Activation and deprotection of F-BODIPYs using boron trihalides

Article abstract of DOI:10.1039/c4cc02706j

The activation of F-BODIPYs with boron trihalides, followed by treatment with a nucleophile, effects facile substitution at boron; using water as the nucleophile promotes deprotective removal of the -BF₂ moiety and thereby production of the corresponding parent dipyrrin salt in quantitative yield under extremely mild conditions. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02706j

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Activation and deprotection of F-BODIPYs using
boron trihalides†
Cite this: Chem. Commun., 2014,
50, 7028
Travis Lundrigan, T. Stanley Cameron and Alison Thompson*
Received 11th April 2014,
Accepted 6th May 2014
DOI: 10.1039/c4cc02706j
www.rsc.org/chemcomm
The activation of F-BODIPYs with boron trihalides, followed by treat- substitute at the boron centre of the Cl-BODIPY, with the hope of
ment with a nucleophile, effects facile substitution at boron; using generating the dihydroxy O-BODIPY, which we knew to be
water as the nucleophile promotes deprotective removal of the –BF2 unstable.25 Reaction of F-BODIPY 1a with BCl3 (1 eq.), under
moiety and thereby production of the corresponding parent dipyrrin an inert atmosphere, achieved complete conversion to the
salt in quantitative yield under extremely mild conditions.
Cl-BODIPY.23 We were then delighted to discover that removal
of the solvent and subsequent dissolution of the Cl-BODIPY in
Compounds containing the 4,4-difluoro-4-bora-3a,4a-diaza-s- excess acetone : water (10 : 1), afforded a quantitative yield of
indacene (F-BODIPY) framework are used as dyes, as fluorescent the dipyrrin as its HCl salt (Table 1, entry 1). The HCl salt was
probes in biological systems, and as materials in electrolumines- isolated as an orange solid after extraction from the acetone–
cent devices.1–3 The wide utility of these compounds derives from water solution with CH2Cl2.
their high thermal and photochemical stabilities, as well as their
The scope of this mild F-BODIPY deprotection extends to
chemical robustness and tunable fluorescence properties.4–6 various functionalities around the dipyrrinato core (Table 1):
Recent research has focused on the synthesis of BODIPYs with alkyl and keto substituents (entries 1–5) were tolerated, and
substituents other than fluorine at the boron centre, with the goal F-BODIPYs featuring a meso-phenyl group (entries 5 and 6),
of creating BODIPYs with unique spectroscopic properties. A wide were also converted to their HCl salts in quantitative yields. The
range of B-alkynyl (E-BODIPY) and B-alkyl (C-BODIPY) derivatives F-BODIPY 1g, featuring an ester substituent, was successfully
have thus been synthesized, alongside other variants7–21 including converted to the Cl-BODIPY. However, the addition of water was
Cl-BODIPYs, compounds that allow for facile substitutions at the followed by complete decomposition of the material, rather
boron center courtesy of the weaker B–Cl bond cf. B–F bond.22,23 than isolation of the dipyrrin as its HCl salt.
For many years the removal of the –BF2 moiety from F-BODIPYs,
Cognisant that HBr salts of dipyrrins are more crystalline
to generate the dipyrrin, lay unconquered but recently we pub- than other HX salts,26 F-BODIPYs 1a and 1g were reacted with
lished an effective deprotection route involving rather harsh BBr3. The reactions were carried out in the same manner as
treatment with alkoxides to exploit the Lewis acidic nature of described above but with the initial addition of BBr3, instead of
boron.24,25 Herein we report the deprotection of F-BODIPYs to BCl3. Pleasingly, the revised protocol quantitatively converted
generate their dipyrrin salts under extremely mild conditions the F-BODIPYs 1a and 1g into the dipyrrin HBr salts 2a and 2g,
involving BX3 Lewis acids and water. The strategy relies upon a respectively (Table 1, entries 1 and 7, parentheses). Given this
prior activation of the BODIPY B–X bond, and as such is also an success, we hypothesised that the reaction of F-BODIPYs with
effective route by which to substitute at boron. The same strategy BBr3 gives the corresponding Br-BODIPYs,23 an interesting
promotes facile nucleophilic substitution at boron.
proposition given that we had previously been unable to isolate
Earlier work with Cl-BODIPYs revealed their sensitivity to air Br-BODIPYs after the reaction of lithium dipyrrinato salts with
and moisture.22,23 Therefore, we formally investigated the course BBr3.22 The F-BODIPY 1a was thus dissolved in anhydrous CCl4,
of the reaction when water is introduced as the nucleophile to and BBr3 was then added. The reaction mixture was sub-
sequently concentrated in vacuo to quantitatively return the
Department of Chemistry, Dalhousie University, 6274 Coburg Road, PO Box 15000,
Br-BODIPY 3a, the first Br-BODIPY to be isolated (Scheme 1).
11B NMR characterisation clearly revealed a singlet at À5.89 ppm,
Halifax, Nova Scotia, B3H 4J3, Canada. E-mail: Alison.Thompson@dal.ca;
Fax: +1 902-494-1310; Tel: +1 902-494-6421
cf. the triplet at 0.76 ppm for the starting material F-BODIPY.
† Electronic supplementary information (ESI) available: Experimental procedures
The isolation of this material supports the notion that the depro-
tection protocol, as described for 1a and 1g above, occurs through
and NMR spectra. CCDC 996669. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4cc02706j
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Table 1 Conversion of F-BODIPYs to dipyrrin HCl salts
Scheme 1 Synthesis of a Br-BODIPY.
F-BODIPY
Product
Isolated yield (%)
Entry
1
the solution turned a dull yellow, characteristic of a dipyrrin salt.
After an aqueous work-up, an orange powder was recovered.
Complete characterisation of this compound revealed it to be the
first HBF4 salt of a dipyrrin, isolated in quantitative yield
(Table 2, entry 1). 11B NMR spectroscopy revealed a boron singlet
at À0.65 ppm, indicating the BF4 counter-ion.27 Curiously, if a
large excess of water was added to the reaction mixture (rather
than the addition of just 3 eq. water), the original fluorescent
bright orange of the F-BODIPY would be returned and starting
material was quantitatively recovered. Clearly the stoichiometry
of the added water dramatically alters the outcome of the
protocol: excess water quenches the BF3, yet controlled amounts
of water react at the boron centre of the F-BODIPY, courtesy of
Lewis acid pre-activation by BF3.
499 (499%)a
2
3
4
499
499
499
The scope of the deprotective method, i.e. F-BODIPY activa-
tion by BF3 followed by the controlled addition of water, was
briefly explored by varying the alkyl substituents around the
dipyrrinato core (Table 2, entries 1–3). Decreasing extents of
Table 2 Conversion of F-BODIPYs to dipyrrin HBF4 salts
5
6
499
F-BODIPY
Product
Isolated yield (%)
Entry
1
499
499
7
N/A (499%)a
2
3
91
80
a
Yields for the synthesis of the HBr salt using BBr3.
the Br-BODIPY: reaction with water would then produce the
unstable dihydroxy O-BODIPY, followed by decomposition to
liberate the dipyrrin.
To continue exploring the reactions of F-BODIPYs with
boron trihalides, we turned our attention to the fluoro analogue.
The F-BODIPY 1a was dissolved in anhydrous CH2Cl2 and treated
with BF3ÁOEt2 (1 eq.). The reaction mixture immediately changed
from a fluorescent bright orange to a fluorescent red/purple
colour, indicative of an interaction/activation between the
F-BODIPY and the added BF3. The reaction mixture was stirred
for 10 minutes, and then 3 eq. water was added; 2 eq. to give the
dihydroxy O-BODIPY, plus one 1 eq. to result in hydrolysis of
the covalent N–B bond thus liberating boric acid. At this point
4
5
45
5
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Fig. 2 Proposed activation of F-BODIPYs by BF3.
Scheme 2 Synthesis of a C-BODIPY.
to overall loss of the BF2 moiety and accompanying formation
of boric acid, alongside formation of the BF4 anion (boron from
BF3ÁOEt2).
Fig. 1 Ellipsoid diagram (50%, H atoms omitted) of HBF4 salt 4b.
substitution around the pyrrolic scaffold resulted in reduced
The formation of the activated intermediate is further
yields of the dipyrrin HBF4 salts. Furthermore, moving from supported by its reaction with a nucleophile other than water.
meso-H to meso-phenyl substitution resulted in a drastic Indeed, reaction of 1a with BF3ÁOEt2, followed by treatment
decrease in yield (entries 4 and 5 cf. 1). In each case, the with 2 eq. of EtMgBr resulted in complete conversion to the
remaining starting material could always be recovered. These corresponding C-BODIPY (5a) as shown in Scheme 2. Clearly
results suggest that the electron-donating ability of the sub- the B–F bond is more susceptible to nucleophilic attack in the
stituents alter the degree of activation induced by the addition presence of BF3ÁOEt2, as it has been shown previously that the
of BF3, and thereby affect the degree of subsequent substitution reaction of 1a with 2 eq. of EtMgBr does not reach completion
at boron by water: formation of the dihydroxy O-BODIPY is at room temp.23
critical to the deprotective removal of the BF2 moiety and
consequent liberation of the dipyrrin.
In an attempt to characterise the activated intermediate
(Fig. 2), we treated 1a with 1 eq. of BF3ÁOEt2, and analysed the
It has been documented that the HBr salts of dipyrrins are corresponding 11B and 19F NMR spectra. The spectra clearly
crystalline and are thus more commonly synthesized and used indicated activation of the F-BODIPY boron centre. In the 11B
than other HX salts.26 However, we herein report that dipyrrin spectrum, the triplet of the starting material (1a) presented as a
HBF4 salts easily surpass the HBr variants in terms of crystal- rather sharp singlet alongside a singlet corresponding to the BF3
linity. Indeed, our dipyrrin HBF4 salts were easily crystallised boron center: in neither case was coupling was observed between
via the slow evaporation of solvent from a CH2Cl2 solution. boron and fluorine. Meanwhile, in the 19F NMR spectrum, the
A single crystal of 4b-HBF4 was characterised using X-ray crystal- typical quartet of 1a was absent and instead a severely depressed
lography (Fig. 1), clearly indicating the BF4 counter-ion.‡ It (low intensity) broad singlet signal was observed. Since the
should be noted that the when the microcrystalline material anticipated coupling between boron and fluorine was not
was left on the bench top, after several months we occasionally observed, we used variable temperature 11B and 19F NMR to
witnessed loss of the BF4 counter ion. However, when the salt look for exchange processes. At À60 1C the coupling between
was left in crystalline form the material remained unchanged. boron and fluorine was revealed. However, as the temperature
To investigate exchange of the BF4 counterion, we treated a was increased (Fig. 3), the signals coalesced. These results
solution of 4a-HBF4 in CH2Cl2 with aqueous HBr, followed by an suggest facile room-temperature exchange of the fluorine atoms
aqueous work-up, and we achieved complete conversion of the on the F-BODIPY with those of the BF3 present in solution.
4a-HBF4 salt to the 4a-HBr salt.
The formation of dipyrrin HBF4 salts using BF3ÁOEt2 and
Deprotection via reaction of F-BODIPYs with BF3ÁOEt2 and controlled amounts of water provides potential insight into the
the controlled addition of water must clearly proceed through an traditional route used for the synthesis of F-BODIPYs. F-BODIPYs
alternative pathway to those involving BCl3 and BBr3 whereby the are typically synthesised by reacting the dipyrrin HBr salt, or free-
corresponding Cl/Br-BODIPYs are unequivocally formed as inter- base, with excess NEt3 (6 eq.) and BF3ÁOEt2 (9 eq.).28 Despite these
mediates. We propose that the addition of BF3ÁOEt2 to F-BODIPYs excesses, the reaction is surprisingly moisture-sensitive. With the
results in activation of a B–F bond of the F-BODIPY (Fig. 2).16 In knowledge that BF3ÁOEt2 activates F-BODIPYs, we can now appreci-
the absence of a nucleophile, the activation is terminated when ate that the formation of F-BODIPYs under non-anhydrous condi-
the Lewis acid is quenched during work-up, and thus quantitative tions is reversible, and that even the anhydrous process is
recovery of the F-BODIPY ensues. In the presence of a nucleo- susceptible to non-productive interference by nucleophiles.
phile, such as water, the activated BODIPY is susceptible to attack
To summarize, we have developed an extremely high yielding
at boron to result in cleavage of the BODIPY B–F bonds en route and mild methodology for the deprotection of F-BODIPYs using
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Notes and references
‡ Crystallographic data, compound 4b (CCDC 996669): C15H21N2BF4,
F.W. 316.15. Primitive orthorhombic, Pnma (#62), Z = 4, a = 17.4172(8) Å,
b = 7.0912(4) Å, c = 13.2491(8) Å, b = 100.216(2)1, V = 1636.38(15) Å3,
T = 173(1) K, 10 434 reflections (2620 unique, Rint = 0.052), R = 0.0595
(2.5s), Rw = 0.0654 (2.5s, 1130 reflections).
1 N. Boens, V. Leen and W. Dehaen, Chem. Soc. Rev., 2012, 41, 1130–1172.
2 Y. Cakmak, S. Koleman, S. Duman, Y. Dede, Y. Dolen, B. Kilic,
Z. Kostereli, L. T. Yildirim, A. L. Dogan, D. Guc and E. U. Akkaya,
Angew. Chem., Int. Ed., 2011, 50, 11937–11941.
3 S. Koleman, O. A. Bozdemir, Y. Cakmak, G. Barin, S. Erten-Ela,
M. Marszalek, J.-H. Yum, S. M. Zakeeruddin, M. K. Nazeeruddin,
M. Gratzel and E. U. Akkaya, Chem. Sci., 2011, 2, 949–954.
4 M. Benstead, G. H. Mehl and R. W. Boyle, Tetrahedron, 2011, 67,
3573–3601.
5 A. Loudet and K. Burgess, Chem. Rev., 2007, 107, 4891–4932.
6 R. Ziessel, G. Ulrich and A. Harriman, New J. Chem., 2007, 31, 496–501.
7 L. H. Davies, B. Stewart, R. W. Harrington, W. Clegg and L. J. Higham,
Angew. Chem., Int. Ed., 2012, 124, 5005–5008.
8 P. Hewavitharanage, P. Nzeata and J. Wiggins, Eur. J. Chem., 2012, 3,
13–16.
9 Y. Kubota, J. Uehara, K. Funabiki, M. Ebihara and M. Matsui,
Tetrahedron Lett., 2010, 51, 6195–6198.
10 K.-M. Liu, M.-S. Tsai, M.-S. Jan, C.-M. Chau and W.-J. Wang, Tetrahedron,
2011, 67, 7919–7922.
11 C. Goze, G. Ulrich, L. J. Mallon, B. D. Allen, A. Harriman and
R. Ziessel, J. Am. Chem. Soc., 2006, 128, 10231–10239.
12 C. Goze, G. Ulrich and R. Ziessel, Org. Lett., 2006, 8, 4445–4448.
13 C. Goze, G. Ulrich and R. Ziessel, J. Org. Chem., 2007, 72, 313–322.
14 A. Harriman, G. Izzet and R. Ziessel, J. Am. Chem. Soc., 2006, 128,
10868–10875.
Fig. 3 VT NMR spectra of 1a and BF3ÁOEt2.
15 Y. Gabe, T. Ueno, Y. Urano, H. Kojima and T. Nagano, Anal. Bioanal.
Chem., 2006, 386, 621–626.
¨
16 S. Liu, T.-P. Lin, D. Li, L. Leamer, H. Shan, Z. Li, F. P. Gabbaı and
Cl- and Br-BODIPYs as in situ intermediates. Furthermore, we
have isolated the first Br-BODIPY. We have highlighted the
benefit of using either the chloro- or bromo-intermediate over
the other, based on the characteristic stability of the resulting
HX salt and the virtue of the substituents about the dipyrrolic
framework. We also demonstrate the use of BF3ÁOEt2 to deprotect
F-BODIPYs, via the activation of the boron centre of the BODIPY.
These reactions provide the first HBF4 salts of dipyrrins, which are
P. S. Conti, Theranostics, 2013, 3, 181–189.
17 H. Kim, A. Burghart, M. B. Welch, J. Reibenspies and K. Burgess,
Chem. Commun., 1999, 1889–1890.
18 C. Tahtaoui, C. Thomas, F. Rohmer, P. Klotz, G. Duportail, Y. Mely,
D. Bonnet and M. Hibert, J. Org. Chem., 2007, 72, 269–272.
19 C. Bonnier, W. E. Piers, M. Parvez and T. S. Sorensen, Chem. Commun.,
2008, 4593–4595.
20 T. W. Hudnall and F. P. Gabbai, Chem. Commun., 2008, 4596–4597.
21 C. Bonnier, W. E. Piers and M. Parvez, Organometallics, 2011, 30,
1067–1072.
extremely crystalline. This same strategy can be used to achieve 22 T. Lundrigan, S. M. Crawford, T. S. Cameron and A. Thompson,
Chem. Commun., 2012, 48, 1003–1005.
23 T. Lundrigan and A. Thompson, J. Org. Chem., 2013, 78, 757–761.
24 S. M. Crawford and A. Thompson, Org. Lett., 2010, 12, 1424–1427.
extremely mild nucleophilic substitution at boron. Furthermore,
we suggest caution should Lewis acid-induced activation of a
peripheral substituent of a BODIPY be required: activation of the 25 D. A. Smithen, A. E. G. Baker, M. Offman, S. M. Crawford, T. S.
Cameron and A. Thompson, J. Org. Chem., 2012, 77, 3439–3453.
26 T. E. Wood and A. Thompson, Chem. Rev., 2007, 107, 1831–1861.
27 R. D. Falcone, B. Baruah, E. Gaidamauska, C. D. Rithner, N. M. Correa,
BX2 moiety is likely to ensue, followed by nucleophilic substitu-
tion at boron that may result in undesired overall loss of boron
from the BODIPY framework.
J. J. Silber, D. C. Crans and N. E. Levinger, Chem. – Eur. J., 2011, 17,
6837–6846.
28 T. Lundrigan, A. E. G. Baker, L. E. Longobardi, T. E. Wood,
D. A. Smithen, S. M. Crawford, T. S. Cameron and A. Thompson,
Org. Lett., 2012, 14, 2158–2161.
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC) and the Killam Trusts for
financial support of this work.
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Chem. Commun., 2014, 50, 7028--7031 | 7031