Carboxylic acids as alternative electrophiles in ether synthesis
Lead Research Organisation:
University of Nottingham
Department Name: Sch of Chemistry
Abstract
Ethers are vital functional groups in organic chemistry and occur across a plethora of natural products as well as in solvents, polymers and fine chemicals. The agrochemical and pharmaceutical industries are particularly reliant on aryl ethers, which feature in around 35% of recently published library compounds.
Despite their abundance, only a select few reactions are can be used to synthesise ethers on a commercial scale. One of the most prolific is the Williamson ether synthesis, in which strong electrophiles such as an alkyl halide or pseudohalide is substituted by an alcohol. Whilst robust and high yielding, this procedure uses strong, stoichiometric bases and often requires less sustainable solvents such as DMF to minimise the competing elimination reaction. Additionally, alkyl halides are carcinogenic and are often made from corresponding alcohols in an additional step which reduces overall efficiency.
In the pursuit of more sustainable processes, reductive procedures have emerged as promising new strategies for heteroatom alkylation. In the context of ether synthesis, most method development has focussed on use of carbonyl-based electrophiles, however reactions involving ketones/aldehydes typically have a very limited substrate scope and a selective ester reduction requires an additional step to form the appropriate starting material.
This project aims to use carboxylic acids as electrophiles in a reductive variation of the Williamson ether synthesis. Similar strategies have recently been developed for amine synthesis, however despite the practicality of these methods, the oxygen analogue is far less explored. The key advantage of this methodology would replacement of alkyl halides with carboxylic acids, which are abundant, bench stable and inexpensive.
Despite their abundance, only a select few reactions are can be used to synthesise ethers on a commercial scale. One of the most prolific is the Williamson ether synthesis, in which strong electrophiles such as an alkyl halide or pseudohalide is substituted by an alcohol. Whilst robust and high yielding, this procedure uses strong, stoichiometric bases and often requires less sustainable solvents such as DMF to minimise the competing elimination reaction. Additionally, alkyl halides are carcinogenic and are often made from corresponding alcohols in an additional step which reduces overall efficiency.
In the pursuit of more sustainable processes, reductive procedures have emerged as promising new strategies for heteroatom alkylation. In the context of ether synthesis, most method development has focussed on use of carbonyl-based electrophiles, however reactions involving ketones/aldehydes typically have a very limited substrate scope and a selective ester reduction requires an additional step to form the appropriate starting material.
This project aims to use carboxylic acids as electrophiles in a reductive variation of the Williamson ether synthesis. Similar strategies have recently been developed for amine synthesis, however despite the practicality of these methods, the oxygen analogue is far less explored. The key advantage of this methodology would replacement of alkyl halides with carboxylic acids, which are abundant, bench stable and inexpensive.
Planned Impact
This CDT will have a positive impact in the following areas:
PEOPLE. The primary focus is people and training. Industry needs new approaches to reach their sustainability targets and this is driving an increasing demand for highly qualified PhD graduates to lead innovation and manage change in the area of chemicals production. CDT based cohort training will provide industry ready scientists with the required technical competencies and drive to ensure that the sector retains its lead position in both innovation and productivity. In partnership with leading chemical producers and users, we will provide world class training to satisfy the changing needs of tomorrow's chemistry-using sector. Through integrated links to our Business School we will maximise impact by delivering dynamic PhD graduates who are business aware.
ECONOMY. Sustainability is the major issue facing the global chemical industry. Not only is there concern for our environment, there is also is a strong economic driver. Shareholders place emphasis on the Dow Jones Sustainability Index that tracks the performances of the sector and engenders competition. As a result, major companies have set ambitious targets to lower their carbon footprints, or even become carbon neutral. GSK CEO Sir Andrew Witty states that "we have a goal to reduce our emissions and energy use by 45% compared with 2006 levels on a per unit sales basis... " Our CDT will help companies meet these challenges by producing the new chemistries, processes and people that are the key to making the step changes needed.
SOCIETY. The diverse range of products manufactured by the chemical-using industries is vital to maintain a high quality of life in the UK. Our CDT will have a direct impact by ensuring a supply of people and new knowledge to secure sustainability for the benefit of all. The role of chemistry is often hidden from the public view and our CDT will provide a platform to show chemical sciences in a positive light, and to demonstrate the importance of engineering and applications across biosciences and food science.
The "green and sustainable" agenda is now firmly fixed in the public consciousness, our CDT will be an exemplar of how scientists and engineers are providing solutions to very challenging scientific and technical problems, in an environmentally benign manner, for the benefit of society. We will seek sustainable solutions to a wide range of problems, whilst working in sustainable and energy efficient facilities. This environment will engender a sustainability ethos unique to the UK. The CNL will not only serve as a base for the CDT but also as a hub for science communication.
Public engagement is a crucial component of CDT activities; we will invite input and discussion from the public via lectures, showcases and exhibition days. The CNL will form a hub for University open days and will serve as a soft interface to give school children and young adults the opportunity to view science from the inside. Through Dr Sam Tang, public awareness scientist, we have significant expertise in delivering outreach across the social spectrum, and she will lead our activities and ensure that the CDT cohorts engage to realise the impact of science on society. Martyn Poliakoff, in his role as Royal Society Foreign Secretary, will ensure that our CDT dovetails with UK science policy.
KNOWLEDGE. In addition to increasing the supply of highly trained people, the results of the PhD research performed in our CDT will have a major impact on knowledge. Our student cohorts will tackle "the big problems" in sustainable chemistry, and via our industrial partners we will ensure this knowledge is applied in industry, and publicised through high level academic outputs. Our knowledge-based activities will drive innovation and economic activity, realising impact through creation of new jobs and securing the future.
PEOPLE. The primary focus is people and training. Industry needs new approaches to reach their sustainability targets and this is driving an increasing demand for highly qualified PhD graduates to lead innovation and manage change in the area of chemicals production. CDT based cohort training will provide industry ready scientists with the required technical competencies and drive to ensure that the sector retains its lead position in both innovation and productivity. In partnership with leading chemical producers and users, we will provide world class training to satisfy the changing needs of tomorrow's chemistry-using sector. Through integrated links to our Business School we will maximise impact by delivering dynamic PhD graduates who are business aware.
ECONOMY. Sustainability is the major issue facing the global chemical industry. Not only is there concern for our environment, there is also is a strong economic driver. Shareholders place emphasis on the Dow Jones Sustainability Index that tracks the performances of the sector and engenders competition. As a result, major companies have set ambitious targets to lower their carbon footprints, or even become carbon neutral. GSK CEO Sir Andrew Witty states that "we have a goal to reduce our emissions and energy use by 45% compared with 2006 levels on a per unit sales basis... " Our CDT will help companies meet these challenges by producing the new chemistries, processes and people that are the key to making the step changes needed.
SOCIETY. The diverse range of products manufactured by the chemical-using industries is vital to maintain a high quality of life in the UK. Our CDT will have a direct impact by ensuring a supply of people and new knowledge to secure sustainability for the benefit of all. The role of chemistry is often hidden from the public view and our CDT will provide a platform to show chemical sciences in a positive light, and to demonstrate the importance of engineering and applications across biosciences and food science.
The "green and sustainable" agenda is now firmly fixed in the public consciousness, our CDT will be an exemplar of how scientists and engineers are providing solutions to very challenging scientific and technical problems, in an environmentally benign manner, for the benefit of society. We will seek sustainable solutions to a wide range of problems, whilst working in sustainable and energy efficient facilities. This environment will engender a sustainability ethos unique to the UK. The CNL will not only serve as a base for the CDT but also as a hub for science communication.
Public engagement is a crucial component of CDT activities; we will invite input and discussion from the public via lectures, showcases and exhibition days. The CNL will form a hub for University open days and will serve as a soft interface to give school children and young adults the opportunity to view science from the inside. Through Dr Sam Tang, public awareness scientist, we have significant expertise in delivering outreach across the social spectrum, and she will lead our activities and ensure that the CDT cohorts engage to realise the impact of science on society. Martyn Poliakoff, in his role as Royal Society Foreign Secretary, will ensure that our CDT dovetails with UK science policy.
KNOWLEDGE. In addition to increasing the supply of highly trained people, the results of the PhD research performed in our CDT will have a major impact on knowledge. Our student cohorts will tackle "the big problems" in sustainable chemistry, and via our industrial partners we will ensure this knowledge is applied in industry, and publicised through high level academic outputs. Our knowledge-based activities will drive innovation and economic activity, realising impact through creation of new jobs and securing the future.
