Hippuric acid
{{chembox
| Watchedfields = changed
| verifiedrevid = 443857913
| ImageFile = Hippuric acid.svg
| ImageAlt = Structural formula of hippuric acid
| ImageFile1 = Hippuric acid.jpg
| ImageAlt1 = Recrystallised hippuric acid
| IUPACName = N-Benzoylglycine
| PIN = Benzamidoacetic acid
| OtherNames = {{ubl|Hippuric acid|Benzoyl glycocoll|Benzoyl amidoacetic acid}}
| Section1 = {{Chembox Identifiers
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = TE0865N2ET
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C01586
| InChI = 1/C9H9NO3/c11-8(12)6-10-9(13)7-4-2-1-3-5-7/h1-5H,6H2,(H,10,13)(H,11,12)
| InChIKey = QIAFMBKCNZACKA-UHFFFAOYAD
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 461
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C9H9NO3/c11-8(12)6-10-9(13)7-4-2-1-3-5-7/h1-5H,6H2,(H,10,13)(H,11,12)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = QIAFMBKCNZACKA-UHFFFAOYSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 495-69-2
| PubChem = 464
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID =451
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 18089
| SMILES = OC(=O)CNC(=O)c1ccccc1
}}
| Section2 = {{Chembox Properties
| C=9 | H=9 | N=1 | O=3
| Appearance =
| Density = 1.371 g/cm3
| MeltingPtC = 187 to 188
| MeltingPt_notes =
| BoilingPtC = 240
| BoilingPt_notes = (decomposes)
| Solubility =
}}
| Section3 = {{Chembox Hazards
| ExternalSDS = [http://fscimage.fishersci.com/msds/62353.htm Material Safety Data Sheet]
| MainHazards =
| FlashPt =
| AutoignitionPt =
}}
}}
Hippuric acid (Gr. hippos, horse, ouron, urine) is a carboxylic acid and organic compound. It is found in urine and is formed from the combination of benzoic acid and glycine. Levels of hippuric acid rise with the consumption of phenolic compounds (such as in fruit juice, tea, and wine). The phenols are first converted to benzoic acid, and then to hippuric acid and excreted in urine.{{cite HMDB|author1-link=David S. Wishart|url=http://www.hmdb.ca/metabolites/HMDB0000714|title=Showing metabocard for Hippuric acid (HMDB0000714)}}
Hippuric acid crystallizes in rhombic prisms which are readily soluble in hot water, melt at 187 °C, and decompose at about 240 °C.{{EB1911|inline=y|wstitle=Hippuric Acid|volume=13|page=523}} High concentrations of hippuric acid may also indicate a toluene intoxication, however, scientists have called this correlation into question, because there are other variables that affect levels of hippuric acid.{{cite journal|pmid=19891605|year=2010|last1=Pero|first1=RW|title=Health consequences of catabolic synthesis of hippuric acid in humans|volume=5|issue=1|pages=67–73|journal=Current Clinical Pharmacology|doi=10.2174/157488410790410588}} When many aromatic compounds such as benzoic acid and toluene are taken internally, they are converted to hippuric acid by reaction with the amino acid glycine.
Synthesis
A modern synthesis of hippuric acid involves the acylation of glycine with benzoyl chloride ("Schotten–Baumann reaction").{{OrgSynth | title = Hippuric acid | collvol = 2 | year = 1932 | volume = 12 | pages = 40 | collvolpages = 328 | prep = cv2p0328 | first1 = A. W. | last1 = Ingersoll | first2 = S. H. | last2 = Babcock | doi = 10.15227/orgsyn.012.0040}}
Physiology
Biochemically, hippuric acid is produced from benzoic acid and glycine, which occurs in the liver, intestine, and kidneys.{{cite journal | vauthors = Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G|author-link7=Gary Siuzdak | title = Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 10 | pages = 3698–3703 | date = March 2009 | pmid = 19234110 | pmc = 2656143 | doi = 10.1073/pnas.0812874106|doi-access=free |bibcode=2009PNAS..106.3698W }} In terms of mechanism, benzoic acid is converted to benzoyl CoA, an acylating agent.{{cite journal |pmid=8301581 |date=1994 |last1=Chiba |first1=M. |last2=Poon |first2=K. |last3=Hollands |first3=J. |last4=Pang |first4=K. S. |title=Glycine Conjugation Activity of Benzoic Acid and its Acinar Localization in the Perfused Rat Liver |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=268 |issue=1 |pages=409–416 }}
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.{{Cite journal|last1=Hopper|first1=Christopher P.|last2=De La Cruz|first2=Ladie Kimberly|last3=Lyles|first3=Kristin V.|last4=Wareham|first4=Lauren K.|last5=Gilbert|first5=Jack A.|last6=Eichenbaum|first6=Zehava|last7=Magierowski|first7=Marcin|last8=Poole|first8=Robert K.|last9=Wollborn|first9=Jakob|last10=Wang|first10=Binghe|date=2020-12-23|title=Role of Carbon Monoxide in Host–Gut Microbiome Communication|journal=Chemical Reviews|language=en|volume=120|issue=24|pages=13273–13311|doi=10.1021/acs.chemrev.0c00586|pmid=33089988 |s2cid=224824871 |issn=0009-2665}} Similarly, toluene reacts with CYP450 to form benzaldehyde.{{Cite journal|last1=Hopper|first1=Christopher P.|last2=Zambrana|first2=Paige N.|last3=Goebel|first3=Ulrich|last4=Wollborn|first4=Jakob|date=2021|title=A brief history of carbon monoxide and its therapeutic origins|journal=Nitric Oxide|language=en|volume=111-112|pages=45–63|doi=10.1016/j.niox.2021.04.001 |pmid=33838343 |s2cid=233205099 |issn=1089-8603}}
Hippuric acid has been reported to be a marker for Parkinson's disease.{{cite news |title=Parkinson's smell test explained by science |url=https://www.bbc.com/news/uk-scotland-47627179 |access-date=11 March 2023 |work=BBC News |publisher=BBC |date=20 March 2019}}
Reactions
Hippuric acid is readily hydrolysed by hot caustic alkalis to benzoic acid and glycine. Nitrous acid{{Contradictory inline|Glycolic acid#History|reason=Possible contradiction, the other article claims nitric acid and nitrogen dioxide.}} 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,{{cite journal |last1=Liebig |first1=Justus |title=Ueber die Säure, welche in dem Harn der grasfressenden vierfüssigen Thiere enthalten ist |journal=Annalen der Physik und Chemie |date=1829 |volume=17 |issue=11 |pages=389–399 |doi=10.1002/andp.18290931104 |bibcode=1829AnP....93..389L |url=https://zenodo.org/record/1883346 |trans-title=On the acid which is contained in the urine of grass-eating, four-footed animals |language=German}} Liebig named hippuric acid on p. 390: "Da ich die Säure aus dem Pferdeharn vorzugsweise untersucht habe, so werde ich sie, in Ermanglung eines passenderen Namens, mit Hippursäure bezeichnen." (Since I have especially investigated the acid from horse urine, then, for want of a more suitable name, I will designate it with [the name] "hippuric acid".) and in 1834 he determined its constitution,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. 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
| title = Ueber die Regeneration der Hippursäure
|trans-title=On the regeneration of hippuric acid
| author = Dessaignes V.
| journal = Annalen der Chemie und Pharmacie
| volume = 87
| issue = 3
| pages = 325–327
| year = 1853
| url = https://zenodo.org/records/1427048/files/article.pdf
| doi = 10.1002/jlac.18530870311}} See also: Dessaignes (1853) [http://gallica.bnf.fr/ark:/12148/bpt6k29948/f255.item.zoom "Note sur la régénération de l'acide hipparique,"] Comptes rendus, 37 : 251–252. It was also formed by heating benzoic anhydride with glycine,{{cite journal
| title = Synthese von Hippursäure und Hippursäureäthern
|trans-title=Synthesis of hippuric acid and hippuric acid esters
| author = Curtius T.
| journal = Berichte der Deutschen Chemischen Gesellschaft
| volume = 17
| issue = 2
| pages = 1662–1663
| year = 1884
| url = https://zenodo.org/record/1425365
| doi = 10.1002/cber.18840170225|author-link=Theodor Curtius
}} and by heating benzamide with monochloroacetic acid.
See also
- para-Aminohippuric acid
- ortho-Iodohippuric acid
- Methylhippuric acid (three different isomers)
References
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