Organic radicals are typically unstable at ambient conditions. A molecule with an unpaired electron was once thought impossible until Moses Gomberg proved otherwise in 1900. The history of the discovery of organic radical is fascinating and worthwhile reading. The discovery has had significant, widespread impacts throughout many scientific disciplines. Today we know a lot more about organic radicals—how to design, synthesize and use them in various applications.
Our research focuses on the design and synthesis of organic radicals as building blocks for organic magnets, contrast agents for biomedical imaging and spin labels for biophysical studies. Each project has its own challenges.
The quest for organic magnets is one of the most challenging endeavors. We have successfully prepared a series of very high-spin organic molecules with the record spin quantum numbers (S) and reported the breakthrough first organic polymer with magnetic ordering. This achievement is the product of ingenious structural design and innovative experimental methods for efficient generation of the radicals. We overcame many obstacles, solving many difficult problems that forced us to come up with innovative approaches and sophisticated experimental methods for the synthesis and characterization of organic radicals. Our current objective is an organic polymer magnet that is stable and orders magnetically at ambient conditions – a tremendous challenge.
The challenges in the development of organic radical contrast agents (ORCAs) for MRI is the design and synthesis of radicals that possess combined properties of resistance to reduction in vivo, high water relaxivity, long shelf-life, and favorable pharmacokinetic profile. Nitroxides are among the most stable radical that have a wide range of applications in chemistry, biochemistry and biomedicine. However, in vivo applications of conventional nitroxides are rather limited, with a half-life (reduction plus excretion) of 2.1 ± 0.3 min in the mouse bloodstream. We design and synthesize new nitroxides that are resistant to in vivo reduction and devise a design strategy that exploit prior knowledge about dendrimers and PEGylation, particularly their applications to drug design, to prepare ORCAs with optimized MRI properties. We recently reported an i.v. injectable ORCA that has a long shelf‐life and provides enhanced MRI in mice for over 1 h. This result demonstrates that ORCA can be designed to have high relaxivity to provide high resolution images of mouse organs. Our current objective is ORCAs of a smaller molecular size that would undergo efficient renal filtration/excretion—another big challenge to maximize water relaxivity and solubility of small scaffold with limited surface functionalization.
The challenges in the development of new spin labels is the design and synthesize ultra-rigid, small-sized spin labels that would enable accurate, very long distance measurements by pulsed EPR at temperatures significantly above 77 K (boiling point of liquid nitrogen) and ultimately at physiological temperatures. We are developing novel nitroxides devoid of methyl groups in which steric protection of the radicals is achieved using rigid, ring structures to inhibit the dynamic effect and at the same time provide adequate stability of the radicals. Also, we are developing unnatural amino acid spin labels that are resistant to reduction by ascorbate. These labels have great potential for enabling the structure-function study of expressed proteins in biological environments.
There is plenty to write about all these challenges! A lot of the results have already been published, though some aspects are left out of scientific publishing. It may be interesting and useful to share here as blog posts on “behind the scene” and details technical challenges.
So, stop by soon to check these out!