Mechanism and Origins of Site‐Selectivity of Template‐Directed C−H Insertion of Quinolines

The template‐directed C−H insertion of α,β‐unsaturated esters into quinoline was interrogated by using computational quantum chemistry. An energetically viable mechanism for this complex multistep transformation was elucidated, with attention paid throughout to conformational flexibility and alternative ligand binding modes. The selectivity was found to correlate with distortion from a tetrahedral geometry for the carbon atom involved in C−H insertion, a parameter that can be applied to future template design. Not so simple: Modern computational chemistry (DFT on reaction coordinates, extensive conformational searches, multiple means of treating entropy) has been used to probe the mechanism of a complex organometallic reaction – template‐directed C−H insertion of α,β‐unsaturated esters into quinoline – providing a deep dive into the origins of site selectivity and demonstrating that previous simple models are not sufficient.