Exploiting Chalcogen Bonding and Non-Covalent Interactions in Isochalcogenourea Catalysis: Catalyst Preparation, Mechanistic Studies and Applications
Lead Research Organisation:
University of St Andrews
Department Name: Chemistry
Abstract
The ability to synthetically manipulate and prepare specific molecular structures with defined bespoke properties is the main goal of synthetic chemistry, with applications that span the breadth of contemporary science ranging from materials chemistry to chemical biology. Catalysis provides society with efficient industrial processes that minimize energy consumption, waste production and the formation of harmful by-products. This research proposal aims to bring together these two areas, through developing a range of effective catalysts and generating an understanding of their fundamental properties. The developed catalysts will be used to uncover new and effective routes to prepare high value (chiral) materials that will be of interest to the global synthetic community as well as the pharmaceutical and agrochemical industries.
This proposal aims to generate a fundamental understanding of how a particular class of simple organic molecule, known as an isochalcogenourea, is able to catalyze a wide range of selective chemical transformations. Through developing an understanding of how each step in a particular process works, and by comprehending how the rate of each step if effected by a change in catalyst structure, we hope to reveal the factors that provide control in the products formed and ultimately lead to more effective reaction processes.
The use of organic materials as catalysts is often grouped under the term "organocatalysis". One of the main advantages of this approach is that typical transformations may be performed under relatively mild, 'greener' conditions, thus offering key sustainability benefits. By contrast, catalysis using metals usually requires more stringent conditions, including the rigorous exclusion of moisture and oxygen as well as the use of typically expensive metal systems. However, metal-derived catalyst systems still substantially outperform organocatalytic analogues; with high catalyst loadings still necessary in the majority of organocatalytic reactions. As a result, there has been limited uptake to date of organocatalytic approaches in industrial settings despite the clear 'green' advantages. A step change in catalyst efficiency will be required before the broader usage of organocatalytic approaches occurs. A more detailed mechanistic understanding of the inter-relation between catalyst structure and product is essential to underpin future developments. This proposal will demonstrate a fundamental quantitative understanding of the roles of isochalcogenoureas in catalysis. Through understanding these processes we will deliver a series of catalysts that can be used at very low concentration to allow synthetic access to the broad range of scaffolds required by the chemical and pharmaceutical industries.
This proposal aims to generate a fundamental understanding of how a particular class of simple organic molecule, known as an isochalcogenourea, is able to catalyze a wide range of selective chemical transformations. Through developing an understanding of how each step in a particular process works, and by comprehending how the rate of each step if effected by a change in catalyst structure, we hope to reveal the factors that provide control in the products formed and ultimately lead to more effective reaction processes.
The use of organic materials as catalysts is often grouped under the term "organocatalysis". One of the main advantages of this approach is that typical transformations may be performed under relatively mild, 'greener' conditions, thus offering key sustainability benefits. By contrast, catalysis using metals usually requires more stringent conditions, including the rigorous exclusion of moisture and oxygen as well as the use of typically expensive metal systems. However, metal-derived catalyst systems still substantially outperform organocatalytic analogues; with high catalyst loadings still necessary in the majority of organocatalytic reactions. As a result, there has been limited uptake to date of organocatalytic approaches in industrial settings despite the clear 'green' advantages. A step change in catalyst efficiency will be required before the broader usage of organocatalytic approaches occurs. A more detailed mechanistic understanding of the inter-relation between catalyst structure and product is essential to underpin future developments. This proposal will demonstrate a fundamental quantitative understanding of the roles of isochalcogenoureas in catalysis. Through understanding these processes we will deliver a series of catalysts that can be used at very low concentration to allow synthetic access to the broad range of scaffolds required by the chemical and pharmaceutical industries.
Planned Impact
This project involves fundamental synthetic chemistry and catalysis research focused in a topical area of increasing international attention. Our proposed research will establish a fundamental understanding of a range of Lewis base catalysts that utilize and exploit 1,5-O---Ch contacts (chalcogen bonding; Ch = S, Se) to promote effective catalytic processes. This project will provide impact in the following areas:
1. Knowledge: This project will deliver fundamental and innovative knowledge advances, contributing to our understanding of chalcogen bonding and its potential for exploitation and application in catalytic reaction processes. We anticipate that the development of new catalytic species with exceptional catalytic performance - aimed at using ppm catalysts concentrations for effective processes - may be used broadly by synthetic chemists in many research areas and industry, thus fostering broader research development. In addition, the key mechanistic understanding developed in this project will showcase the application of using quantitative data analysis to developing reaction understanding and optimization.
2. People: In a 2017 'RSC Chemistry World' article by a consortium of key industrialists, a highlighted a skills shortage in the pharmaceutical and agrochemical industries of synthetic chemists trained with a quantitative mindset. The PDRAs on this project will specifically meet this skills shortage, through being trained in both synthesis and key quantitative mechanistic analysis, allowing them to make quantitative predictions to inform process development. These skills will make them highly competitive in industrial as well as the academic jobs markets. Through working both individually and as a team, as well as participating in collaborative training placements, the PDRAs will be endowed with a valuable set of general transferable and employment-related skills always demanded by employers.
3. Knowledge Transfer: Organocatalysis offers significant potential to industry, however, is under-utilised at present due to a general need for high catalyst loadings combined with a lack of fundamental quantitative understanding. This work will deliver a series of high performing catalysts capable of working effectively at industrially viable concentrations, as well as providing a quantitative study of their activity in a range of processes to address this gap. To aid knowledge transfer we will (i) use site visits to each industrial partners (AstraZeneca and Syngenta) to promote knowledge exchange and identify valuable target applications; (ii) promote knowledge transfer through CDT and EaSI-CAT engagement; and (iii) demonstrate impact through knowledge translation using the Knowledge Transfer Centre (KTC) at St Andrews.
4. Society and Economy: Catalysis plays a key role in society. The development of a fundamental understanding of catalytic processes leads to more effective procedures that minimize waste. The increasing popularity of organocatalysis stems in part from sustainable chemistry advantages as these processes generally operate in more user-friendly, 'green' conditions. Although it is hard to speculate where the specific developments in this project will directly lead, it is clear that any major advances in catalysis will broadly benefit society in terms of health and quality of life. Letters of support from Syngenta and AstraZeneca show the interest of pharmaceutical and agrochemical industries in this area of research. We will also demonstrate broad impact through public engagement and outreach channels to the broader public.
1. Knowledge: This project will deliver fundamental and innovative knowledge advances, contributing to our understanding of chalcogen bonding and its potential for exploitation and application in catalytic reaction processes. We anticipate that the development of new catalytic species with exceptional catalytic performance - aimed at using ppm catalysts concentrations for effective processes - may be used broadly by synthetic chemists in many research areas and industry, thus fostering broader research development. In addition, the key mechanistic understanding developed in this project will showcase the application of using quantitative data analysis to developing reaction understanding and optimization.
2. People: In a 2017 'RSC Chemistry World' article by a consortium of key industrialists, a highlighted a skills shortage in the pharmaceutical and agrochemical industries of synthetic chemists trained with a quantitative mindset. The PDRAs on this project will specifically meet this skills shortage, through being trained in both synthesis and key quantitative mechanistic analysis, allowing them to make quantitative predictions to inform process development. These skills will make them highly competitive in industrial as well as the academic jobs markets. Through working both individually and as a team, as well as participating in collaborative training placements, the PDRAs will be endowed with a valuable set of general transferable and employment-related skills always demanded by employers.
3. Knowledge Transfer: Organocatalysis offers significant potential to industry, however, is under-utilised at present due to a general need for high catalyst loadings combined with a lack of fundamental quantitative understanding. This work will deliver a series of high performing catalysts capable of working effectively at industrially viable concentrations, as well as providing a quantitative study of their activity in a range of processes to address this gap. To aid knowledge transfer we will (i) use site visits to each industrial partners (AstraZeneca and Syngenta) to promote knowledge exchange and identify valuable target applications; (ii) promote knowledge transfer through CDT and EaSI-CAT engagement; and (iii) demonstrate impact through knowledge translation using the Knowledge Transfer Centre (KTC) at St Andrews.
4. Society and Economy: Catalysis plays a key role in society. The development of a fundamental understanding of catalytic processes leads to more effective procedures that minimize waste. The increasing popularity of organocatalysis stems in part from sustainable chemistry advantages as these processes generally operate in more user-friendly, 'green' conditions. Although it is hard to speculate where the specific developments in this project will directly lead, it is clear that any major advances in catalysis will broadly benefit society in terms of health and quality of life. Letters of support from Syngenta and AstraZeneca show the interest of pharmaceutical and agrochemical industries in this area of research. We will also demonstrate broad impact through public engagement and outreach channels to the broader public.
Publications
Abdelhamid Y
(2022)
Isothiourea-Catalyzed [2 + 2] Cycloaddition of C(1)-Ammonium Enolates and N-Alkyl Isatins.
in Organic letters
Zhou Z
(2024)
Enantioselective Synthesis in Continuous Flow: Polymer-Supported Isothiourea-Catalyzed Enantioselective Michael Addition-Cyclization with a-Azol-2-ylacetophenones
in Organic Process Research & Development
Description | We have developed a series of isochalcogenourea and probed the structural factors that lead to selectivity in benchmark reactions. |
Exploitation Route | The effective catalysts that have been developed could potentially be applied in the preparation of fine chemicals on scale for manufacture. |
Sectors | Agriculture Food and Drink Chemicals Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
Title | CCDC 2153991: Experimental Crystal Structure Determination |
Description | Related Article: Yusra Abdelhamid, Kevin Kasten, Joanne Dunne, Will C. Hartley, Claire M. Young, David B. Cordes, Alexandra M. Z. Slawin, Sean Ng, Andrew D. Smith|2022|Org.Lett.|24|5444|doi:10.1021/acs.orglett.2c02170 |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
URL | http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc2b9dln&sid=DataCite |
Title | Data underpinning "Unveiling the impact of CF2 motif in the Isothiourea Catalyst Skeleton: Evaluating C(3)-F2-HBTM and its Catalytic Activity" |
Description | |
Type Of Material | Database/Collection of data |
Year Produced | 2023 |
Provided To Others? | Yes |
URL | https://research-portal.st-andrews.ac.uk/en/datasets/data-underpinning-unveiling-the-impact-of-cf2-m... |
Title | data underpinning "Isothiourea-Catalyzed [2+2] Cycloaddition of C(1)-Ammonium Enolates and N-Alkyl Isatins" |
Description | |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
URL | https://risweb.st-andrews.ac.uk/portal/en/datasets/data-underpinning-isothioureacatalyzed-22-cycload... |