A FRET fluorescent chemosensor SPAQ for Zn2+ based on a dyad bearing spiropyran and 8-aminoquinoline unit

Article abstract of DOI:10.1016/j.tetlet.2010.04.127

A novel FRET fluorescent sensor SPAQ containing 8-aminoquinoline (donor) and spiropyran derivative (acceptor) was designed and synthesized for detecting Zn²⁺. The probe successfully exhibited a fluorescence turn on and ratiometric response for Zn²⁺ in ethanol solution with high selectivity. Upon excitation at 370 nm, the modulation of the emission intensity of SPAQ at 645 and 470 nm was achieved in the presence of Zn²⁺ by fluorescent resonance energy transfer (FRET) and chelation-enhanced fluorescence (CHEF) effects.

Full text of DOI:10.1016/j.tetlet.2010.04.127

Tetrahedron Letters 51 (2010) 3550–3554
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Tetrahedron Letters
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A FRET fluorescent chemosensor SPAQ for Zn2+ based on a dyad bearing
spiropyran and 8-aminoquinoline unit
*
Jian-Fa Zhu, Han Yuan, Wing-Hong Chan , Albert W. M. Lee
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel FRET fluorescent sensor SPAQ containing 8-aminoquinoline (donor) and spiropyran derivative
(acceptor) was designed and synthesized for detecting Zn2+. The probe successfully exhibited a fluores-
cence turn on and ratiometric response for Zn2+ in ethanol solution with high selectivity. Upon excitation
at 370 nm, the modulation of the emission intensity of SPAQ at 645 and 470 nm were achieved in the
presence of Zn2+ by fluorescent resonance energy transfer (FRET) and chelation enhanced fluorescence
(CHEF) effects.
Received 19 March 2010
Revised 27 April 2010
Accepted 29 April 2010
Available online 4 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The design and synthesis of metal chemosensors with high
selectivity and sensitivity is an active field of supramolecular
chemistry.1 Especially of considerable importance are sensing
probes targeting heavy and/or transition metal (HTM) ions, such
as zinc cations.2 Despite having many commercial Zn2+ sensors,
chemists have continued their efforts in developing new sensing
devices to improve their sensitivity, selectivity, and application
scope.3 Due to the intrinsic sensitivity of fluorescent turn-on sen-
sors, such a design has been drawn much attention in the sensor
community. Most of the currently reported Zn2+ fluorescent turn-
on sensors have operated on chelation enhanced fluorescence
(CHEF) effect or inhibition of photo-induced electron transfer
(PET) quenching pathway as a result of the metal binding event.3a,c
Recently, a number of ratiometric fluorescent Zn2+ sensors, which
allow the quantitation of Zn2+ by measuring the ratio of fluores-
cence intensities at two different wavelengths upon metal binding,
have been reported.3d,g,4 A ratiometric detection not only can in-
crease the selectivity and sensitivity of a measurement, but also
can eliminate most of the possible variability due to differences
in instrumental efficiency and content of the effective dye.5 There-
fore, there is a huge demand and potential for exploring novel fluo-
rophores for ratiometic Zn2+ sensing.
Spiropyrans (SPs) are photochromic compounds that can isom-
erize in response to UV–Vis irradiation as a result of a reversible
heterolytic cleavage of the spiro C–O bond followed by cis–trans
isomerization which generates a metastable merocyanine (ME).6
By appending an additional receptive site in position C80 on the
benzopyran moiety, the isomerization of SP to ME could be modu-
lated by specific metal ions. The metal ion mediated ring opening
of SP to ME is characterized by its color change from colorless to
red, recognized readily by the naked-eyes. Spiropyran-based
chemosensors for alkali, alkaline earth, and lanthanides metals
have been reported.7 We have found that by superseding the com-
monly used nitro-group in C60-position with a tert-butyl group, a
more photostationary closed SP form can be resulted. Such a
photostationary SP derivative is an ideal molecular platform for
the design of molecular/ion optical sensing probes. In this context,
we have developed novel spiropyran-based chemosensors 1 and 2
for the colorimetric and fluorescent detection of Cu2+ (Scheme 1).8
To continue our interests in the sensor development, herein, a new
fluorogenic sensor SPAQ (3), capable of illustrating Zn2+—triggered
fluorescence resonance energy transfer (FRET) changes has been
synthesized. Based on the FRET changes, SPAQ bearing spiropy-
ran–aminoquinoline moieties can respond selectively to zinc ion
in ethanol solution to give ratiometric fluorescence output signals.9
To achieve the required selectivity towards a specific metal ion,
it is necessary to complement the optical and binding properties of
the spiropyran backbone with an appropriate multi-ligating group
such that optical signal changes can be induced in response to the
metal recognition event. Commercially available 8-aminoquinoline
CH3
N
L =
L =
1
2
CH3
6'
N
O
N
O
8'
HN
L
N
3
SPAQ
L =
* Corresponding author. Tel.: +825 34117076; fax: +825 34117348.
E-mail address: whchan@hkbu.edu.hk (W.-H. Chan).
Scheme 1. Structures of spiropyran-based fluorescent sensors.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.127

J.-F. Zhu et al. / Tetrahedron Letters 51 (2010) 3550–3554
3551
is a judicious choice to be appended on the spiropyran scaffold for
the design of fluorescent Zn2+ sensor. After conjugating 8-amino-
quinoline to spiropyran backbone via a CH2 spacer at the C80 car-
bon, the resultant sensor 3, SPAQ on one hand would possess a
tridentate ‘ONN’ binding site for Zn2+ and on the other hand would
provide opportunity to construct a FRET relay between the two flu-
orophoric subunits present in the system. To assemble the sensing
probe, the requisite spiropyran precursor 6 was prepared from 2-
hydroxy-3-hydroxymethyl-5-tert-butylbenzaldehyde (4) in two
synthetic operations as shown in Scheme 2.10 Condensation reac-
tion between 4 and N-methyl-2,3,3-trimethylindolenine in ethanol
gave good yield of spiropyran derivative 5 which underwent a fast
nucleophilic substitution reaction with thionyl chloride to afford
the corresponding chloride 6. The crude labile 6 without purifica-
tion was allowed to conjugate with 8-aminoquinoline to give rise
to multifunctional spiropyran-based fluorescent sensor SPAQ (3)
in 44% yield.11 On the other hand, controlled compound 7, without
the spiropyran subunit, bearing the same tridentate ‘ONN’ binding
site as the sensor was synthesized by reductive amination of 4-t-
butylsalicyaldehyde with 8-aminoquinoline in the presence of so-
dium borohydride.
The metal mediated interconversion of the colorless functional-
ized SP to the red colored ME is well known to be solvent depen-
dent. Thus, the metal binding property of sensor 3 was initially
investigated in acetonitrile and ethanol solution separately. The
formation of red colored ME derivative was observed readily by
adding 1 equiv of a variety of different transition metal ions to
the colorless ACN solution of SPAQ. In contrast, in ethanol solution
of the probe, among a total of 13 metal cations being studied (vide
infra), only Cu2+, Zn2+, Co2+ and Ni2+ can immediately turn the color
of the solution from colorless to red (Fig. S1, ESI). To evaluate the
viability of using SPAQ for detecting Zn2+ in ethanol solution, its
signal response toward Zn2+ was recorded in both absorption and
emission spectra. As shown inFigure 1, two broad absorption peaks
centered at 380 and 540 nm emerged when SPAQ was titrated
with increasing concentration of Zn2+. On the basis of non-linear
fitting, the binding constant was found to be 7.2 ꢀ 104 Mꢁ1. More-
over, a Job’s plot, which exhibits a maximum at 0.5 mole fraction of
Zn2+, indicates that a 1:1 complex is formed (Fig. S2, ESI).
On the other hand, when excited at 520 nm, upon addition of
5 equiv of Zn2+ to SPAQ solution, ca. 170-fold increase in fluores-
cence intensity of SPAQ at 645 nm was observed. The emergence
of this fluorescent turn-on signal as a result of the formation of
sensor–Zn2+ complex can be rationalized as a combination of inter-
nal charge transfer (ICT) and chelation enhanced fluorescence
(CHEF).12 Other metal ions being studied was unable to turn on
the fluorescent signal of the sensor (Fig. S3, ESI), apparently, SPAQ
is well qualified as a fluorescent turn-on chemosensor for detecting
Zn2+. To unravel whether the metal binding event will affect the
photophysical properties of the 8-aminoquinoline moiety, the fluo-
rescent signal response of the controlled compound 7 toward Zn2+
was recorded with excitation at 370 nm. Upon the addition of
10 equiv of Zn2+, the emission peak at 470 nm was reduced only
by about 10% (Fig. S4, ESI). When excited at 370 nm, the emission
spectrum of SPAQ overlaps significantly with the long wave
absorption peak of SPAQ–Zn2+ (Fig. S5, ESI). To explore the possi-
bility of developing a ratiometric Zn2+ sensor, we examined
whether fluorescence energy transfer (FRET) occurs in our sensing
dyad by exciting the quinoline moiety at 370 nm. As shown in
Figure 2, upon increasing the concentration of Zn2+, the long wave
fluorescent peak at 645 nm of the probe enhances with concomi-
tant reduction of its short wave fluorescent peak at 470 nm. A dis-
tinctive isoemissive peak at 570 nm is evident. When 5 equiv of
Zn2+ was added, the ratio of the emission intensity at 645 and
470 nm (I645 nm/I470 nm) increased from 0.05 (free SPAQ) to 3.26
(Zn2+/SPAQ—complex) (inset in Fig. 2). Additionally, the extent of
fluorescence quenching of SPAQ caused by Zn2+ at 470 nm was
much greater than that of the controlled compound. Conceivably,
in addition to the Inner Filter Effect exhibited by the merocyanine
moiety of SPAQ, a fairly efficient FRET appeared to take place. Sig-
nificantly, the validity of SPAQ as a ratiometric fluorescent chemo-
sensor for Zn2+ can be established.
CHO
N
OH
SOCl2
N
O
OH
DCM, 0oC, 5 min
ethanol, rt, overnight
75%
HO
5
4
N
NH
N
NH2
N
O
N
O
Cl
ACN/DCM, 85 oC,
3 h, 44%
6
3
CHO
N
N
OH
NH2
NH
OH
NaBH4, rt, 85%
7
Scheme 2. Synthesis of sensor SPAQ (3).

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J.-F. Zhu et al. / Tetrahedron Letters 51 (2010) 3550–3554
a
b
550000
500000
450000
400000
0.8
0.6
0.4
0.2
0.0
10 eq. Zn2+
5 eq. Zn2+
10 eq. Zn2+
350000
2.5 eq. Zn2+
0.9 eq. Zn2+
0.5 eq. Zn2+
0.1 eq. Zn2+
0 eq. Zn2+
5 eq. Zn2+
2.5 eq. Zn2+
300000
0.9 eq. Zn2+
250000
0.5 eq. Zn2+
0.1 eq. Zn2+
0 eq. Zn2+
200000
150000
100000
50000
0
200
300
400
500
600
700
600
700
Wavelength (nm)
800
Wavelength (nm)
Figure 1. (a) UV–Vis spectra of SPAQ (20 l lM)
M) upon the titration of Zn2+ (0–10 equiv) in ethanol solution; (b) fluorescence emission spectra (kex = 520 nm) of SPAQ (10
upon the titration of Zn2+ (0–10 equiv) in ethanol solution.
340000
320000
300000
280000
260000
240000
220000
200000
180000
160000
140000
120000
100000
80000
5
4
3
2
1
10 eq. Zn2+
5 eq. Zn2+
3.5 eq. Zn2+
2.5 eq. Zn2+
1.5 eq. Zn2+
1.0 eq. Zn2+
0 eq. Zn2+
60000
40000
20000
0
400
600
800
0
Wavelength (nm)
No metal Zn2+ Hg2+ Pb2+ Co2+ Cd2+ Ni2+ Ca2+ Mg2+ Cu2+ Li+ Ag+ Na+ K+
Figure 2. Fluorescence emission spectra (kex = 370 nm) of SPAQ (20 lM) upon the
Figure 3. Metal ion selectivity profiles of SPAQ (20 lM) in the presence of various
titration of Zn2+ (0–10 equiv) in ethanol solution. (Inset) Ratiometric calibration
metals ions in ethanol solution (kex = 370 nm): (black bars) fluorescence emission
curve I645 nm/I470 nm as a function of Zn2+ concentration.
intensity ratio of 645 nm to 470 nm in the presence of 5 equiv of Zn2+, Hg2+, Pb2+
,
Co2+, Cd2+, Ni2+, Ca2+, Mg2+, Cu2+, Li+, Ag+, Na+ and K+; (grey bars) fluorescence
emission intensity ratio of 645–470 nm in the presence of 5 equiv of Zn2+, followed
by adding 5 equiv of Hg2+, Pb2+, Co2+, Cd2+, Ni2+, Ca2+, Mg2+, Cu2+, Li+, Ag+, Na+ and K+.
The selectivities of SPAQ to various metal ions were examined
systematically. Among 13 metal ions being studied, upon excita-
tion at 370 nm, only Zn2+ induced a dramatic fluorescence change
of SPAQ with respect to the ratio of the emission intensity at 645
and 470 nm and a much less variation (i.e., <0.5) was obtained
by interacting the probe with Pb2+ and Hg2+ separately. Common
competing metal ions in Zn2+ determination such as Mg2+, Ca2+
and Cd2+ did not respond to SPAQ. The titration of sensor SPAQ
with Zn2+ in the presence of potential competing metal ions was
further determined. The results shown (red bar, Fig. 3) revealed
that except Pb2+ all other common cations did not significantly
of the H15 proton from 6.57 to 7.59 was observed as a result of
changing the closed SP form of the sensor to the opened metal
complexed ME form. In consistent with the ring opening isomeri-
zation of the spiropyran moiety triggered by Zn2+ ion, the two dou-
blets at d 5.74 and 6.93 ascribed to the vinyl protons of the
dihydropyran ring of SPAQ almost coalesced as a multipet at
7.61 and a doublet at 8.78 which was assigned to the two vinyl
protons of the opened metal complex (i.e., H11 and H12). A large vi-
nyl coupling constant of 15.9 Hz observable for H12 confirmed the
trans double bond character of the metal complex. A notable
downfield shift of the N-methyl group signal from 2.71 to 3.91
was observed which corroborated with the formation of a pyrroli-
dium ring. The ‘ONN’ binding mode of the sensor to metal as pro-
posed in Figure 5 can be rationalized by observing the shift of the
crucial protons. For instance, after coordinating with Zn2+, the
broad singlet assigned to the N–H (6.45 ppm) experienced a large
upfield shift to 5.14 whereas the CH2 adjacent to the amino group
(4.24 ppm) split as a doublet of triplets, presumably due to the
restriction of bond rotation as a result of complex formation. The
resonates at 6.57 and 7.00 ascribed to the proton ortho-(H6) and
para-(H4) to the amino group underwent a large downfield shift
change the effect by the existence of 5 equiv of Zn2+
.
Furthermore, the binding mode of the complex was studied by
mass and 1H NMR spectroscopic method. Convincing evidence on
the 1:1 binding mode of the complex of sensor SPAQ and Zn2+
was obtained by the observation of a peak of [SPAQ-Zn-ClO4]+ of
m/z 652.2 from FAB-MS method (Fig. S6, ESI).
The poor solubility of zinc salts in ethanol forced us to conduct
the NMR binding experiments in CD3CN-d3. By using 2D 1H NMR
techniques (i.e., 1H–1H COSY and 1H–1H NOESY), we are able to as-
sign all individual proton signals of SPAQ and SPAQ–Zn2+ complex
(Fig. S7, ESI). Upon addition of 1 equiv of Zn2+ to the CD3CN-d3
solution of SPAQ, all aromatic protons underwent a different ex-
tent of downfield shift (Fig. 4). Particularly, a huge downfield shift

J.-F. Zhu et al. / Tetrahedron Letters 51 (2010) 3550–3554
3553
Figure 4. Partial 1H NMR spectra (400 MHz) of SPAQ (20 mM) in CD3CN-d3: (a) free SPAQ; (b) SPAQ + 1 equiv of Zn2+
.
2+
N
Zn
N
O
O
2+
Zn
N
NH
H
N
N
Figure 5. Binding model of SPAQ and Zn2+
.
to 8.12, 8.04, respectively. The binding of Zn2+ by the quinoline N
promoted a downfield shift for all aromatic protons in the hetero-
cyclic ring (i.e., H1, H2 and H3). Interestingly, the H8 and H9 of phen-
oxy ring underwent a relatively small downfield shift (i.e., less than
0.3 ppm), indicating that the binding of electron rich phenoxy
group with the metal only slightly reduce the electron density of
the aromatic ring. Further addition of Zn2+ into the 1:1 Zn2+–SPAQ
solution did not induce any additional change in its NMR spectrum
(Fig. S8, ESI). Thus, the 1:1 binding mode is further substantiated.
In conclusion, we have developed a new sensitive and selective
fluorescent sensor SPAQ for detecting Zn2+. Depending on the exci-
tation wavelength, in response to Zn2+, SPAQ can behave either as a
fluorescent turn-on sensor or as a FRET ratiometric fluorescent sen-
sor. The binding mode of the metal complex was established by
combined UV–Vis, fluorescence and 1H NMR spectroscopic
method.
Supplementary data
Supplementary data (UV–Vis spectra of SPAQ interacting with
various metal ions, a Job’s plot between SPQA and Zn2+, fluores-
cence spectra of SPAQ and compound 7 upon the titration of
Zn2+ and other metal ions, overlapping of the emission spectrum
of SPAQ with the absorption spectrum of SPAQ–Zn2+, FAB-MS
spectrum of SPAQ–Zn2+
,
1H–1H NOESY spectra of SPAQ and
1H NMR, 13C
SPAQ–Zn2+ 1H NMR titration of SPAQ with Zn2+
;
;
NMR and HRMS spectrum of SPAQ) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2010.04.127.
References and notes
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Acknowledgement
The work was supported by a grant from the Research Grant
Council of Hong Kong (HKBU 200407).

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J.-F. Zhu et al. / Tetrahedron Letters 51 (2010) 3550–3554
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11. Spectral data for SPAQ: Mp: 61–63 °C; 1H NMR (400 MHz, CDCl3): 8.68 (1H, dd,
J = 4.2, 1.7 Hz), 8.01 (1H, dd, J = 8.3, 1.7 Hz), 7.33 (1H, dd, J = 8.2, 4.2 Hz), 7.23
(2H, m), 7.08 (1H, td, J = 7.6, 1.2 Hz), 7.00 (1H, dd, J = 7.3, 0.8 Hz), 6.98–6.94
(2H, m), 6.85 (1H, d, J = 10.2 Hz), 6.77 (1H, td, J = 7.5, 0.8 Hz), 6.49 (1H, d,
J = 7.7 Hz), 6.43 (2H, m), 5.68 (1H, d, J = 10.2 Hz), 4.29 (2H, dd, J = 12.9, 6.1 Hz),
2.70 (3H, s), 1.32 (3H, s), 1.21 (9H, s), 1.18 (3H, s); 13C NMR (100 MHz, CDCl3):
149.52, 148.11, 146.59, 144.76, 142.28, 138.25, 136.76, 135.87, 129.81, 128.56,
127.79, 127.39, 126.34, 124.13, 122.43, 121.37, 121.22, 118.97, 118.84, 117.84,
113.53, 106.75, 105.13, 104.39, 51.35, 42.30, 34.01, 31.47, 29.01, 25.82, 20.44.
HRMS (MALDI-TOF): calcd for [M+1]+ of C33H35N3O, 490.2853; found,
490.2870.
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