1-Chloro-2-(chloromethyl)-4-nitrobenzene
[CAS# 69422-57-7]

Identification

• Classification: Chemical reagent >> Organic reagent >> Nitro compound
• Name: 1-Chloro-2-(chloromethyl)-4-nitrobenzene
• Molecular Formula: C₇H₅Cl₂NO₂
• Molecular Weight: 206.03
• CAS Registry Number: 69422-57-7
• EC Number: 999-833-9
• SMILES: C1=CC(=C(C=C1[N+](=O)[O-])CCl)Cl

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Boiling point: 317.9±27.0 ºC 760 mmHg (Calc.)^*
• Flash point: 146.0±23.7 ºC (Calc.)^*
• Index of refraction: 1.589 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS05;GHS07 Danger
• Hazard Statements: H302-H314-H335
• Precautionary Statements: P260-P261-P264-P270-P271-P280-P301+P317-P301+P330+P331-P302+P361+P354-P304+P340-P305+P354+P338-P316-P319-P321-P330-P363-P403+P233-P405-P501

Discovory and Applicatios

The chemical substance 1-chloro-2-(chloromethyl)-4-nitrobenzene is a dihalogenated nitrobenzene derivative with a chloromethyl group, recognized in organic chemistry as a versatile synthetic intermediate, particularly in pharmaceutical, agrochemical, and materials chemistry. Its discovery and applications are well-documented in the literature, rooted in the development of substituted aromatics and regioselective functionalization techniques.

The origins of this compound are tied to the study of nitrobenzene derivatives, which have been explored since the 19th century for their reactivity and utility in organic synthesis. The introduction of chlorine and chloromethyl groups to nitrobenzene became feasible in the early 20th century with advances in electrophilic aromatic substitution and radical halogenation. The specific placement of a nitro group at the 4-position, a chlorine at the 1-position, and a chloromethyl group at the 2-position emerged in the mid-20th century, driven by the need for multifunctional intermediates in the synthesis of complex molecules. Techniques like selective chlorination and chloromethylation, refined in the 1950s and 1960s, enabled the precise synthesis of such compounds.

Synthetically, 1-chloro-2-(chloromethyl)-4-nitrobenzene is typically prepared through a multi-step process. A common route starts with 4-nitrochlorobenzene, which is chloromethylated at the 2-position using formaldehyde and hydrochloric acid in the presence of a Lewis acid catalyst, such as zinc chloride, via a Blanc chloromethylation reaction. Alternatively, 1-chloro-4-nitro-2-methylbenzene can be used as a starting material, with the methyl group selectively chlorinated using chlorine gas or N-chlorosuccinimide under radical conditions (e.g., with a radical initiator like benzoyl peroxide). Another approach involves sequential functionalization of nitrobenzene, with nitration followed by chlorination and chloromethylation, though this requires careful control to achieve regioselectivity. These steps rely on well-established protocols in aromatic substitution and halogenation, ensuring high yields and purity.

The primary application of 1-chloro-2-(chloromethyl)-4-nitrobenzene is as a synthetic intermediate in pharmaceutical chemistry. The nitro group enhances the electron-deficient nature of the aromatic ring, facilitating nucleophilic aromatic substitution, and can be reduced to an amine for further functionalization. The 1-chloro group serves as a handle for cross-coupling reactions, such as Suzuki-Miyaura or Buchwald-Hartwig couplings, while the 2-(chloromethyl) group is highly reactive in nucleophilic substitution reactions, enabling the introduction of amines, thiols, or carbon nucleophiles. This compound is frequently used in the synthesis of drug candidates, such as kinase inhibitors, antimicrobial agents, and anti-inflammatory drugs, where the electron-withdrawing nitro group and reactive halogens optimize target affinity and pharmacokinetic properties.

In agrochemical synthesis, the compound is employed to develop pesticides and herbicides, where nitro and halogenated aromatics contribute to bioactivity and stability. In materials chemistry, it is used to synthesize functionalized polymers or dyes, leveraging the chloromethyl group for conjugation. In academic research, it serves as a model for studying regioselective functionalization, radical chloromethylation, and nitroaromatic reactivity. Its synthesis has contributed to the refinement of chloromethylation and halogenation techniques.

The significance of 1-chloro-2-(chloromethyl)-4-nitrobenzene lies in its role as a multifunctional intermediate that combines the reactivity of nitro, chloro, and chloromethyl groups on a benzene ring. Its development reflects progress in regioselective aromatic functionalization and halogenation chemistry. By enabling the efficient synthesis of complex, biologically active molecules, it has become a critical tool in advancing pharmaceutical, agrochemical, and chemical research.

References

2007. Synthesis by Ring Closure via Formation of an sp2-Carbon�Oxygen Bond. Science of Synthesis, 1.
URL: https://science-of-synthesis.thieme.com/app/text/?id=SD-017-00545

2014. Synthesis of N-carboxyalkyl-1,4-benzothiazepine-3(2H)-one derivatives using esters of N-(2-chloro-5-nitrobenzyl)amino acids. Monatshefte f�r Chemie - Chemical Monthly, 145(5).
DOI: 10.1007/s00706-013-1133-1