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.
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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.
There are several ways to name the alkylthiols:
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.
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.
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 νSH band appears near 2400 cm−1 in the IR spectrum.[2] In a colorimetric test, thiols react with nitroprusside.
In industry, methanethiol is prepared by the reaction of hydrogen sulfide with the methanol. This method is employed for the industrial synthesis of methanethiol:
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 an acid catalyst or UV light. Halide displacement, using the suitable organic halide and sodium hydrogen sulfide has also been utilized.[8]
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:
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]
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]
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]
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.
Thiols, or more particularly their conjugate bases, are readily alkylated to give thioethers:
Relative to the alcohols, thiols are fairly acidic. Butanethiol has a pKa of 10.5 vs 15 for butanol. Thiophenol has a pKa of 6 vs 10 for phenol. Thus, thiolates can be obtained from thiols by treatment with alkali hydroxides.
Thiols, especially in the presence of base, are readily oxidized by reagents such as iodine to give an organic disulfide (R–S–S–R).
Oxidation by more powerful reagents such as sodium hypochlorite or hydrogen peroxide yields sulfonic acids (RSO3H).
Oxidation by oxygen in the presence of heterogeneous [14] catalysts:
Thiols participate in thiol-disulfide exchange:
This reaction is especially important in nature.
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.
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.[3] 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.[15] 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.
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.
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 stability of metal thiolates parallels that of the corresponding sulfide minerals.
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