In organic chemistry, a thiol (;Dictionary Reference: thiol θεῖον Henry George Liddell, Robert Scott, A Greek–English Lexicon) or thiol derivative is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl group, or a sulfanyl group. 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 blend of "thio-" with "alcohol".
Many thiols have strong odors resembling that of garlic, cabbage or rotten eggs. Thiols are used as odorants to assist in the detection of natural gas (which in pure form is odorless). The smell of natural gas is due to the addition of thiol.
Nomenclature Thiols are sometimes referred to as mercaptans ()Dictionary Reference: mercaptan or mercapto compounds, a term introduced in 1832 by William Christopher Zeise and is derived from the Latin ('capturing mercury')Oxford American Dictionaries (Mac OS X Leopard). because the thiolate group () bonds very strongly with mercury compounds.See: On p. 13 the word "mercaptan" is coined. German translation: From p. 378: " … nenne ich den vom Quecksilber aufgenommenen Stoff Mercaptum (von: Corpus mercurio captum) … " ( … I name the substance [that is] absorbed by mercury "mercaptum" (from: the body (substance) [that] has been absorbed by mercury) … ) German translation is reprinted in: Summarized in: "Mercaptan" (ethyl thiol) was discovered in 1834 by the Danish professor of chemistry William Christopher Zeise (1789–1847). He called it "mercaptan", a contraction of "corpus mercurio captans" (mercury-capturing substance) [p. 88], because it reacted violently with mercury(II) oxide ("deutoxide de mercure") [p. 92]. The article in Annales de Chimie et de Physique (1834) was translated from the German article:
There are several ways to name the alkylthiols: The suffix -thiol is added to the name of the alkane. This method is nearly identical to naming an alcohol and is used by the IUPAC, e.g. would be methanethiol. The word mercaptan replaces alcohol in the name of the equivalent alcohol compound. Example: would be methyl mercaptan, just as is called methyl alcohol. The term sulfhydryl- or mercapto- is used as a prefix, e.g. mercaptopurine.
Physical properties Odor Many thiols have strong odors resembling that of garlic. The odors of thiols, particularly those of low molecular weight, are often strong and repulsive. The spray of skunks consists mainly of low-molecular-weight thiols and derivatives. These compounds are detectable by the human nose at concentrations of only 10 parts per billion. Human sweat contains (R)/(S)-3-methyl-3-sulfanylhexan-1-ol (3M3SH), detectable at 2 parts per billion and having an onion-like (S enantiomer) and fruity, grapefruit-like odor (R enantiomer). (Methylthio)methanethiol (; MTMT) is a strong-smelling volatile thiol, also detectable at parts per billion levels, found in male mouse urine. Lawrence C. Katz and co-workers showed that MTMT functioned as a semiochemical, activating certain mouse olfactory sensory neurons, and attracting female mice. Copper has been shown to be required by a specific mouse olfactory receptor, MOR244-3, which is highly responsive to MTMT as well as to various other thiols and related compounds. A human olfactory receptor, OR2T11, has been identified which, in the presence of copper, is highly responsive to the gas odorants (see below) ethanethiol and t-butyl mercaptan as well as other low molecular weight thiols, including allyl mercaptan found in human garlic breath, and the strong-smelling cyclic sulfide thietane.
Thiols are also responsible for a class of wine faults caused by an unintended reaction between sulfur and yeast, as well as the "skunky" odor of beer that has been exposed to ultraviolet light.
Not all thiols have unpleasant odors. For example, furan-2-ylmethanethiol contributes to the aroma of roasted coffee, whereas grapefruit mercaptan, a monoterpenoid thiol, is responsible for the characteristic scent of grapefruit. The effect of the latter compound is present only at low concentrations. Concentrated samples have an unpleasant odor.
In the United States, distributors are required to add thiols, originally ethanethiol, to natural gas (which is naturally odorless) after the deadly New London School explosion in New London, Texas, in 1937, although many distributors were odorizing gas prior to this event. Most currently-used gas odorants contain mixtures of mercaptans and sulfides, with t-butyl mercaptan as the main odor constituent in natural gas and ethanethiol in liquefied petroleum gas (LPG, propane). 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, both with 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. For this reason also, thiols and their corresponding sulfide functional group isomers have similar solubility characteristics and boiling points, whereas the same is not true of alcohols and their corresponding isomeric ethers.
Structure and bonding Thiols having the structure R−S−H, in which an alkyl group (R) is attached to a sulfhydryl group (SH), are referred to as alkanethiols or alkyl thiols. Thiols and alcohols have similar connectivity. Because sulfur atoms are larger than oxygen atoms, C−S bond lengths—typically around 180 picometres—are about 40 picometers longer than typical C−O bonds. C−S−H angles approach 90°, whereas the angle for the C−O−H group is more obtuse. In solids and liquids, the hydrogen-bonding between individual thiol groups is weak, and thus thiols are more volatile than the corresponding alcohols. The main cohesive forces for thiols involves Van der Waals interactions between the highly polarizable divalent sulfur centers.
The S−H bond is much weaker than the O−H bond as reflected in their respective bond dissociation energies (BDE). For , the BDE is , while for , the BDE is . Hydrogen-atom abstraction from a thiol gives a thiyl radical with the formula , where R = alkyl or aryl.
Characterization Volatile thiols are easily and almost unerringly detected by their distinctive odor. Sulfur-specific analyzers for gas chromatographs are useful. Spectroscopic indicators are the D2O-exchangeable SH signal in the 1H NMR spectrum (33S is NMR-active but signals for divalent sulfur are very broad and of little utility). The νSH band appears near 2400 cm−1 in the IR spectrum. In the nitroprusside reaction, free thiol groups react with sodium nitroprusside and ammonium hydroxide to give a red colour.
Preparation In industry, methanethiol is prepared by the reaction of hydrogen sulfide with 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 used.John S Roberts, "Thiols", in Kirk-Othmer Encyclopedia of Chemical Technology, 1997, Wiley-VCH, Weinheim.
Another method entails the alkylation of sodium hydrosulfide. (X = Cl, Br, I) This method is used for the production of thioglycolic acid from chloroacetic acid.
Laboratory methods In general, on the typical laboratory scale, the direct reaction of a haloalkane with sodium hydrosulfide is inefficient owing to the competing formation of sulfides (overalkylation). Instead, alkyl halides are converted to thiols via an S-alkylation of thiourea. This multistep, one-pot process proceeds via the intermediacy of the isothiouronium salt, which is hydrolyzed in a separate step:.
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.. A related two-step process involves alkylation of thiosulfate to give the thiosulfonate ("Bunte salt"), followed by hydrolysis. The method is illustrated by one synthesis of thioglycolic acid:
Organolithium compounds and Grignard reagents react with sulfur to give the thiolates, which are readily hydrolyzed:.
Phenols can be converted to the thiophenols via rearrangement of their O-aryl dialkylthiocarbamates..
Thiols are prepared by reductive dealkylation of sulfides, especially benzyl derivatives and thioacetals.
Thiophenols are produced by S-arylation or the replacement of diazonium leaving group with sulfhydryl anion ():
Classes of thiols Alkyl and aryl thiols Alkyl thiols are the simplest thiols. Methanethiol (, methyl mercaptan), ethanethiol (, ethyl mercaptan), propanethiol (), butanethiols (, n-butyl mercaptan and tert-Butyl mercaptan, are common reagents. While these thiols have the characteristic unpleasant odors, some thiols are responsible for the flavor and fragrance of foods, e.g. furan-2-ylmethanethiol. 1-Hexadecanethiol is a lipophilic alkylthiol.
Aryl thiols include the parent thiophenol (). Pentachlorobenzenethiol has pesticidal properties.
Dithiols 1,3-Propanedithiol and 1,2-ethanedithiol are reagents in organic chemistry. Dimercaptosuccinic acid is a chelating agent. Lipoic acid, a naturally occurring modification of 1,3-propanedithiol, is a cofactor for many enzymes. Dithiothreitol is a reagent in biochemistry.
Unsaturated thiols Vinyl thiols are rare, but other unsaturated thiols are numerous. A textbook unsaturated thiol is grapefruit mercaptan, which exists as two enantiomers, each with distinct odors. The main component of skunk spray is a butenylthiol.
Thioalcohols 2-Mercaptoethanol is a reagent in biochemistry. 3-Mercaptopropane-1,2-diol is a medicine. These compounds have high solubility in water owing to the presence of OH substituent(s).
Thiol-carboxylic acids Cysteine and penicillamine have the formula , where R = H and , respectively. Cysteine is common amino acid, and penicillamine has medicinal properties. Coenzyme A and glutathione are more complicated thiol-containing derivatives. Cysteine-rich proteins called metallothionein have high affinity for heavy metals. Thiocarboxylic acids, with the formula , can be considered thiols also. Thioacetic acid is one example.
Aminothiols Cysteine and penicillamine also are classified as an aminothiols. One variation is cysteamine ().
Reactions Thiols form sulfides, thioacetals, and thioesters, which are analogous to ethers, acetals, and esters, respectively.
Acidity Thiols are easily deprotonated. Relative to the alcohols, thiols are more acidic. The conjugate base of a thiol is called a thiolate. Butanethiol has a pKa of 10.5 vs 15 for butanol. Thiophenol has a pKa of 6, versus 10 for phenol. A highly acidic thiol is pentafluorothiophenol () with a pKa of 2.68. Thus, thiolates can be obtained from thiols by treatment with alkali metal hydroxides.
S-Based nucleophilicity The conjugate base of thiols are potent nucleophiles. They alkylate to give sulfides: (B = base) Many electrophiles participate in this reaction. α,β-Unsaturated carbonyl compounds add thiols, especially in the presence of base catalysts. Thiolates react with carbon disulfide to give thioxanthate ().
Redox Thiols, especially in the presence of base, are readily oxidized by reagents such as bromine and iodine to give an organic disulfide ().