Chirality sensing and size discrimination of anions by macrotricyclic cyclen-disodium complexes

Article abstract of DOI:10.1002/open.201402049

Two macrotricyclic ligands composed of two face-to-face octadentate metal chelates were synthesized. These cage-shaped disodium complexes had special recognition ability for various counter anions. Specific chiral dicarboxylates bound to the complexes within the cavity and exhibited chirality induction properties. For instance, N-Boc-Asp dianion strongly induced circular dichroism (CD) signals, but N-Boc-Glu dianion, which is one carbon longer, did not. Chirality on Na⁺: The first example of chirality sensing on Na⁺ was achieved by a macrotricyclic host composed of two octadentate cyclen-Na⁺ complexes. Chiral N-Boc-Asp dianions coordinated to the Na⁺ at the cavity, resulting in the chirality induction of the cage molecule, but N-Boc-Glu dianion, which is one carbon longer, did not.

Full text of DOI:10.1002/open.201402049

DOI: 10.1002/open.201402049
Chirality Sensing and Size Discrimination of Anions by
Macrotricyclic Cyclen–Disodium Complexes**
Hiroshi Ito* and Satoshi Shinoda[a]
Two macrotricyclic ligands composed of two face-to-face octa-
dentate metal chelates were synthesized. These cage-shaped
disodium complexes had special recognition ability for various
counter anions. Specific chiral dicarboxylates bound to the
complexes within the cavity and exhibited chirality induction
properties. For instance, N-Boc-Asp dianion strongly induced
circular dichroism (CD) signals, but N-Boc-Glu dianion, which is
one carbon longer, did not.
Na+ is an abundant and essential cation in biology and
chemistry.[1] Pedersen’s discovery of Na+-selective capturing by
dibenzo-18-crown-6-ether led to the dawn of supramolecular
chemistry,[2] and various molecular switching systems triggered
by Na+ capture have since been reported.[3,4] However, there
are few reports to date in which Na+ serves as the active
center for molecular recognition due to its weak interactions
with guest species and high lability. Development of Na+ com-
plexes that can recognize the stereochemistry of anions would
create novel regio- and stereoselective reactions because Na+
Figure 1. a) D–L interconversion of metal–octadentate cyclen complex.
b) Macrocyclic ligand based on bis(sodium–octadentate complexes) in this
study. c) Chiral mono- and dicarboxylates for external chirality source in this
study.
salts are common ionic substrates in classic organic reactions.
Octadentate cyclens,[5] which are characterized by a cyclen
ring and four metal-ligating side arms, are one example of po-
tential candidate ligands for this purpose. These ligands can
coordinate alkali, alkaline earth, and lanthanide metal cations
to form quadruple-stranded metal helicates. In general, their
metal complexes, such as [1·Ln]3+, exist as a racemic mixture
of two coordination isomers, D and L forms, which are distin-
guished by the helical sense of the propeller structure (Fig-
ure 1a). We previously reported various octadentate cyclen–
Na+, Ca2+ and Ln3+ complexes with chiral carboxylates, such
as N-Boc-l-proline anion (l-3ꢀ), coordinated to Ca2+ and Ln3+
centers to induce circular dichroism (CD) on the absorption
bands of their side arm chromophores.[6] However, such chirali-
ty induction was not achieved with Na+ complexes due to
rapid interconversion of the side chains and decreased stability
of the complexes.[7] Cage compounds like cryptands precisely
recognize guest molecules by their rigid molecular frame-
works.[8] Recently, there have been several reports on macrocy-
clic cyclens.[9] They and their transition metal complexes have
superior molecular recognition abilities compared to non-mac-
rocyclic cyclens.
Here we report the first macrotricyclic ligands based on two
octadentate cyclens and the anion recognition properties of
their Na+ complexes (Figure 1b,c). The macrotricyclic ligands
2a,b contain two amide-type octadentate cyclens joined face-
to-face by two m-xylyl linkers. Density functional theory (DFT)
calculations (BY3LYP/6-31G*) on the [2a·Na2]2+ complex indi-
cated that helical conformations with homochirality, (D,D)- and
(L,L)-forms, have a large enough cavity to encapsulate small
molecules (see figure S4 in the Supporting Information).
Ligands 2a,b were synthesized as shown in Scheme 1. The
macrotricyclic framework 8 was constructed by a 2:2 conden-
sation of dichloride 7[10a] and 1,7-di-N-Boc-cyclen 6[10b] under
dilute conditions. Compounds 2a,b were obtained as free li-
gands by deprotection of 8 with TFA/CH2Cl2 and subsequent
introduction of the respective amide side chains 11 a,b.[10c,d]
Non-macrocyclic ligand 1b was synthesized as a reference
compound.
[a] Dr. H. Ito, Prof. Dr. S. Shinoda
Department of Chemistry, Osaka City University and JST, CREST
Sugimoto, Sumiyoshi-ku, Osaka 558-8585 (Japan)
E-mail: h-ito@sci.osaka-cu.ac.jp
[**] This article is part of the Virtual Special Issue “Molecular Sensors”
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/open.201402049.
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modifications or adaptations are
made.
The crystal structure of [2a·Na2](ClO4)2 (Figure 2, see
table S1)[11,12] showed that a (D,L)-disodium complex was
formed in the solid state. Counter anions (ClO4ꢀ) were located
outside the cavity. This coordination geometry is popular for
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Scheme 1. Synthesis of macrocyclic cyclen ligands 2a–b. Reagents and condi-
tions: a) K2CO3, KI, molecular sieves 4ꢂ, xylene, reflux, 18 h, 14%; b) TFA/
CH2Cl2, RT, overnight, 96%; c) chloroacetyl chloride, Et3N, CH2Cl2, 08C!RT,
overnight, 72% (11a); chloroacetyl chloride, aq NaOH, 08C!RT, overnight,
54% (11b); d) Cs2CO3, acetonitrile, reflux, 6 h, 68% (2a), 80% (2b).
1
Figure 3. Partial H NMR spectra of 2b with various sodium salts [300 MHz,
0.4 mm, CDCl3/CD3OD (9:1, v/v), RT]. a) none; b) NaPF6 (2 equiv); c) l-3·Na
(2 equiv); d) l-4·2Na (1 equiv); e) l-5·2Na (1 equiv).
the complex forms a one-handed helical structure (D,D or
L,L) (see figure S4). By using the 2-H proton as a probe, the
conformational changes on the macrotricyclic ligand frame-
work can be monitored. When two equivalents of N-Boc-l-pro-
line (l-3·Na) were added to 2b, no spectral differences with
[2b·Na2](PF6)2 were found, suggesting that [2b·Na2]2+ formed
similar dinuclear complex structures independent of the coun-
ter anions. On the other hand, distinct differences were found
in the case of divalent chiral counter anions. Although l-4·2Na
and l-5·2Na were hardly soluble in CDCl3/CD3OD (9:1, v/v),
their mixtures with 2b were soluble in this mixed solvent. The
1H NMR spectrum of [2b·Na2](l-4) showed that the 2-H signal
was significantly downfield shifted compared to that of
[2b·Na2](PF6)2. A smaller downfield shift was observed in
[2b·Na2](l-5), with some precipitation of l-5·2Na.
Figure 2. Crystal structure of [2a·Na2](ClO4)2. a) side view; b) the octadentate
cyclen portion around a sodium cation (blue). Counter anions and solvents
were omitted for clarity.
octadentate cyclen–sodium complexes with amide side
chains,[13] suggesting that the macrocyclic framework does not
affect Na+ coordination. It was found that the [2a·Na2]2+ com-
plex has a sufficient cavity size for anion recognition with two
sodium cations at each end, although the isopropyl side chains
filled the cavity, causing a distorted framework in the solid
state.
Structures of the [2b·Na2]2+ complexes in solution were ana-
lyzed by 1H NMR spectroscopy in CDCl3/CD3OD (9:1, v/v)
(Figure 3). The signal for the cyclen ring (2.57 ppm) of
[2b·Na2](PF6)2 is distinctly broadened compared to 2b, which
indicates a slow exchange between (D,D)-, (D,L)-, and (L,L)-
isomers. The overlapped peaks of the aromatic protons of the
3,5-dimethoxybenzene moiety were distinctly upfield shifted
and separated. A more significant change was observed at the
2-H of the m-xylyl linkers, which occurred at 6.88 ppm in the
free ligand and 7.61 ppm in the disodium complex. This un-
usual peak shift is rationalized by the unique position of the
proton. Molecular calculations indicate that the complex has
enough space for the xylyl groups to freely rotate when it
forms the meso-structure (D,L), while the 2-H of the xylyl link-
ers is forced in the direction of the center of the cavity when
The chiral anion bound with the disodium complex induced
circular dichroism (CD) in the absorption region of the dime-
thoxybenzene moiety (Figure 4). The induced CD observed
when l-4·2Na was added to 2b strongly implied that one of
the helical structures was more stable than the other due to
the interaction between the chiral counter dianion (l-4)2ꢀ and
the dicationic complex [2b·Na2]2+. Because the mirror image
spectrum was obtained by the addition of d-4·2Na, the chirali-
ty of guest anion 4 could be finely transferred to the disodium
complex host. As no induced CD was observed with the refer-
ence compound 1b (2 equiv) and l-4·2Na, the macrotricyclic
form was effective for CD responses to the absolute configura-
tion of an included chiral guest. Notably, the adduct of l-5·2Na
with 2b showed no induced CD signals, indicating that this
macrotricyclic host could precisely discriminate a one-carbon
chain length difference in the guest molecular structure.
The binding constant of [2b·Na2]2+ and (l-4)2ꢀ in CDCl3/
CD3OD (9:1, v/v) at room temperature was estimated to be 2ꢁ
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tral analyses showed that the disodium complexes changed
their conformations dynamically in solution. CD, absorption,
and 1H NMR spectral analyses showed the chirality transfer
from the bound anions to the complex framework. Dicarboxy-
lates were strongly bound to the sodium complexes within the
cavity. Moreover, (N-Boc-l-Asp)2ꢀ strongly induced CD, but
(N-Boc-l-Glu)2ꢀ, which is one carbon longer than (N-Boc-l-
Asp)2ꢀ, did not. This superior selectivity was derived from the
restricted distance between the two Na+ cations and the direc-
tions of the binding sites. This is the first example of chirality
sensing by a sodium complex host, and we are now examining
a more precise mechanism of anion recognition by the metal
complexes using this ligand system.
Figure 4. Absorption (bottom) and CD (top) spectra of 2b with various
sodium salts [0.4 mm in CDCl3/CD3OD (9:1, v/v), 0.5 mm quartz cell, RT].
None (b), l-4·2Na (1 equiv, c), d-4·2Na (1 equiv, c), l-5·2Na
(1 equiv, a).
Acknowledgements
This work was supported in part by a Grant-in-Aid for Young Sci-
entists (B) from the Japan Society for the Promotion of Science
(24750133), and a Sasakawa Scientific Research Grant from the
Japan Science Society.
105 mꢀ1 by the integrated peak ratio of the Boc signals in the
1H NMR spectrum at 1.0ꢁ10ꢀ5 m (see figure S5), because com-
plexation equilibrium is slow on the NMR timescale. The com-
plex was stable enough to show the mass peak at m/z 1884
for [(2b·Na2)·(l-4)·H]+ by ESI-MS (see figure S6). In the NOESY
spectrum, interactions between dimethoxybenzene groups of
[2b·Na2]2+ and the Boc group of (l-4)2ꢀ indicated strong bind-
ing of (l-4)2ꢀ to [2b·Na2]2+, probably by the coordination of
the carboxylates to both sodium cations (Figure 5).
Keywords: chirality · cyclen · host–guest systems · macrocyclic
ligands · sodium
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Received: August 28, 2014
Published online on September 17, 2019
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ChemistryOpen 2014, 3, 238 – 241 241