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<p>The alkylation of thiourea with halogenacetic acids has been known for over 150 years, yet the detailed mechanisms remain not fully understood. This work systematically investigates the reaction of thiourea with bromoacetic acid under various conditions – water, alcohols (methanol, ethanol, 2-propanol, hexadecan-1-ol), acetonitrile, and diethyl ether – at room temperature and upon heating. Five distinct products were isolated and characterized, including the previously unreported 2-hydroxy-4-oxo-4,5-dihydrothiazol-3-onium bromide (<b>8</b>), whose crystal structure was determined by X-ray diffraction. Thermogravimetric analysis revealed decomposition without melting for all products. Density functional theory calculations (B3LYP and M06-2X with 6-311 + + G** basis set) elucidated the preferred protomers and rotamers of each compound, the nature of hydrogen bonding in dimeric species, and the complete reaction pathway. The key finding is that the initial alkylation step occurs in all solvents, but subsequent cyclization to the cyclic imine (<b>9</b>) and oxidation to thiazolidine-2,4-dione (<b>11</b>) proceed only in protic solvents (water and alcohols) under acidic conditions. The dimeric product <b>8</b> forms exclusively in protic environments through stoichiometric pairing of <b>11</b> with its protonated form <b>[11 + H]⁺</b>. This work resolves long-standing contradictions in the literature and provides a solvent-dependent mechanistic rationale for this classic reaction.</p>

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+ 150 years of studying thiourea alkylation reactions with halogenacetic acids: still news?

  • 期刊论文

  • 发表日期：

    2026年7月8日

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  • Julia V. Bakhtiyarova,
  • Heejin Park,
  • Semen R. Romanov,
  • Anton P. Fedonin,
  • Olga N. Kataeva,
  • Irina V. Galkina,
  • Enrico Benassi

摘要

The alkylation of thiourea with halogenacetic acids has been known for over 150 years, yet the detailed mechanisms remain not fully understood. This work systematically investigates the reaction of thiourea with bromoacetic acid under various conditions – water, alcohols (methanol, ethanol, 2-propanol, hexadecan-1-ol), acetonitrile, and diethyl ether – at room temperature and upon heating. Five distinct products were isolated and characterized, including the previously unreported 2-hydroxy-4-oxo-4,5-dihydrothiazol-3-onium bromide (8), whose crystal structure was determined by X-ray diffraction. Thermogravimetric analysis revealed decomposition without melting for all products. Density functional theory calculations (B3LYP and M06-2X with 6-311 + + G** basis set) elucidated the preferred protomers and rotamers of each compound, the nature of hydrogen bonding in dimeric species, and the complete reaction pathway. The key finding is that the initial alkylation step occurs in all solvents, but subsequent cyclization to the cyclic imine (9) and oxidation to thiazolidine-2,4-dione (11) proceed only in protic solvents (water and alcohols) under acidic conditions. The dimeric product 8 forms exclusively in protic environments through stoichiometric pairing of 11 with its protonated form [11 + H]⁺. This work resolves long-standing contradictions in the literature and provides a solvent-dependent mechanistic rationale for this classic reaction.