Palladium (0) Catalyzed C-C and C-N Coupling of Heterocyclic Compounds: Synthesis, Characterization, Biological Evaluation and DFT Studies

Abstract

Transition metal catalysis is of great importance due to its fascinating chemistry, and vast applicability, enabling the carbon-carbon (C-C) and carbon-heteroatom (C-X) bond formation possible. Among them, the superiority of palladium (Pd0 )-catalyzed method is attributed to the fact that they are usually one-pot reaction. So, the need for purification and isolation of intermediate products in a multistep reaction could be avoided. Secondly, a single catalyst is enough to complete a multipart process. With the desired substrate molecule and suitable conditions, high yields of products can be achieved. The current study was therefore designed to synthesize novel nitrogen-based heterocyclic compounds such as arylated pyridine and pyrimidine derivatives through C-C and carbon-nitrogen (C-N) bond coupling, using Pd0 as a catalyst. For the synthesis of C-C bond, the calculated amount of 2,6-dibromopyridine and 2- and 5-bromopyrimidine was treated with a variety of boronic acid in the presence of Pd0 catalyst, suitable solvent system, and base at elevated temperature in a pressure tube. Several novel arylated pyridine and pyrimidine derivatives were formed in excellent yield by mean of Pd0 -catalyzed Suzuki-Miyaura protocol. For C-N bond formation, Buchwald-Hartwig coupling protocol was followed by treating different aromatic amines with the above-mentioned starting materials under altered conditions to develop a novel C-N coupling scheme. The reaction was monitored by TLC and purified by column chromatography. Reactions were performed using various solvents, bases, and Pd catalysts to get the desired products. However, the obtained results were not promising in terms of C-N coupled product synthesis, and the applied schemes could not generate the desired outcomes. Structure elucidation of the synthesized compounds was done via different characterization techniques like 1H-NMR, 13C-NMR, IR, GSMS, UV-Visible, and X-ray diffraction (XRD) analysis. The geometry optimization was done at the M06 method with /6-311G** basis set of DFT. Furthermore, the same method and basis set was used for the natural bond orbitals (NBOs) assessment of the synthesized compounds following a program package NBO 3.1. Meanwhile, the frontier molecular orbitals (FMOs) and UV-Visible study were accomplished by applying the TD-DFT at M06/6-311G** level. Furthermore, global reactivity parameters (GRP) were quantified by utilizing HOMO, LUMO, and their corresponding energy gaps. The extent of global electrophilicity (ω), chemical potential (μ), electronegativity (X), global hardness (η), and softness (σ) values were assessed. The non-linear optical (NLO) parameters including dipole moment (μ), average polarizability ⟨α⟩, and first hyperpolarizability (β) were quantified using HF, LC-BLYP, CAM-B3LYP, M062X, and M06 methods with 6-311G** basis set. The GaussView 5.0 software package was utilized to manage the input files. The results gathered from the output files were further interpreted by using Chemcraft, Avogadro, and GaussSum programs. The theoretical calculated maximum absorption (λDFT) for all the compounds displayed good agreement with experimentally (λExp) obtained results in methanol solvent. The NBO analysis revealed that the stabilization in the network of organic compounds was due to hypercoagulative interactions. Indeed, FMO and NBO results confirmed the intramolecular charge transfer (ICT) processes in analyzed compounds. The NLO analysis xx yielded promising NLO results for the studied compounds. In summary, the comparative data showed that studied compounds might be exceptional, NLO organic materials. It was expected that the newly synthesized compounds may act like drugs; therefore, their potential against different microbes was evaluated. In that context, the biological activities of some representative compounds were analyzed which included antimicrobial, anti-quorum sensing activity, and 15-Lox inhibition activity. The minimum inhibitory concentration (MIC) of synthesized compounds was determined for bacterial strain Staphylococcus aureus and Escherichia coli against standard antibiotic Ciprofloxacin. The synthesized compounds showed moderate to good antimicrobial activity. The obtained results indicated that none of the compounds demonstrated any anti quorum sensing activity and 15-Lox inhibition activity. In conclusion, the majority of the synthesized compounds are recommended for future NLO applications as well as drug synthesis.