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Thiol
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Thiol with a   blue highlighted sulfhydryl group.

In organic chemistry, a thiol (/ˈθaɪɒl/;[1] from Ancient Greek θεῖον (theion) 'sulfur'[2]), or thiol derivative, is any organosulfur compound of the form R−SH, where R represents an alkyl or other organic substituent. The −SH 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 (−OH) 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), and the smell is due to the smell of the thiol used as the odorant.

Nomenclature

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Thiols are sometimes referred to as mercaptans (/mərˈkæptænz/)[3] or mercapto compounds,[4][5][6] a term introduced in 1832 by William Christopher Zeise and is derived from the Latin mercurio captāns ('capturing mercury')[7] because the thiolate group (RS−) bonds very strongly with mercury compounds.[8]

There are several ways to name the alkylthiols:[citation needed]

  • 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. CH3SH would be methanethiol.
  • 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.
  • The term sulfhydryl- or mercapto- is used as a prefix, e.g. mercaptopurine.

Physical properties

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Odor

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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.[9][10][11][12][13] These compounds are detectable by the human nose at concentrations of only 10 parts per billion.[14] 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).[15] (Methylthio)methanethiol (MeSCH2SH; 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.[16] 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.[17] 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.[18]

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).[19] 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

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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

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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.[20] 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 CH3S−H, the BDE is 366 kJ/mol (87 kcal/mol), while for CH3O−H, the BDE is 440 kJ/mol (110 kcal/mol).[21] Hydrogen-atom abstraction from a thiol gives a thiyl radical with the formula RS•, where R = alkyl or aryl.

Characterization

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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[22]). The νSH band appears near 2400 cm−1 in the IR spectrum.[4] In the nitroprusside reaction, free thiol groups react with sodium nitroprusside and ammonium hydroxide to give a red colour.

Preparation

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In industry, methanethiol is prepared by the reaction of hydrogen sulfide with methanol. This method is employed for the industrial synthesis of methanethiol:

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 an acid catalyst or UV light. Halide displacement, using the suitable organic halide and sodium hydrogen sulfide has also been used.[23]

Another method entails the alkylation of sodium hydrosulfide.

RX + NaSH → RSH + NaX (X = Cl, Br, I)

This method is used for the production of thioglycolic acid from chloroacetic acid.

Laboratory methods

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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:[24][25]

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.[26] 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:

ClCH2CO2H + Na2S2O3 → Na[O3S2CH2CO2H] + NaCl
Na[O3S2CH2CO2H] + H2O → HSCH2CO2H + NaHSO4

Organolithium compounds and Grignard reagents react with sulfur to give the thiolates, which are readily hydrolyzed:[27]

RLi + S → RSLi
RSLi + HCl → RSH + LiCl

Phenols can be converted to the thiophenols via rearrangement of their O-aryl dialkylthiocarbamates.[28]

Thiols are prepared by reductive dealkylation of sulfides, especially benzyl derivatives and thioacetals.[29]

Thiophenols are produced by S-arylation or the replacement of diazonium leaving group with sulfhydryl anion (SH−):[30][31]

ArN+
2 + SH− → ArSH + N2

Classes of thiols

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Alkyl and aryl thiols

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Alkyl thiols are the simplest thiols. Methanethiol (CH3SH, methyl mercaptan), ethanethiol (C2H5SH, ethyl mercaptan), propanethiol (C3H7SH), butanethiols (C4H9SH, 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 (C6H5SH). Pentachlorobenzenethiol has pesticidal properties.

Dithiols

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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

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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.[32]

Thioalcohols

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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

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Cysteine and penicillamine have the formula HSCR2CH(NH2)CO2H, where R = H and CH3, 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 HS(O)CR, can be considered thiols also. Thioacetic acid is one example.

Aminothiols

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Cysteine and penicillamine also are classified as an aminothiols. One variation is cysteamine (HSCH2CH2NH2.

Reactions

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Thiols form sulfides, thioacetals, and thioesters, which are analogous to ethers, acetals, and esters, respectively.

Acidity

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Thiols are easily deprotonated.[33] 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 (C6F5SH) with a pKa of 2.68. Thus, thiolates can be obtained from thiols by treatment with alkali metal hydroxides.

Synthesis of thiophenolate from thiophenol

S-Based nucleophilicity

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The conjugate base of thiols are potent nucleophiles. They alkylate to give sulfides:

RSH + R′Br + B → RSR′ + [HB]Br  (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 (RSCS−
2).

Redox

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Thiols, especially in the presence of base, are readily oxidized by reagents such as bromine and 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 can also yield sulfonic acids (RSO3H).

R−SH + 3 H2O2 → RSO3H + 3 H2O

Oxidation can also be effected by oxygen in the presence of catalysts:[34]

2 R–SH + 1⁄2 O2 → RS−SR + H2O

Thiols participate in thiol-disulfide exchange:

RS−SR + 2 R′SH → 2 RSH + R′S−SR′

This reaction is important in nature.

Metal ion complexation

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With metal ions, thiolates behave as ligands to form transition metal thiolate complexes. The term mercaptan is derived from the Latin mercurium captans (capturing mercury)[7] because the thiolate group bonds so strongly with mercury compounds. According to hard/soft acid/base (HSAB) theory, sulfur is a relatively soft (polarizable) atom. This explains the tendency of thiols to bind to soft elements and ions such as mercury, lead, or cadmium. The stability of metal thiolates parallels that of the corresponding sulfide minerals. Sodium aurothiolate is an antiarthritic drug.[35]

Thiyl radicals

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Main article: Thiyl radical

Free radicals derived from mercaptans, called thiyl radicals, 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.[6] 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.[36] 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).[37] Thiyl intermediates also are produced by the oxidation of glutathione, an antioxidant in biology. Thiyl radicals (sulfur-centred) can transform to carbon-centred radicals via hydrogen atom exchange equilibria. The formation of carbon-centred radicals could lead to protein damage via the formation of C−C bonds or backbone fragmentation.[38]

Because of the weakness of the S−H bond, thiols can function as scavengers of free radicals.[39]

Biological importance

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

Cysteine and cystine

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As the functional group of the proteinogenic amino acid cysteine, the thiol group plays a very 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.[40]

Sulfhydryl groups in the active site of an enzyme can form noncovalent bonds with the enzyme's substrate as well, contributing to covalent catalytic activity in catalytic triads. Active site cysteine residues are the functional unit in cysteine protease catalytic triads. 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

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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. Dihydrolipoic acid, a dithiol, is the reduced form of lipoic acid, a cofactor in several metabolic processes in mammals. Methane biosynthesis, the principal hydrocarbon on Earth, arises from the reaction mediated by coenzyme M (2-mercaptoethyl sulfonic acid) and coenzyme B (7-mercaptoheptanoylthreoninephosphate). 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.

Drugs

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Drugs containing thiol group:

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Thiol

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from Grokipedia
A thiol, also known as a mercaptan, is an organosulfur compound characterized by the presence of a sulfhydryl (-SH) bonded to a carbon atom, serving as the sulfur analog to the hydroxyl group (-OH) in alcohols. These compounds have the general formula R-SH, where R is an alkyl or , and they exhibit distinctive properties such as a strong, often unpleasant odor reminiscent of or rotten eggs due to their volatility and low molecular weights in simple cases like or . Thiols are named using the suffix "-thiol" for the parent chain (e.g., for CH₃CH₂SH) or as "mercapto-" substituents when not the principal function, reflecting their historical association with mercury capture in early chemical studies. Physically, they are typically colorless liquids or solids with boiling points lower than those of analogous alcohols due to weaker hydrogen bonding, but they are more acidic (pKa around 10-11) than alcohols (pKa 15-18), allowing easier to form nucleophilic thiolate anions (RS⁻). Chemically, thiols are highly reactive, undergoing oxidation to disulfides (R-S-S-R) under mild conditions like exposure to air or iodine, a reversible process central to their biological roles; they also participate in nucleophilic substitutions, such as SN2 reactions with alkyl halides, far more efficiently than alcohols due to sulfur's . In biology and medicine, thiols play critical roles in and defense, with residues forming bridges that stabilize protein structures like insulin, and molecules such as (a thiol) scavenging (ROS) to protect cells from oxidative damage. Therapeutic thiols, including N-acetylcysteine, are employed as mucolytics, antidotes for acetaminophen overdose, and agents to mitigate ROS-induced diseases like cancer and neurodegeneration by replenishing levels. Industrially, thiols serve as odorants for detecting odorless (e.g., tert-butyl mercaptan), reducing agents in synthesis, and intermediates in pharmaceutical and production, leveraging their reactivity for thiol-ene in materials like hydrogels and coatings.

Fundamentals

Nomenclature

Thiols are organosulfur compounds characterized by the presence of a sulfhydryl (-SH) functional group covalently bonded to a carbon atom. This group, also known as thiol or mercapto, distinguishes thiols from other sulfur-containing compounds like sulfides or disulfides./Thiols_and_Sulfides/Nomenclature_of_Thiols_and_Sulfides) In , simple thiols are named by replacing the "-e" ending of the corresponding with the suffix "-thiol," with the position of the -SH group indicated by the lowest possible number. For example, CH₃SH is , and CH₃CH₂SH is . When the -SH group serves as a rather than the principal functional group, the prefix "mercapto-" (or the modern "sulfanyl-" in some contexts) is used. A common example is mercaptoacetic acid (HSCH₂COOH), where the group takes precedence, and -SH is treated as a prefix. Historically, thiols have been referred to as mercaptans, a term derived from Latin meaning "mercury-capturing," reflecting their ability to form insoluble mercury salts. Common names often retain this tradition, such as methanethiol for CH₃SH and thiophenol for C₆H₅SH, especially for aromatic derivatives. In multifunctional compounds, the -SH group has a specific order of precedence in IUPAC naming: it ranks below carboxylic acids, esters, acid halides, amides, nitriles, aldehydes, ketones, and alcohols, but above amines, ethers, and halides. Thus, in a molecule containing both -SH and -OH, the alcohol receives the suffix "-ol," and the thiol is named as a "mercapto-" substituent (e.g., 2-mercaptoethanol for HSCH₂CH₂OH). Similarly, in compounds with carboxylic acids, the acid suffix is used, with -SH as "mercapto-." This hierarchy ensures consistent naming based on the senior functional group.

Structure and Bonding

The sulfur atom in the thiol (-SH) adopts sp³ hybridization, forming bonds to carbon and hydrogen while accommodating in the remaining sp³ orbitals. This configuration leads to a C-S-H bond angle of approximately 96–100° in aliphatic thiols, as observed in where the angle measures 100.3°; the slightly acute angle arises from the larger of compared to oxygen, resulting in less effective orbital overlap and stronger lone pair repulsion. In contrast, the analogous C-O-H bond angle in alcohols, such as , is around 108.5°, reflecting oxygen's smaller size and closer adherence to ideal tetrahedral geometry. The C-S bond length in thiols averages about 1.82 Å, significantly longer than the typical 1.43 Å C-O bond in alcohols, due to the poorer overlap of carbon's 2p orbitals with sulfur's larger 3p orbitals. Similarly, the S-H bond exhibits a dissociation energy of approximately 365–366 kJ/mol, weaker than the 439–460 kJ/mol for the O-H bond in alcohols, attributable to the lower bond polarity and reduced orbital overlap involving sulfur's valence electrons. The S-H bond possesses moderate polarity, with sulfur's (2.58) lower than oxygen's (3.44), yielding a smaller dipole moment than in alcohols and consequently weaker intermolecular hydrogen bonding. This diminished hydrogen bonding capacity results in lower points for thiols compared to isomeric alcohols, as the attractive forces are dominated by van der Waals interactions rather than strong H-bonds./Thiols_and_Sulfides/Thiols_and_Sulfides) In aryl thiols like thiophenol, one of the sulfur lone pairs can delocalize into the aromatic π-system through resonance, conjugating the p-orbital on sulfur with the benzene ring and thereby influencing the group's reactivity, such as enhancing acidity relative to aliphatic thiols. This delocalization stabilizes the molecule but is less pronounced than in phenols due to sulfur's poorer π-donation ability.

Physical Properties

Odor and Sensory Characteristics

Thiols are renowned for their pungent, often unpleasant odors, typically described as skunk-like, garlic-like, or reminiscent of rotten cabbage, which arise primarily from the sulfhydryl (-SH) functional group. This distinctive smell is detectable at extremely low concentrations due to their low olfactory thresholds; for instance, methanethiol has an odor threshold of 0.002 ppm in air, allowing human detection well below levels that pose immediate health risks. The intensity of these odors correlates with molecular structure, where lower molecular weight and the presence of the -SH group enhance volatility and sensory potency compared to analogous oxygen-containing compounds like alcohols. In homologous series of alkanethiols, odor thresholds increase with chain length, meaning shorter-chain thiols exhibit stronger, more pervasive smells. Ethanethiol exemplifies this in practical applications, added to odorless at concentrations around 1-10 ppm to serve as a leak warning due to its strong rotten-egg and high volatility. However, not all thiols evoke aversion; structural variations can yield more agreeable scents. For example, 4-methyl-4-sulfanylpentan-2-one imparts tropical, , and box-tree notes to wines, with an threshold as low as 4.2 ng/L, contributing positively to varietal aromas. In , certain thiols enhance desirable flavors, such as 2-furanmethanethiol, which delivers a potent roasted aroma in brewed and even traces in some wines. From a and perspective, the low odor thresholds of thiols function as an early alert for potential , as many are irritants to the , eyes, and skin at elevated concentrations. Exposure to high levels can cause headaches, , and central nervous system effects, though may diminish perceived warning over time. In industrial settings, such as gas distribution, thiols are intentionally odorized but sometimes masked or diluted to mitigate nuisance while retaining benefits.

Boiling Points and Solubility

Thiols exhibit boiling points that are generally lower than those of their isomeric alcohols, primarily because the S-H bond forms weaker bonds compared to the O-H bond in alcohols. For instance, (CH₃CH₂SH) has a boiling point of 35 °C, while (CH₃CH₂OH) boils at 78 °C. This difference arises from the reduced intermolecular attraction in thiols, leading to easier vaporization. As the carbon chain length increases in of aliphatic thiols (CH₃(CH₂)ₙSH), boiling points rise due to enhanced van der Waals forces, though the increment is smaller than in corresponding alcohols. The following table compares boiling points for a selection of straight-chain thiols and their alcohol analogs, illustrating the consistent trend:
CompoundFormulaBoiling Point (°C)Alcohol Analog Boiling Point (°C)
CH₃SH6: 65
CH₃CH₂SH35: 78
1-PropanethiolCH₃(CH₂)₂SH68: 97
CH₃(CH₂)₃SH98: 118
1-PentanethiolCH₃(CH₂)₄SH127: 138
Data sourced from standard physical property compilations. Branching in the alkyl chain reduces boiling points by decreasing molecular surface area and thus van der Waals interactions; for example, 2-methyl-2-propanethiol () boils at 64 °C, lower than the straight-chain 1-butanethiol at 98 °C despite similar molecular weights. Regarding solubility, thiols display greater affinity for nonpolar solvents than alcohols owing to the lower polarity of the S-H group, making them more lipophilic overall. They are typically miscible with alcohols, ethers, and hydrocarbons but show decreasing with increasing chain length due to reduced hydrogen bonding with . is highly water-soluble at 23.3 g/L at 20 °C, while longer-chain examples like 1-propanethiol have limited solubility of about 1.9 g/L at 25 °C, and 1-butanethiol is only slightly soluble (0.6 g/L at 20 °C). Thiols generally have densities higher than those of analogous hydrocarbons but comparable to alcohols, reflecting the influence of the polar S-H group. For example, has a density of 0.862 g/mL at 20 °C, denser than (0.5 g/mL) but similar to (0.789 g/mL). Branching tends to slightly decrease density by compacting the molecule. Viscosity values are low, indicative of their fluid nature; , for instance, has a dynamic viscosity of approximately 0.00032 Pa·s at 20 °C. These properties facilitate thiols' use in applications requiring moderate polarity and volatility, such as in and odorants.

Analytical Characterization

Spectroscopic Methods

(NMR) is a primary technique for identifying thiols through their distinct proton and carbon chemical shifts. In ¹H NMR, the -SH proton typically appears as a broad singlet between 1 and 3 ppm, with the exact position varying based on concentration, , and hydrogen bonding effects that can cause exchange broadening. For ¹³C NMR, the alpha carbon attached to the atom in aliphatic thiols exhibits chemical shifts in the range of 15 to 46 ppm, influenced by the degree of substitution and the of the SH group, which deshields the alpha position compared to analogous hydrocarbons. Infrared (IR) provides characteristic absorption bands for the S-H and C-S functionalities in thiols. The S-H stretching vibration occurs as a weak to medium sharp band at 2550–2600 cm⁻¹, distinct from O-H stretches due to its higher and lack of hydrogen bonding broadening. The C-S stretching mode appears as a weak band between 600 and 700 cm⁻¹, often observed in the fingerprint region and useful for confirming the presence of the thioether-like linkage in thiols. Ultraviolet-visible (UV-Vis) reveals weak absorptions for simple aliphatic thiols, primarily due to n→σ* transitions of the lone pairs around 190–220 nm with low molar absorptivities (ε < 100 M⁻¹ cm⁻¹), making them transparent in the visible range. In contrast, thiols with conjugated systems, such as aromatic thiols, exhibit stronger π→π* or charge-transfer bands shifted to longer wavelengths (λ_max > 230 nm) with higher ε values, enabling detection at higher concentrations. Mass spectrometry (MS), particularly MS, aids in thiol identification through characteristic fragmentation patterns. A common fragment results from the loss of the HS• radical (mass 33 Da), leading to a prominent peak at [M - 33]⁺, often via α-cleavage adjacent to the atom; this is especially diagnostic for aliphatic thiols where the molecular may be weak. In tandem MS (MS/MS), additional losses like CS (mass 44 Da) can occur, but the HS• elimination remains a hallmark for confirming thiol structure.

Chemical and Physical Tests

Thiols can be detected and confirmed through several classical qualitative chemical tests that exploit their reactivity with heavy metal salts and oxidizing agents. These low-tech methods are particularly useful in settings for preliminary identification before more advanced spectroscopic . One common involves the reaction of thiols with iodine, where the characteristic purple color of the iodine solution decolorizes due to oxidation forming disulfides. The reaction proceeds as 2RSH + I₂ → RSSR + 2HI, allowing for rapid qualitative detection of thiol groups in organic samples. A related method is the sodium plumbite test, commonly known as the Doctor test, which uses a solution of sodium plumbite (prepared from and ) to detect mercaptans in hydrocarbons or other samples. Upon shaking the sample with the reagent, the formation of a dark precipitate or discoloration occurs due to lead mercaptide precipitation, confirming the presence of thiols while helping differentiate them from sulfides, which react differently upon addition of sulfur powder. This test is standardized for industrial applications, such as assessing thiol content in petroleum products. For physical assessment of purity, thiols are evaluated by measuring their and , which are compared against literature values for the pure compound. For example, 1-octanethiol exhibits a of 1.4540 at 20°C and a of approximately 0.841 g/mL at 25°C; deviations from these values indicate impurities or degradation. These non-destructive measurements provide quick confirmation of sample integrity in analytical workflows.

Synthesis

Laboratory Methods

In laboratory settings, thiols are frequently prepared on a small scale through reactions of alkyl halides with sulfur-containing nucleophiles. One common approach utilizes (NaSH) in a direct SN2 displacement: \ceRX+NaSH−>RSH+NaX\ce{RX + NaSH -> RSH + NaX} This reaction is most effective for primary and secondary alkyl halides, typically conducted in polar aprotic solvents such as or dioxane under , often with catalytic alumina to enhance selectivity and yields of 75–80%, as demonstrated in the preparation of triphenylmethyl mercaptan from . A widely adopted alternative involves , which reacts with the alkyl halide to form an isothiouronium salt intermediate, followed by alkaline to liberate the thiol. The process is particularly suitable for primary halides and proceeds in high-boiling solvents like with bases such as . For instance, is synthesized from ethyl bromide by refluxing the reactants in to form the salt, then hydrolyzing under basic conditions, achieving excellent yields up to 90% with minimal side products like olefins. Thiols can also be generated via reduction of disulfides, a versatile method when symmetrical or unsymmetrical disulfides are available as precursors. The general transformation employs reducing agents: \ceRSSR+2[H]−>2RSH\ce{RSSR + 2 [H] -> 2 RSH} (NaBH4) serves as a mild, selective reductant, often in protic solvents like or without requiring an inert atmosphere, delivering yields exceeding 90% for dihydroxybenzenethiols and other functionalized substrates. Lithium aluminum hydride (LiAlH4), a more potent agent, is applied in anhydrous ether solvents for recalcitrant disulfides, consistently providing good yields in small-scale reactions. An additional laboratory route entails the preparation and subsequent of thiocarbonates or derived from alcohols using . Alcohols are treated with CS2 and a base (e.g., NaOH) to form O-alkyl salts (ROCS2Na), which undergo under basic or acidic conditions to afford the corresponding thiols. This indirect method facilitates conversion from readily available alcohols, with optimized protocols using phase-transfer catalysts like yielding 60–91% for various alkyl , making it ideal for research-scale synthesis of simple aliphatic thiols.

Industrial Production

Industrial production of thiols primarily relies on the utilization of (H₂S) derived as a from petroleum refining processes, such as of and crude oil, which generates substantial quantities of this feedstock for large-scale thiol synthesis. This approach transforms an environmental into valuable chemicals, with global H₂S production exceeding millions of tons annually from refining operations. Key processes emphasize catalytic methods to achieve high yields and economic viability, often operating under elevated temperatures and pressures to handle the gaseous and reactive nature of the reactants. A prominent industrial route involves the reaction of alcohols with H₂S, typically over catalysts like alumina or zeolites promoted with metals, to produce simple alkyl thiols. For instance, is manufactured by reacting with H₂S at temperatures of 300–450°C and pressures up to 20 atm, yielding up to 90% selectivity with catalysts such as K₂WO₄/Al₂O₃. This process minimizes byproduct formation, like , by maintaining excess H₂S, and is favored for its use of inexpensive feedstocks derived from and refining byproducts. Similar catalytic hydrothiolation applies to for production, though at slightly higher temperatures due to the larger alkyl chain. Another established method is the hydrogenolysis of disulfides using gas over metal catalysts, such as or on supports, to cleave the S–S bond and regenerate thiols for or direct use. This is particularly applied in the production of tert-butyl mercaptan, where di-tert-butyl is reduced at 200–300°C and 10–30 atm, achieving near-complete conversion in continuous flow reactors. The process is efficient for recovering thiols from oxidative side products in streams, enhancing overall utilization in facilities. Among major industrial thiols, serves primarily as an odorant additive for and , with production scaled to meet regulatory requirements for , typically in quantities of thousands of tons per year globally. , used extensively in biochemical applications as a and in industrial formulations for inhibition and synthesis, is produced via the reaction of with H₂S in a 1:1 molar ratio at 50–80°C and 25–100 atm, using bis(β-hydroxyethyl) thioether as a to maintain a homogeneous phase and ensure by preventing gas buildup. Annual production of exceeds 10 million pounds in high-volume facilities. considerations for all processes include handling under inert atmospheres to mitigate flammability (flash points around 0–30°C) and , with strict ventilation and monitoring required due to the compounds' pungent odors and potential for respiratory at low concentrations (e.g., 0.5 ppm threshold for ).

Classes of Thiols

Aliphatic and Aromatic Thiols

Aliphatic thiols are organosulfur compounds characterized by a thiol (-SH) group attached to a saturated or unsaturated aliphatic carbon chain, typically without additional functional groups. Straight-chain aliphatic thiols, such as 1-propanethiol (CH₃CH₂CH₂SH), feature an unbranched skeleton, resulting in relatively simple linear structures that confer high volatility and low boiling points. Branched aliphatic thiols, exemplified by tert-butyl mercaptan ((CH₃)₃CSH), incorporate alkyl substituents on the carbon adjacent to the sulfur, which can influence steric properties while maintaining the core reactivity of the thiol moiety. These compounds are notorious for their intense, unpleasant odors—often described as skunk-like or cabbage-like—and their volatility makes them ideal for use as odorants in and to signal leaks. Aromatic thiols consist of a thiol group directly bonded to an aromatic ring, with (C₆H₅SH) as the archetypal member and derivatives like p-toluenethiol (CH₃C₆H₄SH) providing structural variations through ring substitution. appears as a colorless to pale yellow liquid with a strong garlic-like odor and limited solubility (approximately 0.8 g/L at 25°C). The enhanced stability of aromatic thiols arises from resonance delocalization, wherein the sulfur conjugates with the π-system of the aromatic ring, lowering the S-H bond dissociation energy and stabilizing thiyl radicals formed during reactions. Despite this stability, aromatic thiols pose significant health risks, exhibiting high (oral LD₅₀ in rats ~50 mg/kg) via dermal absorption, , or , often inducing , respiratory distress, and tissue irritation. In industrial contexts, and its derivatives serve as key intermediates in the synthesis of amber-colored dyes, pharmaceuticals, and pesticides. A key distinction in properties between these classes lies in reactivity trends, particularly nucleophilicity, where aliphatic thiols surpass aromatic counterparts due to the absence of delocalization in aliphatic thiolates, which preserves the on for nucleophilic attack. This is apparent in thiol-Michael additions, where aliphatic thiols like 1-hexanethiol often achieve higher yields and faster rates than under neutral or basic conditions, as the aromatic in thiophenolate reduces lone-pair availability. Biologically, allyl mercaptan (CH₂=CHCH₂SH), a simple unsaturated aliphatic thiol, occurs in ( ) as a of formed via enzymatic cleavage of , imparting the vegetable's signature pungency and contributing to its organosulfur profile associated with and effects.

Polyfunctional Thiols

Polyfunctional thiols are organosulfur compounds featuring multiple thiol (-) groups or a thiol group combined with other functional moieties, enabling enhanced reactivity, , and versatility in synthetic applications compared to monofunctional thiols. These molecules often exhibit synergistic interactions between functional groups, influencing their stability, solubility, and coordination behavior. While simple aliphatic and aromatic thiols serve as basic building blocks, polyfunctional variants introduce complexity for advanced material design. Dithiols, containing two thiol groups, are prominent polyfunctional thiols valued for their chelating capabilities with metal ions. For instance, 1,2-ethanedithiol (HSCH₂CH₂SH) forms stable complexes with transition metals such as , , and through bidentate coordination via its vicinal sulfurs. Similarly, 1,3-propanedithiol (HSCH₂CH₂CH₂SH) coordinates with to yield porous gold-thiol polymers, leveraging its propyl spacer for flexible ligand geometry. These chelating properties arise from the ability of dithiolate anions to bridge metals, enhancing stability in coordination compounds. Unsaturated thiols incorporate carbon-carbon double bonds alongside thiol groups, promoting through thiol-ene click reactions or radical additions. Allyl mercaptan (CH₂=CHCH₂SH), for example, undergoes efficient to polythioethers, where the allyl moiety participates in ene addition with thiols under mild conditions. Vinyl thiols (e.g., CH₂=CHSH derivatives) are less common due to challenges during synthesis but enable step-growth networks when stabilized, offering low oxygen inhibition and rapid curing in coatings. Their dual functionality supports the formation of crosslinked polymers with tunable mechanical properties. Heterofunctional thiols combine a thiol group with amino, hydroxy, or moieties, imparting amphiphilic or reactive characteristics. Aminothiols like (HSCH₂CH₂NH₂) feature a primary that enhances solubility and nucleophilicity, though stabilization against oxidation remains a key challenge due to the reactive amine-thiol synergy. Hydroxythiols, such as (HSCH₂CH₂OH), are synthesized via addition to and serve as reducing agents in synthesis, with the hydroxyl group aiding hydrogen bonding for improved material cohesion. Thiol-acids like (HSCH₂COOH) exhibit acidic properties (pKa ≈ 3.7 for , ≈10.3 for thiol) and form strong metal complexes, useful as ligands in . Applications of polyfunctional thiols span polymer networks and metal coordination, where they enable and stable catalysts. In polymers, dithiols and unsaturated variants facilitate thiol-yne or thiol-ene crosslinking to yield flexible polythioethers or urethanes with enhanced toughness. As ligands, they provide multidentate binding for heavy metal sequestration or stabilization, improving colloidal dispersion. However, synthesis challenges include controlling oxidation to disulfides during preparation—often addressed by inert atmospheres or reductive workups—and managing reactivity in multifunctional systems, which can lead to side reactions like intramolecular cyclization. These hurdles are mitigated in industrial routes using thiol-disulfide exchange or halide displacement under controlled conditions.

Chemical Reactions

Acidity and Deprotonation

Thiols exhibit moderate acidity due to the polar S–H bond, with typical pKa values ranging from 10 to 11 for aliphatic thiols. For example, has a pKa of 10.6 in at 25 °C. Aromatic thiols are significantly more acidic, with displaying a pKa of 6.6, owing to stabilization of the thiolate anion by the phenyl ring, which delocalizes the negative charge. Compared to alcohols, thiols are more acidic by approximately 5 pKa units; for instance, has a pKa of around 15.9, while ethanethiol's is 10.6./06:Alcohols_and_an_introduction_to_thiols_amines_ethers_and_sulfides/6.01:(Brnsted)_Acidity_of_Alcohols_Thiols_and_Amines) This difference arises primarily from the larger atomic size of , which results in a weaker S–H bond due to poorer orbital overlap between sulfur's 3p and hydrogen's 1s orbitals, facilitating easier ./06:Alcohols_and_an_introduction_to_thiols_amines_ethers_and_sulfides/6.01:(Brnsted)_Acidity_of_Alcohols_Thiols_and_Amines) Additionally, the greater of better stabilizes the negative charge on the thiolate anion relative to the less polarizable oxygen in ions./06:Alcohols_and_an_introduction_to_thiols_amines_ethers_and_sulfides/6.01:(Brnsted)_Acidity_of_Alcohols_Thiols_and_Amines) Deprotonation of thiols generates thiolate anions (RS⁻), as described by the equilibrium: RSH⇌RS−+H+\text{RSH} \rightleftharpoons \text{RS}^- + \text{H}^+ The acid dissociation constant KaK_a is defined as Ka=[RS−][H+][RSH]K_a = \frac{[\text{RS}^-][\text{H}^+]}{[\text{RSH}]}, with pKa = -log⁡Ka\log K_a quantifying the position of equilibrium; lower pKa values indicate a greater tendency toward deprotonation. Thiolates readily form salts with strong bases, such as (NaH), yielding stable thiolates like sodium ethanethiolate, which are soluble in polar solvents and useful in synthesis. influence this equilibrium: in protic solvents like , hydrogen bonding stabilizes the thiolate, promoting deprotonation compared to aprotic or nonpolar solvents like , where the protonated thiol predominates at neutral . In , deprotonation is less favorable than in due to weaker of the anion.

Nucleophilicity and Substitution

Thiolates (RS⁻) exhibit high nucleophilicity due to the of , enabling efficient bimolecular (SN2) reactions with primary and secondary alkyl halides to form thioethers. In these reactions, the thiolate acts as a strong , attacking the carbon atom bearing the leaving group in a concerted backside displacement, as exemplified by the of zinc-bound thiolates with methyl , which proceeds via an associative SN2 pathway influenced by coordination and solvent effects. This high reactivity contrasts with oxygen analogs like alkoxides, which are less effective under similar conditions, highlighting sulfur's superior nucleophilicity in SN2 processes. As soft nucleophiles according to the hard-soft acid-base (HSAB) theory, thiolates preferentially react with soft electrophiles, such as those with high polarizability or low charge density, facilitating selective substitutions in synthesis. For instance, in the stereospecific substitution of α-chlorinated lactones or tertiary chlorides adjacent to carbonyls, alkylthiols deliver inverted configuration products via SN2 mechanisms, underscoring their affinity for soft carbon centers over harder ones. Similarly, enantioconvergent SN2 reactions of tertiary bromides with thiolcarboxylates, catalyzed by chiral phase-transfer agents, yield tertiary thioesters, demonstrating practical synthetic utility in constructing complex carbon-sulfur bonds while adhering to HSAB selectivity. Thiol-ene additions represent another key manifestation of thiol nucleophilicity, encompassing both base-catalyzed Michael additions to activated s and radical-initiated variants with unactivated s. In the thiol-Michael addition, the deprotonated thiolate adds conjugately to electron-deficient s like acrylates or maleimides, forming β-thioethers in a step-growth process often catalyzed by amines or phosphines; this reaction's efficiency stems from the thiolate's nucleophilic attack on the β-carbon, enabling applications in crosslinking and surface functionalization. Radical-initiated thiol-ene reactions, by contrast, proceed via a chain mechanism: a thiyl radical (RS•) adds anti-Markovnikov to the , followed by abstraction from another thiol to propagate the chain, achieving near-quantitative yields in photopolymerizations for biomaterials and synthesis. These pathways differ mechanistically, with the Michael variant relying on ionic nucleophilicity and the radical version on homolytic addition, yet both exploit sulfur's versatility for modular organic transformations. Thiol-disulfide exchange is a key nucleophilic reaction involving thiolates attacking disulfides, represented as: RS−+R’S-SR”⇌RS-SR”+R’S−\text{RS}^- + \text{R'S-SR''} \rightleftharpoons \text{RS-SR''} + \text{R'S}^- This reversible proceeds via nucleophilic attack at one sulfur atom, forming a transient anionic intermediate, and is base-catalyzed, with equilibrium depending on thiol pKa values and sterics. It is crucial in , signaling, and synthetic disulfide formation. Nucleophilic routes to disulfides also leverage thiolate reactivity, particularly through substitution with sulfenyl chlorides (RSCl). In this process, a thiolate attacks the electrophilic sulfur of RSCl, displacing to form an unsymmetrical (RSSR'), often as an intermediate in broader synthetic sequences under conditions to avoid side . This SN2-like substitution at sulfur is highly efficient for preparing mixed disulfides, as seen in the reaction of arene- or fluoroalkyl-sulfenyl chlorides with thiols, providing a controlled alternative to oxidative dimerization.

Redox Processes

Thiols undergo reactions primarily involving oxidation to disulfides and higher oxidation states, as well as the reverse reduction processes. The fundamental two-electron oxidation of two thiol molecules yields a bond, represented by the equation: 2RSH→RSSR+2H++2e−2 \text{RSH} \rightarrow \text{RSSR} + 2\text{H}^+ + 2\text{e}^- This process can be mediated by mild oxidants such as molecular iodine (I₂) or atmospheric oxygen (air), which facilitate the formation of symmetrical disulfides under ambient conditions. Further oxidation of thiols or disulfides with stronger agents like hydrogen peroxide (H₂O₂) leads to higher oxidation states, including sulfinic acids (RSO₂H) and sulfonic acids (RSO₃H). These transformations typically proceed via transient sulfenic acid (RSOH) intermediates and are relevant in oxidative environments where excess oxidant is present. The reduction of disulfides back to thiols is achieved using nucleophilic agents such as phosphines (e.g., tris(2-carboxyethyl)phosphine, TCEP) or dithiothreitol (DTT), which cleave the S-S bond in biochemical contexts by transferring electrons or forming transient adducts. The behavior of thiols is governed by their standard reduction potentials; for instance, the one-electron oxidation potential for RSH to the thiyl radical (RS•) is approximately 0.8 V, enabling thiols to act as effective antioxidants by scavenging through facile .

Coordination with Metals

Thiols, particularly in their deprotonated thiolate form (RS⁻), function as soft Lewis bases within the framework of Hard-Soft Acid-Base (, displaying a pronounced preference for coordination with soft Lewis metal ions such as Hg²⁺ and Ag⁺ due to favorable orbital overlap and matching. This soft-soft interaction results in highly stable mononuclear complexes, exemplified by the linear Hg(SR)₂ species where mercury(II) binds two thiolate s with short Hg-S bond lengths of approximately 2.34–2.36 Å, as confirmed by (EXAFS) spectroscopy. Analogous coordination occurs with silver(I), forming Ag(SR) complexes that exhibit two-coordinate linear or polymeric structures depending on the ligand and conditions. The thermodynamic stability of these thiolate-metal complexes significantly surpasses that of analogous oxygen-donor ligands, reflecting the HSAB selectivity; for instance, the stability constant for Ag⁺ binding to thiols reaches log β₁ ≈ 12–13 (e.g., log K = 13.0 for 2-mercaptoethanol-Ag⁺), whereas oxygen analogs like alcohols or carboxylates yield log K values below 5 under similar conditions. For Hg²⁺-thiolate, overall stability constants are even more pronounced, with log β₂ ≈ 40 for Hg(SR)₂ formations in aqueous media at low , driven by the strong covalent character of Hg-S bonds. In multidentate thiols such as 1,2-ethanedithiol, the further enhances complex stability through gains from ring formation, yielding bidentate coordination that creates strained yet robust five-membered PdS₂C₂ rings in complexes like the dimeric [Pd₂(SCH₂CH₂S)₄(PPh₃)₂]. This increases overall stability by 10⁴–10⁶ fold compared to monodentate thiol analogs, as quantified by stepwise formation constants where the second binding step (intramolecular) dominates due to reduced . These coordination properties underpin practical applications in metal extraction, where thiol-functionalized materials such as metal-organic frameworks selectively bind and remove like Hg²⁺ and Pb²⁺ from aqueous solutions with capacities exceeding 500 mg g⁻¹. In , thiolate ligands stabilize transition metals like Pd²⁺ in homogeneous systems for cross-coupling reactions, leveraging the tunable lability of M-S bonds to facilitate ligand exchange and turnover. For , dithiol chelators such as dimercaptosuccinic acid (DMSA) form excretable M(SR)₂ complexes with Hg²⁺, Cd²⁺, and Pb²⁺, enhancing urinary elimination and mitigating toxicity in clinical settings.

Thiyl Radicals

Formation Mechanisms

Thiyl radicals (RS•) are primarily generated from thiols (RSH) through homolytic cleavage of the S-H bond, which requires energy input due to the relatively weak bond strength with a dissociation energy of approximately 365 kJ/mol for aliphatic thiols and around 330 kJ/mol for aromatic thiols. This process can be initiated thermally at elevated temperatures, photochemically via (UV) irradiation, or chemically using radical initiators such as (AIBN). For instance, UV light at wavelengths around 254 nm effectively induces S-H bond homolysis in aromatic thiols like benzenethiol, producing thiyl radicals in solution. Another key mechanism involves oxidation pathways, particularly one-electron oxidation of the thiolate anion (RS⁻), which is the deprotonated form of the thiol prevalent under physiological or basic conditions. Oxidants such as ions facilitate this transfer; for example, the reaction RS⁻ + Fe³⁺ → RS• + Fe²⁺ generates the thiyl radical while reducing the metal center. This pathway is common in enzymatic and Fenton-like systems where thiols act as reductants, leading to radical formation as an intermediate step. Photochemical generation specifically from thiols often overlaps with homolytic cleavage but can involve photoexcitation leading to direct S-H bond breaking without additional input. In contrast to Norrish-type reactions observed in thioethers, thiol photolysis focuses on the labile S-H bond, enabling controlled radical production in synthetic applications. Detection of thiyl radicals typically relies on (EPR) spectroscopy, which captures their characteristic g-values (around 2.01–2.02) and hyperfine splitting patterns from and adjacent nuclei. This technique has confirmed RS• signals in both model systems and biological matrices, providing direct evidence of their transient existence with lifetimes on the order of microseconds.

Radical Reactivity and Applications

Thiyl radicals exhibit significant reactivity through to unsaturated bonds, particularly in thiol-ene reactions, where they add to alkenes in an anti-Markovnikov fashion. The mechanism involves the thiyl radical (RS•) attacking the terminal carbon of the , generating a carbon-centered radical: RS• + CH₂=CH₂ → RS-CH₂-CH₂•. This step is highly efficient due to the low bond dissociation energy of the S-H bond in thiols, facilitating rapid propagation, and has been extensively studied computationally to confirm the driven by radical stability. The reversibility of this can occur under certain conditions, distinguishing thiyl radical behavior from alkoxy radicals, which favor different regiochemistry. Another key reactivity pathway for thiyl radicals is hydrogen abstraction from C-H bonds in hydrocarbons or other thiols, enabling processes. These abstractions are slower than additions but play a critical role in propagating radical chains, such as in the of unsaturated fatty acids or β- transfers in organometallic contexts. In , thiyl radicals facilitate catalytic chain transfer by abstracting from growing polymer chains or monomers, controlling molecular weight and polydispersity without terminating the chain. This activity is particularly pronounced in biological systems, where thiyl radicals from residues promote prooxidative transfer in proteins. Disulfide radical anions (RSSR⁻•) serve as important intermediates in thiyl radical chemistry, formed via equilibrium with thiyl radicals and thiolates: RS• + RS⁻ ⇌ RSSR⁻•. These species are stabilized in the presence of excess thiolates and exhibit reduction potentials that influence their reactivity, often undergoing electron transfer or cleavage reactions. Pulse radiolysis studies have quantified their lifetimes and equilibria, showing pH-dependent behavior that affects radical persistence in aqueous environments. Applications of thiyl radical reactivity span polymer synthesis, antioxidant mechanisms, and organic transformations. In free radical polymerization, thiyl radicals act as mediators in thiol-ene click reactions, enabling step-growth processes for materials like hydrogels with precise control over network structure. As antioxidants, thiols generate thiyl radicals that scavenge peroxyl radicals in chains, though they can also propagate oxidation if not balanced. The Barton-McCombie deoxygenation exemplifies synthetic utility, where thiyl radicals are generated from O-thiocarbonyl alcohol derivatives upon reduction with , facilitating selective C-O bond cleavage and hydrogen atom transfer to form deoxygenated products with high efficiency.

Biological Significance

Role in Proteins and Amino Acids

Thiols play a critical role in and function primarily through the cysteine, which contains a thiol (-SH) group in its side chain. The structure of cysteine is HS-CH₂-CH(NH₂)COOH, where the thiol group has a pKa of approximately 8.3, allowing it to exist predominantly in the protonated form under physiological conditions but to deprotonate and become nucleophilic in more basic microenvironments within proteins. This property enables cysteine residues to form covalent bonds (S-S) between two thiol groups, which stabilize protein tertiary and quaternary structures by linking distant parts of the polypeptide chain or different subunits. The oxidized dimer of , known as cystine (CySSCy), forms when two cysteine thiols undergo oxidation to create an intermolecular bridge, a process favored in the oxidizing extracellular environment where cystine predominates over free to maintain balance. In proteins, these bridges are essential for proper folding, as they constrain the conformational of the unfolded state and promote the native structure, particularly in secreted proteins exposed to oxidative conditions outside the cell. Thiol-disulfide exchange reactions, involving the nucleophilic attack of a thiolate on a bond, establish a dynamic equilibrium that regulates and in the (ER). The enzyme (PDI) catalyzes these exchanges by forming transient mixed disulfides with substrate cysteines, facilitating the rearrangement of incorrect disulfide bonds to achieve the correct native configuration. Representative examples illustrate the structural importance of these bonds: human insulin features three disulfide bridges—two interchain (A7-B7 and A20-B19) and one intrachain (A6-A11 in the A chain)—that are vital for its stability and . Similarly, antibodies such as (IgG) rely on multiple intrachain and interchain bonds to maintain the integrity of their Fab and Fc domains, ensuring proper binding and effector functions.

Involvement in Cofactors and Enzymes

Thiols play critical roles in biological systems as components of cofactors that facilitate enzymatic reactions, particularly in metabolic pathways involving acyl group transfer and processes. (CoA), a pantetheine derivative featuring a terminal thiol group (-SH), acts as an acyl carrier by forming high-energy bonds with fatty acids, enabling their activation and transfer during . For instance, in , and utilize the thiol of CoA to shuttle two-carbon units for chain elongation by . Lipoic acid, a dithiol-containing cofactor, is covalently attached to the E2 subunit of the pyruvate dehydrogenase complex, where it undergoes cycling between its reduced dithiol (dihydrolipoamide) and oxidized forms to mediate the oxidative of pyruvate. This cycling involves nucleophilic attack by the dithiol on the substrate, followed by transfer of the and regeneration via lipoamide dehydrogenase, linking to the . Glutathione (GSH), a thiol composed of glutamate, , and , functions primarily as a cellular by scavenging through its nucleophilic thiol group, which forms bonds with oxidants to produce oxidized glutathione (GSSG). The GSH/GSSG ratio serves as a key indicator of cellular status, maintained by , and perturbations in this ratio influence signaling pathways and enzyme activities under . In enzymatic catalysis, thiols enable nucleophilic mechanisms in cysteine proteases, such as , where the active-site residue deprotonates to form a thiolate that attacks the carbonyl carbon of substrates, forming a covalent acyl-enzyme intermediate before . This thiolate, stabilized by a nearby , exemplifies the nucleophilicity of thiols in hydrolytic cleavage essential for protein degradation.

Applications in Medicine and Drugs

Thiols play a significant role in medicinal applications, particularly through synthetic compounds that leverage their nucleophilic and redox properties for therapeutic purposes. One prominent example is N-acetylcysteine (NAC), a thiol-containing derivative of the amino acid cysteine, which serves as a mucolytic agent by breaking disulfide bonds in mucus glycoproteins to reduce viscosity in respiratory conditions. NAC is also the standard antidote for acetaminophen (paracetamol) overdose, where it replenishes depleted glutathione (GSH) stores in the liver, thereby detoxifying the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) and preventing hepatotoxicity. Another key thiol drug is D-penicillamine, a chelating agent structurally featuring a thiol (-SH) group attached to a beta-methylated backbone, derived from penicillin but lacking antibacterial activity. It is primarily used in the treatment of , a causing accumulation, by forming stable complexes with excess copper ions to promote their urinary excretion and reduce hepatic and neurological damage. Captopril represents a thiol-based inhibitor in cardiovascular medicine, functioning as an () inhibitor with a mercaptoacyl group that coordinates directly with the zinc ion at the enzyme's , thereby blocking the conversion of I to II and lowering . This zinc-binding mechanism enhances captopril's potency and selectivity, making it a cornerstone therapy for and . Emerging applications of thiols focus on their potential to combat in neurodegenerative diseases. For instance, a completed randomized, placebo-controlled phase 2 pilot study of NAC in patients (NCT07093944) assessed its ability to mitigate oxidative damage by boosting GSH levels and reducing . Similarly, a completed phase 2 of combination therapies incorporating NAC with other cofactors (L-carnitine tartrate, , and serine) in patients demonstrated a significant 29% improvement in cognitive function as of 2023. These efforts highlight thiols' promise in addressing imbalances central to neurodegeneration.

References

  1. https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_%28Organic_Chemistry%29/Thiols_and_Sulfides/Thiols_and_Sulfides
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC7286615/
  3. https://www.acdlabs.com/iupac/nomenclature/79/r79_390.htm
  4. https://web.pdx.edu/~wamserc/C334F99/9notes.htm
  5. https://www1.udel.edu/chem/valhalla/nomenclature.html
  6. https://homepages.bluffton.edu/~bergerd/classes/CEM221/Handouts/nomenclature-1.PDF
  7. https://www.chemistrysteps.com/naming-thiols-and-sulfides/
  8. http://chem.ucalgary.ca/courses/350/Carey5th/useful/nomen.html
  9. https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Organic_Chemistry_(Morsch_et_al.)/17%3A_Alcohols_and_Phenols/17.02%3A_Properties_of_Alcohols_and_Phenols
  10. https://cccbdb.nist.gov/exp2x.asp?casno=74931&charge=0
  11. https://discovery.dundee.ac.uk/files/76397003/molecules_25_03094.pdf
  12. https://wwwn.cdc.gov/TSP/MMG/MMGDetails.aspx?mmgid=221&toxid=40
  13. https://pubs.acs.org/doi/abs/10.1021/jf506135c
  14. https://www.acs.org/molecule-of-the-week/archive/e/ethanethiol.html
  15. https://waterhouse.ucdavis.edu/whats-in-wine/volatile-thiols
  16. https://pubs.acs.org/doi/10.1021/jf990660r
  17. https://www.ncbi.nlm.nih.gov/books/NBK594274/
  18. https://pubchem.ncbi.nlm.nih.gov/compound/Ethanethiol
  19. https://pubchem.ncbi.nlm.nih.gov/compound/Ethanol
  20. https://www.engineeringtoolbox.com/boiling-melting-organic-sulfur-sulfide-thiophene-structure-mercaptane-thiol-density-molweight-d_1946.html
  21. https://pubchem.ncbi.nlm.nih.gov/compound/tert-Butyl-mercaptan
  22. https://pubchem.ncbi.nlm.nih.gov/compound/Methanethiol
  23. https://pubchem.ncbi.nlm.nih.gov/compound/Propane-1-thiol
  24. https://pubchem.ncbi.nlm.nih.gov/compound/Butanethiol
  25. https://organicchemistrydata.org/hansreich/resources/nmr/?page=05-hmr-02-delta/
  26. https://www.jstage.jst.go.jp/article/bunsekikagaku1952/26/1/26_1_64/_article
  27. https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/spectrpy/infrared/infrared.htm
  28. https://chem.libretexts.org/Ancillary_Materials/Reference/Reference_Tables/Spectroscopic_Reference_Tables/Infrared_Spectroscopy_Absorption_Table
  29. https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Organic_Chemistry_(Morsch_et_al.)/14%3A_Conjugated_Compounds_and_Ultraviolet_Spectroscopy/14.08%3A_Interpreting_Ultraviolet_Spectra-_The_Effect_of_Conjugation
  30. https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/am-pdf/10.1002/rcm.7630
  31. https://www.masterorganicchemistry.com/2015/07/05/thiols-and-thioethers/
  32. https://www.iso.org/standard/11271.html
  33. https://pubchem.ncbi.nlm.nih.gov/compound/1-Octanethiol
  34. https://www.ebatco.com/wp-content/uploads/2013/12/Refractive-Index-Measurements-to-Compare-Chemical-Purity-1.pdf
  35. https://doi.org/10.1007/s12039-024-02300-7
  36. https://www.sciencedirect.com/science/article/abs/pii/S0920586116306800
  37. https://aet.irost.ir/article_976_a38a804c3227c93e000914ecfc71e847.pdf
  38. https://pubs.acs.org/doi/10.1021/ie00048a006
  39. https://www.sciencedirect.com/science/article/abs/pii/S156673671200074X
  40. https://patents.google.com/patent/WO2007070496A2/en
  41. https://pubs.acs.org/doi/10.1021/ja01277a045
  42. https://nj.gov/health/eoh/rtkweb/documents/fs/0894.pdf
  43. https://patents.google.com/patent/US3710439A/en
  44. https://pubchem.ncbi.nlm.nih.gov/compound/2-Mercaptoethanol
  45. https://pubchem.ncbi.nlm.nih.gov/compound/2-Methylpropane-2-thiol
  46. https://primis.phmsa.dot.gov/rd/FileGet/8632/21093_final_report_2014-04-21.pdf
  47. https://pubchem.ncbi.nlm.nih.gov/compound/Thiophenol
  48. https://digitalcollections.wesleyan.edu/_flysystem/fedora/2023-03/22056-Original%20File.pdf
  49. https://pmc.ncbi.nlm.nih.gov/articles/PMC7146530/
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC10972302/
  51. https://www.mdpi.com/1420-3049/24/18/3247
  52. https://pubs.acs.org/doi/10.1021/acs.biomac.6b00005
  53. https://pubs.acs.org/doi/10.1021/ja00845a018
  54. https://academic.oup.com/chemlett/article/42/4/407/7389515
  55. https://pubs.acs.org/doi/abs/10.1021/ic50197a023
  56. https://patents.google.com/patent/US3503940A/en
  57. https://pubs.acs.org/doi/10.1021/ma502460t
  58. https://www.sciencedirect.com/science/article/pii/S2095177919309025
  59. https://patents.google.com/patent/US3086997A/en
  60. https://pubchem.ncbi.nlm.nih.gov/compound/1133
  61. https://pubs.acs.org/doi/10.1021/acs.macromol.0c00239
  62. https://www.chem.indiana.edu/wp-content/uploads/2018/03/pka-chart.pdf
  63. https://pubs.acs.org/doi/10.1021/acs.jpcc.2c00416
  64. https://openstax.org/books/organic-chemistry/pages/18-7-thiols-and-sulfides
  65. https://pubs.acs.org/doi/10.1021/ja042591p
  66. https://doi.org/10.1021/ic800697s
  67. https://doi.org/10.1016/j.chempr.2020.11.022
  68. https://doi.org/10.1021/cm402180t
  69. https://doi.org/10.1039/b917102a
  70. https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_(Organic_Chemistry)/Thiols_and_Sulfides/Disulfide_Formation_and_Reduction
  71. https://russchemrev.org/RCR172pdf
  72. https://pmc.ncbi.nlm.nih.gov/articles/PMC3613173/
  73. https://doi.org/10.1021/bi00014a034
  74. https://pubmed.ncbi.nlm.nih.gov/15568811/
  75. https://doi.org/10.1016/j.freeradbiomed.2008.05.004
  76. https://pubs.acs.org/doi/10.1021/acs.est.8b00919
  77. https://link.springer.com/article/10.1023/A:1009699617808
  78. https://onlinelibrary.wiley.com/doi/10.1002/etc.5620180103
  79. https://chem.libretexts.org/Bookshelves/Inorganic_Chemistry/Supplemental_Modules_and_Websites_%28Inorganic_Chemistry%29/Coordination_Chemistry/Complex_Ion_Equilibria/Stability_of_Metal_Complexes_and_Chelation
  80. https://pubs.acs.org/doi/10.1021/es0705238
  81. https://pubs.acs.org/doi/10.1021/cr900134a
  82. https://pmc.ncbi.nlm.nih.gov/articles/PMC6767255/
  83. https://macmillan.princeton.edu/wp-content/uploads/JJ_Thiyl-Radicals.pdf
  84. https://pubs.acs.org/doi/10.1021/acsearthspacechem.1c00310
  85. https://www.sciencedirect.com/science/article/abs/pii/B9780323902199000017
  86. https://pubmed.ncbi.nlm.nih.gov/26329537/
  87. https://www.osti.gov/servlets/purl/1394076
  88. https://link.springer.com/article/10.1007/BF03166170
  89. https://pubs.acs.org/doi/10.1021/ac200418s
  90. https://pubs.acs.org/doi/10.1021/ja01514a032
  91. https://www.sciencedirect.com/science/article/abs/pii/S0014305718312746
  92. https://pubs.acs.org/doi/abs/10.1021/ja305441d
  93. https://pubs.acs.org/doi/10.1021/om00046a004
  94. https://pubs.acs.org/doi/10.1021/tx049856y
  95. https://pmc.ncbi.nlm.nih.gov/articles/PMC7365990/
  96. https://www.sciencedirect.com/science/article/abs/pii/S003238619900292X
  97. https://pubs.acs.org/doi/10.1021/j100310a022
  98. https://pubs.rsc.org/en/content/articlelanding/1999/p2/a901155b
  99. https://pmc.ncbi.nlm.nih.gov/articles/PMC10619894/
  100. https://www.beilstein-journals.org/bjoc/articles/19/116
  101. https://www.mdpi.com/2073-4360/4/2/1025
  102. https://pubs.acs.org/doi/abs/10.1021/ol050886h
  103. https://www.sciencedirect.com/science/article/abs/pii/S0040402018303077
  104. https://pubchem.ncbi.nlm.nih.gov/compound/L-_-Cysteine
  105. https://pmc.ncbi.nlm.nih.gov/articles/PMC7191308/
  106. https://pmc.ncbi.nlm.nih.gov/articles/PMC5884717/
  107. https://pmc.ncbi.nlm.nih.gov/articles/PMC3506382/
  108. https://pmc.ncbi.nlm.nih.gov/articles/PMC4312752/
  109. https://pmc.ncbi.nlm.nih.gov/articles/PMC3078216/
  110. https://pubmed.ncbi.nlm.nih.gov/14744022/
  111. https://pmc.ncbi.nlm.nih.gov/articles/PMC3338938/
  112. https://pmc.ncbi.nlm.nih.gov/articles/PMC7731229/
  113. https://pmc.ncbi.nlm.nih.gov/articles/PMC6723188/
  114. https://pmc.ncbi.nlm.nih.gov/articles/PMC6272787/
  115. https://pmc.ncbi.nlm.nih.gov/articles/PMC2696075/
  116. https://pmc.ncbi.nlm.nih.gov/articles/PMC2767454/
  117. https://med.stanford.edu/content/dam/sm/bogyolab/documents/15266051.pdf
  118. https://www.ncbi.nlm.nih.gov/books/NBK537183/
  119. https://pmc.ncbi.nlm.nih.gov/articles/PMC8719286/
  120. https://www.ncbi.nlm.nih.gov/books/NBK513316/
  121. https://pmc.ncbi.nlm.nih.gov/articles/PMC7467227/
  122. https://pmc.ncbi.nlm.nih.gov/articles/PMC9664202/
  123. https://pubmed.ncbi.nlm.nih.gov/15236580/
  124. https://clinicaltrials.gov/study/NCT07093944
  125. https://clinicaltrials.gov/study/NCT04044131
  126. https://pubmed.ncbi.nlm.nih.gov/36703196/
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