Symmetrical and non-symmetrical 2,5-diaryl-1,3,4-oxadiazoles: Synthesis and photophysical properties

Article abstract of DOI:10.1016/j.tetlet.2015.05.005

We report herein the synthesis of 2,5-diaryl-1,3,4-oxadiazoles containing both electron-donating and withdrawing substituents as well as bis- and tris-2,5-disubstituted-1,3,4-oxadiazoles containing electron-donating substituents. The photophysical properties of the synthesized compounds were studied using UV-Vis and fluorescence spectroscopy. The aryl substitution pattern was found to have a marked impact on both luminescence efficiency and other photophysical properties. An increase in the number of electron-donating groups and/or the number of heterocyclic rings provided a red shift of the emission maxima, as well as an increase of the Stokes shifts. The same effect was observed for mono-1,3,4-oxadiazoles containing push-pull substituents on the aryl rings.

Full text of DOI:10.1016/j.tetlet.2015.05.005

Accepted Manuscript
Symmetrical and non-symmetrical 2,5-diaryl-1,3,4-oxadiazoles: synthesis and
photophysical properties
Codruța C. Paraschivescu, Niculina D. Hădade, Anca G. Coman, Arnaud
Gautier, Federico Cisnetti, Mihaela Matache
PII:
S0040-4039(15)00794-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.05.005
TETL 46277
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 March 2015
26 April 2015
2 May 2015
Please cite this article as: Paraschivescu, C.C., Hădade, N.D., Coman, A.G., Gautier, A., Cisnetti, F., Matache, M.,
Symmetrical and non-symmetrical 2,5-diaryl-1,3,4-oxadiazoles: synthesis and photophysical properties,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.05.005
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Symmetrical and non-symmetrical 2,5-
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photophysical properties
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Codruța C. Paraschivescu, Niculina D. Hădade, Anca G. Coman, Arnaud Gautier, Federico Cisnetti, Mihaela
Matache∗
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Tetrahedron Letters
journal homepage: www.elsevier.com
Symmetrical and non-symmetrical 2,5-diaryl-1,3,4-oxadiazoles: synthesis and
photophysical properties
Codruța C. Paraschivescu,a Niculina D. Hădade,b Anca G. Coman,a Arnaud Gautier,c,d Federico Cisnetti,c,d
Mihaela Matachea,∗
a University of Bucharest, Faculty of Chemistry, 90-92 Panduri Street, RO-050663-Bucharest, Romania
b Faculty of Chemistry and Chemical Engineering, “Babeṣ-Bolyai” University, 11 Arany Janos Str., RO-400028-Cluj-Napoca, Romania
c Université Clermont Auvergne, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France
d CNRS, UMR 6296, ICCF, F-63171 Aubiere, France
ARTICLE INFO
ABSTRACT
Article history:
Received
We report herein the synthesis of 2,5-diaryl-1,3,4-oxadiazoles containing both electron-donating
and withdrawing substituents as well as bis- and tris-2,5-disubstituted-1,3,4-oxadiazoles
containing electron-donating substituents. The photophysical properties of the synthesized
compounds were studied using UV-Vis and fluorescence spectroscopy. The aryl substitution
pattern was found to have a marked impact on both luminescence efficiency and other
photophysical properties. An increase in the number of electron-donating groups and/or the
number of heterocyclic rings provided a red shift of the emission maxima, as well as an increase
of the Stokes shifts. The same effect was observed for mono-1,3,4-oxadiazoles containing push-
pull substituents on the aryl rings.
Received in revised form
Accepted
Available online
Keywords:
2,5-diaryl-1,3,4-oxadiazoles
fluorescence
oxidative cyclisation
bis(trifluoroacetoxy)iodobenzene
heterocycles
2009 Elsevier Ltd. All rights reserved.
In the search for new molecules with remarkable
optoelectronic properties, the 1,3,4-oxadiazole core has found a
central place, mainly due to its electron-deficient character.1 In
particular, the 2,5-diaryl-1,3,4-oxadiazole core has been largely
exploited in order to access new materials for use as electron-
transporting compounds for the preparation of Organic Light-
Emitting Diodes (OLEDs).1,2 Moreover, recent publications
indicate useful applications of the 1,3,4-oxadiazole scaffolds as
sensors for various cations3 or anions.4 In addition, metal
complexes of 1,3,4-oxadiazoles have gained attention as gelators
of organic solvents,5 molecular logic gates and fluorescent
switches6 or simply due to displaying interesting
photoluminescent properties.7 Polymers or copolymers
containing the 1,3,4-oxadiazole core have also been reported to
exhibit good luminescence properties.8
method of choice for their preparation. We recently reported a
smooth, room temperature synthesis of 1,2-(bis-1,3,4-oxadiazol-
2-yl)benzenes
I
(Figure
1)
using
PIFA
(bis(trifluoroacetoxy)iodobenzene) as an oxidative cyclization
agent.15
Figure 1. Structure of 1,2-bis(1,3,4-oxadiazol-2-yl)benzenes bearing 4-
methoxyphenyl or 3,4,5-(trimethoxy)phenyl substituents
The influence of the number of heterocyclic rings and the
nature of their substituents9,10 have been studied in order to
provide structurally diversified molecules with improved
photoelectronic properties. In this context, synthetic strategies to
prepare such molecules have been investigated.11,12 Essentially,
1,3,4-oxadiazoles can be obtained by the dehydration of N,N-
diacylhydrazines,13 oxidative cyclization of N-acyl-hydrazones14
or the Huisgen reaction of tetrazoles and acid chlorides.9 Due to
the ready availability of N-acylhydrazones from aldehydes and
carboxylic acid hydrazides and the mild conditions required for
—the—he—terocyclic ring closure, oxidative cyclisation is often the
In a continuation of our work, we have examined in detail the
fluorescent properties of 2,5-diaryl-1,3,4-oxadiazoles bearing one
or three methoxy groups as substituents on the aryl rings and we
describe herein these properties. In addition, other 2,5-
disubstitued-1,3,4-oxadiazoles were synthesized for comparative
purposes. Therefore, we set out to evaluate the influence of the
substituents and the number of the heterocyclic rings on the
absorption and emission properties with the aim of developing
compounds with improved photophysical properties.
∗Corresponding author. Tel.: +4-021-305-1440; fax: +4-021-412-0140; e-mail: mihaela.matache@g.unibuc.ro

2
Figure 2. Structures of the compounds studied
Scheme 1. Synthesis of the 2,5-disubstituted 1,3,4-oxadiazoles 1a-e, 2a-d and 3a,b
We prepared three series of compounds possessing various
numbers of 2,5-disubstituted-1,3,4-oxadiazole rings and/or
substituents with different electronic properties as depicted in
Figure 2. The synthesis of the compounds was performed as
described in Scheme 1. Firstly, condensation of benzaldehydes
4a-c with the corresponding hydrazides 5a-c afforded, after
filtration, the expected acylhydrazines 6a-d.
phthalaldehyde
7
with the hydrazides 5a,b yielded the
corresponding acylhydrazines 8b,c,e,f which were further
converted into the oxadiazoles 2b,c,e,f by oxidation. Compounds
2a and 2d were synthesized as previously described.15
Compounds 3a,b were obtained by following the same two step
strategy starting from 1,3,5-benzene trihydrazide 9 and p-
methoxybenzaldehyde or 3,4,5-trimethoxybenzaldehyde to afford
hydrazones 10a,b and their subsequent oxidative cyclisation (see
ESI for general procedures).
Treatment of compounds 6a-d with 1.1 equivalents of PIFA at
room temperature triggered the ring closure and provided the
oxadiazoles 1a-d in very good yields. Compound 1e was
synthesized by esterification of 1d (see ESI). Besides the
symmetrical 2,5-disubstituted-1,3,4-oxadiazole 1a, this procedure
allowed the synthesis of non-symmetrical structures containing
on one side an electron rich and on the other side an electron-
donating or electron-withdrawing substituent grafted on the aryl
rings. In a similar manner, condensation of meta- and para-
All compounds were characterized by NMR and HRMS
analysis (see ESI for the NMR and MS spectra of the
compounds). Notably, an increase of the number of the
heterocyclic moieties leads to a decrease of the solubility in
organic solvents.

3
The fluorescence spectra were each collected under identical
conditions for all compounds (20% DMSO-phosphate buffer 10-2
mol L-1, pH=7.4, Figures 3 and 4) and the fluorescence quantum
yields ( 10%) were determined using quinine sulfate in 0.5 M
H2SO4, Φ = 0.55).16 Our choice to perform the measurements in
aqueous medium is based on our intent for further use of the
oxadiazoles as fluorescent tags under biological conditions.17 The
photophysical properties of all compounds are summarized in
Tables 1-3 and Figures 3-4.
Table 1. Photophysical properties of oxadiazoles 1a-e
a
ε@λex
(L mol-1
cm-1 × 10-4)
Stokes
shift (nm;
cm-1 × 10-3)
Figure 4. Excitation (dotted lines) and emission (plain lines) spectra of
compounds 2a-c and 3a (5 × 10-7 mol L-1).19
λex
λem
Cmpn.
Φ
(nm)
(nm)
Regarding bis- and tris-oxadiazoles bearing methoxyphenyl
(2a-c, 3a, Figure 4) or trimethoxyphenyl (2d-f, 3b, see ESI), one
can note the following features. ortho-Substituted compound 2a
is an interesting brilliant fluorophore with a large Stokes shift.
The blue shift observed in the case of the excitation of 2a vs. 1a
(26 nm) as compared to 2b vs. 1a (1 nm) is consistent with the
lack of planarity for the ortho substituted 2a.9 On the other hand,
meta-substituted 2b shows a smaller Stokes shift and a reduced
quantum yield, which may be correlated with inefficient
communication between the oxadiazole moieties. The tris-
oxadiazole 3a presents a spectral signature quite similar to 2b, as
the oxadiazole moieties are likewise unable to interact. This
“isolated oxadiazole” behaviour is also consistent with the
similar excitation wavelengths for 1a, 2b and 3a. The para-
substitution in 2c results in a very weak emission. Compounds
2d-f and 3b, bearing trimethoxyphenyl substituent(s) are
generally less emissive than their methoxyphenyl counterparts.
Compound 2e displays a spectral signature quite similar to that of
2b albeit with a larger Stokes shift (see ESI).
1a
1b
1c
1d
1e
307
308
308
307
307
2.48
2.98
2.20
2.97
NDb
370
415
465
415
478
63; 5.55
107; 8.37
157;10.96
108; 8.48
0.23
0.085
0.11
0.085
171; 1.55 <0.01
aThe molar extinction coefficient was calculated from the UV-Vis spectra at
the indicated excitation wavelength;18 bnot determined
Superimposition of the spectra of compounds 1a-e and
quinine shows that compounds 1a-d are easily detected in highly
diluted solutions. Interestingly, 1a is a more brilliant (ε×Q)
fluorophore than quinine (even though its quantum yield is only
0.23) due to a higher molar absorptivity at the excitation
maximum.
Table 2. Photophysical properties of oxadiazoles 2a-f
a
ε@λex
(L mol-1
cm-1× 10-4)
Stokes shift
(nm; cm-1
10-3)
λex
λem
Cmpn.
×
Φ
(nm)
(nm)
2a
2b
2c
2d
2e
2f
281
308
~320
294
308
294
4.18
1.86
NDb
NDb
2.40
NDb
456
388
434
402
430
418
175; 13.66
80; 6.69
0.082
0.03
114; 8.21
108; 9.14
122; 9.21
124; 10.09
<0.01
<0.01
0.026
<0.01
Figure 3. Excitation (dotted lines) and emission (plain lines) spectra of
compounds 1a-e as well as quinine. (5 × 10-7 mol L-1) 19
The excitation maxima of compounds 1a-e are very similar:
λex,max~308 nm (Figure 3, Table 1) which indicate that the
substituents grafted on the oxadiazole core have no significant
influence on the absorption properties. On the contrary, the
emission maxima of compounds 1a-e (Figure 3) – hence their
Stokes shifts – are different and are dependent on the electronic
polarization due to the aromatic ring substituent(s). Indeed, an
increase in the number of the methoxy substituents (1a vs. 1b)
resulted in a bathochromic shift of 45 nm. The same pattern was
observed, in an even larger extent, when a methoxy group from
compound 1a was replaced by an electron-withdrawing
substituent: 1a vs. 1c (MeO vs. CN, shift: 95 nm), 1a vs. 1d
aThe molar extinction coefficient was calculated from the UV-Vis spectra at
the indicated excitation wavelength18; b not determined
Table 3. Photophysical properties of oxadiazoles 3a-b
a
ε@λex
(L mol-1
cm-1× 10-4)
Stokes shift
(nm; cm-1
10-3)
λem
λex,
(nm)
Cmpn.
×
Φ
(nm)
3a
3b
309
334
5.83
1.91
425
515
116; 8.83
181;10.52
0.012
0.018
-
(MeO vs. CO2 , shift: 55 nm) and 1a vs. 1e (MeO vs. CO2Me,
aThe molar extinction coefficient was calculated from the UV-Vis spectra at
the indicated excitation wavelength18
shift: 105 nm). Intriguingly, compound 1a displayed the highest
quantum yield obtained for all compounds tested. Compounds
1b, 1d and particularly 1c have reasonable luminescence
intensities and quantum yields combined with large Stokes shifts,
a desirable property in fluorescence assays.
A comparison of the whole set of compounds discussed herein
is difficult due to the variation of several structural and electronic
parameters. However, for each subset of compounds containing a
given aromatic substituent motif (methoxy: 1a, 2b, 3a;
trimethoxy: 1b, 2e, 3b), a regular trend in terms of the
bathocromic emission shift (and an increase in the Stokes shift)

4
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may be observed, although at the expense of the luminescence
intensity.
In conclusion, we have synthesized and studied the fluorescent
properties in aqueous medium of three series of compounds
containing one, two or three 1,3,4-oxadiazole rings and
substituents with various electronic properties. The compounds
bearing only electron-donating substituents on the aryl ring
displayed an increase of the emission wavelength which was also
observed with an increase of the number of heterocyclic rings
and the number of methoxy groups. The same behaviour is
observed for the Stokes shifts. Importantly, the same results are
obtained for compounds containing only one heterocyclic ring by
the introduction of push-pull substituents on the aryl rings. In
addition, the small size of the oxadiazole ring, an amide
isostere,20 as well as their good photophysical properties may
mean these are candidates for use in protein fluorescent tagging.
It might be interesting to study the behaviour of bis- and tris-
oxadiazoles containing compounds bearing push-pull groups
system for such applications.
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Acknowledgments
Financial support by the National Research Council (CNCS)
of Romania, project PN-II-PT-PCCA-2011-3.1-0595, as well as
project PN-II-RU-TE-2012-3-0471 are gratefully acknowledged.
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18. Measurements were performed on a minimum of eight different
dilutions using 20% DMSO-phosphate buffer 0.01 mol L-1 from
stock solutions of compounds dissolved in DMSO with
concentrations varying between 2 x10-5 mol L-1 and 6.5 x10-5 mol
L-1 and the extinction coefficients were calculated as an average of
the individual values resulted for each sample.
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Details of the experimental procedures for the synthesis of the
N-acylhydrazones, 2,5-disubstituted-1,3,4-oxadiazoles, NMR and
HR-MS spectra as well as the experimental procedures for the
study of the absorption and emission properties are described.
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Che, C.-M. Chem. Asian. J. 2008, 59–69; b) Qu, S.; Wang, L.;