4-Acetamidophenol
[CAS# 103-90-2]

Identification

• Classification: API >> Antipyretic analgesics >> Antipyretic and analgesic
• Name: 4-Acetamidophenol
• Synonyms: p-Hydroxyacetanilide; Acetaminophen; Paracetamol; N-Acetyl-4-aminophenol; APAP
• Molecular Formula: C₈H₉NO₂
• Molecular Weight: 151.16
• CAS Registry Number: 103-90-2
• EC Number: 203-157-5
• SMILES: CC(=O)NC1=CC=C(C=C1)O

Properties

• Melting point: 168-172 °C
• Density: 1.293 g/mL
• Water solubility: 14 g/L (20 °C)
• alpha: 23

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H412
• Safety Statements: P264-P264+P265-P270-P273-P280-P301+P317-P302+P352-P305+P351+P338-P321-P330-P332+P317-P337+P317-P362+P364-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	4	H332
Specific target organ toxicity - single exposure	STOT SE	2	H371
Skin sensitization	Skin Sens.	1B	H317
Specific target organ toxicity - single exposure	STOT SE	1	H370
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Germ cell mutagenicity	Muta.	2	H341
Acute toxicity	Acute Tox.	4	H312
Skin sensitization	Skin Sens.	1	H317
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Chronic hazardous to the aquatic environment	Aquatic Chronic	4	H413
Skin mild irritation	Skin Mild Irrit. 99	3	H315
Respiratory sensitization	Resp. Sens.	1	H334
Carcinogenicity	Carc.	2	H351
Eye irritation	Eye Irrit.	2	H320
Respiratory sensitization	Resp. Sens.	1B	H334
Specific target organ toxicity - single exposure	STOT SE	3	H336

Discovery and Applications

4-Acetamidophenol, commonly known as paracetamol or acetaminophen, is a widely used over-the-counter medication recognized for its pain-relieving and fever-reducing properties. Its molecular formula is C8H9NO2, and it belongs to the class of drugs known as analgesics and antipyretics. The discovery of 4-acetamidophenol marked a significant advancement in medical therapeutics, providing an effective alternative to other pain relievers that often had more severe side effects.

The history of 4-acetamidophenol dates back to the late 19th century. In 1877, a German chemist named Harmon Northrop Morse first synthesized the compound by reducing p-nitrophenol with tin in glacial acetic acid. However, its medicinal properties were not immediately recognized. It wasn't until the 1940s that paracetamol's full potential as a pain reliever and fever reducer became apparent. Scientists discovered that it was a less toxic metabolite of phenacetin, another analgesic that was widely used at the time but had been associated with harmful side effects such as kidney damage. This led to the development and marketing of paracetamol as a safer alternative.

Paracetamol works primarily by inhibiting the production of prostaglandins in the brain, which are chemicals responsible for pain and fever. Unlike non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin and ibuprofen, paracetamol does not have significant anti-inflammatory properties, making it particularly useful for treating pain and fever without irritating the stomach lining or causing gastrointestinal issues.

One of the main applications of 4-acetamidophenol is in the treatment of mild to moderate pain, including headaches, muscle aches, toothaches, arthritis, and menstrual cramps. It is also commonly used to reduce fever in patients of all ages. Due to its safety profile, paracetamol is often recommended for use in children and individuals who cannot tolerate NSAIDs. It is available in various forms, including tablets, capsules, liquid suspensions, and suppositories, making it accessible for different patient needs.

In addition to its widespread use as a single-ingredient medication, paracetamol is often combined with other active ingredients in multi-symptom relief products. For example, it is commonly found in combination with caffeine in products designed to treat headaches or with codeine in prescription medications for more severe pain. This versatility has made paracetamol a staple in both prescription and over-the-counter medicine cabinets worldwide.

Despite its safety and efficacy, there are risks associated with the misuse of 4-acetamidophenol. The most significant concern is liver toxicity, which can occur if paracetamol is taken in excessive doses. The liver metabolizes paracetamol, and high doses can overwhelm its capacity, leading to the accumulation of a toxic metabolite known as N-acetyl-p-benzoquinone imine (NAPQI). This can cause severe liver damage and potentially be fatal if not treated promptly. To mitigate this risk, dosage guidelines are strictly recommended, and patients are advised not to exceed the maximum daily limit.

In recent years, the widespread availability and use of paracetamol have prompted discussions about its environmental impact. Residues of 4-acetamidophenol have been detected in water bodies, raising concerns about potential ecological effects. Research into improving the environmental safety of pharmaceuticals, including paracetamol, is ongoing, with efforts focused on developing more sustainable manufacturing processes and better wastewater treatment technologies.

In conclusion, 4-acetamidophenol is a significant chemical substance that has had a profound impact on healthcare due to its effectiveness as a pain reliever and fever reducer. Since its discovery and introduction as a safer alternative to other analgesics, it has become one of the most commonly used medications globally, valued for its accessibility, safety, and versatility.

References

1. Synthesis: Hinsberg, O. (1892). "Über die Synthese des Paracetamols." Berichte der deutschen chemischen Gesellschaft, 25(2), 2415-2418.

2. Applications: Toms, L., et al. (2008). "Single dose oral paracetamol (acetaminophen) for postoperative pain in adults." Cochrane Database of Systematic Reviews, (1), CD004602.
DOI: 10.1002/14651858.CD004602.pub2

3. Review: Ghanem, C. I., et al. (2016). "Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity." Pharmacological Research, 109, 119-131.
DOI: 10.1016/j.phrs.2016.02.020