Application Research of 4-Fluorobenzylamine

Introduction

4-Fluorobenzylamine, with the chemical formula C₇H₈FN (Figure 1), is an important aromatic amine derivative featuring a fluorine atom substituted at the para position (-p) of the benzylamine backbone. Its molecular structure consists of a benzene ring, a methylene group (-CH₂-), a primary amino group (-NH₂), and a fluorine atom, where the fluorine and the -CH₂NH₂ moiety are positioned opposite each other on the benzene ring--this para substitution pattern endows it with unique chemical properties distinct from its ortho- or meta-isomers. 4-Fluorobenzylamine is a crucial intermediate in the synthesis of astemizole (an antiallergic drug) and flupirtine (an analgesic drug).

Synthesis of 4-Fluorobenzylamine

4-Fluorobenzylamine was prepared using 4-fluorobenzaldehyde, ammonia and hydrogen gas as raw materials, ethanol as solvent and Raney Ni as catalyst. The pressure of H2 was 1. 5~2. 0 MPa．The influence of reaction conditions on the yield and conversion was investigated and the optimum conditions were determined as follows: n (p-fluorobenzaldehyde) :n (NH₃)=1.0:2.5，m (p-fluorobenzaldehyde):m(ethanol)=1.0:1.3, reaction temperature 60 ~65°C , the amount of Raney Nibeing 5% of p-fluorobenzaldehyde，reaction time 7~8 h. Under these conditions，the selectivity from p-fluorobenzaldehyde to 4-fluorobenzyamine is 95. 3%, the yield is more than 85% and the purity of 4-fluorobenzylamine is>99% after purification．[1]

Enhanced removal of p-fluoronitrobenzene using bioelectrochemical system

p-Fluoronitrobenzene (p-FNB) tends to accumulate in industrial effluents because of its recalcitrant properties. Approaches to the removal of p-FNB always encounter conflicts between treatment efficiency and economic efficiency. A bioelectrochemical system (BES) was established to facilitate the removal and mineralization of p-FNB. The treatment cost was reduced by using inexpensive electrode materials and reducing the electrical energy used. p-FNB was effectively removed using the BES, and the reaction rate was higher than the sum of the rates of two control systems, i.e., a biological system (BS) and an electrocatalytic system (ECS), by a maximum of 62.9% under a voltage of 1.4 V. The voltage is a crucial kinetic factor for the BES performance; as the voltage increased from 0 to 1.4 V, the reaction rate constants for p-FNB removal and defluorination increased from 0.0520 to 0.1811 h^-1 and 0 to 0.0107 h^-1. The synergistic effect of multistrains gave a TOC removal efficiency in the BES of about 34.05%, yet the removal efficiencies were low for the two control. The defluorination reaction rate was significantly slower than the p-FNB removal rate, which indicated that defluorination lagged p-FNB removal, and p-FNB transformation to 4-fluorobenzylamine (p-FA) was the fastest step. The electrochemical assistance provided electrons and accelerated the electron transfer rate in the microbial reduction of p-FNB to 4-fluorobenzylamine. In this study, the critical voltage for defluorination in the BES was 0.8 V, which was approximately 0.2 V lower than that in the ECS. The decrease in the critical voltage for defluorination was based on the production of 4-fluorobenzylamine, which is more electrocatalytically activated. These results demonstrate the mechanism of efficient p-FNB removal and mineralization in a BES.[2]

Synthesis of p-fluorosulfinylaniline

The reaction of 4-fluorobenzylamine and SOCl₂ rendered p-fluorosulfinylaniline in good yield. The obtained dark yellowish liquid compound was characterized by NMR, UV-visible, FT-IR and Raman spectroscopies. The observed features were consistent with the existence of only one conformer, belonging to the CS symmetry group. A tentative assignment of the vibrational modes was performed on the basis of experimental spectra and quantum chemical calculations at different levels of theory (B3LYP and MP2 with 6-31+G(d), 6-311+G(d) and 6-311+G(df) basis sets). The conformational and vibrational properties of p-fluorosulfinylaniline were in good agreement with experimental data reported for other substituted sulfinylanilines and p-halogenanilines.[3]

Thermal dehydrochlorination in the 4-fluoroaniline-trichloroborane system

Borazines are used in chemical vapor deposition processes to produce hybrid graphene-boron nitride nanostructures. As the knowledge on the mechanism of borazine formation is scarce, researchers studied the mechanism of formation of B,B',B''-trichloro-N,N',N''-tri(p-fluorophenyl)borazine (3a) from p-fluoroaniline and boron trichloride employing NMR spectroscopy, X-ray single crystal structure analysis, trapping experiments, and computational chemistry methods up to the coupled cluster CCSD(T) level of theory. These studies suggest the initial formation of the 1 : 1 adduct 1a (ArNH₂BCl₃, Ar = 4-fluorophenyl) with a dative B-N bond that could be fully characterized including single crystal X-ray diffraction. Adduct 1a undergoes unimolecular hydrogen chloride elimination with a first-order rate constant of k1 = 3.03(7) × 10^-2 min^-1 in toluene at 100 °C. This rate constant is in very good agreement with the one derived (k1=3.18×10^-2 min-1) from computed activation parameters (ΔH‡373.15=28.1kcal mol^-1, ΔS‡373.15=1.56 eu, ΔG‡373.15=27.6 kcal mol^-1). The product of the first hydrogen chloride evolution is anilinodichloroborane ArNHBCl₂(2a). Compound 2a cannot be isolated in a pure form due to instability, but its presence as a transient reactive intermediate can be derived from NMR spectroscopy. Reactive intermediates other than anilinodichloroborane cannot be assigned by NMR spectroscopy. We propose that the mechanism of formation of borazine 3a involves the reaction of 2a with 4-fluoroaniline as the rate determining step.[4]

References

[1] LIU GS, et al. Synthesis of p-Fluorobenzylamine[J].Fine Chemicals,2014,31(02):270-272.DOI:10.13550/j.jxhg.2014.02.026.

[2] Feng H, Zhang X, Liang Y, et al. Enhanced removal of p-fluoronitrobenzene using bioelectrochemical system. Water Res. 2014;60:54-63. doi:10.1016/j.watres.2014.03.027

[3] Páez Jerez AL, Flores Antognini A, Cutin EH, Robles NL. Synthesis, characterization and vibrational properties of p-fluorosulfinylaniline. Spectrochim Acta A Mol Biomol Spectrosc. 2015;137:300-305. doi:10.1016/j.saa.2014.08.040

[4] Hahn J, Krieg M, Keck C, Maichle-Mössmer C, Fink RF, Bettinger HF. Thermal dehydrochlorination in the 4-fluoroaniline-trichloroborane system: identification of reactive intermediates involved in the formation of B,B',B''-trichloro-N,N',N''-tri((4-fluoro)phenyl)borazine. Dalton Trans. 2018;47(48):17304-17316. doi:10.1039/c8dt03954b

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