2-Chloro-3-methylpyrazine
[CAS# 95-58-9]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrazines
• Name: 2-Chloro-3-methylpyrazine
• Molecular Formula: C₅H₅ClN₂
• Molecular Weight: 128.56
• CAS Registry Number: 95-58-9
• EC Number: 202-434-8
• SMILES: CC1=NC=CN=C1Cl

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Boiling point: 169.5±35.0 ºC 760 mmHg (Calc.)^*, 191.8 ºC (Expl.)
• Flash point: 70.2±11.5 ºC (Calc.)^*
• Index of refraction: 1.53 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS05;GHS07 Danger
• Hazard Statements: H302-H315-H318-H319-H335
• Precautionary Statements: P261-P264-P264+P265-P270-P271-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P305+P354+P338-P317-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2A	H319
Skin irritation	Skin Irrit.	2	H315

Discovory and Applicatios

2-Chloro-3-methylpyrazine is a halogenated heteroaromatic compound consisting of a six-membered pyrazine ring with a chlorine atom at the second position and a methyl group at the third position. Pyrazine derivatives have been studied for over a century due to their prevalence in natural products, pharmaceuticals, and agrochemicals. The substitution of a chloro atom at the 2-position increases the electrophilic character of the ring, making it a reactive site for nucleophilic substitution reactions. The methyl group at the 3-position provides steric hindrance and electron-donating effects, which influence the chemical reactivity and the electronic properties of the ring system. These features render 2-chloro-3-methylpyrazine a valuable intermediate in organic synthesis.

The compound can be synthesized by selective halogenation of 3-methylpyrazine or by functionalization of pre-halogenated pyrazine derivatives. The choice of reagents, solvent, and temperature is critical to achieving high selectivity and preventing over-halogenation or side reactions such as oxidation or polymerization. The product is usually obtained as a colorless to pale yellow crystalline solid or liquid, depending on the purification and storage conditions. Proper handling ensures that the compound maintains its stability and reactivity for subsequent synthetic applications.

2-Chloro-3-methylpyrazine is widely used as a building block in the synthesis of substituted pyrazines, which are of significant interest in medicinal and agrochemical chemistry. The chloro substituent enables nucleophilic aromatic substitution reactions with amines, thiols, or alkoxides, allowing the introduction of diverse functional groups at the 2-position. This selective modification is valuable for constructing heterocyclic scaffolds with desired biological or chemical properties. The methyl group remains largely unreactive under mild conditions but can influence the orientation and electronic properties of additional substituents introduced onto the pyrazine ring.

In pharmaceutical research, derivatives of 2-chloro-3-methylpyrazine have been used to develop compounds with antibacterial, antifungal, or anticancer activities. The pyrazine core serves as a scaffold for molecular interactions, while selective substitution at the 2- and 3-positions allows tuning of physicochemical properties, binding affinity, and metabolic stability. Its use as an intermediate facilitates the rapid assembly of libraries of compounds for structure–activity relationship studies, enabling optimization of pharmacological properties and selectivity.

In agrochemistry, 2-chloro-3-methylpyrazine has been incorporated into molecules designed for herbicidal or fungicidal activity. The heteroaromatic system provides structural rigidity, while functionalization at the halogenated site allows modulation of biological activity. By serving as a versatile intermediate, it enables the synthesis of diverse pyrazine derivatives that are environmentally stable and effective against target pests or pathogens.

Beyond medicinal and agrochemical applications, 2-chloro-3-methylpyrazine is utilized in materials chemistry and organic methodology research. It serves as a substrate in cross-coupling reactions, such as Suzuki–Miyaura or Buchwald–Hartwig couplings, to build extended heteroaromatic systems for organic electronics, fluorescent probes, or functional polymers. Its predictable reactivity patterns and the combination of electron-withdrawing and electron-donating substituents allow systematic investigation of reaction mechanisms, catalyst performance, and regioselectivity in heterocyclic chemistry.

Physically, 2-chloro-3-methylpyrazine is moderately soluble in polar organic solvents and slightly soluble in water. It is stable under ambient conditions but should be protected from strong oxidants, acids, or bases that may degrade the heterocyclic ring. Storage in a tightly closed container in a cool, dry place ensures that the compound retains its chemical integrity for laboratory or industrial use. Its stability, combined with its reactive sites, makes it a reliable intermediate for the construction of a variety of substituted pyrazine derivatives.

Overall, 2-chloro-3-methylpyrazine is an important heteroaromatic intermediate valued for its chemical versatility. Its combination of a chloro substituent and a methyl group enables selective functionalization and derivatization, facilitating the synthesis of bioactive compounds, agrochemicals, and functional materials. The compound’s predictable reactivity, stability, and structural features make it a cornerstone in heterocyclic and synthetic organic chemistry.

References

2019. Generating the Blood Exposome Database Using a Comprehensive Text Mining and Database Fusion Approach. Environmental Health Perspectives, 127(9).
DOI: 10.1289/ehp4713

2010. Alkylpyrazines: alarm pheromone components of the little fire ant, Wasmannia auropunctata (Roger) (Hymenoptera, Formicidae). Insectes Sociaux, 57(2).
DOI: 10.1007/s00040-010-0075-4