Though there are hundreds of different tetrazole derivatives reported since 1885, calixarenes with tetrazole functional groups attached in any orientation are rather limited in literature with the earliest publication in 2005104. The most recent are D’Alessio’s work on lanthanoid complexation by either the di-, tri- or tetra-tetrazole functionalised calixarene, all of which have the tetrazoles attached to the lower rim of the calixarenes.92,105,106
The only other tetrazole attached on the lower rim of the calixarene been reported are by Chen and Chung.107 Their calixarenes have phenylazo moieties attached on the upper rim and bistetrazoles on the lower rim. Their preferred synthetic procedure is different to D’Alessio’s choice of the Koguro method92
. They chose to use the Witterberger method79, which uses dibutyltin oxide and trimethylsilyl azide to react with the organic nitriles in anhydrous toluene, achieving a high yield of 87% after purification via flash chromatography. They utilised their p-phenylazo bistetrazole calixarene for the application of Ca2+ sensing with the debutylated bistetrazoles calixarenes as the control reference. Through 1H NMR titration experiments, Chen identified that the calcium ion was bound at the lower rim of the calixarene interacting with the partially deprotonated phenol and the nitrogen of one of the tetrazole (Figure 1.21).
17
Figure 1.21: The only other known example of tetrazoles attached on the lower rim of the calixarenes.107 The rest of the tetrazole-functionalised calixarenes in literature have tetrazoles attached on the upper rim of the calixarene (Figure 1.22).
Figure 1.22: Examples of tetrazoles on the upper rim of the calixarene in literature.31,104,108
Each of these unique calixarenes has their own distinct applications. These start from anion sensors with the strongest affinity for chloride among others (a),108 ability to coordinate with palladium forming a 2:2 complex (b),104 and even a sugar linker in replacement of a triazole unit (c).31
18 1.2.5 Tetrazole applications
Beside the uses in tetrazole-functionalised calixarenes, tetrazoles in general have a long history of applications. These include gas generating molecules and explosives,109,110 ligands for complexation, phase transfer catalyst111 and the vast majority on biological active substances,64 which could possess numerous medicinal properties such as anti-allergic, antimicrobial, antifungal, antiviral, antihistaminic, anti-inflammatory, anti-ulcer, anti-tubercular, anti-hypersensitive, anxiety, cytostatic, hypotensive, nootropic and many more. The versatility in the applications of tetrazoles is due to their chemical properties as a hydrogen bond donor and acceptor, high content of nitrogen and coordinating ligand.
Tetrazoles have a rather high enthalpy of formation, thus the outcome of the decomposition will result in releasing a significant amount of energy along with liberating two nitrogen molecules. This trait permits them to function as gas generators, explosives and even components of missiles propellants.109,110
Tetrazoles are ideal for biological applications as they are metabolically stable isosteres of organic substrates with carboxyl and amide groups.112,113 This means that they can be interchangeable as they have similar physiochemical properties which often results in similar biological properties. The 5-substituted tetrazoles have similar electron withdrawing effects on organic substrates to that of carboxyl groups. Both tetrazoles and their corresponding carboxylic acid derivatives have similarly low pKa values of 4.5-4.9 and 4.2-4.4 respectively in water.113 Tetrazoles, like their corresponding carboxylic acid, also formed stable anions within the physiological pH range at around 7.4.113
As tetrazoles are considered as a weak heterocyclic bases,114 they have the pronounced ability to form hydrogen bonds similarly to that of pyrimidine and purine bases.115 The two nitrogen atoms in the heterocycle, as well as the pyrrole hydrogen atom of the tetrazole, are all able to simultaneously participate in the formation of intermolecular hydrogen bonding. This attribute enables tetrazoles to be involved in multicentre intermolecular hydrogen bonding with the surrounding functional groups of the active pocket sites of the enzymes. In addition, the tetrazole anion, tetrazolide, being planar and aromatic could also be involved in active ion-dipole and ion-ion interactions with electron deficient molecules. Though one must also consider the overall localised charge density116 and the size of the interface117 when replacing the functional groups with tetrazoles. As compared to carboxyl group, the heterocycle is comparatively larger which may result in steric hindrance and less favourable orientation reducing the overall binding affinity with the receptive site.
Tetrazoles are generally more lipophilic than carboxylates, as the larger substituent allows the negative charges to be distributed over a greater number of atoms. Hansh reported that anionic tetrazoles are about ten times more lipophilic than their carboxylate counterparts.118 This is one of the important factors to consider in drug
19
design as the molecule requires high permeability in order to naturally cross the cell membrane (Lipinski’s rule of five)119.
The tetrazole functional group being unknown in nature has virtually no natural enzymes designed to alter or metabolise them. The number of biological degradation pathways is very scarce, thus making them more biologically stable. Incorporating the tetrazole ring into an organic substrate often leads to not only an increase in efficacy but also prolonging the intended action of the drug without an increase in acute toxicity.120 All these qualities make tetrazoles an attractive candidate for synthetic drugs in the pharmaceutical industry. In fact, there are already many highly effective drugs with a pharmaceutical active ingredient (API) that contains the tetrazole ring.64 The World Health Organisation (WHO) using the analogue-based drug discovery (ABDD) method, as well as the Food and Drug Adminstration (FDA), declared that tetrazole rings as an important structural unit when designing new drugs.64
Another important feature of tetrazoles is that they can be used as organic ligands to form stable metal complexes. This can be proved useful in analytical chemistry such as in systems to remove heavy metal ions in a liquid mixture121 and also corrosion inhibitors122. Tetrazoles containing lanthanoid complexes could possibly be used in biomedical analysis such as magnetic resonance imaging (MRI) contrast agents, fluoroimmunoassays and cellular imaging for the diagnosis of diseases.123–126 Due to its photophysical properties, these complexes can also be applied in material science such as light emitting diodes, lasers, optical fibres and optical display.125,127,128 Hence, a part of this project is to investigate the photophysical properties of lanthanoid complexes and clusters as it is sensible to explore the benefits of such systems.