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Durham e-Theses
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Mechanism-Guided Studies of Brønsted Acid and Base Organocatalysis

LINDSAY, ANITA,GERALDINE (2010) Mechanism-Guided Studies of Brønsted Acid and Base Organocatalysis. Doctoral thesis, Durham University.



We have studied the mechanism of the reaction of N-Boc imines and acetylacetone in the presence and absence of chiral phosphoric acid catalysts. In order to gain mechanistic insight into the asymmetric Mannich reaction, a structurally homologous series of N-Boc imines and BINOL-derived phosphoric acid and thiophosphoric acid catalysts were synthesised. The degree of asymmetric catalysis was evaluated by chiral HPLC analysis of the products of catalysed Mannich reactions.

Knowledge of the acidity difference between the phosphoric acid catalysts and the iminium ions is essential in order to determine the likely extent of proton transfer, full or partial, between these two species in the course of the Mannich reaction. The determination of aqueous pKa values of iminium ions was attempted by construction of pH-rate profiles for hydrolysis using UV-Vis spectrophotometry. Estimates of the second-order rate constant for acid-catalysed hydrolysis (kH, M-1s-1) and the first-order rate constant for the solvent reaction (k0, s-1) for each imine were extracted from the rate-profiles, however, pKa values could not be obtained for reasons that will be discussed. Iminium ion pKa values were determined in dimethyl sulfoxide by adopting a bracketing indicator method with use of UV-Vis spectrophotometry and pKa values in the range 0.65-1.61 were observed for the series of N-Boc aryl iminium ions. The pKa values of (thio)phosphoric acid catalysts were also estimated in dimethyl sulfoxide using this approach and values in the range 2.21-3.86 were obtained. The determination of pKa values of phosphoric acids in water and acetonitrile was unsuccessful due to the poor solubility of the catalyst in these media.

Rate constants for the uncatalysed Mannich reaction of each imine with acetylacetone have been quantified using 1H NMR spectroscopy in CD2Cl2, CDCl3 and CD3CN. It was found that the solvent effect on the rate of the Mannich reaction was small, with the fastest reaction occurring in CD3CN. Altering the imine substituent was found to have a larger effect on the rate. We also aimed to determine rate constants for the catalysed Mannich reaction using 1H NMR spectroscopy. However, in all cases complete hydrolysis of the imine substrate occurred before the first time-point could be obtained. All efforts to suppress hydrolysis proved unsuccessful.

Azolium ion organocatalysts were also investigated. These are the conjugate acids of N-heterocyclic carbenes, a class of highly successful nucleophilic/Brønsted base organocatalysts. As these carbenes are generated in situ from azolium ions during organocatalytic reactions, knowledge of the acidity of the parent ion is much sought after. This thesis describes the determination of aqueous pKa values of imidazolium and triazolium ions using a kinetic approach. Second-order rate constants for the deprotonation of these azolium ions by deuterioxide ion (kDO, M-1s-1) in D2O at 25 C were determined by 1H NMR spectroscopy. These kDO values could be used to calculate values for kHO (M-1s-1), the second-order rate constant for deprotonation of the azolium ion by hydroxide ion to give the carbene/ylide in water. Evidence is presented that the reverse rate constant for carbene protonation by solvent water is limited by solvent reorganisation and occurs with a rate constant of kHOH = kreorg = 1011 s-1. Values for kHO and kHOH permitted the calculation of reliable carbon acid pKa values for ionisation of the azolium ions in water. The effects of the N-substituents and counter ion on kHO and pKa values are discussed. Of the triazolium ions studied, kDO values of 3.66 × 107- 6.47 × 108 M-1s-1 were observed with corresponding pKa values of 16.6-17.8. For N,N-dialkylated imidazolium ions, kDO values of 1.03 × 102 - 1.07 × 102 M-1s-1 were obtained which yielded pKa values of 23.3-23.4.

Item Type:Thesis (Doctoral)
Award:Doctor of Philosophy
Keywords:organocatalysis, mechanism, Mannich reaction, N-heterocyclic carbenes, N-Boc imines, phosphoric acids.
Faculty and Department:Faculty of Science > Chemistry, Department of
Thesis Date:2010
Copyright:Copyright of this thesis is held by the author
Deposited On:04 Jun 2010 11:53

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