Axially chiral BODIPYs

Article abstract of DOI:10.1039/c4cc00851k

The synthesis and resolution of a class of chiral organic fluorophores, axially chiral 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (Ax*-BODIPY), is described. Ax*-BODIPYs were prepared through a modular synthesis combined with a late stage Heck functionalisation. Resolution was achieved by preparative chiral HPLC. Absolute stereochemical assignment was performed by comparison of experimental ECD spectra with TD-DFT calculations. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00851k

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Axially chiral BODIPYs†
Reinner I. Lerrick,ab Thomas P. L. Winstanley,a Karen Haggerty,a Corinne Wills,a
William Clegg,a Ross W. Harrington,a Patrick Bultinck,c Wouter Herrebout,d
Andrew C. Bennistona and Michael J. Hall*a
Cite this:DOI: 10.1039/c4cc00851k
Received 31st January 2014,
Accepted 18th March 2014
DOI: 10.1039/c4cc00851k
www.rsc.org/chemcomm
The synthesis and resolution of a class of chiral organic fluoro- excess of a solution by optical measurements.7 A number of chiral
phores, axially chiral 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes fluorophores have been reported, the most widely studied being the
(Ax*-BODIPY), is described. Ax*-BODIPYs were prepared through a lanthanide coordination complexes,8 1,10-bi-2-naphthols (BINOL) and
modular synthesis combined with a late stage Heck functionalisa- helicenes.9 Chiral molecules containing the BODIPY fluorophore
tion. Resolution was achieved by preparative chiral HPLC. Absolute have been synthesised, typically through the decoration of the
stereochemical assignment was performed by comparison of BODIPY core with chiral appendages.10 An example of a resolved
experimental ECD spectra with TD-DFT calculations.
BODIPY based around an asymmetric boron atom (B*-BODIPY)
with the chirality embedded in the core structure of the fluorophore
The boron-dipyrromethene dyes (BODIPY)1 are among the most widely itself has been described (1),11 whilst a number of unresolved
used organic fluorophores, finding utility in an array of applications boron-centred chiral BODIPYs have been reported based on the
including photodynamic therapy,2 biological imaging3 and fluorescence intramolecularly B–O bonded BODIPY and the closely related
sensing.4 The continuing popularity of the BODIPYs derives from the aza-BODIPY systems (2–4) (Fig. 2).12
combination of robust synthetic protocols with desirable physical
properties such as thermal, chemical and photochemical stability, high
fluorescence quantum yield, low intrinsic triplet-state formation, high
extinction coefficients and good solubility (Fig. 1).5
Fig. 1 General structure of a boron-dipyrromethane dye (BODIPY).
Fig. 2 Chiral BODIPY and aza-BODIPYs.
Chiral fluorophores have been explored for the selective sensing of
chiral molecules,6 including attempts to determine the enantiomeric
In this manuscript we present a general approach for the syn-
thesis, resolution and absolute stereochemical determination of a
class of axially chiral BODIPYs (Ax*-BODIPY), based on restricted
rotation of aromatic substituents in the meso-position (or 8-position).
The rotation of aryl substituents at the meso-position of
BODIPYs has been previously studied because of the influence
this has on both the S1 lifetime and the fluorescence quantum
yield of the fluorophore.13 These results have been applied in
a School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne,
NE1 7RU, UK. E-mail: m.hall@ncl.ac.uk; Fax: +44 (0)191 222 6929;
Tel: +44 (0)191 222 7321
b School of Chemistry, Nusa Cendana University, Indonesia
c Department of Inorganic and Physical Chemistry, Ghent University,
Krijgslaan 281-S3, 9000 Gent, Belgium
d Department of Chemistry, University of Antwerp, Groenenborgerlaan 171,
2020 Antwerp, Belgium
† Electronic supplementary information (ESI) available: UV/Vis and fluorescence the development of BODIPY ‘‘rotors’’ for fluorescence sensing
of microenvironment viscosity.14
spectra for 8-(rac), 9-(rac) and 10-(rac), ECD spectra of 10-(+) and 10-(ꢀ),
computational approaches towards predicted ECD and VCD spectra of 10-(+)
and 10-(ꢀ), HPLC trace for the resolution of 10-(rac), experimental procedures for
compounds 6–10, 1H and 13C spectra for compounds 6–10. Crystallographic data
for 9-(rac) and 10-(rac). CCDC 984417 and 984418. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4cc00851k
Our design strategy for a resolvable atropisomeric Ax*-
BODIPY system therefore involved provision for (a) a high rotational
barrier for an aryl substituent at the meso-position (b) chemically
differentiable groups on the ortho-positions of the meso-aryl
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BF2 chelation to give 8-(rac) and subsequent bromination. 9-(rac) is a
useful starting point for the synthesis of different axially chiral
BODIPY systems through the use of metal-catalysed cross-
coupling reactions. In our case we chose to functionalise
9-(rac) via a Heck reaction with ethyl acrylate, differentiating
the 2- and 6-positions, to give the target 10-(rac) (Scheme 1).
Compounds 8-(rac), 9-(rac) and 10-(rac) gave UV/Vis absor-
bance (lmax = 515, 526, 538 nm) and fluorescence (lmax = 525,
540, 555 nm) spectra typical of the BODIPY class of fluoro-
phores, with high extinction coefficients and moderate to good
fluorescence quantum yields (ESI†).
The asymmetry of compounds 8-(rac), 9-(rac) and 10-(rac) was
observable by NMR spectroscopy, the 1H NMR spectrum showing
five different methyl environments in each case. Restricted rota-
tion of the meso-aryl group imposes a diastereotopic relationship
on the two fluorine atoms. This was observable in the 19F NMR
spectrum as an ABX coupling pattern, each fluorine peak showing
both geminal 19F–19F and 19F–11B coupling (ESI† and Fig. 4).16
Fig. 3 General design of Ax*-BODIPYs.
substituent (X and Y) and (c) chemically differentiable groups
on the 2/6-positions (A and B) of the BODIPY core (Fig. 3).15
In order to ensure a high rotational barrier for ortho-substituted
meso-aryl groups we opted to include methyl groups in both the
1- and 7-positions of the BODIPY fluorophore. The introduction of
ortho-functionalised meso-aryl substituents was anticipated to be
straightforward, through the application of condensation-based
synthetic routes towards BODIPY systems. Finally to allow synthetic
flexibility we decided to chemically differentiate at the 2/6-positions
via a late stage metal-catalysed cross-coupling reaction.
Synthesis of 10-(rac) started with the deprotonation of 2,4-
dimethyl-1H-pyrrole (5) with EtMgBr and subsequent C-2 selective
acylation with 2-methylbenzoyl chloride to give (3,5-dimethyl-1H-
pyrrol-2-yl)(o-tolyl)methanone (6). Pyrrole 6 was then brominated at
the 4-position to give (4-bromo-3,5-dimethyl-1H-pyrrol-2-yl)(o-tolyl)-
methanone (7), followed by acid-catalysed condensation with
3-ethyl-2,4-dimethyl-1H-pyrrole and subsequent BF2 chelation to give
9-(rac). A complementary route to 9-(rac) was also investigated invol-
ving condensation of pyrrole 6 with 3-ethyl-2,4-dimethyl-1H-pyrrole,
Fig. 4 (a) Simulated (using gNMR)17 and (b) experimental 19F NMR spectra
of 10-(rac). Note the asymmetry in the spectra due to 10B coupling.
Crystallisation of both 9-(rac) and 10-(rac) by slow diffusion
(DCM/petrol) gave single crystals suitable for X-ray analysis.
9-(rac) and 10-(rac) gave monoclinic crystals, both with the
centrosymmetric space group P21/c. In both cases four mole-
cules are present per unit cell, two of each of the (R)- and (S)-
enantiomers (ESI† and Fig. 5).
Fig. 5 Part of the crystal structure of 10-(rac) showing both (R)-10 and (S)-10.
The planes defined by the ortho-methylphenyl group and the
1,2-dihydro-1,3l4,2l4-diazaborinine ring in both 9-(rac) and
10-(rac) are close to orthogonal, with twist angles of 85.9 and
85.7 degrees, respectively, suggesting significant steric hindrance
around the chiral axis.
10-(rac) was well resolved by semi-preparative chiral HPLC
(Chiralpak AD-H, Heptane/IPA 85/15) giving sufficient of both
enantiomers of 10 for further study (ESI†). Both enantiomers of
10 gave identical 1H NMR spectra to that of 10-(rac), whilst giving
Scheme 1 Synthesis of 10-(rac). (i) (a) EtMgBr, Et2O, reflux, 1 h (b) 2-methyl-
benzoyl chloride, rt, 24 h (ii) Br2, DCM, rt, 24 h (iii) (a) 2,4-dimethyl-3-ethyl-
pyrrole, TFA, DCM, rt, 18 h (b) i-Pr2NEt, BF3OEt2, rt, 12 h (iv) ethyl acrylate,
Et3N, Pd(OAc)2, PPh3, DMF, 100 1C, 12 h.
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weak but opposite [a]D values of +13.0 and ꢀ13.0 respectively Notes and references
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In conclusion, we have reported a synthetically flexible route to a
class of axially chiral fluorophores (Ax*-BODIPYs), including resolu-
tion and absolute stereochemical determination by combined ECD/
TD-DFT. Further research will focus on the interactions of Ax*-
BODIPYs with chiral analytes in solution and applications to sensing.
The authors thank the Indonesian Ministry of National Education
(R.I.L.) for funding, ESPRC for X-ray facilities at Newcastle University
(EP/F03637X/1) and Dr Mike Probert (Newcastle) for crystallographic
support, the EPSRC National Mass Spectrometry Service, Diamond
Light Source for access to beamline I19, Bernard Costello, James Law
and Dick Fielding (Applied Photophysics Ltd.) for ECD measure-
ments and Prof. William McFarlane (Newcastle) for NMR support.
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18 Sampling for 72 hours and combination of the spectra of 10-(+) and
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2X spectrometer gave no detectable VCD signals with a significant
signal-to-noise ratio.
19 ROA measurements were attempted using a BioTools ChiralRaman
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