Triazole/Tetrazole

Product List

Introduction

Triazoles and tetrazoles are aromatic five-membered heterocycles containing respectively three and four nitrogen atoms. The formulas of Triazole and Tetrazole and tetrazole are C₂H₃N₃ and CH₂N₄ respectively. (Fig.1). The isomeric 1,2,4-triazole ring was first mentioned by Bladin as early as 1885. The aptitude of the 1,2,4-triazole ring to bind metal ions was established a few decades later, and the first crystal structure of one of the resulting adducts was published in 1962. In 1886, Bladin proposed the term tetrazole for a five-membered heteroarene including four nitrogens.

Fig. 1 The structure of 1,2,3-Triazole, 1,2,4-Triazole and Tetrazole with ring numbering (cited from Wikipedia)

Triazoles exhibit biological activity, notably as antifungals, antimicrobials, and enzymatic inhibitors. The azide-alkyne Huisgen cycloaddition is a mild and selective reaction that gives 1,2,3-triazoles as products. The reaction has been widely used in bioorthogonal chemistry and in organic synthesis. Triazole rings are relatively stable functional groups, and triazole linkages can be used in a variety of applications, such as replacement of the phosphate backbone of DNA. Tetrazoles have applications in both material science and pharmaceuticals. Tetrazoles can tolerate a wide range of chemical environments, from strongly acidic to basic as well as oxidizing and reducing conditions. Tetrazoles are metabolically stable bioisosteres of the carboxylic acid group and can serve as precursors to a variety of nitrogen-containing heterocycles by the Huisgen rearrangement. They also function as simple lipophilic spacers displaying two substituents in the appropriate manner, where the connectivity patterns of the embedded tetrazole units bear a striking resemblance to those of their 1,2,3-triazole analogues.

Applications

Pharmaceutical Chemistry:

Antisense oligonucleotides are attractive therapeutic agents for several types of disease. One of the most promising modifications of antisense oligonucleotides is the introduction of bridged nucleic acids. As Obika group reported[1], they designed novel bridged nucleic acids, triazole-bridged nucleic acid (TrNA), and tetrazole-bridged nucleic acid (TeNA), whose sugar conformations are restricted to N-type by heteroaromatic ring-bridged structures. They then successfully synthesized TrNA and TeNA and introduced these monomers into oligonucleotides. In UV-melting experiments, TrNA-modified oligonucleotides exhibited increased binding affinity toward complementary RNA and decreased binding affinity toward complementary DNA, although TeNA-modified oligonucleotides were decomposed under the annealing conditions. Enzymatic degradation experiments demonstrated that introduction of TrNA at the 3’-terminus rendered oligonucleotides resistant to nuclease digestion.

Fig.1 Triazole- and Tetrazole-Bridged Nucleic Acids

Material Chemistry:

Polymers containing triazole or tetrazole, respectively are well known as energetic materials. While polymers containing triazoles made by click reaction are found easily, polymers containing tetrazole groups such as polyvinyl tetrazole are very rare and begin to grab the attention as energetic polymers, recently. However, they have limitation for application to energetic binder due to their low solubility in organic solvent. To improve their solubility, many efforts are in progress.

The 1,2,3-triazole ring can bridge metal ions in five different coordination modes, which are depicted in Fig.2. In its protonated form, this heteroarene can act as a dinucleating ligand (2,3- and 1,3-binding modes; Fig.2 A). The deprotonated ring may function as a dinucleating (1,2- and 1,3-binding modes; Fig.2 B) or a trinucleating ligand (1,2,3-binding mode; Fig.2 B), thus providing for a high versatility in the preparation of coordination materials. By the end of 2009, more than fifty papers describing the single-crystal X-ray structures of 1,2,3-triazole-containing coordination polymers were published, involving twenty different ligands. For instance, the first X-ray structure of a coordination polymer bearing this heteroaromatic ring was reported in 198, with the utilization of 1,2,3-benzotriazole to prepare [Zn₂(L3)₄]_n exhibiting a three-dimensional architecture.

Fig.2 Bridging coordination modes of (A) 1,2,3-triazole (μ2,3 and μ13) and (B) 1,2,3-triazolate (μ1,2 , μ1,3and μ1,2,3). M symbolizes a metal ion.

References

1. Triazole- and Tetrazole-Bridged Nucleic Acids: Synthesis, Duplex Stability, Nuclease Resistance, and in Vitro and in Vivo Antisense Potency, J. Org. Chem. 2017, 82, 1, 12–24
2. Triazoles and tetrazoles: Prime ligands to generate remarkable coordination materials, Coordination Chemistry Reviews. 2011, 255, 485-546