4-Chloronicotinic acid
[CAS# 10177-29-4]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyridine compound >> Pyridine derivative
• Name: 4-Chloronicotinic acid
• Synonyms: 4-Chloropyridine-3-carboxylic acid; 4-Chloro-3-pyridinecarboxylic acid
• Molecular Formula: C₆H₄ClNO₂
• Molecular Weight: 157.56
• CAS Registry Number: 10177-29-4
• EC Number: 628-434-1
• SMILES: C1=CN=CC(=C1Cl)C(=O)O

Properties

• Density: 1.5±0.1 g/cm³, Calc.^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P270-P271-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
Skin irritation	Skin Irrit.	2	H315
Acute toxicity	Acute Tox.	4	H302
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2A	H319
Acute toxicity	Acute Tox.	4	H312
Acute toxicity	Acute Tox.	4	H332

Discovery and Applications

4-Chloronicotinic acid is a halogenated derivative of nicotinic acid, featuring a chlorine atom at the 4-position of the pyridine ring. Its molecular formula is C₆H₄ClNO₂, and it contains both a carboxylic acid functional group and a pyridine nitrogen, which confer useful chemical reactivity and biological relevance. The compound appears as a crystalline solid and is commonly used in organic synthesis, pharmaceutical research, and agrochemical development.

The discovery and preparation of 4-chloronicotinic acid can be traced back to investigations into halogen-substituted pyridinecarboxylic acids. It is typically synthesized through chlorination of nicotinic acid or nicotinic acid derivatives using reagents such as phosphorus oxychloride or other halogenating agents under controlled conditions. Electrophilic substitution on the pyridine ring generally leads to selective substitution at the 4-position, guided by the directing effects of the nitrogen atom and the carboxylic acid group.

4-Chloronicotinic acid serves as an important building block in heterocyclic chemistry. The presence of a chlorine substituent allows for nucleophilic aromatic substitution reactions, making it useful for the synthesis of a wide variety of substituted pyridines. This property is particularly important in the pharmaceutical and agrochemical industries, where pyridine derivatives are commonly found in active ingredients and intermediates.

One of the primary applications of 4-chloronicotinic acid is in the preparation of neonicotinoid insecticides, including compounds such as imidacloprid and acetamiprid. In these syntheses, 4-chloronicotinic acid is often used as a key precursor, undergoing reactions with heterocyclic amines or other nucleophiles to form active molecules that target nicotinic acetylcholine receptors in insects. These compounds exhibit high potency against a range of agricultural pests while maintaining relatively low toxicity to mammals when used according to safety guidelines.

In medicinal chemistry, 4-chloronicotinic acid and its derivatives have been evaluated for potential therapeutic properties, particularly as ligands or scaffolds for drug-like molecules. While the acid itself is not typically used as a drug, its chemical framework is incorporated into more complex structures during drug development. The presence of the chlorine atom and the pyridine ring allows for interactions with biological targets and contributes to metabolic stability in some contexts.

Analytical characterization of 4-chloronicotinic acid is performed using standard techniques, including nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, mass spectrometry (MS), and high-performance liquid chromatography (HPLC). These methods confirm the presence of the characteristic pyridine ring, carboxylic acid group, and chlorine substituent. The compound is soluble in polar organic solvents and slightly soluble in water, which supports its manipulation in laboratory and industrial settings.

In materials chemistry, chlorinated pyridines like 4-chloronicotinic acid are sometimes explored for their ability to coordinate with metal ions, forming metal-organic complexes or coordination polymers. These applications are typically secondary to its primary role in the synthesis of bioactive molecules, but the compound's functional groups make it a candidate for broader utility in coordination chemistry.

Commercially, 4-chloronicotinic acid is available from chemical suppliers in high-purity grades for use in research and manufacturing. It is handled using standard laboratory safety protocols, including the use of gloves, protective clothing, and proper ventilation, due to its potential to cause irritation upon contact or inhalation.

Overall, 4-chloronicotinic acid is a valuable synthetic intermediate with well-established applications in the production of insecticides and functionalized pyridine derivatives. Its predictable reactivity and structural versatility have made it a commonly used compound in industrial and academic chemical research.

References

2019. Synthesis of azachromones and azachromanones. Chemistry of Heterocyclic Compounds, 55(11).
DOI: 10.1007/s10593-019-02570-x

2019. Synthesis and properties of 2,3-heteroannulated thiochromones - hetero analogs of thioxanthone. Chemistry of Heterocyclic Compounds, 55(2).
DOI: 10.1007/s10593-019-02426-4

1995. Nature of the reducing agent and mechanism of the reductive condensation of trichloromethylarenes with hydroxylamine and hydrazines in pyridine. Chemistry of Heterocyclic Compounds, 31(6).
DOI: 10.1007/bf01169070