Abstract
Chiral alcohols have broad applications in the pharmaceutical industry as they are used as starting materials or intermediates in the synthesis of optically active drug molecules. This study seeks to provide insight into the use of chiral-at-ruthenium complexes derived from coordinating structurally simple and cost effective bipyridine system with Ru as opposed to sterically hindered catalysts for asymmetric transfer hydrogenation of aromatic ketones. These types of complexes derive their chirality from the induction of helical arrangement of achiral ligand coordinated with metal especially transition metal. This contrasts with conventional chiral metal complexes in which the overall chirality resides exclusively within the ligand coordination sphere. Hence, the entire chirality of the former is restricted to the metal center. The choice of ruthenium metal in this study relies on its configurational stability and high catalytic potential in hydrogenation reaction. The background of the research is laid out in the introductory chapter one and review chapter two.
In chapter three we present the designed and synthesized chiral-at-ruthenium complexes of bipyridine (Λ/Δ-1'), 4,4’-dimethylbipyridine (Λ/Δ-2'), 5,5’-dimethylbipyridine (Λ/Δ-3'), 4,4’-ditert-butylbipyridine (Λ/Δ-4'), 4,7-diphenyl-1,10-phenanthroline (Λ/Δ-5'), phenanthroline (Λ/Δ-6') and 5,5’-bistrifluoromethylnipyridine (Λ/Δ-7') with characterization by nuclear magnetic resonance (NMR), ultraviolet-visible (UV-Vis), Fourier transform infra-red (FTIR), circular dichroism (CD) spectroscopy, CHN elemental analysis, high resolution mass spectrometry and single-crystal X-ray diffraction (SC-XRD) techniques. The intermediate diastereomeric complexes were synthesized through a chiral auxiliary-mediated method to enable their separation on column chromatography before the irreversible replacement of the chiral ligand with acetonitrile ligand in a stereospecific fashion to form the corresponding enantiomeric complexes. These complexes were thoroughly elucidated by NMR spectroscopy while the CD spectroscopy was used to differentiate and confirm the optical activity of the enantiomers with further validation by SC-XRD through the Flack parameters of the crystalline complexes. These results are described in chapter four.
The UV-Vis displays absorptions around 300, 370 and 535 nm which are attributed to π → π*, metal-to-ligand charge transfer and d → d transitions, respectively, for the diastereomers, while the absorptions observed in the enantiomeric complexes are transitions due to π → π* at 300 nm and the d → d at 425 nm. This hypsochromic shift in the d → d transition may be attributed to the replacement of the chiral bidentate auxiliary ligand with the monodentate acetonitrile ligand. All
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the complexes exhibit vibrational frequencies around 1600 and 3060 cm-1 due to the stretching vibrations of aromatic C=C and sp2 hybridized C-H stretching modes. The enantiomers exhibit a diagnostic frequency associated with the -C≡N stretching vibrations of the acetonitrile monodentate ligand around 2350 cm-1. The complexes exhibit mirror-image Cotton effects at wavelengths of approximately 270, 290, 320, 390 and 460 nm. Complexes, Λ-1', and Δ-1' crystallized in chiral space groups of P32 and P31 of trigonal crystal system, respectively, and Δ-5' in P121 of triclinic crystal system. This further confirms the chirality being located at the ruthenium center since the coordinating ligands are achiral. Having established the formation of the complexes, further investigation was made to prove the stability of the complexes by subjecting Δ-1' to variable temperature NMR and CD spectroscopy to check any form of isomerization and racemization, over a range of temperature from 20 to 80 °C at 10 °C intervals. It was discovered that the complex, Δ-1', was stable over the temperature range.
Chapter five explains how Δ-1' was applied to catalyze the transfer hydrogenation of some aromatic ketones in isopropanol and sodium hydroxide at 60 – 70 °C with the aim of achieving stereoselectivity. Moderate to high and excellent enantioselectivities were observed for some ketones, except for acetophenone and 2-naphthyl methyl ketone where no appreciable enantioselectivities were observed. Excellent enantioselectivities of 100% ee were observed for 1-phenylbutanol, 2g, (with a retention time of 5.99 min) under the catalytic asymmetric hydrogenation with Δ-1' at 2% catalyst loading. The opposite congener, Ʌ-1', also afforded an excellent 100% ee for the optical antipode of 1-phenylbutanol which has a retention time of 3.24 min. 4,4’-dimethyl (Δ-2'), 5,5’-dimethyl (Δ-3'), 4,4’-ditertbutyl (Δ-4'), 5,5’-difluoromethyl (Δ-7') substituted derivatives of Δ-1', including 4,7-diphenyl-1,10-phenanthroline (Δ-5') and 1,10-phenanthroline (Δ-6') were subjected to the same reaction conditions to catalyze butyrophenone, 1g, to 2g to evaluate the impact of varying steric and electronic effects. The catalysts Δ-2' – Δ-5' and Δ-7' also yielded excellent enantioselectivity (of 100% ee) while Δ-6' afforded 70% ee. This was attributed to the rigidity of Δ-6' compared to the other catalysts which possess some degree of flexibility. In terms of the substrate scope, steric influence in proximity of the reactive carbonyl functional group has profound effect on the enantioselectivity as observed for 1-(o-tolyl)ethan-1-ol, 2b, as against 1-(p-tolyl)ethan-1-ol (2d) and 1-(m-tolyl)ethan-1-ol (2c) with 100%, 47% and 42% ee, respectively. Therefore, the catalysts have to be proved highly enantioselective towards asymmetric transfer hydrogenation of aromatic ketones.