Chiral Concepts in s-Block Metal Amide Chemistry

Lead Research Organisation: University of Strathclyde
Department Name: Pure and Applied Chemistry

Abstract

Organolithium reagents (i.e., compounds that contain a direct bond between a lithium and a carbon atom) are extremely important reagents in chemical synthesis. It has been estimated that 95% of all pharmaceuticals rely upon the use of these cornerstone reagents at some point in their preparation. In general, organolithium compounds are very reactive; however, this is sometimes coupled with the compounds exhibiting a lack of selectivity even when the reactions are carried out at very low, cryogenic temperatures. This is a massive hurdle to the synthetic chemist! To overcome this situation, less reactive, but more selective compounds [such as organomagnesium (e.g., Grignard) or organozinc (e.g., Reformatsky) reagents] are often used; however, these reagents are often too inert. Recent research has shown that by combining a lithium reagent with a magnesium (or zinc) one, a whole new and in many cases surprising chemistry can be produced. Fascinatingly, in these cases the reactivity cannot be replicated using the monometallic compounds on their own!

Another important theme of this work is the generation of organic molecules (i.e., molecules which contain no metal atoms) which can be used as building blocks for key pharmaceuticals. Just as human beings have a left and a right hand, certain organic molecules (known as chiral compounds) can also be considered left- or right-handed. In medicine, it is common that only one handed form of an organic molecule has the required therapeutic effect; it is also usual for the other handed form to induce nasty side effects. Therefore it is critical that the synthetic chemist can easily produce only one handed form of a specific organic compound. In chemistry this is known as enantioselective synthesis.

This research will systematically investigate the two aforementioned topics and combine them for the first time - that is enantioselective synthesis using alkali metal-magnesium or alkali metal-zinc complexes. During the first part of this research many new mixed-metal compounds which contain chiral molecules will be prepared. Various analytical techniques will be used to determine their structure, both in solution and in the solid state. Then a systematic study of how these compounds react with organic molecules will be conducted.

It is envisaged that in the near future these new "bimetallics" will be used to complement the well known organolithium reagents that presently corner the market in the pharmaceutical industry.

Another area which will be explored is the chemistry of alkali metal amides. Despite their widespread usage, the structural chemistry of alkali metal amides and their complexes continues to spring many fascinating surprises. We have recently observed that molecular rings of various sizes - consisting only of alkali metal cations and amide anions - can capture anions (such as hydroxide and chloride) in the presence of chiral diamine ligands. This new direction in s-block macrocyclic chemistry turns conventional crown ether chemistry on its head and opens the door for simple alkali metal amide/diamine compositions to be utilised in anion recognition chemistry.

Results from this new direction within synergic chemistry will undoubtedly appeal to a broad spectrum of academics, including inorganic, organometallic and organic chemists, as well as to supramolecular chemists due to the strong structural and coordination chemistry nature of the area. This new methodology in enantioselective synthesis will also be of considerable interest to researchers in the chemical industry (fine chemicals, pharmaceutical, agrochemical etc.) who strive to produce chiral molecules (new and old!) in a facile manner.

Planned Impact

Variety of academics including those in coordination, inorganic, organometallic, organic and materials chemistry fields

Industrial chemists who utilise metallation, i.e. those involved in pharmaceuticals, perfumery, agrochemicals and fine chemicals industries

Ultimately, general public when new technology is implemented by the aforementioned industries

Full details are provided in the Pathways to Impact document.

Publications

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Armstrong DR (2013) Evaluating cis-2,6-dimethylpiperidide (cis-DMP) as a base component in lithium-mediated zincation chemistry. in Chemistry (Weinheim an der Bergstrasse, Germany)

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Francos J (2016) Synthetic and reactivity studies of hetero-tri-anionic sodium zincates. in Dalton transactions (Cambridge, England : 2003)

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Francos J (2014) Complexity in seemingly simple sodium magnesiate systems. in Dalton transactions (Cambridge, England : 2003)

 
Description Through the award of this Fellowship, we have discovered that mixed metal compounds can be used to perform enantioselective reactions at temperatures approaching ambient. Normally these reactions, which produce a left or right handed form of a molecule, are performed using single metal compounds but at temperatures as low as -100°C - temperatures which have a high energy cost to industry.

We have also produced a whole host of new alkali metal compounds which incorporate common salts such as sodium chloride. These studies show that these salts, commonly viewed as innocent bystanders, can greatly affect the structural chemistry (and hence reactivity) of important metal reagents.

Finally, this project laid the foundations for the discovery of a new general metallation protocol which was explored more fully in EP/L001497/1
Exploitation Route Through this Fellowship, the Principal Investigator has established a new international collaboration with Professor Philippe Gros (Nancy, France), a synthetic organic chemist, to further investigate the use of bimetallic reagents in deprotonative and metal-halogen exchange chemistries. It is highly likely that the results garnered from future studies from the marriage of our organic/inorganic synthetic investigations will be of great interest to the synthetic chemistry community and will be utilised by them in the near future.
Sectors Chemicals

 
Title Monodentate coordination of the normally chelating chiral diamine (R,R)-TMCDA 
Description The data set contains a MS word document containing X-ray and NMR data as well as synthetic protocols. In addition X-ray files are included 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact Not Applicable 
 
Title Structural studies of cesium, lithium/cesium and sodium/cesium bis(trimethylsilyl)amide (HMDS) complexes 
Description The data set contains two MS word documents containing supplementary information (one for X-ray crystallographic data, the other NMR spectroscopic data) and supports the related research publication. In the paper a new method for preparing CsHMDS is reported. In addition, the structures and syntheses of two polymeric mixed alkali metal HMDS complexes are detailed. Finally, the structural chemistry (solid- and solution-state) of CsHMDS with different multidentate donors is described. 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact n/a 
 
Title Templated Deprotonative Metalation of Polyaryl Systems: Facile Access to Simple, Previously Inaccessible Multi-iodoarenes 
Description "MS Word document containing supplementary information on X-ray and NMR (Nuclear Magnetic Resonance) data for all compounds in the related paper. Data embargo until 24/11/17" 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact Not Applicable 
 
Description Philippe Gros 
Organisation University of Lorraine
Country France 
Sector Academic/University 
PI Contribution First paper published in Organometallics. My team carried out the synthetic work, helped compose project and drafted the initial manuscript.
Collaborator Contribution Had constructive meetings both at Strathclyde and Nancy with Philippe Gros. During these meetings, Philippe helped shape the directions of the project, suggesting particular molecules to focus our attention on.
Impact Organometallics 2015, 34, 2550-2557
Start Year 2014
 
Description Project partnership with Astra Zeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Astra Zeneca worked with the research team and assisted/contributed to the project outcomes
Start Year 2011