Development of Ion Pairing Strategies that Utilise Cations to Control Selectivity in Transition Metal-Catalysed Functionalisation of C–H Bonds

Inspired by enzymes, strategies incorporating attractive non-covalent interactions have emerged as a powerful tool to control selectivity in organic synthesis through small molecule catalysis. The ubiquity of charged intermediates across these transformations has recently highlighted ion pairing as a promising interaction to this end. The formidable challenge of selective C–H bond functionalisation through transition metal catalysis offers an ideal platform to investigate the potential of invoking control through ion pairing interactions. The ion pairing strategies explored in this thesis focus on how cations may be used to influence such reactivity at their closely associated anions. Chapter 2 focusses on the iridium-catalysed borylation of aromatic C(sp2)–H bonds. The lack of regiocontrol for 1,2-disubstituted arenes under standard conditions has previously been addressed by introducing an ion pairing interaction between a cationic substrate and an anionic ligand to favour meta-selective borylation. Building upon this work, Chapter 2.2 explores whether selective borylation may still be achieved when inverting the polarity of the substrate–ligand interaction. Disappointingly, the cationic ligands investigated were unable to promote meta-selective functionalisation of tetrabutylammonium salts of anionic aromatic sulfonates. Concurrent studies by Madalina Mihai revealed that borylation of the same substrates with neutral bipyridine ligands proceeded with an unexpected para-selectivity. Working closely with Madalina, Chapter 2.3 extends this methodology to the tetrabutylammonium salts of sulfonated phenols, benzyl alcohols, anilines, and benzylamines, as well as benzenesulfonates. Mechanistic studies suggest that the bulky tetrabutylammonium counterion sterically inhibits catalyst oxidative addition into the meta-C–H bond, thereby promoting para-selective borylation. Chapter 3 investigates the rhodium-catalysed intermolecular amination of benzylic C(sp3)–H bonds. Though amination at a methylene C–H bond typically introduces a new stereocentre in the product molecule, sparingly few enantioselective variants of this transformation are known. Taking inspiration from previously reported ion pairing strategies and building upon preliminary results obtained by Alex Fanourakis, Chapter 3.2 details how chiral cations may induce enantioselectivity in the intermolecular benzylic amination of phenyl alkyl alcohols and carboxylic acids through ion pairing to a negatively charged dirhodium complex. This thesis highlights the generality of ion pairing strategies towards addressing selectivity challenges in transition metal-catalysed functionalisations of C–H bonds. It is hoped that the results presented herein will stimulate novel ion pairing strategies to further realise their potential in organic synthesis.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• Williams, Benjamin

Advisor dc:contributor.advisor

• Phipps, Robert

• Organic chemistry
• Ion pairing
• Non-covalent interactions
• C-H functionalisation
• Transition metal catalysis
• Ir-catalysed C-H borylation
• Rh-catalysed C-H amination
• Regioselectivity
• Enantioselectivity

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/7f60b8ae-50cb-461f-bd58-9f277f506ff2/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.77981

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/330537