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<p>The kinetic and thermodynamic pathways for the preparation of 1-(4,6-dimethylpyrimidin-2-yl)-3-phenylthiourea (Reaction I) and 1-(4,6-dimethylpyrimidin-2-yl)-3-phenylurea (Reaction II) were investigated using density functional theory (B3LYP/6-31G(d, p) and B3LYP/6-311 + + G(d, p)) in both the gas phase and the ionic liquid ethylpyridinium iodide ([EPy]I) at 328.15&#xa0;K. Intrinsic Reaction Coordinate (IRC) analysis revealed that, under the present computational conditions, the reactions proceed most consistently via a concerted pathway involving synchronous N–H proton transfer and N–C bond formation. Natural Bond Orbital (NBO) and nonlinear optical (NLO) analyses were further employed to elucidate electronic factors affecting reactivity. In [EPy]I, Reaction I exhibited a ~ 2.3&#xa0;kcal·mol⁻¹ reduction in the activation free energy (Δ<i>G</i><sup>‡</sup>: 47.3 → 45.0&#xa0;kcal·mol⁻¹), corresponding to a ~ 35-fold increase in the forward rate constant. This kinetic enhancement arises from transition state stabilization through HOMO–LUMO gap widening, increased sulfur polarizability, and dipole moment growth, all of which promote charge delocalization. Reaction II, in contrast, was thermodynamically favored, with Δ<i>G</i>° = −8.4&#xa0;kcal·mol⁻¹ and an equilibrium constant (<i>K</i><sub>eq</sub>) of 1.6 × 10⁶ in [EPy]I, exceeding the stability of Reaction I. Although both reactions accelerated in the ionic liquid, the solvent effect was stronger for Reaction I, while Reaction II mainly benefited from suppressed reverse rates, shifting the equilibrium toward product formation. Overall, these computational findings not only rationalize the mechanistic divergence between thiourea and urea derivatives but also provide practical guidance for solvent and condition selection in future experimental synthesis.</p>

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Reactivity pathways of pyrimidine-derived thiourea and urea formation: a DFT-based kinetic and thermodynamic study in ionic liquid

  • 期刊论文

  • 发表日期：

    2026年6月18日

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  • Masoumeh Jafari,
  • Leila Hajiaghababaei,
  • Jamshid Najafpour,
  • Ashraf Sadat Shahvelayati

摘要

The kinetic and thermodynamic pathways for the preparation of 1-(4,6-dimethylpyrimidin-2-yl)-3-phenylthiourea (Reaction I) and 1-(4,6-dimethylpyrimidin-2-yl)-3-phenylurea (Reaction II) were investigated using density functional theory (B3LYP/6-31G(d, p) and B3LYP/6-311 + + G(d, p)) in both the gas phase and the ionic liquid ethylpyridinium iodide ([EPy]I) at 328.15 K. Intrinsic Reaction Coordinate (IRC) analysis revealed that, under the present computational conditions, the reactions proceed most consistently via a concerted pathway involving synchronous N–H proton transfer and N–C bond formation. Natural Bond Orbital (NBO) and nonlinear optical (NLO) analyses were further employed to elucidate electronic factors affecting reactivity. In [EPy]I, Reaction I exhibited a ~ 2.3 kcal·mol⁻¹ reduction in the activation free energy (ΔG‡: 47.3 → 45.0 kcal·mol⁻¹), corresponding to a ~ 35-fold increase in the forward rate constant. This kinetic enhancement arises from transition state stabilization through HOMO–LUMO gap widening, increased sulfur polarizability, and dipole moment growth, all of which promote charge delocalization. Reaction II, in contrast, was thermodynamically favored, with ΔG° = −8.4 kcal·mol⁻¹ and an equilibrium constant (Keq) of 1.6 × 10⁶ in [EPy]I, exceeding the stability of Reaction I. Although both reactions accelerated in the ionic liquid, the solvent effect was stronger for Reaction I, while Reaction II mainly benefited from suppressed reverse rates, shifting the equilibrium toward product formation. Overall, these computational findings not only rationalize the mechanistic divergence between thiourea and urea derivatives but also provide practical guidance for solvent and condition selection in future experimental synthesis.