Carbon-centered alkyl radicals

Autoxidation is achemical reaction that usually takes place at ambient temperatures between atmospheric oxygen and a lipid substrate. In the presence of an initiator such as light, heat, or metal ions, unsaturated lipids (LH) form carbon-centered alkyl radicals (L ) ... 

The initiation reaction is the hemolytic abstraction of hydrogen to form a carbon-centered alkyl radical in the presence of an initiator. Under normal oxygen pressure, the alkyl radical reacts rapidly with oxygen to form the peroxy radical, which in turn reacts with more unsaturated lipids to form hydroperoxides. The lipid-free radical thus formed can further react with oxygen to form a peroxy radical. Hence, the autoxidation is a free radical chain reaction. Because the rate of reaction between the alkyl radical and oxygen is fast, most of the free radicals are in the form of the peroxy radical. Consequently, the major termination takes place via the interaction between two peroxy radicals. 

H. Reaction of Cu(I) with Carbon-Centered Alkyl Radicals... 

Lipid peroxidation proceeds through a chain reaction initiated by the attack of free radicals on PUFAs and propagated by reaction of the formed carbon-centered alkyl radicals (R°) with oxygen. The resulting peroxyl radicals can further abstract hydrogen atoms from PUFAs to produce finally hydroperoxides. 

Desaturation of alkyl groups. This novel reaction, which converts a saturated alkyl compound into a substituted alkene and is catalyzed by cytochromes P-450, has been described for the antiepileptic drug, valproic acid (VPA) (2-n-propyl-4-pentanoic acid) (Fig. 4.29). The mechanism proposed involves formation of a carbon-centered free radical, which may form either a hydroxy la ted product (alcohol) or dehydrogenate to the unsaturated compound. The cytochrome P-450-mediated metabolism yields 4-ene-VPA (2-n-propyl-4pentenoic acid), which is oxidized by the mitochondrial p-oxidation enzymes to 2,4-diene-VPA (2-n-propyl-2, 4-pentadienoic acid). This metabolite or its Co A ester irreversibly inhibits enzymes of the p-oxidation system, destroys cytochrome P-450, and may be involved in the hepatotoxicity of the drug. Further metabolism may occur to give 3-keto-4-ene-VPA (2-n-propyl-3-oxo-4-pentenoic acid), which inhibits the enzyme 3-ketoacyl-CoA thiolase, the terminal enzyme of the fatty acid oxidation system. 

Besides new insight into the reactivity of free radicals, methods for die production of carbon-centered free radicals have also seen major improvements in die last several years. One very common new mediod is to use tin-based reagents as radical chain carriers. Trialkyltin radicals readily abstract bromine or iodine from carbon to produce a carbon-centered free radical. Placement of a bromide or iodide substituent on a substrate dius permits formation of a carbon-centered free radical at diat position using tin-based mediodology. This process was initially developed for die reduction of alkyl halides, and it remains an excellent synthetic method for diat purpose. The complete chain mechanism for die reduction is shown. 

The mechanism of action for such peroxidic compounds involves a reductive activation by iron in haem, released as a result of hemoglobin digestion by Plasmodium. This irreversible redox reaction affords carbon-centered free radicals causing the alkylation of haem and of proteins. One such protein (the sarcoplasmic-endoplasmic reticulum ATPase PfATP6) appears to be critical for parasite survival, and there is no indication for resistance by the parasite. However, treatment is expensive and recrudescence of malaria occurs often. Moreover, it was found that at high doses such compounds are neurotoxic. 

As described earlier carbon-centered radicals can be efficiently generated by homolysis of an alkylcobalt(III) species. This species can be synthesized by a reductive process from an alkyl halide and a nucleophilic Co(I) reagent [1-6). This chapter describes the recent advances in cobalt-initiated carbon-centered free radicals (generated via a reductive process) in organic synthesis. The cobalt-mediated free-radical reactions generated via this protocol can be broadly divided into the following two categories. 

In the GiflV reaction of cyclohexane in the presence of P(OMe)3, ketone and a new product were formed instead of the expected alcohol. This new product was identified as cyclohexyl dimethyl phosphate l, 49 jf a carbon-centered cyclohexyl radical was an intermediate, one would expect the catalytic conversion of trimethyl phosphite into trimethyl phosphate in the presence of dioxygen. The latter reaction was indeed observed when genuine cyclohexyl radicals were photochemically generated under similar conditions to those employed in the Gif reaction l. So, once again this demonstrates that Gif-oxidation does not produce free alkyl radicals. 

Alkyl radical (R ) (carbon-centered free radical) Peroxy radical (R-00 ) (oxygen-centered radical) Alkoxy radical (R-0 )... 

Carbon-centered radicals have been shown to undergo addition reactions with azirine-3-carboxylates. Methyl 2-(2,6-dichlorophenyl)azirine-2-carboxylate thus reacts with alkyl and aryl iodides in the presence of triethylborane to give aziridines in good yields. The radical approaches from the opposite face to the aryl substituent, giving the cis products as single diastereoisomers (Scheme 4.43) [63],... 

The hydrogen abstraction addition ratio is generally greater in reactions of heteroatom-centered radicals than it is with carbon-centered radicals. One factor is the relative strengths of the bonds being formed and broken in the two reactions (Table 1.6). The difference in exothermicity (A) between abstraction and addition reactions is much greater for heteroatom-centered radicals than it is for carbon-centered radicals. For example, for an alkoxy as opposed to an alkyl radical, abstraction is favored over addition by ca 30 kJ mol"1. The extent to which this is reflected in the rates of addition and abstraction will, however, depend on the particular substrate and the other influences discussed above. 

In this section wc consider the properties and reactions of three classes of carbon-centered radicals alkyl radicals (3.4. l.l), aryl radicals (3.4.1,2) and acyl radicals (3.4.1.3). 

Rate constants tor reactions of carbon-centered radicals tor the period through 1982 have been compiled by Lorand340 and Asmus and Bonifacio- 50 and for 1982-1992 by Roduner and Crocket.3 1 The recent review of Fischer and Radom should also be consulted.j41 Absolute rate constants for reaction with most monomers lie in the range 105-106 M"1 s"1. Rate data for reaction of representative primary, secondary, and tertiary alkyl radicals with various monomers are summarized in Table 3.6. 

In the absence of heteroatom containing substituents (e.g. halo-, cyano-), at or conjugated with the radical center, carbon-centered radicals have nucleophilic character. Thus, simple alkyl radicals generally show higher reactivity toward electron-deficient monomers (eg. acrylic monomers) than towards electron-rich monomers (e.g, VAc, S) - Table 3.6. 

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... 

The new reaction appears to be a simple one-step procedure, which is particularly suitable for tertiary alkyl-aryldiazenes for which alternative synthetic routes are less convenient. However, aryl radicals or alkyl radicals in which the carbon-centered radical is bonded to an electron-withdrawing group (COOR, COR, CONR2, CN, S02R, etc.) do not add to diazonium salts or give only poor results (Citterio et al., 1982 c). This indicates that the radical must be a relatively strong nucleophile in order to be able to react with a diazonium ion. 

The carbon-centered radical R, resulting from the initial atom (or group) removal by a silyl radical or by addition of a silyl radical to an unsaturated bond, can be designed to undergo a number of consecutive reactions prior to H-atom transfer. The key step in these consecutive reactions generally involves the intra-or inter-molecular addition of R to a multiple-bonded carbon acceptor. As an example, the propagation steps for the reductive alkylation of alkenes by (TMSfsSiH are shown in Scheme 6. 

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. 

The first example of an intermolecular radical addihon/intermolecular trapping domino reactions of an acyclic system in a stereocontrolled fashion to build stereo-genic centers at the a- and 3-carbons was described by Sibi and coworkers [59]. Enantioselective addition of in-sitw-prepared alkyl radical to crotonate or cinnamate,... 

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