C–N Coupling of 3‐Aminothiophene with Substituted Benzenediazonium Cations: Carbon Nucleophilicity, Hyper‐Ortho Effects, and Predictive Modeling of Structural Analogs

This review has kinetically investigated the electrophilic attack of 3-aminothiophene 1 by a series of para-substituted benzenediazonium cations 7a-7h in 50% H₂O-50% Me₂SO at 20 °C using stopped-flow spectrophotometry. No kinetic isotope effect is observed with the 2-deuterio-3-aminothiophene, confirming that the rate-determining step is a carbon-based electrophilic aromatic substitution (S_EAr) at the C-2 position. The Hammett plot with σ_p values shows nonlinearity due to electron-donating substituents. However, a linear relationship is obtained using the Yukawa-Tsuno equation, highlighting the resonance contribution via the r(σ_p ⁺ - σ_p) term. An excellent linear correlation (R² ≈ 0.9968) is observed between log k₁ and the experimental electrophilicity parameter E of the diazonium cations, as defined in the Mayr-Patz equation, allowing the determination of the carbon nucleophilicity parameters of 3-aminothiophene: N = 9.37 and s_N = 1.18. Importantly, a strong linear relationship is established between N and the Hammett σ⁺ constants for 3-substituted 3-aminothiophenes (R² = 0.9763), described by the equation: N = 6.72 - 2.01 σ⁺. This correlation not only demonstrates the pronounced enaminic behavior of 3-aminothiophenes but also enables the prediction of N values for unmeasured analogs, confirming that substituent-π-system interactions govern nucleophilic reactivity via a hyper-ortho electronic effect.