The Primary Phosphine Renaissance

Lead Research Organisation: Newcastle University
Department Name: School of Chemistry

Abstract

My research interests focus on novel organophosphorus compounds with applications in catalysis, materials and medicine. Our most recent breakthrough came with asymmetric primary phosphines; these contain a chiral carbon-based backbone attached to a phosphorus atom, which is also bonded to two hydrogens. In overly simplistic terms, we describe the phosphorus centre as also possessing a 'lone pair of electrons', through which it can bind to metals and behave as a ligand. The reactivity of the P-H bonds make them ideal starting materials for the synthesis of tertiary phosphines, a crucial class of ligand used in making products as diverse as mint flavourings and anti-Parkinson's drugs. However primary phosphines (unlike their nitrogen counterparts) have a fearsome reputation for being spontaneously flammable, occasionally explosive and often toxic; phenylphosphine is no longer sold in the UK by a major chemical manufacturer due to its hazardous nature. Primary phosphines are so reactive because they can form strong P=O bonds with dioxygen from the air. However the P-H bond is also highly reactive, which means we can convert these bonds into highly useful P-C, P-Cl, P-OR or P-N functionality with ease.Our research has discovered chiral primary phosphines which are air-stable, white solids. Of the very few known air-stable primary phosphines, sterics and negative hyperconjugation from a heteroatom (O or N) elsewhere in the molecule have been used to account for this stability. Our compounds often don't possess these features so another factor must be responsible for their stability; instead we have accumulated significant evidence to propose that increasing conjugation also leads to a greater resistance to oxidation.We have been fortunate enough to get some 'firsts'; an X-ray crystal structure of an optically pure primary phosphine; the first electrochemical study, which revealed that the removal of an electron is more difficult when the extent of conjugation is greater (the first step in P oxidation by aerobic oxygen); we were also the first to bubble dioxygen through bench chloroform solutions of our stable phosphines and found that they were still resistant to oxidation.To exploit these early findings we will elucidate the rules about what degree of conjugation in necessary to afford air-stability. If we lower the resonance stability by incorporating heteroatoms (whose p orbitals don't overlap so well with the pi system on the rings), do we see a breakdown in oxidative resistance? Can electron withdrawing groups similarly offer enhanced stability? We will use molecular modelling to understand and predict why the sensitivity to dioxygen is related to conjugation, and back this up with synthetic studies. We will also look beyond phosphorus to see if we can extend the principle of conjugative stabilisation to primary arsines, other hydrides and carbenes.Whilst we predict these properties for new molecules, we will also prepare new chiral ligands from these unique starting materials. We will synthesise new phosphonite, phospholane and phosphoramidite ligand libraries. Industry use sensitive primary phosphines in manufacturing important phosphine ligands; can we design safer variants with built in conjugation to reduce these hazards? Water-soluble phosphines will be made by hydrophosphination of formaldehyde to yield catalysts capable of operating under aqueous and biphasic conditions; the latter allows for the recovery of expensive, toxic transition metals from the products.We will also study low oxidation state rhenium coordination chemistry using phosphines built from the primary compounds. This is an understudied area of highly interesting chemistry as it allows us to make new imaging agents for disease. We will functionalise the phosphines with biomolecules and fluorescent tags and then substitute in radioactive technetium and rhenium isotopes (with our Oxford collaborators) to study in vitro and in vivo imaging.

Publications

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Bange CA (2016) Zirconium-catalyzed intermolecular hydrophosphination using a chiral, air-stable primary phosphine. in Dalton transactions (Cambridge, England : 2003)

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Davies L (2016) Air-stable fluorescent primary phosphine complexes of molybdenum and tungsten in Journal of Coordination Chemistry

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Davies LH (2012) Air-stable, highly fluorescent primary phosphanes. in Angewandte Chemie (International ed. in English)

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Davies LH (2014) Re and (99m)Tc complexes of BodP3--multi-modality imaging probes. in Chemical communications (Cambridge, England)

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Davies LH (2014) BR2BodPR2: highly fluorescent alternatives to PPh3 and PhPCy2. in Dalton transactions (Cambridge, England : 2003)

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Fairlamb, Ian J. S.; Lynam, Jason M.; Humphrey, M. G.; Cifuentes, Mariana; Liddle, Stephen W.; Higham, Lee; Wheatley, Andrew E. H.; Wright, Dominic S.; Layfield, Richard A.; O'Hara, Charles (2011) Organometallic Chemistry

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Fey N (2014) Setting P-Donor Ligands into Context: An Application of the Ligand Knowledge Base (LKB) Approach in Phosphorus, Sulfur, and Silicon and the Related Elements

 
Description Since starting the Fellowship the research group has; (i) developed a computational model capable of predicting which phosphines known and novel, will react violently in air and which will be air-stable; (ii) proposed a mechanism for the oxidation of phosphines by aerobic oxidation; (iii) shown that air-stable primary phosphines can be a gateway to previously inaccessible effective asymmetric phosphines for catalysis; (iv) developed the first fluorescent air-stable primary phosphines and are investigating their applications as dual- and triple-agents for disease imaging and (v) successfully began to expand the concept of air-stable primary phosphines beyond molecules with just one -PH2 group to two.

In 2005 an international review stated that 'the stability of these compounds is not understood'. In 2015, we were invited to write a review of the following decade's work in this area, as a result of our Fellowship publications. The research community now has a theoretical explanation for this air-stability, a computational model was developed by us to predict the stability of as yet unknown primary phosphines and we have published 16 papers, a review and 4 invited book chapters as a result and developed worldwide collaborations. Six such examples have been commercialised.

We have therefore demonstrated that air-stable primary phosphines can indeed be explained, predicted and be important gateway compounds to chiral catalysts for pharmaceutical building blocks and as precursors for new diseased cell imaging probes, which were the intended deliverables proposed from the Fellowship award.
Exploitation Route Our invited review of the field in 2015 underlines all the key findings from the research which was funded by the Fellowship. The LJH group joined PhoSciNet, the leading European consortium of phosphorus research chemists and we have disseminated our findings at a range of broad and narrow international conferences, in addition to the development of our own dedicated website where we discuss these findings.

As a result, the funded research has been broadcast to the community in a variety of ways, and international collaborative projects have already begun in fields as diverse as polymers, biomedicine, cluster chemistry and catalysis where researchers are beginning to get exposed to our findings and capitalise on them. Commercially available samples will also assist with their greater uptake which we hope to achieve in the near future.
Sectors Agriculture, Food and Drink,Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology,Security and Diplomacy

URL http://leejohnhighamresearch.co.uk/
 
Description The DFT model developed here: Stewart B, Harriman A, Higham LJ. Predicting the Air Stability of Phosphines. Organometallics 2011, 30(20), 5338-5343 allows the researcher to predict whether a known, or even unknown, phosphine will be air-stable or not. This has repercussions for health and safety and employee training in the Chemical Industry. The model has been used by one company to assist in their phosphine design. The compounds prepared by us and published here: https://www.thieme-connect.de/DOI/DOI?10.1055/s-0032-1316825 have been commercialised at http://aachem.co.uk/portfolio-item/dr-lee-higham/ with Fluorochem following an EPSRC Impact Acceleration Award.
First Year Of Impact 2011
Sector Chemicals,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description EPSRC Impact Acceleration Award
Amount £10,855 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 12/2017
 
Description Addition of a number of phosphines synthesised by us to the Ligand Knowledge Base (LKB) 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution We have prepared several new phosphine ligands
Collaborator Contribution Our ligands were added to the LKB which helps to forecast which type of catalysis the new ligands will be effective in
Impact Publication in the journal Phosphorus, Sulfur, Silicon and the Related Elements
Start Year 2013
 
Description Dalton Trans. 
Organisation Case Western Reserve University
Country United States 
Sector Academic/University 
PI Contribution Joint publication with Professor John Protasiewicz on using primary phosphines with potential optoelectronic applications.
Start Year 2011
 
Description Naphthoxaphospholes as examples of fluorescent phospha-acenes 
Organisation Case Western Reserve University
Department Department of Chemistry
Country United States 
Sector Academic/University 
PI Contribution My collaborator at Case Western used our molecular modelling to help explain some of the observations in his fluorescent systems.
Collaborator Contribution With the stability of the system accounted for, my collaborators studied the fluorescent properties of these molecules and their applications.
Impact Laughlin FL, Rheingold AL, Deligonul N, Laughlin BJ, Smith RC, Higham LJ, Protasiewicz JD. Naphthoxaphospholes as examples of fluorescent phospha-acenes. Dalton Transactions 2012, 41(39), 12016-12022.
Start Year 2012
 
Description Primary phosphines and their reactivity toward metal clusters 
Organisation Lund University
Department Department of Biochemistry and Structural Biology
Country Sweden 
Sector Academic/University 
PI Contribution We have prepared air-stable chiral primary phosphines which were reacted with iron clusters, and their electrocatalytic behaviour was established by our collaborators in Lund, Sweden
Collaborator Contribution The partners synthesised the clusters and carried out the catalytic testing
Impact The science was published in Dalton Transactions in 2017
Start Year 2012
 
Description SET for Britain Annual Research Exhibition at the Houses of Parliament 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Presentation of our work by my PhD student Laura Davies which resulted in her winning the 2012 silver medal for chemistry.
Year(s) Of Engagement Activity 2012
URL http://www.setforbritain.org.uk/2012event.asp