Synthesis of functionalized organoselenium materials: Selenides and diselenides containing cholesterol

Article abstract of DOI:10.1002/ejoc.201500124

Abstract A simple and efficient procedure for the synthesis of three new series of chalcogen liquid crystals, based on selenides and diselenides, containing cholesterol in their structure, is described. Thermal and liquid crystalline properties were investigated by POM, DSC, TGA and XRD scattering. Six of the nine molecules synthesized showed liquid crystal properties, with smectic mesomorphism. All the compounds presented good thermal stability. The smectic mesomorphism was confirmed through XRD analysis. The morphology of the surface of the films was investigated by using atomic force microscopy (AFM). All prepared diselenides showed good glutathione peroxidase like activity and one of the diselenides was 3.3 times more active than the standard Ebselen.

Full text of DOI:10.1002/ejoc.201500124

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DOI: 10.1002/ejoc.201500124
Synthesis of Functionalized Organoselenium Materials: Selenides and
Diselenides Containing Cholesterol
Tiago E. Frizon,[a,b] Jamal Rafique,[a] Sumbal Saba,[a] Ivan H. Bechtold,[c] Hugo Gallardo,[a]
and Antonio L. Braga*[a]
Keywords: Liquid crystals / Mesophases / Selenium / Steroids
A simple and efficient procedure for the synthesis of three
new series of chalcogen liquid crystals, based on selenides
sented good thermal stability. The smectic mesomorphism
was confirmed through XRD analysis. The morphology of the
and diselenides, containing cholesterol in their structure, is surface of the films was investigated by using atomic force
described. Thermal and liquid crystalline properties were in-
vestigated by POM, DSC, TGA and XRD scattering. Six of
the nine molecules synthesized showed liquid crystal proper-
ties, with smectic mesomorphism. All the compounds pre-
microscopy (AFM). All prepared diselenides showed good
glutathione peroxidase like activity and one of the diselen-
ides was 3.3 times more active than the standard Ebselen.
selenium derivatives have been studied in relation to the
architecture of organic materials of technological interest;
such compounds exhibit behavior that may be suitable for
use in electroconductive polymers, organic semiconductors,
and liquid crystals.[9–15] Despite the potentially beneficial
properties of applying diorganodiselenide compounds as
constituent units in organic functionalized materials, to our
knowledge, only the disulfide structures have been investi-
gated.[16,17]
Introduction
In recent years, interest in organochalcogen compounds
has been driven by their potential applications in modern
organic synthesis of materials and in catalysis.[1,2] Addition-
ally, diorganodiselenides, the selenium counterpart of or-
ganic peroxides, play an important role in organochalcogen
chemistry, because they are stable, easy to handle, and suffi-
ciently reactive to produce electrophilic, nucleophilic, and
radical species.[3,4] The design of new organoselenium com-
pounds, along with other developments, is attracting con-
siderable attention, particularly because of their ability to
mimic natural compounds with important biological prop-
erties, such as antioxidant, antitumor, antimicrobial, and
antiviral activity.[5–8] In addition, it has been shown that the
presence of different chalcogen atoms in organic com-
pounds can induce changes in their photophysical proper-
ties.[9,10] Moreover, the photophysical properties allied with
their liquid crystalline character mean that such materials
are promising for optical device applications, such as emis-
sive LC displays, polarized organic lasers, and anisotropic
OLEDs. However, examples of the use of selenium com-
pounds as liquid crystalline materials are rare.[9] Organo
In this context, the aim of this study was to associate
the remarkable properties of selenium with the structure of
cholesterol, to generate an important class of biological and
synthetic materials in which the molecules are macroscopi-
cally arranged in a periodic helicoidal structure.[18,19]
Cholesterol is a well-known natural product that appears
as a building block in molecular associations. Its versatility
comes from its unique structural features, which are not
found in other compounds. Cholesterol is extensively incor-
porated in molecular systems for a number of reasons: (i) it
is commercial availability; (ii) it has a rigid structure with
eight chiral centers; and (iii) the structure can be easily deri-
vatized.[18–20] Derivatives of cholesterol are present in sev-
eral unique aggregates, including liquid crystals, organic
gels, and monolayers, making it a versatile building block
in organic synthesis.[21,22] The self-assembly of cholesterol-
derived compounds into thermotropic liquid crystalline
(LC) phases is well known. In fact, the first observation
of LC phases was reported for cholesteryl benzoates and
cholesteryl acetates.[23] According to their chemical nature,
cholesteric liquid crystals can be divided into: (a) steroidal,
mainly cholesterol esters; (b) nonsteroidal, better known as
chiral nematics; and (c) induced cholesteric systems,
comprised of a nematic matrix and an optically active
[a] Department of Chemistry LabSelen, Federal University of
Santa Catarina (UFSC),
88040-900 Florianópolis, Brazil
E-mail: braga.antonio@ufsc.br
http://ppgqmc.posgrad.ufsc.br/braga/
[b] Department of Materials Science and Engineering,
Universidade do Extremo Sul Catarinense,
88806-000 Criciúma, SC, Brazil
[c] Department of Physics, Federal University of Santa Catarina
(UFSC),
88040-900 Florianópolis, Brazil
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500124.
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A. L. Braga et al.
FULL PAPER
dopant (OAD), which can be either mesogenic or non- first carried out, generating the selenolate anion in situ
mesogenic.[18–20]
(Scheme 1). In this anionic species of selenium, the corre-
Recently, our group combined the structures of organo- sponding bromo-aliphatic acid in EtOH was added and the
selenides and diorganodiselenides with the remarkable mixture was stirred at room temperature for 24 h. For
properties of oxadiazoles for the synthesis of new fluores- selenide 3, cleavage of dibutyl diselenide was first carried
cent liquid crystals. This was the first report of the synthesis out by using the procedure described above, and the
and characterization of diorganodiselenide oxadiazole de- selenolate anion generated was subsequently added to a
rivatives, with potential use as organic functional materi- solution of bromoacetic acid in tetrahydrofuran (THF), and
als.[24]
the mixture was stirred at room temperature for 24 h. The
In this paper, we describe preliminary studies on the ther- acid selenides 1–3 were obtained with 63, 79, and 75%
mal and photophysical properties of selenium liquid crys- yield, respectively.[31,32]
tals containing cholesterol, to demonstrate their potential
application as functional organic materials. Previously, we
have found that such compounds exhibit good glutathione
peroxidase (GPx)-like activity, indicating their potential for
use in the treatment of diseases related to oxidative stress.[25]
Scheme 1. Intermediate selenides 1–3.
Results and Discussion
For the synthesis of alkyl diselenide 4–6, sodium boro-
hydride was added to a solution containing selenium and
Synthesis
Liquid crystalline compounds containing cholesterol in
their structures have been shown to have potential applica-
tion in the diagnosis of cancer and diseases of the cardio-
vascular and circulatory systems. The cholesteric phase
transition in these compounds plays a key role in their im-
plementation, not only as liquid crystalline materials but
also as biomaterials.[26]
The introduction of chalcogen is designed to provide an-
tioxidant, antitumor, antimicrobial, and antiviral properties
as well as, most importantly, electronic transmission for
possible application as semiconductors.[27–30] The first stage
in the synthesis of three new series of compounds contain-
ing the cholesterol molecule in their structures and with li-
quid crystal properties was the synthesis of selenide and
diselenide intermediates and subsequent esterification with
cholesterol.
water, in an ice bath (Scheme 2). The mixture was briefly
heated by using a heat gun to complete the dissolution of
selenium (ca. 15 min). The reddish-brown aqueous solution
of Na2Se2 was cooled to room temperature and then
bromo-aliphatic acid was added. The resulting yellow solu-
tion was stirred for 3 h. The aqueous layer was extracted
several times with diethyl ether and ethyl acetate, and the
organic extracts were combined and dried (Na2SO4). The
residue was purified by chromatography (ethyl acetate/hex-
ane, 50%) to obtain compounds 4, 5, and 6, with 79, 87,
and 85% yield, respectively.[33]
Scheme 2. Intermediate selenides 4–6.
For the synthesis of selenides 1 and 2, the cleavage of
The methodology used to obtain the aromatic diselenides
diphenyl diselenide with sodium borohydride in EtOH was (Scheme 3).[34–37] began with the transformation of aro-
Figure 1. Yields obtained in the synthesis of the target compounds derived from cholesterol.
2
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Functionalized Organoselenium Materials
matic amines (2-aminobenzoic acid, 3-aminobenzoic acid, purification by column chromatography are shown in Fig-
and 4-aminobenzoic acid) into their respective diazonium ure 1.
salts, using NaNO2 and HCl, which were added to a solu-
tion of K2Se2 (prepared using KOH and elemental selen-
ium), resulting in diselenides 7, 8, and 9 with 51, 48, and
Thermal and Mesomorphic Behavior
43% yield, respectively.
The mesomorphic properties of the final compounds
were investigated by polarized optical microscopy (POM),
differential scanning calorimetry (DSC), and X-ray diffrac-
tion (XRD) analysis. The thermal stability was verified by
thermogravimetric analysis (TGA). The transition tempera-
tures and enthalpy values (kJmol–1) of the compounds were
collected from the second heating scan and are summarized
in Table 1. According to the TGA traces, all compounds
exhibited good thermal stability and their decomposition
Scheme 3. Intermediate selenides 7–9.
The synthesis of the nonsymmetrical selenides 10–12 and temperatures were between 203 and 330 °C.
symmetrical diselenides 13–18 was carried out through the
Six of the nine molecules synthesized displayed liquid
esterification of selenides 1–3 and diselenides 4–9 with the crystal properties. Compounds 12 and 15 exhibited a SmC*
steroid cholesterol, employing a standard procedure that is mesophase, whereas compounds 16–18 showed a chiral en-
widely used to activate carbonyl groups in a nucleophilic antiotropic smectic A (SmA*) mesophase. Compound 14
substitution, using N,N-dicyclohexylcarbodiimide (DCC)/4- displayed both SmC* and SmA* mesophases on heating,
(N,N-dimethylamino)pyridine (DMAP). The yields ob- but only SmC* on cooling. Compound 11 remained in a
tained in the synthesis of cholesterol derivatives 10–18 after supercooled state until room temperature.
Table 1. Transition temperatures (°C) and associated enthalpy values (kJmol–1, in parentheses) for compounds 10–18.
[a] DSC (10 °C min–1). [b] TGA, onset of decomposition (10 °C min–1).
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For the symmetric alkyl diselenides 13–15, a dependence pound 17 at 189 °C. Similar textures were observed for
of the melting points on the chain length was observed, as compounds 16 and 18.
expected. It can be seen that as the internal chain length
increases the melting points decrease and the clearing
points increase, reducing the liquid crystalline range. Com-
pound 13, with only two internal spacer CH2 groups, did
not show liquid crystalline behavior, but by increasing the
number of internal spacer CH2 groups to four, the appear-
ance of two mesophases for compound 14 (SmC* and
SmA*) was observed. With a further increase in the internal
chain length, the rigidity of the molecule decreased, leading
to the appearance of only one mesophase SmC* for com-
pound 15. When the number of internal spacer CH2 groups
Figure 4. Batonnet texture of SmA* mesophase presented by di-
selenide 17 at 189 °C.
was more than four, the compounds can assume other con-
formations, although some of them are not appropriate,
leading to the loss of mesomorphism.[38]
Compounds 12, 14, and 15 presented similar schlieren
texture of the mesophase SmC*. A representative texture
presented by compound 14 at 90 °C is shown in Figure 2.
The DSC thermogram (Figure 5) for compound 18 indi-
cated clearly the presence of two endothermic peaks during
the heating cycles. On cooling, DSC analysis revealed an
isotropic–SmA* transition at 176.6 °C and a SmA*–crystal
transition at 88 °C.
Figure 2. Schlieren texture of the mesophase SmC* observed on
cooling the isotropic liquid at 90 °C, for diselenide 14.
Figure 5. DSC traces of compound 18 for rates of 10 °C min–1; 2nd
The DSC thermogram (Figure 3) for compound 12 indi- heating and cooling runs are shown.
cated clearly the presence of two endothermic peaks, during
For the formation of the mesomorphism, one must con-
heating cycles. On cooling, the DSC trace displays the same
behavior as that seen during the heating cycle, presenting
only one type of mesophase (SmC*). The DSC thermogram
for compound 14 had three peaks during the heating cycle,
representing mesophase transitions at 83 °C to a SmC*,
90 °C to an SmA* mesophase, and 114 °C to the isotropic
liquid. During the cooling cycle, two peaks were observed
and it was possible to note the presence of only the SmC*
mesophase at between 112 and 87 °C.
sider the most stable conformation and structure of diselen-
ide shown in the trans form. It is well known that molecules
with dielement Y–Y (Y = S or Se) bonds are prone to exist
in skewed conformations.[39–41] The dihedral C–Y–Y–C
angles for these compounds are much the same, with their
mean angle falling somewhere between 80–90°. Consider-
ation should be given to compound 16, with a close-contact
O···Se interaction, providing greater linearity and stability
to the molecule, resulting in a higher clearing point. The
temperature range of the mesomorphic behavior observed
for compounds 16–18 was 27 to 90 °C.
X-ray Diffraction
XRD experiments were carried out on compounds 12
and 18 to investigate the smectic structure exhibited by the
mesophases by following a procedure published else-
where.[42] All the recorded patterns contained a sharp peak
in the low-angle region, arising from the reflection of the
X-ray beam on the smectic layers, and corresponding
higher-order peaks identified by the Miller indices (hkl).
Figure 3. DSC traces of compounds 12 and 14 (respectively a and
b) at a rate of 10 °C min–1; 2nd heating and cooling runs are shown.
Compounds 16–18 have a higher structural rigidity than The interlayer spacing was obtained by applying Bragg’s
those of 12–14 cited above. This is a characteristic of great law to the first maximum (001). Figure 6 shows the pattern
importance for obtaining mesomorphic compounds of of compound 12 in the SmC* (153 °C), and the spectrum
SmA. Figure 4 shows the texture SmA* presented by com- was very similar for compound 18.
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Functionalized Organoselenium Materials
lower, which is related to the inclination of the molecules
and to the conformational disorder of the aliphatic chains.
In the case of compound 18, l = 43.3 Å, considering the
most extended configuration.
In this case, a difference of only 1.5 Å is observed with
respect to the interlayer distance (d001), which can be con-
sidered to be associated with the conformational disorder
of the aliphatic chains where, as in the SmA* phase, the
molecules are oriented perpendicular to the molecular
planes.
Morphological Aspects of Thin Films
Atomic force microscopy (AFM) was used to investigate
the morphological aspects of spin-coated films of LC com-
pounds 10–18. The films obtained presented good homo-
geneity, as demonstrated by the AFM image of the film for
compound 12 (Figure 7), with a mean surface roughness
of around 7.5 nm. In addition, the films did not show the
formation of crystallized domains.
Figure 6. XRD pattern for compound 12 in the SmC* phase at
153 °C, with the Miller indices indicated. Inset shows the halo in
the wide-angle region.
The smectic order was confirmed by considering the ra-
tio between the value obtained for the interlayer spacing of
the first maximum (d001) and the values obtained for the
secondary peaks (d00x, with x = 2 and 3). It is well known
that this ratio must obey the relation 1:2:3 in smectic phases
(see all values of d001/d00x in Table 2). The inset of Fig-
ure 6 shows a diffuse halo in the high-angle region that is
related to the short-range correlations between neighboring
molecules within the smectic layers, corresponding to an
average distance of 5.2 Å.
Figure 7. AFM images showing the surface morphology of solid
films of compound 12.
Table 2. X-ray diffraction data for the mesophases of compounds
12 and 18 on cooling. Schematic representation of the dimeric
structure formed by selenide 12 in the SmC* layers.
Glutathione Peroxidase-Like Activity
Compound
Phase/T [°C] Length [Å]
(hkl) dobs [Å] d001/d00x
Glutathione peroxidase-like activity for all the diselen-
ides 13–18, was evaluated according to the Tomoda’s
method,[44,45] using benzenethiol as a glutathione alterna-
tive. The reduction of H2O2 was monitored through the UV
absorption increase at 305 nm, due to diphenyl disulfide
formation. Ebselen was used as a standard in our studies
(Table 3, entry 7). Most of the diselenides showed catalytic
activity that was comparable to that of Ebselen, confirming
that diselenide is a viable group to obtain GPx-mimetic
agents. Notably, alkyl derivatives 14 and 15 provided the
best results (entries 2 and 3). For example, compound 14
was 3.39 times more active than Ebselen, whereas 15 was
001
002
003
38.9
19.4
12.8
2.00
3.03
12
SmC*/153
SmA*/18
12 l = 27.5
ld = 42.3
001
002
003
41.8
20.9
14.0
2.00
2.98
18
l = 43.3
Selenide 12
The molecular length (l) of each compound was esti-
mated by using the ChemBio3D Ultra Software, version
11.0.1. The molecular length calculated for compound 12
was l = 27.5 Å. On comparing this length with the interlayer
distance of d001 = 38.9 Å, a tendency toward the formation
of antiparallel dimers can be noted, which is due to the
well-known close-contact interaction between O and Se,[43]
as illustrated in Table 2. Comparing ld with d001 reveals
that the distance measured for the SmC* layers is 3.4 Å
Table 3. GPx-like activity of diselenides 13–18.
Entry
Catalyst
T50 [min]
Efficiency relative to Ebselen
1
2
3
4
5
6
7
13
14
15
16
17
138.34 (Ϯ3.46)
44.76 (Ϯ0.52)
76.10 (Ϯ1.23)
126.81 (Ϯ1.87)
108.70 (Ϯ2.80)
117.05 (Ϯ2.43)
152.17 (Ϯ3.35)
1.09
3.39
1.99
1.19
1.39
1.30
1.00
18
Ebselen
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viously described procedures.[42] The scans were realized in con-
tinuous mode from 2 to 30° (2θ angle) with the samples in the
smectic phases by cooling from the isotropic state.
1.99 times more active. Aromatic compounds 16–18 pre-
sented activity around 1.19–1.39 times higher than Ebselen.
Further biological studies are in progress in our group.
IR Spectroscopic Analysis: IR spectra were recorded with a Perkin–
Elmer Spectrum 100 FTIR spectrometer with a resolution of
4 cm–1 and in the 400–4000 cm–1 wavenumber range (40 scans were
co-added for the final spectrum). The compounds were sandwiched
between two KBr windows and gently heated with a heating gun
to better spread the sample. The measurements were taken at room
temperature (25 °C).
Conclusions
We have synthesized three new series of chalcogen liquid
crystals, based on selenides and diselenides, containing cho-
lesterol in their structure. Six of the nine synthesized mol-
ecules showed liquid crystal properties. For the series of
Atomic Force Microscopy (AFM): AFM was used to investigate the
alkyl diselenides, a dependence of the melting points on the morphological aspects of spin-coated films of compounds 10–18.
The AFM measurements were carried out with Shimadzu SPM-
9700 equipment, with dynamic mode scanning.
number of internal spacer CH2 groups was observed. With
an increase in the length of the internal chain, the com-
pounds can assume other conformations, although some of
them are not appropriate, leading to a loss of mesomor-
phism. Selenide 12 and alkyl diselenides 14 and 15 exhibited
a SmC* mesophase, whereas aryl diselenides 16–18, with
a higher structural rigidity, showed a chiral enantiotropic
smectic A (SmA*) mesophase. All synthesized compounds
presented good thermal stability. The smectic mesomor-
phism was confirmed with the support of XRD analysis,
from which we observed that compound 12 adopts a di-
meric layered structured, as a result of the close inter-
molecular proximity, most likely from the nonbonding in-
teraction between the O and Se atoms. Diselenides 13–18
all showed good catalytic activity that was comparable to
that of Ebselen. Thus, we have described herein a new class
of selenium compounds, containing cholesterol, with poten-
tial application as a new material with antioxidant proper-
ties. Further biological studies are in progress in our group.
Mass Spectrometry: The mass spectrometry (MS) system consisted
of a hybrid triplequadrupole/linear ion trap mass spectrometer (Q
Trap 3200, Applied Biosystems/MDS Sciex, Concord, Canada).
Analyst version 1.5.1 was used for the LC/MS/MS system control
and data analysis. The mass spectrometry was tuned in the negative
and positive modes by infusion of a polypropylene glycol solution.
The experiments were performed with a TurboIonSpray source
(electrospray-ESI). High-resolution mass spectra (HR-MS) were re-
corded with a Bruker BioApex 70e FT-ICR (Bruker Daltonics,
Billerica, USA) instrument in ESI mode.
Determination of GPx-Like Activity: The catalytic GPx model reac-
tion (H2O2 + 2PhSHǞ2H2O + PhSSPh) was initiated by the ad-
dition of H2O2 (final concentration: 5 mm) to a solution of meth-
anol (or ethanol when necessary), final volume: 1 mL, of thi-
ophenol (PhSH) (final concentration 2 mm) containing the selen-
ium catalyst (final concentration: 0.1 mm) at 25(Ϯ3) °C. The re-
duction of H2O2 was monitored by UV spectrophotometry, at
305 nm, through the formation of PhSSPh. The reaction was moni-
tored for 150 s, at least three times under the same conditions. Ac-
tivities of the compounds were compared with the activity of Eb-
selen as a positive control.
Experimental Section
Materials and Characterization: All of the reagents were commer-
cially available and were used without further purification. Organic
solvents were of commercial grade and were dried by traditional
methods. Column chromatography was performed by using column
silica gel (230–400 mesh), and thin-layer chromatograph (TLC) was
performed by using silica gel GF254 (0.25 mm), both purchased
from Merck. 1H and 13C NMR spectra were recorded with a Varian
VXR spectrometer operating at 400 and 100.6 MHz, respectively.
Melting points were determined with a Nikon Optishot 2 micro-
scope equipped with a Mettler FP-82 Hot Stage. Elemental analysis
was carried out with a Leco CHNS-932 instrument.
Acknowledgments
The authors are grateful to the Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior (CAPES), the Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq/INCT), the In-
stitutos Nacionais de Ciência e Tecnologia – Catálise (INCT-Catál-
ise), the The World Academy of Sciences (TWAS) and the Fun-
dação de Amparo à Pesquisa do Estado de São Paulo/Programa de
Apoio a Núcleos de Excelência (FAPESC/PRONEX) for financial
support. The Laboratório Central de Biologia Molecular Estrutu-
ral (CEBIME-UFSC) is thanked for the HRMS analysis.
Thermal Analysis: Thermal transitions and enthalpies were deter-
mined from DSC measurements obtained using TA equipment with
a Q2000 module or a Perkin–Elmer DSC-7 applying a heating/
cooling rate of 10 °Cmin–1 and a nitrogen flow of 50 mLmin–1.
Thermal stability was investigated by TGA with a Shimadzu ana-
lyzer with a TGA-50 module, a heating rate of 10 °Cmin–1 and
nitrogen flow of 20 mLmin–1. Mesomorphic textures were deter-
mined with a Nikon Optishot 2 microscope equipped with a
Mettler Toledo FP-82 Hot Stage and a Nikon Coolpix 995 digital
camera.
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Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O50124
/KAP1
Date: 20-04-15 15:13:00
Pages: 8
A. L. Braga et al.
FULL PAPER
Liquid Crystals
A new series of selenide and diselenide
liquid crystals containing cholesterol were
synthesized and characterized. Most of the
materials presented good thermal stability
with SmC* and SmA* phases over a wide
temperature range. The prepared diselen-
ides also have potential biological appli-
cations, and they showed good antioxidant
properties.
T. E. Frizon, J. Rafique, S. Saba,
I. H. Bechtold, H. Gallardo,
A. L. Braga* ..................................... 1–8
Synthesis of Functionalized Organoselen-
ium Materials: Selenides and Diselenides
Containing Cholesterol
Keywords: Liquid crystals / Mesophases /
Selenium / Steroids
8
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Eur. J. Org. Chem. 0000, 0–0