Hippuric acid ( Gr. ''hippos'', horse, ''ouron'', urine) is a

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...

and organic compound. It is found in

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...

and is formed from the combination of

benzoic acid Benzoic acid is a white (or colorless) solid organic compound with the formula , whose structure consists of a benzene ring () with a carboxyl () substituent. It is the simplest aromatic carboxylic acid. The name is derived from gum benzoin, wh ...

and

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...

. Levels of hippuric acid rise with the consumption of phenolic compounds (such as

fruit juice Juice is a drink made from the extraction or pressing of the natural liquid contained in fruit and vegetables. It can also refer to liquids that are flavored with concentrate or other biological food sources, such as meat or seafood, such as ...

tea Tea is an aromatic beverage prepared by pouring hot or boiling water over cured or fresh leaves of ''Camellia sinensis'', an evergreen shrub native to East Asia which probably originated in the borderlands of southwestern China and north ...

and

wine Wine is an alcoholic drink typically made from fermented grapes. Yeast consumes the sugar in the grapes and converts it to ethanol and carbon dioxide, releasing heat in the process. Different varieties of grapes and strains of yeasts are m ...

). The

phenols In organic chemistry, phenols, sometimes called phenolics, are a class of chemical compounds consisting of one or more hydroxyl groups (— O H) bonded directly to an aromatic hydrocarbon group. The simplest is phenol, . Phenolic compounds are c ...

are first converted to

, and then to hippuric acid and excreted in

. Hippuric acid crystallizes in rhombic prisms which are readily soluble in hot water, melt at 187 °C, and decompose at about 240 °C. 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. When many aromatic compounds such as

and

toluene Toluene (), also known as toluol (), is a substituted aromatic hydrocarbon. It is a colorless, water-insoluble liquid with the smell associated with paint thinners. It is a mono-substituted benzene derivative, consisting of a methyl group (CH3) at ...

are taken internally, they are converted to hippuric acid by reaction with the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

Synthesis

A modern synthesis of hippuric acid involves the

acylation In chemistry, acylation (or alkanoylation) is the chemical reaction in which an acyl group () is added to a compound. The compound providing the acyl group is called the acylating agent. Because they form a strong electrophile when treated with ...

with

benzoyl chloride Benzoyl chloride, also known as benzenecarbonyl chloride, is an organochlorine compound with the formula . It is a colourless, fuming liquid with an irritating odour, and consists of a benzene ring () with an acyl chloride () substituent. It is ...

: :

Physiology

Biochemically, hippuric acid is produced from

by direct glycine acylation. It is one of the two conjugates of benzoic acid produced metabolically, the other being the

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...

. Both are eliminated from the body in urine. Benzoic acid is introduced into the body by ingestion (sodium benzoate is used as a

preservative A preservative is a substance or a chemical that is added to products such as food products, beverages, pharmaceutical drugs, paints, biological samples, cosmetics, wood, and many other products to prevent decomposition by microbial growth or by ...

) and by

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

of pharmaceutical agents such as

benzyl benzoate Benzyl benzoate is an organic compound which is used as a medication and insect repellent. As a medication it is used to treat scabies and lice. For scabies either permethrin or malathion is typically preferred. It is applied to the skin as a ...

. Hippuric acid may be formed from the essential amino acid

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...

through at least two pathways. Phenylalanine undergoes

biotransformation Biotransformation is the biochemical modification of one chemical compound or a mixture of chemical compounds. Biotransformations can be conducted with whole cells, their lysates, or purified enzymes. Increasingly, biotransformations are effected w ...

to form an

alpha-keto acid In organic chemistry, keto acids or ketoacids (also called oxo acids or oxoacids) are organic compounds that contain a carboxylic acid group () and a ketone group ().Franz Dietrich Klingler, Wolfgang Ebertz "Oxocarboxylic Acids" in Ullmann's En ...

phenylpyruvic acid Phenylpyruvic acid is the organic compound with the formula C6H5CH2C(O)CO2H. It is a keto acid. Occurrence and properties The compound exists in equilibrium with its E- and Z-enol tautomers. It is a product from the oxidative deamination of p ...

, which can tautomerize to a reactive enol. The benzylic carbon is reactive which undergoes

peroxidation Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical cha ...

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 In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...

to form an alpha-keto-beta-peroxylactone intermediate followed by formation of

carbon monoxide Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...

carbon dioxide Carbon dioxide (chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is transpar ...

, and benzaldehyde. Alternatively, under certain conditions, phenylpyruvic acid may undergo a redox mechanism, such as

Iron(II) In chemistry, iron(II) refers to the element iron in its +2 oxidation state. In ionic compounds (salts), such an atom may occur as a separate cation (positive ion) denoted by Fe2+. The adjective ferrous or the prefix ferro- is often used to s ...

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 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...

to benzoic acid followed by conjugation to glycine for formation of hippurate which undergoes urinary excretion. Similarly, toluene reacts with CYP450 to form benzaldehyde.

Reactions

Hippuric acid is readily

hydrolyse Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolys ...

d by hot caustic

alkali In chemistry, an alkali (; from ar, القلوي, al-qaly, lit=ashes of the saltwort) is a basic, ionic salt of an alkali metal or an alkaline earth metal. An alkali can also be defined as a base that dissolves in water. A solution of a ...

s to

and glycine.

Nitrous acid Nitrous acid (molecular formula ) is a weak and monoprotic acid known only in Solution (chemistry), solution, in the gas phase and in the form of nitrite () salts. Nitrous acid is used to make diazonium salts from amines. The resulting diazoni ...

converts it into benzoyl glycolic acid, C₆H₅C(=O)OCH₂CO₂H. Its ethyl

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

reacts with

hydrazine Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly toxic unless handled in solution as, for example, hydrazine ...

to form hippuryl hydrazine, C₆H₅CONHCH₂CONHNH₂, which was used by

Theodor Curtius ''Geheimrat'' Julius Wilhelm Theodor Curtius (27 May 1857 – 8 February 1928) was professor of Chemistry at Heidelberg University and elsewhere. He published the Curtius rearrangement in 1890/1894 and also discovered diazoacetic acid, hydra ...

for the preparation of hydrazoic acid.

History

Justus von Liebig Justus Freiherr von Liebig (12 May 1803 – 20 April 1873) was a German scientist who made major contributions to agricultural and biological chemistry, and is considered one of the principal founders of organic chemistry. As a professor at t ...

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 Victor Dessaignes (31 December 1800 – 4 January 1885) was a French lawyer, physician and chemist. Dessaignes conducted experiments on organic acids and was involved in the synthesis of hippuric acid. He was also involved in characterizing and nami ...

(1800–1885) synthesized it by the action of

on the zinc salt of glycine. It was also formed by heating benzoic anhydride with glycine, and by heating

benzamide Benzamide is a organic compound with the chemical formula of C6H5C(O)NH2. It is the simplest amide derivative of benzoic acid Benzoic acid is a white (or colorless) solid organic compound with the formula , whose structure consists of a benz ...

with

monochloroacetic acid Chloroacetic acid, industrially known as monochloroacetic acid (MCA), is the organochlorine compound with the formula ClCH2CO2H. This carboxylic acid is a useful building block in organic synthesis. It is a colorless solid. Related compounds a ...

References

* {{Authority control Acetic acids Benzamides Phenyl compounds

Synthesis

Physiology

Reactions

History

See also

References