New Insights, New Catalysts and New Processes using Enantioselective Carbonylations.

Lead Research Organisation: University of St Andrews
Department Name: Chemistry

Abstract

This project is in the field of chemo-catalysis. Catalysis is used somewhere in the manufacture of most everyday items (plastics, drugs, food supplements, flavours/fragrances, finishes and coatings). Amongst the most important reactions, generally used in the manufacture of diverse products such as varnishes, plastics, banana flavouring and anti-inflammatories!, are those that use carbon monoxide as a building block. Carbon monoxide is one of the cheapest chemicals and can come from coal, oil, gas and renewables. Due to the low price of carbon monoxide and the fact that it can, in the presence of a catalyst, react in a very clean fashion with other molecules, these catalytic carbonylation reactions generate very little waste and are economical even at very large scale (Millions of tonnes).
These features also potentially make this type of reaction a clean and economical way to make much higher value, more sophisticated molecules such as drugs. However, to make these molecules, exquisite control of several types of selectivity is needed.
For example, many drugs exist as two mirror image forms (optical isomers) and one isomer must be made prefentially. The other optical isomer is often inactive, or in fact can cause an alternative biological effect (The side effects of Thalidomide are a tragic example of one optical isomer causing unwanted biological effects). This has led to a massive research effort by chemists to develop chemical reactions that are capable of selectively producing a single optical isomer ('Asymmetric Synthesis'). Significant developments have been made in this area, with several Nobel prizes in chemistry being awarded to some of the pioneers in asymmetric synthesis.
The investigators group has recently obtained exciting preliminary results developing catalysts that can control several aspects of selectivity in model studies on a few types of carbonylation, including excellent selectivity to one optical isomer. This new project addresses building on these results to develop routes to different target chemicals.
Development of new types of carbonylation or the ability to work on hitherto unreactive substrates is needed for the higher value fine chemicals/pharma intermediates sector. A number of potentially exciting new reactions such as combining several reaction into one stage of a synthesis, and one reactor, one set of solvents, purification etc. are proposed.
This project will also gain mechanistic insights on the new catalyst and use this information to generate refined catalyst design and rational design of catalysts to accomplish new tasks. Overall the project has the potential to impact on fundamental knowledge, generate proof of concept for new industrial targets, and provide better, more benign routes to a range of important chemicals.

Planned Impact

The project combines mechanism and catalyst optimisation studies with new applications. This project incorporates developing an understanding of how an important catalyst system operates. That information will be used to improve (already state-of-the-art) performance and to develop more sustainable routes to new targets. The potential impact is significant and broad. Potential economic impacts are three-fold. Potentially short-medium-term direct impacts, medium-long term direct impacts, and indirect impacts. The project is built upon two exciting preliminary studies, and recognising the possibilities for shorter term direct impact, patents are filed. Companies who manufacture pharmaceuticals and fragrances may wish to licence this technology if this further research is carried out. The project is also aiming to increase the range of chemicals that can be advantageously made using this technology. This provides further opportunities for a broader range of companies who may have products that could be economically accessed using this technology once it is extended in scope. The fundamental understanding of how these catalysts work can impact in different sectors, such as commodity chemicals where this general class of reaction is widely applied, and understanding is vital to improve catalyst activity, stability, branched selectivity etc.
There may also be new variants of this reaction that could spring from the principles built up here that could be useful for industry and might form new collaborative research with the investigators. There are also sure to be indirect impacts; this project is in the discipline of Catalysis. This field is known to contribute in a huge way to the global economy. It has been estimated that the majority of all products (not just chemicals) use catalysis at some stage in their production. Catalysis relies, to a strong extent, on using previous research results in ways that were not foreseen initially. Thus, many commercially applied reactions have relied on information from a range of academic studies on unrelated challenges in totally different topics. In the same way, a novel project such as this is also likely to indirectly impact other economically important catalysis projects. The fact that this project does address real industrial issues, and is also novel, and not following the crowd in an academic context increases the odds of these indirect impacts on knowledge and possibly the commercial sector. In addition several foreseeable indirect impacts are noted in the case for support and/or the pathway to impact document.
The project has teamed up with a commercial partner that offers technology to end users (and markets its own generic drugs). Another company has been identified with a possible interest. Both manufacture in the north-east of England. It is frequently noted that the UK economy depends on development of high-tech, high value manufacturing. Regardless if this makes it to a significant commercial application, it is envisaged that this new technology will be available in a company's portfolio of technology. It therefore can be envisaged to help underpin the UK and EU's position in high-tech manufacturing. If a full commercial process is commissioned, then this secures manufacturing jobs. It is also likely to be a greener route to a target, producing less waste, lower energy demand etc. This therefore could contribute to european targets to develop more sustainable processes, and the European reputation in this area. Other socio-economic impacts include possible export and transfer of knowledge. When overseas companies support follow-on projects in the investigators laboratories, this is an export of knowledge. If this grant enables this to be sustained, it contributes in cash terms and in sustaining St Andrews reputation as a global recognised centre for research.

Publications

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Dingwall P (2017) Understanding a Hydroformylation Catalyst that Produces Branched Aldehydes from Alkyl Alkenes. in Journal of the American Chemical Society

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Iu L (2019) High iso Aldehyde Selectivity in the Hydroformylation of Short-Chain Alkenes. in Angewandte Chemie (International ed. in English)

 
Description This project is still very much ongoing, but has already realised some key findings.
The most progress has been made in our technology for making aldehydes from alkenes (hydroformylation)
We have used computational chemistry techniques to allow us to explain why our rather unique catalyst delivers the selectivity it delivers. Rather than just offering a suggestion backed up by DFT using many assumption, d-lableing, kinetics and detection of intermediates enabled us to be sure the DFT was looking at exactly the right part of the catalytic cycle and correct catalyst intermediate. This may prove useful to any group designing selective catalysts for this type of transformation (published in JACS). The expertise built using in situ spectroscopy of these systems was also used to identify the catalyst resting states and speciation for another catalytic system for hydroformylation that had been studied in the group. This also revealed that some conclusion in the literature were not likely to be quite as reported, since it was unlikely to be any association between ligands and rhodium under the reaction conditions. We have developed a one-pot procedure for converting alkenes into chiral amines (with a reducing agent added halfway through). This has significant further potential and we also reported the use of this type of reaction to prepare key intermediates to a new antibiotic. Carbon monoxide is a desirable agent at large scale production, since it is very cheap, and reacts in a very clean way, but is difficult to handle for non-specialists working at smaller scales. Since some non-specialists such as drug discovery researchers might desire to use this type of transformation, but be unwilling to invest in equipment, we studied the use of paraformaldehyde as a surrogate for carbon monoxide. We have successfully accomplished this giving very high selectivity in a matter of minutes in a user-friendly protocol. This is being developed further, with new dual catalysts systems. We have also gained understanding of our Pd catalysts, improved the synthesis and method of operation and showcased their use in a convenient synthesis of Flurbiprofen.
Exploitation Route As described, non-specialists may now be interesting in using some of the protocols we developed. Our understanding of the catalysts is enabling to other specialists in homogeneous catalysis.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

 
Description In addition to non-academic impacts, the research in this award, combined with an award from our EPSRC Impact acceleration account has realised a non-academic impact. The synthesis of our catalysts was optimised and steamlined, making it more suitable for producing in larger amounts. Strem chemical expressed an interesting in selling the catalyst (or more correctly the key component of the catalyst), and we have entered an agreement to supply them periodically. The catalyst is now available for sale in the Strem on-line catalogue. This therefore makes a small economic impact through Strem and the University of St Andrews. The real aim in promoting this is that an end-user now has lower barrier to use this catalysts in research, which already could leave to enhanced innovation, but hopefully one day to an application that would generate a significant economic impact, along with societal impacts associated with more efficient synthesis. An industrial company is continuing to funding a long-term project using derivatives of this catalyst, designed using knowledge obtained in this project. This development is ongoing and under CDA, and is generating novel intellectual property.
First Year Of Impact 2015
Sector Chemicals,Manufacturing, including Industrial Biotechology
Impact Types Economic

 
Description EPSRC Catalysts Hub
Amount £177,000 (GBP)
Organisation Research Complex at Harwell 
Department UK Catalysis Hub
Sector Public
Country United Kingdom
Start 03/2017 
End 03/2019
 
Description EPSRC Impact Acceleration Account
Amount £12,615 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 02/2016 
End 10/2017
 
Description eastman phase 3
Amount £318,000 (GBP)
Organisation Eastman Kodak Company (Kodak) 
Sector Private
Country United States
Start 10/2018 
End 09/2021
 
Description none: please see narrative impact.
Amount £47,000 (GBP)
Organisation Eastman Kodak Company (Kodak) 
Sector Private
Country United States
Start 02/2018 
End 07/2018
 
Title A highly enantioselective alkene methoxycarbonylation enables a concise synthesis of (S)-flurbiprofen. (dataset) 
Description NMR spectra of substrates and products. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Title Data Underpinning - Composition of catalyst resting states for rhodium hydroformylation catalysts derived from bulky mono-phosphorus ligands 
Description NMR and IR raw data 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Title Data underpinning - Diastereoselective and branched-aldehyde-selective tandem hydroformylation-hemiaminal formation: synthesis of functionalised piperidines and amino-alcohols 
Description Proton and carbon NMR's that support the synthesis of the compounds and intermediates within the paper. The FID files are accessible so that the NMR's can be accessed from a programme such as MestRenova or Topspin. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Title Underpinning data: High iso aldehyde selectivity in the hydroformylation of short-chain alkenes 
Description NMR data. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
 
Title Understanding a Hydroformylation Catalyst that Produces Branched Aldehydes from Alkyl Alkenes (dataset) 
Description Data underpinning Understanding a Hydroformylation Catalyst that Produces Branched Aldehydes from Alkyl Alkenes (DFT data and NMR data) 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Title underpinning data: Isomerisation versus carbonylative pathways in the hydroxy-carbonylation, methoxy-carbonylation, and amino-carbonylation of N-tosyl 3-pyrroline. 
Description DFT data and selection of NMR files 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
 
Title (S,S,S)-BOBPHOS 
Description The key component in our most important catalysts studied in this grant is commercially available in the Strem catalogue. See: https://www.strem.com/catalog/v/15-0557/52/phosphorus_1373349-83-7 
Type Of Technology New Material/Compound 
Year Produced 2017 
Impact Development ongoing and under CDA.