Stable and Persistent Free Radicals

Crystalline substance is not rapidly attacked by oxygen, although solutions are air sensitive the compound is stable to high temperature in the absence of oxygen. 

Stable in solution for days, even in the presence of air. Indefinitely stable in solid state. Thermally stable up to 300 C. 

Stable to oxygen stable to extended storage as a solid. Slowly decomposes in solution. 

Entry 3 has only alkyl substituents and yet has a significant lifetime in the absence of oxygen. The tris(/ rr-butyl)methyl radical has an even longer lifetime with a half-life of about 20 min at 25°C. The steric hindrance provided by the rm-butyl substituents greatly retards the rates of dimerization and disproportionation reactions of these radicals. They remain highly reactive toward oxygen, however. The term persistent radicals is preferable to the term stable radicals in discussing these species, since their extended lifetimes have more to do with kinetic factors than inherent stability.  

There are only a few functional groups which contain an Unpaired electron and are stable in a wide variety of molecular environments. The best examples are the nitroxide radicals and there are numerous specific nitroxides which have been characterized. 

Most organic free radicals have very short lifetimes, but various structural features enhance stability. Radicals without special stabilization rapidly dimerize or disproportionate. The usual disproportionation process involves transfer of a hydrogen from the carbon to the radical site, leading to formation of an alkane and an alkene. 

Many of these compounds are very stable under normal conditions, and heterolytic reactions can be carried out on other functional groups in the molecule without destroying the nitroxide group.  

For reviews of the preparation, reactions, and uses of nitroxide radicals, see J. F. W. Keana, Chem. Rev. 78, 37 (1978) L. J. Berliner (ed.), Spin-Labelling, Vol. 2, Academic Press, New York, 1979. 

For a review of various types of persisent radicals, see D. Griller and K. U. Ingold, Chem. Res. 9 13 (1976). 

Radicals also rapidly abstract hydrogen atoms from many types of solvents, and most radicals are highly reactive toward oxygen. 

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. 

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Although the existence of the stable and persistent free radicals is of significance in establishing that free radicals can have extended lifetimes, most free-radical reactions involve highly reactive intermediates that have fleeting lifetimes and are present at very low concentrations. The techniques for study of radicals under these conditions are the subject of the next section. 

The proposal by Moses Gomberg in 1900 of the formation of the stable and persistent free radical triphenylmethyl was a major landmark that set the stage for the rapid development of free radical chemistry in the 20th Century. Prior to Gomberg s proposal, the theory of free radicals had risen to prominence and then fallen into disrepute, but his work immediately attracted the attention of the world chemical community, and led to the ultimate acceptance of this once controversial concept. 

Stable Free Radicals. Stable free radicals are a small minority of the more than 6 million chemical compounds known by 2005. The oxygen molecule is paramagnetic (S = 1). In 1896, Ostwald stated that "free radicals cannot be isolated." Only four years later, Gomberg123 made triphenylmethyl (Fig. 11.63), the first proven stable and persistent free radical [48] An infinitely stable free radical used as a reference in EPR is diphenyl-picryl hydrazyl (DPPH). Other persistent free radicals are Fremy s124 salt (dipotassium nitrosodisulfonate K+ O3S-NO-SO3- K+) 2,2-diphenyl-l-picrylhydrazy (DPPH)l, Galvinoxyl (2,6-di-tert-butyl-a-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-l-ylidene)-p-... 

Disulfur and diselenium dihalides (chlorides and bromides) constitute a useful class of reagents for many synthetic applications. In the field of solid-state materials, it is a useful reagent for making metal chalcogenide halides and nitrogen chalcogenide heterocycles as stable and persistent free radicals. 

Therefore the preparation of such radicals represents a colossal step forward in the study of stable carbon free radicals. These species are called inert free radicals (IFRs) instead of just stable or persistent free radicals. Inert free radicals are thus trivalent-carbon species possessing a general stability considerably higher than that of the overwhelming majority of normal tetravalent carbon compounds and materials. 

TABLE 3. Representative Persistent, Stable, and Inert Free Radicals... 

A similar discussion (40) has been presented for free radicals, for which the distinction between stable and persistent has been introduced. The same distinction should be made for carbocations, stability being determined by structure and persistence by environment (degree of anion stabilization). 

Nitroxides are persistent free radicals [1] which can often be isolated and handled as kinetically stable species. Nitroxides react rapidly with carbon free-radical intermediates [2] with well-characterized rate constants [3], and can thus be used as kinetic and mechanistic probes, as well as to trap carbon radicals in synthetic processes. They are easily oxidized or reduced, and thus have a rich redox chemistry that has been utilized for a variety of oxidations. As nitroxides have an unpaired electron, they are paramagnetic and thus ESR active, making them valuable as spin labels for biomolecules [4] and as spin traps for transient radicals [5]. In addition, nitroxides have been developed as organic ferromagnetic materials [6]. The synthesis of nitroxides has been reviewed in 1994 [7]. This review will focus on the synthetic applications of nitroxides. 

In 1958, Fyons et al. (2429) first observed free radicals by electron spin resonance (ESR) in whole cigarette smoke that was condensed at liquid oxygen temperature. These workers reported that whole cigarette smoke contains two populations of free radicals, an unstable population that can only be observed at -183°C and that vanishes when the condensate is warmed to 60°C, and a persistent, stable population that exists for several days at room temperature. The unstable population of free radicals included those in the vapor phase of whole cigarette smoke and the more stable population of free radicals included those found in the particulate phase of whole smoke. As a result, the early examination of the chemical and physical characteristics of free radicals in tobacco smoke was conducted mainly on free radicals in the particulate phase. In 1969, Tully et al. (27A115) were the first to publish a study of the free radicals in the vapor phase of cigarette MSS that was condensed at liquid oxygen temperature. 

In the mid-1980s, the first technique that relies on the reversible termination of radicals with a stable free radical was developed in the group of E. Rizzardo at CSIRO in Australia. Rizzardo and co-workers found that nitroxide-stable free radicals were able to add to carbon-centered radicals to form alkoxy amines (9). In certain cases these alkoxy amines are thermally unstable, so that they enter into an equilibrium between (transient) carbon-centered radical and (persistent) nitroxide radical on one side, and alkoxy amine on the other side. TEMPO was initially the most frequently used nitroxide in conjunction with the polymerization of styrene and its derivatives. The TEMPO-polystyrene adduct requires temperatures of 120° C or above in order to establish an equilibrium at which polymerization takes place. Around the mid-1990s Georges and co-workers focused on the TEMPO-mediated pol5unerization of styrene (10), and developed various strategies to overcome intrinsic weaknesses of the system. They used camphor sulfonic acid to enhance the rate of polymerization (11). This rate enhancement was later elucidated to be due to the destruction of excess nitroxide that builds up during the polymerization. 

It has been known for a long time that pyrolysis of organic materials produces paramagnetic materials (1 3), and that the paramagnetism is very persistent. If the pyrolysis is carried out below 600 C or so, the paramagnetism is believed to be due to free radicals that are produced in intermediate stages of the process by which heteroatoms are eliminated from the material and a carbon network is formed (4,5), These free radicals are often very stable, and persist in the sample over hundreds or even thousands of years. The number and nature of these radicals can be investigated with electron spin resonance (ESR) spectra. 

A free radical (often simply called a radical) may be defined as a species that contains one or more unpaired electrons. Note that this definition includes certain stable inorganic molecules such as NO and NO2, as well as many individual atoms, such as Na and Cl. As with carbocations and carbanions, simple alkyl radicals are very reactive. Their lifetimes are extremely short in solution, but they can be kept for relatively long periods frozen within the crystal lattices of other molecules. Many spectral measurements have been made on radicals trapped in this manner. Even under these conditions, the methyl radical decomposes with a half-life of 10-15 min in a methanol lattice at 77 K. Since the lifetime of a radical depends not only on its inherent stabihty, but also on the conditions under which it is generated, the terms persistent and stable are usually used for the different senses. A stable radical is inherently stable a persistent radical has a relatively long lifetime under the conditions at which it is generated, though it may not be very stable. 

Studies on the formation and reactivity of P-centered radicals continue to be a versatile source of mechanistic information and reactions of interest in synthetic chemistry. Various new persistent or stable P-centered radicals have been described and could find applications as paramagnetic probes. The possibility of influencing the properties of organic free radicals bearing an appropriately located phosphorus group should find interesting applications. 

For the field I was inadvertently entering (Walling had asked Kharasch if he could join his group), 1937 was a landmark year. Free radicals of course first entered organic chemistry in 1900 with Gomberg s preparation and identification of triphenylmethyl, but the chemistry and properties of such stable or persistent species had remained largely a chemical curiosity... 

Allyl Free Radicals. Ayscough and Evans (3) have recently studied, by ESR measurements, the types of allylic free radicals produced by gamma-irradiation of several monomeric olefins. In irradiated polyethylene the allyl free radical is quite stable, persisting for several months at room temperature (31). The presence of these allyl free radicals is most noticeable in the case of high density polyethylene, and this type of free radical is undoubtedly the cause of the slow oxidation of polyethylene at room temperature, which lasts for 40 or more days after irradiation (10). Williams and Dole (40) could observe little if any oxidation of low density polyethylene when it was exposed to air after irradiation. By oxidation we mean formation of carbonyl groups as detected by infrared absorption studies at 1725 cm"1. Parenthetically, it should be noted that adding an oxygen. molecule to a free radical produces initially another type of free radical, a peroxy free radical, but in this paper we shall not discuss free radicals of this or any other types except those of hydrocarbons. 

Since only free radicals give an esr spectrum, the method can be used to detect the presence of radicals and to determine their concentration. Furthermore, information concerning the electron distribution (and hence the structure) of free radicals can be obtained from the splitting pattern of the esr spectrum (esr peaks are split by nearby protons).141 Fortunately (for the existence of most free radicals is very short), it is not necessary for a radical to be persistent for an esr spectrum to be obtained. Esr spectra have been observed for radicals with lifetimes considerably less than 1 sec. Failure to observe an esr spectrum does not prove that radicals are not involved, since the concentration may be too low for direct observation. In such cases the spin trapping technique can be used.142 In this technique a compound is added that is able to combine with very reactive radicals to produce more persistent radicals the new radicals can be observed by esr. The most important spin-trapping compounds are nitroso compounds, which react with radicals to give fairly stable nitroxide radicals 143 RN=0 + R —> RR N—O. 

Stable radicals were formed during diagenesis of the organic sediment, and they have persisted ever since. The detailed mechanism of enzymatic reactions is not well understood, but it is known that stable free radicals can be produced. Steelink (18) has found that humic acids from soils, peats, and lignites have moderately high concentrations of free radicals, and since the... 

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