Hydroquinone

Hydroquinone

Hydroquinone
Names
Preferred IUPAC name Benzene-1,4-diol [1]
Other names Hydroquinone [1] Idrochinone Quinol 4-Hydroxyphenol 1,4-Dihydroxybenzene p-Dihydroxybenzene p-Benzenediol
Identifiers
CAS Number	123-31-9  Y
3D model (JSmol)	Interactive image
Beilstein Reference	605970
ChEBI	CHEBI:17594  Y
ChEMBL	ChEMBL537  Y
ChemSpider	764  Y
DrugBank	DB09526
ECHA InfoCard	100.004.199
EC Number	204-617-8
Gmelin Reference	2742
KEGG	D00073  Y
PubChem CID	785
RTECS number	MX3500000
UNII	XV74C1N1AE  Y
UN number	3077, 2662
CompTox Dashboard (EPA)	DTXSID7020716
InChI InChI=1S/C6H6O2/c7-5-1-2-6(8)4-3-5/h1-4,7-8H Y Key: QIGBRXMKCJKVMJ-UHFFFAOYSA-N Y InChI=1/C6H6O2/c7-5-1-2-6(8)4-3-5/h1-4,7-8H Key: QIGBRXMKCJKVMJ-UHFFFAOYAX
SMILES c1cc(ccc1O)O
Properties
Chemical formula	C6H6O2
Molar mass	110.112 g·mol−1
Appearance	White solid
Density	1.3 g cm−3, solid
Melting point	172 °C (342 °F; 445 K)
Boiling point	287 °C (549 °F; 560 K)
Solubility in water	5.9 g/100 mL (15 °C)
Vapor pressure	10−5 mmHg (20 °C) [2]
Acidity (pKa)	9.9 [3]
Magnetic susceptibility (χ)	−64.63×10−6 cm3/mol
Structure
Dipole moment	1.4±0.1  D [4]
Pharmacology
ATC code	D11AX11 ( WHO )
Hazards
GHS labelling:
Pictograms
Signal word	Danger
Hazard statements	H302, H317, H318, H341, H351, H400
Precautionary statements	P201, P202, P261, P264, P270, P272, P273, P280, P281, P301+P312, P302+P352, P305+P351+P338, P308+P313, P310, P321, P330, P333+P313, P363, P391, P405, P501
NFPA 704 (fire diamond)	[5] 2 1
Flash point	165 °C (329 °F; 438 K)
Lethal dose or concentration (LD, LC):
LD50 (median dose)	490 mg/kg (mammal, oral) 245 mg/kg (mouse, oral) 200 mg/kg (rabbit, oral) 320 mg/kg (rat, oral) 550 mg/kg (guinea pig, oral) 200 mg/kg (dog, oral) 70 mg/kg (cat, oral) [6]
NIOSH (US health exposure limits):
PEL (Permissible)	TWA 2 mg/m3 [2]
REL (Recommended)	C 2 mg/m3 [15-minute] [2]
IDLH (Immediate danger)	50 mg/m3 [2]
Related compounds
Related benzenediols	Pyrocatechol Resorcinol
Related compounds	1,4-benzoquinone
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y  verify  (what is  YN ?) Infobox references

Hydroquinone, also known as benzene-1,4-diol or quinol, is an aromatic organic compound that is a type of phenol, a derivative of benzene, having the chemical formula C₆H₄(OH)₂. It has two hydroxyl groups bonded to a benzene ring in a para position. It is a white granular solid. Substituted derivatives of this parent compound are also referred to as hydroquinones. The name "hydroquinone" was coined by Friedrich Wöhler in 1843. ^[7]

In 2022, it was the 268th most commonly prescribed medication in the United States, with more than 900,000 prescriptions. ^{[8] [9]}

Production

Hydroquinone is produced industrially in two main ways. ^[10]

• 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. ^[11]
• 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):

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. ^{[12] [13] [14] [15] [16] [17]} 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. ^[12]
• Hydroquinone and its derivatives can also be prepared by oxidation of various phenols, such as aniline and DIPB. ^[18] 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. ^[19]
• Hydrolysis of chlorophenol. ^[18]

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. ^[20]

Reactions

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. ^[10]

Redox

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 (C₆H₆O₂·C₆H₄O₂), is formed. This complex dissolves in hot water, dissociating both quinone molecules in solution. ^[21]

Amination

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: ^[10]

C₆H₄(OH)₂ + CH₃NH₂ → HOC₆H₄NHCH₃ + H₂O

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

C₆H₄(OH)₂ + 2 C₆H₅NH₂ → C₆H₄(N(H)C₆H₅)₂ + 2 H₂O

Uses

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. ^[22]

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.

Skin depigmentation

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. ^{[23] [24]}

In 2006, the United States Food and Drug Administration revoked its previous approval of hydroquinone and proposed a ban on all over-the-counter preparations. ^[25] The FDA officially banned hydroquinone in 2020 as part of a larger reform of the over-the-counter drug review process. ^[26] The FDA stated that hydroquinone cannot be ruled out as a potential carcinogen. ^[27] 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. ^[28]

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. ^{[25] [27] [29]} NTP evaluation showed some evidence of long-term carcinogenic and genotoxic effects. ^[30]

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. ^[31] Several such agents are already available or under research, ^[32] including azelaic acid, ^[33] kojic acid, retinoids, cysteamine, ^[34] 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. ^[35]

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.

Natural occurrences

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. ^[36]

Hydroquinone is thought to be the active toxin in Agaricus hondensis mushrooms. ^[37]

Hydroquinone has been shown to be one of the chemical constituents of the natural product propolis. ^[38]

It is also one of the chemical compounds found in castoreum. This compound is gathered from the beaver's castor sacs. ^[39]

References

1. "Front Matter". Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 691. doi:10.1039/9781849733069-FP001. ISBN   978-0-85404-182-4.
2. NIOSH Pocket Guide to Chemical Hazards. "#0338". National Institute for Occupational Safety and Health (NIOSH).
3. "Hydroquinone" (PDF). OECD SIDS . UNEP Publications. Archived from the original (PDF) on 20 October 2016. Retrieved 17 September 2018.
4. Lander, John J.; Svirbely, John J. Lander, W. J. (1945). "The Dipole Moments of Catechol, Resorcinol and Hydroquinone". Journal of the American Chemical Society. 67 (2): 322–324. Bibcode:1945JAChS..67..322L. doi:10.1021/ja01218a051.
5. "Archived copy" (PDF). Archived (PDF) from the original on 2 February 2014. Retrieved 25 January 2014.
6. "Hydroquinone". Immediately Dangerous to Life or Health Concentrations (IDLH). National Institute for Occupational Safety and Health (NIOSH).
7. F. Wöhler (1844) "Untersuchungen über das Chinon" (Investigations of quinone), Annalen der Chemie und Pharmacie, 51 : 145-163. From page 146: "Das so erhaltene Destillat … enthält … einen neuen, krystallisierenden Körper, den ich unter dem Namen farbloses Hydrochinon weiter unten näher beschreiben werde." (The distillate so obtained … contains … a new, crystallizable substance, that I will describe, under the name of colorless hydroquinone, further below in more detail.) [Note: Wöhler's empirical formula for hydroquinone (p. 152) is incorrect because (1) he attributed 25 (instead of 24) carbon atoms to the molecule, and (2) as many chemists at the time did, he used the wrong atomic masses for carbon (6 instead of 12) and oxygen (8 instead of 16). With these corrections, his empirical formula becomes: C₁₂H₁₂O₄. Dividing the subscripts by 2, the result is: C₆H₆O₂, which is correct.]
8. "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
9. "Hydroquinone Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
10. 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.
11. Gerhard Franz, Roger A. Sheldon "Oxidation" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2000 doi : 10.1002/14356007.a18_261
12. Reppe, Walter; Kutepow, N; Magin, A (1969). "Cyclization of Acetylenic Compounds". Angewandte Chemie International Edition in English. 8 (10): 727–733. doi:10.1002/anie.196907271.
13. Hubel, Karl; Braye, Henri (1960). Process for the preparation of substituted cyclic compounds and products resulting therefrom US3149138 A (PDF). Union Carbide Corp.
14. Pino, Piero; Braca, Giuseppe; Sbrana, Glauco (1964). Preparation of hydroquinone US3355503 A (PDF). Lonza Ag.
15. Walter, Reppe; Magin, August (1966). Production of hydroquinones US3394193 A (PDF). Basf Ag.
16. Piero, Pino; Giuseppe, Braca; Frediano, Settimo; Glauco, Sbrana (1967). Preparation of hydroquinone US3459812 A (PDF). Lonza Ag.
17. Holmes, J.; Hagemeyer, H. (1971). Process for the production of hydroquinone US 3742071 A (PDF). Eastman Kodak Co.
18. Shi Y, Xia Y, Xu G, Wen L, Gao G, Zong B (28 October 2021). "Hydrogen peroxide and applications in green hydrocarbon nitridation and oxidation". Chinese Journal of Chemical Engineering (Review article). 41: 145–161. doi:10.1016/j.cjche.2021.09.030. S2CID   240248911.
19. 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. On pages 341-342, the preparation and properties of l'acide pyro-kinique (pyroquinic acid or hydroquinone) are discussed.
    • Roscoe, Henry (1891). A Treatise on Chemistry, Volume 3, Part 3. London: Macmillan & Co. p. 165.
20. Shi et al. 2021, p. 159.
21. Streitwieser, Andrew (1992). Introduction to organic chemistry. Heathcock, Clayton H., 1936-, Kosower, Edward M. (4th ed.). Upper Saddle River, N.J.: Prentice Hall. ISBN   978-0139738500. OCLC   52836313.
22. Additive manufacturing of ceramics from preceramic polymers Additive manufacturing 2019 vol. 27. pp 80-90
23. Council Directive 76/768/EEC of 27 July 1976 on the approximation of the laws of the Member States relating to cosmetic products
24. "Clear N Smooth Skin Toning Cream recalled". 4 October 2011. Retrieved 4 April 2018.
25. United States Food and Drug Administration (2006). Skin Bleaching Drug Products for Over-the-Counter Product Use; Proposed Rule (PDF) (Report). 1978N-0065. Archived (PDF) from the original on 16 May 2011.
26. "Congress Enacts OTC Monograph Reform". JD Supra. Retrieved 19 December 2021.
27. Research, Center for Drug Evaluation and. "About the Center for Drug Evaluation and Research - Hydroquinone Studies Under The National Toxicology Program (NTP)". www.fda.gov. Archived from the original on 22 January 2017. Retrieved 12 February 2017.
28. Campaign For Safe Cosmetics - Hydroquinone Archived 27 November 2010 at the Wayback Machine
29. Olumide, YM; Akinkugbe, AO; Altraide, D; Mohammed, T; Ahamefule, N; Ayanlowo, S; Onyekonwu, C; Essen, N (April 2008). "Complications of chronic use of skin lightening cosmetics". International Journal of Dermatology. 47 (4): 344–53. doi:10.1111/j.1365-4632.2008.02719.x. PMID   18377596. S2CID   8159382.
30. "Hydroquinone 10022-H". ntp.niehs.nih.gov. Archived from the original on 1 October 2017. Retrieved 18 August 2023.
31. Draelos, Zoe Diana (1 September 2007). "Skin lightening preparations and the hydroquinone controversy". Dermatologic Therapy. 20 (5): 308–313. doi: 10.1111/j.1529-8019.2007.00144.x . ISSN   1529-8019. PMID   18045355. S2CID   24913995.
32. Bandyopadhyay, Debabrata (1 January 2009). "Topical treatment of melasma". Indian Journal of Dermatology. 54 (4): 303–309. doi: 10.4103/0019-5154.57602 . ISSN   0019-5154. PMC   2807702 . PMID   20101327.
33. Mazurek, Klaudia; Pierzchała, Ewa (1 September 2016). "Comparison of efficacy of products containing azelaic acid in melasma treatment". Journal of Cosmetic Dermatology. 15 (3): 269–282. doi:10.1111/jocd.12217. ISSN   1473-2165. PMID   27028014. S2CID   25303091.
34. Mansouri, P.; Farshi, S.; Hashemi, Z.; Kasraee, B. (1 July 2015). "Evaluation of the efficacy of cysteamine 5% cream in the treatment of epidermal melasma: a randomized double-blind placebo-controlled trial". The British Journal of Dermatology. 173 (1): 209–217. doi:10.1111/bjd.13424. ISSN   1365-2133. PMID   25251767. S2CID   21618233.
35. "Hydroquinones". Phenols—Advances in Research and Application: 2013 Edition. Scholastic. 2013. p. 76.
36. Organic Chemistry, Solomon and Fryhle, 10th edition, Wiley Publishing, 2010.^{[ page needed ]}
37. Joval, E; Kroeger, P; N (April 1996). "Hydroquinone: the toxic compound of Agaricus hondensis". Planta Medica. 62 (2): 185. doi:10.1055/s-2006-957852. PMID   17252436. S2CID   260249338.
38. Burdock, G.A. (1998). "Review of the biological properties and toxicity of bee propolis (propolis)". Food and Chemical Toxicology. 36 (4): 347–363. doi:10.1016/S0278-6915(97)00145-2. PMID   9651052.
39. The Beaver: Its Life and Impact. Dietland Muller-Schwarze, 2003, page 43 (book at google books)

External links

• International Chemical Safety Card 0166
• NIOSH Pocket Guide to Chemical Hazards