Photophysical studies of 2,6-dibrominated BODIPY dyes substituted with 4-benzyloxystyryl substituents

Article abstract of DOI:10.1142/S1088424617500420

A series of novel 2,6-dibrominated BODIPY dyes with styryl groups at the 3,5-positions has been prepared, and their photophysical properties have been analyzed to assess their potential utility for use as photosensitizers in photodynamic therapy and in bi

Full text of DOI:10.1142/S1088424617500420

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2017; 21: 431–438
DOI: 10.1142/S1088424617500420
Published at http://www.worldscinet.com/jpp/
Photophysical studies of 2,6-dibrominated BODIPY dyes
substituted with 4-benzyloxystyryl substituents
Bokolombe P. Ngoy, Nthabeleng Molupe, Jessica Harris, Gertrude Fomo,
John Mack*◊ and Tebello Nyokong◊
Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa
Dedicated to Professor Claudio Ercolani on the occasion of his 80th birthday.
Received 26 December, 2016
Accepted 14 April, 2017
ABSTRACT: A series of novel 2,6-dibrominated BODIPY dyes with styryl groups at the 3,5-positions
has been prepared, and their photophysical properties have been analyzed to assess their potential utility
for use as photosensitizers in photodynamic therapy and in bioimaging.
KEYWORDS: BODIPYs, singlet oxygen, Knoevenagel condensation, photophysics, fluorescence,
TD-DFT calculations
recent years there has been a strong research focus on
INTRODUCTION
the synthesis and physicochemical studies of structurally
Photosensitization is the most important photoreaction
modified BODIPY dyes that absorb the near infrared
in the context of singlet oxygen applications such as
(NIR) region [18–22] which is most useful for biomedical
photodynamic therapy (PDT) [1], antimicrobial photo-
applications. In this paper, we report the photophysical
dynamic therapy (PACT) [2, 3], and the photodegradation
properties of BODIPY dyes functionalized with
of organic pollutants [4]. The first singlet excited state
p-hydroxybenzaldehyde and p-benzyloxybenzaldehyde
of molecular oxygen lies at a relatively low energy and
to form styryl groups at the 3,5-positions through
hence can be readily accessed through energy transfer
Knoevenagel condensation reactions and we make use of
from the triplet manifold of a photoexcited organic dye
TD-DFT calculations to analyze trends in their electronic
[5]. Singlet oxygen is cytotoxic and is hence useful for
structures and optical properties.
laser related biomedical applications. Photosensitizers
such as porphyrins, phthalocyanines, naphthalocyanines,
chlorins, bacteriochlorins, and texaphyrins [6–9] are
among the most widely used dyes in PDT research.
Structurally modified boron dipyrromethene (BODIPY)
EXPERIMENTAL
Materials
dyes [10–13] can also be used in this context. This family
of dyes was first reported by Treibs and Kreuzer [14],
and their derivatives have since been studied for a wide
range of applications, such as use as laser dyes [15],
as fluorescent switches [16] and as chemosensors [17].
Halogenation of BODIPY dyes enables a heavy atom
effect which enhances the rate of intersystem crossing
and hence the singlet oxygen quantum yield [18–20]. In
2,4-Dimethylpyrrole, 4-bromobenzaldehyde, 4-formy-
lbenzoic acid, 4-nitrobenzaldehyde, 4-hydroxybenzal-
dehyde, trifluoroacetic acid, p-chloranil, triethylamine,
boron trifluoride diethyl etherate, N-bromosuccinimide,
diphenylisobenzofuran, acetic acid, and piperidine were
obtained from Sigma-Aldrich and were used without
further purification unless otherwise noted. Dried
solvents (supplied by Merck or Minema) were used for
spectroscopic measurements, and 2,4-dimethylpyrrole
was distilled before use.
SPP full member in good standing
*Dr. John Mack, email: j.mack@ru.ac.za.
Copyright © 2017 World Scientific Publishing Company

432
B. P. NGOY ET AL.
Instrumentation
carried out using a tunable laser system consisting of
a Nd:YAG laser (355 nm, 135 mJ/4–6 ns) pumping an
optical parametric oscillator (OPO, 30 mJ/4–6 ns) with
a wavelength range of 420–2300 nm (NT-342B, Ekspla).
All photophysical measurements were made in triplicate
to ensure accuracy.
Ground state electronic absorption spectra were
recorded on a Shimadzu UV-2550 spectrophotometer
while fluorescence excitation and emission spectra were
measured on a Varian Eclipse spectrofluorimeter. 1H NMR
spectra were recorded either on a Bruker 600 MHz or 300
MHz spectrometer in CDCl3 or THF-d8. Mass spectrometry
was performed using a Bruker AutoFLEX III Smartbeam
MALDI-TOF mass spectrometer and a dithranol matrix.
Time-resolved fluorescence lifetime experiments were
carried out in aerated solvents, by using a Picoquant
GmbH time-correlated single photon counting (TCSPC)
device containing a LDH-P-670 diode laser with a 44 ps
pulse width and 20 MHz rate repetition. Exponential decay
curves were analyzed by using Picoquant’s Fluofit software
package.
Synthesis
4-Benzyloxybenzaldehyde was prepared as a precursor
for the Knoevenagel condensation reactions (Scheme1)
and BODIPY dyes 2a–2c were synthesized following
three-step experimental procedure by synthesizing
the BODIPY core followed by halogenations and
Knoevenagel condensation to afford the desired target
compounds (Schemes 2 and 3). The synthetic procedures
used for the 8-(4-nitrophenyl) [30] and 8-(4-bromophenyl)
[31] derivatives of 1,3,5,7-tetramethylBODIPY (2a_H
and 2b_H) and their 2,6-dibrominated analogs (2a_Br
and 2b_Br) [32, 33] have been reported previously, and
the literature procedures were followed in each case. The
absence of an 1H NMR peak for 2,6-position protons was
Photophysical measurements
The fluorescence quantum yields of BODIPY dyes
2a–2c were obtained by using the comparative method
with either Rhodamine 6G or zinc phthalocyanine
(ZnPc) as the standard [23, 24]. The standard and
sample solutions were excited at the same wavelength,
and the solutions had identical optical densities. Singlet
oxygen quantum yields (ΦΔ) were determined in DMF,
DMSO, EtOH, and THF solutions (in air without
bubbling oxygen) using the relative method with
Rose Bengal or ZnPc as the reference compound and
1,3-diphenylisobenzofuran (DPBF) as the singlet oxygen
scavenger [25–29]. Solutions of the sample and reference
photosensitizers containing DPBF were prepared in
the dark and irradiated at a crossover wavelength.
Photoirradiation for singlet oxygen determinations was
OH
O
Benzyl bromide, K2CO3
CH3CN, r.t., overnight
O
H
O
H
(1)
Scheme 1. Synthesis of 4-benzyloxybenzaldehyde (1).
TFA
p-chloranil
TEA
BF3.OEt2
R
H
N
+ R-CHO
DCM, r.t.
N
N
B
F
F
R
B
R
R
Br
Br
NBS (2.4 eq)
(1), AcOH
piperidine
Benzene, 2 h
N
F
N
F
Br
N
Br
N
DCM, 2 h
N
F
N
B
F
F
B
F
2a/b_H
2a/b_Br
NO2
Br
2a/b
O
O
R =
(a)
(b)
Scheme 2. Synthesis of BODIPY dyes 2a and 2b from two meso-aryl-substituted 1,3,5,7-tetramethyl BODIPYs (2a/b_H) and their
2,6-dibromo-substituted analogues (2a/b_Br).
Copyright © 2017 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2017; 21: 432–438

PHOTOPHYSICAL STUDIES OF 2,6-DIBROMINATED BODIPY DYES SUBSTITUTED WITH 4-BENZYLOXYSTYRYL
433
OH
Br
Br
H
AcOH
O
Br
Br
N
F
N
F
Br
Br
B
N
F
N
piperidine
Benzene, 2 h
B
F
2c
2b_Br
OH
HO
Scheme 3. Synthesis of BODIPY dye 2c from 8-(4-bromophenyl)-2,6-dibromo-1,3,5,7-tetramethyl BODIPY (2b_Br).
checked to confirm the purity of 2a_Br and 2b_Br, which
were obtained in 20% and 75% yield, respectively.
2,6-Dibromo-1,7-methyl-4-bromophenyl-BODIPY
(0.1777 mmol) was dissolved in distilled benzene (50 ml).
3 eq of 4-hydroxybenzaldehyde was added and the solution
stirred for 30 min. Under Dean-Stark reflux, the solution
was heated gently in the presence of glacial acetic acid
(0.4 ml) and piperidine (0.4 ml) for 45 min. The solution
was cooled, then washed with water. The product was
extracted using DCM, dried with anhydrous sodium
sulfate and then filtered. The solvent was removed, and the
product was isolated using silica column chromatography
with 7:1 (v/v) petroleum ether/ethyl acetate as the eluent.
2c was obtained as a dark green solid.
4-Benzyloxybenzaldehyde (1).
A
solution of
4-hydroxybenzaldehyde (4 g, 1 eq), benzyl bromide (5.6 g,
1 eq) and potassium carbonate (11.3 g, 2.5 eq) in 150 mL
of acetonitrile was stirred at room temperature overnight.
The solvent was evaporated on a rotary evaporator and the
crude product was diluted with dichloromethane, washed
with water (3 × 30 mL), dried over magnesium sulfate,
concentrated to give the target compound 1 in 95% yield
as a white solid after recrystallization from hot ethanol;
IR (KBr, v, cm-1): 3056 (ArC-H), 2745–2829 (aliph), 1685
(C=O), 1574–1599 (C=C). 1H NMR (300 MHz, THF-d8):
δ 9.89 (s, 1H), 7.85 (d, J = 18.5 Hz, 2H), 7.49 (m, 2H),
7.42 (m, 3H), 7.15 (m, 2H), 5.21 (s, 2H) ppm. 13C NMR
(75 MHz, THF-d8): δ = 189.43, 163.50, 136.70, 131.37,
130.60, 128.33, 127.83, 127.40, 114.90, 69.91 ppm.
BODIPY dyes (2a–2c). Glacial acetic acid (1 mL)
and piperidine (1 mL) in benzene (50 mL) were added to
solutions of 2,6-dibromo-1,7-methyl-4-nitrophenyl-BODIPY
or 2,6-dibromo-1,7-methyl-4-bromophenyl-BODIPY (1 eq)
and 4-benzyloxybenzaldehyde (2 eq). The mixture was
refluxed for 2 h using a Dean-Stark apparatus to remove
water formed during the reaction. The crude product was
concentrated and then diluted with dichloromethane,
washed with hydrochloric acid, sodium hydrogen carbonate,
and brine. The target compounds 2a and 2b were obtained
in very low and 20% yield, respectively, as dark green solids
after silica column chromatography with petroleum ether-
ethylacetate (4:1 v/v).
2c:Yield (147 mg, 74%): 1H NMR (600 MHz, THF-d8)
δ 8.31 (d, J = 16.6 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H), 7.79
(d, J = 16.6 Hz, 2H), 7.68 (d, J = 8.5 Hz, 5H), 7.56 (d,
J = 8.2 Hz, 2H), 7.00 (d, J = 8.5 Hz, 5H), 1.67 (s, 6H)
ppm. MALDI-TOF (M+H): Calc. for C33H25B1Br3F2N2O2:
770.9, found: 771.1.
Theoretical calculations
The density functional theory (DFT) method was used
to carryout geometry optimizations for2a–2cby using the
B3LYP functional of the Gaussian 09 program package
[34] with 6-31G(d) basis sets. The same approach was
used to calculate the electronic absorption properties by
using the time-dependent DFT (TD-DFT) method with
the CAM-B3LYP functional, which includes a long-range
correction of the exchange potential and incorporates an
increasing fraction of Hartree–Fock (HF) exchange as
the interelectronic separation increases. The polarized
continuum model was used to provide a tetrahydrofuran
solvation environment for the geometry optimizations
and the TD-DFT calculations.
1
2a: H NMR (600 MHz, CDCl3): δ 8.18 (d, J =
16.6 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.68 (d, J =
8.6 Hz, 6H), 7.52 (d, J = 7.2 Hz, 4H), 7.48 (s, 4H), 7.41
(d, J = 7.3 Hz, 2H), 7.25 (s, 2H), 7.09 (s, 4H), 5.19 (s,
4H), 1.52 (s, 6H) ppm. MALDI-TOF (M+H): Calc. for
C47H37B1Br2F2N3O4: 916.1, found: 917.1.
RESULTS AND DISCUSSION
2b: 1H NMR (600 MHz, CDCl3) δ 8.15 (s, 1H), 8.13 (s,
1H), 7.75–7.69 (m, 2H), 7.63 (dd, J = 10.3, 7.7 Hz, 6H),
7.48 (d, J = 7.4 Hz, 4H), 7.46–7.41 (m, 4H), 7.41–7.34
(m, 2H), 7.25–7.20 (m, 2H), 7.04 (d, J = 2.7 Hz, 4H), 5.16
(s, 4H), 1.48 (s, 6H) ppm. MALDI-TOF (M+H): Calc. for
C47H37B1Br3F2N2O2: 951.0, found: 951.9.
Synthesis
A series of novel halogenated and styrylated BODIPY
dyes 2a–2c were prepared using standard synthetic
procedures so that their potential suitability for use in
Copyright © 2017 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2017; 21: 433–438

434
B. P. NGOY ET AL.
biomedical applications could be assessed. As has been
reported previously [21], halogenation and styrylation
both result in a red shift of the main BODIPY spectral
band, Fig. 1. The introduction of bromine atoms and nitro
groups at the para-positions of the meso-aryl ring at the
bridging 8-position of the BODIPY core provides scope
for further structural modifications that would enable
nanoparticle conjugation [35]. Nanoparticle conjugates
are known to selectively accumulate in cancer tumors due
to the enhanced permeability and retention effect. Studies
on 2,6-diiodinated-3,5-styrylBODIPYs have suggested
that the introduction of electron donating meso-aryl
substituents in this context, such as aniline rings [35],
could enhance the singlet oxygen quantum yield values
[10, 11, 36, 37]. Benzyloxy groups were added to the
styryl groups at the para-positions of the phenyl rings
to form 2a and 2b so that their effect on the optical and
photophysical properties could be explored.
lie in the range of 668–684 nm, while emission bands are
observed in the 680–720 nm region (Table 1). The band
maxima of 2a–2c (Table 1) lie in the therapeutic window
(620–850 nm) making these chromophores potentially
useful for photodynamic therapy and bioimaging.
Trends in the optical properties and electronic structures
of 2a–2c (Figs 3–5) have been analyzed through a
comparison of calculated TD-DFT spectra with those of
model complexes of the analogous 1,3,5,7-tetramethyl-
substituted BODIPY core with either H or Br atoms at
the 2,6-positions corresponding to the precursors shown
in Schemes 2 and 3. In each case, the transition to the
S1 state that gives rise to the main spectral band in the 600–
700 nm region is predicted to be dominated by the
HOMO → LUMO one-electron transition, Table 1, while
the other intense bands that are observed in the 300–
400 nm region (Fig. 1) can be assigned to transitions that
are associated with MOs that are largely localized on the
styryl groups (Fig. 5). As has been reported previously
[21], when styryl groups replace the methyl group at the
3,5-positions of the BODIPY core, there is a significant
decrease of the HOMO−LUMO gap (Fig. 4) and hence
a large red-shift of the main BODIPY spectral band
Optical spectroscopy
Figure 2 contains normalized absorption spectra of 2a
and 2b in a series of different solvents. The band maxima
Fig. 1. Normalized absorption spectra of 2b_H, 2b_Br, and 2c (Schemes 2 and 3) in dichloromethane.
Fig. 2. Solvent dependence of the absorption spectra of 2a and 2b.
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PHOTOPHYSICAL STUDIES OF 2,6-DIBROMINATED BODIPY DYES SUBSTITUTED WITH 4-BENZYLOXYSTYRYL
435
Table 1. The main spectral bands in the TD-DFT spectra of the B3LYP optimized
geometries of the two sets of tautomers of 2a–2c at the CAM-B3LYP/6-31G(d) level
of theory.
Calca
Expb
Wave functionc =
2a_H
2a_Br
2a
(S0 → S1) 23.1
(S0 → S1) 22.3
(S0 → S1) 16.6
(S0 → S1) 23.3
(S0 → S1) 22.4
(S0 → S1) 16.8
(S0 → S1) 17.0
432
449
601
430
446
595
588
(0.63) 19.8
(0.73) 18.8
(1.08) 14.7
(0.64) 19.9
(0.73) 18.8
(1.07) 14.9
(1.06) 14.9
506
532
680
502
532
670
669
98% HOMO → LUMO; …
98% HOMO → LUMO; …
95% HOMO → LUMO; …
98% HOMO → LUMO; …
98% HOMO → LUMO; …
95% HOMO → LUMO; …
96% HOMO → LUMO; …
2b_H
2b_Br
2b
2c
a Calculated band energies (103.cm-1) and wavelengths (nm), with oscillator strengths
in parentheses (f). b Observed energies (103.cm-1) and wavelengths (nm) in THF or
dichloromethane. c The wave functions based on the eigenvectors predicted by TD-DFT.
Fig. 3. MO energies and angular nodal patterns of the HOMO and LUMO of 2a and 2b and model complexes with
no styryl moieties and either protons (_H) or bromine atoms (_Br) at the 2,6-positions.
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436
B. P. NGOY ET AL.
Fig. 4. MO energies of 2a–2c and model complexes with methyl groups replacing the styryl moieties and either protons (_H)
or bromine atoms (_Br) at the 2,6-positions. Occupied MOs are highlighted with small black diamonds. Gray lines are used to
denote the HOMO and LUMO, while the HOMO−LUMO gap values are highlighted with gray diamonds and are plotted against a
secondary axis.
(Fig. 5), since there are larger MO coefficients on
the styryl group in the HOMO, due to the larger MO
coefficients at the points of attachment on the BODIPY
core (Fig. 3). The smaller red shift that is associated with
bromination at the 2,6-positions (Fig. 5) can be readily
explained by the mesomeric effect that is associated with
the lone pair orbitals of the bromine atom, since there is
a relative destabilization of the HOMO (Fig. 4), which
has larger MO coefficients at these positions (Fig. 3). The
attachment of a benzyloxy group at the para-position of
the phenyl ring of the styryl group in the structure of 2b
has a similar effect on the energies of the frontier MOs to
the hydroxyl group of 2c (Fig. 4), so the spectra of 2b and
2c are predicted to be very similar, which matches what
is observed experimentally (Table 2).
Photophysical properties
Table 2 provides the main photophysical parameters
for 2a–2c. The fluorescence lifetime values (tT) lie
in the 2.0–3.5 ns range. In the absence of structural
modifications, BODIPY dyes have unusually high
fluorescence quantum yield values due to the rigid
structure of the BODIPY core and very low triplet state
quantum yield values [38]. Structural modifications can
be used to form BODIPY dyes that have a combination
of significant fluorescence and singlet oxygen quantum
yield values. The combined utility for bioimaging and
singlet oxygen generation along with the introduction of
Fig. 5. Calculated TD-DFT spectra of 2a and 2b and model
meso-aryl groups that can be further modified to enable
complexes with methyl groups replacing the styryl moieties and
nanoparticle conjugation makes the dyes potentially
either protons (_H) or bromine atoms (_Br) at the 2,6-positions
suitable for use in theranostics [39–43]. The introduction
of the BODIPY core (Scheme 2). Gray diamonds are used to
of bromine atoms to form the 2b_Br 1,3,5,7-tetramethyl
precursor results in a relatively high singlet oxygen
quantum yield due to the heavy atom effect (Table 2). The
highlight the lowest energy transition that is assigned to the
main spectral band (Table 2). Details of the calculations for this
band are provided in Table 1.
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PHOTOPHYSICAL STUDIES OF 2,6-DIBROMINATED BODIPY DYES SUBSTITUTED WITH 4-BENZYLOXYSTYRYL
437
Table 2. Photophysical parameters for 2a–2c, including the
wavelengths of the band maxima in the absorption (lmax) and
emission (lem) spectra, the fluorescence lifetimes (tF) and
the fluorescence (ΦF) and singlet oxygen (ΦΔ) quantum yield
values.
fluorescence and singlet oxygen quantum yield values
making them potentially suitable for use in theranostics.
The presence of benzyloxy moieties on the styryl groups
results in a relatively low singlet oxygen quantum yield
value and has almost no effect on the wavelength of
the main BODIPY spectral band when a comparison
is made with an analgous dye that contains hydroxyl
groups, but enhanced solubility is anticipated in polar
solvents, since aggregation due to π–π stacking of the
planar styryl groups is hindered. Studies are underway to
identify structural modifications that further enhance the
photophysical properties of styrylated BODIPY dyes in
a manner that makes them suitable for use in biomedical
applications.
Solvent
lmax [nm]
lem [nm] tF [ns] ΦF ΦΔ
2a
2b
EtOH
DMSO
DMF
THF
676
683
680
680
668
677
670
670
532
530
666
680
676
674
702
715
711
703
—
2.31 0.11 0.19
3.04 0.09 0.28
3.33 0.07 0.24
3.42 0.13 0.34
EtOH
DMSO
DMF
THF
3.04
2.90 0.12 0.26
0.11
—
0.23
715
707
698
543
546
706
716
712
701
—
—
3.45 0.19 0.27
3.81 0.30 0.65
Acknowledgements
2b_Br EtOH
Financial support was provided by an NRF of South
Africa CSUR grant (uid: 93627) to JM and a Pearson
Young Memorial Scholarship to NM. Theoretical
calculations were carried out at the Center for High
Performance Computing in CapeTown and photophysical
measurements were made possible by the were made
possible by the Laser Rental Pool Programme of the
Council for Scientific and Industrial Research (CSIR) of
South Africa.
DMSO
—
0.18 0.82
2c
EtOH
DMSO
DMF
THF
2.72 0.09 0.16
—
—
0.21 0.10
0.26 0.10
3.15 0.21 0.11
values for 2a–2c are significantly lower, however, since
the introduction of the styryl groups can be expected to
result in S1 states with significant intramolecular charge
transfer character, since there are greater MO coefficients
on the styryls in the HOMO than in the LUMO (Fig. 3).
This is known to result in enhanced rates of non-radiative
decay, especially when polar solvents are used [44, 45].
A comparison of the singlet oxygen quantum yield values
for 2b and 2c demonstrates that the incorporation of the
benzyloxy groups slightly enhances the ΦΔ, possibly
due to a change in the efficiency of energy transfer from
the T1 state of the BODIPY dye, while in contrast, the
fluorescence quantum yield values are somewhat lower
possibly due to the enhanced conformational flexibility
(Table 2). Since there is no red shift of the absorption
band towards the center of the therapeutic window, there
is no obvious advantage derived from incorporating these
groups beyond the possibility of enhanced solubility in
the context of aqueous solvents, if for example the meso-
aryl ring of 2a were further modified to introduce a
quaternized nitrogen atom, as π–π stacking involving the
planar styryl groups would be hindered.
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