Facile meso-BODIPY annulation and selective sensing of hypochlorite in water

Article abstract of DOI:10.1021/ol403405n

Annulated BODIPY chalcogenide (Se, Te) systems were synthesized from their respective bis(oformylphenyl) dichalcogenide intermediates. The annulated BODIPY selenide product was confirmed by X-ray diffraction. The red-shifted telluride version was found to

Full text of DOI:10.1021/ol403405n

Letter
pubs.acs.org/OrgLett
Facile meso-BODIPY Annulation and Selective Sensing of
Hypochlorite in Water
Sudesh T. Manjare,‡,§ Jin Kim,§ Yunho Lee,§ and David G. Churchill*,§
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS)
§Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), 373−1 Guseong−dong, Yuseong−gu,
Daejeon, 305−701, Republic of Korea
S
* Supporting Information
ABSTRACT: Annulated BODIPY chalcogenide (Se, Te)
systems were synthesized from their respective bis(o-
formylphenyl)dichalcogenide intermediates. The annulated
BODIPY selenide product was confirmed by X-ray diffraction.
The red-shifted telluride version was found to be sensitive and
selective for hypochlorite detection, reversible upon treatment
with biothiols.
rganoselenium compounds are of growing importance in
hydrogen peroxide with chloride gives rise to endogenous
Omedicinal and materials chemistry. Recent inroads into hypochlorous acid, which protects the immune system against
the invasion of pathogens. However, excess production of this
strong oxidant can also lead to diseases such as lung injury,
atherosclerosis, rheumatoid arthritis, and cardiovascular dis-
ease.7 Thus, to understand the role of hypochlorous acid in
living systems, it is very important to monitor its concentration
in aqueous solutions accurately. Probes for the detection of
hypochlorous acid have been reported in the literature,9 but
often do not underscore issues of selectivity, sensitivity,
reversibility, water solubility, and low probe molecular weight.
Molecular weight in fact revolves around the notion of blood
brain barrier passage based on “drug likeness” with guidelines
suggesting that low MW values, e.g., <500 are preferred.9g
Thus, in this work, we are presenting novel annulated BODIPY
selenide and telluride systems and bis(BODIPY)diselenide
systems and chemosensing results.
enzymology, medicine, and bioorganic chemistry have profiled
heterocyclic selenium-containing compounds that possess
biological activity including anti-inflammatory, antitumor,
antifungal, and antibacterial properties. Antioxidative and
enzymatic properties (e.g., glutathione peroxidase-like activ-
ities) are, in many researchers’ minds, among the most crucial
systems to fully understand.1−3 A great number of novel
heterocycles bearing single or multiple nitrogen, oxygen, sulfur,
selenium, or tellurium sites have been investigated over the
years; many of these are heterocyclic pharmacophores bearing
biological activity.4 One important challenge for organo-
chalcogen chemists has been to synthesize novel heterocyclic
systems. The routes toward ring formation are sometimes
complex and poorly accessible. Annulation reactions are vital in
synthetic organic chemistry; they hold very modest precedent
in polypyrrole chemistry5 with respect to, e.g., the secondary
attachment ortho substituent on a meso aryl group. However,
these reports are few and extend to only O- and N-bridging
atoms.6 Surprisingly, no annulations have yet been reported for
BODIPY species to the best of our knowledge, although the
BODIPY systems have been widely derivatized and heralded as
an extremely versatile platform.
Molecular probes are currently essential in efforts to
understand the presence and concentration of analytes such
as reactive oxygen species (ROS) in biological systems. These
species are thought to play a very important role in diabetes,
cancer, and neurodegenerative disease disorders such as
Parkinson’s and Alzheimer’s disease.7 ROS, often discussed in
connection with nitrogen-based RNS analogues, include
hydrogen peroxide (H2O2), hypochlorite (−OCl), superoxide
(O2•−), hydroxyl radical (•OH), nitric oxide (NO), and
peroxynitrite (ONOO−).8 Specifically, hypochlorous acid
(HOCl) is a potential antimicrobial agent that plays a
significant role in the immune system. The reaction of
The synthesis of selenium- and tellurium-containing
compounds 2−4 is outlined in Scheme 1. Bis(o-formylphenyl)-
diselenide and bis(o-formylphenyl)ditelluride systems (1)10
were treated with excess pyrrole in the presence of a catalytic
amount of trifluoroacetic acid (TFA) under nitrogen.
Intermediates 2a and 2b were isolated and characterized.
Bis(BODIPY)diselenide (3) was synthesized from dipyrro-
methane diselenide intermediate (2a). The annulated BODIPY
selenide (4a) was obtained as a secondary product in a reaction
that yielded 3 and was purified and isolated in 11% yield.
However, the analogous compound of 4a, annulated BODIPY
telluride 4b, was the only product from reaction with
dipyrromethane ditelluride intermediate 2b.
The 1H NMR spectrum of 4a revealed seven singly
integrating and one doubly integrating signals (Figure S27).
These peaks indicated a strikingly different compound type.
Received: November 24, 2013
© XXXX American Chemical Society
A
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Letter
Scheme 1. Reaction Pathway in
Bis(BODIPY)dichalcogenide (3) Formation and
Scheme 2. Plausible Mechanism for the Formation of
Annulated Product 4
Unexpected Annulated Products 4a and 4b
As per our knowledge, the annulated BODIPY selenide and
BODIPY telluride (4a and 4b) are the first examples of
selenium and tellurium that exists directly attached, to a pyrrole
ring in, e.g., meso porphyrin or BODIPY chemistry. Also, it is
the first such report of a system that involves direct and facile
formation of such a group. Importantly, due to the geometrical
effect imparted by annulation, the aryl group becomes more
coplanar (14° torsion angle) with the BODIPY body.
The mass spectral value (SI) obtained approximated in value
half of the molecular weight calculated for 3; an annulated
product was thus formulated (4a), and X-ray structural data was
acquired (Figure 1), confirming the unexpected and unique
The molecular structure of 4a is depicted in Figure 1 with
parameters found in Table S1. The divalent selenium atom
(C15−Se1−C3) forms an angle of 97.8(2)°. The C−Se bond
́
lengths (Se1−C15 1.884(4) and Se1−C3 1.849(4) Å) are
shorter than those expected for a single bond, indicating partial
CSe double bond character. Molecule 4a, including its aryl
group and BODIPY body, is largely planar, with a [C4−C5−
C10−C15] torsion angle of 14.2°.
Compounds 3, 4a, and 4b (probes) were then screened with
ROS (e.g., O2•−, H2O2, BuOOH, −OCl, OH, and BuO•).
The spectroscopic properties of the probes were determined
under physiological conditions in water−ethanol (v/v = 99/1,
0.1 M PBS, pH 7.5). In this assay, 3 mL samples of probe
solutions (3, 4a, and 4b) were treated with 7 equiv of ROS (in
water). When the sensing ability of the probes was tested with
various ROS, bis(BODIPY)diselenide 3 did not show any
fluorescence with ROS. Both annulated BODIPY probes (4a
and 4b) showed selective detection of hypochlorite; however,
the annulated telluride species 4b showed an extremely fast
response together with high sensitivity (62-fold) bearing a
strong red fluorescence (Figure 2a). This is in contrast with the
annulated BODIPY selenide 4a (10-fold; Figure S57). Upon
addition of hypochlorite (6.6 μM) to a solution of 4b, the
fluorescence quantum yield (ΦF) increased from 0.06 to 0.23.
In particular, a steady increase in fluorescence intensity was
observed, effected by even additions of hypochlorite concen-
tration (Figure 2b), and the detection limit was found to be 3.7
μM. Equilibration became even clearer with further exper-
imentation. In terms of kinetics, tellurium oxidation is
extremely fast for probe 4b; it was thus difficult to obtain
meaningful time-dependent fluorescence data involving a
steady increase in emission intensity under this normal
protocol. To work around this, hypochlorite was added to
the probe solution a short time (2.5 min) after spectral
collection began; this sharp “turn-on” event emphasized the
t
•
t
Figure 1. Molecular structure of compound 4a (CCDC #955225).
́
Cell lengths (Å) a = 7.3600(15), b = 10.043(2), c = 17.403(4); Cell
angles (°) α = 85.74(3), β = 89.65(3), γ = 89.41(3); Space group = P-
́
1; System = Triclinic; Selected bond lengths (Å) and angles (°): Se1−
C15 1.884(4), Se1−C3 1.849(4), N1−B1 1.532(5), N2−B1 1.538(6),
F1−B1 1.396(5), C15−Se1−C3 97.8(2), N2−B1−N1 105.1(3), and
F1−B1−F2 109.3(3). Hydrogen atoms are omitted for clarity.
structure of 4a. Analogously, compound 4b showed nine
1
aromatic signals in the H NMR spectrum (Figure S36). The
mass spectrum showed [M+Na]+ peaks with the expected
isotopic pattern.
A mechanism for the formation of 4a and 4b is proposed in
Scheme 2. Compound 2 was treated with 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) followed by treatment of
triethylamine to give compound 5, which was isolated and
confirmed by 1H NMR spectroscopy in the case of the
selenium analogue (Figure S46). These standard conditions
were introduced by Dolphin et al. and Lindsey et al.11a,b Finally,
BF3·Et2O was added to give compound 4. The formation of the
product involves E−E bond cleavage and Se−C/Te−C bond
formation. The reaction was also monitored by TLC, which
showed a crisp new spot after addition of each reagent (Figure
S50).
B
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PET mechanism has been discussed previously in the
literature.9
In conclusion, the first examples of BODIPY annulation were
discovered. A plausible mechanism for product formation
involves discrete E−E bond cleavage and E−C bond formation
steps. The X-ray structure of the annulated BODIPY selenide
was obtained. The annulated BODIPY telluride was highly
sensitive and selective (detection limit 3.7 μM and 62-fold) for
hypochlorite. A red-shifted detection (λex = 597 nm) is
provided which can be acquired under physiologically relevant
conditions (water−ethanol: v/v = 99/1, 0.1 M PBS, pH 7.5).
Also, the tellurium probe showed reversibility with biothiols. In
the future, this annulated BODIPY telluride probe can be used
in living neuronal cells for the detection of hypochlorite. The
bis(BODIPY)diselenide was also synthesized and characterized
and did not show any activity with ROS.
ASSOCIATED CONTENT
* Supporting Information
■
S
Methods, experimental procedures, additional spectral data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
Figure 2. (a) Emission spectra of probe 4b (45 × 10−6 M, water−
*E-mail: dchurchill@kaist.ac.kr.
Notes
ethanol: v/v = 99/1, 0.1 M PBS, pH 7.5) with ROS (O2•−, H2O2,
t
tBuOOH, −OCl, •OH, and BuO•) (333 μM in water, 7 equiv)
incubated for 5 min at rt. (b) Emission spectra of probe 4b (45 × 10−6
M, water−ethanol: v/v = 99/1, 0.1 M PBS, pH 7.5) with increasing
concentration of −OCl (3.3−63.3 μM in water) incubated for 5 min at
rt. (c) Reversibility cycles of probe 4b (45 × 10−6 M, water−ethanol:
v/v = 99/1, 0.1 M PBS, pH 7.5) with hypochlorite and glutathione
(GSH).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Molecular Logic Gate Laboratory operated by Prof. D. G.
Churchill (D. G. C.) acknowledges support from the NRF
(National Research Foundation) of Korea (2011−0017280).
Dr. S. T. Manjare acknowledges the support from Institute of
Basic Science (IBS), Korea.
velocity and saturation in the probe/analyte reaction that gives
rise to fluorescence (Figure S53).
REFERENCES
■
In order to understand the cycling capacity of probe 4b, the
solution of probe 4b, oxidized with hypochlorite, was treated
with glutathione, N-acetyl-L-cysteine, homocysteine, and L-
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the tellurium oxide species 4bO could revert to its original
reduced state (4b). The results obtained showed a quenching
of fluorescence intensity after the addition of biothiols (Figure
S54), and again a fluorescence increase with addition of
hypochlorite. This process can be cycled with GSH (∼10 redox
cycles) (Figure 2c) with 4b to demonstrate the reversibility of
ROS probing. This may be useful in monitoring the dynamic
variations of hypochlorite in living systems. However, in the
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(see SI, Figure S60 and accompanying text). The elaborated
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