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dc.contributor.advisorLloyd-Jones, Guy
dc.contributor.advisorLawrence, Andrew
dc.contributor.authorDale, Harvey J. A.
dc.date.accessioned2022-08-09T15:54:24Z
dc.date.available2022-08-09T15:54:24Z
dc.date.issued2022-08-09
dc.identifier.urihttps://hdl.handle.net/1842/39304
dc.identifier.urihttp://dx.doi.org/10.7488/era/2555
dc.description.abstractControlling the regioselectivity of ambident nucleophiles towards electrophilic functionalisation is a perennial problem in heterocyclic chemistry. The N-alkylation of triazoles poses a particular challenge in this regard: complex mixtures of regioisomers often arise under typical conditions, and the intrinsic regioselectivity is unswayed by solvent effects, by temperature, and even by the structure of alkylating agent itself. To address this challenge, a new organocatalytic strategy for the regioselective N-alkylation of triazole anions – protective phase-transfer catalysis – has been developed following mechanistically guided discovery and optimisation, informed by in situ 1H NMR reaction monitoring, X-ray crystallographic analysis, 1H DOSY NMR, and electronic structure calculations. Central to this new strategy is an amidinium or guanidinium receptor, which serves both as a strongly coordinating phase-transfer catalyst and a non-covalent protecting group. Intimate ion pairs formed in solution between triazole anions and the catalytic receptor retain the overall reactivity of liberated triazole anions but, by virtue of regioselective hydrogen bonding, exhibit N-alkylation selectivities that are completely inverted (1,2,4-triazole) or substantially enhanced (1,2,3-triazole) compared to the parent anions (rr up to 99:1). Whilst the alkylation of azoles typically proceeds irreversibly, acylation is often reversible. Such behaviour lends azole anions naturally to acyl transfer catalysis, especially in the electrophilic activation of weak acyl donors that are inert towards prevailing aprotic Lewis bases. Despite initial reports of remarkable catalytic aptitude, the mechanistic basis of azole-catalysed acyl transfer has nevertheless been almost completely neglected. Azole anions have been presumed to operate much like privileged aprotic Lewis bases – epitomised by DMAP and other N’,N’-dialkylaminopyridines – yet the two regimes differ in fundamental respects, mechanistic nuances abound, and detailed studies are virtually non-existent in the literature. Using extensive reaction monitoring by in situ and stopped-flow 1H and 19F NMR spectroscopy, steady-state kinetic analysis and numerical kinetic simulations, variable-temperature NMR, isotopic labelling, 1H DOSY NMR and electronic structure calculations, a holistic mechanism for acyl transfer catalysis with azole anions has been assembled using the catalytic aminolysis of p-fluorophenyl acetate as a prototypical system. The global kinetics of aminolysis have been elucidated under four distinct sets of conditions, and the key elementary steps underpinning catalysis deconvoluted by a full gamut of intermediate studies, transition state probes (LFERs, 12C/13C and 14N/15N KIEs, Eyring analyses), and free energy calculations. All evidence points to a single overarching mechanism based on Lewis base n-π* catalysis, yet even within this common mechanistic framework a diverse array of kinetic regimes can emerge. Seemingly trivial changes to the solvent, auxiliary base, and azole can elicit profound changes in the temporal evolution, thermal sensitivity, and inhibition of catalytic acyl transfer – mechanistic insights that are likely to have broad ramifications for acylative kinetic resolutions, and for azole-mediated organocatalysis at large.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionH. J. A. Dale, G. R. Hodges and G. C. Lloyd-Jones, J. Am. Chem. Soc., 2019, 141, 7181.en
dc.subjectn/aen
dc.titleAzole anions: catalysed and catalystsen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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