General route to symmetric and asymmetric meso -CF3-3(5)- aryl(hetaryl)- and 3,5-diaryl(dihetaryl)-BODIPY dyes

Article abstract of DOI:10.1021/ol200360f

A general efficient route to hitherto inaccessible symmetric and asymmetric meso-CF₃-BODIPY dyes has been developed. The key stages include the reduction of available 2-trifluoroacetylpyrroles to the corresponding alcohols which are further condensed with pyrroles. The method allows the BODIPY with 3(5)aryl(hetaryl) and 3,5-diaryl(hetaryl) substituents to be readily assembled. The BODIPY dyes synthesized fluoresce (?_f = 0.56-1.00) in the 560-680 nm region.

Full text of DOI:10.1021/ol200360f

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2524–2527
General Route to Symmetric and
Asymmetric meso-CF3-3(5)-Aryl(hetaryl)-
and 3,5-Diaryl(dihetaryl)-BODIPY Dyes
Lubov N. Sobenina,† Alexander M. Vasil’tsov,† Olga V. Petrova,†
Konstantin B. Petrushenko,† Igor A. Ushakov,† Gilles Clavier,‡
Rachel Meallet-Renault,‡ Albina I. Mikhaleva,† and Boris A. Trofimov*,†
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy
of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian Federation, and PPSM, ENS
Cachan, CNRS UniverSud, 61 av President Wilson 94230 Cachan, France
boris_trofimov@irioch.irk.ru
Received February 8, 2011
ABSTRACT
A general efficient route to hitherto inaccessible symmetric and asymmetric meso-CF3-BODIPY dyes has been developed. The key stages include
the reduction of available 2-trifluoroacetylpyrroles to the corresponding alcohols which are further condensed with pyrroles. The method allows
the BODIPY with 3(5)aryl(hetaryl) and 3,5-diaryl(hetaryl) substituents to be readily assembled. The BODIPY dyes synthesized fluoresce (Φf =
0.56À1.00) in the 560À680 nm region.
BODIPY dyes (4,4-difluoro-4-bora-3a,4a-diaza-s-inda-
cene) possess many distinctive and desirable properties such
as high molar absorption coefficient, fluorescence quantum
yields, and long wavelength emission.1 Photochemical and
chemical stabilities of the boron dipyrromethene chromofore
are higher than those of many other dyes, and extended π-
electron conjugation can be modified by introduction of
substituents, affording red-shifted BODIPY derivatives.
Applications of BODIPY to optical chemosensors,2
fluorescent biolabeling reagents,3 light-harvesting
materials,4 nanotechnology,5 optoelectronic devices,6 and
photodynamic therapy reagents7 have been studied exten-
sively. Biochemical application of BODIPY includes con-
jugation with a variety of biomolecules such as lipids,8
proteins,9 DNA,10 carbohydrates,11 and cholesterol.12
BODIPY’s absorption and emission properties can
be tuned by introducing appropriate substituents onto the
BODIPY framework.13 The meso-aryl group and the
BODIPY framework interact weakly since the two moi-
eties are almost orthogonal to each other.14 Hence, any
modifications to the meso-aryl group do not noticeably
influence the position of absorption and fluorescence
† Siberian Branch of the Russian Academy of Sciences.
‡ PPSM.
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r
10.1021/ol200360f
Published on Web 04/15/2011
2011 American Chemical Society

bands. A more appropriate way to modulate the properties
of the BODIPY chromophore is the introduction of
different aryl substituents to the 3- and 5-positions of the
BODIPY core. However, in the single publication on the
meso-CF3-substituted BODIPY derivative it was shown
that this strongly electron-withdrawing group caused a
deep (∼30 nm) bathochromic shift compared to that of the
congeners with aryl substituents in this position.15
Meanwhile, the BODIPY dyes with a meso-CF3-group
are desirable targets because they might have at least two
benefits as a biochemical probe. First, the probe is small.
Second, the CF3-group is known to be useful as an NMR
marker.15
The combination of a CF3 group, aryl or hetaryl moi-
eties, and BODIPY scaffold in one molecule may result in
synergism of their properties and, hence, to higher perfor-
mance optical materials.
Herein, we describe a general synthetic strategy for
preparation of symmetric and asymmetric meso-CF3-sub-
stituted BODIPY dyes having aryl or hetaryl substituents.
The thiophene substituent was chosen for its known16
ability to enhance fluorescence properties owing to its
easier electron delocalization compared to benzene. This
narrows optical band gaps due to a better effective π-
conjugation. This usually leads to a bathochromic shift of
the absorption and emission wavelengths. Until now, only
a few such BODIPY dyes have been synthesized,17 mostly
due to the difficulty in preparation of the necessary
thiophene functionalized starting materials.
To the best of our knowledge, so far BODIPY dyes with
a meso-CF3-group and 3,5-diaryl substituents are un-
known. The known meso-CF3-BODIPY dyes have been
synthesized via the intermediate, di(pyrrol-2-yl)trifluoro-
methane, which in turn, was obtained by condensation of
pyrrole and 2,2,2-trifluoro-1-methoxyethanol in 48% yield.15
A promising general strategy for the synthesis of sym-
metric and asymmetric BODIPY dyes with a meso-CF3-
group and 3,5-diaryl(hetaryl) substituents could be based
on the reaction of 2-trifluoroacetylpyrroles 1,2 with pyr-
roles having a vacant R-position of the pyrrole ring.
However, we have found that pyrroles 1,2 (as opposed to
2-acetylpyrroles1c) in this reaction (CF3COOH, rt, 1 h or
P2O5, rt, 15À16 h) proved to be inactive. Taking into account
that pyrrolcarbinols condense with pyrroles in acidic media
to give corresponding dipyrromethanes18 we used 2,2,2-
trifluoro-1-(pyrrol-2-yl)-1-ethanols 3,4, products of reduc-
tion of pyrroles 1,2with NaBH4, as a key intermediate for the
synthesis of the dipyrromethanes 9aÀe, Table 1.
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3
the target BODIPY dyes in a yield up to 84% (Table 1).
Thus, we have developed a general effective route to a
novel family of the meso-CF3-3,5-diaryl(hetaryl)-BODI-
PY dyes, prospective fluorophores, based on easily avail-
able 2-aryl- and 2-hetarylpyrroles. These pyrroles, in-
cluding 2-(2-thienyl)pyrrole, are readily obtained from
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Org. Lett., Vol. 13, No. 10, 2011
2525

Pyrroles 1 and 2 were obtained by trifluoroacetylation of
corresponding pyrroles 6 and 7 with trifluoroacetic anhy-
dride in high yields.22
Table 1. Synthesis of Meso-CF3-BODIPY 10aÀe
The absorption and fluorescence spectra of the synthe-
sized BODIPYs (n-hexane, rt) in the region of wavelengths
>450 nm are shown in Figure 1. In all cases, the spectra of
excitation of fluorescence fully complied with the absorp-
tion ones. The only reported representative of the BODI-
PY series with meso-CF3-substituent displays the
following spectral characteristics: λmax,abs = 548 nm,
λmax,f = 554 nm, ε = 89000 MÀ1 cmÀ1, Φf = 1.00 in
3
CH2Cl2.15 Among the synthesized BODIPYs, very close
quantum yield and molar extinction coefficient are ob-
served for compound 10d (Table 2), but its absorption and
fluorescence bands are strongly shifted to red area (similar
to the spectral properties of aza-BODIPY dyes1b) owing to
a greater extent of the π-system and donor abilities of the
thiophene ring.
As seen from Table 2, the Φf value increases from
mono- to disubstituted representatives and is highest
(1.00) for dithienyl derivative 10d. Generally, thienyl-
substituted BODIPYs absorb and fluoresce at a longer
wavelengths then the corresponding phenyl congeners.
The lengthing of the conjugation by the introduction
of the second phenyl or thienyl moiety expectedly leads
to the intensity enhancement and bathochromic shifts
of the absorption and fluorescence bands (Figure 1).
The thienyl derivatives 10c,d have fairly narrow ab-
sorption and fluorescence bands with well-defined vi-
brational structure and small ΔνSt (∼200 cmÀ1). Their
fluorescence bands almost mirror the corresponding
absorption bands. The most intensive vibronic transi-
tion is always the 0À0 one. All this evidence that the
geometry of the BODIPY 10c,d in the ground (S0) and
the first electronically excited state (S1) is close to
planar. This conclusion is supported by the observation
that the ΔνSt of BODIPY 10c,d coincide with ΔνSt of
flat 3,5-dichloro-8-trifluoromethyl-BODIPY (ΔνSt
=
200 cmÀ1).15
Replacement of thienyl rings by the bulkier phenyl sub-
stituent (BODIPY 10a,b) augment the ΔνSt value and broad-
ens and smears the thin structure of the absorption and
fluorescence bands so that 0À1 vibronic transitions appears
only as shoulders (Figure 1). These spectral changes corre-
spond to a more significant deviation of the phenyl rings from
the BODIPY plane as compared to the thienyl derivatives
10c,d (calculated dihedral angles ∼40° for 10a,b and ∼20° for
10c,d, respectively; see the Supporting Information).This is
predicted result of a greater steric hindrance exerted by ortho-
hydrogen atoms of the phenyl rings. The compound 10e has a
substantially lower Φf and largest ΔνSt, in comparison with
10aÀd. This is probably due to the strong violation of the
planarity of the π-system (calculated dihedral angles ∼39°,
∼56°, and ∼35° for 2-, 3-, and 5-phenyls of 10e, correspond-
ingly; see the Supporting Information) and a more significant
change in molecular geometry upon excitation.
alkylaryl(hetaryl)ketones and acetylene (through the
corresponding ketoximes)20 by Trofimov reaction21 in
a one-pot procedure. In contrast, the introducing
of thienyl substituent to the BODIPY core was pre-
viously realized by the multistep synthesis involving
3,5-dichlorosubstituted dipyromethanes via the Suzuki
coupling.17c
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Moscow, 2002; Vol. 1, pp 334À352. (b) The Chemistry of Hydroxyla-
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2526
Org. Lett., Vol. 13, No. 10, 2011

Figure 1. Normalized absorption and fluorescence spectra of BODIPY 10aÀd in n-hexane: 1,5- (10a), 2,6- (10b), 3,7- (10c), 4,8- (10d).
Table 2. Photophysical Data of BODIPY 10aÀe Recorded in n-Hexane
absorption coefficient
λmax,f
(nm)
λmax,ex
(nm)
Stokes shift
fluorescence quantum
BODIPY
λmax,abs (nm)
(ε, MÀ1 cmÀ1
)
(ΔνSt, cmÀ1
)
τf (ns)
yield (Φf)
10a
10b
10c
10d
10e
561
592
589
665
613
36000
48000
63000
85000
31000
578
622
597
674
653
561
591
589
665
616
520
820
4.5
6.4
5.6
5.5
0.56a
0.74a
0.67a
1.00b
0.06b
230
200
1000
a Rhodamine 6G as standard (Φf = 0.95, ethanol).23 b Nile blue as standard [(Φf = 0.27, 0.5% (v/v) 0.1 M HCl in ethanol].24
Like thienyl derivatives 10c,d, the phenyl substituted
BODIPY 10a,b have an approximate mirror symmetry
of absorption and fluorescence spectra; 0À0 vibronic transi-
tion remaining as the strongest one. Consequently, the shape
of phenyl-containing BODIPY molecules changes just
slightly upon excitation, being relatively nonplanar in the
S1 state.
These inferences are in accordance with DFT/BP86/
def2-TZVP and TD-BP86/def2-TZVP quantum-chemical
calculations (see the Supporting Information).
In conclusion, a general route to a new family of the
BODIPY fluorophores with the meso-trifluoromethyl
moiety has been devised. The original features of the
new methodology involve the reduction of the available
2-trifluoroacetylpyrroles followed by the condensation of
the alcohols, thus produced, with pyrroles.
The methodology for the first time allows both sym-
metric and asymmetric BODIPY dyes with meso-trifluor-
omethyl moieties to be easily assembled. All BODIPYs are
highly fluorescent (with the exception of compound 10e)
with Φf > 0.5 and small Stokes shifts.
Acknowledgment. We are grateful to the Presidium of
RAS (Project Nos. 7.5, 93, and 5.9.1) for financial support.
This work was also carried out with the financial support
of the leading scientific schools by the President of the
Russian Federation (Grant No. NSh-3230.2010.3).
Supporting Information Available. Detailed experimen-
tal procedures, 1H, 11B, 13C, 15N, and 19F NMR spectra
for all new compounds, and DFT calculation data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 10, 2011
2527