4-Piperazinobenzonitrile
[CAS 68104-63-2]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Piperazine
• Name: 4-Piperazinobenzonitrile
• Synonyms: 1-(4-Cyanophenyl)piperazine; 4-(N-Piperazinyl)benzonitrile
• Molecular Formula: C₁₁H₁₃N₃
• Molecular Weight: 187.24
• CAS Registry Number: 68104-63-2
• EC Number: 625-042-2
• SMILES: C1CN(CCN1)C2=CC=C(C=C2)C#N

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Melting point: 83 - 86 °C (Expl.)
• Boiling point: 381.6±27.0 °C 760 mmHg (Calc.)^*
• Flash point: 184.6±23.7 °C (Calc.)^*
• Index of refraction: 1.602 (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
Eye irritation	Eye Irrit.	2	H319
Acute toxicity	Acute Tox.	4	H302
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	4	H312
Acute toxicity	Acute Tox.	4	H332
Eye irritation	Eye Irrit.	2A	H319

Discovery and Applications

4-Piperazinobenzonitrile is an aromatic nitrile compound containing a piperazine ring attached to a benzene ring. It belongs to the class of nitrogen-containing heterocyclic aromatic compounds and is characterized by the combination of a cyano group, an aromatic framework, and a piperazine functional group. The compound is mainly used as an intermediate in organic synthesis, particularly in the preparation of molecules containing aryl piperazine structures.

The development of piperazine-containing aromatic compounds is closely related to the expansion of heterocyclic chemistry and medicinal chemistry. Piperazine is a six-membered nitrogen-containing heterocycle containing two nitrogen atoms at opposite positions in the ring. Since its introduction into synthetic chemistry, piperazine derivatives have attracted attention because the ring provides useful chemical properties, including basicity, water compatibility after salt formation, and the ability to participate in hydrogen bonding.

4-Piperazinobenzonitrile consists of a benzene ring substituted with two important functional groups. A cyano group is attached directly to the aromatic ring, forming a benzonitrile structure, while a piperazine ring is connected through one of its nitrogen atoms at the para position relative to the cyano group. This arrangement gives the molecule a symmetrical para-substituted aromatic framework.

The nitrile group is an important functional feature of the molecule. It contains a carbon-nitrogen triple bond in which both atoms are sp-hybridized, producing a linear structure. The nitrile nitrogen has a lone pair of electrons and can participate as a hydrogen bond acceptor. The cyano group also withdraws electron density from the aromatic ring, influencing the electronic properties and reactivity of the benzene system.

The piperazine ring provides the compound with additional nitrogen functionality. One nitrogen atom is bonded to the aromatic ring, while the other remains available for further chemical modification. The piperazine nitrogen atoms are basic and can be protonated by acids to form salts. This property is common among piperazine derivatives and is frequently used in the preparation of water-soluble forms of related compounds.

The para arrangement of the cyano group and piperazine substituent affects the electronic distribution of the aromatic ring. The piperazine nitrogen attached to the ring can donate electron density through resonance, while the cyano group withdraws electron density through inductive and resonance effects. The interaction of these substituents creates a substituted aromatic system with tunable electronic properties.

The main application of 4-piperazinobenzonitrile is as a synthetic building block. Aromatic piperazine derivatives are widely used in medicinal chemistry because the piperazine ring is present in many biologically active molecules. The nitrile group provides an additional functional handle that can be retained or transformed during further synthesis.

The compound has been used in the preparation of more complex nitrogen-containing molecules. The free piperazine nitrogen can undergo reactions such as alkylation, acylation, and sulfonylation, allowing chemists to introduce various substituents. The nitrile group can also participate in transformations that convert it into other functional groups, including amides and carboxylic acids under suitable conditions.

In pharmaceutical research, piperazine-containing intermediates are valuable because the piperazine ring can improve molecular interactions and influence physicochemical properties of drug candidates. Many synthetic programs use substituted piperazines as modular components that allow systematic modification of molecular structures.

The compound also represents a useful example of combining aromatic and heterocyclic structural elements. The benzene ring provides a rigid hydrophobic framework, while the piperazine ring contributes polarity and hydrogen-bonding capability. This combination is frequently employed in the design of functional organic molecules.

Overall, 4-piperazinobenzonitrile is an aromatic heterocyclic intermediate containing a para-substituted benzonitrile framework and a piperazine ring. Its importance comes from the versatility of its nitrile and piperazine functional groups, which allow further chemical modification and make it a valuable building block in organic synthesis and medicinal chemistry research.

References

2026. Crystallographic fragment screening discovers novel micromolar active inhibitors and druggable hotspots of SARS-CoV-2 PLpro. International Journal of Biological Macromolecules.
DOI: 10.1016/j.ijbiomac.2026.150689

2021. Design, synthesis, and evaluation of novel, selective γ-butyrolactones sigma-2 ligands. Medicinal Chemistry Research.
DOI: 10.1007/s00044-021-02771-0