Density functional theory is used to explore the origins of the chemoselectivity and regioselectivity of activation of C?F bonds in pentafluoropyridine with [Ni(PR3)2] species. Experimentally, Ni-fluoride species are observed and activation occurs preferentially at the 2-position (i.e., the C?F bond ortho to the pyridyl nitrogen). This is in marked contrast to related platinum reagents, which form Pt-alkyl species featuring fluorophosphine ligands with activation occurring exclusively at the 4-position. Using a model nickel complex, [Ni(PMe 3)2], computed potential energy surfaces reveal two distinct types of reaction pathways: conventional oxidative addition and phosphine-assisted C?F bond activation. In the latter, the activated fluorine is transferred first to the phosphine ligand before migrating to the metal center. The phosphine-assisted routes lie substantially above their oxidative addition counterparts unless activation occurs at the 2-position, where coordination of the pyridyl nitrogen stabilizes both the metallophosphorane intermediate and the preceding transition state. The result is a lowering of the barrier such that the phosphine-assisted route becomes competitive with conventional oxidative addition. This "neighboring group acceleration" is unique to the phosphine-assisted pathway and, moreover, is unique to activation at the 2-position because it depends on the ability of the nitrogen to participate in a benzyne-like, pyridin-1,2-diyl coordination mode. © 2010 American Chemical Society.