Understanding Primary Phosphines

Unique, Air-Stable Phosphines for Catalysis and Imaging

Despite their value as essential synthetic precursors, primary phosphines retain a fearsome reputation in the mind of many an organic chemist. The same features that make them essential starting materials for the synthesis of ligands, catalysts, drug molecules, polymers and macrocycles, are also responsible for their more troublesome properties. The P-H bond is extremely reactive and a primary phosphine has two of them! While the bonds are easily substituted to make otherwise inaccessible materials, they are also often prone to rapid oxidation. These phosphines rapidly form stable P=O bonds and can even over oxidise to phosphoric acids. In the case of smaller molecules particularly, this leads to a class of compounds with the winning combination of volatility, toxicity, noxious scents and a tendency to pyrophoricity. No wonder they are considered difficult to handle.

Primary phosphines with increasing steric hindrance and therefore increasing oxidative stability

Primary phosphines that avoid these pitfalls do exist though! Traditionally created through heavy substitution close to the phosphorous atom: large groups shield the reactive centre from oxygen, slowing degradation, but also make further functionalisation difficult, limiting their use.

Accessible and Useful Primary Phosphines

More recently, electronics rather than sterics, have been identified as a method of stabilising phosphines. Researchers in the Higham Group at Newcastle University discovered that crystalline chiral primary phosphines with a binapthyl backbone were stable in air indefinitely. Hypothesising that extended π-conjugation reduces the relative contribution of phosphorous to the highest occupied molecular orbital (HOMO), lowering its reactivity to oxidation, they developed a computational model to rationalise primary phosphine stability. Recognising that inclusion of heteroatoms also reduced the rate of oxidation, likely by raising the energy of the singly occupied molecular orbital (SOMO) of the radical cation intermediate, they were able to use DFT calculations to consider both the HOMO and SOMO and create novel air-stable primary phosphines.

Through these studies, both air-stable chiral phosphines, suitable for the creation of asymmetric catalysts, and fluorescent primary phosphines, capable of multimodal imaging, are available.

Chiral Phosphines, Phosphiranes and Phosphonites Available

Now, a range of chiral phosphorous-based ligands, including MOP ligands, are accessible through a multigram synthesis of the atropisomeric binapthyl precursors. (S)-P_1° and (R)-P_1°OMe can be readily converted into a range of ligands, offering fine control over the sterics and electronics of the resultant metal complex. These BINAP derivatives are easily obtained through one-pot reactions and a number of ligand test kits are available. Like their parent compounds, these ligands show interesting properties. The phosphirane compounds ((S)-PX and (R)-PXOMe) are indefinitely air stable and withstand refluxing in toluene. Previously reported phenylphosphiranes decompose above 0 °C.

Ligands with tunable electronic properties suitable for hydrosilylation reactions

BODIPY-based Primary and Tertiary Phosphines for Cell Imaging

The understanding that extended π-systems and heteroatoms lead to more stable phosphines inspired a range of fluorescent primary phosphines. Based on the BODIPY structure, prized in biological research, these compounds have high predicted SOMO energies. In practice, they last more than a week in air without signs of oxidation, despite a totally unencumbered phosphorous atom. The dimethyl analogue PBodMe shows particularly desirable photophysical properties: λ_abs = 512 nm, λ_em = 526 nm, ε = 79,000 M⁻¹ cm⁻¹ , Φ = 0.33 in THF at room temperature.

Fluorescent phosphorous ligands and complexes derived from air-stable primary phosphines

With an unhindered phosphorous, these BODIPYs are easily converted into a range of ligands, suitable for complexation with metals relevant to biological imaging. For example, reaction with vinyldiphenylphosphine produces the tridentate ligand BodP₃, which retains its convenient fluorescent properties when complexed with metals such as Re and ^99mTc. The former has been used to image prostate carcinoma cells and the latter combines the functionality of an in vitro fluorescent probe with an in vivo SPECT radio-imaging agent.

For more information on using these, or related compounds, please get in touch or contact Lee Higham.

1. James T. Fleming, Lee J. Higham, Primary phosphine chemistry, Coordination Chemistry Reviews, 297–298, 2015, 127-145
2. Arne Ficks, William Clegg, Ross W. Harrington, Lee J. Higham, Air-Stable Chiral Primary Phosphines: A Gateway to MOP Ligands with Previously Inaccessible Stereoelectronic Profiles, Organometallics 2014, 33, 22, 6319–6329
3. Laura H. Davies, Beverly Stewart, Ross W. Harrington, William Clegg, Lee J. Higham, Air-Stable, Highly Fluorescent Primary Phosphanes, Angewandte Chemie International Edition, 2012, 51, 20, 1433-7851
4. Laura H. Davies,  Benjamin B. Kasten, Paul D. Benny,  Rory L. Arrowsmith, Haobo Ge, Sofia I. Pascu,  Stan W. Botchway, William Clegg, Ross W. Harrington,  Lee J. Higham, Re and ^99mTc complexes of BodP₃ – multi-modality imaging probes, eChem. Commun., 2014, 50, 15503-15505