Hydroquinone#Skin depigmentation

Hydroquinone is produced industrially in two main ways.Phillip M. Hudnall "Hydroquinone" in Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. 2005 Wiley-VCH, Weinheim. {{doi|10.1002/14356007.a13_499}}.

• The most widely used route is similar to the cumene process in reaction mechanism and involves the dialkylation of benzene with propene to give 1,4-diisopropylbenzene. This compound reacts with air to afford the bis(hydroperoxide), which is structurally similar to cumene hydroperoxide and rearranges in acid to give acetone and hydroquinone.Gerhard Franz, Roger A. Sheldon "Oxidation" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2000 {{doi|10.1002/14356007.a18_261}}
• A second route involves hydroxylation of phenol over a catalyst. The conversion uses hydrogen peroxide and affords a mixture of hydroquinone and its ortho isomer catechol (benzene-1,2-diol):

::{{chem2 | C6H5OH + H2O2 -> C6H4(OH)2 + H2O }}

Other, less common methods include:

• A potentially significant synthesis of hydroquinone from acetylene and iron pentacarbonyl has been proposed.{{cite journal|author1=Reppe, Walter |author2=Kutepow, N |author3=Magin, A |title=Cyclization of Acetylenic Compounds|journal=Angewandte Chemie International Edition in English|year=1969|volume=8|issue=10|pages=727–733|doi=10.1002/anie.196907271}}{{cite book|author1=Hubel, Karl |author2=Braye, Henri|title=Process for the preparation of substituted cyclic compounds and products resulting therefrom US3149138 A|year=1960|publisher=Union Carbide Corp.|url=https://docs.google.com/viewer?url=patentimages.storage.googleapis.com/pdfs/US3149138.pdf}}{{cite book|author1=Pino, Piero |author2=Braca, Giuseppe |author3=Sbrana, Glauco |title=Preparation of hydroquinone US3355503 A|year=1964|publisher=Lonza Ag|url=https://docs.google.com/viewer?url=patentimages.storage.googleapis.com/pdfs/US3355503.pdf}}{{cite book|author1=Walter, Reppe |author2=Magin, August|title=Production of hydroquinones US3394193 A|year=1966|publisher=Basf Ag|url=https://docs.google.com/viewer?url=patentimages.storage.googleapis.com/pdfs/US3394193.pdf}}{{cite book|author1=Piero, Pino |author2=Giuseppe, Braca |author3=Frediano, Settimo |author4=Glauco, Sbrana |title=Preparation of hydroquinone US3459812 A|year=1967|publisher=Lonza Ag|url=https://docs.google.com/viewer?url=patentimages.storage.googleapis.com/pdfs/US3459812.pdf}}{{cite book|author1=Holmes, J. |author2=Hagemeyer, H.|title=Process for the production of hydroquinone US 3742071 A|year=1971|publisher=Eastman Kodak Co.|url=https://docs.google.com/viewer?url=patentimages.storage.googleapis.com/pdfs/US3742071.pdf}} Iron pentacarbonyl serves as a catalyst, rather than as a reagent, in the presence of free carbon monoxide gas. Rhodium or ruthenium can substitute for iron as the catalyst with favorable chemical yields but are not typically used due to their cost of recovery from the reaction mixture.
• Hydroquinone and its derivatives can also be prepared by oxidation of various phenols, such as aniline and DIPB.{{Cite journal |vauthors=Shi Y, Xia Y, Xu G, Wen L, Gao G, Zong B |date=28 October 2021 |title=Hydrogen peroxide and applications in green hydrocarbon nitridation and oxidation |doi=10.1016/j.cjche.2021.09.030 |journal=Chinese Journal of Chemical Engineering |type=Review article |volume=41 |pages=145–161|s2cid=240248911}} Examples include Elbs persulfate oxidation and Dakin oxidation.
• Hydroquinone was first obtained in 1820 by the French chemists Pelletier and Caventou via the dry distillation of quinic acid.See:
• Pelletier and Caventou (1820) "Recherches chimiques sur les quinquinas" (Chemical investigations of quinquinas [i.e., the bark of various Cinchona trees]), Annales de Chimie et de Physique, 2nd series, 15 : 289–318, 337-364. [http://babel.hathitrust.org/cgi/pt?id=hvd.hx3dvm;view=1up;seq=347 On pages 341-342], the preparation and properties of l'acide pyro-kinique (pyroquinic acid or hydroquinone) are discussed.
• {{cite book|last=Roscoe|first=Henry|title=A Treatise on Chemistry, Volume 3, Part 3|year=1891|publisher=Macmillan & Co.|location=London|pages=165|url=https://books.google.com/books?id=HEY9AAAAYAAJ&pg=PA165}}
• Hydrolysis of chlorophenol.

The latter three methods are generally less atom-economical than oxidation with hydrogen peroxide, and their commercial practice in China produced serious pollution in 2022.{{sfn|Shi|Xia|Xu|Wen|2021|p=159}}

The reactivity of hydroquinone's hydroxyl groups resembles that of other phenols, being weakly acidic. The resulting conjugate base easily undergoes O-alkylation to give mono- and diethers. Similarly, hydroquinone is highly susceptible to ring substitution via Friedel–Crafts alkylation. This reaction is often used for the production of several popular antioxidants, namely 2-tert-butyl-4-methoxyphenol (BHA). The useful dye quinizarin is produced by diacylation of hydroquinone with phthalic anhydride.

Hydroquinone can be reversibly oxidised under mild conditions to give benzoquinone. Naturally occurring hydroquinone derivatives, such as coenzyme Q, exhibit similar reactivity, wherein one hydroxyl group is exchanged for an amino group. Given the conditional reversibility and relative ubiquity of reagents, oxidation reactions of hydroquinones and hydroquinone derivatives are of significant commercial use, often used at an industrial scale.

When colorless hydroquinone and benzoquinone - bright yellow in solid form - are cocrystallized at a 1:1 ratio, a dark-green crystalline charge-transfer complex (melting point 171 °C), known as quinhydrone ({{chem2|C6H6O2*C6H4O2}}), is formed. {{Citation needed|date=March 2025}}This complex dissolves in hot water, dissociating both quinone molecules in solution.{{Cite book|title=Introduction to organic chemistry|author=Streitwieser, Andrew|date=1992|publisher=Prentice Hall|others=Heathcock, Clayton H., 1936-, Kosower, Edward M.|isbn=978-0139738500|edition= 4th|location=Upper Saddle River, N.J.|oclc=52836313}}

An important reaction involves the conversion of hydroquinone to its mono- and di-amine derivatives. One such derivative, methylaminophenol, used in photography, is produced according to the stochiometry:

:{{chem2 | C6H4(OH)2}} + {{chem2 | CH3NH2 | link=methylamine}} {{chem2|-> HOC6H4NHCH3 + H2O }}

Diamines - used in the rubber industry as antiozone agents - aminated from aniline, are formed via a similar pathway:

:{{chem2 | C6H4(OH)2}} + 2 {{chem2 | C6H5NH2 | link=aniline }} {{chem2 | -> C6H4(N(H)C6H5)2 + 2 H2O }}

Hydroquinone has a variety of uses principally associated with its action as a reducing agent that is soluble in water. It is a major component in most black and white photographic developers for film and paper where, with the compound metol, it reduces silver halides to elemental silver.

There are various other uses associated with its reducing power. As a polymerisation inhibitor, exploiting its antioxidant properties, hydroquinone prevents polymerization of acrylic acid, methyl methacrylate, cyanoacrylate, and other monomers that are susceptible to radical-initiated polymerization. By acting as a free radical scavenger, hydroquinone serves to prolong the shelflife of light-sensitive resins such as preceramic polymers.[https://www.researchgate.net/publication/331309080_Additive_Manufacturing_of_Ceramics_from_Preceramic_Polymers_A_Versatile_Stereolithographic_Approach_Assisted_by_Thiol-Ene_Click_Chemistry Additive manufacturing of ceramics from preceramic polymers] Additive manufacturing 2019 vol. 27. pp 80-90

Hydroquinone can lose a hydrogen cation from both hydroxyl groups to form a diphenolate ion. The disodium diphenolate salt of hydroquinone is used as an alternating comonomer unit in the production of the polymer PEEK.

Hydroquinone is used as a topical application in skin whitening to reduce the color of skin. It does not have the same predisposition to cause dermatitis as metol does. This is a prescription-only ingredient in some countries, including the member states of the European Union under Directives 76/768/EEC:1976.{{CELEX|31976L0768|text=Council Directive 76/768/EEC of 27 July 1976 on the approximation of the laws of the Member States relating to cosmetic products}}{{cite web|url=https://www.beskinformed.com/hydroquinone/clear-n-smooth-skin-toning-cream-recalled/|title=Clear N Smooth Skin Toning Cream recalled|date=4 October 2011|access-date=4 April 2018}}

In 2006, United States Food and Drug Administration revoked its previous approval of hydroquinone and proposed a ban on all over-the-counter preparations.{{cite report | author = United States Food and Drug Administration | year = 2006 | title = Skin Bleaching Drug Products for Over-the-Counter Product Use; Proposed Rule | url = https://www.fda.gov/OHRMS/DOCKETS/98fr/78n-0065-npr0003.pdf | docket = 1978N-0065 | url-status = dead | archive-url = https://web.archive.org/web/20110516100158/https://www.fda.gov/OHRMS/DOCKETS/98fr/78n-0065-npr0003.pdf | archive-date = 16 May 2011 }} The FDA officially banned hydroquinone in 2020 as part of a larger reform of the over-the-counter drug review process.{{Cite web|title=Congress Enacts OTC Monograph Reform|url=https://www.jdsupra.com/legalnews/congress-enacts-otc-monograph-reform-96907/|access-date=19 December 2021|website=JD Supra|language=en}} The FDA stated that hydroquinone cannot be ruled out as a potential carcinogen.{{Cite web|url=https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm203112.htm|title=About the Center for Drug Evaluation and Research - Hydroquinone Studies Under The National Toxicology Program (NTP)|last=Research|first=Center for Drug Evaluation and|website=www.fda.gov|language=en|access-date=12 February 2017|url-status=dead|archive-url=https://web.archive.org/web/20170122222134/https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm203112.htm|archive-date=22 January 2017}} This conclusion was reached based on the extent of absorption in humans and the incidence of neoplasms in rats in several studies where adult rats were found to have increased rates of tumours, including thyroid follicular cell hyperplasias, anisokaryosis (variation in nuclei sizes), mononuclear cell leukemia, hepatocellular adenomas and renal tubule cell adenomas. The Campaign for Safe Cosmetics has also highlighted concerns.[http://www.safecosmetics.org/article.php?id=289 Campaign For Safe Cosmetics - Hydroquinone] {{webarchive|url=https://web.archive.org/web/20101127071016/http://safecosmetics.org/article.php?id=289 |date=27 November 2010 }}

Numerous studies have revealed that hydroquinone, if taken orally, can cause exogenous ochronosis, a disfiguring disease in which blue-black pigments are deposited onto the skin; however, skin preparations containing the ingredient are administered topically. The FDA had classified hydroquinone in 1982 as a safe product - generally recognized as safe and effective (GRASE), however additional studies under the National Toxicology Program (NTP) were suggested in order to determine whether there is a risk to humans from the use of hydroquinone.{{cite journal |author1=Olumide, YM |author2=Akinkugbe, AO |author3=Altraide, D |author4=Mohammed, T |author5=Ahamefule, N |author6=Ayanlowo, S |author7=Onyekonwu, C |author8=Essen, N | title=Complications of chronic use of skin lightening cosmetics| date= April 2008 | volume = 47 | issue = 4 | pmid=18377596 |pages = 344–53 | journal = International Journal of Dermatology | doi=10.1111/j.1365-4632.2008.02719.x|s2cid=8159382 }} NTP evaluation showed some evidence of long-term carcinogenic and genotoxic effects.{{Cite web |title=Hydroquinone 10022-H |url=https://ntp.niehs.nih.gov/static/whatwestudy/testpgm/status/ts-10022-h.html |url-status=live |archive-url=https://web.archive.org/web/20171001031226/https://ntp.niehs.nih.gov/testing/status/agents/ts-10022-h.html |archive-date=1 October 2017 |access-date=18 August 2023 |website=ntp.niehs.nih.gov |language=en-US}}

While hydroquinone remains widely prescribed for treatment of hyperpigmentation, questions raised about its safety profile by regulatory agencies in the EU, Japan, and USA encourage the search for other agents with comparable efficacy.{{Cite journal|last=Draelos|first=Zoe Diana|date=1 September 2007|title=Skin lightening preparations and the hydroquinone controversy|journal=Dermatologic Therapy|volume=20|issue=5|pages=308–313|doi=10.1111/j.1529-8019.2007.00144.x|issn=1529-8019|pmid=18045355|s2cid=24913995|doi-access=free}} Several such agents are already available or under research,{{Cite journal|last=Bandyopadhyay|first=Debabrata|date=1 January 2009|journal=Indian Journal of Dermatology|volume=54|issue=4|pages=303–309|doi=10.4103/0019-5154.57602|issn=0019-5154|pmc=2807702|pmid=20101327|title=Topical treatment of melasma |doi-access=free }} including azelaic acid,{{Cite journal|last1=Mazurek|first1=Klaudia|last2=Pierzchała|first2=Ewa|date=1 September 2016|title=Comparison of efficacy of products containing azelaic acid in melasma treatment|journal=Journal of Cosmetic Dermatology|volume=15|issue=3|pages=269–282|doi=10.1111/jocd.12217|issn=1473-2165|pmid=27028014|s2cid=25303091}} kojic acid, retinoids, cysteamine,{{Cite journal|last1=Mansouri|first1=P.|last2=Farshi|first2=S.|last3=Hashemi|first3=Z.|last4=Kasraee|first4=B.|date=1 July 2015|title=Evaluation of the efficacy of cysteamine 5% cream in the treatment of epidermal melasma: a randomized double-blind placebo-controlled trial|journal=The British Journal of Dermatology|volume=173|issue=1|pages=209–217|doi=10.1111/bjd.13424|issn=1365-2133|pmid=25251767|s2cid=21618233}} topical steroids, glycolic acid, and other substances. One of these, 4-butylresorcinol, has been proved to be more effective at treating melanin-related skin disorders by a wide margin, as well as safe enough to be made available over the counter.{{cite book|title=Phenols—Advances in Research and Application: 2013 Edition|date=2013|page=76|chapter=Hydroquinones|publisher=Scholastic}}

In the anthraquinone process substituted hydroquinones, typically anthrahydroquinone are used to produce hydrogen peroxide which forms spontaneously on reaction with oxygen. The type of substituted hydroquinone is selected depending on reactivity and recyclability.

Hydroquinones are one of the two primary reagents in the defensive glands of bombardier beetles, along with hydrogen peroxide (and perhaps other compounds, depending on the species), which collect in a reservoir. The reservoir opens through a muscle-controlled valve onto a thick-walled reaction chamber. This chamber is lined with cells that secrete catalases and peroxidases. When the contents of the reservoir are forced into the reaction chamber, the catalases and peroxidases rapidly break down the hydrogen peroxide and catalyze the oxidation of the hydroquinones into p-quinones. These reactions release free oxygen and generate enough heat to bring the mixture to the boiling point and vaporize about a fifth of it, producing a hot spray from the beetle's abdomen.Organic Chemistry, Solomon and Fryhle, 10th edition, Wiley Publishing, 2010.{{page needed|date=October 2016}}

Hydroquinone is thought to be the active toxin in Agaricus hondensis mushrooms.{{cite journal | doi=10.1055/s-2006-957852 |author1=Joval, E |author2=Kroeger, P |author3=N | title=Hydroquinone: the toxic compound of Agaricus hondensis| date= April 1996 | volume = 62 | issue = 2 |pages = 185 | journal = Planta Medica | pmid=17252436|s2cid=260249338 }}

Hydroquinone has been shown to be one of the chemical constituents of the natural product propolis.{{cite journal | last1 = Burdock | first1 = G.A. | year = 1998 | title = Review of the biological properties and toxicity of bee propolis (propolis) | journal = Food and Chemical Toxicology | volume = 36 | issue = 4| pages = 347–363 | doi = 10.1016/S0278-6915(97)00145-2 | pmid = 9651052 }}

It is also one of the chemical compounds found in castoreum. This compound is gathered from the beaver's castor sacs.The Beaver: Its Life and Impact. Dietland Muller-Schwarze, 2003, page 43 ([https://books.google.com/books?id=HZ5WjXB5Pr8C&dq=Castoreum+beekeeping&pg=PA43 book at google books])

{{Reflist}}

• [http://www.inchem.org/documents/icsc/icsc/eics0166.htm International Chemical Safety Card 0166]
• [https://www.cdc.gov/niosh/npg/npgd0338.html NIOSH Pocket Guide to Chemical Hazards]

{{Other dermatological preparations}}

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Category:Photographic chemicals

Category:IARC Group 3 carcinogens

Category:Reducing agents