Ca2+-induced folding of a chiral ditopic receptor based on a Pybox ligand and enhancement of anion recognition

Article abstract of DOI:10.1039/c0cc05799a

A chiral Pybox ligand bearing two urea units was developed for a Ca ²⁺-induced folding ligand. 11 Ca²⁺ complexation of the Pybox ligand afforded chiral foldamer formation with coordination of the urea carbonyls to Ca²⁺. The halide-ion affinity of the foldamer was enhanced compared to Ca²⁺-free Pybox ligands.

Full text of DOI:10.1039/c0cc05799a

As featured in:
Showcasing research from the laboratory of Professor
Tatsuya Nabeshima, University of Tsukuba, Japan
Ca2+-induced folding of a chiral ditopic receptor based
on a Pybox ligand and enhancement of anion recognition
A chiral Pybox ligand bearing two urea units was developed for a
Ca2+-responsive artificial folding system inspired by Ca2+-controlled
biological processes. The Ca2+ Pybox foldamer showed stronger
·
halide-ion affinity than the corresponding Ca2+-free ligand; thus
the Ca2+-induced folding enhanced the halide-ion recognition.
See Tatsuya Nabeshima et al.,
Chem. Commun., 2011, 47, 6801.
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COMMUNICATION
Ca2+-induced folding of a chiral ditopic receptor based on a Pybox
ligand and enhancement of anion recognitionwz
Masaki Yamamura,ab Junya Miyake,a Yuki Imamuraa and Tatsuya Nabeshima*ab
Received 27th December 2010, Accepted 4th February 2011
DOI: 10.1039/c0cc05799a
A chiral Pybox ligand bearing two urea units was developed for
a Ca2+-induced folding ligand. 1 : 1 Ca2+ complexation of the
Pybox ligand afforded chiral foldamer formation with coordination
of the urea carbonyls to Ca2+. The halide-ion affinity of the
foldamer was enhanced compared to Ca2+-free Pybox ligands.
In biological systems, a calcium ion plays an important role in
Fig. 1 Schematic complexation process of Pybox with Ca2+ and the
controlling biomolecular functions such as reactivity modulation,
crystal structure of 22Ca(ClO4)2. Hydrogen atoms and the counter
energy conversion to movement, binding affinity control, and
anions, ClO4ꢁ, were omitted for clarity.
so on.1 For example, ATP hydrolysis of Ca2+-ATPases starts
after binding Ca2+ ions, and the Ca2+ binding of troponin
regulates muscle fiber contraction. These modulations of
protein function are accompanied by a Ca2+ ion-induced
conformational change. In order to develop ion-responsive
artificial systems in terms of biomolecular implication, artificial
dynamic folding systems, which are analogues for biomolecules
such as DNA and a-helix, have been constructed by utilizing
metal ion complexation.2 Chiral foldamers have attracted
much attention because of their application to chiral molecule
sensors, asymmetric catalysts, and chiral optical materials.
However, there have been only a few reports of foldamer
formation triggered by Ca2+ ions,3 though analogous foldamers
with transition metals have been well studied.4 Transition
metal-induced transoid–cisoid conformational changes in
bipyridine and terpyridine derivatives are suitable for
forming artificial foldamers and related supramolecules.5
2,6-Bis(oxazolinyl)pyridine (Pybox) ligand, an NNN-tridentate
ligand, is expected to be more useful than a terpyridine for a
functional folding module because the Pybox framework can
be easily derivatized to a chiral Pybox with a functional unit.6
The chiral Pybox ligands have been widely utilized for
catalytic asymmetric reactions.6 The recent reports on
Ca2+-catalyzed asymmetric reactions using chiral Pybox
demonstrated an advantage of the PyboxꢀCa2+ complex as a
chiral catalytic species.7 Pybox ligands have also been
employed for supramolecular chiral self-assembling8 and
chirality induction.9 We envisaged that a Ca2+ complex of
Pybox has a potential for Ca2+-triggered folding modules
because metal complexation of Pybox would drive the
equilibrium to the transoid structure useful for helical folding.
First, we clarified the structure of a PyboxꢀCa2+ complex
because none of the PyboxꢀCa2+ complexes have been well
characterized. The crystal structure of 22Ca(ClO4)2 (Fig. 1)
clearly showed the transoid conformer with an NNN
ligation.10 Conversely, the cisoid conformer of the free Pybox
ligand is a global energy-minimized structure at a DFT
calculation level, and hence the complexation process should
afford the conformational change in Pybox from cisoid to
transoid.11 The Ca2+-induced conformational change
encouraged us to design and synthesize Pybox-based ditopic
receptor 1 bearing 4-nitrophenylurea groups, which act as a
ligand to a metal12 as well as an anion-detecting unit by
utilizing optical and chiroptical changes.13
a Graduate School of Pure and Applied Sciences,
University of Tsukuba, Tsukuba, Ibaraki, 305-8571, Japan.
E-mail: nabesima@chem.tsukuba.ac.jp; Fax: +81 29-853-4507;
Tel: +81 29-853-4507
b Tsukuba Research Center for Interdisciplinary Materials Science
(TIMS), University of Tsukuba, Tsukuba, Ibaraki, 305-8571, Japan
w This article is part of a ChemComm ‘Supramolecular Chemistry’
web-based themed issue marking the International Year of Chemistry
2011.
z Electronic supplementary information (ESI) available: Synthesis and
characterization of 1 and X-ray analysis of 22Ca(ClO4)2 and all
spectroscopic titration experiments. CCDC 805519. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc05799a
Fig. 2 UV-vis spectral change in 1 on the addition of Ca2+ in 1 : 4
MeCN/CHCl3, [1] = 10 mM. Inset shows the titration curve plotted at
362 nm.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6801–6803 6801

DFT-optimized structure of the P-isomer, the distance between
Ha and Hc is shorter than 3 A to be detectable in NOE. In the
case of the M-isomer, the NOE correlation between Ha and Hb
should be observed. Because the observed NOE peaks were
assigned to both the diastereomers, the two isomers were found
to exist in equilibrium. Only one set of sharp signals were
1
observed in the H NMR spectra, indicating that the signals of
Fig. 3 (a) CD spectrum and calculated rotatory strengths of 1ꢀCa2+
.
the two diastereomers were averaged on the NMR time scale.
The CD spectra of 1ꢀCa2+ showed a drastic increase in the
Cotton effect upon complexation (Fig. 3). The Cotton effects
were observed as an S-shape in the absorption region for
the 4-nitrophenylurea groups, which means that the circular
dichroism was derived from exciton coupling of the two
chromogenic fragments.16 The transition rotatory strengths were
calculated on the basis of a TD-DFT method, which proved that
the negative Cotton effect is assigned to the P-isomer and that the
predicted CD signal of the M-isomer is positive.11,17 The
TD-DFT results indicate that the major conformation of
1ꢀCa2+ is identified as the P-isomer. The calculated energy
difference in the two isomers also supports that the P-isomer is
more stable by 20.3 kJ molꢁ1 than the M-isomer.
The anion-recognition ability of 1 and 1ꢀCa2+ was evaluated
by spectroscopic titration. Upon addition of chloride anions to a
1 : 4 MeCN/CHCl3 solution of 1ꢀCa2+, a bathochromic shift of
1ꢀCa2+ (328 nm to 342 nm) was observed in the presence of 5 eq.
of Clꢁ with isosbestic points (Fig. 4b). Conversely, the
bathochromic shift of 1 (340 nm to 342 nm) is very small
(Fig. 4a), but both the lmax values of 1 and 1ꢀCa2+ are almost
the same in the saturated region of titration. These spectral
changes account for the competitive coordination of the
urea carbonyl oxygens and a chloride anion to Ca2+. The
coordination of the chloride to Ca2+ in 1ꢀCa2+ would result in
a similar lmax (342 nm) to 1 due to disturbance in the carbonyl
coordination. The 1H NMR spectra revealed that no Ca2+
dissociation from the complex 1ꢀCa2+ took place in CD3CN
upon the addition of Clꢁ because the 1ꢀCa2+ exclusively existed
after the addition of Clꢁ ions in CD3CN. The hydrogen bonding
of N–H in 1ꢀCa2+ to Clꢁ should contribute to this Clꢁ
binding.12,13 The hydrogen bonding of the urea moieties was
evidenced by the lower-field shift of N–H in the 1H NMR spectra
Calculations were carried out at a two-layered ONIOM TD-DFT
theory level. (b) P- and M-isomers of 1ꢀCa2+
.
In the UV-vis spectroscopic titration of 1 with Ca(ClO4)2, a
blue shift of lmax assigned to the transition of nitrophenylurea
moieties (340 nm to 328 nm) was observed with an isosbestic
point. The binding isotherm clearly showed a strong 1 : 1
complexation (log Kc > 7) in 1 : 4 MeCN/CHCl3 (Fig. 2). The
ESI-MS also confirmed the 1 : 1 stoichiometry because a
signal assigned to 1ꢀCa2+ (m/z = 349.6) was observed without
any other species such as 1nꢀCa2+ (n Z 2). These results are
noteworthy because Pybox ligands without side chains can
afford a 1 : 2 complex with various metal ions.14 The ancillary
coordination of the urea carbonyls to Ca2+ may contribute to
the discrete formation of the 1 : 1 complex. A 2D NOESY
spectrum of 1ꢀCa2+ showed significant NOE correlation peaks
between protons of the oxazoline rings (Ha shown in Fig. 3b)
and the side chains (Hb, Hc, Hd). These NOE correlation peaks
indicate the close proximity between the oxazoline rings and
side chains, which may result from the coordination of the
urea carbonyls to the Ca2+ ion (Fig. 3b). In contrast, the
corresponding NOE peaks were not observed in the case of 1
at all. The IR spectroscopy indicated the effective coordination
of the urea carbonyls to the Ca2+ ion.15 The CQO stretching
band of the urea group of 1 in 1 : 4 MeCN/CHCl3 was
significantly shifted from 1704 to 1620 cmꢁ1 by the addition
of Ca2+ ions, showing the CQO bond elongation induced by
ligation of the carbonyl oxygen to the Ca2+ ion. The UV-vis,
ESI-MS, NMR, and IR spectra confirmed the foldamer
formation by the 1 : 1 complexation of 1 with a Ca2+ ion.
Due to the chirality in the oxazoline ring, the foldamer 1ꢀCa2+
has two diastereomers, P and M-helical isomers. In the
Fig. 4 UV-vis and CD spectral changes on the addition of Clꢁ in 1 : 4 MeCN/CHCl3 (a) 1 and (b) 1ꢀCa2+. 0 r [Clꢁ]/[1] r 4, [1] = [1ꢀCa2+] = 10 mM.
(c) Job’s plot for 1ꢀCa2+ vs. Clꢁ and (d) CD titration curves plotted at 365 and 324 nm.
c
6802 Chem. Commun., 2011, 47, 6801–6803
This journal is The Royal Society of Chemistry 2011

Table 1 Association constants (log K11 and log K12) for a halide
anion in MeCN containing 1% H2O
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Clꢁ
Brꢁ
Iꢁ
—
c
c
1
3.26(4)a
—
5.5(1),a 3.73(6)b
1ꢀCa2+
6.0(2),a 4.06(8)b
5.50(8),a 3.1(2)b
a
b
c
log K11 (Mꢁ1). log K12 (Mꢁ1). Not determined due to too small
spectral change.
of the mixture of 1ꢀCa2+ and Clꢁ.18 The CD spectra of 1ꢀCa2+
were also changed by the addition of Clꢁ accompanied by a
bathochromic shift of lmax (Fig. 4b). The change in the Cotton
effect indicates that the conformational change in the foldamer
was induced by the anion. In contrast, the CD spectra of 1
showed little change upon titration with Clꢁ ions (Fig. 4a). These
facts suggest that the folded structure of 1ꢀCa2+ is important for
the CD changes. Thus, the formation of the chiral foldamer
enabled Clꢁ ion detection by UV-vis and CD spectral changes.
The CD spectral titration of 1ꢀCa2+ with a Clꢁ ion and a
Job’s plot (Fig. 4c and d) clearly showed the 1 : 2 association.
Although the binding strength was not accurately estimated
due to the multi-stepwise equilibrium and the very strong
affinity for Clꢁ, the first and the second association constants,
log K11 and log K12 (Mꢁ1) for 1ꢀCa2+, are >7. These values
are over 500 times larger than that of 1 (log K11 = 4.27(2)).
The most reasonable explanation for the affinity enhancement
is that the association with Clꢁ was reinforced by electrostatic
interaction with the Ca2+ ion.12 The contact of the anion with
the cation generally enhanced the association constants as seen
in ion pair recognition.19 To quantitatively estimate the anion
affinity, the titration was performed in MeCN containing 1%
H2O because H2O, a solvent competitive with hydrogen
bonding, should decrease the binding affinity. The log K11
values were determined through nonlinear least-squares curve
fitting of the titration isotherms. The log K11 value of 1 is
3.26(4) for the Clꢁ ion (Table 1). Spectral changes for Brꢁ and
Iꢁ ions were too small to determine the log K11. Conversely,
1ꢀCa2+ exhibited the two-step binding to anions with
association constants, K11 and K12. The K11 value for Clꢁ is
500 times larger than the K11 value of 1. In Brꢁ and Iꢁ, the
association constants are smaller than in Clꢁ. The enhancement
of the anion affinity and the large spectral change triggered by
Ca2+ ions facilitated the halide ion detection.
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S. Kobayashi, J. Am. Chem. Soc., 2010, 132, 7890–7892.
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H. Maeda, N. Tohnai and M. Miyata, Chem. Lett., 2003, 32,
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J. Am. Chem. Soc., 2007, 129, 270–271.
9 T. Moriuchi, X. Shen and T. Hirao, Tetrahedron, 2006, 62,
12237–12246.
10 The crystallographic data: C34H46N6O12Cl2Ca, monoclinic, P21,
a = 17.061(6), b = 11.823(4), c = 21.703(7) A, b = 109.419(4)1,
V = 4129(2) A3, MW = 841.75, Z = 4, Dcalc = 1.354 g cmꢁ3
,
22 542 measured, 15 952 independent, GOF = 1.026, R1[I > 2s(I)]
= 0.0622, wR2(all data) = 0.1550, CCDC 805519.
11 Geometries were optimized using PBE1PBE functional and
6-31G(d,p) basis set.
12 V. Amendola, D. E. Go
E. Monzani and F. Sancenon, Inorg. Chem., 2005, 44, 8690–8698.
13 M. Boiocchi, L. D. Boca, D. E. Gomez, L. Fabbrizzi, M. Licchelli
´
mez, L. Fabbrizzi, M. Licchelli,
´
´
and E. Monzani, J. Am. Chem. Soc., 2004, 126, 16507–16514.
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M. Shizuma, Chem. Lett., 2010, 39, 564–566.
15 E. R. Sanchez, M. C. Gessel, T. L. Groy and M. T. Caudle, J. Am.
Chem. Soc., 2002, 124, 1933–1940.
In summary, we described the Ca2+-induced folding
behavior of the Pybox-based ditopic receptor 1, in which the
coordination of the urea oxygens to Ca2+ was involved. The
1ꢀCa2+ foldamer showed the UV-vis and CD spectral changes
responsive to the halide anions. A chiral information transfer
by guest-response of the chiral foldamer is now under
investigation.
16 M. Klessinger and J. Michl, Excited States and Photochemistry of
Organic Molecules, VCH, New York, 1995, pp. 139–178.
17 TD-DFT calculations were performed using
a two-layered
ONIOM method, where two nitrophenyl units were treated with
high level theory, PBE1PBE/6-311++G (d,p), and the rest were
treated with low level theory, PBE1PBE/6-31G(d,p). An ONIOM
method: S. Dapprich, I. Komaromi, K. S. Byun, K. Morokuma
and M. J. Frisch, J. Mol. Struct., 1999, 462, 1–21.
This study was supported by Grants-in-Aid for Scientific
Research from MEXT of Japan.
18 A counter ion seriously often affects the binding properties of such a
ditopic receptor, but the addition of Bu4N+ClO4 to 1 and 1ꢀCa2+
ꢁ
resulted in no shift in the dH of the N–H proton, meaning that the
hydrogen-bonding interaction of N–H with a counter ClO4 anion
ꢁ
did not disturb the anion binding of the urea units. See ESIz.
19 (a) G. J. Kirkovits, J. A. Shriver, P. A. Gale and J. L. Sessler,
J. Inclusion Phenom. Macrocyclic Chem., 2001, 41, 69–75 and
references cited therein; (b) J. M. Mahoney, K. A. Stucker,
H. Jiang, I. Carmichael, N. R. Brinkmann, A. M. Beatty,
B. C. Noll and B. D. Smith, J. Am. Chem. Soc., 2005, 127,
2922–2928.
Notes and references
1 (a) R. R. Crichton, in Biological Inorganic Chemistry:
An Introduction, Elsevier, Amsterdam, 2008, ch. 11, pp. 183–196;
(b) A. J. Doig, in Protein Folding, Misfolding and Aggregation, ed.
V. Munoz, Royal Society of Chemistry, Cambridge, 2008, ch. 1,
pp. 1–21; (c) A. M. Gordon, E. Homsher and M. Regnier,
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6801–6803 6803