# Synthesis and Biological Activity of 1,3,4-Oxadiazoles Used in Medicine and Agriculture
## 2 Chemistry of Oxadaizoles  
These compounds are composed of a five-membered heterocyclic ring containing two nitrogen atoms and one oxygen atom. Due to the different arrangement of the het-ero  
Figure 1: Possible applications of 1,3,4-oxadiazole derivatives. atoms, oxadiazoles exist in different isomeric forms, e.g., 1,3,4-oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole and 1,2,5-oxadiazole (Figure 2). Aromatic systems are so-called azoxins, while five-membered cyclic molecules with the same number of nitrogen and oxygen atoms that have been partially reduced are known as furoxanes [19]. Given the presence of and open ring, i.e., the diazo-ketone tautomer, 1,2,3-oxadiazole is an extremely unstable structure. It was known as a condensed derivative with benzene in solution [21], as well as in mesoionic substances, so-called \"sydnones\" (Figure 3) [22]. In contrast to 1,2,3-oxadiazoles, other isomers, namely 1,2,4-oxadiazoles, are thermodynamically stable. Their reactivity is mainly influenced by their aromaticity. The high reactivity to ring rearrangement reactions is attributed to the relatively low aromaticity of 1,2,4-oxadiazoles [23; 24]. On the basis of the performed calculations, it was found that the aromaticity index for 1,2,4-oxadiazole was lower than for the furan molecule [25]. In recent years, many 1,2,4-oxadiazole derivate structures have been detected using X-ray structure spectroscopy (1-4) [26; 27]. The structures that can be used in energetic materials [28] and complex compounds based on 1,2,4-oxadiazole derivatives that can bind copper or cobalt cations, and have biological activity, have been determined [29; 30; 31] (Figure 4). Due to the realtively low aromaticity and high susceptibility of the O-N bond to reduction, 1,2,4-oxadiazoles are investigated for the possibility of rearrangement into other  
Figure 3: Acyldiazomethane tautomer [21]. Figure 2: Isomeric structures of oxadiazoles [20]. heterocyclic compounds. Moreover, the nitrogen and carbon atoms present in the molecule are characterized by nucleophilic and electrophilic characteristics, while the entire ring has the properties of an electron withdrawing group, which leads to increased reactivity of the attached substituents [27; 32; 33]. Colloquially called furazan, 1,2,5-Oxadiazole is another isomeric form of oxadiazole. The furazan ring is very susceptible to breaking. For example, the presence of sodium hydroxide in aqueous solution is able to completely cleave the heterocyclic ring [34]. Due to its high positive enthalpy of formation and high density, furazan and their oxides (furaxan) have recently gained popularity in the synthesis of high-energy and explosive materials. These compounds improve the oxygen balance and also release nitrogen gas, which is harmless to the environment, during decomposition [35]. The most stable isomeric structure among all isomeric oxadiazol is unsubstituted 1,3,4-oxadiazole. The basic unit of 1,3,4-oxadiazol is a liquid with a boiling point of 150 \({}^{\circ}\)C. Lower alkyl derivatives are also liquids. Aryl substituents significantly increase melting and boiling points, especially in the case of symmetrical derivatives. Substitution with different functional groups at the 2 and 5 positions of the oxadiazole ring typically lowers the melting and boiling points. The solubility of 1,3,4-oxadiazololes in water is determined by the type of substituents on the heterocyclic ring. With two methyl groups, 1,3,4-Oxadiazole is completely soluble in water, while aryl substituents lower the solubility significantly. Oxadiazololes can be converted to other five-membered heterocycles: the use of hydrazine hydrate converts 1,3,4-oxadiazololes to triazolamines, while thiourea converts the 1,3,4-oxadiazol ring to the thiadiazole [36; 37; 38]. Oxadiazololes belong to a group of compounds capable of transporting electrons efficiently and blocking electron holes. Such activity is demonstrated by both low-molecular-weight derivatives as well as polymers and dendritic forms [39; 40; 41].