5,6-Dichloronicotinic acid
[CAS 41667-95-2]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyridine compound >> Pyridine derivative
• Name: 5,6-Dichloronicotinic acid
• Synonyms: 5,6-Dichloropyridine-3-carboxylic acid
• Molecular Formula: C₆H₃Cl₂NO₂
• Molecular Weight: 192.00
• CAS Registry Number: 41667-95-2
• EC Number: 609-951-1
• SMILES: C1=C(C=NC(=C1Cl)Cl)C(=O)O

Properties

• Density: 1.6$+/-$0.1 g/cm³ Calc.^*
• Melting point: 164 - 168 $degree$C (Expl.)
• Boiling point: 342.1$+/-$37.0 $degree$C 760 mmHg (Calc.)^*
• Flash point: 160.7$+/-$26.5 $degree$C (Calc.)^*
• Index of refraction: 1.606 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P271-P280-P302+P352-P304+P340-P305+P351+P338-P319-P321-P332+P317-P337+P317-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
Eye irritation	Eye Irrit.	2	H319
Eye irritation	Eye Irrit.	2A	H319
Acute toxicity	Acute Tox.	4	H302

Discovery and Applications

5,6-Dichloronicotinic acid is a halogenated derivative of nicotinic acid (pyridine-3-carboxylic acid), in which two chlorine atoms are substituted on the pyridine ring at the 5- and 6-positions. Its molecular formula is C₆H₃Cl₂NO₂. The compound belongs to the class of chlorinated heteroaromatic carboxylic acids and is structurally characterized by a pyridine ring bearing both a carboxyl group and electron-withdrawing chlorine substituents.

The core structure of 5,6-dichloronicotinic acid is based on nicotinic acid, a naturally occurring pyridine carboxylic acid related to vitamin B₃ (niacin). In this derivative, the introduction of chlorine atoms at positions 5 and 6 significantly alters the electronic properties of the aromatic ring. Chlorine is an electron-withdrawing substituent through inductive effects and can also participate weakly in resonance interactions, which influences the acidity and reactivity of the carboxyl group as well as the overall reactivity of the heteroaromatic system.

The carboxyl group at the 3-position is responsible for the acidic character of the molecule, allowing it to form salts and participate in typical carboxylic acid reactions such as esterification, amidation, and conversion to acid chlorides. The presence of two chlorine atoms increases the electron deficiency of the pyridine ring, making it more susceptible to nucleophilic aromatic substitution under appropriate conditions compared to unsubstituted nicotinic acid.

Compounds of this type are typically synthesized through stepwise halogenation of nicotinic acid or related pyridine intermediates. Electrophilic chlorination under controlled conditions can introduce chlorine atoms onto the activated positions of the pyridine ring. Because pyridine rings are generally deactivated toward electrophilic substitution, such reactions often require strong activating or directing conditions, or the use of pre-functionalized intermediates followed by selective substitution.

5,6-Dichloronicotinic acid is primarily used as a chemical intermediate in organic synthesis. The presence of both a carboxyl group and reactive chlorine substituents makes it a useful building block for the preparation of more complex heterocyclic compounds. The chlorine atoms can be displaced by nucleophiles such as amines, alkoxides, or thiols, enabling the synthesis of substituted nicotinic acid derivatives with diverse functional groups.

In medicinal and agrochemical research, halogenated pyridine carboxylic acids are often used as intermediates for the synthesis of biologically active compounds. The electron-deficient nature of the chlorinated pyridine ring allows for selective functionalization, which is valuable in the construction of heterocyclic frameworks found in pharmaceuticals, herbicides, and other bioactive molecules.

The carboxylic acid group also allows for further derivatization, including formation of esters and amides, which can modify the compound’s solubility, reactivity, and biological properties. These transformations are commonly used in synthetic chemistry to access libraries of structurally related compounds for screening purposes.

From a physicochemical perspective, the combination of a polar carboxyl group and electron-withdrawing chlorine substituents results in a compound with relatively high polarity and strong intermolecular interactions, including hydrogen bonding and dipole–dipole interactions. These properties influence its solid-state behavior and solubility in polar solvents.

Overall, 5,6-dichloronicotinic acid is a chlorinated heteroaromatic carboxylic acid derived from nicotinic acid. Its structure combines a reactive pyridine ring with both carboxyl and chloro substituents, making it a versatile intermediate in organic synthesis, particularly for the construction of substituted pyridine-based compounds used in chemical and pharmaceutical research.

References

2023. Synthesis and Antifungal Activity of Indole Derivatives. Chemistry of Natural Compounds.
DOI: 10.1007/s10600-023-03929-5

2018. Tetrahydroacridine derivatives with dichloronicotinic acid moiety as attractive, multipotent agents for Alzheimer's disease treatment. European Journal of Medicinal Chemistry.
DOI: 10.1016/j.ejmech.2018.01.014