4-Amino-3,5-dichloropyridine
[CAS# 22889-78-7]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyridine compound >> Chloropyridine
• Name: 4-Amino-3,5-dichloropyridine
• Synonyms: 3,5-Dichloro-4-pyridinamine
• Molecular Formula: C₅H₄Cl₂N₂
• Molecular Weight: 163.00
• CAS Registry Number: 22889-78-7
• EC Number: 245-304-6
• SMILES: C1=C(C(=C(C=N1)Cl)N)Cl

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Melting point: 159 - 161 ºC (Expl.)
• Boiling point: 250.8±35.0 ºC 760 mmHg (Calc.)^*
• Flash point: 105.5±25.9 ºC (Calc.)^*
• Index of refraction: 1.623 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS05;GHS06;GHS07 Danger
• Hazard Statements: H300-H302-H310-H315-H318-H319-H330-H335
• Precautionary Statements: P260-P261-P262-P264-P264+P265-P270-P271-P280-P284-P301+P316-P301+P317-P302+P352-P304+P340-P305+P351+P338-P305+P354+P338-P316-P317-P319-P320-P321-P330-P332+P317-P337+P317-P361+P364-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Serious eye damage	Eye Dam.	1	H318
Acute toxicity	Acute Tox.	1	H310
Acute toxicity	Acute Tox.	2	H300
Acute toxicity	Acute Tox.	1	H330
Eye irritation	Eye Irrit.	2	H319
Acute toxicity	Acute Tox.	4	H302
Acute toxicity	Acute Tox.	4	H312
Acute toxicity	Acute Tox.	4	H332
Chronic hazardous to the aquatic environment	Aquatic Chronic	4	H413
Acute toxicity	Acute Tox.	1	H300
Eye irritation	Eye Irrit.	2A	H319
Acute toxicity	Acute Tox.	2	H330

Discovory and Applicatios

4-Amino-3,5-dichloropyridine is a chlorinated aminopyridine in which two chlorine atoms occupy the 3- and 5-positions of the pyridine ring and an amino group is located at the 4-position. It belongs to a group of halogenated heteroaromatic compounds that were developed following the emergence of systematic halogen substitution chemistry in pyridine derivatives in the early twentieth century. The introduction of chlorine atoms into the pyridine nucleus was investigated to modulate physicochemical properties, including electron distribution, basicity, and reactivity patterns. The subsequent incorporation of an amino group provided additional synthetic utility due to its nucleophilic nature and its ability to participate in condensation and coupling reactions. As a result, 4-amino-3,5-dichloropyridine became an important intermediate in the preparation of more complex functional organic molecules.

The discovery and development of this compound are connected with the broader field of substituted pyridine chemistry, in which halogenated pyridines served as key precursors for the synthesis of agrochemicals, pharmaceuticals, and dyes. Electrophilic chlorination and nucleophilic substitution methodologies were refined to achieve regioselective halogen incorporation at activated ring positions. The subsequent installation of the amino group provided access to orthogonally functionalized species. Owing to the electron-withdrawing effect of the chlorine atoms, the reactivity of the pyridine core can be directed to favor substitution at predetermined positions. This development opened pathways to structurally diverse derivatives important in industrial and academic research.

In chemical synthesis, 4-amino-3,5-dichloropyridine is employed as a versatile intermediate. The amino substituent allows the compound to serve as a nucleophile in reactions such as amide formation, urea formation, carbamate synthesis, and heterocycle construction. The chlorine atoms can undergo metal-catalyzed cross-coupling reactions under appropriate conditions, offering a route to carbon–carbon or carbon–heteroatom substituted pyridine derivatives. Selective transformation of either chlorine atom expands the range of accessible substituted products, enabling stepwise introduction of additional functional groups. These properties make the compound suitable for constructing more elaborate pyridine-containing structures used in medicinal chemistry and materials science.

Within medicinal chemistry, this compound is used as a fragment for the elaboration of bioactive molecules. Halogenated aminopyridines have been incorporated into screening libraries to explore structure–activity relationships, taking advantage of their electronic and steric tunability. The presence of both chloro substituents and an amino group enables rational modification to adjust lipophilicity, solubility, metabolic stability, and target-binding interactions. As such, 4-amino-3,5-dichloropyridine has been utilized in the synthesis of experimental agents designed to interact with enzymes, receptors, or nucleic acid binding sites where aromatic heterocycles are required.

Applications of the compound extend beyond medicinal development. It is used in the synthesis of specialty chemicals and functional intermediates for crop protection research. Its structural framework is implemented in the design of agents with improved environmental stability and controlled biological activity. The compound also finds application in the development of advanced intermediates for dyes and pigments that employ heteroaromatic chromophores. In addition, its defined reactivity profile has made it useful in methodological studies directed at selective substitution on highly functionalized aromatic systems.

From a practical standpoint, 4-amino-3,5-dichloropyridine is typically handled as a stable crystalline solid under standard conditions. It is soluble in polar organic solvents suitable for synthetic transformations and workup. Its reactivity requires routine laboratory precautions, including control of moisture and avoidance of incompatible reagents, to maintain stability during storage and use.

As a consequence of its discovery within systematic halogenation chemistry and its subsequent adoption in synthetic methodology, 4-amino-3,5-dichloropyridine remains an established intermediate supporting research in chemical synthesis, medicinal chemistry, agrochemical development, and functional materials.

References

Sainsbury S F (1966) Aromatic chlorination. Part V. Chlorination of pyridines and related compounds. Journal of the Chemical Society C: Organic 1966 676–680.

Katayama H, Nishikata T, Lipshutz B H (2004) Pd-catalyzed amination of dihalogenated pyridines in aqueous media. Tetrahedron Letters 45 14 2555–2558.

Everson D A, Buonomo J A, Weix D J (2014) Nickel-catalyzed cross-electrophile coupling of 2-chloropyridines with alkyl bromides. Synlett 25 2 233–238 DOI: 10.1055/s-0033-1340151