Fluorescent Molecular Rotors of Organoboron Compounds from Schiff Bases: Synthesis, Viscosity, Reversible Thermochromism, Cytotoxicity, and Bioimaging Cells

Article abstract of DOI:10.1021/acs.joc.6b02802

We report the design, synthesis, and characterization of two new fluorescent molecular rotors of boron derived from Schiff bases: (2,4,8,10-tetra-tert-butyl-6-phenyldibenzo[d,h][1,3,6,2]dioxazaboronine (3) and 1,4-bis(2,4,8,10-tetra-tert-butyldibenzo[d,h][1,3,6,2]dioxazaboronin-6-yl)benzene (4), as well as the free ligand 2-[[(3,5-di-tert-butyl-2-hydroxyphenyl)imino]methyl]-4,6-di-tert-butylphenol 1. All compounds were fully characterized by NMR (¹H,¹¹B, and¹³C), IR, UV/vis, fluorescence spectroscopy, and high-resolution mass spectrometry. The crystal structures of 3 and 4 showed tetracoordinated boron atoms with semiplanar skeleton ligands. The free rotation of the fluorescent molecular rotor, only observed in the binuclear compound, was decreased with increasing viscosity, while the quantum yield was increased. Interestingly, the property of reversible thermochromism was found in organoboron 4 in the solid state. DFT calculations to determine the both complexes have free rotation around the CPh-B1 bond. The boron compounds 3 and 4 have shown low cytotoxicity activity in cell line A-431 and low green staining in cells.

Full text of DOI:10.1021/acs.joc.6b02802

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Article
Fluorescent molecular rotors (FMRs) of organoboron
compounds from Schiff bases: Synthesis, viscosity,
reversible thermochromism, cytotoxicity and bioimaging cells.
Marisol Ibarra-Rodriguez, Blanca M. Muñoz-Flores, H. V. Rasika Dias, Mario Sanchez,
Alberto Gómez-Treviño, Rosa Santillan, Norberto Farfan, and Victor Manuel Jimenez-Perez
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02802 • Publication Date (Web): 30 Jan 2017
Downloaded from http://pubs.acs.org on January 30, 2017
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Fluorescent molecular rotors (FMRs) of organoboron compounds from
Schiff bases: Synthesis, viscosity, reversible thermochromism,
cytotoxicity, and bioimaging cells.
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Marisol IbarraꢀRodriguez,1 Blanca M. MunozꢀFlores,1 H. V. Rasika Dias,2 Mario Sanchez,3
Alberto GomezꢀTreviño,1 Rosa Santillan,4 Norberto Farfán,5 and Víctor M. Jimenezꢀ
Perez,1,*
1
Universidad Autónoma de Nuevo León, Facultad de Ciencias Químicas, Ciudad
Universitaria, 66451 Nuevo León, México.
2
Department of Chemistry and Biochemistry, The University of Texas at Arlington,
Arlington, Texas 76019ꢀ0065.
3
Centro de Investigación en Materiales Avanzados, S.C., Alianza Norte 202, PIIT,
Carretera MonterreyꢀAeropuerto Km. 10, C. P. 66628, Apodaca, Nuevo León, México.
4 Departamento de Química, Centro de Investigación y de Estudios Avanzados del IPN,
A. P. 14ꢀ740, C. P. 07000, D. F., México.
5
Facultad de Química, Departamento de Química Orgánica, Universidad Nacional
Autónoma de México, Ciudad Universitaria, 04510 México D. F., México.
*Eꢀmail address: victor.jimenezpr@uanl.edu.mx (V. M. JiménezꢀPérez).
Keywords: Fluorescent molecular rotor, Viscosity sensor, reversible thermochromism, low
cytotoxicity, Confocal, DFT.
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Abstract
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Here we report the design, synthesis, and characterization of two new fluorescent
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molecular rotors of boron derived from Schiff bases: (2,4,8,10ꢀtetraꢀtertꢀbutylꢀ6ꢀ
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phenyldibenzo[d,h][1,3,6,2]dioxazaboronine
3
and
1,4ꢀbis(2,4,8,10ꢀtetraꢀtertꢀ
butyldibenzo[d,h][1,3,6,2]dioxazaboroninꢀ6ꢀyl)benzene 4, as well as the free ligand 2ꢀ
{[(3,5ꢀdiꢀtꢀbutylꢀ2ꢀhydroxyphenyl)imino]methyl}ꢀ4,6ꢀdiꢀtꢀbutylꢀphenol 1. All compounds
were fully characterized by NMR (1H, 11B, and 13C), IR, UV/vis, fluorescence
spectroscopy, and high resolution mass spectrometry. The crystal structures of 3 and 4
showed tetracoordinated boron atoms with semiplanar skeleton ligand. The free rotation of
the fluorescent molecular rotor, just observed in the binuclear compound, was decreased by
the viscosity while the quantum yield was increased. Interesting, the property of reversible
thermochromism was found in organoboron 3 in the solid state. DFT calculations to
determine the both complexes have free rotation around the CPhꢀB1 bond. The boron
compounds (3ꢀ4) shown low cytotoxicity activity in cell line Aꢀ431 and low green staining
in cells.
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1. INTRODUCTION
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Fluorescent molecular rotors (FMRs) with viscosity sensitive quantum yields1 have
received tremendous attention due to the potential application in the detection of
biomolecular interactions,2 polymerization processes,3 and microviscosity.4 Viscosity plays
an important role in living organisms, and the fluorescence imaging with molecular rotors
is a technique that helps viscosity studies on cellular scale.5 Other potential applications of
rotors involve their use as sensors to measure viscosity in bioꢀfluid.6 Organoboron
compounds are interesting in this regard. Different types of luminescent rotors of boron are
known such as BODIPYs, chalcone derivatives, and boronates (chart 1, IꢀX).7 The
BODIPYs are the most widely studied group. Benniston and coꢀworkers reported that the
compound I can be used to record how certain fluids respond to applied pressures and
changes of viscosity in the medium. The mechanism involves the gyration of
mesophenylene ring and accompanying distortion of the dipyrromethene framework.8 In
another example, Shiraishi et al. reported that the compound V serves as a fluorescent
thermometer in water and the fluorescence increases in the copolymer due to increase in
viscosity,9 with the behavior similar to that reported in compound II in which the
fluorescence intensity increases with the restricted rotation of the phenyl group in the
medium of high viscosity. This property can be exploited as a practical and versatile tool to
measure microviscosity.10 Other groups have investigated chalcone derivatives.
Klymchenko and coꢀworkers reported that the compound VII shows solvatochromic
property and acts as a viscosityꢀsensitive molecular rotor.11 The organoboron compounds
show low cytotoxicity.12 The synthetic methods however involve several steps and require
specific conditions as anhydrous atmospheres as evident in the BODIPY chemistry.13
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Fluorescent sensors have received attention because they have advantages in terms
of sensitivity, selectivity and the easy detection of the fluorescence changes of the
systems.14 Previously, transition metal complexes have been reported that exhibit the
property of change in color at different temperatures. This phenomenon is called
luminescent thermochromism and represents an important area of solid state chemistry.15
The thermochromic materials are potentially useful in thermometers, as temperature
sensors, and in the development of warning signals and optoelectronic display devices.16
An interesting study of the thermochromism properties of copper pyrazolates was reported
by Dias and coꢀworkers which is a promising compound for sensor applications.17 Other
examples involve copper iodine clusters that show reversible luminescence
thermochromism, with intense orange emissions,18 and Au1ꢀCu1 phosphine complexes that
exhibit reversible emission change from yellow to green.19 Other group has investigated
triarylboron compounds and their utility as excellent realꢀtime and reversible temperature
indicator with a concentration independent feature.20
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Recently, our research group reported the synthesis of a series of novel compounds
of luminescent boron derivatives of tridentate ligands with good solubility in polar
solvents.21 In this work, we describe the synthesis of luminescent boron derivatives of
Schiff bases that act as molecular rotors and their use as cell markers.
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Chart 1. Luminescent molecular rotors of organoboron compounds.
2. RESULTS AND DISCUSSION
2.1. Synthesis
Previously, similar binuclear organoboron compounds derived from tridentated ligands
have been synthesized and characterized by common spectroscopic and spectrometric
methods. However, due to the low solubility in some organic solvents, the crystal structures
were not possible to isolated as well as in solution characterization.22 In order to improve
the solubility, we have designed a new Schiff base ligand 2 which was prepared by
condensation reaction of 3,5ꢀdiꢀtertꢀbutylꢀ2ꢀhydroxybenzaldehyde with 3,5ꢀdiꢀtertꢀbutylꢀ6ꢀ
hydroxyaniline (1), the boron compounds 3 and 4 were obtained by condensation of
phenylboronic acid and diꢀacid with the ligand under reflux in acetonitrile (Scheme 1),
respectively. The resulting organoboron complexes are soluble in several organic solvents;
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both complexes were stable in the solid state. The compounds were fully characterized by
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NMR (1H, B, and C), IR spectroscopy and mass spectrometry. The complexes 3 and 4
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were characterized by single crystal Xꢀray diffraction (vide infra).
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Scheme 1. Synthesis of ligand 2 and organoboron compounds 3 and 4.
2.2. Solution and solid structures
The existence of the N→B coordination bond was evidenced by 11B NMR spectra for the
compound 3 with one broad signal of 7.88 ppm indicative of tetraꢀcoordinated boron
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atom.23 In the C spectra of boron for complexes, the signals for C7 are shifted to low
frequencies (151.73, 147.14 ppm), with respect to the ligand (165.45 ppm) owing to the
coordination to boron and the imine proton is observed at (3) 8.78 ppm, (4) 8.13 ppm.24 IR
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spectral analysis showed that the C=N stretching vibration bands for 3ꢀ4 were shifted to
lower wavenumbers in comparison with the ligand.25 The mass spectra of boron derivatives
showed the base peak corresponding to the molecular ion peak and for complex 4, the first
fragmentation of the complex by removing the methyl substituent groups tertꢀbutyl and the
fragment of ligand coordinated to a boron atom 446.32 m/z (6.17%); the isotopic
distribution of parent ions in the spectra demonstrated the presence of two atoms of boron
in the organoboron 4. The comparison of predicted theoretical and experimental isotopic
distributions of spectra for compound 4 is given in figure 1.
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Figure 1. Comparison of theorical and experimental isotopic distributions of spectra of
the [M+H]+ of compound 4, the spectrum clearly indicates the presence of two boron
atoms.
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2.3. Xꢀray structure
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Complexes 3 and 4 crystallized from slow evaporation of ACN and THF/acetone.
Suitable single crystals for Xꢀray analysis were obtained for 3 and 4, and their molecular
structures are shown in Figure 2 and 3, while data collection and refinement parameters and
bond lengths and angles are available in Supporting Information, Table S1, and S2. Both
complexes crystallized within the P21/n space group and are monoclinic. Complex 3
crystallized as orange block, and 4 crystallized as orange diamond with one molecule of
solvent acetone.
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The crystal structures of 3 and 4 display tetracoordinated boron atoms with distorted
tetrahedral geometry and the formation of two fused heterocycles of five and six members.
The BꢀO bond distances [3 (1.454ꢀ1.477Å), 4 (1.451ꢀ1.471Å)] are characteristic for
tetracoordinated boron complexes, and are comparable to the previously reported values.26
The BꢀN bond lengths [3 (1.596 Å), 4 (1.560ꢀ1.587 Å)] suggest strong coordination of the
nitrogen atoms with boron atoms because are they are less than the estimated covalent NꢀB
distance; this is confirmed by the tetrahedral character of 89.8 and 90.0ꢀ91.7% for each
molecule.27 The distortion of the tetrahedral geometry causes the boron atom to lie outside
the plane from the salicylidene ring (3: plane: N1ꢀC1ꢀC2ꢀC3ꢀO1, θ = 0.519 Å, 4: plane:
N1ꢀC1ꢀC2ꢀC3ꢀO1, θ = 0.407 Å). Crystal structures of 3 and 4 show various close
intermolecular[3 (H7ꢀC15, 2.80 Å), 4 (Imine HꢀO other molecule, 2.291, 2.514 Å); (Imine
HꢀAcetone oxygen, 2.222 Å); (H of acetone with ring (centroid 1 and 2, see Supporting
Information, Figure S18), 2.921 and 2.771 Å)] and intramolecular interactions [3 (H19ꢀO1,
2.603 Å), (H15ꢀO2, 2.758 Å); 4 (H15ꢀN1, 2.515), (H19ꢀO1, 2.975), (H16ꢀO3, 2.510)], see
Figure 4.
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Figure 2. View of the structure of the 3. Ellipsoids are drawn at the 30% probability level.
Distances: B(1)ꢀO(1) 1.4536 (18), B(1)ꢀO(2) 1.4774(19), B(1)ꢀN(1) 1.596(2), B(1)ꢀC(14)
1.609(2) Å. Bond angles: O(2)ꢀB(1)ꢀC(14) 111.61 (11), O(1)ꢀB(1)ꢀC(14) 113.77 (11),
O(2)ꢀB(1)ꢀN(1) 95.13(11), O(2)ꢀB(1)ꢀO(1) 112.75(11), N(1)ꢀB(1)ꢀC(14) 110.81(11), O(1)ꢀ
B(1)ꢀN(1) 111.33(12)˚
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Figure 3. View of the structure of the 4. Ellipsoids are drawn at the 30% probability level.
Distances: B(1)ꢀC(14) 1.591(3), B(1)ꢀO(1) 1.451(3), B(1)ꢀO(2) 1.455(3), B(1)ꢀN(1)
1.587(6), B(2)ꢀC(17) 1.593(3), B(2)ꢀO(4) 1.471 (3), B(2)ꢀN(2) 1.563(6), B(2)ꢀO(3)
1.460(3) Å. Bond angles: O(2)ꢀB(1)ꢀC(14) 114.83(19), O(1)ꢀB(1)ꢀC(14) 112.56(19), O(2)ꢀ
B(1)ꢀN(1) 91.4(2), O(1)ꢀB(1)ꢀN(1) 90.8(2), O(2)ꢀB(1)ꢀO(1) 110.57(18), N(1)ꢀB(1)ꢀC(14)
110.0(2), O(4)ꢀB(2)ꢀC(17) 113.03(18), O(3)ꢀB(2)ꢀC(17) 111.89(18), O(3)ꢀB(2)ꢀN(2)
90.8(3), N(2)ꢀB(2)ꢀO(4) 91.9(2), O(4)ꢀB(2)ꢀO(3) 111.45(18), C(17)ꢀB(2)ꢀN(2) 114.5(2)˚.
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Figure 4. Intramolecular interactions of the 3 and 4 [3 (H19ꢀO1, 2.603), (H15ꢀO2, 2.758);
4 (H15ꢀN1, 2.515), (H19ꢀO1, 2.975), (H16ꢀO3, 2.510)].
2.4. Photophysical Characterization
The optical properties of compounds were obtained in THF, chloroform, and
methanol (Table 1). The absorption and emission spectra for 3 and 4 are shown in figure 5.
For compounds 3 and 4, the absorption bands show two λmax in 319 and 460 nm, which can
be ascribe to the HOMOꢀLUMO electronic transition; the molar extinction coefficients (ε)
of 3ꢀ4 were in the range of 4000ꢀ21000 Mꢀ1cmꢀ1 in different solvents. The optical band gaps
(eV) are characteristics of semiconductor materials. The fluorescence spectrum of
complexes 3 and 4 show emissions around 520 nm in THF and CHCl3. However, it is
interesting to observe both compounds showed one emission at 386 nm in methanol. This
behavior is due to the difference of solvent dynamic viscosities (Table 1) as has been
reported by molecular rotors.28
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Table 1. Photophysical data of compounds 3 and 4.
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Dyn.
viscosity
[mPa⋅s]
Comp.
3
Solvent
λabs[nm] ε*104 [M ꢀ1cm ꢀ1] Eg [eV] λem [nm]
ΦF [%]
THF
319, 455
324, 460
320, 447
319, 455
322, 461
319, 450
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1.9
0.5
2.1
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0.4
2.41
2.35
2.41
2.41
2.33
2.41
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387
512
523
385
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0.60
0.55
0.55
0.60
0.002
0.09
0.68
0.10
1.69
0.56
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Chloroform
Methanol
THF
4
Chloroform
Methanol
Figure 5. Absorption and emission spectrum of compounds 3 and 4 in THF, CHCl3, and
MeOH.
Fluorescence measurements of mononuclear 3 and dinuclear 4 in methanol/glycerol
mixtures of different viscosities (% of glycerol) show that the fluorescence quantum yield
increases with increasing of solvent viscosity (Figure 7) according to the FӧsterꢀHoffman
equation.29 The observed increase in fluorescence intensity is consistent with the restricted
rotation of the phenyl (bonded to the boron atom see Figure 6) in the medium of high
viscosity and dissipate energy by intramolecular rotation, the photoactivated molecule may
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relax by non radiative decay processes. The emission intensity increased more for
compound 4 with the medium viscosity (see. Table 2), because it has two points of rotation
in the structure of the molecule, in the literature, we find this behavior for ligands and
complex.30
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Figure 6. Fluorescence spectra of compounds 3 and 4 in binary mixtures of methanol and
glycerol in different ratios.
Figure 7. Correlation of the fluorescence quantum yield (ΦF) of organoboron 3 (A) and 4
(B) with the viscosity of the medium r2 values (goodness of fit) is (0.98 ꢀ 0.95).
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Table 2. Spectroscopic properties of compounds 3 and 4 in binary mixtures of methanol
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and glycerol.
Glycerol
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Compound 3
Compound 4
fraction
(v/v)
0
ΦF [%]
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1.59
2.35
4.50
ΦF [%]
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1.15
2.87
5.21
λabs[nm]
447
λem [nm]
387
λabs[nm] λem [nm]
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2.5 Reversible thermochromism
The organoboron 4 shows the ability to behave as a thermochromic material; the
luminescence property was modified when the complex was exposed to different
temperatures. When it was heating at 215 °C, the color changed from yellow to orange and
a decreased of luminescence intensity under UV radiation to the naked eye; but when it was
cooling at room temperature the property returns (Figure 8 AꢀC).31 The thermochromic
property of 4 was determined by luminescence spectroscopy in the solid state (Figure 9).
However, compound 4 was grinding during 2 minutes on mortar the luminescence property
was lost it (see Supporting Information, Figure S19), similar to that reported by Seki et al.32
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Figure 8. Fluorescence image of compound 4. A) Under Vis and UV light at 25 °C.
B) Under Vis and UV light at 215 °C. C) After cooling under Vis and UV light at 25 °C.
Figure 9. Luminescence spectra of compound 4 at room temperature, after heating
and after grinding.
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2.6. DFT calculations
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In order to explain the molecular behavior for complexes 3ꢀ4, we performed a
theoretical study using the density functional theory (DFT, B3LYP) in combination with
the 6ꢀ31G(d,p) basis set. All structures were characterized by calculating their frequencies.
Our results suggest that structure 4 with trans conformation is more stable than cis by only
1.38 kcal/mol, the explanation for this is because the structure with cis conformation has
more steric hindrance (Figure 10). Interestingly, the structure which has crystallized and
characterized by Xꢀray has no symmetry, because one of the two ligands is displaced by
60°. This behavior could be attributed to acetone trapped into the crystal lattice (see
Supporting Information, Figure S18).
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To better understand the process of rotation of the aromatic ring for complex 4, we
have followed two strategies, the first was to rotate only one ligand, and the second was to
rotate only the aromatic ring, keeping the two ligands fixed, both rotating processes were
performed every 30° along the potential energy surface (Figure 10). The results of these
calculations can be observed in Figure 11. The energy barrier value for complex 4 to rotate
the aromatic ring is higher because of steric effects generated by the tert-butyl groups.
However, when only one ligand is rotated the relative energy value (energy barrier) is
smaller.
On the other hand, the rotation of the phenyl group in the complex 3 was also
studied. Complex 3 shows an energy barrier value of 6.26 kcal/mol by rotating the CPhꢀB1
bond every 30°, with these results we can mention that both complexes present free
rotation.
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Figure 10. Rotation of ligand and phenyl groups in complexes 3 and 4.
In addition, we have also calculated the UVꢀvis spectra in both complexes, 3 and 4.
The experimental (460 and 461 nm, respectively) absorption values are very similar to
those calculated (463 and 465 nm, respectively).When we explored the rotational energy
barrier of the rotational ligand and phenyl groups, we found that for the complex 4 to 120°,
the degree of absorption (482 nm) is slightly higher than that found in the global minimum
(465 nm). This difference is due to the structure 4 (120°) involves πꢀπ transitions (see
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Supporting Information, Figure S1). It is important to mention that the B3LYP method
tends to slightly modify the energies of the rotation barriers,33 compared to other functional
ones. We have used B3LYP because of its wide use in organic molecules.
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Molecular orbitals and their energies for the complexes 3 and 4 are shown in Figure
12 The electron density is mostly located on the ligands of both complexes, the electronic
transitions, which mainly involves the HOMOꢀ1
→ LUMO and HOMO → LUMO+1
frontier orbitals for the binuclear, that corresponds to the πꢀπ* transitions (Supporting
Information, Tables S4ꢀ6).
Figure 11. Rotation barrier energies for complex 4. Blue line belongs to the
rotation of the phenyl group, while the red line belongs to the rotation of CPhꢀB1 bond.
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Figure 12. HOMO and LUMO molecular orbitals, and their energies involved in
the electronic transitions for complexes 3 and 4.
2.7. Cytotoxicity activity and cell images
In vitro cytotoxicity activity of organoboron 3 and 4 were evaluated on epidermoid
carcinoma cell line Aꢀ431 in different concentrations (from 20 to 1µg/ml) for 24 hours. As
DMSO was the dissolvent used for the compounds, its toxicity was analyzed. The viability
of the cells shows lower toxicity for organoboron 3 and 4 in all tested concentrations (20ꢀ38
µM, 20 µg/ml highest concentration) see Figure 13, this behavior such molecules already
reported that having low cytotoxicity to 10 µM.34 The dinuclear shows lower cytotoxicity
and tends to be less soluble and less penetrate compound in the cell.
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To determine the capacity of the organoboron compounds to produce fluorescent
stain on cells, A431, and B16F10 cells were treated with 10 ꢀg/mL for 2 h and then
analyzed by confocal laser microscopy, cells treated with the organoboron compounds 3ꢀ4
presented a low green staining, due to poor solubility of the compounds in the polar
solvents, that fluorescence was observed from the cytoplasm in both cases. (Figure 14)
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Figure 13. Effects of organoboron 3 and 4 on viability of A431 cells. Cell proliferation was
determined by MTS, were treated with different concentration of the compounds 3 and 4
(20, 10, 5, 2, 1µg/ml) over 24 hrs.
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Figure 14. Staining of cells with organoboron compounds. Confocal microscopy of
melanoma cells B16F10 (AꢀB) and Aꢀ431 (CꢀD) treated with 10 µg/ml of each compound
for 2 h.
3. CONCLUSIONS
In summary, we describe the synthesis, characterization in solution, solid state and Xꢀ
ray structure of two new fluorescent organoboron compounds. The binuclear show that the
fluorescence quantum yield increases strongly with increasing solvent viscosity, due to the
property rotor molecular, it was corroborated through B3LYP and it organoboron has the
property of thermochromism reversible. Both fluorescent organoboron compounds have
shown low cytotoxicity which is good for potential medical application but and poor
capacity of staining cells. In order to improve the hydrophilicity of fluorescent molecular
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rotors of organoboron compounds, we are working on it. The binuclear molecular rotor
showed reversible thermochromism as well as viscoꢀ and solvoluminescene, our best
knowledge is the first example which showed this multiꢀresponse.
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4. EXPERIMENTAL SECCION
4.1. Material and equipment
All starting materials and solvents were used without further purification.
Compound 1 was synthesized as previously reported.35 Melting points were performed on
an MelꢀTemp apparatus and are uncorrected. Highꢀ resolution mass spectrum was obtained
by LC/MSD TOF with APCI as ionization source. Infrared spectra were recorded using a
27 FTꢀIR spectrophotometer equipped with a ATR accessory with a single reflection ZnSe
ATR crystal. UV spectra were obtained with a UV/VIS spectrophotometer and emission
measurements were performed on a spectrofluorometer. 1H, 13C and 11B NMR spectra were
recorded on a DPX 400. Chemical shifts (ppm) are relative to (CH3)4Si for 1H and 13C. 11B
NMR spectra were referenced externally to BF3OEt2. Mass spectra were recorded on an
API 2000 LC/MS/MS System.
4.2. Crystal Structure Determination:
The crystals of 3 and 4 were covered with a layer of hydrocarbon oil that was
selected and mounted with paratoneꢀN oil on a cryoꢀloop, and immediately placed in the
lowꢀtemperature nitrogen stream at 100(2) K. The data for 3 and 4 were recorded on a
Diffractometer equipped, a graphite monochromator, and a Mo Kα fineꢀfocus sealed tube
(λ = 0.71073 Å). The structure was solved by direct methods using SHELXSꢀ9736 and
refined against F2 on all data by fullꢀmatrix leastꢀsquares with SHELXLꢀ97.37 All of the
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software manipulations were done under the WINꢀGX environment program set.38 All
heavier atoms were found by Fourier map difference and refined anisotropically. Some
hydrogen atoms were found by Fourier map differences and refined isotropically. The
remaining hydrogen atoms were geometrically modeled and are not refined.
Crystallographic data for the structure reported in this paper have been deposited in the
Cambridge Crystallographic Data Centre: CCDC 1518382 and 1518383.
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4.3.
Synthesis
of
(E)ꢀ2,4ꢀdiꢀtertꢀbutylꢀ6ꢀ((3,5ꢀdiꢀtertꢀbutylꢀ2ꢀ
hydroxybenzylidene)amino)phenol (2)
A solution of 3,5ꢀdiꢀtertꢀbutylꢀ6ꢀhydroxyaniline (1) 0.66 g (3 mmol) and 3,5ꢀdiꢀtertꢀ
butylꢀ2ꢀhydroxybenzaldehyde 0.70 g (3 mmol) in acetonitrile were heated under reflux for
48 h, using a DeanꢀStark apparatus for removal of water by azeotropic distillation. The
reaction mixture slowly cooled to room temperature, the solvent is evaporated and adding
hexane, the precipitated solid is filtered and discarded; liquor filtrate is concentrated and
added acetonitrile, it was allowed to evaporate slowly, after 5 days yellow crystals is
obtained, crystals lose brightness to passage of time may crystallizing with solvent. The
compound is soluble in hexane, to give 0.72 g (Yield: 54.9 %). M. P.: 104ꢀ105 oC. 1H NMR
(400 MHz, C6D6, 298K) δ = 1.29 (s, 9H, t Buꢀ5), 1.31 (s, 9H, t Buꢀ10), 1.60 (s, 9H, t Buꢀ3),
1.63 (s, 9H, t Buꢀ12), 6.83 (d,1H, H4), 6.98 (d, 1H, H11), 7.43 (d, 1H, H9), 7.60 (d, 1H,
H6), 8.13 (s, 1H, H7), 12.92 (s, 1H, OH). 13C NMR (100 MHz, C6D6, 298K) δ = 29.8 (CH3,
t Buꢀ3), 29.9 (CH3, t Buꢀ12), 31.8 (CH3, t Buꢀ5), 31.9 (CH3, t Buꢀ10), 113.5 (C4), 122.9
(C6), 127.9 (C11), 128.1 (C9), 165.5 (C7). HETCOR [δH/δC]: 1.29/31.25 (CH3, t Buꢀ5),
1.59/29.34 (CH3, t Buꢀ3), 6.89/113.93 (H4/C4), 6.98/127.4 (H11/C11), 7.42/122.46
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(H6/C6), 7.60/127.99 (H9/C9), 8.12/165.94 (H7/C7). COSY [δH/δH]: 7.43/6.82 (H6/H4),
7.60/6.98 (H9/H11). HRMS (APCI/TOFꢀQ) m/z: [M+1]+ calcd for C29H43NO2 438.3367,
found: 438.3368. IR ν (cmꢀ1) 3063 (OH), 1629 (C=N). UVꢀVis (THF): λabs/max, εmax*104:
342 nm, 2.5 Mꢀ1cmꢀ1. Fluorescence (THF): λFluor/max: 507 nm.
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4.4. Synthesis of 2,4,8,10ꢀtetraꢀtertꢀbutylꢀ6ꢀphenyldibenzo[d,h][1,3,6,2]dioxazaboronine
(3).
A solution of 2 (0.219 g, 0.5 mmol) and phenylboronic acid (0.064 g, 0.52 mmol) in
acetonitrile were heated under reflux for 48 h, using a DeanꢀStark apparatus for the removal
of water by azeotropic distillation. The reaction mixture was slowly warmed to room
temperature, the solvent was concentrated and allowed to evaporate slowly at 12 hours,
orange crystals is obtained. The compound is soluble in THF. Yield of 0.26 g (82.5%). M.
P.: 258ꢀ259 oC. 1H NMR (400 MHz, THFꢀd8, 298K) δ = 1.32 (s, 9H, t Buꢀ5), 1.33 (s, 9H, t
Buꢀ10), 1.45 (s, 9H, t Buꢀ3), 1.48 (s, 9H, t Buꢀ12), 6.98 (t, 1H, Hꢀp), 7.26 (m, 2H, Hꢀo and
m), 7.32 (d, 1H, H11), 7.58 (d, 1H, H4), 7.51 (d, 1H, H6), 7.64 (d, 1H, H9), 8.78 (s, 1H,
H7). 13C NMR (100 MHz, THFꢀd8, 298K) δ = 29.9 (CH3, t Buꢀ12), 30.2 (CH3, t Buꢀ3), 31.9
(CH3, t Buꢀ10), 32.2 (CH3, t Buꢀ5), 35.1 (Cquater, t Buꢀ5), 35.6 (Cquater, t Buꢀ10), 35.7 (Cquater
,
t Buꢀ3), 36.3 (Cquater, t Buꢀ12), 110.9 (C6), 120.7 (C10), 126.1 (C11), 126.8 (C4), 127.8 (Cꢀ
p), 132.3 (Cꢀo and m), 133.0 (C9), 136.7 (C5), 140.1 (C12), 142.8 (C3), 142.6 (C1), 151.7
(C7), 155.1 (C2), 155.8 (C13). HETCOR [δH/δC]: 1.46/30 (CH3, t Buꢀ3/Cꢀt Buꢀ3),
1.32/31.91 (CH3, t Buꢀ5/Cꢀt Buꢀ5), 6.96/127.8 (Hꢀp/Cꢀp), 7.25/132.33 (Hꢀo and m/Cꢀo and
m), 7.32/126.11 (H11/C11), 7.39/126.81 (H4/C4), 7.52/110.98 (H6/C6), 7.63/132.95
(H9/C9), 8.80/151.66 (H7/C7). COSY [δH/δH]: 7.26/6.97 (Hꢀo and m/Hꢀp). 11B NMR (128
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MHz, THFꢀd8, 298K) δ = 7.88 ppm. HRMS (APCI/TOFꢀQ) m/z: [M+1]+ calcd for
C35H46BNO2 524.3694, found: 524.3696. IR ν (cmꢀ1) 2957 (CꢀHaromatic), 1627 (C=N). UVꢀ
Vis (THF): λabs/max, εmax*104: 455 nm, 1.4 Mꢀ1cmꢀ1. Fluorescence (THF): λFluo/max: 514 nm.
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4.5 Synthesis of 1,4ꢀbis(2,4,8,10ꢀtetraꢀtertꢀbutyldibenzo[d,h][1,3,6,2]dioxazaboroninꢀ6ꢀ
yl)benzene (4).
A solution of 2 (0.44 g, 1 mmol), benzene 1,4ꢀdiboronic acid (0.083 g, 0.5 mmol)
and acetic acid (0.5 ml) in acetonitrile were heated under reflux for 48 h, using a Deanꢀ
Stark apparatus for the removal of water by azeotropic distillation. The reaction mixture
was slowly warmed to room temperature; precipitated solid is filtered and washed with
hexane. The compound is partially soluble in acetone and THF, it crystallizes separately in
acetone and a mixture of (THF/acetonitrile/acetone), obtaining yellowꢀorange crystals.
Yield 0.38 g (80.31%). M.P.: 350ꢀ352 ° C. 1H NMR (400 MHz, THFꢀd8, 298K) δ = 1.20 (s,
18H, t-Buꢀ5), 1.23 (s, 18H, tꢀBuꢀ10), 1.32 (s, 18H, tꢀBuꢀ3), 1.36 (s, 18H, tꢀBuꢀ12, 6.98 (d,
4H, Hꢀ15), 7.06 (d, 2H, H11), 7.15 (d, 2H, H4), 7.18 (d, 2, H6), 7.46 (d, 2H, H9), 8.13 (d,
2H, H7). 13C NMR (100 MHz, THFꢀd6, 298K) δ = 28.2 [(CH3) tꢀBuꢀ12], 28.5 [(CH3) tꢀBuꢀ
3], 30.3 [(CH3) tꢀBuꢀ10], 30.6 [(CH3) tꢀBuꢀ5], 33.1 [(Cquater) tꢀBuꢀ5], 33.5 [(Cquater) tꢀBuꢀ
10], 33.7 [(Cquater) tꢀBuꢀ3], 34.3 [(Cquater) tꢀBuꢀ12], 108.1 (C4), 124.1 (C11), 124.3 (C6),
129.3 (C15), 131.2 (C9), 147.1 (C7), 153.1 (C2), 153.8 (C13), 153.8 (C8). HETCOR
[δH/δC]: 6.95/129.33 (H15/C15), 7.07/124.18 (H11/C11), 7.09/107.98 (H4/C4), 7.16/124.27
(H6/C6), 7.47/131.16 (H9/C9), 8.15/147.03 (H7/C7). COSY [δH/δH]: 7.46/7.06 (H9/H11).
11B NMR (128 MHz, THFꢀd8, 298K) δ = 8.42 ppm. HRMS (APCI/TOFꢀQ) m/z: [M+1]+
calcd for C64H86B2N2O4 969.6846, found: 969.6844. IR ν (cmꢀ1) 2955 (CꢀHaromatic), 1617
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(C=N). UVꢀVis (THF): λabs/max, εmax*104: 455 nm, 2.1 Mꢀ1cmꢀ1. Fluorescence (THF):
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4.6 Absorbance, emission and luminescence quantum yields
UVꢀVis absorption spectra were measured on a 365 spectrophotometer. Optical
band gap (Eg) was determined from the intercept with the X axis of the tangent of the
absorption spectrum drawn at absorbance of 0.1. The emission spectra have been recorded
with a spectrofluorometer, by exciting 10 nm below the longer wavelength absorption band.
Fluorescence quantum yields in solution were determined according to the procedure
reported in literature39 and using quinine sulphate in H2SO4 0.1 M as the standard. Three
solutions with absorbance at the excitation wavelength lower than 0.1 were analyzed for
each sample and the quantum yield was averaged. The viscosity of the solvent mixture
(methanol/glycerol) was determined in ViscometerꢀViscoLab 3000.
4.7 Cytotoxicity assays in cells and cell image.
Human epidermoid carcinoma ATCC cell line A431 was employed to test the
cytotoxic effects of compound 3 and 4. A431 cells was maintained in Dulbecco’s Modified
Eagle Media (DMEM) with 4 mM Lꢀglutamine and supplemented with 10% Foetal Bovine
Serum, 100 IU/mL penicillin and 100 g/mL streptomycin. Culture of cell line was carried
o
out at 37 C in an Incubator with a 95% air and 5% CO2 atmosphere. Cytotoxicity of
compound 3 and 4 were tested against this cell lines at 1, 2, 5, 10 and 20 µg/ml. Tumour
cells were seeded in 24ꢀwell tissue culture plates with 5x104 cells/well and twentyꢀfour
hours after platting they were supplemented by triplicate with compound 3 and 4. All
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dilutions were prepared with fresh culture media and plates were incubated for 5 days.
Cells in plates were washed with PBS pH=7.4 to remove death cells. Surviving cells were
measured by the MTS method [3ꢀ(4,5ꢀdimethylthiazolꢀ2ꢀyl)ꢀ5ꢀ(3ꢀcarboxymethoxyphenyl)ꢀ
2ꢀ(4ꢀsulfophenyl)ꢀ2Hꢀtetrazolium] and related to the mock cell population by measuring
absorbance at 590 nm to establish cell viability with previous microscopic analysis for
morphological changes exploration in cells.
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B16F10 murine melanoma cells were seeded in 12ꢀwell plates on polyꢀlysine coated
sterile coverslips at a density of 1x105 cells per well in 1 mL of DMEM/F12 media
supplemented with 10% fetal bovine serum and maintained at 37°C in a controlled humid
atmosphere of 5% CO2 and 95% air. Twenty four hours later the medium was renewed and
cells were exposed to the compounds at a concentration of 10 ꢀg/ mL (6.5 ppm) for two
hours. Untreated cells or treated with DMSO were used as controls. Supernatants were
removed and coverslips were washed once with 1 mL of PBS, mounted on microscope slips
using Vectashield and imaged using confocal laser microscopy. Samples were excited at
458 nm and the fluorescence emission was measured at 478–612 nm for compounds 3ꢀ4.
4.8 Computational details
All calculations were performed using GAUSSIAN 09 software package.40 The
geometry of structures 3 and 4 were fully optimized with the B3LYP l/6ꢀ31G(d,p)
method.41 The minimal were characterized by calculating their vibrational modes at the
same level of theory. In order to know the rotation energy of the phenyl group and one of
the ligands, the bonds involved for that rotation were rotated by 30 ° to 180 °, or 360 °,
depending on the case. Results were visualized using the Chemcraft program v1.7.
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Author Information
Corresponding author
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Eꢀmail: victor.jimenezpr@uanl.edu.mx
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Supporting Information
Xꢀray crystallographic data for 3 and 4 in CIF format. Tables of crystallographic
refinement parameters and geometric features for 3 and 4. NMR spectra for 2ꢀ4, Mass
spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENTS
This research was financially supported by CONACYT (grant: 240011). M. I. R. thanks
the scholarship (227695) from CONACYT. The authors thank the Laboratory of
Immunology and Virology of FCBꢀUANL for the bioimaging cells. H.V.R.D
acknowledges the financial support received by the US National Science Foundation (CHEꢀ
1265807).
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