:Thiophene

Thiophene was discovered by Viktor Meyer in 1882 as a contaminant in benzene.{{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}} 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.{{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}}

Thiophene and especially 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.

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.{{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}}

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 as P₄S₁₀ such as in the 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 butanol. These reagents are contacted with an oxide catalyst at 500–550 °C.{{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 }}.

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 °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°.Cambridge Structural Database 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.

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 sulfides. For example, the sulfur atom resists alkylation and 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.{{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}} 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):{{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}}{{cite encyclopedia|doi = 10.1002/047084289X.rt254.pub2|encyclopedia = 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}}

File:Oxidation of thiophene with trifluoroperacetic acid.png

In the minor reaction pathway, a Prilezhaev epoxidation{{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}} results in the formation of thiophene-2,3-epoxide that rapidly rearranges to the isomer thiophene-2-one. Trapping experiments{{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}} 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. If the reaction mixture is not anhydrous, this minor reaction pathway is suppressed as water acts as a competing base.

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.{{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}}{{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}}{{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}}{{ 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 }}

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).{{OrgSynth | author = Henry Y. Lew and C. R. Noller| title = 2-Iodolthiophene| collvol = 4 | collvolpages = 545 | year = 1963 | prep = CV4P0545}} 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.

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

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

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.{{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}}

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.Rauchfuss, T. B., "The Coordination Chemistry of Thiophenes", Progress in Inorganic Chemistry 1991, volume 39, pp. 259-311. {{ISBN|978-0-471-54489-0}}

Thienothiophene251-41-2.png|Thieno[3,2-b]thiophene, one of the four thienothiophenes

2,2'Bithiophene.png|2,2'-Bithiophene

EDOT.svg|3,4-Ethylenedioxythiophene (EDOT), the precursor to commercial antistatic and electrochromic displays

Benzothiophene numbering.svg|Benzothiophene

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.{{OrgSynth | author = E. Jones and I. M. Moodie | title = 2-Thiophenethiol| collvol = 6 | collvolpages = 979| year = 1988 | prep = CV6P0979}} Oxidation of thienyllithium gives 2,2'-dithienyl, (C₄H₃S)₂. Thienyl lithium is employed in the preparation of higher order mixed cuprates.{{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 }} Coupling of thienyl anion equivalents gives dithienyl, an analogue of biphenyl.

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.

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

{{reflist}}

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

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Category:Simple aromatic rings