Computational Assessment of the Mechanistic Journey in Chan-Lam-Based Arylation of Imidazoles.

Cu(II)-catalyzed C-N bond formation reactions remain one of most widely practiced and powerful protocols for the synthesis of value-added chemicals, bioactive molecules, and materials. Despite numerous experimental contributions, the overall mechanistic understanding of the C-N coupling reaction based on the Chan-Lam (CL) reaction methodology is still limited and underdeveloped, particularly with respect to the use of different substrates and catalytic species. Herein, we report an in-depth DFT-based study on the mechanism of N-arylation of imidazoles following Collman's experimental setup. Our findings unfold for the first time the ligand-based CL coupling catalyzed by the [Cu(II)(OH)TMEDA]2Cl2 complex. The transmetalation step with an energy span of 26.2 kcal mol-1 is rate-determining, while the subsequent disproportionation and reductive elimination are relatively facile (δE = 16.4 kcal mol-1) in comparison to the CL amination of secondary amines. The final oxidative catalyst regeneration results in the presence of O2, accompanying an energy span of 12.8 kcal mol-1, where hydrogen transfer from the coordinated water allows the reduction of superoxo linkage. Couplings performed in the presence of a combination of bidentate sp3-N ligands with single and double -(CH2)- spacer units afford a kinetically facile transformation (24.5 kcal mol-1). Furthermore, our results agree with the experimental outcomes of regioselective couplings of substituted imidazoles.

Mechanistic Avenues in the Chan-Lam-Based Etherification Reaction: A Computational Exploration.

Invited for the cover of this issue is the group of Koley and co-workers at the Indian Institute of Science Education and Research (IISER) Kolkata. The image depicts the industrial generation of the product from the available starting materials in a catalytic cycle. Read the full text of the article at 10.1002/chem.202302983.

Mechanistic Avenues in the Chan-Lam-Based Etherification Reaction: A Computational Exploration.

Ongoing advances in CuII -catalyzed aerobic oxidative coupling reactions between arylboronic esters and diverse heteroatom nucleophiles have strengthened the development of the general Chan-Lam (CL)-based reaction protocol, including C-O bond formation methodologies. In-depth mechanistic understanding of CL etherification with specific emphasis on different reaction routes and their energetics are still lacking, even though the reaction has been experimentally explored. Here, we present a DFT-guided computational study to unravel the mechanistic pathways of CL-based etherification. The computational findings provide some interesting insights into the fundamental steps of the catalytic cycle, particularly the rate-determining transmetalation event. An aryl boronic ester-coordinated, methoxide-bridged CuII intermediate that acts as resting state undergoes transmetalation with an activation barrier of 20.4 kcal mol-1 . The energy spans of the remaining fundamental steps leading to the methoxylated product are relatively low. The minor p-cresol product requires an additional 14.2 kcal mol-1 energy span to surmount in comparison to the favored route. Hammett studies for the substituted aryl boronic esters reveal higher reaction turnovers for electron-rich aryl systems. The results agree with previously reported spectroscopic and kinetic observations. For a series of alcohol substrates, it was observed that, except for cyclohexanol, moderate to high etherification turnovers are predicted.

Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration.

Phospholipase A2 (PLA2) promotes inflammation via lipid mediators and releases arachidonic acid (AA), and these enzymes have been found to be elevated in a variety of diseases, including rheumatoid arthritis, sepsis, and atherosclerosis. The mobilization of AA by PLA2 and subsequent synthesis of prostaglandins are regarded as critical events in inflammation. Inflammatory processes may be treated with drugs that inhibit PLA2, thereby blocking the COX and LOX pathways in the AA cascade. To address this issue, we report herein an efficient method for the synthesis of a series of octahydroquinazolinone compounds (4a-h) in the presence of the catalyst Pd-HPW/SiO2 and their phospholipase A2, as well as protease inhibitory activities. Among eight compounds, two of them exhibited overwhelming results against PLA2 and protease. By using FT-IR, Raman, NMR, and mass spectroscopy, two novel compounds were thoroughly studied. After carefully examining the SAR of the investigated compounds against these enzymes, it was found that compounds (4a, 4b) containing both electron-donating and electron-withdrawing groups on the phenyl ring exhibited higher activity than compounds with only one of these groups. DFT studies were employed to study the electronic nature and reactivity properties of the molecules by optimizing at the BLYP/cc-pVDZ. Natural bond orbitals helped to study the various electron delocalizations in the molecules, and the frontier molecular orbitals helped with the reactivity and stability parameters. The nature and extent of the expressed biological activity of the molecule were studied using molecular docking with human non-pancreatic secretory phospholipase A2 (hnps-PLA2) (PDB ID: 1DB4) and protease K (PDB ID: 2PWB). The drug-ability of the molecule has been tested using ADMET, and pharmacodynamics data have been extracted. Both the compounds qualify for ADME properties and follow Lipinski's rule of five.