1-Bromo-2,3,4-trifluorobenzene

Nucleophilic Aromatic Substitution (SNAr) Reactions

The electron-deficient nature of the aromatic ring in this compound makes it an excellent substrate for nucleophilic aromatic substitution (SNAr) reactions. The strong inductive effect of the fluorine atoms activates the ring toward attack by nucleophiles.

Regioselectivity of Fluorine Displacement

In SNAr reactions involving polyfluorinated aromatic compounds, a fluorine atom is typically displaced rather than a bromine atom. The regioselectivity of this displacement is governed by the ability of the electron-withdrawing groups to stabilize the intermediate Meisenheimer complex. For this compound, nucleophilic attack is anticipated to occur preferentially at the C-4 position. This preference is because the negative charge of the intermediate anion is effectively stabilized by the adjacent fluorine at C-3 and the fluorine at C-2, which is para to the site of attack.

Influence of Electronic and Steric Properties on SNAr Pathways

The efficiency and pathway of SNAr reactions are heavily influenced by both electronic and steric factors.

Electronic Properties: The primary driving force for SNAr in this molecule is the powerful electron-withdrawing inductive effect (-I) of the three fluorine atoms. govtpgcdatia.ac.in This effect reduces the electron density of the π-system, making the aromatic ring electrophilic and thus susceptible to attack by nucleophiles. govtpgcdatia.ac.in The presence of multiple fluorine atoms enhances the stability of the negatively charged σ-complex (Meisenheimer complex) that forms during the reaction, lowering the activation energy for the substitution. govtpgcdatia.ac.in The substitution pattern is directed to positions that best stabilize this intermediate, typically ortho or para to the activating fluorine atoms. govtpgcdatia.ac.in

Steric Properties: While electronic effects are dominant, steric hindrance can also influence the reaction. The fluorine atoms at the C-2 and C-3 positions may provide some steric shielding. However, in highly electron-poor systems like this compound, the electronic activation is generally the deciding factor for reactivity and regioselectivity.

Suzuki-Miyaura Coupling Protocols

The Suzuki-Miyaura coupling is a robust method for forming carbon-carbon bonds, valued for its mild conditions and functional group tolerance. acs.org this compound has been successfully employed in such reactions to synthesize polyfluorinated biphenyls. acs.org The reaction typically involves a palladium catalyst, a phosphine (B1218219) ligand, and a base to couple the aryl halide with an organoboron compound. nih.gov

An example protocol demonstrates the successful coupling of this compound with a boronic acid derivative, highlighting the viability of this substrate in forming highly electron-poor biaryl compounds. acs.org

Stille Coupling and Other Carbon-Carbon Bond Forming Reactions

The Stille coupling is another powerful C-C bond-forming reaction that pairs an organostannane with an organic halide, catalyzed by palladium. organic-chemistry.org This reaction is known for its versatility and tolerance of a wide array of functional groups. organic-chemistry.org

Given the demonstrated reactivity of this compound as an electrophile in Suzuki-Miyaura coupling, it is a strong candidate for participation in Stille coupling and other related palladium-catalyzed cross-coupling reactions. While specific literature examples for the Stille coupling of this compound were not identified in the search, its electronic properties suggest it would readily undergo oxidative addition to a Pd(0) center, the initial step in the catalytic cycle of many cross-coupling reactions, including Stille, Heck, and Negishi couplings.

Grignard Reagent Formation and Applications

The presence of a bromine atom on the aromatic ring of this compound allows for the formation of the corresponding Grignard reagent, 2,3,4-trifluorophenylmagnesium bromide. This organomagnesium compound is a valuable intermediate in organic synthesis, enabling the introduction of the 2,3,4-trifluorophenyl moiety onto various substrates. The formation is typically achieved through the reaction of this compound with magnesium metal in an anhydrous ether solvent, such as tetrahydrofuran (B95107) (THF).

The reactivity of this Grignard reagent is demonstrated in its use for creating carbon-carbon bonds. For instance, it can be used in reactions with ketone derivatives. One documented application involves the reaction of a Grignard reagent prepared from a trifluorobromobenzene isomer with a substituted cyclohexyl acetyl chloride in the presence of iron acetylacetonate (B107027) to form a ketone derivative. googleapis.com Similarly, the Grignard reagent derived from 1-bromo-2,3-difluorobenzene (B1273032) has been reacted with trans-4-propylcyclohexylcyclohexenone. ambeed.com While these examples involve closely related structures, they illustrate a primary application pathway for the Grignard reagent of this compound: nucleophilic addition to carbonyl compounds and acid chlorides to forge new C-C bonds, leading to more complex molecular architectures.

Table 1: Representative Applications of Related Trifluorophenyl Grignard Reagents

Directed ortho-Metallation and Halogen Migration Phenomena

Directed ortho-metallation (DoM) is a powerful strategy for regioselective functionalization of aromatic rings, guided by a directing metalation group (DMG). wikipedia.org A DMG, typically a heteroatom-containing functional group, coordinates to an organolithium reagent (like n-butyllithium), facilitating deprotonation at the adjacent ortho position. wikipedia.orgorganic-chemistry.org In polyhalogenated aromatic systems, fluorine atoms can act as moderate directing groups, and their electronic influence significantly acidifies the ortho-protons.

For fluorinated bromo-benzenes, a competition exists between direct deprotonation (lithiation) and bromine-lithium exchange. The outcome is highly dependent on the reaction conditions, particularly the base used and the temperature. Studies on related compounds, such as 1-bromo-2,4-difluorobenzene, show that strong, non-nucleophilic bases like lithium diisopropylamide (LDA) tend to cause deprotonation at the most acidic site, which is typically the position between two fluorine atoms or ortho to a fluorine atom. psu.edu For this compound, the most acidic proton is expected to be at the C5 position, flanked by a fluorine (at C4) and a bromine (at C1). Lithiation at this site would yield a functionalized product after quenching with an electrophile.

The use of alkyllithium reagents like n-BuLi at low temperatures often favors bromine-lithium exchange over deprotonation. psu.edu However, the specific regiochemistry of metallation for this compound itself is a subject of detailed investigation. Research on 1,2,3-trifluorobenzene (B74907) has shown that ortho-lithiation can occur, which upon quenching with bromine yields this compound, demonstrating the directing effect of the fluorine atoms. thieme-connect.de Halogen migration, such as an anionic-Fries rearrangement, can sometimes occur in ortho-lithiated species, although this is more common with groups like carbamates. uwindsor.ca

Electrophilic Substitution Reactions on the Aromatic Ring

Electrophilic aromatic substitution (SEAr) is a fundamental reaction class for aromatic compounds. researchgate.net In this compound, the reactivity and regioselectivity of such substitutions are governed by the combined electronic effects of the four halogen substituents. Both bromine and fluorine are deactivating groups due to their inductive electron-withdrawal, making the ring less reactive towards electrophiles than benzene. However, they are also ortho-, para-directing because of resonance effects where their lone pairs can stabilize the arenium ion intermediate.

The directing influence in a poly-substituted ring is a cumulative effect. Fluorine is more electronegative but a better resonance donor than bromine. In cases of conflict, the orientation of the incoming electrophile is determined by the net activation/deactivation and steric hindrance. For fluorinated aromatics, electrophilic attack is often directed to the position para to a fluorine atom. Given the substitution pattern of this compound, the two available positions for substitution are C5 and C6. The C5 position is ortho to the C4-fluorine and meta to the C3- and C2-fluorines. The C6 position is ortho to the bromine and the C2-fluorine. Predicting the major product requires careful consideration of the competing directing effects. Synthesis of derivatives like 1-bromo-3,4-difluoro-2-nitrobenzene (B1613911) highlights that nitration is a possible electrophilic substitution pathway for related compounds.

Reduction Reactions (if applicable to derivatives)

While this compound itself does not typically undergo reduction of the aromatic ring or the halogens under standard conditions, its derivatives can participate in important reduction reactions. A common synthetic strategy involves introducing a functional group that can be subsequently reduced.

For example, if an electrophilic nitration reaction were performed to yield a nitro-1-bromo-2,3,4-trifluorobenzene derivative, the nitro group could be readily reduced to an amino group (-NH2). This transformation is typically accomplished using reducing agents like hydrogen gas with a palladium catalyst, or metals such as tin or iron in acidic media. smolecule.com This pathway provides a route to polyfluoro-bromo-anilines, which are versatile building blocks for pharmaceuticals and agrochemicals.

Table 2: Potential Reduction of a Functionalized this compound Derivative

Electronic Structure Calculations (e.g., Density Functional Theory)

Density Functional Theory (DFT) is a widely employed computational method for investigating the electronic structure of molecules like this compound. These calculations provide a theoretical framework for understanding the molecule's geometry, stability, and reactivity.

A common approach involves geometry optimization using a functional such as B3LYP combined with a basis set like 6-311++G(d,p). researchgate.netijastems.org This level of theory has been shown to provide optimized geometric bond lengths and bond angles that are in good agreement with experimental values for similar halogenated benzene derivatives. researchgate.netijastems.org The calculations would reveal the planarity of the benzene ring and the specific bond lengths and angles influenced by the electron-withdrawing fluorine and bromine substituents. For instance, deformations in the benzene ring, such as changes in CCC bond angles and CC bond lengths, can be precisely quantified. researchgate.net

Key electronic properties that can be determined from DFT calculations include the energies of the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO). The HOMO-LUMO energy gap is a critical parameter that reflects the chemical reactivity and kinetic stability of the molecule. irjweb.com A smaller gap generally indicates higher reactivity. For this compound, the HOMO is expected to be localized primarily on the benzene ring and the bromine atom, while the LUMO would be an anti-bonding orbital distributed over the aromatic system.

Table 1: Representative Calculated Electronic Properties of this compound (Illustrative)

Note: The values in this table are illustrative and would be obtained from specific DFT calculations (e.g., B3LYP/6-311++G(d,p)).

Reaction Mechanism Elucidation via Computational Modeling

Computational modeling is instrumental in elucidating the mechanisms of chemical reactions involving this compound. A key area of investigation is nucleophilic aromatic substitution (SNAr), where the bromine atom acts as a leaving group.

DFT calculations can be used to map the potential energy surface of a reaction, identifying reactants, products, intermediates, and transition states. researchgate.net For the SNAr reaction of this compound with a nucleophile, computational models can predict the regioselectivity by comparing the activation energies for substitution at different positions. The calculations would likely show that the electron-withdrawing fluorine atoms activate the benzene ring towards nucleophilic attack.

The mechanism can be investigated by locating the transition state structure for the rate-determining step. The geometry of the transition state provides crucial information about the bond-breaking and bond-forming processes. For some SNAr reactions, a stepwise mechanism involving a stable Meisenheimer complex (a σ-complex intermediate) is predicted, while for others, a concerted mechanism may be favored. researchgate.net Computational studies can distinguish between these pathways by calculating the energies of the intermediates and transition states. researchgate.net Intrinsic Reaction Coordinate (IRC) calculations can then be performed to confirm that the identified transition state connects the reactant and product states on the potential energy surface.

Table 2: Illustrative Calculated Energy Profile for a Hypothetical SNAr Reaction of this compound

Note: This table presents hypothetical data to illustrate the type of information obtained from computational modeling of a reaction mechanism.

Prediction of Spectroscopic Parameters

Computational chemistry provides a powerful means to predict and interpret the spectroscopic data of this compound, including its NMR and vibrational (infrared and Raman) spectra.

NMR Spectroscopy: DFT calculations, often using the Gauge-Including Atomic Orbital (GIAO) method, can predict the nuclear magnetic shielding tensors, which are then converted into chemical shifts (δ). By comparing the calculated chemical shifts for ¹H, ¹³C, and ¹⁹F with experimental data, the accuracy of the computational model can be assessed and assignments of the spectral peaks can be confirmed. For complex spectra with overlapping signals, calculated chemical shifts can be invaluable for accurate interpretation. 52.86.42 Furthermore, spin-spin coupling constants (J-coupling) can also be calculated, providing further confirmation of the molecular structure. 52.86.42

Vibrational Spectroscopy: The vibrational frequencies and intensities for both infrared (IR) and Raman spectra can be calculated using DFT. researchgate.netijastems.org These calculations involve computing the second derivatives of the energy with respect to the atomic coordinates. The calculated harmonic frequencies are often systematically higher than the experimental frequencies due to the neglect of anharmonicity and basis set limitations. Therefore, they are typically scaled by an empirical factor to improve agreement with experimental data. amanote.com The calculated vibrational spectra can aid in the assignment of the observed absorption bands to specific vibrational modes of the molecule, such as C-H stretching, C-F stretching, and benzene ring deformations.

Table 3: Comparison of Experimental and Illustrative Calculated Spectroscopic Data for this compound

Note: Experimental data is sourced from public databases like PubChem. nih.gov Calculated values are illustrative and depend on the specific computational methodology employed.

Synthesis of Biologically Active Scaffolds in Pharmaceutical Chemistry

Synthesis of Fluorinated Polymers

This compound is a precursor for developing high-performance fluorinated polymers. The presence of the trifluorinated phenyl ring can impart desirable characteristics to the resulting polymer, such as high thermal stability, chemical resistance, and specific dielectric properties. The bromo-substituent provides a reactive handle for polymerization reactions, allowing it to be incorporated into polymer backbones or side chains.

The bromine atom can be utilized in various coupling reactions or converted into other functional groups, such as a Grignard reagent, to facilitate polymerization. This reactivity makes it a building block for specialized polymers like poly(arylene ether)s. researchgate.netbwise.kr Poly(arylene ether)s are a class of engineering thermoplastics known for their high glass transition temperatures, excellent mechanical strength, and resistance to oxidation and hydrolysis. researchgate.net The inclusion of the trifluorophenyl moiety from this compound can enhance these properties and also lower the material's dielectric constant, which is advantageous for applications in microelectronics. mdpi.com

While direct polymerization of this compound is not commonly documented, its role as a monomer can be inferred from the chemistry of similar fluorinated aromatic compounds. For instance, the bromo group in related molecules serves as a site for creating functional polymers with tailored properties. smolecule.com The synthesis of fluorinated poly(arylene ether)s often involves the nucleophilic aromatic substitution reaction between a bisphenol and a highly activated fluoroaromatic compound, such as decafluorobiphenyl. bwise.krmdpi.com this compound can be functionalized to create novel monomers for such polycondensation reactions.

Precursors for Liquid Crystalline Materials

The unique electronic and steric properties of the 2,3,4-trifluorophenyl unit make this compound a key intermediate in the synthesis of liquid crystalline materials. The introduction of fluorine atoms into the aromatic core of a molecule can significantly influence its mesomorphic behavior, including transition temperatures and the stability of liquid crystal phases. smolecule.com

Detailed research has shown the synthesis of novel banana-shaped liquid crystals that incorporate a 1,5-disubstituted 2,3,4-trifluorophenyl moiety. psu.edu These bent-core liquid crystals are of significant interest due to their potential to form ferroelectric phases from achiral molecules. The synthetic strategy for these materials often involves the sequential functionalization of 1,2,3-trifluorobenzene (B74907). psu.edu this compound serves as a more direct precursor, with the bromine atom providing a specific site for molecular elaboration through cross-coupling reactions, such as the Suzuki coupling, which are invaluable in liquid crystal synthesis. psu.edu The high lateral polarity generated by the three adjacent fluorine atoms is a crucial factor in the design of these advanced materials. psu.edu

The bromo-group can be converted into a boronic acid or used directly in coupling reactions with other aromatic fragments to construct the complex, anisotropic molecules required for liquid crystallinity. psu.edu This allows for the precise assembly of calamitic (rod-shaped) or discotic (disc-shaped) mesogens where the trifluorophenyl unit is a core structural element.

Synthesis of Fluorinated Fluorophores

Fluorination is a powerful strategy in the design of advanced fluorescent dyes (fluorophores), as it can significantly enhance photostability, improve quantum yields, and tune absorption and emission wavelengths. nih.govresearchgate.net While the literature extensively documents the use of its isomer, 1-bromo-2,4,5-trifluorobenzene, in the synthesis of fluorinated xanthones, acridones, and rhodamine analogues, the underlying synthetic principles are applicable to this compound. nih.govresearchgate.netacs.orgnih.gov

The general approach involves using the bromo-substituent as a synthetic handle. nih.gov For example, a Grignard reagent can be formed from the bromo-compound, which then acts as a nucleophile in reactions with aldehydes or esters to construct the core of the fluorophore. nih.govresearchgate.net This is followed by oxidation and cyclization steps, often involving nucleophilic aromatic substitution (SNAr) of the fluorine atoms, to yield the final heterocyclic dye system. nih.govwalisongo.ac.idnih.gov

Using this compound instead of its more common isomer would lead to a different substitution pattern on the resulting fluorophore. This structural change would alter the electronic distribution within the molecule, likely resulting in novel photophysical properties, such as shifted absorption and emission maxima. This provides a pathway to new classes of fluorinated fluorophores with potentially unique applications in bioimaging, sensing, and materials science. For example, the synthesis of fluorinated acridones has been achieved through an iterative SNAr reaction sequence on a fluorinated benzophenone (B1666685) precursor, a strategy adaptable for derivatives of this compound. walisongo.ac.idnih.gov

Photochemical Degradation Studies

Chemical Hydrolysis and Oxidation Processes

Information on the chemical hydrolysis and oxidation of 1-Bromo-2,3,4-trifluorobenzene is also limited. Hydrolysis, the reaction with water, is generally not a significant degradation pathway for aromatic halides under typical environmental pH conditions unless activated by other functional groups.

Microbial Metabolism in Aerobic and Anaerobic Conditions

Direct studies on the microbial metabolism of this compound under either aerobic or anaerobic conditions have not been identified in the available literature. However, general principles of the biodegradation of halogenated aromatics can provide some insight.

Under aerobic conditions , bacteria often utilize dioxygenase enzymes to initiate the breakdown of aromatic rings. For some chlorinated and brominated benzenes, this leads to the formation of halogenated catechols, which are then further metabolized. nih.gov The presence of multiple halogen substituents can sometimes hinder this process.

Under anaerobic conditions , a common degradation mechanism is reductive dehalogenation, where a halogen atom is removed and replaced by a hydrogen atom. This process is particularly important for highly halogenated compounds. For instance, some microbial communities have been shown to reductively dehalogenate chlorinated benzenes. scholaris.ca It is plausible that this compound could undergo anaerobic reductive debromination. The fate of the resulting trifluorobenzene would then depend on the metabolic capabilities of the microbial community present. The degradation of fluorinated aromatic compounds is generally considered more challenging for microorganisms due to the strength of the carbon-fluorine bond. ethz.ch

Comparative Studies with Chlorinated Analogues

While direct comparative studies involving this compound are lacking, research on other halogenated benzenes provides a basis for comparison. Generally, the carbon-bromine bond is weaker than the carbon-chlorine bond, which in turn is weaker than the carbon-fluorine bond. This suggests that, in processes like reductive dehalogenation, debromination would be more favorable than dechlorination or defluorination.

Studies on mixed microbial cultures have demonstrated the complete biotransformation of compounds like lindane (hexachlorocyclohexane) to non-toxic end products, showcasing the potential of microbial consortia in degrading complex halogenated molecules. scholaris.ca The degradation of mixtures of substituted benzenes has also been observed, indicating that some microbial strains possess versatile enzymatic machinery. nih.gov However, the specific capabilities of microorganisms to degrade a mixed bromo-fluoro substituted benzene (B151609) like this compound have yet to be determined.