Nitroxide Radicals: Properties, Synthesis and Applications - Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds - page 198

O

N
O

N O

N
O

N
O

N

N
O

N
O

O

Proxyl Tempo

DBN TMIO

TMAO

Scheme 5.33 Nitroxides classified by increasing ease of reduction

reduction is the following: pyrrolidine (PROXYL) < pyrroline < acyclic (DBN) < isoindoline (TMIO)

azaphenalene (TMAO) (Scheme 5.33). The rate constant for the
pyrrolidine nitroxide radicals may be 30 to 40 times less than for similar piperidine nitroxide radicals.
Most nitroxides undergo reversible oxidation to the corresponding oxo-ammonium cation. The trend of
oxidation potentials is not the inverse of the trend for reduction potentials. Generally, the lowest oxidation
potentials are observed for the azaphenalene derivatives and the highest for the isoindoline derivatives.
Piperidine and pyrrolidine derivatives have intermediate oxidation potentials. Oxazolidine derivatives are
not easily oxidized due to the electro-withdrawing effect of the oxygen atom in the ring that destabilizes
the positive charge of the resulting oxo-ammonium cation.
As a general rule, the principal factor affecting the redox potentials of a nitroxide is the nature of the
ring. The substituents on the ring have a relatively small effect, except for azaphenalene-type nitroxides.
It can be assumed that the ability of nitroxides to be oxidized or reduced can be related to the flexibility
of the molecule, that is, how easily the nitrogen atom can be pyramidalized in the hydroxylamine and
planarized in the oxo-ammonium cation. It is also observed that changing the groups surrounding the
nitroxide moiety can have an effect on the oxidation and the reduction potentials. For instance, replacing
the methyl groups by ethyl or cyclohexyl groups in the isoindoline, imidazoline, or piperidine series led
to a decrease of the reduction rate by weak reductants. 173 - 175

piperidine (TEMPO) < oxazolidine <

5.6.3 Approaches to improve the resistance of nitroxides toward bioreduction
Nitroxides are interesting probes and reporters in biological systems. However, their reduction by biore-
ductants, such as ascorbate anion, thiols and enzymatic pools, has limited their use in vivo . To circumvent
this limitation, two approaches have been developed that are based on the synthesis of sterically hindered
nitroxides and on the inclusion of nitroxides into host molecules.
Replacing the methyl groups by ethyl or cyclohexyl groups in the isoindoline, 176 imidazoline, 177 or
piperidine 178 (Schemes 5.34 and 5.35) series led to a significant decrease of the reduction rate in in vitro
experiments, in blood or in liver homogenates.
In the late 1970s, Rassat et al . 179

reported the partial protection of TEMPO to ascorbate reduction by

adding β -cyclodextrin in the media. This approach has been successfully expanded to the spin trapping

O O

N

N O

N

N
O

N
O

O

Scheme 5.34 Sterically hindered nitroxides with improved resistance to bioreduction