Single Heteroatom Fine-Tuning of the Emissive Properties in Organoboron Complexes with 7-(Azaheteroaryl)indole Systems

Article abstract of DOI:10.1021/acs.joc.6b00265

The application of organoboron compounds as light-absorbing or light-emitting species in areas as relevant as organic electronics or biomedicine has motivated the search for new materials which contribute to the progress of those applications. This articl

Full text of DOI:10.1021/acs.joc.6b00265

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Article
Single heteroatom fine tuning of the emissive properties in
organoboron complexes with 7-(azaheteroaryl)indole systems.
Miriam Más-Montoya, Laura Usea, Arturo Espinosa Ferao, Maria Fernanda Montenegro, Carmen
Ramirez de Arellano, Alberto Tárraga, Jose Neptuno Rodriguez-Lopez, and David Curiel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00265 • Publication Date (Web): 18 Mar 2016
Downloaded from http://pubs.acs.org on March 19, 2016
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Single heteroatom fine tuning of the emissive properties in
organoboron complexes with 7ꢀ(azaheteroaryl)indole systems.
†
†
†
‡
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Miriam MásꢀMontoya, Laura Usea, Arturo Espinosa Ferao, María F. Montenegro, Carmen
§
†
‡
†
Ramírez de Arellano, Alberto Tárraga, José N. RodríguezꢀLópez and David Curiel. *
†
Department of Organic Chemistry, Faculty of Chemistry, University of Murcia, Campus of
Espinardo, Murcia 30100, Spain.
‡
Department of Biochemistry and Molecular Biology A, School of Biology, University of
Murcia, Campus of Espinardo, Murcia 30100, Spain.
§
Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, c/ Vicente
Andrés Estelles s7n, Burjassot 46100, Spain.
Eꢀmail: davidcc@um.es
ABSTRACT: The application of organoboron compounds as lightꢀabsorbing or lightꢀemitting
species in areas as relevant as organic electronics or biomedicine has motivated the search for
new materials which contribute to the progress of those applications. This article reports the
synthesis of fourꢀcoordinate boron complexes based on the unexplored 7ꢀ
(azaheteroaryl)indole ligands. An easy synthetic approach has enabled the fine tuning of the
electronic structure of the organoboron species by modifying a heteroaromatic component in
the conjugated system. Besides, a comprehensive characterization by Xꢀray diffraction,
absorption and emission spectroscopy, both in solution and in the solid state, cyclic
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voltammetry and computational methods have evidenced the utility of this simple strategy.
Large Stokes shifts have been achieved in solid thinꢀfilms which show a range of emitted light
from blue to orange. The synthesized compounds have been used as biocompatible
fluorophores in cell bioimaging.
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INTRODUCTION
Organoboron complexes have become very useful chromophores and fluorophores due
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to their applicability in relevant areas as electroluminescent devices, lasers, organic
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photovoltaics, bioimaging, biomedicine or sensing. Due to the interest in exploring
new materials which adapt to the requirements of these and other applications, organic
chemistry has enormously contributed to the development of innovative synthetic
ligands and their boron complexes. The Bodipy structure represents one of the most
attractive fourꢀcoordinate boron skeletons whose physical and chemical properties
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have been thoroughly studied. Nevertheless, the search for alternative bidentate
ligands that combine a wide variety of CꢀC, NꢀC, NꢀN, NꢀO or OꢀO sites for the
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coordination of boron has rendered excellent results. One of the main objectives in the
design of these ligands aims at the achievement of tunable electronic properties
through simple synthetic approaches. In this regard, the rich chemistry of indoleꢀbased
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compounds becomes an optimum testꢀbench which, with a few exceptions, still
remains unexplored in the context of organoboron species.
Herein we report the synthesis and comprehensive study of the luminescent properties
of a family of novel 7ꢀ(azaheteroaryl)indole ligands and their corresponding fourꢀ
coordinate boron complexes. The strategy to accomplish a fine modulation of the
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electronic structure of the πꢀconjugated system consists on modifying the electronic
effects from structurally related heteroaromatic units such as benzoxazole,
benzothiazole, benzimidazole or pyridine.
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RESULTS AND DISCUSSION
The synthesis of the ligands and complexes was carried out as depicted in Scheme 1.
Scheme 1. Synthetic route to ligands and organoboron complexes.
Among the variety of synthetic methods for the preparation of indole derivatives, the Bartoli
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synthesis is especially useful to access 7ꢀsubstituted indoles. In this regard, using oꢀ
nitrobenzaldehyde and either oꢀaminophenol, oꢀaminothiophenol or oꢀphenylenediamine as
starting materials, led to the isolation of 2ꢀ(2ꢀnitrophenyl)benzoxazole, 2, 2ꢀ(2ꢀ
nitrophenyl)benzothiazole, 3, or 2ꢀ(2ꢀnitrophenyl)benzimidazole, 4, respectively. An alkyl
chain was attached to compound 4 to produce the Nꢀoctylbenzimidazole, 5, prior to the indole
synthesis. Finally, the Bartoli reaction between vinylmagnesium bromide and the nitro group
in 2, 3 and 5 yielded the corresponding 7ꢀ(azaheteroaryl)indoles 6, 7 and 8. Additionally, 7ꢀ
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pyridꢀ2ꢀyl)indole, 9, was synthesized according to reported methods. The boron complexes,
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0, 11, 12 and 13 were obtained by refluxing the indoleꢀbased ligands with triphenylborane in
toluene solution. The full structural characterization of all the intermediate and final products
was carried out by NMR spectroscopy and HRMS.
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All the organoboron complexes showed a high thermal stability. The thermogravimetric
analysis did not evidence any significant mass loss below the range 260ꢀ310 ºC for the
compounds 10ꢀ13 (Figure S16).
The solid state structure of some of the novel boron complexes, 10 and 12, could be
determined by single crystal Xꢀray diffraction (Figure S13). The differences observed in the
solid state indicate the distinction in the electron donor ability of the heteroaromatic
substructures and show the adequacy of our molecular design to modulate the electronic
properties of the boron complexes.
Regarding the absorption spectroscopy, all the ligands showed two sets of bands within the
ranges 235ꢀ245 nm and 325ꢀ350 nm, ascribed to πꢀπ* transitions (Figure 1A). The lower
energy band in acetonitrile solution follows the trend 8 (317 nm) < 9 (323 nm) < 6 (345 nm)
<
7 (354 nm), which falls below the lower limit of the visible radiation. Formation of the
boron complexes causes a remarkable red shift of the absorption bands. These reach the
visible range 12 (393 nm) < 13 (409 nm) < 10 (413 nm) < 11 (440 nm), and the complexes
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0ꢀ13 become colored (Figure 1B). The electronic effects resulting upon coordination of the
boron atom and the planarization of the πꢀconjugated ligand entail a narrowing of the energy
gap between the ground state and the first singlet excited state. Apart from the mentioned
band shift, the profile of the absorption spectra is very similar for the ligands and the boron
complexes which reveals that the absorption bands are ligandꢀcentered. At this point, it is
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worth noticing how a minor alteration in the structure of the heteroaromatic ligand, enables a
fine tuning of the electronic properties in the synthesized boron complexes.
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Figure 1. Absorption (dashed plot) and emission spectra (continuous plot) of ligands (A) and
ꢀ5
complexes (B) in CH CN (2x10 M). 6&10, grey; 7&11, orange; 8&12, blue; 9&13, green.
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As far as the emission spectra are concerned, the ligands again reveal the effect of the
heteroarene on the emission wavelength (Figure 1A). As expected, the fluorescence of the
boron complexes is displaced towards longer wavelengths (460ꢀ530 nm). Whereas the ligands
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ꢀ9 show a very weak emission, the corresponding boron complexes 10ꢀ13 display a
perceptible quantum yield enhancement, reaching a value of 44% in the case of the
benzimidazole derivative 12 (Table 1). It is likely that the increase in the rigidity of the boron
complex structure contributes to favor the radiative decay from the excited state. In this
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regard, the lifetime of the first excited state could be determined by fitting the TCSPC (Time
Correlated Single Photon Counting) decay to a monoexponential model. Longer lifetimes are
measured for the complexes with the benzoazaheteroaromatic systems 10ꢀ12 than pyridine 13
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(Table 1). Another property, which could spark interest in the applicability of the synthesized
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complexes as luminescent materials, is the moderate to large Stokes shifts detected, reaching
a value of 110 nm for compound 13.
Table 1. Optical and electrochemical characterization.
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10
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12
13
345
354
317
323
413
440
393
409
λmax. abs. [nm] (ε)
Optical gap [eV]
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(
12·10 ) (19·10 ) (11·10 ) (13·10 ) (11·10 ) (7.5·10 ) (12·10 ) (8·10 )
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393
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409
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370
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383
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490
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527
2.65
461
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519
a
λem. [nm]
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(0.057) (0.002) (0.160) (0.002) (0.33) (0.19) (0.44) (0.12)
(Ф)
c
τ (ns)
Epa [mV]
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1367
11.29
1271
8.80
1.20
d
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1469
1266
1224
1199
1162
(
1210) (1215) (1110) (1055) (1220) (1150) (1090) (1060)
ꢀ2.15 ꢀ2.28 ꢀ2.10 ꢀ1.96 ꢀ2.92 ꢀ3.05 ꢀ2.78 ꢀ2.77
(ꢀ1.70) (ꢀ1.82) (ꢀ1.38) (ꢀ1.47) (ꢀ2.26) (ꢀ2.41) (ꢀ1.92) (ꢀ2.25)
ꢀ5.55 ꢀ5.56 ꢀ5.45 ꢀ5.40 ꢀ5.56 ꢀ5.49 ꢀ5.43 ꢀ5.40
(Eonset) [mV]
e
LUMO [eV]
g
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theo) [eV]
f
HOMO [eV]
g
(theo) [eV]
(ꢀ5.76) (ꢀ5.71) (ꢀ5.59) (ꢀ5.53) (ꢀ5.67) (ꢀ5.59) (ꢀ5.51) (ꢀ5.46)
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a
λexc (6)= 290 nm; λexc (7)= 240 nm; λexc (8)= 270 nm; λexc (9)= 280 nm; λexc (10)= 380 nm; λexc
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(11)= 410 nm; λexc (12)= 360 nm; λexc (13)= 370 nm; Quantum yield determined in ethanol
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solution at room temperature using anthracene as reference; Excited state lifetime; Anodic
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e
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peak potential; ELUMO= E
+ Optical gap; Calculated as EHOMO= ꢀ(4.34 + Eox onset);
HOMO
HOMO and LUMO energies determined by DFT.
Additionally, the solvent effect on the optical properties of the boron complexes was studied
in toluene, dichloromethane, ethanol and acetonitrile (Figure S17). In general, all the
compounds exhibited a subtle hypsochromic shift in their absorption bands upon increasing
the solvent polarity. Conversely, the fluorescence spectra turned out to be much less sensitive
to the solvent polarity with only a minor bathochromic shift being observed for compounds
10, 11 and 13. Accordingly, LippertꢀMataga plots revealed that compounds 10ꢀ13 have a very
similar dipole moment both in the ground state and in the first singlet excited state (Figure
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S18; Table S3). Thus, the measured Stokes shifts are ascribed to a structural reorganization
in the excited state which does not necessarily imply a significant change in the dipole
moment of the molecule.
With the aim of getting a better understanding about the electronic structure of the ligands and
the boron complexes, their electrochemical characterization was also carried out. Cyclic
voltammetry performed with compounds 6ꢀ9 displayed oneꢀelectron irreversible waves for all
of them (Figure 2).
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Figure 2. Cyclic voltammetry of the ligands (dashed plot) and the boron complexes
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continuous plot) in CH Cl (10 M), TBAPF (0.1 M), T=25ºC, scan rate: 100 mV/s,
2 2 6
reference electrode: SCE, working electrode: Pt. 6&10, grey; 7&11, orange; 8&12, blue;
9&13, green.
As it could be inferred from the comparison with the electrochemistry of plain indole, the
redox process detected by cyclic voltammetry corresponded to the oxidation of the indole
fragment in the structure of the ligand. Regarding the observed trend for the anodic peak
potentials, 9 (1224 mV) < 8 (1266 mV) < indole (1342 mV) < 6 (1406 mV) < 7 (1469 mV), it
evidenced the electron releasing effect of the pyridine and the Nꢀoctylbenzimidazole attached
to the indole system. Conversely, the benzoxazole and benzothiazole exerted an electron
withdrawing effect over the indole system that consequently oxidized at higher potentials. As
far as the cyclic voltammetry of the boron complexes 10ꢀ13 is concerned, an irreversible
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behavior was also observed and they maintained the previously discussed trend in their
potentials but with a slight cathodic shift. Anyhow, by correlating the onset value of the
oxidation wave with the energy of the HOMO it can be concluded that the energies
determined for the ligands 6ꢀ9 and the corresponding complexes 10ꢀ13 are almost identical
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(
Table 1). Approximating the HOMOꢀLUMO energy gap from the low energy onset in the
absorption spectrum, the LUMO energy can be indirectly estimated by using the
electrochemically measured HOMO energy. Accordingly, a much lower LUMO is obtained
for the complexes 10ꢀ13 than the ligands 6ꢀ9. Therefore, it can be concluded that
complexation of the diphenylboron fragment mainly causes a stabilization of the LUMO,
leaving the HOMO virtually unaffected.
The characterization of the compounds was further explored by computational methods, using
DFT (Density Functional Theory) calculations. Regarding the orbital distribution (Figures 3
and S19), in the case of the ligands, although the HOMO is located over the whole conjugated
system, a major contribution from the indole component is detected. Upon boron
complexation, the location of the HOMO on the indole fragment is even more significant.
These results are in good agreement with the previous discussion about the electrochemical
oxidation being centered on the indole system. Besides, an antibonding interaction is
detected between the nitrogen πꢀorbitals in the ligand and the BꢀCphenyl σꢀbonds. This
weak interaction becomes manifest in a minor increase of the HOMO energy of the
boron complexes when compared to the DFT results of the corresponding ligands
(Figure S19). Consequently, the subtly higher HOMO correlates well with the slight
cathodic shift previously discussed. In any case, the DFT calculations confirmed a
good consistency of the HOMO energies within the series 6ꢀ13. Differently, the LUMO
is distributed all over the conjugated system (Figures 3 and S19), with a lower contribution
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from the five membered ring in the indole fragment. Considering the important contribution
of the 7ꢀazaheteroaryl component to the LUMO, the coordination of the boron atom by the
nitrogen in the heteroaromatic component will result in a stabilization of the LUMO energy,
as it has been experimentally observed.
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Besides, TDꢀDFT (Time DependentꢀDFT) calculations were also employed to confirm the
identity of the electronic transitions in the absorption spectra (Table S4). Accordingly, the
general behavior for the series of boron complexes could be exemplified by the results
obtained for the compound 10. The calculations show a predicted absorption spectrum
coincident with the experimental result. Three bands at 429 nm, 369 nm and 286 nm are
ascribed to the transitions between the energy states S →S , S →S and S →S respectively.
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In turn, the molecular orbital contribution to these transitions confirm the πꢀπ* identity
previously mentioned.
Figure 3. HOMO and LUMO energies (experimental: columns; theoretical: black dashes) and
DFT isosurfaces exemplified for compounds 6 and 10.
Due to the potential utility of the novel boron complexes as chromophores or fluorophores to
be applied as materials in their solid state, the absorption and emission spectra were also
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studied for thin films prepared by spinꢀcoating on quartz substrates (Film thickness: 30ꢀ80
nm). As it can be observed in Figure S19 the absorption spectra are well overlapped with
those obtained in solution, which implies that identical energy states are involved in the
transitions. A slight red shift is more clearly detected for the complexes 9 and 10, presumably
due to intermolecular interactions in the solid state. Interestingly, when thin films are
analyzed by emission spectroscopy the spectral shift towards longer wavelengths is more
significant. In agreement with these results, the technically appealing property of achieving
long Stokes shifts is considerably enhanced for the samples in the solid state, with compounds
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0, 11 and 13 showing values as large as 122 nm, 125 nm and 129 nm, respectively. This
larger energy shift even leads to a change in the color of the emitted light by the solid thinꢀ
film when compared to the color of the fluorescence in solution (Figure 4). The range of
colors covered by the solid emission are: 10, orange, 11, yellowꢀgreenish, 12, blue and 13
green, which emphasizes the utility of the reported approach to achieve a fine tuning of the
emissive properties of fourꢀcoordinated boron complexes. Additionally, a remarkable
quantum yield enhancement was obtained for the thinꢀfilms upon excitation at 360 nm: 10
(0.45), 11 (0.33), 12 (0.69) and 13 (0.23). These results also reinforce the potential
applicability of some of these organoboron complexes as solid state lightꢀemitters.
Figure 4. Fluorescence of boron complexes 10ꢀ13 in solution and thin films.
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Besides, regarding the possible uses of these fluorophores and due to the relevant role
that biocompatible organic dyes play in cell imaging, the boron complexes were
studied in bioimaging experiments (Figure 5).
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Figure 5. Confocal microscopy images (A: λ = 488 nm; B: λ = 561 nm) of human
exc
exc
breast cancer cells MCF7 with fluorophore 11
.
They permeated well into human breast cancer cells MCF7 (uptake time < 2h) and,
excepting compound 12, they displayed low cytotoxicity (Figure S21). Cellular
staining was studied by confocal microscopy at different excitation wavelengths. The
images demonstrated that the delivered exogenous compounds are predominantly
located in the perinuclear area, probably associated to endocytic vesicles.
CONCLUSION
In summary, a new series of organoboron complexes has been obtained via a simple
synthetic route of 7ꢀazaheteroarylindole ligands. A fine modulation of the electronic
structure has been achieved by modifying one heteroatom in the structure of the ligand
which subsequently enabled the emission of fluorescence with a range of different
colors. Large Stokes shifts have been detected in solution but more importantly in the
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solid state, reinforcing the interest of the organoboron species as emissive materials.
The fluorescent properties of the fourꢀcoordinate boron complexes have proved to be
useful in human breast cancer cell bioimaging.
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EXPERIMENTAL SECTION
General Methods. Reagents used as starting materials were purchased from commercial
sources and were used without further purification. Solvents were dried following the usual
protocols (THF, Et O and Toluene were distilled from sodium wire with benzophenone
2
indicator; CH CN and CH Cl were distilled from CaCl ; EtOH and MeOH were distilled
3
2
2
2
from magnesium and stored with molecular sieves). Unless stated otherwise, all reactions
were carried out under nitrogen atmosphere. Column chromatography was run with silica gel
60 A CC 70ꢀ200 ꢁm as stationary phase, using HPLC grade solvents. Melting points are not
1
corrected. Unless stated otherwise, all spectra were recorded at room temperature. HꢀNMR
1
3
and CꢀNMR spectra were recorded on spectrometers having frequencies of 200MHz,
300MHz or 400MHz, for proton nuclei and 50 MHz, 75 MHz or 100MHz, respectively, for
carbon nuclei. Chemical shifts are referred to the residual peak from the deuterated solvent.
Mass spectrometry was recorded on HPLCꢀMS TOF instrument. Thermogravimetric analysis
was carried out at a heating rate of 10 ºC/min under nitrogen. Absorption spectra were
recorded on a UVꢀvisꢀNIR spectrophotometer equipped with a Tungsten halogen visible
source with quartz window and a deuterium arc UV source. A Hg lamp module was used as
standard for automatic wavelength accuracy validation. Emission spectra were recorded on a
fluorescence spectrophotometer with a Xe lamp as an excitation source. TCSPC experiments
were carried out in a spectrophotometer, with a pulsed nanoLED (λ = 372 nm), double slit
exc.
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monochromator and photomultiplier TBXꢀ04. The thinꢀfilm thicknesses were measured with a
profilometer. Solid state quantum yields were measured at room temperature, using a xenon
light source (150 W) and an integrating sphere (3.3 inches). Electrochemistry was recorded
using platinum electrodes as working and counterꢀelectrode and Ag/AgCl or SCE as reference
electrode. Decamethylferrocene or ferrocene were used as internal reference. Quantum
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chemical calculations were performed with the ORCA electronic structure program package.
All geometry optimizations were run in redundant internal coordinates with tight convergence
criteria, using the B3LYP functional together with the new efficient RIJCOSX algorithm and
the def2ꢀTZVP basis set. Solvent effects (CH Cl ) were taken into account via the COSMO
2
2
solvation model. From these geometries all reported data were obtained by means of singleꢀ
point (SP) calculations using the same functional and the more polarizeddef2ꢀTZVPP basis
set. Reported energies are uncorrected for the zeroꢀpoint vibrational term. A semiempirical
correction accounting for the major part of the contribution of dispersion forces to the energy
was included.
X-ray structure determination: Compound 10: crystals suitable for Xꢀray experiments were
ꢀ
obtained by evaporation from CHCl , C H BN O, M = 398.25, triclinic, P1, a = 10.4924(4),
3
27 19
2
b = 10.6628(4), c = 18.4160(4) Å, a = 74.5955(19)º, b = 84.469(2)º, g = 89.0236(13)º, U =
3
1
977.01(12) Å , T = 120(1) K, Z = 4, 11869 reflections measured, 8520 unique (R
=
int
0.0371), hydrogen atoms refined as riding, two independent molecules in the asymmetric unit,
R1 (I > 2s(I)) = 0.0547 and wR2 (all data) = 0.1396. Compound 12: single crystals suitable
for Xꢀray experiments were obtained by reꢀcrystallization from CHCl /pentane. C H BN ,
3
35 36
3
M = 509.48, orthorhombic, Pbca, a = 12.742(3), b = 14.710(3), c = 29.880(6) Å, U =
3
5
600.9(19) Å , T = 120(1) K, Z = 8, 16954 reflections measured, 4947 unique (R = 0.1764).
int
Methyl hydrogen atoms refined as rigid, others riding. Despite the low ratio observed/unique
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reflections the structure refined to a CꢀC bond precision of 0.0087 Å, with R1 (I > 2s(I)) =
0
.1087 and wR2 (all data)
=
0.3150. CCDCꢀ1449799 and CCDCꢀ1449800
(www.ccdc.cam.ac.uk/data_request/cif).
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Cell cultures and apoptosis assays: The human cancer cell line MCF7 was obtained from the
American Type Culture Collection (ATCC) and were maintained in appropriate culture media
supplemented with 10% fetal calf serum and antibiotics under standard tissue culture
conditions. Cell viability was evaluated by a colorimetric assay for mitochondrial function
using the 3ꢀ(4,5ꢀdimethylthiazolꢀ2ꢀyl)ꢀ2,5ꢀdiphenyltetrazolium bromide cell proliferation
assay. For this assay, cells were plated in a 96ꢀwell plate at a density of 1000–2000 cells per
well. Compounds were added once at the beginning of each experiment. The Hoechst staining
5
method was used to detect apoptosis. Replicate cultures of 1 × 10 cells per well were plated
in 6ꢀwell plates. The cells were subjected to the specified treatments for 72 hr. After
exchanging the medium for fresh medium, the cells were incubated with 5 ꢁL of Hoechst
33342 solution per well at 37°C for 10 min and then observed under a fluorescence
microscope. Strong fluorescence was observed in the nuclei of apoptotic cells, while weak
fluorescence was observed in nonꢀapoptotic cells. Quantification of the apoptotic cells was
performed by counting the cells in four random fields in each well.
Microscopy: The imaging of organoboron compounds in live cells was performed using a
confocal microscope. Images were collected following specific laser excitation and
appropriated emission filters. Before live confocal microscopy, the cells were incubated in
serum free Dulbecco’s modified Eagle’s medium (DMEM) for 1 hour with organoboron
compounds. After this time, the cells were extensively washed with DMEM. During imaging,
the cells were incubated on a heated stage at 37°C in DMEM. Images were processed with
different software packages.
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ꢀ[(2ꢀNitrobenzylidene)amino]phenol, 1: A solution of 2ꢀnitrobenzaldehyde (1 g, 9.16
mmol), 2ꢀaminophenol (1.38 g, 9.16 mmol) and P O (0.13 g, 10 mol%) in methanol (50 mL)
2
5
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under nitrogen atmosphere was refluxed for 48 hours. Once the reaction was concluded, the
crude was cooled to room temperature and the solvent was evaporated under vacuum. Then,
the crude was dissolved in ethyl acetate, washed with water, dried over anhydrous Na SO and
2
4
concentrated by rotary evaporation. The resulting residue was treated with diethyl ether to
1
obtain 1 as a yellow solid (1.65 g, 80%). M.p.: 95ꢀ98 ◦C. HꢀNMR (400 MHz, CDCl ) δ 6.94ꢀ
3
6
.97 (m, 1H), 7.03 (dd, J =4 Hz, J =1.2 Hz, 1H), 7.14 (s, 1H), 7.24ꢀ7.28 (m, 1H), 7.34ꢀ7.37
1 2
(m, 1H), 7.62ꢀ7.66 (m, 1H), 7.73ꢀ7.77 (m, 1H), 8.06ꢀ8.08 (m, 1H), 8.25ꢀ8.28 (m, 1H), 9.17 (s,
1
3
1H). CꢀNMR (50 MHz, CDCl ) δ 115.4, 116.3, 120.3, 124.6, 129.5, 130.2, 130.5, 131.4,
3
+
1
33.4, 134.6, 149.3, 152.0, 152.7. HRMS (ESIꢀTOF) m/z: [M+H] Calcd for C H N O
1
3
10
2
3
2
43.0764; Found: 243.0772.
ꢀ(2ꢀNitrophenyl)benzoxazole, 2: Ag O (1.48 g, 6.40 mmol) was added over a solution of 2ꢀ
2
2
[
(2ꢀnitrobenzylidene]amino)phenol, 1, (0.5 g, 2.07 mmol) in dichloromethane and the
resulting mixture was refluxed for 24 hours. Then, the reaction mixture was allowed to cool
down, the excess of Ag O was removed by filtration and the solvent was evaporated under
2
reduced pressure. The crude was subject to silica gel column chromatography eluting with
ethyl acetate:nꢀhexane (1:1) to afford the pure title compound (0.31 g, 62%) as a yellow solid.
1
R : 0.61. M.p.: 99ꢀ102 ◦C. HꢀNMR (300 MHz, CDCl ) δ 7.39ꢀ7.42 (m, 2H), 7.57ꢀ7.60 (m,
f
3
1H), 7.67ꢀ7.78 (m, 2H), 7.81ꢀ7.84 (m, 1H), 7.90 (dd, J = 7.8 Hz, J =1.5 Hz, 1H), 8.15 (dd,
1
2
1
3
J = 7.2 Hz, J =1.8 Hz, 1H). CꢀNMR (75 MHz, CDCl ) δ 110.9, 120.7, 121.4, 124.2, 124.9,
1
2
3
+
1
26.0, 131.4, 131.8, 132,3, 141.5, 149.2, 151.0, 158.8. HRMS (ESIꢀTOF) m/z: [M+H] Calcd
for C H N O 241.0608; Found: 241.0615.
1
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ꢀ(2ꢀNitrophenyl)benzothiazole, 3: Over a solution of 2ꢀnitrobenzaldehyde (1.21 g, 7.99
mmol) in methanol, 2ꢀaminothiophenol (1 g, 7.99 mmol) and P O (113.4 mg, 10 mol%) were
2
5
successively added. The resulting mixture was refluxed for 48 hours. Once the reaction was
concluded, the crude was cooled to room temperature and the solvent was evaporated under
vacuum. Then, the residue was dissolved in ethyl acetate, washed with water, dried over
anhydrous Na SO and concentrated by rotary evaporation. The resulting crude was purified
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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28
29
30
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60
2
4
by silica gel column chromatography using dichloromethane:hexane (1:1) as eluent to afford
1
the pure expected compound as a yellow solid (0.5 g, 30%). R : 0.35. M.p.: 120ꢀ122 ◦C. Hꢀ
f
NMR (300 MHz,CDCl ) δ 7.43ꢀ7.46 (m, 1H), 7.48ꢀ7.56 (m, 1H), 7.64 (td, J =7.8 Hz, J =1.8
3
1
2
Hz, 1H), 7.71 (td, J =7.5 Hz, J =1.5 Hz, 1H), 7.79ꢀ7.82 (m, 1H), 7.92ꢀ7.96 (m, 2H), 8.07ꢀ8.10
1
2
13
(m, 1H). CꢀNMR (50 MHz, CDCl ) δ 121.5, 123.9, 124.5, 125.8, 126.5, 128.1, 130.9, 131.8,
3
+
1
2
32.3, 135.8, 148.9, 153.5, 162.3. HRMS (ESIꢀTOF) m/z: [M+H] Calcd for C H N O S
1
3
8
2
2
57.0379; Found: 257.0390.
ꢀ(2ꢀNitrophenyl)benzimidazole, 4: oꢀPhenylenediamine (1.09 g, 10.0 mmol) was added
2
over a solution of 2ꢀnitrobenzaldehyde (1 g, 6.62 mmol) in dimethylformamide (50 mL) and
the resulting mixture was stirred at 120 ◦C under nitrogen atmosphere for 14 hours. The
reaction was cooled to room temperature and the solvent was removed under reduced
pressure. The resulting crude was treated with diethyl ether to obtain a pale brown precipitate
1
which corresponds to the pure title compound (1 g, 63%). M.p.: 259ꢀ262 ◦C. HꢀNMR (400
MHz, DMSOꢀd ) δ 7.24 (bs, 2H), 7.58 (bs, 1H), 7.64 (bs, 1H), 7.73ꢀ7.77 (m, 1H), 7.84ꢀ7.88
6
13
(m, 1H), 7.97 (d, J=8 Hz, 1H), 8.02 (d, J=8 Hz, 1H), 13.05 (s, 1H). CꢀNMR (75 MHz,
DMSOꢀd ) δ 121.7, 129.3, 131.9, 133.1, 134.3, 140.9, 141.0, 142.6, 144.7, 153.6, 157.4,
6
+
1
59.0.HRMS (ESIꢀTOF) m/z: [M+H] Calcd for C H N O 240.0768; Found: 240.0772.
1
3
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2
ꢀ(2ꢀNitrophenyl)ꢀ1ꢀoctylbenzimidazole,
5:
Over
a
solution
of
2ꢀ(2ꢀ
nitrophenyl)benzimidazole, 4, (2 g, 8.36 mmol) in dimethylformamide (30 mL) at room
temperature, potassium hydroxide (1.41 g, 25.08 mmol) and 1ꢀbromooctane (8.08 g, 41.8
mmol) were sequentially added. The resulting mixture was stirred at 100 ◦C for 10 hours.
After cooling at room temperature, the solvent was removed by rotary evaporation and the
0
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8
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7
8
9
0
resulting residue was purified by column chromatography on silica gel eluting with ethyl
1
acetate:hexane (2:1) to obtain 5 (2.11 g, 72%) as a yellow oil. R : 0.62. HꢀNMR (300 MHz,
f
DMSOꢀd ) δ 0.79 (t, J=6.9 Hz, 3H), 1.09ꢀ1.19 (m, 10H), 1.62 (quint, J=7.2 Hz, 2H), 4.14 (t,
6
J=7.5 Hz, 2H), 7.22ꢀ7.27 (m, 1H), 7.29ꢀ7.35 (m, 1H), 7.64 (d, J=6.3 Hz, 1H), 7.68 (d, J=7.8
1
3
Hz, 1H), 7.85ꢀ7.93 (m, 3H), 8.21ꢀ8.25 (m, 1H). CꢀNMR (75 MHz, DMSOꢀd ) δ 13.9, 21.9,
6
25.8, 28.2, 28.3, 28.8, 31.0, 43.7, 110.9, 119.3, 121.9, 122.7, 124.8, 125.1, 131.4, 132.1,
+
1
33.6, 135.0, 142.5, 148.6, 149.0. HRMS (ESIꢀTOF) m/z: [M+H] Calcd for C H N O
2
1
25
3
2
3
52.2020; Found: 352.2025.
ꢀ(Indolꢀ7ꢀyl)benzoxazole, 6: Vinylmagnesium bromide (18 mL, 12.5 mmol) was added
2
dropwise over a solution of 2 (1.5 g, 6.25 mmol) in dry THF (50 mL) at ꢀ50 ◦C under nitrogen
atmosphere. The reaction mixture was stirred at this temperature for 48 hours. Then, a
saturated aqueous solution of NH Cl (50 mL) was added and the crude was allowed to reach
4
room temperature. The solvent was evaporated by rotary evaporation and the reaction crude
was extracted with diethyl ether (3x70 mL). The combined organic layers were washed with a
saturated aqueous solution of NH Cl (100 mL), water (100 mL), and brine (100 mL), dried
4
over anhydrous Na SO and the solvent was evaporated under reduced pressure. The crude
2
4
was purified by silica gel column chromatography eluting with dichloromethane:hexane (1:1)
1
to obtain 6 (450 mg, 30%) as a yellow solid. R : 0.77. M.p.: 140ꢀ142 ◦C. HꢀNMR (300 MHz,
f
CDCl ) δ 6.65ꢀ6.67 (m, 1H), 7.23ꢀ7.29 (m, 2H), 7.35ꢀ7.38 (m, 2H), 7.42ꢀ7.43 (m, 1H), 7.61ꢀ
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1
.64 (m, 1H), 7.77ꢀ7.80 (m, 1H), 7.85 (dd, J =7.8 Hz, J =0.6 Hz, 1H), 8.04ꢀ8.06 (m, 1H),
1
2
13
0.73 (s, 1H). CꢀNMR (75 MHz, CDCl ) δ 102.8, 109.8, 110.6, 119.5, 121.2, 124.5, 124.8,
3
+
124.9, 125.3, 128.7, 134.0, 142.1, 150.0, 162.6. HRMS (ESIꢀTOF) m/z: [M+H] Calcd for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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43
44
45
46
47
48
49
50
51
52
53
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C H N O 235.0866; Found: 235.0874.
15
10
2
2ꢀ(Indolꢀ7ꢀyl)benzothiazole, 7: A solution of 2ꢀ(2ꢀnitrophenyl)benzothiazole, 3, (1.5 g, 6
mmol) in dry THF (50 mL) was cooled to ꢀ50 ◦C under nitrogen atmosphere. At this
temperature, vinylmagnesium bromide (17 mL, 12 mmol) was added dropwise and the
resulting mixture was stirred for 48 hours. The evolution of the reaction was followed by thin
layer chromatography and once completed, a saturated aqueous solution of NH Cl (50 mL)
4
was added and the crude was allowed to reach room temperature. The solvent was evaporated
by rotary evaporation and the reaction crude was extracted with diethyl ether (3x70 mL). The
combined organic layers were washed with a saturated aqueous solution of NH Cl (100 mL),
4
water (100 mL), and brine (100 mL), dried over anhydrous Na SO and the solvent was
2
4
evaporated under reduced pressure. The crude was purified by silica gel column
chromatography eluting with dichloromethane:hexane (1:3) to isolate 7 (0.53 g, 35%) as a
1
yellow solid. R : 0.52. M.p.: 112ꢀ114 ◦C. HꢀNMR (400 MHz, CDCl ) δ 6.66ꢀ6.67 (m, 1H),
f
3
7
.20ꢀ7.26 (m, 1H), 7.38ꢀ7.45 (m, 1H), 7.50ꢀ7.53 (m, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.82 (d,
1
3
J=7.5 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 10.99 (s, 1H). CꢀNMR (50
MHz, CDCl ) δ 102.4, 116.4, 119.4, 121.4, 122.0, 122.5, 124.0, 124.9, 125.3, 126.1, 128.9,
3
+
1
33.1, 133.6, 153.8, 167.9. HRMS (ESIꢀTOF) m/z: [M+H] Calcd for C H N S 251.0637;
15
10
2
Found: 251.0640.
2
ꢀ(Indolꢀ7ꢀyl)ꢀ1ꢀoctylbenzimidazole,
8:
A
solution
of
2ꢀ(2ꢀnitrophenyl)ꢀ1ꢀ
octylbenzimidazole, 5, (1 g, 2.49 mmol) in dry THF (50 mL) was cooled to ꢀ50 ◦C under
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nitrogen atmosphere. At this temperature, vinylmagnesium bromide (12.21 mL, 8.55 mmol)
was added dropwise and the resulting mixture was stirred for 48 hours. The evolution of the
reaction was followed by thin layer chromatography and once completed, a saturated aqueous
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solution of NH Cl (50 mL) was added and the crude was allowed to reach room temperature.
4
The solvent was evaporated by rotary evaporation and the reaction crude was extracted with
diethyl ether (3x70 mL). The combined organic layers were washed with a saturated aqueous
solution of NH Cl (100 mL), water (100 mL), and brine (100 mL), dried over anhydrous
4
Na SO and the solvent was evaporated under reduced pressure. The crude was purified by
2
4
silica gel column chromatography eluting with ethyl acetate:hexane (1:1) to isolate the desired
1
compound (0.30 g, 30.2%) as a brown oil. R : 0.70. HꢀNMR (400 MHz, CDCl ) δ 0.89 (t,
f
3
J=6.9 Hz, 3H), 1.26ꢀ1.45 (m, 9H), 2.01 (quint, J=7.2 Hz, 2H), 4.45 (t, J=7.5 Hz, 2H), 6.64ꢀ
6
1
.66 (m, 1H), 7.24ꢀ7.28 (m, 1H), 7.33ꢀ7.37 (m, 2H), 7.38 (t, J=2.8 Hz, 1H), 7.46ꢀ7.50 (m,
1
3
H), 7.53 (d, J=7.6 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.85ꢀ7.89 (m, 1H), 10.60 (s, 1H). Cꢀ
NMR (100 MHz, CDCl ) δ 14.0, 22.6, 26.8, 29.0, 29.1, 29.9, 31.7, 45.2, 102.4, 109.9, 113.1,
3
118.9, 119.4, 120.4, 122.3, 122.6, 122.7, 125.3, 129.0, 135.1, 135.7, 142.9, 151.4. HRMS
+
(
ESIꢀTOF) m/z: [M+H] Calcd for C H N 346.2278; Found: 346.2284.
23 27 3
3
(
N -B)ꢀ2ꢀ[1ꢀ(Diphenylboryl)indolꢀ7ꢀyl]benzoxazole, 10: A solution of 2ꢀ(indolꢀ7ꢀ
yl)benzoxazole, 6, (0.50 g, 2.16 mmol) and triphenylborane (0.79 g, 3.24 mmol) in dry
toluene (30 mL) under nitrogen atmosphere was refluxed for 48 hours. The reaction mixture
was cooled to room temperature and the solvent was evaporated under reduced pressure. The
crude was purified by silica gel column chromatography eluting with ethyl acetate: hexane
(
1:5) to afford the pure title compound (30 mg, 3%) as a yellow solid. R : 0.40. M.p.: 227ꢀ229
f
1
◦
C. HꢀNMR (300 MHz, CDCl ) δ 6.62 (d, J=3 Hz, 1H), 7.18ꢀ7.42 (m, 15H), 7.67, (d, J=8.1
3
1
3
Hz, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H). CꢀNMR (75 MHz, CDCl ) δ 102.7,
3
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02.9, 103.5, 111.4, 117.9, 118.4, 118.6, 126.2, 126.6, 127.3, 128.7, 129.2, 132.5, 133.4,
11
39.1, 149.5, 162.0. BꢀNMR (128.34 MHz, CDCl ) δ 3.85 (s). HRMS (ESIꢀTOF) m/z:
3
+
[M+H] Calcd for C H BN O 398.1700; Found: 398.1698.
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3
(
N -B)ꢀ2ꢀ[1ꢀ(Diphenylboryl)indolꢀ7ꢀyl]benzothiazole, 11: A mixture of 2ꢀ(indolꢀ7ꢀ
yl)benzothiazole, 7, (717 mg, 2.87 mmol) and triphenylborane (1.04 g, 4.31 mmol) in dry
toluene (30 mL) under nitrogen atmosphere was heated at reflux temperature and the reaction
progress was followed by thin layer chromatography. Once the reaction was concluded (48
hours), it was cooled to room temperature and the solvent was evaporated under vacuum. The
crude was treated with diethyl ether to obtain a yellow solid (307 mg, 31%) which
1
corresponds to the pure title compound. M.p.: 229ꢀ232 ◦C. HꢀNMR (300 MHz) δ 6.55 (d, J=
2
.7 Hz, 1H), 7.09ꢀ7.13 (m, 2H), 7.16ꢀ7.25 (m, 7H), 7.33ꢀ7.39 (m, 5H), 7.60 (d, J=7.5 Hz, 1H),
1
3
7
.75ꢀ7.83 (m, 2H), 7.86ꢀ7.88 (m, 1H). CꢀNMR (75 MHz, CDCl ) δ 102.7, 111.0, 118.7,
3
118.9, 122.0, 122.5, 126.2, 126.5, 127.2, 127.4, 128.2, 129.4, 130.0, 132.6, 133.5, 135.8,
11
+
1
45.9, 168.9. BꢀNMR (128.34 MHz, CDCl ) δ 4.87 (s). HRMS (ESIꢀTOF) m/z: [M+H]
3
Calcd for C H BN S 414.1471; Found: 414.1473.
2
7
19
2
3
(
N -B)ꢀ2ꢀ[1ꢀ(Diphenylboryl)indolꢀ7ꢀyl]ꢀ1ꢀoctylbenzimidazole, 12: A mixture of 8 (245 mg,
0
.71 mmol) and triphenylborane (258 mg, 1.07 mmol) in dry toluene (40 mL) under nitrogen
atmosphere was heated at reflux temperature and the reaction progress was followed by thin
layer chromatography. Once the reaction was concluded (48 hours), it was cooled to room
temperature and the solvent was evaporated under vacuum. The residue was subjected to
column chromatography on silica gel eluting with dichloromethane:hexane (1:1) to isolate 12
1
(
136 mg, 38%) as a yellow solid. R : 0.71. M.p.: 201ꢀ203 ◦C. HꢀNMR (400 MHz, CDCl ) δ
f
3
0.92 (t, J=6.9 Hz, 3H), 1.26ꢀ1.63 (m, 10H), 2.12 (quint, J=7.2 Hz, 2H), 4.66 (t, J=7.5 Hz, 2H),
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.60 (d, J=2.8 Hz, 1H), 7.12ꢀ7.20 (m, 9H), 7.26ꢀ7.35 (m, 8H), 7.45 (d, J=8 Hz, 1H), 7.64 (d,
1
3
J=7.6 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H). CꢀNMR (75 MHz, CDCl ) δ 14.1, 22.6, 26.9, 29.1,
3
29.1, 31.7, 46.3, 102.2, 107.0, 109.8, 116.9, 118.1, 118.7, 124.4, 125.9, 126.1, 127.1, 129.9,
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1
32.4, 133.5, 134.4, 135.0, 138.2, 146.7. BꢀNMR (128.34 MHz, CDCl ) δ 3.67 (s). HRMS
3
+
(ESIꢀTOF) m/z: [M+H] Calcd for C H BN 509.3111; Found: 509.3112.
35 36
3
1
(N ꢀB)ꢀ7ꢀ[1ꢀ(Diphenylboryl)pyridꢀ2ꢀyl]indole, 13: A mixture of 7ꢀ(2ꢀpyridꢀ2ꢀyl)indole (76.2
mg, 0.39 mmol) and triphenylborane (95 mg, 0.39 mmol) in dry toluene (30 mL) under
nitrogen atmosphere was refluxed for 48 hours. Then, the reaction mixture was allowed to
reach room temperature and the solvent was evaporated by rotary evaporation. The remaining
residue was purified by preparative thin layer chromatography using dichloromethane:hexane
(2:1) as eluent to obtain 13 as a pure yellow solid (58 mg, 41%). R : 0.66. M.p.: 211ꢀ213 ◦C.
f
1
HꢀNMR (300 MHz, CDCl ) δ 6.59 (d, J=2.8 Hz, 1H), 7.10ꢀ7.23 (m, 13H), 7.67 (d, J=7.6 Hz,
3
13
1H), 7.81 (d, J=8 Hz, 1H), 7.94ꢀ7.98 (m, 1H), 8.25 (d, J=8 Hz, 1H), 8.46ꢀ8.48 (m, 1H). Cꢀ
NMR (75 MHz, CDCl ) δ 101.9, 113.6, 116.6, 118.70, 120.6, 121.6, 125.5, 126.5, 127.4,
3
11
1
29.9, 132.2, 133.4, 136.3, 140.1, 146.2, 151.9. BꢀNMR (128.34 MHz, CDCl ) δ 4.00 (s).
3
+
HRMS (ESIꢀTOF) m/z: [M+H] Calcd for C H BN 358.1756; Found: 358.1750.
25
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ACKNOWLEDGMENT
This research has been funded by the Spanish Ministry of Economy and Competitivity
Projects: (DC and AT) CTQ2014ꢀ58875ꢀR; (JNRL) SAF2013ꢀ48375ꢀC2ꢀ1ꢀR) and
(
Fundación Séneca Región de Murcia (Project: (JNRL) 15230/PI/10 and 19304/PI/14).
AE thanks the resources from Servicio de Cálculo Científico (University of Murcia), as
well as the financial support from COST action CM1302.
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ASSOCIATED CONTENT
Supporting Information. NMR spectra; Xꢀray structures; thermogravimetric analysis; cyclic
voltammetry; TDꢀDFT calculations; solvent effects; LippertꢀMataga plots; thin film
absorption and emission spectra; Cell cultures and apoptosis assays.
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(
16) ORCAꢀan ab initio, density functional and semiempirical program package. Written by F.
Neese. Version 2.8.0, Universität Bonn, 2010. Web page: http://www.thch.uniꢀ
bonn.de/tc/orca/.
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