Albelwe, Bayan L.
(2025)
Sterically demanding pincer ligands for transition metal chemistry.
PhD thesis, University of Nottingham.
Abstract
This work involves the development of new bulky ligands based on the carbazole framework to bind to a range of metals. The overall aim is to use these ligands to stabilise transition metal complexes that may prove useful in catalysis and small molecule activation. In this project, the novel ONO pincer pre-ligand 3,6-di-tert-butyl-1,8-bis(((triisopropylsilyl)oxy)methyl)-9H-carbazole 6 was synthesised and characterised by X-ray diffraction, NMR spectroscopy, mass spectrometry and elemental analysis. The bidentate imine ligands 1-phenyl-N-(pyridin-2-ylmethyl)methanimine 7 and [6-(methyl)-2-(iminophenylmethyl)pyridine] 8, known in the literature have been synthesised to further investigate their coordination chemistry. While 7 was not isolated successfully, X-ray crystallographic analysis revealed 7a, indicating the formation of a pyrazine ring under the reaction conditions used. The synthesis of 8 was confirmed by NMR spectroscopy and mass spectrometry.
Following the procedures used above, the synthesis of two novel NNNNN pentadentate pre-ligands 3,6-di-tert-butyl-1,8-bis(N-(6-methylpyridin-2-yl)methanimine)-9H-carbazole 9 and 3,6-di-tert-butyl-1,8-bis(N-(pyridin-2-ylmethyl)methanimine)-9H-carbazole 10 featuring sterically demanding imino pyridine Schiff groups on a carbazole backbone were attempted. Although the 1H NMR spectrum of a crude reaction mixture indicated the presence of 9, no evidence was obtained for the formation of 10. This might be due to the steric hindrance of the flanking groups.
The direct deprotonation of 6 was challenging and varying reaction conditions were attempted. Using KH and KHMDS resulted in the formation of two novel potassium salts of 6, 11 and 12, respectively. However, during crystallisation of 11, crystals were obtained suitable for X-ray diffraction (XRD) which revealed a structure that was assigned to 11b, as a minor product. Furthermore, three novel lithium salts of 6 were obtained when deprotonating 6 with LiHMDS (13, 14 and 14a). The 1H NMR spectra of 12 and 13 illustrated the effect the size of the central metal atom employed can have on the obtained spectra.
Further investigations into complexes based on the NNN pincer ligand 5, bearing naphthyl flanking groups which was previously synthesised by the group have also been conducted. Attempts to form a nickel hydride complex with pre-ligand 5 were attempted using Ni(COD)2. During crystallisation of the crude reaction mixture, X-ray diffraction suggested the formation of a nitrogen oxide compound, but no formation of the targeted nickel complex. By reacting 5 with copper acetate, complex 20 has been successfully obtained and characterised by XRD, NMR spectroscopy, mass spectrometry, elemental analysis, UV/Vis spectroscopy and IR spectroscopy. EPR spectroscopy was attempted but the assignment of the obtained spectrum was challenging. The reaction between deprotonated 6 and ZnCl2 resulted in formation 17a, and the reaction between deprotonated 6 and FeCl2(THF)1.5, in the presence of an excess of LiHMDS, resulted in formation complex 18a. The structure obtained from XRD for 18a that the pre-ligand undergoes substitution of the siloxy groups under the complexation conditions employed, resulting in a carbazole functionalised with two hexamethyldisilazane moieties.
The percent buried volume was measured for 5 and 6 and that showed %VBur, 62.2 and 68.2, respectively, indicating that 6 is bulkier.
Discussion on COVID-19 remains essential due to its lasting impact on global health, economy, and society. Despite widespread vaccination efforts, new variants and the threat of Long COVID continue to challenge public health systems. The docking studies of several carbazole derivatives with the active site of the main protease (Mpro) of SARS-CoV-2 may provide valuable insights into their potential as therapeutic agents during the COVID-19 pandemic. These studies not only emphasise the promising antiviral potential of carbazole derivatives but also allow for a comparative analysis with currently approved drugs, including Remdesivir, 2’-Deoxy-2’2’-fluorcytidine, and Favipiravir. The ranking of these carbazole derivatives based on their binding affinities and interactions with the active site is presented, highlighting their potential efficacy relative to the approved drugs. Additionally, the study provides an in-depth analysis of the conformational changes observed in the carbazole derivatives before and after docking, which could influence their binding and activity. These findings contribute to the ongoing search for effective antiviral agents and offer a potential pathway for the development of new therapeutics
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