Piceol

Piceol
Chemical structure of piceol
Names
Preferred IUPAC name
1-(4-Hydroxyphenyl)ethan-1-one
Other names
1-(4-Hydroxyphenyl)ethanone
4-Hydroxyacetophenone
4'-Hydroxyacetophenone
p-Hydroxyacetophenone
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.002.548
UNII
  • InChI=1S/C8H8O2/c1-6(9)7-2-4-8(10)5-3-7/h2-5,10H,1H3
    Key: TXFPEBPIARQUIG-UHFFFAOYSA-N
  • InChI=1S/C8H8O2/c1-6(9)7-2-4-8(10)5-3-7/h2-5,10H,1H3
    Key: TXFPEBPIARQUIG-UHFFFAOYSA-N
  • CC(=O)C1=CC=C(C=C1)O
Properties
C8H8O2
Molar mass 136.150 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Piceol is a phenolic compound found in the needles and in mycorrhizal roots of Norway spruces (Picea abies).[1][2] Picein is the glucoside of piceol.[3]

Chemical production

In the industrial chemical synthesis of 4-hydroxyacetophenone, phenol reacts with acetic acid or preferably with acetic anhydride in the presence of anhydrous hydrogen fluoride (HF) or hydrofluoric acid as solvent and acylation catalyst—instead of aluminum chloride (AlCl3), which must be used in stoichiometric amounts and generates problematic waste—to initially form acetic acid phenyl ester (I). This intermediate is converted to 4-hydroxyacetophenone (II) via a Fries rearrangement. As by-products (< 10 %), the isomer 2′-hydroxyacetophenone (III) and traces of 4-acetoxyacetophenone (4-acetylphenyl acetate) (IV) are also formed.[4]

Working with HF and hydrofluoric acid as solvents, as well as their recovery, requires complex processes and costly equipment made of special materials such as Hastelloy C-276 and surface coatings of fluoropolymers (e.g. Teflon), due to their high toxicity and corrosiveness.[5]

Since the product 4-HAP strongly retains HF, it must be removed by distillation using, for example, n-hexane.[6] Impurities are separated through multiple recrystallization steps from ethanol–water mixtures or similar solvents.[7]

Properties

Pure 4-hydroxyacetophenone is a white crystalline powder that dissolves readily in lower alcohols and diethyl ether. Its odour ranges from odourless[7] to floral.[8] The substance is readily biodegradable and approved for use in food under FEMA/GRAS #4330 (GRAS = generally recognized as safe).[9]

Applications

4-Hydroxyacetophenone exhibits antioxidant, fungicidal, and bacteriostatic properties[7] and is therefore used to stabilize cosmetic formulations.[10]

Uses

Piceol is used in the synthesis of several pharmaceutical drugs including octopamine, sotalol, bamethan, and dyclonine.

Piceol can be used to make acetaminophen by condensation with hydroxylamine and subsequent Beckmann rearrangement in acid.[11]

4-Vinylphenol (4-hydroxystyrene) can be synthesized through a multi-step reaction sequence from 4-hydroxyacetophenone (II). First, 4-HAP is acetylated with acetic anhydride to form 4-acetoxyacetophenone (IV). Catalytic hydrogenation of (IV) yields 4-acetoxyphenylmethylcarbinol (V), which is then dehydrated upon heating to produce 4-acetoxystyrene (4-vinylphenyl acetate) (VI).[12] Finally, the acetyl group can be hydrolyzed under basic or acidic catalysis to yield the target compound 4-hydroxystyrene (VII).[13]

Chain polymerization of 4-vinylphenol produces poly(4-hydroxystyrene), which serves as a resin binder in photoresists. During the polymerization of 4-hydroxystyrene, chain termination reactions can occur through hydrogen abstraction from the phenolic hydroxyl group, resulting in lower molar masses and broader molar mass distributions. Therefore, the protected precursor 4-acetoxystyrene (VI) is often polymerized, after which the acetyl protecting group is removed via a polymer-analogous reaction.

A seven-step synthesis of the beta-2-sympathomimetic salbutamol (albuterol) also starts from 4-hydroxyacetophenone and yields the racemate.[14]

The neurotransmitter Octopamine can be obtained by reacting 4-HAP with amyl nitrite or preferably tert-butyl nitrite in the presence of hydrogen chloride to form 4-hydroxyisonitrosoacetophenone, followed by catalytic hydrogenation. Under more intensive hydrogenation conditions, tyramine—the decarboxylation product of the amino acid tyrosine—is formed.[15][16]

A standard route to the peripheral vasodilator Bamethane also starts from 4-hydroxyacetophenone. In this process, the compound is first protected by a benzoyl group, brominated at the methyl group, reacted with n-butylamine to form a secondary amine, and finally hydrogenated over a palladium catalyst to yield the racemic end product.[17]

The naturally occurring homologous series compound Synephrine (oxedrine) can be synthesized analogously from 4-HAP, but its use is now considered obsolete due to questionable efficacy and safety concerns.[18]

Alkylation of 4-HAP, e.g. with 1-bromobutane, produces 4-butoxyacetophenone, from which the local anaesthetic dyclonine can be obtained.

The analgesic Paracetamol can also be produced industrially from 4-hydroxyacetophenone by reaction with bis(hydroxylammonium) sulfate (NH3OH)2SO4 to form the corresponding oxime, followed by a Beckmann rearrangement to yield 4-acetamidophenol (acetaminophen).[19]

However, this process proved economically uncompetitive due to high investment and environmental costs (e.g. disposal of sulfate generated from hydroxylammonium sulfate). A production plant commissioned in 1990 by Hoechst Celanese Corp. in Bishop, TX, with a capacity of 9,000 tons per year, was shut down in 2001.

Anticonvulsants are also possible by Mannich reaction:[20]

Metabolism

Diprenylated derivatives of piceol can be isolated from Ophryosporus macrodon.[21]

4-Hydroxyacetophenone monooxygenase is an enzyme that transforms piceol into O-acetylhydroquinone. This enzyme is found in Pseudomonas fluorescens.

See also

References

  1. ^ Løkke, H. (1990). "Picein and piceol concentrations in Norway spruce". Ecotoxicology and Environmental Safety. 19 (3): 301–9. doi:10.1016/0147-6513(90)90032-z. PMID 2364913.
  2. ^ Münzenberger, Babette; Heilemann, Jürgen; Strack, Dieter; Kottke, Ingrid; Oberwinkler, Franz (1990). "Phenolics of mycorrhizas and non-mycorrhizal roots of Norway spruce". Planta. 182 (1): 142–8. doi:10.1007/BF00239996. PMID 24197010.
  3. ^ Løkke, Hans (1990). "Picein and piceol concentrations in Norway spruce". Ecotoxicology and Environmental Safety. 19 (3): 301–309. doi:10.1016/0147-6513(90)90032-Z. PMID 2364913.
  4. ^ EP 0167286, K.G. Davenport, C.B. Hilton, G.N. Mott, D.L. Keene, "Process for producing 4-hydroxyacetophenone", published 1986-01-08, assigned to Celanese Corp. 
  5. ^ "Recommendation on Materials of Construction for Anhydrous Hydrogen Fluoride (AHF) and Hydrofluoric Acid Solutions (HF)" (PDF). Eurofluor. 2017-11-02. Retrieved 2022-04-01.
  6. ^ US 4663485, C.D. Murphy, D.L. Keene, D.D. Lindley, "Process for purifying 4-hydroxyacetophenone", published 1987-5-5, assigned to Celanese Corp. 
  7. ^ a b c WO 2018068902, R. Pillai, S. Siegel, E. Suess, K. Bolte, Y. Liuxin, "Method for purification of 4-hydroxyacetophenone", published 2018-04-19, assigned to Symrise AG, Sino-High (China) Co. Ltd. 
  8. ^ George A. Burdock (2010), Fenaroli’s Handbook of Flavor Ingredients, 6th Edition, Boca Raton, FL, U.S.A.: CRC Press, p. 908, ISBN 978-1-4200-9077-2
  9. ^ "GRAS Flavoring Substances 23" (PDF). food technology. FEMA Expert Panel. August 2007. Retrieved 2022-04-02.
  10. ^ EP 3122316, J. Pruns, T. Raschke, B. Nissen, "Öl in Wasser-Emulsionen mit einem Gehalt an 4-Hydroxyacetophenon und anionischen Emulgatoren", published 2018-06-27, assigned to Symrise AG 
  11. ^ U.S. patent 4,524,217
  12. ^ US 5274175, B.N. Shah, D.Q. Tran, D.L. Keene, "Process for the preparation of 4-acetoxyphenylmethyl carbinol", published 1993-12-28, assigned to Hoechst Celanese Corp. 
  13. ^ B.B. Corson, W.J. Heintzelman, L.H. Schwartzman, H.E. Tiefenthal, R.J. Lokken, J.E. Nickels, G.R. Atwood, F.J. Pavlik (1958), "Preparation of vinylphenols and isopropenylphenols", J. Org. Chem., vol. 23, no. 4, pp. 544–549, doi:10.1021/jo01098a012{{citation}}: CS1 maint: multiple names: authors list (link)
  14. ^ Ruben Vardanyan, Victor Hruby (2016), Synthesis of Best-Seller Drugs, Amsterdam, NL: Elsevier Inc., p. 360, ISBN 978-0-12-411492-0
  15. ^ US 3966813, G. Satzinger, W.D. Herrmann, "Process for the preparation of 1-(m- and p-hydroxyphenyl)-2-aminoethanol", published 1976-6-29, assigned to Warner-Lambert Co. 
  16. ^ US 5175368, A.M. Tafesh, J.A. McDonough, G.N. Mott, "Process for the preparation of arylalkylamines and substituted arylalkylamines", published 1992-12-29, assigned to Hoechst Celanese Corp. 
  17. ^ F. von Bruchhausen, S. Ebel, A.W. Frahm, E. Hackenthal (1993), Hagers Handbuch der Pharmazeutischen Praxis, Band 7, 5. Aufl., Berlin: Springer-Verlag, p. 367, ISBN 978-3-642-63429-1{{citation}}: CS1 maint: multiple names: authors list (link)
  18. ^ "Einstufung von Synephrin-haltigen Produkten, Stellungnahme der Gemeinsamen Expertenkommission". Bundesamt für Verbraucherschutz und Lebensmittelsicherheit. 2021-09-21. Retrieved 2022-04-04.
  19. ^ US 4524217, K.G. Davenport, C.B. Hilton, "Process for producing N-acyl-hydroxy aromatic amines", published 1985-6-18, assigned to Celanese Corp. 
  20. ^ Keshari, Amit K.; Tewari, Aseem; Verma, Shweta S.; Saraf, Shailendra K. (2017). "Novel Mannich-bases as Potential Anticonvulsants: Syntheses, Characterization and Biological Evaluation". Central Nervous System Agents in Medicinal Chemistry. 17 (3). doi:10.2174/1871524917666170717113524. ISSN 1871-5249.
  21. ^ Sigstad, Elizabeth; Catalán, César A.N.; Diaz, Jesús G.; Herz, Werner (1993). "Diprenylated derivatives of p-hydroxyacetophenone from Ophryosporus macrodon". Phytochemistry. 33: 165–169. doi:10.1016/0031-9422(93)85415-N.
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