Mandelic acid

Last updated
Mandelic acid [1]
Kwas migdalowy.svg
(R)-Mandelic acid molecule ball.png
Mandlova kyselina.jpg
Names
Preferred IUPAC name
Hydroxy(phenyl)acetic acid
Other names
  • Amygdalic acid [2]
  • Amygdalinic acid [2]
  • Benzoglycolic acid [2]
  • α-Hydroxy-α-toluic acid [2]
  • α-Hydroxyphenylacetic acid
  • 2-Hydroxy-2-phenylacetic acid
  • Paramandelic acid [2]
  • Phenylglycolic acid [2]
  • Phenylglycollic acid [2]
  • Phenylglyconic acid [2]
  • α-Phenylhydroxyacetic acid [2]
  • Phenylhydroxyacetic acid [2]
Identifiers
3D model (JSmol)
510011
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.001.825 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 202-007-6
218213
KEGG
PubChem CID
RTECS number
  • OO6300000
UNII
  • InChI=1S/C8H8O3/c9-7(8(10)11)6-4-2-1-3-5-6/h1-5,7,9H,(H,10,11) Yes check.svgY
    Key: IWYDHOAUDWTVEP-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C8H8O3/c9-7(8(10)11)6-4-2-1-3-5-6/h1-5,7,9H,(H,10,11)
    Key: IWYDHOAUDWTVEP-UHFFFAOYAD
  • O=C(O)C(O)c1ccccc1
Properties
C8H8O3
Molar mass 152.149 g·mol−1
AppearanceWhite crystalline powder
Density 1.30 g/cm3
Melting point 119 °C (246 °F; 392 K) optically pure: 132 to 135 °C (270 to 275 °F; 405 to 408 K)
Boiling point 321.8 °C (611.2 °F; 595.0 K)
15.87 g/100 mL
Solubility soluble in diethyl ether, ethanol, isopropanol
Acidity (pKa)3.41 [3]
1.5204
Thermochemistry
0.1761 kJ/g
Pharmacology
B05CA06 ( WHO ) J01XX06 ( WHO )
Hazards
Flash point 162.6 °C (324.7 °F; 435.8 K)
Related compounds
Related compounds
 mandelonitrile, phenylacetic acid, vanillylmandelic acid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Mandelic acid is an aromatic alpha hydroxy acid (AHA) with the molecular formula C6H5CH(OH)CO2H. It is a white crystalline solid that is soluble in water and polar organic solvents. Its principal use in organic synthesis is as a useful precursor to various drugs.

Contents

Properties

At room temperature, mandelic acid is a white or colorless solid with a faint odor. [4] It is highly soluble in diethyl ether [5] but less so in water and ethanol. [2] [4] [6] It is insoluble in petroleum ether. [5]

The molecule is chiral. The racemic mixture is known as paramandelic acid.

Isolation, synthesis, occurrence

Mandelic acid was discovered in 1831 by the German pharmacist Ferdinand Ludwig Winckler (1801–1868) while heating amygdalin, an extract of bitter almonds, with diluted hydrochloric acid. The name is derived from the German "Mandel" for "almond". [7]

Mandelic acid is usually prepared by the acid-catalysed hydrolysis of mandelonitrile, [8] which is the cyanohydrin of benzaldehyde and can be synthesized in various ways: [9]

Hydrolysis of mandelonitrile.png

Alternatively, it can be prepared by a substitution reaction from bromophenylacetic acid, as well as by hydrolysis routes starting from various α,α-dihaloacetophenones. [10] It also arises by an isomerization reaction upon heating phenylglyoxal with various alkalis. [11] [12]

Biosynthesis

Mandelic acid is a substrate or product of several biochemical processes called the mandelate pathway. Mandelate racemase interconverts the two enantiomers via a pathway that involves cleavage of the alpha-CH bond. Mandelate dehydrogenase is yet another enzyme on this pathway. [13] Mandelate also arises from trans-cinnamate via phenylacetic acid, which is hydroxylated. [14] Phenylpyruvic acid is another precursor to mandelic acid.

Derivatives of mandelic acid are formed as a result of metabolism of adrenaline and noradrenaline by monoamine oxidase and catechol-O-methyl transferase. The biotechnological production of 4-hydroxy-mandelic acid and mandelic acid on the basis of glucose was demonstrated with a genetically modified yeast Saccharomyces cerevisiae , in which the hydroxymandelate synthase naturally occurring in the bacterium Amycolatopsis was incorporated into a wild-type strain of yeast, partially altered by the exchange of a gene sequence and expressed. [15]

It also arises from the biodegradation of styrene [16] and ethylbenzene, as detected in urine.

Uses

Cosmetics

Mandelic acid can be a component of chemical face peels analogous to other alpha hydroxy acids. [2] Mandelic acid is one of the most common chemical components of the "superficial peel" class, which destroy all or part of the epidermis while remaining safe to use on all Fitzpatrick skin types. [17] [18] [19] The American Academy of Dermatology says there is insufficient evidence to recommend chemical peels (including those with mandelic acid) as a treatment for acne vulgaris. [20] While noting it was widely used in cosmetic products, known to be effective, and frequently prescribed for acne, mandelic acid was among the ingredients not recommended for acne in a 2025 Journal of the American Academy of Dermatology literature review's expert panel, because it is rarely covered by insurance and more costly than treatments with similar effects such as vitamin A derivatives. [21]

Pharmaceuticals

Mandelic acid is widely used for pharmaceuticals as a precursor to various drugs. [22] [ better source needed ]

The drugs cyclandelate and homatropine [23] are esters of mandelic acid.[ citation needed ] Homatropine dilates eyes for eye exams and wears off quickly. [23] This effect was discovered by chemist Alfred Ladenburg in 1880 and was preferred because the previous mixture caused blurry vision for days. Mandelic acid replaced tropic acid in the synthesis of homatropine. [23] [24] [25]

Toxicology

Mandelic acid levels in human urine are a standard biomarker for styrene exposure in industrial hygiene. The unstable metabolite styrene-(7,8)-oxide (styrene oxide) is oxidized into mandelic acid and phenylglyoxylic acid, then exits the body in urine. [26] [27] It is also a biomarker for ethylbenzene exposure. [26] [28] [29] Daily end-of-shift urine collection to monitor styrene exposure is recommended by American Conference of Governmental Industrial Hygienists (ACGIH). [30]

History

Mandelic acid was discovered in 1831 by the German pharmacist Ferdinand Ludwig Winckler (1801–1868) while heating amygdalin, an extract of bitter almonds, with diluted hydrochloric acid. The name is derived from the German "Mandel" for "almond". [7]

The short-acting eye dilation effect as part of homatropine was discovered by chemist Alfred Ladenburg in 1880. Mandelic acid then replaced tropic acid in the synthesis of homatropine. [31] [23] [24]

Takeru Higuchi and Roy Kuramoto demonstrated one of the earliest forms of pharmaceutical cocrystals in studies published during 1954 that involved mandelic acid. [32]

Safety and handling

Mandelic acid is moderately toxic if ingested. [4] [33] It is poisonous if injected. [33] Frequent absorption can result in kidney irritation. [33] When burning, mandelic acid emits acrid smoke and fumes. [33]

Exposing the white crystal form to light will darken to brown and decompose the crystals over time. [4] [5] [33]

See also

References

  1. ↑ Merck Index , 11th Edition, 5599.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 Ash, Michael (2004). Handbook of Preservatives. Endicott, NY: Synapse Info Resources. p. 444. ISBN   978-1-890595-66-1. Handbook of Preservatives at Google Books.
  3. ↑ Bjerrum, J., et al. Stability Constants, Chemical Society, London, 1958.
  4. 1 2 3 4 Hawley's Condensed Chemical Dictionary. Wiley. March 15, 2007. doi:10.1002/9780470114735.hawley10203. ISBN   978-0-471-76865-4 . Retrieved September 10, 2025.
  5. 1 2 3 Ritzer E, Sundermann R (March 11, 2003). "Hydroxycarboxylic Acids, Aromatic; 4.4. Mandelic Acid". Ullmann's Encyclopedia of Industrial Chemistry. New York: Wiley. doi:10.1002/14356007.a13_519. ISBN   978-3-527-30385-4 . Retrieved September 10, 2025.
  6. ↑ Harris, Bruce D. (April 15, 2001). "Mandelic Acid". Encyclopedia of Reagents for Organic Synthesis. Chichester, United Kingdom: John Wiley & Sons, Ltd. doi:10.1002/047084289x.rm017. ISBN   978-0-471-93623-7 . Retrieved September 10, 2025.
  7. 1 2 See:
  8. ↑ Ritzer, Edwin; Sundermann, Rudolf (2000). "Hydroxycarboxylic Acids, Aromatic". Ullmann's Encyclopedia of Industrial Chemistry . Weinheim: Wiley-VCH. doi:10.1002/14356007.a13_519. ISBN   3527306730.
  9. ↑ Corson, B. B.; Dodge, R. A.; Harris, S. A.; Yeaw, J. S. (1926). "Mandelic Acid". Org. Synth. 6: 58. doi:10.15227/orgsyn.006.0058.
  10. ↑ J. G. Aston; J. D. Newkirk; D. M. Jenkins & Julian Dorsky (1952). "Mandelic Acid". Organic Syntheses ; Collected Volumes, vol. 3, p. 538.
  11. ↑ Pechmann, H. von (1887). "Zur Spaltung der Isonitrosoverbindungen". Berichte der Deutschen Chemischen Gesellschaft. 20 (2): 2904–2906. doi:10.1002/cber.188702002156.
  12. ↑ Pechmann, H. von; Muller, Hermann (1889). "Ueber α-Ketoaldehyde". Berichte der Deutschen Chemischen Gesellschaft. 22 (2): 2556–2561. doi:10.1002/cber.188902202145.
  13. ↑ Kenyon, George L.; Gerlt, John A.; Petsko, Gregory A.; Kozarich, John W. (1995). "Mandelate Racemase: Structure-Function Studies of a Pseudosymmetric Enzyme". Accounts of Chemical Research. 28 (4): 178–186. doi:10.1021/ar00052a003.
  14. ↑ Lapadatescu, Carmen; Giniès, Christian; Le QuéRé, Jean-Luc; Bonnarme, Pascal (2000). "Novel Scheme for Biosynthesis of Aryl Metabolites from l-Phenylalanine in the Fungus Bjerkandera adusta". Applied and Environmental Microbiology. 66 (4): 1517–1522. Bibcode:2000ApEnM..66.1517L. doi:10.1128/AEM.66.4.1517-1522.2000. PMC   92016 . PMID   10742235.
  15. ↑ Mara Reifenrath, Eckhard Boles: Engineering of hydroxymandelate synthases and the aromatic amino acid pathway enables de novo biosynthesis of mandelic and 4-hydroxymandelic acid with Saccharomyces cerevisiae. Metabolic Engineering 45, Januar 2018; S. 246-254. doi : 10.1016/j.ymben.2018.01.001.
  16. ↑ Engström K, Härkönen H, Kalliokoski P, Rantanen J. "Urinary mandelic acid concentration after occupational exposure to styrene and its use as a biological exposure test" Scand. J. Work Environ. Health. 1976, volume 2, pp. 21-6.
  17. ↑ Chee-Leok Goh, Joyce Teng Ee Lim (February 27, 2023). "Chemical Peels". Rook's Textbook of Dermatology. Wiley. doi:10.1002/9781119709268.rook160. ISBN   978-1-119-70921-3 . Retrieved September 10, 2025.
  18. ↑ Lee, Kachiu C.; Wambier, Carlos G.; Soon, Seaver L.; Sterling, J. Barton; Landau, Marina; Rullan, Peter; Brody, Harold J. (2019). "Basic chemical peeling: Superficial and medium-depth peels". Journal of the American Academy of Dermatology. 81 (2). American Academy of Dermatology: 313–324. doi:10.1016/j.jaad.2018.10.079 . Retrieved September 11, 2025. Common superficial peels include glycolic acid (GA), salicylic acid (SA), Jessner solution (JS), retinoic acid, lactic acid, mandelic acid, pyruvic acid (PA), and trichloroacetic acid (TCA) 10% to 35%.
  19. ↑ Quiñonez, Rebecca L.; Agbai, Oma N.; Burgess, Cheryl M.; Taylor, Susan C. (2022). "An update on cosmetic procedures in people of color. Part 2: Neuromodulators, soft tissue augmentation, chemexfoliating agents, and laser hair reduction". Journal of the American Academy of Dermatology. 86 (4). American Academy of Dermatology: 729–739. doi: 10.1016/j.jaad.2021.07.080 . Retrieved September 11, 2025. The superficial chemexfoliants, 35% to 70% glycolic acid (GA), 20% to 30% salicylic acid (SA), 40% mandelic acid (MA), Jessner solution, 88% lactic acid, phytic acid, and <15% trichloroacetic acid remove the stratum corneum and penetrate to various depth of the epidermis, resulting in an improvement in pigmentation and textural roughness.
  20. ↑ Reynolds, Rachel V.; Yeung, Howa; Cheng, Carol E.; et al. (May 2024). "Guidelines of care for the management of acne vulgaris". Journal of the American Academy of Dermatology . 90 (5). American Academy of Dermatology: 1006.e1–1006.e30. doi: 10.1016/j.jaad.2023.12.017 . Retrieved September 11, 2025.
  21. ↑ Alvarez, Gabriella V.; Kang, Bianca Y.; Richmond, Alexandra M.; et al. (April 13, 2025). "Skincare ingredients recommended by cosmetic dermatologists: A Delphi consensus study". Journal of the American Academy of Dermatology. American Academy of Dermatology. doi:10.1016/j.jaad.2025.04.021 . Retrieved September 11, 2025.
  22. ↑ Wang, Zerong (September 15, 2010). "Mandelic Acid Synthesis". Comprehensive Organic Name Reactions and Reagents. Wiley. doi:10.1002/9780470638859.conrr408. ISBN   978-0-471-70450-8 . Retrieved September 10, 2025.
  23. 1 2 3 4 Griffith R, Dukat M (April 26, 2021). "Cholinergics/Anticholinergics". Burger's Medicinal Chemistry and Drug Discovery. Wiley. doi:10.1002/0471266949.bmc094.pub3. ISBN   978-0-471-26694-5 . Retrieved September 10, 2025.
  24. 1 2 Rama Sastry, B. V. (January 15, 2003). "Anticholinergic Drugs". Burger's Medicinal Chemistry and Drug Discovery. Wiley. doi:10.1002/0471266949.bmc095. ISBN   978-0-471-26694-5 . Retrieved September 10, 2025.
  25. ↑ Patrick, G. L. (September 9, 2005). "History of Drug Discovery". Encyclopedia of Life Sciences (eLS). Wiley. doi:10.1002/9780470015902.a0003090.pub2. ISBN   978-0-470-01617-6 . Retrieved September 10, 2025.
  26. 1 2 Hopf BN, Fustinoni S (February 10, 2021). "Biological Monitoring of Exposure to Industrial Chemicals". Patty's Industrial Hygiene. Wiley. doi:10.1002/0471435139.hyg042.pub3. ISBN   978-0-471-29784-0 . Retrieved September 10, 2025.
  27. ↑ Mooney, Aisling; Ward, Patrick G.; O’Connor, Kevin E. (July 6, 2006). "Microbial degradation of styrene: biochemistry, molecular genetics, and perspectives for biotechnological applications". Applied Microbiology and Biotechnology. 72 (1): 1–10. doi:10.1007/s00253-006-0443-1. ISSN   0175-7598. EBSCOhost   21908913 . Retrieved September 10, 2025.
  28. ↑ Boogaard, P. J. (September 15, 2011). "Biomonitoring of the Workplace and Environment". General, Applied and Systems Toxicology. New York: Wiley. doi:10.1002/9780470744307.gat126. ISBN   978-0-470-72327-2 . Retrieved September 10, 2025.
  29. ↑ Kerzic, P. J. (December 27, 2023). "Aromatic Hydrocarbons—Benzene and Other Alkylbenzenes". Patty's Toxicology. Wiley. doi:10.1002/0471125474.tox051.pub3. ISBN   978-0-471-31943-6 . Retrieved September 10, 2025.
  30. ↑ Banton M, Rushton EK, Steneholm A (July 3, 2023). "Styrene, Polyphenyls, and Related Compounds. 2.3.6 Biomonitoring/Biomarkers". Patty's Toxicology. Wiley. doi:10.1002/0471125474.tox119.pub2. ISBN   978-0-471-31943-6 . Retrieved September 11, 2025.
  31. ↑ Sneader, WE (August 15, 2007). "Drug Discovery (The History), 1.3 Alkaloid Analogues". Van Nostrand's Scientific Encyclopedia. Wiley. doi:10.1002/9780471743989.vse9887. ISBN   978-0-471-33230-5 . Retrieved September 11, 2025.
  32. ↑ Shan N, Zaworotko MJ (April 26, 2021). "Polymorphic Crystal Forms and Cocrystals in Drug Delivery (Crystal Engineering), 3.2 Case Studies of Pharmaceutical Cocrystals". Burger's Medicinal Chemistry and Drug Discovery. Wiley. doi:10.1002/0471266949.bmc156.pub2. ISBN   978-0-471-26694-5 . Retrieved September 11, 2025. Perhaps, the earliest examples of pharmaceutical cocrystals were described in a series of studies conducted in the 1950s by Higuchi and his coworkers (65, 66), who studied complex formation between macromolecules and certain pharmaceuticals; for example, complexes of polyvinylpyrrolidone (PVP) with sulfathiazole, procaine hydrochloride, sodium salicylate, benzylphenicillin, chloramphenicol, mandelic acid, caffeine, theophylline, and cortisone were isolated (65, 66).
  33. 1 2 3 4 5 "Mandelic Acid 90-64-2". Sax's Dangerous Properties of Industrial Materials. New York: Wiley. October 15, 2004. doi:10.1002/0471701343.sdp41653. ISBN   978-0-471-47662-7 . Retrieved September 10, 2025.
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