Study on the synthesis of novel 5-substituted 2-[2-(pyridyl)ethenyl]-1,3,4-oxadiazoles and their acid–base interactions

Abstract A series of novel 5-substituted 2-[2-(pyridyl)ethenyl]-1,3,4-oxadiazoles were efficiently synthesized by cyclocondensation of the appropriate 3-(pyridyl)acrylohydrazides with triethyl orthoesters in the presence of glacial acetic acid. The products were identified by means of spectroscopic methods and their pK A ionization constants were determined. The influence of substituents on the basicity of the pyridine system has been discussed. Graphical Abstract


Introduction
1,3,4-Oxadiazoles belong to the group of five-membered aromatic heterocycles, containing one oxygen and two nitrogen atoms. Many of these compounds exhibit a wide range of pharmaceutical and biological activities such as antibacterial, antiviral, anti-inflammatory, analgesic, or anticonvulsant [1][2][3][4][5][6]. Additionally, 1,3,4-oxadiazole derivatives act as potential agents in the treatment of cancer and AIDS [7][8][9][10]. They are also used extensively in agriculture as herbicides, fungicides, or insecticides [11,12]. These heterocyclic molecules are applied in the production of heat-resistant polymers, blowing agents, optical brighteners, and anti-corrosion agents [13][14][15][16]. Conjugated p-electronic arrangements based on the electron-deficient 1,3,4-oxadiazole ring feature excellent electron-transporting properties with much higher quantum efficiency in comparison to conventional fluorescent emitters using silicon and its solid solutions (doped silicon). Therefore, they are used as monomers in the production of fluorescent emitters for organic light-emitting diodes, photovoltaic cells, scintillators, and photosensitive materials [13][14][15][16]. However, many of the previously investigated compounds applied in organic electronics suffer from their poor processability and low thermal and chemical stability. Due to these facts, the study on designing and synthesis of new organic conjugated materials whose physicochemical properties may be easily modified seems to be reasonable.
In continuation of our studies on the application of a,bunsaturated acid hydrazides in the synthesis of conjugated 2-[2-(aryl)ethenyl]-1,3,4-oxadiazole derivatives, we investigated structures possessing the pyridylethenyl moiety at the a position [57]. Herein, we report the synthesis of three types of 3-(pyridyl)acrylohydrazides and their reactions with triethyl orthoesters. The presence of the acid-sensitive pyridyl fragment is particularly important because it allows the acid-base modification of the physical properties of the indicated structures which may serve as potential monomers for optoelectronics.
In a typical synthetic procedure, the starting aldehydes were treated with malonic acid in pyridine in the presence of piperidine as a catalyst under Knoevenagel-Doebner reaction conditions. Condensation and successive decarboxylation of intermediate dicarboxylic acids occurred giving a,b-unsaturated monocarboxylic acids, 3-(pyridyl)acrylic acids 2a-2c in high yields. The resulting acids were neutralized with potassium hydroxide to form the appropriate potassium salts 3a-3c which were then used in a one-pot, two-step synthesis, yielding acid hydrazides 5a-5c. First, the potassium salts 3a-3c were treated with ethyl chloroformate and finally excess amounts of hydrazine hydrate. The reaction conducted at low temperature in acetonitrile solution resulted in the formation of the desired hydrazides 5a-5c in satisfactory yields (73-79 %, Scheme 2). The same hydrazides 5a-5c were also prepared by the typical two-step transformation from the appropriate 3-(pyridyl)acrylic acids 2a-2c by esterification with methanol and thionyl chloride followed by treatment with hydrazine hydrate. However, the low yields of the final hydrazides 5a-5c (35-44 %) made the above synthetic procedure unattractive.

Scheme 1
in glacial acetic acid, yielding a series of 2-[2-(pyridyl)ethenyl]-1,3,4-oxadiazoles 6a-6i substituted at the 5-position with a phenyl or an alkyl group that have not previously been reported in the literature. The commercially available triethyl orthoesters play the dual role of the synthon introducing the methylene carbon atom and highboiling solvent.
Generally, the reaction yields increased with the increasing bulk of substituent R on the orthoester. The best results were obtained in the case of derivatives with a phenyl group at the 5-position (R = Ph 88-94 %, Table 1), due to the presence of an extended conjugated system and a higher boiling point of triethyl orthobenzoate (b.p. 240°C) in contrast to the boiling points of the rest of the orthoesters (b.p. 142-152°C). The rest of 1,3,4-oxadiazoles with electron-donating alkyl groups were prepared in lower yields. We have also observed an influence of the position of the pyridine nitrogen atom on the reaction yields. The highest values were obtained in the reactions conducted with 3-(2-pyridyl)acrylohydrazide (5a, 74-92 %) and 3-(4pyridyl)acrylohydrazide (5c, 76-94 %, Table 1).
Our previous studies on the reactions of 3-(2furyl)acrylohydrazide or 3-(2-thienyl)acrylohydrazide with triethyl orthoesters [45,57] have shown that the reaction times were relatively shorter (1. 5-4 h), what testifies to the higher reactivity of hydrazide reagents containing a furan or thiophene ring in comparison to their pyridine-containing counterparts.
The structures of new products were confirmed with elemental analysis and spectroscopic methods ( 1 H and 13 C NMR, MS, UV, IR). In the series of 2-[2-(pyridyl)ethenyl]-1,3,4-oxadiazoles 6a-6i, the diagnostic signals in the 1 H NMR spectra are two doublets with the coupling constants J = 16.4 Hz associated with two protons of the ethylene group. The value of the coupling constants suggests that E geometric isomers of these compounds are formed in the reaction. The proton adjacent to pyridine ring at the b position to the 1,3,4-oxadiazole ring is seen in the range between 7.44 and 7.72 ppm, while the proton a-CH = appears at high fields in the range of 7.08-7.57 ppm. Interestingly, analysing the spectra of 2-[2-(2-pyridyl)ethenyl]-1,3,4-oxadiazoles 6a-6c, one should notice the characteristic ethylene a-CH= and b-CH= proton shifts. These two protons are observed at a much lower field due to the neighbouring pyridine nitrogen atom. Furthermore, the two protons C2 00 -H and C6 00 -H of the phenyl group substituted at 5-position of the 1,3,4-oxadiazole ring of 6c, 6f, and 6i are shifted in the 1 H NMR spectra to lower fields and appear as a doublet of doublets in the range from 8.10 to 8.13 ppm. Such significant changes in the chemical shifts could result from the proximity of these atoms to the ring's nitrogen and oxygen atoms. In the 13 C NMR spectra of 1,3,4-oxadiazoles 6a-6i, the characteristic signals are peaks of ethylene carbon atoms a-CH= and b-CH=, which are observed in ranges of 112-114 ppm and 133-139 ppm, respectively. The ring carbon atom C2 is seen in the range between 163 and 166 ppm, while the location of the second carbon atom C5 depends on the type of the substituent and appears between 164 and 170 ppm.
Each of the analysed compounds consists of three rings: I (the pyridine ring containing atoms C8-C13), II (the oxadiazole ring containing atoms O1-C5), and III (the phenyl ring containing atoms C14-C19). The values of the I/II, I/III, and II/III dihedral angles are collected in Table 2. According to collected data, it was concluded that both molecules adopt coplanar conformation. The near planarity of the systems favours the formation of intramolecular hydrogen bonds and p-electron delocalization. The C-C bonds located between the aromatic rings (C2-C6, C6-C7, C7-C8, and C5-C14) exhibit intermediate values due to pelectron delocalization in the molecules. This effect is more pronounced in the more coplanar structure 6c.
The twist along the C2-C6, C7-C8, and C5-C14 bonds is illustrated by torsion angles and it is rather small in both compounds ( Table 2). In the studied molecules, the remaining bond lengths and angles are normal and are in good agreement with the geometry of similar derivatives of 1,3,4-oxadiazole [58][59][60]. These structures are stabilized by two intramolecular hydrogen bonds C7-H7ÁÁÁO1 and C15-H15AÁÁÁO1 (Table 3) which give rise to the fivemembered ring systems in all cases and confirm existence of E geometrical form of both compounds.
Considering the fact that physical properties of compounds are also strongly dependent on their ability to acidbase interactions, the pK A values of 5-substituted 2-[2-(pyridyl)ethenyl]-1,3,4-oxadiazoles 6a-6i were determined ( Table 4). The determination of the pK A dissociation constants was performed according to the spectrophotometric method of Albert and Serjeant [61] in 50 % aqueous methanol solution (10 -5 M, room temperature) due to the low solubility of the examined compounds in water. The

Conclusion
In conclusion, we have synthesized a series of novel 5-substituted 2-[2-(pyridyl)ethenyl]-1,3,4-oxadiazoles in the reactions of three types of differently substituted 3-(pyridyl)acrylohydrazides with triethyl orthoesters in glacial acetic acid. This easy and efficient method has the advantage of providing the desired products in high yields, which makes it a useful addition to the existing synthetic protocols. The presence of the acid-sensitive pyridyl fragment is particularly important because it allows the electronic properties modification of the indicated structures by acid-base interactions, which makes them especially attractive for optoelectronic applications.