Controlling Site-Selectivity in Palladium-Catalysed Cross-Coupling Reactions using Non-Covalent Interactions Between Ligand and Substrate

Controlling selectivity in chemical reactions is a fundamental challenge in organic synthesis. This thesis explores controlling the site-selectivity of palladium-catalysed cross-coupling reactions by using a non-covalent interaction between a ligand and substrate. A library of phosphine ligands were synthesised that incorporate an anionic or hydrogen bond acceptor group. They were first evaluated in the Mizoroki-Heck reaction with alkenes that bear a complementary hydrogen bond donor group with the intention of engineering a favourable non-covalent substrate-ligand interaction to achieve two goals. Firstly, to overcome the innate challenge of using trisubstituted alkenes as substrates and secondly, to control the regioselectivity of the migratory insertion step. However, this was met with limited success. The ligand library was then evaluated in the Suzuki-Miyaura reaction of dihaloarenes that bear a hydrogen bond donor group. Employing a sulfonated dialkylbiaryl phosphine ligand (sSPhos) in the Suzuki coupling of 3,4-dichloroarenes bearing a benzyl N-triflyl amide resulted in highly site-selective oxidative addition to occur in the meta position. Mechanistic studies suggest that rather than a hydrogen bonding interaction that was initially sought, the amide is deprotonated, and the associated cation engages in an attractive electrostatic interaction with the sulfonate group which guides cross-coupling to the meta position. This counterintuitive combination of anionic ligand and anionic substrate demonstrates an alternative design principle when considering the application of non-covalent interactions to direct catalysis. Other Brønsted acidic groups on the 3,4-dichlorobenzene motif were also shown to participate in the electrostatic interaction including carboxylic acids, phosphoric acids, sulfonic acids, and sulfamic acids. Following oxidative addition alkynes (Sonogashira coupling), anilines (Buchwald-Hartwig coupling) and electron-deficient arenes (Fagnou coupling) were all shown to be viable coupling partners, the latter representing a rare example of non-covalent interactions being used in conjunction with palladium-catalysed C-H functionalisation. Finally, by systematically changing the size of the cation and the position of the sulfonate group on the ligand scaffold, it was possible to achieve site-selective Suzuki coupling of isomeric di-, tri- and tetra-chlorinated arenes.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Golding, William

Advisor dc:contributor.advisor

• Phipps, Robert

• Suzuki
• Cross-Coupling
• Non-covalent
• Site-selective

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a1372e47-9154-4443-ab0e-9b530ff3a14e/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0001-6956-4961

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/317446