Selective complexation of metals with isoxazolidine-containing fluorophores

Article abstract of DOI:10.1016/j.tetlet.2004.10.171

A series of 1,3-dipolar cycloaddition products of functionalized nitrones with 1,3-propene sultone and maleimide was synthesized through a multi-step scheme. Their fluorescent response to different metal ions was examined. Selective quenching of the fluorescent materials by Cu(II), Fe(III), and Ru(III) in acetonitrile was demonstrated, providing access to new chemosensor design for selected transition metals.

Full text of DOI:10.1016/j.tetlet.2004.10.171

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 173–176
Selective complexation of metals with isoxazolidine-containing
fluorophores
Lei Fang,a Wing-Hong Chanb,* and Yong-Bing Hea
aDepartment of Chemistry, Wuhan University, Wuhan 430072, China
bDepartment of Chemistry and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and
Synthesis, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
Received 23 August 2004; revised 14 October 2004; accepted 19 October 2004
Abstract—A series of 1,3-dipolar cycloaddition products of functionalized nitrones with 1,3-propene sultone and maleimide was
synthesized through a multi-step scheme. Their fluorescent response to different metal ions was examined. Selective quenching of
the fluorescent materials by Cu(II), Fe(III), and Ru(III) in acetonitrile was demonstrated, providing access to new chemosensor
design for selected transition metals.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The development of new molecular system for lumines-
cent detection of transition metal ions is an important
aspect for both environment and biological application.1
In order to obtain new recognition property, we recently
introduced an isoxazolidine ring into the sensor scaffold
to replace the traditional binding site like free amine or
pyridine as the recognition element.
copper(II) provides us a direct access to design practical
luminescence chemosensors for transition metal ions.
Synthesis of 5a–f was undertaken according to the syn-
thetic protocol developed in our laboratory.3a The func-
tionalized nitrones were prepared in high yield by the
multi-step synthesis as shown in Scheme 1. To qualify
as potential fluorescent chemosensors, pyrene moiety
was appended into the scaffold of the dipolar. However,
in the last step of the 1,3-dipolar cycloaddition reaction,
the chemical yields were varied by different substitute
groups present in the dipolars. Starting with different
o-substituted benzaldehydes gave us different products,
which are modified on the sidearm of the isoxazolidine
ring. Compounds 5b and 5c are polyether substituted
while 5d and 5f contain ester moiety as a potential
chelating group; 5e was assembled by introducing a
pyridine group onto the N-benzyl sidearm. In the cyclo-
addition, bicyclic adduct 5f was obtained when malei-
mide was used as the dipolarphile instead of propene
sultone.
As an effective dipolarophile and precursor of chiral
auxiliary, a,b-unsaturated sultones have been developed
by us for many years.2 Recently, we did a systematic
work on investigation of 1,3-dipolar cycloadditions of
such sultones with nitrones, which give the correspond-
ing isoxazolidine derivatives in highly stereo- and regio-
selective manners.3 To explore analytical applications of
these cycloadducts, fluorophores and potential chelating
groups can be introduced onto the isoxazolidine ring by
modifying the structure of nitrones prior to the 1,3-dipo-
lar cycloaddition. One of the product 6 containing pyren-
yl group shows highly selective and sensitive fluorescent
response to Ag(I) ion in aqueous condition through
intermolecular excimer formation.4 Encouraged by the
finding, based on compound 6, a series of derivative
analogues 5a–f were synthesized. Their selective fluores-
cent response toward iron(III), ruthenium(III), and
With 5a and its derivatives 5b–f in hand,5 we studied
their fluorescence property and response to different me-
tal ions. All the compounds mentioned above have
strong fluorescent emission at wavelength of 378 and
397nm due to the presence of a pyrenyl group. Under
the same concentration (5 · 10À6 M), emission intensi-
ties of 5e and 5f are relatively lower than that of the
other analogues, by 37% and 64%, respectively. The
observation is conceivably due to the intra-molecular
Keywords: Fluorophores; Quenching; Selective metal complexation;
1,3-Dipolar cycloaddition.
*
Corresponding author. Tel.: +852 3411 7063; fax: +852 3411 7348;
e-mail: whchan@hkbu.edu.hk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.171

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L. Fang et al. / Tetrahedron Letters 46 (2005) 173–176
R
R
R
R
ii
i
iii
O
NOH
C
H
C
NHOH
N
CHO
H2
1a-e
2a-e
3a-e
4d
4a-e
a: R =
b: R =
c: R =
d: R =
H
O
v
OCH3
iv
O
O
R
O
OH
O
O
O
OCH3
OCH3
OCH3
H
O
H
O
H
N
N
O
N
O
NH
O
O
H
H
S
H
S
O
e: R =
O2
O2
O
N
5f
5a~e
6
Scheme 1. Synthesis of 5a–f. Reagents and conditions: (i) NH2OHÆHCl, KOH/H2O, 70ꢁC, 2h, (ii) NaBH3CN, HCl/methanol, rt, 2h, (iii) 1-
pyrenecarboxaldehyde/benzene, N2 atmosphere, reflux, 9–12h, (iv) 1,3-propene sultone/toluene, N2 atmosphere, reflux, 24h, (v) maleimide/toluene,
N2 atmosphere, reflux, 24h.
photo-induced electron transfer (PET) from the extra
nitrogen atom in the molecules to the fluorophores.1f,6
cited fluorophore. Emission intensities of 5e in presence
of 20equiv of Fe3+, Cu2+, and Ru3+ do not regenerate at
77K compared with that at room temperature. Such
observation corroborates that it is ET rather than eT
process be responsible for the quenching.1e,g The low
energy level (d-orbital) of Cu2+, Fe3+, and Ru3+ is suit-
able for a double electron exchange energy transfer.8
This electronic ET process, which does not induce any
separation of charge but only electron circulation, is
not affected by solvent immobilization occurring at
low temperature (Fig. 2). Even though we cannot ex-
clude the heavy atom effect completely, observation of
no quenching effect of other heavy metals like Hg2+
and Ag+ in the same condition leads us to believe that
quenching by heavy atom effect is negligible in the pre-
sent system.
Fluorescent response of 5a–f to cations was recorded in
acetonitrile at
a
diluted concentration around
5 · 10À6 M. Addition of CuCl2, RuCl3, or FeCl3 led to
drastically immediate fluorescence quenching (Fig. 1).
This effect could not be observed through addition of
other metal ions including alkali metal ions, alkali earth
metal ions, and common transition metal ions like Hg2+
,
Ag+, Zn2+, Ni2+, Mn2+, and Co2+, even a large excess
(i.e., 50equiv) of the metal ions was used. On the other
hand, excessive addition of these metal cations to the
host molecules 5a–f did not induce any change in their
absorption spectra in the wavelength range of 300–
380nm. Conceivably, 5a–f have no association to the
cations in acetonitrile.7
Stability constants (Ks) of 5a–f with Ru3+, Cu2+, and
Fe3+ were measured through the decreasing fluorescence
intensities when titrating the metal ions to the acetonit-
rile solutions of 5a–f (Table 1).9 Fully quenching of fluor-
escence intensity indicates a nonradiative complex
formation. Furthermore, good linear Besesi–Hildebrand
plots were obtained for the complexes, which is indica-
The fundamental mechanism of such fluorescent
quenching is likely operative via Dexter typed electron
transfer. When a metal ion and a fluorophore form com-
plex via a specific spacer, the close distance between
them allows energy transfer (ET) or electron transfer
(eT) involving the d-orbitals of the metal ion and the ex-
Figure 1. Fluorescence emission spectra of compound 5e (5.6 · 10À6 M): (a) titrated with RuCl3, CRu: 9.2, 18.4, 27.6, 36.8, 46, 55.2 (10À6 M), (b)
titrated with CuCl2, CCu: 8, 16, 24, 32, 40, 48, 98 (10À6 M).

L. Fang et al. / Tetrahedron Letters 46 (2005) 173–176
175
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Valeur, B. Chem. Eur. J. 2004, 10, 4480–4490.
Figure 2. Electron circulation of the energy transfer process (double-
electron exchange mechanism) involving an excited fluorophore and a
d9 metal ion.
2. (a) Lee, A. W. M.; Chan, W. H.; Jiang, L. S.; Poon, K. W.
Chem. Commun. 1997, 611–612; (b) Chan, W. H.; Lee, A.
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W. H.; Lee, A. W. M.; Xia, P. F.; Wong, W. Y. Lett. Org.
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Table 1. The complex stability (Ks) constant of 5a–f versus different
metal ions (104 MÀ1
)
Ks
Ru3+
Cu2+
Fe3+
5a
5b
5c
5d
5e
5f
1.2 0.1
1.7 0.2
1.4 0.1
1.2 0.1
4.8 0.5
1.7 0.2
0.57 0.06
0.71 0.08
0.55 0.06
0.68 0.08
0.53 0.06
0.68 0.07
1.8 0.2
2.0 0.2
1.9 0.2
1.7 0.2
1.9 0.2
1.8 0.2
4. Yang, R. H.; Chan, W. H.; Lee, A. W. M.; Xia, P. F.;
Zhang, H. K.; Li, K. A. J. Am. Chem. Soc. 2003, 125, 2884–
2885.
5. Synthetic procedure and characterization data of selected
compound: 4e: The mixture of 3e (200mg) and 1-pyrene-
carboxyaldehyde (200mg) in 30mL dry benzene was
refluxed for overnight under nitrogen protection. The
cooled solution was refrigerated and the precipitate formed
was filtered out. The solid obtained was washed by diethyl
ether (3 · 15mL) to afford bright yellow powders as the
pure nitrone product 4e (230mg, 60%). 1H NMR
(270MHz, CDCl3) d: 5.31 (s, 2H), 5.42 (s, H), 7.03–7.13
(m, 3H), 7.36–7.43 (m, 3H), 7.61–7.64 (m, 1H), 7.94–8.22
(m, 8H), 8.48–8.54 (m, 2H), 9.90 (d, J = 8.4Hz, 1H). 13C
NMR (67MHz, CDCl3) d: 67.2, 71.0, 112.1, 121.2, 121.3,
121.3, 121.5, 121.9, 122.5, 122.7, 123.5, 125.0, 125.5, 125.9,
125.9, 126.0, 127.5, 128.3, 128.3, 130.3, 130.8, 132.2, 132.5,
136.8, 148.9, 149.1, 156.4, 156.6. 5e: Nitrone 4e (167mg)
and 1,3-propene sultone (49mg) in 20mL of toluene was
heated to reflux under the nitrogen atmosphere for 48h.
After removal of toluene and the residue was purified by
flash chromatography column (diluted by petroleum ether:
ethyl acetate = 1.5:1) to give pale yellow solid 5e as the pure
product (72mg, 34%). Mp > 230ꢁC (decomposed). 1H
NMR (270MHz, CDCl3) d: 4.05 (d, J = 3.8Hz, 2H), 4.35
(dd, J1 = 11.1Hz, J2 = 3.0Hz, 2H), 4.50 (d, J = 11.1Hz,
1H), 4.83 (s, 2H), 5.23 (br, 1H), 5.33 (dd, J1 = 6.75Hz,
J2 = 2.97Hz, 1H), 6.592–6.959 (m, 5H), 7.07–7.16 (m, 1H),
7.37–7.43 (m, 1H), 7.90–8.20 (m, 9H), 8.64 (d, J = 9.5Hz,
1H). 13C NMR (67MHz, CDCl3): 53.9, 69.1, 70.3, 80.2,
111.6, 1129, 120.0, 120.6, 121.1, 1219, 124.4, 124.7, 125.0,
125.5, 125.5, 126.1, 127.1, 128.1, 128.3, 128.7, 128.9, 130.4,
130.9, 131.1, 131.7, 136.0, 136.9, 148.3, 149.1, 155.8, 156.5.
IR (KBr): 759.39, 849.06, 948.37, 1041.76, 1158.06,
1242.29, 1367.65cmÀ1. HRMS (TOF MS): C33H27N2O5S,
calcd: 563.1640, found: 563.1617.
tive to the formation of a 1:1 complex. It is noteworthy
that Ru(III) and Fe(III) exhibited stronger quenching
abilities than that of Cu(II).
Changing the structure of the sidearm groups of 5a–f
gave no different Ks except for 5e with Ruthenium(III).
It may due to the too weak binding abilities of polyether
and ester groups in 5b–d and 5f toward metal cations.
On the other hand, the imide and sultone moiety incor-
porating into the fluorescent materials seemingly exerted
no influence to the chelation. Higher Ks observable for
the complex of 5e and Ru(III) demonstrates the poten-
tial means to improve the binding capacity of a sensor
by modification of the N-sidearm of isoxazolidine deriv-
atives. If the chelating group on the benzyl o-sidearm is
strong enough, a sensor with highly affinity and selectiv-
ity to Ru(III) or Fe(III) based on isoxazolidine structure
could be developed.
In summary, we have synthesized isoxazolidine-contain-
ing fluorophores 5a–f in considerable yields by a con-
venient procedure, we also studied their selective
complexation toward Fe(III), Cu(II), and Ru(III), which
provides us a new insight into the design of chemosen-
sors for transition metals.
Acknowledgements
6. (a) Photoinduced Electron Transfer; Fox, M. A., Chanon,
M., Eds.; Elsevier: Amesterdam, 1988; Parts A–D; (b)
Wasielewski, M. R. Chem. Rev. 1992, 92, 435–461; (c)
Kavarnos, G. J. Fundamentals of Photo-Induced Electron
Transfer; VCH: Weinheim, NY, 1993; (d) Kavarnos, G. J.;
Turro, N. J. Chem. Rev. 1986, 86, 401–449.
The work described in this paper was partly supported
by a grant from the University Grants Committee of
the Hong Kong Special Administrative Region, China
(Project No. AoE/P-10/01) and a grant from Hong
Kong Baptist University (FRG/03-04/II-15).
7. The UV–visible absorption spectra of 2a–f (5 · 10À6 M)
with different cations (20equiv) in acetonitrile was meas-
ured in the wavelength range of 300–380nm
(kmax = 342nm). It is impossible to analyze the details of
absorption change when RuCl3, FeCl3, and CuCl2 were
added to the hosts because these inorganic compounds
References and notes
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L. Fang et al. / Tetrahedron Letters 46 (2005) 173–176
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