Masters Degrees (Chemistry)
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Browsing Masters Degrees (Chemistry) by Subject "Ab-unsaturated ketone"
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Item Open Access Studies directed at the stereoselective synthesis of flavonoids through the hydrogenation of prochiral precursors(University of the Free State, 2008-11) Van Tonder, Johannes Henning; Bezuidenhoudt, B. C. B.; Steenkamp, J. A.English: The in vitro studies of biologically active flavonoids are hampered by the inaccessibility of all monomeric units in enantiomerically pure form. Although a number of these scalemic flavonoids can be obtained synthetically, current methodologies are tedious and often result it low yields and e.e.s being obtained. Stereoselective conjugated hydrogenation of the more readily available prochiral a,b-unsaturated carbonyl flavonoid motifs, i.e. flavones, isoflavones and flavonols, provide a plausible solution to this problem and was therefore investigated during the first part of this dissertation. Since the stereoselective 1,4-reduction of an a,b-unsaturated system also contains an element of regioselectivity, a regioselective hydrogenation study was conducted first before the reaction would be extended to include stereoselective aspects. Because Wilkinson’s catalyst is commercially available, has the potential to be modified with chiral ligands and is a well known hydrogenation catalyst, it was chosen as catalyst for the initial evaluation of the idea. While Wilkinson’s catalyst is well known for hydrogenation of ordinary alkenes, no literature on it being used for the reduction of a,b-unsaturated carbonyl compounds could be found, so the effectiveness of this catalyst in the hydrogenation of differently substituted nonflavonoid substrates were first investigated. In this regard a solvent study on chromone, evaluating acetone, tetrahydrofurane and dichloromethane (DCM), showed DCM to be the solvent of choice for this reaction and led to the formation of 4-chromanone in 7.8 %, 14.3 % and 46.2 % respectively. By using 2-cyclohexenone as substrate, optimum hydrogenation conditions were determined to be ca. 30 bar and 100 oC, because reactions at higher temperatures (110 oC) and pressures (40 bar) were inhibited by rhodium fall-out. In order to evaluate the effect of different levels of substitution around the olefinic double bond on the reaction rate for cyclic- as well as acyclic olefins, 2-cyclohexenone, 3-methyl-2- cyclohexenone, 3-buten-2-one, 3-penten-2-one, 4-methyl-3-penten-2-one, 3-methyl-3-penten- 2-one, crotonaldehyde, and chalcone were subjected to the hydrogenation reaction. While no hydrogenation could be achieved for the trisubstituted acyclic ketones, i.e. 4- methyl-3-penten-2-one and 3-methyl-3-penten-2-one, as well as crotonaldehyde, the trisubstituted cyclic equivalent, 3-methyl-2-cyclohexenone, indeed gave the saturated ketone albeit with a very low reaction rate [kobs = 0.000174644 s-1 (80 oC and 20 bar)]. The hydrogenation rates of the remaining acyclic substrates, 3-buten-2-one and 3-penten-2-one (kobs = 0.0245703 and 0.000226852 s-1 respectively at 80 oC and 10 bar), followed the expected order of monosubstituted > disubstituted, while the effect of a cyclic structure proved to be rather insignificant (kobs = 0.000254025 s-1 for 2-cyclohexenone). Aromatic disubstitution, however, reduced the reaction rate by ca. 50 % (kobs = 0.000143572 s-1 for chalcone). While the reaction rate (kobs) for the volatile substrates could easily be determined by GC and GC/MS analysis, the reactor set-up and analytical methodology were changed for the flavonoid like solid substrates. For these solids, reactions were followed by NMR and t½ (time to achieve 50 % conversion) used as indication of the reaction rate. In order to be able to compare t½ with the previously measured reaction rate, the hydrogenation of chalcone was repeated and it was found that the concentration of the reactant has a major influence on the rate of the reaction. In a study where the concentration of chalcone was varied between 0.083 M and 0.50 M the optimum concentration was determined as 0.166 M (t½ = 27 min.) for reactions at 80 oC, 20 bar hydrogen pressure and a catalyst concentration of 0.72 mM. Extension of the reaction to chromone indicated the heterocyclic ring to have a profound influence on the reaction rate (t½ = 72 h vs. 27 min. for chalcone), while the flavonoid substrates, flavone and 4',7-dimethoxyisoflavone, having trisubstituted double bonds could not be hydrogenated at all using Wilkinson’s catalyst. In a completely different approach, the introduction of chirality into a planar flavonoid molecule (flavone or isoflavone type compound) by means of an arene metal complex was investigated. If a bulky tricarbonylmetal centre could be directed to one face of the A-ring of a flavonoid unit, that face of the adjacent unsaturated heterocyclic C-ring would become inaccessible to a hydrogenating reagent. In order to investigate the feasibility of such an approach, the tricarbonylchromium(0) complexes of several mononuclear and flavonoid type substrates were to be synthesised. Compounds like benzene, toluene, anisole, chlorobenzene, acetophenone, and chromanone were therefore subjected to thermolysis (72 h) with hexacarbonylchromium(0) in refluxing dibutyl ether-THF and it was found that while the activated substrates showed excellent reactions (85 - 98 % conversion), conversions for the compounds containing deactivating substituents [acetophenone (40 %) and chromanone (28 %)] were rather low. With the knowledge of the mononuclear substrates in hand, the study was extended to the flavonoids where selectivity between the two aromatic rings would be a major issue in the success of the envisaged methodology. Although successful from a reaction point of view (products obtained in 33 and 43 % yield respectively), reaction of the carbonyl containing substrates 4',7-dimethoxyisoflavone and flavone, with hexacarbonylchromium(0), however, yielded only the ‘unwanted products’, tricarbonyl(B-h6-4',7-dimethoxyisoflavone)- chromium(0) and tricarbonyl(B-h6-flavone)chromium(0). In an effort to move complex formation to the A-ring of the flavonoid moiety, substrates with increasing levels of reduced heterocyclic rings like chroman-4-ol, flavan-4-ol, flavan, and 7-methoxyflavan, were subjected to the reaction with hexacarbonylchromium(0). Although the first two compounds still contained a 4-subsitutent with a negative inductive effect, it is known that a benzylic OH group is capable of directing complexation towards the adjacent aromatic ring and it was hoped that this influence would facilitate reaction onto the A-ring. Formation of cis- and trans-tricarbonyl(h6-chroman-4-ol)chromium(0) in an ca. 3:1 ratio (14 % yield) from the reaction of chroman-4-ol with the chromium reagent, confirmed the benzylic–OH to be capable of directing the attacking chromium moiety to the anticipated face of the adjacent aromatic ring. Reaction of the flavan-4-ol substrate, however, indicated the A-ring still not to be the preferred binding site, since tricarbonyl(B-h6-flavan-4-ol)chromium(0) and tricarbonyl(A-h6-flavan-4-ol)chromium(0) were formed in 2.8 and 1.7 % yields, respectively. Finally, reaction of both flavan and 7-methoxyflavan, the latter with an activated dihydroxylated A-ring, yielded products originating from complexation onto both the A- and B-rings, i.e. tricarbonyl(A-h6-flavan)chromium(0), tricarbonyl(B-h6-flavan)chromium(0), tricarbonyl(A-h6-7-methoxyflavan)chromium(0), and tricarbonyl(B-h6-7-methoxyflavan)- chromium(0) as well as the bimetallic complex from the 7-methoxyflavan.