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The case for homogeneous ester hydrogenation
Authors: Dr Antonio Zanotti-Gerosa, R&D Director at Johnson Matthey and Dr Lucy Milner, NBD Manager at Johnson Matthey
A revolution in homogeneous hydrogenation catalysis is in full swing. This has been triggered by a renewed enthusiasm for operationally simple, cost-effective and sustainable transformations and is supported by the continuous evolution of more active, chemoselective and efficient catalyst families. Amongst the emerging transformations, homogeneous ester hydrogenation (EH) using ruthenium-based catalysts has now become an exciting and industrially viable addition to the catalytic toolbox. Dr Antonio Zanotti-Gerosa, R&D Director, and Dr Lucy Milner, NBD Manager, discuss the reasons that should, and will, lead to an ever-increasing implementation of this technology.
economical manufacture. As such, large players including Firmenich, Takasago, Givaudan and DSM have all developed proprietary technology in this field.
A
Building on its track record as a trusted and innovative catalyst supplier, Johnson Matthey has licensed a world-leading class of EH catalysts and made the technology accessible for all of the company’s fine chemicals customers. Examples of such catalysts, developed by Professor Dmitri Gusev of Wilfrid Laurier University’s research group, are illustrated in Figure 1.
As with any emerging technology, effective propagation into new markets
can only occur when a product meets the unique demands of each user. The most valuable benefits for each stakeholder will depend both on the industry and their role within the development chain (Figure 2). Applications within the pharmaceutical industry require the catalyst to be tolerant of diverse and complex functionalities, ideally operating at low pressure to allow easy outsourcing of the route to CMOs. Applications in the agrochemical, flavour and fragrances, fine and commodity chemical industries will face additional pressure on factors such as process
efficiency, low catalyst loadings and, desirably, catalyst recyclability. All end-users require safe and reproducible chemistry, selective processes and simple reaction work-ups – all of which are key benefits offered by homogeneous EH catalysis.
Why should industry use homogeneous ester hydrogenation?
The economic case The fine chemicals industry has been using hydride reductions for many decades and most chemists are familiar with the technology from lab-scale experiments to large-scale applications. Bulk prices of the most common hydride reagents can range anywhere between €5 and €20 per kilogram. Even considering stoichiometric (or higher) molar ratios, this appears cheap compared to the headline price tag of a homogeneous catalyst. However, in an optimized process, only a minimal amount of catalyst is required for converting large amounts of starting material to product. A rough estimate for the point where an EH catalytic process becomes more competitive than a hydride process (purely looking at the cost of reagents) sits around the catalyst molar ratio of 10,000/1. This threshold, which has been achieved and surpassed on several targets, will be lower in the case of high-value substrates (eg chiral substrates) or where the catalytic route provides significantly enhanced selectivity or yield. Besides this very basic cost model, a more sophisticated analysis should include the cost savings associated with simpler work-up and much-reduced waste generation.
Safety, simplicity and sustainability
Figure 1: Typical Gusev catalysts as developed by the research group of Professor Dmitri Gusev at Wilfrid Laurier University.
Summer 2020
Any chemist who has run hydride reductions can intuitively appreciate the advantages of avoiding the handling of hazardous reagents and the complex, exothermic work-up (think LiAlH4
!), which produces several times the reaction volume in organic and contaminated aqueous waste. In lab- 31
t the beginning, innovations in the homogeneous ester hydrogenation (EH) field have largely been driven by the flavours & fragrances industry. This is motivated by their high number of primary alcohol targets which require robust, selective and
Catalysis
Figure 2: The value in using homogeneous EH from discovery to launch.
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