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Title: Mechanistic insights into organocatalysis
Author: Dingwall, Paul
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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With a resurgence of interest at the turn of the millennium, organocatalysis has become an established field in chemical research. Proline, in particular, has played a central role in the profusion of research. As the archetypal organocatalyst, proline mediated transformations have acted as a point of reference against which the performance of new developments in the field are benchmarked and compared. The field as a whole has benefited from a timely merging of complementary experimental, kinetic, and computational studies, through which a comprehensive picture of reaction mechanisms has been drawn. The research documented in this thesis attempts to build on this successful multi-faceted approach to elucidate further mechanistic insights into organocatalysis. The proline mediated conjugate addition of aldehydes to nitroalkenes has been investigated via a 'kinetics first' approach, through the use of Reaction Progress Kinetic Analysis (RPKA) methodology. It was discovered that proline is irreversibly removed from the catalytic cycle via initiation of a polymerisation reaction of the nitrostyrene substrate. Additionally, it was found that this off-cycle pathway was not limited to proline alone, but also occurs with a number of secondary amine compounds, including other organocatalysts. The synthesis of two constrained bicyclic proline analogues was carried out in order to experimentally verify their computationally predicted behaviour in a benchmark aldol reaction. Excellent agreement between the experimentally determined and computationally predicted product enantioselectivity was found. Kinetic investigation of these bicyclic proline analogues revealed deactivation of the catalyst to be interfering with the catalytic cycle and so critically impairing their activity as compared to proline. The catalytic capability of these catalysts was explored, revealing universally poor behaviour in all but the reaction for which they were designed. An intriguing case of a lack of selectivity in the HPESW reaction was explored computationally and the decrease in stability of the anti transition state relative to the syn was determined as the cause. A brief exploration of the application of modern DFT functionals, M062X and ωB97XD, in a synthetically relevant setting was conducted and their extremely poor performance noted, compared to the excellent and highly accurate performance of the B3LYP functional. With the recent description of a new stereochemical and mechanistic regime for organocatalysts lacking a directing group, termed Curtin-Hammett kinetics, a kinetic investigation of the diphenylprolinol silyl ether mediated α-selenation reaction was undertaken to generalise this regime across a further carbonyl α-functionalisation reaction. A kinetic profile for the reaction was observed through the use of the RPKA methodology. The shape, an initial spike followed by zero order kinetics, closely resembles that of the conjugate addition and α-chlorination reactions. Further exploration revealed product selectivity to be a function of both the reaction solvent, correlated to dielectric constants, and the electronic properties of the aryl rings of the catalyst. An in-depth computational investigation of the conformational preferences of two important species on the catalytic cycle, the starting material and product selenoenamines, was undertaken in order to probe the underlying cause of the solvent-dependent reversal on selectivity. In agreement with experimental findings in the literature, the starting material enamine was found to have a high energetic preference for the anti E enamine in a number of solvents, dependent on the both the conformation of the pyrrolidine ring and the exocyclic CPH2OTMS group for each enamine C-N rotamer. This implies a solvent-dependent change in starting material enamine conformational preference is unlikely to explain the effect of solvent on product selectivity. Study of the product selenoenamine in various solvents found the relative thermodynamic stabilities of the E and Z enamines to change with solvent, with the Z enamine more stable in the gas-phase and non-polar solvents but little-to-no difference in stability between the E and Z enamines in polar solvents. This suggests that the experimental observation of the E enamine only in toluene is not thermodynamically preferred but is rather the result of an inherent kinetic preference. The above evidence supports the proposed hypothesis that solvent dependent product selectivity is the result of the erosion of kinetic preferences due to equilibration of relative intermediates in the catalytic cycle, as opposed to a change of enamine conformation in the stereogenic carbon-carbon bond forming step.
Supervisor: Armstrong, Alan Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available