4-Hydroxybenzoic acid

Last updated
4-Hydroxybenzoic acid
4-Hydroxybenzoic acid.svg
4-Hydroxybenzoic-acid-3D-balls.png
Names
Preferred IUPAC name
4-Hydroxybenzoic acid
Other names
p-Hydroxybenzoic acid
para-Hydroxybenzoic acid
PHBA
4-hydroxybenzoate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.002.550 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 202-804-9
KEGG
PubChem CID
UNII
  • InChI=1S/C7H6O3/c8-6-3-1-5(2-4-6)7(9)10/h1-4,8H,(H,9,10) Yes check.svgY
    Key: FJKROLUGYXJWQN-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C7H6O3/c8-6-3-1-5(2-4-6)7(9)10/h1-4,8H,(H,9,10)
    Key: FJKROLUGYXJWQN-UHFFFAOYAQ
  • O=C(O)c1ccc(O)cc1
  • c1cc(ccc1C(=O)O)O
Properties
C7H6O3
Molar mass 138.122 g·mol−1
AppearanceWhite crystalline
Odor Odorless
Density 1.46 g/cm3
Melting point 214.5 °C (418.1 °F; 487.6 K)
Boiling point N/A, decomposes [1]
0.5 g/100 mL
Solubility
log P 1.58
Acidity (pKa)4.54
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Irritant
NFPA 704 (fire diamond)
NFPA 704.svgHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 0: Will not burn. E.g. waterInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
0
0
250 °C (482 °F; 523 K)
Lethal dose or concentration (LD, LC):
2200 mg/kg (oral, mouse)
Safety data sheet (SDS) HMDB
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 ?)

4-Hydroxybenzoic acid, also known as p-hydroxybenzoic acid (PHBA), is a monohydroxybenzoic acid, a phenolic derivative of benzoic acid. It is a white crystalline solid that is slightly soluble in water and chloroform but more soluble in polar organic solvents such as alcohols and acetone. 4-Hydroxybenzoic acid is primarily known as the basis for the preparation of its esters, known as parabens, which are used as preservatives in cosmetics and some ophthalmic solutions. It is isomeric with 2-hydroxybenzoic acid, known as salicylic acid, a precursor to aspirin, and with 3-hydroxybenzoic acid.

Contents

Natural occurrences

It is found in plants of the genus Vitex such as V. agnus-castus or V. negundo , and in Hypericum perforatum (St John's wort). It is also found in Spongiochloris spongiosa , a freshwater green alga.

The compound is also found in Ganoderma lucidum , a medicinal mushroom with the longest record of use.

Cryptanaerobacter phenolicus is a bacterium species that produces benzoate from phenol via 4-hydroxybenzoate. [2]

Occurrences in food

4-Hydroxybenzoic acid can be found naturally in coconut. [3] It is one of the main catechins metabolites found in humans after consumption of green tea infusions. [4] It is also found in wine, [5] in vanilla, in Macrotyloma uniflorum (horse gram), carob [6] and in Phyllanthus acidus (Otaheite gooseberry).

Açaí oil, obtained from the fruit of the açaí palm (Euterpe oleracea), is rich in p-hydroxybenzoic acid (892±52 mg/kg). [7] It is also found in cloudy olive oil [ citation needed ] and in the edible mushroom Russula virescens (green-cracking russula).[ citation needed ]

p-Hydroxybenzoic acid glucoside can be found in mycorrhizal and non-mycorrhizal roots of Norway spruces ( Picea abies ). [8]

Violdelphin is an anthocyanin, a type of plant pigments, found in blue flowers and incorporating two p-hydroxybenzoic acid residues, one rutinoside and two glucosides associated with a delphinidin.

Agnuside is the ester of aucubin and p-hydroxybenzoic acid. [9]

Biosynthesis

Chorismate lyase is an enzyme that transforms chorismate into 4-hydroxybenzoate and pyruvate. This enzyme catalyses the first step in ubiquinone biosynthesis in Escherichia coli and other Gram-negative bacteria.

Benzoate 4-monooxygenase is an enzyme that utilizes benzoate, NADPH, H+ and O2 to produce 4-hydroxybenzoate, NADP+ and H2O. This enzyme can be found in Aspergillus niger .

4-Hydroxybenzoate also arises from tyrosine. [10]

Metabolism

As an intermediate

The enzyme 4-methoxybenzoate monooxygenase (O-demethylating) transforms 4-methoxybenzoate, an electron acceptor AH2 and O2 into 4-hydroxybenzoate, formaldehyde, the reduction product A and H2O. This enzyme participates in 2,4-dichlorobenzoate degradation in Pseudomonas putida .

The enzyme 4-hydroxybenzaldehyde dehydrogenase uses 4-hydroxybenzaldehyde, NAD+ and H2O to produce 4-hydroxybenzoate, NADH and H+. This enzyme participates in toluene and xylene degradation in bacteria such as Pseudomonas mendocina . It is also found in carrots ( Daucus carota ).

The enzyme that 2,4'-dihydroxyacetophenone dioxygenase transforms 2,4'-dihydroxyacetophenone and O2 into 4-hydroxybenzoate and formate. This enzyme participates in bisphenol A degradation. It can be found in Alcaligenes species.

The enzyme 4-chlorobenzoate dehalogenase uses 4-chlorobenzoate and H2O to produce 4-hydroxybenzoate and chloride. It can be found in Pseudomonas species.

The enzyme 4-hydroxybenzoyl-CoA thioesterase utilizes 4-hydroxybenzoyl-CoA and H2O to produce 4-hydroxybenzoate and CoA. This enzyme participates in 2,4-dichlorobenzoate degradation. It can be found in Pseudomonas species.

The enzyme 4-hydroxybenzoate polyprenyltransferase uses a polyprenyl diphosphate and 4-hydroxybenzoate to produce diphosphate and 4-hydroxy-3-polyprenylbenzoate. This enzyme participates in ubiquinone biosynthesis.

The enzyme 4-hydroxybenzoate geranyltransferase utilizes geranyl diphosphate and 4-hydroxybenzoate to produce 3-geranyl-4-hydroxybenzoate and diphosphate. Biosynthetically, alkannin is produced in plants from the intermediates 4-hydroxybenzoic acid and geranyl pyrophosphate. This enzyme is involved in shikonin biosynthesis. It can be found in Lithospermum erythrorhizon .

The enzyme 3-hydroxybenzoate—CoA ligase uses ATP, 3-hydroxybenzoate and CoA to produce AMP, diphosphate and 3-hydroxybenzoyl-CoA. The enzyme works equally well with 4-hydroxybenzoate. It can be found in Thauera aromatica .

Biodegradation

The enzyme 4-hydroxybenzoate 1-hydroxylase transforms 4-hydroxybenzoate, NAD(P)H, 2 H+ and O2 into hydroquinone, NAD(P)+, H2O and CO2. This enzyme participates in 2,4-dichlorobenzoate degradation. It can be found in Candida parapsilosis .

The enzyme 4-hydroxybenzoate 3-monooxygenase transforms 4-hydroxybenzoate, NADPH, H+ and O2 into protocatechuate, NADP+ and H2O. This enzyme participates in benzoate degradation via hydroxylation and 2,4-dichlorobenzoate degradation. It can be found in Pseudomonas putida and Pseudomonas fluorescens .

The enzyme 4-hydroxybenzoate 3-monooxygenase (NAD(P)H) utilizes 4-hydroxybenzoate, NADH, NADPH, H+ and O2 to produce 3,4-dihydroxybenzoate (protocatechuic acid), NAD+, NADP+ and H2O. This enzyme participates in benzoate degradation via hydroxylation and 2,4-dichlorobenzoate degradation. It can be found in Corynebacterium cyclohexanicum and in Pseudomonas sp.

The enzyme 4-hydroxybenzoate decarboxylase uses 4-hydroxybenzoate to produce phenol and CO2. This enzyme participates in benzoate degradation via coenzyme A (CoA) ligation. It can be found in Klebsiella aerogenes (Aerobacter aerogenes).

The enzyme 4-hydroxybenzoate—CoA ligase transforms ATP, 4-hydroxybenzoate and CoA to produce AMP, diphosphate and 4-hydroxybenzoyl-CoA. This enzyme participates in benzoate degradation via CoA ligation. It can be found in Rhodopseudomonas palustris .

Coniochaeta hoffmannii is a plant pathogen that commonly inhabits fertile soil. It is known to metabolize aromatic compounds of low molecular weight, such as p-hydroxybenzoic acid.

Glycosylation

The enzyme 4-hydroxybenzoate 4-O-beta-D-glucosyltransferase transforms UDP-glucose and 4-hydroxybenzoate into UDP and 4-(beta-D-glucosyloxy)benzoate. It can be found in the pollen of Pinus densiflora .

Chemistry

The Hammett equation describes a linear free-energy relationship relating reaction rates and equilibrium constants for many reactions involving benzoic acid derivatives with meta- and para-substituents.

Chemical production

4-Hydroxybenzoic acid is produced commercially from potassium phenoxide and carbon dioxide in the Kolbe-Schmitt reaction. [11] It can also be produced in the laboratory by heating potassium salicylate with potassium carbonate to 240 °C, followed by treating with acid. [12]

Chemical reactions

4-Hydroxybenzoic acid has about one tenth the acidity of benzoic acid, having an acid dissociation constant Ka = 3.3×10−5 M at 19 °C.[ citation needed ] Its acid dissociation follows this equation:

HOC6H4CO2H ⇌ HOC6H4CO−2 + H+

Chemical use

Vectran is a manufactured fiber, spun from a liquid crystal polymer. Chemically it is an aromatic polyester produced by the polycondensation of 4-hydroxybenzoic acid and 6-hydroxynaphthalene-2-carboxylic acid. The fiber has been shown to exhibit strong radiation shielding used by Bigelow Aerospace and produced by StemRad. [13]

4,4′-Dihydroxybenzophenone is generally prepared by the rearrangement of p-hydroxyphenylbenzoate. Alternatively, p-hydroxybenzoic acid can be converted to p-acetoxybenzoyl chloride. This acid chloride reacts with phenol to give, after deacetylation, 4,4′-dihydroxybenzophenone.

Examples of drugs made from PHBA include nifuroxazide, orthocaine, ormeloxifene and proxymetacaine.

Bioactivity and safety

4-Hydroxybenzoic acid is a popular antioxidant in part because of its low toxicity. The LD50 is 2200 mg/kg in mice (oral). [14]

4-Hydroxybenzoic acid has estrogenic activity both in vitro and in vivo, [15] and stimulates the growth of human breast cancer cell lines. [16] [17] It is a common metabolite of paraben esters, such as methylparaben. [15] [16] [17] The compound is a relatively weak estrogen, but can produce uterotrophy with sufficient doses to an equivalent extent relative to estradiol, which is unusual for a weakly estrogenic compound and indicates that it may be a full agonist of the estrogen receptor with relatively low binding affinity for the receptor. [16] [18] [19] It is about 0.2% to 1% as potent as an estrogen as estradiol. [18]

See also

Related Research Articles

In enzymology, a 4-hydroxybenzoyl-CoA reductase (EC 1.3.7.9) is an enzyme found in some bacteria and archaea that catalyzes the chemical reaction

In enzymology, a 3-hydroxybenzoate 2-monooxygenase (EC 1.14.99.23) is an enzyme that catalyzes the chemical reaction

In enzymology, a 3-hydroxybenzoate 4-monooxygenase (EC 1.14.13.23) is an enzyme that catalyzes the chemical reaction

In enzymology, a 3-hydroxybenzoate 6-monooxygenase (EC 1.14.13.24) is an enzyme that catalyzes the chemical reaction

In enzymology, a 4-hydroxybenzoate 1-hydroxylase (EC 1.14.13.64) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">4-hydroxybenzoate 3-monooxygenase</span> Flavoprotein

The enzyme 4-hydroxybenzoate 3-monooxygenase, also commonly referred to as para-hydroxybenzoate hydroxylase (PHBH), is a flavoprotein belonging to the family of oxidoreductases. Specifically, it is a hydroxylase, and is one of the most studied enzymes and catalyzes reactions involved in soil detoxification, metabolism, and other biosynthetic processes.

In enzymology, a 4-hydroxybenzoate 3-monooxygenase [NAD(P)H] (EC 1.14.13.33) is an enzyme that catalyzes the chemical reaction

In enzymology, a 4-methoxybenzoate monooxygenase (O-demethylating) (EC 1.14.99.15) is an enzyme that catalyzes the chemical reaction

In enzymology, a benzoate 4-monooxygenase (EC 1.14.14.92, Formerly EC 1.14.13.12) is an enzyme that catalyzes the chemical reaction

In enzymology, a benzoyl-CoA 3-monooxygenase (EC 1.14.13.58) is an enzyme that catalyzes the chemical reaction:

In enzymology, a vanillate monooxygenase (EC 1.14.13.82) is an enzyme that catalyzes the chemical reaction

In enzymology, a 4-hydroxybenzaldehyde dehydrogenase (EC 1.2.1.64) is an enzyme that catalyzes the chemical reaction

In enzymology, a 2,4'-dihydroxyacetophenone dioxygenase (EC 1.13.11.41) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Protocatechuate 3,4-dioxygenase</span>

In enzymology, a protocatechuate 3,4-dioxygenase (EC 1.13.11.3) is an enzyme that catalyzes the chemical reaction

In enzymology, a 4-chlorobenzoyl-CoA dehalogenase (EC 3.8.1.7) is an enzyme that catalyzes the chemical reaction

The enzyme 4-hydroxybenzoate decarboxylase (EC 4.1.1.61) catalyzes the chemical reaction

In enzymology, a 4-hydroxybenzoate—CoA ligase is an enzyme that catalyzes the chemical reaction

The enzyme 4-hydroxybenzoyl-CoA thioesterase (EC 3.1.2.23) catalyzes the reaction

<span class="mw-page-title-main">Protocatechuic acid</span> Chemical compound

Protocatechuic acid (PCA) is a dihydroxybenzoic acid, a type of phenolic acid. It is a major metabolite of antioxidant polyphenols found in green tea. It has mixed effects on normal and cancer cells in in vitro and in vivo studies.

<span class="mw-page-title-main">Benzoyl-CoA</span> Chemical compound

Benzoyl-CoA is the thioester derived from benzoic acid and coenzyme A. The term benzoyl-CoA also include diverse conjugates of coenzyme A and aromatic carboxylic acids. Benzoate, vanillin, anthranilic acid, 4-ethylphenol, p-cresol, phenol, aniline, terephthalic acid, [3-hydroxybenzoic acid, and phenylalanine are all metabolized to benzoyl-CoA. Additionally, cinnamic acid, p-coumaric acid, ferulic acid, toluene, caffeic acid, benzyl alcohol, and mandelic acid are suspected to be processed similarly.

References

  1. ↑ "4-Hydroxybenzoic acid" (PDF). International Programme on Chemical Safety (IPCS). Archived from the original (PDF) on 24 September 2015. Retrieved 10 January 2015.
  2. ↑ Juteau, P.; Côté, V.; Duckett, M.-F.; Beaudet, R.; Lépine, F.; Villemur, R.; Bisaillon, J.-G. (January 2005). "Cryptanaerobacter phenolicus gen. nov., sp. nov., an anaerobe that transforms phenol into benzoate via 4-hydroxybenzoate". International Journal of Systematic and Evolutionary Microbiology. 55 (1): 245–250. doi: 10.1099/ijs.0.02914-0 . PMID   15653882.
  3. ↑ Dey, G.; Chakraborty, M.; Mitra, A. (April 2005). "Profiling C6–C3 and C6–C1 phenolic metabolites in Cocos nucifera". Journal of Plant Physiology. 162 (4): 375–381. doi:10.1016/j.jplph.2004.08.006. PMID   15900879.
  4. ↑ Pietta, P. G.; Simonetti, P.; Gardana, C.; Brusamolino, A.; Morazzoni, P.; Bombardelli, E. (1998). "Catechin metabolites after intake of green tea infusions". BioFactors. 8 (1–2): 111–118. doi:10.1002/biof.5520080119. PMID   9699018. S2CID   37684286.
  5. ↑ Tian, R.-R.; Pan, Q.-H.; Zhan, J.-C.; Li, J.-M.; Wan, S.-B.; Zhang, Q.-H.; Huang, W.-D. (2009). "Comparison of phenolic acids and flavan-3-ols during wine fermentation of grapes with different harvest times". Molecules. 14 (2): 827–838. doi: 10.3390/molecules14020827 . PMC   6253884 . PMID   19255542.
  6. ↑ Goulas, V.; Stylos, E.; Chatziathanasiadou, M. V.; Mavromoustakos, T.; Tzakos, A. G. (2016). "Functional Components of Carob Fruit: Linking the Chemical and Biological Space". International Journal of Molecular Sciences. 17 (11): 1875. doi: 10.3390/ijms17111875 . PMC   5133875 . PMID   27834921.
  7. ↑ Pacheco Palencia, L. A.; Mertens-Talcott, S.; Talcott, S. T. (June 2008). "Chemical composition, antioxidant properties, and thermal stability of a phytochemical enriched oil from Açaí (Euterpe oleracea Mart.)". Journal of Agricultural and Food Chemistry. 56 (12): 4631–4636. doi:10.1021/jf800161u. PMID   18522407.
  8. ↑ Münzenberger, B.; Heilemann, J.; Strack, D.; Kottke, I.; Oberwinkler, F. (1990). "Phenolics of mycorrhizas and non-mycorrhizal roots of Norway spruce". Planta. 182 (1): 142–148. doi:10.1007/BF00239996. PMID   24197010. S2CID   43504838.
  9. ↑ Hoberg, E.; Meier, B.; Sticher, O. (September 2000). "An analytical high performance liquid chromatographic method for the determination of agnuside and p-hydroxybenzoic acid contents in Agni-casti fructose". Phytochemical Analysis. 11 (5): 327–329. doi:10.1002/1099-1565(200009/10)11:5<327::AID-PCA523>3.0.CO;2-0.
  10. ↑ Acosta, Manuel Jesús; Vazquez Fonseca, Luis; Desbats, Maria Andrea; Cerqua, Cristina; Zordan, Roberta; Trevisson, Eva; Salviati, Leonardo (2016). "Coenzyme Q biosynthesis in health and disease". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1857 (8): 1079–1085. doi: 10.1016/j.bbabio.2016.03.036 . PMID   27060254.
  11. ↑ Edwin Ritzer and Rudolf Sundermann "Hydroxycarboxylic Acids, Aromatic" in Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. doi : 10.1002/14356007.a13_519
  12. ↑ Buehler, C. A.; Cate, W. E. (1943). "p-Hydroxybenzoic acid". Organic Syntheses ; Collected Volumes, vol. 2, p. 341.
  13. ↑ Charles Fishman, Dan Winters (2016-04-11). "This Expandable Structure Could Become the Future of Living in Space". Smithsonian Magazine. Retrieved 2020-12-07.
  14. ↑ Lewis, R. J., ed. (1996). Sax's Dangerous Properties of Industrial Materials. Vol. 1–3 (9th ed.). New York, NY: Van Nostrand Reinhold. p. 2897.
  15. 1 2 Khetan, S. K. (23 May 2014). Endocrine Disruptors in the Environment. Wiley. p. 109. ISBN   978-1-118-89115-5.
  16. 1 2 3 Pugazhendhi, D.; Pope, G. S.; Darbre, P. D. (2005). "Oestrogenic activity of p-hydroxybenzoic acid (common metabolite of paraben esters) and methylparaben in human breast cancer cell lines". Journal of Applied Toxicology. 25 (4): 301–309. doi:10.1002/jat.1066. PMID   16021681. S2CID   12342018.
  17. 1 2 Gabriel, J. (April 2013). Holistic Beauty from the Inside Out: Your Complete Guide to Natural Health, Nutrition, and Skincare. Seven Stories Press. p. 31. ISBN   978-1-60980-462-6.
  18. 1 2 Lemini, C.; Silva, G.; Timossi, C.; Luque, D.; Valverde, A.; González Martínez, M.; Hernández, A.; Rubio Póo, C.; Chávez Lara, B.; Valenzuela, F. (1997). "Estrogenic effects of p-hydroxybenzoic acid in CD1 mice". Environmental Research. 75 (2): 130–134. Bibcode:1997ER.....75..130L. doi:10.1006/enrs.1997.3782. PMID   9417843.
  19. ↑ OECD (November 2004). OECD Guidelines for the Testing of Chemicals / OECD Series on Testing and Assessment Detailed Background Review of the Uterotrophic Bioassay. OECD Publishing. p. 183. ISBN   978-92-64-07885-7.

4-Hydroxybenzoic acid at Phenol-Explorer .eu

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