Thiophene
What Is Thiophene
Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a planar five-membered ring, it is aromatic as indicated by its extensive substitution reactions. It is a colorless liquid with a benzene-like odor. In most of its reactions, it resembles benzene. Compounds analogous to thiophene include furan (C4H4O), selenophene (C4H4Se) and pyrrole (C4H4NH), which each vary by the heteroatom in the ring.
Advantages of Thiophene
Wide range of uses
Thiophenes are useful as an anti-microbial, nematicidal, antioxidant, anti-malarial, anti-influenza, anti-inflammatory, and larvicidal.
Thiophenes also have a cytotoxic effect
The oxidative metabolism of the thiophene ring influences the toxicity of this compound.
Diverse pharmacological activities
Thiophene has been established as the potential entity in the largely growing chemical world of heterocyclic compounds possessing promising pharmacological characteristics. A series of thiophene compounds can be synthesized through various synthetic routes, with diverse pharmacological activities.
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Properties of Thiophene
At room temperature, thiophene is a colorless liquid with a mildly pleasant odor reminiscent of benzene, with which thiophene shares some similarities. Thiophene is considered aromatic, although theoretical calculations suggest that the degree of aromaticity is less than that of benzene. The participation of the lone electron pairs on sulfur in the delocalized pi electron system is significant. As a consequence of its aromaticity, thiophene does not exhibit the properties seen for conventional thioethers. For example the sulfur atom is not alkylated by methyl iodide. Although the sulfur atom is unreactive, the flanking CH centers are susceptible to attack by electrophiles.
The high reactivity of thiophene toward sulfonation is the basis for the separation of thiophene from benzene, as thiophene and benzene are difficult to separate by distillation due to the mere 4 °C difference in their boiling points at ambient pressure. Treatment of thiophene-benzene mixtures with sulfuric acid results in preferential sulfonation of the thiophene to give water-soluble thiophene sulfonic acid.
Thiophenes are important heterocyclic compounds and are recurring building blocks in organic chemistry with applications in pharmaceuticals. The benzene ring of a biologically active compound may often be replaced by a thiophene without loss of activity. This is seen in examples such as the NSAID lornoxicam, the thiophene analog of piroxicam.
Thiophenes are used as synthetic intermediates, taking advantage of the susceptibility of the carbon atoms adjacent to S toward electrophilic reactions. Desulfurization of the resulting ring using Raney nickel affords 1,4-disubstituted butanes. The polymer formed by linking thiophene through its 1,5 positions is called polythiophene. Polythiophenes become electrically conductive upon partial oxidation, i.e. they become "organic metals".
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 thiphene by Viktor Meyer in the year of its discovery. Thiophenes are classically prepared by the reaction of 1,4-diketones with sulfiding reagents such as Lawesson's reagent or P4S10. Specialized thiophenes can be synthesized via the Gewald reaction, which involves the condensation of two esters in the presence of elemental sulfur.
Thiophene and its derivatives occur in petroleum, sometimes in concentrations up to 1-3%. The thiophenic content of liquids from oil and coal is removed via the hydrodesulfurization (HDS) process. In HDS, the liquid or gaseous feed is passed over a special form of molybdenum disulfide 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.
Reactivity of Thiophene
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.
1.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. 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):
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. Trapping experiments 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.
2.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). 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.
3.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.
4.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.
5.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.
Thiophene is a five membered heteroaromatic compound containing a sulfur atom at 1 position. It is considered to be a structural alert with formula C4H4S, chemical name is thiacyclopentadiene.
Thiophene was discovered as a contaminant in benzene. It has the molecular mass of 84.14 g/mol, density is 1.051 g/ml and Melting Point is − 38 °C. It is soluble in most organic solvents like alcohol and ether but insoluble in water. The “electron pairs” on sulfur are significantly delocalized in the π electron system and behaves extremely reactive like benzene derivative. Thiophene forms a azeotrope with ethanol like benzene. The similarity between the physicochemical properties of benzene and thiophene is remarkable. For example, the boiling point of benzene is 81.1 °C and that of thiophene is 84.4 °C (at 760 mmHg) and therefore, both are a well known example of bioisosterism. It can be easily sulfonated, nitrated, halogenated, acylated but cannot be alkylated and oxidized.
In medicinal chemistry, thiophene derivatives are very important heterocycles exhibiting remarkable applications in different disciplines. In medicine, thiophene derivatives shows antimicrobial, analgesic and anti-inflammatory, antihypertensive, and antitumor activity while they are also used as inhibitors of corrosion of metals or in the fabrication of light-emitting diodes in material science.
Thiophene derivatives show high antimicrobial activity against various microbial infections. Different approaches were made to prove thiophene as antimicrobial agent by different scientist for the discovery of most active thiophene derivatives to the present scenario.
The standard drug used in this study was ‘Ampicillin’ for evaluating antibacterial activity which showed (50, 100, and 50 μg/ml) MIC against E. coli, P. aeruginosa and S. aureus, respectively. For antifungal activity ‘Griseofulvin’ was used as a standard drug, which showed (100, 100, and 100 μg/ml) MIC against C. albicans, A. niger, and A. clavatus, respectively. Among the synthesized derivatives, Compound 4 was found to be good active against P. aeruginosa.
Various Thiophene Examples in Everyday Chemistry
Thiophene has found its way into numerous practical applications, spanning from pharmaceuticals and agrochemicals to material science and industry. Agrochemicals are chemicals used in agriculture, such as pesticides, fungicides, and insecticides, among others.
Pharmaceuticals
Many pharmaceutical compounds contain thiophene as a critical building block. Examples include the muscle relaxant tizanidine and the antipsychotic clozapine. Both these molecules integrate a thiophene ring in their structure, making the latter part of the vast domain of biologically active compounds embodying thiophene.
Agrochemicals
Thiophene compounds are found in certain pesticides and herbicides used in agriculture. One example is trifloxysulfuron, a herbicide used for broadleaf weed control that contains thiophene.
Material Science
Thiophenes also find use in the field of material science. Polythiophenes, a class of polymers containing the thiophene structure, are notable for their electronic properties and are used in organic semiconductors and solar cells.
Why Is Thiophene Aromatic?
Thiophene is considered aromatic due to several key factors that align with the criteria of aromaticity
Cyclic structure
Thiophene has a five-membered ring structure, which is essential for aromatic compounds. The ring consists of four carbon atoms and one sulfur atom.
Planarity
The structure of thiophene is planar, allowing for effective overlap of p-orbitals across the ring. This planarity is crucial for the delocalization of electrons.
Conjugation
Thiophene features alternating single and double bonds (or resonance structures), which allows for the delocalization of π-electrons. The presence of the sulfur atom contributes to the electron density in the ring.
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