Novel concepts for the C-H functionalization of aromatic compounds

The functionalization of aromatic compounds is a key step in the production of many organic chemicals and pharmaceuticals. Currently, inert C-H bonds need to be pre-functionalized before they can be used in transition metal mediated coupling reactions. The associated cost of the pre-functionalization renders this procedure inaccessible for most bulk chemicals, while a direct route circumventing any pre-functionalization would be more superior in terms of atom and step economy. In this PhD dissertation, direct C-H functionalization pathways were developed and optimized. In the first part of this work, the oxidative dimerization of simple arenes (e.g. toluene, anisole, benzene) to biaryls was investigated. The reaction is thermodynamically driven by the use of an oxidant. The biaryl products are excellent precursors for alternative plasticizers and plastics which could replace the disputed endocrinic disruptors Bisphenol A and phthalates. The homogeneous reaction is in the most performant case catalyzed by ionic Pd(II), which requires the use of strongly acidic additives (e.g. p-toluenesulfonic acid). The multitude of C-H bonds present in organic reactants, and the poor differentiation between these bonds result in a poor regioselectivity. So far, a regioselective reaction has only been accomplished with electronically activated reactants and reactants with directing, coordinating groups. Here we have shown that confinement of cationic Pd in the pores of a zeolite allows for a shape-selective C-H activation. The hydrophobicity and isolation of ionic Pd(II) inside the framework of for example high silica zeolite Beta improves the catalytic performance with record TONs up to 450, and selectivity for the p,p'-dimer of ~80% in the case of toluene as reactant. In a second part, the technology of the first chapter was explored for the synthesis of 4,4'-biphenol. To that aim, methods to incorporate gold nanoparticles in zeolites were investigated as well. Different pathways starting from phenol, cumene and anisole were investigated, but the reaction was only successful starting from anisole. The dealkylation of the 4,4'-bianisyl was shown to proceed with HCl instead of the conventional HBr-mediated process. Finally, template-free zeolite Beta was shown to enable higher Pd TONs and selectivities compared to the more expensive, templated zeolite Beta. In the next part, the technology was expanded to the heterocoupling of heteroaromatic reactants with simple arenes. A high chemoselectivity and yield for the heterocoupled product could be obtained in the heterocoupling of toluene and benzofuran by tweaking the reaction parameters and using pivalic acid as carboxylic acid additive. A shape-selective para C-H activation of toluene was observed which could be easily transposed to anisole. In the last part, the C(sp3)-H arylation of amides (e.g. N‑methylpyrrole) with heteroaromatics was explored using a metal-free zeolite catalyst. The low bond dissociation energy of the C-H bond in the a-position of the amide [DDV1] allows for a facile radical H-abstraction mediated by oxidants (e.g. oxygen, peroxides). The obtained intermediate was used in a subsequent coupling reaction with heteroarenes (e.g. N-methylpyrrole) for which acidic zeolites were found to be excellent promotors. Higher yields were observed with TBEC as oxidant (up to 84%), while a solvent screening showed the possibility to work with propylene carbonate as a solvent if desired. The technology exhibited a broad substrate scope and could be applied to free, non-substituted amides (e.g. acetamide) or carbamates in order to obtain C-N coupled products.

Jaar van publicatie:2021

Toegankelijkheid:Closed