Conformational pre-organization in privileged bidentate directing groups

Abstract

The 8-aminoquinoline (AQ) auxiliary occupies a privileged position among bidentate N , N -directing groups in transition metal catalysis, yet the structural basis of its catalytic performance has been rarely examined. Combining a crystallographic survey of free (non-metalated) reaction products with density functional theory (DFT) analysis of model compounds, we show that AQ is conformationally pre-organized and avoids the energetic penalty of reorganization required for binding. In every free-product structure, AQ is locked in a planar, chelation-ready geometry, whereas auxiliaries containing C(sp3)-based spacers—including 2-pyridylmethylamine (PM) and its gem -dimethyl (PIP) and gem -diethyl (PDE) congeners—mostly rest in an anti conformation and must reorganize to bind. This pre-organization is a concrete, measurable structural property that distinguishes AQ from flexible C(sp3)-linked auxiliaries and is a contributing factor that governs which one a shared Pd(II) catalyst preferentially engages under competition, highlighting a design principle for removable bidentate directing groups.