Thiol

Thiol with a blue highlighted sulfhydryl group.

In organic chemistry, a thiol ( /ˈθaɪˌɒl/) is an organosulfur compound that contains a carbon-bonded sulfhydryl (–C–SH or R–SH) group (where R represents an alkane, alkene, or other carbon-containing group of atoms). Thiols are the sulfur analogue of alcohols (that is, sulfur takes the place of oxygen in the hydroxyl group of an alcohol), and the word is a portmanteau of "thio" + "alcohol," with the first word deriving from Greek θεῖον ("thion") = "sulfur". ^{[note 1]} The –SH functional group itself is referred to as either a thiol group or a sulfhydryl group.

Many thiols have strong odors resembling that of garlic, and indeed the odor of garlic itself is due to a thiol. Thiols are used as odorants to assist in the detection of natural gas (which in pure form is odorless), and the "smell of natural gas" is due to the smell of the thiol used as the odorant.

Thiols are often referred to as mercaptans.^[2][3] The term mercaptan is derived from the Latin mercurium captans (capturing mercury)^[4] because the thiolate group bonds so strongly with mercury compounds.

Structure and bonding

Thiols and alcohols have similar molecular structure. The major difference is the size of the chalcogenide, C–S bond lengths being around 180 picometers in length. The C–S–H angles approach 90°. In the solid or molten liquids, the hydrogen-bonding between individual thiol groups is weak, the main cohesive force being van der Waals interactions between the highly polarizable divalent sulfur centers.

Due to the lesser electronegativity difference between sulfur and hydrogen compared to oxygen and hydrogen, an S–H bond is less polar than the hydroxyl group. Thiols have a lower dipole moment relative to the corresponding alcohol.

Nomenclature

There are several ways to name the alkylthiols:

• The preferred method (used by the IUPAC) is to add the suffix -thiol to the name of the alkane. The method is nearly identical to naming an alcohol. Example: CH₃SH would be methanethiol.
• An older method, the word mercaptan replaces alcohol in the name of the equivalent alcohol compound. Example: CH₃SH would be methyl mercaptan, just as CH₃OH is called methyl alcohol.
• As a prefix, the terms sulfanyl or mercapto are used. Example: mercaptopurine.

Physical properties

Odor

Many thiols have strong odors resembling that of garlic. The odors of thiols are often strong and repulsive, particularly for those of low molecular weight. The spray of skunks consists mainly of low-molecular-weight thiol compounds.^[5][6] These compounds are detectable by the human nose at concentrations of only 10 parts per billion.^[7]

Thiols are also responsible for a class of wine faults caused by an unintended reaction between sulfur and yeast and the "skunky" odor of beer that has been exposed to ultraviolet light.

Not all thiols have unpleasant odors. For example, grapefruit mercaptan, a monoterpenoid thiol, is responsible for the characteristic scent of grapefruit. This effect is present only at low concentrations. The pure mercaptan has an unpleasant odor.

Natural gas distributors began adding thiols, originally ethanethiol, to natural gas, which is naturally odorless, after the deadly New London School explosion in New London, Texas, in 1937. Most gas odorants utilized currently contain mixtures of mercaptans and sulfides, with t-butyl mercaptan as the main odor constituent. In situations where thiols are used in commercial industry, such as liquid petroleum gas tankers and bulk handling systems, an oxidizing catalyst is used to destroy the odor. A copper-based oxidation catalyst neutralizes the volatile thiols and transforms them into inert products.

Boiling points and solubility

Thiols show little association by hydrogen bonding, with both water molecules and among themselves. Hence, they have lower boiling points and are less soluble in water and other polar solvents than alcohols of similar molecular weight. Thiols and thioethers have similar solubility characteristics and boiling points.

Characterization

Volatile thiols are easily and almost unerringly detected by their distinctive odor. S-specific analyzers for gas chromatographs are useful. Spectroscopic indicators are the D₂O-exchangeable SH signal in the ¹H NMR spectrum (S has no useful "NMR isotopes"). The ν_SH band appears near 2400 cm⁻¹ in the IR spectrum.^[2] In a colorimetric test, thiols react with nitroprusside.

Preparation

In industry, thiols are prepared mainly by the reaction of hydrogen sulfide with the related alcohol. This method is employed for the industrial synthesis of methanethiol and ethanethiol:

CH₃OH + H₂S → CH₃SH + H₂O

Such reactions are conducted in the presence of acidic catalysts. The other principal route to thiols involves the addition of hydrogen sulfide to alkenes. Such reactions are usually conducted in the presence of a metal catalyst.^[8]

Laboratory methods

Many methods are useful for the synthesis of thiols on the laboratory scale. The direct reaction of a halogenoalkane with sodium hydrosulfide is generally inefficient owing to the competing formation of thioethers:

CH₃CH₂Br + NaSH → CH₃CH₂SH + NaBr

CH₃CH₂Br + CH₃CH₂SH → (CH₃CH₂)₂S + HBr

Instead, alkyl halides are converted to thiols via a S-alkylation of thiourea. This multistep, one-pot process proceeds via the intermediacy of the isothiouronium salt, which is hydrolyzed in a separate step:^[9]

CH₃CH₂Br + SC(NH₂)₂ → [CH₃CH₂SC(NH₂)₂]Br

[CH₃CH₂SC(NH₂)₂]Br + NaOH → CH₃CH₂SH + OC(NH₂)₂ + NaBr

The thiourea route works well with primary halides, especially activated ones. Secondary and tertiary thiols are less easily prepared. Secondary thiols can be prepared from the ketone via the corresponding dithioketals.^[10]

Organolithium compounds and Grignard reagents react with sulfur to give the thiolates, which are readily hydrolyzed:^[11]

RLi + S → RSLi

RSLi + HCl → RSH + LiCl

Phenols can be converted to the thiophenols via rearrangement of their O-aryl dialkylthiocarbamates.^[12]

Many thiols are prepared by reductive dealkylation of thioethers, especially benzyl derivatives and thioacetals.^[13]

Reactions

Akin to the chemistry of alcohols, thiols form thioethers, thioacetals and thioesters, which are analogous to ethers, acetals, and esters. Thiols and alcohols are also very different in their reactivity, thiols being easily oxidized and thiolates being highly potent nucleophiles.

S-alkylation

Thiols, or more particularly their conjugate bases, are readily alkylated to give thioethers:

RSH + R'Br + base → RSR' + [Hbase]Br

Acidity

Relative to the alcohols, thiols are fairly acidic. Butanethiol has a pK_a of 10.5 vs 15 for butanol. Thiophenol has a pK_a of 6 vs 10 for phenol. Thus, thiolates can be obtained from thiols by treatment with alkali hydroxides.

Synthesis of thiophenolate from thiophenol

Redox

Thiols, especially in the presence of base, are readily oxidized by reagents such as iodine to give an organic disulfide (R–S–S–R).

2 R–SH + Br₂ → R–S–S–R + 2 HBr

Oxidation by more powerful reagents such as sodium hypochlorite or hydrogen peroxide yields sulfonic acids (RSO₃H).

R–SH + 3H₂O₂ → RSO₃H + 3H₂O

Oxidation by oxygen in the presence of heterogeneous ^[14] catalysts:

2R–SH + 1/2O₂ → RS–SR + H₂O

Thiols participate in thiol-disulfide exchange:

RS–SR + 2 R'SH → 2 RSH + R'S–SR'

This reaction is especially important in nature.

Metal ion complexation

Thiolates, the conjugate bases derived from thiols, form strong complexes with many metal ions, especially those classified as soft. The term mercaptan is derived from the Latin mercurium captans (capturing mercury)^[4] because the thiolate group bonds so strongly with mercury compounds. The stability of metal thiolates parallels that of the corresponding sulfide minerals.

Thiyl radicals

For the chemistry of the SH radical, see Sulfanyl.

Free radicals derived from mercaptans, called thiyl or thiol radical or mercapto radical, are commonly invoked to explain reactions in organic chemistry and biochemistry. They have the formula RS where R is an organic substituent such as alkyl or aryl.^[15] They arise from or can be generated by a number of routes, but the principal method is H-atom abstraction from thiols. Another method involves homolysis of organic disulfides.^[8] In biology thiyl radicals are responsible for the formation of the deoxyribonucleic acids, building blocks for DNA. This conversion is catalysed by ribonucleotide reductase (see figure).^[16] Thiyl intermediates also are produced by the oxidation of glutathione, an antioxidant in biology. Thiyl radicals are also intermediates in the vulcanization process. For example, the vulcanization of polyisoprene results when mercapto radicals couple forming disulfide and polysulfide crosslinks.

The catalytic cycle for ribonucleotide reductase, demonstrating the role of thiyl radicals in producing the genetic machinery of life.

Biological importance

Cysteine and cystine

As the functional group of the amino acid cysteine, the thiol group plays an important role in biology. When the thiol groups of two cysteine residues (as in monomers or constituent units) are brought near each other in the course of protein folding, an oxidation reaction can generate a cystine unit with a disulfide bond (-S-S-). Disulfide bonds can contribute to a protein's tertiary structure if the cysteines are part of the same peptide chain, or contribute to the quaternary structure of multi-unit proteins by forming fairly strong covalent bonds between different peptide chains. A physical manifestation of cysteine-cystine equilibrium is provided by hair straightening technologies.

Sulfhydryl groups in the active site of an enzyme can form noncovalent bonds with the enzyme's substrate as well, contributing to catalytic activity. Active site cysteine residues are the functional unit in cysteine proteases. Cysteine residues may also react with heavy metal ions (Zn²⁺, Cd²⁺, Pb²⁺, Hg²⁺, Ag⁺) because of the high affinity between the soft sulfide and the soft metal (see hard and soft acids and bases). This can deform and inactivate the protein, and is one mechanism of heavy metal poisoning.

Cofactors

Many cofactors (non-protein-based helper molecules) feature thiols. The biosynthesis and degradation of fatty acids and related long-chain hydrocarbons is conducted on a scaffold that anchors the growing chain through a thioester derived from the thiol Coenzyme A. The biosynthesis of methane, the principal hydrocarbon on earth, arises from the reaction mediated by coenzyme M, 2-mercaptoethyl sulfonic acid.Thiolates, the conjugate bases derived from thiols, form strong complexes with many metal ions, especially those classified as soft. The term mercaptan is derived from the Latin mercurium captans (capturing mercury)[4] because the thiolate group bonds so strongly with mercury compounds. The stability of metal thiolates parallels that of the corresponding sulfide minerals.

Sulfhydryl groups in the active site of an enzyme can form noncovalent bonds with the enzyme's substrate as well, contributing to catalytic activity. Active site cysteine residues are the functional unit in cysteine proteases. Cysteine residues may also react with heavy metal ions (Zn2+, Cd2+, Pb2+, Hg2+, Ag+) because of the high affinity between the soft sulfide and the soft metal (see hard and soft acids and bases). This can deform and inactivate the protein, and is one mechanism of heavy metal poisoning. [edit]

Examples of thiols

Methanethiol – CH3SH [m-mercaptan] Ethanethiol – C2H5SH [e- mercaptan] 1-Propanethiol – C3H7SH [n-P mercaptan] 2-Propanethiol – CH3CH(SH)CH3 [2C3 mercaptan] Butanethiol – C4H9SH [n-butyl mercaptan] tert-Butyl mercaptan – C(CH3)3SH [t-butyl mercaptan] Pentanethiols – C5H11SH [pentyl mercaptan]

Coenzyme A Glutathione Cysteine 2-Mercaptoethanol Dithiothreitol/dithioerythritol (an epimeric pair) 2-Mercaptoindole Metallothioneins

See also

• Doctor sweetening process
• Thiol-disulfide exchange

Footnotes

1. ^ The Greek adjective theios, a, on (θεῖος, α, ον) means "divine",^[1] but appears as a noun to mean "brimstone" in the Bible (c.f. Luke 17:29 "ἔβρεξεν πῦρ καὶ θεῖον ἀπ' οὐρανοῦ καὶ ἀπώλεσεν πάντας." ("it rained fire and sulfur from the sky, and destroyed them all."), brimstone being an alternative name for sulfur.

References

1. ^ θεῖος. Liddell, Henry George; Scott, Robert; A Greek–English Lexicon at Perseus Project
2. ^ ^{a b} Patai, Saul “The chemistry of the thiol group” Saul Patai, Ed. Wiley, London, 1974. ISBN 0471669490.
3. ^ R. J. Cremlyn “An Introduction to Organosulfur Chemistry” John Wiley and Sons: Chichester (1996). ISBN 0 471 95512 4.
4. ^ ^{a b} Oxford American Dictionaries (Mac OS X Leopard).
5. ^ Wood W. F., Sollers B. G., Dragoo G. A., Dragoo J. W. (2002). "Volatile Components in Defensive Spray of the Hooded Skunk, Mephitis macroura". Journal of Chemical Ecology 28 (9): 1865. doi:10.1023/A:1020573404341. PMID 12449512. 
6. ^ William F. Wood. "Chemistry of Skunk Spray". Dept. of Chemistry, Humboldt State University. http://users.humboldt.edu/wfwood/chemofskunkspray.html. Retrieved January 2, 2008. 
7. ^ Aldrich, T.B. (1896). "A chemical study of the secretion of the anal glands of Mephitis mephitica (common skunk), with remarks on the physiological properties of this secretion.". J. Exp. Med. 1 (2): 323–340. doi:10.1084/jem.1.2.323. PMC 2117909. PMID 19866801. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2117909. 
8. ^ ^{a b} Kathrin-Maria Roy “Thiols and Organic sulphides” in Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH Verlag, Weinheim. doi:10.1002/14356007.a26_767
9. ^ Speziale, A. J. (1963), "Ethanedithiol", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv4p0401 ; Coll. Vol. 4: 401 .
10. ^ S. R. Wilson, G. M. Georgiadis (1990), "Mecaptans from Thioketals: Cyclododecyl Mercaptan", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv7p0124 ; Coll. Vol. 7: 124 .
11. ^ E. Jones and I. M. Moodie (1990), "2-Thiophenthiol", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv6p0979 ; Coll. Vol. 6: 979 .
12. ^ Melvin S. Newman and Frederick W. Hetzel (1990), "Thiophenols from Phenols: 2-Naphthalenethiol", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv6p0824 ; Coll. Vol. 6: 824 .
13. ^ Ernest L. Eliel, Joseph E. Lynch, Fumitaka Kume, and Stephen V. Frye (1993), "Chiral 1,3-oxathiane from (+)-Pulegone: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv8p0302 ; Coll. Vol. 8: 302 
14. ^ Heterogeneous catalytic demercaptization of light hydrocarbon feedstock. A. G. Akhmadullina, B. V. Kizhaev, G. M. Nurgalieva, I. K. Khrushcheva and A. S. Shabaeva, et al. Chemistry and Technology of Fuels and Oils, 1993, Volume 29, Number 3, Pages 108–109
15. ^ R. J. Cremlyn “An Introduction to Organosulfur Chemistry” John Wiley and Sons: Chichester (1996). ISBN 0 471 95512 4.
16. ^ JoAnne Stubbe, Daniel G. Nocera, Cyril S. Yee, Michelle C. Y. Chang "Radical Initiation in the Class I Ribonucleotide Reductase:  Long-Range Proton-Coupled Electron Transfer?" Chem. Rev., 2003, 103 (6), pp 2167–2202. doi:10.1021/cr020421u

External links

• Applications, Properties, and Synthesis of w-Functionalized n-Alkanethiols and Disulfides — the Building Blocks of Self-Assembled Monolayers by D. Witt, R. Klajn, P. Barski, B.A. Grzybowski at Northwestern University.
• Mercaptan, by The Columbia Electronic Encyclopedia.
• What is Mercaptan?, by Columbia Gas of Pennsylvania and Maryland.
• What Is the Worst Smelling Chemical?, by About Chemistry.