8-Functionalization of alkyl-substituted-3,8-dimethyl BODIPYs by Knoevenagel condensation

Article abstract of DOI:10.1021/ol401993p

New 8-alkenylBODIPYs have been synthesized by Knoevenagel condensation between a series of alkyl-substituted-3,8-dimethylBODIPYs and aromatic or aliphatic aldehydes. This is in clear contrast with literature precedents, which indicate that this reaction occurs exclusively on the methyl group at C-3. The change in hybridization of the carbon at the 8-position (from sp³ to sp²) determines the fluorescence emission of the BODIPY, while the presence of electron-donating or -withdrawing groups leads to intramolecular charge transfer processes.

Full text of DOI:10.1021/ol401993p

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
8‑Functionalization of Alkyl-Substituted-
3,8-Dimethyl BODIPYs by Knoevenagel
Condensation
†
Eduardo Palao, Antonia R. Agarrabeitia,* Jorge Banuelos-Prieto,
,†
‡
~
Teresa Arbeloa Lopez, Inigo Lopez-Arbeloa, Diego Armesto, and Maria J. Ortiz*
‡
‡
†
,†
~
´
ꢀ
´
Departamento de Quımica Organica I, Facultad de Ciencias Quımicas,
Universidad Complutense, 28040 Madrid, Spain, and Departamento de Quımica Fısica,
´
´
´
Universidad del Paıs Vasco/EHU, Apartado 644, 48080 Bilbao, Spain
mjortiz@quim.ucm.es
Received July 16, 2013
ABSTRACT
New 8-alkenylBODIPYs have been synthesized by Knoevenagel condensation between a series of alkyl-substituted-3,8-dimethylBODIPYs and
aromatic or aliphatic aldehydes. This is in clear contrast with literature precedents, which indicate that this reaction occurs exclusively on the
methyl group at C-3. The change in hybridization of the carbon at the 8-position (from sp3 to sp2) determines the fluorescence emission of the
BODIPY, while the presence of electron-donating or -withdrawing groups leads to intramolecular charge transfer processes.
~
Among organic dyes, the 4,4-difluoro-4-bora-3a,4a-
diaza-s-indacenes, commonly known as BODIPYs, are a
very interesting family of dyes with unique properties that
have attracted increasing interest for their technological
and/or biomedical applications,1 as shown by more than
600 articles published in this area during the past year.
Many of their applications require derivatization of the
meso-position to obtain new BODIPY dyes with interest-
ing photophysical properties.
Various approaches have been described in the literature
for the functionalization of the meso-position in BODIPYs.
Thus, the synthesis of BODIPYs using suitably substituted
pyrroles and aromatic aldehydes, or acid chlorides, allows
the incorporation of different substituents at the 8-position,
although this route has some limitations.1
Pena-Cabrera et al. have successfully prepared new
8-substituted BODIPY dyes, with emission from the blue
to red spectral region, by nucleophilic aromatic substitu-
tion,2 or by a direct LiebeskindꢀSrolg cross-coupling3
with the boronic acid of 8-methylthioBODIPY.
Recently, Dehaen et al.4 have described the versatile
synthesis of new meso-functionalized BODIPYs by nu-
cleophilic substitution of 8-halogenated BODIPYs by
nitrogen, oxygen, or sulfur nucleophiles as well as transi-
tion metal-catalyzed cross-coupling reactions (Suzuki, Stille,
and Sonogashira).
~
(2) (a) Banuelos, J.; Martı
´
n, V.; Gomez-Duran, C. F. A.; Arroyo
Cordoba, I. J.; Pena-Cabrera, E.; Garcıa-Moreno, I.; Costela, A.; Perez-
Ojeda, M. E.; Arbeloa, T.; Lopez Arbeloa, I. Chem.;Eur. J. 2011, 17,
~
´
ꢀ ꢀ
7261. (b) Osorio-Martınez, C. A.; Urıas-Benavides, A.; Gomez-Duran,
´ ´
~
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C. F. A.; Banuelos, J.; Esnal, I.; Lopez Arbeloa, I.; Pena-Cabrera, E.
~
† Universidad Complutense.
J. Org. Chem. 2012, 77, 5434.
‡ Universidad del Paı
´
s vasco/EHU.
(3) (a) Pena-Cabrera, E.; Aguilar-Aguilar, A.; Gonzalez-Domı
´
nguez,
M.; Lager, E.; Zamudio-Vazquez, R.; Godoy-Vargas, J.; Villanueva-
Garcıa, F. Org. Lett. 2007, 9, 3985. (b) Lager, E.; Liu, J.; Aguilar-Aguilar,
A.; Tang, B. Z.; Pena-Cabrera, E. J. Org. Chem. 2009, 74, 2053. (c)
~
ꢀ
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(1) (a) Loudet, A.; Burgess, K. Chem. Rev. 2007, 107, 4891. (b)
Ulrich, G.; Ziessel, R.; Harriman, A. Angew. Chem., Int. Ed. 2008, 47,
1184. (c) Benniston, A. C.; Copley, G. Phys. Chem. Chem. Phys. 2009,
11, 4124. (d) Benstead, M.; Mehl, G. H.; Boyle, R. W. Tetrahedron 2011,
67, 3573. (e) Boens, N.; Leen, V.; Dehaen, W. Chem. Soc. Rev. 2012, 41,
1130. (f) Kamkaew, A.; Lim, S. H.; Lee, H. B.; Kiew, L. V.; Chung, L. Y.;
Burgess, K. Chem. Soc. Rev. 2013, 42, 77.
´
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Arroyo, I. J.; Hu, R.; Tang, B. Z.; Lopez, F. I.; Pena-Cabrera, E.
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r
10.1021/ol401993p
XXXX American Chemical Society

On the other hand, the Knoevenagel reaction using
aromatic aldehydes is a facile and versatile route to effec-
tively tune BODIPY dyes for near-infrared emission. Ac-
cording to literature precedents, this reaction takes place
usually on the methyl groups in positions 3 and/or 5,
yielding mono- and distyryl-BODIPYs.1,5 The syntheses
of 3,5,7-tristyryl- and 1,3,5,7-tetrastyryl-derivatives by this
route have been also reported.6 In all the cases studied of
BODIPYs with an aryl group in the 8-position, the results
show that the methyl groups in positions 3 and 5 are the
most acidic.5,6 Even in the case of the 1,3,5,7,8-penta-
methylBODIPY, literature precedents show that the reac-
tion takes place regioselectively at the C-3 and C-5 methyl
groups.7 As far as we are aware, there is only one report8 of
meso-styryl derivatives that were synthesized by regio-
selective Knoevenagel-type condensation of two commer-
cially available BODIPYs (PM597 and PM567). This
unusual reactivity was justified due to the presence of
two methyl groups at positions 1 and 7, in addition to
ethyl or tert-butyl groups at positions 2 and 6 of the
BODIPY. Thus, the reaction at the meso-position could
relieve the structural strain of these highly substituted
BODIPYs, overriding the anticipated lower acidity of the
meso-methyl protons.
Within the research done in our group, we were inter-
ested in carrying out the Knoevenagel condensation
between BODIPY 1a (PM546) and 4-acetamidobenzalde-
hyde (2a). Based on literature precedents the condensation
product at the methyl group in position 3 was expected.
However, contrary to these expectations, the 8-styryl
derivative 3a was obtained, exclusively (Scheme 1). No
3-styryl product was formed in this reaction. The structure
of 3a was confirmed by X-ray diffraction analysis (Figure S1).
The formation of 3a cannot be justified by steric factors8
due to the absence of alkyl groups at the 2- and 6-positions.
Furthermore, this result implies that the methyl group
at the 8-position of 1a is the most acidic, in clear contrast
with earlier observations in studies on the condensation of
1awith otheraldehydesthatindicatedthat the correspond-
ing 3-styryl derivative is always obtained.7 Therefore,
Scheme 1. Knoevenagel Condensation of BODIPYs 1a and 1b
this result was totally unexpected and prompted us to
investigate the possible extension of this unusual regio-
selectivity to 8-methylBODIPYs 1a and 1b using different
aromatic aldehydes (Scheme 1). BODIPY 1b has been
synthesized for the first time in this work.
Knoevenagel reaction of 1a with aldehydes 2b and 2c in
the presence of piperidine and AcOH, using benzene as
solvent, afforded the 8-styryl derivatives 3b (24%) and 3c
(23%), respectively, as the only products. These results are
in clear contrast with literature precedentsthatsuggest that
the condensation only occurs on the methyl at C-3.
The Knoevenagel condensation of 1a was extended to
aldehydes 2d and 2e. Again in these instances, the corre-
sponding 8-styryl products 3d (25%) and 3e (12%), re-
spectively, were obtained as the major products, althought
the 3-styryl analogues 4a (11%) and 4b (8%) were also
formed in lower yields. This results is in clear contrast with
literature precedents that indicated that 4a and 4b are the
only products formed in these reactions.7a,c The main
difference between our reaction conditions and those
reported in the literature is the solvent used in the reac-
tions. Therefore, in order to clarify this discrepancy, the
reactions of 1a with aldehydes 2d and 2e were reinvesti-
gated under the same conditions described in the literature,
using chlorobenzene and toluene as solvents, instead of
benzene. Under these conditions, compounds 3d, 3e, 4a,
and 4b are formed in the same percentage as in the herein
reported study, demonstrating that the condensation takes
place preferentially on the methyl group at C-8.
These results demonstrated that the 8-Knoevenagel
reaction could be extended to BODIPYs unsubstituted at
the 2- and 6-positions and suggests that other 8-methyl-
BODIPYs with different substitution patterns could also
undergo this reaction. Thus, 3,5,8-trimethylBODIPY 1b
was studied in order to determine whether this reaction
could also occur with substrates without any steric hin-
drance around position 8. Thus, the condensation of 1b
(5) For example, see: (a) Rurack, K.; Kollmannsberger, M.; Daub, J.
Angew. Chem., Int. Ed. 2001, 40, 385. (b) Ziessel, R.; Ulrich, G.;
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Eur. J. 2009, 15, 1359. (c) Zhu, S.; Zhang, J.; Vegesma, G. K.; Pandey,
R.; Luo, F.-T.; Green, S. A.; Liu, H. Chem. Commun. 2011, 47, 3508. (d)
Kolemen, S.; Bozdemir, O. A.; Cakmak, Y.; Barin, G.; Erten-Ela, S.;
Marszalek, M.; Yum, J.-H.; Zakeeruddin, S. M.; Nazeeruddin, M. K.;
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Gratzel, M.; Akkaya, E. U. Chem. Sci. 2011, 2, 949. (e) Boens, N.; Qin,
W.; Baruah, M.; De Borggraeve, W. M.; Filarowski, A.; Smisdom, N.;
Ameloot, M.; Crovetto, L.; Talavera, E. M.; Alvarez-Pez, J. M. Chem.;
Eur. J. 2011, 17, 10924.
(6) (a) Buyukcakir, O.; Bozdemir, O. A.; Kolemen, S.; Erbas, S.;
Akkaya, E. U. Org. Lett. 2009, 11, 4644. (b) Bura, T.; Retailleau, P.;
Ulrich, G.; Ziessel, R. J. Org. Chem. 2011, 76, 1109. (c) Kostereli, Z.;
Ozdemir, T.; Buyukcakir, O.; Akkaya, E. U. Org. Lett. 2012, 14, 3636.
(d) Zhu, S.; Zhang, J.; Vegesna, G.; Tiwari, A.; Luo, F.-T.; Zeller, M.;
Luck, R.; Li, H.; Green, S.; Liu, H. RSC Adv. 2012, 2, 404.
(7) (a) Wang, D.-C.; Peng, X.-J.; Cui, A.-J.; He, C.; Fan, J.-L. Acta
Crystallogr. 2006, E62, o5789. (b) Niu, S.; Ulrich, G.; Retailleau, P.;
Ziessel, R. Org. Lett. 2011, 13, 4996. (c) Evans, C. W.; Latter, M. J.; Ho,
D.; Peerzade, S. A. M. A.; Clemons, T. D.; Fitzgerald, M.; Dunlop,
S. A.; Iyer, K. S. New J. Chem. 2012, 36, 1457.
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Lett. 2011, 13, 5870.
B
Org. Lett., Vol. XX, No. XX, XXXX

with 2a, 2c, 2d, and 2e afforded the meso-styryl derivatives
3fꢀi, respectively, in 43% to 83% yield. Compound 1b
proved to be more reactive than 1a affording the corre-
sponding meso-styryl derivatives after shorter reaction
times and in higher yields than in the case of BODIPY
1a. This is probably due to less steric hindrance for the
attack at the methyl at position 8 in 1b than in 1a.
We extended the study to asymmetric BODIPY dyes 1c9
and 1d. BODIPY 1d has been synthesized for the first time
in this work. The reaction of these compounds with the
aldehyde 2a produced the expected meso-styryl products 3j
and 3k, exclusively, in 49% and 55% yields, respectively
(Figure 1).
At this point, we were interested in checking the possi-
bility of extending the 8-Knoevenagel reaction to aliphatic
aldehydes. Thus, the reaction of BODIPY 1b with isobu-
tyraldehyde (2f) takes place smoothly at the meso-position
yielding the corresponding condensation product 3l in
71% yield (Figure 1). These additional examples add fur-
ther support to the proposal that meso-methyl BODIPY
dyes are more prone to undergo the 8-Knoevenagel reac-
tion that the corresponding 3-methyl derivatives, contrary
to previous reports.7
Figure 2. Electrostatic potential mapped onto the electronic
density (b3lyp/6-31þþg**) for compounds 1a and 1b.
on the methyl group in the 8 position. Thus, the reaction of
1a in the presence of acetic acid-d4 and piperidine-d11 was
followed by NMR spectroscopy. The results obtained
show that the hydrogens on the methyl group at C-8 are
replaced by deuterium at a much faster rate than the
hydrogens of the methyl groups at positions 3 and 5
(Supporting Information) clearly demonstrating that the
hydrogens of the methyl group at C-8 are more acidic than
those at positions 3 and 5.
Finally, 3,5,8-tristyryl BODIPYs can be easily synthe-
sized by the strategy reported herein. Thus, condensation
of 1a with a large excess of aromatic aldehyde 2d yields the
corresponding 3,5,8-tristyryl dye 5a (35%). Similarly,
condensation of the 8-styryl derivative 3g with isobutyr-
aldehyde (2f) affords compound 5b in 53% yield (Figure 3).
Figure 1. Structures of asymmetricBODIPYs1cꢀd and 8-alkenyl
derivatives 3jꢀl.
Such regioselectivity, especially in compound 1b, can be
understood by means of theoretical calculations. Other
authors have justified the reactive sites to Knoevenagel
reaction identifying the most acid protons by the charge
distribution.6a,8 We make use of the potential electrostatic
maps as an intuitive way to localize the most susceptible
methyls to undergo such a reaction. The results obtained in
thisstudy show that the positivechargedensity (blue color)
is placed at the upper part of the molecule, in line with the
dipole moment orientation (Figure 2).
Accordingly, the methyl group at 8-position should
undergo the condensation reaction morereadilythanthose
at positions 3 and 5. Moreover, in compound 1b the
positive charge density is more concentrated around the
8-methyl than in compound 1a, supporting the higher
reactivity toward Knoevenagel condensation for the for-
mer compound observed experimentally.
Figure 3. Structures of trialkenyl-BODIPYs 5aꢀb.
The regioselectivity observed in this reaction allows an
easy and direct synthetic route for the preparation of
8-alkenyl BODIPYs, of which only a few examples are
reported in the literature.3c,8,10 The new alkenyl BODIPYs
derivatives are suitable substrates for subsequent function-
alization.
Alkylated BODIPYs 1a, 1b, and 1d show very high
fluorescence emissions (approaching 100% in Table S1).
The only exception is compound 1c (φ = 0.70), where just
one pyrrole ring is alkylated and the induced asymmetry in
the charge distribution enhances the nonradiative path-
ways. The spectral band positions depend on the degree of
alkylationand onthepositioninwhichtheyare attachedto
the BODIPY core (Table S1). The addition of a vinyl
group at the 8 position (3l) leads to a bathochromic shift in
terms of a resonant interaction. However, such electronic
At this point, it was considered necessary to obtain
additional evidence on the higher acidity of the hydrogens
~
ꢀ
a-Moreno, I.; Lopez-
Arbeloa, I.; Costela, A.; Infantes, L.; Perez-Ojeda, M. E.; Palacios-
(9) Banuelos, J.; Agarrabeitia, A. R.; Garcı
´
(10) (a) Yakubovskyi, V. P.; Shandura, M. P.; Kovtun, Y. P. Eur. J.
Org. Chem. 2009, 3237. (b) Yakubovskyi, V. P.; Shandura, M. P.;
Kovtun, Y. P. Dyes Pigm. 2010, 87, 17.
ꢀ
Cuesta, M.; Ortiz, M. J. Chem.;Eur. J. 2010, 16, 14094.
Org. Lett., Vol. XX, No. XX, XXXX
C

coupling drastically drops the fluorescence efficiency (from
1 to0.12). Thiseffectcaused bythe changeofhybridization
of the carbon at the meso position from sp3 to sp2 was
related to a marked increase in the nonradiative deactiva-
tion pathways.3c Recently, it has been theoretically pro-
posed that such relaxation is due to an increase of the
vibrational motion out of plane of the pyrroles.11 This
structural flexibility enhances the internal conversion and
is reflected in its high Stokes shift (1550 cmꢀ1).
Besides, the attachment of electron donor (N(Me)2 σp
þ
=
ꢀ1.711, OMe ꢀ0.648 and NHCOMe ꢀ0.249) or electron
acceptor (NO2 σpþ = 0.740 and CN 0.74) groups at the
para position of the 8-styryl moiety leads to a consider-
able decrease in the fluorescence efficiency, due to the
population of an intramolecular charge transfer (ICT)
state. Indeed, the BODIPY moiety can behave as an
electron donor or acceptor depending on the attached
functionalization. In some compounds a broad and weak
red band (assigned to the ICT emission) has been de-
tected, following that from the locally excited state, which
is drastically quenched (Figure 4). In the rest of the 8-styryl
derivatives, the ICT is so favored that its fluorescence emission
is negligible and almost no emission was detected.12
Figure 5. Cyclic voltammograms for 8-alkenyl derivatives of dye
1b, bearing vinyl (3l), amine (3i), or nitro (3g and 5b) groups, in
acetonitrile.
addition of vinyl (3l) brings the cathodic wave closer to the
anodic reducing the energy gap. The presence of amino (3i)
makes the compound easier to oxidize (0.893 V), while the
presence of nitro groups (3g and 5b) makes it easier to
reduce (ꢀ0.549 V). These results confirm the electron
donating and withdrawing ability of each moiety and sup-
port the presence of an ICT process (where the BODIPY
core acts as an acceptor or donor respectively) as the main
nonradiative pathway.
In summary, previous studies have led to the conclusion
that the Knoevenagel condensation in methyl-substituted
BODIPYs takes place usually on the methyl groups in po-
sitions 3 and/or 5, yielding mono- and distyryl-BODIPYs.
In contrast with these observations, the results of the current
study show that alkyl-substituted-3,8-dimethyl BODIPYs
undergo Knoevenagel condensation at the 8-position using
aromatic and aliphatic aldehydes. These results allow an easy
strategy for the meso functionalization of the BODIPY core
using this condensation reaction. These results open the
possibility of incorporating other functionalizations at the
meso-position based on the acidity of the methyl groups at
this position. Further work in this area is in progress.
Figure 4. Fluorescence spectra of the 8-p-acetamidostyryl deriv-
atives (3a, 3f, 3j, 3k) in acetonitrile.
In the trialkenyl derivatives 5a and 5b, the spectral bands
are significantly shifted toward the red part of the visible
spectra (Table S1). Furthemore, the fluorescence efficiency
is very low, due to the sp2 hybridization of the carbon atom
at position 8 and also to the ICT process from the methoxy
or nitro groups, as stated above.
Acknowledgment. This work was supported by Projects
MAT2010-20646-C04-02 and -04 of the Spanish Ministerio
de Economia y Competitividad (MINECO) and IT339-10
of Basque Goberment. X-ray diffraction data were pro-
vided by SGI/IZO-SGIker of the UPV/EHU.
Electrochemical measurements of the reference com-
pound 1b reveal an irreversible oxidation at 1.377 V and
a reversible reduction at ꢀ0.958 V (Figure 5). Further
Supporting Information Available. Detailed experimen-
tal procedures, NMR spectra. Photophysical, electroche-
mical, X-ray crystal, and computational data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Chibani, S.; Le Guennic, B.; Charaf-Eddin, A.; Laurent, A. D.;
Jacquemin, D. Chem. Sci. 2013, 4, 1950.
~
ꢀ
(12) Esnal, I.; Banuelos, J.; Lopez Arbeloa, I.; Costela, A.; Garcıa-
´
ꢀ
Moreno, I.; Garzon, M.; Agarrabeitia, A. R.; Ortiz, M. J. RSC Adv.
2013, 3, 1547.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX