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
editThioamides are typically prepared by treating amides with phosphorus sulfides such as phosphorus pentasulfide, a reaction first described in the 1870s.[2][3] An alternative to P2S5 is its more soluble analogue Lawesson's reagent.[4] The Willgerodt-Kindler reaction can give benzylthioamides via an analogous process.[5] These transformations can be seen in the synthesis of tolrestat.
The reaction of nitriles with hydrogen sulfide also affords thioamides:
Imidoyl chlorides react with hydrogen sulfide to produce thioamides.
Reactions
editA well-known thioamide is thioacetamide, which is used as a source of the sulfide ion.
Thioamides are precursors to heterocycles.[6] Such approaches often exploit the nucleophilicity of the thione-like sulfur.[7]
Structure
editThe 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.[8]
- RC(=S)NR'2 ↔ RC(−S−)=N+R'2
Some thioamides exhibit the phenomenon of atropisomerism, reflecting the partial double bond character of their C-N bonds.[9]
Thioamides in biochemistry and medicine
editThioamides or anti-thyroid drugs are also a class of drugs that are used to control thyrotoxicosis.
Thioamides have been incorporated into peptides as isosteres for the amide bond.[10] Peptide modifications are analogues of the native peptide, which can reveal the structure-activity relationship (SAR). Analogues of peptides can also be used as drugs with an improved oral bioavailability.
Thioamides inhibit the enzyme thyroid peroxidase in the thyroid, reducing the synthesis of triiodothyronine (T3) and thyroxine (T4), thereby blocking uptake of iodotyrosines from the colloid. They also block iodine release from peripheral hormone. Maximum effects occur only after a month, since hormone depletion is caused by reduced synthesis, which is a slow process.
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.
- ^ Jagodziński, Tadeusz S. (2003). "Thioamides as Useful Synthons in the Synthesis of Heterocycles". Chemical Reviews. 103: 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.
- ^ 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
- ^ Artis, Dean R.; Lipton, Mark A. (1998). "Conformations of Thioamide-Containing Dipeptides: A Computational Study". J. Am. Chem. Soc. 120 (47): 12200–12206. doi:10.1021/ja982398t.