Convergent heteroditopic cyclo[6]aramides as macrocyclic ion-pair receptors for constructing [2]pseudorotaxanes

Article abstract of DOI:10.1039/c4cc02557a

A strategy of using amide groups as the only functionality was developed to construct convergent heteroditopic cyclo[6]aramides that are able to strongly bind dibutylammonium chloride in chloroform (>10⁵ M^-1), leading to the formation of [2]pseudorotaxanes. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02557a

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Convergent heteroditopic cyclo[6]aramides as
macrocyclic ion-pair receptors for constructing
[2]pseudorotaxanes†
Cite this: Chem. Commun., 2014,
50, 8024
Received 7th April 2014,
Accepted 30th April 2014
Jinchuan Hu,a Long Chen,a Jie Shen,b Jian Luo,a Pengchi Deng,a Yi Ren,a
Huaqiang Zeng,b Wen Feng*a and Lihua Yuan*a
DOI: 10.1039/c4cc02557a
www.rsc.org/chemcomm
A strategy of using amide groups as the only functionality was intramolecular H-bonding interactions to direct folding of their
developed to construct convergent heteroditopic cyclo[6]aramides macrocyclic backbones.13 A majority of these H-bonded macro-
that are able to strongly bind dibutylammonium chloride in chloroform cyclic compounds feature full amide linkages that link the
(>105 MÀ1), leading to the formation of [2]pseudorotaxanes.
aromatic repeating units to form H-bonded non-collapsible
backbones.14 In particular, those with interior amide oxygen
Ditopic ion-pair receptors boast enhanced binding affinity, atoms pointing inwards are of great interest in light of their
recognition and selectivity1 compared to monotopic receptors ability to tightly bind ions, efficiently transport ions across a
that are able to bind either cations or anions. These advantageous membrane,15 and accommodate valinomycin in their interior.16
features have encouraged the design of many ditopic host Recently, we have demonstrated highly efficient kinetic macro-
molecules with interesting applications such as salt extraction, cyclizations,13b enabling the production of H-bonded macrocycles
salt solubilisation, and membrane transportation.2 Among the of varying diameters, the smallest being cyclo[6]aramide 1 (Fig. 1),
ditopic receptors reported so far, heteroditopic macrocycles which exhibit efficient extraction abilities towards lanthanide and
derived from calixarenes,3 crown ethers,4 calix[4]pyrroles,5 actinide ions.17 It was found that the introduction of bulkier side
pillar[5]arenes6 and aromatic amides7 represent a mainstream chains in the macrocyclic exterior turns these otherwise strongly
approach due to their convergence and efficacy in regulating aggregational macrocycles18 into nonaggregational ones,19 such
ion pairing within a well-defined cavity. In many cases, amide as 1. As a result, a very large binding constant (2 Â 104 MÀ1) in a
linkages often function as an essential part of binding sites for moderately polar medium, CD3COCD3, was observed between
recognizing anions such as halides,8 dihydrogen phosphate9
and nitrate ions10 via H-bonding. Accordingly, much progress
has been made using amide groups in constructing rotaxanes
and catenanes through anion-templated assembly.11 However,
there is still much to be done in the design of convergent
heteroditopic receptors,1 and synergistic actions involving both
anion-recognizing amide H-atoms and cation-binding amide
carbonyl O-atoms within the same macrocyclic framework for
recognition of organic ion pairs, remain unexplored.
Shape-persistent H-bonded aromatic macrocycles12 are an
emerging class of functional macrocycles that rely on the use of
a Key Laboratory for Radiation Physics and Technology of Ministry of Education,
Institute of Nuclear Science and Technology, College of Chemistry, Analytical &
Testing Center, Sichuan University, Chengdu, 610064, China.
E-mail: lhyuan@scu.edu.cn, wfeng9510@scu.edu.cn; Fax: +86 28 85418755
b Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
Fig. 1 Chemical structures of cyclo[6]aramides 1 (fully H-bonded) and 2
(partially H-bonded) and alkylammonium halides G1–G4. Green and pink
represent locked and rotatable amide bonds, respectively. For 2, three
conformers I–III can be generated by rotating up to two rotatable amides.
Computationally at the level of B3LYP/6-31G(d,p) in CHCl3, I and II are of
similar stability, and are much more stable than III.
138669, Singapore
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, analytical data and crystallographic data. CCDC 976842 (2b) and
976751 (2bÁG1). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4cc02557a
8024 | Chem. Commun., 2014, 50, 8024--8027
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nonaggregational 1 and the loosely associated ion-pair dibutyl-
ammonium hexafluorophosphate.19b With the use of intimate
ion pairs such as dibutylammonium chloride G1, however, the
binding constant decreased significantly to 2 Â 103 MÀ1 even in
CDCl3.† This suggests that the chloride anion must have
impeded the interaction between 1 and the dibutylammonium
cation. Given these results and the need to improve the binding, a
design strategy was implemented in ion-pair receptor 2 that
exploits the synergistic actions of both anion- and cation-binding
groups to enhance the binding affinity and for simultaneous
recognition of ion pairs.
As illustrated by the unique convergent heteroditopic cyclo[6]-
aramides, 2, we report here some rare examples where amide
linkages serve as the only functionality for efficient ion-pair recogni-
tion that further leads to the formation of [2]pseudorotaxanes.
Unlike 1, which has a rigid framework enforced by six three-
center H-bonds (green), two such H-bonds are removed to
produce two rotatable amide bonds (pink) in 2. By rotating
up to two rotatable amide bonds, conformers I, II and III are
possible for 2 (Fig. 1). Our ab initio optimizations of the various
conformers at the level of B3LYP/6-31G(d,p) in CHCl3, followed
Fig. 2 X-ray structure of macrocycle 2b: (a) top and (b) side views. Only
hydrogen atoms involved in H-bonds are shown for clarity. The dashed
pink lines indicate intramolecular H-bonds A–H with A = 2.009 Å, B =
2.207 Å, C = 2.269 Å, D = 2.022 Å, E = 1.974 Å, F = 2.309 Å, G = 2.293 Å and
H = 2.048 Å.
by computing the energies at the B3LYP/6-311+G(2d,p) level, those in 2b, which contains less H-bonds. The diameter of the cavity
reveal I and II to be of similar stability, and much more stable in 2b measures 8.07 Å, which is large enough to accommodate guest
than III.† The rotational energy barriers for rotating one amide molecules or ions. The interplanar distance between two adjacent
in 2c were computationally determined, at the same level, to be macrocycles is 7.07 Å,† suggestive of the absence of intermolecular
4.82 and 4.10 kcal molÀ1 for converting I to II and II to I, p–p stacking interactions. It should be noted that the structure
respectively.† These computational results suggest that I and II determined in the solid state corresponds to the slightly less stable
are the dominant conformers for 2 in solution and that these conformer II, possibly because of a crystal packing effect that
two conformers are readily interconvertible by rotating around overrides the small difference in stability between I and II.†
a relatively unhindered amide bond. We further propose that
The first indication of binding between ion-pair receptor 2a and
only in conformation I is 2 able to bind contact ion-pairs via its guest G1 (cation and anion, respectively) came from high resolution
six convergently aligned and appropriately spaced binding sites electrospray ionization mass spectrometry (HRESI-MS).† In
in close proximity, i.e., two H-bond donors from amide H-atoms the positive ion mode, a highly intense ion fragment, [2a2
+
as the anion-binding site and four H-bond acceptors from amide (n-Bu)2NH2 + K]2+, was found at m/z = 1787.4301 for 2aÁG1.
carbonyl O-atoms as the cation-binding site. In other words, an Meanwhile, a peak at m/z = 1735.0875, corresponding to
ion-pair such as secondary alkylammonium chloride G1 would be [2a + Cl]À, was also observed in the negative ion mode. Similar
able to thread through macrocycle 2 to form [2]pseudorotaxane. results were obtained for the complexation of G1 by 2b.†
This speculation is remarkable in that many ion-pair receptors Consistent with the complexation of ion-pair G1 by 2a,
have been reported for the recognition of primary alkylammonium 1H NMR spectra of 2a show significant downfield shifts for
halides,1 but very few for secondary alkylammonium halides.4,20 the amide and aromatic protons Hj, Hk and Hg upon the
Prompted by the above computational findings, macrocycles of 2 addition of one equivalent of G1 (Fig. 3). Similarly, the signals
with different side chains were synthesized through bimolecular arising from the ammonium ion (–NH2+–) (0.56 ppm) and
[5+1] cyclization reactions.† By tuning the bulkier side chains, 2a methylene protons H1 (0.65 ppm) of G1 also experienced
was found to be largely nonaggregational in chloroform, greatly upfield and downfield shifts, respectively. The residence of
facilitating the accurate determination of the binding constants.†
It has been exceptionally challenging to grow single crystals
of aromatic oligoamide macrocycles such as 1 with introverted
amide carbonyl oxygen atoms since the first report a decade
ago.13a After many attempts, single crystals of 2b, which is
structurally analogous to 1, were obtained by slow evaporation
of a solution of 2b in chloroform and ethanol (1 : 1, v/v).
Surprisingly, macrocycle 2b has a flat backbone (Fig. 2), rather
than a shallow bowl conformation as seen in the computationally
determined structure of 1.18,21 This could be attributed to the
Fig. 3 Partial 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a) 1.0 mM
cyclo[6]aramide 2a, and (b) 1.0 mM 2a and G1. *: Solvent (CHCl3).
larger strains imposed by more intramolecular three-center
H-bonds in 1 that cause larger conformational distortion than
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The binding affinities of nonaggregational 2a and alkyl-
ammonium halides were then determined by 1H NMR titration
experiments (Table 1).† The association constant Ka for 2a and
G1 was calculated to be 1.8 Â 105 MÀ1 in CDCl3 based on H1 in
G1. This value is ca. 90 fold larger than that of 1.† In addition,
the association constants of complexes 2aÁG1 and 2aÁG4 were
found to be 290 Æ 40 MÀ1 in CDCl3–DMSO-d6 (17 : 3, v/v) and
2.3 Æ 0.9 Â 104 MÀ1 in CD3CN–CDCl3 (2 : 3, v/v), which are
much larger than the previously reported values of 10 MÀ1 and
475 MÀ1 for the similar complexes, respectively.4,20 These
comparative data indicate that 2a strongly binds secondary
alkylammonium chloride ion-pairs, offering dramatic enhance-
ment by factors of ca. 29 and 48, respectively. By varying the
anionic constituent, the binding ability of 2a for ClÀ, BrÀ and IÀ
was found to decrease in the order G1 > G2 > G3, suggesting
that G1 fits best into the cavity of 2a. In other words, ditopic
receptor 2a is very selective for the chloride ion. In addition, the
binding constant for 2aÁG4 was determined to be 2.2 Â 105 MÀ1
in CDCl3, which is comparable to the value for 2aÁG1. This
implies that different organic cations have negligible influence
upon the binding of ion-pairs.
Fig. 4 X-ray structure of complex 2bÁG1: (a) top and (b) side views. Only
hydrogen atoms involved in H-bonds are shown and solvent molecules
are omitted for clarity. The chloride anion is shown as a CPK model. The
dashed pink lines indicate intermolecular H-bonds I–N with I = 2.517 Å,
J = 2.142 Å, K = 2.177 Å, L = 2.692 Å, M = 2.564 Å and N = 2.497 Å.
In conclusion, a unique convergent heteroditopic macrocyclic
ion-pair receptor was constructed based on cyclo[6]aramide 2
with only one type of functionality for binding the ion-pair,
leading to an unprecedented high binding affinity (>105 MÀ1 in
CDCl3) towards secondary ammonium chlorides and producing
[2]pseudorotaxanes. Analysis of the solid state structures of both
the receptor alone and its ion-pair complex with G1 reveals a
complexation-induced conformational change. When coupled
with the fact that fully H-bonded rigid receptor 1 exhibits a
much lower binding affinity than partially H-bonded 2a toward
G1, this highlights the importance of introducing flexible amide
bonds to promote favourable conformational changes for enhan-
cing the binding affinity. With ready synthetic availability and
peripheral tunability, modularly tunable heteroditopic ion-pair
receptors based on cyclo[6]aramides offer good promise in
the wide application of constructing mechanically interlocked
architectures. Detailed studies on these aspects are currently
being investigated and will be reported in due course.
This work was supported by the National Natural Science
Foundation of China (21172158), the Doctoral Program of the
Ministry of Education of China (20130181110023), the National
Science Foundation for Fostering Talents in Basic Research of
the National Natural Science Foundation of China (J1210004
and J1103315), the Open Project of State Key Laboratory of
Supramolecular Structure and Materials (SKLSSM201408) and
the Open Project of State Key Laboratory of Structural Chemistry
(20140013) and the Analytical & Testing Center of Sichuan
University for NMR measurements and X-ray analysis.
the ion-pair G1 in the cavity of 2a was probed by a 2D ROESY
experiment involving 2a (10 mM) and G1 (10 mM) in CDCl3,†
which revealed a strong ROE correlation between H1 of G1 and
Hb of 2a.
The formation of ion-pair complex 2bÁG1 was confirmed by
X-ray analysis of a single crystal grown by slow evaporation of a
solution of 2b and G1 in CH2Cl2 (Fig. 4). The crystal structure
clearly showed threading of the dibutylammonium group
through the cavity of the macrocycle to form a [2]pseudorotaxane,
which is stabilized by six H-bonds (I, J, K, L, M and N). The
chloride anion is engaged in four H-bonds, three of which are
associated with the anion-binding cleft formed by three H-bond
donors from the macrocycle with the remaining charge-assisted
H-bond formed with the cationic NH group of G1. Ion-pair
complexation is further stabilized by two charge-assisted H-bonds
between the cationic NH group and the two amide carbonyl oxygen
atoms in 2b. In striking contrast to the crystal structure of 2b where
conformer II is dominant, conformer I is the prevailing isomer for
2a in the presence of G1. This implies a favoured equilibrium
toward I that is driven by complexation-induced conformational
changes in the presence of G1.
Table 1 Association constants (Ka/MÀ1 a
guests (G1, G2, G3 and G4) by host 2a at 298 K
) for the complexation of various
Guest
Solvent
Ka/MÀ1
G1
G1
G2
G3
G4
G4
CDCl3
(1.8 Æ 0.8) Â 105
(2.9 Æ 0.4) Â 102
(1.2 Æ 0.8) Â 104
(5.5 Æ 1.7) Â 103
(2.2 Æ 1.1) Â 105
(2.3 Æ 0.9) Â 104
CDCl3–DMSO-d6 (17 : 3, v/v)
CDCl3
CDCl3
CDCl3
Notes and references
1 For selected reviews, see: (a) G. J. Kirkovits, J. A. Shriver, P. A. Gale
and J. L. Sessler, J. Inclusion Phenom. Macrocyclic Chem., 2001, 41, 69;
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B. Antonioli, Kluwer, London, UK, 2005, p. 137; (c) S. K. Kim and
CD3CN–CDCl3 (2 : 3, v/v)
The association constant Ka values were obtained by 1H NMR
a
titration.
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