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<p>Regioselectivity in pyrazole synthesis remains a formidable challenge. This work systematically investigates the mechanisms governing the acid-catalyzed cyclization of 4,4-dimethoxybutan-2-one with methylhydrazine, <i>tert</i>-butylhydrazine and phenylhydrazine using a combined experimental and DFT approach. Before ketal hydrolysis, reaction predominantly occurs at the exposed C2 carbonyl carbon. Upon hydrolysis, a reactive oxocarbenium intermediate forms an ultra-deep thermodynamic trap with a Gibbs free energy change ∆G of approximately − 33&#xa0;kcal/mol at the C4 site. However, the final product distribution is constrained by nucleophile-specific kinetics. For methylhydrazine, the non-negligible ketal cleavage barrier allows this unhindered nucleophile to target the protonated C2 site (+ 0.758 <i>e</i>) under charge control, yielding 69.8% of the 3-methylpyrazole isomer. Conversely, the bulkier <i>tert</i>-butylhydrazine experiences fierce, short-range Pauli exclusion principal repulsion near 1.75 Å with the C2 skeleton, forcing a flux redistribution into the C4 channel (55.4%:44.6% 3-methyl/5-methyl ratio). Remarkably, phenylhydrazine exhibits 100% selectivity for the 3-methyl product, driven by a long-range polarization trapping mechanism induced by transient orbital alignment with the C2 carbon. Collectively, this work clarifies how electronic, steric, and orbital effects cooperatively dictate pyrazole.</p>

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Regioselective synthesis of N-substituted pyrazoles from 4,4-Dimethoxybutan-2-one: an experimental and DFT investigation

  • 期刊论文

  • 发表日期：

    2026年7月11日

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  • Yiming Sun,
  • Ruicheng Liu,
  • Xiumei Bai,
  • Danila R. Chernyavskiy,
  • Ilya A. Yakushev,
  • Vyacheslav A. Chertkov,
  • Aytan G. Muradova,
  • Victor V. Temnov,
  • Elena K. Beloglazkina,
  • Alexander V. Finko

摘要

Regioselectivity in pyrazole synthesis remains a formidable challenge. This work systematically investigates the mechanisms governing the acid-catalyzed cyclization of 4,4-dimethoxybutan-2-one with methylhydrazine, tert-butylhydrazine and phenylhydrazine using a combined experimental and DFT approach. Before ketal hydrolysis, reaction predominantly occurs at the exposed C2 carbonyl carbon. Upon hydrolysis, a reactive oxocarbenium intermediate forms an ultra-deep thermodynamic trap with a Gibbs free energy change ∆G of approximately − 33 kcal/mol at the C4 site. However, the final product distribution is constrained by nucleophile-specific kinetics. For methylhydrazine, the non-negligible ketal cleavage barrier allows this unhindered nucleophile to target the protonated C2 site (+ 0.758 e) under charge control, yielding 69.8% of the 3-methylpyrazole isomer. Conversely, the bulkier tert-butylhydrazine experiences fierce, short-range Pauli exclusion principal repulsion near 1.75 Å with the C2 skeleton, forcing a flux redistribution into the C4 channel (55.4%:44.6% 3-methyl/5-methyl ratio). Remarkably, phenylhydrazine exhibits 100% selectivity for the 3-methyl product, driven by a long-range polarization trapping mechanism induced by transient orbital alignment with the C2 carbon. Collectively, this work clarifies how electronic, steric, and orbital effects cooperatively dictate pyrazole.