2-[(5-Bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene
[CAS 1030825-20-7]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Thiophene compound
• Name: 2-[(5-Bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene
• Molecular Formula: C₁₈H₁₄BrFS
• Molecular Weight: 361.27
• CAS Registry Number: 1030825-20-7
• EC Number: 807-103-7
• SMILES: CC1=C(C=C(C=C1)Br)CC2=CC=C(S2)C3=CC=C(C=C3)F

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 438.3±40.0 °C 760 mmHg (Calc.)^*
• Flash point: 218.9±27.3 °C (Calc.)^*
• Index of refraction: 1.617 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H317-H319-H335
• Safety Statements: P261-P264-P264+P265-P271-P272-P280-P302+P352-P304+P340-P305+P351+P338-P319-P321-P332+P317-P333+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Skin sensitization	Skin Sens.	1	H317
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319

chemBlink Chemical Story

2-[(5-bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene is a substituted biaryl thiophene derivative composed of a central thiophene ring bearing two aromatic substituents, one of which is further extended through a benzylic linker. The structure is characterized by multiple halogen substitutions, aromatic ring systems, and a sulfur-containing heterocycle, all contributing to a predominantly hydrophobic and rigid molecular framework.

The core of the molecule is thiophene, a five-membered aromatic heterocycle containing one sulfur atom. Thiophene is a planar, electron-rich aromatic system in which the sulfur atom contributes one lone pair to the aromatic sextet. This delocalization stabilizes the ring and allows it to participate in π-conjugation with adjacent aromatic substituents. Thiophene derivatives are commonly used as structural motifs in organic materials and medicinal chemistry due to their stability and electronic properties.

At the 5-position of the thiophene ring is a 4-fluorophenyl substituent. This is a directly attached phenyl ring bearing a fluorine atom at the para position. The phenyl group contributes significant hydrophobic character and π-electron density, while the fluorine substituent introduces strong inductive electron-withdrawing effects. The carbon–fluorine bond is highly polarized and chemically robust, and its presence can influence the electronic distribution of the entire aromatic system.

At the 2-position of the thiophene ring is a benzylic substituent, specifically a (5-bromo-2-methylphenyl)methyl group. This substituent consists of a benzene ring attached via a methylene (–CH₂–) linker to the thiophene core. The benzene ring itself is substituted with a bromine atom at the 5-position and a methyl group at the 2-position.

The bromine atom is a large, polarizable halogen substituent that exerts both inductive electron-withdrawing effects and weak resonance donation depending on the context. Its size contributes significant steric influence on the aromatic ring’s conformation and intermolecular interactions. The methyl group provides electron donation through hyperconjugation and increases local hydrophobicity.

The benzylic methylene linker introduces limited rotational freedom between the thiophene core and the substituted phenyl ring. This allows the aromatic systems to adopt multiple relative orientations, although steric effects from the ortho substituent and bromine can restrict preferred conformations.

From a structural perspective, the molecule consists almost entirely of aromatic and heteroaromatic systems, resulting in a rigid, planarized, and hydrophobic framework. The thiophene and phenyl rings can participate in π–π stacking interactions, which may influence solid-state packing behavior and intermolecular associations.

Physicochemically, the compound is expected to be highly lipophilic due to the dominance of aromatic hydrocarbons and the absence of strongly polar functional groups. The only heteroatom present is sulfur in the thiophene ring, which contributes modest polarity but does not significantly increase hydrophilicity. The halogen substituents (bromine and fluorine) increase molecular polarizability and influence intermolecular dispersion forces.

Chemically, the thiophene ring is relatively stable under neutral conditions but can undergo electrophilic substitution at activated positions under suitable conditions. The aromatic rings are generally stable, while the benzylic position represents a potential site for oxidation under strong oxidative conditions, as benzylic C–H bonds are typically more reactive than aromatic C–H bonds.

The halogen substituents are chemically stable under most conditions, although carbon–bromine bonds can serve as potential synthetic handles in cross-coupling reactions in broader synthetic contexts. The fluorine substituent is particularly strong and generally inert under typical chemical conditions.

Overall, 2-[(5-bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene is a halogenated, highly aromatic thiophene derivative featuring a benzylic-linked substituted phenyl group and a directly attached fluorophenyl group. Its structure is dominated by rigid aromatic systems and halogen substituents, resulting in a hydrophobic, electronically conjugated molecular framework with limited polarity and significant conformational flexibility at the benzylic linkage.

References

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DOI: 10.1038/s42004-026-01954-3

2015. Synthesis of SGLT2 Inhibitor Canagliflozin. Synfacts.
DOI: 10.1055/s-0034-1380758