Indeno-furan based colorimetric and on-off fluorescent pH sensors

Article abstract of DOI:10.1016/j.jphotochem.2015.04.001

In this study, pH on-off fluorescent chemosensors based on indeno-furan derivatives have been designed, synthesized and characterized. The designed sensors were based on the change in structure of phenazine/ quinoxaline unit and keeping indeno-furan as common unit. These compounds exhibit pH dependent on/off fluorescence and thus act as fluorescent pH sensors. The change in fluorescence of 3a and 3b is reversible within the wide pH range of 2-11. The color change of these sensors could also be detected by naked eyes thus making them promising candidates as colorimetric pH indicators also.

Full text of DOI:10.1016/j.jphotochem.2015.04.001

Accepted Manuscript
Title: Indeno-furan based colorimetric and on-off fluorescent
pH sensors
Author: Komal Aggarwal Jitender M. Khurana
PII:
S1010-6030(15)00114-8
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jphotochem.2015.04.001
JPC 9864
To appear in:
Journal of Photochemistry and Photobiology A: Chemistry
Received date:
Revised date:
Accepted date:
14-1-2015
20-3-2015
1-4-2015
Please cite this article as: Komal Aggarwal, Jitender M.Khurana, Indeno-furan
based colorimetric and on-off fluorescent pH sensors, Journal of Photochemistry and
Photobiology A: Chemistry http://dx.doi.org/10.1016/j.jphotochem.2015.04.001
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Indeno-furan based colorimetric and on-off fluorescent pH sensors
Komal Aggarwal and Jitender M. Khurana*
Department of Chemistry, University of Delhi, Delhi-110007, India
*Corresponding author. Tel.: +91 11 2766772; fax: +91 1 27667624
E-mail addresses: jmkhurana1@yahoo.co.in; jmkhurana@chemistry.du.ac.in
Graphical Abstract
Highlights
 Two novel indeno-furan derivatives have been synthesized.

pH dependent absorption and emission properties of these sensors were investigated.
 Both the sensors 3a and 3b showed visible color change also.
Abstract
In this study, pH on-off fluorescent chemosensors based on indeno-furan derivatives have
been designed, synthesized and characterized. The designed sensors were based on the
change in structure of phenazine/ quinoxaline unit and keeping indeno-furan as common unit.
These compounds exhibit pH dependent on/off fluorescence and thus act as fluorescent pH
sensors. The change in fluorescence of 3a-3b is reversible within the wide pH range of 2 to
11. The color change of these sensors could also be detected by naked eyes thus making them
promising candidates as colorimetric pH indicators also.
Keywords: Indeno-furan, colorimetric, fluorescence, pH sensor
1

1. Introduction
The design, synthesis and study of new fluorescence-based pH sensors have attracted our
attention because of their potential applications as transducers in enzymatic biosensors for the
determination of glucose [1,2], creatinine [2], urea [2,3], penicillin [2,4-5], acetylcholine [6],
organophosphorous pesticides [7] and halogenated hydrocarbons [8]. The determination and
control of pH has wide range of applications in environmental monitoring [9,10], bio-
processing [11] and biomedical diagnostics [12]. The pH is generally measured by glass
electrodes and photometrically. The measurement of physiological pH using fluorescence
technique is advantageous over other detection techniques due to its high sensitivity,
specificity, high signal-to-noise ratio and minimal damage to living samples. Another
advantage of fluorescent pH sensors over the pH electrodes are their wide pH scales. Also,
pH-sensitive (halochromic) materials are of recent interest because they show color change by
varying pH. The basis of colour change is protonation or deprotonation of the dye molecule
causing a different electron configuration and thus, a different colour [13].
Recently, novel organic dyes based on anthracene derivatives [14], benzoxazole,
benzothiazole [15], coumarin [16], fluorescein [17], rhodamine B [18], BODIPY [19],
hydroxyazobenzene [20], chromenoquinoline [21], pteridine [22], naphthalene diimides [23]
and optical chemical sensors [24] have been investigated as fluorescent pH sensors. Most
commonly available fluorescent pH sensors are suitable for pH from 4 to 9. They are
promising materials for determining neutral pH values of normal body fluids [25]. However
there are only a few optical pH sensors for use at high or low pH [26-27]. And therefore the
focus is on developing pH sensors available in different pH ranges.
Indenone derivatives act as key precursors and the intermediates in the synthesis of bioactive
natural products [28] and pharmaceuticals [29]. They have also been used as fluorescent
binding agents of estrogen receptor [30], peroxisome proliferator-activated receptor [31],
selective inhibitors of cyclooxygenase-2 (COX-2) [32] and topoisomerase I inhibitors [33].
Moreover, furan derivatives serve as the building blocks in synthetic chemistry and have been
found in many naturally occurring compounds [34, 35]. Furan fused compounds connected
through vinylic linkages are widely studied due to their electronic properties [36,37] and as
starting materials for photochemical reactions [38-40]. Furthermore, π-conjugated organic
systems are highly versatile materials for the development of efficient electronic devices [41].
Therefore, combination of the novel properties of indenone and furan derivatives with the π-
conjugated organic systems offers a novel area of research. We focused on investigating such
2

novel organic systems which can be employed as pH sensors. To our best knowledge,
reversible colorimetric and fluorescent probes are very rare. It is still a challenge to design
such chemosensors for biological applications.
2. Experimental
2.1. Materials
All the starting materials were of GR quality of Merck and all solvents used were of HPLC
grade. Melting points were determined on a Tropical Lab equip apparatus and are
uncorrected. IR (KBr) spectra were recorded on Perkin-Elmer FTIR spectrophotometer and
the values are expressed as νmax cm-1. Mass spectral data were recorded on Agilent 6520 Q-
Tof (ESI-HRMS) Mass Spectrometer. The 1H NMR and 13C NMR spectra were recorded on
Jeol JNM ECX-400P at 400 MHz and 100 MHz, respectively using TMS as an internal
standard. The chemical shift values are recorded on δ scale and the coupling constants (J) are
in Hertz. UV-vis absorption spectra were recorded on an Analytikjena Specord 250
spectrophotometer. Fluorescence spectra were measured at Cary Eclipse fluorescence
spectrophotometer. All spectroscopic measurements were done at room temperature. The
photophysical properties of all the compounds (3a-b) were recorded in dilute concentrations
(1 × 10-5 M) in 90% MeOH. The pH of each solution was determined using a thermoelectrod
pH meter (Innova Lab Thermoelectron Corporation). To obtain the proper fluorescence
intensity values, fluorescence data has already been corrected for the inner filter effect caused
by reduction of the excitation beam and emission signal because of absorption by quencher
and fluorophore [42].
Single crystals suitable for X-ray diffraction were grown by evaporation of dimethyl
sulfoxide solution of compound 3b at room temperature. X-ray intensity data were collected
on an Oxford Diffraction Xcalibur CCD diffractometer with graphite monochromated Mo Kα
radiation (λ = 0.71073Å) at 298 K. The data was collected at 293 K and the structures were
resolved by direct methods and refined by full-matrix least-squares on F2 (SHELXL-97)
[43]. All calculations were carried out using the WinGX package of the crystallographic
programs [44]. CCDC 1042887 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data
request/cif or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 (0)1223
3

336 33; email: deposit@ccdc.cam.ac.uk. Crystallographic data collection and experimental
details are summarized in Table 1.
The fluorescence quantum yield (Φf) of 3a-3b were measured at different pH relative to
quinine sulfate in 0.5M H2SO4 (Φf = 0.546) as secondary standard and was calculated on the
basis of the equation (1) [45], where n0 and n are the refractive indices of the solvents, A0 and
A are the absorbances, Φfo and Φf are the fluorescence quantum yields and the integrals
denote the area of the fluorescence band for the standard and the sample, respectively.
Φf = Φfo [n2 Ao ʃ If (λf )dλf / n2 A ʃ Ifo(λf )dλf]
(1)
o
2.2. General procedure for the synthesis of 2a-2b [46]
A mixture of 2-hydroxynaphthalene-1,4-dione (1.0 mmol), o-phenylenediamine/ 2,3-
diaminomaleonitrile (1.0 mmol), and 5 mL of glacial acetic acid was placed in a 50 mL
round-bottomed flask and the contents were stirred magnetically in an oil-bath maintained at
70°C until an orange/ green solid was formed. The progress of a reaction was monitored by
TLC using ethyl acetate: petroleum ether (40: 60) as eluent for disappearance of o-phenylene
diamine/ 2,3-diaminomaleonitrile. After completion of the reaction, the reaction mixture was
allowed to cool to room temperature and 5 mL of ethanol: water (10:90) was added. The
material was stirred and the solid so obtained was filtered at pump, washed with water and
characterized.
2.3. General procedure for the synthesis of indeno-furan derivatives (3a-3b)
Ninhydrin (1mmol), benzo[a]phenazin-5-ol/ 6-hydroxybenzo[f]quinoxaline-2,3-dicarbonitrile
(1 mmol) and 5 mL of glacial acetic acid were taken in a 50 mL round bottomed flask. The
reaction mixture was heated in an oil-bath maintained at 100°C and the progress of the
reaction was monitored by TLC using ethyl acetate: petroleum ether (40: 60) as eluent for
disappearance of ninhydrin. After completion of the reaction, the reaction mixture was
allowed to cool to room temperature and 5 mL of ethanol: water (10:90) was added dropwise
with stirring. The solid product obtained was filtered at pump and washed with water. The
products were identified by their spectral data.
3.4. Spectral data
2.4.1. 10a,15a-Dihydroxy-10aH-benzo[a]indeno[2',1':4,5]furo[2,3-c]phenazin-15(15aH)-
one (3a)
Yellow solid, Yield: 94%, M.p. 172-174°C; 1H NMR (400 MHz, DMSO-d6) δ: 6.79 (s, 1H, -
OH), 7.59 (t, 1H, J = 7.3 Hz, Ar-H), 7.71 (d, 1H, J = 7.3 Hz, Ar-H), 7.86- 7.91 (m, 3H, Ar-
4

H), 7.93-7.98 (m, 1H, Ar-H), 8.09 (d, 1H, J = 7.9 Hz, Ar-H), 8.13-8.15 (m, 2H, Ar-H), 8.26
13
(d, 2H, J = 08.6 Hz, Ar-H), 8.59 (s, 1H, -OH), 9.13 (bs, 1H, Ar-H); C NMR (100 MHz,
DMSO-d6) δ: 196.88, 172.10, 156.56, 147.23, 142.08, 141.76, 139.76, 139.19, 136.34,
131.91, 131.39, 130.65, 130.52, 129.95, 129.38, 129.22, 128.72, 125.51, 125.14, 123.38
123.02, 122.70, 112.42, 111.67, 85.03; IR (KBr, cm-1) νmax = 3324, 3070, 2960, 1706, 1595,
1425, 1249, 885, 762; HRMS (ESI) m/z [M+ + H] calculated for C25H15N2O4 407.1032,
found 407.1026.
2.4.2. 9a,14a-Dihydroxy-14-oxo-14,14a-dihydro-9aH-benzo[f]indeno[2',1':4,5]furo[2,3-
h]quinoxaline-2,3-dicarbonitrile (3b)
Green solid, Yield: 92%, M.p. 263-264°C; 1H NMR (400 MHz, DMSO-d6) δ: 7.66 (bs, 1H, -
OH), 7.75 (bs, 1H, -OH), 7.92-8.00 (m, 4H, Ar-H), 8.11 (s, 1H, Ar-H), 8.21 (d, 1H, J = 6.9
13
Hz, Ar-H), 8.96 (d, 2H, J = 6.4 Hz, Ar-H); C NMR (100 MHz, DMSO-d6) δ: 196.21,
172.12, 159.48, 141.28, 138.33, 136.80, 132.31, 131.71, 131.29, 130.21, 125.96, 125.32,
123.30, 123.08, 115.13, 114.88, 113.71, 111.95, 84.04; IR (KBr, cm-1) νmax = 3285, 3096,
2956, 1702, 1589, 1411, 1255, 862, 774; HRMS (ESI) m/z [M+] calculated for C23H10N4O4
406.0702, found 406.0361.
3. Results and discussion
3.1. Synthesis
We report the design and synthesis of novel indeno-furan derivatives 3a and 3b in this paper as
shown in Scheme 1. The synthesis of both the compounds was achieved firstly we synthesize
benzo[a]phenazine-5-ol (2a) and 6-hydroxy benzo[f]quinoxaline-2,3-dicarbonitrile (2b) via
condensation of 2-hydroxynaphthalene-1,4-dione and o-phenylenediamine (1a)/
diaminomaleonitrile (1b) in glacial acetic acid at 70oC. Then, the reaction of ninhydrin with
benzo[a]phenazine-5-ol/ 6-hydroxy benzo[f]quinoxaline-2,3-dicarbonitrile catalyzed by glacial
acetic acid at 100oC led to the formation of desired compounds 3a and 3b in good yields.
NH2
NH2
NC
NC
NH2
NH2
O
O
OH
OH
NC
NC
N
N
1b
1a
N
N
AcOH, 70oC
AcOH, 70oC
24 h
HO
30 min
2a
2b
5

O
O
O
OH
HO
OH
HO
O
2b
NC
NC
N
2a
O
N
O
AcOH, 100oC
AcOH, 100oC
N
O
N
3b
3a
Scheme 1: Synthesis of indeno-furan derivatives (3a and 3b)
The structures of both the compounds have been assigned based on spectral data. It can be
inferred from the structures that both the compounds have the indeno-furan unit as the common
feature. The side chain on the furan ring varies from phenazine unit in 3a to quinoxaline unit in
3b.
Fig. SI1 shows the 1H NMR spectra of compound 3a in presence and absence of D2O. 1H NMR
study revealed the presence of two hydroxyl groups. In 1H NMR spectrum of 3a, two singlets
appeared at δ 8.59 and 6.79 corresponding to two –OH protons. These two –OH protons are
exchangeable with D2O indicating the presence of two –OH groups (Fig. SI1(b)).
However, the final confirmation of the structure of 9a,14a-Dihydroxy-14-oxo-14,14a-
dihydro-9aH-benzo[f]indeno[2',1':4,5]furo[2,3-h]quinoxaline-2,3-dicarbonitrile (3b) has been
achieved by X-ray crystallography (Fig. 1). The molecular structure of 3b shows that the
fused indeno-furan system is deviated from planarity and forms gable-shaped structure with
an angle of 67.57° between the indenone and furan planes (Fig. 1). Both the compounds were
then investigated for their application as pH sensors.
6

Fig. 1: X-ray crystal structure (ORTEP diagram) of 3b
3.2. Effect of pH on photophysical properties of compounds 3a and 3b
The UV-vis absorption and emission spectra of compounds (3a-3b) were measured at pH range
from 2 to 11. UV-vis absorption and emission spectra are shown in Figs. 2-3, and the data is
listed in Table SI1.
It can be inferred from the above data that the indeno-furan derivative fused with phenazine
moiety showed two absorption bands at 231 nm and 274 nm in short wavelength region and a
very weak band at 413 nm in long wavelength region at pH 2. It was also observed that band at
274 nm showed splitting in acidic medium but with increase in pH from 2 to 11, this splitting
disappeared and rest of the band remained unaffected indicating that the ground state is not
affected by varying pH from 2 to 11 as shown in Fig. 2(a). Varying pH also gave rise to two
isosbestic points at 347 nm and 441 nm, revealing the existence of equilibrium between keto
and enol form within the pH range of 2-11.
7

Fig. 2: (a) Absorption spectra of compound 3a and (b) Fluorescence spectra of compound 3a
(λexc = 270 nm) at pH 2 to 11 in 90% methanol.
It was observed from Fig. 2(b) that the fluorescence emission of 3a is turned on at low pH
values with dual emission and turned off at high pH values. This c ould be attributed to
ionization and deionization under acidic and basic conditions, respectively. The plausible
mechanism for the quenching of fluorescence during excitation in basic media could be due to
deprotonation of one of the OH group which results in the photoinduced electro transfer (PET)
[47] in a molecule.
However, fluorescence enhancement under acidic conditions of 3a may be associated with
deactivation of the nitrogen lone pairs from the phenazine ring due to the formation of the
quaternary nitrogen upon protonation which elicits the possibility of PET process from furan
moiety to the phenazine group (Scheme 2).
O
O
O
OH
O
HO
HO
H
OH
HO
O
O
OH
H
OH
H
N
N
O
N
N
N
N
3a
Weak fluorescent
Strong Fluorescent
Scheme 2: Proposed mechanism for fluorescence change of compound 3a induced by pH
change.
UV-vis study of compound 3b having quinoxaline substituent showed three absorption bands at
248 nm, 282 nm and 408 nm (Fig. 3(a)). When pH was increased from 2 to 4, absorption bands
showed blue shift and appeared at 229 nm, 251 nm and 402 nm, respectively. Further increase
in pH from 4 to 11, resulted in slight red shift of absorption bands at 229 nm and 251 nm to 253
8

nm and 269 nm, respectively. Disappearance of absorbance band at 402 nm was also observed
at pH > 9, resulting in slight colour change from low to high pH (from pH 4 to 11).
Fig. 3: (a) Absorption spectra of compound 3b and (b) Fluorescence spectra of compound 3b
(λexc = 260 nm) at pH 2 to 11 in 90% methanol.
The fluorescence behavior of compound 3b is shown in Fig. 3(b) and data listed in Table SI1.
The fluorescence of 3b is found to be strong at low pH with dual emission bands at 411 nm and
490 nm. The emission band at ~490 nm disappeared completely at high pH values resulting in a
single emission band at ~415 nm. This red-shift in the emission spectra with the decrease of pH
can be explained due to the protonation of the quinoxaline moiety in the compound 3b, which
elicited a strong PET process from furan moiety to the quinoxaline group like in compound 3a.
The ratios of fluorescence intensities of 3a at 478 nm and 385 nm and for 3b at 494 nm and 409
nm showed a small change in the emission ratios from 1 at pH 2 to 8.5 at pH 11 for 3a and
from 0.3 at pH 2 to 3.6 at pH 11 for 3b (Fig. 4).
Fig. 4: Sigmoidal correlation of the ratios of fluorescence intensity vs pH for 3a and 3b.
9

The plot of emission based intensity vs pH exhibited ‘‘S” shaped graph for compounds 3a-3b
(Fig. 4) and its quantitative relationship can be described by the equilibrium function [48] as:
pH - pKa = log (IFmax – IF)/ (IF – IFmin
)
Compounds 3a and 3b showed pKa values of 4.99 and 4.69, respectively. These pKa values
almost match the typical pH values of acidic organelles (pH 4-6) [17(b)], suggesting that both
the compounds could be suitable for monitoring pH variations in the acidic environments.
Furthermore, both the compounds 3a and 3b also showed reversible colorimetric changes.
Compound 3a shows a color change from orange to yellow when pH was increased from 7 to
11 while no such color change was observed when pH was changed from neutral to acidic. In
case of compound 3b color changes from light orange to light yellow when pH was increased
from 7 to 11 as shown in Fig. 5. It can be inferred from these results that compounds 3a and
3b show both colorimetric and fluorescent responses to changes in pH.
Fig. 5: Visible color change in 3a and 3b with changing pH
3.3. Reversibility of the sensors
The changes under acidic and basic conditions in the fluorescence spectra of 3a and 3b are
completely reversible. The reversible nature and reproducibility of both the sensors have been
examined by recording the ratio of fluorescence intensity at 478 nm and 385 nm with respect to
the change of pH from acidic (pH 2.0) to basic (pH 11.0) range and vice versa upto 6 cycles. A
representative diagram is shown in the Fig. 6 for 3a. The reversibility between the protonated
and deprotonated forms of the sensor 3a has been observed. Thus the sensors might be
applicable for real time pH monitoring.
10

Fig. 6: The ratio of fluorescence intensity at 478 nm and 385 nm of 3a (10 μM, λexc = 270 nm)
upon consecutive addition of HCl (0.1 N) and NaOH (0.1 N) solution up to 6 cycles.
4. Conclusion
In conclusion, we have designed novel fluorescent pH compounds which have been
characterized by their spectral data. pKa values for these sensors have been found to be 4.99,
and 4.69 indicating that these compounds could be employed as sensor for monitoring pH
variations in acidic environment. Both the sensors 3a and 3b showed visible color change also.
Therefore, the novel compounds can be used as a color-tunable pH sensors in the range of pH =
7-10.
Acknowledgments
KA thanks Council of Scientific & Industrial Research (CSIR), New Delhi, India for the
grant of Junior and Senior Research Fellowships.
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Table 1: Crystal data and structure refinement for compound 3b
Identification code
Empirical formula
Formula weight
Shelxl
C27 H22 N4 O6 S2
562.61
Temperature
293(2) K
Wavelength
0.71073 Å
Crystal system, space group
Unit cell dimensions
Triclinic, P -1
a = 8.205(5) Å
b = 12.931(4) Å
c = 13.623(10) Å
1363.1(14) Å3
2
α = 106.72(4)°
β = 95.87(10)°
γ = 96.06(6)°
Volume
Z
Calculated density
Absorption coefficient
F(000)
1.371 g/cm3
0.244 mm-1
584
Crystal size
0.02 x 0.01 x 0.01 mm
3.09 to 25.00 deg.
Theta range for data collection
16

Limiting indices
-9<=h<=9, -15<=k<=15, -16<=l<=16
9998 /4695 [R(int) = 0.1032]
97.6 %
Reflections collected / unique
Completeness to θ = 25.00°
Absorption correction
Semi-empirical from equivalents
1.00000 and 0.43439
Max. and min. Transmission
Refinement method
Full-matrix least-squares on F2
4695 / 1 / 352
Data / restraints / parameters
Goodness-of-fit on F2
0.981
Final R indices [I>2sigma(I)]
R indices (all data)
R1 = 0.0864, wR2 = 0.2031
R1 = 0.1261, wR2 = 0.2360
0.640 and -0.580 e.Å-3
Largest diff. peak and hole
17