Thioamide

File:Thioamide.png

General structure of a thioamide

A thioamide (rarely, thionamide, but also known as thiourylenes) is a functional group with the general structure Template:Chem2, where Template:Chem2 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.

Synthesis

Thioamides are typically prepared by treating amides with phosphorus sulfides such as phosphorus pentasulfide, a reaction first described in the 1870s. An alternative to P₂S₅ is its more soluble analogue Lawesson's reagent. The Willgerodt-Kindler reaction can give benzylthioamides via an analogous process. These transformations can be seen in the synthesis of tolrestat.

File:Tolrestat synthesis.svg

The reaction of nitriles with hydrogen sulfide also affords thioamides:

Thionamide Synthesis

Imidoyl chlorides react with hydrogen sulfide to produce thioamides.

File:Reaktion Imidchloride und Hydrogensulfid.svg

Reactions

A well-known thioamide is thioacetamide, which is used as a source of the sulfide ion.

Thioamides are precursors to heterocycles. Such approaches often exploit the nucleophilicity of the thione-like sulfur.

Structure

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.

Template:Chem2 ↔ Template:Chem2

Some thioamides exhibit the phenomenon of atropisomerism, reflecting the partial double bond character of their C-N bonds.

Thioamides in biochemistry and medicine

Thioamides 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. 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.