Shape-selective fluorescent sensing ensemble using a tweezer-type metalloreceptor

Article abstract of DOI:10.1021/ol060641k

A fluorescent sensing ensemble for pyridine-derived compounds is described. The receptor portion of the ensemble is prepared from a bisimidazole pyridine which coordinates copper to form a well-defined cavity. Small heteroaromatic guests such as adenine b

Full text of DOI:10.1021/ol060641k

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2163-2166
Shape-Selective Fluorescent Sensing
Ensemble Using a Tweezer-Type
Metalloreceptor
Jeffrey P. Plante and Timothy E. Glass*
Department of Chemistry, UniVersity of MissourisColumbia,
Columbia, Missouri 65211
GlassT@missouri.edu
Received March 15, 2006
ABSTRACT
A fluorescent sensing ensemble for pyridine-derived compounds is described. The receptor portion of the ensemble is prepared from a
bisimidazole pyridine which coordinates copper to form a well-defined cavity. Small heteroaromatic guests such as adenine bind strongly in
the cavity. The fluorescent response is provided by a dye which is coordinated to the receptor and quenched by the metal ion. The dye is
released upon guest binding providing up to 25-fold fluorescence increases.
The molecular recognition of biologically important analytes
continues to be a driving goal of supramolecular chemistry.
Typically, artificial receptors are designed to recognize the
intended guest using hydrogen bonding, ion-ion interactions,
hydrophobic effects, metal-ligand interactions, covalent
bonds, or some combination thereof. For molecular recogni-
tion under physiological conditions, hydrogen bonding is less
important than other interactions, particularly the hydropho-
bic effect and metal-ligand interactions. We have been
interested in the recognition of various classes of biological
analytes including amines, carboxylates, and lipids.1 As part
of an effort to develop selective sensors for nucleotides, we
report herein a metalloreceptor2 for the recognition of
heterocyclic aromatics, including adenine, which incorporates
a shape-selective binding pocket with a molecular tweezer3
design.
displacement techniques which allow these receptors to be
used as visible and fluorescent sensing ensembles.4 Metal-
ligand interactions offer strong association and defined
geometries which are less solvent dependent than other
noncovalent interactions. Our metallotweezer design is based
on a pyridine bisimidazole5 framework as shown in Scheme
1. The metal organizes a binding pocket between the
appended aryl substituents with the metal ion at the base of
this pocket allowing the guest to interact both with the ligand
and the metal. This type of receptor is structurally related to
(2) (a) Tobey, S. L.; Anslyn, E. V. J. Am. Chem. Soc. 2003, 125, 14807-
14815. (b) Haddou, H. A.; Sumaoka, J.; Wiskur, S. L.; Folmer-Andersen,
J. F.; Anslyn, E. V. Angew. Chem., Int. Ed. 2002, 41, 4014-4016. (c)
Goodman, M. S.; Hamilton, A. D.; Weiss, J. J. Am. Chem. Soc. 1995, 117,
8447-8455. (d) Kim, K. H.; Song, R.; Kim, K. M. J. Am. Chem. Soc.
2003, 125, 7170-7171. (e) Kimura, E.; Ikeda, T.; Shionoya, M. Pure Appl.
Chem. 1997, 69, 2187-2195. (f) Kickham, J. E.; Loeb, S. J.; Murphy, S.
L. Chem.-Eur. J. 1997, 3, 1203-1213. (g) Nabeshima, T.; Nishida, D.;
Akine, S.; Saiki, T. Eur. J. Inorg. Chem. 2004, 3779-3782. (h) Cho, N.
S.; Lee, C. H.; Kim, Y.-J.; Choi, J. S.; Kang, S. K. Heterocycles 2004, 63,
2827-2836.
Metalloreceptors have become a valuable tool in supramo-
lecular chemistry particularly with the advent of dye-
(1) (a) Secor, K. E.; Glass, T. E. Org. Lett. 2004, 6, 3727-3730. (b)
Shorthill, B. J.; Avetta, C. T.; Glass, T. E. J. Am. Chem. Soc. 2004, 126,
12732-12733. (c) Raker, J.; Glass, T. E. J. Org. Chem. 2002, 67, 6113-
6116.
(3) Zimmerman, S. C. Top. Curr. Chem. 1993, 165, 71-102.
(4) McCleskey, S. C.; Metzger, A.; Simmons, C. S.; Anslyn, E. V.
Tetrahedron 2002, 58, 621-628.
10.1021/ol060641k CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/22/2006

Scheme 1. Recognition of Adenine by a Designed Metalloreceptor
Lehn’s aryl-substituted terpyridines.6 The terpyridines them-
selves are competent receptors for aromatic guests; however,
metal coordination distorts the alignment of the aryl groups
producing a “pinch angle” which can inhibit guest binding.7
In compound 2, imidazole ligands were incorporated as they
have good metal binding properties and the five-membered
rings produce a coordination site in which the aryl substit-
uents are arranged in a nearly parallel disposition (the vectors
C1-C4 and C1′-C4′ are nearly parallel). Furthermore, the
methyl substituent of the imidazole (5IM) provides steric
buttressing of the anisole substituent, enforcing a near
perpendicular anisole-imidazole arrangement, ideal for guest
recognition. The receptor was designed with the expectation
that, using a metal ion such as copper, the guest would fill
the fourth coordination site of a square planar complex8 and
would have appropriate interactions with both the metal and
the aromatic binding pocket. The remaining coordination sites
on the metal could ultimately be useful for further host-
guest interactions.
generate the final ligand 1. Reaction of ligand 1 with copper
perchlorate produced the 2:1 complex 6 (Scheme 3). Forma-
Scheme 3. Coordination Properties of Ligand 1a
The bisimidazole ligand 1 was synthesized as shown in
Scheme 2. Anisaldehyde was condensed with formamide and
Scheme 2. Synthesis of Ligand 1
a Perchlorate counterions are omitted from the ORTEP plots for
clarity.
tion of the dimeric complex is not surprising given that the
ligand is also a good guest for the first formed metallo-
(5) (a) Vermonden, T.; Branowska, D.; Marcelis, A. T. M.; Sudho¨lter,
E. J. R. Tetrahedron 2003, 59, 5039-5045. (b) Stupka, G.; Gremaud, L.;
Bernardinelli, G.; Williams, A. F. Dalton Trans. 2004, 407-412.
(6) (a) Petitjean, A.; Khoury, R. G.; Kyritsakas, N.; Lehn, J. M. J. Am.
Chem. Soc. 2004, 126, 6637-6647. (b) Hannan, G. S.; Arana, C. R.; Lehn,
J. M.; Baum, G.; Fenske, D. Chem.-Eur. J. 1996, 2, 1292-1302.
(7) Vlasse, M.; Rojo, T.; Beltran-Porter, D. Acta Crystallogr., Sect. C:
Cryst. Struct. Commun. 1983, C39, 560-563.
(8) Evans, D. A.; Murray, J. A.; Matt, P.; Norcross, R. D.; Miller, S. J.
Angew. Chem., Int. Ed. Engl. 1995, 34, 798-800.
(9) Sisko, J.; Mellinger, M.; Sheldrake, P. W.; Baine, N. H. Tetrahedron
Lett. 1996, 37, 8113-8116
(10) Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey, R. W.;
Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y. H.; Marsh, K.; Warner,
R.; Lee, J. Y.; Zielinski-Mozng, N.; Frost, D.; Rosenberg, S. H.; Sham, H.
L. J. Med. Chem. 2002, 45, 1697-1711.
toluene sulfinic acid to afford isocyanate 3 upon dehydration.9
Cycloaddition of 3 with the methyl imine of acetaldehyde
gave imidazole 4.10 The imidazole was brominated and
stannylated followed by coupling with dibromopyridine to
2164
Org. Lett., Vol. 8, No. 10, 2006

receptor. To circumvent this coordination preference, 1 was
treated with copper chloride to produce the 1:1 complex
followed by anion exchange using silver perchlorate to
generate the metalloreceptor 2.
The geometry and stoichiometry of binding were deter-
mined by X-ray analysis. For example, crystallization of 2
with 1 equiv of pyridine gave complex 7 (Figure 1). As
Figure 1. ORTEP plot of complex 7. Perchlorate counterions are
omitted for clarity.
anticipated, the metal adopts a square planar geometry in
which the anisole rings are splayed at an angle of 24.2° (angle
between the C1-C4 and C1′-C4′ vectors). The torsional
angle between each anisole ring and its adjacent imidazole
ring is 52.6°, in which the two anisole groups are nearly
parallel aligned with each other and the guest. Thus, the
metalloreceptor has a pocket which is ideally suited for
recognition of heteroaromatic guests.
Figure 2. Fluorescent titration data (λex ) 384 nm) for (a) addition
of complex 2 to DMASP (10 µM) in acetone and (b) addition of
pyridine to a solution of complex 2 (40 µM) and DMASP (10 µM)
in acetone.
Unfortunately, other alkyl nucleobases were not sufficiently
soluble in acetone for binding constants to be determined.
To probe the selectivity of the receptor, several other
nonbiological guests were assayed. The data demonstrate that
the receptor is very shape selective in that flat aromatic guests
such as adenine bind well and larger guests (lutidine and
piperidine) do not bind to any measurable extent. Among
Guest recognition by complex 2 was then explored
spectroscopically. The absorption spectrum of compound 2
has a λmax ) 386 nm in acetone solvent which increases
slightly upon the addition of guests. To assess binding
constants more easily, a fluorescence dye displacement assay
was developed. Dimethylaminostyrylpyridine (DMASP) is
a common fluorophore whose emission is largely quenched
upon association with the receptor due to spin-orbit coupling
with the copper ion.11 The binding of DMASP by the receptor
(Ka ) 1.1 × 105 M-1) was determined by absorption and
fluorescence titrations (Figure 2a). Addition of guests to a
mixture of DMASP and complex 2 produces a 25-fold
fluorescence increase as the DMASP is released from the
metal (Figure 2b). Thus, the combination of 2 and DMASP
makes an efficient sensing ensemble for aromatic ligands
with an excellent fluorescent response.
Table 1. Binding Constants for Guests with Compound 2 in
Acetone
a
guest
Ka (M-1
)
ethyl-adenine
4-(dimethylamino)pyridine
pyridine
pyridine-2-aldehyde
isonicatinamide
4-cyanopyridine
benzene
8.8 × 104
5.1 × 106
2.6 × 104
2.3 × 104 b
1.7 × 104
1.1 × 103
8.6 × 102
Using the standard methods for displacement assays,12 the
binding of adenine was found to be quite strong (Table 1).
b
lutidine
piperidine
-
b
(11) (a) Hortlata´, M. A.; Fabbrizzi, L.; Marcotte, N.; Storneo, F.; Taglietti,
A. J. Am. Chem. Soc. 2003, 125, 20-21. (b) Bonizzoni, M.; Fabbrizzi, L.;
Piovani, G.; Taglietti, A. Tetrahedron 2004, 60, 11159-11162.
(12) Connors, K. A. Binding Constants; John Wiley and Sons: New
York, 1987; pp 175-177.
-
a Error in Ka is (15% based on triplicate titration. b Determined by UV
titration.
Org. Lett., Vol. 8, No. 10, 2006
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the guest with appropriate shape, the trends in binding affinity
follow the electronics of the guest, with the more electron-
rich guests binding tighter. Interestingly, the electron-poor
pyridine-2-aldehyde binds nearly as well as pyridine itself
due to coordination of the aldehyde oxygen with the metal.13
Indeed, simple aromatics such as benzene bind without any
metal coordination, though with much lower affinity. Thus,
both the metal affinity and shape complimentarity are
important for guest selection.
currently being extended to water-soluble systems with
expanded binding pockets and carefully crafted metal
coordination sites with a view toward the preparation of very
selective sensors for biologically important analytes.
Acknowledgment. This work was supported by the
National Institutes of Health (R01 GM59245) and the
University of Missouri Research Board.
Supporting Information Available: Experimental pro-
cedures including characterization data and spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, a novel molecular tweezer system has been
developed which utilizes metal coordination at the bottom
of a defined shape-selective cavity. This methodology is
(13) As observed in the solid-state structure; see Supporting Information.
OL060641K
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Org. Lett., Vol. 8, No. 10, 2006