MASSEY, RICHARD,STEPHEN (2013) Mechanistic studies of azolium ions and their role in organocatalysis. Doctoral thesis, Durham University.
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Azolium ion precursors to N-heterocyclic carbenes (NHCs) have risen to prominence as versatile organocatalysts for a broad range of synthetic transformations. In recent years, methodologies have been developed for the generation and exploitation of azolium homoenolates, azolium enolates, and acyl azolium intermediates, leading to a diverse range of asymmetric products. It is common in many synthetic procedures to generate the active NHC in situ by deprotonation of the parent azolium ion. Knowledge of the kinetic and thermodynamic acidities of these species is therefore an essential first step in understanding their catalytic behaviour.
We have used a kinetic method to determine kinetic acidities and aqueous pKa values for a set of triazolium, thiazolium and imidazolium ions at the C(3)-H or C(2)-H positions. Using 1H NMR spectroscopy to follow deuterium exchange, pseudo-first-order rate constants for exchange, kex (s-1), were determined at a range of pDs in D2O at 25 °C and I = 1.0 (KCl), from which second-order rate constants for deprotonation by deuteroxide ion, kDO (M-1 s-1) could be obtained. By application of a secondary solvent isotope effect (kDO/kHO = 2.4), corresponding values of kHO were calculated. General base catalysis experiments support the conclusion that the 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. These values of kHO and kHOH permitted the calculation of carbon acid pKa values for ionisation of the azolium ion in water. For a homologous series of catalytically-relevant triazolium salts, the effect of the N-aryl substituent on values of kDO and pKa was probed, and comparisons between azolium ion families will be made. The pD-rate profile of an N-C6F5 substituted triazolium ion indicates that in acidic media, protonation at the N(1) position may occur to give a dicationic triazolium ion.
Using this methodology, the kinetic acidities of the conjugate acids of ‘mesoionic’ or ‘abnormal’ carbenes were also investigated. For a series of 1,2,3-triazolium ions and C(2)-alkylated 1,3-imidazolium ions, rate constants for exchange at the C(4)-H and C(5)-H positions were determined. Our results suggest that these sites are 105-fold less acidic than the C(3)-H and C(2)-H positions of ‘classical’ triazolium and imidazolium ions. To explain the deviation from a first-order dependence on deuteroxide ion for the imidazolium ions in strong KOD solution, we have proposed a number of exchange pathways that proceed via a hydrate. The effects of N-aryl substituent and counterion on kDO and pKa are also discussed.
We have also conducted mechanistic studies of the triazol-3-ylidene-catalysed benzoin condensation. In situ 1H NMR spectroscopic studies of the reaction in triethylamine-buffered methanol-d4 at 25 °C show that the 3-(hydroxyaryl)triazolium adduct, generated from addition of the NHC to the aldehyde, is the only intermediate observed over the course of the reaction. Evidence is presented to show that the formation of these intermediates under these conditions is reversible, and reliable equilibrium and rate constants for the formation of these species have been determined using independent approaches. Our results suggest that N-mesityl substituents on the catalyst, and ortho-alkoxyl groups on the aromatic aldehyde result in significantly enhanced equilibrium concentrations of this intermediate. Slow deprotonation of these intermediates results in the benzoin product. Rate constants for the deprotonation step suggest that electron-deficient adducts result in the fastest rates of deprotonation.
Finally, an initial rates study of the benzoin condensation at catalytic concentrations of azolium ion precatalyst has also been undertaken. An HPLC analysis method was used to determine the concentrations of benzoin and benzaldehyde over the course of the reaction in triethylamine-buffered methanol at 50 °C. Our results suggest that the thiazolium-catalysed reaction is first-order with respect to aldehyde over the full range of benzaldehyde concentrations studied (0.32 – 1.60 M). In contrast, the triazolium-catalysed reaction displays a first-order dependence at low aldehyde concentrations, before changing to a zero-order dependence at higher benzaldehyde concentrations. From the maximum rate of catalysis in this zero-order region, the effect of N-aryl substituent on rate of turnover was investigated for a homologous series of triazolium precatalysts.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Keywords:||N-heterocyclic carbene NHC organocatalysis mechanistic benzoin condensation azolium triazolium pKa acidity|
|Faculty and Department:||Faculty of Science > Chemistry, Department of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||23 Jul 2013 10:53|