A novel 8-hydroxyquinoline-pyrazole based highly sensitive and selective Al(III) sensor in a purely aqueous medium with intracellular application: Experimental and computational studies

Article abstract of DOI:10.1039/c5nj03153b

A new 8-hydroxyquinoline-pyrazole based highly sensitive and selective Al³⁺ sensor, 8Q-NH-Pyz (H₂L³), was found to exhibit a turn-on fluorescence enhancement (FE) as high as 157 fold with K_d = (1.76 ± 0.06) × 10^-5 M. The 1:1 binding stoichiometry was revealed from the linear fit of (F_max - F₀)/(F - F₀) vs. 1/[Al³⁺] of the fluorescence titration data which was further substantiated by Job's method and HRMS studies. The LOD determined by 3σ methods was found to be 4.29 nM and quantum yields were determined to be 0.002 and 0.28 for the ligand and its Al³⁺ complex, respectively. The tentative coordination environment in the [Al(L³)(H₂O)]⁺ complex was delineated by DFT calculations. TDDFT calculations reveal spectral features comparable to the experimental ones. This constitutes the first report on the fluorescence sensing of Al³⁺ and hence F^- in a purely aqueous medium.

Full text of DOI:10.1039/c5nj03153b

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A novel 8ꢀhydroxyquinoline—pyazole based highly sensitive and
selective Al(III) sensor in purely aqueous medium with intracellular
application: experimental and computational studies†
Abu Saleh Musha Islama, Rahul Bhowmicka, Hasan Mohammada, Atul Katarkarb, Keya Chaudhurib and
Mahammad Alia*
(LINE INCLUDED FOR SPACING ONLY - DO NOT DELETE THIS TEXT)
A new 8ꢀhydroxyquinolinꢀpyrazole based highly sensitive and selective Al3+ sensor, 8QꢀNHꢀPyz (H2L3) was found to exhibit a turnꢀ
on fluorescence enhancement (FE) as high as 157 fold with Kd (1.76 ± 0.06) x 10ꢀ5 M. The 1:1 binding stoichiometry was revealed from
the linear fit of (FmaxꢀF0)/(FꢀF0) vs. 1/[Al3+] of the fluorescence titration data which was further substantiated by Job’s method and
HRMS studies. LOD determined by 3σ methods was found to be 4.29 nM and quantum yields determined to be 0.002 and 0.28 for the
ligand and its Al3+ complex, respectively . The tentative coordination environment in the [Al(L3)(H2O)]+ complex was delineated by
DFT calculations. The TDDFT calculations reveal the spectral features comparable to the experimental ones. This constitutes the first
report on the fluorescent sensing of Al3+ and hence Fꢀ in purely aqueous medium.
Introduction
Molecular sensors are highly valuable tools for selective
recognition of chemical and biological species.1 Though, analyte
selective molecular sensors are plenty in the literature the
detection of Al3+ has always been a problematic task due to the
lack of its spectroscopic characteristics and poor coordination
ability.2 Despite of being a nonꢀessential element, the detection
of Al3+ is of great interest due to its potential toxicity arising out
of its widespread application in automobiles, computers,
packaging materials, electrical equipment, machinery food
additives and building construction.3,4 It is well known that 40%
of soil acidity is due to aluminium toxicity.5
Here, we are reporting a highly selective Al3+ probe containing
potential N3O3 donor atoms that binds selectively to Al3+ in
presence of other metal ions. Although few reports on Al3+ ion
sensors are available in the literature most of them are operative
in nonꢀaqueous or mixed aqueous solvents, but not in pure
aqueous medium, except one, which was carried out at pH 7.4 in
tris buffer (Table S1). Towards this end, we are going to
disclose, for the first time, an Al3+ sensor (H2L3) which operates
in purely aqueous medium.
Although quite
chromatography6, accelerator mass spectroscopy (AMS)7,
graphite furnace atomic absorption spectrometry (GFAAS)8
a
number of analytical methods like
,
neutron activation analysis (NAA)9, inductively coupled plasmaꢀ
atomic emission spectrometry (ICPꢀAES)10, inductively coupled
plasmaꢀmass spectrometry (ICPꢀMS)11, laser ablation
microprobe mass analysis (LAMMA)12, electro thermal atomic
absorption spectrometry (ETAAS)13 etc. are available, the
fluorescence chemo sensing is found to be the best choice; as it
is the simplest, sensitive, fast and inexpensive technique14
offering significant advantages over other methods.15 Hence,
recently the design and synthesis of Al3+ selective fluorescent
probes has received intense attention of the chemists.16ꢀ18
Compared to other metal ions, only a few fluorescent chemo
sensors have been reported for the detection of Al3+,19ꢀ25 For
practical applications, it is necessary to develop Al3+ sensors that
are easily prepared and possess selective and sensitive signalling
mechanisms.
aDepartment of Chemistry, Jadavpur University, 188,
Raja Subodh Chandra Mullick Rd, Kolkata, West Bengal
700032,E-mail:m_ali2062@yahoo.com
Scheme 1. Synthesis of targeted probe H2L3.
bDepartment of Molecular & Human Genetics Division ,
CSIR-Indian Institute of Chemical Biology , 4 Raja S.C.
Mallick Road, Kolkata-700032, India.
Results and Discussion
† Electronic supplementary information (ESI) available:
Detailed experimental procedures and additional spectroscopic
data.
see DOI:*******
(Quinolinꢀ8ꢀyloxy)ꢀacetic acid ethyl ester
, Quinolinꢀ8ꢀ
yloxy)ꢀacetic acid hydrazide(L1) and (3ꢀ(3,5ꢀDimethylꢀpyrazolꢀ
1ꢀylmethyl)ꢀ2ꢀhydroxyꢀ5ꢀmethylꢀbenzaldehyde (HL2) were
1

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synthesized as outlined in Scheme 1. The probe (8QꢀNHꢀ
Pyz, H2L3) was then prepared by a simple Schiff base
condensation between L1 and HL2 in MeOH. This ligand
is suitable for Al3+ recognition and characterized by NMR
(Fig. S1, S2, S3, S4), ESIꢀMS+ (Fig.S5) and IR studies
(Fig. S6).
The UVꢀVis spectrum of sensor 8QꢀNHꢀPyz was recorded in 10
mM HEPES buffer at pH 7.2, which displayed wellꢀdefined
bands at 330 nm. On gradual addition of Al3+ there is a decrease
in absorbance at 330 nm along with the development of a new
band at 380 nm (Fig. 1).This indicates a complexation between
8QꢀNHꢀPyz and Al3+. However, no such significant change in
the absorption spectrum of 8QꢀNHꢀPyz was observed with other
tested metal cations.
In the absence of Al3+, 8QꢀNHꢀPyz is very weakly fluorescent
owing to the combined effects of excited state intramolecular
proton transfer (ESIPT) from phenolic –OH to azomethainꢀN
and rotation across the C=N bond (cis/trans isomerization).The
fluorescence enhancement observed for compound 8QꢀNHꢀPyz
in the presence of Al3+ ions was attributed to the chelation
enhanced fluorescence (CHEF) effects arising through
coordination of pyrazoleꢀN, pheoxidoꢀO and amidoꢀO, etherealꢀ
O, quinolineꢀN along with one water molecule; as delineated by
HRMS analysis and DFT calculations (vide infra) . As a result of
metal coordination both ESIPT and rotational isomerisation are
efficiently blocked.
Fig.2 (a) Fluorescence titration of 8QꢀNHꢀPyz (20 ꢁM) in pH
7.2, HEPES buffer by the gradual addition Al3+ with λex = 380
nm, λem = 470 nm. Inset; (b) BenesiꢀHilderbrandplot; (c) UV
exposed image.
A
Kd value of (1.76
± 0.06) x M unambiguously
10ꢀ5
demonstrates moderately strong binding of 8QꢀNHꢀPyz
a
towards Al3+. The 1:1 stoichiometry of Al3+ complex with 8Qꢀ
NHꢀPyz was delineated by Job's Method (Fig. S9) was further
confirmed by ESIꢀMS+ (m/z) mass spectrometry [Al(8QꢀNHꢀ
Pyz)(H2O)]+(m/z = 485.65) (Fig. 3 & S10) while that for [8Qꢀ
NHꢀPyz+ H]+ is 444.2029. Al3+ detection was not perturbed by
biologically abundant Na+, K+, Ca2+ etc. metal ions and several
transition metal ions, namely Cr3+, Mn2+, Fe2+, Fe3+, Co2+, Ni2+,
Cu2+, and heavy metal ions like Cd2+, Pb2+ (Fig. 4). Several
anions also cause no interference (Fig. 5) except Fꢀ.
Fig. 1. Absorption titration of 8QꢀNHꢀPyz (20ꢁM) with Al3+ (0ꢀ200ꢁM)
in pH 7.2, 10 mM HEPES buffer.
The emission spectra of 8QꢀNHꢀPyz and its fluorescence
titration with Al3+ were recorded in 10 mM HEPES buffer at pH
7.2 (Fig. 2). A plot of F.I. vs. [Al3+] gives a nonꢀlinear curve
with decreasing slope at higher concentration of Al3+ (Fig S7) A
BenesiꢀHiderband plot (Eqn 1) of [FmaxꢀFo)/(FꢀFo)] vs. 1/[Al3+]
gives straight line with slope Kd =(1.76 ± 0.06) x 10ꢀ5 M with
complexation. The LOD of Al3+ calculated by using 3σ method
was found to be 4.29 nM. (Fig. S8)
Fig.3. HRMS spectra of (a) 8QꢀNHꢀPyz and (b) Al3+‒8QꢀNHꢀPyz
complex in the positive mode.
2

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Fig. 4(a). Spectral plot of different cations; (b) Bar chart illustrating fluorescence response of 8QꢀNHꢀPyz at 470 nm (λex = 380 nm)
towards different cations in HEPES buffer pH 7.2. Conditions: 8QꢀNHꢀPyz= 20 ꢁM, Mn+ = 80 ꢁM; where,Mn+ = Al3+, Ca2+, Cd2+,
Co2+, Cr3+, Cu2+,Fe3+, K+, Mg2+, Mn2+, Na+, Pb2+, Zn2+, Sm3+,Dy3+,La3+.(c) Bar chart illustrating selectivity of Al3+–8QꢀNHꢀPyz
complex over other cations.
Fig.5. (a) Bar chart illustrating fluorescence response of 8QꢀNHꢀPyz at 470 nm (λex = 380 nm) towards different anions in HEPES
buffer pH 7.2; (b) Spectral plot 8QꢀNHꢀPyz in presenceof different anions and Al3+. 8QꢀNHꢀPyz = 20 ꢁM, Xnꢀ = 80 ꢁM; where,
ꢀ
ꢀ
ꢀ
ꢀ
anions are Clꢀ, Br,ꢀ Iꢀ , Fꢀ, SCNꢀ , NCSꢀ , CNꢀ , PPi , NO3 , NO2 , SO42ꢀ, BrO3 , N3ꢀ , CH3COOꢀ , S2O32ꢀ, S2O42ꢀ, HSO4ꢀ , HSO3ꢀ , AsO2
,
H2AsO4; (c) Bar chart illustrating selectivity of Al3+–8QꢀNHꢀPyz complex towards Fꢀ ion in presence of other anions.
with Al3+ ion through quinolinꢀN atom. The other quinoline
protons are also slightly downꢀfield shifted.
In order to support the binding of Al3+ with the receptor
1
8QꢀNHꢀPyz the H NMR titration was performed in DMSOꢀd6
1
and D2O (Fig. 6 and Table 1). The H NMR spectrum of 8Qꢀ
NHꢀPyzcontains signals for the HC=N (azomethaine, H) (f) at
8.46 ppm and phenolic ꢀOH proton (b) at 11.74(s), The imine
proton(a), quinoline protons (g) and (h) appear at 12.35(s), 8.96
(d) and 8.38(d) ppm, respectively. The other quinoline protons
appear in the region 7.28ꢀ7.62 ppm. The chemical shifts for other
protons appear in the usual positions. Addition of 1 equivalent of
Al(NO3)3·9H2O leads to a slight down field shift of azomethaine
proton (8.46 to 8.49 ppm) while phenolic ꢀOH and imine protons
vanish completely. All these clearly suggest the enol form
[C(=N)(OH)] of C(=O)NH group which on coordination to Al3+
losses the proton along with phenolicꢀOH. The quinoline protons
(g) and (h) are down field shifted to 9.04 and 8.70 ppm
respectively which again supports its participation to bonding
1
Fig.6. Selected portion of HꢀNMR spectra of (A) 8QꢀNHꢀPyz and (B)
Al3+‒8QꢀNHꢀPyz complex.
3

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Table 1.Selected chemical shifts of 8QꢀNHꢀPyz and Al3+‒8Qꢀ
NHꢀPyz complex.
investigated. Experimental results showed that the free 8QꢀNHꢀ
Pyz (10 µM) is very weakly fluorescent in the pH range 2.0ꢀ10.
However, in presence of 18 µM of Al3+ the FI increases steadily
with the increase in pH reaches a maximum at pH ~8.0 then
decreases rapidly with further increase in pH (Fig.9). This
observation clealy indicates the presence of different Al3+
species ([Al(H2O)5(OH)]2+, [Al(H2O)2(OH)2]+ [Al(H2O)3(OH)3]
and [Al(H2O)2(OH)4]ꢀ) and relative amounts changes with the
change in pH. At pH ≥ 8.0 [Al(H2O)3(OH)3] species dominates
and Al3+ comes out of the complex in this form and as a
consequence FI decreases.
Proton No.
8QꢀNHꢀPyz
(ppm)
12.35
8QꢀNHꢀPyz + Al3+
(ppm)
ꢀ
(a)
(b)
(f)
11.72
8.46
ꢀ
8.49
9.04
8.70
8.96
8.38
(g)
(h)
Fꢀ Quenching. The advancement in fluorescent techniques make
it possible to simultaneously monitor fluoride ions, in particular,
sense and visualize it inside the living cells.26 In order to study
the reversible binding of Al3+ to 8QꢀNHꢀPyz a fluorescence
quenching experiment was performed by titrating to 8QꢀNHꢀ
Pyz–Al3+ complex prepared in situ by reacting 20 µM 8QꢀNHꢀ
Pyz and 20 µM Al3+ against [Fꢀ] (0ꢀ20 µM) (Fig 7(a)). A plot
of FI vs. [Fꢀ] gives a nonꢀlinear curve (Fig 7(b))
.
Figure 8. (a) Change in Fluorescence Intensity of 8QꢀNHꢀPyz
(20 ꢁM) upon addition of one equivalent of Al3+ and then 1
equivalent of Fꢀ and regeneration of fluorescence upon further
addition slight excess Al3+. (b) is the corresponding bar plot.
Conditions:HEPES buffer (10 mM) in water at pH 7.2., λex = 380
nm.
Fig. 7 (a) Fluorescence titration spectra of (8QꢀNHꢀPyz +
Al3+complex, 20 µM each) with TBAF (0ꢀ20 ꢁM)in HEPES
buffer pH 7.2. λex = 380 nm. (b) Plot of F.I. vs. [Fꢀ].
The reversibility of a probe is one of the essential requirements
for sensing applications. Therefore, the reversibility of 8QꢀNHꢀ
Pyz was examined by the alternate addition of Al3+ and Fꢀ. As
shown in Fig. 8, on the addition of Al3+ to a solution of 8QꢀNHꢀ
Pyz a remarkable enhancement in emission intensity at 470 nm
was observed. Again, on adding one equivalent of Fꢀ, it
effectively deꢀmetallates Al3+ ion from 8QꢀNHꢀPyz–Al3+
complex leading to the bleaching of emission band at 470 nm.
However, on further addition of Al3+ in slight excess of one
equivalent to the resulting solution 8QꢀNHꢀPyz recovers its
fluorescence up to 90% of its original value. This clearly
establishes the reversible binding of Al3+ towards 8QꢀNHꢀPyz
which is important for the fabrication of devices to sense the
Al3+.
Fig. 9. Fluorescence intensity vs. pH plot at 470 nm 8QꢀNHꢀPyz
10 ꢁM, (detonated by black circles) and 8QꢀNHꢀPyz + Al3+
complex (denoted in blue triangle).
Geometry optimization and electronic structure
pHꢀtitration.
The optimized geometry of 8QꢀNHꢀPyz (H2L3) and its Al3+
complex, [Al(L3)(H2O)]+, is shown in Fig. 10. Both H2L3 and
[Al(L3)(H2O)]+ complex has C1 point group. The nature of all
To study the practical applicability of the probe the effect of pH
on the fluorescence response of 8QꢀNHꢀPyz towards Al3+ was
4

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Fig. 10. Optimized geometry of ligand 8QꢀNHꢀPyz and complex [Al(L3)(H2O)]+.
stationary points for both the free ligand and its Al3+ complex
were confirmed by carrying out normal mode analysis. All the
frequencies turned out to be positive, which proved the global
minima of H2L3 and [Al(L3)(H2O)]+. The composition of the
complex as [[Al(L3)(H2O)]+ is based on HRMS studies which
displayed the presence of one water molecules in the molecular
fragment. The central metal is in octahedral geometry
coordinated through pyrazoleꢀN16, phenoxidoꢀO34, amidoꢀO23,
etherealꢀO17, quinolineꢀN37 along with one water molecule
(O57). The geometry around the central metal atom is distorted
octahedral, the basal plane being occupied by pyrazoleꢀN16,
quinolineꢀN37, pheoxidoꢀO34 and etherealꢀO17 while the axial
positions are occupied by amidoꢀO23 and waterꢀO57.
with HOMO − LUMO energy gap of 2.524 eV. These
compositions are useful in understanding the nature of transition
as well as the absorption spectra of both the ligand and complex.
It is important to note that the azomethaineꢀN did not
coordinate to metal center while the quinolineꢀN and etherealꢀO
coordinate to the metal centre probably to relive some steric
strain imposed by the bulky 8ꢀhydroxyquinoline moiety and
methyl groups present in 3,5ꢀdimethyl pyrazole rings. Some
important optimized geometrical parameters of the free ligand
and complex are listed in Table S2 and Table S3.
Fig. 11. Frontier molecular orbital of ligand 8QꢀNHꢀPyz (H2L3)
and complex [Al(L3)(H2O)]+.
In case of 8QꢀNHꢀPyz in the ground state, the electron density
resides mainly on HOMO˗2, HOMO˗3, HOMO˗4 and LUMO+4
molecular orbitals of the pyrazole moiety as well as 2ꢀhydroxyꢀ
5ꢀmethylꢀbenzaldehyde fragment of the ligand; while for
The ligand 8QꢀNHꢀPyz shows three absorption bands at 336,
300, and 288 nm in aqueous medium at room temperature. These
three bands are assigned to S0→ S1, S0→ S4 and S0→ S8
electronic transitions, respectively (Fig. S11). The absorption
energies along with their oscillator strengths are given in Table
S4. The complex [Al(L3)(H2O)]+ shows two absorption bands at
385 and 337 nm (Fig. S12) in water at room temperature and the
corresponding calculated absorption bands are located at 382.26,
and 335.16 nm which are in excellent agreement with our
experimental results (Table S5). These two absorption bands can
be assigned to the S0→S2, and S0→S3 transitions, respectively
(Table S5).
HOMO and LUMO molecular orbitals
a
considerable
contribution comes only from 2ꢀhydroxyꢀ5ꢀmethylꢀ
benzaldehyde moiety. Again, in case of HOMOꢀ1 and LUMO+1
molecular orbitals the electronic contributions come from the
quinoline moiety. The energy gap between HOMO and LUMO
is 4.09 eV (Fig. 11). In case of [Al(L3)(H2O)]+complex HOMOꢀ
2 and HOMOꢀ1 molecular orbitals carries most of the electron
density in the 2ꢀhydroxyꢀ5ꢀmethylꢀbenzaldehyde moiety while
in LUMO orbital electron resides mainly on quinoline moiety
5

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Fig. 12. The phase contrast and fluorescence images of HepG2 cells were captured after incubation with 8QꢀNHꢀPyz, (8QꢀNHꢀPyz
+Al3+) and (8QꢀNHꢀPyz +Al3+ + Fꢀ) for 30 min at 37°C.
with 10 µM 8QꢀNHꢀPyz +20 µM Al3+ for 30 min followed by
Cell imaging studies
addition of 5, 10 and 20 µM Fꢀ for another 30 min and
fluorescence images were taken. In this case, HepG2 cells
showed almost complete quenching of fluorescence in presence
of 20 µM Fꢀ due to removal of Al3+ from the 8QꢀNHꢀPyz–Al3+
complex by Fꢀ ions which manifests a reversible binding of 8Qꢀ
NHꢀPyz towards Al3+, satisfying one of the crucial requirements
for in vivo monitoring of a chemical species.
Taking into consideration the excellent sensing performance of
8QꢀNHꢀPyz towards Al3+, we decided to utilize 8QꢀNHꢀPyz for
the fluorescence imaging of Al3+ into the living HepG2 cell. For
this purpose we have determined the cytotoxic effect of 8QꢀNHꢀ
Pyz on HepG2 cells, which was found not to affect the cell
viability as confirmed by MTT assay (Fig. S13). More than 80%
cell viability was observed for 8QꢀNHꢀPyz at 10 µm after which
the viability of HepG2 cells decreases slightly (viability curve).
Hence further experiments were carried out with 10 µm of 8Qꢀ
NHꢀPyz.
Moreover, we find out logic gate operation; namely INHIBIT
logic gate which involves a particular combination of logic
functions AND and NOT. For our system we correlate it by
taking two input signals namely Input A (Al3+) and input B (Fꢀ)
along with fluorescence signal of the ligand 8QꢀNHꢀPyz at 470
nm as output. For input, the presence and absence of Al3+ and Fꢀ
are assigned as 1(onꢀstate) and 0 (offꢀstate) respectively. For
output, we assign the enhanced fluorescence of 8QꢀNHꢀPyz
(H2L3) as 1 (onꢀstate) and the quenched fluorescence as 0 (offꢀ
state) (Fig. 13 b, truth table). In the absence of both inputs (Al3+
or Fꢀ) 8QꢀNHꢀPyz remains in offꢀstate form. Now, input A leads
to significant fluorescence enhancement with interaction with
free receptor in its occupied state leading to onꢀstate.
The intracellular imaging behaviours of 8QꢀNHꢀPyz on HepG2
cells with the aid of fluorescence microscopy displayed no
visible intracellular fluorescence when treated with 10 µM 8Qꢀ
NHꢀPyz (Fig. 12). Fluorescence images of HepG2 cells were
taken separately for another three sets of experiments where
cells were incubated with 10 µM 8QꢀNHꢀPyz and 10, 20 and 40
µM Al3+ for 30 min where bright fluorescence was observed.
Similarly, in another sets of experiments, cells were incubated
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Fig. 13 (a) Output signals (at 470 nm) of the logic gate in presence of different inputs; (b) corresponding truth table of the logic gate;
(c) general representation of the symbol of an INHIBIT gate.
Conclusion
Physical Measurements
In summary, we have synthesized a potential hexaꢀcoordinating
The Fourier Transform Infrared Spectra (4000 – 400 cmꢀ1) of the
(N3O3) probe 8QꢀNHꢀPyz for selective recognition of Al3+, in
presence of large number of background metal ions in purely
aqueous medium at pH 7.2 (HEPES buffer), which was found to
undergo 1:1 complexation. The probe itself is very weakly
fluorescent due to combined PET effect arising out of the transfer
of proton from phenolicꢀOH to azomethaineꢀN in the excited
state and rotational isomerisation across the C=N double bond of
the azomethaine group. It becomes fluorescent only in presence
of Al3+ which causes PET as well as cisꢀtrans isomerisation
ligands were recorded on
a PerkinꢀElmer RX I FTꢀIR
spectrophotometer with solid KBr disc. Electronic spectra were
recorded on an Agilent 8453 Diodeꢀarray UVꢀvis
spectrophotometer using HPLC grade H2O as solvent with 1 cm
quartz cuvette in the range 200ꢀ900 nm. Fluorescence studies
were performed in PTI (Model QMꢀ40) spectrofluorimeter, 1H
NMR spectrum were recorded on a Bruker 300 MHz spectrometer
using trimethylsilane as an internal standard in DMSO (d6) and
D2O. ESIꢀMS+ (m/z) of the amine, ligand (8QꢀNHꢀPyz (H2L3)
blocking through selective coordination to the Al3+
. The
and complex [Al(L3)(H2O)]+ were recorded on
a HRMS
complexation of 8QꢀNHꢀPyz to Al3+ was confirmed by 1H NMR
and ESIꢀMS+ studies and further strengthened by DFT
calculations on both the free ligand and its Al3+ complex. The
Fluorescence titration helps us to delineate Kd = 1.76 x 10ꢀ5 M.
The reversible binding of Al3+ to 8QꢀNHꢀPyz was confirmed by
reacting with excess Fꢀ both in extraꢀ and intracellular conditions.
spectrometer (Model: QTOF Micro YA263).
Solution preparation for UVꢀVis absorption and fluorescence
studies
For both UVꢀVis and fluorescence titrations, stock solution of 1.0
x 10ꢀ3 M of the probe 8QꢀNHꢀPyz was prepared in CH3CNꢀ
MeOH. Similarly, another 1.0 x 10ꢀ3 M stock solution of
Al(NO3)3.9H2O and 1.0 x 10ꢀ3 M stock solution of tetrabutyl
ammonium fluoride (TBAF) in water were prepared. Other metal
ions as well as anions were prepared in MeOH– H2O. A solution
of 10.0 mM HEPES buffer was prepared and pH was adjusted to
7.20 by using HCl and NaOH. Ionic strength of the buffer was
maintained at 50 mM (NaCl) throughout the measurements. 2.5
ml of this buffered solution was pipetted out into a cuvette to
which was added 20 ꢁM of the probe and metal ions were added
incrementally starting from 0 to 36 ꢁM in a regular interval of
volume and UVꢀVis and fluorescence spectra were recorded for
each solution.
Experimental
Materials and Methods.
The 8ꢀHydroxyquinoline, ethyl chloroacetate (Sigma Aldrich),
hydrazine hydrate (Sigma Aldrich), absolute ethanol and salts of
Al3+, Ca2+, Cd2+, Co2+, Cr3+, Cu2+, Fe3+, K+, Mg2+, Mn2+, Na+,
Ni2+, Pb2+, Zn2+ ,Sm3+ ,Dy3+ and La3+ were obtained from
commercial suppliers and used without further purification.
Solvents like MeOH, MeCN etc (Merck, India) were of reagent
grade.
7

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Syntheses
Computational details
Preparation of (Quinolinꢀ8ꢀyloxy)ꢀacetic acid hydrazide (L1).
Ground state electronic structure calculations in methanol solution
of both the ligand and complex have been carried out using DFT
method28 associated with the conductorꢀlike polarizable
continuum model (CPCM).29 Becke’s hybrid function30 with the
LeeꢀYangꢀParr (LYP) correlation function31 were used throughout
the study. The geometry of the ligand and complex were fully
optimized without any symmetry constraints. The nature of all
stationary points for both the free ligand and its Al3+ complex
were confirmed by carrying out normal mode analysis. On the
basis of the optimized ground state geometry, the absorption
spectral properties 8QꢀNHꢀPyz and complex [Al(L3)(H2O)]+ in
water were calculated by timeꢀdependent density functional
theory (TDDFT)32 associated with the conductorꢀlike polarizable
continuum model (CPCM).29 We have computed the lowest 40
singlet– singlet transitions and the presence of electronic
correlation in the TDDFT (B3LYP) method33 enables to get
accurate electronic excitation energies. For H atoms we used 6ꢀ
31G basis set; for C, N, O and Al atoms we employed 6ꢀ31+G(d)
basis sets for the optimization of the ground state. The calculated
electron density plots for frontier molecular orbitals were
prepared by using Gauss View 5.1 software. All the calculations
were performed with the Gaussian 09W software package.34
Gauss Sum 2.1 program35 was used to calculate the molecular
orbital contributions from groups or atoms.
(a) (Quinolinꢀ8ꢀyloxy)ꢀacetic acid hydrazide was synthised by the
reported method with slight modification.27 In a typical procedure,
a mixture of 8ꢀhydroxyquinoline (0.05 mole), ethyl chloroacetate
(0.05 mole) and anhydrous K2CO3 (0.05 mole) in dry acetone was
refluxed on a water bath for 18 h. The mixture was then filtered
and solvent was removed under reduced pressure. The resulting
solid was purified by column chromatography on silica gel, using
petroleum ether: ethyl acetate (3:1) as the eluant to afford 2 (85%
yield) as yellow oil.
The reulting (Quinolinꢀ8ꢀyloxy)ꢀacetic acid ethyl ester (0.05
mole) and hydrazine hydrate (0.10 mole) in ethanol were refluxed
on a water bath for 5 h. After cooling, the solid that separated out
was filtered and washed with water, dried and recrystallized from
ethanol. Needle shaped crystals were obtained. Yield 75 % (L1):
1H NMR (300 MHz DMSO):4.41(s, 2H, ꢀNH2), 4.75 (s, 2H, ꢀ
CH2), 7.25 (d, 1H), 7.50 ꢀ 7.61(m, 3H, –ArH),8.38 (d,1H,–ArH),
8.92 (d,1H, –ArH), 9.46 (s, 1H, ꢀNH) (Fig. S1).
Preparation
of
(3ꢀ(3,5ꢀDimethylꢀpyrazolꢀ1ꢀylmethyl)ꢀ2ꢀ
hydroxyꢀ5ꢀmethylꢀbenzaldehyde. (HL2)
2ꢀChloromethylꢀ6ꢀcarbaldehydeꢀ4ꢀmethylphenol (1.515 g, 8.2
mmol) was dissolved in 15 ml dry THF in a round bottom flask.
3,5ꢀDimethylpyrazole (0.788 g, 8.2 mmol) and triethylamine
(Et3N) (1.659 g, 16.4 mmol) were dissolved in 10 ml dry THF and
this mixture was added dropwise to the 2ꢀchloromethylꢀ6ꢀ
carbaldehydeꢀ4ꢀmethylphenol solution. A rapid precipitation of
Et3N•HCl was observed and the colour of the solution turned to
bright yellow (Scheme 1). After 24 hours of stirring, the
precipitate was filtered off and subsequently the solvent (THF)
was removed under reduced pressure to afford an oily product that
yielded a yellow crystalline solid after 2 days at 4 °C. The solid
product was then filtered and washed with cold ether. Yield 72%.
1 H NMR (in DMSOꢀd6): δ in ppm 2.23–2.28 (9 H, m, –ArCH3),
5.27 (2H, s, –CH2), 7.09 (1H, s, –ArH), 7.27 (1H, s, –ArH), 7.28
(1H, s, –ArH), 9.88 (1H, s, –CHO), 11.23 (1H, brs, –ArOH) (Fig.
S2).
Cell culture
Human hepatocellular liver carcinoma cells, HepG2 cell lines,
were procured from National Center for Cell Science, Pune, India,
and used throughout the study. Cells were cultured in DMEM
(Gibco BRL) supplemented with 10% FBS (Gibco BRL), and a
1% antibiotic mixture containing Penicillin, Streptomycin and
Gentamicin (Gibco BRL) at 37°C in a humidified incubator with
5% CO2 and cells were grown to 60ꢀ80% confluence, harvested
with 0.025% trypsin (Gibco BRL) and 0.52 mMH2EDTA2ꢀ (Gibco
BRL) in phosphateꢀbuffered saline (PBS), plated at the desired
cell concentration and allowed to reꢀequilibrate for 24 h before
any treatment.
Preparation of (Quinolinꢀ8ꢀyloxy)ꢀacetic acid [3ꢀ(3,5ꢀ
dimethylꢀpyrazolꢀ1ꢀylmethyl)ꢀ2ꢀhydroxyꢀ5ꢀmethylꢀ
benzylidene]ꢀhydrazide.8QꢀNHꢀPyz (H2L3)
Cell Cytotoxicity Assay
To test the cytotoxicity of 8QꢀNHꢀPyz assay was performed as
per the procedure described earlier.36
L1 (0.434 g, 2 mmol) was dissolved in 25 mL MeOH. To this
solution was added HL2 (0.488 g, 2 mmol) drop wise and
refluxed for 2h and then the reaction mixture was filtered out and
evaporated to dryness in rotaꢀevaporator. White solid of H2L3
obtained was purified by recrystallization from ethanol. (yield,
78.34%). : 1HꢀNMR (in DMSOꢀd6) (δ, ppm): 2.08ꢀ2.16(s,9H,),
4.95(s,2H,ꢀCH2), 5.09(s,2H,ꢀCH2),5.83 (s,1H), 6.62 (s, 1H, ꢀ
ArH), 7.20 (s,1H, ꢀArH), 7.30 (d,1H,ꢀArH), 7.50 ꢀ 7.62 (m,3H, ꢀ
ArH), 8.38 (d,1H,ꢀArH) , 8.46 ( s, 1H, azomethaine), 8.96 (d,1H,ꢀ
ArH), 11.74 (s,1H,ꢀOH) and 12.35 (s,1H,ꢀNH).(Fig. S3). ESIꢀ
MS+ (m/z): 444.20 (8QꢀNHꢀPyz (H2L3) +H+) (Fig. S5).
After treatment with 8QꢀNHꢀPyz at different doses of 1, 10, 20,
40, 60, 80 and 100 ꢁM, respectively, for 12 h, 10 ꢁl of MTT
solution (10 mg/ml PBS) was added to each well of a 96ꢀwell
culture plate and again incubated continuously at 37ºC for a
period of 3 h. All the media were removed from wells and 100 ꢁl
acidic isopropyl alcohol was added into each well. The
intracellular formazan crystals (blueꢀviolet) formed were
solubilized with 0.04 N acidic isopropyl alcohol and absorbance
of the solution was measured at 595 nm with a microplate reader
(Model: THERMO MULTI SCAN EX). The cell viability was
expressed as the optical density ratio of the treatment to control.
Values were expressed as mean ± standard errors of three
8

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independent experiments. The cell cytotoxicity was calculated as
% cell cytotoxicity = 100% ꢀ % cell viability (Fig. S12).
5
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HepG2 Cells were incubated with 10 ꢁM 8QꢀNHꢀPyz (the
stock solution 1 mM was prepared by dissolving 8QꢀNHꢀPyz to
the mixed solvent (DMSO: water = 1:9 (v/v)) in the culture
medium, allowed to incubate for 30 min at 37 °C. After
incubation, cells were washed twice with phosphateꢀbuffered
saline (PBS). Bright field and fluorescence images of HepG2 cells
were taken by a fluorescence microscope (Leica DM3000,
Germany) with an objective lens of 40X magnification.
Fluorescence images of HepG2 cells were taken separately from
another set of experiment where cells incubated separately with
10µM 8QꢀNHꢀPyz and 10, 20 and 40 µM Al3+ for 30 min.
Similarly, in another set of experiment, cells were incubated with
10 µM 8QꢀNHꢀPyz + 20 µM Al3+ in three sets and then 5, 10 and
20 µM of Fꢀ were added separately for 30 min and fluorescence
images were taken. HepG2 cells showed almost complete
quenching of fluorescence due to removal of Al3+ from the
complex.
7
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Acknowledgement
Financial support from DST (Ref. SR/S1/ICꢀ20/2012) New Delhi
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10

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DOI: 10.1039/C5NJ03153B
A novel 8-hydroxyquinoline—pyazole based highly sensitive and
selective Al(III) sensor in purely aqueous medium with intracellular
application: experimental and computational studies.
Abu Saleh Musha Islama, Rahul Bhowmicka, Hasan Mohammada, Atul Katarkarb, Keya Chaudhurib and
Mahammad Ali* a
A new 8-hydroxyquinolin-pyrazole based probe senses Al3+ and hence Al3+—8Q-NH-Pyz complex
mediated F- in purely aqueous medium.