Nickel Catalysis
Lead Research Organisation:
University of Strathclyde
Department Name: Pure and Applied Chemistry
Abstract
Nickel often has quite different reactivity to palladium (Figure 1). Nickel will react with a wide range of electrophiles, enlarging the scope of possible substrates and introducing opportunities for orthogonal synthesis; it is less prone to undergo B-hydride elimination, allowing the use of alkyl coupling partners. Despite the opportunities promised by this enhanced reactivity, the toxicity of nickel and the familiarity of robust palladium-catalysed methods can hamper the uptake of nickel catalysis in the pharmaceutical industry. The FDA limit for nickel in pharmaceuticals is slightly higher than for palladium (20 ppm versus 10 ppm), despite the slightly higher oral toxicity of nickel. The recycling of palladium can be cost-effective, whereas nickel is too cheap to warrant recycling. The promise of nickel catalysis lies in new reactions and/or new feedstocks, rather than as a direct competitor to palladium; the detailed understanding of mechanism, selectivity, and structure/activity relationships is essential to achieving these aims.
Various aryl electrophiles have been used in cross-coupling (including many phenol derivatives), but alkyl alcohol derivatives are underexplored. Chlorides, bromides, and tosylates have been used but can also be employed in palladium catalysis (with specific ligands); for other alcohol derivatives, most examples are limited to reactions at a benzylic site, while many conditions do not lead to reaction with functional groups such as pivalate. This project will quantify the reactivity of Ni0 with these underexploited substrates, generating information about fundamental reactivity that will lead to new catalytic reactions. In addition, the practical aspects of removing nickel from the product will be considered using robust analytical methods.
Nickel catalysis can enable the cross-coupling of sp3-centres to build the drug molecules of the future, moving away from flat and aromatic systems. However, our mechanistic understanding of these processes is incomplete, and there are concerns about the toxicological implications of nickel. This project will address the challenges of deploying exciting nickel-catalysed procedures in the synthesis of pharmaceuticals by: (i) conducting detailed kinetic studies of the oxidative addition of alkyl halides to Ni0, (ii) studying deleterious B-hydride elimination processes, and (iii) quantifying the levels of nickel present in reaction mixtures after workup and purification.We elucidated - using techniques such as EPR spectroscopy - that all of these reactions lead to NiI products; we proposed a mechanism for the formation of NiI from Ni0 based on mechanistic and kinetic studies, including low temperature NMR spectroscopy. The next stage of our research programme is to quantify the reactivity of other ligands and other substrates, because this works towards a 'users guide' to catalyst selection for different applications based on rate data, decreasing the need for the screening of large numbers of reaction conditions.
Various aryl electrophiles have been used in cross-coupling (including many phenol derivatives), but alkyl alcohol derivatives are underexplored. Chlorides, bromides, and tosylates have been used but can also be employed in palladium catalysis (with specific ligands); for other alcohol derivatives, most examples are limited to reactions at a benzylic site, while many conditions do not lead to reaction with functional groups such as pivalate. This project will quantify the reactivity of Ni0 with these underexploited substrates, generating information about fundamental reactivity that will lead to new catalytic reactions. In addition, the practical aspects of removing nickel from the product will be considered using robust analytical methods.
Nickel catalysis can enable the cross-coupling of sp3-centres to build the drug molecules of the future, moving away from flat and aromatic systems. However, our mechanistic understanding of these processes is incomplete, and there are concerns about the toxicological implications of nickel. This project will address the challenges of deploying exciting nickel-catalysed procedures in the synthesis of pharmaceuticals by: (i) conducting detailed kinetic studies of the oxidative addition of alkyl halides to Ni0, (ii) studying deleterious B-hydride elimination processes, and (iii) quantifying the levels of nickel present in reaction mixtures after workup and purification.We elucidated - using techniques such as EPR spectroscopy - that all of these reactions lead to NiI products; we proposed a mechanism for the formation of NiI from Ni0 based on mechanistic and kinetic studies, including low temperature NMR spectroscopy. The next stage of our research programme is to quantify the reactivity of other ligands and other substrates, because this works towards a 'users guide' to catalyst selection for different applications based on rate data, decreasing the need for the screening of large numbers of reaction conditions.
People |
ORCID iD |
David Nelson (Primary Supervisor) | |
Megan Greaves (Student) |
Publications
Greaves ME
(2020)
Unexpected Nickel Complex Speciation Unlocks Alternative Pathways for the Reactions of Alkyl Halides with dppf-Nickel(0).
in ACS catalysis
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
EP/R512114/1 | 01/10/2017 | 31/12/2022 | |||
1959228 | Studentship | EP/R512114/1 | 01/10/2017 | 30/09/2021 | Megan Greaves |
Description | The formation of carbon-carbon bonds which is instrumental for modern day life (pharmaceuticals, agriculture, cosmetics etc) using a nickel catalyst. As opposed to a palladium catalyst which is now described as a precious metal and therefore has a much higher price when compared to nickel. Palladium is likely to run out within the next few decades and therefore an alternative is necessary for these reactions once palladium can no longer be sourced. The mechanism of these carbon-carbon bond forming reactions has been elucidated. Meaning that specific class of reactions are now better understood than ever before meaning it is easier to optimise these reactions in the future, to give higher yielding reactions. |
Exploitation Route | The outcomes may be used both in industry and academia. The results will be built upon in the same group at the University of Strathclyde to ensure reactions are optimised correctly. Eventually, with optimised conditions, industry may turn to nickel catalysis to replace palladium and this work may be used to help optimise their reactions. |
Sectors | Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology |
Description | AstraZeneca Case Studentship |
Amount | £108,000 (GBP) |
Organisation | AstraZeneca |
Sector | Private |
Country | United Kingdom |
Start | 10/2017 |
End | 09/2021 |
Description | Dial-a-Molecule Summer School 2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Summer school for postgraduates to learn about novel technologies in chemistry |
Year(s) Of Engagement Activity | 2019 |
URL | https://generic.wordpress.soton.ac.uk/dial-a-molecule/summerschool19/ |
Description | Inorganic Reaction Mechanisms-Inorganic Biochemistry joint Discussion Group Meeting 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Discussion group from two areas of chemistry. Postgraduates and academics involved in debates and discussion about presented work both orally and posters. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.rsc.org/events/detail/36681/inorganic-reaction-mechanisms-inorganic-biochemistry-joint-d... |
Description | Mechanistic processes in organometallic chemistry Faraday Discussion 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | The aim of this meeting is to spark discussion about own work and pre-print paper from/with academics from across the globe |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.rsc.org/events/detail/29947/mechanistic-processes-in-organometallic-chemistry-faraday-di... |
Description | RSC Physical Organic Chemistry Postgraduate Meeting 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | This meeting is designed for postgraduate students to share their research amongst other postgraduates to spark discussion |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.rsc.org/events/detail/34913/rsc-physical-organic-chemistry-postgraduate-meeting-2018 |
Description | RSc Scottish Organic Meeting 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | Aim of the meeting is to share research with postgraduates and academics to spark discussion/ideas around our work |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.rsc.org/events/detail/30094/46th-scottish-regional-meeting-of-the-rsc-organic-division-2... |