Nitroxides

Nitroxides.—A new synthesis of several doxyl nitroxides from oxazolines has been described.  

Talkoxy/ benzoyloxy/ isopropoxycarbonyloxy, hydroxy/ thiyl/ phosphiny/ ) and more reactive carbon-ccntcrcd radicals 

Busfield and coworkers extended the technique to the study of less reactive carbon-centered radicals e.g. cyanoisopropyl) and short propagating radicals The very low concentration of nitroxide required to allow limited propagation was maintained by feeding with a syringe pump. 

The reaction between nitroxides and carbon-centered radicals occurs at near (but not at) diffusion controlled rates. Rate constants and Arrhenius parameters for coupling of nitroxides and various carbon-centered radicals have been determined. The rate constants (20 °C) for the reaction of TEMPO with primary, secondary and tertiary alkyl and benzyl radicals are 1.2, 1.0, 0.8 and 

5x 10 M s respectively. The corresponding rate constants for reaction of 115 are slightly higher. If due allowance is made for the afore-mentioned sensitivity to radical structure and some dependence on reaction conditions/ the reaction can be applied as a clock reaction to estimate rate constants for reactions between carbon-centered radicals and monomers or other substrates.  

Major advantages of this method over other trapping techniques are that typical conditions for solution/bulk polymerization can be employed and that a very wide range of initiating systems can be examined. The application of (he 

Quantitative nitroxide-trapping experiments should be carried out under thoroughly de-oxygenated conditions since oxygen will act as a competitive radical trap for carbon-centred radicals. Consequently, several freeze-thaw degassing cycles using pressures 10 3 mm Hg are usually required. 

In trapping experiments, nitroxides will only trap carbon-centred radicals, and not oxygen-centred ones. This is particularly important since oxygen-centred radicals are often used as initiators (Section 10.2). The nitroxide should also not undergo other reactions, such as addition to double bonds or H-abstraction this increases the probability that it will trap selectively carbon-centred radicals which act as chain carriers in many synthetically useful organic reactions, as propagating species in polymerisations and as reactive intermediates in biological pathways. 

The reaction between nitroxides and carbon-centered radicals occurs at near (but not at) diffusion controlled rates. Rate constants and Arrhenius parameters for coupling of nitroxides and various carbon-centered radicals have been determined.508 311 The rate constants (20 °C) for the reaction of TEMPO with primary, secondary and tertiary alkyl and benzyl radicals are 1.2, 1.0, 0.8 and 0.5x109 M 1 s 1 respectively. The corresponding rate constants for reaction of 115 are slightly higher. If due allowance is made for the afore-mentioned sensitivity to radical structure510 and some dependence on reaction conditions,511 the reaction can be applied as a clock reaction to estimate rate constants for reactions between carbon-centered radicals and monomers504 506 07312 or other substrates.20 

Nitroxides have the property of quenching fluorescence. Thus radical trapping with nitroxides containing fluorophores (e.g. 114) can be monitored by observing the appearance of fluorescence.511015 The method is highly sensitive and has been applied to quantitatively determine radical yields in PLP experiments (Section 

Various light-induced reactions including hydrogen atom abstraction, electron transfer and (3-scission occur under the influence of UV light. Certain 

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Figure Bl.15.14. Comparison of 95.1 GHz (A) and 9.71 GHz (B) EPR spectra for a frozen solution of a nitroxide spin label attached to insulin measured at 170 K.

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... 

Eor antioxidant activity, the reaction of aminyl radicals with peroxy radicals is very beneficial. The nitroxyl radicals formed in this reaction are extremely effective oxidation inhibitors. Nitroxides function by trapping chain-propagating alkyl radicals to give hydroxylamine ethers. These ethers, in turn, quench chain propagating peroxy radicals and in the process regenerate the original nitroxides. The cycHc nature of this process accounts for the superlative antioxidant activity of nitroxides (see Antioxidants). Thus, antioxidant activity improves with an increase in stabiUty of the aminyl and nitroxyl radicals. Consequendy, commercial DPA antioxidants are alkylated in the ortho and para positions to prevent undesirable coupling reactions. 

Nitroxyl radicals of diarylamines can also be obtained on oxidation with hydrogen peroxide in the presence of vanadium ions. Resonance helps stabili2e these radicals. Eor example, the nitroxide from 4,4 -dimethoxydiphenylainine [63619-50-1] is stable for years, whereas the radical from the unsubstituted diphenylamine caimot be isolated. Substitution in the ortho and para positions also increases the stabiUties of these nitroxides by inhibiting coupling reactions at these sites. However, they are not as stable as the stericaHy hindered tetramethylpiperidyl radical. 

Most of the LFRP research ia the 1990s is focused on the use of nitroxides as the stable free radical. The main problems associated with nitroxide-mediated styrene polymerizations are slow polymerization rate and the iaability to make high molecular weight narrow-polydispersity PS. This iaability is likely to be the result of side reactions of the living end lea ding to termination rather than propagation (183). The polymerization rate can be accelerated by the addition of acids to the process (184). The mechanism of the accelerative effect of the acid is not certain. 

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. 

Piperidine nitroxide ESR, 2, 143 <69JOP(50)2630) Piperidine)platinum(ll), cis-dichloro<7 -ethylene)-(2,6-dimethyl-X-ray, 2, 109 <80MI20406)... 

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... 

Dibenz[6, ejazepines conformation, 7, 499 11H-Dibenz[6, ejazepines oxidation, 7, 525 reduction, 7, 517 synthesis, 7, 532, 533 Dibenz[6,/]azepines N-acyl derivatives UV spectra conformation, 7, 499 mass spectrum, 7, 501 nitroxide... 

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. 

Many nitroxides are very stable under normal conditions, and heterolytic reactions can be carried out on other fimctional groups in the molecule without destroying the nitroxide group. Nitroxides are very useful in biochemical studies by virtue of being easily detected paramagnetic probes. ... 

Synthesis and applications of optically active cyclic nitroxides 98T667. 

Pyrazolylethynylphenylnitroxides 101-104 are quite stable in solid state as well as in solution at ambient temperature. They have typical 2-imidazoline nitroxide EPR spectra. Figures 4 and 5 illustrate the EPR spectra of nitroxides 101 and 102. 

The spectrum of radical 101 appears as a quintet (1 2 3 2 1) caused by the hyperfine interaction (HFI) with two equivalent nitroxide nitrogen nuclei (<2n = 0.74 mT), each line of the quintet being additionally split due to hyperfine... 

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. 

The first steps towards living radical polymerization were laken by Otsu and colleagues283 in 1982. In 1985, this was taken one step further with the development by Solomon et al.l0 of nitroxide-mediated polymerization (NMP). This work was first reported in the patent literature30 and in conference papers but was not widely recognized until 1993 when Georges et aL, applied the method in... 

Most radicals are transient species. They (e.%. 1-10) decay by self-reaction with rates at or close to the diffusion-controlled limit (Section 1.4). This situation also pertains in conventional radical polymerization. Certain radicals, however, have thermodynamic stability, kinetic stability (persistence) or both that is conferred by appropriate substitution. Some well-known examples of stable radicals are diphenylpicrylhydrazyl (DPPH), nitroxides such as 2,2,6,6-tetramethylpiperidin-A -oxyl (TEMPO), triphenylniethyl radical (13) and galvinoxyl (14). Some examples of carbon-centered radicals which are persistent but which do not have intrinsic thermodynamic stability are shown in Section 1.4.3.2. These radicals (DPPH, TEMPO, 13, 14) are comparatively stable in isolation as solids or in solution and either do not react or react very slowly with compounds usually thought of as substrates for radical reactions. They may, nonetheless, react with less stable radicals at close to diffusion controlled rates. In polymer synthesis these species find use as inhibitors (to stabilize monomers against polymerization or to quench radical reactions - Section 5,3.1) and as reversible termination agents (in living radical polymerization - Section 9.3). 

The identification of both phenylethyl and 1-phenyl-1,2,3,4-lelrahydronaphthalenyl end groups in polymerizations of styrene retarded by FeCl3/DMP provides the most compelling evidence for the Mayo mechanism.316 The 1-phenyl-1.2,3,4-tetrahydronaphthalenvl end group is also seen amongst other products in the TEMPO mediated polymerization of styrene,317318 However, the mechanism of formation of radicals 96 in this case involves reaction of the nitroxide with the Diels-AIder dimer (Scheme 3.63). The mechanism of nitroxide mediated polymerization is discussed further in Section 9.3.6. 

Nitrones arc generally more stable than nitroso-compounds and arc therefore easier to handle. However, the nitroxides formed by reaction with nitrones [e.g. phenyl /-butyl nitrone (109)]483 484 have the radical center one carbon removed from the trapped radical (Scheme 3.86). The LPR spectra are therefore less sensitive to the nature of that radical and there is greater difficulty in resolving and assigning signals. Nitrones are generally less efficient traps than nitroso-compounds.476... 

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