Light-Activated Approaches to Highly Challenging Organic Electron Transfer Reactions
Lead Research Organisation:
University of Strathclyde
Department Name: Pure and Applied Chemistry
Abstract
Reduction and oxidation are central to chemistry and biology and relate to the addition of electrons or the removal of electrons from substances. Until now, many important but difficult reductions have only been accomplished with very powerful metal reducing agents, like sodium, but we have recently discovered simple neutral organic compounds, composed exclusively of the plentiful elements carbon, hydrogen and nitrogen, that act as powerful reducing agents. In 2012, we found that these substances become even more powerful reducing agents when irradiated with ultra-violet light and are even able to donate electrons to benzene rings that contain no significant electron-withdrawing groups.
We now propose to develop this approach to determine the scope of the chemistry, using visible light to trigger the reactions, rather than untraviolet light, and converting our transformations it into protocols that use our electron donors catalytically.
We believe that the principal reactions that are currently undertaken by sodium dissolved in liquid ammonia can be undertaken by our reagents in organic solvent and irradiated with light. This will not only add economic benefit through use of catalytic processes, but also convenience and enhancements in safety through avoiding reactive species like sodium that are hazardous both to use and to transport.
We now propose to develop this approach to determine the scope of the chemistry, using visible light to trigger the reactions, rather than untraviolet light, and converting our transformations it into protocols that use our electron donors catalytically.
We believe that the principal reactions that are currently undertaken by sodium dissolved in liquid ammonia can be undertaken by our reagents in organic solvent and irradiated with light. This will not only add economic benefit through use of catalytic processes, but also convenience and enhancements in safety through avoiding reactive species like sodium that are hazardous both to use and to transport.
Planned Impact
Who will benefit from the research?
We are exploring advances that should have wide application in industry. They will benefit chemists in all sectors who are engaged in preparative chemistry.
(i) The pharmaceuticals industry would use our methods in preparing substances that will be tested for use in human healthcare. (We attach 2 letters of support to illustrate the views of industry on the potential impact of our research).
(ii) Likewise the agrochemicals industry could use our chemistry in enhancing food production, both through animal healthcare and crop production.
(iii) The knowledge gained from our work should have broader implications for the organic electronics industry since their molecules function through electron transfer and we are extending the limits for electron transfer in neutral organic molecules.
(iv) Our work could also impact on the renewable fuels industry, since we will obtain information about how key steps occur in conversion of carbon dioxide to methane by methanogens.
As a result of using our methods, the general public will benefit indirectly through provision of medicines and enhanced food production, and the economy should benefit through improved processes being used in UK industry.
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How will they benefit from the research?
(i) The pharmaceuticals industry and (ii) the agrochemicals industry routinely need to remove protecting groups from alcohols, acids and amines. Very frequently these are benzyl or benzyloxycarbonyl groups that are removed by aggressive reagents like sodium in liquid ammonia. Reductions of arenes with the same reagents are also used by these industries as rapid routes to access some of their key target molecules.
A big disadvantage is that the use and transport of sodium is hazardous since it reacts violently with water. Liquid ammonia is also hazardous, particularly on a large scale, because of the possibility of unintentional venting as a gas. The alternative common method of deprotection of benzyl and benzyloxycarbonyl groups uses hydrogen gas and noble metal catalysts. Reactions with hydrogen gas on a large scale are dangerous, since it forms explosive mixtures with air. In addition, palladium catalysts are expensive and the activated catalyst must be carefully disposed of to avoid fire risks. These disadvantages would be avoided by our reagents.
By contrast, the protocols that we are proposing use organic reducing agents that are composed simply of the abundant elements carbon, hydrogen and nitrogen, and are therefore easily and economically prepared. Moreover they are transported and manipulated in the form of convenient air-stable and moisture-stable non-hygroscopic salts.
An additional benefit is that our reagents can be regenerated throughout the reaction and so they can be used catalytically. This means that their use causes minimal or zero waste and therefore industry would avoid the costs of treating that waste.
Our reagents have the added benefit of using visible light to make them fully reactive, and this use of activation without adding additional reagents is economical. Our regeneration route involves electrochemical regeneration at -1 V, while our photoactivated donors can achieve reductions equivalent to -3.5 V, again saving electricity costs.
We are exploring advances that should have wide application in industry. They will benefit chemists in all sectors who are engaged in preparative chemistry.
(i) The pharmaceuticals industry would use our methods in preparing substances that will be tested for use in human healthcare. (We attach 2 letters of support to illustrate the views of industry on the potential impact of our research).
(ii) Likewise the agrochemicals industry could use our chemistry in enhancing food production, both through animal healthcare and crop production.
(iii) The knowledge gained from our work should have broader implications for the organic electronics industry since their molecules function through electron transfer and we are extending the limits for electron transfer in neutral organic molecules.
(iv) Our work could also impact on the renewable fuels industry, since we will obtain information about how key steps occur in conversion of carbon dioxide to methane by methanogens.
As a result of using our methods, the general public will benefit indirectly through provision of medicines and enhanced food production, and the economy should benefit through improved processes being used in UK industry.
-----------------------------------------------------
How will they benefit from the research?
(i) The pharmaceuticals industry and (ii) the agrochemicals industry routinely need to remove protecting groups from alcohols, acids and amines. Very frequently these are benzyl or benzyloxycarbonyl groups that are removed by aggressive reagents like sodium in liquid ammonia. Reductions of arenes with the same reagents are also used by these industries as rapid routes to access some of their key target molecules.
A big disadvantage is that the use and transport of sodium is hazardous since it reacts violently with water. Liquid ammonia is also hazardous, particularly on a large scale, because of the possibility of unintentional venting as a gas. The alternative common method of deprotection of benzyl and benzyloxycarbonyl groups uses hydrogen gas and noble metal catalysts. Reactions with hydrogen gas on a large scale are dangerous, since it forms explosive mixtures with air. In addition, palladium catalysts are expensive and the activated catalyst must be carefully disposed of to avoid fire risks. These disadvantages would be avoided by our reagents.
By contrast, the protocols that we are proposing use organic reducing agents that are composed simply of the abundant elements carbon, hydrogen and nitrogen, and are therefore easily and economically prepared. Moreover they are transported and manipulated in the form of convenient air-stable and moisture-stable non-hygroscopic salts.
An additional benefit is that our reagents can be regenerated throughout the reaction and so they can be used catalytically. This means that their use causes minimal or zero waste and therefore industry would avoid the costs of treating that waste.
Our reagents have the added benefit of using visible light to make them fully reactive, and this use of activation without adding additional reagents is economical. Our regeneration route involves electrochemical regeneration at -1 V, while our photoactivated donors can achieve reductions equivalent to -3.5 V, again saving electricity costs.
Publications
Hanson S
(2015)
Pushing the Limits of Neutral Organic Electron Donors: A Tetra(iminophosphorano)-Substituted Bispyridinylidene
in Angewandte Chemie
Hanson SS
(2015)
Pushing the limits of neutral organic electron donors: a tetra(iminophosphorano)-substituted bispyridinylidene.
in Angewandte Chemie (International ed. in English)
Zhou S
(2014)
Organic super-electron-donors: initiators in transition metal-free haloarene-arene coupling
in Chem. Sci.
Doni E
(2014)
Evolution of neutral organic super-electron-donors and their applications.
in Chemical communications (Cambridge, England)
Massey R
(2016)
Proton transfer reactions of a bridged bis -propyl bis -imidazolium salt
in Journal of Physical Organic Chemistry
Zhou S
(2014)
Identifying the roles of amino acids, alcohols and 1,2-diamines as mediators in coupling of haloarenes to arenes.
in Journal of the American Chemical Society
Barham JP
(2016)
KOtBu: A Privileged Reagent for Electron Transfer Reactions?
in Journal of the American Chemical Society
Doni E
(2013)
Overturning established chemoselectivities: selective reduction of arenes over malonates and cyanoacetates by photoactivated organic electron donors.
in Journal of the American Chemical Society
Doni E
(2015)
Electron transfer-induced coupling of haloarenes to styrenes and 1,1-diphenylethenes triggered by diketopiperazines and Potassium tert-butoxide.
in Molecules (Basel, Switzerland)
Doni E
(2014)
Reductive decyanation of malononitriles and cyanoacetates using photoactivated neutral organic super-electron-donors
in Org. Chem. Front.
Description | Organic electron donors are activated through activation by light to achieve reactions that were never witnessed before. This feeds into many areas of research, and underpins our collaboration in a recent Prosperity Partnership commencing Jan 2019. Our work focused on 'super electron donors' which are uniquely powerful organic reagents. The concept developed here has gained traction worldwide, with recent international lecture tours and with invitations to write 2 reviews (published) and a book chapter (being finalised) |
Exploitation Route | This chemistry can be used to derive further applications of organic electron donors in replacing metal-based reagents; this has potential applications to the prepatation of new medicines in efficient and envrionmetally friendly ways (EPSRC Prosperity Partnership commencing Jan 2019). |
Sectors | Chemicals Healthcare Pharmaceuticals and Medical Biotechnology |
URL | http://www.johnmurphygroup.com/research-interests.html |
Description | Our quest was to explore how light could empower electron transfer reactions. Dealing with already powerful ground state electron donors, discovered and developed by us, we applied them to challenging electron transfer reactions. We consistently achieved greater reducing power than electron donors being used by international competitors and showed that even very negative potentials could be reached (e.g. in the reductions of benzenes) by organic electron donors. This inspired a lot of work worldwide in photoredox catalysis to find corresponding reagents that could approach our potentials. That work is coming to fruition and very powerful photocatalysts (organic as well as based on transition metal complexes) are now available for achieving challenging reductions and oxidations in a catalytic manner. The study of photoredox reactions has been embraced by the pharmaceutical industry and is being used by a number of international companies for the preparation of medicines. Assessing the impact of one's own work is always more difficult than assessing the work of others. I cannot say that we were principal players in developing the technology that industry uses, but I can say that our work contributed to the impetus and inspiration for academic colleagues internationally to develop reagents of sufficient potency to make this viable. Our work in the photoredox area continues through an exploration of the role of potassium tert-butoxide in generating Super Electron Donors, both in the ground state and in excited state, as well as in photoredox-catalysed reactions including Smiles rearrangements. Our work is published in major international journals. In industry, the fruits of our research contribute to the ongoing GSK-SU joint PhD programme (led in SU by Prof Kerr) which has been outstandingly successful in providing very large numbers of chemistry PhD students for UK plc and also (ii) the ongoing EPSRC co-funded Prosperity Partnership between GSK, University of Strathclyde and University of Nottigham EP/S035990/1 'Accelerated Discovery and Development of New Medicines: Prosperity Partnership for a Healthier Nation' Our ongoing influence in the area is seen in conference invitations: Thus, this year, 2022, Prof Murphy will be a Plenary Speaker at the Reaction Mechanisms Conference, Boulder, Colorado, and Keynote Speaker at the 25th International Conference on Physical Organic Chemistry (ICPOC-25) in Hiroshima, Japan as well as Invited Speaker at the Pacific Symposium on Radical Chrmistry (PSRC-12, Kyoto, Japan) (now postponed until 2023). |
First Year Of Impact | 2014 |
Sector | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | Accelerated Discovery and Development of New Medicines: Prosperity Partnership for a Healthier Nation |
Amount | £5,495,023 (GBP) |
Funding ID | EP/S035990/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2019 |
End | 12/2024 |
Description | Accelerated Discovery and Development of New Medicines: Prosperity Partnership for a Healthier Nation |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | I am leader for one of 5 themes; and am a member of a second theme. I represented University of Strathclyde as party of the panel of 3 who were interviewed at EPSRC for this grant |
Collaborator Contribution | GSK are the lead industrial partners who are collaborating with the University of Strathclyde and theUniversity of Nottingham in this Prosperity Partnership, which addresses accelerated discovery and development of new medicines. |
Impact | The collaboration has just started, so,as yet, there are no outputs, but they will be reported under that collaborative grant to RCUK. |
Start Year | 2019 |
Description | 2 Lectures at Univrsite de Bordeaux |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | 2 Lectures at Universite de Bordeaux, principally to a postgraduate audience, on the discoveries arising from our research |
Year(s) Of Engagement Activity | 2017 |
Description | 2 Research Colloquia at U Regensburg |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Graduate Research Training Group in Photocatalysis, U Regensburg, Germany |
Year(s) Of Engagement Activity | 2016 |
Description | Lecture at Ecole Polytechnique |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Lecture at Ecole polytechnique, principally to a postgraduate audience, on the discoveries arising from our research |
Year(s) Of Engagement Activity | 2017 |
Description | Lecture at U de Grenoble |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Lecture at Universite de Grenoble, principally to a postgraduate audience, on the discoveries arising from our research |
Year(s) Of Engagement Activity | 2017 |
Description | Lecture at U. Paris 6 (Diderot) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Lecture at Universite Paris 6 (Diderot), principally to a postgraduate audience, on the discoveries arising from our research |
Year(s) Of Engagement Activity | 2017 |
Description | Lecture at Univeriste Pierre et Marie Curie, Paris |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Lecture to postgraduate students, other researchers and prfoessional chemists on our research in electron transfer |
Year(s) Of Engagement Activity | 2017 |
Description | Lecture at Universite de Montpellier |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Lecture at Universite de Montpellier, principally to a postgraduate audience, on the discoveries arising from our research |
Year(s) Of Engagement Activity | 2017 |
Description | Lecture at Universite de Mulhouse |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Lecture at Universite de Mulhouse, principally to a postgraduate audience, on the discoveries arising from our research |
Year(s) Of Engagement Activity | 2017 |
Description | Lecture at Universitet Uppsala |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Lecture at Universitet Uppsala, Sweden, principally to a postgraduate audience, on the discoveries arising from our research |
Year(s) Of Engagement Activity | 2017 |
Description | Research Colloquium Imperial College, London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | 'Lecture to young chemists', Imperial College London |
Year(s) Of Engagement Activity | 2017 |
Description | Research Colloquium University of Sussex |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Visitor : Invited talk : Departmental Research colloquium. |
Year(s) Of Engagement Activity | 2013 |
Description | Research Colloquium at U Claude Bernard, Lyon |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Visitor : Invited talk : Deaprtmental Research colloquium . |
Year(s) Of Engagement Activity | 2015 |
Description | Research Colloquium at U Southampton |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Contributor : Invited talk : U Spouthampton |
Year(s) Of Engagement Activity | 2013 |