Steric strain release-directed regioselective functionalization of meso-methyl bodipy dyes

Article abstract of DOI:10.1021/ol202490p

Starting from some meso-methyl Bodipy dyes, the corresponding meso-styryl derivatives were synthesized by regioselective Knoevenagel-type condensation with different aromatic aldehydes. The reactions were driven by the alleviation of the structural strain

Full text of DOI:10.1021/ol202490p

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5870–5873
Steric Strain Release-Directed
Regioselective Functionalization of
meso-Methyl Bodipy Dyes
Neelam Shivran,† Soumyaditya Mula,† Tapan K. Ghanty,‡ and
Subrata Chattopadhyay*,†
Bio-Organic Division, Theoretical Chemistry Section, Bhabha Atomic Research Centre,
Mumbai-400085, India
schatt@barc.gov.in
Received September 14, 2011
ABSTRACT
Starting from some meso-methyl Bodipy dyes, the corresponding meso-styryl derivatives were synthesized by regioselective Knoevenagel-type
condensation with different aromatic aldehydes. The reactions were driven by the alleviation of the structural strain of the alkyl substituted
Bodipys that could override the differential acidities of the methyl protons at the pyrrole ring of the Bodipy moiety.
The dipyrromethene-BF2 (4,4-difluoro-4-bora-3a,4a-
diaza-s-indacene, Bodipy, Figure 1) compounds are val-
ued for their optoelectronic applications.1 Functionaliza-
tion of the Bodipy core is an important synthetic goal as it
helps in tuning their property to light and electron
transfer induced processes, improving hydrophilicity and
anchoring to various mattrices for widening the scope of
their applications. Most of the previous research, directed
to this end, was targeted to functionalization of the pyrrole
moieties of the Bodipy core by(i) halogenation followedby
organometallic coupling to introduce alkene/alkyne/arene
substitutions;2a,b (ii) direct neucleophilic substitution;2cÀe
and (iii) de novo syntheses of the Bodipy core from
modified pyrroles.2f,g However, substitution at the pyrrole
moiety may bring about undesirable changes in the physi-
cal properties, affecting the targeted function adversely.
For example, the presence of electron-donating groups in
the pyrrole ring would reduce the fluorescence quantum
yields of the Bodipy molecules especially in polar solvents.3
Instead, meso-functionalization of the Bodipy moiety
with an alkyl/arylalkyl moiety would provide new Bodipy-
based functional molecules without perturbing the photo-
electronic properties. The presence of sp/sp2-hybridized
carbon at the meso-position adversly affects the fluorescence
and lasing efficiency of the Bodipy molecules.4 Earlier,
LiebeskindÀSrogl cross-coupling of a 8-thiomethylbodipy
† Bio-Organic Division.
‡ Theoretical Chemistry Section.
(1) (a) Ziessel, R.; Ulrich, G.; Harriman, A. New J. Chem. 2007, 31,
496–501. (b) Loudet, A.; Burgess, K. Chem. Rev. 2007, 107, 4891–4932.
(c) Ulrich, G.; Ziessel, R.; Harriman, A. Angew. Chem., Int. Ed. 2008, 47,
1184–1201. (d) Erten-Ela, S.; Yilmaz, D.; Icli, B.; Dede, Y.; Icli, S.;
Akkaya, U. E. Org. Lett. 2008, 10, 3299–3302. (e) Oleynik, P.; Ishihara,
Y.; Cosa, G. J. Am. Chem. Soc. 2007, 129, 1842–1843. (f) Kumaresan,
D.; Thummel, R. P.; Bura, T.; Ulrich, G.; Ziessel, R. Chem.;Eur. J.
2009, 15, 6335À6339 and references cited therein.
(2) (a) Rohand, T.; Qin, W.; Boens, N.; Dehaen, W. Eur. J. Org.
Chem. 2006, 4658–4663. (b) Wan, C.-W.; Burghart, A.; Chen, J.;
Bergstroem, F.; Johansson, L. B.-A.; Wolford, M. F.; Kim, T. G.; Topp,
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3694–3698. (e) Rohand, T.; Baruah, M.; Qin, W.; Boens, N.; Dehaen, W.
Chem. Commun. 2006, 266–268. (f) Burghart, A.; Kim, H.; Welch, M. B.;
Thoresen, L. H.; Reibenspies, J.; Burgess, K.; Bergstroem, F.; Johansson,
L. B. A. J. Org. Chem. 1999, 64, 7813–7819. (g) Chen, J.; Burghart, A.;
Derecskei-Kovacs, A.; Burgess, K. J. Org. Chem. 2000, 65, 2900–2906.
(3) Kim, T.-I.; Park, S.; Choi, Y.; Kim, Y. Chem.;Asian J. 2011, 6,
1358–1361.
(4) (a) Mula, S.; Ray, A. K.; Banerjee, M.; Chaudhuri, T.; Dasgupta,
K.; Chattopadhyay, S. J. Org. Chem. 2008, 73, 2146–2154. (b) Jones,
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r
10.1021/ol202490p
Published on Web 10/12/2011
2011 American Chemical Society

with various boronic acids has been used for meso-function-
alization of the Bodipy moiety.5 However, this requires
reagents that are expensive and/or have to be synthesized
by multistep routes. Direct synthesis of these types of
Bodipy molecules via the condensation of substituted pyr-
roles with aliphatic aldehydes/acid chlorides has inherent
limitations due to the instability of the required acid chlor-
ides and nonreactivity of the aldehydes.1aÀc
highly twisted meso-substituents are largely decoupled
from the Bodipy core.9 Costela et al. showed that the
meso-H analogue of 2a is planar.10 We envisaged that a
Knoevenagel-type condensation of the Bodipy molecules
at the meso-Me group would alleviate such an unfavor-
able steric interaction. Thus, the release of steric strain
may drive the condensation selectively at the meso-posi-
tion, overriding the least acidity of the meso-methyl
protons. In this study, we proved the hypothesis by
selective meso-functionalization of the Bodipy dyes
2a and 2b using readily available and inexpensive reagents
(Scheme 1 and Table 1).
Scheme 1
Figure 1. General structure of Bodipy core (1), structures of
commercially available Bodipy dyes, PM597 (2a) and PM567 (2b).
The commercially available Bodipy dyes PM597 (2a)
and PM567 (2b) (Figure 1) contain CH3 substitutions at
the pyrrole rings and at the C-8 (meso-) position. Mulli-
ken-charge analysis of the 1,3,5,7,8-pentamethyl Bodipy
dye showed that the electron density on the core carbon
atoms follows the order C-8 > C-1/7 > C-3/5. Thus, the
CH3 groups at those positions can undergo the base-
catalyzed Knoevenagel-type condensation with various
aryl aldehydes according to their relative acidities C-3/5
> C-1/7 > C-8. This strategy provides another avenue
for functionalization of the Bodipy moiety and has been
exploited extensively to develop C-3/C-5 styryl Bodipy
derivatives with red-shifted fluorescence.6,7 In all these
studies, the chosen Bodipy substrates had an aryl sub-
stituent at the meso-position, ensuring the reaction to
proceed regioselectively at the C-3 and C-5 methyl
groups. More recently, syntheses of tri- and tetrastyryl
Bodipys by this route are also reported under specific
conditions.8 However, this strategy has never been used
for meso-functionalization.
Table 1. Regioselectivity of the Reaction
Bodipy
aldehyde, R1
product, R1, R2
% yielda
2a
2a
2a
2b
2b
2b
3a, OMe
3b, OH
3c, NO2
3a, OMe
3c, NO2
3d, Br
4a, OMe, t-Bu
4b, OH, t-Bu
4c, NO2, t-Bu
4d, OMe, Et
4e, NO2, Et
4f, Br, Et
65
50
67
10b
55
61
a Based on isolation. b 13% 3-styryl analogue was also isolated.
Initially, we carried out the condensation between 2a
and 3a in the presence of piperidine and AcOH.6a The dye
2a is highly twisted due to a strong coaxial steric repulsion
between the 2- (and 6-) tert-butyl and other methyl groups
at the pyrrole moieties. The steric distortion in 2a is even
more in the excited state, resulting in an uncharacteristi-
cally high Stokes shift (∼1350 cmÀ1), compared to other
Bodipy dyes.11 Hence, its condensation was expected to
take place regioselectively at the meso-position to reduce
the steric strain. True to our expectation, the reaction
proceeded uneventfully to furnish compound 4a,12 the
Our previous conformational analysis revealed that, in
the planar form of 2b, the van der Waals radii of the
hydrogen atoms of the C-1/C-7 and meso-Me groups can
overlap. This makes the meso-site spatially crowded to
force the Me groups out of the Bodipy plane. Thus, the
(6) (a) Dost, Z.; Atilgan, S.; Akkaya, E. U. Tetrahedron 2006, 62,
8484–8488. (b) Rurack, K.; Kollmannsberger, M.; Daub, J. Angew.
Chem., Int. Ed. 2001, 40, 385–387.
(7) (a) Mula, S.; Ulrich, G.; Ziessel, R. Tetrahedron Lett. 2009, 50,
6383–6388. (b) Mula, S.; Elliott, K.; Harriman, A.; Ziessel, R. J. Phys.
Chem. A 2010, 114, 10515–10522. (c) Lee, H. Y.; Bae, B. R.; Park, J. C.;
Song, H.; Han, W. S.; Jung, J. H. Angew. Chem., Int. Ed. 2009, 48, 1239–
1243. (d) Guliyev, R.; Coskun, A.; Akkaya, E. U. J. Am. Chem. Soc.
2009, 131, 9007–9013. (e) Yuan, M.; Zhou, W.; Liu, X.; Zhu, M.; Li, J.;
Yin, X.; Zheng, H.; Zuo, Z.; Ouyang, C.; Liu, H.; Li, Y.; Zhu, D. J. Org.
Chem. 2008, 73, 5008–5014. (f) Liu, J.-Y.; Ermilov, E. A.; Roder, B.
Chem. Commun. 2009, 1517–1519 and references cited therein.
(8) (a) Buyukcakir, O.; Bozdemir, O. A.; Kolemen, S.; Erbas, S.;
Akkaya, E. U. Org. Lett. 2009, 11, 4644–4647. (b) Bura, T.; Retailleau,
P.; Ulrich, G.; Ziessel, R. J. Org. Chem. 2011, 76, 1109–1117.
~
(9) Arbeloa, F. L.; Banuelos, J.; Martinez, V.; Arbeloa, T.; Arbeloa,
I. L. Int. Rev. Phys. Chem. 2005, 24, 339–374.
(10) Costela, A.; Garcıa-Moreno, I.; Pintado-Sierra, M.; Amat-
´
Guerri, F.; Sastre, R.; Liras, M.; Arbeloa, F. L.; Prieto, J. B.; Arbeloa,
I. L. J. Phys. Chem. A 2009, 113, 8118–8124.
ꢀ
(11) Prieto, J, B.; Arbeloa, F. L.; Martınez, V. M.; Lopez, T. A.;
´
Arbeloa, I. L. J. Phys. Chem. A 2004, 108, 5503–5508.
(12) All compounds were fully characterized by NMR and mass
spectroscopy, as well as elemental analyses.
Org. Lett., Vol. 13, No. 21, 2011
5871

Figure 3. Chemical and X-ray crystal structure of 5.
Figure 2. X-ray crystal structure of 4a.
products. Nevertheless, the formation of the 4d sup-
ported our steric factor hypothesis.
meso-styryl analogue of 2a as the single product within
30 min. Earlier, condensation of 2b with benzaldehyde,
under similar conditions, furnished the 3-styryl derivative
in a very low yield (<3%) along with a large number of
unidentified products.13 Thus, our results with 2a indi-
cated the steric factor as the major driving force for the
regioselectivity of the reaction, which was also confirmed
by analyzing the X-ray crystal structure of 4a (Figure 2).
The degree of steric relaxation in forming 4a was evident
from the dihedral angle (C3ÀC4ÀC5ÀC6) between the
two pyrrole units and the torsion angles (C1ÀC2ÀC3À
C4 and C6ÀC7ÀC8ÀC9) of the pyrrole rings in 2a and
4a. The crystallographic data revealed that the torsion
angles of the pyrrole rings of 4a were significantly less
than those of 2a (3.8°),11 while the C3ÀC4ÀC5-C6 dihe-
dral angle of 4a was much less than that of 2a (172.8°)11
(see Supporting Information). These suggested that the
Bodipy chromophore of 4a was comparatively more
planner than that in 2a. Subsequently, the synthetic
strategy was extended for the condensation of 2a with
3b as well as 3c to obtain the meso-styryl Bodipy com-
pounds 4b and 4c respectively.
However, the condensation between the dye 2b and
3a, under the same conditions, afforded the meso-styryl
(4d) and C-3 styryl analogues of 2b in 10% and 13%
yields respectively as the major isolated compounds
along with some unanalyzed products (possibly poly-
styryl and degradation products). Based on the avail-
able X-ray crystallography data, the torsion angle
(0.8°) of the pyrrole rings in 2b is much less than that
in 2a.11 Hence, the release of steric strain due to the
condensation at the meso-position of the dye 2b will be
much less than that with 2a. Thus, it was expected that
the reaction course may be dictated by the steric factor
as well as the higher acidities of the C-3/C-5 methyl
protons in 2b, resulting in the formation of a mixture of
We reasoned that use of more electrophilic aldehydes
might negate the acidity factor of the meso and pyrrole
Me protons to direct the condensation at the meso-posi-
tion even with the less strained molecule 2b. To confirm
this, 2b was subjected to condensation with 3c. The
reaction was slow and attained an equilibrium at 4 h to
furnish the meso-styryl analogue 4e along with the recov-
ered dye 2b (40%). Formation of the C-3 and/or C-5
styryl derivatives was not noticed, despite the higher
acidities of the designated Me protons. This also estab-
lished that relaxation of steric strain was the major
determinant of the reaction. The reaction proceeded
through the intermediacy of a pink colored stable product
that could be isolated (30% yield at 2 h) and characterized
as 5 by spectroscopy, CHN analysis, and X-ray crystal-
lography (Figure 3). To the best of our knowledge, this is
the first report of isolation and characterization of the
intermediate in a Knovenagel type condensation with the
Bodipy dyes. The intermediacy of compound 5 in the
reaction was confirmed by its conversion to 4e along with
some amount of 2b on heating in the presence of piper-
idine and AcOH. The partial recovery of 2b also ex-
plained the sluggishness of the reaction and moderate
yield of 4e due to the attainment of an equilibrium. In a
similar manner, the styryl derivative 4f could also be
synthesized by condensing the dye 2b with 3d.
As potential applications of the new method, a few
new Bodipy compounds were synthesized using some of
the above meso-styryl Bodipy compounds. For example,
the highly fluorescent dye 6 was synthesized (Scheme 2)
by catalytic hydrogenation of 4d that showed a very
weak fluorescence (vide infra). Interestingly, compound
6 could not be synthesized via the conventional route of
condensing kryptopyrrole (7) with p-methoxydihydro-
cinnamaldehyde, due to the low reactivity of the arylalk-
yl aldehydes.1b The polystyryl Bodipys are useful func-
tional molecules. Previously, Akkaya et al. synthesized a
tetrastyryl Bodipy (A4 system),8a while Ziessel et al.
synthesized polystyryl Bodipy dyes with AB, A2B2, and
(13) Costela, A.; Garcıa-Moreno, I.; Pintado-Sierra, M.; Amat-
´
Guerri, F.; Lirasc, M.; Sastre, R.; Arbeloae, F. L.; Prietoe, J. B.;
Arbeloae, I. L. J. Photochem. Photobiol. A: Chem. 2008, 198, 192–199.
5872
Org. Lett., Vol. 13, No. 21, 2011

The excited state of the Bodipy core has inherent charge
redistribution toward the meso-position.1d The presence of
the electron-withdrawing meso-styryl group would facil-
itate it further and may alter the localization of the HOMO
and LUMO. For example, our theoretical calculations
revealed that the HOMO and LUMO of 8 were mostly
localized on the Bodipy and meso-styryl moieties respec-
tively (Figure 4). Hence the emission process with the
meso-styryl Bodipys is likely to be nonradiative, explaining
their very weak fluorescence. However, such an excited
state charge distribution would facilitate rapid electron
injection into the conduction band of TiO2.1d This may be
important in using the meso-styryl compounds as potential
sensitizers for designing new dye sensitized solar cells.
Scheme 2
ABCD systems.8b In the present work, the Bodipy com-
pound 4e was condensed with 3a to furnish the 3,5,8-
tristyryl substituted Bodipy dye 8, belonging to a new AB2
system of the polystyryl Bodipy dye.
For stabilizing the radical anions the meso-position of
the indacene framework is of crucial importance. The cyclic
voltammetric results (Table S1) of some selected Bodipy
compounds (2b, 4d, and 8) revealed reversible cathodic
waves, assigned to the one-electron reduction of the Bodipy
units.7b Compound 4d (Ered° = À1.36 V) was easily
reducible by ∼220 mV than 2b (Ered° = À1.58 V), while
reduction of the tristyryl compound 8 was even easier by
∼600 mV than 2b. These suggested better stability of the
radical anions due to meso-styryl modification. However,
this modification alone did not alter the oxidation poten-
tial, as is reflected by the same Eox° value (1.02 V) of 2b and
4d. In the case of 8, two anodic waves were observed; the
first oxidation step (Eox° = 0.75 V) was assigned to the
removal of one electron from the Bodipy core, and
the higher potential (Eox° = 1.23 V) could be due to the
oxidation of the styryl residue at C-3/5.7b
Figure 4. (a) HOMO and (b) LUMO of 8 calculated by DFT.
In short, we have tactically used the steric strain of the
Bodipy moieties to functionalize them at the meso-posi-
tion. The styryl substitutions at the meso-position alle-
viate the steric strain of the parent Bodipys. The strain
release is more for 2a, to furnish the products in high
yield. For the less strained Bodipy 2b, the meso-selectivity
could be achieved by increasing the electrophilicity of the
aldehyde. The new meso-styryl Bodipys could be useful
for development of chemical sensors and DSSCs. Further
work in this area is in progress.
The spectroscopic properties (Table S2) of all the
compounds, recorded in CH2Cl2, revealed that the
meso-styryl Bodipys (4aÀe) were much less fluorescent
(Φfl < 0.01) with reduced Stokes shifts, compared to the
corresponding precursor Bodipys. The results were con-
sistent with a previous report10 and provide direct evi-
dence of the steric relaxation after the meso-styryl
modification. Interestingly, saturation of the styryl dou-
ble bond as in 6 augmented the fluorescence (Φfl = 0.76)
significantly, offering the possibility of constructing on/
off chemical sensors. The rather large red shifts (8À
Supporting Information Available. Synthetic proce-
dures, analytical and photophysical data, and NMR
spectra of all compounds; electrochemical, X-ray crystal,
and computational data of selected compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ꢁ
13 nm) of the absorption λmax vis-a-vis the excitation
Acknowledgment. We thank the NSCXRD facility, IIT
Bombay, for the crystallographic data.
λ
max of 4aÀe indicated complex excited state transition.
Org. Lett., Vol. 13, No. 21, 2011
5873