4-tert-Butylbenzyl bromide
[CAS# 18880-00-7]

Identification

• Classification: Organic raw materials >> Hydrocarbon compounds and their derivatives >> Hydrocarbon halide
• Name: 4-tert-Butylbenzyl bromide
• Synonyms: 1-(Bromomethyl)-4-(1,1-dimethylethyl)benzene
• Molecular Formula: C₁₁H₁₅Br
• Molecular Weight: 227.14
• CAS Registry Number: 18880-00-7
• EC Number: 242-643-1
• SMILES: CC(C)(C)C1=CC=C(C=C1)CBr

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*, 1.236 g/mL (Expl.)
• Melting point: 8 - 12 ºC (Expl.)
• Boiling point: 270.2 ºC 760 mmHg (Calc.)^*, 304.9 - 306.4 ºC (Expl.)
• Flash point: 105.9±11.8 ºC (Calc.)^*, 110 ºC (Expl.)
• Index of refraction: 1.529 (Calc.)^*, 1.545 (Expl.)

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

Safety Data

• Hazard Symbols: GHS05 Danger
• Hazard Statements: H314
• Precautionary Statements: P260-P264-P280-P301+P330+P331-P302+P361+P354-P304+P340-P305+P354+P338-P316-P321-P363-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin corrosion	Skin Corr.	1B	H314
Serious eye damage	Eye Dam.	1	H318
Substances or mixtures corrosive to metals	Met. Corr.	1	H290

• Transport Information: UN 3265

Discovory and Applicatios

4-tert-Butylbenzyl bromide, with the molecular formula C₁₁H₁₅Br and CAS number 18880-00-7, is an organic compound featuring a benzyl bromide core substituted with a tert-butyl group at the 4-position. It is recognized in organic chemistry as a versatile synthetic intermediate, particularly in pharmaceutical, agrochemical, and materials chemistry. Its discovery and applications are well-established in the literature, stemming from the development of functionalized benzyl halides and regioselective synthesis techniques.

The discovery of 4-tert-butylbenzyl bromide is rooted in the broader exploration of benzyl halides, which began in the 19th century due to their reactivity in nucleophilic substitution reactions. The introduction of alkyl substituents, such as the tert-butyl group, to aromatic rings became significant in the early 20th century as chemists sought to modulate steric and electronic properties of synthetic intermediates. The specific synthesis of 4-tert-butylbenzyl bromide emerged in the mid-20th century, driven by the pharmaceutical industry’s need for reactive building blocks to construct complex molecules. The tert-butyl group was incorporated to enhance lipophilicity and steric bulk, improving the pharmacokinetic properties of derived compounds. Advances in Friedel-Crafts alkylation and selective bromination techniques during the 1950s and 1960s enabled the efficient production of this compound, establishing it as a valuable reagent.

Synthetically, 4-tert-butylbenzyl bromide is typically prepared from 4-tert-butyltoluene. A common method involves radical bromination of the methyl group using N-bromosuccinimide (NBS) in the presence of a radical initiator, such as benzoyl peroxide or azobisisobutyronitrile, in a solvent like carbon tetrachloride. This selectively brominates the benzylic position to form the bromomethyl group while preserving the tert-butyl substituent. Alternatively, the compound can be synthesized by starting with 4-tert-butylbenzyl alcohol, which is converted to the bromide using phosphorus tribromide or hydrobromic acid. The tert-butyl group is typically introduced to toluene via Friedel-Crafts alkylation with tert-butyl chloride and a Lewis acid catalyst, such as aluminum chloride, prior to bromination. These methods rely on well-established protocols in aromatic substitution and halogenation, ensuring high regioselectivity and yield.

The primary application of 4-tert-butylbenzyl bromide is as a synthetic intermediate in pharmaceutical chemistry. The benzyl bromide moiety is a highly reactive electrophile, readily undergoing nucleophilic substitution with amines, thiols, or oxygen nucleophiles to form carbon-nitrogen, carbon-sulfur, or carbon-oxygen bonds. This reactivity makes it a key building block for synthesizing drug candidates, including antihypertensive agents, analgesics, and anti-inflammatory compounds. The tert-butyl group enhances lipophilicity and steric hindrance, improving the binding affinity and metabolic stability of derived molecules. The compound is also used in the synthesis of quaternary ammonium salts and other functionalized aromatics, which serve as intermediates for receptor modulators and enzyme inhibitors.

In agrochemical synthesis, 4-tert-butylbenzyl bromide is employed to prepare pesticides and herbicides, where the tert-butyl group contributes to bioactivity and environmental stability. In materials chemistry, it is used to synthesize functionalized polymers, ligands, or liquid crystals, leveraging the bromomethyl group for conjugation and the tert-butyl group for solubility. In academic research, the compound is studied for its reactivity in nucleophilic substitution, radical bromination mechanisms, and the electronic effects of tert-butyl substitution on aromatic systems. Its synthesis has contributed to the refinement of selective bromination and alkylation techniques.

The significance of 4-tert-butylbenzyl bromide lies in its role as a multifunctional intermediate that combines the high reactivity of a benzyl bromide with the steric and lipophilic properties of a tert-butyl group. Its development reflects progress in regioselective aromatic functionalization and halogenation chemistry. By enabling the synthesis of complex, biologically active molecules, it has become an essential tool in advancing pharmaceutical, agrochemical, and materials research.

References

2006. A Convenient Method for the Preparation of Benzyl Isocyanides. Synthesis, 2006(3).
DOI: 10.1055/s-2005-918517

2008. A One-Pot, Solid-Phase Synthesis of Secondary Amines from Reactive Alkyl Halides and an Alkyl Azide. Synlett, 2008(1).
DOI: 10.1055/s-2007-990927

2020. 4-t-Butylbenzylation of carboxylic acid for GC�MS analysis. SN Applied Sciences, 2(5).
DOI: 10.1007/s42452-020-2646-y