Photorelease of La3+ with turn-on fluorescent detection

Article abstract of DOI:10.1016/j.jphotochem.2014.05.007

Photorelease of La³⁺ with turn on fluorescent detection is described. Complex (1) is synthesized by treatment 2,2′-(((ethane-1,2- diylbis(oxy)bis(2,1-phenylene))bis(methanylylidene)) bis(azanylylidene))diphenol with LaCl₃·7H₂

Full text of DOI:10.1016/j.jphotochem.2014.05.007

Accepted Manuscript
Title: Photorelease of La3 with turn-on fluorescent detection
+
Author: Yongchao Hao Xu Zhang Yi Chen
PII:
S1010-6030(14)00203-2
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jphotochem.2014.05.007
JPC 9671
To appear in:
Journal of Photochemistry and Photobiology A: Chemistry
Received date:
Revised date:
Accepted date:
31-3-2014
5-5-2014
13-5-2014
Please cite this article as: Y. Hao, X. Zhang, Y. Chen, Photorelease of La3 with turn-
+
on fluorescent detection, Journal of Photochemistry and Photobiology A: Chemistry
(2014), http://dx.doi.org/10.1016/j.jphotochem.2014.05.007
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3+
Photorelease of La with turn-on fluorescent detection
Yongchao Hao, Xu Zhang and Yi Chen*
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute
of Physics and Chemistry, The Chinese Academy of Sciences, Beijing, 100190, China. Tel: +86
1
0 82543595; Fax: +86 10 62564049. E-mail: yichen@mail.ipc.ac.cn
3+
Keywords: photorelease, La , fluorescent monitoring, photochemistry.
3+
Abstract: Photorelease of La with turn on fluorescent detection is described. Complex (1) is
synthesized by treatment 2,2’-(((ethane-1,2-diylbis(oxy)bis(2,1-phenylene))bis(methanylylidene))
bis(azanylylidene))diphenol with LaCl •7H O in 1:1 molar ratio. Upon irradiation with UV light,
3
2
3+
1
undergoes La release and converts to 1,2-bis(2-(benzoxazol-2-yl)phenoxy)ethane (2). It is
found that 2 exhibits strong fluorescence emission and the turn-on fluorescence is detected
during the photo-conversion of 1 to 2, which is beneficial for monitoring the photo-release of
3+
La . Moreover, an excellent (R = 0.9963) linear correlation between the ratio of optical density
OD /OD ) with irradiation time is obtained when 1 is photo-converted to 2, which is beneficial
(
1
2
3
+
for controlling or regulating the quantity of La -released.
1
. Introduction
The light-activated release provides a powerful tool for the rapid introduction of a variety of
species to biological systems with spatial and temporal control, allowing the time-resolved study
of the ensuing events [1-5]. Metal photo-release has currently attracted considerable attention
1
Page 1 of 20

because of its potential since it will be a valuable tool for the delivery of biologically active
metals, which are an essential cofactor in numerous enzymes [6-9], or of toxic metal ions to
study the mechanisms of metal-ion trafficking and applications, such as chemotherapy, by means
of inducing cell death by catalyzing DNA and RNA cleavage or by binding active sites of
proteins competition with essential metals [10-13].
3+
Lanthanum (La ) plays an important role in biological systems [14,15]. Lanthanum is a high-
valence rare-earth metal used as a substitute for calcium as a blocker [16,17] of several
nonselective ion channels in different systems based on the blocking activity of lanthanum
including connexin hemichannels, murin frontal cortex networks, tobacco BY-2 cells, or the
+
outward K channel [18-21]. Although lanthanides have been known for their diversity in
biological effects [22-24], and the application of lanthanides in medicine has high potential [25-
2
8], the mechanism of the biological effects of lanthanides is not clearly known [29-31],
3
+
3+
specially at molecular and genetic level. Lanthanides (Ln ) including lanthanum (La ) are
3
+
exogenous ions, the concentration of Ln has great influenced on their biological effects [32,33].
Therefore, it is required that the development of a simple and efficient way to delivery
3+
exogenous lanthanides (Ln ) to biological systems. Photo-trigged release is a promising tool,
and can fulfill to molecules/ions release with spatial, temporal and quantitative control. In this
3+
paper, we report a prototype for La photo-release. Complex 1 is prepared by employing 2,2’-
(((ethane-1,2-diylbis(oxy)bis(2,1-phenylene))bis(methanylylidene))bis(azanylylidene))diphenol
3+
as ligand (Scheme 1), it is found that upon irradiation the solution of 1 in DMSO, the bound La
can be released and the ligand is converted to 1,2-bis(2-(benzoxazol-2-yl)phenoxy)ethane 2. It is
also found that accompanying the process of photoconversion, turn on fluorescence is observed,
3
+
which is beneficial to monitor the photorelease of La .
2
Page 2 of 20

O
N
O
O
O
light
3
H O
2
N
O
N
O
O
La
Cl
N
O
La3+
1
2
3
+
Scheme 1. Outline of photorelease of La form complex 1.
2
. Experimental
2
.1.
General
H NMR spectra were recorded at 400 MHz with TMS as an internal reference and DMSO-d6
1
as solvent. HRMS spectra were recorded with Q-Exactive MS spectrometer (Thermo Fisher).
UV absorption spectra and fluorescence spectra were measured on an absorption
spectrophotometer (Hitachi U-3010) and a fluorescence spectrophotometer (F-2500),
respectively. IR spectra (KBr) were recorded on spectrophotometers Excalibur 3100 (Varian).
All chemicals for synthesis were purchased from commercial suppliers, and solvents were
purified according to standard procedures. Reactions were monitored by TLC silica gel plate
(60F-254). Column chromatography was performed on silica gel (70-230 mesh). A UV lamp (36
2
watt) was used as light sources for photo-release (irradiation energy: 4.3 mW/cm ).
2
.2.
Materials.
2
.2.1. Synthesis of complex 1.
The complex 1 was synthesized by reaction of lanthanum (III) salt and the ligand in amount
equal to metal: ligand molar ratio of 1:1. The synthetic route for 1 was presented in Scheme 2,
and the detailed procedures were as follows. (a) To the solution of salicylaldehyde (6.1 g, 50
3
Page 3 of 20

mmol) and 1,2-dibromoethane (4.7 g, 25 mmol) in acetonitrile (150 ml) was added potassium
carbonate (6.9 g, 50 mmol) and potassium iodide (0.4 g, 2.5 mmol). The solution mixture was
refluxed. When no starting material (salicylaldehyde) was detectable by TLC plate, the solution
was concentrated and the crude product was added to water (100 ml) and the solution mixture
was extracted with dichloromethane (50 ml  3). The combined organic solution was dried over
Na SO , the resulting solution was concentrated and the crude product was purified by flash
2
4
column chromatography (petroleum ether / ethyl acetate, 2:1) to afford intermed product
dialdehyde in 80% yield. (b) A solution of dialdehyde (0.54 g, 2 mmol) in absolute ethanol (20
ml) was heated to dissolved completely, to the solution was added a solution of 2-aminophenol
(436 mg, 4 mmol) in absolute ethanol (10 ml), the solution mixture was reflexed till the
dialdehyde was disappeared. The crude product was purified by recrystallization from ethanol to
1
afford ligand in 80% yiled. H NMR (400 MHz, DMSO-d , ppm): 7.47 (d, J = 7.7 Hz, 2H), 7.29
6
(t, J = 7.5 Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 6.97 (t, J = 7.5 Hz, 2H), 6.95-6.82 (m, 4H), 6.80 (s,
2
H), 6.78-6.68 (m, 2H), 6.62-6.51 (m, 4H), 4.51 (d, J = 3.2 Hz, 4H). HRMS (EI) Calcd for
+
C H N O , (M ): 452.1736. Found: 452.1741. (c) To the boiling solution of ligand (452 mg,
28
24
2
4
1
.0 mmol) in ethanol (100 ml) was added dropwise a solution of lanthanum (III) chloride
heptahydrate (371 mg, 1.0 mmol) in ethanol (10 ml). The mixture solution was refluxed for 1 hr
and then cooled down to ambient temperature. The yellow crystalline was filtered off, washed
with ethanol (10 ml  3), and pure complex 1 was obtained after vacuum-dried without further
-1
purification. Yield: 96%. M.p.  300 C. IR (ν, cm ): 3570.14, 3556.87, 3410.64 (br), 1645.21,
1
1
601.90, 1573.20, 1286.23, 1182.07. H NMR (400 MHz, DMSO-d , ppm): 8.74 (s, 2H), 7.90-
6
7
.78 (m, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.8 Hz, 4H), 7.21 (dd, J = 7.5, 1.8 Hz, 2H),
4
Page 4 of 20

6
3
.95 (t, J = 7.5 Hz, 2H), 6.85-6.78 (m, 4H), 4.61 (s, 4H). HRMS (EI) calcd for C H ClLaN O
28 22 2 4
+
H O (M +Na): 701.0547. Found: 701.4920.
2
CHO
Br
Br
O
O
CHO
OH
OHC
dialdehyde
NH2
OH
O
O
O
N
O
N
LaCl3 7H O
2
3
H O
2
N
O
N
O
La
Cl
OH HO
ligand
1
Scheme 2. Synthetic route for complex 1.
2
.2.2 Synthesis of photo-product 2
The synthetic route for 2 was presented in Scheme 3, and the detailed procedure was as
follows. A mixture of 1 (226 mg, 0.5 mmol) and lead acetate, Pb(OAc) (244 mg, 0.55 mmol),
4
dissolved in 20 ml of CHCl was refluxed till no starting material was detected by TLC plate.
3
The solution was filtered and the filtrate was extracted with CH Cl -H O (v/v = 1:1, 10 ml × 3).
2
2
2
The conbined organic solution was dried over Na SO . The resulting solution was concentrated
2
4
and the crude product was purified by flash column chromatography (petroleum ether/CH Cl ,
2
2
1
1
7
:1) to afford 2. Yield: 15%. H NMR (400 MHz, DMSO-d ): 8.55 (dt, J = 8.0, 1.6 Hz, 2H),
6
.72-7.70 (m, 2H), 7.50-7.31 (m, 10H), 7.11 (t, J = 7.6 Hz, J = 7.2 Hz, 2H), 4.62 (s, 4H). TOF-
1
2
+
MS (EI) calcd for C H N O S (M ): 480.0966. Found: 480.0991.
28
20
2
2 2
5
Page 5 of 20

O
N
O
N
O
N
O
Pb (Ac)4
CHCl3
O
N
O
OH HO
ligand
2
Scheme 3. Synthesis of 2.
3
. Results and discussion
3+
3
.1. Photorelease of La
3+
Photorelease of La from complex 1 was performed in DMSO solution. Upon irradiation with
4
-1
-1
2
54 nm light, the absorption of complex 1 at max = 352 nm ( = 1.5  10 L mol cm , in
DMSO) decreased with the increase of irradiation time, accompanying this process, a new band
at max = 320 nm appeared (Fig. 1). The absorption of 320 nm attributed to the photo-product 2,
3
+
whose structure is suggested in Scheme 1. Further study found that the photorelease of La from
complex 1 could also be performed in other organic solvents such as ethanol (EtOH) and N,N-
dimethylformamide (DMF), the obtained results were similar to that in DMSO. It was worth
3+
noting that the photorelease of La could not performed in aqueous solution since 1 was
insoluble in water. The investigation of 1 in mixture solution of H O-DMSO found that the
2
3+
photorelease of La could be conducted in H O-DMSO (v/v = 5/95) mixture solution with H O
2
2
not more than 5%.
6
Page 6 of 20

1.4
1.2
1.0
0.8
0.6
0.4
0.2
200
250
300
350
400
450
wavelength (nm)
Fig. 1. Absorption changes of 1 (50μM, in DMSO) with UV light irradiation (irradiation
wavelength: λ = 254 nm, irradiation periods: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 min).
3
+
The kinetics of photorelease of La was investigated by determination the optical density
OD) changes of 1 with different irradiation time according to Fig. 1. The ratio of OD352 nm
maximum absorption of complex 1) to OD320 nm (maximum absorption of photo-product 2) as
(
(
function of irradiation time was presented in Fig. 2. The linear correlation between the OD320nm
/
3
+
OD352nm with irradiation time is excellent (R = 0.9963) in the process of La -photorelease till it
3
+
was completed. Photorelease with ratiometric detection suggested that the amount of La release
could be manipulated via controlling irradiation time, which is beneficial for the regulation of
3+
La release in terms of quantity, location and time.
7
Page 7 of 20

2.2
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
R = 0.9963
0
2
4
6
8
10 12 14 16 18 20 22
Irradiation time (min)
Fig. 2. The plot of optical density changes of 1 (50μM, in DMSO) with different irradiation
time (irradiation wavelength: λ = 254 nm, irradiation periods: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18,
2
0 min). OD320 nm: optical density at 320 nm, OD352nm: optical density at 352 nm.
3
+
3
.2. Fluorescence monitoring of photorelease of La
In term of our previously study [34,35], phenolic Schiff bases are photo-converted to
benzoxazole derivatives accompanying metal-ion photo-release, and a strong fluorescence is
detected at the same time. Complex 1 showed no fluorescence in DMSO solution using 352 nm
or 320 nm as excitation wavelength. Upon irradiating the solution of 1 in DMSO, the turn on
fluorescence (λ = 364 nm), which attributed to the emission of photo-product 2, was observed.
em
As presented in Fig. 3, the fluorescence was increased with increase of irradiation time till the
3+
photorelease of La was completed, which provides a convenient method to monitor the process
3+
of photorelease of La .
8
Page 8 of 20

500
400
300
200
100
0
350
400
450
500
550
wavelength (nm)
Fig. 3. Fluorescence changes of 1 (50μM, in DMSO) with UV light irradiation (irradiation
wavelength: λ = 254 nm, irradiation periods: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 min,
excitation wavelength: λ = 290 nm).
ex
To check the chemical structure of photo-product 2 and elucidate the fluorescence properties
of photo-product 2, pure 2 was prepared by treatment of the ligand with Pb(OAc) in CHCl3
4
(Scheme 3) (detailed procedure see experimental section). The TLC (thin layer chromatography)
test showed that both photo-product 2 and pure 2 has the same value of R (R = 0.26, elute: ethyl
f
f
acetate/petroleum = 1 : 2, v/v) at the TLC plate. Moreover, it was found that both absorption and
emission profiles of 2 were similar to those of pure 2, and absorption (max = 320 nm) and
emission (λ = 364 nm) maxima were at the same position (Fig.s 1 and 3 vs. Fig. 4). Obtained
em
results confirmed that photo-product 2 has the same chemical structure as that of pure 2. Further
study found that 2 exhibited strong fluorescence in DMSO, and a large fluorescence quantum
yield (ϕ = 0.76) was obtained using quinine sulphate as a standard.
f
9
Page 9 of 20

1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
200
250
300
350
400
450
wavelength (nm)
Fig. 4. Absorption and fluorescence of 2 in DMSO solution (50 μM, irradiation wavelength:
λex = 290 nm).
3
.3. Possible mechanism for the photoreaction
A possible mechanism for the photoreaction consists of a two-step sequence involving the
formation of benzoxazoline followed by oxidation and dehydration (Scheme 4) [36]. Preliminary
investigation found that benzoxazoline formation is a prerequisite to convert a Schiff base into
benzoxazoline by photon induction. Control experiments showed that oxygen in the air played a
minor role in the conversion reaction. A similar conversion was obtained (detection by
absorption spectroscopy) when the irradiation of 1 was carried out in an air saturated solution or
in degassed solution, although the mechanism for the photoreaction in the absence of oxygen is
not known. It is worth noting that complex 1 is stable at ambient temperature and no significant
change (detection by absorption spectral) was detected when a solution of 1 was kept in the dark,
which indicates that the conversion of 1 into 2 did not occur in the absence of light.
1
0
Page 10 of 20

O
H
O
O
N
H
O
hv
3
H O
2
N
O
N
O
O
La
Cl
H
N
La3+
H
O
1
benzoxazoline
O
N
hv
O
O
N
O
2
Scheme 4. A possible pathway for the photo-conversion of 1 into 2.
3
.4. Control experiments
3+
The binding of 2 with La was investigated. No significant absorption changes were detected
upon addition of LaCl 7H O to a solution of 2 in DMSO, which indicated that no (or only weak)
3
2
3+
1
binding between 2 and La . To confirm this suggestion, H NMR studies of 2 with and without
3+
1
3+
addition of La were performed. It was found that H NMR spectrum of 2 with addition of La
3
+
agreed quite well with that of 2 without addition of La , except for the signal at δ = 3.3 ppm,
which is attributed to the proton of H O resulting from the addition of LaCl 7H O. As presented
2
3
2
3
+
in Fig. 5, the signals of 2 with addition of La (above), assigned to the aromatic protons in the
3
+
range of 7.93 – 7.05 ppm, are exactly as same as those of 2 without addition of La (below), no
significant chemical shifts were detected. These results confirmed that there was no (or only a
3
+
very weak) binding between 2 and La .
1
1
Page 11 of 20

b
a
8
.0
7.9
7.8
7.7
7.6
7.5
ppm
7.4
7.3
7.2
7.1
7.0
1
Fig. 5. Partial H NMR spectra of 2 with (a) and without (b) addition of LaCl 7H O (solvent:
3
2
DMSO-d6).
3
+
Further investigation found that the fluorescence of 2 was not affected by La . As presented
3
+
in Fig. 6, the emission spectral of 2 (both profile and strength) with addition of La was exactly
3
+
as same as that of 2 without addition of La , no significant fluorescence changes were detected,
3
+
which indicated that La did not quench the fluorescence of 2. In addition, control experiments
showed that 2 is photostable, and no distinct changes in absorption or fluorescence was detected
after the solution of 2 was irradiated for 60 min with 320 nm light. No significant binding
3+
between 2 and La and no distinct fluorescence quench/decrease are beneficial for application of
3+
photorelease of La with fluorescent monitoring.
1
2
Page 12 of 20

10000
8000
6000
4000
2000
0
350
400
450
500
550
wavelength (nm)
Fig. 6. Fluorescence of 2 (50μM, in DMSO) with (red) and without (black) addition of LaCl3
7
H O (100μM). Irradiation wavelength: λ = 290 nm.
2
ex
4
. Conclusions
3+
A platform for La -photorelease with fluorescence monitoring has been developed. Although
the system presented herein has some shortcomings including unable to be performed in aqueous
solution, irradiation, excitation and detection in short wavelength region, the system has some
advantages such as controlled photo-release and turn on fluorescence monitor. Controlled photo-
release system is great beneficial for the drug delivery in terms of quantity, location and time as
improved control maximizes therapeutic effect while minimizing side effects. From a practical
viewpoint, it is desirable for the system to be used in buffer solution and with visible light
irradiation, excitation and detection. Modifying molecular structure to meet the requirements,
and exploring the applications in biological processing will be the subject of future studies.
Acknowledgments
1
3
Page 13 of 20

This work was supported by the National Natural Science Foundation of China (No
1302197) and National Basic Research Program of China (2010CB934103).
2
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1
7
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[
1
8
Page 18 of 20

Graphical Abstract
O
N
O
O
O
light
3
H O
2
N
O
N
O
O
La
N
O
La3+
Cl
strong emission
1
9
Page 19 of 20

Highlights
3
+
(
(
(
1) A platform for La -photorelease with turn on fluorescence monitoring has been developed.
2) La-complex is synthesized by employing a Schiff base derivative as ligand.
3
+
3) La-complex undergoes photorelease of La and photo-converts to fluorescent benzoxazole
derivative.
2
0
Page 20 of 20