AA-STARR: Aromatic Amine Synthesis by Tapping Aminium Radical Reactivity
Lead Research Organisation:
University of Leeds
Department Name: Sch of Chemistry
Abstract
Aromatic amines are amongst the most important chemical motifs, featuring in functional molecules such as colourants, pharmaceutical drugs and agrochemicals. Indeed, the foundation of the modern chemical industry was driven in large part by the development of new dyestuffs based on aromatic amines in the 1850s.
Despite the significance of aryl amines, methods for their production can still involve wasteful multi-step processes with noxious waste streams. More modern methods have been developed such as the so-called Buchwald-Hartwig coupling, but these require the use of pre-functionalised substrates (which carry their own waste inventory) and catalysts based upon the scarce precious metal palladium.
In this work, we will develop methods to directly aminate aromatic rings using simple and cheap reagents in conjunction with light sources (ultra-violet and visible). The reactions exploit active species known as aminium radicals. Reactions of aminium radicals have been known for over 100 years, but they remain underexploited. We have recently developed ways to harness these reactive species to give highly productive amination of aromatics. Further, the reactivity allows us to access unusual molecular structures which will find applications in drug discovery and the preparation of fluorescent materials.
Our objectives are to (i) create a suite of conditions to achieve the amination reactions; (ii) to demonstrate this in the creation of a wide range of novel molecules with diverse structures; (iii) develop a new variant in which the aromatic ring is 'destroyed' in the process, allowing access to very different products from the same type of starting materials. We will demonstrate non-academic impact of our work by making novel molecular 'building blocks' available to buy (through a project partner), and by creating a unique library of small molecules known as fragments which can be used for screening programmes in drug discovery.
Despite the significance of aryl amines, methods for their production can still involve wasteful multi-step processes with noxious waste streams. More modern methods have been developed such as the so-called Buchwald-Hartwig coupling, but these require the use of pre-functionalised substrates (which carry their own waste inventory) and catalysts based upon the scarce precious metal palladium.
In this work, we will develop methods to directly aminate aromatic rings using simple and cheap reagents in conjunction with light sources (ultra-violet and visible). The reactions exploit active species known as aminium radicals. Reactions of aminium radicals have been known for over 100 years, but they remain underexploited. We have recently developed ways to harness these reactive species to give highly productive amination of aromatics. Further, the reactivity allows us to access unusual molecular structures which will find applications in drug discovery and the preparation of fluorescent materials.
Our objectives are to (i) create a suite of conditions to achieve the amination reactions; (ii) to demonstrate this in the creation of a wide range of novel molecules with diverse structures; (iii) develop a new variant in which the aromatic ring is 'destroyed' in the process, allowing access to very different products from the same type of starting materials. We will demonstrate non-academic impact of our work by making novel molecular 'building blocks' available to buy (through a project partner), and by creating a unique library of small molecules known as fragments which can be used for screening programmes in drug discovery.
Planned Impact
The non-academic impact of the project will be delivered in a number of ways.
People: the project will deliver a highly trained PDRA with experience across a range of techniques and methods, including synthetic organic chemistry; photochemistry; continuous chemistry; DFT calculations; molecular property analysis. Additionally, through the knowledge transfer secondment to our project partner, the PDRA will gain commercial insight and experience. They will therefore be a highly marketable potential employee.
Knowledge: the project will deliver access to novel and potentially highly valuable small molecules which can be exploited in high throughput 'fragment-based' screens as potential ligands for proteins. We will make these fragments available both to our own collaborators (at the Structural Genomics Consortium and the University of Leeds) and to interested external partners (through a simple MTA arrangement). In this way we will maximise the chances of the biological relevance of the molecules created being demonstrated, with the potential for follow-on impact in the biomolecular sciences. We will also exchange information with project partners from the EPSRC-funded "photo-electro" consortium, and look for opportunities to apply the novel photochemically-mediated transformations developed herein to their novel photochemical reactor designs, with the intention of demonstrating the potential to move towards manufacture.
Economic: many of the products of our new chemistry could find application as building blocks or reagents in discovery science. The added economic value of having access to such novel species in the pharmaceutical industry has been documented. We will seek to make attractive building blocks/reagents available through our project partner Redbrick Molecular Ltd. This will be achieved through a secondment during which the PDRA on the project will transfer photochemical technology to Redbrick, driving additional value.
Society: we will highlight the historical and potential future roles of photochemistry to the general public by creating digital teaching resources as well as a practical (visual) demonstration of radical photochemistry that can be used in Schools, at Science Fairs and on University open-days.
People: the project will deliver a highly trained PDRA with experience across a range of techniques and methods, including synthetic organic chemistry; photochemistry; continuous chemistry; DFT calculations; molecular property analysis. Additionally, through the knowledge transfer secondment to our project partner, the PDRA will gain commercial insight and experience. They will therefore be a highly marketable potential employee.
Knowledge: the project will deliver access to novel and potentially highly valuable small molecules which can be exploited in high throughput 'fragment-based' screens as potential ligands for proteins. We will make these fragments available both to our own collaborators (at the Structural Genomics Consortium and the University of Leeds) and to interested external partners (through a simple MTA arrangement). In this way we will maximise the chances of the biological relevance of the molecules created being demonstrated, with the potential for follow-on impact in the biomolecular sciences. We will also exchange information with project partners from the EPSRC-funded "photo-electro" consortium, and look for opportunities to apply the novel photochemically-mediated transformations developed herein to their novel photochemical reactor designs, with the intention of demonstrating the potential to move towards manufacture.
Economic: many of the products of our new chemistry could find application as building blocks or reagents in discovery science. The added economic value of having access to such novel species in the pharmaceutical industry has been documented. We will seek to make attractive building blocks/reagents available through our project partner Redbrick Molecular Ltd. This will be achieved through a secondment during which the PDRA on the project will transfer photochemical technology to Redbrick, driving additional value.
Society: we will highlight the historical and potential future roles of photochemistry to the general public by creating digital teaching resources as well as a practical (visual) demonstration of radical photochemistry that can be used in Schools, at Science Fairs and on University open-days.
People |
ORCID iD |
| Stephen Marsden (Principal Investigator) | |
| John Plane (Co-Investigator) |
| Description | Compounds known as aromatic amines are found in a wide variety of effect chemicals, from dyes to pharmaceuticals. Methods for their production are therefore extremely important: in discovery laboratory settings, the ease and speed of making the compounds is paramount, while on a larger scale economic and environmental considerations become the dominant factor. In this project, a new, clean way to make aromatic amines has been developed, based upon highly reactive nitrogen species generated by light (photochemical activation). This has allowed us to access interesting new 3-dimensional molecular architectures which, on account of their structures, have unique and potentially useful properties - for example, we can tune the basicity of the nitrogen atom (how effective it is at reacting with acid), photochemical properties (how they absorb and emit light) and electrochemical properties (how easily they are oxidised) by incorporating cyclic systems of different size. These properties have application in, for example, drug development (making compounds more soluble in the bloodstream) or in developing new sensor systems based on fluorescence. |
| Exploitation Route | The findings about how to control molecular properties of aromatic amines are now being investigated in conjunction with a pharmaceutical company, leading to new potential 'bioisosteres' for deployment in drug discovery programmes. We are also investigating applications of the tunable photochemical properties to molecular dyes used in biological applications in collaboration with medics at the University of Leeds. |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |
| Description | Impact Acceleration Account - University of Leeds 2017 |
| Amount | £3,255,321 (GBP) |
| Funding ID | EP/R511717/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2021 |
| End | 03/2022 |