Theoretical Study on Mechanism of Copper(I)-Catalyzed Cross-Coupling between Aryl Halides and Alkylamines

Density functional theory method B3LYP was used to study the mechanism of amination reactions between aryl bromides and alkylamines catalyzed by Cu(I) species with 1,3-diketone ligands. Through systematic evaluation of the relative concentrations of possible copper species in solution and oxidative addition of these species with aryl bromide, we propose that the active catalyst is a neutral three-coordinate 1,3-diketonate-ligated Cu(I)(amine) complex. Oxidative addition of aryl bromide to this species is the rate-limiting step of the catalytic cycle. These results explain why for basic alkylamine substrates, diamine ligands are ineffective, because for diamine ligands, formation of such a neutral Cu(I) complex containing both ligand and nucleophile is thermodynamically unfavorable. Interestingly, I he active catalyst Cu(I)(diketonate)(amine) complex is essentially akin to the active catalyst Cu(I)(diamine)(amidate) proposed in copper-catalyzed coupling of amides with aryl halides. Therefore, this implies that for an acidic substrate a neutral ligand is preferred, while for basic substrate an acidic ligand is necessary to achieve high efficiency. Our results also show that anionic copper(I) complexes with two molecules of deprotonated necleophiles or ligands are not reactive. Therefore, the wise selection of appropriate ligand and base combinations for a specific nucleophile to generate a neutral copper(I) complex containing both ligand and nucleophile is the key point to the success of these copper-catalyzed cross-coupling reactions. These insights should be helpful for our understanding and further development of more efficient reaction protocols for copper-catalyzed coupling of more challenging electrophiles such as aryl chlorides and tosylates and other types of nucleophiles.