Sulfoxide

A sulfoxide is a chemical compound containing a sulfinyl (SO) functional group attached to two carbon atoms. It is a polar functional group. Sulfoxides are the oxidized derivatives of sulfides. Examples of important sulfoxides are alliin, a precursor to the compound that gives freshly crushed garlic its aroma, and dimethyl sulfoxide (DMSO), a common solvent.[1]

Sulfoxide-tetrahedral
Sulfoxide group

Structure and bonding

Sulfoxides feature a pyramidal sulfur center with relatively short S–O distances. In DMSO, the S–O distance is 1.531 Å.[2]

Sulfoxides are generally represented with the structural formula R−S(=O)−R', where R and R' are organic groups. The bond between the sulfur and oxygen atoms is intermediate of a dative bond and a polarized double bond.[3] The double-bond resonance form implies 10 electrons around sulfur (10-S-3 in N-X-L notation). However, as is true for other formally hypervalent species, octet expansion by d-orbital participation is no longer believed to be an important contributor to the electronic structure of sulfoxides. Instead, any double-bond character of the S−O bond may be accounted for by donation of electron density into C−S antibonding orbitals ("no-bond" resonance forms in valence-bond language). Nevertheless, due to its simplicity and lack of ambiguity, the IUPAC recommends use of the expanded octet double-bond structure to depict sulfoxides, rather than the dipolar structure or structures that invoke "no-bond" resonance contributors.[4] The S–O interaction has an electrostatic aspect, resulting in significant dipolar character, with negative charge centered on oxygen. A lone pair of electrons resides on the sulfur atom, giving it tetrahedral electron-pair geometry and trigonal pyramidal shape (steric number 4 with one lone pair; see VSEPR theory). When the two organic residues are dissimilar, the sulfur is a chiral center, for example, in methyl phenyl sulfoxide.

The energy required to invert this stereocenter is sufficiently high that sulfoxides are optically stable, that is, the rate of racemization is slow at room temperature.

Preparation

Sulfoxides are typically prepared by oxidation of sulfides.[5] A typical oxidant is hydrogen peroxide. Oxidation of thioanisole can be effected with periodate.[6] In these oxidations, care is required to avoid over oxidation to the sulfone. Dimethyl sulfide is oxidized to dimethyl sulfoxide and then to dimethyl sulfone.[7] Unsymmetrical sulfides are prochiral, thus their oxidation gives chiral sulfoxides. Certain reagents or catalysts effect enantioselective oxidations.

Diaryl sulfoxides can be prepared by Friedel-Crafts arylation of sulfur dioxide using acid catalyst:

2 ArH + SO2 → Ar2SO + H2O

Aryl sulfoxides

Both aryl sulfinyl chlorides and diaryl sulfoxides can be prepared from arenes through reaction with thionyl chloride in the presence of catalysts such as BiCl3, Bi(OTf)3, LiClO4, or NaClO4.[8][9]

Reactions

Sulfoxides, such as DMSO, have basic character, being excellent ligands and readily alkylated. Similarly, they can be oxidized to sulfones.

Alkyl sulfoxides are susceptible to deprotonation of α-CH groups by strong bases, such as sodium hydride:[10]

CH3S(O)CH3 + NaH → CH3S(O)CH2Na + H2

In the Pummerer rearrangement, alkyl sulfoxides react with acetic anhydride to give migration of the oxygen from sulfur to the adjacent carbon as an acetate ester.

Pummerer Rearrangement Scheme
Pummerer Rearrangement Scheme

Sulfoxides form complexes with transition metals.[11]

Cis-fac-dichlorotetrakis(dimethyl-sulfoxide)ruthenium(II)-from-xtal-2008-3D-balls
RuCl2(dmso)4, a representative metal complex of a sulfoxide. The DMSO is coordinated to Ru in two ways, through O and through S.
Cis-fac-dichlorotetrakis(dimethyl-sulfoxide)ruthenium(II)-from-xtal-2008-3D-balls
RuCl2(dmso)4, a representative metal complex of a sulfoxide. The DMSO is coordinated to Ru in two ways, through O and through S.

Applications

Chiral sulfoxides find application in certain drugs such as esomeprazole and armodafinil, and they are also employed as chiral auxiliaries.[12] DMSO is widely used as a solvent in the laboratory.

Natural occurrence

Methionine sulfoxide forms from the amino acid methionine and its accumulation is associated with aging. The enzyme DMSO reductase catalyzes the interconversion of DMSO and dimethylsulfide.

References

  1. ^ "Syntheses of Sulphones, Sulphoxides and Cyclic Sulphides" Saul Patai, Zvi Rappoport, Eds., 1995, John Wiley & Sons. ISBN 9780470666357. doi:10.1002/9780470666357
  2. ^ R. Thomas, C. B. Shoemaker and K. Eriks "The molecular and crystal structure of dimethyl sulfoxide, (H3C)2SO". Acta Crystallogr. 1966, vol. 21, 12–20. doi:10.1107/S0365110X66002263.
  3. ^ Terence P. Cunningham, David L. Cooper, Joseph Gerratt, Peter B. Karadakov and Mario Raimondi (1997). "Chemical bonding in oxofluorides of hypercoordinate sulfur". Journal of the Chemical Society, Faraday Transactions. 93 (13): 2247–2254. doi:10.1039/A700708F.CS1 maint: Multiple names: authors list (link)
  4. ^ Brecher, Jonathan (2008). "Graphical representation standards for chemical structure diagrams" (PDF). Pure and Applied Chemistry. 80: 277–410 (on p. 389).
  5. ^ Kathrin-Maria Roy "Sulfones and Sulfoxides" Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. doi:10.1002/14356007.a25_487
  6. ^ Carl R. Johnson, Jeffrey E. Keiser "Methyl Phenyl Sulfoxide" Org. Synth. 1966, volume 46, 78. doi:10.15227/orgsyn.046.0078
  7. ^ http://www.chem.harvard.edu/groups/myers/handouts/10_Directed_Ortho.pdf
  8. ^ Le Roux, C.; Mazières, S. P.; Peyronneau, M.; Roques, N. (2003). "Catalytic Lewis Acid Activationof Thionyl Chloride: Application to the Synthesis of ArylSulfinyl Chlorides Catalyzed by Bismuth(III) Salts". Synlett (5): 0631–0634. doi:10.1055/s-2003-38358.
  9. ^ Bandgar, B. P.; Makone, S. S. (2004). "Lithium/Sodium Perchlorate Catalyzed Synthesis of Symmetrical Diaryl Sulfoxides". Syn. Commun. 34 (4): 743–750. doi:10.1081/SCC-120027723.
  10. ^ Iwai, I.; Ide, J. (1988). "2,3-Diphenyl-1,3-Butadiene". Organic Syntheses.CS1 maint: Multiple names: authors list (link); Collective Volume, 6, p. 531
  11. ^ Mario Calligaris "Structure and bonding in metal sulfoxide complexes: an update" Coordination Chemistry Reviews 2004, vol. 248, pp. 351-375. doi:10.1016/j.ccr.2004.02.005
  12. ^ Oxidation of sulfides to chiral sulfoxides using Schiff base-vanadium (IV) complexes Ángeles Gama, Lucía Z. Flores-López, Gerardo Aguirre, Miguel Parra-Hake, Lars H. Hellberg, and Ratnasamy Somanathan Arkivoc MX-789E 2003 Online article
Albendazole

Albendazole, also known as albendazolum, is a medication used for the treatment of a variety of parasitic worm infestations. It is useful for giardiasis, trichuriasis, filariasis, neurocysticercosis, hydatid disease, pinworm disease, and ascariasis, among others. It is taken by mouth.Common side effects include nausea, abdominal pains, and headaches. Potentially serious side effects include bone marrow suppression which usually improves on stopping the medication. Liver inflammation has been reported and those with prior liver problems are at greater risk. It is pregnancy category C in the United States and category D in Australia, meaning it may cause harm if taken by pregnant women. Albendazole is a broad-spectrum antihelminthic agent of the benzimidazole type.Albendazole was developed in 1975. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is between 0.01 and 0.06 USD per dose. In the United States, however, it is very expensive. As of 2015 it costs about 201 USD per dose.

Alliin

Alliin is a sulfoxide that is a natural constituent of fresh garlic. It is a derivative of the amino acid cysteine. When fresh garlic is chopped or crushed, the enzyme alliinase converts alliin into allicin, which is responsible for the aroma of fresh garlic.

Garlic has been used since antiquity as a therapeutic remedy for certain conditions now associated with oxygen toxicity, and, when this was investigated, garlic did indeed show strong antioxidant and hydroxyl radical-scavenging properties, it is presumed owing to the alliin contained within. Alliin has also been found to affect immune responses in blood.Alliin was the first natural product found to have both carbon- and sulfur-centered stereochemistry.

Alliinase

In enzymology, an alliin lyase (EC 4.4.1.4) is an enzyme that catalyzes the chemical reaction

an S-alkyl-L-cysteine S-oxide an alkyl sulfenate + 2-aminoacrylate

Hence, this enzyme has one substrate, S-alkyl-L-cysteine S-oxide, and two products, alkyl sulfenate and 2-aminoacrylate.

This enzyme belongs to the family of lyases, specifically the class of carbon-sulfur lyases. The systematic name of this enzyme class is S-alkyl-L-cysteine S-oxide alkyl-sulfenate-lyase (2-aminoacrylate-forming). Other names in common use include alliinase, cysteine sulfoxide lyase, alkylcysteine sulfoxide lyase, S-alkylcysteine sulfoxide lyase, L-cysteine sulfoxide lyase, S-alkyl-L-cysteine sulfoxide lyase, and alliin alkyl-sulfenate-lyase. It employs one cofactor, pyridoxal phosphate.

Many alliinases contain a novel N-terminal epidermal growth factor-like domain (EGF-like domain).

Anticestodal agent

An anticestodal agent is a drug used to combat tapeworm infection. It derives its name from Cestoda.

Examples include:

albendazole

albendazole sulfoxide

dichlorophen

niclosamide

quinacrine

DMSO reductase

DMSO reductase is a molybdenum-containing enzyme that catalyzes reduction of dimethyl sulfoxide (DMSO) to dimethyl sulfide (DMS). This enzyme serves as the terminal reductase under anaerobic conditions in some bacteria, with DMSO being the terminal electron acceptor. During the course of the reaction, the oxygen atom in DMSO is transferred to molybdenum, and then reduced to water.

DMSO reductase (DMSOR) and other members of the DMSO reductase family are unique to bacteria and archaea. Enzymes of this family in anaerobic oxidative phosphorylation and inorganic-donor-based lithotrophic respiration. These enzymes have been engineered to degrade oxoanions.

DMSOR catalyzes the transfer of two electrons and one oxygen atom in the reaction: The active site of DMSOR contains molybdenum, which is otherwise rare in biology.

Deuterated DMSO

Deuterated DMSO, also known as dimethyl sulfoxide-d6, is an isotopologue of dimethyl sulfoxide (DMSO, (CH3)2S=O)) with chemical formula ((CD3)2S=O) in which the hydrogen atoms ("H") are replaced with their isotope deuterium ("D"). Deuterated DMSO is a common solvent used in NMR spectroscopy.

Dichlorotetrakis(dimethylsulfoxide)ruthenium(II)

Dichlorotetrakis(dimethyl sulfoxide) ruthenium(II) describes coordination compounds with the formula RuCl2(dmso)4, where DMSO is dimethylsulfoxide. Both cis and trans isomers are known, but the cis isomer is more common. The cis isomer (pictured) is a yellow, air-stable solid that is soluble in some organic solvents. These compounds have attracted attention as possible anti-cancer drugs.

Diethyl sulfoxide

Diethyl sulfoxide, C4H10OS, is a sulfur-containing organic compound.

Dimethyl sulfoxide

Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula (CH3)2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water. It has a relatively high melting point. DMSO has the unusual property that many individuals perceive a garlic-like taste in the mouth after contact with the skin.In terms of chemical structure, the molecule has idealized Cs symmetry. It has a trigonal pyramidal molecular geometry consistent with other three-coordinate S(IV) compounds, with a nonbonded electron pair on the approximately tetrahedral sulfur atom.

Dimethyl sulfoxide (data page)

This page provides supplementary chemical data on dimethyl sulfoxide.

Glutaredoxin

Glutaredoxins are small redox enzymes of approximately one hundred amino-acid residues that use glutathione as a cofactor. Glutaredoxins are oxidized by substrates, and reduced non-enzymatically by glutathione. In contrast to thioredoxins, which are reduced by thioredoxin reductase, no oxidoreductase exists that specifically reduces glutaredoxins. Instead, glutaredoxins are reduced by the oxidation of glutathione. Oxidized glutathione is then regenerated by glutathione reductase. Together these components compose the glutathione system.Like thioredoxin, which functions in a similar way, glutaredoxin possesses an active centre disulfide bond. It exists in either a reduced or an oxidized form where the two cysteine residues are linked in an intramolecular disulfide bond. Glutaredoxins function as electron carriers in the glutathione-dependent synthesis of deoxyribonucleotides by the enzyme ribonucleotide reductase. Moreover, GRX act in antioxidant defence by reducing dehydroascorbate, peroxiredoxins, and methionine sulfoxide reductase. Beside their function in antioxidant defence, bacterial and plant GRX were shown to bind iron-sulfur clusters and to deliver the cluster to enzymes on demand.

Iodate

An iodate is a conjugate base of iodic acid. In the iodate anion, iodine is bonded to three oxygen atoms and the molecular formula is IO−3. The molecular geometry of iodate is trigonal pyramidal.

Iodate can be obtained by reducing a periodate with a thioether. The byproduct of the reaction is a sulfoxide.Iodates are a class of chemical compounds containing this group. Examples are sodium iodate (NaIO3), silver iodate (AgIO3), and calcium iodate (Ca(IO3)2). Iodates resemble chlorates with iodine instead of chlorine.

In acidic conditions, iodic acid is formed. Potassium hydrogen iodate (KH(IO3)2) is a double salt of potassium iodate and iodic acid and an acid as well. Iodates are used in the iodine clock reaction.

Potassium iodate, like potassium iodide, has been issued as a prophylaxis against radioiodine absorption in some countries.

Methionine sulfoxide

Methionine sulfoxide is the organic compound with the formula CH3S(O)CH2CH2CH(NH2)CO2H. It is an amino acid that occurs naturally although it is formed post-translationally.

Oxidation of the sulfur of methionine results in methionine sulfoxide or methionine sulfone. The sulfur-containing amino acids methionine and cysteine are more easily oxidized than the other amino acids. Unlike oxidation of other amino acids, the oxidation of methionine can be reversed by enzymatic action, specifically by enzymes in the methionine sulfoxide reductase family of enzymes. The three known methionine sulfoxide reductases are MsrA, MsrB, and fRmsr. Oxidation of methionine results in a mixture of the two diastereomers methionine-S-sulfoxide and methionine-R-sulfoxide, which are reduced by MsrA and MsrB, respectively. MsrA can reduce both free and protein-based methionine-S-sulfoxide, whereas MsrB is specific for protein-based methionine-R-sulfoxide. fRmsr, however, catalyzes the reduction of free methionine-R-sulfoxide. Thioredoxin serves to recycle by reduction some of the methionine sulfoxide reductase family of enzymes, whereas others can be reduced by metallothionein.

Methylsulfonylmethane

Methylsulfonylmethane (MSM) is an organosulfur compound with the formula (CH3)2SO2. It is also known by several other names including methyl sulfone and dimethyl sulfone (DMSO2). This colorless solid features the sulfonyl functional group and is considered relatively inert chemically. It occurs naturally in some primitive plants, is present in small amounts in many foods and beverages, and is marketed as a dietary supplement. It is sometimes used as a cutting agent for illicitly manufactured methamphetamine. It is also commonly found in the atmosphere above marine areas, where it is used as a carbon source by the airborne bacteria Afipia.

Oxfendazole

Oxfendazole is a broad spectrum benzimidazole anthelmintic. Its main use is for protecting livestock against roundworm, strongyles and pinworms. Oxfendazole is the sulfoxide metabolite of fenbendazole.

Oxfendazole is an anthelmintic (wormer) compound used in veterinary practice. It comes under the chemical class of the benzimidazoles. This drug is barely used in horses, goats, sheep, and cattle. It is very scarcely applied on dogs and cats. The drug for livestock is majorly available in the form of pills, tablets, drenches, bolus, etc. They are meant for oral consumption. Several drenches are allowed for intraruminal injection in some of the countries. Few countries also prefer injectables and pour-ons. For pet dogs, the drug is available in the form of drenches.

Pfitzner–Moffatt oxidation

The Pfitzner–Moffatt oxidation, sometimes referred to as simply the Moffatt oxidation, is a chemical reaction for the oxidation of primary and secondary alcohols to aldehydes and ketones, respectively. The oxidant is a combination of dimethyl sulfoxide (DMSO) and dicyclohexylcarbodiimide (DCC). The reaction was first reported by J. Moffatt and his student K. Pfitzner in 1963.

Protein-methionine-S-oxide reductase

Protein-methionine-S-oxide reductase (EC 1.8.4.6, methionine sulfoxide (protein) reductase, methionine sulfoxide peptide reductase, protein (methionine sulfoxide) reductase, Met(O)-peptide reductase, peptide methionine sulfoxide reductase, protein-L-methionine:oxidized-thioredoxin S-oxidoreductase) is an enzyme with systematic name protein-L-methionine:thioredoxin-disulfide S-oxidoreductase. This enzyme catalyses the following chemical reaction

protein L-methionine + thioredoxin disulfide protein L-methionine S-oxide + thioredoxin

Dithiothreitol can replace a reduced thioredoxin in the reverse reaction.

Swern oxidation

The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride, dimethyl sulfoxide (DMSO) and an organic base, such as triethylamine. The reaction is known for its mild character and wide tolerance of functional groups.

The by-products are dimethyl sulfide (Me2S), carbon monoxide (CO), carbon dioxide (CO2) and—when triethylamine is used as base—triethylammonium chloride (Et3NHCl). Of the volatile by-products, dimethyl sulfide has a strong, pervasive odour and carbon monoxide is acutely toxic, so the reaction and the work-up needs to be performed in a fume hood. Dimethyl sulfide is a volatile liquid (B.P. 37 °C) with an unpleasant odour at high concentrations.

Tienilic acid

Tienilic acid (INN and BAN) or ticrynafen (USAN) is a loop diuretic drug with uric acid-lowering (uricosuric) action, formerly marketed for the treatment of hypertension. It was approved by FDA on May 2, 1979, and withdrawn in 1982, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis.Criminal charges were brought against SmithKline executives with regard to hiding data related to toxicity while gaining FDA approval. The company pleaded guilty to 14 counts of failure to report adverse reactions and 20 counts of selling a misbranded drug.Tienilic acid was found to act as a suicide substrate at the cytochrome P450 enzymes involved in drug metabolism. However, the metabolic reaction carried out by these enzymes converted tienilic acid to a thiophene sulfoxide which was highly electrophilic. This encouraged a Michael reaction leading to alkylation of a thiol group in the enzyme's active site. Loss of water from the thiophene sulfoxide restored the thiophene ring and resulted in tienilic acid being covalently linked to the enzyme, thus inhibiting the enzyme irreversibly.In addition sera of patients who had liver failure after taking this drug contained antibodies recognizing CYP2C9 able to hydroxylate the drug and to give covalent binding.The above explanation is a hypothesis. It is still not known (after 15 years) if the reactive intermediate which inactivates the CYP2C9 is the thiophene sulfoxide or the thiophene epoxide. The target on the protein is also not known (could be multiple). However tienilic acid is a good mechanism based inhibitor of CYP2C9 and seems to inactivate it stoichiometrically. Progress in proteomics may one day give the answer.

Recent studies indicate that in fact the primary metabolite of tienilic acid (5-OH tienilic acid) cannot be derived from a thiophene-S-oxide intermediate as was previously hypothesized. It was determined to be derived from a thiophene epoxide intermediate and this reactive intermediate is then likely a cause for the covalent binding to as well as mechanism-based inactivation of CYP2C9.

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