Thiophene

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Thiophene
Full displayed formula of thiophene Skeletal formula showing numbering convention
Ball-and-stick model Space-filling model
Identifiers
CAS number 110-02-1 YesY
PubChem 8030
ChemSpider 7739 YesY
UNII SMB37IQ40B YesY
ChEBI CHEBI:30856 YesY
ChEMBL CHEMBL278958 YesY
RTECS number XM7350000
Jmol-3D images Image 1
Properties
Molecular formula 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)
Refractive index (nD) 1.5287
Viscosity 0.8712 cP at 0.2 °C
0.6432 cP at 22.4 °C
Hazards
MSDS External MSDS
EU classification not listed
NFPA 704
Flammability code 3: Liquids and solids that can be ignited under almost all ambient temperature conditions. Flash point between 23 and 38 °C (73 and 100 °F). E.g., gasoline) Health code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g., chloroform Reactivity (yellow): no hazard code Special hazards (white): no codeNFPA 704 four-colored diamond
Flash point −1 °C (30 °F; 272 K)
Related compounds
Related thioethers Tetrahydrothiophene
Diethyl sulfide
Related compounds Furan
Pyrrole
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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Infobox references

Thiophene, also commonly called thiofuran, is a heterocyclic compound with the formula C4H4S. Consisting of a flat five-membered ring, it is aromatic as indicated by its extensive substitution reactions. Related to thiophene are benzothiophene and dibenzothiophene, containing the thiophene ring fused with one and two benzene rings, respectively. Compounds analogous to thiophene include furan (C4H4O) and pyrrole (C4H4NH).

Isolation, occurrence[edit]

Thiophene was discovered as a contaminant in benzene.[1] It was observed that isatin forms a blue dye if it is mixed with sulfuric acid and crude benzene. The formation of the blue indophenin was long believed to be a reaction with benzene. Victor Meyer was able to isolate the substance responsible for this reaction from benzene. This new heterocyclic compound was thiophene.[2]

Thiophene and its derivatives occur in petroleum, sometimes in concentrations up to 1–3%. The thiophenic content of oil and coal is removed via the hydrodesulfurization (HDS) process. In HDS, the liquid or gaseous feed is passed over a form of molybdenum disulfide catalyst under a pressure of H2. Thiophenes undergo hydrogenolysis to form hydrocarbons and hydrogen sulfide. Thus, thiophene itself is converted to butane and H2S. More prevalent and more problematic in petroleum are benzothiophene and dibenzothiophene.

Synthesis and production[edit]

Reflecting their high stabilities, thiophenes arise from many reactions involving sulfur sources and hydrocarbons, especially unsaturated ones, e.g. acetylenes and elemental sulfur, which was the first synthesis of thiophene by Viktor Meyer in the year of its discovery. Thiophenes are classically prepared by the reaction of 1,4-diketones, diesters, or dicarboxylates with sulfiding reagents such as P4S10. Specialized thiophenes can be synthesized similarly using Lawesson's reagent as the sulfiding agent, or via the Gewald reaction, which involves the condensation of two esters in the presence of elemental sulfur. Another method is the Volhard–Erdmann cyclization.

Thiophene is produced on a scale of ca. 2M kg per year worldwide. Production involves the vapor phase reaction of a sulfur source, typically carbon disulfide, and butanol. These reagents are contacted with an oxide catalyst at 500–550 °C.[3]

Properties[edit]

At room temperature, thiophene is a colorless liquid with a mildly pleasant odor reminiscent of benzene, with which thiophene shares some similarities. The high reactivity of thiophene toward sulfonation is the basis for the separation of thiophene from benzene, which are difficult to separate by distillation due to their similar boiling points (4 °C difference at ambient pressure). Like benzene, thiophene forms an azeotrope with ethanol.

The molecule is flat; the bond angle at the sulphur is around 93 degrees, the C-C-S angle is around 109, and the other two carbons have a bond angle around 114 degrees. The C-C bonds to the carbons adjacent to the sulphur are about 1.34A, the C-S bond length is around 1.70A, and the other C-C bond is about 1.41A (figures from the Cambridge Structural Database).

Reactivity[edit]

Thiophene is considered aromatic, although theoretical calculations suggest that the degree of aromaticity is less than that of benzene. The "electron pairs" on sulfur are significantly delocalized in the pi electron system. As a consequence of its aromaticity, thiophene does not exhibit the properties seen for conventional thioethers. For example the sulfur atom resists alkylation and oxidation. However, oxidation of a thiophene ring is thought to play a crucial role in the metabolic activation of various thiophene-containing drugs, such as tienilic acid and the investigational anticancer drug OSI-930. In these cases 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.[4][5][6][7][8]

Toward electrophiles[edit]

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).[9] Thiophene brominates 107 times faster than does benzene.[3]

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.[10][11]

Desulfurization by Raney nickel[edit]

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.

Lithiation[edit]

Not only is thiophene reactive toward electrophiles, it is also readily lithiated with butyl lithium to give 2-lithiothiophene, which is a precursor to a variety of derivatives, including dithienyl.[12]

Coordination chemistry[edit]

Thiophene exhibits little thioether-like character, but it does serve as a pi-ligand forming piano stool complexes such as Cr(η5-C4H4S)(CO)3.[13]

Uses[edit]

Thiophenes are important heterocyclic compounds that are widely used as building blocks in many agrochemicals and pharmaceuticals.[3] The benzene ring of a biologically active compound may often be replaced by a thiophene without loss of activity.[14] This is seen in examples such as the NSAID lornoxicam, the thiophene analog of piroxicam.

Polythiophene[edit]

The polymer formed by linking thiophene through its 2,5 positions is called polythiophene. Polythiophene itself has poor processing properties. More useful are polymers derived from thiophenes substituted at the 3- and 3- and 4- positions. Polythiophenes become electrically conductive upon partial oxidation, i.e. they become "organic metals."[15]

References[edit]

  1. ^ Viktor Meyer (1883). "Ueber den Begleiter des Benzols im Steinkohlenteer" [On a substance that accompanies benzene in coal tar]. Berichte der Deutschen chemischen Gesellschaft 16: 1465–1478. doi:10.1002/cber.188301601324. 
  2. ^ Ward C. Sumpter (1944). "The Chemistry of Isatin". Chemical Reviews 34 (3): 393–434. doi:10.1021/cr60109a003. 
  3. ^ a b c Jonathan Swanston "Thiophene" in Ullmann’s Encyclopedia of Industrial Chemistry Wiley-VCH, Weinheim, 2006. doi:10.1002/14356007.a26_793.pub2.
  4. ^ Mansuy, D., Valadon, P., Erdelmeier, I., Lopez-Garcia, P., Amar, C., Girault, J. P., and Dansette, P. M. (1991). "Thiophene S-oxides as new reactive metabolites: Formation by cytochrome-P450 dependent oxidation and reaction with nucleophiles". J. Am. Chem. Soc. 113 (20): 7825−7826. doi:10.1021/ja00020a089. 
  5. ^ Treiber, A., Dansette, P.M., Amri, H.E., Girault, J.-P., Ginderow, D., Mornon, J.-P., Mansuy, D. (1997). "Chemical and Biological Oxidation of Thiophene:  Preparation and Complete Characterization of Thiophene S-Oxide Dimers and Evidence for Thiophene S-Oxide as an Intermediate in Thiophene Metabolism in Vivo and in Vitro". J. Am. Chem. Soc. 119 (7): 1565−1571. doi:10.1021/ja962466g. 
  6. ^ Rademacher PM, Woods CM, Huang Q, Szklarz GD, Nelson SD (2012). "Differential Oxidation of Two Thiophene-Containing Regioisomers to Reactive Metabolites by Cytochrome P450 2C9". Chem. Res. Toxicol. 25 (4): 895–903. doi:10.1021/tx200519d. PMID 22329513. 
  7. ^ Mansuy D, Dansette PM (2011). "Sulfenic acids as reactive intermediates in xenobiotic metabolism". Archives of Biochemistry and Biophysics 507 (1): 174–185. doi:10.1016/j.abb.2010.09.015. 
  8. ^ Dansette, PM, Rosi, J, Debernardi, J, Bertho G, Mansuy D (2012). "Metabolic Activation of Prasugrel: Nature of the Two Competitive Pathways Resulting in the Opening of Its Thiophene Ring". Chem. Res. Toxicol. 25 (5): 1058–1065. doi:10.1021/tx3000279. 
  9. ^ Henry Y. Lew and C. R. Noller (1963), "2-Iodolthiophene", Org. Synth. ; Coll. Vol. 4: 545 
  10. ^ W. S. Emerson and T. M. Patrick, Jr. (1963), "2-Vinylthiophene", Org. Synth. ; Coll. Vol. 4: 980 
  11. ^ K. B. Wiberg and H. F. McShane (1955), "2-Chloromethylthiophene", Org. Synth. ; Coll. Vol. 3: 1 
  12. ^ E. Jones and I. M. Moodie (1988), "2-Thiophenethiol", Org. Synth. ; Coll. Vol. 6: 979 
  13. ^ Rauchfuss, T. B., "The Coordination Chemistry of Thiophenes", Progress in Inorganic Chemistry 1991, volume 39, pp. 259-311. ISBN 978-0-471-54489-0
  14. ^ Daniel Lednicer (1999). The Organic Chemistry of Drug Synthesis 6. New York: Wiley Interscience. p. 187. ISBN 0-471-24510-0. 
  15. ^ J. Roncali (1992). "Conjugated poly(thiophenes): synthesis, functionalization, and applications". Chem. Rev. 92 (4): 711–738. doi:10.1021/cr00012a009. 

External links[edit]