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| Names | |||
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| Preferred IUPAC name Thiophene[1] | |||
| Other names Thiofuran Thiacyclopentadiene Thiole | |||
| Identifiers | |||
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3D model (JSmol) | |||
| ChEBI | |||
| ChEMBL | |||
| ChemSpider |
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| ECHA InfoCard | 100.003.392 | ||
| RTECS number |
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| UNII | |||
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| Properties | |||
| C4H4S | |||
| Molar mass | 84.14 g/mol | ||
| Appearance | colorless liquid | ||
| Density | 1.051 g/mL, liquid | ||
| Melting point | −38 °C (−36 °F; 235 K) | ||
| Boiling point | 84 °C (183 °F; 357 K) | ||
| −57.38·10−6 cm3/mol | |||
Refractive index (nD) | 1.5287 | ||
| Viscosity | 0.8712 cP at 0.2 °C 0.6432 cP at 22.4 °C | ||
| Hazards | |||
| Occupational safety and health (OHS/OSH): | |||
Main hazards | Toxic | ||
| GHS labelling:[2] | |||
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| Danger | |||
| H225,H302,H319,H412 | |||
| P210,P260,P262,P273,P305+P351+P338,P403+P235 | |||
| NFPA 704 (fire diamond) | |||
| Flash point | −1 °C (30 °F; 272 K) | ||
| Safety data sheet (SDS) | External MSDS,External MSDS | ||
| Related compounds | |||
Relatedthioethers | Tetrahydrothiophene Diethyl sulfide | ||
Related compounds | Furan Selenophene Pyrrole | ||
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |||
Thiophene is aheterocyclic compound with the formula C4H4S. Consisting of a planar five-membered ring, it isaromatic as indicated by its extensivesubstitution reactions. It is a colorless liquid with abenzene-like odor. In most of its reactions, it resemblesbenzene. Compounds analogous to thiophene includefuran (C4H4O),selenophene (C4H4Se) andpyrrole (C4H4NH), which each vary by theheteroatom in the ring.
Thiophene was discovered byViktor Meyer in 1882 as a contaminant in benzene.[3] It was observed thatisatin (anindole) forms a bluedye if it is mixed withsulfuric acid and crude benzene. The formation of the blue indophenin had long been believed to be a reaction of benzene itself.Viktor Meyer was able to isolate thiophene as the actual substance responsible for this reaction.[4]
Thiophene and especially its derivatives occur inpetroleum, sometimes in concentrations up to 1–3%. The thiophenic content ofoil andcoal is removed via thehydrodesulfurization (HDS) process.
Thiophene derivatives have been detected at nanomole levels in 3.5 billions year old Martian soil sediments (Murray Formation, Pahrump Hills) by the roverCuriosity 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. Thiophenes are classically prepared by the reaction of 1,4-diketones, diesters, or dicarboxylates with sulfidizing reagents such asP4S10 such as in thePaal-Knorr thiophene synthesis. Specialized thiophenes can be synthesized similarly usingLawesson's reagent as the sulfidizing agent, or via theGewald reaction, which involves the condensation of twoesters in the presence of elemental sulfur. Another method is theVolhard–Erdmann cyclization.
Thiophene is produced on a modest scale of around 2,000 metric tons per year worldwide. Production involves the vapor phase reaction of a sulfur source, typicallycarbon disulfide, and a C-4 source, typicallybutanol. These reagents are contacted with an oxidecatalyst at 500–550 °C.[6]
Thiophene is a colorless liquid at room temperature. The high reactivity of thiophene toward sulfonation is the basis for the separation of thiophene from benzene, which are difficult to separate bydistillation due to their similar boiling points (4 °C difference at ambient pressure). Like benzene, thiophene forms anazeotrope with ethanol.
The molecule is flat; the bond angle at the sulfur is around 93°, the C–C–S angle is around 109°, and the other two carbons have a bond angle around 114°.[7] The C–C bonds to the carbons adjacent to the sulfur are about 1.34 Å, the C–S bond length is around 1.70 Å, and the other C–C bond is about 1.41 Å.[7]
Thiophene is considered to be aromatic, although theoretical calculations suggest that the degree of aromaticity is less than that of benzene. The "electron pairs" on sulfur are significantlydelocalized in thepi electron system. As a consequence of its aromaticity, thiophene does not exhibit the properties seen for conventionalsulfides. For example, the sulfur atom resists alkylation and oxidation.
Oxidation can occur both at sulfur, giving a thiopheneS-oxide, as well as at the 2,3-double bond, giving the thiophene 2,3-epoxide, followed by subsequentNIH shift rearrangement.[8] Oxidation of thiophene bytrifluoroperacetic acid also demonstrates both reaction pathways. The major pathway forms theS-oxide as an intermediate, which undergoes subsequentDiels-Alder-typedimerisation and further oxidation, forming a mixture ofsulfoxide andsulfone products with a combined yield of 83% (based onNMR evidence):[9][10]
In the minor reaction pathway, aPrilezhaev epoxidation[11] results in the formation of thiophene-2,3-epoxide that rapidlyrearranges to theisomer thiophene-2-one.[9] Trapping experiments[12] demonstrate that this pathway is not aside reaction from theS-oxide intermediate, whileisotopic labeling withdeuterium confirm that a1,2-hydride shift occurs and thus that a cationic intermediate is involved.[9] If the reaction mixture is notanhydrous, this minor reaction pathway is suppressed as water acts as a competing base.[9]
Oxidation of thiophenes may be relevant to the metabolic activation of various thiophene-containing drugs, such astienilic acid and the investigational anticancer drug OSI-930.[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 byelectrophiles. Halogens give initially 2-halo derivatives followed by 2,5-dihalothiophenes; perhalogenation is easily accomplished to give C4X4S (X = Cl, Br, I).[17] Thiophene brominates 107 times faster than does benzene. Acetylation occurs readily to give2-acetylthiophene, precursor tothiophene-2-carboxylic acid andthiophene-2-acetic acid.[6]
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.[18][19]
Desulfurization of thiophene withRaney nickel affordsbutane. When coupled with the easy 2,5-difunctionalization of thiophene, desulfurization provides a route to 1,4-disubstituted butanes.
The polymer formed by linking thiophene through its 2,5 positions is calledpolythiophene. Polymerization is conducted by oxidation using electrochemical methods (electropolymerization) or electron-transfer reagents. An idealized equation is shown:
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 asEDOT (ethylenedioxythiophene). 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 formingpiano stool complexes such as Cr(η5-C4H4S)(CO)3.[21]
![Thieno[3,2-b]thiophene, one of the four thienothiophenes](/mt/?noimg=&dark=on&url=https%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aThienothiophene251-41-2.png)
Upon deprotonation, thiophene converts to the thienyl group, C4H3S−. Although the anion per se does not exist, theorganolithium derivatives do. Thus reaction of thiophene withbutyl lithium gives 2-lithiothiophene, also called 2-thienyllithium. This reagent reacts with electrophiles to give thienyl derivatives, such as the thiol.[22] Oxidation of thienyllithium gives 2,2'-dithienyl, (C4H3S)2. Thienyl lithium is employed in the preparation of higher ordermixed cuprates.[23] Coupling of thienyl anion equivalents givesdithienyl, an analogue of biphenyl.
Fusion of thiophene with a benzene ring givesbenzothiophene. Fusion with two benzene rings gives eitherdibenzothiophene (DBT) or naphthothiophene. Fusion of a pair of thiophene rings gives isomers ofthienothiophene.
Thiophenes are important heterocyclic compounds that are widely used as building blocks in many agrochemicals and pharmaceuticals.[6] The benzene ring of a biologically active compound may often be replaced by a thiophene without loss of activity.[24] This is seen in examples such as theNSAIDlornoxicam, the thiophene analog ofpiroxicam, andsufentanil, the thiophene analog offentanyl.
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