Thiophene

On Mars

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] It represents an important milestone for the mission of the Mars Science Laboratory (MSL) in the long and elusive quest of organic matter on the red planet. Heating at high temperature (500° to 820 °C) of lacustrine mudstone samples by the Sample Analysis at Mars (SAM) instrument allowed gas chromatography-mass spectrometry (GC-MS) analyses of the evolved gases and the detection of aromatic and aliphatic molecules including several thiophene compounds.^[6] The presence of carbon-sulfur bonds in macromolecules could have contributed to the preservation of organic matter at very long-term. It is estimated that ~ 5 % of organic molecules analysed by the SAM instrument contains organic sulfur. It remains unknown whether the origin and the mode of formation of these molecules is biotic or abiotic,^[7] but their discovery put forward the puzzling question of thiophenic compounds as a possible ancient biosignature on Mars. Detailed analyses of carbon isotopes (δ¹³C) at trace level by a next generation of Martian rovers, such as Rosalind Franklin,^[8] will be necessary to determine if such organic molecules are enriched in light carbon (¹²C) as living micro-organisms usually are on Earth.

Oxidation

Oxidation can occur both at sulfur, giving a thiophene S-oxide, as well as at the 2,3-double bond, giving the thiophene 2,3-epoxide, followed by subsequent NIH shift rearrangement.^[11] Oxidation of thiophene by trifluoroperacetic acid also demonstrates both reaction pathways. 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):^[12][13]

In the minor reaction pathway, a Prilezhaev epoxidation^[14] results in the formation of thiophene-2,3-epoxide that rapidly rearranges to the isomer thiophene-2-one.^[12] Trapping experiments^[15] demonstrate that this pathway is not a side reaction from the S-oxide intermediate, while isotopic labeling with deuterium confirm that a 1,2-hydride shift occurs and thus that a cationic intermediate is involved.^[12] If the reaction mixture is not anhydrous, this minor reaction pathway is suppressed as water acts as a competing base.^[12]

Oxidation of thiophenes may be relevant to the metabolic activation of various thiophene-containing drugs, such as tienilic acid and the investigational anticancer drug OSI-930.^{[16][17][18][19]}

Alkylation

Although the sulfur atom is relatively unreactive, the flanking carbon centers, the 2- and 5-positions, are highly susceptible to attack by electrophiles. Halogens give initially 2-halo derivatives followed by 2,5-dihalothiophenes; perhalogenation is easily accomplished to give C₄X₄S (X = Cl, Br, I).^[20] Thiophene brominates 10⁷ times faster than does benzene. Acetylation occurs readily to give 2-acetylthiophene, precursor to thiophene-2-carboxylic acid and thiophene-2-acetic acid.^[9]

Chloromethylation and chloroethylation occur readily at the 2,5-positions. Reduction of the chloromethyl product gives 2-methylthiophene. Hydrolysis followed by dehydration of the chloroethyl species gives 2-vinylthiophene.^[21][22]

Desulfurization by Raney nickel

Desulfurization of thiophene with Raney nickel affords butane. When coupled with the easy 2,5-difunctionalization of thiophene, desulfurization provides a route to 1,4-disubstituted butanes.

Polymerization

The polymer formed by linking thiophene through its 2,5 positions is called polythiophene. Polymerization is conducted by oxidation using electrochemical methods (electropolymerization) or electron-transfer reagents. An idealized equation is shown:

n C₄H₄S → (C₄H₂S)_n + 2n H⁺ + 2n e⁻

Polythiophene itself has poor processing properties and so is little studied. More useful are polymers derived from thiophenes substituted at the 3- and 3- and 4- positions, such as EDOT (ethylenedioxythiophene). Polythiophenes become electrically conductive upon partial oxidation, i.e. they obtain some of the characteristics typically observed in metals.^[23]

Coordination chemistry

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.^[24]

Thienyl

Upon deprotonation, thiophene converts to the thienyl group, C₄H₃S⁻. Although the anion per se does not exist, the organolithium derivatives do. Thus reaction of thiophene with butyl lithium gives 2-lithiothiophene, also called 2-thienyllithium. This reagent reacts with electrophiles to give thienyl derivatives, such as the thiol.^[25] Oxidation of thienyllithium gives 2,2'-dithienyl, (C₄H₃S)₂. Thienyl lithium is employed in the preparation of higher order mixed cuprates.^[26] Coupling of thienyl anion equivalents gives dithienyl, an analogue of biphenyl.

Ring-fused thiophenes

Fusion of thiophene with a benzene ring gives benzothiophene. Fusion with two benzene rings gives either dibenzothiophene (DBT) or naphthothiophene. Fusion of a pair of thiophene rings gives isomers of thienothiophene.