More Detail on Stable Phosphorus Centred Radicals Research
Stable radicals are of intense fundamental interest because they challenge conventional bonding concepts, and they are crucial in a variety of chemical, biological and medicinal applications, such as organic synthesis, polymer production, biological and medicinal EPR and materials science. Our primary goal is to synthesize novel stable radicals with significant unpaired electron population at phosphorus. The promising motifs will be tested in various applications (e.g. as spin labels). Our work benefits from close collaboration with physicists and biologists, who verify the potential of our new compounds in appropriate applications.
The synthesis of stable P centred radicals is not only highly topical, it is also very challenging. To date, no phosphorus centred radical stable enough to be compatible with biological conditions, has been reported in the literature.
Phosphorus Centred Radicals in Spin Labelling
Electron Paramagnetic Resonance (EPR) spectroscopy of site-directed spin labelled biomolecules is becoming a powerful tool for the study of the structure, dynamics, interaction and function of complex biological systems. High-field EPR in combination with site-specific spin labelling can provide detailed information on transient intermediates of proteins and other biomolecules while staying in their working states on biologically relevant time scales. A variety of structural and dynamics data can be obtained, e.g. information on specificity and directionality of transmembrane transfer processes in proteins, structure and dynamics of large molecular weight proteins in solution and potential changes of their mobility during biological processes, as well as fast conformational transitions of proteins and RNAs in solution, protein folding and re-folding (e.g. in the process of ion-channel formation).
Our goal in this context is the development of novel paramagnetic motifs, which will be superior to currently used spin labels. The nuclear magnetic prerequisites of phosphorus are very favourable for spin labelling. Phosphorus is monoisotopic (31P 100% natural abundance) and has spin 1/2. Moreover, 31P provides larger coupling anisotropy (direction-dependent character) than does the unpaired electron in a nitroxide N-O π* orbital. Phosphorus based spin labels have potential to open up major new opportunities in the understanding of fast chemical and biochemical processes and in improving the sensitivity and resolution of techniques to understand local structure around paramagnetic centres.
Dynamic Nuclear Polarisation (DNP) with Phosphorus Centred Radicals as Paramagnetic Agents
DNP is as a major NMR enhancement technique predicted to drive the NMR of tomorrow. Various experimental modifications exist to enhance signal intensities in NMR spectra using DNP, in all of them the diamagnetic sample is mixed with small quantity of stable radical, and the large polarization of the electron spins (achieved by microwave irradiation of the EPR spectrum at low temperature) is transferred to the nuclei in question (such as 13C or other nuclei of choice). DNP uses stable radicals, since its mechanism requires an unpaired electron. Currently, the TEMPO radical (or its modifications such as biradicals with two TEMPO-like spin labels attached to a rigid molecule) and trityl radicals are used to achieve hyperpolarization. Phosphorus centred radicals with large hyperfine coupling (comparable to Zeeman splitting of nuclei in question) are expected to make the hyperpolarization more efficient and their development is therefore highly desirable.
Syntheses of phosphorus centred radicals
Central to our effort is diminishing the chemical reactivity of the new motifs in order to make them compatible with biological conditions. The number of reports of stable and highly persistent phosphorus centred radicals has been accelerating consistently over last decade, however to synthesise a stable radical is still considered a significant achievement. The chemistry of stable and persistent phosphorus radicals is remarkable by the variety of means that can confer stability to radical centres; a large variety of electronic and steric effects have been employed to achieve inertness. Despite this variety, only a few fundamental classes are observed amongst stable and persistent P centred radicals. Perhaps the highest proportion of radicals is (traditionally well studied) phosphinyl radicals R2P. (1 – 6, see Figure 5). These include a vanadium redox couple resonance stabilised 1, push-pull (captodative) effect stabilised 2, phosphorus analogue of hydrazyl 3, a quinone derived anion radical 4, as well as 5 and 6 with bulky but flexible sterically protective shielding, conveniently described as jack in the box., 
Radicals with an unpaired electron localised predominantly in π P=C and P=P orbitals form a second fundamental class of phosphorus centred radicals. Neutral, cation radical and anion radical species, were generated from precursors containing low coordinate phosphorus atoms. The tetrakis(imidophosphate) radical is the only known stable λ5-P radical, though it is very reactive towards moisture and oxygen. The diphosphacyclobutenyl radical 7 (Scheme 1) is a phosphorus containing rather than a phosphorus centred radical, as very little spin density is present at the P atoms. 7 is however the most inert (air tolerant at r.t.) of all phosphorus containing radicals. No stable or significantly persistent phosphonyl R2P.(O), phosphoniumyl R3P.+ or phosphoranyl radicals R4P.+ have been reported recently.
Remarkably, all significantly stable radicals are π-type radicals, i.e. their unpaired electron is localised in π-geometry orbital often delocalised over several atoms. Other shared stabilizing features are (significant) steric protection, and many also have lone-pair rich nature (many n orbitals of similar energy to π orbitals).
Our medium term objective in this area is the design and selection of stable (biologically compatible) radical motifs with large spin density on the phosphorus atom(s), possessing favourable EPR characteristics for each of the techniques (such as maximum hyperfine coupling anisotropy or a very large magnitude of hyperfine coupling).
. In line with leading references (P. P. Power, Chem. Rev., 2003, 103, 789-809 and R. G. Hicks, Org. Biomol. Chem., 2007, 5, 1321-1338), stable radical indicates a species that can be isolated and shows no sign of decomposition under an inert atmosphere at room temperature, whereas a persistent radical has a relatively long lifetime under the conditions it is generated and can be observed by conventional spectroscopic methods, but cannot be isolated.
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