Regioselective 2,6-dihalogenation of BODIPYs in 1,1,1,3,3,3-hexafluoro-2- propanol and preparation of novel meso-alkyl polymeric BODIPY dyes

Article abstract of DOI:10.1039/c3ra41298a

Regioselective 2,6-halogenation of BODIPYs in hexafluoro-2-propanol (HFIP) afforded products in less than 5 min. Halogenated BODIPYs were subjected to Pd-catalyzed cross-coupling reactions to form novel meso-alkyl polymeric BODIPY dyes.

Full text of DOI:10.1039/c3ra41298a

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Regioselective 2,6-dihalogenation of BODIPYs in
1,1,1,3,3,3-hexafluoro-2-propanol and preparation of
Cite this: DOI: 10.1039/c3ra41298a
novel meso-alkyl polymeric BODIPY dyes3
Liang Wang,a Jian-Wei Wang,a Ai-jun Cui,a Xiao-Xiao Cai,a Yan Wan,a Qun Chen,a
Ming-Yang He*a and Wei Zhang*b
Received 8th January 2013,
Accepted 3rd April 2013
DOI: 10.1039/c3ra41298a
www.rsc.org/advances
Regioselective 2,6-halogenation of BODIPYs in hexafluoro-2-
propanol (HFIP) afforded products in less than min.
5
Halogenated BODIPYs were subjected to Pd-catalyzed cross-
coupling reactions to form novel meso-alkyl polymeric BODIPY
dyes.
4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) represents an
important class of fluorescent dyes because of their excellent
photophysical and electrochemical properties such as high
photoluminescent quantum yields, large molar absorption coeffi-
cients, narrow emission bands, high chemical stability, and good
bioavailability.1,2 They have broad applications as labels for
reagents and biomarkers,3,4 chemosensors,5,6 energy transfer
cassettes,7,8 supramolecular polymers9 and for photodynamic
therapy.10 A significant amount of effort has been spent on the
synthesis of BODIPYs dyes to modify their spectroscopic and
electronic properties. Halogenated BODIPYs are common pre-
cursors for further functionalization.11 For example, 3,5-haloge-
nated BODIPYs (Fig. 1, A) could be used for SNAr reactions and
palladium-catalyzed cross-coupling reactions.12–16 The 2,6-haloge-
nated BODIPYs (Fig. 1, B) are potential sensitizers for photo-
dynamic therapy (PDT).17,18 They can also be derivatized by metal-
catalyzed cross-coupling reactions.19–21
Fig. 1 3,5- and 2,6-dihalogenated BODIPYs.
unique properties such as low toxicity, low nucleophilicity, high
polarity, strong hydrogen bond donating capability, and good
solvation capability with water. They have been used as green
solvents for many organic transformations.27–30
A range of solvents were screened for the direct halogenation of
1,3,5,7-tetramethyl BODIPY 1a with N-halosuccinimide (NXS). It
was found that solvents have a dramatic impact on the reaction
time and product yield (Table 1). NCS reactions in common
Table 1 Optimization of reaction conditions for the dihalogenation of 1aa
Direct electrophilic halogenation of BODIPYs is well-documen-
ted in the literature. N-Bromosuccinimide (NBS),20 bromine,22
23
NBS-AIBN, and CuBr2 have been used for the bromination of
BODIPYs. Regioselective bromination has also been reported in
the synthesis of tetra- and hexa-brominated meso-thienyl
BODIPYs,24 mono- to hepta-brominated pyrrolic-unsubstituted
BODIPYs,25 and 2,6-dibromoBODIPYs.26 Introduced in this paper
is a new process for regioselective 2,6-dihalogenation of BODIPYs
using fluorinated alcohol as a solvent. Fluorinated alcohols have
NXS
Entry (equiv.)
Additive
Solvent (equiv.)
Yield
Time
Product (%)b
1
2
3
4
5
6
7
8
9
NCS (4.0) CH2Cl2
NCS (4.0) EtOAc
NCS (4.0) CH3CN
NCS (4.0) MeOH
—
12 h
12 h
12 h
12 h
2a
2a
2a
2a
42
trace
13
27
82
100
100
100
90
—
—
—
NCS (2.4) MeOH thiourea (0.05) 30 min 2a
aJiangsu Province Key Laboratory of Fine Petro-Chemical Technology, Changzhou
University, Changzhou 213164, P. R. China. E-mail: lwcczu@126.com;
Fax: +86-519-86330251; Tel: +86-(0)13961477422
NCS (2.4) HFIP
NBS (2.4) HFIP
NIS (2.4) HFIP
NCS (1.2) HFIP
—
—
—
—
5 min
5 min
1 min
5 min
2a
2b
2c
2dc
bDepartment of Chemistry, University of Massachusetts Boston, MA 02125, USA.
a
b
E-mail: wei2.zhang@umb.edu
Reaction conditions: 1a (0.2 mmol), NXS, solvent (2 mL), 25 uC.
c
Yield was determined by 1H NMR. mono-chlorinated product.
Electronic supplementary information (ESI) available: Experimental section and
3
characterization data. See DOI: 10.1039/c3ra41298a
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Table 2 Dihalogenation of BODIPYs (1) in HFIPa
organic solvents such as CH2Cl2, EtOAc, CH3CN and MeOH at
room temperature for 12 h gave the dichlorinated product 2a in
less than 42% yield (Table 1, entries 1–4). Addition of a catalytic
amount of thiourea in MeOH increased the yield to 82% and
reduced the reaction time to 30 min (Table 1, entry 5). Using
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as a solvent, the NCS and
NBS reactions were completed in 5 min to give product 2a or 2b in
quantitative yield (Table 1, entries 6 and 7). The reaction with the
more active NIS gave 2c in less than 1 min (Table 1, entry 8). In
addition, reaction with 1.2 equiv. of NCS afforded
monochloroBODIPY 2d in 90% yield together with a small
amount of dichloroBODIPY. These results are attributed to the
hydrogen bonding effect between HFIP and NXS which makes X+
more electrophilic.31,32
2b, X = Br, 92%
2c, X = I, 90%
2f, X = Br, 82%b
2g, X = I, 80%b
2h, X = Br, 88%
2i, X = I, 86%
The regioselectivity of halogenation of unsubstituted BODIPY
1b was also studied. The reaction gave 2,6-dibromoBODIPY 2e in
90% isolated yield. No 3- or 5-bromoBODIPYs were detected in the
reaction mixture (Scheme 1).
The scope of dihalogenation of BODIPYs was also examined.
Dibromination and diiodination reactions were conducted since
bromo- and iodoBODIPYs are reactive intermediates and could be
used for further modifications. The results shown in Table 2
indicate that BODIPYs with meso-aryl and meso-alkyl groups gave
the corresponding products in good to excellent yields. BODIPYs
modified with morpholine, bis(chloromethyl)amine, and schiff
base have good compatibility. A diBODIPY was tetrabrominated in
the presence of 4.8 equiv. of NBS.
2j, X = Br, 95%
2k, X = I, 92%
2l, X = Br, 95%
2m, X = I, 93%
2n, X = Br, 91%
2o, X = I, 90%
There are several reports on the preparation of polymeric
BODIPY dyes by Pd-catalyzed coupling reactions.33–35 The linkers
could be 1,4-phenylenebisboronic acid, 1,4-diethynylbenzene and
related structures. Complementary to the polymeric meso-aryl
BODIPY dyes, we prepared four novel polymeric meso-alkyl
BODIPY dyes by Pd-catalyzed coupling reactions of dihalogenated
BODIPYs (Scheme 2). Thus, a reaction mixture of 2,6-dibromo- or
2,6-diiodoBODIPYs 2 was distilled to remove HFIP and the residue
was reacted with 1,4-phenylenebisboronic acid under general
Suzuki reaction conditions to give polymeric BODIPY dyes 3a–d
bearing different lengths of meso-alkyl chain. The HFIP solvent
could be reused in up to four cycles.
2p, X = Br, 90%
2q, X = I, 85%
2r, 91%
2s, 84%
2t, 83%
2u, 81%
2v, 87%c
a
Reaction conditions: 1 (0.2 mmol), NBS or NIS (2.4 equiv.), HFIP (2
mL), 25 uC, 5 min for bromination or 1 min for iodination, isolated
b
c
yields. 15 min reaction time. 4.8 equiv. of NBS.
Unsubstituted meso-alkyl BODIPY 1c has a strong absorption
band at 492 nm and an emission band at 513 nm, and a high Wf of
0.949 (Fig. 2). Its 2,6-diborominate analog 2l has a red-shift of 28
nm for the absorption band and 32 nm for the emission band. Its
Wf is decreased to 0.471. The results are similar to those reported
for bromoBODIPYs due to the heavy-atom effect36,37 The
polymeric BODIPY dye 3a (Mn = 17 110 g mol21, polydiversity:
1.17) has bathochromic shifts of 53 and 61 nm for the absorption
and emission bands, respectively. The Wf is increased to 0.601 due
to the enhanced conjugation relative to 2l. In all cases the polarity
of the solvents had little effect on the spectra of the meso-alkyl
BODIPYs, the dihalogenated BODIPYs, and the polymeric BODIPY
dyes.
Scheme 1 Regioselective dibromination of BODIPY 1b.
Scheme 2 Synthesis of polymeric BODIPY dyes.
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Table 3 Photophysical properties of meso-alkyl BODIPY polymeric dyes
Polymer Solvent labs(nm) lem (nm) Stokes shift (nm) Wfa
3a
3b
3c
3d
hexane
CH2Cl2 545
THF 545
ethanol 543
hexane 548
CH2Cl2 547
THF 547
ethanol 545
hexane 548
CH2Cl2 546
THF 546
ethanol 546
hexane 548
CH2Cl2 546
THF 546
ethanol 544
546
573
574
577
578
578
580
581
581
577
578
580
581
577
578
580
579
27
29
32
35
30
33
34
36
29
32
34
35
29
32
34
35
0.615
0.601
0.593
0.566
0.515
0.501
0.493
0.466
0.485
0.471
0.453
0.426
0.485
0.471
0.453
0.426
a
Fluorescence quantum yields (W) were calculated using Rhodamine
B in anhydrous ethanol (W = 0.73).
Fig. 2 Normalized absorption (solid lines) and emission (dashed lines) spectra of
BODIPYs 1c (black), 2l (red) and 3a (blue) in dichloromethane.
The thermal stabilities of the monomers 1c, 2l and polymer 3a
were evaluated by thermogravimetric analysis (TGA). Fig. 3 showed
that 1c and 2l lost 5% of their weight at 270 uC and 310 uC,
respectively. The polymeric BODIPY dye 3a did not decompose
until 335 uC, which suggests it has improved thermal stability.
Different alkyl groups such as n-C5H11, n-C11H23, n-C17H35 were
incorporated into the meso-position and their photophysical
properties were investigated (Table 3). It was found that the
polymeric BODIPYs 3a–d have a red-shift of about 50–60 nm
compared to the corresponding monomeric BODIPYs. The polarity
of the solvents and chain length of the alkyl groups at the meso-
position have no significant impact on their photophysical
properties, while the fluorescence quantum yield is decreased
when the chain length of the alkyl group is increased.
BromoBODIPY monomers with a longer alkyl chain have higher
solubility which resulted in polymers with increased molecular
weight. Good thermal stabilities were also found for the polymeric
Solid-state polymeric BODIPY fluorescence dyes 3a–d were
obtained to evaluate the effect of polymer aggregation and their
optical properties. The fluorescence spectra of the polymers in the
solid state retained most of their spectral features in solution and
exhibited significant red shift for both absorption and emission
maxima in CH3CN solution (3a: 585 and 617 nm; 3b: 562 and 603
nm; 3c: 571 and 602 nm; 3d: 656 and 608 nm). The results
indicate the presence of intermolecular electronic interactions
and/or increased coplanarity of the polymer in the solid state.
In summary, we have developed a new process for regioselec-
tive 2,6-dihalogenation of BODIPYs in HFIP using
N-halosuccinimide as the halogen source. The reactions were
completed in 1–5 min to give the corresponding products in
excellent yields. Fast reaction times, additive-free synthesis and
ease of operation make this protocol complementary to the
existing literature methods. The non-toxic and green HFIP solvent
could be readily recycled by distillation. Further modifications of
2,6-dihalogenated BODIPYs via Suzuki coupling reactions gener-
ated novel meso-alkyl polymeric BODIPYs. They have improved
thermal stability and have potential for use as fluorescent
materials. Other functionalization of BODIPYs is currently under-
way in our group and will be reported in due course.
BODIPYs 3b–d (see ESI ).
3
Acknowledgements
This paper is dedicated to Professor Dennis P. Curran on the
occasion of his 60th birthday. The support of the Priority
Academic Program Development of Jiangsu Higher Education
Institution is fully acknowledged.
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