LAUSR

Aromatic nucleophilic substitution (SNAr) is a widely employed synthetic method for modifying thiophene derivatives. Herein, we computationally investigate the reaction mechanism of 2‐methoxy‐3‐X‐5‐nitrothiophenes with pyrrolidine (where X = NO2, CN, SO2CH3, COCH3, CO2CH3, CONH2 or H). This SNAr reaction follows a stepwise pathway: initially, pyrrolidine adds to the C2 position of the 2‐methoxy thiophene partner. Then, the release of methanol is triggered by a proton transfer from the newly formed ammonium intermediate to the methoxy group. With excess pyrrolidine, this proton transfer is catalyzed by an additional pyrrolidine molecule. We establish linear correlations between the experimental electrophilicity and the Gibbs free energy barrier, Parr electrophilicity (ω), and molecular softness (S). Local reactivity descriptors for the C2 position are generally non‐informative, except for the population of the CO bond basin, the C2 population of the ELFLUMO function, and the condensed electrophilicity index ω+(C2). This theoretical approach provides a robust method to further predict electrophilicity parameters in versatile thiophene derivatives chemistry.