Boosting Palladium-Catalyzed Aryl–Nitro Bond Activation Reaction by Understanding the Electronic, Electrostatic, and Polarization Effect: A Computational Study from a Basic Understanding to Ligand Design

Although palladium-catalyzed aryl–nitro bond activation reaction has recently gained a lot of interest, it still requires rather harsh conditions. We here systematically explore the substituent effect on oxidative addition steps, known as the rate-determining step, by density functional theory simulations based on a Nakao’s nitrogen heterocyclic carbene (NHC) ligand. The key aryl ring on the catalyst, ring A, acts as a π-donor and stabilizes the palladium center of the transition state, and thus an electron-rich ring A is expected to lower the barrier. However, the polarization and electrostatic effects were shown to be more important, although they were often ignored before. These effects originate from through-space interaction with a nitro group in the resting state, and the overall effect is that any polarizable or partly negative group near ortho- or meta-site of ring A is harmful for the reaction. Based on these discoveries, we proposed a list of guidelines for successful ligand developments and designed several new ligands. These ligands exhibit a significantly lower barrier than the reported Nakao’s ligand by as large as ∼5 kcal/mol, in both gas phase and solvent with a moderate dipole. These candidates will promote further experimental studies and enhance the ability to improve ligands in a rational and predictive manner.