C-H functionalization of quinoline N-oxides catalyzed by Pd(II) complexes: a computational study

Paulo J Costa; Frederico F Martins; Chao Pi; Xiuling Cui; Maria José Calhorda

doi:10.1039/d3cp02445h

C-H functionalization of quinoline N-oxides catalyzed by Pd(II) complexes: a computational study

Phys Chem Chem Phys. 2023 Aug 30;25(34):22755-22767. doi: 10.1039/d3cp02445h.

Authors

Paulo J Costa¹, Frederico F Martins¹, Chao Pi², Xiuling Cui², Maria José Calhorda¹

Affiliations

¹ BioISI - Instituto de Biossistemas e Ciências Integrativas, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal. mjcalhorda@ciencias.ulisboa.pt.
² College of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, People's Republic of China.

PMID: 37605868
DOI: 10.1039/d3cp02445h

Abstract

Pd(II) catalysts, particularly the acetate salt in acetic acid, tended to favor regioselective C-H activation of quinoline N-oxides (QOs) at the C2 position. However, Pd(II)Cl₂ was shown to catalyze their C-H activation at C8 and, in the presence of water, C8-H activation was accompanied by the formation of 2-quinolinones. The aim of the DFT study described in this work was to shed light on the complete mechanism of these competing catalytic reactions, when PdCl₂ reacts with QO and benzaldehyde in dichloroethane. C-H activation of QO was the first step of the reaction and involved either a metallacycle, with a C_QO-Pd(II) σ-bond and a C(8)-H-Pd(II) agostic bond, or an η³-QO complex, with three carbon atoms of the heteroring of QO binding PdCl₂. The first situation led to the unusual C8 activation and the second to C2 activation. The σ-metallacycle undergoes C8-H activation and the energy of the TOF determining the transition state to form the product is ∼17 kcal mol^-1, while for the reaction through the π-metallacycle (C2-H activation) the corresponding energy is higher (∼29 kcal mol^-1) and thus is not competitive under the same conditions. The reaction proceeding through the σ-complex, activating the C8 position, is preferred, in agreement with experimental results. Both reactions involve oxidation of Pd(II) to Pd(IV) and the catalyst is regenerated. When small amounts of water are added to the reaction mixture, C8-H activation (acylation) results from the same σ-metallacycle with the same barrier, but the simultaneous formation of 2-quinolinones is more complicated. It starts with OH^- attack at the C2 position, and is followed by the migration of two hydrogen atoms, and the final reductive elimination step ends with Pd(0). The higher barriers for the migration and reoxidation of Pd(0) are associated with the more demanding reaction conditions. The different reactivity of Pd(II)(OAc)₂ under analogous conditions is clarified, as it is only capable of forming the above mentioned π-complex and thus of activating the C2 position of QO. This catalyst can preferentially activate the C8-H bond under rather different conditions, including in particular acetic acid medium, as shown by other authors.