Electron Dynamics in Alkane C-H Activation Mediated by Transition Metal Complexes.

Alkanes, ideal raw materials for industrial chemical production, typically exhibit limited reactivity due to their robust and weakly polarized C-H bonds. The challenge lies in selectively activating these C-H bonds under mild conditions. To address this challenge, various C-H activation mechanisms have been developed. Yet, classifying these mechanisms depends on the overall stoichiometry, which can be ambiguous and sometimes problematic. In this study, we utilized density functional theory calculations combined with intrinsic bond orbital (IBO) analysis to examine electron flow in the four primary alkane C-H activation mechanisms: oxidative addition, σ-bond metathesis, 1,2-addition, and electrophilic activation. Methane was selected as the representative alkane molecule to undergo C-H heterolytic cleavage in these reactions. Across all mechanisms studied, we find that the CH3 moiety in methane consistently uses an electron pair from the cleaved C-H bond to form a σ-bond with the metal. Yet, the electron pair that accepts the proton differs with each mechanism: in oxidative addition, it is derived from the d-orbitals; in σ-bond metathesis, it resulted from the metal-ligand σ-bonds; in 1,2-addition, it arose from the π-orbital of the metal-ligand multiple bonds; and in electrophilic activation, it came from the lone pairs on ligands. This detailed analysis not only provides a clear visual understanding of these reactions but also showcases the ability of the IBO method to differentiate between mechanisms. The electron flow discerned from IBO analysis is further corroborated by results from absolutely localized molecular orbital energy decomposition analysis, which also helps to quantify the two predominant interactions in each process. Our findings offer profound insights into the electron dynamics at play in alkane C-H activation, enhancing our understanding of these critical reactions.

Catalytically Relevant Organocopper(III) Complexes Formed through Aryl-Radical-Enabled Oxidative Addition.

Stepwise oxidative addition of copper(I) complexes to form copper(III) species via single electron transfer (SET) events has been widely proposed in copper catalysis. However, direct observation and detailed investigation of these fundamental steps remain elusive owing largely to the typically slow oxidative addition rate of copper(I) complexes and the instability of the copper(III) species. We report herein a novel aryl-radical-enabled stepwise oxidative addition pathway that allows for the formation of well-defined alkyl-CuIII species from CuI complexes. The process is enabled by the SET from a CuI species to an aryl diazonium salt to form a CuII species and an aryl radical. Subsequent iodine abstraction from an alkyl iodide by the aryl radical affords an alkyl radical, which then reacts with the CuII species to form the alkyl-CuIII complex. The structure of resultant [(bpy)CuIII(CF3)2(alkyl)] complexes has been characterized by NMR spectroscopy and X-ray crystallography. Competition experiments have revealed that the rate at which different alkyl iodides undergo oxidative addition is consistent with the rate of iodine abstraction by carbon-centered radicals. The CuII intermediate formed during the SET process has been identified as a four-coordinate complex, [CuII(CH3CN)2(CF3)2], through electronic paramagnetic resonance (EPR) studies. The catalytic relevance of the high-valent organo-CuIII has been demonstrated by the C-C bond-forming reductive elimination reactivity. Finally, localized orbital bonding analysis of these formal CuIII complexes indicates inverted ligand fields in σ(Cu-CH2) bonds. These results demonstrate the stepwise oxidative addition in copper catalysis and provide a general strategy to investigate the elusive formal CuIII complexes.

WISP3-dependent regulation of type II collagen and aggrecan production in chondrocytes.

OBJECTIVE: WISP3 (Wnt-1-inducible secreted protein 3) is a member of the CCN (connective tissue growth factor, cysteine-rich 61, nephroblastoma overexpressed) family of connective tissue growth factors. WISP3 mutations have been linked to progressive pseudorheumatoid dysplasia (PPRD). The present study was conducted to investigate whether WISP3 is responsible for the expression of cartilage-specific molecules. METHODS: WISP3 expression in human cartilage was assessed by immunostaining with anti-WISP3 antibody. The effect of WISP3 on chondrocyte-specific gene regulation was determined by transfecting human chondrocyte lines C-28/I2 and T/C-28a2 with a WISP3 expression vector. Alterations in WISP3-mediated messenger RNA and protein expression of cartilage-specific molecules were assessed by reverse transcriptase-polymerase chain reaction and immunoblotting. RESULTS: Immunohistochemistry experiments demonstrated that WISP3 protein is expressed in the midzone chondrocytes of normal adult articular cartilage, in chondrocyte clusters of osteoarthritic cartilage, and in the zone of proliferating chondrocytes of fetal growth cartilage. Human chondrocyte lines C-28/I2 and T/C-28a2 transfected with a WISP3 expression vector produced increased amounts of the cartilage-specific matrix molecules type II collagen and aggrecan, in part via activation of the sex-determining region Y-type high mobility group box (SOX) family of transcription factors. In contrast, a mutant WISP3, previously found to be associated with PPRD, had impaired effects on cartilage-specific gene expression. CONCLUSION: Our experimental results suggest that WISP3 supports cartilage integrity by regulating the expression of type II collagen and aggrecan, and mutations linked with PPRD can compromise this function and produce cartilage loss.