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Solid Catalysts for activation of aromatic C-H bonds

Periodic Reporting for period 3 - H-CCAT (Solid Catalysts for activation of aromatic C-H bonds)

Reporting period: 2020-01-01 to 2021-06-30

• The H-CCAT project devises solid hybrid materials that are superior catalysts for
C-H activation on aromatic compounds, and develops innovative procedures to produce and shape these catalytic materials in an economically and environmentally beneficial way. The catalysts will allow sustainable production of pharmaceutically relevant compounds or other specialty chemicals. The targeted reactions comprise:
• (i) Oxidative C-H/C-H couplings, in which an organic molecule is linked via its C-H bond to an aromatic reactant with another C-H bond, and
• (ii) Non-oxidative C-H/C-X couplings, in which an organic molecule with a hetero-atom (X) is coupled to the C-H bond of the aromatic reactant.
• Depending on the reaction, catalysts are selected and developed starting from two material classes:
• (i) Metal-Organic Framework (MOF) materials: these are porous, crystalline and sometimes flexible hybrid materials, made from an inorganic metal-(oxo) cluster (e.g. Zr, Al, Fe,...) and organic linkers. These MOFs will be used for C-H/C-H coupling and for C-H/C-X coupling;
• (ii) Porous hybrid silicas, which are hybrid materials made from a silicate scaffold with organic surface groups, and which acquire porosity by templating with organic surfactant micelles. These will be used for C-H/C-X coupling.
• The active catalytic sites will be designed in these porous hybrid host materials using combinations of active metals and organic ligands, all linked with robust bonds to the host matrix with engineered porosity. Shaping processes will be developed in function of catalytic demonstration at pilot scale. Shaping will be up-scaled to pilot capacities to demonstrate the relevance and performance of the obtained materials in terms of properties (activity, absence of metal leaching, selectivity), reproducibility, quality control and costs and benefits for industrial applications in pharmaceutical production. Greening of the reactants, solvents and processes will be studied, strictly avoiding toxic compounds, and LCA will be performed to demonstrate the environmental benefits both in materials preparation and in pharmaceuticals production.
The H-CCAT project is currently advancing well within the estimated timeline. More specifically, the steps prior to scale-up were developed to a large extent, while first steps for the scale-up and final utilization of the method were already undertaken. Custom building blocks that include anchoring sites for the active Pd-catalysts were synthesized and employed for the preparation of novel MOF and hybrid silica materials. A systematic library of these and already known MOF and hybrid silica materials were tested in the oxidative and non-oxidative arene-arene coupling and in the alkenylation of aromatics. For each reaction, the best first-generation catalytic system was already identified and further characterized before and after the reaction to further understand the most important characteristics of the materials that are responsible for the success of the material. These insights can further be utilized to develop improved ligands for second-generation catalysts. The currently most performant materials can all be scaled up and larger quantities of the corresponding MOF material as well as related hybrid silica materials were prepared for further testing. One crucial step for the implementation of the materials is shaping, which was performed for reference materials, which possess similar mechanical behaviour as the final catalyst for the process. Suitable binders that do not interfere with the reaction were identified and shaped bodies were prepared from them. These were mechanically tested and promising methods for the shaping of the final catalysts were identified. Currently, the planning for the final testing of the catalyst for the upscaled C-H functionalization is fully underway and first steps towards a final design of the reactor are taken.
Leaching resistance and robustness of the active sites. H-CCAT targets less than 20 ppm metal traces under both batch and continuous flow catalytic conditions, which is in the range of the admissible noble metal contamination in API synthesis. This ambitious target will be reached by using molecularly pre-designed active sites in which the strongly bonding ligands keep the metals (Pd, Ru, Ni, ..) well-fixed to the hybrid material.
Material robustness. Rather than classical polymers (e.g. polystyrene based ones) H-CCAT uses robust materials, with strong Si-C and Si-O-Si bonds in the hybrid silica, or with the particularly stable coordinative bonds in Zr4+ and Cr3+ MOF materials. These readily withstand temperatures ≥ 150°C, which is the required temperature for e.g. the dehydrogenative processes.
The academic partners are world-leading groups in the field of catalysis and nanoporous materials. This will allow to go well beyond the state-of-the-art and to achieve important breakthroughs. The (industrial) partners are key players in the value chain; this will decrease the time-to-market for the new catalysts and speed up adoption of the catalytic processes in pharmaceutical production.
Some of the key molecules for which J&J could use C-H activation technology include Rilpivirine in the first place, and also Ibrutinib and VX-787. All the key molecules are APIs with a massive societal and economic importance, with potentially 107-108 treatments per year worldwide for Rilpivirine and VX-787, or even more.
H-CCAT will overcome the main bottlenecks in current API production.
First, the catalysts of H-CCAT will reach much higher TON, because of their intrinsic resistance against deactivation; consequently, they can also be used at higher temperatures (e.g. for C-H/C-X coupling), which raises TOF. In fact, other factors than catalyst cost then start to dominate process economics, both regarding cost of goods and regarding cost of operation. In the synthesis of a typical API, overall costs are ~ equally split in goods and raw materials (50%) and operational costs (50%). These can be significantly reduced by reducing the cost of goods and reducing operational costs by reaching higher step economy and reducing the number of unit operations by making the process heterogeneous. Additionally, H-CCAT will reinforce its positive economic benefits through the minimisation of downtime of the plants and flexibilisation of the production (with respect to temporal planning).

Finally, H-CCAT will have several positive environmental impacts:
1) Synthesis via C-H/C-H coupling or C-H/C-X coupling will produce significantly less waste (halides, borates, …), or even no waste at all (for the C-H/C-H coupling under oxygen). 2) Efficient metal immobilization strongly reduces the production of metal-contaminated wastes (e.g. liquids), and also makes the APIs much safer for the patient to ingest;
3) Some of the more toxic intermediates can be avoided.
4) H-CCAT will devote specific efforts to realize flow, reducing the environmental impact of the synthesis.
5) Preference will be given to use less harmful reagents and solvents.
The positive environmental impacts will be demonstrated through an LCA assessment.
Overview H-CCAT partners