(Transition) metal-catalysed electrophilic amination of simple arenes

Promovendus/a: Lisa Van Emelen

Promotor(en): Prof. dr. ir. Dirk De Vos, Prof. dr. Dimitrios Sakellariou

Arylamines are important intermediates in the production of diverse valuable chemicals, ranging from dyes to pharmaceuticals. Ideally, simple arenes and amines could be directly coupled to yield the corresponding arylamine, but this reaction is energetically unfavourable. The synthesis of arylamines is therefore typically a multi-step process, starting from pre-functionalized molecules, which results in significant amounts of (salt) waste. However, recently, (transition metal-catalysed) direct arene C-H amination, has emerged as a fundamentally greener method to construct aromatic C-N bonds. Chapter 1 discusses the state-of-the-art methods in arene C-H amination in the context of the principles of green chemistry. This dissertation focuses on electrophilic amination (EA), in which a leaving group (LG) is installed on the amine (or other nitrogen coupling partner) to enable the coupling reaction. Thus far, most EAs were limited to inherently more reactive arenes and/or nitrogen coupling partners with large LGs, which lowers the applicability and sustainability. Moreover, the often precious metals employed as catalysts are usually dissolved in the reaction mixture (homogeneous catalyst), complicating their recovery and purification of the reaction product. Thus, EAs of simple arenes, using atom-efficient nitrogen coupling partners are highly desirable. Furthermore, immobilization of the metal catalyst on a support and limited use of additives are coveted. In this dissertation, three catalytic systems are presented that cover these aspects.

Catalyst immobilization is not straightforward in EA, since often the active metal detaches from the support or the latter is not stable enough under the reaction conditions. In Chapter 2, a copper complex (CuII(2,2’-bipyridine)), which had been previously employed in the amination of simple arenes with hydroxylamine-O-sulfonic acid, was entrapped in the pores of zeolite Beta using a so-called ship-in-a-bottle approach. The complex was assembled within the narrow pores of the zeolite, after which it couldn’t escape. This catalyst proved more active and stable than other evaluated materials, yielding up to 59 % arylamines. Moreover, the catalyst could be easily recycled and outperformed similar, earlier reported homogeneously catalysed systems in terms of turnover number.

Many arenes contain multiple C-H bonds of similar reactivity. Especially when meta-C-H bond amination is targeted, a specific directing group (DG) on the arene and tailored catalysts are often needed. In Chapter 3, a ligand-free, palladium/silver-catalysed meta-selective amidation of arenes without DG using O-acetylated acetohydroxamic acid (AcNHOAc) as the nitrogen coupling partner is discussed. Up to 50 % yield was achieved, with up to 76 % selectivity for the meta-C-H bonds. Based on a combination of kinetic and spectroscopic experiments, the interaction between the palladium catalyst and coupling partner was studied, as well as the role of silver; and a mechanism was proposed.

Many EA reactions rely on precious metal catalysts, such as rhodium, iridium or palladium. It would be attractive from both an ecological and economical viewpoint to use cheaper and more abundant metals, such as iron. Nevertheless, only few examples were reported and most of them use (very) high amounts of catalyst. As discussed in Chapter 4, the amount of iron catalyst needed in a previously reported EA with AcNHOAc could be reduced from 200 to 5 mol%, by moving to a greener solvent (acetic acid) and increasing the temperature. Furthermore, a broad catalyst screening revealed that besides iron(III) citrate monohydrate, also other compounds, in particular bismuth chloride, were competent. Nevertheless, due to the instability of AcNHOAc and product inhibition, yields remained rather low (≤ 31 %). Kinetic and spectroscopic data hinted at an electrophilic aromatic substitution mechanism, but the exact nature of the reactive intermediate remains unclear.

In summary, three catalytic systems that employ atom-efficient nitrogen coupling partners have been developed for the electrophilic amination of simple arenes. Moreover, valuable mechanistic information and catalyst characterization data were obtained.