Thiocarboxylic acid

Thione form (carbothioic O-acid)
Thiol form (carbothioic S-acid)

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 (RC(S)OH) and a thiol form (RC(O)SH).[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]

C6H5C(O)Cl + KSH → C6H5C(O)SH + KCl

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:

NC5H3(COCl)2 + 2 H2S + 2 C5H5N → [C5H5NH+][HNC5H3(COS)−2] + [C5H5NH]Cl

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 pKa of 2.48 compared with 4.20 for benzoic acid, and thioacetic acid has a pKa 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 intermediate, which is then hydrolyzed:

R−X + CH3COS− → R−SC(O)CH3 + X−
R−SC(O)CH3 + H2O → R−SH + CH3CO2H

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 the amine to initiate an amide-forming acyl substitution but does 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][12]


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.[13]

See also

References

  1. ^ Cremlyn, R.J. (1996). An introduction to organosulfur chemistry. Chichester: Wiley. ISBN 0-471-95512-4.
  2. ^ Matthys J. Janssen (1969). "Thiolo, Thiono and Dithio Acids and Esters". In Saul Patai (ed.). Carboxylic Acids and Esters. PATAI'S Chemistry of Functional Groups. pp. 705–764. doi:10.1002/9780470771099.ch15. ISBN 978-0-470-77109-9.
  3. ^ a b Dong, Liao-Bin; Rudolf, Jeffrey D.; Kang, Dingding; Wang, Nan; He, Cyndi Qixin; Deng, Youchao; Huang, Yong; Houk, K. N.; Duan, Yanwen; Shen, Ben (2018). "Biosynthesis of thiocarboxylic acid-containing natural products". Nature Communications. 9: 2362. Bibcode:2018NatCo...9.2362D. doi:10.1038/s41467-018-04747-y. PMC 6006322. PMID 29915173.
  4. ^ Budzikiewicz, Herbert (2010). "Microbial Siderophores". In Kinghorn, A. Douglas; Falk, Heinz; Kobayashi, Junichi (eds.). Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products, Vol. 92 [Progress in the Chemistry of Organic Natural Products]. Vol. 92. pp. 1–75. doi:10.1007/978-3-211-99661-4_1. ISBN 978-3-211-99660-7. PMID 20198464.
  5. ^ Noble, Jr., Paul; Tarbell, D. S. (1952). "Thiobenzoic Acid". Organic Syntheses. 32: 101. doi:10.15227/orgsyn.032.0101.
  6. ^ Collier, S. J. (2007). "Product class 8: Thiocarboxylic S-acids, selenocarboxylic Se-acids, tellurocarboxylic Te-acids, and derivatives". In Panek, J. S. (ed.). 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. Science of Synthesis. Stuttgart: Georg Thieme Verlag. p. 1600. doi:10.1055/sos-sd-020-01480. ISBN 978-3-13-144691-6.
  7. ^ Hildebrand, U.; Ockels, W.; Lex, J.; Budzikiewicz, H. (1983). "Zur Struktur Eines 1:1-Adduktes von Pyridin-2,6-Dicarbothiosäure und Pyridin". Phosphorus and Sulfur and the Related Elements. 16 (3): 361–364. doi:10.1080/03086648308080490.
  8. ^ M. R. Crampton (1974). "Acidity and hydrogen-bonding". In Saul Patai (ed.). The Chemistry of the Thiol Group. Chichester: John Wiley & Sons Ltd. p. 402.
  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. doi:10.1002/9780470771099.ch15
  10. ^ a b "21.1.2.6.1: Variation 1: From Thiocarboxylic Acids". Science of Synthesis: Houben–Weyl Methods of Molecular Transformations. Vol. 21: Three Carbon-Heteroatom Bonds: Amides and Derivatives, Peptides, Lactams. Georg Thieme Verlag. 2005. pp. 52–54. ISBN 978-3-13-171951-5.
  11. ^ a b Xie, Sheng; Zhang, Yang; Ramström, Olof; Yan, Mingdi (2016). "Base-catalyzed synthesis of aryl amides from aryl azides and aldehydes". Chem. Sci. 7 (1): 713–718. doi:10.1039/C5SC03510D. PMC 5952891. PMID 29896355.
  12. ^ Shangguan, Ning; Katukojvala, Sreenivas; Greenberg, Rachel; Williams, Lawrence J. (2003). "The Reaction of Thio Acids with Azides: A New Mechanism and New Synthetic Applications". Journal of the American Chemical Society. 125 (26): 7754–7755. Bibcode:2003JAChS.125.7754S. doi:10.1021/ja0294919. PMID 12822965.
  13. ^ Ogawa Akiya; Sonoda Noboru (1995). "Acylsulfur, -selenium, or -tellurium functions". In Moody, Christopher J. (ed.). Comprehensive Organic Functional Group Transformations. Vol. 5. Oxford, UK: Pergamon. pp. 244–246. ISBN 0-08-042326-4. LCCN 95-31088.