The reactivity of main group organometallics, such as organolithium compounds (RLi) and Grignard reagents (RMgX), is quite straightforward. In these species the R group usually exhibits nucleophilic reactivity without any possibility of inducing electrophilic character. In contrast, in organopalladium complexes, researchers can switch the reactivity from electrophilic to nucleophilic relatively simply. Although σ-aryl and σ-vinylpalladium complexes are commonly used as electrophiles in C-C bond-forming reactions, recent research has demonstrated that they can also react with carbon-heteroatom multiple bonds in a nucleophilic manner. Nevertheless, researchers have completely ignored the issue of controlling the ambiphilic nature of such species. This Account describes our efforts toward selectively promoting the same starting materials toward either electrophilic α-arylation or nucleophilic addition reactions to different carbonyl groups. We could tune the properties of the σ-arylpalladium intermediates derived from amino-tethered aryl halides and carbonyl compounds to achieve chemoselective transformations. Therefore, chemists can control the ambiphilic nature of such intermediates and, consequently, the competition between the alternative reaction pathways by the adequate selection of the reaction conditions and additives (base, presence/absence of phenol, bidentate phosphines). The nature of the carbonyl group (aldehydes, ketones, esters, and amides) and the length of the tether connecting it to the aniline moiety also play an important role in the outcome of these processes. Our joint computational and experimental efforts to elucidate the reaction mechanism of these palladium-catalyzed transformations suggest that beyond the formation of the four-membered azapalladacycle, two major factors help to control the dual character of the palladium(II) intermediates derived from 2-haloanilines. First, their high nucleophilicity strongly modifies the interaction of the metal center with the carbonyl group. Second, the additive phenol exchanges the iodide ligand to give an arylpalladium(II) phenoxide complex, which has a beneficial effect on the arylation. The formation of this transient intermediate not only stabilizes the arylpalladium moiety, thus preventing the nucleophilic attack at the carbonyl group, but also assists the enolization reaction, which takes place in a more favorable intramolecular manner. The azapalladacycle intermediate is, in the words of J. R. R. Tolkien, "the one ring to bring them all and in the darkness to bind them." With this intermediate, we can easily achieve the synthesis of a variety of heterocyclic systems by selectively promoting electrophilic α-arylation or nucleophilic addition reactions from the same precursors.
