Organosulfur chemistry

Organosulfur chemistry examines how organic compounds containing sulfur are made and what properties they have. Though these compounds are often linked to bad smells, some of the sweetest substances known—like saccharin—are organosulfur derivatives. Sulfur is essential for life, and nature is full of organosulfur compounds. Two of the 20 standard amino acids, cysteine and methionine, are organosulfur, and both penicillin and sulfa drugs contain sulfur. While sulfur-based antibiotics have saved countless lives, sulfur mustard is a lethal chemical weapon. Fossil fuels—coal, petroleum, and natural gas—come from ancient organisms and always contain organosulfur compounds; removing them is a key task for oil refineries.

Sulfur belongs to the chalcogen group with oxygen, selenium, and tellurium, so organosulfur compounds are expected to resemble carbon–oxygen, carbon–selenium, and carbon–tellurium compounds. A classic test for detecting sulfur in compounds is the Carius halogen method.

Organosulfur compounds are grouped by their sulfur-containing functional groups, listed roughly in order of how common they are.

**Sulfides** Sulfides, once called thioethers, have a C−S−C bond. Compared to C−C bonds, C−S bonds are longer—since sulfur atoms are larger than carbon—and about 10% weaker. For example, the S−C single bond in methanethiol is 183 pm long, and in thiophene it is 173 pm. The C−S bond dissociation energy in thiomethane is 89 kcal/mol (370 kJ/mol), versus 100 kcal/mol (420 kJ/mol) for methane; replacing hydrogen with a methyl group lowers it to 73 kcal/mol (305 kJ/mol). A carbon–oxygen single bond is shorter than a C−C bond. Dimethyl sulfide and dimethyl ether have bond dissociation energies of 73 and 77 kcal/mol (305 and 322 kJ/mol), respectively.

Sulfides are usually made by alkylating thiols. Alkylating agents include alkyl halides, epoxides, aziridines, and Michael acceptors. They can also be prepared through the Pummerer rearrangement. In the Ferrario reaction, phenyl ether reacts with elemental sulfur and aluminum chloride to form phenoxathiin.

Thioacetals and thioketals have a C−S−C−S−C bond sequence and are a subclass of sulfides. Thioacetals are useful for "umpolung" of carbonyl groups, and both thioacetals and thioketals can protect carbonyl groups in organic synthesis.

These sulfur compound classes also appear in saturated and unsaturated heterocyclic structures, often with other heteroatoms—examples include thiiranes, thiirenes, thietanes, thietes, dithietanes, thiolanes, thianes, dithianes, thiepanes, thiepines, thiazoles, isothiazoles, and thiophenes. The last three are aromatic sulfur heterocycles. Thiophene’s resonance stabilization is 29 kcal/mol (121 kJ/mol), compared to 20 kcal/mol (84 kJ/mol) for furan, its oxygen analog. This difference arises because oxygen’s higher electronegativity pulls electrons away from the aromatic ring current. Still, as an aromatic substituent, the thio group releases electrons less effectively than the alkoxy group. Dibenzothiophenes—tricyclic heterocycles with two benzene rings fused to a central thiophene ring—are common in heavier petroleum fractions.

**Thiols, disulfides, polysulfides** Thiols have the functional group R−SH. They resemble alcohols structurally but differ greatly in chemical behavior: thiols are more nucleophilic, more acidic, and oxidize more easily. Their acidity can differ by 5 pKa units. The small electronegativity difference between sulfur (2.58) and hydrogen (2.20) means hydrogen bonding in thiols is weak. Aliphatic thiols form monolayers on gold, a topic of interest in nanotechnology. Some aromatic thiols can be made via the Herz reaction. Removing the hydrogen atom yields a thiyl radical, an unstable reaction intermediate.

Disulfides (R−S−S−R) have a covalent sulfur–sulfur bond and are important for crosslinking—in biochemistry, for protein folding and stability, and in polymer chemistry, for rubber crosslinking. Longer sulfur chains exist too, as in the natural product varacin, which has an unusual pentathiepin ring (a five-sulfur chain cyclized onto a benzene ring).

**Inorganic thioesters** Esters of thiols with inorganic acids, such as Bunte salts (from a thiol and sodium hydrogen sulfate), generally have properties predictable from those of thiols and the acid. Some are biologically significant. Thiophosphate esters are widely used in pharmacology and agriculture because the group tends to block enzymes that break down phosphates. S-Nitrosothiols, or thionitrites, attach a nitroso group to a thiol (R−S−N=O). They have drawn attention in biochemistry as donors of nitrosonium ion (NO+) and nitric oxide (NO), which may act as signaling molecules in living systems, especially in vasodilation.

**Thioic acid derivatives** Thiocarboxylic acids (RC(O)SH) and dithiocarboxylic acids (RC(S)SH) are well known. They resemble carboxylic acids structurally but are more acidic. Thioesters have the general structure R−C(O)−S−R. They are related to regular esters (R−C(O)−O−R) but hydrolyze and react more easily. Thioesters from coenzyme A are prominent in biochemistry, particularly in fatty acid synthesis. Thioamides, with the formula R1C(=S)N(R2)R3, are more common than thioketones and thioaldehydes. They are typically prepared by...