Thioamide
A thioamide (rarely, thionamide, but also known as thiourylenes) is a functional group with the general structure R1−C(=S)−NR2R3, where R1, R2 and R3 are any groups (typically organyl groups or hydrogen). Analogous to amides, thioamides exhibit greater multiple bond character along the C-N bond, resulting in a larger rotational barrier.[1]
Synthesis
[edit]Thioamides are typically prepared by treating amides with phosphorus pentasulfide, a reaction first described in the 1870s.[2][3] An alternative to P2S5 is its more soluble analogue Lawesson's reagent.[4] These transformations can be seen in the synthesis of tolrestat.
Specialized methods
[edit]The Willgerodt-Kindler reaction provides a route to thioamides from aryl-alkyl ketones.[5]
Nitriles react with hydrogen sulfide to afford thioamides. The reaction can be catalyzed by both base and acid:[6]: 415–417
Imidoyl chlorides react with hydrogen sulfide to produce thioamides.
Thioacylation is possible, but not with thioic acids, as amines preferentially displace the sulfur. Thionoesters form amidines with primary amines, but thioacylate secondary amines perfectly well.[6]: 420–421 Thioketenes, dithiocarboxylic acids, and their thioesters attack amines of all sorts to give thioamides. The aryl acids react slowly, but much faster with a Hauser base.[6]: 421–423 Trans-thioamidation is also possible, especially from a thiourea.[6]: 422–423 Carbon acids attack isothiocyanates to give thioamides.[6]: 424–426
Reactions
[edit]In the presence of silver and mercury salts, thioamides characteristally hydrolyze to give the amide:[7]
- RC(S)NH2 + H2O + Hg(O2CCH3)2 → RC(O)NH2 + 2 HO2CCH3 + HgS
In qualitative inorganic analysis, thioacetamide is in fact used as a source of the sulfide ion.
Thioamides are Brønsted amphoteric, protonating at S and deprotonating at N or the α carbon.[6]: 436, 458 Strong nucleophiles may displace either substituent at the electrophilic carbon atom.[6]: 439–441
Conversely, electrophiles typically attack at N. Alkyl halides and alcohols attack either S or N, but often rearrange to a net S-alkylation.[6]: 442–448 For example, the thioamide of azetidine slowly rearranges to the 1,3‑thiazadihydrothiazine.[8]
More easily than the corresponding amides, thioamides oxidize and reduce.[6]: 441, 449 Although reduction with Raney nickel is popular, the reaction requires stoichiometric nickel, because the sulfur will poison any hydrogenation catalyst.[6]: 441–442 Oxidation does not proceed past the quasi-sulfine.[6]: 450–451
Thioamides are precursors to heterocycles.[9] Such approaches often exploit the nucleophilicity of the thione-like sulfur.[10]
Structure
[edit]The C(R)(N)(S) core of thioamides is planar. Using thioacetamide as representative: the C-S, C-N, and C-C distances are 1.68, 1.31, and 1.50 Å, respectively. The short C-S and C-N distances indicate multiple bonding.[11]
- RC(=S)NR'2 ↔ RC(−S−)=N+R'2
Nevertheless, thioamides do not protrope or form zwitterions,[6][page needed] unless the one of the R′ groups is an electron-donating heteroatom (e.g., in a thio-hydrazide).[12]
Some thioamides exhibit the phenomenon of atropisomerism, reflecting the partial double bond character of their C-N bonds.[13]
In biochemistry and medicine
[edit]
.
Thiopurines, mimics of purines, are used to treat a number of autoimmune diseases. Some thioamides are used to control thyrotoxicosis. They inhibit the enzyme thyroid peroxidase in the thyroid, suppressing the synthesis of triiodothyronine (T3) and thyroxine (T4), thereby blocking uptake of iodotyrosines from the colloid. They also block iodine release from peripheral hormone.
Thioamides have been incorporated into peptides as isosteres for the amide bond. Natural examples include the polythioamides: thioviridamide, thioholgamide A, and closthioamide.[14]
Some herbicides are contain thioamide groups.[6]: 463
Related compounds
[edit]Thioureass are a subset of thioamides. Some are items of commerce and some are bioactive.
Selenoamides are analogues of thioamides but with Se in place of S. They are uncommon.
References
[edit]- ^ Wiberg, Kenneth B.; Rablen, Paul R. (1995). "Why Does Thioformamide Have a Larger Rotational Barrier Than Formamide?". J. Am. Chem. Soc. 117 (8): 2201–2209. doi:10.1021/ja00113a009.
- ^ "Preparation of Thiamides". Journal of the Chemical Society, Abstracts. 34: 396. 1878. doi:10.1039/CA8783400392.
- ^ Gompper, R.; Elser, W. (1973). "2-Methylmercapto-N-Methyl-Δ2-Pyrroline". Organic Syntheses; Collected Volumes, vol. 5, p. 780.
- ^ Shabana, R.; Scheibye, S.; Clausen, K.; Olesen, S.O.; Lawesson, S.-O. (1980). "Studies on Organophosphorus Compounds XXXI. Synthesis of Thiolactams and Thioimides". Nouveau Journal de Chimie. 1980 (4): 47.
- ^ Rolfs, Andreas; Liebscher, Jürgen (1997). "3-Morpholino-2-Phenylthioacrylic Acid Morpholide and 5-(4-Bromobenzoyl-2-(4-Morpholino)-3-Phenylthiophene". Organic Syntheses. 74: 257. doi:10.15227/orgsyn.074.0257.
- ^ a b c d e f g h i j k l m Walter, W.; Voss, J. (1970). "The chemistry of thioamides". In Zabicky, Jacob (ed.). The Chemistry of Amides. The Chemistry of Functional Groups. London: Interscience (Wiley). pp. 383–475. doi:10.1002/9780470771235. ISBN 0-471-98049-8. LCCN 76-116520.
- ^ Corsaro, Antonino; Pistarà, Venerando (1998). "Conversion of the thiocarbonyl group into the carbonyl group". Tetrahedron. 54 (50): 15027–15062. doi:10.1016/S0040-4020(98)00880-1.
- ^ Potts KT, Sapino C (1972). "Thiocarbonyl halides". In Saul Patai (ed.). Acyl Halides. The Chemistry of Functional Groups. p. 369. doi:10.1002/9780470771273.ch11. ISBN 9780470771273.
- ^ Jagodziński, Tadeusz S. (2003). "Thioamides as Useful Synthons in the Synthesis of Heterocycles". Chemical Reviews. 103 (1): 197–228. doi:10.1021/cr0200015. PMID 12517184.
- ^ Schwarz, George (1945). "2,4-Dimethylthiazole". Organic Syntheses. 25: 35. doi:10.15227/orgsyn.025.0035.
- ^ Trevor W. Hambley; David E. Hibbs; Peter Turner; Siân. T. Howard; Michael B. Hursthouse (2002). "Insights into Bonding and Hydrogen Bond Directionality in Thioacetamide from the Experimental Charge Distribution". J. Chem. Soc., Perkin Trans. (2): 235–239. doi:10.1039/B109353C.
- ^ Walter, W.; Reubke, K. J. (1970). "The chemistry of thiohydrazides". In Zabicky, Jacob (ed.). The Chemistry of Amides. The Chemistry of Functional Groups. London: Interscience (Wiley). p. 497. doi:10.1002/9780470771235. ISBN 0-471-98049-8. LCCN 76-116520.
- ^ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, p. 184, ISBN 978-0-471-72091-1
- ^ Huang, Guang; Cierpicki, Tomasz; Grembecka, Jolanta (2024). "Thioamides in medicinal chemistry and as small molecule therapeutic agents". European Journal of Medicinal Chemistry. 277 116732. doi:10.1016/j.ejmech.2024.116732. PMC 12009601. PMID 39106658.