Sulfonamide

For the medical use of chemicals within this group, see Sulfonamide (medicine).

Not to be confused with Sulfamide.

The structure of the sulfonamide group

In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure R−S(=O)₂−NR₂. It consists of a sulfonyl group (O=S=O) connected to an amine group (−NH₂). Relatively speaking this group is unreactive. Because of the rigidity of the functional group, sulfonamides are typically crystalline; for this reason, the formation of a sulfonamide is a classic method to convert an amine into a crystalline derivative which can be identified by its melting point. Many important drugs contain the sulfonamide group. ^[1]

A sulfonamide (compound) is a chemical compound that contains this group. The general formula is R−SO₂NR'R" or R−S(=O)₂−NR'R", where each R is some organic group; for example, "methanesulfonamide" (where R = methane, R' = R" = hydrogen) is CH₃SO₂NH₂. Any sulfonamide can be considered as derived from a sulfonic acid by replacing a hydroxyl group (−OH) with an amine group.

In medicine, the term "sulfonamide" is sometimes used as a synonym for sulfa drug, a derivative or variation of sulfanilamide. The first sulfonamide was discovered in Germany in 1932. ^[2]

Synthesis and reactions

Sulfonamides can be prepared in the laboratory in many ways. The classic approach entails the reaction of sulfonyl chlorides with an amine. ^{[ citation needed ]}

RSO₂Cl + R'₂NH → RSO₂NR'₂ + HCl

A base such as pyridine is typically added to absorb the HCl that is generated. Illustrative is the synthesis of sulfonylmethylamide. ^[3] The reaction of primary and secondary amines with benzenesulfonyl chloride is the basis of the Hinsberg reaction, a method for detecting primary and secondary amines.

Sulfonamides undergo a variety of acid-base reactions. The N-H bond can be deprotonated. The alkylsulfonamides can be deprotonated at carbon. Arylsulfonamides undergo ortho-lithiation. ^[4]

Sultams

"Sultam" redirects here and is not to be confused with Sultan.

Sultams are cyclic sulfonamides. Bioactive sultams include the antiinflammatory ampiroxicam and the anticonvulsant sulthiame. Sultams are prepared analogously to other sulfonamides, allowing for the fact that sulfonic acids are deprotonated by amines. They are often prepared by one-pot oxidation of disulfides or thiols linked to amines. ^[5] An alternative synthesis of sultams involves initial preparation of a linear sulfonamide, followed by intramolecular C-C bond formation (i.e. cyclization), a strategy that was used in the synthesis of a sultam-based deep-blue emitter for organic electronics. ^[6]

• Sulfonamide-based compounds
• 
  Saccharin, a cyclic sulfonamide that was one of the first artificial sweeteners discovered
• 
  Sulfanilamide, a compound that foreshadowed the development of sulfa drugs
• 
  Sulfamethoxazole is a widely used antibiotic.
• 
  Ampiroxicam is a sultam used as an antiinflammatory drug.
• 
  Hydrochlorothiazide is a drug that features both acyclic and cyclic sulfonamide groups.
• 
  Camphorsultam is a sultam used as a chiral auxiliary in organic synthesis.

Disulfonimides

The disulfonimides are of the type R−S(=O)₂−N(H)−S(=O)₂−R' with two sulfonyl groups flanking an amine. ^[7] As with sulfinamides, this class of compounds is used as catalysts in enantioselective synthesis. ^{[7] [8] [9]}

Bis(trifluoromethanesulfonyl)aniline is a source of the triflyl (CF₃SO+2) group.

See also

• Sulfamide  — the sulfonamide parent compound
• Sulfamic acid  — HOSO₂NH₂
• Sulfinamide  — compounds of the form RS(=O)NR′R″

References

1. Actor, P.; Chow, A. W.; Dutko, F. J.; McKinlay, M. A. "Chemotherapeutics". Ullmann's Encyclopedia of Industrial Chemistry . Weinheim: Wiley-VCH. doi:10.1002/14356007.a06_173. ISBN   978-3-527-30673-2.
2. Levy, Stuart B. (2002). The antibiotic paradox : how the misuse of antibiotics destroys their curative powers (2 ed.). Cambridge, Massachusetts: Perseus Publ. p. 51. ISBN   9780738204406.
3. de Boer, Th. J.; Backer, H. J. (1954). "p-Toluenesulfonylnitrosamide". Org. Synth. 34: 96. doi:10.15227/orgsyn.034.0096.
4. Tanaka, Kazuhiko (1991). "Sulfonic Acids, Esters, Amides and Halides as Synthons". In Saul Patai, Zvi Rappoport (ed.). Sulphonic Acids, Esters and their Derivatives (1991). PATAI'S Chemistry of Functional Groups. pp. 401–452. doi:10.1002/0470034394.ch11. ISBN   978-0-470-03439-2.
5. Rassadin, V.; Grosheva, D.; Tomashevskii, A. Sokolov, V. "Methods of Sultam Synthesis" Chemistry of Heterocyclic Compounds 2013, Vol. 49, p39-65. 27. doi : 10.1007/s10593-013-1231-3.
6. Virk, Tarunpreet Singh; Ilawe, Niranjan V.; Zhang, Guoxian; Yu, Craig P.; Wong, Bryan M.; Chan, Julian M. W. (2016). "Sultam-Based Hetero[5]helicene: Synthesis, Structure, and Crystallization-Induced Emission Enhancement". ACS Omega. 1 (6): 1336–1342. doi:10.1021/acsomega.6b00335. PMC   6640820 . PMID   31457199.
7. James, Thomas; van Gemmeren, Manuel; List, Benjamin (2015). "Development and Applications of Disulfonimides in Enantioselective Organocatalysis". Chem. Rev. 115 (17): 9388–9409. doi:10.1021/acs.chemrev.5b00128. PMID   26147232.
8. Treskow, M.; Neudörfl, J.; Giernoth, R. (2009). "BINBAM – A New Motif for Strong and Chiral Brønsted Acids". Eur. J. Org. Chem. 2009 (22): 3693–3697. doi:10.1002/ejoc.200900548.
9. García-García, P.; Lay, F.; García-García, P.; Rabalakos, C.; List, B. (2009). "A Powerful Chiral Counteranion Motif for Asymmetric Catalysis". Angew. Chem. Int. Ed. 48 (24): 4363–4366. doi: 10.1002/anie.200901768 . hdl: 10251/65104 . PMID   19437518.

Further reading

• Greenwood, David. Antimicrobial Drugs: Chronicle of a twentieth century medical triumph (Oxford University Press, 2008) popular history; summary