Piceol

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]

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
CAS Number	99-93-4 Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:28032
ChemSpider	7189
ECHA InfoCard	100.002.548
PubChem CID	7469
UNII	G1L3HT4CMH Y
CompTox Dashboard (EPA)	DTXSID0029133
InChI 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
SMILES CC(=O)C1=CC=C(C=C1)O
Properties
Chemical formula	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

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]

Synthesis of 4-hydroxyacetophenone (4-HAP)

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.^{[citation needed]}

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

4-Vinylphenol (4-hydroxystyrene)^{[citation needed]} 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]

Synthesis of 4-vinylphenol from 4-hydroxyacetophenone (4-HAP)

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]

Synthesis of octopamine+tyramine from 4-hydroxyacetophenone (4-HAP)

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]

Synthesis of bamethane from 4-hydroxyacetophenone (4-HAP)

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,^{[citation needed]} 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]

Synthesis of paracetamol from 4-hydroxyacetophenone (4-HAP)

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

• Paroxypropione, where the acetyl group is replaced by a propionyl group.
• Apocynin