Chemical Reactivity of 1,3,4-Thiadiazole
1,3,4-Thiadiazole is a five-membered, aromatic, weakly basic, planer, electron-deficient, conjugated heterocyclic ring system comprised of two carbon atoms, one sulfur atom, and two pyridine-like nitrogen atoms present at the 3- and 4-positions of the ring. The dipole moment (3.25 D) for 1,3,4-thiadiazole suggests that it is a polar symmetric molecule with pseudo-aromatic character. The carbon atoms at the 2- and 5-positions are electron deficient because of the inductive effect of nitrogen and sulfur and thus they are inert toward electrophilic substitution but reactive toward nucleophilic attack.
It was first synthesized in 1882 by Emil Fischer and the nature of the ring system was determined in 1890. The weak basicity of 1,3,4-thiadiazole is because of high aromaticity of the ring and the inductive effect of sulfur. It is quite stable in aqueous acidic medium but underwent ring cleavage in aqueous base.
1,3,4-Thiadiazole-Based Drugs in Clinical Use
The 1,3,4-thiadiazole scaffold has wide-ranging applications as pharmaceuticals, agrochemicals, and also in material science. As pharmaceuticals, numerous drugs have been developed such as antiinflammatory, antihypertensive, anti-HIV, antidepressant, local anesthetic, and anticonvulsant drugs. It has also been used in the treatment of various disorders. Currently, there are a number of compounds available on the market in clinical use. Methazolamide acts as a carbonic anhydrase inhibitor, is useful in the treatment of glaucoma and reduction of high pressure inside the eyes, and prevents blindness, nerve damage, and vision loss. Acetazolamide is another drug used in the treatment of glaucoma, epileptic seizure, dural ectasia, and periodic paralysis. Sulfamethizole, a thiadiazole derivative, has been used as an antimicrobial agent. 1,3,4-Thiadiazole, a bioisostere of the thiazole ring, has been used in the synthesis of cephalosporine and cefazedone, which are used as antibiotics. Megazole is another 1,3,4-thiadiazole-based drug, widely used in the treatment of African trypanosomes, also known as sleeping sickness. Azetepa, a phosphoruscontaining drug, has been used for the treatment of cancer. Tebtheuron is known as a broad-spectrum herbicide and is used to control a variety of weeds and herbaceous and woody plants. Numerous thiadiazole derivatives are patented as bactericides, insecticides, and fungicides.
Some of the thiadiazole derivatives have technological uses as dyes, corrosion and oxidation inhibitors, optically active liquid crystals, and optoelectronic materials.
Chemical Reactivity
Atomic charges have been calculated by the DFT method. The maximum charge was found at the S atom (0.818) and thus it is the favorite position for soft nucleophilic attack. The atomic charge on each carbon is −0.3275. Because of the presence of the two pyridine-like nitrogen atoms in the ring, which make the C2 - and C5 -positions electronically poor, nucleophilic substitution of the leaving groups present at either the C2 - or C5 -position becomes highly facile. However, the atomic charge on N3 and N4 (−0.0308) makes them preferential sites for electrophilic attack and readily N-alkylated or N-acylated. In strongly basic conditions the thiadiazole ring leads to ring fission.
Physical Properties
In the 1 H NMR of parent 1,3,4-thiadiazole, the C2 and C5 protons being equivalent resonated extremely downfield at 9.12 ppm compared to benzene protons because both protons are linked to the electron-deficient heterocyclic ring. The presence of electron-donating groups such as alkyl, aryl, and amino substituents shifted the resonance upfield. These groups also facilitate the electrophilic substitution reactions. The chemical shift of C2 and C5 carbon atoms in the 13C NMR of parent 1,3,4-thiadiazole resonated at 153.1 ppm. The presence of aryl substituent shifts the resonance further downfield.
