Solvent-dependent selective fluorescence assay of aluminum and gallium ions using julolidine-based probe

Article abstract of DOI:10.1016/j.dyepig.2013.07.035

The selective assay of aluminum and gallium ions is reported using fluorescence enhancement of a julolidine-based probe (PJI) in aqueous and nonaqueous solvents. The binding properties of PJI with metal ions were investigated by UV-vis, fluorescence, and electrospray ionization mass spectrometry. PJI gave no fluorescence in water, dimethylformamide, and methanol. The addition of aluminum ions switches on the fluorescence of the sensor PJI in both buffer and dimethylformamide, while other metal ions show no significant fluorescence changes. However, in methanol, its fluorescence can be selectively turned from a turn-on fluorescent sensor for gallium ions. The complex stability constants (K_a) for the respective stoichiometric 1:1 complexation of PJI with aluminium and gallium ions were obtained by fluorimetric titrations.

Full text of DOI:10.1016/j.dyepig.2013.07.035

Dyes and Pigments 99 (2013) 1016e1021
Contents lists available at ScienceDirect
Dyes and Pigments
journal homepage: www.elsevier.com/locate/dyepig
Solvent-dependent selective fluorescence assay of aluminum and
gallium ions using julolidine-based probe
Jin Young Noh a, Soojin Kim b, In Hong Hwang a, Ga Ye Lee b, Juhye Kang a, So Hyun Kim b,
**
,
b,
*
Jisook Min c, Sungsu Park b, Cheal Kim a , Jinheung Kim
a Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul, Republic of Korea
b Department of Chemistry and Nano Science, Global Top5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea
c National Forensic Service, Seoul 158-707, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The selective assay of aluminum and gallium ions is reported using fluorescence enhancement of a
julolidine-based probe (PJI) in aqueous and nonaqueous solvents. The binding properties of PJI with
metal ions were investigated by UVevis, fluorescence, and electrospray ionization mass spectrometry. PJI
gave no fluorescence in water, dimethylformamide, and methanol. The addition of aluminum ions
switches on the fluorescence of the sensor PJI in both buffer and dimethylformamide, while other metal
ions show no significant fluorescence changes. However, in methanol, its fluorescence can be selectively
turned from a turn-on fluorescent sensor for gallium ions. The complex stability constants (Ka) for the
respective stoichiometric 1:1 complexation of PJI with aluminium and gallium ions were obtained by
fluorimetric titrations.
Received 22 June 2013
Received in revised form
28 July 2013
Accepted 29 July 2013
Available online 22 August 2013
Keywords:
Aluminum ions
Fluorescence chemosensor
Gallium ions
Ó 2013 Elsevier Ltd. All rights reserved.
Julolidine
Turn-on sensor
Solvent dependence
1. Introduction
been implicated as one of possible factors of Alzheimer’s disease
due to the accumulation of oxidative damage induced by the ions
The development of fluorescent sensors for selective detection
of various biologically and environmentally relevant metal ions has
been associated with an increasing interest in the potential impact
of their toxic effects. Due to the widespread use of aluminum in
food additives, aluminum-based pharmaceuticals, and cooking/
storage utensils, human exposure to aluminum has increased. In
addition, the frequent use of aluminum foil, vessels, and trays for
convenience has moderately increased the possibility of aluminum
inclusion in food. Long-term ingestion enables aluminum ions to
spread throughout all tissues in humans and animals, and even-
tually accumulate in the bone. The iron binding protein is the main
carrier of Al3þ in plasma. Aluminum ions can enter the brain and
reach the placenta and fetus by the carrier. Aluminum ions may
stay for an extended time in various organs and tissues before they
are excreted through the urine. In addition, aluminum ions have
and may result in damage to the central nervous system in humans
[1e4]. The sensitive bio-imaging of Al3þ in the cell will be essential
for understanding the mechanism by which aluminum ions cause
aluminum-induced human diseases, including Alzheimer’s disease
[2,3]. Thus, the development of selective detection and bio-imaging
techniques of Al3þ is important to control the concentration levels
in the biosphere and minimize the adverse effect on human health.
Several types of small molecules have been examined for fluores-
cence Al3þ detection [5e16]. However, only a few of these probes
has been utilized for imaging Al3þ in living cells.
Gallium is used in electronic devices, usually in the form of
gallium arsenide. Gallium compounds are also used as possible
diagnostic and antitumor agents. Aluminum and gallium have a
very similar chemistry such as always having a þ3 oxidation state.
However, fluorescent chemosensors for gallium ions are even rare
than those for aluminum ions, even though other techniques for
trace gallium determination, such as ion exchange, adsorption,
extraction, and atomic absorption spectrometry, have been
developed. A few fluorescent chemosensors for Ga3þ detection
have been reported, but their selectivity for Ga3þ towards Al3þ was
very poor [17,18]. A need therefore remains for the development of
* Corresponding author. Department of Chemistry and Nano Science, Ewha
Womans University, Seoul 120-750, Republic of Korea. Tel.: þ82 2 3277 4453;
fax: þ82 2 3277 3419.
** Corresponding author.
E-mail addresses: chealkim@snust.ac.kr (C. Kim), jinheung@ewha.ac.kr (J. Kim).
0143-7208/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.dyepig.2013.07.035

J.Y. Noh et al. / Dyes and Pigments 99 (2013) 1016e1021
1017
PJI
N
OHC
HO
Al(NO3)3
HO
N
HO
N
+
N
O
O
HO
CH3OH, N2
HO
X
X
(X = NO3- or H2O)
Al
N
HO
NH2
N
N
X
Scheme 1. Synthesis of the fluorescent sensor ortho-phenyljulolidineimine (PJI).
Scheme 2. Proposed structure of a 1:1 complex of PJI and Al3þ
.
receptor towards various metal ions, such as Naþ, Kþ, Agþ, Ca2þ
Mg2þ, Ni2þ, Cd2þ, Mn2þ, Co2þ, Cu2þ, Zn2þ, Hg2þ, Pb2þ, Al3þ, Cr3þ
,
,
new and improved chemosensors for the selective determination
of Ga3þ
.
Fe3þ, Ga3þ, and In3þ, the fluorescence spectral response of the
aqueous buffer (10 mM TriseHCl pH ¼ 7.0) solution of PJI was
examined in the presence of each metal ion (Fig. 1a). Significant
spectral changes were observed only in the case of Al3þ. The fluo-
rescence intensity ratio (IAl/IGa) of PJI measured in the presence of
Al3þ and Ga3þ was 32, which was the highest relative to those re-
ported with other chemosensors [5,6,15,23]. In contrast, treatment
with other metal ions resulted in no significant changes, demon-
On the other hand, some molecular metal complexes containing
Schiff base-type compounds are known to exhibit antitumor and
antioxidative activities [19,20]. Schiff base organic ligands incor-
porating a fluorescent moiety have been used to assay specific
metal ions. Although some Schiff base-type Al3þ chemosensors
were recently reported [5e7,15e16], examples of water-soluble
sensors that can be used for cell imaging and biological samples
are rare. Chemosensors based on julolidine exhibit a selective
sensing for Cu2þ and Fe3þ [21,22]. In this study, we report the
metal-binding properties of another julolidine-based imine probe,
strating that PJI is even highly selective for Al3þ over Ga3þ and In3þ
.
The turn-on fluorescence response of PJI was observed for Al3þ
with emission bands at 482 and 512 nm. Upon addition of Al3þ, the
fluorescence intensity of PJI increased by 100-fold (fluorescence
which is the
p-conjugated Schiff base receptor, and that exhibits
enhanced fluorescence with high selectivity upon binding to Al3þ
in water and dimethyl formamide (DMF), but to Ga3þ in CH3OH. The
possible application of the probe as an intracellular sensor of Al3þ is
also reported by confocal fluorescence microscopy.
quantum yield
F
¼ 0.096). The fluorescence spectral changes of PJI
revealed the presence of an incremental amount of Al3þ. The
fluorometric titration curve showed a steady and smooth increase
with increasing Al3þ concentration, which demonstrated an effi-
cient fluorescence response (Fig. 1b and Fig. S1a). The binding af-
finity of PJI towards Al3þ was quantified based on fluorescence
titration experiments, affording the association constant (Ka) of
1 ꢀ 107 Mꢁ1 (Fig. S1b). Binding analysis using the Benesi-
Hildebrand plot established that a 1:1 complex of PJI and Al3þ
was responsible for the observed fluorescence enhancement
2. Results and discussion
The chemosensor, ortho-phenyljulolidineimine (PJI) was pre-
pared using 8-hydroxyjulolidine-9-carboxaldehyde and 2-
aminophenol with 72% yield (Scheme
1 and Supporting
Information). To understand the binding properties of this PJI
(a)
(b)
200
250
,
,
200
150
100
50
150
100
50
Al
K , Mg
,
Mn
0
0
0
2
4
6
8
10
12
450
500
550
600
3+
[Al ] / [Ligand]
Wavelength (nm)
(c)
0.6
(d)
100
419.18
0.4
0.2
0.0
416
418
420
422
50
0
300
350
400
450
500
550
600
300
400
500
600
m/z
Wavelength (nm)
Fig. 1. (a) Emission spectra of PJI (0.5
m
M) in the absence and presence of various metal ions (4.0
m
M) using El ¼ 450 nm in 10 mM Tris buffer (pH ¼ 7.0). (b) Fluorescence titration of
PJI with Al3þ in aqueous solution. (c) UVevis spectral changes of PJI (10
m
M) as a function of the Al3þ concentration in 10 mM Tris buffer. (d) ESI-MS of PJI (1.0
m
M) þ Al3þ (1.0
mM) in
Tris buffer (inset, Calculated isotope pattern represented by bars under the peak cluster). All fluorescence spectra were acquired in 10 mM Tris buffer with excitation at 450 nm at
room temperature. A methanol stock solution of PJI was used for all experiments.

1018
J.Y. Noh et al. / Dyes and Pigments 99 (2013) 1016e1021
The emission profiles of PJI (0.5 m
M) or its Al3þ-bound form were
unperturbed in the presence of 160 equiv of Naþ, Kþ, Ca2þ, Mg2þ
,
Ni2þ, Cd2þ, Mn2þ, Zn2þ, and Hg2þ (Fig. 2). In addition, PJI was also
selective over Agþ at 16-fold excess and over Co2þ, Pb2þ, and Ga3þ
at 8-fold excess. The fluorescence profiles of PJI were somewhat
perturbed by In3þ, but PJI remained selective for Al3þ over In3þ at 2-
fold excess.
300
200
100
0
In order to explore the fluorescence enhancement of PJI with
Al3þ according to solvents, the fluorescence responses of PJI were
examined in dimethylformamide (DMF) and methanol. The fluo-
rescence response of PJI upon addition of Al3þ in DMF showed two
similar emission bands at 493 and 520 nm, which were shifted due
to solvent polarity relative to those observed in the buffer. PJI was
also highly selective for Al3þ over competing metal ion analytes
(Fig. 4a). Fluorescence enhancement upon treatment with Al3þ
appeared as high as 400-fold (Fig. 4b).
L
Al Ag Ca Cd Cr Hg K Mg Mn Zn Pb Co Cu Fe Ga In Na Ni
When the fluorescence properties of PJI were examined in
methanol, the selectivity for metal ions was changed unexpectedly.
Fig. 5a shows the fluorescence spectra of PJI upon addition of metal
ions in CH3OH. Similar to the data in buffer and DMF, Al3þ enhanced
the emission of PJI to some extent, while no significant changes of
the fluorescence were observed with other competing metal ions.
Interestingly, the addition of gallium ions changed the emission
signals of PJI remarkably and the intensity was much greater than
that of Al3þ. Upon addition of Ga3þ, the fluorescence intensity of PJI
Fig. 2. Relative fluorescence of PJI and its complexation with Al3þ in the presence of
various metal ions. The response of PJI was included as controls. Left to right: PJI alone
(L corresponds to PJI) and PJI þ Al3þ þ M (M ¼ Al3þ, Agþ, Ca2þ Cd2þ, Cr3þ, Hg2þ Kþ
,
Mg2þ, Mn2þ Zn2þ, Pb2þ, Co2þ Cu2þ, Fe3þ, Ga3þ, In3þ, Naþ, Ni2þ). Conditions: 0.5
mM PJI,
8 equiv Al3þ, and 8 equiv other metal ions (lex ¼ 450 nm).
(Scheme 2). Al3þ could be detected down to 0.13
mM based on the
3a/slope when 5 mM PJI was employed. In the pH dependence study
of PJI-Al3þ, emission at 482 nm was only observed at pH 5.5e7.5
(Fig. 3, Fig. S2).
The absorption spectra of PJI changed upon addition of Al3þ ions
(Fig. 1c). The band at 430 nm decreased without a marked shift and
a weak UV band was observed around 300 nm. The presence of two
clear isosbestic points for PJI supports the formation of a complex
with only one stoichiometry (Fig. 3) .
1000
(a)
3+
Al
800
600
The 1:1 complexation between PJI and Al3þ was also evidenced
by using Job’s plot and electrospray ionization mass (ESI-MS)
spectral analysis. The positive mass spectrum exhibited one
intense peak at m/z ¼ 419 corresponding to the ion [PJI e
2Hþ þ Al3þ þ CH3OH þ 3H2O]þ (Fig. 1d). The formulation of this ion
was corroborated by isotope distribution patterns that matched the
calculated pattern (Fig. 1d, inset). The 1H NMR spectra of PJI
recorded in nonprotic solvent upon addition of increasing Al3þ
showed significant spectral changes (Fig. S3a). Two hydroxyl pro-
tons of PJI at 9.5 and 14.2 ppm progressively disappeared upon
treatment with Al3þ, indicating that the OH protons were depro-
tonated upon complexation.
400
Ligand
200
0
450
500
550
600
Wavelength, nm
500
400
300
200
100
0
(b)
1000
800
600
400
200
0
[Al ]
400
450
500
550
600
650
700
2
3
4
5
6
7
8
9
10 11 12
Wavelength (nm)
pH
Fig. 4. (a) Emission spectra of PJI (2
various metal ions using El ¼ 450 nm in DMF. (b) Fluorescence response of PJI (2
to Al3þ (0e4
M) in DMF.
m
M) in the absence and presence of 10 equiv of
Fig. 3. pH dependence of the fluorescence intensity for solutions containing 0.5
and 4.0 M aluminum ions at 482 nm in 10 mM phosphate buffer.
mM PJI
m
M)
m
m

J.Y. Noh et al. / Dyes and Pigments 99 (2013) 1016e1021
1019
(b)
(a)
1400
1000
Ga
486 nm
1200
1000
800
600
400
200
0
800
600
400
200
0
516 nm
[Ga
]
Al
450
500
550
600
650
450
500
550
600
650
Wavelength (nm)
Wavelength (nm)
(c)
(d)
100
50
0
520.80
0.4
PJI
518 520 522 524 526 528
0.2
0.0
300
400
500
600
500
550
600
650
Wavelength (nm)
m/z
Fig. 5. (a) Emission spectra of PJI (2
m
M) in the absence and presence of 7 equiv of various metal ions using El ¼ 450 nm in CH3OH. (b) Fluorescence response of PJI (2
m
M) to Ga3þ
(0e18
mM) in CH3OH. (c) Absorption spectral changes of PJI (10
m
M) as a function of the Ga3þ concentration. (d) ESI-MS of PJI þ Ga3þ in methanol (inset, Calculated isotope pattern
represented by bars under the peak cluster). All experiments were performed using CH3OH. All fluorescence spectra were acquired with excitation at 450 nm.
increased by 1400-fold (
F
¼ 0.152) (Fig. 5b and Fig. S4). This turn-
cells. Strong fluorescence was observed in the cells previously
exposed to Al(NO3)3 at 10 and 100 M, as shown in Fig. 6a. Over
fifty cells from the images of each treatment were randomly
selected and the fluorescence intensities of individual cells were
quantified using Image J program (Fig. 6b). Based on the mean
on response was accompanied by red shifts in emission (486 and
516 nm) maxima due to solvent polarity. The intensity ratio (IGa/IAl)
of PJI was 6.4, which is the highest relative to those reported with
other fluorescence chemosensors [16]. The fluorescence titration of
PJI afforded the association constant value Ka ¼ 2.5 ꢀ 106 Mꢁ1
m
fluorescence intensity data of cells, the cells exposed to the 0.1 mM
(Fig. S5). The detection limit was 0.10
m
M. The 1H NMR spectra of PJI
Al3þ were discernible from the unexposed cells. These results
indicate that the fluorescence intensities in the exposed cells
depended on the Al(NO3)3 concentrations. The PJI chemosensor
bound to intracellular Al3þ and emitted fluorescence, thus
demonstrating its suitability for determining the exposure level of
cells to aluminum ions.
recorded in nonprotic solvent upon addition of gallium ions also
showed a progressive disappearance of two OH protons (Fig. S3b).
The fluorescence responses of PJI were unperturbed by Naþ, Kþ,
Agþ, Ca2þ, Mg2þ, Ni2þ, Cd2þ, Mn2þ, Co2þ, Cu2þ, Zn2þ, Hg2þ, Pb2þ
,
and Al3þ at 35-fold excess. Addition of more than 2 equiv In3þ
resulted in almost half fluorescence intensity by Ga3þ. The UVevis
absorption changes upon addition of various concentrations of
Ga3þ showed a bathochromic shift from 392 to 440 nm (Fig. 5c). A
clear isosbestic point was observed at 410 nm.
3. Conclusions
We have described a unique fluorescent chemosensor PJI for
aluminum and gallium and its solvent-dependent properties. PJI
exhibited excellent selectivity for Al3þ and Ga3þ in different sol-
vents over competing relevant metal ions and a large turn-on
response for detecting these ions. Furthermore, PJI is capable of
mapping aluminum levels in cells and this class of fluorophores
might be exploited as specific and effective sensors for intracellular
aluminum ions.
These fluorescence spectra implied a structural change in PJI
upon complexation with Ga3þ. To clarify the structural change upon
complexation of PJI and Ga3þ, ESI-MS analyses were carried out. The
ESI-MS results of a PJI þ Ga3þ solution exhibited a positive ion at m/
z ¼ 521 corresponding to [PJI e 2Hþ þ Ga3þ þ 4CH3OH þ H2O]þ
(Fig. 5d), the isotope distribution pattern of which is consistent with
the formulation (Fig. 5d, inset). The ESI-MS results and Benesi-
Hildebrand plot established
a 1:1 binding stoichiometry for
PJI- Ga3þ
.
4. Experimental section
Then, we studied the bioimaging application of PJI for mapping
aluminum ions in living cells. HeLa cells were first exposed to
4.1. Materials and instrumentation
various concentrations (0e100
incubated with the chemosensor (5
m
M) of Al(NO3)3 for 5 h and then
M) for 30 min. Low back-
m
All solvents and reagents (analytical and spectroscopic grades)
were obtained from SigmaeAldrich (St. Louis, MO, USA) and used as
received. Water was purified with a MilliQ purification system. The
metal ion solutions were prepared with metal nitrate salts in
methanol. NMR spectra were recorded on a Varian 400 spectrom-
ground fluorescence was observed in the cells (Fig. 6a) that had not
been exposed to Al(NO3)3. The background fluorescence derived
from cellular metal ions, such as Naþ, Ca2þ, Mg2þ, Zn2þ, etc, which
also afforded low fluorescence with PJI (Fig. 1a). Weak but still
discernible fluorescence was observed in the cells previously
eter (Palo Alto, CA, USA). Chemical shifts (
d) are reported in ppm,
exposed Al(NO3)3 at 0.1 and 1 mM, compared to the unexposed
relative to tetramethylsilane Si(CH3)4. Absorption spectra were

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J.Y. Noh et al. / Dyes and Pigments 99 (2013) 1016e1021
Fig. 6. (a) Observation of Al3þ in HeLa cells exposed to various concentrations (0e100
intensities of cells from each treatment. The scale bar in the image indicates 50 m. Over fifty cells from the images of each treatment were randomly selected and the fluorescence
mM) of Al(NO3)3 for 5 h using the chemosensor (5 mM) and (b) the mean fluorescence
m
intensities of individual cells were quantified using Image J program. Graph data presentation: mean ꢃ std (standard deviation). *p-value (t-test) < 0.0001, p-value (F-test) > 0.05. **
p-value (t-test) < 0.0001, p-value (F-test) < 0.05. *** p-value (t-test) < 0.0001, p-value (F-test) < 0.0001.
recorded at 25 ꢂC using a PerkineElmer model Lambda 2S UV/Vis
spectrometer (Waltham, MA, USA). Emission spectra were recorded
on a PerkineElmer LS45 fluorescence spectrometer. Electrospray
ionization mass spectra (ESI MS) of M3þ-PJI complexes were
collected on a Thermo Finnigan (San Jose, CA, USA) LCQTM
Advantage MAX quadrupole ion trap instrument, by infusing
4.3. Fluorescence measurements
PJI was dissolved in methanol, and the PJI stock solution was
diluted in water, DMF, or methanol to make the final concentration
of 0.5 mM. Then, metal ions including Al(NO3)3 and Ga(NO3)3 was
added to 3 mL of a chemosensor solution. After mixing, fluores-
samples directly into the source at 25
mL/min using a syringe pump.
cence spectra were obtained at room temperature.
The spray voltage was set at 4.7 kV and the capillary temperature at
70 ꢂC.
4.4. Fluorescent imaging of intracellular Al3þ in cells
4.2. Synthesis of ortho-phenyljulolidineimine (PJI)
HeLa cells (CCL-2, ATCC, Manassas, VA, USA) were cultured in
DMEM (Dulbecco’s Modified Eagle Medium, Invitrogen, Carlsbad,
CA, USA) supplemented with 100 units/ml Penicillin and Strepto-
mycin (Invitrogen, Carlsbad, CA, USA), and 10% FBS (Fetal Bovine
Serum, Invitrogen) in a humidified incubator at 37 ꢂC with 5% CO2.
For fluorescent imaging of Al3þ, cells were seeded onto a 35 mm
tissue culture plate at a density of 105 cells. Al(NO3)3 solutions were
prepared by diluting10 mM Al(NO3)3 in 10 mM Bis-Tris (pH 7.1)
with serum free DMEM. At 1 day after the seeding, the cells were
2-aminophenol (0.55 g,
5 mmol) was mixed with 8-
hydroxyjulolidine-9-carboxaldehyde (1.13 g, 5 mmol) in absolute
methanol. The mixture was refluxed for 3 h under nitrogen. The
solution was then cooled to room temperature and the solvent was
evaporated. The brown product was recrystallized from methanol.
The yield of PJI was 82% (1.26 g). 1H NMR (methanol-d4, 400 MHz)
d:
9.02 (s, 1H), 8.15 (d, 1H, J ¼ 8.0 Hz), 7.71 (t, 1H, J ¼ 7.6 Hz), 7.57 (m,
3H), 4.01 (m, 4H), 3.31 (m, 4H), 2.58 (m, 4H). 13C NMR (DMSO-d6,
treated with Al(NO3)3 at various concentrations (1e100
After the treatment, the cells were three times washed with PBS
containing 10 mM Bis-Tris. Then, they were incubated with 5 M PJI
chemosensor for 30 min at room temperature to stain intracellular
Al3þ. The chemosensor (5
M) has been prepared by diluting the
chemosensor (10 mM) in methanol with PBS containing 10 mM Bis-
mM) for 5 h.
100 MHz):
d 161.62, 157.91, 149.93, 146.79, 134.40, 129.59, 125.83,
119.61, 118.16, 116.12, 112.49, 108.44, 105.47, 49.42, 49.07, 26.79,
21.63, 20.66, 20.08. Calcd for C19H20N2O2 (308.37): C, 74.00; H, 6.54;
N, 9.08%. Found: C, 74.25; H, 6.61; N, 9.21%. FAB MS m/z (Mþ): calcd,
308.37; found, 308.39.
m
m

J.Y. Noh et al. / Dyes and Pigments 99 (2013) 1016e1021
1021
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This work was supported by the National Research Foundation of
Korea Grant funded by the Korea Government (2012008875,
2012001725, NRF-2013R1A2A2A03015101), the Converging Research
Center Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Technology
(2011K000675), the National R&D program of the Ministry of Edu-
cation, Science and Technology (MEST), Korea: Development of Mo-
lecular Sensing Technology (Code number 2012-009832), and BK21
(to S.K. and G.Y.L.).
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