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<p>In this work, we propose a halogen-tuning framework that links electronic reactivity descriptors to enzyme recognition for halomethyl acetates (fluoromethyl, chloromethyl, and bromomethyl acetate). Density Functional Theory calculations were performed at the B3LYP/6-311G(d, p) level to explain structure property relationships across the F/Cl/Br substitution axis. Geometry optimization shows a systematic elongation of the C5-X bond (F &lt; Cl &lt; Br), while the ester carbonyl remains nearly invariant, suggesting a localized substituent effect. Frontier orbital energies analysis and global descriptors reveal that bromomethyl acetate is the softest and most electronically labile derivative, exhibiting the smallest HOMO-LUMO energy gap, whereas the fluorinated analogue demonstrates the highest kinetic stability. Simulated FT-IR, <sup>1</sup>H/<sup>13</sup>C NMR (GIAO), and TD-DFT UV-Vis spectra provide complementary fingerprints showing halogen-driven electronic modulation. Topological analyses (MEP, DOS, RDG/NCI/DORI) map the redistribution of electron density and weak interaction regions that rationalize the observed trends. Molecular docking against acetylcholinesterase (AChE; PDB: 1EVE) indicates a monotonic enhancement of binding affinity with increasing halogen polarizability, with bromomethyl acetate exhibiting the strongest predicted affinity. Collectively, these results establish a predictive structure reactivity recognition reasoning for halomethyl acetates and support their consideration as electrophile-tuned model systems for exploring substituent-dependent recognition tendencies.</p>

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Halogen-dependent electronic regulation of reactivity and acetylcholinesterase recognition in halomethyl acetates: a predictive DFT-docking framework

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Mahmood Dahham Abed Abed ,
  • Omar M. Saeed Younus Tahhan,
  • Ahmed Muhsin Mohammed Youns Fto,
  • Mehmet Hanifi Kebiroğlu,
  • Niyazi Bulut

摘要

In this work, we propose a halogen-tuning framework that links electronic reactivity descriptors to enzyme recognition for halomethyl acetates (fluoromethyl, chloromethyl, and bromomethyl acetate). Density Functional Theory calculations were performed at the B3LYP/6-311G(d, p) level to explain structure property relationships across the F/Cl/Br substitution axis. Geometry optimization shows a systematic elongation of the C5-X bond (F < Cl < Br), while the ester carbonyl remains nearly invariant, suggesting a localized substituent effect. Frontier orbital energies analysis and global descriptors reveal that bromomethyl acetate is the softest and most electronically labile derivative, exhibiting the smallest HOMO-LUMO energy gap, whereas the fluorinated analogue demonstrates the highest kinetic stability. Simulated FT-IR, 1H/13C NMR (GIAO), and TD-DFT UV-Vis spectra provide complementary fingerprints showing halogen-driven electronic modulation. Topological analyses (MEP, DOS, RDG/NCI/DORI) map the redistribution of electron density and weak interaction regions that rationalize the observed trends. Molecular docking against acetylcholinesterase (AChE; PDB: 1EVE) indicates a monotonic enhancement of binding affinity with increasing halogen polarizability, with bromomethyl acetate exhibiting the strongest predicted affinity. Collectively, these results establish a predictive structure reactivity recognition reasoning for halomethyl acetates and support their consideration as electrophile-tuned model systems for exploring substituent-dependent recognition tendencies.