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.
People |
ORCID iD |
Lee Higham (Principal Investigator) |
Publications
Abdel-Magied A
(2017)
Synthesis and characterization of chiral phosphirane derivatives of [(µ-H)4Ru4(CO)12] and their application in the hydrogenation of an a,ß-unsaturated carboxylic acid
in Journal of Organometallic Chemistry
Bange C
(2016)
Zirconium-Catalyzed Alkene Hydrophosphination and Dehydrocoupling with an Air-Stable, Fluorescent Primary Phosphine
in Inorganics
Bange CA
(2016)
Zirconium-catalyzed intermolecular hydrophosphination using a chiral, air-stable primary phosphine.
in Dalton transactions (Cambridge, England : 2003)
Clarke E
(2011)
The synthesis of P-stereogenic MOP analogues and their use in rhodium catalysed asymmetric addition
in Journal of Organometallic Chemistry
Davies L
(2014)
B R 2 BodPR 2 : highly fluorescent alternatives to PPh 3 and PhPCy 2
in Dalton Trans.
Davies L
(2014)
Organometallic Chemistry - Volume 39
Davies L
(2016)
Air-stable fluorescent primary phosphine complexes of molybdenum and tungsten
in Journal of Coordination Chemistry
Davies LH
(2012)
Air-stable, highly fluorescent primary phosphanes.
in Angewandte Chemie (International ed. in English)
Davies LH
(2014)
Re and (99m)Tc complexes of BodP3--multi-modality imaging probes.
in Chemical communications (Cambridge, England)
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
Fey N
(2015)
Setting P-Donor Ligands into Context: An Application of the Ligand Knowledge Base (LKB) Approach
in Phosphorus, Sulfur, and Silicon and the Related Elements
Ficks A
(2013)
Chiral MOP-phosphonite ligands: synthesis, characterisation and interconversion of ?1,?6-(s-P, p-arene) chelated rhodium(I) complexes.
in Dalton transactions (Cambridge, England : 2003)
Ficks A
(2012)
MOP-phosphonites: a novel ligand class for asymmetric catalysis.
in Dalton transactions (Cambridge, England : 2003)
Ficks A
(2011)
Taming functionality: easy-to-handle chiral phosphiranes.
in Chemical communications (Cambridge, England)
Ficks A
(2014)
Air-Stable Chiral Primary Phosphines: A Gateway to MOP Ligands with Previously Inaccessible Stereoelectronic Profiles
in Organometallics
Fleming J
(2015)
Primary phosphine chemistry
in Coordination Chemistry Reviews
Fleming J
(2017)
Coinage Metal Complexes of Phosphonite Analogues of 2-Diphenylphosphino-1,1'-binaphthyl (H-MOP) and 2-Diphenylphosphino-2'-methoxy-1,1'-binaphthyl (MeO-MOP)
in European Journal of Inorganic Chemistry
Fleming JT
(2016)
A comparison of MOP-phosphonite ligands and their applications in Rh(i)- and Pd(ii)-catalysed asymmetric transformations.
in Dalton transactions (Cambridge, England : 2003)
Fleming JT
(2016)
The design of second generation MOP-phosphonites: efficient chiral hydrosilylation of functionalised styrenes.
in Dalton transactions (Cambridge, England : 2003)
Hiney R
(2011)
Organometallic Chemistry
Laughlin FL
(2012)
Naphthoxaphospholes as examples of fluorescent phospha-acenes.
in Dalton transactions (Cambridge, England : 2003)
Nigam S
(2016)
Structurally optimised BODIPY derivatives for imaging of mitochondrial dysfunction in cancer and heart cells.
in Chemical communications (Cambridge, England)
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 | Public |
Country | United Kingdom |
Start | 09/2016 |
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 |