The effects of bromine atoms on the photophysical and photochemical properties of 3-cinnamoylcoumarin derivatives

Article abstract of DOI:10.1039/c8nj00966j

Eight coumarin derivatives (T1-T8) with or without modification using one or two bromine atoms were synthesized through the aldol condensation reaction. Their photophysical, photochemical and electrochemical properties were investigated. It was shown that

Full text of DOI:10.1039/c8nj00966j

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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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The effects of bromine atom on the photophysical and
photochemical properties of 3-cinnamoylcoumarin derivatives
Zhiyuan Sun,a,c, Yu Wang,a,c, De-Cai Fang,b,*, Yuxia Zhao,a,*
Received 00th January 20xx,
Accepted 00th January 20xx
Abstract: Eight coumarin derivatives (T1–T8) with or without modification of one or two bromine atoms were synthesized
through aldol condensation reaction. Their photophysical, photochemical and electrochemical properties were
investigated. It was shown that the position and the number of bromine atoms had a great effect on the properties of
these compounds. When bromines were linked on the coumarin ring (mainly in LUMO) directly, the absorption and
emission spectra of T2–T5 all displayed red shifts but no obvious difference was found on their photochemical properties
compared to T1 without modification. On the contrary, T6 and T7 with one bromine linked on the benzene ring (mainly in
HOMO) exhibited enhanced capability of generating singlet oxygen and decreased photostability caused by the
transformation between two conformers, while T8 with two bromines on the benzene ring was photobleached rapidly due
to a great difference in torsional angle between substituted phenyl ring and linkage part in ground state and excited state.
DOI: 10.1039/x0xx00000x
www.rsc.org/
yield (Φꢀ), is a vital essential in the PDT process.
In previous research, many reports had shown that the
Introduction
introduction of heavy atom onto a molecular structure could
Coumarin (2H-1-benzopyran-2-one) is
a natural substance
improve its
Φ
ꢀ. Chandra et al.[23] studied the intramolecular external
found in many plants. The linking of benzene and α-pyrone serves
as a good coplanar π–π conjugation, which can be used in many
fields, especially for constructing laser dyes and medical
reagents.[1,2] Over the past decades, large amounts of natural or
synthetic coumarin derivatives have attracted many attentions for
their biochemical and pharmaceutical activity.[3-7] Some reviews
have summarized many important medicinal properties of coumarin
and its derivatives.[8-11] In cancer chemotherapy, some in vitro
studies against renal cell carcinoma indicated that coumarin and 7-
hydroxycoumarin were potent cytotoxic and cytostatic agents.[12-14]
Furthermore, coumarins exhibited antitumor activities at different
stages of cancer formation through various mechanisms, such as
inducing cell apoptosis, or inhibiting DNA-associated enzymes.[15,16]
However, chemotherapy is often associated with some systemic side
effects.[17] Photodynamic therapy (PDT) is a noninvasive protocol for
the treatment of tumors.[18-20] In clinical applications, PDT is realized
by delivery of a photosensitizer (PS) to tumor sites firstly and then
irradiation of the PS with a specific wavelength. Under irradiation,
the PS can be excited to its higher-energy excited singlet state, then
undergoes intersystem crossing (ISC) to form a more stable excited
triplet state, further reacts with molecular oxygen to generate
reactive oxygen species (ROS), such as singlet oxygen (1O2), which
finally triggers the tumor ablation.[21,22] Thus, the production
capability of ROS for a PS, especially its singlet oxygen quantum
heavy atom effect in benzo- and naphtho-norbornenes by
theoretical analysis and experimental measurements. They
concluded that the introduction of one or two bromine atoms could
improve the spin-orbit coupling effectively. O'Shea et al.[24] designed
a series of novel PSs through introducing two bromine atoms onto a
BODIPY PS. The results exhibited that the novel PSs could produce
more singlet oxygen and had better antibacterial PDT activity in
vitro against S. aureus, MRSA and E. coli. Hamblin et al.[25]
synthesized phenothiazine derivatives by introducing different
heavy atoms (O, S, Se) onto the prototype structure. They found
that the ISC efficiency and
Φꢀ value of a PS would increase with the
adding of atomic number (Se > S > O). Detty et al.[26] studied the
heavy atom effects based on the chalcogenapyrylium dyes and
proved that the
Φꢀ value was increased from 0.0004 for a pyrylium
dye (O) to 0.12 for a tellurapyrylium dye (Te). However, some
opposite results were also reported. Detty et al.[27] found that the
Φ
ꢀ value decreased after introducing Se atoms into a porphyrin PS.
Gonsalves et al. studied a series of brominated derivatives of
porphyrin and it was indicated that the Φꢀ value didn’t change or
even decrease with the adding of bromine atoms on the phenyl
rings.[28] Therefore, the effects of heavy atoms on the structure-
property relationship of PSs still need more investigation. In our
earlier research,[29] we proved that a series of coumarin derivatives
had obvious anti-tumor PDT activity. In addition, it was interesting
to find that the
Φꢀ values of these PSs were affected significantly by
the substituent at the 7-position of coumarin ring. In order to
explore more potential of coumarins for PDT, we design and
synthesize eight coumarin derivatives (T1–T8, shown in Figure 1)
with or without modification using one or two bromine atoms on
different position of coumarin ring or benzene ring. Through
investigating their structure-property relationship, we hope to
illuminate the effects of heavy atom on coumarins and provide
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guidance for further studies.
Experimental
Materials
All solvents were analytical pure grade. The 4-(dimethylamino)
benzaldehyde, 3,5-Dibromoaniline, 3-bromo-N,N-dimethylaniline,
salicylaldehyde and bromo-hydroxybenzaldehyde were purchased
from Energy Chemical. 1,3-Diphenylisobenzofuran (DPBF) and
2,2,6,6-Tetramethylpiperidine (TEMP) was from J&K chemical Ltd.
Synthesis
The synthesis routes and characterizations of T1–T8 are shown
in Figure
1 and described in supporting information (SI),
Figure 1. The synthesis routes of T1–T8.
respectively. 3-acetyl-2H-chromen-2-one and its bromo-derivatives
were synthesized according to previous reports.[30,31] Three
brominated 4-(dimethylamino)benzaldehyde compounds were
synthesized according to literatures.[32,33]
which were very helpful in assigning calculated electronic
transitions to experimental absorption bands. Additionally, the
geometric parameters of the corresponding excited states and
emission spectra were also obtained by optimizing with TD-
PBE1PBE+IDSCRF. As we know, the PBE0 has poor polarization
description and CT overestimation, leading to the error cancellation
[43,49,50]. However, the non-polar nature of the solvent involved in
this paper will not change too much for absorption at least. For
comparison, CAM-B3LYP[51] and WB97XD[52] functionals were
employed to calculate absorption and emission spectra, too.
Characterization method
1H NMR and 13C NMR spectra were recorded on a Bruker
AV400 (400 MHz) spectrometer with CDCl3 as solvent and
tetramethylsilane as internal standard. Absorption spectra were
measured using Hitachi U-3900 UV/Vis spectrophotometer.
Fluorescence spectra were obtained by
spectrophotometer.
a Hitachi F-4500
To determine ΦΔ, 1,3-Diphenylisobenzofuran (DPBF) was used
as scavenger[34] and tetraphenylporphyrin (TPP) in toluene as
reference.[35] The concentrations of all PSs were adjusted to possess
the same absorbance (Abs = 0.1) at 473 nm, and the initial
concentration of DPBF was consistent in all samples. To ensure the
saturation of air, all solutions were stirred vigorously during the
experimental procedure. The interference from the photobleaching
of PSs was deducted through checking the photostability of pure
PSs solutions at 400 nm under a same illumination dose. Electron
paramagnetic resonance (EPR) spectra were monitored on Bruker
ESP-300E. TEMP was employed as trapping agents for singlet
oxygen. Samples were dissolved in air-saturated toluene with a
concentration of 10−5 mol/L for T1-T8.
The photostability of all PSs was studied by real-time
monitoring the absorption spectra change of pure PSs solutions
under irradiation of a 415 nm laser with 22 mW cm-2 illumination
intensity. In order to investigate the electrochemical properties of
these PSs, cyclic voltammetry tests were performed using Ag/AgCl
as reference electrode, a 3 mm diameter platinum gauze electrode
as working electrode, and a platinum wire electrode as counter
electrode with 50 mV s-1 scanning rate. The electrolyte was
Results and discussion
Absorption spectra
The absorption spectra (Figure 2) of T1–T8 in toluene solution all
show a strong charge transfer (CT) absorption band with a peak
varying within 390−470 nm, and a localized absorption band of
coumarin moiety around 300−350 nm (Table 1), depending upon
substituents. What’s more, it could be concluded that the main
contribution to the CT bands of these PSs was π→π* transitions due
to their large molar extinction coefficients. Interestingly, compared
to the prototype PS T1, the introduction of bromine atoms onto the
coumarin ring (T2–T5) result in a redshift of the CT band while an
opposite-blueshift appears when bromines are linked on the
benzene ring (T6–T8). Additionally, the shifts of T6–T8 are more
remarkable than those of T2–T5, which means the main
composition of these CT bands is from the right dimethylamino
group to the central carbonyl group.
acetonitrile (5.0 mL) containing 0.1
M tetrabutylammonium
hexafluorophosphate (TBAPF6) and 1 × 10-4 M PSs.
1.0
T1
T2
Theoretical calculation
0.8
0.6
0.4
0.2
0.0
T3
T4
T5
T6
T7
T8
Quantum chemical calculations were carried out using the
Gaussian 09 program package.[36] The ground-state geometries of
T1–T8 were obtained from full optimizations using DFT with
PBE1PBE functional[37] and 6-31G(d) basis set. The effects of solvent
were included using the polarized continuum model (PCM)[38,39] and
IDSCRF[40] cavity, in which the solvent toluene was employed for
simulating the experimental conditions. On the basis of optimized
geometry for ground states, TD-DFT[41,42] calculations were
performed using PBE1PBE functional (TD-PBE1PBE+IDSCRF) within
adiabatic approximation to predict excitation energies, which had
successfully been applied to solutions[43-48]. The oscillator strengths
(f) of transitions and ground to excited state electric transition
dipole moments were also calculated by the same method,
300 350 400 450 500 550 600
Wavelength (nm)
Figure 2. The normalized UV-Vis absorption of T1–T8 in toluene.
2 | J. Name., 2012, 00, 1-3
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Table 1. The photophysical, photochemical and electrochemical
parameters of T1−T8.
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
Compd
T1
T2
T3
T4
T5
T6
T7
T8
abs
λmax
448
459
459
458
468
440
391
416
(nm)
T1+DPBF
T2+DPBF
T3+DPBF
T4+DPBF
T5+DPBF
T6+DPBF
DPBF
εmax (104
M-1cm-1)
2.36
2.18
1.70
608
1.84
604
2.39
620
2.17
562
1.90
560
1.40
536
fl
λmax
584
5198
36
612
5447
14
(nm)
Δνss
5339 5278 5238 4934 7718 5382
(cm-1)
Φf (10-4)
18
27
11
66
36
79
0
20 40 60 80 100 120 140 160 180
Sd(Φf)
(10-5)
Eox (V)
2.12
0.80
0.71
0.98
1.41
1.03
1.41
1.02
0.70
1.03
2.83
1.15
3.54
1.28
7.07
1.29
Irradiation time (s)
Figure 4. Decay of the absorbance of DPBF at 400 nm.
abs
λmax is the absorption maximum, εmax is the molar absorption
fl
influence on ΦΔ values of T2–T5 compared to that of T1. However,
T6 with one bromine was linked onto the benzene ring can generate
more singlet oxygen compared with others. It is a pity that the
absorption decay of DPBF for T7 and T8 cannot be obtained because
T7 and T8 have no absorption at 473 nm and DPBF is unstable using
415 nm as the light source. Even so, it is clear that the heavy atom
effect is closely related to the modification sites of bromines.
Electron spin resonance spectra was further used to qualitative
evaluate the production of singlet oxygen.[55,56] Using TEMP as 1O2
trapping reagent, the time dependent of EPR signal (inset in Figure
5) of the oxidation product TEMPO, which exhibits triplet peaks in
equal intensity, was measured in toluene solutions of T1–T8 under
an identical irradiation intensity. Although EPR is generally used to
qualitatively evaluate the production of singlet oxygen, it still can be
confirmed from the results (shown in Figure 5) that T6 and T7 have
much stronger ability to produce singlet oxygen compared to other
PSs. Combining the different effects of bromines on the absorption
spectra of T2–T5 and T6–T8, it can be further deduced that whether
the heavy atom effect can play a role is decided by the substituted
position of bromines, which is consistent with the pervious report
by O’Shea et al.[55] Here, it is strange that T8 with two bromine
atoms on the benzene ring shows no ability to produce singlet
oxygen. To look for the reason, the photobleaching property and
oxidation-reduction potential of T1–T8 were examined in the
following sections.
coefficient at λmaxabs, λmax is the fluorescence emission maximum,
Φf is the fluorescence quantum yield, Sd(Φf) is the standard
deviation, Eox is the oxidation potential in acetonitrile
1.0
T1
T2
T3
T4
0.8
0.6
T5
T6
T7
T8
0.4
0.2
0.0
500
550
600
650
700
750
Wavelength
Figure 3. The normalize fluorescence emission spectra of T1–T8 in
toluene (The excitation wavelength is fixed at 400 nm).
Fluorescence emission spectra
The fluorescent emission spectra of these PSs in toluene are
shown in Figure 3. The fluorescence emission maximum (λmaxfl) of
the prototype PS T1 without bromine substituent lies in 584 nm
under the excitation wavelength of 400 nm. Similar to their
absorption spectra, the fluorescence emission spectra of T2–T5 also
0.4
20 G
T1
T2
T3
T4
0.3
exhibit
a redshift, while those of T6–T8 present a blueshift
compared to T1 (Table 1). The fluorescence quantum yields (Φf) of
T1–T8 in toluene are very low, in the range of 0.0011 to 0.0136,
using fluorescein sodium in 0.1 M sodium hydroxide solution (Φf =
0.9)[53] as the reference. All values are too small, indicating the
stronger nonradiative deactivation of the excited state.
T5
T6
T7
T8
TEMP
0.2
0.1
0.0
Singlet oxygen
PDT is based on the photooxidation of target tissues. Up to
now, the major damage mechanism has been concluded to the
generation of ROS, especially singlet oxygen. In most studies, the ΦΔ
of a PS was used to estimate its PDT potential.[54] Using DPBF as the
scavenger, the absorption decay of DPBF in solutions containing T1–
T6 were determined. The results are very interesting. Due to the
slope of the decay curves in Figure 4, it is inferred that the
introduction of bromine atom onto the coumarin ring has slightly
0
5
10
15
20
25
30
Irradiation time (s)
Figure 5. EPR signal intensity of TEMP-1O2 adducts as a function of
irradiation time (irradiated at 415 nm) for toluene solutions of T1–
T8.
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T1-T5
0
-20
-40
-60
-80
T7
T6
T1
T2
T3
T4
T5
T6
T7
T8
T8
Figure 7. The calculated HOMO and LUMO orbitals for T1–T8, along
with their corresponding orbital energies (in eV).
-100
0
20
40
60
80
100
T (s)
of 3.339 eV between LUMO and HOMO among T1–T8. The
calculated emission spectra present the same trend with the
experimental results, although there are some wavenumber
differences between them. Through comparing the calculated
results (listed in Table S1) from three different functionals, PBE1PBE,
CAM-B3LYP and WB97XD, it can be seen that PBE1PBE is the most
proper one for these PSs.
Figure 6. The photostability of T1–T8 in toluene with the irradiation
time.
Photostability
As shown in Figure 6 and Figure S1, T1–T5 presented excellent
photostability. There is no any decay of their absorption spectra
after 90s irradiation by a 415 nm laser. However, T6–T8 show
inferior photostability, especially T8. The absorption maxima of T6
and T7 decrease 19% and 17%, respectively, after 90s irradiation,
while the datum of T8 is more than 70% only after 12s irradiation.
Obviously, when bromine atoms are linked on the phenyl ring, the
excited states of the major molecular skeleton become unstable.
The possible reason will be discussed in the following section of
theoretical calculation.
It is interesting to notice that the HOMO orbitals of all PSs mainly
locate in the right benzene ring, while their corresponding LUMOs
lie in the left coumarin ring (Figure 7). Combining with the fact that
only T6 and T7 with bromine atoms attached on the benzene ring
show increased capability to generate singlet oxygen. We speculate
that the heavy atomic effect mainly depend on its influence on
HOMO orbitals. Here, T8 looks like an exception. From the
calculated ground state and excited state structures of all PSs (Table
S2), it can be seen that the torsional angle between substituted
phenyl ring and linkage part is ca. 29.8° in ground state and
becomes ca. 48.0° in the excited state for T8. Obviously, the
introduction of bromine made the benzene ring become much
easier to be rotated in the excited state, and thus the stability of the
excited state decreased, resulting in a rapid photobleaching of T8.
For T6 and T7, there are two different conformers. In their ground
states, the exchange between two conformers is difficult. However,
it can become easy in their excited states, leading to the relative
inferior photostability of T6 and T7.
Electrochemical Property
The oxidation-reduction potentials of the PSs were investigated
by cyclic voltammetry. The results are listed in Table 1 and shown in
Figure S2. Compared to the prototype PS T1, the introduction of
bromine atoms onto the coumarin ring (T2–T5) or benzene ring (T6–
T8) both results in an increased oxidation potential,[57,58] which are
in good agreement with the following calculation results.
Theoretical calculation
The obtained frontier orbitals (HOMO and LUMO) for T1–T8
are quite close, as depicted in Figure 7, from which it can be
observed that the molecular orbital lobes of HOMO and LUMO are
mainly distributed on different parts. The right part is electron-
donating (mainly in HOMO) and left part is electron-accepting
(mainly in LUMO). The middle part -C(O)-CH=CH- behaves as a
conjugated linkage, on which both HOMO and LUMO orbitals have
the molecular orbital lobes. According to excitation selectivity, the
overlap of HOMO and LUMO takes place at this region, which is
confirmed by calculated absorption spectra (listed in Table 2). The
calculated emission spectra indicate that the –C(O)-C bond is
stretched from 1.459 to 1.513 Å for PS T1, further confirming the
relaxation of this region. Such orientation is to stabilize the
excitation state structure via the shortening of two adjacent C-C
bonds of C(O)-C (left and right).
Table 2. The calculated absorption (in nm) and emission
wavenumbers (in nm) of T1−T8 and their corresponding oscillator
strengths, along with experimental measurements.
Compound
T1
T2
T3
T4
T5
T6
T7
T8
476a
341c
448b
499
345
459
496
349
459
493
344
458
514
352
468
458
339
440
434
340
391
442
339
416
abs
λmax
0.62
0.55
1.02
0.58
0.71
0.57
0.91
0.53
0.67
0.65
0.72
0.63
0.44
0.57
0.47
fa
0.87c
600a
584b
642
612
639
608
633
604
670
620
567
562
573
560
576
536
fl
The data in Table 2 also show that there are two absorption
peaks for each compound, similar to experimental results in Figure 2
λmax
abs
and Figure S1. The second number of λmax in Table 2 belongs to
fe
0.38
0.36
0.37
0.37
0.35
0.40
0.38
0.28
a: calculated; b: experimental; c: the third excited state. λmaxabs is the
the excitation of -CH=CH- double bond, quite close for all PSs (339-
352 nm). However, the property of –C(O)-C bond might be affected
by both left and right substituent groups, leading to the first
fl
absorption maximum, fa is the absorption oscillator strengths, λmax
is the fluorescence emission maximum, fe is the emission oscillator
strengths.
abs
number of λmax vary within 391−459 nm (experimental) and
434−514 nm(calculated). Herein, the PS T7 has the shortest
absorption wavenumber due to the biggest energy level difference
4 | J. Name., 2012, 00, 1-3
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15 A. G, Al-Sehemi, S. R. El-Gogary, Chin. J. Chem., 2012, 30
316-320.
,
Conclusions
A series of coumarin derivatives modified by one or two
bromine atoms were synthesized through aldol condensation
reaction. It was shown that the modification position and the
16 T. F. Zhu, Y. Wang, W. L. Ding, J. Xu, R. H. Chen, J. Xie, W. J.
Zhu, L. Jia and T. L. Ma, Chem. Biol. Drug Des., 2015, 85, 385.
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number of bromine atoms both had
a great effect on the
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photophysical and electrochemical properties of these PSs. In this
study, linking bromine atoms on the benzene ring (mainly in HOMO)
directly was beneficial to increase the singlet oxygen yields of target
PSs, but at the same time it also led to a decline in their
photostability, especially for T8. The reason was revealed by
theoretical calculation. The results will provide a potential guidance
for the design of new PSs in photodynamic therapy.
Phthalocyanines, 2001, 5, 105-129.
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Conflicts of interest
There are no conflicts of interest to declare.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (61575208), the Austrian-Chinese
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