Organosulfur compounds

Organosulfur compounds are organic compounds that contain sulfur.^[1] They are often associated with foul odors, but many of the sweetest compounds known are organosulfur derivatives, e.g., saccharin. Nature abounds with organosulfur compounds—sulfur is essential for life. Two of the 20 common amino acids are organosulfur compounds, and the antibiotics penicillin (pictured below) and sulfa drugs both contain sulfur. While sulfur-containing antibiotics save many lives, sulfur mustard is a deadly chemical warfare agent. Fossil fuels, coal, petroleum, and natural gas, which are derived from ancient organisms, necessarily contain organosulfur compounds, the removal of which is a major focus of oil refineries.

Sulfur shares the chalcogen group with oxygen, selenium and tellurium, and it is expected that organosulfur compounds have similarities with carbon-oxygen, carbon-selenium and carbon-tellurium compounds, which is true to some extent.

A classical chemical test for the detection of sulfur compounds is the Carius halogen method.

Classes of organosulfur compounds

Organosulfur compounds can be classified according to the sulfur-containing functional groups, which are listed (approximately) in decreasing order of their occurrence.

• Illustrative organosulfur compounds
• 

  Allicin, the active flavor compound in crushed garlic

• 

  R-cysteine, an amino acid containing a thiol group

• 

  Methionine, an amino acid containing a thioether

• 

  Diphenyl disulfide, a representative disulfide

• 

  Dibenzothiophene, a component of crude oil

• 

  Perfluorooctanesulfonic acid, a controversial surfactant

• 

  Lipoic acid, an essential cofactor of four mitochondrial enzyme complexes.

• 

  Penicillin core structure, where "R" is the variable group.

• 

  Sulfanilamide, a sulfonamide antibacterial, called a sulfa drug.

• 

  Sulfur mustard, a chemical warfare agent.

Thioethers, thioesters, thioacetals

These compounds are characterized by C–S–C bonds^[2][3] Relative to C–C bonds, C–S bond are both longer, because S is larger than carbon, and about 10% weaker. Representative bond lengths in sulfur compounds are 183 pm for the S-C single bond in methanethiol and 173 pm in thiophene. The C–S bond dissociation energy for thiomethane is 89 kcal/mol (370 kJ/mol) compared to methane's 100 kcal/mol (420 kJ/mol) and when hydrogen is replaced by a methyl group the energy decreases to 73 kcal/mol (305 kJ/mol).^[4] The single carbon to oxygen bond is shorter than that of the C–C bond. The bond dissociation energies for dimethyl sulfide and dimethyl ether are respectively 73 and 77 kcal/mol (305 and 322 kJ/mol.

Thioethers are typically prepared by alkylation of thiols. They can also be prepared via the Pummerer rearrangement. In one named reaction called the Ferrario reaction phenyl ether is converted to phenoxathiin by action of elemental sulfur and aluminium chloride ^[5]

Thioacetals and thioketals feature C–S–C–S–C bond sequence. They represent a subclass of thioethers. The thioacetals are useful in "umpolung" of carbonyl groups.

Thioesters have general structure R–CO–S–R. They are related to regular esters but are more reactive.

The above classes of sulfur compounds also exist in saturated and unsaturated heterocyclic structures, often in combination with other heteroatoms, as illustrated by thiiranes, thiirenes, thietanes, thietes, dithietanes, thiolanes, thianes, dithianes, thiepanes, thiepines, thiazoles, isothiazoles, and thiophenes, among others. The latter three compounds represent a special class of sulfur-containing heterocycles that are aromatic. The resonance stabilization of thiophene is 29 kcal/mol (121 kJ/mol) compared to 20 kcal/mol (84 kJ/mol) for the oxygen analogue furan. The reason for this difference is the higher electronegativity for oxygen drawing away electrons to itself at the expense of the aromatic ring current. Yet as an aromatic substituent the thio group is less effective as an activating group than the alkoxy group. Dibenzothiophene (see drawing), a tricyclic heterocycle consisting of two benzene rings fused to a central thiophene ring occurs widely in heavier fractions of petroleum, along with its alkyl substituted derivatives.

Thiols, disulfides, polysulfides

Thiol group contain the functionality R–SH. Thiols are structurally similar to the alcohol group, but these functionalities are very different in their chemical properties. Thiols are more nucleophilic, more acidic, and more readily oxidized. This acidity can differ by 5 pKa units.^[6]

The difference in electronegativity between sulfur (2.58) and hydrogen (2.20) is small and therefore hydrogen bonding in thiols is not prominent. Aliphatic thiols form monolayers on gold, which are topical in nanotechnology.

Certain aromatic thiols can be accessed through a Herz reaction.

Disulfides R–S–S–R with a covalent sulfur to sulfur bond are important for crosslinking: in biochemistry for the folding and stability of some proteins and in polymer chemistry for the crosslinking of rubber.

Longer sulfur chains are also known, such as in the natural product varacin which contains an unusual pentathiepin ring (5-sulfur chain cyclised onto a benzene ring).

Sulfoxides, sulfones and thiosulfinates

A sulfoxide, R-S(O)-R, is the S-oxide of a thioether, a sulfone, R-S(O)₂-R, is the S,S-dioxide of a thioether, a thiosulfinate, R-S(O)-S-R, is the S-oxide of a disulfide, and a thiosulfonate, R-S(O)₂-S-R, is the S,S-dioxide of a disulfide. All of these compounds are well known with extensive chemistry, e.g., see dimethyl sulfoxide, dimethyl sulfone, and allicin (see drawing).

Sulfimides, sulfoximides, sulfonediimines

Sulfimides (also called a sulfilimine) are sulfur-nitrogen compound of structure R₂S=NR', e.g., the nitrogen analog of sulfoxides. They are of interest in part due to their pharmacological properties. When two different R groups are attached to sulfur, sulfimides are chiral. Sulfimides form stable α-carbanions.^[7] Sulfoximides (also called sulfoximines) are tetracoordinate sulfur-nitrogen compounds, isoelectronic with sulfones, in which one oxygen atom of the sulfone is replaced by a substituted nitrogen atom, e.g., R₂S(O)=NR'. When two different R groups are attached to sulfur, sulfoximides are chiral. Much of the interest in this class of compounds is derived from the discovery that methionine sulfoximide (methionine sulfoximine) is an inhibitor of glutamine synthetase.^[8] Sulfonediimines (also called sulfodiimines, sulfodiimides or sulfonediimides) are tetracoordinate sulfur-nitrogen compounds, isoelectronic with sulfones, in which both oxygen atoms of the sulfone is replaced by a substituted nitrogen atom, e.g., R₂S(=NR')₂. They are of interest because of their biological activity and as building blocks for heterocycle synthesis.^[9]

S-Nitrosothiols

S-Nitrosothiols, also known as thionitrites, are compounds containing a nitroso group attached to the sulfur atom of a thiol, e.g. R-S-N=O. They have received considerable attention in biochemistry because they serve as donors of the nitrosonium ion, NO⁺, and nitric oxide, NO, which may serve as signaling molecules in living systems, especially related to vasodilation.^[10]

Sulfur halides

A wide range of organosulfur compounds are known which contain one or more halogen atom ("X" in the chemical formulas that follow) bonded to a single sulfur atom, e.g.: sulfenyl halides, RSX; sulfinyl halides, RS(O)X; sulfonyl halides, RSO₂X; alkyl and arylsulfur trichlorides, RSCl₃ and trifluorides, RSF₃;^[11] and alkyl and arylsulfur pentafluorides, RSF₅.^[12] Less well known are dialkylsulfur tetrahalides, mainly represented by the tetrafluorides, e.g., R₂SF₄.^[13]

Thioketones, thioaldehydes, and related compounds

Compounds with double bonds between carbon and sulfur are relatively uncommon, but include important compounds carbon disulfide, carbonyl sulfide, and thiophosgene. Thioketones (RC(=S)R') are uncommon with alkyl substituents, but one example example is thiobenzophenone. Thioaldehydes are rarer still, reflecting their lack of steric protection ("thioformaldehyde" exists as a cyclic trimer). Thioamides, with the formula R₁C(=S)N(R₂)R₃ are more common. They are typically prepared by the reaction of amides with Lawesson's reagent. Isothiocyanates, with formula R-N=C=S, are found naturally. Vegetable foods with characteristic flavors due to isothiocyanates include wasabi, horseradish, mustard, radish, Brussels sprouts, watercress, nasturtiums, and capers.

S-Oxides and S,S-dioxides of thiocarbonyl compounds

The S-oxides of thiocarbonyl compounds are known as thiocarbonyl S-oxides or sulfines, R₂C=S=O, and thiocarbonyl S,S-dioxides or sulfenes, R₂C=SO₂. These compounds are well known with extensive chemistry, e.g., see syn-propanethial-S-oxide and sulfene.

Triple bonds between carbon and sulfur

Triple bonds between sulfur and carbon in sulfaalkynes are rare and can be found in carbon monosulfide (CS) ^[14] and have been suggested for the compounds F₃CCSF₃ ^[15][16] and F₅SCSF₃ ^[17]. The compound HCSOH is also presented as having a formal triple bond ^[18].

Thiocarboxylic acids and thioamides

Thiocarboxylic acids (RC(O)SH)) and dithiocarboxylic acids (RC(S)SH) are well known. They are structurally similar to carboxylic acids but more acidic. Thioamides are analogous to amides.

Sulfonic, sulfinic and sulfenic acids, esters, amides, and related compounds

Sulfonic acids have functionality R-S(=O)₂-OH^[19]. They are strong acids that are typically soluble in organic solvents. Sulfonic acids like trifluoromethanesulfonic acid is a frequently used reagent in organic chemistry. Sulfinic acids have functionality R-S(O)-OH while sulfenic acids have functionality R-S-OH. In the series sulfonic-sulfinic-sulfenic acids, both the acid strength and stability diminish in that order.^[20][21] Sulfonamides, sulfinamides and sulfenamides, with formulas R-SO₂NR'₂, R-S(O)NR'₂, and R-SNR'₂, respectively, each have a rich chemistry. For example, sulfa drugs are sulfonamides derived from aromatic sulfonation. Chiral sulfinamides are used in asymmetric synthesis, while sulfenamides are used extensively in the vulcanization process to assist cross-linking. Thiocyanates, R-S-CN, are related to sulfenyl halides and esters in terms of reactivity.

Sulfonium, oxosulfonium and related salts

A sulfonium ion is a positively charged ion featuring three organic substituents attached to sulfur, with the formula [R₃S]⁺. Together with their negatively charged counterpart, the anion, the compounds are called sulfonium salts. An oxosulfonium ion is a positively charged ion featuring three organic substituents and an oxygen attached to sulfur, with the formula [R₃S=O]⁺. Together with their negatively charged counterpart, the anion, the compounds are called oxosulfonium salts. Related species include alkoxysulfonium and chlorosulfonium ions, [R₂SOR]⁺ and [R₂SCl]⁺, respectively.

Sulfonium, oxosulfonium and thiocarbonyl ylides

Deprotonation of sulfonium and oxosulfonium salts affords ylides, of structure R₂S⁺C^-R'₂ and R₂S(O)⁺C^-R'₂. While sulfonium ylides, for instance in the Johnson-Corey-Chaykovsky reaction used to synthesize oxiranes, are sometimes drawn with a C=S double bond, e.g., R₂S=CR'₂, the ylidic carbon-sulfur bond is highly polarized and is better described as being ionic. Sulfonium ylides are key intermediates in the synthetically useful Stevens rearrangement. Thiocarbonyl ylides (RR'C=S⁺C^-RR') can form by ring-opening of thiiranes, photocyclization of aryl vinyl sulfides,^[22] as well as by other processes.

Sulfuranes and persulfuranes

Sulfuranes are relatively specialized functional group that are tetravalent, hypervalent sulfur compounds, with the formula SR₄ ^[23] and likewise persulfuranes are hexavalent SR₆. All-carbon hexavalent complexes have been known for the heavier representatives of the chalcogen group, for instance the compound hexamethylpertellurane (Te(Me)₆) was discovered in 1990 ^[24] by reaction of tetramethyltellurium with xenon difluoride to Te(Me)₂)F₂ followed by reaction with diethylzinc. The sulfur analogue hexamethylpersulfurane SMe₆ has been predicted to be stable ^[25] but has not been synthesized yet.

The first ever all-carbon persulfurane actually synthesized in a laboratory has two methyl and two biphenyl ligands ^[26]:

It is prepared from the corresponding sulfurane 1 with xenon difluoride / boron trifluoride in acetonitrile to the sulfuranyl dication 2 followed by reaction with methyllithium in tetrahydrofuran to (a stable) persulfurane 3 as the cis isomer. X-ray diffraction shows C-S bond lengths ranging between 189 and 193 pm (longer than the standard bond length) with the central sulfur atom in a distorted octahedral molecular geometry.

Computer simulation suggests that these bonds are very polar with the negative charges residing on carbon.

Naturally occurring organosulfur compounds

Not all organosulfur compounds are foul-smelling pollutants. Penicillin and cephalosporin are life-saving antibiotics, derived from fungi. Gliotoxin is a sulfur-containing mycotoxin produced by several species of fungi under investigation as an antiviral agent. Compounds like allicin and ajoene are responsible for the odor of garlic, and lenthionine contributes to the flavor of shiitake mushrooms. Many of these natural products also have important medicinal properties such as preventing platelet aggregation or fighting cancer.

Organosulfur compounds in pollution

Most organic sulfur compounds in the environment are naturally occurring, as a consequence of the fact that sulfur is essential for life and two amino acids contain this element.

Some organosulfur compounds in the environment, are generated as minor by-products of industrial processes such as the manufacture of plastics and tires.

Selected smell-producing processes are organosulfur compounds produced by the coking of coal designed to drive out sulfurous compounds and other volatile impurities in order to produce 'clean carbon' (coke), which is primarily used for steel production.

Organosulfur compounds in fossil fuels

Odours occur as well in chemical processing of coal or crude oil into precursor chemicals (feedstocks) for downstream industrial uses (e.g. plastics or pharmaceutical production) and the ubiquitous needs of petroleum distillation for (gasolines, diesel, and other grades of fuel oils production.

Organosulfur compounds might be understood as smelly contaminants that need to be removed from natural gas before commercial uses, from exhaust stacks and exhaust vents before discharge. In this latter context, organosulfur compounds may be said to account for the pollutants in sulfurous acid rain, or equivalently, said to be pollutants within most common fossil fuels, especially coal.

Basis for odor of organosulfur compounds

Humans and other animals have an exquisitely sensitive sense of smell toward the odor of low valent organosulfur compounds such as thiols, thioethers, and disulfides. Malodorous volatile thiols are protein degradation products found in putrid food, so sensitive identification of these compounds is crucial to avoiding intoxication. Low valent volatile sulfur compounds are also found in areas where oxygen levels in the air are low, posing a risk of suffocation. It has been found that copper is required for the highly sensitive detection of certain volatile thiols and related organosulfur compounds by olfactory receptors in mice. Whether humans, too, require copper for sensitive detection of thiols is not yet known.^[27]

See also

References