Synthesis and functionalization of new polyhalogenated BODIPY dyes. Study of their photophysical properties and singlet oxygen generation

Article abstract of DOI:10.1016/j.tet.2011.11.070

A theoretical and experimental study on the iodination of BODIPY dyes with different degrees of substitution has been developed. Polyhalogenated BODIPYs synthesized in this work are the first examples of this type of dyes with more than two halogen atoms

Full text of DOI:10.1016/j.tet.2011.11.070

Tetrahedron 68 (2012) 1153e1162
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and functionalization of new polyhalogenated BODIPY dyes. Study
of their photophysical properties and singlet oxygen generation
,
a
a
b
Maria J. Ortiz a , Antonia R. Agarrabeitia , Gonzalo Duran-Sampedro , Jorge Banuelos Prieto ,
*
~
b
c
c
c
ꢀ
Teresa Arbeloa Lopez , Walter A. Massad , Hernan A. Montejano , Norman A. García ,
Inigo Lopez Arbeloa
b
~
a
ꢀ
Departamento de Química Organica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain
b Departamento de Química Física, UPV-EHU, Apartado 644, 48080 Bilbao, Spain
c Departamento de Química, Universidad Nacional de Río Cuarto, 5800 Río Cuarto, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
A theoretical and experimental study on the iodination of BODIPY dyes with different degrees of sub-
stitution has been developed. Polyhalogenated BODIPYs synthesized in this work are the first examples
of this type of dyes with more than two halogen atoms in the BODIPY core and they can be selectively
functionalized. Surprisingly, the position in which halogen is attached has a marked effect in the pho-
tophysical properties and modulates the fluorescence capacity of the resulting BODIPY. These iodinated
BODIPYs are efficient singlet oxygen generators.
Received 8 September 2011
Received in revised form 7 November 2011
Accepted 23 November 2011
Available online 28 November 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Polyiodinated BODIPYs
Electrophilic substitution reactions
Nucleophilic substitution reactions
Cross-coupling
Singlet oxygen generation
1. Introduction
In addition, halogenated BODIPY dyes can find applications as
probes for photodynamic therapy (PDT), a noninvasive methodol-
Along the last years the number of contributions in the literature
about 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes
has increased exponentially, due to their advantageous photo-
physical properties, such as a high fluorescence quantum yield, low
tripletetriplet absorption, and high photostability.1 In addition,
these dyes present a high number of applications.2 The contribu-
tions directed at modifying the structure using new synthetic
procedures have grown clearly in a similar way. In general, most
synthetic routes are focused on the introduction of suitable sub-
stituents at an appropriate position of the indacene core, in most
cases to extend the conjugation and to optimize their spectroscopic
properties. Typical approaches to this problem include:
ogy for the treatment of malignant tumours and age related mac-
ular degeneration. The treatment requires a combined application
of a photosensitizer and light of a wavelength matched to the lmax
of the photosensitizer in order to generate cytotoxic reactive oxy-
gen species (e.g., 1O2) that eradicate tumours via cellular damage,
via vasculature damage and, possibly, by response of the immune
system.7 The generation of reactive oxygen species requires the
population of the triplet state of the dye. BODIPYs do not undergo
efficient intersystem crossing to the triplet excited state. However,
the presence of heavy atoms increases the quantum yield of in-
tersystem crossing. Thus, it has been shown that iodine or bromine
incorporation into the BODIPY nucleus enhanced intersystem
crossing and a few promising sensitizers for use in PDT have been
reported in the last few years as an alternative to the porphyrin-
based photosensitizers.8
There are three different ways to achieve halogenated BODIPYs:
halogenation of the pyrrole ring,6a,9 halogenation of the dipyrro-
methane precursors4a,10 or electrophilic substitution reactions on
the BODIPY dye previously synthesized.1,6cee,g,8beg,11 The latter re-
actions have been studied,1 showing that positions 2 and 6 of the
BODIPY core are the most susceptible to electrophilic attack.
However, there is not a definitive study on the regioselectivity in
Knoevenagel-type condensation of methyl-substituted BODIPYs,1,3
5
nucleophilic substitution,1,4 LiebeskindeSrogl reaction or palla-
€
dium coupling reactions (Sonogashira, Suzuki.).1,3i,4f,6 Haloge-
nated BODIPYs are the most useful building blocks for these
synthetic strategies.1,4,6
* Corresponding author. Tel.: þ34 913 944 309; fax: þ34 913 944 103; e-mail
address: mjortiz@quim.ucm.es (M.J. Ortiz).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.070

1154
M.J. Ortiz et al. / Tetrahedron 68 (2012) 1153e1162
these reactions for unsubstituted BODIPYs. In most cases studied
some of the other positions are blocked by substituents, although
the bromination with NBS of a 1,3,5,7-unsubstituted BODIPY has
been described recently,12 providing mono- and dibrominated
BODIPYs at the 2- and 6-positions with high regioselectivity. In this
be taken into account. Thus, there is a considerable sterical hin-
drance at 1- and 7-positions, due to the bulky phenyl group at
meso-position, and also to the large size of the iodine atom,
avoiding the incorporation of iodine at those sites.
Therefore, the combination of electronic and steric factors pre-
dicts that positions 2 and 6 are the most favourable for electrophilic
substitution in compound 1. The presence of the halogen atom
modifies the charge distribution as shown in the ESI (Fig. 1S, ESI).
Successive iodinations should occur on the most negative charged
carbons, but taking into account that the adjacent positions of the
phenyl group in compound 1 are inaccessible to iodine due to steric
factors.
The sterical hindrance at positions 1 and 7 in compound 1 is not
present in alkyl-substituted BODIPY 2 and 3. As a consequence, the
iodination should be controlled by electronic factors, meaning that
the reaction should take place at the positions with the highest
negative charge. At a first sight, all the free positions are susceptible
to be iodinated. However, the electrostatic potential map shows
a high positive density around the meso carbon (Fig. 2), hampering
the approach of the electrophilic iodine atom. Indeed, such effect
should be clearer at 8-position since typically the dipole moment of
BODIPYs is oriented along the transversal axis, with the negative
charge density located in the fluorine atoms and the positive
density centred at the meso-position. Thus, in BODIPY 3 the meso-
position cannot be iodinated, although is free and the carbon is
characterized by a negative charge (Fig. 3S, ESI). Therefore, it should
be expected that 5- and 6-positions will be first iodinated in
BODIPY 2 and 3, since the halogen can easily come around, al-
though they have lower negative charge than 7- and 8-position.
study none of the regioisomeric products, such as a-bromo-BODI-
PYs, were detected in the reaction mixture, even when an excess of
the brominating agent was used.12
Based on this background, in this work we report a novel the-
oretical, experimental, and photophysical study on the iodination
of a series of BODIPYs 1e3 with different degrees of substitution
(Fig. 1). In addition, we have carried out a preliminary study of the
selective functionalization and singlet oxygen generation of some
of these halogenated BODIPYs.
Fig. 1. Chemical structures of the BODIPY dyes 1e3.
2. Results and discussion
2.1. Theoretical study
The mesomeric structures of the BODIPY core indicate that the
2- and 6-positions have the lower positive charge, so they should be
most susceptible to electrophilic attack.1 In this work, a computa-
tional study on compounds 1e3 gives the Mulliken charge distri-
bution and the electrostatic potential map shown in Fig. 2. The
electronic charge distribution of these BODIPY dyes is characteristic
2.2. Synthesis
To test these hypotheses, we have synthesized BODIPY dyes 1,14
215 and 3,16 using the methods previously described, and we have
investigated the iodination reactions of these compounds with ICl
or I2/HIO3 by using different concentrations of the iodination re-
agents and at different reaction times. The products obtained in the
halogenation reactions of these BODIPY dyes are shown in Fig. 3
and Table 1.
of a cyanine-like delocalized
ESI).
p
-system13 (Fig. 2, and Figs. 1Se3S in
The experimental results show that is possible to obtain selec-
tively mono-, di-, tri- and tetraiodinated products of BODIPYs 1, 2
and 3. These are the first examples of this type of dyes with more
than two halogen atoms in the BODIPY core. Thus, iodination of
these dyes with ICl in almost equimolecular ratio (Table 1, entries 1,
10 and 14), gives the monoiodo-BODIPYs 4a, 5a and 6a, re-
spectively, in high yield. When two and a half equivalents are used
(Table 1, entries 2, 11 and 15), diiodo-BODIPYs 4b, 5b, 5c, 6b and 6c,
are obtained. These compounds can be separated easily by column
chromatography. Compound 5b is obtained with much lower yield
than 6b probably due to steric hindrance by the methyl group in the
meso-position.
Although it is possible to obtain the triiodo derivative 4c (Table
1, entry 3), the yield is low because it is always accompanied of
diiodo 4b and tetraiodo 4d derivatives, furthermore, in this case it is
hard to separate the isomers chromatographically. A mixture of
polyhalogenated derivatives with iodide and chlorine (4d, 4e, 4f
and 4g) in different positions of the BODIPY 1 are obtained with
higher ratios of reagents (Table 1, entries 4 and 5). Similarly, BODIPY
dyes 2 and 3 give rise to trihalogenated derivatives 5d, 5e, 6d and
6e, respectively (Table 1, entries 12 and 16). The formation of
chlorinated products is in agreement with bibliographic data17
showing that the reaction of iodine chloride with aromatic com-
pounds can lead to chlorinated and/or iodine derivatives depend-
ing on the reaction conditions.
Fig. 2. Electrostatic potential map (blue-positive and red-negative) and Mulliken
charge of BODIPYs 1e3.
According to the values shown in Fig. 2, for dye 1, positions 1-
and 7 are the most favourable for an electrophilic attack. However,
in order to predict the iodination site steric interactions should also
To prevent the formation of chlorinated derivatives, we carried
out the iodination reactions using I2/HIO3 as a halogenating agent

M.J. Ortiz et al. / Tetrahedron 68 (2012) 1153e1162
1155
due to the steric hindrance of the phenyl group, and then the halo-
genation occurs at the 2- and 6-positions, followed by the 3- and 5-
positions. In the case of the BODIPY 2, the electrophilic attack takes
place in all positions, while in the BODIPY 3 the iodination reaction
does not occur in the meso-position. The lack of iodination at this
position is probably due to the high positive charge density at the
meso-position, which prevents electrophilic substitution (Fig. 2).
2.3. Selective functionalization
The easily obtained polyhalogenated derivatives are valuable
synthetic precursors for selective functionalization allowing the
development of a variety of symmetric and asymmetric BODIPY
compounds that are difficult to obtain by alternative pro-
cedures.1,4,6 It is known that 3,5-dichloroBODIPY derivatives can
undergo substitution of the chlorine atoms by a wide range of ox-
ygen, carbon, nitrogen, and sulfur nucleophiles. Furthermore, the
reaction conditions can be adjusted to obtain either mono- or di-
substituted products.1,4
In this work, we have carried out nucleophilic substitution
reactions of 2,3,5,6-tetraiodo BODIPY 4d with 4-metoxyaniline,
b-alanine and sodium diethyl malonate. In the first two cases only
monosubstituted derivatives 7 and 8 were obtained, respectively,
even when the reaction is carried out with an excess of the reagent
and under reflux (Scheme 1).
These results contrast with those previously reported for the
3,5-dicloroderivatives4 and a possible explanation could be that the
presence of iodine atoms next to electron-donor groups increase
the charge density of the system preventing the second nucleo-
philic substitution reaction to occur. To test this hypothesis, we
treated compound 4d with sodium diethyl malonate. Under these
conditions, the mono and disubstituted BODIPY derivatives 9 and
10 were obtained. Furthermore, compound 9 afford the asymmetric
derivative 11 by reaction with 4-methoxyaniline. In these cases, the
absence of electron-donating groups allows the second SNAr. The
iodinated derivatives can be used in Pd-coupling reactions. Thus,
a triplet Suzuki coupling reaction of 7 yielded the highly func-
tionalized dye 12 (Scheme 1).
Fig. 3. Structures of the halogenated BODIPY dyes.
(Table 1, entries 6e9, 13 and 17). In these conditions, tetraiodo 4d
and triiodo derivatives 5e and 6e are obtained with good yields.
The data obtained indicate that, in principle, any free BODIPY
position can undergo the electrophilic attack, which increase the
synthetic utility of this reaction. Thus, whereas the 1- and 7-
positions of BODIPY 1 do not undergo electrophilic substitution,
2.4. Photophysical properties
The photophysical properties of BODIPY 1 (Table 2, and Table 1S
in ESI) are conditioned by the presence of the phenyl group at meso-
position. It has been previously reported that the free rotation of
such ring greatly increases the internal conversion processes and it
can interact with the BODIPY core distorting the indacene planar-
ity.18 The absence of substituents at 1- and 7-positions enables the
rotation of the phenyl ring (twisted 50ꢀ from the BODIPY plane).19
Hence, compound 1 is characterized by a very low fluorescence
Table 1
Reaction conditions and yields of isolated products of BODIPYs 1e3
Entry
Agenta
Ratio
t (min)
Products (yield, %)d
BODIPY 1
1
2
3
4
5
6
7
8
9
A
A
A
A
A
B
B
B
B
1:1b
30
60
120
180
360
30
60
60
180
4a (75)
1:2.5b
1:3.5b
1:4.5b
1:8b
4a (14), 4b (72)
4b (22), 4c (45), 4d (8)
4d (10), 4e (5), 4f (21), 4g (40)
4d (25), 4f (24), 4g (20)
4a (70)
4a (15), 4b (69)
4b (15), 4c (30), 4d (30)
4d (64)
quantum yield (f<0.04) and lifetime (s<700 ps). Successive io-
1:1:0.8c
1:2.5:2c
1:3.5:3c
1:4.5:4c
dination gives rise to a progressive bathochromic shift of the
spectral bands (Table 2 and Fig. 4). In fact, the tetraiodinated de-
rivative 4d emits in the red region of the visible spectra (around
590 nm). The halogenation of the BODIPY core should induce
a decrease in the fluorescence capacity due to the heavy atom ef-
fect, which increases the intersystem crossing probability (Fig. 4).
This influence is observed for the monoiodo and the diiodo de-
rivatives 4a and 4b, respectively. Surprisingly, further addition of
iodine atoms to the BODIPY core leads to an increase in the in-
tensities of the absorption and also in the fluorescence emission.
For instance, the tetraiodinated derivative 4d shows a very high
BODIPY 2
10
11
12
13
A
A
A
B
1:1.3b
1:2.5b
1:6b
30
60
180
180
5a (95)
5a (8), 5b (10), 5c (67)
5c (6), 5d (35), 5e (20)
5c (5), 5e (48)
1:4.5:4c
BODIPY 3
14
15
16
17
A
A
A
B
1:0.8b
1:2.5b
1:8b
30
90
300
300
6a (81)
6a (13), 6b (34), 6c (35)
6d (30), 6e (35)
6e (54)
molar absorption (around 11ꢁ104 Mꢂ1 cmꢂ1
, twice the non-
1:5:4.5c
iodinated BODIPY 1) and even higher than other non-halogenated
BODIPYs (9ꢁ104 Mꢂ1 cmꢂ1).18b Besides, the fluorescence quantum
yield for compound 4d is 0.1, much higher than 0.034, which is the
value reported for the non-iodinated BODIPY 1.14
a
Halogenating reagent: A¼ICl, B¼I2/HIO3.
Molar ratio BODIPY/ICl.
Molar ratio BODIPY/I2/HIO3.
Yield of isolated product.
b
c
d

1156
M.J. Ortiz et al. / Tetrahedron 68 (2012) 1153e1162
Scheme 1. Synthetic scheme for the preparation of BODIPY dyes 7e12.
Table 2
Theoretical simulations of the absorption transition confirm the
progressive bathochromic shift with the iodination degree and the
enhancement of the absorption probability of 4d with regard to the
rest of derivatives (Table 2S, ESI). Compound 4d shows a uniform
charge distribution in the pyrrole moiety, whereas in the rest of the
series it is more irregular (Fig. 1S, ESI). That means that the negative
charge on nitrogen, and on positions 1-, 2- and 3, and their corre-
sponding symmetrical ones, is nearly the same (around ꢂ0.255).
Accordingly, the delocalization is improved, in concordance with
the pushepull effect (substitution at the beginning and ending of
the delocalized system).14 Therefore, substitution at 3- and 5-
positions counteracts in part the non-radiative processes (heavy
atom effect and phenyl free rotation) improving the fluorescence
efficiency of the dye. It seems that the iodine presence at those
positions extents the chromophoric electronic density far away
from the phenyl ring (Fig. 1S, ESI) diminishing the deleterious effect
in fluorescence owing to its free motion.
Photophysical properties of BODIPY 1, 2 and 3 and their iodinated derivatives in
c-hexane. (The full data list for BODIPYs 1, 2 and 3 series are included in Tables 1S, 3S
and 4S in the ESI)
lab (nm)
3
lfl (nm)
f
s
(ps)
max
(104 Mꢂ1
cmꢂ1
)
BODIPY 1
1
4a
4b
4c
4d
500.5
523.5
548.5
563.5
581.0
6.9
2.2
4.3
4.8
11.6
516.0
540.0
567.5
577.5
593.0
0.036
0.034
0.012
0.060
0.099
323
184
117
327
678
BODIPY 2
2
5a
5b
5c
5e
504.0
517.5
515.5
532.0
531.5
3.3
4.6
2.9
9.8
1.7
515.0
532.0
538.5
546.0
554.5
0.96
0.13
0.05
0.20
0.10
5460
560
259
1021
331
On the other hand, the absence of the bulky phenyl group in
BODIPY 2 and 3 leads to highly fluorescence molecules, as is charac-
teristic of this dye family (Table 2, and Tables 3Se4S, ESI). The ab-
sorption probability is not very high due to the asymmetric
substitution pattern, which leads to charge separation between the
pyrroles (Fig. 2). The incorporation of an iodine atom at 6-position (5a
and 6a) implies a drastic decrease of the intensity of the fluorescence
emission, which is attributed tothe enhancement in theprobabilityof
intersystem crossing, as mentioned above (Table 2). However, further
halogenation leads to entirely different results depending of the po-
sition in which the iodine is attached. The incorporation of a second
iodine atom at position 7 (5b and 6b) has a minimum effect on the
wavelengthof theabsorption bandpositionbutinducesa reductionof
the intensity of the fluorescence emission, in agreement with the
heavy atom effect. In contrast, the incorporation of a second iodine
atom at position 5 (5c and 6c) gives rise to a bathochromic spectral
shift and increases the absorption probability and fluorescence effi-
ciency (Table 2) in concordance with the pushepull effect. Again, the
electronic distribution of 5c and 6c in the pyrrole rings is uniform
(Figs. 2Se3S, ESI), in good agreement with the influence observed for
the iodo-derivatives from BODIPY 1. Therefore, the results obtained in
the present study confirm that substitution at the ends of the delo-
BODIPY 3
3
6a
6b
6c
6e
512.5
528.0
527.5
542.0
543.5
2.9
6.3
5.6
7.6
6.9
517.5
538.5
537.0
550.5
551.5
0.70
0.11
0.05
0.26
0.07
5240
489
212
1041
358
Absorption (lab) and fluorescence (lfl) wavelength of the maximum; molar ab-
sorption ( max) at the maximum wavelength; fluorescence quantum yield ( ) and
lifetime ( ). Present lifetimes are the main component of the decay curve, which is
3
f
s
analyzed as biexponential but with a negligible long lifetime.
calized
p-system is advantageous for the fluorescence ability of the
dye. In the triiodinated derivatives (5e and 6e), the incorporation of
iodine at 7- and 5-positions has the opposite influence in the photo-
physics of the dye. As a result, the effect of both iodine atoms is
counteracted. That means, whereas substitution at 7-position should
increase the intersystem crossing, without altering the band position,
Fig. 4. Fluorescence spectra of BODIPY 1 and its iodinated derivatives 4aed in c-
hexane, scaled by their fluorescence quantum yield.

M.J. Ortiz et al. / Tetrahedron 68 (2012) 1153e1162
1157
substitution at 5-position should favour the fluorescence ability and
give rise to a bathochromic shift. Consequently, their spectral bands
are placed close to those of the diiodinated derivative (5c and 6c) and
their fluorescence capacity is similar to that of the monoiodinated
ones (5a and 6a) (Table 2). Indeed, the electronic distribution in the
triiodinated derivatives is less uniform and the system is less aromatic
(Figs. 2Se3S, ESI). Quantum mechanical simulation of the absorption
transition nicely reproduces the shift of the band depending on the
iodine position in the chromophore and describes qualitatively well
the evolution of the absorption probability (Table 2S, ESI).
Finally, we should note the close correlation between the fluo-
rescence quantum yield and the lifetime with both changing the
number of halogens appended to BODIPY and the environmental
properties. Such evolutions are controlled mainly by the non-
radiative processes, thus the lower the fluorescence efficiency the
faster the decay from the excited state.
532 nm-excitation. The reference was Rose Bengal (RB) with
a quantum yield FDRB for 1O2 production of 0.71 determined in this
work using perinaphthenone (PN) with FD ¼1 as a reference
RB
compound (Fig. 4S, ESI). The results obtained are FD ¼0.83þ7%,
4b
FD ¼0.86þ9% and FD ¼0.87þ6%, all these values are in the range
4c
4d
of those exhibited by compounds recognized as efficient 1O2 pho-
tosensitizer (Fig. 5S, ESI).
The results obtained show that the introduction of iodine atoms
in 3 and/or 5 positions does not produce a significant increase in
the efficiency of 1O2 generation and they are in good agreement
with those arising from the photophysical properties, showing that
substitution at 3 or 5-position favours the fluorescence ability. It is
clear that additional studies are needed to clarify the influence of
the iodine atoms positions over the efficiency of singlet oxygen
generation of these compounds. Nevertheless, the obvious conse-
quence of the investigation described above is that these poly-
iodinated BODIPYs are efficient photosensitizers for the generation
of 1O2 and additionally they can be suitably functionalized at of 3-
and 5-positions for their possible use as PDT agents.
Finally, we should note the close correlation between the fluo-
rescence quantum yield and the lifetime with both changing the
number of halogens appended to BODIPY and the environmental
properties. Such evolutions are controlled mainly by the non-
radiative processes, thus the lower the fluorescence efficiency the
faster the decay from the excited state.
3. Conclusion
We have demonstrated that it is possible to control the degree
of iodination in the BODIPY core, which allows the synthesis of
mono-, di- and polyiodinated derivatives. These are the first ex-
amples of this type of dyes with more than two halogen atoms in
the BODIPY core. Moreover, considering the easy synthetic route
of these polyhalogenated derivatives, the reaction could be ex-
tended to other dyes of this family, with different degrees of
substitution. Another interesting observation in this study is that
polyhalogenated compounds can be valuable synthetic precursors
for the selective incorporation of the desired functional groups in
a specific position of the BODIPY. Quantum mechanical calcula-
tions can predict the position in which iodine atoms will be in-
corporated and explain why some positions are inaccessible to the
iodine atom. Moreover, the position in which halogen is attached
modulates the photophysical properties of the resulting BODIPY.
In general, substitution at 3- or 5-positions improves the ab-
sorption and fluorescence transition probability efficiency while
in the rest of positions leads to an important reduction of the
fluorescence ability owing to the heavy atom effect, which acti-
vates the intersystem crossing processes. Triplet state population
via intersystem crossing leads to a high efficiency of 4bed as 1O2
generators. Further work is in progress to complete the study over
the triplet state (singlet oxygen generation and phosphorescence
spectra) and finally to explore the applicability of these novel
BODIPYs appropriately functionalized in PDT.
2.5. Singlet oxygen generation
Typically BODIPYs are characterized by very low triplet state
population. However, iodinated derivatives 4, 5 and 6 show low
fluorescence yields mainly due to the triplet state population via
the intersystem crossing process promoted by the so-called in-
ternal heavy atom effect.2a,9a Therefore they could be good singlet
oxygen (1O2) generators after energy transfer from excited triplet
state to ground state oxygen.
The transient absorption spectra of 4b and 4d dyes obtained by
laser flash photolysis in MeCN solution were recorded in the range
between 250 and 850 nm. The spectra of each dye present negative
bands caused by depletion of the ground state, which are practi-
cally the same that the corresponding one for ground state ab-
sorption, revealing the lack of photoproduct generation under the
selected laser experimental conditions. As a typical example, the
case of 4b is shown in Fig. 5.
4. Experimental section
4.1. General
Starting materials and reagents used in the preparation of
BODIPYs are commercially available unless synthesis is described.
The solvents were dried and distilled, before use. Spectral data of
the known compounds were in accordance with the literature data.
Flash column chromatography was performed using silica gel
Merck 60 (230e400 mesh). 1H and 13C NMR spectra were recorded
with a Bruker Avance-DPX-300 spectrometer (300 MHz for 1H and
75 MHz for 13C) and a Bruker Avance III spectrometer (700 MHz for
1H and 176 MHz for 13C). The spectra were recorded in CDCl3 or
CD3OD. 1H NMR chemical shifts are reported in parts per million
Fig. 5. Transient absorption spectra of 4b in MeCN recorded at different times after the
laser pulse: (B, 1
ms), ( , 4
ms), ( , 8
ms) and ground state absorption spectrum (
).
The monoexponential decay of the spectrum for 4b and 4d is in
agreement with the recovery in the bleaching regions. It worth
noting that similar transient spectra were reported for the triplet
state of others dipyrromethene dyes.20 All these observations
strongly suggest that the observed absorptions correspond to
a unique transient species, which is assigned to the electronically
excited triplet state of the dyes investigated.
relative to tetramethylsilane (
vent signal as the internal reference. 13C NMR chemical shifts are
reported in ppm with CDCl3
¼77.67 ppm) as the internal stan-
dard. Chemical shift multiplicities are reported as s¼singlet,
d
¼0.00 ppm), using the residual sol-
We examined the ability of compounds 4bed with two or more
(d
atoms of iodine to generate 1O2. This was done in CH3CN using

1158
M.J. Ortiz et al. / Tetrahedron 68 (2012) 1153e1162
d¼doublet, t¼triplet, q¼quartet and m¼multiplet. IR spectra (in
cmꢂ1) were recorded in a Bruker Tensor-27-FTIR spectrophotom-
eter. Melting points were determined in open capillaries and are
uncorrected. Mass spectra were registered by electron impact (EI)
at 70 eV, by electrospray ionization (ESI) and by atmospheric
pressure chemical injection (APCI) in a VGI2-250 spectrometer.
High resolution mass spectra were determined by electrospray
ionization in the positive mode (ESIþ) in an Accurate-Mass Q-TOF
LC/MS 6520 (Agilent Technologies).
100), 407 (7), 280 (22), 265 (18), 203 (10), 139 (10); HRMS-ESIþ:
calcd for (C16H11BF2I2N2þHþ) 534.9153 found 534.9146.
4.3.3. BODIPY 1 with ICl (1:3.5). According to the method A, BOD-
IPY 1 (70 mg, 0.25 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and ICl
(142 mg, 0.87 mmol) in MeOH (5 mL) for 120 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded, by or-
der of elution, 4b (29 mg, 22%), 4,4-difluoro-2,3,6-triiodo-8-(4-
tolyl)-4-bora-3a,4a-diaza-s-indacene (4c) (74 mg, 45%) as a green
solid and 4,4-difluoro-2,3,5,6-tetraiodo-8-(4-tolyl)-4-bora-3a,4a-
diaza-s-indacene (4d) (16 mg, 8%) as a green solid.
4.2. General procedure for the synthesis of halogenated
BODIPYs
4.3.3.1. Compound 4c. Mp 253.2e253.7 ꢀC; 1H NMR (700 MHz,
CDCl3):
d
7.80 (1H, s, H-5), 7.34 (2H, d, J¼8.1 Hz, H-20), 7.27 (2H, d,
4.2.1. Method A: iodination reaction with ICl. To a solution of
BODIPY in a CH2Cl2/MeOH mixture (1:1) was added dropwise
a solution of ICl in MeOH. The BODIPY/ICl ratio is indicated in each
case. This mixture was refluxed for 30e360 min. After cooling, the
solvent was evaporated under vacuum. The crude product was
dissolved in CH2Cl2, washed with H2O, dried over MgSO4, filtered
and concentrated to dryness. The halogenated BODIPYs were pu-
rified by flash chromatography on silica gel (eluent hexane/EtOAc).
J¼8.1 Hz, H-30), 7.00 (1H, s, H-1), 6.96 (1H, s, H-7), 2.40 (3H, s, CH3);
13C NMR (176 MHz, CDCl3):
d 148.6 (CH), 143.4 (C), 142.3 (C), 139.3
(C), 137.8 (CH), 137.4 (CH), 135.9 (C), 130.5 (CH), 129.7 (C), 129.6
(CH), 115.1 (CeI), 90.2 (CeI), 72.8 (CeI), 21.6 (CH3); IR (neat): 1536,
1237, 1089 cmꢂ1; MS (APCIꢂ) m/z (%): 660 (Mꢂ, 100), 602 (40), 585
(25), 533 (42); HRMS-ESIþ: calcd for (C16H10BF2I3N2þHþ) 660.8119
found 660.8109.
4.3.3.2. Compound 4d. Mp 283.2e284.0 ꢀC; 1H NMR (700 MHz,
4.2.2. Method B: iodination reaction with I2/HIO3. Iodic acid dis-
solved in a minimum amount of water was added dropwise to
a solution of BODIPY and iodine in EtOH. The BODIPY/I2/HIO3 ratio
is indicated in each case. This mixture was refluxed for
30e300 min. After cooling, the solvent was evaporated under
vacuum. The crude product was dissolved in CH2Cl2, washed with
H2O, dried over MgSO4, filtered and concentrated to dryness. The
halogenated BODIPYs were purified by flash chromatography on
silica gel (eluent hexane/EtAcO).
CDCl3):
d
7.31 (2H, d, J¼7.7 Hz, H-20), 7.27 (2H, d, J¼7.7 Hz, H-30),
6.91 (2H, s, H-1 and H-7), 2.40 (3H, s, CH3); 13C NMR (176 MHz,
CDCl3): d 142.2 (C), 140.5 (C), 139.3 (C), 137.5 (CH), 130.4 (CH), 129.6
(CH), 129.1 (C), 115.9 (CeI), 90.9 (CeI), 21.6 (CH3); IR (neat): 1536,
1320,1215,1086 cmꢂ1; MS (APCIꢂ) m/z (%): 786 (Mꢂ,100), 677 (50);
HRMS-ESIþ: calcd for (C16H9BF2I4N2þHþ) 786.7086 found
786.7080.
4.3.4. BODIPY 1 with ICl (1:4.5). According to the method A, BODIPY
1 (70 mg, 0.25 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and ICl
(183 mg,1.12 mmol) in MeOH (5 mL) for 180 min were reacted. Flash
chromatography using hexane/EtAcO (98:2) afforded, by order of
elution, 3-chloro-4,4-difluoro-2,6-diiodo-8-(4-tolyl)-4-bora-3a,4a-
diaza-s-indacene (4e) (7 mg, 5%) as a green solid, 3,5-dichloro-4,4-
difluoro-2,6-diiodo-8-(4-tolyl)-4-bora-3a,4a-diaza-s-indacene (4f)
(32 mg, 21%) as a green solid, 3-chloro-4,4-difluoro-2,5,6-triiodo-8-
(4-tolyl)-4-bora-3a,4a-diaza -s-indacene (4g) (69 mg, 40%) asa green
solid and 4d (20 mg, 10%).
4.3. Iodination reactions of BODIPYs 1e3
4.3.1. BODIPY 1 with ICl (1:1). According to the method A, BODIPY 1
(70 mg, 0.25 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and ICl (41 mg,
0.25 mmol) in MeOH (5 mL) for 30 min were reacted. Flash chro-
matography using hexane/EtAcO (98:2) afforded, byorderofelution,
4,4-difluoro-2-iodo-8-(4-tolyl)-4-bora-3a,4a-diaza-s-indacene (4a)
(76 mg, 75%) as an orange solid and starting BODIPY 1 (10 mg, 14%).
4.3.1.1. Compound 4a. Mp 166.2e166.8 ꢀC; 1H NMR (700 MHz,
4.3.4.1. Compound 4e. Mp 259.8e260.3 ꢀC; 1H NMR (700 MHz):
CDCl3):
d
7.92 (1H, s, H-5), 7.76 (1H, s, H-3), 7.39 (2H, d, J¼7.7 Hz, H-
d
7.79 (1H, s, H-5), 7.34 (2H, d, J¼7.7 Hz, H-20), 7.29 (2H, d, J¼7.7 Hz,
20), 7.28 (2H, d, J¼7.7 Hz, H-30), 6.97 (1H, s, H-1), 6.96 (1H, d,
H-30), 7.05 (1H, s, H-1), 7.01 (1H, s, H-7), 2.41 (3H, s, CH3); 13C NMR
J¼4.2 Hz, H-7), 6.53 (1H, d, J¼4.2 Hz, H-6), 2.41 (3H, s, CH3); 13C
(176 MHz):
d 148.1 (CeCl and CH), 144.5 (C), 142.4 (C), 138.4 (CH),
NMR (176 MHz, CDCl3):
d
147.0 (C), 146.4 (CH), 145.6 (CH), 141.9 (C),
137.2 (CH), 135.7 (C), 135.0 (C), 130.6 (CH), 129.6 (CH), 129.4 (C), 76.3
(CeI), 72.4 (CeI), 21.6 (CH3); IR (neat): 1373, 1239, 1046 cmꢂ1; MS
(APCIꢂ) m/z (%): 568 (Mꢂ, 100), 549 (30), 473 (40), 441 (35); HRMS-
ESIþ: calcd for (C16H10BClF2I2N2þHþ) 568.8763 found 568.8759.
136.1 (CH), 135.8 (C), 135.1 (C), 133.1 (CH), 130.6 (CH), 129.4 (CH),
119.6 (CH), 70.8 (CeI), 21.5 (CH3); IR (neat): 1539, 1258, 1111 cmꢂ1
;
MS (APCIꢂ) m/z (%): 408 (Mꢂ, 100); HRMS-ESIþ: calcd for
(C16H12BF2IN2þHþ) 409.0182 found 409.0178.
4.3.4.2. Compound 4f. Mp 253.6e254.1 ꢀC; 1H NMR (700 MHz):
4.3.2. BODIPY 1 with ICl (1:2.5). According to the method A, BOD-
IPY 1 (70 mg, 0.25 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and ICl
(102 mg, 0.63 mmol) in MeOH (5 mL) for 60 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded, by or-
der of elution, 4,4-difluoro-2,6-diiodo-8-(4-tolyl)-4-bora-3a,4a-
diaza-s-indacene (4b) (96 mg, 72%) as a green solid and 4a (14 mg,
14%).
d
7.31 (2H, d, J¼7.7 Hz, H-20), 7.28 (2H, d, J¼7.7 Hz, H-30), 7.00 (2H, s,
H-1 and H-7), 2.41 (3H, s, CH3); 13C NMR (176 MHz):
d 148.2 (CeCl),
142.9 (C), 142.3 (C), 137.9 (CH), 134.8 (C), 130.5 (CH), 129.6 (CH),
129.0 (C), 76.6 (CeI), 21.5 (CH3); IR (neat): 1542, 1363, 1233,
1100 cmꢂ1; MS (APCIꢂ) m/z (%): 602 (Mꢂ, 100), 583 (22), 507 (28),
475 (28); HRMS-ESIþ: calcd for (C16H9BCl2F2I2N2þHþ) 602.9373
found 602.9369.
4.3.2.1. Compound 4b. Mp 210.0e210.7 ꢀC; 1H NMR (700 MHz,
4.3.4.3. Compound 4g. Mp 260.0e260.5 ꢀC; 1H NMR (700 MHz):
CDCl3):
d
7.80 (2H, s, H-3 and H-5), 7.37 (2H, d, J¼7.7 Hz, H-20), 7.29
d
7.31 (2H, d, J¼7.7 Hz, H-20), 7.28 (2H, d, J¼7.7 Hz, H-30), 7.00 (1H, s,
(2H, d, J¼7.7 Hz, H-30), 7.05 (2H, s, H-1 and H-7), 2.41 (3H, s, CH3);
H-7), 6.92 (1H, s, H-1), 2.41 (3H, s, CH3); 13C NMR (176 MHz):
d 148.6 (CeCl), 142.3 (C), 141.7 (C), 139.1 (C), 138.1 (CH), 137.4 (CH),
13C NMR (176 MHz, CDCl3):
d
147.1 (CH), 145.1 (C), 141.4 (C), 136.6
(CH), 134.9 (C), 129.5 (CH), 129.2 (C), 128.5 (CH), 71.1 (CeI), 20.5
135.0 (C), 130.5 (CH), 129.6 (CH), 129.1 (C), 115.3 (CeI), 90.6 (CeI),
(CH3); IR (neat): 1539, 1254, 1114 cmꢂ1; MS (EI) m/z (%): 534 (Mþ,
77.2 (CeI), 21.6 (CH3); IR (neat): 1542, 1224, 1094 cmꢂ1; MS (APCIꢂ)

M.J. Ortiz et al. / Tetrahedron 68 (2012) 1153e1162
1159
m/z (%): 694 (Mꢂ, 75), 585 (100), 439 (50); HRMS-ESIþ: calcd for
(C16H9BClF2I3N2þHþ) 694.7730 found 694.7721.
4.3.11.2. Compound 5c. Mp 223.6e224.1 ꢀC; 1H NMR (700 MHz):
6.96 (1H, s, H-7), 2.52 (3H, s, CH3eC3), 2.37 (3H, s, CH3eC8), 2.35
d
(2H, q, J¼7.7 Hz, CH2), 2.25 (3H, s, CH3eC1), 1.00 (3H, t, J¼7.7 Hz,
4.3.5. BODIPY 1 with ICl (1:8). According to the method A, BODIPY
1 (60 mg, 0.21 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and ICl
(272 mg, 1.68 mmol) in MeOH (5 mL) for 360 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded, by or-
der of elution, 4f (30 mg, 24%), 4g (29 mg, 20%) and 4d (39 mg,
25%).
CH3CH2); 13C NMR (176 MHz):
d
163.8 (C), 141.9 (C), 138.8 (C), 136.9
(C),136.6 (C),134.8 (C),128.3 (CH),100.2 (CeI), 84.3 (CeI),17.2 (CH2),
15.8 (CH3), 14.4 (CH3), 14.2 (CH3), 13.4 (CH3); IR (neat): 1582, 1318,
1200, 1236 cmꢂ1; MS (EI) m/z (%): 514 (Mþ, 98), 499 (100); HRMS-
ESIþ: calcd for (C14H15BF2I2N2þHþ) 514.9466 found 514.9451.
4.3.12. BODIPY 2 with ICl (1:6). According to the method A, BODIPY
2 (75 mg, 0.29 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and ICl
(282 mg, 1.74 mmol) in MeOH (5 mL) for 180 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded, by or-
der of elution, 5c (9 mg, 6%), 3-chloro-6-ethyl-1,2-diiodo-5,7,8-
trimethyl-4-bora-3a,4a-diaza-s-indacene (5d) (55 mg, 35%) as an
orange solid and 2-ethyl-5,6,7-triiodo-1,3,8-trimethyl-4-bora-
3a,4a-diaza-s-indacene (5e) (37 mg, 20%) as a red solid.
4.3.6. BODIPY 1 with I2/HIO3 (1:1:0.8). According to the method B,
BODIPY 1 (83 mg, 0.29 mmol), I2 (74 mg, 0.29 mmol) in EtOH
(20 mL) and HIO3 (41 mg, 0.23 mmol) for 30 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded 4a
(83 mg, 70%) and starting BODIPY 1 (16 mg, 19%).
4.3.7. BODIPY 1 with I2/HIO3 (1:2.5:2). According to the method B,
BODIPY 1 (83 mg, 0.29 mmol), I2 (185 mg, 0.73 mmol) in EtOH
(20 mL) and HIO3 (102 mg, 0.58 mmol) for 60 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded 4b
(107 mg, 69%) and 4a (18 mg, 15%).
4.3.12.1. Compound 5d. Mp 275.1e275.6 ꢀC; 1H NMR
(700 MHz):
J¼7.7 Hz, CH2), 2.29 (3H, s, CH3eC7), 1.00 (3H, t, J¼7.7 Hz, CH3CH2);
13C NMR (176 MHz):
163.5 (C), 142.5 (C), 138.9 (C), 137.6 (C), 137.5
d 2.84 (3H, s, CH3eC5), 2.47 (3H, s, CH3eC8), 2.36 (2H, q,
d
4.3.8. BODIPY 1 with I2/HIO3 (1:3.5:3). According to the method B,
BODIPY 1 (73 mg, 0.26 mmol), I2 (231 mg, 0.91 mmol) in EtOH
(20 mL) and HIO3 (137 mg, 0.78 mmol) for 60 min were reacted.
Flash chromatography using hexane/EtAcO (95:5) afforded, by or-
der of elution, 4b (21 mg,15%), 4c (51 mg, 30%) and 4d (61 mg, 30%).
(CeCl), 135.4 (C), 132.6 (C), 90.0 (CeI), 89.5 (CeI), 19.1 (CH3), 17.3
(CH2), 15.3 (CH3), 14.3 (CH3), 13.5 (CH3); IR (neat): 1566, 1369, 1186,
1088 cmꢂ1; MS (APCIꢂ) m/z (%): 548 (Mꢂ, 98), 456 (30), 421 (100);
HRMS-ESIþ: calcd for (C14H14BClF2I2N2þHþ) 548.9076 found
548.9066.
4.3.9. BODIPY 1 with I2/HIO3 (1:4.5:4). According to the method B,
BODIPY1(70 mg,0.25 mmol), I2 (286 mg,1.12 mmol)inEtOH(20 mL)
and HIO3 (176 mg, 1 mmol) for 180 min were reacted. Flash chro-
matography using hexane/EtAcO (95:5) afforded 4d (126 mg, 64%).
4.3.12.2. Compound 5e. Mp235.6e236.1 ꢀC; 1HNMR (700 MHz):
d
2.78 (3H, s, CH3eC3), 2.46 (3H, s, CH3eC8), 2.34 (2H, q, J¼7.7 Hz,
CH2), 2.27 (3H, s, CH3), 0.98 (3H, t, J¼7.7 Hz, CH3CH2); 13C NMR
(176 MHz): d 163.1 (C), 142.2 (C), 140.3 (C), 138.8 (C), 138.1 (C), 137.1
(C), 100.4 (CeI), 97.8 (CeI), 93.7 (CeI), 19.1 (CH3), 17.2 (CH2), 15.3
(CH3), 14.3 (CH3), 13.8 (CH3); IR (neat): 1610, 1332, 1250, 1120,
1098 cmꢂ1; MS (APCIþ): 663 ([MþNa]þ, 100), 607 (30); HRMS-ESIþ:
calcd for (C14H14BF2I3N2þHþ) 640.8432 found 640.8420.
4.3.10. BODIPY 2 with ICl (1:1:3). According to the method A,
BODIPY 2 (60 mg, 0.23 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and
ICl (49 mg, 0.30 mmol) in MeOH (5 mL) for 30 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded 2-ethyl-
4,4-difluoro-6-iodo-1,3,8-trimethyl-4-bora-3a,4a-diaza-s-indacene
(5a) (85 mg, 95%) as an orange solid. Mp 160.2e160.7 ꢀC; 1H NMR
4.3.13. BODIPY 2 with I2/HIO3 (1:4.5:4). According to the method B,
BODIPY 2 (85 mg, 0.32 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and
ICl (366 mg, 1.44 mmol) in MeOH (5 mL) for 120 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded, by or-
der of elution, 5c (8 mg, 5%) and 5e (98 mg, 48%).
(300 MHz):
d 7.39 (1H, s, H-5), 6.95 (1H, s, H-7), 2.49 (3H, s,
CH3eC8), 2.40 (3H, s, CH3eC3), 2.34 (2H, q, J¼7.6 Hz, CH2CH3), 2.25
(3H, s, CH3eC1), 0.98 (3H, t, J¼7.6 Hz, CH3CH2); 13C NMR (75 MHz):
d
162.8 (C), 142.0 (C), 139.7 (CH), 138.9 (C), 136.2 (C), 135.3 (C), 134.7
(C), 127.6 (CH), 67.0 (CeI), 17.1 (CH2), 16.4 (CH3), 14.4 (CH3), 14.2
(CH3), 13.3 (CH3); IR (neat): 1561, 1177 cmꢂ1; MS (ESIꢂ): 387
[MꢂH]ꢂ; HRMS-ESIþ: calcd for (C14H16BF2IN2þHþ) 389.0499 found
389.0491.
4.3.14. BODIPY 3 with ICl (1:0.8). According to the method A, BOD-
IPY 3 (70 mg, 0.28 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and ICl
(36 mg, 0.22 mmol) in MeOH (5 mL) for 30 min were reacted. Flash
chromatography using hexane/EtAcO (98:2) afforded 2-ethyl-4,4-
difluoro-6-iodo-1,3-dimethyl-4-bora-3a,4a-diaza-s-indacene (6a)
(85 mg, 81%) as an orange solid and starting BODIPY 1 (10 mg, 14%).
4.3.11. BODIPY 2 with ICl (1:2.5). According to the method A,
BODIPY 2 (63 mg, 0.24 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and
ICl (97 mg, 0.6 mmol) in MeOH (5 mL) for 60 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded, by or-
der of elution, 2-ethyl-4,4-difluoro-6,7-diiodo-1,3,8-trimethyl-4-
bora-3a,4a-diaza-s-indacene (5b) (8 mg, 10%) as an orange solid,
2-ethyl-4,4-difluoro-5,6-diiodo-1,3,8-trimethyl-4-bora-3a,4a-
diaza-s-indacene (5c) (83 mg, 67%) as a red solid and 5a (8 mg, 8%).
4.3.14.1. Compound 6a. Mp 174.4e174.8 ꢀC; 1H NMR (700 MHz):
d
7.41 (1H, s, H-5), 6.96 (1H, s, H-8), 6.80 (1H, s, H-7), 2.49 (3H, s,
CH3eC3), 2.33 (2H, q, J¼7.7 Hz, CH2), 2.10 (3H, s, CH3eC1), 1.00 (3H,
t, J¼7.7 Hz, CH3CH2); 13C NMR (176 MHz):
d 165.9 (C), 142.2 (C),
140.8 (CH), 136.9 (C), 136.0 (C), 133.2 (C), 129.8 (CH), 122.0 (CH), 67.1
(CeI), 17.3 (CH2), 14.1 (CH3), 13.6 (CH3), 9.6 (CH3); IR (neat): 1601,
1368, 1346, 1140, 1090 cmꢂ1; MS (APCIꢂ) m/z (%): 374 (Mꢂ, 70), 359
(100), 339 (20); HRMS-ESIþ: calcd for (C13H14BF2IN2þHþ) 375.0343
found 375.0335.
4.3.11.1. Compound 5b. Mp 201.5e202.0 ꢀC; 1H NMR
(700 MHz):
d 7.49 (1H, s, H-5), 2.87 (3H, s, CH3eC3), 2.45 (3H, s,
CH3eC8), 2.36 (2H, q, J¼7.7 Hz, CH2), 2.30 (3H, s, CH3eC1), 1.00 (3H,
t, J¼7.7 Hz, CH3CH2); 13C NMR (176 MHz):
d
163.1 (C), 142.8 (C),
4.3.15. BODIPY 3 with ICl (1:2.5). According to the method A,
BODIPY 3 (70 mg, 0.28 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and
ICl (114 mg, 0.7 mmol) in MeOH (5 mL) for 90 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded, by or-
der of elution, 2-ethyl-4,4-difluoro-6,7-diiodo-1,3-dimethyl-4-
bora-3a,4a-diaza-s-indacene (6b) (48 mg, 34%) as an orange solid,
140.3 (C), 139.0 (CH), 137.1 (C), 135.6 (C), 132.6 (C), 89.8 (CeI), 85.5
(CeI), 18.7 (CH3), 17.2 (CH2), 15.3 (CH3), 14.3 (CH3), 13.5 (CH3); IR
(neat): 1567, 1370, 1221, 1072 cmꢂ1; MS (APCIꢂ) m/z (%): 514 (Mꢂ,
50), 513 (100); HRMS-ESIþ: calcd for (C14H15BF2I2N2þHþ) 514.9466
found 514.9458.

1160
M.J. Ortiz et al. / Tetrahedron 68 (2012) 1153e1162
2-ethyl-4,4-difluoro-5,6-diiodo-1,3-dimethyl-4-bora-3a,4a-diaza-
s-indacene (6c) (49 mg, 35%) as a red solid and 6a (14 mg, 13%).
4.5. Synthesis of 4,4-difluoro-2,3,6-triiodo-5-(4-methoxyphen
ylamino)-8-(4-tolyl)-4-bora-3a,4a-diaza-s-indecene (7)
4.3.15.1. Compound 6b. Mp 226.7e227.3 ꢀC; 1H NMR
BODIPY 4d (40 mg, 0.05 mmol) and 4-methoxyaniline (13 mg,
0.1 mmol) in CH3CN (20 mL) were refluxed for 8 h. Flash chroma-
tography using hexane/EtAcO (95:5) afforded BODIPY 7 (31 mg,
77%) as a purple solid. Mp 213.4e213.9 ꢀC; 1H NMR (700 MHz,
(300 MHz):
d 7.45 (1H, s, H-5), 6.95 (1H, s, H-8), 2.48 (3H, s,
CH3eC3), 2.35 (2H, q, J¼7.5 Hz, CH2), 2.15 (3H, s, CH3eC1), 1.02 (3H,
t, J¼7.5 Hz, CH3CH2); 13C NMR (75 MHz):
d 167.0 (C), 142.7 (C), 140.5
(CH),138.0 (C),136.6 (C),134.9 (C),122.6 (CH), 94.0 (CeI), 80.8 (CeI),
17.4 (CH2), 14.0 (CH3), 13.8 (CH3), 9.7 (CH3); IR (neat): 1613, 1241,
1183, 1120, 1073, 982 cmꢂ1; MS (APCIþ) m/z (%): 500 (Mþ, 50), 481
(100), 374 (98); HRMS-ESIþ: calcd for (C13H13BF2I2N2þHþ)
500.9304 found 500.9311.
CDCl3):
d
8.03 (1H, s, NH), 7.25 (2H, d, J¼8.4 Hz, H-20), 7.21 (2H, d,
J¼8.4 Hz, H-30), 7.12 (2H, d, J¼8.4 Hz, H-300), 7.11 (1H, s, H-7), 6.86
(2H, d, J¼8.4 Hz, H-200), 6.52 (1H, s, H-1), 3.77 (3H, s, OCH3), 2.36
(3H, s, CH3); 13C NMR (176 MHz, CDCl3):
d 159.6 (C), 157.0 (C), 144.9
(CH), 140.2 (C), 137.7 (C), 134.3 (C), 131.1 (C), 130.1 (CH), 129.3 (CH),
129.2 (CH), 128.6 (CH), 127.9 (C), 114.5 (CH), 96.0 (CeI), 83.9 (CeI),
66.8 (CeI), 55.6 (OCH3), 21.4 (CH3); IR (neat): 3363, 1583, 1249,
1091 cmꢂ1; MS (APCIꢂ) m/z (%): 659 (Mꢂꢂ122, 10), 558 (100), 508
(20), 340 (35); HRMS-ESIþ: calcd for (C23H17BF2I3N3OþHþ)
781.8647 found 781.8638.
4.3.15.2. Compound 6c. Mp 222.4e222.8 ꢀC; 1H NMR
(700 MHz):
d 6.81 (1H, s, H-8), 6.78 (1H, s, H-7), 2.51 (3H, s,
CH3eC3), 2.34 (2H, q, J¼7.7 Hz, CH2), 2.09 (3H, s, CH3eC1), 1.01 (3H,
t, J¼7.7 Hz, CH3CH2); 13C NMR (176 MHz):
d 166.8 (C), 142.0 (C),
137.0 (C), 136.5 (C), 130.6 (CH), 120.0 (CH), 102.0 (CeI), 84.8 (CeI),
17.4 (CH2), 14.1 (CH3), 13.7 (CH3), 9.6 (CH3); IR (neat): 1615, 1322,
1265, 1138, 1109 cmꢂ1; MS (APCIþ) m/z (%): 500 (Mþ, 15), 481 (80),
374 (100), 361 (45); HRMS-ESIþ: calcd for (C13H13BF2I2N2þ)
499.9226 found 499.9233.
4.6. Synthesis of 3-(2-carboxyethylamino)-4,4-difluoro-2,5,6-
triiodo-8-(4-tolyl)-4-bora-3a,4a-diaza-s-indecene (8)
BODIPY 4d (60 mg, 0.08 mmol) and 3-aminopropanoic acid
(40 mg, 0.46 mmol) in CH3CN (20 mL) were refluxed for 4 h. Flash
chromatography using hexane/EtAcO (98:2) afforded BODIPY 8
(44 mg, 77%) as an orange solid. Mp >300 ꢀC; 1H NMR (700 MHz,
4.3.16. BODIPY 3 with ICl (1:8). According to the method A, BODIPY
3 (70 mg, 0.28 mmol) in CH2Cl2/MeOH (10 mL/10 mL) and ICl
(364 mg, 2.24 mmol) in MeOH (5 mL) for 300 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded, by or-
der of elution, 3-chloro-6-ethyl-4,4-difluoro-1,2-diiodo-5,7-
dimethyl-4-bora-3a,4a-diaza-s-indacene (6d) (45 mg, 30%) as an
orange solid and 2-ethyl-4,4-difluoro-5,6,7-triiodo-1,3-dimethyl-4-
bora-3a,4a-diaza-s-indacene (6e) (61 mg, 35%) as a red solid.
CD3OD):
H-7), 4.08 (2H, t, J¼6.3 Hz, NHCH2), 2.50 (2H, t, J¼6.3 Hz,
CH2COOH), 2.33 (3H, s, CH3); 13C NMR (176 MHz, CD3OD):
177.6
d
7.22 (4H, s, H-20 and H-30), 7.04 (1H, s, H-1), 6.20 (1H, s,
d
(COOH),159.3 (C),141.8 (CH),139.4 (C),136.7 (C),135.9 (C),130.7 (C),
129.9 (CH), 128.8 (CH), 126.3 (C), 124.4 (CH), 91.2 (CeI), 81.6 (CeI),
72.8 (CeI), 41.6 (NHCH2), 35.5 (CH2COOH), 20.0 (CH3); IR (neat):
3350, 1740, 1570, 1254, 1091 cmꢂ1
;
HRMS-ESIꢂ: calcd for
4.3.16.1. Compound 6d. Mp 256.1e256.6 ꢀC; 1H NMR
(C19H15BF2I3N3O2ꢂHþ) 745.8290 found 745.8300.
(700 MHz):
J¼7.7 Hz, CH2), 2.13 (3H, s, CH3eC7),1.01 (3H, t, J¼7.7 Hz, CH3eCH2);
13C NMR (176 MHz):
167.2 (C), 142.4 (C), 138.8 (CeCl), 137.7 (C),
d 6.86 (1H, s, H-8), 2.48 (3H, s, CH3eC5), 2.33 (2H, q,
4.7. Synthesis of 3-diethoxycarbonylmethyl-4,4-difluoro-
2,5,6-triiodo-8-(4-tolyl)-4-bora-3a,4a-diaza-s-indecene (9)
d
136.9 (C),134.6 (C),121.6 (CH), 94.3 (CeI), 84.2 (CeI),17.4 (CH2),14.0
(CH3), 13.8 (CH3), 9.7 (CH3); IR (neat): 1617, 1373, 1238, 1139, 1020,
972 cmꢂ1; MS (APCIþ) m/z (%): 534 (Mþ, 15), 515 (100), 408 (40),
359 (75), 223 (65); HRMS-ESIþ: calcd for (C13H12BClF2I2N2þHþ)
534.8920 found 534.8911.
BODIPY 4d (130 mg, 0.16 mmol), diethyl malonate (0.03 mL,
0.18 mmol) and NaH (6 mg, 0.25 mmol) in CH3CN (20 mL) were
refluxed for 1 h. Flash chromatography using hexane/EtAcO (9:1)
afforded BODIPY
9
(96 mg, 71%) as
a
pink solid. Mp
178.3e178.8 ꢀC; 1H NMR (700 MHz, CDCl3):
d
7.34 (2H, d, J¼8.4 Hz,
4.3.16.2. Compound 6e. Mp 262.3e262.8 ꢀC; 1H NMR
H-20), 7.27 (2H, d, J¼8.4 Hz, H-30), 7.06 (1H, s, H-1), 6.91 (1H, s, H-
7), 5.53 (1H, s, CH(CO2Et)2), 4.24 (4H, q, J¼7.0 Hz, OCH2CH3), 2.40
(3H, s, CH3), 1.25 (6H, t, J¼7.0 Hz, OCH2CH3); 13C NMR (176 MHz,
(700 MHz):
J¼7.7 Hz, CH2), 2.15 (3H, s, CH3eC1), 1.03 (3H, t, J¼7.7 Hz, CH3CH2);
13C NMR (176 MHz):
167.7 (C), 142.4 (C), 138.7 (C), 138.0 (C), 137.1
(C), 121.1 (CH), 100.5 (CeI), 97.9 (CeI), 93.6 (CeI), 17.4 (CH2), 14.0
d 6.82 (1H, s, H-8), 2.51 (3H, s, CH3eC3), 2.36 (2H, q,
d
CDCl3): d 165.0 (COO), 152.2 (C), 143.0 (C), 142.2 (C), 139.8 (CH),
139.1 (C), 137.3 (CH), 135.4 (C), 130.5 (C), 129.6 (CH and C), 114.3
(CeI), 90.1 (CeI), 77.0 (CeI), 62.7 (OCH2CH3), 52.1 (CH(CO2Et)2),
21.6 (CH3), 14.1 (OCH2CH3); IR (neat): 1761, 1740, 1570, 1251,
(CH3), 13.8 (CH3), 9.7 (CH3); IR (neat): 1616, 1235, 1133, 1089 cmꢂ1
;
MS (APCIþ) m/z (%): 626 (Mꢂ, 100); HRMS-ESIþ: calcd for
(C13H12BF2I3N2þHþ) 626.8276 found 626.8269.
1089 cmꢂ1
840.8514 found 840.8499.
;
HRMS-ESIþ: calcd for (C23H20BF2I3N2O4þNaþ)
4.3.17. BODIPY 3 with I2/HIO3 (1:5:4.5). According to the method B,
BODIPY 3 (110 mg, 0.44 mmol) in I2 (559 mg, 2.20 mmol) in EtOH
(20 mL) and HIO3 (348 mg, 1.98 mmol) for 300 min were reacted.
Flash chromatography using hexane/EtAcO (98:2) afforded 6e
(149 mg, 54%).
4.8. Synthesis of 3,5-bis(diethoxycarbonylmethyl)-4,4-
difluoro-2,6-diiodo-8-(4-tolyl)-4-bora-3a,4a-diaza-s-indecene
(10)
BODIPY 4d (50 mg, 0.06 mmol), diethyl malonate (0.04 mL,
0.26 mmol) and NaH (3 mg, 0.13 mmol) in CH3CN (20 mL) were
refluxed for 1 h. Flash chromatography using hexane/EtAcO (98:2)
4.4. Selective functionalization. General procedure
A solution of halogenated BODIPY and nucleophilic reagent in
CH3CN (20 mL) was refluxed for 1e8 h under argon atmosphere.
After that time, the solvent was removed under reduced pressure
and the resulting mixture was dissolved in EtAcO and washed with
H2O. The extract was dried over MgSO4, filtered and concentrated
to dryness. The product was purified by flash chromatography on
silica gel (eluent hexane/EtOAc).
afforded BODIPY 10 (40 mg, 73%) as
a
d
purple solid. Mp
7.36 (2H, d, J¼8.1 Hz,
212.3e212.8 ꢀC; 1H NMR (300 MHz, CDCl3):
H-20), 7.28 (2H, d, J¼8.1 Hz, H-30), 7.05 (2H, s, H-1 and H-7), 5.48
(2H, s, CH(CO2Et)2), 4.23 (8H, q, J¼7.2 Hz, OCH2CH3), 2.41 (3H, s,
CH3), 1.24 (12H, t, J¼7.2 Hz, OCH2CH3); 13C NMR (176 MHz, CDCl3):
d
165.1 (COO), 151.2 (C), 145.3 (C), 142.2 (C), 139.5 (CH), 135.1 (C),
130.6 (CH), 129.9 (C), 129.5 (CH), 76.2 (CeI), 62.6 (OCH2CH3), 52.1

M.J. Ortiz et al. / Tetrahedron 68 (2012) 1153e1162
1161
(CH(CO2Et)2), 21.5 (CH3), 14.0 (OCH2CH3); IR (neat): 1760, 1743,
1580,1255,1090 cmꢂ1; HRMS-ESIꢂ: calcd for (C30H31BF2I2N3OꢂHþ)
849.0163 found 849.0185.
picosecond resolution). Excitation was performed with a 470 nm
diode laser and a 575 nm LED, both purchased by Picoquant. The
emission was monitorized at the maximum emission wavelength.
The fluorescence lifetime was obtained from the slope after
deconvolution of the instrument response signal. The goodness of
the deconvolution was controlled by the chi-squared statistical
parameter and from the analysis of the residuals. Radiative and
4.9. Synthesis of 3-diethoxycarbonylmethyl-4,4-difluoro-2,6-
diiodo-5-(4-methoxyphenylamino)-8-(4-tolyl)-4-bora-3a,4a-
diaza-s-indecene (11)
non-radiative rate constants were calculated as follows; kfl¼
f/s and
BODIPY 9 (30 mg, 0.04 mmol) and 4-methoxyaniline (7 mg,
0.05 mmol) in CH3CN (20 mL) were refluxed for 2 h. Flash chro-
matography using hexane/EtAcO (8:2) afforded BODIPY 11
(20 mg, 70%) as a red solid. Mp 162.1e162.6 ꢀC; 1H NMR
knr¼(1ꢂf)/s.
4.11.2. Computational details. Ground state geometries and charge
distributions were calculated at the Density Functional Theory
using the hybrid method B3LYP, together with the lanl2dz basis set,
especially parameterized to describe heavy atoms (i.e., iodine).
Absorption transition was simulated by the Time Dependent
method from the ground state.
(700 MHz, CDCl3):
d
7.89 (1H, s, NH), 7.28 (2H, d, J¼8.4 Hz, H-20),
7.21 (2H, d, J¼8.4 Hz, H-30), 7.12 (1H, s, H-7), 7.11 (2H, d, J¼8.4 Hz,
H-300), 6.86 (2H, d, J¼8.4 Hz, H-200), 6.62 (1H, s, H-1), 5.37 (1H, s,
CH(CO2Et)2), 4.24 (8H, q, J¼7.0 Hz, OCH2CH3), 3.77 (3H, s, OCH3),
2.37 (3H, s, CH3), 1.25 (12H, t, J¼7.0 Hz, OCH2CH3); 13C NMR
(176 MHz, CDCl3):
d
166.4 (COO), 159.5 (C), 156.7 (C), 144.8 (CH),
4.12. Singlet oxygen generation
140.1 (C), 139.2 (C), 133.9 (C), 133.4 (C), 133.0 (C), 130.5 (C), 130.2
(CH and CH), 129.2 (CH), 129.1 (CH), 128.0 (C), 114.5 (CH), 70.3
(CeI), 65.9 (CeI), 62.2 (OCH2CH3), 55.6 (OCH3), 52.0 (CH(CO2Et)2),
21.4 (CH3), 14.1 (OCH2CH3); IR (neat): 3363, 1765, 1740,1583,
1249, 1091 cmꢂ1; HRMS-ESIþ: calcd for (C30H28BF2I2N3OþNaþ)
836.0077 found 836.0081.
Individual argon-saturated solutions of 4b and 4d Abs532 ca. 0.1
were irradiated with a flash photolysis apparatus. A nanosecond
Nd/YAG laser system (Spectron) at 532 nm was used for excitation,
employing a 150-W Xenon lamp as a source for the analyzing light.
The detection system comprised a PTI monochromator and a red-
extended photomultiplier (Hamamatsu R666). The signal, ac-
quired and averaged by a digital oscilloscope (HewlettePackard
54504A), was transferred via an HPIB parallel interface to a PC
where it was analyzed and stored.
4.10. Synthesis of 4,4-difluoro-2,3,6-(4-formylphenyl)-5-(4-
methoxyphenylamino)-8-(4-tolyl)-4-bora-3a,4a-diaza-s-
indecene (12)
The efficiency of O2(1Dg) production by 4b, 4c and 4d in CH3CN
was determined by the comparative method already described.21,22
The initial intensities of the emission decay curves at 1270 nm (I0)
were determined for air-equilibrated solutions (Abs532 ca. 0.2) as
a function of laser fluence (LE). The output at 532 nm of the already
mentioned Spectron Nd/Yag laser was employed as the excitation
source. LE was varied using neutral density filters. FD values for 4b
and 4d were obtained by comparison of the slopes of the linear
plots I0 versus LE with that of a reference compound, all with ab-
sorbance matched solutions at 532 nm. The reference was Rose
BODIPY 7 (30 mg, 0.04 mmol) was dissolved in DME (20 mL).
4-Formylphenyl boronic acid (36 mg, 0.24 mmol) and
Na2CO3 (13 mg, 0.12 mmol) were added in the presence of a cata-
lytic amount of tetrakis(triphenylphosphine)palladium (3 mg,
0.0006 mmol). The reaction mixture was stirred under ultrasound
irradiation for 5 h at 75 ꢀC with a power of 720 W. After addition
of H2O (50 mL), the organic layer was extracted with EtOAc, dried
over MgSO4, filtered and concentrated to dryness. Flash chroma-
tography using hexane/EtOAc (95:5) afforded BODIPY 12 (57 mg,
46% yield) as
a
purple solid. Mp 190.6e191.1 ꢀC; 1H NMR
10.0 (1H, s, CHO), 9.83 (1H, s, CHO), 9.78 (1H,
Bengal (RB) with a FD ¼0.71 for O2(1Dg) generation determined in
RB
(700 MHz, CDCl3):
d
this work. For the determination of FD the already described
RB
s, CHO), 7.99 (1H, br s, NH), 7.86 (2H, d, J¼8.3 Hz, 2CH), 7.69 (2H, d,
J¼8.1 Hz, 2CH), 7.60 (2H, d, J¼8.3 Hz, 2CH), 7.44 (2H, d, J¼7.9 Hz,
2CH), 7.43 (2H, d, J¼8.3 Hz, 2CH), 7.28 (2H, d, J¼7.9 Hz, 2CH), 7.14
(2H, d, J¼8.3 Hz, 2CH), 7.03 (2H, d, J¼8.1 Hz, 2CH), 6.99 (1H, s, CH),
6.76 (1H, s, CH), 6.69 (2H, d, J¼8.8 Hz, 2CH), 6.39 (2H, d, J¼8.8 Hz,
2CH), 3.53 (3H, s, OCH3), 2.41 (3H, s, CH3); 13C NMR (176 MHz,
technique was employed with emission at 355 nm. Perinaph-
thenone (PN), with FD ¼1 in MeCN, was utilized as reference
PN
(Fig. 4S, ESI).23
The detection of O2(1Dg) phosphorescence was determined
using a previously described system.24 Briefly, a Nd/YAG laser
(Spectron) was used for the excitation (532 nm) of the sensitizer
RB (Abs532¼0.4), and the emitted radiation O2(1Dg) phosphores-
cence at 1270 nm was detected at right angles using an amplified
Judson J16/8Sp germanium detector, after passing through two
Wratten filters. The output of the detector was coupled to a digi-
tal oscilloscope and to a personal computer for the signal pro-
cessing. Usually, six shots were needed for averaging, so as to
achieve a good signal to noise ratio, from which the I0 value was
obtained.
CDCl3):
d 190.9 (CHO), 190.8 (CHO), 190.7 (CHO), 157.0 (C), 155.3
(C), 142.9e124.4 (C and CH), 120.5 (CH), 113.1 (CH), 54.4 (OCH3),
20.4 (CH3); IR (neat): 3370, 2854, 2732, 1698, 1597, 1449, 1205,
1099 cmꢂ1; MS (APCIꢂ) m/z (%): 715 (Mꢂ, 100), 666 (60), 576 (10);
HRMS-ESIþ: calcd for (C44H32BF2N3O4þHþ) 716.2534 found
716.2530.
4.11. Photophysical properties
4.11.1. Photophysics. Diluted BODIPY solutions were prepared by
adding the corresponding solvent after evaporation of an adequate
amount of a concentrated solution in acetone. Absorption and
fluorescence spectra were recorded on a Varian model Cary 4E
spectrophotometer and an SPEX Fluorolog 3-22 spectrofluorimeter,
respectively. The fluorescence spectra were corrected from the
wavelength dependence of the detector sensibility. Fluorescence
quantum yield was determined using an adequate commercial
BODIPY (PM567 and PM597)18b as reference. Radiative decay
curves were registered with the time correlated single-photon
counting technique (Edinburgh Instruments, model FL920, with
Acknowledgements
This work was supported by Projects MAT2007-65778-C02-02,
MAT2010-20646-C04-02 and 04 of the Spanish MICINN, GR35/10-A
of the UCM/BSCH and S-PE09UN61 of Gobierno Vasco.
Supplementary data
These data include copies of 1H and 13C NMR spectra for
all compounds, tables and figures of photophysical properties
and singlet oxygen generation. Supplementary data associated

1162
M.J. Ortiz et al. / Tetrahedron 68 (2012) 1153e1162
Levy, J. G. In CRC Hanboock of Organic Photochemistry and Photobiology; CRC:
New York, NY, 2004; Chapter 147, pp 1e17; (f) Berg, K. In Photodynamic
Therapy at the Cellular Level; Research Signpost: Kerala, India, 2007; Chapter 1,
pp 1e16; (g) Krasnovsky, A. A., Jr. In Photodynamic Therapy at the Cellular
Level; Research Signpost: Kerala, India, 2007; Chapter 2, pp 17e63; (h) Ar-
mesto, D.; Sastre, R. In Aplicaciones recientes de la luz en medicina, medio
with this article can be found in the online version, at
doi:10.1016/j.tet.2011.11.070. These data include MOL files and
InChiKeys of the most important compounds described in this
article.
~
ambiente y nuevos materiales; Editorial Complutense: Espana, 2010; Chapter 2,
pp 35e59.
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