Halogen Substitution Research Articles

Insights into Halogen-Induced Changes in 4-Anilinoquinazoline EGFR Inhibitors: A Computational Spectroscopic Study.

The epidermal growth factor receptor (EGFR) is a pivotal target in cancer therapy due to its significance within the tyrosine kinase family. EGFR inhibitors like AG-1478 and PD153035, featuring a 4-anilinoquinazoline moiety, have garnered global attention for their potent therapeutic activities. While pre-clinical studies have highlighted the significant impact of halogen substitution at the C3'-anilino position on drug potency, the underlying mechanism remains unclear. This study investigates the influence of halogen substitution (X = H, F, Cl, Br, I) on the structure, properties, and spectroscopy of halogen-substituted 4-anilinoquinazoline tyrosine kinase inhibitors (TKIs) using time-dependent density functional methods (TD-DFT) with the B3LYP functional. Our calculations revealed that halogen substitution did not induce significant changes in the three-dimensional conformation of the TKIs but led to noticeable alterations in electronic properties, such as dipole moment and spatial extent, impacting interactions at the EGFR binding site. The UV-visible spectra show that more potent TKI-X compounds typically have shorter wavelengths, with bromine's peak wavelength at 326.71 nm and hydrogen, with the lowest IC50 nM, shifting its lambda max to 333.17 nm, indicating a correlation between potency and spectral characteristics. Further analysis of the four lowest-lying conformers of each TKI-X, along with their crystal structures from the EGFR database, confirms that the most potent conformer is often not the global minimum structure but one of the low-lying conformers. The more potent TKI-Cl and TKI-Br exhibit larger deviations (RMSD > 0.65 Å) from their global minimum structures compared to other TKI-X (RMSD < 0.15 Å), indicating that potency is associated with greater flexibility. Dipole moments of TKI-X correlate with drug potency (ln(IC50 nM)), with TKI-Cl and TKI-Br showing significantly higher dipole moments (>8.0 Debye) in both their global minimum and crystal structures. Additionally, optical spectral shifts correlate with potency, as TKI-Cl and TKI-Br exhibit blue shifts from their global minimum structures, in contrast to other TKI-X. This suggests that optical reporting can effectively probe drug potency and conformation changes.

Tunability of Photovoltaic Functions via Halogen Substitution [(Ade)2 CdX4](X = Cl, Br): A Class of Three-Dimensional Organic-Inorganic Hybrid Materials.

Two new three-dimensional organic-inorganic hybrid crystalline materials, [(Ade)2 CdCl4] (1) and [(Ade)2 CdBr4] (2), were obtained by the slow evaporation of adenine (Ade) and cadmium chloride in aqueous solution at room temperature with hydrochloric acid and hydrobromic acid used as halogen sources. The structural, thermal, optical, and electrical properties were characterized by single-crystal X-ray diffraction, infrared spectroscopy, thermogravimetric analysis, variable-temperature-variable-frequency dielectric constant analysis, and electrochemical tests. With increasing the substitution of Cl by Br, the composition of the material changed and the space group shifted from P-1 to P21/m, with a significant blue-shift in the fluorescence emission. Changing the temperature induced the deformation of the three-dimensional framework structure formed by hydrogen bonding interactions, leading to dielectric anomalies. Cyclic voltammetry tests showed the good reversibility of the electrolysis process. The structural diversity of the complexes was realized by modulating the halogen composition, and a new method for designing novel organic-inorganic hybrids with controllable photoelectric functionality was proposed.

Conformational Stability and Vibrational Relaxation as a Function of Halogen Substitution in Benzene sulfonamides: A Theoretical Study

AbstractStudying the vibrational energy flow within molecules can help us better understand their reactivity and facilitate the design of novel functional groups for potential drug candidates. This study examined the conformation of benzene sulfonamide in solvents and vacuum. Potential energy surfaces were computed for the two possible conformations, showing that the conformers’ stability varied with the medium. Additionally, the vibrational energy redistribution of halogen‐substituted benzene sulfonamide conformers was studied in solvents and vacuums. The lifetimes of the halogen stretching mode C−X (where X=F, Cl, or Br) in the substituted benzene sulfonamides were calculated and compared. The solvent and vacuum media lifetimes followed the order: C−Cl&gt;C−Br&gt;C−F. However, the degree of delocalization of vibrational energy was found to vary between them.

Two halogenated coplanar Schiff base complexes: Insights into the impact of halogen substitution on intermolecular interactions via theoretical calculations

The manipulation of intermolecular interaction intensities significantly influences a wide range of domains in material science, attracting widespread attention from researchers. In this study, we used a strategy distinct from the adjustment of molecular skeletons, through the introduction of different halogenated ligands, two new coplanar halogenated Schiff base complexes with large conjugate structure [CuII(3,5-Cl-Salphmen)]·DMF(CuL3,5-Cl) and [CuII(3Br-5Cl-Salphmen)]·DMF(CuL3Br5Cl), where 3,5-Cl-Salphmen(H2L3,5-Cl) = N,N′-bis(3,5-dichlorosalicylidene)- diamine, 3Br-5Cl-Salphmen(H2L3,5-Br) = N,N′-bis(3‑bromo-5-chlorosalicylidene)- diamine were obtained. The effects of different substituted atoms on molecular orbitals, energy levels, intermolecular interstrength are analyzed in detail by DFT theory calculations, and compared with CuII-3,5-Br-Salphmen(CuL3,5-Br) and non-halogenated analogues CuII-Salphmen(CuLH). Analysis results show that the strategy of increasing molecular conjugation by the substitution of different halogen atoms can not only effectively modulate the charge distribution on the benzene ring but also can precisely control the binding energy as well as strength of intermolecular interactions.

A group of emerging heterocyclic nitrogenous disinfection byproducts: Formation and cytotoxicity of halopyridinols in drinking water

Recently, a new group of halopyridinol disinfection byproducts (DBPs) was reported in drinking water. The in vivo developmental and acute toxicity assays have shown that they were more toxic than a few commonly known aliphatic DBPs such as bromoform and iodoacetic acid. However, many pyridinol DBPs with the same main structures but different halogen substitutions were still unknown due to complicated water quality conditions and various disinfection methods applied in drinking water treatment plants. Studies on their transformation mechanisms in drinking water disinfection were quite limited. In this study, comprehensive detection and identification of halopyridinols were conducted, and five new halopyridinols were first reported, including 2-chloro-3-pyridinol, 2,6-dichloro-3-pyridinol, 2-bromo-5-chloro-3-pyridinol, 2,4,6-trichloro-3-pyridinol and 2,5,6-trichloro-3-pyridinol. Formation conditions and mechanisms of the halopyridinols were explored, and results showed that chlorination promoted their formation compared with chloramination. Halopyridinols were intermediate DBPs that could undergo further transformation/degradation with increasing contact time, disinfectant dose, bromide concentration, and pH. The in vitro cytotoxicity of the halopyridinols was evaluated using human hepatocellular carcinoma cells. Results showed that the cytotoxicity of 3,5,6-trichloro-2-pyridinol was the highest (EC50 = 474.3 μM), which was 13.0 and 1.6 times higher than that of 2-bromo-3-pyridinol (EC50 = 6214.5 μM) and tribromomethane (EC50 = 753.6 μM), respectively.

Tert-Butyl substituted aza-BODIPY-based bromides for phototherapy

Asymmetric mono - and dibromides aza-BODIPYs at 6-site were prepared. The singlet oxygen yield of monobromide MBr-azaBDP with the direct attachment of the –Br group at 6-site was higher than that of vinyl dibromide DBr-azaBDP. Self-assembled MBr-azaBDP-NPs with laser irradiation possessed a photothermal conversion capability. Monobromide MBr-azaBDP was discovered to be an effective PDT-PTT combined therapeutic agent and prospective candidate for tumor phototherapy by integrating tert-butyl free rotation and halogen substitution. However, comparing to MBr-azaBDP, DBr-azaBDP as a fluorescent dye possesses narrower full width at half maxima, higher molar extinction coefficient and fluorescence quantum yield.

Influence of Solvents and Halogenation on ESIPT of Benzimidazole Derivatives for Designing Turn-on Fluorescence Probes.

This work reports a theoretical investigation of the solvent polarity as well as the halogenation of benzimidazole derivatives during excited state intramolecular proton transfer (ESIPT). It details how the environment and halogen substitution may contribute to the efficiency of ESIPT upon keto-enol tautomerism and exploits this effect to design fluorescence sensing. For this purpose, we first examine the conformational equilibrium of benzimidazole derivatives containing different halogen atoms, which results in intramolecular proton transfer, using density-functional theory (DFT) combined with the polarizable continuum model (PCM). Then we evaluate the fluorescence of the benzimidazole derivatives in different dielectric constants within time-dependent DFT (TD-DFT) approaches. Our results quantitatively allow the determination of large Stokes shifts in nonpolar solvents around 100 nm. These theoretical results are in agreement with experimental solvatochromism studies of benzimidazoles. The effect of halogenation, with fluorine, chlorine, and bromine, is less important than solvent polarization when ESIPT takes place. Thus, halogenation can be properly chosen depending on the interest of the synthesis of benzimidazole-based turn-on fluorescence in appropriate solvents.

Quantum Chemical-Based Investigations and Lipophilicity Evaluations on Some Structurally Related Quinazoline Derivatives

This work was chiefly conceived to explore the substituent effects on thermodynamic, electronic and lipophilic characteristics of some quinazoline derivatives (Q1-Q4) from theoretical aspects. The variations caused by methyl, ethyl, chlorine and bromine substituents on the same carbon of the aromatic ring were evaluated with a computational approach. In accordance with this purpose, simultaneously, DFT-based calculations were performed for vacuum and two different surroundings (DMSO and water) on methaqualone (Q1), etaqualone (Q2), mecloqualone (Q3), and mebroqualone (Q4) compounds by using the B3LYP functional and 6-311++G(d, p) split-valence triple zeta basis set. The computed thermodynamic quantities revealed that the halogen substitution was more preferable. The effect of substituent modification on electrostatic surface features was evaluated visually by molecular electrostatic potential (MEP) mapping technique. To shed light on the chemical reactivity behaviors of the Q1-Q4, DFT-based reactivity identifiers were computed. Also, the intramolecular interactions affected by substitution were evaluated on the basis of the Natural Bond Orbital (NBO) theory. The NBO results revealed that π-π* interactions predominate for each compound. The lipophilic character analyzes of the mentioned compounds were evaluated both numerically and visually. The data of both methods support each other.

Impact of halogens in ruthenium complexes on spin-forbidden transitions and near-infrared absorption

Capturing near-infrared light is crucial for improving solar energy conversion. Spin-forbidden transitions in metal complexes absorb lower-energy photons than spin-allowed transitions without exchange-energy loss. However, their potential in molecular engineering is underutilized. In this study, Ru complexes with linear X–Ru–X structures by substituting halogens were synthesized to control the spin–orbit interactions. Perturbation theory has shown discrepancies in estimating these interactions, but applying the two-component ZORA relativistic Hamiltonian has reduced these issues. Halogen substitution has increased the intensity of spin-forbidden transition by 20%, indicating a promising avenue for optimizing solar energy devices.

Boosting the thermoelectric properties of layered SnSb2Te4 compound by microstructure regulation combined with heterovalent halogen substitution

The layered IVV2Te4-based compounds have recently received significant attention due to their intrinsically low lattice thermal conductivities. However, the influence of microstructure regulation and halogen doping on their thermoelectric properties has been scarcely studied. In this work, we systematically investigated the anisotropic thermoelectric transport properties of pristine SnSb2Te4 compounds with varied microstructures manipulated by ball milling. With the help of thermoelectric transport models, the optimal ball milling time is estimated based on the calculation of quality factor. Furthermore, the remarkably improved Seebeck coefficient is achieved by the introduction of halogen elements into Te sites, which is attributed to reduced carrier concentration and converged carrier pockets. As a result, a maximal zT ∼0.4 at 725 K is achieved in SnSb2(Te0·94I0.06)4 sample aligned with the SPS pressure direction with a ball-milling time of 1 h, which demonstrates a 35 % enhancement over the pristine sample. This work provides an insightful guide to elevate the thermoelectric properties of layered IVVI2Te4-based compounds.

Dimerized Acceptors with Conjugate‐Break Linker Enable Highly Efficient and Mechanically Robust Organic Solar Cells

AbstractDesigning new acceptors is critical for intrinsically stretchable organic solar cells (IS‐OSCs) with high efficiency and mechanical robustness. However, nearly all stretchable polymer acceptors exhibit limited efficiency and high‐performance small molecular acceptors are very brittle. In this regard, we select thienylene‐alkane‐thienylene (TAT) as the conjugate‐break linker and synthesize four dimerized acceptors by the regulation of connecting sites and halogen substitutions. It is found that the connecting sites and halogen substitutions considerably impact the overall electronic structures, aggregation behaviors, and charge transport properties. Benefiting from the optimization of the molecular structure, the dimerized acceptor exhibits rational phase separation within the blend films, which significantly facilitates exciton dissociation while effectively suppressing charge recombination processes. Consequently, FDY‐m‐TAT‐based rigid OSCs render the highest power conversion efficiency (PCE) of 18.07 % among reported acceptors containing conjugate‐break linker. Most importantly, FDY‐m‐TAT‐based IS‐OSCs achieve high PCE (14.29 %) and remarkable stretchability (crack‐onset strain [COS]=18.23 %), significantly surpassing Y6‐based counterpart (PCE=12.80 % and COS=8.50 %). To sum up, these findings demonstrate that dimerized acceptors containing conjugate‐break linkers have immense potential in developing highly efficient and mechanically robust OSCs.

Dimerized Acceptors with Conjugate-Break Linker Enable Highly Efficient and Mechanically Robust Organic Solar Cells.

Designing new acceptors is critical for intrinsically stretchable organic solar cells (IS-OSCs) with high efficiency and mechanical robustness. However, nearly all stretchable polymer acceptors exhibit limited efficiency and high-performance small molecular acceptors are very brittle. In this regard, we select thienylene-alkane-thienylene (TAT) as the conjugate-break linker and synthesize four dimerized acceptors by the regulation of connecting sites and halogen substitutions. It is found that the connecting sites and halogen substitutions considerably impact the overall electronic structures, aggregation behaviors, and charge transport properties. Benefiting from the optimization of the molecular structure, the dimerized acceptor exhibits rational phase separation within the blend films, which significantly facilitates exciton dissociation while effectively suppressing charge recombination processes. Consequently, FDY-m-TAT-based rigid OSCs render the highest power conversion efficiency (PCE) of 18.07 % among reported acceptors containing conjugate-break linker. Most importantly, FDY-m-TAT-based IS-OSCs achieve high PCE (14.29 %) and remarkable stretchability (crack-onset strain [COS]=18.23 %), significantly surpassing Y6-based counterpart (PCE=12.80 % and COS=8.50 %). To sum up, these findings demonstrate that dimerized acceptors containing conjugate-break linkers have immense potential in developing highly efficient and mechanically robust OSCs.

Design, synthesis, characterization and evaluation of methionine-ABO based TSPO ligand

A novel series of molecules based on the acetamidobenzoxazolone (ABO) skeleton has been developed for diagnosing pathological conditions characterized by over-expression of the 18 kDa translocator protein (TSPO) in organs. To enhance the targeting of TSPO, methionine methyl ester was incorporated into the ABO structure, yielding ABMO 2-[2-(2-oxo-benzoxazol-3-yl)-acetylamino]-4-methylsulfanyl-butyric acid methyl ester, for potential biomedical applications. Two analogs, ABMO-Br and ABMO-Cl, with halogen substitutions at the 5th position of benzoxazolone, were designed and validated in silico for their pharmacokinetic properties, adherence to drug-like criteria, and blood-brain barrier penetration ability.Docking studies revealed the affinity of the designed molecules towards both native and mutant forms of TSPO. Based on in silico analysis, halogen derivatives were selected for synthesis. An efficient three-step synthetic procedure was employed to produce ABMO-Cl/Br, which were purified by column chromatography and characterized by NMR spectroscopy.The resultant ligands were radiolabeled with 99mTc, exhibiting significant stability in saline solution for up to 24 h. Blood kinetic studies conducted on New Zealand rabbits demonstrated substantial clearance from blood within 1 hr. Ex vivo and in vivo biodistribution studies confirmed uptake of the ligands in TSPO-rich organs. In conclusion, these studies validated the ability of these compounds to cross the blood-brain barrier in animal models. These findings underscore the potential of ABMO-Cl/Br as SPECT markers targeting TSPO. Further investigations using animal models are warranted to fully elucidate the utility of these ligands in diagnosing TSPO-related conditions.

Cytotoxicity of emerging halophenylacetamide disinfection byproducts in drinking water: Mechanism and prediction

Halophenylacetamides (HPAcAms) have been identified as a new group of nitrogenous aromatic disinfection byproducts (DBPs) in drinking water, but the toxicity mechanisms associated with HPAcAms remain almost completely unknown. In this work, the cytotoxicity of HPAcAms in human hepatoma (HepG2) cells was evaluated, intracellular oxidative stress/damage levels were analyzed, their binding interactions with antioxidative enzyme were explored, and a quantitative structure-activity relationship (QSAR) model was established. Results indicated that the EC50 values of HPAcAms ranged from 2353 μM to 9780 μM, and the isomeric structure as well as the type and number of halogen substitutions could obviously induce the change in the cytotoxicity of HPAcAms. Upon exposure to 2-(3,4-dichlorophenyl)acetamide (3,4-DCPAcAm), various important biomarkers linked to oxidative stress and damage, such as reactive oxygen species, 8‑hydroxy-2-deoxyguanosine, and cell apoptosis, exhibited a significant increase in a dose-dependent manner. Moreover, 3,4-DCPAcAm could directly bind with Cu/Zn-superoxide dismutase and induce the alterations in the structure and activity, and the formation of complexes was predominantly influenced by the van der Waals force and hydrogen bonding. The QSAR model supported that the nucleophilic reactivity as well as the molecular compactness might be highly important in their cytotoxicity mechanisms in HepG2 cells, and 2-(2,4-dibromophenyl)acetamide and 2-(3,4-dibromophenyl)acetamide deserved particular attention in future studies due to the relatively higher predicted cytotoxicity. This study provided the first comprehensive investigation on the cytotoxicity mechanisms of HPAcAm DBPs.

Predicting Organometallic Intermediates in the Surface-Assisted Ullmann Coupling of Chrysene Isomers.

On-surface polymerization of functional organic molecules has been recently recognized as a promising route to persistent low-dimensional structures with tailorable properties. In this contribution, using the coarse-grained Monte Carlo simulation method, we study the initial stage of the Ullmann coupling of doubly halogenated chrysene isomers adsorbed on a catalytically active (111) crystalline surface. To that end, we focus on the formation of labile metal-organic precursor structures preceding the covalent bonding of chrysene monomers. Four monomeric chrysene units with differently distributed halogen substituents were probed in the simulations, and the resulting precursor structures were compared and quantified. Moreover, the effect of (pro)chirality of chrysene tectons on the structure formation was elucidated by running separate simulations in enantiopure and racemic systems. The calculations showed that suitable manipulation of the halogen substitution pattern allows for the creation of diverse precursor architectures, ranging from straight and winded chains to cyclic oligomers with enantiopure, racemic, and nonracemic composition. The obtained findings can be helpful in developing synthetic strategies for covalent polymers with predefined architecture and functionality.

Chemodivergent Synthesis of Benzofurans and 2,3‐Dihydrobenzofurans via Tandem Oxidative Annulation of Enaminones and Salicylaldehydes

Comprehensive SummaryChemodivergent synthesis of benzofurans and 2,3‐dihydrobenzofurans has been realized. Under a reaction system consisting of DBDMH and K2CO3 as promotors, controlled conditions enabled the formation of two sets of valuable heterocycles from the tandem transformation of enaminones and salicylaldehydes. The key to success was the identification of the reaction parameters, in which the imine intermediate which was formed by transient halogenation coupling and substitution processes underwent either aldol condensation/annulation or imine hydrolysis/aldol condensation. The additives NH4Cl or Fe2(SO4)3 controlled the unique selectivity of this reaction. A broad substrate scope of enaminones and salicylaldehydes has been employed in this reaction, demonstrating excellent functional group tolerance and versatility.

Simulated sunlight/periodate-triggered formation of toxic halogenated bisphenols in highly saline water.

Periodate (PI)-based oxidation using the activators, such as metal ions and light irradiation, has emerged as a feasible treatment strategy for the effective remediation of contaminated water and wastewater. Given the pervasive nature of PI residues and solar exposure during application, the role of solar light in remediating the challenging highly saline water matrices needs to be elucidated. In this study, bisphenol A (BPA) was selected as the targeted micropollutant, which can be efficiently eliminated by the simulated sunlight (SSL)/PI system in the presence of high-level Cl- (up to 846.0 mM) at pH 7.0. The presence of different background constituents of water, such as halides, nitrate, and dissolved organic matter, had no effect, or even accelerated BPA abatement. Particularly, the ubiquitous Br- or I- appreciably enhanced the BPA transformation efficiency, which may be ascribed to the generation of high-selective reactive HOBr or HOI. The in silico predictions suggested that the transformation products generated by halide-mediated SSL/PI systems via halogen substitutions showed greater persistence, bioaccumulation, and aquatic toxicity than BPA itself. These findings highlighted a widespread phenomenon during PI-based oxidative treatment of highly saline water, which needs special attention under solar light illumination.

Halogen-modulated mechanical force-induced luminescence enhancement and chromism of AIE-active tetraphenylethylene-based chalcone derivatives

In this paper, four new tetraphenylethylene-based chalcone derivatives (E)-1-phenyl-3-(4-(1,2,2-triphenylvinyl)phenyl)prop-2-en-1-one (PLPE), (E)-1-(4-fluorophenyl)-3-(4-(1,2,2-triphenylvinyl)phenyl)prop-2-en-1-one (PLPE-F),(E)-1-(4-chlorophenyl)-3-(4-(1,2,2-triphenylvinyl)phenyl)prop-2-en-1-one (PLPE-Cl), (E)-1-(4-bromophenyl)-3-(4-(1,2,2-triphenylvinyl)phenyl)prop-2-en-1-one (PLPE-Br) with different halogen substitutions were reported, and the effects of halogens on their photophysical properties, aggregation-induced emission behaviors and mechano-responsive luminescent properties were systematically investigated. Interestingly, aggregation-induced emission enhancement (AIEE) behaviors were observed for PLPE, PLPE-F, PLPE-Cl, and PLPE-Br. Moreover, upon grinding, all of the four compounds displayed mechanical force-induced luminescence enhancement and red-shifted behaviors, which was found to be reversible in the case of fuming with dichloromethane (DCM) vapors or heat treatment. In particular, upon grinding, PLPE-F showed the highest contrast fluorescence response behaviors (red-shifted 49 nm and solid fluorescence quantum yield increased 20-fold). Furthermore, the results of powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and field emission scanning electron microscopy (FESEM) measurements indicated that reversible phase transitions between the ordered crystalline state and the disordered amorphous form was crucial to their interesting mechanical force-induced luminescence enhancement and chromism. And the obvious red shifts of fluorescence emission are ascribed to the increased molecular conjugations via the planarization of molecular conformations. Moreover, halogen-substituted PLPE-F, PLPE-Cl, PLPE-Br have more twisted conformations than PLPE, which are responsible for their higher contrast mechanical force-induced luminescence chromism. Hence, the present study provides a new strategy to construct new advanced high-contrast mechanical force-induced luminescence enhancement and chromism luminescent materials with the introduction of halogen atoms.

Theoretical and electrochemical analysis of halogenated salmphen-type dinuclear copper(II) complex: The influence of halogenated ligands on bandgap

The predictable control of energy levels in coordination polymer is an essential issue in molecular science. To explore a simple and feasible strategy for tuning the energy levels of Schiff base materials, the present work synthesized a novel halogen-substituted cofacial Schiff base compound, CuII2(2-Cl-Salmphen)2 (Cu-2-Cl-Salmphen), and the non-halogenated analogue CuII2(H-Salmphen)2 (Cu-H-Salmphen) was introduced for comparison. Experimental results show that the introduction of halogen atoms can effectively increase the absorbance and decrease the impedance of the compound. Further theoretical analyses revealed that the substitutional halogen atoms can not only enlarge the conjugation area but also change the electron density and the molecular orbital energy levels, thus enabling modulation of the bandgap values of the compounds. Besides, NCI studies have demonstrated that the substitution of halogens can form additional intermolecular interaction pathways, adjusting the interactions between adjacent molecules.

Renewing Halogen Substitution Strategy for the Rational Design of High‐Curie Temperature Metal‐Free Molecular Antiferroelectrics

AbstractMetal‐free molecular antiferroelectric (AFE) holds a promise for energy storage on account of its unique physical attributes. However, it is challenging to explore high‐curie temperature (Tc) molecular AFEs, due to the lack of design strategies regarding the rise of phase transition energy barriers. By renewing the halogen substitution strategy, we have obtained a series of high‐Tc molecular AFEs of the halogen‐substituted phenethylammonium bromides (x‐PEAB, x=H/F/Cl/Br), resembling the binary stator‐rotator system. Strikingly, the p‐site halogen substitution of PEA+ cationic rotators raises their phase transition energy barrier and greatly enhances Tc up to ~473 K for Br‐PEAB, on par with the record‐high Tc values for molecular AFEs. As a typical case, the member 4‐fluorophenethylammonium bromide (F‐PEAB) shows notable AFE properties, including high Tc (~374 K) and large electric polarization (~3.2 μC/cm2). Further, F‐PEAB also exhibits a high energy storage efficiency (η) of 83.6 % even around Tc, catching up with other AFE oxides. This renewing halogen substitution strategy in the molecular AFE system provides an effective way to design high‐Tc AFEs for energy storage devices.