Custom-tailored ligand systems simplify the synthesis of fine chemicals

Industrial-scale homogeneous catalysts

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The production of homogeneous catalysts requires very complex chemistry. Consequently, industrial quantities of ligands and homogeneous catalysts have always been scarce for speciality chemical applications. The new internal start-up Degussa Homogeneous Catalysts now markets a set of products and technologies which have been developed in the Degussa Project House Catalysis.

Antje Gerber

While efficient industrial catalytic processes have been established in the field of oil refining as well as in the industrial-scale manufacture of basic chemicals – for example, through cracking, oxo reactions, oxidations and hydrations – these types of direct catalytic process are still rare in the production of fine chemicals, more than ten million metric tons of which are manufactured annually. Among the reasons for this is that “time to market“ is more vital to this segment than a manufacturing process optimised down to the last detail for the purpose of producing the highest possible yield. Owing to their functionality, fine chemicals are used as polymer additives and stabilisers, pigments, vitamins and flavouring agents, and are also important starting products for nearly all known crop-protection agents and pharmaceuticals.
Strong demand for catalytic processes in fine chemistry
Even now, many fine chemical syntheses are still carried out with classic organic reactions that are more than 100 years old. These include nitrations, hydrolyses, Friedel-Crafts reactions and halogenations. The disadvantage of these methods is the occurrence of stoichiometric – and frequently even hyperstoichiometric – quantities of salts that have to be separated and discarded. They also often require complicated protective group techniques, such as the halogenations and dehalogenations that are needed for chemo- and region-specific activation of a functionality. This is why these conventional production processes often generate several tons of waste per ton of target product. With active ingredients for medicines or crop-protection agents, the amount of waste produced can sometimes exceed the target product by a factor of one hundred. Given these facts and the need for sustainability, there is a tremendous demand for innovative and versatile catalytic methods for new, environmentally safe fine chemical processes (green chemistry). Enantioselective processes for the production of enantiomerically pure substances are a particularly important goal, since over 80 % of the active ingredients currently being developed in the pharmaceutical industry are chiral compounds.
Of the many different synthetic methods, asymmetric catalysis is in many cases the most economically and environmentally useful process. Homogeneous and biocatalytic methods currently dominate this field. Yet despite intensive research (Fig. 1), they are still under-utilised in industrial processes, owing in part to the shortage of industrial quantities of the ligands necessary for homogeneous catalysis. Also, catalyst productivities (TON) and activities (TOF) still render the majority of known asymmetric reactions unsuitable for industrial demands.
Broad product range
Beginning in January 2004, Degussa Homogeneous Catalysts, a new internal start-up of Degussa AG, Düsseldorf, will close these gaps by marketing products and technologies in the field of homogeneous catalysts that have been developed in Degussa’s Catalysis Project House. Headquartered in Hanau-Wolfgang, Degussa Homogeneous Catalysts offers a product range comprising ligands and metal complex catalysts. Many of these catalysts are already available in industrial quantities. Additionally, the internal start-up will offer services for the rapid identification of homogeneous catalysts. These products and services significantly improve access to enantiomerically pure active substances, which makes them particularly attractive for the pharmaceuticals industry. Already one of the leading suppliers of heterogeneous catalysts, the company also has extensive experience in the use of biocatalysts.
The new unit offers screening and testing of catalysts with the high-throughput and combinatorial methods developed by the project house, as well as access to Degussa’s own catalyst library, which contains several thousand ligands and catalysts for screening.
Enantiomerically pure ingredients
In the field of ligands, Degussa Homogeneous Catalysts currently markets ten patented product families, including ligands for asymmetrical hydrogenation and palladium-catalysed coupling reactions. Examples include the two ligands cataCXium A and catASium M (Fig. 2), which were developed in cooperation with the Institute for Organic Catalysis at Rostock University (IfOK).
CataCXium A has proved an outstanding ligand in numerous reactions, including Suzuki couplings with chloro aromatics. These ligands achieve catalyst productivity figures (TON; mol product/mol catalyst) of up to 20 000 in the conversion of phenylboric acid with various chloro aromatics.
catASium M ligands enable the industrial application of asymmetric hydrogenation. Typically, they display very high activity and selectivity in numerous asymmetric hydrogenations and are superior to other ligands in many standard reactions. In rhodium-catalysed asymmetric hydrogenation, excellent enantioselectivities can be achieved with catASium M at a hydrogen pressure of only one atmosphere. A TON of 20 000 and a TOF of 4 000 h-1 for the hydrogenation of an itaconic acid derivative (Fig. 3) was reached, for instance, with an enantiomeric excess of >95 % ee.
Another example is a single-step asymmetric reductive amination which Degussa developed in cooperation with IfOK. This reaction allows the direct conversion of ketones with amines or ammonia to enantiomerically pure amines with the aid of the catASium D ligand (Fig. 4). Since enantiomerically pure amines are needed for the manufacture of numerous pharmaceutical and agro-chemical ingredients, this new reaction is particularly attractive to the fine chemicals market.
Palladium-catalysed C-C couplings
High catalyst productivity and activity are extremely important not only in asymmetric processes but also in palladium-catalysed C-C coupling reactions, which are widely used to synthesise active ingredients. In this area, too, Degussa has cooperated with IfOK to develop innovative ligand systems (Fig. 5). Known as cataCXium P (pyrrole aryl phosphane) lig-ands, these systems achieve a TON of up to 20 000 and yields of >95 % in the Suzuki coupling with the use of only 0.005 mol% palladium. These ligands are also available in industrial quantities.
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