A Computational Study of Gold(I)-Catalyzed Isomerization of Cyclooctyne: A Case Study on the Mechanism of C(sp³)–H Insertion by Cationic Gold Alkyne Complexes and Model Studies

Cationic gold-alkyne chemistry is a vital component of homogeneous gold catalysis due to its ability to access a wide range of reactive intermediates. Direct C(sp3)–H insertion by the cationic gold-alkyne complex is an emergent reaction in this area without a well-defined reactive intermediate. Gold(I)-catalyzed isomerization of cyclooctyne facilitated by trans-annular C(sp3)–H insertion ( Eur. J. Inorg. Chem. 2016, 995−1001) is used as a case study to investigate the mechanism of this process with density functional theory (DFT) calculations. Natural resonance theory (NRT) calculations are used to analyze the reactive intermediate in terms of familiar resonance structures. It is found that “slippage” or deformation of the gold ion coordination from η2 to η1 increases the NRT weighting of the vinyl cation resonance structure from 12% to 25% leading to its C(sp3)–H insertion reactivity. In addition, DFT calculations and a distortion-interaction analysis are used to rationalize the catalyst-dependent regioselectivity observed in the reaction. Lastly, model studies investigating the impact of the alkyne substrate and ancillary ligand show that electron-withdrawing substituents and electron deficient ligands lower Gibbs activation energy for C(sp3)–H insertion, which suggests strategies to further improve the reaction through catalyst design.