Compounds analogous to thiophene include furan (C4H4O), selenophene (C4H4Se) and pyrrole (C4H4NH), which each vary by the heteroatom in the ring.

[3] It was observed that isatin (an indole) forms a blue dye if it is mixed with sulfuric acid and crude benzene.

Thiophene derivatives have been detected at nanomole levels in 3.5 billions year old Martian soil sediments (Murray Formation, Pahrump Hills) by the rover Curiosity at Gale crater (Mars) between 2012 and 2017.

[5] Reflecting their high stabilities, thiophenes arise from many reactions involving sulfur sources and hydrocarbons, especially unsaturated ones.

The first synthesis of thiophene by Meyer, reported the same year that he made his discovery, involves acetylene and elemental sulfur.

Specialized thiophenes can be synthesized similarly using Lawesson's reagent as the sulfidizing agent, or via the Gewald reaction, which involves the condensation of two esters in the presence of elemental sulfur.

Thiophene is produced on a modest scale of around 2,000 metric tons per year worldwide.

The major pathway forms the S-oxide as an intermediate, which undergoes subsequent Diels-Alder-type dimerisation and further oxidation, forming a mixture of sulfoxide and sulfone products with a combined yield of 83% (based on NMR evidence):[9][10] In the minor reaction pathway, a Prilezhaev epoxidation[11] results in the formation of thiophene-2,3-epoxide that rapidly rearranges to the isomer thiophene-2-one.

[13][14][15][16] Although the sulfur atom is relatively unreactive, the flanking carbon centers, the 2- and 5-positions, are highly susceptible to attack by electrophiles.

Polythiophenes become electrically conductive upon partial oxidation, i.e. they obtain some of the characteristics typically observed in metals.

[20] Thiophene exhibits little sulfide-like character, but it does serve as a pi-ligand forming piano stool complexes such as Cr(η5-C4H4S)(CO)3.

Thiophenes are important heterocyclic compounds that are widely used as building blocks in many agrochemicals and pharmaceuticals.