Highly selective detection of nerve-agent simulants with BODIPY dyes

Article abstract of DOI:10.1002/chem.201304475

Two chromo-fluorogenic probes, each based on the boron dipyrromethene core, have been developed for the detection of nerve-agent mimics. These chemosensors display both a color change and a significant enhancement of fluorescence in the presence of diethy

Full text of DOI:10.1002/chem.201304475

DOI: 10.1002/chem.201304475
Full Paper
&
Chemosensors
Highly Selective Detection of Nerve-Agent Simulants with BODIPY
Dyes**
Andrea Barba-Bon,[a, b] Ana M. Costero,*[a] Salvador Gil,[a] Anthony Harriman,*[c] and
Fꢀlix Sancenꢁn[b]
Abstract: Two chromo-fluorogenic probes, each based on
the boron dipyrromethene core, have been developed for
the detection of nerve-agent mimics. These chemosensors
display both a color change and a significant enhancement
of fluorescence in the presence of diethylcyanophosphonate
(DCNP) and diisopropylfluorophosphate (DFP). No interfer-
ence from other organophosphorus compounds or acids has
been observed. Two portable chemosensor kits have been
developed and tested to demonstrate its practical applica-
tion in real-time monitoring.
Introduction
following limitations is prevalent in each of these protocols:
low response, lack of specificity, limited selectivity, poor sensi-
tivity, operation complexity, nonportability, difficulties in real-
time monitoring, and false positive readings.
Nerve agents are among the most important and lethal classes
of chemical-warfare agents (CWAs). Nerve agents such as Sarin,
Soman, or Tabun are organophosphonate derivatives, in which
the phosphorus atom is electrophilic by nature and can bind
easily with the hydroxy group of the serine unit of the acetyl-
cholinesterase enzyme (AChE). This reaction renders the
enzyme nonfunctional,[1] thus resulting in acetylcholine accu-
mulation in the synaptic junctions that hinders muscle relaxa-
tion.[2] Because of the extreme toxicity, facile production, and
ready accessibility relative to more conventional weapons,
there is always the possibility of CWA attack by military re-
gimes and terrorist organizations. As a consequence, intense
research effort has been directed to the development of sensi-
tive and selective analytical protocols for their detection. Sev-
eral approaches have been proposed, including the use of an
enzymatic assay,[3] ion-mobility spectroscopy,[4] lanthanide lumi-
nescence,[5] electrochemistry,[6] photonic crystals,[7] microcanti-
levers,[8] and optical-fibre arrays.[9] However, at least one of the
The development of chromogenic and fluorogenic probes
has gained increased interest in recent years to overcome
these limitations.[10] Colorimetric and fluorimetric detection are
particularly appealing as they are low-cost systems capable of
performing quantitative analysis with widespread technologies.
These techniques also offer the possibility of detecting ana-
lytes with the “naked eye”. Notwithstanding the intrinsic inter-
est in the design of such probes, the reported examples have
certain limitations; the most important being the false positive
or negative responses in the presence of nontoxic compounds,
such as acids.[11] Buffered solutions have been used to curtail
this problem, but even under these conditions acids are impor-
tant competitive agents that interfere with the sensing experi-
ments.[10d,12] Therefore, we have been stimulated to design sys-
tems capable of discriminating between the target molecule
and acidic media.
Taking the above concept into consideration and following
our interest in the development of probes for the detection of
nerve agents,[10c,11c,13] we report herein the use of boron dipyr-
romethene (BODIPY) dyes as signaling systems for the selective
detection of these chemicals (Scheme 1). It is widely recog-
[a] A. Barba-Bon, Prof. A. M. Costero, Prof. S. Gil
Centro de Reconocimiento Molecular y Desarrollo Tecnolꢀgico (IDM)
Universidad de Valencia, Doctor Moliner 50,
46100 Burjassot, Valencia (Spain)
Fax: (+34)963543831
E-mail: ana.costero@uv.es
[b] A. Barba-Bon, Dr. F. Sancenꢀn
Centro de Reconocimiento Molecular y Desarrollo Tecnolꢀgico (IDM)
Universidad Politꢁcnica de Valencia
Camino de Vera s/n, 46022 Valencia (Spain)
[c] Prof. A. Harriman
Molecular Photonics Laboratory, School of Chemistry
Bedson Building, Newcastle University
Newcastle upon Tyne, NE17RU (UK)
Fax: (+44)1912228660
E-mail: anthony.harriman@newcastle.ac.uk
[**] BODIPY=boron dipyrromethene
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304475.
Scheme 1. Molecular formulae of target compounds 1 and 2 and control
compound 3.
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nized that BODIPY dyes are excellent fluorophores with wide-
spread applications as probes in natural and artificial systems.
These probes possess valuable characteristics, such as intense
absorption and fluorescence transitions in the visible-spectral
region, high molar-absorption coefficients and fluorescence
quantum yields, and good stability toward thermal and photo-
chemical degradation.[14]
phenyl]ethanol (1) and 2-2-{2-[methyl(phenyl)amino]ethoxy}
ethanol (2) as reactive units for the quantitative detection of
nerve agents. In a first step, the hydroxy group was phos-
phorylated to form a phosphoester intermediate that under-
goes rapid intramolecular N-alkylation to afford the corre-
sponding cation (Scheme 2). The change in the electronic dis-
tribution promoted by these processes allows the colorimetric
and/or fluorescent detection of nerve agents. A crucial feature
of any successful analytical protocol is the prevention of false
positives produced by other species, such as acidic media.
Consequently, we made a deliberate attempt to design chemo-
sensors capable of discriminating between nerve agents and
acidic interferences. To achieve this goal, we introduced the
pyridine moiety at the meso-position (Scheme 1). It has been
demonstrated previously that the fluorescence emission of pyr-
idyl-BODIPY can be quenched reversibly by protonation of the
pyridine nitrogen atom.[17] This simple strategy introduces the
necessary functionality to avoid false positives caused by ad-
ventitious acid contaminants. In fact, the pyridine moiety is
more basic than the terminal amino group and will be the first
point of reaction in the presence of acid, thus triggering the
characteristic signal response (i.e., little effect on the absorp-
tion profile but a significant change in fluorescence intensity).
On the other hand, generation of the cyclic ammonium salt is
the most favorable reaction in the presence of the nerve
agent, thereby giving rise to the accompanying change of
color. The system was designed in such a way that even in the
presence of both species (i.e., nerve agent and acid) a response
will be reported.
Results and Discussion
Design of the sensory agents
Traditionally, the development of chromo- and fluorogenic
probes relies on the design of two components: 1) a binding
or reactive site and 2) a chromo-fluorogenic trigger. For the
fluoro-colorimetric event, we selected the BODIPY core due to
the properties cited above. Probes 1 and 2 (Scheme 1) were
designed that contain two chemo-sensing moieties to avoid
acid interference. Firstly, there is a nucleophilic hydroxy group
that provides a suitable reactive site for electrophilic phospho-
rus atoms,[10c,11c,15] such as those functionalities likely to persist
in nerve agents. Secondly, each chromophore is equipped with
a basic pyridine moiety that is known to react with sacid.[16]
The intention is to keep these two units in electronic isolation
where they can react with the relevant species in solution,
thus giving a disparate response to the trapping of each re-
agent and discriminating between the target and acid. In addi-
tion, the corresponding phenyl derivative 3 was prepared for
control experiments because this compound lacks the acid-
sensitive meso-pyridine residue.
Our research group has previously reported the use of 2-[2-
(dimethylamino)phenyl]ethanol moieties in the detection of
nerve agents.[10c,11c] The nucleophilic hydroxy group is easily
phosphorylated by the nerve agent, thus forming a phos-
phoester, which is displaced in a second step by the attack of
the nitrogen atom to give a five-membered-ring quaternary
ammonium salt (Scheme 2a). Following these earlier results,
we decided to explore the use of both 2-[2-(dimethylamino)-
Synthesis of the probes
Reagents 1 and 2 were synthesized by using the Knoevenagel
condensation on BODIPY 4 according to previously reported
procedures.[14b,18] Thus, 4 in benzene was condensed with the
corresponding aldehyde in the presence of acetic acid and pi-
peridine (Scheme 3). Prior to this work, starting compound 4
was synthetized according to a reported procedure[14b,19] by
condensation of 2,4-dimethylpyr-
role with 4-pyridinecarboxalde-
hyde in the presence of trifluoro-
acetic acid (TFA) as a catalyst,
followed by oxidation with para-
chloranil (Scheme 4). The boron
difluoride bridging unit was in-
troduced by treatment with
boron trifluoride diethyl etherate
(BF3·Et2O) in the presence of
triethylamine (TEA).
Preparation of aldehyde 7 ne-
cessitated a three-step synthesis
(Scheme 5). Thus 2-(2-aminophe-
nyl)ethanol was transformed into
2-[2-(dimethylamino)phenyl]-
ethanol (5) by reaction with io-
domethane. This amino com-
Scheme 2. Proposed outline for the chromo-fluorogenic sensing paradigm. ICT=internal charge transfer.
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Scheme 6. Synthetic protocol used for the preparation of aldehyde 9.
Ts =para-toluenesulfonyl.
was treated with ethylene glycol to give the required 4-{[2-(2-
hydroxyethoxy)ethyl](methyl) amino}benzaldehyde. By follow-
ing the same procedure, the important control compound 3
was prepared from 8-phenyl-1,3,5,7-tetramethyl-BODIPY and al-
dehyde 9.
Scheme 3. Synthetic protocol used for the preparation of probes 1 and 2.
Spectroscopic properties
Figure 1 shows the absorption and fluorescence spectra re-
corded for 1 and 2 in acetonitrile (10À5 m). The absorption
Scheme 4. Synthetic protocol used for the preparation of compound 4.
DDQ=2,3-dichloro-5,6-dicyano-para-benzoquinone.
Figure 1. Normalized absorption and fluorescence spectra (lex =530 nm) re-
corded for 1 (g) and 2 (c) in CH3CN.
spectral profiles are reminiscent of those characterized for vari-
ous related BODIPY dyes,[20,21] with an intense transition seen
at approximately l=570 and 610 nm for 1 and 2, respectively,
and both spectra exhibited a shoulder at shorter wavelength
(ca. l=530 nm). The fluorescence spectra display a small
Stokes shift with good mirror symmetry, as is often the case
with BODIPY dyes.[20–21] The emission maxima are in the range
of l=575–620 nm.
Scheme 5. Synthetic protocol used for the preparation of aldehyde 7.
NBS=N-bromosuccinimide.
verted into the corresponding bromo derivative 6 by reaction
with N-bromosuccinimide catalyzed with ammonium acetate.
In turn, the latter reagent was lithiated with nBuLi and then
converted into the formyl derivative 7 by reaction with N,N-di-
methylformamide (DMF).
The effect of the solvent on the spectroscopic properties of
1 and 2 were investigated at room temperature; the electronic
absorption and emission spectra recorded for 1 in several sol-
vents are shown in Figure 2 (see the Supporting Information
for 2) and the photophysical data collected for both com-
pounds are listed in Table 1. In all the solvents studied, two ab-
sorption peaks are seen clearly with relatively narrow spectral
bandwidths. The lower energy band is assigned to the 0–0
The synthesis of aldehyde 9 was achieved following a two-
step procedure starting from 4-[(2-hydroxyethyl)(methyl)-
amino]benzaldehyde (Scheme 6). The first step consists of tosy-
lation with para-toluenesulfonyl chloride in dichloromethane
in the presence of triethylamine. The obtained derivative 8
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Figure 2. Enlargement of the main absorption peak (left) and fluorescence emission peak (right) of 1 in several solvents to emphasize the solvatochromic
shifts. The intensities in this figure are normalized to the same value at the wavelength of the maximum intensity.
sensitivity toward the solvent polarity. In contrast, the emission
Table 1. Photophysical properties recorded for BODIPY compounds
1 and 2 in several solvents.
energies of 1 and 2 are much more sensitive to the solvent po-
larity. On increasing the solvent polarity, a significant redshift is
observed. The fluorescence quantum yields F are weak, which
is explained in terms of efficient charge transfer from the ap-
pended amino-alcohol moieties to the styryl-BODIPY core.[22]
Compound 3 (10À5 m in acetonitrile) exhibits an absorption
peak at l=598 nm (e=8400mÀ1 cm À1) and is essentially non-
fluorescent at room temperature (see the Supporting Informa-
tion and Figure 3).
Probe Solvent
labs, max
lem, max
Dn[a] e [mÀ1 cmÀ1] F[b]
[nm]
[nm]
1
acetonitrile
MTHF
569.4
573
573
575
572
577
574
575
668.2
637
657.4
622.4
640.8
632.8
171 30800
2481 36100
1753 33400
2177 32600
1415 33100
1725 35000
1618 36000
0.0141
0.1888
0.2802
0.2506
0.3732
0.0662
0.3217
dibutyl ether
1,4-dioxane
cyclohexane
toluene
carbon tetra-
chloride
2
acetonitrile
MTHF
dibutyl ether
1,4-dioxane
cyclohexane
toluene
607.5
611
609.5
607.5
607.5
616
616
675.5
651
663.3
636.1
655.5
642.86
227 62100
1562 57200
1045 34100
1384 16800
740 45100
978 50600
864 35900
0.002
0.068
0.075
0.073
0.140
0.050
0.078
Sensing capability
Analytical studies were carried out with diethylcyanophospho-
nate (DCNP) and diisopropylfluorophosphate (DFP) in acetoni-
trile (Scheme 7). Given the extreme toxicity of the nerve agents
sarin, soman, and tabun,[1a] the control compounds DCNP and
DFP were used as models for the design of indicators and
sensing systems. In general, these controls have similar reactiv-
ity but lack the acute toxicity. As a first step, studies were car-
ried out with 2 in acetonitrile solution (10À5 m). Typically, the
carbon tetra-
chloride
609
[a] Stokes shift. [b] Quantum yields were calculated using Rhodamine B in
ethanol (FEtOH =0.49) as a standard. MTHF=2-methyltetrahydrofuran.
band of a strong S0–S1 transition,
with the maximum ranging from
l=570 to 577 nm for 1 and
from l=608 to 617 nm for 2.
The (more- or less-pronounced)
shoulder on the high-energy
side of the main band is attribut-
ed to the 0–1 vibrational band
of the same transition. The S0–S1
transition of the BODIPY core
seems to possess some small
degree of charge-transfer charac-
ter due to the presence of the
Figure 3. Absorption (left) and fluorescence (right) spectra (lex =530 nm) recorded for 2 (10À5 m in CH3CN) alone
styryl group because the absorp-
tion maximum shows a slight and in the presence of DCNP or DFP.
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shift (from l=569 to 558 nm) of
the absorption band (a color
modulation from purple to pink;
see the Supporting Information).
There is also the accompanying
dramatic emission enhancement
and blueshift to l=575 nm with
increasing DCNP/DFP concentra-
tion. (Figure 5)
The color changes are as-
cribed to intramolecular N-alkyla-
tion to give a five-membered-
ring quaternary ammonium salt
in 1 and the corresponding mor-
pholino cation in 2 (Scheme 2).
The effect of this transformation
Scheme 7. Molecular formulae of the nerve agents and different organophosphorus derivatives.
is to switch off the electron-donating ability of the tertiary
amino group, thus leading to loss of the charge-transfer char-
acter. The observation of the weak BODIPY emission (F=0.014
and 0.002 for 1 and 2, respectively) before cyclization is strong
testament for such an intramolecular charge transfer from the
amino group. The revival of the vibronic-structured emission
band together with the emission enhancement (F=0.22 and
0.23 for 1 and 2, respectively, after recognition) is in good
accord with this hypothesis (Figure 6).
To evaluate the applicability of these BODIPY dyes for the
detection of nerve-agent simulants, the limits of detection
(LOD) were determined by using the equation: LOD=KꢃSb1/S,
where K=3, Sb1 is the standard deviation of the blank solu-
tion, and S is the slope of the calibration curve.[23] Both dyes
showed lower LOD values for DCNP than for DFP, which is in
agreement with the trend observed by using other chromo-re-
agents (Table 2).[10e,24] Compound 2 showed a somewhat lower
LOD than 1. This difference in the responses is ascribed to the
easier cyclization of the phosphorylated derivative of 1 relative
to the restricted conformation that occurs with 2. In dye 1, the
Figure 4. Visual changes observed for 2 in the presence of acid or DCNP;
under daylight (left) and irradiation conditions at l=254 nm (right).
addition of DCNP and DFP resulted in a blueshift (from l=608
to 560 nm) of the absorption band (a color modulation from
blue to pink, which is easily detected with the naked eye;
Figure 4) and a dramatic enhancement and blueshift for the
fluorescence, which now appears at l=570 nm.
Comparable behaviour was observed on the addition of
DCNP and DFP to solutions of 1 in acetonitrile; namely, a blue-
Figure 5. Absorption (left) and fluorescence (right) response (lex =530 nm) of 2 (10À5 m in CH3CN) to the successive addition of incremental amounts of DCNP
(inset spectra: amplification of the weak band at l=725 nm).
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Figure 6. Silica gel plate of 1 (10À3 m) (center) in the presence of acid (left)
and DCNP (right).
Figure 7. The polyethylene oxide membranes of 1 (top) and 2 (bottom) in
the absence and presence of DCNP (30 ppm) and HCl (50 ppm) vapors (from
left to right).
Table 2. Derived limit of detection (LOD) for dyes 1 and 2.
Probe
Simulant
LOD UV [ppm]
LOD Fluor. [ppm]
1
DCNP
DFP
DCNP
DFP
0.28
0.43
4.52
7.35
0.10
0.39
4.01
6.10
are well explained in terms of protonation at the terminal
amino group. It is notable that these same changes are not ob-
served in buffered media (see the Supporting Information). To
further confirm the crucial importance of the pyridine moiety
to avoid false readings, competitive studies were carried out.
For this purpose, DCNP and DFP were added to a solution con-
taining the dye in acidified media. In all cases, a clear color
change could be observed by the naked eye. The reactivity
with other organophosphorus compounds (Scheme 7) was
2
nucleophilic nitrogen atom and the phosphorylated hydroxy
group are connected by two aromatic carbon atoms in
a plane, which imposes a restricted conformation to the ethyl
chain that contains the phosphate group and promotes the in-
tramolecular cyclization.
Finally, the reactivity of 1 and
2 toward DCNP was studied in
different media (Table 3). A simi-
lar behavior was observed in all
cases; on the addition of DCNP,
a blueshift of the absorption
band (a color modulation from
purple to pink or blue to pink
for 1 and 2, respectively) and
a dramatic emission enhance-
ment was observed. (Figure 7)
Table 3. Photophysical properties of BODIPY dyes 1 and 2 in several solvents alone and in the presence of
DCNP.
Solvent
Compound
labs [nm]
lem [nm]
e [mÀ1 cmÀ1
]
F[a]
acetonitrile
1
569.4
558.6
607.5
565.5
573.0
562.0
611.3
568.9
573.0
561.5
609.5
571.0
575.0
563.0
607.5
569.3
577.0
566.0
616.0
570.0
574.5
565.0
609.0
568.4
570.4
560.4
609.0
569.5
575.0
575.0
616.0
568.9
668.2
577.0
675.5
569.5
637.0
576.0
651.0
570.1
657.4
577.8
663.3
570.4
640.8
576.0
655.5
578.3
638.2
576
30800
33000
62100
76500
36100
40700
57200
63400
33400
36540
34100
62800
32600
36800
16800
65900
35000
35300
50600
65300
36000
40100
35900
60100
30500
34000
59100
61500
0.014
0.218
0.002
0.231
0.189
0.403
0.068
0.374
0.280
0.399
0.075
0.392
0.250
0.437
0.073
0.405
0.062
0.387
0.05
0.398
0.321
0.402
0.078
0.381
0.016
0.210
0.002
0.284
1+DCNP
2
2+DCNP
1
1+DCNP
2
2+DCNP
1
1+DCNP
2
2+DCNP
1
1+DCNP
2
2+DCNP
1
1+DCNP
2
2+DCNP
1
1+DCNP
2
2+DCNP
1
1+DCNP
2
MTHF
dibutyl ether
1,4-dioxane
Competing reagents
As expected, the addition of pro-
tons to solutions of 1 and 2
(10À5 m) in CH3CN results in ex-
tinction of fluorescence from the
BODIPY unit, but without
marked changes in the corre-
sponding absorption spectra.
This behavior demonstrates that
protonation takes place on the
pyridine moiety because the ad-
dition of protons to the control
compound 3 induces a drastic
blueshift of its absorption band
and a dramatic enhancement of
the emission. These latter effects
toluene
carbon tetrachloride
water/acetonitrile (3:1)
642.8
572.8
575.3
576
618.5
570.6
2+DCNP
[a] Quantum yields were calculated using Rhodamine B in ethanol (FEtOH =0.49) as a standard.
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also studied under comparable conditions. However, it proved
impossible to detect any change in the absorption or fluores-
cence spectral profiles or intensities recorded for 1 and 2 (see
the Supporting Information). Such behaviour indicates that
there is no reaction between the fluorescent dye and these
particular phosphate derivatives (Table 4).
they are less prone to false readings in the presence of acids
because preferential protonation on the pyridine moiety pro-
tects the terminal aniline unit. In consequence, the sensing
mechanism is still working in the presence of acids, thus avoid-
ing a false negative response. In addition, the signaling abilities
are retained in the solid state, thus allowing the development
of simple colorimetric tests for the presence of nerve-agent
simulants in the gaseous and liquid phases. To the best of our
knowledge, the dyes reported herein are the first such probes
to display the necessary discrimination between nerve agents
and acidic residues.
Table 4. Photophysical properties recorded for the BODIPY dyes 1 and 2
alone and in the presence of both the nerve-agent simulant and acid.
Compound
labs [nm]
e [mÀ1 cmÀ1
]
lem [nm]
F[a]
1
569
559
559
569
608
565
565
608
30800
33000
32800
30800
62100
76500
61400
62100
575
575
575
610
616
567
569
725
0.014
0.218
0.197
6ꢃ10À6
0.002
0.231
0.230
8ꢃ10À6
1+DCNP
1+DFP
1+HCl
2
2+DCNP
2+DFP
2+HCl
Experimental Section
General remarks
CH2Cl2 and CH3CN were distilled from P2O5 under Ar prior to use.
Benzene was distilled from CaH2 under Ar prior to use. THF was
distilled from Na/benzophenone under Ar prior to use. All the
other solvents and starting materials were purchased from com-
mercial sources where available and were used without purifica-
tion. Silica gel 60 F254 (Merck) plates were used for TLC analysis.
Colum chromatography was performed on silica gel (60, 40–63 ꢄ).
1H and 13C NMR (300 MHz) spectra were determined on a Bruker
AV 300 spectrometrer. Chemical shifts are reported in parts per mil-
lion (ppm), calibrated to the solvent-peak set. High-resolution mass
spectra were recorded in the positive-ion mode on a VG-AutoSpec
mass spectrometer.
[a] Quantum yields were calculated using Rhodamine B in ethanol
(FEtOH =0.49) as a standard.
Development of a chemosensor kit
Having demonstrated the sensing capability of the new
BODIPY dyes, we decided to take a further step and extend
their applicability to real-time monitoring. Thus, two different
test strips for the colorimetric (and fluorescent) detection of
nerve-agent simulants in the gas phase were developed.
To this end, hydrophobic polyethylene oxide films and silica-
gel plates containing probes 1 and 2 were prepared. In a typi-
cal assay, the films or plates were placed into a container hold-
ing the nerve-agent simulant (30 ppm introduced as an aero-
sol). Alternatively, the strips were exposed to solutions contain-
ing DCNP, DFP, and/or acid in acetonitrile. A similar chromo-
genic behavior was noted in both the solution and the gas
phase; typically, this constitutes a color modulation from
purple to pink and an increase in fluorescence for the strips
containing probe 1. Similar behavior was noted with 2 in the
presence of DCNP and DFP. Critically, the strips remained fluo-
rescent. No change in strip color was observed in the presence
of acid.
Synthesis and characterization of BODIPY derivatives
2-[2-(Dimethylamino)phenyl]ethanol (5): A mixture of 2-(2-amino-
phenyl)ethanol (2 mL, 15.2 mmol) and K2CO3 (4.4 g, 32.4 mmol) in
CH3CN (60 mL) was stirred at room temperature for 40 min. Iodo-
methane (1.99 mL, 30.4 mmol) was added dropwise to the reaction
mixture, which was heated to reflux for 3 h. The suspension was fil-
tered, and the resulting solid was washed with CH3CN. The filtered
solution was concentrated under vacuo and re-dissolved in CH2Cl2.
The resulting solution was extracted with water, and the organic
layer was washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo to yield 5 (2.157 g, 86.3%) as a brown oil.
1H NMR (300 MHz, CDCl3): d=7.25–7.10 (m, 3H), 7.04 (m, 1H), 5.20
(t, J=2.0 Hz, 1H), 3.82 (m, 2H), 2.98 (t, J=6 Hz, 2H), 2.66 ppm (s,
6H); HRMS (EI): m/z (%) calcd for C10H16NO: 166.115 [M+1]+;
found: 166.232.
2-[5-Bromo-2-(dimethylamino)phenyl]ethanol (6): 2-[2-(Dimethy-
lamino)phenyl]ethanol (5) (1.05 g, 6.36 mmol) and NH4OAc (5.21 g,
6.74 mmol) were dissolved in CH3CN (50 mL). N-Bromosuccinimide
(1.2 g, 6.68 mmol) was added to the reaction mixture, which was
stirred at room temperature. After completion of the reaction, as
indicated by TLC analysis, the mixture was concentrated in vacuo
and extracted with CH2Cl2/H2O (1:1). The organic portion was sepa-
rated from the extract, dried, and concentrated to yield 6 (1.456 g,
Conclusion
We have report herein two BODIPY derivatives for the chromo-
and fluorogenic detection of nerve-agent simulants. The reac-
tion of 1 or 2 with DCNP or DFP results in phosphorylation of
a hydroxy group. In a second step, the reaction leads to an in-
tramolecular N-alkylation, thus giving a five-membered-ring
quaternary ammonium salt in 1 and the corresponding mor-
pholino cation in 2. These transformations are evidenced by
a significant blueshift for the lowest-energy absorption transi-
tion, which is easily detected by the naked eye. There is an ac-
companying escalation in the fluorescence yield, which is
made more remarkable by the shift from the far-red to the
blue region. A critical feature of these new reagents is that
1
94%) as a dark-orange oil. H NMR (300 MHz, CDCl3): d=7.28–7.19
(m, 2H), 6.97 (m, 1H), 3.79 (m, 2H), 2.90 (m, 2H), 2.59 ppm (s, 6H);
HRMS (EI): m/z (%) calcd for C10H15BrNO: 245.019 [M+1]+; found:
245.128.
4-(Dimethylamino)-3-(2-hydroxyethyl) benzaldehyde (7): A solu-
tion of bromide 6 (350 mg, 1.43 mmol) in anhydrous THF (10 mL)
was cooled to À788C under Ar. nBuLi (2 mL, 3.16 mmol) in hexane
(1.6m) was added dropwise with stirring to the reaction mixture,
which was then warmed to 08C. After stirring 30 min at this tem-
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perature, dry dimethylformamide (122 mL, 1.57 mmol) was added
at À788C. The resulting mixture was allowed to warm to room
temperature and stirred at room temperature for 3 h. Water was
added and the reaction mixture was extracted with CH2Cl2 and
water. The separated organic layer was dried over anhydrous
MgSO4, filtered, concentrated, and purified by column chromatog-
raphy on silica gel with ethyl acetate/hexane (1:1) as the eluent to
afford aldehyde 7 (258 mg, 93.4%) as a yellow oil. 1H NMR
(300 MHz, CDCl3): d=9.75 (s, 1H) 7.66–7.54 (m, 2H), 7.06 (t, J=
7.6 Hz,1H), 3.79 (t, J=6.4 Hz, 2H), 2.92 (m, J=6.4 Hz, 2H),
2.70 ppm (s, 6H); HRMS (EI): m/z (%) calcd for C11H16NO2: 194.110
[M+1]+; found: 194.242.
yellow solid. 1H NMR (300 MHz, CDCl3): d=9.57 (s, 1H) 7.50 (m,
4H), 7.07 (m, 2H), 6.42 (t, J=5.8 Hz, 2H), 4.08 (t, J=5.5 Hz, 2H),
3.54 (t, J=5.5 Hz, 2H) 2.79 (s, 3H), 2.20 ppm (s, 3H); HRMS (EI): m/z
calcd (%) for C17H20NO4S: 334.4212 [M+1]+; found: 334.2104.
4-{[2-(2-Hydroxyethoxy)ethyl](methyl)amino}benzaldehyde (9):
K2CO3 (332 mg, 2.4 mmol) was added to ethylene glycol (35 mL,
0.6 mmol) dissolved in dry CH3CN (30 mL). The white suspension
was heated to reflux for 1 h and then 8 (200 mg, 0.6 mmol) in dry
CH3CN (10 mL) was added dropwise over 60 min. Subsequently,
the reaction was heated to reflux for 16 h. The suspension was fil-
tered, and the solvent was removed by evaporation. The crude
product was purified by column chromatography on silica gel with
ethyl acetate/hexane (3:2 to 5:1) as the eluent to obtain aldehyde
9 (74.6 mg, 53%) as a yellow precipitate.1H NMR (300 MHz, CDCl3):
d=9.66 (s, 1H) 7.66 (m, 2H), 6.67 (m, 2H), 3.63 (m, 6H), 3.49 (m,
2H), 3.04 ppm (s, 3H); HRMS (EI): m/z (%) calcd for C12H18NO3:
224.2683 [M+1]+; found: 224.1208.
5,5-Difluoro-1,3,7,9-tetramethyl-10-(pyridin-4-yl)-5H-dipyrro-
lo[1,2-c:2’,1’-f][1,3,2]diazaborinin-4-ium-5-uide (4): 2,4-Dimethyl-
pirrole (2 mL, 19.42 mmol) and 4-pyridinecarboxaldehyde (0.9 mL,
9.24 mmol) were dissolved in anhydrous CH2Cl2 (150 mL). Trifluoro-
acetic acid (50 mL, 0.5 mmol) was added, and the solution was
stirred at room temperature for 50 min. A solution of DDQ (2.27 g,
9.24 mmol) in CH2Cl2 (8mL) was added. Stirring was continued for
50 min, followed by the addition of triethylamine (20 mL). After
stirring for 30 min, BF3·OEt2 (20 mL) was added to the reaction mix-
ture, which was stirred for 2 h at room temperature. After the
evaporation of the solvents under reduced pressure, the crude
product was purified by column chromatography on silica gel with
ethyl acetate/hexane (1:1) as the eluent to give the BODIPY deriva-
(E)-5,5-Difluoro-7-(4-{[2-(2-hydroxyethoxy)ethyl]-
(methyl)amino}styryl)-1,3,9-trimethyl-10-(pyridin-4-yl)-5H-dipyr-
rolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-4-ium-5-uide (2): BODIPY de-
rivative
4 (36.5 mg, 0,11 mmol) and aldehyde 9 (29.1 mg,
0.13 mmol) were dissolved in a mixture of benzene (16 mL), acetic
acid (317 mL), and piperidine (350 mL, 3.52 mmol). Any water
formed during the reaction was removed azeotropically by heating
in a Dean–Stark apparatus for 4 h. The reaction mixture was con-
centrated under reduced pressure and then subjected to column
chromatography on silica gel with ethyl acetate as the eluent to
yield the desired dye 2 (13.3 mg, 33%) as blue crystals. 1H NMR
(300 MHz, CDCl3): d=8.77 (dd, J=4.4, 1.5 Hz, 2H), 7.49 (m, 3H),
7.34 (dd, J=4.4, 1.6 Hz, 2H), 7.20 (s, 1H), 6.72 (d, J=8.7 Hz, 2H),
6.62 (s, 1H), 5.99 (s, 1H), 3.70 (m, 4H), 3.62 (m, 2H), 3.56 (m, 2H),
3.06 (s, 3H), 2.59 (s, 3H), 1.45 (s, 3H), 1.41 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=155.6, 153.5, 150.2, 149.8, 144.2, 142.3, 140.1,
138.6, 134.6, 132.1, 130.0, 129.6, 123.9, 120.9, 118.4, 113.8, 112.1,
72.5, 68.6, 61.8, 52.2, 42.5, 21.5, 14.3, 14.2 ppm; HRMS (EI): m/z (%)
calcd for C30H34BF2N4O2: 531.4227 [M+1]+; found: 531.2748; UV/
Vis (CH3CN) lmax =607.5; lem =642.9 nm.
1
tive 4 (1.15 g, 38%) as red crystals. H NMR (300 MHz, CDCl3): d=
8.71 (dd, J=4.3 and 1.6 Hz, 2H), 7.24 (dd, J=4.3 and 1.6 Hz, 2H),
5.94 (s, 2H), 2.49 (s, 6H), 1.34 ppm (s, 6H); 13C NMR (75 MHz,
CDCl3): d=157.1, 151.1, 144.0, 142.9, 138.1, 130.6, 123.7, 122.2,
15.1, 15.0 ppm; HRMS (EI): m/z calcd (%) for C18H19BF2N3: 326.1635
[M+1]+; found: 326.1641; UV/Vis (CH3CN): lmax =500.4, lem
=
510 nm.
(E)-7-[4-(Dimethylamino)-3-(2-hydroxyethyl)styryl]-5,5-difluoro-
1,3,9-trimethyl-10-(pyridin-4-yl)-5H-dipyrrolo[1,2-c:2’,1’-f]-
[1,3,2]diazaborinin-4-ium-5-uide (1): BODIPY derivative 4 (100 mg,
0.3 mmol) and aldehyde 7 (60 mg, 0.3 mmol) were dissolved in
a mixture of benzene (30 mL), acetic acid (862.5 mL), and piperidine
(950 mL, 9.6 mmol). Any water formed during the reaction was re-
moved azeotropically by heating in a Dean–Stark apparatus for
14 h. The reaction mixture was concentrated under reduced pres-
sure and then subjected to column chromatography on silica gel
with ethyl acetate/hexane (2:1) to yield the desired dye 1 (42 mg,
(E)-5,5-Difluoro-7-(4-{[2-(2-hydroxyethoxy)ethyl]-
(methyl)amino}styryl)-1,3,9-trimethyl-10-phenyl-5H-dipyrro-
lo[1,2-c:2’,1’-f][1,3,2]diazaborinin-4-ium-5-uide (3): 8-Phenyl-
1,3,5,7-tetramethyl-BODIPY (42.7 mg, 0.11 mmol) and aldehyde 9
(29.1 mg, 0.13 mmol) were dissolved in a mixture of benzene
(15 mL), acetic acid (315 mL), and piperidine (325 mL, 3.3 mmol).
Any water formed during the reaction was removed azeotropically
by heating in a Dean–Stark apparatus for 5 h. The reaction mixture
was concentrated under reduced pressure and then purified by
column chromatography on silica gel with ethyl acetate/hexane
(3:1) as the eluent to yield the desired dye 3 (6.4 mg, 11%) as blue
1
26.6%) as purple crystals. H NMR (300 MHz, CDCl3): d=8.73 (d, J=
4.8 Hz, 2H) 7.51 (d, J=15.8 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.32 (d,
J=2.0 Hz, 1H), 7.27 (dd, J=4.8, 1.6 Hz, 2H), 7.12 (dd, J=12.4,
6.7 Hz, 2H), 6.55 (s, 1H), 5.97 (s, 1H), 3.86–3.75 (m, 2H), 2.99 (dd,
J=9.9, 4.4 Hz, 2H), 2.69 (s, 6H), 2.54 (s, 3H), 1.39 (s, 3H), 1.36 ppm
(s, 3H); 13C NMR (75 MHz, CDCl3): d=155.5, 153.5, 150.3, 149.8,
144.0, 142.3, 139.8, 138.6, 134.5, 132.0, 129.9, 129.6, 123.9, 120.9,
118.4, 114.1, 112.1, 61.8, 47.5, 39.1, 21.5, 15.0, 14.5 ppm; HRMS (EI):
m/z (%) calcd for C29H31BF2N4O: 501.2912 [M+1]+; found:
501.2627; UV/Vis (CH3CN): lmax =569.4, lem =575 nm.
1
crystals. H NMR (300 MHz, CDCl3): d=7.43 (d, J=8.7 Hz, 3H), 7.40
(d, J=1.9 Hz, 2H), 7.28–7.21 (m, 3H), 7.16 (s, 1H), 6.63 (d, J=
8.9 Hz, 2H), 6.52 (s, 1H), 5.90 (s, 1H), 3.67–3.59 (m, 4H), 3.55 (d, J=
5.2 Hz, 2H), 3.52–3.47 (m, 2H), 3.02 (d, J=16.3 Hz, 3H), 2.52 (s, 3H),
1.94 (s, 3H), 1.35 (s, 3H), 1.31 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=156.55, 154.56, 151.28, 148.51, 145.21, 143.29, 141.10,
139.57, 135.38, 133.12, 130.55, 127.70, 124.92, 121.91, 119.37,
115.05, 113.05, 110.45, 109.42, 73.46, 69.57, 62.81, 53.22, 40.13,
22.46, 15.78, 15.13 ppm.
2-[(4-Formylphenyl)(methyl)amino]ethyl 4-methylbenzenesulfo-
nate (8):
A
solution of 4-[(2-hydroxyethyl)(methyl)amino]-
benzaldehyde (1 g, 5.6 mmol) and Et3N (1.15 mL, 7.3 mmol) in an-
hydrous CH2Cl2 (50 mL) was stirred for 10 min at room tempera-
ture. para-Toluenesulfonyl chloride (1.6 g, 8.4 mmol) was added to
the reaction mixture, which was stirred for 22 h. The reaction mix-
ture was extracted with a saturated solution of NaHCO3. The or-
ganic phase was dried over anhydrous MgSO4, filtered, and con-
centrated under reduced pressure and then subjected to column
chromatography on silica gel with ethyl acetate/hexane (1:1) as
the eluent to yield the desired product 8 (862 mg, 46%) as a pale-
Spectroscopic studies
All the solvents were purchased at spectroscopic grade from Al-
drich Chemicals Co., were used as received, and were free of fluo-
rescent impurities. The absorption and fluorescence spectra were
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recorded on a Hitachi U3310 spectrophotometer and a Hitachi
F4500 spectrofluorimeter, respectively. Fluorescence quantum
yields were measured at room temperature in N2-purgued solu-
tions of the corresponding solvent relative to Rhodamine B
(FEtOH =0.49)[25] at l=525 nm.
General procedure for determination of the limits of
detection
Increasing amounts of the corresponding simulant solutions (in
acetonitrile) were added to the corresponding receptor in acetoni-
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Membrane preparation
Polyethylene oxide (2 g, Mw =400000 Dalton) was slowly added to
a solution of 1 or 2 (2 mg) in dichloromethane (40 mL). The mix-
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mixture was poured into a glass plate (40 cm2) and kept in a dry
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Preparation of the silica gel plates
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solution of 1 or 2 in acetonitrile (10À3 m) and then dried in air.
Acknowledgements
We thank the Spanish Government (MAT2012–38429-C04–02)
for support. A.B.B. acknowledges the award of a predoctoral
FPI fellowship. SCSIE (Universidad de Valencia) is gratefully ac-
knowledged for all the equipment employed. Dr. S. Royo is
thanked for support with some of the synthetic chemistry.
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Keywords: boron · fluorescent probes · neurological agents ·
phosphorylation · sensors
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Received: November 15, 2013
Published online on && &&, 0000
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FULL PAPER
For all to see: Two new boron dipyrro-
methene (BODIPY) derivatives have
been synthesized and used as naked-
eye colorimetric and fluorescence
probes for the detection of nerve-agent
simulants (see picture; DCNP=diethyl-
cyanophosphonate, DFP=diisopropyl-
fluorophosphate). Selectivity to nerve-
agent simulants versus acidic media has
been achieved. Two portable chemosen-
sor kits have been used in real-time
monitoring.
&
Chemosensors
A. Barba-Bon, A. M. Costero,* S. Gil,
A. Harriman,* F. Sancenꢀn
&& – &&
Highly Selective Detection of Nerve-
Agent Simulants with BODIPY Dyes
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Chem. Eur. J. 2014, 20, 1 – 10
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ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!