An extremely stable host-guest complex that functions as a fluorescence probe for calcium ions

Article abstract of DOI:10.1002/chem.200600090

Herein, we report a crown ether based molecular cage that forms extremely stable supramolecular complexes with dimethyldiazapyrenium (DMDAP) ions in CD₃CN through the collaboration of multiple weak C-H...O hydrogen bonds. The very strong bindin

Full text of DOI:10.1002/chem.200600090

DOI: 10.1002/chem.200600090
An Extremely Stable Host–Guest Complex That Functions as a Fluorescence
Probe for Calcium Ions
Chi-Feng Lin,[a] Yi-Hung Liu,[a] Chien-Chen Lai,[b] Shie-Ming Peng,[a] and
Sheng-Hsien Chiu*[a]
In memory of Tong-Ing Ho
Abstract: Herein, we report a crown
ether based molecular cage that forms
extremely stable supramolecular com-
plexes with dimethyldiazapyrenium
(DMDAP) ions in CD3CN through the
À
DMDAP substantially in equimolar
solutions at concentrations as low as
cage and DMDAP is highly selective
toward Ca2+ ions—relative to other bi-
ologically important Li+, Na+, K+, and
Mg2+ ions—and causes a substantial in-
crease in the fluorescence intensity of
the solution. As a result, this molecular
cage/DMDAP complex behaves as a
supramolecular fluorescence probe for
the detection of Ca2+ ions in solution.
1”10À5 m. Remarkably,
a
1”10À5
m
equimolar solution of the molecular
collaboration of multiple weak
C
Keywords: calcium · fluorescence ·
H···O hydrogen bonds. The very strong
binding affinity in this host–guest
system allows the molecular cage to
bleach the fluorescence signal of
host–guest systems
cages · sensors · supramolecular
chemistry
·
molecular
AHCTREUNG
AHCTREUNG
Introduction
trin-based supramolecular host–guest systems[7] have been
applied in many elegant supramolecular sensing complexes,
1:1 host–guest mixtures have yet to be applied as fluores-
cence probes in submillimolar concentrations for the detec-
tion of trace amounts of Ca2+ ions. Part of the difficulty in
developing supramolecular host–guest complexes that oper-
ate as optical sensors at low concentrations is that a very
strong binding affinity must exist between the host and
guest species to avoid a strong background signal from the
fluorescent, free species.[8] Herein, we report a crown ether
based molecular cage[9] that forms extremely stable supra-
Artificial optical sensors that respond selectively to biologi-
cally important metal ions (e.g., Li+, Na+, K+, Mg2+, and
Ca2+) have attracted much attention for their potential use
in chemical and biological applications.[1] Because of the im-
portance of ionic calcium in physiological processes,[2] che-
mosensors that display specificity toward Ca2+ ions are in
particular demand.[3] Currently, most fluorescence detectors
are prepared by covalently linking molecular receptors to
fluorophores; signal processing is achieved through variation
of the moleculeꢀs electronic nature[4] or of the chromo-
phoreꢀs properties[3f,5] after association with the metal ion.
Although indicator-displaceable ensembles[6] and cyclodex-
molecular
complexes
with
dimethyldiazapyrenium
(DMDAP) ions in CD3CN through the collaboration of mul-
À
tiple weak C H···O hydrogen bonds. The very strong bind-
ing affinity in this host–guest system allows the molecular
cage to substantially bleach the fluorescence signal of
DMDAP in equimolar solutions at concentrations as low as
1”10À5 m. Remarkably, a 1”10À5 m equimolar solution of the
molecular cage and DMDAP is highly selective toward Ca2+
ions: the solution displays a substantial increase in its fluo-
rescence intensity in the presence of Ca2+, but much less so
in the presence of Li+, Na+, K+, or Mg2+ ions. As a result,
this molecular cage/DMDAP complex behaves as a supra-
molecular fluorescence probe for the detection of Ca2+ ions
in solution.
[a] C.-F. Lin, Y.-H. Liu, Prof. S.-M. Peng, Prof. S.-H. Chiu
Department of Chemistry, National Taiwan University
No. 1, Sec. 4, Roosevelt Road, Taipei, Taiwan (ROC)
Fax : (+886)2-3366-1677
E-mail: shchiu@ntu.edu.tw
[b] Prof. C.-C. Lai
Department of Medical Genetics and Medical Research
China Medical University Hospital, Taichung, Taiwan (ROC)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
Results and Discussion
Inspired by
a jawlike ditopic
[18]crown-6 (18C6) host that is
capable of forming stable face-to-
face complexes with diammoni-
um ions through multiple N+
À
H···O hydrogen bonds[10] and by
the crown ether bis(para-phenyl-
ene)[34]crown-10
(BPP34C10),
which forms a pseudorotaxane-
like complex with DMDAP
through aryl–aryl interactions
[11]
À
and C H···O hydrogen bonds,
we expected that the cage-like
host 1 would form a very stable
complex with DMDAP in solu-
tion, that is, one that would be
Scheme 1. Synthesis of molecular cage 1.
À
stabilized through multiple weak C H···O hydrogen bonds
between the methyl and a-pyridinium protons of the
DMDAP ion and the oxygen atoms of the triethylene glycol
chains of molecular cage 1 (Figure 1).[12] In addition, we ex-
pected that the capture of DMDAP within molecular cage 1
would quench the fluorescence emission of the DMDAP ion
through intermolecular, radiationless, energy-transfer[13] or
charge-transfer[14] processes, and we hoped that the addition
of a metal ion to this solution would cause the dissociation
of the complex [1ꢀDMDAP]2+ to release free DMDAP
ions into solution with a concomitant increase in the fluores-
cence emission intensity of the mixture.
chol 2 with triethyleneglycol monotosylate (3) under basic
conditions gave the tetraol 4, which we then reacted with
tosyl chloride to give the tetrakistosylate 5. The [1+1] mac-
rocyclization reaction of 5 and the biscatechol 2 gave the de-
sired molecular cage 1 in 8% yield.
1
The H NMR spectrum of an equimolar mixture of molec-
ular cage 1 and DMDAP[PF6]2 in CD3CN (4 mm) at room
G
temperature displays significant changes in the chemical
shifts of the protons of the complex relative to those of its
free components (Figure 2). To confirm that the disappear-
We synthesized molecular cage 1 from 2,3,6,7-tetrahy-
droxy-9,10-dimethyl-9,10-dihydro-9,10-ethanoanthracene
(2)[15] in three steps (Scheme 1). The reaction of the biscate-
1
Figure 2. Partial H NMR spectra (400 MHz, CD3CN, 298 K) of a) molec-
ular cage 1, b) an equimolar mixture of 1 and DMDAP
ACHTREUNG
DMDAP
A
a
mixture of
1
ACHTREUNG
(10 mm).
ance of the signals of the free species in the spectrum is due
to complete complexation of both components, rather than
being the result of fast rates of exchange in the complexa-
tion/decomplexation processes under these conditions, we
1
used H NMR spectroscopy to monitor a nonstoichiometric
mixture of molecular cage 1 (4 mm) and DMDAP[PF6]2
G
(10 mm) in CD3CN; we observed two sets of signals, which
integrated in a 2:3 ratio, with the stronger absorption set
corresponding to the signals of the free DMDAP ions (Fig-
ure 2d). This observation suggests that the binding stoichi-
Figure 1. Design of molecular cage 1 for the complexation of DMDAP.
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4595

S.-H. Chiuet al.
ometry of the molecular cage 1 to DMDAP is 1:1 and that
the exchange rates for their complexation and decomplexa-
tion are slow under these conditions.[16] We did not observe
1
any signals of the free species in the H NMR spectra upon
diluting an equimolar mixtures of molecular cage 1 and
DMDAP[PF6]2 from 1 mm to 10 mm (Figure 3), suggesting
G
that the binding between molecular cage 1 and DMDAP is
extremely tight.[17]
Figure 4. ORTEP plot of the solid state structure of [1ꢀDMDAP]2+. The
À
dashed lines indicate intracomplex C H···O hydrogen bonds (see Sup-
porting Information for the bond lengths and bond angles).
Figure 3. Partial 1H NMR spectra (400 MHz, CD3CN, 298 K) of equimo-
lar mixtures of 1 and DMDAP
c) 0.01 mm.
A
1
The H NMR spectra of the complex display a downfield
shift for the signal of the protons of the methyl group of
DMDAP and spreading of the protons of the ethylene
glycol signals of molecular cage 1; these features suggest the
À
possible existence of C H···O hydrogen bonds in the com-
plex.[18] The upfield shifts of the signals of the aromatic pro-
tons of both 1 (from d=6.81 to 6.14 ppm) and DMDAP
(from d=9.79 and 8.79 ppm to d=9.26 and 8.19 ppm, re-
spectively) suggest possible shielding between the aromatic
rings of the two components in the complex. These results
support our proposed molecular geometry for complex
Figure 5. The corresponding fluorescence spectra (MeCN, 1”10À5 m,
298 K; excitation at 247 nm) of equimolar mixtures of 1, DMDAP, and a)
Li+, b) Na+, c) K+, d) Mg2+, and e) Ca2+
.
[(1ꢀDMDAP)]
C
were much weaker than that observed for Ca2+ ions, sug-
gesting that the interactions of the first four ions with mo-
lecular cage 1 are much weaker than those of the last one
(Figure 5). The value of the fluorescence enhancement ratio
[(FÀF0)/F0] after we had added one equivalent of Ca2+ ions
to an equimolar mixture of molecular cage 1 and DMDAP-
solution of molecular cage 1 and DMDAP[PF6]2 in CH3CN.
N
The solid-state structure confirms the binding geometry in
complex [1ꢀDMDAP]2+ (Figure 4),[19] in which fourteen C
À
H···O hydrogen bonds formed between the methyl and a-
pyridinium protons of DMDAP and the oxygen atoms on
the ethylene glycol chains of molecular cage 1. Although C
[PF6]2 (1”10À5 m) was at least ten times higher than those
À
H···O hydrogen-bonding interactions are quite weak, the
multiple copies of this weak interaction lead to a very stable
complex [1ꢀDMDAP]2+ in solution.
determined after the addition of the same amount of Li+,
Na+, K+, and Mg2+ ions in the same solution (Figure 6);
this result suggests that this molecular cage/DMDAP com-
plex displays good selectivity toward Ca2+ ions among this
set of biologically important metal ions.[20]
Figure 5 provides a comparison of the emission spectra
observed upon addition of molecular cage 1 to a solution of
DMDAP
[PF6]2 ([1]=[DMDAP
[PF6]2]=1”10À5 m); it is clear
The 1H NMR spectrum of a 2:1 molar ratio mixture of
molecular cage 1 and KPF6 displayed a discernable shift in
the signals of the ethylene glycol protons, but the shift
seems to be quite different to the one in the spectrum of a
mixture of 1 and Ca2+ (see Supporting Information); there-
fore, we suspected that the modes of complexation of mo-
that one equivalent of molecular cage 1 quenches the fluo-
rescence of DMDAP substantially under these conditions.
We monitored the fluorescence intensities of the supramo-
lecular system in the presence of various metal ions. For
Li+, Na+, K+, and Mg2+ ions, the fluorescence changes
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Chem. Eur. J. 2006, 12, 4594 – 4599

Host–Guest Systems
FULL PAPER
Figure 6. Fluorescence enhancement ratio profiles of a solution of 1 and
DMDAP (1”10À5 m in MeCN) in the presence of equimolar selected
metal ions. Excitation was performed at 247 nm; emission was monitored
at 423 nm.
lecular cage 1 to these two types of ions may be different.
We grew single crystals suitable for X-ray crystallography
through liquid diffusion of isopropyl ether into 1:2 molar
ratio solutions of molecular cage 1 and Ca(ClO4)2 or KPF6
G
in CH3CN. The solid-state structures reveal that the com-
plexation of molecular cage 1 with Ca2+ ions utilized only
one of the triethylene glycol chains of each crown ether
moiety[21] (Figure 7), whereas the complex formed with the
two K+ ions involved the cooperation of all of the triethyl-
ene glycol loops[22] (i.e., each K+ ion was bound to all eight
oxygen atoms of each crown ether unit; Figure 7). Because
the complexation geometries of the molecular cage 1 to
these metal ions involve either one or two triethylene glycol
chains, it is not evident why 1 has a much stronger binding
affinity toward Ca2+ ions than toward Li+, Na+, K+, or
Mg2+ ions; presumably it results from a combination of ef-
fects including the size of the pseudocrown etherꢀs cavity
and the charge densities, sizes, and coordination numbers of
the cations.[3f,23]
Figure 7. ORTEP plots of the solid state structures of [1ꢀCa2]4+·8H2O
(top) and [1ꢀK2]2+·2MeCN (bottom).
ed, were obtained from commercial sources. Anhydrous CH2Cl2 and
MeCN were obtained by distillation from CaH2 under N2. Reactions
were conducted under N2 or Ar atmospheres. Thin-layer chromatography
(TLC) was performed on Merck 0.25 mm silica gel (Merck Art. 5715).
Column chromatography was undertaken over Kieselgel 60 (Merck, 70–
230 mesh). Melting points are determined by Fargo MP-2D melting point
apparatus. Fluorescence spectra were recorded on Hitachi F-4500. In
NMR spectra, the deuterated solvent was used as the lock, while either
the solventꢀs residual protons or TMS was employed as the internal
standard. Chemical shifts are reported in parts per million (ppm). Multi-
plicities are given as s (singlet), d (doublet), t (triplet), q (quartet), m
(mutiplet), and br (broad).
Conclusion
À
We have demonstrated that the presence of multiple C
H···O hydrogen-bonding interactions can lead to the forma-
tion of an extremely stable supramolecular complex be-
tween molecular cage 1 and DMDAP[PF6]2. The strong
G
binding affinity between these two species allows this com-
plex to act as a fluorescence probe under dilute conditions
(1”10À5 m), in which Ca2+ ions respond highly selectively
with respect to Li+, Na+, K+, and Mg2+ ions. This result
suggests that supramolecular host–guest complexes can be
used as efficient optical probes for detecting analytes at low
concentrations, as long as the binding affinity between the
host and guest is sufficiently strong, yet labile.
X-ray crystallographic analysis: CCDC-294241, CCDC-294242, and
CCDC-294243 contain the supplementary crystallographic data for
[1ꢀDMDAP]
[PF6]2·H2O,
[1ꢀK2]
U
and
[(1ꢀCa2]-
AHCTREUNG
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Tetraol 4: A mixture of K2CO3 (13 g, 94.2 mmol), 2 (2.6 g, 8.6 mmol), and
3 (11.7 g, 38.5 mmol) in CH3CN (150 mL) was heated under reflux for
48 h. The crude product obtained after evaporation of the organic solvent
was partitioned between CH2Cl2 (500 mL) and H2O (500 mL); the organ-
ic layer was collected, dried (MgSO4), and concentrated to afford a
Experimental Section
General: All glassware, stirrer bars, syringes, and needles were either
oven- or flame-dried prior to use. All reagents, unless otherwise indicat-
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4597

S.-H. Chiuet al.
yellow liquid (4.2 g). This crude material was used directly in the next re-
action without purification.
[6] Most of these supramolecular sensing ensembles comprise acyclic
receptors and indicators; see: S. L. Wiskur, H. Ait-Haddou, J. J. Lav-
igne, E. V. Anslyn, Acc. Chem. Res. 2001, 34, 963–972.
Tetrakistosylate 5: A solution of TsCl (4.9 g, 25.7 mmol) in CH2Cl2
[7] a) A. Ueno, Supramol. Sci. 1996, 3, 31–36; b) T. Hayashita, A. Ya-
mauchi, A.-J. Tong, J. C. Lee, B. D. Smith, N. Teramae, J. Inclusion
Phenom. Macrocyclic Chem. 2004, 50, 87–94.
(25 mL) was added over 10 min to
a solution of tetraol 4 (4.2 g,
5.0 mmol) and triethylamine (3.6 mL, 25.7 mmol) in CH2Cl2 (50 mL) at
08C. The mixture was slowly warmed to room temperature, stirred for a
further 12 h, and then partitioned between CH2Cl2 (300 mL) and H2O
(300 mL). The organic layer was separated, dried (MgSO4), concentrated,
and purified (SiO2; EtOAc/hexane, 7:3) to afford the tetrakistosylate 5 as
a pale-yellow liquid (2.5 g, 35%). 1H NMR (400 MHz, CDCl3): d=1.52
(s, 4H), 1.83 (s, 6H), 2.40 (s, 12H), 3.55–3.80 (m, 32H), 4.00–4.15 (m,
16H), 6.85 (s, 4H), 7.29 (d, J=8 Hz, 8H), 7.76 ppm (d, J=8 Hz, 8H);
13C NMR (100 MHz, CDCl3): d=19.0, 21.9, 36.4, 41.4, 68.7, 69.3, 69.6,
70.0, 70.6, 70.7, 109.1, 127.5, 129.4, 132.4, 139.7, 144.2, 145.9 ppm; HR-MS
(FAB): m/z calcd for C70H91O24S4: 1443.4783 [M+H]+; found: 1443.4794.
[8] Because of insufficiently strong binding between the host and the in-
dicator—that is, to avoid any possible background signal from the
free indicator—supramolecular optical probes were generally pre-
pared as solutions containing millimolar concentrations of the host
and micromolar concentrations of the indicator. See: a) A. P. Bisson,
V. M. Lynch, M.-K. C. Monahan, E. V. Anslyn, Angew. Chem. 1997,
109, 2435–2437; Angew. Chem. Int. Ed. Engl. 1997, 36, 2340–2342;
b) K. Niikura, A. P. Bisson, E. V. Anslyn, J. Chem. Soc. Perkin
Trans. 2 1999, 1111–1114; c) Ref. 7b.
[9] Noncovalent molecular cages have been prepared; see: a) M. Kim,
G. W. Gokel, J. Chem. Soc. Chem. Commun. 1987, 1686–1688;
b) J. M. C. Kerckhoffs, F. W. B. van Leeuwen, A. L. Spek, K. Kooij-
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5895–5900; Angew. Chem. Int. Ed. 2003, 42, 5717–5722; c) M.
Yoshizawa, S. Miyagi, M. Kawano, K. Ishiguro, M. Fujita, J. Am.
Chem. Soc. 2004, 126, 9172–9173; cryptand-type host molecules
may be considered as the simplest covalently linked molecular
cages; see: d) K. A. Nielsen, J. O. Jeppesen, E. Levillain, N. Thorup,
J. Becher, Org. Lett. 2002, 4, 4189–4192; e) D. F. Perkins, L. F.
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ands may also be considered as covalently linked molecular cages;
see: g) A. Collet, J.-P. Dutasta, B. Lozach, J. Canceil, Top. Curr.
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105.
Molecular cage 1: K2CO3 (5.3 g, 38.4 mmol) was added to a solution of
biscatechol
2 (276 mg, 0.93 mmol) and tetrakistosylate 5 (1.3 g,
0.93 mmol) in CH3CN (100 mL) at room temperature. The mixture was
heated under reflux for 12 days and then the organic solvent was evapo-
rated under reduced pressure. The crude product was partitioned be-
tween CH2Cl2 (250 mL) and H2O (250 mL) and then the organic layer
was collected, dried (MgSO4), and concentrated to give a yellow solid,
which was purified (SiO2; MeOH/CH2Cl2, 5:95) to afford the molecular
cage 1 as a white solid (78 mg, 8%). M.p. >2888C (decomp); 1H NMR
(400 MHz, CDCl3): d=1.50 (s, 8H), 1.77 (s, 12H), 3.60–3.90 (m, 32H),
3.95–4.10 (m, 16H), 6.72 ppm (s, 8H); 13C NMR (100 MHz, CDCl3): d=
19.0, 36.3, 41.3, 69.8, 69.9, 71.0, 108.3, 139.5, 145.7 ppm; HR-MS (FAB):
m/z calcd for C60H77O16: 1053.5212 [M+H]+; found: 1053.5216.
[10] a) T. L. Tarnowski, D. J. Cram, J. Chem. Soc. Chem. Commun. 1976,
661–663; b) R. C. Helgeson, T. L. Tarnowski, D. J. Cram, J. Org.
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Acknowledgements
This study was supported by the National Science Council, Taiwan (NSC-
94-2113M-002-011).
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[17] If we assume that the observation of no free species in the H NMR
1
spectrum of the equimolar mixture of molecular cage
DMDAP[PF6]2 at 10 mm concentration suggests that the free species
presented in the solution are less than 5%, then the binding con-
stant (Ka) between molecular cage 1 and DMDAP[PF6]2 may be es-
timated to be as high as 3.8”107 mÀ1
1 and
AHCTREUNG
AHCTREUNG
.
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[19] Crystal data for [1ꢀDMDAP]
C
¯
1calcd =1.263 gcmÀ3
,
m , T=295 K, orange red
(MoKa)=0.141 cmÀ1
A
plates; 7312 independent measured reflections, F2 refinement, R1 =
0.1338, wR2 =0.2919.
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Host–Guest Systems
FULL PAPER
[20] For practical usage, calcium sensors, which only operate in non-
aqueous solvents may need further modification in order to operate
in water.
[22] Crystal data for [1ꢀK2]
space group P21/n, a=14.2301(4), b=13.6183(4), c=21.8428(7) Š,
b=98.336(2)8, V=4188.2(2) Š3, Z=2, 1calcd =1.257 gcmÀ3
m-
(MoKa)=0.237 cmÀ1, T=295 K, colorless plates; 7367 independent
G
[21] Crystal data for [1ꢀCa2]
C
ACHTREUNG
measured reflections, F2 refinement, R1 =0.0907, wR2 =0.2359. The
solid state structure of a related diester crown ether complexing
with KPF6 also reveals a centered K+ ion bound through ion–dipole
interactions to all eight ether oxygen atoms of the crown ether; see:
H. W. Gibson, H. Wang, K. Bonrad, J. W. Jones, C. Slebodnick, L. N.
Zackharov, A. L. Rheingold, B. Habenicht, P. Lobue, A. E. Ratliff,
Org. Biomol. Chem. 2005, 3, 2114–2121.
ˆ
a=101.5440(5), b=91.7530(5), g=108.3000(5)8 V=2060.23(4) Š3,
Z=1, 1calcd =1.487 gcmÀ3, m(MoKa)=0.489 cmÀ1, T=295 K, colorless
plates; 9416 independent measured reflections, F2 refinement, R1 =
0.0665, wR2 =0.1975. A triethylene glycol ligand adopting a crown
ether like conformation while complexing with a Ca2+ center, with
water and other ligands in a pentagonal bipyramidal geometry, has
been observed previously. See: a) R. D. Rogers, A. H. Bond, Acta
Crystallogr. Sect. C 1992, 48, 1782–1785; b) G. Hundal, M. Marti-
nez-Ripoll, M. S. Hundal, N. S. Poonia, Acta Crystallogr. Sect. C
1996, 52, 789–792.
[23] S. Watanabe, S. Ikishima, T. Matsuo, K. Yoshida, J. Am. Chem. Soc.
2001, 123, 8402–8403.
Received: January 20, 2006
Published online: March 24, 2006
Chem. Eur. J. 2006, 12, 4594 – 4599
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4599