Hippuric acid

Synthesis

A modern synthesis of hippuric acid involves the acylation of glycine with benzoyl chloride ("Schotten–Baumann reaction"). :[[File:Hippuric acid Schotten-Baumann.svg|400px]]

Physiology

Biochemically, hippuric acid is produced from benzoic acid and glycine, which occurs in the liver, intestine, and kidneys. In terms of mechanism, benzoic acid is converted to benzoyl CoA, an acylating agent.

Hippuric acid may be formed from the essential amino acid phenylalanine through at least two pathways. Phenylalanine undergoes biotransformation to form an alpha-keto acid, phenylpyruvic acid, which can tautomerize to a reactive enol. The benzylic carbon is reactive which undergoes peroxidation followed by the competing pathways to either react with the alpha carbon subsequently form an dioxetanol intermediate followed by formation of oxalic acid and benzaldehyde, or, peroxidation can react with the carboxyl group to form an alpha-keto-beta-peroxylactone intermediate followed by formation of carbon monoxide, carbon dioxide, and benzaldehyde. Alternatively, under certain conditions, phenylpyruvic acid may undergo a redox mechanism, such as Iron(II) donating an electron, to directly release carbon dioxide, followed by carbon monoxide, for the formation of a stable toluene radical which is resolved by an antioxidant such as ascorbate. In all of the aforementioned cases, benzaldehyde undergoes biotransformation via CYP450 to benzoic acid followed by conjugation to glycine for formation of hippurate which undergoes urinary excretion. Similarly, toluene reacts with CYP450 to form benzaldehyde.

Hippuric acid has been reported to be a marker for Parkinson's disease.

Reactions

Hippuric acid is readily hydrolysed by hot caustic alkalis to benzoic acid and glycine. Nitrous acid converts it into benzoyl glycolic acid, C6H5C(=O)OCH2CO2H. Its ethyl ester reacts with hydrazine to form hippuryl hydrazine, C6H5CONHCH2CONHNH2, which was used by Theodor Curtius for the preparation of hydrazoic acid.

Hippuric acid has also been used in Erlenmeyer–Plöchl synthesis of phenylalanine and other amino acids, the reaction proceeding via an oxazolone or "azlactone" intermediate.

History

Justus von Liebig showed in 1829 that hippuric acid differed from benzoic acid and he named it, and in 1834 he determined its constitution, while in 1853 French chemist Victor Dessaignes (1800–1885) synthesized it by the action of benzoyl chloride on the zinc salt of glycine.{{cite journal |trans-title=On the regeneration of hippuric acid |trans-title=Synthesis of hippuric acid and hippuric acid esters

References

References

1. "Showing metabocard for Hippuric acid (HMDB0000714)".
2. {{EB1911
3. (2010). "Health consequences of catabolic synthesis of hippuric acid in humans". Current Clinical Pharmacology.
4. (1932). "Hippuric acid".
5. (March 2009). "Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites". Proc. Natl. Acad. Sci. U.S.A..
6. (1994). "Glycine Conjugation Activity of Benzoic Acid and its Acinar Localization in the Perfused Rat Liver". The Journal of Pharmacology and Experimental Therapeutics.
7. (2020-12-23). "Role of Carbon Monoxide in Host–Gut Microbiome Communication". Chemical Reviews.
8. (2021). "A brief history of carbon monoxide and its therapeutic origins". Nitric Oxide.
9. (20 March 2019). "Parkinson's smell test explained by science". BBC.
10. (1829). "Ueber die Säure, welche in dem Harn der grasfressenden vierfüssigen Thiere enthalten ist". Annalen der Physik und Chemie.
11. Liebig, Justus (1834) [https://babel.hathitrust.org/cgi/pt?id=umn.31951d00316737j;view=1up;seq=587 "Ueber die Zusammensetzung der Hippursäure"] (On the composition of hippuric acid), ''Annalen der Physik und Chemie'', '''32''' : 573–574.