Thiocarboxylic acid explained

In organic chemistry, thiocarboxylic acids or carbothioic acids are organosulfur compounds related to carboxylic acids by replacement of one of the oxygen atoms with a sulfur atom. Two tautomers are possible: a thione form and a thiol form .^{[1] [2]} These are sometimes also referred to as "carbothioic O-acid" and "carbothioic S-acid" respectively. Of these the thiol form is most common (e.g. thioacetic acid).

Thiocarboxylic acids are rare in nature, however the biosynthetic components for producing them appear widespread in bacteria.^[3] Examples include pyridine-2,6-dicarbothioic acid,^[4] and thioquinolobactin.^[3]

Synthesis

Thiocarboxylic acids are typically prepared by salt metathesis from the acid chloride, as in the following conversion of benzoyl chloride to thiobenzoic acid using potassium hydrosulfide according to the following idealized equation:^[5]

Covalent sulfides, such as P₂S₅, generally give poor yields unless catalyzed with triphenylstibine oxide.^[6]

2,6-Pyridinedicarbothioic acid is synthesized by treating the diacid dichloride with a solution of H₂S in pyridine:

This reaction produces the orange pyridinium salt of pyridinium-2,6-dicarbothioate. Treatment of this salt with sulfuric acid gives colorless the bis(thiocarboxylic acid), which can then be extracted with dichloromethane.^[7]

Reactions

At neutral pH, thiocarboxylic acids are fully ionized. Thiocarboxylic acids are about 100 times more acidic than the analogous carboxylic acids. Thiobenzoic acid has a pK_a of 2.48 compared with 4.20 for benzoic acid, and thioacetic acid has a pK_a near 3.4 compared with 4.72 for acetic acid.^[8] Alkylation of the corresponding thioate ion gives a thioester.^[9]

The conjugate base of thioacetic acid, thioacetate, is a reagent used for installing thiol groups via the displacement of alkyl halides by a two-step process. The halide is displaced to give a thioester intermedate, which is then hydrolyzed:

Thiocarboxylic acids react with various nitrogen functional groups, such as organic azide, nitro, and isocyanate compounds, to give amides under mild conditions.^{[10] [11]} This method avoids needing a highly nucleophilic aniline or other amine to initiate an amide-forming acyl substitution, but requires synthesis and handling of the unstable thiocarboxylic acid.^[11] Unlike the Schmidt reaction or other nucleophilic-attack pathways, reaction with an aryl or alkyl azide begins with a [3+2] cycloaddition. The resulting heterocycle expels N₂ and the sulfur atom to give the monosubstituted amide.^[10]

Halogens or their equivalents (e.g. sulfuryl chloride) oxidize thiocarboxylic acids to acylsulfenyl halides. The latter are unstable, and decay over the course of several hours to the free halogen and the diacyl disulfide.^[12]

See also

• Dithiocarboxylic acid
• Thiocarbamate
• Thiocarbonate
• Thiocarbonic acid

Notes and References

1. Book: Cremlyn. R.J.. An introduction to organosulfur chemistry. 1996. Wiley. Chichester. 0-471-95512-4.
2. Book: Carboxylic Acids and Esters. Thiolo, Thiono and Dithio Acids and Esters. Matthys J. Janssen. Saul Patai. 1969. 10.1002/9780470771099.ch15. PATAI'S Chemistry of Functional Groups. 705–764 . 978-0-470-77109-9 .
3. 10.1038/s41467-018-04747-y . Biosynthesis of thiocarboxylic acid-containing natural products . 2018 . Dong . Liao-Bin . Rudolf . Jeffrey D. . Kang . Dingding . Wang . Nan . He . Cyndi Qixin . Deng . Youchao . Huang . Yong . Houk . K. N. . Duan . Yanwen . Shen . Ben . Nature Communications . 9 . 2362 . 29915173 . 2018NatCo...9.2362D . 6006322 .
4. Book: Budzikiewicz, Herbert . 10.1007/978-3-211-99661-4_1 . 2010 . Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products, Vol. 92 . A. Douglas . Kinghorn . Heinz . Falk . Junichi . Kobayashi . 92 . Progress in the Chemistry of Organic Natural Products . Microbial Siderophores . 1–75 . 20198464 . 978-3-211-99660-7.
5. Paul . Noble, Jr. . D. S. . Tarbell . Thiobenzoic Acid . Organic Syntheses . 32 . 101 . 1952 . 10.15227/orgsyn.032.0101.
6. Book: Collier, S. J. . Category 3, Compounds with Four and Three Carbon Heteroatom Bonds: Three Carbon—Heteroatom Bonds: Esters, and Lactones; Peroxy Acids and R(CO)OX Compounds; R(CO)X, X=S, Se, Te . 2007 . Georg Thieme Verlag . 978-3-13-144691-6 . Panek . J. S. . Science of Synthesis . Stuttgart . 1600 . en . Product class 8: Thiocarboxylic S-acids, selenocarboxylic Se-acids, tellurocarboxylic Te-acids, and derivatives . 10.1055/sos-sd-020-01480.
7. 10.1080/03086648308080490 . Zur Struktur Eines 1:1-Adduktes von Pyridin-2,6-Dicarbothiosäure und Pyridin . 1983 . Hildebrand . U. . Ockels . W. . Lex . J. . Budzikiewicz . H. . Phosphorus and Sulfur and the Related Elements . 16 . 3 . 361–364 .
8. Book: M. R. Crampton. 402. Acidity and hydrogen-bonding. The Chemistry of the Thiol Group. Saul Patai. 1974. John Wiley & Sons Ltd. Chichester.
9. Matthys J. Janssen "Carboxylic Acids and Esters" in PATAI's Chemistry of Functional Groups: Carboxylic Acids and Esters, Saul Patai, Ed. John Wiley, 1969, New York: pp. 705–764.
10. Book: 21.1.2.6.1: Variation 1: From thiocarboxylic acids . 52–54 . Science of Synthesis: Houben–Weyl Methods of Molecular Transformations . 21: Three Carbon-Heteroatom Bonds: Amides and Derivatives; Peptides; Lactams . Georg Thieme Verlag . 2005 . 978-3-13-171951-5.
11. Chem. Sci. . 2016 . 7 . 713–718 . Base-catalyzed synthesis of aryl amides from aryl azides and aldehydes . Sheng . Xie . Yang . Zhang . Olof . Ramström . Mingdi . Yan . 1 . 10.1039/C5SC03510D . 29896355 . 5952891.
12. Book: Comprehensive Organic Functional Group Transformations. 5. Christopher J.. Moody. Pergamon. Oxford, UK. 1995. 95-31088. 0-08-042326-4. Acylsulfur, -selenium, or -tellurium functions. Ogawa Akiya. Sonoda Noboru. 244-246.