View source for Thiophene

{{Short description|Sulfur-containing aromatic compound}}
{{chembox
| Watchedfields = changed
| verifiedrevid = 477174322
| Name = Thiophene
| ImageFileL1_Ref = {{chemboximage|correct|??}}
| ImageFileL1 = Thiophene-2D-full.svg
| ImageNameL1 = Full displayed formula of thiophene
| ImageFileR1_Ref = {{chemboximage|correct|??}}
| ImageFileR1 = Thiophene-2D-numbered.svg
| ImageNameR1 = Skeletal formula showing numbering convention
| ImageFileL2 = Thiophene-CRC-MW-3D-balls-A.png
| ImageNameL2 = Ball-and-stick model
| ImageFileR2 = Thiophene-CRC-MW-3D-vdW.png
| ImageNameR2 = Space-filling model
| PIN = Thiophene<ref>{{cite book |author=[[International Union of Pure and Applied Chemistry]] |date=2014 |title=Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 |publisher=[[Royal Society of Chemistry|The Royal Society of Chemistry]] |pages=141 |doi=10.1039/9781849733069 |isbn=978-0-85404-182-4}}</ref>
| OtherNames = Thiofuran<br/>Thiacyclopentadiene <br/>Thiole
|Section1={{Chembox Identifiers
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 30856
| SMILES = c1ccsc1
| PubChem = 8030
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 7739
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = SMB37IQ40B
| InChI = 1/C4H4S/c1-2-4-5-3-1/h1-4H
| InChIKey = YTPLMLYBLZKORZ-UHFFFAOYAY
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 278958
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C4H4S/c1-2-4-5-3-1/h1-4H
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = YTPLMLYBLZKORZ-UHFFFAOYSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 110-02-1
| RTECS = XM7350000
 }}
|Section2={{Chembox Properties
| Formula = C<sub>4</sub>H<sub>4</sub>S
| MolarMass = 84.14 g/mol
| Appearance = colorless liquid
| Density = 1.051 g/mL, liquid
| MeltingPtC = −38
| BoilingPtC = 84
| Viscosity = 0.8712 c[[Poise (unit)|P]] at 0.2&nbsp;°C<br>0.6432  c[[Poise (unit)|P]] at 22.4&nbsp;°C
| RefractIndex = 1.5287
| MagSus = −57.38·10<sup>−6</sup> cm<sup>3</sup>/mol
 }}
|Section3={{Chembox Structure
| Dipole =
 }}
|Section7={{Chembox Hazards
| MainHazards = Toxic
| ExternalSDS = [http://physchem.ox.ac.uk/MSDS/TH/thiophene.html External MSDS], [http://www.mathesongas.com/pdfs/msds/MAT23380.pdf External MSDS]
| GHSPictograms = {{GHS02}}{{GHS07}}
| GHSSignalWord = danger
| HPhrases      = {{HPhrases|H225|H302|H319|H412}}
| PPhrases      = {{PPhrases|P210|P260|P262|P273|P305+P351+P338|P403+P235}}
| GHS_ref       = <ref>GHS: [https://gestis.dguv.de/data?name=010090 GESTIS 010090]</ref>
| NFPA-H = 2
| NFPA-F = 3
| NFPA-R = 0
| FlashPtC = −1
 }}
|Section8={{Chembox Related
| OtherFunction_label = [[thioether]]s
| OtherFunction = [[Tetrahydrothiophene]]<br>[[Diethyl sulfide]]
| OtherCompounds = [[Furan]]<br>[[Selenophene]]<br>[[Pyrrole]]
  }}
}}

'''Thiophene''' is a [[heterocyclic compound]] with the formula C<sub>4</sub>H<sub>4</sub>S. Consisting of a planar five-membered ring, it is [[aromaticity|aromatic]] as indicated by its extensive [[substitution reaction]]s. It is a colorless liquid with a [[benzene]]-like odor.  In most of its reactions, it resembles [[benzene]]. Compounds analogous to thiophene include [[furan]] (C<sub>4</sub>H<sub>4</sub>O), [[selenophene]] (C<sub>4</sub>H<sub>4</sub>Se) and [[pyrrole]] (C<sub>4</sub>H<sub>4</sub>NH), which each vary by the [[heteroatom]] in the ring.

==Isolation and occurrence==
Thiophene was discovered by [[Viktor Meyer]] in 1882 as a contaminant in benzene.<ref>{{cite journal| first = Viktor | last = Meyer | title = Ueber den Begleiter des Benzols im Steinkohlenteer |trans-title=On a substance that accompanies benzene in coal tar | journal = [[Berichte der Deutschen Chemischen Gesellschaft]] | year = 1883 | volume = 16 | pages = 1465–1478 | url = https://zenodo.org/record/1425291 | doi = 10.1002/cber.188301601324}}</ref>  It was observed that [[isatin]] (an [[indole]]) forms a blue [[dye]] if it is mixed with [[sulfuric 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.<ref>{{cite journal| last = Ward C. | first = Sumpter | title = The Chemistry of Isatin | journal = [[Chemical Reviews]] | year = 1944 | volume = 34 | issue = 3 | pages = 393–434 | doi = 10.1021/cr60109a003}}</ref>

Thiophene and especially its derivatives occur in [[petroleum]], sometimes in concentrations up to 1–3%. The thiophenic content of [[Petroleum|oil]] and [[coal]] is removed via the [[hydrodesulfurization]] (HDS) process. 

===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 (rover)|Curiosity]]'' at Gale crater (Mars) between 2012 and 2017.<ref name="Voosen2018">{{cite journal|last1=Voosen|first1=Paul|title=NASA rover hits organic pay dirt on Mars|journal=Science|year=2018|issn=0036-8075|doi=10.1126/science.aau3992|s2cid=115442477}}</ref>

==Synthesis and production==
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-di[[ketone]]s, diesters, or dicarboxylates with sulfidizing reagents such as [[phosphorus pentasulfide|P<sub>4</sub>S<sub>10</sub>]] such as in the [[Paal–Knorr synthesis|Paal-Knorr thiophene synthesis]].  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. Another method is the [[Volhard–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, typically [[carbon disulfide]], and a C-4 source, typically [[n-Butanol|butanol]].  These reagents are contacted with an oxide [[catalyst]] at 500–550&nbsp;°C.<ref name="Ullmann">{{cite book| first = Jonathan | last = Swanston |chapter = Thiophene | title = Ullmann's Encyclopedia of Industrial Chemistry | publisher = Wiley-VCH | location = Weinheim | date = 2006 | doi = 10.1002/14356007.a26_793.pub2| isbn = 3527306730 }}.</ref>

==Properties and structure==
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 by [[distillation]] due to their similar boiling points (4&nbsp;°C difference at ambient pressure).  Like benzene, thiophene forms an [[azeotrope]] 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°.<ref name=CSD>Cambridge Structural Database</ref> The C–C bonds to the carbons adjacent to the sulfur are about 1.34&nbsp;[[Ångström|Å]], the C–S bond length is around 1.70&nbsp;Å, and the other C–C bond is about 1.41&nbsp;Å.<ref name=CSD/>

==Reactivity==
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 significantly [[delocalized]] in the [[pi electron]] system.  As a consequence of its aromaticity, thiophene does not exhibit the properties seen for conventional [[thioether|sulfide]]s.  For example, the sulfur atom resists alkylation and oxidation.

===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.<ref>{{cite journal |author=Treiber, A., Dansette, P. M., Amri, H. E., Girault, J.-P., Ginderow, D., Mornon, J.-P., Mansuy, D.|year=1997|title= 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''|journal= J. Am. Chem. Soc.|volume= 119|issue=7| pages = 1565–1571 | doi = 10.1021/ja962466g|last2=Dansette|last3=El Amri|last4=Girault|last5=Ginderow|last6=Mornon|last7=Mansuy|bibcode=1997JAChS.119.1565T }}</ref>  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 reaction|Diels-Alder]]-type [[dimerization (chemistry)|dimerisation]] and further oxidation, forming a mixture of [[sulfoxide]] and [[sulfone]] products with a combined yield of 83% (based on [[NMR]] evidence):<ref name = ThiopheneOxidation>{{cite journal|title = Mechanism of the Aromatic Hydroxylation of Thiophene by Acid-Catalyzed Peracid Oxidation|first = Alexander|last = Treiber|journal = [[J. Org. Chem.]]|year = 2002|volume = 67|issue = 21|pages = 7261–7266|doi = 10.1021/jo0202177|pmid = 12375952}}</ref><ref name = eEROS>{{cite encyclopedia|doi = 10.1002/047084289X.rt254.pub2|encyclopedia = [[Encyclopedia of Reagents for Organic Synthesis|e-EROS Encyclopedia of Reagents for Organic Synthesis]]|chapter = Trifluoroperacetic Acid|first1 = Kenneth C.|title = Encyclopedia of Reagents for Organic Synthesis|last1 = Caster|first2 = A. Somasekar|last2 = Rao|first3 = H. Rama|last3 = Mohan|first4 = Nicholas A.|last4 = McGrath|first5 = Matthew|last5 = Brichacek|year = 2012|isbn = 978-0471936237}}</ref>

[[File:Oxidation of thiophene with trifluoroperacetic acid.png|frameless|center|500px]]

In the minor reaction pathway, a [[Prilezhaev reaction|Prilezhaev epoxidation]]<ref>{{cite book|chapter = Prilezhaev reaction|pages = 274–281|last = Hagen|first = Timothy J.|chapter-url = https://books.google.com/books?id=WZ0DxnPNAdAC&pg=PA274|title = Name Reactions of Functional Group Transformations|editor1-first = Jie Jack|editor1-last = Li|editor2-first = E. J.|editor2-last = Corey|editor2-link = Elias James Corey|publisher = [[John Wiley & Sons]]|year = 2007|isbn = 9780470176504}}</ref> results in the formation of thiophene-2,3-epoxide that rapidly [[rearrangement reaction|rearranges]] to the [[isomer]] thiophene-2-one.<ref name = ThiopheneOxidation />  Trapping experiments<ref>{{cite book|pages = 471–482|chapter = 8.8 Miscellaneous Experiments for Studying Mechanism|chapter-url = https://books.google.com/books?id=gY-Sxijk_tMC&pg=PA474|title = Modern Physical Organic Chemistry|first1 = Eric V.|last1 = Anslyn|first2 = Dennis A.|last2 = Dougherty|author-link1 = Eric V. Anslyn|author-link2 = Dennis A. Dougherty |publisher=University Science Books |year = 2006|isbn = 9781891389313}}</ref> demonstrate that this pathway is not a [[side reaction]] from the ''S''-oxide intermediate, while [[isotopic labeling]] with [[deuterium]] confirm that a [[Sigmatropic reaction|1,2-hydride shift]] occurs and thus that a cationic intermediate is involved.<ref name = ThiopheneOxidation />  If the reaction mixture is not [[anhydrous]], this minor reaction pathway is suppressed as water acts as a competing base.<ref name = ThiopheneOxidation />

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.<ref>{{cite journal |author=Mansuy, D., Valadon, P., Erdelmeier, I., López García, P., Amar, C., Girault, J. P., and Dansette, P. M.|year=1991|title= Thiophene ''S''-oxides as new reactive metabolites: Formation by cytochrome-P450 dependent oxidation and reaction with nucleophiles|journal= J. Am. Chem. Soc.|volume= 113| issue=20| pages = 7825–7826 | doi = 10.1021/ja00020a089|bibcode=1991JAChS.113.7825M }}</ref><ref>{{cite journal |author=Rademacher P. M., Woods C. M., Huang Q., Szklarz G. D., Nelson S. D. |year=2012|title=Differential Oxidation of Two Thiophene-Containing Regioisomers to Reactive Metabolites by Cytochrome P450 2C9| journal=Chem. Res. Toxicol.|volume=25 |issue=4|pages=895–903| doi =10.1021/tx200519d |pmid=22329513|pmc=3339269|last2=Woods|last3=Huang|last4=Szklarz|last5=Nelson}}</ref><ref>{{cite journal |author=Mansuy D., Dansette P. M. |year=2011|title=Sulfenic acids as reactive intermediates in xenobiotic metabolism |journal=Archives of Biochemistry and Biophysics |volume=507 |issue=1|pages=174–185|doi=10.1016/j.abb.2010.09.015|pmid=20869346|last2=Dansette|url=https://zenodo.org/record/898058}}</ref><ref>{{ cite journal | author = Dansette, PM, Rosi, J, Debernardi, J, Bertho G, Mansuy D  | journal = [[Chem. Res. Toxicol.]] | year = 2012 | volume = 25 | pages = 1058–1065 | doi = 10.1021/tx3000279 | title =Metabolic Activation of Prasugrel: Nature of the Two Competitive Pathways Resulting in the Opening of Its Thiophene Ring | issue = 5 | last2 = Rosi | last3 = Debernardi | last4 = Bertho | last5 = Mansuy | pmid = 22482514 }}</ref>

===Alkylation===
Although the sulfur atom is relatively unreactive, the flanking carbon centers, the 2- and 5-positions, are highly susceptible to attack by [[electrophile]]s.  Halogens give initially 2-halo derivatives followed by 2,5-dihalothiophenes; perhalogenation is easily accomplished to give C<sub>4</sub>X<sub>4</sub>S (X = Cl, Br, I).<ref>{{OrgSynth | author = Henry Y. Lew and C. R. Noller| title = 2-Iodolthiophene| collvol = 4 | collvolpages = 545 | year = 1963 | prep = CV4P0545}}</ref>  Thiophene brominates 10<sup>7</sup> times faster than does benzene.  Acetylation occurs readily to give [[2-Acetylthiophene|2-acetylthiophene]], precursor to [[thiophene-2-carboxylic acid]] and [[thiophene-2-acetic acid]].<ref name="Ullmann" />

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.<ref>{{OrgSynth | author = W. S. Emerson and T. M. Patrick Jr. | title = 2-Vinylthiophene| collvol = 4 | collvolpages = 980 | year = 1963 | prep = CV4P0980}}</ref><ref>{{OrgSynth | author = K. B. Wiberg and H. F. McShane| title = 2-Chloromethylthiophene| collvol = 3 | collvolpages = 1 | year = 1955 | prep = CV3P0197}}</ref>

===Desulfurization===
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.

[[File:Desulfurization & reduction thiophene derivatives by raney nickel.svg|frameless|centre|400px]]

===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 C<sub>4</sub>H<sub>4</sub>S   →   (C<sub>4</sub>H<sub>2</sub>S)<sub>n</sub>  +  2n H<sup>+</sup>  +  2n e<sup>−</sup>

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 [[3,4-Ethylenedioxythiophene|EDOT (ethylenedioxythiophene)]].  Polythiophenes become electrically conductive upon partial oxidation, i.e. they obtain some of the characteristics typically observed in metals.<ref>{{cite journal | author = J. Roncali | title = Conjugated poly(thiophenes): synthesis, functionalization, and applications | year = 1992 | journal = [[Chem. Rev.]] | volume = 92 | issue = 4 | pages = 711–738 | doi = 10.1021/cr00012a009}}</ref>

===Coordination chemistry===
Thiophene exhibits little sulfide-like character, but it does serve as a pi-ligand forming [[piano stool complexes]] such as Cr(''η''<sup>5</sup>-C<sub>4</sub>H<sub>4</sub>S)(CO)<sub>3</sub>.<ref>Rauchfuss, T. B., "The Coordination Chemistry of Thiophenes", Progress in Inorganic Chemistry 1991, volume 39, pp. 259-311. {{ISBN|978-0-471-54489-0}}</ref>

==Thiophene derivatives==
<gallery caption="Some Thiophenes" widths="180px" heights="120px">
Thienothiophene251-41-2.png|Thieno[3,2-''b'']thiophene, one of the four [[thienothiophene]]s
2,2'Bithiophene.png|[[2,2'-Bithiophene]]
EDOT.svg|[[3,4-Ethylenedioxythiophene]] (EDOT), the precursor to commercial antistatic and [[electrochromism|electrochromic displays]]
Benzothiophene numbering.svg|[[Benzothiophene]]
</gallery>

===Thienyl===
Upon deprotonation, thiophene converts to the thienyl group, C<sub>4</sub>H<sub>3</sub>S<sup>−</sup>. 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.<ref>{{OrgSynth | author = E. Jones and I. M. Moodie | title = 2-Thiophenethiol| collvol = 6 | collvolpages = 979| year = 1988 | prep = CV6P0979}}</ref>  Oxidation of thienyllithium gives 2,2'-dithienyl, (C<sub>4</sub>H<sub>3</sub>S)<sub>2</sub>.  Thienyl lithium is employed in the preparation of higher order [[mixed cuprates]].<ref>{{cite journal | last1 = Lipshutz | first1 = Bruce H. | author-link = Bruce H. Lipshutz | last2 = Moretti | first2 = Robert | last3 = Crow | first3 = Robert | year = 1990 | title = Mixed Higher-order Cyanocuprate-induced Epoxide Openings: 1-Benzyloxy-4-penten-2-ol | journal = Org. Synth. | volume = 69 | page = 80 | doi = 10.15227/orgsyn.069.0080 }}</ref>  Coupling of thienyl anion equivalents gives [[2,2'-Bithiophene|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]].

==Uses==
Thiophenes are important heterocyclic compounds that are widely used as building blocks in many agrochemicals and pharmaceuticals.<ref name="Ullmann" />  The benzene ring of a biologically active compound may often be replaced by a thiophene without loss of activity.<ref name="Lednicer1999">{{cite book
| author = Daniel Lednicer
| title = The Organic Chemistry of Drug Synthesis
| publisher = Wiley Interscience
| volume = 6
| year = 1999
| location = New York
| pages = 187
| isbn = 0-471-24510-0 }}</ref> This is seen in examples such as the [[Non-steroidal anti-inflammatory drug|NSAID]] [[lornoxicam]], the thiophene analog of [[piroxicam]], and [[sufentanil]], the thiophene analog of [[fentanyl]].

==References==
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{{reflist}}

==External links==
*[http://www.inchem.org/documents/icsc/icsc/eics1190.htm International Chemical Safety Card 1190]
*{{cite EB1911|wstitle=Thiophen|volume=26}}

{{sulfur compounds}}
{{Authority control}}

[[Category:Thiophenes| ]]
[[Category:Simple aromatic rings]]