4'-Hydroxyacetophenone
[CAS 99-93-4]

Identification

• Classification: Biochemical >> Amino acids and their derivatives >> Isoleucine derivative
• Name: 4'-Hydroxyacetophenone
• Synonyms: 1-(4-Hydroxyphenyl)ethanone; 4-Acetylphenol; p-Hydroxyacetophenone
• Molecular Formula: C₈H₈O₂
• Molecular Weight: 136.15
• CAS Registry Number: 99-93-4
• EC Number: 202-802-8
• SMILES: CC(=O)C1=CC=C(C=C1)O

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*
• Melting point: 109 - 111 °C (Expl.)
• Boiling point: 313.0 °C 760 mmHg (Calc.)^*, 361.3 - 362.7 °C (Expl.)
• Flash point: 121.2±12.4 °C (Calc.)^*, 166 °C (Expl.)
• Solubility: water: 10 g/L (22 °C), methanol: 0.1 g/mL (Expl.)
• Index of refraction: 1.552 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335-H412
• Safety Statements: P261-P264-P264+P265-P270-P271-P273-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Eye irritation	Eye Irrit.	2	H319
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412
Acute toxicity	Acute Tox.	4	H302
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2A	H319

chemBlink Chemical Story

4'-Hydroxyacetophenone, CAS 99-93-4, is an aromatic hydroxy ketone used in organic synthesis and also found in nature. It is also known as 4-hydroxyacetophenone, p-hydroxyacetophenone, or piceol. Its molecular formula is C₈H₈O₂ and its molecular weight is 136.15. Structurally, it contains a phenolic hydroxyl group and an acetyl group at opposite positions of a benzene ring.

Those two functional groups give the molecule two very different kinds of chemistry.

The phenolic OH can be alkylated, acylated, protected, or used as a connection point in the construction of larger molecules.

The acetyl group provides a reactive carbonyl and an adjacent methyl group. It can participate in condensation, reduction, oxidation, oxime formation, and other carbonyl transformations.

One particularly interesting transformation connects this relatively simple aromatic ketone with one of the world's most familiar medicines: acetaminophen, also known internationally as paracetamol.

At first glance, 4-hydroxyacetophenone and acetaminophen look surprisingly similar.

4-Hydroxyacetophenone contains:

HO-C₆H₄-COCH₃

Acetaminophen contains:

HO-C₆H₄-NHCOCH₃

The difference is only one nitrogen atom inserted between the aromatic ring and the acetyl-derived carbonyl group.

Installing that nitrogen is possible through one of the classic rearrangements of organic chemistry: the Beckmann rearrangement.

The first step converts the ketone into an oxime by reaction with hydroxylamine:

HO-C₆H₄-COCH₃

→

HO-C₆H₄-C(=NOH)CH₃

The oxime is then subjected to suitable acidic or catalytic conditions.

During the Beckmann rearrangement, one group attached to the original carbonyl carbon migrates to nitrogen while the carbon-nitrogen framework reorganizes.

With the appropriate 4-hydroxyacetophenone oxime, this rearrangement produces N-acetyl-p-aminophenol:

acetaminophen.

The transformation is remarkable because the acetyl group has not simply been removed and replaced.

Instead, the connectivity of the molecule has been reorganized.

A carbon-carbon relationship in the starting ketone becomes a carbon-nitrogen relationship in the product.

This chemistry attracted considerable attention as an alternative manufacturing route to acetaminophen.

Conventional acetaminophen production commonly proceeds through p-aminophenol followed by acetylation. Researchers and industrial chemists investigated routes beginning with phenol, converting it to 4-hydroxyacetophenone, forming the oxime, and then using the Beckmann rearrangement to produce acetaminophen.

Patents issued in the early 1990s describe integrated processes based specifically on this sequence.

In one such process, 4-hydroxyacetophenone was reacted with a hydroxylamine salt and base to form its ketoxime. The oxime was then subjected to a Beckmann rearrangement catalyst to produce N-acetyl-p-aminophenol.

Process research subsequently examined catalysts and solvents for this transformation, including heterogeneous acid catalysts intended to address some of the practical problems associated with strongly acidic conventional conditions.

The route also became useful for teaching chemistry.

A recent Journal of Chemical Education experiment uses the conversion of 4-hydroxyacetophenone toward paracetamol to illustrate carbonyl reactivity and the Beckmann rearrangement.

Students can therefore encounter the same molecular transformation both as a fundamental organic reaction and as part of the history of pharmaceutical process chemistry.

4'-Hydroxyacetophenone has another identity outside the synthetic laboratory.

Under the name piceol, it occurs naturally.

Natural-product databases report it from plant sources, and it has been classified as a plant and fungal metabolite.

Its occurrence has also been reported in foods and beverages. Regulatory and chemical databases list natural occurrence in materials including coffee, cloudberry, mango, cranberry, and other botanical or food sources.

The U.S. Food and Drug Administration lists 4-hydroxyacetophenone in its food-substance inventory as a flavoring agent or adjuvant, with FEMA number 4330.

This gives the molecule an interesting double identity.

In nature, it can be one of many small aromatic compounds produced or encountered in biological systems.

In an organic chemistry laboratory, the same molecule becomes a versatile construction material.

The phenolic OH can be modified.

The ketone can be transformed.

And through oxime formation followed by molecular rearrangement, the ketone can even become the amide functionality of acetaminophen.

The Beckmann reaction is especially instructive because it shows that organic synthesis is not always about adding more atoms to a molecule.

Sometimes the atoms needed for the target are already almost all present.

The challenge is connectivity.

Which atom is bonded to which?

4'-Hydroxyacetophenone and acetaminophen demonstrate this beautifully.

The starting material already contains the aromatic ring.

It already contains the phenolic OH.

It already contains the two-carbon acetyl fragment.

What it lacks is nitrogen and the correct arrangement of those atoms.

Oxime formation introduces nitrogen.

Rearrangement puts it in the right place.

A familiar pain reliever can therefore emerge not by constructing an entirely new molecular skeleton, but by teaching an existing skeleton a new way to connect its atoms.

References

1. PubChem. 4'-Hydroxyacetophenone, CID 7469. CAS 99-93-4. Molecular formula C₈H₈O₂; molecular weight 136.15.

2. US 4,954,652. Production of acetaminophen. Preparation of 4-hydroxyacetophenone oxime followed by Beckmann rearrangement to N-acetyl-p-aminophenol.

3. US 5,155,273. Production of acetaminophen. Integrated process based on 4-hydroxyacetophenone, oxime formation, and Beckmann rearrangement.

4. "Solvent effects in the liquid phase Beckmann rearrangement of 4-hydroxyacetophenone oxime over H-Beta catalyst." Study of the acetaminophen process route.

5. "Two-Step Synthesis of Paracetamol (Acetaminophen), a Practical Illustration of Carbonyl Reactivity for Year-One Biosciences Students." Journal of Chemical Education.

6. U.S. Food and Drug Administration. Substances Added to Food: 4-Hydroxyacetophenone, CAS 99-93-4, FEMA No. 4330.