14)2K+ (Figure 7b). In such complexes, K+ ions are six-
coordinated, sandwiched and stabilized by two binding pockets,
each formed by one strongly-coordinating pyridone O-atom (K+--
-O distance = 2.67 Å) and two additional moderately strong
coordination bonds (K+---O-CH3 distance = 3.15 Å and K+---O=C
distance = 3.02 Å). Due to the hydrophobic pushes from the two
adjacent methyl groups with the shortest K+---H-CH2O distance
of 3.35 Å, K+ ions of 1.38 Å in radius would have to occupy an
off-center position within the cavity similarly measuring 1.4 Å in
radius. The inter-planar distance between the two pentamer
molecules of 14 in the complex is around 3.3 Å, suggesting a nice
fit of potassium ion into the binding pocket that enables efficient
aromatic - stacking to take place. This further suggests that
larger cations such as Cs+ and Rb+ ions may be forced into the
vicinity of the hydrophobic methyl groups in 14, and in the
meantime may enlarge the inter-planar distance that disfavors
aromatic - stacking interactions. Consequently, sterically
hindered pentamers containing two or more alkoxy groups of A or
D are expected not to bind larger Cs+ (1.67 Å) and Rb+ (1.52 Å)
ions, which is consistent with experimental data obtained on 6
and 10-20 (Figure 6c and Table S1). Instead, smaller ions such as
K+ (1.38 Å), Ag+ (1.15 Å), Na+ (1.02 Å) and Ca2+ (1.15 Å) are
preferred by these hosts. Structure-wise, we propose that all the
11 structurally similar pentameric hosts 10-20 form a 2:1
sandwiched structure with K+ ions. In the case of Ag+ (1.15 Å),
Na+ (1.02 Å) and Ca2+ (1.15 Å), 1:1 complexes should be formed
since (1) these smaller cations actually prefer to stay in an off-
center position as inferred from the computationally determined
structures using pentamer 2b (Figure 8b-d) and (2) formation of
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2:1 sandwiched structure would shorten the inter-planar distance
macrocyclic hybrid pentamers of diverse structures. These hybrid
of ~3.3 Å observed in the crystal structure of (14)2K+, thereby
disfavoring aromatic - stacking interactions. Due to the
presence of three hydrophobic groups occupying both sides of the
pentameric plane (Figure 4), both hosts 6a and 6b highly likely
form only 1:1 complexes with all the recognizable metal ions.
The facts that smaller metal ions such as Ba2+, K+, Ag+, Na+
and Ca2+ and larger Rb+ ions all are computationally found to
occupy the cavity center of 2b, and stay coplanar with the
pentameric backbone in 2b, and that the Tl+ ion deviates
vertically from the pentameric plane by only 0.8 Å strongly
suggest the formation of 1:1 complexes between these metal ions
and hosts 2b and 7-9 (Figurer 8). In light of its computationally
determined vertical deviation of about 2.0 Å from the slightly
twisted pentameric plane in 2b (Figure 8e) and depending on its
concentration, Cs+ ion expectedly is able to form both 1:1 and 2:1
sandwiched complexes with hosts 2b and 7-9. Structural
optimization of a 2:1 sandwiched complex (2b)2Cs+ reveals an
inter-planar distance of 3.8 Å (Figure S4b), which is close to the
typical aromatic - distance of 3.4 Å.
pentamers are uniquely characterized by having a H-bond-
rigidified shape-persistent near-planar pentameric skeleton that
effectively and convergently preorganizes differential electronic
traits (e.g., O- and F-atoms) and influential steric/hydrophobic
(e.g., methyl and ethyl groups) factors into an ultra-small yet
adjustable cavity of up to 1.4 Å in radius, thereby permitting a
systematic and combinatorial evolution of circular pentamers with
an ability to selectively recognize Cs+, K+ or Ag+ ions in the
presence of 19 other metal ions. The wealth and diversity of
circularly folded hybrid pentamers sensible from their large
sequence space upon additional incorporations of pyridine N-
oxides, sulfanes,11a thiol groups or halogen atoms11b into the same
pentameric framework11c open up a whole new dimension of
scientific research, encompassing enormous complexation/
inclusion capacities from which the best complementary binding
motif responding to a specific metal ion of interest may be
identified. Further exquisite modifications and ensuring
applications of these cavity-containing ion-binding circular
synthons should offer wider perspectives and achievements that
have not been made possible before.
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a)
b)
c)
d)
ASSOCIATED CONTENT
Supporting Information. Synthetic procedures for 5-20 as
1
well as a full set of characterization data including H NMR, 13C
NMR, (HR)MS, X-ray crystal file/data sheet for 2b, 5, 6 and 14,
ICP data for 2 and 6-23 and computational details. This material
is available free of charge via the Internet at http://pubs.acs.org.
2b●Ca2+
2b●Ag+
2b●K+
2b●Na+
(1.00 Å)
(1.15 Å)
(1.38 Å)
(1.02 Å)
e)
f)
g)
h)
AUTHOR INFORMATION
Corresponding Author
hqzeng@ibn.a-star.edu.sg
Author Contributions
丄Y.L., J.S. and C.S. contributed equally to the work.
2b●Cs+
2b●Rb+
2b●Ba2+
2b●Tl+
(1.67 Å)
(1.52 Å)
(1.35 Å)
(1.50 Å)
Notes
The authors declare no competing financial interest.
Figure 8. The computationally optimized structures of partially hydrated
2b●[M(H2O)n]m+ (n = 2 or 3 and m = 1 or 2) complexes containing two or
three axially coordinated water molecules at the level of B3LYP/6-
31G(d,p) in chloroform. All the CPK models were built based on the van
der Waals radius (Gray: H = 1.20 Å; Green: C = 1.70 Å; Blue: N = 1.55 Å;
Red: O =1.52 Å). The yellow atoms in all the structures refer to metal
cations whose radii were specified in the respective parenthesis. In all the
structures except for 2b●[Cs(H2O)3]+ (e) for which three water molecules
on the same side were included in the computation, the metal ions are
assumed to be six-coordinated, and all the coordinated water molecules
have been removed for clarity of view. From the calculated structures
where most of the metal ions stay coplanar with the planar pentameric
backbone, it can be seen that the cavity in 2b is too small for both Cs+ and
Tl+ ions that are above the slightly twisted pentameric planes by about 2.0
and 0.8 Å, respectively, just right for K+, Rb+ and Ba2+ ions, and slightly
too big for Ag+, Na+ and Ca2+ ions.
ACKNOWLEDGMENT
This work was supported by the Institute of Bioengineering
and Nanotechnology (Biomedical Research Council, Agency for
Science, Technology and Research, Singapore).
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for fine-tuning ion-binding affinity and selectivity. Nevertheless, our
preliminary results show that synthesis of these monomeric building
blocks such as pyridone N-oxide and their subsequent incorporation
into the pentameric framework turned out to be synthetically very
challenging, and we are currenlty working to improve and optimize
the synthetic methdologies. For instance, even thought monomeric
unit F can now be synthesized satisfactorily in our laboratory, for
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dimer or higher oligomers as such amide coupling steps tend to give
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diffusion of cyclohexane into dichloromethane over a few weeks at
room temperature.
(9) The crescent shape is used here to deduce the likely backbone
curvature inducible by multiple units E that are to be incorporated
into
a circularly folded pentamer and are rigidified by the
macrocyclic ring constraint to take up a crescent shape. But do note
that these acyclic oligomers consisting of multiple units E won’t
adopt a crescent shape similar to that of (B)3. Instead, the acyclic
oligomers (E)n will take a linear geometry via alternative H-bonds
formed between amide carbonyl O-atom and H-atom of the phenolic
hydroxyl group. See Ref 10b.
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