A new series of fluorescent 5-methoxy-2-pyridylthiazoles with a pH-sensitive dual-emission

Article abstract of DOI:10.1039/b604910a

A new series of fluorophores, 5-methoxy-2-(2-, 3- or 4-pyridyl)thiazoles (2-, 3- or 4-MPT, respectively), were synthesized and their photophysical properties investigated. 2- and 4-MPT are highly fluorescent in polar solvents. Combined with theoretical calculations, studies of the excited state lifetimes in different solvents reveal that their fluorescence mainly results from the internal charge transfer excited state. Acidobasic properties of their ground states and excited states were studied with steady and transient fluorescence spectroscopy. 2- and 4-MPT displayed a pH sensitive fluorescent behavior with a dual-emission in the range 2 to 6 in an aqueous system. the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2006.

Full text of DOI:10.1039/b604910a

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A new series of fluorescent 5-methoxy-2-pyridylthiazoles with a
pH-sensitive dual-emissionw
Ming-Hua Zheng,ab Jing-Yi Jin,ab Wei Suna and Chun-Hua Yan*a
Received (in Montpellier, France) 4th April 2006, Accepted 19th May 2006
First published as an Advance Article on the web 14th June 2006
DOI: 10.1039/b604910a
A new series of fluorophores, 5-methoxy-2-(2-, 3- or 4-pyridyl)thiazoles (2-, 3- or 4-MPT,
respectively), were synthesized and their photophysical properties investigated. 2- and 4-MPT are
highly fluorescent in polar solvents. Combined with theoretical calculations, studies of the excited
state lifetimes in different solvents reveal that their fluorescence mainly results from the internal
charge transfer excited state. Acidobasic properties of their ground states and excited states were
studied with steady and transient fluorescence spectroscopy. 2- and 4-MPT displayed a pH
sensitive fluorescent behavior with a dual-emission in the range 2 to 6 in an aqueous system.
both the ground and the excited states were investigated. 2-
Introduction
and 4-MPT displayed a ratiometric pH-sensitive fluorescence
behavior with a dual-emission.
Optical pH sensors have been extensively applied in analytical
chemistry, biochemistry, cellular biology and medicine.1 In
particular, pH sensors based on the change of fluorescence
exhibit a lot of advantages such as high sensitivity and ease of
miniaturization.2 For the practical measurement of pH, a
ratiometric fluorescent pH sensor with a dual-emission is more
attractive due to its insensitivity to sample orientation, probe
concentration, photobleaching and background fluorescence.3
Many efforts have been made to develop a ratiometric fluor-
escent pH sensor in various ranges to meet different
demands.4,5
Results and discussion
Synthesis
Reaction of pyridyl carboxylic acid chloride and glycine
methyl ester hydrochloride in the presence of triethylamine
(TEA), and subsequently followed by a reaction with Law-
esson’s reagent8 resulted in the formation of the MPTs
(Scheme 1).
However, the design of a pH-sensitive fluorophore with a
dual-emission is delicate. There are still challenges from the
viewpoints of both synthesis and quantum yield.5a Recently
Jullien and co-workers reported a new series of fluorescent
5-aryl-2-pyridyloxazoles (PYMPO) as ratiometric fluorescent
pH sensors with a dual-emission.5b In fact, 1,3-thiazole can act
as a spacer between the electron donor and acceptor as a
structural analog of 1,3-oxazole,6 which has been previously
demonstrated in Thiazole Orange (TO) as a fluorescent label
for biological systems in 1986.7 In the present work, we report
the synthesis and optical properties of a new series of fluor-
ophores, 5-methoxy-2-(2-, 3- or 4-pyridyl)thiazoles (2-, 3- or
4-MPT, respectively). The fluorescence quantum yields of the
2- and 4-substituted isomers (2- and 4-MPT) are high in polar
solvents. Studies of both the steady and transient fluorescence
spectra disclose that an internal charge transfer (ICT) excited
state is evolved upon excitation, which is supported by theo-
retical calculations. The acidobasic properties of the MPTs in
Optical properties
The absorption and fluorescence maxima of the MPTs are
collected in Table 1. All MPTs are fluorescent, and especially
the fluorescence quantum yields of 2- and 4-MPT are very high
and comparable to a reported series of 1,3-oxazole derivati-
ves.5b The fluorescence intensity of the MPTs increased pro-
portionally to their concentration between 10ꢀ7 to 10ꢀ5 M,
thus the emission is attributed to the monomeric species but
not the dimer or excimer (see Fig. S10 in ESIw).
A typical charge transfer process in MPTs can be concluded
experimentally. A bathochromic shift of the fluorescence
emission of the MPTs was observed as the polarity of the
solvents increased. According to a theoretical model of the
photoinduced charge transfer for the push–pull conjugated
molecules,12 increasing the polarity of the solvent has no
significant effect on the wavelength of absorption whereas it
a Beijing National Laboratory for Molecular Sciences, State Key Lab
of Rare Earth Materials Chemistry and Applications & PKU-HKU
Joint Lab in Rare Earth Materials and Bioinorganic Chemistry,
Peking University, Beijing 100871, China
b Department of Chemistry, Yanbian University, Yanji, Jilin 133002,
China
w Electronic supplementary information (ESI) available: Absorption
and excitation spectra, steady fluorescence spectra of MPTs and
fluorescence decay curves of 2- and 4-MPTs at different pH. See
DOI: 10.1039/b604910a
Scheme 1 Synthesis of 5-methoxy-2-pyridylthiazole.
ꢁc
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Table 1 Photophysical properties of MPTs. Maximaa of absorption labs and of steady fluorescence emissionb lem, molar absorption coefficients
emax ꢂ 5%, fluorescence quantum yieldsc F ꢂ 5%, the Stokes shifts DS and the lifetimed of the excited states t in different solvents
Solvent
(Df)e
n-Hexane
(0.0002)
Chloroform
(0.149)
Tetrahydrofuran
(0.210)
Dichloromethane
(0.219)
Acetonitrile
(0.306)
Methanol
(0.309)
Waterf
(0.320)
2-MPT
4-MPT
3-MPT
a
l
abs/nm
log (emax/Mꢀ1 cmꢀ1
em/nm
320
4.20
384
0.73
5208
2.5
312
3.98
371
322
4.30
390
0.91
5415
2.8
320
3.70
385
0.67
5276
1.2
323
4.34
392
0.90
5450
2.8
319
4.06
388
0.48
5575
1.3
321
4.21
391
0.94
5577
2.9
317
3.93
385
0.59
5572
1.4
313
4.01
381
0.36
5702
1.2
320
3.92
397
0.88
6061
3.2
318
3.70
391
0.59
5871
2.5
321
3.93
397
0.94
5963
3.2
322
3.64
404
0.56
6303
4.7
323
4.21
403
0.74
6146
3.6
322
3.99
406
0.43
6425
2.3
)
)
)
l
F
DS/cmꢀ1
t/ns
l
abs/nm
log (emax/Mꢀ1 cmꢀ1
em/nm
l
F
0.12
5097
—
DS/cmꢀ1
t/ns
g
l
abs/nm
log (emax/Mꢀ1 cmꢀ1
em/nm
309
4.22
367
314
4.18
378
313
4.28
379
311
3.98
388
0.2
313
3.89
396
312
4.29
406
l
F
0.10
5115
—
0.31
5392
—
0.25
5564
—
0.26
6696
—
0.16
7421
—
DS/cmꢀ1
t/ns
6381
—
g
g
g
g
g
g
All spectra were recorded at 293 K. General concentrations of analysts were 25 and 1 mM, respectively, for measurement of absorption and
b
c
steady fluorescence emission. Excited at 310, 320 and 310 nm for 2-MPT, 4-MPT and 3-MPT, respectively. Relative quantum yields were
evaluated using quinine sulfate (F = 0.48 ꢂ 0.2) in 0.5 M H2SO4, excited at 313 nm) as the standard compound.9 d Lifetimes of the excited state of
2-MPT were fitted monoexponentially, and lifetimes of the excited states of 4-MPT and 3-MPT were fitted double-exponentially and calculated
with the corresponding weights.10 e Df was the orientation polarizability (Lippert’s solvent polarity parameter),4a,11 which was used to correlate the
f
g
Stokes shifts and the polarities of solvents. The aqueous solutions were prepared using twice distilled water. Difficult to obtain accurate data
because of the low fluorescence quantum yields.
promotes a red shift in the emission, resulting in an increasing
Stokes shift of the MPTs with the polarity of solvent as listed
in Table 1.
located at the methoxy group and the thiazole ring in the
HOMO (Fig. 1), while in the LUMO, the electron density is
located at the pyridyl ring. Based on experimental and theo-
retical results, it can be deduced that the ICT excited states of
MPTs are evolved upon excitation and photoinduced charge
transfer occurs from the electron donating 5-methoxy group to
the 2-pyridyl ring.
Studies of the fluorescence decays of the MPTs reveal that
the lifetimes of the fluorescent excited state of MPTs were also
affected by the polarity of the solvents (Table 1).
Theoretical calculations
Acidobasic properties of the ground and excited states
Density functional calculations of MPTs were performed at
the B3LYP/6-31G(d,p) level using Gaussian 03.13 Geometry
optimization produced similar coplanar structures for all
MPTs (see Fig. S17 in ESIw). The electron density is mainly
Both the maxima of the absorption and the fluorescence of
MPTs were red shifted with the decrease in pH. The typical
evolution of the pH-dependent absorption and emission of
MPTs is illustrated in Fig. 2.
Such bathochromic absorption and emission are assigned to
the protonated form, MPT–H1. Theoretically, protonation
occurs at the nitrogen atom of the pyridyl ring, giving rise to
an acidic MPT–H1. Compared with the parent MPT, proto-
nation decreases the energy difference between the HOMO
and LUMO5b in the protonated MPT–H1 and thus favors
charge transfer from the methoxy group to the pyridyl ring
through the thiazole ring. The photophysical data of the
protonated form of the MPTs are collected in Table 2.
A clear and fixed isosbestic point is observed in the evolu-
tion of both the UV-Vis absorption and fluorescence emission
spectra at different pH for every MPT, which indicated the
presence of an equilibrium of protonation between the acidic
and basic forms of MPTs in solution (Scheme 2).
The pKa (MPT–H1/MPT) value of the ground states of
MPTs were then calculated from the UV-Vis absorption
titration experiments. For the excited states of MPTs, an
increased pKa* ([MPT–H1]*/[MPT]*) could be anticipated
Fig. 1 HOMO and LUMO of MPTs at the B3LYP/6-31G(d,p) level
of theory calculated by Gaussian 03.
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Table 2 Photophysical data of the protonated MPTs. Maximaa of
absorption labs and of steady fluorescence emissionb
lem, molar
absorption coefficients emax ꢂ 5%, fluorescence quantum yieldsc F ꢂ
5%, lifetimesd of the excited states t at pH = 1.0, pKa and pKa* of the
ground statese and excited states, respectively, in an aqueous system
at 293 K
2-MPT–H1
4-MPT–H1
3-MPT–H1
l
abs/nm
log (emax/Mꢀ1 cmꢀ1
em/nm
364
4.25
455
0.76
3.7
369
4.05
445
0.47
9.4
331
4.10
514
0.01
—
3.3
)
l
F
t/ns
f
pKa ꢂ 0.1
1.6
8.2
4.3
12.4
pKa*
11.2
a
All spectra measurements were taken at 293 K. General concentra-
tions of analysts were 25 mM and 1 mM, respectively, for measurement
of absorption and steady fluorescent emission. Excited at 360, 360
and 330 nm for 2-MPT, 4-MPT and 3-MPT, respectively, at pH =
b
c
1.0. Relative quantum yields were evaluated using quinine sulfate
(F = 0.48 ꢂ 0.2) in 0.5 M H2SO4 (excited at 313 nm) as the standard
compound.12 d Lifetimes of the excited state of 2-MPT were fitted
monoexponentially, and 4-MPT and 3-MPT were fitted double-ex-
ponentially, and calculated according to the lifetimes and the corre-
sponding weights.10 e pKa values of the ground state were evaluated
f
from UV titration experiments. Difficult to obtain accurate data
because of the low fluorescence quantum yields of 3-MPT.
sponding MPT ground state, indicating that photoinduced
charge transfer occurred upon excitation of the MPTs.
Fig. 2 Evolution of absorption and fluorescence emission of (a)
2-MPT excited at 350 nm and (b) 4-MPT excited at 355 nm with pH
in an aqueous system at 293 K. Solid line: absorption; dashed line:
fluorescence.
Mechanism of pH sensing
Due to the dual-emission and the high fluorescence quantum
yields of MPTs, 2- and 4-MPT may be expected to be applied
in a ratiometric fluorescent pH sensor. Although they are
structural analogs of PYMPO, the protonation–deprotona-
tion processes of the excited state were somewhat different
according to studies of the fluorescence decay of 2- and
4-MPT in the measured pH ranges. The lifetimes of both
(2-MPT)* and (2-MPT–H1)* were fitted monoexponentially
(Table 3). At pH o 3.0, the extracted lifetimes of the
fluorescent excited states (lem = 400 nm excited at 310 nm)
dropped as pH was lowered, attributed to a dynamic quench-
ing by the proton according to the Stern–Volmer analysis
(Fig. 3).4a The fitted kQ = 0.5 ꢃ 1010 Mꢀ1 sꢀ1 indicated that
the dynamic quenching of the fluorescence of 2-MPT by
the proton was diffusion-controlled.5b Meanwhile, the lifetime
of the excited state of 2-MPT–H1 (lem = 455 nm excited
at 365 nm) did not change at pH below 3.0, indicating a
stable fluorescence (2-MPT–H1)*. Based on the extracted
lifetimes of (2-MPT)* and (2-MPT–H1)*, 3.4 and 3.8 ns,
respectively, it is postulated that the protonation of 2-MPT*
because the photoinduced charge transfer results in a larger
population of electrons at the pyridine ring. According to
the Forster cycle, we evaluated the pK * values from
¨
a
eqn. (1):4a
2.3RT(pKa ꢀ pKa) = Na[hn(MPT) ꢀ hn(MPT–H1)] (1)
*
where the ionization entropies DS0 and DS0* of MPT–H1 and
(MPT–H1)*, respectively, are reasonably assumed to be
equal, R is the gas constant, T is the absolute temperature,
n(MPT) and n(MPT–H1) are the energy differences (corre-
sponding to the 0–0 transitions) between the excited state and
the ground state of MPT and MPT–H1, respectively, and Na
is Avogadro’s number. After converting the frequency (nꢀ1
)
into the wavenumber (cmꢀ1) and estimating the 0–0 transi-
tions of MPT and MPT–H1 by means of the wavenumber
average (eqn. (2)) between the corresponding maxima of
absorption and emission, eqn. (3)14 is obtained.
ꢀ1
ꢀ1
n0–0 = (nabs þ nemꢀ1)/2
(2)
pKa* ꢀ pKa = 2.1ꢃ10ꢀ3[nabs(MPT)ꢀ1þnem(MPT)ꢀ1
ꢀ nabs(MPT–H1)ꢀ1 ꢀ nem(MPT–H1)ꢀ1] (3)
From the estimated pKa* values (Table 2), the excited state of
Scheme 2 Schematic representation of the protonation equilibria of
the ground and excited states of MPTs.
MPT is significantly more basic compared with the corre-
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Table 3 Lifetimes t of 2-MPT and 4-MPT at different pHa
2-MPT
4-MPT
lem = 400 nm
(lex = 310 nm)
lem = 455 nm
(lex = 365 nm)
lem = 400 nm
(lex = 320 nm)
lem = 445 nm
(lex = 365 nm)
0
0
t ꢂ 0.1/ns
w2
t ꢂ 0.1/ns
w2
t1 ꢂ 0.1/ns
—
t2 ꢂ 0.1/ns
w2
t1 ꢂ 0.1/ns
t2 ꢂ 0.1/ns
w2
pH
c
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
a
1.2
2.2
2.9
3.3
3.4
3.4
3.4
3.4
3.4
3.4
3.4
1.017
1.057
1.051
1.003
1.039
1.009
1.054
1.015
1.065
1.060
1.054
b
3.8
3.8
3.8
3.8
1.019
1.019
1.006
1.012
0.3 (76.14)
0.3 (77.97)
0.3 (77.67)
0.3 (71.79)
0.3 (70.36)
10.4 (23.86)
10.0 (22.03)
10.3 (22.33)
10.8 (28.21)
10.2 (29.64)
1.029
1.043
1.025
1.034
1.020
2.1 (13.43)
2.1 (29.32)
2.1 (57.85)
2.1 (77.53)
2.1 (91.40)
2.1 (91.20)
2.1 (90.34)
2.1 (90.48)
2.1 (90.73)
2.1 (89.91)
12.8 (86.57)
12.5 (70.68)
12.1 (42.15)
11.9 (22.47)
9.5 (18.60)
9.0 (8.80)
8.4 (9.66)
8.4 (9.52)
9.0 (9.27)
8.6 (10.09)
1.052
1.013
1.024
1.007
1.071
1.005
1.008
1.071
1.010
0.943
b
—
b
—
c
Determined at 293 K. Difficult to obtain accurate data due to the weak fluorescence under the measurement conditions. Not determined.
resulted in the generation of (2-MPT–H1)* and the subse-
quent deprotonation of (2-MPT–H1)* should not occur in the
Conclusions
In the present work, we successfully developed a new series of
excited state.
fluorophores with synthetic simplicity and high fluorescence
The double-exponentially fitted lifetime of the excited states
quantum yields. The internal charge transfer excited states are
of 4-MPT implied that there are two components responsible
evolved upon excitation, and have been investigated and
for the fluorescence, which leads to a different pH sensing
analysed according to both experimental results and theore-
mechanism from 2-MPT. We assign component 1 of 4-MPT*
tical calculations. Although different kinetics influenced the
(lem = 400 nm, excited at 320 nm) as the main fluorescent
species because the percentage of component 1 decreased as
protonation processes of 2- and 4-MPT in the ground and
excited states, both of them displayed a pH-sensitive fluores-
the pH value dropped (Table 3), which is consistent with the
cence behavior with a dual-emission.
evolution of the steady fluorescences. The lifetime of compo-
nent 1 is almost constant in pH 6.0–1.5. Regarding the proton
Experimental
as the quencher of the fluorescence of 4-MPT (lem = 400 nm,
excited at 320 nm), formation of a stable complex 4-MPT–H1
in the ground state is responsible for the observed static
quenching. Meanwhile, the lifetime of component 10 of
(4-MPT–H1)* is unvaried as 0.3 ns at pH o 3, similar to
the case of (2-MPT–H1)*. Therefore, the fluorescent excited
state of (4-MPT–H1)* mainly originates from the excitation of
the protonated 4-MPT, and the possibility of deprotonation in
the excited state might be low.
Materials and methods
All reactions were performed under argon atmosphere using
purified solvents by standard methods. All chemicals were
purchased from Acros and used as received without further
purification. For all spectrometric measurements, HPLC
grade solvents were degassed before use. For chromatography,
100–200 mesh silica gel (Qingdao, China) was used.
The UV-Vis absorption spectra were measured with a
Hitachi U-3010 spectrophotometer and the fluorescence spec-
tra were recorded on a Hitachi F-4500 fluorescence spectro-
photometer. Time-resolved fluorescence spectra were obtained
using an Edinburgh FLS920 fluorescence spectrophotometer.
The instrument was operated with a thyratron-gated flash
lamp filled with hydrogen at a pressure of 0.5 atm. The lamp
was operated at a frequency of 40 kHz and the pulse width of
the lamp under operating conditions was about 1.2 ns. The
lifetimes were estimated from the measured fluorescence decay
curves and the lamp profile using a nonlinear least squares
iterative fitting procedure. NMR spectra were recorded on a
Varian Mercury 200 spectrometer. Chemical shifts were re-
ported in ppm using tetramethylsilane (TMS) as the internal
standard. IR spectra were recorded on a Nicolet 5MX-S
infrared spectrometer. Elemental analyses (C, H, N) were
performed on an Elementar Vario EL analyzer.
All spectra measurements were recorded at 20 1C. Unless
mentioned otherwise, concentrations of analysts were 25 mM
Fig. 3 Stern–Volmer analysis of the lifetimes of the excited state of
2-MPT below pH 3.0.
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and 1 mM, respectively, for measurement of UV-Vis absorp-
tion and fluorescence emission spectra. The pH values were
adjusted by addition of 0.1 M HCl and then determined by a
pH-meter at 20 1C.
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5-Methoxy-2-(3-pyridyl)thiazole (3-MPT). Yield: 58%. Mp:
47–48 1C. IR (KBr, cmꢀ1): 1529, 1491, 1426, 1419, 1312, 1285,
1277, 1219, 961, 811. 1H NMR (CDCl3, 200 MHz): d =
9.03–9.02 (m, 1H), 8.62–8.59 (m, 1H), 8.13–8.09 (m, 1H),
7.39–7.33 (m, 1H), 7.19 (s, 1H), 3.99 (s, 3H). 13C-NMR
(CDCl3, 50 MHz): d = 164.6, 150.1, 147.4, 144.4, 154.0,
131.4, 124.7, 122.8, 61.7. Calcd for C9H8N2OS: 192.0357,
HRMS (m/z): 192.0358. Anal. calcd for C9H8N2OS: C 56.23,
H 4.19, N 14.57; found: C 56.48, H 4.29, N 14.12%.
12 D. Laage, W. H. Thompson, M. Blanchard-Desce and J. T. Hynes,
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5-Methoxy-2-(4-pyridyl)thiazole (4-MPT). Yield: 50%. Mp:
56–57 1C. IR (KBr, cmꢀ1): 1595, 1525, 1494, 1458, 1419, 1313,
1286, 1276, 1221, 988, 830, 818, 800. H NMR (CDCl3, 200
1
MHz): d = 8.66 (d, J = 5.8 Hz, 2H), 7.69 (d, J = 5.8 Hz, 2H),
7.23 (s, 1H), 4.00 (s, 3H). 13C NMR (CDCl3, 50 MHz): d =
164.9, 151.7, 150.1, 141.3, 123.0, 119.5, 61.6. Calcd for
C9H8N2OS: 192.0357, HRMS (m/z): 192.0358. Anal. calcd
for C9H8N2OS: C 56.23, H 4.19, N 14.57; found: C 56.40, H
3.91, N 14.28%.
14 For comparison, we also calculated the pKa* values of 5-(40-
methoxyphenyl)-2-(pyridyl)oxazole (2- and 4-PYMPO) with eqn.
(3) and found that our results (11.7 and 12.8 for 2- and 4-PYMPO,
respectively) were in good agreement to the reported values (11.6
and 12.7 for 2- and 4-PYMPO, respectively) given in ref. 5b.
Acknowledgements
The authors thank the NSFC (No. 20201009, 20221101,
20490210) for financial support.
ꢁc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2006
1196 | New J. Chem., 2006, 30, 1192–1196