4-Bromomethylphenylacetic acid
[CAS# 13737-36-5]

Identification

• Classification: Chemical reagent >> Organic reagent >> Fatty acid
• Name: 4-Bromomethylphenylacetic acid
• Synonyms: 2-[4-(bromomethyl)phenyl]acetic acid
• Molecular Formula: C₉H₉BrO₂
• Molecular Weight: 229.07
• CAS Registry Number: 13737-36-5
• EC Number: 604-016-4
• SMILES: C1=CC(=CC=C1CC(=O)O)CBr

Properties

• Density: 1.6±0.1 g/cm³ Calc.^*
• Melting point: 179 - 183 ºC (Expl.)
• Boiling point: 343.1±22.0 ºC 760 mmHg (Calc.)^*
• Flash point: 161.3±22.3 ºC (Calc.)^*
• Index of refraction: 1.599 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07;GHS08 Danger
• Hazard Statements: H315-H319-H334-H335
• Precautionary Statements: P233-P260-P261-P264-P264+P265-P271-P280-P284-P302+P352-P304+P340-P305+P351+P338-P319-P321-P332+P317-P337+P317-P342+P316-P362+P364-P403-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Respiratory sensitization	Resp. Sens.	1	H334
Acute toxicity	Acute Tox.	4	H332
Germ cell mutagenicity	Muta.	2	H341

• Transport Information: UN 3261

Discovory and Applicatios

4-Bromomethylphenylacetic acid, with the molecular formula C₉H₉BrO₂ and CAS number 13737-36-5, is an organic compound featuring a phenylacetic acid core substituted with a bromomethyl group at the 4-position. It is recognized in organic chemistry as a valuable synthetic intermediate, particularly in pharmaceutical and fine chemical synthesis. Its discovery and applications are well-established in the literature, stemming from the development of functionalized aromatics and halogenated building blocks.

The discovery of 4-bromomethylphenylacetic acid is tied to the broader exploration of phenylacetic acid derivatives, which began in the early 20th century due to their utility in organic synthesis. The introduction of halogenated methyl groups, such as bromomethyl, to aromatic rings became feasible with advances in selective halogenation techniques in the mid-20th century. The specific synthesis of 4-bromomethylphenylacetic acid emerged as part of efforts to create reactive intermediates for pharmaceutical applications, particularly for drugs requiring a phenylacetic acid scaffold. By the 1960s and 1970s, improvements in radical halogenation and electrophilic substitution enabled the regioselective introduction of bromomethyl groups, facilitating the compound’s production. Its development was driven by the need for versatile building blocks that could undergo nucleophilic substitution or cross-coupling reactions to construct complex molecules.

Synthetically, 4-bromomethylphenylacetic acid is typically prepared from 4-methylphenylacetic acid. A common method involves radical bromination 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 methyl group to form the bromomethyl moiety while preserving the acetic acid side chain. Alternatively, the compound can be synthesized from 4-(bromomethyl)benzyl alcohol or related precursors, followed by oxidation to the carboxylic acid. Another approach starts with 4-(bromomethyl)benzonitrile, which is hydrolyzed to the carboxylic acid and subsequently modified to introduce the acetic acid group. These methods rely on well-established protocols in aromatic halogenation and functional group transformations, ensuring high yields and purity.

The primary application of 4-bromomethylphenylacetic acid is as a synthetic intermediate in pharmaceutical chemistry. The phenylacetic acid core is a common structural motif in drugs, including analgesics, anti-inflammatory agents, and cardiovascular medications, due to its ability to engage in hydrogen bonding and hydrophobic interactions. The bromomethyl group is a highly reactive electrophile, enabling nucleophilic substitution reactions with amines, thiols, or oxygen nucleophiles to form diverse derivatives. This reactivity makes it a key building block for synthesizing biologically active compounds, such as enzyme inhibitors or receptor agonists. Additionally, the bromine atom can participate in cross-coupling reactions, such as Suzuki-Miyaura or Stille couplings, to introduce aryl or alkenyl groups, expanding its synthetic utility. The compound has been used in the preparation of intermediates for antihypertensive agents and other therapeutic molecules, where its functionalized aromatic structure enhances target specificity.

In fine chemical synthesis, 4-bromomethylphenylacetic acid is employed to create specialty chemicals, such as ligands or molecular probes, where the bromomethyl group facilitates conjugation. In academic research, it serves as a model for studying radical bromination, nucleophilic substitution kinetics, and the electronic effects of substituents on aromatic reactivity. Its synthesis and reactivity have contributed to the refinement of selective halogenation techniques and the design of multifunctional aromatic intermediates.

The significance of 4-bromomethylphenylacetic acid lies in its role as a versatile intermediate that combines the biological relevance of the phenylacetic acid scaffold with the synthetic flexibility of a bromomethyl group. Its development reflects progress in regioselective halogenation and aromatic functionalization. By enabling the synthesis of complex, biologically active molecules, it has become an essential tool in advancing pharmaceutical and chemical research.

References

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URL: https://pubmed.ncbi.nlm.nih.gov/38388838

2013. Supramolecular Chemistry of Organoplatinum(IV) Complexes Bearing Ligands with Remote Carboxylic Acid Substituents. Journal of Inorganic and Organometallic Polymers and Materials
DOI: 10.1007/s10904-013-9959-x

2010. Synthesis and Biological Evaluation of a Novel Anti-malarial Lead. Medicinal Chemistry Research
DOI: 10.1007/s00044-010-9325-2