One pot solvent-free solid state synthesis, photophysical properties and crystal structure of substituted azole derivatives

Article abstract of DOI:10.1016/j.molstruc.2018.12.095

A solvent-free solid state method has been developed to synthesize three series of substituted azole derivatives (including 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole) in high yields by condensation cyclization of N,N′-bishydrazide derivatives with corresponding cyclization agents, respectively. This general method avoids the use of organic solvents, saves cost and resources, simplifies post-processing and increases reaction rates. These compounds have been fully characterized by ¹H NMR, ¹³C NMR, elemental analysis and MS. The structure of 2,5-di (4-tertbutylphenyl)-1,3,4-oxadiazole has been determined by single crystal X-ray diffraction analysis. The cell parameters are as follows: monoclinic crystal system, Cc space group, a = 18.735 (2) ?, b = 6.3375 (8) ?, c = 16.824 (2) ? and α = γ = 90°; β = 98.292 (2). The electronic absorption and fluorescent properties of these compounds have been systematically investigated for the first time. The relationships between heterocyclic structures and photophysical properties have been discussed. The alteration of emission and absorption wavelengths can be elucidated by hybrid atoms' electronegativity and Substituents' Hammett constants. This approach proposes a novel insight to provide a great number of novel substituted azole derivatives with good photophysical properties by a general green method.

Full text of DOI:10.1016/j.molstruc.2018.12.095

Accepted Manuscript
One pot solvent-free solid state synthesis, photophysical properties and crystal
structure of substituted azole derivatives
Yanting Du, Zilu Wan, Lianqin Chen, Lamei Wu
PII:
S0022-2860(18)31528-X
DOI:
https://doi.org/10.1016/j.molstruc.2018.12.095
MOLSTR 26032
Reference:
To appear in: Journal of Molecular Structure
Received Date: 30 September 2018
Revised Date: 20 December 2018
Accepted Date: 23 December 2018
Please cite this article as: Y. Du, Z. Wan, L. Chen, L. Wu, One pot solvent-free solid state synthesis,
photophysical properties and crystal structure of substituted azole derivatives, Journal of Molecular
Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2018.12.095.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphic Contents
Three series of substituted azole derivatives have been generally prepared by one pot
solvent-free solid state method, and the relationship between their structures and
electronic absorption and fluorescent properties have been systematically investigated.

ACCEPTED MANUSCRIPT
One pot solvent-free solid state synthesis, photophysical properties
and crystal structure of substituted azole derivatives
Yanting Dua, Zilu Wana, Lianqin Chena,b*, Lamei Wu
a
Key Laboratory of Catalysis and Materials Science of the State Ethnic Affairs Commission & Ministry of
Education, South-Central University for Nationalities, Wuhan, 430074, P. R. China.
b Department of Chemistry, University of Wisconsin-Platteville, Platteville, 53818, United States
Corresponding Author:
Lianqing Chen, Tel. & Fax. +86-27-67842752
E-mail: lqchen@mail.scuec.edu.cn; chenlia@uwplatt.edu.
1

ACCEPTED MANUSCRIPT
Abstract
A solvent-free solid state method has been developed to synthesize three series of substituted azole derivatives
(including 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole) in high yields by condensation cyclization of
N,N’-bishydrazide derivatives with corresponding cyclization agents, respectively. This general method avoids the
use of organic solvents, saves cost and resources, simplifies post-processing and increases reaction rates. These
1
compounds have been fully characterized by H NMR, 13C NMR, elemental analysis and MS. The structure of
2,5-di (4-tertbutylphenyl)-1,3,4-oxadiazole has been determined by single crystal X-ray diffraction analysis. The
cell parameters are as follows: monoclinic crystal system, Cc space group, a = 18.735(2) Å, b = 6.3375(8) Å, c =
16.824(2) Å and
α =γ = 90°; β = 98.292(2). The electronic absorption and fluorescent properties of these
compounds have been systematically investigated for the first time. The relationships between heterocyclic
structures and photophysical properties have been discussed. The alteration of emission and absorption wavelengths
can be elucidated by hybrid atoms’ electronegativity and Substituents’ Hammett constants. This approach proposes
a novel insight to provide a great number of novel substituted azole derivatives with good photophysical properties
by a general green method.
Keywords: Substituted azole derivatives; one-pot synthesis; solvent-free solid state; photophysical properties;
Hammett substituent constants.
2

ACCEPTED MANUSCRIPT
1. Introduction
Substituted azole derivatives (including 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole) are very
important members within the five-membered aromatic heterocyclic families [1]. There is a persistent growing
interest in the synthetic research of substituted azole derivatives due to its wide application and excellent properties
[2, 3]. Recently, 1,3,4-thiadiazole derivatives have been frequently used as the fundamental pharmacophores in the
design of new molecular drugs due to their good biochemical activity [4, 5] and 1,2,4-triazole derivatives have been
well known for their biological and pharmaceutical activities, such as antifungal, antiviral, antimicrobial activities
and potent inhibitory activity [6, 7]. Most recently, 1,3,4-oxadiazole derivatives have also attracted increasing
attention due to their excellent electron transport properties in the area of organic optoelectronic materials, which
can be employed as two-photo absorption chromophores [8], second-order nonlinear optical materials [9] and
charge transfer materials in the organic light emitting diodes [10].
Thus far, numerous synthetic methods have been developed to prepare substituted azole derivatives, such as
dehydration of diacylhydrazines methods, oxidative cyclization of aldehyde N-acylhydrazones synthesis and
Dess-Martin reagent methods for 1,3,4-oxadiazole derivatives [11]; dehydration cyclization methods, Lawesson
regent or microwave mediated reaction combinatorial synthesis [12] and polymer supported synthesis for
1,3,4-thiadiazole derivatives [13]; tetrazine rearrangement method [14], microwave mediated reaction [15] and
one-pot solvothermal method for 1,2,4-triazole derivatives [16] and, etc. However, these synthetic methods are
separated, not general to prepare azole derivatives and typically carried out in the presence of organic solvents.
Therefore, isolation of the pure products requires complicated solvent separation and purification steps, which
results in a substantial decrease in yield for products and can be environmentally hazardous processes. A green and
efficient way to reduce environmental impact and increase yields is to generate the synthetic procedure in the
3

ACCEPTED MANUSCRIPT
absence of organic solvent, such as solvent-free or solid state synthetic methods, which have some advantages
including reducing cost, increasing reaction yield, simple post-processing and minimal the negative effects on the
environmental resource comparing to conventional solvent reaction.
Up to date, a great number of efforts have been adopted to develop some novel solid state or solvent-free
methods for effective preparation of a wide range of aromatic heterocyclic compounds. K. Tanaka and F. Toda have
reported that many organic reactions proceed efficiently in the solid state [17]. Wang and Qin discovered
solvent-free synthesis of pyrazole derivatives with diketones and hydrazine hydrate as raw materials [18]. Kaupp
and Schmeyers found carbonyl compounds can be prepared by the solid state reactivity of hydrazine-hydroquinone
complexes [19]. The aldol condensation reactions between ketones and aldehydes can be carried out with solid state
grinding synthetic method in the absence of solvent at ambient conditions [20]. Indeed, in many cases, solvent-free
solid state organic reaction occurs more selectively and efficiently than does its solution counterpart, since
molecules in a crystal state are arranged regularly and tightly. Solvent-free solid state synthesis seems to be a highly
useful technique, however, to our knowledge, which has not been applied to general synthesis of substituted azole
derivatives.
Substituted azole derivatives have been extensively studied, and their heterocyclic structure and photophysical
properties have been studied [21]. Moreover, as far as we know, less systematic survey on the relationship between
their substituted heterocyclic structure and electronic absorption, fluorescence properties are closely related with the
electronic characters of substituted azole derivatives. There is an urgent need to understand the relationship between
their heterocyclic structure and photophysical properties, which will be benefit a lot to design more novel
fluorescent heterocyclic molecules to tune luminescent or charge transfer properties.
Herein, a solvent-free solid state synthetic process was employed to obtain three series of substituted azole
derivatives in high yields by condensation cyclization of N,N’-bishydrazide derivatives with deferent cyclization
agents and fully characterized by NMR, elemental analysis and MS. The crystal structure of
4

ACCEPTED MANUSCRIPT
2,5-di(4-tertbutylphenyl)-1, 3, 4-oxadiazole has also been determined. We will discuss how the hybrid atoms in
five-membered aromatic heterocyclic rings and substitutes with different position or electronic effect on the
aromatic ring of 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole tune their electronic absorption and
fluorescent properties.
2. Experimental Section
2.1. General information
WRS-4 Melting Point apparatus was used to collect melting points (uncorrected) data. 1H NMR and 13C NMR
were performed on AVANCEꢀ-400MHz spectrometer with CDCl3 or DMSO-d6 as solvent. Fourier transform
infrared spectroscopy (FT-IR) was obtained on a NeXUS 470 spectrometer using KBr pellet technique. Single
crystal diffractometer SMART APEX II was employed for crystal structure determination. Elemental analysis of
carbon, hydrogen, and nitrogen were carried out on a Carlorerba-1106 microanalyzer. VJ-ZAB-3F Mass
Spectrometer determined Mass Spectra (FAB-MS). The UV-Vis absorption spectroscopy was measured using a
Shimadzu UV-2600 spectrophotometer. Photoluminescence (PL) spectra were recorded on a Hitachi F-7000
Fluorescence Spectrophotometer. Solution of quinine bisulfate (10-5 M in 1.0 N H2SO4) was used as a reference (Φf
2
= 0.546, as standard). The equation Φs=Φr (ηs ArIs/ηr2AsIr) was employed to calculate the sample’ quantum yields of
fluorescence, where Φr is the quantum yield of the reference, ηs is the refractive index of the solvent, Φs is the
quantum yield of the samples, Is and Ir are the integrated areas of emission bands, As and Ar are the absorbance of
the sample and the reference at the wavelength of excitation [22].
The raw materials, such as acyl chlorides and hydrazine hydrate, were purchased from Aladdin Reagents Co.,
Ltd. The intermediates, i.e. 4-methoxy-N'-(4-methoxybenzoyl)benzohydrazide [23], N'-benzoylbenzo-hydrazide
[24], 4-tert-butyl-N'-(4-tert-butylbenzoyl)benzohydrazide [25], 4-methyl-N'-(4-methylbenzoyl)benzohydrazide [26],
4-nitro-N'-(4-nitrobenzoyl)benzohydrazide, 4-fluoro-N'-(4-fluorobenzoyl)benzohydrazide [27], 3-fluoro-N'-(3-fluoro
5

ACCEPTED MANUSCRIPT
benzoyl)benzohydrazide, 2-fluoro-N'-(2-fluorobenzoyl)benzohydrazide and N'-nicotinoylnicotino-hydrazide [28]
were synthesized according to literature procedure. TLC test was used silica gel GF-254 (Qingdao Ocean Chemical
Co., Ltd.). All silica gel column chromatography was performed with use of silica gel (200~300 mesh). Other
chemicals were of analytical grade quality obtained from commercial suppliers (Wuhan Guoyao Chemical Reagent
Co. Ltd.) and used directly without further purification.
2.2. One pot solvent-free solid state synthesis of Type I~III azole derivatives.
Scheme 1 General synthetic procedure of Type I~III azole derivatives.
General synthetic procedure was as follows: N,N’-bishydrazide derivatives powder (10 mmol) and the
corresponding cyclization agents (30 mmol) were slowly added into the agate mortar at room temperature. The
mixture was carefully ground using a pestle for about 0.5 h, and then transferred the uniform fine powder into a
dried 100 mL Teflon-lined autoclave with the rate of 1 °C/min and heated to the reaction temperature in the electric
oven and kept for a few hours. After cooling naturally to room temperature, the white or light yellow precipitate was
washed with distilled water several times, filtered and further purified by recrystallization in 85% ethanol to give the
products.
6

ACCEPTED MANUSCRIPT
2.2.1 One pot solvent-free solid state synthesis of Type I 1,3,4-oxadiazole derivatives (I-1~11).
Scheme 2 Solvent-free solid state synthesis of 1, 3, 4-oxadiazole derivatives I-1~11
2,5-bis(4-methoxyphenyl)-1,3,4-oxadiazole (I-1): white powders, mp: 161.5-161.9ꢁ. 1H NMR (400MHz, CDCl3) δ:
8.16(2H, d, J=4.0Hz, Ph), 8.04(2H, d, J=8.8Hz, Ph), 7.26(2H, s, Ph), 7.15(2H, s, Ph), 3.26(6H, s, OCH3). 13C NMR
(400MHz, CDCl3) δ: 164.5, 158.9, 127.2, 124.1, 115.0, 56.1. Anal.Calcd. for C16H14N2O3: C, 68.07; H, 5.00; N,
9.92; O, 11.37; Found: C, 68.45; H, 5.23; N, 10.13%. MS (FAB): m/e, calculated 282.10(M+), found 282.13(M+).
1
2,5-di(4-tertbutylphenyl)-1,3,4-oxadiazole (I-2): transparent column-shaped crystals, mp: 173.6-174.3ꢁ. H NMR
(400MHz, CDCl3) δ: 7.91(4H, m, Ph), 7.35(4H, m, Ph), 1.38(18H, m, CH3). 13C NMR (400MHz, CDCl3) δ: 164.3,
147.2, 134.6, 126.6, 125.3, 34.1, 31.7. Anal.Calcd. for C22H26N2O: C, 79.00; H, 7.84; N, 8.38; Found: C, 79.36; H,
7.55; N, 8.60%. MS (FAB): m/e, calculated 334.20(M+), found 334.21(M+).
1
2,5-di(p-tolyl)-1,3,4-oxadiazole (I-3): colorless needle crystals, mp: 174.9-175.4ꢁ. H NMR (400MHz, CDCl3) δ:
7.99(4H, d, J=3.6Hz, Ph), 7.30(4H, d, J=4.8Hz, Ph), 2.42(6H, s, CH3).13C NMR (400MHz, CDCl3) δ: 164.6, 142.4,
129.6, 126.7, 121.2, 21.4. Anal. Calcd. for C16H14N2O: C, 76.78; H, 5.64; N, 11.19; Found: C, 76.72; H, 5.67; N,
11.13%. MS (FAB): m/e, calculated 250.11(M+), found 250.13(M+).
2,5-di(m-tolyl)-1,3,4-oxadiazole (I-4): white powders, mp: 72.5-73.1 ꢁ . 1H NMR (400 MHz, CDCl3) δ:
13
7.81-7.87(3H, m, J=4.4Hz, Ph), 7.23-7.31(5H, m, J=8.8Hz, Ph), 2.44(6H, s, CH3). C NMR (400MHz, CDCl3) δ:
7

ACCEPTED MANUSCRIPT
164.7, 138.9, 130.4, 129.2, 129.1, 126.1, 124.5, 24.6. Anal. Calcd. for C16H14N2O: C, 76.78; H, 5.64; N, 11.19;
Found: C, 76.54; H, 5.70; N, 11.32%. MS (FAB): m/e, calculated 250.11(M+), found 250.13(M+).
2,5-di(o-tolyl)-1,3,4-oxadiazole (I-5): white powders, mp: 121.7-122.1 ꢁ . 1H NMR (400MHz, CDCl3) δ:
13
7.78-7.85(3H, m, J=4.4Hz, Ph), 7.30-7.46(5H, m, J=8.8Hz, Ph), 2.45(6H, s, CH3). C NMR (400MHz, CDCl3) δ:
164.5, 137.3, 136.8, 129.6, 128.7, 126.3, 17.7. Anal. Calcd. for C16H14N2O: C, 76.78; H, 5.64; N, 11.19; Found: C,
76.62; H, 5.57; N, 11.43%. MS (FAB): m/e, calculated 250.11(M+), found 250.13(M+).
1
2,5-di(phenyl)-1,3,4-oxadiazole (I-6): colorless needle crystals, mp: 138.6-139.1ꢁ. H NMR (400MHz, CDCl3) δ:
8.02-8.04(4H, m, J=8.0Hz, Ph), 7.41-7.51(6H, m, J=9.6Hz, Ph). 13C NMR (400MHz, CDCl3) δ: 161.5, 129.3, 128.8,
127.5, 126.2. Anal. Calcd. for C14H10N2O: C, 75.66; H, 4.54; N, 12.60; Found: C, 75.76; H, 4.51; N, 12.58%. MS
(FAB): m/e, calculated 222.08(M+), found 222.06(M+).
1
2,5-dis(4-fluorophenyl)-1,3,4-oxadiazole (I-7): white needle crystals, mp: 200.6-201.2ꢁ. H NMR (400MHz,
CDCl3) δ: 8.13(4H, d, J=4.8Hz, Ph), 7.23(4H, d, J=12.8Hz, Ph). 13C NMR (400MHz, CDCl3) δ: 163.8, 161.8, 129.5,
120.8, 115.9. Anal. Calcd. for C14H8F2N2O: C, 65.12; H, 3.12; N, 10.85; Found: C, 64.98; H, 3.16; N, 10.59%. MS
(FAB): m/e, calculated 258.06(M+), found 258.08(M+).
1
2,5-bis(3-fluorophenyl)-1,3,4-oxadiazole (I-8): white powders, mp: 133.6-134.2ꢁ. H NMR (400MHz, CDCl3) δ:
8.02-8.37(3H, m, Ph), 7.22-7.50(5H, m, Ph).13C NMR (400MHz, CDCl3) δ: 164.7, 163.4, 130.9, 127.8, 123.3, 116.0,
116.1. Anal. Calcd. for C14H8F2N2O: C, 65.12; H, 3.12; N, 10.85; Found: C, 65.29; H, 3.09; N, 10.76%. MS (FAB):
m/e, calculated 258.06(M+), found 258.08(M+).
1
2,5-bis(2-fluorophenyl)-1,3,4-oxadiazole (I-9): light yellow powders, mp: 112.7-113.1ꢁ. H NMR (400MHz,
CDCl3) δ: 8.16-8.25(3H, m, J=3.6Hz, Ph), 7.28-7.55(5H, m, J=10.4Hz, Ph). 13C NMR (400MHz, CDCl3) δ: 163.9,
159.4, 131.1, 128.6, 124.3, 122.9, 116.0. Anal. Calcd. for C14H8F2N2O: C, 65.12; H, 3.12; N, 10.85; Found: C, 65.32;
H, 3.56; N, 11.02%. MS (FAB): m/e, calculated 258.06(M+), found 258.08(M+).
8

ACCEPTED MANUSCRIPT
1
2,5-bis (4-nitrophenyl)-1,3,4-oxadiazole (I-10): light yellow powders, mp: 213.5-214.0ꢁ. H NMR (400MHz,
CDCl3) δ: 8.43-8.45(4H, m, J=7.6Hz, Ph), 8.36-8.38(4H, m, J=4.8Hz, Ph). 13C NMR (400MHz, CDCl3) δ: 164.2,
148.4, 132.3, 128.1, 121.6. Anal. Calcd. for C14H8N4O5: C, 53.85; H, 2.58; N, 17.94; Found: C, 53.52; H, 2.44; N,
17.81%. MS (FAB): m/e, calculated 312.05(M+), found 312.04(M+).
1
3,3'-(1,3,4-oxadiazole-2,5-diyl)dipyridine (I-11): light yellow powders, mp: 189.9-190.1ꢁ. H NMR (400MHz,
CDCl3) δ: 9.35(2H, s, Ph), 8.80(2H, d, J=6.4Hz, Ph), 8.45(2H, d, J=3.6Hz, Ph), 7.55(2H, m, J=4.8Hz, Ph). 13C
NMR (400MHz, CDCl3) δ: 164.2, 149.1, 148.4, 134.1, 124.5, 123.9. Anal. Calcd. for C12H8N4O: C, 64.28; H, 3.60;
N, 24.99; Found: C, 64.11; H, 3.69; N, 24.65%. MS (FAB): m/e, calculated 224.07(M+), found 224.04(M+).
2.2.2 One pot solvent-free solid state synthesis of Type II 1,3,4-thiadiazole derivatives (II-1~9).
Scheme 3 Solvent-free solid state synthesis of 1, 3, 4-thiadiazole derivatives II-1~9
2,5-bis(4-methoxyphenyl)-1,3,4-thiadiazole (II-1): white powders, mp: 194.6-195.0ꢁ. 1H NMR (400MHz, CDCl3)
δ: 7.81(4H, d, J=8.0Hz, Ph), 7.37(4H, d, J=12.0Hz, Ph), 3.28(6H, s, OCH3). 13C NMR (400MHz, CDCl3) δ: 174.6,
159.4, 128.6, 123.7, 114.3, 55.1. Anal.Calcd. for C16H14N2O2S: C, 64.41; H, 4.73; N, 9.39; Found: C, 64.32; H, 5.01;
N, 9.64%. MS (FAB): m/e, calculated 298.08(M+), found 298.05(M+).
2,5-di(p-tolyl)-1,3,4-thiadiazole (II-2): white powders, mp: 163.3-163.8ꢁ. 1H NMR (400MHz, CDCl3) δ: 7.88(4H,
13
d, J=4.0Hz, Ph), 7.28(4H, d, J=3.6Hz, Ph), 2.42(6H, s, CH3). C NMR (400MHz, DMSO) δ: 175.7, 138.4, 130.4,
129.6, 127.4, 24.4. Anal. Calcd. for C16H14N2S: C, 72.15; H, 5.30; N, 10.52; Found: C, 72.27; H, 5.65; N, 10.19%.
9

ACCEPTED MANUSCRIPT
MS (FAB): m/e, calculated 226.09(M+), found 226.07(M+).
1
2,5-di(m-tolyl)-1,3,4-thiadiazole (II-3): white needle crystals, mp: 91.9-92.4ꢁ. H NMR (400MHz, CDCl3) δ:
7.85-7.87(4H, t, J=10.4Hz, Ph), 7.46-7.30(4H, m, J=14.4Hz, Ph), 2.45(6H, s, CH3). 13C NMR (400MHz, CDCl3) δ:
175.0, 138.7, 133.5, 130.3, 129.2, 129.1, 124.5, 24.6. Anal. Calcd. for C16H14N2S: C, 72.15; H, 5.30; N, 10.52;
Found: C, 72.24; H, 5.16; N, 10.37%. MS (FAB): m/e, calculated 226.09(M+), found 226.07(M+).
1
2,5-di(o-tolyl)-1,3,4-thiadiazole (II-4): light yellow crystals, mp: 124.9-125.4ꢁ. H NMR (400MHz, CDCl3) δ:
7.76-7.65(4H, t, J=11.6Hz, Ph), 7.44-7.32(4H, m, J=12.4Hz, Ph), 2.58(6H, s, CH3). 13C NMR (400MHz, CDCl3) δ:
174.9, 137.7 132.4, 129.9, 129.1, 128.3, 125.2, 26.3. Anal. Calcd. for C16H14N2S: C, 72.15; H, 5.30; N, 10.52;
Found: C, 72.66; H, 5.54; N, 10.83%. MS (FAB): m/e, calculated 226.09(M+), found 226.07(M+).
1
2,5-di(phenyl)-1,3,4-thiadiazole (II-5): light yellow powders, mp: 142.9-143.3ꢁ. H NMR (400MHz, CDCl3) δ:
8.02(4H, d, J=6.4Hz, Ph), 7.51-7.42(6H, m, J=12.8Hz, Ph). 13C NMR (400MHz, CDCl3) δ: 175.0, 133.5, 129.3,
128.8, 127.5. Anal. Calcd. for C14H10N2S: C, 70.56; H, 4.23; N, 11.76; Found: C, 70.43; H, 4.15; N, 11.69%. MS
(FAB): m/e, calculated 238.06(M+), found 238.07(M+).
1
2,5-bis(4-fluorophenyl)-1,3,4-thiadiazole (II-6): light yellow powders, mp: 210.3-211.1ꢁ. H NMR (400MHz,
CDCl3) δ: 8.03(4H, d, J=6.8Hz, Ph), 7.20(4H, d, J=10.4Hz, Ph). 13C NMR (400MHz, CDCl3) δ: 174.8, 140.3, 129.1,
126.3, 123.1, 120.5, 109.7. Anal. Calcd. for C14H8F2N2S: C, 61.30; H, 2.94; N, 10.21; Found: C, 61.61; H, 2.65; N,
10.42%. MS (FAB): m/e, calculated 274.04(M+), found 274.07(M+).
1
2,5-bis(3-fluorophenyl)-1,3,4-thiadiazole (II-7): light yellow powders, mp: 138.4-139.0ꢁ. H NMR (400MHz,
CDCl3) δ: 8.47-8.02(3H, m, J=5.6Hz, Ph), 7.50-7.12(5H, m, J=14.0Hz, Ph). 13C NMR (400MHz, CDCl3) δ: 175.2,
165.4, 135.1, 130.8, 123.2, 115.9, 115.5. Anal. Calcd. for C14H8F2N2S: C, 61.30; H, 2.94; N, 10.21; Found: C, 61.08;
H, 2.85; N, 10.13%. MS (FAB): m/e, calculated 274.04(M+), found 274.07(M+).
1
2,5-bis(2-fluorophenyl)-1,3,4-thiadiazole (II-8): light yellow powders, mp: 117.9-118.2ꢁ. H NMR (400MHz,
CDCl3) δ: 8.46(2H, m, J=5.2Hz, Ph), 7.51-7.23(6H, m, J=11.6Hz, Ph). 13C NMR (400MHz, CDCl3) δ: 175.3, 158.4,
10

ACCEPTED MANUSCRIPT
131.4, 129.3, 124.8, 123.6, 116.0. Anal. Calcd. for C14H8F2N2S: C, 61.30; H, 2.94; N, 10.21; Found: C, 61.36; H,
2.56; N, 10.25%. MS (FAB): m/e, calculated 274.04(M+), found 274.07(M+).
1
2,5-bis(4-nitrophenyl)-1,3,4-thiadiazole (II-9): light yellow powders, mp: 272.2-272.9ꢁ. H NMR (400MHz,
CDCl3) δ: 8.40(4H, d, J=4.4Hz, Ph), 8.23(4H, d, J=5.6Hz, Ph). 13C NMR (400MHz, CDCl3) δ: 174.3, 148.4, 139.7,
128.4, 121.6. Anal. Calcd. for C14H8N4O4S: C, 51.22; H, 2.46; N, 17.07; Found: C, 51.35; H, 2.39; N, 17.45%. MS
(FAB): m/e, calculated 328.03(M+), found 328.01(M+).
2.2.3 One pot solvent-free solid state synthesis of Type III 1,2,4-triazole derivatives (III-1~5).
Scheme 4 Solvent-free solid state synthesis of 1, 2, 4-triazole derivatives III-1~5
3,5-bis(4-methoxyphenyl)-4H-1,2,4-triazole (III-1): white powders, mp: 197.2-197.6ꢁ. 1H NMR (400MHz, CDCl3)
δ: 8.14(2H, s, Ph), 8.02(2H, d, J=4.4Hz, Ph), 7.54(2H, s, Ph), 7.34(2H, s, Ph), 3.24(6H, s, OCH3). 13C NMR
(400MHz, DMSO) δ: 163.7, 157.2, 127.3, 123.7, 114.7, 55.6. Anal.Calcd. for C16H15N3O2: C, 68.31; H, 5.37; N,
14.94; Found: C, 68.14; H, 5.54; N, 14.75%. MS (FAB): m/e, calculated 281.12(M+), found 281.14(M+).
1
3,5-di(p-tolyl)-4H-1,2,4-triazole (III-2): white powders, mp: 245.4-246.2ꢁ. H NMR (400MHz, DMSO) δ:
14.08(1H, s, N-H), 8.08(4H, d, J=5.6Hz, Ph), 7. 31(4H, d, J=15.2Hz, Ph), 2.35(6H, s, CH3). 13C NMR (400MHz,
DMSO) δ: 157.6, 137.5, 128.6, 127.7, 127.3, 25.9. Anal.Calcd. for C16H15N3: C, 77.08; H, 6.06; N, 16.85; Found: C,
77.09; H, 6.01; N, 16.90%. MS (FAB): m/e, calculated 249.13(M+), found 249.13(M+)..
1
3,5-di(phenyl)-4H-1,2,4-triazole (III-3): white needle crystals, mp: 191.1-191.7ꢁ. H NMR (400MHz, DMSO) δ:
13
14.49(1H, s, N-H), 8.05(4H, d, J=7.6Hz, Ph), 7. 51-7.41(6H, m, J=15.6Hz, Ph). C NMR(400MHz, DMSO ) δ:
156.7, 131.2, 128.7, 128.8, 125.7. Anal.Calcd. for C14H11N3: C, 76.00; H, 5.01; N, 18.99; Found: C, 75.86; H, 5.19;
11

ACCEPTED MANUSCRIPT
N, 18.95%; MS (FAB): m/e, calculated 221.10(M+), found 221.11(M+).
1
3,5-bis(4-fluorophenyl)-4H-1,2,4-triazole (III-4): light yellow needle crystals, mp: 260.8-261.3ꢁ. H NMR
(400MHz, CDCl3) δ: 8.04(4H, d, J=9.6Hz, Ph), 7. 17(4H, d, J=12.4Hz, Ph).13C NMR (400MHz, CDCl3) δ: 163.8,
156.9, 128.9, 126.3, 115.0. Anal.Calcd. for C14H9F2N3: C, 65.37; H, 3.53; N, 16.34; Found: C, 65.21; H, 3.59; N,
16.41%. MS (FAB): m/e, calculated 257.08(M+), found 257.08(M+).
1
3,5-bis(4-nitrophenyl)-4H-1,2,4-triazole (III-5): yellow powders, mp: 316.5-317.3ꢁ. H NMR (400MHz, DMSO)
δ: 8.39(4H, t, J=8.4Hz, Ph), 8.31(4H, t, J=5.6Hz, Ph). 13C NMR(400MHz, DMSO) δ: 163.2, 156.6, 129.4, 126.7,
116.8. Anal.Calcd. for C14H9N5O4: C, 54.02; H, 2.91; N, 22.50; Found: C, 54.14; H, 2.84; N, 22.61%. MS (FAB):
m/e, calculated 311.07(M+), found 311.05(M+).
2.3. X-ray crystallography analysis
A Bruker SMART APEX2 CCD detector diffractometer with graphite-monochromatic Mo Kα (0.71073 Å)
radiation was used to collect data. A transparent column-shaped crystal of 2, 5-di(4-tertbutylphenyl)-
1,3,4-oxadiazole (dimensions 0.41 x 0.32 x 0.24 mm3) suitable for X-ray diffraction studies was mounted in inert oil
on a glass fibre for the cell determination. An empirical absorption correction using the program DIFABS was
applied (-24≤h≤23, -6≤k≤8, -21≤l≤21). A least-squares fit of 100 accurately centred reflections (4.90°<2θ <55.00°)
was used to determine the unit cell parameters and the non-hydrogen atoms were refined by full-matrix least squares
on F2 using olex-2 program [29]. Hydrogen atoms were introduced at calculated positions. All non-hydrogen atoms
were described with anisotropic thermal parameters. All figures were prepared using program Mercury for windows
[30]. A summary of the refinement details and the resulting factors for this compound are given in Table 1.
Table 1 Crystal data and structure refinement for 2, 5-di(4-tertbutylphenyl)-1,3,4-oxadiazole.
Empirical formula
Formula weight
Temperature
C22H26N2O
370.48
273 (2) K
0.71073 Å
Wavelength (Mo-Ka)
12

ACCEPTED MANUSCRIPT
Crystal system, space group
Monoclinic, Cc
a = 18.735(2) Å, = 90°
b = 6.3375(8) Å, = 98.292(2)°
c = 16.824 Å, = 90 °
1976.8(4) Å3
α
Unit cell dimensions
β
γ
Volume
Z, Calculated density
Absorption coefficient
F(000)
4, 1.24483 mg/m3
0.076 mm-1
792
Completeness to θ = 27.50
Reflections collected / unique
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (F2)
99.3 %
6069/4119 [R(int) = 0.0159]
1.051
aR1 = 0.0707, bwR2 = 0.2191
aR1 = 0.0975, bwR2 = 0.2640
aR1= ∑ [ |Fo|–|Fc| ] /∑ | Fo |;
3. Results and discussion
3.1. A facile novel general synthetic method for azole derivatives--one pot solvent-free solid state method
A lot of synthetic methods have been employed to prepare substituted azole derivatives, however, these
synthetic procedure are separated, not general and typically performed in the presence of solvents. In this study,
three serials of substituted azole derivatives were generally synthesized for the first time by one pot solvent-free
solid state condensation reaction of N,N’-bishydrazide derivatives with corresponding cyclization agents in high
yields. The solvent-free solid state reaction is a green synthetic method of producing substituted azole derivatives in
the absence of organic solvent, which owns many advantages: reduced pollution, low costs, high efficiency and
simplicity in process and handling [31]. The reason about the efficient occurrence of solid state reactions is that the
gasified cyclization agents dissolves the reactant and forms aerosols, making the reacting molecules be able to move
freely and faster [32]. Meanwhile, the yields were greatly improved in the absence of solvent, and most of these
products were isolated by a simple recrystallization technique. However, to the best of our knowledge, the
solvent-free solid state method was applied to the general synthesis of substituted azole derivatives for the first time.
In view of the novel method, the general synthetic routes were adopted as shown in Scheme 5.
13

ACCEPTED MANUSCRIPT
Scheme 5 One pot solvent-free solid state general synthesis procedure of Type I~III azole derivatives
In type I reaction, three kinds of cyclization agents including Phosphorus pentoxide (P2O5), Polyphosphoric
acid (PPA) and Phosphorus oxychloride (POCl3) were used to adjust reaction condition and improve the yields of
condensation cyclization. It can be found that three reagents worked well and obtained the products in high yields.
Compared to other synthetic methods of 1,3,4-oxadiazole derivatives, this procedure was greener and more effective
[33]. However, POCl3 reacts upon contact with water to release hydrogen chloride and give phosphorus oxides,
which make the grinding very dangerous in the moisture circumstances. Based on the above considerations, the
solid state grinding reaction to use POCl3 as cyclization agents must be carefully operated in the glove box and
shorted the grinding time to 5 minutes. During the process of cyclization condensation, Phosphorus pentaoxide is
not only a cyclization agent, but also a dehydrating agent. The water produced by the reaction is quickly absorbed
by phosphorus pentaoxide, which is beneficial to the positive reaction.
To further verify this method, Phosphorus pentasulfide (P2S5) and thiourea were used as cyclization agents to
promote the cyclization reaction in type II reaction. Thiourea is commonly employed as a source of sulfide, which
supplies a good sulfide candidate for cyclization synthesis of 1,3,4-thiadiazole derivatives. Same to P2O5, P2S5 acts
as not only a cyclization agent, but also a dehydrating agent, which further promotes the condensation cyclization. It
14

ACCEPTED MANUSCRIPT
can be found that two kinds of cyclization agents both create a good effect. Due to the decomposition of thiourea in
high temperature, the reaction yield using thiourea as the cyclization agent is less than that of P2S5 in type II process.
Compared to other synthetic methods of 1,3,4-thiadiazole derivatives, this procedure shows certain advantages
avoiding use of a large number of organic solvents [34].
There are fewer reports about the synthetic routes of 1,2,4-triazole derivatives [35]. To develop a novel and
green method, three cyclization agents, such as NH4Cl, NH4HCO3 and (NH4)2CO3, were employed to improve the
yields of condensation cyclization in type III reaction. It can be found that all of three reagents can provide
ammonia gas in situ and promote cyclization reaction. Generally, ammonium salts adopt the same strategy consistent
with the Paal-Knorr synthesis to generate pyrrole from 1,4-diketones with a primary amide or ammonia gas [36].
The mass spectra of substituted azole derivatives all appear corresponding molecular ion peaks, respectively.
1H-NMR spectra of these compounds show well-resolved multilets for the phenyl or aryl heterocyclic protons. The
protons of methoxyl group give a strong single peak at 3.24~3.28 ppm, respectively. Elemental analyses of these
compounds are good agreement with the expected formula of their structures. It is worth noting that this green
synthetic method has been developed for generally preparing three series of substituted azole derivatives, which is a
tremendous advance to quickly and conveniently obtain more five-membered aromatic heterocyclic compounds.
The reaction conditions and yields of Type I~III azole derivatives are summarized in Table 2.
Table 2 Specific reaction conditions and yields of Type I~III azole derivatives
Temperature Time Yield
Temperature Time Yield
Temperature Time Yield
Compounds
Number Substituted Group
I-1
(ꢁ)
(h)
P2O5
(%)
(ꢁ)
(h)
PPA
(%)
(ꢁ)
(h)
POCl3
(%)
Type
4-methoxyphenyl
4-tertbutylphenyl
p-tolyl
200
200
200
200
5
5
4
5
99
98
97
96
200
200
200
200
5
5
4
5
99
98
98
97
180
180
180
180
5
5
4
5
95
95
94
93
I-2
I-3
I-4
Type I
1,3,4-oxadi
azole
m-tolyl
derivatives
I-5
I-6
o-tolyl
200
200
4
4
97
98
200
200
4
4
98
99
180
180
4
4
95
98
phenyl
15

ACCEPTED MANUSCRIPT
I-7
4-fluorophenyl
3-fluorophenyl
2-fluorophenyl
4-nitrophenyl
3-pyridine
200
200
200
200
200
4
5
5
5
6
97
98
96
92
89
200
200
200
200
200
4
5
5
5
6
96
94
96
89
86
180
180
180
180
180
4
5
5
5
6
93
92
87
84
81
I-8
I-9
I-10
I-11
Number
II-1
II-2
II-3
II-4
Type
Substituted Group
4-methoxyphenyl
p-tolyl
P2S5
Thiourea
200
200
200
200
200
200
200
200
200
5
4
4
4
4
4
5
5
5
99
98
98
97
99
96
95
94
89
180
180
180
180
180
180
180
180
180
5
4
4
4
4
4
5
5
5
89
88
87
86
92
86
84
81
78
m-tolyl
Type II
o-tolyl
1, 3,
4-thiadiazol II-5
phenyl
e
II-6
4-fluorophenyl
3-fluorophenyl
2-fluorophenyl
4-nitrophenyl
Substituted Group
4-methoxyphenyl
p-tolyl
derivatives
II-7
II-8
II-9
Type
Number
NH4Cl
NH4HCO3
(NH4)2CO3
III-1
III-2
III-3
III-4
III-5
180
180
180
180
180
5
4
4
4
5
97
96
98
94
91
180
180
180
180
180
5
4
4
4
5
94
93
92
91
81
180
180
180
180
180
5
4
4
4
5
96
95
94
93
86
Type III
1, 2,
phenyl
4-triazole
derivatives
4-fluorophenyl
4-nitrophenyl
3.2. Crystal structure of 2,5-di(4-tertbutylphenyl)-1,3,4-oxadiazole
Single crystal of 2,5-di(4-tertbutylphenyl)-1,3,4-oxadiazole suitable for X-ray diffraction studies was obtained
by slow evaporation of a dilute ethanol solution of this compound. The ORTEP drawing of 2,5-di (4-tertbutylphenyl)
-1,3,4-oxadiazole is shown in Fig. 1. The selected bond lengths (Å) and angles (°) are given in Table 3.
Fig. 1 ORTEP drawing of 2, 5-di(4-tertbutylphenyl)-1, 3, 4-oxadiazole with the thermal ellipsoids representing at 50 % probability
16

ACCEPTED MANUSCRIPT
level. All hydrogen atoms have been omitted for clarity.
In the crystal structure, the five-member oxadiazole ring is twisted slightly away from the plane of C2-C7
benzene ring due to the steric hindrance. The dihedral angle between them is 15.487(236)°. The five-member
oxadiazole ring isn’t also coplanar with C13-C18 benzene ring, and the dihedral angle between them is
17.979(233)°. Two 4-tertbutylphenyl groups lie in the C2-C7 and C13-C18 benzene plane respectively in spite of
the steric interference from the adjacent 4-tertbutyl moiety. The bond distances of C12-N1 (1.278(6) Å) and C1-N2
(1.271(7) Å), have an average trend, which is a result of π-electron delocalization. Similarly, the bond lengths of
C1-O1 (1.342(6) Å) and C(12)-O(1) (1.363(6) Å) have small difference.
Table 3 Selected bond lengths (Å) and angles (°) for 2, 5-di(4-tertbutylphenyl)-1,3,4-oxadiazole
Bond Lengths (Å)
Bond Angles (°)
C(1)-N(2)
1.271(7)
1.278(6)
1.342(6)
1.363(6)
1.400(4)
1.450(7)
1.454(6)
1.504(8)
1.547(7)
1.434(8)
1.540(8)
1.564(10)
1.438(9)
1.510(9)
1.519(13)
N(2)-C(1)-O(1)
N(1)-C(12)-O(1)
C(1)-O(1)-C(12)
O(1)-C(1)-C(2)
O(1)-C(12)-C(13)
C(1)-N(2)-N(1)
N(1)-C(12)-C(13)
C(12)-N(1)-N(2)
N(2)-C(1)-C(2)
C(15)-C(16)-C(19)
C(17)-C(16)-C(19)
C(15)-C(16)-C(17)
C(4)-C(5)-C(8)
C(6)-C(5)-C(8)
C(4)-C(5)-C(6)
111.0(5)
111.9(4)
103.8(2)
121.0(5)
119.0(4)
108.1(5)
128.9(4)
105.1(5)
128.0(5)
121.4(5)
120.2(6)
118.5(5)
122.8(5)
123.7(6)
113.4(5)
C(12)-N(1)
C(1)-O(1)
C(12)-O(1)
N(1)-N(2)
C(1)-C(2)
C(12)-C(13)
C(5)-C(8)
C(16)-C(19)
C(8)-C(9)
C(8)-C(11)
C(8)-C(10)
C(19)-C(22)
C(19)-C(21)
C(19)-C(20)
In the crystal packing, there exists an effective overlap of the benzene rings between two adjacent molecules
(Fig. 2). The shortest separation distance is about 4.713 Å, which is sufficiently short to suggest π-π stacking
interactions.
17

ACCEPTED MANUSCRIPT
Fig. 2 Crystal packing diagram of 2, 5-di(4-tertbutylphenyl)-1,3,4-oxadiazole, showing the intermolecular interactions. All hydrogen
atoms have been omitted for clarity.
3.3. UV-vis absorption spectra
Fig. 3, 4 and 5 display the electronic absorption spectra of substituted azole derivatives (including 1,3,
4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole derivatives) in the dichloromethane solution, respectively. All
compounds show a strong and distinct absorption band in the region of 271-343 nm, with molar extinction
coefficient at about 10,000 mol-1cm-1, ascribed to the characteristic B-band absorption of phenyl and five-membered
aromatic heterocyclic rings.
UV-vis absorption spectra of 1,3,4-oxadiazole derivatives were shown in Fig. 3. With increasing the
electron-donating ability of the 4-substituents on the phenyl ring, the maximum absorption peak of stronger
electron-donating methoxy group at 4-position (4-MeO (I-1)) blue shifts 19 nm comparing to hydrogen at
4-position (4-H (I-6)), while the electron withdrawing -NO2 group at the 4-position shifts the absorption maximum
towards the red 28 nm (refer to the corresponding data for compounds 4-MeO (I-1), 4-t Bu (I-2), 4-Me (I-3), 4-H
(I-6), 4-F (I-7) and 4-NO2 (I-10) in Table 4). Similarly, the maximum electronic absorption peak of stronger
electron-accepting fluorine at 3-position (3-F (I-8)) red shifts 15 nm comparing to the electron-donating methyl at
3-position (3-Me (I-4)). It can be obviously observed that changing the position of substitute from 3-position to 2 or
4-position, a marked hypsochromic shift of the maximum absorption wavelengths (refer to the corresponding data
18

ACCEPTED MANUSCRIPT
for compounds 3-Me (I-4), 2-Me (I-5) and 4-Me (I-3); 3-F (I-8), 2-F (I-9) and 4-F (I-7) in Table 4). For example,
when changing the positions of methyl or fluorine substitute according to the order of 3-, 2-, and 4-position, the
electronic absorption peaks blue shift about 4 and 12 nm, respectively. It can be concluded that the meta substitutes
with respect to oxadiazole ring result a larger red shift on the absorption maximum than the ortho substitutes. This
may be related to the electron-deficient property of oxadiazole moiety.
Similarly tendencies were observed in Fig. 4 (Uv-vis spectra of 1,3,4-thiadiazoles in the CH2Cl2 solution) and
Fig. 5 (Uv-vis spectra of 1,2,4-triazoles in the CH2Cl2 solution), respectively. With increasing the electron-donating
ability of the 4-substituents on the phenyl ring, the absorption maximum shifts hypsochromicly, while increasing the
electron withdrawing ability of the 4-substituents on the phenyl ring, the absorption maximum makes bathochromic
shift. It can be seen that nitro substituted compounds (4-NO2 (II-9) and 4-NO2 (III-5)) have maximum absorption
peak at 343 and 325 nm, respectively, which may be related to the π electron transition of the conjugated system.
Among all substituent groups, the nitro group which has strongest electron withdrawing effect, makes excited state
electrons more dispersed and the excited state energy state lower, resulting in the longest electronic absorption
wavelength.
The types of hybrid atoms in five-membered aromatic heterocyclic rings also effect on their maximum
absorption wavelength. For example, by changing the types of hybrid atoms according to the order of -O-, -NH-,
and -S-, the electronic absorption peaks of 4-H (I-6), 4-H (III-3) and 4-H (II-5) bathochromic shift 10 and 22 nm,
respectively, which may be related to the electronegativity scale of hybrid atoms: O (3.44) > N (3.04) > S (2.58).
With the same substitutes substituents on the phenyl ring, the similarly tendency was observed from 1,3,
4-oxadiazole, 1,2,4-triazoles to 1,3,4-thiadiazoles.
Table 4 Photophysical data of substituted azole derivatives.
Compounds
λmax Absa
λmax Em (nm)
Stoke’s
FWHM
Hamett.s Φf c (%)
19

ACCEPTED MANUSCRIPT
shift
(nm)
(nm)
33
ubs.
Numbe
r
Type
Substituted Group
4-methoxyphenyl
nm
logε
Solution a
Film b
Const σ
271
4.1
332
333.5
61
-0.268
65.6
I-1
4-tertbutylphenyl
p-tolyl
280
284
296
3.9
4.0
3.9
339.5
345.5
356.5
341.5
347
59.5
61.5
60.5
34
22
32
-0.190
-0.170
-0.069
65.4
81.0
78.1
I-2
I-3
I-4
m-tolyl
358
Type I
1,3,4-oxad
iazole
o-tolyl
288
3.8
349
352
61
26
76.4
I-5
phenyl
290
299
311
302
318
301
296
304
320
308
312
315
331
323
343
281
294
300
306
325
3.9
4.1
3.8
4.3
3.9
4.0
4.1
4.2
3.8
4.0
3.8
4.1
3.9
4.0
4.2
4.3
3.9
4.1
4.0
4.2
359
368
380
373.5
409
365.5
350
361
379
367
372
381
396
385
434
363
371
382.5
375
422
368
353
363
382
369
373
382
399
387
447
343
349
368
380
430
69
69
69
71.5
91
64.5
54
57
59
59
60
66
65
61
91
60
53
65
71
93
32
32
35
22
33
34
31
32
33
28
29
30
28
31
28
32
33
30
32
36
0
63.6
78.2
75.5
74.1
73.2
70.1
58.3
53.1
51.2
53.0
56.4
53.5
53.6
584
I-6
derivatives
4-fluorophenyl
3-fluorophenyl
2-fluorophenyl
4-nitrophenyl
3-pyridine
0.062
0.337
I-7
I-8
I-9
0.778
I-10
I-11
II-1
II-2
II-3
II-4
4-methoxyphenyl
p-tolyl
-0.268
-0.17
m-tolyl
-0.069
Type II
o-tolyl
1, 3,
phenyl
0
4-thiadiaz II-5
ole
4-fluorophenyl
3-fluorophenyl
2-fluorophenyl
4-nitrophenyl
0.062
0.337
II-6
derivatives
II-7
II-8
II-9
III-1
0.778
-0.268
-0.170
0
56.3
60.3
61.4
62.7
68.8
66.7
4-methoxyphenyl
p-tolyl
341
347
365
377
418
c
Type III
III-2
1, 2,
III-3
4-triazole
phenyl
4-fluorophenyl
4-nitrophenyl
b
0.062
0.778
III-4
derivatives
III-5
a
In CH2Cl2 solution at 298.2 K. In PMMA film (5 % weight ratio). Quantum yield of fluorescence was measured in CH2Cl2 solution
relative to quinine bisulfate (10-5 M in 1.0 N H2SO4 Φf = 0.546, as standard).
20

ACCEPTED MANUSCRIPT
Fig. 3 UV-vis absorption spectra of compounds I-1~11 with different electronic effect of substitutes.
Fig. 4 UV-vis absorption spectra of compounds II-1~9 with different electronic effect of substitutes
.
21

ACCEPTED MANUSCRIPT
Fig. 5 UV-vis absorption spectra of compounds III-1~5 with different electronic effect of substitutes.-
3.4. Fluorescent properties
The PL spectra of substituted azole derivatives were collected in the solution of dichloromethane (Fig. 6-8) and
in PMMA (polymethylmethacrylate) film (5 % weight ratio) at 298.2 K, respectively. It can be found that all
substituted azole derivatives have good fluorescence quantum yields in solutions at room temperature, and large
Stoke’s shifts (53-93 nm) (Table 4). All substituted azole derivatives exhibite a broad structureless emission in the
wavelength range of 332-434 nm, attributed to the π-π* electron transition of conjugated system. Their emission
spectra displayed the same tendency with the electronic absorption spectra when altering the kinds, positions of
substitutes and the types of hybrid atoms in five-membered heteroaromatic ring. When changing the kinds of
4-position substituent group on the phenyl ring, the emission peaks hypsochromic shift with increasing the
electron-donating ability of substitutes. 4-MeO (I-1) exhibits shortest emission peak at 332 nm, blue shifting 77 nm
related to the strongest electron-withdrawing ability 4-NO2 (I-10). On changing the position of methyl or fluorine
substitutes, according to the order of 3-, 2-, and 4-position, a systematically hypsochromic shift (~ 11 or 12 nm) of
22

ACCEPTED MANUSCRIPT
the emission peaks is observed. As concerning the types of hybrid atoms in five-membered aromatic heterocyclic
rings, the weaker the electronegativity are, the lower energy emission occurs, which leads to longer wavelength of
fluorescence emission and makes a red shift. By changing the types of hybrid atoms according to the order of -O-,
-NH-, and -S-, the emission peaks of 4-H (I-6), 4-H (III-3) and 4-H (II-5) red shift 6 and 13 nm, respectively. The
fluorescent emission wavelength of these compounds in PMMA film displayed a little bit red shift comparing to
their emission in solution due to the aggregation effect of luminescent substances, except the nitro substituted
compounds (4-NO2 (I-10), 4-NO2 (II-9) and 4-NO2 (III-5), which has an significantly larger bathochromic shift
(~13 nm), presumably due to the strong π-π stacking interactions as discussed in crystal packing structure (vide
supra).
Fig. 6 Fluorescent emission spectra of compounds I-1~11 with different electronic effect of substitutes.
23

ACCEPTED MANUSCRIPT
Fig. 7 Fluorescent emission spectra of compounds II-1~9 with different electronic effect of substitutes.
Fig. 8 Fluorescent emission spectra of compounds III-1~5 with different electronic effect of substitutes.
3. 5. Relationship between heterocyclic structures and photophysical properties
24

ACCEPTED MANUSCRIPT
The above observations from emission and electronic absorption wavelengths can be rationalized in terms of
the hybrid atoms’ electronegativity and Hammett substituent constants. In the different series of substituted azole
derivatives, the types of hybrid atoms in five-membered aromatic heterocyclic ring play an important role to tune
the maximum wavelengths of both electronic absorption and emission spectra according to the electronegativity’s
order of hybrid atoms: O (3.44) > N (3.04) > S (2.58).
However, in the same class of substituted azole derivatives, the alteration of absorption and emission
wavelengths can be elucidated by Substituents’ Hammett constants σ, which is a characteristic of the electronic
effect of substituted groups [37]. Generally, electron-donating groups show negative σ values and electron-accepting
substituents exhibit positive values at para-position. The σ value also varies with its position on the aryl ring. As
given in Table 4, the σ values (at 4-position) have the following order: -NO2 > -F>-H> -Me > -tBu > -MeO, which
are good agreement with both the maximum emission and electronic absorption peaks. The larger the σ value is, the
longer the maximum emission and absorption wavelengths are (refer to the corresponding data for compounds
4-NO2 (I-10), 4-NO2 (II-9) and 4-NO2 (III-5) in Table 4).
4. Conclusions
In summary, we have developed a novel strategy for one pot synthesis of substituted azole derivatives by use of
solvent-free solid state method with condensation cyclization of 1,4’-dihydrazide derivatives in high yields. The
studies revealed that the fluorescence emission and absorption wavelength can be rationalized in terms of the hybrid
atoms’ electronegativity among of different five-membered aromatic heterocyclic ring, however, in the same series
of substituted azole derivatives, the maximum absorption and emission peaks can be systematic tuned by changing
the kinds and positions of substituent groups on the phenyl ring of azole derivatives. The alterations of absorption
and emission wavelengths correlate well with the order of Substituents’ Hammett constants. This novel approach is
expected to provide a perfect reference for designing and developing more five-membered aromatic heterocyclic
25

ACCEPTED MANUSCRIPT
fluorescent molecules and charge transfer materials, which is of great value with promising application.
5. Supplementary materials
Crystallographic data for the structural analyses have been deposited with the Cambridge Crystallographic
Data Center, CCDC reference numbers for 2,5-di(4-tertbutylphenyl)-1,3,4-oxadiazole is 1848802. Copies of this
information may be obtained free of charge from email: www:http://www.ccdc.cam.ac.uk or
deposit@ccdc.cam.ac.uk.
Conflicts of interest
The authors declare that they have no conflicts of interests.
Acknowledgments
This work has been supported by National Natural Science Foundation of China (No. 20702064, 21177161and
31402137), Hubei Province Science Fund for Distinguished Yong Scholars (No. 2013CFA034) and the Program for
Excellent Talents in Hubei Province (RCJH15001). The Opening Project of Key Laboratory of Green Catalysis of
Sichuan Institutes of High Education (LYZ1107) and the Fundamental Research Funds for the Central University,
South-Central University for Nationalities (CZP17077).
References
[1] M. Rafiq, M. Saleem, F. Jabeen, M.Hanif, S. Y. Seo, S. K. Kang, K. H. Lee, Facile synthesis, biological
evaluation and molecular docking studies of novel substituted azole derivatives, J. Mol. Struct., 2017, 1138:
177-191.
[2] I. Yildizoren, I. Yalcin, E. Akisener, Synthesis and structure-activity relationships of new antimicrobial active
multisubstituted benzazole derivatives, Eur.J. Med.Chem., 2004, 35(34): 291-298.
[3] D. Srinivas, V. D. Ghule, S. P. Tewari, K. Muralidharan, Synthesis of amino, azido, nitro, and nitrogen-rich
azole-substituted derivatives of 1H-benzotriazole for high-energy materials applications, Chemistry, 2012,
26

ACCEPTED MANUSCRIPT
18(47): 15031-15037.
[4] A. A. Kadi, E. S. Al-Abdullah, I. A. Shehata, E. E. Habib, T. M Ibrahim, A. A. El-Emam, Synthesis,
antimicrobial and anti-inflammatory activities of novel 5-(1-adamantyl)-1, 3, 4-thiadiazole derivatives, Eur.J.
Med.Chem., 2010, 45 (11): 5006-5011.
[5] L.J. Li, H.Ding, B.G.Wang, S.Yu, Y.Zou, X.Chai, Q. Wu, Synthesis and evaluation of novel azoles as potent
antifungal agents, Bioorg & Med. Chem. Lett., 2014, 24(1): 192-194.
[6] [6] P. M. d. M. Guedes, J. A. Urbina, M. d. Lana, L. C. C. Afonso, V. M. Veloso, W. L. Tafuri, G. L. L. M.
Coelho, E. Chiari, M. T. Bahia, Activity of the new triazole derivative albaconazole against trypanosoma
(Schizotrypanum) cruzi in dog hosts, Antimicrob.Agents .CH., 2004, 48 (11): 4286.
[7] S. Yu, X. Chai, Y. Wang, Y. Cao, J. Zhang, Q. Wu, D. Zhang, Y. Jiang, T. Yan, Q. Sun, Triazole derivatives
with improved in vitro antifungal activity over azole drugs, Drug Des. Dev. Ther., 2014, 8: 383-390.
[8] Y. Qian, W. Huang, Z. F. Lu, Y. P. Cui, Two-photon absorption and optical power limiting properties of
multibranch 1, 3, 4-oxadiazole derivatives, Chem. J. Chine. U., 2007, 28 (12): 2369-2372.
[9] C. R. Moylan, R. D. Miller, R. J. Twieg, K. M. Metterton, V. Y. Lee, T. J. Matray, C.Nguyen, Synthesis and
nonlinear optical properties of donor-acceptor substituted triaryl azole derivatives, Chem. Mater. , 1993, 5,
1499-1508.
[10] A. Paun, N. D. Hadade, C. C. Paraschivescu, M. Matache, 1, 3, 4-Oxadiazoles as luminescent materials for
organic light emitting diodes via cross-coupling reactions, J. Mater. Chem. C, 2016, 4 (37): 8596-8610.
[11] C. D. Codruta, C. C. Paraschivescu, I. Dumitru, M. Matache, I. Baciu, L. L. RuTă, Convenient preparation of
unsymmetrical 2, 5-disubstituted 1, 3, 4-oxadiazoles promoted by Dess–Martin reagent, Tetrahedron Lett.,
2009, 50(17):1886-1888.
[12] L. Chai, Y. Zhao, X. Tian, Synthesis of 2, 5-disubstituted-1, 3, 4-thiadiazole under microwave irradiation,
Lanzhou Jiaotong Univ., 2005, 24(3):151-158.
[13] J. Y. Hwang, H. S. Choi, D. H. Lee, Solid-phase synthesis of 1, 3, 4-oxadiazole and 1, 3, 4-thiadiazole
derivatives via selective, reagent-based cyclization of acyldithiocarbazate resins, J. Comb. Chem. 2005, 7,
816-819.
[14] J. F. Geldard, F. Lions, The organic chemistry of a new weak field tridentate chelating agent 3, 5-Di
(2-pyridyl)-1, 2, 4-triazole, J. Org.Chem., 1965, 30 (1): 318-319.
[15] K. S. Yeung, M. E. Farkas, J. F. Kadow, N. A. Meanwell, A base-catalyzed, direct synthesis of 3,
5-disubstituted1, 2, 4-triazoles from nitriles and hydrazides, Cheminform, 2005, 46 (19): 3429-3432.
27

ACCEPTED MANUSCRIPT
[16] L. Cheng, W. X. Zhang, B. H. Ye, A. J. Lin, X. M. Chen, In situ solvothermal generation of 1, 2, 4-triazolates
and related compounds from organonitrile and hydrazine hydrate:ꢀ a mechanism study, Inorg. Chem., 2016,
46(4): 1135-43.
[17] K. Tanaka, F. Toda, Solvent-free organic synthesis, Chem. Rev., 2000, 100, 1025-1074.
[18] B. Lee, P. Kang, K. H. Lee, J. Cho, W. Nam, W. K. Lee , N. H. Hur, Solid-state and solvent-free synthesis of
azines, pyrazoles, and pyridazinones using solid hydrazine, Tetrahedron Lett., 2013, 54(11): 1384-1388.
[19] G. Kaupp, J. Schmeyers, J. Boy, Waste-free solid-state syntheses with quantitative yield, Chemosphere, 2001,
43(1): 55-61.
[20] G. Kaupp, Je. Schmeyers, J. Boy, Quantitative solid-state reactions of amines with carbonyl compounds and
isothiocyanates, Tetrahedron, 2000, 56(36):6899-6911.
[21] M. L. Keshtov, E. I. Mal’tsev, D. A. Lypenko, M. A. Brusentsova, M. A. Sosnovyi, V. A Vasnev, A. S.
Peregudov, A. V. Vannikov, A. R. Khokhlov, New carbazole-containing polyphenylquinoxalines: Synthesis,
photophysical, and electroluminescent properties, Polym.Sci.A., 2006, 48(11): 1135-1146.
[22] M. Saleem, K. H. Lee, Synthesis, characterization and photophysical properties of novel azole derivatives, J.
Fluoresc., 2015, 25(2): 217-226.
[23] K. K. V. RajꢂB. Narayana, N. S Kumari, B. K. Sarojini, Synthesis of some bioactive 2-bromo-5-methoxy-Nꢃ
-[4-(aryl)-1, 3-thiazol-2-yl] benzohydrazide derivatives, Eur.J.Me. Chem., 2007, 42(3): 425-429.
[24] K. M. Loo, S. W. Ng, 4-Hydrꢄoxy-Nꢃ-(4-hydroxyꢄbenzoꢄyl) benzoꢄhydrazide, Acta. Crystallogr. Sect. E.
Struct. Rep. Online., 2009, 65(5):o969- o969.
[25] A. O. Abdelhamid, S. M. Gomha, A. S. Shawali, Utility of N-aryl 2-aroylhydrazono-propanehydrazonoyl
chlorides as precursors for synthesis of new functionalized 1, 3, 4-thiadiazoles with potential antimicrobial
activity, J.A.R., 2015, 6(6): 885-893.
[26] Y. Ishikawa, K. Watanabe, (E)-4-methyl-N'-[(4-oxo-4H-chromen-3-yl) methyl-idene] benzohydrazide, Acta
Crystallogr., 2014, 70(Pt 5): o565-o565.
[27] H. K. Fun, M. Hemamalini, V. Sumangala, N'-(4-fluoro-benzyl-idene)-2-(4-fluoro-phen-yl) acetohydrazide,
Acta Crystallogr., 2011, 67(Pt 11): o2835- o2835.
[28] H. J. Xu, L. Q. Sheng, Z. D. Liu, S. C. Shao, (E)-N'-(3-fluoro-benzyl-idene)-2-hydroxy-benzohydrazide, Acta
Crystallogr., 2009, 65(Pt 4): o666- o666.
[29] O. V. DolomanovꢂL. J. Bourhis, R. J. Gildea, J. A. K. Howard, H. Puschmann, OLEX2: a complete structure
solution, refinement and analysis program, J. Appl. Crystallogr., 2010, 42 (2):339-341.
28