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Theoretical Mechanistic Investigation of a Decarboxylative Heck Reaction with an Electron-Rich Olefin and Possible Catalyst Entrapment by the Heck Product
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
(English)Manuscript (preprint) (Other academic)
Keyword [en]
palladium(II), dft, reaction mechanisms, heck, decarboxylation
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-242258OAI: oai:DiVA.org:uu-242258DiVA: diva2:782900
Available from: 2015-01-22 Created: 2015-01-22 Last updated: 2015-03-11
In thesis
1. Palladium(II)-Catalyzed Heck Reactions: Domino Reactions, Decarboxylations, Mechanistic Studies & Continuous Flow Applications
Open this publication in new window or tab >>Palladium(II)-Catalyzed Heck Reactions: Domino Reactions, Decarboxylations, Mechanistic Studies & Continuous Flow Applications
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes research efforts dedicated to the development of palladium(II)-catalyzed oxidative Heck and Heck/Suzuki domino reactions, and the applications of a new microwave heating technology, purpose-built for continuous flow in organic synthesis.

Paper I describes the development of a ligand-modulated approach for attaching aryl groups to a chelating vinyl ether. By switching the ligand being used, selectivity for the arylation could be shifted to obtain three different outcomes: internal α- or terminal β-arylation, as well as a serendipitously discovered domino α,β-diarylation process. The latter was proposed to be an effect of para-benzoquinone, effectively acting as a stabilizing π-acidic ligand with the ability to suppress β-hydride elimination.

Paper II explores the performance of a new microwave heating technology in combination with continuous flow. The novel nonresonant microwave applicator allowed rapid heating of common laboratory solvents and reaction mixtures above their boiling points with stable and reproducible temperature profiles. The technology was successfully applied to small-scale method development and subsequent scale-out of palladium-catalyzed reactions, heterocycle synthesis and classical organic transformations such as the Fischer indole synthesis.

Paper III focuses on developing regioselective oxidative decarboxylative Heck reactions with electron-rich olefins. Successful internal α-arylations were achieved using various olefins and ortho-substituted aromatic acids. The mechanism was also studied by ESI-MS analysis. Key cationic organopalladium intermediates were identified, as well as an unexpected palladium(II)-complex which was isolated and characterized. Its experimentally deduced structure was in accordance with the lowest energy minimum found by DFT calculations. Preliminary findings suggested that the complex acts as a catalyst trap.

Paper IV studies the mechanism of the reaction in Paper III by means of DFT calculations. Reductive elimination was identified as the rate-determining step when using a linear enamide as the olefin, due to its propensity to form low energy chelates. Its chelating properties also played a key role in the stability of the isolated palladium(II)-complex. The complex, which can act as a catalyst trap, was characterized by X-ray crystallography.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 194
Keyword
palladium(II), dft, reaction mechanisms, esi-ms, heck, decarboxylation, microwave, continuous flow
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-242259 (URN)978-91-554-9149-9 (ISBN)
Public defence
2015-03-13, B41, Uppsala Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-02-19 Created: 2015-01-22 Last updated: 2015-03-11

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Larhed, Mats

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