Nitroxide, radicals

Although nitroxide radicals do not seem to exist in naturally biological systems, they are relatively non-toxic, and survive as such for considerable periods after administration. This property makes them important as spin-labels in biological systems, ESR spectroscopy being an ideal technique for studying their behaviour. However, in these studies their radical nature is not significant chemically it is the presence of an unpaired electron, and the remarkable stability of these species that is utilized. However, nitroxides can act as electron donors and acceptors, and we compare them here with ascorbate radicals (Section 1.4). 

The reason for the stability of nitroxides is 2-fold on the one hand, the unpaired electron is almost equally shared by nitrogen and oxygen (in a 7r -orbital). In the dimers [1.13] these electrons are forced into the N-N ir-bond, and the delocalization has to be overcome to do this. 

Hence the bonds are long and weak, and readily break. Also, all stable nitroxides, such as (Me3C)2 NO, have very bulky R-groups which 

This contrasts with the ascorbate system in which two ascorbate radicals give ascorbate + dehydroascorbate. 

Nevertheless, the ionization potential for R2NO radicals is quite low so they can act as e -donors, and they can also act as e--accep-tors, especially in the presence of proton donors which react to give R2N-OH molecules. (NB R2NO+ cations are isoelectronic with ketones and hence should be relatively stable. They can in principle add water to give R2N(OH)2+ or R2N(0H)0 derivatives.) 

The chemistry of nitroxide radicals has been extensively reviewed (e.g. Forrester et al., 1968 Rozantsev, 1970 Rozantsev and Scholle, 1971 Aurich and Heiss, 1976 Berliner, 1976 Keana, 1978). They are -radicals, the unpaired electron occupying a if orbital between the oxygen and nitrogen atoms [4]. Since there is also an N—O o-bond, and two electrons fill a -bonding orbital between these atoms, the effective N—O bond order is 1.5. The nitroxide function is frequently represented as a hybrid of the two structures [5a] and [5b]. The result of this electron delocalization is a relatively stable structure. An alternative view of the absence of any significant tendency 

The above description implies that the nitrogen centre is planar, but it is clear that in many nitroxides the energy required to introduce quite substantial pyramidal distortion is small (Lajzerowicz-Bonneteau, 1976). Nevertheless, the discussion in the following pages generally assumes planar nitrogen. 

The stability of nitroxides will be well known to readers acquainted with the spin-labelling technique (Berliner, 1976), but it must be recognized that nitroxides employed as spin labels or spin probes are almost invariably di-t-alkyl nitroxides. Diaryl and many aryl t-alkyl nitroxides are also sufficiently persistent to be isolated, and it has recently been shown that several acyl t-alkyl nitroxides can also be obtained pure (Perkins and Ward, 1973 Alewood et al., 1978). However, other nitroxides are less persistent. Monosubstituted nitroxides, RN(H)Q-, rapidly disproportionate to nitroso- 

The latter reaction frequently has negligible activation energy and an anomalously low pre-exponential factor (Adamic et al., 1971) such unusual kinetic behaviour may lead to dramatic changes in the relative concentrations 

In the spin-trapping context, diaryl or aryl t-alkyl nitroxides are effectively stable. Both, however, when present in very high concentrations, may decay slowly by a bimolecular process (10), provided that steric constraints do not twist the aryl group out of conjugation with the nitroxide function. In contrast, 

Accepting the enthalpy of dimerization for reaction 22 of ca 21 10 kJmol (an averaged value from results in two nonpolar solvents ) to apply to the gas phase. 

A casual perusal of the literature shows there are numerous measurements for the enthalpy of formation of monooximes. Table 2 presents available data. There is also a computational study of oximes. However, as is so often the case, there are more data than one thinks and less than one needs. 

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Figure Bl.16.16 shows an example of RTPM in which the radical species is TEMPO (10), a stable nitroxide radical, while the triplet state is produced by photoexcitation of benzophenone (11) [45].

Goudsmit G H and Paul H 1993 Time-resolved EPR investigation of triplet state Cgg. Triplet-triplet annihilation, CIDEP, and quenching by nitroxide radicals Chem. Phys. Lett. 208 73-8... 

The hterature suggests that more than one mechanism may be operative for a given antiozonant, and that different mechanisms may be appHcable to different types of antiozonants. All of the evidence, however, indicates that the scavenger mechanism is the most important. All antiozonants react with ozone at a much higher rate than does the mbber which they protect. The extremely high reactivity with ozone of/)-phenylenediamines, compared to other amines, is best explained by their unique abiUty to react ftee-tadicaHy. The chemistry of ozone—/)-PDA reactions is known in some detail (30,31). The first step is beheved to be the formation of an ozone—/)-PDA adduct (32), or in some cases a radical ion. Pour competing fates for dissociation of the initial adduct have been described amine oxide formation, side-chain oxidation, nitroxide radical formation, and amino radical formation. 

DL-Alk-2-enopyranos-4-uIose, 2,3-dideoxy-synthesis, 1, 426 Alkoxy nitroxide radicals pyridines ESR, 2, 146 Alkyl cyanides trimerization, 3, 503 Alkylating agents as pharmaceuticals, 1, 157 Alkylation... 

There are only a few fimctional groups that contain an unpaired electron and yet are stable in a wide variety of structural environments. The best example is the nitroxide group, and numerous specific nitroxide radicals have been prepared and characterized. The unpaired electron is delocalized between nitrogen and oxygen in a structure with an N—O bond order of 1.5. 

Nitroxides are iV, iV-disubsdnited nitric oxide radicals, the unpaired electron being delocalized between the nitrogen and oxygen The reduction of 2-methyl-2-nitropropane with sodium or electrochemically yields di-r-butyl nitroxide as the final product " Such nitroxide radicals are important for the snidy of a organic ferromagnet... 

Adding a radical trap like BulNO to the reaction mixture this reacts with radicals (R ) forming nitroxide radicals Bul(R )NO that can be detected by ESR. 

N-Alkoxylamines 88 are a class of initiators in "living" radical polymerization (Scheme 14). A new methodology for their synthesis mediated by (TMSlsSiH has been developed. The method consists of the trapping of alkyl radicals generated in situ by stable nitroxide radicals. To accomplish this simple reaction sequence, an alkyl bromide or iodide 87 was treated with (TMSlsSiH in the presence of thermally generated f-BuO radicals. The reaction is not a radical chain process and stoichiometric quantities of the radical initiator are required. This method allows the generation of a variety of carbon-centered radicals such as primary, secondary, tertiary, benzylic, allylic, and a-carbonyl, which can be trapped with various nitroxides. 

There is some evidence in favor ° of the captodative effect, some of it is from ESR studies. However, there is also experimental and theoretical evidence against it. There is evidence that while FCH2 and p2CH are more stable than CH3, the radical Cp3- is less stable that is, the presence of the third F destabilizes the radical. " Certain radicals with the unpaired electron not on a carbon are akso very stable. Diphenylpicrylhydrazyl is a solid that can be kept for years. We have already mentioned nitroxide radicals. Compound 29 is a nitroxide radical so stable that reactions can be performed on it without affecting the unpaired electron (the same is true for some of the chlorinated triarylmethyl radicals mentioned above ). ot-Trichloromethylbenzyl(rer/-butyl)aminoxyl (30) is extremely stable. In... 

Despite the usual loss of optical activity noted above, asymmetric radicals can be prepared in some cases. For example, asymmetric nitroxide radicals are known. An anomeric effect was observed in alkoxy radical (31), where the ratio of 31a/31b was 1 1.78. ... 

Small amounts of cyclized products are obtained after the preparation of Grignard reagents from 5-hexenyl bromide.9 This indicates that cyclization of the intermediate radical competes to a small extent with combination of the radical with the metal. Quantitative kinetic models that compare competing processes are consistent with diffusion of the radicals from the surface.10 Alkyl radicals can be trapped with high efficiency by the nitroxide radical TMPO.11 Nevertheless, there remains disagreement about the extent to which the radicals diffuse away from the metal surface.12... 

The following reaction illustrates conversion of a nitroxide radical-bearing alcohol by CDI and azide ion to a spin-labeled ester of azido formic acid, which is used for the labeling of amino acids, giving carbamates [137]... 

Figure 5. Nitroxide radicals and their SOMO (a) nitronyl nitroxide and (b) imino nitroxide.

Spin density in interacting nitronyl nitroxide radicals... 

The presence of /3-hydrogen in the nitroxide radical may lead to disproportionation reactions. In spin-trapping experiments, N-t-butyl-a-phenyl nitrone yields rather unstable spin adducts. This type of radical can be stabilized by coordination to Nin. The Ni11 complex with N-oxy-A-r-butyl-(2-pyridyl)phenylmethanamine (923) reveals a distorted octahedral geometry with antiferromagnetic interactions between the unpaired electrons of the metal ion and the radical spins.00... 

The X-ray structure of zinc naphthalocyanate has been determined with Zn—N bond lengths of 1.983(4) A.829 Pentanuclear complexes with a zinc phthalocyanine core and four ruthenium subunits linked via a terpyridyl ligand demonstrate interaction between the photoactive and the redox active components of the molecule. The absorbance and fluorescence spectra showed considerable variation with the ruthenium subunits in place.830 Tetra-t-butylphthalocyaninato zinc coordinated by nitroxide radicals form excited-state phthalocyanine complexes and have been studied by time-resolved electron paramagnetic resonance.831... 

The nitroxide radical (from processes 5 and 6 and attack by other radicals on the parent piperidine) is found in photo-oxidizing PPH samples in concentrations of M. x 10 M (initial piperidine level 5 x 10-3M) up to the embrittlement point of the PPH film (7.). Nitroxides are well known to scavenge carbon centered radicals (but not peroxyl radicals) in both polymers and liquid alkanes (reaction 7) (10, 8). In the liquid phase k7 is... 

Interaction of the nitroxide radical and this powerful oxidant was very... 

Various hybrid compounds comprised of two types of nitroxide radicals and either a pentamethine (Cy5) or trimethine cyanine (Cy3) were synthesized by Sato and co-workers [32]. These compounds seem to be promising fluorescent chemo-sensors for the measurement of reducing species such as Fe2+, ascorbic acid, and hydroxyl radicals. 

Sato S, Tsunoda M, Suzuki M, Kutsuna M, Takido-uchi K, Shindo M, Mizuguchi H, Obara H, Ohya H (2009) Synthesis and spectral properties of polymethine-cyanine dye-nitroxide radical hybrid compounds for use as fluorescence probes to monitor reducing species and radicals. Spectrochim Acta A 71 2030-2039... 

When the lifetime of the radicals is very short and direct ESR detection is not an option, spin trapping is used to detect radicals at ambient temperatures. The method is based on the scavenging of radicals, P, by a spin trap, leading to the formation of a spin adduct with higher stability in most cases, this adduct is a nitroxide radical. 

In microphase-separated systems, ESR spectra may consist of a superposition of two contributions, from nitroxides in both fast and slow-tumbling regimes. Such spectra provide evidence for the presence of two types of domains with different dynamics and transition temperatures. This case was detected for a HAS-derived nitroxide radical in heterophasic polyfacrylonitrile-butadiene-styrene) (ABS) as shown in Figure 5, the fast and slow components in the ESR spectrum measured represent nitroxide radicals located in butadiene-rich (B-rich) and styrene/acrylonitrile-rich (SAN-rich) domains, respectively [40]. These two components were determined by deconvoluting the ESR spectrum of HAS-NO measured at 300 K. 

Figure 4 ESR of nitroxide radicals (a) Molecular axes of the nitroxide (b) ESR spectra of oriented nitroxide radicals, with the molecular axes x, y, and z along the external magnetic field, respectively and (c) ESR spectra of randomly oriented nitroxide radicals motionally averaged (upper) and rigid limit (lower) regimes.

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