Synthesis and photophysical properties of monomeric and dimeric halogenated aza-BODIPYs

Article abstract of DOI:10.1016/j.molstruc.2019.127108

In this study, the effects of incorporation of halogen atoms at different positions and dimerization on the photophysical properties of the aza-BODIPYs were investigated. Aza-BODIPY derivative carrying chlorine atoms on the para-position of the distal phe

Full text of DOI:10.1016/j.molstruc.2019.127108

Journal Pre-proof
Synthesis and photophysical properties of monomeric and dimeric halogenated aza-
BODIPYs
H. Şeyma Çınar, Şennur Özçelik, Kerem Kaya, Öznur Dülger Kutlu, Ali Erdoğmuş,
Ahmet Gül
PII:
S0022-2860(19)31214-1
DOI:
https://doi.org/10.1016/j.molstruc.2019.127108
MOLSTR 127108
Reference:
To appear in: Journal of Molecular Structure
Received Date: 3 July 2019
Revised Date: 17 September 2019
Accepted Date: 20 September 2019
Please cite this article as: H.Ş. Çınar, Ş. Özçelik, K. Kaya, Ö.Dü. Kutlu, A. Erdoğmuş, A. Gül, Synthesis
and photophysical properties of monomeric and dimeric halogenated aza-BODIPYs, Journal of
Molecular Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.127108.
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Graphical Abstract
Synthesis and Photophysical Properties of Monomeric and Dimeric Halogenated Aza-
BODIPYs
H. Şeyma Çınar, Şennur Özçelik, Kerem Kaya, Öznur Dülger Kutlu, Ali Erdoğmuş, Ahmet
Gül
Photophysical properties of dimeric and halogenated aza-BODIPYs were investigated and
compared with tetra-phenyl aza-BODIPY. The aza-BODIPY derivative carrying bromine
atoms at the central core showed the highest efficiency of singlet oxygen generation.

Synthesis and Photophysical Properties of Monomeric and Dimeric Halogenated Aza-
BODIPYs
H. Şeyma Çınar[a], Şennur Özçelik*[a], Kerem Kaya[a], Öznur Dülger Kutlu[b], Ali
Erdoğmuş[b], Ahmet Gül*[a]
[a] Department of Chemistry, Istanbul Technical University, Maslak, Istanbul, 34469, Turkey
[b] Department of Chemistry, Yildiz Technical University, Davutpasa, Istanbul, 34210, Turkey
* Corresponding author.
E-mail address: ahmetg@itu.edu.tr; oksuzse@itu.edu.tr (A. Gül; Ş. Özçelik)
1

Abstract: In this study, the effects of incorporation of halogen atoms at different positions
and dimerization on the photophysical properties of the aza-BODIPYs were investigated.
Aza-BODIPY derivative carrying chlorine atoms on the para-position of the distal phenyl
groups (4) and its core-brominated analogue (5) were prepared to establish the external and
internal heavy atom effects. Dimerization of aza-BODIPY 4 through oxidative homocoupling
with FeCl3 yielded the target homonuclear aza-BODIPY dimer (6). All of the aza-BODIPY
derivatives prepared in this study were fully characterized by using UV-Vis, Fluorescence,
NMR (1H, 13C, 11B and 19F), Mass and X-Ray spectroscopy techniques. The photophysical
properties were fully characterized and compared to those of the tetra-phenyl aza-BODIPY
derivative (A). Singlet oxygen generation experiments were also performed. The aza-
BODIPY derivative possessing bromine atoms at the central core displayed the utmost
efficiency for singlet oxygen generation.
Keywords: Aza-BODIPY; photophysics; singlet oxygen generation; PDT; bromination
1. Introduction
Photodynamic therapy (PDT), noninvasive method for treatment of superficial tumors, is
being recognized as an alternative to the conventional cancer therapies. This technique is
consisted of two simple procedures; transferring of photosensitizing agent into the tumor and
activating the sensitizer by illuminating the tumor with light of the appropriate wavelength.
Upon absorption of the light, photosensitizer is light-activated from its ground state into
excited singlet state. In order to obtain photodynamic effect, the photosensitizer of minimum
dark toxicity should undergo electron spin conversion from its excited singlet state to triplet
state. Singlet oxygen, the damaging specie in PDT, is generated by the energy transfer from
excited triplet photosensitizer to molecular oxygen. This spin-forbidden transition at
2

photosensitizer, called as inter system crossing (ISC), has a crucial role on the effectiveness of
PDT as the amount of singlet oxygen generated in this method depends directly on ISC step 1-
3. ISC is commonly enhanced by spin-orbit perturbations due to the presence of heavy atom 3
on either the absorbing core of the molecule (internal heavy atom effect) 4 or on the peripheral
positions of the structure (external heavy atom effect) 4-6
.
Porphyrins, chlorins, and bacteriochlorins, most widely clinically used PDT sensitizers, are
cyclic tetrapyrroles 7, 8. These agents have some compelling drawbacks such as toilsome
preparations, troubles in purification and challenging modifications for the optimization of
their photophysical properties 9.
Over the last ten years, a novel PDT photosensitizer class that structurally based on
dipyrromethene (DPM) and azadipyrromethene (ADPM) chromophors has emerged. DPM
and ADPM can be considered structurally as half of porphyrin and porphyrazine, respectively.
These bidentate ligands have attracted much attention for their photophysical properties
comparable to those of porphyrinoids. Furthermore these ligands have many synthetic
advantages over porphyrins; they keep away from low-yield macrocyclization step and
burdensome purification processes. Moreover, bidentate motif allows these ligands to display
an enormous versatility of metal coordination geometries in comparison to the rigid square-
planar geometry of cyclic tetrapyrroles 10. The most studied compounds of these chromophors
are the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes, BODIPYs. BODIPYs can be considered
as candidates for ideal photosensitizers owing to their advantegous features such as their
strong absorption in the range of 500-600 nm with high molar absorption coefficients,
emission in the NIR region, moderate to high fluorescence quantum yields, and high
photostability 1, 9, 11-15. Due to these significant properties, the number of the researches on
BODIPY derivatives for various applications has increased recently 3, 16-20
.
3

The deep penetration into the tissue, an obligatory for an efficient photosensitizer, can be
achieved by strong absorptions and emissions in the low energy regions (650–900 nm) 1, 21, 22
.
So, numerous chemical modifications have been applied to extend their absorptions to longer
wavelengths. One of the under-examined strategy is replacement of the methine group at the
8-position of the core unit with nitrogen yielding a new class of compounds,
azadipyrromethenes boron difluoride (known as as aza BODIPY) 23. The presence of
nitrogen atom rather than carbon in aza-BODIPY structure causes significant photophysical
properties by lowering the HOMO-LUMO energy gap 24. Aza-BODIPYs’ absorption and
emission wavelengths are red-shifted for about 100 nm when compared to those of BODIPYs
25-29
.
As the nitrogen atom decreases the S1−T1 energy gap by restricting the spatial
overlapping between the HOMO and LUMO, the population of triplet states may be
increased in aza-BODIPYs in contrast to the conventional BODIPYs 30. Furthermore, aza-
9
BODIPYs’ molar absorption coefficients are much higher than those of porphyrins . These
superior photophysical properties of aza- BODIPY facilitate an efficient singlet-oxygen
generation. Consequently, aza-BODIPY agents have a higher chance to be evaluated in
clinical treatment than any other derivatives of BODIPY class 9, 31, 32
.
Aza-BODIPYs’ ability for singlet oxygen generation can be improved by the help of heavy
1,
atom effect; either by attaching halogen atoms to the core or to the peripheral phenyl rings
33. It is reported in the literature that ISC mechanism is only affected by the number of heavy
atoms at the 2,6 positions of the BODIPY core 4, 34, as the heavy atoms at 2,6-position of aza-
BODIPY core increase the probability of ISC due to internal heavy atom effect 35. This
internal heavy atom effect was examined by the studies conducted on their fluorescence and
phosphorescence properties as well as on their ability to generate singlet oxygen of aza-
BODIPY 4, 12, 34, 36, 37. On the other hand, in the case of aza-BODIPY derivative carrying
4

bromine atom as a substituent on the phenyl groups, no remarkable decrease in the quantum
yield was monitored 36, 38
.
Dimerization leading photoinduced electron transfer (PET) can be the other chemical
39
modification to achieve an adequate triplet state generation . The number of the studies on
dimeric aza-BODIPY derivatives is so limited in the literature. These papers are reporting on
40-42
dimeric structures are pyrrolopyrro aza-BODIPYs (PPAB)
benzodipurrolidone-based
43
dimeric aza-BODIPYs and isoindigo-based dimeric aza-BODIPYs 44. There is only one
paper reporting on the preparation of aza-BODIPY dimer through oxidative homocoupling
with FeCl3 45. Photophysical measurements in this paper revealed that absorption maxima of
the dimers were shifted to longer wavelengths when compared to the corresponding
monomers 44.
In this study, it is aimed to investigate the influence of incorporation of halogen atoms and
dimerization on the photophysical and photochemical properties of aza-BODIPY derivatives
as well as on their efficiencies of singlet oxygen generation for their potential use as
photosensitizers for photodynamic therapy. In line with this purpose, aza-BODIPY that is
substituted with Cl atoms at the para position of the distal phenyl groups and its 2,6-
dibrominated analogue were synthesized for elucidating the effect of halogen atoms at
different positions in the aza-BODIPY system. Dimerization of the aza-BODIPY bearing
chlorine atoms at distal phenyl rings was accomplished by oxidative homo-coupling with
FeCl3. All of the compounds were fully characterized and their photophysicochemical
properties, including fluorescence behavior and their efficiencies for singlet oxygen
generation were examined in THF.
5

2. Experimental Section
2.1. General techniques
Perkin Elmer Spectrum One FT-IR spectrometer and Scinco S-3100 spectrophotometer with a
1 cm and 1 mm path length cuvette were used to obtain the IR and UV-Vis spectra of the
compounds, respectively. 1H (500 MHz), 13C (126 MHz), 11B (160 MHz), and 19F (470 MHz)
NMR spectra of the compounds were recorded on Agilent VNMRS 500 MHz spectrometer.
Tetramethylsilane (TMS) for 1H and 13C NMR, CF4 for 19F NMR and BF3·Et2O for 11B NMR
were used as references. Fluorescence excitation and emission measurements were conducted
on a Varian Eclipse spectrofluorometer using a 1 cm path length cuvette at room temperature.
Mass results were obtained by Bruker Daltonics. X-Ray analysis was realized by Bruker D8
Venture. Melting points of the compounds were recorded on Büchi Melting Point B-540.
Fluorescence-quenching experiments were performed with blended films of P3HT/MxLy in a
1:1 (wt/wt) ratio in HPLC-grade chloroform (400 µL).
2.2. Quantification of singlet oxygen generation
Photo-irradiation was done by using a General Electric quartz line lamp (300W). A 600 nm
glass cut off filter (Schott) and a water filter was used to filter off ultraviolet and infrared
radiations respectively. An interference filter (Intor, 670 nm or 700 nm with a bandwidth of
40 nm) was additionally placed in the light path before the sample. Light intensities were
measured with a POWER MAX5100 (Molelectron detector incorporated) power meter.
2.3. Materials
4-chlorobenzaldehyde, acetophenone, ethanol (EtOH), sodium hydroxide (NaOH),
nitromethane, diethylamine, 1 N hydrochloric acid (HCl), ammonium acetate, n-butanol, N,N-
6

diisopropylethylamine, boron trifluoride diethyl etherate, dichloromethane (DCM), n-hexane,
n-pentane, chloroform (CHCl3), petroleum ether, bromine, ethyl acetate, and iron(III) chloride
were of reagent grade quality obtained from commercial suppliers. Tetra-phenyl derivative
(A) was prepared according to the reported procedure 45, 46
.
2.4. Synthesis of 3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (1) 47
A solution of 4-chlorobenzaldehyde (5.60 g, 39.0 mmol) and acetophenone (4.78 g, 4.64 mL,
39.0 mmol) in ethanol was cooled down to 0oC. A solution of NaOH (4.80 g, 120 mmol) in
100 mL of ethanol/water mixture (1:1, v/v) was added dropwise. The reaction mixture was
stirred at room temperature for 24 h. The resulting off-white product was filtered, washed
with cold water and cold ethanol, and dried at room temperature, yield: 7.55 g, (76%). m.p.
1
106−109 °C. H NMR (500 MHz, CDCl3): δ = 8.01 (d, J = 7.2 Hz, 2H), 7.76 (d, J = 16 Hz,
1H), 7.62 – 7.55 (m, 3H), 7.54 – 7.48 (m, 3H), 7.39 (d, J = 8.4 Hz, 2H) ppm. IR (KBr): ῡ
3059 (w, Ar-CH), 1655 (s, C=O), 1603 (m, Ar-C=C), 686 (s, C-Cl) cm-1
2.5. Synthesis of 3-(4-chlorophenyl)-4-nitro-1-phenylbutan-1-one (2) 47
To a solution of compound 1 (2.00 g, 8.24 mmol) and diethylamine (4.30 mL, 41.2 mmol) in
ethanol (45 mL) was added nitromethane (3.00 mL, 49.5 mmol) and the mixture was heated at
reflux for 48 h. The reaction mixture was cooled to room temperature and quenched with 1 N
HCl (10 mL). The resulting precipitate was isolated by filtration, washed with cold water and
ethanol, and dried at room temperature, yield: 2.11 g, (84%). m.p. 88 °C. 1H NMR (500 MHz,
CDCl3): δ = 7.91 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.46 (dd, J = 7.8, 7.5 Hz, 2H),
7.31 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 4.81 (dd, J = 12.6, 6.4 Hz, 1H), 4.66 (dd, J
= 12.6, 8.2 Hz, 1H), 4.22 (quint, J = 7.0 Hz, 1H), 3.48 – 3.38 (m, 2H) ppm. IR (KBr): ῡ 3064
(w, Ar-CH), 1679 (s, C=O), 1544, 1362 (s, O=N-O) cm-1.
7

2.6. Synthesis of aza-dipyrromethene compound (3) 47
A round bottom flask was charged with compound 2 (1.00 g, 3.29 mmol), ammonium acetate
(8.88 g, 115 mmol), and n-butanol (10.0 mL) and heated at reflux for 48 h. During the course
of the reaction, product precipitated from reaction mixture. The reaction mixture was cooled
to room temperature and filtered. Isolated product was washed with cold ethanol to yield the
1
product as a dark-blue solid, yield: 310 mg (36%). M.p. 338−340 °C. H NMR (500 MHz,
CDCl3): δ = 7.98 (d, J = 8.4 Hz, 4H), 7.96 (d, J = 7.9 Hz, 4H), 7.55 (t, J = 7.9, 7.2 Hz, 4H),
7.49 (m, 2H), 7.41 (d, J = 8.4 Hz, 4H), 7.19 (s, 2H) ppm. IR (KBr): ῡ 3260 (w, NH), 3060(w,
Ar-CH), 1594 (s, C=C), 1240 (m, C-N) cm-1. UV-Vis (CH2Cl2): λmax 600 nm
2.7. Synthesis of aza-BODIPY compound (4) 47
Compound 3 (100 mg, 193 µmol) in dichloromethane was treated with N,N-
diisopropylethylamine (350 µL, 2.01 mmol) and stirred for 1 h at room temperature under N2
atmosphere. Then, the reaction mixture was cooled down to 0oC and boron triflouride diethyl
etherate (870 µL, 8.68 mmol) was added and it was stirred at room temperature under N2
atmosphere for 24 h. Then the mixture was washed with water (3×100 mL), the organic layer
was dried over sodium sulphate and evaporated to dryness. Purification by column
chromatography on silica eluting first with n-hexane/ dichloromethane (5:1) and then with n-
pentane/chloroform (3:5) afforded target aza-BODIPY, yield: 86.2 mg (79%); m.p. 249 °C.
1H NMR (500 MHz, CDCl3): δ = 8.04 − 8.02 (m, 4H), 7.98 (d, J = 8.7 Hz, 4H), 7.50 − 7.49
13
(m, 6H), 7.46-7.45 (d, J = 8.7 Hz, 4H), 7.02 (s, 2H) ppm. C NMR (126 MHz, CDCl3): δ =
159.9, 145.4, 142.8, 135.8, 131.3, 131.1, 130.6, 130.4, 129.6, 128.9, 128.6, 119.2 ppm. 11B
NMR (160 MHz, CDCl3): δ = 1.08, 0.88, 0.68 ppm. 19F NMR (470 MHz, CDCl3): δ = -
131.36, -131.43, -131.49, -131.56 ppm. IR (KBr): ῡ 3059 (w, Ar-CH), 1592 (s, C=C), 1480
(m, B-N), 1110 (m, B-F), cm-1 HRMS: m/z calcd. for [M]+ 566.240; found 566.652.
8

2.8. Synthesis of core-brominated aza-BODIPY compound (5)
To a solution of aza-BODIPY 4 (150 mg, 265 µmol) in dichloromethane (15 mL), Br2 (43.1
µL) in dichloromethane (5.00 mL) was added dropwise at room temperature. The reaction
mixture was stirred at room temperature for 6 h. Solvent was evaporated and the residue was
purified by column chromatography on silica gel eluting with petroleum ether/
1
dichloromethane (1:1), yield: 163 mg (85%). m.p. 275 °C. H NMR (500 MHz, CDCl3): δ =
7.81 (d, J = 8.5 Hz, 4H), 7.71 (d, J = 7.0 Hz, 4H), 7.50 − 7.47 (m, 6H), 7.45 (d, J = 8.5 Hz,
13
4H) ppm. C NMR (126 MHz, CDCl3): δ = 158.7, 144.1, 143.6, 136.1, 131.8, 131.1, 130.2,
11
129.1, 128.9, 128.4, 128.1, 110.6 ppm. B NMR (160 MHz, CDCl3): δ = 0.29, 0.11, -0.06
19
ppm. F NMR (470 MHz, CDCl3): δ = -131.98, -132.04, -132.11, -132.17 ppm. IR (KBr): ῡ
3060 (w, Ar-CH), 1590 (s,C=C), 1466 (m, B-N), 1128 (m, B-F), 692 (m, C-Br) cm-1
2.9. Synthesis of aza-BODIPY dimer (6)
To a solution of compound 4 (50.0 mg, 83.0 µmol) in dichloromethane (20 mL), anhydrous
FeCl3 (65.0 mg, 400 µmol) was added. The reaction mixture was stirred for 30 min at room
temperature to perform oxidative dimerization. Then, nitrogen-flashed H2O (40 mL) was
added to the mixture and it was stirred for additional 1 h. The organic phase is washed with
H2O (2 x 50 mL), dried over Na2SO4, and concentrated to dryness on a rotary evaporator. The
solid residue was purified by column chromatography on silica gel eluting fist with petroleum
ether/ dichloromethane (1:1), then with n-hexane/chloroform (2:1), and then by preparative
thin layer chromatography on silica gel eluting with n-hexane/EtOAc (3:1) to afford the
product as a dark blue solid, yield: 6.10 mg (13%). mp. 379 °C. 1H NMR (500 MHz, CDCl3):
δ = 8.11 − 8.06 (m, 4H), 7.92 (d, J = 8.6 Hz, 2H), 7.87 (d, J = 8.6 Hz, 2H), 7.58 − 7.52 (m,
6H), 7.43 − 7.39 (m, 6H), 7.33 − 7.27 (m, 8H), 7.19 − 7.17 (m, 4H), 7.07 (d, J = 8.4 Hz, 2H),
9

11
7.03 (d, J = 8.8 Hz, 4H) ppm. B NMR (160 MHz, CDCl3): δ = 1.17 (dd, J = 37, 22 Hz,
2×BF2) ppm. 19F NMR (470 MHz, CDCl3): δ = -122.10 (m), -127.79 (m), -145.05 (m), -
147.74 (m) ppm. IR (KBr): ῡ 3050 (w, Ar-CH), 1594 (s,C=C), 1468 (m, B-N), 1124 (m, B-F),
694 (m, C-Cl) cm-1 MS (ESI+): m/z calcd for C64H38Cl4N6Na4 [M-2BF2+4 Na]+2 1124.808;
found 1124.4262.
3. Results and Discussion
3.1. Synthesis and Characterization
The synthetic route followed for preparation the target aza-BODIPY compounds is given in
Scheme 1. Aza-BODIPY derivative carrying Cl atoms at the para positions of distal phenyl
groups (4) was prepared to elucidate the effect of halogen atoms on photophysical properties
of the aza-BODIPY dye according to a reported method with some modifications 47. The aza-
BODIPY dye 4 was prepared in an easy four step route starting from chalcone, 3-(4-
chlorophenyl)-1-phenylprop-2-en-1-one (1). Compound 1 prepared through the aldol
condensation reaction between 4-chloro benzaldehyde and acetophenone in 76 % yield.
10

Scheme 1. Synthesis of aza-BODIPY derivatives 4, 5 and 6. i) EtOH, NaOH ii) EtOH,
CH3NO2, DEA iii) CH3COONH4, n-BuOH iv) BF3.OEt2, DIEA, DCM v) DCM, Br2
vi) DCM, FeCl3
Michael addition reaction between 1 and nitromethane in ethanol in the presence of
diethylamine as a base yielded 3-(4-dimethylaminophenyl)-4-nitro-1-phenylbutan-1-one (2) in
84 % yield which after heating with ammonium acetate in n-butanol at reflux for 48 hours
gave dark-blue colored aza-dipyrromethene derivative 3 in 36 % yield. Aza-dipyrromethene 3
was subsequently converted into the target aza-BODIPY derivative 4 (black-yellow silvery
colored compound with 79% yield) by stirring dipyrromethene compound 3 with boron
triflouride diethyl etherate using diisopropylethylamine (i-Pr2EtN) as a base in
dichloromethane at room temperature for 24 h. With the goal of investigating the internal
heavy atom effect, bromine atoms were introduced at the free β-position of both pyrrole rings
11

of 4 as the pyrrole ring is very reactive to electrophilic aromatic substitution. Core-brominated
aza-BODIPY derivative (5) (85% yield) was readily obtained as deep-purple solid by reacting
4 with bromine in dichloromethane at room temperature.
There is a limited number of study on the dimeric BODIPY molecules in which the monomers
are attached directly to each other without any spacer. One of them revealed a red shift in UV-
Vis spectra and an advanced singlet oxygen generation efficiency compared to that of its
monomers 39. The only paper on the synthesis of homonuclear aza-BODIPY dimer
demostrated that the molecule showed enhanced electronic interactions and bathochromic
shift toward near-infrared region 45. Hence, aza-BODIPY dimer was designed and synthesized
through the oxidative homo-coupling of 4 in the presence of FeCl3. The target compound was
obtained as a dark green solid after purification by column chromatography on silica gel
followed by preparative thin layer chromatography in 13% yield.
Characterization of the structures was conducted by using UV-Vis, Fluorescence, NMR (1H,
13C, 11B and 19F), and Mass and X-Ray spectroscopy techniques. The spectroscopic data of the
compounds 1-6 confirmed the proposed structures. The IR spectrum of compound 3 clearly
evidences the formation of aimed dipyrromethene structure by a characteristic NH stretching
band at 3260 cm-1 and the disappearance of the NO2 stretching bands at 1362 cm-1 and 1544
cm-1 due to symmetric and asymmetric stretching modes of the group.
1
In the H NMR spectrum of 3 taken in CDCl3, aromatic proton peaks appeared at 7.98-7.94,
7.57-7.53, 7.49-7.45 and 7.41-7.40 ppm as quartet, triplet, multiplet and doublet, respectively,
13
while the pyrrolic protons came out at 7.19 ppm as a singlet peak, as expected. The C
NMR of 3 could not be obtained due to low solubility of the molecule in CDCl3.
The disappearance of the characteristic NH stretching band and presence of B-N and B-F
stretching bands at 1480 and 1110 cm-1 in the FT-IR spectrum of aza-BODIPY 4 indicated the
1
successful complexation of 3 with boron trifloride diethyl etherate. The H-NMR of
12

compound 4 in CDCl3 also confirmed the proposed structure. In the 1H NMR spectrum of 4,
aromatic protons nearest to the electronegative chlorine atoms of the distal phenyl groups
were observed at 7.99-7.97 ppm as a doublet, the others appeared at 7.46-7.45 ppm as
doublets with a roof effect. On the other hand, protons of the proximal phenyl units which are
the ones nearest to the core were shown at 8.04-8.02 ppm because of the inductive effect in
there these protons were more deshielded than the other proximal aromatic protons that were
observed as a multiple peak at 7.50-7.49 ppm. Furthermore; the peak of pyrrolic protons was
shifted upfield (7.02 ppm) compared to that of dipyrromethene 3 (7.19 ppm). The proposed
aza-BODIPY structure was also confirmed clearly by the presence of the characteristic
molecular ion peaks at m/z = 566.652 [M]+ in the mass spectrum. 11B spectrum of 4 exhibited
a peak at 0.88 ppm confirming the presence of tetra coordinated boron atom as expected 48, 49
.
The successful chealation with BF2 was evidenced also by 19F NMR spectroscopy with
+
signals at δ = -131.36, -131.43, -131.49, and -131.56 ppm 50.
In the FT-IR spectrum of core-brominated aza-BODIPY 5, the B-N, B-F, and C-Br stretching
vibrations were observed at 1466, 1128, and 692 cm-1, respectively. In the 1H NMR spectrum
of 5 taken in CDCl3, aromatic protons of the distal phenyl groups nearest to the
electronegative chlorine atoms appeared at 7.82-7.81 ppm as they were more deshielded due
to the inductive effect of the halogens compared to other two protons on the ring which were
observed at 7.46-7.44 ppm as doublets with a roof effect. The aromatic protons of the
proximal phenyl units which are the nearest protons to the core therefore to electronegative
bromine atoms, were more deshielded due to the inductive effect in there and their signal
came out at 7.72-7.71 ppm, while the other protons of proximal phenyl groups were observed
11
at 7.50-7.47 ppm. The B NMR of 5 showed peaks at 0.29, 0.11, and -0.06 ppm indicating
19
the presence of tetracoordinated boron atom. F NMR spectrum of 5, the peaks at -131.98,-
132.04, -132.11,-132.17 ppm are seen due to the coupling of fluorine atom with 11B atom.
13

Contrary to the 1H NMR spectrum of 4 having four sets of aromatic protons and one pyrrolic
proton, the protons of dimeric aza-BODIPY 6 were observed as eight sets at 8.11 − 8.06,
7.93-7.91, 7.87-7.85, 7.58 − 7.52, 7.42 − 7.39, 7.32 − 7.26, 7.19 − 7.17, 7.07-7.02 ppm as a
multiplet, doublet, doublet, multiplet, multiplet, multiplet, multiplet, multiplet, respectively,
11
indicating the unsymmetrical nature of dimeric aza-BODIPY. The B NMR of 6 involved a
doublet of doublet peak at 1.17 ppm while in the 19F NMR spectrum displayed four multiplets
at -122.10, -127.79, -145.05, -147.74 ppm owing to the inequivalence of the four fluorine
atoms in the two BF2 units 45, 50, 51. The presence of the peaks at m/z = 1124.4262 [M-
2BF2+4Na]+2 in the mass spectrum of aza-BODIPY dimer corresponding to decomposition
products also confirmed the proposed dimeric aza-BODIPY structure such as the peak at 927
can be attributed to [M-2BF2-3 Cl]; the peak at 991 is for [M-4 Cl] and the one at 1049 is for
[M-BF2-Cl]- 50, 52, 53
.
Aza-BODIPY 4 carrying chlorine atom at the para position of the distal phenyl groups and its
brominated analogue 5 exhibited high solubility in THF, CH2Cl2, CHCl3 and DMSO while
the aza-dipyrromethene derivative 3 is slightly soluble in CHCl3 and DMSO. The solubility of
dimer is relatively low when compared to those of 4 and 5. Altough the intra and inter
hydrogen bonding presence in 5 revealed by X-Ray analysis, the solubility of this aza-
+
BODIPY is high in common solvents. This can be explained by the incorporation of BF2
group into the structure and the existence of bromine atoms. Dimeric derivative 6 is soluble in
THF and slightly soluble in CHCl3. The relatively low solubility of the dimer could emerge
from high intermolecular π-π interactions or enlarged surfaced of aromatic structures.
3.2. Crystal Structure
The single crystal of 5 with dimensions 0.01x0.02x0.40mm was grown by slow evaporation
of chloroform solution. The crystal was mounted on a micromount and attached to a
14

goniometer head on a Bruker D8 VENTURE diffractometer equipped with PHOTON100
detector and measured with graphite monochromated Mo-Kα radiation (λ = 0.71073 Å) using
1.0° of ꢀ and ϕ rotation frames at room temperature. The structure has been solved by
54
intrinsic method SHELXS-1997 (Sheldrick, 1997)
and refined by SHELXL-2014/7
56
(Sheldrick, 2014) 55. Molecular drawings are generated using OLEX2. Ver. 1.2-dev
.
Thermal ellipsoids are plotted in Figure 1. Figure 2 shows the crystal packing of the structure
showing π—π interaction and hydrogen bonding and Figure 3 shows the halogen-π stacking.
The Crystal data and structure refinement parametersof 5 is given in Table 1. Table S1-S3
(see supporting information) contain the selected bond lengths, bond and torsion angles for 5.
CCDC 1819243 contains the supplementary crystallographic data for 5. Further details on
crystal data, data collection, and refinements can be found on the supporting information.
5 crystallizes in a monoclinic lattice with P21/c space group with unit cell containing 4
molecules and the whole crystal lattice is strongly stabilized by π—π stacking, halogen—π
stacking and also by intra and intermolecular hydrogen bonding which facilitates the
molecular packing. Although the phenyl rings do not show co-planarity with the boron-
dipyrromethene core due to the large dihedral angles of all the phenyl rings attached to the
aza-BODIPY (C15…C20 phenyl ring and C21…C26 ring has 70.5o and 53o dihedral angles
with respect to the boron-dipyrromethene core) there is a parallel (face-to-face) π—π stacking
occurring between all the aromatic rings with the same centroid—centroid distance of 5.58 Å
(Figure 2). Besides π—π stacking, the crystal lattice contains Cl-π and Br- π stacking, forming
a 2-dimensional supramolecular assembly. (Figure 3) Br2-C9…C13 centroid distance is 3.72
Å and Br2-C13 bond distance is 3.33 Å (1) showing an edge-on Br- π stacking and Cl1-
C9….C13 centroid distance is 4.21 Å and Cl1-C13 distance is 3.30 Å(1) showing also an
edge-on Cl- π stacking. The asymmetric unit of the molecule indicates the presence of overall
half symmetry due to a 2-fold rotational axis as well as a mirror plane passing through B1-N2
15

of the central boron-dipyrromethene unit 57, 58. This observation was also confirmed from the
exactly similar bond parameters between one-half of the molecule with its other half. The
two B-N bond lengths lie in the range of 1.532(2)-1.557(2) Å, which supports well with
reported bond lengths proving the usual delocalization between electron deficient boron and
electron rich nitrogen center 58-60. The boron center has a tetrahedral geometry, coordinated to
two nitrogen atoms from the azadipyrrinato chelate and two fluoride ions, with bond distances
23
and angles similar to the other aza-BODIPYs reported in the literature . There is also an
intramolecular hydrogen bonding occurring between C11-H1---F1 with 2.31 Å distance and
124.8 (7) angle which is obviously much smaller than the sum of van der Waals radii for
hydrogen and fluorine atoms (2.67 Å) 44. Intermolecular hydrogen bonding exist between
phenyl ring hydrogen and second fluorine atom with 2.52 Å (7) distance.(C20-H10---F2). The
fluorine atoms are perpendicular to the boron-dipyrromethene core. Unexpected non-planarity
of the boron-dipyrromethene core is observed due to the dihedral angle of 1.66o between C5-
N2-C4-C3 and C5-N2-C4-N1 planes.
Figure 1. ORTEP drawing of 5 with atom labeling scheme. Ellipsoids are drawn at 50%
probability level.
16

Figure 2. Crystal Packing motif of 5 showing face-to-face π stacking.
Figure 3. Crystal Packing motif of 5 showing face-to-face π stacking.
17

Table 1. Crystal data and structure refinement parameters of 5
Property
Empirical formula
5
C32H18BBr2Cl2F2N3
291(0)
T(K)
0.71073
λ(Å)
Monoclinic
P21/c
Crystal system
Space group
Unit cell dimensions: (Å, º)
18.032(19)
5.583(6)
28.379(3)
2850.7(5)
90°
a
b
c
V(Å3)
α
93.83(3)
β
90°
γ
4
Z
Absorption coefficient (mm-1)
3.073
Dcalc (g/cm3)
F(000)
1.687
1432
0.01 x 0.02 x 0.40
2.26 to 25.00
-21≤h≤20
-6≤k≤6
Crystal size (mm)
θ range for data collection (º)
Index ranges
-32≤l≤33
84210
Reflections collected
Independent reflections
4769
97.3
4769/380
1 /0.779
Coverage of independent reflections (%)
Data/parameters
Max. and min. transmission
R1 = 0.096
wR2 = 0.251
R1 = 0.177
wR2 = 0.333
1.040
Final R indices [I≥2σ(I)]
R indices (all data)
Goodness-of-fit on F2
Largest difference in peak and hole (e Å-3)
0.647/-1.286
3.3 Absorption and Fluorescence Properties
The ground state electronic absorption spectra of BODIPY compounds A, 4, 5 and 6 were
measured in THF (Fig. 4). Maximum absorbances of the BODIPY derivatives were observed
at 650, 651, 659 and 702 nm, respectively. A THF solution of tetra-phenyl aza-BODIPY (A)
depicted a maximum wavelength, λmax at 650 nm. It was observed that the absorption
18

spectrum of 4 was nearly identical with that of A revealing that introduction of chlorine atoms
onto the para positions of distal phentl groups has no significant affect on both absorption
wavelength and band shape. On the other hand, direct attachment of bromine atoms at the 2,6-
position of the central core caused a batochromic shift of 5 nm. This demonstrated that
presence of heavy atoms on the core of aza-BODIPY structure has a higher impact on the
absorption wavelength when compared with substitiutions at the para positions of the distal
25
phenyl groups . In the case of transition from monomer to dimer; absorbance maximum of
dimeric aza-BODIPY 6 is red-shifted of about 50 nm when compared with aza-BODIPY 4.
The exctintion coefficient of the investigated aza-BODIPYs were in the range of 75000-
61
92000 M-1cm-1 which were found to be higher than those of porphyrins and chlorines
.
These high exctition coefficients with absorptions in the therapeutic window are advantages
over other PDT photosensitizers as these strong absorptions can facilitate higher singlet
oxygen generations.
Fig 4. Absorption spectra of BODIPY derivatives A, 4, 5 and 6 in THF (1x10-5 M).
Figure 5 demonstrates the fluorescence spectra of the corresponding aza-BODIPY derivatives.
Excitation of aza-BODIPY derivatives in THF solution at 600 nm gave florescence spectra
which were the mirror images of absorbance spectra with Stoke shifts in the range of 24-34
nm. The fluorescence emission maxima appeared at 674, 679, 684 and 736 nm for A, 4, 5 and
19

6 respectively (Fig. 5). Florescence spectra showed a similar trend with the absorption
spectra; emission wavelength of core-brominated aza-BODIPY 5 was more red-shifted than
aza-BODIPY 4 carrying chlorine atoms on the distal phenyl groups. This is in alignment with
literature informing that substitution at pyrrolic positions has a higher influence on the
electronic structure of the BODIPY core than substitution on the phenyl ring 62. Dimerization
through the pyrrollic positions showed a high impact on the fluorescence properties; emission
maximum of dimeric aza-BODIPY 6 (736 nm) showed a significant batochromic shift of 57
nm with a large Stokes shift of 34 nm when compared with its monomer 4 (679 nm). This
huge red-shift may be attributed to the interactions inside a linear alignment of the same
chromophores according to the exciton model of Kasha and also partially due to a higher
degree of conjugation 45.
Fluorescence quantum yields (ΦF) were determined by comparative method 63, Eq. (1)
2




A






F
ns
ref
s
Eq. 1
Φs = Φref








2
nref
F
A
ref
s




where F and FStd are the areas under the fluorescence curves of the BODIPY derivatives (4 to
6) and the reference, respectively. A and AStd are the absorbances of sample and reference at
the excitation wavelength, and n2 and n2 Std are the refractive indices of solvents
(nTHF:1.407, nEtOH:1.361) used for the sample and the reference measurements,
respectively. Fluorescein was used as a standard; =0.79 in ethanol64. The sample and the
standard were excited at the same relevant wavelength. The solvent effect on the quantum
yield was studied in THF and the emission spectra of compounds 4 to 6 in the solvent were
also compared to that of the reference under the same conditions (Fig. 5). The calculated
quantum yields (ΦF) in the solvent (THF) are 0.175 for A, 0.162 for 4, 0.003 for 5 and 0.100
for 6 (Table 2). Theses calculated quantum yields are all lower than the quantum yield of the
20

reference Fluorescein in ethanol (0.70). The chlorinated aza-BODIPY 4 did not show a
remarkable decrease in fluorescence quantum yield (0.162) when compared with that of the
tetra-phenyl aza-BODIPY A (0.175). This may be attributed to non-dominant heavy atom
effect as the chlorine atoms are far away from the central core. In the case of core-brominated
aza-BODIPY 5; the lowest fluorescence quantum yield was observed indicating an efficient
heavy atom effect. The fluorescence quenching of dimeric aza-BODIPY 6 was more
significant than that of 4 but still higher than that of dibrominated derivative 5. This may be
caused by the possible loss of photosensitizer planarity promoting non-radiative decay to the
ground state 36.
Figure 5. Emission spectra of compounds A to 6 in THF (a), Normalized Emission spectra
(b).
21

Table 2. Spectral and photophysical properties of BODIPY derivatives (A,4,5 and 6) in THF
solution
Compound Q
Emission Stoke ε
ΦF
band λEm (nm) Shifts (log)
λmax
(nm)
(nm)
A
4
650
651
659
702
674
679
684
736
24
28
25
34
4.93 0.175
4.90 0.162
4.96 0.003
4.88 0.100
5
6
3.4. Quantification of singlet oxygen generation
Photodynamic therapy (PDT) is a novel method for cancer treatment based on destroying the
cancer cells by singlet oxygen generated during a photocatalytic reaction. Enhanced spin-orbit
perturbations is vital for an effective PDT photosensitizer because energy is transferred from
the photosensitizer to the ground state oxygen in the final step of singlet oxygen generation
36. In order to investigate their potential use as a photosensitizer in PDT; a comparative study
of singlet oxygen production in THF was conducted to research the abilitiy of aza-BODIPY
derivatives 4, 5 and 6 to produce singlet oxygen. The singlet oxygen generation capabilities
of prepared aza-BODIPYs were determined using DPBF as a quencher of singlet oxygen in
THF 65. When the absorption band of DPBF at 416 nm reduced by light irradiation, no
significant changes on the absorption bands of BODPIY derivatives in THF solutions were
seen (Fig. 6 as an example for 6). A negligible singlet oxygen generation for the aza-
BODIPY derivative carrying chlorine atom at the para position of the distal phenyl ring was
obtained. Substitution of chloro atoms on aryl groups did not enhance the singlet oxygen
generation. In contrast; core substitiution had a significant effect on the efficiency of singlet
oxygen generation, dibrominated aza-BODIPY showed the highest singlet oxygen production
22

among the investigated aza-BODIPY compounds. This indicated that attaching heavy atoms
at the central core is an appropriate way to produce singlet oxygen (Fig. 7).
Figure 6. Electronic absorption spectral changes for compound 5 during the determination of
singlet oxygen quantum yield in THF.
Figure 7. Decrease in the absorbance of the singlet oxygen trap DPBF molecule at 417 nm in
THF for BODIPY derivatives (A to 6).
4. Conclusions
In conclusion, aza-BODIPY derivative 4, 5 and 6 were prepared to investigate the influence
of heavy atom effect and dimerization on the photophysical properties of aza-BODIPYs. In
order to investigate the external heavy atom effect, the aza-BODIPY derivative substituted
23

with chlorine atoms on the para-position of distal phenyl groups (4) was prepared by
following a reported procedure with some modifications. Bromination at the free β-positions
of 4 with bromine in dichloromethane yielded core-brominated aza-BODIPY (5) that was
used to establish the internal heavy atom effect on the photophysical properties. To evaluate
dimerization effect on the photophysical properties of aza-BODIPY dyes, dimeric aza-
BODIPY (6) was prepared by a homo-coupling reaction using FeCl3 as an oxidizing agent.
All of the compounds except for 4 are novel and their chemical structures are elucidated by
using UV-Vis, Fluorescence, IR, NMR (1H, 13C, 11B and 19F), and MS and X-Ray spectral
data. X-Ray analysis of 5 revealed a crystal lattice with π—π stacking and halogen—π
stacking that form a 2-dimensional supramolecular assembly. Beside these stackings, the
crystal latice is also strongly stabilized by intra and intermolecular hydrogen bonding. The
presence of hydrogen bonding did not show a significant effect on the solubility of aza-
BODIPY 5.
Photophysicochemical properties of the aza-BODIPY derivatives were also investigated to
examine their fluorescence behaviors and singlet oxygen generation abilities and compared
with those of tetra-phenyl aza-BODIPY A. The absorption spectra of BODIPY compounds in
THF revealed that direct attachment of bromine atoms at central core has a higher impact on
the absorption wavelength when compared with substitiutions at the para positions of the
distal phenyl groups. Dimerization caused a significant batochromic shift in the absorbance
maximum of about 50 nm when compared with that of monomeric aza-BODIPY 4. Emission
wavelength of core-brominated aza-BODIPY 5 was more red-shifted than aza-BODIPY 4
informing that substitution at pyrrolic positions has a higher influence on the electronic
structure of the BODIPY core than substitution on the phenyl ring. Dimerization through the
pyrrollic positions showed a high impact on the fluorescence properties; emission maximum
of dimeric aza-BODIPY 6 showed a significant batochromic shift of 57 nm with a large
24

Stokes shift of 34 nm when compared with its monomer 4. The fluorescence quenching of
dimeric aza-BODIPY 6 was more significant than that of 4 but still higher than that of
dibrominated derivative 5 indicating an efficient heavy atom effect. As a conclusion, the
newly synthesized compounds particularly the brominated derivative (5) having a high
extinction coefficient with a strong absorption in the therapeutic window can be evaluated as
a photosensitizer for photodynamic therapy applications via type II mechanism.
Acknowledgments
This work was supported by the Research Fund of Istanbul Technical University. AG thanks
Turkish Academy of Sciences (TUBA) for partial support.
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27

Research Highlights
ꢀ Aza-BODIPY derivatives with chlorine atoms on the para-position of the distal phenyl
groups and its core-brominated analogue were prepared.
ꢀ Novel dimeric aza-BODIPY was prepared through oxidative homocoupling with
FeCl3.
ꢀ The effects of incorporation of halogen atoms at different positions and dimerization
on their photophysical properties were investigated.
ꢀ The aza-BODIPY derivative carrying bromine atoms at the central core displayed the
utmost efficiency for singlet oxygen generation.