Boron asymmetry in a BODIPY derivative

Article abstract of DOI:10.1021/ol100109j

A boradiazaindacene (BODIPY) fluorophore with a chirality held on the central boron has been synthesized and the racemate resolved. Dissymetrization of the BODIPY core was obtained by oxidation of the 3-methyl group to the corresponding carboxaldehyde. A hydrogen bond between the aldehyde proton and the fluorine on the boron atom was evidenced by both ¹H NMR and X-ray diffraction. Chiral high-performance liquid chromatography as well as circular dichroism confirm the persistence of both enantiomers.

Full text of DOI:10.1021/ol100109j

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1672-1675
Boron Asymmetry in a BODIPY
Derivative
Alexandre Haefele,† Chantal Zedde,‡ Pascal Retailleau,§ Gilles Ulrich,*,† and
Raymond Ziessel*,†
LCOSA, ECPM, UMR 7515, CNRS-UdS, 25 rue Becquerel,
67087 Strasbourg Cedex 02, France, SPCMIB, UniVersite´ Paul Sabatier, UMR
5068, 31062 Toulouse Cedex 9, France, and Laboratoire de Crystallochimie,
ICSN-CNRS, Baˆt 27, 1 aVenue de la Terrasse, 91198 Gif-sur-YVette, France
gulrich@unistra.fr; ziessel@unistra.fr
Received January 15, 2010
ABSTRACT
A boradiazaindacene (BODIPY) fluorophore with a chirality held on the central boron has been synthesized and the racemate resolved.
Dissymetrization of the BODIPY core was obtained by oxidation of the 3-methyl group to the corresponding carboxaldehyde. A hydrogen bond
between the aldehyde proton and the fluorine on the boron atom was evidenced by both 1H NMR and X-ray diffraction. Chiral high-performance
liquid chromatography as well as circular dichroism confirm the persistence of both enantiomers.
The demand for sophisticated luminophores to be used in
modern biological labeling and advanced optoelectronic
devices has stimulated chemists to engineer organic dyes
with novel fluorescence properties.1 The boradiazaindacene,
BODIPY, family, in particular, has been subject to intense
development because of the inherent stability, chemical
versatility, high brightness, and exceptional fluorescence
properties of these dyes.2 Advanced applications in various
fields such as sensors,3 energy-transfer cassettes,4 biological
labeling,5 or photovoltaic devices have been investigated.6
Chemically, the central core supports postsynthetic func-
tionalization, enabling fine-tuning of the optical and physical
properties of the dyes.2 A significant breakthrough was
brought by the replacement of the fluorine of the boron atom
by various functional substituents,7 allowing the generation
of energy-transfer cassettes and wires,8 soft materials,9
polymers,10 and water-soluble dyes.11 The chemistry at boron
(4) (a) Wan, C.-W.; Burghart, A.; Chen, J.; Bergstro¨m, F.; Johansson,
L. B.-A.; Wolford, M. F.; Kim, T. G.; Topp, M. R.; Hochstrasser, R. M.;
Burgess, K. Chem.sEur. J. 2003, 9, 4430–4431. (b) Ziessel, R.; Goze, C.;
Ulrich, G.; Ce´sario, M.; Retailleau, P.; Harriman, A.; Rostron, J. P.
Chem.sEur. J. 2005, 11, 7366–7378.
† CNRS-UdS. LCOSA fax: (+) 33.3.68.85.27.61.
‡ Universite´ Paul Sabatier.
(5) Haughland, R. P. Handbook of Fluorescent Probes and Research
Products, 9th ed.; Molecular Probes Inc.: Eugene, OR, 2002; pp 36-46.
(6) (a) Erten-Ela, S.; Yilmaz, M. D.; Icli, B.; Dede, Y.; Icli, S.; Akkaya,
E. U. Org. Lett. 2008, 10, 3299–3302. (b) Kumaresan, D.; Thummel, R. T.;
Bura, T.; Ulrich, G.; Ziessel, R. Chem.sEur. J. 2009, 15, 6335–6339. (c)
Rousseau, T.; Cravino, A.; Bura, T.; Ulrich, G.; Ziessel, R. Chem. Commun.
2009, 1673–1675.
§ ICSN-CNRS.
(1) Lakowicz, J. R. Principles of Fluorescence Spectroscopy, 3rd ed.;
Springer: Singapore, 2006.
(2) (a) Loudet, A.; Burgess, K. Chem. ReV. 2007, 107, 4891–4932. (b)
Ulrich, G.; Harriman, A.; Ziessel, R. Angew. Chem., Int. Ed. 2008, 47, 1202–
1219.
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Chem., Int. Ed. 2005, 44, 3694–398. (b) Goze, C.; Ulrich, G.; Ziessel, R.
J. Org. Chem. 2007, 72, 313–322. (c) Goze, C.; Ulrich, G.; Ziessel, R.
Org. Lett. 2006, 8, 4445–4448.
(3) (a) Saki, N.; Dinc, T.; Akkaya, E. U. Tetrahedron 2006, 62, 2721–
2725. (b) Ziessel, R.; Ulrich, G.; Harriman, A.; Alamiry, M. A. H.; Stewart,
B.; Retailleau, P. Chem.sEur. J. 2009, 15, 1359–1369.
10.1021/ol100109j  2010 American Chemical Society
Published on Web 03/17/2010

has also made possible both mono- and heterodisubstitu-
tion,12 paving the way to chiral BODIPYs asymmetric at
boron. It may be noted here that most known chiral organic
fluorophores are based on binaphthol modules and have been
used in chiral recognition processes, such as to determine
the enantiomeric purity of chiral amines, amino acids, and
alcohols.13
tion around the boron atom and facilitating chromatographic
resolution on a chiral solid phase.
To obtain an unsymmetrical dipyrromethene ligand bound
to B, a selective dichlorodicyanoquinone (DDQ) oxidation
of the methyl group in the substitution position 3 of dye 1
was used to give the corresponding aldehyde 2 (Scheme 1).20
Interestingly, the proton signal of the aldehyde at δ 10.39
ppm appears as a triplet because of coupling with the two
fluoride atoms (JHF ) 1.9 Hz). This pronounced through-
space coupling is confirmed by the 13C NMR peak of the
formyl group (triplet at 186.1 ppm, JCF ) 3.3 Hz). Full
confirmation of the nature of 2 was obtained from the X-ray
crystal structure (Figure 1). The structure was solved under
space group C2/c, although the apparent 2-fold symmetry
of the molecule is the result of 1:1 disorder of the oxygen
substituent over two sites on carbon atoms located on the
C3 and C5 positions of dipyrromethene. In the boraphenyl-
dipyrromethene unit, 18 atoms are quasi-coplanar with a root-
mean-square deviation of 0.038 Å. The molecules lie in
sheets, parallel to the (101) plane, formed by antiparallel
linear arrays involving head-to-tail halogen bonding (F· · ·I)
laterally connected by CH· · ·O bonds. Between sheets, an
overlap in the projection of the pyrrole units brings several
carbon atoms into ∼3.5 Å contact distances.
Stable, asymmetric boron complexes are rare, and only a
few can be resolved because of facile dissociation/inversion
processes.14 The stability of asymmetric N-donor complexes
of boron is related to the strength of the N-B bond.15 The
activation enthalpy for racemization can be correlated to the
length of this bond, and thus in the case of a BODIPY, we
anticipated that the presence of an N-donor chelate would
ensure good stability, inhibiting stereochemical rearrange-
ment and allowing resolution using chiral high-performance
liquid chromatography (HPLC).16
The few examples of enantiomerically pure BODIPY
fluorophores known were obtained by decorating the central
core with an asymmetric carbon17 and not by utilization of
the potential asymmetry at boron. Notice that racemic
mixtures of boron dipyrrin derivatives18 and azadipyr-
romethene dyes have recently been prepared.19 We present
here the first synthesis and resolution of an asymmetric boron
B*-BODIPY, with its chirality arising solely from the
stereochemistry at boron, and describe the optical properties
of both enantiomers.
Scheme 1. Synthesis of the B*-BODIPY Racemate
The following requirements were envisaged as necessary
to obtain a stable B* chiral BODIPY: (i) lateral differentiation
of the dipyrromethene core; (ii) introduction of a polar group
suitable for intramolecular association with a BF unit; (iii)
use of polyaromatic residues causing moderate steric conges-
(8) (a) Harriman, A.; Izzet, G.; Ziessel, R. J. Am. Chem. Soc. 2006,
128, 10868–10875. (b) Harriman, A.; Mallon, L. J.; Goeb, S.; Ulrich, G.;
Ziessel, R. Chem.sEur. J. 2009, 15, 4553–4564. (c) Harriman, A.; Mallon,
L. J.; Elliot, K. J.; Haefele, A.; Ulrich, G.; Ziessel, R. J. Am. Chem. Soc.
2009, 131, 13375–13386.
(9) (a) Camerel, F.; Bonardi, L.; Schmutz, M.; Ziessel, R. J. Am. Chem.
Soc. 2006, 128, 4548–4549. (b) Camerel, F.; Bonardi, L.; Ulrich, G.;
Charbonnie`re, L.; Donnio, B.; Bourgogne, C.; Guillon, D.; Retailleau, P.;
Ziessel, R. Chem. Mater. 2006, 18, 5009–5021.
(10) Nagai, A.; Miyake, J.; Kokado, K.; Nagata, Y.; Chujo, Y. J. Am.
Chem. Soc. 2008, 130, 15276–15278.
(11) (a) Niu, S. L.; Ulrich, G.; Ziessel, R.; Kiss, A.; Renard, P.-Y.;
Romieu, A. Org. Lett. 2009, 11, 2049–2052. (b) Niu, S.-L.; Ulrich, G.;
Retailleau, P.; Harrowfield, J.; Ziessel, R. Tetrahedron Lett. 2009, 50, 3840–
3844.
(12) (a) Murase, S.; Tominaga, T.; Kohama, A. Eur. Patent 1253151a,
2002. (b) Goze, C.; Ulrich, G.; Mallon, L. J.; Allen, B. D.; Harriman, A.;
Ziessel, R. J. Am. Chem. Soc. 2006, 128, 10231–1029.
(13) Pu, L. Chem. ReV. 2004, 104, 1687–1716.
(14) (a) Toyota, S.; Ito, F.; Nitta, N.; Hakamata, T. Bull. Chem. Soc.
Jpn. 2004, 77, 2081–2088. (b) Toyota, S.; Ito, F.; Yamamoto, T.; Akashi,
H.; Iwanaga, T. Bull. Chem. Soc. Jpn. 2006, 79, 796–798.
(15) Heard, P. J. Chem. Soc. ReV. 2007, 36, 551–569.
The iodophenyl group lies essentially orthogonal to the
BODIPY platform (dihedral angle of ca. 80°) probably to
minimize interactions with the adjacent methyl groups,
though possibly also because of intersheet F· · ·aromatic
interactions. The formyl residue lies in the same plane as
the BODIPY core, with a maximum deviation of 7.1(3)°.
After several heterodisubstituted E-BODIPY (E ) ethynyl)
derivatives were investigated,7 attention was focused on the
monoaryl-substituted compound obtained by the reaction at
(16) (a) Charoy, L.; Valleix, A.; Toupet, L.; Le Gall, T.; Pham van
Chuong, P.; Mioskowski, C. Chem. Commun. 2000, 2275–2276. (b)
Imamoto, T.; Morishita, H. J. Am. Chem. Soc. 2000, 122, 6329–6330. (c)
Braun, M.; Schlecht, S.; Engelmann, M.; Frank, W.; Grimme, S. Eur. J.
Org. Chem. 2008, 5221–5225.
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1139. (b) Gossauer, A.; Nyddegger, F.; Kiss, T.; Sleziak, R.; Stoeckli-Evans,
H. J. Am. Chem. Soc. 2004, 126, 1772–1780. (c) Mocszar, I.; Huszthy, P.;
Maidics, Z.; Kadar, M.; Klara, T. Tetrahedron 2009, 65, 8250–8258.
(18) Ikeda, C.; Maruyama, T.; Nabeshima, T. Tetrahedron Lett. 2009,
50, 3349–3351.
(20) Sathyamoorthi, G.; Wolford, L. T.; Haag, A. M.; Boyer, J. H.
Heteroat. Chem. 1994, 5, 245–249.
(19) Carreira, E.; Zhao, W. PCT Patent WO 2006058448, 2006.
Org. Lett., Vol. 12, No. 8, 2010
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Figure 1. ORTEP view of compound 2. Displacement ellipsoids
are drawn at the 30% probability level. Selected distances (Å):
C4-N1 1.354(20); N1-B1 1.543(18); B1-F1 1.385(16).
low temperature of naphthylmagnesium bromide with the
symmetrical F-BODIPY 1 (Scheme 1). The BODIPY core
of dye 3 was then rendered unsymmetrical by selective
oxidation with DDQ previously developed for compound 2,
leading to the aldehyde 4rac as a racemic mixture. Again,
through-space coupling of the formyl proton to fluorine, as
seen for 2, was apparent in the 1H NMR spectra (Figure 2).
Resolution of 4rac was achieved by HPLC using a
Chiralcel-OD column and a mixture of hexane/isopropyl
alcohol as the mobile phase.21 The enantiomers 4a and 4b
were separated by 1.3 min in the elution sequence. As
expected, they have identical NMR (Figure 2) and mass and
optical spectra. Interestingly, repeated chromatography of the
separated enantiomers gave single peaks for both, illustrating
the stability of the B center toward inversion even under
exposure to full daylight.
Figure 2.
1H NMR spectra of 1, 2 (CDCl3, RT), 3, 4a, and 4b
(CD2Cl2, RT).
methylene protons of the ethyl substituents (Figure 2). A
further confirmation of the enantiomeric nature of 4a and
4b is the circular dichroic (CD) spectra showing the perfect
mirror image of both compounds (Figure 3).
The unsymmetrical nature of the BODIPY core is apparent
in the doubling of signals in the aliphatic region. The
asymmetry at B, associated with the apparently slow rotation
of the iodophenyl unit, is reflected in the AA′BB′ multiplets
observed for the iodophenyl protons. The asymmetry at B
is also reflected in the diastereotopicity observed for the
(21) Experimental Procedure for HPLC Separation. Analytical and
preparative resolutions of 4rac were performed on Chiralcel-OD (Daicel)
columns. The analytical separations employed an isocratic eluent of 10%/
90% isopropyl alcohol/heptane and a flow of 1 mL/min with UV detection
at 277 nm on a 250 × 4.6 mm column. HPLC system: Waters, Alliance
pump 2696, UV detector 2996, running under Empower software (Waters).
The preparative separations used a 250 × 10 mm column, eluent 5%/95%
isopropyl alcohol/heptane, a flow of 4.7 mL/min, and UV detection at 277
nm. HPLC system: Pump Delta prep 4000, UV 486, manual injection of
1.5-2 mL. The racemic precursor was solubilized in the eluent, filtered,
and then injected (3-4 mg/injection). Each fraction was monitored by
analytical HPLC, and mixed fractions were collected and reinjected. A total
of 17 mg of 4rac was purified in six injections, giving 6.2 mg of 4a and 5.8
mg of 4b.
Figure 3. CD spectra of 4rac, 4a, and 4b in CH2Cl2 at RT.
The absorption spectrum of compound 2 shows a strong
absorption at 283 nm attributed to the carbonyl absorption
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Org. Lett., Vol. 12, No. 8, 2010

quantum yield of 25% are all consistent with a singlet-based
excited-state manifold in 4a and 4b.
In summary, an enantiomerically pure B*-BODIPY was
prepared by appropriate substitution on the boron and the
dipyrromethene core. Introduction of a formyl substituent
on one pyrrole unit both renders the chelate unsymmetrical
and stabilizes the configuration at B via hydrogen bonding
to the fluoro ligand. Thus, the enantiomers are stable to
inversion even in full daylight at room temperature. This
first example of a resolved fluorophore with a central chiral
boron could serve as a model to build similar reporters with
selective recognition groups in the near environment of the
chiral center, which could serve for fluorimetric chiral
recognition. Further work along these lines is in progress.
Figure 4. Absorption (blue line), emission (green line), and
excitation (red line) spectra of 4a, in CHCl3 at RT and at a
concentration of ca. 1 × 10-6 M.
Acknowledgment. This work was supported by the Centre
National de la Recherche Scientifique and the Ministe`re de
la Recherche et des Nouvelles Technologies. We are indebted
to Prof. J. Harrowfield (ISIS, Strasbourg, France) for his
comments on the manuscript and Prof. Gilles Muller and
Jamie L. Lunkley of San Jose´ State University (San Jose´,
CA) for preliminary CD measurements. We also thank Dr.
Andrei Klymchenko of the Faculty of Pharmacy in Stras-
bourg for fruitful discussions.
band (see the Supporting Information). The typical S0-S1
transition band found for 1 and 3 at 526 nm with a shoulder
at 501 nm is also found for dyes 2, 4a, and 4b but with a
hypochromic and slight bathochromic shift of the lower
energy band to 534 nm and an enhanced shoulder at 511
nm (Figure 4). This may be due to the strong conjugation of
the carbonyl function with the BODIPY π system. The X-ray
structure confirms that the aldehyde lies in the same plane
as the dipyrromethene core, favoring pronounced orbital
overlap. The excited-state lifetime (τ of around 2.50 ns), the
radiative rate constant (kr of about 8 × 107 s-1), and the
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100109J
Org. Lett., Vol. 12, No. 8, 2010
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