Synthetic approach of hydroxy-acetophenone-directed Rh(III) catalyzed C-H o-alkylation via 1,4 addition: Insights from DFT and docking methodology

• Published in: Journal of molecular structure 2025-04, Vol.1327, p.141248, Article 141248
• Main Authors: Sivakumar, Pakkirisamy, Ganesh, Pothapragada S.K. Prabhakar, Muthuraja, Perumal, Bharanidharan, Sarangapani, Rajamohan, Rajaram, Kamatchi, Subramaniyan
• Format: Article
• Language: English
• Subjects: 1,4 addition; ADME property; Anti-inflammation activity; C–H activation; DFT approach; Molecular docking
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.141248

•Rh(III)-catalyzed 1,4-addition approach, yielding ortho-alkylated succinimide derivatives under mild conditions.•A redox-neutral pathway is confirmed, excluding the formation of Heck reaction products.•Density Functional Theory is employed to optimize molecular structures using the B3LYP/6-311++G(d,p) basis set.•Docking analyses revealed strong drug-protein interactions, supporting the chemical reactivity insights.•A superior anti-inflammatory and anti-diabetic activities for the synthesized compounds compared to standard drugs. This study presents a Rh(III)-catalyzed 1,4-addition approach, utilizing a directing group to functionalize the o-carbon of ester-containing acetophenone groups with maleimides, yielding ortho-alkylated succinimide derivatives under mild conditions. The method demonstrates broad substrate versatility and achieves high yields. A redox-neutral pathway is confirmed, excluding the formation of Heck reaction products. Density Functional Theory (DFT) is employed to optimize molecular structures of the molecules (3a, 3b, and 3c) using the B3LYP/6-311++G(d,p) basis set and analyze electronic properties, including HOMO-LUMO gaps, dipole moments, polarizability, and hyperpolarizability, to assess nonlinear optical (NLO) properties. Molecular Electrostatic Potential (MEP) maps identified sites for hydrogen bonding and electrophilic/nucleophilic interactions. Docking analyses revealed strong drug-protein interactions, supporting the chemical reactivity insights. Biological evaluations demonstrated superior anti-inflammatory and anti-diabetic activities for the synthesized compounds compared to standard drugs, highlighting their potential as effective therapeutic alternatives for managing inflammation and diabetes. [Display omitted]