Substituent Effects and the Energetics of Noncatalyzed Aryl Halide Aminations: A Theoretical Investigation

[Image: see text] We report the influence of substituents and physical conditions on activation energies for the noncatalyzed amination (C–N cross-coupling reactions) of aryl halides. We uncover a significant correlation between the barrier heights of the C–N bond formation and Hammett σ parameters—a formal measure of the electron-withdrawing or -donating ability of substituents on the aryl halides. Our results indicate that such correlations are useful predictive tools for the amination of aryl halides over a wide range of substituent types. From 54 cases studied (six substituents occupying specific positions relative to halogen atoms), the 2-COOHPhI + NH(2)(n)Pr amination reaction is predicted to possess the lowest noncatalyzed activation free energy (135.6 kJ mol(–1)) using the B3LYP method. The lower barriers for the 2-COOHPhX (for X = Cl, Br, and I) compounds are shown to originate from collusion between steric and electronic effects—specifically, the momentary formation of a hydrogen bond between an oxygen site on the ortho-COOH and the lone pair of the entering amine. Internal reaction coordinate (IRC) path calculations afforded us these and other key insights into the nature of the reactions. The control exerted by substituents on the arrangement of the transition state structure, as well as the sensitivity of the reaction barriers to temperature and solvent polarity, are discussed. These results offer new perspectives from which to assess the nature of the C–N bond formation and suggest new avenues for future exploration, especially in progress toward the metal-free amination of aryl compounds.