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]

General structure of a thioamide

Synthesis

Thioamides 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, in 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

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

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

Thioamides have been incorporated into peptides as isosteres for the amide bond.^[14] 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.

Some herbicides are contain thioamide groups.^[6]: 463

Thioamides are a class of anti-thyroid drugs used to control thyrotoxicosis. 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.