Functionality by Radical Reactions

In this section, we will focus on intramolecular functionalization. Such reactions normally achieve selectivity on the basis of proximity of the reacting centers. In acylic molecules, intramolecular functionalization normally involves hydrogen-atom abstraction via a six-membered cyclic transition state. The net result is introduction of functionality at 

Ichinose, S. Matsunaga, K. Fugami, K. Oshima, and K. Utimoto, Tetrahedron Lett. 30 3155 (1989). 

SECTION 10.3. REACTIONS INVOLVING FREE-RADICAL INTERMEDIATES 

One example of this type of reaction is the photolytically initiated decomposition of N-chloroamines in acidic solution, which is known as the Hofmann-Loffler reaction The initial products are -chloroamines, but these are usually converted to pyrrolidines by intramolecular nucleophilic substitution. 

A closely related procedure results in formation of y-lactones. Amides are converted to AT-iodoamides by reaction with iodine and f-butyl hypochlorite. Photolysis of the AT-iodoamides gives lactones via iminolactone intermediates.  

The introduction of halogen substituents by free-radical substitution was discussed in Section 12.3 of Part A. Halogenation is a fairly general method for functionalization but is limited to the site in the molecule which is most reactive toward halogen atoms. Halogenations at benzylic and allylic positions are therefore the most useful synthetic reactions. 

Pfenninger, C. Heuberger, and W. Graf, Helv, Chim. Acta 63, 2328 (1980). 

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Sources of Radical Intermediates Introduction of Functionality by Radical Reactions Addition Reactions of Radicals with Substituted Alkenes Cyclization of Free-Radical Intermediates Fragmentation and Rearrangement Reactions... 

The dual ability of carbonyl, alkenyl, and alkynyl groups to act as radical precursors as well as radical acceptors is of great importance for synthetic applications, since it would diversify the formation of carbon-carbon bonds by radical reactions. Each functional group has unique characteristics, which permit the generation of radicals from multiple bonds or the addition of radicals to multiple bonds in a selective manner. 

Asymmetric dihydroxylation of trifluoromethylalkenes is also useful for construction of enantio-enriched trifluoromethylated diols usable for trifluoromethylated amino acids with chiral hydroxyl group. Thus, Sharpless AD reaction of 16 provides diol 17 with excellent enantioselectivity. Regioselective and stereospecific replacement of the sulfonate moiety in 18 with azide ion enables the introduction of nitrogen functionality. A series of well-known chemical transformation of 19 leads to 4,4,4-trifluorothreonine 20 (see Scheme 9.6) [16]. Dehydroxylative-hydrogenation of 21 by radical reaction via thiocarbonate and subsequent chemical transformation synthesize enantio-enriched (S)-2-amino-4,4,4-trifluoro-butanoic acid 22 [16]. Both enantiomers of 20 and 22 were prepared in a similar manner from (2R,3S)-diol of 17. 

Boutevin [2], in his review on Telechelic oligomers by radical reactions developed the categories of functional initiators, i.e., diazoic compounds, hydrogen peroxide, and oxygenated substances. He examined the different reactivities and combinations of such initiators with monomers in order to synthesize telechelic oligomers. Boutevin [2] also summarized the monomers able to totally recombine or to avoid termination by disproportionation. He showed a quantitative amount of recombination only for styrene, acrylates, dienes, and acrylonitrile [31-33]. 

Owing to the hydrophobic nature of POs, to overcome the lack of possible interactions with a polar substrate, suitable functionalities are inserted during the polymer preparation and/or by post-modification processes, which are generally performed in the melt by radical reactions. Acid, ester, anhydride, hydroxy, amino, oxazoline, and other functionalities have been grafted/anchored onto—or embodied into—the backbone of POs (Boffa and Novak 2000, Passaglia et al. 2009) and these functional POs have been successfully used for providing effective interactions with polar compounds. In particular, depending... 

Ideal mechanism of PO functionalization by radical-mediated post-modification reaction. 

Heteroarenes have been photochemically functionalized by PET reactions forming new C—C bonds both in an inter- and intramolecular fashion via a similar mechanism [46]. The heteroarenes could serve both as electron donor (e.g. pyrroles or indoles) or electron acceptor (e.g. cyanopyridines or cyanopyrazines). Again, fragmentation of the radical cation, coupled with the radical anion and loss of the anion, led to overall ipso-substitution. In addition to the cyano group, halides could also function as leaving groups, such that in some cases an attack at an unsubstituted position took place [46],... 

The reaction of perfluoroalkyl iodides with alkenes affords the perfluoro-alkylated alkyl iodides 931. Q.a-Difluoro-functionalized phosphonates are prepared by the addition of the iododifluoromethylphosphonate (932) at room temperature[778], A one-electron transfer-initiated radical mechanism has been proposed for the addition reaction. Addition to alkynes affords 1-perfluoro-alkyl-2-iodoalkenes (933)[779-781]. The fluorine-containing oxirane 934 is obtained by the reaction of allyl aicohol[782]. Under a CO atmosphere, the carbocarbonylation of the alkenol 935 and the alkynol 937 takes place with perfluoroalkyl iodides to give the fluorine-containing lactones 936 and 938[783]. 

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. 

In practice vapours of the hydrocarbon halide, e.g. methyl chloride, are passed through a heated mixture of the silicon and copper in a reaction tube at a temperature favourable for obtaining the optimum yield of the dichlorosilane, usually 250-280°C. The catalyst not only improves the reactivity and yield but also makes the reaction more reproducible. Presintering of the copper and silicon or alternatively deposition of copper on to the silicon grains by reduction of copper (I) chloride is more effective than using a simple mixture of the two elements. The copper appears to function by forming unstable copper methyl, CUCH3, on reaction with the methyl chloride. The copper methyl then decomposes into free methyl radicals which react with the silicon. 

Any substance capable of reacting with free radicals to form products that do not reinitiate the oxidation reaction could be considered to function as free-radical traps. The quinones are known to scavenge alkyl free radicals. Many polynuclear hydrocarbons show activity as inhibitors of oxidation and are thought to function by trapping free radicals [25]. Addition of R to quinone or to a polynuclear compound on either the oxygen or nitrogen atoms produces adduct radicals that can undergo subsequent dimerization, disproportionation, or reaction with a second R to form stable products. 

When a polymer is prepared by radical polymerization, the initiator derived chain-end functionality will depend on the relative significance and specificity of the various chain end forming reactions. Tlius, for the formation of telechelic polymers ... 

Chains with uttdesired functionality from termination by combination or disproportionation cannot be totally avoided. Tn attempts to prepare a monofunctional polymer, any termination by combination will give rise to a difunctional impurity. Similarly, when a difunctional polymer is required, termination by disproportionation will yield a monofunctional impurity. The amount of termination by radical-radical reactions can be minimized by using the lowest practical rate of initiation (and of polymerization). Computer modeling has been used as a means of predicting the sources of chain ends during polymerization and examining their dependence on reaction conditions (Section 7.5.612 0 J The main limitations on accuracy are the precision of rate constants which characterize the polymerization. 

A final class of multifunctional initiators is based on the use a (muUi)functional polymer and a low molecular weight redox agent. Radicals on the polymer chain arc generated from the polymer bound functionality by a redox reaction. Ideally, no free initiating species are formed. The best known of this class are the polyol-redox and related systems. Polymers containing hydroxy or glycol and related functionality are subject to one electron oxidation by species such as ceric ions or periodate (Scheme 7.23).266,267 Substrates such as cellulose,... 

A side reaction in NMP is loss of nilroxide functionality by thermal elimination. This may occur by disproportionation of the propagating radical with nitroxide or direct elimination of hydroxy lam ine as discussed in Section 9.3.6.3. In the case of methacrylate polymerization this leaves an unsaturated end group.1" The chemistry has also been used to prepare macromonomers from PMMA prepared by ATRP (Section 9.7.2.1),... 

A small library of highly functionalized pyrrolines 95 was synthesized by reaction of allylic and propargylic isocyanides 94 with thiols followed by radical cyclization (Scheme 33). The radical reaction was carried out using a radical initiator (AIBN) under flash heating microwave irradiation [67]. 

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