Cl-BODIPYs: A BODIPY class enabling facile B-substitution

Article abstract of DOI:10.1039/c1cc16351e

Cl-BODIPYs, synthesized in high yields from dipyrrins under air- and moisture-free conditions, are extremely facile to substitution at boron compared to their corresponding F-BODIPYs, opening up a new route to BODIPYs functionalized at boron.

Full text of DOI:10.1039/c1cc16351e

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COMMUNICATION
Cl-BODIPYs: a BODIPY class enabling facile B-substitutionw
Travis Lundrigan, Sarah M. Crawford, T. Stanley Cameron and Alison Thompson*
Received 12th October 2011, Accepted 29th October 2011
DOI: 10.1039/c1cc16351e
Cl-BODIPYs, synthesized in high yields from dipyrrins under
air- and moisture-free conditions, are extremely facile to sub-
stitution at boron compared to their corresponding F-BODIPYs,
opening up a new route to BODIPYs functionalized at boron.
literature examples of the reaction of a dipyrrin or dipyrrinato
complex with a boron trihalide other than a BF3 adduct. In the
first example, a dipyrrin bearing a catechol-functionalized meso-
position was treated with BCl3 to give a mixture of three cyclic
oligomers where the boron centre linked one dipyrrin to another
by binding to the dipyrrin moiety of one molecule and the
catechol moiety of the second molecule.16 In the second example,
a series of three dipyrrins, featuring protected phenols in the
a-positions, were exposed to BBr3. These reactions resulted in the
isolation of phenoxy O-BODIPYs, presumably via (unisolated)
Br-BODIPY intermediates.17 Although BODIPY analogues of
the heavier halogens have not been isolated, BCl2, BBr2 and BI2
b-diketiminato complexes, which are structurally related to
dipyrrins, can be generated via treatment of a silyl protected
b-diketiminate with BCl3, BBr3 and BI3.18,19 All of these
complexes were prepared and manipulated in a dry and oxygen-
free atmosphere and were characterized using single-crystal
X-ray diffraction studies.18,19 Similarly, structurally related di-
boryl BF2, BCl2 and BBr2 complexes of porphyrins are known.20
F-BODIPYs are routinely synthesized from dipyrrins or
dipyrrin salts via reaction with excess triethylamine and BF3ꢀ
OEt2. We have shown previously that the symmetrical
BODIPYs 2a and 2b may be generated in high yields from the
corresponding dipyrrin HBr salts as shown in Scheme 1.21
Compounds containing the 4,4-difluoro-4-bora-3a,4a-diaza-s-
indacene (F-BODIPY) framework have wide application as
dyes, fluorescent probes in biological systems, and materials
for incorporation into electroluminescent devices.1,2 Their wide
utility is due to their high thermal and photochemical stability,
chemical robustness and tunable fluorescence properties.1,2
Substitution of the fluorine atoms at the boron centre to
give B-aryl, B-alkenyl, B-alkoxy and B-aryloxy derivatives,
often under harsh conditions, generates a wide variety of
C-BODIPY3–6 and O-BODIPY7–10 compounds. Recently,
more exotic BODIPY derivatives have been synthesized,11,12
including an H-BODIPY.13 However, to our knowledge,
dihalogen BODIPY analogues of the heavier halogens have
not been reported. This is unsurprising as boron-halogen bond
strengths decrease in the order F c Cl 4 Br 4 I. Conse-
quently, B–Cl, B–Br and B–I bonds are much more labile than
B–F bonds.14 The majority of B-substitution reactions starting
from F-BODIPYs either require high temperatures or occur
at room temperature in low yields (o60%). Due to the
increased lability of the boron halogen bonds in X-BODIPYs,
B-substitution in these derivatives would likely occur under
milder conditions in higher yields, when compared to their
corresponding F-BODIPYs. Changing the substitution at the
BODIPY boron centre from fluorine to the heavier halogens will
presumably have a significant effect on the fluorescence properties
of the resulting X-BODIPYs: the presence of the heavier halogens
will likely facilitate fluorescence quenching and enhance non-
radiative decay pathways by increasing spin–orbit coupling.
There is only one reported BODIPY analogue that contains
a B–X bond (X a F). In this example, a meso-methyl
substituted dipyrrinato sodium complex was treated with
PhBCl2 to produce the BODIPY analogue bearing one chloride
and one phenyl substituent at the boron centre.15 There are two
Scheme 1 Synthesis of F-BODIPYs 2.
We postulated that reacting dipyrrins with BCl3, BBr3 or BI3
would provide access to X-BODIPYs. Under air- and moisture-
free conditions, and using BCl3 as shown in Scheme 2, the first
Cl-BODIPYs, 3a and 3b, were successfully synthesized in yields
of 98% and 97%, respectively. Indeed, to solutions of 1a and 1b
in toluene one equivalent of BCl3 was added drop-wise, with
immediate visual effects: for 1a, the solution changed from yellow
to red-orange with a green fluorescent tinge; the orange solution
of 1b became dark red with a pink fluorescent tinge. In each case
the reaction mixture was stirred for 1 h at room temperature, then
filtered over Celite, and the filtrate concentrated in vacuo to give a
red powder. Both products are stable under an inert atmosphere,
but succumb to decomposition in air and/or moisture.
Department of Chemistry, Dalhousie University, 6274 Coburg Road,
PO BOX 15000, Halifax, Nova Scotia, B3H 4J3, Canada.
E-mail: Alison.Thompson@dal.ca; Fax: 902-494-1310;
Tel: 902-494-6421
w Electronic supplementary information (ESI) available: Experimental
procedures and NMR spectra. CCDC 842813. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c1cc16351e
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This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1003–1005 1003

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Scheme 2 Synthesis of Cl-BODIPYs.
The Cl-BODIPYs exhibit significant fluorescence in
solution although, unsurprisingly, less than the corresponding
F-BODIPYs. The quantum yields for complexes 3a and 3b
were measured in dichloromethane and were found to be
fF = 0.45 and 0.40, respectively: emission at 546 nm for
both. Although these quantum yields are significantly lower
than those of the corresponding F-BODIPY analogues
(fF = 1.00 for 2a and fF = 0.82 for 2b) these Cl-BODIPYs still
exhibit considerable fluorescence. This decrease in fluorescence
quantum yield for the Cl-BODIPYs is unsurprising, as the
heavier halogens facilitate fluorescence quenching.
Scheme 3 Synthesis of boronium salts 4 using boron trihalides.
The methodology used to produce Cl-BODIPYs 3a and 3b
was evaluated utilizing BBr3 and BI3. In both cases a single,
common product was isolated in impure form, and we were
unable to purify it satisfactorily. The product was deep red in
solution but still exhibited slight fluorescence. The reaction
was conducted in a variety of solvents, with toluene producing
the best results. The crude material was washed with hexanes
and filtered over Celite. Further attempts at purification
included filtering the reaction mixture through both a silica
and alumina plug. However, the instability of the product
resulted in decomposition during these procedures.
Fig. 1 Thermal Ellipsoid Diagram (50%) of 4aI. Hydrogen atoms
have been removed for clarity.
between the planes made up by the dipyrrinato units. This
orthogonality of dipyrrinato ligands is a common feature of
homoleptic dipyrrinato complexes and is enforced by the steric
crowding of the methyl groups in the 1- and 9-positions of the
dipyrrinato ligand.23 There is some observable disorder in an
ethyl group attached to one of the dipyrrinato ligands.
We postulated that X-BODIPYs might be generated in situ,
by way of similar methodology classically used for the synthesis
of F-BODIPYs (shown in Scheme 1), and then trapped via
the addition of an alcoholic solvent to give the corresponding
well-known O-BODIPYs. To test this theory we added six
equivalents of triethylamine to a dichloromethane solution of
the dipyrrin hydrobromide salts (1aHBr, 1bHBr), followed by
nine equivalents of the boron trihalide as a 1.0 M solution in
dichloromethane (in the case of BCl3 and BBr3) or as a solid (in
the case of BI3). After 24 h, the solution was treated with methanol
resulting in an immediate colour change. The consequent deep red
solutions were subjected to an aqueous work-up and the resulting
mixtures were purified over neutral alumina.
Having explored the reactions of BCl3, BBr3, and BI3 with
dipyrrins, we turned our attention to the reactivity of the new
Cl-BODIPYs. Due to the difference in boron-halogen bond
strengths between the B–F and B–Cl bond, we expected that
substitution at the boron atom in the Cl-BODIPYs would be
much more facile than in the corresponding F-BODIPYs. To
investigate the differences in reactivity, we synthesized dialkyl,
diaryl and dialkoxy BODIPYs from the new Cl-BODIPYs
(Scheme 4) and applied the same conditions to F-BODIPYs.
Dialkyl C-BODIPYs (7a and 7b) and O-BODIPYs (5a and 5b)
were synthesized in quantitative yields at room temperature
from Cl-BODIPYs 3, while the diaryl C-BODIPY 6a was
synthesized with a 50% yield (Table 1). As EtMgBr was added
to solutions of 3a and 3b in anhydrous diethyl ether, in each
case an orange precipitate formed immediately as the solutions
became red-orange. Synthesis of the O-BODIPYs was
achieved by adding NaOMe to a solution of each Cl-BODIPY
in anhydrous methanol, resulting in orange solutions with a
bright green fluorescent tinge. Upon completion, the reaction
mixture was washed with water and extracted with ethyl
acetate. The combined organic layers were dried over Na2SO4
and concentrated in vacuo to give the O-BODIPY products 5a
and 5b as orange and red crystalline solids, respectively. The
diaryl C-BODIPY 6a was synthesized by addition of PhLi to a
solution of 3a in anhydrous THF resulting in an immediate
colour change to dark red with a red fluorescent tinge. After
As expected, the heavier halogen X-BODIPY analogues were
not isolated from the reaction mixtures and, interestingly, neither
were the corresponding O-BODIPYs. The resulting products were
deep red in colour and not fluorescent. Characterization revealed
the first dipyrrinato boronium cations, 4a and 4b, isolated with a
counter-anion corresponding to the boron trihalide used, as
shown in Scheme 3. In all cases, isolated starting material made
up the mass balance.
X-ray diffraction-quality crystals of 4aI, containing an iodide
counterion, were grown and analyzed. The X-ray crystal
structurez is shown in Fig. 1. The environment around the boron
is tetrahedral with N-B-N angles ranging from 106.67(16)1 to
112.07(16)1 and the B–N bond lengths range from 1.547(2) A
to 1.550(2) A, which is within the sum of covalent radii for
the B and N atoms (1.55 A).22 The two dipyrrinato units
are nearly orthogonal to each other, with 951 and 851 angles
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1004 Chem. Commun., 2012, 48, 1003–1005
This journal is The Royal Society of Chemistry 2012

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significant fluorescence in solution, although they emit less
intensely than the corresponding F-BODIPYs. Cl-BODIPYs
are facile to substitute at boron, using mild conditions and
short reaction times, to give high yields of BODIPY analogues
that have previously been somewhat challenging to prepare
from the corresponding F-BODIPYs. Given the increased
reactivity of Cl-BODIPYs over F-BODIPYs, we anticipate
that this new class of compound will see significant application
as a synthetic intermediate. Attempts to utilize classical con-
ditions (BX3 and NEt3) for the synthesis of X-BODIPYs (X a
F), met with the isolation of the first boronium salts featuring
dipyrrinato ligands.
We acknowledge the Natural Sciences and Engineering
Research Council of Canada (NSERC) and Dalhousie
University for financial support, and Dr Adeeb Al-Sheikh
Ali (Taibah University) for preliminary contributions.
Scheme 4 Synthesis of C- and O-BODIPYs from Cl-BODIPYs 3.
Table 1 Summary of F-BODIPY 2a and Cl-BODIPY 3a reactivitya
Starting material
Notes and references
Cl-BODIPY 3a F-BODIPY 2a
B-Substitution conditions
z Crystallographic data, compound 4aI (CCDC 842813): C34H46N4BI,
F.W. 648.48. Primitive monoclinic, P21/c, Z = 4, a = 10.9061(4) A,
b
NaOMe, MeOH, 3 h, 22 1C 5a, 98%
No Reaction
6a and 6b (1.0 : 0.2)
after 24 h, 36%
7a, 67%
= 14.5040(5) A, c = 21.1718(7) A, b = 100.216(2)1,
PhLi, THF, 1 h, 22 1C
6a, 50%
7a, 98%
V = 3295.91(20) A3, T = 173(1)K, 25 370 reflections (9298 unique,
Rint = 0.042), R = 0.0361(3s), Rw = 0.0414(3s, 6538 reflections).
EtMgBr, Et2O, 3 h, 22 1C
a
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Percentage yields correspond to isolated yields.
1 h the reaction mixture was filtered over Celite and the
resulting filtrate was concentrated in vacuo to give a crude
red-brown powder containing the desired product 6a
(50% isolated yield) as well as several other compounds in minor
amounts, including the trisubstituted meso-phenyl derivative 6b:
we have shown previously that when B-arylation reactions are
carried out on meso-H F-BODIPYs, unwanted meso-substituted
byproducts are also produced.21,24
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When the corresponding F-BODIPY 2a was treated under
the same conditions, only trace product was observed. This is
unsurprising as reported procedures for O-BODIPY synthesis
starting from F-BODIPYs require treatment with sodium
methoxide at elevated temperature7 or treatment with methanol
following pre-activation with AlCl3:10 using Cl-BODIPYs,
rather than F-BODIPYs, is clearly more fruitful. O-BODIPY
syntheses from phenols via an intramolecular process are the
exception and proceed at room temperature.9,17 When
F-BODIPY 2a was treated with PhLi under the same conditions
used to generate 6a from Cl-BODIPY 3a, a mixture of 6a and
the corresponding meso-phenyl substituted derivative (6b) was
generated in a 36% overall yield after an extended reaction
time. Procedures for diaryl C-BODIPY synthesis are routinely
carried out at room temperature with yields o50%.3,25 When
F-BODIPY 2a was treated under the same conditions used to
generate 7, C-BODIPY 7a was produced in 67% yield. This
yield was much lower than that obtained when starting from
Cl-BODIPY 3a. This is in agreement with the reported
procedures for dialkyl C-BODIPY formation which are either
conducted at room temperature with yields under 60%25,26 or
elevated temperature with high yields.21
In short, the first BODIPYs featuring chloro substituents at
the boron centre are reported. Cl-BODIPYs are easily synthesized
under inert conditions, using dipyrrin free bases and BCl3.
Cl-BODIPYs are stable under inert conditions and exhibit
26 L. Li, B. Nguyen and K. Burgess, Bioorg. Med. Chem. Lett., 2008,
18, 3112–3116.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1003–1005 1005